Rigid dipeptide mimetics: Efficient synthesis of enantiopure indolizidinone amino acids

Article abstract of DOI:10.1021/jo961872f

An effective means to synthesize indolizidinone amino acids has been developed and furnishes all possible stereoisomers of these conformationally rigid mimetics of peptide secondary structures. Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/reductive amination/lactam cyclization sequence that furnished stereoselectively azabicyclo[3.4.0]alkane amino acid 1. Enantiopure (3S,6S,9S)- and (3R,6R,9R)-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylic acids ((3S,6S,9S)- and (3R,6R,9R)-1) were respectively synthesized from L- and D-N-(PhF)glutamates 2 (PhF = 9-(9-phenylfluorenyl)). Slow addition of sodium bis(trimethylsilyl)amide to 2 provided good to excellent yields of β-keto esters 3, which were subsequently hydrolyzed and decarboxylated to give symmetric α,ω-bis[N-(PhF)amino]azelate δ-ketones 5. Augmentation of hydrogen pressure increased diastereoselectivity in reductive aminations with 5 and afforded 5-alkylprolines 8 and 10. Lactam formation on exposure of 10 to triethylamine and N-protection with di-tert-butyl dicarbonate gave methyl-2-oxo-3-[N-(BOC)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylate (12) which on C-terminal ester hydrolysis with hydroxide ion gave enantiopure [N-(BOC)amino]indolizidinone acid 1. Alternatively, hydride addition to ketone 5a gave symmetric α,ω-bis[N-(PhF)amino]azelate δ-alcohol 7a, which upon mesylation and intramolecular S(N)2 displacement by the PhF amine gave specifically cis-5-alkylproline 15 that was similarly converted to (3S,6S,9S)-1. In addition, epimerization of the C-9 stereocenter of (3S,6S,9S)-[N-(BOC)amino]indolizidinone methyl ester 12 with NaN(SiMe₃)₂ and ester hydrolysis gave (3S,6S,9R)-indolizidinone amino acid (3S,6S,9R)-1. By providing efficient methodology for synthesizing all of the possible stereoisomers of enantiopure indolizidinone amino acid 1, our route is specifically designed to enhance the general use of these peptide mimetics in the exploration of conformation-activity relationships of various biologically active peptides.

Full text of DOI:10.1021/jo961872f

J . Org. Chem. 1996, 61, 9437-9446
9437
Rigid Dip ep tid e Mim etics: Efficien t Syn th esis of En a n tiop u r e
In d olizid in on e Am in o Acid s
Henry-Georges Lombart and William D. Lubell*
De´partement de chimie, Universite´ de Montre´al, C.P. 6128, Succursale Centre Ville,
Montre´al, Que´bec, Canada H3C 3J 7
Received October 3, 1996X
An effective means to synthesize indolizidinone amino acids has been developed and furnishes all
possible stereoisomers of these conformationally rigid mimetics of peptide secondary structures.
Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/reductive
amination/lactam cyclization sequence that furnished stereoselectively azabicyclo[3.4.0]alkane amino
acid 1. Enantiopure (3S,6S,9S)- and (3R,6R,9R)-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-
9-carboxylic acids ((3S,6S,9S)- and (3R,6R,9R)-1) were respectively synthesized from L- and D-N-
(PhF)glutamates 2 (PhF ) 9-(9-phenylfluorenyl)). Slow addition of sodium bis(trimethylsilyl)amide
to 2 provided good to excellent yields of â-keto esters 3, which were subsequently hydrolyzed and
decarboxylated to give symmetric R,ω-bis[N-(PhF)amino]azelate δ-ketones 5. Augmentation of
hydrogen pressure increased diastereoselectivity in reductive aminations with 5 and afforded
5-alkylprolines 8 and 10. Lactam formation on exposure of 10 to triethylamine and N-protection
with di-tert-butyl dicarbonate gave methyl 2-oxo-3-[N-(BOC)amino]-1-azabicyclo[4.3.0]nonane-9-
carboxylate (12) which on C-terminal ester hydrolysis with hydroxide ion gave enantiopure
[N-(BOC)amino]indolizidinone acid 1. Alternatively, hydride addition to ketone 5a gave symmetric
R,ω-bis[N-(PhF)amino]azelate δ-alcohol 7a , which upon mesylation and intramolecular SN2
displacement by the PhF amine gave specifically cis-5-alkylproline 15 that was similarly converted
to (3S,6S,9S)-1. In addition, epimerization of the C-9 stereocenter of (3S,6S,9S)-[N-(BOC)amino]-
indolizidinone methyl ester 12 with NaN(SiMe3)2 and ester hydrolysis gave (3S,6S,9R)-indolizidinone
amino acid (3S,6S,9R)-1. By providing efficient methodology for synthesizing all of the possible
stereoisomers of enantiopure indolizidinone amino acid 1, our route is specifically designed to
enhance the general use of these peptide mimetics in the exploration of conformation-activity
relationships of various biologically active peptides.
In tr od u ction
Azabicyclo[X.Y.0]alkane amino acids are an important
class of dipeptide analogues having restrained backbone
and side-chain conformations (Figure 1).1-17 The growing
use of these dipeptide surrogates in the investigation of
structure-activity relationships of various biologically
X Abstract published in Advance ACS Abstracts, December 1, 1996.
(1) We have adopted the nomenclature and ring system numbering
previously used in refs 3a and 5a in order to maintain clarity and
consistency when comparing these different heterocyclic systems.
(2) Synthesis and use of 2-oxo-3-phthalimido-7-thia-1-azabicyclo-
[4.3.0]nonane-9-carboxylic acid are described in: (a) Nagai, U.; Sato,
K. Tetrahedron Lett. 1985, 26, 647. (b) Nagai, U.; Sato, K.; Nakamura,
R.; Kato, R. Tetrahedron 1993, 49, 3577.
(3) The use of 2-oxo-3-amino-7-thia-1-azabicyclo[4.3.0]nonane-9-
carboxylic acid in peptide analogues includes: gramicidin S-ana-
logues: (a) Sato, K.; Nagai, U. J . Chem. Soc., Perkin Trans. I 1986,
1231. (b) Bach, A. C., II; Markwalder, J . A.; Ripka, W. C. Int. J . Pept.
Protein Res. 1991, 38, 314. Growth hormone-releasing factor ana-
logues: (c) Sato, K.; Hotta, M.; Dong, M.-H.; Hu, H.-Y.; Taulene, J . P.;
Goodman, M.; Nagai, U.; Ling, N. Int. J . Pept. Protein Res. 1991, 38,
340. Cyclosporin A analogues: (d) Belshaw, P. J .; Meyer, S. D.;
J ohnson, D. D.; Romo, D.; Ikeda, Y.; Andrus, M.; Alberg, D. G.; Schultz,
L. W.; Clardy, J .; Schreiber, S. L. Synlett 1994, 381. Tendamistat
mimetic: (e) Etzkorn, F. A.; Guo, T.; Lipton, M. A.; Goldberg, S. D.;
Bartlett, P. A. J . Am. Chem. Soc. 1994, 116, 10412. Cyclic RGD
peptides: (f) Haubner, R.; Schmitt, W.; Ho¨lzemann, G.; Goodman, S.
L.; J onczyk, A.; Kessler, H. J . Am. Chem. Soc. 1996, 118, 7881.
F igu r e 1. Representative examples of indolizidinone amino
acid analogues.
Additional examples, such as enkephalin, LRF, GRF, dermorphin, and
somatostatin, are reviewed in ref 2b.
(4) (a) Synthesis of 2-oxo-3-amino-8,8-dimethyl-7-thia-1-azabicyclo-
[4.3.0]nonane-9-carboxylic acid is described in: Nagai, U.; Kato, R.;
Sato, K.; Ling, N.; Matsuzaki, T.; Tomotake, Y. In Peptides: Chemistry
and Biology, Proceedings of the Tenth American Peptide Symposium;
Marshall, G. R., Ed.; ESCOM: Leiden, 1988; pp 129-130. (b) Synthesis
of 2-oxo-3-amino-8-phenyl-7-thia-1-azabicyclo[4.3.0]nonane-9-carboxylic
acid is described in: Nagai, U.; Kato, R. Peptides: Chemistry and
Structural Biology, Proceedings of the Eleventh American Peptide
Symposium; Rivier, J . E.; Marshall, G. R., Eds.; ESCOM: Leiden, 1989;
pp 653-654.
active peptides has created a demand for new methodol-
ogy for synthesizing these peptide mimetics.1-17 Ideally,
approaches for making azabicycloalkane amino acids
should overcome three important challenges. First, the
fused azacycloalkane heterocycle should be synthesized
unambiguously in a predictable manner. Second, chiral
centers should be introduced with stereocontrol at the
S0022-3263(96)01872-5 CCC: $12.00 © 1996 American Chemical Society

9438 J . Org. Chem., Vol. 61, No. 26, 1996
Lombart and Lubell
Sch em e 1. Gen er a l Ap p r oa ch for Syn th esizin g Aza bicyclo[X.Y.0]a lk a n e Am in o Acid s
R- and bridge-head carbons. Finally, the appendage of
side chains onto the heterocycle is desired in order to
synthesize analogues that mimic both peptide backbone
and side-chain geometries.4,7,8,10
peptide bioactivity. For example, a thiaindolizidinone
amino acid with 3S,6R,9R-stereochemistry was recently
used to stabilize the active conformation in a potent
analogue of cyclosporin A.3d Indolizidinone amino acids
with 3S,6R,9S-stereochemistry have also been shown to
adopt both type II′ â-turn and γ-turn conformations in
mimetics of different biologically active peptides.3a,b,e The
all-carbon indolizidinone system was selected for syn-
thesis,7-12 instead of thia and oxaanalogues,2-6 because
of three reasons. First, the methylene protons add
increased rigidity to the indolizidinone by creating ad-
ditional gauche interactions. Side-chain functional groups
may be appended at the ring carbons. Finally, analogues
possessing saturated thiazo and oxazo ring systems are
inherently more prone to degradation via processes that
may hydrolyze the masked aldehyde during metabolism
in vivo as well as during peptide synthesis.
We now provide full details of our method for synthe-
sizing indolizidinone amino acid 1.11 Several observa-
tions have led to improvements in overall yield and
efficiency. For example, a relationship between hydrogen
pressure and diastereoselectivity in the reductive ami-
nation step was observed and employed to control the
bridge-head carbon stereochemistry. A new route featur-
ing the activation and intramolecular displacement of a
symmetric alcohol has been explored to stereospecifically
synthesize (3S,6S,9S)-1. Regioselective enolization of
indolizidinone amino ester now gives access to epimers
at C-9. Moreover, the number of steps to synthesize 1
has been reduced via the employment of dimethyl N-
(PhF)glutamate (2b) in the Claisen condensation/reduc-
tive amination/lactam cyclization sequence. Because
indolizidinone amino acid 1 is suitable for incorporation
into peptides using standard techniques,12 our route is
specifically designed to enhance the general use of these
By targeting initially on the synthesis of azabicyclo-
[3.4.0]alkane amino acids, we are developing a general
approach in order to meet this criterion. Our method
utilizes configurationally stable N-(9-(9-phenylfluorenyl))-
amino dicarboxylates in a Claisen condensation/reductive
amination/lactam cyclization sequence in order to furnish
stereoselectively azabicycloalkane amino acids (Scheme
1, PhF ) 9-(9-phenylfluorenyl)).11 Employment of dif-
ferent amino dicarboxylates, such as glutamate, aspar-
tate, and longer amino dicarboxylates, in this scheme is
designed to provide a variety of heterocyclic ring sizes.
