.
Angewandte
Communications
DOI: 10.1002/anie.201307302
Synthetic Methods
Generation of Stereochemically Defined Tetrasubstituted
Enolborinates by 1,4-Hydroboration of a,b-Unsaturated Morpholine
Carboxamides with (Diisopinocampheyl)borane**
Christophe Allais, Andy S. Tsai, Philippe Nuhant, and William R. Roush*
The enantioselective synthesis of acyclic all-carbon quater-
nary centers remains a significant challenge in organic
[
1]
synthesis. In view of the tremendous utility of enantiose-
lective aldol reactions in organic synthesis, extension of this
reaction to the enantioselective synthesis of all-carbon
quaternary centers from stereochemically defined tetrasub-
[
2,3]
stituted enolates would be highly valuable.
However,
attempts to generate such enolates or enolate equivalents
by deprotonation of acyclic carbonyl compounds in most
cases lead to geometric mixtures, which translates to poor
[3,4]
diastereoselectivity in the subsequent aldol reaction.
Thus,
alternative methods for generation of acyclic tetrasubstituted
enolates or their synthetic equivalents have been devel-
[5–8]
oped.
Noteworthy among these, a highly stereoselective
carbocupration of chiral ynamides followed by oxidation of
the resultant vinylcuprate has been developed by Marek and
[8]
co-workers. Nevertheless, the development of a simple,
highly stereocontrolled method for synthesis of stereochem-
ically defined tetrasubstituted enolates from readily available
achiral starting materials remains an important objective.
Toward this end, we report herein a simple procedure by
which stereodefined tetrasubstituted enolborinates are gen-
erated with exceptional stereoselectivity by 1,4-hydrobora-
Scheme 1. 1,4-Reductive aldol reactions of substituted a,b-unsaturated
l
amides with (Ipc) BH.
2
tuted a,b-unsaturated amides (4). Subsequent aldol reactions
of 5 should faithfully relay the enolborinate geometry to the
all-carbon quaternary stereocenter in 6 via the transition state
[9,10]
tion reactions
of unsaturated morpholine carboxamides
[
2]
with (diisopinocampheyl)borane [(Ipc) BH], and demon-
TS-II. To the best of our knowledge, stereodefined tetra-
substituted enolates have not been successfully generated
with high stereochemical control by using alternative reduc-
2
strate that the tetrasubstituted enolborinates undergo highly
enantio- and diastereoselective aldol reactions with repre-
sentative achiral aldehydes.
[
9,10,12,13]
tive aldol procedures,
but several have been generated
We recently reported that the 1,4-hydroboration of the
by 1,4-addition of organometallic reagents to unsaturated
carbonyl derivatives.
l
[5a,m,q,r,14]
morpholine acrylamide 1 with ( Ipc) BH provides the enol-
2
2
3
[11a]
borinate Z(O)-2 via TS-I (Scheme 1, where R = R = H).
We began by using the a-methylacryl carboxamide 7 as
the substrate to probe the effect of an a substituent on the 1,4-
hydroboration and the subsequent aldol reaction. Com-
pounds bearing a a,a-dimethyl-b-hydroxy quaternary center
Treatment of Z(O)-2 with aldehydes provided the syn-aldol
products 3 with exceptional diastereo- and enantioselectivity
(
ꢀ 20:1 d.r. and 96–98% ee). By virtue of the transition state
[9,12]
[15]
TS-I proposed for the 1,4-hydroboration reaction,
we
are often generated by using Mukaiyama aldol methods.
d
anticipated that this procedure could be used to generate
1,4-Hydroboration of 7 (1.1 equiv) with ( Ipc) BH (1 equiv)
2
stereodefined tetrasubstituted enolborinates (5) from substi-
in Et O at ambient temperature for 3 hours with subsequent
2
addition of an aldehyde (0.85 equiv) and heating the reaction
mixture at 508C in sealed tube for 16 hours gave the aldol
products 9 (Scheme 2; see the Supporting Information for the
variables studied during the optimization of this reaction).
Results of the reductive aldol reactions of 7 with a range of
representative aldehydes are presented in Scheme 2. The
aldol reactions of the enolborinate 8 are more sluggish than
conventional aldol reactions of less substituted enolborinates
owing to the hindered nature of 8, and required heating at
reflux overnight. Nevertheless 9a–e were obtained in good
yield (66–84%) and with excellent enantioselectivity (91-
96% ee). The absolute stereochemistry of the products 9 was
[
+]
[+]
[+]
[
*] Dr. C. Allais, Dr. A. S. Tsai, Dr. P. Nuhant, Prof. Dr. W. R. Roush
Department of Chemistry, The Scripps Research Institute
1
30 Scripps Way, 3A2, Jupiter FL 33458 (USA)
E-mail: roush@scripps.edu
Homepage: http://www.scripps.edu/roush
+
[
] These authors contributed equally to this work.
[
**] Financial support provided by the National Institutes of Health
(
GM038436) and a postdoctoral fellowship to AST (CA162504) are
gratefully acknowledged.
1
2888
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 12888 –12891