Asymmetric synthesis of tetracyclic substructures of Strychnos indole alkaloids

Article abstract of DOI:10.1016/S0957-4166(03)00251-9

The addition of the enolate of methyl 1-methyl-2-indoleacetate 1 and lithium 2-(lithiomethyl)indole-1-carboxylate 5 to pyridines and N-alkylpyridinium salts bearing a chiral auxiliary at the 3-position (tolylsulfinyl, acyl iron complexes, bornane-10,2-sultam), with subsequent acid cyclization of the resulting dihydropyridines, is investigated.

Full text of DOI:10.1016/S0957-4166(03)00251-9

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TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1691–1699
Asymmetric synthesis of tetracyclic substructures of Strychnos
indole alkaloids
Mercedes Amat,a,* M.-Dolors Coll,a Nu´ria Llor,a Carmen Escolano,a Elies Molins,b
Carles Miravitllesb and Joan Boscha,*
aLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
bInstitut de Cie`ncia de Materials (CSIC), Campus UAB, 08193 Cerdanyola, Spain
Received 5 March 2003; accepted 10 March 2003
Abstract—The addition of the enolate of methyl 1-methyl-2-indoleacetate 1 and lithium 2-(lithiomethyl)indole-1-carboxylate 5 to
pyridines and N-alkylpyridinium salts bearing a chiral auxiliary at the 3-position (tolylsulfinyl, acyl iron complexes, bornane-10,2-
sultam), with subsequent acid cyclization of the resulting dihydropyridines, is investigated. © 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
head character of carbons 3 and 15, the configuration
at the dihydropyridine 4-carbon (C-15) would deter-
mine that of C-3 in the cyclization to the tetracyclic
1,5-methanoazocino[4,3-b]indole system B via a dihy-
dropyridinium cation (bond formed C3ꢀC7) and, after-
wards, that of the quaternary C-7 center in the closure
of the five-membered C-ring (bond formed C6ꢀC7).2,3
An inspection of the polycyclic structure of Strychnos
alkaloids,1 for instance dihydroakuammicine, reveals
that the stereogenic carbons common to two or more
rings are configurationally correlated and that their
relative and absolute configurations could be unam-
biguously attained starting from a suitably functional-
ized enantiopure 2-(1,4-dihydro-4-pyridylmethyl)indole
A (Scheme 1). In fact, as a consequence of the bridge-
The development of the above synthetic strategy would
require the generation of a chiral non-racemic 1,4-
dihydropyridine4 by diastereofacial-selective addition of
an appropriate indole-containing nucleophile to an acti-
vated pyridine or pyridinium salt carrying a chiral
auxiliary at the 3-position.5,6 Although the addition of
indole-containing enolates to N-alkylpyridinium salts
bearing an electron-withdrawing group at the 3-posi-
tion has extensively been used in our laboratory as the
initial step of a general and versatile method for the
synthesis of indole alkaloids in the racemic series,7 there
are few examples of the use of this methodology for the
enantioselective synthesis of alkaloids.8
In this paper we report the results of applying the
strategy depicted in Scheme 1 for the preparation of
enantiopure tetracyclic ABDE substructures of Strych-
nos alkaloids using several chiral auxiliaries Y*.
Scheme 1.
2. Results and discussion
Initially, we planned to use a sulfinyl group as the
chiral auxiliary. The electron-withdrawing nature of
* Corresponding authors. Tel.: +34 93 4024538; fax: +34 93 4024539;
e-mail: amat@farmacia.far.ub.es; jbosch@farmacia.far.ub.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00251-9

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M. Amat et al. / Tetrahedron: Asymmetry 14 (2003) 1691–1699
However, when chiral non-racemic nicotinoyl iron com-
plex (R)-615 was treated with 2-(lithiomethyl)indole 5
and the crude mixture was trapped with methyl chloro-
formate, only a nearly equimolecular mixture of C-2
diastereomeric 1,2-dihydropyridines 7 and 7% (57:43
ratio; absolute configuration at C-2 not determined)
were obtained (Scheme 3). The chemical shift of H-2 (l
ꢀ5.0) and C-2 (l ꢀ53.3) of the dihydropyridine ring
were of diagnostic value.
this group should allow an efficient nucleophilic attack
of a 2-indoleacetic ester enolate on the 4-position of the
pyridine ring. Although the preparation of enantiopure
(S)-3-(p-tolylsulfinyl)pyridine has been reported in the
literature,9 to test the feasibility of the methodology we
undertook a model study using the racemic tolylsulfi-
nylpyridinium salt rac-2, which was easily accessible by
methylation of the corresponding pyridine with methyl
iodide (Scheme 2).
