An expeditious enantiospecific total synthesis of (-)-crassalactone C

Article abstract of DOI:10.1055/s-0032-1318303

A concise and expeditious approach for the total synthesis of bioactive styryllactone (-)-crassalactone C is presented from tartaric acid. The main features of the synthesis include the desymmetrization of dimethylamide of tartaric acid and the effective use of cinnamoyl ester as a protecting group as well as a reactant in the ring-closing metathesis reaction. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318303

PAPER
▌785
paper
An Expeditious Enantiospecific Total Synthesis of (–)-Crassalactone C
Total Synthesis of (–)-Crassalactone C
Kavirayani R. Prasad,* S. Mothish Kumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore, 560 012, India
E-mail: prasad@orgchem.iisc.ernet.in
Received: 31.12.2012; Accepted after revision: 31.01.2013
cinnamoylation. We reasoned that the bis-cinnamoyl ester
5 evades the selective cinnamoylation of the benzylic hy-
droxy group and offers advantage in the RCM reaction to
form the lactone 4 (Scheme 1), which can be elaborated to
Abstract: A concise and expeditious approach for the total synthe-
sis of bioactive styryllactone (–)-crassalactone C is presented from
tartaric acid. The main features of the synthesis include the desym-
metrization of dimethylamide of tartaric acid and the effective use
of cinnamoyl ester as a protecting group as well as a reactant in the crassalactone C (2) by intramolecular Michael addition of
ring-closing metathesis reaction.
the hydroxy group to the unsaturated lactone. γ-Hydroxy-
amide 6 was chosen as an appropriate precursor for the
synthesis of the bis-cinnamoyl ester 5.
Key words: crassalactone C, natural products, stereoselective syn-
thesis, styryllactone
O
Ph
Crassalactones B (1) and C (2) (Figure 1) are a class of
styryllactones isolated from a cytotoxic ethyl acetate sol-
uble extract of the leaves and twigs of Polyalthia crassa.1
Crassalactones are derivatives of goniofufurone (3), a fu-
rano-furan natural product isolated from Annonacae sp. In
general, styryllactones were found to exhibit varied bioac-
tivity including anti-tumor activity.2 Crassalactone C (2)
was the subject of synthetic investigation and five total
syntheses have been reported for this natural product.
Popsavin et al. reported the first total synthesis of crassa-
lactone C in a multistep sequence from D-xylose.3 Later
the same group reported three new syntheses from D-xy-
lose or D-glucose.4 Sharma and Mallesham disclosed the
synthesis of crassalactone C from diacetone D-glucose in-
volving a series of steps.5 We have been interested in the
synthesis of styryllactone and other related natural prod-
ucts from chiral pool tartaric acid and our efforts have cul-
minated in the synthesis of a number of styryllactone
natural products.6 Herein, we disclose a concise and expe-
ditious approach for the total synthesis of (–)-crassalac-
tone C.
O
HO
HO
HO
H
H
O
O
Ph
O
O
O
Ph
O
Ph
(–)-crassalactone C (2)
O
4
O
O
O
Ph
Ph
OH
O
O
O
Ph
NMe2
O
O
6
O
5
Scheme 1 Retrosynthesis for crassalactone C (2)
At the outset, the synthetic sequence commenced with the
synthesis of γ-hydroxyamide 6 from the bis-N,N-dimeth-
ylamide 7 of tartaric acid. Although desymmetrization of
tartaric acid amide with alkyl and aryl Grignard reagents
was facile,7 desymmetrization with vinylmagnesium bro-
mide turned out to be a formidable task. After a series of
optimization reactions, it was found that the addition of
1.2 equivalents of vinylmagnesium bromide to 7 fur-
nished the product amide 8 in 71% yield. However, the
amide 8 was found to be stable at room temperature for
few hours only. Storing the amide for a longer time either
at room temperature or in refrigerator led to the formation
of an unidentifiable white precipitate. Reduction of the
keto group in the amide 8 was also a delicate reaction. The
optimized reduction condition turned out to be the addi-
tion of a mixture of sodium borohydride/cerium(III) chlo-
ride to a solution of the amide in methanol, which
furnished the product alcohol 6 as a single diastereomer.8
Addition of sodium borohydride to a methanol solution of
OR2
H
O
H
O
O
H
OR1
R1 = cinnamoyl, R2 = H; crassalactone B (1)
R
R
1 = H, R2 = cinnamoyl; crassalactone C (2)
1 = R2 = H = goniofufurone (3)
Figure 1 Crassalactone B and C and goniofufurone
Although, crassalactones are cinnamoyl esters of goniofu-
furone, the main problem in the conversion of goniofufu-
rone (3) into crassalactone C (2) is regioselective
SYNTHESIS 2013, 45, 0785–0790
Advanced online publication: 21.02.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1318303; Art ID: SS-2012-T1007-OP
© Georg Thieme Verlag Stuttgart · New York

786
K. R. Prasad, S. M. Kumar
PAPER
8 pre-complexed with cerium(III) chloride produced the
alcohol 10 as a mixture of diastereomers. We presumed
that the alcohol 10 was formed by Michael addition of
methanol to the unsaturated ketone resulting in the ketone
9 which on subsequent reduction with sodium borohy-
dride resulted in the alcohol 10 (Scheme 2).9 This was
confirmed by isolation of the ketone 9 by reaction of 8
with methanol in presence of cerium(III) chloride.
