Article

pubs.acs.org/joc

The Garuganin and Garugamblin Diarylether Heptanoids: Total

Synthesis and Determination of Chiral Properties Using Dynamic
NMR
Zhi-Qiang Zhu, M. Quamar Salih, Edward Fynn, Alex D. Bain,*, and Christopher M. Beaudry*,

Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, Oregon 97331, United States
Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4M1, Canada

S Supporting Information
*

Figure 1. Diarylether heptanoid natural products that lack stereogenic centers.

RESULTS AND DISCUSSION

Synthesis of the Garuganin and Garugamblin Diarylether Heptanoids. We decided to prepare 714 to
investigate their chiral properties. We envisioned the vinylogous
ABSTRACT: The synthesis of the garuganin and garugamblin diarylether heptanoids using an intramolecular Ullmann coupling
is reported. Alkene stereoisomers, vinylogous ester regioisomers, and -diketone congeners are also synthesized. The chiral
ester DAEHs, exemplied by general structures 17 or 18,
properties and free energies of activation for racemization of the garuganin and garugamblin diarylether heptanoids and
arising from the corresponding vinylogous acid 19 (Scheme 1).
congeners are determined using dynamic NMR methods. A combination of techniques including coalescence measurements, line
shape analysis, and selective inversion experiments are used to measure racemization barriers. None of the garuganin or
garugamblin diarylether heptanoids are chiral, despite their reported specic rotation values.

Scheme 1. Retrosynthetic Analysis of the Garuganin and

Garugamblin DAEHs

The Journal of Organic Chemistry

Article

INTRODUCTION

Chirality is of paramount importance to medicine, biology, and

chemistry.1 When molecules contain sp3 hybridized stereogenic
centers, chirality can be readily identied. In molecules without
stereogenic centers, the presence of chirality is not as easily
recognized. Experimental determination of the presence or
absence of chirality is not trivial, particularly when attempting
to distinguish between racemic and achiral materials. It is our
contention that the chiral properties of many cyclophane
natural products are not well understood. Herein, we describe
the use of dynamic NMR methods to experimentally determine
the chiral properties of the garuganin and garugamblin
diarylether heptanoid (DAEH) natural products.
Diarylether heptanoids (DAEHs) represent a class of natural
products isolated from terrestrial woody plants.2 DAEHs share
a highly conserved oxa[1.7]metaparacyclophane architecture.
These natural products display a range of biological activities3
and have attracted interest from synthetic chemists.4 Figure 1
shows the 16 natural DAEHs that do not possess a stereocenter
and their specic rotation values. Interestingly, despite their
highly conserved structures, some (though not all) DAEHs
were isolated as optically active compounds.5 We recently
reported the synthesis, free energies of activation for

racemization, and absolute stereochemistry of the DAEHs

that display a heptanone ansa bridge, specically 16.6
Myricatomentogenin, jugcathanin, galeon, and pterocarine are
chiral molecules that undergo racemization at temperatures in
excess of 200 C with half-lives of several hours. However,
acerogenin C and acerogenin L undergo rapid racemization at
temperatures above 60 C.6
The garuganin and garugamblin DAEHs (714) share a
highly conserved molecular architecture. These compounds
dier only in the substitution pattern at C2C4 and the
methylation pattern of the 1,3-diketone.7 As shown in Figure 1,
ve of these compounds were reported to be optically active,
suggesting that they are chiral nonracemic compounds. Three
of these compounds were isolated without mention of optical
activity or chirality, and it is unclear if they are achiral, racemic,
or chiral nonracemic molecules. Nogradi and co-workers
synthesized garuganin III, garugamblin I, and garugamblin II
Although
using a Wittig macrocyclization approach.4ac

d natural products that lack stereogenic centers.

USSION
ganin and Garugamblin Diarye decided to prepare 714 to
erties. We envisioned the vinylogous
by general structures 17 or 18,
ing vinylogous acid 19 (Scheme 1).
2013 American Chemical Society
Figure 3. 1H NMR spectra of 32, 7, 41, and
14 (CDCl3, 400 MHz).

2881

vinylogo
they w
bilomer
Simp
Ullmann
phenolic
ring wa
alternati
diketon
be prep
thus beg
The
cinnama
the lithi
aldol pr
gave
coupling
Comp
sequenc
the brom
With th
key ma
stoichio
yields fo
for mate
predicte
The
desmeth

vinylogous acids from hot methanolic extraction, and that

they were the thermodynamically favored isomer or stabilomer (vide infra).
Simplication of the macrocycle by way of an intramolecular
this strategy would require regio- and stereoselective
8
Ullmann couplingvinylogous
leads
toformation,
bromophenols
the
ester
it would allow a 20.
uniedPositioning
strategy for
the formation
all thethe
garuganins
garugamblins, rich
and it phenyl
phenolic functional
groupof on
moreandelectron
could provide access to isomeric DAEH structures for
ring was anticipated
to give
a smoother
cyclization
investigation.
Moreover,
we considered the
possibility thatthan an
the vinylogous esters had formed upon isolation of the
alternative approach
with an electron-rich bromoarene. The -

