Synthesis of the Kopsia alkaloids (+/-)-pauciflorine B, (+/-)-lahadinine B, (+/-)-kopsidasine, (+/-)-kopsidasine-N-oxide, (+/-)-kopsijasminilam and (+/-)-11-methoxykopsilongine

Article abstract of DOI:10.1016/S0040-4020(02)00243-0

Pictet-Spengler condensation of 13 with tryptamine gave 14, which was converted into 17. Treatment of 17 with phenyl chloroformate resulted in 18, which underwent transannular cyclization to,give 19. The more stable cyano-analog 22 was made by treating 18 with Tf2O/DMAP to geenrate 18f, and quenching the reaction with trimethylsilyl cyanide. Treatment of 22 with acryloyl chloride (excess) at 75 deg C gave 23, which was directly treated with N-hydroxy-2-thiopyridone/Et3N to give 24. Irradiation of 24 in the presence of r-BuSH resulted in reductive decarboxylation to give 26 and a small amount o fthe 2-thiopyridyl ether 25. Protection of the aniline nitrogen in 26 required the use of triphosgene/pyridine followed by methanol. The final step for the conversion of 27 into 28 required conjugate reduction of the α,β-unsaturated ester followed by α-hydroxylation and gave 28 (11,12-demethoxy lahadinine B). Exposure of 26 to Phl(OAc)2/MeOH cleanly gave 26a, which was directly reduced with Zn/AcOH to 29. Conversion of 29 into 30 proceeded as before, and when 30 was treated with AgBF4/THF followed by aqueous NaHCO3 it was converted into (+/-)-kopsidasine 2, completely chracterized as its derived N-oxide 2a. Treatment of 26 with AgBF4/THF followed by aqueous NaHCO3, gave 31. Oxidation of 31 with m-chloroperoxybenzoic acid resulted in the N-oxdide 32 which underwent fragmentation to give 33 when exposed to trifluoroacetic anhydrde. when the diene 33 was treated with Mn(dpm), (cat)/PhSiH3/O2 in isopropyl alcohol at 0 deg C, it was converted into kopsijasminilam 4. Peracetic acid in ErOAc (10 percent) was used to quench the AgBH4/THF conversion of 28 into 37, and resulted in 42/42a (4:1, 65 percent) along with small amounts of 38 and 41c. Application of these procedures, with some modifications, to the 11,12-dimethoxy substituted system gave (+/-)-lahadinine B 64. Treatment of 64 with triethylsilane in the presence of trifluoroacetic acid cleanly converted it into 11-methoxykopsilongine 65 (93 percent). Treatment of (+/-)-lahadinine B 64 with AgBF4/THF followed by work-up with EtOAc/MeCO3H (10 percent) gave (+/-)-pauciflorine 6 and the double bond isomer 6a.

Full text of DOI:10.1016/S0040-4020(02)00243-0

TETRAHEDRON
Pergamon
Tetrahedron 58 42002) 3423±3443
Synthesis of the Kopsia alkaloids ꢀ^)-pauci¯orine B,
ꢀ^)-lahadinine B, ꢀ^)-kopsidasine, ꢀ^)-kopsidasine-N-oxide,
ꢀ^)-kopsijasminilam and ꢀ^)-11-methoxykopsilongine
Philip Magnus,p Lewis Gazzard, Lindsay Hobson, Andrew H. Payne, Trevor J. Rainey,
²
Neil Westlund and Vince Lynch
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
Received 12 February 2002; accepted 26 February 2002
AbstractÐPictet±Spengler condensation of 13 with tryptamine gave 14, which was converted into 17. Treatment of 17 with phenyl
chloroformate resulted in 18, which underwent transannular cyclization to give 19. The more stable cyano-analog 22 was made by treating
18 with Tf2O/DMAP to generate 18f, and quenching the reaction with trimethylsilyl cyanide. Treatment of 22 with acryloyl chloride 4excess)
at75 8C gave 23, which was directly treated with N-hydroxy-2-thiopyridone/Et3N to give 24. Irradiation of 24 in the presence of t-BuSH
resulted in reductive decarboxylation to give 26 and a small amount of the 2-thiopyridyl ether 25. Protection of the aniline nitrogen in 26
required the use of triphosgene/pyridine followed by methanol. The ®nal step for the conversion of 27 into 28 required conjugate reduction of
the a,b-unsaturated ester followed by a-hydroxylation and gave 28 411,12-demethoxy lahadinine B). Exposure of 26 to PhI4OAc)2/MeOH
cleanly gave 26a, which was directly reduced with Zn/AcOH to 29. Conversion of 29 into 30 proceeded as before, and when 30 was treated
with AgBF4/THF followed by aqueous NaHCO3 it was converted into 4^)-kopsidasine 2, completely characterized as its derived N-oxide 2a.
Treatment of 26 with AgBF4/THF followed by aqueous NaHCO3, gave 31. Oxidation of 31 with m-chloroperoxybenzoic acid resulted in the
N-oxide 32 which underwent fragmentation to give 33 when exposed to tri¯uoroacetic anhydride. When the diene 33 was treated with
Mn4dpm)3 4cat)/PhSiH3/O2 in isopropyl alcohol at0 8C, it was converted into kopsijasminilam 4. Peracetic acid in EtOAc 410%) was used to
quench the AgBF4/THF conversion of 28 into 37, and resulted in 42/42a 44:1, 65%) along with small amounts of 38 and 41c. Application of
these procedures, with some modi®cations, to the 11,12-dimethoxy substituted systems gave 4^)-lahadinine B 64. Treatment of 64 with
triethylsilane in the presence of tri¯uoroacetic acid cleanly converted it into 11-methoxykopsilongine 65 493%). Treatment of 4^)-lahadinine
B 64 with AgBF4/THF followed by work-up with EtOAc/MeCO3H 410%) gave 4^)-pauci¯orine 6 and the double bond isomer 6a. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
1980s was dominated by the use of indole-2,3-quinodi-
methanes as reactive intermediates for the synthesis of the
more complicated kopsanes.7
The history of the kopsane alkaloids began with the iso-
lation of kopsine 1 in 1890, Scheme 1.1 Classical structural
degradation studies of kopsine and structurally related alka-
loids uncovered many remarkable chemical transforma-
tions,2 but the structure of kopsine remained elusive until
the advent of high-resolution mass spectrometry in the
1960s.3 Con®rmation of the correct structure for kopsine
was obtained by X-ray crystallography.4 During the last
forty years or so there have been many reports of the iso-
lation and structure determination of a large number of new
Kopsia alkaloids with various degrees of oxidation.5 The
Kopsia alkaloids have attracted some attention as targets
for total synthesis,6 and our own efforts in this area in the
In 1982 Hesse8 reported the structure of kopsidasine 2 4and
its derived N-oxide), which was the ®rst example of a
kopsane alkaloid where oxidation has taken place at C-21
resulting in the hemiaminal functionality. The structure of
paucidactine A 3 further illustrates the varying and high
degree of oxidation of the core kopsane skeleton that can
take place.9 The X-ray structure of the spirocyclic amide
kopsijasminilam 4, a possible `Grob-type' fragmentation
productof a hemiaminal has been described, htus placing
the structural assignments on a ®rm basis.10 In 1996 the
structures of the Kopsia alkaloids pauci¯orine A and B 5/
6 were published,11 and apart from their unusually strained
structure, it was claimed that they selectively `inhibited
melanin synthesis of B16 melanoma cells at 13 mg mL21
without any cytotoxicity towards the cultured cells'.
Keywords: Kopsia alkaloids; pauci¯orine B; tryptamine.
Corresponding author. Tel.: 11-512-471-3966; fax: 11-512-471-7839;
p
e-mail: p.magnus@mail.utexas.edu
Author for inquiries concerning the X-ray data. Complete crystallo-
²
While the indole-2,3-quinodimethane strategy was applic-
able to the synthesis of kopsanes that lacked the hemiaminal
graphic details for compounds 2a, 6, 18, 19, 19a, 20, 21, 22b, 28, 35,
36, 39, 40, 42, 42c and 64 are deposited in the Cambridge data base.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020402)00243-0

3424
P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
Scheme 1. Structures of some typical Kopsia alkaloids.
functionality,7 this approach did not readily lend itself to
these new structural types. Consequently, we adopted a
completely different synthetic strategy that was based upon
4at the time) a hypothetical biogenetic pathway.12,13 Grob
fragmentation of 7 leads to 6. The structure of 7 is the clas-
sical Kopsia skeleton, which can be derived from 8, Scheme
2. Two transannular cyclizations of 9 have the potential to
provide a concise route to the homoannular diene 8. Iso-
gramine-type fragmentation of 10 should provide access to
9,14 and 10 is available from the classical Pictet±Spengler
reaction of a tryptamine derivative and a pyruvate ester.15
mine rather than the far less accessible 6,7-dioxygenated
tryptamine derivatives. Ozonolysis of 12 followed by
reductive work-up provided 13 487%).16 Pictet±Spengler
condensation of 13 with tryptamine 4containing
0.05 equiv. of tryptamine´HCl) gave 14, which was treated,
without puri®cation, with 1-hydroxybenzotriazole/1-[3-
4dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
4EDCI)/Et3N in dimethylformamide to give 15. Itshould be
noted that the use of the dimethyl ester derivative of 13 was
unsuccessful because the methyl ester derivative of 14 could
not be converted into 15, and as a consequence the reactions
in Scheme 3 are required. Belleau's reagent17 converted 15
into 16, and W-2 Raney Nickel or Ni2B/H2 desulfurization18
gave 17. Treatment of 17 with phenyl chloroformate/
ClCH2CH2Cl heated at re¯ux resulted in 18, the structure
of which was con®rmed by X-ray crystallography. Several
2. Synthesis of the homoannular diene 19
All of our preliminary studies were conducted with trypta-
Scheme 2. Proposed biogenetic origin of pauci¯orine and retrosynthetic analysis.

P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
3425
Scheme 3. Synthesis of tetracyclic amine 17 and fragmentation to give 18.
other chloroformate induced fragmentations of 17 were
tried, but phenyl chloroformate gave the best results.
methane containing 4-dimethylaminopyridine heated at
re¯ux19 eventually gave a deep purple solution of the
iminium ion 18f. Quenching the purple solution with
aqueous NaHCO3 gave 19 as yellow crystals whose struc-
ture was con®rmed by X-ray crystallography. Dissolving 19
in tri¯uoroacetic acid gave a purple solution 4lmax 544 nm).
Treatment of 19 with tri¯uoromethanesulfonic anhydride in
the presence of ethyl vinyl ether gave 19a 4X-ray). The
yields of 19 were somewhatvariable 446±72%), and hte
compound was not stable to chromatography other than
neutral alumina.
It was anticipated that treatment of 18 with a powerful
electrophile had the potential to cause both transannular
reactions 49 to give 8, Scheme 2) to take place resulting in
19, Scheme 4. Activation of 18 to give 18a should resultin
18b, which on proton loss to 18c and iminium ion formation
generates 18d, which can cyclize to give 18e. The iminium
ion 18e can lose a proton and eliminate ±OPh to give 18f. In
the event treatment of 18 with tri¯ic anhydride in dichloro-
Scheme 4. Formation of the homoannular diene 19.

3426
P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
Scheme 5.
3. Reactions of the homoannular diene 19
19. Consequently, we made the more robust cyano-analog
22 by treating 18 with Tf2O/DMAP to generate 18f, and
quenching the reaction with trimethylsilyl cyanide, Scheme
6. This procedure improved the yield of the homoannular
diene derivative, and was more reproducible. In retrospect
the choice of the cyano derivative 22 was somewhatfortui-
tous since we became aware that this functionality is present
in the lahadinine Kopsia alkaloids. In 1997, Kam reported
the isolation and structure determination of lahadinine B
64 from Kopsia pauci¯ora, Scheme 12.21 Consequently,
we could now consider the conversion of 22 into 11,12-
demethoxylahadinine B 28.
All attempted [214] cycloaddition reactions with the homo-
annular diene 19 were unsuccessful, and the only reaction
pathway observed was the formation of carbazoles among
otherwise complex mixtures. It was found that treatment of
19 with benzyl chloroformate in the presence of proton
sponge resulted in formation of the o-cyclohexadienone
20 495%), which also was resistant to [214] cycloaddition
chemistry, Scheme 5. Heating 20, for example, with maleic
anhydride in toluene or xylene at re¯ux resulted in the
formation of 21 4X-ray). It was evident that the hemiaminal
hydroxyl group in 19 needed to be protected, or replaced
with a more robust functional group.20
4. Synthesis of ꢀ^)-demethoxy-lahadinine B 28
ꢀ1†
Initially, we found that replacing the hemiaminal hydroxyl
group with an ±OMe or ±SPh 4via acid catalyzed exchange)
gave the required derivatives, but they were no better
behaved in attempted [214] cycloaddition chemistry than
Scheme 6. Installation of 16a-hydroxyl group.

P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
3427
Scheme 7. Aniline a-methoxylation.
Mn4dpm)3 4cat)/i-PrOH, Cl4CH2)2Cl 42:1)/O2 gave 28
411,12-demethoxy lahadinine B) in 86% yield as a single
stereoisomer whose structure and stereochemistry was
con®rmed by X-ray crystallography.25
ꢀ2†
5. Synthesis of ꢀ^)-kopsidasine 2 and
ꢀ^)-kopsidasine-N-oxide 2a
It seemed reasonable to attempt to convert 26 into kopsida-
sine, and thus provide unequivocal evidence for its struc-
The improved stability of the homoannular diene 22 did
indeed solve the above problems. For example, treatment
of 22 with maleic anhydride in toluene at 1008C for 6 h gave
the endo-adduct 22a 483%), Eq. 41). Interestingly, heating
22a at higher temperatures 41658C) resulted in the retro-
Diels±Alder 4or retro-Mannich) reaction to give back the
starting materials. Also nitroethylene reacted with 22 at
758C to give 22b 485%) 4X-ray), Eq. 42). Treatment of
22b with n-Bu3SnH/AIBN4cat)/PhH re¯ux gave a complex
Â
ture. Treatment of 26 with Pb4OAc)4 or Fremys salt
following literature protocols for the hydroxylation of
tryptamines and tryptophans26 did notproceed siast-
factorily. Whereas, exposure of 26 to PhI4OAc)2/MeOH
cleanly gave 26a, which was directly reduced with Zn/
AcOH to 29, Scheme 7.27 Conversion of 29 into 30
proceeded as before, and when 30 was treated with
AgBF4/THF followed by aqueous NaHCO3 itwas converted
into 4^)-kopsidasine 2. While the spectral data for 2
compared well with the literature,3 an authentic sample of
2 was notavailable, whereas a sample of hte derived
N-oxide 2a exists.28 Consequently, 2 was converted into
2a by treatment with m-chloroperoxybenzoic acid
4mCPBA). Comparison of synthetic 2a with natural 2a by
1
mixture that did not contain 4by H NMR) the expected
adduct 26. Consequently, we decided to use the very reac-
tive acryloyl chloride as the dienophile.
Treatment of 22 with acryloyl chloride 4excess) at 758C
gave 23, which was directly treated with N-hydroxy-2-thio-
pyridone/Et3N to give 24 469% from 22).22 Irradiation of
24 in the presence of t-BuSH resulted in reductive
decarboxylation to give 26 and a small amount of the 2-thio-
pyridyl ether 25. Protection of the aniline nitrogen in 26
required the use of triphosgene/pyridine followed by
methanol, as described by Danishefsky,23 to give 27
490%), and was used directly in the next step.
1
tlc 4multiple elutions) and H/13C NMR con®rmed their
identity, and an X-ray crystal structure of 2a unequivocally
demonstrated the structure of 2a.
6. Synthesis of ꢀ^)-kopsijasminilam 4
Treatment of 26 with AgBF4/THF followed by aqueous
29
The ®nal step for the conversion of 27 into 28 requires the
conjugate reduction of the a,b-unsaturated ester followed
by a-hydroxylation of the now saturated ester. In 1990,
Isayama et al. reported a single step method for accomplish-
ing the above.24 Treatment of 27 with PhSiH342.5 equiv.)/
NaHCO3 gave 31, and now we were in a position to
examine the Polonovski fragmentation, Scheme 8.30 Oxi-
dation of 31 with m-chloroperoxybenzoic acid 4m-CPBA)
resulted in the N-oxide 32 which underwenthte required
fragmentation to give 33 when exposed to tri¯uoroacetic

3428
P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
Scheme 8. Polonovski fragmentation.
anhydride 4TFAA). When the diene 33 was treated with
Mn4dpm)3 4cat)/PhSiH3/O2 in isopropyl alcohol at0 8C, it
was converted into kopsijasminilam 4 4after work-up with
aqueous Na2S2O3).13 We had hoped that kopsijasminilam
would react further with the above reduction±oxidation
reagent to install the 16a-hydroxyl group. In the event,
further exposure of 4 to Mn4dpm)3 4cat)/PhSiH3/O2 in
isopropyl alcohol at25 8C did not result in the expected
a-hydroxy ester, but rather fragmentation of the putative
Mn4dpm)2-enolate 4a and oxidation a-to the amide resulted
in 34. Dehydration 4BF3´OEt2) of 34 gave 35 whose struc-
ture was con®rmed by X-ray. Attempted protection of
33 through bromination of the diene with pyridinium
tribromide gave 36 4X-ray).
Scheme 9.

