Stereoselective aldol reactions. Reaction of chiral ester titanium enolate with aldehydes

Stereoselective aldol reactions. Reaction of chiral ester titanium enolate with aldehydes

TcuahcdronIxtters Vol 33 No 4 pp 457460 Prmtedm Great nrllaln 1992 0040 4039.92 $7 Do + 00 Pergamm Rass plr Stereoselective Aldol Reactions. Reacti...

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TcuahcdronIxtters Vol 33 No 4 pp 457460 Prmtedm Great nrllaln

1992

0040 4039.92 $7 Do + 00 Pergamm Rass plr

Stereoselective Aldol Reactions. Reaction of Chiral Ester Titanium Enolate with Aldehydes Yihn Xlang*, Enc Oltvrer and Nathalle Oulmet

Merck Ffossf Cenffe for Thefapeuf/c Research P 0 Box r005, fonre Clalfe-Dorval, Quebec H9R 4P8, Canada

Abstracf The cbml ester 7 was evoked under TiC/JEf,N [email protected] and reacted wth aldehydes to give moderas to good sfereoselectrvrbes The c/m/ auxhary group can be removed by ample sapon~ffcafm and recovered Stereoselectlve aldol reactions has been ane of the most actively studied subjects in orgamc chemistry during the last decade ’ Among the numerous methodologies now available, the most successful process IS probably utilizing the choral boron enolate,la d which often gives a high level of stereoselectlon More recently, 0 A Evans and his co-workers have generated choral chlorotitanlum enolates by applying TICIJE~N conditlons,2 which provides a much simpler experimental operatron and a high level of stereoselection upon reaction with electrophlles Unfortunately this methodology IS so far limited to ketones and activated carboxyl derivatives We now wish to report work which demonstrates that the ester 1 can also be enollzed under TICI,/E&N condltlons This enolate reacts with aldehydes to give aldols with moderate to good diastereoselecbvlty Since simple alkyl esters had been reported not to enolize in the TiCI.+/EbN system! we prepared the ester 1, consldenng that the sulfonamldo group m the molecule should react readily with titanium chlonde to form a new Lewis acld,lef which lies very close to the carbonyl group of the ester This internal Lewis acid complexation may then promote enolization

TosWEfN

The ester 1 was prepared from (1 R,2S)-norephednne in two simple steps (1) sulfonation wrth 1 05 eq of ptoluenesulfonyl chloride and 1 3 eq of tnethylamme in CH,C12 at 2O’C for IO h (92%), (2) acylation with 1 5 eq of propionyl chlonde and 2 eq of tnethylamlne in CH,CI, at 2O’C to give, after Rash chromatography, crystallme ester 1 [m p 82&C, [aID = -20’ (c 1 1, CHCI,) ] In 80% yield

458

SO,Tol 1) TICI~/CH~CI~/O”C 2) Et3N

*

C”3 1

2

Successive treatment of the ester 1 wrth 1 05 eq of TICI, In CH,CI, at O’C for 15 mm and then wrth 2 1 eq of tnethylamrne at O’C resulted a dark brown solution

The dark brown color appeared only when the second eq of

tnethylamme was added to the reaction mrxture This appears to mdrcate that the sulfonamrdo group reacted with TiCI, prror to enolrzatron

A ‘H-NW

spectroscoprc study showed that under these condrtrons the ester 1 was completely transformed

Into a srngle enolate, presumably 2 3

Scheme

0

0

PH

Xo+Ph

+

CH2C12/-40°C

PhCHO

Al tam

0

XovPh

+

70 0

OH

XovPh Me

Me

2

OH

Xo”Ph Me

+

A2

tie

+

Si

63

s2

183

30

total yield 94%

2 +

PhCHOITiCI,

CH,Ci2/-76°C

b

Al

ratto

2 6

+

A2

31

+

+

Si

52

46

69 5

total ymld 96%

The titanium enolate 2 reacted with benzaldehyde drastereoselectrvrty,

the major dlastereomer

at -40% In 2 h and gave aldol adduct with a moderate

being the an$aldol A, as mdrcated In the Scheme 4 On the other hand, when the

enolate 2 was reacted with the pre-formed 1 1 complex of bonzaldehvde

and TICI,, the reaction was complete at -78°C in

a few minutes and gave the syn aldol S, as the major Isomer with good drastereoselectrvity

(see Scheme)

459

We examined the influence of the amount and type of the Lewis acrd used in the pre-mlxrng with the aldehydes on the drastereoselectMy The best dlastereoselectivlty

of the reactions

Various Lewis acids such as BCI,, AU,,

S&I,

was obtained when equal amounts of TiCI, and aldehyde were mixed prior to the reaction

the enolate 2 Further experiments were conducted to examine the scope of

this

enolate 2 gave good

with

while reaction of alrphatic aldehydes gave moderate diastereoselectivltles

diastereoselectivihes,

TIC&

w&t

reaction Several aldehydes and ketals were

reacted with enolate 2 As summanzed In the Table, reactlons of aromatlc aldehydes and ketals

Table

and TiCI, were tested

Promoted

A!dol Reactton

YIELDC

of Enolate

PERCENTAGE

1%1

A.

