N-Cbz sulfilimines as valuable intramolecular nucleophiles for the stereoselective synthesis of (-)-deoxocassine and (+)-desoxoprosophylline

Article abstract of DOI:10.1016/j.tet.2008.08.031

N-Cbz sulfilimine, prepared from the corresponding sulfoxide using the Burgess reagent, has been employed as an intramolecular nucleophile for the regio- and stereoselective preparation of a bromo-carbamate from an alkene. The bromo-carbamate has been utilized as an advanced common synthon for the synthesis of deoxocassine and desoxoprosophylline employing the ene and amidomercuration as key reactions.

Full text of DOI:10.1016/j.tet.2008.08.031

Tetrahedron 64 (2008) 10055–10061
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N-Cbz sulfilimines as valuable intramolecular nucleophiles for the
stereoselective synthesis of (ꢀ)-deoxocassine and (þ)-desoxoprosophylline
*
Sadagopan Raghavan , Shaik Mustafa
Organic Division I, Indian Institute of Chemical Technology, 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 13 June 2008
Received in revised form 12 August 2008
Accepted 13 August 2008
Available online 15 August 2008
N-Cbz sulfilimine, prepared from the corresponding sulfoxide using the Burgess reagent, has been
employed as an intramolecular nucleophile for the regio- and stereoselective preparation of a bromo-
carbamate from an alkene. The bromo-carbamate has been utilized as an advanced common synthon for
the synthesis of deoxocassine and desoxoprosophylline employing the ene and amidomercuration as key
reactions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
N-Cbz sulfilimine
Sulfoxide
Burgess reagent
(ꢀ)-Deoxocassine
(þ)-Desoxoprosophylline
1. Introduction
OH
O
OH
OH
O
O
N
H
HO
N
H
HO
N
H
Piperidine alkaloids possessing a 2,3- or 2,3,6-substitution,
particularly a hydroxy group at 3-position occur widely in nature.1
The hydroxylated piperidines display a wide range of biological
activities since they mimic carbohydrates in enzymatic processes.2
They have been useful in the understanding of biochemical path-
ways by virtue of their ability to selectively inhibit enzymes in-
volved in the processing of glycoproteins.3 Numerous compounds
possessing either the 2,6-cis or 2,6-trans substitution pattern have
11
10
5
(+)-azimic acid 2
(-)-cassine 1
(+)-julifloridine 3
OH
OH
O
N
H
N
H
9
9
OH
OH
(-)-prosopinine 5
(-)-prosophylline 4
been discovered, in addition to ones with 3a- and 3b-configura-
Figure 1.
tions. Typical representatives of this class of compounds include
(ꢀ)-cassine 1, (þ)-azimic acid 2, (þ)-julifloridine 3, (ꢀ)-proso-
phylline 4, and (ꢀ)-prosopinine 5, Figure 1. Members of this class
occur among the alkaloids of various species of the plant genera
Cassia and Prosopis.4
Not surprisingly, because of their medical potential, interesting
structural features and to showcase the potential of new synthetic
methodologies, which are more efficient than those currently in
existence, the piperidine alkaloids have been popular synthetic
targets.
using the Burgess reagent, (b) its function as an intramolecular
nucleophile for the regio- and stereoselective preparation of
bromo-carbamates from an alkene, and (c) the utilization of the
former as a common advanced intermediate in the synthesis of
(ꢀ)-deoxocassine 6 and (þ)-desoxoprosophylline 7, Scheme 1.6
2. Results and discussion
As a part of our investigations into the chemistry of sulfil-
imines,5 we wish to describe herein (a) a facile method for the
preparation of N-Cbz sulfilimines from the corresponding sulfoxide
2.1. Synthesis of (L)-deoxocassine
(ꢀ)-Deoxocassine7 6, a simple analog of the natural alkaloid
(ꢀ)-cassine8 1, was selected as the target for application of our
methodology. By a retrosynthetic analysis, 6 was envisioned to be
obtained from unsaturated carbamate 7 by a stereoselective
* Corresponding author. Tel.: þ91 40 27191643; fax: þ91 40 27160512.
E-mail addresses: sraghavan@iict.res.in, purush101@yahoo.com (S. Raghavan).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.031

10056
S. Raghavan, S. Mustafa / Tetrahedron 64 (2008) 10055–10061
CbzN
OH
O
S
OH
O
S
OH
S
p-Tol
p-Tol
p-Tol
Br
NHCbz
Bromo-carabamate
Sulfoxide
N-Cbz-Sulfilimine
R1
R2
N
11
H
X
6, X = R2 = H; R1 = OH, (-)-deoxocassine
7, X = R2 = OH;R1 = H, (+)-desoxoprosophylline
Scheme 1.
STol-p
O
S
OP
OH
OP
p-Tol
Br
NHCbz
N
11
HN
Cbz Br
H
8
10
6
7
CbzN
OP
P = Protecting group
S
p-Tol
9
Scheme 2.
amidomercuration. Carbamate 7 can be derived from amino alcohol
derivative 8, which in turn can readily be obtained from sulfilimine
9, Scheme 2.
followed by the ene reaction furnished homoallyl sulfide 17
cleanly as single isomer. The Pummerer intermediate 16
without isolation was reacted with 1-tetradecene in the pres-
ence of stoichiometric amounts of SnCl4 at 0 ꢁC for 30 min to
yield 17, Scheme 3.
The configuration at the newly introduced stereogenic center
in 17 was not assigned till after amidomercuration, vide infra.
The entire carbon framework was introduced and it only
remained to cyclize the unsaturated carbamate to form the pi-
peridine ring. Toward this end, debromination of 17 was effected
by treatment with n-tributyltin hydride in refluxing benzene in
the presence of cat. amounts of AIBN to furnish acetonide 18.
Deprotection of the acetonide using cat. CSA in methanol pro-
ceeded cleanly to yield alcohol 19, which was protected as its
a
The synthesis began with silyl ether9 10, which on treatment
with the Burgess reagent10 11 in anhydrous benzene furnished
an equimolar mixture of readily separable sulfilimines 12.11
Deprotection of the silyl group yielded allyl alcohol 13, which
could also be separated as syn and anti isomers.12 As we had
earlier proven the stereoconvergency (at carbon) in the re-
actions of anti-13 and syn-13,9 we proceeded ahead with the
mixture. Reaction of 13 with NBS yielded bromo-carbamate 14
regio- and stereoselectively.13 Protection of 14 as its N,O-aceto-
nide using 2,2-dimethoxypropane and cat. amounts of CSA
yielded acetonide 15. Subjecting 15 to an one-pot Pummerer
CbzN
OP
CbzN
OP
O
S
OTBS
Et3NSO2NCbz 11
PhH, 0 °C to rt
S
S
+
p-Tol
p-Tol
p-Tol
12anti, P = TBS
13anti, P = H
10
12syn, P = TBS
13syn, P = H
TBAF
THF
TBAF
THF
1 R2
S
OMe
OMe
Cat. CSA, DCM
O
R1 R2
S
OH
R
NCbz
TFAA, DCM
NBS,H2O
Toluene
p-Tol
p-Tol
Br
NHCbz
Br
15syn, R1 = O, R2 =
15anti, R2 = O, R1 =
14syn, R1 = O, R2 =
14anti, R2 = O, R1 =
O
O
NCbz
NCbz
Br
S
S
p-Tol
p-Tol
11
F3C(O)CO
Br
SnCl4
17
16
10
Scheme 3.

