A new asymmetric synthesis of (R)-3-methylpyrrolidine alkaloids starting from (S)-malic acid

Article abstract of DOI:10.3987/com-01-9266

Diastereoselective methylation of dimethyl (S)-malate (8) followed by two three-step reductive dehydroxylation procedures afforded dimethyl (R)-2-methylsuccinate (16) in 80.2% and 84.7% ee respectively, the later was further transformed into the natural enantiomers of ant venom alkaloids (R)-leptothoracine (1) and (R)-3-methyl-N-(2-phenylethyl)pyrrolidine (2) and (3R, 2'S)-3-methyl-N-(2-methylbutyl)pyrrolidine (3).

Full text of DOI:10.3987/com-01-9266

HETEROCYCLES, Vol. 55, No. 8, pp. 1505 - 1518, Received, 6th June, 2001
A
NEW
ASYMMETRIC
SYNTHESIS
OF
(R)-3-METHYLPYRROLIDINE ALKALOIDS STARTING FROM
(S)-MALIC ACID
Xiao Zheng,b Pei Qiang Huang,a, b * Yuan Ping Ruan, b Albert W. M. Lee,c
and Wing Hong Chanc
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
bDepartment of Chemistry, Xiamen University, Xiamen 361005, P. R. China
c Department of Chemistry, Hong Kong Baptist University, Hong Kong, P. R. China
Abstract --- Diastereoselective methylation of dimethyl (S)-malate (8) followed by two three-step
reductive dehydroxylation procedures afforded dimethyl (R)-2-methylsuccinate (16) in 80.2%
and 84.7% ee respectively, the later was further transformed into the natural enantiomers of ant
venom alkaloids (R)-leptothoracine (1) and (R)-3-methyl-N-(2-phenylethyl)pyrrolidine (2) and (3R,
2’S)-3-methyl-N-(2-methylbutyl)pyrrolidine (3).
Substituted pyrrolidine moiety is found in a large number of naturally occurring pyrrolidine,
pyrrolizidine, indolizidine and tropane alkaloids. Most of them are either ant venom alkaloids1 or
alkaloids extracted from the skin of neotropical poison frogs,2 which are characterized by the presence of
trans-2,5-disubstituted pyrrolidine skeleton,3 other substituted pyrrolidine is relatively rare. In 1995,
Veith et al. reported4 the isolation of five N-alkylated 3-methylpyrrolidine (1-5), the same group reported
their absolute configurations.5 Since then, a racemic synthesis,4 a chiral synthesis6 and one asymmetric
synthesis7 have been reported. In connection with a program aiming at the development of (S)-malic
acid–based methodology,8 we would like to report herein a new asymmetric synthesis of these alkaloids.
As shown in Scheme 1, a simple retrosynthetic analysis implicates methyl (2S, 3R)-3-methylmalate (7)
as a key intermediate which could be obtained by methylation of dimethyl (S)-malate (8).
The synthesis of the requisite (R)-2-methyl-1,4-butanediol (17) began with the esterification (MeOH,
SOCl2, room temperature, 36 h ) of easily available (S)-malic acid. Methylation9 of dimethyl (S)-malate

N
N
N
N
N
1
3
2
4
5
HO
Ph
S
HO
MeO2C
N
R
CO2Me
TsO
OTs
6
7
1-5
Scheme 1
(2.2 equiv., LDA, MeI, THF, -78°C, 40 h) (Scheme 2) led to an inseparable diastereomeric mixture of
dimethyl (2S, 3R)- and (2S, 3S)-3-methylmalates9 in which the desired anti-isomer (7) predominated
1
(de=79.8% as indicated by H-NMR, combined yield 72%). Since the diastereomers (7) will become
inseparable enantiomers after cleavage of hydroxyl group, the separation of minor diastereomer from the
enriched diastereomeric mixture of 7 (only anti-isomer is showed in Scheme 2) via derivatizaion is
necessary. For this purpose, mesylate (9), benzoate (10) and tosylate (11) were prepared respectively
from 7. Although mesylate (9) and benzoate (10) were still inseparable by flash chromatography, the
diastereomeric tosylates (11) turned out to be separable by flash chromatography.
After serving as a valuable derivative for diastereomer separation, the second role of the tosyloxy group
in 11 is as a leaving group. The displacement of tosyloxy group by thiophenol merits some comments.
As shown in Scheme 3 (Method A), the reaction of lithium thiophenolate at -10°C-0°C (method 1,
PhSLi / THF, -10°C-0°C) gave disappointing low selectivity, a total of three products (12-14) can be
1
isolated and/or observed by H-NMR (12 and 13 are inseparable by column chromatography). The
structure of two minor products was tentatively assigned as 13 and 14. The formation of 13 and 14
might implicate that during the formation of 12, the desired SN2 substitution reaction is accompanied by
elimination reaction leading to the formation of dimethyl 2-methylfumarate (15). Subsequent reaction of
thiophenolate with dimethyl 2-methylfumarate (15) would lead to a total of six regio- and stereoisomers
(12-14), including the antipode of 12. However, since compound (14) is optically active, this might
implicates that the epimerization of 12 contributed as well to the formation of 14. Fortunately, the
reaction of potassium thiophenolate with tosylate (11) (method 2) was showed to be
much more selective. Further improvement of the combined yield resided on the direct treatment of

