Asymmetric aldol reaction with diisopinocampheyl enolborinates of propionates

Article abstract of DOI:10.1021/ol802850w

A convenient and general, reagent-controlled, diastereo-and enantioselective aldol reaction of diisopinocampheylboron enolates of esters, followed by reduction, has been developed as an alternative to crotylboration-ozonolysis. This protocol was then expl

Full text of DOI:10.1021/ol802850w

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1467-1470
Asymmetric Aldol Reaction with
Diisopinocampheyl Enolborinates of
Propionates
P. Veeraraghavan Ramachandran* and Debarshi Pratihar
Department of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
chandran@purdue.edu
Received December 10, 2008
ABSTRACT
A convenient and general, reagent-controlled, diastereo- and enantioselective aldol reaction of diisopinocampheylboron enolates of esters,
followed by reduction, has been developed as an alternative to crotylboration-ozonolysis. This protocol was then exploited for the double
diastereoselective synthesis of the C11-C17 subunit of (-)-dictyostatin.
Pinane-mediated asymmetric crotylboration1 and enolbora-
tion-aldolization2 are highly diastereo- and enantioselective
Scheme 1
carbon-carbon bond-forming reactions routinely employed
for the syntheses of complex molecules bearing ꢀ-methyl
hydroxyl units. Although repetitive crotylboration3 and
enolboration-aldolization of ketones2 and amides4 have been
exploited for polyketide syntheses, the potential application
of the enolboration-aldolization of esters remains relatively
unexplored. In continuation of our project on the total
synthesis of potent tubulin polymerizing anticancer agent
(-)-dictyostatin (Scheme 1),5 we were confronted with the
need for sufficient quantities of the subunits for a practical
(1) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(2) (a) Cowden, C. J.; Paterson, I. Organic Reactions; John Wiley &
Sons: New York, 1997; Vol. 51, pp 1-209. (b) Paterson, I.; Wallace, D. J.;
Velazquez, S. M. Tetrahedron Lett. 1994, 35, 9083. (c) Paterson, I.; Lister,
M. A. Tetrahedron Lett. 1988, 29, 585. (d) Evans, D. A.; Vogel, E.; Nelson,
J. V. J. Am. Chem. Soc. 1979, 101, 6120.
(3) For a review on crotylboration for synthesis, see: Ramachandran,
synthesis of its analogs and homologues. Our initial approach
using Brown’s “higher crotylboration”6 was inadequate
because of the cumbersome preparation of the expensive
starting allenes. Our ensuing investigations were channelled
P. V. Aldrichimica Acta 2002, 34, 23.
(4) (a) Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre,
D. J.; Bartoli, J. Pure Appl. Chem. 1981, 53, 1109. (b) Evans, D. A.; Bartroli,
J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127. (c) Oppolzer, W.; Blagg,
J.; Rodriguez, I.; Walther, E. J. Am. Chem. Soc. 1990, 112, 2767.
10.1021/ol802850w CCC: $40.75
Published on Web 03/05/2009
2009 American Chemical Society

