Applications of vinylogous Mannich reactions. Total synthesis of the angiotensin converting enzyme inhibitor (-)-A58365A

Article abstract of DOI:10.1016/S0040-4020(02)00631-2

A concise enantiospecific synthesis of the angiotensin converting enzyme inhibitor (-)-A58365A (7) has been achieved following a strategy in which a vinylogous Mannich reaction and a lactone-lactam rearrangement served as the key transformations. The trimethylsilyloxyfuran derived from 25, which was prepared from the known sulfoxide 16, served as the nucleophilic partner in a vinylogous Mannich reaction with the chiral N-acyliminium ion that was generated in situ from the aminal 26. Addition of a further quantity of TMSOTf cleaved the N-Boc group from the adducts 27 to give a mixture of diastereomeric amino butenolides 28. Treatment of this mixture with LiOMe/MeOH furnished 10, and acid-catalyzed hydrolysis of the methyl ester groups delivered (-)-A58365A in 37% overall yield over the longest linear sequence of eight steps.

Full text of DOI:10.1016/S0040-4020(02)00631-2

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 6323±6328
Applications of vinylogous Mannich reactions. Total synthesis of
the angiotensin converting enzyme inhibitor (2)-A58365A
Andreas Reichelt, Scott K. Bur and Stephen F. Martinp
Department of Chemistry and Biochemistry, The University of Texas, Austin, TX 78712, USA
Dedicated to Professor Yoshito Kishi in recognition of his many contributions to organic chemistry and his receipt of the Tetrahedron Prize
Received 20 May 2002; accepted 6 June 2002
AbstractÐA concise enantiospeci®c synthesis of the angiotensin converting enzyme inhibitor (2)-A58365A (7) has been achieved
following a strategy in which a vinylogous Mannich reaction and a lactone±lactam rearrangement served as the key transformations. The
trimethylsilyloxyfuran derived from 25, which was prepared from the known sulfoxide 16, served as the nucleophilic partner in a vinylogous
Mannich reaction with the chiral N-acyliminium ion that was generated in situ from the aminal 26. Addition of a further quantity of TMSOTf
cleaved the N-Boc group from the adducts 27 to give a mixture of diastereomeric amino butenolides 28. Treatment of this mixture with
LiOMe/MeOH furnished 10, and acid-catalyzed hydrolysis of the methyl ester groups delivered (2)-A58365A in 37% overall yield over the
longest linear sequence of eight steps. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
The design and development of general and ef®cient
strategies for alkaloid synthesis has long been an important
objective in our laboratories. It is perhaps a truism that one
cannot long engage in alkaloid synthesis without encounter-
ing the Mannich reaction, a transformation that plays a
central role in the biogenesis of these natural products.
Indeed, the venerable Mannich reaction and its variants
represent one of the more powerful constructs for alkaloid
synthesis.1 A number of years ago we became interested in
the vinylog of the Mannich reaction as a tool for the rapid
assembly of skeletal frameworks commonly found in
alkaloid natural products. We have since employed various
types of vinylogous Mannich reactions as key steps in
executing concise syntheses of a number of alkaloids.2
Numerous combinations of linear and cyclic dienols and
iminium ions may participate in vinylogous Mannich addi-
tions to produce substituted d-amino-a,b-unsaturated car-
bonyl compounds, which are highly versatile intermediates
in alkaloid synthesis. However, we have been particularly
interested in one useful version of this bond construction
that is illustrated by the sequence of transformations
depicted in Scheme 1. When trialkylsilyloxyfurans 1 add
to cyclic iminium ions 2, two diastereomeric aminoalkyl
butenolides are produced with 3 typically being the major
adduct.2b,3 Signi®cantly, butenolides 3 and their saturated
Scheme 1.