In theory, side chains may be added to the heterocycle
via alkylations and additions on the N-(PhF)amino
ketone intermediates.18 By employing inexpensive glutam-
ic acid as chiral educt in this approach, we have devel-
oped an efficient synthesis of enantiopure indolizidinone
amino acid 1 that gives access to all of the possible
stereoisomers of these interesting dipeptide mimetics.
Indolizidinone amino acid 1 was selected as our first
target because azabicyclo[3.4.0]alkane amino acids have
been well studied in peptide structures, and because their
different configurational isomers have been used to
illustrate the importance of particular conformations for
(5) Syntheses of 2-oxo-5-oxa-3-amino-1-azabicyclo[4.3.0]nonane-9-
carboxylic acids are reported in: (a) Baldwin, J . E.; Hulme, C.;
Schofield, C. J .; Edwards, A. J . J . Chem. Soc., Chem. Commun. 1993,
935. (b) Slomczynska, U.; Chalmers, D. K.; Cornille, F.; Smythe, M.
L.; Beusen, D. D.; Moeller, K. D.; Marshall, G. R. J . Org. Chem. 1996,
61, 1198.
(6) Synthesis and analysis of Leu-enkephalin analogues containing
2-oxo-5-oxa-3-amino-1-azabicyclo[4.3.0]nonane-9-carboxylic acid are
reported in: Claridge, T. D. W.; Hulme, C.; Kelly, R. J .; Lee, V.; Nash,
I. A.; Schofield, C. J . Bioorg. Med. Chem. Lett. 1996, 6, 485.
(7) The synthesis of a 2-oxo-3-amino-4-benzyl-1-azabicyclo[4.3.0]-
nonane-9-carboxylic acid analogue that serves as a model antagonist
of the tachykinin NK-2 receptor is reported in: Hanessian, S.; Ronan,
B.; Laoui, A. Bioorg. Med. Chem. Lett. 1994, 4, 1397.
(12) Lombart, H.-G.; Lubell, W. D. In Peptides: Chemistry, Structure
and Biology; Kaumaya, P. T. P, Hodges, R. S., Eds.; ESCOM Sci. Pub.
B. V.: Leiden, 1996; p 695.
(8) The synthesis of 2(S)-amino-3-oxo-11b(R)-hexahydroindolizino-
[8,7-b]indole-5(S)-carboxylate is reported in: (a) de la Figuera, N.;
Rozas, I.; Garc´ıa-Lo´pez, M. T.; Gonza´lez-Mun˜iz, R. J . Chem. Soc.,
Chem. Commun. 1994, 613. (b) de la Figuera, N.; Alkorta, I.; Rozas,
I.; Garc´ıa-Lo´pez, M. T.; Herranz, R.; Gonza´lez-Mun˜iz, R. Tetrahedron
1995, 51, 7841.
(9) An alternative strategy to prepare 2-oxo-3-amino-1-azabicyclo-
[4.3.0]nonane-9-carboxylic acid is reported in: Mueller, R.; Revesz, L.
Tetrahedron Lett. 1994, 35, 4091.
(10) The synthesis of a 2-oxo-3-amino-3-benzyl-1-azabicyclo[4.3.0]-
nonane-9-carboxylic acid analogue is reported in: Colombo, L.; Di
Giacomo, M.; Scolastico, C.; Manzoni, L.; Belvisi, L.; Molteni, V.
Tetrahedron Lett. 1995, 36, 625.
(11) Preliminary results were reported in part: (a) Lombart, H.-G.;
Lubell, W. D. J . Org. Chem. 1994, 59, 6147. (b) Lombart, H.-G.; Lubell,
W. D. In Peptides 1994 (Proceedings of the 23rd European Peptide
Symposium); Maia, H. L. S., Ed.; ESCOM: Leiden 1995; p 696.
(13) Synthesis of 5-amino-9-oxo-1-azabicyclo[4.3.0]nonane-8-carbox-
ylic acid analogues are described in: Dominguez, M. J .; Garc´ıa-Lo´pez,
M. T.; Herranz, R.; Martin-Martinez, M.; Gonza´lez-Mun˜iz, R. J . Chem.
Soc., Perkin Trans. 1 1995, 2839 and references therein.
(14) Synthesis and use of 2-oxo-3-amino-1-azabicyclo[4.3.0]nonane-
6-carboxylic acid analogues as type VI â-turn peptide mimetics are
described in: (a) Dumas, J .-P.; Germanas, J . P. Tetrahedron Lett. 1994,
35, 1493. (b) Gramberg, D.; Robinson, J . A. Tetrahedron Lett. 1994,
35, 861. (c) Kim, K.; Dumas, J .-P.; Germanas, J . P. J . Org. Chem. 1996,
61, 3138. (d) Gramberg, D.; Weber, C.; Beeli, R.; Inglis, J .; Bruns, C.;
Robinson, J . A. Helv. Chim. Acta 1995, 78, 1588.
(15) 1,4-Diazabicyclo[4.3.0]nonane-9-carboxylic acid analogues are
described in: Fobian, Y. M.; d’Avignon, D. A.; Moeller, K. D. Bioorg.
Med. Chem. Lett. 1996, 6, 315.
(16) [4.3.0]Pyrazolidinones 2-carboxylic acid analogues have been
synthesized as potential antibacterial agents: Ternansky, R. J .;
Draheim, S. E. Tetrahedron Lett. 1988, 29, 6569.

Synthesis of Indolizidinone Amino Acids
J . Org. Chem., Vol. 61, No. 26, 1996 9439
Ta ble 1. Cla isen Con d en sa tion of N-(P h F )Glu ta m a tesa
Sch em e 2. Syn th esis of
5-Oxo-2,8-bis[N-(P h F )a m in o]a zela tes 5 via Cla isen
Con d en sa tion s of N-(P h F )Glu ta m a tes 2
MN(SiMe3)2 temp
entry
R
(mol %)
(°C)
[2] % 3 % rcvd 2 % 4
a
b
c
d
e
f
g
h
i
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
Li (110)
Na (110)
K (110)
Na (110)
Na (110)
Na (50)
Na (220)
Na (110)
Na (110)
Na (110)
-78 0.3
-78 0.5
-78 0.3
-30 0.5
-20 0.5
-78 0.3
-78 0.7
-30 0.1
-30 1.0
52
69
45
27
100
2
2
2
80
77
24
52
75
69
10
15
6
69
42
6
25
25
22
5
13
j
-50 0.45 65
a
Isolated yields.
peptide mimetics in the exploration of conformation-
activity relationships of various biologically active pep-
tides.
tion proceeds via regioselective enolization of the ω-ester.
Sodium enolates generated with NaN(SiMe3)2 as base
gave the best yields of â-keto ester 3. Lithium enolates
were less reactive, and potassium enolates gave no
condensation products at all in reactions using bis-
(trimethylsilyl)amide bases. Although potassium eno-
lates react well under alkylation conditions,19 we have
yet to acylate the potassium enolate of N-(PhF)glutamate
2a .20a Attempts were also unsuccessful to effect Claisen
condensation with methoxide in methanol. The Claisen
condensation was usually complete after 2 h. Since
enolization of the condensation product depletes base,
and since excess base consumes electrophile, the stoichi-
ometry and the rate of addition of NaN(SiMe3)2 to 2a
were both important for obtaining good yields of â-keto
ester 3 (Table 1, entries b, f, and g).
Dimethyl N-(PhF)glutamate (2b) was employed next
in the Claisen condensation using conditions optimized
with R-tert-butyl γ-methyl N-(PhF)glutamate (2a ) at -50
°C (Table 1, entry j). Synthesis of 2b proceeded in
excellent yield by esterification of glutamate in metha-
nolic HCl followed by phenylfluorenation.23 Because the
kinetic γ-esterification as well as the R-tert-butyl esteri-
Resu lts a n d Discu ssion
Syn th esis of r,ω-Diam in o Dicar boxylate via Clais-
en Con d en sa tion of N-(P h F )Glu ta m a tes. The Clais-
en condensation of N-(PhF)amino dicarboxylates is an
effective means for preparing functionalized R,ω-diamino
dicarboxylates (Scheme 2). For example, slow addition
of sodium bis(trimethylsilyl)amide (1 M in THF) to a
solution of (2S)-R-tert-butyl γ-methyl N-(PhF)glutamate
((2S)-2a ) in THF at -30 °C provided (2S,4RS,8S)-di-tert-
butyl 4-carbomethoxy-5-oxo-2,8-bis[N-(PhF)amino]aze-
late ((2S,4RS,8S)-3a ) in 80% yield (Table 1, entry d). Like
the alkylation,19 acylation,20 aldol,21 and Dieckmann22
reactions of amino dicarboxylates, this Claisen condensa-
(17) Recent representative examples of other azabicyclo[X.Y.0]-
alkane amino acid derivatives include the following: (a) Flynn, G. A.;
Giroux, E. L.; Dage, R. C. J . Am. Chem. Soc. 1987, 109, 7914. (b) Flynn,
G. A.; Beight, D. W.; Mehdi, S.; Koehl, J . R.; Giroux, E. L.; French, J .
F.; Hake, P. W.; Dage, R. C. J . Med. Chem. 1993, 36, 2420. (c) Attwood,
M. R.; Hassall, C. H.; Kro¨hn, A.; Lawton, G.; Redshaw, S. J . Chem.
Soc., Perkin Trans. I 1986, 1011. (d) Thomas, W. A.; Whitcombe, I. W.
A. J . Chem. Soc., Perkin Trans. II 1986, 747. (e) Robl, J . A. Tetrahedron
Lett. 1994, 35, 393. (f) Thorsett, E. D. Actual. Chim. The´r. 1986, 13,
257. (g) Cornille, F.; Slomczynska, U.; Smythe, M. L.; Beusen, D. D.;
Moeller, K. D.; Marshall, G. R. J . Am. Chem. Soc. 1995, 117, 909.
(18) (a) Lubell, W. D.; Rapoport, H. J . Am. Chem. Soc. 1988, 110,
7447. (b) Lubell, W. D.; J amison, T. F.; Rapoport, H. J . Org. Chem.
1990, 55, 3511. (c) Sharma, R.; Lubell, W. D. J . Org. Chem. 1996, 60,
202. (b) Gill, P.; Lubell, W. D. J . Org. Chem. 1995, 60, 2658.
(19) (a) Humphrey, J . M.; Bridges, R. J .; Hart, J . A.; Chamberlin,
A. R. J . Org. Chem. 1994, 59, 2467. (b) Gmeiner, P.; Feldman, P. L.;
Chu-Moyer, M. Y.; Rapoport, H. J . Org. Chem. 1990, 55, 3068. (c) Wolf,
J .-P.; Rapoport, H. J . Org. Chem. 1989, 54, 3164. (d) Koskinen, A. M.
P.; Rapoport, H. J . Org. Chem. 1989, 54, 1859. (e) Christie, B. D.;
Rapoport, H. J . Org. Chem. 1985, 50, 1239.
(23) Dimethyl N-(PhF)glutamate was prepared according to the
procedure described for dimethyl N-(PhF)aspartate: (a) J amison, T.
