Stereoselective total synthesis of styryl-lactones: (+)-crassalactones B and C, (+)-howiionol A, (+)-tricinnamate, (+)-goniofufurone and (+)-dicinnamoyl goniofufurone

Article abstract of DOI:10.1016/j.tetasy.2010.10.016

The total synthesis of (+)-crassalactone B, (+)-crassalactone C, (+)-howiionol A, (+)-tricinnamate, (+)-goniofufurone, and (+)-dicinnamoyl goniofufurone is achieved by a 'chiron approach' starting from diacetone d-glucose (DAG). Mitsunobu inversion, Wittig olefination and ring closing metatheses were used as key steps for (+)-howiionol A and (+)-tricinnamate. Meldrum's acid was used for the synthesis of (+)-crassalactone C, (+)-goniofufurone, and (+)-dicinnamoyl goniofufurone. Yamaguchi esterification was used for (+)-crassalactone B, while a Grignard reaction followed by concomitant deallylation was first reported in the synthesis of (+)-dicinnamoyl goniofufurone.

Full text of DOI:10.1016/j.tetasy.2010.10.016

Tetrahedron: Asymmetry 21 (2010) 2646–2658
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective total synthesis of styryl-lactones: (+)-crassalactones B and C,
(+)-howiionol A, (+)-tricinnamate, (+)-goniofufurone, and (+)-dicinnamoyl
goniofufurone
⇑
Gangavaram V. M. Sharma, Samala Mallesham
Organic Chemistry Division-III, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 September 2010
Accepted 19 October 2010
The total synthesis of (+)-crassalactone B, (+)-crassalactone C, (+)-howiionol A, (+)-tricinnamate, (+)-gon-
iofufurone, and (+)-dicinnamoyl goniofufurone is achieved by a ‘chiron approach’ starting from diacetone
D
-glucose (DAG). Mitsunobu inversion, Wittig olefination, and ring closing metatheses were used as key
steps for (+)-howiionol A and (+)-tricinnamate. Meldrum’s acid was used for the synthesis of (+)-crassa-
lactone C, (+)-goniofufurone, and (+)-dicinnamoyl goniofufurone. Yamaguchi esterification was used for
(+)-crassalactone B, while a Grignard reaction followed by concomitant deallylation was first reported in
the synthesis of (+)-dicinnamoyl goniofufurone.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
OH
O
4
Styryl-lactones (+)-crassalactone B 1, (+)-crassalactone C 2, (+)-
goniofufurone 4, and (+)-howiionol A 5 are natural heterocyclic
compounds from the Annonaceae family, while, (+)-tricinnamate 6
and (+)-dicinnamoyl goniofufurone 3 are un-naturalstyryl-lactones.
The new styryl-lactones 1 and 2 were isolated1 from a cytotoxic
ethyl acetate soluble extract from the leaves and twigs of Polyalthia
crassa along with known 42 and 5.3 The isolation of 4 was earlier2a
reported from the stem bark of Goniothalalamus giganteus and the
absolute stereochemistry was determined through synthetic
work.2b–e Likewise 5 was reported previously by Chen et al.3a and
its stereochemistry was confirmed1,3b by single-crystal X-ray dif-
fraction analysis. The biological evaluation1 of the new isolates 1
and 2 including synthetic 6 revealed that they possess excellent
antitumoral properties as well as antibiotic potential with lower
toxicity than 4 and 5. The structures of lactones 1 and 2 were
assigned based on the NMR, EI-MS, and IR spectroscopy1 and semi-
synthesis1 from 4, while, 1 and 2 are natural 8-O-cinnamoyl and 6-O-
cinnamoyl derivatives of 4 which were confirmed by synthesis.4a,b
Compound 3 is a 6,8-di-O-cinnamoyl derivative of 4 and 1–4 contain
five contiguous stereocenters (4R,5S,6R,7R,8R). Likewise, 5, a 8-O-
cinnamoyl derivative of (+)-goniotriol5 and a synthetic (+)-tricinna-
mate 6,7,8-tri-O-cinnamoyl derivative, contain four asymmetric
stereocenters (5S,6R,7R,8R) in their structures. In a continuation of
our interest on the total synthesis of natural products,6 we herein re-
port the first stereoselective total synthesis of 6 besides the total
synthesis of 1–5 by an easily accessible pathway.
O
6
3
2 O
3
7
O
6
4
8
7
O
2
8
7
O
5
O
O
4
O
3
5 O
1
8
1
O
2
6 5
HO
O
O
O
O
1
(+)-CrassalactoneB 1
(+)-Dicinnamoyl
Goniofufurone 3
(+)-CrassalactoneC 2
O
O
O
OH
O
4
5
3
4
OH
O
3
8
4
O
7
5
3
2
2
O
8
7
6
5
8
O
O
6
2
HO
O
1
O
7
1
O
O
6
1
OH
O
(+)-Howiionol A 5
(+)-Goniofufurone 4
(+)-Tricinnamate 6
O
2. Results and discussions
2.1. Synthesis of (+)-crassalactone B 1, (+)-goniofufurone 4 and
(+)-tricinnamate 6
Initially, it was envisaged that the absolute configuration at
C(2), C(3), and C(4) of diacetone D-glucose (DAG) could be corre-
lated to C(4), C(5) and C(6) of 1. Thus, from the retrosynthetic anal-
ysis, as depicted in Scheme 1, 1 could be envisioned from lactone 7
by a Yamaguchi esterification followed by debenzylation, while, 3
could be realized only by debenzylation. Compound 7 could, in
turn, be made from 8 by the addition of Meldrum’s acid, which
would result in a concomitant lactonization. Lactol 8, in turn,
would be realized from carbinol 9, which could come from DAG
11 by Mitsunobu inversion and simple chemical transformations.
⇑
Corresponding author.
E-mail address: samalamm@gmail.com (S. Mallesham).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.016

G. V. M. Sharma, S. Mallesham / Tetrahedron: Asymmetry 21 (2010) 2646–2658
BnO
2647
BnO
O
O
1, 3
OH
OH
HO
RO
O
O
7
8
O
6
HO
O
HO
O
OH
5
1
O
O
O
O
O
4
6
2
O
311
RO
HO
OH
RO
O
9
10
Scheme 1.
2.2. Retrosynthesis
2.3. Synthesis of (+)-crassalactone B 1
Similarly, 6 could be realized from 10 by ring closing metathesis
(RCM), esterification and PDC oxidation, which in turn could be ob-
tained from the common intermediate 9. Thus, the three com-
pounds 1, 3, and 6 could be very efficiently synthesized from the
common intermediate 9 that could be prepared from the abun-
Accordingly, commercially available D-(+)-glucose derivative 11
was treated with NaH and allyl bromide (Scheme 2) in THF to
afford 12 in 95% yield. Selective deprotection of the 5,6-O-isopro-
pylidene group in 12 with 60% aq acetic acid at room temperature
gave diol 13 (90%), which on oxidative cleavage (NaIO4) in aq
MeOH at room temperature afforded aldehyde 14 (92%).
dantly available
D
-glucose derivative, DAG 11.
O
HO
O
O
O
O
O
O
O
O
HO
O
a
b
c
O
O
O
O
O
HO
11
12
(95%)
13 (90%)
OR1
RO
O
OH
O
O
O
O
H
g
d
O
O
O
O
+
O
RO
O
9
14
(90%)
15
(81%)
R1 = H, R
15a R1=
9
= allyl
4:1 (74%)
e
R
= allyl
f
(72%)
cinnamoyl
; R = allyl
OBn
OBn
RO
OBn
O
O
O
O
OH
j
h
i
RO
O
OH
8 (74%)
RO
O
O
16 (85%)
17
(84%)
R = allyl
R = allyl
R = allyl
OH
OBn
OBn
O
O
O
l
k
RO
O
O
O
O
O
O
HO
O
O
(78%)
18
R = cinnamo
7 (81%)
yl
1 (80%)
Scheme 2. Reagents and conditions: (a) allyl bromide, NaH, THF, 0 °C–rt, 4 h; (b) 60% aq AcOH, rt, 12 h; (c) NaIO4, MeOH/H2O (5:1), rt, 3 h; (d) PhMgBr (1.1 equiv), THF, 0 °C–
rt, 2 h; (e) cinnamic acid, PPh3, DIAD, dry THF, 0 °C–rt, 5 h; (f) K2CO,MeOH, rt, 2 h; (g) BnBr, NaH, THF, 0 °C–rt, 6 h; (h) 30% aq AcOH, 80 °C, 12 h; (i) Meldrum’s acid, Et3N, DMF,
40 °C, 16 h; (j) 10% Pd/C, H2O, PTSA, MeOH, 80 °C, 12 h; (k) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, cinnamic acid, DMAP, toluene, rt, 3 h; (l) TiCl4, CH2Cl2, 0 °C rt, 2 h.

2648
G. V. M. Sharma, S. Mallesham / Tetrahedron: Asymmetry 21 (2010) 2646–2658
Grignard reaction of 14 upon treatment with PhMgBr in THF
afforded two chromatographically separable diastereomers 15
-ido-) and 9 (
-gluco-) in a 4:1 ratio7 in 74% overall yield. The for-
mation of the
ylmethylene)triphenyl phosphorane in toluene afforded a mixture
of products 10 (58%) and 20 (13%).
(
L
D
A highly diluted solution of diene 10 in dry toluene was heated
at reflux in the presence of Grubbs’ catalyst II (20 mol %) to afford
cyclic triol 21 (61%), which on esterification (DCC, DMAP) with cin-
namic acid in CH2Cl2 afforded 22 in 64% yield. Finally, allylic oxida-
tion of 22 with PDC in CH2Cl2 at reflux gave 6 in 85% yield,
L-ido compound as major and D-gluco compound as
the minor isomer can be explained by 1,2- and 1,3-chelation8 of
the metal ion with oxygen atoms.
Carbinol 15 was subjected to Mitsunobu inversion9 on treat-
ment with cinnamic acid, PPh3, and DIAD in dry THF to give cinna-
mate 15a (72%), which on subsequent hydrolysis with excess
K2CO3 in MeOH afforded 9 in 81% yield. The spectroscopic data of
the hydrolysis product showed matching spectroscopic data with
the minor isomer 9, obtained during the Grignard reaction.
The hydroxy group in 9 was protected as a benzyl ether on reac-
tion with benzyl bromide and NaH in THF to afford 16 in 85% yield.
Compound 16, on reaction with 30% aq AcOH at 80 °C, underwent
hydrolysis to give lactol 8 (74%), which on treatment with Mel-
drum’s acid4,8 and Et3N in DMF gave 17 in 84% yield. The allyl group
in 17 was deprotected with 10% Pd–C, H2O, and PTSA in MeOH to af-
ford the alcohol 7 (81%). Yamaguchi esterification10 of 7 with cin-
namic acid gave 18 in 78% yield, which on final debenzylation on
treatment with TiCl4 in CH2Cl2 at room temperature afforded 1 in
[a]
D = +180.0 (c 0.22, CHCl3); Lit.1
[a
]D = +175.8 (c 0.2, CHCl3).
Further, compound 20 (Scheme 5) was treated with Pd/C and
PTSA in aq MeOH to afford 4 in 77% yield, [
a
]D = +43.9 (c 0.11,
CHCl3); Lit.2e
[
a]
D = +39.5 (c 1.0, CHCl3).
HO
HO
O
O
a
RO
O
O
HO
O
(77%)
O
20
4
R = allyl
Scheme 5. Reagents and conditions: (a) 10% Pd/C, H2O, PTSA, MeOH, 80 °C, 8 h.
80% yield, [
a]
D = +31.6 (c 1.0, CHCl3); Lit. (synthetic)4b
D = +8.0 (c 0.5, EtOH).
[a]D = +45.7
2.6. Synthesis of (+)-howiionol A 5, (+)-tricinnamate 6, (+)-
crassalactone C 2
(c 0.5, EtOH); Lit. (natural product)1 [
a]
2.4. Synthesis of (+)-goniofufurone 4
From the retrosynthetic analysis of 5 and 6 as shown Scheme 6,
both could be prepared from ester 23 by RCM reaction, which in
turn could be realized from 24 by reaction with (ethoxycarbonyl-
methylene)triphenyl phosphorane. Similarly, compound 2 could
be envisioned from 24 by the addition of Meldrum’s acid which
would result in concomitant lactone formation. The crucial inter-
mediate 24 in turn could be obtained from 15a by simple acid
hydrolysis, which in turn could be made from 11.
Likewise treatment of lactone 7 (Scheme 3) with TiCl4 in CH2Cl2
at 0 °C to room temperature afforded 4 in 86% yield, [a]D = +34.2 (c
0.18, CHCl3); Lit.2e
[a]D = +39.5 (c 1.0, CHCl3).
BnO
O
HO
O
a
2.7. Synthesis of (+)-howiionol A 5
HO
HO
O
O
O
O
Accordingly, carbinol 15 (Scheme 7) was subjected to Mitsun-
obu inversion9 on treatment with cinnamic acid, PPh3, and DIAD
in dry THF to give cinnamate 15a in 72% yield. Similarly, the minor
product 9, obtained by Grignard reaction, on esterification with
cinnamoyl chloride and Et3N in CH2Cl2 afforded 15a in 86% yield.
Acid hydrolysis of 15a (30% aq AcOH) at 80 °C gave diol 24
(70%), which on further Wittig reaction with (ethoxycarbonyleth-
ylene)triphenyl phosphorane in toluene afforded ester 23 in 72%
yield (no cyclized product was observed in this reaction).
7
4
(86%)
Scheme 3. Reagents and conditions: (a) TiCl4, CH2Cl2, 0 °C–rt, 2 h.
2.5. Synthesis of (+)-tricinnamate 6
Compound 9 (Scheme 4) on reaction with 30% aq. AcOH at 80 °C
gave lactol 19 (65%), which on treatment with (methoxycarbon-
O
HO
OH
HO
HO
OH
O
O
O
O
O
a
OH
b
+
RO
OH
O
RO
RO
OH
19 (65%)
RO
O
O
9
10 (58%)
20
(13%)
R = allyl
O
OR
O
O
HO
OR
O
OH
O
OH
O
e
c
d
OR
OR
OR
OR
O
OH
OH
OH
6
22 (64%)
(85%)
(61%)
10
21
Scheme 4. Reagents and conditions: (a) 30% aq acetic acid, reflux, 12 h; (b) Ph3P@CHCOOCH3, toluene, reflux, 2 h; (c) Grubbs-II, toluene, reflux, 24 h; (d) cinnamic acid, DCC,
DMAP, CH2Cl2, rt, 12 h; (e) PDC, NaOAc, CH2Cl2, reflux, 12 h.

