A simple and general chiral silicon Lewis acid for asymmetric synthesis: Highly enantioselective [3 + 2] acylhydrazone-enol ether cycloadditions

Article abstract of DOI:10.1021/ja052307+

A highly diastereo- and enantioselective [3 + 2] acylhydrazone-enol ether cycloaddition mediated by a simple chiral silane Lewis acid is described. The reactions are highly practical, as demonstrated by a larger scale (5 g of the hydrazone) reaction in which the product was obtained after recrystallization in 93% yield and 99% ee. Evidence for a stepwise mechanism and a model for the asymmetric induction are presented, as well. Copyright

Full text of DOI:10.1021/ja052307+

Published on Web 06/23/2005
A Simple and General Chiral Silicon Lewis Acid for Asymmetric Synthesis:
Highly Enantioselective [3 + 2] Acylhydrazone-Enol Ether Cycloadditions
Seiji Shirakawa, Pamela J. Lombardi, and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received April 9, 2005; E-mail: leighton@chem.columbia.edu
[3 + 2] Cycloaddition reactions of azomethine imines, diazoal-
kanes, and nitrile imines1 provide access to medicinally important
pyrazolidine and pyrazoline derivatives,2 and both chiral auxiliary-
controlled diastereoselective3 and catalytic enantioselective4 variants
of such reactions have been reported. More recently, Kobayashi
has established that related acylhydrazone-olefin cycloadditions
may be catalyzed by (chiral) Lewis acids.5 We have established a
program to develop chiral silicon-based Lewis acids for asymmetric
synthesis, motivated by the significant practical advantages that
could accrue to the use of silicon. Our strategy for inducing Lewis
acidity in silanes is ring-strain, and we have documented that simply
constraining allyl- and crotylsilanes in a five-membered ring leads
to type I allyl-/crotylation reagents for both aldehydes and acyl-
hydrazones.6 In an effort to generalize this strategy beyond allylation
chemistry, we recently developed an enantioselective Friedel-Crafts
reaction promoted by silanes 1 (Scheme 1).7 That the same simple
silane Lewis acid might promote other acylhydrazone-nucleophile
combinations is an attractive possibility, and we, therefore, set out
to investigate acylhydrazone-olefin cycloadditions in this context.
was carried out (Table 1). A variety of aliphatic and aromatic and
heteroaromatic aldehyde-derived benzoylhydrazones performed
consistently well in the reaction, giving good yields and excellent
diastereo- and enantioselectivities in every case.
Table 1. Enantioselective [3 + 2] Cycloaddition Reactions
entry
R
yield (%)
dra
ee (%)b
1
2
3
4
PhCH2CH2
BnOCH2
i-Pr
Cy
t-Bu
84
85
76
79
76
80
66
81
96:4
>97:3
96:4
>97:3
>97:3
>97:3
>97:3
95:5
90
90
94
95
98
94
93
95
5
6c,d
7c
8c
Ph
p-F-C6H4
2-furyl
a Determined by 1H NMR spectroscopy. b Determined by chiral HPLC.
Scheme 1
c Reaction temp. ) 40 °C. d Reaction time ) 50 h.
To establish that the reaction performs well on a larger scale,
entries 1 and 3 were repeated using 5 g of the hydrazone (Scheme
3). Employing only 1.2 equiv of both the vinyl ether and silanes 1,
we obtained the products after a single recrystallization in 91 and
93% yields, respectively, each as a single diastereomer in 99% ee.
In addition, it proved trivial to recover the pseudoephedrine in 99%
yield by simple extraction during the workup. Given this perfor-
mance under near-ideal reaction conditions, it may justifiably be
claimed that this is a highly practical process.
Our studies began with the benzoylhydrazone of dihydrocinna-
maldehyde and ethyl vinyl ether (Scheme 2). Previously reported
phenylsilanes 1 (easily prepared as a 2:1 mixture of diastereomers
in a single step from pseudoephedrine and phenyltrichlorosilane)
was found to mediate the cycloaddition, giving the pyrazolidine
product in 61% yield with 6:1 diastereoselectivity and 77% ee. The
use of tert-butyl vinyl ether led to an improvement in both diastereo-
and enantioselectivity, and the reaction was found to perform best
in toluene at room temperature. Under these conditions, the product
was obtained in 84% yield with excellent (96:4) diastereoselectivity
and 90% ee.
Scheme 3
It was also of interest to investigate â-substituted enol ethers as
this would lead to the synthesis of pyrazolidines bearing three
stereocenters. (Z)-tert-Butyl propen-1-yl ether was indeed found
to be a viable dipolarophile for the reaction, leading to 2 with good
diastereoselectivity and excellent enantioselectivity (Scheme 4).
While Kobayashi has advanced a concerted mechanism for the Zr-
catalyzed acylhydrazone-olefin cycloadditions,5b this reaction
represents the first example of a â-substituted dipolarophile being
