Stereoselective synthesis of dipeptide β-turn mimetics: 7-Benzyl and 8-phenyl substituted azabicyclo[4.3.0]nonane amino acid esters

Article abstract of DOI:10.1021/jo0203591

A stereoselective method has been developed for the synthesis of 7- and 8-substituted dipeptide β-turn mimetic azabicyclo[4.3.0]nonane amino acid esters. The allyl groups were introduced in high diastereoselectivity, controlled by 3-phenyl or 4-benzyl groups in pyroglutamic acid derivatives 3 or 9, respectively. The precursors, dehydroamino acids 7 and 13 derived from 5 or 11, underwent asymmetric hydrogenations with Burk's DuPHOS Rh(I)-based catalysts to furnish α-amino acid derivatives in high stereoselectivity. The resulting amino acids 8 and 14 were converted to the β-turn mimetics 6,5-bicyclic lactams 1a-d in high yields.

Full text of DOI:10.1021/jo0203591

Ster eoselective Syn th esis of Dip ep tid e â-Tu r n Mim etics: 7-Ben zyl
a n d 8-P h en yl Su bstitu ted Aza bicyclo[4.3.0]n on a n e Am in o Acid
Ester s†
Wei Wang,‡ J ianqing Yang, J infa Ying, Chiyi Xiong, J unyi Zhang, Chaozhong Cai, and
Victor J . Hruby*
Department of Chemistry, University of Arizona, Tucson, Arizona 85721
hruby@u.arizona.edu
Received May 31, 2002
A stereoselective method has been developed for the synthesis of 7- and 8-substituted dipeptide
â-turn mimetic azabicyclo[4.3.0]nonane amino acid esters. The allyl groups were introduced in high
diastereoselectivity, controlled by 3-phenyl or 4-benzyl groups in pyroglutamic acid derivatives 3
or 9, respectively. The precursors, dehydroamino acids 7 and 13 derived from 5 or 11, underwent
asymmetric hydrogenations with Burk’s DuPHOS Rh(I)-based catalysts to furnish R-amino acid
derivatives in high stereoselectivity. The resulting amino acids 8 and 14 were converted to the
â-turn mimetics 6,5-bicyclic lactams 1a -d in high yields.
In tr od u ction
In the recent past, there has been an increasing
interest in the development of rigid dipeptide â-turn
mimetics to try to mimic or induce â-turn secondary
structural features of peptides and proteins that are
thought to play important roles in molecular recognition
and biological activity.1-3 A great deal of effort has
focused on the design and synthesis of small constrained
F IGURE 1. Azabicyclo[X.Y.0]alkane amino acids.
mimetics of reverse-turn structures to provide a better
understanding of the molecular basis of peptide and
protein interactions. Several peptide mimetic systems
have been proposed to mimic different types of reverse-
turns.1 Azabicyclo[X.Y.0]alkane amino acids are particu-
larly attractive because of their ability to serve as
conformationally fixed surrogates of peptide turn second-
ary structures (Figure 1).1b The growing use of these
dipeptide surrogates in the investigation of structure-
activity relationships of various biologically peptides has
created a demand for new methodology for synthesizing
these peptide mimetics. Several procedures have been
developed for the synthesis of such bicyclic lactams.1,2 In
these approaches, one particularly effective and versatile
route, developed by Lubell and co-workers, has been
employed for the preparation of enantiopure indolizidi-
none-type bicyclic lactam systems.1,3
Although quite a few successes have been reported in
obtaining mimetics which can force or stabilize â-turns,
little success has been reported in incorporating mimetics
for the active site of peptide hormone or neurotransmitter
receptors because of the lack of appropriately positioned
side chain groups. In the event of molecular recognition,
the backbone conformations of peptides and proteins
provide critical templates for the three-dimensional
structures when interacting with their receptors/accep-
tors. However, the overall shape and intrinsic stereo-
electronic properties of the peptides and proteins impor-
tant for molecule recognition, signal transduction,
enzymatic specificity, immunomodulation, and other
* To whom correspondence should be addressed: Professor Victor
J . Hruby, Department of Chemistry, University of Arizona, 1306 E.
University Blvd., Tucson, AZ 85721, USA. Phone: (520) 621-6332.
Fax: (520) 621-8407.
† In memory of Mr. J ianqing Yang.
‡ Current address: Genomics Institute of the Novartis Research
Foundation, 9390 Towne Centre Dr., Suite 200, San Diego, CA 92121.
(1) For recent reviews for the use of lactam-based peptidomimetics,
see: (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789-12854. (b) Halab, L.; Gosselin,
F.; Lubell, W. D. Biopolymers (Pept. Sci.) 2000, 55, 101-122. (c) Kim,
H.-O.; Kahn, M. Comb. Chem. High Throughput Screening 2000, 3,
167-183. For reviews on the solid-phase synthesis of â-turn mimetic
libraries, see: (d) Souers, A. J .; Ellman, J . A. Tetrahedron 2001, 57,
7431-7448. (e) Burgess, K. Acc. Chem. Res. 2001, 34, 826-835.
(2) For recent examples for the synthesis of â-turn mimetics, see:
(a) Manzoni, L.; Belvisi, L.; Scolastico, C. Synlett 2000, 1287-1288.
(b) Manzoni, L.; Colombo, M.; May, E.; Scolastico, C. Tetrahedron 2001,
57, 249-255. (c) Beal, L. M.; Liu, B.; Chu, W.; Moeller, K. D.
Tetrahedron 2000, 56, 10113-10125. (d) Angioini, M.; Araneo, S.;
Belvisi, L.; Cesarotti, E.; Checchia, A.; Crippa, L.; Manzoni, L.;
Scolastico, C. Eur. J . Org. Chem. 2000, 2571-2581. (e) Angiolini, M.;
Araneo, S.; Belvisi, L.; Cesarotti, E.; Checchia, A.; Crippa, L.; Manzoni,
L.; Scolastico, C. Eur. J . Org. Chem. 2000, 2571-2581. (f) Hanessian,
S.; McNaughton-Smith, G. Bioorg. Med. Chem. Lett. 1996, 6, 1567-
1572. (g) Hanessian, S.; Ronan, B.; Laoui, A. Bioorg. Med. Chem. Lett.
1994, 4, 1397-1400. (h) Kim, H.-O.; Nakanishi, H.; Lee, M. S.; Kahn,
M. Org. Lett. 2000, 2, 301-302. (i) Boatman, P. D.; Ogbu, C. O.; Eguchi,
M.; Kim, H. O.; Nakanishi, H.; Cao, B.; Shea, J . P.; Kahn, M. J . Med.
Chem. 1999, 42, 1367-1375.
(3) For recent development of the synthesis of â-turn mimetics with
side chain functionalities by Lubell and co-workers, see: (a) Gosselin,
F.; Lubell, W. D. J . Org. Chem. 1998, 63, 7463-7471. (b) Gosselin, F.;
Lubell, W. D. J . Org. Chem. 2000, 65, 2163-2171. (c) Polyak, F.; Lubell,
W. D. J . Org. Chem. 1998, 63, 5937-5949. (d) Polyak, F.; Lubell, W.
D. J . Org. Chem. 2001, 66, 1171-1180. (e) Feng, Z.; Lubell, W. D. J .
Org. Chem. 2001, 66, 1181-1185.
10.1021/jo0203591 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/02/2002
J . Org. Chem. 2002, 67, 6353-6360
6353

Wang et al.
SCHEME 1. Gen er a l Ap p r oa ch for th e Syn th esis of Aza bicyclo[X.Y.0]a lk a n e Am in o Acid s
biological effects usually depend on the arrangement of
the side chain groups of amino acid residues in three-
dimensional space. The side chain moieties involved
directly in the binding are critical for biological activity
and selectivity for receptors/acceptors or subtype recep-
tors and ligands. Their 3D architecture (topography)
and stereoelectronic properties provide the critical
complementary shape and chemical properties that favor
efficient molecular recognition.
Lubell and co-workers using a Claisen condensation/
reductive amination/lactam cyclization method. However,
to the best of our knowledge, the 8-phenyl substituted
analogues, which can mimic dipeptide Ala-Phe, have not
been reported in the literature. The hydrophobic benzyl
and phenyl groups are very attractive because they could
improve peptide-receptor affinity by interacting with
hydrophobic pockets of receptors.
