Tandem chain extension-aldol reaction: syn selectivity with a zinc enolate.

Article abstract of DOI:10.1021/ol016788n

A tandem chain extension-aldol reaction was developed in which beta-keto esters are transformed to alpha-substituted-gamma-keto esters in an efficient zinc-mediated, one-pot reaction. The diastereoselectivity of the reaction ranged from good to excellent

Full text of DOI:10.1021/ol016788n

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4169-4171
Tandem Chain Extension−Aldol
Reaction: Syn Selectivity with a Zinc
Enolate
,†
Sujen Lai,† Charles K. Zercher,* Jerry P. Jasinski,§ Seth N. Reid,§ and
Richard J. Staples‡
Department of Chemistry, UniVersity of New Hampshire, Durham,
New Hampshire 03824, Department of Chemistry, Keene State College,
229 Main Street, Keene, New Hampshire 03435-2001, and Department of Chemistry
and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
ckz@christa.unh.edu
Received September 20, 2001
ABSTRACT
A tandem chain extension−aldol reaction was developed in which â-keto esters are transformed to r-substituted-γ-keto esters in an efficient
zinc-mediated, one-pot reaction. The diastereoselectivity of the reaction ranged from good to excellent with syn stereochemistry observed for
â-keto ester and amide substrates and anti-stereochemistry observed for a â-keto imide.
Preparation of nucleophilic zinc ester enolates used in mixed
aldol reactions through the action of zinc metal on R-bro-
moesters is known as the Reformatsky reaction.1 Reactions
of zinc enolates generated in this fashion from esters and
amides have been studied under kinetically and thermody-
namically controlled reaction conditions with mixed, often
confusing, results. Furthermore, diastereoselection of the
traditional ester-based Reformatsky reactions has rarely
exceeded 50% de. Similarly, a general method for performing
highly stereoselective zinc-mediated aldol reactions on ester
or amide enolates has not been reported,2 although incor-
poration of chiral imide-based auxiliaries has provided
beneficial stereochemical influences in traditional Refor-
matsky reactions.3
An underlying assumption of the Zimmerman-Traxler
model4 is that the enolate is an oxygen-bound species, yet a
preponderance of evidence has demonstrated that the Re-
formatsky intermediate (zinc ester enolate) exists in nonpolar
solvents as a dimeric species with significant covalent
interaction between the zinc and the R-carbon.5 While
isomerization from the carbon-bonded zinc intermediate to
a zinc enolate has been proposed,6 the lack of enolate
structural knowledge has hindered development of diaste-
reoselective zinc enolate reactions.
We have been investigating a zinc-mediated reaction in
which a â-keto ester is transformed to a γ-keto ester7 through
(4) Zimmerman H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920.
(b) Evans, D, A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
(c) Heathcock, C. H. ComprehensiVe Carbanion Chemistry; Buncel, E.,
Durst, T., Eds.; Elsevier, Amsterdam, The Netherlands, 1984; Part 5B, p
177.
† University of New Hampshire.
§ Keene State College.
‡ Harvard University.
(1) (a) Rathke, M. W.; Weipert, P. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press, Inc.: New York, 1991; Vol. 2, p 277.
(b) Fu¨rstner, A. Synthesis 1989, 571.
(2) (a) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: Orlando, 1984; Vol. 3, p 111.
(3) (a) Ito, Y.; Terashima, S. Tetrahedron Lett. 1987, 28, 6625. (b) Ito,
Y.; Terashima, S. Tetrahedron Lett. 1987, 28, 6629. (c) Ito, Y.; Terashima,
S. Tetrahedron 1991, 47, 2821.
(5) (a) Orsini, F.; Pelizzoni, F.; Ricca, G. Tetrahedron 1984, 40, 2781.
(b) Orsini, F.; Pelizzoni, F.; Ricca, G. Tetrahedron Lett. 1982, 23, 3945.
(c) Dekker, J.; Budlezaar, P. H. M.; Boersma, J.; van der Kerk, G. J. M.;
Spek, A. L. Organometallics 1984, 3, 1403.
(6) Dewar, M. J. S.; Metz, K. M., Jr. J. Am. Chem. Soc. 1987, 109, 6553.
(7) (a) Brogan, J. B.; Zercher, C. K. J. Org. Chem. 1997, 62, 6444. (b)
Verbicky, C. A.; Zercher, C. K. J. Org. Chem. 2000, 65, 5615. (c)
Hilgenkamp, R.; Zercher, C. K. Tetrahedron 2001, 57, 8793.
10.1021/ol016788n CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/22/2001