G. V. M. Sharma, S. Mallesham / Tetrahedron: Asymmetry 21 (2010) 2646–2658
2649
5
6
2
O
RO
RO
RO
O
OH
O
OC2H5
O
OH
OH
11
R1O
O
R1O
O
OH
15a
24
23
R = cinnamo
= allyl
yl
R = cinnamo
R1 = allyl
yl
R1
R = cinnamo
yl
Scheme 6.
OH
O
O
O
9
O
b, 86%
OR
RO
HO
O
O
O
OH
a, 72%
O
O
c
d
O
O
OH
(70%)
O
O
O
15a
24
15
R = cinnamo
yl
R = cinnamo
yl
OR
O
O
RO
OR
O
OH
OC2H5
(72%)
e
f
O
O
OH
OH
O
OH
23
25 (70%)
R = cinnamo
(82%)
26
R = cinnamo
yl
yl
R = cinnamo
yl
O
O
OR
OR
O
O
g
h
O
OH
O
OH
(74%)
5
R = cinnamo
yl
27 (69%)
R = cinnamo
yl
Scheme 7. Reagents and conditions: (a) cinnamic acid, PPh3, DIAD, dry THF, 0 °C–rt, 5 h; (b) cinnamoyl chloride, Et3N, CH2Cl2, 0 °C–rt, 12 h; (c) 30% aq acetic acid, reflux, 14 h;
(d) Ph3P@CHCOOEt, toluene, reflux, 2 h; (e) Grubbs-II, toluene, reflux, 12 h; (f) 2,2 DMP, PTSA, CH2Cl2, rt, 3 h; (g) PDC, NaOAc, CH2Cl2, reflux, 12 h; (h) CF3COOH, CH2Cl2, 0 °C–
rt, 24 h.
A highly diluted solution of diene 23 in dry toluene was heated
at reflux under a nitrogen atmosphere in the presence of Grubbs’
catalyst II (20 mol %) to afford olefin 25 in 70% yield. The diol unit
in 25 was treated with 2,2-dimethoxypropane and PPTS in CH2Cl2
to afford 26 (82%), which on oxidation with PDC in CH2Cl2 at reflux
gave the lactone 27 in 69% yield. Finally, treatment of 27 with
CF3COOH in CH2Cl2 resulted in removal of the acetonide protecting
group and afforded 5 in 74% yield, [
a]D = +104.8 (c 0.22, CHCl3);
Lit.1
[a]D = +122 (c 0.1, CHCl3).
2.8. Synthesis of (+)-tricinnamate 6
The diol 25 was subjected to esterification (Scheme 8) with cin-
namic acid in the presence of DCC and DMAP in CH2Cl2 to afford 22

2650
G. V. M. Sharma, S. Mallesham / Tetrahedron: Asymmetry 21 (2010) 2646–2658
O
OR
O
OR
OR
O
O
b
a
OR
22 (73%)
OR
OH
OR
OR
OH
(82%)
25
6
Scheme 8. Reagents and conditions: (a) cinnamic acid, DCC, DMAP, CH2Cl2, 0 °C–rt, 12 h; (b) PDC, NaOAc, CH2Cl2, reflux, 12 h.
O
RO
RO
O
O
O
OH
a
b
O
R1O
R =
OH
R1O
O
O
24
28
(85%)
cinnamoyl
R1 = allyl
HO
O
O
R =
cinnamoyl
2 (81%)
R1 = allyl
Scheme 9. Reagents and conditions: (a) Meldrum’s acid, Et3N, DMF, 40 °C, 16 h; (b) 10% Pd/C, PTSA MeOH, 80 °C, 12 h.
OH
HO
O
OH
HO
O
O
O
O
O
H
O
a
O
+
O
O
O
O
14
29
30
4:1 (74%)
OH
OR
O
OH
HO
OR
RO
O
O
O
O
O
c, (79%)
b
+
O
HO
O
HO
O
O
30
29
O
31 (62%)
32
d, (71%)
OR
RO
O
f
e
O
OH
RO
O
OH
33 (69%)
RO
O
3 (83%)
Scheme 10. Reagents and conditions: (a) PhMgBr (3 equiv), THF, 0 °C–rt, 10 h; (b) cinnamic acid, PPh3, DIAD, dry THF, 0 °C–rt, 5 h; (c) cinnamoyl chloride(1 equiv), Et3N,
CH2Cl2, rt, 12 h; (d) cinnamoylchloride (2 equiv), Et3N, CH2Cl2, rt, 12 h; (e) 30% aq acetic acid, THF, cat. HCl, reflux, 12 h; (f) Meldrum’s acid, Et3N, DMF, 40 °C, 36 h.
in 73% yield. Olefin 22 upon allylic oxidation with PDC in CH2Cl2 at
reflux gave lactone 6 in 82% yield, [
D = +176.2 (c 0.2, CHCl3); Lit.1
D = +175.8 (c 0.2, CHCl3).
2 in 81% yield, [a] [a]D = +108.6 (c
D = +108 (c 0.37, CHCl3); Lit.4
0.5, EtOH).
a]
[a]
2.10. Synthesis of (+)-dicinnamoyl goniofufurone 3
2.9. Synthesis of (+)-crassalactone C 2
Aldehyde 14 (Scheme 10) was treated with 3 equiv of PhMgBr in
Similarly, the diol 24 (Scheme 9) was treated with Meldrum’s
acid and Et3N in DMF to afford 28 in 85% yield. Deprotection of
the allyl group in 28 with 10% Pd/C, H2O, PTSA in MeOH afforded
THF to induce phenyl group addition followed by concomittant deal-
lylation resulting in 29 (L-ido-) and 30 (D-gluco-) as chromatograph-
ically separable diastereomers in a 4:1 ratio, in 74% overall yield.

G. V. M. Sharma, S. Mallesham / Tetrahedron: Asymmetry 21 (2010) 2646–2658
2651
2.11. Proposed mechanism for the formation of 29
L-Ido Configuration
Br
H
O
O
O
Ph
Mg
O
5
PhMgBr
O
H
5
Ph
MgBr
O
O
H
4
4
3
O
1
O
O
1
O
O
3
O
2
2
14
O
O
1,2-chelation of
metal ion with
C5-O and C4-O
PhMgBr
Ph
O
Br
OH
O
Mg
MgBr
H
O
5
O
Ph
H2O
O
O
4
3
O
O
HO
1
O
O
O
O
2
29
O
MgBr
+
MgBr
Ph
Ph
1,2-chelation of
metal ion with
C4-O and C3-O
2.12. Proposed mechanism for the formation of 30
The major diol 29 was subjected to Mitsunobu inversion9 on
treatment with cinnamic acid, PPh3, and DIAD in dry THF to furnish
ester 31 (62%), which on further esterification with cinnamoyl
D-Gluco Configuration
Ph
BrMg
Br
Ph
O
O
Mg
O
H
H
O
5
5
O
O
3
O
H
PhMgBr
4
1
H
4
H
3
O
O
O
O
O
2
O
2
14
1
O
O
1,3-chelation of
metal ion with
C5-O and C3-O
PhMgBr
Br
Ph
Mg
O
HO
Ph
H
O
5
BrMg
O
H
O
H2O
H
O
O
Ph Mg
Br
4
+
BrMg
3
H
O
O
2
HO
O
O
1
Ph
30
O
O
O
1,2-chelation of
metal ion with
C4-O and C3-O

