Cyclic sulfamidates as vehicles for the synthesis of substituted lactams

Article abstract of DOI:10.1021/ol048036+

(Chemical Equation Presented) A structurally diverse series of mono- and disubstituted 1,2- and 1,3-cyclic sulfamidates react with stabilized enolates, including malonate and phosphonoacetate variants, to provide, after lactamization, substituted and α-fu

Full text of DOI:10.1021/ol048036+

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4727-4730
Cyclic Sulfamidates as Vehicles for the
Synthesis of Substituted Lactams
John F. Bower,† Jakub Svenda,† Andrew J. Williams,†
ˇ
Jonathan P. H. Charmant,†,‡ Ron M. Lawrence,§ Peter Szeto,§ and
Timothy Gallagher*,†
School of Chemistry, UniVersity of Bristol, Bristol, BS8 1TS, UK, and Chemical
DeVelopment, GlaxoSmithKline, Medicines Research Centre, SteVenage, SG1 2NY UK
t.gallagher@bristol.ac.uk
Received September 27, 2004
ABSTRACT
A structurally diverse series of mono- and disubstituted 1,2- and 1,3-cyclic sulfamidates react with stabilized enolates, including malonate and
phosphonoacetate variants, to provide, after lactamization, substituted and
r-functionalized pyrrolidinone and piperidinone derivatives.
Cyclic sulfamidates 1 represent a readily accessible and
versatile set of amino alcohol-derived electrophiles that
undergo facile and regiospecific nucleophilic substitution at
the O-bearing carbon center.1
thiomorpholinones in a highly stereocontrolled manner
(Scheme 1).3
Scheme 1. Piperazinones and Thiomorpholinones from
1,2-Cyclic Sulfamidates
This reactivity profile makes 1,2- and 1,3-cyclic sulfami-
dates equivalent to activated aziridines and azetidines
respectively, and the reaction of cyclic sulfamidates with
simple nucleophiles, e.g., CN-, F-, N3 , has been reported.2
-
This sequence involves nucleophilic ring opening (via N
or S) and a subsequent lactamization step to create the
heterocyclic framework. However, the reactivity of cyclic
sulfamidates toward synthetically more versatile carbon-
based nucleophiles such as enolates have been less widely
exploited.4 In this paper we describe the reactivity of a series
of readily available and structurally representative cyclic
sulfamidates toward functionalized enolates that leads, via
initial nucleophilic ring opening and subsequent lactamiza-
In earlier work we demonstrated that enantiomerically pure
1,2-cyclic sulfamidates react efficiently with R-amino and
R-thiol esters to provide substituted piperazinones and
† University of Bristol.
‡ Structural Chemistry Group, University of Bristol.
§ GlaxoSmithKline.
(1) For a recent and very comprehensive review, see: Mele´ndez, R. E.;
Lubell, W. D. Tetrahedron 2003, 59, 2581-2616.
(2) Details of nucleophilic displacements up until 2003 are available in
ref 1. For very recent work leading to â2,2-amino acids via 1,2-cyclic
sulfamidates, see: Avenoza, A.; Busto, J. H.; Corzana, F.; Jime´nez-Ose´s,
G.; Peregrina, J. M. Chem. Commun. 2004, 980-981.
(3) Williams, A. J.; Chakthong, S.; Gray, D.; Lawrence, R. M.; Gallagher,
T. Org. Lett. 2003, 5, 811-814.
10.1021/ol048036+ CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/17/2004

