A synthetic approach to diverse 3-acyltetramic acids via O- to C-acyl rearrangement and application to the total synthesis of penicillenol series

Article abstract of DOI:10.1021/jo300527f

For the efficient approach to medicinally important α-branched 3-acyltetramic acids, the key reaction of O- to C- acyl rearrangement using α-amino-acid-derived 4-O-acyltetramic acids was extensively examined in the presence of various metal salts. Use of

Full text of DOI:10.1021/jo300527f

Article
pubs.acs.org/joc
A Synthetic Approach to Diverse 3-Acyltetramic Acids via O- to
C-Acyl Rearrangement and Application to the Total Synthesis of
Penicillenol Series
Tetsuya Sengoku, Yuta Nagae, Yasuaki Ujihara, Masaki Takahashi, and Hidemi Yoda*
Department of Materials Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Naka-ku, Hamamatsu,
Shizuoka 432-8561, Japan
S
* Supporting Information
ABSTRACT: For the efficient approach to medicinally important
α-branched 3-acyltetramic acids, the key reaction of O- to C- acyl
rearrangement using α-amino-acid-derived 4-O-acyltetramic acids
was extensively examined in the presence of various metal salts. Use
of CaCl2 or NaI dramatically changed the results in the reac-
tion efficiency and rapidly brought about the desired α-branched
3-acyltetramic acids in markedly improved yields. We also discuss an
epimerization at C5 stereocenter under the rearrangement
conditions as well as the tolerance for structural variation at C3
and C5. In addition to the preceding success in the total synthesis of
new cytotoxic tetramic acid, penicillenol A1, this methodology could be also applied to the first total synthesis of penicillenol A2.
C-acyl rearrangement of 4-O-acyltetramic acids C has been
demonstrated to enable indirect installation of acyl groups into
the tetramic acid ring systems.7 This methodology, however,
has limited applicability only for the reactions of the substrates
bearing linear migratory segments that would be preferred on
steric grounds6f,7d and would be incompatible with complicated
migratory segments such as α-branched alkylcarbonyl groups.
In this regard, we have recently overcome this problem by the
use of CaCl2 as an effective additive, giving a marked improve-
ment in the reaction efficiency for the formation of the 3-
acyltetramic acid bearing α-methyloctanoyl moiety. Moreover,
we accomplished the first total synthesis of penicillenol A1
through N-methylation of amide and subsequent removal of
TBS protecting group (Scheme 1).8 Despite less accumulated
information available for the synthesis of 3-acyltetramic acid
derivatives, our previous work gave some indication of a rich
opportunity for accessing diverse 3-acyltetramic acids with the
other branched segments. In an attempt to examine the validity
and generality of this synthetic methodology and to expand its
utility, we explored the scope of the reaction with a diverse set
of the substrates. In the present article, we provide a full
account of our efforts in developing the synthetic approach to
variously substituted 3-acyltetramic acids and demonstrate the
versatility for the remaining synthetic challenge associated with
the total synthesis of naturally occurring antibacterial
penicillenol A2.
INTRODUCTION
■
2,4-Pyrrolidinedione derivatives, so-called tetramic acids, can
serve as one of the basic building blocks for bioactive molecules
found in a variety of natural products from marine organisms,
fungi, and bacteria.1 Among these compounds, 3-acyl-
substituted tetramic acids (Figure 1) have proven particularly
appealing to the medicinal community because of their remark-
able potency such as antiviral and antitumor activities (tenuazonic
acid),2a herbicidal activity (macrocidin A),2b inhibitory activi-
ties against bacterial RNA polymerases (streptolydigin),2c,d anti-HIV
activity (Sch 213766),2e and cytotoxicity (penicillenols A1,2).2f In
particular, extensive research focused on streptolydigin, whose
outstanding inhibitory activity against bacterial RNA polymer-
ase has received particular attention over the past decade,
provided an important stimulus for understanding mechanistic
complexities of the biological events.3 Despite the great
significance of 3-acyltetramic acids, development of compre-
hensive and efficient protocols for this type of compound is
substantially less advanced, because there is an intrinsic
difficulty in accessing this structural system.4−10 In this context,
one of the conventional strategies for the preparation of this
class of compounds has utilized Dieckmann-type cyclization of
β-ketoamides A (Figure 2).4,5 This synthetic method faces the
risk of epimerization at the C5 stereocenter, which would be
attributed to enolization equilibrium under the basic conditions,
thus making this methodology unsuitable for stereoselective
synthesis.5d,e,h,j,l Another possible synthetic strategy involves
direct acylation of C3-unsubstituted tetramic acids B with the
use of acid chlorides.6 This has a limited functional group
tolerance, because harsh conditions of operation employing
Lewis acids such as BF3·OEt2 are essential to drive the reaction
smoothly. Alternatively, a synthetic approach based on O- to
Received: March 12, 2012
Published: April 17, 2012
© 2012 American Chemical Society
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Figure 1. Structures of naturally occurring 3-acyltetramic acids.
Similarly, such effects could be observed for the reactions with
the use of the other metal salts such as NaCl (entry 3), KF
(entry 6), or CeCl3 (entry 8) to afford 6a in moderate yields,
while FeCl3 would be detrimental to the transformation to
result in decomposition of the substrate (entry 9). Among the
various metal salts examined, CaCl2 (71%, entry 7) and NaI
(70%, entry 4) exhibited the marked performances to generate
6a, and we therefore conclude that these materials would be the
optimal additives to promote the O- to C-acyl rearrangement
processes efficiently. In an analogy to closely related systems,
the mechanism of rearrangement could be understood on the
basis of primary process, namely, a C−O bond-cleavage and
recombination of the migrating ion pairs.13 The presence of
ionic species in the metal salts may help in stabilization of the in
situ generated ion pairs that would be bound together by weak
Coulombic attraction, thus facilitating the formation of 3-
acyltetramic acids.
As seen in Figure 4, a wide variety of 4-O-acyl tetramic acids
5 were shown to undergo the intramolecular transformations in
the presence of CaCl2 to give the corresponding 3-acyltetramic
acids 6. Indeed, the substrates bearing the substituted benzoyl
and α-branched alkylcarbonyl moieties 5a−m showed remark-
ably high reactivities to generate 6a−m in satisfactory yields
(51−79%), respectively, whereas the sterically demanding tert-
butyl analogue 5n failed to afford the desired compound,
decomposing to 4n under conditions identical to those for the
other substrates. Furthermore, no obvious difference was
observed in the reaction efficiency when the C5-substituent
on the tetramate core was varied, and all the series of 4-O-acyl
tetramic acids derived from isoleucine 5b−g, phenylalanine 5h,
alanine 5i, serine 5j, and threonine 5k−m gave the
corresponding rearrangement products 6b−m in moderate to
good yields. These results suggest that the course of the
reaction is not influenced by the structural properties of the
tetramate cores but rather by those of the acyl groups on the
Figure 2. Conventional synthetic approaches to 3-acyltetramic acids.
RESULTS AND DISCUSSION
■
4-O-Acyltetramic acids with a variety of substituents 5a−n were
prepared as shown in Figure 3.6f,7d,11 A series of 3-unsubstituted
tetramic acids 4a−e obtained through condensation−decarbox-
ylation sequences in good yields from N-Boc or N-Cbz protected
amino acids 3a−e12 could be condensed with a range of carboxylic
acids in the presence of DCC and DMAP to provide 5a−m. For
the preparation of 5n, esterification of 4b using Piv2O as a
condensing agent was preferred over the above synthetic protocol,
affording the best yield of the desired product.
With these compounds in hand, we turned our focus toward
investigating the O- to C-acyl rearrangement of 5 to obtain 3-
acyltetramic acids 6. To optimize this process, a similar series of
experiments were undertaken with 5a under various reaction
conditions (Table 1). Without any metal salts, the reaction at
room temperature led to give only a 10% yield of the desired
product 6a for a period of 24 h along with recovery of the
starting material (entry 1). In contrast, the reaction in the
presence of LiBr (1.5 equiv) showed complete consumption of the
starting material and gave distinctly better yield of 6a (43%, entry 2).
8
Scheme 1. Synthesis of Penicillenol A1
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Figure 3. Preparation of 4-O-acyltetramic acids 5. Isolated yields of products are indicated below each entry. *See ref 11.
Table 1. O- to C-Acyl Rearrangement of 5a in the Presence
of Various Metal Salts
C5 diastereomers were in situ generated for the cases of the
substituted benzoyl series 6b−d, as revealed by the H NMR
1
analysis. Apparently, the occurrence of the epimerization can be
understood in terms of pathways involving deprotonation of
the C5−H and enolization to form planar structures of the
relevant enolates. Through inspection of the stereochemical
control for the product formation, a higher degree of
epimerization was observed as an increase in the reaction
time. Actually, prolongation of the reaction time to ensure
complete consumption of the reactants led to increases in the
relative ratios of the epimeric isomers over the desired ones,
where 5c representing the typical example gave a ratio of 70:30
(6c/epimer) for 16 h as compared with 78:22 for 1 h along
with 5b (83:17 for 3 h) and 5d (87:13 for 3 h). On the other
hand, the series of 4-O-alkylcarbonyl tetramic acids 5e−m
underwent fast reactions that completed within 1 h, affording
the enantiomerically pure products. In such cases, the
epimerization was exclusively avoided, probably because of
substantially much slower rates as compared to the O- to C-acyl
rearrangement processes. In this regard, we found that a
noticeable epimerization of the recovered substrate took place
a
entry
additive
time/h
yield/%
1
2
3
4
5
6
7
8
9
24
8
24
4
24
24
3
10
43
46
70
29
44
71
55
LiBr
NaCl
NaI
MgBr2
KF
CaCl2
CeCl3
FeCl3
7
24
b
0
a
b
Isolated yields. 5a was not recovered.
oxygen atoms. As for stereochemical integrity of the reaction
products, it should be noted that small amounts of the epimeric
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Figure 4. Acyl rearrangement of 4-O-acyltetramic acids in the presence of CaCl2. Isolated yields are indicated below each entry. *Reaction time and
1
diastereomeric ratio determined by H NMR are indicated in parentheses.
