Amino-zinc-enolate carbometalation reactions: Application to ring closure of terminally substituted olefin for the asymmetric synthesis of cis- and trans-3-prolinoleucine

Article abstract of DOI:10.1021/jo026535n

The amino-zinc-enolate cyclization reaction is a straightforward route for the synthesis of 3-substituted prolines. As classical intramolecular carbometalation reactions, the applicability of the addition of zinc to a double bond was limited to a substrat

Full text of DOI:10.1021/jo026535n

Am in o-Zin c-En ola te Ca r bom eta la tion Rea ction s: Ap p lica tion to
Rin g Closu r e of Ter m in a lly Su bstitu ted Olefin for th e Asym m etr ic
Syn th esis of cis- a n d tr a n s-3-P r olin oleu cin e
Philippe Karoyan,*,† J ean Quancard,† and J acqueline Vaissermann,‡ and Ge´rard Chassaing†
UMR CNRS 7613, Structure et Fonction de Mole´cules Bioactives, Universite´ Paris VI, case 45,
4 place J ussieu 75252 Paris Cedex 05, France, and URA CNRS 400, Chimie des Me´taux de Transition,
Universite´ Paris VI, case 42, 4 place J ussieu 75252 Paris cedex 05, France
karoyan@ccr.jussieu.fr
Received October 8, 2002
The amino-zinc-enolate cyclization reaction is a straightforward route for the synthesis of
3-substituted prolines. As classical intramolecular carbometalation reactions, the applicability of
the addition of zinc to a double bond was limited to a substrate in which the terminal alkene carbon
was unsubstituted. Being interested in the synthesis of cis- and trans-3-prolinoleucine derivatives
for our structure-activity relation (SAR) studies, we focused our effort on the preparation of these
compounds by amino-zinc-enolate cyclization of terminally substituted double bonds. Herein we
report that the attachment of an activating group such as cyclopropyl to the terminal olefin carbon
allows the amino-zinc-enolate cyclization of a terminally substituted alkene. The reaction is
stereospecific, leading to a trans-3-substituted proline derivative, whereas a cis stereochemistry
was observed with the amino-zinc-enolate cyclization of terminally nonsubstituted olefins. Absolute
configurations obtained for the 3-prolinoleucine were established by X-ray analysis, NMR, and
optical activity comparison of the cis and trans derivatives obtained by an unambiguous pathway.
In tr od u ction
(such as tachykinins,6 bradykinins,7 opioid peptides,8
cholecystokinin,9 angiotensin I,I10 and PLG11) and have
served in the development of enzyme inhibitors.12 Fur-
thermore, functionalized pyrrolidine rings derived from
proline have also been viewed as constrained non-peptide
â-turn mimetics,13 as peptidomimetics with improved
The anionic cyclization of olefinic alkylmetals provides
a regiospecific and highly stereoselective route to func-
tionalized carbocycles.1 The reactivity of the organome-
tallic species, concerning the nature of both metals
(lithium, magnesium, aluminum, ...) and olefin (termi-
nally substituted or unsubstituted, activated or unacti-
vated), is well documented.2 Recently, the carbocycliza-
tion of stabilized carbanion has been studied.3 In this last
example, the difficulty for the reaction to occur may be
due to an endothermic process (involving the conversion
of a stabilized enolate anion to an unstabilized sp3 or sp2
carbanion) associated with the nature of the alkene or
alkyne (substituted or unsubstituted). Among these reac-
tions, the amino-zinc-enolate cyclization, which we
reported,4 allows the synthesis of cis-3-substituted pro-
lines. These molecules are chimeras combining the amino
acid side chain functionality with proline conformational
rigidity.5 They are used as probes in structure-activity
relationship (SAR) studies of biologically active peptides
(6) Sagan, S.; Karoyan, Ph.; Chassaing, G.; Lavielle, S. J . Biol.
Chem. 1999, 34, 23770.
(7) Kaczmarek, K.; Li, K.-M.; Skeean, R.; Dooley, D.; Humblet, C.;
Lunney, E.; Marshall, G. R. In Peptides: Chemistry, Structure and
Biology; Hodges, R. S., Smith, J . A., Eds.; ESCOM Science Publishers
B. V.: Leiden, The Netherlands, 1994; p 687.
(8) (a) Mosberg, H. I.; Kroona, H. J . Med. Chem. 1992, 35, 4498. (b)
Mosberg, H. I.; Lomize, A. L.; Wang, C.; Kroona, H.; Heyl, D. L.;
Sobczyk-Kojiro, K.; Ma, W.; Mousigian, C.; Porreca, F. J . Med. Chem.
1994, 37, 4371. (c) Nelson, R. D.; Gottlieb, D. I.; Balasubramanian, T.
M.; Marshall, G. R. In Opioid Peptides: Medicinal Chemistry; NIDA
Research Monograph 69; Rapaka, R. S. R. S., Barnett, G., Hawks, R.
L., Eds.; 1986; p 204.
(9) (a) Holladay, M. W.; Lin, C. W.; May, C. S.; Garvey, D. S.; Witte,
D. G.; Miller, T. R.; Wolfram, C. A. W.; Nadzan, A. M. J . Med. Chem.
1991, 34, 457. (b) Tilley, J . W.; Danho, W.; Madison, V.; Fry, D.;
Swistok, J .; Makofske, R.; Michalewsky, J .; Schwartz, A.; Weatherford,
S.; Triscari, J .; Nelson, D. J . Med. Chem. 1992, 35, 4249. (c) Kolodziej,
S. A.; Nikiforovitch, G. V.; Skeean, R.; Lignon, M.-F.; Martinez, J .;
Marshall, G. R. J . Med. Chem. 1995, 38, 137.
† UMR CNRS 7613, Structure et Fonction de Mole´cules Bioactives.
‡ URA CNRS 400, Chimie des Me´taux de Transition.
(1) Bailey, W. F.; Gavaskar, K. B. Tetrahedron. 1994, 20, 5957.
(2) Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J .-F. J . Org.
Chem. 1995, 60, 863 and references therein.
(10) (a) Marshall, G. R. Tetrahedron 1993, 49, 3547. (b) Plucinska,
H.; Kataoka, T.; Yodo, M.; Cody, W. L.; He, J . X.; Humblet, C.; Lu, G.
H.; Lunney, E.; Major, T. C.; Panek, R. L.; Schelkun, P.; Skeean, R.;
Marshall, G. R. J . Med. Chem. 1993, 36, 1902.
(3) Kitagawa, O.; Suzuki, T.; Inoue, T.; Wtanabe, Y.; Taguchi, T. J .
Org. Chem. 1998, 63, 9470.
(11) Evans, M. C.; J ohnson, R. L. Tetrahedron 2000, 56, 9801.
(12) (a) Ghose, A. K.; Logan, M. E.; Treasurywala, A. M.; Wang, H.;
Wahl, R. C.; Tomczuk, B. E.; Gomrawaram, M. R.; J aeger, E. P.;
Wendoloski, J . J . J . Am. Chem. Soc. 1995, 117, 4671. (b) Hutton, J . J .,
J r.; Marglin, A.; Witkop, B.; Kurtz, J .; Berger, A.; Udenfriend, S. Arch.
Biochem. Biophys. 1968, 125, 779.
(4) (a) Karoyan, Ph.; Chassaing, G. Tetrahedron Lett. 1997, 38, 85.
(b) Lorthiois, E.; Marek, I.; Normant, J .-F. Tetrahedron Lett. 1997, 38,
89. (c) Karoyan, Ph.; Chassaing, G. Tetrahedron: Asymmetry 1997, 8,
2025. (d) Karoyan, Ph.; Chassaing, G. Tetrahedron Lett. 2002, 43, 2,
253. (e) Karoyan, Ph.; Chassaing, G. Tetrahedron Lett. 2002, 43, 1221.
(5) Sharma, R.; Lubell, W. D. J . Org. Chem. 1996, 61, 202.
(13) Horwell, D. C.; Naylor, D.; Willems, H. M. G. BioMed. Chem.
Lett. 1997, 7, 31.
10.1021/jo026535n CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/13/2003
2256
J . Org. Chem. 2003, 68, 2256-2265

Amino-Zinc-Enolate Carbometalation Reactions
SCHEME 1
bioactivity and metabolic stability,8-10 and as scaffold to
build up low molecular weight primary screening librar-
ies.14 Several approaches have been developed for the
synthesis of 3-substituted prolines involving inter- or
intramolecular cyclization, or functionalization of a pro-
line derivative.15-55 Some of them provide access to
enantiopure 3-prolinoamino acids in quantities suitable
for peptide synthesis. However, the functionalization is
often limited to side chains that do not really mimic the
side chain of natural amino acids. In the course of our
peptide SAR studies using 3-substituted prolines, we
were interested in the preparation of (2S,3S) and (2S,3R)-
prolinoleucines. Three pathways (namely A, B, and C)
have been explored for the synthesis of these probes
(Scheme 1). Pathways A and B are based on the amino-
zinc-enolate cyclization of R,â,â-trisubstituted hindered
olefins, involving the conversion of a secondary stabilized
carbanion to a tertiary unstabilized organometallic spe-
cies. Pathway C is based on the dialkylation of a chiral
sulfone, which we described recently.4e Here, we report
our results with a complete study of the stereochemistry
of these 3-prolinoleucines.
(14) (a) Murphy, M. M.; Schullek, J . R.; Gordon, E. M.; Gallop, M.
