Enantioselective enolborination [15]

Full text of DOI:10.1021/ja973686c

1098
J. Am. Chem. Soc. 1998, 120, 1098-1099
nation). Enantioselective deprotonation of achiral Cs symmetric
Enantioselective Enolborination
cyclic ketones by chiral lithium amide bases to form chiral lithium
enolates has developed into a powerful tactic for asymmetric
synthesis and several applications to natural product synthesis
have appeared.9 Although kinetic resolutions of racemic ketones
by enantioselective deprotonation have been demonstrated,10 the
process in not particularly well suited to this application and
various limitations are expected with meso bifunctional substrates
(i.e. diketones).11 Specifically, poor enantiotopic group selectivity
is likely to result3,4 in cases where deprotonation occurs with only
modest levels of substrate-controlled regio- and/or stereoselec-
tivity.12 In searching for alternative methods to achieve enanti-
oselective enolization, we considered enolborination.
Dale E. Ward* and Wan-Li Lu
Department of Chemistry, UniVersity of Saskatchewan
110 Science Place, Saskatoon SK S7N 5C9, Canada
ReceiVed October 23, 1997
The development of new strategies and methodologies for
asymmetric synthesis continues to attract considerable attention.1
Although the majority of known methods involve transformation
of an achiral substrate by enantioselective addition to a π-bond
(i.e., an enantiotopic face selective reaction), the use of enan-
tiotopic group selective reactions to effect desymmetrization of
achiral Cs (or Ci) symmetric substrates or kinetic resolution of
chiral substrates has recently emerged as a powerful strategy for
asymmetric synthesis.2 Few design elements are available to
guide the development of new nonenzymatic enantiotopic group
selective reactions, and many of the successful examples2 involve
application of previously established “reagent-controlled” enan-
tioface selective reactions to chiral or Cs symmetric substrates
that impart significant “substrate-controlled” selectivity.3,4 In this
paper, we report the use of “double stereodifferentiation”5 to
achieve highly enantioselective enolborination of both chiral and
Cs symmetric ketones by reaction with chlorobis(isopinocam-
pheyl)borane (1) (Ipc2BCl or DIP-Chloride)6 in the presence of a
chiral diamine.
Despite the widespread use of boron enolates for stereoselective
synthesis,13 to the best of our knowledge, enantioselective
enolborination has not previously been reported. Indeed, in an
early example Paterson et al.14 inferred that the enantiotopic group
selectivity (E) of enolborination of a racemic ketone with
enantiopure Ipc2BCl was less than ca. 2:1. To further investigate
the potential of this process, we examined the enantioselectivity
of enolborination of 4-tert-butylcyclohexanone (5) with Ipc2BCl
(1) under a variety of conditions (Scheme 1). Reaction of 5 with
(-)-1 (1.5 equiv) in the presence of Et3N (1.5 equiv) at -78 °C
in pentane gave 7 in 85% yield with modest selectivity (7a:7b )
1.7:1).15,16 The selectivity was relatively insensitive (1.4-1.7:1)
to changes in solvent (toluene, THF, CH2Cl2, ether), concentration
(0.02-0.2 M), or order of addition of the reagents, but was
modulated by temperature (1.1:1, 0 °C; 2.6:1, -131 °C) and the
i
i
nature of the tertiary amine used (1.1-2.0:1; Pr2EtN, Pr2MeN,
iPrMe2N, EtMe2N, Pr3N, TMEDA).17 Similarly, poor enantiose-
lectivity was observed for enolborination of 5 with (-)-Ipc2BBr
(1.5:1) or with 218 (1.1:1).
The diastereoselectivity of face selectiVe reactions can often
be enhanced by exploiting the strategy of “double stereodiffer-
entiation”.5 In principle, the enantioselectivity of group selectiVe
We have been interested in processes for desymmetrization of
Cs (or Ci) symmetric bifunctional substrates where enantiotopic
groups can react sequentially.7 In these cases, it becomes possible
to obtain products with very high stereoisomeric purity from
reactions with modest enantioselectivity4 or even from mixtures
of substrate stereoisomers.8 Both the efficiency and efficacy of
these processes are improved with recycling, especially if the
enantioselectivity is not outstanding.4,8 Because recycling requires
that the product(s) (or byproducts) be efficiently converted back
into the starting material(s), enantiotopic group selective reactions
that are easily “reversed” are desirable.4,8 Ketone enolization is
an ideal reaction for application in these processes because it is
both synthetically useful and easily “reversible” (e.g., by proto-
(9) For a review, see: (a) Cox, P. J.; Simpkins, N. S. Tetrahedron:
Asymmetry 1991, 2, 1-26. Also see ref 2b. (b) For a comprehensive list of
references, see: Aoki, K.; Tomioka, K.; Noguchi, H.; Koga, K. Tetrahedron
1997, 53, 13641-13656.
