An improved total synthesis of (+)-macroline and alstonerine as well as the formal total synthesis of (-)-talcarpine and (-)-anhydromacrosalhine-methine

Article abstract of DOI:10.1021/jo061652u

An intramolecular Pd-catalyzed α-vinylation process is described. This cyclization has been employed for the enantiospecific total synthesis of gram quantities of both (+)-macroline 3 and the macroline equivalent 4. This sequence is compared to the enolate-driven cross-coupling process. The intermediate 4 was also converted into (-)-alstonerine 1 via modification of an intramolecular Tsuji-Wacker oxidation. This sequence resulted in an improved total synthesis of (-)-talcarpine 5 and (-)-anhydromacrosalhinemethine 6 as well.

Full text of DOI:10.1021/jo061652u

An Improved Total Synthesis of (+)-Macroline and Alstonerine as
Well as the Formal Total Synthesis of (-)-Talcarpine and
(-)-Anhydromacrosalhine-methine
Xuebin Liao, Hao Zhou, Jianming Yu, and James M. Cook*
Department of Chemistry, UniVersity of WisconsinsMilwaukee, Milwaukee, Wisconsin 53201
capncook@uwm.edu
ReceiVed August 8, 2006
An intramolecular Pd-catalyzed R-vinylation process is described. This cyclization has been employed
for the enantiospecific total synthesis of gram quantities of both (+)-macroline 3 and the macroline
equivalent 4. This sequence is compared to the enolate-driven cross-coupling process. The intermediate
4 was also converted into (-)-alstonerine 1 via modification of an intramolecular Tsuji-Wacker oxidation.
This sequence resulted in an improved total synthesis of (-)-talcarpine 5 and (-)-anhydromacrosalhine-
methine 6 as well.
Introduction
(+)-macroline-related derivative, (-)anhydromacrosalhine-
methine 6, was coupled with pleiocarpamine to provide the
bisindole macrocarpamine (Scheme 1).8 Furthermore, (-)-alsto-
nerine 1 is the desmethoxy analogue of alstophylline 2, the latter
alkaloid of which was coupled with (+)-macroline 3 to furnish
macralstonine 7 (Figure 1).7 In keeping with our interest in the
total synthesis of Alstonia bisindole alkaloids macralstonine 7,
villastonine 8, and macrocarpamine 9, we report here an
improved total synthesis of (-)-alstonerine 1 and (+)-macroline
3, as well as the efficient preparation of the more stable
(+)-macroline equivalent 4 on a gram scale.
Although a total synthesis of (-)-alstonerine 19 and
(+)-macroline 310 had been carried out previously, efforts have
been underway to provide a route to furnish gram quantities of
the (+)-macroline equivalent 4 as well as the biogenetic
intermediate 3. Recently, Liu had designed a more practical route
to the enantiomer of 3 via a sarpagine intermediate;11 conse-
quently, this strategy was modified to provide a route to natural
3 as well as 4. This approach also afforded a key intermediate
for the preparation of (-)-alstonerine 1, by a strategy which
It has been reported that a number of bisindole alkaloids
isolated from Alstonia1,2 species have been shown to exhibit
antimalarial activity3 against the drug-resistant K1 strains of
Plasmodia falciparum including villasltonine 8 and macrocar-
pamine 9 (IC50 values of 0.27 and 0.35 µM,4 respectively). In
addition, these bisindoles were assessed for cytotoxic activity
against human lung cancer cell lines. The bisindoles exhibited
pronounced cytotoxic activity against two cell lines with IC50
values of 2-10 µM.5 Bisindoles are of special significance
because they often exhibit more potent biological activity than
their corresponding monomeric components.3,4 The biomimetic
coupling of (+)-macroline 3 with the obligatory monomeric
alkaloids to provide Alstonia bisindoles macralstonine 7 and
villalstonine 8 was pioneered by Le Quesne.6,7 In addition, a
(1) Elderfield, R. C.; Gilman, R. E. Phytochemistry 1972, 11, 339.
(2) Hamaker, L. K.; Cook, J. M. The Synthesis of Macroline-related
Sarpagine Alkaloids. In Alkaloids: Chemical and Biological PerspectiVes;
Pelletier, S. W., Ed.; Elsevier Science: New York, 1995; Vol. 9, p 23.
(3) Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J. D.; Said, I. M.; Kirby,
G. C.; Warhurst, D. C. Phytother. Res. 1992, 6, 121.
(4) Keawpradub, N.; Kirby, G. C.; Steele, J. C. P.; Houghton, P. J. Planta
Med. 1999, 65, 690.
(5) Keawpradub, N.; Houghton, P. J. Phytochemistry 1997, 46, 757.
(6) Burke, D. E.; DeMarkey, C. A.; Le Quesne, P. W.; Cook, J. M. J.
Chem. Soc., Chem. Commun. 1972, 1346.
(8) Gan, T.; Cook, J. M. J. Org. Chem. 1998, 63, 1478.
(9) Zhang, L. H.; Cook, J. M. J. Am. Chem. Soc. 1990, 112, 4088.
(10) (a) Bi, Y.; Cook, J. M. Tetrahedron Lett.. 1993, 34, 4501. (b) Bi,
Y.; Zhang, L. H.; Hamaker, L. K.; Cook, J. M. J. Am. Chem. Soc. 1994,
116, 9027.