thiophenol with tosylate (11) in the presence of potassium carbonate (method 3), the total yield was
90%.
HO
HO
MsO
LDA
MeI
MsCl
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
THF
-78oC
7
(S)-8
9
p-TsCl
PhCOCl
p-TsO
p-TsO
PhCOO
MeO2C
MeO2C
CO2Me MeO2C
CO2Me
CO2Me
10
anti-11 syn-11
Scheme 2
PhS
PhS
SPh
+
+
anti-11
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
14
Method 1.
Method 2. PhSK / EtOH, rt
Method 3.
12 : 13 : 14 = 36 : 24 : 40
12 : 13 : 14 = 90 : 5 : 5
12 : 1 3: 14 = 90 : 5 : 5
combined yield 71%
combined yield 84%
combined yield 90%
PhSLi / THF, -10°C~0°C
PhSH / K2CO3 / Et2O, 5°C
LAH
Raney Ni
XO
(R)-17. X=H
OX
MeO2C
CO2Me
12/13
MeO2C
CO2Me
15
(R)-16
(R)-18. X=Bz
Scheme 3 ( Method A )
Since 12 and 13 are inseparable by column chromatography, this mixture (in a ratio of 94.7 : 5.3) was
subjected directly to Raney Nickel desulfidation (room temperature, 12 h), the reaction ran smoothly,
affording the desired dimethyl (R)-methyl succinate (16)10 [80.2% ee as indicated by chiral HPLC
analysis of 1811] in a yield of 97%. The observed modest enantiomeric excess of 16 confirmed the
mechanism considerations mentioned above, namely, the modest ee is due to the presence of both

racemic 13 and a small portion of antipode of 12.
In order to improve the enantiomeric excess of diester (16), an alternative approach (Scheme 4, Method
B) was exploited. Thus, the reaction of anhydrous LiCl with tosylate (11) in hot dry DMF for 9 h yielded
chloride (19) as a mixture of two inseparable diastereomers (combined yield 76%). The diastereomeric
1
ratio is 53 : 47 as calculated from H-NMR spectrum. The stereochemistry of isomeric 19 was not
assigned. Although 19 can be dechlorinated to dimethyl (R)-methylsuccinate (16) under radical
conditions, an environmentally friendly procedure was adopted to achieve the reductive dechlorination.
To our delight, the hydrogenolysis (H2, 10% Pd/C, NEt3 MeOH, 6 h) of the diastereomeric mixture (19)
afforded cleanly dimethyl (R)-methylsuccinate (16) in 89% yield. Since chloride (19) is volatile, care
must take to avoid the evaporation of 19, in such a way, the overall yield for the transformation of 11 to
16 is 81%.
Cl
H2, 10%Pd/C
LAH
LiCl, DMF
11
MeO2C
CO2Me
MeO2C
CO2Me
(R)-16
19
N
RNH2
N
N
TsCl
TsO
OTs
HO
OH
2
3
1
(R)-6
Scheme 4 ( Method B )
Ph
(R)-17
Lithium aluminium hydride reduction of 16 (LAH, THF, 0°C-rt, 6 h, 82%) then yielded known
(R)-2-methyl-1,4-butanediol6 (17) as a colorless oil {[α]D20 +11.7° (c 1.92, MeOH), 84.7% ee; lit.,12a for
(R-17): [α]D22 +14.4° (c 2.0, MeOH); lit.,6 [α]D20 +9.42° (c 1.04, MeOH), 65% ee; lit.,6 [α]D20 +13.9° (c
1.35, MeOH), 97% ee; lit.,12b (S)-(17): [α]D20 –14.4° (c 0.6, MeOH); lit.,6 [α]D20 –13.8° (c 1.24, MeOH),
96% ee}. The enantiomeric excess of diol (R-17) thus formed is 84.7 % as determined by chiral HPLC
analysis of its dibenzoate derivative (18).11 These results indicate that partial racemization occur during
the transformation of diastereomeric pure 11 to 17, since the conversion of 16 to 17 was performed
under racemization free conditions.6 The observed partial racemization might occur during the formation

of 19 or 16.
Under the tosylation conditions (p-TsCl, Pyridine, DMAP, CH2Cl2, 0-5°C) diol (17) was ditosylated to
give compound (R-6),7 which upon treatment with 3-methylbutylamine at room temperature for 4 days
afforded the desired natural enantiomer of ant venom alkaloid (R)-3-methyl-N-(3-methylbutyl)-
pyrrolidine (leptothoracine) (1)6, 7 {[α]D20 –1.54° (c 0.95, EtOH), 84.7 % ee; lit.,6 for (R-1): [α]D20–1.80°
20
(c 0.96, EtOH ); (S-1): [α]D +1.81° (c 3.03, EtOH)} in a yield of 66%. Similarly, the reaction of
ditosylate (R-6) with 2-phenylethylamine afforded the expected alkaloid (R)-3-methyl-N-
20
(2-phenylethyl)pyrrolidine (2)7 { [α]D –1.87° ( c 0.99, EtOH), 84.7% ee} in excellent yields (96%).
Finally, the reaction of R-6 with (S)-(-)-2-methylbutylamine afforded 3 in a yield of 71%. The low yields
of R-1 and R-3 compared with those of R-2 might due to the volatility of pyrrolidine (1) and (3).
In conclusion, we have developed a new seven-step asymmetric synthesis of (R)-3-methylpyrrolidine
alkaloids from available dimethyl (S)-malate. The overall yield for alkaloids (R-1), (R-2) and (R-3) is
15.9%, 23.1% and 17.1% respectively. The enantiomeric excess of the final products is 84.7%.
EXPERIMENTAL
IR spectra were measured with a Nicolet Avatar 360 FT-IR spectrophotometer using film NaCl
1
techniques. H-NMR spectra were recorded in CDCl3 on a Varian unity + 500 spectrometer with
tetramethylsilane as an internal standard. Chemical shifts are expressed in δ (ppm) units downfield from
TMS. MS spectra were recorded by Finnigan Mat-LCQ ( ESI direct injection). HRFABMS spectra were
recorded on a Bruker APEX-II FTMS apparatus. Optical rotations were measured with Perkin-Elmer
341 automatic polarimeter. Elemental analyses were performed using a Vario EL III analyser. THF and
ether used in the reactions were dried by distillation over metallic sodium and benzophenone;
dichloromethane was distilled over P2O5. Silica gel (Zhifu, 300-400 mesh) from Yian-Tai Silica gel
Factory (China) was used for column chromatography, eluting (unless otherwise stated) with ethyl
acetate/petroleum ether (PE) (60-90°C) mixtures. HPLC analyses were performed with a Chiralcel® OB
column, eluting with hexane / iso-propanol (95/5, v/v) mixtures, on a Waters HPLC 510 instrument.
Dimethyl (2S, 3R)-3-methylmalate (7)
To a stirred cold solution of diisopropylamine (5.5 mL, 39.3 mmol) in THF (17 mL) was added
dropwise a 1.6 M solution of n-BuLi in hexanes (22.6 mL, 36.1 mmol). The mixture was stirred at 0°C

