Enantioselective Total Synthesis of Wieland-Gumlich Aldehyde and (-)-Strychnine

Article abstract of DOI:10.1002/(SICI)1521-3765(20000218)6:4<655::AID-CHEM655>3.0.CO;2-6

A total synthesis of (-)-strychnine in 15 steps from 1,3-cyclohexanedione in 0.15% overall yield is described. The sequence followed in the assembling of rings is: E → AE [2-(2-nitrophenyl)-1,3-cyclohexanedione] → ACE (3a-aryloctahydroindol-4-one) → ACDE (arylazatricyclic core) → ABCDE (strychnan skeleton) → ABCDEF (Wieland-Gumlich aldehyde) → ABCDEFG (strychnine). The key steps of the synthesis are the enantioselective construction of the 3a-(2-nitrophenyl)-octahydroindol-4-one ring system and the closure of the piperidine ring by a reductive Heck cyclization to generate the pivotal intermediate (-)-14. In contrast, a Lewis acid promoted α-alkoxy-propargylic silane-enone cyclization did not lead to synthetically useful azatricyclic ACDE intermediates. The introduction of C-17 and the closure of the indoline ring by reductive amination of the α-(2-nitrophenyl) ketone moiety complete the strychnan skeleton from which, via the Wieland-Gumlich aldehyde, the synthesis of (-)-strychnine is achieved.

Full text of DOI:10.1002/(SICI)1521-3765(20000218)6:4<655::AID-CHEM655>3.0.CO;2-6

FULL PAPER
Enantioselective Total Synthesis of Wieland ± Gumlich Aldehyde
and ( )-Strychnine
Daniel SoleÂ, Josep Bonjoch,* Silvina García-Rubio, Emma PeidroÂ, and Joan Bosch*[a]
Abstract: A total synthesis of ( )-
strychnine in 15 steps from 1,3-cyclo-
hexanedione in 0.15% overall yield is
described. The sequence followed in the
assembling of rings is: E ! AE [2-(2-
of the synthesis are the enantioselective
construction of the 3a-(2-nitrophenyl)-
octahydroindol-4-one ring system and
the closure of the piperidine ring by a
reductive Heck cyclization to generate
the pivotal intermediate ( )-14. In con-
trast, a Lewis acid promoted a-alkoxy-
propargylic silane-enone cyclization did
not lead to synthetically useful azatricy-
clic ACDE intermediates. The introduc-
tion of C-17 and the closure of the
indoline ring by reductive amination of
the a-(2-nitrophenyl) ketone moiety
complete the strychnan skeleton from
which, via the Wieland ± Gumlich alde-
hyde, the synthesis of ( )-strychnine is
achieved.
nitrophenyl)-1,3-cyclohexanedione]
!
ACE (3a-aryloctahydroindol-4-one) !
ACDE (arylazatricyclic core)
!
Keywords: alkaloids ´ natural prod-
ucts ´ nitrogen heterocycles ´ palla-
dium ´ total synthesis
ABCDE (strychnan skeleton) ! ABC-
DEF (Wieland ± Gumlich aldehyde) !
ABCDEFG (strychnine). The key steps
general and flexible synthetic entry to the Strychnos alka-
loids,[11] involving the elaboration of the indole nucleus in the
last synthetic steps. Our synthesis utilizes a common hexahy-
droindolone intermediate 2 (see Scheme 2), which incorpo-
rates a latent indole ring (the nitrophenyl ketone moiety) and
has the required functionality (an enone) for the closure of the
piperidine D ring. The versatility of this strategy lies in the fact
that, depending on the functionality present in the substituent
on the nitrogen, closure of the piperidine ring (bond formed
C-15/C-20) can be effected by different methodologies to give
azapolycyclic compounds bearing different piperidine sub-
stituents, which can be further elaborated into the variety of
two-carbon substituents present at C-20 in Strychnos alka-
loids. In fact, we have employed three different procedures
for the closure of the bridged piperidine D ring: i) an
intramolecular Michael-type conjugate addition;[11a,e] ii) a
Ni(COD)2-promoted biscyclization,[11b,c,e] and iii) an intramo-
lecular cyclization of an enone-propargylic silane system[11d,e]
(Scheme 2). As the key hexahydroindolone 2 is also accessible
in nonracemic form as a result of the prochiral character of its
Introduction
The classical total synthesis of strychnine by Woodward[1] in
1954 represented a milestone in the field of organic synthesis.
Considering its molecular weight, strychnine is one of the
most complex natural products: only twenty-four skeletal
atoms are assembled in seven rings, resulting in six stereo-
genic centers five of them in the core cyclohexane ring.
Probably because of its complexity, and also its pharmaco-
logical and extremely toxic properties,[2] strychnine has always
fascinated synthetic organic chemists,[3] although it was not
revisited until almost forty years after the first synthesis.[4]
Five research groups have succeeded in synthesizing this
mythical molecule in recent years, either via isostrychnine[5] or
via the Wieland ± Gumlich aldehyde[6] (Scheme 1).[7] Two of
those syntheses[6c,d] have culminated in the enantioselective
total synthesis of the natural enantiomer ( )-strychnine.[8]
In fact, strychnine is probably the most representative of
the Strychnos alkaloids,[9] a broad group of indole alkaloids,
most of them with a common pentacyclic ABCDE skeleton, a
two-carbon chain at C-20, and an oxidized one-carbon
substituent at C-16.[10] Taking advantage of these common
structural features during the last decade we have developed a
precursor,
a 2-allyl-2-aryl-1,3-cyclohexanedione, our ap-
proach also makes possible the enantioselective synthesis of
Strychnos alkaloids.[11e, 12]
The application of the above strategy to the enantioselec-
tive synthesis of strychnine requires the construction of a
pentacyclic ABCDE system bearing substituents at C-16 and
C-20 with the appropriate functionality for the building of the
two additional rings at the final stages of the synthesis. We
detail here our studies in this context, which have culminated
in a new, short synthesis of ( )-strychnine from the 3aR,7aS
enantiomer of the key intermediate 2.[8]
Â
[a] Prof. Dr. J. Bonjoch, Prof. Dr. J. Bosch, Dr. D. Sole,
Â
Dr. S. García-Rubio, E. Peidro
Laboratory of Organic Chemistry
Faculty of Pharmacy, University of Barcelona
Av. Joan XXIII s/n, 08028-Barcelona (Spain)
Fax : (‡ 34)93-4021896
E-mail: bonjoch@farmacia.far.ub.es, jbosch@farmacia.far.ub.es
Chem. Eur. J. 2000, 6, No. 4
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655

J. Bonjoch, J. Bosch et al.
FULL PAPER
on the synthesis of this aldehyde.
Consequently, we needed to in-
stall a hydroxyethylidene sub-
stituent with an E stereochemis-
try at the piperidine 3-position
(C-20) during the closure of the
piperidine ring and introduce a
formyl substituent at C-16. Two
of the methodologies we had
explored for the closure of the
piperidine D ring of Strychnos
alkaloids seemed to be promis-
ing a priori for the stereoselec-
tive elaboration of C-20 E-con-
figurated double bond: the intra-
molecular conjugate addition of
a propargylic silane upon an
enone and the metal-promoted
cyclization of a vinyl iodide upon
an alkene. Initially, we planned
to take advantage of the former
methodology. Thus, the use of a
propargylic silane 3 bearing an
a-alkoxy substituent would gen-
erate an alkoxyvinylidene side
chain (i.e., A)[14] that could be
further elaborated into the re-
quired 20(E)-hydroxyethylidene
substituent (Scheme 3).
H
N
H
N
O
O
Woodward (1954)
OR
N
H
N4-C21
I
Isostrychnine
N
H
C15-C20
O
Bn
H
5
X
Y
Rawal (1994)
N
N4
6
C
H
21
20
3
D
7
A
B
N
E
15
N
H
H
H
CO2Me
OR
O
O
N
H
Kuehne (1993, 1998)
H
I
Strychnine (1)
N4-C21
N
H
CO2Me
CO2Me
C15-C20
Wieland-Gumlich aldehyde
N
Stork (1992)
O
C3-C7
C3-C7
and C5-C6
O
N
H
H
CH2
+
N
CO2Me
OR
H
N
H
Magnus (1992)
I
HO
NR2
O
NO2
H
OtBu
this work
Overman (1993)
Scheme 1. Previous syntheses of strychnine.
To develop this approach we focused our attention on the
bicyclic propargylic silanes 3a and 3b (see Scheme 5), which
should be easily accessible by alkylation of 2 with propargylic
halides 7a and 7b, respectively. These alkylating agents were
prepared as outlined in Scheme 4. Reaction of 4-[(tert-
butyldimethylsilyl)oxy]-2-butynal (4)[15] with tris(trimethylsi-
lyl)aluminum etherate resulted in an efficient transfer of a
nucleophilic trimethylsilyl group[16] by 1,2-addition to the
aldehyde; this affords an a-silyl aluminum alkoxide[17] which
was trapped in situ with either acetic anhydride or (methoxy-
methyl)chloride (MOMCl) to provide a-alkoxypropargylic
silanes 5a,b. Selective removal of the TBDMS protecting
group by treatment with 10-camphorsulfonic acid (CSA),[18]
followed by reaction of the resulting propargylic alcohols 6a,b
with methyltriphenoxyphosphonium iodide gave the corre-
sponding iodides 7a,b.
Alkylation of racemic hexahydroindolone 2[11e, 19] with
propargylic iodides 7a,b afforded the required enone-prop-
argylic silane derivatives 3a,b. However, contrary to our
interests, although the expected closure of the piperidine ring
did occur on treatment of 3a,b with Lewis acids, the desired
20-vinylidene derivatives Awere not obtained; three different
products, alcohol 8, ketone 9, and cyclopropane 10,[20] were
isolated from the reaction mixtures instead. The outcome of
the cyclization was slightly different depending on the Lewis
acid employed (Scheme 5, Table 1). Starting from 3a, the best
overall yields were obtained using BF3 ´ Et2O: Alcohol 8 was
formed as the major product along with variable amounts of
ketone 9. Increasing reaction temperatures resulted in the
formation of considerable amounts of cyclopropane 10. The
Results and Discussion
Initial plans and results: the propargylic silane approach
Bearing in mind the known easy conversion of Wieland ±
Gumlich aldehyde to strychnine,[13] we focused our attention
Abstract in Spanish: Se describe la síntesis total de la ( )-
estricnina a partir de la 1,3-ciclohexanodiona mediante un
proceso de 15 etapas sintØticas con un rendimiento global del
0.15%. La estrategia sintØtica utilizada implica la siguiente
secuencia de ensamblaje de anillos: E ! AE [2-(2-nitrofenil)-
1,3-ciclohexanodiona] ! ACE (3a-ariloctahidroindol-4-ona)
Â
! ACDE (nucleo arilazatricíclico) ! ABCDE (esqueleto de
estricnano) ! ABCDEF (aldehído de Wieland ± Gumlich) !
