Azabicyclic amino acids by stereoselective dearomatizing cyclization of the enolates of N-nicotinoyl glycine derivatives

Article abstract of DOI:10.1021/ol062126s

On activation by pyridine N-acylation, enolates of N-nicotinoyl and N-isonicotinoyl glycine and alanine derivatives cyclize to yield 6,5-azabicyclic or 6,4-azaspirocyclic lactams. With an N-α-methyl-p-methoxybenzyl group the cyclization is diastereoselect

Full text of DOI:10.1021/ol062126s

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5325-5328
Azabicyclic Amino Acids by
Stereoselective Dearomatizing
Cyclization of the Enolates of
N-Nicotinoyl Glycine Derivatives
Gareth Arnott, Jonathan Clayden,* and Stuart D. Hamilton
School of Chemistry, UniVersity of Manchester,
Oxford Road, Manchester M13 9PL, U.K.
j.p.clayden@man.ac.uk
Received August 29, 2006
ABSTRACT
On activation by pyridine N-acylation, enolates of N-nicotinoyl and N-isonicotinoyl glycine and alanine derivatives cyclize to yield 6,5-azabicyclic
or 6,4-azaspirocyclic lactams. With an N- -methyl-p-methoxybenzyl group the cyclization is diastereoselective; hydrogenation and deprotection
yields azabicyclic amino acids in 94:6 er.
r
Dearomatizing intramolecular nucleophilic addition of anions
to aromatic rings has proved a useful strategy for building
bicyclic scaffolds carrying synthetically versatile functional
groups.1,2 The cyclization of N-benzyl benzamides, for
example, provides useful intermediates for the synthesis of
the cyclic kainoid amino acids.3 For dearomatization to be
viable, however, the cyclization must be propelled by a
considerable driving force and for this reason has been
successful only with relatively unstable, basic anions such
as benzyllithiums,4 restricting subsequent synthetic applica-
tion of the reaction. We now report success in the dearo-
matizing cyclization of the enolates of amino acid derivatives
provided the acceptor is an electron-deficient pyridine ring,
which may be activated toward attack by N-acylation eVen
in the presence of the enolate.
We had previously observed that N-benzyl pyridinecar-
boxamides, on lithiation, will cyclize to yield fused or spiro
(1) For an overview of recent work in this area, see: (a) Clayden, J.,
Stravinsky: Total synthesis of kainoids by dearomatizing anionic cyclization.
In Strategies and Tactics in Organic Synthesis; Harmata, M., Ed.; Academic
Press: 2004; Vol. 4, pp 72-96. (b) Clayden, J.; Kenworthy, M. N. Synthesis
2004, 1721. (c) Clayden, J.; Knowles, F. E.; Menet, C. J. J. Am. Chem.
Soc. 2004, 110, 9278.
(2) For examples of dearomatizing anionic cyclizations from other
research groups, see: (a) Ferna´ndez, I.; Ortiz, F. L.; Tejerina, B.; Granda,
S. G. Org. Lett. 2001, 3, 1339. (b) Go´mez, G. R.; Ortiz, F. L. Synlett 2002,
781. (c) Fernandez, I.; Ortiz, F. L.; Velazquez, A. M.; Granda, S. G. J.
Org. Chem. 2002, 67, 3852. (d) Aggarwal, V. K.; Alonso, E.; Ferrara, M.;
Spey, S. E. J. Org. Chem. 2002, 67, 2335. (e) Breternitz, H.-J.; Schaumann,
E.; Adiwidjaja, G. Tetrahedron Lett. 1991, 32, 1299. (f) Padwa, A.;
Filipkowski, M. A.; Kline, D. N.; Murphree, S. S.; Yeske, P. E. J. Org.
Chem. 1993, 58, 2061. (g) Crandall, J. K.; Ayers, T. A. J. Org. Chem.
1992, 57, 2993.
(3) (a) Clayden, J.; Read, B.; Hebditch, K. R. Tetrahedron 2005, 61,
5713. (b) Clayden, J.; Knowles, F. E.; Baldwin, I. R. J. Am. Chem. Soc.
2005, 127, 2412. (c) Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron
2002, 58, 4727. (d) Clayden, J.; Tchabanenko, K. Chem. Commun. 2000,
317. (e) Clayden, J.; Knowles, F. E.; Menet, C. J. Tetrahedron Lett. 2003,
44, 3397. (f) Ahmed, A.; Bragg, R. A.; Clayden, J.; Tchabanenko, K.
Tetrahedron Lett. 2001, 42, 3407.
(4) (a) Ahmed, A.; Clayden, J.; Rowley, M. Chem. Commun. 1998, 297.
(b) Ahmed, A.; Clayden, J.; Yasin, S. A. Chem. Commun. 1999, 231. (c)
Clayden, J.; Menet, C. J.; Mansfield, D. J. Org. Lett. 2000, 2, 4229. (d)
Clayden, J.; Knowles, F. E.; Menet, C. J. Synlett 2003, 1701. (e) Clayden,
J.; Turnbull, R.; Pinto, I. Org. Lett. 2004, 6, 609. (f) Clayden, J.; Turnbull,
R.; Helliwell, M.; Pinto, I. Chem. Commun. 2004, 2430. (g) Clayden, J.;
Purewal, S.; Helliwell, M.; Mantell, S. J. Angew. Chem., Int. Ed. 2002, 41,
1049.
10.1021/ol062126s CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/18/2006

