A short synthesis of both enantiomers of enterolactone

Article abstract of DOI:10.1139/v99-220

A short and efficient synthesis of both enantiomers of enterolactone, a mammalian lignan, is described. The overall yield for the natural enterolactone, over seven steps, was 19% and for its enantiomer 27%.

Full text of DOI:10.1139/v99-220

1546
Enantioselective synthesis of peperomins A, C, D,
and analogs — Examination of diastereoselective
cuprate conjugate additions to N-enoyl-4-
diphenylmethyl-2-oxazolidinones
Mukund P. Sibi, Michael D. Johnson, and T. Punniyamurthy
Abstract: A concise and general route to secolignans has been developed. The first total synthesis of secolignans
peperomin A (1a), peperomin C (1b), and peperomin D (1c) was accomplished in ~28% overall yield over five
synthetic steps. Peperomin analogs (1d) and (1e), possessing two differentially substituted aryl groups, were syn-
thesized by a highly selective conjugate addition. The overall yield for the analogs 1d and 1e were 27 and 26%,
respectively.
Key words: peperomins, secoliganans, conjugate additions, 4-diphenylmethyl-oxazolidin-2-one.
Résumé : On a mis au point une voie d’accès concise et générale conduisant aux sécolignanes. On a réalisé la pre-
mière synthèse totale des sécolignanes pépéromine A (1a), pépéromine C (1b) et pépéromine D (1c), avec un rende-
ment global d’environ 28% sur cinq étapes. Les analogues 1d et 1e de la pépéromine qui possèdent deux groupes
aryles substitués de façon différente ont aussi été synthétisés par le biais d’une addition conjuguée hautement sélective.
Les rendements globaux des synthèses des analogues 1d et 1e sont respectivement de 27 et 26%.
Mots clés : pépéromines, sécolignanes, additions conjuguées, 4-diphénylméthyloxazolidin-2-one.
[Traduit par la Rédaction] Sibi et al. 1555
O
H3CO
O
Introduction
O
O
O
H
H
H
H
H
H
O
O
H3CO
Recently, a novel and unusual class of lignans were iso-
lated from Peperomia japonica Makino by Chen et al. (1).
Three lignans, peperomins A, B, and C, with a novel seco
structure, were isolated from this perennial herb. Peperomin
D was also recently isolated from Peperomia glabella (2).
The use of aqueous and alcoholic decoctions of the herb as
folk medicine for the treatment of malignant tumors has
been noted (1). Two other secolignans with insect antifeedant
activity have also been isolated from Peperomia dindigulensis
(3). These secolignans have structural features that are pres-
ent in the combretastatins (4) and podophyllotoxin (5). In
view of the high tubulin inhibitory activity of the combretastatins
and podophyllotoxin, the evaluation of the biological activity
of peperomins and their analogs could be important. The
structure-activity relationship in this novel secolignan series
could shed more light on the conformational requirements
for tubulin binding at the colchicine–podophyllotoxin site.
Towards this end we have started a program on the prepara-
tion and biological evaluation of peperomins and analogs.
Only a single racemic synthesis of peperomin C has been re-
ported in the literature so far (6). This paper describes the
first total synthesis of peperomins A, C, D, and two analogs.
O
O
O
H3CO
H3CO
H3CO
H3CO
H3 CO
1b Peperomin C
OCH3
O
O
O
O
1a Peperomin A
1c Peperomin D
H3CO
H3CO
H3CO
O
O
H
H
H
H3CO
O
O
H3CO
H3CO
H
H3CO
O
O
O
O
1d Peperomin analog
1e Peperomin analog
We have been investigating methodologies for the prepa-
ration of succinates with various substituents on the carbon
backbone and their application to the synthesis of butyrolactone
Received January 10, 2001. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on October 22, 2001.
Dedicated with heartfelt appreciation to Victor Snieckus — mentor, teacher, and a friend.
M.P. Sibi,1 M.D. Johnson,2 and T. Punniyamurthy. Department of Chemistry, North Dakota State University, Fargo, ND 58105–
5516, U.S.A.
1Corresponding author (telephone: (701) 231-8251; fax: (701) 231-8831; e-mail: Mukund_Sibi@ndsu.nodak.edu).
2Taken in part from the M.S. thesis of M.D. Johnson, North Dakota State University, Fargo, North Dakota, October 1998.
Can. J. Chem. 79: 1546–1555 (2001)
DOI: 10.1139/cjc-79-11-1546
© 2001 NRC Canada

Sibi et al.
1547
Scheme 1.
Scheme 3.
O
O
O
O
OR
OR
NH
O
a
Xc
Xc
b
Ph
Ar
Xc = Chiral auxiliary
12 Ar = 3,4-Methylenedioxy-
Xc
O
R2
n-BuLi
O
R
O
R
ArCuBr
3
5
OR
Ph
Xc
11
R1
O
5-methoxyphenyl, 86%
13 Ar = 3,4,5-Trimethoxyphenyl, 89%
14 Ar = 3,4-Methylenedioxyphenyl, 91%
O
O
2
Xc
Xc
CO2t-Bu
4
4
Ar
Xc
d for 18,19
c
Ar
Xc
Ar
O
NaHMDS
LAH
e for 20
Scheme 2.
Ar
O
O
O
CO2t-Bu
15 84%
16 81%
17 89%
18 64% (98% de)
19 66% (98% de)
20 74% (98% de)
O
O
R1
Xc
R1
R1
O
H
O
H
R2
O
R2
R2
H3C
O
7
8
9
f
O
Ar
Ar
NaHMDS
O
Ar
Ar
21 74%
22 75%
23 56%
1a 98% (av. 10:1 ds)
1b 98% (av. 10:1 ds)
1c 80% (av. 12:1 ds)
R1
Xc
10
Key: (a) 1.0 equiv. n-BuLi, 1.1 equiv. ClCOAr, -78°C, 3h, THF; (b) (i) 3.1 equiv.
Mg, (ii) 3.0 equiv. ArBr, (iii) 1.5 equiv. CuBr-(CH3)2S, -48 to 0°C, 3 h, 3:1
THF-(CH3)2S; (c) (i)1.1 equiv. NaHMDS, (ii)1.5 equiv. t-BuO2CCH2I,-78 to
-48°C, 6 h, THF; (d) (i) 5.0 equiv. LAH (1 M), 20 h, THF, (ii) Silica gel;
(e) (i) LiOH/H2O2; (ii) BH3, (iii) PTSA; (f) (i)1.1 equiv. NaHMDS, (ii)1.5
equiv. CH3I, 3 h, -78°C.
natural products (Scheme 1) (for other selected approaches
to substituted succinates see refs. 7a–c; for an example of
enolate alkylation leading to similar structures see ref. 7d).
Recently, we described a novel route to paraconic and lignan
natural products by the conjugate addition of radical inter-
mediates starting from fumarates (3 J 2) (8). We have also
reported on alternate routes to paraconic acids using succinates
as starting materials (5 J 2) (9). The chiral auxiliary ap-
pended b-aryl propionates have also served as starting mate-
rials in the synthesis of lignan natural products (6 J 2) (10).
These three disconnections, however, were not suited for the
preparation of the secolignans and an alternate approach (4 J
2) was required.
The synthetic strategy for the preparation of peperomins is
shown in Scheme 2. The design is based on the conjugate
addition of an aryl group to the enoyloxazolidinone 10 (Xc =
chiral auxiliary). The conjugate addition is followed by electro-
phile incorporation in a step-wise manner to furnish 9. The
strategy provides the flexibility for the introduction of differ-
ent aryl groups by either varying the nucleophile or the
enoyloxazolidinone leading to a variety of b,b-diaryl propionic
acids (for procedures describing methodologies for the syn-
thesis of enantiomerically enriched 3,3-diaryl propanoic ac-
ids and derivatives see refs. 11a–f; for a recent effort see
ref. 11g). The next step in the sequence involves chemo-
selective reduction of the carbonyl bearing the chiral auxil-
iary and cyclization to provide 8. Enolate alkylation of 8
from the less-hindered face establishes the required trans
stereochemistry in the natural products. The key bond con-
struction in our synthesis is a conjugate addition of an aryl
copper reagent to a chiral enoate. Of the variety of chiral
auxiliaries examined for conjugate additions, the oxazo-
lidinones have generally been inferior in terms of selectivity.
Recently, several groups have undertaken a study of various
auxiliaries in the addition of copper reagents to enoates (for
a comparative study of chiral auxiliaries see ref. 12). Hruby
and co-workers (13; for NMR studies see ref. 13b) have
shown that the oxazolidinone derived from phenylglycinol
provides high selectivity in the addition of aryl coppers to
cinnamates. We describe the use of an oxazolidinone de-
rived from diphenylalanine in conjugate additions to acyclic
systems using copper nucleophiles and determine its effec-
tiveness in controlling stereochemistry at the b-carbon with
the traditional oxazolidinones.