ABCDEFG (estricnina). Las etapas clave de la síntesis son la
Â
construccion enantioselectiva del sistema de 3a-(2-nitrofenil)-
octahidroindol-4-ona y el cierre del anillo de piperidina para
generar el intermedio azatricíclico clave ( )-14, que se realiza
Â
mediante una ciclacion de Heck reductiva. En cambio, una
Â
ciclacion intramolecular a-alcoxipropargilsilano-enona pro-
movida por acidos de Lewis no condujo a intermedios
azatricíclicos ACDE de interØs sintØtico. La introduccion del
carbono C-17 y el cierre del anillo de indolina mediante
Â
Â
Â
Â
aminacion reductiva de la agrupacion de a-(2-nitrofenil)
cetona completan el esqueleto de estricnano, a partir del cual,
a travØs del aldehído de Wieland ± Gumlich, se accede a la ( )-
estricnina.
656
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Chem. Eur. J. 2000, 6, No. 4

Total Synthesis of ( )-Strychnine
655±665
O
H
N
Michael
N
N
H
H
cyclization
O
NO2
O
H
O
NO2
Ni0-promoted
double cyclization
H
H
H
C
E
N
H
N
N
D
20
I
A
B
N
H
R2
N
16
H
H
O
O
N
NO2
NO2
R1
2
Strychnos alkaloids
Addition of a
propargylic silane
H
N
H
SiMe3
.
O
NO2 O
NO2
H
Scheme 2. Synthesis of Strychnos alkaloids.
SiMe3
(7a,b)
N
H
N
H
SiMe3
OR
N
H
SiMe3
OR
Strychnine
OR
I
2
.
K2CO3, 2-butanone
O
NO2
O
NO2
H
O
NO2
OR
A
3
a R = Ac
b R = MOM
3a,b
Scheme 3. First synthetic approach to strychnine.
MLm
H
N
H
N
O
H
OTBDMS
OTBDMS
RO
a
.
+
SiMe3
Me3Si
5
4
NO2
O
NO2
O
H
H
A
OR
MLn
OR
1,2-silyl shift
H2O
OH
I
RO
Me3Si
RO
b
c
H
H
N
N
N
Me3Si
6
7
O
SiMe3
OR
a R = Ac
NO2
O
O
NO2
O
+
H
path b
path a
b R = MOM
9
OAc
MLn
Scheme 4. Synthesis of propargylic iodides 7a and 7b. a) (Me3Si)3Al ´
Et2O, Et2O/pentane, 788C, then Ac2O, 4-DMAP, 258C, 57%, or MOMCl,
DIPEA, 258C, 30%; b) CSA, CH2Cl2/MeOH, 258C, 53% (6a), 63% (6b);
path a
path b
H
‡
c) (PhO)3P MeI , DMF, 08C, 82%.
H
N
H
SiMe3
NO2
NO2
O
H
H
SiMe3
use of TiCl4 gave alcohol 8 as the only product, although in
lower yields (26 ± 33%), whereas EtAlCl2 led to complex
mixtures from which cyclopropane 10 was isolated as the
major product. On the other hand, treatment of propargylic
silane 3b with BF3 ´ Et2O afforded alcohol 8 (55%) as the only
identifiable product.
H
10
AcO
8
OH
H
Scheme 5. Lewis acid-promoted cyclization of propargylic silanes 3a and
3b.
The unexpected course of the Lewis acid-promoted cycli-
zation of propargylic silanes 3a,b can be rationalized as
outlined in Scheme 5. Instead of the expected desilylation
leading to allene A, the vinylic carbocation generated in the
conjugate addition of the propargylic silane to the enone
moiety undergoes a rapid 1,2-silyl shift to give a more stable
allylic a-oxycarbocation, which can follow two competing
reaction pathways. Intramolecular nucleophilic attack of the
Table 1. Lewis acid-promoted cyclizations of propargylic silanes 3a,b.
Entry
Propargylic silane
Lewis acid
Solvent
T [8C]
t [h]
8 [%]
9 [%]
10 [%]
1
2
3
4
5
6
3a
3a
3a
3a
3a
3b
BF3 ´ Et2O[a]
BF3 ´ Et2O[a]
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
CH2Cl2
25
reflux
25
80
60
20
5
3
2
1
53 ± 57
42
33
26
±
8 ± 16[c]
±
20
±
±
10 ± 20
±
10[c]
±
[b]
TiCl4
TiCl4
[b]
±
< 5
±
[a, d]
EtAlCl2
BF3 ´ Et2O[a]
25
20
55
[a] 4 equiv. [b] 6 equiv. [c] Trace amounts of the C20 epimer. [d] Complex reaction mixture.
Chem. Eur. J. 2000, 6, No. 4
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J. Bonjoch, J. Bosch et al.
FULL PAPER
enolate on the less substituted end of the allylic cation (path
a), with subsequent hydrolysis of the ester or ether function
during the work up yields cyclopentanol 8.[21] Alternatively,
nucleophilic attack of the enolate on the more substituted end
of the allylic cation (path b) leads directly to cyclopropane 10.
Diketone 9 presumably arises from the presence of adventi-
tious water during the reaction.
ble 2) did not afford cyclized products bearing the C-16
methoxycarbonyl group; only ester 13 resulting from methoxy-
carbonylation of the initially formed vinyl palladium inter-
mediate was isolated, although in low yield. Unfortunately,
under the above conditions, cyclization was not fast enough to
compete with direct carbonylation. On the other hand, when
the reaction was carried out in the presence of LiCN[24b] as the
trapping agent (entry 4, Table 2), the azatricyclic com-
pound 14, which lacks the C-16 substituent, was the only
isolable compound. Using methyl acrylate[24c] in order to
introduce a three-carbon substituent at C-16 gave complex
reaction mixtures, from which the N-unsubstituted amine 2
was isolated together with small amounts of 14 (entry 5,
Table 2).
Although the Pd-promoted tandem cyclization-cross cou-
pling processes involving the interception of s-alkylpalladium
intermediates with vinylic stannanes have been described,[24d]
treatment of 11 with the Pd catalyst in the presence of
tributylvinyltin did not afford the desired product; only
azatricyclic compound 14 and diene 15, formed by a prema-
ture intermolecular cross-coupling reaction, could be isolated
from the reaction mixtures (entries 6 ± 8, Table 2).
The intramolecular Heck-type reaction: completion of the
CDE core
In light of the above results we turned our attention to a more
direct strategy for the introduction of the hydroxyethylidene
substituent, consisting in the Pd-catalyzed cyclization of a
vinylic iodide upon the enone moiety (Scheme 6). Intra-
molecular coupling reactions of vinyl halides with alkenes
OR
N
H
H
N
I
Pd0
O
NO2
NO2
O
H
Pd
OR
11 R = TBDMS
B
I
Besides the relatively small difference between cyclization
and direct coupling rates, the main problem seemed to be the
failure of the trapping agent to intercept the s-alkylpalladium
intermediate B. It should be noted that a critical difference
between the previously reported successful tandem cycliza-
tion-capture processes[24] and the process depicted in
Scheme 6 is that the intermediate B is not a simple s-
alkylpalladium complex but is actually the keto tautomer of a
palladium enolate.[26] In this context, it is known that in the
Heck reaction with electron deficient olefins two competing
reaction pathways can operate,[27] namely substitution (in-
volving b-H elimination) and 1,4-conjugate addition (involv-
ing reduction of the s-alkylpalladium intermediate), the latter
being a variant of the Heck reaction that has received
comparatively little attention from the synthetic stand-
point.[28] In fact, azatricyclic compound 14 can be envisaged
as the 1,4-conjugate addition product. For this reason, we
decided to take advantage of this Pd-promoted reductive
cyclization and introduce the functionalized C-17 carbon
atom later in a subsequent synthetic step.
quencher
N
H
Strychnine
NO2
O
H
Q = CO2Me
Q
OR
CH=CH-CO2Me
CH=CH2
Scheme 6. Second synthetic approach to strychnine.
have proved to be useful for the closure of the piperidine ring
of Strychnos alkaloids (bond formed C-15/C-20), in a process
resulting in the stereoselective incorporation of an exocyclic
E-ethylidene[22] or E-hydroxyethylidene[23] double bond at
C-20. Our intention was to take advantage of a tandem Pd-
promoted cyclization-capture process that would allow both
the closure of the hydroxyethylidene-bearing piperidine ring
and the introduction of an appropriate substituent at C-16.
Thus, we expected that the transient alkylpalladium inter-
mediate B arising from the cyclization, with no b-hydrogen
available for b-elimination, would be stable enough to be
intermolecularly trapped with a suitable quencher.[24]
The required 3a-arylhexahy-
Although there is some controversy[29] about the nature of
the reducing agent in the reductive form of the Heck reaction,
tertiary amines with a-hydrogen atoms such as Et3N are
assumed to be the reductants in most cases.[30] After consid-
droindol-4-one (11) was pre-
pared by alkylation of racemic
OR
OR
Br
N
H
H
N
(12)
I
see Table 2
I
2[19] with allylic bromide 12.[25]
Disappointingly, all attempts to
promote a tandem cyclization-
capture process from 11 under a
variety of experimental condi-
tions failed (Scheme 7 and Ta-
ble 2). Thus, treatment of 11
with several Pd catalysts at 1 ±
3 atm of CO[24a] in the presence
of MeOH (entries 1 ± 3, Ta-
2
K2CO3, LiI, CH3CN
(74%)
O
NO2
NO2
O
N
H
11
14
OR
R = TBDMS
OR
OR
OR
N
H
N
H
H
CO2Me
O
O
O
NO2
NO2
NO2
13
15
16
Scheme 7. Pd-promoted cyclization of vinyl iodide 11.
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Chem. Eur. J. 2000, 6, No. 4

Total Synthesis of ( )-Strychnine
655±665
Table 2. Pd-promoted cyclizations of vinylic iodide 11.
