N-sulfinyl beta-amino Weinreb amides: synthesis of enantiopure beta-amino carbonyl compounds. Asymmetric synthesis of (+)-sedridine and (-)-allosedridine.

Article abstract of DOI:10.1021/ol034119z

[reaction: see text] N-Sulfinyl beta-amino Weinreb amides are prepared by condensation of sulfinimines with the potassium enolate of N-methoxy-N-methylacetamide. These new chiral building blocks are useful for the asymmetric synthesis of beta-amino carbon

Full text of DOI:10.1021/ol034119z

ORGANIC
LETTERS
2003
Vol. 5, No. 6
925-927
N-Sulfinyl â-Amino Weinreb Amides:
Synthesis of Enantiopure â-Amino
Carbonyl Compounds. Asymmetric
Synthesis of (+)-Sedridine and
(−)-Allosedridine
Franklin A. Davis,* Kavirayani R. Prasad, M. Brad Nolt, and Yongzhong Wu
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received January 22, 2003
ABSTRACT
N-Sulfinyl â-amino Weinreb amides are prepared by condensation of sulfinimines with the potassium enolate of N-methoxy-N-methylacetamide.
These new chiral building blocks are useful for the asymmetric synthesis of â-amino carbonyl compounds, as illustrated here by the concise
enantioselective syntheses of sedum alkaloids (+)-sedridine and (−)-allosedridine.
Unlike nonracemic N-protected R-amino aldehydes and
ketones, which are valuable and widely used building blocks
for the asymmetric synthesis of amine derivatives,1 â-amino
carbonyl compounds have found relatively few applications.
However, â-amino carbonyl moieties are not only found in
natural products,2 but are potentially useful intermediates for
Wittig-type condensations3-7 and natural product,4,5 1,3-
amino alcohol,8 and â-amino acid synthesis. What has
undoubtedly impeded their general use in asymmetric
syntheses is the lack of convenient methods for their
preparation as single enantiomers. For example, â-amino
aldehydes are usually not isolated but prepared in solution
because of their tendency to self-condense.9 However, in
1998, we disclosed that certain sulfinimine-derived N-Cbz
and N-Boc â-amino aldehydes are stable crystalline solids
and could be used in the stereoselective synthesis of alkaloids
such as (+)-phenylpiperidine and (+)-dihydropinidine.3 In
this paper, we report a general solution to the problem of
â-amino carbonyl asymmetric construction employing new
sulfinimine-derived enantiopure N-sulfinyl â-amino Weinreb
amides.
(1) For reviews, see: (a) Fisher, L. E.; Muchowski, J. M. Org. Prep.
Proced. Int. 1990, 22, 399. (b) Jurczak, J.; Golebiowski, A. Chem. ReV.
1989, 89, 149.
(2) For a review, see: Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58,
5957.
(3) Davis, F. A.; Szewczyk J. M., Tetrahedron Lett. 1998, 39, 5951.
(4) Louis, C.; Mill, S,; Mancuso, V.; Hootele, C. Can. J. Chem. 1994,
72, 1347.
Weinreb amides are valuable carbonyl equivalents for the
synthesis of carbonyl compounds.10 Although â-amino
Weinreb amides have been described previously, they have
(5) Davies, S. B.; McKervey, M. A. Tetrahedron Lett. 1999, 40, 1229.
(6) (a) Rodriguez, M.; Aumelas, A.; Martinez, J. Tetrahedron Lett. 1990,
31, 5153. (b) Rodriguez, M.; Heitz, A.; Martinez, J. Tetrahedron Lett. 1990,
31, 7319. (c) Limal, D.; Quesnel, A.; Briand, J.-P. Tetrahedron Lett. 1998,
39, 4239.
(7) Toujas, J.-L.; Toupet, L.; Vaultier, M. Tetrahedron 2000, 56, 2665.
(8) Jefford, C. W.; Wang, J. B. Tetrahedron Lett. 1993, 34, 2911.
(9) Asymmetric synthesis of â-amino carbonyl compounds: reduction
of â-amino esters or nitriles, see refs 3 and 8 of this article. Toujas, J.-L.;
Jost, E., Vaultier, M. Bull. Soc. Chem. Fr, 1997, 134, 713. Arndt-Eistert
reaction, see ref 6 of this article.
(10) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(b) For an excellent review on applications of Weinreb amides, see: Sibi,
M. P. Org. Prep. Proced. Int. 1993, 25, 15.
10.1021/ol034119z CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/12/2003