counterparts 4 are structural arrays that are found in a
number of alkaloids. Moreover, compounds related to 4
were known to undergo facile lactone±lactam rearrange-
ments to generate the indolizidine (nˆ1) or quinolizidine
(nˆ2) ring systems 5 that are common to many biologically
important alkaloids.2c,4 Although the transformation of
butenolides like 3 to the bicyclic unsaturated lactams 6 is
unknown, related reorganizations have been reported.2d,5 It
is noteworthy that others have recognized the importance of
this variant of the vinylogous Mannich reaction for the
syntheses of alkaloids4b,c,e,6 peptidomimetics,4d and other
biologically active compounds.4f,7
Keywords: vinylogous Mannich reaction; enantioselection; lactone±lactam
rearrangement.
p
Corresponding author. Tel.: 11-512-471-3915; fax: 11-512-471-4180;
e-mail: sfmartin@mail.utexas.edu
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00631-2

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A. Reichelt et al. / Tetrahedron 58 (2002) 6323±6328
Because of our interest in developing new applications of
the vinylogous Mannich reaction, we were attracted to the
hydroxy indolizidine (2)-A58365A (7) as a potential target.
(2)-A58365A and its homolog A58365B (8) were isolated
from the fermentation broth of the soil bacterium
Streptomyces chromofuscus NRRL 15089 by researchers
at Lilly Research Laboratories and were found to be potent
angiotensin converting enzyme inhibitors effective at nano-
molar concentrations.8 Despite the appearance of four
different syntheses of 7,9±12 we envisioned that this
compound might be more readily prepared by deploying a
Mannich-based strategy.
Inasmuch as there are no stereogenic centers in the A ring
of 7, the stereoselectivity of the reaction between 13 and 14
to give 12 was irrelevant. We had considerable experience
with vinylogous Mannich reactions involving substrates
related to 13 and 14 and were thus con®dent of the viability
of this addition. However, we anticipated that the subse-
quent conversion of 12 into 9 via 11 or a related inter-
mediate might prove somewhat more challenging as we
had previously experienced dif®culties with lactone±lactam
rearrangements of butenolide derivatives.2d It should not
escape notice that application of this same plan to the
piperidine analogue of 14 would provide access to (2)-
A58365B (8).
2. Results and discussion
The synthesis of (2)-A58365A (7) commenced with the
conversion of commercially available thiophenylacetic
acid (15) into the known sulfoxide 16 in 77% yield accord-
ing to published procedures.13 Base-induced Michael addi-
tion of 16 to benzyl acrylate and subsequent sulfoxide
elimination afforded an inseparable mixture (ca. 12:1) of
the desired butenolide 17 together with its exo-isomer 19
in 89% combined yield. Treatment of this mixture with
trimethylsilyl tri¯uoromethanesulfonate (TMSOTf) in the
presence of Et3N generated an intermediate trimethylsilyl-
oxyfuran that was then allowed to react in situ with freshly
prepared benzenesulfenyl chloride14 to provide the desired
butenolide 18 in 83% overall yield (Scheme 3).
In developing the plan for the synthesis of 7 that is outlined
in Scheme 2, we bene®ted in several important ways from
the elegant work of our predecessors. The last step in several
syntheses of 7 involved hydrogenolysis of the dibenzyl
diester 9,9,12 and although the corresponding dimethyl
ester 10 had been prepared, it had not been directly trans-
formed into 7.9,10 Hence, the initial target of our endeavors
was 9. It was also known that introduction of the C(7)±C(8)
double bond by oxidation was fraught with dif®culty as the
B ring was prone to undergo facile concomitant oxidation,
thereby resulting in reduced yields of the desired
product.10,11b It would thus be optimal if the hydroxy
pyridone A ring were generated directly in the correct
oxidation state.
Based upon the foregoing discussion, we envisioned that the
vinylogous Mannich adduct 12 (RˆBn) would be an ideal
precursor of 9. Removal of the nitrogen protecting group
from 12 and opening of the butenolide ring was anticipated
to proceed with spontaneous loss of thiophenoxide to
generate 11, which would then undergo cyclization to 9.
Scheme 3.
