A novel and versatile method for the enantioselective syntheses of tropane alkaloids

Article abstract of DOI:10.1007/s11426-013-4998-2

A full account of the novel and flexible approach to hydroxylated 8-azabicyclo[3,2,1]octan-3-ones and 9-azabicyclo[3,3,1] nonan-3-ones is presented. Using keto-lactams as the starting materials, this two-step method consists of silyl enol ether formation with TBDMSOTf, lactam activation with Tf₂O/DTBMP, and halide-promoted cyclization. Radical dechlorination of the resulting 1-halotropan-3-ones led to the corresponding hydroxylated tropan-3-ones, which can be hydrogenated to yield 3α,6β- dihydroxytropanes. Starting from optically active keto-lactams, the method has been applied to the enantioselective syntheses of (+)-(1S,3S,5R,6S)-pervilleine C (6), (+)-(1S,3R,5S,6R)-valeroidine (3), (+)-(1S,3S,5R,6S)-dibenzoyloxytropane (8), and (+)-(1S,3S,5R,6S)-merredissine (9).

Full text of DOI:10.1007/s11426-013-4998-2

SCIENCE CHINA
Chemistry
February 2014 Vol.57 No.2: 252–264
doi: 10.1007/s11426-013-4998-2
• ARTICLES •
· SPECIAL ISSUE · The Frontiers of Chemical Biology and Synthesis
A novel and versatile method for the enantioselective syntheses of
tropane alkaloids
MAO ZhongYi, HUANG SuYu, GAO LongHui, WANG AiE & HUANG PeiQiang*
Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005, China
Received August 30, 2013; accepted September 17, 2013; published online November 20, 2013
A full account of the novel and flexible approach to hydroxylated 8-azabicyclo[3,2,1]octan-3-ones and 9-azabicyclo[3,3,1]
nonan-3-ones is presented. Using keto-lactams as the starting materials, this two-step method consists of silyl enol ether for-
mation with TBDMSOTf, lactam activation with Tf2O/DTBMP, and halide-promoted cyclization. Radical dechlorination of
the resulting 1-halotropan-3-ones led to the corresponding hydroxylated tropan-3-ones, which can be hydrogenated to yield
3,6-dihydroxytropanes. Starting from optically active keto-lactams, the method has been applied to the enantioselective
syntheses of (+)-(1S,3S,5R,6S)-pervilleine C (6), (+)-(1S,3R,5S,6R)-valeroidine (3), (+)-(1S,3S,5R,6S)-dibenzoyloxytropane (8),
and (+)-(1S,3S,5R,6S)-merredissine (9).
synthetic methods, tropane alkaloids, cyclization, activation, amides
droxytropanes such as ()-Bao Gong Teng A (2), ()-(3S,
6S)-valeroidine (3), and ()-erycibelline, although more and
more dihydroxytropane alkaloids derived from 3,6-tro-
panediol (4) have been isolated in the form of mono- and
diesters [7–12], in addition to polyhydroxytropane alkaloids
(calystegines) [13]. For example, 11 new tropane alkaloids,
pervilleines A-H, pervilleine A N-oxide, and cis-pervilleines
B and F have been isolated from the roots of Erythroxylum
pervillei Baillon collected in southern Madagascar [12].
Among them, pervilleines B, C, and F (5–7) displayed
promising MDR-inhibitory activities [14], and were select-
ed for further development through the RAID (Rapid Ac-
cess to Invention Development) program of the U.S. Na-
tional Cancer Institute [12c]. The bioactivity of this class of
alkaloids has been demonstrated to be highly dependent on
absolute stereochemistry [16a, c]. However, the absolute
configuration of most of the dihydroxytropane alkaloids, e.g.
3,6-dibenzoyloxytropane (8) and merredissine (9), re-
mains unknown [4, 11, 12, 15]. Recently, Perlmutter and
co-workers [7b] reported the first enantioselective synthesis
of pervilleine C, which allowed the confirmation of the
1 Introduction
Tropane alkaloids comprise more than 200 naturally occur-
ring molecules, which are characterized basically by the
N-methyl-8-azabicyclo[3,2,1]octane skeleton [1]. Many of
these alkaloids have found medical applications in ancient
time as well as in modern medicine [1, 2]. Cocaine (1, Fig-
ure 1) is undoubtedly the most well-known member, due to
its remarkable analgesic activity and the associated addic-
tion problem [3a]. The singular structural feature of tropane
alkaloids and their broad spectra of bioactivities (e.g., anal-
gesic, anesthetic, anticholinergic, antiemetic, and antihy-
pertensive) have made them attractive synthetic targets [4].
To date, much effort has been devoted to the total synthesis
of these molecules as well as their analogs [5], and a num-
ber of ingenious synthetic strategies have been reported [5,
6].
Less attention has been paid to the synthesis of dihy-
*Corresponding author (email: pqhuang@xmu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2013
chem.scichina.com link.springer.com

Mao ZY, et al. Sci China Chem February (2014) Vol.57 No.2
253
Figure 1 Structures of some tropane alkaloids.
absolute configuration of this alkaloid as 1S,3S,5R,6S. Nei-
ther the enantioselective synthesis nor the absolute stereo-
chemistry of other members of this subgroup of alkaloids
has ever been reported.
recently been communicated [19], including a novel lactam-
activation-based cyclization reaction for the construction of
the hydroxylated azabicyclo[3,2,1]octan-3-one and 9-azabi-
cyclo[3,3,1]nonan-3-one-ring systems, as well as the con-
version of the former into 6-silyloxytropan-3-one 10b,
3,6-dihydroxytropane 4, and ()-pervilleine B (5). We
report herein the full accounts of this study, which include
the enantioselective syntheses of (+)-pervilleine C (6), ()-
(3S, 6S)-valeroidine (3), ()-(3S,6S)-dibenzoyloxytropane
(8) and ()- merredissine (9). Through this work, the abso-
lute configuration of some of the above alkaloids has been
determined.
In addition, 6S enantiomers of esters of 3,6-dihydroxy-
tropane 4 have been shown to be bioactive analogues of the
muscarinic agonist BGT-A [16], a dihydroxytropane alka-
loid isolated from the Chinese medicinal plant Bao Gong
Teng [8]. Moreover, racemic O-TBDMS-protected 6-
hydroxytropan-3-one (10a) has been used to develop co-
caine antagonists and partial agonists [3]. A so-called 6-
hydroxylated WIN analogue has thus been found to possess
nanomolar potency at the DAT and NET, and micromolar
potency at the SERT in vivo, which means that it is capable
of attenuating cocaine’s locomotor activity (AD50 = 94
mg/kg) [3a]. From the acetate derivative of 10b, ()-6-
acetoxy-nortropane has been developed as a potent and se-
lective M2-receptor agonist with extremely high affinity
(Ki = 2.6 nM) [3b]. Therefore, the development of an enan-
tioselective approach to O-TBDMS-protected 6-hydroxy-
tropan3-one (10a) and 3,6-dihydroxytropane (4) is highly
desirable [17].
In our general program on the asymmetric synthesis of
bioactive alkaloids [18], we have recently reported a novel
enantioselective synthesis of ()-Bao Gong Teng A (2) [7b].