for 15 min and then cooled to -78°C. A solution of dimethyl (R)-malate (2.99 g, 18.5 mmol) in THF (4.5
mL) was added dropwise (30 min). After stirred at -78°C for 1.5 h, methyl iodide (2.7 mL, 43.0 mmol)
was added dropwise. The mixture was stirred at -78°C for 44 h, and then quenched by adding a solution
of 3.70 g of glacial acetic acid in 5.0 mL of THF at -78°C. The resulting mixture was allowed to reach rt
and then diluted by dichloromethane (200 mL). After careful addition of a saturated sodium bicarbonate
(20 mL), the mixture was poured into a separatory funnel. The organic layer was washed successively
with water (10 mL), a saturated solution of sodium bicarbonate (10 mL) and brine (10 mL), dried with
anhydrous Na2SO4. Removal of the solvent under reduced pressure followed by flash chromatographic
purification on silica gel (eluent: EtOAc / PE = 1 : 2) afforded colorless liquid (7) 9a (2.35 g, 72%) as
20
an inseparable diastereomeric mixture (anti : syn = 89.9 : 10.1 as indicated by 1H-NMR) as an oil. [α]D
20
–5.21°(c 1.52, Et2O) {lit.,9a,b [α]D –4.1° ( c 1.035, ether), anti: syn = 91 : 1 determined by GC}. IR:
3496, 2985, 2956, 2887, 1743, 1438, 1382, 1210, 1142, 1103, 1069, 1047, 1008, 839, 802 cm-1.
1H-NMR (500 Mz, CDCl3): major anti-isomer: δ 1.28 (d, J = 7.30 Hz, 3H, C3-CH3), 3.02 (dq, J = 3.73,
7.30 Hz, 1H, H-3), 3.10-3.30 (br, s, 1H, -OH), 3.65 (s, 3H, COOCH3), 3.78 (s, 3H, COOCH3), 4.26 (d, J
= 3.73 Hz, 1H, H-2) ppm; MS (ESI): 375.4 (2M++23, 42), 199.6 (M++23, 100), 177.6 (M++1, 22).
Dimethyl (2S, 3R)-3-methyl-2-O-mesylmalate (9)
To a solution of 7 (176 mg, 1.0 mmol) in anhydrous CH2Cl2 (5 mL) were added successively
triethylamine (0.42 mL, 3.0 mmol) and MsCl (0.25 mL, 3.0 mmol) at 0°C. After stirred at rt for 1 h, the
reaction mixture was diluted with ether (10 mL) and stirring continued for 30 min. The mixture was
filtered over celite, concentrated under reduced pressure and the residue was subjected to flash
chromatographic purification (eluent: EtOAc: PE = 1 : 2) providing a colorless oily mixture of anti-9 /
20
syn-9 isomers (232 mg, 92.7%, anti : syn = 89.9 : 10.1) as an oil. [α]D –31.1° (c 0.96, CHCl3). IR:
3103, 3022, 2995, 2957, 2851, 1739, 1652, 1437, 1361, 1207, 1175, 1050, 1019, 961, 834, 788, 734 cm-1.
1H-NMR (500 Mz, CDCl3): major anti-isomer: 1.32 (d, J = 7.29 Hz, 3H, C3-CH3), 3.19 (s, -SO2CH3),
3.22 (dq, J = 5.12, 7.29 Hz, 1H, H-3), 3.68 (s, 3H, COOCH3), 3.84 (s, 3H, COOCH3), 5.18 (d, J = 5.12
Hz, 1H, H-2). MS (ESI): 531.5 (2M++23, 100), 277 (M++23, 20), 272 (M++18, 40), 255 (M++1, 9), 254
(M+, 1). HRESIMS calcd for [ C8H14O7S+Na ]+: 277.0352; found: 277.0357.

