Studies toward the synthesis of (R)-(+)-harmicine

Article abstract of DOI:10.1002/cjoc.201200672

The study toward the total synthesis of (R)-(+)-harmicine is reported in this paper. The enantioselective synthesis of pyrrolidinone, the main backbone of of (R)-(+)-harmicine, has been completed by the methodology based on photo-induced Wolff rearrangement of α-diazo-β-carbonyl compounds. Copyright

Full text of DOI:10.1002/cjoc.201200672

FULL PAPER
DOI: 10.1002/cjoc.201200672
Studies toward the Synthesis of (R)-(＋)-Harmicine
Mo, Fanyang(莫凡洋)
Li, Fei(李飞)
Qiu, Di(邱頔)
Zhang, Yan*(张艳)
Wang, Jianbo*(王剑波)
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
The study toward the total synthesis of (R)-(＋)-harmicine is reported in this paper. The enantioselective syn-
thesis of pyrrolidinone, the main backbone of of (R)-(＋)-harmicine, has been completed by the methodology based
on photo-induced Wolff rearrangement of α-diazo-β-carbonyl compounds.
Keywords
diastereoselective synthesis, (R)-( ＋ )-harmicine, diazo compounds, Wolff rearrangement,
photo-induced reaction
Introduction
efficient preparation of racemic harmicine, employing
their newly developed Rh-catalyzed cyclohydrocarbon-
ylation-bicyclization of N-allylic amides of arylacetic
acids.[5] Previous literatures have showed that most of
the syntheses of harmicine starts from tryptamine, and
the chiral centers are established through asymmetric
catalytic reactions. In general, chiral ligands with com-
plicated structure are needed to achieve the high enanti-
oselectivity.
Recently, we have developed a new approach toward
the enantioselective construction of pyrrolidine ring,
based on diastereoselective nucleophilic addition of
lithium enolate of α-diazoacetate to chiral N-sulfinyl
imine and Wolff rearrangement.[6-8] Herein, we report
the application of this methodology in the synthesis of
(R)-(＋)-harmicine (1) (Figure 1).
(R)-(＋)-Harmicine (1), a tetracyclic β-carboline al-
kaloid, was first isolated from the leaves of Kopsia grif-
fithii by Sim et al.[1] in 1998. This natural product con-
tains a tetrahydro-β-carboline unit and a pyrrolidine unit.
It exhibits strong anti-leishmania activity. The synthesis
of (R)-(＋)-harmicine has attracted great interest be-
cause of its unique structure and potential biological
activities. A variety of investigations on the synthesis of
harmicine have been reported, either in the form of ra-
cemic mixture or in the form of optically pure isomers.
Knölker and Agarwal reported the first synthesis of ra-
cemic harmcine, starting from 4,9-dihydro-3H-pyrido-
[3,4-b]indole.[2a] Three years later, another three-step
approach of the synthesis of racemic harmcine was
completed from the readily available 4,4-diethoxybutan-
1-amine.[2b] Subsequently, Czarnocki and coworkers
achieved the enantioselective synthesis of optically pure
(R)-(＋)-harmicine via the asymmetric transfer hydro-
genation (ATH) reaction in 2007.[3a] In the same year,
Allin and coworkers completed a facile asymmetric
synthesis of (R)-(＋)-harmicine via a step of highly di-
atereoselective N-acyliminium cyclzation methodology
developed by the same group.[3b] On the other hand,
Jacobsen and coworkers completed the synthesis of
(R)-(＋)-harmicine starting from tryptamine. The key
step in Jacobsen’s synthesis is the enantioselective
Pictet-Spengler-type cyclization of hydroxylactam by
chiral thiourea catalysis.[4a] More recently, a cascade
one pot condensation including intramolecauler cycliza-
tion and Pictet-Spengler reaction for the synthesis of
racemic harmicine was completed by Jana and co-
worker.[4b] In 2009, Ojima and coworkers reported the
Experimental
All reactions with air- and moisture-sensitive com-
ponents were performed under a nitrogen atmosphere.
Anhydrous ethyl ether, toluene, benzene and tetrahy-
drofuran were freshly distilled from Na before use. Di-
chloromethane was distilled from calcium hydride. The
boiling point of petroleum ether is between 60 and 90
℃. 200—300 mesh silica gel for the chromatography
was employed. 1H NMR (300 MHz) and 13C NMR (70
MHz) spectra were measured on a Bruker-400 ARX
spectrometer. Chemical shifts are reported relative to
tetramethylsilane (TMS) as the internal standard. Mass
spectra were determined on a VG ZAB-HS mass spec-
trometer. IR was recorded with a Nicolet Avatar 330
FT-IR infrared spectrometer.