2652
G. V. M. Sharma, S. Mallesham / Tetrahedron: Asymmetry 21 (2010) 2646–2658
chloride and Et3N in CH2Cl2 gave diester 32 in 79% yield. Likewise,
the minor diol 30, on reaction with cinnamoyl chloride and Et3N in
CH2Cl2 gave 32 in 71% yield. Treatment of ester 32 with 30% aq
AcOH and cat. HCl in THF at reflux gave lactol 33 (69%), which
on treatment with Meldrum’s acid and Et3N in DMF afforded 3 in
tion, the reaction mixture was neutralized with solid NaHCO3 and
extracted with EtOAc (3 ꢁ 50 mL). The combined organic layers
were dried (Na2SO4) and evaporated. The crude product was purified
by column chromatography (60–120 silica gel, 1:1 EtOAc/n-hexane)
to afford 13 (4.0 g, 90%) as a yellow viscous mass. [
a
]D = ꢀ106.0 (c
83% yield, [
a
]D = ꢀ102.7 (c 0.24, CHCl3).
0.5, CHCl3); IR (Neat): 3406, 3383, 2980, 1352, 1116, 1066, 1052,
870 cmꢀ1; 1H NMR (200 MHz, CDCl3): d 5.90 (m, 1H, olefinic), 5.85
(d, 1H, J = 3.7 Hz, H-1), 5.32 (dd, 1H, J = 1.5, 15.8 Hz, olefinic), 5.21
(dd, 1H, J = 1.5, 15.8 Hz, olefinic), 4.51 (dd, 1H, J = 3.7 Hz, H-2), 4.19
(dd, 1H, J = 5.5, 7.4 Hz, H-4), 4.12–3.87 (m, 4H, allylic CH2, H-6),
3.80 (dd, 1H, J = 2.9, 8.5 Hz, H-3), 3.71 (dd, 1H, J = 2.9, 8.5 Hz, H-5),
2.83 (br s, –OH), 2.52 (br s, –OH), 1.48 (s, 3H, –CH3), 1.31 (s, 3H, –
CH3); 13C NMR (50 MHz, CHCl3): d 113.8, 117.4, 111.4, 104.8, 81.9,
81.3, 79.5, 70.9, 68.6, 64.0, 26.4, 25.9; HRMS m/z [M+Na]+: calcd
for C12H20O6 Na, 283.1157; found: 283.1162.
3. Conclusion
Thus, in conclusion, is work that reports the synthesis of six styryl
lactones 1–6, while, reporting the first synthesis of (+)-tricinnamate
6. All of the six lactones were synthesized from a common interme-
diate derived from D-glucose and simple synthetic methods. A com-
bination of Mitsunobu inversion, Meldrum’s acid lactone ring
formation, Yamaguchi esterification, Wittig olefination, and RCM
reaction was used successfully in the work described.
4.1.3. (3aR,5S,6S,6aR)-6-(Allyloxy)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3] dioxole-5-carbaldehyde 14
4. Experimental
To a solution of diol 13 (3.3 g, 12.69 mmol) in aq MeOH (45 mL,
MeOH/H2O (5:1)), NaIO4 (3.84 g, 19.03 mmol) was added and
stirred at room temperature for 3 h. The solvent was evaporated
and reaction mixture was extracted with CH2Cl2 (2 ꢁ 50 mL). The
combined organic layers were dried (Na2SO4) and evaporated to
give aldehyde 14 (2.66 g, 92%) as a thick yellow liquid, which
was used as such for the next reaction. 1H NMR (200 MHz, CDCl3):
d 9.60 (s, 1H, CHO), 6.08 (d, 1H, J = 3.7 Hz, H-1), 5.77 (m, 1H, ole-
finic), 5.29 (1H, dd, J = 1.5, 15.8 Hz, olefinic), 5.18 (1H, dd, J = 1.5,
15.8 Hz, olefinic), 4.54 (d, 1H, J = 3.7 Hz, H-4), 4.45 (t, 1H,
J = 2.5 Hz, H-2), 4.20 (1H, dd, J = 2.5 Hz, H-3), 4.07 (dd, 1H, J = 2.9,
8.5 Hz, allylic CH), 3.92 (dd, 1H, J = 2.9, 8.5 Hz, allylic CH), 1.48 (s,
3H, –CH3), 1.30 (s, 3H, –CH3); ESIMS: m/z 251 [M+Na]+.
4.1. General methods
Solvents were dried over standard drying agents and were
freshly distilled prior to use. Chemicals were purchased and used
without further purification. All column chromatographic separa-
tions were performed using silica gel (Acme’s, 60–120 mesh).
Organic solutions were dried over anhydrous Na2SO4 and concen-
trated below 40 °C in vacuo. 1H NMR (200 MHz, 300 MHz and
400 MHz) and 13C NMR (50 MHz and 75 MHz) spectra were
measured with a Varian Gemini FT-200 MHz spectrometer, Bruker
Avance 300 MHz, Varian Inova 400 MHz, and Varian Unity Inova-
500 MHz with tetramethylsilane as an internal standard for
solutions in CDCl3. J values are given in Hertz. IR spectra were
recorded on at Perkin–Elmer IR-683 spectrophotometer with NaCl
optics. Optical rotations were measured with JASCO DIP 300
digital polarimeter at 25 °C. Mass spectra were recorded on
CEC-21–11013 or Fannigan Mat 1210 double focusing mass spec-
trometers operating at a direct inlet system or LC/MSD Trap SL
(Agilent Technologies).
4.1.4. (R)-((3aR,5R,6S,6aR)-6-(Allyloxy)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3] dioxol-5-yl)(phenyl)methanol 9 and
(S)-((3aR,5R,6S,6aR)-6-(allyloxy)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3] dioxol-5-yl)(phenyl)methanol 15
To a suspension of Mg (0.84 g, 35.0 mmol) in dry THF (10 mL),
bromobenzene (0.7 mL, 12.82 mmol) was added at room tempera-
ture and stirred for 30 min. It was cooled to 0 °C and a solution of
14 (2.66 g, 11.66 mmol) in dry THF (15 mL) was added dropwise.
After 2 h, the reaction mixture was treated with aq NH4Cl solution
(10 mL) and extracted with EtOAc (2 ꢁ 50 mL). The combined ex-
tracts were washed with water (30 mL), brine (30 mL), dried
(Na2SO4), and concentrated to give a crude residue, which was
purified by column chromatography to afford the mixture of 15
(2.11 g, 59%) and 9 (0.53 g, 15%) in overall 74% yield as a yellowish
red syrup in 4:1 ratio. First eluted was minor isomer 9 (60–120 sil-
4.1.1. (3aR,5S,6S,6aR)-6(Allyloxy)-5-((R)-2,2-dimethyl[1,3] dioxo-
lan-4-yl)-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]dioxole 12
To a cooled (0 °C) suspension of NaH (1.0 g, 42.3 mmol, 60% w/w
dispersion in paraffin oil) in THF (50 mL), a solution of 11 (5.0 g,
19.23 mmol) in THF (50 mL) was added dropwise. After 15 min, allyl
bromide (1.8 mL, 21.15 mmol) was added at 0 °C and stirred at room
temperature for 4 h. After completion of the reaction, it was treated
with satd aq NH4Cl solution (20 mL) and extracted with EtOAc
(2 ꢁ 50 mL). The combined organic layers were washed with water
(40 mL), brine (40 mL), dried (Na2SO4), and evaporated to give crude
residue, whichwaspurifiedby columnchromatography(60–120sil-
ica gel, 1.5:8.5 EtOAc/n-Hexane) to afford 12 (5.5 g, 95%) as a light
ica gel, 1.2:8.8 EtOAc/n-hexane). [
(Neat): 3479, 2986, 2934, 1437, 1378, 1076, 1023 cmꢀ1
(300 MHz, CDCl3): 7.40–7.25 (m, 5H, Ar-H), 5.92 (d, 1H,
a
]
D = ꢀ48.7 (c 0.37, CHCl3); IR
;
1H NMR
d
J = 3.7 Hz, H-1), 5.85 (m, 1H, olefinic), 5.25 (dq, 2H, J = 1.5 Hz, ole-
finic), 4.99 (d, 1H, J = 6.0 Hz, H-5), 4.50 (d, 1H, J = 3.7 Hz, H-2),
4.23 (dd, 1H, J = 3.7, 6.8 Hz, H-4), 4.18–4.10, 3.98–3.91 (2dt, 2H,
J = 1.5, 3.0 Hz, allylic CH2), 3.85 (d, 1H, J = 3.0 Hz, H-3), 3.01 (br s,
–OH), 1.45 (s, 3H, –CH3), 1.27 (s, 3H, –CH3); 13C NMR (75 MHz,
CHCl3): d 141.3, 133.2, 128.4, 127.6, 125.9, 118.4, 111.5, 105.1,
82.8, 82.3, 81.6, 72.1, 70.0, 26.6, 26.1; HRMS m/z [M+Na]+: calcd
for C17H22O5Na, 329.1364; found: 329.1357.
yellow liquid. [
a
]
D = ꢀ58.3 (c 0.51, CHCl3); IR (Neat): 2986, 2935,
1373, 1216, 1076, 1022, 849 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d
5.87 (m, 1H, olefinic), 5.82 (d, 1H, J = 3.7 Hz, H-1), 5.30 (dd, 1H,
J = 1.5, 15.8 Hz, olefinic), 5.18 (dd, 1H, J = 1.5, 15.8 Hz, olefinic),
4.49 (d, 1H, J = 3.7 Hz, H-2), 4.25 (dd, 1H, J = 6.0, 7.5 Hz, H-4), 4.12–
3.86 (m, 6H), 1.49 (s, 3H, –CH3), 1.42 (s, 3H, –CH3), 1.32 (s, 3H, –
CH3), 1.28 (s, 3H, –CH3); 13C NMR (50 MHz, CHCl3): d 133.9, 116.9,
111.4, 108.7, 105.0, 82.6, 81.2, 80.1, 72.2, 71.0, 67.0, 26.6, 26.6,
26.0, 25.1; HRMS m/z [M+Na]+: calcd for C15H24O6Na, 323.1470;
found: 323.1486.
The second eluted was its C-5 epimer 15 (silica gel 60–120
mesh, 1.5:8.5 EtOAc/n-hexane) as the major diastereomer.
[a]
D = ꢀ10.7 (c 1.2, CHCl3); IR (Neat): 3485, 2985, 2929, 1455,
1378, 1217, 1076, 1019 cmꢀ1 1H NMR (200 MHz, CDCl3): d 7.39
;
4.1.2. (R)-1-((3aR,5R,6S,6aR)-6-(Allyloxy)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3] dioxol-5-yl)ethane-1,2-diol 13
A mixture of 12 (5.2 g, 17.33 mmol) in 60% aq AcOH (50 mL) was
stirred at room temperature for 12 h. After completion of the reac-
(d, 2H, J = 7.3 Hz, Ar-H), 7.32–7.23 (m, 3H, Ar-H), 5.93 (d, 1H,
J = 3.6 Hz, H-1), 5.85–5.72 (m, 1H, olefinic), 5.25 (d, 1H,
J = 17.6 Hz, olefinic), 5.16 (d, 1H, J = 10.2 Hz, olefinic), 4.96 (d, 1H,
J = 8.0 Hz, H-5), 4.47 (d, 1H, J = 3.6 Hz, H-2), 4.20 (dd, 1H, J = 3.6,

