The formal synthesis of 3-epi jaspine B using stereoselective intramolecular oxa-Michael addition

Article abstract of DOI:10.1016/j.tetasy.2010.07.018

The formal synthesis of 3-epi jaspine B was achieved by using a stereoselective intramolecular oxa-Michael addition. The diacetate derivative of 3-epi jaspine B was also synthesized.

Full text of DOI:10.1016/j.tetasy.2010.07.018

Tetrahedron: Asymmetry 21 (2010) 1963–1970
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Tetrahedron: Asymmetry
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The formal synthesis of 3-epi jaspine B using stereoselective intramolecular
oxa-Michael addition
b
G. Srinivas Rao a, Neela Sudhakar a, B. Venkateswara Rao a, , S. Jeelani Basha
*
a Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b Nuclear Magnetic Resonance Division, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 March 2010
Revised 8 July 2010
Accepted 14 July 2010
Available online 10 August 2010
The formal synthesis of 3-epi jaspine B was achieved by using a stereoselective intramolecular
oxa-Michael addition. The diacetate derivative of 3-epi jaspine B was also synthesized.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
jaspine B 2 using an intramolecular oxa-Michael addition reaction
for building the tri-substituted furan moiety.
Sponges of the genus Jaspis (family Coppatiidae) have received
considerable attention from scientists in recent times because of
the interesting pharmacological properties of their chemical com-
ponents. Among these, modified peptides,1 nucleosides,2 sterols
and other triterpene derivatives,3 cytotoxic macrolides,4 and bro-
minated tyrosine derivatives5 are particularly worth mentioning.
Recent studies on the marine sponge pachastrissa sp. by Higa and
co-workers6 led to the isolation of a cyclic anhydrophyto sphingo-
sine, which they named as pachastrissamine 1. Later Debitus et al.7
independently reported the isolation of pachastrissamine 1 from
the marine sponge Jaspis sp., which they named as jaspine B 1
(Fig. 1).
As per the retro-synthesis (Scheme 1), compound 6 is the key
precursor for the synthesis of 3-epi jaspine B 2. The tri substituted
furan moiety 6 can be prepared from 7 by an intramolecular oxa-
Michael addition reaction. The compound 7 was envisaged to de-
rive from 8, which in turn can be prepared from
D
-(ꢀ)-isoascorbic
acid. One of the key aspects of the synthesis is to study the stereo-
chemical outcome of the intramolecular oxa-Michael addition in
the construction of the THF skeleton and it was anticipated that
the major compound will have the acetate group in a trans position
to the benzyloxy group.
2. Results and discussion
Jaspine B 1 showed remarkable cytotoxicity (IC50 0.24 lM)
against A549 human lung carcinoma cell line using the ATP lite
assay and also proved to be the most potent compound yet to be
isolated from the Jaspis genus on this cell line, cf. pectenotoxin II
As shown in Scheme 2, enantiomerically pure (R)-ethyl 2-(ben-
zyloxy)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)acetate 8, the start-
ing precursor of our strategy was prepared from
D
-(ꢀ)-isoascorbic
(IC50 >10
(IC50 = 10.5
l
l
M),8 bengamide
Y
(IC50 = 12.8
l Z
M),9 bengamide
acid using a standard literature procedure.15 The ester functional-
ity of compound 8 was reduced to an alcohol using LiAlH4 in THF to
yield compound 9. The compound 9 was oxidized under Swern
conditions, followed by Wittig reaction with PPh3CHCOOEt at
0 °C, and gave the compound 10 as separable trans and cis isomers
mixture in a 9:1 ratio with 92% yield. Deprotection of the acetonide
group in compound 10 was achieved using 80% aqueous acetic acid
to give diol 7, which on further treatment with NaH in THF at
ꢀ40 °C, underwent 5-exo-trig intramolecular oxa-Michael addi-
tion16 regio-selectively to give the inseparable cyclic compounds
6a and 6b in a ratio of 10:1 (approximately) and the ratio was con-
firmed by 1H NMR integrations.
M).10 Canels et al. reported that 3-epi jaspine B 2 also
showed comparable activity with that of jaspine B 1.11 Because of
the presence of a tri-substituted THF ring in jaspine B 1, a common
structural motif present in a large number of bioactive compounds,
jaspine B 1 attracted the attention of many synthetic chemists and
biologists. Many synthetic approaches have been developed for
jaspine B 1 and its isomers.12 Our group published the first total
synthesis of jaspine B 1 and its C2 epimer 4.13a Recently we also
published the synthesis of the C2 and C3 epimer 5 and an enantio-
mer of jaspine B 3 and their biological activity in comparison to jas-
pine B 1.13b In continuation of our work in the synthesis of
bioactive heterocycles using the intramolecular hetero-Michael
addition,14 herein we report the stereoselective synthesis of 3-epi
The alcohol functionality of compound 6 was converted into the
corresponding mesylate, which upon treatment with NaN3 in DMF
at 120 °C afforded inseparable azido compounds 11a and 11b in a
ratio of 10:1 (approximately) and the ratio was confirmed by 1H
NMR integrations (Scheme 2). The ester and azide functionality
* Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.018

1964
G. S. Rao et al. / Tetrahedron: Asymmetry 21 (2010) 1963–1970
H2N
H2N
H2N
H2N
H2N
OH
OH
OH
OH
OH
C14H29
C14H29
C14H29
C14H29
C14H29
O
O
O
O
O
4
1
2
3
5
Figure 1. Jaspine B and its stereoisomers.
