Cyclic sulfamidates as precursors to alkylidene pyrrolidines and piperidines

Article abstract of DOI:10.1021/ol7022104

(Chemical Equation Presented) The reaction of the dienolate of ethyl acetoacetate (and related dienolates) with a range of 1,2- and 1,3-cyclic sulfamidates provides an entry to substituted and enantiopure alkylidenated pyrrolidines and piperidines. These

Full text of DOI:10.1021/ol7022104

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4909-4912
Cyclic Sulfamidates as Precursors to
Alkylidene Pyrrolidines and Piperidines
John F. Bower,† Peter Szeto,‡ and Timothy Gallagher*,†
School of Chemistry, UniVersity of Bristol, Bristol BS8 1TS, U.K., and Synthetic
Chemistry, GlaxoSmithKline, Medicines Research Centre, SteVenage SG1 2NY, U.K.
t.gallagher@bristol.ac.uk
Received September 8, 2007
ABSTRACT
The reaction of the dienolate of ethyl acetoacetate (and related dienolates) with a range of 1,2- and 1,3-cyclic sulfamidates provides an entry
to substituted and enantiopure alkylidenated pyrrolidines and piperidines. These heterocycles function as convenient precursors to heterocyclic
â
-amino acid derivatives.
Alkylidene variants of pyrrolidines and piperidines (1 and
2) represent a versatile family of N-heterocycles which have
found numerous applications in a variety of synthetic
settings.1 The most common route to members of this class
of compound involves alkylidenation of a lactam precursor
by activation of the otherwise unreactive carbonyl unit. In
this regard, the classical Eschenmoser sulfide contraction of
thiolactams has found widespread application2 as has lactam
activation via the corresponding iminoether.3,4 While ef-
ficient, these approaches necessarily rely on first obtaining
a suitably substituted (and enantiopure) lactam precursor.
We are interested in heterocyclic alkylidenes 1 and 2 as
suitable intermediates for the synthesis of substituted (and
enantioenriched) homoproline and homopipecolinic acid
derivatives, respectively. Accordingly, we sought a direct
but flexible entry which would provide access to range of
substitution patterns, and in this paper, we disclose our
studies in this area. We have explored the reactivity of 1,2-
and 1,3-cyclic sulfamidates 3 with both heteroatom and
carbon-based nucleophiles to provide a variety of N-
heterocyclic scaffolds, including 4 and 5 (Scheme 1).5,6
† University of Bristol.
‡ GlaxoSmithKline.
(1) For a review on the synthesis and reactivity of alkylidene pyrrolidines,
see: Elliott, M. C.; Wood, J. L.; Wordingham, S. V. Trends Heterocycl.
Chem. 2005, 10, 73-95.
(2) (a) Fischli, A.; Eschenmoser, A. Angew. Chem., Int. Ed. 1967, 6,
866-868. (b) Yamada, Y.; Miljkovic, D.; Wehrli, P.; Golding, B.; Lo¨liger,
P.; Keese, R.; Mu¨ller, K.; Eschenmoser, A. Angew. Chem., Int. Ed. 1969,
8, 343-348. (c) Roth, M.; Dubs, P.; Go¨tschi, E.; Eschenmoser, A. HelV.
Chim. Acta, 1971, 54, 710-734. For other selected examples of this method,
see: (d) Gossauer, A.; Hinze, R.-P.; Zilch, H. Angew. Chem., Int. Ed. 1977,
16, 418-418. (e) Shiosaki, K.; Rapoport, H. J. Org. Chem. 1985, 50, 1229-
1239. (f) Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925-3927.
(3) For selected examples of lactam alkylidenation via the intermediacy
of imino ethers, see: (a) Ce´le´rier, J.-P.; Deloisy, E.; Lhommet, G.; Maitte,
P. J. Org. Chem. 1979, 44, 3089-3089. (b) Coppola, G. M.; Damon, R. E.
A. J. Heterocyclic Chem. 1990, 27, 815-817. (c) Millet, R.; Domarkas, J.;
Rombaux, P.; Rigo, B.; Houssin, R.; He´nichart, J.-P. Tetrahedron Lett. 2002,
43, 5087-5088.
(4) For other selected approaches to alkylidene pyrrolidines, see: (a)
Breuer, E.; Zbaida, S. J. Org. Chem. 1977, 42, 1904-1910. (b) Hannick,
S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833-3835. (c) Lambert, P. H.;
Vaultier, M.; Carrie´, R. J. Org. Chem. 1985, 50, 5352-5356. (d) Shaw, K.
J.; Luly, J. R.; Rapoport, H. J. Org. Chem. 1985, 50, 4515-4523. (e)
Michael, J. P.; Hosken, G. D.; Howard, A. S. Tetrahedron 1988, 44, 3025-
3036. (f) Jacobi, P. A.; Brielmann, H. L.; Hauck, S. I. J. Org. Chem. 1996,
61, 5013-5023. (g) Jacobi, P. A.; Buddhu, S. C.; Fry, D.; Rajeswari, S. J.
Org. Chem. 1997, 62, 2894-2906. (h) Langer, P.; Freifeld, I. Chem.
Commun. 2002, 2668-2669. (i) Elliott, M. C.; Wordingham, S. V. Synthesis
2006, 1162-1170.
(5) For a review on the synthesis and reactivity of cyclic sulfamidates,
see: Mele´ndez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581-2616.
10.1021/ol7022104 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/20/2007

