Stereoselective synthesis of (-)-synparvolide B

Article abstract of DOI:10.1016/j.tetasy.2011.04.024

The stereoselective synthesis of (-)-synparvolide B, isolated from Syncolostemon parviflorus, has been accomplished from (S)-ethyl lactate. A 1,2-chelation controlled allylation, Sharpless asymmetric epoxidation, Brown asymmetric allylation and RCM reactions were used as the key steps.

Full text of DOI:10.1016/j.tetasy.2011.04.024

Tetrahedron: Asymmetry 22 (2011) 866–871
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of (ꢀ)-synparvolide B
a,
⇑
a
a,b
Gowravaram Sabitha , Allu Senkara Rao , Jhillu Singh Yadav
a
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b
KingSaud University, PO Box 2455, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of (ꢀ)-synparvolide B, isolated from Syncolostemon parviflorus, has been
accomplished from (S)-ethyl lactate. A 1,2-chelation controlled allylation, Sharpless asymmetric epoxida-
tion, Brown asymmetric allylation and RCM reactions were used as the key steps.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 28 March 2011
Accepted 8 April 2011
Available online 14 June 2011
1
. Introduction
to undertake its total synthesis. So far, only a single report has ap-
peared for the synthesis of this molecule.
5
Six-membered lactones are important both in synthetic applica-
tions and also as naturally occurring compounds.1 In particular,
,b-unsaturated d-lactones containing a polyoxygenated chain
2
. Results and discussion
a
show antimicrobial, antifungal activities, or cytotoxicity against
human tumor cells. Three such poly hydroxyl d-pyrones, syn-
Looking at the structure of synparvolide B retrosynthetically,
2
we envisaged that the pyranone could be obtained by olefin ring-
closing metathesis (RCM) of the homoallyl acrylate 4, which in turn
could be prepared via asymmetric allylation of the aldehyde pre-
pared in situ from chiral propargylic alcohol 5 by Lindlar’s reduc-
tion of the triple bond followed by oxidation of the resulting
alcohol and acylation of the homo allylic alcohol (Scheme 1). The
remaining polyoxygenated chain could be prepared from ethyl lac-
tate 8 by using 1,2-chelation controlled allylation and Sharpless
asymmetric epoxidation reactions as the key steps.
parvolide A 1, synparvolide B 2 and synparvolide-C 3 (Fig. 1) were
3
isolated in 1996 by Davies-Coleman and Rivette from the leaves of
Syncolostemon parviflorus, a medicinal plant that is used as an eme-
tic to treat a loss of appetite. Spectroscopic and chemical evidence
were used to establish the structures of synparvolides A–C. These
a,b-unsaturated six membered lactone molecules contain an acet-
ylated side chain. As a part of our program on the synthesis of bio-
4
logically active lactones, synparvolide B 2 attracted our attention
The synthesis of synparvolide B 2 began with the homoallylic
alcohol 11 with a syn-configuration (Scheme 2), prepared from
6
(
S)-ethyl lactate 8, according to a literature procedure reported
OAc
OAc
O
t
from (R)- Bu lactate through MOM ether formation, reduction of
the ester function, oxidation of the alcohol to the aldehyde, which
without purification was subjected to a 1,2-chelation controlled
OAc OH
O
OAc OH
O
7
allylation. The MOM group of compound 11 was deprotected
O
O
O
and the resulting diol was protected to give acetonide 7, anticipat-
ing that the MOM group could be used at a later stage for its selec-
tive removal in the presence of acetate groups. The oxidative
cleavage of the terminal double bond in 7 gave the aldehyde, which
was then subjected to Wittig olefination for the homologation of
Synparvolide A 1
Synparvolide B 2
OAC
OH
the chain using a stabilized ylide, Ph
unsaturated ester 13. The ester group was reduced with DIBAL-H
in CH Cl
to give alcohol 14. The Sharpless epoxidation8 of allyl
alcohol 14 with L-(+)-DIPT and TBHP afforded the epoxy alcohol
(94:6 dr). The minor diastereomer was separated at a later stage
by column chromatography. Alcohol 6 was converted to the chlo-
ride with triphenylphosphine and CCl at reflux and was then trea-
3
P@CHCOOEt to give a,b-
H
H
O
OH
Synparvolide C 3
Figure 1.
2
2
O
6
a
,b-Unsaturated lactones.
4
9
⇑
Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
ted with n-BuLi in THF to give acetylenic alcohol 15 as reported.
The protection of secondary hydroxyl group in 15 as the MOM
0
957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.04.024

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 866–871
867
OAc
O
RCM
OAc OH
O
O
OMOM
O
2
O
4
O
O
O
O
OH
OH
O
O
O
O
OMOM
7
6
5
OH
OEt
O
8
Scheme 1. Retrosynthetic analysis of synparvolide B 2.
OR
OMOM
OH
OR
O
b
c
d
e
OEt
82%
76%
92%
75%
O
10
OH
O
7
8
; R = H
a
11; R = MOM
9
; R = MOM
1
2; R = H
O
O
O
OEt
f
OH
g
OH
84%
94%
O
O
13
O
O
O
14
O
6
O
O
OH
j
h
i
75%
OH
8
1%
9
2%
O
OR
O
OMOM
O
OMOM
17
1
1
5; R = H
5
6; R = MOM
O
O
k
l
81%
85%
OMOM
O
O
O
O
OMOM
OH
18
4
O
OH
m
n
90%
OMOM
O
87%
O
OH
OMOM
O
19
20
O
O
OAc
OAc
o
p
90%
92%
OAc OMOM
O
OAc OH
O
21
O
synparvolide B 2
O
Scheme 2. Reagents and conditions: (a) MOM-Cl, DIPEA, dry CH
2) allyltributyltin, MgBr , dry CH Cl
ꢁOEt
rt, 3 h, 92%; (e) (1) OsO /NMO, acetone/H
CH Cl , 0 °C, 1 h, 84%; (g) Ti(OiPr) , (+)-DIPT, TBHP, dry CH
81% from two steps); (3) MOMCl, DIPEA, dry CH Cl , 0 °C–rt, 2 h, 91%; (i) EtMgBr, (CH
DMSO, dry CH Cl , 0 °C–rt, 10 h; (2) (+)-IPC B(allyl) (1.0 M solution in pentane), dry diethylether, ꢀ100 °C, 30% H
crude); (l) acryloylchloride, TEA, DMAP, dry CH Cl , 0 °C, 1 h, 85%; (m) Grubbs’-I, dry CH Cl , reflux, 15 h (90%); (n) PPTS, MeOH, 0 °C–rt, 24 h, 87%; (o) Ac
CH Cl , 0 °C–rt, 30 min, 90%; (p) TiCl , CH Cl , 0 °C to rt, 1 h, 82%.
