An expedient route to montanine-type amaryllidaceae alkaloids: Total syntheses of (-)-brunsvigine and (-)-manthine

Article abstract of DOI:10.1021/jo801089y

(Chemical Equation Presented) The first total syntheses of (-)-brunsvigine (1) and (-)-manthine (2) were accomplished in 10 and 18 steps, respectively. (-)-Quinic acid was converted to enone 12 in live steps. Iodination of enone 12 followed by stereoselec

Full text of DOI:10.1021/jo801089y

An Expedient Route to Montanine-Type Amaryllidaceae Alkaloids:
Total Syntheses of (-)-Brunsvigine and (-)-Manthine
An-Wei Hong, Tsung-Hui Cheng, Vellingiri Raghukumar, and Chin-Kang Sha*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 300, Taiwan, ROC
cksha@mx.nthu.edu.tw
ReceiVed June 2, 2008
The first total syntheses of (-)-brunsvigine (1) and (-)-manthine (2) were accomplished in 10 and 18
steps, respectively. (-)-Quinic acid was converted to enone 12 in five steps. Iodination of enone 12
followed by stereoselective reduction yielded R-iodo allylic alcohol 16. Conversion of alcohol 16 into
Weinreb amide 11 followed by anionic cyclization gave bicyclic enone 10. Stereoselective reduction of
enone 10 and subsequent protection afforded pivaloate 9. Grignard addition of 8 to 9 and detosylation
afforded amine derivative 19. Pictet-Spengler cyclization of 19 with Eschenmoser′s salt and subsequent
hydrolysis gave enantiomerically pure (-)-brunsvigine (1). For the total synthesis of (-)-manthine (2),
the key intermediate 7 was hydrolyzed to diol 21. Conversion of 21 into 22 followed by regioselective
cleavage with DIBAL furnished alcohol 25. Alcohol 25 was converted to the corresponding triflate 26,
which on treatment with CsOAc and 18-crown-6 gave stereoinverted acetate 27. Hydrolysis of acetate
27 followed by methylation afforded compound 29. Detosylation of 29 afforded amine derivative 30.
Pictet-Spengler cyclization of 30 followed by debenzylation gave alcohol 33. Finally, methylation of
alcohol 33 afforded (-)-manthine (2).
Introduction
(-)-Brunsvigine and (-)-manthine, which are representative
members of montanine-type Amaryllidaceae alkaloids 1-6,1-3
incorporate an intriguing pentacyclic 5,11-methanomorphan-
thridine as the core skeleton. These alkaloids differ only in the
stereochemistry of the C2 and C3 oxygen substituents in the E
ring (Figure 1).4 When Wildman and co-workers initiated the
investigation of Amaryllidaceae alkaloids in 1955,5 they isolated
(-)-manthine (2) from Haemathus species and (-)-brunsvigine
(1) from BrunsVigia cooperi and BrunsVigia radulosa Herp.1,2
These montanine-type alkaloids possess important biological
(1) Dry, L. J.; Poynton, M. E.; Thompson, M. E.; Warren, F. L. J. Chem.
Soc. 1958, 4701.
(2) Inubushi, Y.; Fales, H. M.; Warnhoff, E. W.; Wildman, W. C. J. Org.
Chem. 1960, 25, 2153.
FIGURE 1. Structure of montanine-type Amaryllidaceae alkaloids.
(3) Wildman, W. C.; Brown, C. L. J. Am. Chem. Soc. 1968, 90, 6439.
(4) (a) Martin, S. F. The Amaryllidaceae Alkaloids. In The Alkaloids; Brossi,
A., Ed.; Academic Press: San Diego, CA, 1987; Vol. 30, p 252. (b) Lewis, J. R.
Nat. Prod. Rep. 1993, 10, 291. (c) Viladomat, F.; Bastida, J.; Codina, C.;
Campbell, W. E.; Mathee, S. Phytochemistry 1995, 40, 307.
(5) Wildman, W. C.; Kaufman, C. J. J. Am. Chem. Soc. 1955, 77, 1248.
activities including anxiolytic, antidepressant, and anticonvul-
sant-type effects.6,7 In conjunction with these activities, the
unique pentacyclic structure of these alkaloids has stimulated
considerable interest from the synthetic community.
