Mimicry of peptide backbone geometry and heteroatomic side-chain functionality: Synthesis of enantiopure indolizidin-2-one amino acids possessing alcohol, acid, and azide functional groups

Article abstract of DOI:10.1021/jo001251t

Indolizidinone amino acids possessing various heteroatomic side chains at their 5- and 7-positions have been synthesized through modification of hydroxymethyl indolizidinone amino acids 5 and 6. Displacements of the methanesulfonates from alcohols 5 and 6 with sodium azide, as well as oxidation of alcohol 5, have been used to furnish orthogonally protected indolizidin-2-one diamino carboxylates 7 and 8, and indolizidin-2-one amino dicarboxylate 9. Both 5- and 7-hydroxymethylindolizidinone amino acids 5 and 6 were obtained from sequences commencing with the Claisen condensation of α-tert-butyl γ-methyl 1-N-(PhF)-L-glutamate to furnish di-tert-butyl 4-carbomethoxy-5-oxo-2,8-di-[N-(PhF)amino]azelate 10 (PhF = 9-(9-phenylfluorenyl)). Subsequent hydride reduction of 10 to an isomeric mixture of diols 12, selective protection of the primary alcohol as tert-butyldimethylsilyl ether 14 and oxidation of the secondary alcohol gave di-tert-butyl 4-tert-butyldimethylsilyloxymethyl-5-oxo-2,8-di-[N-(PhF)amino]azelate 15 as a separable diastereomeric mixture. Linear ketone 15 and alcohol 14 were then converted to the indolizidinone heterocycles by routes featuring reductive aminations, methanesulfonate displacements, and lactam cyclizations. A series of rigid scaffolds designed to mimic the conformations of dipeptides possessing serine, lysine, and glutamate residues has thus been synthesized by this new route for installing heteroatomic side-chain functional groups onto the indolizidin-2-one system.

Full text of DOI:10.1021/jo001251t

J . Org. Chem. 2001, 66, 1171-1180
1171
Mim icr y of P ep tid e Ba ck bon e Geom etr y a n d Heter oa tom ic
Sid e-Ch a in F u n ction a lity: Syn th esis of En a n tiop u r e
In d olizid in -2-on e Am in o Acid s P ossessin g Alcoh ol, Acid , a n d Azid e
F u n ction a l Gr ou p s
Felix Polyak 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
Lubell@chimie.umontreal.ca
Received August 17, 2000
Indolizidinone amino acids possessing various heteroatomic side chains at their 5- and 7-positions
have been synthesized through modification of hydroxymethyl indolizidinone amino acids 5 and 6.
Displacements of the methanesulfonates from alcohols 5 and 6 with sodium azide, as well as
oxidation of alcohol 5, have been used to furnish orthogonally protected indolizidin-2-one diamino
carboxylates 7 and 8, and indolizidin-2-one amino dicarboxylate 9. Both 5- and 7-hydroxymeth-
ylindolizidinone amino acids 5 and 6 were obtained from sequences commencing with the Claisen
condensation of R-tert-butyl γ-methyl l-N-(PhF)-L-glutamate to furnish di-tert-butyl 4-carbomethoxy-
5-oxo-2,8-di-[N-(PhF)amino]azelate 10 (PhF ) 9-(9-phenylfluorenyl)). Subsequent hydride reduction
of 10 to an isomeric mixture of diols 12, selective protection of the primary alcohol as tert-
butyldimethylsilyl ether 14 and oxidation of the secondary alcohol gave di-tert-butyl 4-tert-
butyldimethylsilyloxymethyl-5-oxo-2,8-di-[N-(PhF)amino]azelate 15 as a separable diastereomeric
mixture. Linear ketone 15 and alcohol 14 were then converted to the indolizidinone heterocycles
by routes featuring reductive aminations, methanesulfonate displacements, and lactam cyclizations.
A series of rigid scaffolds designed to mimic the conformations of dipeptides possessing serine,
lysine, and glutamate residues has thus been synthesized by this new route for installing
heteroatomic side-chain functional groups onto the indolizidin-2-one system.
In tr od u ction
structures of up to 30% of all alkaloids.4 Diversification
of such azabicycloalkane amino acids by appendage of
different pharmacophores onto the amine and carboxylate
handles may thus provide library members exhibiting
biological activity (i.e., cardiotonic, antiarrhythmic, utero-
tonic, immunostimulatory, and neuroexcitatory activity)
which has inspired more than a century of research to
synthesize their heterocycle counterparts (Figure 1).4
We have introduced methodology for synthesizing a
variety of azabicyclo[X.Y.0]alkane amino acids stereose-
lectively from N-(PhF)aminodicarboxylates of different
chain-lengths (Scheme 1, PhF ) 9-(9-phenylfluorenyl)).5-7
Azabicyclo[X.Y.0]alkane amino acids serve as tools for
rigidifying peptide structures in order to probe conforma-
tion-activity relationships in peptide science.1,2 They can
also be employed in medicinal chemistry as inputs for
targeted library synthesis in which different pharma-
cophores are systematically displayed for studying rec-
ognition events.2,3 The sub-group of indolizidinone and
quinolizidinone amino acids are particularly attractive
scaffolds for functionalization by combinatorial technol-
ogy, because of their relationship to indolizidine and
quinolizidine ring systems which are present in the
(1) Reviewed in: Halab, L.; Gosselin, F.; Lubell, W. D. Biopolymers,
Peptide Science 2000, 55, 101-122. We have adopted the nomenclature
and ring system numbering used in ref 2 in order to maintain clarity
and consistency when comparing these different heterocyclic systems.
(2) (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789. Recent examples since the
publication of this review include those cited in ref 2 of ref 8 below, as
well as (b) syntheses of the 5, 5-, 5, 6- and 5,7-fused 1-azaoxobicycloal-
kane N-(BOC)amino tert-butyl esters: Angiolini, M.; Araneo, S.;
Belvisi, L.; Cesarotti, E.; Checchia, A.; Crippa, L.; Manzoni, L.;
Scolastico, C. Eur. J . Org. Chem. 2000, 2571-2581. (c) Synthesis of
the 5,6-fused 1-azaoxobicycloalkane N-(Cbz)amino esters: Mulzer, J .;
Schu¨lzchen, F.; Bats, J .-W. Tetrahedron 2000, 56, 4289. (d) Synthesis
of N-(BOC)amino ∆5-dehydropyrroloazepinone methyl ester: Gros-
smith, C. E.; Senia, F.; Wagner, J . Synlett 1999, 1660-1662. (e)
Thiaindolizidinone peptide ORL1 receptor antagonist: Becker, J . A.
J .; Wallace, A.; Garzon, A.; Ingallinella, P.; Bianchi, E.; Cortese, R.;
Simonin, F.; Kieffer, B. L.; Pessi, A. J . Biol. Chem. 1999, 274, 27513-
27522. (f) Spirocyclic thiaindolizidinone peptides with SH3 domain
affinity: Witter, D. J .; Famiglietti, S. J .; Cambier, J . C.; Castelhano,
A. L. Bioorg. Med. Chem. Lett. 1998, 8, 3137-3142. (g) Oxaindolizidi-
none amino acid: Estiarte, M. A.; Rubiralta, M.; Diez, A.; Thormann,
M.; Giralt, E. J . Org. Chem. 2000, 65, 6992-6999.
(3) Alternative examples of scaffolds for peptide mimicry and
combinatorial chemistry include: (a) Hirschmann, R.; Nicolaou, K. C.;
Pietranico, S.; Salvino, J .; Leahy, E. M.; Sprengeler, P. A.; Furst, G.;
Smith III, A. B.; Strader, C. D.; Cascieri, M. A.; Candelore, M. R.;
Donaldson, C.; Vale, W.; Maechler, L. J . Am. Chem. Soc. 1992, 114,
9217. (b) Hirschmann, R.; Sprengeler, P. A.; Kawasaki, T.; Leahy, J .
W.; Shakespeare, W. C.; Smith III, A. B. J . Am. Chem. Soc. 1992, 114,
9699. (c) Barry, J . F.; Davis, A. P.; Nieves Pe´rez-Payan, M.; Elsegood,
M. R. J .; J ackson, R. F. W.; Gennari. C.; Piarulli, U.; Gude, M.
Tetrahedron Lett. 1999, 40, 2849. (d) Eguchi, M.; Lee, M. S.; Nakanishi,
H.; Stasiak, M.; Lovell, S.; Kahn, M. J . Am. Chem. Soc. 1999, 121,
12204. (e) Guan, Y.; Green, M. A.; Bergstrom, D. E. J . Comb. Chem.
2000, 2, 297 and refs 2-9 therein.
(4) Recent reviews include: (a) Broggini, G.; Zecchi, G. Synthesis
1999, 905. (b) Michael, J . P. Nat. Prod. Rep. 1997, 14, 21. (c) Ohmiya,
S.; Saito, K.; Murakoshi, I. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 1995; Vol. 47, pp 1-114. For additional
examples see ref 1 in ref 6a below.