Results and discussion
Initial targets for examining the feasibility of our method-
ology were the simpler peperomins A, C, and D, since these
compounds do not possess a chiral center at the benzylic
carbon. This would allow us to establish reaction conditions
for the conjugate additions (protocols for conjugate addi-
tions to enoyloxazolidinones has been established, see ref. 14a;
for other contributions from the Hruby group see ref. 14b;
14c–h; for work on superquat oxazolidinone auxiliaries see
ref. 14i). The synthesis of peperomin A, C, and D started
with the acylation of the 4-diphenylmethyl-2-oxazolidinone
auxiliary developed in our laboratory (Scheme 3) (15).3 Treat-
ment of 11 with n-BuLi provided the anion which was acylated
with 3-[3>,4>-methylenedioxy-5>-methoxy-phenyl]-2-propenoyl
3 For the synthesis of chiral auxiliary 11 see ref. 15a. This chiral auxiliary is available commercially from Aldrich Chemical Company; see
ref. 15b. For the application of this auxiliary in synthesis see ref. 15c.
© 2001 NRC Canada

1548
Can. J. Chem. Vol. 79, 2001
chloride (16).4 3,4-(Methylenedioxy)-5-methoxybenzaldehyde
was transformed into the corresponding acid chloride:
(a) Ph3P=CHCO2Et (1.1 equiv), 70°C, 16 h, C6H6, 92%
(96% E-isomer); (b) (i) 2.2 equiv NaOH, reflux, 20 min,
99%; (ii) 3.2 equiv oxalyl chloride, 25°C, 3 h, 93%. to fur-
nish 12 in high yield. The required cinnamic acid (17) was
prepared by HWE reaction between 3,4-methylenedioxy-5-
methoxybenzaldehyde (18) and phosphanoacetic acid. Cinna-
mates 13 and 14 were prepared in high yields using 3-[3>,4>,5>-
trimethoxyphenyl]-2-propenoyl chloride and 3-[3>,4>-methyl-
enedioxyphenyl]-2-propenoyl chloride and lithiated 11, re-
spectively. The two-step protocol for the introduction of the
substituents was then undertaken (19).5 Reaction of 12 with the
copper reagent prepared from 3,4-methylenedioxy-5-methoxy
bromobenzene (20) gave 15 in 84% yield. Similarly, treat-
ment of 13 and 14 with the copper reagent derived from
3,4,5-trimethoxy bromobenzene and 3,4-methylenedioxy bromo-
benzene (21) gave 16 and 17, respectively. The next step in-
volved the introduction of the acetic acid chain. This was
accomplished in respectable chemical yield and excellent
diastereoselectivity (>98%) by treatment of 15 and 16 with
sodium hexamethyldisilazide followed by quenching of the
sodium enolate with tert-butylbromoacetate. The diastereose-
some examples of diastereoselective alkylation at the 3-
position see ref. 26). Generation of the sodium enolate of 21
and quenching with methyl iodide gave a 10:1 to 12:1 mix-
ture of the methylated product. The use of LDA as the base
in the alkylation gave a 8:1 mixture of the alkylated products
(stereoselectivity of alkylations in substituted butyrolactones
has been examined, see ref. 27). Attempts to improve
diastereoselectivity by variation of reaction conditions were
unrewarding. The two diastereomers were inseparable by
chromatographic methods. However, the major diastereomer
(1a) could be separated and purified by careful
recrystallization. The major diastereomer was established to
posses the 3,4-trans stereochemistry by comparison of its
spectral data with those reported for peperomin A (1). The
synthesis of 1b followed a similar reaction sequence but
starting with 22 and spectral data of the major diastereomer
(~10:1 ds) was consistent with those reported for peperomin
C (1). The overall yields for peperomin A (1a) and
peperomin C (1b) were 28% (five steps) and 28% (five
steps), respectively. The alkylation of 23 using NaHMDS as
the base gave peperomin D (1c) with moderate to good
diastereoselectivity and chemical yield. The spectral charac-
teristics of the synthetic material were consistent with those
reported in the literature for the natural product (2). The
overall yield for peperomin D (1c) is ~27% over seven
steps.
The synthesis of peperomin analogs (1d and 1e) required
the development of a diastereoselective conjugate addition
protocol using copper reagents. Several groups have recently
compared the effectiveness of different auxiliaries in conju-
gate additions and noted that the camphor sultams are quite
good (28).7 Hruby and co-workers (see ref. 13. For selected
examples from a large body of work see ref. 29)8 have also
demonstrated that an oxazolidinone derived from phenyl-
glycinol is an excellent chiral auxiliary in conjugate addition
to enoates using organocuprates as nucleophiles. We have
recently shown that a chiral auxiliary derived from diphenyl-
alanine is superior to Evans-type oxazolidinones in conju-
gate radical additions (30). Thus, we wished to briefly evaluate
the utility of this auxiliary in conjugate addition using cup-
rates as nucleophiles. The protocol developed by Hruby and
co-workers was adapted as the standard reaction conditions
(the addition of Grignard reagent with the use of copper bro-
mide – dimethyl sulfide complex as the copper source). Re-
actions with a variety of substrates with simple as well as
more functionalized aromatic nucleophiles were investigated.
Results from these experiments are shown in Table 1. The
diastereoselectivity in the conjugate additions was determined
by NMR and HPLC analyses. The data in the table indicates
that the diastereoselectivity was very high. The addition of
Grignard reagent derived from 3,4-methylenedioxy-5-methoxy-
1
lectivity in the alkylation step was established by H NMR
analysis (400 MHz) of the crude product. The alkylation of
17 using bromo-tert-butylacetate gave moderate yields (60%).
A change of the leaving group to an iodo group gave 20 in
higher yields (74%). Similar small increments in chemical
efficiency were also noted for simple substrates as well as
the alkylation precursor for peperomin analogs (vide infra).
Thus, the iodoacetates were used in all the alkylation reac-
tions (for a recent example of variation in chemical effi-
ciency and selectivity in enolate alkylations with haloacetates
see ref. 22).
With the desired succinates at hand, chemoselective re-
duction of the carbonyl attached to the chiral auxiliary was
achieved by using LAH at low temperatures (23). Work-up
of the reduction product followed by silica gel column chro-
matography furnished the butyrolactones 21 and 22 directly
in good yields over two steps.6 Reduction of 20 using LAH
was not clean, providing the desired alcohol as well as an
over-reduced diol (reduction of imide as well as the ester).
Thus, an alternate sequence was devised. The chiral auxil-
iary in 20 was selectively hydrolyzed using LiOH–H2O2 (24).
The resulting acid ester was reduced chemoselectively using
borane (25). Lactonization using catalytic amounts of p-tolu-
enesulfonic acid gave 23. The three-step sequence could be
carried out with good efficiency without isolation of the in-
termediates.
Introduction of the 3-substituent in butyrolactones by eno-
late alkylation has been well established in the literature (for
4 3,4-(Methylenedioxy)-5-methoxybenzaldehyde was transformed into the corresponding acid chloride: (a) Ph3P=CHCO2Et (1.1 equiv),
70°C, 16 h, C6H6, 92% (96% E-isomer); (b) (i) 2.2 equiv NaOH, reflux, 20 min, 99%; (ii) 3.2 equiv oxalyl chloride, 25°C, 3 h, 93%.
5 For a review on enantioselective conjugate addition see ref. 19b. For other recent reviews see ref. 19c.
6 The chiral auxiliary was recovered in >95% yield.
7 (S)-4,4-Dimethylpyroglutamate as a chiral auxiliary, see ref. 28a. Addition of Yamamoto’s reagent with high selectivity to N-enoyloxa-
zolidinones; see ref. 28b. Comparison of auxiliaries see ref. 28c. Others: Oppolzer and Helmchen auxiliary; see ref. 28d–f. Addition of aryl
Grignards and (or) coppers to oxazolidinone enoates see ref. 28g. Addition to 4-phenyl-oxazolidinone derived enoates see ref. 28h. For
other efforts in the area see ref. 28i.
8 Williams has recently shown that 4-benzyloxazolidinone is a useful chiral auxiliary in conjugate additions using Yamamoto’s reagent. See
ref. 12b.
© 2001 NRC Canada

Sibi et al.
1549
Table 1. Diastereoselective conjugate additions to enoyloxazolidinones.
O
O
O
O
Ar1
Ar
Ar1 MgBr, CuBrSMe2
-78°C, THF
O
N
Ar
O
N
CHPh2
CHPh2
25-30
12, 13,14, 24
Entry
Ar
Ar1
Ph
Product
Yield (%)
de (%)
1
2
3
4
5
6
3,4-(OCH2O)-5-MeOPh (12)
3,4,5-(MeO)3Ph (13)
3,4,5-(MeO)3Ph (13)
3,4,5-(MEO)3Ph (13)
3,4-(OCH2O)Ph (14)
Ph (24)
25
26
27
28
29
30
90
89
88
90
97
95
94
97
95
96
97
92
3,4-(OCH2O)-5-MeOPh
3,4-(OCH2O)Ph
Ph
Ph
3,4-(OCH2O)Ph
aYields are for purified materials.
bdes were determined by NMR analysis.