F.; Rapoport, H. Org. Synth. 1992, 71, 226. (b) Paz, M. M.; Sardina, J .
J . Org. Chem. 1993, 58, 6990. γ-Methyl N-(PhF)glutamate was
prepared by esterification according to: (c) Hanby, W. E.; Waley, S.
G.; Watson, J . J . Chem. Soc. 1950, 3239. Phenylfluorenation was
according to refs 19d and 23a.
(24) Three different tert-butyl esterification methods were examined
in order to synthesize R-tert-butyl γ-methyl N-(PhF)glutamate (2a ).
γ-Methyl N-(PhF)glutamate was initially prepared by reaction of O-tert-
butyl N,N′-diisopropylisourea and γ-methyl N-(PhF)glutamate in 75%
yield as described in ref 19d. Comparable yields were obtained, and
2a was conveniently purified when the acid was treated with 400 mol
% of N,N-dimethylformamide di-tert-butyl acetal in benzene according
to the general procedure described in: (a) Widmer, U. Synthesis 1983,
135. In our hands, the most efficient and least expensive method to
prepare 2a employed O-tert-butyl trichloroacetimidate as described in
the Experimental Section. This procedure was modified from the
methods described in: (b) Armstrong, A.; Brackenridge, I.; J ackson,
R. F. W.; Kirk, J . M. Tetrahedron Lett. 1988, 29, 2483. (c) Yue, C.;
Thierry, J .; Potier, P. Tetrahedron Lett. 1993, 34, 323. (d) Wessel, H.
P.; Iversen, T.; Bundle, D. R. J . Chem. Soc., Perkin Trans. 1 1985,
2247.
(20) (a) Ibrahim, H. H.; Lubell, W. D. J . Org. Chem. 1993, 58, 6438.
(b) Atfani, M.; Lubell, W. D. J . Org. Chem. 1995, 60, 3184. (c) Zee-
Cheng, R. K.-Y.; Olson, R. E. Biochem. Biophys. Res. Commun. 1980,
94, 1128.
(21) (a) Baldwin, J . E.; North, M.; Flinn, A.; Moloney, M. G.
Tetrahedron 1989, 45, 1453. (b) Baldwin, J . E.; North, M.; Flinn, A.;
Moloney, M. G. Tetrahedron 1989, 45, 1465.
(22) Bergmeier, S. C.; Coba´s, A. A.; Rapoport, H. J . Org. Chem. 1993,
58, 2369.

9440 J . Org. Chem., Vol. 61, No. 26, 1996
Lombart and Lubell
Sch em e 3. Syn th esis of
Ta ble 2. Hyd r olysis a n d Deca r boxyla tion of Ester 3a a
[N-(BOC)a m in o]in d olizid in on e Meth yl Ester 12 via
Red u ctive Am in a tion w ith Azela te 5
temp
entry
conditions
(°C) solvent n (mol %) % 5a % 4a
a
b
c
d
e
f
g
h
i
NaOH (2 N)
NaOH (2 N)
LiOH (2 N)
LiOH (2 N)
LiOH (2 N)
LiOH (2 N)
LiOH (2 N)
NaOH (2 N)
NaOH (2 N)
KO(SiMe3)2
66
25
25
25
66
66
66
THF
THF
THF
THF
THF
THF
THF
2000
1000
2000
1000
1000
500
300
500
500
150
52
68
58
67
70
77
74
99
99
c
12
e
9
4
12
5
20
25b dioxane
101
25
dioxane
Et2O
j
k
DMSO-H2O 160
DMSO
d
a
b
Isolated yields. Reaction time was 24 h. c 3a was recovered
unchanged. 3a decomposed. e 4a was not isolated.
d
fication steps are avoided, the preparation of 2b is
simpler and higher yielding than that for 2a (2a ) three
steps, 44% yield; 2b ) two steps, 88% yield).23,24 With
the conditions optimized on 2a , the Claisen condensation
of dimethyl ester 2b gave lower yields than the reaction
with 2a ; however, multigram quantities of â-keto ester
3b could be obtained in 60% yield after chromatography.
N-(PhF)pyroglutamate 4 was isolated from the Claisen
condensation reaction mixtures. Pyroglutamate forma-
tion was favored at higher temperatures. For example,
the condensation of dimethyl ester 2b at 0 °C gave
N-(PhF)pyroglutamate methyl ester (4b ) as the major
product. Glutamate 2 was destroyed when the Claisen
condensation was run at room temperature leaving
behind considerable amounts of base-line material on
TLC. Pyroglutamate 4 most likely arises from decom-
position of the enolate with loss of methoxide to form a
ketene intermediate that undergoes intramolecular cy-
clization onto the phenylfluorenyl nitrogen. The steric
bulk of the R-tert-butyl ester seems to retard the forma-
tion of N-(PhF)pyroglutamate 4a , which was a minor
component of the product from the condensation of R-tert-
butyl γ-methyl N-(PhF)glutamate (2a ).
yield by employing D-glutamate in the sequence described
above (Scheme 2).
(2S,8S)-Dimethyl 5-oxo-2,8-bis[N-(PhF)amino]azelate
((2S,8S)-5b; Scheme 2) was obtained in 81% overall yield
after chromatography via hydrolysis and decarboxylation
of â-keto ester 3b followed by esterification of 2,8-
diaminoazelaic acid 6 with iodomethane and potassium
carbonate in dimethyl sulfoxide. Hydrolysis of dimethyl
azelate 5b with NaOH in DMSO regenerated 2,8-diamino
azelaic acid 6 in 95% yield after precipitation and
recrystallization. Treatment of azelaic acid 6 with tert-
butyl trichloroacetimidate in dichloromethane:cyclohex-
ane provided an alternative means to synthesize di-tert-
butyl diaminoazelate 5a which was furnished in 76%
yield.24b-d
(2S,8S)-Di-tert-butyl 5-oxo-2,8-bis[N-(PhF)amino]aze-
late ((2S,8S)-5a ) was synthesized via hydrolysis and
decarboxylation of â-keto ester 3a (Table 2). When the
hydrolysis was conducted in refluxing THF, pyro-
glutamate 4a was again isolated. Its formation may
result from a retro-Claisen reaction and subsequent
cyclization via the mechanism described above. â-Keto
ester 3a remained unchanged after treatment with
potassium trimethylsilanolate in ether for 24 h25 and
decomposed on heating in wet DMSO at 160 °C.26 The
best conditions for decarboxylation of â-keto ester 3a
employed 2 N NaOH in dioxane and afforded quantita-
tively azelate 5a . In addition, we found that isolation of
â-keto ester 3a was unnecessary, and glutamate (2S)-2a
could be converted to symmetric azelate (2S,8S)-5a in
75% overall yield after Claisen condensation, hydrolysis,
decarboxylation, and chromatography. (2R,8R)-Di-tert-
butyl diaminoazelate (2R,8R)-5a was prepared in similar
A streamlined process gave 2,8-diaminoazelate di-
methyl ester 5b in 51% overall yield from dimethyl
N-(PhF)glutamate (2b) via a sequence in which â-keto
ester 3b and 2,8-diaminoazelaic acid 6 were not isolated
(Scheme 3). The added advantage was the ability to
recoup 39% of starting dimethyl N-(PhF)glutamate (2b)
as the other product isolated from chromatography of 5b.
Evidently, pyroglutamate 4b was hydrolyzed to N-(PhF)-
glutamate during the decarboxylation of 3b with NaOH
in dioxane. Subsequent esterification of N-(PhF)glutamate
provided 2b for reuse in the Claisen condensation.
Accounting for the recovery of starting 2b, the overall
yield of (2S,2R)-5b from L-glutamic acid was 72%.
Syn th esis of In d olizid in on e Am in o Acid 1. In-
dolizidinone amino acid 1 was synthesized from diami-
noazelate 5 via two different routes: one featuring
reductive amination of symmetric δ-amino ketone 5
(Schemes 3), the other involving hydride reduction of 5
followed by activation and intramolecular displacement
of symmetric δ-amino alcohol 7 (Scheme 5). In the
reductive amination sequence, hydrogenation of diami-
(25) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.
(26) (a) Krapcho, A. P. Synthesis 1982, 805. (b) Krapcho, A. P.
Synthesis 1982, 893.

Synthesis of Indolizidinone Amino Acids
J . Org. Chem., Vol. 61, No. 26, 1996 9441
Sch em e 4. Syn th esis of 12 via Red u ctive
Am in a tion of 5a
Sch em e 5. Syn th esis of
[N-(BOC)a m in o]in d olizid in on e Meth yl Ester 12 via
Alcoh ol 7a
Ta ble 3. In flu en ce of H2 P r essu r e on Red u ctive
Am in a tion of 5a a
entry H2 P (atm)
acid
TFA
TFA
TFA
6 N HCl
6 N HCl
6 N HCl
% (6S)-12 % (6R)-12
dr
a
b
c
d
e
f
1
6
11
1
6
11
41
52
54
45
64
66
22
10
6
22
8
65:35
84:16
90:10
67:33
89:11
96:4
3
a
Isolated yields.
noazelate 5a with palladium-on-carbon as catalyst in 9:1
EtOH:AcOH proceeded by cleavage of the phenylfluorenyl
groups, intramolecular imine formation, protonation, and
hydrogen addition to the iminium ion intermediate.
Because of symmetry, either amine of azelate 5 can
condense with the δ-ketone in order to furnish the same
5-alkylproline tert-butyl ester 8. Diamino diester 8 was
not isolated at this time; instead, the tert-butyl esters
were removed by acid solvolysis with either TFA or 6 N
HCl to furnish diamino acid 9. Methyl 2-oxo-3-[N-(BOC)-
amino]-1-azabicyclo[4.3.0]nonane-9-carboxylate (12) was
then obtained in 60-70% overall yields from 5a after
esterification of 9 with methanolic HCl, lactam cycliza-
tion, N-acylation of ester 11 with di-tert-butyl dicarbonate
and Et3N in CH2Cl2, and chromatography (Scheme 4).
A study of the influence of hydrogen pressure on the
diastereoselectivity of the reductive amination was per-
formed by measuring the ratio of (2S,6S,9S)- and
(2S,6R,9S)-[N-(BOC)amino]indolizidinone methyl esters
12 after their isolation from the reaction sequence
described above (Table 3). We used this indirect method
for ascertaining the diastereoselectivity of hydrogenation
because 5-alkylprolines 8 and 9 were inseparable by
chromatography and because their NMR spectra lacked
distinguishable diastereomeric signals. [N-(BOC)amino]-
indolizidinone methyl esters 12 were conveniently sepa-
rated by chromatography with 1:1 EtOAc:hexanes as
eluant. Increased hydrogen pressure was found to aug-
ment the diastereoselectivity in the reductive amination
step with (2S,8S)-5a such that the ratio of (6S)-12 to (6R)-
12 rose from 2:1 up to 24:1 as H2 pressure was increased
from 1 to 11 atm. In addition, we observed that [N-
(BOC)amino]indolizidinone methyl esters 12 were ob-
tained in higher yields when 6 N HCl was used to
deprotect 8 instead of TFA (Table 3). Employment of
(2R,8R)-5a in this reaction sequence gave similar yields
and diastereomeric ratios of (3R,6R,9R)- and (3R,6S,9R)-
[N-(BOC)amino]indolizidinone methyl esters 12.
di-tert-butyl dicarbonate. In order to recycle 14 into
[N-(BOC)amino]indolizidinone methyl ester 12, the BOC
groups were first removed with HCl gas in CH2Cl2 to
provide 5-alkylproline 10 as the hydrochloride salt.