A. J . Am. Chem. Soc. 1995, 117, 7029. (b) Karoyan, Ph.; Triolo, A.;
Nannicini, R.; Giannotti, D.; Altamura, M.; Chassaing, G.; Perrotta,
E. Tetrahedron Lett. 1999, 40, 71.
(15) Moc, O. A.; Warner, D. T. J . Am. Chem. Soc. 1948, 70, 2763.
(16) Moc, O. A.; Warner, D. T. J . Am. Chem. Soc. 1949, 71, 2586.
(17) Sanno, J . J . Pharm. Soc. 1958, 78, 1113.
(18) Osugi, K. Yakugaku Zasshi 1958, 78, 1361; Chem. Abstr. 1959,
53, 8113d.
(19) Gershon, H.; Scala, A. J . Org. Chem. 1961, 26, 2347.
(20) J ackson, A. H.; Kenner, G. W.; Terry, W. G. Tetrahedron Lett.
1962, 20, 921.
(21) Cox, D. A.; J ohnson, A. W.; Mauger, A. B. J . Chem. Soc. 1964,
5024.
Resu lts a n d Discu ssion
(22) Mauger, A. B.; Irreverre, F.; Witkop, B. J . Am. Chem. Soc. 1966,
88, 2019.
P a th w a y A. It is well-known that the common orga-
nometallic (Li, Mg) reagents decrease in stability in the
order Me > primary alkyl > secondary alkyl > tertiary
alkyl56 and that the isomerization of linear to cyclic
organometallic species implies a thermodynamically
favored process.1 Thus, the synthesis of prolinoleucine
via amino-zinc-enolate cyclization of R,â,â-trisubsti-
tuted olefins seems not to be thermodynamically favored.
However, while the simple amino-lithium-enolate car-
bocyclization of R-substituted olefin was not observed, the
transmetalation of the lithium enolate by zinc salts
(23) Kollonitsch, J .; Scott, A. N.; Doldouras, G. A. J . Am. Chem. Soc.
1966, 88, 3624.
(24) Sarges, R.; Tretter, J . R. J . Org. Chem. 1974, 39, 1710.
(25) Ha¨usler, J .; Schmidt, U. Liebigs. Ann. Chem. 1979, 1881.
(26) Titouani, S. L.; Lavergne, J .-P.; Viallefont, Ph. Tetrahedron
1980, 36, 2961.
(27) Ha¨usler, J . Liebigs. Ann. Chem. 1981, 1073.
(28) Mooiver, H. H.; Hiemstra, H.; Fortgens, H. P.; Speckamp, W.
N. Tetrahedron Lett. 1987, 28, 3285.
(29) Yoo, S. E.; Lee, S. H.; Kim, N. J . Tetrahedron Lett. 1988, 29,
2195.
(30) Belokon, Y. N.; Bulychev, A. G.; Pavlov, V. A.; Fedorova, E. B.;
Tsyryapkin, V. A.; Bakhmutov, V. A.; Belikov, V. M. J . Chem. Soc.,
Perkin Trans. 1 1988, 2075.
(31) Chung, J . Y. L.; Wasicak, J . T.; Arnold, W. A.; May, C. S.;
Nadzan, A. M.; Holladay, M. W. J . Org. Chem. 1990, 55, 270.
(32) Esch, P. M.; Hiemstra, H.; de Boer, R. F.; Speckamp, W. N.
Tetrahedron Lett. 1990, 31, 759.
(44) Carpes, M. J .; Miranda, P. C. M.; Correia, C. R. D. Tetrahedron
Lett. 1997, 38, 1872.
(33) Langlois, N.; Andriamialisoa, R. Z. Tetrahedron Lett. 1991, 32,
3057.
(34) Mosberg, H. I.; Kroona, H. B. J . Med. Chem. 1992, 35, 4498.
(35) Moss, W. O.; J ones, A. C.; Wisedale, R.; Mahon, M. F.; Molloy,
K. C.; Bradbury, R. H.; Hales, N. J .; Gallagher, T. J . Chem. Soc., Perkin
Trans. 1 1992, 2615.
(45) Reference 5.
(46) Reference 9a.
(47) Sasaki, N. A.; Dockner, M.; Chiaroni, A.; Riche, C.; Potier, P.
J . Org. Chem. 1997, 62, 765.
(48) Blanco, M.-J .; Paleo, M. R.; Penide, C.; Sardina, F. J . J . Org.
Chem. 1999, 64, 8786.
(36) Garner, P.; Ozdemir, D. J . Org. Chem. 1994, 59, 4.
(37) Humphrey, J . M.; Bridges, R. J .; Hart, J . A.; Chamberlin, A.
R. J . Org. Chem. 1994, 59, 2467.
(38) Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahedron: Asym-
metry 1994, 5, 351.
(49) Damour, D.; Doerflinger, G.; Pantel, G.; Labaudinie`re, R.;
Leconte, J .-P.; Sable´, S.; Vuilhorgne, M.; Mignani, S. Synlett 1999, 2,
189.
(50) Mamai, A.; Hughes, N. E.; Wurthmann, A.; Madalengoita, J .
S. J . Org. Chem. 2001, 66, 6483.
(39) Udding, J . H.; Tuijp, J . M.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron Lett. 1994, 6, 1907.
(40) Udding, J . H.; Tuijp, J . M.; Hiemstra, H.; Speckamp, W. N. Bull.
Soc. Chim. Belg. 1994, 103, 329.
(41) Baldwin, J . E.; Adlington, R. M.; Gollins, D. W.; Godfrey, C. R.
A. Tetrahedron 1995, 51, 5169.
(42) Cotton, R.; J ohnston, A. N. C.; North, M. Tetrahedron 1995,
51, 8525.
(51) Duan, S.; Moeller, K. D. Tetrahedron 2001, 57, 6407.
(52) Kamenecka, T. M.; Park, Y.-J .; Lin, L. S.; Lanza, T., J r.;
Hagmann, W. K. Tetrahedron Lett. 2001, 42, 8571.
(53) Laabs, S.; Muˆnch, W.; Bats, J . W.; Nubbemeyer, U. Tetrahedron
2002, 58, 1317.
(54) Pellegrini, N.; Schmitt, M.; Guery, S.; Bourguignon, J .-J .
Tetrahedron Lett. 2002, 43, 3243.
(55) Flament-Robin, C.; Wang, Q.; Chiaroni, A.; Sasaki, A. Tetra-
hedron 2002, 58, 10475.
(56) Harvey, J . N.; Viehe, H. G.; J . Prakt. Chem. 1995, 337, 253.
(43) Waid, P. P.; Flynn, G. A.; Huber, E. W.; Sabol, J . S. Tetrahedron
Lett. 1996, 24, 4091.
J . Org. Chem, Vol. 68, No. 6, 2003 2257

Karoyan et al.
SCHEME 2
SCHEME 3
resulted in a nearly quantitative cyclization.4a The par-
ticular reactivity of zinc-enolate led us to explore the
scope of the amino-zinc-enolate carbometalation.
The starting material was prepared by N-alkylation
of N-(S)-R-methylbenzylglycine ethyl ester57 1 with 5-iodo-
2-methyl-2-pentene58 in dry DMSO with a moderate yield
(Scheme 2). All attempts for cyclization of olefin 2 (Et2O
or THF, -78 °C, LDA, ZnBr2, room temperature to reflux)
failed and the starting material was recovered after
hydrolysis of the reaction mixture. These results can be
explained by an endothermic process involving the
conversion of a secondary stabilized enolate anion to a
tertiary unstabilized, hindered, sp3 carbanion.
lowed by a subsequent alkylation with bromoacetate
esters (benzyl or ethyl) led to compound 5.
Compound 5 was metalated with LDA in Et
2O at -78
°C (Scheme 3) and no cyclization of the corresponding
lithium-enolate was observed since hydrolysis of the
reaction mixture produced the starting olefin. However,
the addition of 3 equiv of ZnBr2 at -78 °C resulted in a
regio- and diastereoselective cyclization reaction, leading
after hydrolysis to compound 7, as a single diastereoiso-
mer with a 68% yield. The cyclopropyl ring opening
(which should allow the conversion of a tertiary, hin-
dered, unstabilized, organometallic species to a primary
one) is not observed. The simple relief of strain around
the link between the π-system and the cyclopropyl group
provides a potent thermodynamic force associated with
this amino-zinc-enolate cyclization process. The higher
reactivity of the cyclopropylethylene derivative 5 com-
pared to the 1,1-dialkylethylene derivative 2 may simply
reflect a decrease in angle strain of the cyclopropylidene
system along the reaction coordinate.
These findings led us to explore the activation of
the substituted olefin toward nucleophilic attack via
pathway B.
P a th w a y B. Some studies have been reported on the
attachment of moderately activating groups to olefins for
carbocyclization59 and it has been shown that the cyclo-
propyl moiety in contrast with the isopropyl moiety
exhibits a higher reactivity in 1,3-dipolar cycloadditions
when linked to double bonds.60 This group was suitable
as it has the required structure for the prolinoleucine and
the starting materials were obtained as described in
Scheme 3. Alkylation of (S)-R-methylbenzylamine with
1-tosyloxy-3-cyclopropylidene propane61 3 in DMF fol-
The unexpected relative trans stereochemistry of the
oily compound 7 was first established by using standard
1H, 13C, and COSY NMR techniques and by differential
nuclear Overhauser effects on the fully deprotected
proline derivative 8, obtained by hydrogenolysis over
palladium charcoal (Scheme 4). Indeed, if poor informa-
3
tion was given by J (R-â) (6.4 Hz), no NOE effect was
observed between HR and Hâ, whereas a strong NOE
effect was observed between HR and Hꢀ. The relative
trans stereochemistry was also supported by epimerisa-
(57) Porzi, G.; Sandri, S.Tetrahedron: Asymmetry 1996, 7, 189.