Scheme 1. Chain Extension-Reformatsky Reaction
Table 1. Chain Extension-Reformatsky Reactions
SM
R
R′
R′′
yield, %a
6:7b
1a
1b
1c
1d
1e
1f
tBu
tBu
Arc
Me
Me
Me
OMe
OMe
OEt
OMe
OMe
NPhMe
Ph
97 (57)
61d
12:1 (17:1)
9:1
7:1
>20:1
15:1
3:1g
Arc
Arc
tBu
Ph
57
85d
61e
Me
46f
a Total isolated yield of purified isomers. b Syn:anti ratio of aldols
1
determined by integration of the H NMR of the crude reaction material.
c Ar ) 3,4-(OMe)2C6H3. d Only the syn isomer was isolated. e The O-
methylated syn isomer 9 (7%) was not included in the total. f The
O-methylated syn isomer 10 (40%) was not included in the total. g If the
O-methylated syn isomer 10 is included, syn:anti selectivity is >5:1.
reliance on 1H NMR coupling constants (3JHH) a risky
proposition. However, a trend consistent with the literature9
was observed in which the anti isomer possesses a larger
3JHH than the syn isomer.
Yields for the reaction range from 60% to 95%, and in all
cases the diastereocontrol is greater than 75% de. Enhanced
diastereoselectivity (entry b), with modest diminishment of
yield, is observed when the aldol portion of the reaction is
performed at -78 °C. The reaction appears to be operating
under kinetic control, since no evidence of reversibility has
been observed and diastereoselectivity is independent of
reaction time.
In two instances small amounts (7%) of O-methylated
aldol products 8 and 9 were isolated from the reaction
mixture. Treatment of the syn-aldol product 6c with the
Furukawa reagent confirmed the structure and stereochem-
istry of 8 and suggested that 8 is generated during the tandem
reaction by reaction of the hydroxide with the electrophilic
carbenoid. The syn stereochemistry of compound 9 was
confirmed in a similar fashion.
An effort to apply this tandem reaction methodology to a
â-keto imide resulted in a complete reversal of stereochem-
ical consequences. The anti-aldol isomer 10 was isolated as
the sole product (60%) of the reaction, a result consistent
with the proposal of Heathcock that excess metal counterions
can influence stereochemical control through an open transi-
tion state.10 Since the tandem chain extension-aldol reaction
is performed with at least 4 equiv of zinc, effective syn-
aldol generation with control of absolute stereochemistry is
unlikely using imide auxiliaries.
Uncommon syn diastereocontrol in the ester and amide
zinc enolate reactions may be due to an inherent bias for
Z-enolate (11, Figure 1) formation via complexation with
the ketone carbonyl.11 A comparison between the tandem
chain extension-aldol reaction and kinetically controlled
the influence of the Furukawa reagent, ethyl(iodomethyl)-
zinc8 (Scheme 1). The reaction mechanism is believed to
involve intermediacy of a donor-acceptor cyclopropane 2,
which upon fragmentation and protonation provides the
chain-extended ester 4. NMR investigations of similar chain
extension reactions have suggested that the cyclopropane is
not a persistent intermediate and that a ring-opened species
is formed rapidly.7b Deuterium quenching of the chain
extension reaction suggested that a zinc enolate (3) similar
to a Reformatsky intermediate may be present in the reaction.
We report herein the development of a tandem chain
extension-aldol reaction that facilitates the diastereoselective
formation of R-substituted-γ-keto esters, products that were
not accessible through the chain extension of R-substituted-
â-keto esters.7a The tandem chain extension-aldol reaction
proceeds efficiently with â-keto ester and amide starting
materials (Table 1). For example, treatment of methyl
pivaloylacetate 1a with diethylzinc and methylene iodide,
followed by addition of benzaldehyde, resulted in an isolated
95% yield of two aldol products 6a and 7a in a syn:anti
ratio of 12:1. The appearance of multiple hemiacetal isomeric
forms, in addition to open chain aldols, serves to complicate
analysis of the reactions. For example, the syn isomer 6a
appears in CDCl3 as a 1:1:1 mixture of open chain and two
hemiacetal forms. It was noteworthy that hemiacetal forms
are generally more prevalent for the syn isomers 6 than for
the anti isomers 7, thereby making the appearance of
hemiacetal forms a useful predictor for stereochemical
assignment.
(9) (a) Stiles, M.; Winkler, R. R.; Chang, Y.; Trayner, L. J. Am. Chem.
Soc. 1964, 86, 3337. (b) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.;
Olmstead, H. D. J. Am. Chem. Soc. 1973, 95, 3310.
(10) Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 1990,
55, 173.
(11) Generation of the proposed zinc enolate through traditional Refor-
matsky chemistry on an R-bromo-γ-keto ester would be informative. We
have attempted to make this starting material, but have been hindered by
the predictable elimination reaction.
Stereochemical assignments were made by comparison to
literature compounds or by X-ray crystal structure. The
presence of a hydrogen bond acceptor (ketone) on the C2
side chain makes stereochemical assignment through a
(8) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24,
53-58.
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Org. Lett., Vol. 3, No. 26, 2001

acceptor cyclopropane13 suggests the syn-selective zinc-
mediated reactivity reported herein is the result of an alternate
pathway.
In conclusion, a zinc enolate, which has been generated
in a zinc-mediated chain extension reaction, has provided
modest to excellent syn selectivity in a variety of aldol
reactions. Although the presence of a ketone provides
homoenolate character to the zinc nucleophile,14 the involve-
ment of this ketone appears limited to stereoselective enolate
formation.
Acknowledgment. This research was supported by a
grant from the National Institutes of Health (GM60967-01).
Figure 1.
Supporting Information Available: Characterization
data for all compounds and experimental procedures. Crystal
structure data for 6b, 6d, 6e, 9, and 10. This material is
available free of charge via the Internet at http://pubs.acs.org.
Reformatsky reactions12 with similar steric influences and
solvent polarities suggests that the ketone is vital to the
diastereocontrol. An alternate explanation for the aldol
reaction would be nucleophilic attack of the donor-acceptor
cyclopropane 2 on the aldehyde. However, the anti-selectivity
observed in the titanium(IV)-mediated reaction of a donor-
OL016788N
(13) (a) Reissig, H-U.; Holzinger, H,; Glomsda, G. Tetrahedron 1989,
(12) (a) Gaudemar-Bardone, F.; Gaudemar, M. Bull. Soc. Chim. Fr. 1969,
2088. (b) Canceill, J.; Basselier, J-J.; Jacques, J. Bull. Soc. Chim. Fr. 1967,
1024.
45, 3139.
(14) (a) Crimmins, M. T.; Nantermet, P. G. Org. Prep. Proced. Int. 1993,
25, 41.
Org. Lett., Vol. 3, No. 26, 2001
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