In that work, a highly diastereoselective BF3OEt2/SmI2-
mediated aza-pinacolic cyclization method was developed
for the construction of the hydroxylated tropane skeleton B
from the bifunctional N,O-acetal-aldehyde A (Scheme 1)
[7b]. As a continuation of that study, we set out to explore a
novel enantioselective approach to 6-hydroxytropan-3-one
10b and its homologues. The preliminary results have
2 Experimental
2.1 Materials and methods
Melting points were uncorrected. Infrared spectra were
1
measured using film KBr pellet techniques. H NMR spec-
tra were recorded in CDCl3 with tetramethylsilane as an
internal standard. Chemical shifts are expressed in δ (ppm)
units downfield from TMS. Mass spectra were obtained
using electrospray ionization and an ICR analyzer (ESI-MS)
for high-resolution mass spectra (HRMS). Silica gel
(300400 mesh) was used for flash column chromatography,
eluted (unless otherwise stated) with ethyl acetate/hexane.
Ether and THF were distilled over sodium benzophenone
ketyl under N2. Dichloromethane was distilled over calcium
hydride under N2.
2.2 Synthesis
()-(1S,3S,5R,6S)-Pervilleine C (6)
A suspension of 6-silyloxytropan-3-one (1R,5R,6S)-10a
[19] (16 mg, 0.059 mmol) and PtO2 (8 mg) in EtOH (1 mL)
was stirred at room temperature under 50 atm of hydrogen
for 30 h. The mixture was filtered through a pad of Celite,
and the filtrate was concentrated under reduced pressure.
Scheme 1 Our previous approach to oxygenated tropane skeleton B.

254
Mao ZY, et al. Sci China Chem February (2014) Vol.57 No.2
The residue was dissolved in 1 mL of acetone and p-
toluenesulfonic acid monohydrate (44 mg, 0.236 mmol) was
added to the resulting solution. The mixture was stirred at
50 °C for 2 h. Then saturated aqueous NaHCO3 was added
until pH 8. The solvent was removed under reduced pres-
sure, and the crude product was used in the next step with-
out purification.
aqueous NaHCO3 (3 mL). The organic layers were separat-
ed and the aqueous layer was extracted with EtOAc (3 × 3
mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography (CH2Cl2/MeOH, v/v = 40/1) to give 8 (17
mg, yield: 80% over 3 steps) as a white solid. []2D0
=
To a solution of the crude diol and DMAP (1 mg) in tol-
uene (3 mL) were added Et3N (0.082 mL, 0.59 mmol) and
(E)-3-(3,4,5-trimethoxyphenyl)acryloyl chloride (TmcCl, 81
mg, 0.35 mmol). The reaction mixture was refluxed over-
night. The mixture was cooled down to 0 °C, and quenched
with saturated aqueous NaHCO3 (3 mL). The organic layer
was separated and the aqueous layer extracted with EtOAc
(3 × 3 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by
flash chromatography (CH2Cl2/MeOH, v/v = 40/1) on silica
gel to give (1S,3S,5R,6S)-pervilleine C (6) (33 mg, 90%
over 3 steps) as a white solid. M.p. 55–62 °C (lit. M.p.
+23.0 (c = 0.21, CHCl3) lit. []20 = +26.2 (c = 0.4, CHCl3)}
D
[4d]; IR (film) max: 2930, 2851, 1723, 1661, 1623, 1599,
1
1449, 1317, 1275, 1113, 1067, 1026, 806, 707 cm1; H
NMR (400 MHz, CDCl3)  1.81 (d, J = 15.2 Hz, 1H), 2.06
(d, J = 15.2 Hz, 1H), 2.232.41 (m, 3H), 2.60 (s, 3H), 2.77
(dd, J = 14.1, 7.5 Hz, 1H), 3.39 (br s, 1H), 3.403.45 (m,
1H), 5.34 (t, J = 5.1 Hz, 1H), 5.86 (dd, J = 3.0, 7.5 Hz, 1 H),
7.407.60 (m, 6H), 8.008.05 (m, 2H), 8.078.12 (m, 2H);
13C NMR (100 MHz, CDCl3)  33.2, 34.7, 36.2, 40.1, 59.9,
65.9, 67.6, 80.1, 128.4, 128.6, 129.51, 129.53, 130.36,
130.41, 132.9, 133.0, 165.7, 166.4; HRMS (ESI) calcd for
C22H23NO4 [M + H+]: 366.1700; found: 366.1700.
53–57 °C) [12a]; []2D0 = +30 (c = 0.1, CHCl3) {lit. []20 =
D
()-(1S,3S,5R,6S)-Merredissine (9)
+29 (c 0.1, CHCl3)} [12a]; IR (film) max: 2937, 2848, 1702,
To a solution of 10a (16 mg, 0.059 mmol) in EtOH (1 mL),
PtO2 (8 mg) was added. The suspension was stirred at room
temperature under 50 atm of hydrogen for 30 h. The mix-
ture was filtered through a pad of Celite, and the filtrate was
concentrated under reduced pressure. Then the crude prod-
uct was dissolved in 1 mL acetone and was added
p-toluenesulfonic acid monohydrate (44 mg, 0.236 mmol).
The mixture was stirred at 50 °C for 8 h. Then saturated
aqueous NaHCO3 was added until pH 8. The solvent was
removed under reduced pressure, and the crude product was
used in the next step without purification.
1633, 1582, 1504, 1454, 1418, 1336, 1309, 1275, 1244,
1
1169, 1151, 1126, 1056, 1038, 1005, 826, 750 cm1; H
NMR (400 MHz, CDCl3)  1.69 (d, J = 15.2 Hz, 1H), 1.90
(d, J = 15.2 Hz, 1H), 2.322.18 (m, 3H), 2.59 (s, 3H), 2.72
(dd, J = 14.0, 7.6 Hz, 1H), 3.31 (br s, 1H), 3.39 (m, 1H),
3.963.87 (m, 18H), 5.21 (t, J = 4.8 Hz, 1H), 5.73 (dd, J =
7.2, 2.8 Hz, 1H), 6.35 (d, J = 16.0 Hz, 1H), 6.38 (d, J = 16.0
Hz, 1 H), 6.74 (s, 2H), 6.88 (s, 2H), 7.56 (d, J = 16.0 Hz,
1H), 7.71 (d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
 31.1, 32.5, 37.0, 38.4, 56.1, 56.2, 59.1, 60.9, 64.9, 67.0,
79.3, 105.2, 105.5, 117.4, 117.6, 129.77, 129.82, 140.2,
144.6, 145.2, 153.4, 165.9, 166.8; MS (ESI) m/z 598 (M +
H+, 100%). HRMS (ESI) calcd for C32H39NO10 [M + H+]:
598.2647; found: 598.2658.
To a solution of the crude diol and DMAP (1 mg) in tol-
uene (3 mL), Et3N (0.082 mL, 0.59 mmol) and p-anisoyl
chloride (81 mg, 0.35 mmol) were added. The reaction
mixture was refluxed overnight. After the reaction was fin-
ished, the mixture was cooled down to 0 °C and quenched
with saturated aqueous NaHCO3 (3 mL). The organic layers
were separated and the aqueous layer was extracted with
EtOAc (3 × 3 mL). The combined organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified
by flash chromatography (CH2Cl2/MeOH, v/v = 40/1) to
()-(1S,3S,5R,6S)-3α,6β-Dibenzoyloxytropane (8)
To a solution of 10a (16 mg, 0.059 mmol) in EtOH (1 mL),
PtO2 (8 mg) was added. The suspension was stirred at room
temperature under 50 atm of hydrogen for 30 h. The mix-
ture was filtered through a pad of Celite, and the filtrate was
concentrated under reduced pressure. Then the crude prod-
uct was dissolved in the 1 mL acetone then added p-toluene-
sulfonic acid monohydrate (44 mg, 0.236 mmol) to the so-
lution. The mixture was stirred at 50 °C for 8 h. Then satu-
rated aqueous NaHCO3 was added until pH 8. The solvent
was removed under reduced pressure, and the crude product
was used in the next step without purification.