The stage was now set for the key vinylogous Mannich
reaction. In the event, 18 was ®rst treated with TMSOTf
in the presence of base to generate the intermediate silyloxy-
furan 20 (Scheme 4). The known aminal 2115 and an addi-
tional portion of TMSOTf were then added, and the reaction
was allowed to proceed at 2788C to give a mixture of
adducts 22. These compounds were not isolated, but rather
excess TMSOTf was simply added to the reaction to effect
Scheme 2.

A. Reichelt et al. / Tetrahedron 58 (2002) 6323±6328
6325
of the reaction progress more dif®cult. Because 23 was in
short supply at that time, we therefore decided to prepare the
corresponding dimethyl ester 28 following the same pro-
cedures used to obtain 23 (Scheme 5). Accordingly,
sulfoxide 16 was ®rst transformed into the butenolide 25
in 73% overall yield. When the trimethylsilyloxyfuran
prepared in situ from 25 was allowed to react with the
known aminal 2621 in the presence of TMSOTf, the
expected vinylogous Mannich reaction ensued to generate
27, deprotection of which furnished 28 as a mixture (ca.
53:41:4:2)16 of stereoisomeric adducts. We were delighted
to discover that treatment of 28 with lithium methoxide in
MeOH induced the desired lactone±lactam rearrangement
to deliver 10 in 75% yield.
At this stage, we brie¯y considered the possibility of
converting 10 into 9 in order to intersect with Danishefsky's
synthesis of 7.9 However, we were also intrigued by the
more attractive possibility of transforming 10 directly into
7. Indeed, heating an aqueous solution of 10 under re¯ux in
the presence of DOWEXw 50WX8-200 ion-exchange resin
furnished (2)-A58365A (7) in 97% yield.
Scheme 4.
the removal of the N-Boc protecting group, thereby furnish-
ing 23 in 91% yield from 18 as a mixture of four dia-
stereomers (ca. 46:43:6:5).16 Inasmuch as this mixture
would converge to a single compound in the subsequent
lactone±lactam rearrangement, the diastereomers were not
individually isolated and characterized.
Thus far our plan had proceeded smoothly according to
our expectations. We were therefore ill-prepared for the
troubles that followed. Despite rather extensive experimen-
tation, we were unable to effect the requisite reorganization
of 23 into 9. Initial experiments to induce the lactone±
lactam rearrangement directly by heating 23 in DMF or
toluene were unsuccessful.2c,4a±c We then examined the
feasibility of using various nucleophiles such as benzyl-
oxide, cyanide,17 azide,18 or a methyl toluenesulfona-
mide±DBU system2d,19 in different solvents. Each of these
reagents would have been anticipated to open the lactone
ring to give an acyclic intermediate of the form 11 that
would then cyclize to 9. Under mild conditions, starting
material was invariably recovered from all of these experi-
ments, whereas under more forcing conditions, mixtures of
unidenti®ed products were obtained. Attempted activation
of the secondary amine nitrogen with Me3Al or Me2AlCl
according to the Weinreb protocol also led to the formation
of complex mixtures.20
Scheme 5.
We and others had previously found that aminoalkyl
butyrolactones may undergo facile lactone±lactam
rearrangement in the presence of methoxide in methanol.2c,4
However, use of these conditions to promote the conversion
of 23, which was in fact a mixture of four different
stereoisomers, into 9 would have been complicated by trans-
esteri®cation of the benzyl esters in both 23 and 9. T he
occurrence of such side reactions would render monitoring
This concise enantiospeci®c synthesis of (2)-A58365A (7)
clearly exempli®es the utility of the vinylogous Mannich
reaction followed by lactone±lactam rearrangement as a
powerful strategy for alkaloid synthesis. Systematic optimi-
zation of the reaction sequence allowed us to incorporate
multiple steps into one-pot operations, thereby providing 7
in 37% overall yield in a longest linear sequence of only

6326
A. Reichelt et al. / Tetrahedron 58 (2002) 6323±6328
eight steps from commercially available starting materials.
The synthesis is readily scalable to prepare gram quantities
of 7. Further applications of vinylogous Mannich reactions
to problems in alkaloid synthesis are the subject of current
investigations in our laboratories, and the results of these
will be reported in due course.
