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Tetrahedron 64 (2008) 2683e2723

www.elsevier.com/locate/tet

Tetrahedron report number 828

Synthesis of six-membered oxygenated heterocycles through

carboneoxygen bond-forming reactions
Igor Larrosa a, Pedro Romea b,*, Fèlix Urpı́ b,*
a
School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, UK
b
Departament de Quı́mica Orgànica, Universitat de Barcelona, Martı́ i Franqués 1e11, 08028 Barcelona, Catalonia, Spain
Received 12 November 2007

Contents

1. Introduction and scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2684

2. SN2-Mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2684
3. SN1-Mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2685
4. Epoxide-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2686
5. Alkene-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2690
5.1. Stoichiometric cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2691
5.1.1. Mercury-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2691
5.1.2. Halo-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2692
5.1.3. Seleno-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2693
5.2. Catalytic cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2694
5.2.1. Palladium-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2694
5.2.1.1. Catalysis by Pd(0) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2694
5.2.1.2. Catalysis by Pd(II) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2695
5.2.2. Other metal-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2699
5.3. Acid-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2699
6. Allene-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2700
7. Alkyne-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2700
8. Other metal-promoted cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2704
8.1. Cyclizations of 4-alkynols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2704
8.2. Cyclizations of diazo compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2706
8.3. Intramolecular etherification of aryl and vinyl halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2709
9. Intramolecular conjugate additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2710
9.1. 6-exo Ring closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2710
9.2. 6-endo Ring closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2713
10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2717
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2717
References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2717
Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2723

* Corresponding authors. Tel.: þ34 93 4039106 (P.R.); tel.: þ34 93 4021247 (F.U.).
E-mail addresses: pedro.romea@ub.edu (P. Romea), felix.urpi@ub.edu (F. Urpı́).

0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.092
2684 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

R1
O
O R2
N
O OMe O O O

O
H N OMe O O
O N O
MeO OMe O O
O Br N
O O
OH
OH

1 leucascandrolide A 2a phorboxazole A, R1 = OH, R2 = H

2b phorboxazole B, R1 = H, R2 = OH

Figure 1.

1. Introduction and scope
Six-membered oxygenated heterocycles, or pyrans, are prob-
ably one of the most common structural motifs spread across
natural products, from simple glucose to structurally complex
metabolites such as leucascandrolide A (1),1 phorboxazole A
(2a) and B (2b),2e4 and the even more elaborated architectures
present in palytoxin, maitotoxin, and other marine natural prod-
ucts (Fig. 1).5
Due to the remarkably rich array of functionalities and chiral
centers that these heterocycles can incorporate, their stereose-
lective preparation has become a continuous challenge for
organic synthesis practitioners.6e10 They can be synthesized
by means of five-membered ring expansions (e.g., BaeyereVil-
liger oxidation of cyclopentanones11), cycloaddition processes
(e.g., Hetero-DielseAlder reactions12), or intramolecular cycli-
zations.13 Classical examples of these cyclizations are the
lactonisation of d-hydroxy acids or the thermodynamically
favorable conversion of d-hydroxy aldehydes into the corre-
sponding hemiacetals, which, in turn, can be easily modified
(e.g., C-glycosidation reactions14) to provide other pyran-based
structures. In addition to these processes, there is a set of impor-
tant methodologies based on the cyclization of an oxygenated
precursor that affords pyran structures in a highly efficient
and straightforward manner.
Considering the crucial ring-forming step (or the parallel
transform in the retrosynthetic sense), the cyclization methodol-
ogies can be classified into three types, represented in Figure 2.
Type 1 gathers those methodologies based on O1eC2 bond
formation15 (or disconnection in the retrosynthetic sense),
which encompass SN2- and SN1-mediated cyclizations, metal-
promoted processes, and Michael-like reactions. Likewise,
Type 2 and 3 methodologies affect C2eC3 and C3eC4 bond
formation, respectively, which include Prins sequences, Peta-
siseFerrier rearrangements, or ring-closing metathesis
reactions.
4 clearly proved in the successful construction of tetrahydropyr-
3 3
O 2
O 2
O A (2a)2d and B (2b).3b Noteworthy, either 2,6-cis-tetrahydro-
1
Type 1 Type 2 Type 3
Figure 2.
The aim of this report is to highlight Type 1 methodologies
addressed to the stereoselective construction of di- and tetra-
hydropyrans and their application to the synthesis of natural
products, with special attention being paid to the most recent
contributions.
2. SN2-Mediated cyclizations
Transformations based on an SN2-mediated cyclization of
a hydroxy precursor represent the simplest strategy leading
to di- and tetrahydropyran. They only require a suitable com-
bination of base (B: tertiary amine, alkoxide, hydride; see
Scheme 1) and leaving group (X: sulfonate, halide; see
Scheme 1) to promote a 6-exo-tet process16 with inversion of
the configuration at the CeX center in accordance with the
pattern dictated by the Williamson reaction (see path A in
Scheme 1). Thus, the stereochemistry of the resulting tetrahy-
dropyran relies exclusively on the configuration of the acyclic
precursor.
path A path B
B
OH X
O X OH
–H
O
Scheme 1.
With regard to the reactivity of such systems, cyclizations
that involve leaving groups placed on a primary position
take place smoothly,17 whereas those located on a secondary
position often require a more accurate control of the reaction
conditions.18 Even in such a challenging situation, this strat-
egy enjoys an interesting synthetic potentiality, as has been
ans embedded in leucascandrolide A (1),1f and phorboxazole
pyran (see 4 and 8 in Scheme 2) or 2,6-trans-tetrahydropyran
(see 6 and 10 in Scheme 2) is obtained by simple application
of the same experimental conditions. Thus, both stereochemistries
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2685

S 7 S 7
NaH
S OH OTs PhH, 90 °C S O
3 3
OPMB 75% OPMB 11 7 OTBDPS
3 4
TBSO OTs OMe O
15 3
11 7 OTBDPS OTBS OPMB
1) HF·pyr, pyr 5
1 O OMe O
15 3 2) NaH, PhH, 60 °C
OH OPMB 73%
6

OH

11 OPiv 1) MsCl, Et3N

15 15 11
2) TsOH, MeOH
O O OPiv
O 3) NaH, PhMe, O
N N
O
72%
PMBO 7 PMBO 8

OTBDPS OTBDPS

15 11 15 11
O O
O 9 NaH O 9
2a N N
O PhH, TsO
5
PMBO PMBO
5 89% HO

PivO 10 9 OPiv

Scheme 2.

are available, depending on the configuration of the reacting 3. SN1-Mediated cyclizations

center.
Remarkably, an SN2-mediated cyclization has also been
used for the assemblage of C5eC9 tetrahydropyran of phor-
boxazole A (2a) in the final stages of the synthesis.2h Thereby,
alcohol 11 is easily converted into its mesylate 12, the silicon
protecting group at C5 is selectively removed and the simple
exposure of the resulting hydroxy mesylate 13 to Et3N affords
the desired 2,6-trans-tetrahydropyran 14 in an excellent yield
(Scheme 3).
In contrast to the above-mentioned methodologies, SN1-
mediated cyclizations take advantage of the stability of allylic
and benzylic carbocations to drain the process represented in
Scheme 1 along path B.19,20 Now, the planarity of the carbo-
cationic intermediate does not exert any control on the config-
uration of the new stereocenter and the stereochemical
outcome of the cyclization relies on the stereogenic elements
of the substrate and the experimental conditions.

O
OTBDPS
N
O

Br
OMe O
OR1 OR2
MeO O OPMB 5
N
O
OMe
OTBDPS OTBDPS Et3N
11 R1: H R2: TES MeCN,
MsCl, Et3N, 99% O
12 R1: Ms R2: TES OTBDPS 86%
PPTS cat., MeOH, 98% N
13 R1: Ms R2: H
O

Br 9
OMe O
2a
O
MeO O OPMB 5
N
O
OMe
OTBDPS 14 OTBDPS

Scheme 3.
2686 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

TBSO OTBS TBSO OTBS TBSO OTBS OTBS

Cl Cl Cl Cl OTBS

HO
OTBS 12b OTBS 12b OTBS 12b
O
45%
H H H dr 5:1 H

15 16 17

Scheme 4.

Thereby, cyclization of benzylic allylic alcohol 15 during
an aqueous work-up is supposed to proceed through cationic
intermediate 16, which undergoes ring closure followed by
the release of the silicon protecting group (Scheme 4).19d
The stereochemistry of the major diastereomer 17 arises
from the preferential attack of the OTBS oxygen from the
opposite side of C12b methyl.
Better results are typically obtained for 2,6-cis-tetrahydro-
pyrans, which are usually the most stable diastereomers. For
instance, construction of the C22eC26 2,6-cis-tetrahydro-
pyran of phorboxazole A (2a) has been achieved through an
intramolecular SN1-mediated cyclization of alcohol 18, as
shown in Scheme 5. Actually, the stereochemical outcome of
this transformation is consistent with the internal capture of
a transoid allylic cation at C26 by the C22 b-methoxymethyl
ether and dealkylation of the resulting oxonium species.2d,21
Propargylic carbocations can also participate in these
cyclizations, since they are easily generated by treatment of
Co2(CO)6ealkynol complexes with either Brønsted or Lewis
acid22 and are stable enough to be intramolecularly trapped
by oxygenated nucleophiles. Indeed, ring closure of diol 20
affords tetrahydropyrans 21 in excellent overall yield (Scheme
6).23 Remarkably, the thermodynamically more stable 2,3-
trans derivative is increasingly obtained with long reaction
times or higher temperatures.
Furthermore, epoxides can also act as nucleophiles and, in
particular, precursors containing a protected epoxy alcohol
moiety participate in highly regio- and stereoselective
cyclizations. For instance, treatment of carbonates 22a or
b (Scheme 7) with BF3$OEt2 followed by protecting group
transformations furnishes 2,6-cis-tetrahydropyran 23a or b as
a sole diastereomer through a putative propargylic carboca-
tion,24 which has provided a new entry to a formal synthesis
of (þ)-muconin 24.25
4. Epoxide-mediated cyclizations
Since the seminal studies on the intramolecular epoxide
opening carried out by Nicolaou et al.26 established the struc-
tural criteria required for the regio- and stereocontrolled
synthesis of six-membered oxygenated heterocycles overrid-
ing the competitive formation of the corresponding five- or
seven-membered counterparts, acid-catalyzed cyclizations of
hydroxy epoxides have become a common approach to the
stereoselective construction of tetrahydropyrans.27
The regioselectivity of the cyclization for g-hydroxy epox-
ides greatly depends on the geometry of the epoxide. Indeed,
cis-epoxides reliably afford the 5-exo ring closure probably
because these systems do not easily assume the planar ar-
rangements necessary for maximum stabilization in the transi-
tion states leading to six-membered rings (Eq. 1 in Scheme 8).
On the other hand, trans-epoxides enable the desired 6-endo
process provided that a p-orbital adjacent to the epoxide
unit activates the CeO bond close to it and stabilizes the
developing positive charge in the transition state (Eq. 2 in
Scheme 8). In both cases, these cyclizations are accompanied

OMOM OPMB
22
OH 22 OPMB O
Tf2O, pyr
N 26 OTES N 26 OTES 2a
R CH2Cl2, –20 °C R
O 55% O
18 19

Scheme 5.

H H
OBn OBn OBn
1) BF3·OEt2, CH2Cl2, T, t
+
Co2(CO)6 2) CAN, acetone, 0 °C
HO HO O O
H H
C5H11 T (°C) t (h) trans-cis Yield (%) C5H11 C5H11
20 21-trans 21-cis
20 0.33 10:1 94
–20 2.5 1.2:1 70
–20 18 9.9:1 87

Scheme 6.
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2687

TMS Co2(CO)6 OH
O O
OBoc OBoc
22a OH TMS Co2(CO)6 22b
BF3·OEt2, CH2Cl2 BF3·OEt2, CH2Cl2
–20 °C, 4 h rt, 3 h
t-BuO
O O O
TMS
O (CO)6Co2
(CO)6Co2 O
O
TMS Ot-Bu

OH (CO) 6Co2
O OH
(CO)6Co2 OBoc TMS OH
O
1) CAN, acetone, rt, 30 min
TMS
1) Ac2O, CH2Cl2, rt, 30 min 55% 2) K2CO3, MeOH, rt, 6 h
70%
2) CAN, acetone, rt, 10 min 3) CH2(OMe)2, CSA, rt , 3 h

OAc

OBoc
O O O
O
23a 23b

O O
O OH OH
n-C12H25
OH (+)-muconin 24

Scheme 7.

H H
HO HO 7-endo
HO 5-exo 6-endo 6-exo
O O (1) O (3)
H favored favored HO
R R OH R O R HO R O
H OH H
cis epoxide R
cis epoxide
H H
5-exo 6-endo HO HO 6-exo
HO 7-endo
O O (2) O (4)
H favored favored favored favored HO
R R OH R O R H O R O
R: CH2X R: CH=CH2 H R: CH=CH2 OH R: CH2X H
trans epoxide R
trans epoxide
Scheme 8.
Scheme 9.

by inversion of the stereochemistry at the carbon undergoing

nucleophilic attack.
A similar analysis was performed for d-hydroxy epoxides.
In these systems, cis-epoxides exhibit low selectivity for the
7-endo ring closure irrespective of the R substituent, preferen-
tially forming the corresponding tetrahydropyran (Eq. 3 in
Scheme 9). Conversely, the R substituent plays a crucial role
in the case of trans-epoxides. As expected on kinetic grounds,
any saturated substituent favors the 6-exo process and yields
almost exclusively the six-membered ring, whereas, once
again, a p-orbital close to the epoxide directs the attack to
the allylic position and produces the oxepane ring (Eq. 4 in
Scheme 9).
These models account for most of the synthetic approaches
found across the most recent literature.28 For instance, con-
struction of the bicyclic ether core of (þ)-sorangicin A (25
in Scheme 10) illustrates some of the aforementioned trends.
Exposure of epoxide 26 to aqueous acid produces tetrahydro-
pyran 27 through a 6-exo ring closure (see Eq. 4 in Scheme 9),
without observing alternative 7-endo or even 5-endo cycliza-
tions. Furthermore, 27 can be easily converted into epoxy
alcohol 28, which is subjected to an acid-mediated cyclization
that follows a 5-exo pathway (see Eq. 1 in Scheme 8). Interest-
ingly, three steps can be combined in a one-pot, three-step
sequence that delivers the bicyclic ether 29 in a 62% overall
yield.29,30
Similarly, a parallel set of experimental conditions based on
the use of a Lewis acid (Ti(i-PrO)4 activation in hot benzene)
have been devised for the assemblage of the C22eC26 2,6-cis-
tetrahydropyran 31 from 30 in a route to phorboxazole A (2a)
(Scheme 11).2c
2688 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

6-exo
HO OH OH 5-endo
O Ph O
O H3O
O HO
O Ph OTs
OH
HO 26 7-endo 27 OTs
OH
1) 10% HCl, rt, 18 h
62% 2) 10% NaOH, rt OH
3) 10% HCl, rt, 4 h

O O
O O Ph O
(+)-sorangicin A Ph H3O
O HO 5-exo
25
6-endo
O
HOOC 29 OH 28

Scheme 10.

