Cyclopropanation reactions of pyroglutamic acid-derived synthons with akylidene transfer reagents

Article abstract of DOI:10.1021/jo9816109

The cyclopropanation of unsaturated lactams 1 and 3 derived from pyroglutamic acid with nucleophilic alkylidene transfer reagents is investigated. Good-to-modest yields of cyclopropanes were obtained with most sulfur ylides explored. Syn/anti selectivity was found to be dependent on the synthon as well as the sulfur ylide. This cyclopropanation methodology is used in the synthesis of arginine and glutamic acid analogues.

Full text of DOI:10.1021/jo9816109

J . Org. Chem. 1999, 64, 547-555
547
Cyclop r op a n a tion Rea ction s of P yr oglu ta m ic Acid -Der ived
Syn th on s w ith Ak ylid en e Tr a n sfer Rea gen ts
Rui Zhang, Ahmed Mamai, and J ose S. Madalengoitia*
Department of Chemistry, University of Vermont, Burlington, Vermont 05405
Received August 6, 1998
The cyclopropanation of unsaturated lactams 1 and 3 derived from pyroglutamic acid with
nucleophilic alkylidene transfer reagents is investigated. Good-to-modest yields of cyclopropanes
were obtained with most sulfur ylides explored. Syn/anti selectivity was found to be dependent on
the synthon as well as the sulfur ylide. This cyclopropanation methodology is used in the synthesis
of arginine and glutamic acid analogues.
Sch em e 1
As part of our program aimed at the development of
mimics of the poly-L-proline type II (PPII) secondary
structure by the synthesis of oligopeptides composed of
proline templated amino acids (PTAAs), we are involved
in developing methods for the synthesis of substituted
proline analogues.1 Of special interest to us is the
synthesis of PTAAs based on the 3-aza-bicyclo[3.1.0]-
hexane ring system (5-8, Scheme 1) because molecular
modeling studies show that these will enforce a ø1 angle
∼ -60° (gauche relative to the amine) and a ø2 angle ∼
-155° (∼ trans). These PTAAs are critical for our studies
because several NMR and X-ray crystal structures of
receptor-bound PPII helices show that a ø1 angle ∼ -60°
and a ø2 angle ∼ 180° are common in the nonprolyl amino
acids in the PPII helices. There are limited examples of
this class of amino acids in the literature. Witkop
reported the synthesis of trans-3,4-methylene-L-proline,
a naturally occurring amino acid isolated from Aesculus
parviflora, and Nagasaka details the cyclopropanation
of a pyroglutamic acid derived R,â-unsaturated lactam
which could be further transformed into trans-3,4-
methylene-L-proline.2-4 For our purposes, we sought to
explore methodology which (1) could introduce additional
substitution into the cyclopropane ring, (2) was selective
for the anti isomer, and (3) was amenable to scale-up
(appropriate for the multigram synthesis of PTAAs). To
introduce additional substitution into the cyclopropane
ring, we envisioned that reaction of an appropriately
substituted nucleophilic alkylidene transfer reagent with
an unsaturated pyroglutamic acid derived synthon could
potentially afford entry to the target structures.5 Because
comprehensive studies of the stereochemistry of the
cyclopropanation reaction of cyclic Michael acceptors with
sulfur ylides are few and there are contrasts in the
stereochemical outcome of this transformation, we first
sought to investigate this issue.5b,6 This paper reports the
scope and limitations of this transformation with two
synthons derived from pyroglutamic acid (O,N-acetal 1
and N-Boc-pyrrolinone 3 (Scheme 1)) and the synthesis
of arginine and glutamic acid PTAA analogues from a
cyclopropanated intermediate.7,8
The synthesis of the unsaturated O,N-acetal 1 from
(5S,8R)-1-aza-7-oxa-8-phenylbicyclo[3.3.0]octan-2-one has
been reported through an enolization, selenylation, oxi-
dation, and elimination sequence in 56% overall yield.7
We have found that trapping of the enolate with TMSCl
followed by treatment with PhSeCl and oxidation of the
resultant selenide with H2O2 affords the unsaturated
O,N-acetal 1 in 72% yield from the saturated lactam,
improving the efficiency of the process. Among the PTAAs
of interest to us is the leucine analogue 5, which should
be accessible from the product obtained by reaction of
* To whom correspondence should be addressed.
(1) (a) Zhang, R.; Brownewell, F.; Madalengoitia, J . S. J . Am. Chem.
Soc. 1998, 120, 3894. (b) Zhang, R.; Madalengoitia, J . S. Tetrahedron
Lett. 1996, 37, 6235.
(2) Fujimoto, Y.; Irreverre, F.; Karle, J . M.; Karle, I. L.; Witkop, B.
J . Am. Chem. Soc. 1971, 93, 3471.
(3) Nagasaka, T.; Imai, T. Chem. Pharm. Bull. 1997, 45, 36.
(4) (a) For a review of cyclopropane amino acids, see: Stammer, C.
H. Tetrahedron 1990, 46, 2231. (b) For a construction of 2,3- and 4,5-
methanoproline, see: Hanessian, S.; Reinhold: U.; Gentile, G. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1881 and references therein.
(5) (a) For a comprehensive review, see: Trost, B. M.; Melvin, L.
S., J r. Sulfur Ylides: Emerging Synthetic Intermediates; Academic
Press: New York, 1975. (b) Romo, D.; Meyers, A. I. J . Org. Chem. 1992,
57, 6265. (c) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503 and
references therein.
(6) (a) Pyne, S. G.; Dong, Z.; Skelton, B. W.; White, A. H. J . Org.
Chem. 1997, 62, 2337. (b) J ung, M. E.; Rayle, H. L. J . Org. Chem. 1997,
62, 4601.
(7) Baldwin, J . E.; Moloney, M. G.; Shim, S. B. Tetrahedron Lett.
1991, 32, 1379.
(8) Ohfune, Y.; Tomita, M. J . Am. Chem. Soc. 1982, 104, 3511.
10.1021/jo9816109 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/30/1998

548 J . Org. Chem., Vol. 64, No. 2, 1999
Ta ble 1. Resu lts of Cyclop r op a n a tion of Syn th on 1 a n d Syn th on 3 w ith Su lfu r Ylid es
Zhang et al.
anti/syn ratio of 2
anti/syn ratio of 4
sulfur ylide
product
(yield %)
(yield %)
-
Ph2S+-CMe2
a : R′ ) R′′ ) Me
(89)
(76)
(60)
(79)
(trace)
(19)
-
Me2S+(O)-CH2
b: R′ ) R′′ ) H
-
PhS+(O)(NMe2)-CH2
b: R′ ) R′′ ) H
Ph2S+-CH-CH3
c: R′ ) H; R′′ ) CH3
d : R′ ) CH3; R′′ ) H
e: R′ ) H; R′′ ) CHdCH2
f: R′ ) CHdCH2; R′ ) H
g: R′ ) H, R′′) C2H5
h : R′ ) C2H5, R′′ ) H
i: R′ ) H; R′′ ) CO2Me
j: R′ ) CO2Me; R′′ ) H
2.5:1 (84)
4:1 (54)
Ph2S+-CH-CHdCH2
Ph2S+-CH-C2H5
1:5 (60)
1.3:1 (82)
1:1 (78)
1:1 (68)
3:1 (62)
1:1 (82)
Me2S+-CH-CO2Me
diphenylsulfonium isopropylide with either 1 or 3.9
Cyclopropanation of 1 and 3 with diphenylsulfonium
isopropylide in THF at -78 °C smoothly afforded the
products 2a and 4a in 89% and 79% yields, respectively
(Table 1). The products 2a and 4a arise from cyclopro-
panation of the less hindered “exo” face. The stereochem-
ical assignments were confirmed by single-crystal X-ray
diffraction of 2a or from coupling constants.10
affording a 3:1 mixture of anti-4g and syn-4h products,
respectively, in 62% yield. Although the diastereomers
4g and 4h were inseparable, assignments of these
products in the inseparable mixture were accomplished
by comparison with pure 4g and 4h obtained by catalytic
hydrogenation of pure anti vinyl cyclopropane 4e and syn
vinyl cyclopropane 4f, respectively. Interestingly, the
stereochemical outcome of these reactions is in contrast
to results observed by Meyers for reaction of sulfur ylides
with a related bicyclic lactam for which the syn isomers
are favored.5b
Examples of the efficient use of norleucine as a
methionine isostere also make the PTAA norleucine
analogue 6 a potential target for us.11 It was expected
that access to this molecule would be possible through
cyclopropanation of either 1 or 3 with diphenylsulfonium
allylide followed by hydrogenation of the resultant vinyl
cyclopropane.12 Treatment of 1 with diphenylsulfonium
allylide in THF at -40 °C for 4 h afforded the exo-anti
product 2e and exo-syn product 2f in 60% yield, in a 1:5
ratio, respectively, (Table 1) thus favoring the undesired
isomer.13 Reaction of the other synthon 3 with diphenyl-
sulfonium allylide in THF at -78 °C increased the
proportion of anti isomer, affording a 1:1 mixture of
isomers in 68% yield. Stereochemistry for these products
was assigned from either NOEs or coupling constants.14
We next investigated an alternative approach to 6
involving reaction of synthons 1 and 3 with diphenylsul-
fonium n-propylide. The synthesis of the sulfonium salt
n-propyldiphenylsulfonium triflate has been reported, but
in 1.6% yield from n-propanol.15 A modified procedure
which accomplishes this transformation in 34% overall
yield is reported in the Experimental Section. Reaction
of 1 with diphenylsulfonium n-propylide resulted in a
reversal of selectivity in comparison with the vinyl
cyclopropane series, affording a 1.3:1 ratio of anti-2g to
syn-2h in 82% yield. Reaction of 3 with diphenylsulfo-
nium n-propylide further improved the anti selectivity
To access the norvaline PTAA 7, we next investigated
the introduction of the two-carbon fragment with diphen-
ylsulfonium ethylide. Interestingly, reaction of the bicy-
clic lactam 1 with diphenylsulfonium ethylide in THF at
-78 °C was also anti selective, affording the isomers anti-
2c and syn-2d in 84% yield and 2.5:1 ratio, respectively.
