Catalytic asymmetric [4 + 2] cycloadditions of ketenes and N-thioacyl imines: Alternatives for direct Mannich reactions of enolizable imines

Article abstract of DOI:10.1021/ja074845n

Asymmetric cinchona alkaloid-catalyzed ketene-N-thioacyl imine cycloadditions afford enantioenriched cis-4,5-disubstituted 1,3-thiazin-6-one heterocycles with high absolute and relative stereocontrol. These cycloadditions enable a strategy for executing catalytic asymmetric direct Mannich additions to enolizable, unactivated imines. The ketene and imine reaction components are both generated in situ from readily available acid chlorides and α-amido sulfones, respectively. Copyright

Full text of DOI:10.1021/ja074845n

Published on Web 09/06/2007
Catalytic Asymmetric [4 + 2] Cycloadditions of Ketenes and N-Thioacyl
Imines: Alternatives for Direct Mannich Reactions of Enolizable Imines
Xuan Xu, Kan Wang, and Scott G. Nelson*
UniVersity of Pittsburgh Center for Chemical Methodologies and Library DeVelopment, Department of Chemistry,
UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received July 2, 2007; E-mail: sgnelson@pitt.edu
Mannich reactions are attractive and versatile strategies for
establishing nitrogen-bearing stereocenters with concomitant C-C
bond construction.1 Accordingly, there have emerged a variety of
highly successful solutions to stereoselective Mannich additions,
including asymmetric catalytic variants.2 However, the inherent
incompatibility of reaction conditions that affect enolate formation
with enolizable imine electrophiles has functioned to limit the
number of successful direct Mannich processes useful for aliphatic
imines.3 Indeed, direct catalyzed Mannich reactions affording R,â-
disubstituted Mannich adducts with high absolute and relative
stereocontrol are especially rare. As one solution to Mannich
Figure 1. Alkaloid-catalyzed ketene-N-thioacyl imine cycloadditions.
reactions adhering to these design criteria, we describe the utility
of cinchona alkaloid (1 or 2)-catalyzed cyclocondensations of acid
chlorides and R-amido sulfones as effective surrogates for catalytic
asymmetric Mannich addition reactions (Figure 1). These reactions
deliver enantioenriched Mannich adducts masked as cis-4,5-
disubstituted thiazinone heterocycles that exhibit useful behavior
as activated ester equivalents.
Direct Mannich additions necessarily incorporate mechanisms
for in situ formation of the requisite enolate nucleophile. Aliphatic
imine Mannich substrates are subject to thermodynamically driven
imine-to-enamine tautomerization under the basic reaction condi-
tions necessary for enolate formation. Enolizable imines, therefore,
are generally poor substrates for catalyzed direct Mannich processes.
Based on our success developing acyl halide-aldehyde cyclocon-
densations as surrogates for direct catalytic asymmetric aldol
additions, we were interested whether a similar reaction design
would yield Mannich-type reactions compatible with enolizable,
unactivated imines.4 Accordingly, in situ ketene generation would
Figure 2. Mechanism for ketene-N-thioacyl imine [4 + 2] cycloadditions.
replace the typical enolization event in the Mannich reaction
sequence (Figure 2). Concomitant in situ imine generation, via base-
(>98% ee, 95:5 cis:trans) along with ∼20% of the N-acylated
mediated elimination of R-amido sulfone 3, provided a mechanism
enamine 7 (eq 1).
for affording the maximum kinetic advantage to the catalyzed
ketene-imine addition reaction relative to competing tautomeriza-
tion.5,6 Presuming imine formation would not be instantaneous, we
expected the reaction of the ketene-derived enolate 4 with low
concentrations of imine 5 to minimize the enamine formation that
would accompany extended exposure of 5 to the reaction conditions.
Successfully realizing this reaction design proved to be critically
dependent on utilizing N-thioacyl imine electrophiles that afforded
formal [4 + 2] cycloadducts 6 with ketene reaction partners.7,8
Establishing the veracity of this reaction design followed from
the experience we gained developing alkaloid-catalyzed ketene-
aldehyde cycloadditions.4 Thus, a catalyst system composed of
O-trimethylsilylquinine (1) and LiClO4 was evaluated in the
condensation of R-amido sulfone 3a, used as a representative
enolizable imine precursor, and propionyl chloride.9 Reacting 3a
with propionyl chloride in the presence of 10 mol % of 1, LiClO4,
and i-Pr2NEt (9:1 CH2Cl2/Et2O, -78 °C) afforded the cis-
disubstituted thiazinone 6a with near perfect enantioselection
The enamine byproduct 7 could be eliminated by using 20 mol %
of catalyst that, presumably, increases the cycloaddition reaction
rate relative to catalyst-independent imine tautomerization. Indeed,
enhanced reaction fidelity offsets the need for higher catalyst
loadings as the basic alkaloid is efficiently recovered from the
reaction mixtures by standard acid-base extraction techniques. The
critical role in situ imine generation played in the success of these
reactions was evident from attempts to utilize pregenerated imines
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J. AM. CHEM. SOC. 2007, 129, 11690-11691
10.1021/ja074845n CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Cinchona Alkaloid-Catalyzed Ketene-N-Thioacyl Imine [4
+ 2] Cycloadditionsa
Scheme 1
yieldb
(%)
6
% ee
(cis:trans)c,d
entry
R1
R2
R3
a
b
c
d
e
f
g
h
i
Me
CH2CH2Ph
C6H11
CH2OBn
Et
Et
Et
Et
Et
