A chemoenzymatic total synthesis of (+)-clividine

Article abstract of DOI:10.1021/jo201005d

The title compound, ent-1, the non-natural enantiomeric form of the lycorenine-type alkaloid (-)-clividine (1), has been prepared using the enantiomerically pure (ee >99.8%) cis-1,2-dihydrocatechol 3 as starting material. A key feature associated with the

Full text of DOI:10.1021/jo201005d

ARTICLE
pubs.acs.org/joc
A Chemoenzymatic Total Synthesis of (+)-Clividine
Lorenzo V. White, Brett D. Schwartz, Martin G. Banwell,* and Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia
S Supporting Information
b
ABSTRACT: The title compound, ent-1, the non-natural enantio-
meric form of the lycorenine-type alkaloid (À)-clividine (1), has been
prepared using the enantiomerically pure (ee >99.8%) cis-1,2-dihy-
drocatechol 3 as starting material. A key feature associated with the
closing stages of the synthesis involved the diastereoselective addition
of a nitrogen-centered radical onto a pendant cyclohexene to establish
the cis-fused D-ring and the required stereochemistry at C11b in the
final product ent-1.
’ INTRODUCTION
The natural product (À)-clividine was originally isolated from
the bush lilly Clivia miniata Regel,1 a species native to South Africa.
Extracts of the plant’s rhizome have been used in traditional Zulu
medicine to ameliorate the effects of fever, as a treatment for snake-
bites and to relieve pain more generally while extracts of the whole
plant have been used to assist with and hasten childbirth. The
structure, 1 (Figure 1), of (À)-clividine was assigned by D€opke and
Bienert1 in 1970 using a combination of spectroscopic and chemical
Figure 1. Structures of compounds 1, ent-1, and 2.
correlation studies and thus establishing it as a member of the
lycorenine-type class of Amaryllidaceae alkaloid.2
In 1973 Irie and co-workers reported3 a total synthesis of the
functionalization of the developing C-ring as well as attachment
of the fully substituted A-ring and thus following the strategy we
racemic modification of clividine using a DielsÀAlder reaction
employed recently5 in the synthesis of the structure, 2, erro-
between a 1-aryl-1,3-butadiene and maleic anhydride to establish
neously assigned to the natural product nobilisitine A. So, the
enantiomerically pure cis-1,2-dihydrocatechol 3,6 readily derived
from a whole-cell biotransformation of bromobenzene, was con-
verted into the bromohydrin 4 upon treatment with N-bromo-
succinimide (NBS) in wet tetrahydrofuran (THF).7 Product 4
was itself transformed into the corresponding acetonide under
standard conditions and thus affording compound 5 in 92% yield
(from 3). Reaction of the last compound with NaH followed by a
3-fold excess of the lithium anion derived from acetonitrile then
afforded, presumably via the corresponding epoxide, the γ-
hydroxynitrile 6 as a single diastereoisomer in 87% yield. The
structure of this compound was confirmed by single-crystal X-ray
analysis, details of which are provided in the Supporting Infor-
mation. Subjection of compound 6 to a BartonÀMcCombie
deoxygenation sequence8 gave, on treatment of the derived
xanthate ester 7 (93%) with tri-n-butyltin hydride, the nitrile 8
(87%). Subjection of the last compound to SuzukiÀMiyaura
cross-coupling9 with the readily obtained arylboronate ester 910
then afforded the required arylated cyclohexane 10 in 95% yield.
Once again, the structure of this compound was confirmed by
the A- and C-rings of the target. Extensive manipulation of the
anhydride ring associated with the resulting adduct then allowed for
construction of the D-ring. The lactonic B-ring was formed in the
final stages of the synthetic sequence using a combination of
FriedelÀCrafts alkylation chemistry (to install the required one-
carbon unit onto the aromatic ring) and an OsO4-mediated alkene
dihydroxylation reaction. Unfortunately, given the racemic nature of
the resulting product, no particularly useful comparisons could be
made between the natural product and the synthetic material. Since
no additional studies related to the synthesis of clividine have been
carried out in the intervening period,4 the development of an
enantioselective total synthesis of the (À)- or (+)-forms of this
compound seemed warranted. Accordingly, we now report a syn-
thesis of(+)-clividine (ent-1) from an enantiomerically pure starting
material of clearly defined configuration and using, in the closing
stages, a novel and diastereoselective cyclization of a nitrogen-
centered radical to establish the cis-fused D-ring of the target as
well as the required R-configuration at C11b.
’ RESULTS AND DISCUSSION
The opening stages of the present synthesis of (+)-clividine
(ent-1) are shown in Scheme 1 and involve appropriate
Received: May 18, 2011
Published: June 06, 2011
r
2011 American Chemical Society
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Scheme 1. Synthesis of Compounds 10 and 13, Precursors to (+)-Clividine (ent-1) and C11b-epi-(+)-Clividine (C11b-epi-ent-1)
ARTICLE
single-crystal X-ray analysis (see Supporting Information for
details). In a rather demanding step that required extensive
experimentation to establish effective conditions, compound
10 was subjected to chemoselective reduction using hydrogen
in the presence of a large excess of Raney-cobalt11 and thereby
affording the requisite primary amine 11 that was immediately
protected, using standard conditions, as the corresponding Alloc-
derivative 12 (86% from 10). N-Methylation of compound 12
was readily effected by treating it with lithium hexamethyldisil-
azide and then methyl iodide, and by such means compound 13
was obtained in 93% yield.
The Alloc-protected secondary amine 13 served as the sub-
strate in what was hoped would be the closing stages of the
synthesis of (+)-clividine. Thus, as shown in Scheme 2, com-
pound 13 was subjected to Alloc-deprotection using Pd(PPh3)4
in the presence of an excess of dimedone12 and thereby leading to
the required secondary amine 14 in 94% yield. In order to ensure
the cyclohexenyl double bond was sterically accessible during the
foreshadowed nitrogen-centered radical reaction,13,14 compound
14 was subjected to acetonide hydrolysis and lactonization using
aqueous acetic acid and thus delivering lactone 15 (84%), which
was immediately N-chlorinated using N-chlorosuccinimide
(NCS) and thereby giving compound 16 that was used directly
in the pivotal nitrogen-centered radical reaction. In the event,
treatment of this substrate with tri-n-butyltin hydride and azobis-
isobutyronitrile (AIBN) in refluxing benzene for 1 h afforded a
diastereoisomerically pure product in 67% yield. This proved to
be the C-11b epimer of (+)-clividine (C11b-epi-ent-1) as deter-
mined by single-crystal X-ray analysis of the readily derived oxalic
acid salt (see Supporting Information for details).15 This out-
come clearly suggests that the benzylic radical formed after the
initial cis-selective cyclization process16 reacts preferentially at
the R-face with tri-n-butyltin hydride to generate the observed
product. Presumably this preference reflects the greater steric
demands imposed by the flanking D-ring over the similarly
positioned B-ring in the intermediate benzylic radical.
Given the stereochemical outcome associated with the con-
version 16 f C11b-epi-ent-1 and our explanation for this, we
reasoned that the O-TBDPS-protected form of compound 16
would generate a benzylic radical wherein the steric demands
imposed by the bulky OH protecting group would now direct tri-
n-butyltin hydride to react at the β-face of this intermediate, thus
generating the stereochemical array required for the synthesis of
(+)-clividine. In order to investigate this possibility, compound
10 was subjected to a tandem acetonide hydrolysis/lactonization
sequence (Scheme 3) using acetic acid/water, and the hydroxyl
group within the resulting product 17 (84%) was protected,
under standard conditions, as the corresponding TBDPS-ether
18 (80%). Raney-cobalt-mediated reduction of the nitrile residue
within this last compound resulted in the formation of the anti-
cipated primary amine 19 (82%) which was immediately pro-
tected, using standard conditions, as the corresponding allyl
carbamate 20 (90%). N-Methylation of compound 20 was
achieved by successive treatment of it with LiHMDS and then
methyl iodide, and the product 21 (94%) so formed was
subjected to Alloc group cleavage under the conditions1 used
previously for the conversion 13 f 14.