Triethylamine in CH2Cl2 at room temperature was then
used to liberate the amine and convert 10 into lactam
11 (Scheme 3). Conversion was monitored by proton
NMR on examination of the disappearance of the methyl
ester singlets for 10 (3.87 and 3.89 ppm) and the
augmentation of the methyl ester singlet for 11 (3.73
1
ppm). By following lactam cyclization with H NMR, we
could time the addition of di-tert-butyl dicarbonate to the
reaction mixture in order to avoid formation of 14 and
thereby enhance the overall yield of [N-(BOC)amino]-
indolizidinone methyl esters 12.
(2S,8S)-2,8-Diaminoazelate dimethyl ester 5b was next
transformed into [N-(BOC)amino]indolizidinone methyl
ester 12 using the experience gained with azelate 5a .
Treatment of (2S,8S)-5b with palladium-on-carbon under
6 atm of H2 in 10:1 EtOH:AcOH furnished primarily
indolizidinone 11 with some 5-alkylproline 10 after
removal of the catalyst by filtration and evaporation of
solvent. Without further purification, the mixture was
first exposed to Et3N in CH2Cl2 for 3 h at room temper-
ature and then N-acylated with di-tert-butyl dicarbonate.
Purification by chromatography provided respectively
(2S,6S,9S)- and (2S,6R,9S)-[N-(BOC)amino]indolizidi-
none methyl esters 12 in 81% and 2% overall yields
(Scheme 3).
An alternative method to prepare indolizidinone amino
ester 12 was studied that featured activation and in-
tramolecular displacement of symmetric alcohol 7. The
intramolecular SN2 displacement was specifically exam-
ined with (2S,8S)-di-tert-butyl 5-hydroxy-2,8-bis[N-(PhF)-
amino]azelate ((2S,8S)-7a ) which was synthesized in 89%
yield from reduction of diamino ketone 5a with NaBH4
in MeOH. Treatment of 7a with carbon tetrabromide,
triphenylphosphine, and diisopropylethylamine in THF
at 25 °C for 1 h provided stereospecifically (2S,5S,3′S)-
tert-butyl 5-[3′-[N-(PhF)amino]-3′-[(methyloxy)carbonyl]-
propyl]-N-(PhF)prolinate ((2S,5S,3′S)-15) in 86% yield.19d
Methyl 5-[3′-[N-(BOC)amino]-3′-[(methyloxy)carbonyl]-
propyl]-N-(BOC)prolinate (14) was isolated in varying
yields from the reaction sequence to synthesize 12. The
formation of 14 is due to incomplete lactam formation
and subsequent N-acylation of the secondary amine with

9442 J . Org. Chem., Vol. 61, No. 26, 1996
Lombart and Lubell
Ta ble 4. Syn th esis of 1 via Hyd r olysis of Meth yl Ester
12a
Sch em e 6. Syn th esis a n d En a n tiom er ic P u r ity of
In d olizid in on e Am in o Acid 1
% yieldb
mol
entry
12
base
%
solvent (9S)-1 (9R)-1
a
b
c
d
e
f
g
h
i
(3S,6S,9S) LiOH (2 N) 1000 THF
(3S,6S,9S) LiOH (2 N) 2000 THF
52
64
97
83
74
95
60
92
10
82
86
29
36
(3S,6S,9S) LiOH (1 N)
(3S,6S,9S) LiOH (2 N)
(3S,6S,9S) LiOH (1 N)
(3S,6S,9S) LiOH (2 N)
200 THF
200 THF
120 THF
200 dioxane
6
13
5
30
5
84
5
6
(3S,6S,9S) NaOH (2 N) 1000 THF
(3S,6S,9S) NaOH (2 N) 200 dioxane
(3R,6R,9R) LiOH (2 N)
(3S,6R,9S) LiOH (1 N)
(3S,6R,9S) LiOH (2 N)
200 THF
150 THF
200 dioxane
j
k
l
(3S,6S,9R) NaOH (2 N) 200 dioxane
95
a
Unless noted, the reaction was conducted for 1-2 h at rt in 1:1
(v:v) base:solvent. Isolated yields. c Heated at reflux.
b
Stereospecific formation of cis-5-alkylproline (2S,5S,3′S)-
15 was also achieved in quantitative yield by mesylation
of 7a with methanesulfonyl chloride, Et3N, and DMAP
in CH2Cl2 at 0 °C followed by heating at reflux. Since
the steric effects of the nitrogen- and carboxylate-protect-
ing groups may alter the relative energies of the diaster-
eomeric transition states for intramolecular SN2 displace-
ment, we are presently examining other derivatives of 7
in order to prepare trans-5-alkylproline (2S,5R,3′S)-15.
N-PhF-5-alkylproline (2S,5S,3′S)-15 was transformed
into [N-(BOC)amino]indolizidinone methyl ester 12 by
hydrogenolysis of the PhF groups with palladium-on-
carbon as catalyst to give 8, which was converted to 12
as previously described.
[N-(BOC)amino]indolizidinone acid 1 was synthesized
via hydrolysis of ester 12 (Scheme 6). Epimerization of
the C-9 center competed with ester hydrolysis and
afforded mixtures of 9S- and 9R-diastereomers 12 that
were separated by chromatography on silica gel using
AcOH in EtOAc as eluant.27 By controlling the stoichi-
ometry of hydroxide ion in the hydrolysis of (3S,6S,9S)-
12, the amount of epimerization was significantly re-
duced and (3S,6S,9S)-1 was furnished in >90% yields
(Table 4). Furthermore, hydrolysis of (3R,6R,9R)- and
(3S,6R,9S)-[N-(BOC)amino]indolizidinone methyl esters
12 with LiOH furnished respectively (3R,6R,9R)- and
(3S,6R,9S)-1 in similar yields. Alternatively, enolization
of ester (3S,6S,9S)-12 with NaN(SiMe3)2 in THF provided
a 10:1 mixture of (3S,6S,9R)- and (3S,6S,9S)-12 in 92%
yield. (3S,6S,9R)-Methyl 2-oxo-3-[N-(BOC)amino]-1-
azabicyclo[4.3.0]nonane-9-carboxylate ((3S,6S,9R)-12) was
then hydrolyzed quantitatively with LiOH in dioxane to
afford (3S,6S,9R)-[N-(BOC)amino]indolizidinone acid
((3S,6S,9R)-1.
F igu r e 2. ORTEP view of indolizidinone methyl ester 12.
Ellipsoids drawn at 40% probability level. Hydrogens repre-
sented by spheres of arbitrary size.28
of δ-keto R-amino ester with hydrogen and palladium-
on-carbon as catalyst gave predominantly 5-alkylprolines
with cis-stereochemistry.20a Configurational assignments
were supported by NMR experiments in which the
nuclear Overhauser effects were measured when the
signals of the C-3, C-6, and C-9 protons were irradiated
in methyl 2-oxo-3-[N-(BOC)amino]-1-azabicyclo[4.3.0]-
nonane-9-carboxylates 12.11a For example, irradiation of
the bridge-head proton (C-6, δ ) 3.7) of (3S,6S,9S)-12
produced significant nuclear Overhauser effects at the
C-3 (δ ) 4.15) and C-9 (δ ) 4.5) protons. On the other
hand, irradiation of the C-6 (δ ) 3.64) proton of
(3S,6S,9R)-12 produced a significant nuclear Overhauser
effect only at the C-3 (δ ) 3.93) proton. Crystallization
of (3S,6S,9S)-methyl 2-oxo-3-[N-(BOC)amino]-1-azabicyclo-
[4.3.0]nonane-9-carboxylate ((3S,6S,9S)-12) from metha-
nol and X-ray crystallographic analysis confirmed the
NMR assignments (Figure 2).28
In the crystal structure of (3S,6S,9S)-indolizidinone 12,
the dihedral angles of the backbone atoms constrained
inside the heterocycle (ψ ) -176° and φ ) -78°) resemble
the values of the central residues in an ideal type II′
â-turn (ψ2 ) -120° and φ3 ) -80°).29 Furthermore, these
values compare well with those observed in the crystal
Assign m en t of Ster eoch em istr y a n d En a n tio-
m er ic P u r ity of In d olizid in on e Am in o Acid 1. The
bridge-head stereochemistry of [N-(BOC)amino]indoliz-
idinone acid 1 was originally assigned based on analogy
with our previous work in which the reductive amination
(28) The structure of 12 was solved at l’Universite´ de Montre´al X-ray
facility using direct methods (SHELXS 86): C15H24N2O5; Mr ) 312.36;
orthorhombic, colorless crystal; space group P212121; unit cell dimen-
sions (Å) a ) 6.793(2), b ) 14.847(3), c ) 16.712(4); volume of unit cell
(Å3) 1685.5(7); Z ) 4; R1 ) 0.0353 for I > 2σ(I), wR2 ) 0.0828 for all
data; GOF ) 0.869. The author has deposited the atomic coordinates
for the structure of 12 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.
(27) Epimerization of 12 during basic hydrolysis is similar to
racemization of N-methylamino esters under similar conditions; see,
for examples: Boger, D. L.; Chen, J .-H.; Saionz, K. W. J . Am. Chem.
Soc. 1996, 118, 1629 and ref 24 therein.
(29) Ball, J . B.; Alewood, P. F. J . Mol. Recogn. 1990, 3, 55.

Synthesis of Indolizidinone Amino Acids
J . Org. Chem., Vol. 61, No. 26, 1996 9443
1,1,1,3,3,3-hexamethyldisilazane and CH2Cl2 were distilled
from CaH2 and CHCl3 from P2O5; triethylamine (Et3N) was
distilled from BaO. Final reaction mixture solutions were
dried over Na2SO4. The solvent systems used are as follows:
eluant A, EtOAc:hexanes (1:5); eluant B, EtOAc:hexanes (1:
9); eluant C, EtOAc:hexanes (1:2); eluant D, CHCl3:MeOH:
AcOH (8:1:0.5); eluant E, EtOAc:hexanes (1:3); eluant F,
n-BuOH:AcOH:H2O (4:1:1); eluant G, EtOAc:hexanes (1:1);
eluant H, EtOAc:hexanes (2:1); eluant I, EtOAc:AcOH (20:1).
