Development of a new lewis acid-catalyzed [3,3]-sigmatropic rearrangement: The allenoate-Claisen rearrangement

Article abstract of DOI:10.1021/ja028090q

A new Lewis acid-catalyzed Claisen rearrangement has been developed that allows the stereoselective construction of β-amino-α,β,ε,ζ-unsaturated-γ,δ-disubstituted esters from simple allylic amines and allenoate esters. This reaction, which is contingent up

Full text of DOI:10.1021/ja028090q

Published on Web 10/29/2002
Development of a New Lewis Acid-Catalyzed [3,3]-Sigmatropic
Rearrangement: The Allenoate-Claisen Rearrangement
Tristan H. Lambert and David W. C. MacMillan
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received August 9, 2002
Table 1. Lewis Acid-Catalyzed Allenoate-Claisen Rearrangement
Over the last 90 years, the Claisen rearrangement has become a
preeminent technology for the rapid construction of complex organic
architecture, securing its widespread use in both natural product
and medicinal agent synthesis.1 To date, more than 15 variants of
this powerful [3,3]-isomerization have been documented, including
a variety of asymmetric methods;2 however, only one example of
an enantioselective catalytic Claisen has been accomplished.2d As
part of an ongoing program to develop sigmatropic rearrangements
that are amenable to enantioselective catalysis we recently reported
the acyl-Claisen reaction,3a a metal-mediated addition-rearrange-
ment sequence that is readily extended to enantioselective3b and
iterative cascade sequences.3c In this communication we outline the
design of a new Lewis acid-catalyzed Claisen rearrangement that
allows the stereoselective production of â-amino-R,â,ꢀ,ú-unsatur-
ated-γ,δ-disubstituted esters from simple allenoate esters and allylic
amines (eq 1). We expect this catalytic addition-rearrangement
sequence will also provide a valuable platform for the development
of a new enantioselective Claisen protocol.
entry
Lewis acid
mol % cat.
% yield
syn:antia
1
2
3
4
5
6
7
8
9
10
-
-
5
5
10
10
10
10
10
10
5
NR
82
86
87
86
83
81
83
95
93
-
Yb(OTf)3
Sn(OTf)2
Cu(OTf)2
TiCl4‚THF2
AlCl3
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
MgBr2‚Et2O
FeCl3
Zn(OTf)2
Zn(OTf)2
1
a Product ratios determined by H NMR analysis.
The proposed allenoate-Claisen reaction was first evaluated using
(E)-crotyl pyrrolidine with benzyl 2,3-pentadienoate and a variety
of Lewis acids. As outlined in Table 1, this new rearrangement
was successful with a broad range of metal salts of diverse Lewis
acidity including AlCl3, Cu(OTf)2, FeCl3, and Zn(OTf)2. Impor-
tantly, high levels of reaction efficiency and diastereocontrol were
observed in all metal-mediated cases (entries 2-10, 81-95% yields,
g98:2 syn:anti), while rearrangement adducts were not detected
in the absence of Lewis acid (entry 1). The superior catalytic
efficiency exhibited by Zn(OTf)2 prompted us to select this metal
salt for further exploration.
Experiments that probe the scope of the allylamine substrate are
summarized in Table 2. Considerable variation in the steric demand
of the olefin substituent (R1 ) H, Me, i-Pr, and Ph, entries 1-5) is
possible without loss in efficiency or stereocontrol (80-97% yield,
>94:6 syn:anti). The reaction also appears quite general with respect
to the tertiary amine moiety (entries 3, 6, and 7, 81-97% yield,
g94:6 dr). In accord with established Claisen protocols,1 the relative
sense of stereoinduction can be dictated by judicious selection of
olefin geometry on the allyl component. While high levels of syn-
stereocontrol can be secured with trans-allylic amines (entries 1,
3, and 4, >94:6 syn:anti), the anti-adduct is readily accessed using
the cis-isomer (entry 2, <2:98 syn:anti).
As revealed in Table 3, significant modification in the allenoate
structure can be tolerated. Steric and electronic variation of the
allenic substituent (R2 ) H, Cl, Me, allyl, i-Pr, and Ph, entries 1-6)
has apparently little influence on reaction selectivity (g93:7 dr).
Moreover, the stereoselective installation of γ-amino substituents
can be accomplished using γ-phthalyl allenic esters (entry 7, 75%
yield, 91:9 syn:anti).
As outlined in eq 1, we envisioned that a broad range of allenic
esters4 (1) might be activated toward the 1,4-conjugate addition of
tertiary allylamines (2) using Lewis acids. Accordingly, this acti-
vation-addition step would provide zwitterionic allyl-vinylammo-
nium complexes (3) that exhibit the appropriate charge orientation
to rapidly participate in [3,3]-bond reorganization. As part of our
