Efficient synthesis of enantiopure pyrrolizidinone amino acid

Article abstract of DOI:10.1021/jo034739d

Enantiopure (3S,5R,8S)-3-[N-(Boc)amino]-1-azabicyclo[3.3.0]octan-2-one 8-carboxylic acid (1) was synthesized in nine steps and 16% overall yield from aspartate β-aldehyde 7. Carbene-catalyzed acyloin condensation of 7, followed by acetylation and samarium

Full text of DOI:10.1021/jo034739d

Efficien t Syn th esis of En a n tiop u r e P yr r olizid in on e Am in o Acid
Evelyne Dietrich and William D. Lubell*
De´partement de chimie, Universite´ de Montre´al, C. P. 6128, Succ. A, Montre´al, Que´bec, Canada H3C 3J 7
lubell@chimie.umontreal.ca
Received May 30, 2003
Enantiopure (3S,5R,8S)-3-[N-(Boc)amino]-1-azabicyclo[3.3.0]octan-2-one 8-carboxylic acid (1) was
synthesized in nine steps and 16% overall yield from aspartate â-aldehyde 7. Carbene-catalyzed
acyloin condensation of 7, followed by acetylation and samarium iodide reduction, gave linear
precursor (2S,7S)-R,ω-diamino-4-oxosuberate 11, which was converted to N-(Boc)aminopyrrolizidin-
2-one carboxylic acid 1 by a reductive amination/lactam cyclization sequence. X-ray analysis of
(3S,5R,8S)-methyl N-(Boc)aminopyrrolizidin-2-one carboxylate 21 showed that its internal backbone
dihedral angles (ψ ) -149°, φ ) -49°) were in good agreement with the ideal values for a type II′
â-turn. Proton NMR experiments on N′-methyl-N-(Boc)aminopyrrolizidin-2-one carboxamide 23
demonstrated significantly different NH chemical displacements and temperature coefficients
suggestive of solvent shielded and exposed hydrogens indicative of a turn conformation. Because
pyrrolizidinone amino acids can serve as conformationally rigid dipeptide surrogates, this synthesis
should facilitate their application in the exploration of conformation-activity relationships of various
biologically active peptides.
In tr od u ction
Pyrrolizidinone amino acids are conformationally rigid
dipeptide surrogates in which the peptide backbone is
constrained within a fused 5,5-bicyclic structure (Figure
1).1-11 These azabicyclo[3.3.0]octanone amino acids have
been used to study conformation-activity relationships
of biologically active peptides. For example, thiapyrroliz-
idinone 2 has been inserted into an active mimic of the
dopamine receptor modulating peptide Pro-Leu-Gly-NH2
(PLG) in support of the hypothesis that its bioactive
conformation possesses a type II â-turn.6 Interest in the
synthesis of such bicyclic structures was initially evoked
due to their structural relationship to â-lactam antibiot-
ics, such as the penicillins and carbapenems.12-32 In most
cases, the antibacterial activity of these γ-lactams has
(1) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789-12854.
(2) Dietrich, E.; Lubell, W. D. In Peptides 2002; Benedetti, E.,
Pedone, C., Eds.; 2002; pp 202-203.
F IGURE 1. Representative azabicyclo[3.3.0]alkane amino
acid analogues.6,11,31,33
(3) Baldwin, J . E.; Lee, V.; Schofield, C. J . Heterocycles 1992, 34,
903-906.
(4) Genin, M. J .; J ohnson, R. L. J . Am. Chem. Soc. 1992, 114, 8778-
8783.
(5) Genin, M. J .; Mishra, R. K.; J ohnson, R. L. J . Med. Chem. 1993,
36, 3481-3483.
(6) Subasinghe, N. L.; Bontems, R. J .; McIntee, E.; Mishra, R. K.;
J ohnson, R. L. J . Med. Chem. 1993, 36, 2356-2361.
(7) Baures, P. W.; Ojala, W. H.; Costain, W. J .; Ott, M. C.; Pradhan,
A.; Gleason, W. B.; Mishra, R. K.; J ohnson, R. L. J . Med. Chem. 1997,
40, 3594-3600.
(8) Subasinghe, N. L.; Khalil, E. M.; J ohnson, R. L. Tetrahedron Lett.
1997, 38, 1317-1320.
(9) Khalil, E. M.; Pradhan, A.; Ojala, W. H.; Gleason, W. B.; Mishra,
R. K.; J ohnson, R. L. J . Med. Chem. 1999, 42, 2977-2987.
(10) Angiolini, M.; Araneo, S.; Belvisi, L.; Cesarotti, E.; Checchia,
A.; Crippa, L.; Manzoni, L.; Scolastico, C. Eur. J . Org. Chem. 2000,
2571-2581.
(11) Qiu, W.; Gu, X.; Soloshonok, V. A.; Carducci, M. D.; Hruby, V.
J . Tetrahedron Lett. 2001, 42, 145-148.
been low due to their poor electrophilicity; however,
pyrazolidinone 3, bearing electron-withdrawing substit-
uents, exhibited enhanced acylating potential and potent
(12) Baldwin, J . E.; Chan, M. F.; Gallacher, G.; Monk, P.; Prout, K.
J . Chem. Soc., Chem. Commun. 1983, 250-252.
(13) Baldwin, J . E.; Chan, M. F.; Gallacher, G.; Otsuka, M.; Monk,
P.; Prout, K. Tetrahedron 1984, 40, 4513-4525.
(14) Baldwin, J . E.; Lee, E. Tetrahedron 1986, 42, 6551-6554.
(15) Baldwin, J . E.; Lowe, C.; Schofield, C. J . Tetrahedron Lett. 1986,
27, 3461-3464.
(16) Boyd, D. B.; Foster, B. J .; Hatfield, L. D.; Hornback, W. J .;
J ones, N. D.; Munroe, J . E.; Swartzendruber, J . K. Tetrahedron Lett.
1986, 27, 3457-3460.
(17) J ungheim, L. N.; Sigmund, S. K.; Fisher, J . W. Tetrahedron
Lett. 1987, 28, 285-288.
10.1021/jo034739d CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/13/2003
6988
J . Org. Chem. 2003, 68, 6988-6996

Synthesis of Enantiopure Pyrrolizidinone Amino Acid
antibacterial activity.31 Although the potency of pyrroliz-
idinone amino acids which do not encompass heteroatoms
in the bicycle have been typically lower than their fused
4,5-bicyclic counterparts, a resurgence of attention to-
ward constructing these γ-lactam analogues has been
generated because they may serve as â-lactamase inhibi-
tors, as suggested by the ability of tricyclic pyrrolizidi-
none 4 to improve the activity of the antibiotic ceftazidine
against â-lactamase producing strains.33 In addition,
pyrrolizidinone amino acids share structural homology
with pyrrolizidine alkaloids and may thus be employed
as scaffolds in parallel syntheses to prepare libraries with
members that may exhibit biological activity similar to
that of their alkaloid counterparts.34
In the context of our program in peptide mimicry, we
have employed related azabicyclo[X.Y.0]alkane amino
acids as constrained dipeptide surrogates in order to
systematically study structure-activity relationships of
various biologically active peptides.35-37 Having previ-
ously developed effective syntheses of indolizidinone,38-43
quinolizidinone,44 and pyrroloazepinone44 amino acid
analogues with stereocontrol and potential for adding
side chains onto the heterocycle, we were interested
in expanding this methodology to furnish pyrrolizi-
dinone amino acids, because the smaller ring size of
this heterocyclic system would favor alternative pep-
tide backbone geometry. Although several syntheses
of azabicyclo[3.3.0]octanone amino acids have been
reported,3,4,6-20,22,24-26,28,29,31-33,45,46 the majority provide
analogues with multiple heteroatoms in the fused 5,5-
bicycle. To our knowledge, only one synthesis of pyrroliz-
idinone amino acid 1 has been reported to provide entry
to enantiomerically enriched material in the form of its
tert-butyl ester.10 This approach required pig-liver es-
terase mediated desymmetrization of 2,5-cis-dicarbe-
thoxy-N-benzylpyrrolidine to provide the corresponding
monocarboxylic acid with 80% ee and 13 additional steps
with separation of diastereomeric mixtures to furnish the
tert-butyl ester of 1 in an overall yield of 5%.10 Because
these approaches did not meet our requirements for
producing sufficient quantity of enantiopure material in
suitably protected form for peptide synthesis, we chose
to develop a more effective method for synthesizing
pyrrolizidin-2-one amino acid 1.