Received: January 23, 2013

Published: March 5, 2013

dx.doi.org/10.1021/jo400157d | J. Org. Chem. 2013, 78, 28812896

CH203 Lecture 34
November 24, 2014

Alkene reac:ons

A-B

H3C

CH3

CH3

CH3

CH3

CH3

syn addition product

anti addition product

Addi:on of HX

Addi:on of HBr to an alkene happens in two steps. First the alkene

acts as a nucleophile and forms a bond with the electrophilic
hydrogen of HBr. Then the bromide anion, which is now the
nucleophile, bonds to the carboca:on, which is now the electrophile.

Addi:on of HOH acid-catalyzed hydra:on

Step 1: Make a new bond between a nucleophile (pi bond) and an electrophile (H+).
:

C H3 C H = C H 2 + H O H

slow, rate
determining

C H3 C H C H 3

A 2o carbocation
intermediate

:O H
H

Step 2: Make a new bond between a nucleophile (H2O) and an electrophile (a
carboca:on intermediate) to give an oxonium ion (O+).
C H3 C H C H 3 +

:O - H
:

fast

C H3 C H C H 3
:

O+

H
H
H

An oxonium ion

Step 3: Take a proton away from the oxonium (acid-base reac:on).

C H3 C H C H 3 + H O H
:O H
H

O:

O+

fast

C H3 C H C H 3

Carboca:on rearrangements 1,2 shiUs

H3C

H3C
H3C

H3
C

CH3

2o carbocation

H3C

H3C

CH3

H3C

CH3

H3C

H
CH3

3o carbocation

The driving force is rearrangement of a less stable carboca:on to a

more stable one. Ini:al hyperconjuga:on leads to greater and greater
lling of the empty p orbital of the carboca:on by the electron
density of the C-C sigma bond un:l the system rearranges into the
more stable congura:on of the ter:ary carboca:on.

Carboca:on rearrangements 1,2 shiUs

H3C
H3C

CH3

2o carbocation

H3C

H3C

CH3

H3C

H3C

H
CH3

3o carbocation

The mechanism is the same as that of the 1,2-alkyl shiU.

Alkenes addi:on of Br2 and Cl2

The rst step is the pi electrons ac:ng as the nucleophile to form new bonds
with the bromine electrophile with displacement of bromide. The
intermediate ca:onic three-membered ring containing bromine is called a
bromonium ion.

Alkenes addi:on of Br2 and Cl2

In the second step, a bromide atom acts as a nucleophile and forms a new
bond to one of the carbons of the bromonium ring, breaking it apart and to
leave the 1,2 dibromide. Addi:on of the bromide atom is constrained to
happen from the opposite, or an:, side of the molecule from the bromonium
ring and coplanar with the C-Br bond in the bromonium ring.

Alkene reagent table

Alkenes halohydrins
Treatment of an alkene with Br2 or Cl2 in water forms a halohydrin - a
compound containing OH and X on adjacent carbons. This reac:on is both
regioselec-ve (OH adds to the more subs:tuted carbon) and an--
stereoselec-ve (OH and X add an: coplanar).

Alkenes hydrobora:on/oxida:on

Hydrobora:on is the two-step reac:on of an alkene with a borane followed

by oxida:on. H and OH are added across the double bond to give a non-
Markovnikov product. This reac:on is regioselec-ve (boron bonds to the less
hindered carbon) and syn stereoselec-ve (H and B add to the same face of
the carbon-carbon double bond.

Alkenes hydrobora:on/oxida:on

Borane, BH3, is in equilibrium with the dimer diborane, B2H6, a toxic gas which
reacts violently with atmospheric oxygen. It is stabilized for use in the lab by
complexing it with tetrahydrofuran to give a Lewis acid-base adduct.

Alkenes hydrobora:on/oxida:on

Borane, BH3, adds to an alkene in a concerted regioselec:ve and syn-

stereoselec:ve fashion. The coordina:on of the alkene (Lewis base) and the boron
atom (Lewis acid) is guided by the larger bulk of the boron group rela:ve to the
hydrogen. Boron adds to the less hindered carbon. The regiochemistry is also
aided by the slight polarity of the B-H bond. The small nega:ve character of the
hydrogen atom seeks to align with the alkene carbon most able to carry a
developing posi:ve character as the other carbon forms a sigma bond to boron.
Thus hydrogen ends up on the more subs:tuted carbon.

Alkenes hydrobora:on/oxida:on

Alkenes hydrobora:on/oxida:on

H3C

H1

H3C

H2

BH3

H
H3C
H3C

BH2
H1
H2

H2O2,
OH-

H
H3C
H3C

OH
H1
H2

The migra:on of the alkyl group from boron to oxygen in the oxida:on step
occurs with reten:on of stereochemistry.