HO
OBn
H2N
OBn
intramolecular
OH
C
Michael addition
O
OEt
HO
OEt
O
14H29
HO
O
O
7
6
2
HO
HO
OBn
O
OEt
O
O
O
O
HO
OH
8
D-(-)-isoascorbic acid
Scheme 1. Retrosynthetic analysis.
HO
HO
OBn
OEt
OBn
O
O
OH
ref. 15
b
O
a
O
O
O
O
HO
OH
9
8
D-(-)-isoascorbic acid
OBn
OBn
OEt
OEt
d
c
O
HO
O
HO
O
O
7
10
HO
N3
OBn
OBn
e
R1
R2
R1
R2
O
O
11
6
6a: R1=H, R2=CH2COOEt,
11a: R1=H, R2=CH2COOEt,
11b: R1=CH2COOEt, R2=H.
6b: R1=CH2COOEt, R2=H.
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, 0 °C to rt, 2 h, 95%; (b) (i) DMSO, (COCl)2, CH2Cl2, ꢀ78 °C, 2 h then DIPEA; (ii) PPh3CHCOOEt, CH2Cl2, 0 °C, 1 h, (92% for two
steps); (c) (i) 80% aq AcOH, 0 °C to rt, 8 h, 98%; (d) NaH, THF, 0.5 h, ꢀ40 °C, 96% (6a/6b = 10:1 ratio); (e) (i) MsCl, Et3N, CH2Cl2, DMAP (cat), 0 °C to rt, 1 h; (ii) NaN3, DMF, 120 °C,
8 h, (90% for two steps) (11a/11b = 10:1 ratio).
in compound 11 was reduced with LiAlH4 in THF and the crude
amine was treated with (Boc)2O to give chromatographically sepa-
rable compounds 12 and 13 in the ratio of 10:1. The confirmation
of structures 12 and 13 was achieved by detailed 1D and 2D NMR
studies including DQFCOSY and NOESY experiments. For 12 NOE
cross peaks were observed between NHa-Hf, NHa-OH and PhCH2-
He, whereas for 13 the NOE cross peaks were observed between
NHa-Hd, NHa-He, NHa-Hc1 and Hc-Hf (Fig. 2).
C
12H25PPh3þBrꢀ in THF at ꢀ78 °C to give cis olefin 14 exclusively
with 23% overall yield (for two steps). When compound 13 was
subjected under similar conditions of oxidation and Wittig reaction
it also gave the same compound 14 with 21% overall yield
(Scheme 3). The confirmation of the structure 14 was achieved
by detailed 1D and 2D NMR studies including DQFCOSY and NOESY
experiments and NOE cross peaks were observed between Ha-He,
Hd-Hf and He-PhCH2 (Fig. 2).
The compound 12 was oxidized under TEMPO/BAIB conditions
and the resultant aldehyde was treated with excess Wittig reagent
The formation of 14 from 13 can be explained on the basis of a
mechanism proposed by Davies et al. (Scheme 4).17 Oxidation of 13

G. S. Rao et al. / Tetrahedron: Asymmetry 21 (2010) 1963–1970
1965
Figure 2. NOE correlations.
N3
BocHN
BocHN
OBn
OBn
OBn
+
a
b
R1
R2
OH
OH
O
13
O
O
12
11
BocHN
OBn
BocHN
OH
c
O
C11H23
C14H29
O
15
14
Scheme 3. Reagents and conditions: (a) (i) LiAlH4, THF, 0 °C to rt, 1 h, aq NaoH then (Boc)2O, 0 °C, 2 h, 90% (12 compound 82% and 13 compound 8%); (b) (i) BAIB, TEMPO (cat),
CH2Cl2, rt, 2 h; (ii) C12H25PPh3þBrꢀ, KOtBu, THF, ꢀ40 °C, 1 h (23% from 12 and 21% from 13 for two steps); (c) 10% Pd/C, H2, EtOH, 12 h, 95%.
gave aldehyde 16 which might have undergone 1,2-elimination via
enolate 17 to give 18. Re-cyclisation of the resultant compound 18
would generate the thermo-dynamically favored 2,3-anti aldehyde
19 (C2 epimer of 16), which was trapped by the twelve carbon Wit-
tig ylide to give the olefin 14. Hydrogenation of 14 under Pd/C–H2
conditions gave 15, whose spectral data are in good agreement
with the reported values; conversion of 15 to 3-epi jaspine B 2
was recently reported by Canels et al.11a Very recently another syn-
thesis of 3-epi jaspine B 2 was reported by Yoshimitsu et al.11b
(Scheme 3). In an attempt to improve the yield, a modified protocol
was envisaged from 11 based on the above strategy. Reduction of
the ester in diastereomeric mixture 11 with DIBAL-H gave alcohol
20 as a diastereomeric mixture. Oxidation of 20 followed by reac-
tion with 12 carbon chain Wittig reagent gave 21 as a single stereo-
isomer (Scheme 5).