To mimic the backbone and side chain conformations
of â-turns, a synthetic strategy requires stereocontrolled
introduction of side chain functionalities. Furthermore,
the synthesis of such â-turn mimetics should be easily
accessible from readily available or prepared starting
materials. To fulfill the criteria, recently we have devel-
oped two efficient methods to construct dipeptide â-turn
mimetics in high stereoselectivity.4 Our continuing efforts
in this area are directed toward the development of
efficient methods for the synthesis of other â-turn mi-
metics with appendages of side chain functionalities.
Herein, we would like to report an approach for introduc-
ing alkyl and aryl side chains onto the azabicyclo[X.Y.0]-
alkane amino acids in a highly stereocontrolled manner
(Scheme 1). The strategy involves starting from easily
synthesized and optically pure â- or γ-substituted pyro-
glutamic acid derivatives.5,6 Stereoselectively introducing
allyl groups at the C5 position of â- or γ-substituted
pyroglutamic acid derivatives and the elaboration of them
can afford dehydroamino acids, which can undergo asym-
metric hydrogenations followed by deprotection and
lactam cyclization to furnish substituted 6/5 fused bicyclic
â-turn mimetics (Scheme 1). In this study, benzyl and
phenyl groups are successfully introduced at positions 7
and 8 in high diastereoselectivity (Schemes 2 and 3). The
synthesis of 7-benzyl analogues has been reported by
Resu lts a n d Discu ssion
Syn th esis of 7-Ben zyl Aza bicyclo[4.3.0]n on a n e
Am in o Acid Der iva tives 1a ,b. The synthesis of 7-ben-
zyl azabicyclo[4.3.0]nonane amino acid derivatives 1a ,b
is illustrated in Scheme 2, starting from pyroglutamic
ethyl ester 2. Ethyl (2S,4R)-1-Boc (tert-butoxycarbonyl)-
4-benzylpyroglutamate (3) was prepared by a modifica-
tion of literature procedures.6 A related literature pro-
cedure only gave a moderate yield (∼59%).7 However,
longer reaction times gave a higher yield (up to 76%)
without sacrificing stereoselectivity. Only one diastere-
omer was formed with a 4S configuration, as observed
in the literature. Selective reduction of the lactam moiety
of 3 with Super-Hydride (LiBEt3H) in THF at -78 °C
and subsequent reaction of the resulting hemiaminal in
methanol in the presence of a catalytic amount of
p-toluenesulfonic acid (p-TsOH) gave the corresponding
aminal 4 as two isomers in 93% yield. The crude product
4 was pure enough for the next step reaction without
further purification. When 4 was treated with BF3‚OEt2
and allyltrimethylsilane at -40 °C, following a literature
procedure,8 only about 20% of the desired product 5 was
obtained with the rest of the decomposed products.8
However, when the reaction temperature was lowered
to -78 °C, the reaction yield was significantly improved
to 76%. The allylsilane addition to the N-acyliminium
derived from 4 gave exclusively trans product related to
the 4-benzyl group. The outcome is consistent with what
was observed in the 3-phenyl pyroglumatic ester by
Moeller and co-workers.8 The nucleophile attacked the
N-acyliminium ion from the si-face of the molecule
because the re-face was blocked by the benzyl group
(Figure 2). The ethyl ester group has little effect on the
addition. The observed stereochemistry is opposite to that
of R‚Cu-complex addition to the N-acyliminium to give
(4) For more recent methods from our laboratory, see: (a) Wang,
W.; Xiong, C.-Y.; Hruby, V. J . Tetrahedron Lett. 2001, 42, 3159-3161.
(b) Qiu, W.; Gu, X.; Soloshonok, V. A.; Carducci, M. D.; Hruby, V. J .
Tetrahedron Lett. 2001, 42, 145-148.
(5) For a recent review regarding the synthesis of pyroglutamic acid
derivatives, see: Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999,
10, 2245-2303.
(6) For methods developed in our laboratory for the synthesis of
â-substituted pyroglutamic acid and proline derivatives, see: (a)
Soloshonok, V. A.; Cai, C.; Hruby, V. J . Tetrahedron Lett. 2001, 41,
135-139. (b) Soloshonok, V. A.; Cai, C.; Hruby, V. J . Angew. Chem.,
Int. Ed. 2000, 39, 2172-2175. (c) Soloshonok, V. A.; Cai, C.; Hruby,
V. J .; Van Meervelt, L.; Yamazaki, T. J . Org. Chem. 2000, 65, 6688-
6696. (d) Soloshonok, V. A.; Cai, C.; Hruby, V. J .; Van Meervelt, L.
Tetrahedron 1999, 55, 12045-12058. (e) Soloshonok, V. A.; Cai, C.;
Hruby, V. J .; Van Meervelt, L.; Mischenko, N. Tetrahedron 1999, 55,
12031-12044. (f) Soloshonok, V. A.; Cai, C.; Hruby, V. J . Tetra-
hedron: Asymmetry 1999, 10, 4265-4269.
(7) Ezquerra, J .; Pedregal, C.; Rubio, A.; Yruretagoyena, B.;
Escribano, A.; Sanchez-Ferrando, F. Tetrahedron 1993, 49, 8665-
8678.
(8) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K. D.
J . Org. Chem. 2000, 2484-2493.
6354 J . Org. Chem., Vol. 67, No. 18, 2002

Stereoselective Synthesis of Dipeptide â-Turn Mimetics
SCHEME 2. Syn th esis of 7-Ben zyl Aza bicyclo[4.3.0]n on a n e Am in o Acid Der iva tivesa
a
(a) LiHMDS, BnBr, THF, -78 °C, 76%. (b) (i) Super-Hydride, THF, -78 °C; (ii) pTsOH (cat.), MeOH, two steps (93%). (c) BF3sOEt2,
Me3SiCH2CHdCH2, 76%. (d) O3, then Me2S, 5 d, 63%. (e) (MeO)2P(O)CH(NHCbz)COOCH3, DBU, CH2Cl2, rt, 4 h, 100%. (f) Rh(I)(COD)-
(S,S)-Et-DuPHOS, H2 (75 psi), 24 h, MeOH, 95%. (g) Rh(I)(COD)-(R,R)-Et-DuPHOS, H2 (75 psi), 24 h, MeOH, 96%. (h) (i) 30% TFA,
CH2Cl2, 2 h; (ii) TEA, CH2Cl2, 5 days, 76-83%.
SCHEME 3. Syn th esis of 8-P h en yl Aza bicyclo[4.3.0]n on a n e Am in o Acid Der iva tivesa
a
(a) (i) LiBEt3H, THF, -78 °C; (ii) p-TsOH (cat.), MeOH, rt, overnight. (b) CH2dCHCH2Si(CH3)3, BF3sEt2O, -40 °C, 3 steps (74%).
(c) O3, CH2Cl2, -78 °C, then Me2S, rt, 5 d, 81%. (d) (MeO)2P(O)CH(NHCbz)COOCH3, DBU, CH2Cl2, rt, 6 h, 90%. (d) Rh(I)(COD)-(S,S)-
Et-DuPHOS, H2 (70 psi), 24 h, MeOH, 100%. (e) Rh(I)(COD)-(R,R)-Et-DuPHOS, H2 (70 psi), 24 h, MeOH, 100%. (f) (i) 30% TFA, CH2Cl2,
rt, 1 h; (ii) TEA, CH2Cl2, 6 d, 83-87%.
cis products related to the 4-benzyl group reported in the
literature (Figure 2).9 However, in the latter case, the
ester group played a dominant role in the control of
stereochemistry through formation of a Cu(I) complex to
block the â-face, whereas the 4-benzyl group had little
effect on the allyl addition (Figure 2).9 Because of
rotamers (cis and trans) in the proline derivative 5,
to give 5a with a “clean” 1H NMR to allow us to determine
the stereochemistry of the allyl group (Scheme 2). The
stereochemistry of the resulting allyl addition product
was assigned as the S configuration in 5a by NOE
experiments that showed 1.4%, 1.5%, and 1.1% enhance-
ment in Ha, Hb, and Hd, respectively, by irradiation of
Hc (Figure 3). No NOE effect on He was observed by
irradiation of the same Hc. The stereochemistry at C5 of
the proline derivative position was further confirmed by
NOE experiments of the final product 1a (Figure 3).