Alkenes oxida:ons and reduc:ons

Oxida-on is the loss of electrons.
Alterna:vely, the loss of H, the gain of O, or both.
Reduc-on is the gain of electrons.
Alterna:vely, the gain of H, the loss of O, or both.

Alkenes oxida:on with OsO4

OsO4 oxidizes an alkene to a glycol - a compound with OH groups on adjacent

carbons. Oxida:on is syn stereoselec:ve.

Alkenes oxida:on with OsO4

O

O
Os

H2C

O
O

CH2

O
Os

H2C

CH2

O
NaHCO3

O
Os

HO
H2C

OH
CH2

OsO4 adds to an alkene in a 1,3-dipolar cycloaddi-on. Six electrons move in

concert in the transi:on state to form the new bonding pa\ern.

Alkenes oxida:on with O3

Treatment of an alkene with ozone followed by a weak reducing agent such as

dimethylsulde, (CH3)2S, cleaves the alkene double bond and forms two carbonyl groups
in its place.

Alkenes oxida:on with O3

The ini:al intermediate is the unstable molozonide, which rapidly rearranges

to an ozonide. The ozonide is reduced to the carbonyl products by the
dimethylsulde.

Alkenes oxida:on with O3

Ozone also adds to an alkene in a 1,3-dipolar cycloaddi-on. The unstable

molozonide undergoes a retro 1,3-dipolar cycloaddi:on to give two
molecules which move around inside the solvent shell un:l they are oriented
for yet another 1,3-dipolar cycloaddi:on to give the ozonide.

Alkenes oxida:on with O3

H

H3C

1. O3
2. Me2S or Zno/AcOH

H3C
O

O
CH3

CH3
CH3

CH3

Reduc:ve workup.

H3C

1. O3
2. H2O2

H3C

OH
O

O
CH3

CH3
CH3

CH3

Oxida:ve workup.

Alkenes oxida:on with O3

Alkenes oxida:on with peracids

H3C

CH3

H3C

+
H

OH
H3C

CH3

H3C

OH

Peracids react with alkenes to give epoxides, three membered rings containing
one oxygen. The reac:on is concerted, and the stereochemistry of the reactant
alkene is preserved in the product.

Alkenes oxida:on with peracids

Alkenes cataly:c reduc:on

Most alkenes react with H2 in the

presence of a transi:on metal
catalyst to give alkanes. Commonly
used transi:on metal catalysts are
Pt, Pd, Ru, and Ni. The process is
called cataly-c reduc-on or
cataly-c hydrogena-on. Addi:on of
the hydrogens occurs with syn
stereoselec:vity.

Alkenes cataly:c reduc:on

The mechanism of cataly:c hydrogena:on:

(a) H2 and alkene are absorbed on metal surface.
(b) An H is transferred to the alkene, making a new C-H bond.
(c) The second C-H bond is formed (syn addi:on) and the
alkane desorbed.

Alkenes cataly:c reduc:on

Even though addi:on occurs with syn stereoselec:vity, some

product may appear to result from trans addi:on.

Alkenes cataly:c reduc:on

During the reduc:on, the alkene may rearrange on the catalyst surface to an
isomeric alkene. Reduc:on of this alkene can give products which are not
those which would come from pure syn addi:on to the star:ng material.

Alkenes cataly:c reduc:on

Isomeriza:on of alkenes on a cataly:c metal surface can be quite extensive.

The reduc:on of alkene 1 with tri:um gas over a palladium catalyst gave
alkane 2 with measurable 3H atoms on every carbon of the none carbon amide
group.

Alkenes reduc:on with homogenous catalysts

Alkenes can be reduced with hydrogen gas and soluble metal complexes,
called homogenous catalysts. The metal and ligands bound to the metal can
be chosen to give ne control over the reduc:on. Radioac:ve prostaglandin E1
was obtained by reduc:on of the alkene over tri:um gas and Wilkinsons
catalyst, chlorotris(triphenylphosphine)rhodium(I). These condi:ons
selec:vely reduced a cis alkene with no products of double bond migra:on -
and leU a trans alkene untouched.

Alkenes reduc:on with chiral homogenous catalysts

Ph

Ph

HP
RuCl3
HP
Ph

Ph

Many homogenous catalysts have been prepared based on chiral ligands. (R)-
BINAP-RuCl3 catalyzes the asymmetric hydrogena:on of alkenes if the double
bond is near a func:onal group which can complex to the Ru and guide the
catalyst to the proper face of the alkene.

Alkenes reduc:on with chiral homogenous catalysts

Alkenes cataly:c reduc:on

Heats of hydrogena:on demonstrate and measure the rela:ve stability of

alkenes. Here, the dierence shows that trans-2-butene is more stable than
cis-3-butene by 4.2 kJ/mol.