(58) Biernacki, W.; Gdula, A. Synthesis 1979, 37.
(59) (a) Bailey, W. F.; Gavaskar, K. V. Tetrahedron 1994, 50, 5957.
(b) Fournet, G.; Balme, G.; Barieux, J .-J .; Gore, J . Tetrahedron 1988,
44, 5821.
(60) Brandi, A.; Cordero, F. M.; De Sarlo, F. Tetrahedron. 1992, 48,
3323 and references therein.
(61) Zefirov, N, S.; Kozhushkov, S. I.; Kuznetsova, T.S; Lukin, K.
A.; Kazimirchik, I. V. J . Org. Chem. USSR 1988, 4, 605.
2258 J . Org. Chem., Vol. 68, No. 6, 2003

Amino-Zinc-Enolate Carbometalation Reactions
SCHEME 4
SCHEME 5a
a
Reagents and conditions: (i) THF, -78 °C, LDA, ZnBr2, -78 °C to rt, then CuCN/2LiCl, PhSSO2Ph, 74%. (ii) CH2Cl2, THF (4 equiv),
mCpBA (2 equiv), 80%. (iii) THF/DMPU (3/1), -78 °C, LDA, CH3I, 93%. (iv) THF/DMPU (3/1), -78 °C, LDEA, CH3I, 68%. (v) MeOH,
Na/Hg (4 equiv), KH2PO4 (3 equiv), 82%. (vi) H2/PdC, MeOH, Boc2O, 91%.
tion assays of compound 10 obtained from 7b after
removal of the chiral auxiliary over palladium charcoal
in the presence of Boc2O. Considering that the cis
derivative should epimerise toward the more stable trans
isomer in the presence of a base, 10 was treated with
LDA and the reaction mixture was quenched by a
saturated NH4Cl solution at room temperature. In these
conditions, the derivative 10 was recovered unchanged
confirming the supposed trans configuration.
Despite several attempts, crystallization of compound
7 failed and even though the reaction led to one stereo-
isomer with a trans relative stereochemistry, we have
not been successful in the determination of the absolute
configurations of the newly created chiral centers.
P a th w a y C. To determine the absolute configurations
of the chiral centers created during the cyclization
process, we focused our effort on the synthesis of cis- and
trans-prolinoleucines via an unambiguous pathway based
on dialkylation of a chiral sulfone62 obtained through the
amino-zinc-enolate cyclization of R-substituted olefin
(Scheme 5). The thioether 12 was obtained in a “one-pot”
procedure starting from olefin 11,4c which was subjected
to amino-zinc-enolate cyclization. The cyclic organozinc
compound was then reacted with PhSSO2Ph63 after a new
transmetalation step with the THF-soluble CuCN salts,64
leading to compound 12 as a single isomer. The thioether
12 was then oxidized to the sulfone 13 by mCpBA (2
equiv) in the presence of TFA (4 equiv) to avoid N-
oxidation. This general precursor has the (2S,3R) con-
figuration as previously demonstrated by hydrolysis of
the zinc derivative.4a Compound 13 presents three po-
tentially acidic centers (Scheme 5), namely hydrogens 2,
6, and 7. Deuterium incorporation experiments have
shown that at -78 °C, the most acidic center was in
position 7, the steric hindrance of the chiral auxiliary on
the nitrogen preventing abstraction of the proton 2, R to
the ester function. After deprotonation with LDA at -78
°C, the sulfone 13 was cleanly monoalkylated in position
7 with methyliodide, creating a new chiral center with
poor diastereoselectivity (65/35), leading to derivative 14.
The second alkylation, which could only be achieved
by changing LDA with LDEA, a less hindered base, led
cleanly to the crystalline derivative 15 when the tem-
perature was kept strictly at -78 °C. Otherwise, a
mixture of diastereoisomers was obtained when the
temperature was brought to room temperature before the
addition of the electrophile. The structure and absolute
(62) The anion stabilizing properties of sulfonyl groups have been
extensively exploited in organic synthesis, for references see: Simp-
king, N. S. Sulfone in Organic Syntheses; Pergamon: Oxford, UK, 1993.
(63) Chemla, F.; Karoyan Ph. Org. Synth. 2000, 78, 99.
(64) Vaupel, A.; Knochel, P. J . Org. Chem. 1996, 61, 5743.
J . Org. Chem, Vol. 68, No. 6, 2003 2259

Karoyan et al.
SCHEME 6a
a
Reagents and conditions: (i) THF/DMPU (1/1), BrCH2CO2CH3, K2CO3, 92%. (ii) THF, -78 °C, LDA, ZnBr2, -78 °C ro rt, then CuCN/
2LiCl, PhSSO2Ph, 74%. (iii) CH2Cl2, THF (4 equiv), mCpBA (2 equiv), 80%. (iv) THF/DMPU (3/1), -78 °C, LDA, CH3I, (93%). (v) THF/
DMPU (3/1), -78 °C, LDIEA, CH3I, (66%). (vi) MeOH, Na/Hg (4 equiv), KH2PO4 (3 equiv). (vii) H2/PdC/MeOH, Boc2O (63%, two steps).
(viii) THF, LDA -78 °C to rt, aq NH4Cl, (95%). (ix) LiOH/H2O/MeOH (96%).
SCHEME 7
was performed with compound 24 obtained after desul-
fonylation and subsequent catalytic hydrogenation over
palladium charcoal in the presence of Boc2O. Depro-
tonation of the R-center with LDA at -78 °C, followed
by quenching of the reaction mixture at room tempera-
ture with aqueous NH4Cl resulted in a quantitative
epimerisation of the R-center leading to the trans deriva-
tive 25. After saponification, the Boc-protected (2S,3R)-
trans-prolinoleucine 26 was obtained and was suitable
for peptide synthesis.
Having established unambiguously by X-ray analysis
the absolute configuration of the prolinoleucine obtained
F IGURE 1. Cameron view of compound 15. X-ray crystal data
for 15: C29H33N1O4S1; M ) 491.6; orthorhombic space group
P212121; a ) 7.197(4) Å, b ) 14.153(1) Å, c ) 25.985(3) Å; V )
2647(1) Å3; Z ) 4; T ) 295 K; µ ) 0.15 mm -1; Enraf-Nonius
Mach-3 diffractometer, radiation Mo KR (0.71069 Å), reflections
total 3656 (1 < θ < 25°); reflections observed 1423 (>3σ(I));
parameters refined 193; refinement on F (CRYSTALS), R )
0.0639, Rw ) 0.0805, GOF ) 1.15; ∆Fmin ) -0.31 e/Å3,
∆Fmax ) +0.38 e/Å3.
by pathway C, we were able to deduce the absolute
configuration of prolinoleucine 7 obtained by amino-
zinc-enolate cyclization of the R,â,â-trisubstituted olefin.
The cyclopropyl ring opening by catalytic hydrogenation
65
over PtO2 followed by Boc protection led to compound
9 (Scheme 4). The simple comparison of NMR spectra and
optical activity of compound 9 with those of compounds
17 and 26 allowed us to conclude (Scheme 7) a trans
relative stereochemistry for compound 9 with 2S,3R
absolute configuration, S-methylbenzyl inducing the S-
configuration of the R-center.
configuration of the sulfone 15 chiral centers were
established by X-ray analysis (Figure 1).
The derivative 17, which was suitable for peptide
synthesis, was obtained after a desulfonylation step by
Na/Hg amalgam, followed by catalytic hydrogenolysis
over palladium charcoal in the presence of Boc2O.
The trans isomer, with (2S,3R) absolute configuration
was obtained as described by the Scheme 6, starting from
the previously described (R)-but-3-enyl-(1-phenyl-ethyl)-
amine 18, which was alkylated with methylbromoacetate
in a mixture of THF/DMPU (1/1) yielding 19 (92%). After
the same reaction sequence described in Scheme 5, the
cis isomer 23 was isolated. Epimerisation of the R-center
A cis stereochemistry was observed for the product
obtained by amino-zinc-enolate cyclization of the R-sub-
stituted olefin4a (Scheme 8). This stereochemistry was
explained by a chairlike transition state where zinc
interacts with nitrogen, the double bond, and the enolate
oxygen.4a A similar transition state leading to the cis-
isomer (Scheme 8) shows a strong steric hindrance
(65) Robl, J . A.; Cimarusti, M. P.; Simpkins, L. M.; Brown, B.; Ryono,
D. E.; Bird, J . E.; Asaad, M. M.; Schaeffer, T. R.; Trippodo, N. C. J .
Med. Chem. 1996, 39, 494.
2260 J . Org. Chem., Vol. 68, No. 6, 2003

Amino-Zinc-Enolate Carbometalation Reactions
SCHEME 8
SCHEME 9
between the enolate moiety and the cyclopropyl group.
If a product-like transition state is considered, a preva-
lent interaction appears between the ester function and
the cyclopropylmetal group formed after cyclization.
Thus, in that case the more stable trans diastereoisomer
should be the major product.
idene explains the relative trans stereochemistry ob-
tained for the cyclic compound. In this transition state,
the chiral inductor adopts a position in which the methyl
group bound to the chiral center has a lowered steric
hindrance with both hydrogens in position γ when one
face of the cyclopropylidene is concerned rather than the
other one, S-(R)-methylbenzyl group leading to the S
configuration in position 2.