(5) (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, The Netherlands, 1995, 696. (c) Lombart, H.-G.; Lubell, W. D.
J . Org. Chem. 1996, 61, 9437.
10.1021/jo001251t CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/30/2001

1172 J . Org. Chem., Vol. 66, No. 4, 2001
Polyak and Lubell
side chains onto this heterocycle, we have now developed
a method for synthesizing orthogonally protected in-
dolizidin-2-one amino acids that possess heteroatomic
side chains at the 5- and 7-positions.10 Besides their
homology with dipeptide structures possessing serine,
lysine, and glutamate residues, these new scaffolds
possess three sites suitable for diversification via com-
binatorial techniques.
Seeking to differentiate the side-chain functional group
from the carboxylate groups destined to become the
peptide backbone, we selected to introduce the side chain
at the oxidation state of an alcohol. The product from the
Claisen self-condensation of γ-methyl R-tert-butyl N-PhF-
L-glutamate,5 â-keto ester 10, proved to be a practical
starting material because its synthesis avoided the
decarboxylation and alkylation steps for introducing
groups onto δ-ketoazelate 118 and because several ste-
reoselective methods for â-keto ester reduction could be
later employed to furnish specific isomers.11 The synthe-
ses of 5- and 7-hydroxymethyl indolizidinone amino acids
5 and 6 have now been accomplished by sequences that
commence with the reduction of â-ketoester intermediate
10 to diol 12 and feature selective protection, reductive
aminations, methanesulfonate displacements, and lactam
cyclizations. The alcohol groups of 5- and 7-hydroxym-
ethyl indolizidinone amino esters 16 and 17 have also
been used for the introduction of other side-chain func-
tionality including azido, formyl, and carboxylate groups.
F igu r e 1. Indolizidin-2-one, 5- and 7-alkyl-, and 5,7-dialky-
lindolizidin-2-one amino acids 1-9.
Resu lts a n d Discu ssion
Stereocontrol has been attained at the ring-fusion and
along the peptide backbone by employing L- and D-
aminodicarboxylates in diastereoselective transforma-
tions.1 For example, the employment of glutamic acid in
our Claisen condensation/reductive amination/lactam
cyclization sequence gave access to all of the possible
stereoisomers of enantiopure azabicyclo[4.3.0]alkane,
indolizidin-2-one amino acid 1 (Figure 1).5 The use of
aspartic acid in our olefination/reductive amination/
lactam cyclization sequence has furnished the related
azabicyclo[3.4.0]alkane, indolizidin-9-one amino acid in
enantiopure form.6 Employment of aspartate and pyro-
glutamate using the olefination entry has recently led
to the syntheses of enantiopure azabicyclo[4.4.0]alkane,
quinolizidinone amino acid as well as azabicyclo[5.3.0]-
alkane, pyrroloazepinone amino acid, both from the same
linear precursor.7
In light of the importance of amino acid side chains as
sites for interaction in various recognition events, we
developed an approach for appending a variety of alkyl
side chains onto the azabicyclo[X.Y.0]alkane heterocycle.8
The power of this strategy was demonstrated by the
syntheses of enantiopure 5-benzyl-, 7-benzyl-, and 5,7-
dibenzyl indolizidin-2-one amino acids 2-4 via a route
involving alkylation of a common N-(PhF)amino ketone
intermediate 11.8 These benzyl indolizidinone amino
acids may respectively serve as constrained dipeptide
surrogates for Phe-Pro, Ala-Phe, and Phe-Phe.9 Extend-
ing the versatility of our strategy for introducing alkyl
Reduction of â-keto ester 10 with NaBH4 in alcoholic
solvents could be controlled to provide either diol 12 or
â-hydroxy ester 13 as mixtures of diastereomers in 89%
or 96% respective yields (Scheme 2).12 Selective protection
of the primary alcohol by silation of 12 with chloro tert-
butyldimethylsilane (TBDMSCl), Et3N, and DMAP in
dichloromethane gave siloxymethyl ketone 14 in 96%
yield.13 Oxidation of the secondary alcohol of silyl ether
14 with oxalyl chloride and DMSO in dichloromethane
gave ketones 15 in 97% yield as a mixture of diastereo-
mers that were separable by column chromatography.14
Syn th esis of 5- a n d 7-Hyd r oxym eth yl a n d Meth -
ylin d olizid in on e Am in o Ester s 16-19 by Red u ctive
Am in a tion . Intramolecular reductive amination was
examined to prepare the pyrrolidine ring of the hy-
droxymethyl indolizidinone system (Scheme 3). In the
synthesis of 7-benzyl indolizidinones,8 we found that
treatment of diastereomerically pure (4S)- or (4R)-4-
benzyl ketones with palladium-on-carbon at 9 atm of
hydrogen in a 9:1 EtOH-AcOH solution, followed by
lactam cyclization and protection, resulted in 5:1 to 8:1
ratios of (3S,6S,7S,9S)- and (3S,6S,7R,9S)-7-benzyl in-
dolizidinones 3. Epimerization of the alkyl-branched
stereocenter was concluded to have occurred via an
iminium ion-enaminium ion equilibrium prior to hydro-
gen addition to the dehydropyrrolidine.8
Considering epimerization as a means for controlling
stereoselectivity in the synthesis of hydroxymethylin-
(6) (a) Gosselin, F.; Lubell, W. D. J . Org. Chem. 1998, 63, 7463. (b)
Gosselin, F.; Lubell, W. D. In Peptides 1998. Proceedings of the 25th
European Peptide Symposium; Bajusz, S., Hudecz, F., Eds; Akade´mia
Kiado´: Budapest, Hungary, 1998; 660.
(7) Gosselin, F.; Lubell, W. D. J . Org. Chem. 2000, 65, 2163.
(8) Polyak, F.; Lubell, W. D. J . Org. Chem. 1998, 63, 5937.
(9) Polyak, F.; Lubell, W. D. In Peptides 1998. Proceedings of the
25th European Peptide Symposium; Bajusz, S., Hudecz, F., Eds;
Akade´mia Kiado´: Budapest, Hungary, 1998; 688.
(10) Preliminary results were reported: Polyak, F.; Lubell, W. D.
In Peptides: Chemistry, Structure and Biology; Fields, G, Barany, G.,
Eds; ESCOM: Leiden, The Netherlands, 2000; 150-152.
(11) Reviewed in: Noyori, R.; Tokunaga, M.; Kitamura, M. Bull.
Chem. Soc. J pn. 1995, 68, 36.
(12) Soai, K.; Oyamada, H.; Takase, M.; Ookawa, A. Bull. Chem.
Soc. J pn. 1984, 57, 1948.
(13) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 99.
(14) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.

Mimicry of Peptide Backbone Geometry
J . Org. Chem., Vol. 66, No. 4, 2001 1173
Sch em e 1. Gen er a l Ap p r oa ch for Syn th esizin g Alk yl-Br a n ch ed Aza bicyclo[X.Y.0]a lk a n e Am in o Acid s
Sch em e 2. Syn th esis of Siloxym eth yl
Sch em e 3. Syn th esis of 5- a n d 7-Hyd r oxym eth yl-
a n d Meth ylin d olizid in on e Am in o Ester s via
Red u ctive Am in a tion
δ-Ketoa zela tes 15
dolizidinones, we exposed a diastereomeric mixture of
siloxymethyl ketones 15 to our standard reductive ami-
nation/lactam cyclization/N-protection sequence. Hydro-
genation of 15 with palladium-on-carbon in 9:1 EtOH-
AcOH under hydrogen atmosphere caused removal of the
phenylfluorenyl groups and conversion to the 5-alkyl-
proline. The tert-butyl esters and tert-butyldimethylsilyl
ether were removed with TFA in dichloromethane and
the carboxylates were esterified using methanol and
thionyl chloride. Treatment with triethylamine in dichlo-
romethane caused lactam cyclization and liberation of the
primary amine which was protected with di-tert-butyl
dicarbonate to furnish N-(BOC)amino indolizidinone
esters.
Four N-(BOC)amino indolizidinone esters were isolated
by chromatography of the final reaction mixtures from
this route. After hydrogenation at 10 atm of hydrogen
followed by completion of the sequence, three N-(BOC)-
amino methyl esters were isolated as major products:
(3S,6S,7R,9S)-7-hydroxymethylindolizidinone (6S,7R)-17
(14% yield), (3S,5S,6R,9S)-5-methylindolizidinone (5S,6R)-
18 (3% yield), and (3S,6S,7R,9S)-7-methylindolizidinone
(6S,7R)-19 (12% yield). The compound (3S,5S,6R,9S)-N-
(BOC)amino 5-hydroxymethyl indolizidinone methyl es-
ter (5S,6R)-16 was obtained in trace amounts from the
process at 10 atm of hydrogen and became a more
significant product (8%) from the sequence featuring
hydrogenation at 1 atm of hydrogen.