G. V. M. Sharma, S. Mallesham / Tetrahedron: Asymmetry 21 (2010) 2646–2658
2653
8.0 Hz, H-4), 3.97 (dd, 1H, J = 5.1, 12.4 Hz, allylic CH), 3.70 (dd, 1H,
J = 5.8, 12.4 Hz, allylic CH), 3.39 (d, 1H, J = 2.2 Hz, H-3), 2.74 (br s,
–OH), 1.46 (s, 3H, –CH3), 1.27(s, 3H, –CH3);13C NMR (75 MHz, CHCl3):
d 139.5, 133.3, 128.1, 127.9, 127.0, 117.5, 111.6, 104.9, 84.5, 81.9,
81.6, 72.3, 70.6, 26.5, 26.0; HRMS m/z [M+Na]+: calcd for C17H22O5Na,
329.1364; found: 329.1360.
4.36, 4.21 (d, 2H, J = 11.3 Hz, benzylic CH2), 4.20–3.98 (m, 2H,
allylic CH2), 4.17 (dt, 1H, J = 3.0, 8.3 Hz, H-4), 4.04 (d, 1H,
J = 2.2 Hz, H-3), 1.37 (s, 3H, –CH3), 1.24 (s, 3H, –CH3); 13C NMR
(75 MHz, CHCl3): d 139.4, 138.2, 134.2, 129.9, 128.3, 128.2, 128.0,
127.8, 127.7, 127.5, 127.1, 125.9, 117.4, 111.4, 104.9, 82.8, 82.2,
81.4, 78.1, 71.4, 70.3, 26.6, 26.2; HRMS m/z [M+Na]+: calcd for
C24H28O5Na, 419.1834; found: 419.1836.
4.1.5. (R)-((3aR,5R,6S,6aR)-6-(Allyloxy)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3] dioxol-5-yl)(phenyl)methyl
cinnamate 15a
4.1.8. (3R,4R,5R)-4-(Allyloxy)-5-((R)-benzyloxy(phenyl)methyl)-
tetrahydrofuran-2,3-diol 8
To a stirred solution of 15 (2 g, 6.53 mmol) in dry THF (20 mL),
PPh3 (2.56 g, 9.79 mmol) and cinnamic acid (1.06 g, 7.83 mmol)
were added. After 20 min, DIAD (1.97 g, 9.79 mmol) was added at
0 °C and reaction mixture was stirred at room temperature for
5 h. It was quenched with satd aq NaHCO3 solution (20 mL) and ex-
tracted with EtOAc (2 ꢁ 50 mL). The combined organic layers were
washed with water (20 mL), brine (20 mL), dried (Na2SO4), and
evaporated. The resulting residue was purified by column chroma-
tography (60–120 silica gel, 1:9 EtOAc/n-hexane) to furnish 15a
A mixture of 16 (0.42 g, 1.06 mmol) in 30% aq AcOH (5 mL) was
stirred at reflux for 12 h. After completion of the reaction, the reac-
tion mixture was neutralized with solid NaHCO3 and extracted
with EtOAc (3 ꢁ 20 mL). The combined organic layers were dried
(Na2SO4) and evaporated. The crude residue was purified by col-
umn chromatography (60–120 silica gel, 3:7 EtOAc/n-hexane) to
afford 8 (0.28 g, 74%) as a yellow liquid. [
a
]
D = ꢀ41.2 (c 1.4, CHCl3);
IR (Neat): 3411, 3030, 2927, 1723, 1494, 1452, 1063 cmꢀ1; 1H NMR
(300 MHz, CDCl3): d 7.47–7.17 (m, 10H, Ar-H), 5.90–5.76 (m, 1H,
olefinic), 5.27 (t, 1H, J = 1.7, 3.4 Hz, H-1), 5.19 (m, 2H, olefinic),
4.62 (d, 1H, J = 9.4 Hz, H-5), 4.52 (d, 1H, J = 8.7 Hz, H-4), 4.42–
4.19 (m, 3H, benzylic CH2, H-2), 4.14–3.92 (m, 3H, allylic CH2, H-
3) 2.46 (br s, 2 ꢁ –OH); 13C NMR (75 MHz, CHCl3): d 139.3, 138.0,
137.9, 134.4, 133.8, 128.2, 128.1, 127.9, 127.7, 127.5, 127.4,
117.7, 117.0, 103.0, 96.3, 83.9, 82.9, 81.6, 81.3, 79.1, 78.3, 74.0,
71.7, 71.3, 70.2; HRMS m/z [M+Na]+: calcd for C21H24O5Na,
379.1521; found: 379.1519.
(2.05 g, 72%) as a white solid, mp 100–103 °C; [
0.75, CHCl3); IR (Neat): 2998, 2924, 1713, 1374, 1166,
1022 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.67 (d, 1H, J = 16.0 Hz,
a]D = +79.0 (c
;
olefinic), 7.51–7.42 (m, 4H, Ar-H), 7.35–7.22 (m, 6H, Ar-H), 6.44
(d, 1H, J = 16.0, olefinic), 6.01 (d, 1H, J = 9.6 Hz, H-5), 5.84 (d, 1H,
J = 3.7 Hz, H-1), 5.78 (m, 1H, olefinic), 5.27 (dd, J = 1.3, 10.3 Hz,
1H, olefinic), 5.16 (d, 1H, J = 10.3 Hz, olefinic), 4.52–4.46 (m, 2H,
H-2, H-4), 4.10 (q, 1H, J = 5.6 Hz, allylic CH), 3.98 (d, 1H,
J = 3.2 Hz, H-3), 3.91 (q, 1H, J = 6.2 Hz, allylic CH), 1.45 (s, 3H, –
CH3), 1.28 (s, 3H, –CH3); 13C NMR (75 MHz, CHCl3): d 164.9,
145.3, 138.3, 134.2, 133.8, 130.4, 128.9, 128.4, 128.3, 128.1,
127.5, 118.4, 117.8, 111.7, 105.3, 82.1, 81.5, 81.0, 72.3, 71.5, 26.9,
26.3; HRMS m/z [M+Na]+: calcd for C26H28O6Na, 459.1783; found:
459.1765.
4.1.9. (3aR,5R,6S,6aS)-6-(Allyloxy)-5-((R)-
benzyloxy(phenyl)methyl)-tetrahydro furo [3,2-b]furan-2(5H)-
one 17
To a stirred solution of 8 (0.25 g, 0.70 mmol) in dry DMF (4 mL),
Meldrum’s acid (0.20 g, 0.14 mmol) and Et3N (cat) were added at
0 °C and the reaction mixture was stirred at 40 °C for 16 h. The sol-
vent was removed in vacuum using toluene as a co-solvent. The ob-
tained crude residue was purified by column chromatography (60–
120 silica gel, 1:9 EtOAc/n-hexane) to afford 17 (0.22 g, 84%) as a
4.1.6. (R)-((3aR,5R,6S,6aR)-6-(Allyloxy)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3] dioxol-5-yl)(phenyl)methanol 9
To a stirred solution of 15a (1.35 g, 3.18 mmol) in MeOH
(15 mL), K2CO3 (1.33 g, 9.55 mmol) was added at room tempera-
ture and stirring was continued for 2 h. It was quenched with satd
aq NH4Cl solution (5 mL), MeOH was removed, and the residue was
extracted with EtOAc (2 ꢁ 50 mL). The combined EtOAc extracts
were washed with H2O (10 mL), brine (10 mL), dried (Na2SO4),
evaporated, and the residue was purified by column chromatogra-
phy (60–120 silica gel, 1.2:8.5 EtOAc/n-hexane) to furnish 9 (0.8 g,
81%) as a yellowish red liquid. The spectral data of 9 and 9 (minor
isomer) obtained in Grignard reaction (Section 4.1.4) are compara-
ble with each other.
white powder, mp 88–90 °C; [
a]
D = ꢀ0.9 (c 0.44, CHCl3); IR (Neat):
3449, 2920, 2852, 1787, 1139, 1070 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d 7.39–7.19 (m, 10H, Ar-H), 5.91–5.78 (m, 1H, olefinic),
5.27 (dd, 1H, J = 1.5, 17.3 Hz, olefinic), 5.16 (dd, 1H, J = 1.1,
10.3 Hz, olefinic), 4.85 (s, 2H, H-8, H-4), 4.58 (d, 1H, J = 8.8 Hz, H-
7), 4.36, 4.23 (2d, 2H, J = 19.8 Hz, benzylic CH2), 4.29 (d, 1H,
J = 3.0 Hz, H-5), 4.10–4.04 (m, 3H, allylic CH2, H-6), 2.57 (dt, 1H,
J = 2.8, 18.7 Hz, –COCH), 2.43 (d, 1H, J = 18.7 Hz, COCH); 13C NMR
(75 MHz, CHCl3): d 175.4, 139.1, 137.9, 133.8, 128.4, 128.2, 127.7,
127.5, 117.9, 84.9, 83.2, 80.5, 78.0, 76.8, 72.0, 70.1, 35.8; HRMS
m/z [M+Na]+: calcd for C23H24O5Na, 403.1521; found: 403.1504.
4.1.7. (3aR,5R,6S,6aR)-6-(Allyloxy)-5-((R)-
benzyloxy(phenyl)methyl)-2,2-dimethyl-tetrahydrofuro[2,3-
d][1,3]dioxole 16
4.1.10. (3aR,5S,6S,6aR)-5-((R)-Benzyloxy(phenyl)methyl)-6-
hydroxy-tetrahydro furo[3,2-b]furan-2(5H)-one 7
To a stirred and cooled (0 °C) suspension of NaH (0.07 g,
2.87 mmol, 60% w/w dispersion in paraffin oil) in THF (2 mL), a
solution of 9 (0.4 g, 1.37 mmol) in THF (2 mL) was added dropwise.
After 15 min, BnBr (0.17 mL, 1.43 mmol) was added at 0 °C and
stirring was continued at room temperature for 6 h. The reaction
mixture was treated with satd aq NH4Cl solution (5 mL) and ex-
tracted with EtOAc (2 ꢁ 30 mL). Combined organic layers were
washed with water (10 mL), brine (10 mL), dried (Na2SO4), and
evaporated. The crude residue was purified by column chromatog-
raphy (60–120 silica gel, 1:9 EtOAc/n-hexane) to afford 16 (0.44 g,
To a stirred solution of 17 (0.18 g, 0.47 mmol) in MeOH (2 mL),
10% Pd–C (cat), PTSA (cat), and H2O (8 mg, 0.47 mmol) were added
and stirred at 80 °C for 12 h. The reaction mixture was filtered
through Celite, the filtrate was dried (Na2SO4), evaporated, and
the residue was purified by column chromatography (60–120 silica
gel, 2.5:7.5 EtOAc/n-hexane) to afford 7 (0.13 g, 81%) as a white so-
lid, mp 108–110 °C; [
a
]
D = ꢀ57.7 (c 0.44, CHCl3); IR (Neat): 3420,
2927, 1722, 1452, 1060, 754 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d
7.47–7.21 (m, 10H, Ar-H), 5.00 (t, 1H, J = 4.5 Hz, H-8), 4.79 (d, 1H,
J = 4.5 Hz, H-7), 4.74 (d, 1H, J = 5.2 Hz, H-5), 4.55, 4.32 (2d, 2H,
J = 11.3 Hz, benzylic CH2), 4.43 (s, 1H, H-4), 4.00 (dd, 1H, J = 2.2,
5.2 Hz, H-6), 3.86 (br s, –OH), 2.62 (dd, 2H, J = 6.0, 18.8 Hz, –
COCH2); 13C NMR (75 MHz, CHCl3): d 175.3, 137.5, 137.0, 128.8,
128.6, 128.1, 127.8, 127.1, 87.3, 83.3, 80.1, 74.0, 71.3, 35.9; HRMS
m/z [M+Na]+: calcd for C20H20O5Na, 363.1208; found: 363.1205.
85%) as a light yellow liquid. [
a]
D = ꢀ36.2 (c 2.0, CHCl3); IR (Neat):
2922, 1464, 1450, 1019 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.32–
7.23 (m, 10H, Ar-H), 5.91–5.77 (m, 1H, olefinic), 5.77 (s, 1H, H-1),
5.27 (t, 1H, J = 7.5, 17.4 Hz, olefinic), 5.13 (d, 1H, J = 9.8 Hz, H-5),
4.61 (t, 1H, J = 7.5, 17.4 Hz, olefinic), 4.48 (d, 1H, J = 3.0 Hz, H-2),