OH
OH
Ph
O
O
O
O
PhMgBr (3 equiv), THF
NMe2
–15 °C, 0.5 h
74%
O
O
11
6
OH
OH
O
O
NaBH4
+
Ph
Ph
O
MeOH, –78 °C
NMe2
NMe2
O
4 h
O
O
O
O
97%
OH
OH
O
O
O
O
MgBr
13 (major)
12 (minor)
THF, –15 °C, 0.5 h
71%
OTBS
NMe2
i) TBDMSCl, imidazole, DMAP
O
O
CH2Cl2, reflux, 6 h, 83 %
8
7
6
Ph
ii) PhMgBr, THF, –15 °C, 0.5 h
98%
NMe2
O
O
O
O
addition of a mixture of NaBH4 and CeCl3
to a MeOH solution of 3, –78 °C, 30 min
87%
14
OH
OTBS
OTBS
O
O
O
O
NaBH4/CeCl3
6
+
Ph
Ph
MeOH, –78 °C, 0.5 h
dr = 78:22
NMe2
O
NMe2
OH
OH
O
15 (71%)
16 (13%)
O
O
CeCl3, MeOH
r.t., 0.5 h
80%
NaBH4/CeCl3
MeOH, −78 °C
30 min, 58%
8
OH
O
O
O
O
O
HF/Py, THF
r.t., 12 h, 93%
MeO
OH OMe
15
Ph
10
9
OH
12
Scheme 2 Synthesis of γ-hydroxyamide 6
Scheme 3 Synthesis of 1,4-diol 12
After establishing the procedure for the synthesis of γ-hy-
droxyamide 6 in good yield, application of the amide in
the synthesis of crassalactone C was undertaken. Thus,
addition of phenylmagnesium bromide to 6 furnished the
hydroxy ketone 11 in 74% yield. Reduction of the ketone
in 11 with sodium borohydride produced a separable mix-
ture of 1,4-diols 12 and 13 in 25:75 ratio in which the al-
cohol 13 was the major isomer. Reduction of the hydroxy
ketone 11 pre-complexed to cerium(III) chloride with so-
dium borohydride did not change the outcome of the reac-
tion. Taking a cue from our earlier studies on the
reduction of γ-hydroxy ketones similar to 11 derived from
tartaric acid,10 we reasoned that the siloxy ketone 14
would perhaps mitigate the 1,4-induction and can exert
exclusive 1,2-stereocontrol in the reduction leading to the
required diastereomer. This was indeed the case and the
reduction of siloxy ketone 14 pre-complexed to ceri-
um(III) chloride with sodium borohydride produced the
alcohols 15 and 16 in 78:22 ratio. The major diastereomer
15 was isolated in 71% yield. As expected, simple reduc-
tion of the ketone 14 with sodium borohydride without the
presence of cerium(III) chloride reversed the selectivity
and produced the diastereomeric alcohols 15 and 16 in
19:81 ratio. Deprotection of the tert-butyldimethylsilyl
ether in 15 with hydrogen fluoride–pyridine gave the 1,4-
diol 12 in 93% yield (Scheme 3).
Cinnamoylation of the diol 12 afforded the bis-cinnamoyl
ester 5 in 99% yield. Ring-closing metathesis reaction of
5 with Grubbs’ second-generation catalyst (Grubbs II) re-
sulted in the butyrolactone 17 in 92% yield. Deprotection
of the acetonide in 17 afforded the 1,2-diol 4 (85% yield),
which on reaction with DBU furnished (–)-crassalactone
C (2) in 61% yield (Scheme 4).11 The spectral and physi-
cal data of the synthesized crassalactone C are in complete
agreement with that reported in literature.1,3
Following a similar sequence 1,4-diol 13 was elaborated
to 7-epi-crassalactone C (18) (see Scheme 5 and Support-
ing Information for the synthesis).
In conclusion, a facile, concise and expeditious enantio-
specific synthesis of crassalactone C has been accom-
plished in 15% overall yield from the dimethylamide of
tartaric acid in 10 linear steps. The main features of the
synthesis are desymmetrization of tartaric acid amide with
vinylmagnesium bromide and subsequent elaboration.
The synthesis also showcased the effective use of cinnam-
oyl ester which negated the use of additional protecting
groups.
Synthesis 2013, 45, 785–790
© Georg Thieme Verlag Stuttgart · New York

PAPER
Total Synthesis of (–)-Crassalactone C
787
of the solvent gave a residue that was purified by column chroma-
tography (silica gel, PE–EtOAc, 1:1) to yield 8 (0.59 g, 71%) as a
colorless oil; [α]D22 +4.0 (c 0.6, CHCl3).
IR (neat): 2940, 1705, 1654, 1501, 1404, 1260, 1154 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.74–6.70 (m, 1 H), 6.45 (dd, J =
17.5, 1.3 Hz, 1 H), 5.88 (dd, J = 10.6, 1.3 Hz, 1 H), 5.39–5.37 (m, 1
H), 4.87 (d, J = 5.5 Hz, 1 H), 3.14 (s, 3 H), 2.98 (s, 3 H), 1.43 (s, 3
H), 1.40 (s, 3 H).
O
O
O
Ph
Ph
O
O
cinnamoyl chloride
12
Ph
Et3N, DMAP, CH2Cl2, r.t., 12 h
99%
O
5
O
13C NMR (100 MHz, CDCl3): δ = 197.3, 168.0, 132.4, 130.8, 112.3,
O
80.9, 75.2, 37.0, 35.9, 26.3, 26.1.
4 M HCl, THF
O
Grubbs II cat.
HRMS: m/z [M + Na] calcd for C11H17NNaO4: 250.1055; found:
250.1052.
r.t., 48 h
85%
Ph
CH2Cl2, reflux, 20 h
O
92%
(2R,3S,4R)-4-Hydroxy-2,3-(isopropylidenedioxy)-N,N-dimeth-
ylhex-5-enamide (6)
OR
R = cinnamoyl
17
A soln of CeCl3·7 H2O (2.3 g, 6.22 mmol) dissolved in MeOH (20
mL) was cooled to 0 °C, and to this NaBH4 (0.32 g, 8.3 mmol) was
added portionwise and the mixture was allowed to stir for 10 min.