toward a more efficient diisopinocampheylboron triflate
(Ipc2BOTf, 2)-mediated aldol reaction of esters.
tivity. The enolization of 1a with (-)-2 in the presence of
iPr2NEt at -78 °C for 4 h and aldolization of 4a at -78 °C
for 4 h achieved only a 3:2 mixture of syn- (major) and anti-
products (entry 1, Table 1). The ratio of the syn-product could
Very few reports on the boron-mediated aldol reaction of
esters have appeared in the literature since the description
of (E)-enolborinates of thioesters by Masamune three decades
ago.7 This could be attributed to the report of a failed attempt
to enolize methyl propionate using dibutylboron triflate.8
Successful B-bromodiazaborolidine and B-iododicyclohex-
ylborane-mediated aldol reaction of esters were later reported
by Corey9 and Brown,10 respectively.11 A decade ago
Masamune and Abiko amended the literature12 with the
dialkylboron triflate-mediated enolization of esters, followed
by aldolization of aldehydes, which led to a substrate-
controlled asymmetric aldol reaction of norephedrine-derived
ester enolates.12b-d They obtained either syn- or anti-R-
methyl-ꢀ-hydroxy esters, depending on the alkyl group on
boron.12d Herein, we report a convenient and general,
reagent-controlled, diastereo- and enantioselective aldol
reaction of diisopinocampheylboron enolates of esters (Scheme
2) and its application to the double diastereoselective
synthesis of the C11-C17 subunit of (-)-dictyostatin.
i
be increased to 6:1 by replacing Pr2NEt with Et3N, under
similar conditions. Subsequently, a change in the enolization
temperature to 0 °C for 5 h dramatically increased the syn-
diastereomer ratio to 97:3.
The optimal conditions were finally established by com-
mencing the enolate formation at -78 °C for 30 min and
then warming to 0 °C for 4 h, followed by aldolization at
-78 °C, when the hydroxy ester was obtained in 85% yields
with a 99:1 diastereoselectivity and 98:2 enantioselectivity.
Notably, the enolization temperature influences the diaste-
reoselectivity, whereas the aldolization conditions have little
or no effect.
Scheme 3
.
Effect of Ester Group on Stereo- and
Enantioselectivity
Scheme 2
Under these standardized conditions, we examined the
stereoselection by varying the alkyl group of the propionates
(1b-e) and identified methyl propionate (1a) as the ester of
choice for the preparation of syn-aldols. Although the
enantioselectivity remained high, a gradual decrease of syn-
diastereoselectivity was observed for ethyl, benzyl, and
isopropyl esters (1b-d). The enolization was very slow for
tert-butyl propionate (1e) (Scheme 3), and aldolization
provided the anti-aldol (9a) essentially exclusively in 50%
yields with 60% ee, much higher than typically observed
for the anti-aldols obtained with diisopinocampheyl boron
enolates of ketones.2a The reversal of diastereoselection is
similar to what has been noted earlier by Corey, Brown, and
Masamune.9-10,12 Remarkably, when Et3N was replaced with
iPr2NEt, the anti-selectivity increased from 1:4 to 95:5 for
1d and the exclusive anti-aldol product was achieved with
1e (Scheme 4).
With prior knowledge that the stereochemical course of
the ester-aldol reaction can be controlled by choosing
appropriate reagents and amines,13 the enolization of methyl
propionate (1a) with diisopinocampheylboron triflate (2),
prepared from diisopinocampheylborane and triflic acid,2a
and subsequent aldolization of cinnamaldehyde (4a)14 was
optimized to achieve maximum diastereo- and enantioselec-
(5) (a) Ramachandran, P. V.; Srivastava, A.; Hazra, D. Org. Lett. 2007,
9, 157. For other total syntheses of dictyostatin, see: (b) Paterson, I.; Britton,
R.; Delgado, O.; Meyer, A.; Poullennec, K. G. Angew. Chem., Int. Ed. 2004,
43, 4629. (c) Shin, Y.; Fournier, J.; Fukui, Y.; Bruckner, A. M.; Curran,
D. P. Angew. Chem., Int. Ed. 2004, 43, 4633. (d) O’Neil, G. W.; Phillips,
A. J. J. Am. Chem. Soc. 2006, 128, 5340.
(6) Brown, H. C.; Narla, G. Tetrahedron Lett. 1997, 38, 219.
(7) (a) Hirama, M.; Masamune, S. Tetrahedron Lett. 1979, 2225.
(8) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem.
Soc. 1981, 103, 3099.
These processes were then extended to a diverse set of
aldehydes. Under the optimized conditions for syn-aldols
(9) (a) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am.
Chem. Soc. 1989, 111, 5493. (b) Corey, E. J.; Kim, S. S. J. Am. Chem.
Soc. 1990, 112, 4976.
(10) (a) Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B. J. Org.
Chem. 1992, 57, 499. (b) Brown, H. C.; Dhar, R. K. J. Org. Chem. 1992,
57, 2716. (c) Ganesan, K.; Brown, H. C. J. Org. Chem. 1994, 59, 2336.
(11) Boron-mediated aldol reactions of glycolates have been reported.
(a) Andrus, M. B.; Sekhar, B. B. V. S.; Meredith, E. L.; Dalley, N. K. Org.
Lett. 2000, 2, 3035. (b) Lang, F.; Zewge, D.; Song, Z. J.; Biba, M.; Dormer,
P.; Tschaen, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 2003, 44,
5285.
(12) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Org. Chem. 1996, 61,
2590. (b) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997,
119, 2586. (c) Abiko, A.; Liu, J.-F.; Buske, D. C.; Moriyama, S.; Masamune,
S. J. Am. Chem. Soc. 1999, 121, 7168. (d) Inoue, T.; Liu, J.-F.; Buske,
D. C.; Abiko, A. J. Org. Chem. 2002, 67, 5250.
(13) Abiko, A.; Liu, J.-F. Acc. Chem. Res. 2004, 37, 387.
(14) Cinnamaldehyde (4a) was chosen because of the ease in the
chromatographic separation of the product aldol.
1468
Org. Lett., Vol. 11, No. 7, 2009

