Diastereoselective synthesis of α,α-disubstituted γ-carboxypyroglutamates via Sm(III)-azomethine ylide cycloadditions

Article abstract of DOI:10.1021/jo961418b

Sm(III)-azomethine ylides 2 have been generated from ketones 1. Cycloaddition of ylides 2 with α,β-unsaturated esters 3 through a transition state chelation-controlled by the metal allowed for the asymmetric synthesis of γ-carboxypyroglutamates having a quaternary α-carbon that are potentially useful in the synthesis of neuroprotective agents.

Full text of DOI:10.1021/jo961418b

J . Org. Chem. 1997, 62, 479-484
479
Dia ster eoselective Syn th esis of r,r-Disu bstitu ted
γ-Ca r boxyp yr oglu ta m a tes via Sm (III)-Azom eth in e Ylid e
Cycloa d d ition s
Carlos Alvarez-Ibarra,* Aurelio G. Csa´ky¨, Isabel Lo´pez de Silanes, and M. Luz Quiroga
Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense,
28040 Madrid, Spain
Received J uly 24, 1996X
Sm(III)-azomethine ylides 2 have been generated from ketones 1. Cycloaddition of ylides 2 with
R,â-unsaturated esters 3 through a transition state chelation-controlled by the metal allowed for
the asymmetric synthesis of γ-carboxypyroglutamates having a quaternary R-carbon that are
potentially useful in the synthesis of neuroprotective agents.
The implication of glutamate receptors in Alzheimer’s
disease1,2 and the therapeutic potential of substituted
glutamic acid derivatives in the treatment of epilepsy3
and stroke4 has paved the way for the asymmetric
F igu r e 1.
synthesis of these unnatural R-amino acids. In particu-
lar, certain derivatives of δ-carboxyglutamic acid are
potent antagonists of the NMDA receptor with potential
application in drug design of neuroprotective agents.5
Pyroglutamates (5-oxopyrrolidine-2-carboxylates) can
be thought of as glutamic acid derivatives having the
carboxylate γ to nitrogen internally protected (Figure 1,
R1 ) H).6,7 The conformational constraints induced by
these subunits in peptides can lead to their enhanced
bioactivity and stability, which has found pharmacologi-
cal use.8 Thus, R-alkyl R-amino acids have assumed an
important role in bioorganic chemistry as subunits for
the definition of the secondary structure in de novo design
of peptides and proteins.9 However, few efforts have been
directed toward the preparation of glutamic derivatives
with quaternary carbons7,10 (Figure 1, R1 ) alkyl), despite
the significant conformational modifications that this
substitution could induce in peptides. For example, a
total synthesis of (+)-lactacystin, a novel neurotrophic
agent with an R-quaternized pyroglutamate skeleton, has
been recently reported.2
erocyclic rings with good diastereoselectivity.11 Highly
substituted proline derivatives have been synthesized by
using metalloazomethine ylides as the dipole.12,13 This
approach affords prolines C-substituted on C-5. In order
to prepare pyroglutamate derivatives instead of prolines,
we have chosen the iminodithiocarbonate14 group as the
azomethine counterpart in place of aldimines or ketimines.
Sulfur-substituted azomethine ylides have been used
frequently as synthetic equivalents of otherwise relatively
accesible nitrile ylides by a cycloaddition and elimination
sequence to give cycloaddition products one oxidation
state higher than that expected from simple azomethine
ylides.15 In this work we have developed the synthetic
equivalence between the iminodithiocarbonate group and
the lactam moiety of the pyroglutamic derivatives.16
High diastereoselectivities in the cycloaddition process
could be expected by using Sm(III)-azomethine ylides as
1,3-dipoles due to the high coordination number of this
cation,17 which should favor tightly coordinated reaction
intermediates.
1,3-Dipolar cycloadditions constitute one of the most
useful methods for the synthesis of five-membered het-
We describe herein the generation of the Sm(III)-
azomethine ylides 2 via SmI2-induced fragmentation18 of
X Abstract published in Advance ACS Abstracts, December 15, 1996.
(1) Bridges, R. J .; Geddes, J . W.; Monaghan, D. T.; Cotman, C. W.
In Excitatory Amino Acids in Health and Disease; Lodge, D., Ed.;
Wiley: New York, 1988; p 321.
(2) Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.; Sprengeler,
P. A.; Smith, A. B., III. J . Am. Chem. Soc. 1996, 118, 358.
(3) Patel, S.; Chapman, A. G.; Millan, M. H.; Meldrum, B. S. In
Excitatory Amino Acids in Health and Disease; Lodge, D., Ed.; Wiley:
New York, 1988; p 353.
(9) (a) Khosla, A.; Stachowiak, K.; Smeby, R. R.; Bumpus, F. M.;
Piriou, F.; Litner, K., Fermandjian, S. Proc. Natl. Acad. Sci. U.S.A.
1981, 78, 757. (b) Valle, G.; Crisma, M.; Toniolo, C.; Beisswenger, R.;
Rieker, A.; J ung, G. J . Am. Chem. Soc. 1989, 111, 6828. (c) Fang, C.;
Ogawa, T.; Suemune, H.; Sakai, K. Tetrahedron Asymmetry 1991, 2,
389. (d) Fuji, K.; Tanaka, K.; Mizuchi, M.; Hosoi, S. Tetrahedron Lett.
1991, 32, 7277. (e) Altmann, K.-H.; Altmann, E.; Mutter, M. Helv.
Chim. Acta 1992, 75, 1198. (f) Stinson, S. C. Chem. Eng. News 1992,
252, 46. (g) Berkowitz, D. B.; Smith, M. K. J . Org. Chem. 1995, 60,
1233.