Entry
1
Catalyst (equiv)
Pd(PPh3)4 (1)
Additives (equiv)
Solvent (ratio)
T [8C] (t [h])
Products[%]
CO[a]
MeOH (8), TEA (2)
CO[b]
MeOH (8), Et4NCl (2)
CO[b], TEA (4)
C6H6/CH3CN
1:1
C6H6
100 (4.5)
13 (36)
2
3
4
5
6
7
8
Pd(OAc)2 (0.5)
PPh3 (1)
Cl2Pd(PPh3)2 (0.5)
80 (1)
90 (5)
80 (24)
82 (1)
80 (4)
66 (2)
90 (2)
13 (30)
13 (20)
14 (5)
MeOH/DMF
1:2
C6H6
Pd(OAc)2 (0.5)
PPh3 (1)
Pd(PPh3)4 (0.5)
LiCN (3.6)
ˆ
CH2 CHCO2Me (5)
CH3CN
C6H6
2 (45)
14 (5)
TEA (2)
ˆ
Pd(OAc)2 (0.5)
PPh3 (1)
Pd(PPh3)4 (0.5)
Bu3SnCH CH2 (1.2)
14 (15)
15 (42)
14 (35)
15 (47)
2 (20)
14 (5)
15 (15)
14 (56)
Ag2CO3 (2)
ˆ
Bu3SnCH CH2 (1.1)
CuI (1)
THF
ˆ
Pd(OAc)2 (0.5)
Bu3SnCH CH2 (1.1)
DMF
TBACl (1.2)
DIPEA (2.5)
none
9
10
11
12
13
14
15
Pd(OAc)2 (0.5)
PPh3 (1)
Pd(OAc)2 (0.3)
PPh3 (0.6)
Pd(OAc)2 (0.4)
PPh3 (0.8)
Pd(OAc)2 (1)
PPh3 (2)
Pd(OAc)2 (0.5)
PPh3 (1)
(CH3CN)2PdCl2 (0.5)
PPh3 (1)
Pd(OAc)2 (0.5)
PPh3 (1)
TEA
TEA
DIPEA
THF[c]
THF
90 (0.5)
90 (1)
none
14 (53)
14 (46)
14 (43)
14 (42)
none
95 (5)
TEA (2)
TEA (2)
Bu3SnH (1.1)
Et3SiH (1.1)
66 (1.5)
66 (27)
80 (1)
C6H6
14 (15)
16 (43)
14 (13)
16 (30)
THF
66 (1)
[a] 3 atm. [b] 1 atm. [c] The use of other solvents resulted in lower yields of 14: DMF, 10%; CH3CN, 29%.
erable experimentation, optimum conditions for the cycliza-
tion of 11 were found with the use of Pd(AcO)2 and PPh3 as
the catalyst in Et3N at 908C (entries 9 and 10, Table 2). Under
these conditions the intramolecular Pd-catalyzed (0.3 equiv)
conjugate addition of 11 (entry 10, Table 2) afforded the
azatricyclic derivative 14 in acceptable yield (53%). Bases
and solvents other than Et3N were also examined. DIPEAwas
less efficient from the synthetic standpoint and gave the best
result (46%) when operating with 0.4 equiv of Pd(AcO)2
(entry 11, Table 2). Although the cyclized product 14 could
also be obtained in acceptable yield in THF containing Et3N
(entries 12 and 13, Table 2), other solvents such as DMF or
CH3CN gave very low yields. The use of K2CO3, Ag2CO3, and
NaOAc as the base in different solvents resulted in worse
yields. Finally, the use of Bu3SnH[31] (entry 14, Table 2) or
Et3SiH[32] (entry 15, Table 2) as reductants[33] resulted in the
formation of the uncyclized reduced product 16 and the
desired azatricyclic compound 14; this gives evidence once
again that cyclization was not fast enough to compete with the
premature capture of the vinylpalladium intermediate.
The retention of the stereochemistry at the C-20 double
bond after the Pd-catalyzed ring closure was inferred
from the 13C NMR chemical shifts of C-15 (d 31.0) and C-21
(d 54.3) in 14. These values are in agreement with an E
configuration for the O-protected hydroxyethylidene chain as
they are indicative of the steric interaction between C15-H
(but not C21-H) and the bulky tert-butyldimethylsilyloxy-
methyl group.
The total synthesis of ( )-strychnine
Once a convenient procedure for the incorporation of the E-
hydroxyethylidene chain at the piperidine 3-position in the
racemic series was established, synthesizing enantiopure 14,
with the natural configuration at the stereogenic centers was
simply a matter of starting from the appropriate enantiopure
vinyl halide 11. This compound was obtained in enantioen-
riched form as outlined in Scheme 8, taking advantage of the
short procedure we had developed for the preparation of cis-
3a-(2-nitrophenyl)octahydroindol-4-ones, consisting in the
ozonolysis of 2-allyl-2-aryl-1,3-cyclohexanedione (17), fol-
lowed by a double reductive amination from the resulting
diketo aldehyde.[34] The use of a-(S)-methylbenzylamine as
the aminocyclization agent resulted in the generation of the
chiral nonracemic octahydroindolone ( )-18 (97:3 mixture of
cis diastereomers) in 37% yield.[11e] N-Dealkylation of ( )-18
via a urethane, generation of the enone moiety via a seleno
derivative, and, finally, alkylation with the allylic bromide 12
afforded the enantioenriched vinyl halide ( )-11. The overall
yield from ( )-18 (six steps) was 27%.
Reductive Heck-type cyclization of ( )-11, under the best
conditions found in the racemic series (entry 9, Table 2),
afforded ( )-14, from which the oxidized C-17 was introduced
by methoxycarbonylation of the corresponding enolate with
methyl cyanoformate (67% yield). The resulting b-keto ester
(‡)-19, which exists in enol form, contains all the strychnine
carbons except the two derived from acetate. To complete the
Chem. Eur. J. 2000, 6, No. 4
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0947-6539/00/0604-0659 $ 17.50+.50/0
659

J. Bonjoch, J. Bosch et al.
FULL PAPER
adjustment of the oxidation level by partial reduction of ester
21 with DIBAH in toluene at 408C afforded the Wieland ±
Gumlich aldehyde.[37, 38]
Ph
CH3
O
O
N
H
H
d
a-c
Although the conversion of the Wieland ± Gumlich alde-
hyde to strychnine had been reported many years ago[13] and
there would therefore seem to be little need to repeat it, we
reproduced the described protocol for the sake of completion
and thus achieved the enantioselective total synthesis of the
natural product. The resulting ( )-strychnine was identical to
a natural specimen, as determined by TLC as well as IR,
1H NMR, and 13C NMR spectroscopy. The [a]2D5 value was
O
NO2
NO2
O
HO
(-)-18
17
e-i
H
N
Cl-
OR1
H
H
N
H
+
j
I
O
O
NO2
NO2
119.4 (c ˆ 0.35 in CHCl3) [lit[13] [a]D25
ˆ
139 (c ˆ 2.0 in
(-)-11
R
1 = TBDMS
CHCl3)], which represents 86% ee.[39]
k
In summary, we have completed a short enantioselective
synthesis of ( )-strychnine (15 steps from commercially
available 1,3-cyclohexanedione in 0.15% overall yield). The
synthesis proceeds via the Wieland ± Gumlich aldehyde and
starts from the prochiral dione 17 (which preforms the A and
E rings of strychnine), from which the pyrrolidine, piperidine,
and indoline rings are successively built in three well-differ-
entiated phases: i) generation of the first chiral nonracemic
intermediate, the 3a-(2-nitrophenyl)octahydroindol-4-one
[( )-18], which contains the crucial quaternary C-7 center;
ii) closure of the piperidine ring by a reductive Heck-type
cyclization that ensures the stereoselective incorporation of
the C-20 E-configurated double bond; and iii) closure of the
indoline ring in an advanced synthetic stage by reductive
cyclization of the a-(2-nitrophenyl) ketone moiety. In con-
junction with our previous work,[11] the synthesis of strychnine
reported here makes evident not only the usefulness of our
strategy for the enantioselective synthesis of Strychnos
alkaloids but also how the use of common synthetic inter-
mediates can provide a flexible access to a large number of
structurally related natural products.
H
N
H
N
m
16
N
H
NO2
O
H
H
H
OH
R2
(-)-14 R2 = H
(+)-19 R2 = CO2Me
OR1
CO2Me
20 (H-16β)
21 (H-16α)
n
l
o
H
N
N
H
p
H
N
H
HO
N
H
H
H
H
O
O
O
H
Strychnine (1)
Wieland-Gumlich
aldehyde
Scheme 8. Enantioselective synthesis of ( )-strychnine. a) 2-IC6H4NO2,
K2CO3, DMSO, 85 ± 908C, 72%; b) BrCH2CH CH2, K2CO3, acetone,
reflux, 85%; c) toluene, sealed tube, 180 ± 1908C, 80%; d) O3, CH2Cl2,
788C, then (S)-PhCH(CH3)NH2 ´ HCl, NaBH3CN, iPrOH, 37%;
e) ClCO2CHClCH3, 1358C, 72%; f) HN(SiMe3)2, Me3SiI, CH2Cl2/pentane
1:1, 208C; g) PhSeCl, (PhSe)2, THF, 70%; h) O3, CH2Cl2, 788C, then
ˆ
ˆ
iPr2NH, 72%; i) MeOH, reflux; j) (Z)-BrCH2CI CHCH2OTBDMS (12),
K2CO3, LiI, CH3CN, 508C, 74%; k) Pd(OAc)2, PPh3, Et3N, 908C, 53%;
l) LiN(SiMe3)2, HMPA, THF, 788C, then NCCO2Me, 67%; m) Zn dust,
H2SO4, MeOH, reflux, 36%; n) NaH, MeOH, reflux, 72%; o) DIBAL-H,
toluene, 408C, 65%; p) CH2(CO2H)2, Ac2O, NaOAc, AcOH, 1108C,
49%.
Experimental Section
General methods: All reactions were carried out under an argon
atmosphere with dry, freshly distilled solvents under anhydrous conditions.
All commercially available reagents were used without further purification.
TLC was carried out on SiO2 coated glass plates (silica gel 60 F254, Merck),
and the spots were located with UV light, iodoplatinate reagent or 1%
aqueous KMnO4. Chromatography refers to flash chromatography and was
carried out on SiO2 (silica gel, SDS, 230 ± 400 mesh ASTM). Unless
otherwise noted, drying of organic extracts during workup of reactions was
performed over anhydrous Na2SO4. Evaporation of solvents was accom-
plished with a rotatory evaporator. Optical rotations were recorded with a
Perkin ± Elmer 241 polarimeter. 1H NMR and 13C NMR spectra were
recorded with a Varian 300 or a Varian VXR-500 instrument. Chemical
shifts are reported in ppm downfield from Me4Si. IR spectra were recorded
on a Nicolet 205 FT-IR spectrophotometer, and only noteworthy absorp-
tions are listed. Microanalyses and HRMS were performed by Centro de
synthesis of the Wieland ± Gumlich aldehyde only the closure
of the indoline ring and the reduction of the ester group to an
aldehyde remained to be done. The reductive cyclization of
the a-(2-nitrophenyl) ketone moiety was satisfactorily accom-
plished by treatment of (‡)-19 with zinc dust in 10%
methanolic sulfuric acid. Under the reaction conditions, that
also caused the removal of the TBDMS protecting group, the
initially formed anilinoacrylate intermediate undergoes fur-
ther reduction to an epimeric mixture of esters 20 and 21
(ratio approximately 9:1). This mixture was equilibrated to
pure 21, which has the natural, most stable stereochemistry at
C-16, by treatment with NaH in refluxing MeOH. The
pentacyclic ester 21[35] was isolated in 26% overall yield from
(‡)-19. The relative configuration at C-16 in esters 20 and 21
was clearly determined from the vicinal coupling constant
between H-15 and H-16, which is larger (J ˆ 9.9 Hz) in ester
21, with the natural H-15/H-16 cis strychnine stereochemistry,
than in 20 (H-15/H-16 trans, J ˆ 3.7 Hz).[36] Finally, further
Â
Investigacion y Desarrollo (CSIC), Barcelona.
