Total synthesis of indole alkaloid (±)-subincanadine F via SmI 2-mediated ring opening and bridge-forming Mannich reaction

Article abstract of DOI:10.1021/jo061724h

(Chemical Equation Presented) The first total synthesis of (±)-subincanadine F, a bioactive indole alkaloid structurally featuring a 1-azabicyclo[4.3.1]-decane unit, has been realized from 1-(para-methoxybenzyl)- tryptamine in six steps. The bridge-contai

Full text of DOI:10.1021/jo061724h

Total Synthesis of Indole Alkaloid
(()-Subincanadine F via SmI2-Mediated Ring
Opening and Bridge-Forming Mannich Reaction
Peng Gao,†,‡ Yanqin Liu,† Lei Zhang,†,§ Peng-Fei Xu,‡
Shaowu Wang,§ Yong Lu,| Mingyuan He,| and
Hongbin Zhai*,†,‡
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai, China 200032, State Key Laboratory of
Applied Organic Chemistry and Department of Chemistry,
Lanzhou UniVersity, Lanzhou, Gansu, China 730000, Institute of
Organic Chemistry, School of Chemistry and Materials Science,
Anhui Normal UniVersity, Wuhu, Anhui, China 41000, and
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal
UniVersity, Shanghai, China 200062
FIGURE 1. Subincanadines A-G.
zhaih@mail.sioc.ac.cn
featuring a 1-azabicyclo[4.3.1]decane framework, which dis-
played prominent in vitro cytotoxicity against murine lymphoma
L1210 cells (IC50 ) 2.4 µg/mL) and human epidermoid
carcinoma KB cells (IC50 ) 4.8 µg/mL) on the basis of the
preliminary biological experiments.2 There is rising interest in
the assembly of the subincanadine family of alkaloids because
of their unique structural characteristics and impressive phar-
macological activity.3
ReceiVed August 19, 2006
In this paper, we wish to report a concise synthesis of (()-
subincanadine F (3), featuring the construction of the tetracyclic
core by SmI2-mediated ring opening and bridge-forming Man-
nich reactions as key steps. As shown in Scheme 1, the synthesis
commenced from 1-(para-methoxybenzyl)tryptamine (4), a
known intermediate4 obtainable in one step from commercially
available tryptamine. A reaction of 4 with R,â-diketoester 55
(140 mol %) in acetonitrile at room temperature for 8 h afforded
in a 75% yield the tetracyclic ketoester 6 as a yellow solid.
The generation of 6 presumably results from the initial N-
alkylation and iminium ion formation followed by Pictet-
Spengler-type cyclization as depicted in Scheme 2.6 The present
one-pot procedure for the tetracycle assembly, involving the
sequential D/C ring construction promoted by HCl generated
in situ, is advantageous, concise, and practical.
The first total synthesis of (()-subincanadine F, a bioactive
indole alkaloid structurally featuring a 1-azabicyclo[4.3.1]-
decane unit, has been realized from 1-(para-methoxybenzyl)-
tryptamine in six steps. The bridge-containing tetracyclic
framework of subincanadine F was efficiently assembled by
a SmI2-mediated ring opening followed by an acid-mediated
Mannich reaction. In addition, the tetracyclic ketoester 6, a
key intermediate potentially useful for synthesizing structur-
ally related indole alkaloids as well, was obtained in one
step from R,â-diketoester 5.
(2) (a) Kobayashi, J.; Sekiguchi, M.; Shimamoto, S.; Shigemori, H.;
Ishiyama, H.; Ohsaki, A. J. Org. Chem. 2002, 67, 6449. (b) Ishiyama, H.;
Matsumoto, M.; Sekiguchi, M.; Shigemori, H.; Ohsaki, A.; Kobayashi, J.
Heterocycles 2005, 66, 651.
(3) (a) Liu, Y.; Luo, S.; Fu, X.; Fang, F.; Zhuang, Z.; Xiong, W.; Jia,
X.; Zhai, H. Org. Lett. 2006, 8, 115. (b) Suzuki, K.; Takayama, H. Org.
Lett. 2006, 8, 4605.
(4) Guengoer, T.; Malabre, P.; Teulon, J. M. Synth. Commun. 1994, 24,
2247.