Scheme 2. Synthesis of C11b-epi-(+)-Clividine
The ensuing secondary amine 22 (89%) was then subjected to
N-chlorination using NCS as the halogen-transfer agent. Com-
pound 23 (93%) thus obtained reacted smoothly with tri-n-butyltin
hydride/AIBN to give the anticipated cyclization product 24
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Scheme 3. Completion of the Synthesis of (+)-Clividine
thick silica gel 60 F254 plates. Eluted plates were visualized using a
254 nm UV lamp and/or by treatment with a suitable dip followed by
heating. These dips included a mixture of phosphomolybdic acid:ceric
sulfate:sulfuric acid (concd): water (37.5 g:7.5 g:37.5 g:720 mL). The
retardation factor (Rf) values cited here have been rounded at the first
decimal point. Flash chromatographic separations were carried out
following protocols defined by Still et al.18 with silica gel 60 (40À
63 μm) as the stationary phase and using the AR- or HPLC-grade
solvents indicated. Starting materials and reagents were generally available
from commercialcompaniesand wereusedassupplied. Dryingagents and
other inorganic salts were purchased from commercial suppliers. THF,
dichloromethane, and benzene were dried using a solvent purification
system that is based upon a technology originally described by Grubbs
et al.19 Spectroscopic grade solvents were used for all analyses. Where
necessary, reactions were performed under a nitrogen atmosphere.
Bromohydrin 5. A magnetically stirred solution of diol 3 (5.00 g,
26.2 mmol) in THF/water (80 mL of a 4:1 v/v mixture) maintained
under nitrogen at 0 °C was treated with NBS (5.12 g, 28.8 mmol) in
small portions over 0.17 h. The ensuing mixture was allowed to warm to
18 °C over 4 h and then treated with Na2S2O3 (3.00 g). After a further
0.5 h, NaCl (3.00 g) was added and the aqueous phase extracted with
diethyl ether (3 Â 50 mL). The combined organic phases were then
dried (Na2SO4), filtered, and concentrated under reduced pressure to
give an orange oil. This material was immediately dissolved in 2,
2-dimethoxypropane (75 mL) and the resulting solution treated with
p-toluenesulfonic acid (500 mg, 2.62 mmol) before being stirred at
18 °C for 2 h. After this time, NaHCO3 (100 mL of a saturated aqueous
solution) was added to the reaction mixture which was then extracted
with ethyl acetate (3 Â 50 mL). The combined organic phases were then
dried (Na2SO4), filtered, and concentrated under reduced pressure to
yield an orange oil that was subjected to flash chromatography (silica, 1:4
v/v ethyl acetate/hexane elution). Concentration of the appropriate
fractions (Rf = 0.8 in 1:1 v/v ethyl acetate/hexane) afforded bromohydrin
5 (7.90 g, 92%) as a white foam, [R]D +15.6 (c 1.5, CDCl3). 1H NMR
(400 MHz, CDCl3) δ 6.36 (m, 1H), 4.68 (d, J = 5.1 Hz, 1H), 4.61 (m,
1H), 4.33À4.26 (complex m, 2H), 2.96 (broad s, 1H), 1.53 (s, 3H), 1.42
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 130.8, 124.0, 112.1, 78.0, 76.2,
70.6, 48.1, 27.9, 26.4. IR (KBr) νmax 3444, 2986, 2929, 1643, 1453, 1371,
1350, 1216, 1158, 1059, 1009, 967, 861, 791 cmÀ1. MS (EI, 70 eV) m/z
315, 313, and 311 [(M À CH3•)+, 50, 100, and 53%], 255, 253, and 251
(16, 32, and 17), 174 and 172 (15 and 16), 145 (5), 110 (7), 84 (18), 59
(10). HRMS: (M À CH3•)+ calcd for C9H1279Br81BrO3: 312.8898;
found: 312.8899.
Nitrile 6. A magnetically stirred solution of bromohydrin 5 (5.85 g,
17.8 mmol) in THF (60 mL) maintained under a nitrogen atmosphere
was cooled to 0 °C and then treated with NaH (0.78 g of a 60%
suspension in mineral oil, 19.6 mmol). The ensuing mixture was stirred
at 0 °C for 0.25 h before being added, dropwise, to a magnetically stirred
solution of acetonitrile (3.73 mL, 71.36 mmol) and n-BuLi (32 mL of a
1.6 M solution in THF, 53.52 mmol) in THF (100 mL) maintained at
À78 °C. After 0.25 h, the reaction mixture was quenched with NH4Cl
(50 mL of a saturated aqueous solution) and the separated aqueous
phase extracted with ethyl acetate (3 Â 50 mL). The combined organic
phases were washed with CuSO4 (1 Â 50 mL of a 10% w/v solution) and
then dried (Na2SO4), filtered, and concentrated under reduced pressure
to give a light-yellow oil that was subjected to flash chromatography
[(silica, 1:1 v/v ethyl acetate/hexane elution). Concentration of the
appropriate fractions (Rf = 0.4) afforded nitrile 6 (4.47 g, 87%) as a gold-
colored powder, mp 112.8À114.6 °C, [R]D À20.3 (c 1.5, CDCl3). 1H
NMR (400 MHz, CDCl3) δ 6.01 (d, J = 1.4 Hz, 1H), 4.65 (dd, J = 5.2 and
1.9 Hz, 1H), 4.49 (dd, J = 5.2 and 2.3 Hz, 1H), 3.70 (d, J = 8.8 Hz, 1H),
2.81À2.72 (complex m, 2H), 2.62 (dd, J = 17.6 and 8.3 Hz, 1H), 2.37
(broad s, 1H), 1.42 (s, 3H), 1.42 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ 128.9, 125.0, 117.7, 110.9, 78.3, 77.1, 70.1, 37.7, 27.3, 26.5, 19.5. IR
(83%). Treatment of compound 24 with HF pyridine in THF at
3
0 f 18 °C then gave (+)-clividine (99%), the structure of which
followed from the derived spectral data and a single-crystal X-ray
analysis of the readily obtained picrate salt (see Supporting
Information for details).15
The 1H NMR spectral data obtained on (+)-clividine (ent-1)
compared favorably with those reported by Irie3 for the syn-
thetically derived racemate (entry 1, Table 1). Various other
comparisons (Table 1) of the spectral data reported1 for the
alkaloid (À)-clividine with those acquired on its synthetically
derived optical antipode clearly established that they are enan-
tiomers. Because the enantiomer of the starting cis-1,2-dihydro-
catechol 3 is available17 the worked described here provides a
straightforward means for preparing (À)-clividine (1).