If the structure of the amino-zinc-enolate likens to
the Reformatzky reagent, which exists as an equilibrium
between the O- and C-metalated species,66 this equilib-
rium, as shown by Van Koten,67 is completely displaced
toward the O-metalated species when zinc is bounded to
R-amino nitrogen, the amino-zinc-enolate adopting in
that case a Z configuration. Moreover, a further study
realized by Lorthiois et al. on this reaction has shown
that asymmetric induction was governed by a π-chelation
between the aromatic ring of the chiral auxiliary and the
amino-zinc-enolate.68 Therefore, the following transi-
tion states are postulated during the amino-zinc-
enolate cyclization process of the R,â,â-trisubstituted
olefin to explain the observed stereochemistry (Scheme
9):
Con clu sion
The amino-zinc-enolate cyclization is a straightfor-
ward route for the short-step asymmetric syntheses of
3-substituted prolines. It has been applied for the prepa-
ration of cis and trans prolinoleucine. The relative
stereochemistry obtained for the cyclic compound is
governed by the nature of the alkenes. A cis stereochem-
istry is obtained for the R-substituted olefin whereas a
trans stereochemistry is observed for the olefin activated
by a hindered cyclopropyl group. The absolute configu-
ration of the chiral centers created after cyclization has
been determined by comparison of the NMR spectra and
optical activity with cis- and trans-prolinoleucine ob-
tained via an unambiguous pathway. We are currently
working on peptides incorporating these probes for con-
formational studies.
A product-like transition state involving a perpendicu-
lar approach of the enolate moiety and the cyclopropyl-
(66) Dekker: J .; Schouten, A.; Budzelaar, P. H. M.; Boersma, J .;
Van der Kerk, G. J . M.; Spek, A. L.; Duisenberg, A. J . M. J . Organomet.
Chem. 1987, 320, 1.
(67) Van der Steen, F. H.; Boersma, J .; Spek, A. L.; Van Koten, G.
J . Organomet. Chem. 1990, 390, C21.
(68) Lorthiois, E.; Marek, I.; Normant, J .-F. J . Org. Chem. 1998,
63, 2442.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. Tetrahydrofuran (THF) and
diethyl ether (Et2O) were distilled from sodium benzophenone
and kept over 4 Å molecular sieves. Dimethyl sulfoxide
J . Org. Chem, Vol. 68, No. 6, 2003 2261

Karoyan et al.
(DMSO), triethylamine (NEt3), and dichloromethane (CH2Cl2)
were distilled from CaH2. MeOH was distilled from Mg. Dry
dimethylformamide (DMF) and other reagents were com-
mercially available. Zinc bromide (ZnBr2) was dried by fusion
under flame and nitrogen; the fused salts were allowed to
solidify under nitrogen and then dissolved in dry diethyl ether
(1 or 1.3 M). Lithium chloride (LiCl) was dried with a heat
gun under reduced pressure. After cooling under nitrogen,
CuCN was added, followed by dry THF (1 M), the mixture was
then stirred until complete dissolution (1 h). Lithium dieth-
ylamide (LDEA, 1 M) was prepared prior to use as follows:
BuLi (1 equiv) was added to freshly distilled diethylamine (1
equiv) in dry THF at -78 °C under argon. The temperature
was brought to 0 °C and the base was stored at this temper-
ature. Anhydrous reactions were performed under an argon
atmosphere; glasswares were flame-dried prior to use under
a stream of nitrogen. Usual workup means that the organic
layer was washed twice with aqueous saturated NH4Cl (NH4-
Cl/NH4OH (1 M), 2/1 until complete decoloration for the
cyclization-transmetalation by copper salts reactions, followed
by brine), dried over MgSO4, and evaporated in vacuo.
(S)-[3-Cyclop r op ylid en ep r op a n e-(1-p h en yl-eth yl)-a m i-
n o]-ben zyl a ceta te ester 5a : Benzylbromoacetate (2.05 mL,
31 mmol) and dry NEt3 (3.5 mL, 25 mmol) were added to a
solution of (S)-3-cyclopropylidenepropane-(1-phenyl-ethyl)-
amine 4 (2.5 g, 12.4 mmol) in dry DMSO (15 mL). The reaction
mixture was stirred overnight at rt. Et2O and water were
added. The organic layer was decanted and washed once with
brine, dried over MgSO4, and concentrated to form a yellow
oil. After purification by flash chromatography (cyclohexane/
ethyl acetate, 99/1), a pale yellow oil (2.8 g, 68%) was obtained.
[R] 20 -30 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.25
D
(m, 10H), 5.7 (m, 1H), 5.15 (s, 2H), 4.1 (q, 1H, J ) 6.6 Hz),
3.54 (d, AB system, 1H, 2J ) 17.3 Hz), 3.4 (d, AB system, 2J )
17.3 Hz), 2.76 (m, 2H), 2.35 (m, 2H), 1.38 (d, 3H, J ) 6.6 Hz),
1.02 (m, 2H), 0.96 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 172.3,
144.7, 136.1, 130, 128.6, 128.3, 127.6, 127, 116.1, 66.1, 60.5,
51.7, 51, 30.5, 19.5, 2.5, 1.8. Anal. Calcd for C23H27NO2: C,
79.08; H, 7.78; N, 4.01. Found: C, 79.21; H, 8.33; N, 4.10.
(S)-[3-Cyclop r op ylid en ep r op a n e-(1-p h en yl-eth yl)-a m i-
n o]-eth yl a ceta te ester 5b: Same protocol as for 5a : from
(S)-3-cyclopropylidenepropane-(1-phenyl-ethyl)-amine 4 (600
mg, 2.98 mmol), dry DMSO (5 mL), ethylbromoacetate (700
µL, 6 mmol), and dry NEt3 (840 µL, 6 mmol). After purification
by flash chromatography (cyclohexane/ethyl acetate, 99/1), a
(S)-(1-P h en yl-eth ylam in o)-eth yl acetate ester 1: Freshly
distilled ethylbromoacetate (33.2 mL, 0.3 mol) was added
dropwise at 0 °C to a solution of L-(-)-R-methylbenzylamine
(38.6 mL, 0.3 mol) in dry DMSO (100 mL) under argon. After
5 min of stirring at rt dry NEt3 (41.6 mL, 0.3 mol) was added.
The solution was stirred for 10 min and ethyl acetate was
added. After the usual workup and concentration, the residual
pale yellow liquid was distilled under reduced pressure yield-
ing a colorless liquid (54.8 g, 88%): 1H NMR (200 MHz; CDCl3)
δ 7.3-7.28 (m, 5H), 4.12 (q, 2H, J ) 7.3 Hz), 3.75 (q, 1H, J )
pale yellow oil (2.8 g, 68%) was obtained. [R]20 -29 (c 1,
D
CHCl3): 1H NMR (400 MHz, CDCl3) δ 7.3 (m, 5H), 5.73 (m,
1H), 4.15 (q, 2H, J ) 7.2 Hz), 4.08 (q, 1H, J ) 6.7 Hz), 3.47 (d,
2
2
AB system, 2H, J ) 17.3 Hz), 3.32 (d, AB system, 2H, J )
17.3 Hz), 2.74 (m, 2H), 2.34 (m, 2H), 1.37 (d, 3H, J ) 6.7 Hz),
1.27 (tr, 3H, J ) 7.2 Hz), 1.02 (m, 2H), 0.97 (m, 2H). 13C NMR
(100 MHz, CDCl3) δ 172.4, 144.8, 128.3, 127.7, 126.9, 116.1,
110.7, 60.5, 60.3, 51.6, 51, 30.4, 19.5, 14.4, 2.5, 1.8. Anal. Calcd
for C18H25NO2: C, 75.26; H, 8.71; N, 4.87. Found: C, 75.95;
H, 9.07; N, 4.98.
2
6.5 Hz), 3.23 (AB system, 2H, J ) 3 Hz), 1.36 (d, 3H, J ) 6.5
Hz), 1.21 (tr, 3H, J ) 7.3 Hz). 13C NMR (100 MHz, CDCl3) δ
172.7, 144.8, 128.6, 127.3, 126.9, 60.8, 57.8, 57.8, 49, 41.1, 24.4,
14.3. Anal. Calcd for C12H17NO2: C, 69.56; H, 8.21; N, 6.76.
Found: C, 69.31; H, 8.37; N, 6.71.
3-Cyclopr opyl-1-(1-ph en yl-eth yl)-pyr r olidin e-2-car box-
ylic-a cid -ben zyl ester 7a : LDA (2.2 mL, 4.4 mmol) was
added at -78 °C to a solution of amine 5a (1.4 g, 4 mmol) in
dry diethyl ether (8 mL) under argon. ZnBr2 (1 M, 12 mL) was
then added at the same temperature. The reaction mixture
was stirred as the temperature was brought to rt. Et2O was
added. A pale yellow oil (950 mg, 68%) was obtained after the
(S)-[P en t-3-en yl-4-m eth yl-(1-p h en yl-eth yl)-a m in o]-eth -
yl a ceta te ester 2: 5-Iodo-2-methyl-2-pentene19 (5.46 g, 26
mmol) and NEt3 (3.61 mL, 26 mmol) were added to a stirred
solution of (S)-R-methylbenzylglycine ethyl ester 1 (4.14 g, 10
mmol) in dry DMSO (12 mL) under argon and heated at 50
°C for 48 h. The mixture was cooled and diluted with CH2Cl2.