used in a Lewis acid-promoted version of this reaction. Such
substrates can provide a direct probe of this issue, and the fact that
Scheme 2
Having established the feasibility of and optimal conditions for
the reaction, a survey of the scope with respect to the hydrazones
9
9974
J. AM. CHEM. SOC. 2005, 127, 9974-9975
10.1021/ja052307+ CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 6 a
the cis-enol ether leads to the product with a trans relationship
between the methyl and Ot-Bu groups is indicative of a stepwise
mechanism for these silane-promoted reactions. The possibility that
the cis-enol ether might be isomerizing to trans and then engaging
in a concerted reaction was excluded by the poor results (28% yield
of a mixture of four products) observed when the cycloaddition
was performed with the trans-enol ether. An additional control
experiment (a sample of a cycloaddition product (Table 1, entry 1)
enriched in the minor cis diastereomer was resubjected to the
reaction conditions and was recovered unchanged) excluded the
possibility that the aminal center might be equilibrating following
a concerted reaction.
a Conditions: (a) AcCl, pyridine, DMAP, CH2Cl2; (b) TMSOTf,
CH2dCHCH2SiMe3, CH2Cl2, -15 °C; (c) SmI2, MeOH, THF.
enol ether cycloaddition. The reactions proceed smoothly in toluene
at ambient temperature. In addition, silanes 1 may be readily
prepared in bulk in a single step from (S,S or R,R) pseudoephedrine
and phenyltrichlorosilane. The former is inexpensive and easily
recoverable, and the latter is available at a nominal cost. The process
may thus lay a formidable claim to a high degree of practicality
despite the requirement for a full equivalent of silanes 1. Finally,
and importantly, silanes 1 have now been shown to be highly
effective chiral Lewis acids for two different reactions of acylhy-
drazones. The ability of silanes 1 to promote other useful
transformations is under active investigation.
Scheme 4
In a previous study, it was demonstrated by X-ray crystallography
that the reaction of silanes 1 with the benzaldehyde-derived
benzoylhydrazone leads to structure 3 (R ) Ph, Scheme 5).6e
Notable features of this structure include (1) the coalescence of
both diastereomers of 1 into a single structure, (2) the protonation
of the pseudoephedrine amino group, presumably leading to a
significant increase in silane Lewis acidity,8 and (3) the isomer-
ization of the CdN bond from trans (in the hydrazone) to cis (in
the complex). On the basis of this structure, a plausible model may
be advanced in which the enol ether approaches from the exposed
si face of the hydrazone and is oriented so as to minimize steric
interactions between the bulky t-BuO group and the complexed
hydrazone (4, Scheme 5). Importantly, this model also correctly
rationalizes the observed cis relationship between the phenethyl
and methyl groups in 2 (see 4 and 5, R′ ) Me). For the reactions
in Table 1 (R′ ) H), the origin of the high levels of diastereose-
lectivity for the trans relationship between the t-BuO and R groups
is not immediately obvious, but is presumably due to steric/
conformational factors as 5 undergoes ring closure.
Acknowledgment. This work was supported by a grant from
the NSF (CHE-04-53853). S.S. is a recipient of a Japan Society
for the Promotion of Science Research Fellowship. P.J.L. is a
recipient of a Pfizer Diversity in Organic Chemistry Fellowship.
Support from Amgen, Merck Research Laboratories, and the
Astellas USA Foundation is also gratefully acknowledged.
Note Added after ASAP Publication. After this article was
published ASAP on June 23, 2005, a processing error that caused
some structures in Scheme 1 to be incorrect was discovered. The
corrected version was published ASAP on June 24, 2005.
Supporting Information Available: Experimental procedures,
characterization data, and stereochemical proofs. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Scheme 5
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That the cycloaddition products are aminals suggests an op-
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promoted by TMSOTf could be carried out to give 8 in 65% yield
10
(Scheme 6). Hydrazide reduction with SmI2 then delivered
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differentially protected diamine 9 in 87% yield, demonstrating that
in addition to substituted pyrazolidines, this method can provide
efficient access to 1,3-diamines, as well.
We have described a simple chiral silane Lewis acid for the
highly diastereo- and enantioselective [3 + 2] benzoylhydrazone-
JA052307+
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J. AM. CHEM. SOC. VOL. 127, NO. 28, 2005 9975