’ EXPERIMENTAL SECTION
General Experimental Procedures. Unless otherwise stated,
proton (1H) and carbon (13C) NMR spectra were recorded at 400
and 100 MHz, respectively. Unless otherwise specified, spectra were
acquired at 20 °C in deuterochloroform (CDCl3) that had been filtered
through basic alumina immediately prior to use. Chemical shifts are
recorded as δ values in parts per million (ppm). Infrared spectra (νmax
)
were analyzed as thin films on KBr plates (for liquids) or as a KBr disk
(for solids). Melting points are uncorrected. Analytical thin layer
chromatography (TLC) was performed on aluminum-backed 0.2 mm
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Table 1. Comparison of Data Derived from (+)-Clividine (ent-1)a with Those Reported for (()-Clividineb and (À)-Clividine (1)c
entry
data type
(À)-clividine
(()-clividine
(+)-clividine
1
1H NMR
NRd
δH 7.50 (s, 1H), 6.95 (s, 1H),
6.04 (s, 2H),
δH 7.47 (s, 1H), 6.91 (s, 1H), 6.03 (d, J = 1.3 Hz, 1H),
6.02 (d, J = 1.3 Hz, 1H), 4.56 (t, J = 2.6 Hz, 1H),
3.95 (td, J = 8.7 and 2.6 Hz, 1H), 3.21 (m, 1H),
2.63 (dd, J = 9.3 and 2.2 Hz, 1H), 2.51 (dd, J = 9.3 and
7.4 Hz, 1H), 2.40À2.32 (complex m, 3H),
2.13 (s, 3H), 2.09 (d, J = 4.2 Hz, 1H),
2.07 (d, J = 4.2 Hz, 1H), 1.84 (m, 2H)
+60.6 at 22 °C (c 1.0, CDCl3)
312 (Δε = +2.20),
4.58 (t, J = 3.0 Hz, 1H),
3.98 (dd, J = 8.5 and 3.0 Hz, 1H),
2.16 (s, 3H)
2
3
specific rotation
À75 at 22 °C (c 0.2, CHCl3) NAe
CD (nm)
313 (Δε = À1.96),
270 (Δε = À5.52),
246 (Δε = +1.55)
308 (log ε = 3.74),
267 (log ε = 3.75),
225 (log ε = 4.39)
(in MeOH)
NA
272 (Δε = +5.73),
249 (Δε = À1.87)
308 (log ε = 3.65),
4
5
UV/visible (nm)
NR
266 (log ε = 3.64),
225 (log ε = 4.26)
(in MeOH)
IR (cmÀ1
)
3595, 1715, 1035, and
940 (CHCl3)
3350 and 1705 (KBr)
3588, 1713, 1041, and 941 (CHCl3)
6
7
mass spectrum
M+•, 317
NR
M+•, 317
melting point (°C) 195À197
170À172
186À187
a Data derived from present work. b Data obtained from ref 3. c Data obtained from ref 1. d NR = not reported. e NA = not applicable.
(KBr) νmax 3436, 2990, 2934, 2893, 2245, 2189, 1644, 1423, 1382, 1373,
1274, 1229, 1162, 1107, 1058, 1041 cmÀ1. MS (EI, 70 eV) m/z 290 and
288 [(M+H)+, both <1%], 274 and 272 (both 80), 260 and 258 (both 10),
214 and 212 (both 28), 202 and 200 (both 22), 186 and 184 (both 24), 133
(100), 82 (33), 59 (59). HRMS: (M + H)+ calcd for C11H1481BrNO3:
290.0215; found: 290.0214.
further 0.5 h. The cooled reaction mixture was treated NH4Cl (50 mL of
a saturated aqueous solution) and the separated aqueous phase extracted
with Et2O (3 Â 40 mL). The combined organic phases were then dried
(Na2SO4), filtered, and concentrated under reduced pressure to yield a
yellow oil that was dissolved in acetonitrile (50 mL). The resulting
solution was washed with pentane (3 Â 30 mL) and then concentrated
under reduced pressure, and the light-yellow oil thus obtained was
subjected to flash chromatography (silica, dichloromethane elution).
Concentration of the appropriate fractions (Rf = 0.25 in 1:2 v/v ethyl
acetate/hexane) afforded bromide 8 (3.06 g, 87%) as a golden foam,
[R]D +29.1 (c 3.0, CDCl3). 1H NMR (400 MHz, CDCl3) δ 6.09 (m,
1H), 4.51À4.46 (complex m, 2H), 2.82 (m, 1H), 2.46 (dd, J = 16.3 and
6.0 Hz, 1H), 2.40 (dd, J = 16.3 and 6.3 Hz, 1H), 2.31 (m, 1H), 1.64 (m,
1H), 1.40 (s, 3H), 1.40 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 131.8,
125.9, 117.4, 109.8, 76.1, 73.3, 30.5, 30.3, 27.4, 26.4, 22.9. IR (KBr) νmax
2986, 2933, 2247, 1644, 1455, 1435, 1381, 1370, 1350, 1314, 1227, 1155,
1073, 1043 cmÀ1. MS (EI, 70 eV) m/z 273 and 271 (M+•, both <1%),
258 and 256 (98 and 100), 216 and 214 (20 and 22), 198 and 196
(61 and 63), 171 and 169 (both 55), 117 (21), 94 (18), 77 (35), 65 (32).
HRMS: M+• calcd for C11H1479BrNO2: 271.0208; found: 271.0210.
Acetonide 10. A magnetically stirred solution of bromide 8 (5.42 g,
19.91 mmol) in degassed THF/water (200 mL of a 9:1 v/v mixture) was
treated with boronate ester 920 (8.16 g, 27.9 mmol), Et3N (28 mL, 199.1
Xanthate 7. A magnetically stirred solution of compound 6 (4.00 g,
13.9 mmol) in THF (80 mL) maintained under nitrogen was cooled to
0 °C and then treated with NaH (0.83 mg of a 60% suspension in mineral
oil, 20.8 mmol). The ensuing mixture was warmed to 18 °C over 0.5 h
and then cooled again to 0 °C, treated with CS2 (0.84 mL, 13.9 mmol),
warmed to 18 °C over 0.5 h, cooled again to 0 °C, treated with MeI
(0.95 mL, 15.3 mmol), and then allowed to warm to 18 °C over a further
0.5 h. The reaction mixture was then quenched with NH4Cl (50 mL of a
half-saturated solution) and the aqueous phase extracted with Et2O (3 Â
40 mL). The combined organic phases were then washed with water
(1 Â 40 mL) before being dried (Na2SO4), filtered, and concentrated
under reduced pressure. The ensuing light-yellow oil was subjected to
flash chromatography (silica, 1:9 v/v ethyl acetate/hexane f1:4 v/v
ethyl acetate/hexane gradient elution). Concentration of the appro-
priate fractions (Rf = 0.3 in 1:3 v/v ethyl acetate/hexane) afforded
xanthate 7 (4.89 g, 93%) as a gold-colored foam, [R]D À105.5 (c 2.0,
CDCl3). 1H NMR (CDCl3, 400 MHz) δ 6.08 (d, J = 2.0 Hz, 1H), 5.91
(dd, J = 10.2 and 2.1 Hz, 1H), 4.70 (dd, J = 5.0 and 2.4 Hz, 1H), 4.67 (dd,
J = 5.0 and 2.1 Hz, 1H), 3.28 (m, 1H), 2.62 (dd, J = 16.8 and 4.8 Hz, 1H),
2.62 (s, 3H), 2.45 (dd J = 16.8 and 7.8 Hz, 1H), 1.46 (s, 3H), 1.40
(s, 3H). 13C NMR (CDCl3, 100 MHz) δ 216.0, 127.9, 125.6, 116.9,
111.5, 78.7, 78.0, 73.9, 35.1, 27.4, 26.7, 19.5 (one signal obscured or
overlapping). IR (KBr) νmax 2987, 2932, 2249, 1718, 1643, 1483, 1423,
1382, 1372, 1191, 1106, 1068, 980, 870 cmÀ1. HRMS: (M + Na)+ calcd
for C13H16BrNO3S2: 399.9653; found: 399.9653.