at a rate of 96:4 (5b/epimer) when the enantiomerically pure
5b was treated with Et3N (1.5 equiv) and in the presence of
CaCl2 (1.5 equiv) in CH2Cl2 at room temperature,14 as
observed by H NMR, while no epimerization of the product
occurred when 6b was treated under the same conditions
(Figure 5). These findings confirm that the formation of
conclude that the metal salts serve a dual purpose of
suppressing the epimerization under the conditions employed
as well as enhancing the product formation.15
1
As our continuing interest in the context of the present
studies, we considered that a properly designed 3-acyltetramic
acid obtained through the O- to C-acyl rearrangement would
serve as a substrate pertinent to achieving the total synthesis of
natural products such as penicillenols, which have been isolated
from the culture broth of a fungus Penicillium sp. as cytotoxic
agents.2f In our previous work, the total synthesis of
penicillenol A1 1 and its C9-epimer has been completed by
employing 6l,m, respectively.8 Following the above synthetic
strategy, we considered that the synthesis of penicillenol A2, a
C5-epimer of penicillenol A1, would be achieved using
D-allothreonine as a starting chiral source. Thus, we turned
to synthesize this natural product to demonstrate the versatil-
ity of this synthetic methodology for a generous supply of
3-acyltetramic acids (Scheme 2). The synthesis started with a
56:44 mixture of L-threonine and D-allothreonine, which could
be prepared by isomerization of L-threonine.16 When this
material was allowed to react under conditions identical to that
for 4e, a 61:39 inseparable diastereomeric mixture of 9 was
obtained. Subsequent condensation of this material with (S)-2-
methyloctanoic acid17 afforded a mixture consisting of 10 and
its diastereoisomeric counterpart 5m, which could be separated
by silica gel column chromatography. The enantiomerically
1
Figure 5. Comparison of H NMR spectra on H5 of 5b or 6b (300
MHz, CDCl3, δ in ppm). (a) 5b, (b) 5b after treatment with Et3N (1.5
equiv) and CaCl2 (1.5 equiv) in CH2Cl2 at room temperature, (c) 6b,
and (d) 6b after treatment with Et3N (1.5 equiv) and CaCl2 (1.5
equiv) in CH2Cl2 at room temperature.
3-acyltetramic acids competes with the epimerization proceed-
ing at comparable rates. From the above considerations, we can
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Scheme 2. Total Synthesis of Penicillenol A2
was purified by column chromatography (silica gel, hexane/EtOAc =
1/1) to give 4b (1.01 g, 86%) as a white powder: dp 94−100 °C;
[α]D27 −71.7 (c 1.04, CHCl3); IR (KBr) 3178 (N−H), 3098 (N−H),
pure 10 underwent the O- to C-acyl rearrangement followed by
N-methylation to produce 12 in 58% yield over two steps. At
the final step, the TBS group of 12 could be removed by
exposure to methanolic HCl (2%) to give 2 in 65% yield as a
90:10 mixture of Z:E isomers.
1
2936 (C−H), 1772 (CO), 1694 (CO) cm−1; H NMR (300
MHz, CDCl3) δ 6.59 (brs, 1H), 3.92 (d, J = 4.2 Hz, 1H), 2.97 (s, 2H),
1.89 (m, 1H), 1.46−1.26 (m, 2H), 1.00 (d, J = 6.9 Hz, 3H), 0.92 (t, J =
7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 207.8 (C), 172.5 (C),
69.1 (CH), 41.6 (CH), 37.6 (CH), 24.2 (CH2), 15.1 (CH3), 11.4
(CH3). Anal. Calcd for C8H13NO2: C, 61.91; H, 8.44; N, 9.03. Found:
C, 62.02; H, 8.58; N, 8.64.
Identification of this product was performed by spectroscopic
analyses and optical rotatory measurements. As a consequence,
1H NMR, 13C NMR, and IR spectroscopic data of 2 appeared
to be fully consistent with those of the natural penicillenol A2,
22
(S)-5-((tert-Butyldimethylsilyloxy)methyl)-4-oxo-2-pyrroli-
done (4d). To a solution of Meldrum’s acid (951 mg, 6.60 mmol) and
protected amino acid 3d (2.12 g, 6.00 mmol) in dichloromethane
(30 mL) at 0 °C were added EDCI (1.38 g, 7.20 mmol) and DMAP
(1.10 g, 9.00 mmol). After stirring for 2 h at room temperature, the
reaction mixture was filtered through a pad of Celite. The filtrate was
washed with 5% aqueous NaHSO4 solution, water, and brine. The
organic phase was dried over Na2SO4, filtered, and evaporated to give
the crude mixture. This material was dissolved in EtOAc (90 mL), and
the solution was refluxed for 1 h until completion of the reaction
(monitored by TLC) and concentrated under reduced pressure. A
suspension containing the residue and Pd/C (31.2 mg) in EtOH
(9.0 mL) was stirred under hydrogen atmosphere for 2 h. The reaction
mixture was filtered through a pad of Celite, and the residue was
washed with EtOAc. The filtrate was concentrated under reduced
pressure, and the residue was purified by column chromatography
(silica gel, CHCl3/MeOH = 40:1) to give 4d (891 mg, 61%) as a pale
although the optical rotation of 2 {[α]D +49.2 (c 0.137,
MeOH)} showed a significant difference to that reported in the
literature2f {[α]D25 +386.7 (c 0.135, MeOH)}.18 Unfortunately,
other data to be discussed were unavailable except that the
optical rotations of both penicillenols fluctuated significantly
because of their low solubilities in MeOH.19 Further measure-
ments of the synthetic sample of 1 and 2 in CHCl3 allowed us
to reevaluate the optical activities, giving constant values of
23
22
[α]D −47.6 (c 0.918) for 1 and [α]D +27.8 (c 0.864) for 2.
Although an obvious reason for the observed difference in the
[α]D values remains unclear at present, we are reasonably
confident with the complete spectroscopic characterization that
the synthetic approach described above should ensure
completion of the first total synthesis of penicillenol A2 with
the complete structure and absolute stereochemistry.20
27
yellow solid: dp 78−84 °C; [α]D −53.7 (c 1.03, CHCl3); IR (KBr)
CONCLUSION
■
3200 (N−H), 3104 (N−H), 2930 (C−H), 1778 (CO), 1690 (C
O) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.43 (brs, 1H), 4.01 (brt, J =
3.3 Hz, 1H), 3.92 (dd, J = 3.3, 10.5 Hz, 1H), 3.77 (dd, J = 2.4, 10.5 Hz,
1H), 2.91 (s, 2H), 0.84 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 206.5 (C), 172.3 (C), 66.0 (CH2), 63.0 (CH),
41.4 (CH2), 25.6 (CH3), 18.0 (CH3), −5.8 (CH3), −5.9 (CH3). Anal.
Calcd for C11H21NO3Si: C, 54.29; H, 8.70; N, 5.76. Found: C, 54.44;
H, 8.43; N, 5.93.
The synthesis of 3-acyltetramic acids via O- to C-acyl
rearrangement has been systematically investigated. We
demonstrated that the presence of metal salts significantly
improved the product yields to produce the desired 3-acyltetramic
acids, and a variety of substituents were found to be well
tolerated. Coupled with our preceding report on the success in
synthesizing penicillenol A1, this synthetic method has been
demonstrated to allow for completing the first total synthesis of
penicillenol A2.
(S)-5-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-4-oxo-2-pyrro-
lidone (4e). To a solution of Meldrum’s acid (1.50 g, 10.3 mmol) and
protected amino acid 3e (3.45 g, 9.39 mmol) in dichloromethane
(35 mL) at 0 °C were added DCC (2.13 g, 10.3 mmol) and DMAP
(1.49 g, 12.2 mmol). After stirring for 10 h at 0 °C, the reaction mixture
was filtered through a pad of Celite, and the residue was washed with
CH2Cl2. The filtrate was washed with 5% aqueous NaHSO4 solution
and brine. The organic phase was dried over Na2SO4, filtered, and
evaporated to give the crude mixture. The solution of this material in
EtOAc (200 mL) was refluxed for 5 h until completion of the reaction
(monitored by TLC). After removal of the solvent by evaporation,
the suspension containing the residue and Pd/C (500 mg) in EtOAc
(50 mL) was stirred under hydrogen atmosphere for 12 h. The mixture
was filtered through a pad of Celite, and the residue was washed with
EtOAc. The filtrate was concentrated under reduced pressure, and the
residue was purified by column chromatography (silica gel, hexane/
EtOAc = 3/1−2/1−1/1) to give 4e (911 mg, 38%, 3 steps) as a white
EXPERIMENTAL SECTION
■
(S)-5-((S)-sec-Butyl)-4-oxo-2-pyrrolidone (4b). To a solution of
Meldrum’s acid (1.20 g, 8.33 mmol) and protected amino acid 3c
(1.76 g, 7.61 mmol) in dichloromethane (50 mL) at 0 °C were added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(EDCI) (1.75 g, 9.13 mmol) and DMAP (1.39 g, 11.4 mmol). After
stirring for 5 h at room temperature, the reaction mixture was poured
into EtOAc (150 mL) and extracted. The organic layer was washed
with brine and 5% aqueous NaHSO4 solution, dried over Na2SO4, and
filtered. The filtrate was refluxed for 1 h until completion of the
reaction (monitored by TLC) and concentrated under reduced
pressure. The residue was treated with 1:1 TFA/dichloromethane (2.0 mL)
for 1 h. After removal of the solvent by evaporation, the crude product
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29
powder: dp 122−124 °C; [α]D −84.8 (c 1.10, CHCl3); IR (NaCl)
161.5 (C), 141.2 (C), 131.5 (CH), 129.4 (CH), 126.6 (C), 108.9
(CH), 63.0 (CH), 36.4 (CH), 23.1 (CH2), 15.8 (CH3), 11.9 (CH3).