(4) Steinberg, G. K.; Saleh, J .; Kuniss, D.; De la Paz, R.; Zarnegar,
S. R. Stroke 1989, 20, 1247.
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Protein Res. 1993, 41, 567.
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Garc´ıa Ruano, J . L. Tetrahedron Lett. 1993, 34, 4989.
(7) Differentiation of the carboxylates of glutamic acid derivatives
has also been successfully achieved via phenylfluorenyl N-protection.
See: (a) Koskenin, A. M. P.; Rapoport, H. J . Org. Chem. 1989, 54, 1859.
(b) Ibrahim, H. H.; Lubell, W. D.; J . Org. Chem. 1993, 58, 6438.
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D. E.; Kahn, M.; Madison, V. S.; Rusiecki, V.; Sarabu, R.; Sepinwall,
J .; Vincent, G. P.; Voss, M. E. J . Med. Chem. 1993, 36, 3099. (d)
Burgess, K.; Ho, K.-K.; Pettitt, B. M. J . Am. Chem. Soc. 1995, 117, 54.
(10) The creation of an asymmetric quaternary center is one of the
most challenging problems in organic chemistry. See, for example: (a)
ApSimon, J . W.; Collier, T. L. Tetrahedron 1986, 42, 5157. (b) Martin,
S. F. Tetrahedron 1990, 46, 419. (c) Fuji, K. Chem. Rev. 1993, 93, 2037.
(11) (a) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley Inter-
science: New York, 1984. (b) Vedejs, E.; West, F. G. Chem. Rev. 1986,
86, 941. (c) Grigg, R. Tetrahedron Asymmetry 1995, 6, 2475.
(12) See, for example: (a) Anunziata, R.; Cinquini, M.; Cozzi, F.;
Raimondi, L.; Pilati, T. Tetrahedron Asymmetry 1991, 2, 1329. (b) Barr,
D. A.; Dorrity, M. J .; Grigg, R.; Hargreaves, S.; Malone, J . F.;
Montgomery, J .; Redpath, J .; Stevenson, P.; Thornton-Pett, M. Tetra-
hedron 1995, 51, 273. (c) Allway, P.; Grigg, R. Tetrahedron Lett. 1991,
32, 5817 and references cited therein.
(13) (a) Galley, G.; Liebscher, J .; Pa¨tzel, M. J . Org. Chem. 1995,
60, 5005. (b) Waldman, H.; Bla¨ser, E.; J ansen, M.; Letschert, H.-P.
Chem. Eur. J . 1995, 1, 150.
(14) (a) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1975, 14, 424. (b)
Hoppe, D.; Beckmann, L. Liebigs Ann. Chem. 1979, 2066.
S0022-3263(96)01418-1 CCC: $14.00 © 1997 American Chemical Society

480 J . Org. Chem., Vol. 62, No. 3, 1997
Alvarez-Ibarra et al.
Sch em e 1
in the reaction of ketone 1a (Table 1, entry 1). Ethyl
2-benzoylpropionate (6) was isolated in 50% yield.
Monitoring of the reaction of ketone 1a with ester 3a
by TLC (hexane-ethyl acetate, 80:20) showed the forma-
tion of alaninate 5a at the early stages of the process at
the expense of the starting material.20 In a similar
fashion, formation of phenylglycinate 5b was observed20
in the reactions of ketone 1b.
On the other hand, treatment of ketone 7 with SmI2
(2.0 equiv) in THF and ester 3a (1.5 equiv) in the
presence of tBuOH (1.0 equiv) allowed for the formation
of lactone 8a (95% de). Compound 8a isomerized on
standing in CHCl3 solution (72 h, 25 °C) to a 55:45
mixture of 8a and 8b.
Discu ssion
Gen er a tion of Ylid es 2 a n d Cycloa d d ition w ith
Ester s 3. The generation of radical anions by a single
electron transfer from SmI2 is a well-documented pro-
cess.21 These radical anions are readily prone to unimo-
lecular fragmentation22 to produce a radical species plus
an anion. This process is kinetically favored over dimer-
ization or C-C bond formation. Out of the two possible
reaction paths for the unimolecular fragmentation, the
one that produces the most stable anionic fragment will
be thermodynamically favored23 (eqs 1 and 2).
Ta ble 1. 1,3-Dip ola r Cycloa d d ition of Azom eth in e Ylid es
2 w ith Ester s 3. Syn th esis of 4
no.
R1
R2
4
4, dea (%)
4,b %
1
2
3
4
CH3
CH3
PhCH2
PhCH2
CH3
iBu
4a
4b
4c
4d
80
80
80
85
85
80
75
75
CH3
iBu
In the presence of SmI2, ketyl radical formation from
ketones 1a ,b is to be expected.21,24 Steric hindrance
would prevent dimerization or C-C bond-forming pro-
cesses at the expense of the unimolecular fragmentation
to ylides 2 (Scheme 2, path A). The latter will be
thermodynamically favored as a consequence of extended
resonance stabilization.25
This reaction pathway is supported by the following
facts: (1) When the reactions of ketones 1a ,b (1.0 equiv)
with ester 3a (1.5 equiv) and SmI2 (1.0 equiv) were
a
Determined by integration of the 1H-NMR spectra (CDCl3, 300
b
MHz) of the crude reaction products. Pure isolated yields.
compounds 114 and their 1,3-dipolar cycloaddition with
the R,â-unsaturated esters 3. This affords the pyro-
glutamates 4, which are γ-carboxyglutamic derivatives
in which a quaternary center has been asymmetrically
introduced in the R-position of the amino acid moiety
(Scheme 1).
Resu lts
(15) (a) Padwa, A.; Haffmanns, G.; Tomas, M. Tetrahedron Lett.
