Stereoselective synthesis of (-)-allosedamine and (1R,3R)-HPA-12 from β-p-toluenesulfonamido-γ,δ-unsaturated sulfoxide

Article abstract of DOI:10.1016/j.tet.2004.04.019

A stereoselective synthesis of (-)-allosedamine and HPA-12 is disclosed. The key steps of the synthesis include the diastereoselective synthesis of a β-sulfonamido unsaturated sulfoxide, elaboration of a bromohydrin via intramolecular sulfinyl group participation and a ring-closing metathesis reaction for the construction of the piperidine ring of allosedamine.

Full text of DOI:10.1016/j.tet.2004.04.019

Tetrahedron 60 (2004) 5059–5067
Stereoselective synthesis of (2)-allosedamine and (1R,3R)-HPA-12
from b-p-toluenesulfonamido-g,d-unsaturated sulfoxideq
*
Sadagopan Raghavan and A. Rajender
Organic Division I, Indian Institute of Chemical Technology, Habsiguda, Hyderabad 500 007, India
Received 12 January 2004; revised 18 March 2004; accepted 8 April 2004
Abstract—A stereoselective synthesis of (2)-allosedamine and HPA-12 is disclosed. The key steps of the synthesis include the
diastereoselective synthesis of a b-sulfonamido unsaturated sulfoxide, elaboration of a bromohydrin via intramolecular sulfinyl group
participation and a ring-closing metathesis reaction for the construction of the piperidine ring of allosedamine.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
imines has received less attention.6 Most of the literature
reports are concerned with the addition of sulfoxide anions
to imines derived from aromatic aldehydes7 and to the best
of our knowledge there is only one report on the addition of
the carbanion derived from (S)-tert-butyl phenylmethyl-
sulfoxide to imines derived from a,b-unsaturated
aldehydes.8
1,3-Aminoalcohols are constituents of many synthetic1 and
natural products2 possessing potent physiological activity.
They are useful as ligands and as chiral auxiliaries in
asymmetric synthesis.3 We recently disclosed the prep-
aration of protected b-amino g,d-unsaturated sulfoxides 2
and their regio- and stereoselective elaboration into 1,3-
aminoalcohol derivatives 3.4 The unsaturated sulfoxides 2
were prepared from the Garner aldehyde 1 using a multistep
sequence of straightforward reactions (Scheme 1). This
study demonstrated the potential of the sulfinyl group as an
intramolecular nucleophile to regio- and stereoselectively
functionalize an olefin and the importance of the relative
configurations of the sulfinyl group and the carbon bearing
the amino substituent on the stereoselectivity of bromo-
hydrin formation.
We disclose herein the diastereoselective addition of
the anion of methyl p-tolyl sulfoxide 4 with N-Ts imine
5, derived from cinnamaldehyde, to yield the
protected b-amino g,d-unsaturated sulfoxide 6 and its
elaboration to (2)-allosedamine 7 and (1R,3R)-HPA-12, 8
(Eq. (1)).
However, for protected b-amino g,d-unsaturated sulfoxides
2 to be useful synthons, it is important that they be
accessible in one or two steps from readily available starting
materials.
An attractive route to synthon 2 would be the direct addition
of sulfoxide stabilized anions to N-substituted imines. The
use of chiral sulfoxide stabilized carbanions for asymmetric
C–C bond formation, via alkylation or addition to CvO
and activated CvC bonds has been studied extensively.5
However, the addition of sulfoxide stabilized carbanions to
ð1Þ
q IICT Communication No. 040317.
Keywords: (2)-Allosedamine; (1R,3R)-HPA-12; Protected b-amino
sulfoxide; Bromohydrin; Pummerer reaction; Ring-closing metathesis
reaction.
*
Corresponding author. Tel.: þ9104027160123; fax: þ9104027160512;
e-mail address: sraghavan@iict.ap.nic.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.019

5060
S. Raghavan, A. Rajender / Tetrahedron 60 (2004) 5059–5067
Scheme 1.
asthma, bronchitis and pneumonia.10 Though several routes
to racemic allosedamine have been disclosed,11 stereo-
selective asymmetric syntheses are few in number.12,13 We
describe herein a stereoselective synthesis of (2)-alloseda-
mine taking advantage of the potential of the sulfinyl group
as an intramolecular nucleophile to regio- and stereo-
selectively functionalize an olefin4,14 (Scheme 2, retro-
synthetic analysis). The piperidine ring of allosedamine was
envisaged to be elaborated via dialkylation of the dianion
derived from 9 using a suitable 1,3-dielectrophile.
The first step of the synthesis required the stereoselective
preparation of the unsaturated sulfoxide 6. Kagan and
co-workers6b have pointed out the influence of temperature,
both during anion generation from the chiral sulfoxide and
addition of the anion with the imine, on the diastereo-
selectivity of b-amino sulfoxide formation. Thus anion
generation from 4 and subsequent addition of the anion with
the imine 515 were conducted at different temperatures and
the results are tabulated in Table 1. Not surprisingly, the
best diastereoselectivity (ca. 3:1 of 6s/6a) was observed
when the anion was generated at 278 8C and subsequently
reacted with the imine at 278 8C over a period of 15 min
(entry 2). The diastereoselectivity eroded when the reaction
was allowed to proceed for longer periods of time at 278 8C
(entry 3) or when the reaction was carried out at higher
temperatures (entries 4 and 5). The temperature at which the
anion was generated did not profoundly influence the
diastereoselectivity (entry 1). The observed results can be
rationalized by invoking intermediates I and II which are in
equilibrium, higher temperatures favour more rapid equi-
libration to give the thermodynamic isomer II (Scheme 3).
Scheme 2.
Table 1. Reaction of lithium anion of (R)-methyl p-tolyl sulfoxide 4 and
imine 5
Entry
T1a (8C)
T2b (8C)
Time (min)
Yield (%)
Ratioc
6s
6a
1
2
3
4
5
230
278
278
230
242
278
278
278
278–80
242
15
15
90
120
30
82
81
71
53
62
70
75
60
53
58
30
25
40
47
42
a
Temperature at which lithium anion of (R)-methyl p-tolyl sulfoxide was
generated.
Temperature at which the reaction was carried out.
Ratios were determined by 1H NMR analysis of the crude reaction
mixture.
b
c
2. Results and discussion
The diastereomers 6s and 6a were readily separated by
column chromatography and the structures assigned to
them by comparison of their H NMR data with that of
related compounds previously synthesized by us.4,16 The
2.1. Synthesis of (2)-allosedamine
1
Allosedamine 7, was isolated from Lobelia inflata,9 the
crude extract of which has been utilized for the treatment of
Scheme 3.

S. Raghavan, A. Rajender / Tetrahedron 60 (2004) 5059–5067
5061
Scheme 4. 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, 2 h, 80%; (d) m-CPBA, CHCl3, 0 8C, 10 min, 93%; (e) LDA, HMPA, I(CH2)3I 13 or TfO(CH2)3OTf 14, THF, 278 to 220 8C, 2 h.
unsaturated sulfoxide 6s on treatment with NBS afforded
regio- and stereospecifically the bromohydrin 10. The
structure was assigned to 10 based on our studies on the
related unsaturated sulfoxide prepared from methyl phenyl-
sulfoxide.4 The bromine atom in 10 was removed by
treatment with n-tributyltin hydride to afford the amino-
alcohol 11. Protection of the hydroxy group in 11 by
treatment with t-butyldiphenylchlorosilane in dichloro-
methane as the solvent afforded the silyl ether 12.
Generation of the dianion of 12 using excess LDA and
subsequent treatment with 1,3-diiodopropane 13, with the
intention of elaborating the piperidine ring did not bear fruit.