To a solution of crude diol and DMAP (1 mg) in toluene
(3 mL), Et3N (0.082 mL, 0.59 mmol) and benzoyl chloride
(81 mg, 0.35 mmol) were added. The reaction mixture was
refluxed overnight. After reaction was finished, the mixture
was cooled down to 0 °C and quenched with saturated
give 9 (21 mg, 83% over 3 steps) as a white solid. []2D0
=
+27.7 (c = 0.1, CHCl3) []20 = +44.0 (c = 0.5, MeOH) lit.
D
[]2D0 = 8.6 (c = 0.2, MeOH)} [15]; IR (film) max: 2928,
2850, 1707, 1606, 1510, 1481, 1421, 1350, 1256, 1168,
1
1104, 1032, 848 cm1; H NMR (400 MHz, CDCl3)  1.81
(d, J = 15.0 Hz, 1 H), 2.05 (d, J = 15.0 Hz, 1 H), 2.232.39
(m, 3 H), 2.61 (s, 3 H), 2.77 (dd, J = 14.1, 7.7 Hz, 1 H),
3.39 (br s, 1 H), 3.403.45 (m, 1 H), 3.86 (s, 3 H), 3.87 (s, 3
H), 5.31 (t, J = 4.9 Hz, 1 H), 5.85 (dd, J = 3.0, 7.5 Hz, 1 H),

Mao ZY, et al. Sci China Chem February (2014) Vol.57 No.2
255
6.92 (d, J = 8.8Hz, 2 H), 6.98 (d, J = 8.8 Hz, 2 H), 7.99 (d,
J = 8.8 Hz, 2 H), 8.06 (d, J = 8.8 Hz, 2 H); 13C NMR (100
MHz, CDCl3)  33.1, 34.6, 36.2, 40.0, 55.3, 55.4, 60.0, 65.8,
67.0, 79.6, 113.6, 113.8, 122.7, 122.8, 131.47, 131.49,
163.3, 163.4, 165.4, 166.1; HRMS (ESI) calcd for
C24H27NO6 [M + H+]: 426.1911; found: 426.1910.
171.2, 171.5; MS (ESI) m/z 196 (M + Na+, 100%); HRMS
(ESI) calcd for C7H11NO4 [M + Na+]: 196.0586; found:
196.0580.
(2R,3R)-1-Methyl-5-oxopyrrolidine-2,3-diyl diacetate (32)
To an ice-bath-cooled solution of (2R, 3R)-31 (2.00 g, 11.56
mmol) in CH2Cl2 (50 mL), DMAP (cat.), Ac2O (3.3 mL,
34.68 mmol), and Et3N (4.8 mL, 34.68 mmol) were succes-
sively added. After stirring overnight at room temperature,
the reaction was quenched with saturated aqueous NaHCO3
(15 mL) and water (15 mL) at 0 °C. The organic layer was
separated and the aqueous layer was extracted with EtOAc
(3 × 30 mL). The combined organic layers were washed
with brine (2 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel eluted with
EtOAc/PE (v/v = 1:2) to afford compound (2R,3R)-32
(R)-1-Methyl-2,5-dioxopyrrolidin-3-yl acetate (30)
To a stirred solution of (R)-malic acid (67 g, 500 mmol) in
350 mL of toluene, 49 mL of 40% aqueous CH3NH2 was
added. After stirring for 0.5 h, the mixture was heated to
reflux in flask equipped with a Dean-Stark trap and 46 mL
of H2O was collected over a 48 h period. EtOH (150 mL)
was added, the mixture was concentrated, and the residue
was distilled to give the desired imide (50.5 g, 78%). To an
ice-bath cooled solution of imide (12.9 g, 100 mmol) in
CH2Cl2 (200 mL) were successively added DMAP (cat.),
Ac2O (18.8 mL, 200 mmol), and Et3N (34.9 mL, 250 mmol).
After stirring overnight at room temperature, the reaction
was quenched with saturated aqueous NaHCO3 (30 mL) and
water (30 mL) at 0 °C. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (3 × 40 mL).
The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chro-
matography on silica gel eluted with EtOAc/PE (v/v = 1:2)
to afford compound 30 (14.2 g, 83%) as a colorless oil.
(3.35 g, 93%) as a colorless oil. []2D0 = +74 (c = 1.0,
CHCl3); IR (film) max: 2937, 1750, 1719, 1380, 1236, 1084,
1
1003 cm1; H NMR (500 MHz, CD3CN)  2.03 (s, 3H),
2.07 (s, 3H), 2.49 (dd, J = 16.7, 8.3 Hz, 1H), 2.63 (dd, J =
16.7, 8.3 Hz, 1H), 2.79 (s, 3H), 5.34 (dt, J = 5.4, 8.3 Hz,
1H), 6.25 (d, J = 5.4 Hz, 1H); 13C NMR (125 MHz, CD3CN)
 20.7, 20.9, 27.9, 34.3, 66.8, 84.3, 170.9, 171.4, 172.2; MS
(ESI) m/z 238 (M + Na+, 100%); HRMS (ESI) calcd for
C9H13NO5 [M + Na+]: 238.0691; found: 238.0689.
[]2D0 = +24 (c = 1.0, CHCl3) IR (film) max: 2953, 1750,
(2R/S,3R)-1-Methyl-5-oxo-2-(2-oxopropyl)pyrrolidin-3-
ylacetate (33)
1
1707, 1438, 1384, 1224, 1127, 1030 cm1; H NMR (500
MHz, CDCl3)  2.13 (s, 3H), 2.63 (dd, J = 18.3, 4.6 Hz, 1H),
3.01 (s, 3H), 3.14 (dd, J = 18.3, 8.7 Hz, 1H), 5.43 (dd, J =
8.7, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)  20.4, 24.9,
35.7, 67.4, 169.7, 173.2, 173.5; MS (ESI) m/z 194 (M + Na+,
100%); HRMS (ESI) calcd for C7H9NO4 [M + Na+]:
194.0429; found: 194.0426.
To an ice-bath-cooled solution of (2R, 3R)-32 (800 mg, 3.73
mmol) and trimethyl(prop-1-en-2-yloxy)silane (0.9 mL,
5.60 mmol) in anhydrous CH2Cl2 (18 mL), TIPSOTf (0.094
mL, 0.37 mmol) was added. After stirring for 1 h at 0 °C,
the reaction was stirred for 3 h at room temperature and
then quenched with saturated aqueous NaHCO3 solution (5
mL). The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (3 × 5 mL). The combined or-
ganic layers were washed with brine (2 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography
on silica gel eluted with EtOAc to afford compound 33 (756
mg, 95%) as an inseparable diastereomeric mixture in a
(2R,3R)-2-Hydroxy-1-methyl-5-oxopyrrolidin-3-yl acetate
(31)
To a cold solution (40 °C) of (R)-imide 30 (2.00 g, 11.7
mmol) in THF (150 mL), NaBH4 (0.667 g, 17.55 mmol)
was added in one portion. The resulting mixture was stirred
at 40 °C for 15 min and saturated aqueous NaHCO3 (20 mL)
was slowly added. After being stirred for 30 min, the mix-
ture was filtered through silica gel. The filtrate was concen-
trated under reduced pressure and then EtOAc was added.