Because of their remarkable pharmacological activities, indole
alkaloids have been an attractive and rewarding source for
developing new drug entities.1 From 2002 to 2005, subinca-
nadines A-G (1a-c, 2a,b, 3, and 1d; Figure 1) were isolated
by Kobayashi and co-workers from the barks of the Brazilian
medicinal plant Aspidosperma subincanum Mart.2 Among these
intriguing polycyclic compounds was subincanadine F (3),
(5) Wasserman, H. H.; Kuo, G.-H. Tetrahedron 1992, 48, 7071.
(6) Wasserman and co-workers once reported the efficient synthesis of
an analogue of 6 (where the indolic nitrogen was unprotected), which
consisted of the initial preparation of a crystalline vinyl tricarbonyl
monohydrate from 5 via dehydrohalogenation with a saturated aqueous
bicarbonate solution, followed by sequential Michael addition/intramolecular
aminal formation/Pictet-Spengler cyclization in the presence of boron
trifluoride etherate in dichloromethane at -78 °C. However, a less
satisfactory yield (approximately 18%) for the tetracycle formation was
observed when Wasserman’s two-step protocol was applied to tryptamine.
For Wasserman’s two-step protocol, see: (a) Wasserman, H. H.; Fukuyama,
J.; Murugesan, N.; van Duzer, J.; Lombardo, L.; Rotello, V.; McCarthy, K.
J. Am. Chem. Soc. 1989, 111, 371. (b) Wasserman, H. H.; Parr, J. Acc.
Chem. Res. 2004, 37, 687.
† Shanghai Institute of Organic Chemistry.
‡ Lanzhou University.
§ Anhui Normal University.
| East China Normal University.
(1) (a) Atta-ur-Rahman; Basha, A. Indole Alkaloids; Harwood Aca-
demic: Amsterdam, The Netherlands, 1997. (b) Wright, C. W.; Phillipson,
J. D. Phytother. Res. 1990, 4, 127.
10.1021/jo061724h CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/14/2006
J. Org. Chem. 2006, 71, 9495-9498
9495

SCHEME 1. Synthesis of (()-Subincanadine F (3)a
a E ) CO2 Bu, TFAA ) trifluoroacetic anhydride, PMB = para-methoxybenzyl.
t
SCHEME 2. Formation of 6a
ably containing four stereoisomers), and the dehydration of
which with TFAA/DBU/DMAP10 generated enone 9 (as a pair
of geometric isomers of close Rf values, E/Z ) 10:1) in an
excellent combined yield (94%).
Considerable endeavors were then devoted to the remaining
tasks for the synthesis of subincanadine F, that is, the removal
t
of CO2 Bu and PMB. Reaction of 9 with AlCl3 in benzene at
room temperature for 4 h selectively furnished the decarboxy-
lation product 10 in only a moderate yield (53%), which
represented the optimum result obtained for this particular
transformation under various experimental conditions. PMB
deprotection could not be realized in reasonable yields by
treating 10 with a Lewis acid (AlCl3,11 TiCl4, or F3B‚OEt2), a
protic acid (TFA12 or HClO413), an oxidizing agent (DDQ14 or
CAN), a base (LDA15), or with the Pd(OAc)2/Et3SiH/Et3N16
reagent system. Finally, heating 9 in 0.5 M hydrochloric acid
under reflux for 4 h resulted in full deprotection, and (()-
subincanadine F (3) was produced in a 28% yield.17 For
comparison, a lower yield (10%) for 3 was observed when the
same conditions were applied to the decarboxylation product
10. The TFA salt18 of subincanadine F (3) displayed spectral
data in full consistence with those reported in the literature.2a
In summary, the first total synthesis of (()-subincanadine F
(3), a bioactive indole alkaloid structurally featuring a
1-azabicyclo[4.3.1]decane unit, has been accomplished in six
t
a E ) CO2 Bu.
We envisaged that the tetracyclic core of subincanadine F
could be easily accessed from ketoester 6 by skeletal reorga-
nization. The central theme of this strategy was based on the
disconnection of the C/D ring conjunction of 6 followed by
insertion of a one-carbon linker at the breakup points. To our
delight, the samarium diiodide mediated ring-opening7 of 6
furnished the 6/5/9 tricycle 7 in an 86% yield. Exposure of 7 to
formalin (i.e., aqueous formaldehyde solution, 37%) in the
presence of hydrochloric acid for 1 h led to the tetracycle 8 in
an 83% yield. Thus, the tetracyclic 1-azabicyclo[4.3.1]decane
framework of subincanadine F was constructed in three steps
from 4.
