Tandem asymmetric transformations: An asymmetric 1,2-migration from a higher order zincate coupled with a stereoselective homoaldol reaction

Full text of DOI:10.1021/ja962123i

11970
J. Am. Chem. Soc. 1996, 118, 11970-11971
Scheme 1
Tandem Asymmetric Transformations: An
Asymmetric 1,2-Migration from a Higher Order
Zincate Coupled with a Stereoselective Homoaldol
Reaction
J. Christopher McWilliams,* Joseph D. Armstrong, III,*
Nan Zheng, M. Bhupathy, R. P. Volante, and Paul J. Reider
Department of Process Research
Merck Research Laboratories, Box 2000
Mail Drop R80Y-360, Rahway, New Jersey 07065
ReceiVed June 24, 1996
Scheme 2
Scheme 3
The preparation of organic compounds of high optical purity
is becoming an increasingly important objective. To this end,
numerous examples of methods involving chiral catalysts (both
natural and unnatural) and covalently-bonded chiral auxiliaries
can be cited.1 Although often highly stereoselective, these
methods typically embrace a single event in which bond-forming
or bond-breaking takes place on a given substrate. For
molecules with multiple stereocenters it would be desirable to
couple several distinct asymmetric transformations in a single-
vessel reaction sequence. In this paper we describe the
development of such a tandem asymmetric process, which
couples a 1,2-migration with a homoaldol reaction.
The reaction of the titanium homoenolate derived from 3 with
N-(tert-butoxycarbonyl)phenylalaninal (6) is known to yield the
homoaldol product 4a as a single isomer (Scheme 1).2 The
overall conversion of 1 to 4a requires four individual steps,
including two stereodefining steps.3 The recent development
of one-carbon, organozinc homologation reagents prompted an
exploration into the possibility of streamlining the overall
transformation of 1 to 4a.4 The success of such a process would
require two distinct asymmetric transformations: an asymmetric
homologation and an asymmetric homoaldol.
Initial attempts to homologate the preformed lithium enolate
7 with bis(iodomethyl)zinc (8) were met with limited success,
producing moderate yields of the methyl and ethyl derivatives
9 and 10, respectively (Scheme 2).5 The following experimental
observations suggested the reactivity of the lithium enolate 7
was attenuated by 8: The conversions to 9 and 10 were
established rapidly upon addition of 8 to 7 at -70 °C, with no
change over time. If 7 was added to 1.1 equiv of 8 (“inverse
addition”), only 3% of 9 was formed at -70 °C. However, if
7 was added to a solution containing 0.6 equiv of 8, a 60%
conversion to 9 was observed. The deep yellow color indicative
of 7 rapidly dissipated upon addition of approximately 0.5
equivalents of 8. Finally, in situ IR spectroscopy clearly
indicated the disappearance of the lithium enolate 7 upon
addition to 8, with concurrent formation of a new species.6 We
believe these results are consistent with the formation of carbon-
bound enolate zincate 11 (Scheme 3).7
Having established 11 was unreactive, a mechanism proceed-
ing through another species must account for the observed
reactivity under conditions in which 8 is added to 7. Since that
reaction pathway is only available in the early phases of the
addition, we propose that the higher order zincate 12a is
responsible for the formation of 9.8 Presumably, this species
increases the electron density at the zinc center, driving the 1,2-
migration to 13a.9 This mechanistic scheme is fully consistent
with the observed results. During the initial stages of the
addition of 8 to 7, the presence of a large excess of free lithium
enolate 7 can either drive the 1,2-migration through the higher
order zincate 12a or can react with ethyl iodide to produce 10.5
As the addition of 8 continues, all lithium enolate 7 has been
effectively “quenched” as the zincate species 11 or 13a. A
combined maximum yield of 50% for 9 and 10 would be
expected with this order of addition. In contrast, inverse
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley
& Sons, Inc.: New York, 1994. (b) Wong, C.-H; Whitesides, G. M. Enzymes
in Synthetic Organic Chemistry; Tetrahedron Organic Chemistry Series;
Pergamon Press: Tarrytown, NY, 1994; Vol. 12.