The formation of both 5- and 7-methyl indolizidinone
amino esters 18 and 19 was most likely due to the
elimination of the siloxy group via an enamine interme-
diate to form an R,â-unsaturated imine that was subse-
quently reduced (Figure 2). Their isolation adds addi-
tional proof of the existence of an imine to enamine
equilibrium during the reductive amination of δ-keto
R-amino esters.8 Recently, we have taken advantage of
this elimination process in order to form a related
azadiene intermediate in a stereoconvergent approach to
5,6-dialkylpipecolates.15
(15) Swarbrick, M. E.; Lubell, W. D. Chirality 2000, 12, 366-373.

1174 J . Org. Chem., Vol. 66, No. 4, 2001
Polyak and Lubell
methanesulfonyl chloride, triethylamine, and DMAP in
dichloromethane, followed by intramolecular substitution
on heating at a reflux. The 5-alkylprolines were directly
converted to the fully protected indolizidinone amino
acids by tert-butyl ester, silyl ether and PhF group
solvolysis with TFA, esterification with methanol and
thionyl chloride, lactam cyclization on stirring with
triethylamine in dichloromethane, and N-acylation with
di-tert-butyl dicarbonate. The diastereomeric and regioi-
someric hydroxymethylindolizidinone N-(BOC)amino es-
ters 16 and 17 were finally separated by chromatography
on silica gel.
In total, this process has produced one 5-hydroxym-
ethylindolizidinone amino ester 16 and four different
7-hydroxymethylindolizidinone amino ester diastereo-
mers 17. In three of the four cases, a single 5-alkylproline
was synthesized from each alcohol diastereomer. As
previously seen in the benzyl series, cyclizations with
(4R,5R)- and (4S,5R)-14 gave 4-substituted cis-5-alkyl-
proline diastereomers that were respectively converted
to 7-hydroxymethylindolizidinone amino esters (6S,7S)-
and (6S,7R)-17. Furthermore, cyclization with (4S,5S)-
14 gave the 4-substituted 5-alkylproline trans-diastere-
omer, that was converted to (6R,7R)-17, and indicated
that the steric effects from the 4S-group promoted a
transition state providing trans- rather than cis-5-alky-
lproline diastereomer. Contrary to the stereoselective
result of the benzyl series, the cyclization with (4R,5S)-
14 provided the less substituted 5-alkylproline cis-
diastereomer along with a minor amount of the 4,5-
dialkylproline trans-diastereomer, which were converted
to their respective 5- and 7-hydroxymethylindolizidinone
amino esters (5S,6R)-16 and (6R,7S)-17. The formation
of a mixture of 5-alkylprolines from cyclization of alcohol
(4R,5S)-14 demonstrated a competition of steric and
stereochemical forces in the methanesulfonate displace-
ment, which may be governed by varying the size of the
protecting group on the hydroxymethyl substituent. In
the siloxymethyl series, the methanesulfonate displace-
ment approach has proven again to be an effective means
for selectively generating alkyl-branched azabicyclo[4.3.0]-
alkane ring systems. The final protected amino acid
analogues, (3S,5S,6R,9S)- and (3S,6S,7R,9S)-3-N-(BOC)-
amino-5-hydroxymethyl-indolizidin-2-one-9-carboxylic ac-
ids 5 and 6, were respectively obtained in 86% and 85%
yields from ester hydrolysis employing potassium trim-
ethylsilanolate in ether without epimerization (Schemes
5 and 6).16
F igu r e 2. Mechanism for methylindolizidinone formation
from the reductive amination of 15.
Syn th esis of 5- a n d 7-Hyd r oxym eth ylin d olizid i-
n on e Am in o Ester s 16 a n d 17 by Meth a n esu lfon a te
Disp la cem en ts. Hydride reduction of δ-oxo azelates,
methanesulfonation, and intramolecular displacement by
the phenylfluorenylamine have proven effective for syn-
thesizing 5-alkylproline intermediates for the preparation
of indolizidinone amino acids.5c,8,10 Specific formation of
the cis-5-alkylproline diastereomer from symmetrical di-
tert-butyl δ-hydroxy-R,ω-di-[N-(PhF)amino]azelate was
first observed in the synthesis of the parent indolizidi-
none heterocycle and required the attack of each of the
two amines fifty percent of the time in the SN2 displace-
ment of the methanesulfonate.5c A significant difference
in the energy of the transition state leading to the favored
cis- over the trans-5-alkylproline diastereomer was ob-
served in the cyclizations of most of the δ-hydroxy R,â-
diaminoazelates that we had previously studied.5c,8 In the
syntheses of 5- and 7-benzylindolizidinone amino esters
of 2 and 3, however, stereochemistry at the alkyl-
branched 4-position influenced significantly the transi-
tion state for displacement of the 5S-methanesulfonate,
and the 4S -benzyl group created a significant steric effect
to promote a transition state providing the trans- rather
than the cis-5-alkylproline diastereomer.8 Continuing our
investigation with δ-hydroxy R,â-diaminoazelate 14, we
have now found that the 4S and, to a lesser extent, the
4R-tert-butyldimethylsilyloxymethyl group both can ex-
hibit sufficient steric effects to promote transition states
that furnish the trans-5-alkylproline diastereomer in the
cyclization of the 5S-methanesulfonate.
Syn th esis of In d olizid in on e Am in o Acid s P os-
sessin g Azid e, F or m yl, a n d Ca r boxyla te F u n ction s.
With an effective method for synthesizing hydroxymeth-
ylindolizidinone amino esters 16 and 17 in hand, we
began investigating the conversion of their alcohol groups
into other side-chain functionality (Schemes 5 and 6).
Two approaches have so far been investigated. One
involving hydroxyl group activation as a methane-
sulfonate followed by displacement with sodium azide
gave orthogonally protected diamino indolizidinone car-
boxylates 7 and 8. The other employing a two step
oxidation of the alcohol furnished indolizidinone amino
dicarboxylate 9.10
The influences of stereochemistry and substituent on
the methanesulfonate displacements were examined as
in the cyclization of the di-tert-butyl δ-hydroxy γ-benzyl
R,ω-di-[N-(PhF)amino]azelates by the synthesis and cy-
clization of all four siloxymethyl alcohols 14. As before,
the four secondary alcohols 14 were obtained by inde-
pendent reductions of ketones (4S)- and (4R)-15 using
sodium borohydride in ethanol with low diastereoselec-
tivity (Scheme 4). Mixtures of (5R)- and (5S)-alcohols 14
were obtained from hydride reduction of both alkyl-
branched isomers and were directly used in the subse-
quent reaction sequence, which featured activation with
Activation of alcohols 16 and 17 with methanesulfonyl
chloride and triethylamine in dichloromethane gave the
respective methanesulfonates 20 and 21 in 82% and 79%
(16) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.

Mimicry of Peptide Backbone Geometry
J . Org. Chem., Vol. 66, No. 4, 2001 1175
Sch em e 4. Syn th esis of 5- a n d 7-Hyd r oxym eth ylin d olizid in on e Am in o Ester s 16 a n d 17 via
Meth a n esu lfon a te Disp la cem en ts
Sch em e 5. Syn th eses of Or th ogon a lly P r otected
In d olizid in on e Dia m in o Acid 7 a n d In d olizid in on e
Am in o Dica r boxyla te 9
Sch em e 6. Syn th esis of Or th ogon a lly P r otected
In d olizid in on e Dia m in o Ca r boxyla te 8
indolizidin-2-one N-(Boc)amino ester (5S)-16 with pyri-
dinium chlorochromate in dichloromethane containing 4
Å molecular sieves to furnish aldehyde 22 in 74% yield
(Scheme 5).17 Exposure of aldehyde 22 to NaClO2 in a
t-BuOH-MeCN solution buffered with aqueous NaH2-
PO4 yielded orthogonally protected carboxylate 9 in
72%.18 Orthogonally protected with base-labile methyl
ester, acid-labile BOC group, and reducible azide func-
tionality, diamino indolizidinone carboxylates 7 and 8
and indolizidinone amino dicarboxylate 9 all offer diverse
potential for elaboration into peptide mimics.
yields. Displacement of the active ester with sodium azide
in DMF at 80 °C furnished the respective azides 7 and 8
in 68% and 79% yields. Constrained Glu-Pro surrogate
9 was next synthesized by oxidation of 5-hydroxymethyl
(17) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 2647.
(18) (a) Lubell, W. D.; J amison, T. F.; Rapoport, H. J . Org. Chem.
1990, 55, 3511. (b) Bal, B. S.; Childers, W. E., J r.; Pinnick, H.
Tetrahedron 1981, 37, 2091.

1176 J . Org. Chem., Vol. 66, No. 4, 2001
Polyak and Lubell
Sch em e 7. En a n tiom er ic P u r ity of
7-Hyd r oxym eth ylin d olizid in on e Am in o Ester 17
at the 5-, 6-, and 7-positions was assigned by analysis of
NOESY and ROESY spectra of 16-19.