2654
G. V. M. Sharma, S. Mallesham / Tetrahedron: Asymmetry 21 (2010) 2646–2658
4.1.11. (2R,3S,3aS,6aR)-2-((R)-Benzyloxy(phenyl)methyl)-5-oxo-
hexahydro furo [3,2-b] furan-3-yl cinnamate 18
CHCl3): d 175.4, 138.9, 128.8, 128.4, 125.9, 87.5, 83.0, 77.0, 74.5,
73.5, 36.0; HRMS m/z [M+Na]+: calcd for C13H14O5Na, 273.0738;
found: 273.0726.
To a stirred solution of cinnamic acid (0.03 g, 0.22 mmol) in dry
THF (5 mL), Et3N (0.063 g, 0.61 mmol) was added at 0 °C. After
5 min, 2,4,6-trichlorobenzoyl chloride (0.08 g, 0.31 mmol) was
added and stirring was continued at room temperature for 2 h un-
der at nitrogen atmosphere. The reaction mixture was filtered and
the filtrate was evaporated. The resulting anhydride was dissolved
in toluene (2 mL) and treated with alcohol 7 (0.07 g, 0.20 mmol) in
toluene (2 mL) and DMAP (0.05 g, 0.40 mmol) in toluene (2 mL). It
was stirred at room temperature for 1 h and filtered through Celite.
The filtrate was evaporated and residue was purified by column
chromatography (60–120 silica gel, 1.5:8.5 EtOAc/n-hexane) to af-
4.1.14. (3R,4R,5R)-4-(Allyloxy)-5-((R)-hydroxy(phenyl)methyl)-
tetrahydrofuran-2,3-diol 19
A mixture of 9 (0.6 g, 1.96 mmol) in 30% aq AcOH (10 mL) was
stirred at reflux for 12 h. Work-up was as described for 8 and puri-
fication by column chromatography (60–120 silica gel, 3:7 EtOAc/
n-hexane) gave 19 (0.34 g, 65%) as a colorless liquid. [
0.5, CHCl3); IR (Neat): 3421, 3022, 2922, 1715, 1494, 1152,
1063 cmꢀ1 1H NMR (300 MHz, CDCl3): 7.29 (m, 5H, Ar-H), 5.89
a]D = +38.6 (c
;
(m, 1H, olefinic CH), 5.45–4.62 (m, 5H, olefnic CH2, H-1, H-5, H-
4), 4.12–3.64 (m, 4H, allylic CH2, H-2, H-3), 3.51–3.33 (m, 3 ꢁ –
OH), 13C NMR (75 MHz, CHCl3): d 137.9, 137.4, 135.0, 134.9,
128.5, 127.6, 127.5, 117.4, 117.3, 96.8, 92.7, 83.2, 81.2, 78.2, 74.9,
74.8, 74.6, 73.80, 73.74, 72.27; ESIMS: m/z 289 [[M+Na]+.
ford 18 (0.07 g, 78%) as a white solid, mp 102–103 °C; [
(c 1.0, CHCl3); IR (Neat): 3449, 3030, 2927, 1723, 1494, 1452,
1063 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.65 (d, 1H, J = 15.8 Hz,
a
]D = ꢀ41.3
;
olefinic), 7.49 (m, 2H, Ar-H), 7.41–7.34 (m, 8H, Ar-H), 7.20–7.02
(m, 5H, Ar-H), 6.20 (d, 1H, J = 15.8 Hz, olefinic), 5.74 (d, 1H,
J = 3.0 Hz, H-6), 4.86 (t, 2H, J = 4.5 Hz, H-5, H-4), 4.42 (d, 1H,
J = 9.0 Hz, H-8), 4.39, 4.06 (2d, 2H, J = 11.3 Hz, benzylic CH2) 4.23
(dd, 1H, J = 3.0, 9.0 Hz, H-7), 2.63, 2.56 (dd, 1H, J = 5.2, 18.8 Hz, –
COCH), 2.46 (d, 1H, J = 18.8 Hz, –COCH); 13C NMR (75 MHz, CHCl3):
d 175.0, 165.4, 146.3, 138.6, 137.3, 134.0, 130.9, 129.1, 128.8,
128.7, 128.6, 128.5, 128.4, 128.0, 127.8, 116.9, 85.2, 82.4, 77.5,
77.1, 74.8, 69.9, 35.8; HRMS m/z [M+Na]+: calcd for C29H26O6Na,
493.1627; found: 493.1616.
4.1.15. (3aR,5R,6S,6aS)-6-(Allyloxy)-5-((R)-
hydroxy(phenyl)methyl)-tetrahydro furo[3,2-b]furan-2(5H)-
one 20 and (4S,5R,6R,7R,E)-Methyl 5-(allyloxy)-4,6,7-
trihydroxy-7-phenylhept-2-enoate 10
To a stirred solution of (methoxy carbonylmethylene)triphenyl
phosphorane (0.55 g, 1.69 mmol) in dry toluene (5 mL), a solution
of lactol 19 (0.3 g 1.13 mmol) in dry toluene (5 mL) was added
dropwise at reflux and stirring was continued for 2 h. The reaction
mixture was concentrated under reduced pressure to give a crude
residue, which was purified by column chromatography (60–120
silica gel, 3:7 EtOAc/n-hexane) to afford a mixture of 10 (0.22 g,
58%) and 20 (0.05 g, 13%) in 71% overall yield in a 4:1 ratio. First
eluted was cyclized product 20 as a white solid, mp 76–78 °C;
4.1.12. (2R,3S,3aS,6aR)-2-((R)-Hydroxy(phenyl)methyl)-5-oxo-
hexahydrofuro[3,2-b]furan-3-yl cinnamate 1
To a stirred solution of 18 (0.05 g, 0.10 mmol) in CH2Cl2 (1 mL),
TiCl4 (0.02 g, 0.11 mmol) in CH2Cl2 (1 mL) was added at 0 °C and
stirred at room temperature for 2 h. Saturated NaHCO3 solution
(10 mL) was added at 0 °C and extracted with CHCl3 (3 ꢁ 10 mL).
The combined organic layers were washed with water (10 mL),
brine (10 mL), dried (Na2SO4), and concentrated. The crude residue
was purified by column chromatography (60–120 silica gel, 3:7
EtOAc/n-hexane) to afford 1 (0.03 g, 80%) as a white solid, mp
[a]
+18.4 (c 0.81, CHCl3); IR (Neat): 3461, 2925, 1744, 1465,
D
1142, 1063 cmꢀ1 1H NMR (200 MHz, CDCl3): d 7.35–7.25 (m, 5H,
;
Ar-H), 5.95–5.82 (m, 1H, olefinic CH), 5.26 (q, 2H, J = 18.2 Hz,
olefinic CH2), 4.94–4.84 (m, 2H, H-5, H-8), 4.20–4.02 (m, 3H, H-4,
H-7, H-6), 2.76 (br s, –OH), 2.58 (t, 2H, J = 6.0, 13.6 Hz, –COCH2);
13C NMR (75 MHz, CHCl3): d 175.1, 141.1, 133.1, 128.4, 127.9,
126.2, 118.7, 84.8, 83.2, 81.8, 77.1, 71.9, 71.9; HRMS m/z
[M+Na]+: calcd for C16H18O5Na, 313.1051; found: 313.1061.
168–171 °C; [
a
]
D = +31.6 (c 1.0, CHCl3); IR (KBr): 3422, 2923,
1772, 1712, 1634, 1451, 1159, 1036 cmꢀ1
;
1H NMR (500 MHz,
CDCl3): d 7.82 (d, 1H, J = 16.1 Hz, olefinic), 7.58 (dd, 2H, J = 2.2,
7.4 Hz, Ar-H), 7.45–7.31 (m, 8H, Ar-H), 6.53 (d, 1H, J = 16.1 Hz, ole-
finic), 5.74 (d, 1H, J = 2.9 Hz, H-6), 5.03–5.00 (m, 2H, H-5, H-4), 4.67
(d, 1H, J = 8.0 Hz, H-8), 4.26 (dd, 1H, J = 2.2, 8.0 Hz, H-7), 2.93 (br s,
–OH), 2.71 (dd, 1H, J = 19.0, 5.8 Hz, COCH), 2.62 (d, 1H, J = 19.0 Hz,
COCH); 13C NMR (125 MHz, CHCl3): d 174.8, 166.5, 147.6, 140.3,
133.7, 131.1, 129.0, 128.5, 128.4, 126.8, 116.0, 85.2, 83.0, 77.3,
77.2, 75.4, 70.8, 35.6; HRMS m/z [M+Na]+: calcd for C22H20O6Na,
403.1157; found: 403.1165.
Second eluted was triol ester 10 as
D = ꢀ17.1 (c 1.6, CHCl3); IR (neat): 2924, 2840, 1733, 1514,
1451, 1120, 1015, 750 cmꢀ1 1H NMR (200 MHz, CDCl3):
7.70–7.21 (m, 5H, Ar-H), 6.90 (dd, 1H, J = 5.8, 3.6 Hz, olefinic),
6.09 (d, 1H, J = 5.8 Hz, olefinic), 5.86 (m, 1H, olefinic), 5.70
(q, 2H, J = 8.1 Hz, olefinic), 4.72 (s, 1H, H-7), 4.33 (s, 1H, H-4),
4.24–4.05 (m, 2H, allylic CH2), 3.82 (s, 1H, H-6), 3.58 (s, 3H,
–OCH3), 3.52 (s, 1H, H-5), 3.45 (s, 2H, 2 ꢁ –OH), 2.80 (d, –OH,
J = 7.0 Hz); HRMS m/z [M+Na]+: calcd for C17H22O6Na, 345.1314;
found: 345.1321.
a colorless liquid,
[a]
;
d
4.1.13. (3aR,5R,6S,6aR)-6-Hydroxy-5-((R)-
hydroxy(phenyl)methyl)-tetrahydro furo[3,2-b]furan-2(5H)-
one 4
4.1.16. (1R,2R)-1-((2R,3S)-3-Hydroxy-3,6-dihydro-2H-pyran-2-
yl)-2-phenylethane-1,2-diol 21
To a stirred solution of 7 (0.04 g, 0.12 mmol) in CH2Cl2 (1 mL),
TiCl4 (0.02 g, 0.13 mmol) in CH2Cl2 (1 mL) was added at 0 °C and
stirred at room temperature for 2 h. The reaction mixture was
worked up as described for 1 and this was purified by column chro-
matography (60–120 silica gel, 4.5:5.5 EtOAc/n-hexane) to give 4
To a stirred solution of 10 (0.18 g, 0.55 mmol) in dry toluene
(50 mL), Grubbs-II (catalytic amount) was added and stirred at
reflux for 24 h. Then, it was stirred for an additional 1 h at room
temperature in open air to deactivate the catalyst. The reaction
mixture was filtered through Celite, concentrated, and the residue
was purified by column chromatography (60–120 silica gel, 3:7
EtOAc/n-hexane) to afford 21 (0.08 g, 61%) as a gummy syrup.
(25 mg, 86%) as a white solid, mp 152–155 °C; [
0.18, CHCl3); [ D = +20.0 (c 0.5, EtOH); IR (KBr): 3415, 3340,
2915, 1757, 1457, 1452, 1392, 1160, 1023 cmꢀ1 1H NMR
(500 MHz, CDCl3): 7.44–7.33 (m, 5H, Ar-H), 5.18 (d, 1H,
a]D = +34.2 (c
a
]
;
d
[a]
D = +62.3 (c 0.32, CHCl3); IR (neat): 3473, 3030, 2924, 1510,
J = 4.7 Hz, H-8), 5.10 (t, 1H, J = 4.3, 8.8 Hz, H-4), 4.86 (d, 1H,
J = 4.0 Hz, H-5), 4.39 (s, 1H, H-6), 4.30 (br s, –OH), 4.08 (dd, 1H,
J = 2.8, 4.7 Hz, H-7), 3.09 (br s, –OH), 2.75 (dd, 1H, J = 18.8, 5.9 Hz,
–COCH), 2.66 (d, 1H, J = 18.8 Hz, –COCH); 13C NMR (125 MHz,
1451, 1120 cmꢀ1 1H NMR (200 MHz, CDCl3): d 7.54–7.19 (m, 5H,
;
Ar-H), 5.80 (br s, 2H, olefinic), 4.80 (s, 1H, H-8), 4.11–3.37
(m, 5H, H-5, H-6, H-7, 2 ꢁ –OH); 13C NMR (75 MHz, CHCl3): d
140.9, 129.7, 128.4, 127.8, 126.6, 125.9, 76.0, 75.0, 74.7, 66.1,