4-[(tert-Butyldimethylsilyl)oxy]-1-(trimethylsilyl)-2-butynyl acetate (5a):
Tris(trimethylsilyl)aluminum etherate[16b] (11.7 mmol, 37 mL of 0.32m
solution in pentane) was added dropwise to a cooled ( 788C) solution
of 4-[(tert-butyldimethylsilyl)oxy]-2-butynal[15] (4, 2 g, 11.7 mmol) in Et2O
(20 mL). After the solution was stirred at 788C for 1 h, Ac2O (5.9 mL,
62 mmol), and a catalytic amount of 4-DMAP were added. The mixture
was stirred at room temperature for 16 h, poured into an ice-cold saturated
aqueous sodium potassium tartrate solution, and extracted with Et2O. The
organic layer was washed with saturated aqueous sodium potassium
660
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0947-6539/00/0604-0660 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 4

Total Synthesis of ( )-Strychnine
655±665
tartrate solution, dried and concentrated, and the residue was purified by
chromatography (from hexane to 97:3 hexane/EtOAc) to give 5a (2.1 g,
57%). 1H NMR (300 MHz, CDCl3): d ˆ 5.21 (s, 1H; CHOAc), 4.36 (s, 2H;
CH2O), 2.01 (s, 3H; CH3), 0.90 (s, 9H; C(CH3)3), 0.14 (s, 9H; Si(CH3)3),
0.11 (s, 6H; Si(CH3)2); 13C NMR (75 MHz, CDCl3): d ˆ 170.6 (CO), 86.4
(C), 81.6 (C), 58.2 (CHOAc), 51.8 (CH2O), 25.7 ((CH3)3), 20.8 (CH3), 18.2
(C), 4.0 (Si(CH3)3), 5.2 (Si(CH3)2); IR (film): nÄ ˆ 1747, 1252, 1228,
1 mmol) and anhydrous K2CO3 (0.14 g, 1 mmol) were added to a solution of
crude racemic hexahydroindolone 2 ´ HCl[11e] (0.2 g, 0.68 mmol) in 2-buta-
none (10 mL). The mixture was heated at reflux for 5 h. The solvent was
removed in vacuo, and the residue was partitioned between H2O and
CH2Cl2. The organic extracts were dried and concentrated, and the
resulting residue was purified by chromatography (from hexane to 1:1
hexane/EtOAc) to give enone 3a (0.2 g, 66%). 1H NMR (300 MHz,
CDCl3): d ˆ 7.80 (d, J ˆ 8.0 Hz, 1H; H-3'), 7.65 ± 7.50 (m, 2H; H-5', H-6'),
7.42 (td, J ˆ 8.0, 1.6 Hz, 1H; H-4'), 6.86 (dm, J ˆ 10.2 Hz, 1H; H-6), 6.19
(dd, J ˆ 10.2, 1.2 Hz, 1H; H-5), 5.13, 5.07 (2t, J ˆ 2.0 Hz, 1H; CHSi), 3.63
(dt, J ˆ 6.3, 2.2 Hz, 1H; H-7a), 3.59 (m, 2H; H-2), 3.20 ± 3.00 (m, 2H; H-3),
2.81 (dm, J ˆ 19.3 Hz, 1H; H-7), 2.60 ± 2.40 (m, 3H; H-7, NCH2), 2.08, 2.06
(2s, 3H; CH3CO), 0.08 ± 0.05 (m, 9H; Si(CH3)3); 13C NMR (75 MHz,
CDCl3): d ˆ 196.7 (C-4), 170.3 and 170.2 (COO), 148.7 (C-2'), 146.0 and
145.9 (C-6), 136.8 and 136.6 (C-1'), 132.5 and 132.4 (C-5), 130.1 and 130.0
(C-5'), 127.9 (C-6'), 127.5 (C-4'), 124.8 and 124.7 (C-3'), 81.9 (C), 81.8 (C),
81.7 (C), 81.6 (C), 65.4 and 65.3 (C-7a), 58.5 (C-3a), 57.8 (CHOAc), 49.8 (C-
1
839 cm ; C15H30O3Si2 (314.6) ´ 1ꢁ4H2O: calcd C 56.46, H 9.63; found C 56.20,
H 9.49.
1-[(tert-Butyldimethylsilyl)oxy]-4-(methoxymethoxy)-4-(trimethylsilyl)-2-
butyne (5b): The title compound was obtained analogous to the prepara-
tion of 5a from the reaction of aldehyde 4 (4 g, 23.5 mmol), tris(trime-
thylsilyl)aluminum etherate (12.1 mmol, 87 mL of 0.14m solution in
pentane), MOMCl (9.3 mL, 122 mmol), and ethyldiisopropylamine
(10.5 mL, 61 mmol), and subsequent chromatography (from hexane to
1
98:2 hexane/EtOAc): 5b (2.24 g, 30%). H NMR (300 MHz, CDCl3): d ˆ
4.92 (d, J ˆ 6.4 Hz, 1H; OCH2O), 4.50 (d, J ˆ 6.4 Hz, 1H; OCH2O), 4.34 (d,
J ˆ 1.8 Hz, 2H; CH2O), 4.07 (t, J ˆ 1.8 Hz, 1H; CHSi), 3.30 (s, 3H; OCH3),
0.87 (s, 9H; C(CH3)3), 0.12 (s, 9H; Si(CH3)3), 0.08 (s, 6H; Si(CH3)2);
13C NMR (75 MHz, CDCl3): d ˆ 94.8 (OCH2O), 86.2 (C), 82.6 (C), 58.5
2), 39.7 (CH2N), 36.4 and 36.1 (C-3), 26.2 and 25.9 (C-7), 20.6 (CH3), 4.3
1
(Si(CH3)3); IR (film): nÄ ˆ 1730, 1673, 1528, 1367 cm
; C23H28N2O5Si
(440.6): calcd C 62.70, H 6.41, N 6.36; found C 62.82, H 6.31, N 6.35.
cis-1-[4-(Methoxymethoxy)-4-(trimethylsilyl)-2-butynyl]-3a-(2-nitrophen-
yl)-1,2,3,3a,7,7a-hexahydroindol-4-one (3b): The title compound was
obtained analogous to the preparation of 3a from 2 ´ HCl (0.3 g, 1 mmol)
and propargylic iodide 7b (0.44 g, 1.5 mmol), and subsequent chromatog-
raphy (from hexane to 1:1 hexane/EtOAc): enone 3b (113 mg, 25%).
1H NMR (300 MHz, CDCl3): d ˆ 7.74 (dd, J ˆ 8.0, 1.5 Hz, 1H; H-3'), 7.58 ±
7.45 (m, 2H; H-5', H-6'), 7.37 (ddd, J ˆ 8.0, 7.0, 1.6 Hz, 1H; H-4'), 6.81 (dm,
J ˆ 10.2 Hz, 1H; H-6), 6.15 (dm, J ˆ 10.2 Hz, 1H; H-5), 4.81, 4.78 (2d, J ˆ
6.4 Hz, 1H; OCH2O), 4.43, 4.42 (2d, J ˆ 6.4 Hz, 1H; OCH2O), 3.98, 3.96
(2t, J ˆ 1.9 Hz, 1H; CHSi), 3.59 (m, 1H; H-7a), 3.55 (m, 2H; H-2), 3.27,
3.26 (2s, 3H; OCH3), 3.16 ± 2.95 (m, 2H; H-3), 2.76 (dm, J ˆ 19.2 Hz, 1H;
H-7) 2.52 ± 2.40 (m, 3H; H-7, NCH2), 0.06 ± 0.03 (m, 9H; Si(CH3)3);
13C NMR (75 MHz, CDCl3): d ˆ 197.0 (C-4), 148.0 (C-2'), 146.2 and 146.1
(C-6), 137.1 (C-1'), 132.7 (C-5), 130.2 (C-5'), 128.3 and 128.1 (C-6'), 127.8 (C-
4'), 125.1 (C-3'), 94.7 (OCH2O), 83.1 (C), 81.3 (C), 65.5 (C-7a), 58.8 (C-3a),
(CHSi), 55.2 (OCH3), 51.8 (CH2O), 25.7 ((CH3)3), 18.2 (C),
(Si(CH3)3), 5.2 (Si(CH3)2); IR (film): nÄ ˆ 1250, 1081, 1032, 838 cm
4.0
1
.
4-Hydroxy-1-(trimethylsilyl)-2-butynyl acetate (6a): A catalytic amount of
10-camphorsulfonic acid was added to a cooled (08C) solution of ester 5a
(2 g, 6.5 mmol) in 1:1 CH2Cl2/MeOH (50 mL). After the solution was
stirred for 1 h at 08C and 1 h at room temperature, the solvent was removed
in vacuo, and the residue was partitioned between saturated aqueous
Na2CO3 and CH2Cl2. The organic layer was dried and concentrated, and the
residue was purified by chromatography (from hexane to 3:2 hexane/
EtOAc) to give 6a (0.69 g, 53%). 1H NMR (300 MHz, CDCl3): d ˆ 5.19 (s,
1H; CHOAc), 4.32 (s, 2H; CH2O), 2.09 (s, 3H; CH3), 1.76 (brs, 1H; OH),
0.14 (s, 9H; Si(CH3)3); 13C NMR (75 MHz, CDCl3): d ˆ 170.9 (CO), 86.3
(C), 82.1 (C), 58.2 (CHOAc), 50.7 (CH2O), 20.7 (CH3), 4.2 (Si(CH3)3); IR
(film): nÄ ˆ 3600 ± 3200, 1748, 1251, 1231, 845 cm 1; HRMS: calcd for
C9H16O3Si: 200.0869; found 200.0876; C9H16O3Si (200.3) ´ 1ꢁ4H2O: calcd C
52.77, H 8.12; found C 52.38, H 7.89.
58.4 (CHO), 55.3 (CH3), 50.1 (C-2), 40.0 (CH2N), 36.8 and 36.6 (C-3), 26.6
1
and 26.5 (C-7), 4.1 (SiCH3); IR (film): nÄ ˆ 1673, 1527, 1355 cm
.
