Stereoselective Synthesis of 4-Pyranones Using Aldol/Vinylogous Aldol Reaction Sequence Catalyzed by Chiral Phosphine Oxide

Nathan Ray Alim,1 Shunsuke Kotani,1,2 Shiki Miyazaki,1 Yasushi Shimoda,1 Masaharu Sugiura,1 Makoto Nakajima1
1Graduate School of Pharmaceutical Sciences, Kumamoto University
2Priority Organization for Innovation and Excellence, Kumamoto University

1. Abstract and Introduction 2. Background:Enantioselective

Introduction: Conventional Synthetic Schemes
Double Aldol Reaction
Enantioselective Aldol/Vinylogous Aldol Reaction: 4-Pyranone Synthesis Previous synthetic strategies
SiAr3
(S)-BINAPO Hetero Diels-Alder Reaction O
(10 mol %) O O Yamamoto (1988)
SiCl4 (3.0 eq.) Ph Al Me
OMe O O iPr NEt (5.0 eq.)
OH P O O
2 Ph OSiMe 3 1) catalyst (10 mol %)
+ O
Me toluene, 0 °C, 2 h Me Me
Ar H CH 2Cl 2 (0.5 M) Ar O Ar Ph + SiAr3
P MeO
–60 ˚C, 24 h Ph Ph H 2) CF3CO2H catalyst
(4.0 eq) O Me O Ph
up to 70% yield J. Am. Chem. Soc. 1988, 110, 310.
93% yield Ar = 3,5-xylyl
3 new bonds and 2 stereocenters up to 98% ee (S)-BINAPO 96% ee
are constructed in one step. 2,3-dihydro-4-pyranones
Tandem Vinylogous Mukaiyama-Aldol Reaction-Pyranone Cyclization
Denmark (2007) catalyst (5 mol %)
4-Pyranone: Structure and Biological Activities O SiCl4 (1.5 eq.)
OH O O
4-Pyranone
R 3SiO OSiR 3 +
CH3 Me Ph H iPr
2NEt
(20 mol %) Ph Et
F 3C Et CH2Cl2, 2 h
N Me
O O SiR3 = TMS, TES, TBS, TIPS
TFA (0.1 mol %)
S CH 2Cl2, 0 °C
O Me Me O O
MeO OMe HN HO O
O ∗ N O O N Me Me
+
Cl P P
HO Curcuminoid OH O N N
N N Et O Ph Et O Ph
(anticancer) OH O Me Me
Me Me
66-93% yield, 39-69% ee, 90-92% de
Tipranavir Flavopyridol
O OH catalyst J. Org. Chem. 2007, 72, 5668.
(anti-HIV) (anti-HIV)

3. Background: Double Aldol Reactions

Enantioselective Branched-type Double Aldol Reaction Enantioselective Linear-type Double Aldol Reaction
(S)-BINAPO (10 mol %) (S)-BINAPO (10 mol %)
SiCl4 (4.0 eq.) SiCl4 (4.0 eq) OH O OH
O OH O
O O iPr NEt (5.0 eq.)
2
up to dr = 97/3 O Cy 2NMe (5.0 eq) ∗ up to dr = 92/8
+ Ar ∗ R up to 97% ee + R2 ∗ ∗ R2 up to 98% ee
Ar R H ∗ R2 H
CH 2Cl 2/EtCN, –60 °C, 24 h R1 CH 2Cl 2/EtCN, –40 °C, 24 h R1
HO R two stereocenters three stereocenters
Cy = Cyclohexyl
Chem. Eur. J. 2011, 17, 7992. Angew. Chem. Int. Ed. 2013, 52, 3461.