(7) Burke, D. E.; Cook, J. M.; Le Quesne, P. W. J. Am. Chem. Soc.
1973, 95, 546.
(11) Liu, X.; Zhang, C.; Liao, X.; Cook, J. M. Tetrahedron Lett. 2002,
43, 7373.
10.1021/jo061652u CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/07/2006
8884
J. Org. Chem. 2006, 71, 8884-8890

ImproVed Total Synthesis of (+)-Macroline and Alstonerine
FIGURE 1. Macroline-related indole alkaloids.
SCHEME 1
provided an improved route for the total synthesis of macral-
stereospecific sequence via the enolate-mediated cross-coupling
process which was followed by a Wittig reaction/hydrolysis
sequence (see ref 13). Because the conditions14a employed for
the enolate-driven palladium-coupling process were different
stonine 76 as well as an improved route to macrocarpamine 9.8
Results and Discussion
The synthesis began with the readily available (-)-Na-methyl
tetracyclic ketone 11 prepared on a >300 g scale from ester 10
(>98% ee).12 This ester 10 had been converted into the key
intermediate, Na-methylvellosimine 16, via an enantiospecific,
(12) Yu, P.; Wang, T.; Li, J.; Cook, J. M. J. Org. Chem. 2000, 65,
3173.
(13) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.;
Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565.
J. Org. Chem, Vol. 71, No. 23, 2006 8885

Liao et al.
TABLE 1. Summary of Conditions for the r-Vinylation Process
Furthermore, to the best of our knowledge, this is the first
reported Pd(0)-catalyzed R-vinylation process in which the
cheaper DPEphos was employed in the case of a Z-ethylidene
(see 15). Gratifyingly, the desired Z-ethylidene 15 was obtained
in 82% yield, as illustrated in Scheme 2. This is an improvement
over the previous process16 employed for the synthesis of
(-)-koumidine (Scheme 2).16 It is clear the E-2 elimination
process was prohibited because there was no hydrogen atom
anti to the iodide in 14 and the bidentate DPEphos suppressed
the â-elimination in the case of the Z-ethylidene 14. The
modifications outlined in Table 1 also avoid the potential
intramolecular attack of a vinyl halide on the carbonyl group.
Since the conditions of the Pd(0)-mediated R-vinylation had
been optimized (Table 1), the low catalyst loadings and
homogeneous reaction conditions could be employed to more
readily scale up the carbon-carbon bond formation to provide
pentacyclic ketone 13. In the previous enolate-driven cross-
coupling process,14a higher temperatures (80 °C) and larger
quantities of phosphine ligand (Ph3P) were employed, although
the yield was still 80%.
Pd(dba)2
(mol %)
T
(°C)
yield
(%)
ligand (mol %)
base
2
2.4 (Xantphos)
2.4 (Xantphos)
2.4 (DPEphos)
2.4 (DPEphos)
2.4 (DPEphos)
(1.5 equiv) NaO-t-Bu
(1.5 equiv) NaO-t-Bu
(1.5 equiv) NaO-t-Bu
(1.5 equiv) NaO-t-Bu
(3.0 equiv) K3PO4
65
65
65
65
80
60
55
75
80
50
0.8
0.8
2
0.8
Since gram quantities of Na-methylvellosimine 16 were now
in hand, the aldehyde function was reduced with sodium
borohydride to afford affinisine 17 in over 90% yield, the
spectral data and optical rotation of which were identical to the
natural product.20 As shown in Scheme 3, the hydroxyl group
of affinisine was then protected as the triisopropylsilyl group,
and this was followed by a hydroboration-oxidation sequence
at 25 °C (see Scheme 3). The desired C(19) secondary alcohol
could be acquired in very good yield, accompanied by 7% of
the tertiary alcohol. In some runs, very little or no tertiary
alcohol was observed.11,20 Analogous to the earlier work of
Liu,11 the Nb-nitrogen atom in the sarpagine series had been
readily attacked by the first equivalent of borane. This served
to protect the Nb-nitrogen function from N-oxide formation
during the hydrogen peroxide-mediated process. This sequence
provided a mixture of Nb-protected products (boranes)20 which
were prepurified by a simple wash column on silica gel for the
borane adducts were less polar than the free base and much
easier to chromatograph. This mixture was then stirred in the
presence of 2 equiv of HOAc in refluxing THF for 5 h, after
which the desired secondary alcohol 19, with the free Nb-
nitrogen function, was obtained in 85% overall yield. Because
of the basicity of the Nb-nitrogen moiety in the sarpagine series,
the conversion of the C(19) secondary alcohol into the carbonyl
group necessary to set up a retro-Michael reaction was not
simple. Attempts at oxidation of monol 19 with TPAP or SO3‚
Py returned only starting material, while Swern oxidation
provided inconsistent results, accompanied by baseline material.