1
complicating the H NMR, the Boc group was removed
(9) Collado, I.; Ezquerra, J .; Pedregal, C. J . Org. Chem. 1995, 60,
5011-5015.
J . Org. Chem, Vol. 67, No. 18, 2002 6355

Wang et al.
F IGURE 2.
F IGURE 3.
With the optically pure intermediate 5 in hand, we
elaborated it to give the final products 1a ,b in high yields
and high stereoselectivity. Ozololysis, followed by Me2S
reduction of the double bond in compound 5, afforded
aldehyde 6 in 63% yield. The key intermediate, dehydro-
amino acid 7, was obtained with the (Z) isomer as the
major product via the Horner-Emmons olefination of
aldehyde 6 in a quantitative yield.10 A mixture of the
two (Z) and (E) isomers was used for the asymmetric
hydrogenations without separation. The resulting dehy-
droamino ester 7 underwent asymmetric hydrogenations
to give the R-amino acid derivatives in high diastereo-
selectivity. The Burk’s catalysts [Rh(I) (COD) (S,S)-Et-
DuPHOS or (R,R)-Et-DuPHOS]OTf were employed as the
catalyst in high yields (>95%) and high diastereoselec-
tivity (>96% ee).11 We tried to determine the diastereo-
selectivity of asymmetric hydrogenations using 1H NMR.
Unfortunately, the two existing rotamers in 8 compli-
cated their evaluation. However, only one diastereomer
was observed on the basis of TLC analysis. At this point,
we did not make a further effort to determine diastereo-
selectivity. However, only one diastereomer, 1a or 1b,
was obtained from the amino acid ester 8a or 8b,
respectively, after cleavage of the NR-Boc group and
cyclization. It should be noted that Scolastico and co-
workers employed Rh(I) Prophos or (+)/(-)BitianP cata-
lysts for asymmetric hydrogenations with similar dehy-
droamino acid derivative substrates to have achieved
good diastereoselectivities (72-80% de).1e However, we
have successfully used Burk’s catalysts to synthesize
many novel amino acids and dipeptide â-turn mimetics
in high enantioselectivity and/or diastereoselectivity
under low to medium hydrogen pressure and, hence, have
used them here.4a,12 The new absolute configurations
were assigned as S in 8a and R in 8b on the basis of
the selectivity of the (S,S)-Et-DuPHOS and (R,R)-Et-
DuPHOS ligands, respectively.13 The formation of the
new chiral centers in 8a ,b was well controlled by asym-
metric hydrogenations. Compounds 8a ,b were converted
to the final products 1a ,b in two steps. Deprotection of
the NR-Boc group by TFA was followed by intramolecular
lactamization in the presence of TEA in CH2Cl2 to afford
1a ,b in 76-83% yields. It took a long time to complete
the lactamization reaction, which was monitored by TLC,
at room temperature because of the steric hindrance of
the secondary amine. It was found that the reaction rates
were similar despite the different configurations in 8a
and 8b. Increasing the reaction temperature should
facilitate lactamization.2e The stereochemistry at position
6 of (S)-configuration in 1a was further verified by NOE
experiments. Strong NOE effects (∼1.5%) were observed
at H3 and H9 via irradiation of H6. Furthermore, the
irradiation of H9 generated a 0.5% NOE effect for H3. In
addition, the optical rotation of (3S,6S,7S,9S)-2-oxo-3-
N-(Boc)amino-7-benzyl-1-azabicyclo[4.3.0]nonane-9-car-
23
boxylic acid ([R]D -6.0 (c 1.2, CHCl3)) derived from 1a
is similar to that of the compound synthesized by Lubell
and co-workers ([R]D -5.9 (c 2.0, CHCl3)).3c
20
Syn th esis of 8-P h en yl Aza bicyclo[4.3.0]n on a n e
Am in o Acid Der iva tives 1c,d . Using a similar strategy,
we also synthesized novel 8-phenyl substituted â-turn
mimetics 1c,d (Scheme 3). The starting material â-phenyl
pyroglutamic ester 9 was efficiently prepared using our
highly stereocontrolled Michael addition method.6 Re-
cently, we have developed an efficient route for asym-
metric synthesis of a variety of â-substituted pyroglutam-
ic acids and proline derivatives.6 The key step was the
asymmetric Michael addition, which was well controlled
by two chiral auxiliaries, for example, the proline-based
chiral Ni(II) complex and the Evans chiral auxiliary in
high diastereoselectivity (>98% de).6 The same proce-
(12) We and others have used the DuPHOS-based catalysts for the
synthesis of novel amino acids. See: (a) Hiebl, J .; Kollmann, H.;
Rovenszky, F.; Winkler, K. J . Org. Chem. 1999, 64, 1947-1952. (b)
Wang, W.; Xiong, C. Y.; Yang, J . Q.; Hruby, V. J . Tetrahedron Lett.
2001, 42, 7717-7719. (c) Wang, W.; Zhang, J .; Xiong, C.; Hruby, V. J .
Tetrahedron Lett. 2002, 43, 2137-2140. (d) Wang, W.; Xiong, C.; Yang,
J .; Hruby, V. J . Synthesis 2002, 94-98. (e) Wang, W.; Xiong, C.; Zhang,
J .; Hruby, V. J . Tetrahedron 2002, 58, 3101-3110.
(10) For the synthesis of the intermediate phosphate and dehy-
droamino acids, see: Schmidt, U.; Griesser, H.; Leitenberger, V.;
Lieberknecht, A.; Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992,
487-490.
(11) For recent reviews regarding the applications of DuPHOS-based
catalysts in asymmetric hydrogenations, see: (a) Burk, M. J .; Gross,
M. F.; Harper, T. G. P.; Kalberg, C. S.; Lee, J . R.; Martinez, J . P. Pure
Appl. Chem. 1996, 68, 37-44. (b) Burk, M. J . Acc. Chem. Res. 2000,
33, 363-372.
(13) Burk, M. J .; Feaster, J . E.; Nugent, W. A.; Harlow, R. L. J .
Am. Soc. Chem. 1993, 115, 10125-10138.
6356 J . Org. Chem., Vol. 67, No. 18, 2002

Stereoselective Synthesis of Dipeptide â-Turn Mimetics
chromatography was performed using silica gel (230-400
mesh). Thin-layer chromatography (TLC) was performed on
13 181 silica gel-based sheets with a fluorescent indicator.
Unless otherwise stated, yields refer to isolated yields of
dures were employed to convert lactam 9 into the
intermediate aminal 10 in two steps by selective reduc-
tion of lactam 9 to a hemiaminal, followed by reaction
with methanol in the presence of a catalytic amount of
p-TsOH. Interestingly, it was found that when 10 was
treated with BF3‚Et2O at -40 °C and allyltrimethylsi-
lane, a good yield (over 74%) was observed with formation
of exclusively the trans product related to the 3-phenyl
group. In this case, the 3-phenyl group controlled the
stereochemistry of an allylsilane addition to the N-
acyliminium derived from 10, as was observed in 5 for
the 4-benzyl group and by Moeller and co-workers.8 The
aldehyde 12 was obtained by ozololysis, followed by Me2S
reduction of the double bond in 11 in 81% yield. Then
the product was reacted with the phosphonate (MeO)2P-
(O)CH(NHCbz)COOMe in the presence of DBU to give
dehydroamino ester 13 in 90% yield with a 13/1 ratio of
(Z)/(E). Asymmetric hydrogenations of 13 in the presence
of [(COD)(S,S)-Et-DuPHOS Rh(I)]OTf or [(COD)(R,R)-Et-
DuPHOS Rh(I)]OTf afforded amino acids (S)-14a and
(R)-14b, respectively, in quantitative yields and high
diastereoselectivity. Again, only one isomer was obtained
on the basis of TLC analysis. The final â-turn mimetic
products 1c,d were obtained as one isomer in each case
in two steps, deprotection and lactamization, in high
yields. Again, a long reaction time was required for the
lactamization reactions. The conformation effect in (S)-
14a and (R)-14b had little influence on the lactamization.