O
Previous Work: Branched-type Double Aldol Reaction Ph THIS WORK: Linear-type Aldol/Vinylogous Aldol Reaction
P
(S)-BINAPO (10 mol %) Ph O
O OH (S)-BINAPO (10 mol %)
SiCl4 (1.5 eq.) H Ph
O P SiCl4 (3.0 eq.) OH
+ PhCHO Cy 2NMe (10 eq.) Ph Ph OMe O
+ PhCHO iPr NEt (5.0 eq.)
MeO O 2
CH 2Cl 2 / EtCN (1 / 1) Ph O Ph
(2.5 eq.)
–60 °C, 24 h
O Ph (S)-BINAPO CH 2Cl 2, –60 °C, 24 h
Cy = Cyclohexyl 69% yield, 91% ee (major) 1st aldol
1st aldol Cyclization
Stereoselective reaction
reaction cyclization
Cl3 Cl3 Cl3
Cl3 Enolization Cl3
Si Cl3Si Si SiCl3 Si
Si at α-position Si O OSiCl 3
Cl3Si iPr O
Cy2NMe PhCHO OMe O O 2NEt OMe O O PhCHO OMe O O
O O O O
MeO Ph
Ph Ph Ph Ph
MeO Ph MeO Ph 2nd aldol
reaction Cl3SiO Ph Enolization Vinylogous-Aldol
at γ-position Reaction

4. Enantioselective Aldol/Vinylogous Aldol Reaction

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

Entry X Amine Conc. [M] Temp. [°C] Time [h] Yield [%] Ee [%] Entry X Yield [%] Ee [%]

1 2.5 iPr 0.1 –40 3 36 82 1 MeO 51 98

2NEt

2 2.5 iPr 0.1 –60 10 55 85 2 EtO 47 93

2NEt

3 2.5 iPr 0.1 –78 48 24 87 3 TMSO trace -

2NEt

4 2.5 iPr 0.05 –60 13 43 93 4 AcO trace -

2NEt

5 4 iPr 0.05 –60 24 51 98 X-ray structure of the

2NEt
2,3-dihydro-4-pyranone adduct
6 4 Cy 2NMe 0.05 –60 24 60 82

7 4 Cy 2NEt 0.05 –60 24 56 86 Substrate Scope: Aldehyde

8 4 nBu 0.05 –60 24 15 42 (S)-BINAPO (10 mol %)
3N O
SiCl4 (3.0 eq.)
OMe O iPr NEt (5.0 eq.)
2 OH
+ RCHO
Screening of catalysts
CH 2Cl 2 (0.05 M), –60 °C, 24 h R O R
chiral phosphine oxide (10 mol %) O
(4.0 eq.)
SiCl4 (3.0 eq.)
OMe O iPr NEt (5.0 eq.) OH
+ PhCHO 2
O O O
(4.0 eq.) CH 2Cl 2 (0.05 M), –60 °C, 24 h Ph O Ph
OH OH OH
CN TMS Br tBu
O O O
O O O O O O
Ph Ph Ph Ph Ph 51% yield Br 70% yield Br H 3CO 35% yield OCH3
P P P P P
Ph Ph Ph Ph O Ph 98% ee 96% ee 93% ee
O O
Ph Ph Ph Ph O Ph
P P P P P
Ph Ph Ph Ph Ph OH OH
O O O O O
O
O O
CN TMS Br tBu
51% yield 26% yield 43% yield 53% yield 26% yield 48% yield 28% yield
98% ee 32% ee 93% ee 93% ee 79% ee 96% ee 85% ee

Possible Reaction *
* *
Mechanism P P
P P O O P P
O O Cl3 O O
(S)-BINAPO Cl3Si
SiCl4 Si Cl OSiCl3 O
SiCl4 SiCl3 SiCl3 3
i MeO O O O Si OMe OSiCl3 Work-up
OMe O iPr NEt
2 OMe O O OMe O OSiCl3 Pr 2NEt PhCHO
Ph MeO O O
Cl3SiO O
Cl3SiO OH
PhCHO Ph H Ph Ph
Ph Ph Ph Ph O Ph Ph O Ph
Enolization MeO
1st Aldol Reaction at γ-position Vinylogous aldol reaction Cyclization