S. Raghavan, S. Mustafa / Tetrahedron 64 (2008) 10055–10061
10057
acetate 20 to chemoselectively involve the carbamate in the
2.2. Synthesis of (D)-desoxoprosophylline
amidomercuration reaction. Studies into intramolecular amido-
mercuration of carbamates have revealed that the stereo-
selectivity of these cyclizations are dependant on the reaction
conditions resulting in kinetic or thermodynamic control of the
The interesting structural features and the varied biological
activity of (þ)-desoxoprosophylline 22 has attracted the attention
of synthetic chemists and several reports detail its synthesis. Many
among them rely on chiral pool starting materials16 and there are
only a handful reports on asymmetric syntheses.17 The synthesis of
22 commenced from homoallyl sulfide 17, which on treatment with
excess sodium nitrite in DMF18 yielded the alcohol 23. Deprotection
of the acetonide using cat. CSA and protection of the resulting diol
24 as its silyl ether using TBS-OTf in the presence of 2,6-lutidine
furnished 25 cleanly. Amidomercuration of 25 using mercuric tri-
fluoroacetate followed by demercuration using LiBH4 furnished the
oxazolidinone 26 via concomitant desilylation under the reaction
conditions, Scheme 5. The structure of alcohol 26 was confirmed by
NOE studies on the acetate derivative 27. The p-tolyl thio group was
removed by hydrogenolysis by treatment with Ra-Ni to furnish
alcohol 28. Attempted Mitsunobu reaction on 28 using chloroacetic
acid19 as the acid partner only returned unreacted starting material.
We therefore resorted to an oxidation–reduction sequence to pre-
pare the inverted alcohol. In the event, treatment of 28 with IBX in
products. The stereoselective cyclization of 3-alkenyl carbamates
proceeds under equilibrating conditions.14 Thus treatment of 20
with mercuric trifluoroacetate in DCM at rt overnight followed
15
by reductive demercuration using LiBH4 at low temperature
and gradual warming furnished 2,6-cis di-substituted piperidine
derivative 21 by concomitant deacetylation. The structure of 21
was proven unambiguously by NOE experiments. NOE were
observed between (a) the methyl and alkyl chain indicating their
axial disposition, (b) methyl and C4 H, (c) C2 and C3 H, and (d)
C4 H and alkyl chain proton, Scheme 4. Thus the structure of 21
also helps to assign the configuration of the newly established
stereogenic center in 17 as depicted. The synthesis of deox-
ocassine was completed by subjecting 21 to hydrogenolysis us-
ing Ra-Ni in ethanol, Scheme 4. Synthetic deoxocassine had
physical properties in excellent agreement to those reported in
the literature.7f
O
STol-p
NCbz
OP
S
p-Tol
Cat. CSA, MeOH
n-BuSnH, AIBN
17
PhH
HN
Cbz
18
10
10
19, P = H
Ac2O, Et3N,
DMAP, CH2Cl2
20, P = OAc
STol-p
H
H
OH
OH
10
6
H
Hg(OTFA)2, CH2Cl2
Ra-Ni, H2, EtOH
Me
N
H
LiBH4
STol-p
4
3
Cbz
N
H
N
OH
11
11
2
Cbz
H
21
6, (-)-deoxocassine
Scheme 4.
OP
O
NCbz
OH
p-TolS
S
NaNO2, DMF
Cat. CSA, MeOH
OP
Cbz
24, P = H
p-Tol
17
HN
TBS-OTf,
2,6-Lutidine,
DCM
23
10
10
25, P = TBS
X
R2
R1
O
OP
Hg(OC(O)CF3)2, DCM
then LiBH4
IBX, EtOAc
N
O
N
O
11
11
O
Ac2O, Et3N,
DMAP, CH2Cl2
29, R1, R2 = O
30, R1 = OH, R2 = H
26, P = H, X = STol-p
27, P = Ac, X = STol-p
28, P = X = H
NaBH4, MeOH
Ra-Ni, EtOH
OH
OH
8N KOH, EtOH
N
H
11
22, (+)-desoxoprosophylline
Scheme 5.

10058
S. Raghavan, S. Mustafa / Tetrahedron 64 (2008) 10055–10061
refluxing ethyl acetate furnished the corresponding ketone 29,
which was not stable to column chromatography on silica gel. The
crude product was reduced with NaBH420 to yield alcohol 30 as the
sole product. Deprotection of the oxazolidinone was achieved by
base promoted hydrolysis21 to afford (þ)-desoxoprosophylline 22
with physical characteristics that were in excellent agreement with
those reported in the literature.16a
137.8, 137.6, 132.2, 130.5, 128.1, 127.9, 127.4, 127.2, 117.5, 69.4, 67.4,
59.4, 25.7, 21.4, 18.0, ꢀ4.1, ꢀ5.0; MS (FAB) 458 [MþH]þ; HRMS (FAB)
m/z calcd for C25H36NO3SiS 458.2185; found 458.2210.
4.1.2. Sulfilimine 13
To a solution of syn-12 (3.35 g, 7.39 mmol) in anhydrous THF
(15 mL) at rt was added tetra n-butyl ammonium fluoride (11.3 mL,
1 M in THF,11.3 mmol) dropwise and stirred for 30 min. The solvent
was evaporated under reduced pressure to yield a viscous oil,
which was purified by column chromatography using 50% EtOAc/
petroleum ether (v/v) to afford sulfilimine syn-13 (2.36 g,
3. Conclusion
In summary, we have described a novel asymmetric synthesis of
(ꢀ)-deoxocassine and (þ)-desoxoprosophylline using a sulfilimine
as an intramolecular nucleophile. The sulfilimine was readily
obtained from the corresponding sulfoxide using the Burgess re-
agent as the source of the carbamate moiety. The route disclosed
is suitable for the synthesis of several related natural products
by (a) varying the nucleophile used for bromide displacement
(C-heteroatom and C–C bonds can be made), (b) varying the chain
length of the alkene employed in the Pummerer ene reaction, and
(c) the conditions of amidomercuration, using kinetic rather than
thermodynamic conditions to prepare 2,6-trans di-substituted
piperidine derivatives.22
6.9 mmol) in 93% yield as a gummy liquid. TLC, Rf (50% EtOAc/
25
hexane) 0.20; [
a]
ꢀ103 (c 2.25, CHCl3); IR (neat) 3445, 2924, 1626,
D
1384, 1259 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
7.7 (d, J¼7.6 Hz, 2H),
7.4–7.2 (m, 7H), 5.9–5.8 (m, 1H), 5.3 (d, J¼16.6 Hz, 1H), 5.2 (d,
J¼10.6 Hz, 1H), 5.1 (ABq, J¼12.8 Hz, 2H), 4.4–4.3 (m, 1H), 3.4 (dd,
J¼12.8, 9.1 Hz, 1H), 3.1 (dd, J¼12.8, 3.8 Hz, 1H), 2.4 (s, 3H); 13C NMR
(75 MHz, CDCl3) 164.5, 143.5, 137.4, 137.2, 131.5, 130.7, 128.3, 128.0,
127.7, 127.0, 116.9, 68.3, 67.8, 57.1, 21.5; MS (FAB) 344 [MþH]þ;
HRMS (FAB) m/z calcd for C19H21NO3NaS 366.1139; found 366.1146.
