Stereoselective total synthesis of (-)-nupharamine utilizing an α-chlorosulfide and a sulfinimine for C-C bond formation

Article abstract of DOI:10.1039/c5ob01750e

An efficient stereoselective synthesis of the nuphar alkaloid, (-)-nupharamine, is reported. The key features include the Lewis acid catalyzed reaction of an α-chlorosulfide with a silyl ketene acetal for C-C bond formation, creation of the stereocenter at C2 by a diastereoselective reaction of allyl indium with a sulfinimine and reductive amination for the introduction of the C6 stereocenter of the piperidine ring.

Full text of DOI:10.1039/c5ob01750e

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Stereoselective total synthesis of (−)-nupharamine
utilizing an α-chlorosulfide and a sulfinimine for
C–C bond formation†
Cite this: DOI: 10.1039/c5ob01750e
Sadagopan Raghavan* and Sheelamanthula Rajendar
Received 21st August 2015,
Accepted 13th October 2015
An efficient stereoselective synthesis of the nuphar alkaloid, (−)-nupharamine, is reported. The key fea-
tures include the Lewis acid catalyzed reaction of an α-chlorosulfide with a silyl ketene acetal for C–C
bond formation, creation of the stereocenter at C2 by a diastereoselective reaction of allyl indium with a
sulfinimine and reductive amination for the introduction of the C6 stereocenter of the piperidine ring.
DOI: 10.1039/c5ob01750e
www.rsc.org/obc
Introduction
Nuphar alkaloids comprise the family of sesquiterpenoid and
triterpenoid alkaloids possessing piperidine, indolizidine and
quinolizidine ring systems that are isolated from aquatic
plants of the genus Nuphar (Nymphaeaceae).1 Nupharamine
(1), was isolated from the Japanese water lily, Nuphar japonica,2
found in Japan and Korea. It has been used as a diuretic and
for the treatment of stomach ache.3 Other members of the
family have been shown to possess antibiotic,4a antifungal,4b
potent immunosuppressive,4c central paralytic effects,5a,b,c and
antitumor activities.5d,e The structural motif common to
nuphar alkaloids is the trisubstituted piperidine ring with a
methyl group at C-3 and a 3-furyl substituent at the C-6 posi-
tion. Nuphar alkaloids have been targets for asymmetric syn-
thesis due to their significant biological properties. The total
synthesis of nupharamine 1 (Fig. 1) has been reported by
several groups, utilizing a Diels–Alder strategy,6 an intra-
molecular aza-Wittig reaction,7 a cross-metathesis/reductive
amination reaction,8 an intramolecular Mannich reaction9 and
allenic hydroxylamine cyclisation10 as key steps.
Fig. 1 Nuphar alkaloid, nupharamine.
be obtained by reductive amination of an amino ketone
obtained from sulfinamide 2 which can be obtained by an ally-
lation followed by cross-metathesis from sulfinimine 3. Com-
pound 3 was envisaged to be obtained from β-keto sulfide 4
which in turn can be traced to sulfide 5 and silyl enol ether 6.
The synthesis began with the Michael addition of thiophe-
nol 7 to methyl methacrylate 8 to furnish racemic ester 9. LAH
reduction furnished alcohol 10, enzymatic resolution of which
using vinyl acetate and Amano lipase furnished optically pure
sulfide 11 (45% yield, 99% ee).11 The protection of 11 under
standard conditions using TBDPS-Cl afforded the silyl ether 5.
The treatment of sulfide 5 with N-chlorosuccinimide furnished
α-chlorosulfide 1212,13 which without isolation was reacted
with silyl ketene acetal 6, prepared from the corresponding
ketone,14 in the presence of catalytic amounts of ZnBr2 to yield
keto sulfide 4,15 as an inseparable mixture of diastereomers in
a 2 : 1 ratio. The thiophenyl residue in 4 was chemoselectively
hydrogenolyzed using RANEY®-Ni pre-treated with acetone16
to furnish compound 13, Scheme 2.
Results and discussion
Herein, we describe the stereoselective synthesis of (−)-nuphar-
amine 1 by employing a Lewis acid catalyzed reaction of an
α-chlorosulfide with a silyl ketene acetal, diastereoselective
allylation of a t-butyl sulfinimine for C–N bond construction
and reductive amination as key steps. The retrosynthetic ana-
lysis is depicted in Scheme 1. Nupharamine was visualized to
The keto group in 13 was protected as its ketal using ethyl-
ene glycol17 in the presence of catalytic amounts of p-toluene-
sulfonic acid to afford 14. Deprotection of the silyl ether in 14
using TBAF furnished the alcohol 15, which on oxidation
using DMP18 yielded the aldehyde 16. Treatment of 16 with
Division of Natural Product Chemistry, Indian Institute of Chemical Technology,
Hyderabad 500007, India. E-mail: sraghavan@iict.res.in
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob01750e
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 1 Retrosynthetic analysis of nupharamine.
Scheme 2 Synthesis of compound 13.