Melting points are uncorrected. Mass spectral data, HRMS
and MS (EI and FAB), were obtained by the Universite´ de
Montre´al Mass Spec. facility. Unless otherwise noted, 1H
NMR (300/400 MHz) and 13C NMR (75/100 MHz) spectra were
recorded in CDCl3. Chemical shifts are reported in ppm (δ
units) downfield of internal tetramethylsilane ((CH3)4Si),
residual CHCl3 (δ 7.27 and 77), or residual MeOH (δ 3.31 and
49.15), and coupling constants are reported in hertz. Chemical
shifts of PhF aromatic carbons are not reported for the 13C
NMR spectra. Analytical thin-layer chromatography (TLC)
was performed by using 2 × 6 cm aluminum-backed silica gel
plates coated with a 0.2 mm thickness of silica gel 60 F254
(Merck). Chromatography was performed using Kieselgel 60
(230-400 mesh).
structure of a (3S,6R,9S)-6-thiaindolizidinone â-turn
dipeptide analogue (ψ ) -161° and φ ) -69°).2b The
observed value of the φ dihedral angle of (3S,6S,9S)-12
is also similar to that of an ideal inverse γ-turn confor-
mation (ψ2 ) -80°).30
The enantiomeric purity of (6S)-12, produced from both
R-tert-butyl γ-methyl N-(PhF)glutamate (2a ) and di-
methyl N-(PhF)glutamate (2b), was determined after
conversion to (1′R)- and (1′S)-N-(R-methylbenzyl)ureas
16. Trifluoroacetic acid in CH2Cl2 removed quantita-
tively the N-BOC protecting group, and the TFA salt was
acylated with either (R)- or (S)-R-methylbenzyl isocyanate
in THF with triethylamine (Scheme 6).20a Observation
of the diastereomeric methyl ester singlets by 400 MHz
1H NMR spectroscopy in C6D6 during incremental addi-
tions of the opposite isomer demonstrated 16 to be of
>99% diastereomeric excess. Hence ester 12, azelates
5, and 2-oxo-3-[N-(BOC)amino]-1-azabicyclo[4.3.0]nonane-
9-carboxylic acids 1 are all presumed to be of >99%
enantiomeric purity.
(2S)-r-ter t-Bu tyl γ-Meth yl N-(P h F )Glu ta m a te ((2S)-
2a ).24 A solution of γ-methyl N-(PhF)glutamate (16.1 g, 40
mmol) in CH2Cl2 (40 mL) was treated with a solution of O-tert-
butyl trichloroacetimidate [17.5 g, 80 mmol, 200 mol %,
prepared as described for O-benzyl trichloroacetimidate in ref
23d: Rf ) 0.26 in eluant A; 1H NMR δ 1.58 (s, 9 H)] in
cyclohexane (160 mL). The mixture was stirred for 3 days,
filtered, and treated with a second solution of imidate (17.5 g,
80 mmol, 200 mol %) in cyclohexane (160 mL). After stirring
for 2 days at room temperature (rt), the precipitate was
removed by filtration and the solution was evaporated under
vacuum leaving a residue that was purified by chromatography
using 9:1 hexane:EtOAc as eluant. Evaporation of the col-
lected fractions gave a white solid that was recrystallized from
isooctane, (2S)-2a : 14.8 g (81%); Rf ) 0.55 in eluant A, Rf )
0.50 in eluant B; mp 99-100 °C (lit.19d mp 100 °C); [R]20D -246°
(c 1.08, CHCl3); HRMS calcd for C29H32NO4 (MH+) 458.2352,
found 458.2331.
Con clu sion
In the context of our research on general methods for
making azabicyclo[X.Y.0]alkane amino acids, we have
developed an efficient process for synthesizing enan-
tiopure indolizidinone amino acid 1 (X ) 4, Y ) 3). (2S)-
N-(PhF)glutamates (2S)-2a and (2S)-2b were used in a
Claisen condensation/reductive amination/lactam cycliza-
tion sequence to provide enantiopure (3S,6S,9S)-indoliz-
idinone amino acid 1 in 61% (7 steps) and 41% (5 steps,
64% accounting for recovery of 2b) respective overall
yields. By employing D-glutamate, (3R,6R,9R)-1 was
synthesized in similar yield. The indolizidinone C-6
bridge-head center was created with stereocontrol in
favor of the concave cis-isomer by augmenting hydrogen
pressure in the reductive amination step as well as by
mesylation of alcohol 7a and intramolecular SN2 dis-
placement by the PhF amine. Convex (3S,6R,9S)-1 was
synthesized, albeit with less stereocontrol, by lowering
hydrogen pressure in the reductive amination step.
Regioselective enolization of indolizidinone amino ester
12 gave access to C-9 epimers and was specifically used
to synthesize (3S,6S,9R)-1. All of the possible configura-
tions of indolizidinone amino acid 1 can therefore be
stereoselectively generated via this approach.
Furthermore, because alkylation of amino ketones 3
and 5 may be used to add side chains with stereocontrol
at different positions on the indolizidinone,18 and because
different length R-amino dicarboxylates may be employed
to make alternative heterocycles,31 our strategy has great
potential for preparing a variety of azabicyclo[X.Y.0]-
alkane amino acids. This efficient method for synthesiz-
ing rigid dipeptide mimetics should thus be of general
utility for the study of structure-activity relationships
in peptide chemistry and biology.
(2R)-r-ter t-Bu tyl γ-m eth yl N-(P h F )glu ta m a te ((2R)-2a ):
synthesized from (2R)-γ-methyl N-(PHF)glutamate (2 g, 5
mmol) in the same way which gave 1.71 g (75%) of (2R)-2a ;
[R]20 248° (c 1.04, CHCl3).
D
(2S,8S)-Di-ter t-bu tyl 5-Oxo-2,8-bis[N-(P h F )a m in o]a ze-
la te ((2S,8S)-5a ). A solution of NaN(SiMe3)2 (5.95 mL, 5.95
mmol, 110 mol %, 1 M in THF) was added over 30 min to a
-30 °C solution of (2S)-2a (2.44 g, 5.41 mmol, 100 mol %) in
THF (5.5 mL). The reaction mixture was stirred for an
additional 1.5 h at -30 °C and then partitioned between EtOAc
(30 mL) and 1 M NaH2PO4 (50 mL). The aqueous phase was
extracted with EtOAc (3 × 30 mL), and the organic layers were
combined and evaporated to a residue which was normally
used in the next reaction without purification.
Purification by chromatography on silica gel using a gradi-
ent of 10-30% EtOAc in hexanes as eluant gave first recovered
2a (25%, Rf ) 0.50 in eluant B) followed by a 1.2:1 mixture of
(2S,4RS,8S)-di-tert-butyl 4-carbomethoxy-5-oxo-2,8-bis[N-(PhF)-
amino]azelate ((2S,4RS,8S)-3a ) (74%): Rf ) 0.44 in eluant A,
Rf ) 0.40 in eluant B; 1H NMR δ 1.2 (s, 36 H), 1.6-1.75 (m, 4
H), 1.9 (t, 2 H), 2.3-2.6 (m, 4 H), 2.7-2.95 (m, 2 H), 3.15 (s, 2
H), 3.6 (s, 3 H), 3.75 (br s, 3 H), 3.95 (m, 2 H), 7.2-7.7 (m, 52
H); 13C NMR δ 27.78, 27.8, 29, 29.1, 33.3, 33.4, 38.4, 38.6, 52.1,
52.3, 54.9, 55, 55.6, 55.9, 72.85, 72.91, 80.7, 80, 169.6, 170.2,
174.82, 174.85, 204, 204.8; HRMS calcd for C57H59N2O7 (MH+)
883.4323, found 883.4327.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted all reactions were run
under argon atmosphere and distilled solvents were trans-
ferred by syringe. Tetrahydrofuran (THF) and ether were
distilled from sodium/benzophenone immediately before use;
On larger scale and at elevated temperatures, we isolated
(2S)-tert-butyl N-(PhF)pyroglutamate ((2S)-4a ): Rf ) 0.45 in
eluant C; mp 203-205 °C) lit.19d mp 199-202 °C); [R]20
D
-120.6° (c 1.3, CHCl3); 1H NMR δ 1.23 (s, 9 H), 1.85 (m, 1 H),
2.15-2.4 (m, 2 H), 2.67 (m, 1 H), 3.9 (d, 1 H), 7.2-7.8 (m, 13
H); 13C NMR δ 25, 27.4, 30.9, 61.5, 73, 81.2, 171.3, 176.3;
HRMS calcd for C28H27NO3 (M+) 425.1991, found 425.1981.
The crude condensation product was dissolved in dioxane
(7 mL), treated with 2 M NaOH (6.75 mL, 500 mol %), and
(30) Madison, V.; Kopple, K. D. J . Am. Chem. Soc. 1980, 102, 4855.
(31) We have recently reported a method to prepare L- and D-R-
amino dicarboxylates of six to eight carbon chain lengths with high
enantiomeric purities: Pham, T.; Lubell, W. D. J . Org. Chem. 1994,
59, 3676.

9444 J . Org. Chem., Vol. 61, No. 26, 1996
Lombart and Lubell
stirred at reflux for 1 h when TLC (eluant B) showed complete
disappearance of starting 2a . The mixture was partitioned
between EtOAc (15 mL) and NaH2PO4 (1 M, 15 mL), and the
aqueous phase was extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine, dried, and
evaporated to a foam that was purified by chromatography
using a gradient of 10-20% EtOAc in hexanes as eluant.
Evaporation of the collected fractions gave 1.66 g (75%) of
(2S,8S)-di-tert-butyl 5-oxo-2,8-bis[N-(PhF)amino]azelate ((2S,8S)-
5a ) which recrystallized from hexane:Et2O: Rf ) 0.52 in eluant
100 mol %) and iodomethane (0.89 mL, 14.3 mmol, 200 mol
%), and stirred at rt for 3 h. Brine (50 mL) was added, and
the reaction mixture was extracted with EtOAc (3 × 50 mL).
The combined organic layers were washed with 0.65 M sodium
thiosulfate and brine, dried, and evaporated to a foam that
was purified by chromatography using a gradient of 10-30%
EtOAc in hexanes as eluant. First to elute was recovered (2S)-
2b (1.14 g, 39%) followed by (2S,8S)-5b (1.34 g, 51%): Rf )
0.38 in eluant E; mp 135-136 °C; [R]20 -259.5° (c 1, CHCl3);
D
1H NMR δ 1.61-1.66 (m, 2 H), 2.29-2.49 (m, 2 H), 2.53 (t, 1
H, J ) 6.5), 2.95 (br s 1 H), 3.26 (s, 3 H), 7.1-7.7 (m, 13 H);
13C NMR δ 28.7, 38.7, 55.5, 54.8, 72.8, 176.4, 208.9; HRMS
calcd for C49H45N2O5 (MH+) 741.3328, found 741.3352. Es-
terification of pure 6 and chromatography gave (2S,8S)-5b,
which recrystallized from hexane/Et2O in 86% yield.
A, Rf ) 0.48 in eluant B; mp 129 °C; [R]20 -174.9° (c 2.2,
D
MeOH); [R]20D -224.1° (c 2.2, CHCl3); 1H NMR δ 1.05 (s, 9 H),
1.55 (m, 2 H), 2.25 (m, 1 H), 2.4 (m, 2 H), 3 (br s, 1 H), 7-7.6
(m, 13 H); 13C NMR δ 27.8, 29.3, 38.9, 55.1, 72.9, 80.6, 174.9,
209.8; HRMS calcd for C55H57N2O5 (MH+) 825.4267, found
825.4230. Anal. Calcd for C55H56N2O5: C, 79.96; H, 6.96; N,
3.39. Found: C, 79.97; H, 7.04; N, 3.40. When pure 3a was
used, (2S,8S)-5a was obtained in 99% yield.