Scheme 1. Cyclic Sulfamidates as Precursors to
N-Heterocycles
Scheme 3. Synthesis of Alkylidenepyrrolidine 8aa
a For other examples, see Table 1.
with NaH (1 equiv) and then n-BuLi (1 equiv) at 0 °C prior
to addition of the cyclic sulfamidate.
The N-benzylated phenylalanine-derived cyclic sulfamidate
7a, which serves to illustrate the process involved, reacted
efficiently at room temperature to afford adduct 8a in 79%
yield after N-sulfate hydrolysis and cyclization; the latter
occurred spontaneously under the acidic conditions em-
ployed. The stereochemistry of 8a was determined by a
Nucleophilic attack occurs exclusively at the C-O bond in
a highly stereospecific (SN2) manner to afford an N-sulfate
intermediate which, after acid-promoted hydrolysis and
lactamization, delivers the target heterocycles.
We reasoned that an enolate-based strategy relying on
the reaction of 1,2- and 1,3-cyclic sulfamidates with the
dianion 6 of ethyl acetoacetate (and related nucleophiles)
would also provide a general entry to alkylidenepyrrolidines
and -piperidines. Acid-promoted hydrolysis of the result-
ing N-sulfate intermediate and cyclization would afford
heterocycles 1 and 2 which can be converted to the
requisite amino acid derivatives under reductive conditions
(Scheme 2).
Table 1. Alkylidene Pyrrolidines and Piperidines via the
Dienolate of 6 and Cyclic Sulfamidates 7a-f
Scheme 2
Using a structurally representative set of cyclic sulfami-
dates 7a-f we have been able to generate a range of
substituted and enantiopure adducts 8a-f in good to moder-
ate yield (Scheme 3 and Table 1).7 Formation of dianion 6
was achieved by successive treatment of ethyl acetoacetate
(6) (a) Williams, A. J.; Chakthong, S.; Gray, D.; Lawrence, R. M.;
Gallagher, T. Org. Lett. 2003, 5, 811-814. (b) Bower, J. F.; Sˇvenda, J.;
Williams, A. J.; Charmant, J. P. H.; Lawrence, R. M.; Szeto, P.; Gallagher,
T. Org. Lett. 2004, 6, 4727-4730. (c) Bower, J. F.; Szeto, P.; Gallagher,
T. Chem. Commun. 2005, 5793-5795. (d) Bower, J. F.; Chakthong, S.;
Sˇvenda, J.; Williams, A. J.; Lawrence, R. M.; Szeto, P.; Gallagher, T. Org.
Biomol. Chem. 2006, 4, 1868-1877. (e) Bower, J. F.; Szeto, P.; Gallagher,
T. Org. Biomol. Chem. 2007, 5, 143-150. (f) Bower, J. F.; Riis-Johannessen,
T.; Szeto, P.; Whitehead, A. J.; Gallagher, T. Chem. Commun. 2007, 728-
730. (g) Bower, J. F.; Williams, A. J.; Woodward, H.; Szeto, P.; Lawrence,
R. M.; Gallagher, T. Org. Biomol. Chem. 2007, 5, 2636-2644. (h) Bower,
J. F.; Szeto, P.; Gallagher, T. Org. Lett. 2007, 9, 3283-3286.
a In these cases, racemic cyclic sulfamidate was employed.
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Org. Lett., Vol. 9, No. 23, 2007