1983, 24, 4304. (b) Padwa, A.; Haffmanns, G.; Tomas, M. J . Org. Chem.
1984, 49, 3314. (c) Kraus, G. A.; Nagy, J . O. Tetrahedron 1985, 41,
3537. (d) Turro, N. J .; Cha, Y.; Gould, I. R.; Padwa, A.; Gasdaska, J .
R.; Tomas, M. J . Org. Chem. 1985, 50, 4415. (e) Tsuge, O.; Kanemasa,
S.; Matsuda, K. J . Org. Chem. 1986, 51,1997. (f) Padwa, A.; Gasdaska,
J . R.; Tomas, M.; Turro, N. J .; Cha, Y.; Gould, I. R. J . Am. Chem. Soc.
1986, 108, 6739. (g) Tsuge, O.; Kanemasa, S.; Yamada, T.; Matsuda,
K. J . Org. Chem. 1987, 52, 2523. (h) Padwa, A.; Gasadaska, J . R.;
Haffmanns, G.; Rebello, H. J . Org. Chem. 1987, 52, 1027. (i) Pearson,
W. H.; Stevens, E. P. Tetrahedron Lett. 1994, 35, 2641.
(16) (a) Bachi, M. D.; Melman, A. J . Org. Chem. 1995, 60, 6242. (b)
Bachi, M. D.; Melman, A. Synlett 1996, 60.
Gen er a tion of Ylid es 2 a n d Cycloa d d ition to
Ester s 3. Compounds 1 were obtained by acylation or
benzylation of N-[bis(methylthio)methylene]alanine ethyl
ester (5a ) or phenylalanine ethyl ester (5b) (KOtBu, THF)
as previously described.14 Addition of a THF solution of
1a ,b (1.0 equiv) and the corresponding ester 3 (1.5 equiv)
to a freshly prepared 0.1 M solution of SmI2 in THF (1.0
equiv) followed by in situ hydrolysis (1 N HCl) of the
initial adducts19 allowed for the isolation of pyro-
glutamates 4 in good yields (Scheme 1, Table 1).
(17) Evans, W. J .; Gummersheimer, T. S.; Ziller, J . W. J . Am. Chem.
Soc. 1995, 117, 8999.
(18) This reaction constitutes a novel application of SmI2 in organic
synthesis. See: Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96,
307.
(19) Alvarez Ibarra, C.; Csa´ky¨, A. G.; Mart´ınez, M.; Quiroga, M. L.
Tetrahedron Lett. 1996, 37, 6573.
(20) This observation was confirmed by aqueous quenching of the
reaction followed by isolation and characterization of 5a ,b.
(21) Eo Sm(II)/Sm(III) ) -1.55 V. See: Hasegawa, E.; Curran, D.
P. J . Org. Chem. 1993, 58, 5008.
(22) (a) Kochi, J . K. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 7, p 849.
(b) Dalko, P. I. Tetrahedron 1995, 51, 7579.
Only two out of the four possible diastereomers were
observed in the 1H-NMR spectra of the crude reaction
products, and one stereoisomer was always formed in
large excess. Fractional crystallization of the mixture
allowed for the isolation of the major one as a single
diastereomer. A slight drop in yield was noticed upon
increasing the steric volume of either R1 or R2, whereas
diastereoselectivity was scarcely modified.
On the other hand, treatment of ketone 1c with SmI2
and ester 3a under the aforementioned reaction condi-
tions gave rise to pyroglutamate 4a in only 45% yield.
However, the same diastereoselectivity was observed as
(23) Melton, C. E. In Mass Spectrometry of Organic Ions; McLafferty,
F. W., Ed.; Academic Press: New York, 1963; p 65.
(24) Redox potential of acetone: E ) -0.925 V. See: Kita, H.;
Ishikura, S.; Katayama, A. Electrochim. Acta 1975, 20, 441.

Synthesis of R,R-Disubstituted γ-Carboxypyroglutamates
Sch em e 2
J . Org. Chem., Vol. 62, No. 3, 1997 481
Sch em e 3
quenched (H2O addition) prior to completion, 5a and 5b
were isolated together with the corresponding adducts
9a ,b. Esters 5a ,b should arise from protonation of ylides
2. This proves that ketones 1a ,b fragment prior to
reaction with the dipolarophile (Scheme 2). (2) At this
stage the formation of adducts 9 could be explained either
by the cycloaddition of the azomethine ylides 2 (path A)
or by the radical addition of species 10 (path B). It could
also explain the formation of adducts 9 (Scheme 2, path
B). In order to rule out the second possibility, ketones
1a ,b were treated with ester 3a (1.0 equiv), SmI2 (2.0
Sch em e 4
t
equiv), and BuOH (1.0 equiv). Now, the presence of a
second equivalent of SmI2 should enforce the reduction
of the hypothetical radical species 10 to the anions 2
(Scheme 2, path C), thus securing the cycloaddition
pathway. Ester 5a ,b should stem from competition of
ylides 2 between protonation by tBuOH and cycloaddition
with ester 3a . If a change in mechanism were operating,
a change in diastereoselectivity should be observed.
However, the reaction afforded esters 5a ,b and adducts
9a ,b after quenching with H2O, and the latter were
obtained with the same diastereoselectivity as in previous
runs.26,27 This excludes the participation of path B in the
formation of 9a ,b and hence 4a ,b. (3) The presence of
the ester moiety in 1 is crucial for the outcome of the
process, in order to thermodynamically favor the forma-
tion of ylides 2 (Scheme 2, path A). Thus, lactone 8a was
kinetically formed in the reaction of 3a with ketone 7, in
which the ester group had been replaced by phenyl.