As in our previous syntheses of heterocycle systems
with larger ring sizes, we have pursued approaches to
pyrrolizidinone amino acid 1 featuring preparation of a
linear R,ω-diaminodicarboxylate precursor that could be
converted to the bicycle by reductive aminations, meth-
anesulfonate displacements, and lactam cyclizations. In
pursuit of an R,ω-diaminosuberate for synthesizing the
fused 5,5-bicycle, we found that crossed Claisen conden-
sations between N-(PhF)aspartate diester 9 and N-(PhF)-
glutamate diester 6 failed to provide â-ketoester 10.39 The
more reactive aspartate â-aldehyde 7 was later found to
undergo aldol condensation with the lithium enolate of
glutamate diester 6 to provide â-hydroxyester 8 as a
mixture of diastereomers. Oxidation of alcohol 8 using
DMSO and oxalyl chloride followed by triethylamine
furnished â-ketoester 10 (m/z ) 869.5), which was then
decarboxylated on treatment with 2 N sodium hydroxide
in dioxane to provide ketone 11. (2S,7S)-Di-tert-butyl
4-oxo-2,7-bis[N-(PhF)amino]suberate (11) was isolated
from this unoptimized process in only 6% overall yield
from glutamate 6 (Scheme 1, PhF ) 9-(9-phenylfluore-
nyl)). Before trying to optimize this route, we considered
another more convergent approach featuring acyloin
condensation of aldehyde 7 in order to prepare ketone
11 by way of R-hydroxy ketone 15 (Scheme 2). Although
reducing metals have been employed to effect dimeriza-
tion of esters and aldehydes to provide acyloins and diols,
respectively,47-49 we selected instead to examine the use
of stabilized carbenes as catalysts to effect the acyloin
condensation.50-53 This approach has now been developed
(18) J ungheim, L. N.; Sigmund, S. K.; J ones, N. D.; Swartzendruber,
J . K. Tetrahedron Lett. 1987, 28, 289-292.
(19) J ungheim, L. N.; Sigmund, S. K. J . Org. Chem. 1987, 52, 4007-
4013.
(20) Hashiguchi, S.; Natsugari, H.; Ochiai, M. J . Chem. Soc., Perkin
Trans. 1 1988, 2345-2352.
(21) Indelicato, J . M.; Pasini, C. E. J . Med. Chem. 1988, 31, 1227-
1230.
(22) J ungheim, L. N.; Barnett, C. J .; Gray, J . E.; Horcher, L. H.;
Shepherd, T. A.; Sigmund, S. K. Tetrahedron 1988, 44, 3119-3126.
(23) Shepherd, T. A.; J ungheim, L. N. Tetrahedron Lett. 1988, 29,
5061-5064.
(24) Allen, N. E.; Boyd, D. B.; Campbell, J . B.; Deeter, J . B.; Elzey,
T. K.; Foster, B. J .; Hatfield, L. D.; Hobbs, J . N., J r.; Hornback, W. J .;
Hunden, D. C.; J ones, N. D.; Kinnick, M. D.; Morin, J . M., J r.; Munroe,
J . E.; Swartzendruber, J . K.; Vogt, D. G. Tetrahedron 1989, 45, 1905-
1928.
(25) Baldwin, J . E.; Freeman, R. T.; Lowe, C.; Schofield, C. J .; Lee,
E. Tetrahedron 1989, 45, 4537-4550.
(26) Baldwin, J . E.; Freeman, R. T.; Schofield, C. J . Tetrahedron
Lett. 1989, 30, 4019-4020.
(27) Holmes, R. E.; Neel, D. A. Tetrahedron Lett. 1990, 31, 5567-
5570.
(28) Ternansky, R. J .; Draheim, S. E. Tetrahedron Lett. 1990, 31,
2805-2808.
(29) Ternansky, R. J .; Draheim, S. E. Tetrahedron 1992, 48, 777-
796.
(30) Ternansky, R. J .; Draheim, S. E.; Pike, A. J .; Counter, F. T.;
Eudaly, J . A.; Kasher, J . S. J . Med. Chem. 1993, 36, 3224-3229.
(31) Ternansky, R. J .; Draheim, S. E. J . Med. Chem. 1993, 36, 3219-
3223.
(32) Svete, J .; Presˇeren, A.; Stanovnik, B.; Golicˇ, L.; Golicˇ-Grdado-
lnik, S. J . Heterocycl. Chem. 1997, 34, 1323-1328.
(33) Hanessian, S.; Buckle, R.; Bayrakdarian, M. J . Org. Chem.
2002, 67, 3387-3397.
(34) Liddell, J . R. Nat. Prod. Rep. 2002, 19, 773-781.
(35) Halab, L.; Gosselin, F.; Lubell, W. D. Biopolymers (Peptide Sci.)
2000, 55, 101-122.
(36) Halab, L.; Becker, J . A. J .; Darula, Z.; Tourwe´, D.; Kieffer, B.
L.; Simonin, F.; Lubell, W. D. J . Med. Chem. 2002, 45, 5353-5357.
(37) Roy, S.; Lombart, H.-G.; Lubell, W. D.; Hancock, R. E. W.;
Farmer, S. W. J . Peptide Res. 2002, 60, 198-214.
(38) Lombart, H.-G.; Lubell, W. D. J . Org. Chem. 1996, 61, 9437-
9446.
(39) Gosselin, F.; Lubell, W. D. J . Org. Chem. 1998, 63, 7463-7471.
(40) Polyak, F.; Lubell, W. D. J . Org. Chem. 1998, 63, 5937-5949.
(41) Polyak, F.; Lubell, W. D. J Org. Chem. 2001, 66, 1171-1180.
(42) Feng, Z.; Lubell, W. D. J . Org. Chem. 2001, 66, 1181-1185.
(43) Cluzeau, J .; Lubell, W. D. Israel J . Chem. 2001, 41, 271-281.
(44) Gosselin, F.; Lubell, W. D. J . Org. Chem. 2000, 65, 2163-2171.
(45) Chuang, T.-H.; Sharpless, K. B. Helv. Chim. Acta 2000, 83,
1734-1743.
(46) An 8-alkyl-substituted pyrrolizidin-2-one amino acid analogue
was made to prove stereochemical assignments of the glutamate
receptor antagonist kaitocephalin: Okue, M.; Kobayashi, H.; Shin-ya,
K.; Furihata, K.; Hayakawa, Y.; Seto, H.; Watanabe, H.; Kitahara, T.
Tetrahedron Lett. 2002, 43, 857-860.
(47) Bloomfield, J . J .; Owsley, D. C.; Nelke, J . M. Org. React. 1976,
23, 259-403.
(48) Namy, J . L.; Souppe, J .; Kagan, H. B. Tetrahedron Lett. 1983,
24, 767-770.
(49) Fu¨rstner, A.; Csuk, R.; Rohrer, C.; Weidmann, H. J . Chem. Soc.,
Perkin Trans. 1 1988, 1729-1734.
(50) Enders, D.; Breuer, K.; Raabe, G.; Runsink, J .; Teles, J . H.;
Melder, J .-P.; Ebel, K.; Brode, S. Angew. Chem., Int. Ed. Engl. 1995,
34, 1021-1023.
(51) Stetter, H.; Kuhlmann, H. Org. Synth. 1984, 62, 170-177.
(52) Teles, J . H.; Melder, J .-P.; Ebel, K.; Schneider, R.; Gehrer, E.;
Harder, W.; Brode, S.; Enders, D.; Breuer, K.; Raabe, G. Helv. Chim.
Acta 1996, 79, 61-83.