Scheme 4.
bromobenzene (31) to 13 gave 26, the intermediate in peper-
omin analog (1d) synthesis, in excellent yield and diastereo-
selectivity (entry 2). Similarly, intermediate for analog 1e,
was also obtained with high efficiency (entry 3). Conjugate
additions to other substrates either varying the nucleophile
or the acceptor did not diminish the selectivity (entries 1, 4,
5, and 6). Thus, the 4-diphenylmethyl substituted enoyl oxa-
zolidinones undergo conjugate additions with high selectivity.
The efficient shielding of the b-carbon in conjugate addi-
tions by 4-phenyl- and 4-diphenylmethyl-oxazolidinones may
suggest that these likely have similar structural organization
in the transition states (structures 31 and 32). In conjugate
additions with 4-benzyloxazolidinones (13), the C-4-benzyl
bond rotation (33) may play a role in the observed low se-
lectivity. The high selectivity observed for organocuprate ad-
dition to 4-phenyl and 4-diphenylmethyl derived enoates is
in stark contrast to conjugate radical additions where only
auxiliary 11 showed high selectivity. Thus, the results de-
picted in the table and previous work from our laboratory
(30) clearly show that the diphenylalanine-derived oxazolid-
inone can shield the b-carbon effectively in both organo-
cuprate and radical conjugate additions.
OMe
OMe
MeO
MeO
MeO
a
ArCuBr
X
c
X
c
MeO
Ar
O
O
13 X = Chiral Auxiliary
c
26 Ar = 3,4-methylenedioxy-
5-methoxyphenyl, 89%
27 Ar = 3,4-methylenedioxyphenyl, 88%
OMe
c
LiOH
BH
PTSA
MeO
MeO
CO t-Bu
2
b
NaHMDS
X
c
3
Ar
O
34 Ar = 3,4-methylenedioxy-
5-methoxyphenyl, 75%
35 Ar = 3,4-methylenedioxyphenyl, 75%
O
O
MeO
MeO
MeO
MeO
H C
3
d
O
O
MeO
MeO
NaHMDS
MeI
H
H
Ar
Ar
36 Ar = 3,4-methylenedioxy-
5-methoxyphenyl, 57%
37 Ar = 3,4-methylenedioxyphenyl, 56%
1d 80% (av. 8:1 ds)
1e 80% (av. 8:1 ds)
O
O
H
H
O
O
M
M
N
N
O
O
Key: (a) (i) 3.1 equiv. Mg, (ii) 3.0 equiv. ArBr, (iii) 1.5 equiv. CuBr-(CH ) S,
3 2
-48 to 0°C, 3 h, 3:1 THF-(CH ) S; (b) (i)1.1 equiv. NaHMDS,
3
(ii)1.5 equiv. t-BuO CCH I,-78 to -48°C, 6h , THF; (c) (i) LiOH/H O ,
2
Ar
Ar
2
(ii) BH , (iii) PTSA; (d) (i)1.1 equiv. NaHMDS, (ii)1.5 equiv. CH I, 3h, -78°C.
2
2 2
3
3
31
M = Lewis acid
32
O
H
face selectivity. The succinates were converted to the lac-
tones 36 and 37, respectively by a hydrolysis–reduction–
lactonization sequence. The overall yield for the three steps
without purification of the intermediates was excellent. With
the lactones at hand, the final installation of the C-3 methyl
group was uneventful. As observed in the previous alkyla-
tions (vide supra), the diastereoselectivities in these reac-
tions were only moderate (highest ds of 8:1). All attempts at
purification of the diastereomeric mixture were not success-
ful. The structural characteristics (1H and 13C NMR chemi-
cal shifts) of analog 1d are similar to those reported for the
natural product peperomin B (1). The structure for the major
O
M
N
O
Ar
33
The basic methodology used in the synthesis of pepero-
mins A, C, and D was adapted for the synthesis of the more
complex analogs 1d and 1e (Scheme 4). Installation of the
two-carbon chain on the conjugate addition products 26 and
27 furnished 34 and 35. The diastereoselectivity in these al-
kylations was high with the chiral auxiliary controlling the
© 2001 NRC Canada

1550
Can. J. Chem. Vol. 79, 2001
diastereomer (trans stereochemistry) of 1d and 1e are con-
sistent with the observed H NMR coupling constants and
spectral similarities to the natural peperomins. The overall
yield for 1d and 1e were 27 and 26%, respectively.
In conclusion, we have developed a simple and efficient
strategy for the synthesis of secolignans peperomin A, C, D,
and two analogs. Additionally, we have also shown that 4-
diphenylmethyl oxazolidin-2-one (11) is an excellent auxil-
iary in diastereoselective conjugate addition of organocuprates
to enoates. The extension of the present methodology for the
synthesis of analogs and biological evaluation of the secoli-
gnans is currently underway in our laboratory.
THF was added dropwise to the solution over 8 min. The so-
lution was stirred at –78°C for 3 h. The reaction was quenched
with 10 mL NH4Cl. The reaction mixture was extracted with
ethyl acetate. The combined organics were washed with wa-
ter followed by brine and dried over MgSO4. Removal of
solvent under reduced pressure followed by flash column
purification of the crude mixture gave 5.0 g of the acylated
product (89% yield).
1
(4R)-4-(Diphenylmethyl)-3-[3-(3>,4>-methylenedioxy-5>-
methoxyphenyl)-2(E)-propenoyl]-2-oxazolidinone (12)
25
Yield: 86%; mp 88–90°C.
[a]D
–192.8 (c 0.98, CHCl3).
1
Rf 0.7 (50:50, EtOAc:hexanes). H NMR (400 MHz, CDCl3)
d: 3.94 (s, 3H), 4.48 (dd, J = 2.7, 8.0 Hz, 2H), 4.81 (d, J =
5.4 Hz, 1H), 5.44 (m, 1H), 6.04 (s, 2H), 6.78 (d, J = 1.1 Hz,
1H), 6.85 (d, J = 1.1 Hz, 1H), 7.22 (m, 10H), 7.70 (s, 2H).
13C NMR (100 MHz, CDCl3) d: 50.6, 56.4, 56.5, 64.7, 102.0,
109.6, 115.1, 127.0, 127.7, 128.3, 128.6, 128.7, 128.8, 129.3,
138.0, 139.6, 143.6, 146.2, 149.2, 153.4, 164.9. Anal. calcd.
for C27H23NO6: C 70.89, H 5.07, N 3.06; found: C 70.81, H
5.12, N 2.91.
Experimental
General experimental details
Methylene chloride (CH2Cl2) was distilled from calcium
hydride. Tetrahydrofuran (THF), diethyl ether (Et2O), and
benzene were distilled from benzophenone–ketyl prior to
use. Methanol (MeOH) was distilled from magnesium turn-
ings and I2. Acetone was dried from KMnO4 and K2CO3.
Most of the organic compounds utilized in this study were
purchased from Aldrich Chemical Company. All glassware
were oven dried, assembled hot, and cooled under a stream
of dry nitrogen before use. Reactions with air-sensitive ma-
terials were carried out by standard syringe techniques. All
reactions were run under an atmosphere of nitrogen unless
otherwise noted.
(4R)-4-(Diphenylmethyl)-3-[3-(3>,4>,5>-trimethoxyphenyl)-
2(E)-propenoyl]-2-oxazolidinone (13)
Yield: 89%; mp 70 to 71°C. [a]2D5 –182.4 (c 0.95, CHCl3).
1
Rf 0.5 (50:50, EtOAc:hexanes). H NMR (400 MHz, CDCl3)
d: 3.89 (overlapping s, 9H), 4.45 (m, 2H), 4.82 (d, J =
5.4 Hz, 1H), 5.44 (m, 1H), 6.82 (s, 2H), 7.22 (m, 10H), 7.75
(d, J = 2.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) d: 50.5,
56.1, 56.4, 60.9, 64.8, 105.6, 115.8, 126.9, 127.7, 128.3,
128.6, 128.8, 129.3, 129.9, 138.0, 139.6, 140.4, 146.5, 153.3,
153.5, 164.9. Anal. calcd. for C28H27NO6: C 71.02, H 5.75,
N 2.96; found: C 70.94, H 5.76, N 2.84.
Chromatography and instrumentation
Thin layer chromatographic analyses (TLC) were performed
on silica gel Whatmann-60F glass plates and components
were visualized by illumination with UV light or by staining
with phosphomolybdic acid. Flash column chromatography
was performed using E. Merck silica gel 60 (230–400 mesh).