Finally, Dess-Martin oxidation23 of the diastereomeric mixture
of 19a,b provided the desired ketone 20 in 82% yield. As
illustrated in Scheme 3, the ketone 20 was then stirred in THF
at 0 °C with methyl iodide to furnish the Nb-methiodide salt to
set up a retro-Michael reaction analogous to the earlier biomi-
metic work of Le Quesne.21 This salt was stirred under modified
conditions with t-BuOK in refluxing THF/EtOH to provide the
(+)-macroline equivalent 4 via the retro-Michael reaction in
greater than 90% yield. The overall yield of this stable macroline
from the recent Buchwald-Hartwig arylation reactions, efforts
were directed toward intramolecular R-vinylation under the
conditions of the arylation process. If successful, this would
permit lower catalyst loading14 and be effective for both E and
Z ethylidenes, and the homogeneous reaction conditions might
provide a faster rate, thereby permitting facile scale-up. With
these goals in mind, advantage was taken of the mechanistic
studies reported on the Pd(0)-catalyzed R-vinylation.15 Certainly,
vinyl iodides would be quite reactive for the oxidative-addition
step. If nucleophilic substitution of iodide by the enolate
nucleophile in the coupling process was comparably slow, an
E-2 elimination could occur to provide the alkyne byproduct;
moreover, Z-ethylidenes were not always compatible with the
previous reaction conditions because â-elimination might oc-
cur.16 For these reasons, a bidentate ligand17 was considered
key to the success of this endeavor. Xantphos had been
employed by Buchwald18 in the R-arylation process due to the
large bite angle which facilitated the reductive elimination step
and suppressed the â-elimination in comparison to the other
steps. Initially, this Pd(0)-mediated process with the Xantphos
ligand provided the coupling product 13 (Table 1) here in 60%
yield. When the ratio of Pd(0)/Xantphos was increased, the yield
of 13 decreased. Excess ligand may have decreased the amount
of active Pd(0)/L2 species,19 which would retard the oxidative-
addition step. Because one of the principle byproducts arises
from the base-mediated E-2 elimination step (to alkyne) from
vinyl iodide 12, a slower rate of reaction would provide more
of the byproduct and lower yield. Since the bite angle of
DPEphos is similar to Xantphos, the cheaper DPEphos was then
studied in this R-vinylation. With DPEphos as the ligand, a
cleaner reaction was observed and the yield of the E-ethylidene
13 improved to 80%. Use of a weaker base such as K3PO4 (see
Table 1) in the process resulted in lower yields of 13.
(14) (a) Wang, T.; Cook, J. M. Org. Lett. 2000, 2, 2057. (b) Sole´, D.;
Peidro´, E.; Bonjoch, J. Org. Lett.. 2000, 2, 2225.
(15) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
(b) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211.
(16) Cao, H.; Yu, J.; Wearing, X.; Zhang, C.; Liu, X.; Deschamps, J.;
Cook, J. M. Tetrahedron Lett. 2003, 44, 8013.
(17) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes,
P. Chem. ReV. 2000, 100, 2741.
(18) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360.
(20) Liu, X. Ph. D Thesis, University of Wisconsin-Milwaukee, 2002.
(21) Esmond, R. W.; LeQuesne, P. W. J. Am. Chem. Soc. 1980, 102,
7116.
(22) Federici, E.; Palazzino, G.; Nicoletti, M.; Galeffi, C. Planta Med.
2000, 66, 93.
(19) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2002, 100, 3009.
(23) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
8886 J. Org. Chem., Vol. 71, No. 23, 2006

ImproVed Total Synthesis of (+)-Macroline and Alstonerine
SCHEME 2
SCHEME 3
equivalent 4 was (from tryptophan methyl ester 10) 20.4%.
When 4 was stirred in THF with tetrabutylammonium fluoride
monohydrate, (+)-macroline 3 was obtained in 86% yield, the
spectral data and optical rotation of which were in excellent
agreement with those reported in the literature.26
With an efficient synthesis of the (+)-macroline equivalent
4 in hand, modification of the conditions of the Tsuji-Wacker
oxidation permitted one-pot conversion of 4 into (-)-alstonerine
1 in 60% yield (includes four transformations)24 and the alkaloid
1 could be further converted into (-)-anhydromacrosalhine-
methine 6 and (-)-talcarpine 5, analogous to the earlier work
of LeQuesne,25 Yu,12 and Gan et al.8 The mass and NMR spectra
data of (-)-alstonerine 1 were in excellent agreement with those
reported in the literature.27 Analogous to the earlier work of Le
Quesne,25 Gan,8 and Yu,12 this constituted an improved total
synthesis of the biogenetic intermediate (-)-anhydromacrosal-
hine-methine 6 as well as (-)-talcarpine 5.25,28
(24) Liao, X.; Zhou, H.; Wearing, X.; Ma, J.; Cook, J. M. Org. Lett.
2005, 7, 3501.
(25) Garnick, R. L.; Le Quesne, P. W. J. Am. Chem. Soc. 1978, 100,
4213.
(26) Hesse, M.; Hurzeler, H.; Gemenden, C. W.; Joshi, B. S.; Taylor,
W. I.; Schmid, H. HelV. Chim. Acta 1965, 48, 689. Hesse, M.; Bodmer, F.;
Gemenden, C. W.; Joshi, B. S.; Taylor, W. I.; Schmid, H. HelV. Chim.
Acta 1966, 49, 1173.
(27) Le Quesne, P. W.; Cook, J. M.; Elderfield, R. C. J. Chem. Soc.,
Chem. Commun. 1969, 1306.
(28) Naranjo, J.; Pinar, M.; Hess, M.; Schmid, H. HelV. Chim. Acta 1972,
55, 752.
J. Org. Chem, Vol. 71, No. 23, 2006 8887

Liao et al.
103.5, 108.6, 116.4, 118.0, 118.7, 120.7, 127.3, 136.2, 137.2, 139.7;
IR (NaCl) 2910, 1469 cm-1; HRMS calcd for C20H24N2 308.1889,
found 308.1883. This material was employed directly in the next
step.