Anal. Calcd for C15H16ClNO3: C, 61.33; H, 5.49; N, 4.77. Found: C,
61.14; H, 5.76; N, 4.82.
3199 (N−H), 3111 (N−H), 1777 (CO), 1709 (CO) cm−1; H
1
NMR (300 MHz, CDCl3) δ 7.90 (brs, 1H), 4.21 (dq, J = 2.7, 6.6 Hz,
1H), 3.80 (brd, J = 2.6 Hz, 1H), 2.90 (s, 2H), 1.24 (d, J = 6.6 Hz, 3H),
0.82 (s, 9H), 0.04 (s, 3H), −0.02 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 206.8 (C), 172.9 (C), 70.2 (CH), 68.1 (CH), 41.3 (CH2), 25.5 (CH3),
20.3 (CH3), 17.7 (C), −4.5 (CH3), −5.4 (CH3). Anal. Calcd for
C12H23NO3Si: C, 55.99; H, 9.01; N, 5.44. Found: C, 55.66; H, 8.75; N,
5.59.
(S)-2-((S)-sec-Butyl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl Isobu-
tyrate (5e). The crude product was purified by column chromatog-
raphy (silica gel, hexane/EtOAc = 1/1) to give 5e (52.9 mg, 52%) as a
white powder: dp 88−92 °C; [α]D25 +45.9 (c 0.880, CHCl3); IR (KBr)
3234 (N−H), 3103 (N−H), 2935 (C−H), 1778 (CO), 1687 (C
1
O), 1652 (CC) cm−1; H NMR (300 MHz, CDCl3) δ 7.36 (brs,
General Procedure for the Preparation of the 4-O-
Acyltetramic Acids. To a solution of carboxylic acid (1.1−1.4
equiv) in dichloromethane at 0 °C were added DCC (1.2−1.9 equiv)
and DMAP (0.2−0.3 equiv). After stirring for 5 min at the same
temperature, 4 (1.0 equiv) was added. It was stirred at room
temperature until completion of the reaction (monitored by TLC).
The reaction mixture was filtered through a pad of Celite, and the
residue was washed with EtOAc. The filtrate was washed with
saturated aqueous NH4Cl solution and brine. The organic phase was
dried over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the crude product afforded 4-O-acyltetramic acid 5.
(S)-2-Benzyl-5-oxo-2,5-dihydro-1H-3-pyrrolyl Benzoate (5a).
The crude product was rinsed with Et2O (5 mL) to give 5a (40.1 mg,
1H), 6.08 (s, 1H), 4.21 (t, J = 1.5 Hz, 1H), 2.74 (sep, J = 6.9 Hz, 1H),
1.85 (m, 1H), 1.39−1.13 (m, 8H), 1.03 (d, J = 6.9 Hz, 3H), 0.90 (t, J =
7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.2 (C), 172.6 (C),
165.5 (C), 108.2 (CH), 62.8 (CH), 36.1 (CH), 34.4 (CH), 22.9
(CH2), 18.5 (CH3), 18.4 (CH3), 15.8 (CH3), 11.8 (CH3). Anal. Calcd
for C12H19NO3: C, 63.98; H, 8.50; N, 6.22. Found: C, 64.26; H, 8.83;
N, 6.59.
(S)-2-((S)-sec-Butyl)-5-oxo-2,5-dihydro-1H-3-pyrrolyl 2-
Methylbutanoate (5f). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 1/1) to give 5f (48.0 mg,
70%) as a white powder: dp 95−99 °C; IR (KBr) 3233 (N−H), 3100
(N−H), 2936 (C−H), 1778 (CO), 1686 (CO), 1652 (CC)
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.72 (brs, 2H), 6.09−6.08 (m,
30
86%) as a white powder: dp 113−115 °C; [α]D −34.3 (c 0.978,
2H), 4.20 (brt, J = 1.5 Hz, 2H), 2.57 (m, 2H), 1.84 (m, 2H), 1.74 (m,
2H), 1.59 (m, 2H), 1.38−1.13 (m, 4H), 1.25 (d, J = 7.2 Hz, 3H), 1.24
(d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.9 Hz, 6H), 0.97 (t, J = 7.5 Hz, 3H),
0.96 (t, J = 7.4 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 7.4 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 174.7 (C), 172.4 (C), 172.3 (C),
165.7 (2C), 108.3 (CH), 63.2 (CH), 41.5 (CH), 41.4 (CH), 36.3
(CH), 36.2 (CH), 26.6 (CH2), 26.4 (CH2), 23.0 (CH2), 22.9 (CH2),
16.4 (CH3), 16.1 (CH3), 16.0 (CH3), 12.0 (2CH3), 11.5 (CH3), 11.4
(CH3). Anal. Calcd for C13H21NO3: C, 65.25; H, 8.84; N, 5.85. Found:
C, 64.92; H, 8.49; N, 5.80.
CHCl3); IR (KBr) 3193 (N−H), 3075 (N−H), 2895 (C−H), 1752
(CO), 1696 (CO), 1612 (CC) cm−1; H NMR (300 MHz,
1
CDCl3) δ 8.00 (m, 2H), 7.67 (m, 1H), 7.51 (m, 2H), 7.32−7.22 (m,
5H), 6.55 (s, 1H), 6.21 (s, 1H), 4.59 (dd, J = 5.1, 8.1 Hz, 1H), 3.22
(dd, J = 5.1, 13.5 Hz, 1H), 2.91 (dd, J = 8.1, 13.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 172.9 (C), 165.8 (C), 162.2 (C), 136.0 (C), 134.5
(C), 130.3 (CH), 129.2 (CH), 128.9 (2CH), 128.0 (CH), 127.2 (CH),
108.0 (CH), 100.6 (CH), 59.0 (CH), 38.7 (CH2). Anal. Calcd for
C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C, 74.02; H, 5.45; N,
5.17.
(S)-2-((S)-sec-Butyl)-5-oxo-2,5-dihydro-1H-3-pyrrolyl Ben-
zoate (5b). The crude product was purified by column chromatog-
raphy (silica gel, hexane/EtOAc/AcOH = 66/33/1) to give 5b (106
(S)-2-((S)-sec-Butyl)-5-oxo-2,5-dihydro-1H-3-pyrrolyl Cyclo-
hexanecarboxylate (5g). The crude product was purified by
column chromatography (silica gel, hexane/EtOAc = 1/1) to give
5g (124 mg, 90%) as a white powder: dp 112 −117 °C; [α]D28 +33.1
(c 1.02, CHCl3); IR (KBr) 3235 (N−H), 3104 (N−H), 2932 (C−H),
27
mg, 91%) as a white powder: dp 106−114 °C; [α]D +1.97 (c 1.05,
CHCl3); IR (KBr) 3198 (N−H), 3072 (N−H), 2935 (C−H), 1765
1
1
(CO), 1682 (CO), 1616 (CC) cm−1; H NMR (300 MHz,
1773 (CO), 1692 (CO), 1652 (CC) cm−1; H NMR (300
CDCl3) δ 8.10 (m, 2H), 7.93 (brs, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.53
(t, J = 7.5 Hz, 2H), 6.28 (s, 1H), 4.38 (brd, J = 3.0 Hz, 1H), 1.97 (m,
1H), 1.44 (m, 1H), 1.24 (m, 1H), 1.09 (d, J = 6.9 Hz, 3H), 0.93 (t, J =
7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4 (C), 165.5 (C),
162.3 (C), 134.4 (C), 130.2 (CH), 128.9 (CH), 128.2 (CH), 108.7
(CH), 63.1 (CH), 36.3 (CH), 23.1 (CH2), 15.8 (CH3), 11.9 (CH3).
Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C,
69.84; H, 6.56; N, 5.55.
MHz, CDCl3) δ 7.51 (brs, 1H), 6.06 (s, 1H), 4.19 (t, J = 1.5 Hz, 1H),
2.49 (m, 1H), 2.00−1.12 (m, 13H), 1.03 (d, J = 6.9 Hz, 3H), 0.89 (t,
J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4 (C), 171.5 (C),
165.6 (C), 108.1 (CH), 62.9 (CH), 43.2 (CH), 36.1 (CH), 28.6
(CH2), 28.4 (CH2), 25.4 (CH2), 25.1 (CH2), 25.0 (CH2), 22.8 (CH2),
15.9 (CH3), 11.8 (CH3). Anal. Calcd for C15H23NO3: C, 67.90; H,
8.74; N, 5.28. Found: C, 67.64; H, 8.36; N, 5.58.
(S)-2-Benzyl-5-oxo-2,5-dihydro-1H-3-pyrrolyl 2-Methylbuta-
noate (5h). The crude product was purified by column chromatog-
raphy (silica gel, hexane/EtOAc = 1/1−1/2) to give 5h (65.0 mg,
(S)-2-((S)-sec-Butyl)-5-oxo-2,5-dihydro-1H-3-pyrrolyl 4-
Methylbenzoate (5c). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 3/1−1/1) to give 5c
29
77%) as a white powder: dp 70−76 °C; [α]D −41.9 (c 0.515,
27
(113 mg, 91%) as a white powder: dp 112−117 °C; [α]D −2.51 (c
CHCl3); IR (KBr) 3234 (N−H), 2974 (C−H), 1773 (CO), 1685
1
(CO), 1644 (CC) cm−1; H NMR (300 MHz, CDCl3) δ 7.33−
1.05, CHCl3); IR (KBr) 3241 (N−H), 3092 (N−H), 2930 (C−H),
1
1751 (CO), 1690 (CO), 1616 (CC) cm−1; H NMR (300
7.26 (m, 6H), 7.20−7.18 (m, 4H), 6.37 (brs, 2H), 6.02 (s, 2H), 4.40
(dd, J = 4.2, 5.7 Hz, 2H), 3.16 (dd, J = 4.2, 13.7 Hz, 2H), 2.76 (dd, J =
5.7, 13.7 Hz, 2H), 2.62−2.54 (m, 2H), 1.72 (m, 2H), 1.59 (m, 2H),
1.26 (d, J = 6.9 Hz, 3H), 1.25 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 7.4 Hz,
3H), 0.98 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.7
(C), 172.2 (C), 165.8 (C), 136.2 (C), 129.1 (CH), 128.9 (CH), 127.3
(CH), 107.6 (CH), 58.9 (2CH), 41.2 (2CH), 38.5 (CH2), 26.4
(2CH2), 16.1 (2CH2), 14.1 (CH3), 11.3 (CH2). Anal. Calcd for
C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C, 69.92; H, 6.61; N,
5.30.
MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.34−7.30 (m, 2H), 6.25 (s,
1H), 4.36 (brd, J = 3.3 Hz, 1H), 2.46 (s, 3H), 1.96 (m, 1H), 1.44 (m,
1H), 1.26 (m, 1H), 1.09 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 174.1 (C), 165.6 (C), 162.3 (C), 145.6
(C), 130.3 (CH), 129.7 (CH), 125.5 (C), 108.6 (CH), 63.0 (CH), 36.4
(CH), 23.1 (CH2), 21.7 (CH3), 15.9 (CH3), 11.9 (CH3). Anal. Calcd
for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C, 69.92; H, 7.00;
N, 5.12.
(S)-2-((S)-sec-Butyl)-5-oxo-2,5-dihydro-1H-3-pyrrolyl 4-
Chlorobenzoate (5d). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 1/1) to give 5d (120 mg,
91%) as a white powder: dp 88−92 °C; [α]D29 −3.6 (c 1.03, CHCl3);
IR (KBr) 3249 (N−H), 2931 (C−H), 1770 (CO), 1696 (CO),
(S)-2-Methyl-5-oxo-2,5-dihydro-1H-3-pyrrolyl 2-Methylbuta-
noate (5i). The crude product was purified by column chromatog-
raphy (silica gel, CHCl3/MeOH = 30/1) to give 5i (71.5 mg, 82%) as
a white powder: dp 58−65 °C; IR (KBr) 3233 (N−H), 3108 (N−H),
1656 (CC) cm−1; H NMR (300 MHz, CDCl3) δ 8.03 (m, 2H),
2937(C−H), 1776 (CO), 1687 (CO), 1651 (CC) cm−1; H
1
1
7.79 (brs, 1H), 7.51 (m, 2H), 6.27 (s, 1H), 4.37 (brd, J = 3.0 Hz, 1H),
1.95 (m, 1H), 1.48−1.20 (m, 2H), 1.10 (d, J = 6.9 Hz, 3H), 0.93 (t, J =
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.1 (C), 165.3 (C),
NMR (300 MHz, CDCl3) δ 7.92 (brs, 2H), 6.03 (s, 2H), 4.25 (q, J =
6.6 Hz, 2H), 2.59 (m, 2H), 1.75 (m, 2H), 1.60 (m, 2H), 1.37 (d, J =
6.6 Hz, 6H), 1.26 (d, J = 7.2 Hz, 3H), 1.24 (d, J = 7.2 Hz, 3H), 0.98
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Article
(t, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 173.9 (C), 172.2
(C), 172.1 (C), 167.5 (2C), 106.3 (2C), 53.7 (2CH), 41.1 (CH), 41.0
(CH), 26.3 (CH2), 26.2 (CH2), 17.3 (CH3), 16.0 (CH3), 15.9 (CH3),
11.1 (2CH3). Anal. Calcd for C10H15NO3: C, 60.90; H, 7.67; N, 7.10.
Found: C, 60.53; H, 7.54; N, 7.23.
hexane/EtOAc = 1/1) to give 5n (104 mg, 84%) as a yellow powder:
dp 127−133 °C; [α]D27 +17.5 (c 1.32, CHCl3); IR (NaCl) 3199 (N−
H), 3077 (N−H), 2935(C−H), 1772 (CO), 1682 (CO), 1619
(CC) cm−1; 1H NMR (300 MHz, CDCl3) δ 6.07 (s, 1H), 4.22 (brt,
J = 1.5 Hz, 1H), 1.85 (m, 1H), 1.40−1.07 (m, 2H), 1.30 (s, 9H), 1.04
(d, J = 6.9 Hz, 3H), 0.87 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 174.2 (C), 174.0 (C), 165.6 (C), 108.1 (CH), 62.8 (CH),
39.5 (C), 36.2 (CH), 26.7 (CH3), 23.0 (CH2), 15.9 (CH3), 11.8
(CH3). Anal. Calcd for C13H21NO3: C, 65.25; H, 8.84; N, 5.85. Found:
C, 65.13; H, 8.66; N, 6.02.
General Procedure for the Preparation of the 3-Acyltetr-
amic Acids. To a solution of 4-O-acyltetramic acid 5 (1.0 equiv) in
dichloromethane were added CaCl2 (1.5 equiv), DMAP (0.3 equiv),
and Et3N (1.2−1.5 equiv). After the suspension was stirred until
completion of the reaction (monitored by TLC), the reaction was
quenched by addition of 3% aqueous HCl, and the resulting mixture
was extracted with EtOAc. The organic extracts were washed with
water and brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. Purification of the crude
product afforded 3-acyltetramic acid 6.
(S)-2-((tert-Butyldimethylsilyloxy)methyl)-5-oxo-2,5-dihy-
dro-1H-2-pyrrolyl 2-Methylbutanoate (5j). The crude product
was purified by column chromatography (silica gel, hexane/EtOAc =
1/1) to give 5j (46.0 mg, 85%) as a pale yellow oil: IR (KBr) 3173
(N−H), 3086 (N−H), 2927(C−H), 1778 (CO), 1698 (CO),
1
1656 (CC) cm−1; H NMR (300 MHz, CDCl3) δ 6.41 (brs, 1H),
6.28 (brs, 1H), 6.08 (s, 2H), 4.25 (m, 2H), 3.93 (dd, J = 3.3, 10.1 Hz,
2H), 3.60 (dd, J = 7.5, 10.1 Hz, 2H), 2.57 (m, 2H), 1.75 (m, 2H), 1.58
(m, 2H), 1.22 (d, J = 6.9 Hz, 6H), 0.94 (t, J = 7.5 Hz, 6H), 0.86 (s,
18H), 0.04 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 173.6 (C), 172.1
(2C), 163.5 (2C), 108.4 (CH), 63.1 (CH2), 60.0 (2CH), 41.1 (2CH),
26.3 (2C), 25.5 (CH3), 18.1 (CH2), 16.1 (CH3), 16.0 (CH3), 11.2
(2CH3), −5.7 (CH3), −5.8 (CH3). Anal. Calcd for C16H29NO4Si: C,
58.68; H, 8.93; N, 4.28. Found: C, 58.51; H, 8.58; N, 4.67.
(S)-2-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-5-oxo-2,5-di-
hydro-1H-3-pyrrolyl 2-Methylbutanoate (5k). The crude product
was purified by column chromatography (silica gel, hexane/EtOAc =
3/1) to give 5k (77.1 mg, 73%) as a pale yellow oil: IR (KBr) 3219
(N−H), 3085 (N−H), 2932 (C−H), 1779 (CO), 1697 (CO),
(S)-5-Benzyl-3-(α-hydroxybenzylidene)-4-oxo-2-pyrrolidone
(6a). The crude product was washed with MeOH (5 mL) to give 6a
(64.5 mg, 71%) as a white powder: dp 168−169 °C; IR (KBr) 3213
(O−H), 3062 (N−H), 1702 (CO), 1685 (CO), 1669 (CC)
1
1
1623 (CC) cm−1; H NMR (300 MHz, CDCl3) δ 6.89 (brs, 2H),
cm−1; H NMR (300 MHz, CDCl3) δ 8.20 (m, 2H), 7.64−7.48 (m,
6.06 (s, 2H), 4.10−4.00 (m, 4H), 2.52 (m, 2H), 1.76 (m, 2H), 1.54
(m, 2H), 1.26−1.20 (m, 12H), 0.94 (t, J = 7.5 Hz, 6H), 0.82 (s, 18H),
0.03 (s, 6H), −0.01 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 174.1 (C),
172.2 (C), 164.1 (2C), 108.5 (CH), 67.5 (CH), 67.4 (CH), 64.0 (CH),
41.3 (CH), 41.2 (CH), 26.3 (CH2), 26.2 (CH2), 25.5 (CH3), 20.6
(2C), 17.8 (CH3), 16.1 (CH3), 16.0 (CH3), 11.3 (CH3), −4.4 (CH3),
−5.2 (CH3) −5.3 (CH3). Anal. Calcd for C17H31NO4Si: C, 59.79; H,
9.15; N, 4.10. Found: C, 59.53; H, 8.95; N, 4.38.
3H), 7.35−7.21 (m, 5H), 6.86 (brs, 0.97H, Z-isomer), 6.21 (brs,
0.03H, E-isomer), 4.28 (dd, J = 2.7, 8.4 Hz, 0.03H, E-isomer), 4.05
(dd, J = 3.6, 10.1 Hz, 0.97H, Z-isomer), 3.32 (dd, J = 3.6, 13.8 Hz,
1H), 2.71 (dd, J = 10.1, 13.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
192.2 (C), 181.4 (C), 177.1 (C), 136.5 (C), 133.9 (C), 131.7 (CH),
129.7 (CH), 129.2 (CH), 128.9 (CH), 128.2 (CH), 127.2 (CH), 99.5
(C), 62.9 (CH), 38.3 (CH2). Anal. Calcd for C18H15NO3: C, 73.71; H,
5.15; N, 4.78. Found: C, 74.08; H, 5.09; N, 5.00.
