Stereoselective synthesis of (-)-allosedamine

Article abstract of DOI:10.1016/j.tetlet.2003.12.129

A stereoselective synthesis of (-)-allosedamine is disclosed. β-Aminosulfoxide 4 was generated stereoselectively by condensation of the sulfinyl anion 2 with N-Ts imine 3. The bromohydrin 5 was obtained by intramolecular sulfinyl group participation and the piperidine ring of allosedamine was elaborated using the ring-closing metathesis (RCM) reaction.

Full text of DOI:10.1016/j.tetlet.2003.12.129

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1919–1922
Stereoselective synthesis of ())-allosedamineq
Sadagopan Raghavan* and A. Rajender
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500-007, India
Received 7 November 2003; revised 11 December 2003; accepted 24 December 2003
Abstract—A stereoselective synthesis of ())-allosedamine is disclosed. b-Aminosulfoxide 4 was generated stereoselectively by
condensation of the sulfinyl anion 2 with N-Ts imine 3. The bromohydrin 5 was obtained by intramolecular sulfinyl group par-
ticipation and the piperidine ring of allosedamine was elaborated using the ring-closing metathesis (RCM) reaction.
Ó 2004 Elsevier Ltd. All rights reserved.
The alkaloid ())-allosedamine 1, was isolated1 from
Lobelia inflata, the crude extract of which has been used
for the treatment of respiratory disorders such as asth-
ma, bronchitis and pneumonia. Although several syn-
theses of the racemic alkaloid have been reported,2
stereoselective asymmetric syntheses are few in number.3
We report herein a stereoselective route to ())-allosed-
amine, the key steps of which include, the diastereo-
selective condensation of the anion 2, derived from
(R)-methyl p-tolyl sulfoxide with an imine 3 and stereo-
and regioselective preparation of the bromohydrin 5
from the resulting b-aminosulfoxide 4 (Scheme 1).
In contrast to the numerous reports on the addition of
a-sulfinyl carbanions to aldehydes,4 the addition of these
carbanions to imines has received less attention.5 Except
for one report on the addition of the carbanion derived
from (S)-tert-butyl phenyl methyl sulfoxide to an imine
derived from an unsaturated aldehyde,6 most of the
literature reports are concerned with the addition of
sulfoxide anions to imines derived from aromatic alde-
hydes.7
The addition of the anion 2 with imine 38 afforded a
mixture of adducts 4. Kagan has noted the importance
O
X
STol
OH
OH
O
S
NHTs
OH
N
TsHN
Tol
+
Me
H
H
X
Br
1
6
5
O
S
NHTs
O
S
TsN
Tol
+
Tol
4s
3
2
Li
X = Nucleofuge
Scheme 1.
Keywords: Allosedamine; b-Aminosulfoxide; Bromohydrin; Pummerer reaction; Ring-closing metathesis reaction.
q IICT Communication No. 030914.
* Corresponding author. Tel.: +91-04027160123; fax: +91-04027160512; e-mail: sraghavan@iict.ap.nic.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.129

1920
S. Raghavan, A. Rajender / Tetrahedron Letters 45 (2004) 1919–1922
O
S
NHTs
S
Li
O
Tol
Ph
Tol
Ts
N
4s
TsN
O
S
+
Tol
3
2
Li
Ts
Li
O
S
NHTs
N
S
Tol
Tol
Ph
Scheme 2. Reagents and conditions: LDA, THF, )78 °C, add 2, 20 min, then add 3, 15 min, 81%.
O
4a
of reaction temperature in determining the product
diastereoselection.5b Thus anion generation at )78 °C
and condensation at )78 °C afforded the best diaste-
reoselection (3:1 of 4s:4a) in 81% yield. The diastereo-
meric b-aminosulfoxides could be readily separated
by column chromatography and the structure was as-
signed to them based on their 1H NMR spectra (Scheme
2).9
using n-Bu3SnH to yield the 1,3-aminoalcohol 6. The
piperidine ring was envisaged to be elaborated by di-
alkylation at C1 and N using a suitable dielectrophile.12
Thus 6 was protected as its silyl ether 7 by treatment
with t-butyldiphenylchlorosilane and imidazole in di-
chloromethane as the solvent. Subjecting the dianion
(1,3-dinucleophile), derived from compound 7 by treat-
ment with LDA in THF, to treatment with 1,3-diiodo-
propane 9 or 1,3-propanediol ditriflate 10 in the
presence/absence of HMPA afforded varying amounts
of N-allylated 11 and b-elimination product 1212 with no
traces of the piperidine derivative 13 to be detected.