The solid was filtrated and washed with EtOAc to afford
compound (2R,3R)-31 (0.985 g, 81%) as a white solid. M.p.
ratio of 2.5:1 (1H NMR) as a colorless oil. IR (film) max
:
1
2929, 1734, 1687, 1403, 1372, 1232, 1166, 1030 cm1; H
NMR (500 MHz, CDCl3, two diastereomers, major
(M)/minor (m) = 2.5:1, data read from the spectrum of the
diastereomeric mixture) H 1.98 (s, 0.9H, m), 2.02 (s, 2.1H,
M), 2.16 (s, 2.1H, M), 2.18 (s, 0.9H, m), 2.292.37 (m, 1H,
M + m), 2.672.85 (m, 6H, M + m), 3.813.85 (m, 0.7H,
M), 4.184.24 (m, 0.3H, m), 4.914.96 (m, 0.7H, M),
5.345.40 (m, 0.3H, m); 13C NMR (125 MHz, CDCl3)
114116 °C (EtOAc); []2D0 = +22 (c = 0.5, CHCl3); IR
(film) max: 3186, 2933, 1727, 1660, 1434, 1384, 1341,
1
1240, 1073 cm1; H NMR (500 MHz, CD3CN)  2.07 (s,
3H), 2.43 (dd, J = 17.1, 6.5 Hz, 1H), 2.57 (dd, J = 17.1, 8.0
Hz, 1H), 2.78 (s, 3H), 3.99 (d, J = 8.2 Hz, 1H), 5.12 (dd, J =
8.2, 5.3 Hz, 1H), 5.16 (ddd, J = 8.0, 6.5, 5.3 Hz, 1H); 13C
NMR (125 MHz, CDCl3)  20.9, 27.0, 35.1, 68.7, 83.8,
C(major) 20.9, 27.8, 30.5, 36.5, 44.0, 62.2, 71.6, 170.5, 171.6,
204.9; C(minor) 20.6, 27.5, 30.3, 37.3, 40.9, 57.7, 67.9, 169.6,
171.6, 204.9; MS (ESI) m/z 236 (M + Na+, 100%); HRMS

256
Mao ZY, et al. Sci China Chem February (2014) Vol.57 No.2
(ESI) calcd for C10H15NO4 [M + Na+]: 236.0899; found:
236.0903.
and imidazole (240 mg, 3.51 mmol) in anhydrous THF (8
mL), a THF solution of TBDMSCl (352 mg, 2.34 mmol)
was added. After being stirred for 2 days at room tempera-
ture, the reaction was quenched with saturated aqueous
NaHCO3 (5 mL). The organic layer was separated and the
aqueous layer was extracted with EtOAc (3 × 5 mL). The
combined organic layers were washed with brine (2 mL),
dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel eluted with EtOAc/PE (v/v =
1:1) to afford compound 36 (306 mg, 92%) as a colorless oil.
(2S/R,3aR,6aR)-Ethoxy-2,4-dimethyltetrahydro-2H-furo[3,2-
b]pyrrol-5(3H)-one (34) and (4R,5S)-4-hydroxy-1-methyl-
5-(2-oxopropyl)pyrrolidin-2-one (35)
To an ice-bath-cooled solution of 33 (343 mg, 1.61 mmol)
in anhydrous ethanol (6 mL), dropwise acetyl chloride (0.28
mL, 4.03 mmol) was added. After stirring for 1 h at 0 °C,
the reaction was stirred overnight at room temperature. The
solution was neutralized with solid NaHCO3 until pH 7,
filtered, and concentrated under reduced pressure. The resi-
due was purified by flash chromatography on silica gel
eluted with EtOAc to afford compound 35 (185 mg, 67%)
as a single isomer, and diastereomeric mixture 34 (90 mg,
28%) in a ratio of 1.3:1 (1H NMR), which is only partly
separable by flash chromatography.
[]2D0 = 4 (c = 1.0, CHCl3); IR (film) max: 2953, 2929,
1
2851, 1692, 1396, 1360, 1256, 1080, 1061 cm1; H NMR
(400 MHz, CDCl3)  0.07(s, 6H), 0.87 (s, 9H), 2.202.28
(m, 4H), 2.50 (dd, J = 17.3, 7.7 Hz, 1H), 2.63 (dd, J = 17.0,
6.2 Hz, 1H), 2.73 (dd, J = 17.3, 5.2 Hz, 1H), 2.78 (s, 3H),
3.78 (ddd, J = 7.7, 5.2, 2.5 Hz, 1H), 4.05 (dt, J = 6.2, 2.5 Hz,
1H); 13C NMR (100 MHz, CDCl3)  4.8, 17.9, 25.6, 27.9,
30.6, 40.0, 44.3, 65.2, 70.3, 172.5, 205.4; MS (ESI) m/z 308
(M + Na+, 100%); HRMS (ESI) calcd for C14H27NO3Si [M
+ Na+]: 308.1658; found: 308.1653.
Compound 35: white solid. M.p. 5861 °C (EtOAc);
[]2D0 = +53.4 (c = 1.0, CHCl3); IR (film) max: 3393, 2929,
1
1711, 1672, 1365, 1248, 1162, 1034 cm1; H NMR (400
MHz, CDCl3)  2.23 (s, 3H), 2.38 (dd, J = 17.3, 3.7 Hz, 1H),
2.51 (dd, J = 18.2, 9.7 Hz, 1H), 2.71 (dd, J = 17.3, 8.3 Hz,
1H), 2.77 (s, 3H), 2.98 (dd, J = 18.2, 4.0 Hz, 1H), 3.61 (d, J
= 2.8 Hz, 1H), 3.73 (ddd, J = 9.7, 4.0, 2.9 Hz, 1H), 4.07 (m,
1H); 13C NMR (125 MHz, CDCl3)  27.7, 30.6, 38.8, 45.3,
64.7, 70.2, 172.6, 207.2; MS (ESI) m/z 194 (M + Na+,
100%); HRMS (ESI) calcd for C8H13NO3 [M + Na+]:
194.0793; found: 194.0795.
(1R,5S,6R)-6-(tert-Butyldimethylsilyloxy)-1-chloro-8-methyl-
8-azabicyclo[3.2.1]octan-3-one (37)
To a cooled (0 °C) solution of compound 36 (888 mg, 3.12
mmol) in anhydrous CH2Cl2 (16 mL) were added the Et3N
(1.08 mL, 7.8 mmol) and TBSOTf (1.43 mL, 6.24 mmol).
After being stirred at 0 °C for 1 h, the reaction mixture was
allowed to warm to room temperature and stirred overnight.
Then the mixture was quenched with saturated aqueous
NaHCO3 (15 mL) and extracted with CH2Cl2 (3 × 15 mL).
The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated to give
an orange residue, which was used in the next step without
purification. The crude product and 2,6-di-tert-butyl-4-me-
thylpyridine (959 mg, 4.68 mmol) were dissolved in anhy-
drous CH2Cl2 (30 mL) and cooled to 78 °C, then Tf2O
(0.62 mL, 3.74 mmol) was added dropwise. After stirring at
the same temperature for 40 min, a solution of ZnCl2 (3.2
mL, 3.2 mmol, 1 M in Et2O) was added dropwise. The reac-
tion mixture was stirred at 78 °C for 1 h, then the mixture
was warmed to room temperature slowly and kept stirred
for 1 h. The reaction was quenched with saturated aqueous
NaHCO3 (15 mL) and extracted with CH2Cl2 (3 × 15 mL).
The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated to give a
brown oil, which was purified by flash chromatography
(eluent: EtOAc/PE, v/v = 1/12) to give the desired product
37 as a white solid (607 mg, 65% over two steps). M.p.