(3S,6S,9S)- a n d (3S,6R,9S)-Meth yl 2-Oxo-3-[N-(BOC)-
a m i n o ]-1 -a z a b i c y c l o [4 .3 .0 ]n o n a n e -9 -c a r b o x y l a t e
((3S,6S,9S)- an d (3S,6R,9S)-12). A solution of azelate (2S,8S)-
5a (1.78 g, 2.16 mmol) in anhydrous EtOH (60 mL) and AcOH
(6 mL) was treated with palladium-on-carbon (10 wt %, 219
mg) and stirred under 6 atm of hydrogen for 24 h. The mixture
was filtered on Celite, the catalyst was washed with EtOH
(60 mL), and the combined organic phase was evaporated to
give (2S,5RS,3′S)-tert-butyl 5-[3′-amino-3′-(tert-butyloxycar-
bonyl)propyl]prolinate bisacetate ((2S,5RS,3′S)-8): Rf ) 0.46
in eluant F; 1H NMR δ 1.50 (m, 18 H), 1.60-1.90 (m, 4 H), 2.0
(s, 6 H), 2.0-2.2 (m, 3 H), 2.3 (m, 1 H), 3.45 (m, 1 H), 3.55-
3.70 (m, 2H), 4.10 (m, 1 H), 4.45 (d, 1 H); 13C NMR δ 21.9,
26.5, 27.8, 28.9, 30.9, 31.0, 31.7, 49.0, 57.5, 59.2, 69.1, 81.5,
170.6, 176.0.
Ester 8 was dissolved in a solution of 6 N HCl (24 mL) and
CH2Cl2 (24 mL). After stirring for 15 h, TLC (eluant F) showed
complete disappearance of the starting ninhydrin positive
material (Rf ) 0.46) and formation of a new ninhydrin positive
product (Rf ) 0.22). Removal of the volatiles under vacuum
gave (2S,5RS,3′S)-5-[3′-amino-3′-(hydroxycarbonyl)propyl]-N-
prolinate (2S,5RS,3′S)-9: Rf ) 0.22 in eluant F; 1H NMR (CD3-
OD) δ 1.60 (m, 2 H), 1.60-1.80 (m, 2 H), 1.9 (m, 1 H), 2.05-
2.25 (m, 4 H), 2.4 (m, 1 H), 3.65 (m, 1 H), 3.80 (m, 1 H), 4.35
(d, 1 H).
(2R,8R)-Di-ter t-bu tyl 5-Oxo-2,8-bis[N-(P h F )a m in o]a ze-
la te ((2R,8R)-5a ). This compound was prepared from (2R)-
R-tert-butyl γ-methyl N-(PhF)glutamate ((2R)-2a ; 0.914 g, 2
mmol, 100 mol %) in a similar manner using a solution of NaN-
(Si(CH3)3)2 (110 mol %) in THF at -78 °C for the condensation
and 1 M LiOH (500 mol %) in refluxing THF for 12 h for
hydrolysis and decarboxylation. Evaporation of the collected
fractions gave first 315 mg (38%) of (2R,8R)-5a , [R]20 224.4°
D
(c 2.2, CHCl3), followed by 310 mg (37%) of (2R)-4a .
(2S,8S)-Dim eth yl 5-Oxo-2,8-bis[N-(P h F )a m in o]a zela te
((2S,8S)-5b). A solution of NaN(SiMe3)2 (7.9 mL, 7.9 mmol,
110 mol %, 1 M in THF) was added over 30 min to a -50 °C
solution of (2S)-dimethyl N-(PhF)glutamate ((2S)-2b; 2.97 g,
7.15 mmol, 100 mol %)23 in THF (7.15 mL). The reaction
mixture was stirred for 2 h at -50 °C and then partitioned
between EtOAc (30 mL) and 1 M NaH2PO4 (30 mL). The
aqueous phase was extracted with EtOAc (3 × 30 mL). The
organic layers were combined, washed with brine, dried, and
evaporated to a residue that was directly used in the next
reaction.
Purification of the residue by chromatography on silica gel
using a gradient of 10-30% EtOAc in hexanes as eluant gave
first recovered 2b (35%, Rf ) 0.55 in eluant C) followed by
(2S,4RS,8S)-dimethyl 4-carbomethoxy-5-oxo-2,8-bis[N-(PhF)-
amino]azelate ((2S,4RS,8S)-3b; 65%): Rf ) 0.28 in eluant A;
1H NMR δ 1.2 (s, 36 H), 1.6-1.75 (m, 4 H), 1.9 (t, 2 H), 2.3-
2.6 (m, 4 H), 2.7-2.95 (m, 2 H), 3.15 (s, 2 H), 3.6 (s, 3 H), 3.75
(br s 3 H), 3.95 (m, 2 H), 7.2-7.7 (m, 52 H); 13C NMR δ 28.2,
28.4, 32.4, 32.7, 37.8, 38.1, 51.3, 51.4, 51.5, 51.5, 52.1, 52.5,
53.4, 54.2, 54.5, 54.5, 54.9, 55.9, 72.85, 72.91, 169.2, 170.0,
175.6, 175.9, 176.0, 176.0, 204.0, 203.9; HRMS calcd for
C51H47N2O7 (MH+) 799.3411, found 799.3383.
The residue was dissolved in a premixed 0 °C solution of
acetyl chloride (9.9 mL) in MeOH (46 mL), and the solution
was stirred at rt for 24 h when TLC (eluant F) showed
conversion to a new ninhydrin positive product. The volatiles
were removed under vacuum. The crude amino ester hydro-
chloride residue was dissolved in CH2Cl2 (36 mL), treated with
Et3N (2.97 mL, 6.48 mmol, 300 mol %), and stirred at rt for 4
h. Di-tert-butyl dicarbonate (2.3 g, 10.8 mmol, 500 mol %) was
added, and the solution was stirred at rt for 2 h. The mixture
was partitioned between CHCl3 (20 mL) and 1 M NaH2PO4
(20 mL), and the aqueous phase was extracted with CHCl3 (3
× 20 mL). The combined organic layers were washed with
brine, dried, and evaporated to an oil that was chromato-
graphed using eluant G. Evaporation of the collected fractions
gave first (2S,5RS,3′S)-methyl 5-[3′-[N-(BOC)amino-3′-[(meth-
yloxy)carbonyl]propyl]-N-(BOC)prolinate ((2S,5RS,3′S)-14; 180
Last to elute was (2S)-methyl N-(PhF)pyroglutamate ((2S)-
4b) which was recrystallized from CHCl3/Et2O: [R]20 -105°
D
1
(c 1, CHCl3); mp 201-202 °C; H NMR δ 1.85 (m, 1 H), 2.18
(m, 1 H), 2.37 (m, 1 H), 2.71 (m, 1 H), 3.31 (s, 3 H), 3.65 (dd,
1 H, J ) 1.1, 9.3), 7.1-7.7 (m, 13 H); 13C NMR δ 23.9, 30.5,
51.5, 60.1, 72.8, 172.6, 176; HRMS calcd for C25H22NO3 (MH+)
384.1560, found 384.1586.
1
mg, 18%): Rf ) 0.56 in eluant G; H NMR δ 1.34 (s, 36 H),
The crude condensation product was dissolved in dioxane
(32 mL), treated with 2 M NaOH (32 mL, 64.4 mmol, 900 mol
%), and stirred at reflux for 2 h when TLC (eluant A) showed
complete disappearance of starting 2b. The mixture was
acidified with citric acid, and the aqueous phase was extracted
with EtOAc (4 × 15 mL). The combined organic layers were
washed with brine, dried, and evaporated to a solid that was
directly used in the next reaction.
1.58-1.63 (m, 4 H), 1.73-1.86 (m, 8 H), 2.13 (m, 2 H), 3.63 (s,
12 H), 4.11-4.18 (m, 3 H), 4.24 (m, 1 H), 5.11 (br d, 1 H), 5.16
(br d); 13C NMR δ 27.78, 28.07, 28.13, 28.51, 28.95, 29.08,
29.52, 30.02, 30.22, 30.41, 51.75, 51.95, 53.12, 53.29, 57.52,
57.64, 59.19, 59.61, 79.29, 79.42, 79.70, 79.90, 153.54, 154.08,
155.30, 172.99, 173.09, 173.69, 173.55; HRMS calcd for
C21H36N2O8 (MH+) 445.2550, found 445.2536.
Next to elute was (3S,6S,9S)-methyl 2-oxo-3-[N-(BOC)-
amino]-1-azabicyclo[4.3.0]nonane-9-carboxylate ((3S,6S,9S)-12;
452 mg, 67%) as a white solid that recrystallized from hexane/
Purification of the hydrolysis product from pure (2S,4RS,8S)-
3b (2.68 g, 3.36 mmol) using a gradient of 0-10% MeOH in
CHCl3 as eluant gave 1.86 g (78%) of (2S,8S)-5-oxo-2,8-bis[N-
(PhF)amino]azelate (6), which recrystallized from CHCl3/
Et2O: Rf ) 0.23 in eluant G; mp 111-112 °C; [R]20 -17.6° (c
D
1, CHCl3); [R]20 -47.9° (c 6.12, MeOH); H NMR δ 1.45 (s, 9
1
D
Et2O: Rf ) 0.77 in eluant D; mp 158 °C dec; [R]20 -32.8° (c
H), 1.7 (m, 3 H), 2.1 (m, 4 H), 2.45 (m, 1 H), 3.7 (m, 1 H), 3.75
(s, 3 H), 4.15 (m, 1 H), 4.5 (d, 1 H, J ) 7.5), 5.5 (d, 1 H, J )
4.4); 13C NMR δ 26.8, 27.2, 28.3, 28.9, 32.0, 49.9, 52.2, 56.4,
58.1, 79.4, 155.6, 169.1, 172.1; HRMS calcd for C15H25N2O5
D
1
1, CHCl3); H NMR δ 1.62 (m, 1 H), 1.74 (m, 1 H), 2.32-2.45
(m, 2 H), 2.66 (t, 1 H, J ) 5.5), 7.1-7.8 (m, 13 H), 8.1 (br s 1
H); 13C NMR δ 27.2, 38.7, 55.8, 73.0, 175.4, 213.2; HRMS calcd
for C47H41N2O5 (MH+) 713.2984, found 713.3016.
(MH+) 313.1764, found 313.1785. Anal. Calcd for C15H24
-
The crude hydrolysis product was dissolved in dimethyl
sulfoxide (33 mL), treated with K2CO3 (988 mg, 7.15 mmol,
N2O5: C, 57.66; H, 7.75; N, 8.97. Found: C, 57.82; H, 7.76;
N, 8.87.

Synthesis of Indolizidinone Amino Acids
J . Org. Chem., Vol. 61, No. 26, 1996 9445
Last to elute was convex (3S,6R,9S)-12 as an oil (14 mg,
(3S,6S,9S)-12: Rf ) 0.46 in eluant E; [R]20 -44.7° (c 0.8,
D
1
1
2%): Rf ) 0.08 in eluant G; [R]20 -25.3° (c 1.1, MeOH); H
CHCl3); H NMR δ 1.44 (s, 9 H), 1.65-1.75 (m, 3 H), 2.10-
D
NMR δ 1.4 (s, 9 H), 1.69 (m, 1 H), 1.83 (m, 1 H), 1.92-2.05
(m, 2 H), 2.09-2.21 (m, 2 H), 2.44 (m, 1 H), 3.64 (m, 1 H),
3.72 (s, 3 H), 3.93 (m, 1 H), 4.43 (d, 1 H, J ) 9.7), 5.36 (br s,
1 H); 13C NMR δ 27.6, 28.16, 28.23, 28.50, 31.4, 52, 52.0, 57.9,
60.4, 79.3, 155.8, 168.2, 172.1; HRMS calcd for C15H25N2O5
(MH+) 313.1764, found 313.1720.