The resultant mixture was then transferred to a flask containing 8
(0.44 g, 1.93 mmol) in MeOH (15 mL) at –78 °C through a dropper
and the mixture was stirred at this temperature for 0.5 h. When the
reaction was complete (TLC monitoring), it was cautiously
quenched by the addition of H2O (3 mL) and extracted with EtOAc
(3 × 20 mL). The combined organic layers were washed with brine
(20 mL), dried (anhyd Na2SO4), and concentrated. Evaporation of
the solvent gave a crude residue that was purified by column chro-
matography (silica gel, PE–EtOAc, 2:3) to give 6 (0.38 g, 87%) as
a colorless oil; [α]D22 +6.7 (c 1.6, CHCl3).
Ph
O
O
O
HO
H
HO
HO
DBU
O
O
O
THF, r.t., 6 h
61%
Ph
O
H
Ph
OR
4
(–)-crassalactone C (2)
Scheme 4 Total synthesis of crassalactone C (2)
Ph
IR (neat): 3425, 2988, 1646, 1500, 1380, 1257 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.96 (ddd, J = 17.2, 10.5, 5.1 Hz,
1 H), 5.39 (d, J = 17.2 Hz, 1 H), 5.24 (d, J = 10.8 Hz, 1 H), 4.66 (dd,
J = 7.3, 3.4 Hz, 1 H), 4.50 (d, J = 7.3 Hz, 1 H), 4.25 (br s, 1 H), 3.13
(s, 3 H), 2.96 (s, 3 H), 2.78 (br s, 1 H), 1.44 (s, 3 H), 1.38 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.0, 137.1, 116.5, 110.5, 79.9,
74.4, 71.1, 37.1, 35.9, 26.8, 26.1.
HO
H
H
same as in
Scheme 4
O
O
13
O
O
O
Ph
7-epi-crassalactone C (18)
Scheme 5 Total synthesis of 7-epi-crassalactone C (18)
HRMS: m/z [M + Na] calcd for C11H19NNaO4: 252.1212; found:
252.1210.
(2R,3R)-2,3-(Isopropylidenedioxy)-N,N-dimethyl-6-methoxy-4-
oxohexanamide (9)
To stirred soln of 8 (45 mg, 0.12 mmol) in MeOH (1 mL) was added
CeCl3·7 H2O (110 mg, 0.3 mmol) and the mixture was allowed to
stir at r.t. for 0.5 h. When the reaction was complete (TLC monitor-
ing), it was diluted with H2O (5 mL) and extracted with EtOAc (3 ×
10 mL). The combined organic layers were washed with brine (10
mL), dried (anhyd Na2SO4), and concentrated. Evaporation of the
solvent gave a crude residue that was purified by column chroma-
tography (silica gel, PE–EtOAc, 4:6) to give 9 (41 mg, 80%) as a
colorless oil; [α]D22 +12.6 (c 1.4, CHCl3).
NMR spectra were recorded on a Bruker 400 instrument and MS
data were recorded on a Waters Q-TOF machine. Optical rotations
were recorded on Jasco-DIP digital polarimeter and IR spectra were
recorded on a Jasco infrared spectrophotometer. Melting points
were uncorrected. Column chromatography was performed on sili-
ca gel, Acme grade 100–200 mesh; PE (petroleum ether) refers to
the fraction boiling between 60 and 80 °C. TLC plates were visual-
ized either with UV, in an iodine chamber, or with phosphomolyb-
dic acid spray, unless noted otherwise. Unless stated otherwise, all
reagents were purchased from commercial sources and used with-
out additional purification. THF was freshly distilled over Na/ben-
zophenone ketyl and toluene was distilled over P2O5. Unless stated
otherwise, all the reactions were performed under an inert atmo-
sphere.
IR (neat): 2988, 2935, 1722, 1656, 1382, 1259, 1156, 1087, 861
cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.15 (d, J = 5.8 Hz, 1 H), 4.82 (d,
J = 5.8 Hz, 1 H), 3.67–3.63 (m, 2 H), 3.30 (s, 3 H), 3.11 (s, 3 H),
2.96 (s, 3 H), 2.94–2.76 (m, 2 H), 1.41 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 207.5, 168.2, 112.3, 82.3, 74.7,
66.9, 58.8, 39.4, 37.0, 36.1, 26.3, 26.0.
(2R,3R)-2,3-(Isopropylidenedioxy)-N,N-dimethyl-4-oxohex-5-
enamide (8)
To a 2-necked, 100-mL, round bottomed flask equipped with a
magnetic stirbar, rubber septum, and argon inlet was added 7 (0.9 g,
3.68 mmol). This was dissolved in anhyd THF (18 mL) and the soln
was cooled to –15 °C. A freshly prepared soln of 0.3 M vinylmag-
nesium bromide in THF (18 mL, 5.4 mmol) was added at such a rate
that the internal temperature did not rise above –10 °C. When the re-
action was complete (~0.5 h, TLC monitoring), it was cautiously
quenched by the addition of cold 1 M HCl (20 mL) and extracted
with EtOAc (3 × 25 mL). The combined organic extracts were
washed with brine (20 mL) and dried (anhyd Na2SO4). Evaporation
HRMS: m/z [M + Na] calcd for C12H21NNaO5: 282.1317; found:
282.1316.
(2R,3S,4R/S)-4-Hydroxy-2,3-(isopropylidenedioxy)-N,N-di-
methyl-6-methoxyhexanamide (10)
To a soln of 8 (0.2 g, 0.88 mmol) in MeOH (5 mL) was added
CeCl3·7 H2O (0.49 g, 1.32 mmol) at r.t. and the mixture was stirred
at this temperature for 1 h. The mixture was cooled to –78 °C and
NaBH4 (0.067 g, 1.76 mmol) was added portionwise over a period
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 785–790

788
K. R. Prasad, S. M. Kumar
PAPER
of 20 min and it was stirred at –78 °C. When the reaction was com-
plete (TLC monitoring) it was cautiously quenched by addition of
H2O (1 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with brine (10 mL), dried (anhyd
Na2SO4), and concentrated. Evaporation of the solvent gave a crude
residue that was purified by column chromatography (silica gel,
PE–EtOAc, 4:6) to give the alcohol 10 (dr 3:2) (0.12 g, 58%); [α]D
+28.0 (c 1.0, CHCl3).