(10) (a) Kim, H. D.; Kawasaki, H.; Nakajima, M.; Koga, K. Tetrahedron
Lett. 1989, 30, 6537-6540. (b) Bambridge, K.; Simpkins, N. S. Tetrahedron
Lett. 1992, 33, 8141-8144. (c) Bambridge, K.; Clark, B. P.; Simpkins, N. S.
J. Chem. Soc., Perkin Trans. 1 1995, 2535-2541.
(11) For example: the requirement of inverse addition at low temperature;
difficulty in controlling reaction conversion; potential for stereochemical
“leakage” by inter- or intramolecular proton transfer between ketone and
enolate.
(12) For example, the enantioselective deprotonation mediated kinetic
resolution of 2-methylcyclohexanone10a is far more selective than that of
3-methylcyclohexanone10c because of poor substrate-controlled regioselectivity
for the latter. Modest stereoselectivity in deprotonation of acyclic ketones
would similarly limit group selective applications.
(1) Houben-Weyl, StereoselectiVe Synthesis; Helmchen, G., Hoffmann, R.
W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1996.
(2) For reviews, see: (a) Ward, R. S. Chem. Soc. ReV. 1990, 19, 1-19.
(b) Gais, H.-J. In Houben-Weyl, StereoselectiVe Synthesis; Helmchen, G.,
Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1996;
Vol. 1, pp 589-644.
(13) For a review, see: Cowden, C. J.; Paterson, I. Org. React. 1997, 51,
1-200.
(14) Paterson, I.; McClure, C. K.; Schumann, R. C. Tetrahedron Lett. 1989,
30, 1293-1296.
(3) Heathcock, C. H.; Pirrung, M. C.; Lampe, L.; Buse, C. T.; Young, S.
D. J. Org. Chem. 1981, 46, 2290-2300.
(15) Selectivities and yields were measured by oxidation (i. O3; ii. H2-
(4) Enantiotopic group selectivity (E) can be estimated from the following
equation (r ) reagent-controlled selectivity; s ) substrate-controlled selectiv-
ity): E ) ((r)(s) + 1)/(r + s). For a discussion, see: Ward, D. E.; Liu, Y.;
Rhee, C. K. Can. J. Chem. 1994, 72, 1429-1446.
CrO4) of the enolborinates to the known diacids (9,16a,b 10,16c 15,16d and 1816e
)
whose ee values were determined by 1H NMR in the presence of (R)-1-
phenylethylamine (for 9 and 15) or (R)-1-(1-naphthyl)ethylamine (for 10 and
18). The absolute configurations of the major enantiomers of 9, 10, and 18
were determined by optical rotation and that for 15 was assigned by analogy
to the selectivity observed for 9, 10, and 18.
(5) (a) Masamune, S.; Choy, W.; Pedersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1-76. (b) Nakayama, K. J. Chem. Educ. 1990, 67,
20-23. (c) Roush, W. R.; Hoong, L. H.; Palmer, M. A. J.; Straub, J. A.;
Palkowitz, A. D. J. Org. Chem. 1990, 55, 4117-4126.
(16) (a) Tichy, M.; Malon, P.; Fric, I.; Blaha, K. Collect. Czech. Chem.
Commun. 1977, 42, 3591-3604. (b) Cain, C. M.; Cousins, R. P. C.;
Coumbarides, G.; Simpkins, N. S. Tetrahedron 1990, 46, 523-544. (c) Shirai,
R.; Tanaka, M.; Koga, K. J. Am. Chem. Soc. 1986, 108, 543-545. (d) Bassi,
L.; Joos, B.; Gassmann, P.; Kaiser, H. P.; Leuenberger, H.; Kellerschierlein,
W. HelV. Chim. Acta 1983, 66, 92-117. (e) Wong, C. H.; Auer, E.; LaLonde,
R. T. J. Org. Chem. 1970, 35, 517-519.
(17) (a) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem.