(S)-2-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-5-oxo-2,5-di-
hydro-1H-3-pyrrolyl (S)-2-Methyloctanoate (5l). The crude
product was purified by column chromatography (silica gel, hexane/
(S)-5-((S)-sec-Butyl)-3-(α-hydroxybenzylidene)-4-oxo-2-pyr-
rolidone (6b). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc/AcOH = 83/16/1) to
give 6b (78.9 mg, 77%, 6b/5-epimer = 83/17) as an orange oil: IR
(KBr) 3256 (O−H), 1685 (CO), 1660 (CO), 1596 (CC)
24
EtOAc = 3/1−1/1) to give 5l (97.7 mg, 84%) as a colorless oil: [α]D
+30.6 (c 0.660, CHCl3); IR (NaCl) 3219 (N−H), 3088 (N−H), 1776
1
1
(CO), 1701 (CO), 1624 (CC) cm−1; H NMR (300 MHz,
cm−1; H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 7.2 Hz, 2H), 7.60
CDCl3) δ 6.69 (brs, 1H), 6.07 (d, J = 0.9 Hz, 1H), 4.05−3.97 (m,
2H), 2.58 (m, 1H), 1.71 (m, 1H), 1.49 (m, 1H), 1.34−1.22 (m, 11H),
1.22 (d, J = 7.2 Hz, 3H), 0.87 (t, J = 6.0 Hz, 3H), 0.83 (s, 9H), 0.04 (s,
3H), 0.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.9 (C), 172.4
(C), 164.0 (C), 108.6 (CH), 67.5 (CH), 64.0 (CH), 39.8 (CH), 33.4
(CH2), 31.5 (CH2), 29.0 (CH2), 26.9 (CH2), 25.5 (CH3), 22.4 (CH2),
20.7 (CH3), 17.8 (CH3), 16.5 (CH3), 13.9 (C), −4.4 (CH3), −5.2
(CH3). Anal. Calcd for C21H39NO4Si: C, 63.43; H, 9.89; N, 3.52.
Found: C, 63.69; H, 9.54; N, 3.74.
(m, 1H), 7.51 (m, 2H), 7.00 (brs, 1H), 4.16 (brs, 0.04H, 5-epimer, E-
isomer), 4.06 (brd, J = 3.6 Hz, 0.14H, E-isomer), 3.92 (brd, J = 2.7 Hz,
0.13H, 5-epimer, Z-isomer), 3.84 (brd, J = 3.3 Hz, 0.69H, Z-isomer),
2.03 (m, 1H), 1.48−1.16 (m, 2H), 1.10−0.96 (m, 3H), 0.94−0.82 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 193.4 (C), 180.5 (C), 177.8 (C),
133.8 (C), 131.8 (CH), 130.7 (CH), 129.7 (2CH), 128.2 (CH), 128.0
(CH), 100.6 (C), 66.4 (CH), 65.1 (CH), 37.1 (CH), 36.6 (CH), 26.8
(CH2), 23.4 (2CH2), 15.7 (CH3), 15.4 (CH3), 12.8 (CH3), 11.6
(CH3). Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found:
C, 69.19; H, 6.38; N, 5.44.
(S)-2-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-5-oxo-2,5-di-
hydro-1H-3-pyrrolyl (R)-2-Methyloctanoate (5m). The crude
product was purified by column chromatography (silica gel, hexane/
(S)-5-((S)-sec-Butyl)-3-(α-hydroxy-4-methylbenzylidene)-4-
oxo-2-pyrrolidone (6c). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc/AcOH = 66/33/1) to give
6c (70.0 mg, 78%, 6c/5-epimer = 70/30) as a yellow oil: IR (KBr)
24
EtOAc = 3/1−1/1) to give 5l (88.6 mg, 77%) as a colorless oil: [α]D
+3.5 (c 0.769, CHCl3); IR (NaCl) 3226 (N−H), 3083 (N−H), 1777
(CO), 1699 (CO), 1624 (CC) cm−1; H NMR (300 MHz,
3235 (O−H), 1699 (CO), 1657 (CO), 1613 (CC) cm−1; H
1
1
CDCl3) δ 6.54 (brs, 1H), 6.07 (s, 1H), 4.03−3.96 (m, 2H), 2.58 (m,
1H), 1.72 (m, 1H), 1.49 (m, 1H), 1.34−1.24 (m, 11H), 1.23 (d, J =
6.9 Hz, 3H), 0.89−0.82 (m, 12H), 0.04 (s, 3H), 0.01 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 173.8 (C), 172.3 (C), 164.1 (C), 108.6
(CH), 67.7 (CH), 64.0 (CH), 39.9 (CH), 33.2 (CH2), 31.5 (CH2),
29.0 (CH2), 26.9 (CH2), 25.5 (CH3), 22.4 (CH3), 20.7 (CH3), 17.8
(CH3), 16.6 (CH3), 13.9 (C), −4.4 (CH3), −5.2 (CH3). Anal. Calcd
for C21H39NO4Si: C, 63.43; H, 9.89; N, 3.52. Found: C, 63.16; H,
9.65; N, 3.55.
NMR (300 MHz, CDCl3) δ 8.23−8.13 (m, 2H), 7.35−7.29 (m, 2H),
6.83 (s, 1H), 4.13 (brd, J = 3.0 Hz, 0.01H, 5-epimer, E-isomer), 4.04
(brd, J = 4.2 Hz, 0.11H, E-isomer), 3.90 (brd, J = 3.3 Hz, 0.29H, 5-
epimer, Z-isomer), 3.82 (brd, J = 3.3 Hz, 0.59H, Z-isomer), 2.43 (s,
3H), 2.11−1.96 (m, 1H) 1.51−1.19 (m, 2H), 1.06−0.80 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 193.6 (C), 181.8 (C), 181.7 (C), 176.7 (C),
176.4 (C), 137.2 (C), 137.1 (C), 130.8 (2C), 129.3 (2CH), 125.4
(2CH), 125.1 (2CH), 102.1 (C), 100.6 (C), 66.6 (CH), 65.4 (CH),
37.0 (CH), 36.5 (CH), 26.7 (CH2), 23,6 (CH2), 19.6 (CH3), 15.5
(CH3), 12.9 (CH3), 11.6 (2CH3). Anal. Calcd for C16H19NO3: C,
70.31; H, 7.01; N, 5.12. Found: C, 69.92; H, 6.79; N, 5.21.
(S)-2-((S)-sec-Butyl)-5-oxo-2,5-dihydro-1H-3-pyrrolyl Piva-
late (5n). To a solution of tetramic acid 4b (80.0 mg, 0.515 mmol)
in Et2O (1.7 mL) were added Piv2O (144 mg, 0.773 mmol) and
pyridine (61.1 mg, 0.772 mmol). The solution was stirred at room
temperature for 17 h until completion of the reaction (monitored by
TLC). The reaction mixture was concentrated under reduced pressure,
and the residue was purified by column chromatography (silica gel,
(S)-5-((S)-sec-Butyl)-3-(α-hydroxy-4-chlorobenzylidene)-4-
oxo-2-pyrrolidone (6d). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc/AcOH = 66/33/1) to give
6d (83.1 mg, 73%, 6d/5-epimer = 87/13) as a yellow powder: dp 91−
101 °C; IR (KBr) 3222 (O−H), 3075 (N−H), 1707 (CO), 1661
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1
(CO), 1590 (CC) cm−1; H NMR (300 MHz, CDCl3) δ 8.30−
(CH2), 24.8 (CH2), 23.8 (CH2), 23.4 (CH2), 16.5 (CH3), 16.4 (CH3),
11.5 (2CH3). Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12.
Found: C, 70.24; H, 7.23; N, 5.26.
8.20 (m, 2H), 7.58 (brs, 1H), 7.47 (d, J = 8.7 Hz, 2H), 4.18 (brd, J =
2.7 Hz, 0.03H, 5-epimer, E-isomer), 4.09 (brd, J = 3.6 Hz, 0.16H, E-
isomer), 3.93 (brd, J = 2.7 Hz, 0.11H, 5-epimer, Z-isomer), 3.85 (brd,
J = 2.7 Hz, 0.70H, Z-isomer), 2.04 (m, 1H), 1.10−0.96 (m, 3H),
0.94−0.81 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 193.5 (2C), 179.0
(2C), 177.7 (C), 140.1 (CH), 132.1 (C), 131.4 (CH), 131.1 (CH),
130.2 (C), 128.8 (CH), 128.5 (CH), 128.4 (CH), 100.7 (C), 66.5
(CH), 65.2 (CH), 63.7 (CH), 37.1 (CH), 37.0 (CH), 26.7 (CH2), 23.8
(CH2), 23.4 (CH2), 15.7 (CH3), 15.3 (CH3), 12.8 (CH3), 11.6 (CH3),
11.5 (CH3). Anal. Calcd for C15H16ClNO3: C, 61.33; H, 5.49; N, 4.77.
Found: C, 61.13; H, 5.45; N, 4.59.
(S)-5-((S)-sec-Butyl)-3-(1-hydroxy-2-methylpropylidene)-4-
oxo-2-pyrrolidone (6e). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc/AcOH = 90/9/1) to give
6e (34.4 mg, 68%) as an orange powder: dp 83−89 °C; [α]D29 −58.1
(c 1.03, CHCl3); IR (KBr) 3207 (O−H), 3064 (N−H), 1715 (C
O), 1655 (CO), 1610 (CC) cm−1; 1H NMR (300 MHz, CDCl3)
δ 7.12 (brs, 0.82H, Z-isomer), 6.70 (brs, 0.18H, E-isomer), 3.96 (brd,
J = 3.9 Hz, 0.18H, E-isomer), 3.78 (brd, J = 3.6 Hz, 0.82H, Z-isomer),
3.74−3.62 (m, 1H), 1.95 (m, 1H), 1.45−1.19 (m, 8H), 1.02 (d, J = 6.9
Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
197.7 (C), 195.0 (C), 193.2 (C), 176.3 (C), 100.3 (C), 66.8 (CH),
63.3 (CH), 37.0 (CH), 36.9 (CH), 31.8 (CH), 31.0 (CH), 23.9 (CH2),
23.5 (CH2), 18.4 (2CH3), 15.3 (CH3), 11.6 (CH3), 11.5 (CH3). Anal.
Calcd for C12H19NO3: C, 63.98; H, 8.50; N, 6.22. Found: C, 63.65; H,
8.11; N, 6.62.
