Tandem asymmetric aza-Darzens/ring-opening reactions: Dual functionality from the silane Lewis acid

Article abstract of DOI:10.1021/ja9066354

(Chemical Equation Presented) The addition of a stabilized sulfur ylide (generated by the rhodium-catalyzed reaction of Ph₂S with ethyl diazoacetate) to N-acylhydrazones promoted by a chiral silane Lewis acid leads to the highly diastereo- and

Full text of DOI:10.1021/ja9066354

Published on Web 09/24/2009
Tandem Asymmetric Aza-Darzens/Ring-Opening Reactions: Dual
Functionality from the Silane Lewis Acid
S. Corey Valdez and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received August 5, 2009; E-mail: leighton@chem.columbia.edu
The asymmetric synthesis of aziridines has received a significant
procedure is fully compatible with the silane-hydrazone complex
(Scheme 2). After optimization, the product 4a was obtained in 88%
yield and 95% ee. In principle, the sulfide may be used in substo-
ichiometric amounts, but in this case, that procedure led to extensive
dimerization of the ethyl diazoacetate. This is nevertheless a simple
and reliable procedure that employs inexpensive and readily available
starting materials, and we have found it to be preferable to the pro-
cedure described in Scheme 1C.
amount of attention,1 primarily because of their utility in ring-
opening reactions.2 These two processes are typically staged
sequentially, and we wondered whether they might instead be
orchestrated in an efficient and step-economical tandem reaction
sequence. The asymmetric aza-Darzens reaction3,4 seemed espe-
cially relevant in this regard because it seemed plausible that the
Lewis acid (LA) that serves to activate the imine might further
serve to activate the aziridine toward ring-opening nucleophilic
attack (Scheme 1A). Our chiral silane Lewis acid-acylhydrazone
platform has been shown to be effective for a range of nucleophilic
addition reactions,5 and we speculated that it might also be effective
in promoting aza-Darzens reactions and subsequent ring-opening
reactions (Scheme 1B). Exploratory reactions were carried out with
silane (S,S)-1 and hydrazone 2a. Whereas ethyl diazoacetate was
unreactive toward the silane-hydrazone complex, treatment with
the stabilized ylide derived from sulfonium salt 36 and Hunig’s
base led not to the aziridine but rather to ring-opened product 4a
(Scheme 1C). Upon optimization, this reaction was quite effective,
giving 4a in 84% yield as a single regioisomer and diastereomer
(g20:1 rr and dr) in 97% ee. The aziridine is thus clearly formed
in the reaction, but it is still complexed to and activated by the
silane Lewis acid and undergoes a highly regio- and diastereose-
lective ring-opening reaction in the presence of the chloride ion
that is liberated in the silane-hydrazone complexation process. The
reaction may thus be considered as a tandem aza-Darzens/ring-
opening reaction in which the silane Lewis acid performs two
distinct functions as well as a simple synthetic equivalent of and
alternative to alkene aminohalogenation reactions.7
Scheme 2
With optimal conditions identified, an examination of the scope
of the reaction was carried out (Table 1). Substituted benzaldehyde-
derived hydrazones (2a-i) were employed, and in every case the
reactions proceeded smoothly, delivering the products 4a-i in good
yield. In some cases, a significant amount of a minor regioisomeric
product (R-chloro-ꢀ-hydrazido ester) was formed, while in most
cases the major product was formed with excellent levels of
enantioselectivity.
Table 1. One-Pot Aza-Darzens/Ring-Opening Reactions with (S,S)-1
Scheme 1
entry
Ar
yield (%)
rr
ee (%)
1
2
3
4
5
6
7
8
9
Ph (a)
p-Br-C6H4 (b)
p-F-C6H4 (c)
p-NO2-C6H4 (d)
p-CF3-C6H4 (e)
p-CH3-C6H4 (f)
o-Br-C6H4 (g)