J . Org. Chem, Vol. 68, No. 18, 2003 6989

Dietrich and Lubell
SCHEME 1. Cla isen Con d en sa tion a n d Ald ol
Ap p r oa ch es to Dia m in o Su ber a te 11
F IGURE 2. Catalysts used in acyloin condensation of aspar-
tate â-aldehyde 7.51,52,55
TABLE 1. Acyloin Con d en sa tion s of Asp a r ta te
â-Ald eh yd e 7
cat.
base
T
time isolated yield
entry (mol %)
(mol %)
solvent (°C) (h)
(%) of 15
1
2
3
4
5
6
7
8
9
12 (5)
Et3N (30)
EtOH
80
80
80
80
2
2
2
no reaction
37
49
12 (25) NaOAc (50) EtOH
12 (50) Et3N (300) EtOH
12 (100) Et3N (300) EtOH
13 (10)
13 (10)
13 (20)
13 (25)
14 (25)
3.5 24
t-BuOH 80
t-BuOH 80
t-BuOH 80
t-BuOH 80
t-BuOH 80
t-BuOH 80
t-BuOH 80
4
24
4
4
4
30
33
57
63
57
26
51
8
10 13 (75)
11 13 (50)
12 13 (50)
13 13 (50)
4
4
t-BuOH 50a 120
toluene 80
24
34
a
Reaction mixture was initially heated at 80 °C to activate
to deliver multiple gram quantities of ketone 11 in three
steps from aldehyde 7 and 44% overall yield. The
synthesis of enantiopure pyrrolizidinone amino acid 1
was then accomplished by employing ketone 11 in a
sequence featuring our reductive amination/lactam cy-
clization protocol.
catalyst.
(2S,7S)-Di-tert-butyl 4-oxo-2,7-bis[N-(PhF)amino]sub-
erate (11) was synthesized from R-hydroxy ketone 15 in
two steps and 70% overall yield using a samarium iodide
induced R-dehydroxylation (Scheme 2). Although the
R-hydroxyl group may later serve for the introduction of
side-chain groups onto the pyrrolizidinone amino acid,
for our initial goal, the synthesis and application of
ordinary ketone 11 was pursued to avoid complications
from the additional stereocenter and to furnish the
parent heterocycle. Acetylation of alcohol 15 with acetic
anhydride, pyridine, and DMAP furnished diastereomeric
acetates 16 in 78% yield. The acetates were separable
by chromatography; moreover, one diastereomically pure
acetate could be selectively precipitated from methanol.
Isomerically pure 16 and diastereomeric mixtures of
acetates 16, both could be converted effectively to ketone
11 in 90% yield using 220 mol % of freshly prepared SmI2
in THF at -78 °C.56,57
Syn th esis of P yr r olizid in on e Am in o Ester 21.
Pyrrolizidinone amino ester 21 was synthesized from
diamino suberate 11 by a sequence featuring reductive
amination and lactam cyclization (Scheme 2). In the
reductive amination, hydrogenation of diamino suberate
11 with palladium-on-carbon as catalyst in 9:1 EtOH/
AcOH proceeded by cleavage of the phenylfluorenyl
groups, intramolecular imine formation, protonation, and
Resu lts a n d Discu ssion
3-Benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium
chloride (12, Figure 2) had previously been shown to
catalyze the dimerization of butanal in EtOH with
triethylamine at 80 °C to afford 5-hydroxyoctan-4-one in
71-74% yield.51 Examination of the same conditions on
the more functionalized four-carbon aldehyde 7 gave no
reaction (Table 1, entry 1); however, increasing the
stoichiometry of catalyst 12 up to 50 mol % raised the
yield of R-hydroxy ketone 15 to 49% (Table 1, entry 3).
Decomposition of aldehyde 7 was observed under these
hot alkaline conditions; for example, tert-butyl N-(PhF)-
5-azapenta-2,4-dienoate was isolated as one side prod-
uct.54 Switching to 5-methoxy-4,5-dihydro-1,3,4-triphenyl-
1H-1,2,4-triazole (13)52 as catalyst (25 mol %) in tert-butyl
alcohol at 80 °C removed the need for base and gave a
cleaner reaction at a higher substrate-to-catalyst ratio
furnishing 15 in 63% yield after flash chromatography
and precipitation from hexanes. The reaction yield was
not improved using longer reaction times or lower and
higher catalyst-to-substrate ratios. Switching to toluene
as a nonpolar solvent slowed the reaction and resulted
in lower yields. Conducting the reaction at a lower
temperature after initial activation of the catalyst at 80
°C also reduced the reaction rate and produced lower
yields of acyloin 15. Finally, 5-ethoxy-4,5-dihydro-1,3,4-
triphenyl-1H-1,2,4-triazole (14)55 catalyzed the reaction
in a similar way as triazole 13 (Table 1).
(55) (a) Catalyst 14 was obtained by heating 13 in ethanol at reflux
for 20 min, cooling, and filtration of the beige crystalline solid: mp
68-70 °C; 1H NMR (C6D6) δ 1.00 (t, 3H, J ) 7.1), 3.27-3.32 (m, 1H),
3.41-3.47 (m, 1H), 6.82-6.86 (m, 1H), 6.89-7.94 (m, 3H), 6.99-7.07
(m, 5H), 7.26-7.32 (m, 2H), 7.61-7.68 (m, 4H); 13C NMR (C6D6) δ 15.0,
55.6, 100.6, 113.4, 120.4, 122.9, 124.9, 128.6, 128.8, 129.0, 129.2, 129.5,
140.9, 142.7, 145.0; MS 298.1 (M - EtOH + H)+. (b) Trace amounts of
acyloin 15 were observed by TLC from attempts to use chiral carbene
catalysts under conditions reported in: Kerr, M. S.; de Alaniz, J . R.;
Rovis, T. J . Am. Chem. Soc. 2002, 124, 10298-10299. The authors
thank T. Rovis for generous gifts of chiral carbene catalysts.
(53) White, M. J .; Leeper, F. J . J . Org. Chem. 2001, 66, 5124-
5131.
(54) Swarbrick, M. E.; Gosselin, F.; Lubell, W. D. J . Org. Chem.
1999, 64, 1993-2002.
(56) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 1135-1138.
(57) In our hands, samarium iodide could not be generated from a
sample of samarium obtained from Aldrich Chemicals.
6990 J . Org. Chem., Vol. 68, No. 18, 2003

Synthesis of Enantiopure Pyrrolizidinone Amino Acid
SCHEME 2. Syn th esis of Meth yl N-(Boc)a m in op yr r olizid in -2-on e Ca r boxyla te 21
prolines 18 and 17 was inverted from 3.5:1 to 1:4.5 by
diminishing the quantity of acid from 17 000 to 100 mol
% in the reductive amination sequence. After hydrogena-
tion of diamino suberate 11 with palladium-on-carbon as
catalyst in 4:1 EtOH/THF containing 100 mol % AcOH,
prolinate 17 could be isolated in 68% yield and was
accompanied by 15% of â-elimination product 18. Ini-
tially, (3S,5R,8S)-methyl 3-[N-(Boc)amino]-1-azabicyclo-
[3.3.0]octan-2-one 8-carboxylate (21) was obtained in
inconsistent overall yields, at best 42%, from proline 17
by removal of the tert-butyl esters of 17 with 220 mol %
TsOH in toluene/methanol, lactam cyclization with excess
triethylamine in toluene at reflux, and N-protection with
di-tert-butyl dicarbonate and Et3N in CH2Cl2, followed
by chromatography. Attempting to optimize the trans-
esterification sequence, we found that dimethyl ester 20
was obtained in purer form after treatment of proline 17
with 4.35 M HCl in dioxane followed by esterification
with methanolic HCl. Low yields of product 21 were
isolated after treatment of the hydrochloride salt of 20
with excess Et3N in toluene at reflux followed by Boc
protection. By changing the solvent from toluene to
methanol at reflux, the yield of the lactam cyclization was
significantly improved and pyrrolizidinone amino ester
21 could be reproducibly isolated in 68% yield. The best
sequence for obtaining pyrrolizininone amino ester 21
from linear ketone 11 consisted of reductive amination
using 100 mol % of acetic acid to obtain proline 17,
removal of tert-butyl esters with HCl in dioxane, esteri-
fication with methanolic HCl, lactam cyclization using
excess triethylamine in methanol at reflux and Boc
protection using di-tert-butyl dicarbonate and Et3N in
CH2Cl2. The overall yield of ester 21 using this five-step
process was 45% from diaminosuberate 11.
