α,α-Disubstituted Boron Enolates in the Asymmetric Synthesis of Quaternary Carbon Centers

Article abstract of DOI:10.1021/ol0364428

(Equation presented) Reduction of α,α-disubstituted thioglycolate amides with lithium di-tert-butylbiphenylide affords α,α-disubstituted enolates with high Z/E selectivity. Transmetalation of the enolates with dicyclohexylboron bromide facilitates highly

Full text of DOI:10.1021/ol0364428

ORGANIC
LETTERS
2004
Vol. 6, No. 3
405-407
r,r-Disubstituted Boron Enolates in the
Asymmetric Synthesis of Quaternary
Carbon Centers
E. Diane Burke and James L. Gleason*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke St. West,
Montreal, Quebec, Canada, H3A 2K6
jim.gleason@mcgill.ca
Received December 15, 2003
ABSTRACT
Reduction of r,r-disubstituted thioglycolate amides with lithium di-tert-butylbiphenylide affords r,r-disubstituted enolates with high Z/E
selectivity. Transmetalation of the enolates with dicyclohexylboron bromide facilitates highly diastereoselective aldol reaction with aromatic
and r,â-unsaturated aldehydes.
The aldol reaction is one of the most powerful tools in
synthesis. Countless examples of asymmetric aldol reactions
have been reported over the years, mostly focusing on
reactions that produce either â-hydroxy carbonyls (e.g.,
acetate aldols) or R-alkyl-â-hydroxy carbonyls (e.g., propi-
onate aldols). In the case of propionate aldols, control of
syn/anti stereochemistry is a major concern. In many
instances, high syn/anti control can result through the
combination of a single enolate stereochemistry (i.e., E/Z)
reacting within a chairlike (i.e., Zimmerman-Traxler) transi-
tion state. In sharp contrast to acetate and propionate aldols,
there are no general aldol methods for the asymmetric
synthesis of R,R-dialkyl-â-hydroxy carbonyls.1 The reason
for this is the general inaccessibility of acyclic R,R-
disubstituted enolates of defined stereochemistry. Recently,
we described a solution to this problem using a two-electron
reduction of thioglycolate lactams.2 In this communication,
we describe the extension of this methodology to the
formation of R,R-dialkyl-â-hydroxy amides with excellent
control of absolute and relative stereochemistry.
The reduction of 5,7-bicyclic lactam 1a with lithium di-
tert-butylbiphenylide produces (Z)-enolate 2a with 94:6
selectivity (Scheme 1). The stereoselectivity in this reaction
arises from constraints in the bicyclic system that hold the
sulfur rigidly on one face of the carbonyl plane such that
upon two-electron reduction, the E/Z stereochemistry of the
enolate is governed by the relative locations of the R-alkyl
groups in the starting lactam. The (Z)-lithium enolates have
subsequently been employed in highly stereoselective alkyl-
ations to form quaternary carbon stereocenters (e.g., 3).3
Aldol condensation of lithium enolate 2a with benzalde-
hyde at -78 °C in THF proceeded in good yield. The
diastereoselectivity of the reaction could be determined by
HPLC only after S-benzylation of the product. Not surpris-
ingly, the lithium aldol proceeded with low syn/anti selectiv-
ity (52:48). In addition, the facial selectivity with respect to
the approach of the aldehyde on the enolate diastereofaces
was low for both the syn and anti products.4 To improve the
stereoselectivity, transmetalation of the lithium enolates with
various metal halides was investigated (Table 1). Trans-
(1) For approaches to this problem using allylmetal species, see: (a)
Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 898. (b)
Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488. For an alkylation
approach, see: (c) Frater, G. HelV. Chim. Acta 1979, 62, 2825, 2829.
(2) Manthorpe, J. M.; Gleason, J. L. J. Am. Chem. Soc. 2001, 123, 2091.
(3) Manthorpe, J. M.; Gleason, J. L. Angew. Chem., Int. Ed. 2002, 41,
2338.
(4) For purposes of convenience, the syn product is defined as the one
with the larger group at the R-position and the hydroxyl group both forward
when drawn in an extended format.
10.1021/ol0364428 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/06/2004