Attempted alkylation of the dianion from sulfone 8,
derived from sulfoxide 7 by treatment with m-CPBA,
with 1,3-diiodopropane or 1,3-propanediol ditriflate
afforded varying amounts of the N-allylated sulfone 14
and b-elimination product 15 (Scheme 3).
The hydroxy group of allosedamine was introduced
stereo- and regioselectively via bromohydration of 4s
using the sulfinyl group as the intramolecular nucleo-
phile to yield 5.10 The relative disposition of the het-
eroatoms at C2–C4 in 5 was unambiguously proven by
tetrahydrofuran ring formation by a Pummerer type
reaction promoted by t-butyldiphenylchlorosilane in
anhydrous DMF.11 The bromine atom in 5 was removed
H2O
O
S
NHTs
O
S
NHTs
OH
O
S
a
Ph
Tol
Tol
TsHN
4s
Tol
Br
5
Br
O
S
NHTs
O
S
NHTs
OP
OTBDPS
Ph
b
d
Tol
Ph
Tol
O
6, P = H
7, P = TBDPS
8
c
e
e
O
STol
OTBDPS
Y
Y
NTs
X
OTBDPS
Ph
X
OTBDPS
Ph
S
S
+
N
Ph
Tol
Tol
Ts
H
11, X = O, Y =
12, X = O, Y =
15, X = Y = O
13
14, X = Y = O
Scheme 3. Reagents and conditions: (a) NBS, H2O, toluene, rt, 1 h, 84%. (b) n-Bu3SnH, AIBN, benzene, reflux, 1.5 h, 76%. (c) TBDPS-Cl, imidazole,
DCM, rt, 1 h, 78%. (d) m-CPBA, CHCl3, 0 °C, 10 min, 89%. (e) n-BuLi, HMPA, I(CH2)3 9 or TfO(CH2)3OTf 10, THF, )78 to )20 °C, 2 h.

S. Raghavan, A. Rajender / Tetrahedron Letters 45 (2004) 1919–1922
1921
NTs
O
S
NHTs
OP
OP
NTs
OP
c (ii)
b
Ph
Tol
Ph
Ph
Y
X
6, P = H
a
X
18, X = S(O)Tol, Y = H
c (i)
16, P = Ac
20, X = O
21, X = CHCO2Et
19, X = STol, Y = OC(O)CF3
d
OP1
Ph
OH
g
e
ONs
N
P
N
P
Ph
17
H
H
22, P = Ts, P1 = Ac
23, P = H, P1 = H
24, P = H
f
h
1, P = Me
Scheme 4. Reagents and conditions: (a) Ac2O, pyridine, DCM, rt, 4 h, 96%. (b) 17, K2CO3, CH3CN, reflux, 2 h, 90%. (c) (i) TFAA, Et3N, CH3CN,
0 °C, 50 min; (ii) aq NaHCO3, 0 °C, 20 min. (d) Ph3PCHCO2Et, PhH, rt, 30 min, 75% for two steps. (e) G1, toluene, reflux, 16 h, 80%. (f) Na–Hg,
Na2HPO4, MeOH, reflux, 6 h, 78%. (g) H2, Pt/C, AcOEt, rt, 4 h, 95%. (h) 37% aq HCHO, NaCNBH3, AcOH, CH3CN, rt, 4 h, 70%.
The piperidine ring was successfully elaborated by a
ring-closing metathesis reaction.13 N-Alkylation of 16,
derived from alcohol 6, with the nosylate 17, afforded
compound 18. Sulfoxide 18 on treatment with trifluo-
roacetic anhydride in the presence of Et3N, underwent
Pummerer rearrangement14 to yield the intermediate 19,
which on hydrolysis by treatment with aq saturated
sodium bicarbonate yielded the aldehyde 20. The alde-
hyde 20, without purification was subjected to Wittig
olefination with ethyl(triphenylphosphoranylidene)ace-
tate to yield the trans ester 21 exclusively.15 Ester 21 was
subjected to RCM reaction16 using 5 mol % of GrubbsÕ
catalyst (G1) to yield compound 22.17 Deprotection of
the N-Ts group by treatment of 22 with Na–Hg18
afforded alcohol 23 by concomitant deacetylation.