7580 J. Org. Chem. 2008, 73, 7580–7585
10.1021/jo801089y CCC: $40.75 2008 American Chemical Society
Published on Web 09/10/2008

Montanine-Type Amaryllidaceae Alkaloids
SCHEME 1. Retrosynthesis of (-)-Brunsvigine (1) and (-)-Manthine (2)
Since Overman reported the first total synthesis of (()-
pancracine,8 several total syntheses of natural products in this
family have been published. In a series of accounts,9 Hoshino
and co-workers reported two elegant schemes to construct the
5,11-methanomorphanthridine ring system, resulting in prepara-
tion of (()-montanine, (()-coccinine, (()-pancracine, (()-
brunsvigine, and (()-O-acetylmontanine. In 1993, Overman and
Shim reported the first asymmetric total synthesis of (-)-
pancracine10 employing an aza-Cope-Mannich reaction as the
key step. Weinreb et al. reported an enantioselective total
syntheses of (-)-coccinine and (-)-pancracine with a formal
total synthesis of (-)-brunsvigine.11 Ishibashi and co-workers
reported a clever total synthesis of (()-pancracine12 employing
radical cyclization as the key step. Pandey′s group utilized a
1,3-dipolar cycloaddition of a nonstabilized azomethine ylide
to construct the 5,11-methanomorphanthridine ring system.13
Several formal total syntheses of various members of alkaloids
of the montanine type are reported, and the syntheses of
antipodes of the natural products, (+)-coccinine14 and (+)-
brunsvigine,15 have also been described.
We envisaged that the unique 5,11-methanomorphanthridine
ring system of (-)-brunsvigine (1) and (-)-manthine (2) might
be established by a Pictet-Spengler reaction (Scheme 1). The
necessary variation at C2 and C3 stereocenters would be
accessible by taking advantage of synthetic transformations. Key
intermediate 7 would be generated from a coupling of Grignard
8 and compound 9. Compound 9 would be obtained from
reduction and esterification of enone 10. Enone 10 might be
prepared from Weinreb amide 11 via an anionic cyclization.
Weinreb amide 11 could be obtained from commercially
available (-)-quinic acid through a sequence of transformations
of functional groups.
Results and Discussion
Our synthetic efforts began with commercially available (-)-
quinic acid. The requisite chiral enone 12 was prepared from
(-)-quinic acid by adapting a literature procedure.17 Iodination
of enone 12 was accomplished with Johnson′s procedure18 to
provide iodoenone 13. Compound 13 upon treatment with
NaBH4 in the presence of CeCl3 ·7H2O19 afforded a mixture of
epimers 14 and 16, which were separated by column chroma-
tography. As ꢀ-isomer 16 was used in the synthesis, the
unwanted R-isomer 14 was consequently converted into the
required ꢀ-isomer via a Mitsunobu reaction. Treatment of 14
with p-nitrobenzoic acid in the presence of triphenylphosphine
and diethyl azodicarboxylate gave 15. Compound 15 was
hydrolyzed with NaOH in MeOH to give compound 16.
Introduction of the Weinreb amide side chain to compound 16
afforded compound 11. Anionic cyclization of Weinreb amide
11 in the presence of n-BuLi thus furnished the desired bicyclic
enone 10 (Scheme 2).
Although a massive synthetic effort has been directed toward
almost all members of the montanine-type alkaloids, there has
been no report other than our own16 of the total syntheses of
(-)-brunsvigine (1) and (-)-manthine (2). Herein, we report
our total syntheses of enantiomerically pure (-)-brunsvigine
(1) and (-)-manthine (2).
(6) Southon, I. W.; Buckinghham, J. Dictionary of Alkaloids; Chapman &
Hall: New York, 1989; pp 229-735.
(7) Schu¨rmann da Silva, A. F.; de Andrade, J. P.; Bevilaqua, L. R. M.; da
Souza, M. M.; Izquierdo, I.; Henriques, A. T.; Zuanazzi, J. A. S. Pharmacol.,
Biochem. BehaV. 2006, 85, 148.
(8) Overman, L. E.; Shim, J. J. Org. Chem. 1991, 56, 5005.
(9) (a) Ishizaki, M.; Hoshino, O.; Iitaka, Y. Tetrahedron Lett. 1991, 32, 7079.