The confirmation of the structure 21 was achieved by detailed
1D and 2D NMR studies including DQFCOSY and NOESY experi-
ments and NOE cross peaks were observed between Ha-He, Hd-
Hf and He-PhCH2 (Fig. 2). Hydrogenation of 21 under Pd/C–H2 con-
dition followed by (Boc)2O treatment gave 15. Boc deprotection of
the compound 15 with TFA/CH2Cl2 followed by acetylation with
(Ac)2O/CH2Cl2 gave the compound 22 (Scheme 5) and the stereo-

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G. S. Rao et al. / Tetrahedron: Asymmetry 21 (2010) 1963–1970
BocHN
OBn
BocHN
BocHN
BocHN
OBn
OBn
OBn
-H+
a, b
OH
O-
O
O
16
O
13
O
17
BocHN
BocHN
OBn
OBn
O
14
C11H23
O
19
O
O-
18
O
Scheme 4. Reagents and conditions: (a) (i) BAIB, TEMPO (cat), CH2Cl2, rt, 2 h; (ii) C12H25PPh3þBrꢀ, KOtBu, THF, ꢀ40 °C, 1 h, (21% for two steps).
N3
N3
N3
OBn
OBn
OBn
R1
b
a
R1
R2
O
R2
O
20
C11H23
O
21
11
20a: R1=H, R2=CH2CH2OH:
11a: R1=H, R2=CH2COOEt;
11b: R1=CH2COOEt, R2=H.
20b: R1=CH2CH2OH, R2=H.
BocHN
AcHN
OH
OAc
c
d
C14H29
C14H29
O
15
O
22
Scheme 5. Reagents and conditions: (a) DIBAL-H, CH2Cl2, 0 °C to rt, 2 h, 98%; (b) (i) BAIB, TEMPO (cat), CH2Cl2, rt, 2 h, (ii) C12H25PPh3þBrꢀ, KOtBu, THF, ꢀ40 °C, 1 h, (55% for
two steps); (c) 10% Pd/C, H2, EtOH, 12 h then (Boc)2O, 1 h, (96% for two steps); (d) (i) TFA, CH2Cl2, 0 °C; (ii) (Ac)2O, CH2Cl2, 0 °C, (92% for two steps).
as eluent. Melting points were determined on a Fisher John’s melt-
ing point apparatus and are uncorrected. IR spectra were recorded
on a Perkin–Elmer RX-1 FT-IR system. 1H NMR and 13C NMR spec-
tra were recorded using Varian Gemini-200 MHz or Bruker
Avance-300 MHz spectrometer. 1H NMR data are expressed as
chemical shifts in ppm followed by multiplicity (s-singlet; d-dou-
blet; t-triplet; q-quartet; m-multiplet), number of proton(s) and
coupling constant(s) J (Hz). 13C NMR chemical shifts are expressed
in ppm. Optical rotations were measured with Horiba-SEPA-300
digital polarimeter. Accurate mass measurement was performed
on Q STAR mass spectrometer (Applied Biosystems, USA).
Figure 3. NOE correlation.
4.1. (S)-2-(Benzyloxy)-2-((R)-2,2-dimethyl-1,3-dioxo-an-4-yl)
ethanol 9
chemistry was confirmed by detailed 1D and 2D NMR studies
including DQFCOSY and NOESY experiments and NOE cross peaks
were observed between Hd-Hf, Hb-He, and NHAc-Hd (Fig. 3).
To a suspension of LiAlH4 (0.36 g, 10.2 mmol) in dry THF
(10 mL) was added a solution of ester 8 (1.50 g, 5.10 mmol) in
3. Conclusions
THF (15 mL) at 0 °C. The reaction mixture was allowed to warm
to room temperature and stirred for 2 h. The mixture was treated
with water and 15% NaOH solution. The fine white precipitate,
which was formed, was washed with ethyl acetate and discarded.
The filtrate was concentrated and the residue was purified by col-
umn chromatography with ethyl acetate/hexane (1:4) to give alco-
In conclusion, we have developed a strategy for the synthesis of
3-epi jaspine B 2 using a base-induced intramolecular oxa-Michael
addition reaction, which is also useful to make some other analogs
of jaspine B with high stereoselectivity.
holic compound 9 (1.23 g, 95%) as a syrup. ½a D25
¼ þ23:3 (c 1.1,
ꢁ
4. Experimental
CHCl3); IR (KBr): mmax 3455, 2986, 2933, 2881, 1455, 1376, 1214,
1072, 851, 742, 699 cmꢀ1 1H NMR (300 MHz, CDCl3) d: 7.30 (m,
;
TLC was performed on Merck Kiesel gel 60, F254 plates (layer
thickness 0.25 mm). Column chromatography was performed on
silica gel (60–120 mesh) using ethyl acetate and hexane mixture
5H), 4.62 (s, 2H), 4.07 (m, 2H), 3.81 (dd, 1H, J = 6.0, 8.3 Hz), 3.75
(t, 1H, J = 4.5 Hz), 3.63 (m, 1H), 3.47 (m, 1H,), 1.96 (q, 1H,
J = 5.3 Hz), 1.39 (s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3) d:

G. S. Rao et al. / Tetrahedron: Asymmetry 21 (2010) 1963–1970
1967
137.9, 128.5, 127.9, 127.8, 109.2, 79.6, 75.8, 72.6, 66.8, 61.8, 26.6,
25.1; MS (ESI) m/z 275 (M++Na); HRMS (ESI) calcd for C14H20O4Na
(M++Na) m/z 275.1264 found 275.1259.
rated aqueous NH4Cl solution and extracted with EtOAc
(2 ꢂ 20 mL). The organic layer was washed with brine, dried over
anhydrous Na2SO4 and concentrated in vacuo and the residue
was purified by column chromatography with ethyl acetate/hex-
ane (2:3), to give the inseparable mixture 6 as 6a and 6b in 10:1
ratio (0.49 g, 98%) as a colorless liquid.