For example, in the COSY spectrum of (6R,7S)-17 the
C-7 proton (2.02 ppm) exhibited scalar couplings with the
C-6, C-8, and methylene protons. In the NOESY spec-
trum of (6R,7S)-17, the C-7 proton exhibited significant
nOes with the C-9 proton as well as the C-4R proton. On
the other face of the heterocycle, the C-4â proton exhibited
nOes with the C-6 and hydroxymethyl protons. Ad-
ditional nOes between the C-5R proton and the C-3 proton
as well as between the C-5â proton and the hydroxym-
ethyl protons gave further support for the (6R,7S)-
stereochemistry. In the case of the concave isomers, a
clear nOe was observed between the C-3 and C-6 protons.
The various two-dimensional NMR spectra that were
used to assign the relative stereochemistry at the ring-
fusion and alkyl-branched stereocenters of 16-19 are all
provided in the Supporting Information. The stereochem-
ical assignments made for the 5- and 7-positions of 16-
19 were then used to deduce the relative stereochemistry
at the hydroxymethyl branched 4-position of ketone 15
based on the fact that no epimerization happened during
the reaction sequences featuring methanesulfonate dis-
placements. The stereochemistry of alcohols 14 were
similarly deduced from the assignments made for the
ring-fusion 6-positions of 16-19 based on the assumption
that complete inversion of stereochemistry occurred in
the methanesulfonate displacement.
Crystallization of (3S,6S,7R,9S)-methyl 2-oxo-3-N-
(BOC)amino-7-hydroxymethyl-1-azabicyclo[4.3.0]nonane-
9-carboxylate ((3S,6S,7R,9S)-17) from chloroform and
X-ray crystallographic analysis confirmed the NMR as-
signments (Figure 3).22 As in the crystal structures of
related N-(BOC)amino indolizidin-2-one esters,5c,8 the
dihedral angles of the backbone atoms constrained inside
the heterocycle of (3S,6S,7R,9S)-17 resemble the values
of the central residues in an ideal type II′ â-turn.23 For
comparison, we have listed in Figure 4 the values for 17
with those observed in the crystal structures of the
corresponding methyl esters of the parent indolizidinone
245c and its 7-benzyl derivative 25,8 the acid of thiain-
dolizidinone 26,24 and the values for the central residues
of an ideal type II′ â-turn23 and an ideal inverse γ-turn
conformation.25 The presence of the hydroxymethyl sub-
stituent exhibited a noticeable yet relatively minor influ-
ence on the peptide backbone conformation compared to
changes observed upon modification of the bicycle ring-
size.1,7
En a n tiom er ic P u r ity a n d Ster eoch em ica l Assign -
m en ts of 5- a n d 7-Hyd r oxym eth yl In d olizid in on e
Am in o Ester s. The configurational integrity of this new
indolizidin-2-one series was evaluated by determination
of the enantiomeric purity of 7-hydroxymethyl indoliz-
idinone N-(BOC)amino ester (3S,6S,7R,9S)-17 produced
from the methanesulfonate displacement/lactam cycliza-
tion sequence. Portions of alcohol 17 were acylated either
with (R)- or (S)-R-methoxy-R-trifluoromethylphenylacetic
acid using benzotriazolyl-1,1,3,3-tetramethylaminium
tetrafluoroborate (TBTU)19,20 and DIEA in MeCN.21
Measurement of the diastereomeric trifluoromethyl sin-
glets at -72.7 and -72.9 ppm in benzene with trifluo-
romethylbenzene as internal reference (-63.7 ppm) by
19F NMR spectroscopy, using incremental additions of
minor isomer to determine the limits of detection, dem-
onstrated 23 to be of >99% diastereomeric excess. The
high diastereomeric purity of ester 17 indicated that
enantiopure material was produced from the methane-
sulfonate displacement. Hence, 7-hydroxymethyl indoliz-
idinone N-(BOC)amino acids 5 and 6, diamino indoliz-
idinone carboxylates 7 and 8, and indolizidinone amino
dicarboxylate 9, all are presumed to be of >99% enan-
tiomeric purity.
As in the case of the benzyl series,8 the position and
relative stereochemistry of the hydroxymethyl and meth-
yl carbons in indolizidinone N-(BOC)amino esters 16-
19 were determined by two-dimensional NMR experi-
ments. Although less distinct than in the benzyl series,
the majority of the signals for each of the ring protons
was well resolved at discrete chemical shifts (Table 1).
The downfield chemical shifts for the proton signals of
the three amine-bearing carbons appeared in the same
order (C-9 > C-3 > C-6) as in the related benzyl series.8
The C-3 proton was typically identified by its coupling
to the carbamate proton. The C-9 proton was observed
as a sharp triplet or apparent doublet. The point of union
between the appending hydroxymethyl group and the
indolizidinone heterocycle was established by assignment
of the three ring protons exhibiting scalar couplings with
the C-6 proton in the COSY spectra, followed by correla-
tions of these protons to the protons of the appended
methylene and either the C-3 or C-9 protons. Subse-
quently, the relative stereochemistry of the stereocenters
Con clu sion
Toward a general approach for constructing rigid
dipeptide surrogates possessing heteroatomic side chains,
we have developed effective methodology for synthesizing
(22) The structure of 17 was solved at l’Universite´ de Montre´al X-ray
facility using direct methods (SHELXS 96) and refined with SHELXL
96: C16H26N2O6; Mr ) 342.388; orthorhombic, colorless crystal; space
group P212121; unit cell dimensions (Å) a ) 5.386(5), b ) 8.891(2), c )
36.771(17); volume of unit cell (Å3) 1760.9(19); Z ) 4; R1 ) 0.0534 for
F2 > 2∑(F2), wR2 ) 0.1283 for all data; GOF ) 1.018. The author has
deposited the atomic coordinates for the structure of 17 with the
Cambridge Crystallographic Data Center. The coordinates can be
obtained, on request, from the Cambridge Crystallographic Data
Center, 12 Union Road, Cambridge, CB2 1EZ, UK.
(19) Knorr, R.; Trzreciak, A.; Bannwarth, W.; Gillessen, D. Tetra-
hedron Lett. 1989, 30, 1927.
(20) The crystal structures of HBTU, the corresponding PF6 salt,
and HATU indicate that these reagents exist in the form of aminium
salts: Abdelmoty, I.; Albericio, F.; Carpino, L. A.; Foxman, B. M.; Kates,
S. A. Lett. Pept. Sci. 1994, 1, 52.
(23) Ball, J . B.; Alewood, P. F. J . Mol. Recognit. 1990, 3, 55.
(24) Nagai, U.; Sato, K.; Nakamura, R.; Kato, R. Tetrahedron 1993,
49, 3577.
(21) (a) Reviewed in: Parker, D. Chem. Rev. 1991, 91, 1441. (b) Dale,
J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34, 2543.
(25) Madison, V.; Kopple, K. D. J . Am. Chem. Soc. 1980, 102, 4855.

Mimicry of Peptide Backbone Geometry
J . Org. Chem., Vol. 66, No. 4, 2001 1177
Ta ble 1. 1H NMR of 5- a n d 7-Hyd r oxym eth yl a n d Meth ylin d olizid in on e Am in o Ester s 16-19 (R ) CH'2 for 16 a n d 17,
CH3 for 18 a n d 19)
3R
4R
4â
5R
5â
6R/â
7R
7â
8R
8â
9R
R
OMe Ot-Bu NH
(5S,6R)-16 4.17 m 2.35 m 1.86 m
-
2.25 m 3.66 m 1.78 m 2.42 m 2.12 m 2.08 m
4.53 d
3.69 m
3.73 1.43
5.64
(R)
8.4
(6S,7S)-17 4.16 m 2.25 m 1.70 m 1.82 m
1.90 m 3.83 m 2.57 dd
2.37 m 1.97 m
4.30 dd 3.55 dd
3.71 1.39
5.80
(R)
7.1, 5.2
9.4, 4.7 10.8, 7.4
3.69 dd
7.2, 2.9
(6S,7R)-17 4.08 bs 2.48 m 1.67 m 2.12 m
(6R,7R)-17 4.10 bs 2.65 bs 1.71 m 1.74 m
1.72 m 3.50 m
2.30 m 2.11 m 2.08 m
4.40 d
3.58 t
3.65 1.35
3.69 1.38
5.30
5.34
(R)
6.0
4.40 t
4.3
3.40 dd
1.98 m 3.87 m
2.38 m 2.34 dd 1.88 m
8.1, 5.7
(â)
8.8
11.0, 5.7
3.61 dd
10.7, 5.8
3.62 m
(6R,7S)-17 4.09 bs 2.54 bs 1.86 m 1.54 dd
2.29 d 3.62 m 2.02 m
2.49 m 1.70 m
4.48 t
3.75 1.44
3.72 1.43
3.74 1.45
5.26
5.45
5.50
(â)
13.6, 2.5 2.7
8.5
4.51 d
(5S,6R)-18 4.20 m 2.03 m 1.95 m
2.00 m 3.32 m 1.75 m 2.20 m 2.15 m 2.10 m
1.03 d
(R)
9.2
4.49 d
6.3
1.07 d
(6S,7R)-19 4.10 m 2.46 m 1.64 m 1.75 m
1.84 m 3.19 m
2.06 m 2.14 m 1.86 dd
(R)
12.0, 9.1 9.0
6.3
F igu r e 3. Ball and stick representation of 7-hyrdoxymethyl
indolizidinone methyl ester (3S,6S,7R,9S)-17.22
5- and 7-hydroxymethyl indolizidinone amino acids 5 and
6 from â-ketoester 10 by strategies featuring reductive
aminations, methanesulfonate displacements, and lactam
cyclizations. Imine to enamine tautomerization during
the hydrogenation of δ-ketoazelate 15 was accompanied
by â-elimination of the hydroxyl substituent in the
reductive amination sequence such that 5- and 7-hy-
droxymethyl indolizidinone amino esters 16 and 17 were
produced with their 5- and 7-methyl counterparts 18 and
19 as side products. The importance of stereochemistry
and steric bulk were illustrated in the route featuring a
methanesulfonate displacement followed by lactam cy-
clization to selectively furnish 5- and 7-hydroxymethyl
indolizidinone amino esters 16 and 17. Modification of
the alcohol functional group of 16 and 17 has furnished
other side-chain functionality including azide and car-
boxylate groups in orthogonally protected diamino in-
dolizidinone carboxylates 7 and 8 and indolizidinone
amino dicarboxylate 9. In summary, a spectrum of
F igu r e 4. Dihedral angle values from azabicycloalkane
N-(BOC)amino carboxylate X-ray data and ideal peptide turns.