(b) Ishizaki, M.; Hoshino, O. J. Org. Chem. 1992, 57, 7285. (c) Ishizaki, M.;
Kurihara, K.-I.; Tanazawa, E.; Hoshino, O. J. Chem. Soc., Perkin Trans. 1 1993,
101.
(10) Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4662.
(11) (a) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 2050. (b) Jin,
J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 5773.
(12) Ikeda, M.; Hamada, M.; Yamashita, T.; Ikegami, F.; Sato, T.; Ishibashi,
H. Synlett 1998, 1246.
(13) Pandey, G.; Banerjee, P.; Kumar, R.; Puranik, V. G. Org. Lett. 2005, 7,
3713.
(14) Pearson, W. H.; Lian, B. W. Angew. Chem., Int. Ed. 1998, 37, 1724.
(15) Banwell, M. G.; Kokas, O. J.; Willis, A. C. Org. Lett. 2005, 9, 3503.
(16) A preliminary communication of this work has been published: Sha,
C.-K.; Hong, A.-W.; Huang, C.-M. Org. Lett. 2001, 3, 2177.
Total Synthesis of (-)-Brunsvigine (1). Stereoselective
reduction of enone 10 with NaBH4/CeCl3 ·7H2O gave the
corresponding alcohol 18, which was then converted to pivaloate
(17) (a) Elliott, J. D.; Hetmanski, M.; Stoodley, R. J. J. Chem. Soc., Perkin
Trans. 1 1981, 1782. (b) Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker,
M. W.; Chapman, H. H.; Kelley, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.;
Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem. 1998, 63,
4545.
(18) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanyake, C. B. W.;
Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917.
(19) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
J. Org. Chem. Vol. 73, No. 19, 2008 7581

Hong et al.
SCHEME 2. Synthesis of Chiral Azabicyclic Enone 10
SCHEME 3. Total Synthesis of (-)-Brunsvigine
9. The stereochemistry of 9 was unambiguously assigned
through a single-crystal X-ray analysis.20 A CuI-mediated SN2
reaction of 9 with 3,4-(methylenedioxy)phenylmagnesium bro-
mide (8) afforded key intermediate 721 in 76% yield. Detosy-
lation of 7 was executed on titration with sodium naphthalide
at -78 °C to produce amine 19.
drolyzed the ketal group to yield (-)-brunsvigine (1) (Scheme
3) with an overall yield of 12% from chiral enone 12. The
specific rotation [R]23D) -76.3 (c 1.02, EtOH; lit. [R]20
)
D
-76.6 (c 1.0, EtOH)), melting point, and spectral data of 1 agree
with literature data.1,2 To confirm the structure, we converted
the synthetic (-)-brunsvigine (1) to the stable crystalline
diacetate 1a. Structure of 1a was determined by single-crystal
X-ray analysis.20
To complete the synthesis, we treated amine 19 with
dimethylmethyleneimmonium iodide22 and subsequently hy-
Total Synthesis of (-)-Manthine (2). After having success
with the total synthesis of (-)-brunsvigine (1), we turned our
attention to the synthesis of (-)-manthine (2). We began the
synthesis with key intermediate 7 (Scheme 4). However, in this
(20) X-ray data of compounds 16 and 1a are presented in the Supporting
Information.
(21) Tseng, C. C.; Yen, S.-J.; Goering, H. L. J. Org. Chem. 1986, 51, 2892.
(22) Clark, R. C.; Warren, R. L.; Pachler, K. G. R. Tetrahedron 1975, 31,
1855.
7582 J. Org. Chem. Vol. 73, No. 19, 2008

Montanine-Type Amaryllidaceae Alkaloids
SCHEME 4. Total Synthesis of (-)-Manthine
synthetic route, we had to find a suitable method to invert the
C-O bond in the C3 stereocenter.
the complex 23. Reductive cleavage of 23f24 led to formation
of 3-hydroxy product 25 exclusively.