2.30 (m, 4 H), 2.42 (m, 1 H), 3.71 (dddd, 1 H, J ) 10, 10, 5, 5),
4.22 (m, 1 H), 4.54 (d, 1 H, J ) 8.6), 5.66 (d, 1 H, J ) 4.8); 13
C
NMR δ 26.4, 26.8, 28.1, 28.4, 31.8, 49.6, 56.8, 58.5, 79.6, 155.7,
170.3, 174.2; HRMS calcd for C14H23N2O5 (MH+) 299.1607,
found 299.1596.
This was followed by 27 mg (5%) of (3S,6S,9R)-2-oxo-3-[N-
(BOC)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylic acid ((3S,
(3R,6R,9R)- a n d (3R,6S,9R)-Meth yl 2-oxo-3-[N-(BOC)-
a m i n o ]-1 -a z a b i c y c l o [4 .3 .0 ]n o n a n e -9 -c a r b o x y l a t e
((3R,6R,9R)- an d (3R,6S,9R)-12) were prepared from (2R,8R)-
5a (250 mg, 0.30 mmol) in the same manner which gave
6S, 9R)-1): Rf ) 0.28 in eluant I; [R]20 -6.5° (c 1.7, CHCl3);
D
1H NMR δ 1.42 (s, 9 H), 1.65-1.8 (m, 2 H), 1.89 (m, 2 H), 2
(m, 3 H), 2.25 (m, 1 H), 3.6 (br s, 1 H), 3.95 (br s, 1 H), 4.35 (br
s, 1 H), 5.86 (br s, 1 H); 13C NMR δ 27.4, 28.9, 29.1, 30.2, 31.3,
51.5, 60, 60.6, 79.4, 156, 169.7, 176.5; HRMS calcd for
C14H23N2O5 (MH+) 299.1607, found 299.1619.
(3R,6R,9R)-12 [54.5 mg, 60%, [R]20 17° (c 1.1, CHCl3)] and
D
(3R,6S,9R)-8 [4.6 mg, 5%, [R]20 16° (c 0.46, CHCl3)].
D
(3S,6S,9S)-Met h yl 2-Oxo-3-[N-(BOC)a m in o]-1-a za b i-
cyclo[4.3.0]n on a n e-9-ca r b oxyla t e ((3S,6S,9S)-12) fr om
Dim eth yla zela te (2S,8S)-5b. A solution of azelate (2S,8S)-
5b (675 mg, 0.91 mmol) in anhydrous EtOH (23 mL) and AcOH
(2.3 mL) was treated with palladium-on-carbon (20 wt %, 184
mg) and stirred under 6 atm of hydrogen for 48 h. The mixture
was filtered on Celite, the catalyst was washed with EtOH
(30 mL), and the combined organic phases were evaporated
to a solid. The amino ester was dissolved in CH2Cl2 (15 mL),
treated with Et3N (0.83 mL, 1.82 mmol, 200 mol %), and
stirred at rt for 3 h. Di-tert-butyl dicarbonate (993 mg, 4.55
mmol, 500 mol %) was added, and the solution was stirred at
rt for another 2 h. The mixture was partitioned between
CHCl3 (15 mL) and 1 M NaH2PO4 (15 mL), and the aqueous
phase was extracted with CHCl3 (3 × 15 mL). The combined
organic layers were washed with brine, dried, and evaporated
to an oil that was chromatographed using eluant G. First to
elute was (3S,6S,9S)-ethyl 2-oxo-3-[N-(BOC)amino]-1-aza-
Isomeric indolizidinone amino acids 1 were similarly ob-
tained from hydrolysis of 12 with hydroxide ion (Table 4) and
purified by chromatography with 20:1 EtOAc:AcOH as eluant.
(3S,6R,9S)-2-Oxo-3-[N-(BOC)am in o]-1-azabicyclo[4.3.0]-
n on a n e-9-ca r boxylic a cid ((3S,6R, 9S)-1): [R]20 -20.3° (c
D
0.8, CHCl3); 1H NMR δ 1.41 (s, 9 H), 1.55-1.8 (m, 2 H), 1.85-
2.05 (m, 2 H), 2.05-2.15 (m, 3 H), 2.28 (br m, 1 H), 3.63 (br
m, 1 H), 3.90 (m, 1 H), 4.44 (t, 1 H, J ) 5.3), 5.61 (br s, 1 H),
8.2 (br s, 1H); 13C NMR δ 27.7, 28.3, 29.7, 31.5, 31.5, 51.8,
59.5, 60.7, 79.5, 156.0, 169.8, 175.9; HRMS calcd for C14H23N2O5
(MH+) 299.1607, found 299.1594.
(3S,6R,9R)-2-Oxo-3-[N-(BOC)am in o]-1-azabicyclo[4.3.0]-
n on a n e-9-ca r boxylic a cid ((3S,6R,9R)-1): 1H NMR (showed
a 5.4:1 ratio of diastereomers, resonances of the major isomer
are as follows) δ 1.39 (s, 9 H), 1.5-1.7 (m, 3 H), 1.9-2.1 (m, 2
H), 2.1-2.35 (m, 2 H), 2.45 (m, 1 H), 3.6 (m, 1 H), 4.2 (m, 1
H), 4.5 (d, 1 H, J ) 8.7 Hz), 5.4 (m, 1 H).
(3R,6R,9R)-2-Oxo-3-[N-(BOC)am in o]-1-azabicyclo[4.3.0]-
bicyclo[4.3.0]nonane-9-carboxylate: 10 mg (5%); Rf ) 0.29 in
n on a n e-9-ca r boxylic a cid ((3R,6R,9R)-1): [R]20 45.6° (c
D
1
eluant G; [R]20 -13.8° (c 1.2, CHCl3); H NMR δ 1.28 (t, 3H,
D
0.8, CHCl3).
J ) 7.1), 1.44 (s, 9 H), 1.60-1.79 (m, 4 H), 2.03-2.33 (m, 3
H), 2.1 (m, 4 H), 2.45 (m, 1 H), 3.73 (m, 1 H), 4.15 (2, 1 H),
4.17 (qd, 1 H, J ) 7.1, 1.2), 4.49 (d, 1 H, J ) 7.8), 5.52 (br s,
1 H); 13C NMR δ 14.1, 26.8, 27.2, 28.3, 29.1, 32.1, 50.0, 56.5,
58.3, 61.3, 79.4, 155.7, 169.1, 171.6; HRMS calcd for C16H27N2O5
(MH+) 327.1920, found 327.1936. Next to elute was (3S,6S,9S)-
12 (230 mg, 81%) followed by (3S,6R,9S)-12 (6.4 mg, 2%).
(3R,6R,9S)-2-Oxo-3-[N-(BOC)am in o]-1-azabicyclo[4.3.0]-
n on a n e-9-ca r boxylic a cid ((3R,6R,9S)-1): [R]20D 20.5° (c 0.8,
CHCl3).
(3S,6S,9S)-Meth yl 2-Oxo-3-a m in o-1-a za bicyclo[4.3.0]-
n on a n e-9-ca r b oxyla t e H yd r och lor id e ((3S,6S,9S)-11).
Through a solution of (3S,6S,9S)-12 (0.32 mmol, 100 mg) in
CH2Cl2 (2 mL) was bubbled a stream of HCl gas with stirring
at rt for 15 min when TLC (eluant G) showed complete
disappearance of starting 12. The white precipitate was
(3S,6S,9R)-Met h yl 2-Oxo-3-[N-(BOC)a m in o]-1-a za b i-
cyclo[4.3.0]n on a n e-9-ca r b oxyla t e ((3S,6S,9R)-12) via
Ep im er iza tion of (3S,6S,9S)-12. A solution of NaN(SiMe3)2
(0.26 mL, 0.26 mmol, 200 mol %, 1 M in THF) was added over
15 min to a -50 °C solution of (3S,6S,9S)-12 (40 mg, 0.13
mmol, 100 mol %) in THF (0.2 mL). The reaction mixture was
stirred for 1 h at -50 °C followed by 1 h at -20 °C and then
partitioned between EtOAc (5 mL) and 1 M NaH2PO4 (5 mL).
The aqueous phase was extracted with EtOAc (3 × 5 mL). The
organic layers were combined, washed with brine, dried, and
evaporated to an oil (36.6 mg, 92% of a 1:10 ratio of (3S,6S,9S)-
12:(3S,6S,9R)-12 as determined by 1H NMR) that was chro-
matographed using eluant H. Evaporation of the collected
fractions gave first (3S,6S,9S)-12 (2 mg, 5%; Rf ) 0.4 in eluant
H) followed by (3S,6S,9R)-methyl 2-oxo-3-[N-(BOC)amino]-1-
azabicyclo[4.3.0]nonane-9-carboxylate ((3S,6S,9R)-12; 30 mg,
75% of >92% de by 1H NMR): Rf ) 0.37 in eluant H; 1H NMR
δ 1.8 (s, 9 H), 1.4-1.6 (m, 4 H), 1.85 (m, 1 H), 2.12-2.26 (m,
2 H), 2.37 (m, 1 H), 3.67 (s, 3 H), 3.75 (m, 1 H), 4.1 (m, 1 H),
4.5 (t, 1 H, J ) 7.5), 5.5 (br s, 1 H); 13C NMR δ 26.2, 28.0,
28.3, 28.4, 32.6, 50.1, 52.4, 56.4, 58.4, 79.7, 155.7, 169.0, 172.1;
HRMS calcd for C15H25N2O5 (MH+) 313.1764, found 313.1754.
filtered to give 80 mg (100%) of (3S,6S,9S)-11: Rf ) 0.35 in
1
eluant F; mp 85-90 °C; [R]20 -54.9° (c 1, CH3OH); H NMR
D
(CD3OD) δ 1.66-1.79 (m, 2 H), 1.93 (m, 1 H), 2.09 (m, 1 H),
2.17-2.34 (m, 3 H), 2.46 (m, 1 H), 3.73 (s, 3 H), 3.71 (dddd, 1
H, J ) 10.1, 10.1, 5, 5), 4.04 (t, 1 H, J ) 8.6), 4.49 (d, 1 H, J
) 8.7); 13C NMR δ 23.9, 26.6, 29.11, 31.8, 49.0, 52.6, 57.1, 58.6,
167.1, 172.0; HRMS calcd for C10H17N2O3 (MH+) 213.1239,
found 213.1246.
Recycle of (2S,5RS,3′S)-Meth yl 5-[3′-[N-(BOC)a m in o]-
3′-[(m e t h y lo x y )c a r b o n y l]p r o p y l]-N -(B O C )p r o lin a t e
((2S,5RS,3′S)-14) in t o (3S,6S,9S)- a n d (3S,6R,9S)-12.