6-exo 22
PMBO OH O
26 Ti(i-PrO)4
HO 22 HO 26 OPMB 2a
O PhH,
OH
76%
30 31

Scheme 11.

As pointed out in Scheme 8, alkenes adjacent to epoxides
override the common bias favoring the 5-exo ring-closure
mode. This is the behavior observed in the intramolecular
cyclization of a,b-unsaturated epoxide 33, which permits the
regio- and stereoselective preparation of a densely substituted
C8eC12 tetrahydropyran directed toward the synthesis of bre-
venal (32 in Scheme 12).31 Indeed, removal of the PMB group
on 33 triggers a 6-endo cyclization to a tetrahydropyran, which
is subsequently converted into TES ether 34.32
Occasionally, these methodologies are combined in a syn-
thetic sequence. For instance, the tristetrahydropyran substruc-
ture of diol 35, an advanced intermediate toward the synthesis
of thyrsiferol and venustatriol (36a and 36b, respectively, in
Scheme 13), has been regio- and stereoselectively prepared
through three intramolecular cyclizations of g- and d-hydroxy
epoxides.33 The first acid-catalyzed ring closure of hydroxy
epoxide 37 proceeds quantitatively to form 38 with complete
6-exo regioselectivity,y and no competitive 7-endo cyclization
is observed. Next, the construction of tetrahydropyran B takes
advantage of the allylic character of a trans-epoxide. Indeed,
cyclization of hydroxy diepoxide 39 affords the desired six-
membered heterocycle 40 under very mild conditions with
excellent 6-endo regioselectivity. Eventually, Ti(i-PrO)4 acti-
vation of hydroxy epoxide 41 produces the third ring in 58%
yield.
In spite of these accomplishments, it was soon realized that
new methodologies able to switch 5-exo to 6-endo processes
irrespective of the substituent R (see Eqs. 1 and 2 in Scheme
y tivity.9 As partly suggested by the name, their molecular archi-
Actually ring closure to tetrahydropyran A is carried out on a 1:1 epimeric
mixture of 3-bromo derivatives. Interestingly, the experimental conditions pro-
vide a highly efficient kinetic resolution and just hydroxy epoxide 37 un-
dergoes the desired cyclization.
8) were highly desirable. In this context, it has been recently
reported that epoxide openings triggered by bulky silyl triflates
in nitromethane yield the desired tetrahydropyrans regioselec-
tively.34 In addition to these observations, the regioselective
tenet summarized in Scheme 8 favoring 5-exo over 6-endo
ring closures of g-hydroxy epoxides has recently been chal-
lenged in vanadium-catalyzed mediated processes.35 As out-
lined in Scheme 14, the asymmetric oxidation of unsaturated
a-hydroxy esters followed by an epoxidation/cyclization se-
quence using the same chiral catalyst provide regio- (6-endo/
5-exo ratio ca. 4:1) and stereoselectively (dr>88:12, ee>95%)
2,5-trans-tetrahydropyrans in 20e35% yield (the highest theo-
retical yield is 50%).
Hence, this process is divided into two steps. The first step
involves the oxidative resolution (acetone/O2) of a racemic
mixture of a-hydroxy esters (R1, R2sH) using a vanadium
catalyst prepared from VO(i-PrO)3 and the chiral Schiff base
42. Once the alcohol has been chemo- and stereoselectively
oxidized, change of solvent and oxidant to CHCl3/t-BuOOH
promotes a stereoselective epoxidation followed by a fast
cyclization of the resultant hydroxy epoxide. The mechanistic
model that accounts for the stereochemical outcome of the
overall process emphasizes the coordination of the ester
carbonyl to the metal. Such a coordination places the ester
in the pseudoaxial position, which allows an efficient p-facial
discrimination of the carbonecarbon double bond. Finally, the
resultant short-lived epoxide undergoes a backside attack of
the hydroxyl to the corresponding 2,5-trans tetrahydropyran.36
The pursuit for regioselective 6-endo cyclizations has found
its own Holy Grail in the synthesis of fused polycyclic ethers,
a family of marine metabolites with remarkable biological ac-
tectures contain large and highly rigid polycyclic frameworks
of all fused six- to nine-membered oxygenated rings in a well-
defined stereochemical arrangement, as shown in Figure 3.
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2689

12 H
1) DDQ, CH2Cl2-H2O, rt OTES
8 O 8 12
TBDPSO 2) TESOTf, 2,6-lut, CH2Cl2, 0 °C TBDPSO
OPMB O
H Me
89%
33 34
6-endo
Me OH
H H H H
8 O O Me
brevenal 32
H O 12 O
Me O H H
OHC H Me
OH

Scheme 12.

The synthesis of these large and complex structures has
raised much interest in strategies rooted on biogenetic
grounds. Unfortunately, the biosynthesis of these metabolites
is not well understood and current working hypotheses are
rather speculative. In this context, the CaneeCelmereWestley
model, originally proposed for the synthesis of polyether anti-
biotics,37 has inspired most of those hypotheses, which envis-
age that the fused polycyclic ether frameworks might arise
from the cyclization of a polyepoxide precursor through a
cascade of SN2 ring openings.38 Therefore, any biomimetic
strategy must be able to provide a synthetic route to a chiral
polyepoxide with the structural elements to allow for the
regio- and stereoselective 6-endo ring closures required for
the fused tetrahydropyran arrays. Otherwise, alternative path-
ways based on 5-exo cyclizations leading to tetrahydrofurans
would predominate (Scheme 15).39
In this context, a biomimetic approach takes advantage of
endo-selective cyclizations of methoxymethyl epoxy alcohols
controlled by chelation with a suitable Lewis acid. Indeed,
the asymmetric epoxidation of polyene 43 leads to 44 in 56%
isolated yield, and removal of the silicon protecting group pro-
vides quantitatively triepoxide alcohol 45 (Scheme 16). Then,

R
35 R : OH
O OH HO
H
B C thyrsiferol, 36a R: O
O OH
O
A HO
H
Br venustatriol, 36b R: O
OH

O
Br 40 mol% CSA O
OH
HO OAc Et2O,rt, 0.5 h A
OAc
37 Br 38
100%
OH
B 1 equiv PPTS B O
O OTBS O OTBS
O CHCl3, rt, 5 min OH
A O A O
Br 40 70% Br 39 OH

OH O OH
B 0.9 equiv Ti(i-PrO)4 B C
O OH O
O PhMe, 70–80 °C, 3 h O
A O A
Br 41 58% Br 35

Scheme 13.

O 10 mol% VO(i-PrO)3, 11 mol% 42 O

O2
R1 R1
RO acetone, 30 °C, 30–48 h RO
OH R2 OH R2
10 mol% VO(i-PrO)3, 11 mol% 42
t-BuOOH, CHCl3, rt, 24–72 h
R2 t-BuO
HO O O O OR t-Bu
5 R1 [V] t-Bu
2 HO R2 N
R1 O CO2R O H
OH
R2 20–35% t-BuO [V] O OR H OH
R1
dr > 88:12 t-Bu 42
2,5-trans-tetrahydropyran
ee > 95%

Scheme 14.
2690 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

cis A different strategy employs epoxysilanes as starting mate-

R1
O
R2 rials for the cyclizations. It takes advantage of trimethylsilyl
trans trans
groups to achieve highly regioselective openings of the epox-
O ()
n
O ides, and, immediately after the ring closure, the silicon group
R3 R4
is removed by fluoride-promoted protodesilylation.42 As out-
n = 1, 2, 3, or 4
lined in Scheme 18, this approach allows for the straightfor-
R1, R2, R3, R4 : H, Me
ward conversion of triepoxysilane 49 into the large
Figure 3. tetrahydropyran array 50. Indeed, chiral epoxide 49, prepared
from a reagent-controlled Shi epoxidation (dr 90:10), un-
a cascade cyclization catalyzed by La(OTf)3 proceeds in a step- dergoes a cascade of ring openings mediated by a Brønsted
wise mechanism to afford the desired tricyclic ether 46 in 9% base and a fluoride source in a hydroxylic solvent. Finally,
yield.40 the resultant alcohol is acylated to furnish 50 in 20% overall
Lewis acid-mediated endo oxacyclization of polyepoxides yield.
affords cis- or trans-fused polyethers depending on the nature
of the terminal nucleophile. The rationale for such dependence
relies on the mechanism depicted in Scheme 17. Initially, 5. Alkene-mediated cyclizations
Lewis acid activation of a first epoxide triggers the generation
of a bridged onium intermediate, which can evolve through Closely related to the epoxide-mediated cyclizations, there
a tight ion pair to a tertiary carbocation. Therefore, the termi- is an important number of methodologies based on the intra-
nal nucleophile may intercept different species. It has been molecular attack of an oxygenated nucleophile on an olefin
proposed that the cis-fused products arise by trapping of an in- activated by electrophiles. The most common precursors are
termediate close to the carbocation, whereas the trans-fused d-hydroxy alkenes, which afford the corresponding pyrans
derivatives are mainly obtained with a better nucleophile through highly regioselective 6-exo ring closures (Scheme
(i.e., a tertiary carbamate) by adding to an intermediate struc- 19). The rationale for these cyclizations assumes the reversible
turally close to the epoxonium ion. This is the case for dime- formation of a p-complex, which can proceed either directly
thylcarbamate epoxide 47 prepared through stereoselective to the corresponding heterocycle by reaction with the nucleo-
Sharpless and Shi epoxidations of the corresponding alkenes. phile or indirectly by first collapsing to an onium intermediate
Then, BF3$OEt2-promoted oxacyclization of 47 produces the before undergoing nucleophilic attack.43 In any case, cycliza-
desired polyether 48 in 31% isolated yield.41 tion involves the attack of the oxygenated nucleophile on the
opposite face of the electrophile. Therefore, the success of
this strategy mostly relies on the stereocontrolled electrophilic
5-exo ring closure O O
O O
addition to the alkene.
Nu
These cyclizations can be classified as stoichiometric or cat-
Nu alytic, according to the amount of electrophile engaged in the
O process. The stoichiometric electrophile-induced cyclizations
6-endo ring closure
O O routinely involve mercury(II) salts and iodo or seleno reagents
Nu O as activators of the carbonecarbon double bond. Otherwise,
Nu
palladium chemistry dominates the catalytic counterparts, al-
Scheme 15. though other metals are being increasingly employed.

O O
O

MeO MeO O O MeO MeO

O , Oxone

O O O
MeCN, (MeO)2CH2, 0 °C 1.1 equiv La(OTf)3
OR OR 0.3 equiv La2O3
MeO 56% MeO 5.5 equiv H2O
43 R: TBDPS TBAF, THF 44 R: TBDPS CH2Cl2, rt
100% 45 R: H Me
MeO OMe OMe H OMe O
H H
HO O O O La
R R
O O
R
O O HO O La O O
H H 9% H H
OMe O H
OMe
46 Me

Scheme 16.
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2691

O O

R O BF3 R O
O O O O BF3

O O O
O O
R O R O R O O
BF3 BF3 BF3
O O O
tertiary carbocation ion pair epoxonium ion
H H
O O
O O
BF3 BF3
R O O R O O
Me Me
cis-fused trans-fused
O
H Me
O OH
Me2N O 0.01 M BF3·OEt2 O
O O O
CH2Cl2, 20 °C O O
O
Me H
31%
47 48

Scheme 17.

5.1. Stoichiometric cyclizations of 54 with n-Bu3SnH effects the desired demercuriation to 55

5.1.1. Mercury-mediated cyclizations
The electrophiles employed in these processes are mercu-
ry(II) salts and the resultant carbonemercury bonds are usu-
ally reduced with NaBH4 or n-Bu3SnH.44 The course of
these intramolecular oxymercuriations depends on the stability
of the cationic intermediates and, with the exception of one
example,45 they are substrate-controlled processes that usually
lead to the thermodynamically more stable tetrahydropyran.
Thus, the hydroxy alkene must contain the structural elements
required to achieve the desired p-facial discrimination of the
carbonecarbon double bond. This is the case for the d-hy-
droxy alkene 52, an intermediate in the total synthesis of the
antibiotic X-206 (51 in Scheme 20).44a Indeed, steric and con-
formational arguments would be responsible for the outstand-
ing stereocontrolled electrophilic addition of Hg(OAc)2 to the
olefin in such a way that the resulting onium intermediate 53 is
suitably prepared for the intramolecular cyclization leading to
2,6-cis-tetrahydropyran 54 quantitatively. Eventually, treatment
in excellent yield.
The intramolecular oxymercuriation has also been applied
to the assemblage of the C22eC26 tetrahydropyran of phor-
boxazole B (2b). As shown in Scheme 21, treatment of diol
56 with Hg(OAc)2 followed by reaction of the resultant orga-
nomercuriate with iodine furnishes a 5:1 mixture of the 2,6-
cis-tetrahydropyran 57-cis and the corresponding 2,6-trans
isomer. Then, chromatographic purification of the mixture per-
mits the isolation of the desired 57-cis in 71% yield.
Given that the success of such a strategy relies on the p-
facial discrimination of an alkene, any methodology able to
fulfill this requirement should allow for a complete stereochem-
ical control. In this context, mercury(II)-mediated electrophilic
ring-opening reactions of d-hydroxy cyclopropylcarbinol deriv-
atives represent an appealing entry into the asymmetric synthe-
sis of tetrahydropyrans. In this approach, the cyclopropane unit
plays the role of an activated olefin. These highly diastereo-
selective processes usually occur with anchimeric assistance
by the closest alcohol and subsequent nucleophilic backside

H H H H H
HO 1) Cs2CO3, CsF, MeOH, O O
TMS
O O
2) Ac2O, DMAP, pyr, CH2Cl2
O AcO O O
O H H H H H
TMS TMS 20%
49 50

Scheme 18.