2
Cl
2
, 0 °C–rt, 4 h, 95%; (b) LiAlH
4
, dry THF, 0 °C–rt, 1 h, 82%; (c) (1) (COCl)
2
, DMSO, TEA, dry CH
2
Cl
2
ꢀ78 °C, 2 h;
(
2
2
2
2
, ꢀ78 °C to ꢀ10 °C, 16 h (76% for two steps); (3) 3 M HCl, MeOH/CH
O (1:1), rt, 24 h; (2) NaIO , THF/H O (2:1), 0 °C; (3) Ph P@CHCO
Cl
, ꢀ20 °C, 24 h, 94% (94:6 dr, crude); (h) (1) PPh
O) , dry THF, rt, 5 h, 75%; (j) Pd/C, CaCO
(aq), 1 M NaOH, 2 h, (81% for two steps) (90:10 dr,
O, TEA, DMAP, dry
3 2 2
CN (1:1), 0 °C–rt, 2 h, 86%; (d) 2,2-DMP, PPTS, dry CH Cl , 0 °C–
4
2
4
2
3
2
Et, benzene, reflux, 1 h, (75% for three steps); (f) DIBAL-H, dry
, NaHCO , dry CCl
, reflux, 5 h; (2) nBuLi, dry THF, ꢀ78 °C, 3 h,
, H , quinoline, EtOAc, rt, 1 h, 92%; (k) (1) IBX,
2
2
4
2
2
3
3
4
(
2
2
2
n
3
2
2
2
2
2 2
O
2
2
2
2
2
2
2
4
2
2

8
68
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 866–871
ether gave compound 16. The free acetylene of 16 was treated with
EtMgBr to generate the carbanion and was quenched with parafor-
maldehyde to afford propargyl alcohol 5.
4.1.2. (4S,5S)-4-Allyl-2,2,5-trimethyl-1,3-dioxolane 7
To a solution of diol 12 (1.16 g, 10.03 mmol) in anhydrous
2 2
CH Cl (10 mL), 2,2-dimethoxy propane (1.6 mL, 13.03 mmol)
Partial hydrogenation of the triple bond to the Z-olefin with
Lindlar’s catalyst afforded allylic alcohol 17 in 92% yield.
We then focused on assembling the pyranone ring. Oxidation of
and pyridinium p-toluenesulfonate (0.25 g, 1.0 mmol) were added
at 0 °C. The mixture was stirred at ambient temperature for 3 h.
Next, NaHCO was added to neutralize the PPTS and filtered. Re-
3
alcohol 17 using IBX in CH
was subjected to stereoselective allylation with (+)-Ipc
provide the expected homoallylic alcohol 18 in 81% yield (for two
steps) with high diastereoselectivity (90:10 dr). Acylation of alco-
hol 18 with acryloyl chloride followed by RCM11 in the presence of
the first-generation Grubbs’ ruthenium catalyst (10 mol %) in
2
Cl
2
/DMSO afforded the aldehyde, which
moval of solvent and purification by column chromatography [sil-
2
B-(allyl) to
ica gel, PE–EtOAc (9.5:0.5)] gave 7 as colorless liquid; yield: 1.44 g,
2
D
5
92%; ½
aꢂ
¼ þ0:4 (c 2.05, CHCl
3
); IR (neat): 3447, 2923, 2855, 1638,
10
ꢀ1 1
1459, 1218, 1034, 763, 667, 443 cm ; H NMR (CDCl , 300 MHz):
3
d 5.89–5.74 (m, 1H), 5.13–5.03 (m, 2H), 3.76–3.65 (m, 1H), 3.57–
3.45 (m, 1H), 2.30 (dd, J = 7.1, 6.2 Hz, 2H), 1.36 (s, 3H), 1.35 (s,
1
3
CH
tional group manipulation. Thus, the acetonide group was depro-
tected and the resulting diol 20 was acetylated to give
diacetate compound 21. Selective deprotection of the MOM group
2
Cl
2
at reflux afforded lactone 19. Our next task was the func-
3
3H), 1.23 (d, J = 6.0 Hz, 3H); C NMR (CDCl , 75 MHz): d 133.8,
117.1, 107.6, 81.1, 76.2, 36.4, 27.2, 27.0, 17.4; ESI-MS: 179
+
a
[M+Na] .
1
2
was achieved using TiCl
4
to afford the target compound (ꢀ)-syn-
4.1.3. (E)-Ethyl 4-((4S,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl)but-
2-enoate 13
parvolide B 2, whose spectroscopic data were identical to those of
3
the natural product.
N-Methylmorpholine N-oxide (1.25 g, 10.68 mmol) and olefin 7
(
1.39 g, 8.90 mmol) were dissolved in 20 mL of acetone/H
2
O (4:1).