o-CH3-C6H4 (h)
1-naphthyl (i)
88
85
81
82
83
76
81
84
82
g20:1
17:1
11:1
6:1
9:1
g20:1
6:1
95
91
92
94
97
94
86
93
89
10:1
7:1
ꢀ-Chloro-R-hydrazido esters 4 are arguably primarily of interest
as an entry into unusual R-amino acid derivatives by way of
nucleophilic substitution reactions. For example, simply heating 4a
in DMSO at 55 °C led to the isolation of 5, a ꢀ-hydroxy-R-
hydrazido ester derivative, in 79% yield with complete retention
of optical purity (Scheme 3). Similarly, treatment of 4a with phenyl
isothiocyanate gave 2-(phenylimino)thiazolidine 6 in 78% yield.
While many other versions of processes such as these with
heteroatom nucleophiles may be imagined, the use of carbon
nucleophiles was of interest as well. Toward that end, 4a was treated
The synthesis of sulfonium salt 3 requires the use of stoichiometric
amounts of AgBF4 and takes several days. We therefore investigated
whether it might be possible to adapt the procedure of Aggarwal
whereby the ylide is generated in situ by the rhodium-catalyzed reaction
of a sulfide with a diazo ester.8 Indeed, the combination of Ph2S (2
equiv) and ethyl diazoacetate (2 equiv) in the presence of 1 mol %
[Rh(OAc)2]2 generates the ylide derived from 3 in situ, and this
9
14638 J. AM. CHEM. SOC. 2009, 131, 14638–14639
10.1021/ja9066354 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. One-Pot Aza-Darzens/Ring-Opening Reactions with Arenes
with acrolein followed by 10 mol % thiazolium salt 7 and Hunig’s
base. This one-pot procedure produced piperidone derivative 8 in
73% yield.9 Compounds 5, 6, and 8, representing a diverse set of
densely functionalized heterocycles, are thus readily accessible in
just two straightforward steps.
Scheme 3
entry
Ar1
Ar2
yield (%)
ee (%)
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
3-indolyl (a)
80
68
74
65
50
56
94
92
92
92
92
91
5-Br-3-indolyl (b)
5-MeO-3-indolyl (c)
p-Me2N-C6H4 (d)
2-MeO-4-Me2N-C6H3 (e)
3-indolyl (f)
p-CF3-C6H4
Acknowledgment. This work was supported by a grant (CHE-
0809659) from the National Science Foundation. S.C.V. is a
National Science Foundation Graduate Research Fellow. We thank
Prof. G. F. R. Parkin and Mr. Kevin Yurkerwich for X-ray structure
analyses (see the Supporting Information), and the National Science
Foundation (CHE-06-19638) is thanked for the acquisition of an
X-ray diffractometer.
To more fully exploit the ability of the silane Lewis acid to promote
both the aza-Darzens reaction and subsequent ring-opening reactions,
the addition of electron-rich arenes was investigated in order to develop
a single-step synthesis of diarylalanine derivatives.10,11 When the
reaction shown in Scheme 2 was repeated and indole was then added
(and the resulting mixture stirred for 3 days), 9a was isolated in 22%
yield and 92% ee (Scheme 4). Although inefficient, this reaction and
its diastereochemical outcome clearly implied that the conversion of
aziridine intermediate A into initial product B is reversible and that
the silane is competent to activate the aziridine toward attack of the
indole. On the basis of the hypothesis that the conversion of B to A is
rate-limiting, exogenous Lewis acids were screened in the hope of
accelerating this process. Eventually, it was found that ZnCl2 was
particularly effective, leading to 9a in 80% yield and 94% ee. With
an effective synthesis of 9a in hand, its two-step conversion into
protected amino acid 10 was demonstrated.12
Supporting Information Available: Experimental procedures,
characterization data, stereochemical proofs, and CIF files for 4a, 5,
and 9b. This material is available free of charge via the Internet at
http://pubs.acs.org.
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Scheme 4
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