A Superior Chiral Auxiliary in Aldol Condensations: Camphor-Based Oxazolidone

Article abstract of DOI:10.1016/0040-4039(91)80084-J

The aldol reactions from boron enolate derived from camphor-based N-propionyloxazolidone exhibit exceptionally high stereoselection.The initial aldol adducts from lithium mediated reactions equilibrate to furnish erythro isomers.Erythro selection is contr

Full text of DOI:10.1016/0040-4039(91)80084-J

Tetrahedron Letters, Vo132, No 40, pp 5563-5566, 1991
Printed m Great Britain
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A Superior Chiral Aurlll~ry in Aldol Condensations: Camphor-Based Oxazolidone
T u - H s m Yan,* Vir-Vir Chu, Ta-Chin Lin, Woei-Hung Tseng, and Tun-Wen C h e n g
D e p a r t m e n t of Chemistry, National Chung-Hsing University
Taichung, Taiwan 40227, Republic of C h i n a
Abstract: The aldol reactions from b o r o n e n o l a t e derived from c a m p h o r - b a s e d N-proplonyloxazolidone
e x h i b l t exceptionally high stereoselection.
The initial aldol a d d u c t s from l i t h i u m m e d i a t e d reactions
equilibrate to f u m i s h eI'ythro isomers. Erythro selection is controlled by the choice of the enolate counterion.
Over the past few years, the utilization of c a m p h o r as a source of chirality for the preparation of various
enanttomerically enriched c o m p o u n d s has been illustrated by Eliel,1 Hoffman,2 T a b e r ,3 Oppolzer,4 Davls,s
and o t h e r s .6 D r i v e n by the rapidly growing d e m a n d for highly enantiomerically pure ll-hydroxy carbonyl
containing compounds, the development of superior metal-chelated enolates, w h l c h can achieve exceptionally
hlgh diastereoselectivlty, has e v l d e n t l y b e c o m e both d e s i r a b l e and challenging. 7 In the preceding
communicatiions 8 we have s h o w n that (+)-camphor-based i m i d e enolate can display excellent x-topological
differentiation on alkylation reactions. The r e a d y availability of optically pure 2-oxazolidone
2 from
ketoplnic acid 18 made consideration of it very attractive for use as chiral auxiliary in aldol condensations
H e r e t o we d e s c r i b e in detail the d e v e l o p m e n t of enanhoselectlve aldol condensations via the lithium- and
boron-chelated e n o l a t e s derived from the imide
The hthium-chelated {Z)-enolate of 3 was generated u n d e r kinetic conditions (LiN(I-C3HT)2, -78 °C, THF)
The boron-chelated (Z)-enolate 3._~b was p r e p a r e d u n d e r mild conditions from c h i r a l i m i d e and di-n-
3
3
butylboryl trifluoromethanesulfonate. 7d,8,9,1° As the new m e t a l - c h e l a t e d enolates, 3_.~a and 3._bb, p o s s e s s a
relatively rigid c a m p h o r ring w h l c h s e r v e s as a sterically d e m a n d i n g g r o u p to retard the formation of chelated
(E)-enolates 3__cc ( S c h e m e I}, we h o p e d to achieve greater dmstereoselectivities on aldol condensations. I n d e e d
the aldol p r o d u c t s from di-n-butylboryl trffuoromethanesulfonate m e d i a t e d aldol c o n d e n s a t i o n s a l w a y s
c o n s i s t e d of a single erythro d i a s t e r e o m e r within 4 0 0 - M H z IH NMR d e t e c t i o n limits. The illustrated aldol
condensations of enolates, 3_.~a and 3._b_b, with representative aldehydes summarized in T a b l e I were e a r n e d out
according to the following general procedure Aldehyde was a d d e d to the s o l u t i o n containing the h t h i u m
enolate 3__.aa (~0.2M) at -78 °C. The resulting s o l u t i o n was s t i r r e d at -78 °C for 30 mln, q u e n c h e d with 20%
a q u e o u s THF solution, and w o r k e d up In the process of conducting erythro/threo equilibration studies, the
resulting m i x t u r e was q u e n c h e d at -78 °C and s t i r r e d at -5 °C for 30 rain before the u s u a l w o r k u p In the
condensations of the b o r o n enolate 3__b_b with aldehydes, the reaction m i x t u r e was s t i r r e d at -78 °C for 1 hr and
then at room t e m p e r a t u r e for 2 hr. The r e s u l t a n t solution was cooled to 0 °C and q u e n c h e d with a m i x t u r e of
methanol and pH 7 phosphate buffer (2. I). The resultlng borate was oxidized by 30% H202 for 1 hr at 0 °C In all
c a s e s s t u d i e d , the aldol condensations from b o r o n enolate 3._bb exhibited c o m p l e t e erythro stereoselection and
a b s o l u t e stereochemical control. In fact, none of the o t h e r t h r e e diastereoisomeric aldol a d d u c t s c o u l d be
detected by 400-MHz IH NMR Our assignment of the syn configuration is b a s e d on the consideration of the
carbinol resonances in the IH NMR spectra of the c r u d e aldol product, u s i n g the wen-established fact that
5563