The (E)-ethenyl group adjacent to the ketone carbonyl in 3
would ideally be introduced at the stage of 8 since the presence
of PMB and CO2 Bu could block the corresponding reactive
sites that would otherwise interfere with the desired transforma-
tions.8 Treatment of 8 with LDA followed by MeCHO9 at -78
°C furnished the expected aldol condensation products (presum-
(9) The anhydrous acetaldehyde (as a solution in ether) was prepared as
follows: Acetaldehyde (40 wt. % solution in water) was extracted with
ether. The combined ether layers were dried (Na2SO4) at low temperature
and then distilled with a Vigreux column to afford an anhydrous acetal-
dehyde solution in ether in which the mole ratio of MeCHO to Et2O was
t
1
discovered to be 1:3 on the basis of the H NMR spectrum.
(10) For dehydration of aldols with TFAA/DBU/DMAP, see: (a)
Goldstein, S. W.; Overman, L. E.; Rabinowitz, M. H. J. Org. Chem. 1992,
57, 1179. (b) Comins, D. L.; Huang, S.; McArdle, C. L.; Ingalls, C. L.
Org. Lett. 2001, 3, 469. (c) Tanino, K.; Onuki, K.; Asano, K.; Miyashita,
M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003,
125, 1498.
(11) (a) Watanabe, T.; Kobayashi, A.; Nishiura, M.; Takahashi, H.; Usui,
T.; Kamiyama, I.; Mochizuki, N.; Noritake, K.; Yokoyama, Y.; Murakami,
Y. Chem. Pharm. Bull. 1991, 39, 1152. (b) Murakami, Y.; Watanabe, T.;
Kobayashi, A.; Yokoyama, Y. Synthesis 1984, 9, 738.
(12) Boger, D. L.; Fink, B. E.; Hedrick, M. P. J. Am. Chem. Soc. 2000,
122, 6382.
(13) Miki, Y.; Hachiken, H.; Yanase, N. J. Chem. Soc., Perkin Trans. 1
2001, 2213.
(14) Miki, Y.; Hachiken, H.; Kashima, Y.; Sugimura, W.; Yanase, N.
Heterocycles 1998, 48, 1.
(15) Suzuki, H.; Tsukuda, A.; Kondo, M.; Aizawa, M.; Senoo, Y.;
Nakajima, M.; Watanabe, T.; Yokoyama, Y.; Murakami, Y. Tetrahedron
Lett. 1995, 36, 1671.
(7) For a SmI2-mediated reaction, see: Katritzky, A. R.; Wang, J.;
Henderson, S. A. Heterocycles 1998, 48, 1567.
(8) Wiemer’s protocol of ketone carbonyl O-phosphorylation/1,3-
phosphorus shift rearrangement/Horner-Wadsworth-Emmons reaction was
explored on the indolic N-benzyl analogue (rather than N-PMB) of 8. While
the enol phosphonate was easily accessible (LDA; ClP(O)(OEt)2), the action
of LDA (200 mol %) could not effect the 1,3-phosphorus shift rearrange-
ment. Because of this unsuccessful attempt, a different R-ethenylation
strategy was utilized for the PMB-protected ketone 8. For Wiemer’s
protocol, see: (a) Calogeropoulou, T.; Hammond, G. B.; Wiemer, D. F. J.
Org. Chem. 1987, 52, 4185. (b) An, Y.-Z.; Wiemer, D. F. J. Org. Chem.
1992, 57, 317. (c) Baker, T. J.; Wiemer, D. F. J. Org. Chem. 1998, 63,
2613. For an application of Wiemer’s protocol in total synthesis, see: (d)
Sudau, A.; Munch, W.; Bats, J.-W.; Nubbemeyer, U. Eur. J. Org. Chem.
2002, 3315.
(16) Wen, S.-J.; Yao, Z.-J. Org. Lett. 2004, 6, 2721.