The organic layer was washed twice with aqueous saturated
NH4Cl. The aqueous layers were extracted once with CH2Cl2.
The combined organic layers were dried over MgSO4 and
concentrated to afford 9 g of a brown oil that was purified by
flash chromatography yielding 3.1 g (53.6%) of a pale yellow
liquid: [R] 20D -38 (c 1, CHCl3). Rf (cyclohexane/ethyl acetate,
usual workup and purification by flash chromatography (cy-
1
clohexane/ethyl acetate, 97/3): [R] 20 -60.5 (c 1, CHCl3). H
D
NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 7.29 (m, 5H), 5.14 (s,
2H), 3.74 (q, 1H, J ) 7 Hz), 3.25 (d, 1H, J ) 5 Hz), 3 (m, 1H),
2.7 (m, 1H), 2.06 (m, 1H), 1.6 (m, 2H), 1.36 (d, 3H, J ) 7 Hz),
0.78 (m, 1H), 0.41 (m, 2H), 0.05 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 175.4, 144.2, 136.4, 128.8, 128.6, 127.9, 127.4, 70,
66.5, 62.3, 50.3, 50.1, 30.3, 22.9, 16.1, 4.5, 3.9. Anal. Calcd for
1
9/1, UV/PMA) 0.62. H NMR (200 MHz, CDCl3) δ 7.4-7.2 (m,
C
23H27NO2: C, 79.08; H, 7.78; N, 4.01. Found: C, 79.42; H,
5H), 5.06 (m, 1H), 4.17 (q, 2H, J ) 7 Hz), 4.08 (q, 1H, J ) 6.7
Hz), 3.41(AB system, 2H, 2J ) 17 Hz), 2.6 (m, 2H), 2.12 (m,
2H), 1.69 (s, 3H), 1.58 (s, 3H), 1.34 (d, 3H, J ) 6.7 Hz), 1.28
(tr, 3H, J ) 7 Hz). 13C NMR (50 MHz, CDCl3) δ 172.3, 144.8,
132.6, 128.2, 127.6, 126.9, 122, 60.5, 60.2, 51.6, 51.2, 26.8, 25.7,
19.5, 17.7, 14.3. Anal. Calcd for C18H27NO2: C, 74.74; H, 9.34;
N, 4.84. Found: C, 74.82; H, 9.28; N, 4.79.
8.11; N, 3.96.
3-Cyclopr opyl-1-(1-ph en yl-eth yl)-pyr r olidin e-2-car box-
ylic a cid eth yl ester 7b: Same protocol as for 7a : LDA (650
µL, 1.3 mmol), amine 5b (290 mg, 1 mmol), diethyl ether (2
mL), and ZnBr2 (1 M, 3 mL). A pale yellow oil (200 mg, 70%)
was obtained after the usual workup and purification by flash
chromatography (cyclohexane/ethyl acetate, 97/3): [R] 20D -66.5
1
(S )-3-C y c lo p r o p y lid e n e p r o p a n e -(1-p h e n y l-e t h y l)-
a m in e 4: A mixture of (S)-R-methylbenzylamine (3.06 mL,
23.8 mmol), NaI (7.2 g, 47.61 mmol), K2CO3 (6.6 g, 47.61
mmol), and 1-tosyloxy-3-cyclopropylidenepropane22 (4 g, 15.87
mmol) in DMF (30 mL) was heated to 100 °C overnight, and
then cooled to rt. The mixture was diluted with Et2O and water
was added. The organic layer was washed once with brine,
dried over MgSO4, and concentrated. A pale yellow oil was
obtained (1.3 g, 40%) after distillation (120 °C, 0.1 mbar)
followed by chromatography (CH2Cl2/EtOH, 99/1): [R] 20D -34
(c 1, CHCl3). H NMR (400 MHz, CDCl3) δ 7.26 (m, 5H), 4.17
(q, 2H, J ) 7.1 Hz), 3.74 (q, 1H, J ) 6. 8 Hz), 3.17 (d, 1H, J )
5.5 Hz), 2.98 (m, 1H), 2.65 (m, 1H), 2.05 (m, 1H), 1.6 (m, 2H),
1.38 (d, 3H, 5.5 Hz), 1.27 (tr, 3H, J ) 7.1 Hz), 0.8 (m, 1H),
0.45 (m, 2H), 0.1 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 175.6,
144.1, 128.5, 128, 127.3, 70.3, 62.5, 60.7, 50.3, 50, 30.2, 22.6,
16, 14.6, 4.4, 3.7. Anal. Calcd for C18H25NO2: C, 75.27; H, 8.71;
N, 4.87. Found: C, 75.77; H, 9.01; N, 4.85.
3-Cyclop r op yl-p yr r olid in e-2-ca r boxylic a cid 8: A solu-
tion of compound 7a (350 mg, 1 mmol) and Pd/C (150 mg) in
MeOH (2 mL) was stirred for 2 h under hydrogen. After
filtration on a Celite pad, which was washed with EtOH, the
solvent was concentrated leaving a white powder that was
1
(c 1, CHCl3). H NMR (400 MHz, CDCl3) δ 7.31 (m, 5H), 5.73
(m, 1H), 3.80 (q, 1H, J ) 6.5 Hz), 2.62 (m, 2H), 2.38 (m, 2H),
1.37 (d, 3H, J ) 6.5 Hz), 1.05 (m, 4H). 13C NMR (100 MHz,
CDCl3) δ 145.9, 128.5, 126.6, 126.7, 123.1, 116, 58.3, 47.3, 32.5,
24.4, 2.5, 2.
washed with CH2Cl2 (143 mg, 92%): mp >264°C; [R] 20 4 (c
D
1
3
1, H2O). H NMR (400 MHz, CDCl3) δ 3.74 (d, 1H, J ) 8 Hz),
2262 J . Org. Chem., Vol. 68, No. 6, 2003

Amino-Zinc-Enolate Carbometalation Reactions
3.28 (m, 1H), 2.02 (m, 1H), 1.76 (m, 1H), 1.66 (m, 1H), 0.75
(m, 1H), 0.42 (m, 2H), 0.15 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 133.3, 66.3, 48.4, 45.3, 29.9, 13.7, 3.99, 2.92. Anal.
Calcd for C8H13NO2: C, 61.93; H, 8.38; N, 9.03. Found: C,
61.88; H, 8.50; N, 9.15.
reaction mixture was quenched by an aqueous saturated
solution of NH4Cl. Et2O was added. A pale yellow glue (15.9
g, 74%) was obtained after the usual workup and purification
by flash chromatography (cyclohexane/ethyl acetate, 92/8):
1
[R] 20 -25 (c 0.5, CHCl3); H NMR (200 MHz, CDCl3) δ 7.25
D
(m, 15H), 5.13 (s, 2H), 3.74 (q, 1H, J ) 6.6 Hz), 3.67 (s, 3H),
3.51 (d, 1H J 3) 7.2 Hz), 3.15 (m, 1H), 3 (m, 2H), 2.65 (m, 2H),
2.2 (m, 1H), 1.8 (m, 1H), 1.37 (d, 3H, J ) 6.5 Hz). 13C NMR
(50 MHz, CDCl3) δ 172, 144.2, 139.5, 135.5, 133.9, 129.4, 128.9,
128.6, 128.5, 128, 127.3, 66.2, 65.3, 61.8, 57.5, 49.6, 35.9, 29.7,
22.9. Anal. Calcd for C27H29NO4S: C, 75.17; H, 6.73; N, 3.25.
Found: C, 75.06; H, 6.84; N, 3.38.
(2S,3R)-3-Isop r op yl-1-(ter t-bu tyloxyca r bon yl)-p yr r oli-
d in e-2-ca r boxylic a cid 9: Compound 7a (350 mg, 1 mmol)
was dissolved in 4 mL of MeOH/CH3COOH (1/3). PtO2 (100
mg) was added and the reaction mixture was stirred for 5 days
under hydrogen at a pressure of 5 bar, at rt. After concentra-
tion, the crude material was dissolved in MeOH and the pH
was adjusted to 9 with NaHCO3. Boc2O was added and the
reaction mixture was stirred at room temperature for 3 h. After
filtration over a Celite pad and concentration, the crude
material was purified by flash chromatography (CH2Cl2/
MeOH, 9/1). A white powder (60 mg, 23%) was obtained after
crystallization. [R] 20D -43 (c 1, CHCl3); mp 88-90 °C. 1H NMR
(250 MHz, CDCl3) δ 9.8 (broad peak, 1H), 4.1 and 3.95 (2d,
(2S,3S)-3-P h en ylsu lfon ylm eth yl-1-(1-ph en yl-eth yl)-pyr -
r olid in e-2-ca r boxylic a cid ben zyl ester 13: mCpBA (12.6
g, 54.8 mmol) was added portionwise to a cold solution (0 °C)
of 12 (11.8 g, 27.4 mmol) in CH2Cl2 (140 mL) and TFA (8.5
mL, 109 mmol). After the mixture was stirred for 1 h, the
organic layer was washed with 10% Na2S2O3 (1×), 10%
NaHCO3 (3×), and brine (1×), dried over MgSO4, concentrated,
and purified by flash chromatography (cyclohexane/ethyl
3
1H, Boc cis-trans isomerization, J ) 7.5 Hz), 3.55 (m, 1H),
3.4 (m, 1H), 2.17 (m, 1H), 1.95 (m, 1H), 1.70 (m, 2H), 1.46 and
1.42 (2s, 9H, Boc cis-tans isomerization), 0.99 (d, 3H, 3J )
7.5 Hz), 0.95 (d, 3H, 3J ) 7.5 Hz). 13C NMR (62.5 MHz, CDCl3)
δ 179.8, 177.6, 155.33, 153.86, 80.6, 80.4, 62.6, 51.4, 49.5, 46.3,
45.9, 30.3, 28.4, 28.3, 27.6, 26.9, 21.1, 19.5, 19.3. Anal. Calcd
for C13H23NO4: C, 60.68; H, 9.01; N, 5.44. Found: C, 60.71;
H, 9.12; N, 5.32.