P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
3429
Scheme 10. Peroxyaminal fragmentation.
7. Attempted Polonovski fragmentations
contain any of 42 4as judged by the absence of the diagnostic
signal for the alkene proton H NMR d 5.25, Jˆ6.4 Hz).
1
The above ®ndings appeared to indicate that the 16a-hydroxy-
ester functionality should be introduced before any
attempted fragmentation process to the pauci¯orine
skeleton. Consequently, we ®rst studied the Polonovski
fragmentation of 38, Scheme 9. Treatment of demethoxyl-
ahadinine 28 with AgBF4/THF followed by an aqueous
NaHCO3 work-up gave 37, which was oxidized
4m-CPBA) to a single N-oxide 38. Exposure of 38
to TFAA/CH2Cl2 produced 39 4X-ray).31 Attempted
Polonovski rearrangementof 38 with BF3´OEt2 gave a
new N-oxide 4presumably via 39a) isolated as the
BF2-adduct 40 4X-ray). The adduct 40 on treatment with
TFAA/CH2Cl2 gave an intractable mixture that did not
8. Synthesis of ꢀ^)-11,12-Demethoxypauci¯orine 42
On one occasion while converting 28 into 37, t he1H NMR
spectrum of crude 37 was very clean, butafter purifying 37
by chromatography over silica gel eluting with EtOAc/
hexanes 41:2!1:1)/NEt3 41%), the eluents contained 37
and 38, and very surprisingly, 42 and the derived epoxide
42c! Furthermore, we also observed that all of the triethyl-
amine used in the chromatography had been oxidized to
triethylamine N-oxide. This experimentwas reproduced
three times, and each time we isolated 37, 38, 42 and
Scheme 11. 6,7-Dimethoxytryptamine 51. 4a) AcCl/py/1008C, 44 496%). 4b) Fuming HNO3/,68C, 45 482%). 4c) K2CO3/MeOH. 4d) MeI/K2CO3/DMF/358C,
46 472% from 45). 4e) MeNO2/KOH/DMF/EtOH/aqueous work-up HCl/08C followed by Ac2O/NaOAc/re¯ux, 47 473%). 4f) Fe/AcOH/EtOH/re¯ux, 48 485%).
4g) POCl3/DMF/0±258C, 49 492%). 4h) MeNO2/NH4OAc/re¯ux, 50 4100%). 4i) LiAlH4/THF/08C to re¯ux, 51 491%).

3430
P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
Ê
Scheme 12. 4a) CF3CO2H4cat)/CH2Cl2/4 A molecular sieves/0±238C. 4b) EDCI/HOBt/Et3N/DMF/0±238C, 53 467%). 4c) Belleau's reagent/THF/0±238C, 54
4100%). 4d) NiCl2´6H2O/NaBH4/THF/MeOH/08C, 55 477%). 4e) PhOCOCl415 equiv.)/Cl4CH2)2Cl/re¯ux/48 h, 56 447%, 33% recovered 55). 4f) Tf2O/DMAP/
CH2Cl2/re¯ux, followed by aqueous NaHCO3, 57 418%), or work-up with TMSCN/DMAP/CH2Cl2, 58 463%). 4g) Acryloyl chloride/238C/24 h. 4h) 2-Thio-
pyridone-N-oxide4Na salt)/t-BuSH/CH2Cl2/hv, 60 437%), or 2-thiopyridone-N-oxide4Na salt)/4PhSe)2/CH2Cl2/hv, 61 445%). 4i) KN4TMS)2/18-crown-6/THF/
2788C followed by CO2 and Me2SO4, 62 486%). 4j) Mn4dpm)3 45 mol%)/PhSiH3/O2/i-PrOH/Cl4CH2)2Cl, 63 483%). 4k) Ph3SnH/PhMe/re¯ux, 64 494%).
4l) CF3CO2H/Et3SiH/CH2Cl2/238C, 65 493%).
small amounts of 42c. On a fourth attempt only 37 was
formed. It would appear that the simplest explanation
consistent with these observations is that the EtOAc used
during chromatography contained a ®nite amount of a
peracid 4mostlikely peraceict acid). Indeed, when we
deliberately added peracetic acid to EtOAc 410%) and
used it to quench the AgBF4/THF conversion of 28 into
37, we obtained 42/42a 44:1, 65%) along with small
amounts of 38 and 42c. The structures of 42 and 42c were
con®rmed by X-ray crystallography. Epoxidation of 33 gave
42b, which was treated with Mn4dpm)3 4cat)/PhSiH3/O2 to
give 42c.

P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
3431
Since we know that neither N-oxide 38 nor 40 is the source
of demethoxypauci¯orine 42, itis reasonable ot suppose
that the iminium ion intermediate 28a in the conversion
of 28 into 37 adds peracetic acid to generate 41 which
fragments to give 42 and 42a 4Scheme 10).32
The ®nal step involves reductive removal of the PhSe-
substituent. This was achieved through treatment of 63
with triphenyltin hydride in toluene at re¯ux to give 4^)
lahadinine B 64 in 94% yield. Comparison of spectral
data con®rmed that the synthetic material was the same as
the natural compound, apart from [a]D. The structure of 64
was con®rmed by X-ray crystallography.38
9. Synthesis of ꢀ^)-lahadinine B 64, ꢀ^)-11-methoxy-
kopsilongine 65 and ꢀ^)-pauci¯orine B 6
Since we had established the structure of 64 to be correct, its
conversion into 65 would provide unequivocal evidence for
the correctness of the structure of 65. Treatment of 64 with
triethylsilane in the presence of tri¯uoroacetic acid cleanly
converted it into 11-methoxykopsilongine 65 493%).39
Acetylation of vanillin 43 gave 44, which was nitrated
following literature conditions to give 45 and a small
amount of the 6-nitro-isomer 48:1 ratio of isomers).33
Hydrolysis of 45 and O-methylation gave 46,34 which was
exposed to the classical Henry reaction conditions to give
47.35 Reduction of 47 produced the indole 48.36 Vilsmeier
formylation of 48 gave 49, which was converted into 51 via
50 using conditions recently described by Corey37 for the
N-methyl derivative of 48, Scheme 11.
Treatment of 4^)-lahadinine B 64 with AgBF4/THF
followed by work-up with EtOAc/MeCO3H 410%) gave
4^)-pauci¯orine 6 466%) and the double bond isomer 6a
421%). Crystallization of 6 from MeOH/CH2Cl2 gave
crystals suitable for X-ray crystallography which con®rmed
the proposed structure.40
Treatment of 51 with 13 under Pictet±Spengler reaction
conditions that were satisfactory for tryptamine gave 52
4,10%) 4Scheme 12). Whereas, exposure of a mixture of
51 and 13 to tri¯uoroacetic acid 4cat) in dichloromethane in
the presence of molecular sieves at 0±238C gave 52, which
was directly 4without puri®cation) converted into 53 in 67%
yield for the two steps. Belleau's reagent converted 53 into
54, and Ni2B/H2 desulfurization gave 55. The reaction of
55 with PhOCOCl/ClCH2CH2Cl heated at re¯ux was very
slow compared with the demethoxy series, but prolonged
treatment 448 h) gave 56 447%) and recovered 55 433%).
Attempts to drive the reaction to completion diminished
the yield of 56, and more reactive chloroformates such as
4-nitrophenyl chloroformate did not help.
10. Experimental
10.1. Data for compounds
10.1.1. Methyl 2-oxo-6-carboxy-hexanoate 13. Ozone was
bubbled through a solution of 12 48.0 g, 51.2 mmol) in
CH2Cl2 4340 mL) at 2788C for 3.5 h. Dimethyl sul®de
43.76 mL, 51.2 mmol) was added to the mixture, the solu-
tion warmed to room temperature, and stirred for 18 h. The
solution was evaporated in vacuo to give a yellow liquid
which was puri®ed by chromatography over silica gel
eluting with a gradient of EtOAc/hexanes containing 1%
v/v acetic acid to give 13 as a white microcrystalline solid
48.4 g, 87%). IR 4®lm) 3100, 2955, 1729, 1709 cm21. H
1
Treatment of 56 with tri¯ic anhydride in dichloromethane
containing 4-dimethylaminopyridine heated at re¯ux, fol-
lowed by quenching the purple solution with aqueous
NaHCO3 gave 57 418%), whereas quenching the reaction
with trimethylsilyl cyanide resulted in 58 465%). Reaction
of 58 with acryloyl chloride 4excess) at 238C gave 59, which
was directly treated with N-hydroxy-2-thiopyridone 4Na
salt), followed by irradiation in the presence of t-BuSH
resulted in reductive decarboxylation to give 60 437%
from 58). All attempts to convert 60 into its derived
N-CO2Me adductusing a varieyt of conditons 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, pre-
sumably because of steric hindrance. Since we had also
converted 59 into the phenylselenide derivative 61 445%
from 58), we decided to examine its conversion into 62. It
was eventually found that KN4SiMe3)2/18-crown-6/CO2/
2788C followed by dimethyl sulfate gave 62 486%). This
same procedure when applied to 60 was unsuccessful! It
can be speculated that the PhSe-substituent coordinates
the ±NCO2K intermediate suf®ciently to allow O-methyl-
ation before decarboxylation.
NMR 4300 MHz, CDCl3) d 11.5±9.5 41H, br s), 3.87 43H,
s), 2.88 42H, br t, Jˆ7.0 Hz), 2.40 42H, br t, Jˆ7.0 Hz),
1.74±1.64 44H, m). 13C NMR 475 MHz, CDCl3) d 193.6,
179.0, 161.3, 52.9, 38.8, 33.5, 23.7, 22.2. HRMS calcd for
C8H13O5 4MH1) 189.076. Found 189.076.
10.1.2. ꢀ^)-1-ꢀ4-Carboxy-butyl)-2,3,4,9-tetrahydro-1H-
b-carboline-1-carboxylic acid methyl ester 14. A solution
of 13 41.65 g, 8.77 mmol) and tryptamine 41.41 g, 8.77
mmol) in 1,4-dioxane 422 mL) and benzene 422 mL) was
heated at re¯ux for 24 h. Water was continuously removed
Ê
by a Dean-Stark apparatus containing 4 A molecular sieves.
The cooled mixture was evaporated in vacuo to give 14
as a pale brown foam 43.0 g), which was subsequently
used without puri®cation. H NMR indicated ca. 80±90%
purity.
1
10.1.3. ꢀ^)-13b-Carbomethoxy-2,3,4,5,6,7,8,13,13b-octa-
hydro-1H-azepino[10,20:1,2]pyrido[3,4-b]indol-5-one 15.
A solution of crude 14 42.89 g, ,8.23 mmol) and 1-hydroxy-
benzotriazole monohydrate 41.39 g, 9.06 mmol) in DMF
4100 mL) at0 8C was treated with a solution of 1-[3-4di-
methylamino)propyl]-3-ethylcarbodiimide hydrochloride
4EDCI) 41.73 g, 9.05 mmol) and triethylamine 41.30 mL,
9.33 mmol) in DMF 4100 mL). The resulting mixture was
stirred at 08C for 1 h, then at 238C for 20 h, and treated with
pH 7 buffer solution and water 4total 1.2 L), and extracted
The conjugate reduction±oxidation reaction to convert 62
into 63 was conducted with Mn4dpm)3 45 mol%)/PhSiH3/
O2/i-PrOH/Cl4CH2)2Cl and gave 63 in 83% yield. This
reaction did not work at all on the unprotected adduct 61.