Dimethyl (2S, 3R)-3-methyl-2-O-benzoylmalate (10)
To a mixture of 7 (210 mg, 1.19 mmol) and DMAP (cat.) in anhydrous CH2Cl2 (6.0 mL) were added
successively triethylamine (0.124 mL, 1.67 mmol) and benzoyl chloride (0.17 mL, 1.43 mmol) at 0°C.
After stirred at rt for 18 h, the reaction mixture was rechilled to 0°C, water (2 mL) was added, the
aqueous phase was extracted with CH2Cl2 (3×5 mL). The combined organic phase was washed
successively with a 50% aqueous citric acid solution (2.0 mL) and brine (2.0 mL) and dried with
anhydrous Na2SO4. After flash chromatographic purification (eluent: EtOAc / PE = 1 : 6), a colorless
20
oily mixture of anti-10 : syn-10 isomers (289 mg, 86.5%, anti : syn = 89.9 : 10.1) were obtained. [α]D
–1.52° (c 1.30, CHCl3). IR: 3064, 2993, 2954, 2848, 1732, 1601, 1584, 1454, 1436, 1360, 1259, 1110,
1
1027, 854, 833, 801, 760, 712, 687 cm-1. H-NMR (500 Mz, CDCl3): major anti-isomer: 1.32 (d, J =
7.22 Hz, 3H, C3-CH3), 3.28 (dq, J = 5.18, 7.22 Hz, 1H, H-3), 3.75 (s, 3H, COOCH3), 3.80 ( s, 3H,
COOCH3), 5.50 ( d, J = 5.18 Hz, 1H, H-2), 7.44 (2H), 7.60 (1H), 8.00 (2H). MS (ESI): 303.9 (M++23,
100). HRESIMS calcd for [ C14H16O6+Na ]+: 303.0839; found: 303.0845. Anal. Calcd for C14H16O6: C,
60.0; H, 5.7. Found: C, 59.8; H, 5.8.
Dimethyl (2S, 3R)-3-methyl-2-O-tosylmalate (11)
To a solution of 7 (140 mg, 0.79 mmol) in anhydrous CH2Cl2 (1 mL) were added successively pyridine
(0.1 mL, 1.19 mmol), a solution of p-TsCl (182 mg, 0.95 mmol) in anhydrous CH2Cl2 (0.5 mL) and
DMAP (cat.) at 0°C. After stirred at rt for 30 h, the reaction mixture was diluted with CH2Cl2 (15 mL)
and water, the aqueous phase was extracted with CH2Cl2 (3×5 mL). The combined organic phase was
washed successively with a saturated solution of NaHCO3 (1.5 mL) and brine (1.5 mL) and dried with
anhydrous Na2SO4. After flash chromatographic purification (eluent: EtOAc : PE = 1 : 3), pure
anti-isomer (11) (yield, 50%) and a mixture of anti-11 / syn-11 isomers (anti : syn = 89.9 : 10.1, 34%)
20
were obtained, both are colorless oil, the combined yield was 84% (222 mg). anti-11: [α]D – 30.0° (c
1.13, CHCl3). IR: 3066, 2989, 2955, 2850, 1743, 1456, 1437, 1373, 1273, 1191, 1177, 1095, 1018, 831,
768, 749, 667 cm-1. 1H-NMR (500Mz, CDCl3), major anti-isomer: δ 1.16 (d, J = 7.11 Hz, 3H, C3-CH3),
2.44 (s, 3H, SO2Ph-CH3-p), 3.09 (dq, J = 5.72, 7.11 Hz, 1H, H-3), 3.66 (s, 3H, COOCH3), 3.72 (s, 3H,
COOCH3), 5.08 (d, J = 5.72 Hz, 1H, H-2), 7.36 (d, J = 8.20 Hz, 2H), 7.82 (d, J = 8.20 Hz, 2H) ppm.
13C-NMR (125 Mz, CDCl3) δ: 12.22 (Ph-CH3), 21.69 (CH3), 42.05 (C-3), 52.28 and 52.68 (COOMe),
78.15 (C-2), 128.17 and 129.71 (2×Ar–CH), 132.95 (Ar–CH), 145.21 (Ar-C), 167.69 and 171.29 (C=O)

ppm. MS (ESI): 683.4 (2M++23, 80), 354.1 (M++23, 100). HRESIMS calcd for [ C14H18O7S+Na ]+:
353.0665; found: 353.0668. Anal. Calcd for C14H18O7S: C, 50.9; H, 5.5; S, 9.7. Found: C, 51.1; H, 5.7;
S, 9.4.
Dimethyl (2R, 3R)-2-methyl-3-phenylsultanylsuccinate (R-12)
Method 1: To a cooled (-10°C) solution of thiophenol (0.07 mL, 0.67 mmol) in anhydrous THF (0.7 mL)
was added dropwise a solution of n-BuLi in hexane (2.5 M, 0.25 mL, 0.62 mmol), the mixture was
stirred at rt for 0.5 h and then re-cooled to -10 °C. To this mixture was added a THF (0.5 mL) solution of
11 (170 mg, 0.52 mmol). After stirred at 0°C for 4 hours, a saturated NaHCO3 solution (2 mL) was
added. The reaction mixture was diluted with CH2Cl2 (10 mL), the aqueous phase was extracted with
CH2Cl2 (3×5 mL). The combined organic phase was washed with brine (1.5 mL) and dried with
anhydrous Na2SO4. After flash chromatographic purification (eluent: EtOAc : PE = 1 : 10), isomers (12 /
13) were separated from 14, the isomeric ratio was as follows: 12 : 13 : 14 = 36 : 24 : 40, the combined
yield was 71%.
Method 2: To a ice-cooled solution of potassium thiophenolate (310 mg, 2.09 mmol) in absolute
ethanol (1 mL) was added a solution of 11 (330 mg, 1.0 mmol) in absolute ethanol (0.5 mL). After
stirred at rt for 4 h, a saturated NH4Cl solution (2 mL) was added. After evaporation of ethanol at
reduced pressure, to the mixture were added CH2Cl2 (15 mL) and water (2 mL). The resulting mixture
was extracted with CH2Cl2 (3×5 mL). The combined organic phase was washed successively with water
(2 mL) and brine (2 mL) and then dried with anhydrous Na2SO4. After flash chromatographic
purification (eluent: EtOAc: PE = 1 : 10), an inseparable mixture of regio-isomers of 12 / 13, as well as
14 were obtained (ratio : 90 : 5 : 5), the combined yield was 84%.
Method 3: To a ice-cooled suspension of 11 (200 mg, 0.61 mmol) and potassium carbonate (200 mg, 1.4
mmol) in dry ether (6 mL) was added thiophenol (0.17 mL, 1.5 mmol). After stirred at 5°C for 30 h, the
solvent was evaporated at reduced pressure. The residue was purified by flash chromatography on silica
gel (eluent: EtOAc : PE = 1 : 10), an inseparable mixture of regio-isomers of 12 / 13, as well as 14 were
20
obtained (ratio: 90: 5: 5), the combined yield was 90%. syn-isomer (12): [α]D +120° ( c 0.96, CHCl3,
12 : 13 = 94.7 : 5.3). IR: 3059, 2989, 2952, 2881, 2845, 1734, 1583, 1456, 1436, 1377, 1261, 1216, 1154,
1
1066, 1024, 1002, 920, 855, 749, 692 cm-1. H-NMR (500 Mz, CDCl3) δ: 1.44 (d, J = 7.22 Hz, 3H,
C3-CH3), 2.89 (dq, J = 7.22, 10.38 Hz, 1H, H-3), 3.64 (s, 3H, COOCH3), 3.67 (s, 3H, COOCH3), 3.77 (d,