9496 J. Org. Chem., Vol. 71, No. 25, 2006

(m, 1H), 3.75 (s, 3H), 5.00 (d, J ) 16.5 Hz, 1H), 5.23 (d, J ) 16.5
Hz, 1H), 6.77 (d, J ) 9.0 Hz, 2H), 7.02 (d, J ) 8.4 Hz, 2H), 7.08-
7.22 (m, 2H), 7.28 (d, J ) 8.4 Hz, 1H), 7.55 (d, J ) 7.2 Hz, 1H);
13C NMR (CDCl3, 75 MHz) δ 28.3, 28.7, 35.9, 46.1, 46.8, 49.0,
55.2, 82.1, 96.4, 109.9, 113.8, 115.0, 118.4, 118.7, 121.5, 127.6,
128.1, 130.2, 132.0, 136.4, 158.7, 171.6, 180.4; MS (ESI) 449 (M
+ H, 100). HRMS (ESI): (M + H) calcd for C27H33N2O4,
449.2440; found, 449.2435.
steps starting from 1-(para-methoxybenzyl)tryptamine (4). On
the basis of the overall synthetic efficiency, the current route
to (()-subincanadine F constitutes a general method for rapid
synthesis of a number of indole alkaloids with similar structures.
The bridge-containing tetracyclic framework of subincanadine
F was efficiently assembled by a SmI2-mediated ring opening
followed by an acid-mediated Mannich reaction. The tetracyclic
ketoester 6, a key intermediate, is a potential substrate for
synthesizing structurally related indole alkaloids.
Compound 8. A solution of 7 (173 mg, 0.386 mmol) in EtOH
(12 mL) was acidified with 12 M hydrochloric acid to pH 3-7,
and formalin (containing 37 wt % CH2O, 75 µL, 1.0 mmol) was
added. The mixture was stirred at rt for 1 h, neutralized with a
saturated aqueous NaHCO3 solution, concentrated, and extracted
with CH2Cl2. The combined organic extracts were dried (Na2SO4),
filtered, and concentrated to give a residue. The residue was
chromatographed (petroleum ether/EtOAc, 3:1) to afford 8 (147
Experimental Section
Compound 6. To a solution of 4 (345 mg, 1.23 mmol) in
acetonitrile (10 mL) was added dropwise a solution of 5 (380 mg,
1.72 mmol) in acetonitrile (10 mL) at rt. The mixture was stirred
at rt for 8 h, neutralized with a saturated aqueous NaHCO3 solution,
concentrated, and extracted with CH2Cl2. The combined organic
extracts were dried (Na2SO4), filtered, and concentrated to give a
residue. The residue was chromatographed (petroleum ether/EtOAc,
8:1) to afford 6 (412 mg, 75%) as a yellow solid: mp 52-53 °C;
1H NMR (CDCl3, 300 MHz) δ 1.39 (s, 9H), 2.38 (dd, J ) 18.0,
6.3 Hz, 1H), 2.66-2.82 (m, 2H), 3.10-3.51 (m, 5H), 3.75 (s, 3H),
5.45 (d, J ) 17.1 Hz, 1H), 5.60 (d, J ) 17.1 Hz, 1H), 6.73-6.87
(m, 4H), 6.93-7.00 (m, 1H), 7.03-7.13 (m, 2H), 7.51-7.60 (m,
1H); 13C NMR (CDCl3, 75 MHz) δ 16.5, 27.7, 36.8, 43.6, 44.3,
49.1, 55.2, 72.3, 83.1, 110.7, 111.3, 113.7, 118.3, 119.2, 122.4,
126.8, 127.2, 127.3, 130.3, 137.6, 158.3, 168.2, 206.8; MS (ESI)
347 (57), 447 (M + H, 100), 469 (M + Na, 27). HRMS (ESI):
(M + H) calcd for C27H31N2O4, 447.2284; found, 447.2278.