Furthermore, reaction of diphenylsulfonium ethylide with
3 resulted in an increase of the anti/syn ratio to 4:1.
Entry into the PTAA glutamic acid analogue 8 was
envisioned by the use of a stabilized sulfur ylide.16
Treatment of 1 with 3 equiv of methyl dimethylsulfonium
acetylide (MDSA) in THF at room temperature for 30 h
gave the diastereomers 2i and 2j in 78% yield in a 1:1
ratio. The reaction could also be carried out in DMSO in
comparable yields and selectivity but with considerably
shorter reaction times (11 h). To ascertain whether this
ratio of isomers represents a true kinetic distribution or
whether there may be some epimerization occurring
under the reaction conditions, the syn isomer was isolated
and treated with MDSA under the reaction conditions.
This experiment returned only the syn isomer. An
analogous experiment with the anti isomer also returned
only the anti isomer. These results indicate that the 1:1
distribution of products does not result from equilibration
or partial equilibration of the syn/anti isomers under the
reaction conditions. Thermodynamic equilibration of the
two products is possible, however, with 20 mol %
CH3SOCH2- affording a 98:2 mixture of anti/syn products
in 85% yield (Scheme 2).17 Efforts to effect the epimer-
ization with weaker bases, including DBU, MeONa, and
t-BuOK, were unsuccessful. The syn isomer may also be
obtained preferentially. Treatment of a mixture of both
isomers 2i and 2j with KHMDS at -78 °C in THF
followed by kinetic protonation of the resultant enolate
with water affords a 9.3:1 mixture of syn/anti products,
respectively (31% yield). Thus, although the cyclopropa-
nation reaction is not stereoselective, either diastereomer
may be obtained from the diastereomeric mixture. Reac-
tion of the other pyroglutamic acid derived synthon 3
(9) Corey, E. J .; J autelat, M.; Oppolzer, W. Tetrahedron Lett. 1967,
2325.
(10) The stereochemistry of 2a was confirmed by single-crystal X-ray
defraction. The stereochemistry of 4a was assigned from the H1-H2
coupling pattern. Witkop notes that the R-hydrogen in trans methylene
proline is a singlet indicative of a small RH-âH coupling constant,
whereas J RH-âH ) 4.5 Hz for cis methylene proline. The H1 and H2
splitting patterns of 4a are consistent with a small J H1-H2. See ref 2.
(11) Piccione, E.; Case, R. D.; Domcheck, S. M.; Hu, P.; Chaudhuri,
M.; Backer, J . M.; Schlessinger, J .; Shoelson, S. E. Biochemistry 1993,
32, 3197.
(12) LaRochelle, R. W.; Trost, B. M.; Krepski, L. J . Org. Chem. 1971,
36, 1126.
(13) Exo denotes addition to the exo face of the bicyclic lactam,
whereas anti and syn denote the cyclopropane stereochemistry.
(14) The stereochemistry of the vinyl group was assigned by the
presence of a positive NOE between H1 and H3 for the anti isomer
and the absence of a positive NOE between H1 and H3 for the syn
isomer (see Scheme 1 for numbering) or by coupling constants as
described in ref 5b. All additional stereochemical assignments were
accomplished in an analogous manner.
(16) Payne, G. B. J . Org. Chem. 1967, 32, 3351.
(15) Tang, C. S. F.; Rapoport, H. J . Org. Chem. 1973, 38, 2806.
(17) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1962, 84, 866.

Reactions of Pyroglutamic Acid Derived Synthons
J . Org. Chem., Vol. 64, No. 2, 1999 549
Sch em e 2
the group R anti to the π acceptor is less rigorously
enforced than in the transition state leading to 12.
Consequently, when R is small (i.e., R ) Me, Et), the
transition state 11 is favored over transition state 10.
As the size of R increases (R ) CHCH2), however, the
steric repulsion between R and the pyrrolidine ring
disfavors transition state 11 (Scheme 3).22 The reversal
of diastereoselectivity may alternatively be explained by
a later transition state for the addition of diphenylsul-
fonium allylide, which would make it more sensitive to
sterics. The absence of selectivity observed for the reac-
tion of MDSA with both 1 and 3 is less clear.23
Sch em e 3
Some general statements may be made regarding the
reactivity and utility of the two synthons studied. Gener-
ally, N-Boc pyrrolinone 3 is more reactive than 1 toward
cyclopropanation, which should not be surprising because
examples of increased reactivity of R,â-unsaturated amides
bearing an electron-withdrawing group on nitrogen to-
ward 1,4-additions have been reported.24 Chemical yields
are comparable for both synthons. For reactions involving
diphenylsulfonium allylide, diphenylsulfonium ethylide,
and diphenylsulfonium n-propylide, there is a higher
proportion of the anti isomers formed from reaction with
3 versus 1; however, when executing multigram reactions
it must also be considered that the syn/anti isomers
derived from 1 are more easily separable by flash
chromatography than those derived from 3.
with MDSA also afforded a 1:1 mixture of diastereomers
in 82% yield.
We have used this cyclopropanation methodology in the
synthesis of two PTAAs, an arginine PTAA analogue and
a glutamic acid PTAA analogue. The synthesis of the
arginine PTAA analogue 19 (Scheme 4) begins with the
ester 21. Amonolysis of ester 21 in MeOH smoothly gave
the amide 15 in 85% yield. Reduction of the two amides
and oxazolidine functions with LAH in refluxing THF
gave the N-benzyl amino-alcohol 16, which was used
without further purification. The amine 16 was guan-
ylated with 1H-pyrazole-1-carboxamidine hydrochloride
and diisopropylethylamine (DIEA) in DMF, and the
guanidine group was subsequently protected with 2-mes-
itylenesulfonyl chloride (MtsCl) to afford the alcohol 17
in 50% yield from 15.25,26 N-Debenzylation failed to
proceed to completion under standard conditions (H2,
Pd-C) even at high pressures; however, the benzyl group
was easily removed with Pd-C and HCO2NH4 in reflux-
ing MeOH.27 Protection of the resultant amine with di-
Cyclopropanation of 1 with dimethylsulfoxonium me-
thylide afforded the cyclopropane 2b in 75% yield.3,18
However, reaction of 3 with (CH3)2SO+CH2- afforded only
trace amounts of product and a dimerization product.19,20
We attempted the reaction with the less basic ylide,
PhS+ONMe2CH2-; however, this also resulted in a low
yield of cyclopropane (19%). Interestingly, the acidity of
the methine proton was not a problem in the reaction of
3 with the other sulfur ylides used in this study.
An analysis of the transition-state geometry is useful
in rationalizing the stereochemical outcome of these
reactions. Meyers proposes a synclinal-like transition
state for the conjugate addition of the sulfur ylide to the
unsaturated lactam in which the group R is anti to the
π acceptor (see transition state 9, Scheme 3).5b,21 Bond
rotation, followed by nucleophilic displacement of the
sulfonium group, affords the syn cyclopropane 12. The
anti isomer, formed as the minor product, would result
from the transition state in which the R group would be
over the sterically hindered concave face of the lactam.
This model is also consistent with our results. With the
lactams 1 and 3, a synclinal-like transition state should
also be favored by steric and electrostatic factors. How-
ever, it is the orientation of the group R which may now
vary. Because the conjugate addition with 1 and 3 takes
place from the less hindered exo face, the orientation of
(22) Although it is unusual to think of an ethyl group as smaller
than a vinyl group, in this instance, a vinyl group may be considered
more sterically demanding because it is coplanar with the sulfur and
anionic carbon, whereas with the ethyl group, the terminal methyl may
rotate away from the pyrrolidine ring.
(23) A possible explanation for the lack of selectivity is that following
conjugate addition disproportionation scrambles the stereochemistry
at the newly formed stereocenter. Products which arise from this
alternate mechanistic pathway have been reported: (a) Corey, E. J .;
Chaykovsky, M. J . Am. Chem. Soc. 1963, 86, 1640. (b) Tamura, Y.;
Taniguchi, H.; Miyamoto, T.; Tsunekawa, M.; Ikeda, M. J . Org. Chem.
1974, 39, 3519.
(18) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1965, 87, 1353.
(19) J ohnson, C. R.; Haake, M.; Schroeck, C. W. J . Am. Chem. Soc.
1970, 92, 6594.
(20) The dimerization product is formed as a single diastereomer.
We have not attempted to assign relative stereochemistry.
(24) Nagashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K. Tetrahedron
Lett. 1985, 26, 657.
(25) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J . Org. Chem.
1992, 57, 2497.
(26) Yajima, H.; Takeyama, M.; Kanaki, J .; Nishimura, O.; Fujino,
M. Chem. Pharm. Bull. 1978, 26, 3752.
(27) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515.
(21) For a discussion of synclinal transition states, see: Seebach,
D.; Golinski, J . Helv. Chim. Acta 1981, 64, 1413.

550 J . Org. Chem., Vol. 64, No. 2, 1999
Zhang et al.
Sch em e 4
of di-tert-butyl dicarbonate (81%). Finally, PDC oxidation
of 21 gave the PTAA 8 in 63% yield.
We are currently studying the conformational proper-
ties of peptides composed of 3,4-cyclopropyl-substituted
PTAAs and also pursuing the synthesis of bioactive
peptides derived from these novel amino acids.
Exp er im en ta l Section
Gen er a l. Unless otherwise specified, all reagents were
purchased from commercial sources and were used without
further purification. THF was distilled from sodium/benzophe-
none ketyl, and CH2Cl2 was distilled from CaH2. All reactions
were carried out under a N2 atmosphere. Flash chromatogra-
phy was carried out on Selecto silica gel (230-400 mesh). 1D
and 2D NMR spectra were collected in CDCl3 using standard
pulse sequences provided by Bruker.