6-exo
E
+E –H

E E –E
OH OH O O
6-exo
complex
–H
OH
onium intermediate

Scheme 19.
2692 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

H HgOAc
OBOM OBOM
3 7 Hg(OAc)2 H NaCl aq. 3 7
OH R CH2Cl2, rt XcCO OH O R
H OBOM
COXc R COXc X
H 99%
52 53 54 X: HgCl
n-Bu3SnH
55 X: H
PhMe
O OH
3 7 94%
HO O O O O O
OH OH OH
OH O
X-206 OH
51

Scheme 20.

attack of the d-OH, which causes an inversion in the configura-
tion of the reacting center (Scheme 22). Hence, the stereochem-
ical outcome of these cyclizations mostly depends upon the
configuration of the cyclopropane ring.46
This strategy has been applied to the construction of the C3e
C7 tetrahydropyran of zincophorin (58 in Scheme 23).47 The
cyclopropane ring of the advanced intermediate 59 is installed
at the beginning of the synthesis by means of the catalytic
asymmetric cyclopropanation of an allylic diazoacetate.
Then, simple treatment of 59 with Hg(OCOCF3)2 followed by
aqueous work-up cleanly produces 2,6-trans-tetrahydropyran
60. In turn, this organomercuric bromide is subjected to a reduc-
tive demercuriation, which eventually provides 61 in 85% yield
and 93:7 dr.
5.1.2. Halo-mediated cyclizations
Halo-mediated cyclizations are similar to the processes
based on mercury(II) salts. Most of the intramolecular halo-
etherification reactions take advantage of the use of iodine
or N-iodosuccinimide (NIS),48e50 reagents mild enough to
be used on structurally complex substrates. For instance,
NIS-mediated iodoetherification plays a crucial role in the as-
semblage of the G-ring of azaspiracid-1 (62 in Scheme 24),
a prominent member of a family of marine metabolites respon-
sible for human poisoning resulting from the consumption of
tainted shellfish. Initially reported in 1998, azaspiracids were
shrouded in structural ambiguity that partially arises from
the complex and intricate array of sensitive functional groups
embedded in their structure and, only in 2004, have Nicolaou
et al. reported the correct structure of azaspiracid-1 after con-
siderable synthetic work. It is, then, not surprising that the
endeavors applied to the construction of such challenging
compounds have spurred the development of new strategies
(see also Schemes 57 and 91). As represented in Scheme 24,
the intramolecular iodoetherification of the structurally com-
plex alcohol 63 affords iodoether 64, which is reduced with
an excess of n-Bu3SnH in toluene to remove the superfluous
iodine at C29. Thus, the highly advanced intermediate 65 is
obtained through this two-step sequence in 53% yield.
Iodoetherification on substrates containing an allylic alco-
hol turns out to be highly dependent on conformational issues.
Indeed, diol 66a undergoes a facile cyclization to 2,6-cis-tetra-
hydropyran 67a, while the diastereomer 66b fails to give the
expected bicyclic system 67b (Scheme 25).48e The rationale
for such different behavior relies on the conformational anal-
ysis of the allylic moiety. Cyclizations in which the nucleo-
phile is in the R group proceed rapidly (or slowly) through
the favored p-complex 68a (or the disfavored p-complex
68b) when CeOH (or CeH) eclipses the carbonecarbon dou-
ble bond. This is the situation for 66a (or 66b). Thus, cycliza-
tion of 66b requires a more reactive iodinating agent such as
bis(sym-collidine)2IPF6, prepared in situ from bis(sym-collidi-
ne)2AgPF6 and iodine in CH2Cl2. This reagent converts 66b
into the desired tetrahydropyran 67b in 80% yield.

I
22 22
OH 1) Hg(OAc)2, PhMe, 0 °C, 8 h O
2b
26 OH 2) I2, rt, 12 h 26 OH
O O
O 71% O

56 57-cis

Scheme 21.

reductive
HgX2 demercuriation
HO OH HO OH –HX O OH O OH

Hg HgX
X X

Scheme 22.
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2693

CO2Me
H
O O
O
N
O N 0.1% Rh2[5R-MEPY]4
Rh Rh N2
O O
N NOO CH2Cl2,
Rh2[5R-MEPY]4
91% ee > 95%

O 1) Hg(OCOCF3)2, CH2Cl2, rt O
BzO BzO
O OH 2) KBr aq. O OH
H
R 59
60 R: HgBr n-Bu3SnH, PhMe-THF
O OH OH OH
61 R: H –60 °C to rt 3 7
85% dr 93:7 HO O

OH
zincophorin
58

Scheme 23.

A conceptually different approach to electrophile-induced

cyclizations takes advantage of the nucleophilicity of the car-
TeocN
bonyl oxygen of a ketone. As outlined in Scheme 26, if the
carbonyl of a d-alkenyl ketone could trap the p-complex ob-
H
OTBS O tained by treatment of the olefin with an electrophile, then
HO
O H the resultant oxocarbenium intermediate would easily lead to
AcO O
O
O the corresponding acetal.
O
63
O
OH
This idea has been put into practice for the stereoselective
construction of the C1eC5 ring of a new antitumor agent,
NIS, NaHCO3 TeocN
THF, 0 °C, 12 h
62% FR-901464 (69 in Scheme 27). With this target in mind, the
OTBS
H
O NBS-mediated cyclizations of two d-alkenyl ketones, 70 and
O 71, have been tested and, in both cases, a sole diastereomer
O H
AcO
O
O
O
29 has been isolated in good yield.51a Unfortunately, none of the
O X resultant C4eC5 stereochemistries in 72 and 73 match with
64 X: I O
OH
that in FR-901464 and its final total synthesis has recently
cat. Et3B, n-Bu3SnH-PhMe 1:2, 0 °C, 20 min been achieved following an alternative strategy.51b Despite
86%
this failure, the key concept of this methodology maintains
65 X: H a high appeal, as has been proved in a parallel process in the
NH I
arena of alkynols, which has been commented further upon.52,53
A H H
HO B O
O O O G
O O H
O C D O 5.1.3. Seleno-mediated cyclizations
O OH H F
azaspiracid-1 OH Cyclizations based on selenium reagents are not as com-
62 mon as the mercury(II)- or halo-mediated methodologies.54,55
Scheme 24. Moreover, and contrary to these methods, the stereochemical

H O H H I2
HO I2, NaHCO3 HO O
O H
O R OH O
MeCN H
I R OH
H O 0 °C to rt, 2.5 h I2 H 70% H O
HO HO favored complex
66a 67a 68a

H O H H
HO I2, NaHCO3 HO O
O O R
O R H
MeCN H
I HO H
H O < 5% H O I2
HO I2 OH HO
66b 67b disfavored complex
(collidine)2AgPF6, I2, CH2Cl2, rt, 2.5 h 68b
80%

Scheme 25.
2694 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723
O R E O
E –H
O 5 O
NBS
MeOH, MeCN
TESO
O 59%
70
O N
NBS
MeOH, THF
TESO
O 47%
71
outcome of the selenoetherification reactions mostly relies on
the coordination of electrophiles such as phenylselenyl chlo-
ride (PhSeCl) or N-phenylselenophthalimide (NPSP) with
the olefin, which is then followed by the ring-closure step.
Therefore, the stereoselectivity of these cyclizations reflects
the kinetic selectivity for the formation of the onium interme-
diate, which may give access to 2,6-trans-tetrahydropyrans.
This is the trend observed for hydroxy alkene 74. As shown
in Scheme 28, 2,6-trans-tetrahydropyran 75-trans is only
obtained through a selenium-mediated cyclization, whereas
75-cis results from the other methods.50
A more selective reagent has been used for the assemblage of
the C11eC15 2,6-trans-tetrahydropyran of leucascandrolide A
(1) from diol 76 (Scheme 29).1d Unexpectedly, iodine-based
electrophiles show little diastereoselectivity, but this is dramat-
ically improved by the use of selenium reagents. Remarkably,
the bulky 2,4,6-triisopropylphenylselenyl bromide (TIPPSeBr)z
affords 2,6-trans-tetrahydropyran 77 in 74% yield and good
diastereomeric ratio (dr 88:12). Eventually, a tin-free radical
reduction of 77 provides the desired advanced intermediate 78
in 85% yield.
5.2. Catalytic cyclizations
5.2.1. Palladium-mediated cyclizations
In spite of the achievements mentioned above, the use and
removal of stoichiometric amounts of often toxic elements
have fueled research into alternative activators of olefins that
allow the desired intramolecular cyclizations under mild con-
ditions and in a catalytic fashion. In this context, catalytic
methodologies based on the activation of olefins are domi-
nated by the palladium chemistry, which has achieved promi-
nent levels of maturity.13e,56 In this arena, the construction of
heterocycles can proceed through carbonecarbon or carbone
heteroatom bond formation, depending upon the nucleophile
involved in the ring-closure step. In particular, the synthesis
z
TIPPSeBr is prepared in situ from (TIPPSe)2 and bromine.
OR1
R O R R1OH O
E E R
Scheme 26.
Br OMe
TESO 4
O AcO O O
72 O 5 1 OH
5 O OMe
HO
Br H O
TESO 4 FR-901464
O 69
73
Scheme 27.
of pyrans relies on the intramolecular cyclization of hydroxy
alkenes, which implies the suitable activation of the olefin
with a palladium catalyst and the subsequent intramolecular
attack by the alcohol.
Since the reactivity of palladium catalysts is dominated by
their oxidation states, Pd(0) and Pd(II) complexes are consid-
ered independently. Indeed, Pd(0) complexes are fairly nucleo-
philic and the cyclizations of d-hydroxy alkenes leading to
pyrans progress via the p-allylpalladium cations (TsujieTrost
reaction). Otherwise, parallel processes involving Pd(II) com-
plexes take advantage of their electrophilic character and
commonly proceed through the fast and reversible formation
of p-complexes with the carbonecarbon double bond, which
next undergo an intramolecular attack by the nucleophile.
5.2.1.1. Catalysis by Pd(0). Palladium(0) complexes catalyze
the cyclizations of d-hydroxy alkenes containing allylic leav-
ing groups (X: OAc, OCO2R, OPO(OR)2, OAr, Cl, Br). As
shown in Scheme 30, the initial p-complex evolves through
a h3-complex to a p-allyl cation, a highly reactive intermedi-
ate that undergoes intramolecular attack of the hydroxyl to
provide the corresponding pyran. The regioselectivity of this
cyclization is rarely a problem, since 6-exo ring closures are
more favored than their competitive 8-endo counterparts.
From a stereochemical point of view, substrate-controlled
cyclizations usually proceed with retention of configuration
at the reacting center. Coordination of the palladium to the
carbonecarbon double bond occurs on the less-hindered face
opposite to the leaving group and the nucleophile adds to
the cationic p-allylpalladium complex on the opposite face
to the metal. Thus, a net retention of the stereochemistry is
observed.57 Studies on the assemblage of the tetrahydropyran
moiety embedded in zampanolide (79 in Scheme 31) have
demonstrated how highly diastereoselective this strategy can
be. Indeed, Pd(0)-mediated cyclizations of both 80a and 80b
afford, respectively, 2,6-cis- and 2,6-trans-tetrahydropyrans
81 as a single diastereomer in good yields under very mild
conditions.58
Palladium(0) catalysts also offer the opportunity for enan-
tioselective cyclizations. Trost et al. have proved that
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2695

OMe OMe OMe

OBn OBn OBn
Conditions
+
X X
HO O O
OTBDPS Conditions cis-trans Yield (%) OTBDPS OTBDPS
74 75-cis 75-trans
Hg(OAc)2, Br2, THF, rt 100:0 71
NBS, DMF, rt 100:0 77 X: Br, I, or SePh
NIS, CH2Cl2, rt 2.3:1
NPSP, CSA, CH2Cl2, rt 1:1.8 87

Scheme 28.

OTBS 11 OTBS
TIPPSeBr, DTBMP
1
OH OH O CH2Cl2, –78 °C, 2 h O OH O
O 15
OH O
CO2Me 74% X CO2Me
dr 88:12 OH
O TBS
O 76 77 X: TIPPSe MeO OMe
, AIBN, hexane,
78 X: H
85%

Scheme 29.

PdL2 generated by mixing Pd2(dba)3$CHCl3, chiral diphosphine

X Pd(0)L2 X 83, and Et3N in CH2Cl2 at 0  C provides the tetrahydropyran
84 in 80% yield and 94% ee (Scheme 32). Furthermore, the
OH OH
stereocontrol imparted by the catalyst is absolute on the
X PdL2 PdL2X more elaborated chiral substrate 85, and the tetrahydropyran
86-trans or the isomer 86-cis is exclusively formed by switch-
ing the configuration of 83.61
OH OH High stereochemical control has also been observed in
3-complex
-allyl cation –HX d-hydroxy alkenes containing other allylic leaving groups
(Scheme 33). For instance, Pd(0)-catalyzed cyclization of car-
bonate 87 affords the tetrahydropyran 88 in high diastereomeric
–Pd(0)L2 ratio, whereas 90 is obtained with complete stereocontrol from
O O
PdL2
ester 89 in 96% yield.62,63
Scheme 30.
5.2.1.2. Catalysis by Pd(II). As previously mentioned, palla-
intramolecular asymmetric allylic alkylations59 of hydroxy dium(II) catalysts exhibit an electrophilic character that ac-
alkenes can be highly enantioselective, with the nucleophilic counts for the formation of p-complexes with carbone
addition of the alcohol to the p-allylic cation being the enan- carbon double bonds, which easily undergo the addition of
tio-determining step of the process.60 As a case study, treat- nucleophiles. In this manner, the Pd(II)-mediated intramolecu-
ment of the hydroxy alkene 82 with a palladium catalyst lar cyclization of hydroxy alkenes provides a straightforward

BnO BnO
OCO2Et
OBn OBn
HO 5 mol% Pd(PPh3)4 O
O
THF, rt O HO
O O
80a 71% 81-cis N
H
BnO BnO
OCO2Et O
OBn OBn
HO 5 mol% Pd(PPh3)4 O zampanolide
THF, rt 79

80b 68% 81-trans

Scheme 31.
2696 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

DMPS 2 mol% Pd2(dba)3·CHCl3 DMPS 83

6 mol% 83 O O
Ar
O Et3N NH HN
CH2Cl2, 0 °C
OH O PPh2 Ph2P
Ar: 4-NO2Ph 80% ee 94%
82 84
TMS

2 mol% Pd2(dba)3·CHCl3, 6 mol% 83, Et3N

TMS
CH2Cl2, 0 °C Pr O
O
Ar
O 60% dr > 97:3 O 86-trans
TMS
Pr O
OH Ar: 4-NO2Ph
O 2 mol% Pd2(dba)3·CHCl3, 6 mol% ent-83, Et3N
85
CH2Cl2, 0 °C Pr O
O
58% dr > 97:3 O 86-cis

Scheme 32.