Compound 7. A suspension of samarium powder (1.47 g, 9.75
mmol) and I2 (1.90 g, 7.50 mmol) in dry THF (75 mL) was stirred
vigorously under N2 at rt for 30 min. During that course of time,
the color of the reaction mixture changed from purple to yellow-
brown to green and finally to Prussian blue. The mixture was then
refluxed for 1 h to give a solution of SmI2 in THF (0.1 M). To a
solution of 6 (200 mg, 0.448 mmol) in THF (20 mL) was added
dropwise a solution of SmI2 (0.10 M in THF, 16 mL, 1.6 mmol) at
rt. The mixture was stirred at rt for 3 h, quenched with a saturated
aqueous NaHCO3 solution, filtered, concentrated, and extracted with
CHCl3/i-PrOH (4:1). The combined organic extracts were dried
(Na2SO4), filtered, and concentrated to give a residue. The residue
was chromatographed (CH2Cl2/EtOAc, 2.5:1) to afford 7 (173 mg,
86%) as a colorless viscous oil: 1H NMR (CDCl3, 300 MHz) δ
1.39 (s, 9H), 1.79 (td, J ) 12.9, 3.9 Hz, 1H), 1.91 (dt, J ) 12.2,
4.6 Hz, 1H), 2.46-2.72 (m, 3H), 3.02-3.19 (m, 2H), 3.32-3.45
1
mg, 83%) as a white solid: mp 152-154 °C; H NMR (CDCl3,
300 MHz) δ 1.41 (s, 9H), 2.04 (d, J ) 1.2 Hz, 1H), 2.47-2.62 (m,
1H), 2.92 (dt, J ) 11.3, 4.0 Hz, 1H), 3.10-3.34 (m, 3H), 3.34-
3.48 (m, 1H), 3.57 (d, J ) 14.7 Hz, 1H), 3.67-3.80 (m, 1H), 3.74
(s, 3H), 4.42 (dd, J ) 14.7, 3 Hz, 1H), 5.28 (s, 2H), 6.75 (s, 4H),
6.89-6.97 (m, 1H), 7.02-7.15 (m, 2H), 7.55-7.64 (m, 1H); 13C
NMR (CDCl3, 75 MHz) δ 22.1, 27.8, 35.1, 48.2, 52.9, 53.9, 55.0,
56.0, 65.9, 82.4, 111.0, 113.6, 115.7, 118.0, 119.1, 122.2, 127.1,
127.4, 129.5, 130.8, 136.9, 158.2, 168.4, 203.7; MS (ESI) 461 (M
+ H, 100), 483 (M + Na, 28). HRMS (ESI): (M + H) calcd for
C28H33N2O4, 461.2440; found, 461.2435.
Compound 9. A solution of LDA in hexanes (1.9 M, 1.8 mL,
3.4 mmol) was diluted with THF (20 mL) and cooled to -78 °C.
A solution of 8 (752 mg, 1.63 mmol) in THF (5 mL) was then
added dropwise via a syringe. After the mixture was stirred at -78
°C for 1 h, a solution of anhydrous acetaldehyde in ether9 {CH3-
CHO:Et2O ) 1:3 (mole ratio), 1.8 mL, 4.9 mmol} was added at
-78 °C. The mixture was stirred at -78 °C for 1 h, quenched
with a saturated aqueous NaHCO3 solution, concentrated, and
extracted with CHCl3/i-PrOH (4:1). The combined organic extracts
were dried (Na2SO4), filtered, and concentrated to afford the crude
aldol as a yellow oil, which was used without further purification
for the next step.
To a solution of the above-mentioned crude aldol in CH2Cl2 (25
mL) was added DMAP (20 mg, 0.16 mmol). After the solution
was cooled to -42 °C, DBU (1.8 mL, 12 mmol) and trifluoroacetic
anhydride (1.0 mL, 7.1 mmol) were sequentially added. After the
solution was stirred at this temperature for 1 h, additional DBU
(0.8 mL, 5 mmol) was added. The reaction mixture was warmed
to rt and stirred at rt for 30 min. The reaction mixture was quenched
with saturated aqueous NaHCO3 solution and extracted with CH2-
Cl2. The combined organic extracts were dried (Na2SO4), filtered,
and concentrated to give a residue. The residue was chromato-
graphed (petroleum ether/EtOAc, 3:1) to afford 9 (747 mg, 94%
(17) Despite our extensive investigations, the transformation of 9 to 3
was achieved in a 28% yield. Nevertheless, this figure could amount to an
average yield of 53% for each of the two operations considering the fact
t
that both PMB and CO2 Bu were removed in the same step. The indolic
1
for the two steps from 8) as a yellow solid: mp 75-77 °C; H
nitrogen might not require protection under certain circumstances. In our
case, however, indolic nitrogen protection proved to be necessary. Without
indolic N protection, the corresponding intermediates are unstable, and the
yield for the first step and the combined yield for the second and the third
steps dropped to 50% and 10%, respectively (see Scheme 1). Electron-
withdrawing groups (such as Ts and Boc) on indolic nitrogen would retard
the Pictet-Spengler cyclization. We also found that no cyclization product
could be isolated for the reaction of 5 and tryptamine with the indolic
nitrogen protected with a bulky TBDPS group. In addition, if the
1-benzyltryptamine was employed instead of the 1-(para-methoxybenzyl)-
tryptamine at the very beginning then the first five steps (reaching the
counterpart of 9, see Scheme 1) would have behaved essentially in the same
manner. However, the overall yield for decarboxylation (AlCl3, PhH, rt,
96%)11 and debenzylation (excess LDA, THF, -42 °C to rt, 4%)15 decreased
to 3.8%.