Similarly anti-12 (3.45 g, 7.61 mmol) was treated with tetra n-butyl
ammonium fluoride (11.4 mL, 1 M in THF, 11.4 mmol) to furnish
anti-13 (2.44 g, 7.1 mmol) in 93% yield as a gummy liquid. TLC, Rf
25
4. Experimental
(50% EtOAc/hexane) 0.25; [
a]
þ23 (c 0.35, CHCl3); IR (neat) 3445,
D
2924, 1626, 1384, 1259 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d 7.7 (d,
4.1. General remarks
J¼8.3 Hz, 2H), 7.5–7.3 (m, 7H), 5.9–5.8 (m, 1H), 5.4 (d, J¼17.4 Hz,
1H), 5.2 (d, J¼10.6 Hz, 1H), 4.7–4.6 (m, 1H), 3.1–3.0 (m, 2H), 2.4 (s,
All air or moisture sensitive reactions were carried out under
nitrogen atmosphere. Solvents were distilled over Na/benzophe-
none ketyl for THF, over P2O5 followed by CaH2 for DCM, and over
P2O5 for toluene. Commercially available reagents were used
without purification except NBS, which was freshly recrystallized
from hot water before use. Thin layer chromatography was per-
formed on precoated silica gel plates. Column chromatography was
carried out using silica gel (60–120 mesh). NMR spectra were
recorded on a 200, 300 or 400 MHz spectrometer. 1H and 13C NMR
samples were internally referenced to TMS (0.00 ppm). Melting
points are uncorrected.
3H); 13C NMR (75 MHz, CDCl3)
d 165.4, 143.3, 136.8, 130.7, 130.3,
128.3, 128.0, 127.7, 126.8, 116.8, 68.0, 67.0, 58.8, 21.5; MS (FAB)
344 [MþH]þ; HRMS (FAB) m/z calcd for C19H21NO3S 344.1314;
found 344.1324.
4.1.3. Bromo-carbamate 14
To a solution of syn-13 (1.7 g, 5 mmol) in toluene (20 mL) was
added water (0.14 mL, 7.5 mmol) followed by freshly recrystallized
NBS (0.47 g, 6 mmol) and the mixture stirred at rt for 30 min. The
reaction mixture was then diluted with EtOAc (25 mL), washed
with saturated aq NaHCO3 (15 mL), water (15 mL), brine (15 mL),
and dried over Na2SO4. The solvent was evaporated under reduced
pressure to afford the crude product, which was purified by column
chromatography using 50% EtOAc/petroleum ether (v/v) to afford
4.1.1. Sulfilimine 12
To a solution of 10 (6.4 g, 20 mmol) in dry benzene (40 mL)
cooled at 0 ꢁC was added a solution of Burgess reagent 11 (12.5 g,
40 mmol) in dry benzene (60 mL) over a period of 30 min and the
reaction mixture was stirred for 4 h at rt. The reaction was
quenched by the addition of water (20 mL), diluted with EtOAc
(100 mL), washed successfully with water (2ꢂ70 mL) and brine
(100 mL). The organic layer was dried over Na2SO4 and evaporated
under reduced pressure to give a viscous oil, which was purified by
column chromatography using 30% EtOAc/petroleum ether (v/v) to
afford sulfilimine 12 (7.4 g, 16.4 mmol) as a 1:1 mixture of syn and
anti-14 (1.85 g, 4.25 mmol) in 85% yield as a white solid. Mp 102–
25
104 ꢁC; TLC, Rf (50% EtOAc/hexane) 0.30; [
a
]
þ11.5 (c 0.2, CHCl3);
D
IR (KBr) 3332, 2925, 1698, 1530, 1240, 1030, 641 cmꢀ1
;
1H NMR
(200 MHz, CDCl3)
d
7.5 (d, J¼8.3 Hz, 2H), 7.4–7.2 (m, 7H), 5.4 (d,
J¼9.0 Hz, 1H), 5.1 (s, 2H), 4.6 (br s, 1H), 4.5 (d, J¼9.7 Hz, 1H), 3.7 (q,
J¼8.3 Hz, 1H), 3.5–3.2 (m, 3H), 2.5 (d, J¼14.6 Hz, 1H), 2.4 (s, 3H); 13
C
NMR (75 MHz, DMSO-d6)
d 156.5, 142.3, 141.2, 137.4, 130.3, 128.8,
128.2, 128.0, 124.2, 65.9, 65.6, 62.0, 58.0, 33.6, 21.3; MS (FAB) 440
[MþH]þ; HRMS (FAB) m/z calcd for C19H22NO4NaSBr 462.0350;
found 462.0368. Likewise anti-13 was reacted with NBS to afford
syn-14 as a white solid. Mp 98–100 ꢁC; TLC, Rf (50% EtOAc/hexane)
anti isomers in a combined yield of 82%. Data for anti-12: gummy
25
oil; TLC, Rf (30% EtOAc/hexane) 0.35; [
a
]
D
þ8.5 (c 0.35, CHCl3); IR
(neat) 3446, 2928, 1637, 1384, 1258, 1084, 777 cmꢀ1
(300 MHz, CDCl3)
;
1H NMR
0.30; IR (KBr) 3332, 2925, 1698, 1530, 1240, 1030, 641 cmꢀ1 1H
;
d
7.6 (d, J¼8.3 Hz, 2H), 7.4–7.2 (m, 7H), 5.8–5.7 (m,
NMR (200 MHz, CDCl3)
d
7.5 (d, J¼7.8 Hz, 2H), 7.4–7.3 (m, 7H), 5.4
1H), 5.3 (d, J¼17.4 Hz, 1H), 5.2–5.0 (m, 3H), 4.7–4.6 (m, 1H), 3.2 (dd,
(d, J¼9.4 Hz, 1H), 5.1 (s, 2H), 4.9–4.7 (m, 1H), 4.5 (d, J¼10.9 Hz, 1H),
3.7 (q, J¼9.4 Hz, 1H), 3.5–3.3 (m, 2H), 3.2 (dd, J¼14.1, 10.2 Hz, 1H),
2.5 (dd, J¼13.3, 1.6 Hz, 1H), 2.4 (s, 3H); 13C NMR (75 MHz, CDCl3)
J¼12.1, 2.3 Hz, 1H), 2.8 (dd, J¼12.1, 10.6 Hz, 1H), 2.4 (s, 3H), 0.9 (s,
9H), 0.1 (s, 3H), 0.0 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 164.2, 142.9,
138.1, 137.4, 133.0, 130.5, 128.1, 128.0, 127.5, 126.4, 116.8, 67.9, 67.4,
d 158.4,142.1, 136.1, 135.3, 130.2,128.6,128.3,128.1, 124.1, 67.2, 65.4,
59.5, 25.7, 21.4,17.9, ꢀ4.5, ꢀ5.2; MS (FAB) 458 [MþH]þ; HRMS (FAB)
57.4, 56.1, 31.5, 21.4; MS (FAB) 440 [MþH]þ; HRMS (FAB) m/z calcd
m/z calcd for C25H36NO3SiS 458.2185; found 458.2190. Data for
for C19H23NO4SBr 440.0525; found 440.0518.
25
syn-12: gummy oil; TLC, Rf (30% EtOAc/hexane) 0.30; [
a
]
ꢀ17.5 (c
D
1.0, CHCl3); IR (neat) 3446, 2928, 1637, 1384, 1258, 1084, 777 cmꢀ1
;
4.1.4. N,O-Acetonide 15
1H NMR (300 MHz, CDCl3)
d
7.66 (d, J¼8.2 Hz, 2H), 7.4–7.2 (m, 7H),
To a solution of anti-14 (1.85 g, 4.3 mmol) in toluene (9 mL)
were added 2,2-dimethoxypropane (2.2 g, 22 mmol) and catalytic
amounts of (þ/ꢀ)-camphor-10-sulfonic acid (10 mol %). The mix-
ture was stirred for 3 h at 90 ꢁC. Few drops of Et3N were added and
6.0–5.8 (m, 1H), 5.3–5.2 (m, 2H), 5.0 (ABq, J¼12.7 Hz, 2H), 4.3 (m,
1H), 3.5 (dd, J¼12.7, 6.0 Hz, 1H), 3.0 (dd, J¼12.7, 6.0 Hz, 1H), 2.4 (s,
3H), 0.9 (s, 9H), 0.0 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 164.4, 143.1,

S. Raghavan, S. Mustafa / Tetrahedron 64 (2008) 10055–10061
10059
the solvent was removed under reduced pressure. The crude
compound was purified by column chromatography using 20%
EtOAc/petroleum ether (v/v) as the eluent to furnish acetonide
34.7, 32.5, 31.9, 29.7, 29.6, 29.55, 29.52, 29.4, 29.33, 29.3, 29.2, 22.7,
21.0, 14.1; MS (FAB) 580 [MþH]þ; HRMS (FAB) m/z calcd for
C
36H54NO3S 580.3824; found 580.3839. Note. The doubling of peaks
anti-15 (1.73 g, 3.6 mmol) in 85% yield as rotameric mixture.
in 13C is because of rotamers of Cbz group.