restrained scaffolds has thus been prepared with poten-
tial to replicate the backbone geometry and side-chain
function of dipeptide residues possessing serine, lysine,
glutamate, and related amino acids.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, all reactions were run
under nitrogen atmosphere and distilled solvents were trans-
ferred by syringe. Tetrahydrofuran (THF) and ether were
distilled from sodium/benzophenone immediately before use;
CH2Cl2 was distilled from CaH2; CHCl3 from P2O5; triethy-
lamine (Et3N) was distilled from BaO. Final reaction mixture
solutions were dried over Na2SO4. Melting points are uncor-
rected. 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

1178 J . Org. Chem., Vol. 66, No. 4, 2001
Polyak and Lubell
(75/100 MHz) spectra were recorded in CDCl3. Chemical shifts
are reported in ppm (δ units) downfield of internal tetram-
ethylsilane ((CH3)4Si), CHCl3, and C6H6; 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 aluminum-
backed silica plates coated with a 0.2 mm thickness of silica
gel 60 F254 (Merck). Chromatography was performed using
Kieselgel 60 (230-400 mesh).
tion P r otocol. Hydrogenation was performed by stirring a
solution of azelate 15 (ca. 1:1 mixture of diastereomers, 0.5
mmol, 100 mol %) in anhydrous EtOH (30 mL) and AcOH (3
mL) with palladium-on-carbon (10 wt %) under hydrogen
atmosphere (10 atm) for 24 h. The mixture was filtered
through Celite and washed with EtOH (30 mL). The combined
organic solution was evaporated to dryness, and the residue
was triturated with hexane (3 × 10 mL). The remaining solid
was used without additional purification.
(2S,4RS,5RS,8S)-Di-ter t-bu tyl 4-Hyd r oxym eth yl-5-h y-
d r oxy-2,8-d i-[N-(P h F )a m in o]a zela t e ((2S,4RS,5RS,8S)-
12). A solution of â-keto ester 10 (3.6 g, 4.08 mmol, prepared
according to ref 5c) in tert-butyl alcohol (150 mL) and MeOH
(5 mL) was treated with NaBH4 (1 g, 26.3 mmol, 645 mol %),
stirred for 1 h at room temperature and for 6 h at 60 °C, cooled
to room temperature, and diluted with water (100 mL). The
volume was reduced using a rotary evaporator, and the
remaining volume was extracted with EtOAc (2 × 200 mL).
The combined organic phases were washed with brine, dried,
and evaporated to a residue (3.1 g, 88.6%) that was shown by
The tert-butyl esters and silyl ether were solvolyzed by
dissolving the crude product in a 10% solution of TFA in CH2-
Cl2 (50 mL) and stirring overnight. Evaporation of the volatiles
gave a residue which was used without further purification.
Esterification, lactam cyclization, and nitrogen protection
commenced by treatment of the residue in MeOH (20 mL) at
-5 °C with SOCl2 (300 mol %). The solution was stirred at -5
°C for 1 h, at room temperature for 1 h, and at 50 °C for 2 h,
then evaporated. The solid was dissolved in CH2Cl2 (15 mL),
treated with Et3N (500 mol %), stirred at room temperature
for 24 h, treated with di-tert-butyl dicarbonate (500 mol %),
and stirred at room temperature for 2 h. The reaction mixture
was diluted with CH2Cl2 (15 mL), washed with a 1M solution
of NaH2PO4 (5 mL) and brine (5 mL), dried, and evaporated.
The residue was chromatographed with 3:2 hexanes-EtOAc
as eluant. Three compounds were isolated and characterized
by 1H NMR spectroscopy (Table 1). First to elute was (5S,6R)-
proton NMR analysis to contain
a mixture of four diol
diastereomers 12, which was used without additional purifica-
tion: Rf 0.08 (1:3 EtOAc-hexane); LRMS m/z ) 857 (MH+).
(2S,4RS,5RS,8S)-Di-ter t-bu tyl 4-ter t-Bu tyld im eth yl-
siloxym et h yl-5-h yd r oxy-2,8-d i-[N-(P h F )a m in o]a zela t e
((2S,4RS,5RS,8S)-14). A solution of diol 12 (1.0 g, 1.17 mmol)
in CH2Cl2 (15 mL) was treated with Et3N (0.655 mL, 4.68
mmol, 400 mol %), DMAP (14 mg, 0.11 mmol, 10 mol %), and
TBDMSCl (387 mg, 2.57 mmol, 220 mol %), stirred for 6 h at
room temperature, and diluted with water (20 mL). The layers
were separated, and the organic phase was washed with brine,
dried, and evaporated to a residue (1.2 g, 96%) that was shown
by proton NMR analysis to contain a mixture of four silyl ether
diastereomers 14, which was used without additional purifica-
tion: Rf 0.46 (1:3 EtOAc-hexane); LRMS m/z ) 971 (MH+).
(2S,4R,8S)- a n d (2S,4S,8S)-Di-ter t-bu tyl 5-Oxo-4-ter t-
b u t yld im et h ylsiloxym et h yl-2,8-d i-[N-(P h F )a m in o]a ze-
la te ((2S,4R,8S)- a n d (2S,4S,8S)-15). A solution of oxalyl
chloride (0.044 mL, 0.5 mmol, 250 mol %) in CH2Cl2 (1.5 mL)
was cooled to -60 °C and treated with a solution of DMSO
(0.05 mL, 0.7 mmol, 350 mol %) in CH2Cl2 (0.5 mL). The
mixture was stirred for 30 min and treated dropwise with a
solution of alcohol 14 (0.2 g, 0.2 mmol, 100 mol %) in CH2Cl2
(1 mL). The clear solution was stirred for 4 h, treated with
Et(i-Pr)2N (0.21 mL, 1,2 mmol, 600 mol %), and allowed to
warm to room temperature over 1 h. The reaction mixture was
added to aqueous NaH2PO4 (2 mL), the layers were separated,
and the aqueous layer was saturated with solid NaCl and
extracted repeatedly with EtOAc (2 × 5 mL). The combined
organic layers were washed with H2O (5 mL) and brine (5 mL),
dried, and evaporated to give a residue that was purified by
column chromatography using an eluant of 1:3 EtOAc-hexane
to furnish ketone 15 (188 mg, 97%) as a colorless solid: Rf
0.66 (1:3 EtOAc-hexane); LRMS m/z 969 (MH+). Diastereo-
mers 15 (2.3 g) were separated by chromatography on silica
gel using an eluant of hexane to dichloromethane. First to elute
was (2S,4S,8S)-15 (810 mg): [R]20D -46.15 (c 3.18, CHCl3); 1H
NMR δ -0.02 (s, 3 H), -0.02 (s, 3 H), 0.82 (s, 9 H), 1.18 (s, 9
H), 1.24 (s, 9 H), 1.48 (m, 1 H), 1.72 (m, 1 H), 1.85 (m, 1 H),
2.30 (m, 1 H), 2.41 (m, 1 H), 2.54 (m, 1 H), 2.72 (m, 1 H), 2.90
(bs, 2 H), 3.00 (m, 1 H), 3.12 (m, 1 H), 3.48 (m, 1 H), 3.58 (m,
1 H), 7.05 (m, 2 H), 7.0-7.4 (m, 20 H), 7.65 (m, 4 H); 13C NMR
δ -5.6, -5.5, 18.1, 25.8, 27.9, 29.1, 34.2, 41.2, 55.0, 55.3, 65.1,
72.9, 73.5, 77.2, 80.5, 80.8, 174.6, 175.2, 212.5; followed by a
2:3 mixture of (4S)-15 and (4R)-15 (510 mg). Last to elute was
(2S,4R,8S)-15 (820 mg): [R]D20 -41.04 (c 2.4, CHCl3); 1H NMR
δ -0.12 (s, 3 H), -0.08 (s, 3 H), 0.76 (s, 9 H), 1.13 (s, 9 H),
1.15 (s, 9 H), 1.37 (m, 1 H), 1.50 (m, 2 H), 1.80 (m, 1 H), 2.27
(m, 1 H), 2.37 (m, 2 H), 2.47 (m, 2 H), 2.58 (dd, 1 H, J ) 13.6,
8.5), 2.90 (bs, 2 H), 3.11 (m, 1 H), 7.05 (m, 2 H), 7.1-7.4 (m,
20 H), 7.65 (m, 4 H); 13C NMR δ -5.7, -5.6, 18.2, 25.8, 27.8,
29.3, 31.9, 38.9, 50.1, 53.8, 55.4, 62.5, 72.9, 73.0, 77.2, 80.7,
175.1, 175.4, 212.1.