NMR (CDCl3, 300 MHz) δ 1.28 (s, 9H), 1.77 (d, J ) 7.2 Hz, 3H),
2.63-2.78 (m, 1H), 3.02-3.24 (m, 2H), 3.44-3.63 (m, 2H), 3.76
(s, 3H), 3.83 (d, J ) 16.8 Hz, 1H), 3.96 (d, J ) 16.8 Hz, 1H), 4.33
(d, J ) 15.0 Hz, 1H), 5.46 (d, J ) 17.3 Hz, 1H), 5.56 (d, J ) 17.3
Hz, 1H), 6.70-7.02 (m, 8H), 7.52 (d, J ) 7.8 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 13.9, 22.0, 27.6, 49.3, 53.2, 53.5, 55.1, 56.9,
58.5, 82.8, 111.5, 113.4, 116.7, 117.8, 119.0, 121.9, 127.3, 127.6,
129.8, 131.9, 133.4, 136.5, 139.7, 158.2, 169.3, 193.2; MS (ESI)
387 (3), 487 (M + H, 100), 509 (M + Na, 17). HRMS (ESI): (M
+ H) calcd for C30H35N2O4, 487.2597; found, 487.2591.
Compound 10. To a suspension of anhydrous AlCl3 (77 mg,
0.58 mmol) in benzene (3 mL) was added a solution of 9 (31 mg,
0.064 mmol) in benzene (2 mL). The mixture was stirred at rt for
4 h, quenched with a saturated aqueous NaHCO3 solution, filtered,
concentrated, and extracted with CHCl3/i-PrOH (4:1). The combined
organic extracts were dried (Na2SO4), filtered, and concentrated to
give a residue. The residue was chromatographed (CH2Cl2/MeOH,
(18) The 1H and 13C NMR spectroscopic data of the TFA salt of
subincanadine F [rather than subincanadine F (as a free base) itself] was
essentially identical with those for the so-called subincanadine F reported
in the literature.2a This is presumably because of the presence of TFA in
the eluent used for HPLC purification of subincanadine F by Kobayashi
and co-workers.
J. Org. Chem, Vol. 71, No. 25, 2006 9497

40:1) to afford 10 (13 mg, 53%) as a yellow oil: 1H NMR (CDCl3,
300 MHz) δ 1.81 (d, J ) 7.5 Hz, 3H), 2.83-2.97 (m, 1H), 3.00-
3.17 (m, 1H), 3.30-3.44 (m, 2H), 3.44-3.63 (m, 2H), 3.68-3.76
(m, 1H), 3.76 (s, 3H), 3.86 (d, J ) 16.5 Hz, 1H), 4.08 (d, J ) 16.5
Hz, 1H), 5.39 (d, J ) 17.3 Hz, 1H), 5.66 (d, J ) 17.3 Hz, 1H),
6.66 (q, J ) 7.5 Hz, 1H), 6.80 (d, J ) 9.0 Hz, 2H), 6.90 (d, J )
9.0 Hz, 2H), 7.03-7.20 (m, 2H), 7.17-7.30 (m, 1H), 7.46 (d, J )
7.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.7, 23.5, 29.4, 46.1,
50.6, 52.3, 55.3, 55.6, 109.7, 114.2, 114.3, 118.0, 119.3, 122.0,
127.0, 127.5, 130.2, 134.9, 135.1, 135.8, 136.6, 158.8, 194.6; MS
(ESI) 387 (M + H, 100), 409 (M + Na, 6). HRMS (ESI):(M + H)
calcd for C25H27N2O2, 387.2073; found, 387.2067.