Exposure of 25 to trifluoromethanesulfonic anhydride and
pyridine in dichloromethane afforded the corresponding triflate
26. Compound 26 was efficiently transformed to the corre-
sponding stereoinverted acetate 27 using cesium acetate and 18-
crown-6 in toluene.23 Hydrolysis of 27 with sodium methoxide
in methanol gave compound 28. Methylation of compound 28
afforded compound 29. Detosylation of 29 with sodium and
Our next phase of synthesis accordingly began with hydrolysis
of the acetonide moiety in 7 to furnish diol 21. Treatment of
diol 21 with dimethoxymethylbenzene and camphorsulfonic acid
gave intermediate 22. Compound 22 was not isolated and
immediately subjected to regioselective cleavage with diisobu-
tylaluminum hydride (DIBAL)9b to give alcohol 25. This
reaction presumably proceeded through complexation of DIBAL
with an oxygen atom of the acetal unit in 22. Since the axial
oxygen of 22 is more hindered, the DIBAL may prefer to
coordinate with the less hindered equatorial oxygen to form
(23) (a) Shimizu, T.; Hiranuma, S.; Nakata, T. Tetrahedron Lett. 1996, 37,
6145. (b) Hiranuma, S.; Shimizu, T.; Nakata, T.; Kajimoto, T.; Wong, C.-H.
Tetrahedron Lett. 1995, 36, 8247.
J. Org. Chem. Vol. 73, No. 19, 2008 7583

Hong et al.
naphthalene in DME at –78 °C gave amine derivative 30.24
Treatment of 30 at rt with aqueous formaldehyde and methanolic
HCl generated iminium intermediate 31, which readily under-
went Pictet-Spengler cyclization11b,12,25 to give 32. Deprotec-
tion of the benzyl group in 32 followed by methylation finally
1H), 3.34 (br s, 1H), 3.26-3.24 (m, 1H), 3.18-3.16 (m, 1H), 3.07
(d, 1H, J ) 11.1 Hz), 2.25-2.22 (m, 1H), 1.58-1.53 (m, 1H); 13
C
NMR (150 MHz, MeOD/CDCl3) δ 153.2, 148.5, 147.8, 132.8,
124.4, 118.1, 108.4, 107.8, 102.2, 69.6, 67.0, 64.7, 61.0, 56.3, 46.4,
32.7; MS (EI) m/z 287 (M+, 100), 269 (41), 243 (18), 223 (23),
199 (57), 185 (44), 128 (30), 115 (33); HRMS (EI) m/z calcd for
afforded (-)-manthine (2). The specific rotation [R]25.9
)
D
C16H17 N O4 287.1158, found 287.1151; [R]20 ) -76.3 (c 1.02,
D
-78.4 (c 0.50, CHCl3; lit. [R]25.9 ) -80.0 (c 0.51, CHCl3)),
D
EtOH).
melting point, and spectral data of the synthetic (-)-manthine
(1S,13S,15R,16S)-15-(Methylcarbonyloxy)-5,7-dioxa-12-azapenta-
cyclo[10.6.1.02,10.04,8.013,18]nonadeca-2(10),3,8,17-tetraen-16-yl ac-
etate (1a). To a solution of (-)-brunsvigine (1) (9.9 mg, 0.0347
mmol) and 4-(dimethylamino)pyridine (DMAP) (2.0 mg, 0.0164
mmol) in dry pyridine (2 mL) was added acetic anhydride (25.0
mg, 0.208 mmol) at rt with stirring for 17 h. Concentration and
chromatography on a silica gel column (methanol/chloroform) gave
compound 1a (10 mg, 78%). Data for 1a: mp 184-185 °C (lit.
(2) agree satisfactorily with the literature data.3,9
In summary, we have developed a concise and expedient route
toward the total syntheses of (-)-brunsvigine (1) and (-)-
manthine (2). Our syntheses feature an efficient and stereocon-
trolled construction of bicyclic enone 10 employing anionic
cyclization. A sequence of synthetic transformations on bicyclic
enone 10 established the pivotal framework 7. Pictet-Spengler
cyclization was strategically applied to construct the 5,11-
methanomorphanthridine ring system that led to the first total
syntheses of (-)-brunsvigine (1) and (-)-manthine (2). An
extension and further application of this method to the total
synthesis of other alkaloids are under active investigation in
our laboratory.