25
Gummy liquid; TLC, Rf (30% EtOAc/hexane) 0.25; [
a
]
D
þ64 (c 0.5,
CHCl3); IR (neat) 3780, 2926, 1701, 1591, 1383, 1020 cmꢀ1; 1H NMR
(300 MHz, CDCl3)
4.1.7. Acetonide cleavage 19
d
7.55 (d, J¼7.6 Hz, 2H), 7.4–7.5 (m, 7H), 5.1 (ABq,
To a solution of acetonide 18 (1.85 g, 3.0 mmol) in methanol
(9 mL) was added catalytic amount of (þ/ꢀ)-camphor-10-sulfonic
acid (10 mol %) and the reaction mixture was stirred for 24 h at rt.
Few drops of Et3N were added and the solvent was evaporated
under reduced pressure. The crude compound was purified by
column chromatography using 10% EtOAc/petroleum ether (v/v) as
J¼12.1 Hz, 2H), 4.7–4.6 (m, 1H), 4.1–3.9 (m, 1H), 3.8–3.6 (m, 1H),
3.6–3.4 (m, 1H), 3.2–3.0 (m, 1H), 2.9 (dd, J¼12.8, 9.1 Hz, 1H), 2.5 (s,
3H), 1.7–1.5 (m, 6H); 13C NMR (75 MHz, CDCl3) 162.9, 141.9, 140.9,
135.8,130.1,128.7,128.3,128.1,123.9, 96.2, 95.9, 74.1, 73.3, 67.5, 67.3,
63.5, 62.4, 62.0, 31.7, 30.9, 28.6, 27.7, 27.1, 27.0, 21.4; MS (FAB) 480
[MþH]þ; HRMS (FAB) m/z calcd for C22H27NO4SBr 480.0838; found
eluent to afford amino alcohol 19 (1.5 g, 2.8 mmol) in 93% yield
25
480.0841. Data for syn-15: gummy liquid; TLC, Rf (30% EtOAc/
as a gummy liquid. TLC, Rf (20% EtOAc/hexane) 0.30; [
a
]
þ5.0 (c
D
25
hexane) 0.20; [
a]
ꢀ5.0 (c 1.0, CHCl3); IR (neat) 3780, 2926, 1701,
0.45, CHCl3); IR (neat) 3416, 2979, 2932, 1456, 1373, 1216 cmꢀ1
;
D
1591, 1383, 1020 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
7.6 (d, J¼7.7 Hz,
1H NMR (300 MHz, CDCl3)
d
7.4–7.2 (m, 7H), 7.1 (d, J¼7.9 Hz, 2H),
2H), 7.4–7.3 (m, 7H), 5.3–5.0 (m, 2H), 4.3–4.2 (m, 2H), 3.8–3.6 (m,
5.5–5.4 (m, 2H), 5.1–5.0 (m, 3H), 4.0 (q, J¼7.0 Hz, 1H), 3.3–3.2 (m,
2H), 2.9 (ddd, J¼11.3, 8.1, 3.0 Hz, 1H), 2.5–2.4 (m, 1H), 2.3 (s, 3H),
2.2–1.9 (m, 3H), 1.5–1.1 (m, 21H), 0.9 (t, J¼6.8 Hz, 3H); 13C NMR
1H), 3.6–3.5 (m, 1H), 3.3–3.1 (m, 1H), 3.1 (dd, J¼13.6, 5.3 Hz, 1H), 2.5
(s, 3H), 1.8–1.5 (m, 6H); 13C NMR (75 MHz, CDCl3)
d 163.8, 142.1,
139.7, 135.8, 130.1, 128.7, 128.4, 128.1, 124.4, 95.4, 74.2, 73.7, 67.5,
67.3, 62.0, 61.1, 60.8, 32.0, 31.2, 29.6, 28.5, 27.3, 26.6, 21.5; MS (FAB)
480 [MþH]þ; HRMS (FAB) m/z calcd for C22H26NO4NaSBr 502.0663;
found 502.0663.
(75 MHz, CDCl3) d 156.2, 138.0, 136.6, 134.0, 133.8, 132.5, 129.8,
128.4, 128.0, 127.9, 125.7, 74.4, 66.6, 55.9, 47.2, 33.9, 32.6, 31.9, 29.6,
29.5, 29.4, 29.3, 29.2, 28.4, 27.6, 22.6, 21.1, 19.5, 14.1; MS (FAB) 562
[MþH]þ; HRMS (FAB) m/z calcd for C33H50NO3S 540.3511; found
540.3513.
4.1.5. Homoallyl sulfide 17
To a solution of the mixture of 1-tetradecene (1.96 g, 10 mmol)
and acetonide 15 (2.4 g, 5 mmol) in dry DCM (25 mL) under an
atmosphere of nitrogen was added TFAA (2.8 mL, 20 mmol) drop-
wise at 0 ꢁC and stirred for 15 min. Then SnCl4 (0.65 mL, 5.5 mmol)
was added to the reaction mixture at 0 ꢁC and stirred for another
30 min at the same temperature. The reaction mixture was cooled
to ꢀ10 ꢁC and then quenched by the addition of saturated aq
Na2CO3 solution (10 mL). The layers were separated and aqueous
layer extracted with DCM (3ꢂ15 mL). The combined organic layers
were washed successively with water (2ꢂ20 mL), brine (30 mL)
and dried over Na2SO4. The solvent was removed under vacuum
and the residue was purified by column chromatography using 5%
ethyl acetate/petroleum ether (v/v) as the eluent to afford the
4.1.8. Amino alcohol derivative 20
To a solution of the alcohol 19 (950 mg, 1.77 mmol) in dry DCM
(9 mL), cooled at 0 ꢁC were added successively Et3N (0.45 mL,
5.3 mmol), catalytic DMAP (20 mg), and acetic anhydride (0.24 mL,
2.7 mmol) dropwise and the mixture stirred under nitrogen
atmosphere for 1 h. It was then diluted with DCM (15 mL). The
reaction mixture was washed with aq saturated NaHCO3 (15 mL),
water (2ꢂ10 mL), brine (10 mL), dried over anhydrous Na2SO4,
and the solvent was evaporated under reduced pressure to yield
viscous oil, which was purified by column chromatography using
10% EtOAc/petroleum ether to afford the acetate (990 mg,
1.7 mmol) as a gummy oil in quantitative yield. TLC, Rf (20% EtOAc/
25
hexane) 0.30; [
a
]
þ11.0 (c 0.5, CHCl3); IR (neat) 3453, 2925, 1742,
D
product 17 (2.1 g, 3.25 mmol) in 65% yield as viscous oil. TLC, Rf (10%
1539, 1461, 1239, 1112 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.4–7.2
25
EtOAc/hexane) 0.40; [
a
]
þ2.5 (c 1.85, CHCl3); IR (neat) 3320, 1582,
(m, 7H), 7.0 (d, J¼8.3 Hz, 2H), 5.5–5.4 (m, 2H), 5.1 (ABq, J¼12.1 Hz,
2H), 4.9 (t, J¼6.0 Hz, 1H), 4.8 (d, J¼9.8 Hz, 1H), 4.3–4.2 (m, 1H),
3.1 (q, J¼6.8 Hz, 1H), 2.4–2.2 (m, 5H), 2.0–1.9 (m, 5H), 1.4–1.2 (m,
18H), 1.1 (d, J¼6.0 Hz, 3H), 0.9 (t, J¼6.8 Hz, 3H); 13C NMR (75 MHz,
D
1523,1404,1384, 1354,1080 cmꢀ1; 1H NMR (200 MHz, CDCl3)
d 7.4–
7.2 (m, 7H), 7.1 (d, J¼6.7 Hz, 2H), 5.6–5.3 (m, 2H), 5.2 (ABq, J¼
13.5 Hz, 2H), 4.4–4.2 (m, 2H), 3.8–3.4 (m, 2H), 3.1 (t, J¼6.7 Hz, 1H),
2.5–2.2 (m, 4H), 2.1–1.8 (m, 2H), 1.8–1.0 (m, 25H), 0.9 (t, J¼6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3) 137.1, 136.1, 134.2, 133.3, 132.6, 129.9,
128.6, 128.2, 128.0, 126.3, 95.7, 94.9, 79.6, 78.8, 67.2, 67.1, 59.5, 58.9,
53.1, 53.0, 36.3, 32.6, 31.9, 29.65, 29.6, 29.4, 29.2, 27.8, 27.4, 26.6,
26.2, 22.7, 21.1, 14.1; MS (FAB) 659 [MþH]þ; HRMS (FAB) m/z calcd
for C36H53NO3SBr 658.2929; found 658.2915. Note. In the 13C
spectrum, the peak for carbonyl carbon could not be picked up.