EtO2CO H
OBn OBn
HO Pd(0) O Pd(II) R
HO PdII
THF, rt PdII R O
ligand dr δ 2,6-cis
1,3-axial interactions
PPh3 3:2 R OH H
87 88 PdII
83 1:2
Pd(II) R
ent-83 10:1 HO PdII
R O
1.3 mol% Pd2(dba)3·CHCl3 2,6-trans
Cbz Cbz
5.3 mol% ent-83
N OH OAc N O Scheme 35.
THF, rt
O 96% O
89 90
Scheme 33. unfavorable axial interactions are developed on the way to
2,6-trans isomers.
entry to oxygenated heterocycles. The regioselectivity of such The success of such a strategy is intimately related to the
cyclizations is commonly determined by the ring size, which regioselectivity of the b-hydride elimination step. Studies on
facilitates the acquisition of pyrans from d-hydroxy alkenes this issue have proved that it is highly solvent dependent,
through a 6-exo ring closure (Scheme 34).64e66 The nucleo- DMSO being the best choice,68 but, in spite of these accom-
philic attack of the hydroxyl on the corresponding p-complex plishments, these cyclizations have been scarcely applied to
usually occurs anti to the metal to produce a s-alkylpalladiu- the synthesis of natural products.69 This limitation has been
m(II) intermediate, which next undertakes a b-hydride elimi- overcome through the introduction of a hydroxy group at the
nation. Importantly, Pd(0) is produced in the final step and, allylic position.70 As represented in Scheme 36, the key fea-
consequently, a mild re-oxidant to transform Pd(0) back into ture of this process entails the coordination of the allylic alco-
Pd(II) without affecting the substrates or products is required hol, a0 -OH, to the metal. Then, the initial Pdep-complex is
to obtain a process catalytic in palladium; otherwise, the selectively formed on the same face of the double bond as
process must be carried out using stoichiometric amounts of the a0 -OH. This complex determines the approach of the d-
the Pd(II) complex.67 OH to the reacting center (syn attack) and, consequently, the
The rationale for the stereochemical outcome of these stereochemical outcome of the cyclization. Eventually, the re-
cyclizations usually hinges on the relative steric demands of sultant s-complex undergoes a selective Pd(II) elimination
the reversibly formed palladium intermediates.65 Attention is leading to a new olefinic bond. Hence, the overall sequence
then focused on the steric interactions engaged in the alterna- may be considered as a Pd-mediated SN20 process that can pro-
tive approaches outlined in Scheme 35. Hence, 2,6-cis ceed without any oxidant.
arrangements are often preferred, especially in the case where In this context, a chiral starting material can give access to
all the substituents are placed in equatorial positions or clearly disubstituted tetrahydropyrans stereoselectively (Scheme 37).

Pd(II)LnX2 –Pd(0)Ln
PdIILnX2
–HX PdIILnX –HX
OH OH O O
-complex -alkylpalladium

Scheme 34.
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2697

α α α
PdCl2 δ
δ δ ClPd
OH OH O –HCl O –Pd(OH)Cl O
α' α' Pd Cl α' Pd H
OH O HO HO
Cl Cl
H Cl
π-complexes σ-complex

Scheme 36.

Indeed, chiral diols 91a,b afford 2,6-cis- or 2,6-trans-tetrahy-
dropyrans 92 as a single isomer in excellent yields, depending
upon the configuration of the allylic stereocenter, a0 , with per-
fect 1,3-chirality transfer. According to the mechanistic guide-
lines presented in Scheme 37, the p-face selectivity observed
in these cyclizations can be rationalized by considering con-
formations on the a0 -stereocenter, so that the most favored
approaches avoid 1,3-allylic strain.71
This strategy has been successfully applied to the construc-
tion of pyran rings embedded in the structure of laulimalide
(93 in Scheme 38). Moreover, it has been subjected to the
Pd(0)-mediated methodology described in Section 5.2.1 for
the synthesis of the C23eC27 dihydropyran 95. Both the Pd
complexes catalyze the 6-exo-like cyclization of 94 to 95 as
a sole isomer in good-to-excellent yields. Furthermore, the
6-endo-trig cyclization of 96 occurs through a syn-SN20 pro-
cess to give exclusively the desired 2,6-trans-dihydropyran
97 in 60% yield.70a
As shown in Scheme 34, the Pd-mediated intramolecular
addition of a hydroxyl group to an alkene leads to a s-
alkylpalladium(II) intermediate. This intermediate can then
be trapped by CO and the resultant acylpalladium species is
easily converted into the corresponding methyl ester (Scheme
39). Thus, the overall process is a 1,2-alkoxycarbonylation that
avoids any b-elimination. In the case of chiral centers, the in-
sertion of CO into the carbonepalladium bond usually retains
the configuration that arises from the cyclization step, and
so pyran-containing ester groups can be stereoselectively ob-
tained as a result of these transformations.72,73
This methodology has been applied to the synthesis of leu-
cascandrolide A (1)1a and phorboxazole A (2a).2g As shown in
Scheme 40, the intramolecular alkoxycarbonylation of diol 98
in 1:1 MeOHePhCN (the use of benzonitrile facilitates
a cleaner and more efficient process) provides the desired
2,6-cis-tetrahydropyran 99 in 75% yield and dr >10:1. Note-
worthy is the fact that the cyclization is highly selective and
the two alcohols and two alkenes in 98 are completely differ-
entiated, which simplifies the protecting-group strategy. Fur-
thermore, the C22eC26 tetrahydropyran (101) of 2a is
prepared in high yield through the Pd(OAc)2-mediated

S 10 mol% PdCl2(MeCN)2 HO HO
OH THF, 0 °C H
R H H O
HO 72%
91a minimisation of 1,3-allylic strain 92-cis

H
S 10 mol% PdCl2(MeCN)2 OH OH
OH THF, 0 °C
S H H O
HO 79%
91b minimisation of 1,3-allylic strain 92-trans

Scheme 37. Note: Pd atoms have been omitted for clarity.

via Pd(0)-carbonate R: CO2Me

20 mol% Pd2(dba)3, neocuproine

O O
PhMe, 80 °C O
O 23 23
59%
OR O
27 10 mol% PdCl2(MeCN)2 27
OPMB OH THF, 0 °C OPMB
OH
O
23
94 89% 95
OH O O O
via Pd(II)-hydroxyl R: H 27
OPMB O
OPMB
OBz laulimalide
OBz
15 mol% PdCl2(MeCN)2, benzoquinone 93
OH
9 5 THF, –5 °C O
9 5
60%
OH 96 97

Scheme 38.
2698 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

CO O MeOH
PdIILnX
O O PdIILnX –Pd(0)Ln
–HX
-alkylpalladium
Scheme 39.
cyclization of hydroxy alkene 100, although 2.5 equiv of the
Pd(II) reagent is needed for complete conversion because of
its reduction by CO during the course of the reaction (acetoni-
trile is used to minimize such deactivation).74 In turn, the par-
allel ring closure of 102 has been carried out in the presence of
a large excess of p-benzoquinone to afford 2,6-cis-tetrahydro-
pyran 103 in 58% isolated yield.
The s-alkylpalladium(II) intermediates can also be trapped
through a Heck reaction. This possibility is nicely illustrated
by a palladium-catalyzed sequence along the synthesis of a-to-
copherol (104 in Scheme 41).75 Indeed, the reaction of 105
O
with methyl acrylate in the presence of catalytic amounts of
Pd(OCOCF3)2, the chiral ligand 106, and p-benzoquinone
O OMe
affords chroman 107 with 96% ee in 84% yield. This two-
step sequence is assumed to proceed via the enantioselective
oxypalladation of 105. The resultant s-alkylpalladium com-
plex then undergoes a Heck reaction with methyl acrylate
and, finally, a b-hydride elimination delivers the desired
product.
A conceptually different strategy to the synthesis of 2,3-di-
hydro-4H-pyranones such as 109aec takes advantage of the
reactivity of enones. As represented in Scheme 42, it relies
on the oxidative cyclization of b-hydroxy enones 108aec
with PdCl2. Thus, this methodology represents a new approach
to the enantioselective assemblage of these useful intermedi-
ates, based on a 6-endo ring closure of a Pd(II)ep-complex
followed by a completely regioselective b-hydride elimina-
tion, without affecting the integrity of the existing
stereocenters.76

7 OTBDPS CO (1 atm) 7 OTBDPS

10 mol% PdCl2, 4 equiv CuCl2,
O OH OH O OH O 1
3 MeOH-PhCN 1:1, rt, 2 h 3
75% dr > 10:1
98 99 CO2Me
CO2Me
22 CO (1 atm) 22
HO 2.5 equiv Pd(OAc)2 O
N 26 OTIPS MeOH-MeCN 1:1, rt, 3 d N 26 OTIPS
86%
O O
100 101 2a
O O
CO (1 atm)
N 15 OTBDPS 10 mol% PdCl2(MeCN)2 N 15 OTBDPS
Cl Cl
HO 5.5 equiv benzoquinone O
11 MeOH-MeCN 1:1, rt, 1 d 11
102 103
58% CO2Me

Scheme 40.

MeO MeO
PdLn(OCOCF3)2
oxypalladation PdLn(OCOCF3)
OH O
105
H2C=CHCO2Me
10 mol% Pd(OCOCF3)2 O
40 mol% 106 84% 96% ee insertion
OMe
p-benzoquinone
CH2Cl2, rt, 3.5 d

MeO MeO
O -HPdLn(OCOCF3) O
-hydride elimination
O OMe O OMe
107 PdLn(OCOCF3)

MeO
O

O N N

-tocopherol O
106
104

Scheme 41.
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2699

OH O OH O OH O 0.5 mol% [PtCl2(H2C=CH2)]2

Bn OH 1 mol% P(4-CF3Ph)3 Bn O
Ph Ph Ph δ
Cl2CHCHCl2, 70 °C, 24 h
108a 108b 108c 112 60% 113
OH 5 mol% Sn(OTf)4 O Ph
γ
O2, 10 mol% PdCl2,10 mol% CuCl,10 mol% Na2HPO4 Ph MeNO2, Δ, 1 h
DME, 50 °C 114 77% 115
OH O Ph
γ 5 mol% AgOTf
O O O Ph Cl2CHCHCl2, 83 °C, 15 h
116 87% 117

Ph O Ph O Ph O Scheme 44.
109a 109b 109c
61% 74% 50%
118 with Ph3PAuCleAgSbF6 in wet CH2Cl2 gives the enone
Scheme 42.
intermediate 119 that cyclizes to 2,6-cis-tetrahydropyran 120 in
excellent yield (Scheme 45).
A related cyclization involving a 6-endo ring closure of an
a,b-unsaturated ketone has been used to build the dihydropyr-
anyl enone unit of several Alstonia alkaloids, such as alsto- OMe
5 mol% Ph3PAuCl
phylline (110 in Scheme 43).77 Although the detailed 5 mol% AgSbF6 O
mechanism is not clear, the process is believed to involve
HO OH wet CH2Cl2, 35 °C, 2 d O OH
the formation of a Pdep-complex on 111, removal of the
118 O 97% 120
silyl group, and nucleophilic attack of the deprotected alcohol
on the palladium complex. Finally, b-hydride elimination
provides 110, while the Pd(0) is re-oxidized to Pd(II) by 119 HO OH
t-BuOOH.
Scheme 45.

5.2.2. Other metal-mediated cyclizations

Besides palladium chemistry, there is a handful of emerging
catalytic methodologies for the cyclization of d- and g-hy-
droxy alkenes, based on the activation of the olefin by other
metals, e.g., platinum,78 tin,79 silver,80 or cerium81 (Scheme
44). The mechanism that accounts for such processes involves
the electrophilic activation of olefin according to the guide-
lines illustrated in Scheme 19. The regioselectivity is well
defined for d-hydroxy alkenes, whereas ring closure of g-hydr-
oxy alkenes 114 and 116 is apparently ruled by the Markovni-
kov tenet, in which the stabilization provided by substituents
of the olefin seems to support the formation of tetrahydropyr-
ans over their tetrahydrofuran counterparts. Synthetically, the
scope of these approaches is still limited and they cannot com-
pete with the performance of palladium catalysts, but they
offer new avenues to the construction of tetrahydropyrans
and constitute a promising area of research.
Remarkably, gold catalysts can participate in a cascade se-
quence that presumably involves a 6-exo ring closure of a hydroxy
enone intermediate through a metal activation of the carbonecar-
bon double bond.82 Indeed, treatment of homopropargylic ether
5.3. Acid-mediated cyclizations
Acid-mediated cyclizations of hydroxy alkenes represent
a particular class of processes, as they are promoted by stoi-
chiometric or catalytic amounts of Brønsted acids. Although
the mechanistic issues of these cyclizations are rather specula-
tive, their regioselectivity is usually controlled by the Markov-
nikov tenet and most of them involve strong Brønsted acids.
Actually, they are commonly carried out in the presence of
large quantities of these reagents. This is the situation ob-
served during the synthesis of platensimycin (121 in Scheme
46),83 in which treatment of a 2:1 mixture of diastereomers
122a and 122b with TFA (TFAeCH2Cl2 2:1) gives the
cage-like structure 123 in 87% yield, based on the isomer
122a present in the mixture. Interestingly, the undesired dia-
stereomer 122b is recovered unchanged.84
It also occurs that these cyclizations can be carried out
under catalytic conditions.79,85 For instance, the ring closure
of hydroxy vinylsilanes such as 124 to 125 using a catalytic
amount of Brønsted acids has been thoroughly studied

H H
MeO H MeO H
8 mol% Na2PdCl4
Me OTIPS NaOAc, t-BuOOH Me O
N N
N N
1:3:3 AcOH-H2O-dioxane
Me H H Me H H
80 °C, 6 h alstophylline
111 O O
55% 110

Scheme 43.
2700 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

O O 6. Allene-mediated cyclizations
TFA-CH2Cl2 2:1
H
0 °C, 1.5 h Allenes containing a nucleophile can undergo intramolecu-
OH O
lar cyclizations on treatment with transition metal catalysts.89
87%
122a 123 In particular, gold-catalyzed cycloisomerization of b- or d-hy-
O droxyallene gives access to six-membered oxygenated hetero-
HO OH cycles in a straightforward manner. As occurs for alkenes (see
O
H O Scheme 19), the initial coordination of the gold catalyst to one
HOOC N of the terminal double bonds of a b-hydroxyallene such as 132
122b OH H
O
gives rise to the formation of an intermediate, which, upon
platensimycin nucleophilic attack of the oxygen, is converted into a s-gold
121
complex through a 6-endo-trig ring closure (Scheme 49).
Scheme 46.
Subsequent protodemetallation of this complex furnishes the
corresponding dihydropyran 133.90 Likewise, d-hydroxyallene
(Scheme 47). A plausible mechanism for this cyclization in- 134 undergoes a 6-exo-trig hydroalkoxylation to form the cor-
volves the formation of a b-silylcarbenium ion intermediate responding 2-alkenyl tetrahydropyran derivative 135 in excel-
by protonation of the sp2-carbon a to the silyl group and the lent yield.91 Remarkably, gold-mediated hydroalkoxylation of
subsequent intramolecular attack of the hydroxy oxygen on 134 in the presence of the chiral diphosphine 136 affords 135
the cationic center.86 in 96% yield and 88% ee.92

OH O
DMPS 5 mol% TsOH
CHCl3, 60 °C, 4 d
124 86% 125
Scheme 47.
Eventually, Lewis acids can also be involved in the intra-
molecular hydroxyalkoxylation of unactivated olefins, leading
to tetrahydropyrans. These processes presumably proceed
through the formation of a Lewis acideOH complex that
enhances the acidity of the hydroxyl proton.86,87 Furthermore,
polycyclic compounds such as ()-caparrapi oxide and (þ)-8-
epicaparrapi oxide (126 and 127, respectively, in Scheme 48)
have been obtained from hydroxy alkene 128 in the presence
of stoichiometric amounts of chiral LBA (Lewis acid-assisted
chiral Brønsted Acid) complexes 129 and ent-129. Indeed, the
asymmetric ring closure of 128 induced by 129 gives an 81:19
mixture of 130 (>99% ee) and 131 (21% ee), whereas the par-
allel cyclization induced by ent-129 provides a 14:86 mixture
of 130 (27% ee) and 131 (98% ee). Eventually, optically pure
130 and 131 are isolated in 74 and 73% yield by column
chromatography.88
7. Alkyne-mediated cyclizations
DMPS
A conceptually related set of approaches based on the elec-
trophilic activation of carbonecarbon triple bonds have also
proved to be a highly efficient entry into the synthesis of
six-membered oxygenated heterocycles.93 Indeed, the cata-
lytic metal-mediated intramolecular cyclizations of precursors
containing alkynes and different oxygenated nucleophiles can
be exploited for the construction of a wide array of oxygen-
containing heterocycles.
Surprisingly, the simplest strategy based on the use of hy-
droxy alkynes had been scarcely applied to date, but recent
reports on the cyclization of 4- and 5-alkynol have established
the synthetic potential of such an approach. In this context,
palladium94,95 and iridium96 complexes catalyze the 6-endo-
dig ring closure of 2-alkynylbenzyl alcohols with internal
triple bonds to the corresponding isochromenes in good yields.
The mechanism for this transformation is outlined in Scheme
50. As for alkenes or allenes, initial coordination of the metal
to the carbonecarbon triple bond enhances its electrophilicity
and facilitates the attack of the hydroxyl. Then, a protodeme-
tallation step renders the cyclic enol ether and regenerates the
catalytic species.