IR (KBr): 3447, 2987, 2935, 1653, 1382, 1159, 1114, 886 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.66–4.51 (m, 2 H), 3.96–3.84 (m,
0.4 H), 3.87–3.77 (br s, 0.6 H), 3.72–3.47 (m, 2 H), 3.35 (s, 3 H),
3.29 (br s, 0.4 H), 3.16 (s, 1.2 H), 3.14 (s, 1.8 H), 2.97 (s, 1.2 H),
2.96 (s, 1.8 H), 2.75 (br d, J = 6.1 Hz, 0.6 H), 1.86–1.80 (m, 2 H),
1.45 (s, 1.8 H), 1.43 (s, 1.2 H), 1.39 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.31 (m, 5 H), 5.62 (ddd, J =
17.2, 10.8, 6.0 Hz, 1 H), 5.13 (d, J = 17.2, 1 H), 5.08 (d, J = 10.4 Hz,
1 H), 4.66 (d, J = 5.6 Hz, 1 H), 4.18 (t, J = 7.0 Hz, 1 H), 3.87 (dd,
J = 7.6, 3.6 Hz, 1 H), 3.44 (br s, 1 H), 3.00 (br s, 1 H), 2.32 (br d,
J = 6.0 Hz, 1 H), 1.44 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 139.4, 136.9, 128.6, 128.5, 126.9,
116.6, 110.1, 81.1, 80.1, 75.0, 71.6, 27.4, 27.3.
22
HRMS: m/z [M + Na] calcd for C15H20NaO4: 287.1259; found:
287.1256.
Minor Diastereomer 12
[α]D22 +29.7 (c 2.5, CHCl3).
IR (neat): 3402, 2988, 2931, 2905, 1633, 1597, 1380, 1246, 1217,
1073, 702 cm–1.
13C NMR (100 MHz, CDCl3): δ (major) = 168.8, 110.2, 80.4, 74.0,
70.2, 68.5, 58.8, 36.9, 35.7, 33.9, 26.7, 26.1; δ (minor) = 169.5,
110.2, 80.1, 74.8, 70.6, 70.4, 58.7, 37.1, 35.9, 33.0, 26.8, 26.0.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.28 (m, 5 H), 5.73 (ddd, J =
16.8, 10.8, 5.4 Hz, 1 H), 5.16–5.08 (m, 2 H), 4.90 (d, J = 5.2 Hz, 1
H), 4.20 (dd, J = 7.6, 5.2 Hz, 1 H), 4.06 (dd, J = 8.0, 2.4 Hz, 1 H),
3.40 (br s, 1 H), 3.02 (br s, 1 H), 2.53 (br d, J = 6.8 Hz, 1 H), 1.43
(s, 3 H), 1.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 139.1, 137.4, 128.5, 128.1, 126.1,
115.9, 109.5, 79.9, 79.4, 72.7, 71.1, 27.2, 27.1.
HRMS: m/z [M + Na] calcd for C12H23NNaO5: 284.1474; found:
284.1471.
(2S,3S,4R)-2,3-(Isopropylidenedioxy)-4-hydroxy-1-phenylhex-
5-en-1-one (11)
HRMS: m/z [M + Na] calcd for C15H20NaO4: 287.1259; found:
287.1252.
In a two-necked, 25 mL round-bottomed flask equipped with a mag-
netic stirbar, rubber septum, and argon inlet was placed 6 (0.1 g,
0.44 mmol). This was dissolved in anhyd THF (3 mL) and the soln
was cooled to –15 °C. A freshly prepared soln of 0.7 M PhMgBr in
THF (2 mL, 1.31 mmol) was added at such a rate that the internal
temperature did not rise above –15 °C. When the reaction was com-
plete (~0.5 h, TLC monitoring), it was cautiously quenched by the
addition of sat. NH4Cl soln (10 mL) and extracted with EtOAc (2 ×
15 mL). The combined organic extract was washed with brine (10
mL) and dried (anhyd Na2SO4). Evaporation of the solvent gave a
residue that was purified by column chromatography (silica gel,
PE–EtOAc, 3:2) to yield 11 (85 mg, 74%) as a colorless oil; [α]D
–34.5 (c 2.4, CHCl3).
(2R,3R,4R)-4-(tert-Butyldimethylsiloxy)-2,3-(isopropylidene-
dioxy)-N,N-dimethylhex-5-enamide
To a soln of the alcohol 6 (0.14 g, 0.63 mmol) in anhyd CH2Cl2 (3
mL) were added imidazole (0.13 g, 1.89 mmol), DMAP (0.015 g,
0.12 mmol), and TBDMSCl (0.19 g, 1.26 mmol). The resulting
mixture was refluxed for 6 h. When the reaction was complete (TLC
monitoring), the mixture was poured into H2O (10 mL) and extract-
ed with Et2O (3 × 10 mL). The combined ethereal layers were
washed with brine (15 mL) and dried (anhyd Na2SO4). The residue
obtained after evaporation of the solvent was purified by column
chromatography (PE–EtOAc, 1:1) to afford the siloxyamide (0.18
g, 83%) as a colorless oil; [α]D22 +4.6 (c 1.2, CHCl3).
IR (neat): 3486, 2989, 2936, 2873, 1685, 1594, 1379, 1069, 858
cm–1.