(R)-N-tert-butanesulfinamide19 in the presence of Ti(OEt)4 followed by reduction using NaBH4 in MeOH produced
furnished sulfinimine 3. Attempted reactions of 3 with prenyl nupharamine 1 as the sole product7 in 70% yield. The hydride
lithium20 expecting to obtain homoallylic amine derivative 2 delivery to the imine from the face opposite to the bulky C-2
did not bear fruit and the terminal alkene 18 was obtained substituent as depicted in transition state II would explain the
exclusively.21
formation of 1, Scheme 3. The spectroscopic data and optical
Exploring an alternative route, the three component allyla- rotation of nupharamine 1 were in good agreement with those
tion was attempted using aldehyde 16, sulfinamide 17 and reported in the literature,8 {[α]D25 = −37.5 (c 0.7, CHCl3), lit.8
allyl indium, generated in situ, as the reacting partners.22 The [α]D22 = −38.7 (c 0.75, CHCl3)}.
reaction proceeded cleanly to yield homoallyl amine derivative
19 selectively. The reaction outcome can be rationalized by
invoking transition state I, wherein the allyl indium attacks the
sulfinimine from the less hindered face by chelating to the
Conclusions
oxygen atom. The trisubstituted alkene 2 was prepared via
intermolecular olefin cross-metathesis23 between olefin 19 and
2-methyl-2-butene using the second generation Hoveyda–
Grubbs’ catalyst (HG-II, 1.5 mol%) under solvent-free reaction
conditions at 40 °C. Compound 2 on treatment with 4 N HCl24
in dioxane resulted in the concurrent hydration of the trisub-
stituted olefin, deprotection of the sulfinamide and 1,3-dioxo-
lane groups to yield the amine·HCl, which on neutralization,
The α-chlorosulfide prepared from sulfide
5 has been
employed in the reaction with silyl ketene acetal for C–C bond
formation. The t-butyl sulfinamide auxiliary has been
employed for the stereoselective creation of the C-2 stereogenic
center by reaction with allyl indium. A reductive amination
reaction has been utilized to create the C-6 stereocenter. The
synthetic route disclosed can be readily adapted to prepare
other members of nuphar alkaloids.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 3 Synthesis of nupharamine.
(J) are reported in Hertz (Hz). Peak multiplicity is indicated as
follows: s (singlet), d (doublet), t (triplet), q (quartet) and m
(multiplet). Mass spectra were recorded using a Waters mass
Experimental
General information
All materials were used as received from a commercial supplier spectrometer. HPLC spectra were recorded using a Waters
without further purification. All anhydrous reactions were per- 2998 spectrometer. High resolution mass spectra (HRMS) were
formed using oven-dried or flame dried glassware. Tetrahydro- recorded using an Applied Bio-Sciences HRMS spectrometer
furan (THF) was distilled over Na/Ph2CO under a nitrogen and a Thermo LTQ-Orbitrap mass spectrometer. All IR-spectra
atmosphere. Dichloromethane (CH2Cl2), and triethylamine were recorded using a Nexus 870-FT-IR Thermo Nicolet
(TEA) were dried over CaH2 and distilled prior to use. All reac- spectrometer.
tions were monitored by using E. Merck analytical thin layer
Methyl 2-methyl-3-(phenylthio)propanoate (9). To a stirred
chromatography (TLC) plates and analyzed with 254 nm UV solution of freshly distilled methyl methacrylate 8 (20 g,
light and/or anisaldehyde–sulfuric acid or potassium per- 200 mmol, 1 eq.) in benzene (400 mL) at rt was added DBU
manganate or PMA treatment. Silica gel for column chromato- (3 mL, 20 mmol, 0.1 eq.) followed by dropwise addition of thio-
graphy was purchased from Acme (Silica Gel 60–120, phenol 7 (22.4 mL, 220 mmol, 1.1 eq.) over a period of 15 min.
1
100–200 mesh). All H and 13C NMR spectra were recorded in The resulting solution was then stirred at rt for 5 h. The reac-
CDCl3 using Gemini 200, Avance 300, Inova 400, and Inova 500 tion was quenched by the addition of 0.5 N HCl (40 mL) and
spectrometers. Chemical shifts (δ) are reported in parts per the mixture was extracted with EtOAc (2 × 100 mL). The com-
million (ppm) relative to residual CHCl3 as an internal refer- bined organic layers were washed with 1 N NaOH (50 mL) and
ence (1H: δ 7.26 ppm, 13C: δ 77.00 ppm). Coupling constants brine (100 mL), dried over Na2SO4 and concentrated under
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
reduced pressure. The resulting compound was purified by in anhydrous dichloromethane (100 mL) cooled at 0 °C were
silica gel column chromatography using hexanes–EtOAc (98 : 2, added imidazole (6.28 g, 92.4 mmol, 2.2 eq.) and TBDPS-Cl
v/v) as the eluent to afford compound 9 (37.8 g, 180 mmol) in (12.70 g, 46.2 mmol, 1.1 eq.). The reaction mixture was stirred
90% yield as an oil. TLC Rf = 0.4 (5% EtOAc–hexanes). for 1 h before being diluted with dichloromethane (50 mL),
IR (neat): 2948, 1736, 1581, 1437, 1210, 1165, 742, 692 cm−1
.
washed with water (100 mL) and brine (50 mL) and dried over
1H NMR (300 MHz, CDCl3): δ 7.32–7.30 (d, J = 6.8 Hz, 2H), 7.25 Na2SO4. The organic layer was evaporated under reduced
(t, J = 6.8 Hz, 2H), 7.16 (t, J = 6.8 Hz, 1H), 3.64 (s, 3H), 3.23 (dd, pressure to afford the crude compound, which was purified by
J = 12.8, 6.7 Hz, 1H), 2.87 (dd, J = 12.8, 7.5 Hz, 1H), 2.70–2.59 column chromatography on silica gel using hexanes–EtOAc
(m, 1H), 1.26 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): (9.5 : 0.5, v/v) as the eluent to afford compound 5 (16.7 g,
δ 174.8, 135.6, 129.8, 128.7, 126.2, 51.5, 39.4, 37.2, 16.5. MS 40 mmol) in 95% yield as a yellow oil. TLC Rf = 0.42 (5%
(ESI): 233 [M + Na]+. HRMS (ESI): m/z calcd for C11H14O2NaS EtOAc–hexanes). [α]D25 = +18.5 (c 1.0, CHCl3). IR (neat): 2957,
233.0612, found 233.0602.