(S)-3-(1-Hydroxy-2-methylbutylidene)-5-methyl-4-oxo-2-
pyrrolidone (6i). The crude product was purified by column
chromatography (silica gel, CHCl3/MeOH = 80/1−50/1−30/1) to
give 6i (47.1 mg, 67%) as a yellow oil: IR (KBr) 3259 (O−H), 1685
1
(CO), 1656 (CO), 1618 (CC) cm−1; H NMR (300 MHz,
CDCl3) δ 6.19 (brs, 0.8H, Z-isomer), 6.09 (brs, 0.2H, E-isomer), 4.06
(q, J = 7.2 Hz, 0.2H, E-isomer), 3.89 (dq, J = 2.1, 6.9 Hz, 0.8H, Z-
isomer), 3.64 (m, 0.2H, E-isomer), 3.55 (m, 0.8H, Z-isomer), 1.73 (m,
1H), 1.55 (m, 1H), 1.41 (d, J = 6.9 Hz, 0.6H, E-isomer), 1.37 (d, J =
6.9 Hz, 2.4H, Z-isomer), 1.22−1.18 (m, 3H), 0.97−0.90 (m, 3H); 13C
NMR (75 MHz, CDCl3) δ 195.6 (C), 193.6 (C), 175.6 (C), 99.8 (C),
57.7 (CH), 54.4 (CH), 38.0 (CH), 37.6 (CH), 29.6 (CH2), 26.7
(CH2), 17.4 (CH3), 16.5 (CH3), 11.5 (2CH3). Anal. Calcd for
C10H15NO3: C, 60.90; H, 7.67; N, 7.10. Found: C, 60.57; H, 7.27; N,
7.20.
(S)-5-((tert-Butyldimethylsilyloxy)methyl)-3-(1-hydroxy-2-
methylbutylidene)-4-oxo-2-pyrrolidone (6j). The crude product
was purified by column chromatography (silica gel, hexane/EtOAc =
1/1) to give 6j (28.0 mg, 72%) as an orange oil: IR (KBr) 3438 (N−
H), 3234 (O−H), 1708 (CO), 1661 (CO), 1607 (CC) cm−1;
1H NMR (300 MHz, CDCl3) δ 6.43 (brs, 0.9H, Z-isomer), 6.18 (brs,
0.1H, E-isomer), 4.10−3.45 (m, 4H), 1.71 (m, 1H), 1.53 (m, 1H),
1.21−1.16 (m, 3H), 0.95−0.88 (m, 3H), 0.86 (s, 9H), 0.05 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 193.1 (C), 192.0 (C), 176.2 (C), 100.1
(S)-5-((S)-sec-Butyl)-3-(1-hydroxy-2-methylbutylidene)-4-
oxo-2-pyrrolidone (6f). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 1/1) to give 6f (35.5 mg,
74%) as a pale yellow oil: IR (KBr) 3236 (O−H), 1690 (CO), 1658
(C), 64.1 (CH), 63.2 (CH2), 61.2 (CH2), 37.7 (CH), 26.6 (C), 25.6
(CH3), 18.0 (CH2), 16.5 (CH3), 11.5 (CH3), −5.7 (2CH3). Anal.
Calcd for C16H29NO4Si: C, 58.68; H, 8.93; N, 4.28. Found: C, 58.50;
H, 8.56; N, 4.23.
1
(CO), 1609 (CC) cm−1; H NMR (300 MHz, CDCl3) δ 7.07
(S)-5-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-3-(1-hydroxy-
2-methylbutylidene)-4-oxo-2-pyrrolidone (6k). The crude prod-
uct was purified by column chromatography (silica gel, hexane/EtOAc
= 1/2) to 6k (63.4 mg, 86%) as a yellow oil: IR (KBr) 3449 (N−H),
(brs, 0.8H, Z-isomer), 6.73 (brs, 0.2H, E-isomer), 3.95 (d, J = 3.6 Hz,
0.2H, E-isomer), 3.78 (d, J = 2.7 Hz, 0.8H, Z-isomer), 3.57 (m, 1H),
1.97 (m, 1H), 1.74 (m, 1H), 1.54 (m, 1H), 1.38 (m, 1H), 1.26 (m,
2H), 1.21−1.17 (m, 3H), 1.02 (d, J = 6.9 Hz, 3H), 0.95−0.87 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 195.4 (2C), 192.7 (C), 192.5 (C),
176.4 (C), 176.3 (C), 101.6 (C), 101.6 (C), 101.4 (C), 67.0 (CH),
63.5 (CH), 37.6 (CH), 37.4 (CH), 26.9 (CH2), 26.6 (CH2), 23.6
(CH2), 23.5 (CH2), 16.6 (CH3), 16.4 (CH3), 15.7 (2CH3), 11.6
(2CH3), 11.5 (2CH3). Anal. Calcd for C13H21NO3: C, 65.25; H, 8.84;
N, 5.85. Found: C, 65.64; H, 9.00; N, 6.09.
1
3239 (O−H), 1709 (CO), 1660 (CO), 1608 (CC) cm−1; H
NMR (300 MHz, CDCl3) δ 7.17 (brs, 0.8H, Z-isomer), 7.13 (brs,
0.2H, E-isomer), 4.17 (m, 2H), 3.79 (m, 0.2H, E-isomer), 3.62 (m,
0.8H, Z-isomer), 3.48 (m, 2H), 1.67 (m, 2H), 1.48 (m, 2H), 1.30−
1.10 (m, 12H), 0.92−0.77 (m, 24H), 0.05--0.05 (m, 6H); 13C NMR
(75 MHz, CDCl3) δ 193.8 (C), 193.5 (C), 192.2 (C), 176.6 (C), 101.5
(C), 101.1 (C), 68.0 (CH), 67.6 (CH), 65.2 (CH), 37.7 (CH), 37.3
(CH), 27.0 (C), 25.9 (CH2), 25.5 (2CH3), 21.1 (CH3), 21.0 (CH3),
17.7 (CH3), 16.8 (CH3), 16.0 (CH3), 11.7 (CH3), 11.4 (CH3), −4.4
(2CH3), −5.3 (CH3), −5.4 (CH3). Anal. Calcd for C17H31NO4Si: C,
59.79; H, 9.15; N, 4.10. Found: C, 59.72; H, 9.12; N, 4.49.
(S)-5-((S)-sec-Butyl)-3-(cyclohexyl(hydroxy)methylene)-4-
oxo-2-pyrrolidone (6g). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc/AcOH = 83/16/1) to give
30
6g (89.6 mg, 72%) as an orange oil: [α]D −54.5 (c 0.966, CHCl3);
IR (KBr) 3235 (O−H), 1706 (CO), 1657 (CO), 1608 (CC)
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.67 (brs, 0.8H, Z-isomer), 7.31
(brs, 0.2H, E-isomer), 3.95 (d, J = 3.3 Hz, 0.2H, E-isomer), 3.78 (d, J =
2.7 Hz, 0.8H, Z-isomer), 3.46−3.37 (m, 1H), 1.98 (m, 1H), 1.79−1.21
(m, 12H), 1.00 (d, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 0.6H, E-
isomer), 0.89 (t, J = 7.5 Hz, 2.4H, Z-isomer); 13C NMR (75 MHz,
CDCl3) δ 195.0 (C), 192.5 (C), 176.4 (C), 100.4 (C), 67.0 (CH), 41.4
(CH), 40.8 (CH), 37.0 (CH2), 36.9 (CH2), 28.6 (4CH2), 25.4 (2CH2),
25.3 (2CH2) 23.9 (CH2), 23.5 (CH2), 15.6 (CH3), 15.3 (CH3), 11.6
(CH3), 11.5 (CH3). Anal. Calcd for C15H23NO3: C, 67.90; H, 8.74; N,
5.28. Found: C, 67.62; H, 8.34; N, 5.52.
(S)-5-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-3-((S)-1-hy-
droxy-2-methyloctylidene)-4-oxo-2-pyrrolidone (6l). The crude
product was purified by column chromatography (silica gel, hexane/
17
EtOAc = 3/1) to give 6l (37.7 mg, 84%) as a colorless oil: [α]D
−64.1 (c 0.636, CHCl3); IR (NaCl) 3235 (N−H), 3068 (N−H), 1694
1
(CO), 1660 (CO), 1615 (CC) cm−1; H NMR (300 MHz,
CDCl3) δ 5.94 (brs, 0.8H, Z-isomer), 5.67 (brs, 0.2H, E-isomer), 4.14
(m, 1H), 3.78 (dd, J = 0.6, 3.9 Hz, 0.2H, E-isomer), 3.70 (m, 1H), 3.61
(dd, J = 0.6, 4.2 Hz, 0.8H, Z-isomer), 3.59 (m, 1H), 1.66 (m, 1H), 1.47
(m, 1H), 1.32−1.22 (m, 8H), 1.28 (d, J = 6.3 Hz, 3H), 1.19 (d, J = 6.9
Hz, 0.6H, E-isomer), 1.16 (d, J = 6.6 Hz, 2.4H, Z-isomer), 0.86 (t, J =
7.0 Hz, 3H), 0.82 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 193.6 (C), 192.5 (C), 176.6 (C), 104.4 (C), 101.3
(C), 68.0 (CH), 67.6 (CH), 67.4 (CH), 65.2 (CH), 36.1 (CH), 35.9
(CH), 34.0 (CH2), 33.5 (CH2), 31.6 (CH2), 29.1 (CH2), 27.1 (CH2),
25.5 (CH3), 22.5 (CH2), 21.1 (CH3), 20.9 (CH3), 17.7 (C), 16.9
(CH3), 16.5 (CH3), 13.9 (CH3), −4.4 (CH3), −5.4 (CH3). Anal. Calcd
for C21H39NO4Si: C, 63.43; H, 9.89; N, 3.52. Found: C, 63.08; H,
9.55; N, 3.69.