3432
P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
three times with EtOAc 4600 mL). The combined extracts
were washed with brine, dried 4MgSO4), and evaporated in
vacuo to yield an orange-brown solid 43.51 g). Flash
chromatography over silica gel eluting with a gradient of
EtOAc/hexanes gave 15 41.73 g, 67% for two steps) as
microscopic white cubes. Mp 209±209.58C. IR 4®lm)
CDCl3) d 174.9, 136.2, 133.5, 126.8, 121.9, 119.3, 118.4,
110.9, 66.6, 52.4, 50.5, 50.2, 39.4, 30.8, 29.2, 22.9, 19.8
4one signal notobserved). HRMS calcd for C 18H23N2O2
4MH1) 299.176. Found 299.176.
Alternatively 16 can be desulfurized to give 17 using nickel
boride. To a stirred solution of 16 45.36 g, 16.34 mmol) and
nickel4II) chloride hexahydrate 415.53 g, 65.36 mmol) in
THF 4100 mL) and MeOH 4100 mL) at0 8C was added,
portion wise, sodium borohydride 47.42 g, 196.09 mmol)
over a period of 20 min. On addition the green solution
immediately turned black. After complete addition of the
sodium borohydride the mixture was stirred for a further
15 min before being ®ltered through a pad of Celite, wash-
ing with methanol 4300 mL). The ®ltrate was concentrated
in vacuo to ,50 mL of solvent, and partitioned between
water 4150 mL) and EtOAc 4150 mL). The aqueous phase
was extracted with EtOAc 43£150 mL) and the combined
extracts washed with water 4150 mL) and brine 4150 mL),
dried 4Na2SO4), and evaporated in vacuo. The residue was
puri®ed by chromatography over silica gel eluting with 25%
EtOAc/hexanes containing 0.5% v/v triethylamine to give
17 43.5 g, 79%, two steps).
.
3288, 2938, 1738, 1623 cm21 1H NMR 4300 MHz,
CDCl3) d 8.2 41H, br s), 7.52 41H, d, Jˆ8 Hz), 7.34 41H,
d, Jˆ8 Hz), 7.22 41H, t, Jˆ8 Hz), 7.13 41H, t, Jˆ8 Hz), 4.82
41H, dt, Jˆ12.8, 4.0 Hz), 3.81 43H, s), 3.32 41H, ddd, Jˆ
12.8, 8.8, 5.7 Hz), 2.90±2.75 44H, m), 2.27 41H, br t, Jˆ
12 Hz), 2.0±1.75 44H, m), 1.70±1.55 41H, m). 13C NMR
475 MHz, CDCl3) d 176.4, 172.2, 136.3, 131.8, 126.0,
122.8, 119.9, 118.7, 112.1, 111.1, 65.5, 53.3, 42.2, 40.9,
38.1, 25.6, 22.0, 20.6. HRMS calcd for C18H21N2O3
4MH1) 313.155. Found 313.154.
10.1.4. ꢀ^)-13b-Carbomethoxy-2,3,4,5,6,7,8,13,13b-octa-
hydro-1H-azepino[10,20:1,2]pyrido[3,4-b]indol-5-thione
16. To a solution of 15 41.71 g, 5.49 mmol) in anhydrous
THF 4110 mL) at0 8C was added solid Belleau's reagentin
one portion 41.89 g, 3.58 mmol). The resulting solution was
stirred at 08C for 10 min, allowed to warm to 238C, and
stirred for 6 h. Chromatographic grade silica 4ca. 15 g)
was added and the mixture evaporated in vacuo. Flash
chromatography of the residue over silica gel eluting with
10.1.6.
ꢀ^)-5,8,9,10,11,14-Hexahydro-6H-7,14-diaza-
cycloundeca[a]indene-7,13-dicarboxylic acid 13-methyl
ester 7-phenyl ester 18. To a solution of 17 4233 mg,
780 mmol) in 1,2-dichloroethane 43.1 mL) was added
phenyl chloroformate 4979 mL, 7.80 mmol) and the mixture
heated at re¯ux for 24 h. The solution became bright yellow
within a few minutes and heavily clouded within 12 h. The
mixture was cooled to 258C, and excess saturated aqueous
NaHCO3 solution was added. The mixture was stirred
vigorously for several hours and extracted three times
with CH2Cl2. The combined extracts were washed with
water and brine, dried 4Na2SO4), and evaporated in vacuo
to yield an orange-brown oily solid. Flash chromatography
over silica gel eluting with a gradient of EtOAc/hexanes
gave 18 as a colorless, viscous oil which forms a white
crystalline ®lm in vacuo 4216 mg, 66%). Crystals for
X-ray analysis were grown by slow evaporation of a toluene
solution to give 18 as clear, colorless cubes. Mp 170±1718C.
a gradientof EOt Ac/hexanes gave
16 as a pale lemon
yellow microcrystalline solid 41.82 g, 100%). Recrystalli-
zation by diffusion of hexanes vapor into an Et2O solution
gave 16 as clear yellow prisms. Mp 160.5±161.58C 4dec). IR
4®lm) 3396, 2948, 1732 cm21. 1H NMR 4300 MHz, CDCl3)
d 8.1 41H, br s), 7.55 41H, d, Jˆ8 Hz), 7.35 41H, d, Jˆ8 Hz),
7.24 41H, t, Jˆ8 Hz), 7.16 41H, t, Jˆ8 Hz), 5.52 41H, dt,
Jˆ13.3, 4.3 Hz), 4.07 41H, ddd, Jˆ13.3, 8.4, 5.1 Hz), 3.79
43H, s), 3.63 41H, ddd, Jˆ14.6, 7.1, 2.3 Hz), 3.10±2.90 42H,
m), 2.79 41H, ddd, Jˆ14.6, 6.2, 3.0 Hz), 2.65 41H, ddd, Jˆ
14.4, 11.8, 2.5 Hz), 2.06 41H, ddd, Jˆ14.4, 11.0, 3.4 Hz),
2.0±1.6 45H, m). 13C NMR 475 MHz, CDCl3) d 209.9,
171.1, 136.3, 131.6, 125.7, 123.0, 120.1, 118.7, 111.9,
111.2, 69.6, 53.6, 51.9, 47.0, 38.9, 24.0, 23.7, 20.2.
HRMS calcd for C18H21N2O2S 4MH1) 329.132. Found
329.132.
IR 4®lm) 3343, 2947, 1714 cm21 1H NMR 4300 MHz,
.
10.1.5. ꢀ^)-13b-Carbomethoxy-2,3,4,5,6,7,8,13,13b-octa-
hydro-1H-azepino[10,20:1,2]pyrido[3,4-b]indole 17.
CDCl3, 300 K) d 8.10±8.01 41H, br m), 7.65±7.58 41H, br
m), 7.38±6.97 48H, br m), 6.30 41H, d, Jˆ7.8 Hz), 4.8±1.5
412H, br m), 3.77±3.70 43H, m). 4500 MHz, d8-toluene,
373 K) d 7.46 41H, dd, Jˆ7.9, 0.9 Hz), 7.19 40.8H, br s),
7.09 41H, t, Jˆ8.2 Hz), 7.11±6.94 47H, obscured m), 6.81
41H, t, Jˆ7.4 Hz), 6.71 41.2H, br s), 3.81 42H, br t, Jˆ
5.7 Hz), 3.42 43H, s), 3.12 42H, br s), 2.92 42H, t, Jˆ
5.7 Hz), 2.20±2.09 44H, m), 1.65±1.49 44H, m). 13C NMR
475 MHz, d8-toluene, 373 K) d 166.9, 154.9, 152.8, 149.7,
137.4, 127.7, 124.7, 122.6, 121.9, 120.1, 111.3, 51.6, 50.5,
28.8, 27.2 4several signals notobserved or obscured).
HRMS calcd for C25H27N2O4 4MH1) 419.197. Found
419.196.
A
freshly prepared aqueous suspension of W-2 Raney Nickel
419 g) was suspended ®ve times in dry THF 425 mL), and
the solvent decanted. To a vigorously stirred suspension of
the washed metal in THF 430 mL) was added a pale yellow
solution of 16 41.82 g, 5.49 mmol) in THF 420 mL) drop-
wise at23 8C over 10 min; the color dissipated instantly. The
mixture was ®ltered through a pad of Celite which was
washed with EtOAc, and the ®ltrate evaporated in vacuo
to give 17 41.64 g, 100%) as white prisms. Mp 124±
1
1268C. IR 4neat) 3397, 2923, 2843, 1732 cm21. H NMR
4300 MHz, CDCl3) d 8.1 41H, br s), 7.50 41H, dd, Jˆ7.5,
1 Hz), 7.36 41H, dd, Jˆ7.5, 1 Hz), 7.18 41H, dd, Jˆ7.5,
1 Hz), 7.10 41H, dd, Jˆ7.5, 1 Hz), 3.74 43H, s), 3.31 41H,
ddd, Jˆ13.1, 11.0, 4.1 Hz), 3.20 41H, ddd, Jˆ13.1, 5.4,
1.8 Hz), 2.97±2.90 42H, m), 2.87 41H, ddd, Jˆ15.4, 11.0,
5.4 Hz), 2.56 41H, ddd, Jˆ15.4, 4.1, 1.8 Hz), 2.49 41H, ddd,
Jˆ15.0, 7.0, 3.0 Hz), 2.12 41H, ddd, Jˆ15.0, 9.0, 2.0 Hz),
1.75±1.55 45H, m), 1.55±1.35 41H, m). 13C NMR 475 MHz,
10.1.7.
ꢀ^)-12b-Hydroxy-2,3,6,11,12,12b-hexahydro-
1H-6,12a-diazaindeno[7,1-cd]¯uorene-5-carboxylic acid
methyl ester 19. To a solution of 18 4143 mg, 341 mmol)
and 4-N,N-dimethylaminopyridine 4DMAP) 4125 mg, 1.03
mmol) in anhydrous CH2Cl2 417 mL) at0 8C was added
tri¯uoromethanesulfonic anhydride 4287 mL, 1.71 mmol)

P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
3433
dropwise over 4 min. The mixture became bright yellow
during the addition and a precipitate formed after ca.
1 equiv. had been added. After 10 min at 08C the mixture
was allowed to warm to 238C for a further 10 min, and
heated at re¯ux for 24 h 4the mixture became olive-green,
and after 10 min at re¯ux the solution became very deep
purple in color). To the cooled mixture was added excess
saturated aqueous NaHCO3 solution, and the mixture stirred
vigorously for ca. 30 min then extracted three times with
CH2Cl2. The combined extracts were washed with brine,
dried 4Na2SO4), and evaporated in vacuo to yield an
orange-brown oil. Flash chromatography over neutral
alumina eluting with a gradient of EtOAc/hexanes gave
19 451 mg, 46%) as a yellow crystalline ®lm. Recrystalli-
zation by diffusion of pentane vapor into an EtOAc solution
gave 19 as yellow prisms suitable for X-ray analysis. Mp
184±1858C. UV 4CHCl3, 4.93£1025 M) lmax 371 4e
11,300), 297 4e 6900). 41%, v/v TFA in CHCl3, 6.16£
1025 M) lmax 544 4e 1800), 370 4e 11,500), 330 4e 7900),
Rotational doubling and broadening of some signals was
observed. HRMS calcd for C27H27N2O5 4MH1) 459.192.
Found 459.191.
10.1.9. ꢀ^)-12b-ꢀ2,2-diethoxyethyl)-2,3,6,11,12,12b-hexa-
hydro-1H-6,12a-diazaindeno[7,1-cd]¯uorene-5-carboxylic
acid methyl ester 19a. To a solution of the 19 412.4 mg,
38.2 mmol) and DMAP 45.4 mg, 44 mmol) in anhydrous
CH2Cl2 43.8 mL) at0 8C was added a solution of tri¯uoro-
methanesulfonic anhydride in CH2Cl2 4221 mL, 42 mmol),
causing the mixture to become deep orange. Ethyl vinyl
ether 437 mL, 387 mmol) was added dropwise. The mixture
was stirred at 08C for 3 h and then allowed to warm to 238C
for a further 20 h. Excess pH 7 buffer solution was added
and the mixture extracted three times with CH2Cl2.
The combined extracts were washed with brine, dried
4Na2SO4), and evaporated in vacuo to yield a yellow oil.
Flash chromatography over silica gel eluting with a gradient
of EtOAc/hexanes gave 19a 411.1 mg, 68%) as a yellow
crystalline ®lm. Crystals suitable for X-ray analysis were
grown by slow diffusion of pentane vapor into an Et2O
solution gave 19a as clear yellow plates. IR 4®lm) 3387,
306 4e 7300). IR 4®lm) 3354, 2928, 2851, 1678, 1598 cm21
.
1H NMR 4300 MHz, CDCl3) d 9.00 41H, br s), 7.53 41H, dd,
Jˆ7.5, 0.6 Hz), 7.21 41H, td, Jˆ7.5, 1 Hz), 6.97 41H, td,
Jˆ7.5, 1 Hz), 6.88 41H, d, Jˆ7.5 Hz), 6.18 41H, d, Jˆ
2.1 Hz), 3.78 43H, s), 3.34 41H, q, Jˆ8.7 Hz), 3.28 41H,
td, Jˆ13.6, 2.8 Hz), 3.03±2.86 42H, m), 2.51 41H, ddd,
Jˆ13.7, 4.7, 2.2 Hz), 2.5±2.3 42H, m), 1.92±1.65 43H,
m), 1.53 41H, ddd, Jˆ13.1, 4.7, 2.3 Hz). 4300 MHz, C6D6)
d 9.12 41H, br s), 7.39 41H, d, Jˆ7.5 Hz), 6.92 41H, t,
Jˆ7.5 Hz), 6.75 41H, t, Jˆ7.5 Hz), 6.43 41H, d, Jˆ
2.1 Hz), 6.14 41H, d, Jˆ7.5 Hz), 3.53 43H, s), 3.17 41H,
td, Jˆ13.7, 2.7 Hz), 2.97 41H, q, Jˆ8.6 Hz), 2.64±2.48
43H, m), 2.32±2.14 42H, m), 1.70±1.50 43H, m), 1.15
41H, ddd, Jˆ13.0, 5.0, 2.0 Hz). HRMS calcd for
C19H20N2O3 4M1) 324.147. Found 324.147. In some experi-
ments the yield of 19 was as high as 72%, butht is was not
reproducible due to the instability of 19. When the above
reaction mixture was treated with trimethylsilyl cyanide to
give 22, the process becomes reproducible and improves the
yield 4see later).
1
2928, 2866, 1674, 1633 cm21. H NMR 4300 MHz, C6D6)
d 9.37 41H, br s), 7.45 41H, d, Jˆ7.2 Hz), 6.92 41H, t,
Jˆ7.6 Hz), 6.79 41H, t, Jˆ7.4 Hz), 6.39 41H, d, Jˆ
1.4 Hz), 6.24 41H, d, Jˆ7.7 Hz), 4.31 41H, dd, Jˆ6.5,
3.6 Hz), 3.60 43H, s), 3.39±3.28 41H, m), 3.22±3.12 41H,
m), 3.14±2.90 44H, m), 2.75±2.61 42H, m), 2.48 41H, br q,
Jˆ9.0 Hz), 2.33 41H, dd, Jˆ14.3, 3.6 Hz), 2.3±2.1 42H, m),
2.12 41H, dd, Jˆ14.3, 6.5 Hz), 1.70±1.53 42H, m), 1.2±1.0
41H, m), 1.02 43H, t, Jˆ7.0 Hz), 0.87 43H, t, Jˆ7.0 Hz). 13C
NMR 475 MHz, C6D6) d 167.8, 166.2, 144.1, 134.8, 126.9,
124.5, 121.7, 117.2, 109.8, 100.8, 90.9, 66.5, 60.8, 60.1,
50.5, 47.7, 44.9, 40.4, 35.7, 30.2, 22.3, 15.4, 15.3 4two
signals notobserved or obscured). HRMS calcd for
C25H32N2O4 4M1) 424.236. Found 424.237.
10.1.10. Compound 21. A solution of the 20 45.5 mg,
12 mmol) and phenyl vinyl sulfone 43.0 mg, 18 mmol) in
anhydrous toluene 41.2 mL) was heated at 85±908C for
12.5 h. No reaction had occurred as evidenced by TLC
analysis, and the mixture was heated at re¯ux for a further
81 h. The mixture was evaporated in vacuo to yield a yellow
oil. Flash chromatography over silica gel eluting with a
gradientof EOt Ac/hexanes gave 21 43.1 mg, 56%) as a
white crystalline ®lm. Crystals suitable for X-ray analysis
were grown in toluene by slow evaporation to give 21 as
clear, colorless prisms. Mp 186±1878C. IR 4®lm) 3366,
10.1.8. Compound 20. To a solution of 19 44.1 mg,
13 mmol) and proton sponge 48.2 mg, 38 mmol) in CH2Cl2
42.0 mL) at0 8C was added dropwise benzyl chloroformate
44 mL, 28 mmol). The mixture was stirred at 08C for 8 h,
allowed to warm to 238C for a further 18 h, and treated with
excess saturated aqueous NaHCO3 solution with vigorous
stirring for a further 30 min. The mixture was extracted
three times with CH2Cl2, the combined extracts washed
with citric acid 40.5 M) and brine, dried 4Na2SO4), and
evaporated in vacuo. Flash chromatography over silica gel
eluting with 33% EtOAc/hexanes gave 20 45.5 mg, 95%) as
a deep orange oil. Crystals suitable for X-ray analysis were
grown by slow evaporation of a toluene solution to give 20
as clear, orange hexagonal plates. Mp 185±1888C 4dec, soft-
1
2919, 2851, 1703, 1699, 1608 cm21. H NMR 4300 MHz,
CDCl3, 300 K) d 9.84 40.6H, br s), 9.81 40.4H, br s), 8.11
40.4H, d, Jˆ8.0 Hz), 8.08 40.6H, d, Jˆ8.0 Hz), 7.85 40.6H,
s), 7.82 40.4H, s), 7.55±7.40 42.4H, m), 7.32±7.23 41.6H,
m), 7.11±7.00 41.6H, m), 6.88 41.4H, t, Jˆ7.6 Hz), 6.50±
6.39 41H, m), 6.29 41H, d, Jˆ7.4 Hz), 4.90 40.4H, d, Jˆ
12.5 Hz), 4.82 40.4H, d, Jˆ12.5 Hz), 4.55 40.6H, d, Jˆ
12.5 Hz), 4.46 40.6H, d, Jˆ12.5 Hz), 4.03 41.2H, s), 4.01
41.8H, s), 3.79 41H, br t, Jˆ14 Hz), 3.40 41H, br t,
Jˆ12 Hz), 3.12±3.00 41H, m), 2.78±2.66 41H, m), 2.20±
1.85 42H, m), 1.81 43H, d, Jˆ6.0 Hz). Carbamate resonance
causes doubling of signals. 4500 MHz, d8-toluene, 373 K) d
9.61 41H, br s), 8.17 41H, br d, Jˆ7.6 Hz), 7.80 41H, s), 7.23
41H, t, Jˆ7.6 Hz), 7.15 41H, t, Jˆ7.5 Hz), 7.01 41H, d,
Jˆ8 Hz), 6.95±6.75 43H, br m), 6.7±6.35 43H, br m),
ens at170 8C). IR 4®lm) 3313, 2923, 2853, 1652, 1612 cm21
.
1H NMR 4300 MHz, CDCl3) d 9.50 41H, br s), 7.92 40.6H, d,
Jˆ7.5 Hz), 7.73 40.4H, d, Jˆ7.5 Hz), 7.45±7.3 46H, m),
7.42 40.6H, s), 7.40 40.4H, s), 7.15±6.93 42H, m), 5.25±
4.95 42H, m), 3.88 43H, s), 3.82±3.65 41H, m), 3.60
40.6H, dd, Jˆ14.8, 5.7 Hz), 3.50 40.4H, dd, Jˆ14.8,
5.7 Hz), 3.27 40.4H, dd, Jˆ14.8, 9.8 Hz), 3.17 40.6H, dd,
Jˆ14.8, 9.8 Hz), 3.00±2.68 42.6H, m), 2.50 40.4H, dd,
Jˆ14.3, 10.0 Hz), 2.35±2.10 41H, m), 2.1±1.6 43H, m).