(()-Subincanadine F (3). (a) From 9. A mixture of 9 (46 mg,
0.094 mmol) and hydrochloric acid (0.48 M, 10 mL, 4.8 mmol)
was heated at reflux for 4 h, cooled to rt, neutralized with an
aqueous NaHCO3 solution, and extracted with CHCl3/i-PrOH (4:
1). The combined organic extracts were dried (Na2SO4), filtered,
and concentrated to give a residue. The residue was chromato-
graphed (CH2Cl2/EtOAc, 2:1) to afford 3 (7.0 mg, 28%) as a yellow
oil.
6.97 (t, J ) 7.5 Hz, 1H), 7.05 (t, J ) 7.5 Hz, 1H), 7.26 (d, J ) 8.4
Hz, 1H), 7.38 (d, J ) 7.5 Hz, 1H); MS (ESI) 267 (M + H, 100),
299 (M + MeOH + H, 10). HRMS (ESI): (M + H) calcd for
C17H19N2O, 267.1497; found, 267.1492. An analytical sample of
3‚TFA salt was prepared by reacting 3 and TFA (200 mol %) in
CH2Cl2 at rt for 5 min followed by evaporation of the volatiles.
The salt of 3‚TFA was obtained as a yellow amorphous solid: 1H
NMR (CD3OD, 300 MHz) δ 1.87 (d, J ) 7.2 Hz, 3H), 3.06-3.28
(m, 2H), 3.47-3.66 (m, 1H), 3.66-3.90 (m, 1H), 3.96-4.12 (m,
2H), 4.05-4.23 (m, 1H), 4.34 (d, J ) 15.9 Hz, 1H), 4.55 (d, J )
15.9 Hz, 1H), 6.95-7.06 (m, 1H), 7.02 (t, J ) 7.4 Hz, 1H), 7.10
(t, J ) 8.1 Hz, 1H), 7.31 (d, J ) 8.1 Hz, 1H), 7.42 (d, J ) 7.8 Hz,
1H); 13C NMR (CD3OD, 75 MHz) δ 14.2, 20.7, 45.5, 51.6, 51.7,
57.2, 112.1, 112.6, 118.7, 120.4, 123.2, 128.5, 128.7, 132.4, 137.4,
144.0, 189.7; MS (ESI) 267 (M + H, 100), 299 (M + MeOH +
H, 15). HRMS (ESI): (M + H) calcd for C17H19N2O, 267.1497;
found, 267.1492 (note that the MS and HRMS data obtained for
the salt were actually found to be essentially the same as those for
the free amine).
(b) From 10. A mixture of 10 (30 mg, 0.078 mmol) and
hydrochloric acid (0.5 M, 4 mL, 2 mmol) was heated at reflux for
4 h, cooled to rt, neutralized with an aqueous NaHCO3 solution,
and extracted with CHCl3/i-PrOH (4:1). The combined organic
extracts were dried (Na2SO4), filtered, and concentrated to give a
residue. The residue was chromatographed (CH2Cl2/EtOAc, 2:1)
to afford 3 (2 mg, 10%) as a yellow oil: 1H NMR (CD3OD, 300
MHz) δ 1.85 (d, J ) 7.2 Hz, 3H), 2.83-2.96 (m, 1H), 2.98-3.11
(m, 1H), 3.35-3.48 (m, 2H), 3.62-3.77 (m, 3H), 3.92 (d, J )
16.5 Hz, 1H), 4.23 (d, J ) 16.5 Hz, 1H), 6.69 (q, J ) 7.2 Hz, 1H),
Acknowledgment. We thank NSFC, STCSM (“Post-Venus”
Program, No. 05QMH1416), and GCCP of ECNU for financial
support. We are indebted to Prof. Zhiyu Liu of SIOC for
enlightening discussions and kind assistance.
Supporting Information Available: Analytical data for 6-10
and 3 (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JO061724H
9498 J. Org. Chem., Vol. 71, No. 25, 2006