Lactone 8a can be formed by reduction of the carbonyl
group by a single electron transfer process followed by
1,4-addition of the resulting ketyl radical to the R,â-
unsaturated ester via a transition state that probably
involves chelation between the ester group, the oxygen
atom of the ketyl radical, and the sp2 nitrogen of the
iminodithiocarbonate moiety (Scheme 3).28
bonate moiety. Fragmentation of the former gives rise
to ylide 2a , which cycloadds to ester 3a , affording pyro-
glutamate 4a after acid hydrolysis (Scheme 2). Frag-
mentation of the alternate radical anion gives rise to
compound 6 after loss of the bis(methyltio)imine radical
and protonation of the resulting anion (Scheme 4).
It is worth mentioning that we were not able to prepare
ylide 2a either by transmetalation31 with SmCl3 of the
lithium enolates derived from 5a or by deprotonation of
5a with Sm(HMDS)3.32 Compound 9e (Scheme 2, R1 )
The reduction potential of aromatic ketones29 is more
negative than that of aliphatic ones and closer to that
of imines.30 Therefore, upon treatment of ketone 1c with
SmI2 (1.0 equiv) and ester 3a , ketyl anion formation
competes with electron transfer to the iminodithiocar-
(27) Treatment of THF solutions of 7a ,b with 0.5 N HCl gave rise
to pyroglutamates 4a (90% yield) and 4b (85% yield).
(28) (a) Kawatsura, M.; Matsuda, F.; Shirama, H. J . Org. Chem.
1994, 59, 6900. (b) Kawatsura, M.; Dekura, F.; Shirahama, H.;
Matsuda, F. Synlett 1996, 373.
(29) Redox potential of acetophenone: E ) -1.6 V. See: Kryukova,
E. V.; Tomilov, A. P. Zh. Prikl. Khim. 1972, 45, 861. See ref 26 for
comparison with acetone.
(25) Retroaldol condensation has been observed in the nucleophilic
additions of stabilized carbanions to ketones 1a ,b in THF at -78 °C.
See: Alvarez-Ibarra, C.; Domı´nguez, C., Csa´ky¨, A. G.; Mart´ınez Santos,
E.; Quiroga, M. L. Tetrahedron Lett. 1993, 34, 5463.
(26) 2-Methylthio-∆1-pyrrolines 9 were obtained as mixtures of two
diastereomers in equal ratios as that observed for the corresponding
pyroglutamates 4 (Table 1). See ref 18.
(30) Iwasaki, T.; Harada, K. J . Chem. Soc., Chem. Commun. 1974,
338.

482 J . Org. Chem., Vol. 62, No. 3, 1997
Alvarez-Ibarra et al.
H, R2 ) CH3) had been previously obtained with low
diastereoselectivity from the Michael addition of 3a with
N-[bis(methylthio)methylene]glycine ethyl ester (5c, R1
) H) under PTC conditions and from the corresponding
Li or K enolates.33 This procedure failed for compounds
5a (R1 ) CH3) and 5b (R1 ) PhCH2).
Sch em e 5
Str u ctu r a l Assign m en t of P yr oglu ta m a tes 4. Acid
hydrolysis of adducts 9 afforded pyroglutamates 4. The
structural assignment of 4a relies on the comparison of
1
the H-NMR spectrum of 9a with that of 9e33,34 (Scheme
2, R1 ) H, R2 ) CH3) and on the 1D NOE spectra. Thus,
upon irradiation of the CH3-C4 signal of 9a (δ ) 1.15, d,
3J ) 7 Hz) a 5% enhancement was observed for the H-3
Semiempirical calculations (AM1) carried out for the
minimum energy conformations35 of both isomers 8
showed that 8b was thermodynamically more stable by
3 kcal/mol (8a , E ) -40.78 kcal/mol. 8b, E ) -43.75
kcal/mol), in agreement with the isomerization of 8a into
8b observed experimentally. This allowed for the pro-
posed assignment of a (1′S*,3S*,4R*) geometry for 8a and
a (1′R*,3S*,4R*) geometry for 8b (Scheme 5).
Ster eoch em ica l Con sid er a tion s. Sm(III)-azometh-
ine ylides 2 underwent highly stereoselective 1,3-di-
polar cycloadditions with esters 3 (Table 1). We assume
that this good diastereofacial selectivity can be accounted
for by a highly ordered endo transition state13 in which
the Sm(III) cation is coordinated to the heteroatoms of
both dipole and dipolarophile (Figure 2). This type of
coordination would not be possible in an exo transition
state.36
3
signal (δ ) 3.42, d, J ) 10 Hz), whereas no NOE effect
was observed on the CH3S signal (δ ) 2.46, s). On the
other hand, a 2% enhancement of the CH3S signal was
observed upon irradiation of H-3.
The relative configuration of the three contiguous
asymmetric centers of compound 4a has been determined
by its 2D-NOESY spectrum. Thus, the observation of a
cross peak between C-3 methyl and C-4 hydrogen is in
agreement with an anti geometry between the C-3 methyl
and the carboxylate group in C-4. A strong correlation
peak between C-2 and C-3 methyl groups together with
a relatively weak cross-peak between C-2 methyl and C-3
hydrogen allowed for the establishment of a syn geometry
between C-2 and C-3 methyl groups. A weak correlation
between C-2 methyl and C-4 hydrogen was also present,
in agreement with previous assignments.
The examination of the NMR spectra (13C and 1H
shifts, 3J H-H couplings) supported an identical structure
and relative stereochemistry of the ring carbon atoms of
all major isomers of 4 (see Experimental Section). Hence,
in all compounds 4, the relative orientation of the
substituents at C-3/C-4 is anti, and the ester group on
C-2 is always anti to the alkyl substituent on C-3
(Scheme 1).