4.2. (S,E)-Ethyl 4-(benzyloxy)-4-((R)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)but-2-enoate 10
To a solution of (COCl)2 (0.83 mL, 9.52 mmol) in CH2Cl2 (10 mL)
was added DMSO (1.35 mL, 19.05 mmol) at ꢀ78 °C, and the mix-
ture was stirred for 10 min. A solution of alcohol 9 (1.20 g,
4.76 mmol) in CH2Cl2 was added to the resulting mixture, and stir-
ring was continued for another 1 h at ꢀ78 °C. Then DIPEA (6.75 mL,
38.09 mmol) was added at ꢀ78 °C and the reaction mixture was
warmed to 0 °C and stirred for 20 min, water (20 mL) was added
and the reaction mixture was extracted with CH2Cl2 (2 ꢂ 20 mL),
dried over anhydrous Na2SO4. Evaporation of the solvent provided
the crude aldehyde, which was directly used in the next step.
To a solution of aldehyde in CH2Cl2 (15 mL), PPh3CHCOOEt
(2.49 g, 7.14 mmol) was added at 0 °C and stirred for 1 h. The reac-
tion mixture was quenched with water and extracted with CH2Cl2
(2 ꢂ 20 mL). The organic layer was washed with water and brine
and dried over anhydrous Na2SO4. The solvent was removed under
vacuo and the residue was purified by column chromatography
with ethyl acetate/hexane (1:5) to give the compound 10 as trans
(1.26 g, 83%) and cis (0.14 g, 9%) isomers in the ratio of 9:1
(1.40 g, 92% for two steps) as colorless liquids.
4.4.1. Spectral data of major compound
½
a 2D5
ꢁ
¼ ꢀ33:1 (c 1.2, CHCl3); IR (KBr): mmax 3420, 2932, 1716,
1656, 1453, 1370, 1274, 1180, 1096, 1036, 986, 744, 704 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d: 7.32 (m, 5H), 4.62 (s, 2H), 4.13 (m,
4H), 4.00 (dd, 1H, J = 4.9, 9.4 Hz), 3.78 (t, 1H, J = 5.7 Hz), 3.69 (dd,
1H, J = 4.2, 9.4 Hz), 2.50 (m, 2H), 1.25 (t, 3H, J = 7.2 Hz); 13C NMR
(100 MHz, CDCl3) d: 170.5, 137.0, 128.5, 128.1, 127.9, 81.9, 76.6,
73.1, 72.5, 69.2, 60.5, 38.1, 14.0.
MS (ESI) m/z 303 (M++Na); HRMS (ESI) calcd for C15H20O5Na
(M++Na) m/z 303.1202 found 303.1208.
4.5. Ethyl 2-((3R,4S)-4-azido-3-(benzyloxy)tetrahydrofuran-2-
yl)acetate 11a/11b
To a solution of compound 6 (0.60 g, 2.14 mmol) in dry CH2Cl2
(8 mL), at 0 °C were added Et3N (0.75 mL, 5.36 mmol), mesyl chlo-
ride (0.20 mL, 2.57 mmol), and DMAP (3 mg). The reaction mixture
was then stirred at room temperature for 45 min. It was then poured
into water (10 mL) and extracted with CH2Cl2 (2 ꢂ 20 mL). The com-
bined organic layers were washed with brine and dried over anhy-
drous Na2SO4. Evaporation of solvent provided the crude mesylate,
which was directly used for the next step.
To a stirred solution of the crude mesylate in dry DMF (6 mL)
was added NaN3 (0.28 g, 4.29 mmol). The mixture was heated at
120 °C under stirring for 4 h. Then the mixture was diluted with
water and extracted with EtOAc (3 ꢂ 40 mL), the organic phase
was dried over anhydrous Na2SO4, concentrated in vacuo and the
residue was purified by column chromatography with ethyl ace-
tate/hexane (1:12) to give the non-separable azido compound 11
as 11a and 11b in the ratio 10:1 (0.59 g, 90% for two steps) as a
syrup.