Next, OsO (0.02 M in toluene, 0.4 mL) was added, and the solution
was stirred for 24 h at room temperature. After cooling over an ice
bath, the reaction was quenched by the addition of 15 mL of satu-
4
3
. Conclusion
In conclusion, the total synthesis of (ꢀ)-synparvolide B was
3
rated NaHSO . Most of the acetone was removed by rotary evapo-
accomplished in a stereocontrolled manner with 5.6% overall yield
by the creation of stereogenic centers via 1,2-chelation controlled
allylation, Sharpless asymmetric epoxidation, Brown’s asymmetric
allylation. RCM reaction was used for the construction of pyranone
ring.
ration, and the aqueous mixture was extracted three times with
EtOAc (3 ꢃ 20 mL). After removal of the solvent under reduced
pressure the crude diol was used for the next reaction. Sodium per-
iodate (2.48 g, 11.64 mmol) was added to a stirred solution of diol
2
in 20 mL THF/H O (2:1) at 0 °C. After 1 h, the reaction mixture was
filtered and washed with ether (3 ꢃ 30 mL). The filtrate was
4
4
. Experimental
washed with water, brine, dried over anhydrous Na SO and evap-
2
4
orated the solvent to give aldehyde, which was used for the next
reaction.
.1. General
6 6
To a solution of the above aldehyde in C H (20 mL) was added
Reactions were conducted under N
2
in anhydrous solvents such
Ph P@CHCOOEt (4.04 g, 11.60 mmol) and the reaction mixture was
3
as CH
ica-coated plates and visualizing under UV light). n-Hexane (bp
0–80 °C) was used. Yields refer to chromatographically and spec-
2
Cl
2
, THF and EtOAc. All reactions were monitored by TLC (sil-
stirred for 1 h at reflux. After completion of the reaction, monitored
by TLC, C H was removed under reduced pressure, the residue
6
6
6
was dissolved in ether, and petroleum ether was added to it. The
triphenylphosphine oxide crystallized out was filtered off and the
filtrate was concentrated to dryness. The crude product was puri-
fied by column chromatography (eluent: PE–EtOAc, 8:2) to afford
1
13
troscopically ( H and C NMR) homogeneous material. Air sensi-
tive reagents were transferred by syringe or double-ended
needle. Evaporation of solvents was performed at reduced pressure
1
13
on a Buchi rotary evaporator. H and C NMR spectra of samples in
CDCl were recorded on Varian FT-400 MHz and Bruker UXNMR
the pure
steps) as a colorless oil ½
3469, 2983, 2930, 1720, 1655, 1454, 1374, 1313, 1265, 1219,
a,b-unsaturated ester 13 (1.52 g, 75% yield from three
2
D
5
3
a
ꢂ
¼ ꢀ2:2 (c 1.4, CHCl ); IR (neat):
3
FT-300 MHz (Avance) spectrometers. Chemical shift d is reported
relative to TMS (d = 0.0) as an internal standard. Mass spectra were
recorded E1 conditions at 70 eV on ES-MSD (Agilent technologies)
spectrometers. Column chromatography was performed on silica
gel (60–120 mesh) supplied by Acme Chemical Co., India. TLC
was performed on Merck 60 F-254 silica gel plates. Optical rota-
tions were measured with JASCO DIP-370 Polarimeter.
ꢀ
1 1
1175, 1093, 1043, 987, 930, 857, 716, 514 cm
; H NMR (CDCl3,
300 MHz): d 6.98–6.86 (m, 1H), 5.87 (d, J = 15.8 Hz, 1H) 4.17 (q,
J = 6.7 Hz, 2H), 3.76–3.65 (m, 1H), 3.63–3.55 (m, 1H), 2.46–2.39
(m, 2H), 1.37 (s, 3H), 1.35 (s, 3H), 1.30 (t, J = 7.5 Hz, 3H) 1.24 (d,
1
3
J = 6.0 Hz, 3H); C NMR (CDCl , 75 MHz): d 166.0, 143.8, 123.6,
3
108.2, 80.3, 76.2, 60.2, 34.6, 27.2, 26.9, 17.2, 14.1;; ESI-MS: 251
+
[
M+Na] .
4
.1.1. (2S,3S)-Hex-5-ene-2,3-diol 12
To a stirred solution of compound 11 (1.94 g, 12.2 mmol) in
4.1.4. (E)-4-((4S,5S)-2,2,5-Trimethyl-1,3-dioxolan-4-yl)but-2-en-
1-ol 14
CH
the reaction mixture was stirred at the same temperature for 2 h.
The reaction mixture was quenched with solid NaHCO (0.5 g)
3
CN/MeOH (4:1, 20 mL) was added 3 N HCl (2 mL) at 0 °C and
At first, DIBAL-H (7.64 ml, 13.0 mmol) was added to a stirred
solution of ester 13 (1.47 g, 6.50 mmol) in CH Cl (25 mL) at 0 °C
3
2
2
and filtered, after which the solvent was removed under reduced
pressure. The residue was purified by column chromatography [sil-
ica gel, PE–EtOAc (2:8)] to give 12 as a colorless liquid; yield:
and the mixture was allowed to stir at the same temperature for
1 h. After monitoring with TLC, the reaction was quenched with
aq MeOH (1 mL) at 0 °C. Then a saturated solution of sodium potas-
2
5
1
2
9
1
2
.21 g, 86%; ½
a
ꢂ
¼ þ2:4 (c 1.6, CHCl
3
); IR (neat): 3455, 2986,
sium tartrate (15 mL) was added, and extracted with CH Cl2
D
2
935, 1746, 1452, 1376, 1271, 1199, 1157, 1120, 1081, 1039,
(3 ꢃ 15 mL). The organic layer was washed with brine (2 ꢃ
ꢀ1
1
19, 857, 764 cm
H), 5.19–5.09 (m, 2H), 3.66–3.55 (m, 1H), 3.42–3.34 (m, 1H),
.29–2.28 (m, 1H), 2.26–2.12 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H);
;
H NMR (300 MHz, CDCl
3
): d 5.91–5.75 (m,
20 mL) and H O (2 ꢃ 20 mL). The combined organic layer was dried
2
over anhydrous Na SO , concentrated under vacuum and the crude
2
4
1
3
C
alcohol was purified by column chromatography on silica gel (elu-
NMR (75 MHz, CDCl
MS: 139 [M+Na] .