3434
P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
4.65±4.35 42H, br m), 3.78±3.63 42H, br s), 3.66 43H, s),
3.13 41H, ddd, Jˆ14.1, 12.0, 2.2 Hz), 2.94 41H, td, Jˆ13.3,
2.2 Hz), 2.50 41H, br dd, Jˆ13.3, 5.5 Hz), 1.67±1.60 41H,
m), 1.55 43H, d, Jˆ6.0 Hz). HRMS calcd for C27H26N2O5
4M1) 458.184. Found 458.184.
for 5 days. The solvent was removed by distillation under
reduced pressure giving a beige solid. Puri®cation by ¯ash
column chromatography over silica gel eluting with 25±
35% EtOAc/hexanes gave 22b as a pale yellow solid
462 mg, 85%) suitable for X-ray crystallography. Mp
1808C 4dec). IR 4®lm) 3393, 2947, 2861, 2253, 1716,
10.1.11. ꢀ^)-12b-Cyano-2,3,6,11,12,12b-hexahydro-1H-
6,12a-diazaindeno[7,1-cd]¯uorene-5-carboxylic
1611, 1550 cm21 1H NMR 4500 MHz, CDCl3) d 7.43
.
acid
41H, d, Jˆ7.5 Hz), 7.17 41H, td, Jˆ7.5, 1.0 Hz), 7.16 41H,
s), 6.91 41H, td, Jˆ7.5, 1.0 Hz), 6.85 41H, d, Jˆ7.5 Hz),
5.19 41H, br s), 4.95 41H, dd, Jˆ8.5, 6.0 Hz), 3.79 43H, s),
3.31 41H, m), 3.04 41H, m), 2.84 41H, td, Jˆ7.5, 2.0 Hz),
2.72 41H, m), 2.41 41H, dd, Jˆ14.0, 8.5 Hz), 2.36 41H, m),
2.10 41H, m), 2.02 41H, m), 1.97±1.89 42H, m), 1.77 41H,
m), 1.55 41H, m). 13C NMR 4125 MHz, CDCl3) d 163.5,
147.4, 144.1, 131.3, 131.1, 129.1, 123.4, 121.3, 117.4,
111.8, 82.9, 74.0, 68.3, 66.4, 52.3, 49.5, 44.5, 41.1, 37.5,
36.9, 30.6, 16.4. HRMS calcd for C22H23N4O4 4MH1)
407.172. Found 407.172.
methyl ester 22. To a stirred solution of 18 41.19 g,
2.84 mmol) and DMAP 41.04 g, 8.53 mmol) in anhydrous
CH2Cl2 4110 mL) at0 8C under argon was added dropwise
tri¯uoromethanesulfonic anhydride 42.35 mL, 14.2 mmol).
When addition was complete the green solution was
warmed to 238C, and heated at re¯ux to give a deep purple
solution. After 22 h at re¯ux the mixture was cooled to 238C
and trimethylsilyl cyanide 41.50 mL, 11.4 mmol) was added
dropwise to the stirred solution. Solid DMAP 41.39 g,
11.4 mmol) was added portion wise to the solution resulting
in the disappearance of the purple color and the formation of
an orange/brown solution. Saturated aqueous NaHCO3
4200 mL) solution was added and the layers separated.
The aqueous layer was extracted with CH2Cl2 4200 mL),
and the combined extracts washed with water 4200 mL)
and brine 4200 mL), dried 4MgSO4), and evaporated in
vacuo. Puri®cation by ¯ash column chromatography over
silica gel eluting with 25% EtOAc/hexanes gave 22 as a
yellow solid 40.641 g, 68%). Mp 1608C 4dec). IR 4®lm)
10.1.14. ꢀ^)-16-Anhydro-11,12-demethoxy-1-decarbo-
methoxylahadinine B 26. A mixture of 22 40.273 g,
0.812 mmol) and acryloyl chloride 4400 mL, 4.87 mmol)
in degassed anhydrous toluene 43.3 mL) was heated in a
sealed tube at 758C for 5 days. The solventwas evaporaet d
in vacuo to give a dark solid which was dried under high
vacuum for 3 h. This residue was dissolved in anhydrous
CH2Cl2 42.5 mL), and a mixture of 2-mercaptopyridine-N-
oxide 40.165 g, 1.30 mmol) and triethylamine 4226 mL,
1.62 mmol) in anhydrous CH2Cl2 41 mL) was added drop-
wise under argon with stirring in the absence of light for 2 h.
The mixture was cooled to 08C and tert-butyl thiol 4700 mL)
was added. The resultant mixture was irradiated with a
tungsten lamp for 1.5 h, maintaining the temperature
below 108C with an ice/water bath. The solvents were
evaporated in vacuo, and the residue partitioned between
saturated aqueous NaHCO3 420 mL) and EtOAc 420 mL).
The layers were separated and the aqueous extracted with
EtOAc 420 mL). The combined extracts were washed with
saturated aqueous NaHCO3 450 mL), water 450 mL) and
brine 450 mL), and dried 4MgSO4). Puri®cation by ¯ash
column chromatography over silica gel eluting with 20±
50% EtOAc/hexanes gave 26 as a white solid 40.115 g,
39% over three steps). Mp 210±2128C. IR 4®lm) 3365,
3374, 2946, 2866, 2253, 1682, 1639 cm21 1H NMR
.
4500 MHz, CDCl3) d 9.11 41H, br s), 7.58 41H, d, Jˆ
7.5 Hz), 7.23 41H, td, Jˆ7.5, 1.5 Hz), 7.00 41H, td, Jˆ7.5,
1.5 Hz), 6.90 41H, d, Jˆ7.5 Hz), 6.26 41H, d, Jˆ7.5 Hz),
3.79 43H, s), 3.34 41H, td, Jˆ13.0, 2.5 Hz), 3.28 41H, dd,
Jˆ17.0, 8.5 Hz), 3.14 41H, m), 2.96 41H, m), 2.52±2.35
43H, m), 1.92±1.79 42H, m), 1.60±1.53 41H, m). 13C
NMR 4125 MHz, CDCl3) d 167.0, 161.7, 143.2, 132.3,
129.0, 124.0, 122.3, 119.8, 119.3, 117.3, 110.0, 91.2, 64.5,
59.0, 51.2, 46.7, 45.9, 39.6, 29.5, 20.4. HRMS calcd for
C20H20N3O2 4MH1) 334.156. Found 334.155.
10.1.12. Compound 22a. A mixture of 22 493 mg,
0.279 mmol) and maleic anhydride 455 mg, 0.558 mmol)
in degassed anhydrous toluene 42 mL) was heated in a
sealed tube at 1008C for 6 h. The solventwas evaporaetd
in vacuo, and the residue puri®ed by ¯ash column chroma-
tography over silica gel eluting with 25% EtOAc/hexanes to
give 22a as a white solid 4100 mg, 83%). Mp 1808C 4dec).
IR 4®lm) 3382, 2951, 2864, 2256, 1855, 1779, 1719,
1
2944, 2859, 2251, 1713, 1609 cm21. H NMR 4500 MHz,
CDCl3) d 7.42 41H, d, Jˆ7.5 Hz), 7.08 41H, td, Jˆ7.5,
1.0 Hz), 6.95 41H, s), 6.84 41H, td, Jˆ7.5, 1.0 Hz), 6.73
41H, d, Jˆ7.5 Hz), 4.34 41H, br s), 3.80 43H, s), 3.31 41H,
m), 3.02 41H, m), 2.83 41H, td, Jˆ9.0, 1.5 Hz), 2.72 41H,
ddd, Jˆ17.5, 9.0, 1.5 Hz), 2.28 41H, ddd, Jˆ13.5, 7.0,
1.5 Hz), 2.08 41H, m), 1.98±1.80 44H, m), 1.72 41H, m),
1.46 41H, m), 1.26 41H, m), 1.13 41H, ddd, Jˆ13.0, 12.0,
6.0 Hz). 13C NMR 4125 MHz, CDCl3) d 164.5, 149.3,
143.9, 135.3, 133.0, 128.0, 123.8, 120.3, 118.5, 110.9,
70.1, 68.7, 66.1, 52.1, 49.8, 44.8, 41.6, 37.4, 31.9, 31.4,
27.3, 16.5. HRMS calcd for C22H24N3O2 4MH1) 362.187.
Found 362.187.
1
1609 cm21. H NMR 4500 MHz, CDCl3) d 7.44 41H, d,
Jˆ8.0 Hz), 7.19 41H, td, Jˆ8.0, 1.0 Hz), 6.95 41H, s),
6.93 41H, td, Jˆ8.0, 1.0 Hz), 6.91 41H, d, Jˆ8.0 Hz), 5.51
41H, br s), 3.82 43H, s), 3.41 and 3.36 42£1H, 2d, Jˆ8.5 Hz),
3.33 41H, m), 3.06 41H, m), 2.87 41H, m), 2.78 41H, m), 2.73
41H, m), 2.28 41H, ddd, Jˆ14.0, 7.0, 2.5 Hz), 2.10 41H, td,
Jˆ14.0, 4.0 Hz), 1.90 41H, m), 1.75 41H, m), 1.64 41H, m).
13C NMR 4125 MHz, CDCl3) d 169.9, 168.8, 162.8, 147.4,
140.9, 134.8, 131.1, 129.1, 123.7, 121.5, 116.8, 112.1, 72.5,
68.8, 65.9, 52.7, 49.8, 48.4, 44.6, 43.8, 43.4, 36.9, 28.6,
16.7. HRMS calcd for C24H22N3O5 4MH1) 432.156. Found
432.156.
10.1.15. ꢀ^)-16-Anhydro-11,12-demethoxylahadinine B
27. To a stirred solution of 26 4115 mg, 0.318 mmol) in a
mixture of anhydrous CH2Cl2 45.5 mL) and pyridine
41.2 mL) at0 8C under argon was added a solution of tri-
phosgene 4283 mg, 0.954 mmol) in anhydrous CH2Cl2
42 mL) dropwise, resulting in a pink solution containing
10.1.13. Compound 22b. A mixture of the 22 460 mg,
0.180 mmol) and nitroethylene 4900 mL, 1 M soln in
benzene, 0.900 mmol) was heated at 708C in a sealed tube

P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
3435
some precipitate. After 10 min the mixture was allowed to
warm to 238C and stirred for 45 min resulting in complete
dissolution of the precipitate. The mixture was recooled
t o 80C, once again causing precipitation to occur, and
anhydrous MeOH 42.5 mL) was added dropwise. The resul-
tant clear solution was allowed to warm to 238C. After a
further 1 h, pH 7 phosphate buffer 450 mL) was added
and the mixture extracted with EtOAc 42£50 mL). The
combined extracts were washed with water 4100 mL) and
brine 4100 mL) and dried 4MgSO4). Evaporation of the
solvents in vacuo gave a yellow solid. Puri®cation by
¯ash column chromatography over silica gel eluting with
35±50% EtOAc/hexanes gave 27 as a white solid 4120 mg,
resultant solid taken up in EtOAc and ®ltered. Evaporation
of the solvent in vacuo gave the crude 29 40.050 g) which
was used immediately in the next step.
10.1.18. ꢀ^)-16-Anhydro-11,12-demethoxy-13-methoxy-
lahadinine B 30. Triphosgene 498 mg, 0.332 mmol) in
CH2Cl2 41 mL) was added to a solution of 29 and pyridine
40.268 mL, 3.32 mmol) in CH2Cl2 41 mL) at0 8C. The
mixture was stirred at 08C for a further 10 min, and warmed
to room temperature and stirred for 45 min, resulting in
complete dissolution of the precipitate. The mixture was
cooled to 08C and anhydrous MeOH 40.5 mL) was added
dropwise. The resultant clear solution was allowed to warm
to room temperature. After a further 2 h, pH 7 phosphate
buffer 420 mL) was added, and the mixture extracted with
EtOAc 43£20 mL). The combined extracts were washed
with water 430 mL) and brine 430 mL), dried 4Na2SO4),
and evaporated in vacuo to give a brown solid. Puri®cation
by ¯ash chromatography over silica gel, eluting with 50%
EtOAc/hexanes gave 30 427 mg, 54%). Mp 178±1808C.
90%). IR 4®lm) 3350, 2953, 2858, 2254, 1714, 1690 cm21
.
1H NMR 4500 MHz, DMSO-d6, 1008C) d 7.75 41H, d,
Jˆ7.5 Hz), 7.42 41H, dd, Jˆ7.5, 1.0 Hz), 7.28 41H, td, Jˆ
7.5, 1.0 Hz), 7.12 41H, td, Jˆ7.5, 1.0 Hz), 6.84 41H, s), 3.74
43H, s), 3.72 43H, s), 3.13 41H, td, Jˆ14.0, 3.0 Hz), 3.00
41H, m), 2.76 41H, td, Jˆ9.0, 2.0 Hz), 2.64 41H, m), 2.46
41H, td, Jˆ6.5, 2.0 Hz), 2.06 41H, m), 1.95±1.81 42H, m),
1.76±1.67 42H, m), 1.61±1.50 42H, m), 1.40 41H, m), 1.29
41H, td, Jˆ12.5, 7.0 Hz). 13C NMR 4125 MHz, DMSO-d6,
1008C) d 164.2, 152.6, 141.0, 140.2, 134.3, 133.9, 127.6,
123.0, 122.7, 117.5, 114.2, 69.7, 67.4, 65.2, 51.7, 51.0, 48.9,
43.9, 40.1, 38.3, 30.3, 29.8, 23.4, 15.2. HRMS calcd for
C24H26N3O4 4MH1) 420.192. Found 420.192.
1
IR 4®lm) 2949, 2250, 1715, 1686, 1610 cm21. H NMR
4500 MHz, DMSO-d6, 373 K) d 7.66 41H, d, Jˆ8.9 Hz),
6.98 41H, d, Jˆ2.7 Hz), 6.85 41 H, dd, Jˆ8.9, 2.7 Hz),
6.81 41H, s), 3.76 43H, s), 3.73 43H, s), 3.69 43H, s), 3.12
41H, td, Jˆ14.2, 3.1 Hz), 2.99 41H, m), 2.76 41H, td, Jˆ8.7,
1.9 Hz), 2.64 41H, m), 2.46 41H, td, Jˆ6.5, 1.9 Hz), 2.06
41H, m), 1.96±1.85 41H, m), 1.81 41H, td, Jˆ12.9, 2.5 Hz),
1.77±1.65 42H, m), 1.61±1.54 42H, m), 1.40 41H, m), 1.29
41H, td, Jˆ12.3, 6.9 Hz). 13C NMR 4125 MHz, DMSO-d6,
373 K) d 164.2, 155.5, 152.6, 139.9, 135.0, 134.5, 134.4,
117.6, 114.9, 112.9, 109.1, 78.5, 69.7, 67.3, 65.1, 55.1, 51.5,
51.0, 48.8, 43.8, 38.0, 30.2, 29.7, 23.3, 15.2. HRMS calcd
for C25H27N3O5 4MH1) 449.195. Found 449.195.
10.1.16. ꢀ^)-11,12-Demethoxylahadinine B 28. To a
stirred solution of 27 4102 mg, 0.243 mmol) and
Mn4dpm)3 44 mg, 0.010 mmol) in a mixture of isopropanol
42 mL) and 1,2-dichloroethane 41.5 mL) at 08C was
added dropwise phenylsilane 475 mL, 0.608 mmol). When
addition was complete the green-brown solution was stirred
under an oxygen balloon at0 8C for 10 min then at 238C for
6 h. Saturated sodium thiosulfate solution was added slowly
420 mL), and after stirring for 5 min the mixture was
extracted with EtOAc 42£20 mL), and the combined
extracts washed with water 430 mL) and brine 430 mL).
The solution was dried 4MgSO4), and evaporated in vacuo
to give a beige solid. Puri®cation by ¯ash column chroma-
tography over silica gel eluting with 25% EtOAc/hexanes
gave 28 as a white crystalline solid 490 mg, 85%) suitable
for X-ray crystallography. Mp 250±2518C. IR 4®lm) 3284,
2948, 2253, 1736, 1682 cm21. 1H NMR 4500 MHz, CDCl3)
d 7.55 41H, d, Jˆ8.0 Hz), 7.51 41H, td, Jˆ8.0, 1.0 Hz), 7.31
41H, s), 7.22 41H, td, Jˆ8.0, 1.0 Hz), 7.06 41H, td, Jˆ8.0,
1.0 Hz), 3.95 43H, s), 3.72 43H, s), 3.15±3.02 44H, m), 2.96
41H, m), 2.32 41H, m), 1.97±1.87 42H, m), 1.81±1.49 46H,
m), 1.45±1.37 42H, m). 13C NMR 4125 MHz, CDCl3) d
172.4, 156.5, 140.2, 135.1, 128.2, 123.8, 123.6, 118.3,
115.7, 76.1, 73.8, 68.2, 59.8, 53.6, 52.5, 49.1, 44.3, 39.3,
39.0, 36.5, 32.6, 28.6, 23.4, 19.8. HRMS calcd for
C24H28N3O5 4MH1) 438.203. Found 438.202.
10.1.19. ꢀ^)-Kopsidasine 2. Silver tetra¯uoroborate
467 mg, 0.338 mmol) in anhydrous THF 41 mL) was
added to a solution of 30 438 mg, 0.0846 mmol) in
anhydrous THF 41 mL) atroom temperature. Over a period
of 1 h the yellow solution became orange and a yellow
suspension formed. Saturated aqueous NaHCO3 410 mL)
was added and the mixture stirred for 10 min. The mixture
was extracted with EtOAc 43£20 mL), and the combined
extracts were washed with brine 420 mL), dried 4Na2SO4)
and evaporated in vacuo. Flash chromatography over silica
gel, eluting with 50±75% EtOAc/hexanes and 1% v/v
triethylamine gave 2 as a colorless glass, 429 mg, 78%).
1
IR 4®lm) 3417, 2950, br 1713, 1686, 1613 cm21. H NMR
4500 MHz, CDCl3) d 7.86 41H, br d, Jˆ7.6 Hz), 6.84±6.70
43H, m), 3.77 43H, s), 3.75 43H, s), 3.68 43H, s), 3.25±3.15
41H, m), 2.79 41H, m), 2.70 41H, t, Jˆ9.0 Hz), 2.59 41H, m),
2.38±2.27 41H, m), 1.93±1.57 48H, m), 1.38±0.98 42H, m).
13C NMR 4125 MHz, CDCl3) d 166.0, 156.4, 153.7, 143.4,
136.6, 136.3, 135.3, 116.1, 115.6, 112.2, 109.5, 91.37, 71.3,
62.4, 55.6, 51.8, 47.2, 43.4, 42.2, 30.1, 29.6, 29.4, 23.6,
16.3. HRMS calcd for C24H29N2O6 4MH1) 441.203. Found
441.202. The spectral data are in good agreement with the
literature values.
10.1.17. ꢀ^)-16-Anhydro-11,12-demethoxy-13-methoxy-
1-decarbomethoxylahadinine B 29. Iodobenzenediacetate
443 mg, 0.133 mmol) was added in one portion to a suspen-
sion of 26 440 mg, 0.110 mmol) in MeOH 42 mL) at0 8C.
After 45 min at 08C the suspension became an orange solu-
tion. Zinc powder 436 mg, 0.554 mmol) was added and the
orange solution became a yellow suspension. After stirring
the mixture for 30 min at room temperature solid NaHCO3
was added. The solvent was evaporated in vacuo and the
10.1.20. ꢀ^)-Kopsidasine-N-oxide 2a. To a solution of
kopsidasine 2 429 mg, 0.0659 mmol) in CH2Cl2 42 mL)
was added m-chloroperoxybenzoic acid 424 mg, 0.0988
mmol) in CH2Cl2 42 mL). The resultant yellow solution
was stirred at room temperature for 4 h. Water 45 mL) was