CDCl3)
d 170.4, 155.7, 137.0, 136.5, 134.5, 132.5, 132.3, 129.6,
128.4, 128.1, 128.0, 125.3, 76.9, 66.7, 51.4, 47.9, 35.0, 32.6, 31.9, 29.6,
29.5, 29.3, 29.1, 22.6, 20.9, 20.5, 18.9, 14.0; MS (FAB) 604 [MþNa]þ;
HRMS (FAB) m/z calcd for
C35H51NO4NaS 604.3436; found
604.3435.
4.1.9. Amidomercuration 21
To a stirred solution of the acetate 20 (581 mg, 1 mmol) in dry
DCM (5 mL) was added Hg(OCOCF3)2 (853 mg, 2 mmol) at rt. The
reaction mixture was stirred for 16 h, diluted with dry THF (5 mL),
cooled to ꢀ78 ꢁC, and LiBH4 (2 M in THF, 2 mL) was added dropwise
over a period of 15 min. The reaction mixture was gradually
warmed to 0 ꢁC and the solution was stirred for 30 min. After
30 min the reaction was quenched with aqueous saturated solution
of NH4Cl (2 mL). The layers were separated and the aqueous layer
was extracted with diethyl ether (2ꢂ10 mL). The combined organic
layers were washed with water (2ꢂ10 mL), brine (10 mL), dried
over Na2SO4, and the solvent was evaporated under reduced
pressure to yield a viscous oil, which was purified by column
chromatography using 10% EtOAc/petroleum ether (v/v) to afford
4.1.6. Debromination of homoallyl sulfide 18
To a solution of the bromoacetonide 17 (3.2 g, 4.5 mmol) and
n-Bu3SnH (1.44 g, 5.0 mmol) in dry benzene (18.0 mL) was added
AIBN (38 mg, 0.23 mmol) and the mixture was refluxed under an
atmosphere of nitrogen for 3 h. The solvent was evaporated under
reduced pressure and the residue was chromatographed using 5%
EtOAc/petroleum ether (v/v) to afford acetonide 18 (2.1 g,
3.6 mmol) in 80% yield as a gummy oil. TLC, Rf (10% EtOAc/hexane)
25
0.35; [
a
]
þ2.0 (c 0.85, CHCl3); IR (neat) 3235, 1680, 1589, 1219,
D
1184 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.4–7.2 (m, 7H), 7.05 (d,
J¼8.3 Hz, 2H), 5.5–5.3 (m, 2H), 5.1 (ABq J¼12.8 Hz, 2H), 4.2–3.9 (m,
1H), 3.9 (dd, J¼6.8, 3.8 Hz,1H), 3.1–3.0 (m,1H), 2.5–2.2 (m, 5H), 2.1–
1.8 (m, 2H), 1.8–1.0 (m, 25H), 0.9 (t, J¼6.8 Hz, 3H); 13C NMR
the cyclized compound 21 (404 mg, 0.75 mmol) in 75% yield as
25
(75 MHz, CDCl3)
d
173.5, 138.0, 136.9, 134.0, 132.4, 132.3, 129.73,
a gummy liquid. TLC, Rf (20% EtOAc/hexane) 0.35; [
a
]
D
þ11.0 (c 1.0,
129.7, 128.5, 128.0, 126.4, 95.1, 95.0, 82.2, 66.8, 66.7, 54.9, 52.0, 51.9,
CHCl3); IR (neat) 3430, 2924, 1638, 1455, 1235 cmꢀ1 1H NMR
;

10060
S. Raghavan, S. Mustafa / Tetrahedron 64 (2008) 10055–10061
(300 MHz, CDCl3)
d
7.4–7.2 (m, 7H), 7.2–7.1 (d, J¼8.6 Hz, 2H), 5.1 (s,
32.7, 31.9, 29.7, 29.6, 29.4, 29.35, 29.3, 22.7, 21.1, 14.1; MS (FAB) 578
[MþH]þ; HRMS (FAB) m/z calcd for C33H49NO4NaS 578.3274;
found 578.3263.
2H), 4.7–4.5 (m, 1H), 4.2–4.0 (m, 1H), 3.4 (dd, J¼10.2, 5.5 Hz, 1H),
3.2–2.9 (m, 2H, H and OH), 2.4 (s, 3H), 2.0 (dd, J¼13.3, 2.3 Hz, 1H),
1.7–1.4 (m, 3H), 1.4–1.1 (m, 25H), 0.9 (t, J¼7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3)
d
155.3,138.7,136.4,135.0,129.6,128.2,127.7,127.6,
4.1.13. Silyl ether 25
125.8, 70.4, 67.0, 51.2, 50.4, 44.7, 35.2, 33.7, 31.7, 29.4, 29.3, 29.1, 27.1,
To a stirred solution of the diol 24 (721 mg, 1.3 mmol) in dry
CH2Cl2 (2.7 mL) cooled at ꢀ15 ꢁC was added 2,6-lutidine (0.68 mL,
5.8 mmol) followed by TBS-OTf (0.67 mL, 0.29 mmol) and the
mixture stirred at 0 ꢁC for 1 h. The reaction mixture was diluted
with CH2Cl2 (10 mL), washed with water (2ꢂ5 mL), brine (7 mL),
and dried over Na2SO4. The solvent was evaporated under reduced
pressure to afford the crude product, which was purified by column
chromatography using 2% EtOAc/petroleum ether (v/v) to yield 25
22.5, 20.9, 13.9; MS (FAB) 540 [MþH]þ; HRMS (FAB) m/z calcd for
C
33H50NO3S 540.3511; found 540.3513.