mmol), and PdCl2(dppf) CH2Cl2 (1.63 g, 2.00 mmol) and then heated
3
at reflux under an atmosphere of nitrogen for 2 h. The cooled reaction
mixture was diluted with ethyl acetate (50 mL) and washed with H2O
(2 Â 150 mL) and brine (1 Â 100 mL). The combined aqueous phases
were extracted with ethyl acetate (2 Â 50 mL), and the combined
organic phases were then dried (Na2SO4), filtered, and concentrated
under reduced pressure to yield a brown powder that was subjected to
flash chromatography (silica, 1:2 f 1:1 v/v ethyl acetate/hexane
gradient elution]. Concentration of the appropriate fractions (Rf = 0.5
in 1:1 v/v ethyl acetate/hexane) afforded acetonide 10 (7.03 g, 95%) as a
golden foam, [R]D +15.8 (c 1.0, CDCl3). 1H NMR (CDCl3, 400 MHz)
δ 7.41 (s, 1H), 6.70 (s, 1H), 6.03 (d, J = 1.4 Hz, 1H), 6.01 (d, J = 1.4 Hz,
1H), 5.5 (app. t, J = 1.6 Hz, 1H), 4.82 (dd, J = 6.0 and1.6 Hz, 1H), 4.61
(m, 1H), 3.79 (s, 3H), 2.85 (m, 1H), 2.45 (dd, J = 16.7 and 6.7 Hz, 1H),
Bromide 8. A magnetically stirred solution of xanthate 7 (4.89 g,
12.9 mmol) in benzene (80 mL) was heated to reflux while being
maintained under an atmosphere of nitrogen then treated with AIBN
(0.21 g, 1.29 mmol) and n-Bu3SnH (3.83 mL, 14.2 mmol). The ensuing
mixture was heated at reflux for a further 2 h, additional n-Bu3SnH
(0.90 mL, 3.23 mmol) was added, and heating was continued for a
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2.39 (dd, J = 16.7 and 7.1 Hz, 1H), 2.31 (dm, J = 13.8 Hz, 1H), 1.75 (ddd,
J = 13.9, 11.1, and 2.3 Hz, 1H), 1.46 (s, 3H), 1.34 (s, 3H). 13C NMR
(CDCl3, 100 MHz) δ 166.2, 150.6, 147.0, 141.8, 138.5, 127.3, 121.9,
118.1, 111.7, 110.2, 108.6, 101.9, 74.4, 72.6, 51.9, 31.8, 27.9, 27.5, 25.9,
23.3. IR (KBr) νmax 2986, 2916, 2246, 1717, 1613, 1504, 1484, 1436,
1370, 1247, 1156, 1125, 1072, 1036 cmÀ1. MS (EI, 70 eV) m/z 371
(M+•, 16%), 356 (8), 313 (13), 282 (29), 264 (53), 254 (26), 241 (100),
213 (42), 69 (37). HRMS M+• calcd for C20H21NO6: 371.1369; found:
371.1372.
N-Methylamine 14. Dimedone (6.55 g, 46.7 mmol) was dissolved
in magnetically stirred and degassed THF (50 mL), being maintained at
18 °C under nitrogen, and the solution thus obtained was treated with N-
methylcarbamate 13 (2.21 g, 4.67 mmol) and then Pd(PPh3)4 (1.08 g,
0.93 mmol). The ensuing mixture was stirred at 18 °C for 0.25 h, diluted
with dichloromethane (150 mL), and washed with NaHCO3 (3 Â
150 mL of a saturated aqueous solution). The separated organic phase
was dried (Na2SO4), filtered, and concentrated under reduced pressure
to give an orange oil that was subjected to flash chromatography (silica,
1:9 v/v ammonia saturated methanol/dichloromethane elution). Con-
centration of the appropriate fractions (Rf = 0.3) then gave amine 14
(1.70 g, (94%) as a light-yellow oil, [R]D +19.8 (c 2.0, CDCl3). 1H NMR
(CDCl3, 400 MHz) δ 7.37 (s, 1H), 6.72 (s, 1H), 6.01 (m, 1H), 5.98
(m, 1H), 5.49 (s, 1H), 4.77 (dd, J = 6.2 and 1.4 Hz, 1H), 4.55 (m, 1H), 3.77
(s, 3H), 2.69 (t, J = 7.6 Hz, 2H), 2.60À2.48 (complex m, 2H), 2.44
(s, 3H), 2.16 (dt, J = 14.3 and 4.9 Hz, 1H), 1.65À1.56 (complex m, 3H),
1.45 (s, 3H), 1.33 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 166.5, 150.4,
146.7, 139.4, 138.8, 131.6, 122.0, 111.8, 110.0, 108.3, 101.8, 74.8, 73.2,
51.7, 49.1, 36.1, 35.0, 31.9, 28.2, 27.6, 26.0. IR (KBr) νmax 2984, 2931,
2794, 1718, 1613, 1504, 1484, 1436, 1369, 1245, 1190, 1126, 1070, 1036,
930, 882 cmÀ1. MS (EI, 70 eV) m/z 389 (M+•, 4%), 374 (24), 314 (23),
270 (30), 238 (100), 225 (11), 149 (15), 57 (28). HRMS: M+• calcd for
C21H27NO6: 389.1838; found: 389.1837.
Lactone 15. A magnetically stirred solution of compound 14
(0.68 g, 1.73 mmol) in acetic acid/water (30 mL of a 4:1 v/v mixture)
was maintained at 50 °C for 18 h, allowed to cool to 18 °C, quenched
with NaHCO3 (50 mL of a saturated aqueous solution), and extracted
with dichloromethane (4 Â 50 mL). The combined organic phases were
then dried (Na2SO4), filtered, and concentrated under reduced pressure
to yield a yellow oil that was triturated with dichloromethane (10 mL) to
yield lactone 15 (0.46 g, 84%) as a white, crystalline solid, mp 214.3À
216.1 °C, [R]D +41.4 (c 1.5, CD3OD). 1H NMR (CD3OD, 400 MHz) δ
7.38 (s, 1H), 7.22 (s, 1H), 6.36 (s, 1H), 6.09 (app. d, J = 4.9 Hz, 2H),
5.16 (m, 1H), 4.37 (m, 1H), 3.30 (m, 1H), 3.10 (m, 1H), 2.80 (m, 1H),
2.73 (s, 3H), 2.16 (dt, J = 13.5 and 4.6 Hz, 1H), 1.88 (m, 1H), 1.77 (m,
1H), 1.55 (dd, J = 12.3 and 1.7 Hz, 1H) (signal due to OH and NH
protons not observed). 13C NMR (CD3OD, 100 MHz) δ 166.3, 154.8,
149.9, 135.3, 130.2, 127.7, 118.2, 109.1, 103.9, 103.5, 78.4, 66.3, 48.1,
34.1, 33.8, 32.8, 30.9. IR (KBr) νmax 3386, 2922, 2790, 1703, 1615, 1502,
1481, 1393, 1350, 1303, 1276, 1247, 1190, 1139, 1079, 1034, 930,
856 cmÀ1. HRMS: (M + H)+ calcd for C17H19NO5: 318.1341; found:
318.1341.