OCOBn
OCOBn O O
2 equiv 129
CH2Cl2-PrCl 1:1
OH –80 °C, 2 d H H
128
74% dr 81:19 > 99% ee 130 (–)-Caparrapi oxide
Ar 126
OCOBn
O
SnCl4 O O
2 equiv ent-129
OH
CH2Cl2-PrCl 1:1
–80 °C, 2 d H H
OMe
Ar: 2-FPh 129
73% dr 86:14 98% ee 131 (+)-8-Epicaparrapi oxide
127

Scheme 48.
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2701

5 mol% Ph3PAuCl LnAu LnAu

5 mol% AgBF4
Bu β Bu
PhMe, rt, 1 d Bu Bu
HO HO O O
H 32%
132 6-endo-trig 133

5 mol% Au[P(t-Bu)2(o-biphenyl)]Cl Ph
5 mol% AgOTs LnAu Ph
PhMe, rt, 5 min
Ph HO
Ph 98%
6-exo-trig
δ
HO O
2.5 mol% Au2[136]Cl2, 5 mol% AgOTs
134 135
PhMe, –20 °C, 18 h
136

MeO PAr2
96% 88% ee
MeO PAr2

Ar: 3,5-(t-Bu)2-4-MeOPh

Scheme 49.

6-endo-dig H
O O
–MLn
R R
OH MLn OH LnM H

R LnM R
O H O
5-exo-dig –MLn
R R
LnM H

Scheme 50.

As shown in Scheme 50, an alternative pathway involving ynoate initially affords a conjugated adduct, which undergoes
a 5-exo-dig ring closure threatens the success of such method- a 6-endo-dig cyclization. Remarkably, the resultant dihydro-
ology. A comprehensive analysis of the regioselectivity of this pyran contains an exocyclic carbonecarbon double bond
cyclization for palladium catalysts has revealed that the with a well-defined geometry (for an outstanding application
6-endo-dig is favored over the 5-exo-dig mode by alkyl, rather of this palladium-based tandem synthesis and a related ruthe-
than aryl, substitution on the triple bond, low solvent polarity nium process, see Scheme 89).
(dioxane), high temperatures (80e100  C), and dilute condi- Furthermore, a palladium(II)-catalyzed 6-endo-dig cycliza-
tions.94,97 Keeping these limitations in mind, both palladiu- tion of b-hydroxy ynones, similar to that outlined in Scheme
m(II) and iridium(III) catalysts provide a good entry into 42, has recently been disclosed.99 Differently, the s-alkenylpal-
isochromenes 138a,b from 2-alkynylbenzyl alcohols 137a,b ladium intermediate obtained in this reaction undergoes inser-
(Scheme 51). tion of ethyl acrylate to form trisubstituted dihydropyranones
Working in the 4-alkynol arena, a tandem palladium(II)- featuring an alkenyl substituent a to the carbonyl (Scheme
catalyzed reaction offers an appealing entry into the synthesis 53). Thus, the overall process entails a cascade Wackere
of dihydropyrans.98 As represented in Scheme 52, the palla- Heck reaction that involves the chemoselective coupling of
dium-catalyzed addition of a terminal alkyne to a hydroxy two electron-deficient reactants. This WackereHeck sequence
does not affect the stereochemical integrity of the starting b-hy-
droxy ynones 139a,b and affords the corresponding dihydro-
OH 2 mol% PdI2, 4 mol% KI O
pyranones 140a,b in good yields.
dioxane, 80 °C, 3 h Bu Otherwise, 5-alkynols with a terminal triple bond undergo
Bu 63%
137a 138a completely regioselective 6-exo-dig ring closures to exocyclic
PPh3
enol ethers in the presence of palladium,100 iridium,101 plati-
4 mol% Ir
H num,102 or gold102,103 catalysts (Scheme 54). Their mechanism
O
OH
O
PPh3 O is also based on the electrophilic activation of the alkyne ac-
CHCl3, 80 °C, 2 h cording to the guidelines previously described, but, differently,
Pr
Pr
the competitive 7-endo-dig pathway is never observed.
77%
137b 138b Interestingly, the resultant cyclic enol ethers can be the start-
Scheme 51. ing point for further transformations. For instance, treatment of
2702 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

CO2R1
CO2R1 CO2R1
H 10 mol% Pd(OAc)2
4 mol% TDMPP
+
R2 PhH, rt, 2–3.5 d
R
R
OH HO R2 50–60% R O R2

R: alkyl, Ph
R1: Me, Et R2: alkyl

Scheme 52.

O O
O
OH O R2 2
PdLnX2 R 2 PdLnX2 PdLnX CO2Et R CO2Et
R1 –HX
R3 R1 O R3 R1 O R3
R2 R3 R1 OH
Wacker Heck
O
OH O CO2Et
Ph
Ph 20 equiv H2C=CHCO2Et, O2 Ph O Ph
139a 140a 47%
10 mol% [PdCl2(CH3CN)2]
Cu(OAc)2·H2O, PPh3, 20 mol% LiBr O
OH O DME, 20 h, 65 °C CO2Et
Ph
139b Ph O 140b 47% de > 99%

Scheme 53.

H H RO HO
H H H MLn
O O MLn O O
MLn 6-exo-dig 143a R: THP 144a R: THP
–MLn 143b R: TBS 144b R: TBS
OH OR
Scheme 54. 1) 1 mol% [PtCl2(CH2=CH2)], Et2O, rt, 30 min
2) 5 mol% CSA, MeCN-H2O, rt, 4 h Alkynol145:146Yield (%)
3) MgSO4, rt, 5 h 143a 30:1 75
alkynols 141 (Scheme 55) with platinum or gold catalysts leads 143b 20:1 83
O
to the enol ethers, which undergo a Prins-type cyclization + O 144a 9:1 60
O
through an oxocarbenium intermediate that eventually affords O 144b 3.7:1 58

the eight-membered carbocycles 142 as a sole diastereomer 145 146

in excellent yields, irrespective of the catalyst.102
Internal alkynols can also participate in highly regioselective
cycloisomerizations, provided that the resultant enol ethers are
satisfactorily trapped by other nucleophiles. For instance, plat-
inum(II)-catalyzed hydroxyalkoxylation of alkynols 143a,b
and 144a,b deliver selectively spiroketal 145 through initial
6-exo-dig or 6-endo-dig ring-closure modes, respectively
(Scheme 56).104e106
A similar gold-catalyzed 6-exo-dig cyclization plays a cru-
cial role in the synthesis of the trioxadispiroketal of azaspira-
cids (62 in Scheme 24). As represented in Scheme 57 (see also
Scheme 56.
Scheme 91), the assemblage of the AeD rings starting from
alkynol 147 relies on the addition of the C6 hydroxy group
across the C10eC11 alkyne followed by the engagement of
the C13 ketal exocyclic oxygen atom to form the desired spi-
roketal.107 Remarkably, treatment of 147 with catalytic
amounts of AuCl and PPTS furnishes 148 in 75% yield.
A closely related methodology takes advantage of the hy-
droxyl-like character of hemiacetals. Yamamoto et al. have re-
ported that the simultaneous activation of a carbonyl and

H
H OR1
O O O
2 mol% MLn H R1OH
R R R R O R O
88–96%
141 142

MLn: PtCl2(cod), PtCl4, AuCl3 R: Me, Bu, i-Pr, t-Bu, allyl

R1OH: solvent (MeOH, EtOH, MeCOOH, EtCOOH)

Scheme 55.
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2703

OH
PMBO 6
10 MeO H MeO H
O O
OTBDPS OTBDPS
11 Au
O O
147 O H
PMBO
8 mol% AuCl, PPTS +H –Au
MeOH, rt, 20 min
75% PMBO
A –H , –Me2O O O
B O O OTBDPS
O OTBDPS Me
O D
OPMB C O
O
O
148 Me H

62

Scheme 57.

R SnBu3
5 mol% Pd(OAc)2,
R Ph
2 equiv R1OH, benzoquinone BF3·OEt2
O dioxane, rt, 0.5–1 h O 79% O

74–90% OR1
149 H 150 151
1
R: alkyl, aryl R : Me, Et, i-Pr OTMS
AcOH
Pd(OAc)2 –Pd(OAc)2 Ph
Ph
R (AcO)2Pd R PdOAc BF3·OEt2
R 85% O
R1OH
O OH –AcOH O Ph
Pd(OAc)2
1
152
H OR OR1 O

Scheme 58.

a carbonecarbon triple bond by palladium(II) catalysts allows
the construction of cyclic alkenyl ethers from acetylenic alde-
hydes. Indeed, cyclization of 2-alkynylbenzaldehydes 149 pro-
ceeds smoothly in the presence of Pd(OAc)2 to provide acetals
150 in high yields (Scheme 58).108 The authors propose
a mechanism in which the palladium catalyst initially acts as
a Lewis acid, promoting the formation of the corresponding
hemiacetal. Then, coordination of the metal to the alkyne fa-
cilitates the anti attack of the hydroxyl from the side opposite
to the metal via a 6-endo-dig pathway.x The resultant vinylpal-
ladium intermediate is subsequently protonated to afford the
final alkenyl acetal with complete regioselectivity. Noteworthy
is the fact that the high reactivity of the benzylic acetal in 150
(R: Ph, R1: Me) makes possible the introduction of carbon
nucleophiles via HosomieSakurai allylation and Mukaiyama
aldol reactions to afford 151 and 152 in high yields.109
Other oxygenated nucleophiles such as carboxylic acid
derivatives and carbonyls have also been utilized in this type
of cyclization.93a,110 A step forward in this area relies on the
electrophilic activation of the carbonecarbon triple bond of
x teine]2O2-mediated enantioselective oxidative dearomatization
It is worth pointing out that the aromatic ring is crucial to the observed re-
gioselectivity. The reaction of the equivalent carbon-tethered acetylenic alde-
hydes, 4-alkynals, mainly yields the corresponding five-membered acetals
through 5-exo-dig cyclizations.
2-alkynylbenzaldehydes and related systems. Now, the nucle-
ophilic attack of the carbonyl oxygen on the electronically
deficient alkyne produces a 2-benzopyrylium-like intermedi-
ate, which can undergo further transformations that ultimately
offer a rich assortment of structures.111e114
This methodology has been applied to the synthesis of ()-
S-15183a (153 in Scheme 59), a member of the azaphilones,
a family of natural products containing a highly oxygenated
bicyclic core and a quaternary stereocenter.115 The reported
synthesis takes advantage of a gold-mediated cycloisomeriza-
tion of 2-alkynylbenzaldehyde 154 followed by oxidation of
the resultant 2-benzopyrylium salt. As outlined in Scheme
59, a plausible mechanism for this transformation entails the
coordination of the gold catalyst to the triple bond followed
by cyclization and protodemetallation to furnish the 2-benzo-
pyrylium salt. Eventually, oxidation of this salt affords in 84%
overall yield the desired oxygenated heterocycle 155 as a race-
mic mixture.
Having developed a straightforward route to the bicyclic
core, attention was focused on the asymmetric oxidation of
the benzopyrylium salt. However, all attempts were unsuccess-
ful and a new strategy, based on the initial oxidation of the
aromatic ring, was disclosed. Remarkably, the Cu2[()-spar-
of 154 provides a hydroxy derivative, which undergoes the de-
sired cycloisomerization under very mild conditions to afford
()-155 in 98% ee and 84% overall yield (Scheme 60). It is
2704 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

R RCOCl
1) 5 mol% Au(OAc)3
HO O R O R
ClCH2CH2Cl–TFA 10:1, rt i-Pr2NEt, DMAP
O 2) IBX, 5 mol% TBAI, rt O CH2Cl2, rt O
HO RCOO
OH H 84% O 61% O
154 R: –(CH2)6Me (±)-155 (±)-S-15183a
(±)-153
AuLn
oxidation
LnAu R LnAu H
HO HO R HO R
TFA
O O –AuLn O

OH H OH OH CF3COO

Scheme 59.