34-Major diastereomer: colorless oil. []2D0 = +12 (c =
0.5, CHCl3); IR (film) max: 2980, 2929, 1660, 1438, 1400,
1259, 1217, 1150, 1045 cm1; 1H NMR (400 MHz, CD3CN)
 1.12 (t, J = 7.0 Hz, 3H), 1.42 (s, 3H), 1.82 (dd, J = 13.5,
4.1 Hz, 1H), 2.28 (dd, J = 13.5, 7.8 Hz, 1H), 2.35 (d, J =
18.0 Hz, 1H), 2.62 (dd, J = 18.0, 7.0 Hz, 1H), 2.73 (s, 3H),
3.433.53 (m, 2H), 4.23 (ddd, J = 7.8, 6.0, 4.1 Hz, 1H),
4.554.58 (m, 1H); 13C NMR (100 MHz, CD3CN)  16.0,
22.1, 28.1, 38.1, 44.1, 56.9, 65.8, 75.1, 109.1, 173.7; MS
(ESI) m/z 222 (M + Na+, 100%); HRMS (ESI) calcd for
C10H17NO3 [M + Na+]: 222.1106; found: 222.1103.
34-Minor diastereomer: colorless oil. []2D0 = 78 (c =
0.5, CHCl3); IR (film) max: 2976, 2933, 1680, 1440, 1310,
1
1256, 1154, 1041 cm1; H NMR (400 MHz, CD3CN) 
1.00 (t, J = 7.1 Hz, 3H), 1.40 (s, 3H), 1.80 (dd, J = 14.1, 6.7
Hz, 1H), 2.26 (d, J = 17.9 Hz, 1H), 2.31 (d, J = 14.1 Hz,
1H), 2.57 (dd, J = 17.9, 7.7 Hz, 1H), 2.72 (s, 3H), 3.373.48
(m, 2H), 4.22 (dd, J = 6.7, 6.7 Hz, 1H), 4.74–4.78 (m, 1H);
13C NMR (100 MHz, CD3CN)  15.7, 22.4, 28.1, 40.0, 41.6,
57.1, 65.6, 76.8, 109.1, 173.1; MS (ESI) m/z 222 (M + Na+,
100%); HRMS (ESI) calcd for C10H17NO3 [M + Na+]:
222.1106; found: 222.1102.
5658 C (EtOAc/ PE); []2D0 = +24 (c = 1.0, CHCl3); IR
(film) max: 3412, 2952, 2925, 2855, 1711, 1598, 1462,
1
1252, 1112 cm1; H NMR (400 MHz, CDCl3)  0.04 (s,
(4R,5S)-4-(tert-Butyldimethylsilyloxy)-1-methyl-5-(2-oxo-
propyl)pyrrolidin-2-one (36)
6H), 0.86 (s, 9H), 2.102.15 (m, 1H), 2.332.38 (m, 1H),
2.582.70 (m, 6H), 3.00 (dd, J = 15.9, 2.9 Hz, 1H), 3.51 (m,
To an ice-bath-cooled solution of 35 (200 mg, 1.17 mmol)

Mao ZY, et al. Sci China Chem February (2014) Vol.57 No.2
257
1H), 3.84 (dd, J = 7.4, 3.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3)  4.8, 4.7, 18.2, 25.8, 30.6, 39.1, 52.3, 52.5, 66.8,
72.4, 85.7, 204.4; HRMS (ESI) calcd for C14H26ClNO2Si [M
+ Na+]: 326.1319 and 328.1290; found: 326.1322 and
328.1292.
39.4, 40.6, 44.1, 60.6, 66.7, 68.9, 171.9; HRMS (ESI) calcd
for C19H37NO3Si [M+H+]: 356.2615; found: 356.2616.
)-(1S,3R,5S,6R)-Valeroidine (3)
Compound 39 (24 mg, 0.072 mmol) was dissolved in 2 mL
acetone and was added to p-toluenesulfonic acid monohy-
drate, (53 mg, 0.280 mmol). The mixture was stirred at
50 °C for 24 h. Then saturated aqueous NaHCO3 was added
until pH 8. The solvent was removed under reduced pres-
sure, and the residue was purified by flash chromatography
(CH2Cl2/MeOH, v/v = 10/1) to give (+)-valeroidine (+)-3
(10 mg, 61%) as a white solid. M.p. 84 °C (lit. M.p. 80 °C)
(1S,5S,6R)-6-(tert-Butyldimethylsilyloxy)-8-methyl-8-aza-
bicyclo[3.2.1]octan-3-one (38)
To a solution of 1-chlorotropane derivative 37 (300 mg,
0.99 mmol) and ACCN (290 mg, 1.19 mmol) in anhydrous
toluene (5 mL), Bu3SnH (0.79 mL, 2.97 mmol) was added
and the mixture was stirred at 85 C for 5 h. After removing
the solvent under reduced pressure, the residue was purified
by flash chromatography on silica gel (EtOAc/ PE, v/v = 1/4)
[9b]; []2D0 = +8.0 (c = 1.0, EtOH); lit. []2D0 = 9.1 (c =
2.0, EtOH) [9b, d]; IR (film) max: 3386, 2957, 2931, 2871,
1731, 1467, 1427, 1370, 1293, 1261, 1189, 1168, 1120,
1095, 1038, 1002, 939, 798, 741 cm1; 1H NMR (400 MHz,
CDCl3)  0.96 (d, J = 6.5 Hz, 6H), 1.54 (d, J = 15.6 Hz,
1H), 1.69 (d, J = 15.6 Hz, 1H), 1.982.20 (m, 4H),
2.222.35 (m, 2H), 2.582.70 (m, 4H), 3.04 (br s, 1H), 3.22
(br s, 1H), 3.403.47 (m, 1H), 4.60 (dd, J = 2.6, 7,5 Hz, 1H),
5.03 (t, J = 5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) 
22.4, 25.7, 28.7, 30.2, 36.4, 40.7, 44.0, 58.2, 66.8, 67.0,
76.1, 172.1; MS (ESI) m/z 242 (M + H+, 100%).
to give 38 (208 mg, yield: 80%) as a colorless oil. []2D0
=
22 (c = 1.0, CHCl3); IR (film) max: 2952, 2935, 2856,
1717, 1471, 1255, 1115, 1079, 869, 838, 776 cm1;
1H NMR (400 MHz, CDCl3)  0.04 (s, 6H), 0.86 (s, 9H),
2.012.16 (m, 3H), 2.22 (ddd, J = 1.9, 1.9 15.9 Hz, 1H),
2.602.69 (m, 5H), 3.303.35 (m, 1H), 3.563.62 (m, 1H),
4.12 (dd, J = 3.4, 6.9 Hz, 1H); 13C NMR (100 MHz, CDCl3)
 4.82, 4.81, 18.1, 25.8, 38.2, 41.3, 44.4, 46.3, 60.8, 69.5,
77.0, 208.6; HRMS (ESI) calcd for C14H27NO2Si [M + H+]:
270.1884; found: 270.1880.
(1R,3R,5S,6R)-6-(tert-Butyldimethylsilyloxy)-8-methyl-8-
azabicyclo[3.2.1]octan-3-yl 3-methylbutanoate (39)
3 Results and discussion
To a solution of 38 (104 mg, 0.39 mmol) in EtOH (4 mL),
PtO2 (52 mg) was added. The suspension was stirred at
room temperature under 50 atm of hydrogen for 30 h. The
mixture was filtered through a pad of Celite, and the filtrate
was concentrated under reduced pressure to give crude
product which was used in the next step without purifica-
tion.