*
E-mail: wangjb@pku.edu.cn
Received July 3, 2012; accepted August 29, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200672 or from the author.
Chin. J. Chem. 2012, 30, 2297—2302 © 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Mo et al.
FULL PAPER
＝30∶1, V∶V) on silica gel to give carboxylate (4) in
1
97% yield (2.3 g). White solid; H NMR (300 MHz,
H
N
N
CDCl3) δ: 7.70—7.67 (m, 1H), 7.43—7.36 (m, 1H),
7.34—7.28 (m, 2H), 7.24—7.10 (m, 4H), 7.04—7.01
(m, 2H), 5.82 (s, 2H), 4.30 (q, J＝7.2 Hz, 2H), 1.32 (t,
J＝7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ: 161.8,
139.4, 138.2, 128.4, 127.6, 127.0, 126.1, 126.0, 125.1,
122.5, 120.7, 110.9, 110.7, 60.5, 47.7, 14.2.
N
N
H
H
H
H
(R)-(+)-harmicine (1)
O
S
p-Tol
PG'
NH
NH
O
hν
O
C
(1-Benzyl-1H-indol-2-yl)methanol (5) and 1-benzyl-
1H-indole-2-carbaldehyde (6)
N
O
N
PG
N2
PG
Oallyl
Oallyl
O
Carboxylate (4) (4.853 g, 17.4 mmol) was added to a
500 mL round bottom flask and dissolved in THF (100
mL). The solution was cooled to 0 ℃ and lithium alu-
minium hydride (660 mg, 17.4 mmol) was added slowly.
The system was stirred for 30 min at 0 ℃ until the
starting material was completely consumed. Aqueous
sodium hydroxide (15%, 20 mL) and deionized water
(40 mL) was added gradually to quench the reaction and
the precipitate was filtered and washed by ethyl acetate.
Organic layer was separated and dried over anhydrous
sodium sulfate. The solvent was removed by evapora-
tion under vacuum and the crude alcohol (5) was then
dissolved with dichloromethane (25 mL). Manganese
dioxide (7.57 g, 87 mmol) was added to the solution and
the mixture was stirred for another 32 h while moni-
tored by TLC. Excessive manganese dioxide was fil-
tered and washed by ethyl acetate. The filtration was
evaporated under vacuum to remove the solvent. The
residue was purified by flash column chromatography
(petroleum∶ethyl acetate＝50∶1, V∶V) on silica gel
O
S
p-Tol
OLi
N
O
N
H
N2
Oallyl
PG
Figure 1 Synthetic plan for (R)-(＋)-harmicine (1).
Ethyl 1H-indole-2-carboxylate (3)[9]
1H-Indole-2-carboxylic acid (2) (2.0 g, 12.4 mmol)
was dissolved in absolute ethanol (12 mL) and cooled to
0 ℃ by ice-water bath. Sulfuryl dichloride (1.6 mL,
22.4 mmol, 2 equiv.) was added to the solution drop-
wise and the mixture was then refluxed for another 2 h
while monitored by TLC. Ethanol and excessive sul-
furyl dichloride were evaporated under vacuum upon
completion of the reaction. Dichoromethane (20 mL)
was added to dissolve the crude product. The solution
was washed by saturated aqueous sodium carbonate (25
mL×2), and the combined organic layer was dried over
anhydrous sodium sulfate. Crude product 3 was ob-
tained as yellow oil after removing the solvent under
1
to yield carbaldehyde (6) (2.954 g). Compound (5): H
NMR (300 MHz, CDCl3) δ: 7.61—7.58 (m, 1H),
7.24—7.06 (m, 6H), 6.95—6.92 (m, 2H), 6.46 (s, 1H),
5.36 (s, 2H), 4.61 (s, 2H), 1.87 (s, 1H); 13C NMR (75
MHz, CDCl3) δ: 138.6, 137.9, 137.8, 128.7, 127.3,
127.2, 125.9, 122.2, 120.8, 119.8, 109.7, 102.1, 57.4,
46.7. Compound (6): white solid; 72% yield by two
steps; 1H NMR (300 Hz, CDCl3) δ: 9.89 (s, 1H),
7.76—7.73 (m, 1H), 7.37—7.31 (m, 3H), 7.27—7.14
(m, 4H), 7.09—7.07 (m, 2H), 5.82 (s, 2H); 13C NMR
(75 Hz, CDCl3) δ: 182.5, 142.3, 140.5, 137.6, 135.3,
128.5, 127.2, 127.1, 126.5, 123.4, 121.1, 118.2, 110.9,
47.8.