2930, 2858, 1472, 1109, 1084, 738, 700, 503 cm−1 1H NMR
.
2-Methyl-3-(phenylthio)propan-1-ol (10). To a suspension of (300 MHz, CDCl3): δ 7.65–7.59 (m, 4H), 7.38–7.24 (m, 8H), 7.20
LAH (6.0 g, 158 mmol, 1 eq.) in anhydrous THF (150 mL) (t, J = 7.5 Hz, 2H), 7.09 (t, J = 7.5 Hz, 1H), 3.63 (dd, J = 9.8,
cooled at 0 °C was added a solution of compound 9 (33.1 g, 4.5 Hz, 1H), 3.52 (dd, J = 9.8, 6.7 Hz, 1H), 3.21 (dd, J = 12.8,
158 mmol, 1 eq.) in anhydrous THF (60 mL) dropwise over a 6.0 Hz, 1H), 2.66 (dd, J = 12.8, 7.5 Hz, 1H), 2.01–1.86 (m, 1H),
period of 30 min. The reaction mixture was stirred for an 1.06 (s, 9H), 1.09 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz,
additional 30 min at 0 °C and allowed to warm to rt and CDCl3): δ 137.2, 135.5, 133.5, 129.5, 128.7, 128.5, 127.6, 125.3,
stirred for 2 h. The reaction mixture was diluted with ether 67.4, 36.9, 35.7, 26.8, 19.2, 16.2. MS (ESI): 443 [M + Na]+.
(200 mL) and quenched with ice pieces. The reaction mixture HRMS (ESI): m/z calcd for C26H32ONaSSi 443.1835, found
was stirred at room temperature for 1 h, the resulting reaction 443.1846.
mixture was filtered through a pad of Celite, and the filter cake
(S)-5-(tert-Butyldiphenylsilyloxy)-1-(furan-3-yl)-4-methyl-3-
was washed with EtOAc (3 × 200 mL) and MeOH (100 mL). The (R,S)(phenylthio)pentan-1-one (4). To a solution of compound
combined organic layers were washed with brine (100 mL), 5 (4.20 g, 10 mmol, 1 eq.) in anhydrous dichloromethane
dried over Na2SO4, filtered and concentrated under reduced (50 mL) was added the solution of N-chlorosuccinimide (1.5 g,
pressure to afford the crude product. Purification of the crude 11 mmol, 1.1 eq.) in dichloromethane (50 mL) at ambient
residue by silica gel column chromatography using hexanes– temperature and the mixture was stirred for 15 min. Another
EtOAc (8 : 2, v/v) as the eluent afforded racemic alcohol 10 flame-dry rb flask was charged with the solution of freshly pre-
(22.9 g, 126 mmol) in 80% yield as a colorless liquid. TLC Rf = pared silyl ketene acetal 6 (4.28 g, 20 mmol, 2 eq.) in dichloro-
0.12 (20% EtOAc–hexanes). IR (neat): 3390, 2959, 2876, 1583, methane (10 mL) followed by the addition of the above-
1
1478, 1030, 739, 691 cm−1. H NMR (300 MHz, CDCl3): δ 7.35 generated chlorosulfide through cannula and ZnBr2 (1.5 mL,
(t J = 6.7 Hz, 2H), 7.28 (t, J = 6.7 Hz, 2H), 7.17 (t, J = 6.7 Hz, 1.5 mmol, 1.5 M in THF, 0.15 eq.). The mixture was stirred at
1H), 3.64 (dd, J = 10.5, 5.2 Hz, 1H), 3.59 (dd, J = 10.5, 6.0 Hz, rt for 30 min. The reaction was quenched by the addition of
1H), 3.07 (dd, J = 12.8, 6.7 Hz, 1H), 2.84 (dd, J = 12.8, 6.7 Hz, H2O (15 mL). The layers were separated and the aq. layer was
1H), 2.00–1.91 (m, 1H), 1.63 (bs, 1H), 1.04 (d, J = 6.7 Hz, 3H). extracted with EtOAc (2 × 50 mL). The combined organic layers
13C NMR (75 MHz, CDCl3): δ 136.6, 128.7, 125.6, 66.4, 37.1, were washed with brine (50 mL), dried over Na2SO4, filtered
35.3, 16.3. MS (ESI) 205 [M + Na]+. HRMS (ESI): m/z calcd for and concentrated under reduced pressure to furnish the crude
C10H14ONaS 205.0663, found 205.0669.
product, which was purified by column chromatography on
(S)-2-Methyl-3-(phenylthio)propan-1-ol (11). To
a
stirred silica gel using hexanes–EtOAc (9.5 : 0.5, v/v) as the eluent to
solution of ( ) alcohol 10 (18.2 g, 100 mmol, 1 eq.) in anhy- afford sulfide 4 (3.43 g, 6.5 mmol) as an inseparable mixture
drous chloroform cooled at 0 °C were added vinyl acetate of diastereomers in 65% yield as a gummy liquid. TLC Rf = 0.3
(34.4 g, 400 mmol, 4 eq.) and Pseudomonas fluorescens Amano (5% EtOAc–hexanes). IR (neat): 3448, 2959, 2930, 2857, 1725,
Lipase (PFL) (1.1 g). The resulting solution was then stirred at 1467, 1375, 1259, 1111, 1038, 803, 703, 506 cm−1 1H NMR
.