In conclusion, an efficient route to the stable (+)-macroline
equivalent 4 as well as to (+)-macroline 3 has been developed
(from tryptophan methyl ester 10) via a selective hydrobora-
tion-oxidation and retro-Michael ring-opening sequence. This
route to (+)-macroline 3 required 12 reaction vessels and was
accomplished in 18.1% overall yield. It can be employed to
prepare gram quantities of this key biomimetic intermediate for
the synthesis of Alstonia bisindoles. During the improved total
synthesis of (+)-macroline, a new Pd(0)/DPEphos-catalyzed
R-vinylation was developed. This process potentially can be
extended to vinyl bromides (which were employed by Buchwald
et al.) and would be more practical for alkaloids in the
koumidine (Z-ethylidenes) series than the enolate-driven Pd(0)
cross-coupling process previously reported from our laboro-
tary.16 In addition, the intramolecular Tsuji-Wacker oxidation24
was employed to convert the (+)-macroline equivalent 4 into
(-)-alstonerine 1 (12 reaction vessels from tryptophan methyl
ester; 12.6% overall yield). This resulted in the improved total
synthesis of (-)-talcarpine 5 and (-)-anhydromacrolsalhine-
methine 6, as mentioned. This synthesis of (+)-macroline 3 is
an important part of the doubly convergent strategy toward
antimalarial bisindole alkaloids such as villalstonine,7 macro-
carpamine,8 and macralstonine,20 as well as macralstonidine.29
Conversion of (+)-Affinisine (17) into 13-(Triisopropylsila-
nyloxymethyl)-3-ethylidene-12-methyl-1,3,4,7,12,12b-hexahydro-
13-hydroxymethyl-2H,6H-2,6-methanoindolo[2,3-R]quinoliz-
ine (18). A solution of affinisine (17, 1.2 g, 3.9 mmol) in dry CH2Cl2
(40 mL) was cooled to 0 °C, after which 2,6-lutidine (1.8 mL, 15.6
mmol) was added, and this was followed by addition of TIPSOTf
(2.1 mL, 7.8 mmol) to the stirred solution. The mixture was then
allowed to stir for an additional 2 h at 0 °C, after which cold water
(2 mL) was added to quench the reaction. The reaction mixture
was diluted with CH2Cl2 (100 mL) and poured into cold water (20
mL). The aqueous layer was extracted with additional CH2Cl2 (2
× 50 mL), and the combined organic layer was washed with brine
(30 mL) and dried (Na2SO4). The solvent was removed under
reduced pressure to afford the crude product, which was dried in
vacuo to remove the extra 2,6-lutidine before the solid was purified
by chromatography on silica gel (CH2Cl2/CH3OH ) 20:1) to
provide the O-TIPS ether (18, 1.63 g) in 90% yield: 1H NMR (300
MHz, CDCl3) δ 1.65 (dt, J ) 6.8, 1.7 Hz, 3H), 1.72 (dt, J ) 12.0,
3.3 Hz, 1H), 1.90 (qd, J ) 7.5, 1.2 Hz, 1H), 2.16 (ddd, J ) 12.2,
10.1, 2.0 Hz, 1H), 2.74 (d, J ) 15.5 Hz, 1H), 2.85 (dd, J ) 3.9,
1.8 Hz, 1H), 2.90 (d, J ) 6.6 Hz, 1H), 3.15 (dd, J ) 15.4, 5.2 Hz),
3.61 (d, J ) 7.5 Hz, 2H), 3.63 (s, 3H), 3.69 (qt, J ) 14.6, 2.2 Hz,
2H), 4.36 (dd, J ) 9.8, 1.9 Hz, 1H), 5.44 (q, J ) 6.8 Hz, 1H), 7.12
(td, J ) 7.4, 1.0 Hz, 1H), 7.22 (td, J ) 7.0, 1.1 Hz, 1H), 7.31 (d,
J ) 8.1 Hz, 1H), 7.50 (d, J ) 7.7 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 12.3, 12.9, 18.0, 27.1, 29.3, 32.8, 44.2, 49.7, 55.2, 56.2,
66.0, 103.5, 108.8, 117.3, 118.2, 118.9, 121.0, 127.3, 134.5, 137.3,
138.7; IR (NaCl) 2939, 2862, 1741, 1469 cm-1; HRMS calcd for
C29H44N2O1Si1 464.3223, found 464.3213. This material was
employed directly in the next step.
Preparation of 1-[13-(Triisopropylsilanyloxymethyl)-3-eth-
ylidene-12-methyl-1,3,4,7,12,12b-hexahydro-2H,6H-methanoin-
dolo[2,3-R]quinolizine-3-yl]ethanol (19a) and (19b). To a solution
of triisopropylsilyl ether 18 (500 mg, 1.08 mmol) in dry THF (24
mL) was added BH3‚DMS (1M, 10.0 mL, 10.0 mmol) at rt. The
mixture which resulted was stirred at rt for 3 h. The reaction mixture
was then quenched by careful addition of water (4.7 mL) at 0 °C.
At this point, aq NaOH (3N, 20 mL, 60 mmol) was added to the
mixture, and this was followed by addition of H2O2 (30%, 5.0 mL,
43 mmol). The mixture which resulted was allowed to stir at rt for
2 h after which EtOAc (400 mL) and H2O (50 mL) were added.