(2) (a) Armstrong, J. D., III; Hartner, F. W., Jr.; DeCamp, A. E.; Volante,
R. P.; Shinkai, I. Tetrahedron Lett. 1992, 33, 6599. See also: (b) DeCamp,
A. E.; Kawaguchi, A. T.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1991,
32, 1867. (c) Reetz, M. R.; Karin, R.; Griebenow, N. Tetrahedron Lett.
1994, 35, 1969. (d) Reetz, T. R.; Fox, D. N. A.; Tetrahedron Lett. 1993,
34, 1119. (e) Reetz, M. R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531.
(f) Kano, S.; Yokomatsu, T.; Shibuya, S. Tetrahedron Lett. 1991, 32, 233.
(3) The first step in the sequence is a non-stereoselective aldol between
7 and formaldehyde.
(4) (a) Sidduri, A.; Rozema, M. J.; Knochel, P. J. Org. Chem. 1993, 58,
2694 and references cited therein. (b) Knochel, P.; Singer, R. D. Chem.
ReV. 1993, 93, 2117. For an early example of the use of a zinc carbenoid
with a lithium enolate, see: (c) Whitlick, H. W., Jr.; Overman, L. E. J.
Org. Chem. 1969, 34, 1962.
(6) The lithium enolate 7 is identified by IR absobances at 1595 and
1575 cm-1. Upon addition to diethylzinc or 8, new absorbances (1536 and
1567 cm-1, respectively) are observed with the disappearance of the lithium
enolate absorbances.
(7) The assignment of a carbon-bound (as opposed to oxygen-bound)
zincate species for 11 is based upon low-temperature NMR observations.
Enolate zincate 11 is drawn as a monomer for clarity. Prior stuctural studies
on zinc enolates suggest 11 may exist in aggregate forms through dative
Zn-C or Zn-O bonding. For related examples, see: (a) Bolm, C.; Mu¨ller,
J.; Zehnder, M.; Neuburger, M. A. Chem. Eur. J. 1995, 1, 312 and references
sited therein. (b) Fabicao, R. M.; Pajerski, A. D.; Richey, G. H., Jr.; J. Am.
Chem. Soc. 1991, 113, 6680.
(8) The involvement of higher order zincates in 1,2-migrations has been
previously implicated: Harada, T.; Katsuhira, T.; Hattori, K.; Oku, A. J.
Org. Chem. 1993, 58, 2958.
(9) Although implied as a short-lived intermediate in Scheme 3, 12a may
exist only as a transition state structure.
(5) The formation of 10 may arise from alkylation of ethyl iodide, which
is a byproduct of the in situ generation of 8: 2CH2I2 + Et2Zn f 7 + 2EtI.
For preparation of 8, see ref 4a and Supporting Information.
S0002-7863(96)02123-3 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 47, 1996 11971
Table 1. Tandem Asymmetric 1,2-Migration/Homoaldol
Scheme 4
Reactionsa
addition of the lithium enolate 7 to 8 yields negligible amounts
of 9 and 10 because 7 is rapidly quenched in the presence of
excess 8.
With a reasonable mechanistic hypothesis in hand, effecting
good conversions to homoenolate depended upon finding an
appropriate enolate surrogate to serve as the driving force in
the 1,2-migration. It has been established that R-halocyclo-
propylzincs undergo 1,2-migrations in the presence of mono-
and dialkoxides.8,10 Indeed, several alkoxides induced good
conversions to the homologated product 9.11 Lithium benzyl-
alkoxide gives the most consistent conversions. Presumably,
the homologation to an alkoxy zincate 13b proceeds through
the higher order alkoxy zincate 12b.12 The stereoselectivity of
the 1,2 migration is excellent, proceeding with g98% de.13 The
corresponding methyl derivative 2 underwent homologation to
14b with similar stereoselectivity (g97% de).