3
): d 134.2, 118.0, 75.0, 70.2, 37.8, 19.2; ESI-
ent: PE–EtOAc, 7:3) to afford 14 as a colorless liquid; yield: 1.01 g
+
25
D
(84%); ½
a
ꢂ
¼ ꢀ4:7 (c 2.0, CHCl ) IR (neat): 3408, 2981, 2934, 1716,
3

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 866–871
869
1
5
3
3
6
379, 1178, 1082, 992, 522 cmꢀ1; 1H NMR (CDCl
.75–5.66 (m, 2H), 4.13–4.03 (m, 2H), 3.75–3.64 (m, 1H), 3.57–
3
, 300 MHz): d
4.1.7. (4S,5S)-4-((S)-2-(Methoxymethoxy)but-3-ynyl)-2,2,5-
trimethyl-1,3-dioxolane 16
.46 (m, 1H), 2.36–2.23 (m, 2H), 1.35 (s, 6H), 1.23 (d, J = 6.0 Hz,
To a solution of alcohol 15 (0.63 g, 3.45 mmol) in anhydrous
H); 1 C NMR (CDCl
3
, 75 MHz): d 132.0, 127.2, 107.8, 81.5, 76.3,
DCM (6 mL) at 0 °C under nitrogen, was added Pr
6.902 mmol) dropwise and after 5 min, MOMCl (0.33 mL,
.140 mmol) was added drop wise. After stirring for 2 h at room
temperature, the reaction mixture was diluted with water, satu-
rated aqueous NH Cl and brine solution and then dried over
anhydrous Na SO . The residue was purified on silica gel column
chromatography (SiO , ethyl acetate/hexane, 2:8) to afford the
pure 16 as a clear colorless liquid (0.716 g, 91%). ½
c 2.1, CHCl ); IR (neat): 3447, 3270, 2983, 2935, 2890, 1635,
453, 1376, 1233, 1156, 1094, 1030, 924, 856, 818, 659,
i
3
2
NEt (1.27 mL,
+
3.0, 34.8, 27.2, 27.0, 17.4; ESI-MS: 209 [M+Na] .
4
4
.1.5. ((2S,3S)-3-(((4S,5S)-2,2,5-Trimethyl-1,3-dioxolan-4-
4
yl)methyl)oxiran-2-yl)methanol 6
2
4
In a 50 mL two neck round bottomed flask, 10 mL of anhydrous
2
CH
the suspension mixture was cooled to ꢀ20 °C. Next, Ti(OiPr)
0.302 mL, 1.03 mmol) and L-(+) DIPT (0.25 g, 1.03 mmol) in anhy-
drous CH Cl (5 mL) were added subsequently with stirring and
the resulting mixture was stirred for 30 min at ꢀ24 °C. Compound
4 (0.96 g, 5.20 mmol) in anhydrous CH Cl (10 mL) was then
2
Cl
2
was added to 4 Å powdered activated molecular sieves and
25
D
a
ꢂ
¼ ꢀ106:0
4
(
3
(
1
5
4
2
2
ꢀ1
1
14 cm
3
; H NMR (CDCl , 300 MHz): d 4.92 (d, J = 6.9 Hz, 1H),
.56 (d, J = 6.9 Hz, 1H), 4.52 (dt, J = 9.8, 2.9 Hz, 1H), 3.74–3.66
1
2
2
(
m, 2H), 3.36 (s, 3H), 2.34 (d, J = 1.9 Hz, 1H), 1.98–1.91 (m, 1H),
added and the resulting mixture was stirred for another 30 min
at ꢀ24 °C followed by the addition of TBHP (5 M solution in
DCM, 1.35 mL, 6.76 mmol). The resulting mixture was stirred at
the same temperature for 24 h. It was then warmed to 0 °C,
quenched with 0.5 mL of water and stirred for 1 h at room temper-
ature. After that, a 30% aqueous NaOH solution saturated with NaCl
1
3
7
.86–1.79 (m, 1H), 1.35 (s, 3H), 1.34 (s, 3H), 1.25 (d, J = 5.9 Hz,
13
H);
3
C NMR (CDCl , 75 MHz): d; 107.9, 93.9, 82.4, 77.7,
6.7, 73.4, 61.8, 55.6, 38.7, 27.2 (2 ꢃ C), 17.0; ESI-MS: 251
+
[
M+Na] .
4
.1.8. (S)-4-(Methoxymethoxy)-5-((4S,5S)-2,2,5-trimethyl-1,3-
(
2 mL) was then added and the reaction mixture was stirred vigor-
ously for another 30 min at room temperature. The resulting mix-
ture was then filtered through Celite rinsing with CH Cl . The
organic phase was separated and the aqueous phase was extracted
with CH Cl . The combined organic phases were washed with
brine and dried over anhydrous Na SO . The solvent was removed
dioxolan-4-yl)pent-2-yn-1-ol 5
To a suspension of Mg (0.14 g, 5.842 mmol) in anhydrous THF
2
2
(
5 mL) ethyl bromide (0.43 mL, 5.842 mmol) was added dropwise
under a nitrogen atmosphere at 0 °C. Next, it is allowed to stir
for half an hour at room temperature. To this mixture, a Grignard
reagent (EtMgBr) and compound 16 (0.66 g, 2.921 mmol) in anhy-
drous THF (2 mL) were added at 0 °C. After stirring for 2 h at room
temperature, para-formaldehyde (0.26 g) was added to the reac-
tion mixture. The reaction mixture was stirred for another 5 h.
