Diastereoselective addition of chlorotitanium enolate of N-acyl thiazolidinethione to O-methyl oximes: A novel, stereoselective synthesis of α,β-disubstituted β-amino carbonyl compounds via chiral auxiliary mediated azetine formation

Article abstract of DOI:10.1021/ja029871u

We have discovered a novel and highly diastereoselective synthesis of azetinyl thiazolidine-2-thiones that utilizes additions of the chlorotitanium enolates of N-acyl thiazolidin-2-thiones to O-methyl aldoximes. The "anti" azetines can be subsequently con

Full text of DOI:10.1021/ja029871u

Published on Web 03/08/2003
Diastereoselective Addition of Chlorotitanium Enolate of N-Acyl
Thiazolidinethione to O-Methyl Oximes: A Novel, Stereoselective Synthesis
of r,â-Disubstituted â-Amino Carbonyl Compounds via Chiral Auxiliary
Mediated Azetine Formation
Narendra B. Ambhaikar, James P. Snyder, and Dennis C. Liotta*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
Received December 21, 2002; E-mail: dliotta@emory.edu
Carbon-carbon bond-forming reactions involving asymmetric
aldol additions have emerged as powerful tools in organic synthesis.
As demonstrated by the pioneering work of Evans,1 Heathcock,2
and others,3,4 additions of enolates of acyl oxazolidinones, oxazo-
lidinethiones, and thiazolidinethiones to aldehydes can be highly
effective at selectively generating enantiomerically pure syn and
anti aldol products. While, in principle, additions of these enolates
to the CdN bond could be employed to generate â-amino carbonyl
compounds,5 in practice, the approach has only been used in a
handful of cases, most of which involve nonenolizable imines.6,7
0 °C in the presence of 3 equiv of titanium tetrachloride. While
we were able to elucidate the backbone structure of the product
using normal spectroscopic techniques (1H and 13C NMR, IR, and
MS), the absence of both methoxy and carbonyl groups in the
product suggested that the reaction was more complex than a simple
addition process. Surprisingly, X-ray crystallographic analysis
indicated the major product to be azetine 3a (R ) Ph) (Scheme 2,
Figure 1a).
Scheme 1
Figure 1. (a) X-ray structure of 3a (R ) Ph). (b) Transition state model
for enolate addition to 1; new bond hidden by Newman projection.
Recently, we have reported that additions of N-acyl thiazolidi-
nethione enolates to nonenolizable aldimines can be used to produce
either the syn or the anti addition products by appropriate selection
of the group (Z) on the nitrogen (Scheme 1).7 Herein, we report
the first details of a novel reaction of N-acyl thiazolidinethione
enolates with enolizable aldoxime ethers to produce thiazolidine-
thione azetines with excellent diastereoselectivity. Subsequent
addition of an acyl chloride to these azacyclobutene derivatives
leads to the formation of the corresponding N-acyl-R,â-disubstituted
â-amino acid derivatives.
Aldimines, although widely used in organic synthesis, exhibit
lower reactivity than their parent aldehydes and, if enolizable, are
often quite unstable chemically.8-11 We speculated that this latter
issue might be circumvented by employing “imines” that are less
prone to deprotonation, tautomerization, and oligomerization. In
this regard, O-alkyl oximes12-14 seemed well suited for exploring
additions to enolates despite their moderate electrophilicity, because
this deficiency could be overcome by activation with a suitable
Lewis acid. Because of previous successes with combinations of
N-acyl thiazolidine-2-thione 2,15 titanium tetrachloride, and (-)-
sparteine,4,7 we initiated our studies using this approach.
With the structure of the product firmly established, we focused
our attention on improving the efficiency and exploring the scope
and limitations of this novel transformation. By using 4 equiv of
titanium tetrachloride and 2.5 equiv of (-)-sparteine, we obtained
3a (R ) Ph) as a single diastereoisomer in double the originally
observed yield (Table 1). The reaction was also examined using
other aromatic and heteroaromatic oximes with similar outcomes.
It is particularly noteworthy that enolizable O-methyl oximes also
gave the corresponding azetine product. For example, the O-methyl
oxime ethers derived from hydrocinnamaldehyde and cyclohexane
carboxaldehyde produced single “anti” isomers as the major product,
albeit only in moderate yields.
Table 1. Enolate Additions Leading to Azetine 3 Formation16
oxime O-methyl
ether, 1(R)
isolated product
yield (%)
major to minor
product ratio (3/4)
phenyl
1-naphthyl
2-thienyl
2-phenylethyl
cyclohexyl
65
78
60
45
31
>95:5
6:1
15:1
>95:5
>95:5
Scheme 2
The formation of a strained four-membered ring can be rational-
ized as being initiated by the combination of oxime and TiCl4 to