18 (3% yield): [R]D -1.31 (c 3.25, CHCl3); 13C NMR δ 16.2,
20
25.8, 27.4, 28.1, 37.3, 40.4, 50.2, 52.5, 57.8, 63.0, 79.7, 156.8,
168.2, 172.4; LRMS m/z 327 (MH+). Second to elute was
(6S,7R)-19 (12% yield): [R]D20 -12.2 (c 1.82, CHCl3); 13C NMR
δ 17.3, 27.2, 28.8, 31.8, 34.0, 37.2, 49.6, 52.4, 58.5, 63.8, 79.8,
155.9, 168.4, 172.5; LRMS m/z 327 (MH+). Last to elute was
(6S,7R)-17 (14% yield), which exhibited identical character-
istics as material prepared by the methanesulfonate displace-
ment route described below.
(2S,4R,5RS,8S)-Di-ter t-bu tyl 4-ter t-bu tyld im eth ylsi-
loxym e t h yl-5-h yd r oxy-2,8-d i-[N -(P h F )a m in o]a ze la t e
((2S,4R,5SR,8S)-14). A solution of ketone (4R)-15 (12.0 g, 12.4
mmol) in EtOH (250 mL) was treated with NaBH4 (2.36 g, 62
mmol, 500 mol %), stirred for 4 h at room temperature, and
diluted with water (250 mL). The volume was reduced using
a rotary evaporator, and the remaining volume was extracted
with EtOAc (2 × 300 mL). The combined organic phases were
washed with brine, dried, and evaporated to a residue which
was shown by proton NMR analysis to contain a ca. 2:1
mixture of (5R)- and (5S)-alcohols 14 that were used in the
subsequent reactions as a mixture without further purification.
Yield 11.4 g (95%): 1H NMR δ 0.03 (s, 6 H), 0.04 (s, 6 H), 0.88
(s, 9 H), 0.89 (s, 9 H), 1.17 (s, 9 H), 1.18 (s, 9 H), 1.19 (s, 9 H),
1.20 (s, 9 H), 1.3-1.9, 2.5-2.7, 3.1, 3.4-3.7, 3.9 (multiplets
from aliphatic protons of both diastereomers), 7.1-7.8 (mul-
tiplets from aromatic protons of both diastereomers).
(2S,4S,5S,8S)- a n d (2S,4S,5R,8S)-Di-ter t-bu tyl 4-ter t-
b u t yld im et h ylsiloxym et h yl-5-h yd r oxy-2,8-d i-[N-(P h F )-
am in o]azelate ((2S,4S,5S,8S)- an d (2S,4S,5R,8S)-14). These
compounds were prepared by reduction of (4S)-15 (4.7 g, 4.9
mmol) using the protocol described for ketone (4R)-15 above
(NaBH4 0.95 g, 25 mmol, 500 mol % in 50 mL of EtOH). A
mixture of alcohols (4.5 g, 95%) was isolated from which
analytical samples of pure diastereomers were obtained by
column chromatography using 2:98 EtOH-CH2Cl2 as eluant.
The first diastereomer to elute exhibited the following char-
acteristics: 1H NMR δ -0.18 (s, 3 H), -0.11 (s, 3 H), 0.80 (s,
9 H), 1.19 (s, 9 H), 1.22 (s, 9 H), 1.28-1.50 (m, 3 H), 1.52-
1.78 (m, 3 H), 1.84-1.94 (m, 1 H), 2.38 (dd, 1 H, J ) 11.9,
2.4), 2.58 (dd, 1 H, J ) 7.6, 4.1), 2.77 (dd, 1 H, J ) 10.5, 3.4),
3.31 (dd, 1 H, J ) 10.5, 2.5), 3.74-3.80 (m, 1 H), 7.14-7.51
(m, 22 H), 7.66-7.72 (m, 4 H). The second eluting diastereomer
showed: 1H NMR δ -0.18 (s, 3 H), -0.11 (s, 3 H), 0.80 (s, 9
H), 1.18 (s, 9 H), 1.20 (s, 9 H), 1.22-1.38 (m, 2 H), 1.40-1.48
(m, 3 H), 1.57-1.78 (m, 4 H), 1.82-1.90 (m, 1 H), 2.41 (d, 1 H,
J ) 11.7), 2.52-2.60 (m, 1 H), 2.64 (d, 1 H, J ) 10.7), 3.32-
3.42 (m, 1 H), 3.52 (d, 1 H, J ) 11.8), 7.18-7.49 (m, 22 H),
7.68-7.71 (m, 4 H).
Syn th esis of 5- a n d 7-Meth yl a n d Hyd r oxym eth ylin -
d olizid in on e Am in o Ester s 16-19 via Red u ctive Am in a -

Mimicry of Peptide Backbone Geometry
J . Org. Chem., Vol. 66, No. 4, 2001 1179
Gen er a l P r oced u r e for th e Syn th esis of 5- a n d 7-Hy-
d r oxym eth ylin d olizid in on e Am in o Ester s 16 a n d 17 via
Meth a n esu lfon a te Disp la cem en t. Methanesulfonation and
displacement were performed by treating a magnetically
stirred, 0 °C solution of alcohol 14 (0.2-0.3 mmol, 100 mol %)
in CH2Cl2 (5 mL) with methanesulfonyl chloride (200 mol %),
DMAP (10 mol %), and Et3N (300 mol %). The solution was
stirred for 1 h at 0 °C, the ice bath was removed, and the
mixture was stirred an additional 1 h at room temperature.
Toluene (10 mL) was added, and the reaction mixture was
heated at a reflux for 24 h. The solution was allowed to cool
to room temperature and partitioned between EtOAc (15 mL)
and water (5 mL). The organic layer was washed with 2 N
HCl (3 mL), 5% NaHCO3 (3 mL), and water (3 mL), dried, and
evaporated. The crude reaction product was used without
further purification.
The tert-butyl esters, tert-butyldimethylsilyl ether, and PhF
groups were solvolyzed by dissolving the crude reaction
product in a 10% solution of TFA in CH2Cl2 (15 mL) and
stirring the solution at room temperature for 48 h. Evaporation
gave a residue which was triturated with hexane (3 × 10 mL)
to furnish a solid that was used without further purification.
Esterification was performed on treatment of a solution of
the crude product in MeOH at -5 °C with SOCl2 (300 mol %).
The reaction mixture was stirred at -5 °C for 1 h, then at
room temperature for 1 h, and at 50 °C for 2 h. Evaporation
of the volatiles gave a crude residue which was subsequently
used without further purification.
ration of the collected fractions gave 8.5 mg (86%) of acid 5:
[R]D20 -2.9 (c 2.50, CHCl3); 1H NMR δ 1.45 (s, 9 H), 1.72-1.85
(m, 3 H), 1.98-2.16 (m, 2 H), 2.26-2.40 (m, 2 H), 3.63-3.71
(m, 3 H), 4.29 (dd, 1 H, J ) 10.0, 6.2), 4.55 (d, 1 H, J ) 8.7),
5.10 (bs, 2 H), 5.75 (d, 1 H, J ) 6.2); 13C NMR δ 28.3, 28.5,
29.7, 31.6, 41.1, 49.7, 58.6, 59.1, 63.9, 80.1, 155.9, 170.7, 173.0;
HRMS calcd for C15H25N2O6 (MH+) 329.1724, found 329.1713.
