Synthesis of (±)-lahadinine B and (±)-11-methoxykopsilongine

Article abstract of DOI:10.1016/S0040-4039(00)01399-X

6,7-Dimethoxytryptamine 11 was converted into the homoannular diene 19 which underwent a Diels-Alder reaction with acryloyl chloride to give 20. Subsequent radical decarboxylation in the presence of (PhSe)₂ provided 22, which was converted into (±)-lahadinine B 1 and (±)-11-methoxykopsilongine 2, thus confirming their structures. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01399-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9369–9372
Synthesis of ( )-lahadinine B and
( )-11-methoxykopsilongine†
Philip Magnus* and Neil Westlund
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
Received 15 June 2000; revised 30 June 2000; accepted 3 July 2000
Abstract
6,7-Dimethoxytryptamine 11 was converted into the homoannular diene 19 which underwent a
Diels–Alder reaction with acryloyl chloride to give 20. Subsequent radical decarboxylation in the presence
of (PhSe)2 provided 22, which was converted into ( )-lahadinine B 1 and ( )-11-methoxykopsilongine 2,
thus confirming their structures. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Kopsia alkaloids; 6,7-dimethoxytryptamine; lahadinine B; 11-methoxykopsilongine.
In 1997 Kam reported the isolation and structure determination of the cyano-substituted
indole alkaloid lahadinine B 1 from Kopsia pauciflora (Eq (1)).1 During the course of our recent
studies on the synthesis of 11,12-demethoxylahadinine B and related Kopsia alkaloids2,3 we
established a strategy that should, in principle, be applicable to the synthesis of 1 and the related
alkaloid 11-methoxykopsilongine 2.4
(1)
* Corresponding author.
†
Dedicated to Harry H. Wasserman on the occasion of his 80th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01399-X

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While our previous research started with tryptamine, we now required a convenient synthesis
of 6,7-dimethoxytryptamine 11 (Scheme 1). While the sequence of reactions from tryptamine to
11,12-demethoxylahadinine B, eventually, after some optimization, worked reasonably well, it
was not a foregone conclusion that the dimethoxy analog would be so cooperative. Indeed, the
ability of electron-rich indole derivatives to undergo facile C3 protonation and subsequent
dimerization forewarned us that the reactions conditions, and possible whole strategy might
require radical modifications to be successful.
Scheme 1. (a) AcCl/py/100°C, 4 (96%). (b) Fuming HNO3/<6°C, 5 (82%). (c) K2CO3/MeOH. (d) MeI/K2CO3/DMF/
35°C, 6 (72% from 5). (e) MeNO2/KOH/DMF/EtOH/aq. work-up HCl/0°C followed by Ac2O/NaOAc/reflux, 7
(73%). (f) Fe/AcOH/EtOH/reflux, 8 (85%). (g) POCl3/DMF/0–25°C, 9 (92%). (h) MeNO2/NH4OAc/reflux, 10 (100%).
(i) LiAlH4/THF/0°C to reflux, 11 (91%)
Acetylation of vanillin 3 gave 4, which was nitrated following literature conditions to give 5
and a small amount of the 6-nitro-isomer (8:1 ratio of isomers).5 Hydrolysis of 5 and
O-methylation gave 6,6 which was exposed to the classical Henry reaction conditions to give 7.7
Reduction of 7 produced the indole 8.8 Vilsmeier formylation of 8 gave 9, which was converted
into 11 via 10 using conditions recently described by Corey9 for the N-methyl derivative of 8
(Scheme 1).
Treatment of 11 with 12 under Pictet–Spengler reaction conditions that were satisfactory for
tryptamine, gave 13 (<10%) (Scheme 2), whereas exposure of a mixture of 11 and 12 to
trifluoroacetic acid (cat.) in dichloromethane in the presence of molecular sieves at 0–23°C gave
13, which was directly (without purification) converted into 14 in 67% yield for the two steps.
Belleau’s reagent10 converted 14 into 15, and Ni2B/H2 desulfurization11 gave 16. The reaction of
16 with PhOCOCl/ClCH2CH2Cl heated at reflux was very slow compared with the demethoxy
series,3 but prolonged treatment (48 h) gave 17 (47%) and recovered 16 (33%). Attempts to drive
the reaction to completion diminished the yield of 17, and more reactive chloroformates such as
4-nitrophenyl chloroformate did not help.
Treatment of 17 with triflic anhydride in dichloromethane containing 4-dimethylaminopy-
ridine heated at reflux, followed by quenching the purple solution with aqueous NaHCO3 gave
18 (18%), whereas quenching the reaction with trimethylsilyl cyanide resulted in 19 (65%).
Reaction of 19 with acryloyl chloride (excess) at 23°C gave 20, which was directly treated with
N-hydroxy-2-thiopyridone (Na salt),12 followed by irradiation in the presence of t-BuSH
resulted in reductive decarboxylation to give 21 (37% from 19). All attempts to convert 21 into