1
vacuum. H NMR (300 MHz, CDCl3) δ: 9.22 (s, 1H),
7.70—7.67 (m, 1H), 7.44—7.41 (m, 1H), 7.34—7.29
(m, 1H), 7.24—7.23 (m, 1H), 7.17—7.12 (m, 1H), 4.42
(q, J＝7.2 Hz, 2H), 1.42 (t, J＝7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ: 162.1, 136.8, 127.4, 125.2, 122.5,
120.7, 111.8, 108.6, 61.0, 14.3.
Ethyl 1-benzyl-1H-indole-2-carboxylate (4)[9]
Well powdered potassium hydroxide (1.9 g, 34
mmol) was dissolved in anhydrous DMSO (20 mL) un-
der stirring in a 100 mL round-bottomed flask. Car-
boxylate (3) (1.6 g, 8.5 mmol) was added to the solution
and the mixture was stirred for 30 min to give yellow
solution. Then benzyl bromide (2 mL, 17 mmol) was
added and the solution was stirred for 1 h while moni-
tored by TLC. The mixture was cooled to 0 ℃ and the
excessive potassium hydroxide was neutralized by satu-
rated aqueous ammonium chloride solution. Ethyl ether
(30 mL×2) was added to extract the product and or-
ganic layers were combined and washed by deionized
water (20 mL). The organic layer was dried over anhy-
drous sodium sulfate and the solvent was removed by
evaporator under vacuum. The residue was purified by
flash column chromatography (petroleum∶ethyl acetate
(1H-Indol-2-yl) methanol (13)[11]
Lithium aluminum hydride (1.5 equiv.) was added
by portion to the solution of crude product (3) (1 mmol)
in THF (100 mL) under vigorous stirring. Several drops
of aqueous sodium hydroxide (15%) and deionized wa-
ter (50 mL) were gradually added to the reaction system.
The white precipitation was filtered and washed with
ethyl acetate. The organic layer of filtration was sepa-
rated and the water layer was extracted with ethyl ace-
tate. The organic layers were combined and dried over
anhydrous sodium sulfate and the solvent was removed
by evaporator under vacuum. The crude residue was
purified by flash column chromatography (petroleum∶
2298
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2297—2302

Studies toward the Synthesis of (R)-(＋)-Harmicine
ethyl acetate＝30∶1, V∶V) on silica gel to yield a pale
solid compound (13) (＞99%). H NMR (300 MHz,
CDCl3) δ: 8.34 (s, 1H), 7.57—7.48 (m, 1H), 7.24—7.02
(m, 3H), 6.33 (s, 1H), 4.65 (s, 2H), 2.45 (s, 1H).
(m, 2H), 7.17—7.10 (m, 7H), 6.92—6.89 (m, 2H), 5.92
(d, J＝6.2 Hz, 1H), 5.75 (d, J＝6.2 Hz, 1H), 2.35 (s,
3H); 13C NMR (75 MHz, CDCl3) δ: 151.5, 142.0, 141.3,
140.6, 137.7, 133.0, 129.6, 128.3, 126.9, 126.1, 125.9,
124.5, 122.5, 120.8, 115.1, 110.4, 48.0, 21.3; IR (film) ν:
3054, 3031, 2922, 1586, 1451, 1352, 1094, 1070, 807,
749, 736, 725, 694, 684 cm ; EI-MS (m/z, relative in-
tensity): 278 (14), 232 (69), 139 (53), 123 (24), 91 (100),
65 (30). HRMS (ESI) calcd for C23H21N2OS (M＋H)
373.1369; found 373.1368.
1
tert-Butyl 2-formyl-1H-indole-1-carboxylate (15)[11,12]
－
1
Alcohol (13) (4.551 g, 31 mmol) was dissolved to
dichloromethane (100 mL) in a 500 mL round-bottomed
flask under stirring. Manganese dioxide (13.5 g, 155
mmol, 5 equiv.) was then added to the solution and the
mixture was stirred for another 40 h while monitored by
TLC. The excessive manganese dioxide was filtered and
washed by ethyl acetate. The filtration was evaporated
under vacuum to afford the crude aldehyde (14). The
crude product was dissolved in THF and cooled to 0 ℃
by ice-water bath. Then triethyl amine (3.7 g, 1.2
equiv.), di-tert-butyl dicarbonate (Boc2O, 7.9 g, 1.2
equiv.) and N',N'-dimethylaminopyridine (DMAP, 380
mg, 10 mol%) were added to the solution. The ice-water
bath was removed and the mixture was stirred for an-
other 2 h at room temperature. The solvent was evapo-
rated under vacuum and the residue was purified by
flash column chromatography (petroleum∶ethyl acetate
＝40∶1, V∶V) on silica gel to yield aldehyde (15)
(87% yield for two steps). Aldehyde (14), white solid;
1H NMR (300 MHz, CDCl3) δ: 9.86 (s, 1H), 9.72 (s,
1H), 7.83—7.67 (m, 1H), 7.58—7.48 (m, 1H),
7.42—7.38 (m, 1H), 7.29—7.25 (m, 1H), 7.20—7.11
(m, 1H); 13C NMR (75 MHz, CDCl3) δ: 182.3, 138.2,
135.8, 127.1, 123.3, 121.3, 121.0, 115.0, 112.6.