35.3, 25.1; IR (neat) n 1775, 1732, 1439, 1207, 1169,
1082, 1056 cm21; MS (CI1) m/z 171.0653 (C8H10O41H
requires 171.0657), 139 (base).
3.1.2. 3-(2-Oxo-2,5-dihydrofuran-3-yl)propionic acid
benzyl ester (17). Prepared analogously from 1613 and
benzyl acrylate in 89% yield as a pale yellow solid and an
1
inseparable mixture (12:1) of 17 and 19; mp 48±518C; H
NMR d 7.34±7.27 (comp, 5H), 7.06 (t, Jˆ1.8 Hz, 0.92H),
6.88±6.84 (m, 0.08H), 5.12 (s, 0.16H), 5.09 (s, 1.84H), 4.65
(d, Jˆ1.8 Hz, 1.84H), 4.33 (t, Jˆ7.3 Hz, 0.16H), 3.24 (dt,
Jˆ7.4, 1.8 Hz, 0.16H), 2.85±2.81 (m, 0.16H), 2.63±2.61
(comp, 3.68H); 13C NMR for major isomer: d 173.7,
171.9, 145.4, 135.7, 132.2, 128.4, 128.3, 128.2, 70.0, 66.3,
31.6, 20.7; for minor isomer: d 170.2, 169.0, 135.2, 130.8,
128.7, 128.5, 128.4, 128.3, 66.9, 65.2, 35.4, 25.1; IR
(CHCl3) n 1749, 1260, 1228, 1204, 1162, 1081, 1057,
831 cm21; MS (CI1) m/z 247.0971 (C14H14O41H requires
247.0970) (base), 139.
3. Experimental
3.1. General
Unless otherwise noted, solvents and reagents were reagent-
grade and were used without further puri®cation. Tetra-
hydrofuran (THF) and ether (Et2O) were dried by passage
through two columns of activated neutral alumina. Metha-
nol (MeOH) was dried by passage through two columns of
activated molecular sieves. Dichloromethane (CH2Cl2) was
distilled from calcium hydride, whereas benzene was
distilled from sodium. Triethylamine (Et3N) was distilled
from CaH2. Reactions involving air or moisture sensitive
reagents or intermediates were performed under an inert
atmosphere of argon in glassware that had been oven or
¯ame dried. Reaction temperatures are reported as the
temperature of the bath surrounding the vessel. Flash
chromatography was performed using Merck silica gel 60
(230±400 mesh ASTM) according to Still's protocol,22
eluting with solvents as indicated. Melting points are
3.1.3. 3-(2-Oxo-5-phenylthio-2,5-dihydrofuran-3-yl)pro-
pionic acid methyl ester (25). Freshly distilled TMSOTf
(697 mL, 3.85 mmol) was added to a mixture of 24 and its
isomer prepared above (596 mg, 3.50 mmol) and Et3N
(586 mL, 4.20 mmol) in CH2Cl2 (35 mL) at 08C, and the
reaction was stirred at 08C for 1 h. The mixture was cooled
to 2788C, and a solution containing freshly prepared
benzenesulfenyl chloride [from thiophenol (450 mL,
1
uncorrected. H and 13C NMR spectra were obtained as
4.38 mmol)
and
N-chlorosuccinimide
(702 mg,
5.25 mmol) in CH2Cl2 (5 mL)]14 was added. The mixture
was stirred at 2788C for 0.5 h and then poured into
saturated aqueous NaHCO3 (30 mL). The layers were
separated, and the aqueous layer was extracted with
CH2Cl2 (2£30 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. The resulting
yellow oil was puri®ed by ¯ash chromatography eluting
with EtOAc/hexanes (1:1) to give 777 mg (80%) of 25 as
a pale yellow oil; 1H NMR d 7.49±7.46 (m, 2H), 7.35±7.28
(comp, 3H), 6.96 (app q, Jˆ1.6 Hz, 1H), 6.09 (app q,
Jˆ1.6 Hz, 1H), 3.64 (s, 3H), 2.49±2.40 (comp, 3H),
2.31±2.25 (m, 1H); 13C NMR d 172.4, 171.8, 145.50,
134.5, 134.4, 129.3, 129.2, 129.1, 85.5, 51.8, 31.3, 20.4;
IR (neat) n 1770, 1731, 1440, 1202, 1170, 1044, 943, 750,
692 cm21; MS (CI1) m/z 279.0694 (C14H14O4S1H requires
279.0691) (base), 247, 169.