G. V. M. Sharma, S. Mallesham / Tetrahedron: Asymmetry 21 (2010) 2646–2658
2655
64.6; HRMS m/z [M+Na]+: calcd for C13H16O4Na, 259.0946; found:
4 and 4 prepared from 7 (Section 4.1.13) are comparable with each
259.0955.
other.
4.1.20. (R)-((3aR,5R,6S,6aR)-6-(Allyloxy)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3] dioxol-5-yl)(phenyl)methyl
cinnamate 15a
4.1.17. (2E,20E)-((1R,2R)-1-((2R,3S)-3-(Cinnamoyloxy)-3,6-
dihydro-2H-pyran-2-yl)-2-phenylethane-1,2-diyl) bis(3-
phenylacrylate) 22
To a solution of 9 (0.1 g, 0.32 mmol) in dry CH2Cl2 (2 mL), cin-
namoyl chloride (0.06 g, 0.36 mmol) and Et3N (0.15 mL,
0.98 mmol) were added at 0 °C and stirred at room temperature
for 12 h. The reaction mixture was quenched with H2O (2 mL)
and extracted with CH2Cl2 (2 ꢁ 20 mL). The combined organic lay-
ers were washed with water (10 mL), brine (10 mL), dried
(Na2SO4), concentrated, and the residue was purified by column
chromatography (60–120 silica gel, 2:8 EtOAc/n-hexane) to afford
15a (0.12 g, 86%) as a white solid, mp 100–102 °C. The spectral data
of 15a and 15a prepared from 15 (Section 4.1.5) are comparable
with each other.
To a stirred solution of 21 (0.05 g, 0.21 mmol) in dry CH2Cl2
(2 mL), cinnamic acid (0.10 g, 0.76 mmol), DCC (0.14 g, 0.7 mmol)
and DMAP (0.15 g, 1.26 mmol) were added and stirred at room
temperature for 12 h. Then the reaction mixture was treated with
H2O (2 mL) and extracted with CH2Cl2 (2 ꢁ 20 mL). The combined
organic layers were washed with water (10 mL), brine (10 mL),
dried (Na2SO4), and concentrated to give a crude residue, which
was purified by column chromatography (60–120 silica gel, 2:8
EtOAc/n-hexane) to afford 22 (0.08 g, 64%) as a white solid, mp
158–160 °C; [
a
]
D = +297.1 (c 0.9, CHCl3); IR (neat): 2908, 1722,
1514, 1455, 1110, 1060 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 7.67
(d, 1H, J = 15.8 Hz, olefinic), 7.61 (d, 1H, J = 15.8 Hz, olefinic),
7.53 (d, 1H, J = 16.6 Hz, olefinic), 7.48 (d, 8H, J = 8.6 Hz, Ar-H),
7.46–7.09 (m, 12H, Ar-H), 6.42 (d, 1H, J = 16.0 Hz, olefinic), 6.38
(d, 1H, J = 15.8 Hz, olefinic), 6.35 (d, 1H, J = 15.8 Hz, olefinic), 6.14
(d, 1H, J = 6.6 Hz, H-8), 6.12–6.01 (m, 2H, olefinic), 5.84 (t, 1H,
J = 6.2, 11.7 Hz, H-5), 5.27 (t, 1H, J = 2.0, 4.5 Hz, H-7), 4.36 (d, 1H,
J = 17.1 Hz, allylic CH), 4.14 (d, 1H, J = 17.3 Hz, allylic CH),
3.78 (dd, 1H, J = 1.8, 4.9 Hz, H-6); 13C NMR (75 MHz, CHCl3):
d 165.9, 146.8, 145.7, 145.4, 137.3, 130.5, 128.9, 128.4, 128.1,
127.9, 126.5, 126.1, 124.0, 122.5, 117.6, 75.3, 74.8, 73.6, 66.5,
65.0; HRMS m/z [M+Na]+: calcd for C40H34O7Na, 649.2202; found:
649.2210.
4.1.21. (R)-((2R,3R,4R)-3-(Allyloxy)-4,5-dihydroxy-
tetrahydrofuran-2-yl)(phenyl) methyl cinnamate 24
A mixture of 15a (0.8 g, 1.83 mmol) in 30% aq AcOH (10 mL)
was stirred at reflux for 14 h. Work-up was as described for 8
and the reaction was purified by column chromatography (60–
120 silica gel, 3:7 EtOAc/n-hexane) to give 24 (0.51 g, 70%) as a pale
yellow liquid. [
a
]
D = +114.9 (c 0.77, CHCl3); IR (neat): 3422, 3020,
2927, 1722, 1514, 1455, 1112, 1060 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d 7.55 (d, 1H, J = 15.8 Hz, olefinic), 7.49–7.42 (m, 4H, Ar-
H), 7.42–7.28 (m, 6H, Ar-H), 6.41 (d, 1H, J = 17.3, olefinic), 6.38
(d, 1H, J = 15.8 Hz, olefinic), 6.13 (d, 1H, J = 17.3 Hz, olefinic), 5.91
(q, 2H, J = 9.0 Hz, olefinic, H-1), 5.40 (s, 2H, H-5, H-2), 4.78 (dd,
1H, J = 4.5, 9.0 Hz, allylic –CH), 4.13 (t, 1H, J = 9.0 Hz, allylic –CH),
4.09 (s, 1H, H-4), 3.57 (s, 1H, H-3); HRMS m/z [M+Na]+: calcd for
4.1.18. (2E,20E)-((1R,2R)-1-((2R,3S)-3-(Cinnamoyloxy)-6-oxo-
3,6-dihydro-2H-pyran-2-yl)-2-phenylethane-1,2-diyl) bis(3-
phenylacrylate) 6
C23H24O6Na, 419.1470; found: 419.1470.
To a stirred solution of 22 (0.04 g, 0.06 mmol) in CH2Cl2 (1 mL),
PDC (0.12 g, 0.32 mmol) and NaOAc (0.02 g, 0.25 mmol) were
added at 0 °C and stirred at reflux for 12 h. The reaction mixture
was diluted with CH2Cl2 (50 mL) and filtered through Celite; the
solvent was evaporated and the residue was purified by column
chromatography (60–120 silica gel, 2:8 EtOAc/n-hexane) to afford
4.1.22. (4S,5R,6R,7R,E)-Ethyl 5-(allyloxy)-7-(cinnamoyloxy)-4,6-
dihydroxy-7-phenyl hept-2-enoate 23
To a stirred solution of (ethoxycarbonylmethylene)triphenyl
phosphorane (0.5 g, 1.51 mmol) in dry toluene (5 mL), a solution
of lactol 24 (0.4 g, 1.01 mmol) in dry toluene (5 mL) was added
dropwise at reflux and stirring was continued for 2 h. Work-up
was as described for 10 and the reaction was purified by column
chromatography (60–120 silica gel, 3:7 EtOAc/n-hexane) to afford
6 (0.03 g, 85%) as a white solid, mp 190–192 °C; [
a]
D = +180.0 (c
0.1, CHCl3); IR (neat): 2923, 1719, 1635, 1459, 1156 cmꢀ1
;
1H
NMR (500 MHz, CDCl3): d 7.74 (d, 1H, J = 15.6 Hz, olefinic), 7.60
(d, 1H, J = 15.6 Hz, olefinic), 7.53 (d, 1H, J = 16.5 Hz, olefinic),
7.54–7.53 (m, 2H, Ar-H), 7.47 (dd, 2H, J = 6.8 Hz, Ar-H), 7.41–7.30
(m, 13H, Ar-H), 7.25–7.14 (m, 3H, Ar-H), 7.03 (dd, 1H, J = 4.9,
9.7 Hz, H-4), 6.46 (d, 1H, J = 15.6 Hz, olefinic), 6.37 (d, 1H,
J = 15.6 Hz, olefinic), 6.28 (d, 1H, J = 9.7 Hz, H-8), 6.26 (d, 1H,
J = 15.6 Hz, olefinic), 6.21 (d, 1H, J = 9.7 Hz, H-3), 5.93 (t, 1H,
J = 6.8, 4.8 Hz, H-7), 5.52 (t, 1H, J = 4.8, 2.9 Hz, H-5), 4.92 (t, 1H,
J = 3.9 Hz, H-6); 13C NMR (125 MHz, CHCl3): d 165.5, 165.2, 165.1,
161.8, 146.6, 146.3, 146.2, 140.5, 135.6, 134.1, 133.9, 133.4,
130.6, 128.9, 128.8, 128.6, 128.2, 127.2, 124.5, 116.9, 116.8,
116.0, 75.5, 73.3, 71.3, 62.9; HRMS m/z [M+Na]+: calcd for
23 (0.34 g, 72%) as a gummy syrup. [
a
]
D = +129.4 (c 0.51, CHCl3); IR
(neat): 3455, 2925, 1712, 1636, 1308, 1166 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.66 (d, 1H, J = 16.0 Hz, olefinic), 7.52–7.29
(m, 10H, Ar-H), 6.97 (dd, 1H, J = 1.7, 15.6 Hz, H-3), 6.45 (d, 1H,
J = 16.0 Hz, olefinic), 6.15 (dd, 1H, J = 1.7, 15.6 Hz, H-2), 5.95–5.82
(m, 1H, olefinic), 5.82 (d, 1H, J = 8.3 Hz, H-7), 5.26 (dd, 1H, J = 1.5,
17.3 Hz, olefinic), 5.20 (d, 1H, J = 10.1 Hz, olefinic), 4.52 (m, 1H,
H-4), 4.22–4.12 (m, 4H, allylic CH2, –OCH2), 4.02 (d, 1H,
J = 8.3 Hz, H-6), 3.62 (dd, 1H, J = 1.5, 5.1 Hz, H-5), 2.95 (br s, –
OH), 2.50 (br s, –OH), 1.29 (t, 3H, J = 6.9 Hz, –CH3); 13C NMR
(75 MHz, CHCl3): d 165.4, 146.0, 145.8, 137.3, 133.9, 133.8, 130.5,
128.8, 128.5, 128.1, 127.5, 122.0, 118.5, 117.2, 78.7, 75.1, 74.2,
73.5, 72.3, 60.4, 14.1; HRMS m/z [M+Na]+: calcd for C27H30O7Na,
489.1889; found: 489.1893.
C40H32O8Na, 663.1994; found: 663.2018.
4.1.19. (3aR,5R,6S,6aR)-6-Hydroxy-5-((R)-
hydroxy(phenyl)methyl)-tetrahydro furo [3,2-b]furan-2(5H)-
one 4
4.1.23. (1R,2R)-2-Hydroxy-2-((2R,3S)-3-hydroxy-6-oxo-3,6-
dihydro-2H-pyran-2-yl)-1-phenylethyl cinnamate 25
To a stirred solution of 20 (0.03 g, 0.10 mmol) in MeOH (2 mL)
10% Pd-C (cat. amount), PTSA (cat. amount), and H2O (2 mg,
0.47 mmol) were added and the reaction mixture was stirred at
80 °C for 8 h. Work-up was as described for 7 and the reaction mix-
ture was purified by column chromatography (60–120 silica gel,
1:1 EtOAc/n-hexane) to afford 4 (0.02 g, 77%) as a white solid.
To a stirred solution of 23 (0.3 g, 0.64 mmol) in dry toluene
(50 mL), Grubbs-II (cat.amount) was added and stirred at reflux
for 12 h. Then, it was stirred for an additional 1 h at room temper-
ature, in open air, to deactivate the catalyst. Work-up was as de-
scribed for 21 and the reaction mixture was purified by column
chromatography (60–120 silica gel, 3:7 EtOAc/n-hexane) to give
Mp: 150–155 °C; [a]D = +39.9 (c 0.11, CHCl3). The spectral data of
25 (0.16 g, 70%) as a gummy brown syrup. [a]D = +166.2 (c 0.1,