4.1.10. Deoxocassine 6
To a solution of the alcohol 21 (108 mg, 0.2 mmol) in abso-
lute ethanol (10 mL) was added Ra-Ni (1.1 g, 10 times by weight)
and the mixture stirred at rt under hydrogen atmosphere for
2 h. The reaction mass was filtered through a small pad of silica
gel, the filtrate was evaporated under reduced pressure to give
(940 mg, 1.2 mmol) in 93% yield as gummy liquid. TLC, Rf (10%
25
EtOAc/hexane) 0.50; [
a]
þ5.8 (c 2.0, CHCl3); IR (KBr) 3276, 1682,
D
deoxocassine 6 (54 mg, 0.19 mmol) in 94% yield as a white solid.
1566, 1504, 1346, 1267 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.4–7.3
Mp 46–47 ꢁC (lit.7f mp 47–48 ꢁC); [
a
]
ꢀ12.2 (c 0.8, CHCl3) (lit.7f
(m, 7H), 7.1 (d, J¼8.3 Hz, 2H), 5.6–5.4 (m, 2H), 5.3–5.0 (m, 3H), 4.3–
4.1 (m, 2H), 3.6 (dd, J¼9.8, 5.3 Hz, 1H), 3.4 (t, J¼9.8 Hz, 1H), 3.1–3.0
(m, 1H), 2.7–2.5 (m, 1H), 2.4 (s, 3H), 2.1–1.9 (m, 2H), 1.6–1.1 (m,
19H), 1.0–0.8 (m, 21H), 0.2–0.0 (4s, 12H); 13C NMR (75 MHz, CDCl3)
25
D
25
[
a]
ꢀ12.4 (c 0.8, CHCl3)); IR (KBr) 3394, 2916, 2848, 1455 cmꢀ1
;
D
1H NMR (200 MHz, CDCl3)
d
3.5 (m, 1H), 2.8 (q, J¼5.5 Hz, 1H),
2.6–2.5 (m, 1H), 2.2–1.6 (m, 2H), 1.6–0.9 (m, 27H), 0.8 (t,
J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
68.3, 57.5, 56.0, 37.2,
d 155.7, 136.9, 133.0, 132.7, 132.5, 132.0, 129.6, 128.5, 128.0, 127.9,
32.3, 32.1, 30.0, 29.9, 29.8, 29.6, 26.4, 26.0, 22.9, 18.9, 14.3; MS
(FAB) 284 [MþH]þ; HRMS (FAB) m/z calcd for C18H38NO
284.2953; found 284.2958.
127.8, 69.7, 66.6, 62.6, 56.1, 52.1, 32.6, 32.5, 31.9, 29.7, 29.6, 29.5,
29.4, 29.2, 25.9, 25.7, 22.7, 21.0, 14.1, ꢀ2.9, ꢀ4.4, ꢀ4.8, ꢀ5.4; MS
(FAB) 783 [MþH]þ; HRMS (FAB) m/z calcd for C45H77NO4NaSi2S
806.5009; found 806.4990.
4.1.11. Bromine displacement product 23
To a solution of the bromo compound 17 (1.72 g, 2.62 mmol) in
dry DMF (13 mL) was added NaNO2 (1.81 g, 26.2 mmol) under ni-
trogen atmosphere and the mixture heated at 80 ꢁC for 6 h. The
reaction mixture was cooled to rt, diluted with ether (40 mL), and
washed with water (2ꢂ30 mL). The organic layer was separated
and the aqueous layer was extracted with ether (3ꢂ15 mL). The
combined organic layers were washed successively with water
(2ꢂ30 mL), brine (30 mL), dried over anhydrous Na2SO4, and
evaporated under reduced pressure. The crude reaction mixture
was purified by column chromatography using 20% ethyl acetate/
petroleum ether (v/v) as the eluent to afford the alcohol 23 (1.3 g,
4.1.14. Amidomercuration product 26
To a stirred solution of 25 (783 mg, 1 mmol) in dry DCM (5 mL)
was added Hg(OCOCF3)2 (853 mg, 2 mmol) at rt. The reaction
mixture was stirred for 16 h, diluted with dry THF (5 mL), cooled
to 0 ꢁC, and LiBH4 (2 M in THF, 2 mL) was added dropwise over
a period of 15 min. After 30 min the reaction was quenched with
aq saturated solution of NH4Cl (2 mL). The layers were separated
and the aqueous layer was extracted with diethyl ether (2ꢂ10 mL).
The combined organic layers were washed with water (2ꢂ10 mL),
brine (10 mL), dried over Na2SO4, and the solvent was evaporated
under reduced pressure to yield a viscous oil, which was purified
by column chromatography using 30% EtOAc/petroleum ether (v/
2.2 mmol) in 80% yield as viscous liquid. TLC, Rf (20% EtOAc/hexane)
25
0.40; [
a
]
þ5.0 (c 0.5, CHCl3); IR (neat) 3387, 2925, 2855,1711,1516,
v) to afford compound 26 (326 mg, 0.73 mmol) in 73% yield as
D
25
1383, 1272, 1057 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
7.4–7.2 (m, 7H),
a gummy liquid. TLC, Rf (30% EtOAc/hexane) 0.30; [
a]
þ52 (c
D
7.1 (d, J¼6.8 Hz, 2H), 5.6–5.3 (m, 2H), 5.3–5.1 (m, 2H), 4.4–3.9 (m,
2H), 3.8–3.6 (m, 2H), 3.1–3.0 (m, 1H), 2.6–2.3 (m, 4H), 2.1–1.9 (m,
2H), 1.8–1.0 (m, 25H), 0.9 (t, J¼6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) 137.1, 134.2, 133.3, 132.3, 131.7, 129.8, 128.6, 128.3, 128.2,
126.3, 95.1, 67.7, 65.2, 63.3, 62.1, 52.2, 36.3, 32.6, 31.9, 29.6, 29.4,
29.2, 27.4, 27.2, 26.3, 26.2, 24.8, 22.7, 21.0, 14.1; MS (FAB) 618
[MþH]þ; HRMS (FAB) m/z calcd for C36H53NO4NaS 618.3587; found
618.3584. Note. In the 13C spectrum, the peak for carbonyl carbon
could not be picked up.
0.25, CHCl3); IR (KBr) 3424, 2924, 1638, 1520, 1422, 1275 cmꢀ1
NMR (300 MHz, CDCl3)
;
1H
d
7.3 (d, J¼8.3 Hz, 2H), 7.1 (d, J¼8.3 Hz, 2H),
4.3–4.2 (m, 2H), 3.7–3.4 (m, 4H), 2.5–2.2 (m, 5H), 1.8–1.5 (m, 2H),
1.4–1.0 (m, 20H), 0.9 (t, J¼6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
156.5, 137.9, 132.2, 131.8, 130.1, 67.6, 62.8, 56.3, 52.4, 48.8, 31.9,
30.8, 30.3, 29.5, 29.4, 26.7, 22.7, 21.1, 14.1; MS (FAB) 448 [MþH]þ;
HRMS (FAB) m/z calcd for
C26H41NO3NaS 470.2704; found
470.2683.