The organic layer was separated and dried (Na2SO4). The EtOAc
was then removed under reduced pressure, and the residue was flash
chromatographed with EtOAc/hexanes (3:7) to provide the mixture
of isomers at [C(19)] (483 mg) in 90% yield. The BH3 complex
isomer a with the lower Rf value was characterized: 1H NMR (300
MHz, CDCl3) δ 1.03-1.04 (m, 21H), 1.32 (d, J ) 6.1 Hz, 3H),
1.56 (bs, 1H), 1.74-1.82 (m, 2H), 1.99 (q, J ) 7.9 Hz, 1H), 2.10-
2.21 (m, 2H), 2.80 (d, J ) 15.5 Hz, 1H), 2.99 (dd, J ) 8.4, 4.7 Hz,
1H), 3.43 (dd, J ) 15.1, 5.2 Hz, 1H), 3.50 (dd, J ) 15.6, 4.9 Hz,
1H), 3.62-3.70 (m, 2H), 3.67 (3H, s), 3.80 (dd, J ) 10.0, 7.4 Hz,
1H), 3.93-4.03 (m, 1H), 4.25 (d, J ) 9.2 Hz, 1H), 7.10 (td, J )
6.9, 1.0 Hz, 1H), 7.21 (td, J ) 8.1, 1.2 Hz, 1H), 7.31 (d, J ) 8.1
Hz, 1H), 7.46 (d, J ) 7.7 Hz, 1H). The BH3 complex with the
higher Rf value was designated b: 1H NMR (300 MHz, CDCl3) δ
1.02-1.04 (m, 21H), 1.16 (d, J ) 7.1 Hz, 3H), 1.56 (bs, 1H), 1.71-
1.84 (m, 3H), 2.05 (q, J ) 9.4 Hz, 1H), 2.18 (ddd, J ) 12.4, 10.3,
1.7 Hz, 1H), 2.58 (d, J ) 15.1 Hz, 2H), 3.50 (dd, J ) 15.5, 5.0
Hz, 1H), 3.59 (dd, J ) 14.7, 3.4 Hz, 1H), 3.65 (s, 3H), 3.68 (d, J
) 1.8 Hz, 1H), 3.78-3.89 (m, 2H), 4.00 (dd, J ) 10.9 Hz, 7.7 Hz,
1H), 4.24 (d, J ) 8.9 Hz, 1H), 7.10 (td, J ) 7.9, 1.0 Hz, 1H), 7.21
(td, J ) 7.0, 1.1 Hz, 1H), 7.31 (d, J ) 8.1 Hz, 1H), 7.47 (d, J )
7.7 Hz, 1H). This material was used directly in the next step. The
above mixture of isomers (a and b, 450 mg, 0.9 mmol) was
dissolved in THF (27 mL) after which HOAc (0.11 mL, 1.8 mmol)
Experimental Section
General Methods. Reagent and solvent purification, workup
procedures, and analyses were in general performed as described
previously.13 The (+)-Na-methylvellosimine was prepared according
to the published procedure.13
General Procedure for the R-Vinylation. A mixture of
Nb-Z-2′-iodo-butenyltetracyclic ketone 12 (1.0 mmol), Pd(dba)2
(2 mol %), DPEphos (2.4 mol %), NaO-t-Bu (1.5 mmol) in
a solution of THF (20 mL) was degassed under reduced pressure
at a cooling bath temperature of -78 °C and refilled with argon
(three times). The mixture was then heated to 65 °C (oil bath
temperature) under argon for 12 h. Then mixture was quenched
with ice-water and extracted with ethyl acetate. The organic layer
was separated and dried (Na2SO4). The EtOAc was then removed
under reduced pressure, and the residue was flash chromatographed
with EtOAc/hexanes (1:1) to provide the coupling product in 80%
yield.
Sodium Borohydride Mediated Reduction of (+)-Na-Meth-
ylvellosimine (16) To Provide the (+)-3-Ethylidene-12-methyl-
1,3,4,7,12,12b-hexahydro-13-hydroxymethyl-2H,6H-2,6-meth-
anoindolo[2,3-R]quinolizine [(+)-Affinisine (17)]. The (+)-Na-
methylvellosimine (16, 2.0 g, 6.6 mmol) was dissolved in EtOH
(40 mL). The NaBH4 (240 mg, 6.6 mmol) was added to the above
solution in one portion at 0 °C. The mixture was then stirred at 0
°C for 8 h. The reaction mixture was diluted with CH2Cl2 (300
mL) and poured into cold water (50 mL). The aqueous layer was
extracted with additional CH2Cl2 (3 × 80 mL), and the combined
organic layers were washed with brine (80 mL) and dried (K2CO3).
