Enolization of chiral α-silyloxy ketones with dicyclohexylchloroborane. Application to stereoselective aldol reactions

Article abstract of DOI:10.1021/ol006109t

(equation presented) A. i. Chx₂BCl, Et₃N, Et₂O, -78 °C. ii. RCHO B. i. Chx₂BCl, EtMe₂N, pentane, rt. ii. RCHO Comprehensive analysis of the enolization of α-silyloxyketones by Chx₂BCl/R

Full text of DOI:10.1021/ol006109t

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2599-2602
Enolization of Chiral r-Silyloxy Ketones
with Dicyclohexylchloroborane.
Application to Stereoselective Aldol
Reactions
,†
Marta Galobardes, Miguel Gasco´n, Marisa Mena, Pedro Romea,* Fe`lix Urp´ı,* and
Jaume Vilarrasa
Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona, 08028 Barcelona,
Catalonia, Spain
promea@qo.ub.es
Received May 26, 2000
ABSTRACT
Comprehensive analysis of the enolization of r-silyloxyketones by Chx2BCl/R N has allowed us to design stereoselective Chx2BCl-mediated
3
aldol processes that afford syn or anti aldol products and to disclose a hypothesis that accounts for the subtle effects that determine their
enolization.
Enolates constitute the main source of reagents to gain access
to R-substituted carbonyl compounds and have therefore
become useful intermediates for the synthesis of complex
molecules. Provided that the geometry of an enolate deter-
mines the stereochemical outcome of the reactions it takes
part in, the selective formation of enolates represents a key
step in many bond-forming processes.1 Despite the efforts
focused on the development of versatile and highly stereo-
selective enolization methodologies, reliable procedures
leading to ketone-derived E-enolates proved to be elusive
until Brown et al. reported the use of dicyclohexylchloro-
borane, Chx2BCl.2,3 To the best of our knowledge, this bias
has only been inverted when chelating groups (namely, OR
ethers) are positioned R to the carbonyl.4 The purpose of
this letter is to report our findings on the enolization of
R-silyloxy ketones and to disclose a hypothesis that accounts
for the subtle influences that determine the stereoselective
enolization of ketones by the aforementioned Lewis acid.
Our ongoing efforts directed toward the development of
stereoselective processes based on R-chiral ketones5 led us
† furpi@qo.ub.es.
(1) See, for instance: (a) Mekelburger, H. B.; Wilcox, C. S. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol 2, p 99. (b) Heathcock, C. H. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol 2, p 133 and 181. (c) Kim, B. M.; Williams, S. F.; Masamune,
S. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol 2, p 239. (d) Rathke, M. W.; Weipert,
P. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol 2, p 277. (e) Paterson, I. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol 2, p 301. (f) Caine, D. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol 3, p 1. (g) Norin, T. Houben-Weyl. Methods of Organic Chemistry.
StereoselectiVe Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1995; Vol E21a, p
697. (h) Braun, M. Houben-Weyl. Methods of Organic Chemistry. Stereo-
selectiVe Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann,
E., Eds.; Georg Thieme Verlag: Stuttgart, 1995; Vol E21b, p 603.
(2) (a) Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.;
Singaram, B. J. Am. Chem. Soc. 1989, 111, 3441. (b) Brown, H. C.; Dhar,
R. K.; Ganesan, K.; Singaram, B. J. Org. Chem. 1992, 57, 499. (c) Brown,
H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B. J. Org. Chem. 1992, 57,
2716. (d) Ganesan, K.; Brown, H. C. J. Org. Chem. 1993, 58, 7162.
(3) Cowden, C. J.; Paterson, I. In Organic Reactions; Paquette, L., Ed.;
John Wiley & Sons: New York, 1997; Vol. 51, p 1.
(4) (a) Paterson, I.; Wallace, D. J.; Vela´zquez, S. M. Tetrahedron Lett.
1994, 35, 9083. (b) Carda, M.; Murga, J.; Falomir, E.; Gonza´lez, F.; Marco,
J. A. Tetrahedron 2000, 56, 677 and references therein.
(5) (a) Figueras, S.; Mart´ın, R.; Romea, P.; Urp´ı, F.; Vilarrasa, J.
Tetrahedron Lett. 1997, 38, 1637. (b) Esteve, C.; Ferrero´, M.; Romea, P.;
Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 1999, 40, 5079 and 5083.
10.1021/ol006109t CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/28/2000