O2, 2.2 equiv Cu(MeCN)PF6

R
2.4 equiv (–)-sparteine KH2PO4–K2HPO4
O O R
i-Pr2NEt, DMAP buffer pH 7.2
154
CH2Cl2, –78 to –10 °C MeCN, rt O
HO HO
O OH O
84% 98% ee
(–)-155

Scheme 60.

worth emphasizing that the 6-endo-dig ring closure is carried
out without any metal at pH 7.2.116,117
Other systems available for this chemistry are 4-propargyl-
1,3-cyclopentanediones 156 represented in Scheme 61. Metal-
mediated cyclization of these 1,3-diketones admits catalysts
based on palladium,118 platinum, tungsten, and mercury.119
Noteworthy is the fact that the platinum-mediated catalysis
of terminal and substituted alkynes affords exclusively the
bicycles 157 in high yields at room temperature. These
6-endo-dig cyclizations are supposed to proceed under kinetic
control by coordination of the catalyst to the triple bond. Then,
the alkyneemetal complex undergoes anti attack of the car-
bonyl oxygen and the resultant vinylplatinum intermediate is
protonated to afford the oxabicycle 157. Since related 1,3-cy-
clohexadienones are prone to 5-exo-dig ring closures, the ex-
cellent regioselectivity observed for 156 is presumably due
to subtle intrinsic strain on the way to the exo- or endo-bicyclic
systems.
As well as these catalytic processes, there are some stoi-
chiometric metal-free methodologies based on the iodine-
mediated electrophilic activation of the substituted carbone
carbon triple bond of 2-alkynylbenzaldehydes that allow for
the highly efficient construction of six-membered oxygenated
heterocycles120,121 and other carbocycles.122 For instance,
addition of the iodonium ion generated from Ipyr2BF4/HBF4
to the triple bond of 2-alkynylbenzaldehydes 149 leads to an
iodobenzopyrylium salt, which, in turn, reacts with nucleo-
philes and offers a straight and useful access to highly elabo-
rated oxygenated heterocycles 158e161 (Scheme 62).120
Importantly, most of these transformations can be carried out
following a procedure based on the use of iodine.121
8. Other metal-promoted cyclizations
In addition to the methodologies just described, metals can
also catalyze other cyclizations that require the in situ gener-
ation of transition metalecarbenoid species. Such transforma-
tions encompass the cycloisomerization of 4-alkynols via
metal vinylidene complexes and the intramolecular addition
of oxygenated nucleophiles to metal carbenes obtained from
diazo precursors.
This chapter also takes into account a less studied transfor-
mation: the intramolecular etherification of aryl and vinyl
halides catalyzed by palladium and copper.
8.1. Cyclizations of 4-alkynols

O
R 10 mol% PtCl2
O R The transition metal-mediated isomerization of hydroxy
O
THF–dioxane 2:1
O alkynes containing a terminal carbonecarbon triple bond rep-
rt, 24–72 h resents a highly valuable route for preparing 3,4-dihydro-2H-
156 157
R: H, Me pyrans (see Eq. 5 in Scheme 63).123 Unlike the methodologies
PtCl2 76–85%
–PtCl2 previously discussed, these processes proceed through a metal
O O R vinylidene intermediate that undergoes intramolecular attack
R 6-endo-dig
HO HO by an alcohol. Thus, the key element of such cyclizations relies
PtCl2 PtCl2 on providing metal vinylidene intermediates reactive enough to
Scheme 61. sustain a catalytic process. These species arise from the initial
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2705

I
158
Ph O OMe
MeOH
63% I
TMS
Ph O
Ipyr2BF4, HBF4 I 42%
OTMS 159
CH2Cl2, 0 °C to rt
R O H Ph
R I
O H 55% O

R: alkyl, aryl, alkenyl PhNMe2 Ph O Ph

45%
149 160
I

Ph O

161 NMe2

Scheme 62.

MLn MLn
OH HO O OH OH HO
H MLn H MLn H •
(5)
H MLn H
alkynol metal vinylidene 3,4-dihydro-2H-pyran -complex vinylidene intermediate
R R
O N2 MLn O MLn O
(6) O O MLn O MLn
–N2
MLn or
diazo precursor metal carbene tetrahydropyran
–MLn –MLn
Scheme 63.
O O

coordination of a metal to a terminal alkyne (Scheme 64).

Then, the resultant p-complex undergoes either a 1,2-hydro-
gen migration over the triple bond or an oxidative addition
of the C(sp)eH bond to the metal center and subsequent
1,3-shift of the hydride to the alkyne ligand.124,125
The a-carbon in the Cb]Ca]MLn moiety exhibits elec-
trophilic properties and undertakes additions of nucleophiles
that eventually lead to formal anti-Markovnikov products.
Importantly, the intramolecular attack of the hydroxyl on the
Ca-center of the vinylidene intermediate derived from 4-
alkynols must override a competitive pathway arising from
the simple addition to the activated p-complex (Scheme 65).
Thus, the structural elements on the substrate, the catalyst,
and the reaction conditions have to be carefully chosen to
avoid such a 5-exo-dig ring closure. These conditions are
rather stringent and few metals form vinylidene intermediates
that are able to take part in catalytic sequences. To date, this
limited group includes rhodium,126 ruthenium,127 and mostly,
tungsten complexes.123,128
Ruthenium(II) complexes [CpRuCl(PR3)3] catalyze the
highly selective synthesis of lactones and cyclic enol ethers,
Scheme 65.
depending on the phosphine and the amount of N-hydroxysuc-
cinimide employed (Scheme 66).127a Indeed, electron-rich
arylphosphines such as P(4-MeOPh)3 and a large excess of
N-hydroxysuccinimide produce six-membered lactones,
whereas electron-poor arylphosphines such as P(4-FPh)3 and
small amounts of the sodium salt of N-hydroxysuccinimide
provide the corresponding dihydropyrans. Unfortunately,
none of these conditions can be applied to substrates bearing
oxygenated substituents at the propargylic position. Despite
this limitation, the efficiency of ruthenium(II) catalysts has
been proved for the assemblage of structurally complex fused
polyethers such as 163e166 from 162.127b
Tungsten-like chemistry has attracted much attention.123
The most common tungsten complex used for the cycloisome-
rization of 4-alkynols is W(CO)6, which is photochemically
activated in situ to generate the true catalytic species, presum-
ably W(CO)5.129,130 The cyclization is routinely carried out

1,2-hydride shift

MLn MLn R
R H R H MLn
H H
-complex R MLn
oxidative addition 1,3-hydride shift

Scheme 64.
2706 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

10 mol% CpRuCl[P(4-MeOPh)3]3
40 mol% P(4-MeOPh)3, 30 mol% Bu4NPF6
OH
N H H
6 equiv O O , 2 equiv NaHCO3 O
BnO
DMF, 85 °C, 20 h
BnO O O
60% H

O 163
BnO
H 5 mol% CpRuCl[P(4-FPh)3]3
BnO OH 20 mol% P(4-FPh)3, 15 mol% Bu4NPF6
ONa
162 N H H
0.5 equiv O O O
BnO
DMF, 85 °C, 26 h BnO O
70% H
164
H H H H H H
O O O OH
BnO as previously BnO H

BnO O BnO O
H H H H
65%
166 165

Scheme 66.

with 5e25 mol % W(CO)6 and an excess of a tertiary amine
(DABCO often gives better results than Et3N) in THF or tolu-
ene under constant irradiation at 350 nm. Remarkably, these
tungsten-based catalysts tolerate substituents at the propargylic
position and are compatible with a wide variety of functional
groups such as alcohols, ethers, amides, and carbamates.131
This methodology has been successfully applied to the con-
struction of the trisaccharide component of digitoxin (167 in
Scheme 67). Thereby, iterative alkynol cycloisomerization
based on W(CO)6 constitutes the most important feature of
the synthetic sequence that provides glycal 171 and eventually
allows for the total synthesis of digitoxin.132
In addition to W(CO)6, a preformed THF$W(CO)5 complex
has been employed.133,134 Moreover, a recent communication
has disclosed a new catalytic system that does not require pho-
tochemical activation, based on (methoxymethylcarbene)pen-
tacarbonyl tungsten (172 in Scheme 68).135 The optimal
results are obtained with 25 mol % of oxacarbene 172 in the
presence of 10 equiv of Et3N by simple warming to 40  C in
THF. This experimental procedure has been successfully
applied to the synthesis of the altromycin disaccharide 173
via 174 and 175.
8.2. Cyclizations of diazo compounds
Metal carbenes are easily obtained from diazo compounds
in the presence of copper and rhodium complexes. The
accepted mechanism for this transformation combines the
Lewis acid character of the metal complex and the basic
properties of the carbon center of the diazo precursor. Hence,
formation of an acidebase adduct is followed by back dona-
tion of electron density from the metal with concomitant loss
of nitrogen, thus producing the metal carbene (Scheme
69).136,137

H H 25 mol% W(CO)6 H H
O O O O
OH DABCO O
THF, h , 65 °C
TBSO O TBSO O
TBSO TBS H 96% TBSO TBS
168 169

H H H 1) 25 mol% W(CO)6, DABCO H H H

O O O O O OH
O THF, h , 65 °C O H
H H
2) Ac2O, Et3N, CH2Cl2
HO O O HO O O
HO TBS TBSO 81% HO TBS TBSO
171 O O 170

HO O H OH digitoxin
O O O
O O 167
HO H
HO HO

Scheme 67.
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2707

OMe CO
MeO
Et3N + W(CO)5 (Et3N)W(CO)5 Et3N + W(CO)6
h
172

HO O O
H 25 mol% 172
10 equiv Et3N
O O O O O O
CbzHN THF, 40 °C, 12 h CbzHN Me2N
OMOM 83% OMOM OMOM
174 OTIPS 175 OTIPS 173 OMe

Scheme 68.

closure of the polyoxygenated a-diazo ester 177 produces

MLn N2
R1 N2 R1
MLn –N2
R2 R2
diazo compound
Scheme 69.
Stabilized diazo compounds, particularly a-diazo ketones or
esters, are suitable precursors for metal carbenes that exhibit
electrophilic properties at the carbon center, which allow
them to undergo attack of nucleophiles with the eventual release
of the metal. In particular, catalytic conversion of the diazo
groups into the corresponding metal carbenes followed by intra-
molecular reaction with alcohols, ethers, or carbonyls affords
a wide variety of oxygenated heterocycles (see Eq. 6 in Scheme
63). As the reacting roles are clearly defined, the regioselectiv-
ity of such cyclization is not at all troublesome and the only
concern lies in the configuration of the resultant stereocenters.
The use of alcohols as the nucleophilic source for these
cyclizations has been seldom exploited for the synthesis of
pyran-like structures. Probably, more synthetic applications
are lacking because the mechanism of the process is not fully
understood. Studies on the insertion of metal carbenes into
a polar OeH bond suggest that this transformation proceeds
through a concerted pathway, as for parallel reactions with
nonpolar CeH or SieH bonds (Scheme 70).136,138 However,
evidence supporting a stepwise mechanism has also been
reported.139 The latter model entails the formation of an oxo-
nium ylide, either free or associated to the metal, followed by
a rapid [1,2]-hydrogen shift.
This methodology has been applied to the synthesis of
2-deoxy-b-KDO (176 in Scheme 71). Metalecarbene ring
H
O MLn
H –MLn
O MLn
H
H
O MLn O ring closure based on the nucleophilic addition of a carbonyl
–MLn
associated free
oxonium ylide oxonium ylide
Scheme 70.
2,6-trans tetrahydropyran 179a as the sole diastereomer in
R1 MLn
R2 almost quantitative yield when the reaction is carried out
metal carbene with Rh2(OAc)4 in benzene at room temperature.140 Other-
wise, a 4:1 mixture of epimers 179a and 179b is obtained
when benzene is replaced by chloroform or wet benzene.
The rationale for this behavior assumes that the intramolecular
attack proceeds on two alternative chair-like conformations
178a and 178b, the population of which is strongly solvent
dependent.141
Ethers can also react with metal carbenes via an oxonium
ylide intermediate to give six-membered oxygenated hetero-
cycles. Although it is still unclear whether an associated or
free oxonium ylide is the true intermediate for such transfor-
mation, it is generally accepted that these species can evolve
through a [1,2]- or [2,3]-shift for allyl ethers (Scheme 72).
Irrespective of the pathway, copper catalysts usually provide
better results than their rhodium counterparts, presumably be-
cause they favor ylide formation over competitive CeH bond
insertion.
In this context, copper-catalyzed cyclizations of a-diazo
ketones containing an allyl ether have already been applied
to the synthesis of natural products.142,143 As an example, ste-
reoselective oxonium ylide [2,3]-rearrangements have been
used in an iterative approach for the construction of fused pol-
yethers.142 As shown in Scheme 73, treatment of allyl a-diazo
ketone 180 with Cu(tfacac)2 provides the bicyclic compound
181 in 80% yield and excellent diastereomeric ratio. Epimeri-
zation of 181 to the more stable equatorial isomer needed for
eventual iteration and reduction of the resulting mixture
delivers the alcohol 182 in 86% yield. Then, further func-
tional-group manipulations afford the a-diazo ketone 183,
ready for a new cyclizationeepimerizationereduction se-
quence leading via 184 to polyether 185.
The use of carbonyls as oxygenated nucleophiles for the
concerted insertion intramolecular addition to metal carbenes has received much
attention. Attack of the oxygen atom of the C]O bond on
O H a metal carbene produces a transient carbonyl ylide that can
participate in 1,3-dipolar cycloadditions (Scheme 74). Thus,
to a metal carbene represents the first step in a cascade
sequence that gives access to structurally complex bicyclic
stepwise insertion
systems. In this context, rhodium complexes afford higher
yields than the copper adducts, because they enable diazo de-
composition under milder conditions. Thus, cyclization
2708 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

O OH
O N2 CO2Et O HO
O Rh2(OAc)4 O RhLn
CO2Et PhH, rt OH
R 96% R O CO2Et HO O CO2H
15 min O H H H H
R OH HO
177 178a 179a
2-deoxy- -KDO
O
O RhLn O 176
R:
O O CO2Et
OH
R R O CO2Et
O H H
178b 179b

Scheme 71.

R R R
O MLn O MLn O [1,2]–shift O R deals with an intramolecular version of such a cascade se-
quence from a-diazo ketone 190, in which a simple olefin
acts as dipolarophile to obtain diastereoselectively the tricyclic
adduct 191 in 73% yield.148 Surprisingly, the synthetic mate-
O MLn O MLn O O rial shows a higher specific rotation than the samples obtained
[2,3]–shift
from natural sources, which suggests that polygalolide A
might be biosynthesized through a poorly stereoselective
pathway.150
Scheme 72.

H H H
O N2 O O
5 mol% Cu(tfacac)2 1) DBU
CH2Cl2, reflux 2) LiAlH4
O O O O O OH
H H H
80% dr 30:1 86%
180 181 182

H H H H H H
O OH O O O O
1) DBU 5 mol% Cu(tfacac)2
O O 2) LiAlH4 O O CH2Cl2, reflux
O O N2
H H H H H H
86% 80%
185 184 183

Scheme 73.

R O MLn R O MLn R O
cyclization carbonyl ylide
Scheme 74.
methodologies that take advantage of the carbonyl ylide reac-
tivity currently employ rhodium(II) catalysts.144e146
The power of the carbonyl ylide cycloaddition methodol-
ogy for the rapid assemblage of bicyclic systems has been
proved in the stereoselective synthesis of structurally complex
natural products such as zaragozic acid C147 and polygalolide
A148 (186 and 187, respectively, in Fig. 4).149
The first example entails the intermolecular trapping of the
carbonyl ylide intermediate from a-diazo ester 188 with 3-bu-
tyn-2-one to construct the cycloadduct 189 as a single diaste-
reomer in 72% yield (Scheme 75).147 The second example
A B Since the cycloaddition step can be faster than metal
A B R
O decomplexation from the carbonyl ylide, enantioselective tan-
dem sequences can also be achieved by positioning chiral
1,3-dipolar cycloaddition ligands on the rhodium catalyst.151 This approach has been
applied to the synthesis of pseudolaric acid A (192 in Scheme
76).152 Indeed, a substrate-controlled cascade from the a-diazo
ketone 193 in the presence of achiral rhodium catalysts is
found to favor the formation of the oxatricycle 194a, whereas
a chiral Rh2[(S)-bptv]4 catalyst smoothly delivers a mixture
containing the desired diastereomer 194b as the major compo-
nent in 82% overall yield.
Moreover, the stereochemical outcome of these transforma-
tions can also rely on chiral Lewis acids affecting the cycload-
dition step. Although the scope of these transformations is
sometimes narrow, significant levels of enantioselectivity
have been reported for the reaction of carbonyl ylides arising
from a-diazo ketones 195 with substrates able to form chelates
with chiral Pyboxelanthanide triflate catalysts (Scheme
77).153
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2709

O O
MeO
Ph O OH
OAc H
O
HOOC HO O
O Ph
HOOC O
zaragozic acid C polygalolide A O
HO COOH
186 187 O

Figure 4.