bicyclic dihydropyridines.5 The reaction’s rate was enhanced,
its regioselectivity modified, and the products stabilized when
the pyridine was activated by N-acylation. Given an acceptor
as electrophilic as an N-acylpyridine, it seemed reasonable
that rather less basic nucleophiles, such as enolates, might
also undergo the cyclization. Dearomatizing intermolecular
additions to activated pyridines are well-known,6 and our
proposed cyclization would lead directly to structurally
interesting bicyclic or spirocyclic amino acids.
diastereoisomer of 7a has relative stereochemistry opposite
to that formed in related cyclization of N-benzyl nicotina-
mides.5 The spirocyclic â-lactam 4a could also be formed
in excellent yield in the same way (Table 1, entries 1 and
7).
Table 1. Cyclization, Hydrogenation, and Deprotection with
Various N-Protecting Groups
Cyclization precursors 2a and 5a were made by acylating
N,O-di-tert-butyl glycine 1a with nicotinoyl and isonicotinoyl
chloride (Scheme 1). Both esters were treated with KHMDS
3
4 or 7
4g,h or 7g,ha
(yield %)
entry S.M.
R1
R2 (yield %) (yield %)
1
2
3
4
5
2a
2b
2c
2d
2e
2f
t-Bu
Bn
Cum
PMP
PMB
H
H
H
H
H
3a (94)
3b (39) 4b (89)
3c (98) 4c (94)
3d (47) 4d (96)
4a (97)
Scheme 1
3e (68)
4e (85)
4g (70)b
4h (44)b
6
PMB Me 3f (55)
4f (79)
7
8
9
10
5a
5c
5e
5f
t-Bu
Cum
PMB
H
H
H
c
c
c
c
7a (60)d,e
7c (54)d,f
7e (64)d,e,f
7f (43)d,g
7g (74)b
7h (33)b
PMB Me
a Deprotection yield. b Accompanied by 20-50% of 4or 7 (R )
COC6H4OMe). c Compound 6 not isolated. d Yield from 5. e 2:1 mixture
of diastereoisomers. f 1:1 mixture of diastereoisomers. g 6:1 mixture of
diastereoisomers. Stereochemistry assigned by analogy.
In order to establish whether cyclization takes place
immediately on formation of the enolate or after activation
of the pyridine ring by addition of the acylating agent, 2a
was cyclized in an NMR tube. On addition of KHMDS to
2a in d8-THF, only two 2H doublets were observed, at 7.48
and 8.32 ppm, consistent with the formation of 8 but not 9
prior to addition of the chloroformate (Scheme 2). We
Scheme 2
at -20 °C to form the enolate. After 5 min, methyl
chloroformate was added. In both cases, a dearomatizing
cyclization of the enolate onto the pyridine ring resulted,
and dihydropyridines 3a and 6a were isolated. Although 3a
was found to be stable at room temperature, 6a oxidized
rapidly in air, and in order to obtain a stable compound for
characterization it was immediately hydrogenated in high
yield to give the bicyclic γ-lactam 7a as a 2:1 mixture of
diastereoisomers. These were inseparable by chromatogra-
phy, but on standing the major diastereoisomer crystallized
and was isolated and fully characterized. Stereochemistry
was assigned by NOE studies and on the basis of the X-ray
crystal structures reported below; interestingly the major
conclude, remarkable though it is, that the chloroformate
reacts preferentially with the pyridine nitrogen atom faster
than it can undergo Claisen condensation (to give 11) with
the enolate. The varying stereoselectivity of reactions
presented below (Table 2) is also consistent with a mecha-
nism in which electrophilic quench is not preceded by an
irreversible cyclization step.
For wider applicability in synthesis it seemed appropriate
to replace the N-tert-butyl group7 of 2a with an alternative
(5) Clayden, J.; Hamilton, S. D.; Mohammed, R. T. Org. Lett. 2005, 7,
3673.
5326
Org. Lett., Vol. 8, No. 23, 2006