to study the Chx2BCl-mediated aldol reactions of R-OSiR3
ketones 1-4 (see Scheme 1).6 Given the poor chelating
Highly stereoselective aldol reactions were also achieved with
crotonaldehyde (b), isovaleraldehyde (c), and isobutyralde-
hyde (d) as shown in entries 1-4 of Table 1.
Scheme 1
Table 1. Aldol Reactions of Ketones 2 and 4
aldehyde
(R)
yielda
(%)
entry ketone method
dr 5:6 dr 7:8:9
1
2
3
4
5
6
7
8
9
2
2
2
2
2
4
4
4
4
4
A
A
A
A
B
B
B
B
B
A
a (Ph)
99:1b
90
82
92
76
61 (28)
b (MeCHdCH) 98:2c
c (iBu)
d (iPr)
d (iPr)
a (Ph)
b (MeCHdCH)
c (iBu)
d (iPr)
98:2c
98:2c
35:65c
abilities of OSiR3 groups,7 the anti stereoisomer was expected
to be the major aldol product. Unexpectedly, ketones 1-3
afforded essentially pure syn-aldol, whereas a mixture of syn/
anti was obtained in the case of 4 in preliminary experiments,
when enolization was carried out with Et3N in Et2O at -78
°C.8
As syn (anti) aldol products are supposed to evolve from
Z (E) enolborinates through a cyclic chairlike transition state,
it was decided to study the enolization step to gain insight
into these puzzling results. Therefore, the effect of solvent,
amine, temperature, and other variables on stereoselectivity
of Chx2BCl-mediated aldol reactions of 2 and 4 was
evaluated.
First of all, the study of aldol reactions of 2 with
benzaldehyde (a) was addressed. Nonpolar solvents (e.g.,
pentane), higher temperatures, and less bulky amines (e.g.,
EtMe2N) eroded the stereoselectivity, but the 2,4-syn-4,5-
syn stereoisomer, 5a, was always the major component of
the mixtures, contaminated by variable amounts of the 2,4-
syn-4,5-anti one, 6a (see Scheme 2). Optimization of this
12:78:10b 78 (20)
9:83:7b 87 (10)
5:85:10c 83 (15)
4:88:8b 78 (17)
70:30:-c 36 (57)
10
d (iPr)
a Isolated yield. In brackets, recovered ketone. b Diastereomeric ratio by
1
HPLC. c Diastereomeric ratio by H NMR.
Second, the study of aldol reactions of 4 was performed
using isobutyraldehyde. In this case, optimum conditions
previously achieved (method A) afforded a mixture (70:30)
of 2,4-syn-4,5-syn, 7d, and 2,4-syn-4,5-anti, 8d, aldol ste-
reosiomers (see entry 10 in Table 1). However, dramatic
changes in the composition of the crude mixtures were
observed when less polar solvents (e.g., pentane), a less bulky
amine (e.g., EtMe2N), higher temperatures, and lower
concentration (e.g., 0.05 M) were employed. Then, the anti
(8) Brown et al. suggested (see ref 2d) that E-enolborinates are highly
favored by the use of moderately sterically hindered amines, nonpolar
solvents, and low temperatures.
(9) Method A (syn aldol). To a cooled (-78 °C) solution of Chx2BCl
(0.26 mL, 1.2 mmol) in Et2O (3 mL) was added dropwise Et3N (0.21 mL,
1.5 mmol) followed by 2 (216 mg, 1 mmol) in Et2O (2 mL). The reaction
mixture was stirred for 2 h at -78 °C, and the aldehyde (1.5 mmol) was
added. The resulting solution was further stirred at -78 °C for 3 h and
kept at -20 °C overnight. The mixture was partitioned between a pH 7
buffer (20 mL) and Et2O (3 × 20 mL). The combined extracts were dried
(MgSO4) and concentrated in vacuo. The resulting oil was diluted in MeOH
(5 mL), a pH 7 buffer (1 mL), and H2O2 30% (2 mL) at 0 °C; warmed to
room temperature; and stirred for 2 h. It was partitioned between H2O (20
mL) and CH2Cl2 (3 × 20 mL). The combined extracts were washed with
saturated NaHCO3 (15 mL) and brine (15 mL), dried (Na2SO4), and
concentrated in vacuo. Isolation of the aldol product was achieved by column
chromatography, and diastereomeric ratios were determined by 1H NMR
analysis and/or HPLC. The yields and diastereomeric ratios for 5 and 6 are
given in Table 1.
Scheme 2
(10) This isomer has not been isolated. Its stereochemistry has been
assigned on the basis of NMR analysis.
a See ref 9. b See ref 11.
(11) Method B (anti aldol). To a cooled (0 °C) solution of 4 (340 mg,
1 mmol) in pentane (20 mL) was added dropwise Chx2BCl (0.24 mL, 1.1
mmol) and EtMe2N (0.22 mL, 2 mmol). The resulting white suspension
was stirred at 0 °C for 10 min and at room temperature overnight before
cooling at -78 °C. The aldehyde (1.5 mmol) was added, and the mixture
was stirred for 3 h and kept at -20 °C for 2 h. The mixture was partitioned
between a pH 7 buffer (20 mL) and Et2O (3 × 20 mL). The combined
extracts were dried (MgSO4) and concentrated in vacuo. The resulting oil
was diluted in MeOH (2 mL), a pH 7 buffer (4 mL), and H2O2 30% (2
mL) at 0 °C; warmed to room temperature, and stirred for 1 h. It was
partitioned between H2O (20 mL) and CH2Cl2 (3 × 20 mL). The combined
extracts were washed with saturated NaHCO3 (25 mL) and brine (25 mL),
dried (Na2SO4), and concentrated in vacuo. Isolation of the aldol products
was achieved by column chromatography (pure samples of major diaster-
eomers were obtained by MPLC), and diastereomeric ratios were determined
by 1H NMR analysis and/or HPLC. The yields and diastereomeric ratios
for 7-9 are given in Table 1.
reaction led to essentially pure 5a (dr 99:1 by HPLC) in 90%
yield when enolization (method A)9 was carried out in Et2O
(0.2 M, -78 °C, 2 h) with Chx2BCl/Et3N (1.2/1.5 equiv).
(6) (a) Mart´ın, R.; Pascual, O.; Romea, P.; Rovira, R.; Urp´ı, F.; Vilarrasa,
J. Tetrahedron Lett. 1997, 38, 1633. (b) Mart´ın, R.; Romea, P.; Tey, C.;
Urp´ı, F.; Vilarrasa, J. Synlett 1997, 1414.
(7) See, for instance: (a) Reetz, M. T.; Hu¨llmann, M. J. Chem. Soc.,
Chem. Commun. 1986, 1600. (b) Kahn, S. D.; Keck, G. E.; Hehre, W. J.
Tetrahedron Lett. 1987, 28, 279. (c) Shambayati, S.; Blake, J. F.; Wierschke,
S. G.; Jorgensen, W. L.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112,
697.
2600
Org. Lett., Vol. 2, No. 17, 2000