IR (neat): 2988, 2934, 2893, 2859, 1661, 1256, 1074, 838 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.08 (s, 1 H), 8.06 (d, J = 1.2 Hz,
1 H), 7.61–7.57 (m, 1 H), 7.49–7.46 (m, 2 H), 5.95 (ddd, J = 17.1,
10.5, 5.6 Hz, 1 H), 5.39 (dt, J = 17.2, 1.2 Hz, 1 H), 5.25 (dt, J = 10.5,
1.2 Hz, 1 H), 5.08 (d, J = 6.6 Hz, 1 H), 4.61 (dd, J = 6.6, 3.7 Hz, 1
H), 4.25 (br s, 1 H), 2.45 (br d, J = 7.2 Hz, 1 H), 1.52 (s, 3 H), 1.30
(s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 5.98 (ddd, J = 17.2, 10.6, 4.0 Hz,
1 H), 5.32 (d, J = 17.2 Hz, 1 H), 5.21 (d, J = 10.5 Hz, 1 H), 4.64–
4.61 (m, 1 H), 4.52 (dd, J = 6.7, 0.6 Hz, 1 H), 4.39 (br s, 1 H), 3.09
(s, 3 H), 2.94 (s, 3 H), 1.41 (s, 6 H), 0.86 (s, 9 H), 0.03 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 169.3, 136.9, 116.0, 110.8, 80.7,
73.1, 72.3, 37.0, 35.9, 26.8, 26.2, 25.7, 18.2, –4.7, –5.1.
13C NMR (100 MHz, CDCl3): δ = 197.6, 136.8, 135.3, 133.7, 129.5,
128.5, 117.1, 111.2, 79.5, 78.6, 72.0, 26.9, 26.0.
HRMS: m/z [M + Na] calcd for C17H33NNaO4Si: 366.2077; found:
366.2079.
HRMS: m/z [M + Na] calcd for C15H18NaO4: 285.1103; found:
285.1104.
(2R,3R,4R)-4-(tert-Butyldimethylsiloxy)-2,3-(isopropylidene-
dioxy)-1-phenylhex-5-en-1-one (14)
(1S,2S,3S,4R)-2,3-(Isopropylidenedioxy)-1-phenylhex-5-ene-
1,4-diol (12) and (1R,2S,3S,4R)-2,3-(Isopropylidenedioxy)-1-
phenylhex-5-ene-1,4-diol (13) from 11
To a 2-necked, 25-mL, round-bottomed flask equipped with a mag-
netic stirbar, rubber septum, and argon inlet was placed the above-
prepared siloxyamide (0.32 g, 0.92 mmol). This was dissolved in
anhyd THF (5 mL) and the soln was cooled to –15 °C. A freshly pre-
pared soln of 0.7 M PhMgBr in THF (2 mL, 1.37 mmol) was added
at such a rate that the internal temperature did not rise above –10 °C.
When the reaction was complete (TLC monitoring) (~0.5 h), the
mixture was cautiously quenched by the addition of sat. NH4Cl soln
(10 mL) and extracted with EtOAc (2 × 15 mL). The combined or-
ganic extracts were washed with brine (10 mL) and dried (anhyd
Na2SO4). Evaporation of the solvent gave a residue that was puri-
fied by column chromatography (silica gel, PE–EtOAc, 9:1) to yield
14 (0.34 g, 98%) as a colorless oil; [α]D22 +1.4 (c 1, CHCl3).
To a solution of 11 (60 mg, 0.23 mmol) in MeOH (4 mL) at –78 °C
was added NaBH4 (18 mg, 0.45 mmol) and the mixture was stirred
at the same temperature for 4 h. After completion of the reaction
(TLC) it was cautiously quenched by addition of H2O (1 mL) and
extracted with EtOAc (3 × 10 mL). The combined organic layers
were washed with brine (5 mL) and dried (anhyd Na2SO4) and con-
centrated. The residue obtained after evaporation of the solvent was
purified by column chromatography (silica gel, PE–EtOAc, 2:3) to
afford a mixture of 13 and 12 (dr 75:25, 58 mg, 97%) as a colorless
oil; major diastereomer 13 (43 mg, 72%), minor diastereomer 12
(13 mg, 22 %).
IR (neat): 2989, 2956, 2933, 2859, 1692, 1256, 1074, 838 cm–1.
Major Diastereomer 13
1H NMR (400 MHz, CDCl3): δ = 8.06 (s, 1 H), 8.04 (d, J = 1.3 Hz,
1 H), 7.59–7.55 (m, 1 H), 7.48–7.44 (m, 2 H), 6.02 (ddd, J = 17.2,
10.5, 5.1 Hz, 1 H), 5.35 (dt, J = 17.2, 1.6 Hz, 1 H), 5.26 (dt, J = 10.5,
[α]D22 –30.5 (c 1.2, CHCl3).
IR (neat): 3423, 2988, 2931, 2907, 1596, 1376, 1244, 1219, 1076,
1052, 703 cm–1.
Synthesis 2013, 45, 785–790
© Georg Thieme Verlag Stuttgart · New York

PAPER
Total Synthesis of (–)-Crassalactone C
789
1.6 Hz, 1 H), 5.05 (d, J = 6.1 Hz, 1 H), 4.69 (dd, J = 6.0, 4.5 Hz, 1
H), 4.45–4.43 (m, 1 H), 1.48 (s, 3 H), 1.31 (s, 3 H), 0.82 (s, 9 H),
0.03 (s, 3 H), 0.02 (s, 3 H).
residue that was purified by column chromatography (silica gel,
PE–EtOAc, 1:1) to afford alcohol 12 (26 mg, 93%) as a colorless
oil; [α]D22 +29.7 (c 2.5, CHCl3).
13C NMR (100 MHz, CDCl3): δ = 197.5, 136.7, 135.7, 133.4, 129.4,
128.4, 116.5, 111.2, 79.8, 77.4, 72.7, 26.8, 26.1, 25.7, 18.2, –4.6,
–5.0.
IR (neat): 3402, 2988, 2931, 2905, 1633, 1597, 1380, 1246, 1217,
1073, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.28 (m, 5 H), 5.73 (ddd, J =
16.8, 10.8, 5.4 Hz, 1 H), 5.16–5.08 (m, 2 H), 4.90 (d, J = 5.2 Hz, 1
H), 4.20 (dd, J = 7.6, 5.2 Hz, 1 H), 4.06 (dd, J = 8.0, 2.4 Hz, 1 H),
3.40 (br s, 1 H), 3.02 (br s, 1 H), 2.53 (br d, J = 6.8 Hz, 1 H), 1.43
(s, 3 H), 1.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 139.1, 137.4, 128.5, 128.1, 126.1,
115.9, 109.5, 79.9, 79.4, 72.7, 71.1, 27.2, 27.1.