0 °C for 5 h when HPLC using a chiral column revealed the (300 MHz, CDCl3): δ 7.9 (s, 1H), 7.8 (s, 1H), 7.75 (s, 1H), 7.65
absence of (R)-11. (HPLC: ee = 99.0%, Chiralpak IC column, (s, 1H), 7.63–7.44 (m, 8H), 7.39–7.19 (m, 12H), 7.19–7.0 (m,
mobile phase: hexane/isopropanol 98/02, flow rate: 1 mL 10H), 6.66 (s, 1H), 6.59 (s, 1H), 3.72–3.65 (m, 4H), 3.55–3.47
min−1, temperature = 25 °C, detection: UV 220 nm, retention (m, 2H), 3.04 (dd, J = 15.8, 6.9 Hz, 1H), 2.91 (dd, J = 15.8,
time (S)-isomer = 21.67 min, (R)-isomer 19.88 min). The result- 7.9 Hz, 1H), 2.88 (dd, J = 12.8, 6.9 Hz, 1H), 2.82 (dd, J = 12.8,
ing reaction mixture was filtered through a pad of Celite, dried 5.8 Hz, 1H), 2.10–2.04 (m, 1H), 2.03–1.95 (m, 1H), 0.97 (d, J =
over Na2SO4, filtered and concentrated under reduced pressure 8.8 Hz, 3H), 0.93 (s, 9H), 0.86 (d, J = 6.9 Hz, 3H), 0.83 (s,
to yield the crude product. Purification of the crude residue by 9H).13C NMR (75 MHz, CDCl3): δ 192.6, 192.2, 147.4, 147.3,
column chromatography using hexanes–EtOAc (8 : 2, v/v) as the 143.8, 143.7, 135.5, 135.3, 134.7, 133.5, 130.0, 129.7, 129.5,
eluent afforded alcohol 11 (8.19 g, 45 mmol) in 45% yield as a 129.4, 129.3, 129.1, 128.7, 128.5, 127.5, 127.4, 125.7, 125.3,
colorless liquid. [α]2D5 = +11.5 (c 1.0, CH2Cl2).
108.5, 108.3, 67.3, 66.5, 46.0, 44.4, 37.2, 37.0, 35.7, 35.4, 26.8,
(S)-tert-Butyl(2-methyl-3-(phenylthio)propoxy)diphenylsilane 26.6, 19.2, 19.0, 16.3, 16.2. MS (ESI): 551 [M + Na]+. HRMS
(5). To a stirred solution of alcohol 11 (7.64 g, 42 mmol, 1 eq.) (ESI): m/z calcd for C32H36O3NaSSi 551.2047, found 551.2048.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
(R)-5-(tert-Butyldiphenylsilyloxy)-1-(furan-3-yl)-4-methylpentan- afford the alcohol 15 (2.37 g, 10.5 mmol) in 90% yield as an
1-one (13). A suspension of RANEY®-nickel (10 g) in acetone oil. TLC Rf = 0.1 (20% EtOAc–hexanes). [α]2D5 = −11.7 (c 2.0,
(20 mL) was stirred for 30 min at rt. Acetone was removed and CHCl3). IR (neat): 3421, 2954, 2883, 1663, 1465, 1187, 1044,
1
the residue was washed with THF (2 × 20 mL).The solution of 874, 800, 602 cm−1. H NMR (300 MHz, CDCl3): δ 7.38 (s, 1H),
compound 4 (10.4 g, 20 mmol, 1 eq.) in anhydrous THF 7.36 (s, 1H), 6.32 (s, 1H), 4.01–3.96 (m, 2H), 3.92–3.87 (m, 2H),
(30 mL) was added to the suspension of RANEY®-nickel in 3.48 (dd, J = 10.5, 5.6 Hz, 1H), 3.42 (dd, J = 10.5, 6.1 Hz, 1H),
THF (20 mL) and the reaction mixture was stirred at rt for 3 h. 2.01–1.95 (m, 1H), 1.91–1.85 (m, 1H), 1.66–1.59 (m, 1H),
The RANEY®-nickel was removed by filtration through a Celite 1.54–1.47 (m, 1H), 1.26–1.19 (m, 1H), 0.90 (d, J = 6.7 Hz, 3H).
plug and the filter cake was washed with EtOAc (2 × 60 mL). 13C NMR (75 MHz, CDCl3): δ 143.1, 139.8, 127.6, 108.6, 107.7,
The combined filtrates were washed with brine (50 mL), dried 67.6, 64.5 36.8, 35.5, 26.6, 16.5. MS (ESI): 249 [M + Na]+. HRMS
over Na2SO4, filtered and concentrated under reduced pressure (ESI): m/z calcd for C12H18NaO4 249.1097, found 249.1113.
to afford the crude product which was purified by silica gel
(R)-4-(2-(Furan-3-yl)-1,3-dioxolan-2yl)-2-methylbutanal (16).
column chromatography by using hexanes–EtOAc (9.5 : 0.5, v/v) To a stirred solution of alcohol 15 (1.13 g, 5 mmol, 1 eq.) in
as the eluent to afford compound 13 (6.3 g, 15 mmol) in 75% anhydrous dichloromethane (20 mL) was added solid NaHCO3
yield as a yellow liquid. TLC Rf = 0.2 (5% EtOAc–hexanes). (2.0 g, 25 mmol, 5 eq.) followed by the Dess–Martin periodi-
[α]2D5 = −3.5 (c 1.0, CHCl3). IR (neat): 2932, 2860, 1677, 1468, nane (2.5 g, 6.0 mmol, 1.2 eq.). After stirring for 30 min, the
1389, 1154, 1107, 749, 701, 503 cm−1 1H NMR (300 MHz, reaction mixture was filtered through a pad of Celite. The fil-
.