J = 10.38 Hz, 1H, H-2), 7.30-7.50 (m, 5H, -SPh) ppm. 13C-NMR (125 Mz, CDCl3) δ: 15.28 (CH3),
40.71 (C-3), 52.10 and 52.32 (COOMe), 53.19 (C-2), 128.59 (Ar–CH), 128.81, 129.06 (2×Ar–CH),
133.76 (Ar–C), 171.32 and 174.96 (C=O) ppm. MS (ESI): 559 (2M++23, 100), 291 (M++23, 64), 269
(M++1, 53). HRESIMS calcd for [C13H16SO4 + Na]+: 291.0662; found: 291.0663. Regio-isomer (13):
1H-NMR (500 Mz, CDCl3) δ: 1.58 (s, 3H, C2-CH3), 2.64 (d, J = 16.54 Hz, 1H, H-3), 3.07 (d, J = 16.54
Hz, 1H, H-3), 3.64 (s, 3H, COOCH3), 3.66 (s, 3H, COOCH3), 7.30~7.50 (m, 5H, -SPh) ppm.
20
1
anti-isomer (14): [α]D +25.4° (c 1.6, CHCl3). H-NMR (500 Mz, CDCl3) δ: 1.25 (d, J = 6.92 Hz, 3H,
C3-CH3), 2.99 (dq, J = 6.92, 9.92 Hz, 1H, H-3), 3.68 (s, 3H, COOCH3), 3.74 (s, 3H, COOCH3), 3.88 (d,
J = 9.92 Hz, 1H, H-2), 7.30-7.50 (m, 5H, -SPh).
Dimethyl (R)-methylsuccinate (R-16) (prepared via (R-12), Method A)
To an inseparable mixture of 12 and 13 (500 mg, 1.86 mmol, 12 : 13 = 94.7 : 5.3) in ethanol (2 mL), was
added freshly prepared Raney Ni (200 mg in 2 mL of EtOH). After stirred at rt under an atmosphere of
N2 for 12 h, the mixture was filtered over celite. Flash chromatographic purification on silica gel (eluent:
20
EtOAc : PE = 1 : 15) provided known R-16 (289 mg, 97%). [α]D +8.27° (c 1.29, EtOH), 80.2% ee
deduced from R-18. {lit.,10 for (R-16): [α]D17.9 +9.98° (EtOH) }. IR: 2961, 2925, 2853, 1743, 1457, 1261,
1094, 1017, 799 cm-1. 1H-NMR (500 Mz, CDCl3): 1.23 (d, J = 7.18 Hz, 3H, C2-CH3), 2.42 (dd, J = 6.08,
16.54 Hz, 1H, H-3), 2.76 (dd, J = 8.11, 16.54 Hz, 1H, H-3), 2.93 (ddq, J = 6.08, 7.18, 8.11 Hz, 1H, H-2),
3.68 (s, 3H, COOCH3), 3.72 (s, 3H, COOCH3). MS (ESI): 343 (2M++23, 100), 161.7 (M++1, 20).
(R)-2-Methyl-1,4-butanediol (17) (prepared via (R-12), Method A)
To a ice-cooled suspension of LAH (170 mg, 4.5 mmol) in anhydrous ether (1 mL) was added, under an
atmosphere of N2, a solution of 16 (180 mg, 1.12 mmol) in ether (0.5 mL). After stirred at rt for 6 h, the
mixture was cooled with a ice-bath, then wet ether (4 mL), water (0.2 mL), a 10% solution of sodium
hydroxide (0.4 mL) and again water (0.1 mL) were added successively. The mixture was allowed to
reach rt, stirred for 30 min, and filtered through celite. After concentrated at reduced pressure, the
residue was purified by flash chromatography on silica gel (eluent: EtOAc) affording diol (R-17) (99 mg,
85%) as a colorless oil. [α]D20 +10.0° (c 1.73, MeOH), 80.2% ee {lit.,12a for (R-17): [α]D22 +14.4° ( c2.0,
20
20
MeOH); lit.,6 [α]D +9.42° ( c 1.04, MeOH), 65% ee; [α]D +13.9° ( c 1.35, MeOH), 97% ee; lit.,12b
S-17: [α]D20 –14.4° ( c 0.6, MeOH); lit.,6 [α]D20 –13.8° ( c 1.24, MeOH), 96% ee}. IR: 3336, 2925, 2873,