Soc. 1981, 103, 3099-3111. (b) Ganesan, K.; Brown, H. C. J. Org. Chem.
1993, 58, 7162-7169.
(18) Corey, E. J.; Yu, C. M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111,
5495-5496.
(6) For a review on uses of Ipc2BCl, see: Dhar, R. K. Aldrichimica Acta
1994, 27, 43-51.
(7) (a) Wang, Y.-F.; Chen, C.-S.; Girdaukaus, G.; Sih, C. J. J. Am. Chem.
Soc. 1984, 106, 3695-3696. (b) Dokuzokic, Z.; Roberts, N. K.; Sawyer, J.
F.; Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1986, 108, 2034-2039. (c)
Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987, 109,
1525-1529.
(8) (a) Ward, D. E.; How, D.; Liu, Y. J. Am. Chem. Soc. 1997, 100, 1884-
1894. (b) Ward, D. E.; Liu, Y.; How, D. J. Am. Chem. Soc. 1996, 118, 3025-
3026.
S0002-7863(97)03686-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/27/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 5, 1998 1099
Scheme 1
nations of 4-methylcyclohexanone (9) and cis-3,5-dimethylcyclo-
hexanone (13) with Ipc2BCl and 3 or 4 also proceeded with
excellent selectivities (Table 1).15 In addition to oxidation, the
product enolborinates undergo the expected transformations. For
example, reaction of 7b (89% de)22 with PhSeCl followed by
oxidation gave 11 (51% yield, 89% enantiomeric excess (ee));23
alternatively, reaction with acetaldehyde gave the aldol 12 (56%,
90% ee).24,25
To assess the potential of this process for kinetic resolution,
enantioselective enolborinations of (()-16 and of (()-19 with
(-)-1 and (+)-3 or 4 were examined (Table 1). The reactions
were run to low conversions so that the product ratios would
closely approximate the relative reactivity of the substrate
enantiomers. Enolborinations of (()-16 were completely regi-
oselective and occurred with excellent enantiomer selectivity in
favor of the (2R)-isomer. Similar reactions of (()-19 were highly
regioselective and gave preferential enolborination of the (3S)-
isomer. For example, reaction of excess (()-19 with (-)-1 and
4 at -78 °C followed by oxidation gave an ca. 50:1 mixture of
diacids (3S)-10 (90% ee)15 and 18 (ee not determined) in 15%
combined yield consistent with an enantiotopic group selectivity
of at least 13:1 in favor of enolborination of (3S)-19.26 Outstand-
ing selectivity was observed at -131 °C. These results are
particularly significant as the kinetic resolution of 19 by enanti-
oselective deprotonation proceeds poorly.10c The difference in
group selectivity between the two methods is undoubtedly due
to the much higher substrate-controlled4 regioselectivity of
enolization of 19 with boron halides (>30:1 with chlorodicyclo-
hexylborane (Chx2BCl))27 compared to lithium amides (3:1 with
lithium diisopropylamide).10c
In conclusion, we have demonstrated highly enantioselective
enolborination of both achiral and chiral substituted cyclohex-
anones. The method relies on double stereodifferentiation5 to
achieve efficient group selectivity. There is considerable potential
to improve the enantioselectivity by screening various available
or designed amines and boron reagents. The current methodology
complements the previously developed enolizations using chiral
lithium amides9 and gives comparable selectivities. Considering
the already established utility of boron enolates in stereoselective
synthesis,13 enantioselective enolborination should develop into
a powerful tool for asymmetric synthesis.
Table 1. Selectivity of Enolborination of Cyclohexanonesa
selectivityb (yieldb, rxn time)
ketone amine R2BCl
Et3Nd (-)-1d
at -78 °C
at -131 °Cc
7a:7b
5
1.7:1 (85%, 4 h)
2.6:1 (75%, 6 h)
(-)-3 Chx2BCl 1:2.4 (60%, 6 h)
(-)-1
(+)-1
1:2.8 (40%, 6 h)
1:4 (55%, 6 h)
1:16 (75%, 24 h)
19:1 (80%, 10 h)
4
Chx2BCl 2.8:1 (80%, 6 h)
(-)-1
(+)-1
5:1 (80%, 6 h)
2:1 (65%, 6 h)
8a:8b
6
(+)-3 (-)-1
(-)-1
9:1 (80%, 10 h)
17:1 (80%, 4 h)
23:1 (80%, 15 h)
26:1 (80%, 10 h)
14a:14b
4
13
(+)-3 (-)-1
(-)-1
3:1 (60%, 10 h)
12:1 (75%, 10 h)
8:1 (60%, 10 h)
23:1 (65%, 10 h)
17a:17b
4
(()-16e (+)-3 (-)-1
(-)-1
15:1 (15%, 4 h)
>30:1 (15%, 4 h)
>30:1 (15%, 6 h)
>30:1 (15%, 4 h)
Acknowledgment. Financial support from the Natural Sciences and
Engineering Research Council (Canada) and the University of Saskatchewan
is gratefully acknowledged.