The results were consistent with what we observed for
(S)-8a and (R)-8b.
1
products of greater than 95% purity, as estimated by H and
13C NMR spectroscopy. All new compounds were characterized
1
by H, 13C, and HRMS or elemental analysis.
Eth yl (2S,4S)-1-(ter t-Bu toxyca r bon yl)-4-ben zyl P yr o-
glu ta m a te (3). To a solution of pyroglutamic ester 2 (7.4 g,
28.76 mmol) in THF (180 mL) at -78 °C was added a 1.0 M
solution of LiHMDS (31.64 mL, 31.64 mmol) under argon
atmosphere. After the solution was stirred for 1.5 h at -78
°C, benzyl bromide (4.1 mL, 34.51 mmol) in THF (45 mL) was
added into the reaction mixture and the stirring was continued
for 5 h at this temperature. The reaction mixture was
quenched with saturated aqueous NH4Cl (225 mL) at -78 °C
and then was extracted with ether (3 × 100 mL). The combined
organic layers were dried over MgSO4, filtrated, and evapo-
rated to dryness under reduced pressure. The crude product
was purified by flash silica gel chromatography, eluting with
ethyl acetate/hexanes (1/5 then 1/4) to give a white solid (5.78
1
g, 76%). Mp 99-101 °C; H NMR (300 MHz, CDCl3) δ 7.16-
7.32 (m, 5H), 4.46 (dd, 1H, J 1 ) 3.0 Hz, J 2 ) 8.4 Hz), 4.18 (q,
2H, J ) 7.2 Hz), 3.29 (dd, 1H, J 1 ) 4.2 Hz, J 2 ) 13.8 Hz),
2.87-2.98 (m, 1H), 2.66 (dd, 1H, J 1 ) 9.3 Hz, J 2 ) 13.8 Hz),
1.95-2.09 (m, 2H), 1.50 (s, 9H), 1.25 (t, 3H, J ) 7.2 Hz).
(4S)-Nr-ter t-Bu toxycar bon yl-4-ben zyl-5-m eth oxy-L-pr o-
lin e Eth yl Ester (4). To a solution of 3 (5040 mg, 14.52 mmol)
in THF (120 mL) was added Super-Hydride (1.0 M in THF,
17.5 mL) at -78 °C under an Ar atmosphere. After the mixture
was stirred for 35 min at the same temperature, it was
quenched with saturated NaHCO3 (50 mL) and warmed to 0
°C (∼30 min). To the above mixture was added 140 drops of a
30% H2O2 aqueous solution at 0 °C, and the solution was
stirred at 0 °C for 30 min. After removal of THF under reduced
pressure, the remaining aqueous solution was extracted with
diethyl ether (3 × 70 mL). The organic extracts were combined,
dried over MgSO4, filtered, and concentrated under reduced
pressure to give a colorless oil. To the above obtained oily
residue in MeOH (80 mL) was added p-TsOH‚H2O (276 mg,
1.45 mmol), and the mixture was stirred at room temperature
overnight under Ar atmosphere. After the mixture was
quenched with saturated NaHCO3 (15 mL) and the methanol
was removed, the remaining mixture was extracted with
diethyl ether (3 × 70 mL). The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced
pressure to give crude 4 as a colorless oil (4900 mg, 93%). The
crude product was used for the next step reaction without
Con clu sion
We have developed an efficient approach to the syn-
thesis of stereocontrolled side chain appended azabicyclo-
[4.3.0]nonane amino acids in high diastereoselectivity. In
this approach, the allyl group was stereoselectively
introduced at the C5 position, controlled by a 4-benzyl or
3-phenyl group rather than by the ethyl ester group.
Asymmetric hydrogenations using Burk’s Rh(I)-based
catalysts with the chiral ligand (S,S)- or (R,R)-Et-
DuPHOS generated (S) and (R) R-amino acids, respec-
tively, in high stereoselectivity and high yields. This
method could be further exploited for the synthesis of
other diastereomers starting from different substituted
pyroglutamic acid derivatives to give 7/5 azabicyclo[X.Y.0]
amino acids (Scheme 1).2e The synthesis of such â-turn
mimetics using this approach and the incorporation of
these molecules into biologically active peptides and the
study of structure-activity relationships are under in-
vestigation.
1
further purification. H NMR (500 MHz, CDCl3) δ 7.32-7.12
(m, 5H), 5.11 (s, 0.2H), 5.08 (d, 0.4H, J ) 5.0 Hz), 4.92 (d, 0.4H,
J ) 2.5 Hz), 4.48 (t, 0.4H, J ) 9.0 Hz), 4.34-4.08 (m, 3.6H),
3.44 (s, 0.75H), 3.41 (s, 1.5H), 3.35 (s, 0.75H), 2.85 (dd, 0.5H,
J 1 ) 8.0 Hz, J 2 ) 13.5 Hz), 2.66-2.38 (m, 2.5H), 2.26-2.06
(m, 1.5H), 1.85 (m, 0.5H), 1.51 (s, 2.25H), 1.46 (s, 4.5H), 1.40
(s, 2.25H), 1.19-1.30 (m, 3H); HRMS (FAB) calcd for C20H30
NO5 (M + H) 364.2124, found 364.2123.
-
(4S,5S)-Nr-ter t-Bu toxyca r bon yl-5-a llyl-4-ben zyl-L-p r o-
lin e Eth yl Ester (5). To a solution of crude 4 (3180 mg, 8.76
mmol) in Et2O (20 mL) were added allyltrimethylsilane (6.3
mL, 39.42 mmol) and BF3‚Et2O (1.1 mL, 9.02 mmol) at -78
°C under an Ar atmosphere. After 3 h at the same tempera-
ture, the cold bath was removed and the reaction mixture was
warmed to room temperature (∼30 min). The reaction mixture
was diluted with Et2O (50 mL), quenched with NaHCO3 (25
mL), and then extracted with diethyl ether (2 × 60 mL). The
combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure to give the crude product
as a slightly yellow oil. The pure product 5 was obtained as a
colorless oil after flash column chromatography (silica gel, 50
g, 200-400 mesh, hexanes/ethyl acetate 8:1) (2472 mg, 76%).
Exp er im en ta l Section
1
Gen er a l. H and 13C NMR were performed on 300, 500, or
600 MHz spectrometers using TMS and CDCl3 as internal
standards. High-resolution mass spectra (HRMS) were re-
corded on an instrument in the University of Arizona Mass
Spectroscopy Laboratory. Optical rotations were measured on
a polarimeter. Melting points (mp) are uncorrected and were
obtained in open capillaries. Commercially available starting
materials and reagents were of ACS grade or better and used
as received. THF was distilled from Na and benzophenone,
and methylene chloride (CH2Cl2) was distilled from CaH2;
HPLC grade methanol was used for hydrogenations. Column
[R]22 +17.3 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
7.32-7.15 (m, 5H), 5.78 (m, 1H), 5.04 (d, 1H, J ) 17.7 Hz),
J . Org. Chem, Vol. 67, No. 18, 2002 6357

Wang et al.
5.03 (d, 1H, J ) 10.2 Hz), 4.38 (t, 0.4H, J ) 8.1 Hz), 4.25 (t,
0.6H, J ) 8.1 Hz), 4.17 (q, 2H, J ) 6.9 Hz), 3.77 (m, 0.6H),
3.63 (m, 0.4H), 2.78-2.63 (m, 1.6H), 2.54-2.44 (m, 1.4H),
2.36-2.24 (m, 2H), 1.98 (dd, 2H, J 1 ) 5.4 Hz, J 2 ) 8.4 Hz),
1.48 (s, 3.6H), 1.43 (s, 5.4H), 1.26 (t, 3H, J ) 6.9 Hz); 13C NMR
(75 MHz, CDCl3) δ 173.5, 173.2, 154.7, 153.9, 139.8, 135.5,
129.2, 128.7, 126.5, 117.1, 80.2, 63.09, 63.05, 61.13, 61.10, 59.1,
58.8, 43.9, 42.7, 39.7, 39.0, 38.3, 33.2, 32.6, 28.6, 28.5, 14.4,
14.3. HRMS (FAB): calcd for C22H32NO4 (M + H), 374.2331;
found, 374.2325.