2
2
2
4
under reduced pressure and purified by silica gel column chroma-
tography [silicagel, PE–EtOAc (7:3)] to afford 6 (0.98 g, 94%, 94:6
dr) as a viscous liquid. ½
2
D
5
aꢂ
¼ ꢀ24:5 (c 1.65, CHCl
3
); IR (neat):
3
1
3
2
1
1
2
446, 2983, 2933, 2874, 1732, 1639, 1454, 1376, 1240, 1174,
088, 927, 869, 759, 724, 516 cm
ꢀ1
1
The reaction mixture was quenched with saturated NH Cl solution
4
3
; H NMR (CDCl , 300 MHz): d
and filtered over a Celite pad. The filtrate was washed with water,
brine and dried over Na SO . The organic layer was concentrated to
2 4
.96–3.83 (m, 2H), 3.73–3.57 (m, 2H), 3.15–3.06 (m, 2H), 2.92–
.88 (m, 1H), 1.59 (ddd, J = 10.5, 7.5, 3.7 Hz, 1H), 1.38 (s, 3H),
.35 (s, 3H), 1.27 (d, J = 5.2 Hz, 3H); 13C NMR (CDCl
give a crude material, which after column chromatography (SiO2,
3
, 75 MHz): d
ethyl acetate/hexane, 2:8) provided the pure product 5 (0.56 g,
08.1, 79.5, 76.7, 61.4, 58.8, 53.0, 34.8, 27.1, 26.9, 16.9; ESI-MS:
25 [M+Na] .
2
D
5
+
75%) as a liquid. ½
aꢂ
¼ ꢀ19:1 (c 1.45, CHCl ); IR (neat): 3447,
3
2
9
981, 2935, 2894, 1716, 1450, 1376, 1231, 1155, 1091, 1029,
22, 855, 768, 603, 516 cm
ꢀ1
1
3
; H NMR (CDCl , 300 MHz): d 4.91
4
2
.1.6. (S)-1-((4S,5S)-2,2,5-Trimethyl-1,3-dioxolan-4-yl)but-3-yn-
-ol 15
(
(
(
d, J = 6.7 Hz, 1H), 4.61–4.56 (m, 1H), 4.55 (d, J = 6.7 Hz, 1H), 4.26
s, 2H), 3.75–3.64 (m, 2H), 3.36 (s, 3H), 2.08–1.76 (m, 2H), 1.35
To a stirred solution of alcohol 6 (0.93 g, 4.59 mmol) in anhy-
13
3
s, 6H), 1.25 (d, J = 5.2 Hz, 3H); C NMR (CDCl , 75 MHz): d
drous CCl
4 3
(10 mL), TPP (1.777 g, 5.518 mmol) and NaHCO
1
08.0, 94.6, 93.9, 84.2, 83.7, 77.8, 62.1, 55.5, 50.9, 38.8, 27.2
(
0.77 g, 9.198 mmol) were added. The reaction mixture was vigor-
+
(
2 ꢃ C), 17.0; ESI-MS: 281 [M+Na] .
ously refluxed for 5 h and the resulting solid was filtered and
washed with ether. The filtrate was concentrated under reduced
pressure and the residue was dissolved in ether, and petroleum
ether was added to it. The triphenylphosphine oxide, which crys-
tallized out, was filtered off and the filtrate was concentrated to
dryness. The crude was used for the next reaction.
4.1.9. (S,Z)-4-(Methoxymethoxy)-5-((4S,5S)-2,2,5-trimethyl-1,3-
dioxolan-4-yl)pent-2-en-1-ol 17
To a solution of compound 5 (0.51 g, 1.996 mmol) in EtOAc
(5 mL), 3 drops of quinoline and Lindlar’s catalyst (Pd/BaSO
(0.01 g, 0.10 mmol, 5 mol %) were added and stirred at room tem-
perature under an H atm for 1 h. After completion of the reaction,
4
)
To a stirred solution of above crude product in dry THF (8 mL)
was added n-BuLi (2.5 M in hexane 5.518 mL, 13.79 mmol) at
2
ꢀ
78 °C and the reaction mixture was stirred at the same tempera-
the reaction mixture was filtered and the solvent was removed un-
der reduced pressure. The crude product was purified on silica gel
ture for 3 h, and quenched with aqueous NH Cl (5 mL). The reac-
4
tion mixture was evaporated under reduced pressure and the
residue taken in ethyl acetate, washed with water and brine, dried
column chromatography (SiO
the compound 17 (0.47 g, 92%) as a colorless liquid; ½
(c 1.45, CHCl ); IR (neat): 3448, 2982, 2936, 2889, 1638, 1453,
1376, 1232, 1155, 1093, 1029, 923, 860, 770, 515 cm
(CDCl , 300 MHz): d 5.94–5.83 (m, 1H), 5.34 (t, J = 10.5 Hz, 1H),
4.71 (d, J = 6.7 Hz, 1H), 4.66 (td, J = 9.6, 3.2 Hz, 1H), 4.51 (d,
J = 6.7 Hz, 1H), 4.35–4.24 (m, 1H), 4.06–3.95 (m, 1H), 3.80–3.57
(m, 2H), 3.38 (s, 3H), 2.37 (br, OH, 1H), 1.72 (ddd, J = 11.8, 9.8,
2
, ethyl acetate/hexane, 4:6) to afford
2
5
a
ꢂ
¼ ꢀ84:6
D
(
anhydrous sodium sulphate) and concentrated. The residue after
3
ꢀ1
1
silica gel chromatographic purification (1:9 ethyl acetate/hexane)
;
H NMR
2
D
5
afforded 15 (0.32 g, 60%) as a colorless liquid. ½
aꢂ
¼ ꢀ7:8 (c
3
1
1
5
3
3
7
1
.45, CHCl
3
) IR (neat): 3425, 3294, 2983, 2933, 2883, 2095, 1686,
451, 1377, 1239, 1171, 1088, 1044, 930, 855, 649, 564,
; H NMR (CDCl , 300 MHz): d 4.63–4.51 (m, 1H), 3.96–
3
.60 (m, 2H), 2.41 (d, J = 2.2 Hz, 1H), 1.94–1.84 (m, 2H), 1.40 (s,
ꢀ
1 1
15 cm
2.6 Hz), 1.57–1.44 (m, 1H), 1.35 (s, 6H), 1.25 (d, J = 6.0 Hz, 3H);
13
13
H), 1.37 (s, 3H), 1.27 (d, J = 6.0 Hz, 3H);
C NMR (CDCl
3
,
3
C NMR (CDCl , 75 MHz): d 132.2, 131.8, 107.9, 93.2, 78.4,
5 MHz): d 132.0, 127.2, 107.8, 81.5, 76.3, 63..0, 34.8, 27.2, 27.0,
76.8, 67.4, 57.9, 55.2, 38.5, 38.5, 27.2, 27.1, 17.0; ESI-MS: 283
+
+
7.4; ESI-MS: 207 [M+Na] .