4.2.1. Spectral data of trans compound
½
a 2D5
ꢁ
¼ þ11:0 (c 1.3, CHCl3); IR (KBr): mmax 3480, 2985, 2936,
2878, 1720, 1657, 1455, 1373, 1269, 1174, 1074, 850 cmꢀ1 1H
;
NMR (200 MHz, CDCl3) d: 7.28 (m, 5H), 6.85 (dd, 1H, J = 6.0,
15.9 Hz), 6.04 (dd, 1H, J = 1.1, 15.5 Hz), 4.62 (d, 1H, J = 11.7 Hz),
4.41 (d, 1H, J = 11.7 Hz), 4.20 (q, 2H, J = 6.8 Hz), 4.02 (m, 2H),
3.92 (t, 1H, J = 6.0 Hz), 3.81 (m, 1H), 1.35 (m, 9H); 13C NMR
(75 MHz, CDCl3) d: 165.6, 144.5, 137.3, 128.3, 127.7, 123.9, 109.6,
78.7, 77.1, 71.6, 66.5, 60.4, 26.4, 25.0, 14.1; MS (ESI) m/z 343
(M++Na); HRMS (ESI) calcd for C18H24O5Na (M++Na) m/z
343.1538 found 343.1521.
4.3. (4S,5R,E)-Ethyl 4-(benzyloxy)-5,6 dihydroxyhex-2-enoate 7
4.5.1. Spectral data of major compound
½
a 2D5
ꢁ
¼ þ15:4 (c 1.1, CHCl3); IR (KBr): mmax 3031, 2926, 2871,
2102, 1739, 1664, 1497, 1437, 1257, 1171, 1081, 1020, 846, 742,
699 cmꢀ1 1H NMR (300 MHz, CDCl3) d: 7.30 (m, 5H), 4.60 (s,
A solution of compound 10 (1.20 g, 3.75 mmol) in 80% aqueous
acetic acid (15 mL) was stirred for 8 h. The reaction mixture was
neutralized by the addition of saturated NaHCO3 solution and ex-
tracted with EtOAc (2 ꢂ 20 mL). The organic layer was washed
with brine, dried over anhydrous Na2SO4 and concentrated in va-
cuo and the residue was purified by column chromatography with
ethyl acetate/hexane (2:3), to give 7 (1.00 g, 96%) as a colorless li-
;
2H), 4.13 (m, 3H), 3.96 (m, 2H), 3.78 (d, 1H, J = 4.0 Hz), 3.66 (dd,
1H, J = 3.0, 9.6 Hz), 2.62 (m, 2H), 1.26 (t, 3H, J = 7.2 Hz); 13C NMR
(100 MHz, CDCl3) d: 170.2, 137.0, 128.4, 127.9, 127.6, 86.8, 80.0,
72.0, 70.6, 65.6, 60.5, 38.1, 14.0; MS (ESI) m/z 328 (M++Na); HRMS
(ESI) calcd for
328.1273.
C
15H19N3O4Na (M++Na) m/z 328.1259 found
quid. ½a 2D5
¼ þ48:6 (c 1.6, CHCl3); IR (KBr): mmax 3418, 2924, 2936,
ꢁ
2854, 1719, 1657, 1457, 1372, 1275, 1176, 1098, 1036, 986,
712 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d: 7.35 (m, 5H), 6.92 (dd,
4.6. tert-Butyl-(3S,4R,5S)-4-(benzyloxy)-5-(2-hydroxyethyl)-
tetrahydrofuran-3-ylcar-bamate 12 and tert-butyl-(3S,4R,5R)-4-
(benzyloxy)-5-(2-hydroxyethyl)-tetrahydro-furan-3-ylcarbam-
ate 13
1H, J = 6.4, 15.9 Hz), 6.11 (dd, 1H, J = 1.1, 15.9 Hz), 4.68 (d, 1H,
J = 11.7 Hz), 4.41 (d, 1H, J = 11.7 Hz), 4.23 (q, 2H, J = 6.8 Hz), 4.15
(m, 1H), 3.68 (m, 3H), 2.64 (br, 1H), 2.10 (br, 1H), 1.32 (t, 3H,
J = 6.8 Hz); 13C NMR (75 MHz, CDCl3) d: 166.0, 144.7, 137.2,
128.4, 127.9, 124.0, 79.4, 73.2, 71.6, 63.0, 60.6, 14.1; MS (ESI) m/z
303 (M++Na); HRMS (ESI) calcd for C18H24O5Na (M++Na) m/z
303.1209 found 303.1208.
To a suspension of LiAlH4 (0.13 g, 3.61 mmol) in dry THF (5 mL)
was added a solution of azide 11 (0.50 g, 1.64 mmol) in THF
(10 mL) at 0 °C. The reaction mixture was brought to room temper-
ature and stirred for 2 h. The mixture was treated with water and
15% NaOH solution and stirred for 1 h and to it was then added
(Boc)2O (0.37 mL, 1.6 mmol) and stirred for 1 h. The reaction mix-
ture was washed with ethyl acetate. The filtrate was concentrated
and the residue was purified by column chromatography with
ethyl acetate/hexane (3:7) to give pure compounds 12 (0.46 g,
82%) and 13 (0.04 g, 8%) with an overall yield 90% ,as white
solids.