(5R,7S)-5-P h en yl-5,6,7,7a -tetr a h yd r o-6-oxa p yr r olizin -
3-on e (1). (5S,8R)-1-Aza-7-oxa-8-phenylbicyclo[3.3.0]octan-2-
one (48.3 g, 0.238 mol) in THF (100 mL) was added dropwise
to a 0.5 M solution of KHMDS in toluene (475 mL, 0.238 mol)
(diluted with THF (350 mL)) at -78 °C. After the addition was
finished, the resulting mixture was maintained at -78 °C for
30 min, and TMSCl (40 mL, 0.31 mol) in THF (60 mL) was
added dropwise. The solution was allowed to warm to 0 °C
over 1 h and was then maintained at 0 °C for 3 h. PhSeCl
(52.0 g, 0.266 mol) in THF (80 mL) was added at 0 °C, and
the resulting mixture was maintained at room temperature
overnight. The reaction was quenched with saturated aqueous
NaHCO3 (250 mL). The layers were separated, and the
aqueous layer was extracted with EtOAc (3 × 250 mL). The
combined organic layers were dried over Na2SO4 and concen-
trated. Purification by flash chromatography with 3:1 hex-
anes-EtOAc gave a mixture of cis and trans products (71.6 g,
84%).
Sch em e 5
The mixture was dissolved in EtOAc (600 mL) and cooled
to 0 °C, and 30% H2O2 (90 mL) was added. After 20 min at 0
°C, the organic layer was separated, washed with water (2 ×
400 mL) and brine (400 mL), dried over Na2SO4, and concen-
trated. Flash chromatography with 3:1 hexanes-EtOAc af-
forded 1 (34.6 g, 86%): mp 86-87 °C; [R]25 ) +225.1° (c )
D
1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J ) 7.3 Hz,
2H), 7.30-7.37 (m, 3H), 7.18 (dd, J ) 1.8, 5.7 Hz, 1H), 6.13 (s,
1H), 6.07 (dd, J ) 1.2, 5.7 Hz, 1H), 4.52 (dd, J ) 7.1, 8.3 Hz,
1H), 4.18 (dd, apparent t, J ) 7.4 Hz, 1H), 3.34 (dd, apparent
t, J ) 7.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) 176.7, 147.9,
138.5, 128.6, 128.3, 128.1, 125.9, 87.1, 67.8, 64.8 ppm; IR (film)
1684 cm-1; MS (CI) m/z 202 (MH). Anal. Calcd for C12H11NO2:
C, 71.63; H, 5.51; N, 6.96. Found: C, 71.50; H, 5.52; N, 6.99.
(1S,2S,4S,7R) 6-Aza-3,3-dim eth yl-8-oxa-7-ph en yltr icyclo-
[4.3.0.0]n on a n -5-on e (2a ). Diphenylethylsulfonium tetrafluo-
roborate (740 mg, 2.45 mmol) in DME (20 mL) was cooled to
-70 °C. CH2Cl2 (0.17 mL, 2.6 mmol) was added, followed by
cold LDA (2.6 mmol, prepared freshly by the addition of 1.65
mL of 1.6 M n-BuLi in hexane to 370 µL of diisopropylamine
in 5 mL DME at -70 °C). A yellow-green solution resulted
immediately and became cloudy after several minutes. After
30 min, MeI (0.16 mL, 2.5 mmol) was added, and the reaction
mixture was slowly warmed to -50 to -60 °C and maintained
at that temperature with good stirring for 2 h. LDA (2.64
mmol) as above was then added at -70 °C, and an orange color
was produced immediately. After 1 h at -70 °C, the O,N-acetal
1 (201 mg, 0.990 mmol) was added, as a solution in DME (2
mL). The mixture was maintained at -70 °C for 1 h, quenched
with saturated aqueous NaHCO3 (20 mL), and warmed to room
temperature. The aqueous layer was separated and extracted
with Et2O (3 × 30 mL). The combined organic fractions were
dried over Na2SO4 and concentrated. Flash chromatography
with 2.5:1 hexanes-EtOAc afforded 2a (215 mg, 89%) as a
tert-butyl dicarbonate yielded the N-Boc prolinol 18 (84%
yield for two steps). Attempted oxidation of the alcohol
to the carboxylic acid under a variety of conditions (RuCl3/
NaIO4, PDC/DMF, J ones reagent) resulted in low yields
of the PTAA.28,29 To optimize the yield of the PTAA, we
opted for a two-step conversion involving first Swern
oxidation of the alcohol followed by NaClO2 oxidation of
the resultant aldehyde to give the PTAA 19 (76% yield
for two steps) protected for Boc-solid-phase peptide
synthesis.30
The glutamic acid PTAA analogue is also synthesized
from cyclopropane 2i (Scheme 5). Selective reduction of
the amide and oxazolidine groups is accomplished with
BH3 in refluxing THF, yielding the amino-ester 20
(92%).31 The N-Boc protected prolinol 21 was obtained
by hydrogenolysis of 20 with H2/Pd-C in the presence
(28) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(29) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399.
(30) Nicolaou, K. C.; Nikovic, S.; Sarabia, F.; Vourloumis, D.; He,
Y.; Vallberg, H.; Finlay, M. R. V.; Yang, Z. J . Am. Chem. Soc. 1997,
119, 7974.
colorless solid: mp 127-128 °C; [R]25 ) +272.6° (c ) 0.52,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.27-7.39 (m, 5H), 6.30
(s, 1H), 4.19 (dd, J ) 6.3, 7.7 Hz, 1H), 3.71 (dd, J ) 6.3, 9.1
Hz, 1H), 3.51 (dd, J ) 7.7, 9.1 Hz, 1H), 1.91 (dd, J ) 0.9, 6.0
Hz, 1H), 1.89 (d, J ) 6.0 Hz, 1H), 1.32 (s, 3H), 1.18 (s, 3H);
(31) Kornet, M. J .; Thio, P. A.; Tan, S. L. J . Org. Chem. 1968, 33,
3637.

Reactions of Pyroglutamic Acid Derived Synthons
J . Org. Chem., Vol. 64, No. 2, 1999 551
13C NMR (125 MHz, CDCl3) 177.8, 139.5, 128.4, 128.3, 125.8,
88.2, 69.4, 57.5, 34.6, 32.8, 26.2, 25.6, 15.2 ppm; FTIR (film)
1700 cm-1; MS (CI) m/z 244 (MH). Anal. Calcd for C15H17NO2:
C, 74.05; H, 7.04; N, 5.76. Found: C, 73.89; H, 7.06; N, 5.67.
(1S,2S,4R,7R)-6-Aza -8-oxa -7-p h en ylt r icyclo[4.3.0.0]-
n on a n -5-on e (2b). Meth od 1. DMSO (5 mL) was added to a
mixture of 60% NaH dispersion in mineral oil (96 mg, 2.4
mmol) and trimethylsulfoxonium iodide (594 mg, 2.74 mmol).
After 30 min of stirring at room temperature, the reaction
mixture was maintained at 50-60 °C for another 30 min.
Then, a solution of 1 (201 mg, 0.990 mmol) in DMSO (2 mL)
was added dropwise, and the resulting mixture was kept at
that temperature for 1.5 h and then cooled to room tempera-
ture. Water (20 mL) was added, and the mixture was extracted
with Et2O (3 × 30 mL). The combined organic fractions were
dried over Na2SO4, concentrated, and purified by flash chro-
matography (2:1 hexanes-EtOAc) to give 2b (163 mg, 76%)
as a pale oil.
4 h. The reaction was then quenched with saturated aqueous
NaHCO3 (15 mL) and allowed to warm to room temperature.
The aqueous layer was separated and extracted with Et2O (3
× 20 mL). The combined organic fractions were dried (Na2-
SO4) and concentrated. Flash chromatography of the residue
on silica gel with 3:1 hexanes-EtOAc gave the anti product
2e as a colorless solid (30.9 mg, 10%) and the syn product 2f
as a pale yellow oil (153 mg, 50%). An analytical sample of 2e
was obtained by recrystallyzation from CH2Cl2-hexanes: mp
1
87-88 °C; [R]25 ) +256.2° (c ) 0.26, CHCl3); H NMR (500
D
MHz, CDCl3) δ 7.27-7.38 (m, 5H), 6.30 (s, 1H), 5.40 (ddd, J )
8.2, 10.7, 17.0 Hz, 1H), 5.18 (d, J ) 17.0 Hz, 1H), 5.05 (d, J )
10.7 Hz, 1H), 4.20 (dd, J ) 6.4, 8.2 Hz, 1H), 3.94 (dd, J ) 6.4,
9.4 Hz, 1H), 3.44 (dd, J ) 8.2, 9.4 Hz, 1H), 2.15 (dd, J ) 3.8,
5.6 Hz, 1H), 2.12 (ddd, J ) 3.0, 3.8, 8.2 Hz, 1H), 2.08 (ddd, J
) 1.1, 3.0, 5.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) 179.0,
139.3, 135.2, 128.3, 125.8, 115.8, 87.7, 69.2, 60.1, 31.4, 28.8,
26.8 ppm; FTIR (film) 1711 cm-1; MS (CI) m/z 242 (MH). Anal.
Calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.80. Found: C,
74.41; H, 6.35; N, 5.63. 2f: [R]25D ) +288.5° (c ) 0.85, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.28-7.38 (m, 5H), 6.33 (s, 1H),
5.77 (ddd, J ) 8.4, 10.2, 17.0 Hz, 1H), 5.44 (d, J ) 17.0 Hz,
1H), 5.26 (d, J ) 10.2 Hz, 1H), 4.22 (dd, J ) 6.4, 7.6 Hz, 1H),
3.77 (dd, J ) 6.4, 9.1 Hz, 1H), 3.55 (dd, J ) 8.0, 9.1 Hz, 1H),
2.32 (dd, apparent d, J ) 8.4 Hz, 2H), 2.23 (ddd, apparent q,
J ) 8.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) 177.2, 139.3,
130.7, 128.3, 125.8, 120.1, 88.2, 69.3, 57.3, 28.0, 27.6, 26.6 ppm;
FTIR (film) 1708 cm-1; MS (CI) m/z 242 (MH). Anal. Calcd for
Meth od 2. A mixture of (dimethylamino)phenyloxosulfo-
nium methylide (195 mg, 0.72 mmol) in DMSO (1 mL) was
added slowly to 60% NaH dispersion in mineral oil (24 mg,
0.60 mmol) with stirring at room temperature. The mixture
was stirred for 1 h, then 1 (100.6 mg, 0.492 mmol) in DMSO
(1 mL) was added, and the mixture was stirred overnight.