4-(Methoxymethoxy)-4-(trimethylsilyl)-2-butynol (6b): The title com-
pound was obtained analogous to the preparation of 6a from 5b (2 g,
6.3 mmol) and subsequent chromatography (from hexane to 4:1 hexane/
EtOAc): 6b (0.8 g, 63%). 1H NMR (300 MHz, CDCl3): d ˆ 4.94 (d, J ˆ
6.4 Hz, 1H; OCH2O), 4.54 (d, J ˆ 6.4 Hz, 1H; OCH2O), 4.31 (d, J ˆ 1.9 Hz,
2H; CH2O), 4.10 (t, J ˆ 1.9 Hz, 1H; CHSi), 3.34 (s, 3H; OCH3), 1.87 (brs,
1H; OH), 0.15 (s, 9H; Si(CH3)3); 13C NMR (75 MHz, CDCl3): d ˆ 94.8
Lewis acid promoted cyclization of 3a: Freshly distilled BF3 ´ Et2O
(0.15 mL, 1.2 mmol) was added dropwise to a cooled (08C) solution of
propargylic silane 3a (130 mg, 0.3 mmol) in CH2Cl2 (15 mL). After the
solution was stirred for 22 h at room temperature, the mixture was poured
into saturated aqueous Na2CO3, and extracted with CH2Cl2. The organic
layer was dried and concentrated, and the residue was purified by
chromatography (from CH2Cl2 to 19:1 CH2Cl2/MeOH) to give alcohol 8
(68 mg, 57%) and ketone 9 (10 mg, 8%). When the reaction was carried
out under the conditions of entry 2, Table 1, compound 10 was also isolated
after chromatography.
(OCH2O), 86.1 (C), 83.5 (C), 58.6 (CHSi), 55.3 (OCH3), 51.0 (CH2O), 4.1
1
(Si(CH3)3); IR (film): nÄ ˆ 3600 ± 3200, 1250, 1089, 1031, 846 cm
.
4-Iodo-1-(trimethylsilyl)-2-butynyl acetate (7a): Methyltriphenoxyphos-
phonium iodide (3.39 g, 7.5 mmol) was added to a cooled (08C) solution
of alcohol 6a (0.75 g, 3.7 mmol) in DMF (35 mL). After the solution
was stirred for 1 h at 08C, the reaction was quenched by addition of
MeOH (1 mL). The mixture was diluted with Et2O and washed with
saturated aqueous Na2S2O3 and brine. The organic layer was dried and
concentrated, and the residue was purified by chromatography (from
hexane to 9:1 hexane/EtOAc) to give propargylic iodide 7a (0.95 g, 82%).
1H NMR (300 MHz, CDCl3): d ˆ 5.10 (t, J ˆ 2.4 Hz, 1H; CHOAc), 3.74
(d, J ˆ 2.4 Hz, 2H; CH2I), 2.05 (s, 3H; CH3), 0.13 (s, 9H; Si(CH3)3);
13C NMR (75 MHz): d ˆ 170.5 (CO), 84.5 (C), 82.7 (C), 58.3 (CHOAc),
20.8 (CH3), 3.8 (Si(CH3)3), 17.8 (CH2I); IR (film): nÄ ˆ 2240, 1739, 1251,
1229, 845 cm 1; C9H15IO2Si (310.2): calcd C 34.85, H 4.87; found C 34.45,
H 4.86.
(4RS,6SR,7SR,10RS,12SR)-7-Hydroxy-4-(2-nitrophenyl)-8-(trimethylsil-
yl)-1-azatetracyclo[7.3.1.04,12.06,10]tridec-8-en-5-one (8):[40] 1H NMR
(500 MHz, CDCl3): d ˆ 7.67 (dd, J ˆ 8.0, 1.5 Hz, 1H; H-12), 7.55 (ddd,
J ˆ 8.3, 7.0, 1.5 Hz, 1H; H-10), 7.45 (dd, J ˆ 8.3, 1.3 Hz, 1H; H-9), 7.32 (ddd,
J ˆ 8.0, 7.0, 1.3 Hz, 1H; H-11), 5.11 (ddd, J ˆ 5.3, 2.0, 1.0 Hz, 1H; H-18),
3.85 (brs, 1H; H-3), 3.78 (ddd, J ˆ 13.5, 2.0, 1.0 Hz, 1H; H-21a), 3.65 (td,
J ˆ 13.0, 6.5 Hz, 1H; H-5a), 3.35 (d, J ˆ 13.5 Hz, 1H; H-21b), 3.27 (dd, J ˆ
13.0, 8.5 Hz, 1H; H-5b), 3.09 (t, J ˆ 5.3 Hz, 1H; H-16), 3.03 (brs, 1H;
H-15), 2.85 (ddd, J ˆ 15.0, 3.5, 1.3 Hz, 1H; H-14pro-R), 2.71 (ddd, J ˆ 14.5,
13.0, 8.5 Hz, 1H; H-6b), 2.20 (dd, J ˆ 14.5, 6.5 Hz, 1H; H-6a), 2.16 (ddd,
J ˆ 15.0, 5.0, 3.0 Hz, 1H; H-14pro-S), 0.18 (s, 9H; Si(CH3)3); 13C NMR
(75 MHz, CDCl3): d ˆ 213.8 (C-2), 157.9 (C-19), 148.5 (C-13), 142.8 (C-20),
141.8 (C-8), 133.5 (C-10), 129.6 (C-9), 127.3 (C-11), 124.7 (C-12), 84.1 (C-
18), 70.2 (C-3), 63.9 (C-7), 62.2 (C-16), 59.6 (C-5), 51.9 (C-21), 45.1 (C-6),
41.1 (C-15), 21.0 (C-14), 0.1 (Si(CH3)3); IR (film): nÄ ˆ 3700, 1689, 1678,
1530, 1363 cm 1; HRMS: calcd for C21H26N2O4Si 398.1662; found 398.1654;
C21H26N2O4Si (398.5) ´ 1ꢁ2H2O: calcd C 61.89, H 6.68, N 6.87; found C 61.65,
H 6.50, N 6.49.
4-Iodo-1-(methoxymethoxy)-1-(trimethylsilyl)-2-butyne (7b): The title
compound was obtained analogous to the preparation of 7a from alcohol
6b (0.72 g, 3.6 mmol) and subsequent chromatography (from hexane to
1
97:3 hexane/EtOAc): 7b (0.92 g, 83%). H NMR (300 MHz, CDCl3): d ˆ
4.89 (d, J ˆ 6.4 Hz, 1H; OCH2O), 4.53 (d, J ˆ 6.5 Hz, 1H; OCH2O), 4.06 (t,
J ˆ 2.4 Hz, 1H; CHSi), 3.78 (d, J ˆ 2.4 Hz, 2H; CH2I), 3.33 (s, 3H; OCH3),
0.14 (s, 9H; Si(CH3)3); 13C NMR (75 MHz, CDCl3): d ˆ 95.1 (OCH2O), 84.3
(1RS,2SR,7RS,8SR)-2-(2-Acetoxyacetyl)-7-(2-nitrophenyl)-4-azatricy-
clo[5.2.2.04,8]undecan-11-one (9):[40] 1H NMR (300 MHz, CDCl3): d ˆ 7.54 ±
7.47 (m, 2H; H-10, H-12), 7.38 (td, J ˆ 7.7, 1.3 Hz, 1H; H-11), 7.22 (dd, J ˆ
8.0, 1.5 Hz, 1H; H-9), 4.80 (d, J ˆ 16.8 Hz, 1H; CH2O), 4.57 (d, J ˆ 16.8 Hz,
1H; CH2O), 3.27 ± 2.94 (m; 5H), 3.83 (t, J ˆ 3.0 Hz, 1H; H-3), 2.75 (brs,
1H; H-15), 2.67 (dt, J ˆ 18.0, 2.0 Hz, 1H; H-16), 2.61 ± 2.40 (m; 3H), 2.38
(C), 58.8 (CHSi), 55.3 (OCH3), 3.9 (Si(CH3)3), 17.3 (CH2I); IR (film):
1
nÄ ˆ 2240, 1249, 1029 cm
.
cis-1-[4-Acetoxy-4-(trimethylsilyl)-2-butynyl]-3a-(2-nitrophenyl)-
1,2,3,3a,7,7a-hexahydroindol-4-one (3a): Propargylic iodide 7a (0.32 g,
Chem. Eur. J. 2000, 6, No. 4
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0604-0661 $ 17.50+.50/0
661

J. Bonjoch, J. Bosch et al.
FULL PAPER
(dt, J ˆ 14.0, 3.0 Hz, 1H; H-14), 2.20 (dm, J ˆ 14.0 Hz, 1H; H-14), 2.17 (s,
3H; CH3); 13C NMR (75 MHz, CDCl3): d ˆ 211.5 (C-2), 202.6 (C-19), 170.1
(COO), 150.8 (C-13), 134.0 (C-8), 131.8 (C-10), 129.8 (C-9), 128.0 (C-11),
125.4 (C-12), 66.8 (C-18), 64.9 (C-3), 62.0 (C-7), 54.8 (C-5), 48.5 (C-20), 45.2
removed by filtration, and the filtrate was evaporated to give an oil, which
was purified by chromatography (from hexane to 49:1 hexane/EtOAc) to
yield (Z)-1-bromo-4-[(tert-butyldimethylsilyl)oxy]-2-iodo-2-butene (12,
3.75 g, 50%).[5b] 1H NMR (300 MHz, CDCl3): d ˆ 6.27 (t, J ˆ 5.2 Hz, 1H;
ˆ
(C-21), 41.9 (C-16), 39.4 (C-6), 29.6 (C-15), 26.6 (C-14), 20.3 (CH3); IR
CH), 4.32 (s, 2H; CH2Br), 4.28 (d, J ˆ 5.1 Hz, 2H; CH2OSi), 0.90 (s, 9H;
1
(film): nÄ ˆ 1750, 1725, 1699, 1531, 1366 cm
.
C(CH3)3), 0.09 (s, 6H; Si(CH3)2); 13C NMR (75 MHz, CDCl3): d ˆ 140.5
ˆ
ˆ
( CH), 98.7 ( CI), 68.0 (CH2OSi), 42.3 (CH2Br), 25.8 ((CH3)3), 18.2 (C),
5.2 (Si(CH3)2).