CDCl3): δ 7.93 (s, 1H), 7.68–7.63 (m, 4H), 7.46–7.33 (m, 7H), trate was washed with aq. saturated Na2S2O3 (20 mL), saturated
6.74 (d, J = 1.5 Hz, 1H), 3.53 (dd, J = 10.5, 6.1 Hz, 1H), 3.49 (dd, aqueous NaHCO3 (20 mL) and brine (20 mL) and dried over
J = 10.5, 5.2 Hz, 1H), 2.70 (t, J = 6.7 Hz, 2H), 1.92–1.79 (m, 1H), Na2SO4. The solution was filtered and concentrated under
1.78–1.66 (m, 1H), 1.65–1.51 (m, 1H), 1.05 (s, 9H), 0.95 (d, J = reduced pressure to provide the aldehyde 16 (0.9 g, 4 mmol) in
6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 194.7, 146.8, 143.9, 80% yield as a clear colorless oil which was used without
135.6, 133.8, 129.6, 127.6, 108.8, 68.4, 38.1, 35.3, 27.7, 27.0, further purification. TLC Rf = 0.21 (20% EtOAc–hexanes).
19.4, 17.0. MS (ESI): 443 [M + Na]+. HRMS (ESI): m/z calcd for [α]D25 = −13.5 (c 1.0, CHCl3). IR (neat): 2930, 1720, 1664, 1459,
1
C26H32O3NaSi 443.2013, found 443.2018.
1389, 1156, 1108, 756, 602 cm−1. H NMR (300 MHz, CDCl3):
(R)-tert-Butyl(4-(2-(furan-3-yl)-1,3-dioxolan-2-yl)-2-methyl- δ 9.59 (d, J = 1.5 Hz, 1H). 7.39 (s, 1H), 7.37 (s, 1H), 6.32 (s, 1H),
butoxy)diphenylsilane (14). To a stirred solution of compound 4.01–3.97 (m, 2H), 3.92–3.87 (m, 2H), 2.37–2.32 (m, 1H),
13 (6.3 g, 15 mmol, 1 eq.) in benzene (60 mL) cooled at 0 °C, 1.97–1.88 (m, 2H), 1.85–1.78 (m, 1H), 1.50–1.43 (m, 1H), 1.08
ethylene glycol (3.1 mL) and p-toluenesulfonic acid (0.28 g, (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 203.9, 143.1,
1.5 mmol, 0.1 eq.) were added. The resulting mixture was 139.6, 127.2, 108.3, 107.1, 64.4, 45.6, 36.4, 24.1, 13.1. MS (ESI):
stirred at reflux (Dean–Stark system containing benzene in 279 [M + Na]+. HRMS (ESI): m/z calcd for C13H20O5Na
the trap) for 10 h. An aq. saturated solution of NaHCO3 (5 mL) 279.1200, found 279.1203. Note: the mass is for the hemiacetal
was added. The layers were separated and the aqueous layer formed by dissolving the aldehyde in methanol.
was extracted with EtOAc (2 × 50 mL). The combined organic
(R,E)-N-((R)-4-(2-(Furan-3-yl)-1,3-dioxolan-2-yl)-2-methyl-
layers were washed with brine (50 mL), dried over Na2SO4, fil- butylidene)-2-methylpropane-2-sulfinamide (3). To a stirred
tered and concentrated in vacuo. The residue was purified by solution of aldehyde 16 (0.25 g, 1 mmol, 1 eq.) in anhydrous
silica gel column chromatography using hexanes–EtOAc (9 : 1, THF (5 mL) was added Ti(OEt)4 (0.41 mL, 2 mmol, 2 eq.)
v/v) as the eluent to afford compound 14 (5.42 g, 11.7 mmol) under a N2 atmosphere. Then, (R)-tert butanesulfinamide 17
in 78% yield as an oil. TLC Rf = 0.32 (5% EtOAc–hexanes). (0.12 g, 1 mmol, 1 eq.) was added. The reaction solution was
[α]2D5 = +4.1 (c 1.0, CHCl3). IR (neat): 2930, 1459, 1395, 1215, stirred at rt for 5 h. While rapidly stirring, the reaction was
1163, 1104, 767, 702, 606 cm−1 1H NMR (200 MHz, CDCl3): quenched by adding equal volumes of brine (5 mL) and EtOAc
.
δ 7.68–7.61 (m, 5H), 7.44–7.33 (m, 7H), 6.30 (s, 1H), 4.02–3.94 (5 mL). The mixture was diluted with EtOAc (10 mL) and
(m, 2H), 3.90–3.83 (m, 2H), 3.48 (dd, J = 10.1, 5.8 Hz, 1H), 3.41 stirred vigorously for 20 min. The resulting mixture was fil-
(dd, J = 10.1, 6.7 Hz, 1H), 1.98–1.78 (m, 2H), 1.70–1.48 (m, 2H), tered through a pad of Celite, and the filter cake was washed
1.26–1.13 (m, 1H), 1.02 (s, 9H), 0.91 (d, J = 6.7 Hz, 3H). with EtOAc (10 mL). The combined filtrates were washed with
13C NMR (75 MHz, CDCl3): δ 143.1, 139.9, 135.5, 134.0, 129.6, brine (10 mL), the combined organic layers were dried over
129.4, 127.5, 108.7, 107.8, 68.7, 64.6, 37.0, 35.7, 26.9, 26.8, Na2SO4 and concentrated under reduced pressure. The com-
19.2, 16.7. MS (ESI): 465 [M + H]+. HRMS (ESI): m/z calcd for pound was purified by silica gel column chromatography
C28H37O4Si 465.2456, found 465.2465.