The products isolated were the N-allylation product 15 and
the eliminated product 16. The use of 1,3-propane di triflate
14, HMPA as the co-solvent and bases such as LiHMDS,
NaHMDS or KHMDS also gave the same result (Scheme 4).
Attempted elaboration of the piperidine ring on sulfone 17,
obtained from 12 by m-CPBA oxidation, using a variety of
bases and dielectrophiles 13/14 proved disappointing. The
N-allylated product 18 and the elimination product 19 were
the only products obtained. Similar results have been
observed by Najera and co-workers in the attempted
dialkylation of protected b-amino sulfones.17
compound 22 which on treatment with trifluoroacetic
anhydride in the presence of Et3N yielded the Pummerer
intermediate 23.19 Hydrolysis of 23 with saturated aq.
NaHCO3 and treatment of the resulting aldehyde 24 with
ethyl (triphenylphosphoranylidene)acetate yielded the (E)-
ester 25 as the sole product. RCM reaction of 25 in the
presence of 5 mol% of Grubbs’ catalyst (first generation)
proceeded uneventfully to yield 26 which was elaborated to
allosedamine 7 using a straightforward sequence of
reactions. It is noteworthy that an electron deficient olefin
participates in the RCM reaction to afford the product
cleanly.20 Deprotection of the p-toluenesulfonyl group in 26
with Na–Hg21 yielded alcohol 27 by concomitant deacetyl-
ation. Subsequent reduction of the double bond by treatment
with Pt/C under an atmosphere of hydrogen followed by
reductive alkylation with aq. formaldehyde in the presence
of sodium cyanoborohydride22 yielded (2)-allosedamine 7,
with physical characteristics that were in good agreement to
those reported in the literature12d (Scheme 5).
2.2. Synthesis of (1R,3R)-HPA-12
(1R,3R)-N-(3-Hydroxy-1-hydroxymethyl-3-phenylpropyl)-
dodecanamide (HPA-12), 8 is an inhibitor of ceramide
movement from the endoplasmic reticulum to the site of
sphingomyelin synthesis and is a specific inhibitor of
sphingomyelin synthesis in mammalian cells.23 Kobayashi
and co-workers have reported three routes to HPA-12, all of
them exploiting the enantioselective Mannich reaction as
In the search for an alternative route for the construction of
the piperidine ring on 11, we zeroed in on the ring-closing
metathesis (RCM) reaction.18 The aminoalcohol 11, on
treatment with acetic anhydride yielded the acetate 20.
N-Alkylation of 20 with homoallyl nosylate 21, yielded the
Scheme 5. Reagents and conditions: (a) Ac2O, pyridine, DCM, rt, 4 h, 96%; (b) 21, K2CO3, CH3CN, reflux, 2 h, 90%; (c) (i) TFAA, Et3N, CH3CN, 0 8C,
50 min; (ii) aq. NaHCO3, 0 8C, 20 min; (d) Ph3PCHCO2Et, PhH, rt, 30 min, 75% for two steps; (e) Grubbs’ catalyst, toluene, reflux, 16 h, 80%; (f) Na–Hg,
Na2HPO4, MeOH, reflux, 6 h, 78%; (g) H2, Pt/C, AcOEt, rt, 3 h, 90%; (h) 37% aq. HCHO, NaCNBH3, AcOH, CH3CN, rt 4 h, 70%.

5062
S. Raghavan, A. Rajender / Tetrahedron 60 (2004) 5059–5067
Scheme 6. Reagents and conditions: (a) (i) TFAA, 2,6-Lutidine, CH3CN, 0 8C, 5 min; (ii) 20% aq. K2CO3, NaBH4, 0 8C to rt, 15 min, 78%; (b) Ac2O, pyridine,
rt, 2 h, 97%; (c) Et3N, DMAP, C11H23COCl, 0 8C to rt, 4 h, 91%; (d) Na-naphthalenide, DME, 220 8C, 2 min, K2CO3, 24 h, 55%.
the key step.24 While the C–N bond was introduced with
high selectivity, the diastereoselectivity of C–OH bond
formation was modest. We describe herein a highly
stereoselective route to HPA-12 using the acetate 20 as
the key intermediate (Scheme 6). The Pummerer inter-
mediate 29 without isolation was subjected to treatment
with aq. K2CO3 and NaBH4 to yield the alcohol 30, which
was protected as its acetate 31. Treatment of 31 with
dodecanoyl chloride in the presence of Et3N and catalytic
amounts of DMAP afforded the compound 32. Reductive
removal of the p-toluenesulfonyl group using freshly
prepared sodium naphthalenide25 led to the removal of the
acetyl group during workup to yield (1R,3R)-HPA-12,
which had physical characteristics in excellent agreement to
that reported in the literature.24a
The reflux was continued for 2 h and the solution was
cooled to 0 8C. The reaction mixture was diluted with ethyl
acetate (100 mL) and washed with cold 1 N NaOH
(2£50 mL) solution. The organic layer was washed with
water (75 mL), brine (50 mL) and dried over Na2SO4.
Evaporation of the solvent under reduced pressure afforded
a solid that was crystallized from chloroform–petroleum
ether to afford the imine 515 (2.08 g, 7.3 mmol) as colorless
crystals in 73% yield. Mp 202–204 8C. 1H NMR (300 MHz,
CDCl3) d 8.75 (d, J¼9.4 Hz, 1H), 7.82 (d, J¼8.3 Hz, 2H),
7.57–7.38 (m, 6H), 7.32 (d, J¼8.3 Hz, 2H), 6.97 (dd,
J¼15.9, 9.4 Hz, 1H), 2.45 (s, 3H).
3.2. Experimental procedure for the reaction of anion
generated from 4 with imine 5
In conclusion, we have described a stereoselective route to
(2)-allosedamine and (1R,3R)-HPA-12 using the bromo-
sulfonamide 10 as the key intermediate. Efforts are in
progress to prepare diastereomerically pure protected
b-amino sulfoxide 2 and the results will be disclosed in
the future.
Diisopropylamine (2.4 mL, 18 mmol) in THF (27 mL) was
cooled at 0 8C and n-BuLi (9 mL, 2.0 M, 18 mmol) was
added dropwise over 10 min. The reaction mixture was
allowed to stir for 10 min at 0 8C and then cooled to 278 8C.
(R)-Methyl p-tolylsulfoxide 4, (1.85 g, 12 mmol) in THF
(18 mL) was added dropwise via a syringe and stirred for
20 min at this temperature. A solution of the imine 5 (2.65 g,
12 mmol) in THF (12 mL) was added dropwise over a
period of 5 min. After 15 min of stirring at 278 8C, the
reaction mixture was quenched by the addition of aq.
saturated NH4Cl solution (5 mL). The aqueous layer was
extracted with ethyl acetate (75 mL) and the combined
organic layers were washed with brine (50 mL), dried over
Na2SO4 and evaporated under reduced pressure. The
diastereomeric sulfonamides 6s and 6a were separated by
column chromatography using AcOEt/chloroform (23:2,
v/v) as the eluent. The diastereomer 6a eluted first followed
by 6s in 20 and 61% yields, respectively (combined yield
81%).
3. Experimental
3.1. General
All air or moisture sensitive reactions were carried out under
nitrogen atmosphere. Solvents were freshly distilled, THF
over Na/benzophenone ketyl, DCM over P2O5 followed by
CaH2 and toluene over P2O5. Commercially available
reagents were used without further purification except
NBS, which was freshly recrystallized from hot water
before use. Thin layer chromatography was performed with
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
NMR and 13C NMR samples were internally referenced to
TMS (0.00 ppm). Melting points are uncorrected.