1
1457, 1382, 1260, 1035, 798 cm-1. H-NMR (500 Mz, CDCl3 ): δ 0.92 (d, J = 6.99 Hz, 3H, C2-CH3),
1.56 (m, 1H, H-3), 1.62 (m, 1H, H-3), 1.80 (m, 1H, H-2), 3.41 (dd, J = 7.53, 10.57 Hz, 1H, H-1), 3.51 (s,
br, 2H, -OH), 3.55 (dd, J = 4.51, 10.57 Hz, 1H, H-1), 3.64 (m, 1H, H-4), 3.75 (m, 1H, H-4). MS (ESI):
330.7 (3M++ 18, 100). HRESIMS calcd for [2C5H12O2 +H]+: 209.1747; found: 209.1744.
(R)-2-Methyl-1,4-bis(benzoyloxy)butane (18)
To a mixture of diol (17) (52 mg, 0.50 mmol) and DMAP (cat.) in anhydrous CH2Cl2 (2.0 mL) were
added successively pyridine (0.1 mL, 1.25 mmol) and benzoyl chloride (0.13 mL, 1.1 mmol) at 0°C.
After stirred at rt for 6 h, the reaction mixture was diluted with CH2Cl2 (5 mL) and water, the aqueous
phase was extracted with CH2Cl2 (3×5 mL). The combined organic phase was washed successively with
water (1.5 mL), a saturated NaHCO3 solution (1.5 mL) and brine (1.5 mL) and dried with anhydrous
Na2SO4. After filtration and concentration under reduced pressure, the residue was flash
chromatographied (eluent: EtOAc: PE = 1 : 20) to give R-18 (140 mg, 90%) as a colorless oil.
(R)-2-Methyl-1,4-bis(benzoyloxy)butane (18) prepared by different method were subjected to chiral
HPLC analysis using a Chiralcel® OB column. The retention times (tR) for S-18 and R-18 were 15.2 min
and 19.5 min respectively (hexane : i-PrOH = 95 : 5). (R-18) prepared via method A showed 80.2% ee;
20
20
[α]D –6.49° (c 1.48, CHCl3); R-18 prepared via method B showed 84.7% ee; [α]D –7.22° (c 1.21,
CHCl3){lit.,11 for R-18: [α]D20 -9.5° ( c 2.0, CHCl3); (S-18): [α]D20 +9.4° (c 2.0, CHCl3)}. IR: 3063,3034,
2963, 1717, 1602, 1584, 1451, 1390, 1314, 1271, 1176, 1110, 1070, 1026, 968, 709, 687, 675 cm-1.
1H-NMR (500 Mz, CDCl3): 1.14 (d, J = 6.83 Hz, 3H, C2-CH3), 1.76 (m, 1H, H-2), 2.03 (m, 1H, H-3),
2.22 (m, 1H, H-3), 4.27 (d, J = 6.05 Hz, 2H, H-1), 4.46 (m, 2H, H-4), 7.30-8.05 (m, 10H, PhCO).
13C-NMR (125 Mz, CDCl3) : 15.87 (CH3), 30.15 (C-3), 32.43 (C-2), 62.92 (C-1), 69.35 (C-4), 128.33 (4
×Ar–CH), 128.36, 129.15 and 130.21 (2×Ar–CH), 132.90 and 132.93 (Ar–C), 166,55 (2×C=O). MS
(ESI): 646.8 (2M++23, 100), 335.3 (M++23, 5); HRESIMS calcd for [C19H20O4+Na]+: 335.1254; found:
335.1248.
Dimethyl (2RS, 3R)-2-chloro-3-methylsuccinate (19)
A mixture of tosylate (11) (500 mg, 1.52 mmol), anhydrous lithium chloride (97 mg, 2.27 mmol) and
dry DMF (1.5 mL) was stirred at 70°C and under an atmosphere of N2 for 10 h. After chilled to rt, water
(4.5 mL) was added and the mixture was extracted with ether (3×3 mL). The combined organic phase

was washed successively with water (1.5 mL) and brine (1.5 mL) and then dried with anhydrous Na2SO4.
After filtration and concentration under reduced pressure, 19 was obtained as an inseparable
1
diastereomeric mixture (ratio, 53 : 47 calculated from H-NMR spectrum; combined yield 76%) which
was used in the next step.
Dimethyl (R)-methylsuccinate (R-16 ) [prepared via (R-19), Method B]
To a mixture of diastereomers (19) (110 mg, 0.57 mmol) and 10% Pd-C (15 mg) were added methanol
(0.7 mL) and triethylamine (0.12 mL, 0.85 mmol). The mixture was stirred at rt under an atmosphere of
H2 for 12 h. The mixture was filtered over celite. Flash chromatographic purification on silica gel (eluent:
20
EtOAc : PE = 1 : 15) provided known R-16 (80 mg, yield, 89%, 84.7% ee as determined on 18). [α]D
+8.71° ( c 1.10, EtOH).
(R)-2-Methyl-1,4-butanediol (17) [prepared via (R-19), Method B]
(R)-2-Methyl-1,4-butanediol (17) was prepared from (R-16) (prepared via (R-19), method B) following
the procedure described above. [α]D20 +11.7° ( c 1.92, MeOH ), 84.7% ee
(R)-2-Methyl-1,4-bis(p-toluenesulphonyloxy)butane (6)
To a ice-cooled solution of R-17 [104 mg, 1.0 mmol, prepared via R-19, Method B ] and a catalytic
amount of DMAP in anhydrous CH2Cl2 (2 mL) were added successively pyridine (0.23 mL, 2.8 mmol)
and a solution of p-TsCl (476 mg, 2.5 mmol) in anhydrous CH2Cl2 (2 mL). After stirred at 5°C for 10 h,
the reaction mixture was diluted with CH2Cl2 (15 mL) and water, the aqueous phase was extracted with
CH2Cl2 (3×5 mL). The combined organic phase was washed successively with water (1.5 mL), saturated
NaHCO3 solution (1.5 mL) and brine (1.5 mL) and dried with anhydrous Na2SO4. After filtration and
concentration under reduced pressure, the residue was flash chromatographied (eluent: EtOAc : PE = 1 :
5) to give R-6 7 (352 mg, yield, 85%) as a pale yellow oil. [α]D20 +0.92° ( c 1.09, CHCl3), 84.7% ee. IR:
3066, 2967, 2926, 1598, 1456, 1356, 1189, 1175, 1097, 1038, 940, 887, 836, 814, 784, 764 cm-1.
1H-NMR ( 500 Mz, CDCl3): δ 0.86 (d, J = 6.84 Hz, 3H, CH3), 1.46 (m, 1H, H-3), 1.74 (m, 1H, H-3),
1.93 (m, 1H, H-2), 2.46 ( s, 6H, PhCH3 ), 3.79 (dd, J = 5.65, 9.63 Hz, 1H, H-1), 3.83 (dd, 1H, J = 5.43,
13
9.63 Hz, H-1), 4.01 ( m, 2H, H-4) 7.35-7.76 (m, 8H, Ph-H) ppm. C-NMR (125 Mz, CDCl3): δ 15.87
(CH3), 21.64 (2×CH3), 29.40 (C-3), 31.73 (C-2), 67.81 (C-1), 73.95 (C-4), 127.83 and 129.89 (4×