of lithium enolate 2a with dibutylboron triflate (3.0 equiv)
prior to condensation with benzaldehyde improved the syn/
anti selectivity to 83:17 and also provided a significant
increase in absolute stereocontrol. The syn/anti selectivity
was further improved to 91:9 by switching from dibutylboron
triflate to the more sterically demanding dicyclohexylboron
triflate. The syn/anti selectivity in this reaction is very close
to the Z/E ratio of the intermediate enolate (94:6 Z/E).
However, the yield was only modest and the use of fewer
equivalents of boron reagent resulted in reduced selectivity.
A subsequent survey of dicyclohexylboron species showed
that the bromide reagent afforded equivalent stereoselectivity
but with improved and more reproducible yields. In addition,
in the case of boron halides, only 2 equiv of reagent were
necessary to achieve optimum stereoselectivity (vs 3 equiv
for the corresponding triflates).
Scheme 1. Alkylation and Aldol Reactions to Form
Quaternary Carbon Centers
A survey with a series of aldehydes revealed that under
the optimum reaction conditions (2.1 equiv of Cy2BBr), high
stereoselectivity and yields could be achieved with both
aromatic and R,â-unsaturated aldehydes (Table 2). In the
metalation with Cp2ZrCl2 afforded a modest increase in syn/
anti stereocontrol, while titanium and tin enolates afforded
no significant improvement.
Boron enolates are well-known to afford some of the
highest stereoselectivities in aldol condensations.5 However,
in most cases, boron enolates are formed through direct
enolboration of carbonyl substrates. This generally limits
boron enolate formation to more acidic species such as
ketones, imides, and thioesters; simple amides are normally
not substrates for enolboration.6 Transmetalation of lithium
enolates to boron has only been reported in a few isolated
cases. However, yields and the syn/anti stereoselectivity of
subsequent aldol reactions can be variable.7,8 Transmetalation
Table 2. Aldol Reactions of R,R-Disubstituted Boron Enolates
de (syn) yield
entry
R1
Et
Et
Et
Et
Et
Et
R2
syn/antia
(%)a,b
(%)
1
2
3
4
5
6
7
8
Ph-
91:9
91:9
93:7
91:9
98:2
91:9
92:8
91:9
94
98
99
99
95
91
91
99
80
83
81
63
44
95
71
91
4-(MeO)Ph-
4-BrPh-
(E)-PhCHdCH-
CH2dC(Me)-
(E)-MeCHdC(Me)-
Table 1. Transmetalation Effects on Aldol Stereoselectivity
allyl Ph-
Bn Ph-
a Determined by HPLC using a Chiracel-OD column. b The minor
diastereomer has the S-configuration at the quaternary center (structure not
shown).
syn/anti
(5a /6a )a
de (syn)
(%)a,b
yield
(%)
entry
additive
equiv
1
2
3
4
5
6
7
8
9
10
11
12
13
none
TiCl4
Cp2ZrCl2
SnCl4
Bu2BOTf
Bu2BOTf
Cy2BOTf
Cy2BOTf
Bu2BCl
Cy2BCl
Cy2BCl
Cy2BBr
Cy2BBr
52:48
45:55
71:29
46:54
79:21
83:17
69:31
91:9
75:25
73:37
92: 8
55:45
91:9
23
20
52
48
95
92
30
93
81
50
96
93
94
71
nd
nd
nd
48
39
46
53
63
nd
31
nd
80
latter case, higher yields are observed for â-substituted
aldehydes. Some aldol products that have also undergone
1.1
2.0
1.05
2.2
3.0
2.2
3.3
2.1
1.1
2.1
1.1
2.1
(5) Crowden, C. J.; Patterson, I. Org. React. 1997, 51, 1.
(6) Although simple amides have not been reported to undergo enol-
boration, N-acyl isoxazolidines have been shown to be useful substrates.
See: Abiko, A.; Liu, J.-F.; Wang, G.-Q.; Masamune, S. Tetrahedron Lett.
1997, 38, 3261.
(7) Haubenrieich, T.; Hu¨nig, S.; Schulz, H.-J. Angew. Chem., Int. Ed.
Engl. 1993, 32, 398. Fringuelli, F.; Piermatti, O.; Pizzo, F. J. Org. Chem.
1995, 60, 7006. Vicario, J. L.; Badia, D.; Dominguez, E.; Rodriguez, M.;
Carrillo, L. J. Org. Chem. 2000, 65, 3754. For a recent example of
transmetalation from a sodium enolate, see: Lang, F.; Zewge, D.; Song, Z.
J.; Biba, M.; Dormer, P.; Tschaen, D.; Volante, R. P.; Reider, P. J.
Tetrahedron Lett. 2003, 44, 5285. For transmetalation from copper, see:
Lipshutz, B. H.; Papa, P. Angew. Chem., Int. Ed. 2002, 41, 4580.
(8) R,R-Disubstituted boron enolates prepared by treatment of silyl enol
ethers with dibutylboron triflate have been reported to give high dia-
stereoselectivity in aldol condensations. See: Yamago, S.; Machii, D.;
Nakamura, E. J. Org. Chem. 1991, 56, 2098.
a Determined by HPLC using a Chiracel-OD column. b The minor
diastereomer has the S-configuration at the quaternary center (structure not
shown).
406
Org. Lett., Vol. 6, No. 3, 2004