Scheme 2.
Scheme 3.
Interaction of the enolate of ester 110 with pyridinium
salt rac-2 at −30°C, followed by acid cyclization of the
resulting 1,4-dihydropyridine gave the expected tetra-
cyclic derivatives as a mixture of four diastereomers,
cis- and trans-rac-3 and cis- and trans-rac-3% (cis/trans
refers to the relative H5–H6 stereochemistry; 3 and 3%
refers to the relative configuration of the bridgehead
carbons with respect to the sulfur), which were sepa-
rated by flash chromatography (32% overall yield).
Tetracyclic cis sulfide rac-4 was also isolated in 12%
yield.
Although the configuration of tetracycles rac-3 and
rac-3% is not known, the H5–H6 cis/trans relationship
for the pairs of isomers rac-3 (12% yield; 2:3 ratio) and
rac-3% (20% yield; 3:2 ratio)11 was deduced from the
coupling constant of the doublet corresponding to H6
(5 Hz in the cis isomers but 1.5 Hz in the trans isomers)
in the 1H NMR spectra and from the existence of
gauche effects on C4 (in the cis isomers) or C12 (in the
trans isomers) in the 13C NMR spectra.12 The same
criteria allowed the assignment of the relative cis H5–H6
configuration in rac-4. The above results indicated that
the addition of the enolate to the pyridinium salt had
taken place with a low facial stereoselectivity. For this
reason, no further experiments were performed using
enantiopure 2.
Although the chemical yield of the above addition–
acylation sequence was excellent (76%) the regioselec-
tivity of the process was not favorable to our synthetic
interest, probably due to steric factors and the particu-
lar nature of the organolithium derivative 5, which also
bears a lithium carboxylate moiety.
As a further chiral auxiliary we selected (2R)-bornane-
10,2-sultam,16 which has been extensively used by
Oppolzer in a number of enantioselective transforma-
tions, including conjugate nucleophilic additions to N-
enoyl derivatives.
Acylation of this sultam with sodium hydride and
nicotinoyl chloride hydrochloride gave the required
nicotinoylsultam 8 in 92% yield. The addition of 2-
(lithio-methyl)indole 5 to 8 followed by treatment of
the resulting mixture with methyl chloroformate led to
a mixture of the desired 1,4-dihydropyridine 9 (20%; a
single stereoisomer) and 1,2-dihydropyridines 10 and
10% (20%; two stereoisomers in a 2:3 ratio, whose
configuration at C-2 was not determined), which could
be separated after repeated purification by column
chromatography (Scheme 4).
Diagnostic NMR signals for the structural assignment
of these dihydropyridines were those of the sp3 methine
moiety (H-4, l 3.5 and C-4, l 33.8 for the 1,4-isomer
and H-2, l 5.1 and C-2, l 53.0 for the 1,2-isomers). The
absolute configuration of the new stereogenic center in
9 was assigned taking into account the configuration of
the cyclized product trans-12b.
We then turned our attention to chiral a,b-unsaturated
acyl iron complexes, which have been developed by
Davies and used in a variety of stereoselective conju-
gate additions,13 including the regio- and stereoselective
addition of organolithium derivatives to nicotinoyl iron
complexes to give the corresponding 4-alkyl-1,4-
dihydropyridines.14

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M. Amat et al. / Tetrahedron: Asymmetry 14 (2003) 1691–1699
1693
Scheme 4.
Scheme 6.
Unfortunately, all attempts to cyclize N-acyl-1,4-dihy-
dropyridine 9 under acidic conditions (AcOH–dioxane–
H2O3b or HCl–benzene10) to a tetracyclic derivative
resulted in failure, leading to complex unidentifiable
mixtures.
using the same criteria as in the above tetracycles rac-3.