Et
Bn
Bn
Bn
Bn
Bn
Bn
76 (6a)
75 (6b)
51 (6c)
68 (6d)
65 (6e)
59 (6f)
67 (6g)
74 (ent-6h)
72 (6i)
58 (6j)
>98 (95:5)
c
Me
Me
Et
>98 (95:5)
>98 (>97:3)
>98 (>97:3)
>98 (>97:3)
>98 (>97:3)
98 (>97:3)
CH2CH2Ph
CH2CH2Ph
C6H5
CH2CH2CH3
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH2Ph
CH2CH2Ph
C6H5
ester provided the R,â-dipeptide derivative 13 (84%), suggestive
of the thiazinone’s function as an activated ester surrogate.12
Hydride-mediated thiazinone reduction led directly to the enan-
tioenriched â-amino aldehyde derivative 14 (70%).
Cinchona alkaloid-catalyzed ketene-imine cycloadditions offer
useful alternatives to traditional asymmetric Mannich reactions. The
ketene-imine cycloadditions are mechanistically distinct and, in
several aspects, complementary to existing direct Mannich reactions.
These reaction attributes are expected to make these ketene-imine
cycloadditions useful alternatives for executing Mannich-type C-C
bond constructions.
CH2Ph
Me
Me
Me
Et
95 (>97:3)
>98 (>97:3)
>98 (>97:3)
>98 (>97:3)
>98 (>97:3)
j
k
l
nPr
iPr
63 (6k)
59 (ent-6l)
Et
a Catalyst (20 mol %): 1, entries a-g, i-k; 2, entries h, l. b Isolated
yield. c Enantiomeric excess determined by chiral HPLC; minor enantiomer
not observed for values >98. d Diastereomer ratios determined by 1H NMR
analysis of crude product mixtures; minor diastereomer not observed for
values >97:3.
Acknowledgment. Support from the National Institutes of
Health (R01 GM63151 and P50 GM067082) and the Merck
Research Laboratories is gratefully acknowledged.
(e.g., 5) that afforded exclusively enamine 7. Similarly, attempts
to employ the carbamate-derived sulfone 8 as the proelectrophile
afforded no cycloaddition, suggesting that the nucleophilicity of
the thiocarbonyl moiety was critical to the success of this reaction.
The alkaloid-catalyzed ketene-N-thioacyl imine cycloadditions
proved to be generally effective for a variety of alkyl-substituted
ketenes and unactivated imine electrophiles (Table 1). Cycloaddi-
tions involving R-amido sulfones bearing straight chain or branched
alkyl substituents uniformly proceed with nearly complete control
of absolute and relative stereochemistry in affording the 4,5-cis-
disubstituted 1,3-thiazin-6-one derivatives 6a-l (g95% ee, g95:5
cis:trans).10 These formal [4 + 2] cycloadditions are similarly
accommodating of substituted ketenes incorporating aliphatic and
branched alkyl substituents with no deviation in stereoselectivity.
Cycloadditions involving aryl R-amido sulfones (entries f and l)
afford modestly attenuated reaction yields due to competing
formation of the â-lactam adducts (e.g., 9), possessing the
unanticipated trans diastereoselection that was not observed for
alkyl imine electrophiles (eq 2).
Supporting Information Available: Experimental procedures and
1H and 13C spectra (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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(4) (a) Zhu, C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126, 5352-
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review, see: (b) Petrini, M. Chem. ReV. 2005, 105, 3949-3977.
(6) For Lewis base catalyzed [2 + 2] cycloadditions of ketenes and non-
enolizable imines, see: (a) France, S.; Shah, M. H.; Weatherwax, A.;
Wack, H.; Roth, J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206-
1215 and references therein. (b) Lee, E. C.; Hodous, B. L.; Bergin, E.;
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references therein.
(7) For related [4 + 2] ketene cycloadditions, see: (a) Friot, C.; Reliquet,
A.; Reliquet, F.; Meslin, J. C. Synthesis 2000, 695-702. (b) Landreau,
C.; Deniaud, D.; Reliquet, F.; Reliquet, A.; Meslin, J. C. Heterocycles
2000, 53, 2667-2677. (c) Bharatam, P. V.; Kumar, R. S.; Mahajan, M.
P. Org. Lett. 2000, 2, 2725-2728.
(8) For recent examples of alkaloid-catalyzed [4 + 2] ketene cycloadditions,
see: (a) Bekele, T.; Shah, M. H.; Wolfer, J.; Ciby, J.; Abraham, C. J.;
Weatherwax, A.; Lectka, T. J. Am. Chem. Soc. 2006, 128, 1810-1811.
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2006, 128, 13370-13371.
(9) For the preparation of R-amido sulfones 3, see: Engberts, J. B. F. N.;
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(10) See Supporting Information for details of stereochemical proof.
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(12) Similar reactivity is observed for related N-acyl thiazolidinethione
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J. Org. Chem. 2001, 66, 894-902.
Stereoselectivity in the ketene-imine cycloadditions was con-
sistent C-C bond formation proceeding via the quinine-derived
enolate 4; imine approach to the exposed si enolate face would
deliver the carbamodithioate anion 10 (Figure 2).11 The high syn
selectivity characterizing these reactions can be attributed to
enolate-imine addition proceeding through either open or lithium-
coordinated, closed transition states 11 or 12, respectively. Sulfur’s
enhanced nucleophilicity relative to nitrogen dictates that 10
collapses by sulfur addition to the acyl ammonium ion to generate
the formal [4 + 2] cycloadduct 6.
The utility of the enantioenriched cycloadducts as surrogates for
traditional Mannich products was revealed by the ring opening
processes available to the thiazinone heterocycles (Scheme 1).
Amine-mediated ring opening of thiazinone 6i with valine methyl
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