F IGUR E 3. Proposed mechanism for loss of amine during
reductive amination of 11.
hydrogen addition to the iminium ion intermediate. The
dehydro pyrrolidine intermediate was favored thermo-
dynamically relative to its azetidine counterpart, and
hydrogen addition to the iminium ion proceeded stereo-
selectively on the least hindered face to yield 5-alkylpro-
line tert-butyl ester 17 as the cis diastereomer. Prolinate
17 was, however, not the major product when the
hydrogenation was performed with a large excess of
acetic acid; instead, propionate 18 from â-elimination of
the primary amine was isolated in 58% yield. A plausible
mechanism for the formation of 18 features imine forma-
tion, tautomerization to an enamine, â-elimination of the
amine, and subsequent reduction of the resulting R,â-
unsaturated imine intermediate (Figure 3). We have
reported similar elimination reactions during reductive
aminations with δ- and ꢀ-amino ketones possessing
hydroxy, silyloxy, and acetoxy groups at the â-posi-
tion.40,54,58 The propensity of the amine elimination was
shown to be favored by protonation and the ratio of
Syn th esis, Assign m en t of Ster eoch em istr y, a n d
En a n tiom er ic P u r ity of P yr r olizid in on e Am in o
Acid 1. N-(Boc)aminopyrrolizidin-2-one acid 1 was syn-
thesized via hydrolysis of ester 21 (Scheme 3). Epimer-
ization of the C-8 center competed with ester hydrolysis,
when using potassium trimethylsilanolate in ether, and
afforded a 1.5:1 mixture of (8S)- and (8R)-1 in quantita-
(58) Swarbrick, M. E.; Lubell, W. D. Chirality 2000, 12, 366-373.
J . Org. Chem, Vol. 68, No. 18, 2003 6991

Dietrich and Lubell
SCHEME 3. Syn th esis a n d En a n tiom er ic P u r ity of
(3S,5R,8S)-1 a n d Am id e 23
F IGURE 4. Structure of methyl N-(Boc)aminopyrrolizidin-
2-one carboxylate 21 from X-ray crystallography (C, light gray;
N, black; O, dark gray; H, white).
F IGURE 5. Configurational and conformational analyses of
pyrrolizidinone amino acid derivatives 21 and 23. Long-
distance NOE correlations indicated by double-tip arrows.
Probable hydrogen bonds indicated by dotted lines, Paa )
pyrrolizidinone amino acid.
tive yield.38 This epimerization process demonstrated that
our route can be used to synthesize alternative diatereo-
meric configurations of N-(Boc)aminopyrrolizidin-2-one
acid 1. By employing a premixed solution of NaOH and
CaCl2 in a 7:3 2-propanol-H2O solution,59 epimerization
could be suppressed and (3S,5R,8S)-1 was isolated in 79%
yield.
21 were assigned using COSY experiments. The NOESY
spectra of both (3S,5R,8S)- and (3S,5R,8R)-21 showed
long-distance interactions between the ring fusion proton
5 and backbone proton 3. In addition, in the spectrum of
(3S,5R,8S)-21, a second long-range NOE was observed
between the 5 and 7R protons (â-protons are assigned to
be on the same side as the amine function), consistent
with concave geometry (Figure 5). In (8S)-21, the back-
bone proton at position 8 exhibited stronger NOE with
the 7R relative to the 7â proton; the (8R)-isomer exhibited
the opposite NOE intensities. The chemical displace-
ments for the 7R and 7â protons were also indicative of
the stereochemistry at the 8-position. For the (8S)-isomer,
the 7R proton was observed upfield from the 7â proton,
due to the anisotropic effect of the carboxylate group.63
For the (8R)-isomer, the 7R proton was downfield from
the 7â proton.
Diastereomeric (8R)-1 was pursued by a process fea-
turing epimerization of ester (8S)-21. Enolization of ester
(8S)-21 with NaHMDS in THF provided an 8:1 mixture
of (3S,5R,8R)- and (3S,5R,8S)-21 in 68% yield. Hydrolysis
of ester (8R)-21 using a premixed solution of NaOH and
CaCl2 in a 7:3 2-propanol-H2O solution provided iso-
merically pure acid (3S,5R,8R)-1 in 61% yield after
separation of the diatereoisomers by chromatography.
The ring-fusion stereochemistry of N-(Boc)amino-
pyrrolizidin-2-one acid 1 was originally assigned based
on analogy with previous work in which the reductive
amination of δ-keto R-amino ester with hydrogen and
palladium-on-carbon as catalyst gave predominantly
5-alkylprolines with cis stereochemistry.38,40,60,61 Crystal-
lization of (3S,5R,8S)-methyl 3-N-[(Boc)amino]-1-aza-
bicyclo[3.3.0]octan-2-one 8-carboxylate [(3S,5R,8S)-21]
from hexanes and X-ray crystallographic analysis con-
firmed this assignment (Figure 4).62 Configurational
assignments were supported by NMR experiments. Ini-
tially, the signals of the ring protons of both isomers of
In the crystal structure of (3S,5R,8S)-pyrrolizidinone
21, the dihedral angles of the backbone atoms con-
strained inside the heterocycle (ψ ) -149° and φ ) -45°)
(62) The structure of 21 was solved at l’Universite´ de Montre´al X-ray
facility using direct methods (SHELXS 97) and refined with SHELX
L 97: C14H22N2O5; Mr ) 298.336; monoclinic, colorless crystals; space
group C2; unit cell dimensions (Å) a ) 18.601(13), b ) 6.823(2), c )
15.622(7), â ) 124.96(4)°; volume of unit cell (Å3) ) 1624.9(14); Z ) 4;
R ) 0.0472 for F2 > 2σ(F2), ωR(F2) ) 0.1091 for all data; GOF ) 1.007.
The author has deposited the atomic coordinates for the structure of
21 with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.
(59) Pascal, R.; Sola, R. Tetrahedron Lett. 1998, 39, 5031-5034.
(60) Ibrahim, H. H.; Lubell, W. D. J . Org. Chem. 1993, 58, 6438-
6441.
(61) Ho, T. L.; Gopalan, B.; Nestor, J . J ., J r. J . Org. Chem. 1986,
51, 2405-2408.
(63) Mauger, A. B.; Irreverre, F.; Witkop, B. J . Am. Chem. Soc. 1966,
88, 2019-2024.
6992 J . Org. Chem., Vol. 68, No. 18, 2003

Synthesis of Enantiopure Pyrrolizidinone Amino Acid
TABLE 2. Com p a r ison of th e Dih ed r a l An gles fr om
Aza bicyclo[X.Y.0]a lk a n e Am in o Acid s X-r a y Da ta a n d
Id ea l P ep tid e Tu r n s
entry
n
m
R
ψ, deg φ, deg
21
1
1
2
2
1
2
1
2
Me
Me
Me
t-Bu
-149
-141
-176
-163
-120
-45
-34
-78
48
2539
2638
2744
type II′ â-turn i + 1 and
-80
i + 2 residues64
inverse γ-turn i + 2 residue65
-80
resembled the values of the central residues in an ideal
type II′ â-turn (ψ2 ) -120° and φ3 ) -80°).64 Comparison
of the values for pyrrolizidinone 21 with those observed
in the crystal structures of related indolizidinone and
quinolizidinone analogues possessing the same relative
stereochemistry demonstrated the influence of ring-size
on conformation (Table 2).38-40,44 Furthermore, the pyr-
rolizidinone amino acid appeared to adopt the most
concave shape among these dipeptide surrogates sug-
gesting interesting potential for turn mimicry.
The enantiomeric purity of (3S,5R,8S)-21 was deter-
mined after conversion to (2′S)- and (2′R,S)-N′-(p-tolu-
enesulfonyl)prolyl amides 24. The Boc protecting group
was removed with HCl in dioxane and the HCl salt was
acylated with (S)- and (R,S)-N-(p-toluenesulfonyl)prolyl
chlorides with Et3N in CH2Cl2 (Scheme 3). Observation
of the diastereomeric aromatic doublets centered at 6.76
and 6.82 ppm by 400 MHz 1H NMR spectroscopy in C6D6
during incremental additions of the diastereomeric mix-
ture demonstrated (2′S)-24 to be of >98% diastereomeric
excess. Hence ester 21, suberate 11, and N-(Boc)amino
pyrrolizidin-2-one acid 1, all are presumed to be of >98%
enantiomeric purity.