C11b-epi-(+)-Clividine (C11b-epi-ent-1). A magnetically stir-
red solution of amine 15 (95 mg, 0.30 mmol) in dichloromethane
(5 mL) maintained under nitrogen was cooled to À78 °C and then
treated, dropwise, with a solution of NCS (40 mg, 0.3 mmol) in
dichloromethane (5 mL). The ensuing mixture was allowed to warm
to 18 °C and then concentrated under reduced pressure to yield a white
paste that was dissolved in ethyl acetate/hexane (10 mL of 1:4 v/v
mixture). The resulting solution was passed through a pad of TLC-grade
silica that was then washed with ethyl acetate/hexane (50 mL of a 1:1 v/v
mixture). The combined filtrates were concentrated under reduced
pressure, and the light-yellow oil thus obtained, and containing the
N-chloroamine 16, wasdissolvedindegassedbenzene(25 mL) maintained
under nitrogen and containing AIBN (5 mg, 0.025 mmol). The resulting
solution was heated at reflux and then treated, dropwise, with n-Bu3SnH
(88 μL, 0.33 mmol). After addition was complete, the reaction mixture
was heated at reflux for 1 h, treated with additional n-Bu3SnH (20 μL,
0.08 mmol), and heated for a further 0.5 h. The cooled reaction mixture
was then concentrated under reduced pressure and the resulting yellow
oil subjected to flash chromatography (silica, 1:19 v/v ammonia
saturated methanol/dichloromethane elution). Concentration of the
appropriate fractions (Rf = 0.5 in 1:9 v/v ammonia saturated methanol/
dichloromethane) afforded C11b-epi-(+)-clividine (C11b-epi-ent-1)
Carbamate 12. A magnetically stirred mixture of nitrile 10 (1.00 g,
2.69 mmol) and Raney-cobalt (2.00 g, 200% w/w) in MeOH (50 mL,
saturated with ammonia) was maintained under a hydrogen atmosphere
at 18 °C for 18 h. The reaction mixture was then filtered through Celite
and the residual Raney-cobalt washed with MeOH (3 Â 20 mL). The
combined filtrates were concentrated under reduced pressure to afford a
brown oil that was dissolved in pyridine (20 mL). The resulting solution
was cooled to À10 °C and then treated, dropwise over 0.5 h and while
being maintained under nitrogen, with a solution of allyl chloroformate
(0.29 mL, 2.69 mmol) in dichloromethane (15 mL). After a further
0.25 h, the reaction mixture was treated with NaHCO3 (50 mL of a
saturated aqueous solution) and the separated aqueous phase extracted
with dichloromethane (3 Â 30 mL). The combined organic phases were
concentrated under reduced pressure at 25 °C to give a yellow oil that
was subjected to flash chromatography (silica, 1:1 v/v ethyl acetate/
hexane elution). Concentration of the appropriate fractions (Rf = 0.5)
afforded carbamate 12 (1.06 g, 86%) as clear, colorless oil, [R]D À9.4
(c 1.0, CDCl3). 1H NMR (CDCl3, 400 MHz) δ 7.39 (s, 1H), 6.70 (s,
1H), 6.01 (d, J = 1.2 Hz, 1H), 5.99 (d, J = 1.2 Hz, 1H), 5.85 (m, 1H), 5.47
(s, 1H), 5.23 (d, J = 17.3 Hz, 1H), 5.16 (d, J = 10.4 Hz, 1H), 4.92
(m, 1H), 4.77 (dd, J = 4.9 and 1.4 Hz, 1H), 4.56 (m, 1H), 4.50 (d, J =
5.2 Hz, 2H), 3.77 (s, 3H), 3.26 (m, 2H), 2.52 (m, 1H), 2.15 (dt, J = 13.9
and 4.0 Hz, 1H), 1.63 (m, 3H), 1.45 (s, 3H), 1.33 (s, 3H). 13C NMR
(CDCl3, 100 MHz) δ 166.5, 156.2, 150.5, 146.7, 139.5, 138.9, 132.9,
131.1, 121.7, 117.4, 111.8, 110.1, 108.3, 101.8, 74.8, 73.1, 65.3, 51.7, 38.3,
35.0, 31.3, 27.6, 27.6, 26.1. IR (KBr) νmax 3351, 2984, 2934, 1720, 1613,
1529, 1504, 1484, 1436, 1369, 1245, 1188, 1159, 1126, 1070, 1038 cmÀ1
.
HRMS: (M + Na)+ calcd for C24H29NO8: 482.1791; found: 482.1794.
N-Methylcarbamate 13. A magnetically stirred solution of carba-
mate 12 (4.54 g, 9.9 mmol) in THF (85 mL) maintained under nitrogen
was cooled to À78 °C and then treated, dropwise, with LiHMDS
(15 mL of a 1 M solution in THF, 14.81 mmol). The ensuing mixture
was stirred at 18 °C for 0.5 h and then treated with methyl iodide
(1.23 mL, 19.7 mmol). After a further 0.5 h, the reaction mixture was
quenched with NH4Cl (150 mL of a saturated aqueous solution) and the
separated aqueous phase extracted with dichloromethane (3 Â 60 mL).
The combined organic phases were dried (Na2SO4), filtered, and
concentrated under reduced pressure to yield a yellow oil that was
subjected to flash chromatography (silica, 1:1 v/v ethyl acetate/hexane
elution). Concentration of the appropriate fractions (Rf = 0.5) afforded
N-methylcarbamate 13 (4.42 g, 93%) as a clear, colorless oil, [R]D +12.4
1
(c 3.0, CDCl3). H NMR (CDCl3, 400 MHz) δ 7.39 (s, 1H), 6.72
(s, 1H), 6.00 (app. d, J = 11.3 Hz, 2H), 5.91 (m, 1H), 5.50 (d, J = 10.0 Hz,
1H), 5.27 (d, J = 17.1 Hz, 1H), 5.16 (t, J = 10.2 Hz, 1H), 4.78 (m, 1H),
4.56 (m, 3H), 3.77 (s, 3H), 3.35 (m, 2H), 2.90 (s, 3H), 2.44 (m, 1H),
2.18 (d, J = 13.1 Hz, 1H), 1.60 (m, 3H), 1.45 (s, 3H), 1.33 (s, 3H). 13C
NMR (CDCl3, 100 MHz) δ 166.5, 156.0, 150.5, 146.7, 139.5, 139.1,
133.2, 131.3, 131.2, 121.9, 117.2, 117.1, 111.9, 110.1, 108.3, 101.8, 74.8,
73.2, 65.9, 51.7, 46.8, 46.3, 34.6, 34.0, 33.5, 33.0, 32.1, 27.8, 27.5, 26.0
(additional signals due to the presence of carabmate rotamers). IR (KBr)
νmax 2985, 2933, 1704, 1648, 1613, 1503, 1484, 1435, 1402, 1369, 1244,
1203, 1162, 1125, 1070, 1037 cmÀ1. MS (EI, 70 eV) m/z 473 (M+•,
<1%), 415 (3), 383 (5), 342 (6), 308 (10), 298 (13), 282 (38), 238 (23),
128 (100), 84 (58). HRMS: M+• calcd for C25H31NO8: 473.2050;
found: 473.2043.
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(63 mg, 62% from 15) as a white powder, mp 91.8À92.6 °C, [R]D
+
Concentration of the appropriate fractions (Rf = 0.4 in 1:9 v/v ammonia
saturated methanol/dichloromethane) afforded amine 19 (1.04 g, 82%)
as a clear foam, [R]D +11.2 (c 1.0, CDCl3). 1H NMR (CDCl3, 400 MHz) δ
7.76À7.74 (complex m, 4H), 7.49 (s, 1H), 7.44À7.32 (complex m, 6H),
6.99 (s, 1H), 6.24 (s, 1H), 6.05 (s, 2H), 4.96 (m, 1H), 4.45 (t, J = 3.8 Hz,
1H), 2.85 (m, 1H), 2.68 (m, 2H), 1.79 (m, 1H), 1.62 (m, 1H), 1.40
(m, 1H), 1.25 (m, 2H), 1.17 (dd, J = 10.1 and 2.7 Hz, 1H), 1.05 (s, 9H).