The solvent was removed under reduced pressure to afford the crude
product, which was purified by chromatography on silica gel (CH2-
Cl2/CH3OH ) 10:1) to provide (+)-affinisine (17, 1.82 g, 90%):
1H NMR (300 MHz, CDCl3) δ 1.63 (dt, J ) 6.8, 1.7 Hz, 3H),
1.62-1.71 (m, 2H), 1.78 (qd, J ) 7.5, 1.2 Hz, 1H), 2.06 (ddd, J )
12.2, 10.0, 2.0 Hz, 1H), 2.62 (d, J ) 15.3 Hz, 1H), 2.75-2.79 (m,
2H), 3.03 (dd, J ) 15.3, 5.2 Hz, 1H), 3.45-3.66 (m, 4H), 3.61 (s,
3H), 4.19 (dd, J ) 9.8, 2.1 Hz, 1H), 5.39 (q, J ) 6.8 Hz, 1H), 7.08
(td, J ) 7.4, 1.0 Hz, 1H), 7.18 (td, J ) 7.1, 1.1 Hz, 1H), 7.29 (d,
J ) 8.1 Hz, 1H), 7.45 (d, J ) 7.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 12.7, 27.0, 27.5, 29.2, 32.9, 44.3, 49.4, 54.1, 56.3, 65.0,
(29) Zhao, S.; Liao, X.; Cook, J. M. Org. Lett.. 2002, 4, 687.
8888 J. Org. Chem., Vol. 71, No. 23, 2006

ImproVed Total Synthesis of (+)-Macroline and Alstonerine
was added to the above solution. The mixture was then held at
reflux for 5 h. The reaction mixture which resulted was cooled to
rt, and K2CO3 (622 mg, 4.5 mmol) was added, after which the
mixture was stirred for 30 min. The above mixture was then filtered
to remove solids, and they were washed with EtOAc. The solvent
was removed under reduced pressure to afford a crude product,
which was chromatographed [silica gel, CH2Cl2/MeOH (v/v 10:
1)] to provide the mixture of sec-ols (19a and 19b, 412 mg, 0.86
mmol) in 95% yield. 19a: 1H NMR (300 MHz, CDCl3) δ 1.03-
1.06 (m, 21H), 1.31 (d, J ) 6.0 Hz, 3H), 1.45-1.59 (m, 2H), 1.76
(q, J ) 7.7 Hz, 1H), 1.94 (t, J ) 11.2 Hz, 1H), 2.04 (bs, 1H), 2.76
(d, J ) 14.9 Hz, 1H), 3.00-3.14 (m, 2H), 3.26-3.45 (m, 2H),
3.53 (s, 3H), 3.69 (t, J ) 9.0 Hz, 1H), 3.81 (t, J ) 10.2 Hz, 1H),
3.97 (td, J ) 12.0, 6.0 Hz, 1H), 4.11 (d, J ) 9.8 Hz, 1H), 7.09 (t,
J ) 7.4 Hz, 1H), 7.22 (t, J ) 7.0 Hz, 1H), 7.27 (d, J ) 7.2 Hz,
1H), 7.47 (d, J ) 7.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 11.8,
17.9, 22.2, 25.7, 26.9, 29.2, 37.6, 42.6, 44.0, 48.4, 53.1, 55.7, 66.0,
71.5, 103.0, 108.7, 118.2, 118.9, 121.0, 127.2, 137.2, 137.9; IR
(NaCl) 2925, 1470 cm-1; EIMS (m/e, relative intensity) 483 (M+
+ 1, 41), 482 (M+, 100), 481 (41), 437 (31), 295 (16), 253 (17).
19b: 1H NMR (300 MHz, CDCl3) δ 1.04-1.06 (m, 21H), 1.19 (d,
J ) 5.9 Hz, 3H), 1.50-1.56 (m, 2H), 1.86 (q, J ) 8.9 Hz, 1H),
1.97 (td, J ) 11.2, 2.0 Hz, 1H), 2.47 (q, J ) 2.1 Hz, 1H), 2.53 (d,
J ) 15.3 Hz, 1H), 2.63 (dd, J ) 14.1, 5.2 Hz, 1H), 2.82 (t, J ) 6.6
Hz, 1H), 3.11 (dd, J ) 15.4, 5.5 Hz, 1H), 3.35 (dd, J ) 14.1, 10.5
Hz, 1H), 3.66 (s, 3H), 3.73-3.89 (m, 2H), 4.02 (dd, J ) 10.9, 7.6
Hz, 1H), 4.16 (dd, J ) 10.0, 2.8 Hz, 1H), 7.10 (td, J ) 7.4, 1.0
Hz, 1H), 7.21 (td, J ) 7.0, 1.1 Hz, 1H), 7.31 (d, J ) 8.1 Hz, 1H),
7.49 (d, J ) 7.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 11.8,
17.9, 21.5, 22.6, 27.6, 29.2, 37.1, 41.9, 44.0, 48.7, 53.4, 55.4, 66.5,
72.0, 102.7, 108.6, 118.0, 118.6, 120.6, 127.4, 137.1, 139.8; IR
(NaCl) 2939, 1469 cm-1; EIMS (m/e, relative intensity) 483 (M+
+ 1, 54), 482 (M+, 100), 481 (46), 437 (43), 295 (13), 253 (9).
This material was used directly in the next step.
Dess-Martin Oxidation of the Sec-ols (19a) and (19b) To
Provide the 1-[13-(Triisopropylsilanyloxymethyl)-3-ethylidene-
12-methyl-1,3,4,7,12,12b-hexahydro-2H,6H-methanoindolo[2,3]-
quinolizine-3-yl]ethanone (20). To a solution of the sec-ols (19a
and 19b, 400 mg, 0.83 mmol) in CH2Cl2 (30 mL) was added DMP
(704 mg, 1.66 mmol) in one portion at 0 °C. The mixture which
resulted was then stirred at this temperature for 4 h [the reaction
progress was monitored by TLC (EtOAc)]. The reaction mixture
was quenched with a satd solution of aq NaHCO3 (9 mL) and a
satd solution of aq Na2S2O3 (9 mL) after which the mixture was
stirred for 10 min at 0 °C. The aqueous layer was extracted with
additional amounts of CH2Cl2 (3 × 20 mL), and the combined
organic layer was washed with brine (20 mL) and dried (K2CO3).