9371
,
Scheme 2. (a) CF3CO2H(cat.)/CH2Cl2/4 A molecular sieves/0–23°C. (b) EDCI/HOBt/Et3N/DMF/0–23°C, 14 (67%).
(c) Belleau’s reagent/THF/0–23°C, 15 (100%). (d) NiCl2·6H2O/NaBH4/THF/MeOH/0°C, 16 (77%). (e) PhOCOCl (15
equiv.)/Cl(CH2)2Cl/reflux/48 h, 17 (47%, 33% recovered 16). (f) Tf2O/DMAP/CH2Cl2/reflux, followed by aqueous
NaHCO3, 18 (18%), or work-up with TMSCN/DMAP/CH2Cl2, 19 (63%). (g) Acryloyl chloride/23°C/24 h. (h)
2-Thiopyridone-N-oxide (Na salt)/t-BuSH/CH2Cl2/hv, 21 (37%), or 2-thiopyridone-N-oxide (Na salt)/(PhSe)2/
CH2Cl2/hv, 22 (45%). (i) KN(TMS)2/18-crown-6/THF/−78°C followed by CO2 and Me2SO4, 23 (86%). (j) Mn(dpm)3
(5 mol%)/PhSiH3/O2/i-PrOH/Cl(CH2)2Cl, 24 (83%). (k) Ph3SnH/PhMe/reflux, 1 (94%). (l) CF3CO2H/Et3SiH/CH2Cl2/
23°C, 2 (93%)
its derived N–CO2Me adduct using a variety of conditions such as pyridine/triphosgene/MeOH,
pyridine/COCl2/MeOH, NaH/COCl2/MeOH, KH/18-crown-6/COCl2/MeOH, DMAP/ClCO2Me
and KH/18-crown-6/ClCO2Me all failed, presumably because of steric hindrance. Since we had
also converted 20 into the phenylselenide derivative 22 (45% from 19), we decided to examine its
conversion into 23. It was eventually found that KN(SiMe3)2/18-crown-6/CO2/−78°C, followed

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by dimethyl sulfate gave 23 (86%). This same procedure when applied to 21 was unsuccessful!
It can be speculated that the PhSeꢀ substituent coordinates the ꢀNCO2K intermediate suffi-
ciently to allow O-methylation before decarboxylation.
The conjugate reduction–oxidation reaction to convert 23 into 24 was conducted with
tris-(dipivaloylmethanato)manganese(III) (5 mol%)/PhSiH3/O2/i-PrOH/Cl(CH2)2Cl and gave 24
in 83% yield.13 This reaction did not work at all on the unprotected adduct 22. The final step
involves reductive removal of the PhSeꢀ substituent. This was achieved through treatment of 24
with triphenyltin hydride in toluene at reflux to give ( )-lahadinine B in 94% yield. Comparison
of spectral data confirmed that the synthetic material was the same as the natural compound,14
apart from [h]D. The structure of 1 was confirmed by X-ray crystallography.
Since we had established the structure of 1 to be correct, its conversion into 2 would provide
unequivocal evidence for the correctness of the structure of 2. Treatment of 1 with triethylsilane
in the presence of trifluoroacetic acid cleanly converted it into 2 (93%).
Acknowledgements
The National Institutes of Health (GM 32718), The Robert A. Welch Foundation, Merck
Research Laboratories and Novartis are thanked for their support of this research. Dr. Vince
Lynch is thanked for the X-ray structure determination of 1.
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.