tion, to substituted and functionally useful pyrrolidinones and
piperidinones (Scheme 2).
Scheme 3. Malonate as an Effective Carbon Nucleophile
Scheme 2. Pyrrolidinones and Piperidinones via 1,2- or
1,3-Cyclic Sulfamidates and Enolates
We have focused on R-functionalized enolates primarily
for the advantages associated with the use of stabilized
enolates as nucleophiles and also for the additional synthetic
flexibility that these reactants provide within the heterocyclic
product.
The enantiomerically pure phenylalaninol-derived cyclic
sulfamidate 2a5 reacts readily with the enolate of diethyl
malonate and, following treatment with acid (to cleave the
initially formed N-sulfate) and neutralization, lactam 3a (as
a 3:2 mixture of C(3) diastereomers) was isolated in 71%
yield (Scheme 3). This intermediate underwent ester cleavage
and decarboxylation to give pyrrolidinone 4a in 50% overall
yield from 2a. Under similar conditions, cyclic sulfamidate
2b derived from ephedrine gave the trisubstituted pyrroli-
dinone 3b as a single diastereomer in 60% yield, with clean
inversion of stereochemistry at C(4) being observed.6 The
racemic 1,3-sulfamidate 2c afforded piperidinone 3c (57%,
as a 1:1 mixture of diastereomers), which gave 4c (71%)
following decarboxylation. The only issue in this last case
was the need for a separate lactamization step, which was
carried out under basic conditions; while 5-ring lactamization
(leading to 3a and 3b) occurred spontaneously, the corre-
sponding cyclization to form the six-membered ring of 3c
was more sluggish.
4). These reactions proceed in a manner similar to those
outlined in Scheme 3, but certain modifications were
necessary. Using 2a as a model substrate, reaction with
triethyl phosphonoacetate 5 under basic conditions, followed
by acidic hydrolysis and thermally induced lactamization
(PhMe, reflux), gave phosphonate 6a in 96% yield.7 The use
of this intermediate in the Wadsworth-Emmons olefination
process was also validated using paraformaldehyde, cyclo-
hexanone, and butanal to give the exoalkylidene derivatives
7a-c, respectively.8
Similarly, the 4,5-disubstituted cyclic sulfamidate 2b was
converted to trisubstituted lactam-based phosphonate 6b in
The reactivity of a series of cyclic sulfamidates toward a
phosphorus-stabilized enolate has also been studied (Scheme
Scheme 4. Phosphonate-Stabilized Enolates and
Wadsworth-Emmons Olefinations
(4) (a) Baldwin, J. E.; Spivey, A. C.; Schofield, C. J. Tetrahedron:
Asymmetry 1990, 1, 881-884. (b) Boulton, L. T.; Stock, H. T.; Raphy, J.;
Horwell, D. C. J. Chem. Soc., Perkin Trans. 1 1999, 1421-1429. (c) Wei,
L.; Lubell, W. D. Org. Lett. 2000, 2, 2595-2598. (d) Wei, L.; Lubell, W.
D. Can. J. Chem. 2001, 79, 94-104. Cyclic sulfamidates react with certain
carbon-based nucleophiles (cuprates, RLi, -CN) (see ref 1), but specific
examples involving enolates have also been described. Lubell4c,d has shown
that a 1,2-cyclic sulfamidate derived from serine reacts with enolates both
directly and via an elimination-addition sequence, which results in
significant loss of enantiomeric integrity. However, in a related but sterically
more demanding sulfamidate, Boulton4b showed that enolates and silyl enol
ethers failed to react. A 1,3-cyclic sulfamidate derived from homoserine
underwent nucleophilic ring opening with a stabilized enolate.1
(5) (a) Wehn, P. M.; Lee, J. H.; Du Bois, J. Org. Lett. 2003, 5, 4823-
4826. (b) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935-6936. (c) Posakony, J. J.; Grierson, J. R.; Tewson,
T. J. J. Org. Chem. 2002, 67, 5164-5169. 1,2-Cyclic sulfamidates were
prepared as described earlier from the corresponding 2-amino alcohols.3
1,3-Cyclic sulfamidate 2c was prepared using the method of Du Bois.
Subsequent N-benzylation was carried out under Tewson’s phase transfer
conditions. See Supporting Information. A more conventional approach to
2c from the corresponding amino alcohol was examined, but oxidation of
the intermediate 1,3-cyclic sulfamidite was inefficient. Substrates 2a, 2b,
and 2e were prepared using enantiomerically pure starting materials and
2c and 2d were racemic.
(6) The structure of 3b was determined by X-ray crystallographic
analysis. Details are available in Supporting Information.
4728
Org. Lett., Vol. 6, No. 25, 2004