O COMe
5 mol% Rh2(OAc)4 COMe
N2 O OMOM 3 equiv HC CCOMe R1 O
R1 R2 R1 1
R
O R2 186
OTBDPS PhH, reflux, 1 h O O
t-BuO2C
TMSO CO2t-Bu TMSO OTBDPS 72% TMSO
OTBDPS
188 R1: CO2t-Bu R2: (CH2)2OMOM 189
PMBO
OPMB
N2 O
OTBDPS 5 mol% Rh2(OAc)4
O 187
PhCF3, 100 °C, 5 min O
O O O O
OTBDPS
OPMB O 73% O
OTBDPS
190 191

Scheme 75.

OPMB
O
Rh2(OAc)4 iPr N
O O H O
CH2Cl2, 0 °C
N2 H O O
Rh2[(S)-bptv]4
PMBO O 61% dr 3:1 O Rh Rh
O
O
OPMB 194a
O
O
3 mol% Rh2[(S)-bptv]4 O O O
O
PhCF3, –40 °C H
HOOC
193 O OAc
82% dr 1.6:1
O
194b pseudolaric acid A 192

Scheme 76.

8.3. Intramolecular etherification of aryl and vinyl halides
Although the coupling of oxygenated nucleophiles with
aryl halides is a long-established method for the preparation
of aryl ethers, the harsh reaction conditions commonly re-
quired to effect this transformation have restricted its synthetic
scope. Indeed, there are relatively few examples for the
construction of oxygen heterocycles through the intramolecu-
lar etherification of aryl halides.
This lack of synthetic methodologies was covered a few
years ago by a procedure based on intramolecular palladium-
catalyzed carboneoxygen bond formation.154 The reaction
proceeds under mild conditions using bulky and electron-rich
o-biarylphosphines in the presence of weak bases. Remarkably,
the choice of the phosphine turns out to be crucial, since its steric
bulk accelerates the reductive elimination step and minimizes
the competitive b-hydride elimination pathway (Scheme 78).
Aryl chlorides and bromides are suitable substrates for this
transformation. Then, primary as well as secondary substrates
can be cyclized in the presence of bulky dialkylphosphino-
biaryl ligands such as 203a and 203b (Scheme 79). Moreover,
aryl bromides in which the hydroxyl-bearing chain contains
stereocenters and additional functional groups such as amines,
amides, or esters also afford the corresponding heterocycles in
high yields without erosion of the optical purity.
The potential of this transformation has been proved in the
synthesis of several heterocyclic compounds with different
biological activities.154a,155 For instance, the intramolecular
palladium-mediated etherification of the aryl bromide 204
generates the chroman ring 205, which is easily transformed
into (S)-equol (206), a metabolite with a high estrogenic activ-
ity (Scheme 80).155d
In spite of the success of this palladium-catalyzed cycliza-
tion, the pursuit of easy-to-handle reagents and easier proce-
dures is fueling the development of new methodologies. A
recent report on a copper-catalyzed intramolecular coupling
of vinyl bromides is a good example of this emerging chemis-
try.156 As illustrated in Scheme 81, the vinyl bromide 207 is
2710 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

MeO
BnOCH2CHO
10 mol% 196-Sc(OTf)3 O OBn
O
CH2Cl2, –10 °C

O 199 * 96%
exo/endo 12:88
MeO ee (endo) 91%
MeCOCO2Bn, 10 mol% TFA
10 mol% 196-Sc(OTf)3 O
O
CH2Cl2, –25 °C CO2Bn
OR OR
2 mol% O 200 * 98%
O Rh2(OAc)4 O exo/endo 93:7
CH2Cl2 O O O ee (exo) 94%
N2 O O
N O MeO
O O N
195 10 mol% 197-Yb(OTf)3
O
CH2Cl2, –10 °C

O 201 * 94%
exo/endo 82:18
O N O O O O ee (exo) 96%
R2 R2 O
N N O
N O p-BrPhCH2O
R1 R1 N
196 R1: i-Pr R2: H 20 mol% 198-Yb(OTf)3
197 R1: Ph R2: H
O
CH2Cl2, rt
198 R1: Ph R2: Ph
60%
O 202 *exo/endo > 1:99
ee (endo) 96%

*absolute configuration has not been determined

Scheme 77.

reductive
O
elimination
OH OH
O
X PdXLn PdLn O
Pd(0)Ln base
H

X: Cl, Br
-hydride elimination
and
reductive elimination

Scheme 78.

easily transformed into the tetrahydropyran 208 in the pres-
ence of a copper(I) salt and 1,10-phenanthroline.
9. Intramolecular conjugate additions
The venerable Michael reaction has found a fertile field of
application in the synthesis of six-membered oxygenated
heterocycles. As outlined in Scheme 82, intramolecular nucleo-
philic attack of an alcohol on the electronically deficient
C(sp2) or C(sp) center of a,b-unsaturated systems proceeds
smoothly through exo and endo ring-closure modes to provide
the corresponding pyrans.
9.1. 6-exo Ring closures
The most common procedure for the synthesis of tetrahydro-
pyrans based on the Michael reaction involves 6-exo-trig cycli-
zations of a,b-unsaturated hydroxy ketones or esters (see Eq. 7
in Scheme 82). These transformations are usually carried out in
the presence of stoichiometric, or even catalytic, amounts of
base under thermodynamic control, which implies that the con-
figuration of the new stereocenter can be predicted from confor-
mational analysis of the resultant heterocycle. Therefore,
considering that the most stable conformer of saturated six-
membered heterocycles adopts the chair form as a rule, it is
in general anticipated that these cyclizations mainly pro-
vide 2,6-cis-disubstituted tetrahydropyrans.157 As represented
in Scheme 83, this methodology has been largely applied
to the synthesis of leucascandrolide A (1),1d,g,j phorboxazole
A (2a),2c spongistatin 1 (209), and other natural products.158,159
However, careful optimization of the experimental condi-
tions enables the acquisition of the kinetically favored 2,6-
trans diastereomers.160,161 Thereby, cyclization of hydroxy
ester 210 affords either 211-cis or 211-trans tetrahydropyran
under basic conditions (Scheme 84).160b The all-equatorial
211-cis diastereomer is assumed to be the most stable isomer
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2711

of a,b-unsaturated ester 213 with a catalytic amount of base

under equilibrating conditions (THF, 0  C) provides the
P(t-Bu)2 P(t-Bu)2
more stable 2,6-cis-disubstituted tetrahydropyran 214-cis,
whereas low temperatures favor the cyclization to the 2,6-
203a 203b trans derivative 214-trans. Similarly, assemblage of the 2,6-
cis-tetrahydropyran 216-cis from a,b-unsaturated ester 215 is
R 2–3 mol% Pd(OAc) 2 carried out at 35  C, because the 2,6-trans isomer 216-trans
2.5–3.5 mol% 203 predominates when the reaction is conducted at 78  C.
OH 1.5 equiv Cs2CO3
Furthermore, the stereochemical outcome of oxa-Michael
X PhMe, 50 °C, 24 h O R
cyclizations on a,b-unsaturated esters containing an additional
X: Cl, Br R: H, Me 72–85%
hydroxy group at the allylic position is strongly influenced by
Scheme 79. the protecting group and the alkene geometry.163e166 In this
manner, kinetically controlled cyclization in aprotic basic
2.5 mol% Pd(OAc)2
conditions of a,b-unsaturated esters 217 affords 2,3-cis- or
Ar 2.5 mol% 203a Ar 2,3-trans-disubstituted tetrahydropyrans 218, depending on the
1.5 equiv Cs2CO3 geometry of the carbonecarbon double bond. As shown in
MeO Br OH PhMe, 50 °C, 22 h MeO O Scheme 86, tetrahydropyran 218-trans is almost exclusively
204 46% 205 obtained from the (Z)-ester 217-Z, whereas the 218-cis isomer
Ar: 4-MeOPh
OH is prepared in high diastereomeric ratios from (E)-ester 217-E.
In both cases, NaH provides good results, but potassium bases
(S)-equol
pyr·HCl such as KHMDS are the most convenient regarding both
206 HO O 150 °C, 28 h stereoselectivity and rate.164a,b
66% It has also been shown that (E)-a,b-unsaturated ester 219
Scheme 80. cyclizes quantitatively to 2,3-cis-2,6-cis-tetrahydropyran 220
(Scheme 87), whereas (Z)-a,b-unsaturated ester 221 pro-
vides 2,3-trans-2,6-trans-tetrahydropyran 222a, which can
10 mol% CuI
Ph Ph be equilibrated to the thermodynamically more stable 2,3-
20 mol% 1,10-phenanthroline
2 equiv Cs2CO3 cis-2,6-cis 222b.167,168 Theoretical calculations on the intra-
PhMe, , 20 h molecular Michael addition on all these systems emphasize
Br OH O
207 60% 208
the important role of the cation, the conformational
analysis of the a,b-unsaturated esters, and the reversibility
Scheme 81.
of the process for the stereochemical outcome of such
cyclizations.
One of the most appealing features of Michael-mediated
6-exo cyclizations
cyclizations is that they can participate in cascade se-
6-exo-trig
(7) quences.169,170 This is the case for the double-cascade cycliza-
EWG EWG
OH O tion triggered by a 6-exo-trig oxa-Michael addition on the
advanced intermediate 224 en route to tetronasin 1 (223 in
6-endo cyclizations Scheme 88). Indeed, treatment of 224 with KHMDS in toluene
O O
at 0  C gives exclusively the 2,6-cis-disubstituted tetrahydro-
6-endo-dig
(8) pyran 225 in an impressive 67% yield.171
OH O Moreover, a new route to 2,6-cis-tetrahydropyrans based on
O O a tandem alkyneeenone coupling and a Michael addition has
recently been disclosed.172 As illustrated in Scheme 89, the
6-endo-trig
(9) eneeyne coupling of b,g-unsaturated ketone 226 and TMS-
OH O
protected homopropargylic alcohol 227 presumably provides
EWG EWG
6-endo-trig a hydroxy enone, which undergoes a Michael-like cyclization
(10) to afford the C11eC15 2,6-cis-disubstituted tetrahydropyran
OH O
228 in good yield and diastereomeric ratio.173 Mechanistically,
Scheme 82. the preference for the 2,6-cis diastereomer seems to arise from
a late transition state, in which the relative stabilities would
play a significant role. This ruthenium-based sequence is com-
and is predominantly obtained at room temperature and long bined with a palladium-catalyzed dihydropyran synthesis pre-
reaction times. Otherwise, low temperatures and shorter reac- viously reported (see Scheme 52). In this case, coupling of
tion times supply 211-trans in good diastereomeric ratios. terminal alkyne 229 with hydroxy ynoate 230 in the presence
The synthesis of (þ)-SCH-351448 (212 in Scheme 85) of palladium(II) catalysts delivers the C19eC23 dihydropyran
takes advantage of analogous procedures.162 Indeed, treatment 231 in 55% yield. Both processes cover key transformations
2712 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

OTBS OTBS
10 mol% t-BuOK
1
O OH OH THF, 0 °C, 10 min O OH O

CO2Et 80% CO2Et

TBSO dr 9:1 TBSO
OTIPS OTIPS
1.1 equiv NaHMDS
2a
THF, –78 °C, 1 h CO2Et
O OH O O
N CO2Et 87% N
O
Boc Boc
HO
AcO OMe
PMB OPMB
1) AcOH, THF–H2O O O O
O PMBO O O O OH
rt, 48 h O O
2) KOH, MeOH O
AcO HO
PMBO OPMB rt, 24 h OPMB
O O
86% dr > 95:5 HO
OH O
spongistatin 1
209 O OH
H OH
Cl OH

Scheme 83.

OH OH OH

S O 2.2 equiv NaH S 1 equiv NaH S O

THF THF
S O OMe S OH S O OMe
–78 to 0 °C –40 °C to rt
2.5 h MeO O 7h
211-trans 78% dr 81:19 210 61% dr 98:2 211-cis

Scheme 84.

10 mol% t-BuOK 10 mol% t-BuOK

O O THF, –78 °C, 20 min OH O THF, 0 °C, 10 min O O

CO2Bn 86% dr 13:1 CO2Bn 90% CO2Bn

214-trans 213 214-cis

60 mol% t-BuOK 60 mol% t-BuOK

O THF, –78 °C OH THF, from –78 to –35 °C O

CO2Me 74% dr 12.5:1 CO2Me 80% CO2Me

216-trans 215 216-cis

CO2H
OH
O
O O OH O

O OH O O
O
HO
NaO2C (+)-SCH-351448, 212

Scheme 85.

for the total synthesis of 232, a ring-expanded analogue of
bryostatin 1.
Ring closure of the putative intermediate represented in
Scheme 89 is believed to be catalyzed by the ruthenium Lewis
acid. Indeed, Michael-mediated cyclizations can also proceed
under Brønsted acid conditions.174 Although poorly exploited,
this sort of reaction has been applied to 6-exo-trig cyclizations
on a,b-unsaturated ketones for the synthesis of complex natu-
ral products. For instance, deprotection of 1,3-diol in 233 in
acetic acid triggers the formation of 2,6-trans-tetrahydropyran
234 in excellent yield and moderate diastereoselectivity
(Scheme 90);175 reaction of lactol 235 with a stabilized
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2713

H H
OBz OBz OBz OBz
+
CO2Me CO2Me CO2Me
OH O O OH
H H
CO2Me
217-E 218-cis 218-trans 217-Z
2,3-cis-tetrahydropyran 2,3-trans-tetrahydropyran

Ester Base Solvent T (ºC) dr (cis-trans)

217-E KHMDS PhMe –78 9:1

217-E NaH THF –78 9:1
217-Z KHMDS PhMe 0 1:20
217-Z NaH THF 0 1:11

Scheme 86.

