Applications of Mukaiyama aldol reaction

Introduction about Mukaiyama aldol reaction and its application

1. Applications of Mukaiyama
AldolReaction
Presented By :
Gurudutt Dubey
M.Tech. (Pharm.) I Semester
Department of Pharmaceutical Technology (Process Chemistry)
National Institute of Pharmaceutical Education and Research, Mohali, Punjab (India)
1

2. INTRODUCTION
Mukaiyama AldolReactions :
O-Hydro-C-(α-acylalkyl)-addition
2
TrimethylsilylenoletheractsasanenolateinLewisacidcatalysedreaction.
Itisconsideredashydrogenequivalentwhichattacksonaldolhydroxylgroup.
March J. et al.Advance Organic Chemistry 6
th
edition, 2007, 1351R
1
R
2
Me
3SiO
O
R
3
R
4
LewisAcid
CH
2Cl
2
O
R
2
R
1

R
3
R
4
R
1
O
R
2
R
4
OSiMe
3R
3
H
2O
OH

3. 3
Applications in Synthesis of Various Analogs

4. 4
Org. Lett.2012,14, 1168-1171
Direct Use of Esters in the Mukaiyama AldolReaction
Esters can be efficiently used in place of aldehyde R OMe
O
OMe
OSiMe
3
R OMe
OOH
5mol%InI
3
HSiMe
2
Ph
DCM,r.t.,2-12h
R:Alkyl,Benzyl

5. 5
Synthesis of Functionalized Diazoacetoacetates from Diazoacetates
via Mukaiyama ReactionMe
3SiO
C
2H
5O
Ar
H
Ar
N
2
O
O
OO
N
2
C
2H
5O
OH
3mol%Sc(OTf)
3
60-80%
DCM,rt
Diazo Decomposition of Mukaiyama-aldolAdduct
Org. Lett2008, 10(8), 1605-1608Ar
OO
N
2
C
2H
5O
OTBS
1mol%Rh2(OAc)3
DCM,reflux
OO
H OTBSR OTBS
R COOC
2H
5H COOC
2H
5

6. 6
Enantioselectivecatalytic Mukaiyama reaction in aqueous media
Org. Biomol. Chem.2004, 2, 3401-3407Ph
Me
OTMS
Ph
COPh
OH
Me
PhCHO
Ga(OTf)
3+L
*
(20mol%)
TritonX-100(3mol%)
H
2O,0
0
C,72h
41%yield,84%ee N N
But
OH
Ph
HO
Ph
Ph
OH
Ph
L* =

7. 7
VINYLOGOUS MUKAIYAMA ALDOL REACTION
Org. Lett. 2007, 9(26), 5667-5639R
O
OMe
OTBS
N
H
O
N
B
O
Ph
Ts
OMe
O
R
OH
iPrOH
R=Alkyl,Aryl 99%ee
•For one step synthesis of δ-Hydroxy-α,β-unsaturated carbonyl compounds.
•Catalyst: Tryptophane-based B-phenyloxazaborolidinone
•Isopropyl alcholis used to improve the yield of enantioselectiveproduct.

8. VinylogousMukaiyama AldolReaction to Natural Product Synthesis
Intermediate formation in synthesis of Khafrefungin, an antifungal agent
8Org. Lett. 2007, 9(5), 849-852N O N O
O OO
Me
R
2
OH
Me
N O
OO
Me
R
2
OH OTBS
Me
R1
R
1
=H
R
2
CHO
TiCl
4
R
1
=Me
R
2
CHO
TiCl4
1,6,7-RemoteAsymmetricInduction1,7-RemoteAsymmetricInduction

9. VinylogousMukaiyama AldolReaction to Natural Product Synthesis
Intermediate formation in synthesis of Khafrefungin, an antifungal agent
9H
3C(H
2C)
9
O
Me
OH
MeMeMe
O
MeMe
O
OH
OH
OH
O
HO Org. Lett. 2007, 9(5), 849-852
KhafrefunginN O N O
O OO
Me
R
2
OH
Me
N O
OO
Me
R
2
OH OTBS
Me
R1
R
1
=H
R
2
CHO
TiCl
4
R
1
=Me
R
2
CHO
TiCl4
1,6,7-RemoteAsymmetricInduction1,7-RemoteAsymmetricInduction

10. 10
Asymmetric Synthesis ofanti-β-Hydroxy-α-Amino Acid Derivatives
Catalytic Enantio-and DiastereoselectiveAldolReactions of Glycine-Derived
Silicon Enolatewith AldehydesR H
O
R OMe
O
OMe
OSiMe
3
NF
3C
OSiMe
3
Catalyst
toluene/tBuOMe
-20
0
C,12h
0.5Maq.KHSO
4
OH
NHCOCF
3 Catalyst:
1.Zr(OtBu)
4,ligand
2.H
2O(cat.),r.t.,1h
I
OH
OH
I
I
I
Ligand:
J. Am. Chem. Soc.2004,126, 9192-9193

11. 11H
MeO
H H
8
9
10
11
12
13
14
New approach toward the synthesis of steroid skeletons using
Mukaiyama reactions
(D)-Steroid Skeleton :
Tetrahedron2006, 62,1726–1742MeO
OSiR
3
MeO
O
O
TrSbCl
6
C8-C14
bondformation
OSiR
3
8
9
10
11
1213
14
Intermediary step

12. 12