4
(S)-20:(R)-20:21
(()-19e (+)-3 (-)-1
(-)-1
89:11:4.5 (15%, 4 h) >97:3:4.5 (15%, 6 h)
95:5:2 (15%, 4 h) >97:3:<2 (15%, 4 h)
4
Supporting Information Available: Experimental procedures (8
pages). See any current masthead page for ordering information and Web
access information.
a Reaction in pentane (4 and Et3N) or 2:1 ether pentane (3) (0.06 M
in ketone), R2BCl (2 equiv), diamine (1 equiv). b See footnote 15.
c Pentane/N2(l) slush bath. d 1.5 equivalents. e 0.30 M in ketone, 0.4 equiv
of boron reagent and 0.2 equiv of diamine.
JA973686C
(21) That is, given the enolborination selectivities attributable solely to 1
(i.e., the selectivity with Et3N) and to the chiral amine (i.e., the selectivity
with Chx2BCl), under double stereodifferentiation, the matched selectivity is
approximated by the product of those selectivities and the mismatched
selectivity by their ratio.5
(22) Prepared by reaction of 5 with (+)-1 and (-)-3 at -131 °C for 24 h.
NMR analysis of the derived diacid 9 (75% yield) indicated a 16:1 mixture
of enantiomers.
reactions should be modulated by the same effect; however, there
are few literature precedents for such applications.19 We screened
a number of enantiopure tertiary amines in an effort to improve
the enantioselectivity of enolborination of 5. The monoamines
tested20 had only a modest effect on the selectivity of enolbori-
nation of 5 (i.e., 7a:7b <2.6:1); better results were obtained with
the diamines 3 and sparteine (4) (Table 1). The selectivity
observed under conditions of “double stereodifferentiation”
roughly followed the multiplicativity rule21 for most of the amines.
The selectivity of enolborination of 5 with Ipc2BCl and 3 or 4
was particularly sensitive to temperature and reached 89%
diastereomeric excess (de) at -131 °C. Enantioselective enolbori-
(23) The ee was determined by optical rotation: Aoki, K.; Nakajima, M.;
Tomioka, K.; Koga, K. Chem. Pharm. Bull. 1993, 41, 994-996.
(24) Other diastereomers were not detected; however, the diol resulting
from in situ reduction of the ketone in 12 was isolated (15%). Reaction with
C6H5CHO, ChxCHO, or tBuCHO gave diol products nearly exclusively. For
intramolecular reduction of the intermediate 3-oxoalkyl diisopinocampheyl-
borinates, see: Ramachandran, P. V.; Lu, Z.-H.; Brown, H. C. Tetrahedron
Lett. 1997, 38, 761-764.
(25) The ee was determined by 1H NMR analysis of the derived Mosher’s
ester.
(19) For an example, see: (a) Lattanzi, A.; Bonadies, F.; Scettri, A.
Tetrahedron: Asymmetry 1997, 8, 2141-2151. (b) Lattanzi, A.; Bonadies,
F.; Senatore, A.; Soriente, A.; Scettri, A. Tetrahedron: Asymmetry 1997, 8,
2473-2478.
(20) (R)-N,N-Dimethyl-1-(1-naphthyl)ethylamine, (S)-N,N-dimethyl-1-(phe-
nyl)ethylamine, (2S,5S)-N,2,5-trimethylpyrrolidine, and (S,S)-N-methylbis[1-
(phenyl)ethyl]amine were examined.
(26) If 10 is 90% ee (S enantiomer) and if 18 is 100% ee (R enantiomer),
then at least 93% (i.e.13: 1) of the mixture of diacids is derived from (S)-19.
Assuming that r ) 20 and s ) 30,27 the group selectivity is predicted4 to be
12:1.
(27) Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B. J. Org. Chem.
1992, 57, 2716-2721.