(4S,5S)-5-Allyl-4-ben zyl-L-p r olin e Eth yl Ester (5a ). A
solution of 5 (900 mg, 2.41 mmol) in a mixture of CH2Cl2 (8
mL) and TFA (3 mL) was stirred at room temperature under
Ar overnight. Evaporation of solvents gave the product as an
oil (930 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 7.35-7.26
(m, 3H), 7.16-7.14 (m, 2H), 5.76 (m, 1H), 5.32 (d, 1H, J )
14.7 Hz), 5.31 (d, 1H, J ) 11.1 Hz), 4.56 (m, 1H), 4.36-4.18
(m, 2H), 3.64 (m, 1H), 2.88 (dd, 1H, J 1 ) 4.8 Hz, J 2 ) 13.5
Hz), 2.66 (dd, 1H, J 1 ) 7.5 Hz, J 2 ) 13.5 Hz), 2.56-2.35 (m,
3H), 2.31-2.19 (m, 3H), 1.28 (t, 3H, J ) 7.2 Hz); 13C NMR (75
MHz, CDCl3) δ 170.3, 138.1, 131.0, 129.1, 128.8, 127.2, 121.8,
64.1, 64.0, 58.0, 43.7, 37.8, 35.5, 34.9, 14.0. HRMS (FAB): calcd
for C17H24NO2 (M + H), 274.1807; found, 274.1806.
(4S,5S)-Nr-ter t-Bu toxyca r bon yl-5-[(3S)-3-ben zoxyca r -
bon yla m in o-3-m eth oxyca r bon ylp r op yl]-4-ben zyl-L-p r o-
lin e Eth yl Ester (8a ). A hydrogenation bottle was charged
with 7 (630 mg, 1.1 mmol) in degassed methanol (15 mL,
HPLC grade) and then was purged with argon for about 15
min, followed by adding [(S,S)-(COD)-Et-DuPHOS Rh(I)]OTf
(1.56 mg, 0.0022 mmol). After five vacuum/hydrogen cycles,
the reaction bottle was pressurized to an initial pressure of
75 psi. The reaction proceeded for 24 h. After evaporation of
solvent, the crude product was purified by flash column
chromatography, eluting with ethyl acetate/hexanes/methylene
chloride (1:6:1) to afford an oil (600 mg, 95%). [R]23 -6.7 (c
D
0.76, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.34-7.21 (m, 8H),
7.13-7.10 (m, 2H), 5.54 (d, 0.4H, J ) 6.6 Hz), 5.46 (d, 0.6H, J
) 6.6 Hz), 5.09 (dd, 2H, J 1 ) 12.6 Hz, J 2 ) 27.6 Hz), 4.41 (t,
0.8H, J ) 8.4 Hz), 4.30-4.24 (m, 1.2 H), 4.19-4.11 (m, 2H),
3.77 (m, 1H), 3.71 (brs, 2H), 3.66 (m, 1H), 2.66-2.45 (m, 2H),
2.18 (m, 1H), 2.03-1.90 (m, 3H), 1.77-1.55 (m, 3H), 1.46 (s,
3.6H), 1.41 (s, 5.4H), 1.22 (t, 3H, J ) 7.2 Hz); 13C NMR (75
MHz, CDCl3) δ 173.5, 173.4, 173.1, 173.0, 156.2, 154.8, 154.2,
139.5, 139.4, 136.6, 136.5, 129.0, 128.6, 128.5, 128.4, 128.22,
128.15, 128.0, 126.5, 80.3, 80.2, 66.9, 66.8, 62.5, 62.2, 61.2, 61.1,
58.6, 58.1, 54.1, 54.0, 52.4, 45.2, 44.2, 39.4, 33.1, 32.5, 30.6,
30.4, 29.1, 28.7, 28.5, 28.4, 14.3, 14.2. HRMS (FAB): calcd for
(4S,5S)-Nr-ter t-Bu toxyca r bon yl-4-ben zyl-5-[(2-oxoeth -
yl)]-L-p r olin e Eth yl Ester (6). Through a solution of 5 (2472
mg, 8.76 mmol) in CH2Cl2 (35 mL) at -78 °C was bubbled O3
until the solution turned purple. After an additional 15 min,
Ar was passed through the reaction mixture until the solution
became colorless. To the above solution was added Me2S (15
mL, 198.8 mmol), and the mixture was stirred at room
temperature under Ar atmosphere for 5 d. After removal of
solvent under reduced pressure, the residue was purified by
flash column chromatography (silica gel, 32 g, 200-400 mesh,
hexanes/ethyl acetate 6:1) to give pure product 6 as a colorless
oil (1500 mg, 63%). [R]22D -22.4 (c 1.50, CHCl3); 1H NMR (500
MHz, CDCl3) δ 9.78 (brs, 1H), 7.30-7.15 (m, 5H), 4.42 (t,
0.33H, J ) 7.5 Hz), 4.27 (t, 0.67H, J ) 7.5 Hz), 4.19-4.07 (m,
3H), 2.99-2.77 (m, 2H), 2.59-2.54 (m, 2H), 2.28 (m, 1H), 2.04-
1.93 (m, 2H), 1.46 (s, 3H), 1.41 (s, 6H), 1.26 (t, 3H, J ) 7.0
Hz); 13C NMR (75 MHz, CDCl3) δ 201.2, 173.2, 173.1, 153.8,
139.2, 129.1, 128.8, 126.8, 126.7, 81.3, 80.7, 61.4, 61.3, 59.1,
58.7, 58.5, 49.1, 48.3, 46.0, 44.8, 39.24, 39.19, 33.3, 32.6, 28.5,
28.4, 14.4, 14.3. HRMS (FAB): calcd for C21H30NO5 (M + H),
376.2124; found, 376.2111.
C
32H43N2O8 (M + H), 583.3019; found, 583.3020.
(4S,5S)-Nr-ter t-Bu toxyca r bon yl-5-[(3R)-3-ben zoxyca r -
bon yla m in o-3-m eth oxyca r bon ylp r op yl]-4-ben zyl-L-p r o-
lin e Eth yl Ester (8b). In a manner similar to the preparation
of 8a , using [(R,R)-(COD)Et-DuPHOS Rh(I)]OTf as a catalyst
gave 8b in 96% yield. [R]22 -13.3 (c 1.64, CHCl3); H NMR
1
D
(500 MHz, CDCl3) δ 7.35-7.12 (m, 8H), 7.13-7.11 (m, 2H),
5.77 (d, 0.4H, J ) 7.5 Hz), 5.47 (d, 0.6H, J ) 7.5 Hz), 5.10 (s,
2H), 4.43-4.39 (t, 0.8H, J ) 8.5 Hz), 4.24-4.32 (m, 1.2H),
4.15-4.09 (m, 2H), 3.79 (m, 1H), 3.72 (s, 0.8H), 3.71 (s, 1.2H),
3.62 (m, 1H), 2.68-2.45 (m, 2H), 2.19 (m, 1H), 2.03-1.89 (m,
3H), 1.76-1.54 (m, 3H), 1.45 (s, 3.6H), 1.42 (s, 5.4H), 1.29-
1.20 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 173.5, 173.4, 173.0,
172.9, 156.3, 156.1, 154.9, 154.4, 139.6, 139.5, 136.6, 136.5,
129.1, 128.7, 128.6, 128.5, 128.3, 128.2, 126.6, 80.4, 67.0, 66.9,
62.7, 62.5, 61.3, 61.2, 58.9, 58.4, 54.3, 53.9, 52.4, 45.2, 44.3,
39.5, 33.1, 32.7, 30.3, 29.1, 28.6, 28.4, 14.4, 14.3. HRMS
(FAB): calcd for
583.3023.
C32H43N2O8 (M + H), 583.3019; found,
(3S,6S,7S,9S)-Eth yl 2-Oxo-3-Nr-(ben zoxyca r bon yl)a m i-
n o-7-ben zyl-1-azabicyclo[4.3.0]n on an e-9-car boxylate (1a).