1H NMR was recorded on a 500, 400, or 300 MHz spec-
trometer. 13C NMR was recorded on 500 (125) MHz, 400
(100) MHz, and 300 (75) MHz spectrometers using broad
band proton decoupling. Rotations were recorded on a JASCO-
DIP-370 instrument. Elemental analyses were performed on
a PerkinElmer Series II CHNS/O analyzer 2400. Melting
points was determined using a Fisher–Johns melting point
apparatus without correction.
(4R)-4-(Diphenylmethyl)-3-[3-(3>,4>-methylenedioxyphenyl)-
2(E)-propenoyl]-2-oxazolidinone (14)
Yield: 91%; mp 188 to 189°C. [a]2D5 –163.3 (c 1.0,
CH2Cl2). Rf 0.56 (50:50, EtOAc:hexanes). 1H NMR
(400 MHz, CDCl3) d: 4.45 (m, 2H), 4.80 (d, J = 5.1 Hz, 1H),
5.42 (m, 1H), 6.01 (s, 2H), 6.81 (d, J = 8.1 Hz, 1H), 7.22
(m, 12H), 7.70 (s, 2H). 13C NMR (100 MHz, CDCl3) d:
50.7, 56.6, 64.9, 101.8, 107.1, 108.6, 114.8, 125.4, 127.1,
127.9, 128.5, 128.8, 128.9, 129.1, 129.5, 138.3, 139.8, 146.4,
148.4, 150.1, 153.6, 165.2. Anal. calcd. for C26H21NO5: C
73.06, H 4.95, N 3.28; found: C 72.57, H 5.10, N 3.29.
Representative procedure for the acylation of (R)-4-
diphenylmethyl-2-oxazolidinone (compound 13)
To an oven-dried 100 mL three- neck round- bottomed
flask purged with N2 was added 3.50 g (14.69 mmol) of
3,4,5-trimethoxycinnamic acid. To the solid was added 5 mL
(57.23 mmol) of oxalyl chloride dropwise over 2 min and
the mixture was allowed to stir at room temperature (rt) for
1 h. Removal of the excess oxalyl chloride under reduced
vacuum gave 3.65 g of pure acid chloride (97% yield). To an
oven-dried 250 mL three-neck round-bottomed flask purged
with N2 was added 3.0 g (11.86 mmol) of 4-diphenylmethyl-
2-oxazolidinone 11 and 40 mL of dry THF. The reaction
mixture was cooled to –78°C in an acetone – dry ice bath.
To the mixture was added 5.19 mL (12.45 mmol) of n-BuLi
dropwise over 10 min and the mixture was allowed to stir
for 30 min. A solution of 3.35 g (13.05 mmol) of the 3,4,5-
trimethoxy cinnamoyl chloride dissolved in 15 mL of dry
Representative procedure for the conjugate addition —
Preparation of 26
To an oven-dried 100 mL round-bottomed flask purged
with N2 was added 1.43 g (58.9 mmol) of magnesium turn-
ings and 10 mL of dry THF. The flask was placed in a ultra-
sonic bath for 3 min before dropwise addition of 13.18 g
(57 mmol) 5-bromo-3-methoxy-1,2-methylenedioxybenzene
(dissolved in 24 mL of dry THF) over 20 min. To an oven-
dried three-neck 500 mL round-bottomed flask purged with
N2 was added 5.86 g (28.5 mmol) of copper(I) bromide –
dimethyl sulfide complex and 40 mL of dimethyl sulfide
and 80 mL of dry THF. The reaction mixture was cooled to
–48°C in an acetonitrile – dry ice bath. To the mixture was
added the Grignard reagent dropwise over 30 min and the
mixture was allowed to stir for 30 min. A solution of 9.0 g
© 2001 NRC Canada

Sibi et al.
1551
(19.0 mmol) of the cinnamate 13 dissolved in 36 mL of dry
THF was added dropwise to the solution over 30 min. The
solution was stirred at –48°C for 4.5 h. The reaction was
quenched with 30 mL NH4Cl. Excess dimethyl sulfide was
removed using a water aspirator. The residue was extracted
with ethyl acetate. The combined organics was washed with
10% NH4OH, water, followed by brine, and dried over MgSO4.
Removal of solvent under reduced pressure followed by flash
column purification of the crude mixture gave 10.58 g of the
addition product 26 (89% yield).
1H), 5.24 (m, 1H), 5.93 (m, 2H), 6.53 (s, 2H), 6.91 (m, 2H),
7.05 (m, 2H), 7.25 (m, 11H). 13C NMR (125 MHz, CDCl3)
d: 41.1, 46.5, 50.5, 56.6, 56.9, 65.0, 101.6, 102.3, 107.8,
126.9, 127.3, 127.8, 128.1, 128.5, 128.9, 134.1, 138.0, 138.6,
139.7, 143.8, 149.2, 153.7, 171.3. Anal. calcd. for
C33H29NO6: C 74.00, H 5.46, N 2.62; found: C 73.74, H
5.33, N 2.73.
(3(3S),4R)-4-(Diphenylmethyl)-3-[3-(3,3-(3>,4>,5>-
>> >>
>>
trimethoxyphenyl)-(3 ,4 -methylenedioxy-5 -methoxyphenyl)-
propanoyl]-2-oxazolidinone (26)
Yield: 89%; mp 88 to 89°C. [a]2D5 –95.1 (c 1.0, CH2Cl2).
Rf 0.42 (50:50, EtOAc:hexanes). 1H NMR (400 MHz,
CDCl3) d: 3.53 (dd, J = 7.5, 17.2 Hz, 1H), 3.66 (dd, J = 7.5,
16.9 Hz, 1H), 3.81 (s, 3H), 3.84 (s, 6H), 3.87 (s, 3H), 4.39
(d, J = 5.1 Hz, 2H), 4.49 (t, J = 7.2 Hz, 1H), 4.60 (d, J =
5.4 Hz, 1H), 5.23 (m, 1H), 5.92 (s, 2H), 6.46 (s, 2H), 6.52
(s, 2H), 6.82 (d, J = 5.6 Hz, 2H), 7.01 (d, J = 6.7 Hz, 2H),
7.26 (m, 6H). 13C NMR (100 MHz, CDCl3) d: 40.9, 46.7,
50.4, 56.3, 56.6, 56.8, 60.9, 64.8, 101.4, 101.8, 104.9, 107.4,
127.1, 128.0, 128.3, 128.7, 128.9, 129.3, 133.9, 136.7, 137.8,
138.2, 139.2, 139.6, 143.5, 149.0, 153.3, 153.6, 171.1. Anal.
calcd. for C36H35NO9: C 69.11, H 5.64, N 2.24; found: C
69.49, H 5.79, N 2.04.
(4R)-4-(Diphenylmethyl)-3-[3-(3,3-bis-3>,4>-methylenedioxy-
5>-methoxyphenyl)-propanoyl]-2-oxazolidinone (15)
Yield: 84%; mp 90 to 91°C. [a]2D5 –130.8 (c 1.0, CHCl3).
Rf 0.53 (50:50, EtOAc:hexanes). 1H NMR (400 MHz, CDCl3)
d: 3.55 (m, 2H), 3.87 (two s, 6H), 4.40 (d, J = 5.4 Hz, 2H),
4.45 (t, J = 7.5, 1H), 4.62 (d, J = 4.8 Hz, 1H), 5.24 (m, 1H),
5.93 (m, 4H), 6.46 (m, 4H), 6.90 (s, 2H), 7.03 (d, J =
7.0 Hz, 2H), 7.27 (m, 6H). 13C NMR (100 MHz, CDCl3) d:
40.9, 46.1, 50.3, 56.4, 56.6, 64.8, 101.3, 101.7, 101.8, 107.1,
107.4, 127.0, 127.8, 128.2, 128.6, 128.8, 129.3, 133.7, 133.8,
137.7, 138.1, 138.2, 139.4, 143.4, 143.5, 148.8, 148.9, 153.4,
170.8. Anal. calcd. for C35H31NO9: C 68.96, H 5.03, N 2.30;
found: C 68.70, H 4.66, N 2.68.
(4R)-4-(Diphenylmethyl)-3-[3-(3,3-bis-3>,4>,5>-
trimethoxyphenyl)-propanoyl]-2-oxazolidinone (16)
(3(3S),4R)-4-(Diphenylmethyl)-3-[3-(3,3-(3>,4>,5>-
trimethoxyphenyl)-(3 ,4 -methylenedioxyphenyl)-propanoyl]-
>> >>
Yield: 81%; mp 75 to 76°C. [a]2D5 –121.2 (c 0.98, CHCl3).