(S)-5-Benzyl-3-(1-hydroxy-2-methylbutylidene)-4-oxo-2-pyr-
rolidone (6h). The crude product was purified by column
chromatography (silica gel, toluene/EtOAc = 3/1) to give 6h (54.3
mg, 79%) as a yellow oil: IR (KBr) 3234 (O−H), 1706 (CO), 1659
1
(CO), 1608 (CC) cm−1; H NMR (300 MHz, CDCl3) δ 7.33−
7.19 (m, 5H), 5.72 (brs, 0.9H, Z-isomer), 5.47 (brs, 0.1H, E-isomer),
4.18 (dd, J = 3.6, 9.0 Hz, 0.1H, E-isomer), 4.02 (dd, J = 3.5, 10.1 Hz,
0.9H, Z-isomer), 3.55 (m, 2H), 3.26 (m, 1H), 2.69 (m, 1H), 1.68 (m,
1H), 1.53 (m, 1H), 1.21−1.16 (m, 3H), 0.96−0.86 (m, 3H); 13C
NMR (75 MHz, CDCl3) δ 194.2 (C), 193.5 (C), 175.6 (C), 136.5 (C),
136.3 (C), 129.3 (CH), 129.2 (CH), 128.8 (2CH), 127.1 (CH), 100.5
(C), 100.4 (C), 63.4 (CH), 63.3 (CH), 38.1 (CH), 38.0 (CH), 37.6
(2CH2), 33.8 (CH2), 29.6 (CH2), 26.7 (CH2), 26.5 (CH2), 25.5
(S)-5-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-3-((R)-1-hy-
droxy-2-methyloctylidene)-4-oxo-2-pyrrolidone (6m). The
crude product was purified by column chromatography (silica gel,
hexane/EtOAc = 3/1) to give 6m (35.7 mg, 79%) as a colorless oil:
[α]D23 −86.8 (c 1.13, CHCl3); IR (NaCl) 3236 (N−H), 3068 (N−H),
4398
dx.doi.org/10.1021/jo300527f | J. Org. Chem. 2012, 77, 4391−4401

The Journal of Organic Chemistry
Article
1694 (CO), 1660 (CO), 1614 (CC) cm−1; H NMR (300
MHz, CDCl3) δ 6.00 (brs, 0.75H, Z-isomer), 5.73 (brs, 0.25H,
E-isomer), 4.14 (m, 0.25H, E-isomer), 4.12 (m, 0.75H, Z-isomer), 3.77
(dd, J = 0.6, 3.9 Hz, 0.25H, E-isomer), 3.70 (m, 0.25H, E-isomer), 3.60
(d, J = 4.5 Hz, 0.75H, Z-isomer), 3.54 (m, 0.75H, Z-isomer), 1.68 (m,
1H), 1.45 (m, 1H), 1.32−1.24 (m, 8H), 1.29 (d, J = 6.6 Hz, 3H), 1.18
(d, J = 6.9 Hz, 2.25H, Z-isomer), 1.17 (d, J = 6.9 Hz, 0.75H, E-
isomer), 0.87 (t, J = 7.2 Hz, CH3), 0.82 (s, 6.75H, Z-isomer), 0.80 (s,
2.25H, E-isomer), 0.05 (s, 2.25H, Z-isomer), 0.04 (s, 0.75H, E-
isomer), 0.01 (s, 2.25H, Z-isomer), −0.02 (s, 0.75H, E-isomer); 13C
NMR (75 MHz, CDCl3) δ 201.4 (C), 195.2 (C), 193.3 (C), 192.8 (C),
176.5 (C), 169.4 (C), 104.6 (C), 100.9 (C), 100.6 (C), 68.0 (CH),
67.5 (CH), 65.2 (CH), 39.4 (CH), 36.3 (CH), 35.9 (CH2), 33.6
(CH2), 32.9 (CH2), 31.6 (CH2), 29.3 (CH2), 29.2 (CH2), 27.3 (CH2),
27.2 (CH2), 25.5 (CH3), 22.5 (CH2), 21.1 (CH3), 20.8 (CH3), 17.7
(C), 17.2 (CH3), 17.0 (CH3), 13.9 (CH3), −4.4 (2CH3), −5.2 (CH3),
−5.5 (CH3). Anal. Calcd for C21H39NO4Si: C, 63.43; H, 9.89; N, 3.52.
Found: C, 63.35; H, 9.89; N, 3.52.
for 4 h. The reaction mixture was filtered through a pad of Celite, and
the residue was washed with EtOAc. The filtrate was concentrated
under reduced pressure, and the residue was purified by column
chromatography (silica gel, hexane/EtOAc = 3/1−2/1−1/1−1/2) to
give 9 (636 mg, 50%, 3 steps, 5R/5S = 61/39) as a white powder: IR
(NaCl) 3201 (N−H), 3108 (N−H), 1768 (CO), 1702 (CO)
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.85 (brs, 1H, 5S-isomer), 7.41
(brs, 1H, 5R-isomer), 4.21 (dq, J = 2.7, 6.6 Hz, 1H, 5S-isomer), 4.06
(dq, J = 2.4, 6.3 Hz, 1H, 5R-isomer), 3.90 (brs, 1H, 5R-isomer), 3.80
(brd, J = 2.6 Hz, 1H, 5S-isomer), 2.91 (s, 2H, 5S-isomer), 2.89 (brs,
2H, 5R-isomer), 1.24 (d, J = 6.6 Hz, 3H, 5S-isomer), 1.23 (d, J = 6.3
Hz, 3H, 5R-isomer), 0.84 (s, 9H, 5R-isomer), 0.81 (s, 9H, 5S-isomer),
0.06 (s, 3H, 5R-isomer), 0.05 (s, 3H, 5R-isomer), 0.04 (s, 3H, 5S-
isomer), −0.03 (s, 3H, 5S-isomer); 13C NMR (75 MHz, CDCl3) δ
206.8 (C), 205.6 (C), 172.8 (C), 172.3 (C), 70.2 (CH), 69.6 (CH),
69.2 (CH), 68.1 (CH), 41.8 (CH2), 41.3 (CH2), 25.6 (CH3), 25.5
(CH3), 20.3 (CH3), 18.5 (CH3), 17.7 (2C), −4.5 (CH3), −5.0 (CH3),
−5.1 (CH3), −5.4 (CH3). Anal. Calcd for C12H23NO3Si: C, 55.99; H,
9.01; N, 5.44. Found: C, 56.34; H, 8.80; N, 5.81.
1
(3R)-2-Benzyloxycarbonylamino-3-(tert-butyldimethylsilyloxy)-
butanoic Acid (8). To a solution of a 56:44 mixture of L-threonine
and D-allothreonine (1.00 g, 12.6 mmol) in saturated aqueous
NaHCO3 solution (35 mL) was added carbobenzoxy chloride
(CbzCl) (2.15 g, 12.6 mmol) at room temperature. After stirring for
18 h at the same temperature, the reaction mixture was poured into
water. The aqueous layer was washed with Et2O, acidified with
concentrated HCl, and extracted with EtOAc. The combined organic
extracts were dried over anhydrous MgSO4 and concentrated under
reduced pressure. To a solution of the residue (1.73 g) in DMF
(27 mL) were added imidazole (1.16 g, 17.1 mmol), DMAP (100 mg,
0.819 mmol), and TBSCl (2.27 g, 15.0 mmol) at room temperature.
After stirring for 18 h at the same temperature, the reaction mixture
was poured into saturated aqueous NH4Cl solution and extracted with
EtOAc. The combined organic extracts were washed with 3% aqueous
HCl and brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was roughly purified by column
chromatography (silica gel, hexane/EtOAc = 1/1) to afford the crude
sample of 8. To a solution of the crude product in a 1:1 mixture of
water and methanol (6.0 mL) was added an aqueous solution of
K2CO3 (900 mg, in 2.0 mL). After stirring for 3 h, the solution was
acidified to pH 3 with 3 M aqueous HCl. The reaction mixture was
poured into EtOAc and extracted. The organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography (silica gel, hexane/
EtOAc = 1/1) to afford a diastereomeric mixture of 8 (1.80 g, 58%,
2S/2R = 56/44): IR (NaCl) 3400 (N−H), 3091 (O−H), 3067 (N−
H), 1755 (CO), 1691 (CO) cm−1; 1H NMR (300 MHz, CDCl3)
δ 7.37−7.29 (m, 10H), 5.50 (brd, J = 8.7 Hz, 1H), 5.47 (brd, J = 9.3
Hz, 1H), 5.12−5.10 (m, 4H), 4.46 (m, 1H), 4.33−4.30 (m, 2H),
4.13 (m, 1H), 1.28 (d, J = 6.3 Hz, 3H), 1.20 (d, J = 6.3 Hz, 3H),
0.86 (s, 9H), 0.85 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H),
0.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.5 (C), 156.7 (C),
136.1 (C), 128.7 (CH), 128.6 (CH), 128.4 (CH), 128.3 (CH),
128.2 (2CH), 69.7 (CH), 68.5 (CH), 67.3 (CH2), 67.1 (CH2), 59.8
(CH), 59.3 (CH), 25.6 (CH3), 25.5 (CH3), 20.2 (CH3), 19.6 (CH3),
17.8 (C), 17.7 (C), −4.7 (2CH3), −5.3 (CH3), −5.4 (CH3). Anal.
Calcd for C18H29NO5Si: C, 58.83; H, 7.95; N, 3.81. Found: C,
58.87; H, 7.67; N, 3.58.