To a solution of 8a (320 mg, 0.55 mmol) in CH2Cl2 (7.0 mL)
was added TFA (3.0 mL) dropwise at room temperature under
Ar atmosphere, and the mixture was stirred for 2 h. After
removal of the solvent and TFA under reduced pressure, the
residue was dissolved in CH2Cl2 (50 mL), followed by addition
of TEA (0.38 mL, 2.75 mmol). The resulting reaction mixture
was stirred at room temperature under Ar for 5 d. Evaporation
of solvent gave an oil, which was dissolved in ethyl acetate
(80 mL) and then was washed with 1 N HCl aqueous solution
(15 mL) and brine (15 mL). The organic phase was dried over
MgSO4, filtered, and concentrated to give a colorless oil, which
was purified by flash column chromatography (silica gel, 18
(4S,5S)-Nr-ter t-Bu toxyca r bon yl-5-[(Z)-3-ben zoxyca r bo-
n ylam in o-3-m eth oxycar bon ylallyl]-4-ben zyl-L-pr olin e Eth -
yl Ester (7). To a solution of (MeO)2P(O)CH(NHCbz)CO2Me
(1388 mg, 4.19 mmol) in CH2Cl2 (5 mL) at room temperature
was added DBU (0.58 mL, 4.19 mmol) slowly. After ∼10 min,
a solution of 6 (1310 mg, 3.49 mmol) in CH2Cl2 (5 mL) was
added into the above mixture and the resulting mixture was
stirred for 4 h at room temperature under an Ar atmosphere.
The solvent was removed under reduced pressure, and the
residue was dissolved in EtOAc (120 mL). The solution was
washed with 1 N HCl (30 mL) and brine (30 mL), dried over
MgSO4, filtered, and concentrated to give an oil. The crude
product was purified by flash column chromatography (silica
gel, 50 g, 200-400 mesh, hexanes/ethyl acetate/CH2Cl2 5:1:1
then 4:1:1) to give 7 as a clear oil (2020 mg, 100%). [R]22D +34.1
g, 200-400 mesh, EtOAc/hexane 1:4 then 1:2) to give a pure
product (187 mg, 76%). [R]22 -7.9 (c 1.70, CHCl3); H NMR
1
D
1
(500 MHz, CDCl3) δ 7.34-7.12 (m, 10H), 5.83 (d, 1H, J ) 5.5
Hz), 5.10 (s, 2H), 4.47 (d, 1H, J ) 9.0 Hz), 4.18-4.09 (m, 3H),
3.36 (m, 1H), 2.74 (dd, 1H, J 1 ) 6.5 Hz, J 2 ) 13.5 Hz), 2.68
(dd, 1H, J 1 ) 8.0 Hz, J 2 ) 13.5 Hz), 2.41 (m, 1H), 2.07 (dd,
1H, J 1 ) 6.0 Hz, J 2 ) 13.0 Hz), 1.94 (m, 1H), 1.76 (m, 1H),
1.56-1.64 (m, 3H), 1.23 (t, 3H, J ) 7.0 Hz); 13C NMR (75 MHz,
CDCl3) δ 171.6, 168.9, 156.2, 138.9, 136.5, 128.9, 128.7, 128.6,
128.1, 128.0, 126.7, 66.8, 61.5, 61.0, 57.9, 50.5, 47.2, 38.4, 35.2,
27.0, 26.0, 14.1. HRMS (FAB): calcd for C26H31N2O5 (M + H),
451.2233; found, 451.2235.
(c 1.16, CHCl3); H NMR (500 MHz, CDCl3) δ 7.60 (brs, 1H),
7.39-7.23 (m, 8H), 7.14-7.11 (m, 2H), 6.56 (t, 1H, J ) 7.5
Hz), 5.18-5.10 (m, 2H), 4.39 (t, 0.6H, J ) 8.5 Hz), 4.24-4.16
(m, 2.4H), 3.85 (m, 1H), 3.75 (s, 1.2H), 3.72 (s, 1.8H), 2.70 (dd,
0.6H, J 1 ) 7.0 Hz, J 2 ) 14.0 Hz), 2.62-2.46 (m, 3.4H), 2.25
(m, 1H), 2.08-2.01 (m, 2H), 1.41 (s, 3.6H), 1.38 (s, 5.4H), 1.25
(t, 3H, J ) 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 174.3, 174.0,
165.3, 155.1, 154.9, 154.2, 139.3, 136.6, 133.4, 132.5, 129.1,
128.8, 128.7, 128.6, 128.5, 128.3, 128.2, 128.1, 126.8, 126.7,
126.5, 80.8, 67.5, 67.1, 62.4, 62.0, 61.8, 61.5, 59.1, 58.8, 52.3,
45.8, 44.5, 39.4, 34.5, 33.6, 33.5, 32.7, 28.3, 14.4, 14.3. HRMS
(3R,6S,7S,9S)-E t h yl 2-Oxo-3-Nr-(b en zoxyca r b on yl)-
a m in o-7-b en zyl-1-a za b icyclo[4.3.0]n on a n e-9-ca r b oxyl-
a te (1b). In a manner similar to the preparation of 1a ,
(FAB): calcd for
581.2863.
C32H41N2O8 (M + H), 581.2863; found,
6358 J . Org. Chem., Vol. 67, No. 18, 2002

Stereoselective Synthesis of Dipeptide â-Turn Mimetics
compound 8b was treated with TEA in CH2Cl2 to give 1b in
0.67H, J 1 ) 4.2 Hz, J 2 ) 17.1 Hz), 3.13 (dd, 0.33H, J 1 ) 4.5
Hz, J 2 ) 16.8 Hz), 2.82-2.69 (m, 1H), 2.45-2.33 (m, 1H), 2.13-
2.05 (m, 1H), 1.48 (s, 3H), 1.41 (s, 6H), 1.21 (t, 2H, J ) 7.2
Hz), 1.18 (t, 1H, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ
201.1, 172.8, 172.7, 153.6, 153.4, 139.7, 129.0, 127.6, 127.5,
127.3, 81.2, 81.0, 77.4, 66.7, 66.2, 61.4, 61.3, 53.2, 49.4, 48.7,
48.1, 47.3, 39.7, 38.4, 30.0, 28.5, 28.4, 14.4, 14.3. HRMS
(FAB): calcd for C20H28NO5 (M + 1), 362.1967; found, 362.1975.
1
83% yield. [R]22 -36.1 (c 1.80, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 7.33-7.12 (m, 10H), 5.67 (d, 1H, J ) 4.5 Hz), 5.07
(dd, 2H, J 1 ) 12.0 Hz, J 2 ) 25.0 Hz), 4.39 (m, 1H), 4.11 (m,
2H), 3.96 (m, 1H), 3.29 (m, 1H), 2.79 (m, 1H), 2.50 (m, 1H),
2.40 (m, 1H), 2.25 (m, 1H), 1.98-1.78 (m, 4H), 1.56 (m, 1H),
1.21 (t, 3H, J ) 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 171.6,
168.2, 156.5, 138.9, 136.5, 128.9, 128.7, 128.6, 128.1 (2C),
126.6, 66.9, 64.8, 61.3, 57.6, 52.5, 45.4, 37.4, 34.6, 28.3, 26.9,
14.2. HRMS (FAB): calcd for C26H31N2O5 (M + H), 451.2233;
found, 451.2237.