Aldehyde (15): 1H NMR (300 MHz, CDCl3) δ: 10.43 (s,
1H), 8.18—8.15 (m, 1H), 7.68—7.65 (m, 1H),
7.51—7.43 (m, 1H), 7.32—7.26 (m, 1H), 1.72 (s, 9H);
13C NMR (75 MHz, CDCl3) δ: 184.0, 149.7, 137.7,
128.1, 127.3, 123.7, 123.0, 116.3, 116.2, 115.9, 85.5,
28.0.
(S,Z)-tert-Butyl 2-((p-tolylsulfinylimino)methyl)-1H-
indole-1-carboxylate (16)
Yellow solid, 90% yield, [α]2D0 ＋44.5 (c 1.0 in
1
CHCl3); H NMR (300 MHz, CDCl3) δ: 9.35 (s, 1H),
8.28—8.12 (m, 1H), 7.72—7.57 (m, 3H), 7.44—7.23
(m, 5H), 2.40 (s, 3H), 1.72 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ: 154.0, 149.7, 141.7, 141.6, 137.9, 134.9,
129.8, 128.1, 126.9, 124.7, 123.5, 122.0, 115.9, 114.0,
85.5, 28.2, 21.4; IR (film) ν: 2974, 1736, 1570, 1534,
1441, 1382, 1327, 1219, 1159, 1120, 1098, 747, 675
－
1
cm ; EI-MS (m/z, relative intensity): 242 (5), 169 (10),
142 (100), 91 (32), 57 (81), 41 (39). Anal. calcd for
C21H22N2O3S: C 65.95, H 5.80, N 7.32; found C 65.95,
H 5.85, N 7.31.
General procedure for preparation of sulfinimide (10)
and (17)
LiHMDS (2 mL, 2 equiv., 1.0 mol/L solution in
cyclohexane) was added to chilly solution of chiral
sulfinimide (8) in dichloromethane (10 mL) at －78 ℃.
Then the solution of diazoester (9) (1.5 equiv.) in di-
chloromethane was added dropwise to the mixture in 5
min. The system was stirred for another 15 min until no
sulfinimide could be monitored by TLC. Saturated
aqueous ammonium chloride solution (10 mL) was
added to quench the reaction and the solid was melted
by warm blowing. Deionized water (10 mL) was added
to the system and dicholoromethane was used to extract
the product (20 mL×2). Organic layers were combined
and dried over anhydrous sodium sulfate. The solvent
was removed by evaporation under vacuum and the
crude residue was purified by flash column chromatog-
raphy (petroleum∶ethyl acetate＝3∶1, V∶V) on silica
gel to afford the corresponding diazoester.
General procedures for the preparation of sulfinim-
ide (8) and (16)
Carbaldehyde (6) or (15) (13.7 mmol) was added to
a 500 mL round-bottomed flask and dissolved in di-
chloromethane (100 mL). Chiral sulfinamide (7) (2.3 g,
15 mmol) and Ti(OiPr)4 (12.3 mL, 41 mmol) were
added to the solution and the mixture was refluxed for 5
h to complete the reaction. The system was cooled to 0
℃ and was then quenched by saturated aqueous sodium
dicarbonate. The yellow precipitation was filtered and
washed with dichloromethane. Organic layer was sepa-
rated and dried over anhydrous sodium sulfate. The
solvent was removed by evaporation under vacuum and
the crude residue was purified by flash column chroma-
tography (petroleum∶ethyl acetate＝15∶1, V∶V) on
silica gel to yield the sulfinimide (8) or (16).
(R)-Allyl 5-(1-benzyl-1H-indol-2-yl)-2-diazo-5-((S)-4-
methylphenylsulfinamido)-3-oxo-pentanoate (10)
Yellow oil, yield 77%, [α]2D0 ＋26.4 (c 0.86 in
CHCl3); 1H NMR (300 MHz, CDCl3) δ: 7.63—7.57 (m,
1H), 7.34—7.20 (m, 6H), 7.16—7.01 (m, 6H), 6.55 (s,
1H), 5.98—5.85 (m, 1H), 5.58 (dd, J＝23.4, 6.3 Hz,
2H), 5.37—5.22 (m, 3H), 4.69 (d, J＝5.7 Hz, 2H), 4.61
(d, J＝8.4 Hz, 1H), 3.74 (dd, J＝17.4, 10.2 Hz, 1H),
3.51 (dd, J＝17.4, 11.1 Hz, 1H), 2.34 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ: 189.4, 160.6, 141.8, 141.3, 138.9,
137.5, 137.4, 131.2, 129.3, 128.6, 127.2, 127.2, 126.1,
125.1, 122.2, 120.7, 119.9, 119.2, 109.9, 100.9, 65.8,
48.1, 46.7, 45.9, 21.2; IR (film) ν: 3031, 2137, 1715,
(S,Z)-N-((1-Benzyl-1H-indol-2-yl)methylene)-4-mthyl
benzenesulfinimide (8)
Pale yellow oil, 85% yield, [α]2D0 －116.9 (c 1.5 in
1
CHCl3); H NMR (300 Hz, CDCl3) δ: 8.77 (s, 1H),
7.70—7.67 (m, 1H), 7.41—7.38 (m, 2H), 7.29—7.27
Chin. J. Chem. 2012, 30, 2297—2302
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Mo et al.