Rf 0.43 (50:50, EtOAc:hexanes). 1H NMR (400 MHz, CDCl3)
d: 3.60 (dd, J = 7.5, 16.7 Hz, 1H), 3.67 (dd, J = 7.5, 16.7 Hz,
1H), 3.82 (three s, 18H), 4.37 (m, 2H), 4.53 (t, J = 7.5 Hz,
1H), 4.60 (d, J = 4.8 Hz, 1H), 5.22 (m, 1H), 6.51 (s, 2H),
6.56 (s, 2H), 6.85 (m, 2H), 7.02 (d, J = 7.5 Hz, 2H), 7.26
(m, 6H). 13C NMR (100 MHz, CDCl3) d: 40.6, 47.1, 50.3,
56.1, 56.4, 60.8, 64.7, 104.7, 104.9, 127.0, 127.8, 128.1,
128.6, 128.8, 129.2, 136.6, 136.7, 137.7, 138.8, 138.9, 139.4,
153.1, 153.4, 171.0. Anal. calcd. for C37H39NO9: C 69.25, H
6.13, N 2.18; found: C 69.15, H 6.19, N 2.01.
2-oxazolidinone (27)
Yield: 88%; mp 84 to 85°C. [a]2D5 –105.2 (c 1.0, CH2Cl2).
Rf 0.42 (50:50, EtOAc:hexanes). 1H NMR (400 MHz, CDCl3)
d: 3.50 (dd, J = 7.5, 17.2 Hz, 1H), 3.70 (dd, J = 7.8, 17.2 Hz,
1H), 3.81 (s, 3H), 3.84 (s, 6H), 4.39 (d, J = 4.8 Hz, 2H),
4.51 (t, J = 7.2 Hz, 1H), 4.60 (d, J = 5.1 Hz, 1H), 5.23 (m,
1H), 5.91 (s, 2H), 6.52 (s, 2H), 6.74 (m, 3H), 6.82 (d, J =
5.9 Hz, 2H), 7.01 (d, J = 7.2 Hz, 2H), 7.24 (m, 6H). 13C
NMR (100 MHz, CDCl3) d: 40.9, 46.4, 50.3, 56.2, 56.6,
60.9, 64.8, 101.1, 104.9, 108.3, 120.4, 127.1, 127.9, 128.3,
128.4, 128.7, 128.9, 129.3, 136.6, 137.5, 137.8, 139.4, 139.6,
146.3, 147.9, 153.3, 153.5, 171.1. Anal. calcd. for C35H33NO8:
C 70.58, H 5.58, N 2.35; found: C 70.57, H 5.86, N 1.92.
(4R)-4-(Diphenylmethyl)-3-[3-(3,3-bis-3>,4>-
methylenedioxyphenyl)-propanoyl]-2-oxazolidinone (17)
Yield: 89%; mp 86 to 87°C. [a]2D5 –112.7 (c 1.03, CH2Cl2).
Rf 0.50 (50:50, EtOAc:hexanes). 1H NMR (400 MHz, CDCl3)
d: 3.51 (dd, J = 7.5, 17.4 Hz, 1H), 3.58 (dd, J = 7.5, 17.4 Hz,
1H), 4.38 (d, J = 4.8 Hz, 2H), 4.46 (t, J = 7.8 Hz, 1H), 4.61
(d, J = 5.1 Hz, 1H), 5.23 (m, 1H), 5.89 (s, 2H), 5.92 (s, 2H),
6.73 (m, 6H), 6.92 (d, J = 3.2 Hz, 2H), 7.03 (d, J = 6.7 Hz,
2H), 7.27 (m, 6H). 13C NMR (100 MHz, CDCl3) d: 41.2,
45.5, 50.4, 56.4, 64.9, 101.1, 108.3, 108.4, 120.5, 120.8,
127.1, 127.9, 128.3, 128.7, 128.9, 129.4, 137.7, 137.9, 139.5,
146.2, 146.3, 147.8, 147.9, 153.5, 170.9. Anal. calcd. for
C33H27NO7: C 72.12, H 4.95, N 2.55; found: C 71.64, H
5.00, N 2.54.
(3(3S),4R)-4-(Diphenylmethyl)-3-[3-(3,3-(phenyl)-(3>,4>,5>-
trimethoxyphenyl)-propanoyl]-2-oxazolidinone (28)
Yield: 90%; mp 125–127°C. [a]2D5 –131.2 (c 0.42,
1
CH2Cl2). H NMR (500 MHz, CDCl3) d: 3.61 (dd, J = 17.0,
7.1 Hz, 1H), 3.82 (dd, J = 17.0, 8.2 Hz, 1H), 3.85 (s, 3H),
3.88 (s, 6H), 4.41 (m, 2H), 4.65 (m, 2H), 5.25 (m, 1H), 6.59
(s, 2H), 6.85 (m, 2H), 7.27 (m, 13H). 13C NMR (125 MHz,
CDCl3) d: 40.9, 47.0, 50.5, 56.4, 56.7, 61.1, 65.0, 105.3,
126.9, 127.3, 127.9, 128.1, 128.4, 128.9, 129.1, 129.5, 136.8,
138.0, 139.5, 140.0, 143.7, 153.5, 171.4. Anal. calcd. for
C34H33NO6: C 74.03, H 6.03, N 2.54; found: C 74.01, H
5.95, N 2.53.
>> >>
(3(3S),4R)-4-(Diphenylmethyl)-3-[3-(3,3-(phenyl)-(3 ,4 -
methylenedioxy-5 -methoxyphenyl)-propanoyl]-2-
(3(3S),4R)-4-(Diphenylmethyl)-3-[3-(3,3-(3>,4>-
methylenedioxyphenyl)-(phenyl)-propanoyl]-2-oxazolidinone
(29)
>>
oxazolidinone (25)
Yield: 90%; mp 146–148°C. [a]2D5 –140.0 (c 0.69,
Yield: 97%; mp 164–166°C. [a]2D5 –142.5 (c 0.56,
1
1
CH2Cl2). H NMR (500 MHz, CDCl3) d: 3.59 (dd, J = 17.3,
CH2Cl2). H NMR (500 MHz, CDCl3) d: 3.60 (dd, J = 17.5,
7.1 Hz, 1H), 3.70 (dd, J = 17.3, 8.1 Hz, 1H), 3.89 (s, 3H),
4.38 (m, 2H), 4.57 (t, J = 7.5 Hz, 1H), 4.63 (d, J = 5.0 Hz,
7.5 Hz, 1H), 3.67 (dd, J = 17.5, 7.4 Hz, 1H), 4.37 (m, 2H),
4.57 (t, J = 7.6 Hz, 1H), 4.63 (d, J = 5.2 Hz, 1H), 5.23 (m,
© 2001 NRC Canada

1552
Can. J. Chem. Vol. 79, 2001
1H), 5.92 (m, 2H), 6.77 (m, 3H), 6.93 (m, 2H), 7.05 (m,
2H), 7.26 (m, 11H). 13C NMR (125 MHz, CDCl3) d: 41.2,
46.0, 50.5, 56.6, 65.0, 101.2, 108.5, 108.8, 121.2, 126.8,
127.3, 127.9, 128.1, 128.5, 128.9, 129.1, 129.6, 137.9, 138.0,
139.7, 143.9, 146.4, 148.0, 153.7, 171.2. Anal. calcd. for
C32H27NO5: C 76.02, H 5.38, N 2.77; found: C 76.14, H
5.41, N 2.66.
16.9 Hz, 1H), 2.87 (dd, J = 10.9, 16.9 Hz, 1H), 3.61 (t, J =
8.5 Hz, 1H), 3.76 (s, 3H), 3.79 (s, 6H), 3.80 (d, J = 11 Hz,
1H), 3.82 (s, 3H), 3.87 (s, 6H), 4.12 (dd, J = 1.8, 7.3 Hz,
1H), 4.52 (dd, J = 2.4, 8.2 Hz, 1H), 4.65 (d, J = 2.5 Hz, 1H),
5.26 (ddd, J = 3.2, 3.5, 11.0 Hz, 1H), 6.48 (s, 2H), 6.64 (s,
2H), 6.93 (d, J = 6.9 Hz, 2H), 7.25 (m, 8H). 13C NMR
(100 MHz, CDCl3) d: 28.3, 37.7, 43.3, 50.1, 56.1, 56.3, 56.9,
57.2, 60.8, 60.9, 63.9, 81.1, 105.0, 126.9, 127.7, 128.1,
128.5, 128.8, 129.8, 136.3, 136.6, 137.2, 137.9, 140.2, 152.8,
153.3, 153.6, 171.3, 175.2. Anal. calcd. for C43H49NO11: C
68.33, H 6.53, N 1.85; found: C 67.97, H 6.45, N 1.76.
(3(3R),4R)-4-(Diphenylmethyl)-3-[3-(3,3-(3>,4>-methyl-
enedioxyphenyl)-(phenyl)-propanoyl]-2-oxazolidinone (30)
Yield: 95%; mp 78–81°C. [a]2D5 –142.2 (c 0.49, CH2Cl2).