2656
G. V. M. Sharma, S. Mallesham / Tetrahedron: Asymmetry 21 (2010) 2646–2658
CHCl3); IR (neat): 3421, 2924, 1708, 1635, 1168, 1089, 765 cmꢀ1
;
7.48–7.37 (2 m, 10H, Ar-H), 6.97 (dd, 1H, J = 5.5, 9.4 Hz, H-4), 6.48
(d, 1H, J = 16.4 Hz, olefinic, H-2), 6.13 (d, 1H, J = 9.4 Hz, H-3), 6.12
(d, 1H, J = 6.3 Hz, H-8), 4.52 (dd, 1H, J = 3.9, 7.0 Hz, H-7), 4.47 (dd,
1H, J = 3.1, 5.5 Hz, H-6), 4.41 (dd, 1H, J = 2.3, 5.5 Hz, H-5); 13C NMR
(125 MHz, CHCl3): d 165.7, 162.9, 146.3, 143.6, 136.4, 134.0, 130.6,
128.9, 128.7, 128.2, 127.6, 122.9, 117.1, 77.0, 74.6, 73.5, 62.8; HRMS
m/z [M+Na]+: calcd for C22H20O6Na, 403.1157; found: 403.1155.
1H NMR (300 MHz, CDCl3): d 7.68 (d, 1H, J = 16.0 Hz, olefinic),
7.52–7.33, 7.32–7.22 (2 m, 10H, Ar-H), 6.44 (d, 1H, J = 15.8 Hz, ole-
finic), 5.98 (d, 1H, J = 6.8 Hz, H-8), 5.96–5.82 (m, 2H, olefinic), 4.35–
4.23 (m, 2H, allylic –CH2), 4.07–3.99 (m, 2H, H-5, H-7), 3.39 (d, 1H,
J = 2.1 Hz, H-6); 13C NMR (75 MHz, CHCl3): d 165.3, 145.4, 137.4,
134.2, 130.2, 130.0, 128.7, 128.1, 127.4, 126.3, 117.8, 96.1, 75.5,
74.6, 73.5, 73.5, 66.3, 64.6; HRMS m/z [M+Na]+: calcd for
C22H22O5Na, 389.1364; found: 389.1367.
4.1.27. (2E,20E)-((1R,2R)-1-((2R,3S)-3-(Cinnamoyloxy)-3,6-
dihydro-2H-pyran-2-yl)-2-phenylethane-1,2-diyl) bis(3-
phenylacrylate) 22
4.1.24. (R)-((4R,4aR,8aS)-2,2-Dimethyl-4,4a,6,8a-
tetrahydropyrano[3,2-d][1,3] dioxin-4-yl)(phenyl)methyl
cinnamate 26
To a stirred solution of 25 (0.04 g, 0.11 mmol) in dry CH2Cl2
(2 mL), cinnamic acid (0.03 g, 0.24 mmol), DCC (0.05 g, 0.25 mmol)
and DMAP (0.06 g, 0.55 mmol) were added and stirred at room
temperature for 12 h. Worked up as described for 22 from 21
and the reaction purified by column chromatography (60–120 sil-
ica gel, 2:8 EtOAc/n-hexane) to afford 22 (0.05 g, 73%) as a white
solid, mp 158–160 °C. The spectral data of 22 and 22 prepared from
21 (Section 4.1.17) are comparable with each other.
To a solution of 25 (0.1 g, 0.27 mmol) in dry CH2Cl2 (2 mL), 2,2-
dimethoxypropane (0.03 g, 0.3 mmol) and PTSA (catalytic amount)
were added at 0 °C and stirred at room temperature for 3 h. The
reaction mixture was quenched with satd aq NaHCO3 (2 mL) solu-
tion and extracted with CH2Cl2 (2 ꢁ 20 mL). The combined organic
layers were washed with water (10 mL), brine (10 mL), dried
(Na2SO4), concentrated, and the residue was purified by column
chromatography (60–120 silica gel, 1.2:8.8 EtOAc/n-hexane) to af-
4.1.28. (R)-((2R,3S,3aS,6aR)-3-(Allyloxy)-5-oxo-
ford 26 (0.09 g, 82%) as
a
colorless solid. Mp 145–148 °C;
hexahydrofuro[3,2-b]furan-2-yl) (phenyl) methyl cinnamate 28
To a stirred solution of 24 (0.05 g, 0.12 mmol) in dry DMF
(2 mL), Meldrum’s acid (0.04 g, 0.25 mmol) and Et3N (catalytic
amount) were added at 0 °C and the reaction mixture was stirred
at 40 °C for 24 h. Work-up was as described for 17 and the reaction
mixture was purified by column chromatography (60–120 silica
gel, 2:8 EtOAc/n-hexane) to afford 28 (0.04 g, 85%) as a white solid,
[a]D = +243.5 (c 0.5, CHCl3); IR (neat): 3422, 2926, 2914, 1722,
1633, 1168, 1085, 1065 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 7.64
(d, 1H, J = 15.6 Hz, olefinic), 7.53–7.46 (m, 2H, Ar-H), 7.43–7.20
(m, 8H, Ar-H), 6.39 (d, 1H, J = 16.4 Hz, olefinic), 6.08 (d, 1H,
J = 9.3 Hz, H-8), 6.05–5.81 (m, 2H, olefinic), 4.46–4.39, 4.35–4.32
(2 m, 1H, H-5), 4.30 (dd, 1H, J = 2.3, 9.3 Hz, H-7), 4.08–4.05, 4.01–
3.98 (2 m, 2H, allylic –CH2), 3.44 (t, 1H, J = 1.5 Hz, H-6), 1.35 (s,
3H, –CH3), 1.25 (s, 3H, –CH3); 13C NMR (75 MHz, CHCl3): d 164.8,
145.0, 138.3, 134.2, 132.2, 130.3, 128.7, 127.9, 127.3, 123.4,
117.8, 99.0, 72.5, 72.4, 67.5, 66.1, 62.5, 29.7, 29.5; HRMS m/z
[M+Na]+: calcd for C25H26O5Na, 429.1677; found: 429.1683.
mp 135–136 °C; [a]D = +233.5 (c 0.4, CHCl3); IR (KBr): 2915, 1727,
1634, 1459, 1154, 1023 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 7.61 (d,
1H, J = 15.8 Hz, olefinic), 7.49–7.24 (m, 10H, Ar-H), 6.43 (d, 1H,
J = 15.8 Hz, olefinic), 5.98 (d, 1H, J = 9.0 Hz, H-8), 5.79 (m, 1H, ole-
finic) 5.24 (d, 1H, J = 16.6 Hz, olefinic), 5.16 (d, 1H, J = 10.6 Hz, ole-
finic), 4.85 (s, 2H, H-4, H-5), 4.44 (d, 1H, J = 8.3 Hz, H-7), 4.25 (s, 1H,
H-6), 4.16–4.10, 4.01–3.95 (m, 2H, allylic –CH2), 2.56 (d, 1H,
J = 18.8 Hz, –COCH), 2.54 (d, 1H, J = 18.8 Hz, –COCH); 13C NMR
(125 MHz, CHCl3): d 175.2, 164.9, 145.4, 134.1, 133.3, 130.5,
128.8, 128.4, 128.1, 127.5, 118.9, 117.5, 99.9, 84.8, 82.0, 80.1,
72.1, 72.0, 35.9; ESIMS: m/z 443 [[M+Na]+.
4.1.25. (R)-((4R,4aR,8aS)-2,2-Dimethyl-6-oxo-4,4a,6,8a-
tetrahydropyrano[3,2-d][1,3] dioxin-4-yl)(phenyl)methyl
cinnamate 27
To a stirred solution of 26 (0.07 g, 0.17 mmol) in CH2Cl2 (2 mL),
PDC (0.2 g, 0.51 mmol) and NaOAc (0.03 g, 0.34 mmol) were added
at 0 °C and then stirred at reflux for 12 h. Work-up was as de-
scribed for 6 and the reaction mixture was purified by column
chromatography (60–120 silica gel, 2:8 EtOAc/n-hexane) to afford
4.1.29. (R)-((2S,3S,3aR,6aR)-3-Hydroxy-5-oxo-
hexahydrofuro[3,2-b]furan-2-yl) (phenyl) methyl cinnamate 2
To a stirred solution of 28 (0.03 g, 0.07 mmol) in MeOH (2 mL),
10% Pd–C (cat. amount) and PTSA (cat. amount) were added and
stirred at 80 °C for 12 h. The reaction was neutralized with Et3N
(1 mL), filtered through Celite, and concentrated and the residue
was purified by column chromatography (60–120 silica gel, 3:7
EtOAc/n-hexane) to afford 2 (0.02 g, 81%) as a white solid, m.p.
27 (0.05 g, 69%) as a colorless semi solid. [
a]
D = +200 (c 0.1, CHCl3);
IR (neat): 3444, 2926, 1723, 1657, 1163, 1065 cmꢀ1
;
1H NMR
(200 MHz, CDCl3): d 7.70 (d, 1H, J = 16.1 Hz, olefinic), 7.56–7.29
(m, 10H, Ar-H), 6.81 (dd, 1H, J = 5.8, 10.2 Hz, H-4), 6.38 (d, 1H,
J = 16.1 Hz, olefinic), 6.22 (d, 1H, J = 9.5 Hz, H-3), 6.11 (d, 1H,
J = 8.8 Hz, H-8), 5.29 (m, 2H, H-5, H-6), 4.34–4.24 (m, 1H, H-7),
1.35 (s, 3H, –CH3), 1.25 (s, 3H, –CH3); 13C NMR (75 MHz, CHCl3):
d 164.7, 162.5, 145.5, 140.2, 130.3, 128.8, 128.1, 128.0, 127.4,
125.6, 117.4, 99.6, 72.3, 71.7, 69.1, 60.2, 29.6, 29.0; HRMS m/z
[M+Na]+: calcd for C25H24O6Na, 443.1470; found: 443.1474.
145–148 °C; [
a]
D = n+108 (c 0.37, CHCl3); IR (KBr): 3423, 2923,
2853, 1729, 1634, 1459, 1163 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d
7.70 (d, 1H, J = 15.8 Hz, olefinic), 7.48–7.40, 7.38–7.31 (2 m, 10H,
Ar-H), 6.41 (d, 1H, J = 15.8 Hz, olefinic), 5.91 (d, 1H, J = 9.0 Hz, H-
8), 4.90 (q, 1H, J = 4.5 Hz, H-4), 4.90 (s, 1H, H-5), 4.36 (d, 1H,
J = 1.5 Hz, H-6), 4.19 (d, 1H, J = 2.2 Hz, H-7), 4.16 (br s, –OH), 2.67
(dd, J = 18.6, 5.3 Hz, –COCH), 2.56 (d, 1H, J = 18.6 Hz, –COCH); 13C
NMR (75 MHz, CHCl3): d 175.2, 167.4, 147.3, 136.7, 133.9, 130.9,
129.0, 128.6, 128.3, 127.7, 116.6, 87.0, 82.4, 77.1, 77.0, 73.2, 72.8,
35.8; HRMS m/z [M+Na]+: calcd for C22H20O6Na, 403.1157; found:
403.1143.
4.1.26. (1R,2R)-2-Hydroxy-2-((2R,3S)-3-hydroxy-6-oxo-3,6-
dihydro-2H-pyran-2-yl)-1-phenylethyl cinnamate 5
To a stirred solution of 27 (0.03 g, 0.07 mmol) in dry CH2Cl2
(1 mL), CF3COOH (1 mL) and H2O (1 mL) were added at 0 °C and stir-
red at room temperature for 24 h. The reaction mixture was
quenched with satd aq NaHCO3 solution (0.5 mL) and extracted with
CH2Cl2 (2 ꢁ 20 mL). The combined organic layers were washed with
H2O (10 mL), brine (10 mL), dried (Na2SO4), and concentrated and
the residue was purified by column chromatography (60–120 silica
gel, 2:3 EtOAc/n-hexane) to afford 5 (0.02 g, 74%) as colorless nee-
4.1.30. (3aR,5R,6S,6aR)-5-((R)-Hydroxy(phenyl)methyl)-2,2-
dimethyl-tetrahydro furo[2,3-d][1,3]dioxol-6-ol 29 and
(3aR,5R,6S,6aR)-5-((S)-hydroxy (phenyl)methyl)-2,2-dimethyl-
tetrahydro furo [2,3-d][1,3]dioxol-6-ol 30
To a stirred suspension of Mg (0.17 g, 7.0 mmol) in dry THF
(5 mL), bromobenzene (0.3 mL, 5.26 mmol) was added at room
dles, mp 180–182 °C; [
3449, 2924, 1718, 1635, 1459, 1218, 1163, 771 cmꢀ1
(500 MHz, CDCl3): d 7.75 (d, 1H, J = 16.4 Hz, olefinic), 7.55–7.48,
a]
D = +101.4 (c 0.22, CHCl3); IR (Neat):
;
1H NMR