31% overall yield. Lactamization in this latter case occurred
spontaneously upon neutralization, and again complete
inversion of stereochemistry at C(4) was observed. On the
other hand, although 2c did react with the enolate of 5, this
step and in particular the subsequent lactamization were not
efficient reactions.
Scheme 6. Aryl-Substituted Enolates as Nucleophiles:
Synthesis of R-Arylated Lactams
Diethyl malonate and triethyl phosphonoacetate both
provide stabilized enolates that impart additional synthetic
flexibility to the lactam products. We were also interested
in examining less classically stabilized and more basic
enolates in order to define the scope of this methodology
more effectively. (The malonate and phosphonate-derived
products, e.g., 3a-c and 6a/b, are stereochemically labile
at C(3), but less acidic centers offer a possibility of kinetic
control of stereochemistry at this site.)9 Enolates derived from
R-aryl acetates were particularly attractive, as they offered
access to R-arylated pyrrolidinones (Schemes 5 and 6). The
was induced thermally (PhMe, reflux). In the case of
piperidinone 9c, lactamization was evaluated under a series
of different conditions with the use of NaCN (10 mol %) as
a nucleophilic catalyst being most efficient.10,11 Several other
stereochemical points require clarification. The relative
configuration of racemic 9d was established by X-ray
crystallographic analysis (details are available in Supporting
Information), and the SN2 nature of the initial displacement
was clearly demonstrated using the pseudoephedrine-derived
cyclic sulfamidate 2e. This provided 9e (as a single di-
astereomer), a stereoisomer of the two products 9b derived
from the analogous reaction of the ephedrine derivative 2b.
It is also important to note that the R-arylated lactams 9a-c
were isolated as 1.5-2.5:1 mixtures of diastereomers at C(3).
The nitrophenyl derivative 8 provides a relatively stabilized
enolate, but other, more conventional aryl acetates 10 (Ar
) Ph) and 11 (Ar ) 4-MeOC6H4) are also effective (Scheme
6).12 Using 2a as a representative cyclic sulfamidate, enolates
derived from both 10 and 11 provided the R-arylated
analogues 12 and 13 in 73 and 65% yields, respectively, and
as mixtures of diastereomers at C(3).
Scheme 5. Aryl-Substituted Enolates as Nucleophiles:
Synthesis of R-Arylated Lactams (Ar ) 4-NO2C6H4)
In summary, we have demonstrated that a series of
structurally representative 1,2- and 1,3-cyclic sulfamidates,
react well with a variety of both stabilized and more
conventional enolates, leading to heterocyclic products that
(7) R-Phosphonolactams analogous to 6a have been prepared previously
in a number of different ways and utilized in olefination processes. For
recent representative examples, see: Gois, P. M. P.; Afonso, C. A. M. Eur.
J. Org. Chem. 2003, 3798-3810. Gois, P. M. P.; Afonso, C. A. M.
Tetrahedron Lett. 2003, 44, 6571-6573. Du, Y. M.; Wiemer, D. F. J. Org.
Chem. 2002, 67, 5709-5717.
(8) R-Phosphonolactam 6a was a mixture of diastereomers at C(3), which
had no impact on the subsequent Wadsworth-Emmons reaction. In the
case of 6b, a single isomer was isolated and assigned by analogy to 3b.6
(9) In the case of 9b, a 5:2 ratio of C(3) diastereomers was observed,
while single (presumably thermodynamically more stable) diastereomers
were seen for the corresponding malonate and phosphonate adducts 3b and
6b, respectively.
(10) Mori, K.; Tominaga, M.; Takigawa, T.; Matsui, M. Synthesis 1973,
790-791. Ho¨gberg, T.; Stro¨m, P.; Ebner, M.; Ra¨msby, S. J. Org. Chem.
1987, 52, 2033-2036. For an earlier application of cyanide-mediated
lactamization, see ref 3.
(11) Our observations are that the initial nucleophilic displacement
reaction involving 2c occurs efficiently, but the subsequent lactamization
leading to a six-membered ring is more demanding. In addition to NaCN/
MeOH, lactamization to give 9c was also achieved using either p-xylene at
reflux (37%) or EtONa/EtOH at reflux (23%).
(12) A trend is apparent here. Sulfamidate 2a gives lowered yields of
3,5-disubstituted lactams as the enolate becomes more basic: 9a (88%);
12 (73%); 13 (65%). It is also pertinent to mention that attempts to use
simple alkyl enolates, e.g., sodium ethyl propanoate, have failed.
enolate derived from ethyl 4-nitrophenylacetate 8 was studied
most widely and provided a range of substitution patterns
that were determined by the cyclic sulfamidate used. These
reactions paralleled those described earlier: initial nucleo-
philic displacement, N-sulfate cleavage using acid, neutral-
ization, and lactamization. The lactamization step occurred
either spontaneously (upon neutralization with NaHCO3) or
Org. Lett., Vol. 6, No. 25, 2004
4729

can be further utilized in other ways. It is also important to
recognize R-amino acids and 2-amino alcohols are precursors
to 1,2-cyclic sulfamidates (e.g., 2a and 2b), which in turn
provides access to the corresponding enantiomerically pure
nitrogen heterocycles. Other recent work has also defined
new routes to 1,2-, 1,3-, and 1,4-cyclic sulfamidates, which
serves to extend further the potential of these units as
substrates for heterocyclic synthesis.13
Acknowledgment. We thank the EPSRC and GSK
Research & Development for financial support and acknowl-
edge the support provided by the EPSRC Mass Spectrometry
Service Centre at the University of Swansea.
(13) Nicolaou, K. C.; Snyder, S. A.; Nalbandian, A. Z.; Longbottom, D.
A. J. Am. Chem. Soc. 2004, 126, 6234-6235. Liang, J. L.; Yuan, S. X.;
Huang, J. S.; Che, C. M. J. Org. Chem. 2004, 69, 3610-3619. Fruit, C.;
Mu¨ller, P. Tetrahedron: Asymmetry 2004, 15, 1019-1026. Liang, J. L.;
Yuan, S. X.; Huang, J. S.; Yu, W. Y.; Che, C. M. Angew. Chem., Int. Ed.
2002, 41, 3465-3468. Duran, F.; Leman, L.; Ghini, A.; Burton, G.; Dauban,
P.; Dodd, R. H. Org. Lett. 2002, 4, 2481-2483. Nicolaou, K. C.; Huang,
X. H.; Snyder, S. A.; Rao, P. B.; Bella, M.; Reddy, M. V. Angew. Chem.,
Int. Ed. 2002, 41, 834-838. Yu, X. Q.; Huang, J. S.; Zhou, X. G.; Che, C.
M. Org. Lett. 2000, 2, 2233-2236.
Supporting Information Available: Experimental and
1
characterization data, including copies of H and 13C NMR
for all new compounds, and crystallographic details for 3b
and 9d. This material is available free of charge via the
Internet at http://pubs.acs.org.
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