[M+Na] .

8
70
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 866–871
4
.1.10. (4R,7S,Z)-7-(Methoxymethoxy)-8-((4S,5S)-2,2,5-
tography (eluent: PE–EtOAc, 7:3) to give lactone 19 in 90% yield
2
5
trimethyl-1,3-dioxolan-4-yl)octa-1,5-dien-4-ol 18
(0.24 g) as a colorless oil; ½
a
ꢂ
¼ ꢀ26:75 (c 1.85, CHCl
3
); IR (neat):
D
To an ice-cooled solution of 2-iodoxybenzoic acid (0.689 g,
3451, 2929, 1725, 1635, 1379, 1243, 1153, 1091, 1030, 921, 863,
ꢀ1
1
2
.463 mmol) in dry DMSO (1.27 mL, 16.359 mmol) was added a
solution of alcohol 17 (0.42 g, 1.642 mmol) in dry CH Cl (10 mL).
The mixture was stirred at room temperature for 10 h and then fil-
tered through a Celite pad and washed with Et O (25 mL). The
combined organic filtrates were washed with H
O (2 ꢃ 5 mL) and
brine (5 mL), dried over anhydrous Na SO , and concentrated in
3
817, 764, 519 cm ; H NMR (300 MHz, CDCl ): d 6.87–6.79 (m,
2
2
1H), 6.06–6.00 (m, 1H), 5.82–5.74 (m, 1H), 5.49–5.39 (m, 1H),
5.37–5.26 (m, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.61–4.47 (m, 1H),
4.46 (d, J = 6.7 Hz, 1H), 3.78–3.67 (m, 1H), 3.66–3.54 (m, 1H),
3.35 (s, 3H), 2.41–2.31 (m, 2H), 1.82–1.70 (m, 1H), 1.45–1.35 (m,
2H), 1.36 (s, 3H), 1.34 (s, 3H), 1.25 (d, J = 6.0 Hz, 3H); 13C NMR
2
2
2
4
vacuo. The unstable crude aldehyde product was used directly
for the next step without purification by column chromatography.
3
(75 MHz, CDCl ): d 163.5, 144.4, 133.2, 130.2, 121.5, 107.8, 93.5,
78.1, 76.8, 73.8, 67.1, 55.4, 38.7, 29.8, 27.3, 27.1, 17.0; ESI-MS:
+
A
2
solution of (+)-IPC B(allyl) (1.0 M in pentane, 0.95 mL,
349 [M+Na] .
2
.134 mmol) in diethyl ether (5 mL) was cooled to ꢀ100 °C after
which a solution of the above crude aldehyde in 10 ml of diethyl
4.1.13. (R)-6-((3S,5S,6S,Z)-5,6-Dihydroxy-3-
ether was added slowly. The mixture was stirred at ꢀ100 °C for
(methoxymethoxy)hept-1-enyl)-5,6-dihydropyran-2-one 20
To a solution of 19 (0.19 g, 0.607 mmol) in MeOH (1 ꢃ 10 mL,
HPLC quality) a catalytic amount (pinch) of PPTS was added and
stirred for 24 h. After completion of the reaction, the mixture
was quenched with solid NaHCO (0.06 g, 0.071 mmol) and di-
3
rectly concentrated under reduced pressure. The residue was puri-
fied by column chromatography (eluent: PE–EtOAc, 2:8) to afford
2
h and then warmed to 0 °C. The reaction was quenched by the
2 2
dropwise addition of 1 mL of 30% H O (aq) and 1 mL of 1 M NaOH.