The solvent was removed under reduced pressure to provide the
crude product which was chromatographed [silica gel, CH2Cl2/
MeOH (v/v 20:1)] to provide pure ketone (20, 327 mg, 82%): 1H
NMR (300 MHz, CDCl3) δ 1.08-1.09 (m, 21H), 1.38 (d, J ) 12.8
Hz, 1H), 1.76 (q, J ) 7.1 Hz, 1H), 2.00 (t, J ) 11.3 Hz, 1H), 2.21
(s, 3H), 2.37 (d, J ) 1.7 Hz, 1H), 2.67 (d, J ) 15.3 Hz, 1H), 2.95-
3.21 (m, 4H), 3.56 (t, J ) 6.5 Hz, 1H), 3.61 (s, 3H), 3.85 (d, J )
3.2 Hz, 1H), 3.87 (d, J ) 1.2 Hz, 1H), 4.19 (d, J ) 9.1 Hz, 1H),
7.10 (t, J ) 7.4 Hz, 1H), 7.20 (t, J ) 7.4 Hz, 1H), 7.29 (d, J ) 8.1
Hz, 1H), 7.48 (d, J ) 7.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
11.8, 18.0, 26.7, 27.1, 29.0, 29.2, 29.5, 41.9, 42.5, 48.8, 48.9, 53.3,
64.2, 103.3, 108.7, 118.0, 118.7, 120.8, 127.2, 132.1, 137.2, 209.8;
IR (NaCl) 2922, 1707, 1469 cm-1; EIMS (m/e, relative intensity)
481 (M+ + 1, 37), 480 (M+, 88), 479 (38), 437 (54), 252 (100).
Anal. Calcd for C29H44N2O2Si1 : C, 72.45; H, 9.23; N, 5.83.
Found: C, 72.16; H, 9.47; N, 5.79.
was dissolved in THF/EtOH (36 mL/6 mL) after which t-BuOK
(12.7 mL, 1.0 M) was added. The mixture which resulted was
heated to reflux for 2 h after which it was cooled to rt. The EtOAc
(600 mL) and H2O (70 mL) were then added, and the organic layer
was separated. The organic layer was washed with brine (70 mL)
and dried (Na2SO4). The EtOAc was removed under reduced
pressure, and the residue was chromatographed [silica gel, EtOAc/
hexane (v/v 1:1)] to provide (4, 470 mg, 0.95 mmol) in 90% yield:
1H NMR (300 MHz, CDCl3) δ 1.06 (s, 21H), 1.38 (dt, J ) 12.2,
2.9 Hz, 1H), 2.06-2.20 (m, 2H), 2.25 (s, 3H), 2.33 (s, 3H), 2.62
(d, J ) 16.6 Hz, 1H), 3.02 (dt, J ) 13.6, 3.0 Hz, 1H), 3.29 (t, J )
9.3 Hz, 1H), 3.40 (dd, J ) 9.6, 4.3 Hz, 1H), 3.49 (d, J ) 8.9 Hz,
1H), 3.62 (s, 3H), 3.94 (t, J ) 9.4 Hz, 1H), 4.02 (t, J ) 3.2 Hz,
1H), 5.58 (d, J ) 1.5 Hz, 1H), 5.60 (s, 1H), 7.11 (td, J ) 7.8, 1.3
Hz, 1H), 7.16 (td, J ) 7.2, 1.2 Hz, 1H), 7.28 (d, J ) 7.8 Hz, 1H),
7.56 (d, J ) 7.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 11.9,
17.9, 22.0, 26.3, 28.8, 29.4, 30.1, 42.0, 46.2, 53.2, 61.5, 107.4,
108.5, 118.3, 118.6, 120.5, 123.1, 126.6, 133.3, 136.9, 150.9, 198.8;
IR (NaCl) 2937, 2864, 1678, 1468 cm-1; HRMS calcd for
C30H46N2O2Si 494.3328, found 494.3317. This material was
employed directly in the next step.