13C NMR (CDCl3, 100 MHz) δ 163.4, 152.6, 148.0, 136.3, 136.0, 134.4,
133.5, 133.3, 130.3, 129.7, 129.6, 127.6, 127.4, 125.5, 117.5, 109.0, 102.0,
101.9, 77.2, 67.4, 39.5, 39.4, 33.7, 30.2, 27.0, 19.5. IR (KBr) νmax 3369,
2929, 2856, 1712, 1617, 1504, 1479, 1427, 1392, 1350, 1272, 1242, 1189,
1111, 1037, 931 cmÀ1. HRMS: (M + H)+ calcd for C32H35NO5Si:
542.2363; found: 542.2363.
110.2 (c 0.5, CDCl3). 1H NMR (CDCl3, 400 MHz) δ 7.51 (s, 1H), 6.97
(s, 1H), 6.03 (d, J = 1.2 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 4.83 (dd,
J = 12.5 and 2.3 Hz, 1H), 4.23 (dd, J = 5.5 and 2.7 Hz, 1H), 3.80 (dd, J =
12.5 and 1.8 Hz, 1H), 3.18 (app. t, J = 2.7 Hz, 1H), 3.15 (dt, J = 12.7 and
5.5 Hz, 1H), 2.48 (m, 1H), 2.32 (m, 1H), 1.97 (s, 3H), 1.91À1.77
(complex m, 4H), 1.37 (ddd, J = 13.2, 9.1, and 4.6 Hz, 1H). 13C NMR
(CDCl3, 100 MHz) δ 164.4, 152.2, 146.7, 137.9, 118.0, 109.7, 105.2,
101.9, 77.9, 68.3, 63.9, 54.9, 42.3, 36.3, 33.7, 33.2, 27.9. IR (KBr) νmax
3421, 2931, 2788, 1707, 1618, 1503, 1483, 1445, 1388, 1274, 1244, 1132,
1085, 1038, 883, 730 cmÀ1. MS (EI, 70 eV) m/z 317 (M+•, 81%), 300
(4), 228 (10), 162 (9), 126 (14), 96 (100), 82 (83). HRMS: M+• calcd
for C17H19NO5: 317.1263; found: 317.1257.
Alcohol 17. A magnetically stirred solution of acetonide 10 (0.99 g,
2.68 mmol) in acetic acid/water (50 mL of a 4:1 v/v mixture) was heated
at 50 °C for 18 h, allowed to cool to 18 °C, and quenched with NaHCO3
(50 mL of a saturated aqueous solution). The mixture thus obtained was
extracted with dichloromethane (4 Â 50 mL), and the combined organic
phases were then dried (Na2SO4), filtered, and concentrated under
reduced pressure to give a light-yellow oil. Trituration of this material
with dichloromethane (10 mL) then gave alcohol 17 (0.67 g, 84%) as a
white, crystalline solid mp 153.4À154.9 °C, [R]D +41.5 (c 1.0, CD4OD).
1H NMR (DMSO-d6, 400 MHz) δ 7.34 (s, 1H), 7.29 (s, 1H), 6.39
(s, 1H), 6.16 (d, J = 1.1 Hz, 1H), 6.15 (d, J = 1.1 Hz, 1H), 5.33 (d, J =
4.0 Hz, 1H), 5.15 (dd, J = 5.9 and 3.6 Hz, 1H), 4.24 (m, 1H), 3.16 (d, J =
8.0 Hz, 1H), 2.75 (dd, J = 16.9 and 5.7 Hz, 1H), 2.69 (dd, J = 16.9 and
6.4 Hz, 1H), 2.06 (m, 1H), 1.53 (app. t, J = 12.3 Hz, 1H). 13C NMR
(DMSO-d6, 100 MHz) δ 163.5, 152.8, 148.1, 133.1, 127.8, 127.1, 119.3,
117.0, 107.7, 102.5(2), 102.5(1), 76.5, 64.0, 32.8, 29.3, 22.3. IR (KBr)
νmax 3118, 2923, 2852, 2246, 1725, 1716, 1612, 1499, 1481, 1399, 1307,
1281, 1243, 1094, 1079, 1030, 926, 860 cmÀ1. MS (EI, 70 eV) m/z 299
(M+•, 100%), 281 (30), 272 (20), 259 (70), 254 (54), 241 (58), 215
(36), 213 (42), 115 (17), 57 (22). HRMS: M+• calcd for C16H13NO5:
299.0794; found: 299.0801.
Ether 18. A magnetically stirred solution of alcohol 17 (0.89 g,
2.97 mmol) in DMF (30 mL) maintained under nitrogen at 18 °C was
treated with imidazole (1.01 g, 14.9 mmol) and tert-butyldiphenylchlor-
osilane (2.32 mL, 8.92 mmol). After 72 h, the reaction mixture was
quenched with NaHCO3 (30 mL of a half-saturated aqueous solution),
and the aqueous phase was extracted with ethyl acetate (3 Â 20 mL).
The combined organic phases were dried (Na2SO4), filtered, and
concentrated under reduced pressure to yield a yellow oil that was
subjected to flash chromatography (silica, 1:3 v/v ethyl acetate/hexane
elution). Concentration of the appropriate fractions (Rf = 0.8 in 1:2 v/v
ethyl acetate/hexane) afforded ether 18 (1.27 g, 80%) as a white foam,
[R]D +1.0 (c 1.0, CDCl3). 1H NMR (CDCl3, 400 MHz) δ 7.76À7.72
(complex m, 4H), 7.49 (s, 1H), 7.45À7.32 (complex m, 6H), 7.03
(s, 1H), 6.23 (m, 1H), 6.07 (s, 2H), 4.98 (dd, J = 3.5 and 2.6 Hz, 1H),
4.49 (t, J = 3.5 Hz, 1H), 3.18 (m, 1H), 2.48 (dd, J = 16.8 and 7.1 Hz, 1H),
2.37 (dd, J = 7.1 and 16.3 Hz, 1H), 1.89 (m, 1H), 1.39 (m, 1H), 1.05
(s, 9H). 13C NMR (CDCl3, 100 MHz) δ 162.9, 152.8, 148.7, 136.2,
136.0, 133.8, 132.9, 132.3, 129.9, 129.7, 128.8, 127.7, 127.5, 124.9, 118.0,
117.7, 109.0, 102.2, 102.1, 76.5, 67.1, 33.6, 30.1, 27.0, 23.4, 19.5. IR
(KBr) νmax 2930, 2857, 2248, 1713, 1616, 1504, 1480, 1427, 1393, 1349,
1302, 1277, 1243, 1187, 1111, 1037, 911, 737, 703 cmÀ1. HRMS: (M +
Na)+ calcd for C32H31NO5Si: 560.1869; found: 560.1869.
Carbamate 20. A magnetically stirred solution of amine 19 (1.03 g,
1.89 mmol) in pyridine (15 mL) maintained under nitrogen was cooled
to À10 °C and then treated, dropwise over 0.5. h, with a solution of allyl
chloroformate (0.22 mL, 2.08 mmol) in dichloromethane (10 mL).