184 °C); IR (neat) νmax 2938, 2880,1741, 1504, 1480, 1249 cm-1
;
1H NMR (400 MHz, CDCl3) δ 6.51 (s, 1H), 6.45 (s, 1H), 5.88 and
5.85 (AB quartet, 2H, J ) 1.2 Hz), 5.54-5.52 (m, 1H), 5.45 (dd,
1H, J ) 4.0, 4.0 Hz), 4.93 (ddd, 1H, J ) 12.0, 4.0, 4.0 Hz), 4.30
and 3.80 (AB quartet, 2H, J ) 16.8 Hz), 3.32-3.25 (br s, 1H),
3.27 (br s, 1H), 3.08 and 3.04 (AB quartet, 2H, J ) 17.0 Hz),
2.16-2.10 (m, 1H), 2.07 (s, 3H), 1.99 (s, 3H), 1.71 (ddd, 1H, J )
12.0, 12.0, 12.0 Hz); 13C NMR (100 MHz, CDCl3) δ 170.4, 170.0,
156.5, 147.0, 146.1, 131.4, 124.5, 112.1, 107.5, 106.9, 100.8, 68.8,
66.1, 63.0, 61.2, 56.0, 45.4, 30.2, 21.0, 20.9; MS (EI) m/z 371 (M+,
32), 312 (67), 252 (100), 223 (32); HRMS (EI) m/z calcd for
C20H21NO6 371.1369, found 371.1372.
Experimental Section
(1S,13S,15R,19S)-17,17-Dimethyl-5,7,16,18-tetraoxa-12-azahexa-
cyclo[10.9.1.02,10.04,8.013,21.015,19]docosa-2,4(8),9,20-tetraene (20). To
a solution of 19 (75.2 mg, 0.239 mmol) in dry DMF (6 mL) was
added dimethylmethyleneimmonium iodide (812 mg, 4.39 mmol).
The reaction mixture was stirred at 90-100 °C for 6 h. Upon
cooling to 0 °C, the reaction mixture was quenched with water (2
mL) and basified on addition of aqueous NH3 (3 mL). The aqueous
phase was extracted with chloroform (10 mL × 3). The combined
extract was washed with brine (5 mL) and dried over Na2SO4.
Concentration and chromatography on a silica gel column (methanol/
CHCl3 1:30) gave 20 (48 mg, 62%). Data for 20: IR (neat) νmax
(3S,5S,6R,7aS)-3-(1,3-Benzodioxol-5-yl)-1-[(4-methylphenyl)-
sulfonyl]-2,3,5,6,7,7a-hexahydro-1H-6-indolediol (21). To a solu-
tion of 7 (302 mg, 0.644 mmol) in MeOH/ THF (5 mL/5 mL) was
added concd HCl (0.53 mL) at 0 °C with stirring for 10 min. The
mixture was warmed to rt and stirred for an additional 2 h. The
reaction was then quenched with K2CO3 (3 N, 5 mL) and extracted
with dichloromethane (30 mL × 3). The combined organic extract
was washed with brine (15 mL) and dried over Na2SO4. Concentra-
tion and chromatography on a silica gel column (ethyl acetate/n-
hexane 2:1) gave 21 as a white solid (275 mg, 99%). Data for 21:
mp 166.5-166.7 °C; IR (neat) νmax 3411, 2891, 1504, 1491, 1342
1
2983, 2936, 2882, 1503, 1482, 1372 cm-1; H NMR (400 MHz,
CDCl3) δ 6.54 (s, 1H), 6.45 (s, 1H), 5.88 and 5.85 (AB quartet,
2H, J ) 1.4 Hz), 5.69 (dd, 1H, J ) 2.2, 2.2 Hz), 4.48-4.43 (m,
1H), 4.33 and 3.77 (AB quartet, 2H, J ) 17.0 Hz), 4.26 (ddd, 1H,
J ) 11.6, 5.6, 5.6 Hz), 3.33-3.00 (m, 1H), 3.11 (dd, 1H, J ) 10.8,