Water (10 mL) was added, and the mixture was extracted with
Et2O (4 × 10 mL); the combined organic fractions were dried
(Na2SO4) and concentrated. Flash chromatography with 2%
acetone in CH2Cl2 gave 2b (64.6 mg, 60%) as a pale oil: [R]25
D
) +263.4° (c ) 0.35, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.27-7.38 (m, 5H), 6.31 (s, 1H), 4.20 (dd, J ) 6.2, 7.9 Hz, 1H),
3.88 (dd, J ) 6.2, 9.3 Hz, 1H), 3.45 (dd, J ) 7.9, 9.3 Hz, 1H),
2.12 (ddd, J ) 4.6, 5.5, 8.1 Hz, 1H), 2.03 (m, 1H), 1.31 (ddd,
apparent dt, J ) 4.8, 8.4 Hz, 1H), 1.13 (ddd, apparent dd, J )
4.4, 7.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) 180.6, 139.5,
128.3, 125.8, 87.6, 69.4, 60.2, 20.8, 19.9, 14.8 ppm; FTIR (film)
1712 cm-1; MS (CI) m/z 216 (MH). Anal. Calcd for C13H13NO2:
C, 72.54; H, 6.09; N, 6.51. Found: C, 72.42; H, 6.12; N, 6.57.
Rea ction of 1 w ith Dip h en ylsu lfon iu m Eth ylid e. A 1.7
M solution of t-BuLi in pentane (3.10 mL, 5.25 mmol) was
added dropwise to a suspension of diphenylethylsulfonium
fluoroborate (1.54 g, 5.09 mmol) in THF (40 mL) at -78 °C.
After 30 min, O,N-acetal 1 (402 mg, 2.00 mmol) was added as
a solution in THF (2 mL). The resulting mixture was main-
tained at -78 °C for 2 h, quenched with saturated aqueous
NaHCO3 (30 mL), and allowed to warm to room temperature.
The aqueous layer was separated and extracted with Et2O (3
× 30 mL). The combined organic fractions were dried (Na2-
SO4) and concentrated. Purification by flash chromatography
with 3:1 hexanes-EtOAc gave anti product 2c as a colorless
powder (275 mg, 60%) and syn product 2d as a pale oil (110
C
15H15NO2: C, 74.67; H, 6.27; N, 5.80. Found: C, 74.52; H,
6.30; N, 5.80.
Syn t h esis of n -P r op yld ip h en ylsu lfon iu m Tr ifla t e. A
solution of n-propanol (1.02 mL, 13.7 mmol) in CH2Cl2 (25 mL)
was cooled to -15 °C, and dry pyridine (1.33 mL, 16.4 mmol)
was added followed by trifluoromethanesulfonic anhydride
(2.30 mL, 13.7 mmol) in CH2Cl2 (5 mL) with vigorous stirring.
The reaction mixture was allowed to warm to 0 °C over 1 h,
pentane (40 mL) was added, and the resulting mixture was
shaken and filtered. The filtrate was concentrated to within 4
mL of volume under reduced pressure at room temperature.
The solution was cooled to -35 °C, and then diphenylsulfide
(10 mL, 60 mmol) was added. The mixture was allowed to
warm to room temperature, maintained at room temperature
for 20 h, warmed to 45 °C for 30 min, and cooled to room
temperature. Pentane (100 mL) was added, the mixture was
shaken to induce solidification, and then the solid was collected
by filtration. The solid was dissolved in CH2Cl2, triturated with
pentane, and filtered to yield n-propyldiphenylsulfonium tri-
flate (1.8 g, 34% for two steps). 1H NMR spectrum was
consistent with that reported.15
Rea ction of 1 w ith Dip h en ylsu lfon iu m n -P r op ylid e. A
1.7 M solution of t-BuLi in pentane (2.54 mL, 4.31 mmol) was
added dropwise to a suspension of n-propyldiphenylsulfonium
triflate (1.70 g, 4.53 mmol) in THF (30 mL) at -78 °C. After
30 min, O,N-acetal 1 (403 mg, 2.00 mmol) in THF (3 mL) was
added, and the resulting mixture was maintained at -78 °C
for 2 h. The reaction was quenched with saturated aqueous
NaHCO3 (30 mL) and warmed to room temperature. The
aqueous layer was separated and extracted with Et2O (3 × 30
mL). The combined organic fractions were dried (Na2SO4) and
concentrated. Flash chromatography of the residue with 2:1
hexanes-EtOAc gave the anti product 2g as a pale oil (229
mg, 24%). 2c: mp 91-92 °C; [R]25 ) +268.9° (c ) 0.71,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.27-7.37 (m, 5H), 6.29
(s, 1H), 4.16 (dd, J ) 6.2, 7.8 Hz, 1H), 3.88 (dd, J ) 6.2, 9.2
Hz, 1H), 3.41 (dd, J ) 7.8, 9.2 Hz, 1H), 1.88 (dd, J ) 3.8, 5.6
Hz, 1H), 1.80 (ddd, J ) 1.0, 2.6, 5.6 Hz, 1H), 1.51 (m, 1H),
1.15 (d, J ) 5.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) 180.0,
139.5, 128.2, 125.8, 87.5, 69.2, 60.1, 28.8, 27.4, 23.4, 16.6 ppm;
FTIR (film) 1710 cm-1; MS (CI) m/z 230 (MH). Anal. Calcd for
C
14H15NO2: C, 73.34; H, 6.59; N, 6.14. Found: C, 73.23; H,
6.57; N, 6.06. 2d : [R]25D ) +192.1° (c ) 0.78, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 7.27-7.39 (m, 5H), 6.33 (s, 1H), 4.21 (dd,
J ) 6.5, 7.4 Hz, 1H), 3.69 (dd, J ) 6.5, 9.0 Hz, 1H), 3.55 (dd,
J ) 7.4, 9.0 Hz, 1H), 2.10 (m, 2H), 1.60 (m, 1H), 1.27 (d, J )
6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) 177.8, 139.5, 128.3,
128.2, 125.7, 88.1, 69.4, 56.6, 26.4, 25.0, 18.8, 8.2 ppm; FTIR
mg, 47%) and the syn product 2h as a pale oil (170 mg, 35%).
1
2g: [R]25 ) +215.7° (c ) 0.74, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 7.26-7.37 (m, 5H), 6.28 (s, 1H), 4.14 (dd, J ) 6.2,
7.9 Hz, 1H), 3.84 (dd, J ) 6.2, 9.3 Hz, 1H), 3.39 (dd, J ) 7.9,
9.3 Hz, 1H), 1.89 (dd, J ) 3.7, 5.6 Hz, 1H), 1.80 (ddd, J ) 1.0,
2.4, 5.6 Hz, 1H), 1.43 (m, 1H), 1.35 (m, 2H), 1.00 (t, J ) 7.4
Hz, 3H); 13C NMR (125 Hz, CDCl3) 180.0, 139.4, 128.1, 125.6,
87.4, 69.1, 60.0, 30.5, 27.4, 26.0, 24.8, 12.7 ppm; FTIR (film)
1710 cm-1; MS (CI) m/z 244 (MH). Anal. Calcd for C15H17NO2:
(film) 1707 cm-1; MS (CI) m/z 230 (MH). Anal. Calcd for C14H15
-
NO2: C, 73.34; H, 6.59; N, 6.14. Found: C, 73.11; H, 6.68; N,
6.08.
Rea ction of 1 w ith Dip h en ylsu lfon iu m Allylid e. A 1.7
M solution of t-BuLi in pentane (1.5 mL, 2.6 mmol) was added
dropwise to a suspension of diphenylallylsulfonium tetrafluo-
roborate (944 mg, 3.00 mmol) in THF (12 mL) at -78 °C. After
1 h, O,N-acetal 1 (254 mg, 1.26 mmol) in THF (2 mL) was
added, and the resulting mixture was warmed to -40 to -50
°C. The solution was maintained between -40 and -50 °C for
C, 74.05; H, 7.04; N, 5.76. Found: C, 73.79; H, 6.99; N, 5.82.
1
2h : [R]25 ) +224.6° (c ) 0.48, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 7.26-7.38 (m, 5H), 6.31 (s, 1H), 4.20 (dd, J ) 6.3,
7.7 Hz, 1H), 3.69 (dd, J ) 6.3, 9.2 Hz, 1H), 3.52 (dd, J ) 7.7,
9.2 Hz, 1H), 2.12 (m, apparent d, J ) 8.5 Hz, 2H), 1.58 (m,

552 J . Org. Chem., Vol. 64, No. 2, 1999
Zhang et al.
2H), 1.48 (m, 1H), 1.06 (t, J ) 7.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3) 177.9, 139.4, 128.3, 128.2, 125.7, 88.1, 69.4, 56.7, 26.6,
26.0, 25.2, 16.6, 13.5 ppm; FTIR (film) 1705 cm-1; MS (CI) m/z
244 (MH). Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N,
5.76. Found: C, 73.85; H, 7.02; N, 5.72.
Rea ction of 1 w ith Meth yl Dim eth ylsu lfon iu m Acetyl-
id e. A solution of 1 (24.0 g, 0.119 mol) and methyl (dimeth-
ylsulfuranylidene)acetate (48.0 g, 0.357 mol) in DMSO (50 mL)
was stirred at room temperature for 30 h. Water (100 mL) was
added, and the resulting mixture was extracted with Et2O (4
× 150 mL). The combined organic fractions were dried (Na2-
SO4) and concentrated. The residue was purified by flash
chromatography on silica gel (2:1 to 1:2 hexanes-EtOAc) to
give the anti product 2i as a glassy oil (13.0 g, 40%) and the
C32H58N2O8Si2: C, 58.68; H, 8.93; N, 4.28. Found: C, 58.79;
H, 8.95; N, 4.22.