4.1.15. Acetate derivative 27
4.1.12. Aminodiol derivative 24
To a stirred solution of alcohol 26 (18 mg, 0.04 mmol) in dry
DCM (0.2 mL) was added Et3N (0.01 mL, 0.11 mmol) and acetic
anhydride (0.005 mL, 0.06 mmol) at 0 ꢁC. The reaction mixture was
stirred for 2 h at rt. The mixture was diluted with DCM (10 mL) and
washed successfully with water (2ꢂ5 mL), brine (5 mL), the organic
layer was dried over Na2SO4 and the solvent was evaporated under
reduced pressure to yield a viscous oil, which was purified by col-
umn chromatography using 15% EtOAc/petroleum ether (v/v) to
afford acetate 27 (17.7 mg, 0.036 mmol) in 90% yield as gummy
To a solution of 23 (595 mg, 1.0 mmol) in methanol (3 mL) was
added catalytic amount of (þ/ꢀ)-camphor-10-sulfonic acid
(10 mol %) and the reaction mixture was stirred for 24 h at rt. Few
drops of Et3N were added and the solvent was evaporated under
reduced pressure. The crude compound was purified by column
chromatography using 20% EtOAC/petroleum ether (v/v) as eluent
to afford diol 24 (516 mg, 0.93 mmol) in 93% yield as a gummy
25
liquid. TLC, Rf (30% EtOAc/hexane) 0.30; [
a
]
þ24.5 (c 0.55,
D
CHCl3); IR (KBr) 3411, 2924, 1628, 1511, 1374, 1253 cmꢀ1
(300 MHz, CDCl3)
;
1H NMR
liquid. 1H NMR (400 MHz, CDCl3)
d
7.3 (d, J¼7.7 Hz, 2H), 7.1 (d,
d
7.4–7.2 (m, 7H), 7.1 (d, J¼7.6 Hz, 2H), 5.5–5.4
J¼8.4 Hz, 2H), 4.9 (t, J¼2.3 Hz, 1H), 4.4 (td, J¼8.4, 3.1 Hz, 1H), 4.3 (t,
J¼9.2 Hz, 1H) 3.6 (q, J¼3.1 Hz, 1H), 3.6–3.5 (m, 1H), 2.5–2.4 (m, 1H),
2.3 (s, 3H), 2.2–2.1 (m, 4H), 1.8 (td, J¼13.8, 2.3 Hz, 1H), 1.7–1.6 (m,
1H), 1.5–1.2 (m, 20H), 0.9 (t, J¼8.4, 3H). Note. The NOESY spectrum
diagnostically revealed NOE between methine protons at C-2
and C-6.
(m, 2H), 5.3 (d, J¼9.1 Hz, 1H), 5.1 (ABq, J¼12.8 Hz, 2H), 4.0–3.9 (m,
1H), 3.8–3.6 (m, 2H), 3.6–3.4 (m, 2H), 3.0–2.9 (m, 1H), 2.5–2.3 (m,
4H), 2.2–1.9 (m, 3H), 1.6–1.0 (m, 18H), 0.9 (t, J¼7.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3)
d 156.7, 138.2, 136.4, 134.2, 133.9, 132.7,
129.9, 128.5, 128.2, 128.0, 125.6, 73.0, 67.0, 65.1, 55.8, 52.0, 33.5,

S. Raghavan, S. Mustafa / Tetrahedron 64 (2008) 10055–10061
10061
4.1.16. Desulfurization product 28
thankful to CSIR, New Delhi for a fellowship. Financial assistance
from DST (New Delhi) is gratefully acknowledged.
To a solution of the alcohol 26 (89 mg, 0.2 mmol) in absolute
ethanol (10 mL) was added Ra-Ni (890 mg, 10 times by weight), and
the mixture stirred at rt under hydrogen atmosphere for 2 h. The
reaction mass was filtered through a small pad of silica gel, the
filtrate was evaporated under reduced pressure to give the product
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.08.031.
28 (59 mg, 0.18 mmol) in 90% yield as a semi solid. TLC, Rf (30%
25
EtOAc/hexane) 0.25; [
a
]
D
ꢀ15.5 (c 0.3, CHCl3); IR (KBr) 3376, 2928,
2856,1697, 1385, 1256, 1102 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 4.5–
4.2 (m, 2H), 3.9–3.7 (m, 1H), 3.6 (t, J¼6.0 Hz, 1H), 3.1–3.0 (m, 1H),
References and notes
2.5–2.4 (m, 1H), 2.1–2.0 (d, J¼11.3 Hz, 1H), 1.9–1.2 (m, 24H), 0.9 (t,
J¼6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 156.4, 64.9, 62.9, 60.9,
1. (a) Schneider, M. J. In Alkaloids: Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Pergamon: Oxford, 1996; Vol. 10, pp 125–299; (b) Christofidis, J.;
Welter, A.; Jadol, J. Tetrahedron 1977, 33, 977; (c) Cook, G. R.; Beholz, L. G.;
Stille, J. R. J. Org. Chem. 1994, 59, 3575.
57.5, 31.9, 31.2, 31.0, 29.6, 29.3, 26.7, 24.8, 22.6, 14.1; MS (FAB) 326
[MþH]þ; HRMS (FAB) m/z calcd for C19H36NO3 326.2689; found
326.2698.
2. Fodor, G. B.; Colasanti, B. In The Pyridine and Piperidine Alkaloids: Chemistry and
Pharmacology; Pelletier, S. W., Ed.; Alkaloids: Chemical and Biological Per-
spectives; Wiley-Interscience: New York, NY, 1985; Vol. 3, pp 1–90.
3. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645; (b) El Ashry, E. S. H.; Rashed, N.; Shobier, A. H. S. Pharmazie
2000, 55, 331.
4. For selected reviews of piperidine alkaloids, see: (a) Strunz, G. M.; Findlay, J. A.
In The Alkaloids; Brossi, A., Ed.; Academic: New York, NY, 1985; Vol. 26,
pp 89–183; (b) Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, NY, 1985; Vol. 3, pp 1–90; (c)
Angle, S. R.; Breitenbucher, J. G. Stud. Nat. Prod. Chem. 1995, 16, 453; (d)
Schneider, M. J. Alkaloids: Chemical and Biological Perspectives; Elsevier: Oxford,
UK, 1996; Vol. 10, p 155; (e) Andersen, R. J.; Van Soest, R. W. M.; Kong, F. Al-
kaloids: Chemical and Biological Perspectives; Elsevier: Oxford, UK, 1996; Vol. 10,
p 301; (f) Ojima, I.; Iula, D. M. Alkaloids: Chemical and Biological Perspectives;
Elsevier: Oxford, UK, 1999; Vol. 13, p 371; (g) Plunkett, O.; Sainsbury, M. In
Rodd’s Chemistry of Carbon Compounds, 2nd ed.; Sainsbury, M., Ed.; Elsevier:
Amsterdam, 1998, Part F/Part G (partial), pp 365–421; (h) Rodriguez, J. Stud.
Nat. Prod. Chem. (Part E) 2000, 24, 573.
4.1.17. Ketone 29
To a solution of the alcohol 28 (59 mg, 0.18 mmol) in EtOAc
(1 mL) was added IBX (100 mg, 0.36 mmol) and the mixture was
heated at reflux for 6 h. The reaction mixture was filtered through
Celite and the filtrate was evaporated under reduced pressure to
yield keto compound 29 as a viscous oil. The ketone being unstable
to chromatography was used without further purification in the
subsequent reduction.
4.1.18. Alcohol 30
The crude ketone from the previous step was dissolved in MeOH
(1 mL) and NaBH4 (10 mg, 0.27 mmol) was added at 0 ꢁC. The re-
action mixture was stirred for 1 h at the same temperature, diluted
with 10 mL of diethyl ether, washed with water (5 mL) and brine
(5 mL). The organic layer was dried over Na2SO4 and the solvent
was evaporated under reduced pressure to yield a gummy liquid,
which was purified by column chromatography using 30% EtOAc/
5. (a) Raghavan, S.; Naveen Kumar, Ch.; Tony, K. A.; Ramakrishna Reddy, S.; Ravi
Kumar, K. Tetrahedron Lett. 2004, 45, 7231; (b) Raghavan, S.; Naveen Kumar, Ch.
Tetrahedron Lett. 2006, 47, 1585.