On the basis of our recent interest in the development of
amides/lactams as reliable and easily available functional
groups for CC bond formation reactions [20], we envis-
aged that it would be advantageous to use a ketone-lactam
combination (C) to build the hydroxytropan-3-one-ring
system D or E (Scheme 2). The compatibility of silyl enol
ethers with the conditions for amides/lactam activation has
been nicely demonstrated by Bélanger and co-workers [21];
keto-lactams C are easily available from enantiomerically
pure chiral pools such as malic acid and tartaric acid [22].
The hydroxytropanones D or hydroxytropanes E could
serve as readily available precursors for the enantioselective
synthesis of many tropane alkaloids.
For the lactam-activation-based intramolecular cycliza-
tion reaction, the easily available racemic keto-lactam 11
was selected as a model compound. A TBDMSOTf/NEt3
system was used for silyl enol ether formation and the re-
sulting regioisomeric mixture [SEE1a (terminal): SEE1b
(internal) = 6.4:1] was used directly for the cyclization reac-
tion under the previously established lactam activation con-
ditions [20a, 23]. However, no desired product was ob-
served (Table 1, Entry 1) when a CH2Cl2 solution of silyl
enol ether-lactams SEE1a,b (1.0 equiv) was treated succes-
sively with DTBMP (1.2 equiv), triflic anhydride (Tf2O, 1.2
equiv) at 78 °C [24]. Addition of a Lewis acid such as
BF3OEt2 or TMSOTf did not yield any product. (Table 1,
entries 2, 3). However, use of 1.0 equiv of TMSCl as a
To a solution of crude alcohol in anhydrous CH2Cl2 (4
mL), Et3N (0.107 mL, 0.77 mmol) and isovaleryl chloride
(56 mg, 0.464 mmol) were added. The reaction mixture was
stirred overnight. Then the reaction was quenched with sat-
urated aqueous NaHCO3 (3 mL). The organic layers were
separated and the aqueous layer was extracted with CH2Cl2
(3 × 3 mL). The combined organic layer was washed with
brine, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by
flash chromatography (CH2Cl2/MeOH, v/v = 20/1) to give
compound 39 (91 mg, 66% over 2 steps) as a colorless oil.
[]2D0 = 1.5 (c = 1.0, CHCl3); IR (film) max: 2955, 2931,
2856, 1733, 1463, 1293, 1250, 1188, 1080, 1040, 1006, 963,
876, 836, 775 cm1; 1H NMR (400 MHz, CDCl3)  0.06 (d,
J = 2.0 Hz, 6H), 0.89 (s, 9H), 0.98 (d, J = 6.5 Hz, 6H), 1.59
(d, J = 15.2 Hz, 1H), 1.71 (d, J = 15.2 Hz, 1H), 2.032.24
(m, 6H), 2.56 (dd, J = 7.2, 13.5 Hz, 1H), 2.60 (s, 3H), 3.06
(br s, 1H), 3.323.39 (m, 1H), 4.63 (dd, J = 2.8, 7,2 Hz, 1H),
5.00 (t, J = 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) 
4.91, 4.87, 18.0, 22.45, 22.46, 25.76, 25.79, 33.5, 34.8,

258
Mao ZY, et al. Sci China Chem February (2014) Vol.57 No.2
the cyclization of silyl enol ether-lactams SEE1a,b were
established as: Tf2O (1.2 equiv), DTBMP (1.2 equiv), and
ZnCl2 or ZnBr2 (1.01.2 equiv).
The lactam-activation-based cyclization reactions of oth-
er keto-lactams were then investigated. All the silyl enol
ethers were formed as regioisomeric mixtures, which were
subjected to the cyclization conditions without separation.
The results are summarized in Table 2. The results listed in
Table 2 indicate that only the 6-(enolendo)-endo-trig cy-
clization [25] of the terminal silyl enol ether SEE1a (Table
2, entry 1) occurred while the 4-(enolexo)-endo-trig cy-
clization product of the internal silyl enol ether SEE1b (12b)
was not observed. Cyclization of SEE2a,b led only to trace
of 7-(enolendo)-endo-trig and 5-(enolexo)-endo-trig cy-
clization products (16a and 16b), the structures of which are
Scheme 2 A new approach to oxygenated tropane skeletons.
Table 1 Screening of reaction conditions for the cyclization of silyl enol
ethers SEE1a,b
1
tentatively suggested on the basis of H NMR data of mix-
tures (Entry 2). Cyclization of silyl enol ethers SEE3a,b
(Table 2, Entry 3) led only to the formation of the 8-azabi-
cyclo[3,2,1]octane ring system 18b; in other words, only the
6-(enolexo)-endo-trig cyclization of the internal silyl enol
ether SEE3b occurred. Compound 18b was isolated as a
single diastereomer in 75% yield based on SEE3b, whose
stereochemistry at C2 could not be determined without
Entry
1
Lewis acid (equiv)
none
Product (% yield) a)
0
2
BF3·Et2O (1.0)
TMSOTf (1.0)
TMSCl (1.0)
TiCl4 (1.0)
0
3
0
4
12a (12)
0
1
ambiguity by H NMR due to the overlap of the peaks.
5
Subjection of the regioisomeric mixture SEE4a,b (ratio =
3.8:1, generated from keto--lactam 19) to the cyclization
conditions produced the 6-(enolendo)-endo-trig cyclization
reaction of the terminal silyl enol ether SEE4a––namely,
the 9-azabicyclo[3,3,1]nonan-3-one ring system 20a in 65%
yield (entry 4). These results implied that only six-mem-
bered bridged ring systems could be formed in synthetically
useful yields.
The cyclization reactions of the enantiomeric ketolac-
tams 21 (cis-diastereomer) and 23 (trans-diastereomer), eas-
ily available from (S)-malic acid, was also investigated. The
reaction of keto-lactam 21 with TMSOTf (NEt3, CH2Cl2)
yielded the terminal silyl enol ether SEE5a in excellent
regioselectivity (> 20:1), which upon being treated with
Tf2O, DTBMP, and ZnBr2, cyclized to produce the
1-bromotropan-3-one 22a in 50% yield from keto-lactam 21
(Table 2, Entry 5). For trans-keto-lactam 23, the terminal
silyl enol ether SEE6a also formed in excellent regioselec-
tivity, which was subjected to the cyclization conditions to
give the expected 1-bromotropan-3-one 24a in 23% yield
from 23, along with the tetracyclic compound 24b in a yield
of 30% from 23. The formation of compound 24b can be
attributed to a favorable disposition of the benzyloxy group
toward a Friedel-Crafts type reaction with the in situ formed
iminium intermediate [26].
6
AlCl3 (1.0)
12a (27)
12a (41)
13 (67)
13 (77)
12a (86)
12a (88)
12a (67)
12a (40)
12a (14)
13 (50)
0
7
SnCl4 (1.0)
MgBr2 (1.0)
ZnBr2 (1.2)
ZnCl2 (1.2)
ZnCl2 (1.0)
ZnCl2 (0.5)
ZnCl2 (0.25)
ZnCl2 (0.1)
n-Bu4NBr (1.0)
ZnBu2 (1.0)
8
9
10
11
12
13
14
15
16
a) Isolate yield calculated based on the terminal silyl enol ether (major
regioisomer, ratio determined by 1H NMR).