Rea ction of 3 w ith Dip h en ylsu lfon iu m Eth ylid e. 4c
and 4d were synthesized by the same procedure used for the
synthesis of 2c/2d except that synthon 3 (589 mg, 1.99 mmol)
was used instead of 1. Purification by flash chromatography
with 6:1 hexanes-EtOAc afforded an inseparable mixture of
4:1 4c/4d (345 mg, 54% and 70% based on recovered starting
material). The residue (0.34 g, 0.96 mmol) containing both
isomers was dissolved in THF (3 mL) and treated with AcOH
(9 mL) in water (3 mL), and the resulting mixture was stirred
at room temperature for 24 h. NaHCO3 powder was then added
slowly until gas evolution ceased. The mixture was extracted
with EtOAc (3 × 15 mL), and the combined organic fractions
were dried over Na2SO4 and concentrated. Repeated flash
chromatography with 2:3 hexanes-EtOAc gave the alcohols
of 4c (152 mg, 66%) and 4d (23 mg, 10%) as colorless solids.
syn product 2j as a colorless solid (12.4 g, 38%). 2i: [R]25
)
D
+256.9° (c ) 0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.27-
7.49 (m, 5H), 6.29 (s, 1H), 4.22 (dd, J ) 6.2, 8.1 Hz, 1H), 3.95
(dd, J ) 6.2, 9.2 Hz, 1H), 3.72 (s, 3H), 3.48 (dd, J ) 8.1, 9.2
Hz, 1H), 2.62 (dd, J ) 3.3, 6.2 Hz, 1H), 2.51 (ddd, J ) 1.0, 2.4,
6.2 Hz, 1H), 2.25 (dd, apparent t, J ) 2.9 Hz, 1H); 13C NMR
(125 MHz, CDCl3) 177.2, 170.2, 138.8, 128.5, 128.4, 125.7, 87.7,
Alcohol of 4c: colorless cubic crystalline solid from Et2O-
1
hexanes, mp 85-86 °C; [R]25 ) -24.6° (c ) 0.37, CHCl3); H
D
NMR (500 MHz, C6D6) δ 3.89 (dd, J ) 4.3, 4.7 Hz, 1H), 3.65
(m, 2H), 2.62 (br s, 1H), 1.44 (s, 9H), 1.41 (ddd, apparent td,
J ) 1.1, 6.0 Hz, 1H), 1.14 (dd, J ) 3.6, 6.0 Hz, 1H), 0.56 (d, J
) 5.7 Hz, 3H), 0.49 (m, 1H); 13C NMR (125 MHz, C6D6) 172.0,
152.2, 82.4, 64.8, 60.7, 28.8, 28.1, 22.2, 19.7, 16.5 ppm; FTIR
(film) 3483 (br), 1774, 1732, 1714 cm-1; MS (CI) m/z 242 (MH),
142. Anal. Calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.80.
Found: C, 59.81; H, 8.01; N, 5.80. Alcohol of 4d : colorless
69.0, 59.8, 52.4, 28.9, 27.8, 27.2 ppm; FTIR (film) 1722 cm-1
;
MS (CI) m/z 274 (MH). Anal. Calcd for C15H15NO4: C, 65.93;
H, 5.53; N, 5.12. Found: C, 65.71; H, 5.57; N, 5.05. 2j: mp
98-100 °C; [R]25 ) +180.5° (c ) 0.32, CHCl3); 1H NMR (500
D
MHz, CDCl3) δ 7.27-7.34 (m, 5H), 6.32 (s, 1H), 4.21 (dd, J )
6.3, 7.7 Hz, 1H), 4.09 (dd, J ) 6.3, 9.4 Hz, 1H), 3.63 (s, 3H),
3.49 (dd, J ) 7.7, 9.4 Hz, 1H), 2.41-2.47 (m, 3H); 13C NMR
(125 MHz, CDCl3) 175.8, 167.5, 138.9, 128.4, 128.3, 125.8, 87.8,
69.1, 57.6, 52.3, 27.0, 26.3, 24.8 ppm; FTIR (film) 1734, 1717
cm-1; MS (CI) m/z 274 (MH). Anal. Calcd for C15H15NO4: C,
65.93; H, 5.53; N, 5.12. Found: C, 65.85; H, 5.52; N, 5.16.
(1S,2S,5S)-ter t-Bu tyl 3-Aza-6,6-dim eth yl-4-oxo-2-[(1,1,2,2-
tetr a m eth yl-1-sila p r op oxy)m eth yl]bicyclo[3.1.0]h exa n e-
3-ca r boxyla te (4a ). 4a was synthesized as described for 2a
except that synthon 3 (328 mg, 1.09 mmol) was used instead
of 1. Purification by flash chromatography with 8:1 hexanes-
needles from Et2O-hexanes, mp 107-109 °C; [R]25 ) -47.5°
D
1
(c ) 0.1, CHCl3); H NMR (500 MHz, CDCl3) δ 4.00 (dd, J )
3.8, 4.1 Hz, 1H), 3.88 (m, 2H), 2.30 (t, J ) 6.0 Hz, 1H,
disappeared upon addition of D2O), 2.08 (ddd, J ) 1.2, 6.3,
8.8 Hz, 1H), 1.83 (dd, J ) 6.3, 7.7 Hz, 1H), 1.51 (s, 9H), 1.44
(m, 1H), 1.08 (d, J ) 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
172.0, 150.5, 83.4, 65.1, 57.2, 28.1, 25.9, 19.4, 16.2, 7.5 ppm;
FTIR (film) 1766, 1717 cm-1; MS (CI) m/z 242 (MH), 142. Anal.
Calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.80. Found: C,
59.80; H, 8.00; N, 5.88.
EtOAc gave 4a (292 mg, 79%) as a pale oil: [R]25 ) -33.5° (c
Rea ction of 3 w ith Dip h en ylsu lfon iu m Allylid e. The
procedure was as used in the synthesis of 2e/2f except that
synthon 3 (478 mg, 1.59 mmol) was used instead of 1 and the
reaction was finished at -78 °C for 1 h. Repeated flash
chromatography with 96:4 hexanes-EtOAc afforded 4e (187
mg, 35%) as a colorless solid and 4f (180 mg, 33%) as a
D
) 1.05, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.90 (m, 1H),
3.85 (dd, J ) 2.8, 10.1 Hz, 1H), 3.80 (dd, J ) 5.6, 10.1 Hz,
1H), 1.81 (dd, J ) 1.3, 6.3 Hz, 1H), 1.69 (d, J ) 6.3 Hz, 1H),
1.50 (s, 9H), 1.14 (s, 3H), 1.11 (s, 3H), 0.90 (s, 9H), 0.07 (s,
3H), 0.06 (s, 3H); 13C NMR (125 MHz, CDCl3) 172.1, 149.7,
82.5, 63.7, 57.6, 33.5, 28.0, 27.1, 25.9, 25.7, 22.5, 18.1, 14.4,
-5.5 ppm; FTIR (film) 1786, 1750, 1711 cm-1; MS (CI) m/z
370 (MH); 270. Anal. Calcd for C19H35NO4Si: C, 61.75; H, 9.54;
N, 3.79. Found: C, 61.79; H, 9.58; N, 3.83.
colorless oil. 4e: mp 71-73 °C; [R]25 ) -7.2° (c ) 0.65,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.37 (ddd, J ) 8.5, 10.4,
17.0 Hz, 1H), 5.17 (d, J ) 17.0 Hz, 1H), 5.03 (d, J ) 10.4 Hz,
1H), 4.10 (m, 1H), 3.83 (dd, J ) 2.6, 10.2 Hz, 1H), 3.79 (dd, J
) 5.2, 10.2 Hz, 1H), 2.01 (m, 1H), 1.95 (dd, J ) 3.8, 6.2 Hz,
1H), 1.73 (ddd, apparent td, J ) 3.0, 8.5 Hz, 1H), 1.51 (s, 9H),
0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (125 MHz,
CDCl3) 172.3, 150.2, 135.1, 115.6, 82.8, 63.6, 60.2, 28.8, 28.1,
28.0, 25.7, 21.9, 18.1, -5.5 ppm; FTIR (film) 1787, 1754, 1712
cm-1; MS (CI) m/z 368 (MH), 268. Anal. Calcd for C19H33NO4-
Si: C, 62.09; H, 9.05; N, 3.81. Found: C, 62.34; H, 9.15; N,
3.71. 4f: [R]25D ) -29.8° (c ) 0.52, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 5.51 (ddd, J ) 7.0, 10.2, 17.0 Hz, 1H), 5.40 (d, J )
17.0 Hz, 1H), 5.25 (d, J ) 10.2 Hz, 1H), 3.98 (m, 1H), 3.86
(dd, J ) 2.9, 10.2 Hz, 1H), 3.83 (dd, J ) 5.3, 10.2 Hz, 1H),
2.25 (ddd, J ) 1.0, 6.6, 9.2 Hz, 1H), 2.10 (dd, J ) 6.6, 7.7 Hz,
1H), 2.03 (m, 1H), 1.50 (s, 9H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05