3.2.1. 4-Methyl-1-[2-(SR)(4-methylphenylsulfonamido)-
4-phenyl-(2R,3E)-3-butenylsulfinyl]benzene, 6s. Pale
yellow solid. Mp 187–188 8C. 61% (2.6 g). 1H NMR
(200 MHz, CDCl3) d 7.74 (d, J¼8.2 Hz, 2H), 7.49 (d,
J¼8.2 Hz, 2H), 7.36–7.04 (m, 9H), 6.30 (d, J¼15.6 Hz,
1H), 6.09 (d, J¼5.9 Hz, NH), 5.88 (dd, J¼15.6, 7.4 Hz, 1H),
4.43–4.26 (m, 1H), 3.11 (dd, J¼13.4, 7.4 Hz, 1H), 2.89 (dd,
J¼13.4, 6.7 Hz, 1H), 2.40 (s, 3H), 2.32 (s, 3H). 13C NMR
(75 MHz, CDCl3) d 142.6, 141.8, 141.4, 141.1, 131.9,
129.8, 129.2, 128.4, 127.8, 126.7, 126.5, 126.3, 125.6,
3.1.1. N-[3-Phenyl-(2E)-2-propenylidene]-4-methyl-1-
benzenesulfonamide, 5. To a solution of cinnamaldehyde
(1.32 g, 10 mmol) and p-toluenesulfonamide (1.71 g,
10 mmol) in benzene (60 mL) under reflux in a Dean and
Stark apparatus was added BF3·Et2O (50 mg, 0.4 mmol).

S. Raghavan, A. Rajender / Tetrahedron 60 (2004) 5059–5067
5063
124.0, 62.2, 51.7, 20.9, 20.8. [a]2D5¼þ75.0 (c 0.7, CHCl3).
m/z LSIMS 440 [MþþH]. IR (neat) 3453, 1597, 1493, 1365,
1338, 1158 cm21. Anal. calcd For C24H25NO3S2: C, 65.58;
H, 5.73; N, 3.19; S, 14.59. Found: C, 65.43; H, 5.65; N,
3.12; S, 14.51.
130.2, 129.7, 128.3, 127.3, 127.2, 125.5, 123.9, 70.0, 60.9,
49.0, 43.4, 21.4, 21.3. [a]2D5¼263.7 (c 1, acetone). m/z
LSIMS 458 [MþH]þ. IR (neat) 3540, 3272, 1598, 1494,
1398, 1327, 1159 cm21. Anal. calcd for C24H27NO4S2C,
62.99; H, 5.95; N, 3.06; S, 14.07. Found: C, 63.03; H, 5.91;
N, 3.05; S, 14.06.
3.2.2. 4-Methyl-1-[2-(SR)(4-methylphenylsulfonamido)-
4-phenyl-(2S,3E)-3-butenylsulfinyl]benzene, 6a. Color-
less solid. Mp 208–209 8C. 20% (853 mg). 1H NMR
(200 MHz, CDCl3) d 7.72 (d, J¼8.2 Hz, 2H), 7.44 (d,
J¼8.2 Hz, 2H), 7.36–7.10 (m, 9H), 6.48 (d, J¼6.7 Hz, NH),
6.41 (d, J¼15.6 Hz, 1H), 6.03 (dd, J¼15.6, 6.7 Hz, 1H),
4.58–4.42 (m, 1H), 2.94–2.85 (m, 2H), 2.43 (s, 3H), 2.33
(s, 3H). [a]2D5¼þ91.8 (c 1.5, CHCl3). m/z LSIMS 440
[MþþH]. IR (neat) 3340, 1593, 1488, 1363, 1340,
3.2.5. 1-[4-tert-Butyldiphenylsilyloxy-2-(4-methyl-
phenylsulfonamido)-4-phenyl-(2R,4R)-butyl-(SS)-sul-
finyl]-4-methylbenzene, 12. To a solution of the sulfoxide
11 (457 mg, 1 mmol) in dichloromethane (4 mL) was added
imidazole (136 mg, 2 mmol) and TBDPS-Cl (275 mg,
1 mmol) at ambient temperature. The reaction mixture
was stirred for 2 h at room temperature and solvent was
removed under reduced pressure. The residue was diluted
with ether (15 mL) and washed with water (2£10 mL), brine
(10 mL), dried over Na2SO4 and evaporated to afford the
crude product mixture. Purification on silica gel column
using AcOEt/petroleum ether (3:17, v/v) as the eluent
afforded the silyl ether 12 (557 mg, 0.8 mmol) in 80% yield.
1157 cm21
.
3.2.3. N-[2-Bromo-3-hydroxy-1-(SS)(4-methylphenyl-
sulfinylmethyl)-3-phenyl-(1S,2R,3S)-propyl]-4-methyl-
1-benzenesulfonamide, 10. To a solution of sulfoxide 6s
(3.07 g, 7 mmol) in toluene/chloroform (2:1, 35 mL) was
added water (210 mL, 11.7 mmol) followed by N-bromo-
succinimide (1.58 g, 8.4 mmol) and the reaction mixture
stirred at room temperature for 1 h. Then the reaction
mixture was quenched by the addition of aqueous saturated
NaHCO3 (10 mL) solution. The mixture was diluted with
chloroform (40 mL) and the organic layer was washed with
water (25 mL), brine (25 mL) and dried over Na2SO4.
Evaporation of the solvent afforded the crude bromohydrin,
which was purified by column chromatography using
AcOEt/petroleum ether (7:13, v/v) as the eluent to yield
bromohydrin 10 (3.15 g, 5.88 mmol) in 84% yield. Color-
1
Viscous oil. H NMR (200 MHz, CDCl3) d 7.72–7.60 (m,
4H), 7.57–6.97 (m, 17H), 6.79 (d, J¼8.2 Hz, 2H), 5.94 (bs,
NH), 4.70 (t, J¼4.7 Hz, 1H), 3.32–3.26 (m, 1H), 2.92–2.85
(m, 2H), 2.47 (s, 3H), 2.45–2.42 (m, 4H), 2.25–2.18 (m,
1H), 1.06 (s, 9H). m/z LSIMS 696 [MþH]þ. IR (neat) 3522,
1585, 1491, 1398, 1335, 1155 cm21. Anal. calcd for
C40H45NO4S2Si: C, 69.03; H, 6.52; N, 2.01; S, 9.21.
Found: C, 68.83; H, 6.61; N, 2.08; S, 9.02.
3.2.6. 3-Trifluoromethanesulfonyloxypropyl trifluoro-
methanesulfonate, 14. To a solution of Tf2O (5.64 g,
20 mmol) in dry dichloromethane (20 mL) cooled at 0 8C
under nitrogen atmosphere was added 1,3-propanediol
(760 mg, 10 mmol) via a syringe and stirred for 40 min. A
solution of pyridine (1.58 g, 20 mmol) in dry dichloro-
methane (4 mL) was added to the above stirred solution over
a period of 5 min and stirred further for a period of 1 h. The
reaction mixture was allowed to attain room temperature
over a period of 30 min and the solvent was evaporated
under reduced pressure. The residue was diluted with ethyl
acetate (20 mL) and washed successively with aq. CuSO4
solution (2£20 mL), water (2£10 mL), brine (10 mL) and
dried over Na2SO4. The solvent was removed under reduced
pressure to afford 14 (2.71 g, 8 mmol) in 80% yield which
was used in the next step without further purification.
1
less solid. Mp 180–182 8C. H NMR (200 MHz, CDCl3) d
7.86 (d, J¼8.2 Hz, 2H), 7.48–7.24 (m, 11H), 5.32 (d,
J¼10.4 Hz, NH), 4.85 (dd, J¼9.7, 5.2 Hz, 1H), 4.70–4.56
(m, 1H), 4.06 (d, J¼9.7 Hz, 1H), 3.84 (d, J¼5.2 Hz, OH),
3.01 (dd, J¼13.4, 6.0 Hz, H), 2.68 (dd, J¼13.4, 7.4 Hz, 1H),
2.47 (s, 3H), 2.43 (s, 3H). 13C NMR (75 MHz, DMSO-d6) d
143.2, 142.6, 141.4, 140.8, 138.6, 130.1, 129.8, 128.1,
127.9, 127.5, 127.0, 123.8, 73.6, 62.6, 61.9, 49.9, 21.2, 21.0.