solutions in CDCl3 unless otherwise indicated, and chemical
shifts are reported in parts per million (ppm, d) down®eld
from internal standard Me4Si (TMS). Coupling constants
are reported in hertz (Hz). Spectral splitting patterns are desig-
nated as s, singlet; br, broad; d, doublet; t, triplet; q, quartet; m,
multiplet; comp, complex multiplet; and app, apparent. Infra-
red (IR) spectra were recorded either neat on sodium chloride
plates or as solutions in CHCl3 as indicated and are reported in
wavenumbers (cm21) referenced to the 1601.8 cm21 absorp-
tion of a polystyrene ®lm. Percent yields are given for
compounds that were $95% pure as judged by NMR.
3.1.1. 3-(2-Oxo-2,5-dihydrofuran-3-yl)propionic acid
methyl ester (24). Sodium hydride (37 mg of a 60% suspen-
sion in paraf®n oil, 0.98 mmol) was added to a solution of
1613 (985 mg, 4.68 mmol) in THF (47 mL), and the mixture
was stirred at room temperature for 15 min. Freshly distilled
methyl acrylate (1.27 mL, 14.05 mmol) was added, and the
mixture was stirred at room temperature for 1 h and then at
508C for 2 h. The mixture was cooled to room temperature
and partitioned between EtOAc (50 mL) and saturated
aqueous NaHCO3 (6 mL). The aqueous layer was extracted
with EtOAc (2£50 mL), and the combined organic layers
were dried (MgSO4) and concentrated in vacuo. The result-
ing yellow oil was puri®ed by ¯ash chromatography eluting
with EtOAc/hexanes (2:1) to give 723 mg (91%) of an
inseparable mixture (12:1) of 24 and its exocyclic double
bond isomer as a colorless oil; 1H NMR d 7.16 (t, Jˆ1.6 Hz,
0.92H), 6.86±6.81 (m, 0.08H), 4.72 (d, Jˆ1.6 Hz, 1.84H),
4.36 (t, Jˆ7.4 Hz, 0.16H), 3.69 (s, 0.24H), 3.64 (s, 2.76H),
3.20 (dt, Jˆ7.4, 1.8 Hz, 0.16H), 2.89±2.84 (m, 0.16H),
2.60±2.58 (comp, 3.68H); 13C NMR for major isomer: d
173.8, 172.6, 145.4, 132.5, 70.1, 51.7, 31.5, 20.8; for
minor isomer: d 170.3, 169.7, 131.0, 128.6, 65.2, 52.2,
3.1.4. 3-(2-Oxo-5-phenylthio-2,5-dihydrofuran-3-yl)pro-
pionic acid benzyl ester (18). Prepared analogously from
the mixture of 17 and 19 prepared above in 83% yield as a
1
pale yellow oil; H NMR d 7.47±7.45 (m, 2H), 7.37±7.28
(comp, 8H), 6.90 (app q, Jˆ1.6 Hz, 1H), 6.02 (app q,
Jˆ1.6 Hz, 1H), (app d, Jˆ2.0 Hz, 2H), 2.55±2.42 (comp,
3H), 2.37±2.30 (m, 1H); 13C NMR d 171.8, 171.7, 145.6,
135.7, 134.5, 134.4, 129.4, 129.2, 129.1, 128.6, 128.4,
128.3, 85.5, 66.5, 31.6, 20.4; IR (neat) n 1770, 1732,
1440, 1292, 1161, 1046, 943, 748, 695 cm21; MS (CI1)
m/z 355.1004 (C20H18O4S1H requires 355.1004) (base),
201.
3.1.5.