FULL PAPER
－
1
1649, 1462, 1452, 1371, 1302, 1086, 1065, 1017, 831,
1356, 1313, 1285, 1246, 1167, 1014, 730 cm ; EI-MS
(m/z, relative intensity): 474 (3), 374 (8), 283 (7), 218
(9), 91 (100), 57 (21), 41 (44). HRMS (ESI) calcd for
C28H30N4O5Na (M＋Na) 525.2108, found 525.2130.
－
1
730 cm ; EI-MS (m/z, relative intensity): 390 (13), 374
(4), 333 (5), 299 (5), 218 (7), 124 (7), 91 (100), 65 (11),
28 (71); HRMS (ESI) calcd for C30H29N4O4S (M＋H)
541.19040, found 541.1909.
(R)-tert-Butyl 2-(5-(allyloxy)-1-(tert-butoxycarbon-
ylamino)-4-diazo-3,5-dioxopent-yl)-1H-indole-1-car-
boxylate (18)
tert-Butyl 2-((R)-5-(allyloxy)-4-diazo-1-((S)-4-methyl
phenylsulfinamido)-3,5-dioxopentyl)-1H-indole-1-
carboxylate (17)
Yellow solid, 94% yield, [α]2D0 ＋45.0 (c 1.45 in
CHCl3); 1H NMR (300 MHz, CDCl3) δ: 8.04 (d, J＝8.4
Hz, 1H), 7.47 (d, J＝7.2 Hz, 1H), 7.27—7.16 (m, 2H),
6.61 (s, 1H), 6.05 (d, J＝9.0 Hz, 1H), 5.93—5.80 (m,
2H), 5.32—5.24 (m, 2H), 4.65 (d, J＝5.7 Hz, 2H), 3.73
(dd, J＝16.2, 6.0 Hz, 1H), 3.34 (dd, J＝15.9, 5.1 Hz,
1H), 1.72 (s, 9H), 1.43 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ: 190.3, 160.6, 154.8, 150.3, 140.4, 136.7,
131.2, 128.5, 124.0, 122.7, 120.5, 119.1, 115.6, 108.7,
84.6, 79.4, 65.8, 46.6, 43.7, 28.3, 28.1; IR (film) ν: 2977,
2926, 2136, 1718, 1652, 1488, 1453, 1368, 1327, 1158,
1116, 1085, 1054, 911, 769, 735 cm ; EI-MS (m/z,
relative intensity): 384 (5), 328 (15), 284 (16), 270 (15),
226 (10), 145 (20), 57 (100), 41 (71). HRMS (ESI)
calcd for C26H32N4O7Na (M＋Na) 535.2163, found
535.2160.
Dark red solid, 73% yield, [α]2D0 ＋92.4 (c 1.0 in
CHCl3); 1H NMR (300 MHz, CDCl3) δ: 8.04—8.01 (m,
1H), 7.31 (d, J＝8.4 Hz, 2H), 7.50—7.47 (m, 1H),
7.28—7.25 (m, 3H), 7.22—7.16 (m, 1H), 6.68 (s, 1H),
5.96—5.83 (m, 1H), 5.70—5.54 (m, 2H), 5.35—5.25
(m, 2H), 4.66 (dt, J＝5.7, 1.2 Hz, 2H), 3.78—3.71 (m,
1H), 3.51 (dd, J＝16.8, 5.7 Hz, 1H), 2.39 (s, 3H), 1.69
(s, 9H); 13C NMR (75 MHz, CDCl3) δ: 189.8, 160.6,
150.5, 142.2, 141.1, 140.8, 136.7, 131.3, 129.3, 128.5,
125.6, 124.3, 122.8, 120.7, 119.2, 115.7, 109.4, 84.8,
65.8, 50.2, 45.2, 28.1, 21.3; IR (film) ν: 2977, 2926,
2139, 1719, 1650, 1453, 1370, 1326, 1304, 1213, 1156,
1117, 1090, 1065, 910, 810, 768, 734 cm ; EI-MS (m/z,
relative intensity): 300 (17), 284 (15), 267 (10), 246
(38), 209 (23), 170 (23), 144 (24), 124 (65), 91 (100),
77 (24), 44 (73), 39 (47); HRMS (ESI) calcd for
C28H31N4O6S (M＋H) 551.1959, found 551.1965.