Reduction of double bond by treatment of 23 with Pt/C
under an atmosphere of hydrogen afforded nor-allo-
sedamine 24, which was transformed into ())-allosed-
amine 1, by reductive alkylation with formaldehyde in
the presence of sodium cyanoborohydride (Scheme 4).19
The synthetic allosedamine prepared as detailed above
had physical characteristics that were in good agreement
References and notes
1. (a) Wieland, H.; Koschara, K.; Dane, E.; Renz, J.;
Schwarze, W.; Linde, W. Liebigs Ann. Chem. 1939, 540,
103; (b) Schopf, C.; Kauffmann, T.; Berth, P.; Bundshuh,
W.; Dummer, G.; Fett, H.; Habermehl, G.; Wieters, E.;
Wust, W. Liebigs Ann. Chem. 1959, 626, 150.
2. (a) Beyerman, H. C.; Eveleens, W.; Muller, Y. M. F. Recl.
Trav. Chim. Pays-Bas 1956, 75, 63; (b) Lukes, R.; Kovar,
J.; Blaha, K. Collect. Czech. Chem. Commun. 1956, 21,
1475; (c) Beyerman, H. C.; Eenshuistra, J.; Eveleens, W.;
Zweistra, A. Recl. Trav. Chim. Pays-Bas 1959, 78, 43; (d)
Tufariello, J. J.; Ali, S. A. Tetrahedron Lett. 1978, 19,
4647; (e) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am.
Chem. Soc. 1981, 103, 1172; (f) Hootele, C.; Ibebeke-
Bomangwa, W.; Driessens, F.; Sabil, S. Bull. Soc. Chim.
Belg. 1987, 96, 57; (g) Liguori, A.; Ottana, R.; Romeo, G.;
Sindona, S.; Uccella, N. Chem. Ber. 1989, 122, 2019; (h)
Ozawa, N.; Nakajima, S.; Zaoya, K.; Hamaguchi, F.;
Nagasaka, T. Heterocycles 1991, 32, 889.
3. (a) Wakabayashi, T.; Watanabe, K.; Kato, Y. Chem. Lett.
1977, 223; (b) Irie, K.; Aoe, K.; Tanaka, T.; Saito, S. J.
Chem. Soc., Chem. Commun. 1985, 633; (c) Kiguchi, T.;
Nakazono, Y.; Kotera, S.; Ninomiya, I.; Naito, T.
Heterocycles 1990, 31, 1525; (d) Oppolzer, W.; Deeberg,
J.; Tamura, O. Helv. Chim. Acta 1994, 77, 554; (e) Felpin,
F.-X.; Lebreton, J. Tetrahedron Lett. 2002, 43, 225.
4. Solladie, G. Synthesis 1981, 185, and references cited
therein.
5. (a) Tsuchihashi, G. I.; Iriuchijima, S.; Maniwa, K.
Tetrahedron Lett. 1973, 14, 3389; (b) Ronan, B.; March-
alin, S.; Samuel, O.; Kagan, H. B. Tetrahedron Lett. 1988,
29, 6101; (c) Pyne, S. G.; Boche, G. J. Org. Chem. 1989,
54, 2663; (d) Pyne, S. G.; Dikic, B. J. J. Chem. Soc., Chem.
Commun. 1989, 826; (e) Satoh, T.; Sato, T.; Oohara, T.;
Yamakawa, K. J. Org. Chem. 1989, 54, 3973; (f) Mahidol,
C.; Reutrakul, V.; Prapansiri, V.; Panyachotipun, C.
Chem. Lett. 1984, 969.
with those reported in the literature3d (½aꢀ25 )28.8° (c 0.4,
D
20
D
MeOH), lit.3d ½aꢀ )29.8° (c 0.2, MeOH)).
In summary we have disclosed a stereoselective synthesis
of allosedamine. The key steps include (a) diastereo-
selective condensation of the sulfinyl anion with an
imine, (b) regio- and stereoselective bromohydration of
an olefin using the sulfinyl moiety as the intramolecular
nucleophile, (c) RCM reaction to elaborate the piperi-
dine ring.
6. Pyne, S. G.; Dikic, B. J. J. Org. Chem. 1990, 55, 1932, and
references cited therein.
Acknowledgements
7. (a) Bravo, P.; Farina, A.; Kukhar, V. P.; Markovsky, A.