(+)-Macroline (3). To a solution of the macroline equiv-
alent (4) (180 mg, 0.36 mmol) in THF (45 mL) was added
TBAF‚H2O (0.6 mL, 1 M solution in THF) at 0 °C. The solution
which resulted was allowed to stir at rt for 4 h until analysis by
TLC indicated the disappearance of the starting material. Cold
water (30 mL) was added to quench the reaction mixture at 0 °C,
after which the CH2Cl2 (300 mL) was added. The organic layer
was washed with additional water (30 mL) and brine (50 mL)
and dried (Na2SO4). The CH2Cl2 was removed under reduced
pressure, and the residue was chromatographed [silica gel, CH2-
Cl2/MeOH (v/v 20:1)] to provide (+)-macroline (3, 106 mg, 0.31
mmol) in 86% yield: [R]28D ) 18.9 (ethanol, c ) 0.1) (lit.25 [R]28
D
) 19.2 (ethanol)); 1H NMR (300 MHz, CD3CN) δ 1.48-1.60 (m,
1H), 1.95 (br, 1H), 2.29 (s, 3H), 2.43 (s, 3H), 2.71-2.82 (m, 2H),
3.10 (dt, J ) 13.4, 4.6 Hz, 1H), 3.37 (dd, J ) 16.8, 7.5 Hz, 1H),
3.59 (d, J ) 7.3 Hz, 1H), 3.65 (s, 3H), 3.71 (dd, J ) 10.9, 3.1 Hz,
1H), 3.85 (dd, J ) 10.8, 3.0 Hz, 1H), 4.19 (br, 1H), 6.00 (s, 1H),
6.21 (s, 1H), 7.14 (t, J ) 7.8 Hz, 1H), 7.22 (t, J ) 6.9 Hz, 1H),
7.30 (d, J ) 8.0 Hz, 1H), 7.56 (d, J ) 7.5 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 22.1, 26.2, 28.9, 29.9, 31.6, 41.3, 42.7, 53.3, 58.4,
66.0, 106.2, 108.7, 118.4, 118.9, 121.1, 125.6, 126.2, 132.0, 137.0,
149.6, 199.2; IR (NaCl) 2924, 1708, 1674, 1468 cm-1; EIMS (m/
e, relative intensity) 338 (M+, 25), 251 (10), 197 (100), 182 (32),
181 (77), 170 (27); HRMS calcd for C21H26N2O2 338.1994, found
338.1991.
(-)-Alstonerine (1).24,30 To a solution of the macroline equiva-
lent (4) (41 mg, 0.083 mmol) in H2O/t-BuOH/AcOH (1.2 mL/1.2
mL/0.4 mL) were added Na2PdCl4 (29.5 mg, 0.10 mmol) and TBHP
(0.014 mL) at rt, and the mixture which resulted was stirred at 80
°C for 5 h. After the mixture was cooled to rt, ice-water (2 mL)
and a satd solution of aq NaHCO3 (10 mL) were added to the
mixture, and this was followed by addition of EtOAc(50 mL). The
aqueous layer was extracted with additional EtOAc (2 × 30 mL).
The combined organic layer was washed with a satd solution of aq
NaHCO3 and brine and dried (K2CO3). The EtOAc was removed
under reduced pressure, and the residue was purified by preparative
TLC [silica gel,EtOAc/hexane(v/v1:1)] to provide (1) (12.5 mg,
0.034 mmol) in 60% yield. The spectral data were in excellent
agreement with the natural product:31 1H NMR (300 MHz, CDCl3)
δ 1.82 (dd, J ) 12.2, 4.2 Hz, 1H), 1.92 (ddd, J ) 12.2, 11.4, 1.5
Hz, 1H), 2.11 (s, 3H), 2.11-2.19 (m, 1H), 2.35 (s, 3H), 2.53 (d, J
) 16.5 Hz, 1H), 2.64 (dt, J ) 12.4, 4.6 Hz, 1H), 3.11 (d, J ) 6.8
Hz, 1H), 3.36 (dd, J ) 16.4, 6.8 Hz, 1H), 3.68 (s, 3H), 3.90 (t, J
) 1.5 Hz, 1H), 4.19 (ddd, J ) 11.2, 4.0, 1.5 Hz), 4.44 (t, J ) 11.2
Nb-Methylation of Ketone (20) Followed by Base-Mediated
Retro-Michael Reaction To Provide the (+)-Macroline Equiva-
lent (4). To a solution of ketone (20, 500 mg, 1.05 mmol) in THF
(25 mL) was added MeI (222.5 mg, 15.8 mmol) at 0 °C, after which
the mixture was allowed to stir in the dark at 0 °C overnight. The
THF was then removed under reduced pressure, and the residue
(30) Tsuji, J.; Nagashima, H.; Hori, K. Chem. Lett. 1980, 257.
(31) Ratnayake, C. K.; Arambewela, L. S. R.; De Silva, K. T. D.;
Rahman, A. U.; Alvi, K. A. Phytochemistry 1987, 26, 868.
J. Org. Chem, Vol. 71, No. 23, 2006 8889

Liao et al.
Hz, 1H), 7.11 (t, J ) 8.1 Hz, 1H), 7.22 (t, J ) 7.0 Hz, 1H), 7.34
(d, J ) 8.1 Hz, 1H), 7.50 (d, J ) 7.6 Hz, 1H), 7.55 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 22.7, 22.8, 24.9, 29.0, 32.3, 38.4, 41.7,
53.7, 54.6, 67.7, 105.8, 108.9, 117.7, 118.6, 120.7, 121.0, 126.5,
133.1, 137.1, 157.3, 195.4 (lit.23 22.4, 23.0, 25.0, 29.1, 32.3, 38.7,
41.8, 54.0, 54.9, 67.8, 105.9, 109.4, 117.9, 118.9, 121.0, 126.5,
133.4, 137.4, 157.5, 195.4); IR (NaCl) 1650, 1621 cm-1; EIMS
(m/e, relative intensity) 336 (M+, 47), 197 (100), 182 (58), 181
(82), 170 (89); HRMS calcd for C21H24N2O2 336.1846, found
336.1838.
Acknowledgment. We wish to acknowledge the NIMH (in
part) and The Research Growth Initiative of The University of
WisconsinsMilwaukee for support of this work.
Supporting Information Available: 1H and 13C NMR spectra
for 1, 3, 4, 17, 18, and 19a,b. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO061652U
8890 J. Org. Chem., Vol. 71, No. 23, 2006