Formation of unnatural tetracycles 13a (two epimers at
C-1 of unknown absolute configuration at the bridge-
head carbons18) can be accounted for by considering
that, under acidic conditions, the 1,2-dihydropyridine
initially formed by nucleophilic addition of the enolate
to the 6-position of the pyridinium ring is protonated,
and that the resulting 1,2-dihydropyridinium cation
undergoes intramolecular conjugate addition by the
indole ring. Probably, the bulkiness of the chiral auxil-
iary, which hinders the approach of the nucleophile to
the adjacent 4-position of the pyridine ring, is responsi-
ble for this undesirable regioselectivity.
These results prompted us to study a similar nucle-
ophilic addition–cyclization sequence starting from
indoleacetic ester 1 and N-alkylpyridinium salts 11a
and 11b, which were prepared in 97 and 92% yield by
alkylation of nicotinoyl sultam 8 with methyl iodide
and benzyl chloride, respectively. Addition of the eno-
late derived from 1 to pyridinium salt 11a followed by
treatment of the resulting crude mixture of dihydropy-
ridines with HCl in benzene gave a mixture of the
expected tetracycles 12a (10% yield) and the regioiso-
mers 13a (28% yield), which could be separated after
repeated column chromatography (Scheme 5). In some
runs, minor amounts of polyunsaturated amine 14,
formed by the opening of the 1,2-dihydropyridine ring
promoted by the excess of base, were also isolated17
(Scheme 6).
The use of benzylpyridinium salt 11b in the above
two-step sequence led to a similar result and allowed us
to isolate (27% overall yield) the expected tetracycles
12b (two epimers at C-6, cis-12b and trans-12b), again
with the same absolute configuration at the bridgehead
carbons, and two regioisomeric tetracycles 13b and
13%b, both of them with a H1–H2 trans relative stereo-
chemistry (Jꢀ1.5 Hz) and, consequently, with different
absolute configuration (not determined) at the bridge-
head carbons. The absolute configuration at the bridge-
head carbons in tetracycles 12 was unambiguously
established from the X-ray crystallographic analysis of
trans-12b.19 On the other hand, the structural assign-
ment of tetracycles 13 was effected from the 13C NMR
chemical shift values of the bridgehead methine carbons
(l ꢀ23 and 56 for 13 versus l ꢀ29 and 48 for
tetracycles 12).
In conclusion, the results presented here, in conjunction
with those previously reported from a chiral oxa-
zolinylpyridine,6 show that the strategy for the synthesis
of enantiopure tetracyclic precursors of Strychnos alka-
loids based on the enantioselective generation of 1,4-
Scheme 5.
Tetracycles cis-12a and trans-12a epimers at C-618 pos-
sess the same absolute configuration at the bridgehead
carbons, thus indicating that the nucleophilic addition
to the 4-position of the pyridine ring had occurred with
facial selectivity. The relative H5–H6 stereochemistry of
12 was deduced from the H5–H6 coupling constant
dihydropyridines by nucleophilic addition of
a
2-indolylmethyl moiety to pyridines or pyridinium salts
bearing a chiral auxiliary at the 3-position, and their
subsequent acid cyclization, suffers from two main
drawbacks that seriously limit its application: the low

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M. Amat et al. / Tetrahedron: Asymmetry 14 (2003) 1691–1699
facial stereoselectivity, as a consequence of an ineffi-
cient coordination of the nucleophile with the chiral
auxiliary, and/or the low regioselectivity due to the
bulkiness of the chiral auxiliary.
and evaporated to give a residue, which was column
chromatographed.