－
1
－
1
(5R)-3-Allyl N-tert-butyl 5-(1-(tert-butoxycarbonyl)-
1H-indol-2-yl)-2-oxopyrrolidine-1,3-dicarboxylate
(19)
General procedures for preparation of diazoesters 11
and 18
N-Boc protected diazoester (18) was dissolved in
benzene and subjected to irradiation (500 W, Hg lamp,
Pyrex tube) under stirring. The system was kept at room
temperature by cooling water condenser and the irradia-
tion was kepted for 4 h until no IR signal of diazo moi-
The addition product (10) or (17) was dissolved in
methanol and cooled to 0 ℃. Trifluoroacetic acid (TFA,
5.0 equiv.) was added to the solution and the ice-water
bath was removed. The system was warmed to room
temperature gradually and was stirred for another 2 h.
The solvent was removed by evaporating under vacuum
and the crude residue was dissolved in THF and cooled
to 0 ℃. Triethyl amine (6 equiv.), Boc2O (1.2 equiv.)
and N',N'-dimethylaminopyridine (5 mol%) were added
to the solution. Then ice-water bath was taken away and
the mixture was stirred for another 2 h at room tem-
perature. Solvent was removed by evaporation under
vacuum and the residue was purified by flash column
chromatography (petroleum∶ethyl acetate ＝ 10∶1,
V∶V) on silica gel to yield N-Boc protected diazoester
11 or 18.
ety in around 2100 cm－ could be observed. The mix-
1
ture was then transferred to round-bottomed flask. Sol-
vent was removed by evaporation under vacuum and the
residue was purified by flash column chromatography
(petroleum∶ethyl acetate＝10∶1, V∶V) on silica gel
to afford 2-oxopyrrolidine (19). Yield 64%, colorless oil;
1H NMR (300 MHz, CDCl3) δ: 8.09—8.01 (m, 1H),
7.49—7.42 (m, 1H), 7.32—7.18 (m, 2H), 6.42 (s, 1H),
6.04 (d, J ＝ 8.7 Hz, 1H), 5.98—5.85 (m, 1H),
5.40—5.06 (m, 2H), 4.75—4.42 (m, 2H), 3.71 (dd, J＝
12.3, 8.4 Hz, 1H), 2.96—2.85 (m, 1H), 2.54—2.30 (m,
1H), 1.71 (s, 9H), 1.44 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ: 168.8, 168.1, 149.9, 149.2, 139.9, 136.6,
131.3, 131.2, 128.2, 124.3, 123.1, 120.4, 118.7, 115.6,
115.6, 105.7, 105.6, 84.8, 83.6, 66.2, 54.8, 54.7, 47.9,
47.9, 29.5, 28.1, 27.7, 27.6; IR (film) ν: 2932, 1790,
1730, 1454, 1369, 1328, 1290, 1250, 1148, 1117, 1084,
(R)-Allyl 5-(1-benzyl-1H-indol-2-yl)-5-(tert-butoxy-
carbonylamino)-2-diazo-3-oxopentanoate (11)
Yellow solid, 95% yield, [α]2D0 ＋80.5 (c 1.0 in
CHCl3); 1H NMR (300 MHz, CDCl3) δ: 7.58—7.56 (m,
1H), 7.25—7.10 (m, 5H), 7.09—7.00 (m, 3H), 6.46 (s,
1H), 5.99—5.86 (m, 1H), 5.51—5.43 (m, 3H),
5.37—5.28 (m, 2H), 4.88 (d, J＝8.1 Hz, 1H), 4.70 (d,
J＝5.4 Hz, 2H), 3.67 (dd, J＝15.9, 9.3 Hz, 1H), 3.38
(dd, J＝15.9, 9.3 Hz, 1H), 1.29 (s, 9H); 13C NMR (75
MHz, CDCl3) δ: 189.3, 160.9, 154.3, 139.6, 137.6,
137.3, 131.2, 128.5, 127.2, 127.0, 126.0, 122.0, 120.5,
119.7, 119.1, 109.9, 99.6, 79.6, 65.8, 46.6, 44.7, 43.7,
28.0; IR (film) ν: 3346, 2141, 1718, 1678, 1517, 1464,
－
1
913, 848, 769, 739 cm ; EI-MS (m/z, relative intensity):
484 (6), 384 (10), 328 (7), 284 (68), 226 (39), 199 (21),
171 (14), 51 (100), 41 (68). HRMS (ESI) calcd for
C26H32N2O7Na (M＋Na) 507.2102, found 507.2101.