aldol, 8d, became the major component of the mixtures,
contaminated by the syn, 7d, and a third one, 9d, whose
stereochemistry was assumed as 2,4-anti-4,5-anti10 (dr 7d:
8d:9d 4:88:8 by HPLC in an overall 78% yield). The
aforementioned enolization conditions (method B)11 also gave
similar diastereoselectivities with other aldehydes (see
Scheme 2 and entries 6-9 in Table 1).
The broad spectrum of factors (temperature, base, con-
centration, and solvent) that determine the geometry of the
enolborinates hints that the above enolization is a complex
process that depends on subtle influences rooted on thermo-
dynamic and kinetic grounds.
Goodman and Paterson12 have pointed that the geometry
of the initially formed CdO‚BL2Cl complexes (cis or trans
in Scheme 3) conditions the subsequent deprotonation step.
carbonyl-Lewis acid complex and its subsequent deproton-
ation. Provided that several complexes (see I-IV in Scheme
4) are accessible, some issues should be addressed: (i) Which
one is more stable? (ii) Which one is more reactive? (iii)
Which step determines the geometry of the enolborinate?
Assuming that E (Z) enolborinates arise from cis (trans)
complexes, it may be envisioned that stereoelectronic effects
in the initially formed complexes I-IV influence the
subsequent deprotonation step: E-enolborinates would only
arise from cis complexes if a C-H bond may be positioned
antiperiplanar to the CdOB bond (see IV in Scheme 4) to
minimize allylic (1,3) strain13 in a putative late transition
state. If this condition is not easily reached, Z-enolborinates
would be obtained instead, through a chelated or acyclic
complex (see I and II in Scheme 4) irrespective of their
relative stability.
Conformational analysis of R-substituted carbonyls sug-
gests that electrostatic interactions between the C-OB and
the CR-O dipoles make antiperiplanar arrangements II and
III the most stable ones.14,15 Low temperatures must then
stress this trend with syn-syn aldols mainly obtained through
complex II because A(1,3) in the corresponding transition
state is minimized compared to those from III (compare
entries 4-5 and 9-10 in Table 1). Therefore, conformational
issues would play a crucial role in rationalizing the observed
behavior under enolization conditions A. Alternatively,
collusion of high temperatures, an extremely unhindered
amine (EtMe2N), and low concentrations16 may overcome
this bias and produce E-enolborinates from IV; thus, the
major anti aldol stereoisomer might arise from cis com-
plex IV through a cyclic chairlike transition state17
shown in Scheme 4. Relative stability of complexes I-IV
would then justify the trend observed under enolization
conditions B.
Scheme 3
On the basis of electronic and steric preferences, cis
coordination of Chx2BCl to the carbonyl would enhance the
acidity of the R-CH2 and allow unhindered bases to kineti-
cally deprotonate the corresponding complex leading to the
E-enolborinate, whereas the Z-enolborinate would arise from
the less favored trans complex (see Scheme 3).
Exceptions previously reported, namely, R-OR ketones,
might be accommodated to this model assuming that a
chelated complex (see I in Scheme 4) plays a crucial role in
the enolization step. Nevertheless, the intrinsic bias to afford
the corresponding Z-enolborinates observed in the case of
1-4 and the low chelating ability of groups such as OSiR3
suggest that mechanisms other than chelation must cooperate
on their enolization.
Although the proposed model allows accommodation of
the results obtained in the case of R-OSi ketones, it is evident
that it does not account for the quantitative differences
observed for TBS (ketone 2) and TBDPS (ketone 4)
protecting groups (compare entries 4-10 and 5-9). At this
point, it is still unclear the role of the steric size and the
electronic properties of the silicon protecting groups on the
reaction pathway.
It might be argued that the E/Z ratio stems from the balance
of two independent but related steps: formation of the
Scheme 4
Org. Lett., Vol. 2, No. 17, 2000
2601