3.4. Reaction of methyl 1-methyl-2-indoleacetate 1 with
1-methyl-3-(p-tolylsufinyl)pyridinium iodide rac-2
3. Experimental
3.1. General
Following the above general procedure, from ester 1
(285 mg, 1.4 mmol) and pyridinium iodide rac-2 (500
mg, 1.4 mmol) a residue was obtained. Purification by
column chromatography (EtOAc 100%, increasing
polarity with EtOH) gave four fractions. Further purifi-
cation of the first fraction by column chromatography
(3:7 EtOAc/hexane) gave rac-4 (73 mg, 12%) and traces
of 1. The second fraction was a mixture of cis-rac-3
and trans-rac-3, which were separated after an addi-
tional flash chromatography (95:5 Et2O/EtOH) to give
(12% overall yield) pure cis-rac-3 (27 mg) and trans-
rac-3 (45 mg). The third and fourth fractions gave
cis-rac-3% (71 mg) and trans-rac-3% (48 mg), respectively
(20% overall yield). rac-4: mp 154–156°C (EtOAc); IR
(NaCl) 1719, 1610, 1201, 1166, 745 cm−1; 1H NMR
(CDCl3, 200 MHz) l 2.03 (dt, J=12.1, 2.7 Hz, 1H,
H-12), 2.21 (dt, J=12.1, 3.5 Hz, 1H, H-12), 2.31 (s, 3H,
CH3Ar), 3.03 (s, 3H, N2-CH3), 3.11 (br s, 1H, H-5),
3.55 (s, 3H, N7-CH3), 3.88 (s, 3H, OCH3), 4.10 (d,
J=5.1 Hz, 1H, H-6), 4.48 (br s, 1H, H-1), 6.53 (s, 1H,
H-3), 7.10–7.30 (m, 7H, ArH), 7.60 (d, J=7.0 Hz, 1H,
H-11); 13C NMR (CDCl3, 50.3 MHz) l 20.9 (CH3Ar),
31.0 (N7-CH3), 31.6 (C-12), 34.4 (C-5), 41.2 (N2-CH3),
47.6 (C-6), 48.8 (C-1), 52.4 (OCH3), 91.9 (C-4), 109.1
(C-8), 111.1 (C-11b), 118.1 (C-11), 119.6 (C-10), 121.5
(C-9), 126.2 (C-11a), 126.3 (C-o), 129.5 (C-m), 133.4
(C-p), 136.9 (C-i ), 137.4 (C-7a), 146.0 (C-3), 172.8
(CO); m/z 447 (M++29, 7), 419 (M++1, 62), 418 (M+,
100), 241 (14), 240 (79), 216 (16). Anal. calcd for
C25H26N2O2S·1/2 C4H8O2: C, 70.10; H, 6.54; N, 6.06; S,
6.93. Found: C, 69.95; H, 6.43; N, 6.35; S, 6.67. cis-rac-
3: mp 156°C (acetone); IR (NaCl) 1741, 1618, 1470,
Melting points were determined in a capillary tube and
are uncorrected. Unless otherwise indicated, NMR
spectra were recorded at 200 or 300 MHz (1H) and 50.3
or 75 MHz (13C) and chemical shifts are reported in l
values downfield from TMS. Only noteworthy IR
absorptions are listed. Thin-layer chromatography was
done on SiO2 (silica gel 60 F254), and the spots were
located with aqueous potassium permanganate solution
or with iodoplatinate reagent. Column chromatography
was carried out using the flash chromatography tech-
nique. All non-aqueous reactions were performed under
an inert atmosphere. Solvents for chromatography were
distilled at atmospheric pressure prior to use and dried
following standard procedures. Drying of the organic
extracts during the workup of reactions was performed
over anhydrous Na2SO4 or MgSO4. Evaporation of
solvents was accomplished with a rotatory evaporator.
Microanalyses and HRMS were performed by Centre
D’Investigacio´ i Desenvolupament (CSIC), Barcelona.