The mixture was diluted with 10 mL of ethyl acetate and the layers
were separated. The aqueous layer was extracted with (3 ꢃ 10 mL)
ethyl acetate. The combined organic layers were washed with
brine (2 ꢃ 4 mL), dried over magnesium sulfate, filtered and con-
centrated. The crude reaction mixture (90:10 dr) was further puri-
fied by silica gel column chromatography (eluent: PE–EtOAc, 7:3)
to give homoallyl alcohol 18 in 81% yield (0.34 g,) as a clear liquid;
the corresponding diol 20 (0.15 g, 87%) as
a
colorless oil;
2
5
½
aꢂ
3
¼ ꢀ16:5 (c 1.65, CHCl ); IR (neat) 3437, 2980, 2933, 1727,
D
ꢀ
1
1
1378, 1242, 1154, 1091, 1030, 922, 864, 817, 764, 522 cm
; H
2
D
5
½
a
ꢂ
¼ ꢀ21:8 (c 2.0, CHCl
3
); IR (neat): 3444, 3074, 2981, 2937,
NMR (300 MHz, CDCl ): d 6.88–6.83 (m, 1H), 6.05–6.01 (m, 1H),
3
2
6
5
895, 1639, 1446, 1375, 1235, 1160, 1093, 1031, 919, 860, 771,
12, 512 cm
.69–5.60 (m, 1H), 5.32–5.23 (m, 1H), 5.14–5.03 (m, 2H), 4.75 (d,
5.75–5.69 (m, 1H), 5.56 (t, J = 9.9 Hz, 1H), 5.28–5.21 (m, 1H),
4.68–4.59 (m, 2H), 4.52 (d, J = 5.9 Hz, 1H), 3.62–3.50 (m, 2H),
3.38 (s, 3H), 2.47–2.31 (m, 2H), 1.73–1.65 (m, 1H), 1.51–1.44 (m,
ꢀ1
1
3
; H NMR (CDCl , 300 MHz): d 5.87–5.70 (m, 1H),
1
3
J = 6.7 Hz, 1H), 4.68–4.58 (m, 1H), 4.54 (d, J = 6.7 Hz, 1H), 4.52–
3
1H), 1.19 (d, J = 5.9 Hz, 3H); C NMR (75 MHz, CDCl ): d 163.7,
4
1
.42 (m, 1H), 3.77–3.57 (m, 2H), 3.38 (s, 3H), 2.39–2.17 (m, 2H),
.75–1.64 (m,1H), 1.53–1.41 (m, 1H), 1.35 (s, 6H), 1.24 (d,
144.7, 133.8, 129.2, 121.4, 94.4, 73.7, 72.0, 70.9, 68.4, 55.7, 39.3,
29.8, 19.2; ESI-MS: 309 [M+Na] .
+
1
3
J = 5.8 Hz, 3H); C NMR (CDCl
3
, 75 MHz): d 136.7, 134.1, 130.8,
1
17.6, 107.8, 93.3, 78.2, 76.8, 67.7, 60.0, 55.1, 41.2, 38.3, 27.2
4.1.14. (2S,3S,5S,Z)-5-(Methoxymethoxy)-7-((R)-6-oxo-3,6-
dihydro-2H-pyran-2-yl)hept-6-ene-2,3-diyl diacetate 21
+
(
2 ꢃ C), 17.1; ESI-MS: 323 [M+Na] .
Anhydrous Et
0.882 mmol), and DMAP (10 mg) were added to a solution of diol
20 (0.10 g, 0.353 mmol) in anhydrous CH Cl (5 mL) under a nitro-
3 2
N (.0.22 mL, 1.588 mmol), Ac O (0.084 mL,
4
.1.11. (4R,7S,Z)-7-(Methoxymethoxy)-8-((4S,5S)-2,2,5-
trimethyl-1,3-dioxolan-4-yl)octa-1,5-dien-4-yl acrylate 4
2
2
Acryloyl chloride (0.11 mL, 1.39 mmol) was added dropwise un-
gen atmosphere at room temperature. The mixture was stirred at
room temperature for 30 min. The solvent was removed under re-
duced pressure, and the mixture was purified by silica gel column
der N
2
to a solution of 18 (0.35 g, 1.16 mmol), and Et
.32 mmol) in CH Cl (5 ml). The mixture was stirred at 0 °C for
h. After completion, the mixture was poured into brine (2 ml),
Cl
(2 ꢃ 5 mL). The organic phase was
washed with 1 M aq HCl, dried over anhydrous Na SO , and con-
3
N (0.32 ml,
2
1
2
2
chromatography (SiO
(0.117 g, 90%) as a colorless liquid; ½
IR (neat): 3453, 2939, 1737, 1425, 1376, 1231, 1152, 1092, 1035,
2
, ethyl acetate/hexane, 3:7) to afford 21
2
D
5
and extracted with CH
2
2
aꢂ
¼ ꢀ44:9 (c 0.95, CHCl
3
);
2
4
ꢀ1 1
centrated. The crude product was purified by column chromatog-
raphy (eluent: PE–EtOAc, 7:3) to afford the corresponding acrylic
3
917, 817, 764, 603 cm ; H NMR (CDCl , 300 MHz): d 6.85 (ddd,
J = 8.9, 6.9, 2.9 Hz, 1H), 6.04 (dd, J = 7.9, 1.9 Hz, 1H), 5.75 (dd,
J = 7.9, 2.9 Hz, 1H), 5.47 (dd, J = 9.8, 1.9 Hz, 1H), 5.20 (ddd,
J = 11.8, 6.9, 2.9 Hz, 1H), 5.11–5.06 (m, 1H), 5.01–4.94 (m, 1H),
4.64 (d, J = 6.9 Hz, 1H), 4.44 (d, J = 5.9 Hz, 1H), 4.36 (td, J = 8.9,
3.9 Hz, 1H), 3.33 (s, 3H), 2.47–2.38 (m, 1H), 2.33 (dt, J = 18.8,
4.9 Hz, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 1.85 (ddd, J = 11.8, 8.9,
2.9 Hz, 1H), 1.67 (ddd, J = 13.8, 9.8, 4.9 Hz, 1H), 1.20 (d, J = 5.9 Hz,
2
D
5
ester 4 (0.35 g, 85%) as a colorless oil; ½
aꢂ
¼ ꢀ51:4 (c 1.7 l, CHCl
3
);
IR (neat): 3446, 2982, 2933, 1726, 1637, 1448, 1406, 1374, 1238,
ꢀ1
1
1
(
187, 1092, 1030, 987, 922, 861, 811, 767, 514 cm
CDCl , 300 MHz): d 6.39 (dd, J = 15.8, 1.5 Hz, 1H), 6.10 (dd,
J = 17.3, 9.8 Hz, 1H), 5.85–5.56 (m, 3H), 5.53–5.33 (m, 2H), 5.13–
.03 (m, 2H), 4.75 (d, J = 6.7 Hz, 1H), 4.73–4.61 (m, 1H), 4.47 (d,
J = 6.7 Hz, 1H), 3.80–3.69 (m, 1H), 3.66–3.55 (m, 1H), 3.37 (s, 3H),
.53–2.28 (m, 2H), 1.70 (ddd, J = 14.3, 10.5, 2.2 Hz, 1H), 1.48–1.38
; H NMR
3
5
1
3
3
3H); C NMR (CDCl , 75 MHz): d 170.3, 170.2, 163.4, 144.3,
2
(
133.2, 130.0, 121.5, 93.8, 73.6, 71.4, 70.8, 67.2, 55.9, 36.7, 29.8,
1
3
+
m, 1H), 1.37 (s, 3H), 1.35 (s, 3H), 1.25 (d, J = 6.0 Hz, 3H);
C
21.0, 20.8, 16.0; ESI-MS: 393 [M+Na] .