Assign m en t of th e Rela tive Con figu r a tion s of
La cton es 8. The relative configuration of carbons C-3
and C-4 of the lactone moiety of compounds 8a and 8b
has been determined by their 1D-NOE spectra. Satura-
tion of the C-3 methyl group signal of both isomers (8a ,
δ ) 1.04 ppm, d; 8b, δ ) 1.04 ppm, d) allowed for an
enhancement of the H-2R (8a , δ ) 2.16 ppm, dd; 8b, δ )
2.00 ppm, dd) and H-1′ (8a , δ ) 4.85 ppm, s; 8b, δ )
4.61 ppm, s) signals. NOE effects on the phenyl (8a , 8b,
δ ) 7.32-7.20 ppm, m), H-1′ (8a , δ ) 4.85 ppm, s; 8b, δ
) 4.61 ppm, s), H-2â (8a , δ ) 2.83 ppm, dd; 8b, δ ) 2.81
ppm, dd), and H-3 (8a , 8b, 2.47-2.40, m) were noticed
upon saturation of the C-4 methyl group signal of both
isomers (8a , δ ) 1.44 ppm, s; 8b, δ ) 1.50 ppm, s). This
allowed for the establishment of an anti relative disposi-
tion between the C-3 and C-4 methyl groups. However,
the relative configuration of C-1′ remained ambiguous.
F igu r e 2.
The proposed model accounts for the slight drop in
yield observed upon increasing the steric volume of either
R1 or R2. Note that diastereoselectivity scarcely changed
with the size of substituents, as consequence of the
predominance of orbital overlap in the discussed transi-
tion states.
Con clu sion s
The 1,3-dipolar cycloaddition of the Sm(III)-azomethine
ylides 2 with R,â-unsaturated esters 3 takes place under
chelation control by the iminodithiocarbonate group and
the carboxylate groups of dipole and dipolarophile. This
(35) For the AM1 Hamiltonian see: Dewar, M. S. J .; Zoebisch, E.
G.; Healy, E. F.; Stewart, J . J . P. J . Am. Chem. Soc. 1985, 107, 3902.
Minimum energy conformers have been located by simulated anneal-
ing. See: (a) Kirkpatrick, S.; Gelatt, C. D.; Vecchi, M. P. Science 1983,
220, 671. (b) Wilson, S. R.; Cui, W.; Moskowitz, J . W.; Schmidt, K. W.
Tetrahedron Lett. 1988, 29, 4373. The MMX force field was used in
the molecular dynamics simulations: Gajewski, J . J .; Gilbert, K. E.;
McKelvey, J . In Advances in Molecular Modeling; J AI Press: Green-
wich, 1990; Vol. 2. The conformers obtained from the simulated
annealing molecular dynamics calculations were further optimized
manually, searching by rotation of the CH3-C4-C1′-H torsional angle
followed by an AM1 minimization with the Polak-Ribiere conjugated
gradient up to a gradient root mean square <0.1 kcal/A mol. The
minimum energy conformers thus obtained for 8a and 8b differred by
more than 2 kcal from their next minimum energy conformation.
(36) Chelation between carbonyl groups and Sm(III) has been
advanced as an important elements in the stereochemical control of
ketyl radical additions. See ref 28 and references cited therein.
(31) A mixed enolate species of soft reactivity could be formed under
these reaction conditions. See: van der Steen, F. H.; Boersma, J .; Spek,
A.-L., van Koten, G. Organometallics 1991, 10, 2476.
(32) For the preparation of Sm(HMDS)3 from SmCl3 and NaHMDS
see: Bradley, D. C.; Ghotra, J . S.; Hart, F. A. J . Chem. Soc., Dalton
Trans. 1973, 1021. For the generation of ketone Sm(III)-enolates with
Sm(HMDS)3 see: Sasai, H.; Arai, S.; Shibasaki, M. J . Org. Chem. 1994,
59, 2661. This base could be not strong enough for ester deprotonation.
For a comparison of LDA and Li(HMDS) in ester deprotonation see:
Williard, P. G.; Liu, Q.-Y. J . Am. Chem. Soc. 1992, 114, 348.
(33) Alvarez-Ibarra, C.; Csa´ky¨, A. G.; Maroto, M.; Quiroga, M. L. J .
Org. Chem. 1995, 60, 6700.
(34) 1H-NMR (300 MHz, CDCl3) of 9e: δ (ppm) 4.24 (2H, q, 3J ) 7
Hz), 4.19 (1H, dd, 3J ) 6 Hz, 4J ) 2 Hz), 3.77 (3H, s), 3.41 (1H, dd, 3J
) 9 Hz, 4J )2 Hz), 3.05 (1H, m), 2.49 (3H, s), 1.31 (3H, t, 3J ) 7 Hz),
1.21 (3H, d, 3J ) 7 Hz).

Synthesis of R,R-Disubstituted γ-Carboxypyroglutamates
J . Org. Chem., Vol. 62, No. 3, 1997 483
(85%); IR (CHCl3) ν 1710, 1680 cm-1
1H-NMR (300 MHz,
;
allows for the asymmetric synthesis of γ-carboxyglutamic
acid derivatives having the R-carbon quaternized, which
were not accesible by previously reported procedures.33
CDCl3) δ (ppm) 4.23 (2H, qd, J ) 7, 5 Hz), 3.78 (3H, s), 3.45
(1H, d, J ) 10 Hz), 3.18 (1H, td, J ) 7, 10 Hz), 2.45 (3H, s),
1.49-1.32 (3H, m), 1.28 (3H, t, J ) 7 Hz), 1.23 (3H, s), 0.89
(3H, d, J ) 7 Hz), 0.85 (3H, d, J ) 7 Hz); 13C-NMR (75.5 MHz,
CDCl3) δ (ppm) 174.1, 170.5, 169.3, 79.3, 62.2, 61.4, 52.7, 47.1,
39.2, 26.6, 23.6, 21.8, 19.3, 14.2, 13.9. Anal. Calcd for
C15H25NO4S: C, 57.12; H, 7.99; N, 4.44. Found:C, 57.259; H,
8.03; N, 4.61.