group more readily removable during a deprotection step.
A range of base-stable N-protecting groups-Bn, Cum,8 PMP,
and PMB-were surveyed (Table 1). Glycine derivatives
2b-e and 5c,e were made by acylation of the parent amines
1b-e and cyclized under the same conditions as for 2a and
5a (Scheme 1 and Table 1). â-Lactam cyclization product
3c was obtained in excellent yield, but in contrast with 2a
and 2c the cyclizations of less hindered isonicotinamides 2b,
2d, and 2e were accompanied by competing Claisen acylation
yielding 11 (tentatively identified in the crude reaction
product mixture). Bulky protecting groups assist the cycliza-
tion by slowing the competing Claisen reaction and perhaps
also favoring adoption of the reactive conformation. Hydro-
genation of the cyclized products was successful in all cases,
but only with the PMB protecting group was it possible to
achieve clean deprotection. â-Lactam 4g (R ) H) was
formed on treatment of 4e with ceric ammonium nitrate.
Even then, yields of up to 70% were obtained only with
excess CAN, and a significant byproduct was amide 4 (R1
) COC6H4OMe). Nicotinamides 5c and 5e gave, after
hydrogenation, the bicyclic products 7c and 7e in moderate
yield with competing oxidation of the dihydropyridine. Two
diastereoisomers were formed in each case, and the relative
stereochemistry of the more polar and more crystalline one
was confirmed by X-ray crystallography of 7c (Figure 1a).
by hydrogenation to 4f and 7f (Scheme 1 and Table 1).
Compounds 6f and 7f were formed as an inseparable 6:1
mixture of diastereoisomers. Deprotection of the lactams was
achieved by treatment with CAN, but again competing over-
oxidation to an amide 4 or 7 (R1 ) COC6H4OMe) compro-
mised the yield of the products 4g and 4h or 7g and 7h.
The “enolates” of nitriles 12 and 14 cyclized in moderate
yield under similar conditions (though with LDA as base)
(Scheme 3). Isonicotinamides 12a and 12b gave the â-lac-
Scheme 3
tams 13, and nicotinamides 14a and 14b gave the γ-lactams
1
15 as single diastereoisomers (by H NMR, relative stereo-
chemistry unknown); 15b was unstable toward oxidation to
the unusual aromatic azaisoindolone 16.
Hoping both to solve our protecting group problems and
lay the foundation of a new asymmetric method, we modified
the PMB group of 2e by adding a methyl group, making 18
from 17 (Scheme 4). Increased steric bulk meant that
Scheme 4
Figure 1. (a) X-ray crystal structure of 7c; (b) X-ray crystal
structure of anti-19d.
Alanine derivatives 2f and 5f also cyclized cleanly to â-
and γ-lactams 3f and 6f, and the products were stabilized
(6) For leading references, see: (a) Kuethe, J. T.; Comins, D. L. J. Org.
Chem. 2004, 69, 5221. (b) Bennasar, M.-L.; Zulaica, E.; Alonso, Y.; Bosch,
J. Tetrahedron: Asymmetry 2003, 14, 469. (c) Comins, D.; King, L.; Smith,
E.; Fevrier, F. Org. Lett. 2005, 7, 5059. (d) Comins, D. L.; Zheng, X.;
Goehring, R. R. Org. Lett. 2002, 4, 1622. (e) Charette, A. B.; Grenon, M.;
Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829.
(f) Rezgui, F.; Mangeney, P.; Alexakis, A. Tetrahedron Lett. 1999, 40, 6241.
(g) Bennasar, M. L.; Juan, C.; Bosch, J. Tetrahedron Lett. 2001, 42, 585.
(h) Bennasar, M.; Ljimenez, J-M.; Vidal, B.; Sufi, A.; Bosch, J. J. Org.
Chem. 1999, 64, 9605. (i) Bennasar, M. L.; Juan, C.; Bosch, J. Tetrahedron
Lett. 1998, 39, 9275. (j) Lavilla, R.; Gotsens, G.; Gu¨ero, M.; Masdeu, C.;
Santano, C.; Minguillon, C.; Bosch., J. Tetrahedron 1997, 53, 13959. (k)
Bosch, J.; Bennasar, M.-L. Synlett 1995, 587. (l) Wang, X.; Kauppi, A.;
Olsson R.; Almqvist, F. Eur. J. Org. Chem. 2003, 4586. (m) Yamada, S.;
Morita, C. J. Am. Chem. Soc. 2002, 124, 8184. (n) Pabel, J.; Ho¨sl, C.;
Maurus, M.,; Ege, M.; Wanner, K. J. Org Chem. 2002, 65, 9272. (o) Ho¨sl,
C.; Maurus, M.; Pabel, J.; Polborn, K.; Wanner, K. Tetrahedron 2002, 58,
6757.
competition from Claisen acylation during the cyclization
of 18 to 19 was minimal. Furthermore, cyclization of the
Org. Lett., Vol. 8, No. 23, 2006
5327

