5674
J . Org. Chem. 1997, 62, 5674-5675
Ta ble 1. Ster eoselectivity of th e Ta n d em
Ta n d em Ald ol-Tish ch en k o Rea ction s of
Lith iu m En ola tes: A High ly Ster eoselective
Meth od for Diol a n d Tr iol Syn th esis
Ald ol-Tish ch en k o Rea ction (eq 1)a
entry ester/diol R1
R2 yield of 3, % ds, %b yield of 4, %c
1
2
3
4
5
3a /4a
3b/4b
3c/4c
3d /4d
3e/4e
Ph Me
Ph Et
Ph i-Pr
i-Pr Ph
i-Pr i-Pr
98
98
>99
87
41
64
62
72
56d
76
69
73
Paul M. Bodnar, J ared T. Shaw, and K. A. Woerpel*
Department of Chemistry, University of California,
Irvine, California 92697-2025
>99
a
LDA as base, 2.2 equiv of aldehyde. These standard conditions
b
were used unless otherwise noted. Diastereoselectivity deter-
mined by analysis of the unpurified diol 4 by GC. c Overall yield
Received J une 6, 1997
d
from 1. LHMDS as base.
The reactions of metal enolates constitute important
methods for the construction of carbon-carbon bonds.1
Early investigations of aldol reactions employing lithium
ketone enolates provided significant mechanistic infor-
mation,2 although these reactions are not generally as
stereoselective as those of other enolates.1,3 Recently, two
intriguing reports described stereoselective reactions of
lithium ketone enolates:4,5 they react with 2 equiv of
aldehyde to provide anti-1,3-diol derivatives by a se-
quence of aldol addition and intramolecular Tishchenko-
type6 reduction.7-10 Although these reactions possess
significant potential for organic synthesis, the generality
of these transformations has not been investigated. We
report here that the tandem11 aldol-Tishchenko reaction
of lithium enolates is a simple method for the synthesis
of polyoxygenated organic compounds, creating three or
five stereocenters in a single operation with high stereo-
selectivity. These tandem transformations compliment
current aldol technology1 because they represent a dis-
tinct approach to stereocontrol of enolate reactions, in
that C-H bond formation, not C-C bond formation,
determines the stereochemical outcome.
dehyde to confirm stereochemical assignments. When
the lithium enolate of propiophenone2 was treated with
2.2 equiv of acetaldehyde at -78 °C followed by warming
to 22 °C, a mixture of acetates (3a ) was obtained;
hydrolysis provided the diol 4a as a 98:2 mixture of
diastereomers in 41% yield (eq 1; Table 1, entry 1). The
fact that no â-hydroxy ketones were isolated is consistent
with the known reactivity of these enolates: standard
aldol conditions involve the use of 1 equiv of aldehyde,
low temperatures (-78 °C), and extremely short reaction
times.2 The aldol-Tishchenko reaction occurs with high
selectivities and good yields for other aldehydes with little
(<10%) acyl transfer (Table 1).13 The reaction can be
applied to 2-methyl-3-pentanone in place of propiophe-
none (Table 1, entries 4, 5). The stereochemistry of the
products was determined by comparison to reference
compounds and by analysis of the derived 1,3-diol ac-
etonides by 13C NMR spectroscopy.14-16
As part of research directed at utilizing silacyclopro-
pane chemistry for organic synthesis,12 we required a
synthesis of aldol adducts of propiophenone and acetal-
(1) (a) For a recent review of stereoselective aldol reactions, see:
Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317-338.
(b) For a review of lithium enolate aldol reactions, see: Heathcock, C.
H. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I. Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp 181-238.
(2) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.;
Sohn, J . E.; Lampe, J . J . Org. Chem. 1980, 45, 1066-1081.
(3) For recent investigations of aldol reactions employing lithium
enolates, see: Evans, D. A.; Yang, M. G.; Dart, M. J .; Duffy, J . L.
Tetrahedron Lett. 1996, 37, 1957-1960 and references cited therein.
(4) Baramee, A.; Chaichit, N.; Intawee, P.; Thebtaranonth, C.;
Thebtaranonth, Y. J . Chem. Soc., Chem. Commun. 1991, 1016-1017.
(5) Horiuchi, Y.; Taniguchi, M.; Oshima, K.; Utimoto, K. Tetrahedron
Lett. 1995, 36, 5353-5356.
(6) (a) Evans, D. A.; Hoveyda, A. H. J . Am. Chem. Soc. 1990, 112,
6447-6449. (b) The method reported by Evans and Hoveyda has been
applied to the synthesis of rapamycin: Romo, D.; Meyer, S. D.;
J ohnson, D. D.; Schreiber, S. L. J . Am. Chem. Soc. 1993, 115, 7906-
7907.