using hexanes–EtOAc (8 : 2, v/v) as the eluent to furnish com-
(R)-4-(2-(Furan-3-yl)-1,3-dioxolan-2yl)-2-methylbutan-1-ol (15). pound 3 (1.04 g, 3.2 mmol) in 80% yield as an oil. TLC Rf = 0.2
To a solution of compound 14 (5.42 g, 11.7 mmol, 1 eq.) in (20% EtOAc–hexanes). [α]2D5 = −177.5 (c 1.0, CHCl3). IR (neat):
anhydrous THF (45 mL) cooled at 0 °C was added TBAF 3138, 2958, 2868, 1623, 1502, 1462, 1365, 1193, 1074, 1023,
(11.7 mL, 1.0 M in THF, 1 eq.). The reaction mixture was 868, 687 cm−1 1H NMR (300 MHz, CDCl3): δ 7.93 (d, J =
.
stirred at ambient temperature for 5 h and then concentrated 5.2 Hz, 1H), 7.38–7.34 (m, 2H), 6.30 (s, 1H), 4.02–3.94 (m, 2H),
in vacuo. The residue was purified by silica gel column chrom- 3.93–2.84 (m, 2H), 2.69–2.52 (m, 1H), 1.98–1.85 (m, 2H),
atography using hexanes–EtOAc (8 : 2, v/v) as the eluent to 1.83–1.66 (m, 1H), 1.60–1.47 (m, 1H), 1.18 (s, 9H), 1.13 (d, J =
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 172.8, 143.2, 139.9, 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 143.2, 139.9, 134.7,
127.6, 108.6, 107.4, 64.7, 56.4, 37.1, 29.7, 27.6, 22.4, 17.1. MS 127.6, 119.0, 108.6, 107.6, 64.6, 58.3, 55.7, 37.4, 36.0, 26.3,
(ESI): 328 [M + H]+. HRMS (ESI): m/z calcd for C16H26O4NS 24.2, 22.7, 14.8. MS (ESI): 370 [M + H]+. HRMS (ESI): m/z calcd
328.1577, found 328.1576.
for C19H32O4NS 370.2047, found 370.2052.
(R)-N-((4R,5R)-7-(2-(Furan-3-yl)-1,3-dioxolan-2-yl)-3,3,5-methyl-
(R)-N-((3R,4S)-1-(2-(Furan-3-yl)-1,3-dioxolan-2-yl)-3,7-dimethyl-
hept-1-en-4-yl)-2-methylpropane-2-sulfinamide
(18). Lithium oct-6-en-4-yl)-2-methylpropane-2-sulfinamide (2). 2-Methyl-2-
(0.2 g) was added in small pieces to a solution of 3-methylbut- butene (1.5 mL) was collected in a sealed tube, cooled at
2-enyl phenyl ether (0.34 g, 2 mmol, 4 eq.) in dry diethyl ether/ −78 °C, containing compound 19 (0.55 g, 1.5 mmol, 1 eq.) and
dry THF (1 : 1 v/v, 5 mL) under nitrogen, followed by three Hoveyda–Grubbs-II catalyst (19.0 mg, 0.023 mmol, 0.015
drops of methanol. At the first appearance of a green color- eq.). The resulting reaction mixture was slowly warmed to rt
ation, the reaction mixture was cooled to 5 °C and stirred for a and refluxed at 40 °C for 10 h. Excess 2-methyl-2-butene was
further 2 h. The now orange solution was transferred to a evaporated and the residue was purified by column chromato-
stirred solution of compound 3 (0.16 g, 0.5 mmol) in dry graphy on silica gel using hexanes–EtOAc (7 : 3, v/v) to give the
diethyl ether (4 mL) at −78 °C. The resulting mixture was cross-metathesis product 2 (0.46 g, 1.1 mmol) in 78% yield as
stirred at the same temperature for 20 min, and the reaction an oil. TLC Rf = 0.3 (30% EtOAc–hexanes). [α]2D5 = −21.5 (c 1.0,
was then quenched by the slow addition of methanol (15 mL). CHCl3). IR (neat): 3448, 2922, 2852, 1713, 1461, 1214, 1122,
Diethyl ether (10 mL) and water (10 mL) were added, the 1028, 926, 748, 667 cm−1
.
1H NMR (300 MHz, CDCl3):
phases were separated, and the aqueous phase was extracted δ 7.38–7.33 (m, 2H), 6.30 (s, 1H), 5.09 (t, J = 6.8 Hz, 1H),
with diethyl ether (2 × 10 mL). The combined extracts were 4.02–3.98 (m, 2H), 3.92–3.88 (m, 2H), 3.16–3.08 (m, 2H),
washed with brine (10 mL), dried over Na2SO4, filtered, and 2.26–2.12 (m, 2H), 2.03–1.92 (m, 1H), 1.84–1.41 (m, 4H), 1.72
concentrated under reduced pressure to afford the crude (s, 3H), 1.63 (s, 3H), 1.18 (s, 9H), 0.87 (d, J = 6.4 Hz, 3H).