L.; Meille, S. V.; Soloshonok, V. A.; Sorochinsky, A. E.;
Viani, F.; Zanda, M.; Zappala, C. J. Org. Chem. 1997, 62,
3424; (b) Bravo, P.; Guidetti, M.; Viani, F.; Zanda, M.;
Markovsky, A. L.; Sorochinsky, A. E.; Soloshonok, V. A.
Tetrahedron 1998, 54, 12789; (c) Bravo, P.; Capelli, S.;
Crucianelli, M.; Guidetti, M.; Markovsky, A. L.; Meille,
S.R. is thankful to Dr. J. S. Yadav, Director, for con-
stant support and encouragement, to Dr. A. C. Kunwar
for NMR spectra. A.R. is thankful to CSIR (New Delhi)
for the senior research fellowship. Financial assistance
from DST is gratefully acknowledged.

1922
S. Raghavan, A. Rajender / Tetrahedron Letters 45 (2004) 1919–1922
S. V.; Soloshonok, V. A.; Sorochinsky, A. E.; Viani, F.;
Zanda, M. Tetrahedron 1999, 55, 3025.
Chemistry; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 7, p 193.
8. McKay, W. R.; Proctor, G. R. J. Chem. Soc., Perkin
Trans. 1 1981, 2435.
9. The structures were assigned to 4s and 4a by comparison
15. Representative procedure for compound 21. To the
solution of 18 (664 mg, 1.2 mmol) in acetonitrile (6 mL)
cooled at 0 °C was added triethylamine (364 mg, 3.6 mmol)
followed by trifluoroacetic anhydride (1.26 g, 6 mmol) and
stirred for 50 min. An aq 5% NaHCO3 solution (2 mL) was
added at 0 °C and stirred for another 20 min. The reaction
mixture was then extracted with benzene (10 mL), washed
successively with water, brine, dried over Na2SO4 and
used directly in the next step. Reaction with ethyl(triphen-
ylphosphoranilidine)acetate (498 mg, 1.2 mmol) at rt for
30 min afforded the unsaturated ester. The solvent was
removed under reduced pressure to afford the residue,
which was purified by column chromatography using
EtOAc/petroleum ether (1:9, v/v) as the eluent to afford
1
of their H NMR data with sulfoxides 25s and 25a. The
structure of 25s was unambiguously assigned by X-ray
crystallography of the related p-nitrobenzenesulfonamide
derivative. Refer: Raghavan, S.; Rajender, A.; Joseph, S.
C.; Rasheed, M. A.; Ravikumar, K. Tetrahedron: Asym-
metry 2004, 15, 365.
O
S
NHTs
O
S
NHTs
Ph
Ph
Ph
Ph
25s
25a
the a,b-unsaturated ester 21 (449 mg, 0.9 mmol) in 75%
25
yield (for the two steps). Solid. Mp 59–61 °C. ½aꢀ +58.7°
D
(c 2.3, CHCl3). 1H NMR (200 MHz, CDCl3) d (ppm) 7.63
(d, J ¼ 8:2 Hz, 2H), 7.39–7.2 (m, 7H), 6.54 (dd, J ¼ 15:6,
5.2 Hz, 1H), 5.76–5.56 (m, 3H), 5.08–4.93 (m, 2H), 4.56
(m, 1H), 4.12 (q, J ¼ 6:7 Hz, 2H), 3.18 (ddd, J ¼ 15:6,
11.1, 5.9 Hz, 1H), 2.92 (ddd, J ¼ 15:6, 10.4, 5.9 Hz, 1H),
2.56–2.16 (m, 6H), 2.06–1.91 (m, 4H), 1.24 (t, J ¼ 6:7 Hz,
3H). 13C NMR (75 MHz, CDCl3) d (ppm) 14.6, 21.5, 21.9,
36.0, 39.5, 45.2, 55.8, 61.0, 73.0, 117.7, 124.3, 126.8, 127.7,
128.7, 129.1, 130.2, 134.8, 137.5, 140.1, 144.0, 144.7, 165.9.
MS (FAB) 500 [M+H]þ. Anal. Calcd for C27H36NO6S: C,
64.91; H, 6.66; N, 2.80; S, 6.42. Found: C, 65.08; H, 6.85;
N, 2.71; S, 6.46.