(R)-tert-Butyl 2-(1-(tert-butoxycarbonyl)-5-oxo-
pyrrolidin-2-yl)-1H-indole-1-carboxylate (20)
Wolff rearrangement product (19) (454 mg, 0.94
mmol) was dissolved in 20 mL THF at room tempera-
2300
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2297—2302

Studies toward the Synthesis of (R)-(＋)-Harmicine
ture in a 100 mL round-bottomed flask. Morpholine
(261 mg, 3 equiv.) and Pd(PPh3)4 (55 mg, 5 mol %)
were added to the solution and the mixture was stirred
for 6 h. Solvent was removed by evaporating under
vacuum and the residue was purified by flash column
chromatography (petroleum∶ethyl acetate＝5∶1,
V∶V) on silica gel to produce oxopyrrolidine (20)
(0.268 g). White solid, yield 71%, [α]2D0 ＋139.2 (c
0.5 in CHCl3); 1H NMR (300 MHz, CDCl3) δ:
8.09—8.06 (m, 1H), 7.49—7.46 (m, 1H), 7.32—7.20
(m, 2H), 6.44 (s, 1H), 6.00 (d, J＝6.9 Hz, 1H),
3.77—3.73 (m, 1H), 2.71—2.60 (m, 1H), 2.56—2.41
(m, 2H), 2.07—2.01 (m, 1H), 1.92—1.83 (m, 1H), 1.71
(s, 9H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3) δ:
174.4, 150.1, 149.6, 140.9, 136.6, 128.5, 124.1, 123.0,
120.4, 115.6, 105.6, 84.6, 83.0, 56.6, 30.5, 28.1, 27.7,
25.4; IR (film) ν: 2926, 1785, 1731, 1369, 1328, 1305,
Scheme 1 Preparation of chiral sulfinimide (8)
a
CO2H
CO2Et
N
N
H
H
2
3
OH
b
c
d
CO2Et
N
N
Bn
Bn
4
5
O
O
S
S
p-Tol
p-Tol
NH2
N
7
CHO
N
e
N
H
6
8
Bn
Bn
Reagents and conditions: (a) SOCl2 (2 equiv.), EtOH, 0 oC,
then, reflux, 2 h, quant.; (b) BnBr (2 equiv.), KOH (4 equiv.),
DMSO, r.t., 1 h, 97%; (c) LiAlH4 (1 equiv.), THF, r.t., 0.5 h,
>99%; (d) MnO2 (5 equiv.), CH2Cl2, r.t., 32 h, 72%; (e) 7 (1.1
equiv.), Ti(Oi-Pr)4 (3 equiv.), CH2Cl2, reflux, 5 h, 85%.
－
1
1282, 1252, 1152, 1116, 1084, 744 cm ; EI-MS (m/z,
relative intensity): 400 (5), 300 (6), 200 (100), 183 (11),
171 (17), 156 (19), 117 (10), 89 (11), 57 (90), 41 (63),
29 (22). HRMS (ESI) calcd for C22H28N2O5Na [(M＋
Na)＋] 423.1890, found 423.1887.
Scheme 2 Attempted photoinduced Wolff rearrangement/
cyclization
Results and Discussion
O
O
As shown in Scheme 1, starting from commercially
available 1H-indole-2-carboxylic acid (2), crude
ethyl-1H-indole-2-carboxylate (3) was prepared in
quantitative yield by chlorination and subsequent esteri-
fication. Then, the nitrogen of the indole ring was pro-
tected by benzyl group in 97% yield.[9] N-Protected car-
boxylate (4) was subsequently reduced to alcohol (5),
which was then oxidized to aldehyde (6). Ti(Oi-Pr)4-
promoted condensation of aldehyde (6) with chiral
sulfinamide (7) led to the formation of sulfinimide (8) in
85% yield.[7,8]
Oallyl
N2
9
a
O
S
p-Tol
NHBoc
O
NH
b, c
N
O
O
N
O
Bn
11
N2
Oallyl
Bn
10
N2
Oallyl
e
With sulfinimide (8) in hand, diastereoselective ad-
dition of α-diazo-β-oxoester (9)[10] to 8 in the presence
of LiHMDS was carried out (Scheme 2). The addition
reaction proceeded with high diastereoselectivty and 10
were obtained as essentially single stereoisomer. Since
our previous study has indicated that the N-sulfinyl
group was not compatible with the subsequent photo-
chemical conditions,[6b] so the N-sulfinyl group was re-
placed by tert-butyloxycarbonyl (Boc), and the N-Boc
diazo compound (11) was subjected to the photolysis.