(R)-2-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-5-oxo-2,5-di-
hydro-1H-3-pyrrolyl (S)-2-Methyloctanoate (10). The crude
product was purified by column chromatography (silica gel, hexane/
toluene/EtOAc = 1/1/1, CH2Cl2/CHCl3/MeOH = 10/10/1) to give
10 (127 mg, 27%) as a colorless oil: [α]D24 +29.7 (c 1.37, CHCl3); IR
(NaCl) 3207 (N−H), 3091 (N−H), 1778 (CO), 1701 (CO),
1
1621 (CC) cm−1; H NMR (300 MHz, CDCl3) δ 6.05 (brs, 1H),
5.69 (brs, 1H), 4.32 (d, J = 3.3 Hz, 1H), 4.16 (m, 1H), 2.63 (m, 1H),
1.70 (m, 1H), 1.53 (m, 1H), 1.34−1.24 (m, 8H), 1.24 (d, J = 6.9 Hz,
3H), 0.99 (d, J = 6.3 Hz, 3H), 0.91−0.88 (m, 12H), 0.10 (s, 3H), 0.09
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.1 (C), 172.1 (C), 163.1
(C), 108.6 (CH), 67.6 (CH), 63.2 (CH), 39.8 (CH), 33.6 (CH2), 31.6
(CH2), 29.1 (CH2), 27.0 (CH2), 25.7 (CH3), 22.6 (CH3), 17.9 (CH3),
16.6 (CH3), 16.2 (CH3), 14.0 (C), −4.7 (CH3), −5.0 (CH3). Anal.
Calcd for C21H39NO4Si: C, 63.43; H, 9.89; N, 3.52. Found: C, 63.63;
H, 9.52; N, 3.83.
(R)-5-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-3-((S)-1-hy-
droxy-2-methyloctylidene)-4-oxo-2-pyrrolidone (11). The crude
product was purified by column chromatography (silica gel, hexane/
EtOAc = 3/1−1/1) to give 11 (40.1 mg, 93%) as a colorless oil:
20
[α]D +68.8 (c 0.904, CHCl3); IR (NaCl) 3229 (N−H), 3069 (N−
H), 1716 (CO), 1660 (CO), 1610 (CC) cm−1; 1H NMR (300
MHz, CDCl3) δ 6.27 (brs, 0.85H, Z-isomer), 6.06 (brs, 0.15H, E-
isomer), 4.26 (m, 1H), 4.07 (d, J = 3.3 Hz, 0.15H, E-isomer), 3.94 (d,
J = 3.3 Hz, 0.85H, Z-isomer), 3.71 (m, 0.15H, E-isomer), 3.60 (m,
0.85H, Z-isomer), 1.67 (m, 1H), 1.46 (m, 1H), 1.30−1.21 (m, 8H),
1.19 (d, J = 6.9 Hz, 0.45H, E-isomer), 1.17 (d, J = 6.9 Hz, 2.55H, Z-
isomer), 1.10 (d, J = 6.3 Hz, 0.45H, E-isomer), 1.03 (d, J = 6.0 Hz,
2.55H, Z-isomer), 0.88−0.86 (m, 12H), 0.09 (s, 3H), 0.08 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 193.4 (C), 192.9 (C), 176.4 (C), 101.4
(C), 68.3 (CH), 67.5 (CH), 36.1 (CH), 33.8 (CH2), 33.6 (CH2), 31.6
(CH2), 29.2 (CH2), 29.1 (CH2), 27.1 (CH2), 25.6 (CH3), 22.5 (CH2),
17.8 (C), 17.4 (CH3), 16.9 (CH3), 16.7 (CH3), 14.0 (CH3), −4.7
(CH3), −5.0 (CH3). Anal. Calcd for C21H39NO4Si: C, 63.43; H, 9.89;
N, 3.52. Found: C, 63.23; H, 9.50; N, 3.84.
(R)-5-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-3-((S)-1-hy-
droxy-2-methyloctylidene)-1-methyl-4-oxo-2-pyrrolidone
(12). To a solution of 11 (57.5 mg, 0.145 mmol) in THF (2.0 mL)
was added NaHMDS (1.09 M solution in THF, 0.29 mL, 0.32 mmol)
at −78 °C. After stirring for 20 min at −78 °C, MeI (0.090 mL, 1.5
mmol) was added to the mixture. The resulting mixture was warmed
to −40 °C and stirred for 10 h. It was quenched with 5% aqueous
tartaric acid solution (5 mL) and extracted with EtOAc. Combined
organic extracts were washed with H2O and brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was purified by column chromatography (silica gel, hexane/EtOAc =
10/1−7/1−5/1−1/1) to give 12 (37.0 mg, 62%) as a colorless oil:
[α]D20 +32.9 (c 0.371, CHCl3); IR (NaCl) 1712 (CO), 1653 (C
O), 1619 (CC) cm−1; 1H NMR (300 MHz, CDCl3) δ 4.32 (dq, J =
2.4, 6.3 Hz, 1H), 3.80 (d, J = 2.1 Hz, 0.1H, E-isomer), 3.71 (d, J = 2.4
Hz, 0.9H, Z-isomer), 3.57 (m, 1H), 3.08 (s, 2.7H, Z-isomer), 3.03
5-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-4-oxo-2-pyrroli-
done (9). To a solution of Meldrum’s acid (777 mg, 5.39 mmol) and
8 (1.80 g, 4.90 mmol) in dichloromethane (25 mL) at 0 °C were
added EDCI (1.13 g, 5.88 mmol) and DMAP (838 mg, 6.86 mmol).
After stirring for 16 h at room temperature, the reaction mixture was
poured into EtOAc (70 mL) and extracted. The organic layer was
washed with 5% aqueous NaHSO4 solution and brine, dried over
Na2SO4, and filtered. The filtrate was refluxed for 2 h until completion
of the reaction (monitored by TLC) and concentrated under reduced
pressure. The residue was roughly purified by column chromatography
(silica gel, CHCl3/MeOH = 10/1) to give the crude product (1.90 g)
as a yellow oil. A suspension containing the crude product and Pd/C
(100 mg) in EtOAc (10 mL) was stirred under hydrogen atmosphere
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Article
(s, 0.3H, E-isomer), 1.65 (m, 1H), 1.44 (m, 1H), 1.29−1.20 (m, 8H),
1.16 (d, J = 6.6 Hz, 3H), 1.05 (d, J = 6.3 Hz, 3H), 0.88−0.85 (m,
12H), 0.097 (s, 3H), 0.088 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
192.1 (C), 191.7 (C), 174.4 (C), 101.1 (C), 72.4 (CH), 69.0 (CH),
36.0 (CH), 33.7 (CH2), 31.6 (CH2), 29.1 (CH2), 28.3 (CH3), 27.1
(CH2), 25.6 (CH3), 22.5 (CH2), 17.8 (C), 17.4 (CH3), 17.0 (CH3),
13.9 (CH3), −4.8 (CH3), −5.2 (CH3). Anal. Calcd for C22H41NO4Si:
C, 64.19; H, 10.04; N, 3.40. Found: C, 64.57; H, 9.66; N, 3.79.
(+)-Penicillenol A2 (2). A solution of 12 (37.0 mg, 0.0899 mmol)
in 2% HCl−MeOH (3.0 mL) was stirred at 0 °C for 1 h. The mixture
was warmed to room temperature and stirred for an additional 1.5 h.
After removal of the solvent under vacuum, the residue was purified by
column chromatography (silica gel, CHCl3/MeOH = 40/1).
A solution of isolated material in EtOAc (10 mL) was washed with
5% aqueous tartaric acid (10 mL) and brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure to give 2 (17.4 mg,
(5) (a) Boeckman, R. K.; Starrett, J. E.; Nickell, D. G.; Sum, P.-E. J.
Am. Chem. Soc. 1986, 108, 5549. (b) Turos, E.; Audia, J. E.;
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Ley, S. V.; Rodriguez, F. Org. Biomol. Chem. 2005, 3, 274. (h) Cramer,
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M.; Laschat, S.; Frey, W.; Baro, A.; Mathieu, D.; Richter, C.; Schwalbe,
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22
65%) as a colorless oil: [α]D +49.2 (c 0.137, MeOH, averaged value
Kummerlowe, G.; Luy, B.; Schwalbe, H. ChemBioChem 2008, 9,
̈
22
for 10 measurements); [α]D +27.8 (c 0.864, CHCl3); IR (NaCl)
2474. (m) Yoshinari, Y.; Ohmori, K.; Schrems, M. G.; Pfaltz, A.;
Suzuki, K. Angew. Chem., Int. Ed. 2010, 49, 881.
3413 (O−H), 2960 (C−H), 2928 (C−H), 2857 (C−H), 1711 (C
O), 1651 (CO), 1615 (CC) cm−1; 1H NMR (300 MHz, CDCl3)
δ 4.30 (dq, J = 3.3, 6.3 Hz, 1H), 3.84 (d, J = 3.0 Hz, 0.1H, E-isomer),
3.75 (d, J = 3.3 Hz, 0.9H, Z-isomer), 3.58 (m, 1H), 3.11 (s, 2.7H, Z-
isomer), 3.06 (s, 0.3H, E-isomer), 1.66 (m, 1H), 1.46 (m, 1H),1.33−
1.23 (m, 8H), 1.21 (d, J = 6.6 Hz, 3H), 1.17 (d, J = 6.6 Hz, 3H), 0.86
(t, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 192.4 (C), 192.4
(C), 174.6 (C), 100.8 (C), 71.5 (CH), 68.2 (CH), 36.0 (CH), 33.7
(CH2), 31.6 (CH2), 29.1 (CH2), 28.4 (CH3), 27.0 (CH2), 22.4 (CH2),
17.5 (CH3), 17.0 (CH3), 13.9 (CH3); Anal. Calcd for C16H27NO4: C,
64.62; H, 9.15; N, 4.71. Found: C, 64.67; H, 8.83; N, 4.50.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all the new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(8) Sengoku, T.; Wierzejska, J; Takahashi, M.; Yoda, H. Synlett 2010,
2944.
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1990, 2350.
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AUTHOR INFORMATION
■
Corresponding Author
*Fax: +81(53)4781150. E-mail: tchyoda@ipc.shizuoka.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan and the Sasakawa Scientific
Research Grant from The Japan Science Society.
(13) Black, T. H.; Arrivo, S. M.; Schumm, J. S.; Knobeloch, J. M.
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1
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(20) The structural and stereochemical integrity of the synthetic
1
penicillenol A2 were unequivocally confirmed by H and 13C NMR.
For more details on these observations and those for penicillenol A1,
see the Supporting Information.
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