HRMS: m/z [M + Na] calcd for C21H32NaO4Si: 399.1968; found:
399.1962.
(1S,2S,3R,4R)-4-(tert-Butyldimethylsiloxy)-2,3-(isopropyli-
denedioxy)-1-phenylhex-5-en-1-ol (15) and (1R,2S,3R,4R)-4-
(tert-Butyldimethylsiloxy)-2,3-(isopropylidenedioxy)-1-phenyl-
hex-5-en-1-ol (16)
A soln of CeCl3·7 H2O (0.5 g, 1.35 mmol) in MeOH (7 mL) was
cooled to 0 °C, to this NaBH4 (0.08 g, 2.12 mmol) was added por-
tionwise and the mixture was stirred for 10 min. The resultant mix-
ture was transferred to a flask containing 14 (0.32 g, 0.85 mmol) in
MeOH (12 mL) at –78 °C through a dropper and the mixture was
stirred at this temperature for 0.5 h. After completion of the reaction
(TLC monitoring), it was cautiously quenched by the addition of
H2O (5 mL), the excess MeOH was evaporated, and the mixture was
extracted with EtOAc (3 × 15 mL). The combined organic layers
were washed with brine (10 mL), dried (anhyd Na2SO4), and con-
centrated. Evaporation of the solvent gave a crude residue that was
purified by column chromatography (silica gel, PE–EtOAc, 4:1) to
give a mixture of 15 and 16 (dr 78:22, 0.3 g, 93%) as a colorless oil;
major diastereomer 15 (0.23 g, 71%), minor diastereomer 16 (0.044
g, 13%).
HRMS: m/z [M + Na] calcd for C15H20NaO4: 287.1259; found:
287.1252.
(1R,2S,3S,4R)-2,3-(Isopropylidenedioxy)-1-phenylhex-5-ene-
1,4-diol (13) from 16 (minor)
Following the typical procedure for 12 using 16 (44 mg, 0.11
mmol); column chromatography (silica gel, PE–EtOAc, 1:1) afford-
22
ed alcohol 16 (27 mg, 90%) as a colorless oil; [α]D –30.5 (c 1.2,
CHCl3).
IR (neat): 3423, 2988, 2931, 2907, 1596, 1376, 1244, 1219, 1076,
1052, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.31 (m, 5 H), 5.62 (ddd, J =
17.2, 10.8, 6.0 Hz, 1 H), 5.13 (d, J = 17.2 Hz, 1 H), 5.08 (d, J = 10.4
Hz, 1 H), 4.66 (d, J = 5.6 Hz, 1 H), 4.18 (t, J = 7.0 Hz, 1 H), 3.87
(dd, J = 7.6, 3.6 Hz, 1 H), 3.44 (br s, 1 H), 3.00 (br s, 1 H), 2.32 (br
d, J = 6.0 Hz, 1 H), 1.44 (s, 6 H).
Major Diastereomer 15
[α]D22 +28.0 (c 1.7, CHCl3).
13C NMR (100 MHz, CDCl3): δ = 139.4, 136.9, 128.6, 128.5, 126.9,
IR (neat): 3452, 2985, 2955, 2932, 2898, 2859, 1617, 1458, 1376,
1252, 1076, 837 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.29 (m, 5 H), 5.91 (ddd, J =
17.0, 10.8, 5.6 Hz, 1 H), 5.22–5.15 (m, 2 H), 4.74 (d, J = 6.4 Hz, 1
H), 4.09 (t, J = 7.2 Hz, 1 H), 4.02–3.97 (m, 2 H), 3.75 (s, 1 H), 1.40
(s, 3 H), 1.33 (s, 3 H), 0.92 (s, 9 H), 0.04 (s, 6 H).
116.6, 110.1, 81.1, 80.1, 75.0, 71.6, 27.4, 27.3.
HRMS: m/z [M + Na] calcd for C15H20NaO4: 287.1259; found:
287.1256.
(3R,4S,5S,6S)-4,5-(Isopropylidenedioxy)-6-phenyl-3,6-bis[(3-
phenylpropenoyl)oxy]hex-1-ene (5)
To a soln of diol 12 (25 mg, 0.09 mmol) in anhyd CH2Cl2 (1 mL)
were added Et3N (0.1 mL, 0.75 mmol), DMAP (3 mg, 20 mol%),
and cinnamoyl chloride (62 mg, 0.37 mmol). The resulting mixture
was stirred at r.t. for 12 h. Progress of the reaction was monitored
(TLC) and after completion of the reaction, it was poured into H2O
(5 mL) and extracted with Et2O (3 × 10 mL). The combined ethereal
layers were washed with brine (10 mL) and dried (anhyd Na2SO4).
The residue obtained after evaporation of the solvent was purified
by column chromatography (silica gel, PE–EtOAc, 9:1) to afford 5
(51 mg, 99%) as a colorless oil; [α]D22 –66.9 (c 1.8, CHCl3).
13C NMR (100 MHz, CDCl3): δ = 140.2, 136.7, 128.2, 127.8, 126.8,
116.7, 109.1, 82.0, 79.8, 74.0, 72.9, 27.2, 26.8, 25.8, 18.2, –4.4,
–5.0.
HRMS: m/z [M + Na] calcd for C21H34NaO4Si: 401.2124; found:
401.2104.
Minor Diastereomer 16
[α]D22 –3.0 (c 2.5, CHCl3).
IR (neat): 3452, 2985, 2955, 2932, 2898, 2895, 1252, 1126, 1076,
837, 702 cm–1.