CO2R1
OH 6 O 2
PGO t-BuOK PGO CO2R1
THF, 0 °C
OPG 3 OPG
R1: O R2: O
PG: TBDPS 100% dr > 95:5 2,3-cis-2,6-cis
Ph Ph
219 220

OH 6 O 2 6 O 2
PGO CO2R2 t-BuOK PGO CO2R2 t-BuOK PGO CO2R2
PhMe-t-BuOH, rt PhMe, 0 °C
OPG 3 OPG 3 OPG
PG: TBDPS 76% dr > 98:2 2,3-trans-2,6-trans 100% dr 95:5 2,3-cis-2,6-cis
221 222a 222b

Scheme 87.

phosphorane provides enone 236, which is cyclized by treat-
ment with CSA to furnish 2,6-cis-tetrahydropyran 237 as the
sole diastereomer in 73% yield over two steps176 and, eventu-
ally, removal of isopropylidene acetal and silicon protecting
groups in the advanced intermediate 238 en route to bryosta-
tins with HF leads to the C1eC16 fragment 239 containing
two 2,6-cis-tetrahydropyrans.177,178
As well as all of these cyclizations, a 6-exo-dig ring-closure
mode based on a Michael reaction is, in fact, possible. How-
ever, there is no clear example in the literature, because the
enone generated in this cyclization process usually undergoes
a second Michael addition, as can be appreciated in the syn-
thesis of azaspiracids (62 in Scheme 24, see also Scheme
57). In this case, the retrosynthetic analysis of the C27eC40
domain followed by Forsyth et al. relies on a formal Double
Intramolecular Hetero Michael Addition (DIHMA) based on
a 6-exo-dig cyclization followed by a stereoselective 6-exo-
trig ring closure.179 In this manner, the acid-mediated double
intramolecular oxa-Michael addition on dihydroxy ynone
240 gives the bicyclic ketal 241 as a single diastereomer in
excellent yield (Scheme 91).180 Similarly, treatment of ynone
242 with TBAF promotes silyl ether cleavage and addition of
the corresponding oxygen atoms upon C28 to provide in high
yield the targeted FG-ring system 243 present in
azaspiracids.181
9.2. 6-endo Ring closures
Contrary to the Michael-mediated 6-exo-dig cyclizations,
parallel 6-endo-dig processes have been identified as a useful

EtO2C
HO O
MeO2C OMe
224

KHMDS PhMe, 0 °C, 30 min

HO O O
H
OMe
EtO2C
O O
H
OMe H ONa
225 O
67% tetronasin 1
H single diastereomer O 223
CO2Me O

Scheme 88.
2714 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

TBDPSO O

O
TBDPSO O
TMS 10 mol% R
TMS
O [CpRu(MeCN)3]PF6 TMS 11
+ OH O
O O OPMB
acetone, rt, 40 h
15
OH 56% 228
PMBO
O OPMB PMBO
dr 9:1
PMBO 227
226 MeO
OAc
1) 4 mol% Pd(OAc)2 OTBS MeO2C 11
OTBS
4 mol% TDMPP O O
OH O 19 O 23 O 15
O Ph, rt, 1 d OH
+
2) 8 mol% Pd(OCOCF3)2 O (H2C)3
O
2d
H CO2Me OH H
55% O O
CO2Me
229 230 231 19 23

analogue of bryostatin 1 AcO OH

232 CO2Me

Scheme 89.

SEM OSEM
O
O SEMO O O O OH
AcOH
THF– H2O, rt, 19 h O
SEMO OBn OBn
233 95% dr: 2.5:1 234
O
H
O OH OH O O
10 mol% CSA
CH2Cl2, rt, 1 h
BnO OBn BnO OBn BnO OBn
235 236 73% 237
TMS
MeO
OBn OBn
1) 56% HF, MeCN, rt, 24 h O O
O OBn O O
TBSO
2) HC(OMe)3, MeOH, cat PPTS, rt, 3 h
OTBS
34% OH
238 239 OH OBn

Scheme 90.

tool to gain access to pyranones (see Eq. 8 in Scheme 82). In selectivity of these reactions turns out to be highly dependent
particular, 6-endo-dig cyclizations of o-alkynoylphenols upon the experimental conditions. Indeed, base-catalyzed
provide an appealing entry into the synthesis of the heterocy- cyclization of o-alkynoylphenols can proceed through a
clic structures present in many natural products. The 5-exo-dig or 6-endo-dig pathway to afford, respectively,

O 1) 10 mol% CSA
OTBDPS
O O CH2Cl2-MeOH 5:1,
rt, 3.5 h O O
TBDPSO 2) 10 mol% TsOH
240 O 2 41
PhH, rt, 4 h
90%
6-exo-dig 6-exo-trig OTBDPS
O
OH OH O HO

TBDPSO O

Boc OTBS
Boc H
N O
OTBS TBAF N
O O
THF, rt O
O
H
242 85% 243
O

Scheme 91.
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2715

benzofuranones or benzopyranones. According to the experi-
mental results, theoretical calculations on a model ketone
shown in Scheme 92 have revealed that the transition states
for both processes are very close in energy. Nevertheless,
the 6-endo-dig product is thermodynamically favored and
can be obtained under equilibrating conditions in the absence
of proton donors.182
This approach has been successfully applied to the synthe-
sis of several members of a family of antibiotics containing an
anthrapyran core.183,184 As represented in Scheme 93, basic
treatment of ynone 244 under aprotic conditions promotes
a highly selective 6-endo-dig cyclization to the tetracyclic
compound 245 that is further elaborated into the antibiotic
AH-1763 IIa (246).184a Alternatively, this type of cyclization
can also be carried out under acidic conditions, but the mech-
anism is still unclear.185
Overshadowed by 6-exo-trig cyclizations, the related 6-
endo-trig ring-closure mode (see Eq. 9 in Scheme 82) had
traditionally attracted not much attention. However, the in-
creasing interest in the asymmetric synthesis of di- and tetra-
hydropyranones has modified this situation, since this type of
cyclization emerges as an appealing alternative to the hetero-
O OH
O ology. Aldol compounds arising from b-keto esters can partic-
5-exo-dig O 6-endo-dig
H B
O O
O
O O
Scheme 92.
DielseAlder reaction. Initial reports on 6-endo-trig cycliza-
tions of a,b-unsaturated ketones are due to Paterson and Os-
borne.186 In particular, the aldol adducts obtained through
stereoselective reactions from b-chloro vinyl ketones undergo
Lewis acid-mediated cyclizations that eventually give dihydro-
pyranones.187 Application of this methodology to methyl ke-
tone 247 and 3-benzoyloxypropanal supplies aldol 248,
which is easily converted into the desired dihydropyranone
249 (Scheme 94). Further recrystallization provides an enan-
tiomerically pure material that has been employed for the total
synthesis of swinholide A,188a scytophycin C,188b and, more
recently, laulimalide (93 in Scheme 38).188c
Aldol adducts lacking the b-chlorine atom can also take
part in these cyclizations to afford the tetrahydropyranones.
A comprehensive survey of the ability of Brønsted and Lewis
acids as well as palladium(II) complexes to enhance the elec-
trophilicity of enones 250 has identified Amberlyst-15, Al-
(ClO4)3$9H2O, and [Pd(MeCN)4](BF4)2 as suitable catalysts
to carry out the desired 6-endo-trig cyclization (250a,b to
251a,b) under mild conditions (Scheme 95).76b,189 As antici-
pated for a thermodynamically controlled reaction, Amber-
lyst-15 affords the all-equatorial products after extended
reaction times. Interestingly, the palladium-mediated cycliza-
tions are irreversible and give access to the other isomers in
excellent diastereomeric ratios.
O
Another aldol reaction is at the center of a different method-
O
ipate in an acid-mediated Knoevenagel condensation that
generates a highly reactive a,b-unsaturated keto ester, which
H undergoes a 6-endo-trig cyclization based on a reversible
oxa-Michael addition. Finally, decarboxylation of the resultant
O system provides the 2,6-cis-disubstituted tetrahydropyra-
nones.190,191 This methodology has been applied to the prepa-
ration of ()-centrolobine (252 in Scheme 96). The reported
sequence takes advantage of a Mukaiyama aldol reaction to

OBn
OBn OH

O O OH O O O OH O O

O Cs2CO3 O O
acetone, rt, 30 min

O 244 71% O 245 O AH-1763 IIa 246

Scheme 93.

(+)-Ipc2BCl BIpc2
O O O OH
i-Pr2NEt OHC(CH2)2OBz
Cl Et2O, 0 °C Cl –78 to –20 °C Cl OBz
247 1h 20 h 248
56% 80% ee
BzO O TMSOTf, i-Pr2NEt
laulimalide
CH2Cl2, –78 °C to rt, 1.5 h
93
249 O 61% (upgrade to >98% ee by recrystallization)

Scheme 94.
2716 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

OH O 8 mol% HO Ph
[Pd(MeCN)4](BF4)2 M O H O
Ph Ph
CH2Cl2, rt, 3 h H 78%
O
H dr 96:4
250a 251a
M
OH O 8 mol% OH
[Pd(MeCN)4](BF4)2 O
Ph H Ph
CH2Cl2, rt, 3 h 75%
HO Ph O
dr 97:3
250b H 251b

Scheme 95.

OMe OTMS O
1) 1 equiv Yb(OTf)3 MeO2C
TMSO
CH2Cl2, –78 °C, 3 h
+
2) 2 equiv TFA HO
OHC
4-MeOPhCHO
MeO OH 60%
rt, 5 h
OTBS
O
MeO2C

O
O
MeO OH
MeO OH
(±)-centrolobine 252 253

Scheme 96.

OH O O O
1) 10 mol% 254a N
S
Ot-Bu PhMe, –25 °C, 24–38 h
Ar
N N
2) 50 mol% TsOH H H
Ar 255 O Ar H
80 °C, 10–50 h BnO
256a 254a
65–94% 88–94% ee N
N
OH O O 1) 20 mol% 254b O
5 mol% piperidinium acetate S OMe
Ot-Bu PhMe, 4 Å MS, rt, 2 d Ar H
N N
2) 30 mol% TsOH H H N 254b
O 257 O Ph
PhMe, 80 °C, 9 h
H Ph 77% 80% ee flindersiachromanone 256b

Scheme 97.

install the first appendage of the tetrahydropyran. Then, addi-
tion of anisaldehyde and TFA to the reaction mixture affords
the tetrahydropyranone 253 and further functional-group
manipulations deliver ()-centrolobine.192
Closely connected to this methodology, it has recently
been discovered that the chiral thiourea-based catalysts 254,
shown in Scheme 97, activate a-alkylidene-b-keto esters
255 and trigger intramolecular conjugate additions of phenol
to the corresponding flavanones 256. Remarkably, a one-pot
reaction involving the simple b-keto ester 257, hydrocinna-
maldehyde, piperidinium acetate, and chiral thiourea 254b
in the presence of molecular sieves in toluene at room tem-
perature followed by decarboxylation affords the natural
product, flindersiachromanone 256b, in 80% ee and 77%
overall yield.193,194
Although 2,6-cis-disubstituted tetrahydropyranones are usu-
ally the most stable diastereomers, other elements in the
structure can alter this situation. For instance, thermodynami-
cally controlled transannular conjugate addition on
a,b-unsaturated ketone 258 affords 2,6-trans-disubstituted tet-
rahydropyranone 259, used as an advanced intermediate in
a formal total synthesis of ()-apicularen A (260 in Scheme
98). Interestingly, exposure of epimer 258-epi to identical con-
ditions yields the same tetrahydropyranone 259.195
In contrast to the above examples, some 6-endo-trig cycli-
zations match the model reaction represented by Eq. 10 in
Scheme 82.196 For instance, chiral dienyl sulfoxides 261
have been identified as suitable precursors of dihydropyrans.
This process is based on a highly stereoselective conjugated
addition (the examples shown in Scheme 99 afford a single
diastereomer) followed by subsequent transformations of the
resultant allylic sulfoxides 262.197 Interestingly, this methodo-
logy accepts additional stereocenters and other substituents on
the double bond of the dienyl sulfoxide.
 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2717

OMe OMe OMe

O H O H O H
O O O
Amberlyst-15 Amberlyst-15
HO O HO
CDCl3, reflux, 18 h CDCl3, reflux, 23 h
90% 78%
258 259 258-epi
selectivity > 10:1 selectivity > 10:1
O O O
OH
O
O H
O
N
O H

(–)- apicularen A
OH 260

Scheme 98.

O O
H
S S HO
p-Tol LDA p-Tol 10 equiv P(OMe)3
THF, –78 °C to rt MeOH, 50 °C
OH R O R O Ph
3–4 h H 4d
261a R: Ph 262a 84% 263a
261b R: Bu 262b 94% 50%

Scheme 99.

10. Conclusions
As this report proves, the apparently simple construction of
pyrans through CeO bond formation is surprising, with an ex-
tremely varied array of methodologies ranging from the vener-
able SN2- or Michael-based cyclizations to the more recent
transition metal-catalyzed reactions. The scope and synthetic
efficiency of such ring-forming methodologies have already
been established along with the total synthesis of a large num-
ber of structurally complex natural products, but, in spite of
these outstanding achievements, the increasing demand for
more selective processes to gain access in a straightforward
manner to six-membered oxygenated heterocycles is fueling
the development of new concepts and methodologies. Remark-
able examples are the recent developments in epoxide-medi-
ated cyclizations that allow selective formation of the pyrans
over the more favored furans or the spectacular simultaneous
construction of up to three fused tetrahydropyran units in a
cascade sequence. Moreover, emerging methodologies such
as platinum- or gold-catalyzed cyclizations of hydroxy al-
kenes, allenes, and alkynes will undoubtedly play a major
role in further developments in this field.
Acknowledgements
We are grateful for the financial support from the Spanish
Ministerio de Ciencia y Tecnologı́a (Grant CTQ2006-13249/
BQU), the Generalitat de Catalunya (2005SGR00584), and
the Universitat de Barcelona (ACES-UB2006).
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 I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 2723

Biographical sketch

Igor Larrosa graduated from the University of Barcelona in 1999. In 2004, he
completed his Ph.D. under the supervision of Dr. Fèlix Urpı́ and Dr. Pedro
Romea in the area of asymmetric C-glycosidation reactions and natural
product synthesis. Subsequently, he became a postdoctoral research associate
in Professor Anthony G. M. Barrett’s group at Imperial College London, where
he carried out research on methodology development and its applications to
natural product synthesis. In 2007, he was appointed as a lecturer at Queen
Mary, University of London.
Pedro Romea completed his B.Sc. in Chemistry in 1984 at the University of
Barcelona. That year, he joined the group of Professor Jaume Vilarrasa, at the
University of Barcelona and received his Master’s Degree in 1985, and he fol-
lowed Ph.D. studies in the same group from 1987 to 1991. Then, he joined the
group of Professor Ian Paterson at the University of Cambridge (UK), where
he participated in the total synthesis of oleandolide. Back to the University
of Barcelona, he became Associate Professor in 1993. His research interests
have focused on the development of new synthetic methodologies and their
application to the stereoselective synthesis of naturally occurring molecular
structures.

Fèlix Urpı́ received his B.Sc. in Chemistry in 1980 at the University of Bar-
celona. In 1981, he joined the group of Professor Jaume Vilarrasa, at the
University of Barcelona and received his Master’s Degree in 1981 and
Ph.D. in 1988, where he was an Assistant Professor. He then worked as an
NATO postdoctoral research associate in titanium enolate chemistry with
Professor David A. Evans, at Harvard University at Boston. He moved back
to the University of Barcelona and became Associate Professor in 1991. His
research interests have focused on the development of new synthetic methodo-
logies and their application to the stereoselective synthesis of naturally occur-
ring molecular structures.