Con fom a tion a l An a lysis of Meth yl N-(Boc)a m i-
n op yr r olizid in on e Ca r boxa m id e 23. Methyl N-(Boc)-
aminopyrrolizidin-2-one carboxamide 23 was prepared
quantitatively by treating ester 21 with methylamine gas
in methanol (Scheme 3). Proton NMR experiments were
then performed in order to determine if the amide
hydrogen of 23 was involved in an intramolecular hy-
drogen bond. Typically, the chemical shifts of protons
involved in hydrogen bonds exhibit little variation on
changes in solvent composition and temperature.66 Chang-
ing the solvent from deuterated chloroform to deuterated
DMSO caused, respectively, 1.69 and 0.45 ppm downfield
shifts of the signals for the carbamate and the amide
protons, indicating that the later NH was more solvent
shielded (Figure 5). The temperature coefficients of the
NH chemical shifts were recorded in DMSO by heating
at 5° intervals from 298 to 323 K. Although the temper-
ature coefficient of the methyl amide proton (∆δ/∆T )
-5.2) was not in the reported range of a hydrogen bonded
amide within cyclic peptides and larger proteins, it was
F IGURE 6. Influence of temperature on the N-H chemical
shifts of N′-methyl N-(Boc)aminopyrrolizidin-2-one carboxa-
mide 23 in DMSO-d6; Paa ) pyrrolizidinone amino acid.
much less influenced by the changes in temperature
relative to the carbamate proton (∆δ/∆T ) -10.2, Figure
6). The results of the influence of solvent and tempera-
ture on the chemical shifts of the NH signals both
supported the involvement of the methyl amide proton
in an intramolecular hydrogen bond (Figure 5).
Con clu sion
Enantiopure (3S,5R,8S)-pyrrolizidin-2-one amino acid
1 was synthesized from aspartate â-aldehyde 7 via an
acyloin condensation/reductive amination/lactam cycliza-
tion sequence in 9 steps and 16% overall yield. The
pyrrolizidinone C-5 bridge-head center was created with
stereocontrol in favor of the concave cis isomer in the
reductive amination of ketone 11. The relative stereo-
chemistry was demonstrated by NOESY experiements
and by X-ray analysis. The dihedral angles of the back-
bone atoms constrained inside the heterocycle (ψ )
-149° and φ ) -45°) resembled the values of the central
residues in an ideal type II′ â-turn (ψ2 ) -120° and φ3
) -80°) and proton NMR experiments demonstrated
that N-(Boc)aminopyrrolizidin-2-one N′-methylamide 23
adopted an intramolecular hydrogen-bonded turn con-
formation. Epimerization of pyrrolizidinone amino ester
21 gave access to (3S,5R,8R)-1 and demonstrated that
all four concave diastereomers of 1 may be synthesized
by employing L- and D-aspartate as chiral educts in this
sequence. Furthermore, because modification of the R-hy-
droxyl group of ketone 15 and alkylation of amino ketone
11 may be used to add various side chains with stereo-
control at different positions on the pyrrolizidinone, our
strategy offers potential for preparing a variety of
azabicyclo[3.3.0]alkane amino acids posessing side-chain
functional groups at different ring carbons. This efficient
method for synthesizing pyrrolizidinone dipeptide sur-
(64) Ball, J . B.; Alewood, P. F. J . Mol. Recognit. 1990, 3, 55-64.
(65) Madison, V.; Kopple, K. D. J . Am. Chem. Soc. 1980, 102, 4855-
4863.
(66) Kessler, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 512-523.
J . Org. Chem, Vol. 68, No. 18, 2003 6993

Dietrich and Lubell
81.4, 170.1, 173.2, 174.0, 204.3; HRMS calcd for C56H57N2O7
(MH)+ 869.4166, found 869.4146.
rogates should thus be of general utility for the study of
structure-activity relationships in peptide chemistry and
biology.
(2S,7S)-Di-ter t-bu tyl 4-Oxo-2,7-bis[N-(P h F )a m in o]su b-
er a te (11). In a flame-dried flask under N2 atmosphere,
samarium (1.71 g, 11.4 mmol) was suspended in dry THF (15
mL), stirred, and treated with a solution of 1,2-diiodoethane
(2.86 g, 10.2 mmol) in THF (15 mL) which was slowly added
via cannula. The olive green slurry was stirred for 1 h. The
resulting dark-blue slurry of SmI2 was cooled to -78 °C and
treated over 10 min with a solution of (2S,5RS,7S)-di-tert-butyl
4-oxo-5-acetoxy-2,7-bis[N-(PhF)amino]suberate (16, 3.42 g,
3.94 mmol) in THF (30 mL) and methanol (10 mL). The
resulting brown mixture was stirred at -78 °C for 15 min,
warmed to rt, and poured into 100 mL of saturated K2CO3.
The aqueous phase was extracted with Et2O (3 × 75 mL). The
combined organic layers were washed with 5% sodium thio-
sulfate solution (100 mL), dried (Na2SO4), filtered, and con-
centrated. The crude material was purified by flash chroma-
tography using 10% EtOAc in hexanes as eluent. Evaporation
of the collected fractions yielded 2.89 g (90%) of linear ketone
Exp er im en ta l Section
(2S,5RS,7S)-Di-ter t-b u t yl 5-Hyd r oxy-4-oxo-2,7-b is[N-
(P h F )a m in o]su ber a te (15). In a flame-dried three-necked
flask equipped with a reflux condenser, (2S)-tert-butyl 2-[(N-
PhF)amino]-4-oxobutanoate (7, prepared according to ref 54,
200 mg, 0.48 mmol) in dry ethanol (1.5 mL) was treated with
3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride
(12, prepared according to ref 51, 65 mg, 0.24 mmol) and Et3N
(201 µL, 1.44 mmol), heated at reflux for 1 h, cooled, and
evaporated to dryness. The residue was partitioned between
25 mL of EtOAc and 25 mL of 1 M KH2PO4. The aqueous phase
was extracted with EtOAc (2 × 25 mL). The organic phases
were combined, washed with brine (15 mL), dried over Na2-
SO4, filtered, and concentrated. The residue was purified by
flash chromatography using a gradient of 5-10% EtOAc in
hexanes as eluent. Evaporation of the collected fractions
yielded 111 mg (56%) of acyloin 15 as a 1:1 mixture of
diastereomers: Rf ) 0.18 (10% AcOEt/hexanes, UV); 1H NMR
δ 1.15 (s, 9H), 1.19 (s, 9H), 1.20 (s, 9H), 1.23 (s, 9H), 1.25-
1.30 (m, 1H), 1.30-1.52 (m, 1H), 1.73-1.77 (m, 2H), 2.48-
2.56 (m, 2H), 2.70-2.79 (m, 4H), 2.89 (bs, 2H), 3.40 (bs, 3H,
NH), 4.06 (d, 1H, J ) 8.3 Hz), 4.35 (d, 1H, J ) 7.8 Hz), 7.18-
7.36 (m, 44H), 7.68-7.71 (m, 8H); 13C NMR (300 MHz) δ 27.9,
28.0, 36.7, 38.0, 43.4, 43.5, 53.2, 53.6, 53.7, 55.5, 73.1, 73.2,
73.3, 75.2, 81.2, 81.4, 81.6, 173.3, 173.7, 174.0, 174.8, 209.8,
210.6; HRMS calcd for C54H55N2O6 (MH)+ 827.4060, found
827.4080.
In a flame-dried, three-neck flask equipped with a reflux
condenser, (2S)-tert-butyl 2-[(N-PhF)amino]-4-oxobutanoate (7,
8.37 g, 20.2 mmol) in dry tert-butyl alcohol (100 mL) was
stirred at 50 °C and degassed with a stream of nitrogen
bubbles for 15 min. 5-Methoxy 1,3,4-triphenyl-4,5-dihydro-1H-
1,2,4-triazole (13, prepared according to ref 52, 1.66 g, 5.05
mmol) was added to the mixture, which was stirred at 80 °C
for 4 h, cooled, and evaporated to dryness. The residue was
purified by flash chromatography using 5% EtOAc in hexanes
as eluent. Evaporation of the collected fractions followed by
precipitation from hexanes and filtration yielded 5.30 g (63%)
of the desired acyloin as a 1:1 mixture of diastereomers.
