Tandem aldol-Tishchenko reactions of lithium enolates: A highly stereoselective method for diol and triol synthesis

Full text of DOI:10.1021/jo971012e

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.
S0022-3263(97)01012-8 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 17, 1997 5675
Sch em e 1
marium-catalyzed Tishchenko reduction of â-hydroxy
ketones.6,20 Since experiments indicate that the aldol
addition step is reversible (eqs 2, 3), the methyl group
can be placed in the equatorial position in the lowest
energy transition state 8 leading to product. The mecha-
nistic postulate of Scheme 1 differs from the one favored
by Thebtaranonth et al., who proposed that both equiva-
lents of aldehyde and the enolate are brought together
simultaneously in a single transition state.4
Initial attempts to extend this reaction to 3-pentanone
and benzaldehyde failed under the conditions developed
for other ketones. If 3.3 equiv of benzaldehyde were
employed, however, the diol benzoates 9a -d were formed
as an 86:6:5:3 mixture of diastereomers (by GC of the
corresponding acetates 11, vide infra) in 81% yield on a
multigram scale (eq 4). The major diastereomer was
proven to be 9a by hydrolysis to afford triol 10 followed
by acetylation (eq 5); the stereochemistry of 11 was
determined by X-ray crystallography.16 It is noteworthy
that one product was formed almost exclusively, although
15 other stereoisomers of the triol monoester could
possibly have been produced. This reaction can be
considered to be a tandem sequence of two aldol addi-
tions, proton transfer, and intramolecular Tishchenko
reduction steps.
obtained starting from anti-5.18 Therefore, lithium al-
dolates are probably reactive intermediates in the tan-
dem reaction. Since neither the stereochemical relation-
ships of the products 4b,c nor the nature of the alkyl
group (i-Pr or Et) is dependent upon the structure of the
aldolate, the aldol addition step must be reversible and
not stereochemistry-determining.4
To determine the relative rates of the aldol addition
and Tishchenko reduction steps, a solution of the aldolate
was quenched at different temperatures. When isobu-
tyraldehyde (1 equiv) was added to a solution of the
enolate of propiophenone at -78 °C and the mixture was
quenched after 10 s,2 the expected aldol adducts 5 were
formed (eq 3) with poor stereoselectivity (anti:syn ) 46:
54). If the solution of aldolate were warmed to 22 °C
before quenching, the monoester 3c was generated as a
major product (54% yield based on 54% recovered pro-
piophenone) along with the aldol adducts 5 (11% yield,
anti:syn ) 32:68). These results confirm that reduction
is slower than aldol addition, but sufficient quantities of
aldehyde are liberated from aldolates to carry out reduc-
tion.6
These experiments demonstrate that the tandem
lithium aldol-Tishchenko reaction can be used to form
1,3-diol derivatives with high stereochemical control. The
stereoselectivity observed in the reaction appears to be
a result of a rate-determining reduction which allows for
the equilibration of aldolates. This operationally simple
process is also applicable to the stereoselective formation
of a 1,3,5-triol monoester in one step.
Ack n ow led gm en t. This research was supported by
the National Science Foundation and the Donors of The
Petroleum Research Fund, administered by the Ameri-
can Chemical Society. K.A.W. also wishes to thank the
Research Corporation for a Cottrell Scholar Award and
the American Cancer Society for a J unior Faculty
Research Award. The U.S. Department of Education is
acknowledged for support in the form of a GAANN
fellowship to J .T.S. We thank Dr. J ohn Greaves and
J ohn Mudd for mass spectrometric data, Dr. J oseph
Ziller for crystallographic analyses, and Ms. Angie Kim
for expert technical assistance.
The high stereoselectivity of this reaction can be
rationalized by a mechanism involving reversible aldol
addition and hemiacetal formation, followed by rate- and
stereochemistry-determining hydride transfer from a
lithium hemiacetal (Scheme 1). The six-membered tran-
sition state for the Tishchenko reduction (8) resembles
the transition structure identified computationally for
hydride transfer between LiOMe and CH2O19 and pro-
posed by Evans and Hoveyda for the anti selective sa-
Su p p or tin g In for m a tion Ava ila ble: Full characteriza-
tion data, stereochemistry proofs, and X-ray crystallographic
data for 11 (20 pages).
J O971012E
(20) We believe that formation of hemiacetal 7 is also reversible,
since addition of the aldolates 6 to the aldehyde R2CHO is likely to
occur with little stereoselectivity at the newly formed hemiacetal
stereocenter. Only one diastereomer of 7 is capable of undergoing
hydride transfer by the six-membered transition state 8.
(18) Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.;
Singaram, B. J . Am. Chem. Soc. 1989, 111, 3441-3442.
(19) Wu, Y.-D.; Houk, K. N. J . Am. Chem. Soc. 1987, 109, 906-
908.