Exp er im en ta l Section
All starting materials were commercially available research-
grade chemicals and used without further purification. Silica
gel 60 F254 was used for TLC, and the spots were detected
either with UV or with vanillin solution. Flash column
chromatography was carried out on silica gel 60. IR spectra
have been recorded as CHCl3 solutions. Melting points are
uncorrected. 1H and 13C NMR spectra were recorded at 300
and 75.5 MHz, respectively, in CDCl3 solution with TMS as
internal reference, and full assignment of 13C NMR spectra
has been carried out with the aid of the DEPT-135 pulse
sequence. MS spectra were carried out by electron impact at
70 eV. SmI2 was synthesized from Sm and 1,2-diiodoethane.
Worse results were obtained with commercial solutions of SmI2
in THF.
(3S*,4S*,5S*)-5-Ben zyl-5-(eth oxyca r bon yl)-3-(m eth oxy-
ca r bon yl)-4-m eth yl-2-(m eth yth io)-∆1-p yr r olin e (9c): oil
(80%); IR (CHCl3) ν 1710, 1680, 1650 cm-1; 1H-NMR (300 MHz,
CDCl3) δ (ppm) 7.11-7.29 (5H, m), 4.15 (2H, m), 3.75 (3H, s),
3.29 (1H, d, J ) 14 Hz), 3.21 (1H, d, J ) 11 Hz), 2.99, 2.95
(1H, dq, J ) 11, 4 Hz, 2.68 (1H, d, J ) 14 Hz), 2.49 (s, 3H),
1.32 (3H, d, J ) 7 Hz), 1.22 (3H, t, J ) 7 Hz); 13C-NMR (75.5
MHz, CDCl3) δ (ppm) 173.2, 169.7, 169.6, 136.5, 130.7, 128.0,
126.7, 82.2, 62.7, 61.2, 52.7, 45.8, 39.3, 14.2, 14.0, 13.3. Anal.
Calcd for C18H23NO4S: C, 61.87; H, 6.63; N, 4.01. Found: C,
62.05; H, 6.61; N, 4.02.
(3S*,4S*,5S*)-5-Ben zyl-4-isobu tyl-5-(eth oxyca r bon yl)-3-
(m eth oxyca r bon yl)-2-(m eth ylth io)-∆1-p yr r olin e (9d ): oil
(80%); IR (CHCl3) ν 1710, 1690, 1660 cm-1; 1H-NMR (300 MHz,
CDCl3) δ (ppm) 7.28-7.18 (5H, m), 4.20 (2H, m), 3.74 (3H, s),
3.30 (1H, d, J ) 14 Hz), 3.23 (1H, d, J ) 10 Hz), 3.12-3.03
(1H, m), 2.66 (1H, d, J ) 14 Hz), 2.65 (3H, s), 1.76-1.66 (2H,
m), 1.62-1.53 (1H, qd, J ) 14, 7 Hz), 1.25 (3H, t, J ) 7 Hz),
0.93 (3H, d, J ) 7 Hz), 0.87 (3H, d, J ) 6 Hz); 13C-NMR (75.5
MHz, CDCl3) δ (ppm) 173.1, 170.3, 169.4, 136.5, 130.7, 127.8,
126.5, 82.7, 62.3, 61.1, 52.6, 48.7, 39.4, 38.6, 26.5, 23.9, 21.2,
14.1, 13.8. Anal. Calcd for C21H29NO4S: C, 64.42; H, 7.47;
N, 3.58. Found: C, 64.23; H, 7.49; N, 3.59.
Gen er a l P r oced u r e for Cycloa d d ition of Ylid es 2 w ith
Ester s 3. Step -by-Step P r oced u r e (Meth od A). To a
slurry of samarium metal powder (390 mg, 2.6 mmol, flamed
and cooled under argon) in THF (1.3 mL) at room temperature
was added a solution of 1,2-diiodoethane (560 mg, 2.0 mmol)
in THF (2.5 mL). The mixture was stirred at ambient
temperature for 1 h, during which time the reaction’s color
changed from olive-green to deep blue. The resulting solution
was diluted with THF (16 mL), and a solution of 1 (1.9 mmol)
and 3 (2.85 mmol) in THF (0.5 mL) under Ar was added. After
the reaction mixture had been stirred for 1 h, H2O (2.5 mL)
was added, and the mixture was stirred for 15 min and was
extracted with Et2O (3 × 5 mL). The combined organic phases
were dried over MgSO4 and evaporated to dryness. The
products were separated by flash column chromatography
eluting with a mixture of hexane-ethyl acetate (80:20) and
the products 9 used for the next step.
Syn th esis of P yr oglu ta m a tes 4. To a solution of 9 (0.55
mmol) in THF (1.5 mL) was added 0.5 N HCl (1.5 mL) and
the mixture stirred at room temperature for 24 h. The mixture
was neutralized with 0.5 N NaOH and extracted with Et2O (3
× 5 mL). The combined organic phases were dried over MgSO4
and evaporated to dryness. The products were separated from
the unreacted material by flash column chromatography
eluting with a mixture of hexane-ethyl acetate (80:20) and
finally eluted with ethyl acetate.