[a]2D5¼238.8 (c 1, acetone). m/z LSIMS 536 [MþH]þ. IR
(neat) 3405, 3221, 1589, 1370, 1341, 1159 cm21. Anal.
calcd for C24H26BrNO4S2C, 53.73; H, 4.88; N, 2.61; S,
11.95. Found: C, 53.69; H, 4.84; N, 2.62; S, 11.95.
1
3.2.4. N-[3-Hydroxy-1-(SS)(4-methylphenylsulfinyl-
methyl)-3-phenyl-(1R,3R)-propyl]-4-methyl-1-benzene-
sulfonamide, 11. To a stirred solution of bromohydrin 10
(2.68 g, 5 mmol) in benzene (30 mL) were added
successively at room temperature n-Bu3SnH (1.53 g,
5.25 mmol) and AIBN (41 mg, 0.25 mmol). The solution
was refluxed for 90 min when TLC examination revealed
complete consumption of starting material. The solvent was
removed under reduced pressure and the residue was
chromatographed on a silica gel column using AcOEt/
petroleum ether (2:3, v/v) as the eluent to afford the product
11 (1.73 g, 3.8 mmol) in 76% yield. Colorless solid. Mp
55–56 8C. 1H NMR (200 MHz, CDCl3) d 7.77 (d,
J¼8.2 Hz, 2H), 7.32 (d, J¼8.2 Hz, 2H), 7.26–7.11 (m,
9H), 6.86 (d, J¼8.9 Hz, NH), 4.87 (d, J¼8.9 Hz, 1H), 4.58–
4.52 (m, 1H), 3.75 (bs, OH), 2.79–2.67 (m, 2H), 2.39 (s,
6H), 2.12–1.96 (m, 1H), 1.91–1.75 (m, 1H). 13C NMR
(75 MHz, CDCl3) d 143.8, 143.4, 142.0, 139.8, 137.6,
Liquid. H NMR (200 MHz, CDCl3) d 4.67 (t, J¼6.8 Hz,
4H), 2.33 (quintet, J¼6.8 Hz, 2H).
3.3. General procedure for the dialkylation of 12 and 17
To a solution of sulfoxide 12 (35 mg, 0.05 mmol) in THF
(0.5 mL) was added LDA (0.1 mL, 0.1 mmol, 1 M)
dropwise at 278 8C. After stirring for 30 min at this
temperature,
a solution of diiodopropane (33 mg,
0.11 mmol) in THF (0.1 mL) was added dropwise, and
stirring was continued. As the TLC revealed no reaction at
278 8C, the reaction mixture was warmed to 220 8C and
stirred for 3 h. The reaction mixture was quenched by
addition of saturated aq. NH4Cl solution (0.2 mL) and
extracted with ether (2£10 mL). The ether extracts were
washed with brine (10 mL), dried and evaporated. Column
chromatography on silica gel eluting with AcOEt/petroleum
ether (1:9, v/v) afforded the products.

5064
S. Raghavan, A. Rajender / Tetrahedron 60 (2004) 5059–5067
1
3.3.1. 1-[2-Allyl(4-methylphenyl)sulfonamido-4-(tert-
butyldiphenylsilyloxy)-4-phenyl-(2R,4R)-butyl-(SS)-sul-
finyl]-4-methylbenzene, 15. 32% (12 mg). Low melting
Viscous oil. H NMR (200 MHz, CDCl3) d 7.73–7.62 (m,
2H), 7.47–7.18 (m, 17H), 6.27 (dt, J¼15.7, 7.9 Hz, 1H),
5.93 (d, J¼15.7 Hz, 1H), 4.79 (t, J¼6.3 Hz, 1H), 2.47 (s,
3H), 2.37–2.04 (m, 2H), 0.98 (s, 9H). m/z LSIMS 541
1
solid. H NMR (200 MHz, CDCl3) d 7.62–7.57 (m, 2H),
7.46 (d, J¼8.1 Hz, 2H), 7.40–7.08 (m, 19H), 5.56–5.42 (m,
1H), 4.82 (d, J¼9.8 Hz, 1H), 4.57 (d, J¼16.9 Hz, 1H), 4.27
(dd, J¼9.8, 3.7 Hz, 1H), 3.86–3.73 (m, 1H), 3.58 (dd,
J¼15.4, 6.4 Hz, 1H), 3.51 (dd, J¼15.4, 6.4 Hz, 1H), 3.32
(dd, J¼15.1, 6.4 Hz, 1H), 2.78 (dd, J¼15.1, 11.7 Hz, 1H),
2.49 (s, 3H), 2.43 (s, 3H), 2.12–1.96 (m, 2H), 0.98 (s, 9H).
m/z LSIMS 758 [MþNa]þ. IR (neat) 2945, 2826, 1598,
1490, 1393, 1329, 1157 cm21. Anal. calcd for C43H49NO4-
S2Si: C, 70.17; H, 6.71; N, 1.90; S, 8.71. Found: C, 69.78; H,
6.33; N, 1.75; S, 8.56.
[MþH]þ. IR (neat) 2867, 1592, 1334, 1167 cm21
.
3.3.6. 3-Butenyl 4-nitro-1-benzenesulfonate, 21. To a
solution of 3-buten-1-ol (360 mg, 5 mmol) in dry dichloro-
methane (20 mL) was added successively Et3N (1.01 g,
10 mmol) and p-nitrobenzenesulfonyl chloride (1.11 g,
5 mmol) at room temperature under N2. The reaction
mixture was stirred for a period of 4 h. The reaction mixture
was washed with water (10 mL), brine (10 mL) and
evaporated to dryness under reduced pressure. The crude
product mixture was chromatographed on silica gel using
AcOEt/petroleum ether (1:4, v/v) as the eluent to afford the
nosylate 21 (4 mmol) as a pale yellow solid in 80% yield.
Mp 122 8C. 1H NMR (200 MHz, CDCl3) 8.42 (d, J¼8.8 Hz,
2H), 8.19 (d, J¼8.8 Hz, 2H), 5.78–5.55 (m, 1H), 5.18–5.05
(m, 2H), 4.21–4.11 (m, 2H), 2.51–2.36 (m, 2H). m/z
LSIMS 258 [MþþH].
3.3.2. 4-(tert-Butyldiphenylsilyloxy)-1-(SS)(4-methyl-
phenylsulfinyl)-4-phenyl-(E)-1-(4R)-butene, 16. 16%
1
(4 mg). Viscous oil. H NMR (200 MHz, CDCl3) d 7.73–
7.62 (m, 2H), 7.47–7.18 (m, 17H), 6.27 (dt, J¼15.8, 8.2 Hz,
1H), 5.93 (d, J¼15.8 Hz, 1H), 4.71 (dd, J¼7.6, 3.8 Hz, 1H),
2.40 (s, 3H), 2.12–1.96 (m, 2H), 0.98 (s, 9H). m/z LSIMS
524 [MþH]þ. IR (neat) 2848, 1595, 1498, 1357 cm21
.
3.3.7. 4-(SS)(4-Methylphenylsulfinyl)-3-(4-methyl-
phenylsulfonamido)-1-phenyl-(1R,3R)-butyl acetate, 20.
To a stirred solution of 11 (1.37 g, 3 mmol) in dichloro-
methane (12 mL) were added successively pyridine
(474 mg, 6 mmol) and acetic anhydride (331 mg,
3.25 mmol). The reaction mixture was stirred for 4 h and
then diluted with dichloromethane (20 mL). The organic
layer was washed successively with aqueous saturated
CuSO4 solution (2£15 mL), water (15 mL), 5% aq.