Table 1. Optimization of Conditions for syn-Aldol Reaction
enolization condition
entry
amine
temp
aldolization condition
yield (%)
syn:antia
erb
1
2
3
4
5
6
7
8
iPr2NEt
Et3N
Et3N
Et3N
Et3N
iPr2NEt
iPr2NEt
Et3N
-78 °C, 4 h
-78 °C, 4 h
-78 °C, 4 h
-78 °C, 4 h
-78 °C, 5 h
-78 °C, 5 h
-78 °C, 2 h; rt, 8 h
-78 °C, 8 h
-78 °C, 2 h; rt, 8 h
55
72
65
69
57
65
70
85
60:40
85:15
87:13
89:11
90:10
95:5
c
96:4
-78 °C, 2 h; 0 °C, 3 h
-78 °C, 2 h; 0 °C, 3 h
-78 °C, 1 h; 0 °C, 1 h
-78 °C, 0.5 h; 0 °C, 4 h
0 °C, 5 h
96.5:3.5
96.5:3.5
96.5:3.5
97:3
96.5:3.5
98:2
97:3
99:1
-78 °C, 0.5 h; 0 °C, 4 h
-78 °C, 8 h
a Determined from 1H NMR analysis of the crude reaction mixture. b Enantiomeric ratio determined by 19F NMR analysis of the Mosher ester derivative
of the product. c Not determined.
Scheme 4
.
Optimization of Conditions for anti-Aldol Reaction
Table 2. syn-Aldol Reaction of Ester Enolborinatea
(Table 1, entry 8), the reactions of representative aromatic
(4a-d), aliphatic (4f-g), and heterocyclic (4e) aldehydes
proceeded with excellent diastereoselectivity (94-99%) and
enantioselectivity (90-97%) for 5a-g. An aldehyde bearing
an acid-sensitive tert-butylsilyloxy group (4h, entry 9) was
also included, which provided 63% of the corresponding syn-
aldol (2S,3R)-5h in 94:6 diastereo- and 95:5 enantioselec-
tivity. The results are summarized in Table 2. A select series
of aldehydes were converted to the anti-aldols, as sum-
marized in Table 3.
Taking advantage of the natural availability of both
antipodes of R-pinene, the ester enolate E-3a, derived with
the antipode of the reagent, (+)-2, was treated with benzal-
dehyde to provide the hydroxy ester 2R,3R-5b (Table 2, entry
3) in similar de and ee. Comparison of the optical rotations15
of the enantiomers of 5b with those reported confirmed the
ee and the configurations. The stereochemistry of all other
product aldols 5a-h were assigned on the basis of analogy.
Pinene-derived reagents typically override the chirality of
substrates in double diastereoselections.16 A similar effect
was observed in the case of the ester-aldol reaction of chiral
aldehyde 11, derived from the Roche ester (10), with the
antipodes of E-3a. The aldol products 12 were obtained in
a Reaction conditions: (-)-2 (1.3 mmol), prepared from (-)-Ipc2BH
(from (+)-R-pinene) and trifluoromethanesulfonic acid, Et3N (2.2 mmol),
and methyl propionate (1 mmol) were stirred at -78 °C for 30 min and at
0 °C for 4 h; aldehyde (0.94 mmol) was added at -78 °C, and the mixture
was stirred for 8 h. Entry 4, stirred at rt for 5 h. b Isolated yield after column
chromatography. c Determined from 1H NMR analysis of the crude reaction
mixture. d Determined via 1H and 19F NMR spectroscopy of the MTPA
ester. e (+)-2 was used for the aldol reaction.
65% and 60% yields and in 98:2 and 95:5 diastereomeric
ratios, respectively. The absolute stereochemistry of 12 was
confirmed by converting the 2R,3S,4S-diastereomer to 15,
the C11-C17 subunit of (-)-dictyostatin (Scheme 5), as
follows.
(15) Heathcock, C. H.; White, C. T.; Morrison, J. J.; VanDerveer, D. J.
Org. Chem. 1981, 46, 1296.
The secondary alcohol 2R,3S,4S-12 was protected as the
TBS ether to 2S,3R,4S-13, followed by a borane reduction
of the ester to the primary alcohol, 2S,3R,4S-14. Conversion
(16) Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem. 1995,
500, 1.
Org. Lett., Vol. 11, No. 7, 2009
1469

Table 3. anti-Aldol Reaction of Ester Enolborinatea
Scheme 5. Synthesis of C11-C17 Subunit of (-)-Dictyostatin
a Reaction Conditions: (-)-2 (1.3 mmol), iPr2NEt (2.2 mmol), and tert-
butyl propionate (1 mmol) were stirred at -78 °C for 3 h; aldehyde (0.94
mmol) was added at -78 °C, and the mixture was stirred for 8 h. b Isolated
yield after column chromatography. c Determined from 1H NMR of the
crude reaction mixture. d Determined via 1H and 19F NMR spectroscopy of
MTPA ester.
ester enolate aldol reaction-ester reduction will become a
versatile and excellent approach, if not a superior alternative,
to sequential crotylboration-ozonolysis. A second generation
synthesis of (-)-dictyostatin and its trifluoromethyl analogs
are underway and will be reported in due course.
to the sulfone 15 was achieved via a Myers’ alkylation,
lithium amidoborohydride (LAB) reduction, Mitsunobu reac-
Acknowledgment. We acknowledge the support from the
Herbert C. Brown Center for Borane Research. We sincerely
thank Mr. Pravin Gagare, Dept. of Chemistry, Purdue
University for experimental help.
tion, followed by MCPBA oxidation.5a The H NMRs of
1
both 14 and 15 were identical to those reported earlier by
us.
In summary, we have described the first general asym-
metric aldol reaction of diisopinocampheylboron-mediated
enolates of esters. We have also shown the utility of this
protocol with the preparation of the C11-C17 subunit of
(-)-dictyostatin. We believe that this sequential asymmetric
Supporting Information Available: Experimental details
and spectral data of all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL802850W
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Org. Lett., Vol. 11, No. 7, 2009