5-[4-(2-Methoxycarbonylethyl)-5-oxo-2-pheny-
thio-2,5-dihydrofuran-2-yl]pyrrolidine-2-carboxylic acid
methyl esters (28). Freshly distilled TMSOTf (461 mL,
2.55 mmol) was added to a mixture of 25 (644 mg,

A. Reichelt et al. / Tetrahedron 58 (2002) 6323±6328
6327
2.31 mmol) and Et3N (387 mL, 2.78 mmol) in CH2Cl2
(23 mL) at 08C. The mixture was stirred at 08C for 1 h
and then cooled to 2788C. A solution of 2621 (660 mg,
2.55 mmol) in CH2Cl2 (3 mL) and then TMSOTf (84 mL,
0.463 mmol) were added, and the reaction mixture was stir-
red at 2788C for 1 h. Another quantity of TMSOTf
(838 mL, 4.63 mmol) was then added. The cooling bath
was exchanged for an ice bath, and the mixture was stirred
at 08C for 2 h. The mixture was poured into saturated
aqueous NaHCO3 (30 mL), and the layers were separated.
The aqueous layer was extracted with EtOAc (2£30 mL),
and the combined organic layers were dried (MgSO4) and
concentrated in vacuo. The resulting yellow oil was puri®ed
by ¯ash chromatography eluting with EtOAc/hexanes (2:1)
to give 839 mg (90%) of a mixture (53:41:4:2) of four
diastereomers of 28 as a colorless oil. For spectroscopic
characterization an inseparable mixture (53:41) of the two
by ¯ash chromatography eluting with CH2Cl2/MeOH (19:1)
to give 419 (75%) of 22 as a off-white foam; 1H NMR d 7.22
(s, 1H), 5.11 (dd, Jˆ9.4, 3.2 Hz, 1H), 3.72 (s, 3H), 3.60 (s,
3H), 3.14 (ddd, Jˆ17.1, 9.2, 3.9 Hz, 1H), 3.07 (dd, Jˆ17.1,
8.6 Hz, 1H), 2.84±2.71 (m, 2H), 2.59 (br t, Jˆ7.3 Hz, 2H),
2.54±2.46 (m, 1H), 2.31±2.25 (m, 1H); 13C NMR d 173.6,
170.7, 158.8, 135.4, 133.9, 132.3, 128.5, 62.2, 52.7, 51.6,
32.6, 27.2, 26.8, 25.9; IR (neat) n 3165 (br), 1738, 1548,
1437, 1362, 1286, 1207, 1179 cm21; MS (CI1) m/z
296.1139 (C14H17NO61H requires 296.1134) (base), 264;
26
25
[a]D ˆ2195.18 (c 1.5, CH2Cl2); lit. [a]D ˆ2184.88 (c
21
1.5, CH2Cl2).9 [a]D ˆ2169.68 (c 1.5, CH2Cl2).10
3.1.8. (2)-A58365A (7). A solution of 10 (135 mg,
0.457 mmol) in H2O (5 mL) containing DOWEXw
50WX8-200 ion-exchange resin (135 mg) was heated
under re¯ux for 3 h. Noritw SA3-100 (70 mg) was added,
and the mixture was heated under re¯ux for another 10 min.
The solids were removed by ®ltration and then washed with
H2O (2£5 mL). The combined aqueous ®ltrates were
washed with CH2Cl2 (2£10 mL) and concentrated in
1
major isomers was also isolated by chromatography; H
NMR d 7.43±7.40 (comp, 2H), 7.35±7.32 (comp, 1H),
7.29±7.25 (comp, 2H), 6.83 (t, Jˆ1.4 Hz, 0.56H), 6.81 (t,
Jˆ1.4 Hz, 0.44H), 3.86±3.81 (comp, 2H), 3.70 (s, 1.32H),
3.69 (s, 1.68H), 3.63 (s, 1.32H), 3.62 (s, 1.68H), 2.35±2.22
(comp, 3H), 2.20±2.13 (comp, 1H), 2.02±1.80 (comp, 4H);
13C NMR for major isomer: d 175.4, 172.4, 171.5, 148.3,
137.1, 133.9, 129.8, 129.0, 128.1, 98.6, 62.1, 60.0, 52.2,
51.7, 31.4, 29.7, 26.6, 20.1; for minor isomer: d 175.3,
172.4, 171.4, 148.0, 137.3, 137.1, 133.8, 129.8, 128.9,
127.9, 98.4, 62.4, 60.1, 51.7, 31.4, 30.0, 27.0, 20.0; IR
(neat) n 3357, 1770, 1748, 1734, 1716, 1434, 1208, 1026,
753, 694 cm21; MS (CI1) m/z 406.1323 (C20H23NO6S1H
requires 406.1324) (base), 296.