(2S*,3S*,4S*)-E t h yl 4-(m et h oxyca r b on yl)-2,3-d im et h -
ylpyr oglu tam ate (4a): mp 81-83 °C (pentane-Et2O) (method
A, 90%; method B, 85%); IR (CHCl3) ν 3300, 3000, 1740, 1710
1
cm-1; H-NMR (300 MHz, CDCl3) δ (ppm) 6.61 (1H, bs), 4.22
(2H, q, J ) 7 Hz), 3.78 (3H, s), 3.15 (1H, d, J ) 10 Hz), 3.07
(1H, qd, J ) 7, 10 Hz), 1.35 (3H, s), 1.26 (3H, t, J ) 7 Hz),
1.19 (3H, d, J ) 7 Hz); 13C-NMR (75.5 MHz, CDCl3) δ (ppm)
172.9, 170.1, 169.2, 62.8, 62.0, 54.6, 52.9, 40.3, 20.9, 14.1, 14.0.
MS 244 (M + 1), 212, 184, 170, 138, 110. Anal. Calcd for
C11H17NO5: C, 54.31; H, 7.04; N, 5.76. Found: C, 54.25; H,
7.25; N, 5.67.
(2S*,3S*,4S*)-Eth yl 3-isobu tyl-4-(m eth oxyca r bon yl)-2-
m eth ylp yr oglu ta m a te (4b): mp 98-100 (method A, 90%;
method B, 80%); IR (CHCl3) ν 3300, 3000, 1750, 1700 cm-1
;
1H-NMR (300 MHz, CDCl3) δ (ppm) 6.20 (1H, bs), 4.21 (2H,
qd, J ) 7, 3 Hz), 3.79 (3H, s), 3.37 (1H, d, J ) 10 Hz), 3.15
(1H, m), 1.61-1.41 (3H, m), 1.35 (3H, s), 1.30 (3H, t, J ) 7
Hz), 0.93 (3H, d, J ) 6 Hz), 0.87 (3H, d, J ) 6 Hz); 13C-NMR
(75.5 MHz, CDCl3) δ (ppm) 172.8, 170.0, 169.7, 62.0, 54.0, 52.9,
42.8, 41.0, 39.5, 25.9, 24.2, 21.2, 21.0, 14.1; MS 286 (M + 1),
228, 212, 180, 152. Anal. Calcd for C14H23NO5: C, 58.93; H,
8.12; N, 4.91. Found: C, 59.05; H, 8.23; N, 5.03.
On e-P ot Syn th esis of P yr oglu ta m a tes 4 (Meth od B).
To a slurry of samarium metal powder (190 mg, 2.6 mmol,
flamed and cooled under argon) in THF (1.3 mL) at room
temperature was added a solution of 1,2-diiodoethane (560
mg, 2.0 mmol) in THF (2.5 mL). The mixture was stirred
at ambient temperature for 1 h during which time the
reaction’s color changed from olive-green to deep blue. The
resulting solution was diluted with THF (16 mL), and a
solution of 1 (1.9 mmol) and 3 (2.8 mmol) in THF (0.5 mL)
under Ar was added. After the reaction mixture had been
stirred for 1 h, 1 N HCl (25 mL) was added and the mixture
stirred at rt for 24 h. The mixture was neutralized with 0.5
N NaOH and extracted with Et2O (3 × 15 mL). The combined
organic phases were dried over MgSO4 and evaporated to
dryness. The products were separated from the unreacted
material by flash column chromatography eluting with a
mixture of hexane-ethyl acetate (80:20) and finally with ethyl
acetate.
(2S*,3S*,4S*)-E t h yl 2-b en zyl-4-(m et h oxyca r b on yl)-3-
m eth ylp yr oglu ta m a te (4c): mp 98-100 °C (pentane-Et2O)
(method A, 85%, method B, 75%); IR (CHCl3) ν 3300, 3000,
1730, 1690, 1600 cm-1 1H-NMR (300 MHz, CDCl3) δ (ppm)
;
7.30-7.21 (3H, m), 7.07-7.04 (2H, m), 5.92 (1H, bs), 4.14 (2H,
qd, J ) 7, 2 Hz), 3.81 (3H, s), 3.30 (1H, d, J ) 11 Hz), 3.27 (d,
J )11 Hz), 3.10 (1H, qd, J ) 7, 9 Hz), 2.66 (1H, d, J ) 12 Hz),
1.39 (3H, d, J ) 7 Hz), 1.20 (3H, t, J ) 7 Hz); 13C-NMR (75.5
MHz, CDCl3) δ (ppm) 176.8, 169.4, 167.0, 134.3, 129.4, 128.4,
127.5, 66.5, 61.8, 54.4, 52.9, 46.0, 41.5, 39.9, 14.0, 13.5. Anal.
Calcd for C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found: C,
64.11; H, 6.75; N, 4.52.