found relatively few uses because of difficult syntheses and/
or problems in removal of the N-substituents.11 Importantly,
we have found that addition of the potassium enolate of
commercially available N-methoxy-N-methylacetamide 1 to
(S)-(+)-N-benzylidene-p-toluenesulfinamide (2) affords the
corresponding â-amino Weinreb amide 3 in 56% de and 52%
isolated yield of the major diastereoisomer (Scheme 1). Use
responding â-amino carbonyl compounds in good yield
(Scheme 2). Thus, treatment of (+)-3 with 5 equiv of
Scheme 2
Scheme 1
DIBAL-H in THF at -78 °C affords (R)-(+)-5a in 84%
yield.3 With 5 equiv of methylmagnesium bromide or
phenylmagnesium bromide in THF, warming from -78 °C
to room temperature furnishes the methyl and phenyl ketones
(R)-(+)-5b and (R)-(+)-5c in 92 and 84% yields, respec-
tively.
The sedum alkaloids are a large family of 2-substituted
and 2,6-disubstituted piperidines having various combinations
of carbonyl and hydroxyl functionalities in the side chains,
many of which feature the 1,3-amino alcohol moiety.15 These
types of alkaloids have memory-enhancing properties and
may be effective in treating Alzheimer’s disease.16 That
N-sulfinyl â-amino Weinreb amides may provide general
entry into this important class of piperidine alkaloids is
illustrated by the asymmetric synthesis of (+)-sedridine (14)
and (-)-allosedridine (15).17
Our synthesis begins with the preparation of the requisite
sulfinimine, (S)-(+)-N-(6-chloropentylidine)-p-toluene-sul-
finamide (7), in 54% yield by condensation of 5-chloro-
valeroaldeyde with commercially available (S)-(+)-p-tolu-
enesulfinamide (6) using Ti(OEt)4 (Scheme 3).18 Treatment
of the 2-methoxynaphthyl or tert-butane sulfinyl auxiliaries
resulted in poorer des and yields. However, it is worth noting
that the diastereoselectivities for the addition of 1 to other
aliphatic, alkenyl, and aromatic sulfinimines (see below) were
consistently >95% de.12 Alternatively, addition of 5 equiv
of lithium N,O-dimethylhydroxyamine to (SS,R)-(+)-methyl
N-(p-toluenesulfinyl)-3-amino-3-phenyl propanoate (4),13
prepared by addition of the sodium enolate of methyl acetate
to (S)-(+)-2, gave (SS,R)-(+)-3 in 78% yield. This serves to
establish the absolute stereochemistry of the product resulting
from the addition of 1 to (S)-(+) 2 as R. Usually, the addition
of organometallic reagents to sulfinimines can be predicted
assuming six-member chairlike transition states where the
metal ion is coordinated to the sulfinyl oxygen, and the
results described here are in accordance with these observa-
tions.14
Scheme 3
N-Sulfinyl â-amino Weinreb amide (SS,R)-(+)-3, despite
the presence of the acidic sulfinamide proton, reacts with
various organometallic regents normally, affording the cor-
(11) (a) Davies, S. G.; Iwamoto, K.; Smethurst, C. A. P.; Smith, A. D.;
Rodrigues-Solla, H. Synlett 2002, 1146. (b) Davies, S. G.; McCarthy, T.
D. Synlett. 1995, 700. (c) Ref 6 of this article.
(12) Results of these studies will be reported separately in due course.
(13) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M. J. Org. Chem. 1995,
60, 7037.
(14) For reviews on the chemistry of sulfinimines, see: (a) Zhou, P.;
Chen, B.-C.; Davis, F. A. In AdVances in Sulfur Chemistry; Rayner, C. M.,
Ed.; JAI Press: Stamford, CT, 2000; Vol. 2, pp 249-282. (b) Davis, F.
A.; Zhou, P.; Chen. B.-C. Chem. Soc. ReV. 1998, 27, 13. (c) Ellman, J. A.;
Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
of (+)-7 with potassium enolate 1 gives the corresponding
â-amino Weinreb amide (S)-(+)-8 in 76% yield and >95%
de. Reaction of the amide with 5 equiv of MeMgBr in ether
gave the methyl ketone (S)-(+)-9 in 77% yield.
926
Org. Lett., Vol. 5, No. 6, 2003