(3S,6S,7R,9S)-2-Oxo-3-N-(BOC)am in o-5-h ydr oxym eth yl-
1-azabicyclo[4.3.0]n on an e-9-car boxylic Acid ((3S,6S,7R,9S)-
6). The compound was synthesized from 7-hydroxymethyl
indolizidin-2-one N-(BOC)amino ester (6S,7R)-17 (0.03 mmol)
using the same protocol as that described above for the
conversion of ester 16 to acid 5: 85% yield; [R]D20 -0.8 (c 1.58,
1
CHCl3); H NMR δ 1.45 (s, 9 H), 1.63-1.80 (m, 2 H), 2.02-
2.15 (m, 2 H), 2.18-2.30 (m, 2 H), 2.36-2.48 (m, 2 H), 3.52-
3.63 (m, 1 H), 3.70-3.80 (m, 3 H), 4.18-4.30 (m, 1 H), 4.57 (d,
1 H, J ) 8.6), 5.52-5.58 (bs, 1 H); 13C NMR δ 27.5, 28.5, 29.1,
30.4, 47.4, 50.8, 58.7, 59.1, 64.8, 80.4, 156.8, 172.1, 173.5;
HRMS calcd for C15H25N2O6 (MH+) 329.1724, found 329.1714.
(3S,5S,6R,9S)-Meth yl 2-oxo-3-N-(BOC)a m in o-5-m eth -
a n esu lfon yloxym eth yl-1-a za bicyclo[4.3.0]n on a n e-9-ca r -
boxyla te ((3S,5S,6R,9S)-20). The compound was prepared
from 5-hydroxymethyl indolizidin-2-one amino ester 16 (0.06
mmol) using the same procedure as that described below for
the conversion of alcohol 17 to methanesulfonate 21. The
product was obtained in 82% yield and used directly in the
nucleophilic displacement: 1H NMR δ 1.44 (s, 9H), 1.75-1.90
(m, 2H), 2.13-2.20 (m, 1H), 2.23-2.45 (m, 2H), 3.03 (d, 1H, J
) 7), 3.08 (s, 3H), 3.64 (dd, 1H, J ) 9, 6), 3.74 (s, 3H), 3.75
(bs, 1H), 4.11-4.22 (m, 2H), 4.25 (d, 1H, J ) 5), 4.55 (d, 1H,
J ) 7), 5.55 (bs, 1H); 13C NMR δ 28.3, 28.9, 30.7, 31.5, 37.4,
38.9, 49.3, 52.4, 58.0, 58.4, 70.0, 79.7, 155.5, 168.7, 171.9.
(3S,6S,7R,9S)-Meth yl 2-oxo-3-N-(BOC)a m in o-7-m eth -
a n esu lfon yloxym eth yl-1-a za bicyclo[4.3.0]n on a n e-9-ca r -
boxyla te ((3S,6S,7R,9S)-21). Methyl ester (6S,7R)-17 (20 mg,
0.06 mmol) in 5 mL of CH2Cl2 at 0 °C was treated with DMAP
(2 mg, 10 mol %), Et3N (28 µL, 0.2 mmol, 300 mol %), and
then with methanesulfonyl chloride (14 mg, 0.12 mmol, 200
mol %). The ice bath was removed and the mixture was stirred
an additional 1 h at room temperature and partitioned
between EtOAc (15 mL) and water (5 mL). The organic layer
was washed with 2 N HCl (3 mL), 5% NaHCO3 (3 mL), and
water (3 mL), and dried and evaporated to yield 19 mg (77%)
of 21. The product was used directly in the nucleophilic
displacement: 1H NMR δ 1.45 (s, 9 H), 1.65-1.89 (m, 3 H),
2.10 (dd, 1 H, J ) 12.4, 9.6), 2.18-2.26 (m, 2 H), 2.45-2-58
(m, 1 H), 3.05 (s, 3 H), 3.57 (dt,1 H, J ) 9.7, 5.2), 3.76 (s, 3 H),
4.10-4.19 (m, 1 H), 4.27 (ddd, 2 H, J ) 22.2. 10.4, 5.8), 4.56
(d, 1 H, J ) 8.5), 5.12 (bs, 1 H); HRMS calcd for C17H29N2O8S
(MH+) 421.1645, found 421.1627.
Lactam cyclization and amine protection involved the treat-
ment of the reaction product in CH2Cl2 (15 mL) with Et3N (500
mol %) for 24 h at room temperature, followed by addition of
(BOC)2O (500 mol %) and additional stirring at room temper-
ature for 2 h. The mixture was diluted with CH2Cl2 (15 mL),
washed with a 1 M solution of NaH2PO4 (5 mL) and brine (5
mL), dried, and evaporated. The residue was chromatographed
using 3:97 EtOH-CHCl3 as eluant. Evaporation of the col-
lected fractions gave the hydroxymethylindolizidinone amino
esters; proton NMR spectra are recorded in Table 1.
(3S,5S,6R,9S)-Meth yl 2-Oxo-3-N-(BOC)am in o-5-h ydr oxy-
methyl-1-azabicyclo[4.3.0]nonane-9-carboxylate((3S,5S,6R,9S)-
16). [R]D -0.7 (c 1.45, CHCl3);13C NMR δ 20.8, 26.6, 28.2,
20
31.0, 42.9, 49.8, 52.4, 57.7, 58.3, 60.9, 79.6, 155.6, 169.1, 172.5;
HRMS calcd for C16H27N2O6 (MH+) 343.1869, found 343.1884.
(3S,6S,7S,9S)-Meth yl 2-Oxo-3-N-(BOC)am in o-7-h ydr oxy-
methyl-1-azabicyclo[4.3.0]nonane-9-carboxylate((3S,6S,7S,9S)-
20
17). [R]D -2.35 (c 2.02, CHCl3); 13C NMR δ 28.3, 29.1, 31.3,
31.7, 41.3, 49.7, 52.4, 57.9, 58.5, 64.2, 79.7, 155.8, 169.1, 172.1;
HRMS calcd for C16H27N2O6 (MH+) 343.1869, found 343.1855.
(3S,6R,7S,9S)-Meth yl 2-Oxo-3-N-(BOC)am in o-7-h ydr oxy-
methyl-1-azabicyclo[4.3.0]nonane-9-carboxylate((3S,6R,7S,9S)-
17). [R]D -14.3 (c 1.42, CHCl3); 13C NMR δ 27.1, 28.3, 28.6,
(3S,5S,6R,9S)-Meth yl 2-Oxo-3-N-(BOC)a m in o-5-a zid o-
methyl-1-azabicyclo[4.3.0]nonane-9-carboxylate((3S,5S,6R,9S)-
7). The compound was synthesized from methanesulfonate 20
(0.06 mmol) using the same procedure as that described below
for the conversion of methanesulfonate 21 into azide 8: 68%
20
30.9, 42.8, 47.7, 52.3, 57.1, 62.2, 62.3, 79.6, 156.2, 168.0, 172.7;
HRMS calcd for C16H27N2O6 (MH+) 343.1869, found 343.1859.
(3S,6S,7R,9S)-Meth yl 2-Oxo-3-N-(BOC)am in o-7-h ydr oxy-
methyl-1-azabicyclo[4.3.0]nonane-9-carboxylate((3S,6S,7R,9S)-
17). [R]D -6.17 (c 2.27, CHCl3); 13C NMR δ 26.0, 27.0, 28.1,
yield; IR cm-1 2109; H NMR δ 1.45 (s, 9H), 1.72-1.91 (m, 2
20
1
31.5, 47.1, 49.7, 52.2, 57.6, 58.7, 61.6, 79.4, 155.6, 169.1, 172.0;
HRMS calcd for C16H27N2O6 (MH+) 343.1869, found 343.1859.
(3S,6R,7R,9S)-Meth yl 2-Oxo-3-N-(BOC)am in o-7-h ydr oxy-
methyl-1-azabicyclo[4.3.0]nonane-9-carboxylate((3S,6R,7R,9S)-
H), 2.13 (dd, 1 H, J ) 7, 2), 2.15-2.21 (m, 2 H), 2.23-2.29 (m,
1 H) 2.30-2.42 (m, 1 H), 3.44 (t, 2 H, J ) 6), 3.50-3.62 (m, 1
H), 3.74 (s, 3 H), 4.26 (bs, 1 H), 4.53 (dd 1 H, J ) 7, 1), 5.52
(bs, 1 H); 13C NMR δ 28.9, 31.4, 32.1, 39.0, 49.3, 52.4, 53.9,
58.0, 59.2, 77.2, 79.7, 155.6, 168.9, 172.0.
17). [R]D -19.2 (c 2.07, CHCl3); 13C NMR δ 23.1, 28.1, 28.8,
20
30.7, 42.7, 51.6, 52.2, 57.0, 60.7, 61.6, 79.5, 156.1, 168.4, 173.0;
HRMS calcd for C16H27N2O6 (MH+) 343.1869, found 343.1884.