1H NMR (500 MHz, CDCl3) d: 3.57 (dd, J = 17.6, 7.3 Hz,
1H), 3.69 (dd, J = 17.8, 7.8 Hz, 1H), 4.38 (m, 2H), 4.57 (t,
J = 7.5 Hz, 1H), 4.63 (d, J = 5.2 Hz, 1H), 5.25 (m, 1H), 5.90
(s, 2H), 6.76 (m, 3H), 6.92 (m, 2H), 7.05 (m, 2H), 7.27 (m,
11H). 13C NMR (125 MHz, CDCl3) d: 41.3, 46.0, 50.5, 56.6,
65.1, 101.2, 108.5, 108.7, 120.9, 126.9, 127.3, 127.9, 128.1,
128.5, 128.9, 129.1, 129.6, 137.9, 138.0, 139.7, 144.1, 146.3,
148.0, 153.7, 171.3. Anal. calcd. for C32H27NO5: C 76.02, H
5.38, N 2.77; found: C 76.20, H 5.32, N 2.87.
(3(2S),4R)-4-(Diphenylmethyl)-3-[bis-(3>,4>-methyl-
enedioxyphenyl)-methyl]-(4-oxo-butyric acid tert-butyl
ester)-2-oxazolidinone (20)
Yield: 74%; mp 104 to 105°C. [a]2D5 –252.3 (c 0.55,
CHCl3). Rf 0.62 (50:50, EtOAc:hexanes). 1H NMR
(400 MHz, CDCl3) d: 1.47 (s, 9H), 2.50 (dd, J = 3.2,
17.2 Hz, 1H), 2.82 (dd, J = 10.8, 17.2 Hz, 1H), 3.69 (t, J =
8.9 Hz, 1H), 3.85 (d, J = 11.3 Hz, 1H), 4.19 (d, J = 8.8 Hz,
1H), 4.69 (s, 2H), 5.18 (ddd, J = 3.2, 3.2, 11.0 Hz, 1H), 5.85
(m, 2H), 5.93 (s, 2H), 6.77 (m, 6H), 7.00 (d, J = 8.3 Hz,
2H), 7.28 (m, 8H). 13C NMR (100 MHz, CDCl3) d: 28.3,
37.4, 43.1, 50.2, 55.0, 57.0, 64.0, 81.0, 101.1, 107.8, 108.5,
108.7, 108.8, 121.3, 127.0, 127.6, 128.2, 128.4, 128.6, 128.8,
130.0, 134.6, 135.5, 138.1, 140.3, 146.4, 146.6, 147.5, 148.2,
152.9, 171.2, 175.1. Anal. calcd. for C39H37NO9: C 70.58, H
5.62, N 2.11; found: C 70.29, H 5.60, N 1.96.
Representative procedure for alkylation (compound 34)
To an oven-dried 250 mL three- neck round-bottomed
flask purged with N2 was added 10.5 g (16.78 mmol) of 26
and 120 mL of dry THF. The reaction mixture was cooled
to –78°C in an acetone –dry ice bath. To the mixture was
added 18.46 mL (18.46 mmol) of a 1 M NaHMDS–THF so-
lution dropwise over 20 min and the mixture was allowed to
stir for 1 h. To the solution was added 2.92 mL (20.14 mmol)
of tert-butyl iodoacetate dropwise over 6 min. The solution
was stirred at –78°C for 6 h. The reaction was quenched
with 20 mL NH4Cl. The reaction mixture was extracted with
ethyl acetate. The combined organics were washed with wa-
ter, followed by brine, and dried over MgSO4. Removal of
solvent under reduced pressure followed by flash column
purification of the crude mixture led to 9.3 g of the alkylated
product 34 (75% yield).
(3(2S),3(3S),4R)-4-(Diphenylmethyl)-3-[(3>,4>,5>-
>> >>
>>
trimethoxyphenyl)-(3 ,4 -methylenedioxy-5 -methoxyphenyl)-
methyl]-(4-oxo-butyric acid tert-butyl ester)-2-
oxazolidinone (34)
Yield: 75%; mp 231 to 232°C. [a]2D5 –251.4 (c 1.0,
CH2Cl2). Rf 0.46 (50:50, EtOAc:hexanes). 1H NMR
(400 MHz, CDCl3) d: 1.46 (s, 9H), 2.46 (dd, J = 3.2,
16.7 Hz, 1H), 2.82 (dd, J = 10.8, 16.9 Hz, 1H), 3.72 (t, J =
9.1 Hz, 1H), 3.81 (s, 3H), 3.82 (s, 3H), 3.83 (d, J = 11.3 Hz,
1H) 3.86 (s, 6H), 4.20 (d, J = 7.6 Hz, 1H), 4.68 (d, J =
3.5 Hz, 2H), 5.23 (m, 1H), 5.88 (m, 2H), 6.44 (d, J =
10.2 Hz, 2H), 6.57 (s, 2H), 6.98 (d, J = 7.3 Hz, 2H), 7.26
(m, 8H). 13C NMR (100 MHz, CDCl3) d: 28.3, 37.6, 43.1,
50.2, 56.2, 56.4, 57.1, 60.9, 64.1, 81.1, 101.6, 102.6, 104.9,
107.2, 127.0, 127.7, 128.2, 128.6, 128.8, 129.8, 134.0, 135.8,
136.4, 137.1, 138.0, 140.2, 143.2, 148.5, 153.1, 153.6, 171.2,
175.0. Anal. calcd. for C42H45NO11: C 68.19, H 6.13, N
1.89; found: C 67.94, H 6.09, N 1.92.
(3(2S),4R)-4-(Diphenylmethyl)-3-[bis-(3>,4>-methylenedioxy-
5>-methoxyphenyl)-methyl]-(4-oxo-butyric acid tert-butyl
ester)-2-oxazolidinone (18)
Yield: 64%; mp 189 to 190°C. [a]2D5 –289.9 (c 1.09,
CHCl3). Rf 0.63 (50:50, EtOAc:hexanes). 1H NMR (400 MHz,
CDCl3) d: 1.48 (s, 9H), 2.48 (dd, J = 3.2, 17.2 Hz, 1H), 2.82
(dd, J = 10.8, 17.2 Hz, 1H), 3.77 (m, 2H), 3.83 (s, 3H), 3.90
(s, 3H), 4.22 (d, J = 8.6 Hz, 1H), 4.70 (m, 2H), 5.17 (ddd,
J = 3.2, 3.8, 10.8 Hz, 1H), 5.93 (m, 4H), 6.42 (d, J = 5.9 Hz,
2H), 6.51 (s, 1H), 6.62 (s, 1H), 6.99 (d, J = 7.5 Hz, 2H),
7.28 (m, 8H). 13C NMR (100 MHz, CDCl3) d: 28.1, 37.3,
42.9, 50.1, 55.6, 56.3, 56.6, 56.9, 63.9, 80.9, 101.3, 101.4,
101.8, 102.4, 106.9, 107.7, 126.8, 127.5, 128.0, 128.4, 128.6,
129.6, 133.8, 134.2, 135.1, 135.8, 137.9, 140.0, 143.1, 143.6,
148.3, 149.2, 170.9, 174.8. Anal. calcd. for C41H41NO11: C
68.04, H 5.71, N 1.94; found: C 68.03, H 5.73, N 1.73.
(3(2S),3(3S),4R)-4-(Diphenylmethyl)-3-[(3>,4>,5>-
>> >>
trimethoxyphenyl)-(3 ,4 -methylenedioxyphenyl)-methyl]-(4-
oxo-butyric acid tert-butyl ester)-2-oxazolidinone (35)
Yield: 75%; mp 214 to 215°C. [a]2D5 –261.8 (c 1.0,
CH2Cl2). Rf 0.55 (50:50, EtOAc:hexanes). 1H NMR
(400 MHz, CDCl3) d: 1.47 (s, 9H), 2.46 (dd, J = 3.2,
16.9 Hz, 1H), 2.83 (dd, J = 11.0, 17.0 Hz, 1H), 3.62 (t, J =
8.3 Hz, 1H), 3.76 (s, 3H), 3.79 (s, 6H), 3.79 (d, J = 11.3 Hz,
1H), 4.12 (dd, J = 1.9, 8.9 Hz, 1H), 4.53 (dd, J = 2.7,
5.9 Hz, 1H), 4.66 (d, J = 2.7 Hz, 1H), 5.23 (ddd, J = 3.0,
3.5, 11.6 Hz, 1H), 5.94 (s, 2H), 6.42 (s, 2H), 6.78 (d, J =
8.0 Hz, 1H), 6.92 (m, 4H), 7.25 (m, 8H). 13C NMR
(100 MHz, CDCl3) d: 28.3, 37.6, 43.0, 50.1, 56.1, 57.2, 60.8,
(3(2S),4R)-4-(Diphenylmethyl)-3-[bis-(3>,4>,5>-
trimethoxyphenyl)-methyl]-(4-oxo-butyric acid tert-butyl
ester)-2-oxazolidinone (19)
Yield: 66%; mp 90 to 91°C. [a]2D5 –265.4 (c 0.95,
CH2Cl2). Rf 0.33 (50:50, EtOAc:hexanes). 1H NMR
(400 MHz, CDCl3) d: 1.46 (s, 9H), 2.46 (dd, J = 3.5,
© 2001 NRC Canada

Sibi et al.