conjugate addition of the thiolate to a second equivalent of
electrophile are observed in the addition to enals. However,
under the S-benzylation conditions, these revert through a
â-elimination process to give the desired final products.
Although the reaction does not proceed with aliphatic
aldehydes, the R,â-unsaturated aldehydes can provide access
to these substrates through hydrogenation. Examination also
showed that the reaction extends to enolates beyond the
simple ethyl/methyl substitution pattern (entries 7 and 8).9
The syn/anti stereochemistry of the condensation products
was initially determined by cleavage of the amide using
lithium amidoborohydride10,11 and formation of an acetonide
from the resulting diol followed by NOE studies. Subse-
quently, an X-ray crystal structure was obtained of product
5a (Figure 1). This confirmed the assignment of the major
chairlike transition state. In considering possible transition-
state assemblies, we note that there is evidence for loss of
conjugation of the nitrogen lone pair with the π-system in
amide enolates.13 Furthermore, a twisted geometry would
minimize potential A1,3 strain between the nitrogen substit-
uents and the groups at the R-positions on the enolate. If
one considers envelope conformations of the pyrrolidine ring,
two possible transition-state assemblies, shown in Figure 1,
can be considered. In both of these structures, the enolate is
held in a pseudoequatorial position to minimize steric
interactions of the enolate with the pyrrolidine ring. Transi-
tion state 7a is favored over 7b, as the latter would have
significant syn pentane interactions between the enolate
oxygen and the pseudoaxial thioethylene chain.
Figure 2. Potential transition state assemblies.
In conclusion, we have developed a diastereoselective
method for the formation of quaternary carbon centers via
an aldol process. The stereoselectivity of the reaction is con-
trolled by a relatively rare lithium to boron transmetalation
and provides excellent syn stereoselectivity as well as high
diastereofacial selectivity.
Figure 1. X-ray crystal structure of 5a.
stereoisomer as the syn isomer and also showed that the
absolute stereochemistry at the aldol was that depicted in
structure 5a. Although an acyclic transition state cannot be
ruled out,12 the syn stereochemistry is consistent with a
Acknowledgment. The authors thank NSERC and Merck
Frosst, Inc., for funding of this research. E.D.B. thanks
NSERC and the Walter Sumner Foundation for postgraduate
fellowships.
(9) The corresponding anti aldol products could not be produced with
high selectivity. Similar low selectivity was observed in the alkylations of
(E)-enolates using this auxiliary system (ref 3).
(10) (a) Myers, A. G.; Yang, B. H.; Kopecky, D. J.; Tetrahedron Lett.
1996, 37, 3623. (b) Myers, A. G.; Yang, B. H.; Chen. H.; Kopecky, D. J.
Synlett 1997, 5, 457.
Supporting Information Available: Experimental pro-
cedures, characterization data for all new compounds, and
X-ray crystallographic data for structure 5a. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) Due to complications from retro-aldol processes, this reduction only
works on the free (unbenzylated) thiols. These intermediates are easily
isolated directly from the aldol reaction mixture.
(12) The pendant thioethylene chain presumably complexes to 1 equiv
of the boron reagent, thus creating the possibility of an internal Lewis acid-
directed aldol. For examples of external Lewis acids in boron aldols, see:
(a) Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 1990, 55,
OL0364428
173. (b) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747.
(13) (a) Kim, Y.-J.; Streitwieser, A.; Chow, A.; Fraenkel, G. Org. Lett.
1999, 1, 2069. (b) Pugh, J. K.; Streitwieser, A. J. Org. Chem. 2001, 66,
1334.
Org. Lett., Vol. 6, No. 3, 2004
407