Aldol Reaction

34 Pages·2001·0.14 MB·English

α
-Oxygenated Aldol Reactions
William C. Trenkle
Evans Group Meeting
Department of Chemistry
Harvard University
Friday
Febuary 16, 2001
'01-01- Title Page 2/17/01 12:37 PM
Introduction
1. Aldol Reactions of Glycolate Derivatives
2. Hydroxyketone Aldol Reactions
3. Dihydroxyacetone Aldol Reactions
4. Enzyme Mediated Aldol Reactions
'01-02-Intro 2/15/01 10:02 PM
Early Oxygenated Mukaiyama Aldol Study
Me Me
OTMS O OH
Lewis Acid 1. LAH O O
OBn Me HO2C Me
TMSO H 2. acetone 1 3 Me
2
p–TsOH
OBn OBn OBn
OBn OBn
Lewis Acid = BF •OEt , SnCl , TiCl , MgBr ,
3 2 4 4 2 26–54%
ZnCl , ZnCl •OEt , Eu(fod) , Lithium Enolate
2 2 2 3
Best Results:
MgBr provided 28% yield of a 0:19:1:80 ratio of products which favors the all syn product.
2
This is reaction shows a diastereoselection of 19:81 for C1,C2 and 1:99 for C2,C3. (antiperiplanar)
Eu(fod) provided a 53% yield of a 0:80:11:9 ratio of products which favors the anti,syn product.
3
This reaction shows a diastereoselection of 80:20 for C1,C2 and 11:89 for C2,C3. (synclinal)
Me Me Me Me Me Me Me Me
O O O O O O O O
Me Me Me Me
1 3 1 3 1 3 1 3
2 2 2 2
OBn OBn OBn OBn OBn OBn OBn OBn
Takai, K.: Heathcock, C. H. J. Org. Chem. 1985, 53, 3247–3251.
'01-03-Heathcock early aldol 2/15/01 5:08 PM
O
OH OH OH OH OH OH OH
Me
3 7
Me
Proposed Modes of Addition
11 15 19
N
for the Mukaiyama Aldol of
Me Me Me Me OH Me Me Me Me
OH HO
Poly-oxygenated Systems O
23
HO OH
OH 35 OH OH OH OH
PMP Me 39 O 31 27 OH
OH H
O OTPS O Aflastatin A
OH OH
O
H 35 31 PMP
TESO OSiR OTBS TESO O OH OTPS O
3
Lewis Acid mediated
O
C9H19 39 anti aldol reaction C9H19 39 35 31
OPMB PMBO OTBS
OTPS OTPS
OTPS OTPS
R' R'
R' H H O OH OTPS O OH OTPS H R' H
TBSO TBSO
TBSO H H TBSO
H H
X C C R R' R R' C X C
H O H O
H O H O
H O O H
C H O OTBS O OTBS C O
Y C BF3 C BF3 Felkin Felkin C BF3 Y C BF3
C C
O H
Y X Y X
Antiperiplanar Synclinal Synclinal Antiperiplanar
Transition States Transition States Transition States Transition States
R' R'
R' R'
OTPS OTPS
OTPS H O OH OTPS O OH OTPS H OTPS
H H
H H
H TBSO TBSO H
TBSO TBSO
C R R' R R' C
C X C X
O H O H
O H O H
H O O OTBS O OTBS O H
O C H C
BF C BF C
BF C Y 3 Anti-Felkin Anti-Felkin 3 BF C Y
3 3
C Desired C
H O
Y X Y X
X, Y = OSiR , R
'01-04-Coupling Strategy 2/5/00 1:36 PM 3
Proposed Modes of Chelate Controlled Addition (6 and 5 membered chelate)
6 Membered Chelate Addition- Mismatched with the alpha Stereocenter-Poor predicted Selectivity
R' R'
R' R'
H H
H OTPS OTPS O OH OTPS O OH OTPS OTPS H OTPS
TBSO TBSO
TBSO H H TBSO
H H
X C M C M R R' R R' C M X C M
H O H O
H O H O
H O O H
C H O OTBS O OTBS C O
C C
Y C Y C
Felkin Felkin
C C
O Disfavored by Boat formation. H
Y X Y X
Antiperiplanar Synclinal Synclinal Antiperiplanar
Transition States Transition States Transition States Transition States
H H
H H
R' TPSO R' O OH OTPS O OH OTPS TPSO R' R'
TPSO TPSO
H H
H PO PO H
PO PO
M C X M C R R' R R' M C M C X
O H O H
O H O H
O H O OTBS O OTBS H O
H C O C
C C
C Y Anti-Felkin Anti-Felkin C Y
C Desired C
O H
X Y X Y
5 membered Chelate Addition- Mismatched with beta stereocenter but reasonable aldehyde facial selectivity expected
R' R'
R' R'
OTPS OTPS
OTPS H O OH OTPS O OH OTPS H OTPS
H H
H H
H TBSO TBSO H
TBSO TBSO
C R R' R R' C
C X M M C X
M O H O H M
O H O H
H O O OTBS O OTBS O H
O C H C
C C
C Y Anti-Felkin Anti-Felkin C Y
C Desired C
H O
Y X Y X
Antiperiplanar Synclinal Synclinal Antiperiplanar
Transition States Transition States Transition States Transition States
X, Y = OSiR , R
3
'01-05-Chelate Mukaiyama 2/15/01 9:31 PM
Diastereoselective Addition of Boron Ene-diolates
L B
2
O
Me
O
O O OH
L BOTf (2 equiv) BL 1. PhCHO
2 2
R
HO HO Ph
i-Pr2NEt L 2. H2O2
L R
O B
O
Bn R = Me
O
L = Bu syn:anti 35:65
BL
2 L = c-pent syn:anti 20:80
R = OBn
L = Bu only anti 85% yield
Stereochemical Proof:
OMe
H
O OH
H
Me N OMe
2
HO Ph
CHCl , reflux;
OBn 3 OBn
distill 81%
Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103, 3099-3111.