product, which was purified by column chromatography on 13C NMR (75 MHz, CDCl3): δ 143.2, 139.9, 135.4, 127.6,
silica gel using hexanes–EtOAc (8 : 2, v/v) as the eluent to 120.1, 108.6, 107.7, 64.7, 59.3, 55.5, 37.5, 35.8, 30.1, 26.3,
furnish compound 18 (0.12 g, 0.36 mmol) in 72% yield as an 25.9, 22.6, 18.0, 14.8. MS (ESI): 354 [M + H]+. HRMS (ESI): m/z
oil. TLC Rf = 0.1 (20% EtOAc–hexanes). 1H NMR (300 MHz, calcd for C19H32O3NS 354.2111, found 354.2112. Note: the
CDCl3): δ 7.40–7.34 (m, 2H), 6.36 (s, 1H), 5.80 (dd, J = 17.3, mass is for the ketone resulting from the hydrolysis of the
11.3 Hz, 1H), 5.0 (dd, J = 11.3, 1.5 Hz, 1H), 4.96 (dd, J = 17.3, dioxolane.
1.5 Hz, 1H), 4.0–3.96 (m, 2H), 3.90–3.86 (m, 2H), 3.34 (d, J =
9.0 Hz, 1H), 2.89 (d, J = 8.3 Hz, 1H), 2.02–1.95 (m, 1H), butane-2-ol (1). To
1.97–1.82 (m, 1H), 1.76–1.64 (m, 2H), 1.56–1.43 (m, 1H), 1.25 0.4 mmol, 1 eq.) in anhydrous MeOH (4 mL) cooled at 0 °C
(s, 9H), 1.02 (s, 3H), 0.09 (s, 3H), 0.84 (d, J = 6.7 Hz, 3H). was added HCl in 1,4-dioxane (4 M, 0.5 mL, 2 mmol, 5 eq.).
4-((2S,3R,6S)-6-(Furan-3-yl)-3-methylpiperidin-2-yl)-2-methyl-
a
solution of compound (0.15 g,
2
(R)-N-((4S,5R)-7-(2-(Furan-3-yl)-1,3-dioxolan-2-yl)-5-methylhept- The reaction mixture was stirred for 4 h at 0 °C. The solvent
1-en-4-yl)-2-methylpropane-2-sulfinamide (19). To a stirred solu- and excess HCl were removed under reduced pressure. The
tion of aldehyde 16 (0.9 g, 4 mmol, 1 eq.) in anhydrous THF residue was diluted with dichloromethane (5 mL) then washed
(6 mL) were added (R)-N-tert-butanesulfinamide 17 (0.43 g, with aq. saturated solution of Na2CO3 (5 mL), dried over
3.6 mmol, 0.9 eq.), indium powder (0.52 g, 4.4 mmol, 1.1 eq.) Na2SO4, filtered and concentrated under reduced pressure.
and Ti(OEt)4 (1.67 mL, 8 mmol, 2 eq.) at rt. The resulting reac- The crude residue was dissolved in anhydrous MeOH (4 mL)
tion mixture was stirred for 1 h, after which time allyl bromide cooled at 0 °C and NaBH4 (30 mg, 0.8 mmol, 2 eq.) was added
(0.48 mL, 5.45 mmol, 1.36 eq.) was added via a syringe over and the mixture was stirred at the same temperature for 2 h.
2 min at rt. The mixture was heated to 60 °C for 5 h. After The solvent was removed under reduced pressure, and the
cooling to rt, the reaction mixture is carefully added to a reaction mixture was diluted with dichloromethane (5 mL) and
mixture of ethyl acetate : brine (50 mL, 4 : 1 v/v) with stirring. water (2 mL). The layers were separated, and the aqueous layer
The resulting white suspension was filtered through a short was extracted with CH2Cl2 (2 × 5 mL). The combined organic
plug of Celite, and washed with ethyl acetate (20 mL). The layers were dried over NaSO4, filtered and concentrated under
combined filtrates were washed with brine (10 mL), dried over reduced pressure. Purification on silica gel doped with Et3N
Na2SO4, filtered and concentrated under reduced pressure to using dichloromethane–MeOH (95 : 5, v/v) afforded nuphara-
afford the crude product which was purified by column chrom- mine (70 mg, 0.28 mmol) in 70% yield as an oil. TLC Rf =
atography on silica gel using hexanes–EtOAc (7 : 3, v/v) to give 0.3 (5% MeOH–dichloromethane). [α]2D5 = −37.5 (c 0.7, CHCl3).
the amine 20 (1.25 g, 3.4 mmol) in 85% yield as a yellow color {lit.8 [α]D22 = −38.7 (c 0.75, CHCl3)}. IR (neat): 3444, 3019,
oil. TLC Rf = 0.21 (30% EtOAc–hexanes). [α]2D5 = −7.9 (c 1.2, 2923, 2855, 1636, 1461, 1376, 1218, 1079, 769 cm−1
CHCl3). IR (neat): 3448, 2931, 1626, 1389, 1218, 1048, 760, 703, 1H NMR (300 MHz, CDCl3): δ 7.36–7.33 (m, 2H), 6.42 (s, 1H),
613 cm−1 1H NMR (300 MHz, CDCl3): δ 7.38–7.34 (m, 2H), 3.62 (dd, J = 11.5, 2.2 Hz, 1H), 2.42–2.37 (m, 1H), 1.9–1.72
.
.
6.30 (s, 1H), 5.81–5.71 (m, 1H), 5.17–5.11 (m, 2H), 4.0–3.96 (m, (m, 4H), 1.6–1.42 (m, 4H), 1.26–1.13 (m, 2H), 1.21 (s, 3H),
2H), 3.90–3.86 (m, 2H), 3.22–3.17 (m, 2H), 2.41–2.30 (m, 1H), 1.19 (s, 3H), 0.9 (d, J = 6.4 Hz, 3H). MS (ESI): 252 [M + H]+.