After a further 0.25 h, the reaction mixture was treated with NaHCO3
(40 mL of a saturated aqueous solution) and then extracted with
dichloromethane (3 Â 20 mL). The combined organic phases were
then dried (Na2SO4), filtered, and concentrated under reduced pressure
at 25 °C to give a yellow foam that was subjected to flash chromatog-
raphy (silica, 1:1 v/v ethyl acetate/hexane elution]. Concentration of the
appropriate fractions (Rf = 0.6) afforded carbamate 20 (1.07 g, 90%) as a
white foam, [R]D +85.7 (c 1.0, CDCl3). 1H NMR (CDCl3, 400 MHz) δ
7.75 (m, 4H), 7.49 (s, 1H), 7.46À7.32 (complex m, 6H), 6.98 (s, 1H),
6.23 (s, 1H), 6.05 (s, 2H), 5.92 (m, 1H), 5.31 (dm, J = 17.3 Hz, 1H), 5.22
(dm, J = 10.4 Hz, 1H), 4.96 (m, 1H), 4.61 (m, 1H), 4.56 (d, J = 5.1 Hz,
2H), 4.47 (t, J = 3.9 Hz, 1H), 3.22 (m, 1H), 3.09 (m, 1H), 2.82 (m, 1H),
1.78À1.70 (complex m, 2H), 1.54À1.37 (complex m, 1H), 1.28À1.16
(complex m, 1H), 1.04 (s, 9H). 13C NMR (CDCl3, 100 MHz) δ 163.4,
156.1, 152.7, 148.1, 136.3, 136.0, 134.4, 133.3, 133.2, 132.8, 129.8, 129.6,
129.4, 127.6, 127.4, 125.9, 117.7, 117.6, 109.0, 102.0, 101.9(5), 77.06,
67.3, 65.6, 38.3, 35.4, 33.5, 30.0, 27.0, 19.4. IR (KBr) νmax 3368, 2930,
2856, 1710, 1617, 1504, 1479, 1427, 1392, 1359, 1273, 1243, 1112, 1037,
933 cmÀ1. MS (EI, 70 eV) m/z 625 (M+•, 3%), 568 (9), 511 (23), 510
(60), 251 (12), 199 (100), 149 (39), 60 (55), 57 (95). HRMS: M+• calcd
for C36H39NO7Si: 625.2496; found: 625.2515.
N-Methylcarbamate 21. A magnetically stirred solution of carba-
mate 20 (1.10 g, 1.68 mmol) in THF (20 mL) maintained under
nitrogen was cooled to À78 °C and then treated, dropwise, with
LiHMDS (2.25 mL of a 1 M solution in THF, 2.25 mmol). The ensuing
mixture was stirred at À78 °C for 0.5 h, treated with methyl iodide
(0.21 mL, 3.36 mmol) before being warmed to 18 °C, allowed to stand at
this temperature for 0.5 h, and then quenched with NH4Cl (30 mL of a
saturated aqueous solution). The separated aqueous phase was extracted
with dichloromethane (2 Â 40 mL), and the combined organic phases
were then dried (Na2SO4), filtered, and concentrated under reduced
pressure to yield a yellow oil that was subjected to flash chromatography
(silica, 1:1 v/v ethyl acetate/hexane ether elution). Concentration of the
appropriate fractions (Rf = 0.6) afforded N-methylcarbamate 21 (0.90 g,
84%) as a white foam, [R]D +78.6 (c 1.0, CDCl3). 1H NMR (CDCl3,
400 MHz) δ 7.76À7.73 (complex m, 4H), 7.48 (broadened s, 1H),
7.45À7.30 (complex m, 6H), 6.99 (broadened s, 1H), 6.28 (m, 1H),
6.05 (s, 2H), 5.92 (m, 1H), 5.28 (m, 1H), 5.19 (dm, J = 10.7 Hz, 1H),
4.96 (m, 1H), 4.57 (m, 2H), 4.44 (m, 1H), 3.45À3.30 (complex m, 1H),
3.25À3.10 (complex m, 1H), 2.91 (s, 3H), 2.80 (m, 1H), 1.72À1.85
(complex m, 1H), 1.64 (m, 1H), 1.54 (m, 1H), 1.24 (m, 1H), 1.04
(s, 9H). 13C NMR (CDCl3, 75 MHz) δ 166.4, 156.0, 150.5, 146.7, 139.4,
139.1, 133.2, 131.1, 121.9, 117.2, 111.8, 110.1, 108.2, 101.8, 74.8, 73.2,
65.9, 51.7, 46.8, 46.3, 34.6, 34.0, 33.5, 32.9, 32.1, 27.8, 27.5, 26.0 (signals
due to various carbons obscured or overlapping). IR (KBr) νmax 2930,
2857, 1704, 1617, 1504, 1479, 1427, 1394, 1361, 1300, 1273, 1242, 1202,
1111, 1060, 1036 cmÀ1. MS (EI, 70 eV) m/z 639 (M+•, 8%), 583 (45),
Amine 19. A magnetically stirred solution of nitrile 18 (1.25 g,
2.32 mmol) and Raney-cobalt (2.50 g, 200% w/w) in MeOH (75 mL of
ammonia saturated material) was maintained under an atmosphere of
hydrogen at 18 °C for 18 h and then filtered through a pad of Celite, and
the Raney-cobalt thus retained was washed with MeOH (3 Â 20 mL).
The combined filtrates were concentrated under reduced pressure to
afford a brown oil that was subjected to flash chromatography (silica,
1:19 v/v ammonia saturated methanol/dichloromethane elution).
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582 (100), 555 (13), 523 (30), 524 (48), 510 (20), 498 (17), 467 (40),
437 (18). HRMS: M+• calcd for C37H41NO7Si: 639.2652; found:
639.2667.
2.25 (m, 3H), 2.08 (s, 3H), 1.71 (dd, J = 7.8 and 5.0 Hz, 1H), 1.54
(m, 1H), 1.45À1.38 (complex m, 1H), 1.05 (s, 9H). 13C NMR (CDCl3,
100 MHz) δ 165.3, 151.6, 147.2, 140.3, 135.8, 135.7, 133.8, 133.7, 129.7,
127.6, 118.4, 109.8, 107.5, 101.7, 80.1, 68.1, 67.1, 55.9, 45.0, 43.1, 36.4,
29.9, 29.1, 26.8, 19.1 (two signals obscured or overlapping). IR (KBr)
νmax 3071, 2931, 2788, 2249, 1716, 1617, 1504, 1478, 1427, 1387, 1285,
1257, 1111, 1035 cmÀ1. MS (EI, 70 eV) m/z 555 (M+•, 15%), 498 (24),
96 (17), 86 (70), 84 (100), 83 (72). HRMS: M+• calcd for C33H37-
NO5Si: 555.2441; found: 555.2443.