1553
63.9, 81.0, 101.3, 104.9, 108.4, 108.7, 121.1, 126.9, 127.6,
128.1, 128.5, 128.8, 129.8, 134.5, 136.4, 137.1, 138.0, 140.2,
146.8, 148.2, 152.9, 153.2, 171.2, 175.2. Anal. calcd. for
C41H43NO10: C 69.38, H 6.11, N 1.97; found: C 69.17, H
6.17, N 1.99.
(3.26 mmol) of crude alcohol, 15 mg of PTSA, and 30 mL
of benzene. The solution was heated to reflux for 2.0 h be-
fore being allowed to cool to room temperature. The mixture
was washed with NaHCO3 and water before extracting with
ethyl acetate and drying over MgSO4. Removal of solvent
under reduced pressure followed by flash column purifica-
tion of the crude mixture led to 1.2 g of the lactone 36 (89%
yield).
General procedure for the LAH reduction–cyclization
(compounds 21 and 22)
To an oven-dried 25 mL two-neck round-bottomed flask
purged with N2 was added 1.00 g of 18 (1.38 mmol) of
alkylated product and 2 mL of dry THF. The reaction mix-
ture was cooled to –78°C in an acetone – dry ice bath. To
the solution was added 265 mg (6.99 mmol) of LAH in
7 mL of dry THF dropwise over 15 min. The reaction was
stirred at –78°C for 20 h before quenching with ethyl ace-
tate. The mixture was filtered through Celite and dried over
MgSO4. Removal of solvent under reduced pressure led to
the crude alcohol. The crude alcohol cyclized on standing
and (or) during column chromatography over silica gel.
Lactone (410 mg) was obtained after column chromatogra-
phy (74% yield for 21).
(4S)-4-[1-Bis(3>,4>-methylenedioxy-5>-methoxyphenyl)methyl]-
butyrolactone (21)
Overall yield over two steps: 74% (average of three runs);
mp 147 to 148°C. [a]D25 –9.2 (c 0.59, CH2Cl2). Rf 0.4 (50:50,
1
EtOAc:hexanes). H NMR (400 MHz, CDCl3) d: 2.26 (dd,
J = 7.5, 10.2 Hz, 1H), 2.59 (dd, J = 8.3, 9.4 Hz, 1H), 3.24
(m, 1H), 3.57 (d, J = 11.8 Hz, 1H), 3.89 (s, 6H), 3.96 (dd,
J = 6.4, 9.4 Hz, 1H), 4.28 (dd, J = 7.2, 9.4 Hz, 1H), 5.92
(two s, 4H), 6.39 (two s, 4H). 13C NMR (100 MHz, CDCl3)
d: 34.1, 40.1, 55.3, 57.0, 72.0, 101.1, 101.6, 107.7, 134.3,
136.4, 136.8, 143.7, 149.5, 176.5. Anal. calcd. for C21H20O8:
C 63.00, H 5.03; found: C 63.34, H 5.05.
(4S)-4-[1-Bis(3>,4>,5>-trimethoxyphenyl)methyl]-
butyrolactone (22)
General procedure for hydrolysis–reduction–cyclization
(for compounds 23, 36, 37)
To an oven-dried 250 mL three-neck round-bottomed flask
purged with N2 was added 3.00 g (4.05 mmol) of alkylated
product 34, 60 mL of THF, and 15 mL of H2O. The reaction
mixture was cooled to 0°C before the dropwise addition of
3.31 mL (32.4 mmol) of 30% H2O2 over 10 min. To the so-
lution was added 747 mg (17.82 mmol) of LiOH–H2O in
15 mL of H2O dropwise over 20 min. The reaction was
stirred at 0°C for 5 h before being allowed to warm to room
temperature and stirred for 14 h. The reaction was cooled to
0°C before quenching with 4.20 g of Na2SO3 in 20 mL of
H2O. The mixture was washed with H2O and extracted with
CH2Cl2. The aqueous layer was acidified to pH = 2 with
5 M HCl before extraction with ethyl acetate. The organic
extracts were not combined and both were dried over
MgSO4. Removal of solvent from the acid wash under re-
duced pressure led to 1.75 g of crude acid (86% yield).
Evaporation of the neutral fraction provided crude chiral
auxiliary.
Overall yield over two steps: 75% (average of three runs);
mp 168 to 169°C. [a]2D5 –13.0 (c 1.0, CHCl3). Rf 0.16 (50:50,
1
EtOAc:hexanes). H NMR (400 MHz, CDCl3) d: 2.26 (dd,
J = 7.5, 17.8 Hz, 1H), 2.59 (dd, J = 8.0, 18.0 Hz, 1H), 3.32
(m, 1H), 3.64 (d, J = 11.8 Hz, 1H), 3.80 (s, 6H), 3.84 (s,
12H), 3.98 (dd, J = 6.7, 9.4 Hz, 1H), 4.27 (dd, J = 7.2,
9.4 Hz, 1H), 6.45 (s, 4H). 13C NMR (100 MHz, CDCl3) d:
31.9, 38.1, 53.7, 54.2, 58.8, 70.0, 102.7, 135.5, 135.9, 151.8,
174.9. Anal. calcd. for C23H28O8: C 63.88, H 6.53; found: C
63.56, H 6.30.
(4S)-4-[1-Bis(3>,4>-methylenedioxyphenyl)methyl]-
butyrolactone (23)
Overall yield over three steps: 56% (average of three runs);
mp 66 to 67°C. [a]D25 –4.3 (c 1.0, CH2Cl2). Rf 0.44 (50:50,
1
EtOAc:hexanes). H NMR (400 MHz, CDCl3) d: 2.24 (dd,
J = 8.1, 18.0 Hz, 1H), 2.56 (dd, J = 8.6, 18.0 Hz, 1H), 3.27
(m, 1H), 3.64 (d, J = 11.6 Hz, 1H), 3.94 (dd, J = 7.0, 9.4,
1H), 4.25 (dd, J = 7.5, 9.4 Hz, 1H), 5.90 (two s, 4H), 6.70
(m, 6H). 13C NMR (100 MHz, CDCl3) d: 31.1, 34.1, 40.0,
54.8, 72.2, 101.2, 107.7, 108.6, 120.5, 120.6, 128.4, 135.9,
136.4, 146.6, 146.7, 148.2,176.7. Anal. calcd. for C19H16O6:
C 67.06, H 4.74; found: C 67.25, H 4.96.
General procedure for the borane reduction
To an oven-dried 100 mL three-neck round-bottomed
flask purged with N2 was added 1.90 g (3.77 mmol) of crude
acid and 50 mL of dry THF. The reaction mixture was
cooled to –10°C in an acetone – ice bath. To the solution
was added 7.54 mL (7.54 mmol) of a 1 M BH3–THF so-
lution dropwise over 15 min. The reaction was stirred at
–10°C for 6 h before warming to room temperature and
stirred for 14 h. The reaction was quenched with 4 mL of a
1:1 solution of acetic acid and water. The aqueous layer was
washed with a cold saturated solution of NaHCO3 and ex-
tracted with ethyl acetate while being dried over MgSO4.
Removal of solvent under reduced pressure led to 1.43 g of
crude alcohol (75% yield).
>> >>
(4(1S),4S)-4-[1,1-(3>,4>,5>-Methoxyphenyl)-(3 ,4 -
>>
methylenedioxy-5 -methoxyphenyl)methyl]-butyrolactone (36)
Overall yield over three steps: 57% (average of three runs);
mp 77 to 78°C. [a]2D5 –12.8 (c 0.9, CH2Cl2). Rf 0.20 (50:50,
1
EtOAc:hexanes). H NMR (400 MHz, CDCl3) d: 2.26 (dd,
J = 7.5, 17.7 Hz, 1H), 2.59 (dd, J = 8.0, 17.7 Hz, 1H), 3.29
(m, 1H), 3.61 (d, J = 11.8 Hz, 1H), 3.80 (s, 3H), 3.84 (s,
6H), 3.90 (s, 3H), 3.98 (dd, J = 6.4, 9.4 Hz, 1H), 4.28 (dd,
J = 7.0, 9.4 Hz, 1H), 5.93 (d, J = 2.7 Hz, 2H), 6.41 (m, 4H).
13C NMR (100 MHz, CDCl3) d: 27.4, 34.1, 40.1, 55.5, 56.3,
57.0, 60.9, 72.1, 101.1, 101.6, 104.5, 107.8, 134.3, 136.4,
137.1, 137.9, 143.7, 149.5, 153.5, 176.6. Anal. calcd. for
C22H24O8: C 63.45, H 5.81; found: C 63.39, H 6.04.