design plan, we anticipated high levels of diastereoselection in the
carbon-carbon bond-forming event on the basis of (i) π-facial
discrimination in the cumulene addition step,5 leading to selective
formation of the (E)-enamine intermediate (3), and (ii) the propen-
sity of [3,3]-bond isomerizations to populate chairlike transition
states.1 In the context of synthetic utility, this new Claisen process
would allow rapid access to 1,2-disubstituted-â-enamino esters (eq
1), a versatile structural motif6 with respect to reductive,6a oxidative,6b
and π-nucleophile elaboration6c (see Supporting Information).
The proficiency of the allenoate-Claisen rearrangement to rapidly
construct synthetically challenging structural motifs has been exam-
ined. As highlighted with the isomeric substrates geranyl (4) and
* To whom correspondence should be addressed. E-mail: Dmacmill@caltech.edu.
9
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J. AM. CHEM. SOC. 2002, 124, 13646-13647
10.1021/ja028090q CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalyzed Allenoate-Claisen Rearrangement between
Benzyl 2,3-Pentadienoate and Representative Allyl Pyrrolidines
Table 3. Catalyzed Allenoate-Claisen Rearrangement between
Allyl Pyrrolidines and Representative Allenic Esters
a NR2 ) N-pyrrolidine. b Product ratios determined by GLC or 1H NMR
a NR2 ) N-pyrrolidine, NX2 ) N-piperidine. b Ratios determined by GLC
or 1H NMR analysis. c Relative configurations assigned by X-ray analysis,
chemical correlation or by analogy.
analysis. c Relative configurations assigned by X-ray analysis or analogy.
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
neryl (5) pyrrolidine (eqs 2 and 3), complementary access to both
syn and anti configurations of 1,2-tertiary-quaternary carbon stereo-
genicity7 can be accomplished in excellent yield and selectivity (eq
2, 94% yield, >98:2 syn:anti; eq 3, 93% yield, <2:98 syn:anti).
References
(1) For recent reviews of the Claisen rearrangement see: (a) Chai, Y.; Hong,
S.-P.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002,
58, 2905. (b) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter
7.2, p 827. (c) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron
Asymmetry 1996, 7, 1847. (d) Blechert, S. Synthesis 1989, 71. (e)
Kallmerten, J.; Wittman, M. D. Stud. Nat. Prod. Chem. 1989, 3, 233. (f)
Moody, C. J. AdV. Hetrocycl. Chem. 1987, 42, 203. (g) Ziegler, F. E.
Chem. ReV. 1988, 88, 1423. (h) Hill, R. K. In Asymmetric Synthesis;
Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, p 503.
(2) (a) Corey, E. J.; Lee, D.-H. J. Am. Chem. Soc. 1991, 113, 4026. (b)
Kazmaier, U.; Krebs, A. Angew. Chem., Int. Ed. Engl. 1995, 34, 2012.
(c) Maruoka, K.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 1995, 117,
1165. (d) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem.,
Int. Ed. 2001, 40, 4700.
(3) (a) Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc.
1999, 121, 9726. (b) Yoon, T. P.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2001, 123, 2911. (c) Dong, V. M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2001, 123, 2448.
(4) Allenic esters are readily prepared by Wittig reaction with ester phos-
phoranylidenes and acid chlorides: Lang, R. W.; Hansen, H.-J. Org. Synth.
1984, 62, 202.
(5) Seikaly, H. R.; Tidwell, T. T. Tetrahedron 1986, 42, 2613.
(6) For some interesting examples, see: (a) Giuseppe, B.; Cimarelli, C.;
Marcantoni, E.; Palmieri, G. Petrini, M. J. Org. Chem. 1994, 59, 5328.
(b) Schlessinger, R.; Lin, P.; Poss, M. Heterocycles 1987, 25, 315. (c)
Corey, E. J.; Ueda, Y.; Ruden, R. A. Tetrahedron Lett. 1975, 4347. (d)
Michael, J. P.; Joseph, P.; Chang, S.-F.; Wilson, C. Tetrahedron Lett.
1993, 8365. (e) Ishikawa, T.; Udeo, E.; Tani, R.; Saito, S. J. Org. Chem.
2001, 66, 186. (f) Ireland, R. E.; Brown, F. R. J. Org. Chem. 1980, 45,
1868.
(7) For excellent reviews on enantioselective quaternary carbon construction,
see: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40,
4700.
Finally, preliminary studies have revealed that the allenoate-
Claisen rearrangement is a suitable platform for enantioselective
catalysis. Studies toward this goal as well as a full account of this
survey are forthcoming.
Acknowledgment. Support was provided by the NIHGMS (R01
GM61214-01) and the UC-AIDS Research Program. We are grate-
ful to Dr. T. P. Yoon (Harvard University) for helpful discussions.
Supporting Information Available: Experimental procedures,
structural proofs, and spectral data for all new compounds are provided
JA028090Q
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