3
NMR (CDCl , 75 MHz): d 165.3, 133.1, 132.9, 130.7, 130.6, 128.6,
1
1
18.4, 107.8, 93.9, 78.3, 70.2, 68.1, 55.5, 39.3, 38.6, 27.3, 27.2,
7.1; ESI-MS: 377 [M+Na] .
4.1.15. (2S,3S,5S,Z)-5-Hydroxy-7-((R)-6-oxo-3,6-dihydro-2H-
pyran-2-yl)hept-6-ene-2,3-diyl diacetate 2
+
To a stirred solution of compound 21 (0.067 g, 0.181 mmol) in
4
.1.12. (R)-6-((S,Z)-3-(Methoxymethoxy)-4-((4S,5S)-2,2,5-
2 2 4
anhydrous CH Cl (5 mL) was added TiCl (1 M solution in DCM,
trimethyl-1,3-dioxolan-4-yl)but-1-enyl)-5,6-dihydropyran-2-
one 19
0.2 mL, 0.200 mmol) at 0 °C and the reaction mixture was stirred
at the same temperature for 1 h. The reaction mixture was
A solution of Grubbs’ first-generation catalyst G-I (0.069 g,
quenched with solid NaHCO
was removed under reduced pressure. The residue was purified
by silica gel column chromatography (SiO , ethyl acetate/hexane,
3
(20 mg) and filtered. The solvent
0
.084 mmol, 10 mol %) in CH
a solution of 4 (0.30 g, 0.847 mmol) in CH
2
Cl
2
(20 ml) was added dropwise to
Cl (30 mL) at rt, and
2
2
2
2
5
stirring was continued for 15 h at reflux. The solvent was evapo-
rated and the crude product purified by silica gel column chroma-
3:7) to afford 21 (0.048 g, 90%) as a colorless liquid; ½
a
ꢂ
¼ ꢀ10:2
D
5
25
D
(c 2.35, CHCl
3
); lit.
½
aꢂ
3
¼ ꢀ11:0 (c 1.0, CHCl ); IR (neat): 3448,

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 866–871
871
929, 1731,1425, 1377, 1237, 1034, 950, 759, 817 cm 1; 1H NMR
ꢀ
2
J. A. J. Org. Chem. 2002, 67, 6560–6563; (c) Carda, M.; González, F.; Castillo, E.;
Rodríguez, S.; Marco, J. A. Eur. J. Org. Chem. 2002, 2649–2655; (d) Carda, M.;
Rodríguez, S.; Castillo, E.; Bellido, A. A.; Díaz-Oltra, V.; Marco, V. Tetrahedron
(
CDCl
3
, 300 MHz): d 6.90 (ddd, J = 9.6, 5.4, 4.1 Hz, 1H), 6.05 (ddd,
J = 9.8, 1.8, 1.5 Hz, 1H), 5.69–5.57 (m, 2H), 5.39 (ddd, J = 8.8, 6.6,
2003, 59, 857–864.
2
4
2
.0 Hz, 1H), 5.14–5.06 (m, 1H), 5.02 (dq, J = 6.4, 4.9 Hz, 1H), 4.44–
3. Davies-Colemen, M. T.; Rivett, D. E. A. Phytochemistry 1996, 41, 1085–1092.
4
.
.
(a) Sabitha, G.; Gopal, P.; Reddy, C. N.; Yadav, J. S. Tetrahedron Lett. 2009, 50,
.34 (m, 1H), 2.91 (br, OH, 1H), 2.46–2.38 (m, 2H), 2.13 (s, 3H),
6298–6302; (b) Sabitha, G.; Gopal, P.; Reddy, C. N.; Yadav, J. S. Tetrahedron Lett.
1
3
.07 (s, 3H), 1.84–1.61 (m, 2H), 1.22 (d, J = 6.4 Hz, 3H); C NMR
, 75 MHz): d 171.6, 170.3, 163.7, 144.8, 135.8, 127.5, 121.3,
3.8, 72.0, 70.7, 64.4, 38.3, 29.7, 21.0, 20.8, 16.2; ESI-MS: 349
2010, 51, 5736–5739; (c) Sabitha, G.; Reddy, S. S. S.; Yadav, J. S. Tetrahedron Lett.
(
CDCl
3
2010, 51, 6259–6261; (d) Sabitha, G.; Reddy, S. S. S.; Reddy, D. V.; Bhasker, V.;
Yadav, J. S. Synthesis 2010, 3453–3460.
Srihari, P.; Vijaya Bhasker, E.; Reddy, B. A.; Yadav, J. S. Tetrahedron Lett. 2009, 50,
7
5
+
[
M+Na] .
2420–2424.
6
7
.
.
Brabander, J. D.; Vandewalle, M. Synthesis 1994, 855–865.
Keck, G. E.; Abbott, D. E.; Boden, E. P.; Elholm, E. J. Tetrahedron Lett. 1984, 25,
Acknowledgment
3927–3930.
8
.
Sharpless, K. B.; Katsuki, T. J. Am. Chem. Soc. 1980, 102, 5974–5976.
A.S.R. thanks CSIR, New Delhi for the award of fellowship.
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4495–4496; (b) Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron
1
990, 46, 7033–7046.
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