(s, 3H); 13C NMR (125 MHz, CDCl3) 171.6, 149.5, 129.8, 120.4,
82.7, 63.7, 57.3, 29.7, 28.1, 27.5, 25.8, 24.4, 21.2, 18.1, -5.5
ppm; FTIR (film) 1787, 1752, 1712 cm-1; MS (CI) m/z 368
(MH), 268. Anal. Calcd for C19H33NO4Si: C, 62.09; H, 9.05; N,
3.81. Found: C, 62.34; H, 9.15; N, 3.71.
(1S,2S,5R)-ter t-Bu tyl 3-Aza-4-oxo-2-[(1,1,2,2-tetr am eth yl-
1-sila p r op oxy)m et h yl]b icyclo[3.1.0]h exa n e-3-ca r b oxy-
la te (4b). 4b was produced as described in method 2 for the
synthesis of 2b except that synthon 3 (328 mg, 1.09 mmol)
was used instead of 1. Flash chromatography with 5:1 hex-
anes-EtOAc afforded 4b (64 mg, 19%) as a colorless powder,
as well as a dimer of 3 (92 mg, 14%) as a colorless solid. 4b:
mp 68-70 °C; [R]25D ) -52.4° (c ) 0.25, CHCl3); 1H NMR (500
MHz, CDCl3) δ 4.02 (m, 1H), 3.85 (dd, J ) 2.7, 10.1 Hz, 1H),
3.76 (dd, J ) 5.5, 10.1 Hz, 1H), 1.93 (m, 2H), 1.50 (s, 9H), 1.12
(ddd, apparent dt, J ) 5.0, 8.1 Hz, 1H), 0.89 (s, 9H), 0.72 (ddd,
apparent dd, J ) 4.5, 8.1 Hz, 1H), 0.06 (s, 3H), 0.05 (s, 3H);
13C NMR (125 MHz, CDCl3) 173.9, 150.5, 82.6, 63.9, 60.1, 28.1,
25.8, 20.8, 18.2, 14.6, 11.3, -5.5 ppm; FTIR (film) 1789, 1755,
1711 cm-1; MS (CI) m/z 342 (MH), 242. Anal. Calcd for C17H31
-
NO4Si: C, 59.79; H, 9.15; N, 4.10. Found: C, 59.92; H, 9.14;
N, 4.03. Dimer of 3: fine needles from EtOAc-hexanes, mp
181-182 °C; [R]25 ) -11.6° (c ) 0.62, CHCl3); 1H NMR (500
D
MHz, CDCl3) δ 6.91 (d, J ) 6.2 Hz, 1H), 6.20 (d, J ) 6.2 Hz,
1H), 4.34 (m, 1H), 4.11 (d, J ) 10.0 Hz, 1H), 4.07 (d, J ) 10.0
Hz, 1H), 3.89 (dd, J ) 4.3, 10.2 Hz, 1H), 3.72 (dd, J ) 2.2,
10.2 Hz, 1H), 3.31 (d, J ) 9.5 Hz, 1H), 2.64 (dd, J ) 9.9, 18.4
Hz, 1H), 1.96 (dd, J ) 1.3, 18.4 Hz, 1H), 1.54 (s, 9H), 1.53 (s,
9H), 0.89 (s, 9H), 0.84 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H), 0.02
(s, 3H), 0.01 (s, 3H); 13C NMR (125 MHz, CDCl3) 172.3, 168.6,
149.8, 149.5, 148.7, 129.2, 83.5, 83.3, 73.2, 64.9, 64.2, 60.0, 36.5,
33.4, 28.1, 25.8, 25.6, 18.1, 18.0, -5.6, -5.7 ppm; FTIR (film)
1767, 1712, 1688 cm-1; MS (CI) m/z 555, 455. Anal. Calcd for
Rea ction of 3 w ith Dip h en ylsu lfon iu m n -P r op ylid e.
The procedure was as described for the synthesis of 2g/2h
except that synthon 3 (196 mg, 0.580 mmol) was used instead
of 1. Flash chromatography with 10:1 hexanes-EtOAc gave
an inseparable mixture of anti and syn products 4g and 4h as
a pale yellow oil (136 mg, 62%). The pure anti product was
obtained by Pd-C (2 mol %) hydrogenation of 4e followed by
purification on silica gel (15:1 hexanes-EtOAc) to give 4g as
a pale oil: 1H NMR (500 MHz, CDCl3) δ 4.02 (m, 1H), 3.83
(dd, J ) 2.8, 10.1 Hz, 1H), 3.73 (dd, J ) 5.6, 10.1 Hz, 1H),

Reactions of Pyroglutamic Acid Derived Synthons
J . Org. Chem., Vol. 64, No. 2, 1999 553
1.73 (ddd, J ) 1.1, 2.3, 5.7 Hz, 1H), 1.70 (dd, J ) 3.9, 5.7 Hz,
1H), 1.50 (s, 9H), 1.36 (m, 2H), 1.05 (m, 1H), 1.00 (t, J ) 7.4
Hz, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (125
MHz, CDCl3) 173.5, 150.5, 82.5, 63.9, 60.3, 28.1, 27.5, 27.2,
25.8, 24.4, 21.0, 18.2, 13.1, -5.4 ppm; FTIR (film) 1786, 1754,
1711 cm-1; MS (CI) m/z 370 (MH), 270. The pure syn product
was obtained by Pd-C (2 mol %) hydrogenation of 4f followed
by purification on silica gel (15:1 hexanes-EtOAc) to give 4f
as a pale oil: 1H NMR (500 MHz, CDCl3) δ 3.90 (m, 1H), 3.86
(dd, J ) 2.8, 10.0 Hz, 1H), 3.79 (dd, J ) 5.8, 10.0 Hz, 1H),
2.05 (m, 1H), 1.92 (dd, J ) 6.6, 7.2 Hz, 1H), 1.50 (s, 9H), 1.35
(m, 2H), 1.27 (m, 1H), 1.05 (t, J ) 7.2 Hz, 3H), 0.89 (s, 9H),
0.06 (s, 3H), 0.05 (s, 3H); 13C NMR 172.3, 149.7, 82.7, 63.9,
57.0, 28.1, 25.8, 25.7, 24.0, 19.6, 18.2, 16.4, 13.6, -5.4 ppm;
FTIR (film) 1786, 1750, 1710 cm-1; MS (CI) m/z 370 (MH), 270.
Anal. Calcd for C19H35NO4Si: C, 61.75; H, 9.54; N, 3.79.
Found: C, 61.78; H, 9.67; N, 3.84.
9.5 Hz, 1H), 2.54 (dd, J ) 3.3, 6.0 Hz, 1H), 2.39 (dd, J ) 2.2,
6.0 Hz, 1H), 1.80 (dd, apparent t, J ) 2.8 Hz, 1H); 13C NMR
(125 MHz, CDCl3) 178.6, 170.5, 138.9, 128.6, 128.4, 125.8, 87.8,
69.1, 59.5, 29.0, 28.7, 26.4 ppm; FTIR (film) 3413 (br), 3345
(br), 3203 (br), 1705, 1682 cm-1; MS (CI) m/z 259 (MH). Anal.
Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.70. Found: C,
65.03; H, 5.62; N, 10.70.
(1S,2S,5S,6R)-6-(Am in om eth yl)-3-a za -3-ben zylbicyclo-
[3.1.0]h exyl-2-m eth a n ol (16). A solution of the amide 15
(9.70 g, 37.6 mmol) in THF (80 mL) was added dropwise to a
suspension of lithium aluminum hydride (5.71 g, 150 mmol)
in THF (120 mL) at room temperature. After the addition was
complete, the reaction mixture was heated at reflux for 15 h
and then cooled to 0 °C. Saturated aqueous Na2SO4 solution
was added slowly until a white precipitate formed. The mixture
was diluted with EtOAc (150 mL) and filtered through Celite.
The filtrate was dried (Na2SO4) and concentrated to give the
amine 16 (8.74 g) as a pale oil which was used without further
purification: 1H NMR (500 MHz, CDCl3) δ 7.21-7.32 (m, 5H),
3.80 (d, J ) 13.6 Hz, 1H), 3.67 (d, J ) 13.6 Hz, 1H), 3.57 (dd,
J ) 4.6, 10.6 Hz, 1H), 3.52 (dd, J ) 4.5, 10.6 Hz, 1H), 3.19
(dd, J ) 4.7, 10.0 Hz, 1H), 2.99 (dd, apparent t, J ) 4.4 Hz,
1H), 2.61 (d, J ) 10.1 Hz, 1H), 2.57 (d, J ) 6.9, 2H), 2.04 (br
s, 3H), 1.33 (m, 1H), 1.29 (dd, J ) 3.1, 7.2 Hz, 1H), 0.93 (m,
1H); 13C NMR (125 MHz, CDCl3) 140.1, 128.3, 128.1, 126.8,
67.3, 62.9, 58.2, 55.6, 44.5, 29.3, 26.8, 23.2 ppm; FTIR (film)
3359 (br), 3288 (br), 3189 (br) cm-1; MS (CI) m/z 233 (MH).
(1S,2S,5R,6R)-3-Aza-3-ben zyl-6-(((im in o(((2,4,6-tr im eth -
ylp h en yl)su lfon yl)a m in o)m eth yl)a m in o)m eth yl)bicyclo-
[3.1.0]h exyl-2-m et h a n ol (17). The amine 16 (8.74 g), 1H-
pyrazole-1-carboxamidine hydrochloride (5.57 g, 36.7 mmol),
and diisopropylethylamine (DIEA) (6.6 mL, 38 mmol) in DMF
(10 mL) were maintained at room temperature overnight.
Ether (150 mL) was added to induce precipitation, and the
solvent was decanted. The precipitate was dissolved in MeOH
(10 mL), and the precipitation procedure was repeated twice
as above to give the guanylated amine hydrochloride as a pale
foam (11.5 g) which was used without further purification: 1H
NMR (500 MHz, CD3OD) δ 7.23-7.27 (m, 5H), 3.86 (d, J )
13.5 Hz, 1H), 3.79 (d, J ) 13.5 Hz, 1H), 3.65 (dd, J ) 4.3, 11.0
Hz, 1H), 3.54 (dd, J ) 6.2, 11.0 Hz, 1H), 3.28 (m, 1H), 3.06 (d,
J ) 7.2 Hz, 2H), 3.00 (dd, J ) 3.8, 9.3 Hz, 1H), 2.74 (d, J )
9.3 Hz, 1H), 1.47 (m, 2H), 1.29 (m, 1H); 13C NMR (125 MHz,
CD3OD) 158.5, 139.3, 130.1, 129.6, 129.2, 67.3, 62.7, 56.9, 55.4,
44.7, 27.1, 24.3, 23.6 ppm; FTIR (KBr) 3335 (br), 3172 (br),
1662 cm-1; MS (CI) m/z 275 (MH - HCl). The foam (11.4 g)
from above was dissolved in a solution of 4 N NaOH (19.3 mL,
77.0 mmol) and acetone (150 mL), and the solution was then
cooled to 0 °C. A solution of 2-mesitylenesulfonyl chloride
(MtsCl) (8.10 g, 36.7 mmol) in acetone (35 mL) was added
dropwise, and the resulting mixture was stirred at 0 °C for
1.5 h. The solution was concentrated to a volume of about 20
mL at room temperature, water (80 mL) was added, and the
resulting mixture was extracted with CH2Cl2 (3 × 100 mL).