(7) In a synthesis of zaragozic acid A, Heathcock observed diol
monoesters when lithium enolates were treated with excess alde-
hyde: Caron, S.; Stoermer, D.; Mapp, A. K.; Heathcock, C. H. J . Org.
Chem. 1996, 61, 9126-9134.
(8) For a related transformation, see: Molander, G. A.; McKie, J .
A. J . Am. Chem. Soc. 1993, 115, 5821-5822.
(9) Other isolated examples of this reaction have been observed for
other metal enolates. (a) Zinc: ref 5. (b) Samarium: Curran, D. P.;
Wolin, R. L. Synlett 1991, 317-318. (c) Nickel: Burkhardt, E. R.;
Bergman, R. G.; Heathcock, C. H. Organometallics 1990, 9, 30-44.
(10) Recently, Mahrwald reported a titanium-catalyzed tandem
aldol-Tishchenko reaction involving 3-pentanone and aldehydes:
Mahrwald, R.; Costisella, B. Synthesis 1996, 1087-1089.
(11) The utility of tandem reactions in synthesis has been discussed;
see, for example: (a) Tietze, L. F. Chem. Rev. 1996, 96, 115-136. (b)
Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307-338.
(12) (a) Bodnar, P. M.; Palmer, W. S.; Shaw, J . T.; Smitrovich, J .
H.; Sonnenberg, J . D.; Presley, A. L.; Woerpel, K. A. J . Am. Chem.
Soc. 1995, 117, 10575-10576. (b) Bodnar, P. M.; Palmer, W. S.;
Ridgway, B. H.; Shaw, J . T.; Smitrovich, J . H.; Woerpel, K. A. J . Org.
Chem. 1997, 62, 4737-4745.
Experiments were conducted to provide insight into the
reaction mechanism, which most likely includes an aldol
addition step. Treatment of the aldol adduct syn -517 with
LDA followed by 1.1 equiv of propionaldehyde under
conditions similar to eq 1 resulted in a 1:1 ratio of diol
4c and crossover product 4b after hydrolysis (91%
combined yield; eq 2). The same ratio of 4c and 4b was
(13) Representative Experimental: Preparation of Ester 3b. Freshly
distilled diisopropylamine (0.57 mL, 4.4 mmol) was added to 10 mL of
anhydrous THF. To the cooled (0 °C) solution was added 1.2 M n-BuLi
in hexanes (3.6 mL, 4.3 mmol). After 10 min, the reaction mixture was
cooled to -78 °C. To the cooled reaction mixture was added distilled
propiophenone (0.50 mL, 3.8 mmol). After 20 min, distilled propional-
dehyde (0.57 mL, 7.90 mmol) was added dropwise (1 min), and the
resulting solution was stirred for 1 h at -78 °C. The reaction mixture
was then warmed to 22 °C, stirred for 12 h, quenched with 20 mL of
saturated aq NaHCO3, extracted with CH2Cl2, filtered through cotton,
and concentrated in vacuo. Purification by flash chromatography (90:
10 to 70:30 hexanes:EtOAc) provided the product as a colorless oil (712
mg, 76% yield): IR (neat) 3506, 2974, 1703, 1603, 1081 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.33 (m, 5H), 4.91 (m, 1H), 4.80 (m, 1H), 2.81 (d,
J ) 3.7 Hz, 1H), 2.43 (q, J ) 7.6 Hz, 2H), 1.93 (m, 1H), 1.76 (m, 1H),
1.63 (m, 1H), 1.20 (t, J ) 7.5 Hz, 3H), 0.93 (t, J ) 7.5 Hz, 3H), 0.76 (d,
J ) 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 175.4, 142.8, 128.0,
126.7, 125.6, 77.3, 71.7, 43.4, 27.7, 24.8, 9.5, 9.3, 8.9; HRMS (CI) m/ z
calcd for C15H23O3 (M + H)+ 251.1647, found 251.1646. Anal. Calcd
for C15H22O3: C, 71.97; H, 8.86. Found: C, 72.07; H, 8.81.
(14) Rychnovsky, S. D.; Rogers, B.; Yang, G. J . Org. Chem. 1993,
58, 3511-3515.
(15) Evans, D. A.; Rieger, D. L.; Gage, J . R. Tetrahedron Lett. 1990,
31, 7099-7100.
(16) The details are provided as Supporting Information.
(17) (a) Hamana, H.; Sasakura, K.; Sugasawa, T. Chem. Lett. 1984,
1729-1732. (b) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993,
34, 6871-6874.
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