IR (neat): 3063, 3031, 2988, 2928, 1715, 1637, 1248, 1161, 1004,
767 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.29 (m, 5 H), 5.84 (ddd, J =
16.7, 11.0, 6.0 Hz, 1 H), 5.15 (s, 1 H), 5.12 (d, J = 6.5 Hz, 1 H), 4.75
(t, J = 5.6 Hz, 1 H), 4.21 (dd, J = 7.6, 4.8 Hz, 1 H), 3.94 (dd, J = 8.0,
4.0 Hz, 1 H), 3.90–3.87 (m, 1 H), 3.09 (d, J = 6.8 Hz, 1 H), 1.40 (s,
3 H), 1.39 (s, 3 H), 0.91 (s, 9 H), 0.01 (s, 3 H), 0.00 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 140.7, 137.2, 128.3, 127.9, 126.7,
116.4, 109.7, 80.3, 73.7, 73.2, 27.4, 27.2, 25.9, 18.2, –4.4, –4.8.
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 16.0 Hz, 1 H), 7.79 (d,
J = 16.0 Hz, 1 H), 7.56–7.32 (m, 15 H), 6.55 (d, J = 16.0 Hz, 1 H),
6.50 (d, J = 16.0 Hz, 1 H), 6.05 (d, J = 5.6 Hz, 1 H), 5.87 (ddd, J =
16.8, 10.8, 6.4 Hz, 1 H), 5.44 (dd, J = 10.4, 5.5 Hz, 1 H), 5.39 (s, 1
H), 5.32 (dd, J = 16.0, 10.5 Hz, 1 H), 4.39 (t, J = 6.6 Hz, 1 H), 4.22
(dd, J = 6.8, 4.8 Hz, 1 H), 1.47 (s, 3 H), 1.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.8, 165.7, 146.0, 145.7, 136.4,
134.2, 132.5, 130.58, 130.53, 128.9, 128.5, 128.4, 128.27, 128.23,
127.5, 119.1, 117.5, 117.4, 110.8, 79.4, 78.9, 75.5, 73.9, 27.2.
HRMS: m/z [M + Na] calcd for C21H34NaO4Si: 401.2124; found:
401.2125.
(1S,2S,3S,4R)-2,3-(Isopropylidenedioxy)-1-phenylhex-5-ene-
1,4-diol (12) from 15; Typical Procedure
HRMS: m/z [M + Na] calcd for C33H32NaO6: 547.2097; found:
547.2098.
To a soln of 15 (40 mg, 0.10 mmol) in THF (2 mL) in a Nalgene vi-
al, was added a premixed soln of pyridine hydrofluoride–pyridine–
THF (1:1:3) by volume (2.0 mL) at r.t. The reaction was stirred at
this temperature for 12 h. After completion of reaction (TLC moni-
toring), the reaction was quenched by the addition of sat. NaHCO3
soln (3 mL). The aqueous layer was extracted with EtOAc (2 × 15
mL). The combined organic layers were washed with brine (10 mL)
and dried (anhyd Na2SO4). Evaporation of the solvent gave a crude
(5R)-5-{(1S,2S,3S)-1,2-(Isopropylidenedioxy)-3-phenyl-3-[(3-
phenylpropenoyl)oxy]propyl}furan-2(5H)-one (17)
To a soln of 5 (50 mg, 0.095 mmol) in anhyd CH2Cl2 (5 mL) was
added Grubbs II catalyst (8 mg, 10 mol%) under argon atmosphere.
The mixture was allowed to reflux until the reaction was complete
(TLC monitoring). The mixture was passed through a short pad of
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 785–790

790
K. R. Prasad, S. M. Kumar
PAPER
silica gel. The silica pad was washed with Et2O (3 × 10 mL). The
crude residue obtained after evaporation of the solvent was subject-
ed to column chromatography (silica gel, PE–EtOAc, 1:1) to afford
17 (37 mg, 92%) as a pale brown solid; mp 130–133 °C; [α]D
–53.7 (c 2.3, CHCl3).
Acknowledgment
We thank the Department of Science and Technology (DST), New
Delhi for funding of this project. K.R.P. is a Swarnajayanthi fellow
of DST. S.M.K. thanks Council of Scientific and Industrial Re-
search (CSIR), New Delhi for a research fellowship.
22
IR (KBr): 2988, 2926, 1754, 1731, 1636, 1452, 1311, 1154, 1127,
1080, 895 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 16.0 Hz, 1 H), 7.56–
7.54 (m, 2 H), 7.44–7.33 (m, 9 H), 6.54 (d, J = 16.0 Hz, 1 H), 6.19
(d, J = 5.6 Hz, 1 H), 6.14 (d, J = 5.6 Hz, 1 H), 4.65 (dd, J = 13.2, 7.2
Hz, 1 H), 4.55 (s, 1 H), 4.31 (d, J = 7.6 Hz, 1 H), 1.35 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 172.6, 165.6, 152.8, 146.3, 136.1,
134.0, 130.7, 129.0, 128.8, 128.7, 128.2, 126.6, 122.5, 117.1, 111.1,
81.4, 78.7, 76.4, 74.3, 27.1, 26.3.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
(1) Tuchinda, P.; Munyoo, B.; Pohmakotr, M.; Thinapong, P.;
Sophasan, S.; Santisuk, T.; Reutrakul, T. J. Nat. Prod. 2006,
69, 1728.
HRMS: m/z [M + Na] calcd for C25H24NaO6: 443.1471; found:
(2) For a review on the cytotoxic activity and other bioactivity
of styryllactones, see: (a) Mereyala, H. B.; Joe, M. Curr.
Med. Chem.: Anti-Cancer Agents 2001, 1, 293.
(b) Blàzquez, M. A.; Bermejo, A.; Zafra-Polo, M. C.;
Cortes, D. Phytochem. Anal. 1999, 10, 161. (c) de Fatima,
A.; Modolo, L. V.; Conegero, L. S.; Pilli, R. A.; Ferreira, C.
V.; Kohn, L. K.; de Carvalho, J. E. Curr. Med. Chem. 2006,
13, 3371.
443.1472.