The combined organic layers were washed with brine (50 mL),
dried (Na2SO4), and concentrated. The resulting residue was
purified on silica gel eluting with 10% MeOH in CH2Cl2 to
Rea ction of 3 w ith Meth yl Dim eth ylsu lfon iu m Acetyl-
id e. The procedure was as described for the synthesis of 2i/2j
except that synthon 3 (426 mg, 1.42 mmol) was used instead
of 1. Purification by flash chromatography with 5:1 hexanes-
EtOAc afforded 4i (201 mg, 39%) as a colorless solid and 4j
(222 mg, 43%) as a colorless oil. 4i: cottony solid from 1%
EtOAc-hexanes, mp 139-140 °C; [R]25 ) +2.8° (c ) 0.58,
D
1
CHCl3); H NMR (500 MHz, CDCl3) δ 4.11 (m, 1H), 3.85 (dd,
J ) 4.3, 10.4 Hz, 1H), 3.83 (dd, J ) 3.0, 10.4 Hz, 1H), 3.72 (s,
3H), 2.46 (ddd, J ) 1.1, 2.3, 6.2 Hz, 1H), 2.38 (dd, J ) 3.3, 6.5
Hz, 1H), 1.85 (dd, apparent t, J ) 2.9 Hz, 1H), 1.50 (s, 9H),
0.89 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (125 MHz,
CDCl3) 170.5, 170.4, 149.9, 83.2, 63.4, 60.0, 52.4, 29.4, 28.1,
25.8, 24.5, 22.9, 18.1, -5.5 ppm; FTIR (film) 1803, 1758, 1720
cm-1; MS (CI) m/z 400 (MH), 299. Anal. Calcd for C19H33NO6-
Si: C, 57.12; H, 8.32; N, 3.51. Found: C, 57.26; H, 8.38; N,
3.52. 4j: [R]25D ) -44.2° (c ) 0.65, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 4.25 (m, 1H), 3.89 (dd, J ) 2.9, 10.3 Hz, 1H), 3.84
(dd, J ) 5.2, 10.3 Hz, 1H), 3.67 (s, 3H), 2.41 (ddd, J ) 1.0, 6.3,
8.5 Hz, 1H), 2.26 (dd, J ) 6.3, 7.9 Hz, 1H), 2.15 (dd, apparent
t, J ) 8.3 Hz, 1H), 1.51 (s, 9H), 0.89 (s, 9H), 0.06 (s, 3H), 0.05
(s, 3H); 13C NMR (125 MHz, CDCl3) 169.7, 168.6, 149.8, 82.6,
63.7, 57.6, 52.2, 28.0, 25.8, 23.4, 22.0, 18.1, -5.5 ppm; FTIR
(film) 1789, 1752, 1739, 1715 cm-1; MS (CI) m/z 400 (MH),
299. Anal. Calcd for C19H33NO6Si: C, 57.12; H, 8.32; N, 3.51.
Found: C, 57.24; H, 8.24; N, 3.54.
Ep im er iza tion of syn P r od u ct 2j. A 2.0 M solution of
methylsulfinylcarbanion in DMSO (3.17 mL, 6.34 mmol) was
added to a solution of syn product 2j (8.67 g, 31.7 mmol) in
THF (25 mL) at 0 °C, and then the ice bath was removed. The
resulting mixture was maintained at room temperature for
30 min, quenched with H2O (30 mL), and extracted with Et2O
(3 × 30 mL). The combined organic fractions were dried (Na2-
SO4) and concentrated. Purification by flash chromatography
with 2:1 hexanes-EtOAc gave only anti product 2i (7.37 g,
85%).
Ep im er iza tion of a n ti P r od u ct 2i. A solution of anti
product 2i (269 mg, 0.990 mmol) in THF (1.5 mL) was added
dropwise to a 0.50 M solution of KHMDS in toluene (2.4 mL,
1.8 mmol) which was diluted with THF (1 mL) at -78 °C. The
resulting mixture was maintained at -78 °C for 30 min and
quenched with H2O (5 mL). The layers were separated, and
the aqueous layer was extracted with Et2O (3 × 10 mL). The
combined organic fractions were dried (Na2SO4) and concen-
trated. Flash chromatography with 1.5:1 hexanes-EtOAc
afforded syn product 2j (75.8 mg, 28%) and anti product 2i
(7.6 mg, 3%).
afford compound 17 (8.32 g, 50% for three steps) as a white
1
foam: [R]25 ) -14.6° (c ) 1.0, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 7.24-7.27 (m, 2H), 7.18-7.21 (m, 3H), 6.85 (s, 2H),
6.35 (br s, 2H), 6.28 (t, J ) 4.6 Hz, 1H), 3.69 (d, J ) 13.6 Hz,
1H), 3.59 (d, J ) 13.6 Hz, 1H), 3.44 (d, J ) 4.6 Hz, 2H), 3.10
(m, 1H), 3.02 (dd, J ) 3.2, 10.0 Hz, 1H), 2.94 (m, 1H), 2.89 (t,
J ) 4.6 Hz, 1H), 2.73 (br s, 1H), 2.63 (s, 6H), 2.51 (d, J ) 10.0
Hz, 1H), 2.22 (s, 3H), 1.28 (m, 2H), 0.94 (m, 1H); 13C NMR
(125 MHz, CDCl3) 156.3, 140.8, 139.7, 137.9, 137.8, 131.5,
128.3, 128.2, 127.0, 67.0, 62.8, 58.0, 55.3, 43.4, 26.7, 24.8, 23.2,
22.9, 20.8 ppm; FTIR (film) 3443 (br), 3342 (br), 1619, 1552
cm-1; MS (CI) m/z 457 (MH). Anal. Calcd for C24H32N4O3S: C,
63.13; H, 7.06; N, 12.27; S, 7.02. Found: C, 63.06: H, 7.00; N,
12.27; S, 6.87.
(1S,2S,3S,4S,7R)-6-Aza -8-oxa -5-oxo-7-p h en ylt r icyclo-
[4.3.0.0 2,4 ]n on an e-3-car boxam ide (15). Compound 2i (12.2
g, 44.6 mmol) was dissolved in dry MeOH (250 mL), ammonia
gas was bubbled through the solution for 30 min, and the
solution was maintained at room temperature for 40 h. The
solvent was evaporated, and the residue was purified on silica
gel eluting with 5% MeOH in EtOAc to give amide 15 (9.80 g,
85%) as a white solid: mp 160-162 °C; [R]25 ) +220.7° (c )
(1S,2S,5R,6R)-3-Aza-3-[(ter t-bu tyl)oxycar bon yl]-6-(((im i-
n o(((2,4,6-t r im e t h ylp h e n yl)su lfon yl)a m in o)m e t h yl)-
a m in o)m eth yl)bicyclo[3.1.0]h exyl-2-m eth a n ol (18). A so-
lution of N-benzylamine 17 (3.62 mg, 7.93 mmol), 10% Pd-C
D
1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.30-7.36 (m, 5H),
6.39 (br s, 1H), 6.20 (s, 1H), 5.94 (br s, 1H), 4.16 (dd, J ) 5.8,
7.4 Hz, 1H), 3.46 (dd, J ) 5.8, 9.5 Hz, 1H), 3.40 (dd, J ) 7.4,

554 J . Org. Chem., Vol. 64, No. 2, 1999
Zhang et al.
(0.85 g, 0.80 mmol), and ammonium formate (3.10 g, 47.7
mmol) in MeOH (50 mL) was heated at reflux for 30 min. After
cooling, the mixture was filtered through Celite, and the Celite
plug was washed with MeOH (100 mL) and CH2Cl2 (100 mL).
The filtrate was concentrated to yield the secondary amino
alcohol as a white foam (2.57 g) which was used without
purification: 1H NMR (500 MHz, CDCl3) δ 6.88 (s, 2H), 6.51
(br s, 1H), 6.43 (br s, 2H), 3.50 (d, J ) 7.4 Hz, 1H), 3.28 (m,
2H), 3.16 (m, 3H), 2.98 (m, 3H), 2.62 (s, 6H), 2.26 (s, 3H), 1.37
(m, 1H), 1.23 (m, 1H), 0.89 (m, 1H); 13C NMR (125 MHz,
CDCl3) 156.4, 140.9, 137.9, 137.7, 131.5, 62.9, 62.0, 46.4, 42.7,
24.6, 22.9, 22.5, 20.8, 19.3 ppm; FTIR (film) 3436 (br), 3332
(br), 3143 (br), 1620, 1551 cm-1; MS (CI) m/z 367 (MH). The
secondary amino alcohol (2.56 g) from above in CH2Cl2 (60 mL)
and di-tert-butyl dicarbonate (1.53 g, 7.00 mmol) were main-
tained at room temperature for 30 min. The solvent was
removed under reduced pressure, and the residue was purified
on silica gel eluting with 5% MeOH in CH2Cl2 to give the
(br), 3224 (br), 3160 (br), 1702, 1625, 1551 cm-1; HRMS
(electrospray) m/z 481.2130 (481.2121 calcd for C22H33N4O6S,
MH).
(1R,2S,5S,6R)-3-Aza -3-b en zyl-6-m et h oxyca r b on ylb i-
cyclo[3.1.0]h exyl-2-m eth a n ol (20). BH3 (92 mmol, 92 mL)
was added dropwise as a 1 M solution in THF to the amide 2i
(15.4 g, 56.4 mmol) in THF (120 mL), and the resultant
solution was heated at reflux for 1 h. After the solution cooled
to room temperature, the solvent was removed under reduced
pressure, and the residue was dissolved in methanolic hydro-
gen chloride (150 mL). The solution was heated at reflux for 2
h, and the methanol was removed under reduced pressure. The
resulting oil was dissolved in CH2Cl2 (60 mL) and washed with
a 20% aqueous solution of potassium carbonate (100 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 100 mL), and
the combined organic layers were dried over Na2SO4 and
concentrated. Flash chromatography of the residue on silica
gel eluting with 1:1 hexanes-EtOAc afforded the amino ester
20 (13.5 g, 92%) as a pale yellow oil: [R]25D ) -13.5° (c ) 0.22,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.18-7.28 (m, 5H), 3.77
(s, 2H), 3.63 (s, 3H), 3.58 (dd, J ) 4.9, 10.9 Hz, 1H), 3.55 (dd,
J ) 4.7, 10.9 Hz, 1H), 3.14 (dd, app t, J ) 3.9 Hz, 1H), 3.12
(dd, J ) 2.3, 4.7 Hz, 1H), 2.77 (d, J ) 10.2 Hz, 1H), 2.33-2.43
(br s, 1H), 2.00-2.05 (m, 1H), 1.98 (dd, app t, J ) 3.0 Hz, 1H),
1.70 (dd, app t, J ) 3.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
173.3, 139.7, 128.3, 128.0, 126.9, 65.9, 62.3, 57.1, 54.2, 51.6,
alcohol 18 (3.11 g, 84% for two steps) as a colorless foam: [R]25
D
) -29.2 (c ) 0.96, CHCl3); 1H NMR (500 MHz, CDCl3) δ 6.89
(s, 2H), 6.36 (br s, 2H), 6.26 (br s, 1H), 3.96 (t, J ) 5.5 Hz,
0.6H), 3.83 (t, J ) 4.4 Hz, 0.4H), 3.49-03.60 (m, 3H), 3.29-
3.33 (m, 1.6H), 3.18 (m, 0.4H), 3.06 (m, 0.4H), 2.91 (m, 0.6H),
2.64 (s, 6H), 2.26 (s, 3H), 1.41 (s, 9H), 1.33-1.39 (m, 2.4H),
1.29 (m, 0.6H), 0.73 (m, 1H); 13C NMR (125 MHz, CDCl3) 156.2,
155.7, 154.3, 140.6, 137.7, 137.5, 131.3, 80.0, 79.8, 64.9, 63.8,
61.0, 60.7, 47.8, 42.3, 28.3, 28.2, 24.2, 23.4, 22.7, 21.3, 21.0,
20.9, 20.6, 20.3 ppm; FTIR (film) 3441 (br), 3342 (br), 1670,
1622, 1551 cm-1; MS (CI) m/z 467 (MH). Anal. Calcd for
30.6, 27.6, 25.2 ppm; FTIR (film) 3442, 1730, 1437, 1298 cm-1
;
HRMS (CI) m/z 262.1443 (262.1443 calcd for C15H20NO3, MH).