acetate, 7/3), yielding 10.1 g (80%) of a colorless glue. [R]20
D
1
-44.8 (c 1, CHCl3). H NMR (400 MHz, CDCl3) δ 7.79 (d, 2H,
J ) 7.5 Hz), 7.6 (m, 1H), 7.53 (m, 2H), 7.28 (m, 8H), 7.13 (m,
2H), 5.04 (d, 2H, AB system, J ) 4.3 Hz), 3.67 (q, 1H, J ) 6.5
Hz), 3.42 (d, 1H J )7 Hz), 3.14 (m, 1H), 3.06 (m, 2H), 2.79 (m,
2H), 2.2 (m, 1H), 1.8 (m, 1H), 1.32 (d, 3H, J ) 6.5 Hz). 13C
NMR (100 MHz, CDCl3) δ 172.3, 144.5, 139.7, 135.8, 134.1,
129.7, 129.2, 128.9, 128.7, 127.6, 111, 66.5, 66.1, 61.3, 57.8,
49.9, 36.2, 30.5, 30, 27.3, 23.2. Anal. Calcd for C27H29NO4S:
C, 69.97; H, 6.26; N, 3.02. Found: C, 69.90; H, 6.28; N, 3.09.
N-Boc-3-isop r op yl-p yr r olid in e-2-ca r boxylic a cid eth yl
ester 10: A solution of amine 7b (275 mg, 1 mmol) and Pd/C
(80 mg) in MeOH (3 mL) was stirred under H2 atmosphere.
After filtration over a Celite pad, which was washed with
EtOH, the solvent was concentrated, giving an oil. After the
addition of dry EtOH (5 mL), NaHCO3 (92.5 mg, 1.1 mmol),
and Boc2O (337 mg, 1.5 mmol) the reaction mixture was stirred
overnight. Filtration over a Celite pad and purification by flash
chromatography (cyclohexane/ethyl acetate, 9/1) afforded a
(2S,3S)-3-(1-Meth yl-1-ph en ylsu lfon ylm eth yl)-1-(1-ph en -
yl-eth yl)-p yr r olid in e-2-ca r boxylic a cid ben zyl ester 14
(a s a m ixtu r e of tw o d ia ster eoisom er s): LDA (5.5 mL, 11
mmol) was added to a dry THF/DMPU (40 mL, 3/1) solution
of sulfone 13 (4.63 g, 10 mmol) at -78 °C under argon. After
a few seconds of stirring, CH3I (2.52 mL, 40 mmol) was added.
The reaction mixture was stirred for 30 min and brought to
room temperature. Et2O was added. A pale yellow oil was
obtained after the usual workup and concentration. The crude
materials were purified by flash chromatography (cyclohexane/
ethyl acetate, 8/2), yielding 4.4 g (93.6%) of a colorless glue as
a mixture of two diastereoisomers (65/35). 1H NMR (400 MHz,
CDCl3) (major diastereoisomer) δ 7.7-7.2 (m, 15H), 5.14 (AB
systems, 2H, J AB1 ) 11.2 Hz), 3.75 (d, 1H, J ) 7.3 Hz), 3.74,
(q, 1H, J ) 6.7 Hz), 3.39 (m, 1H), 2.9 (m, 2H), 2.7 (m, 1H),
colorless oil (213 mg, 80%): [R]20 -33 (c 1, CHCl3); 1H NMR
D
(200 MHz, CDCl3) δ 4.20-4.04 (q, 2H), 4.05-4.03-3.94-3.92
(2d, 1H, Boc cis-trans isomerization), 3.65-3.34 (m, 2H),
2.01-1.88 (m, 1H), 1.72-1.45 (m, 2H), 1.39-1.34 (2s, 9H),
1.24-1.15 (2tr, 3H), 0.82-0.67 (m, 1H), 0.50-0.41 (m, 2H),
0.17-0.06 (m, 2H). 13C NMR (50 MHz, CDCl3) δ 174, 79.8, 65-
64.55, 60.6, 50-48.9, 45.8-45.6, 30.4-29.8, 28.4-28.3, 14.2-
14.1, 4.18, 3.49.
(S)-[Bu t-3-en yl-(1-ph en yl-eth yl)-am in o]-acetic acid ben -
zyl ester 11: To a solution of (S)-but-3-enyl-(1-phenyl-ethyl)-
amine (12.75 g, 72.7 mmol)4c in a dry THF/DMPU mixture (150
mL, 1/1) was slowly added benzylbromoacetate (12.02 mL, 72.7
mmol). The mixture was stirred for 30 min and dry Na2CO3
(7.72 g, 72.7 mmol) was added. The reaction mixture was
stirred for 4 h at rt and then diluted with Et2O. The organic
layer was filtered through a Celite pad (which was washed
with Et2O) and washed with water (2×) and brine. The
combined aqueous layers were extracted once with Et2O. The
combined organic layers were dried over MgSO4, and concen-
trated yielding 21.3 g (90%) of a pale yellow oil after purifica-
1
1.35 (d, 3H, J ) 6.7 Hz), 1.11 (d, 3H, J ) 7 Hz). H NMR (400
MHz, CDCl3) (minor diastereoisomer)δ 7.7-7.2 (m, 15H), 4.98
(AB system, 2H, J AB1 ) 8 Hz), 3.58 (q, 1H, J ) 6.5 Hz), 3.46
(d, 1H, J ) 6.5 Hz), 3.24 (m, 1H), 3.07 (m, 1H), 2.8 (m, 1H),
2.58 (m, 1H), 2.4 (m, 1H), 1.9 (m, 1H). Anal. Calcd for C28H31
-
NO4S: C, 70.44; H, 6.49; N, 2.93. Found: C, 70.30; H, 6.75;
N, 2.99.
(2S,3S)-3-(1,1-Dim eth yl-1-p h en ylsu lfon ylm eth yl)-1-(1-
p h en yl-eth yl)-p yr r olid in e-2-ca r boxylic a cid ben zyl ester
15: LDEA (1 M, 16.8 mL) was added to a dry THF/DMPU
(3/1, 40 mL) solution of sulfone 14 (4 g, 8.38 mmol) at -78 °C
under argon. After a few seconds of stirring, CH3I (2.1 mL,
33.5 mmol) was added at this temperature. The reaction
mixture was stirred for 1 h and brought to room temperature.
Et2O was added. A pale yellow oil was obtained after the usual
workup and concentration. After two crystallizations (Et2O/
pentane first, then slow evaporation of CHCl3), colorless
tion by flash chromatography (cyclohexane/ethyl acetate: 97/
1
3). [R]20 -28 (c 1, CHCl3). H NMR (250 MHz; CDCl3) δ 7.35
D
(m, 10H), 5.75 (m, 1H), 5.14 (s, 2H), 4.98 (m, 2H), 4.07 (q, 1H,
J ) 6.7 Hz), 3.52 (d, 1H, AB system, J AB) 17.3 Hz), 3.36 (d,
1H, AB system, J AB) 17.3 Hz), 2.71 (m, 2H), 2.22 (m, 2H),
1.36 (d, 3H, J ) 6.7 Hz). 13C NMR (50 MHz; CDCl3) δ 172.1,
144.6, 136.7, 135.9 128.6, 128.3, 127.6, 127, 115.6, 66.1, 60.4,
51.5, 50.8, 32.5, 19.4. Anal. Calcd for C21H25NO2: C, 78.01; H,
7.73; N, 4.33. Found: C, 77.86; H, 7.87; N, 4.34.
needles (2.8 g, 68%) were obtained. [R]20 -21 (c 1, CHCl3);
D
mp 146-148 °C. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, 2H,
J ) 7.3 Hz), 7.65 (m, 1H), 7.55 (m, 2H), 7.3 (m, 5H), 7.11 (m,
2H), 5.05 (d, AB system, 1H, J ) 12 Hz)), 4.99 (d, AB system,
1H, J ) 12 Hz), 3.53 (q, 1H, J ) 6.5 Hz), 3.43 (d, 1H, J ) 6.2
Hz), 3.3 (m, 1H), 3.15 (m, 1H), 2.95 (m, 1H), 2.25 (m, 2H), 1.31
(d, 3H, J ) 6.5 Hz), 1.20 (, s, 3H), 1.14 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 172.7, 145, 135, 134, 129.3, 129.2, 128.9, 128.7,
127.4, 66.4, 64.7, 64.5, 60.8, 49.6, 46, 25.4, 23.9, 22.1, 17.7.
Anal. Calcd for C29H33NO4S: C, 70.87; H, 6.72; N, 2.85.