NaHCO3 solution (2£10 mL), water (10 mL), brine
(10 mL) and dried over Na2SO4. Evaporation of the solvent
under reduced pressure followed by column chromato-
graphy using AcOEt/petroleum ether (1:1, v/v) as the eluent
afforded the acetate 20 (1.44 g, 2.88 mmol) in 96% yield.
3.3.3. 1-[4-(tert-Butyldiphenylsilyloxy)-2-(4-methyl-
phenylsulfonamido)-4-phenyl-(2R,4R)-butylsulfonyl]-4-
methylbenzene, 17. To a solution of sulfoxide 12 (350 mg,
0.5 mmol) in chloroform (2 mL), m-CPBA (123 mg,
0.5 mmol, 60%) was added at 0 8C and the reaction mixture
was stirred at 0 8C for 10 min. The reaction mixture was
diluted with chloroform (15 mL) and washed successively
with 10% aq. sodium bisulfite solution (2£10 mL), 10% aq.
sodium bicarbonate solution (2£10 mL), water (10 mL) and
brine (10 mL). The reaction mixture was dried over
anhydrous Na2SO4 and evaporated under reduced pressure
to afford crude product. Column chromatography using
AcOEt/petroleum ether (1:4, v/v) afforded sulfone 17
1
1
(330 mg, 0.47 mmol) in 93% yield. Viscous oil. H NMR
White solid. Mp 70–72 8C. H NMR (200 MHz, CDCl3) d
(200 MHz, CDCl3) d 7.77–7.65 (m, 2H), 7.54–7.28 (m,
9H), 7.27–6.97 (m, 10H), 6.76 (d, J¼8.2 Hz, 2H), 5.72 (d,
J¼5.9 Hz, NH), 4.80 (t, J¼4.6 Hz, 1H), 3.63 (dd, J¼13.4,
3.1 Hz, 1H), 3.24–3.13 (m, 1H), 2.77 (dd, J¼13.4, 8.9 Hz,
1H), 2.48 (s, 6H), 2.46–2.40 (m, 1H), 2.14–2.07 (m, 1H),
0.97 (s, 9H). m/z LSIMS 712 [MþH]þ. IR (neat) 3522,
1597, 1498, 1398, 1347, 1171 cm21. Anal. calcd for
C40H45NO5S2Si: C, 67.48; H, 6.37; N, 1.97; S, 9.01.
Found: C, 67.03; H, 6.11; N, 2.05; S, 9.26.
7.72 (d, J¼8.2 Hz, 2H), 7.36–7.13 (m, 11H), 6.16 (d,
J¼8.2 Hz, NH), 5.71 (dd, J¼8.9, 4.5 Hz, 1H), 3.98–3.81
(m, 1H), 2.78 (d, J¼5.2 Hz, 2H), 2.45 (s, 3H), 2.42 (s, 3H),
2.41–2.14 (m, 2H), 2.02 (s, 3H). 13C NMR (75 MHz,
CDCl3) d 169.9, 143.3, 142.0, 139.9, 139.8, 137.9, 130.0,
129.7, 128.5, 128.0, 127.2, 126.1, 123.9, 72.4, 60.1, 48.3,
41.2, 21.4, 21.3, 21.0. [a]2D5¼271.8 (c 0.75, CHCl3). m/z
LSIMS 500 [MþH]þ. IR (neat) 3249, 1741, 1596, 1493,
1371, 1327, 1152 cm21. Anal. calcd for C26H29NO5S2: C,
62.50; H, 5.85; N, 2.80; S, 12.83. Found: C, 62.43; H, 5.91;
N, 2.84; S, 12.80.
3.3.4. 1-[2-Allyl(4-methylphenyl)sulfonamido-4-(tert-
butyldiphenylsilyloxy)-4-phenyl-(2R,4R)-butylsulfonyl]-
4-methylbenzene, 18. 30% (11 mg). Low melting solid. 1H
NMR (200 MHz, CDCl3) d 7.78–7.60 (m, 4H), 7.54–7.13
(m, 19H), 5.49–5.28 (m, 1H), 4.75 (d, J¼10.2 Hz, 1H), 4.59
(d, J¼16.5 Hz, 1H), 4.24 (dd, J¼7.9, 4.9 Hz, 1H), 3.90–
3.72 (m, 1H), 3.56–3.50 (m, 1H), 3.42 (dd, J¼15.4, 6.8 Hz,
1H), 3.21 (dd, J¼15.1, 6.8 Hz, 1H), 2.62 (dd, J¼15.1,
4.5 Hz, 1H), 2.46 (s, 3H), 2.41 (s, 3H), 2.35–2.26 (m, 1H),
2.10–2.01 (m, 1H), 0.97 (s, 9H). m/z LSIMS 775 [MþNa]þ.
IR (neat) 2956, 2843, 1591, 1398, 1333, 1171 cm21. Anal.
calcd for C43H49NO5S2Si: C, 68.67; H, 6.57; N, 1.86; S,
8.53. Found: C, 68.43; H, 6.33; N, 1.75; S, 8.56.
3.3.8. 3-[3-Butenyl(4-methylphenyl)sulfonamido)-4-
(SS)(4-methylphenylsulfinyl)-1-phenyl-(1R,3R)-butyl
acetate, 22. Homoallyl nosylate 21 (566 mg, 2.2 mmol) was
added to a stirred mixture of acetate 20 (1.1 g, 2.2 mmol)
and K2CO3 (456 mg, 3.3 mmol) in dry acetonitrile (8.8 mL)
and the reaction mixture was allowed to reflux for 2 h. The
reaction mixture was diluted with ethyl acetate (20 mL) and
washed with water (2£15 mL) followed by brine (15 mL)
solution. After drying over Na2SO4, evaporation of the
solvent under reduced pressure afforded the crude com-
pound which on column chromatography using AcOEt/
petroleum ether (3:7, v/v) as the eluent afforded the
N-alkylated product 22 (1.1 g, 1.98 mmol) in 90% yield.
Viscous oil. 1H NMR (200 MHz, CDCl3) d 7.67 (d,
3.3.5. 4-(tert-Butyldiphenylsilyloxy)-1-(4-methylphenyl-
sulfonyl)-4-phenyl-(E)-1-(4R)-butene, 19. 14% (4 mg).

S. Raghavan, A. Rajender / Tetrahedron 60 (2004) 5059–5067
5065
J¼8.2 Hz, 2H), 7.45 (d, J¼8.2 Hz, 2H), 7.36–7.11 (m, 9H),
5.68–5.48 (m, 2H), 5.04–4.90 (m, 2H), 4.21–4.04 (m, 1H),
3.32–3.24 (m, 1H), 3.19–3.11 (m, 1H), 2.94 (dd, J¼13.4,
7.4 Hz, 1H), 2.79 (dd, J¼13.4, 6.7 Hz, 1H), 2.42 (s, 6H),
2.36–2.10 (m, 4H), 2.02 (s, 3H). 13C NMR (75 MHz,
CDCl3) d 169.8, 143.7, 141.7, 140.4, 139.8, 137.5, 134.2,
130.0, 129.8, 128.5, 128.1, 127.5, 126.3, 123.9, 117.2, 72.8,
62.5, 52.1, 47.1, 40.9, 34.1, 21.5, 21.4, 21.0. [a]2D5¼245.5
(c 2.2, CHCl3). m/z LSIMS 554 [MþþH]. IR (neat) 2977,
1752, 1595, 1488, 1449, 1337, 1142, 1083 cm21. Anal.
calcd for C30H35NO5S2: C, 65.07; H, 6.37; N, 2.53; S, 11.58.
Found: C, 65.43; H, 5.75; N, 2.21; S, 12.01.