3.2. Preparation of 1-methyl-3-(p-tolylsulfinyl)-pyridin-
ium iodide rac-2
A solution of methyl iodide (0.6 mL, 0.66 mmol) in
benzene (1.2 mL) was slowly added to a cooled (0°C)
solution of 3-(p-tolylsulfinyl)pyridine9b (700 mg, 3.22
mmol) in acetone (1 mL). The mixture was stirred for
12 h and the solid was filtered and dried to give rac-2
(930 mg, 80%). rac-2: IR (NaCl) 1053 cm−1; H NMR
1167, 1029, 747 cm−1; H NMR (CDCl3, 200 MHz) l
1
1
(CDCl3, 200 MHz) l 2.34 (s, 3H, CH3Ar), 4.40 (s, 3H,
N-CH3), 7.42 and 7.76 (2d, J=8.1, 4H, ArH), 8.21 (dd,
J=8.2, 6.0 Hz, 1H, H-5), 8.75 (dd, J=8.2, 1.2 Hz, 1H,
H-4), 9.07 (d, J=6.0 Hz, 1H, H-6), 9.39 (s, 1H, H-2);
13C NMR (DMSO, 50.3 MHz) l 21.2 (CH3Ar), 48.9
(N-CH3), 125.6 (C-o), 128.5 (C-5), 130.7 (C-m), 140.4
(C-p), 140.8 (C-4), 142.2 (C-6), 143.1 (C-i ), 147.1 (C-3),
147.8 (C-2).
1.79 (dt, J=12.1, 3.3 Hz, 1H, H-12), 1.89 (dt, J=12.1,
2.7 Hz, 1H, H-12), 2.41 (s, 3H, CH3Ar), 2.74 (m, 1H,
H-5), 3.11 (s, 3H, N2-CH3), 3.56 (s, 3H, N7-CH3), 3.92
(s, 3H, OCH3), 4.10 (d, J=5.2 Hz, 1H, H-6), 4.48 (br s,
1H, H-1), 6.87 (s, 1H, H-3), 7.10–7.30 (m, 5H, ArH),
7.57 (d, J=8.1 Hz, 2H, o-), 7.63 (d, J=7.0 Hz, 1H,
H-11); 13C NMR (CDCl3, 50.3 MHz) l 21.4 (CH3Ar),
29.9 (C-12), 30.0 (C-5), 30.9 (N7-CH3), 41.5 (N2-CH3),
48.5 (C-6), 48.9 (C-1), 52.7 (OCH3), 103.4 (C-4), 109.1
(C-8), 111.4 (C-11b), 118.1 (C-11), 119.7 (C-10), 121.7
(C-9), 125.9 (C-11a, masked), 125.9 (C-o), 129.8 (C-m),
132.5 (C-6a), 136.3 (C-3), 137.3 (C-7a), 141.6 (C-3),
142.5 (C-i ), 172.4 (CO); m/z 475 (M++41, 2), 463
(M++29, 11), 435 (M++1, 73), 419 (30), 418 (57), 387
(22), 386 (61), 297 (25), 296 (100), 240 (52), 239 (10).
Anal. calcd for C25H26N2O3S·1/2 H2O: C, 67.69; H,
6.13; N, 6.31; S, 7.22. Found: C, 67.49; H, 6.10; N,
6.17; S, 6.81. trans-rac-3: mp 154°C (EtOH); IR (NaCl)
1731, 1613, 1470, 1200, 1030, 752 cm−1; 1H NMR
(CDCl3, 200 MHz) l 1.67 (dt, J=12.7, 3.1 Hz, 1H,
H-12), 2.14 (dt, J=12.7, 2.5 Hz, 1H, H-12), 2.43 (s, 3H,
CH3Ar), 3.01 (br s, 1H, H-5), 3.12 (s, 3H, N2-CH3),
3.61 (s, 3H, N7-CH3), 3.64 (s, 3H, OCH3), 4.48 (br s,
1H, H-1), 4.58 (d, J=1.8 Hz, 1H, H-6), 6.77 (s, 1H,
3.3. General procedure for the addition of methyl 1-
methyl-2-indoleacetate 1 to the pyridinium salts rac-2
and 11
LDA (1.5 M in THF, 1.5 mmol) was added to a cooled
(−78°C) solution of ester 1 (1 mmol) in THF (25 mL).
The mixture was stirred for 1 h at this temperature, and
the pyridium salt (1 mmol) was added portionwise.
Then, the mixture was warmed to −30°C and stirred for
2 h. The suspension was acidified to pH 3–4 with a
solution of HCl in benzene. The temperature of the
mixture was raised to −10°C and stirring was continued
for 90 min. The mixture was poured into saturated
aqueous Na2CO3, and the aqueous phase was extracted
with EtOAc. The combined organic phases were dried