Lewis acid produced a cyclization product (12a) bearing a
chlorine atom at the bridgehead carbon in 12% yield (Table
1, Entry 4). Other halide-containing Lewis acids were thus
investigated. As can be seen from Table 1, while the reac-
tion failed with TiCl4, use of AlCl3 and SnCl4 yielded com-
pound 12a in improved yields (27% and 41% respectively,
entries 57). Respectable yields (67% and 77%) of
1-bromotropan-3-one 13 were obtained when MgBr2 or
ZnBr2 was used (entries 8, 9). With the use of 1.01.2 equiv
of ZnCl2 higher than 86% yield (based on the major regioi-
somer of the silyl enol ether SEE1a) was obtained (entries
10, 11). Lower yield was obtained when less than 1.0 equiv
of ZnCl2 was used (Table 1, entries 1214). Use of
n-Bu4NBr also led to 13 in 50% yield (entry 15). The key
role of the halide ion in promoting the cyclization was fur-
ther demonstrated by the use of dibutyl zinc, which failed to
promote the reaction (entry 16). The optimal conditions for
Although much investigation has been devoted to the
chemistry of N--halo-azabicycles, to the best of our know-
ledge, 1-halo-N-alkyl-8-azabicyclo[3,2,1]octanes have not
been investigated. Most of the known 1-halotropanes (-
halo-amines) exhibited remarkable reactivity toward nucle-

Mao ZY, et al. Sci China Chem February (2014) Vol.57 No.2
259
Table 2 Lactam activation-based cyclization reaction of keto-lactams via silyl enol ethers (SEEs)
Entry
Keto-lactam
Silyl enol ether c)
Cyclization mode/Product (Yield) d)
6-(enolendo)-endo-trig
4-(enolexo)-endo-trig
1a)
11
SEE1a,b (6.4:1, 90%)
12b (no observed)
12a (88%)
7-(enolendo)-endo-trig
5-(enolexo)-endo-trig
2 a)
3a)
4a)
15
SEE2a,b (1.3:1, 84%)
SEE3a,b (1.4:1, 81%)
SEE4a,b (3.8:1, 40%)
16a (trace)
16b (trace)
6-(enolexo)-endo-trig
8-(enolendo)-endo-trig
18b (75%)
single isomer
17
18a (no observed)
6-(enolendo)-endo-trig
4-(enolexo)-endo-trig
O
Cl
N
Bn
O
N
O
Bn
19
20b (no observed)
20a (65%)
6-(enolendo)-endo-trig
4-(enolexo)-endo-trig
5 b)
SEE5a,b (> 20:1)
21
22b (no observed)
22a (50% from 21)
6-(enolendo)-endo-trig
6 b)
23
SEE6a,b (> 20:1)
24a (23% from 23)
24b (30% from 23)
a) Method A: (1) TBDMSOTf, Et3N, CH2Cl2, 0°C; (2) Tf2O, DTBMP, ZnCl2, 78 °C~ rt. b) Method B: (1) TMSOTf, Et3N, CH2Cl2, 0 °C; (2) Tf2O,
DTBMP, ZnBr2, 78 °C~ rt. c) Regioisomeric ratio determined by 1H NMR. d) Isolated yield.
ophiles such as LiAlH4 [27]. However, in our case, 1-chloro-
N-methyl-8-azabicyclo[3,2,1]octane exhibited unusual sta-
bility. Attempts to cleave the CX bond by reacting with
LiAlH4 failed. We next tried the radical reactions. After
unsuccessful attempts with SmI2 and Li/THF, radical
dechlorination with AIBN/Bu3SnH was tried. Thus, heating
a mixture of 12a, AIBN (1.2 equiv) and Bu3SnH (2.0 equiv)
in toluene at 80 C for 3 h produced the desired product 25
in 35%, along with a substantial amount of recovered start-
ing material. To our delight, the use of ACCN [28] as a
more stable radical initiator in place of AIBN gave excellent
yield. By heating a mixture of ACCN, Bu3SnH and
1-chlorotropan-3-one 12a in toluene at 85 C for 3 h, the
desired dechlorinated product 25 was obtained in 90% yield
(Scheme 3).
amide-activation with Tf2O, triflyloxyiminium intermediate
F is formed. Because G has not been observed as a product,
and formation of 1-halotropanone 12a/13 from intermediate
G via bridgehead carbocation is less plausible in view of the
highly instability of the latter, Path A is less plausible. Thus,
Path B is more plausible, which involves a halide addition
to the imidate F to give intermediate I, the nitrogen-assisted
elimination of OTf, and subsequent cyclization of the in-
termediate J to give 1-halotropan-3-one 12a/13.
Having established the method for the construction of the
6-hydroxytropan-3-ones D, we next turned our attention to
the enantioselective synthesis of pervilleine B (5). Because
the absolute configuration of all this subgroup of alkaloids
remains unknown except for that of pervilleine C (6) [7d],
we decided to synthesize pervilleine B (5) with absolute
stereochemistry as displayed in Figure 1. The requisite keto-
lactam 26, synthesized in seven steps from (S)-malic acid
The observed remarkable halide effect on the cyclization
reaction can be rationalized, as shown in Scheme 4. After

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Mao ZY, et al. Sci China Chem February (2014) Vol.57 No.2
spectroscopic data (1H and 13C NMR) of our synthetic
product are in agreement with those reported for the natural
product [12a]; however, the sense of the optical rotation is
opposite {[]2D0 = 27 (c = 1.0, CHCl3); lit. []20 = 22.5
D
(c = 0.25, CHCl3)} [12a]. Our synthetic product is thus de-
duced as the enantiomer of the natural ()-pervilleine B, and
the absolute configuration of the natural ()-pervilleine B is
determined as 1R,3R,5S,6R [()-5 in Scheme 6]. Conse-
quently, the absolute configuration of ()-pervilleine B dis-
played in Figure 1 is incorrect [12a].
Scheme 3 Radical de-chlorination of 1-chlorotropan-3-one derivative
12a.
Considering the absolute configuration of )-(1S,3S,5R,
6S)-pervilleine C, another natural product isolated from the
same plant, our conclusion regarding the absolute configu-
ration of pervilleine B is surprising. To further clarify this
issue, the synthesis of )-pervilleine C was undertaken
(Scheme 7). In the event, after catalytic hydrogenation and
desilylation, the resulting crude 3,6-dihydroxytropane 4
was treated with a catalytic amounts of DMAP, 10.0 equiv.
of triethylamine, 6.0 equiv. of acid chloride (TmcCl), and
heated at reflux overnight to produce ()-pervilleine C (6)
as a single diastereomer in 90% yield from 10a. The physi-
Scheme 4 Plausible mechanism for the halide-promoted cyclization
reaction.
cal {[]2D0 = +(2933) (c = 0.10, CHCl3); []20 = +29 (c =
D
0.10, CHCl3)} and spectroscopic data (1H and 13C NMR) of
our synthetic product are in agreement with those reported
for the natural product [12a]. It is thus unambiguously confir-
med that the natural ()-pervilleine B (5) and ()-pervilleine
C (6) indeed possess the opposite absolute configuration.
We next addressed the syntheses of 3,6-dibenzoyloxy-
tropane (8) and merredissine (9). 3,6-Dibenzoyloxy-
tropane (8) is an alkaloid that was first isolated from the
leaves of Erythroxylum cuneatum as an optically inactive
compound [11d], and then from the steams of Erythroxylum
caatingae [11c]. In the latter case, the 3S,6S absolute con-
figuration was proposed without confirmation but no optical
rotation data was reported. Recently, by means of the vibra-
tional circular dichroism technique and the chiral HPLC
method, Muñoz and co-workers were able to correlate the
sense of optical rotation with an enantiomer as ()-(3R,6R)
and ()-(3S,6S)-dibenzoyloxytropane, respectively [4d]. In a
Scheme 5 The three-step procedure for the construction of the tropan-3-
one 10a from keto-lactam 26.