Lactonization
To an oven-dried 50 mL two-neck round- bottomed flask
set up with a condenser purged with N2 was added 1.60 g
© 2001 NRC Canada

1554
Can. J. Chem. Vol. 79, 2001
1
>> >>
(4(1S),4S)-4-[1,1-(3>,4>,5>-Methoxyphenyl)-5-(3 ,4 -
methylenedioxyphenyl)methyl]-butyrolactone (37)
0.50 (50:50, EtOAc:hexanes). H NMR (400 MHz, CDCl3)
d: 0.89 (d, J = 7.3 Hz, 3H), 2.33 (m, 1H), 2.87 (m, 1H), 3.63
(d, J = 11.2 Hz, 1H), 3.76 (dd, J = 8.2, 9.4 Hz, 1H), 4.28
(dd, J = 7.6, 9.4 Hz, 1H), 5.90 (s, 4H), 6.70 (m, 6H). 13C
NMR (100 MHz, CDCl3) d: 15.8, 40.4, 47.3, 55.7, 70.5,
101.2, 107.7, 107.8, 108.6, 108.7, 120.4, 120.8, 135.7, 136.3,
146.7, 148.2, 148.3, 179.8. Anal. calcd. for C20H18O6: C
67.68, H 5.12; found: C 67.21, H 5.08.
Overall yield over three steps: 56% (average of three runs);
mp 69 to 70°C. [a]D25 –4.6 (c 1.0, CH2Cl2). Rf 0.26 (50:50,
1
EtOAc:hexanes). H NMR (400 MHz, CDCl3) d: 2.25 (dd,
J = 8.6, 17.7 Hz, 1H), 2.56 (dd, J = 9.1, 17.7 Hz, 1H), 3.30
(m, 1H), 3.64 (d, J = 11.6 Hz, 1H), 3.78 (s, 3H), 3.82 (s,
6H), 3.94 (dd, J = 7.0, 16.4 Hz, 1H), 4.25 (dd, J = 9.4,
19.1 Hz, 1H), 5.90 (m, 2H), 6.41 (s, 2H), 6.71 (m, 3H). 13C
NMR (100 MHz, CDCl3) d: 34.1, 40.0, 55.3, 56.3, 60.9,
72.1, 101.3, 104.4, 107.7, 108.6, 120.5, 128.4, 135.6, 136.1,
137.0, 137.7, 138.1, 146.8, 148.2, 153.5, 176.6. Anal. calcd.
for C21H22O7: C 65.28, H 5.74; found: C 64.81, H 5.46.
(3S,4S,5R)-3-Methyl-4-[1,1-(3>,4>,5>-methoxyphenyl)-5-
(3 ,4 -methylenedioxy-5 -methoxyphenyl)methyl]-
butyrolactone (peperomin analog (1d))
>> >>
>>
The minor diastereomer could not be separated. Chemical
shifts for the major compound are reported. Yield: 80%; mp
84 to 85°C. [a]2D5 13.9 (c 0.49, CHCl3). Rf 0.26 (50:50,
EtOAc:hexanes). 1H NMR (400 MHz, CDCl3) d: 0.93 (d, J =
7.3 Hz, 3H), 2.35 (m, 1H), 2.90 (m, 1H), 3.61 (d, J =
11.3 Hz, 1H), 3.80 (s, 3H), 3.80 (overlapping with OMe
peaks, dd, 1H) 3.84 (s, 6H), 3.90 (s, 3H), 4.30 (dd, J = 7.6,
9.7 Hz, 1H), 5.94 (s, 2H), 6.41 (d, J = 1.6 Hz, 1H), 6.44 (s,
2H), 6.48 (d, J = 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d: 16.0, 40.3, 47.3, 56.3, 56.4, 57.1, 61.0, 70.4, 101.2, 101.6,
104.7, 107.9, 128.4, 134.4, 136.2, 137.3, 137.7, 143.7, 149.5,
153.6, 179.7. Anal. calcd. for C23H26O8: C 64.18, H 6.01;
found: C 64.14, H 5.55.
Representative methylation procedure (compound 1d)
To an oven-dried 25 mL two-neck round-bottomed flask
purged with N2 was added 400 mg (0.961 mmol) of the
lactone 36 and 7 mL of dry THF. The reaction mixture was
cooled to –78°C in an acetone – dry ice bath. To the mixture
was added 1.15 mL (1.15 mmol) of a 1 M NaHMDS–THF
solution dropwise over 3 min and the mixture was allowed to
stir for 50 min. To the solution was added 0.12 mL
(1.92 mmol) of methyl iodide over 1 min. The solution was
stirred at –78°C for 5 h. The reaction was quenched with
1 mL NH4Cl. The reaction mixture was extracted with ethyl
acetate. The combined organics were washed with water,
followed by brine, and dried over MgSO4. Removal of sol-
vent under reduced pressure followed by flash column puri-
fication of the crude mixture led to 331 mg of the natural
product peperomin B (1d) along with the diastereomer (80%
yield).
(3S,4S,5R)-3-Methyl-4-[1,1-(3>,4>,5>-methoxyphenyl)-5-
(3 ,4 -methylenedioxyphenyl)methyl]-butyrolactone
>> >>
(peperomin analog (1e))
The minor diastereomer could not be separated. Chemical
shifts for the major compound are reported. Yield: 80%; mp
181 to 182°C. [a]2D5 35.3 (c 0.17, CHCl3). Rf 0.34 (50:50,
EtOAc:hexanes). 1H NMR (400 MHz, CDCl3) d: 0.93 (d, J =
7.2 Hz, 3H), 2.35 (m, 1H), 2.90 (m, 1H), 3.63 (d, J =
11.3 Hz, 1H), 3.79 (s, 3H), 3.80 (overlapping with OMe
peaks, dd, 1H), 3.83 (s, 6H), 4.28 (dd, J = 7.6, 9.6 Hz, 1H),
5.92 (s, 2H), 6.43 (s, 2H), 6.74 (s, 3H). 13C NMR
(100 MHz, CDCl3) d: 15.9, 40.4, 47.2, 56.2, 56.3, 60.9, 70.4,
101.3, 104.7, 107.8, 108.7, 120.5, 135.5, 137.2, 137.9,
146.8, 148.3, 153.5, 179.8. Anal. calcd. for C22H24O7: C
65.99, H 6.04; found: C 65.92, H 5.86.
(3S,4S)-3-Methyl-4-[1-bis(3>,4>-methylenedioxy-5>-
methoxyphenyl)methyl]-butyrolactone (peperomin A (1a))
Yield: 98%; mp 143 to 144°C (abs. EtOH) (lit. (1) 143–
145°C). [a]2D5 22.7 (c 0.13, CHCl3) (lit. (1) [a]2D7 20.6 (c
0.14, CHCl3)). Rf 0.5 (50:50, EtOAc:hexanes). 1H NMR
(400 MHz, CDCl3) d: 0.94 (d, J = 7.2 Hz, 3H), 2.34 (m, 1H),
2.84 (m, 1H), 3.57 (d, J = 11.3 Hz, 1H), 3.80 (dd, J = 7.8,
9.7 Hz, 1H), 3.89 (s, 6H), 4.30 (dd, J = 7.5, 9.6 Hz, 1H),
5.93 (s, 4H), 6.38–6.44 (m, 4H). 13C NMR (100 MHz,
CDCl3) d: 15.9, 40.3, 47.3, 56.2, 57.0, 70.4, 101.2, 101.4,
101.6, 107.7, 134.3, 136.2, 136.8, 143.6, 149.4, 179.7. Anal.
calcd. for C22H22O8: C 63.76, H 5.35; found: C 63.84, H 5.22.
Acknowledgement
We thank the National Institutes of Health (CA-60030) for
financial support. We would also like to thank Dr. Jianxie
Chen and Shankar Manyem for experimental assistance.
(3S,4S)-3-Methyl-4-[1-bis(3>,4>,5>-trimethoxyphenyl)methyl]-
butyrolactone (peperomin C (1b))
Yield: 98%; mp 156 to 157°C (EtOAC–hexane), (lit.
(1) 158–160°C). [a]D25 43.3 (c 0.06, CHCl3) (lit. (1) [a]D27
1
42.7 (c 0.06, CHCl3)). Rf 0.22 (50:50, EtOAc:hexanes). H
References
NMR (400 MHz, CDCl3) d: 0.94 (d, J = 7.2 Hz, 3H), 2.37
(m, 1H), 2.92 (m, 1H), 3.64 (d, J = 11.3 Hz, 1H), 3.81 (s,
6H), 3.83 (m, 1H), 3.84 (s, 6H), 3.86 (s, 6H), 4.30 (dd, J =
7.8, 9.7 Hz, 1H), 6.48 (s, 4H). 13C NMR (100 MHz, CDCl3)
d: 15.9, 40.4, 47.5, 56.3, 56.7, 61.0, 70.5, 104.7, 104.9, 137.2,
137.4, 137.6, 153.6, 179.7. Anal. calcd. for C24H30O8: C
64.56, H 6.77; found: C 64.29, H 6.40.
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