2.0 Hz), 3.08-3.03 (br s, 1H), 3.04 (d, 1H, J ) 10.8 Hz), 2.28
(ddd, 1H, J ) 11.6, 5.6, 5.6 Hz), 1.46 (s, 3H), 1.34 (s, 3H), 1.32
(ddd, 1H, J ) 11.6, 11.6, 11.6 Hz); 13C NMR (100 MHz, CDCl3)
δ 155.5 (C), 146.7 (C), 146.0 (C), 132.1 (C), 124.4 (C), 112.2 (CH),
109.4 (C), 107.1 (CH), 106.7 (CH), 100.7 (CH2), 73.6 (CH), 71.6
(CH), 62.0 (CH), 60.7 (CH2), 55.0 (CH2), 45.2 (CH), 33.0 (CH2),
27.7 (CH3), 25.1 (CH3); MS (EI) m/z 327 (M+, 100), 312 (32),
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.59 (d, 2H, J ) 8.0 Hz),
7.20 (d, 2H, J ) 8.0 Hz), 6.51 (d, 1H, J ) 8.0 Hz), 6.29 (dd, 1H,
J ) 8.0, 1.6 Hz), 6.19 (d, 1H, J ) 1.6 Hz), 5.86 (s, 2H), 5.77 (br
s, 1H), 4.12 (br s, 1H), 3.89 (dd, 1H, J ) 10.4, 7.2 Hz), 3.83-3.78
(m, 1H), 3.76-3.68 (br s, 1H), 3.64-3.55 (br s, 1H), 3.26 (dd,
1H, J ) 10.4, 4.4 Hz), 3.13 (br s, 1H), 2.90 (br s, 1H), 2.64-2.57
(m, 1H), 2.38 (s, 3H), 1.79 (ddd, 1H, J ) 11.6, 11.6, 11.6 Hz); 13
C
NMR (100 MHz, CDCl3) δ 147.8 (C), 146.4 (C), 145.2 (C), 143.9
(C), 134.9 (C), 132.9 (C), 129.6 (CH), 127.6 (CH), 123.3 (CH),
120.0 (CH), 108.2 (CH), 107.1 (CH), 101.0 (CH2), 67.6 (CH), 65.0
(CH), 59.0 (CH), 55.9 (CH2), 46.0 (CH), 33.3 (CH2), 21.4 (CH3);
MS (EI) m/z 429 (M+, 34), 411 (12), 385 (67), 230 (32), 201 (41),
135 (52), 91 (100); HRMS (EI) m/z calcd for C20H21NO6S 371.1369,
252 (65), 223 (21), 212 (19); HRMS (EI) m/z calcd for C19H21
N
O4 327.1470, found 327.1472; [R]18.8 ) -83.5 (c 1.33, CHCl3).
D
(-)-Brunsvigine (1). To a solution of 20 (56.0 mg, 0.171 mmol)
in anhydrous MeOH (2 mL) was added concd HCl (0.20 mL, 2.40
mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10
min and then warmed to rt. After stirring for an additional 2 h, the
mixture was cooled to 0 °C, then quenched with water (2 mL) and
extracted with chloroform (30 mL × 2). The combined organic
layer was washed with brine (15 mL) and dried over Na2SO4.
Concentration gave crude product 1. Recrystallization from ethyl
acetate/n-hexane (2:1) gave compound 1 as a colorless crystal (40
mg, 81%): mp 239-241 °C (lit.1,2 243 °C); IR (neat) νmax 3328,
2964, 2876, 1485, 1337, 1236 cm-1; 1H NMR (600 MHz, CDCl3)
δ 6.55 (s, 1H), 6.47 (s, 1H), 5.89 (d, 1H, J ) 1.4 Hz), 5.87 (d, 1H,
J ) 1.4 Hz), 5.76-5.75 (m, 1H), 4.36 (d, 1H, J ) 16.6 Hz),
4.13-4.12 (m, 1H), 3.87 (d, 1H, J ) 16.5 Hz), 3.68-3.64 (m,
found 371.1372; [R]21.6 ) +90.4 (c 1.04, CHCl3).
D
(3S,5S,6R,7aS)-3-(1,3-Benzodioxol-5-yl)-5-(benzyloxy)-1-[(4-
methylphenyl)sulfonyl)]-2,3,5,6,7,7a-hexahydro-1H-6-indolol (25).