(3R)-Nr-ter t-Bu toxycar bon yl-5-m eth oxy-3-ph en yl-L-pr o-
lin e Eth yl Ester (10). To a solution of 9 (560 mg, 1.68 mmol)
in THF (15 mL) was added Super-Hydride (1.0 M in THF, 2.02
mL) at -78 °C under Ar atmosphere. After the mixture was
stirred for 35 min at -78 °C, it was quenched with saturated
NaHCO3 (3.5 mL) and warmed to 0 °C (∼30 min). Then, to
the above mixture was added 10 drops of 30% H2O2 aqueous
solution at 0 °C, and the resulting mixture was stirred at 0
°C for another 30 min. The reaction mixture was extracted
with diethyl ether (3 × 5 mL) after removing the THF under
reduced pressure. The organic extracts were combined, dried
over MgSO4, filtered, and concentrated under vacuum to give
a colorless oil. To the above obtained oil in MeOH (3.5 mL)
was added p-TsOH‚H2O (32 mg, 0.17 mmol), and the mixture
was stirred at room temperature overnight under Ar atmo-
sphere. After the mixture was quenched with saturated
NaHCO3 (3.5 mL) and the solvent was removed, the reaction
mixture was extracted with diethyl ether (3 × 12 mL). The
combined organic extracts were dried over MgSO4, filtered, and
concentrated under vacuum to give crude 10 as a colorless oil
(528 mg, 90%). HRMS (FAB): calcd for C18H24NO4 (M - MeO),
318.1705; found, 318.1708.
(3R,5S)-Nr-ter t-Bu t oxyca r b on yl-5-[(Z)-3-b en zoxyca r -
b on yla m in o-3-m et h oxyca r b on yla llyl]-3-p h en yl-L-p r o-
lin e Eth yl Ester (13). To a solution of (MeO)2P(O)CH(NHCbz)-
CO2Me (300 mg, 0.830 mmol) in CH2Cl2 (3 mL) at room
temperature was added DBU (0.137 mL, 1.00 mmol) slowly,
and after 10 min, to the solution was added a solution of 12
in CH2Cl2 (3 mL). The mixture was stirred for 6 h at room
temperature under Ar atmosphere. After removal of the
solvent under reduced pressure, the reaction mixture was
dissolved in EtOAc (35 mL), washed with 1 N HCl (10 mL)
and brine (10 mL), dried over MgSO4, filtered, and concen-
trated under reduced pressure to give a solid. The crude
product was purified by flash column chromatography (silica
gel, 15 g, 200-400 mesh, hexane/diethyl ether 1:1) to give 395
mg of the (Z) isomer and 30 mg of the (E) isomer (90% overall
yield, Z/E 13:1). [R]26 +66.5 (c 0.85, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 7.72 (s, 0.4H), 7.60 (s, 0.6H), 7.39-7.22 (m,
10H), 6.67 (dd, 1H, J 1 ) 7.2 Hz, J 2 ) 9.0 Hz), 5.24-5.11 (m,
2H), 4.34 (d, 0.4H, J ) 9.6 Hz), 4.30-4.21 (m, 2H), 4.17 (d,
0.6H, J ) 9.3 Hz), 4.11-4.03 (m, 1H), 3.73 (brs, 3H), 3.59-
3.48 (m, 1H), 2.88-2.75 (m, 1H), 2.49-2.23 (m, 2H), 2.08 (d,
0.6H, J ) 6.3 Hz), 2.05 (d, 0.4H, J ) 6.3 Hz), 1.41 (s, 3.6H),
1.36 (s, 5.4H), 1.14 (t, 1.8H, J ) 7.2 Hz), 1.11 (t, 1.2H, J ) 7.2
Hz); 13C NMR (75 MHz, CDCl3) δ 173.9, 173.7, 165.4, 155.1,
155.0, 154.3, 153.9, 139.4, 139.1, 136.6, 133.5, 132.7, 128.9,
128.8, 128.7, 128.6, 128.3, 128.1, 128.0, 127.7, 127.6, 127.5,
127.4, 81.0, 80.9, 77.4, 75.3, 67.1, 67.0, 66.7, 61.7, 61.5, 57.4,
57.2, 48.7, 47.8, 40.3, 38.6, 34.8, 34.3, 28.3, 28.2, 14.3, 14.2.
HRMS (FAB): calcd for C31H39N2O8 (M + H), 567.2706; found,
567.2707.
(3R,5S)-Nr-ter t-Bu toxyca r bon yl-5-a llyl-3-p h en yl-L-p r o-
lin e Eth yl Ester (11). To a solution of crude 10 (420 mg, 1.20
mmol) in Et2O (5 mL) were added allyltrimethylsilane (0.861
mL, 5.42 mmol) and BF3‚Et2O (0.15 mL, 1.24 mmol) at -40
°C under Ar atmosphere. Then, the cold bath was removed
and the reaction mixture was stirred for 30 min. After the
reaction mixture was diluted with Et2O (4 mL) and quenched
with NaHCO3 (4 mL), it was extracted with diethyl ether (3
× 6 mL). The organic extracts were combined, dried over
MgSO4, filtered, and concentrated under vacuum to give the
crude product as a slightly yellow oil. Purification of the crude
product by flash column chromatography (silica gel, 15 g, 200-
400 mesh, hexane/diethyl ether 1:1) gave pure product 11 as
a colorless thick oil (350 mg, 82%, and 74% overall yield from
(3R,5S)-Nr-ter t-Bu toxycar bon yl-4-ph en yl-5-[(3S)-3-ben z-
oxyca r b on yla m in o-3-m e t h oxyca r b on ylp r op yl]-L-p r o-
lin e Eth yl Ester (14a ). To a solution of 13 (140 mg, 0.247
mmol) in degassed MeOH (10 mL, HPLC grade) at room
temperature was added Rh(I)(COD)(S,S)-Et-DuPHOS (0.4 mg,
0.0005 mmol, 0.2 mol %). After five cycles of vacuum/H2, the
reaction was pressed at an initial H2 pressure of 75 psi at room
temperature. After 24 h, the solvent was removed under
reduced pressure and the residue was passed through a short
silica gel column (200-400 mesh, 12 g), eluting with EtOAc/
hexane (1:1) to remove the catalyst. The product was pure
enough for the next step reaction as a colorless oil (143 mg,
100%). [R]23D +31.8 (c 0.56, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.36-7.21 (m, 10H), 5.87 (d, 0.6H, J ) 7.8 Hz), 5.53 (d, 0.4H,
J ) 7.5 Hz), 5.12 (s, 2H), 4.43-4.33 (m, 1H), 4.20-3.97 (m,
4H), 3.75 (s, 1H), 3.73 (s, 2H), 3.52-3.43 (m, 1H), 2.25-2.14
(m, 1H), 2.05-1.82 (m, 4H), 1.62-1.54 (m, 1H), 1.45 (s, 3.6H),
1.40 (s, 5.4H), 1.17 (t, 1.8H, J ) 7.2 Hz), 1.14 (t, 1.2H, J ) 7.2
Hz); 13C NMR (75 MHz, CDCl3) δ 172.8, 172.7, 156.1, 153.8,
139.9, 139.6, 136.4, 136.2, 128.7, 128.4, 128.0, 127.9, 127.3,
127.2, 80.4, 66.8, 66.1, 60.9, 60.3, 57.8, 57.5, 54.2, 53.7, 52.2,
48.1, 47.2, 39.2, 38.3, 31.0, 30.4, 29.3, 28.7, 28.3, 14.1. HRMS
9). [R]24 +62.0 (c 1.25, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
7.35-7.23 (m, 5H), 5.92-5.79 (m, 1H), 5.13 (d, 1H, J ) 17.0
Hz), 5.07 (d, 1H, J ) 10.2 Hz), 4.34-4.00 (m, 4H), 3.51 (q, 1H,
J ) 9.0 Hz), 2.82-2.67 (m, 1H), 2.40-2.30 (m, 1H), 2.18-2.13
(m, 2H), 1.49 (s, 3H), 1.41 (s, 6H), 1.19 (t, 3H, J ) 7.2 Hz); 13
C
NMR (75 MHz, CDCl3) δ 173.0, 154.2, 153.6, 140.2, 139.9,
135.5, 128.9, 127.5, 117.4, 80.5, 80.4, 77.4, 67.1, 66.5, 61.2, 61.1,
58.1, 57.9, 48.2, 47.3, 39.3, 38.6, 38.2, 28.6, 28.5, 14.4, 14.3.
HRMS (FAB): calcd for C21H30NO4 (M + H), 360.2175; found,
360.2170.