(2S,7S)-Di-ter t-bu tyl 5-Acetoxy-4-oxo-2,7-bis[N-(P h F )-
a m in o]su ber a te (16). Acyloin 15 (4.60 g, 5.56 mmol) in THF
(60 mL) was treated with acetic anhydride (2.63 mL, 27.8
mmol), pyridine (1.35 mL, 16.7 mmol), and DMAP (68 mg, 0.56
mmol), stirred for 18 h at rt, diluted with 100 mL of EtOAc,
washed with saturated NaHCO3 (2 × 50 mL), 1 M aq CuSO4
(2 × 50 mL), and brine (50 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
suspended in 50 mL of methanol, stirred at reflux for 10 min
and cooled to rt. The precipitate was isolated by filtration to
afford 1.81 g (37%) of 16 (lower Rf) as a white solid and single
11 as a white solid: Rf ) 0.29 (15% AcOEt/hexanes, UV); mp
1
156-158 °C; [R]20 -225 (c 15.4, CHCl3); H NMR δ 1.20 (s,
D
9H), 1.26 (s, 9H), 1.60-1.65 (m, 2H), 2.08-2.14 (m, 1H), 2.31-
2.60 (m, 4H), 2.86 (t, 1H, J ) 5.6 Hz), 3.21 (bs, 2H), 7.18-
7.40 (m, 22H), 7.70-7.73 (m, 4H); 13C NMR δ 28.0, 28.1, 29.3,
40.3, 48.1, 53.8, 55.3, 73.1, 80.9, 81.3, 173.7, 175.3, 208.0;
HRMS calcd for C54H54N2O5 (M+) 811.4111, found 811.4093.
(2S,2′S,5R)-5-(2′-Am in o-2′-ter t-b u t oxyca r b on ylet h yl)-
p r olin e ter t-Bu tyl Ester (17). A suspension of ketone 11 (500
mg, 0.61 mmol) in 60 mL of a 4:1 solution of absolute ethanol/
THF was treated with AcOH (35 µL, 0.61 mmol) and pal-
ladium-on-carbon (50 mg, 10% by wt). The reaction vessel was
filled, vented, and filled three times under a hydrogen atmo-
sphere; the reaction mixture was stirred under 7 atm of
hydrogen for 24 h, after which time more catalyst (50 mg) was
added; and the reaction was stirred under 7 atm of H2 for
another 24 h. The reaction mixture was filtered onto Celite
and washed with methanol (3 × 10 mL). The combined organic
phases were evaporated under reduced pressure to a residue
that was dissolved in 0.1 M HCl (15 mL) and washed with
Et2O (3 × 10 mL). The aqueous phase was made alkaline to
pH ∼ 9 by adding saturated NaHCO3 solution and extracted
with CHCl3/i-PrOH (4:1, 4 × 10 mL). The combined organic
layers were dried (MgSO4), filtered, and concentrated to a
residue that was purified by flash chromatography using a
gradient of 2-5% MeOH in CH2Cl2. First to elute was (2S,5R)-
5-(2′-tert-butoxycarbonylethyl)proline tert-butyl ester (18, 27
mg, 15%): Rf ) 0.25 (5% MeOH/CH2Cl2); 1H NMR (CD3OD) δ
1.26-1.31 (m, 1H), 1.45 (s, 9H), 1.48 (s, 9H), 1.76-1.92 (m,
4H), 2.06-2.10 (m, 1H), 2.31-2.35 (m, 2H), 2.98-3.01 (m, 1H),
3.57-3.61 (m, 1H); 13C NMR (CD3OD) δ 28.4, 28.5, 31.3, 31.7,
32.4, 34.3, 60.8, 61.6, 81.6, 82.6, 174.5, 175.2; HRMS calcd for
C
16H30NO4 (MH)+ 300.2175, found 300.2178. Next to elute was
(2S,2′S,5R)-5-(2′-amino-2′-tert-butoxycarbonylethyl)proline tert-
butyl ester (17, 132 mg, 68%): Rf ) 0.07 (5% MeOH/CH2Cl2);
1H NMR (CD3OD) δ 1.33-1.38(m, 1H), 1.49 (s, 18H), 1.71-
1.75 (m, 1H), 1.91-1.97 (m, 3H), 2.08-2.11 (m, 1H), 3.15-
3.19 (m, 1H), 3.44-3.47 (m, 1H), 3.60-3.63 (m, 1H); 13C NMR
(CD3OD) δ 28.4, 31.2, 32.6, 40.9, 54.4, 58.1, 61.7, 82.6, 82.7,
175.4, 175.7; HRMS calcd for C16H31NO4 (MH)+ 315.2284,
found 315.2284.
(2S,2′S,5R)-5-(2′-Am in o-2′-h yd r oxyca r bon yleth yl)p r o-
lin e Hyd r och lor id e (19). Di-tert-butyl ester 17 (220 mg, 0.70
mmol) was stirred for 6 h in a solution of 4.35 M HCl in
dioxane (10 mL) and concentrated. The residue was coevapo-
rated with water and then CH2Cl2 to afford hydrochloride 19
as a light yellow foam (194 mg, 99%): Rf ) 0.08 (10% MeOH/
CH2Cl2); 1H NMR (CD3OD) δ 1.83 (bs, 1H), 2.27 (bs, 2H), 2.41
(bs, 2H), 2.55-2.57 (m, 1H), 3.99 (bs, 1H), 4.16 (bs, 1H), 4.48
(bs 1H); 13C NMR (CD3OD) δ 28.1, 29.9, 33.5, 51.7, 59.2, 61.0,
170.8, 171.2; HRMS calcd for C8H15N2O4 (MH - 2 HCl)+
203.1032, found 203.1037.
diastereomer: Rf ) 0.17 (25% Et2O/hexanes, UV); mp 176-
1
177 °C; [R]20 -250 (c 17.0, CHCl3); H NMR δ 1.17 (s, 9H),
D
1.23 (s, 9H), 1.55-1.66 (m, 2H), 1.77 (s, 3H), 2.54-2.61 (m,
3H), 2.90 (bs, 1H), 3.18 (bs, 1H), 3.37 (bs, 1H), 5.28 (d, 1H, J
) 10.9 Hz), 7.13-7.37 (m, 22H), 7.66-7.68 (m, 4H); 13C NMR
δ 20.9, 27.9, 28.1, 35.7, 43.8, 52.8, 72.9, 73.4, 75.9, 170.2, 173.2,
175.2, 204.6; HRMS calcd for C56H57N2O7 (MH)+ 869.4166,
found 869.4181. The filtrate was concentrated and purified by
flash chromatography using 15% Et2O in hexanes as eluent
to yield 1.97 g (41%) of 16 (higher Rf) as a white foam and
single diastereomer: Rf ) 0.22 (25% Et2O/hexanes, UV); [R]20
D
-202 (c 14.4, CHCl3); 1H NMR (400 MHz) δ 1.22 (s, 9H), 1.23
(s, 9H), 1.70-1.82 (m, 2H), 1.98 (s, 3H), 2.31 (dd, 1H, J ) 17.1,
4.5 Hz), 2.56 (dd, 1H, J ) 17.2, 5.2 Hz), 2.67 (bs, 1H), 2.83
(bs, 1H), 3.26 (d, 1H, J ) 6.5 Hz), 3.33 (bs, 1H), 5.43 (dd, 1H,
J ) 10.6, 3.1 Hz), 7.16-7.40 (m, 22H), 7.67-7.69 (m, 4H); 13
C
NMR δ 20.7, 27.9, 28.0, 35.1, 43.8, 52.5, 52.9, 73.3, 75.5, 81.2,
6994 J . Org. Chem., Vol. 68, No. 18, 2003

Synthesis of Enantiopure Pyrrolizidinone Amino Acid
(2S,2′S,5R)-5-(2′-Am in o-2′-m eth oxyca r bon yleth yl)p r o-
lin e Meth yl Ester Hyd r och lor id e (20). Methanol (14 mL)
at 0 °C was treated dropwise with acetyl chloride (3.0 mL, 42.0
mmol) and stirred for 10 min. The resulting solution was added
to hydrochloride 19 (194 mg, 0.70 mmol). The reaction was
stirred at rt for 18 h and concentrated under vacuum to provide
methyl ester hydrochloride 20 as an off-white foam (212 mg,
99%): Rf ) 0.08 (4:1:1 n-BuOH/H2O/AcOH); 1H NMR (CD3-
OD) δ 1.83-1.85 (m, 1H), 2.28-2.31 (m, 2H), 2.38-2.50 (m,
2H), 2.56-2.63 (m, 1H), 3.87 (s, 3H), 3.91 (s, 3H), 3.97 (m, 1H),
4.23-4.26 (m, 1H), 4.55-4.57 (m, 1H); 13C NMR (CD3OD) δ
27.7, 29.6, 33.2, 51.4, 54.1, 54.3, 59.0, 59.2, 169.8, 170.1; HRMS
calcd for C10H19N2O4 (MH - 2 HCl)+ 231.1345, found 231.1340.