21.2. [a]2D5¼2119.0 (c 0.75, CHCl3). m/z LSIMS 400
[MþH]þ. IR (neat) 3032, 2925, 2853, 1744, 1598, 1494,
1374, 1345, 1159, 1096 cm21. Anal. calcd for C22H25NO4S:
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.
3.3.11. 2-[(2R)-1,2,5,6-Tetrahydropyridin-2-yl]-1-phe-
nyl-(1R)-ethan-1-ol, 27. Freshly prepared Na–Hg (6%,
150 mg) was added to a well-stirred mixture of 26 (179 mg,
0.45 mmol) and anhydrous Na2HPO4 (319 mg, 2.25 mmol)
in methanol (9 mL) at room temperature and allowed to
reflux for 6 h. The reaction mixture was quenched with
water (3 mL) and extracted into ethyl acetate (2£15 mL).
The organic layer was washed with brine (15 mL) and dried
over Na2SO4. The solvent was evaporated under reduced
pressure and the crude product was chromatographed on a
small pad of silica gel using CH2Cl2: MeOH (50:1 then
1:10, v/v) as the eluent to afford 27 (71 mg, 0.35 mmol) in
3.3.9. Ethyl 4-[3-butenyl(4-methylphenyl)sulfonamido]-
6-acetoxy-6-phenyl-(E,4R,6R)-2-hexenoate, 25. To
a
solution of the N-homoallyl compound 22, (664 mg,
1.2 mmol) in acetonitrile (6 mL) cooled at 0 8C was added
triethylamine (364 mg, 3.6 mmol) followed by trifluoro-
acetic anhydride (1.26 g, 6 mmol) and the mixture stirred
for 50 min. An aq. 5% NaHCO3 solution (2 mL) was added
at 0 8C and stirred for another 20 min. The reaction mixture
was then extracted into benzene (10 mL) and washed
successively with water (5 mL), brine (5 mL) and dried over
Na2SO4. The benzene solution of the aldehyde was directly
taken ahead to the next step and reacted with ethyl
(triphenylphosphoranylidene)acetate (498 mg, 1.2 mmol).
The reaction was stirred at room temperature for 30 min.
The solvent was removed under reduced pressure to afford a
residue which was purified by column chromatography
using EtOAc/petroleum ether (1:9) as the eluent to afford
the a,b-unsaturated ester 25 (449 mg, 0.9 mmol) in 75%
yield (for the two steps). Pale yellow solid. Mp 59–61 8C.
1H NMR (200 MHz, CDCl3) d 7.63 (d, J¼8.2 Hz, 2H),
7.39–7.20 (m, 7H), 6.54 (dd, J¼15.6, 5.2 Hz, 1H), 5.76–
5.56 (m, 3H), 5.08–4.93 (m, 2H), 4.64–4.47 (m, 1H), 4.12
(q, J¼6.7 Hz, 2H), 3.18 (ddd, J¼15.6, 11.1, 5.9 Hz, 1H),
2.92 (ddd, J¼15.6, 10.4, 5.9 Hz, 1H), 2.56–2.16 (m, 6H),
2.06–1.91 (m, 4H), 1.24 (t, J¼6.7 Hz, 3H). 13C NMR
(75 MHz, CDCl3) d 170.3, 165.9, 144.7, 144.0, 140.1,
137.5, 134.8, 130.2, 129.1, 128.7, 127.7, 126.8, 124.3,
117.7, 73.0, 61.0, 55.8, 45.2, 39.5, 36.0, 21.9, 21.5, 14.6.
[a]2D5¼þ58.7 (c 2.25, CHCl3). m/z LSIMS 500 [MþþH]. IR
(neat) 2957, 2887, 1745, 1590, 1498, 1450, 1343, 1140,
1078 cm21. 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.
1
78% yield. Viscous liquid. H NMR (200 MHz, CDCl3) d
7.40–7.12 (m, 5H), 5.97–5.82 (m, 1H), 5.58–5.44 (m, 1H),
5.12–4.96 (m, 1H), 4.04–3.88 (m, 1H), 3.43–3.24 (m, 1H),
3.03–2.83 (m, 1H), 2.56–1.85 (m, 4H). 13C NMR (75 MHz,
CDCl3) d 144.0, 128.3, 127.1, 126.3, 125.4, 69.4, 51.1, 41.3,
40.3, 29.6. [a]2D5¼239.1 (c 0.8, CHCl3). m/z LSIMS 204
[MþþH]. IR (neat) cm21 3331, 2972, 2845, 1591, 1494.
Anal. calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89.
Found: C, 76.57; H, 8.15; N, 6.66.
3.3.12. 1-Phenyl-2-[(6S)-tetrahydro-6-piperidin-2-yl]-
(1R)-ethan-1-ol, 28. To
a solution of 27 (15 mg,
0.075 mmol) in ethyl acetate (1.5 mL) was added Pt/C
(5 mg, 10% w/w) and the reaction mixture was allowed to
stir under H2 atmosphere for 3 h. The reaction mixture was
filtered through celite and evaporated to dryness under
reduced pressure to afford 28 (14 mg, 0.068 mmol) in 90%
yield. Viscous liquid. 1H NMR (200 MHz, CDCl3) d 7.42–
7.18 (m, 5H), 5.22 (bd, J¼7.4 Hz, 1H), 3.44 (bd,
J¼11.7 Hz, 1H), 3.36–3.21 (m, 1H), 2.91–2.71 (m, 1H),
2.42–2.22 (m, 1H), 2.04–1.66 (m, 6H), 1.51–1.32 (m, 1H).
13C NMR (75 MHz, CDCl3) d 22.0, 22.5, 29.6, 42.1, 44.9,
54.4, 68.4, 125.5, 127.2, 128.4, 143.6. [a]2D5¼228.1 (c 0.2,
methanol). m/z EI 206 [MþþH]. Anal. calcd for C13H19NO,
C, 76.06; H, 9.33; N, 6.82. Found: C, 76.57; H, 9.15; N,
6.66.
3.3.13. 2-[1-Methyl-(6S)-tetrahydro-6-piperidin-2-yl]-1-
phenyl-(1R)-ethan-1-ol, 7. To a solution of the substrate 28
(12 mg, 0.06 mmol) in acetonitrile (0.9 mL) was added 37%
aq. HCHO (0.28 mL, 3.43 mmol), AcOH (20 mL) and
NaCNBH3 (19 mg, 0.33 mmol). The resulting reaction
mixture was stirred at room temperature for 4 h and then
concentrated under reduced pressure. The residue was
extracted into dichloromethane (2£10 mL) and the solvent
was evaporated under reduced pressure. Column chroma-
tography using MeOH/DCM (first with 1:10 v/v then
methanol alone) as the eluent afforded the product 7 in
3.3.10. 2-[1-(4-Methylphenylsulfonyl)-(2R)-1,2,5,6-tetra-
hydropyridin-2-yl]-1-phenyl-(1R)-ethyl acetate, 26. Bis-
(tricyclohexylphosphine)benzylideneruthenium(IV)dichlor-
ide G1 (25 mg, 0.032 mmol) was added to a solution of
diene 25 (324 mg, 0.65 mmol) in toluene and refluxed for
16 h, when TLC revealed the complete consumption of the
starting material. The solvent was removed under reduced
pressure. Column chromatography using EtOAc/petroleum
ether (1:4, v/v) as the eluent afforded the product 26
(207 mg, 0.52 mmol) in 80% yield. Pale yellow solid. Mp
75–76 8C. 1H NMR (200 MHz, CDCl3) d 7.67 (d,
J¼8.9 Hz, 2H), 7.36–7.16 (m, 7H), 5.74 (dd, J¼9.7,
4.5 Hz, 1H), 5.66–5.54 (m, 2H), 4.54–4.41 (m, 1H), 3.77
(dd, J¼14.9, 5.2 Hz, 1H), 3.08 (ddd, J¼14.9, 11.9, 5.2 Hz,
1H), 2.42 (s, 3H), 2.20–1.60 (m, 7H). 13C NMR (75 MHz,
CDCl3) d 170.1, 143.2, 140.5, 138.1, 129.5, 128.5, 128.0,
127.3, 127.2, 126.5, 125.5, 72.7, 50.2, 41.4, 38.0, 29.7, 21.5,
1
70% yield as a solid. Mp 78–80 8C. H NMR (200 MHz,
CDCl3) d 7.40–7.21 (m, 5H), 5.10 (dd, J¼10.4, 3.4 Hz,
1H), 3.02 (d, J¼10.4 Hz, 1H), 2.46 (s, 3H), 2.45–3.32 (m,
1H), 2.17 (ddd, J¼14.9, 10.9, 4.3 Hz, 1H), 1.96–1.53 (m,
6H), 1.32–1.20 (m, 2H). [a]2D5¼228.8 (c 0.4, MeOH)
[lit.12d [a]2D5¼229.8 (c 0.2, MeOH)]. m/z LSIMS 220
[MþH]þ.