To a solution of diol 21 (275 mg, 0.641 mmol) in anhydrous
dichloromethane (15 mL) were added camphorsulfonic acid (15.0
mg, 0.065 mmol) and dimethoxymethylbenzene (0.19 mL, 1.28
mmol) at rt with stirring for 1 h. The mixture was then cooled to
-78 °C. DIBAL (1.0 M solution in toluene, 6.40 mL, 6.40 mmol)
was added dropwise via a syringe. The reaction mixture was stirred
for an additional 40 min and then warmed to rt. The reaction mixture
was quenched with water (5 mL). Subsequent addition of dichlo-
romethane (13 mL) produced a white gel suspension. The resulting
mixture was filtered through Celite; the filtrate was dried over
Na2SO4. Concentration and chromatography on a silica gel column
(ethyl acetate/n-hexane 1:1) gave 25 as a colorless oil (316 mg,
95%). Data for 25: IR (neat) νmax 3542, 2890, 1504, 1490, 1346,
(24) Sungchul, J.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Clossen,
W. D.; Wriede, P. J. Am. Chem. Soc. 1967, 89, 5311.
(25) Keck, G. E.; Webb, R. R., II. J. Am. Chem. Soc. 1981, 103, 3173.
1
1160 cm-1; H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H, J ) 8.0
7584 J. Org. Chem. Vol. 73, No. 19, 2008

Montanine-Type Amaryllidaceae Alkaloids
Hz), 7.35-7.25 (m, 5H), 7.22 (d, 2H, J ) 8.0 Hz), 6.55 (d, 1H, J
) 8.0 Hz), 6.32 (dd, 1H, J ) 8.0, 2.0 Hz), 6.22 (d, 1H, J ) 2.0
Hz), 5.88 (s, 2H), 5.76-5.73 (m, 1H), 4.70 and 4.59 (AB quartet,
2H, J ) 11.4 Hz), 3.91-3.88 (m, 1H), 3.90 (dd, 1H, J ) 10.6, 7.2
Hz), 3.79-3.65 (m, 2H), 3.57-3.50 (m, 1H), 3.25 (dd, 1H, J )
10.6, 4.8 Hz), 2.66 (d, 1H, J ) 11.2 Hz), 2.66-2.60 (m, 1H), 2.40
(s, 3H), 1.79 (ddd, 1H, J ) 11.6, 11.6, 11.6 Hz); 13C NMR (100
MHz, CDCl3) δ 147.7 (C), 146.4 (C), 145.6 (C), 143.7 (C), 137.9
(C), 134.9 (C), 133.0 (C), 129.5 (CH), 128.5 (CH), 127.9 (CH),
127.8 (CH), 127.6 (CH), 121.1 (CH), 120.0 (CH), 108.2 (CH), 107.1
(CH), 101.0 (CH2), 72.3 (CH2), 72.2 (CH), 67.4 (CH), 59.0 (CH),
55.8 (CH2), 46.1 (CH), 34.5 (CH2), 21.4 (CH3); MS (EI) m/z 519
(M+, 2), 475 (47), 384 (100), 320 (16), 229 (37); HRMS (EI) m/z
calcd for C29H29NO6S 519.1715, found 519.1716; [R]22.3D ) +90.0
(c 1.02, CHCl3).
(-)-Manthine (2). To a suspension of NaH (4.9 mg, 0.122
mmol) in anhydrous DMF (0.2 mL) was added a solution of 33
(3.8 mg, 0.012 mmol) in anhydrous DMF (0.2 mL) at 0 °C. The
reaction mixture was stirred at rt for 10 min. Iodomethane (0.015
mL, 0.244 mmol) was added. The resulting mixture was stirred
for an additional 5 h. Upon cooling to 0 °C, the reaction mixture
was quenched with water (0.5 mL) and extracted with dichlo-
romethane (2 mL × 3). The combined extract was washed with
brine (5 mL) and dried over Na2SO4. Concentration and chroma-
tography on a silica gel column (chloroform/methanol 40:1) gave
2 as a light yellow solid (3.3 mg, 89%), and recrystallization of 2
in n-hexane gave colorless crystals. Data for 2: mp 113.7-115.5