4.4. Ethyl 2-((2S(R),3R,4R)-3-(benzyloxy)-4-hydroxy-
tetrahydrofuran-2-yl)acetate 6a/6b
To a suspension of NaH (0.11 g, 60% w/w, 2.75 mmol) in anhy-
drous THF (4 mL), compound 7 (0.50 g, 1.79 mmol) in anhydrous
THF (10 mL) was slowly added at ꢀ40 °C. The mixture was stirred
at the same temperature for about 30 min, quenched with satu-

1968
G. S. Rao et al. / Tetrahedron: Asymmetry 21 (2010) 1963–1970
4.6.1. Spectral data of compound 12
0.09 mmol) and TEMPO free radical (2 mg) and the reaction mix-
Mp: 73–75 °C; ½a 2D5
ꢁ
¼ ꢀ75:6 (c 1.2, CHCl3); IR (KBr):
m
max 3542,
ture was warmed to room temperature for 1 h. The reaction mix-
ture was quenched with saturated sodium thiosulphate solution,
the aqueous mixture was extracted with CH2Cl2 (2 ꢂ 20 mL), the
organic layer was washed with saturated NaHCO3 solution and
brine and dried over anhydrous Na2SO4. Evaporation of the solvent
provided the crude aldehyde, which was directly used for the next
3442, 2940, 2883, 1682, 1537, 1458, 1368, 1315, 1272, 1167, 1104,
1081, 1043, 996, 892, 755, 700 cmꢀ1; 1H NMR (300 MHz, CDCl3) d:
7.31 (m, 5H), 5.07 (d, 1H, J = 7.5 Hz), 4.79 (d, 1H, J = 12.1 Hz), 4.59
(d, 1H, J = 12.1 Hz), 4.09 (m, 1H), 3.91 (m, 1H), 3.79 (m, 2H), 3.68
(m, 2H), 3.55 (d, 1H, J = 3.4 Hz), 2.43 (br, 1H), 1.81 (m, 2H), 1.46
(s, 9H); 13C NMR (75 MHz, CDCl3) d: 155.0 137.6, 128.3, 127.9,
127.7, 88.9, 83.7, 79.7, 72.0, 71.6, 60.6, 56.4, 35.8, 28.3. MS (ESI)
m/z 360 (M++Na); HRMS (ESI) calcd for C18H27NO5Na (M++Na) m/
z 360.1425 found 360.1420.
step. To
C
a
pꢀre-cooled (ꢀ40 °C) solution of the Wittig salt
12H25PPh3þBr (0.15 g, 0.30 mmol) in anhydrous THF (10 mL)
was added KOtBu (0.03 g, 0.27 mmol) in THF (5 mL) under N2 pro-
tection. The orange colored solution was stirred for about 1 h. The
reaction mixture was allowed to settle down, the upper layer was
canulated slowly to the solution of aldehyde in THF (2 mL) at
ꢀ40 °C and stirred for another 30 min. The reaction was then
quenched by saturated NH4Cl solution and washed with EtOAc
(3 ꢂ 10 mL) followed by brine. The combined organic layer was
dried over anhydrous Na2SO4. The solvent was removed under va-
cuo and the residue was purified by column chromatography with
ethyl acetate/hexane (1:7) to give the compound 14 (0.01 g, 21%
for two steps) as a syrup.
4.6.2. Spectral data of compound 13
Mp: 84–86 °C; ½a 2D5
¼ ꢀ56:6 (c 1.5, CHCl3);IR (KBr): mmax 3540,
ꢁ
3442, 2942, 2883, 1685, 1532, 1460, 1368, 1315, 1270, 1167,
1081, 996, 892, 755, 700 cmꢀ1 1H NMR (300 MHz, CDCl3) d: 7.32
;
(m, 5H), 4.79 (m, 2H), 4.58 (d, 1H, J = 12.1 Hz), 4.19 (m, 2H), 4.07
(m, 1H), 3.78 (d, 1H, J = 4.2 Hz), 3.71 (t, 2H, J = 5.7 Hz), 3.53 (m,
1H), 2.25 (br, 1H), 1.98 (m, 1H), 1.71 (m, 1H), 1.45 (s, 9H); 13C
NMR (75 MHz, CDCl3) d: 155.0, 137.8, 128.3, 127.8, 127.6, 83.8,
79.8, 79.2, 71.1, 70.8, 60.6, 55.7, 31.3, 28.3. MS ESI) m/z 360
(M++Na); HRMS (ESI) calcd for C18H27NO5Na (M++Na) m/z
360.1425 found 360.1420.
4.9. tert-Butyl-(3S,4R,5S)-4-hydroxy-5-tetradecyltetrahydro-
furan-3-ylcarbamate 15 from 14
4.7. tert-Butyl-(3S,4R,5S)-4-(benzyloxy)-5-((Z)-tetradec-2-enyl)
tetrahydrofuran-3-yl-carbamate 14 from 12
The suspension of Pd/C (10% on carbon) (5 mg) in an ethanolic
solution of olefin 14 (0.06 g, 0.12 mmol, 5 mL) was stirred under
an H2 atmosphere at room temperature for about 20 h. The Pd/C
was filtered and the solvent was concentrated under vacuo and
the residue was purified by column chromatography with ethyl
acetate/hexane (1:4) to give the compound 15 (0.05 g, 95%) as a
To a solution of compound 12 (0.06 g, 0.18 mmol) in dry CH2Cl2
(2 mL), at 0 °C were added (diacetoxyiodo) benzene (0.09 g,
0.27 mmol) and TEMPO free radical (2 mg), the reaction mixture
was warmed to room temperature and stirred for 1 h. The reaction
mixture was quenched with saturated sodium thiosulphate solu-
tion, the aqueous mixture was extracted with CH2Cl2 (2 ꢂ 20 mL),
the organic layer was washed with saturated NaHCO3 solution and
brine and dried over anhydrous Na2SO4. Evaporation of the solvent
provided the crude aldehyde, which was directly used for the next
step.