5066
S. Raghavan, A. Rajender / Tetrahedron 60 (2004) 5059–5067
3.3.14. 4-Hydroxy-3-(4-methylphenylsulfonamido)-1-
phenyl-(1R,3R)-butyl acetate, 30. To a stirred solution of
20 (1.05 g, 2.1 mmol) and dry 2,6-lutidine (674 mg,
6.3 mmol) in acetonitrile (15 mL) under a nitrogen
atmosphere at 0 8C, neat trifluoroacetic anhydride (1.5 mL,
10.5 mmol) was added dropwise. The reaction mixture was
stirred at 0 8C for 5 min. Aq. 20% K2CO3 solution was
added to adjust pH to 7. Then NaBH4 (400 mg, 10.5 mmol)
was added portionwise and the reaction mixture allowed to
attain room temperature. After 15 min the reaction was
quenched with an aqueous saturated ammonium chloride
solution (5 mL). The reaction mixture was extracted with
ethylacetate (2£15 mL) and the collected organic layers
dried over anhydrous sodium sulfate. Evaporation of the
solvent followed by purification on a silica gel column using
acetone/petroleum ether (1:4, v/v) afforded the b-amino
alcohol 29 (617 mg, 1.64 mmol) in 78% yield. Solid. Mp
159–161 8C. 1H NMR (200 MHz, CDCl3) d 7.69 (d,
J¼8.2 Hz, 2H), 7.34–7.12 (m, 7H), 7.01 (d, J¼8.2 Hz,
NH), 5.60 (dd, J¼10.4, 4.4 Hz, 1H), 4.13–4.04 (m, 1H),
3.38–3.16 (m, 2H and 1-OH), 2.44 (s, 3H), 2.09–1.72 (m,
5H). 13C NMR (75 MHz, CDCl3) d 169.3, 142.6, 141.6,
138.9, 129.7, 128.5, 127.5, 126.4, 125.6, 72.1, 63.7, 51.7,
38.1, 21.1, 20.8. [a]2D5¼þ13.6 (c 0.6, acetone). m/z LSIMS
378 [MþH]þ. IR (neat) 3421, 3249, 1745, 1598, 1496,
1152 cm21. Anal. calcd for C19H23NO5S: C, 60.46; H, 6.14;
N, 3.71; S, 8.49. Found: C, 60.48; H, 6.03; N, 3.79; S, 8.33.
and washed successively with water (2£5 mL), 10% aq.
citric acid solution (5 mL), brine (5 mL) and dried over
Na2SO4. The solvent was evaporated under reduced
pressure and the crude product was purified by column
chromatography on silica gel with AcOEt/petroleum ether
(1:9, v/v) to afford the amide 31 (274 mg, 0.46 mmol) in
1
91% yield. Liquid. H NMR (200 MHz, CDCl3) d 7.72 (d,
J¼8.2 Hz, 2H), 7.40–7.22 (m, 7H), 5.57 (dd, J¼9.7, 4.5 Hz,
1H), 4.73–4.58 (m, 1H), 4.50–4.32 (m, 2H), 2.60–2.16 (m,
7H), 2.11 (s, 3H), 2.0 (s, 3H), 1.71–1.11 (m, 18H), 0.88 (t,
J¼6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 174.1, 170.5,
170.2, 144.9, 140.2, 137.2, 129.9, 128.6, 128.1, 127.7,
126.3, 73.4, 64.2, 56.0, 38.3, 31.9, 29.6, 29.4, 29.2, 29.0,
28.9, 24.7, 22.6, 21.6, 21.2, 20.8, 14.1. [a]2D5¼þ9.66 (c 2.0,
acetone). m/z LSIMS 542 [M2OAc]þ. Anal. calcd for
C33H47NO7S: C, 65.86; H, 7.87; N, 2.33; S, 5.33. Found: C,
65.66; H, 7.42; N, 2.13; S, 5.47.
3.3.17. N-[3-Hydroxy-1-hydroxymethyl-3-phenyl-
(1R,3R)-propyl]dodecanamide, 8. To the substrate 31
(30 mg, 0.05 mmol) in dimethoxyethane (0.5 mL) was
added freshly prepared Na-naphthalenide in dimethoxy-
ethane (the solution of sodium naphthalenide in dimethoxy-
ethane was prepared by adding dimethoxyethane (10 mL) to
a mixture of Na (300 mg, 13 mmol) and naphthalene
(2.05 g, 16 mmol) and stirring the mixture at room
temperature for 2 h) at 220 8C under nitrogen atmosphere
until light green color persisted (ca 2 min). The reaction
mixture was quenched by the addition of water (1 mL).
Solid K2CO3 (140 mg) was added and the reaction mixture
stirred at room temperature for 24 h. The solvent was
evaporated under reduced pressure and the residue was
extracted into ethylacetate (2£5 mL). Column chromato-
graphy using hexane/isopropylalcohol (4:1, v/v) afforded
the product 30 (10 mg, 0.27 mmol) in 55% yield. Solid. Mp
76–78 8C [lit.24a mp 75.5–77 8C]. 1H NMR (200 MHz,
CDCl3) 7.40–7.12 (m, 5H), 6.19 (d, J¼5.9 Hz, NH), 4.62
(bd, J¼7.5 Hz, 1H), 4.19–4.08 (m, 1H), 3.77–3.62 (m, 2H),
2.31–2.13 (m, 2H), 1.68–1.45 (m, 2H), 1.42–1.20 (m,
18H), 0.86 (t, J¼6.7 Hz, 3H). [a]2D5¼236.6 (c 0.56, CHCl3)
[lit.24a¼235.1 (c 0.8, CHCl3)].
3.3.15. 4-Acetoxy-3-(4-methylphenylsulfonamido)-1-
phenyl-(2R,4R)-butyl acetate, 31. To a stirred solution of
30 (377 mg, 1 mmol) in dichloromethane (4 mL) was added
successively pyridine (158 mg, 2 mmol) and acetic
anhydride (122 mg, 1.1 mmol) at room temperature under
N2. The reaction mixture was stirred for a period of 2 h at
room temperature. The reaction mixture was then diluted
with dichloromethane (16 mL) and washed sequentially
with aq. saturated CuSO4 solution (2£10 mL), water
(10 mL), aq. 5% NaHCO3 solution (2£10 mL), water
(10 mL), brine (10 mL) and dried over anhydrous Na2SO4.