Stereoselective reduction of amino ketone 9 was next
explored. With LiBH4 in THF, a 1:1 separable mixture of
the anti:syn 1,3-amino alcohols 10 and 11, in a combined
yield of 69%, resulted (Scheme 4). Reduction with Super-
â-amino ketones19,20 suggests that the modest-to-good 1,3-
asymmetric induction can be interpreted using arguments
similar to those invoked for the hydroxy-directed reduction
of â-hydroxy ketones.21 Here a reagent such as lithium tris-
(tert-butoxy)aluminohydride will deliver an external hydride
via a six-membered chelate involving the keto and amino
groups, while anti selectivity results from intramolecular
hydride delivery from a group bonded to the sulfinyl
nitrogen.
Scheme 4
With the acyclic 1,3-amino alcohols in hand, cyclization
to hydroxy piperidines [2S-(2S)]-(+)-12a and [2R-(2S)]-(+)-
13a was readily accomplished by stirring with NaH/THF in
the presence of 30 mol % 18-crown-6 for 1 h. Isolation by
chromatography afforded these materials in 71-72% yield.
Although removal of the N-sulfinyl protecting group was
accomplished in 52-55% yield by brief stirring with TFA/
MeOH, the alkaloids were contaminated with up to 10% of
the p-tolylsulfinyl byproducts. An improved method for
isolation of 14/15 involved oxidation of the N-sulfinyl groups
in 12a/13a to the tosylates, 12b/13b, with m-CPBA. Reduc-
tive cleavage of the sulfonamides, as reported by Gallagher
et al.,17c with Na/liquid NH3, afforded the pure alkaloids in
70-84% yield. The structures of (+)-sedridine (14) and (-)-
allosedridine (15) were confirmed by comparison of their
properties with literature values, as well as conversion to
their N-Cbz derivatives.17
In summary, the asymmetric synthesis of N-sulfinyl
â-amino Weinreb amides by addition of the potassium
enolate of N-methoxy-N-methylacetamide to sulfinimines or
by the reaction of N-sulfinyl â-amino esters with lithium
N,O-dimethylhydroxyamine is described. These new chiral
building blocks are expected to provide general access to
enantiopure â-amino carbonyl compounds that are valuable
intermediates for asymmetric synthesis. The utility of these
new â-amino carbonyl compounds is illustrated in the concise
asymmetric syntheses of the sedum alkaloids (+)-sedridine
(14) and (-)-allosedridine (15).
Hydride (LiEt3BH) in DCM gave only the anti product
(2R,3S)-(+)-10 in 71% yield. While lithium tri-tert-butoxy-
aluminohydride in THF afforded exclusively the syn amino
alcohol (2R,3S)-(+)-11, the yield was only 34%. Attempts
to improve the yield by increasing the reaction time,
temperature, or amount of reducing reagent resulted in poor
yields, attributable to reactions at the chloro group. The
structural assignments of the alcohols ultimately rests with
their conversions into 14 and 15 (see below); however, the
13C NMR of the C(2) carbons in the anti and syn alcohols
appeared at δ 63.86 and 67.63 ppm, respectively. The
relatively few examples of the stereoselective reduction of
Acknowledgment. We thank Professor Timothy Gal-
lagher, University of Bristol, for providing us with synthetic
procedures for (+)-sedridine (14). We also thank Ashwin
Rao for preliminary studies. This work was supported by a
grant from the NIGMS (GM51982).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) For reviews on sedum and related alkaloids, see: (a) ref 2. (b) Strunz,
G. M.; Findlay, J. A. Pyridine and Piperidine Alkaloids. In The Alkaloids;
Brossi, A., Ed.; Academic Press: New York, 1985; Vol. 26, pp 89-174.
(16) Meth-Cohn, O.; Yu, C.-Y.: Lestage, P.; M.-C.; Cagniard, D.-H.;
Renard, P. Eur. Pat. 1050531, 2000.
(17) For asymmetric syntheses of these alkaloids, see: (a) Takahata, H.;
Kubota, M.; Ikota, N. J. Org. Chem. 1999, 64, 8594. (b) Louis, C.; Hottele,
C. Tetrahedron: Asymmetry 1997, 8, 109. (c) Littler, B. J.; Gallagher, T.;
Boddy, I. K.; Riordan, P. D. Synlett 1997, 22.
(18) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J. Org. Chem. 1999, 64, 1043. (b) Fanelli, D. L.; Szewczyk,
J. M.; Zhang, Y.; Reddy, G. V.; Burns, D. M.; Davis, F. A. Org. Synth.
1999, 77, 50.
OL034119Z
(19) For a review on the reduction of amino ketones that includes a
section on the reduction of acyclic â-amino ketones, see: Tramontini, M.
Synthesis 1982, 605.
(20) (a) Veenstra, S. J.; Kinderman, S. S. Synlett 2001, 1109. (b) Wanner,
K. Th.; Hofner, G. Tetrahedron 1991, 47, 1895. (c) Pilli, R. A.; Russowsky,
D.; Dias, L. C. J. Chem. Soc., Perkin Trans. 1 1990, 1213. (d) Barluenga,
J.; Aguilar, E.; Fustero, S.; Olano, B.; Viado, A. L. J. Org. Chem. 1992,
57, 1219.
(21) Greeves, N. In ComprehensiVe Organic Synthesis; Trost B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 8, Chapter 1, p 1.
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