Through a solution of 5-alkylprolinate 14 (2.82 mmol, 1.25 g)
in CH2Cl2 (10 mL) was bubbled a stream of HCl gas with
stirring at rt for 30 min when TLC (eluant C) showed complete
disappearance of starting 14. The precipitated was filtered
to give a white solid, (2S,5RS,3′S)-methyl 5-[3′-amino-3′-
[(methyloxy)carbonyl]propyl]prolinate hydrochloride ((2S,5RS,
3′S)-10): 892 mg, 100%; Rf ) 0.14 in eluant F; 1H NMR (CD3-
OD) δ 1.72-1.83 (m, 1 H), 1.90-2.10 (m, 4 H), 2.24-2.43 (m,
3 H), 3.70 (m, 1 H), 3.82 (s, 3 H), 3.86 (s, 3 H), 4.15 (dd, 1 H),
4.50 (dd, 1 H); 13C NMR (CD3OD) δ 28.1, 28.5, 28.6, 29.8, 53.6,
53.9, 54.1, 60.9, 61.9, 170.5, 170.6; HRMS calcd for C11H21N2-
O4 (MH+) 245.1577, found 245.1501.
Amino ester hydrochloride 10 (303 mg, 0.95 mmol) was then
dissolved in CH2Cl2 (5 mL) with Et3N (396 µL, 2.85 mmol, 200
mol %) and stirred at rt for 4 h. Di-tert-butyl dicarbonate (623
mg, 2.85 mmol, 300 mol %) was added, and the solution was
stirred at rt for another 2 h. The mixture was partitioned
between CHCl3 (10 mL) and 1 M NaH2PO4 (10 mL), and the
aqueous phase was extracted with CHCl3 (3 × 10 mL). The
combined organic layers were washed with brine, dried, and
evaporated to an oil that was chromatographed with 1:1
(3S,6S,9S)-2-Oxo-3-[N-(BOC)am in o]-1-azabicyclo[4.3.0]-
n on a n e-9-ca r b oxylic Acid ((3S,6S,9S)-1). (3S,6S,9S)-
Methyl 2-oxo-3-[N-(BOC)amino]indolizidine-9-carboxylate
((3S,6S,9S)-12; 563 mg, 1.8 mmol) in dioxane (1.8 mL) was
treated with 2 M LiOH (1.8 mL, 200 mol %) and stirred at rt
for 2 h when TLC (eluant G) showed complete disappearance
of starting 12. The mixture was partitioned between EtOAc
(6 mL) and 1 M NaH2PO4 (6 mL). The aqueous phase was
extracted with EtOAc (3 × 6 mL), and the organic layers were
combined, washed with brine, dried, and evaporated to an oil
that was chromatographed with 20:1 EtOAc:AcOH as eluant.
Evaporation of the collected fractions gave 511 mg (95%) of

9446 J . Org. Chem., Vol. 61, No. 26, 1996
Lombart and Lubell
hexanes:EtOAc as eluant. Evaporation of the collected frac-
tions gave first recovered 14 (58 mg, 12%) followed by
(3S,6S,9S)-12 (175 mg, 59%) and (3S,6R,9S)-12 (15 mg, 5%).
(2S,8S)-Di-ter t-bu tyl 5-Hyd r oxy-2,8-bis[N-(P h F)a m in o]-
a zela te ((2S,8S)-7a ). Sodium borohydride (790 mg, 2.04
mmol, 50 mol %) was added over a period of 5 min to a stirred
solution of (2S,8S)-5a (3.36 g, 4.08 mmol) in EtOH (25 mL).
After stirring for 30 min at rt, TLC (eluant A) showed complete
disappearance of starting 5a . The reaction mixture was
concentrated on a rotary evaporator and then partitioned
between EtOAc (15 mL) and water (25 mL). The aqueous
phase was extracted with EtOAc (3 × 25 mL). The combined
organic layers were washed with brine, dried, and evaporated
to a foam that was purified by chromatography using a
gradient of 10-30% EtOAc in hexanes as eluant. Evaporation
of the collected fractions gave 3.01 g (89%) of 7a as a white
solid: Rf ) 0.28 in eluant A; mp 84-86 °C; 1H NMR δ 1.18 (s,
9 H), 1.20 (s, 9 H), 1.31-1.55 (m, 8 H), 2.47-2.55 (m, 2 H),
3.35-3.40 (m, 1 H), 7.1-7.7 (m, 26 H); 13C NMR δ 27.9, 31.5,
31.6, 33.1, 33.2, 55.9, 56.0, 71.1, 73.1, 80.6, 80.7, 175.0, 175.1;
HRMS calcd for C55H60N2O5 (MH+) 828.4502, found 828.4538.
(2S,5S,3′S)-ter t-Bu tyl 5-[3′-[N-(P h F )a m in o]-3′-(ter t-bu -
t yloxyca r b on yl)p r op yl]-N-(P h F )p r olin a t e ((2S,5S,3′S)-
15). A stirred 0 °C solution of (2S,8S)-7a (83 mg, 0.10 mmol)
in CH2Cl2 (1 mL) was treated with methanesulfonyl chloride
(16 µL, 0.2 mmol, 200 mol %), DMAP (1.2 mg, 0.01 mmol, 10
mol %), and Et3N (24 µL, 0.30 mmol, 300 mol %), stirred for 1
h, brought to rt, stirred for 1 h, and heated at reflux for 24 h.
EtOAc (3 mL) and H2O (1 mL) were added to the reaction
mixture, and the organic layer was sequentially washed with
2 N HCl (1 mL), 5% NaHCO3 (1 mL), H2O (1 mL), and brine,
dried, evaporated, and purified by chromatography with 1:5
EtOAc:hexanes as eluant. Evaporation of the collected frac-
tions gave 80.2 mg (99%) of 15 as a white solid: Rf ) 0.75 in
(96 mg, 0.45 mmol, 500 mol %), and stirred at rt for 2 h. The
mixture was partitioned between CHCl3 (2 mL) and 1 M NaH2-
PO4 (2 mL), and the aqueous phase was extracted with CHCl3
(3 × 2 mL). The combined organic layers were washed with
brine, dried, and evaporated to an oil that was chromato-
graphed with 1:1 hexanes:EtOAc as eluant. Evaporation of
the collected fractions gave first (2S,5S,3′S)-14 (6 mg, 15%)
followed by (3S,6S,9S)-12 (18 mg, 66%).
En a n tiom er ic P u r ity of (3S,6S,9S)-Meth yl 2-Oxo-3-[N-
(BOC)a m in o]-1-a za b icyclo[4.3.0]n on a n e-9-ca r b oxyla t e
((3S,6S,9S)-12). A solution of (3S,6S,9S)-12 (0.06 mmol, 18
mg) in CH2Cl2 (1 mL) was treated with TFA (0.5 mL) and
stirred for 4 h when TLC (eluant F) showed complete disap-
pearance of starting 12. The volatiles were removed under
vacuum, and the residue was dissolved in 1 mL of THF. The
solution was treated with either (R)- or (S)-R-methylbenzyl
isocyanate (16 µL, 0.12 mmol, 200 mol %) and Et3N (8 µL, 0.06
mmol, 100 mol %) and heated at reflux for 3 h. The mixture
was cooled. The volatiles were removed under vacuum, and
the residue was directly examined by NMR. The limits of
detection were determined by observation of the diastereomeric
1
methyl ester singlets in the 400 MHz H NMR in benzene-d6
during incremental additions of diastereomeric urea which
demonstrated (1′S)- and (1′R)-16 to be of >99% diastereomeric
purity.
Ur ea (1′R)-16: 1H NMR (C6D6) δ 1.21 (m, 3 H), 1.33 (d, 3
H, J ) 6.9), 1.47 (m, 3 H), 1.6 (m, 1 H), 2.38 (m, 1 H), 2.83 (m,
1 H), 3.33 (s, 3 H), 4.21 (d, 1 H, J ) 8.2), 4.34 (m, 1 H), 5.13
(m, 1 H), 5.5 (br s, 1 H), 6.05 (br s, 1 H), 7.15 (m, 5 H).
Ur ea (1′S)-16: 1H NMR (C6D6) δ 1.23 (m, 2 H), 1.33 (m, 2
H), 1.39 (d, 3 H, J ) 6.8), 1.47 (m, 1 H), 1.63 (m, 1 H), 2.3 (m,
1 H), 2.81 (m, 1 H), 3.3 (s, 3 H), 4.24 (d, 1 H, J ) 8), 4.45 (m,
1 H), 5.16 (m, 1 H), 5.55 (br s, 1 H), 6.06 (br s, 1 H), 7.15 (m,
5 H).
eluant A; mp 110-111 °C; [R]20 -133° (c 1, CHCl3); 1H NMR
D
δ 1.14 (s, 9 H), 1.39 (s, 9 H), 1.35-1.45 (m, 3 H), 1.52-1.75
(m, 3 H), 1.92 (m, 1 H), 2.35 (m, 1 H), 2.73 (m, 1 H), 3.61 (dd,
1 H, J ) 9, 5.8), 7.1-7.7 (m, 26 H); 13C NMR δ 28.8, 30.0,
30.6, 32.8, 32.9, 56.0, 61.9, 64.7, 73.0, 78.3, 79.5, 79.9, 175.4,
175.5; HRMS calcd for C55H57N2O4 (MH+) 809.4318, found
809.4324.
Ack n ow led gm en t. This research was supported in
part by the Natural Sciences and Engineering Research
Council of Canada and the Ministe`re de l’EÄ ducation du
Que´bec. W.D.L. thanks Bio-Me´ga/Boehringer Ingelheim
Recherche Inc. for a Young Investigator Award. We
thank Sylvie Bilodeau and Dr. M. T. Phan Viet of the
Regional High-Field NMR Laboratory for their as-
sistance in establishing the configurations of lactam 12.
Mr. Eryk Thouin is thanked for helpful suggestions and
work to optimize reaction conditions. The crystal
structure analysis of compound 12 was performed by
Francine Be´langer-Garie´py at l’Universite´ de Montre´al
X-ray facility. We are grateful for a loan of Pd/C from
J ohnson Matthey PLC.
(3S,6S,9S)-Met h yl 2-Oxo-3-[N-(BOC)a m in o]-1-a za b i-
cyclo[4.3.0]n on a n e-9-ca r b oxyla t e ((3S,6S,9S)-12) fr om
(2S,5S,3′S)-15. A solution of (2S,5S,3′S)-15 (71 mg, 0.09
mmol) in EtOH (3 mL) and AcOH (0.3 mL) was treated with
palladium-on-carbon (10 wt %, 10 mg) and stirred under 6 atm
of hydrogen for 24 h. The mixture was filtered on Celite, the
catalyst was washed with EtOH (3 mL), and the combined
organic phase was evaporated to a solid. The solid was
dissolved in a solution of 6 N HCl (1 mL) and CH2Cl2 (1 mL).
After stirring for 15 h, TLC (eluant F) showed complete
disappearance of the starting ninhydrin positive material (Rf
) 0.46) and formation of a new ninhydrin positive product (Rf
) 0.22). The volatiles were removed under vacuum, the
residue was dissolved in a 0 °C solution of acetyl chloride (0.16
mL) in MeOH (1.92 mL), and the solution was stirred at rt for
24 h when TLC (eluant F) showed complete conversion to a
new ninhydrin positive product (Rf ) 0.38). The volatiles were
removed under vacuum. The crude amino ester hydrochloride
residue was dissolved in CH2Cl2 (1.5 mL), treated with Et3N
(0.12 mL, 0.27 mmol, 300 mol %), and di-tert-butyl dicarbonate
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for 2b and γ-methyl N-(PhF)glutamate, 1H and 13C NMR
spectra of 1 and 3-15, 1H NMR spectra of 16, and crystal-
lographic data for 12 (51 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
J O961872F