(2S,3S)-3-P h en ylsu lfan ylm eth yl-1-(1-ph en yl-eth yl)-pyr -
r olid in e-2-ca r boxylic a cid ben zyl ester 12: LDA (25 mL,
50 mmol) was added at -78 °C to a solution of amine 11 (16.15
g, 50 mmol) in dry THF (100 mL) under argon. ZnBr2 (1 M in
Et2O, 125 mL) was then added and the reaction mixture was
stirred as the temperature was brought to rt (4 h). CuCN/2LiCl
(1 M in THF, 50 mL) was then added at 0 °C followed by
PhSSO2Ph (12.5 g, 50 mmol). After 2 h of stirring at rt, the
J . Org. Chem, Vol. 68, No. 6, 2003 2263

Karoyan et al.
Found: C, 70.72; H, 6.88; N, 2.84. X-ray crystal data: C29H33
-
CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.34-7.18 (m, 10H),
3.74-3.72 (q, 1H, J ) 8 Hz), 3.67 (s, 3H), 3.49 (d, 1H, J 3 ) 8
Hz), 3.09-3.06 (m, 1H), 3.04-3.02 (m, 1H), 3-2.99 (m, 1H),
2.74-2.71 (m, 1H), 2.60-2.58 (m, 1H), 2.18-2.15 (m, 1H),
1.83-1.80 (m, 1H), 1.39 (d, 3H, J ) 8 Hz). 13C NMR (62.5 MHz,
CDCl3) δ 173.1, 143.8, 135.8, 129.5, 128.8, 128.2, 127.3, 127,
126.1, 66, 62.5, 61.4, 51, 49.6, 41.3, 35.2, 29.6, 22.4. Anal. Calcd
for C21H25NO2S: C, 70.95; H, 7.09; N, 3.94. Found: C, 70.76;
H, 7.16; N, 3.89.
NO4S; M ) 491.6; orthorhombic space group P212121; a )
7.197(4) Å, b ) 14.153(1) Å, c ) 25.985(3) Å; V ) 2647(1) Å3;
Z ) 4; T ) 295 K; µ ) 0.15 mm -1; Enraf-Nonius Mach-3
diffractometer, radiation Mo KR (0.71069 Å), reflections total
3656 (1 < θ < 25°); reflections observed 1423 (>3σ(I));
parameters refined 193; refinement on F (CRYSTALS), R )
0.0639, Rw ) 0.0805, GOF ) 1.15; ∆Fmin ) -0.31 e/Å3,
∆Fmax ) +0.38 e/Å3.
(2S,3S)-3-Isop r op yl-1-(1-p h en yl-et h yl)-p yr r olid in e-2-
ca r boxylic a cid ben zyl ester 16: KH2PO4 (760.2 mg, 5.58
mmol) and freshly prepared 3% Na/Hg amalgam (4.86 g, 7.40
mmol) were added portionwise to dry solution of sulfone 15
(908.9 g, 1.85 mmol) in freshly distilled MeOH (20 mL). The
mixture was vigorously stirred for 1 h at room temperature.
After filtration over a Celite pad, the crude material was
concentrated and purified by flash chromatography (cyclohex-
ane/ethyl acetate, 98/2) leaving an oil (287 mg, 82%). 1H NMR
(400 MHz, CDCl3): δ 7.28 (m, 10H), 5.07 (d, AB system, 1H,
J ) 12.2 Hz), 5.01 (d, AB system, 1H, J ) 12.2 Hz), 3.66 (q,
1H, J ) 6.5 Hz), 3.48 (d, 1H, J ) 6.7 Hz), 3.18 (m, 1H), 3.09
(m, 1H), 2.02 (m, 2H), 1.81 (m, 1H), 1.33 (d, 3H, J ) 6.5 Hz),
1.26 (m, 1H), 0.85 (d, 3H, J ) 6.5 Hz), 0.82 (d, 3H, J ) 6.5
Hz), 3.54 (s, 3H), 3.53 (q, 1H, J ) 7.5 Hz), 3.4 (d, 1H, J ) 5
Hz), 3.3 (m, 1H), 3.1 (m, 1H), 2.9 (m, 1H), 2.25 (m, 2H), 1.3 (d,
3H, J ) 7.5 Hz), 1.22 (s, 3H), 1.18 (s, 3H). Anal. Calcd for
(2R,3R)-3-P h en ylsu lfon ylm et h yl-1-(1-p h en yl-et h yl)-
p yr r olid in e-2-ca r boxylic a cid m eth yl ester 21: Same
protocol as for compound 13: mCpBA (7.3 g, 32 mmol), 20 (6.2
g, 16 mmol), CH2Cl2 (100 mL), and TFA (5 mL, 64 mmol).
Workup and purification by flash chromatography (cyclohex-
ane/ethyl acetate, 7/3) yielded 9.8 g (80%) of a colorless glue.
[R]20 40 (c 1, CHCl3). 1H NMR (250 MHz, CDCl3) δ 7.87-
D
7.84 (m, 2H), 7.57-7.54 (m, 3H), 7.26-7.22 (m, 5H), 3.7 (q,
1H, J ) 7.5 Hz), 3.58 (s, 3H), 3.4 (d, 1H, J ) 7.5 Hz), 3.25-
3.20 (m, 1H), 3.09-2.09 (m, 3H), 2.8-2.7 (m, 1H), 2.2-2.1 (m,
1H), 1.85-1.75 (m, 1H), 1.32 (d, 3H, J ) 7.5 Hz). 13C NMR
(62.5 MHz, CDCl3) δ 172, 143, 133.8, 129.3, 128.3, 128, 127.2,
65.6, 61.1, 57.5, 51.2, 49.5, 41.3, 35.7, 29.6, 22.6. Anal. Calcd
for C21H25NO4S: C, 65.09; H, 6.50; N, 3.61. Found: C, 64.97;
H, 6.59; N, 3.48.
(2R,3R)-3-(1-Meth yl-1-ph en ylsu lfon ylm eth yl)-1-(1-ph en -
yl-eth yl)-p yr r olid in e-2-ca r boxylic a cid m eth yl ester 22
(a s a m ixtu r e of tw o d ia ster eoisom er s): Same protocol as
for compound 14: LDA (16 mL, 28 mmol), THF/DMPU (70 mL,
3/1), sulfone 21 (10.83 g, 28 mmol), and CH3I (7.05 mL, 112
mmol). After workup, the crude materials were purified by
flash chromatography (cyclohexane/ethyl acetate, 7/3), yielding
10.5 g (93%) of a colorless glue as a mixture of two diastereo-
C
23H29NO2: C, 78.63; H, 8.26; N, 3.98. Found: C, 78.68; H,
8.25; N, 3.88.
(2S,3S)-3-isop r op yl-1-(ter t-bu tyloxyca r bon yl)-p yr r oli-
d in e-2-ca r boxylic a cid 17: A mixture of Amine 16 (250 mg,
0.71 mmol), 10% Pd/C (100 mg), and Boc2O (156 mg, 0.71
mmol) in MeOH (5 mL) was stirred overnight at room
temperature under hydrogen. After filtration over a Celite pad
and concentration, the crude material was purified by flash
chromatography (CH2Cl2/MeOH, 95/5), leaving an oil (168 mg,
91%). [R]20 D 39 (c 1, CHCl3); mp 86-88 °C. 1H NMR (250 MHz,
CDCl3) δ 8.2 (broad peak, 1H), 4.41-4.29 (2d, 1H, Boc cis-
trans isomerization, J ) 7.5 Hz), 3.7 (m, 1H), 3.27 (m, 1H), 2
(m, 2H), 3.28 (m, 1H), 1.45-1.42 (2s, 9H, Boc cis-trans
isomerization), 1.07 (d, 3H, J ) 5 Hz), 0.94 (d, 3H, J ) 5 Hz).
13C NMR (62.5 MHz, CDCl3) δ 178, 80, 62, 51.3, 50.4, 45.7,
29, 28.3, 28.1, 27.5, 22.1, 21.4. Anal. Calcd for C13H24NO4: C,
60.68; H, 9.01; N, 5.44. Found: C, 60.62; H, 9.19; N, 5.36.
(R)-[Bu t -3-en yl-(1-p h en yl-et h yl)-a m in o]-a cet ic a cid
m eth yl ester 19: Methylbromoacetate (6.34 mL, 65 mmol)
was slowly added to a stirred solution of (R)-but-3-enyl-(1-
phenyl-ethyl)-amine (11.37 g, 65 mmol)4c in a dry THF/DMPU
mixture (80 mL, 1/1) at 0 °C under argon. Dry K2CO3 (9.08 g,
65 mmol) was added and the mixture was stirred for 6 h at rt.
Et2O (200 mL) was added and the organic layer was filtered
through a Celite pad (which was washed with Et2O). The
organic layer was washed with water (2×) and brine. The
combined aqueous layers were extracted once with Et2O. The
combined organic layers were dried over MgSO4, and concen-
trated yielding 14.7 g (91.5%) of a pale yellow oil after
purification by flash chromatography (cyclohexane/ethyl ac-
etate, 98/2). [R] 20D 32 (c 1, CHCl3). 1H NMR (250 MHz; CDCl3)
δ 7.38-7.21 (m, 5H), 5.8-5.69 (m, 1H), 5.04-4.93 (m, 2H),
4.05-4.02 (q, 1H, J ) 6.7 Hz), 3.66 (s, 3H), 3.45 (d, AB,
J AB)17.2 Hz, 1H), 3.29 (d, AB, J AB ) 17.2 Hz, 1H), 2.71-2.65
(m, 2H), 2.23-2.17 (m, 2H), 1.35 (d, 3H, J ) 6.7 Hz). 13C NMR
(62.5 MHz; CDCl3) δ 172.5, 144.5, 136.7, 128.2, 127.5, 126.9,
115.5, 60.4, 51.3, 50.7, 32.3, 19.4. Anal. Calcd for C15H21NO2:
C, 72.84; H, 8.56; N, 5.66. Found: C, 72.75; H, 8.71; N, 5.64.