3436
P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
added and the mixture extracted with CH2Cl2 42£5 mL).
The combined extracts were washed with 1% NaOH
410 mL), dried 4Na2SO4), and evaporated in vacuo to give
a yellow glass which was puri®ed by ¯ash chromatography
over silica gel eluting with 3% MeOH/CHCl3 and 1% v/v
triethylamine. Recrystallization of the product from Et2O/
MeOH gave colorless crystals of 2a 414 mg, 46%) suitable
for X-ray crystallography. Mp 168±1708C. IR 4®lm) 3374,
10.1.23. ꢀ^)-16,17-Anhydro-11,12-demethoxypauci¯orine
B 3 3 .Tri¯uoroacetic anhydride 40.169 mL, 1.19 mmol) was
added to a solution of 32 4102 mg, 0.239 mmol) in CH2Cl2
43 mL) at 2308C. The solution was allowed to warm to 08C
over 30 min and stirred for a further 1 h at room tempera-
ture. The mixture was quenched with saturated aqueous
NaHCO3 and extracted with CH2Cl2 43£15 mL). The
combined extracts were washed with water 420 mL) and
brine 420 mL), dried 4Na2SO4), and evaporated in vacuo to
give 33 as a yellow foam, which was used directly in the
nextreaciton. 4The 1H NMR of the crude product showed
the diene 33 to be present in .90%). IR 4®lm) 2949, br
1
2953, br 1715, 1612 cm21. H NMR 4500 MHz, CDCl3,
313 K) d 7.82 41H, br m), 7.43 41H, d, Jˆ2.5 Hz), 6.75
41H, br d, Jˆ7.5 Hz), 6.67 41H, br s), 3.78, 3.77 49H, 2 s),
3.48 41H, br d, Jˆ13.0 Hz), 3.35±3.17 42H, m), 3.14 41H, br
t, Jˆ8.7 Hz), 2.40 41H, m), 2.17±1.71 48H, m), 1.31±1.25
41H, m). 13C NMR 4125 MHz, CDCl3, 313 K) d 165.6,
156.7, 137.7, 115.6, 114.2, 111.2, 102.6, 71.4, 61.2, 59.1,
55.6, 52.1, 45.9, 43.6, 35.6, 30.2, 29.6, 27.4, 20.1 4several
signals obscured or notobserved). HRMS calcd for
C24H29N2O7 4MH1) 457.197. Found 457.198.
1711, 1600 cm21 1H NMR 4300 MHz, CDCl3) d 7.92,
.
7.49 41H, br d, Jˆ8.1 Hz), 7.30±6.97 44H, m), 5.80 41H,
br s), 4.04 41H, t, Jˆ13.2 Hz), 3.95±3.65 47H, m), 3.57 41H,
m), 3.15±2.87 43H, m), 2.76±2.59 41H, m), 2.47 41H, m),
2.20 41H, br t, Jˆ12.9 Hz), 2.00±1.65 43H, m). HRMS calcd
for C23H25N2O5 4MH1) 409.176. Found 409.176.
10.1.21. ꢀ^)-16-Anhydro-11,12-demethylenedioxypauci-
®nine 31. Silver tetra¯uoroborate 4341 mg, 1.75 mmol) in
anhydrous THF 44 mL) was added to a solution of 26
4147 mg, 0.351 mmol) in anhydrous THF 44 mL) atroom
temperature. Over a period of 1 h the yellow solution
became orange and a yellow suspension formed. Saturated
aqueous NaHCO3 415 mL) was added and the mixture
stirred for 10 min. The mixture was extracted with EtOAc
43£30 mL), and the combined extracts were washed with
brine 420 mL), dried 4Na2SO4), and evaporated in vacuo.
Flash chromatography over silica gel eluting with 50±
75% EtOAc/hexanes and 1% v/v triethylamine gave 31 as
a white foam 4139 mg, 97%). IR 4®lm) 3492, 2936, br 1714,
1602 cm21. 1H NMR 4300 MHz, CDCl3) d 7.97 41H, br m),
7.23 42H, br m), 7.03 41H, t, Jˆ7.2 Hz), 6.87 41H, br m),
3.95±3.65 46H, br m), 3.27±3.17 41H, m), 2.80 41H, m),
2.72 41H, t, Jˆ8.7 Hz), 2.61 41H, m), 2.38±2.31 41H, m),
1.96±1.50 48H, m), 1.34±1.00 42H, m). 13C NMR 475 MHz,
CDCl3) d 165.7, 153.7, 143.8, 142.7, 135.5, 135.0, 127.5,
123.5, 122.9, 115.4, 91.1, 77.2, 71.2, 62.3, 60.3, 51.8, 47.2,
43.4, 42.2, 36.8, 29.7, 29.4, 16.2. HRMS calcd for
C23H27N2O5 411.192. Found 411.192.
10.1.24. ꢀ^)-16,17-Anhydro-11,12-demethoxy-15-bromo-
pauci¯orine B 36. To a solution of 33 433 mg, 0.0808
mmol) in CHCl3 41 mL) at 2608C was added pyridinium
hydrogen bromide perbromide 425 mg, 0.0808 mmol). After
1 h the solution was warmed to room temperature, and after
a further 3 h the mixture was quenched with saturated
aqueous sodium bisulphite 45 mL). The aqueous phase
was extracted with CHCl3 43£10 mL), and the combined
extracts were washed with water 415 mL) and brine
415 mL), dried 4Na2SO4) and the solvents evaporated in
vacuo to give an orange ®lm. Puri®cation by ¯ash chroma-
tography over silica gel eluting with 50% EtOAc/hexanes
gave 36 a white glass 425 mg, 63%). Recrystallization from
ether/MeOH gave colorless crystals suitable for X-ray
crystallography 416 mg, 41%). Mp 160±1628C. IR 4®lm)
.
2942, 1712, 1685, 1600 cm21 1H NMR 4300 MHz,
CDCl3) d 7.93, 7.50 41H, d, Jˆ7.8 Hz), 7.40±6.90 44H,
m), 6.04 41H, br d, Jˆ3.6 Hz), 4.59 41H, br d, Jˆ
11.1 Hz), 4.06 41H, t, Jˆ13.5 Hz), 3.95±3.60 46H, m),
3.50 41H, m), 3.30±1.50 48H, m). 13C NMR 4125 MHz,
CDCl3) d 175.6, 166.3, 152.6, 140.5, 134.5, 133.1, 132.2,
128.8, 124.7, 124.2, 123.9, 123.8, 115.1, 73.2, 60.4, 58.8,
52.2, 52.0, 44.5, 42.0, 35.5, 31.0, 29.3. HRMS calcd for
C23H24N2O5Br 4MH1) 487.087. Found 487.085.
10.1.22. ꢀ^)-16-Anhydro-11,12-demethylenedioxypauci-
®nine-N-oxide 32. To a solution of 31 4139 mg, 0.339
mmol) in CH2Cl2 44 mL) was added a solution of m-chloro-
peroxybenzoic acid 4108 mg, 0.441 mmol) in CH2Cl2
44 mL). The resultant yellow solution was stirred at room
temperature for 1.5 h. Water 410 mL) was added and the
mixture extracted with CH2Cl2 42£20 mL). The combined
extracts was washed with 1% NaOH solution 415 mL), dried
4Na2SO4), and evaporated in vacuo to give a yellow glass.
Flash chromatography over silica gel eluting with 5%
MeOH/CHCl3 containing 1% v/v triethylamine gave 32 as
a white foam 4128 mg, 89%). IR 4®lm) 2952, 1718,
10.1.25. ꢀ^)-Kopsijasminilam 4. Phenylsilane 415 mL,
0.122 mmol) was added to a solution of 33 420 mg,
0.049 mmol) and Mn4dpm)3 41 mg, 0.002 mmol) in iso-
propanol 40.75 mL) and 1,2-dichloroethane 40.5 mL) at
2308C. The brown solution was placed under an oxygen
atmosphere and stirred for a further 1 h at 2308C then at 08C
for 1 h. Athtis pointmore phenylsilane 415
mL, 0.122
mmol) and Mn4dpm)3 41 mg, 0.002 mmol) were added,
and the mixture warmed to room temperature for 1 h.
Triethylphosphite 49.2 mL, 0.053 mmol) was added and
the mixture stirred for 45 min open to the atmosphere.
Evaporation of the solvents in vacuo gave a brown oil
which was puri®ed by ¯ash chromatography over silica
gel eluting with 50% EtOAc/hexanes, increasing to 100%
EtOAc to give 4 as a colorless glass, 410 mg, 48%). IR 4®lm)
3418, 1712, 1697, 1600 cm21. 1H NMR 4500 MHz, CDCl3)
d 7.92 and 7.48 41H, br d, Jˆ8.3 Hz), 7.21 41H, m), 7.10
41H, br m), 7.04 41H, t, Jˆ7.3 Hz), 7.01 41H, s), 4.08 41H, br
t, Jˆ13.4 Hz), 3.82±3.71 46H, m), 3.64 41H, br s), 3.48 41H,
1
1601 cm21. H NMR 4300 MHz, CDCl3) d 7.90 41H, br
m), 7.80 41H, d, Jˆ7.5 Hz), 7.21 41H, br t, Jˆ7.5 Hz),
7.06 41H, t, Jˆ7.5 Hz), 6.72 41H, br m), 3.90±3.68 46H,
m), 3.49 41H, m), 3.40±3.00 43H, m), 2.40 41H, m), 2.16±
1.66 48H, m), 1.36±1.29 41H, m). 13C NMR 475 MHz,
CDCl3) d 165.5, 136.8, 128.0, 126.0, 124.0, 114.7, 102.4,
77.2, 71.1, 61.2, 59.0, 52.1, 45.8, 43.5, 35.7, 30.0, 27.3, 20.0
4several signals notobserved or obscured). HRMS calcd for
C23H27N2O6 4MH1) 427.187. Found 427.187.