(3S,5R,8S)-3-[N-(Boc)a m in o]-1-a za bicyclo[3.3.0]octa n -
2-on e 8-Ca r boxylic Acid [(3S,5R,8S)-1]. A 1 M aq solution
of NaOH (201 µL, 0.20 mmol) was added to a solution of ester
(8S)-21 (50 mg, 0.17 mmol) in a 0.8 M solution of CaCl2 in
i-PrOH/H2O (7:3, 5 mL). The reaction mixture was stirred for
4 h and then poured into aq 10% citric acid (15 mL). The
aqueous phase was extracted with CHCl3/i-PrOH (4:1, 5 × 10
mL). The combined organic layers were dried (MgSO4), filtered,
and concentrated to a residue that was purified by flash
chromatography on silica gel using 2% MeOH in CH2Cl2
containing 1% AcOH as eluent to afford acid 1 (38 mg, 79%):
Rf ) 0.20 (10% MeOH/CH2Cl2 + 1% AcOH); [R]20 -80.6 (c
D
1
9.58, MeOH); H NMR (CD3OD) δ 1.45 (s, 9H), 1.53-1.79 (m
3H), 2.02-2.10 (m, 1H), 2.23 (dd, 1H, J ) 13.4, 6.6 Hz), 2.43-
2.57 (m, 1H), 2.63-2.71 (m, 1H), 3.90 (heptet 1H, J ) 5.0 Hz),
4.11 (d, 1H, J ) 9.2 Hz), 4.73 (dd, 1H, J ) 12.0, 7.2 Hz); 13C
NMR (CD3OD) δ 28.8, 30.9, 34.7, 38.5, 56.3, 60.3, 80.7, 158.1,
173.8, 174.3; HRMS calcd. for C13H21N2O5 285.1450 (MH)+,
found 285.1452.
(3S,5R,8S)-Met h yl
3-[N-(Boc)a m in o]-1-a za b icyclo-
[3.3.0]octa n -2-on e 8-Ca r boxyla te [(3S,5R,8S)-21]. A solu-
tion of methyl ester hydrochloride 20 (212 mg, 0.70 mmol) in
MeOH (14 mL) was treated with Et3N (293 µL, 2.10 mmol),
heated at reflux and stirred for 24 h, concentrated to a residue
that was dissolved in CH2Cl2 (14 mL), treated with Et3N (137
µL, 0.98 mmol) and di-tert-butyl dicarbonate (183 mg, 0.84
mmol), stirred at rt for 18 h, diluted with CHCl3 (20 mL), and
washed with 1 M NaH2PO4 (15 mL). The aqueous layer was
extracted with CHCl3 (10 mL), and the combined organic
phases were dried (Na2SO4), filtered, and concentrated to a
residue that was purified by flash chromatography using 50%
EtOAc in hexanes as eluent. Evaporation of the combined
collected fractions gave (3S,5R,8S)-methyl 3-[N-(Boc)amino]-
1-azabicyclo[3.3.0]octan-2-one 8-carboxylate (21) as a white
(3S,5R,8R)-3-[N-(Boc)a m in o]-1-a za bicyclo[3.3.0]octa n -
2-on e 8-Ca r boxylic Acid [(3S,5R,8R)-1] was synthesized
from an 8:1 mixture of (8R)- and (8S)-21 (19 mg, 0.064 mmol)
using the procedure described above for (3S,5R,8S)-1 and
purified on silica gel using a gradient of 2-5% MeOH in CH2-
Cl2 containing 1% AcOH as eluent. First to elute was (8S)-1
(1 mg, 6%), followed by 3 mg (17%) of a 2:1 mixture of (8R)-/
(8S)-isomers and (8R)-1 (11 mg, 61%): Rf ) 0.09 (10% MeOH/
1
CH2Cl2 + 1% AcOH); [R]20 +79.4 (c 8.75, MeOH); H NMR
D
(CD3OD) δ 1.40-1.51 (m, 1H), 1.45 (s, 9H), 1.77-1.80 (m, 1H),
2.02-2.24 (m, 2H), 2.57-2.73 (m, 2H), 3.91-3.96 (m, 1H), 4.37
(t, 1H, J ) 8.1 Hz), 4.58 (dd, 1H, J ) 11.2, 8.1 Hz); 13C NMR
(CD3OD) δ 28.8, 33.1, 33.4, 36.7, 56.7, 57.1, 59.4, 80.7, 157.8,
174.0, 175.7; HRMS calcd for C13H21N2O5 285.1450 (MH)+,
found 285.1438.
solid (143 mg, 68%): Rf ) 0.17 (50% EtOAc/hexanes); [R]20
D
1
-72.6 (c 12.4, MeOH); H NMR δ 1.44 (s, 9H), 1.67-1.76 (m,
2H), 2.05-2.09 (m, 1H), 2.18-2.25 (m, 1H), 2.34-2.48 (m, 1H),
2.95 (quintet, 1H, J ) 5.8 Hz), 3.76 (s, 3H), 3.88 (heptet, 1H,
J ) 5.1 Hz), 4.18 (d, 1H, J ) 8.9 Hz), 4.58-4.66 (m, 1H), 5.20-
5.22 (m, 1H); 13C NMR δ 28.5, 30.3, 33.7, 39.7, 52.7, 55.2, 56.7,
59.2, 80.0, 155.9, 171.5, 172.0; HRMS calcd. for C14H22N2O5
(M+) 298.1529, found 298.1530.
(3S,5R,8S)-N′-Met h yl-3-[N-(Boc)a m in o]-1-a za b icyclo-
[3.3.0]octa n -2-on e 8-Ca r boxa m id e (23). An aqueous solu-
tion of methylamine (40 wt %) was slowly heated from 30°C
to 60°C and the evolving methylamine gas was bubbled
through a solution of (3S,5R,8S)-methyl 3-[N-(Boc)amino]-1-
azabicyclo[3.3.0]octan-2-one 8-carboxylate (21, 19 mg, 0.064
mmol) in MeOH (2 mL) at 0 °C for 2 h. The reaction mixture
was warmed to rt, capped, and left for 18 h. The volatiles were
removed by bubbling argon and the residue was concentrated
under vacuum, yielding carboxamide 23 as a white foam (19
mg, 99%): Rf ) 0.51 (10% MeOH/CH2Cl2); [R]20D -41.6 (c 4.33,
MeOH); 1H NMR δ 1.38 (s, 9H), 1.51-1.65 (m, 1H), 1.91-1.94
(m, 1H), 2.07 (q, 1H, J ) 10.8 Hz), 2.29-2.37 (m, 2H), 2.58
(quintet, 1H, J ) 6.1 Hz), 2.75 (d, 3H, J ) 4.6 Hz), 3.72 (heptet,
1H, J ) 5.1 Hz), 4.06 (d, 1H, J ) 8.1 Hz), 4.19-4.27 (m, 1H),
5.29 (d, 1H, J ) 6.4 Hz), 7.20 (s, 1H); 13C NMR δ 26.7, 28.5,
29.6, 34.5, 35.7, 56.9, 58.1, 59.8, 80.5, 156.0, 170.5, 170.8;
HRMS calcd for C14H24N3O4 298.1767 (MH)+, found 298.1774.