Ar–CH), 132.72 and 132.78 (Ar-CH3), 144.89 (2×Ar-SO2) ppm. MS (ESI): 847.4 (2M++23, 100),
435.4 (M++23, 10). HRESIMS calcd for [C19H24O6S2+Na]+: 435.0907; found: 435.0908. Anal. Calcd for
C19H24O6S2: C, 55.3; H, 5.8; S, 15.5. Found: C, 55.4; H, 6.1; S, 15.4.
(R)-3-Methyl-N-(3-methylbutyl)pyrrolidine [(R)-Leptothoracine] (1)
A mixture of R-6 (240 mg, 0.58 mmol, prepared via R-19, Method B) and 3-methylbutylamine (0.36
mL, 3.1 mmol) was stirred at rt under an atmosphere of N2 for four days. After diluted with ether (5 mL),
filtered through celite, and concentrated at reduced pressure, the residue was purified by flash
chromatography on silica gel [eluent: ether / PE / ammonia = 1 : 1 : 0.01] affording 14-7 (60 mg, 66%) as
20
20
a colorless liquid. [α]D –1.54° (c 0.95, EtOH ), 84.7% ee [deduced from R-18]. {lit.,6 for R-1: [α]D
20
–1.80° (c 0.96, EtOH); S-1: [α]D +1.81° (c 3.03, EtOH), 96% ee}. IR: 2962, 2906, 1412, 1261, 1020,
865, 800, 700 cm-1. 1H-NMR (500 Mz, CDCl3): 0.89 (d, J = 6.55 Hz, 6H, CH3), 1.02 (d, J = 6.86 Hz, 3H,
CH3), 1.28-1.34 ( m, 1H, H-4), 1.35-1.42 (m, 2H, H-2’), 1.58 (m, 1H, H-3’), 1.93-1.98 (m, 1H, H-2),
1.98-2.05 (m, 1H, H-4), 2.24 (m, 1H, H-3 ), 2.34- 2.46 (m, 3H, H-1’, H-5), 2.68 (m, 1H, H-5), 2.83 (m,
13
1H, H-2). C-NMR (125 Mz, CDCl3): 20.22 (Me- (C-3)), 22.71 (Me2CH), 26.69 (C-3’ ), 31.76 (C-3),
32.49 (C-4 ), 37.65 (C-2’), 54.18 (C-1’), 54.99 (C-5), 62.18 (C-2). MS (ESI): 156.5 (M++ 1, 100).
HRESIMS calcd for [C10H21N+H]+: 156.1747; found: 156.1744.
(R)-3-Methyl-N-(2-phenylethyl)pyrrolidine (R-2)
A mixture of R-6 [ 330 mg, 0.8 mmol, prepared via R-19, Method B ] and 2-phenylethylamine (0.5 mL,
4.0 mmol) was stirred at rt under an atmosphere of N2 for two days. After diluted with ether (3 mL),
filtered through celite, and concentrated at reduced pressure, the residue was purified by flash
chromatography on silica gel (eluent: ether / PE / ammonia = 1 : 1 : 0.01) affording R-2 4-7 (146 mg,
yield, 96%) as a colorless liquid. [α]D20 –1.87° (c 1.0, EtOH), 84.7% ee [deduced from R-18]. IR: 3062,
3026, 2954, 2926, 2870, 1785, 1605, 1497, 1453, 1159, 1128, 748, 698 cm-1. 1H-NMR (500 Mz, CDCl3):
δ 1.04 (d, J = 6.77 Hz, 3H, CH3), 1.36 (m, 1H, H-4), 2.00-2.09 (m, 2H, H-2, H-4), 2.27 (m, 1H, H-3),
2.49 ( m, 1H, H-5), 2.60-2.84 (m, 5H, H-1’, H-2’, H-5), 2.90 (m, 1H, H-2), 7.10-7.30 (m, 5H, Ph).
13C-NMR (125 Mz, CDCl3): δ 20.29 (Me- (C-3) ), 31.76 (C-3), 32.52 (C-4), 35.62 (C-2’), 54.15 (C-5),
58.51 (C-1’), 62.19 (C-2), 125.87 (C-5p), 128.22 (2Cm), 128.53 (2Co), 140.41 (Cipso). MS (ESI): 190.5
(M++1, 100); HRESIMS calcd for [C13H19N+H]+: 190.1590; found: 190.1587.