P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
3437
m), 2.98 41H, dd, Jˆ14.1, 3.7 Hz), 2.86 41H, t, Jˆ9.5 Hz),
2.44 41H, m), 2.36±1.60 48H, m). 13C NMR 4125 MHz,
CDCl3) d 171.9, 166.5, 153.5, 145.6, 140.7, 130.7, 129.9,
128.7, 124.9, 123.6, 115.4, 69.6, 69.3, 60.3, 52.7, 52.3, 43.9,
42.3, 41.3, 32.9, 31.2, 26.2, 22.5. HRMS calcd for
C23H27N2O6 4MH1) 427.187. Found 427.186.
amine gave 37 as a white solid 4120 mg, 81%). Mp 182±
1
1828C. IR 4®lm) 3499, 3288, 1732, 1681, 1599 cm21. H
NMR 4300 MHz, CDCl3) d 7.55 41H, d, Jˆ8.1 Hz), 7.34
41H, s), 7.26 41H, d, Jˆ7.2 Hz), 7.16 41H, t, Jˆ7.5 Hz), 7.02
41H, t, Jˆ7.5 Hz), 3.95 43H, s), 3.72 43H, s), 3.25±3.10 42H,
m), 3.07±2.97 41H, m), 2.95±2.77 42H, m), 2.32±2.18 41H,
m), 2.07±1.98 41H, m), 1.93±1.40 49H, m), 1.33±1.22 41H,
m). 13C NMR 475 MHz, CDCl3) d 172.9, 156.5, 140.7,
136.1, 127.2, 123.7, 123.5, 115.8, 90.6, 74.8, 74.3, 59.5,
53.3, 52.3, 47.7, 43.0, 41.5, 36.3, 36.2, 31.6, 28.8, 23.2,
17.1. HRMS calcd for C23H28N2O6 4M1) 428.195. Found
428.193.
10.1.26. Compounds 34 and 35. Phenylsilane 4114 mL,
0.931 mmol) was added to a solution of 33 476 mg,
0.186 mmol) and Mn4dpm)3 45 mg, 0.002 mmol) in iso-
propanol 40.75 mL) and 1,2-dichloroethane 40.5 mL) at
08C. The brown solution was placed under an oxygen
atmosphere and allowed to warm to room temperature and
stirred for a further 18 h. Triethyl phosphite 479 mL,
0.465 mmol) was added, and the mixture was stirred for
45 min open to the atmosphere. Evaporation of the solvents
in vacuo gave a brown oil which was puri®ed by ¯ash
chromatography over silica gel eluting with 0±50%
MeOH/CHCl3 to give 34 as a colorless glass 422 mg,
10.1.28.
ꢀ^)-11,12-Demethylenedioxypauci®nine-N-
oxide 38. To a solution of 37 4120 mg, 0.280 mmol) in
CH2Cl2 44 mL) was added a solution of m-chloroperoxy-
benzoic acid 483 mg, 0.336 mmol) in CH2Cl2 44 mL) at
08C. The resultant yellow solution was stirred at 08C for
20 min. Water 410 mL) was added and the mixture extracted
with CH2Cl2 42£20 mL). The combined extracts were
washed with 1% NaOH solution 415 mL), dried 4Na2SO4),
and the solvents were evaporated in vacuo to give a yellow
glass. Flash chromatography over silica gel eluting with 5%
MeOH/CHCl3 containing 1% v/v triethylamine gave 38 as a
1
26%). IR 4®lm) 3418, 1712, 1680, 1637, 1600 cm21. H
NMR 4300 MHz, CDCl3) d 7.96 41H, d, Jˆ8.1 Hz), 7.45
41H, t, Jˆ8.1 Hz), 7.31 41H, t, Jˆ7.8 Hz), 6.96 41H, d, Jˆ
7.5 Hz), 4.00 41H, m), 4.00±3.65 42H, m), 3.76 43H, s), 3.64
43H, s), 3.46 42H, m), 3.07 41H, m), 2.79 41H, d, Jˆ
13.5 Hz), 2.60±2.00 44H, m), 1.99±1.25 45H, m). A solution
of the diol 34 421 mg, 0.047 mmol) in CH2Cl2 40.5 mL) at
room temperature was treated with BF3´Et2O 46.5 mL,
0.052 mmol). A precipitate immediately formed which
redissolved after 10 min. After 1 h at room temperature
the mixture was quenched with water 43 mL) and extracted
with CH2Cl2 43£10 mL). The combined extracts were
washed with brine 415 mL), dried 4Na2SO4), and the
solvents evaporated in vacuo to give a yellow oil. Puri®-
cation by ¯ash chromatography over silica gel eluting with
5% MeOH/CHCl3 gave the product 35 as a colorless solid
46 mg, 30%). Recrystallization from ether/MeOH gave
colorless crystals suitable for X-ray analysis. Mp 159±
yellow oil 463 mg, 51%). IR 4®lm) 3278, 1731, 1679 cm21
.
1H NMR 4300 MHz, CDCl3) d 8.17 41H, d, Jˆ7.5 Hz), 7.72
41H, br s), 7.52 41H, d, Jˆ8.1 Hz), 7.18 41H, t, Jˆ8.1 Hz),
7.07 41H, t, Jˆ7.2 Hz), 3.97 43H, s), 3.83 41H, m), 3.76 43H,
s), 3.59 41H, br d, Jˆ13.5 Hz), 3.45±3.24 43H, m), 3.06 41
H, br d, Jˆ15.9 Hz), 2.95±2.80 41H, m), 2.34±2.24 41H, m),
2.15±2.09 41H, m), 1.95±1.20 48H, m). 13C NMR 475 MHz,
CDCl3) d 173.0, 156.8, 140.5, 134.3, 127.8, 127.2, 124.3,
114.8, 103.4, 74.7, 73.7, 62.5, 60.5, 53.5, 52.8, 45.7, 43.1,
36.9, 33.6, 29.8, 29.0, 22.2, 18.8. HRMS calcd for
C23H29N2O7 4MH1) 445.197. Found 445.197.
10.1.29. Compound 39. Tri¯uoroacetic anhydride 40.242
mL, 1.70 mmol) was added to a solution of 38 463 mg,
0.141 mmol) and pyridine 4114 mL, 1.41 mmol) in CH2Cl2
42.5 mL) at 2108C. After stirring at 2108C for 1 h saturated
aqueous NaHCO3 45 mL) was added. The aqueous phase
was extracted with CH2Cl2 43£10 mL), and the combined
extracts were washed with 1% NaOH 415 mL), brine
415 mL), dried 4Na2SO4), and evaporated in vacuo to give
a yellow oil. Chromatography over silica gel eluting with
35% EtOAc/hexanes gave 39 productas a colorless glass
447 mg, 75%). Recrystallization from ether/MeOH gave
colorless crystals suitable for X-ray analysis. Mp 205±
1
1618C. IR 4®lm) 3389, 1715, 1694, 1681 cm21. H NMR
4500 MHz, CDCl3) d 7.89 41H, dd, Jˆ8.0, 1.5 Hz), 7.40
41H, td, Jˆ8.5, 1.5 Hz), 7.31 41H, td, Jˆ7.5, 1.5 Hz), 7.05
41H, dd, Jˆ7.5, 1.5 Hz), 5.48 41H, d, Jˆ6.5 Hz), 3.78 43H,
s), 3.86±3.50 42H, m), 3.70 43H, s), 3.20±3.10 42H, m),
3.06±2.82 43H, m), 2.77 41H, dd, Jˆ14.0, 5.0 Hz), 2.58
41H, m), 2.47±2.39 41H, m), 2.24 41H, m), 2.12 41H, dt,
Jˆ13.0, 3.5 Hz), 1.94 41H, dd, Jˆ15.0, 9.0 Hz), 1.83 41H,
dd, Jˆ15.0, 7.0 Hz), 1.72 41H, m). 13C NMR 4125 MHz,
CDCl3) d 172.5, 134.9, 133.8, 131.1, 130.5, 129.9, 128.8,
127.9, 127.1, 125.2, 119.9, 78.7, 53.5, 52.4, 44.7, 44.2, 35.7,
30.4, 29.7, 28.1, 22.7 4two signals not observed). HRMS
calcd for C23H27N2O6 4MH1) 427.187. Found 427.185.
2078C. IR 4®lm) 3310, 1737, 1681 cm21
.
1H NMR
4300 MHz, CDCl3) d 7.62 41H, d, Jˆ8.4 Hz), 7.58 41H,
s), 7.53 41H, d, Jˆ9.0 Hz), 7.27 41H, t, Jˆ8.4 Hz), 7.07
41H, t, Jˆ7.5 Hz), 4.04 41H, m), 3.97 43H, s), 3.72 43H,
s), 3.39 41H, dd, Jˆ11.1, 6.9 Hz), 2.85 41H, br s), 2.52
41H, d, Jˆ17.4 Hz), 2.34 41H, t, Jˆ10.5 Hz), 2.22 41H, d,
Jˆ17.1 Hz), 2.12 41H, m), 2.08 41H, s), 1.95 41H, m), 1.75±
1.50 45H, m). 13C NMR 475 MHz, CDCl3) d 172.1, 156.4,
146.1, 140.7, 132.2, 128.5, 124.2, 123.4, 116.2, 89.4, 77.2,
74.6, 73.7, 60.1, 53.7, 52.6, 49.6, 41.1, 40.2, 34.0, 26.8,
26.4, 23.1 4two signals not observed). HRMS calcd for
C25H26N2O7F3 4MH1) 523.169. Found 523.167.
10.1.27. ꢀ^)-11,12-Demethylenedioxypauci®nine 37.
Silver tetra¯uoroborate 4338 mg, 1.74 mmol) in anhydrous
THF 45 mL) was added to a solution of 28 4152 mg,
0.347 mmol) in anhydrous THF 45 mL) atroom etmpera-
ture. Over a period of 1 h the yellow solution became
orange/brown and a suspension formed. Saturated aqueous
NaHCO3 415 mL) was added and the mixture was stirred for
10 min. The mixture was extracted with EtOAc 43£30 mL),
and the combined extracts were washed with water 420 mL)
and brine 420 mL), dried 4Na2SO4), and evaporated in vacuo
to give a yellow oil. Flash chromatography over silica gel
eluting with 35±50% EtOAc/hexanes and 1% v/v triethyl-
10.1.30. Compound 40. To a solution of 38 462 mg, 0.139
mmol) in CH2Cl2 41 mL) at0 8C was added BF3´Et2O

3438
P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
427 mL, 0.209 mmol). After 45 min at 08C saturated
aqueous NaHCO3 43 mL) was added and the resultant
mixture extracted with CH2Cl2 43£10 mL). The combined
extracts were washed with water 415 mL) and brine
415 mL), dried 4Na2SO4), and evaporated in vacuo. Puri®-
cation by ¯ash chromatography over silica eluting with 5%
MeOH/CHCl3 gave 40 as a colorless glass 460 mg, 87%).
Recrystallization from ether/MeOH gave colorless crystals
suitable for X-ray analysis. Mp 158±1608C. IR 4®lm) 3277,
1736, 1681, 1600 cm21. 1H NMR 4300 MHz, CDCl3) d 7.86
41H, d, Jˆ7.5 Hz), 7.60 41H, d, Jˆ8.1 Hz), 7.45 41H, br s),
7.27 41H, t, Jˆ8.1 Hz), 7.13 41H, t, Jˆ7.5 Hz), 4.06±4.00
42H, m), 3.96 43H, s), 3.86±3.55 45H, m), 3.75 43H, s), 2.83
41H, br d, Jˆ16.2 Hz), 2.60±1.40 48H, m). 13C NMR
475 MHz, CDCl3) d 172.5, 156.3, 140.2, 130.6, 128.7,
126.1, 123.8, 115.8, 112.9, 74.9, 73.5, 65.6, 59.8, 58.9,
53.7, 52.8, 44.5, 37.9, 34.5, 29.8, 22.4, 21.9, 13.8. HRMS
calcd for C23H2811BN2O7F2 4MH1) 493.196. Found
493.195.
41H, t, Jˆ9.5 Hz), 2.85 41H, m), 2.51 43H, m), 2.39 41H, m),
2.20 42H, m), 2.09 42H, m), 1.75 42H, m). 13C NMR
4125 MHz, CDCl3) d 174.9, 172.8, 157.1, 143.1, 140.9,
134.4, 128.1, 124.6, 124.3, 119.6, 115.8, 82.7, 74.1, 59.7,
53.5, 52.7, 44.8, 34.3, 32.1, 29.7, 28.2, 22.1, 21.1. HRMS
calcd for C23H27N2O6 4MH1) 427.187. Found 427.186.
10.1.32. Epoxide 42b. m-Chloroperoxybenzoic acid
474 mg, 0.301 mmol) was added to a solution of the diene
33 482 mg, 0.200 mmol) in CH2Cl2 42 mL) at0 8C. The
solution was stirred for 1 h at 08C and quenched by the
addition of saturated aqueous NaHCO3. The aqueous
phase was extracted with CH2Cl2 42£10 mL). The combined
extracts were washed with 0.5% NaOH solution 410 mL)
and brine 410 mL), dried 4Na2SO4), and evaporated in
vacuo to give a yellow foam 42b 478 mg, crude 92%).
4NMR shows .90% epoxide). IR 4®lm) 2931, 1716, 1693,
1
1601 cm21. H NMR 4300 MHz, CDCl3) d 7.92, 7.50 41H,
br d, Jˆ8.1 Hz), 7.40±6.95 44H, m), 4.21 41H, t, Jˆ
13.8 Hz), 4.00±3.60 46H, m), 3.52±3.40 42H, m), 3.30±
2.95 42H, m), 2.71±2.55 41H, m), 2.50±2.40 41H, m),
2.35±2.15 41H, m), 2.00±1.50 44H, m), 1.43±1.30 41H,
m). HRMS calcd for C23H25N2O6 4MH1) 425.171. Found
425.170.
10.1.31. ꢀ^)-11,12-Demethoxypauci¯orine B 42 and
ꢀ^)-11,12-demethoxy-17,20-isopauci¯orine B 42a. Silver
tetra¯uoroborate 40.135 g, 0.697 mmol) in anhydrous THF
41.5 mL) was added to a solution of 28 461 mg, 0.139 mmol)
in anhydrous THF 41.5 mL) at room temperature. After
15 min a solution of peracetic acid 40.146 mL, 0.697
mmol, 32% in acetic acid) in EtOAc 415 mL) was added.
The brown suspension turned yellow and after 30 min satu-
rated aqueous NaHCO3 420 mL) was added. The mixture
was extracted with EtOAc 43£20 mL), and the combined
extracts were washed with water 430 mL), brine 430 mL),
dried 4Na2SO4), and evaporated in vacuo to give a yellow
glass. Puri®cation by ¯ash chromatography over silica gel
eluting with 35±50% EtOAc/hexanes gave a white solid
439 mg, 65%) as a mixture of double bond isomers. A
portion of the mixture was separated by preparative
chromatography using multiple elutions with 35% EtOAc/
hexanes to give 42 as a white solid 48 mg) which was
recrystallized from ether/MeOH to give colorless crystals
suitable for X-ray analysis. Further puri®cation gave 42a as
a white solid 43 mg).
10.1.33. ꢀ^)-11,12-Demethoxy-19,20-oxapauci¯orine B
42c. Phenylsilane 49 mL, 0.0766 mmol) was added to a
solution of the epoxide 42b 413 mg, 0.0306 mmol) and
Mn4dpm)3 41 mg, 0.001 mmol) in isopropanol 40.75 mL)
and 1,2-dichloroethane 40.25 mL) at 08C. The brown
solution was placed under an oxygen atmosphere and stirred
for a further 10 min at 08C then at room temperature for
18 h. Triethylphosphite 46 mL, 0.0337 mmol) was added
and the mixture was stirred for 45 min open to the atmos-
phere. Evaporation of the solvents in vacuo gave a brown oil
which was puri®ed by ¯ash chromatography over silica gel
eluting with 75% EtOAc/hexanes to give 42c as a white
solid, 46 mg, 48%). Mp 225±2278C. IR 4®lm) 3206, 2926,
1731, 1681, 1603 cm21. 1H NMR 4300 MHz, CDCl3) d 8.69
41H, br s), 7.45 41H, d, Jˆ8.1 Hz), 7.20 41H, t, Jˆ7.5 Hz),
7.07 41H, t, Jˆ7.5 Hz), 6.98 41H, d, Jˆ7.2 Hz), 4.24 41H, br
t, Jˆ13.2 Hz), 3.95 43H, s), 3.85±3.77 41H, m), 3.75 43H, s),
3.37 41H, t, Jˆ10.2 Hz), 3.13 41H, d, Jˆ6.3 Hz), 3.06±2.97
41H, m), 2.82 41H, d, Jˆ14.7 Hz), 2.68 41H, dd, Jˆ14.4,
6.0 Hz), 2.55±2.35 42H, m), 2.28±1.97 41H, m), 2.05±1.85
41H, m), 1.75±1.55 42H, m), 1.37±1.20 42H, m). 13C NMR
4CDCl3, 75 MHz) d 174.1, 172.9, 157.4, 140.3, 134.2, 128.3,
124.4, 124.2, 116.2, 82.3, 75.6, 63.2, 59.3, 57.3, 53.7, 52.7,
44.7, 43.0, 35.5, 33.4, 30.4, 29.5, 21.6. HRMS calcd for
C23H27N2O5 4MH1) 443.183. Found 443.182.
42: Mp dec .1808C, melts 247±2498C. IR 4®lm) 3195,
1
1732, 1681, 1603 cm21. H NMR 4500 MHz, CDCl3) d
8.90 41H, d, Jˆ1.5 Hz), 7.51 41H, d, Jˆ8.0 Hz), 7.18 41H,
td, Jˆ7.5, 1.5 Hz), 7.04 41H, td, Jˆ7.5, 1.0 Hz), 6.94 41H, d,
Jˆ8.0 Hz), 5.27 41H, d, Jˆ6.0 Hz), 4.05 41H, br t, Jˆ
13.5 Hz), 3.96 43H, s), 3.80 43H, s), 3.70 41H, m), 3.31
41H, td, Jˆ10.5, 2.0 Hz), 3.12 41H, br d, Jˆ17.0 Hz), 2.95
41H, dt, Jˆ14.0, 2.5 Hz), 2.88 41H, br d, Jˆ19.0 Hz), 2.71
41H, dd, Jˆ16.5, 6.5 Hz), 2.53 41H, ddd, Jˆ16.0, 9.0,
2.5 Hz), 2.45 41H, br d, Jˆ18.5 Hz), 2.26 42H, m),
2.11 41H, m), 1.89 41H, m), 1.52 41H, m). 13C NMR
4125 MHz, CDCl3) d 175.3, 173.3, 157.5, 140.5, 134.7,
130.5, 128.2, 124.5, 124.3, 122.2, 116.2, 81.9, 75.6, 59.9,
53.6, 52.6, 44.3, 42.8, 37.0, 36.0, 30.4, 29.8, 21.6. HRMS
calcd for C23H27N2O6 4MH1) 427.187. Found 427.187.
10.1.34. 6,7-Dimethoxyindole 48. A 500 mL three-necked
round bottom ¯ask ®tted with a condenser, a mechanical
stirrer and a rubber septum was charged with iron powder
437.6 g), acetic acid 457 mL), EtOH 473 mL) and heated to
958C with vigorous stirring. A suspension of 47 44.00 g,
15.7 mmol) in acetic acid 484 mL) was added to the
re¯uxing mixture over a period of 25 min, and stirring
was continued for 2.5 h. The mixture was allowed to cool,
and ®ltered through Celite into an aqueous solution of
sodium metabisul®te 430.1 g in 280 mL of water). The
solid residues were washed with EtOH 450 mL), and
CH2Cl2 4250 mL). The aqueous and organic layers were
42a: Mp 182±1848C. IR 4®lm) 3205, 1732, 1681, 1603
1
cm21. H NMR 4500 MHz, CDCl3) d 8.71 41H, s), 7.49
41H, d, Jˆ7.5 Hz), 7.17 41H, td, Jˆ7.5, 1.5 Hz), 7.03 41H,
td, Jˆ7.5, 1.0 Hz), 6.96 41H, d, Jˆ7.5 Hz), 6.60 41H, br s),
4.03 41H, m), 3.97 43H, s), 3.80 43H, s), 3.39 41H, m), 3.17