(3S,5R,8R)-Meth yl 3-[N-(Boc)am in o]-1-azabicyclo[3.3.0]-
octa n -2-on e 8-ca r boxyla te [(3S,5R,8R)-21]. To a solution
of ester (8S)-21 (28 mg, 0.094 mmol) in THF (1 mL) at -50 °C
was added dropwise a solution of 1 M NaHMDS in THF (188
µL, 0.188 mmol). The reaction mixture was stirred at -50 °C
for 1 h, warmed to -20 °C, stirred for 1 h, and poured into aq
1 M NaH2PO4 (5 mL). The aqueous phase was extracted with
EtOAc (6 × 5 mL), and the organic layers were combined,
washed with brine (5 mL), dried (Na2SO4), filtered, and
1
concentrated. The H NMR spectrum of the crude material in
C6D6 showed an 8:1 mixture of (8R)-/(8S)-isomers based on the
integration of the signals for the protons at the 8 position. The
crude residue was purified by flash chromatography using 50%
EtOAc in hexanes as eluent. Evaporation of the collected
fractions yielded 19 mg (68%) of (3S,5R,8R)-21 as a white foam
1
(8:1 mixture): Rf ) 0.17 (50% EtOAc/hexanes); H NMR for
En a n tiom er ic P u r ity of (3S,5R,8S)-Meth yl 3-[N-(Boc)-
a m in o]-1-a za bicyclo[3.3.0]n on a n e 8-Ca r boxyla te 21. Es-
ter (8S)-21 (10 mg, 0.034 mmol) was treated with a 5.70 M
solution of HCl in dioxane (1 mL) for 30 min. The solution
was evaporated to amine hydrochloride 20, which was dis-
solved in CH2Cl2 (1 mL) and treated with Et3N (10 µL, 0.075
mmol) and either (S)- or (RS)-N-(p-toluenesulfony)prolyl chlo-
ride (12 mg, 0.041 mmol), stirred for 2 h at rt, diluted with
EtOAc (5 mL), washed sequentially with 1 M NaH2PO4 (3 mL),
saturated NaHCO3 (3 mL), and brine (3 mL), dried (Na2SO4),
filtered, and concentrated. In the case of the (RS)-diatere-
omers, the residue was purified by flash chromatography on
silica gel using 2% MeOH in CH2Cl2 as eluent. Evaporation of
the collected fractions yielded 14 mg (90%) of (2′RS,3S,5R,8S)-
methyl 3-[N-(p-toluenesulfonyl)prolinamido]-1-azabicyclo[3.3.0]-
octan-2-one 8-carboxylate [(2′RS)-24] as a 1:1 mixture of
diastereomers as determined by measuring the signals of the
diastereomeric aromatic doublets at 6.76 and 6.81 ppm: 1H
NMR (400 MHz, C6D6) δ 0.92-1.04 (m, 2H), 1.12-1.36 (m, 8H),
1.45-1.61 (m, 6H), 1.70-1.81 (m, 2H), 1.86 (s, 3H), 1.89 (s,
the major isomer δ 1.43 (s, 9H), 1.46-1.64 (m, 2H), 2.06-2.22
(m, 2H), 2.46-2.50 (m, 1H), 2.93-2.99 (m, 1H), 3.73 (s, 3H),
3.94-3.99 (m, 1H), 4.47 (t, 1H, J ) 7.8 Hz), 4.51-4.59 (m, 1H),
5.16 (bs, 1H); 13C NMR for the major isomer δ 28.5, 31.7, 32.4,
38.6, 52.7, 55.2, 55.7, 58.2, 80.1, 155.8, 171.5, 172.0; HRMS
calcd for C14H22N2O5 (M+) 298.1529, found 298.1543.
(3S,5R,8S)-Meth yl 3-a m in o-1-a za bicyclo[3.3.0]octa n -2-
on e 8-ca r boxyla te h yd r och lor id e (22). (3S,5R,8S)-Methyl
3-[N-(Boc)amino]-1-azabicyclo[3.3.0]octan-2-one 8-carboxylate
(21, 11 mg, 0.036 mmol) was stirred in 5.70 M HCl in dioxane
(1 mL) for 20 min and the volatiles were removed under
reduced pressure to provide amine hydrochloride 22 as a
colorless oil (9 mg, 99%): 1H NMR (CD3OD) δ 1.60-1.71 (m,
1H), 1.90-1.98 (m, 1H), 2.11-2.17 (m, 1H), 2.24-2.29 (m, 1H),
2.50-2.60 (m, 1H), 2.80-2.86 (m, 1H), 3.77 (s, 3H), 4.03-4.09
(m, 1H), 4.20 (d, 1H, J ) 9.2 Hz), 4.40-4.45 (m, 1H); 13C NMR
(CD3OD) δ 30.7, 34.7, 36.1, 53.3, 56.1, 56.3, 61.1, 169.2, 172.8;
HRMS calcd for C9H14N2O3 (M - HCl)+ 198.1004, found
198.1001.
J . Org. Chem, Vol. 68, No. 18, 2003 6995

Dietrich and Lubell
3H), 2.08-2.13 (m, 2H), 2.58-2.64 (m, 1H), 2.67-2.73 (m, 1H),
2.81-2.88 (m, 2H), 2.89-3.04 (m, 2H), 3.15-3.21 (m, 1H),
3.24-3.30 (m, 1H), 3.39 (s, 6H), 3.83-3.86 (m, 2H), 4.21 (dd,
2H, J ) 8.6, 3.1 Hz), 4.31 (dd, 1H, J ) 8.5, 3.2 Hz), 4.86-4.93
(m, 1H), 5.16-5.19 (m, 1H), 6.76 (d, 2H, J ) 7.9 Hz), 6.81 (d,
2H, J ) 7.9 Hz), 7.66 (d, 2H, J ) 8.2 Hz), 7.72 (d, 2H, J ) 8.2
Hz). The residue from the (S)-isomer, (2′S,3S,5R,8S)-methyl
3-[N-(p-toluenesulfonyl)prolinamido]-1-azabicyclo[3.3.0]octan-
2-one 8-carboxylate [(2′S)-24, 99%], was not purified by chro-
matography and was directly analyzed by NMR spectroscopy:
1H NMR (400 MHz, C6D6) δ 0.95-1.04 (m, 1H), 1.12-1.21 (m,
2H), 1.25-1.40 (m, 2H), 1.44-1.60 (m, 3H), 1.76 (quadruplet,
1H, J ) 9.7 Hz), 1.88 (s, 3H), 2.07-2.14 (m, 1H), 2.67-2.73
(m, 1H), 2.86-2.94 (m, 1H), 2.96-3.04 (m, 1H), 3.13-3.19 (m,
1H), 3.39 (s, 3H), 3.85 (d, 1H, J ) 8.3 Hz), 4.19 (dd, 1H, J )
8.6, 3.1 Hz), 4.85-4.90 (m, 1H), 6.80 (d, 2H, J ) 7.9 Hz), 7.71
(d, 2H, J ) 8.2 Hz). The limits of detection were determined
by observation of the diastereomeric aromatic doublets at 6.76
Ack n ow led gm en t. This research was supported in
part by the Natural Sciences and Engineering Research
Council of Canada (NSERC) and the Ministe`re de
l’EÄ ducation du Que´bec. We thank Ms. Sylvie Bilodeau
for assistance in performing NMR experiments, Ms.
Francine Be´langer-Garie´py for performing the X-ray
analysis of 21, and Mr. Dalbir Sekhon for performing
LC-MS experiments. E.D. thanks the Fonds Que´be´cois
de la Recherche sur la Nature et les Technologies
(FQRNT) for a post-graduate scholarship.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal information, H and 13C NMR spectra of compounds (8S)-
1
and (8R)-1, 11, 15, 16-20, (8S)- and (8R)-21, 22, and 23; H
NMR spectra of compounds (2′S)- and (2′RS)-24; COSY and
NOESY spectra of (8S)- and (8R)-21; crystallographic data for
21. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
and 6.81 ppm in the 400 MHz H NMR spectrum of (2′S)-24
in C6D6 during incremental additions of diastereomeric (2′RS)-
24 which demonstrated (2′SS)-24 to be of >98% diastereomeric
purity.
J O034739D
6996 J . Org. Chem., Vol. 68, No. 18, 2003