1
vacuo to give 118 mg (97%) of 7 as a white foam; H
NMR (D2O) d 7.24 (s, 1H), 5.06 (dd, Jˆ10.0, 3.4 Hz,
1H), 3.07 (ddd, Jˆ17.3, 9.5, 3.8 Hz, 1H), 3.00 (dd,
Jˆ17.3, 8.8 Hz, 1H), 2.70±2.61 (m, 2H), 2.58±2.49
(comp, 3H), 2.33±2.27 (m, 1H); 13C NMR d 177.7, 174.2,
159.4, 135.6, 134.9, 134.3, 128.0, 63.3, 32.7, 27.2, 26.3,
25.2; IR (neat) n 3192 (br), 1714, 1530, 1440, 1410,
1284, 1209 cm21
;
(C12H13NO61H requires 268.0821) (base), 250, 241, 208;
MS (FAB1) m/z 268.0817
26
25
[a]D ˆ2196.38 (c 1.0, H2O); lit. [a]D ˆ2199.58 (c 1.0,
25
H2O),8c [a]D ˆ2190.58 (c 0.1, H2O).9
3.1.6. 5-[4-(2-Benzyloxycarbonylethyl)-5-oxo-2-pheny-
thio-2,5-dihydrofuran-2-yl]pyrrolidine-2-carboxylic acid
benzyl esters (23). Prepared analogously from 18 and 2115
in 91% yield as a mixture (46:43:6:5) of four diastereomers
and as a colorless oil. For spectroscopic characterization an
inseparable mixture (46:43) of the two major isomers was
Acknowledgements
We thank the National Institutes of Health (GM 25439), the
Robert A. Welch Foundation, P®zer, Inc, and Merck
Research Laboratories for their generous support of this
research. We also thank Dr Christopher S. Straub for helpful
discussions.
1
isolated by chromatography; H NMR d 7.41±7.38 (comp,
2H), 7.37±7.29 (comp, 11H), 7.26±7.22 (comp, 2H), 6.79
(t, Jˆ1.2 Hz, 0.52H), 6.76 (t, Jˆ1.2 Hz, 0.48H), 5.12 (br s,
2H), 5.06 (br d, Jˆ2.4 Hz, 2H), 3.88±3.80 (comp, 2H),
2.37±2.22 (comp, 3H), 2.18±2.11 (comp, 1H), 2.09±2.01
(comp, 1H), 1.94±1.78 (comp, 3H); 13C NMR for major
isomer: d 174.9, 171.7, 171.5, 148.3, 137.1, 135.7, 135.5,
133.8, 129.7, 128.9, 128.6, 128.5, 128.4, 128.3, 128.2,
128.1, 98.6, 66.8, 66.4, 62.0, 60.1, 31.6, 29.7, 26.6, 20.1;
for minor isomer: d 174.7, 171.8, 171.3, 148.0, 137.3,
135.7, 135.5, 133.7, 129.7, 128.8, 128.6, 128.5, 128.4,
128.3, 128.2, 128.1, 98.4, 66.8, 66.4, 62.3, 60.2, 31.6,
30.0, 26.9, 20.0; IR (neat) n 3355, 1770, 1738, 1732,
1715, 1455, 1440, 1162, 1026, 749, 696 cm21; MS (CI1)
m/z 558.1953 (C32H31NO6S1H requires 558.1950) (base),
448, 407, 355, 294.
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Á
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È
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