P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
3439
separated and the aqueous layer was extracted with CH2Cl2
43£50 mL). The combined extracts were washed succes-
sively with saturated aqueous NaHCO3 45£150 mL), water
42£150 mL), and dried 4MgSO4), ®ltered and evaporated in
vacuo to give a pale yellow solid. Puri®cation by ¯ash
column chromatography over silica gel eluting with
CH2Cl2 gave 48 as pale pink blades 42.349 g, 85%). Mp
99±1018C 4lit.36 102±1038C). IR 4®lm) 3414, 3103, 2993,
2967, 2933, 2836, 1632 cm21. 1H NMR 4300 MHz, CDCl3)
d 8.28 41H, br s), 7.28 41H, d, Jˆ8.5 Hz), 7.11 41H, dd,
Jˆ3.1, 2.6 Hz), 6.85 41H, d, Jˆ8.6 Hz), 6.47 41H, dd, Jˆ
3.2, 2.2 Hz), 4.00 43H, s), 3.92 43H, s). 13C NMR 475 MHz,
CDCl3) d 146.8, 134.4, 130.4, 124.4, 123.8, 115.4, 108.6,
102.6, 60.8, 57.4. HRMS calcd for C10H12NO2 4MH1)
178.087. Found 178.086.
cool to room temperature and quenched by dropwise
addition of water. The mixture was poured into saturated
aqueous Rochelle's Salt 420 mL) and stirred overnight. The
solution was extracted with EtOAc 45£20 mL), and the
combined extracts were dried 4Na2SO4), ®ltered, and evapo-
rated in vacuo to give a brown oil. Puri®cation by ¯ash
column chromatography over silica gel eluting with
CH2Cl2/MeOH 410:111% triethylamine) gave 51 as a
pale brown oil 4103 mg, 91%) that solidi®ed on standing.
IR 4®lm) 3355, 2933, 2835, 1629 cm21. 1H NMR 4300 MHz,
CDCl3) d 8.59 41H, br s), 7.20 41H, d, Jˆ9 Hz), 6.92 41H, s),
6.81 41H, d, Jˆ9 Hz), 3.96 43H, s), 3.89 43H, s), 2.99 42H, br
t, Jˆ6 Hz), 2.85 42H, br t, Jˆ6 Hz), 2.80 41H, m). 13C NMR
475 MHz, CDCl3) d 147.0, 134.4, 130.9, 124.2, 121.9,
113.6, 133.3, 107.9, 60.7, 57.4, 41.8, 28.7. HRMS calcd
for C12H16N2O2 4M1) 220.121. Found 220.122.
10.1.35. 6,7-Dimethoxyindole-3-carboxaldehyde 49. To
DMF 411 mL) at0 8C was added phosphorus oxychloride
48.1 mL, 87.3 mmol) dropwise over 13 min. The solution
was stirred for a further 75 min, and treated with a solution
of 6,7-dimethoxyindole 48 45.151 g, 29.1 mmol) in DMF
411 mL) dropwise to give a yellow solution. The mixture
was warmed to ambient temperature and stirred for a further
80 min, a further portion of DMF 425 mL) was added, and
the yellow suspension was poured into ice-water 4500 mL)
and stirred overnight. The aqueous solution was neutralized
with saturated aqueous NaHCO3, and extracted with EtOAc
44£150 mL). The combined extracts were washed with
water 45£50 mL), dried 4MgSO4), ®ltered and evaporated
in vacuo to give a pale brown crystalline solid. Puri®cation
by ¯ash column chromatography over silica gel eluting with
25% EtOAc 43:1) gave 49 as pale pink cubes 45.463 g,
92%). Mp 132±1358C. IR 4®lm) 3108, 2945, 2838,
10.1.38. ꢀ^)-1-ꢀ4-Carboxy-butyl)-7,8-dimethoxy-2,3,4,9-
tetrahydro-1H-b-carboline-1-carboxylic acid methyl
ester 52. A mixture of 51 41.131 g, 5.141 mmol), 13
Ê
40.966 g, 5.141 mmol) and 4 A molecular sieves 4ca. 5 g)
in CH2Cl2 428 mL) at0 8C was treated with tri¯uoroacetic
acid 40.080 mL, 1.042 mmol) dropwise then allowed to
warm to room temperature and stirred for 24 h. The mixture
was ®ltered through Celite and washed with MeOH
4200 mL). The ®ltrate was evaporated in vacuo to afford
52 a brown oil 42.0 g) used subsequently without further
puri®cation.
10.1.39. ꢀ^)-13b-Carbomethoxy-16,17-dimethoxy-2,3,4,
5,6,7,8,13,13b-octahydro-1H-azepino[10,20:1,2]pyrido-
[3,4-b]indol-5-one 53. To a solution of crude 52 42.0 g)
and 1-hydroxybenzotriazole monohydrate 41.389 g, 10.282
mmol) in DMF 4104 mL) at0 8C was added a solution of
EDCI 41.971 g, 10.282 mmol) and Et3N 41.43 mL, 10.282
mmol) in DMF 467 mL). The resulting mixture was stirred
at0 8C for 1 h, and at room temperature for 24 h, treated with
pH 7 buffer solution and water 4400 mL), and extracted with
EtOAc 45£150 mL). The combined extracts were succes-
sively washed with water 43£200 mL), dried 4Na2SO4),
®ltered and evaporated in vacuo to give a brown oil.
Puri®cation by ¯ash chromatography over silica gel eluting
with 25% EtOAc/hexanes 41:1) gave 41.234 g, 67%).
Crystallization by slow evaporation of hexane/EtOAc
gave 53 as colorless cubes. Mp 192±1938C. IR 4®lm)
1
1625 cm21. H NMR 4300 MHz, CDCl3) d 10.01 41H, s),
9.06 41H, br s), 7.95 41H, d, Jˆ8.7 Hz), 7.78 41H, d,
Jˆ3.0 Hz), 7.02 41H, d, Jˆ8.7 Hz), 4.02 43H, s), 3.95
43H, s). 13C NMR 475 MHz, CDCl3) d 185.0, 148.4,
135.3, 134.1, 131.3, 120.0, 116.8, 110.8, 61.1, 57.0.
HRMS calcd for C11H12NO3 4MH1) 206.082. Found
206.083.
10.1.36. 6,7-Dimethoxy-3-ꢀ2-nitroethenyl)indole 50. A
solution of 49 41.011 g, 4.93 mmol) and NH4OAc
41.140 g, 14.80 mmol) in nitromethane 420.0 mL) was
heated at re¯ux for 40 min to give a red solution. The cooled
mixture was diluted with water 430 mL), and extracted with
CH2Cl2 45£50 mL). The combined extracts were dried
4Na2SO4), ®ltered, and evaporated in vacuo to give 50 as a
red oil 41.22 g, 100%) that solidi®ed on standing. No further
puri®cation was required. IR 4®lm) 3311, 2936, 1611,
3284, 2935, 1735, 1628 cm21
.
1H NMR 4300 MHz,
CDCl3) d 8.16 41H, br s), 7.15 41H, d, Jˆ8.6 Hz), 6.85
41H, d, Jˆ8.7 Hz), 4.77 41H, dt, Jˆ13.0, 4.0 Hz), 4.00
43H, s), 3.91 43H, s), 3.79 43H, s), 3.32 41H, dt, Jˆ13.1,
7.2 Hz), 2.8 44H, m), 2.3 41H, m), 1.97 41H, m), 1.85 41H,
m), 1.62 41H, m). 13C NMR 475 MHz, CDCl3) d 176.3,
171.9, 147.6, 134.4, 131.3, 130.7, 122.6, 133.5, 112.4,
108.4, 65.5, 60.8, 57.3, 53.2, 42.1, 40.5, 37.9, 25.4, 22.0,
20.6. HRMS calcd for C20H25N2O5 4MH1) 373.176. Found
373.176.
1
1516 cm21. H NMR 4300 MHz, CDCl3) d 8.82 41H, br
s), 7.74 41H, d, Jˆ13.5 Hz), 8.24 41H, d, Jˆ13.5 Hz),
7.60 41H, d, Jˆ2.3 Hz), 7.41 41H, d, Jˆ8.6 Hz), 7.02 41H,
d, Jˆ8.7 Hz), 4.04 43H, s), 3.96 43H, s). 13C NMR 475 MHz,
CDCl3) d 148.3, 134.6, 134.1, 133.6, 132.1, 132.0, 120.4,
115.4, 110.2, 109.9, 61.1, 57.0. HRMS calcd for
C12H13N2O4 4MH1) 249.088. Found 249.088.
10.1.40. ꢀ^)-13b-Carbomethoxy-16,17-dimethoxy-2,3,4,
5,6,7,8,13,13b-octahydro-1H-azepino[10,20:1,2]pyrido-
[3,4-b]indol-5-thione 54. To a solution of 53 41.808 g,
5.079 mmol) in dry THF 4110 mL) at0 8C was added solid
Belleau's reagent41.75 g, 4.70 mmol) in one poriton. The
resulting solution was stirred at 08C for 10 min, and
allowed to warm to room temperature and stirred for 15 h.
10.1.37. 6,7-Dimethoxytryptamine 51. To a stirred suspen-
sion of LiAlH4 497 mg, 2.556 mmol) in THF 45 mL) at0 8C
was added a solution of 50 4127 mg, 0.512 mmol) in THF
45 mL) dropwise over a period of 30 min, and the mixture
was heated at re¯ux for 1 h. The mixture was allowed to

3440
P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
Chromatographic grade silica gel 4ca. 15 g) was added, and
the mixture evaporated in vacuo. Puri®cation by ¯ash
chromatography over silica gel eluting with 25% EtOAc/
hexanes gave 54 as a pale yellow solid 41.970 g, 100%).
Crystallization by slow evaporation of EtOAc gave 54 as
clear, pale yellow prisms. Mp 209±2108C. IR 4®lm) 3317,
2937, 2836, 1735, 1632 cm21. 1H NMR 4300 MHz, CDCl3)
d 8.08 41H, br s), 7.18 41H, d, Jˆ8.5 Hz), 6.87 41H, d,
Jˆ8.7 Hz), 5.45 41H, dt, Jˆ13.3, 4.3 Hz), 4.10 41H, m),
4.00 43H, s), 3.92 43H, s), 3.79 43H, s), 3.61 41H, dd, Jˆ
14.5, 4.4 Hz), 3.00±2.75 43H, m), 2.66 41H, m), 2.07 41H,
m), 2.00±1.60 45H, m). 13C NMR 475 MHz, CDCl3) d
209.9, 170.9, 147.8, 134.4, 131.0, 130.9, 122.2, 133.5,
112.3, 108.7, 69.6, 60.8, 57.3, 53.6, 51.8, 47.0, 38.7, 24.0,
23.7, 20.3. HRMS calcd for C20H25N2O4S 4MH1) 389.154.
Found 389.153.
1008C) d 7.64 41H, s), 7.10 41H, t, Jˆ8.1 Hz), 7.2 42H,
dd, Jˆ8.5, 0.6 Hz), 6.95 43H, br m), 6.81 41H, t, Jˆ
6.8 Hz), 6.64 41H, d, Jˆ8.3 Hz), 3.84 43H, s), 3.80 42H, br
m), 3.58 43H, s), 3.39 43H, s), 3.14 42H, br m), 2.89 42H, br
m), 2.10 42H, br m), 1.53 44H, br m). 13C NMR 4125 MHz,
d8-toluene, 1008C) d 166.7, 154.5, 152.6, 148.0, 136.1,
131.7, 125.9, 124.6, 121.9, 114.7, 110.5, 60.4, 58.0, 51.5,
50.4, 27.2, some signals obscured. HRMS calcd for
C20H31N2O6 4MH1) 479.218. Found 479.218.
10.1.43. ꢀ^)-12b-Cyano-7,8-dimethoxy-2,3,6,11,12,12b-
hexahydro-1H-6,12a-diazaindeno[7,1-cd]¯uorene-5-
carboxylic acid methyl ester 58. A solution of 56 4192 mg,
0.402 mmol), and DMAP 4147 mg, 1.203 mmol) in CH2Cl2
49.3 mL) at0 8C was treated with tri¯uoromethanesulfonic
anhydride 40.337 mL, 2.003 mmol) dropwise to give an
olive green solution. The mixture was stirred for a further
20 min at0 8C, warmed to room temperature, and stirred for
a further 30 min. The mixture was heated at re¯ux for a
further 22 h to give a dark purple solution. The solution
was cooled to ambient temperature, stirred for 1.5 h and
treated with a solution of trimethylsilyl cyanide 40.214
mL, 1.608 mmol) and DMAP 4147 mg, 1.203 mmol) in
CH2Cl2 42.0 mL) dropwise to give an orange-brown solu-
tion. After stirring for a further 45 min, saturated aqueous
NaHCO3 410 mL) was added and the mixture stirred for
a further 1 h. The mixture was extracted with CH2Cl2
44£50 mL), and the combined extracts were dried
4Na2SO4), ®ltered, and evaporated in vacuo to give an
orange-brown solid. Puri®cation by ¯ash chromatography
over silica gel eluting with 35% EtOAc/hexanes gave 58
as a yellow solid 499 mg, 63%). Mp 207±2098C. IR 4®lm)
10.1.41. ꢀ^)-13b-Carbomethoxy-16,17-dimethoxy-2,3,4,
5,6,7,8,13,13b-octahydro-1H-azepino[10,20:1,2]pyrido-
[3,4-b]indole 55. A solution of thiolactam 54 41.970 g,
5.077 mmol) and NiCl2´6H2O 44.827 g, 20.308 mmol) in
THF 450 mL) and MeOH 450 mL) at0 8C was treated with
NaBH4 42.881 g, 76.155 mmol) portion wise, an immediate
color change from green to black was observed. Stirring was
continued for 5 min until the effervescence had subsided.
The mixture was ®ltered through celite, and washed through
with MeOH 4250 mL). The solvent was evaporated in vacuo
to give a blue-gray solid which was partitioned between
EtOAc 4150 mL) and water 4150 mL). The layers were
separated and the aqueous layer was extracted with
EtOAc 43£100 mL). The combined extracts were dried
4Na2SO4), ®ltered, and evaporated in vacuo to give a yellow
oil. Puri®cation by ¯ash chromatography over silica gel
eluting with 33% EtOAc/hexanes 42:1) gave 55 as a white
solid 41.400 g, 77%). Crystallization by slow evaporation
from EtOAc gave 55 as clear, colorless cubes. Mp
126±1278C. IR 4®lm) 3337, 2929, 2837, 1735, 1718,
1
3397, 2945, 2867, 2838, 2253, 1682, 1634, 1600 cm21. H
NMR 4300 MHz, CDCl3) d 9.10 41H, br s), 7.24 41H, d,
Jˆ8.2 Hz), 6.53 41H, d, Jˆ8.2 Hz), 3.91 43H, s), 3.86
43H, s), 3.81 43H, s), 3.30 42H, m), 3.17 41H, d, Jˆ13.8
Hz), 2.95 41H, dt, Jˆ11.1, 2.52 Hz), 2.45 43H, m), 1.90
42H, m), 1.57 41H, br d, Jˆ13.0 Hz). 13C NMR 475 MHz,
CDCl3) d 166.8, 161.7, 153.3, 136.7, 133.5, 125.8, 120.2,
119.1, 118.8, 117.5, 105.8, 91.6, 64.7, 60.9, 59.2, 56.1, 51.2,
46.6, 45.9, 39.7, 29.5, 20.5. HRMS calcd for C22H24N3O4
4MH1) 394.177. Found 394.176.
1
1628 cm21. H NMR 4300 MHz, CDCl3) d 8.12 41H, br
s), 7.14 41H, d, Jˆ8.5 Hz), 6.82 41H, d, Jˆ8.7 Hz), 4.01
43H, s), 3.92 43H, s), 3.72 43H, s), 3.29 41H, dt, Jˆ11.1,
4.2 Hz), 3.17 41H, dd, Jˆ13.2, 5.1 Hz), 2.91 42H, m), 2.85
41H, m), 2.50 42H, m), 2.10 41H, m), 1.68 45H, m), 1.43 41H,
m). 13C NMR 475 MHz, CDCl3) d 174.7, 147.2, 134.4,
133.1, 130.5, 123.5, 113.2, 111.0, 107.9, 66.6, 60.8, 57.5,
52.3, 50.3, 50.2, 39.2, 30.8, 29.1, 22.8, 19.7. HRMS calcd
for C20H27N2O4 4MH1) 359.197. Found 359.197.
10.1.44. ꢀ^)-16-Anhydro-1-decarbomethoxylahadinine
B 60. A solution of 58 441 mg, 0.104 mmol) in freshly
distilled acryloyl chloride 41.0 mL) was stirred in a sealed
tube at ambient temperature in the dark for 24 h then
concentrated under reduced pressure to yield a pale brown
solid. The crude solid was dissolved in dichloromethane
41.0 mL, with 1.0 mL wash over) and added to a suspension
of pre-dried 2-mercaptopyridine N-oxide, sodium salt
423 mg, 0.156 mmol; tech., 90%) in dichloromethane
41.0 mL) at0 8C in the dark. The mixture was stirred for
5 min, warmed to room temperature, stirred for a further
2 h, cooled to 08C, and treated with tert-butyl thiol
40.7 mL, excess). The mixture was irradiated with a tung-
sten lamp for 1.75 h 4the reaction temperature was kept
between 0 and 208C). After irradiation the mixture was
concentrated under reduced pressure to give a yellow
solid. Puri®cation by ¯ash column chromatography on silica
gel eluting with hexane±EtOAc 2:1 gave 60 as a colorless
oil 416 mg, 37%). IR 4®lm) 3354, 2942, 2858, 2251, 1714,
10.1.42.
ꢀ^)-5,8,9,10,11,14-Hexahydro-6H-15,16-di-
methoxy-7,14-diazacycloundeca[a]indene-7,13-dicarb-
oxylic acid 13-methyl ester 7-phenyl ester 56. A solution
of 55 487 mg, 0.243 mmol) in 1,2-dichloromethane 42.0 mL)
at room temperature was treated with phenyl chloroformate
40.239 mL, 1.905 mmol) and the mixture heated at re¯ux for
48 h. The mixture was cooled to room temperature, excess
saturated aqueous NaHCO3 410 mL) was added, and the
mixture stirred vigorously for several hours then extracted
with CH2Cl2 45£20 mL). The combined extracts were dried
4Na2SO4), ®ltered, and evaporated in vacuo to give a dark
brown oil. Puri®cation by ¯ash chromatography over silica
gel eluting with 25% EtOAc/hexanes gave 56 455 mg, 47%)
as a yellow oil that solidi®ed on standing. The amine 55 was
also recovered 429 mg, 33%). IR 4®lm) 3348, 2934, 2836,
1
1
1715, 1631, 1593 cm21. H NMR 4500 MHz, d8-toluene,
1623 cm21. H NMR 4CDCl3, 300 MHz) d 7.37 4s, 1H),