(3R,5S)-Nr-ter t-Bu toxycar bon yl-3-ph en yl-5-(2-oxoeth yl)-
L-p r olin e Eth yl Ester (12). A solution of 11 (373 mg, 1.04
mmol) in CH2Cl2 (10 mL) at -78 °C was bubbled with O3 until
the solution turned purple. Then, after an additional 15 min,
Ar was passed through the reaction mixture to get rid of excess
O3. To the above obtained solution was added Me2S (4.60 mL,
62.3 mmol), and the mixture was stirred at room temperature
under Ar atmosphere for 5 d. After removal of the solvent
under reduced pressure, flash column chromatography (silica
gel, 13 g, 200-400 mesh, hexane/diethyl ether 1:1) of the crude
(FAB): calcd for
569.2858.
C31H41N2O8 (M + H), 569.2863; found,
(3R,5S)-Nr-ter t-Bu toxycar bon yl-4-ph en yl-5-[(3R)-3-ben z-
oxyca r b on yla m in o-3-m e t h oxyca r b on ylp r op yl]-L-p r o-
lin e Eth yl Ester (14b). To a solution of 13 (110 mg, 0.194
mmol) in degassed MeOH (8 mL, HPLC grade) at room
temperature was added Rh(I)(COD)-(R,R)-Et-DuPHOS (0.3
mg, 0.0004 mmol, 0.2 mol %). After five cycles of vacuum/H2,
the reaction was pressed at an initial H2 pressure of 75 psi at
room temperature. After 24 h, the solvent was removed under
reduced pressure and the residue was passed through a short
silica gel column (200-400 mesh, 10 g), eluting with EtOAc/
product gave pure 12 as a colorless oil (304 mg, 81%). [R]24
D
+54.5 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.86 (brs,
1H), 7.35-7.22 (m, 5H), 4.57-4.46 (m, 1H), 4.39 (d, 0.33H, J
) 7.5 Hz), 4.24 (d, 0.67H, J ) 7.5 Hz), 4.21-4.10 (m, 2H), 3.49
(t, 0.33H, J ) 7.5 Hz), 3.46 (t, 0.67H, J ) 7.5 Hz), 3.25 (dd,
J . Org. Chem, Vol. 67, No. 18, 2002 6359

Wang et al.
hexane (1:1) to remove the catalyst. The product was pure
enough for the next reaction step as a colorless oil (110 mg,
100%). [R]22D +39.7 (c 1.10, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 7.37-7.22 (m, 10H), 5.59 (d, 0.6H, J ) 7.5 Hz), 5.51 (d, 0.4H,
J ) 7.5 Hz), 5.12 (m, 2H), 4.40-4.36 (m, 1H), 4.20-4.02 (m,
4H), 3.75 (s, 3H), 3.51-3.44 (m, 1H), 2.23-2.17 (m, 1H), 2.03-
1.79 (m, 4H), 1.64-1.58 (m, 1H), 1.47 (s, 3.6H), 1.40 (s, 5.4H),
1.16 (t, 1.8H, J ) 7.0 Hz), 1.13 (t, 1.2H, J ) 7.0 Hz); 13C NMR
(75 MHz, CDCl3) δ 173.2, 173.1, 156.3, 154.3, 153.9, 140.3,
140.0, 136.6, 128.9, 128.6, 128.1, 127.5, 127.4, 80.5, 77.4, 75.3,
67.0, 66.9, 66.2, 61.1, 57.8, 57.6, 54.1, 54.0, 52.5, 48.3, 47.5,
39.7, 38.5, 30.9, 29.8, 29.6, 29.3, 28.5, 28.4, 14.4. HRMS
(3R,6S,8R,9S)-Eth yl 2-Oxo-3-N-(ben zoxyca r bon yl)a m i-
n o-7-ben zyl-1-azabicyclo[4.3.0]n on an e-9-car boxylate (1d).
To a solution of 14b (50 mg, 0.088 mmol) in CH2Cl2 (3.5 mL)
was added TFA (1.5 mL) dropwise at room temperature under
an Ar atmosphere, and the mixture was stirred for 1 h. After
removal of the solvent and TFA, a slightly yellow oil was
obtained. To a solution of the residue in CH2Cl2 (15 mL) was
added Et3N (0.086 mL, 0.62 mmol), and the reaction mixture
was stirred at room temperature under an Ar atmosphere for
6 d. After removal of solvent under reduced pressure, the
residue was dissolved in EtOAc (10 mL), and the solution was
washed with 1 N HCl (2 × 5 mL) and brine (5 mL), dried over
MgSO4, filtered, and concentrated to give a colorless oil (40
mg), which was purified by flash column chromatography
(FAB): calcd for
569.2852.
C31H41N2O8 (M + H), 569.2863; found,
(3S,6S,8R,9S)-Eth yl 2-Oxo-3-N-(ben zoxyca r bon yl)a m i-
n o-7-ben zyl-1-azabicyclo[4.3.0]n on an e-9-car boxylate (1c).
To a solution of 14a (120 mg, 0.211 mmol) in CH2Cl2 (3.5 mL)
was added TFA (1.5 mL) dropwise at room temperature under
Ar atmosphere, and the mixture was stirred for 1 h. After
removal of the solvent and TFA, a slightly yellow oil was
obtained. To a solution of the residue in CH2Cl2 (30 mL) was
added Et3N (0.210 mL, 1.48 mmol), and the reaction mixture
was stirred at room temperature under Ar atmosphere for 6
d. After removal of the solvent under reduced pressure, the
residue was dissolved in EtOAc (20 mL), and the solution was
washed with 1 N HCl (2 × 10 mL) and brine (10 mL), dried
over MgSO4, filtered, and concentrated to give a colorless oil,
which was purified by flash column chromatography (silica gel,
35 g, 200-400 mesh, EtOAc/hexane 1:4) to give a pure product
(80 mg, 87%). [R]23D +111.7 (c 1.16, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.37-7.19 (m, 10H), 5.57 (brs, 1H), 5.11 (m, 2H), 4.72
(s, 1H), 4.29-4.15 (m, 2H), 4.13-4.04 (m, 1H), 3.86-3.75 (m,
1H), 3.51 (d, 1H, J ) 7.5 Hz), 2.53-2.48 (m, 1H), 2.24-2.13
(m, 1H), 2.08-2.00 (m, 2H), 1.94-1.66 (m, 2H), 1.27 (t, 3H, J
) 7.5 Hz); 13C NMR (75MHz, CDCl3) δ 171.2, 168.3, 156.4,
142.1, 136.3, 128.8, 128.4, 127.9 (two overlapped peaks, 127.89
and 127.93), 127.0, 126.6, 66.7, 64.2, 61.4, 54.8, 52.4, 45.8, 39.0,
28.6, 27.6, 14.1. HRMS (FAB): calcd for C25H29N2O5 (M + H),
437.2076; found, 437.2086.
(silica gel, 15 g, 200-400 mesh, EtOAc/hexane 1:4) to give a
1
pure product (36 mg, 83%). [R]23 +117.0 (c 0.52, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 7.37-7.15 (m, 10H), 5.87 (d, 1H, J
) 6.4 Hz), 5.12 (s, 2H), 4.70 (s, 1H), 4.33-4.19 (m, 3H), 3.87-
3.84 (m, 1H), 3.58 (d, 1H, J ) 7.2 Hz), 2.59-2.49 (m, 1H),
2.30-2.04 (m, 3H), 1.86-1.66 (m, 2H), 1.29 (t, 3H, J ) 7.2
Hz); 13C NMR (75 MHz, CDCl3) δ 171.1, 168.9, 156.1, 141.7,
136.4, 128.9, 128.4, 128.0, 127.9, 127.2, 126.3, 66.7, 64.2, 61.6,
54.7, 50.4, 46.6, 39.5, 27.0, 26.7, 14.1. HRMS (FAB): calcd for
C25H29N2O5 (M + H), 437.2076; found, 437.2072.
Ack n ow led gm en t. This work was supported by the
U.S. Public Health Service (DK 17420) and the National
Institute of Drug Abuse (DA 13449 and DA 12394). We
also thank Professor Dominic V. McGrath for the use
of his group’s polarimeter. The views expressed are
those of the authors and not necessarily those of the
USPHS.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
1a -d , 3, 5, 5a , 6, 7, 8a ,b, 11, 12, 13, and 14a ,b. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O0203591
6360 J . Org. Chem., Vol. 67, No. 18, 2002