'01-06-Evans-Ene-diolate 2/6/01 2:33 PM
Diastereoselective Addition of Chiral Boron Ene-diolates
L* B
2
O O O OH
1. LDA 1. PhCHO
R R
HO O HO Ph
* 2.H O
2. L BCl 2 2
2
BL* R
2
R = H, Me, Ph, SMe
d d
syn:anti ~10:1(2- Icr) 1:1–10(4- Icr)
%ee syn 90–99 anti 20–61
yield 50–90%
Me Me
R = OPh R = OPh
L* = L* = 2-dIcr L* = 4-dIcr
syn:anti 4:1 syn:anti 1:4
%ee syn 98 anti 50 %ee syn 96 anti 80
Me Me
combined yield 68% combined yield 70%
Me Me
d d
(2- Icr) (4- Icr)
Fringuelli, F.; Piermatti, O.; Pizzo, F. J. Org. Chem. 1995, 60, 7006-7009.
'01-07-Ene-diolate chiral-lig 2/6/01 2:15 PM
Evans Boron Mediated Aldol Reaction
O O O O OH
Bu BOTf, Et N;
2 3
OBn
O N O N Et
RCHO
OBn Me
Ph Me Ph Me
84%
This methodology is general has been widely adopted and utilized in many syntheses.
Benzyl, methyl, aryl, allyl and alkyl ethers are all tolerated.
O O O O OH OAc Br
TiCl4, i-Pr2NEt; 1. LiBH4 12 12
OAc Me
O N O N 12
H2C=CHCH2CHO 13 2. Ac2O 7 O 13 7 O 13
O 65% O 3. RCM
H
OBn OBn
Bn Bn 7
H H
OBn OAc
laurencin
This example is from Crimmins' formal total synthesis of laurencin
Evans, D. A.; Bender, S. L. Tet. Lett. 1986, 27, 799–802.
Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506–2526.
Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653–5660.
'01-08-Evans-Bu2B-OBn aldol 2/15/01 5:44 PM
Oxy-aldol Approaches to Pederic Acid Analogs
Me OMe
TiCl4, CH2Cl2, Aldehyde TBSO TBSO OH O
O OMe
O
R
i-Pr EtN, –78 °C
2 Me N
BnO OMe
61% of desired
N O
Me OBn Teoc
H 25% rcvd aldehyde
Teoc
O
TBSO TBSO O
Teoc = TMS
O
Me H
Me
Me OH O
MeO H H
Me O N OMe
O O
Me OMe
OMe
Roush, W. R.; Pfeifer, L. A.; Marron, T. G. J. Org. Chem. 1998, 63, 2064-2065.
'01-09-Roush-joc'98-oxyaldol 2/8/01 5:37 PM
II
Sn Mediated Anti Aldol of Benzyloxy Acyl Thiazolidines
S O S O OH S O OH
Sn(OTf) TMEDA RCHO
2
O
S N Bn S N R S N R
CH Cl
2 2
OBn OBn
Using PhCH CH CHO
N Me 2 2
70% of 15:85 mixture syn:anti
Without TMEDA syn:anti 3:1
Appears to be fairly general and gives a 17:83–7:93 ratio depending
on aldehyde (hexanal, c-HexCHO, i-PrCHO, PhCHO).
Use of enantiopure chiral diamine provides the same ratio of
syn:anti in good ee 87–94%. (determination of absolute not indicated)
H
N N
Me
Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1984, 753–756.
'01-10-Mukaiyama-Sn2antialdol 2/14/01 4:44 PM