Com-
pound
C2H d
(ppm)
Com-
pound
C2H d
(ppm)
25s
25a
4.38
4.52
4s
4a
4.36
4.51
10. (a) Raghavan, S.; Rasheed, M. A.; Joseph, S. C.;
Rajender, A. J. Chem. Soc., Chem. Commun. 1999, 1845;
(b) Raghavan, S.; Ramakrishna Reddy, S.; Tony, K. A.;
Naveen Kumar, Ch.; Varma, A. K.; Nangia, A. J. Org.
Chem. 2002, 67, 5838; (c) Raghavan, S.; Joseph, S. C.
Tetrahedron: Asymmetry 2003, 14, 101; (d) Raghavan, S.;
Tony, K. A. J. Org. Chem. 2003, 68, 5002; (e) Raghavan,
S.; Ramakrishna Reddy, S. J. Org. Chem. 2003, 68, 5754;
(f) Raghavan, S.; Rasheed, M. A. Tetrahedron: Asymme-
try 2003, 14, 1371; (g) Raghavan, S.; Rajender, A.
Tetrahedron: Asymmetry 2003, 14, 2093; (h) Raghavan,
S.; Rajender, A. J. Org. Chem. 2003, 68, 7094; (i)
Raghavan, S.; Joseph, S. C. Tetrahedron Lett. 2003, 44,
6713; (j) Raghavan, S.; Ramakrishna Reddy, S. Tetra-
hedron Lett. 2003, 44, 7459; (k) Raghavan, S.; Joseph, S.
C. Tetrahedron Lett. 2003, 44, 8237.
11. Raghavan, S.; Rajender, A.; Rasheed, M. A.; Rama-
krishna Reddy, S. Tetrahedron Lett. 2003, 44, 8253.
12. (a) Caturla, F.; Najera, C. Tetrahedron Lett. 1997, 38,
3789; (b) Costa, A.; Najera, C. Tetrahedron: Asymmetry
2001, 12, 2205.
13. For excellent review, refer to (a) Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. 1997, 36, 2036; (b) Schuster, M.;
Blechret, S. Angew. Chem. 1997, 109, 2124; (c) Furstner,
A. Top. Catal. 1997, 4, 285; (d) Armstrong, S. K. J. Chem.
Soc., Perkin Trans. 1 1998, 371.
16. (a) Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996,
37, 547; (b) Huwe, C. M.; Blechert, S. Synthesis 1997, 61.
17. Representative procedure for compound 22. Bis(tricy-
clohexylphophine) benzylideneruthenium(IV)dichloride
G1 (25 mg, 0.032 mmol) was added to a solution of diene
(324 mg, 0.65 mmol) in toluene (13 mL) and refluxed for
16 h, when TLC revealed the complete consumption of the
starting material. The solvent was removed under reduced
pressure. Column chromatography of the residue using
EtOAc/petroleum ether (1:4, v/v) as the eluent afforded the
product (207 mg, 0.52 mmol) in 80% yield. Solid. Mp 75–
25
D
1
76 °C. ½aꢀ )119.0° (c 0.75, CHCl3). H NMR (200 MHz,
CDCl3) d (ppm) 7.67 (d, J ¼ 8:9 Hz, 2H), 7.36–7.16 (m,
7H), 5.74 (dd, J ¼ 9:7, 4.5 Hz, 1H), 5.66–5.54 (m, 2H),
4.48 (m, 1H), 3.77 (dd, J ¼ 14:9, 5.2 Hz, 1H), 3.08 (ddd,
J ¼ 14:9, 11.9, 5.2 Hz, 1H), 2.42 (s, 3H), 2.20–1.60 (m,
7H). 13C NMR (75 MHz, CDCl3) d (ppm) 21.2, 21.5, 29.7,
38.0, 41.4, 50.2, 72.7, 125.5, 126.5, 127.2, 127.3, 128.0,
128.5, 129.5, 138.1, 140.5, 143.2, 170.1. MS (FAB) 400
[M+H]þ. Anal. Calcd for C27H25NO4S: C, 66.14; H, 6.31;
N, 3.51; S, 8.02. Found: C, 66.03; H, 6.55; N, 3.41; S, 8.07.
18. Stragies, R.; Blechert, S. Tetrahedron 1999, 55, 8179.
19. Bach, T.; Brummerhol, H.; Harms, K. Chem. Eur. J. 2000,
6, 3848.
14. (a) Sugihara, H.; Tanikaya, R.; Kaji, A. Synthesis 1978,
881; (b) Pummerer, R. Chem. Ber. 1909, 42, 2282; (c)
Kennedy, M.; McKervey, M. In Comprehensive Organic