give a highly electrophilic trichlorotitanium iminium intermediate
(i in Scheme 3), which undergoes addition by the enolate to form
ii and subsequent reversible ring closure to form azacyclobutane
iii. Irreversible elimination of bis-trichlorotitanium oxide, O(TiCl3)2,
provides the ultimate driving force to produce the azetines listed
in Table 1. Under similar conditions, the corresponding N-
Although O-methyl benzaldoxime (1, R ) phenyl) failed to react
at lower temperatures (e.g., -70 to -20 °C), product formation
was observed when the reaction was carried out for 12-14 h at
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J. AM. CHEM. SOC. 2003, 125, 3690-3691
10.1021/ja029871u CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
trimethylsilyl benzaldimine17 delivers 3a (R ) Ph) in 85% yield,
possibly through the intermediacy of a trichlorotitanium imine.18,19
Finally, while we have no direct information regarding the transition
state of these reactions, Figure 1b depicts a simple model for
rationalizing the observed anti stereochemistry.
Acknowledgment. We are grateful to Dr. Kenneth Hardcastle
(Emory University) for determining the X-ray structures of
compounds 3 and 5.
Supporting Information Available: Synthetic details, as well as
the X-ray structures for 3 and 5, R ) Ph (CIF and PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
Scheme 3
References
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“Hydrolytic” opening of azetinyl thiazolidine-2-thiones that
produce the corresponding R,â-disubstituted â-amino carbonyl
compounds is, to our knowledge, unprecedented. Initial attempts
involving simple acid/base-catalyzed hydrolysis led to the formation
of complex product mixtures. We speculated that a successful
approach would proceed by selective generation of a reactive
iminium salt20 followed by subsequent hydrolysis. Preliminary
attempts at N-alkylations involving the use of either MeI or Me3-
OBF4 failed apparently because of competition from the nucleo-
philic sulfur in the thiazolidine-2-thione. However, azetines 3 could
be successfully converted to the corresponding N-acyl â-amino
carbonyl compounds 5 by simple exposure to benzoyl chloride,
followed by stirring at room temperature in air (Table 2 and Scheme
4). These reactions presumably involve the formation of an acyl
iminium cation intermediate, followed by a subsequent hydrolysis.
In our hands, benzoyl chloride was found to be superior to other
commonly used acylating agents. The retained absolute stereo-
chemistry of the “anti” â-amino carbonyl compound was confirmed
by X-ray crystallographic analyses of 5a (R ) Ph, see Supporting
Information).
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Scheme 4
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Table 2. Hydrolytic Opening of Azetines 3 To Give 516
R
yield (%)
phenyl
1-naphthyl
2-thienyl
2-phenylethyl
cyclohexyl
78
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5921
6021
44
(16) (i) 1H NMR was employed to determine the presence and the ratio of
diastereoisomers. While none of the other diastereomer was detected in
any of the reactions listed in Scheme 2, a minor byproduct, 4, was detected,
which provides interesting insight into the mechanistic pathway involved.
(ii) In the reactions involving oxime ethers with R ) phenyl, 2-phenylethyl,
and cyclohexyl, none of the minor product 4 was observed after 12 h.
(17) Cainelli, G.; Panunzio, M. Tetrahedron Lett. 1991, 32, 121.
(18) Panunzio, M.; Zarantonello, P. Org. Process Res. DeV. 1998, 2, 49.
(19) Conversion of 1 to a trichlorotitanium imine requires reduction of the
N-O bond, presumably by titanium tetrachloride. Studies aimed at
elucidating the mechanism of this conversion are underway.
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H. Tetrahedron 1985, 41, 4416. Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 381.
38
In summary, we have discovered a novel and highly diastereo-
selective synthesis of azetinyl thiazolidine-2-thiones that utilizes
additions of the chlorotitanium enolates of N-acyl thiazolidin-2-
thiones to O-methyl aldoximes. The “anti” azetines can be
subsequently converted to the corresponding â-amino carbonyl
compounds with retention of stereochemistry. While elucidating
the full scope and limitations of these additions will require
additional study, this approach has excellent potential for becoming
a general method for synthesizing a wide variety of R,â-disubsti-
tuted â-amino carbonyl derivatives.
(21) On the basis of preliminary analyses of crude reaction mixtures, these
reactions may result in low levels (<10%) of epimerization.
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