1
isomers (65/35). H NMR (500 MHz, CDCl3) δ 7.87-7.81 (m,
2H), 7.63-7.5 (m, 3H), 7.29-7.25 (m, 5H), 3.76 (2q, 1H), 3.65
(s, 3H, 65%), 3.57 (s, 3H, 35%), 3.45 (2d, 1H), 3.25-3.20 (m,
1H), 3.09-2.09 (m, 3H), 2.8-2.7 (m, 1H), 2.2-2.1 (m, 1H),
1.85-1.75 (m, 1H), 1.69-1.65 (2 broad d, 6H), 1.11 (d, 3H,
J ) 6.5 Hz, 65%), 1.07 (d, 3H, J ) 6.7 Hz, 35%). 13C NMR
(62.5 MHz, CDCl3) δ 172, 143, 133.8, 129.3, 128.3, 128, 127.2,
65.6, 61.1, 57.5, 51.2, 49.5, 41.3, 35.7, 29.6, 22.6. Anal. Calcd
for C22H24NO4S: C, 65.09; H, 6.50; N, 3.61. Found: C, 64.97;
H, 6.59; N, 3.48.
(2R,3R)-3-(1,1-Dim eth yl-1-p h en ylsu lfon ylm eth yl)-1-(1-
p h en yl-eth yl)-p yr r olid in e-2-ca r boxylic a cid m eth yl ester
23: Same protocol as for compound 16: LDEA (1 M, 50 mL),
THF/DMPU (3/1, 100 mL), sulfone 22 (10 g, 10 mmol), and
CH3I (6.3 mL, 100 mmol). After the usual workup, the leaving
pale yellow oil was crystallized twice (Et2O/pentane) and white
crystals (6.8 g, 66%) were obtained. [R]20 D 11 (c 1, CHCl3); mp
96-98 °C. 1H NMR (250 MHz, CDCl3) δ 7.84-7.80 (m, 2H),
7.7-7.5 (m, 3H), 7.20-7.20 (m, 5H), 3.54 (s, 3H), 3.53 (q, 1H,
J ) 7.5 Hz), 3.4 (d, 1H, J ) 5 Hz), 3.3 (m, 1H), 3.1 (m, 1H), 2.9
(m, 1H), 2.25 (m, 2H), 1.3 (d, 3H, J ) 7.5 Hz), 1.22 (s, 3H),
1.18 (s, 3H). 13C NMR (62.5 MHz, CDCl3) δ 173, 145, 135.4,
133.6, 130.6, 128.8, 128.3, 127.2, 127, 64.3, 63.9, 60.6, 50.7,
49.2, 45.6, 23.4, 21.5, 17.6. Anal. Calcd for C23H29NO4S: C,
66.48; H, 7.08; N, 3.37. Found: C, 66.63; H, 7.16; N, 3.30.
(2R,3R)-3-Isop r op yl-1-(ter t-bu tyloxyca r bon yl)-p yr r oli-
d in e-2-ca r boxylic a cid m eth yl ester 24: KH2PO4 (6.22 g,
45,3 mmol) and freshly prepared 3% Na/Hg amalgam (39.67
g, 60.4 mmol) were added portionwise to a dry solution of
sulfone 23 (6.28 g, 15.1 mmol) in freshly distilled MeOH (70
mL). The mixture was vigorously stirred for 1 h at room
temperature. After filtration over a Celite pad, the crude
material was concentrated. Et2O was added and the organic
layer was washed twice with 10% Na2CO3 and brine, dried
over MgSO4, and concentrated to an oil. A mixture of this oil
(1.87 g, 6.8 mmol), 10% Pd/C (500 mg), and Boc2O (1.63 g, 7.5
mmol) in MeOH was stirred overnight at room temperature
under hydrogen. After filtration over a Celite pad and con-
centration, the crude material was purified by flash chroma-
tography (pentane/ethyl acetate, 95/5), leaving an oil (1.6 g,
(2R,3R)-3-P h en ylsu lfa n ylm et h yl-1-(1-p h en yl-et h yl)-
p yr r olid in e-2-ca r boxylic a cid m eth yl ester 20: Same
protocol as for compound 12: LDA (28.35 mL, 56.7 mmol),
amine 19 (14 g, 56.7 mmol), THF (110 mL), ZnBr2 (1 M in
Et2O, 142 mL), CuCN/2LiCl (1M in THF, 57 mL), and PhSSO2-
Ph (14.2 g, 56.7 mmol). After the usual workup and purifica-
tion by flash chromatography (cyclohexane/ethyl acetate, 92/
8), a pale yellow glue (15 g, 74%) was obtained: [R]20 D 24 (c 1,
2264 J . Org. Chem., Vol. 68, No. 6, 2003

Amino-Zinc-Enolate Carbometalation Reactions
1
87%). [R] 20 -38 (c 1, CHCl3); H NMR (250 MHz, CDCl3) δ
29.3, 29.1, 28.4, 28.3, 27.6, 22.1, 21.5. Anal. Calcd for C14H25-
NO4: C, 61.96; H, 9.29; N, 5.16. Found: C, 61.80; H, 9.43; N,
5.09.
D
4.64-4.55 (2d, 1H, Boc cis-trans isomerization, J ) 7.75 Hz),
3.97-3.96 (2s, 3H, Boc cis-trans isomerization), 3.92 (m, 1H),
3.53 (m, 1H), 2.23 (m, 2H), 2.02 (m, 1H), 1.72-1.66 (2s, 9H,
Boc cis-trans isomerization), 1.30 (d, 3H, J ) 6.5 Hz), 1.16
(d, 3H, 6.5H). 13C NMR (62.5 MHz, CDCl3) δ 172.6, 79.8, 62.3,
61.6, 51.6, 51.4, 50.6, 46.2, 45.9, 29.3, 29.1, 28.4, 28.3, 27.6,
22.1, 21.5. Anal. Calcd for C14H25NO4: C, 61.96; H, 9.29; N,
5.16. Found: C, 61.80; H, 9.43; N, 5.09.
(2S,3R)-3-Isop r op yl-1-(ter t-bu tyloxyca r bon yl)-p yr r oli-
d in e-2-ca r boxylic a cid m eth yl ester 25: LDA (2.52 mL,
5.05 mmol) was added to compound 24 (1.35 g, 5 mmol) in dry
THF at -78 °C under argon. The temperature was brought to
rt and the reaction mixture was quenched by saturated
aqueous NH4Cl. Et2O was added and the organic layer was
washed with brine and dried over MgSO4, leaving an oil (1.28
g, 95%) after concentration and purification by flash chroma-
tography (pentane/ethyl acetate, 95/5). [R] 20D -27 (c 1, CHCl3).
1H NMR (250 MHz, CDCl3) δ 4.64-4.55 (2d, 1H, Boc cis-trans
isomerization, J ) 7.75 Hz), 3.97-3.96 (2s, 3H, Boc cis-trans
isomerization), 3.92 (m, 1H), 3.53 (m, 1H), 2.23 (m, 2H), 2.02
(m, 1H), 1.72-1.66 (2s, 9H, Boc cis-trans isomerization), 1.30
(d, 3H, J ) 6.5 Hz), 1.16 (d, 3H, 6.5H). 13C NMR (62.5 MHz,
CDCl3) δ 172.6, 79.8, 62.3, 61.6, 51.6, 51.4, 50.6, 46.2, 45.9,
(2S,3R)-3-Isop r op yl-1-(ter t-bu tyloxyca r bon yl)-p yr r oli-
d in e-2-ca r boxylic a cid 26: A solution of compound 25 (1.03
g, 4 mmol) and LiOH (95.6 mg, 4 mmol) in CH3CN/H2O (6 mL,
1/1) was stirred for 5 h at rt. After concentration to 3 mL, water
was added. The aqueous phase was extracted twice with ethyl
acetate. The pH was adjusted to 2 by slow addition at 0 °C of
HCl (3 M). The aqueous phase was extracted twice again with
ethyl acetate. The organic layer was dried over MgSO4 and
concentrated, giving an oil, which was crystallized with ether/
pentane yielding white pellets (988 mg, 96%). [R] 20D -44 (c 1,
CHCl3); mp 88-90 °C. 1H NMR (250 MHz, CDCl3) δ 4.1-3.95
(2d, 1H, Boc cis-trans isomerization, J ) 7.5 Hz), 3.55 (m,
1H), 3.4 (m, 1H), 2.17 (m, 1H), 2.02 (m, 1H), 1.70 (m, 1H),
1.46-1.42 (2s, 9H, Boc cis-trans isomerization), 0.99 (d, 3H,
J ) 7.5 Hz), 0.93 (d, 3H, 7.5 Hz). 13C NMR (62.5 MHz, CDCl3)
δ 179.8, 177.6, 155.3, 153.9, 80.6, 80.4, 62.6, 54.4, 49.5, 46.3,
45.9, 30.3, 28.4, 28.3, 27.6, 26.9, 21.1, 19.5, 19.3 Anal. Calcd
for C13H23NO4: C, 60.68; H, 9.01; N, 5.44. Found: C, 60.62;
H, 9.02; N, 5.30.
J O026535N
J . Org. Chem, Vol. 68, No. 6, 2003 2265