However, the subsequent irradiation of 11 with Hg lamp
(500 W) failed to afford the expected cyclization prod-
uct. The irradiation of diazo compound (12), in which
the Boc protecting group was removed, also failed to
afford the expected cyclization product.
It is conceivable that the electronic properties of the
N-protecting group on indole ring may affect the stabil-
ity of the starting material as well as the products. An
electron-rich indole ring may not be compatible under
the irradiation condition. We then considered preparing
diazo compound (18), in which the N-protecting group
is more electron-withdrawing Boc, as the precursor for
d
NH2
d
O
complex mixture
N
O
Bn
N2
Oallyl
12
Reagents and conditions: (a) LiHMDS (2 equiv.), 8, CH2Cl2, -78 oC,
77%; (b) TFA (5 equiv.), MeOH, 0 oC to r.t.; (c) Boc2O (1.1 equiv.),
Et3N (6 equiv.) 5 mol% DMAP, THF, 0 oC to r.t., 95%, two steps;
(d) hν, Hg lamp (500 W), benzene, 4 h; (e) 1) TFA (5 equiv.), MeOH,
0 oC, Cy2NMe
photoinduced Wolff rearrangement. Therefore, we de-
signed to synthesize aldehyde (15), which bears elec-
tron-withdrawing Boc protecting group (Scheme 3).
Starting from carboxylate (3), aldehyde (15) could be
synthesized in three steps with good yield.[11-13]
Sulfinimide (16) was then prepared through the con-
densation of 15 with chiral sulfinamide (7). Again,
highly diastereoselective addition of α-diazo-β-oxoester
(9) to 16 took place in the presence of LiHMDS and led
to the formation of optically pure diazoester (17) in 73%
Chin. J. Chem. 2012, 30, 2297—2302
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2301

Mo et al.
FULL PAPER
Scheme 3 Enantioselective synthesis of indole (20)
was added by portion.
OH
b
a
Conclusions
CO2Et
N
N
H
We have successfully employed the diastereoselec-
tive nucleophilic addition of lithium enolate of
α-diazoacetate to chiral N-sulfinyl imine and subsequent
photoinduced Wolff rearrangement/cyclization in the
synthesis of an intermediate which contains the required
chiral center and three rings for the synthesis of
(R)-(＋)-harmicine. Further study is undergoing and the
results will be reported in due course.
H
3
13
CHO
Boc
c
d
CHO
N
N
H
14
15
O
O
S
S
p-Tol
p-Tol
NH
Acknowledgement
f, g
e
N
O
N
O
The project is supported by the National Natural
Science Foundation of China (No. 21072009,
21172005), National Basic Research Program of China
(973 Program, No. 2009CB825300) and the Research
Fund for the Doctoral Program of Higher Education (No.
20090001120014).
N
H
Boc
17
Boc
N2
Oallyl
16
NHBoc
O
Boc
h
N
N
O
O
N
H
Boc
18
Boc
References
N2
Oallyl
Oallyl
O
19
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Boc
N
i
N
O
N
N
H
H
H
Boc
(R)-(+)-harmicine (1)
20
Reagents and conditions: (a) LiAlH4 (1.5 equiv.), THF, r.t., 1 h,
quant.; (b) MnO2 (5 equiv.), CH2Cl2, r.t., 40 h; (c) Boc2O (1.2
equiv.), Et3N (1.2 equiv.), 10 mol% DMAP, THF, 0 oC to r.t., 2 h,
87%, two steps; (d) 7 (1.1 equiv.), Ti(Oi-Pr)4 (3 equiv.), CH2Cl2,
reflux, 5 h, 90%; (e) LiHMDS (2 equiv.), 9 (1.5 equiv.), CH2Cl2,
-78 oC, 73%; (f) TFA (5 equiv.), MeOH, 0 oC to r.t.; (g) Boc2O
(1.2 equiv.), Et3N (6 equiv.) 5 mol% DMAP, THF, 0 oC to r.t.
94%, two steps; (h) hν 500 W Hg lamp, benzene, 4 h, 64%; (i)
Pd(PPh3)4 (5 mol %), morpholine (3 equiv.), THF, r.t., 6 h, 71%.
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yield. Then the similar steps as for the preparation of 11
were followed to synthesize N-Boc protected compound
18 in 95% yield. To our delight, irradiation of 18 led to
the expected Wolff rearrangement and subsequent cy-
clization afforded 19 in 64% yield. This result testified
our original conjecture that the Wolff rearrangement
was affected by the electronic properties of the N-pro-
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removal of allyl oxycarbonyl group on 3-position of the
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pyrrolidinone (20) could be obtained when Pd(PPh3)4
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(Lu, Y.)
2302
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2297—2302