Further studies addressed to analyze the effect of the
solvent, the concentration, and the differences observed for
TBS and TBDPS groups are in progress and will be reported
in due course.
de Catalunya (1996SGR00102 and 1998SGR00040), and
from the Universitat de Barcelona for a doctorate studentship
to M. Galobardes is gratefully acknowledged.
Supporting Information Available: Spectroscopic data
for compounds 5 and 8. Stereochemical proof of aldol
diastereomers 5a and 8d. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Dr. Ian Paterson for kind
and fruitful discussions. Financial support from the DGICYT,
Ministerio de Educacion y Cultura (PM95-0061 and PB98-
1272), from the Direccio´ General de Recerca, Generalitat
OL006109T
(16) Brown et al. pointed out (see ref 2d) that formation of Chx-derived
E-enolborinates is favored in dilute medium. In preliminary experiments,
we have found that the enolization of 4 in pentane at 0 °C affords a mixture
of syn/anti aldols whose composition depends on the concentration (19:81
at 0.25 M; 8:92 at 0.05 M). This trend suggests that acid-base (Chx2-
BCl-EtMe2N) coordination might play a secondary role in the mechanism
shown in Scheme 4 in the sense of producing new reacting species, as
[Chx2B-NEtMe2]+, whose behavior would be closer to R2BOTf. Therefore,
polar solvents and higher concentrations might favor the formation of
Z-enolborinates through an alternative pathway.
(17) Theoretical calculations of transition states associated to E-enol-
borinates support the preference of the CR-H bond to eclipse the enolborinate
double bond to minimize the allylic strain. See: (a) Vulpetti, A.; Bernardi,
A.; Gennari, C.; Goodman, J. M.; Paterson, I. Tetrahedron 1993, 49, 685.
(b) Bernardi, A.; Gennari, C.; Goodman, J. M.; Paterson, I. Tetrahedron:
Asymmetry 1995, 6, 2613.
(12) (a) Goodman, J. M. Tetrahedron Lett. 1992, 33, 7219. (b) Goodman,
J. M.; Paterson, I. Tetrahedron Lett. 1992, 33, 7223.
(13) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(14) Frenking and Reetz have postulated that conformational effects are
responsible for a significant portion of the energy difference between
competing transition states involved in 1,2-stereoinduction: Frenking, G.;
Ko¨hler, K. F.; Reetz, M. T. Tetrahedron 1991, 47, 8991; Tetrahedron 1993,
49, 3971. See also: Lecea, B.; Arrieta, A.; Coss´ıo, F. P. J. Org. Chem.
1997, 62, 6485.
(15) Dipolar interactions have also been invoked to rationalize the 1,3-
asymmetric induction observed in the Mukaiyama aldol addition of enol
silyl ethers to â-substituted aldehydes. See, for instance: (a) Evans, D. A.;
Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322.
(b) Bonini, C.; Esposito, V.; D’Auria, M.; Righi, G. Tetrahedron 1997, 53,
13419.
2602
Org. Lett., Vol. 2, No. 17, 2000