°C (lit.1,4 114-116 °C); IR (neat) νmax 2851, 1639, 1483, 1235,
1088, 938 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.52 (s, 1H), 6.43
(s, 1H), 5.87 and 5.84 (AB quartet, 2H, J ) 1.5 Hz), 5.54 (br s,
1H), 4.37 and 3.81 (AB quartet, 2H, J ) 16.5 Hz), 3.58 (br s, 1H),
3.52-3.51 (m, 1H), 3.41 (s, 3H), 3.36 (s, 3H), 3.32-3.27 (m, 2H),
3.09-3.01 (m, 2H), 2.31 (ddd, 1H, J ) 13.0, 5.0, 3.5 Hz), 1.42
(dt, 1H, J ) 12.0, 2.5 Hz); 13C NMR (125 MHz, CDCl3) δ 153.6
(C), 146.8 (C), 146.0 (C), 132.1 (C), 124.2 (C), 113.2 (CH), 107.4
(CH), 106.8 (CH), 100.7 (CH2), 77.7 (CH), 76.4 (CH), 60.7 (CH2),
56.8 (CH), 57.4 (CH3), 56.7 (CH3), 55.3 (CH2), 45.6 (CH), 29.1
(CH2); MS (EI) m/z 315 (M+, 44), 300 (9), 284 (26), 257 (52),
229 (36), 197 (21), 155 (34), 141 (70), 128 (100), 115 (62), 91
(24), 77 (19); HRMS (EI) m/z calcd for C18H21NO4 315.1471, found
315.1474; [R]25.9D ) -78.4 (c 0.50, CHCl3; lit.4 [R]25.9D ) -80.0
(c 0.51, CHCl3).
(-)-3-O-Methylpancracine (33). To a solution of 32 (8 mg,
0.021 mmol) in anhydrous dichloromethane (0.3 mL) were added
dimethylsulfide (0.023 mL, 0.306 mmol) and BF3 ·OEt2 (0.039 mL,
0.306 mmol) at rt. The mixture was stirred for 3 h and quenched
with K2CO3 (3 N, 2 mL). The resulting mixture was extracted with
dichloromethane (5 mL × 3). The combined extract was washed
with brine (15 mL) and dried over K2CO3. Concentration and
chromatography on a silica gel column (chloroform/methanol 8:1)
gave 33 as a colorless liquid (2.9 mg, 47%). Data for 33: IR (neat)
ν
max 2849, 1650, 1487, 1222, 937, 731 cm-1; 1H NMR (600 MHz,
CDCl3) δ 6.56 (s, 1H), 6.47 (s, 1H), 5.89 and 5.87 (AB quartet,
2H, J ) 1.4 Hz), 5.60 (br s, 1H), 4.45 and 3.92 (AB quartet, 2H,
J ) 16.3 Hz), 4.06-4.05 (m, 1H), 3.57-3.56 (m, 1H), 3.51-3.49
(m, 1H), 3.36 (s, 3H), 3.34-3.31 (m, 1H), 3.13 (dd, 1H, J ) 10.9,
1.3 Hz), 2.43 (ddd, 1H, J ) 12.7, 4.9, 3.7 Hz), 2.13 (br s, 1H),
1.71 (dt, 1H, J ) 12.8, 2.8 Hz); 13C NMR (150 MHz, CDCl3) δ
147.2 (C), 146.6 (C), 131.0 (C), 129.7 (C), 122.3 (C), 116.5 (CH),
107.6 (CH), 106.9 (CH), 101.0 (CH2), 80.6 (CH), 66.7 (CH), 59.9
(CH2), 59.6 (CH), 57.1 (CH3), 55.3 (CH2), 45.1 (CH), 27.5 (CH2);
MS (EI) m/z 301 (M+, 100), 284 (10), 270 (20), 243 (75), 220
(72), 214 (44), 199 (34), 185 (40), 149 (10), 141 (12), 115 (17), 91
(58), 78 (13), 63 (13); HRMS (EI) m/z calcd for C17H19NO4
Acknowledgment. National Science Council of the Republic
of China (Taiwan) provided financial support.
Supporting Information Available: Experimental proce-
dures, detailed spectral characterization data; 1H and 13C NMR
spectra of compounds 1, 1a, 2, 7, 9-11, 13-16, 18-21, 25,
27-30, 32, and 33; X-ray data (CIF) for 1a and 9. This material
is available free of charge via the Internet at http://pubs.acs.org.
301.1314, found 301.1305; [R]26.0 ) -59.8 (c 0.20, CHCl3).
JO801089Y
D
J. Org. Chem. Vol. 73, No. 19, 2008 7585