(3S*,4S*,5S*)-5-(Eth oxyca r bon yl)-3-(m eth oxyca r bon yl)-
4,5-d im eth yl-2-(m eth ylth io)-∆1-p yr r olin e (9a ): oil (90%);
IR (CHCl3) ν 1710, 1690 cm-1; H-NMR (300 MHz, CDCl3) δ
(2S*,3S*,4S*)-Eth yl 2-ben zyl-3-isobu tyl-4-(m eth oxyca r -
bon yl)p yr oglu ta m a te (4d ): mp 125-127 °C (method A, 85%;
method B, 75%); IR (CHCl3) ν 3300, 3000, 1730, 1700, 1600
cm-1; 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.29-7.25 (3H, m),
7.07-7.04 (2H, m), 5.91 (1H, bs), 4.18 (2H, qd, J ) 7, 2 Hz),
3.80 (3H, s), 3.30 (1H, d, J ) 12 Hz), 3.29 (d, J ) 11 Hz), 3.14
(1H, qd, J ) 6, 3 Hz), 2.66 (1H, d, J ) 12 Hz), 1.81 (1H, m),
1.62 (2H, m), 1.09 (3H, d, J ) 7 Hz), 0.98 (3H, d, J ) 6 Hz),
0.89 (3H, d, J ) 6 Hz); 13C-NMR (75.5 MHz, CDCl3) δ (ppm)
172.1, 170.0, 169.8, 134.5, 129.8, 128.9, 127.7, 66.8, 61.9, 54.4,
1
(ppm) 4.21 (2H, qd, J ) 7, 2 Hz), 3.78 (3H, s), 3.42 (1H, d,
J ) 10 Hz), 3.11 (1H, qd, J ) 6, 10 Hz), 2.46 (3H, s), 1.29 (3H,
t, J ) 7 Hz), 1.27 (3H, s), 1.15 (3H, d, J ) 7 Hz); 13C-NMR
(75.5 MHz, CDCl3) δ (ppm) 174.0, 169.9, 169.5, 78.9, 62.6, 61.4,
52.7, 44.3, 19.0, 14.2, 13.9, 13.7. Anal. Calcd for C12H19
-
NO4S: C, 52.73; H, 7.01; N, 5.12. Found: C, 52.89; H, 7.03;
N, 5.11.
(3S*,4S*,5S*)-4-Isobu tyl-5-(eth oxyca r bon yl)-3-(m eth ox-
yca r bon yl)-5-m eth yl-2-(m eth ylth io)-∆1-p yr r olin e (9b): oil

484 J . Org. Chem., Vol. 62, No. 3, 1997
Alvarez-Ibarra et al.
53.0, 49.2, 40.4, 38.9, 25.9, 24.5, 20.9, 14.0. MS 262 (M + 1),
288, 270, 238, 210. Anal. Calcd for C20H27NO5: C, 66.46; H,
7.53; N, 3.88. Found: C, 66.60; H, 7.71; N, 3.90.
1680 cm-1; 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.28-7.23 (5H,
m), 4.85 (1H, s), 2.83 (2H, dd, J ) 10, 8 Hz), 2.48 (3H, s), 2.47-
2.42 (4H, m, among which 2.45, 3H, s), 2.16 (dd, J ) 4, 13
Hz), 1.44 (3H, s), 1.04 (3H, d, J ) 7 Hz); 13C-NMR (75.5 MHz,
CDCl3) δ (ppm) 176.3, 161.8, 138.4, 129.0, 127.7, 127.3, 89.4,
61.2, 39.2, 37.6, 20.9, 15.2, 14.8, 14.7. Anal. Calcd for
Rea ction of 1a ,b a n d 7 w ith 3a a n d Sm I2 in th e
t
P r esen ce of Bu OH. To a slurry of samarium metal powder
(156 mg, 1.04 mmol, flamed and cooled under argon) in THF
(0.5 mL) at room temperature was added a solution of 1,2-
diiodoethane (224 mg, 0.8 mmol) in THF (1.0 mL). The
mixture was stirred at ambient temperature for 1 h, during
which time the reaction’s color changed from olive-green to
deep blue. The resulting solution was diluted with THF (6.5
C
16H21NO2S2: C, 59.41; H, 6.54; N, 4.33. Found: C, 59.65; H,
6.60; N, 4.44.
(1′R *,3S *,4R *)-3-Me t h yl-4-[1-[b is(m e t h ylt h io)m e t h -
ylen ea m in o]ben zyl]-4-bu ta n olid e (8b): 45:55 mixture with
8a ; 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.32-7.20 (5H, m),
4.61 (1H, s), 2.81 (2H, dd, J ) 10, 8 Hz), 2.47 (3H, s), 2.45-
2.40 (4H, m, among which 2.45, 3H, s), 2.00 (dd, J ) 4, 13
Hz), 1.50 (3H, s), 0.89 (3H, d, J ) 7 Hz); 13C-NMR (75.5 MHz,
CDCl3) δ (ppm) 178.3, 161.8, 139.9, 129.7, 129.4, 126.9, 83.7,
68.3, 41.9, 41.8, 23.4, 15.2, 14.8, 14.6.
t
mL), and a solution of 1a ,b or 7 (0.4 mmol), BuOH (31 mg,
0.4 mmol), and 3 (60 mg, 0.6 mmol) in THF (0.2 mL) under Ar
was added. After the reaction mixture had been stirred for 1
h, H2O (2.5 mL) was added, and the mixture was stirred for
15 min and was extracted with Et2O (3 × 5 mL). The
combined organic phases were dried over MgSO4 and evapo-
rated to dryness. The products were separated by flash
column chromatography, eluting with a mixture of hexane-
ethyl acetate (80:20).
Isom er iza tion of 8a in to 8b. A solution of 8a (172 mg,
0.5 mmol) in CHCl3 (2.0 mL) was stirred at 25°C for 72 h. The
solution was evaporated to dryness under reduced pressure.
(1′S*,3S*,4R*)-3-Meth yl-4-[1-[bis(m eth ylth io)m eth ylen e-
a m in o]ben zyl]-4-bu ta n olid e (8a ): 85%; IR (CHCl3) ν 1750,
Ack n ow led gm en t. The Direccio´n General de In-
vestigacio´n Cient´ıfica y Te´cnica (Project PB93-0025) is
gratefully acknowledged for financial support. UCM
RMN and Elemental Analysis Services are also
acknowledged.
J O961418B