6. For a preliminary account on the synthesis of (þ)-desoxoprosophylline, see:
Raghavan, S.; Mustafa, S. Tetrahedron Lett. 2008, 49, 5169.
petroleum ether (v/v) to afford alcohol 23 (50 mg, 0.15 mmol) in
86% yield as a gummy liquid. TLC, Rf (30% EtOAc/hexane) 0.25; [a]
D
7. (a) Andres, J. M.; Pedrosa, R.; Perez-Encoba, A. Eur. J. Org. Chem. 2007, 1803; (b)
Noel, R.; Vanuci-Bacque, C.; Fargeau-Bellassoued, M.-C.; Lhommet, G. Eur. J.
Org. Chem. 2007, 476; (c) Subba Rao, V. K.; Kumar, P. Tetrahedron 2006, 62,
9942; (d) Leverett, C. A.; Cassidy, M. P.; Padwa, A. J. Org. Chem. 2006, 71, 8591;
(e) Cassidy, M. P.; Padwa, A. Org. Lett. 2004, 6, 4029; (f) Liu, L.-X.; Ruan, Y.-P.;
Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem. 2004, 69, 6001; (g) Ma, D.; Ma, N.
Tetrahedron Lett. 2003, 44, 3963; (h) Kurihara, K.; Sugimoto, T.; Saitoh, Y.;
Igarashi, Y.; Hirota, H.; Moriyama, Y.; Tsuyuki, T.; Takahashi, T. Bull. Chem. Soc.
Jpn. 1985, 58, 3337.
8. (a) Highet, R. J. J. Org. Chem. 1964, 29, 471; (b) Highet, R. J.; Highet, P. F. J. Org.
Chem. 1966, 31, 1275.
9. Raghavan, S.; Mustafa, S. Tetrahedron Lett. 2008, 49, 3216.
10. Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Bella, M.; Reddy, M. V. Angew.
Chem., Int. Ed. 2002, 41, 834.
25
þ24.5 (c 0.3, CHCl3); IR (KBr) 3376, 2928, 2856, 1697, 1385, 1256,
1102 cmꢀ1 1H NMR (200 MHz, CDCl3)
;
d
4.4–4.1 (m, 2H), 3.5 (ddd,
J¼12.1, 9.1, 3.0 Hz, 1H), 3.3 (ddd, J¼10.6, 9.1, 3.0 Hz, 1H), 3.0 (q,
J¼7.6 Hz, 1H), 2.5–2.3 (m, 1H), 2.2–2.0 (m, 1H), 1.9–1.0 (m, 24H), 0.9
(t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 155.9, 69.6, 64.9, 62.6,
57.2, 33.7, 31.9, 30.9, 30.3, 29.8, 29.6, 29.3, 27.0, 26.7, 22.6, 14.0; MS
(FAB) 326 [MþH]þ; HRMS (FAB) m/z calcd for C19H36NO3 326.2689;
found 326.2694.
11. Raghavan, S.; Mustafa, S.; Kailash, R. Tetrahedron Lett. 2008, 49, 4256.
12. The deprotection of the silyl group was necessary because the bromo-
carbamate derived from 12 failed to undergo the Pummerer reaction, see
Ref. 9.
13. For analytical purposes a small amount of the mixture was separated and the
isomers individually characterized.
4.1.19. Desoxoprosophylline 22
To a stirred solution of the alcohol 30 (25 mg, 0.076 mmol) in
ethanol (0.5 mL) was added aq KOH (8 N, 0.5 mL) and the reaction
mixture was heated at 95–100 ꢁC for 24 h. The reaction was cooled
to rt and extracted with dichloromethane (3ꢂ10 mL). The organic
layer was successfully washed with water (2ꢂ10 mL), brine
(10 mL), dried over Na2SO4, and evaporated under reduced pres-
sure to furnish the crude product, which was purified by column
chromatography using 8% MeOH/CHCl3 (v/v) to afford (þ)-desoxo-
prosophylline 22 (20 mg, 0.068 mmol) in 90% yield as a white solid.
Mp 87–88 ꢁC (lit.17c mp 89.5–90 ꢁC); TLC, Rf (10% MeOH/CHCl3)
14. Harding, K. E.; Marman, T. H. J. Org. Chem. 1984, 49, 2838.
15. Takacs, J. M.; Helle, M. A.; Takusagawa, F. Tetrahedron Lett. 1989, 30, 7321.
16. (a) Fuhshuku, K.; Mori, K. Tetrahedron: Asymmetry 2007, 18, 2104; (b)
Tzanetou, E. N.; Kasiotis, K. M.; Magiatis, P.; Haroutounian, S. A. Molecules
2007, 12, 735; (c) Wang, Q.; Sasaki, N. A. J. Org. Chem. 2004, 69, 4767; (d)
Jourdant, A.; Zhu, J. Heterocycles 2004, 64, 249; (e) Dransfield, P. J.; Gore, P. M.;
Prokes, I.; Shipman, M.; Slawin, A. M. Z. Org. Biomol. Chem. 2003, 1, 2723; (f)
Datta, A.; Kumar, J. S. R.; Roy, S. Tetrahedron 2001, 57, 1169; (g) Herdeis, C.;
Tesler, J. Eur. J. Org. Chem. 1999, 1407; (h) Ojima, I.; Vidal, E. S. J. Org. Chem.
1998, 63, 7999; (i) Kadota, I.; Kawada, M.; Muramatsu, Y.; Yamamoto, Y.
Tetrahedron: Asymmetry 1997, 8, 3887; (j) Takao, K.; Nigawara, Y.; Nishino, E.;
Takagi, I.; Maeda, K.; Tadano, K.; Ogawa, S. Tetrahedron 1994, 50, 5681; (k)
Saitoh, Y.; Moriyama, Y.; Hirota, H.; Takahashi, T.; Khuong-Huu, Q. Bull. Chem.
Soc. Jpn. 1981, 54, 488.
þ12 (c 0.22, CHCl3) (lit.17c
[a]
D
þ14.4 (c 0.22, CHCl3)); 1H
25
25
0.25; [
a]
D
NMR (300 MHz, CDCl3)
d
3.82 (dd, J¼10.7, 4.4 Hz, 1H), 3.7 (dd,
J¼10.7, 5.3 Hz, 1H), 3.45 (ddd, J¼9.2, 8.6, 4.5 Hz, 1H), 2.6–2.4 (m,
2H), 2.4–2.3 (m, 1H), 2.1–1.8 (m, 2H), 1.8–1.6 (m, 2H), 1.4–1.0 (m,
22H), 0.9 (t, J¼6.7 Hz, 3H); MS (FAB) 300 [MþH]þ. HRMS (FAB) m/z
calcd for C18H37NO2 299.2824; found 299.2843.
17. (a) Chavan, S. P.; Praveen, C. Tetrahedron Lett. 2004, 45, 421; (b) Ma, N.; Ma, D.
Tetrahedron: Asymmetry 2003, 14, 1403; (c) Yang, C.; Liao, L.; Xu, Y.; Zhang, H.;
Xia, P.; Zhou, W.-S. Tetrahedron: Asymmetry 1999, 10, 2311.
18. Raduchel, B. Synthesis 1980, 292.
19. Dodge, J. A.; Trujillo, J. I.; Preenel, M. J. Org. Chem. 1994, 59, 234.
20. Kano, S.; Yuasa, Y.; Mochizuki, N.; Shibuya, S. Heterocycles 1990, 30, 263.
21. Toyooka, N.; Yosida, Y.; Momose, T. Synlett 1993, 565.
22. (a) Singh, S.; Singh, O. V.; Han, H. Tetrahedron Lett. 2007, 48, 8270; (b) Singh,
O. V.; Han, H. Org. Lett. 2004, 6, 3067.
Acknowledgements
S.R. is thankful to Dr. J.M. Rao, Head, Org. Div. I and Dr. J.S. Yadav,
Director, IICT for constant support and encouragement. S.M. is