(3S,5S,6R,9S)-2-Oxo-3-N-(BOC)am in o-5-h ydr oxym eth yl-
1-azabicyclo[4.3.0]n on an e-9-car boxylic Acid ((3S,5S,6R,9S)-
5). Methyl ester (5S,6R)-16 (10 mg, 0.03 mmol) in 3 mL of
Et2O was treated with KOSiMe3 (5.8 mg, 0.045 mol), stirred
for 10 h at room temperature, treated with a second portion
of KOSiMe3 (5.8 mg, 0.045 mol), and stirred overnight. The
reaction solution was concentrated under reduced pressure.
Water (10 mL) was added, and the pH was adjusted to ∼pH 2
using citric acid. After 10 min of stirring, the solution was
saturated with NaCl and extracted with EtOAc (2 × 10 mL).
The organic solutions were combined and purified by filtration
through silica gel using 20:1 EtOAc-AcOH as eluant. Evapo-
(3S,6S,7R,9S)-Meth yl 2-Oxo-3-N-(BOC)a m in o-7-a zid o-
methyl-1-azabicyclo[4.3.0]nonane-9-carboxylate((3S,6S,7R,9S)-
8). Methanesulfonate 21 was dissolved in DMF (3 mL) and
treated with NaN3 (15 mg, 0.225 mmol, 500 mol %), stirred at
80 °C for 4 h, cooled, and partitioned between EtOAc (10 mL)
and water (5 mL). The organic layer was washed with 2 N
HCl (3 mL), 5% NaHCO3 (3 mL) and water (3 mL), and dried
1
and evaporated to yield 13 mg (79%) of 8: IR cm-1 2099; H
NMR δ 1.45 (s, 9 H), 1.62-1.83 (m, 3 H), 2.01-2.22 (m, 2 H),
2.25-2.38 (m, 1 H), 2.40-2.55 (m, 1 H), 3.42-3.51 (m, 3 H),
3.76 (s, 3 H), 4.12-4.21 (m, 1 H), 4.54 (d, 1 H, J ) 8.8), 5.48
(d, 1 H, J ) 5.1); 13C NMR δ 27.0, 28.3, 29.7, 32.7, 45.0, 50.0,
52.0, 52.5, 57.6, 59.0, 79.6, 155.7, 169.2, 171.9; HRMS calcd
for C16H26N5O5 (MH+) 368.1934, found 368.1926.

1180 J . Org. Chem., Vol. 66, No. 4, 2001
Polyak and Lubell
(3S,5S,6R,9S)-Meth yl 2-Oxo-3-N-(BOC)a m in o-5-for m yl-
1-a za bicyclo[4.3.0]n on a n e-9-ca r boxyla te ((3S,5S,6R,9S)-
22). A solution of alcohol (5S,6R)-16 (20 mg, 0.058 mmol) in
CH2Cl2 (2 mL) was treated with pyridinium chlorochromate
(26 mg, 0.12 mmol, 200 mol %) and 3 Å molecular sieves, and
the suspension was vigorously stirred for 6 h at room temper-
ature. Then the suspension was filtered and evaporated. The
residue was dissolved in EtOAc (5 mL) and filtered through a
1 g bed of silica gel on a glass filter with EtOAc (2 × 5 mL) as
eluant. The combined organic solutions were evaporated to
yield 15 mg (75%) of aldehyde 22: 1H NMR δ 1.45 (s, 9 H),
1.74-2.00 (m, 2 H), 2.11-2.18 (m, 1 H), 2.20-2.32 (m, 1 H),
2.47 (dd, 1 H, J ) 12.6, 6.0), 2.82-2.96 (m, 1 H), 2.92-3.02
(m, 1 H), 3.75 (s, 3 H), 3.92-4.12 (m, 1 H), 4.20-4.29 (m, 1
H), 4.55 (d, 1 H, J ) 8.7), 5.03 (bs, 1 H), 9.76 (s, 1 H); 13C
NMR δ 28.3, 28.9, 29.7, 31.5, 49.3, 51.7, 52.5, 55.4, 57.9, 79.9,
155.5, 168.4, 172.0, 200.1; HRMS calcd for C16H25N2O6 (MH+)
341.1713, found 341.1722.
(3S,5S,6S,9S)-2-Oxo-3-N-(BOC)am in o-1-azabicyclo[4.3.0]-
n on a n e-9-ca r boxym eth yl-5-ca r boxyla te ((3S,5S,6S,9S)-9).
A solution of NaClO2 (270 mg, 3 mmol) and NaH2PO4 (380
mg, 2.7 mmol) in 1.5 mL of water was poured into a stirred
solution of aldehyde 22 (10 mg, 0.3 mmol) in 1:1 acetonitrile-
tert-butyl alcohol (6 mL). Stirring was continued for 30 min
at room temperature, and the mixture was then partitioned
between 10 mL of 1 M H3PO4 and 10 mL of ether. The aqueous
layer was extracted with 3 × 10 mL of ether. The combined
organic phase was washed with brine, dried, and evaporated
to provide acid 9 (7.7 mg, 72%): 1H NMR δ 1.44 (s, 9 H), 1.95-
2.08 (m, 1 H), 2.06 (dd, 1H, J ) 13, 7), 2.23 (dd, 1 H, J ) 14,
6), 2.30 (d, 1 H, J ) 6), 2.42-2.52 (m, 1 H), 2.55-2.65 (m, 1
H), 2.88 (d, 1 H, J ) 14), 3.08 (d, 2 H, J ) 4), 3.76 (s, 3 H),
4.12-4.22 (m, 1 H), 4.62 (d, 1 H, J ) 9), 5.58 (bs, 1 H); 13C
NMR δ 27.0, 28.0, 28.2, 28.3, 35.1, 39.1, 52.6, 58.2, 77.2, 80.0,
155.3, 169.4, 171.4, 173.0.
(2.1 mg, 0.016 mmol), stirred for 6 h at room temperature and
partitioned between EtOAc (5 mL) and water (5 mL). The
organic layer was washed with 10% citric acid (3 mL), 5%
NaHCO3 (3 mL) and water (3 mL), dried and evaporated to
give a crude ester (S)-23 that was directly examined by 19F
and 1H NMR spectroscopy. The same experiment was per-
formed on (6S,7R)-17 using (R)-R-methoxy-R-(trifluoromethyl)-
phenylacetic acid to provide ester (R)-23.
(R)-23. 19F NMR (C6D6 with F3CC6H5 as internal reference,
1
δ ) -63.7) δ -77.94; H NMR δ 1.45 (s, 9 H), 1.66-1.71 (m,
2 H), 1.89-2.10 (m, 2 H), 2.34-2.45 (m, 2 H), 3.34-3.52 (m, 1
H), 3.53 (s, 3 H), 3.75 (s, 3 H), 4.06-4.08 (m, 1 H), 4.33 (d, 2
H, J ) 6), 4.50 (d, 2 H, J ) 9), 5.43 (bs, 1 H), 7.28-7.51 (m, 5
H).
(S)-23. 19F NMR (C6D6 with F3CC6H5 as internal reference,
1
δ ) -63.7) δ -77.74; H NMR δ 1.45 (s, 9 H), 1.59-1.69 (m,
3 H), 1.92-2.02 (m, 2 H), 2.04-2.15 (m, 2 H), 3.38-3.54 (m,
1H), 3.52 (s, 3 H), 3.74 (s, 3 H), 4.08-4.12 (m, 1 H), 4.21 (dd,
2 H, J ) 12, 6), 4.47 (dd, 1H, J ) 11, 5), 5.45 (bs, 1 H), 7.41-
7.51 (m, 5 H).
Ack n ow led gm en t. This research was supported in
part by the Natural Sciences and Engineering Research
Council of Canada, the Ministe`re de l’EÄ ducation du
Que´bec, and the Medical Research Council of Canada.
We thank Sylvie Bilodeau and Dr. M. T. Phan Viet of
the Regional High-Field NMR Laboratory for their
assistance in establishing the configurations of esters
16-19. The crystal structure analysis of compound 17
wasperformedbyFrancineBe´langer-Garie´pyat l’Universite´
de Montre´al X-ray facility. We are grateful for a loan of
Pd/C from J ohnson Matthey PLC. We are grateful for a
gift of γ-methyl glutamate from NSC Technologies.
En a n tiom er ic P u r ity of (3S,6S,7R,9S)-Meth yl 2-Oxo-
3-N-(BOC)a m in o-7-h yd r oxym et h yl-1-a za b icyclo[4.3.0]-
n on a n e-9-ca r boxyla te ((6S,7R)-17). A solution of (6S,7R)-
17 (3 mg, 0.0087 mmol) in 3 mL of MeCN was treated with
(S)-R-methoxy-R-(trifluoromethyl)phenylacetic acid (2.3 mg,
0.01 mmol) followed by TBTU (4.2 mg, 0.013 mmol) and DIEA
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 5-8 and 15-23, COSY and NOESY/ROESY spectra
of 16-19, and crystallographic data for 17. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O001251T