(4RS,6SR,7SR,8RS,10SR)-7-[(E)-2-Acetoxy-1-(trimethylsilyl)vinyl]-4-(2-
nitrophenyl)-1-azatetracyclo[5.3.1.04,10.06,8]undecan-5-one (10):[40] 1H NMR
(300 MHz, CDCl3): d ˆ 7.60 (dd, J ˆ 8.0, 1.4 Hz, 1H; H-12), 7.55 (ddd, J ˆ
8.0, 7.0, 1.4 Hz, 1H; H-10), 7.40 (d, J ˆ 8.0 Hz, 1H; H-9), 7.35 (ddd, J ˆ 8.0,
7.0, 1.4 Hz, 1H; H-11), 7.14 (s, 1H; H-18), 3.57 (d, J ˆ 14.0 Hz, 1H; H-21a),
3.54 (s, 1H; H-3), 3.25 (ddd, J ˆ 12.2, 9.7, 7.7 Hz, 1H; H-5a), 3.01 (ddd, J ˆ
12.2, 7.5, 3.0 Hz, 1H; H-5b), 2.89 (d, J ˆ 14.0 Hz, 1H; H-21b), 2.70 ± 2.60
(m, 2H; H-6b, H-14), 2.55 ± 2.45 (m, 2H; H-6a, H-14), 2.23 ± 2.16 (masked,
1H; H-15), 2.18 (s, 3H; COCH3), 1.96 (d, J ˆ 7.9 Hz, 1H; H-16), 0.22 ± 0.18
(m, 9H; Si(CH3)3); 13C NMR (75 MHz, CDCl3): d ˆ 209.6 (C-2), 167.4
(COO), 150.2 (C-13), 142.5 (C-18), 136.4 (C-8), 132.4 (C-10), 130.3 (C-9),
127.5 (C-11), 124.6 (C-12), 122.8 (C-19), 68.2 (C-3), 60.3 (C-7), 57.9 (C-5),
51.8 (C-21), 44.0 (C-6), 39.2 (C-16), 35.6 (C-20), 24.7 (C-15), 20.8 (CH3),
(3aR,7aS)-N-[(S)-a-Methylbenzyl]-3a-(2-nitrophenyl)octahydroindol-
4-one [( )-18]: This compound was prepared following the previously
reported procedure,[11e] by ozonolysis of 2-allyl-2-(2-nitrophenyl)-1,3-cyclo-
hexanedione (17) and then reaction of the resulting diketo aldehyde with
(S)-a-methylbenzylamine (96% ee) and NaBH3CN.
A 97:3 mixture
(determined by HPLC analysis) of cis-octahydroindolone ( )-18 and the
other cis diastereomer was obtained in 37% yield after column chroma-
tography. A second eluate afforded a 3:1 mixture of the two trans-
octahydroindolones in 8% yield.
(3aR,7aS)-1-{(Z)-4-[(tert-Butyldimethylsilyl)oxy]-2-iodo-2-butenyl}-3a-
(2-nitrophenyl)-1,2,3,3a,7,7a-hexahydroindol-4-one [( )-11]: Chiral non-
racemic tertiary amine ( )-18 was converted to (3aR,7aS)-3a-(2-nitro-
phenyl)-1,2,3,3a,7,7a-hexahydroindol-4-one hydrochloride as previously
reported.[11e] To a solution of this crude hydrochloride (0.4 g, 1.36 mmol)
in CH3CN (20 mL) were added anhydrous K2CO3 (0.38 g, 2.74 mmol),
allylic bromide 12 (1.07 g, 2.74 mmol), and a catalytic amount of LiI. The
mixture was stirred at 508C for 3 h. The solvent was removed in vacuo, and
the residue was partitioned between H2O and CH2Cl2. The organic layer
was washed with water, dried, and concentrated. Purification by chroma-
18.8 (C-14),
0.31 (Si(CH3)3); IR (film): nÄ ˆ 1762, 1688, 1681, 1533,
1366 cm 1; HRMS: calcd for C23H28N2O5Si 440.1768; found 440.1777;
C23H28N2O5Si (440.6) ´ 1.75H2O: calcd C 58.52, H 6.73, N 5.93; found C
58.45, H 6.33, N 5.89.
(Z)-1-Bromo-4-[(tert-butyldimethylsilyl)oxy]-2-iodo-2-butene (12): A sol-
ution of 4-(tetrahydropyran-2-yloxy)-2-butynol[41] (5.38 g, 31.6 mmol) in
Et2O (20 mL) was added dropwise to a cooled (08C) solution of RedAl
(53.7 mmol, 15.5 g of 70% solution in toluene) in Et2O (40 mL). The
resulting solution was slowly warmed to room temperature. The excess of
RedAl was destroyed by addition of AcOEt (1 mL). The mixture was
cooled to 788C, a solution of I2 (10 g, 39.4 mmol) in THF (20 mL) was
added dropwise, and the resulting solution was allowed to warm slowly to
room temperature. The mixture was poured into saturated aqueous sodium
potassium tartrate solution and extracted with Et2O. The organic extracts
were washed with saturated aqueous Na2S2O3 and brine, dried over K2CO3/
Na2SO4, and concentrated. Purification by chromatography (from hexane
to 1:1 hexane/EtOAc) yielded (Z)-3-iodo-4-(tetrahydropyran-2-yloxy)-2-
butenol (4.24 g, 45%). 1H NMR (300 MHz, CDCl3): d ˆ 6.26 (t, J ˆ 5.7 Hz,
tography (CH2Cl2) afforded enone ( )-11 (576 mg, 74%). [a]D20
ˆ
113.4
(c ˆ 1.5 in MeOH); 1H NMR (300 MHz, CDCl3): d ˆ 7.89 (dd, J ˆ 8.0,
1.2 Hz, 1H; H-3'), 7.65 ± 7.53 (m, 2H; H-5', H-6'), 7.41 (td, J ˆ 8.0, 1.8 Hz,
1H; H-4'), 6.86 (ddd, J ˆ 10.2, 4.9, 3.6 Hz, 1H; H-6), 6.15 (ddt, J ˆ 10.2, 2.5,
ˆ
1.9 Hz, 1H; H-5), 5.98 (t, J ˆ 5.0 Hz, 1H; CH), 4.19 (d, J ˆ 5.0 Hz, 2H;
CH2O), 3.77 (t, J ˆ 6.6 Hz, 1H; H-7a), 3.35 (s, 2H; NCH2), 3.11 (dt, J ˆ
10.0, 7.5 Hz, 1H; H-2), 2.92 (td, J ˆ 10.0, 3.5 Hz, 1H; H-2), 2.65 (dddd, J ˆ
19.4, 6.6, 4.9, 1.7 Hz, 1H; H-7), 2.60 ± 2.40 (m, 2H; H-3, H-7), 2.37 (ddd, J ˆ
14.5, 10.0, 7.5 Hz, 1H; H-3), 0.90 (s, 9H; C(CH3)3), 0.07 (s, 6H; Si(CH3)2);
13C NMR (75 MHz, CDCl3): d ˆ 197.3 (C-4), 148.2 (C-2'), 145.3 (C-6), 137.6
ˆ
ˆ
1H; CH), 4.70 (m; 1H), 4.33 (d, J ˆ 11.5 Hz, 1H; CH2OTHP), 4.27 (d, J ˆ
(C-1'), 136.6 ( CH), 132.5 (C-5'), 131.3 (C-5), 127.8 (C-4' and C-6'), 125.2
ˆ
5.7 Hz, 2H; CH2O), 4.21 (d, J ˆ 11.5 Hz, 1H; CH2OTHP), 3.90 (m; 1H),
(C-3'), 104.6 ( CI), 67.8 (CH2O), 66.0 (C-7a), 62.2 (CH2N), 59.4 (C-3a), 49.2
3.55 (m; 1H), 2.00 ± 1.50 (m; 6H).
(C-2), 34.4 (C-3), 25.8 ((CH3)3), 25.2 (C-7), 18.2 (C), 5.2 (Si(CH3)2); IR
(film): nÄ ˆ 1673, 1528, 1352 cm 1; C24H33IN2OSi (520.5): calcd C 50.70, H
5.85, N 4.93; found C 50.74, H 5.97, N 4.92.
A solution of this alcohol (11.8 g, 39.6 mmol), TBDMSCl (13.1 g, 87 mmol),
and imidazole (5.4 g, 79 mmol) in DMF (75 mL) was stirred at room
temperature for 1 h. The mixture was diluted with Et2O and washed with
3% aqueous Na2CO3, saturated aqueous NH4Cl, and water. The organic
extracts were dried and concentrated to give (Z)-4-[(tert-butyldimethyl-
silyl)oxy]-2-iodo-1-(tetrahydropyran-2-yloxy)-2-butene (16.3 g, quantita-
tive), which was used without purification. 1H NMR (300 MHz, CDCl3):
Palladium-promoted tandem cyclization-quenching of vinyl iodide 11:
Attempted tandem cyclization-quenching processes were carried out from
racemic 11 (prepared as above from racemic 2) under the experimental
conditions summarized in Table 2.
Methyl 4-[(tert-butyldimethylsilyl)oxy]-2-{[cis-3a-(2-nitrophenyl)-4-oxo-
ˆ
d ˆ 6.18 (t, J ˆ 5.2 Hz, 1H; CH), 4.69 (t, J ˆ 3.5 Hz; 1H), 4.32 (d, J ˆ
2,3,3a,4,7,7a-hexahydro-1H-indol-1-yl]methyl}-2-(Z)-butenoate
(13):
13.2 Hz, 1H; CH2OTHP), 4.27 (d, J ˆ 5.2 Hz, 2H; CH2OTBDMS), 4.20 (d,
J ˆ 13.2 Hz, 1H; CH2OTHP), 3.54 (m; 1H), 3.89 (m, 1H), 2.00 ± 1.50 (m;
6H), 0.91 (s, 9H; C(CH3)3), 0.09 (s, 6H; Si(CH3)2); 13C NMR (75 MHz,
1H NMR (300 MHz, CDCl3): d ˆ 7.86 (dd, J ˆ 8.0, 1.5 Hz, 1H; H-3'), 7.57
(td, J ˆ 8.0, 1.5 Hz, 1H; H-5'), 7.47 (dd, J ˆ 8.0, 1.5 Hz, 1H; H-6'), 7.40 (td,
J ˆ 8.0, 1.5 Hz, 1H; H-4'), 6.86 (dt, J ˆ 10.2, 4.5 Hz, 1H; H-6), 6.13 (dd, J ˆ
ˆ
ˆ
CDCl3): d ˆ 137.0 ( CH), 101.4 ( CI), 96.8 (CH), 74.0 (CH2OTHP), 67.6
(CH2OSi), 61.8 (CH2), 30.2 (CH2), 25.8 ((CH3)3), 25.3 (CH2), 18.9 (CH2),
18.1 (C), 5.3 (Si(CH3)2).