P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
3441
7.23 4d, Jˆ8.2 Hz, 1H), 6.51 4d, Jˆ8.3 Hz, 1H), 4.61 4s,
1H), 3.97 4s, 3H), 3.95 4s, 3H), 3.93 4s, 3H), 3.42 4t, Jˆ
12 Hz, 1H), 3.14 4d, Jˆ12 Hz, 1H), 2.95 4t, Jˆ9 Hz, 1H),
2.84 4q, Jˆ9 Hz, 1H), 2.43 4dd, Jˆ15, 6 Hz, 1H), 2.05 4m,
4H), 1.71 4bm, 1H), 1.57 4bm, 1H), 1.35 4m, 2H), 1.00 4m,
1H). 13C NMR 4CDCl3, 75 MHz) d 164.4, 152.5, 143.7,
143.0, 135.3, 134.4, 127.1, 118.5, 103.5, 77.1, 70.8, 68.8,
65.8, 60.3, 55.8, 51.8, 49.8, 44.8, 41.5, 37.6, 31.8, 31.3,
27.4, 16.5. HRCIMS calcd for C24H28N2O4, 4MH1)
422.208. Found 422.208.
42H, d, Jˆ6.5 Hz), 7.20 44H, m), 6.74 41H, d, Jˆ8.3 Hz),
6.60 41H, s), 4.00 41H, t, Jˆ7.9 Hz), 3.90 43H, s), 3.85 46H,
br s), 3.83 43H, s), 3.23 41H, br t, Jˆ12.4 Hz), 2.98 42H, dd,
Jˆ14.1, 6.5 Hz), 2.81 41H, t, Jˆ8.4 Hz), 2.68 41H, q, Jˆ
8.3 Hz), 1.95 42H, m), 1.73 43H, m), 1.41 41H, br d, Jˆ
11.7 Hz). 13C NMR 475 MHz, CDCl3) d 166.0, 153.9,
153.7, 138.6, 138.3, 134.4, 133.8, 133.7, 129.4, 128.9,
128.5, 127.3, 118.1, 108.2, 75.4, 68.9, 67.4, 60.8, 56.1,
53.0, 52.4, 50.1, 44.5, 40.8, 40.6, 39.9, 38.6, 30.7, 15.6,
14.1. HRMS calcd for C32H34N3O6Se80 4MH1) 636.161.
Found 636.161.
10.1.45. ꢀ^)-16-Anhydro-1-decarbomethoxy-18-seleno-
phenyllahadinine B 61. A solution of 58 481 mg,
0.2061 mmol) in freshly distilled acryloyl chloride
42.0 mL) was stirred in a sealed tube at ambient temperature
in the dark for 24 h, and concentrated under reduced
pressure to yield a pale brown solid 59. The crude solid
was dissolved in CH2Cl2 42.0 mL, with 2.0 mL wash over)
and added to a suspension of pre-dried 2-mercaptopyridine
N-oxide sodium salt450 mg, 0.3017 mmol, etch., 90%) in
CH2Cl2 43.5 mL) at0 8C in the dark. The mixture was stirred
for 5 min, warmed to room temperature, stirred for a further
1.75 h, cooled to 08C and treated with a solution of diphenyl
diselenide 4371 mg, 1.19 mmol) in CH2Cl2 43.0 mL). The
yellow solution was irradiated with a tungsten lamp for
30 min 4the reaction temperature was kept between 0 and
208C). After irradiation the mixture was evaporated in
vacuo to give a yellow solid. Puri®cation by ¯ash column
chromatography over silica gel eluting with 50% EtOAc/
hexanes gave 61 as a colorless oil 449 mg, 41%). IR 4®lm)
10.1.47. ꢀ^)-18-Selenophenyllahadinine B 63. A dark
brown solution of 62 47 mg, 0.0110 mmol) and tris4dipiva-
loylmethanato)manganese4III) 43 mg, 0.0071 mmol) in iso-
propanol 40.2 mL) and 1,2-dichloroethane 40.5 mL) at 08C
was treated with phenylsilane 450 mL, 0.402 mmol) causing
the mixture to turn pale brown. The solution was placed
under an atmosphere of oxygen and stirred for a further
10 min at0 8C. The mixture was warmed to room tempera-
ture and stirred for 7 days. The solution was treated with
aqueous 1 M Na2S2O3 43 mL) and extracted with CH2Cl2
45£10 mL). The combined extracts were dried 4Na2SO4),
®ltered and evaporated in vacuo to give a pale brown oil.
Puri®cation by ¯ash column chromatography over silica gel
eluting with 50% EtOAc/hexanes gave 63 46 mg, 83%). Mp
2498C 4dec). IR 4®lm) 3351, 2948, 2362, 1740, 1680 cm21
.
13C NMR 475 MHz, CDCl3) d 172.4, 153.7, 138.8, 133.0,
132.8, 130.8, 130.7, 128.8, 126.1, 117.9, 117.4, 107.8, 79.3,
74.1, 67.9, 62.5, 60.0, 56.2, 53.5, 52.3, 49.1, 44.3, 43.4,
41.3, 40.2, 38.9, 37.6, 32.2, 29.6, 20.7. HRMS calcd for
C32H36N3O7Se80 4MH1) 654.172. Found 654.172. Used
directly in the next stage.
1
3380, 2943, 2859, 2839, 2251, 1718, 1622, 1578 cm21. H
NMR 4300 MHz, CDCl3) d 7.37 42H, d, Jˆ7.6 Hz), 7.20
43H, m), 7.08 41H, d, Jˆ8.2 Hz), 7.05 41H, s), 6.40 41H, d,
Jˆ8.2 Hz), 3.88 43H, s), 3.82 43H, s), 3.75 43H, s), 3.29 41H,
br t, Jˆ12.2 Hz), 3.02 41H, br d, Jˆ13.7 Hz), 2.83 41H, t,
Jˆ7.6 Hz), 2.71 41H, q, Jˆ8.3 Hz), 2.52 41H, dd, Jˆ14.0,
8.6 Hz), 2.36 41H, dd, Jˆ14.2, 7.2 Hz), 1.95 42H, m), 1.85
42H, m), 1.50 42H, m). 13C NMR 475 MHz, CDCl3) d 164.1,
152.7, 144.0, 142.2, 134.7, 134.1, 133.8, 129.1, 128.3,
127.7, 126.4, 118.3, 118.1, 104.1, 73.9, 68.5, 67.0, 60.3,
55.9, 52.0, 49.6, 44.6, 43.3, 41.9, 41.5, 38.1, 30.8, 16.1.
HRMS calcd for C30H32N3O4Se80 4MH1) 578.156. Found
578.152.
10.1.48. ꢀ^)-Lahadinine B 64. A solution of 63 47 mg,
0.011 mmol) in toluene 40.75 mL) heated at re¯ux was
treated with a solution of triphenyltin hydride 418 mg,
0.051 mmol) in toluene 40.75 mL), and stirred for a period
of 24 h in the dark. The cooled mixture was evaporated in
vacuo, and puri®ed by ¯ash column chromatography over
silica gel eluting with 50% EtOAc/hexanes to give 64
46 mg, 83%) as a white solid. Crystallization by slow
evaporation from a solution in CH2Cl2/MeOH 42:1, v/v)
gave 64 as colorless needles suitable for X-ray crystal-
lography. IR 4®lm) 2917, 2848, 2352, 1738, 1732, 1714,
10.1.46. ꢀ^)-16-Anhydro-18-selenophenyllahadinine B
62. A solution of 61 417 mg, 0.0295 mmol) and 18-crown-
6 412 mg, 0.0454 mmol) in THF 41.0 mL) at 2788C, under
argon, was treated with a solution of KN4SiMe3)2
40.088 mL, 0.0442 mmol, 1.0 M solution in toluene) to
give an orange-brown solution. The solution was stirred
for a further 10 min, and CO2 gas was passed over the
mixture for 10 min to give a pale yellow solution. The
CO2 inletwas removed, dimhetyl sulfeat 40.012 mL,
0.127 mmol) was added, and stirring continued for 15 min
at 2788C. The mixture was allowed to warm to room
temperature, stirred for a further 30 min and treated with
pH 7 phosphate buffer solution 45 mL). The mixture was
extracted with CH2Cl2 45£15 mL), and the combined
extracts were dried 4Na2SO4), ®ltered, and evaporated in
vacuo to give a pale brown oil. Puri®cation by ¯ash column
chromatography over silica gel eluting with 50% EtOAc/
hexanes gave 62 416 mg, 86%). IR 4®lm) 2948, 2858, 2251,
1802, 1718, 1610 cm21. 1H NMR 4300 MHz, CDCl3) d 7.34
1
1694, 1682, 1651 cm21. H NMR 4500 MHz, CDCl3) d
7.14 41H, d, Jˆ8.2 Hz), 6.61 41H, d, Jˆ8.4 Hz), 6.60 41H,
d, Jˆ0.6 Hz), 3.87 43H, s), 3.84 43H, s), 3.73 43H, s), 3.72
43H, s), 3.04 44H, m), 2.92 41H, ddd, Jˆ9.0, 6.6, 1.8 Hz),
2.39 41H, ddd, Jˆ13.4, 10.8, 1.6 Hz), 1.98 41H, ddd, Jˆ
12.2, 9.2, 6.8 Hz), 1.87 41H, ddd, Jˆ12.8, 10.2, 9.0 Hz),
1.73 41H, ddd, Jˆ13.4, 10.5, 8.3 Hz), 1.70 41H, m), 1.56
45H, m), 1.43 41H, m). 13C NMR 4125 MHz, CDCl3) d
172.5, 157.0, 153.6, 137.9, 133.7, 130.2, 118.5, 117.9,
106.9, 75.3, 73.7, 68.4, 60.1, 59.6, 56.0, 53.5, 52.4, 49.1,
44.3, 39.5, 39.2, 36.7, 32.5, 28.3, 24.9, 20.3. HRMS calcd
for C26H32N3O7 4MH1) 498.224. Found 498.225 4Fig. 1).
10.1.49. ꢀ^)-11-Methoxykopsilongine 65. A solution of
lahadinine B 64 43.5 mg) in dichloromethane 41.3 mL) at
08C under an atmosphere of argon was treated with tri-
¯uoroacetic acid 4450 mL) to give a very pale green/
brown solution. After stirring for a further 5 min the mixture

3442
P. Magnus et al. / Tetrahedron 58 *2002) 3423±3443
4.03 41H, t, Jˆ12.8 Hz), 3.86 43H, s), 3.86 43H, s), 3.80 43H,
s), 3.72 43H, s), 3.64 41H, q, Jˆ9.9 Hz), 3.25 41H, t, Jˆ
10.2 Hz), 3.06 41H, d, Jˆ17.5 Hz), 2.87 43H, m), 2.68 41H,
dd, Jˆ16.4, 6.7 Hz), 2.48 41H, d, Jˆ19.4 Hz), 2.24 42H, m),
2.05 43H, m), 1.50 41H, m). HRCMS calcd for C25H31N2O8
4MH1) 487.208. Found 487.208 4Fig. 2).
Acknowledgements
Figure 1. ORTEP of lahadinine B, 64.
The National Institutes of Health 4GM 32718), The Robert
A. Welch Foundation, Merck Research Laboratories and
Novartis are thanked for their support of this research.
was treated with triethylsilane 4450 mL), stirred for a further
15 min, and warmed to ambient temperature and stirred for
a further 4 days. The mixture was treated with saturated
aqueous sodium hydrogen carbonate 44 mL) and extracted
with dichloromethane 44£15 mL). Puri®cation by ¯ash
column chromatography over silica gel 4hexane/EtOAc
1:1 then neat EtOAc) gave 65 43.5 mg, 93%) as a pale
brown oil. IR 4®lm) 3322, 2929, 2855, 1732, 1682,
References
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1
1613 cm21. H NMR 4CDCl3, 500 MHz) d 6.92 41H, br
m), 6.64 41H, s), 6.54 41H, d, Jˆ8.2 Hz), 3.89 43H, s),
3.82 43H, s), 3.74 43H, s), 3.73 43H, s), 3.06 42H, m), 2.95
41H, br m), 2.89 41H, dd, Jˆ14.9, 2.0 Hz), 2.79 41H, br m),
2.36 42H, m), 2.17 41H, br m), 1.78 42H, m), 1.63 42H, m),
1.47 41H, ddd, Jˆ7.8, 11.1, 13.3 Hz), 1.28 42H, m), 1.05
41H, br t, Jˆ11.1 Hz), 1.40 41H, d, Jˆ14.5 Hz). HRCMS
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10.1.50. ꢀ^)-Pauci¯orine B 6 and ꢀ^)-17,20-isopauci-
¯orine B 6a. A solution of lahadinine B 64 45 mg,
0.010 mmol) in THF 40.4 mL), at ambient temperature
under an atmosphere of argon, was treated with a solution
of silver tetra¯uoroborate 426 mg, 0.134 mmol) in THF
40.1 mL) to give an orange/brown solution. After stirring
the mixture for a further 20 min, a solution of peracetic
acid 410 mL, 32% wtin aceict acid, 0.048 mmol) in
EtOAc 40.8 mL) was added to the mixture to give a pale
yellow solution. After stirring for a further 1 h the mixture
was treated with saturated aqueous sodium hydrogen
carbonate 42 mL), and extracted with CH2Cl2 44£10 mL).
The combined extracts were dried 4Na2SO4), ®ltered, and
concentrated in vacuo to give a pale brown oil. Puri®cation
by ¯ash column chromatography over silica gel 4CH2Cl2/
MeOH 60:1) gave pauci¯orine B 6 43.2 mg, 66%) as a
colorless oil, and 6a 41.0 mg, 21%). Slow evaporation of a
CH2Cl2/MeOH solution of pauci¯orine B provided crystals
suitable for X-ray crystallography. IR 4®lm) 3240, 2923,
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1
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Figure 2. ORTEP of pauci¯orine B, 6.

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ation is probably due to competitive fragmentation of the
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1
40. Dr Kam is thanked for H and 13C NMR spectra of 5.