(5R)-5-{(1R,2R,3S)-1,2-Dihydroxy-3-phenyl-3-[(3-phenylpro-
penoyl)oxy]propyl}furan-2(5H)-one (4)
To a soln of 17 (30 mg, 0.07 mmol) in THF (3 mL) was added 4 M
HCl (3 mL) at r.t. and the mixture was stirred for 2 d at this temper-
ature. When the reaction was complete (TLC monitoring), the vol-
atiles were removed under reduced pressure and the residue was
purified by column chromatography (silica gel, PE–EtOAc, 2:8) to
afford 4 (23 mg, 85%) as a white solid; mp 184–187 °C; [α]D22 –5.4
(c 0.5, MeOH).
(3) Popsavin, V.; Benedeković, G.; Srećo, B.; Popsavin, M.;
Francuz, J.; Kojić, V.; Bogdanović, G. Org. Lett. 2007, 9,
4235.
IR (KBr): 3678, 3442, 1746, 1711, 1268, 1174, 1097, 910, 706
cm–1.
(4) (a) Popsavin, V.; Benedeković, G.; Srećo, B.; Popsavin, M.;
Francuz, J.; Kojić, V.; Bogdanović, G.; Divjaković, V.
Tetrahedron 2009, 65, 10596. (b) Popsavin, V.; Srećo, B.;
Benedeković, G.; Francuz, J.; Popsavin, M.; Kojić, V.;
Bogdanović, G. Eur. J. Med. Chem. 2010, 45, 2876.
(c) Popsavin, V.; Benedeković, G.; Popsavin, M.; Kojić, V.;
Bogdanović, G. Tetrahedron Lett. 2010, 51, 3426.
(5) Sharma, G. V. M.; Mallesham, S. Tetrahedron: Asymmetry
2010, 21, 2646.
(6) (a) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73, 2.
(b) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73,
2916. (c) Prasad, K. R.; Dhaware, M. G. Synthesis 2007,
3697. (d) Prasad, K. R.; Dhaware, M. G. Synlett 2007, 1112.
(e) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2006, 71,
3643. (f) Prasad, K. R.; Gholap, S. L. Synlett 2005, 2260.
(7) For a general approach to the synthesis of -ketoamides by
addition of alkyl or aryl Grignard reagents to tartaric acid
derived amides see: Prasad, K. R.; Chandrakumar, A.
Tetrahedron 2007, 63, 1798.
1H NMR (400 MHz, CDCl3–CD3OD): δ = 7.73 (d, J = 5.7 Hz, 1 H),
7.65 (d, J = 16.0 Hz, 1 H), 7.53–7.52 (m, 2 H), 7.44–7.25 (m, 10 H),
6.48 (d, J = 16.0 Hz, 1 H), 6.14 (d, J = 5.7 Hz, 1 H), 5.84 (d, J = 8.8
Hz, 1 H), 5.24 (d, J = 6.0 Hz, 1 H), 3.99 (d, J = 6.0 Hz, 1 H), 3.88
(d, J = 8.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3–CD3OD): δ = 176.8, 168.5, 157.8,
148.2, 140.7, 136.5, 133.0, 131.2, 130.6, 130.5, 130.0, 123.7, 119.7,
88.5, 77.4, 74.4, 73.4.
HRMS: m/z [M + Na] calcd for C22H20NaO6: 403.1158; found:
403.1159.
(–)-Crassalactone C (2)
A soln of 4 (18 mg, 0.047 mmol) in anhyd THF (5 mL) containing
DBU (2 mg, 30 mol%) was stirred at r.t. for 6 h. The soln was then
filtered through a short pad of silica gel topped with Celite. The
white solid obtained after evaporation of the solvent from the fil-
trate was further purified by column chromatography (silica gel,
PE–EtOAc, 3:7) to give 2 (11 mg, 61%) as a white solid; mp 146–
148 °C (Lit.1,3 147–150 °C); [α]D22 –118.0 (c 0.5, EtOH) [Lit.3 [α]D
+111.6 (c 0.5, EtOH)].
(8) Diastereomeric ratio was determined by 1H NMR.
Formation of the other diastereomers was not observed
within detectable limits in 1H NMR. Formation of the major
diastereomer 6 can be explained by the addition of hydride
in a Felkin–Ahn/Cram open chain model as reported by
Chikasita et al.: Chikashita, H.; Nikaya, T.; Uemura, H.;
Itoh, K. Bull. Chem. Soc. Jpn. 1989, 62, 2121.
(9) Owing to the reactivity of the unsaturated amide as a
Michael acceptor, it is necessary to avoid the addition of
MeOH in the presence of CeCl3·7 H2O.
IR (KBr): 3445, 2927, 1789, 1713, 1634, 1334, 1166, 1067, 1049,
699 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 15.9 Hz, 1 H), 7.54–
7.38 (m, 10 H), 6.46 (d, J = 15.9 Hz, 1 H), 5.99 (d, J = 9.2 Hz, 1 H),
4.98 (s, 2 H), 4.42 (s, 1 H), 4.24 (d, J = 9.3 Hz, 1 H), 4.19 (br s, 1
H), 2.67 (dd, J = 18.7, 4.7 Hz, 1 H), 2.56 (d, J = 18.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 175.4, 167.5, 147.3, 136.7, 133.7,
131.0, 129.0, 128.9, 128.7, 128.4, 127.7, 116.6, 87.0, 82.4, 77.1,
73.1, 72.8, 35.8.
(10) Formation of the major diastereomer 15 in the reduction of
14 can be explained by a Cram chelation model. For a
detailed study on the reduction of similar hydroxy ketones
derived from tartaric acid see: Prasad, K. R.; Chandrakumar,
A. Synthesis 2006, 2159.
(11) Formation of crassalactone C (2) was further confirmed by
the cleavage of the cinnamoyl ester to yield (–)-goniofufurone
(3) in 66% yield.
HRMS: m/z [M + Na] calcd for C22H20NaO6: 403.1158; found:
403.1159.
Synthesis 2013, 45, 785–790
© Georg Thieme Verlag Stuttgart · New York