2 wtth Representattve

Aldehydesa

[ a lo’

OF DIASIEFIEOMERSe Aa

S,

SJ -20 5”

(c 0 8, CHC13)

848

-150’

(c

59 8

-22 7”

(c 0 9,

98 (85jd

26

31

46

89 5

~OphcHo

93

77

73

67

76 3

CJ-W-fz~

82(70)d

29

83

40

(CHB)~CHCHO

99(50)d

21 3

168

1,3,5-Trtoxane

92(76)d

65

935

+4 3” (c 1 0, CHC13)

15 3

847

+32 3” (c 1 0, CHCIa)

21

1 1, THF) THF)

0 0-

80

OMe

(58)d

0

aGeneral

procedure

for the aldol reactton

1 05 mmol of neat TIC& dtopwtse triethylamme

(2 1 mmol)

brown solution

of CHsCla at -78°C wtth vtgorous

was added

was transfered

To a solution of ester i(1 mmol) tn 10 mL of dry CH&ls

via syringe dropwtse

under argon at 0°C resulttng

very slowfy Into a mtxture of aldehyde

After workup

(CH,Cls/aq

ytelds of the four dtastereomers

*The stereochemtstry mers was determmed

of dtastereomers by HPLC

by addttton of

NH4CI), the ratto of dtasteromers

were determmed

bT~o equtvalents

by HPLC

dtsttlled

1 h,

lhts

(2 mmol) and TIC& (2 1 mmol) tn 5 ml

After sttrnng at -76°C for 15 mm, the reactton was quenched

sttrrmg

was added

for 15 mtn. freshly

In a brown solutton 4 After sttrrtng at 0” for

and the major Isomer was purtfted by flash chromatography ‘Total

After stirring

dlsolated

was determmed

NH,CI

by I-IPLC

were used WI all the reacttons yteld of the major dtastereomet(S,)

At, Aa, St and 5s are shown in the scheme’,

‘Opttcal rotation of the mafor dtastereomers

aq

the percentage

of dtastereo-

(Sn)

The major dlastereomer of all the above reactlons were easily purified by flash chromatography and freed

from auxiliary group by mild hydrolysis conditions (LIOHITHF-MeOH)

with no loss of chlrallty The auxiliary group

IS

recoverable and reusable These results show that titanium ester enolate could be an attractive approach for the preparation of choral aldols Work towards further improvement of the dmstereoselectlvities as the auxiliary group IS now underway

by usmg different choral sulfonamide-alcohols

460

References and Notes 1

Reviews (a) Evans, D A , Nelson, J V , Taber, T R Tap~cs Stereo&em

1982, 131

(b) Heathcock, C H Asymmefr/c

Synfhess, Mornson, J D Ed , Acadermc Press, New York, 1984, Vol 3, p 111 (c) Masamune, S , Choy, W , Peterson, J

S , Slta, L R Angew Cbem Int Ed Engl

1985,241

(d) Braun, M Angew

Chem Int Ed Engl 1987,26,:?4

Recent

yorJ (e) Corey, E J , Imwmkelrred, R , Plkul, S , Xlang, Y J Am Chem Sot 1989, 111, 5493 (f) Corey, E J , Kim, S S ,

J Am Chem Sot 1990, 112,4976 2767

(g) Oppolzer, W

Blabb, J , Rodnguez, I , Walter, E , J Am Chem Sot 1990, f12,

(h) Meyers, A G Wlddowson, K L ,J Am Chem Sot 1990, 112,9672

Arsenlyadrs, S ,Cnmmms, M T J Clrg Chem 1991, 562499

(I) Heathcock, C H , Van Draanen, N A r

f~) Thornton, E R , Bonner, M P J Am Chen Sot 1991,

113, 1299 (k) Oppolzer, W , Rognguez, I , Starkemann, C , Walter, E , Teffahedron Left 1990, 31,5019 Starkemann,

C , Rodriguez, I , Bernardmelll, G kxd 1991, 32, 61

2

Evans, D A , Urpl, F , Somers, T ,Clar, J S , Bllodeau, M T J Am Chem Sot 1990, 112,8215

3

The ‘H-NMR sample of 2 was prepared following the same procedure

recorded

(I) Oppolzer, W ,

at 20°C ‘H-NMR (300MHz, CD+&)

(see text) In CD,CI, and the spectrum was

d 7 78 (dd, J = 1 0, 8 0, 2H), 7 40-7 22 (m, 5H), 7 16 (dd, J = 1 0, 8 0, 2H),

4 79 (q, J = 7 3, IH, =CHCH,), 4 48 (d, J = 6 4, 1H OCH), 4 40 (quintet, J = 6 4, 1H, NCH), 2 41 (s, 3H), 1 69 (d, J = 7 3, =CHCH,), 0 87 (d, J = 6 4, 3H)

4

The major isomers of the reactions shown In the Scheme and

III

Table (see text) were Isolated by flash chromatography

and had satisfactory ‘H-NMR, IR and mass spectra The purrty of the isolated aldol products were 197% as determined by HPLC The absolute stereochemistry (LIOH/THF-MeOHI20’C)

of the aldols were determmed by first removing the auxiliary group by mid hydrolysis

and then transforming

the free acrd Into Its methyl ester (CH,NdethedO’C),

the methyl ester was measured and compared with the literature

(Recewed

m USA 30 October 1991)

the optical rotation of