(3R, 2’S)-3-Methyl-N-(2-methylbutyl)pyrrolidine (3)
A mixture of R-6 [168 mg, 0.41 mmol, prepared via R-19, Method B] and (S)-(-)-2-methylbutylamine
(250 mg, 2.87 mmol) was stirred at rt under an atmosphere of N2 for four days. After diluted with ether
(4 mL), filtered through celite, and concentrated at reduced pressure, the residue was purified by flash
chromatography on silica gel (eluent: ether / PE / ammonia = 1 : 1 : 0.01 ) affording 3 4-6 ( 45 mg, 71% )
as a colorless liquid. [α]D20 +17.5° ( c 0.94, EtOH ), 84.7% ee [deduced from R-18]. IR (film) νmax: 2959,
2925, 2873, 2786, 1454, 1376, 1260, 1176, 1097, 1020, 803 cm-1. 1H-NMR ( 500 Mz, CDCl3): 0.88 ( t, J
= 7.37 Hz, 3H, CH3), 0.91 ( d, J = 6.61 Hz, 3H, CH3), 1.01 ( d, J = 6.91 Hz, 3H, CH3), 1.10( m, 1H,
H-3’), 1.33 ( m, 1H, H-4), 1.40-1.54 ( m, 2H, H-2’, H-3’), 1.94-2.05 ( m, 2H, H-2, H-4), 2.19-2.32 ( m,
3H, H-3, H-1’), 2.38 ( m, 1H, H-5 ), 2.70 ( m, 1H, H-5 ), 2.82 ( m, 1H, H-2). 13C-NMR (125 Mz,
CDCl3): 11.37 ( MeCH2), 17.86 (MeCH ), 20.28 ( Me- (C-3) ), 27.88 ( C-3’ ), 31.87 ( C-3 ), 32.46
( C-4 ), 33.77 ( C-2’ ), 54.47 ( C-5 ), 62.58 ( C-2 ), 63.68 ( C-1’). MS (ESI): 156.5 (M++ 1, 100);
HRESIMS calcd for [ C10H21N+H ]+ 156.1747, found 156.1746.
ACKNOWLEDGMENTS
This work is supported by the National Science Fund for Distinguished Young Investigator (29625204),
the NSF of China (29832020), the Visiting Scholar Foundation of Key Lab. In University, the
Foundation for University Key Teacher by the Ministry of Education and Xiamen University. Pei-Qiang
Huang dedicates this paper to the memory of his father.
REFERENCES
1
2
3
D. O’Hagan, Nat. Prod. Rep., 2000, 17, 435.
J. W. Daly, J. Nat. Prod., 1998, 61, 162.
See for example (a) P. Q. Huang, S. Arseniyadis, and H. -P. Husson, Tetrahedron Lett., 1987，28,
547. For a review, see: (b) M. Pichon and B. Figadere, Tetrahedron: Asymmetry, 1996, 7, 927.
V. E. Reder, H. J. Veith, and A. Buschinger, Helv. Chim. Acta, 1995, 78, 73.
R. Koob, C. Rudolph, and H. J. Veith, Helv. Chim. Acta, 1997, 80, 267.
H. J. Veith, M. Collas, and R. Zimmer, Liebigs Ann./Recueil, 1997, 391.
J. Lin, W. H. Chan, A. W. M. Lee, W. Y. Wong, and P. Q. Huang, Tetrahedron Lett., 2000, 41,
2949.
4
5
6
7
8
(a) P. Q. Huang, H. Q. Lan, M. D. Chen, and H. K. Zhang, Chinese J. Org. Chem., 2000, 20, 790 (in

Chinese); (b) C. L. Chen, and P. Q. Huang, J. Xiamen. Univ. ( Nat. Sci. ed. ), 2000, 39, 793 (in
Chinese); (c) L. R. Jin, H. Wu, H. L. Wu, P. Q. Huang, K. Jung, and H. Lim, Chem. Lett., 1999, 687;
(d) P. Q. Huang, Q. F. Chen, C. L. Chen, and H. K. Zhang, Tetrahedron: Asymmetry, 1999, 10, 3827;
(e) P. Q. Huang, X. Zheng, S. L. Wang, J. L. Ye, L. R. Jin, and Z. Chen, Tetrahedron: Asymmetry,
1999, 10, 3309 and references cited there in.
9
(a) D. Seebach and D. Wasmuth, Helv. Chim. Acta, 1980, 63, 197; (b) D. Wasmuth, D. Arigoni, and
D. Seebach, Helv. Chim. Acta, 1982, 65, 344; (c) D. Seebach, J. Aebi, and D. Wasmuth, Org. Synth.,
1984, 63, 109.
10 R. Rossi, P. Diversi, and G. Ingrosso, Gazz. Chim. Ital., 1968, 98, 1391.
11 B. L. Feringa, B. de Lange, and J. C. J. Jong, J. Org. Chem., 1989, 54, 2471.
12 (a) B. Ringdahl, and R. Dahlbom, Acta Pharm. Suec., 1978, 15, 255. (b) H. G. W. Leuenberge, W.
Boguth, R. Barner, M. Schmid, and R. Zell, Helv. Chim. Acta, 1979, 62, 455. (c) G. Bettoni, C.
Cellucci, and F. Berardi, J. Heterocycl. Chem., 1980, 17, 603.