(1R ,2S ,5S ,6R )-3-Aza -3-[(t er t -b u t yl)oxyca r b on yl]-6-
m et h oxyca r b on ylb icyclo[3.1.0]h exyl-2-m et h a n ol (21).
Pd-C (1.8 g) was added to a solution of the alcohol 20 (12.2 g,
46.7 mmol) and di-tert-butyl dicarbonate (11.7 g, 53.7 mmol)
in EtOAc (50 mL). The mixture was stirred overnight under
H2 (200 psi), and the catalyst was filtered off over a Celite pad.
The filtrate was concentrated, and the resulting thick oil was
purified by flash chromatography on silica gel (1:1 hexanes-
C
22H34N4O5S: C, 56.63; H, 7.34; N, 12.01; S, 6.87. Found: C,
56.77; H, 7.40; N, 11.89; S, 6.73.
(1S,2S,5R,6R)-3-Aza-3-[(ter t-bu tyl)oxycar bon yl]-6-(((im i-
n o(((2,4,6-t r im e t h ylp h e n yl)su lfon yl)a m in o)m e t h yl)-
am in o)m eth yl)bicyclo[3.1.0]h exan e-2-car boxylic acid (19).
A solution of oxalyl chloride (440 µL, 5.04 mmol) in CH2Cl2
(25 mL) was cooled to -78 °C, and DMSO (730 µL, 10.3 mmol)
was added dropwise. After 15 min, a solution of compound 12
(2.29 g, 4.91 mmol) in CH2Cl2 (8 mL) was added dropwise over
15 min, and the resulting mixture was maintained at -78 °C
for another 30 min. Triethylamine (4.1 mL, 29.4 mmol) was
added, and the reaction mixture was allowed to warm to -30
°C over 40 min; water (30 mL) was then added to quenched
the reaction. The aqueous layer was extracted with CH2Cl2 (3
× 30 mL), and the combined organic layers were dried (Na2-
SO4) and concentrated. Flash chromatography of the residue
EtOAc) to give the compound 21 as a colorless oil (10.3 g,
1
81%): [R]25 ) -67.9° (c ) 0.2, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 4.02 (dd, app t, J ) 5.1 Hz, 1H), 3.87 (dd, app t, J )
4.5 Hz, 1H), 3.74-3.82 (m, 1H), 3.62 (s, 3H), 3.53-3.58 (m,
1H), 3.39-3.42 (m, 1H), 2.78-2.84 (m, 1H), 2.04 (dd, J ) 2.4,
7.0 Hz, 1H), 1.95-2.01 (m, 1H), 1.94 (dd, J ) 2.8, 7.0 Hz, 1H),
1.40 (s, 9H); 13C (125 MHz, CDCl3) 172.7, 172.5, 155.0, 154.0,
80.2, 79.9, 64.2, 63.5, 60.8, 60.7, 51.6, 47.9, 47.6, 28.9, 28.2,
28.0, 25.7, 25.1, 23.6, 23.4 ppm; FTIR (film) 3450, 1765, 1757,
1735 cm-1; HRMS (CI) m/z 272.1501 (272.1498 calcd for C13H22
-
with 2% MeOH in EtOAc yielded the aldehyde (1.83 g, 80%)
NO5, MH).
1
as a white foam: [R]25 ) -33.2° (c ) 0.75, CHCl3); H NMR
D
(1R ,2S ,5S ,6R )-3-Aza -3-[(t er t -b u t yl)oxyca r b on yl]-6-
m eth oxyca r bon ylbicyclo[3.1.0]h exa n e-2-ca r boxylic a cid
(8). PDC (16.6 g, 44.2 mmol) was added to a solution of the
compound 21 (3 g, 11.0 mmol) in dry DMF (30 mL). The
reaction mixture was maintained at room temperature for 2
days, and the DMF was removed under reduced pressure. The
resulting brown residue was diluted with water (50 mL) and
extracted with EtOAc (4 × 50 mL). The combined organic
layers were dried over Na2SO4 and concentrated. Flash chro-
matography on silica gel (EtOAc) afforded the acid 8 as a white
(500 MHz, CDCl3) δ 9.45 (s, 0.4H), 9.41 (s, 0.6H), 6.89 (s, 2H),
6.30-6.41 (m, 3H), 4.30 (s, 0.4H), 4.19 (s, 0.6H), 3.53 (m, 1H),
3.41 (m, 1H), 3.25 (m, 0.4H), 3.14 (m, 1.2H), 3.02 (m, 0.4H),
2.64 (s, 6H), 2.26 (s, 3H), 1.40-1.55 (m, 5.6H), 1.38 (s, 5.4H),
0.89 (m, 1H); 13C NMR (500 MHz, CDCl3) 199.3, 198.7, 156.2,
154.8, 154.2, 140.9, 137.8, 137.6, 131.5, 80.6, 80.5, 67.2, 66.9,
48.5, 48.2, 42.2, 28.3, 28.2, 22.8, 22.4, 22.1, 22.0, 21.5, 21.3,
20.7, 20.6 ppm; FTIR 3442 (br), 3340 (br), 1735, 1695, 1619,
1551 cm-1; MS (CI) m/z 465 (MH). The aldehyde from above
(1.92 g, 4.13 mmol) and sodium dihydrogenphosphate mono-
hydrate (873 mg, 6.20 mmol) were dissolved in a 4:1 tert-butyl
alcohol-H2O solution (50 mL), and isobutylene (10.3 mL, 20.6
mmol) was added as a 2 M solution in THF. Sodium chlorite
(1.12 g, 12.40 mmol) was added, and the resulting mixture was
maintained at room temperature for another 2 h. Water (20
mL) was added, and the aqueous layer was extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed
with brine (30 mL), dried (Na2SO4), and concentrated to yield
foam (2.0 g, 63%): mp 53-55 °C; [R]25 ) -81.8 (c ) 0.2,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 10.51-10.69 (br s, 1H),
4.43 (s, 0.4H), 4.31 (s, 0.6H), 3.61 (s, 3H), 3.55-3.59 (m, 2H),
2.24 (dd, J ) 7.1, J ) 3.0 Hz, 0.4H), 2.21 (dd, J ) 3.0, J ) 7.1
Hz, 0.6H), 2.07 (dd, J ) 3.4, J ) 7.1 Hz, 0.6H), 2.04 (dd, J )
3.4, J ) 7.1 Hz, 0.4H), 1.57 (dd, app t, J ) 3.0 Hz, 0.6H), 1.53
(dd, app t, J ) 3.0 Hz, 0.4H), 1.41 (s, 3.6H), 1.34 (s, 5.4H); 13
C
NMR (125 MHz, CDCl3) 174.4, 174.0, 172.0, 154.8, 154.2, 80.9,
60.8, 60.4, 51.9, 48.0, 47.8, 29.0, 28.1, 28.0, 25.4, 24.7, 23.8,
23.6 ppm; FTIR (KBr) 3203, 1735, 1727, 1705 cm-1; HRMS
(CI) m/z 286.1284 (286.1290 calcd for C13H20NO6, MH).
compound 13 (1.89 g, 95%) as a white foam: [R]25 ) -23.6 (c
D
1
) 0.9, CHCl3); H NMR (500 MHz, CDCl3) δ 9.43 (br s, 1H),
6.87 (s, 2H), 6.45 (br s, 3H), 4.35 (s, 0.4H), 4.30 (s, 0.6H), 3.46-
3.52 (m, 2.4H), 3.19 (m, 0.6H), 3.05 (m, 0.6H), 2.90 (m, 0.4H),
2.62 (s, 6H), 2.25 (s, 3H), 1.63 (m, 1H), 1.41 (s, 3.6H), 1.37 (s,
5.4H), 1.26 (m, 1H), 0.9 (m, 1H); 13C NMR (500 MHz, CDCl3)
175.3, 174.6, 156.4, 155.5, 154.8, 140.9, 137.9, 137.6, 131.5,
81.1, 80.7, 61.2, 61.0, 48.4, 48.2, 42.3, 28.3, 28.2, 25.3, 24.4,
22.8, 21.6, 21.2, 20.8, 20.5 ppm; FTIR (film) 3443 (br), 3342
Ack n ow led gm en t. The authors thank Dr. William
Cleaver for solving the crystal structure of 2a . Support
for this work has been provided by grants OSR9350540
from NSF Vermont EPSCoR and CA75009 from the
NIH.

Reactions of Pyroglutamic Acid Derived Synthons
J . Org. Chem., Vol. 64, No. 2, 1999 555
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 1, 2a -j, 4a -j, 8, and 15-31, NOESY spectra of 2c-j
and 4c-j, and crystal data, bond lengths and angles, atomic
coordinates, and anisotropic parameters for 2a (83 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O9816109