With a viable asymmetric route to the zinc homoenolate 13b,
transmetalation was affected with (iPrO)TiCl3 (Scheme 4). The
homoaldol reaction with N-(tert-butoxycarbonyl)phenylalaninal
(6) proceeded as previously described, yielding 4a as the only
homoaldol product in 59% yield.2a The overall two-step
transformation to 4a occurred with g98% de.14
a Reactions were run with 5 equiv of aldehyde, except for entries
A-C, in which 0.5 equiv of the corresponding aldehydes was
employed.2 b Refers to stereoselectivity of homoaldol reaction as
determined by GLC after silylation of the crude mixtures or by HPLC.
c Isolated yield. Yields in parentheses are based upon homoenolates
13b or 14b. The molarities of 13b and 14b were determined by HPLC
and corrected for response factors. d Yield based upon aldehyde.2
e Transmetalation with TiCl4. Based upon recovered 9. g Yield of major
f
isomer only.
Scheme 5
Several aldehydes were examined as homoaldol substrates
in this transformation (Table 1).15,16 The highest diastereo-
selectivity in the homoaldol reaction is observed for N-tert-
Boc (butoxycarbonyl) aldehydes derived from L-amino acids
and the titanium homoenolate derived from 13b (entries A and
C). Diastereoselectivity in the homoaldol reaction with aryl
and aliphatic aldehydes decreased with decreasing steric bulk
R to the aldehyde.
In most cases, the major isomers from the tandem 1,2-
migration/homoaldol transformation were isolated in pure form
by simple flash chromatography. Conditions for removal of
the auxiliary were quite mild. Treating representative γ-hy-
droxyamides 4 with p-toluenesulfonic acid monohydrate induces
cyclization to the lactones 15 in good yield (Scheme 5).
Furthermore, the (1R, 2S)-cis-aminoindanol crystallizes from
the toluene solution as the p-toluenesulfonate salt 16 and is
recovered by simple filtration. Thus, this method provides
access to a variety of optically pure γ-lactones.
In conclusion, we have presented a novel approach to the
asymmetric synthesis of organic molecules containing multiple
stereocenters. Our strategy centers on the asymmetric formation
of reactive intermediates, which are further subjected to asym-
metric transformations. A single chiral controlling element (cis-
aminoindanol) is responsible for asymmetric induction in both
disparate transformations. Further studies on the scope and
mechanism of this and related transformations are in progress.
(10) For migrations of halogen-substituted triorganozincates, see: Harada,
T.; Wada, H.; Oku, A. J. Org. Chem. 1995, 60, 5370 and references cited
therein.
(11) The following is a list of representative lithium alkoxides and percent
conversions, respectively: (EtOLi, 35), (nPrOLi, 74-88), (BnOLi, 70-
82, 78% isolated yield), (LiO(CH2)2OLi, 31). Low conversions for the
dialkoxide and lithium ethoxide likely reflects the limited solubility of these
species at -70 °C. Low temperatures and inverse addition of 7 to 8 (thereby
preventing free lithium enolate 7 attack on ethyl iodide) are necessary to
minimize formation of 10 (typically, 3-6% of 10 is still observed).
(12) The alkoxy zincate 13b is drawn as one species for clarity. In situ
IR spectroscopy indicates at least three species in solution, represented by
absorbances at 1637, 1621, and 1602 cm-1.
(13) Ratios were determined by GLC analysis (experimental details are
described in the Supporting Information).
(14) Only the homoaldol product 4a was detected in the crude mixture
(HPLC).
(15) For a recent example of diastereoselective homoaldol reactions of
zinc homoenolates, see: (a) Houkawa, T.; Ueda, T.; Sakami, S.; Asaoka,
M.; Takei, H. Tetrahedron Lett. 1996, 37, 1045. See also: (b) Nakamura,
E.; Oshino, H.; Kuwajima, I. J. Am. Chem. Soc. 1986, 108, 3745.
(16) The stereoselectivity of the homoaldol reaction was determined by
transformation to the lactones (Vide infra) and examination of coupling
constants and NOE effects.
Acknowledgment. We thank Professor David A. Evans and
Professor Paul Knochel for helpful discussions.
Supporting Information Available: Full experimental details for
all compounds (11 pages). See any current masthead page for ordering
and Internet access instructions.
JA962123I