ˆ
10.2, 2.0 Hz, 1H; H-5), 6.06 (t, J ˆ 4.9 Hz, 1H; CH), 4.51 (d, J ˆ 4.9 Hz,
2H; CH2OSi), 3.70 (t, J ˆ 6.5 Hz, 1H; H-7a), 3.49 (s, 3H; OCH3), 3.38 ±
3.31 (m, 2H; NCH2), 3.06 (dt, J ˆ 9.5, 7.8 Hz, 1H; H-2), 2.90 (td, J ˆ 9.5,
3.4 Hz, 1H; H-2), 2.68 (dddd, J ˆ 19.1, 6.5, 4.5, 1.8 Hz, 1H; H-7), 2.55 ± 2.42
(m, 2H; H-3, H-7), 2.35 (ddd, J ˆ 14.2, 9.5, 7.8 Hz, 1H; H-3), 0.89 (s, 9H;
C(CH3)3), 0.05 (s, 6H; Si(CH3)2); 13C NMR (75 MHz, CDCl3): d ˆ 197.4 (C-
A solution of this tetrahydropyranyl ether (7.98 g, 19.4 mmol) and MgBr2 ´
Et2O (25 g, 96.8 mmol) in Et2O (250 mL) was stirred at room temperature
for 24 h. The mixture was poured into water and extracted with Et2O (3 Â
150 mL) and CH2Cl2 (150 mL). The combined organic extracts were dried
and concentrated to give (Z)-4-[(tert-butyldimethylsilyl)oxy]-2-iodo-2-
butenol (6.35 g, quantitative), which was used without purification.
ˆ
4), 167.0 (COO), 148.3 (C-2'), 145.7 (C-6), 144.8 ( CH), 137.8 (C-1'), 132.4
(C-5'), 130.7 (C-5), 127.8 and 127.7 (C-4' and C-6'), 125.2 (C-3'), 67.0 (C-7a),
61.6 (CH2O), 59.3 (C-3a), 53.5 (CH2N), 51.3 (OCH3), 49.8 (C-2), 34.8 (C-3),
25.9 ((CH3)3), 25.2 (C-7), 18.2 (C), 5.3 (Si(CH3)2); IR (film): nÄ ˆ 1715,
1673, 1527, 1355 cm 1; HRMS: calcd for C26H36N2O6Si 500.2357; found
500.2343.
1H NMR (300 MHz, CDCl3): d ˆ 6.17 (tt, J ˆ 5.1, 1.2 Hz, 1H; CH),
ˆ
4.29 ± 4.23 (m; 3H), 2.15 (brs, 1H; OH), 0.91 (s, 9H; C(CH3)3), 0.09 (s, 6H;
Si(CH3)2); 13C NMR (75 MHz, CDCl3): d ˆ 135.5 ( CH), 105.6 ( CI), 71.1
ˆ
ˆ
(CH2OH), 67.6 (CH2OSi), 25.9 ((CH3)3), 18.3 (C), 5.2 (Si(CH3)2).
cis-1-{(E)-4-[(tert-Butyldimethylsilyl)oxy]-2-vinyl-2-butenyl}-3a-(2-nitro-
phenyl)-1,2,3,3a,7,7a-hexahydroindol-4-one (15): 1H NMR (300 MHz,
CDCl3): d ˆ 7.86 (dd, J ˆ 8.0, 1.4 Hz, 1H; H-3'), 7.55 (td, J ˆ 8.0, 1.4 Hz,
1H; H-5'), 7.47 (dd, J ˆ 8.0, 1.4 Hz, 1H; H-6'), 7.37 (td, J ˆ 8.0, 1.4 Hz, 1H;
H-4'), 6.86 (ddd, J ˆ 10.1, 4.7, 3.6 Hz, 1H; H-6), 6.32 (dd, J ˆ 17.4, 11.2 Hz,
1H; H-gem), 6.13 (ddd, J ˆ 10.1, 2.4, 1.9 Hz, 1H; H-5), 5.54 (t, J ˆ 6.0 Hz,
Triphenylphosphine (6.1 g, 23.2 mmol) and N-bromosuccinimide (NBS)
(4.8 g, 27 mmol) were added to a cooled ( 308C) solution of this allylic
alcohol (6.35 g, 19.4 mmol) in CH2Cl2 (300 mL). The mixture was stirred at
this temperature for 2 h, diluted with Et2O, and washed with saturated
aqueous NaHCO3 and brine. The organic extracts were dried, concen-
trated, and then taken up with hexanes. Triphenylphosphine oxide was
ˆ
1H; CH), 5.05 (dd, J ˆ 17.4, 1.5 Hz, 1H; H-cis), 4.87 (dt, J ˆ 11.2, 1.5 Hz,
662
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0604-0662 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 4

Total Synthesis of ( )-Strychnine
655±665
1H; H-trans), 4.30 (d, J ˆ 6.0 Hz, 2H; CH2OSi), 3.68 (t, J ˆ 6.6 Hz, 1H;
H-7a), 3.33 (d, J ˆ 13.0 Hz, 1H; CHN), 3.21 (d, J ˆ 13.0 Hz, 1H; CHN),
3.02 (dt, J ˆ 9.7, 8.2 Hz, 1H; H-2), 2.85 (td, J ˆ 9.7, 3.5 Hz, 1H; H-2), 2.66
(dddd, J ˆ 19.4, 6.8, 4.8, 1.8 Hz, 1H; H-7), 2.55 ± 2.42 (m, 2H; H-3, H-7),
2.41 ± 2.28 (m, 1H; H-3), 0.89 (s, 9H; C(CH3)3), 0.05 (s, 6H; Si(CH3)2);
13C NMR (75 MHz, CDCl3): d ˆ 197.6 (C-4), 148.3 (C-2'), 145.5 (C-6), 137.8
(C-1'), 133.6 (C), 132.3 (C-5'), 131.6 (CH), 131.0 (CH), 127.8 (CH), 127.6
3.8, 2.8 Hz, 1H; H-14pro-S), 0.91 (m, 9H; C(CH3)3), 0.10 (s, 6H; Si(CH3)2);
13C NMR (75 MHz, CDCl3): d ˆ 174.3 and 172.0 (C-2 and C-17), 150.7 (C-
13), 135.8 (C-20), 134.5 (C-8), 131.9 (CH), 131.1 (CH), 127.6 (CH), 124.7
(CH), 124.1 (C-19), 101.7 (C-16), 66.6 (C-3), 59.2 (C-18), 55.9 (C-21), 55.2
(C-7), 54.0 (C-5), 52.1 (OCH3), 37.5 (C-6), 28.7 (C-15), 26.0 ((CH3)3), 25.2
(C-14), 18.4 (C),
5.0 (Si(CH3)2); IR (film): nÄ ˆ 1651, 1610, 1531,
1363 cm 1; HRMS: calcd for C26H36N2O6Si 500.2343; found 500.2363;
C26H36N2O6Si (500.7) ´ 1ꢁ2H2O: calcd C 61.27, H 5.50, N 7.31; found C 61.45,
H 5.83, N 7.06.
ˆ
(CH), 127.5 (CH), 125.1 (C-3'), 116.0 ( CH2), 66.4 (C-7a), 59.5 (CH2O),
54.9 (CH2N), 49.5 (C-2), 34.5 (C-3), 25.9 ((CH3)3), 24.4 (C-7), 18.2 (C), 5.2
1
(Si(CH3)2); IR (film): nÄ ˆ 1673, 1527, 1353 cm
; HRMS: calcd for
Methyl (19E)-18-hydroxy-19,20-didehydro-17-curanoate (21): Zn dust
(25 g) was added to a solution of ester (‡)-19 (185 mg, 0.37 mmol) in 9:1
H2SO4/MeOH (50 mL) and the resulting mixture was heated at reflux for
2 h. After cooling to room temperature, the mixture was filtered and the
filtrate was concentrated. The resulting residue was diluted with water and
treated with saturated aqueous Na2CO3 until turbid. The resulting mixture
was further basified with NH4OH and extracted with EtOAc (3 Â 50 mL).
The aqueous layer was neutralized with 1n HCl and extracted with CH2Cl2
(3 Â 50 mL). The combined organic extracts were dried and concentrated
to give a residue. Chromatography (from CH2Cl2 to 7:3 CH2Cl2/MeOH)
afforded an epimeric mixture of esters 20 and 21 (9:1 ratio, 45 mg, 36%).
20: 1H NMR (300 MHz, CDCl3): d ˆ 7.13 ± 7.04 (m, 2H; H-9, H-11), 6.81 (t,
J ˆ 7.5 Hz, 1H; H-10), 6.63 (d, J ˆ 8.0 Hz, 1H; H-12), 5.55 (t, J ˆ 7.0 Hz,
1H; H-19), 4.25 (dd, J ˆ 12.5, 7.0 Hz, 1H; H-18), 4.17 (m, 2H; H-2, NH),
4.16 (dd, J ˆ 12.5, 7.0 Hz, 1H; H-18), 3.88 ± 3.74 (m, 1H; H-15), 3.81 (s, 3H;
OCH3), 3.67 (d, J ˆ 15.2 Hz, 1H; H-21), 3.61 (brd, J ˆ 3.0 Hz, 1H; H-3),
3.32 (d, J ˆ 15.2 Hz, 1H; H-21), 3.34 ± 3.23 (m, 1H; H-5), 3.02 (dt, J ˆ 11.1,
6.8 Hz, 1H; H-5), 2.72 (t, J ˆ 3.7 Hz, 1H; H-16), 2.60 (brs, 1H; OH), 2.48
(td, J ˆ 13.5, 6.8 Hz, 1H; H-6), 2.30 (ddd, J ˆ 14.0, 3.7, 1.4 Hz, 1H; H-14),
2.13 (dt, J ˆ 13.5, 6.8 Hz, 1H; H-6), 1.73 (ddd, J ˆ 14.0, 3.7, 3.0 Hz, 1H;
H-14).
C26H36N2O4Si 468.2455; found 468.2444.
cis-1-{(E)-4-[(tert-Butyldimethylsilyl)oxy]-2-butenyl}-3a-(2-nitrophenyl)-
1
1,2,3,3a,7,7a-hexahydroindol-4-one (16): H NMR (300 MHz, CDCl3): d ˆ
7.85 (dd, J ˆ 8.0, 1.5 Hz, 1H; H-3'), 7.59 (td, J ˆ 8.0, 1.5 Hz, 1H; H-5'), 7.52
(dd, J ˆ 8.0, 1.5 Hz, 1H; H-6'), 7.41 (td, J ˆ 8.0, 1.5 Hz, 1H; H-4'), 6.86 (dt,
J ˆ 10.2, 4.2 Hz, 1H; H-6), 6.15 (dt, J ˆ 10.2, 2.1 Hz, 1H; H-5), 5.70 ± 5.50
ˆ
(m, 2H; CH), 4.11 (dd, J ˆ 4.2, 1.0 Hz, 2H; CH2OSi), 3.61 (t, J ˆ 6.0 Hz,
1H; H-7a), 3.22 (dd, J ˆ 14.0, 5.0 Hz, 1H; CHN), 3.07 (dd, J ˆ 14.0, 5.5 Hz,
1H; CHN), 3.02 ± 2.93 (m, 2H; H-2), 2.68 (dddd, J ˆ 19.3, 6.5, 4.3, 2.0 Hz,
1H; H-7), 2.55 ± 2.25 (m, 3H; H-3, H-7), 0.88 (s, 9H; C(CH3)3), 0.04 (s, 6H;
Si(CH3)2); 13C NMR (75 MHz, CDCl3): d ˆ 197.5 (C-4), 148.5 (C-2'), 146.0
(C-6), 137.8 (C-1'), 132.5 (C-5'), 131.9 (CH), 130.6 (CH), 127.9 (CH), 127.7
(CH), 127.0 (CH), 125.2 (C-3'), 66.7 (C-7a), 63.2 (CH2O), 59.3 (C-3a), 53.5
(CH2N), 50.5 (C-2), 35.2 (C-3), 25.9 ((CH3)3), 25.8 (C-7), 18.2 (C), 5.2
1
(Si(CH3)2); IR (film): nÄ ˆ 1673, 1527, 1355 cm
; HRMS: calcd for
C24H34N2O4Si 442.2267; found 442.2288.