2.23–2.15 (m, 1H), 2.02–1.95 (m, 1H), 1.84–1.77 (m, 1H), HRMS (ESI): m/z calcd for C15H26O2N 252.1958, found
1.76–1.59 (m, 2H), 1.58–1.49 (m, 1H), 1.18 (s, 9H), 0.87 (d, J = 252.1966.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Organic & Biomolecular Chemistry
Paper
progress was monitored by HPLC. The title compound had
physical characteristics in excellent agreement with the
known literature compound. S. Raghavan and S. Rajendar,
Org. Biomol. Chem., 2015, 13, 5044. For the preparation of
the enantiomer of 11 see: R. Baker, M. J. O’Mahony and
C. J. Swain, J. Chem. Soc., Perkin Trans. 1, 1987, 1623.
12 I. Paterson and I. Fleming, Tetrahedron Lett., 1979, 23, 993.
13 S. Raghavan, V. Vinoth Kumar and L. Raju Chowhan,
Synlett, 2010, 1807.
14 Compound 6 was obtained by a three step sequence (i)
3-furaldehyde was treated with methyl magnesium iodide
to furnish the secondary alcohol; (ii) oxidation with IBX in
DMSO yielded 3-acetylfuran; (iii) the silyl enol ether 6 was
prepared from 3-acetylfuran and tert-butyldimethyl-
chlorosilane under standard conditions in the presence of
ZnCl2/Et3N in benzene; see: A. Benıtez, F. Ruth Herrera,
M. Romero and F. X. Talamas, J. Org. Chem., 1996, 61,
1487.
Acknowledgements
S. Rajendar is thankful to CSIR for SRF fellowship. S.R.
acknowledges funding from DST and CSIR, New Delhi as a
part of XII five year plan programme under the title ORIGIN
(CSC-108).
Notes and references
1 (a) R. T. Lalonde, C. F. Wong and K. C. Das, J. Am. Chem.
Soc., 1972, 94, 8522; (b) B. Maurer and G. Ohloof, Helv.
Chim. Acta, 1976, 59, 1169.
2 Y. Arata and T. Ohashi, Yakugaku Zasshi, 1957, 77, 792.
3 T. Ohashi, Yakugaku Zasshi, 1959, 79, 729.
4 (a) J. T. Wrobel, in The Alkaloids, ed. R. H. F. Manske, Aca-
demic Press, New York, 1967, vol. 9, pp. 441–465;
(b) J. Cybuski and J. T. Wrobel, in The Alkaloids, ed.
A. Brossi, Academic Press, New York, 1989, vol. 35, pp.
215–257; (c) H. Matsuda, H. Shimoda and M. Yoshikawa,
Bioorg. Med. Chem., 2001, 9, 1031.
15 The configuration of the newly created stereocenter of the
major isomer was not established since it was to be
destroyed subsequently.
16 S. A. Snyder and E. J. Corey, J. Am. Chem. Soc., 2006, 128,
740.
17 R. K. Boeckman, M. Ricodel, R. Ferreira, L. H. Mitchell,
P. Shao, M. J. Neeb and Y. Fang, Tetrahedron, 2011, 67,
9787.
18 (a) D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48,
4155; (b) D. B. Dess and J. C. Martin, J. Am. Chem. Soc.,
1991, 113, 7277.
19 D. J. Weix and J. A. Ellman, Org. Lett., 2003, 5, 1317.
20 Prenyl lithium was prepared by reductive cleavage of
phenyl prenyl ether with lithium; see: A. J. Birch,
J. E. T. Corrie and G. S. R. Subba Rao, Aust. J. Chem., 1970,
23, 1811.
5 (a) Y. Arata and T. Ohashi, Yakugaku Zasshi, 1957, 77, 236;
(b) M. Kokate, I. Kawasaki, S. Matsutani, S. Kusumoto and
T. Kaneko, Bull. Chem. Soc. Jpn., 1962, 35, 698;
(c) C. F. Wong, E. Auer and R. T. Lalonde, J. Org. Chem.,
1970, 35, 517; (d) H. Matsuda, T. Morikawa, M. Oda,
Y. Asao and M. Yoshikawa, Bioorg. Med. Chem. Lett., 2003,
13, 4445; (e) H. Matsuda, K. Yoshida, K. Miyagawa,
Y. Nemoto, Y. Asao and M. Yoshikawa, Bioorg. Med. Chem.
Lett., 2006, 16, 1567.
6 (a) Y. Shishido and C. Kibayashi, Tetrahedron Lett., 1991,
32, 4325; (b) J. Barluenga, F. Aznar, C. Ribas and C. Valdes,
J. Org. Chem., 1999, 64, 3736.
7 T. Honda, F. Ishikawa and S. Yamane, J. Chem. Soc., Chem.
Commun., 1994, 499.
21 The configuration at C2 was assigned based on the
precedent.
22 J. C. Gonzalez-Gomez, M. Medjahdi, F. Foubelo and
M. Yus, J. Org. Chem., 2010, 75, 6308.
8 S. Blechert and J. Gebauer, Synlett, 2005, 2826.
9 F. A. Davis and M. Santhanaraman, J. Org. Chem., 2006, 71,
4222.
23 A. K. Chatterjee, D. P. Sanders and R. H. Grubbs, Org. Lett.,
2002, 4, 1939.
24 J. W. Evans and J. A. Ellman, J. Org. Chem., 2003, 68, 9948.
10 R. W. Bates and C. J. Lim, Synlett, 2010, 866.
11 P. Grisenti, P. Ferraboschi, A. Manzocchi and
E. Santaniello, Tetrahedron, 1992, 18, 3827. The reaction
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.