diagnostic NOE enhancement observed between the N-
benzylmethylene moiety and the alkene proton; similar NOE
correlations provided the basis of the assignments shown in
Table 1 for the other substrates studied. Carbamate-protected
cyclic sulfamidates are also suitable for this chemistry, and
Boc-protected derivative 7b was equally effective, affording
8b in 76% yield.8 It is relevant to note that the Boc group
survives the acidic conditions required for hydrolysis of the
N-sulfate intermediate.
Table 2. Reactivity of Cyclic Sulfamidate 7a toward
Substituted Dienolates Derived from 9a-c
The scope and present limitations of this heteroannulation
process are illustrated in Table 1. Other sterically more
demanding and less reactive substrates (Table 1, entries 3-6)
did require elevated temperatures to deliver the target adducts
8c-f albeit in more modest yields. In these cases, prolonged
heating at 50 °C was preferable (24-72 h) as use of higher
temperatures led to degradation of the enolate component.
In some cases, e.g., entry 6, it was still difficult to achieve
complete consumption of the starting cyclic sulfamidate but
heterocycle 8f was nevertheless isolated in a synthetically
useful 45% yield.
The SN2 nature of the nucleophilic displacement step is
clearly demonstrated by directly comparing entries 3 vs 4,
each of which was stereospecific. One limitation of this
dienolate-based methodology involves base-sensitive sub-
strates, such as 7e. In this case, and in addition to 8e (19%),
a substantial amount (30%) of N-benzylcinnamylamine (the
product of elimination of 7e) was also isolated.9
conditions [5% Pt/C (30 wt %), EtOAc, H2 (4 bar)] (Scheme
4).10 Alkylidene reduction occurred without N-debenzylation
Using cyclic sulfamidate 7a, we have explored the scope
of the nucleophilic component (Table 2). For example,
substitution at both C(2) and C(4) of the nucleophile (as in
9a and 9b) is tolerated and the respective products 10a and
10b were obtained in good yield. In the case of 10a, little
stereochemical control was observed at the newly installed
C(3) stereocenter, and the product was isolated as a 3:2
mixture of diastereomers. Additional rings are also tolerated
within the nucleophile as demonstrated by entry 3. In this
case, product 10c was isolated in high diastereoselectivity,
although traces (<10%) of the minor diastereomer were
evident. While the structure of 10b was assigned by NOE
experiments (see the Supporting Information), this was not
possible with 10c as no suitable signals were available, and
a tentative assignment (on steric grounds and by analogy to
8a) is shown in Table 2. More hindered nucleophiles are,
however, not suitable partners for less reactive cyclic
sulfamidates and reaction of the ephedrine derivative 7c with
the dianion derived from 9a resulted in only trace amounts
of the desired adduct.
Scheme 4. Reductive Manipulation of Pyrrolidine 8a
to afford 11 in excellent yield (89%) but modest diastereo-
1
selectivity (5:2 cis/trans by H NMR analysis of the crude
product). The stereochemical outcome of this reaction was
assigned on the basis of NOE experiments, which were
consistent with literature precedent: irradiation of H(5) in
trans-11 showed an enhancement of one of the H(2′)
methylene protons. On this basis, the minor isomer of 11
was assigned as trans and the major component as the cis
diastereomer. Under more forcing conditions [H2 (6 bar),
AcOH, TFA, 10% Pd/C (55 wt %)], hydrogenation of both
the alkene and N-benzyl groups occurred to give â-amino
ester 12 in essentially quantitative yield and with an increased
(9:1) level of cis/trans selectivity.11
Validation of these alkylidene substrates as precursors of
â-amino acids has been carried out on 8a using Rapoport’s
(7) For details of the preparation of cyclic sulfamidates 7a-f, see our
earlier work.6a,,h Cyclic sulfamidates 7a-d were prepared from the
corresponding enantiopure 1,2-amino alcohols, whereas substrates 7e and
7f were most conveniently obtained in racemic form. We have already
demonstrated an ability to exploit enantiomerically pure 3-substituted 1,3-
cyclic sulfamidates (cf. 7f) in related chemistry.6f
In summary, we have shown that a structurally representa-
tive range of 1,2- and 1,3-cyclic sulfamidates undergo
nucleophilic cleavage with the dianion of ethyl acetoacetate
(8) In this case, analysis of the crude reaction product by 1H NMR
indicated the presence of some uncyclized material (in addition to 8b);
complete cyclization then occurred during chromatographic purification.
Analogous observations have been reported by Elliott on related systems.4i
(9) We have previously shown that this substrate has a propensity to
â-elimination under basic conditions.6d
(10) Herna´ndez, A.; Marcos, M.; Rapoport, H. J. Org. Chem. 1995, 60,
2683-2691.
Org. Lett., Vol. 9, No. 23, 2007
4911

to afford, after N-sulfate hydrolysis and cyclization, a range
of substituted and enantiopure alkylidene pyrrolidines and
piperidines. The scope of this chemistry has been probed in
terms of both the nucleophilic and electrophilic components,
and the conversion of a representative alkylidene pyrrolidine
to a C(5)-substituted homoproline derivative (11/12) has been
demonstrated. The direct nature of this methodology, which
complements existing approaches, provides an attractive
entry to alkylidenated lactams, enhanced by the availability
of substituted and enantiopure 1,2- and 1,3-cyclic sulfami-
dates.
Acknowledgment. We thank the EPSRC and GSK for
financial support and Dr. D. M. Lindsay (University of
Bristol) for helpful discussions.
Supporting Information Available: Full experimental
(11) Reduction of exo-alkylidene variants of pyrrolidines and piperidines
to provide â-amino acids has been extensively reported; see: Hashimoto,
N.; Funatomi, T.; Misaki, T.; Tanabe, Y. Tetrahedron 2006, 62, 2214-
2223 and references therein. For an example related to 8a involving a
substituted heterocyclic variant, see: Calvet-Vitale, S.; Vanucci-Bacque´,
C.; Fargeau-Bellassoued, M. C.; Lhommet, G. Tetrahedron 2005, 61, 7774-
7782.
1
details, compound characterization data, and copies of H
and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL7022104
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Org. Lett., Vol. 9, No. 23, 2007