5564
S c h e m e I
N a H - T H F
EtCOCI
L1N{ l-Pr h
~N o
\
/ THr/-7S °d
H
0
two s t e p s
L
2_
3 a
o~ ~o
COOH
,"
X
(
n-Bu)2BOTf
~
N
O
O-M~,~ L
d
EtN( ~ - P r ~ ' C H 2 ~ / / ~ 0 - ~ j ~ . . /
3b
RCHO
-
.
.
.
.
o
~L
RCHO
.
R
R
R
R
3_~a M=I~
a, P h C H O
3b
M=B
b. M e2CHCHO
c, n-PrCHO
_4
5
fi
Z
d, H2C=CHCHO
OMe
HO0~"~
NaOMe-MeOH
~
N
°
-30 °C to -5 °C
R
H O 0 ~ "~0
R
8
a, R= Ph
b, R = CHMe 2
_4
a, R = Ph
b, R = CHMe 2
Jthreo {7~9Hz) > Jerythro ( 3 - 6 H z ) 11 The a b s o l u t e s t e r e o c h e m l c a l a s s i g n m e n t s were m a d e in two c a s e s
Nondestructive r e m o v a l of the c h l r a l a u x i l i a r y 2-- vm m e t h a n o l y s m (NaOMe. 0 °C) of 4a and 4b afforded th~
corresponding k n o w n colorless optmally active m e t h y l e s t e r s 8a ([ct]2°o = - 22 5 Ic 4 8, CHC13)) and 8b ([c~12°D = -

"
5565
8 1 (c 3.1, CHCI3)) for comparison of optical purity.7d,12 The aldol reactions from lithium enolate 3a afforded
erythro and threo products. In aU cases examined, however, the initial kinetic mixture of erythro and threo
aldols can be equilibrated to thermodynamic erythro adducts by quenching the reaction mixture with aqueous
THF and stirring the resulting solution at -5 °C for 0.5 h. The two ez3rthro aldol stereoisomers, 4 and 5, in all
cases reported could be conveniently purified to high optical purity by a single recrystallization or column
chromatography The assignment of stereochemistry of 6 is based on the above equilibration studies of the
initial kinetic aldols (e.g., compare entries 2 vs. 3 and 5 vs. 6) The diastereoselectivity of the aldol reaction
with lithium enolates 3a was generally moderate. The origin of the lower level of the stereoselection could be
largely due to the long Li-O bend length as compared to B-O bond length 7e, 10c Of particular note is the opposite
sense of chirality transfer with lithium as compared to boron enolates (e.g, compare entries 1 vs. 2, 4 vs. 5, and
7 vs 8). This behavior has also been observed by Abdel-Magid et al.7e The origin of this marked difference m
enantioselection may lie in the difference in the coordination numbers of boron and lithium. 13
Table I A1dol Condensations of Metal Enolates 3a and 3__b_b with Representative Aldehydes
entry
etectrophde
e n o l a t e s
erythro/threo a
(~.+5 "6 +]..)
enant~oselecbona
yieldd
(%)
[(~]2°D
deg
(c, CH2CI2)f mp *C
4.5
6"2
1
P h C H O
B(n-Ru)2
>991
>991
b
91
+94
(12 6)
121-122
2
3
4
5
6
7
PhCHO
PhCHO
L1(-78 °C)
Ll(equdlbrabon)
B(n-Bu)2
11
>991
• 991
136
1.4
1"9
• 991
> 991
75
61
92
82
65
92
c
+50 5e
+84 6
(3 7)
(8 8)
4 3 - 4 4
91-92
Me2CHCHO
Me2CHCHO
b
>991
c
L1(-78 °C)
1=.12
1 18
Me2CHCHO Ll(equdlbratlon)
>991
>991
+49 0e
+81 0
(4 0)
100-101
51-52
n-PrCHO
B(n-Bu)2
>991
b
(10 1)
8
9
n-PrCHO
n-PrCHO
Li(-78 °C)
Li(equdtbration)
B(n-Bu) 2
>991
• 991
>991
16
16
c
c
b
85
85
92
+57 5e
+105 7
(5 0)
(7 4)
56-57
10
H2C=CHCHO
>991
103-104
aRabos determ=ned by 400-MHz 1H NMR. bThe erythro-~somer ~ was the only detected product by 400-MHz 1H NMR. CNone of the threo-=somers
could be detected by 1H NMR dSahsfactory spectral data (NMR and IR) and analytical data obtained for all new compounds eoptical rotation of
purified erythro-lsomer 5 fConcentratlon in methylene chlonde (c = g/100ml)
This work provides a practical asymmetric synthesis of ~-hydroxy carbonyl containing compounds both
enantiomers of erythro aldols can be prepared easily via metal and temperature modifications
The
remarkable ease of the preparation of both antipodes of 2 and the exceptional quality of stereocontrol
exhibited by the camphor-based boron enolate 3__~b highlight the synthetic utility of the auxiliary 2.
Aoknowlaclgemants: This work was supported by Grant NSCS0-0208-M005-12 from The National Science
Council of Republic of China.

5566
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9
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C
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H Heathcock and D A E v a n s
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(Receaved m Japan 18 M a r c h 1991)