N-Methylamine 22. A magnetically stirred solution of dimedone
(1.96 mg, 14 mmol) in degassed THF (20 mL) maintained under
nitrogen at 18 °C was treated with N-methylcarbamate 21 (0.89 g,
1.39 mmol) and Pd(PPh3)4 (0.16 g, 0.14 mmol). The ensuing mixture
was stirred for 1 h at this temperature, diluted with dichloromethane
(30 mL), and washed with NaHCO3 (3 Â 50 mL of a saturated aqueous
solution). The separated organic phase was dried (Na2SO4), filtered,
and concentrated under reduced pressure and the orange oil thus
obtained subjected to flash chromatography (silica, 1:19 v/v ammonia
saturated methanol/dichloromethane elution). Concentration of the
appropriate fractions (Rf = 0.4 in 1:9 v/v ammonia saturated methanol/
dichloromethane) afforded N-methylamine 22 (0.69 g, 89%) as a light-
yellow foam, [R]D +8.4 (c 3.0, CDCl3). 1H NMR (CDCl3, 400 MHz) δ
7.77À7.74 (complex m, 4H), 7.49 (s, 1H), 7.44À7.32 (complex m, 6H),
6.99 (s, 1H), 6.25 (s, 1H), 6.04 (s, 2H), 4.95 (m, 1H), 4.45 (t, J = 3.8 Hz,
1H), 2.84 (broadened s, 1H), 2.56 (t, J = 7.6 Hz, 2H), 2.45 (s, 3H), 1.79
(m, 2H), 1.73À1.64 (complex m, 1H), 1.50À1.41 (complex m, 1H),
1.19 (m, 1H), 1.04 (s, 9H). 13C NMR (CDCl3, 100 MHz) δ 163.4,
152.6, 148.0, 136.3, 136.0, 134.4, 133.5, 133.2, 130.1, 129.7, 129.6, 127.6,
127.4, 125.6, 117.6, 108.9, 102.0, 101.9, 77.1, 67.4, 49.2, 36.4, 35.3, 33.7,
30.6, 27.0, 19.4. IR (KBr) νmax 3326, 3070, 2930, 2856, 2794, 2249,
1713, 1617, 1504, 1479, 1427, 1392, 1361, 1350, 1273, 1242, 1189, 1111,
1037 cmÀ1. MS (EI, 70 eV) m/z 555 (M+•, 83%), 498 (100), 467 (57),
277 (38), 238 (33), 199 (70), 96 (30), 83 (81). HRMS: M+• calcd for
C33H37NO5Si: 555.2441; found: 555.2441.
ent-Clividine (ent-1). A magnetically stirred solution of pyrroli-
dine 24 (78 mg, 0.14 mmol) in THF (5 mL) maintained under nitrogen
was cooled to 0 °C and then treated with HF pyridine (200 μL)
3
[CAUTION!] and the ensuing mixture allowed to warm to 18 °C, kept
at this temperature for 48 h, treated with NaHCO3 (10 mL of a saturated
aqueous solution), and extracted with dichloromethane (3 Â 10 mL).
The combined organic phases were dried (Na2SO4), filtered, and
concentrated under reduced pressure to yield a brown oil that was
subjected to flash chromatography (silica, 1:19 v/v ammonia saturated
methanol/dichloromethane elution). Concentration of the appropriate
fractions (Rf = 0.7) afforded ent-clividine (ent-1) (44 mg, 99%) as a white
1
crystalline solid, mp 185.4À186.9 °C, [R]D +60.6 (c 1.0, CDCl3). H
NMR (CDCl3, 400 MHz) see Table 1. 13C NMR (CDCl3, 100 MHz) δ
164.8, 151.9, 147.3, 140.4, 117.8, 109.6, 108.0, 101.8, 80.0, 67.1, 66.2,
56.0, 45.2, 43.0, 36.6, 30.1, 29.5. IR (KBr) νmax 3368, 2932, 2772, 1709,
1618, 1502, 1479, 1447, 1385, 1289, 1256, 1237, 1111, 1076, 1027, 934,
751 cmÀ1. MS (EI, 70 eV) m/z 317 (M+•, 25%), 96 (38), 83 (100), 82
(32). HRMS: M+• calcd for C17H19NO5: 317.1263; found: M+•,
317.1264.
N-Chloroamine 23. A magnetically stirred solution of N-methyla-
mine 22 (0.34 g, 0.61 mmol) in dichloromethane (10 mL) maintained
under nitrogen was cooled to À78 °C and then treated, dropwise, with a
solution of NCS (90 mg, 0.67 mmol) in dichloromethane (5 mL). The
ensuing mixture was allowed to warm to 18 °C over 1 h and then
concentrated under reduced pressure to yield a white paste that was
redissolved in ethyl acetate/hexane (10 mL of 1:4 v/v mixture). The
solution thus obtained was passed through a pad of TLC-grade silica that
was washed with ethyl acetate/hexane (200 mL of a 1:4 v/v mixture).
Concentration of the combined filtrates yielded N-chloroamine 23
’ ASSOCIATED CONTENT
S
Supporting Information. Data derived from the single-
b
crystal X-ray analyses of, as well as CIF files for, the oxalate salt of
compound C11b-epi-ent-1, the picrate salt of compound ent-1,
and compounds 6, 10, and 15; H and 13C NMR spectra of
1
compounds ent-1, C11b-epi-ent-1, 5À8, 10, 12À15, and 17À24.
This material is available free of charge via the Internet at http://
pubs.acs.org.
1
(334 mg, 93%) as a white foam, [R]D +7.6 (c 2.0, CDCl3). H NMR
(CDCl3, 400 MHz) δ 7.77 (d, J = 6.2 Hz, 4H), 7.49 (s, 1H), 7.40À7.33
(complex m, 6H), 7.01 (s, 1H), 6.29 (s, 1H), 6.04 (s, 2H), 4.96 (m, 1H),
4.45 (t, J = 3.8 Hz, 1H), 2.95 (s, 3H), 2.84 (t, J = 7.5 Hz, 2H), 1.89À1.81
(complex m, 2H), 1.59 (m, 1H), 1.27À1.17 (complex m, 2H), 1.06
(s, 9H). 13C NMR (CDCl3, 100 MHz) δ 163.4, 152.6, 148.0, 136.3,
136.0, 134.3, 133.4, 133.2, 129.9, 129.6, 129.5, 127.5, 127.4, 125.7, 117.5,
108.9, 102.0, 101.9, 77.0, 67.3, 63.3, 53.1, 33.7, 33.6, 30.3, 27.0, 19.4. IR
(KBr) νmax 2929, 2856, 1713, 1617, 1504, 1478, 1427, 1392, 1361, 1273,
1241, 1187, 1111, 1037 cmÀ1. HRMS: (M + H)+ calcd for C33H36
35ClNO5Si: 590.2130; found: 590.2131.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: mgb@rsc.anu.edu.au
’ ACKNOWLEDGMENT
We thank the Australian Research Council and the Institute of
Advanced Studies for generous financial support.
Pyrrolidine 24. A magnetically stirred solution of N-chloroamine
23 (0.33 g, 0.57 mmol) and AIBN (10 mg, 0.06 mmol) in benzene
(40 mL) maintained under nitrogen was heated at reflux and then
treated, dropwise, with n-Bu3SnH (0.17 mL, 0.63 mmol). Heating of the
ensuing mixture was continued for 1 h, and then it was treated with
additional n-Bu3SnH (38 μL, 0.14 mmol). After being heated for a
further 0.5 h, the reaction mixture was cooled and then concentrated
under reduced pressure and the resulting yellow oil subjected to flash
chromatography (silica, 1:19 v/v ammonia saturated methanol/dichlor-
omethane elution]. Concentration of the appropriate fractions (Rf =
0.85) afforded pyrrolidine 24 (0.26 g, 83%) as a white foam, [R]D À17.6
(c 2.0, CDCl3). 1H NMR (CDCl3, 400 MHz) δ 7.69À7.67 (complex m,
4H), 7.52 (s, 1H), 7.45À7.33 (complex m, 6H), 6.81 (s, 1H), 6.02 (d, J =
1.3 Hz, 1H), 6.01 (d, J = 1.3 Hz, 1H), 4.39 (m, 1H), 3.93 (m, 1H), 3.05
(t, J = 7.9 Hz, 1H), 2.48 (dm, J = 7.4 Hz, 1H), 2.40 (dm, J = 7.5 Hz, 1H),
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