[19], was treated with TBDMSOTf/NEt3 (CH2Cl2, 0 °C) to
yield the silyl enol ether 27. The crude silyl enol ether 27,
was successively treated with Tf2O, DTBMP, and ZnCl2
(CH2Cl2, 78 °C to rt) to produce the desired product 28 in
65% yield (from 26) as a single diastereomer (Scheme 5).
Radical dechlorination (ACCN, Bu3SnH, toluene, 85 °C)
afforded (1R,5R,6S)-6-silyloxytropan-3-one 10a in 80%
yield. By successive PtO2-catalyzed hydrogenation (H2, 50
atm, EtOH), desilylation (p-TsOH, acetone, 50 °C) and
mono-esterification with TmcCl (TmcCl, Et3N, tol., refl.)
[7f], tropan-3-one 10a was converted to the desired mo-
noester 29 as a single diastereomer in 90% yield over three
steps (Scheme 6). It should be mentioned that in these steps
the purification was unnecessary, except for extraction.
Further esterification (TmbCl, NEt3, DMAP, tol., refl.) of
the sterically more-hindered axial C-3 hydroxyl group in
compound 29 provided pervilleine B (5) in 94% yield. The
Scheme 6 Transformation of tropan-3-one 10a into (+)-pervilleine B and
the absolute configuration of the natural pervilleine B (5).

Mao ZY, et al. Sci China Chem February (2014) Vol.57 No.2
261
35, which was synthesized from (R)-malic acid by similar
procedures as described for the synthesis of its antipode
from (S)-malic acid [19], which is outlined in Scheme 8.
Malimide 30, prepared from (R)-malic acid by condensation
[29] and acetylation, was subjected to regioselective reduc-
tion [30] (NaBH4 in THF/H2O, 40 °C, 30 min) to produce
the hemiaminal 31 in 81% yield, which was acetylated to
give the diacetate 32 in 93% yield. With the observed char-
acteristic vicinal coupling constants between H-4 and H-5
of -lactams 31 and 32 (J4,5 = 5.3 Hz and J4,5 = 5.4 Hz, re-
spectively), 4,5-cis-stereochemistry was assigned for both
compounds 31 and 32 [31]. In the presence of 10 mol% of
TIPSOTf [32], the reaction of compound 32 with silyl enol
ether of acetone gave the -amidoalkylation product 33 as
Scheme 7 Further confirmation of the absolute configuration of per-
villeine C (6).
similar way for the synthesis of ()-pervilleine C (6), PtO2-
catalyzed hydrogenation-desilylation-diesterification of tro-
panone derivative 10a produced 3,6-dibenzoyloxytrop
ane (8) in an overall yield of 80% (Scheme 8). The spectral
(1H and 13C NMR) and physical data {[]2D0 = 23.0 (c =
0.21, CHCl3); lit. []20 = 26.2 (c = 0.4, CHCl3)} of our
1
D
an inseparable diastereomer (dr = 2.5:1, H NMR) in 95%
synthetic 3,6-dibenzoyloxytropane (8) are in agreement
with those reported [4d].
yield. Treatment of the diastereomeric mixture 33 with HCl/
EtOH (anhydrous HCl formed in situ from AcCl and EtOH)
yielded an easily separable trans-diastereomer 35 (yield:
67%) and a diastereomeric mixture of acetal 34 (dr = 1.3:1,
yield: 28%). On the basis of the observed vicinal coupling
constant (J4,5 = 2.9 Hz) of 35 and the formation of the bicy-
clic product 34, the stereochemistry of the major diastere-
omer 36 was determined to be 4,5-trans and that of the mi-
nor diastereomer as cis [31]. The trans-diastereoselective
-amidoalkylation can be attributed to the well-known
neighboring-group participation with the formation of the
bicyclic intermediate. Protection of the hydroxyl group
(TBDMSCl, imidazole, THF) then yielded keto-lactam 36,
the precursor of the key cyclization reaction [33].
()-3,6-Di-(4-methoxybenzoyloxy)tropane (merrediss-
ine, 9) was isolated from Merremia dissecta, but its absolute
configuration was not determined [16]. PtO2-catalyzed
hydrogenation-desilylation-diesterification of tropanone de-
rivative 10a produced merredissine (9) in an overall yield of
1
83%. Most of the H and 13C NMR data of our synthetic
product matched those reported for the natural merredissine
(9) [15], except that minor differences exist for the H and C
surrounding N. To clarify whether the differences might be
caused by trace of acids in the sample or NMR solvent, we
1
registered a H NMR spectrum of our synthetic sample (9)
using K2CO3-prefiltered CDCl3 as the solvent. The two
spectra are essentially identical, which means that we can
One-pot silylation (TBDMSOTf, NEt3)-lactam activation
(Tf2O, DTBMP, ZnCl2, CH2Cl2, 78 °C, rt) of 36 afforded
1-chlorotropan-3-one 37 in 65% yield over two steps. Rad-
ical de-chlorination of 1-chlorotropan-3-one 37 gave tro-
panone 38 in 65% yield. PtO2-catalyzed hydrogenation of
38 yielded tropanol as a single diastereomer that, without
further purification, was treated with isovaleryl chlo-
ride/NEt3 to give ester 39 in 66% yield over two steps. De-
silylation of 39 (p-TsOH, acetone, 50 °C, 24 h) produced
valeroidine (3) in 60% yield. The physical and spectral data
of our synthetic product matched those reported for the nat-
ural ()-(1R,3S, 5R,6S)-valeroidine except for the sense of
1
exclude the influence of trace of acids on the H NMR
spectrum of our synthetic merredissine 9. In addition, re-
markable differences exist not only in the sense but also in
the value of the optical rotation data {[]2D0 = 27.7 (c =
1.0, CHCl3); []20 = 44.0 (c = 0.5, MeOH); lit. []2D0
=
D
8.6 (c = 0.2, MeOH)} [15]. At this stage, we can only con-
clude that we have synthesized the proposed structure of
merredissine (9).
Our next target was the antipode of ()-valeroidine. ()-
Valeroidine (3-isovaleryloxytropan-6-ol) is an alkaloid iso-
lated from Australian drug Duboisia myoporoides [9a]. Its
absolute configuration was once erroneously assigned to
1S,3R,5S,6R (by Hudson’s lactone rule) but was revised to
3S,6S after chemical correlation [9b, c, d]. Its enantiomer is
the tropane core of 6-tigloyloxy-3-hydroxytropane from
leaves of Datura cornigera and 3,6-ditiglooxyloxytro-
pane from Datura ferox, innoxia, and stramonium [9c].
Although ()-valeroidine has been prepared by a combina-
tion of semi-synthesis with resolution [9b], to the best of
our knowledge, the total synthesis of either enantiomer of
valeroidine has not yet been reported.
the optical rotation {[]2D0 = +8.0 (c = 1 EtOH); lit. []2D0
=
Scheme 8 Syntheses of alkaloid 8 and the proposed structure of mer-
redissine 9
The synthesis relied on the cyclization of the keto-lactam

262
Mao ZY, et al. Sci China Chem February (2014) Vol.57 No.2
ococcinine and adaline, respectively. In addition, through
the enantioselective syntheses of (+)-pervilleines B and C,
the absolute configurations of the two natural products have
been determined or confirmed as 1R,3R,5S, 6R and
1S,3S,5R,6S, respectively, which implies that opp- osite
enantiomers exist in the different components of seco-
ndary metabolists within the same plant.
The authors are grateful to the National Basic Research Program of China
(973 Program, 2010CB833200), the National Natural Science Foundation
of China (21072160, 21332007), and the Program for Changjiang
Scholars and Innovative Research Team at the University of the MOE for
financial support.
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Scheme 9 Enantioselective total synthesis of ()-valeroidine.
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