Evaporation of the solvent under reduced pressure followed
by purification on a silica gel column using AcOEt/
petroleum ether (1:3, v/v) as the eluent afforded the
diacetate 31 (406 mg, 0.97 mmol) in 97% yield. Viscous
1
liquid. H NMR (200 MHz, CDCl3) d 7.74 (d, J¼8.2 Hz,
2H), 7.48–7.12 (m, 7H), 5.68 (dd, J¼9.7, 4.5 Hz, 1H), 5.58
(d, J¼8.9 Hz, NH), 4.0–3.84 (m, 2H), 3.76–3.52 (m, 1H),
2.44 (s, 3H), 2.12–1.80 (m, 8H). 13C NMR (75 MHz,
CDCl3) d 170.7, 169.8, 143.6, 140.0, 137.7, 129.8, 128.6,
128.1, 127.0, 126.2, 72.6, 65.7, 49.8, 39.2, 21.5, 21.0, 20.6.
[a]2D5¼þ11.4 (c 0.75, CHCl3). m/z LSIMS 420 [MþH]þ. IR
(neat) 3324, 1754, 1590, 1493, 1148 cm21. Anal. calcd for
C21H25NO6S: C, 60.13; H, 6.01; N, 3.34; S, 7.64. Found: C,
60.43; H, 5.91; N, 2.94; S, 7.80.
References and notes
1. Friedrichs, E.; Christoph, T.; Buschmann, H. In Ullmann’s
Encyclopedia of Industrial Chemistry. McGuire, J. L., Ed.;
Wiley-VCH: Weinheim, 2000. (b) Gais, H.-J.; Griebel, C.;
Buschmann, H. Tetrahedron: Asymmetry 2000, 11, 917.
(c) Carlier, P. R.; Lo, K. M.; Lo, M. M.-C.; Williams, I. D.
J. Org. Chem. 1995, 60, 7511.
2. Benedetti, F.; Norbedo, S. Chem. Commun. 2001, 203.
(b) Carlier, P. R.; Lo, M. M.-C.; Lo, P. C.-K.; Richelson, E.;
Tatsumi, M.; Reynolds, I. J.; Sharma, T. A. Bioorg. Med.
Chem. Lett. 1998, 7, 1511. (c) Chng, B. L.; Ganesan, A.
Bioorg. Med. Chem. Lett. 1998, 8, 487. (d) Musso, D. L.;
Mehta, N. B.; Soroko, F. E. Bioorg. Med. Chem. Lett. 1997, 7,
1. (e) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am.
Chem. Soc. 1997, 119, 4112. (f) Barrett, A. G. M.; Lebold,
S. A. J. Org. Chem. 1991, 56, 4875. (g) Hashiguchi, S.;
Kawada, A.; Natsugari, H. J. Chem. Soc., Perkin Trans. 1
1991, 2435.
3.3.16. 2-Dodecanoyl-(4-methylphenyl)sulfonamido-4-
acetoxy-4-phenyl-(2R,4R)-butyl acetate, 32. A solution
of dodecanoyl chloride (110 mg, 0.5 mmol) in dichloro-
methane (0.25 mL) was added dropwise to a mixture of the
diacetate 31 (210 mg, 0.5 mmol), Et3N (101 mg, 1 mmol)
and DMAP (cat.) in dichloromethane (1.5 mL) at 0 8C under
N2. The reaction mixture was gradually allowed to attain
room temperature and stirred further for a period of 4 h. The
reaction mixture was diluted with dichloromethane (10 mL)

S. Raghavan, A. Rajender / Tetrahedron 60 (2004) 5059–5067
5067
3. Vilaplana, M. J.; Molina, P.; Arques, A.; Andres, C.; Pedrosa,
R. Tetrahedron: Asymmetry 2002, 13, 5. (b) Li, X.; Yeung, C.;
Chan, A. S. C.; Yang, T.-K. Tetrahedron: Asymmetry 1999,
10, 759. (c) Cicchi, S.; Crea, S.; Goti, A.; Brandi, A.
Tetrahedron: Asymmetry 1997, 8, 293. (d) Cho, B. T.; Kim,
N. Tetrahedron Lett. 1994, 35, 4115.
12. 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.; Deerberg, J.; Tamura, O. Helv. Chim.
Acta 1994, 77, 554. (e) Felpin, F.-X.; Lebreton, J. Tetrahedron
Lett. 2002, 43, 225.
4. Raghavan, S.; Rajender, A.; Joseph, S. C.; Rasheed, M. A.;
Kumar, K. R. Tetrahedron: Asymmetry 2004, 15, 365.
5. (a) Walker, A. J. Tetrahedron: Asymmetry 1992, 3, 961.
(b) Carreno, M. C. Chem. Rev. 1995, 95, 1717.
13. A preliminary account of the synthesis of allosedamine has
been described Raghavan, S.; Rajender, A. Tetrahedron Lett.
2004, 45, 1919.
6. (a) Tsuchihashi, G. I.; Iriuchijima, S.; Maniwa, K.
Tetrahedron Lett. 1973, 14, 3389. (b) Ronan, B.; Marchalin,
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. 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.
7. 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, I. V.; Soloshonok,
V. A. Tetrahedron 1998, 54, 12789. (c) Bravo, P.; Capelli, S.;
Crucianelli, M.; Guidetti, M.; Markovsky, A. L.; Meille, S. V.;
Soloshonok, V. A.; Sorochinsky, A. E.; Viani, F.; Zanda, M.
Tetrahedron 1999, 55, 3025.
14. (a) Raghavan, S.; Rasheed, M. A.; Joseph, S. C.; Rajender, A.
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.
15. McKay, W. R.; Proctor, G. R. J. Chem. Soc., Perkin Trans. 1
1981, 2435.
16. In the diastereomer 6a the methine proton at C2 resonated
downfield in comparison to 6s.
17. Caturla, F.; Najera, C. Tetrahedron Lett. 1997, 38, 3789.
(b) Costa, A.; Najera, C.; Sansano, J. M. Tetrahedron:
Asymmetry 2001, 12, 2205.
18. For excellent review refer to (a) Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. 1997, 36, 2036. (b) Schuster, M.;
Blechert, 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.
19. Sugihara, H.; Tanikaya, R.; Kaji, A. Synthesis 1978, 881.
(b) Pummerer, R. Chem. Ber. 1909, 42, 2282. (c) Kennedy,
M.; McKervey, M. Comprehensive Organic Chemistry; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7,
p 193.
8. Pyne, S. G.; Dikic, B. J. Org. Chem. 1990, 55, 1932.
9. (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.
20. Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37,
547. (b) Huwe, C. M.; Blechert, S. Synthesis 1997, 61.
21. Stragies, R.; Blechert, S. Tetrahedron 1999, 55, 8179.
22. Bach, T.; Brummerhop, H.; Harms, K. Chem. Eur. J. 2000, 6,
3838.
10. Gershwin, M. E.; Terr, A. Clin. Rev. Allergy 1996, 14, 241.
11. Beyerman, H. C.; Eveleens, W.; Muller, Y. M. F. Recl. Trav.
Chim. Pays-Bas 1956, 75, 63. (b) Lukes, R.; Kovar, J.; Blaha,
K.; Sindona, G. 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, G.; Uccella,
N. Chem. Ber. 1989, 122, 2019. (h) Ozawa, N.; Nakajima, S.;
Zaoya, K.; Hamaguchi, F.; Nagasaka, T. Heterocycles 1991,
32, 889.
23. Yasuda, S.; Kitagawa, H.; Ueno, M.; Ishitani, H.; Fukasawa,
M.; Nishijima, M.; Kobayashi, S.; Hanada, K. J. Biol. Chem.
2001, 276, 43994.
24. Ueno, M.; Kitagawa, H.; Ishitani, H.; Yasuda, S.; Hanada, K.;
Kobayashi, S. Tetrahedron Lett. 2001, 42, 7863.
(b) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett.
2002, 4, 143. (c) Kobayashi, S.; Hamada, T.; Manabe, K.
J. Am. Chem. Soc. 2002, 124, 5640.
25. Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org.
Chem. 1989, 54, 1548.