Asymmetric Aldol/Vinylogous Aldol Reaction Catalyzed by Chiral Phosphine Oxide:

Stereoselective Synthesis of 4-Pyranones

Nathan Ray Alim,1 Shunsuke Kotani, 1,2 Shiki Miyazaki, 1 Yasushi Shimoda,1 Masaharu Sugiura,1 Makoto Nakajima 1
1Graduate School of Pharmaceutical Sciences, Kumamoto University

2Priority Organization for Innovation and Excellence, Kumamoto University

E-mail: nakajima@gpo.kumamoto-u.ac.jp
1. Abstract 3. Background: 4-Pyranone Construction
Enantioselective Aldol/Vinylogous Aldol Reaction: 4-Pyranone Synthesis
Enantioselective Branched Double Aldol Reaction
(S)-BINAPO
(10 mol %) O (S)-BINAPO (10 mol %)
O
SiCl4 (3.0 eq) Ph SiCl4 (4.0 eq) O OH
OMe O O iPr NEt (5.0 eq)
OH P
2 Ph O O iPr NEt (5.0 eq)
+ 2 up to dr = 97/3
Ph + Ar ∗ R
Ar H CH 2Cl 2 (0.5 M) Ar O Ar Ar CH 2Cl 2/EtCN, –60 °C, 24 h ∗ up to 97% ee
P R H
–60 ˚C, 24 h Ph HO R
(4.0 eq) O
two stereocenters
up to 70% yield Shimoda, Y.; Kotani, S.; Sugiura, M.; Nakajima, M. Chem. Eur. J. 2011, 17, 7992.
3 new bonds and 2 stereocenters up to 98% ee (S)-BINAPO
are constructed in one step. 2,3-dihydro-4-pyranones
4-Previous Work: Branched type Double Aldol Reaction O
Ph
P
2. 4-Pyranones (S)-BINAPO (10 mol %)
SiCl4 (1.5 eq.) O OH
Ph
O H Ph
4-Pyranone: Structure, Biological Activities, Previous Synthesis Scheme + PhCHO Cy 2NMe (10 eq.) P
Ph Ph
MeO CH 2Cl 2 / EtCN (1 / 1) O
O
Biologically active 4-pyranone derivatives
4-Pyranone

(2.5 eq.)
–60 °C, 24 h O Ph (S)-BINAPO
O F 3C Cy = Cyclohexyl
NH 1st aldol
O Stereoselective
reaction
O O Enolization Cl3 cyclization
HN NH 2 S Cl3
O at α-position Si
Pyran ring Ketone 4-Pyranone O Si Cl3Si O OSiCl 3
HN HN Cy2NMe PhCHO
OH O O O O
O HO MeO Ph
Tipranavir MeO Ph 2nd aldol
O CO2H O MeO Ph
(anti-HIV) reaction
OH Cl3SiO Ph
MeO OMe Zanamivir
O ∗
(antiviral) O OH THIS WORK: Aldol/Vinylogous Aldol Reaction
HO Curcuminoid OH O
(S)-BINAPO (10 mol %)
(anticancer)
OMe O SiCl4 (3.0 eq.) OH
iPr NEt (5.0 eq.)
Previous synthetic strategy + PhCHO 2
CH 2Cl 2, –60 °C, 24 h Ph O Ph
Yamamoto (1988)
SiAr3 Cyclization
O 1st aldol Cl3
OSiMe 3 1) catalyst (10 mol %) Cl3
O O reaction Si Cl3
Me toluene, 0 °C, 2 h Me Me Cl3Si Si
+ iPr SiCl3 Si
MeO Al Me OMe O O 2NEt OMe O O PhCHO
Ph H 2) CF3CO2H O OMe O O
Me O Ph O Ph Ph
93% yield Ph Ph
J. Am. Chem. Soc. 1988, 110, 310. 97% ee SiAr3
Enolization Vinylogous-Aldol
catalyst
at γ-position Reaction

4. Aldol/Vinylogous Aldol Reaction

Optimization of Reaction Conditions Substrate Scope: Aldehyde
O
Ph
(S)-BINAPO (10 mol %) O P (S)-BINAPO (10 mol %) O
Ph
SiCl4 (3 eq.) SiCl4 (3.0 eq.)
OMe O iPr NEt (5 eq.)
OH Ph OMe O iPr NEt (5.0 eq.)
OH
+ 2 P + 2
PhCHO Ph RCHO
CH 2Cl 2 Ph O Ph O CH 2Cl 2 (0.05 M), –60 °C, 24 h R O R
(X eq.) (S)-BINAPO (4.0 eq.)

O O O
Entry X Amine Conc. [M] Temp. [°C] Time [h] Yield [%] Ee [%]
OH OH OH
1 2.5 iPr
2NEt 0.1 –40 3 36 82 O O O

2 2.5 iPr
2NEt 0.1 –60 10 55 85 Br Br
51% yield 70% yield 28% yield
98% ee 96% ee 85% ee
3 2.5 iPr
2NEt 0.1 –78 48 24 87
O O
4 2.5 iPr
2NEt 0.05 –60 13 43 93 OH
OH

5 4 iPr
2NEt 0.05 –60 24 51 98 O O

6 4 Cy 2NMe 0.05 –60 24 60 82 H 3CO OCH3

48% yield 35% yield
96% ee 93% ee
7 4 Cy 2NEt 0.05 –60 24 56 86

8 4 nBu
3N 0.05 –60 24 15 42 Substrate Scope: Enone
9 4 iBu 0.05 –60 24 0 - (S)-BINAPO (10 mol %) O
3N
SiCl4 (3.0 eq.)
OR O iPr NEt (5.0 eq.) OH
+ PhCHO 2

CH 2Cl 2 (0.05 M), –60 °C, 24 h Ph O Ph

Screening of catalysts (4.0 eq.)
chiral phosphine oxide (10 mol %)
SiCl4 (3.0 eq.) O
iPr NEt (5.0 eq.)
OMe O 2 Entry Leaving Group [OR] Yield [%] Ee [%]
+ PhCHO OH
CH 2Cl 2 (0.05 M), –60 °C, 24 h O
Ph
(4.0 eq.) Ph O Ph 1 MeO 51 98 P
Ph
2 47 93 Ph
CN tBu EtO P
Ph
O O
O O O 3 TMSO trace -
Ph Ph Ph (S)-BINAPO
P P P
Ph Ph O Ph 4 trace -
AcO
Ph Ph O Ph
P P P
Ph Ph Ph
O O
O O Possibe Reaction Mechanism
*
CN tBu
P P
51% yield 26% yield 26% yield O O Cl3
Br TMS (S)-BINAPO
98% ee 68% ee 89% ee Cl2Si SiCl4 Cl3Si Si
SiCl4
i
O O OMe O iPr NEt
2
OMe O O OMe O OSiCl3 Pr 2NEt MeO O O PhCHO
Ph Ph
P P
Ph Ph PhCHO Ph Ph Ph
Ph Ph Enolization
1st Aldol Reaction
P P at g-position
Ph Ph
O O
Cl3 Cl3 OSiCl3 O
Br TMS O Si Si OMe Work-up
Cl3SiO O OSiCl3
Ph MeO O O Cl3SiO OH
53% yield 43% yield
H Ph Ph
90% ee 89% ee Ph Ph O Ph Ph O Ph
MeO
2nd Aldol Reaction Cyclization SiCl3
(Vinylogous aldol)