G. V. M. Sharma, S. Mallesham / Tetrahedron: Asymmetry 21 (2010) 2646–2658
2657
temperature. After 30 min, the reaction was cooled to 0 °C and a
4.1.33. (R)-((3aR,5R,6S,6aR)-6-(Cinnamoyloxy)-2,2-dimethyl-
solution of 14 (0.4 g, 1.75 mmol) in dry THF (5 mL) was added
dropwise. Stirring was continued at room temperature for 10 h.
Work-up was as described for 15 and the reaction mixture was
purified by column chromatography (60–120 silica gel, 3:7
EtOAc/n-hexane) to afford a mixture of 29 (0.27 g, 59%) and 30
(0.07 g, 15%) in 74% overall yield in a 4:1 ratio. First eluted was
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(phenyl)methyl
cinnamate 32
To a stirred solution of diol 29 (0.05 g, 0.18 mmol) and Et3N
(0.2 mL, 0.90 mmol) in CH2Cl2 (2 mL), cinnamoyl chloride (0.07 g,
0.42 mmol) was added at 0 °C and stirred at room temperature
for 12 h. Work-up and purification as described above afforded
32 (0.07 g, 71%) as a white solid. Mp 125–126 °C; The spectral data
of 32 and 32 prepared from 31 (Section 4.1.33) are comparable
with each other.
minor isomer (30) as a white solid, mp 104–107 °C; [
a
]
;
D = ꢀ56.2
(c 0.72, CHCl3); IR (KBr): 3319, 2928, 1453, 1059 cmꢀ1
1H NMR
(300 MHz, CDCl3): d 7.39–7.25 (m, 5H, Ar-H), 5.92 (d, 1H, J = 3.7,
H-1), 5.19 (s, 1H, H-5), 4.49 (s, –OH), 4.40 (d, 1H, J = 2.9, H-2),
4.08 (d, 2H, J = 4.4, H-4, H-3), 3.79 (br s, –OH), 1.42 (s, 3H, –CH3),
1.26 (s, 3H, –CH3); 13C NMR (75 MHz, CHCl3): d 139.9, 128.6,
128.1, 126.1, 111.6, 104.9, 85.0, 82.1, 75.3, 73.2, 26.7, 26.0; ESIMS:
m/z 289 [M+Na]+.
4.1.34. (R)-((2R,3R,4R)-3-(Cinnamoyloxy)-4,5-dihydroxy-
tetrahydrofuran-2-yl) (phenyl) methyl cinnamate 33
A solution of 32 (0.22 g, 0.42 mmol) in THF (2 mL) and 30% aq
AcOH was treated with (10 mL) cat. amount of concd HCl and stir-
red at reflux for 8 h. The reaction mixture was quenched with NaH-
CO3 and extracted with EtOAc (2 ꢁ 40 mL). The combined organic
layers were dried (Na2SO4), concentrated, and purified by column
chromatography (60–120 silica gel, 3:7 EtOAc/n-hexane) to give
the diol 33 (0.14 g, 69%) as a white solid, mp 128–131 °C;
Second eluted was major diastereomer 29 as a white solid, mp
164–167 °C; [
a]
D = +31.2 (c 0.35, CHCl3); IR (KBr): 3323, 2924,
1493, 1108, 1028 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d.7.47–7.26
(m, 5H, Ar-H), 5.96 (d, 1H, J = 3.7 Hz, H-1), 4.99 (d, 1H, J = 4.4 Hz,
H-5), 4.43 (d, 1H, J = 3.7 Hz, H-2), 4.29 (dd, 1H, J = 2.9, 3.6 Hz, H-
3), 4.09 (t, 1H, J = 4.4 Hz, H-4), 3.21 (d, 1H, J = 5.1 Hz, –OH), 2.70
(d, 1H, J = 5.87 Hz, –OH), 1.45 (s, 3H, –CH3), 1.30 (s, 3H, –CH3);
13C NMR (75 MHz, CHCl3): d 140.1, 128.6, 128.3, 126.7, 112.0,
104.9, 85.4, 82.7, 76.0, 72.5, 26.8, 26.2; HRMS m/z [M+Na]+: calcd
for C14H18O5Na, 289.1051; found: 289.1055.
[a
]
D = ꢀ235.7 (c 0.28, CHCl3); IR (neat): 3416, 2978, 1715, 1319,
1060, 1030 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.63 (d, 1H,
;
J = 16.0 Hz, olefinic), 7.53–7.46 (m, 5H, Ar-H, olefinic –CH), 7.36–
7.24 (m, 11H, Ar-H), 6.39 (d, 1H, J = 16.0 Hz, olefinic), 6.32 (d, 1H,
J = 15.8 Hz, olefinic), 6.02 (d, 1H, J = 9.0 Hz, H-5), 5.44 (d, 1H,
J = 3.9 Hz, H-1), 5.38 (dd, 1H, J = 2.6, 5.4 Hz, H-3), 4.80 (dd, 1H,
J = 4.7, 9.2 Hz, H-4), 4.16 (t, 1H, J = 3.3, 6.4 Hz, H-2), 3.80 (br s, –
OH), 3.51 (br s, –OH); HRMS m/z [M+Na]+: calcd for C29H26O7Na,
509.1576; found: 509.1555.
4.1.31. (R)-((3aR,5S,6S,6aR)-6-Hydroxy-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3] dioxol-5-yl)(phenyl)methyl
cinnamate 31
To a stirred solution of 29 (0.24 g, 0.90 mmol) in dry THF (5 mL),
PPh3 (0.47 g, 1.8 mmol) and cinnamic acid (0.16 g, 1.08 mmol)
were added. After 20 min DIAD (0.03 g, 1.62 mmol) was added at
0 °C and the reaction mixture was stirred at room temperature
for 5 h. Work-up was as described for 15a and the reaction mixture
was purified by column chromatography (60–120 silica gel, 3:7
EtOAc/n-hexane) to furnish 31 (0.22 g, 62%) as a white semi solid,
4.1.35. (R)-((2R,3S,3aS,6aR)-3-(Cinnamoyloxy)-5-oxo-
hexahydrofuro[3,2-b]furan-2-yl)(phenyl) methyl cinnamate 3
To a stirred solution of 33 (0.04 g, 0.08 mmol) in dry DMF
(2 mL), Meldrum’s acid (0.02 g, 0.16 mmol) and Et3N (cat. amount)
were added at 0 °C and the reaction mixture was stirred at 40 °C for
36 h. Work-up was as described for 17 and purification by column
chromatography (60–120 silica gel, 2:8 EtOAc/n-hexane) gave 3
[
a]
D = +116 (c 0.51, CHCl3); IR (neat): 2941, 2844, 1715, 1060,
770 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.76 (d, 1H, J = 16.1 Hz,
;
(0.03 mg, 83%) as a white solid, mp 195–196 °C; [
a
]
D = ꢀ102.7 (c
olefinic), 7.47–7.34 (m, 10H, Ar-H), 6.48 (d, 1H, J = 16.1 Hz, ole-
finic), 5.95 (d, 1H, J = 8.8 Hz, H-5), 5.82 (d, 1H, J = 3.6 Hz, H-1),
4.51 (d, 1H, J = 2.9 Hz, H-2), 4.28 (d, 1H, J = 9.5 Hz, H-4), 4.11 (s,
1H, H-3), 3.80 (br s, –OH), 1.45 (s, 3H, –CH3), 1.30 (s, 3H, –CH3);
13C NMR (75 MHz, CHCl3): d 166.1, 145.8, 137.2, 133.5, 130.2,
128.4, 128.0, 127.2, 116.7, 111.2, 104.6, 84.3, 81.4, 73.6, 72.3,
26.4, 25.7; HRMS m/z [M+Na]+: calcd for C23H24O6Na, 419.1470;
found: 419.1482.
0.24, CHCl3); IR (KBr): 2924, 1721, 1635, 1092, 1029 cmꢀ1
;
1H
NMR (500 MHz, CDCl3): d 7.71 (d, 1H, J = 16.6 Hz, olefinic), 7.53
(d, 1H, J = 16.6 Hz, olefinic), 7.50 (dd, 4H, J = 7.3 Hz, Ar-H), 7.43–
7.32 (m, 11H, Ar-H), 6.46 (d, 1H, J = 16.6 Hz, olefinic), 6.35 (d, 1H,
J = 16.6 Hz, olefinic), 6.04 (d, 1H, J = 9.3 Hz, H-8), 5.81 (d, 1H,
J = 3.1 Hz, H-6), 5.04 (dd, 1H, J = 4.1, 9.3 Hz, H-4), 5.00 (d, 1H,
J = 4.1 Hz, H-4), 4.63 (dd, 1H, J = 3.1, 9.3 Hz, H-6), 2.71 (dd, 1H,
J = 6.2, 18.7 Hz, –COCH), 2.64 (d, 1H, J = 18.7 Hz, –COCH); 13C
NMR (125 MHz, CHCl3): d 174.6, 165.5, 165.4, 146.9, 145.8, 137.5,
134.0, 133.9, 130.8, 130.5, 128.9, 128.8, 128.6, 128.4, 128.2,
127.4, 117.0, 116.1, 85.3, 81.3, 77.5, 74.6, 72.0, 35.8; HRMS m/z
[M+Na]+: calcd for C31H26O7Na, 533.1576; found: 533.1560.
4.1.32. (R)-((3aR,5R,6S,6aR)-6-(Cinnamoyloxy)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(phenyl)methyl
cinnamate 32
To a stirred solution of carbinol 31 (0.19 g, 0.48 mmol) and Et3N
(0.2 mL, 1.52 mmol) in CH2Cl2 (5 mL), cinnamoyl chloride (0.09 g,
0.53 mmol) was added at 0 °C and stirred at room temperature
for 12 h. The reaction mixture was diluted with CH2Cl2 (30 mL),
washed with H2O (10 mL), brine (10 mL), dried (Na2SO4), and con-
centrated and the residue was purified by column chromatography
(60–120 silica gel, 2:8 EtOAc/n-hexane) to afford 32 (0.2 g, 79%) as
Acknowledgment
One of the authors (S.M.) thanks the CSIR, New Delhi, India, for
the financial support in the form of a fellowship.
a white solid, mp 125–126 °C; [
a]
D = ꢀ297.1 (c 0.23, CHCl3); IR
(KBr): 1716, 1630, 1168, 1030 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
References
d 7.63 (d, 1H, J = 16.0 Hz, olefinic), 7.54–7.27 (m, 16H, Ar-H, olefinic
–CH), 6.41 (d, 1H, J = 16.4 Hz, olefinic), 6.34 (d, 1H, J = 16.2 Hz,
olefinic), 6.06 (d, 1H, J = 9.4 Hz, H-5), 5.92 (d, 1H, J = 3.5 Hz, H-1),
5.50 (d, 1H, J = 3.0 Hz, H-3), 4.68 (dd, 1H, J = 3.0, 9.2 Hz, H-4),
4.57 (d, 1H, J = 3.5 Hz, H-2), 1.51 (s, 3H, –CH3), 1.30 (s, 3H, –CH3);
HRMS m/z [M+Na]+: calcd for C32H30O7Na, 549.1889; found:
549.1875.
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