white solid. Mp: 94–96 °C; ½a D25
ꢁ
¼ ꢀ30:2 (c 1.3, CHCl3) {Lit.11
½
a 2D5
ꢁ
¼ ꢀ31:7 (c 1.09, CHCl3)}; IR (KBr): mmax 3351, 2920, 2850,
1688, 1533, 1469, 1391, 1367, 1172, 1078, 1013, 858, 718,
619 cmꢀ1 1H NMR (300 MHz, CDCl3) d: 4.78 (d, 1H, J = 4.5 Hz),
;
4.04 (dd, 1H, J = 6.7, 9.6 Hz), 3.90 (m, 1H), 3.77 (dd, 1H, J = 3.8,
5.7 Hz), 3.64 (m, 2H), 1.60 (m, 2H), 1.45 (s, 9H), 1.28 (m, 24H),
0.87 (t, 3H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) d: 156.4, 85.0,
82.5, 80.2, 70.4, 60.2, 33.7, 32.0, 31.9, 29.7, 29.3, 28.3, 26.0, 22.7,
14.1; MS (ESI) m/z 422 (M++Na); HRMS (ESI) calcd for C23H45NO4Na
(M++Na) m/z 422.3244 found 422.3246.
To
a
pre-cooled (ꢀ40 °C) solution of the Wittig salt
C
12H25PPh3þBrꢀ (0.45 g, 0.90 mmol) in anhydrous THF (20 mL)
was added KOtBu (0.10 g, 0.81 mmol) in THF (5 mL) under N2 protec-
tion. The orange colored solution was stirred for about 1 h. The reac-
tion mixture was allowed to settle down, the upper layer was
canulated slowly to the solution of aldehyde in THF (2 mL) at
ꢀ40 °C and stirred for another 30 min. The reaction was then
quenched by saturated NH4Cl solution and washed with EtOAc
(3 ꢂ 10 mL) followed by brine. The combined organic layer was
dried over anhydrous Na2SO4. The solvent was removedunder vacuo
and the residue was purified by column chromatography with ethyl
acetate/hexane (1:7) to give the compound 14 (0.02 g, 23% for two
4.10. 2-((3R,4S)-4-Azido-3-(benzyloxy)-tetrahydrofuran-2-yl)-
ethanol 20
To a solution of the azide compound 11 (0.12 g, 0.39 mmol) in
dry CH2Cl2 (2 mL), at ꢀ78 °C was added DIBAL-H (0.56 mL,
0.79 mmol) and the reaction mixture was warmed to room tem-
perature, stirred for 1 h, the reaction mixture was quenched with
saturated suspension of NH4Cl solution followed by saturated so-
dium potassium tartarate solution and extracted with CH2Cl2
(3 ꢂ 10 mL). The combined organic layer was washed with brine
and dried over anhydrous Na2SO4. The filtrate was concentrated
and the residue was purified by column chromatography with
ethyl acetate/hexane (3:7) to give the inseparable mixture 20
(0.09 g, 92%) as an oily liquid.
steps) as a syrupy liquid. ½a D25
¼ ꢀ15:2 (c 1.2, CHCl3); IR (KBr): mmax
ꢁ
3445, 2925, 2854, 1711, 1500, 1460, 1367, 1335, 1251, 1170, 1078,
857, 736, 698 cmꢀ1 1H NMR (200 MHz, CDCl3) d: 7.28 (m, 5H),
;
5.40 (m, 1H), 5.30 (m, 1H), 4.75 (d, 1H, J = 12.2 Hz), 4.66 (d, 1H,
J = 7.9 Hz), 4.57 (d, 1H, J = 12.2 Hz), 4.04 (m, 1H), 3.89 (dd, 1H,
J = 4.3, 9.4 Hz), 3.70 (m, 2H), 3.46 (d, 1H, J = 2.8 Hz), 2.29 (m, 2H),
1.88 (m, 2H), 1.45 (s, 9H), 1.30 (m, 18H), 0.88 (t, 3H, J = 7.1 Hz); 13
C
NMR (75 MHz, CDCl3) d: 133.0, 128.3, 128.0, 127.7, 124.0, 87.8,
84.4, 71.9, 71.6, 56.6, 32.0, 31.3, 29.6, 29.5, 29.3, 28.4, 27.3, 22.7,
14.0; MS (ESI) m/z 510 (M++Na); HRMS (ESI) calcd for C30H49NO4Na
(M++Na) m/z 510.3560 found 510.3559.
4.10.1. Spectral data for major compound
½
a 2D5
ꢁ
¼ þ4:5 (c 2.6, CHCl3); IR (KBr): mmax 3424, 2932, 2874,
2101, 1455, 1256, 1081, 743, 699 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d: 7.32 (m, 5H), 4.63 (d, 1H, J = 11.8 Hz), 4.54 (d, 1H, J = 11.8 Hz),
3.90 (m, 4H), 3.71 (m, 3H), 1.93 (m, 1H), 1.85 (q, 2H, J = 6.1 Hz);
13C NMR (75 MHz, CDCl3) d: 137.0, 128.6, 128.1, 127.8, 88.0, 83.1,
72.4, 70.9, 65.7, 60.5, 35.3; MS (ESI) m/z 286 (M++Na); HRMS
(ESI) calcd for C13H17N3O3Na (M++Na) m/z 286.1159 found
286.1167.