chiral N-R-methyl-p-methoxybenzyl amide 18 was highly
diastereoselective,9 with stereoselectivity increasing to 94:6
when LiHMDS was used as a base (Table 2, entries 1-3).
HPLC of 21f using a chiral stationary phase (Whelk-O1)
and was identical with the diastereoselectivity of the cy-
clization.
Cyclization of N-R-methyl-p-methoxybenzyl nicotinamide
23 gave only two out of the four possible diastereoisomers
of 24 but disappointingly lacked diastereoselectivity at the
new ring junction. Hydrogenation and crystallization none-
theless allowed the isolation of 25a (stereochemistry assigned
by NOE studies), which was deprotected to yield a single
isomer of pyrrolidinopiperidine 26.
Table 2. Diastereoselective Cyclization
19
20
21
entry
base
R
(yield %, dr) (yield %) (yield %)
1
2
3
4
5
6
7
8
KHMDS MeOCOa 19a (94, 83/17)
NaHMDS MeOCOa 19a (79, 89/11)
LiHMDS MeOCOa 19a (99, 94/6) 20a (98) 21a (97)
LiHMDS BnOCOa 19b (97, 95/5)
Scheme 5
LiHMDS Fmoca
19c (91, 93/7)
b
LiHMDS CF3SO2 19d (35, 96/4)
LiHMDS menthylc 19e (88, 94/6) 20e (92) 21e (83)d
LiHMDS PhOCOa 19f (82, 94/6)
20f (96) 21f (80)e
a Electrophile ) RCl. b Electrophile ) R2O. c Electrophile ) menthyl-
chloroformate. d 94:6 ratio of diastereoisomers. e 94:6 er.
The diastereoisomers of 19 were inseparable, and both
hydrogenation and deprotection of the â-lactams 19 to yield
20 and hence 21 proceeded in excellent yield.
The reaction was repeated with the electrophiles shown
in Table 2, entries 4-8. In the case of 19d the major product
was crystalline: Figure 1b shows its X-ray crystal structure.
We assume that anti-19 is the major diastereoisomer in the
other cyclizations shown in Table 2. We presume stereose-
lectivity arises because of the way the bulky p-MeOC6H4
group controls the approach of the ester enolate to the
pyridinium ring in a conformation approximating that shown
as 22. The ratio of enantiomers of the final product 21 was
determined by formation of menthylcarbamates 21e and by
In conclusion, intramolecular attack of an enolate anion
on pyridinecarboxamides has proved to be a valuable way
of making a range of new diazabicyclic and diazaspirocyclic
amino acid derivatives, some in enantiomerically enriched
form.
Acknowledgment. We are grateful to Dr. Madeleine
Helliwell (University of Manchester) for determining the
X-ray crystal structures of 7c and anti-19d and to Dr.
Rukhsana Mohammed (AstraZeneca) for valuable discus-
sions. We thank the EPSRC, AstraZeneca, and the National
Science Foundation (South Africa) for support.
(7) In early studies of the cyclization of N-benzyl benzamides (refs 4a-c
and 1a) we found that bulky, base-stable N-protecting groups gave the
highest yields and diastereoselectivities.
(8) Our group (ref 4c) and that of Snieckus (see Metallinos, C. Synlett
2002, 1556) independently introduced the cumyl (-CPhMe2) group for
N-protection of amides during lithiation reactions.
(9) We used this stereocontrolling protecting group in our synthesis of
R-methylkainic acid (ref 3e). We [(a) Bragg, R. A.; Clayden, J.; Menet, C.
J. Tetrahedron Lett. 2002, 43, 1955. (b) Bragg, R. A.; Clayden, J.
Tetrahedron Lett. 1999, 40, 8323. (c) Bragg, R. A.; Clayden, J.; Bladon,
M.; Ichihara, O. Tetrahedron Lett. 2001, 42, 3411] and others [(d) Jullian,
V.; Quirion, J. C.; Husson, H. P. Synthesis 1997, 1091. (e) Myers, A. G.;
Yang, B. H. Org. Synth. 2000, 77, 22. (f) Myers, A. G.; Yang, B. H.; Chen,
H. Org. Synth. 2000, 77, 29] have used chiral N-substituents to control
diastereoselectivity in the reactions of anionic derivatives of amides.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds and
crystallographic data for 7c and anti-19d in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL062126S
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Org. Lett., Vol. 8, No. 23, 2006