4.8. tert-Butyl (3S,4R,5S)-4-(benzyloxy)-5-((Z)-tetradec-2-
enyl)tetrahydrofuran-3-yl-carbamate 14 from 13
To a solution of compound 13 (0.03 g, 0.09 mmol) in dry CH2Cl2
(2 mL), at 0 °C were added (diacetoxyiodo) benzene (0.05 g,

G. S. Rao et al. / Tetrahedron: Asymmetry 21 (2010) 1963–1970
1969
4.11. ((2S,3R,4S)-4-Azido-3-(benzyloxy)-2-((Z)-tetradec-2-eny l)
tetrahydrofuran 21
(30 mL) and the organic layer was washed with saturated aq NH4Cl
solution, water and brine, dried over anhydrous Na2SO4. The sol-
vent was removed on a rotary evaporator and the residue was puri-
fied by column chromatography on silica gel using ethyl acetate/
hexane (1:2) as the eluant to afford the acetate derivative of
To a solution of alcoholic compound 20 (0.05 g, 0.19 mmol) in
dry CH2Cl2 (2 mL), at 0 °C was added (diacetoxy iodo) benzene
(0.09 g, 0.27 mmol) and TEMPO free radical (2 mg) and the reaction
mixture was warmed to room temperature and stirred for 1 h. The
reaction mixture was quenched with saturated sodium thiosul-
phate solution, the aqueous mixture was extracted with CH2Cl2
(2 ꢂ 20 mL), the organic layer was washed with saturated NaHCO3
solution, brine and dried over anhydrous Na2SO4. Evaporation of
the solvent provided the crude aldehyde, which was directly used
in the next step.
3-epi jaspine B 22 (0.018 g, 94%) as a thick syrup. ½a D25
¼ þ11:2 (c
ꢁ
1.1, CHCl3); IR (KBr): mmax 3279, 2923, 2854, 1742, 1654, 1548,
1461, 1372, 1236, 1043, 722 cmꢀ1 1H NMR (500 MHz, CDCl3) d:
;
5.88 (d, 1H, J = 6.6 Hz), 4.64 (dd, 1H, J = 3.2, 5.1 Hz), 4.32 (m, 1H),
4.00 (dd, 1H, J = 5.6, 7.8 Hz), 3.70 (dd, 1H, J = 3.0, 9.8 Hz), 3.64 (dt,
1H, J = 4.9, 8.6 Hz), 2.02 (s, 3H), 1.92 (s, 3H), 1.64 (m, 1H), 1.50
(m, 1H), 1.36 (m, 1H), 1.2 (m, 23 H), 0.88 (t, 3H, J = 6.8 Hz); 13C
NMR (75 MHz, CDCl3) d: 170.7, 169.9, 83.0, 81.8, 71.8, 56.5, 33.5,
31.9, 29.6, 29.6, 29.5, 29.5, 29.3, 25.9, 23.1, 22.7, 21.0, 14.1; MS
(ESI) m/z 406 (M++Na); HRMS (ESI) calcd for C25H39N3O4Na
(M++Na) m/z 406.2950 found 406.2933.
To a pre-cooled (ꢀ40 °C) solution of the Wittig salt C12H25
PPh3þBrꢀ (0.47 g, 0.95 mmol) in dry THF (20 mL) was added slowly
KOtBu (0.09 g, 0.85 mmol) in THF (5 mL) under N2 protection. The
orange color solution was stirred for 1 h and stirring was stopped
to allow the reaction mixture to settle down. The upper layer was
canulated slowly to the solution of aldehyde in THF (2 mL) at
ꢀ40 °C and stirred for another 30 min and then allowed to warm
to room temperature. The reaction was then quenched by saturated
NH4Cl solution at ꢀ40 °C and washed with EtOAc (3 ꢂ 10 mL), fol-
lowed by brine. The combined organic layers were dried over anhy-
drous Na2SO4. The solvent was removed under vacuo and the
residue was purified by column chromatography with ethyl ace-
tate/hexane (1:19) to give the compound 21 (0.04 g, 55% for two
Acknowledgments
G.S.R, S.J.B thanks CSIR-New Delhi, N.S. thanks UGC-New Delhi
for a research fellowship. The authors thank Dr. A. V. S. Sarma for
fruitful discussions. The authors also thank Dr. J. S. Yadav and Dr.
A. C. Kunwar for their support and encouragement. We also thank
DST (SR/S1/OC-14/2007), New Delhi for financial support.
References
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¼ þ6:7 (c 2.8, CHCl3); IR (KBr): mmax 3444,
ꢁ
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698 cmꢀ1; 1H NMR (300 MHz, CDCl3) d: 7.31 (m, 5H), 5.44 (m, 1H),
5.34 (m, 1H), 4.63 (d, 1H, J = 11.3 Hz), 4.53 (d, 1H, J = 12.1 Hz), 4.16
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