(1R,7R,8S)-2-{(E)-2-[(tert-Butyldimethylsilyl)oxy]ethylidene}-7-(2-nitro-
phenyl)-4-azatricyclo[5.2.2.04,8]undecan-11-one
[( )-14]: Pd(OAc)2
(15 mg, 0.066 mmol) and triphenylphosphine (34 mg, 0.13 mmol) were
added to a solution of vinyl iodide ( )-11 (125 mg, 0.22 mmol) in Et3N
(10 mL) at 908C. The solution was stirred at this temperature for 1.5 h. The
mixture was diluted with Et2O and washed with saturated aqueous Na2CO3
and water. The organic layer was concentrated and purified by chromatog-
A solution of esters 20 and 21 (45 mg, 0.13 mmol) in MeOH (5 mL) was
added to a solution of sodium hydride (55%, 45 mg) in MeOH (10 mL).
The resulting mixture was heated at reflux for 5 h. To reesterify any acid
resulting from adventitious hydrolysis, 18% HCl/MeOH (2 mL) was added
and the resulting solution was heated at reflux for 12 h. After cooling to
room temperature, the mixture was concentrated, basified with 10%
aqueous Na2CO3, and extracted with EtOAc. The organic layer was dried
and concentrated to give a residue. Chromatography (from CH2Cl2 to 7:3
CH2Cl2/MeOH) afforded ester 21 (32 mg, 72%). 1H NMR (300 MHz,
CDCl3): d ˆ 7.70 (td, J ˆ 7.6, 1.2 Hz, 1H; H-11), 7.05 (d, J ˆ 7.6 Hz, 1H;
H-9), 6.77 (td, J ˆ 7.6, 1.0 Hz, 1H; H-10), 6.64 (d, J ˆ 7.6 Hz, 1H; H-12),
5.68 (td, J ˆ 7.2, 1.0 Hz, 1H; H-19), 4.25 (brs, 1H; NH), 4.09 (ddd, J ˆ 7.2,
3.8, 1.0 Hz, 2H; H-18), 3.93 (d, J ˆ 9.9 Hz, 1H; H-2), 3.76 (s, 3H; OCH3),
3.54 (t, J ˆ 3.1 Hz, 1H; H-3), 3.53 (d, J ˆ 14.8 Hz, 1H; H-21), 3.26 (m, 1H;
H-15), 3.18 (ddd, J ˆ 12.2, 10.0, 6.9 Hz, 1H; H-5), 3.09 (d, J ˆ 14.8 Hz, 1H;
H-21), 2.85 (ddd, J ˆ 12.2, 8.5, 4.1 Hz, 1H; H-5), 2.63 ± 2.50 (m, 1H; H-6),
2.57 (dd, J ˆ 9.9, 3.9 Hz, 1H; H-16), 2.08 (dt, J ˆ 13.5, 3.6 Hz, 1H; H-14),
2.0 (brs, 1H; OH), 1.95 ± 1.66 (m, 2H; H-14, H-6); 13C NMR (75 MHz,
CDCl3): d ˆ 174.1 (C-17), 148.5 (C-13), 137.1 (C-20), 132.1 (C-8), 128.1 (C-
11), 126.4 (C-19), 121.9 (C-9), 119.1 (C-10), 109.5 (C-12), 66.4 (C-2), 60.8
(C-3), 57.9 (C-18), 57.7 (C-21), 53.8 (C-5), 53.5 (C-7), 52.9 (C-16), 52.3
(OCH3), 42.1 (C-6), 30.2 (C-15), 28.3 (C-14).
raphy (from CH2Cl2 to 98:2 CH2Cl2/MeOH) to give ( )-14 (52 mg, 53%).
1
[a]2D0
ˆ
19.4 (c ˆ 0.8 in MeOH); H NMR (300 MHz, CDCl3):[40] d ˆ 7.49
ˆ
(m; 2H), 7.38 (m; 2H), 5.48 (t, J ˆ 6.3 Hz, 1H; CH), 4.19 (d, J ˆ 6.3 Hz,
2H; OCH2), 3.93 (brs, 1H; H-3), 3.45 (d, J ˆ 14.6 Hz, 1H; H-21eq), 3.27
(m, 1H; H-15), 3.19 (dt, J ˆ 11.0, 7.5 Hz, 1H; H-5a), 3.01 (dt, J ˆ 14.0,
7.5 Hz, 1H; H-5b), 3.01 (d, J ˆ 14.6 Hz, 1H; H-21ax), 2.88 (ddd, J ˆ 11.0,
7.5, 3.6 Hz, 1H; H-6b), 2.71 (dd, J ˆ 17.4, 6.4 Hz, 1H; H-16ax), 2.52 (dt, J ˆ
17.4, 2.1 Hz, 1H; H-16eq), 2.41 ± 2.31 (m, 1H; H-6a), 2.37 (dm, J ˆ 14.0 Hz,
1H; H-14pro-R), 2.18 (ddd, J ˆ 14.0, 3.5, 2.4 Hz, 1H; H-14pro-S), 0.89 (m,
9H; C(CH3)3), 0.06 (s, 6H; Si(CH3)2); 13C NMR (75 MHz, CDCl3): d ˆ
211.1 (C-2), 150.8 (C-13), 138.2 (C-20), 133.4 (C-8), 131.9 (CH), 129.4 (CH),
128.0 (CH), 125.2 (CH), 125.1 (C-19), 65.3 (C-3), 62.2 (C-7), 58.8 (C-18),
54.3 (C-21), 53.7 (C-5), 46.1 (C-16), 39.2 (C-6), 31.0 (C-15), 26.2 (C-14), 25.9
1
((CH3)3), 18.3 (C), 5.1 (Si(CH3)2); IR (film): nÄ ˆ 1704, 1532, 1364 cm
;
HRMS: calcd for C24H34N2O4Si 442.2281; found 442.2288; C24H34N2O4Si
(442.6): calcd C 65.13, H 7.74, N 6.33; found C 64.90, H 7.95, N 6.23.
Methyl (1S,7R,8S)-2-{(E)-2-[(tert-butyldimethylsilyl)oxy]ethylidene}-7-(2-
nitrophenyl)-11-oxo-4-azatricyclo[5.2.2.04,8]undecan-10-carboxylate [(‡)-
19]: Hexamethylphosphoric triamide (HMPA) (0.34 mL, 1.97 mmol) and
a solution of ketone ( )-14 (174 mg, 0.39 mmol) in THF (10 mL) were
added to a cooled ( 788C) solution of LiHMDS (1.2 mmol, 1.2 mL of 1m
solution in THF) in THF (20 mL). After the solution was stirred for 30 min
Strychnine (1): DIBAL-H (0.44 mmol, 0.44 mL of 1m solution in hexane)
was added dropwise to a cooled ( 408C) solution of ester 21 (40 mg,
0.12 mmol) in toluene (7 mL). After 25 min at this temperature, the
reaction was quenched by addition of EtOAc (1 mL), the cooling bath was
removed, and 1n HCl (2 mL) was added. The resulting mixture was stirred
at room temperature for 16 h. Concentrated NH4OH was added, and the
mixture was extracted with EtOAc. The organic extracts were dried and
concentrated to give a residue (40 mg, 65%) in which the main product was
the Wieland ± Gumlich aldehyde.[37]
at
788C, the bath was removed, methyl cyanoformate (125 mL,
1.57 mmol) was added, and the mixture was stirred at room temperature
for an additional 4 h. The reaction was quenched by addition of saturated
aqueous NH4Cl (20 mL) and the resulting solution was extracted with Et2O.
The organic layer was washed with brine, dried, and concentrated. The
residue was purified by chromatography (from CH2Cl2 to 97:3 CH2Cl2/
MeOH) to give ester (‡)-19 (enol form, 122 mg, 62%, 67% based on the
consumed starting ketone) and unreacted ketone ( )-14 (15 mg, 8%).
[a]D20 ˆ ‡226.4 (c ˆ 0.5 in MeOH); 1H NMR (300 MHz, CDCl3):[40] d ˆ 12.5
(brs, 1H; OH), 7.53 ± 7.45 (m; 2H), 7.40 ± 7.32 (m; 2H), 5.49 (td, J ˆ 6.3,
NaOAc (200 mg, 2.4 mmol), malonic acid (200 mg, 1.9 mmol), and Ac2O
(40 mg, 0.4 mmol) were added to a solution of this crude product in acetic
acid (1.5 mL). The mixture was heated at 1108C for 2 h. After cooling to
room temperature, the mixture was diluted with water, basified with
aqueous 50% NaOH, and extracted with EtOAc. The organic extracts were
dried and concentrated, and the residue was purified by chromatography
(from CH2Cl2 to CH2Cl2/MeOH 9:1) to give strychnine (12.5 mg, 49%),
which was identical with an authentic sample by comparison of the
ˆ
1.3 Hz, 1H; CH), 4.43 (ddd, J ˆ 12.9, 6.3, 1.2 Hz, 1H; H-18), 4.30 (ddd,
J ˆ 12.9, 6.3, 1.9 Hz, 1H; H-18), 3.84 ± 3.76 (m, 2H; H-3, H-15), 3.80 (s, 3H;
OCH3), 3.30 (d, J ˆ 12.8 Hz, 1H; H-21eq), 3.17 (d, J ˆ 12.8 Hz, 1H;
H-21ax), 3.25 ± 3.14 (m, 1H; H-5a), 2.97 (dd, J ˆ 12.5, 7.9 Hz, 1H; H-5b),
2.80 (ddd, J ˆ 15.4, 10.7, 7.9 Hz, 1H; H-6b), 2.39 (dd, J ˆ 15.4, 6.8 Hz, 1H;
H-6a), 2.09 (ddd, J ˆ 13.4, 3.6, 2.5 Hz, 1H; H-14pro-R), 1.93 (ddd, J ˆ 13.4,
1H NMR, 13C NMR, TLC data. [a]2D0
[a]2D0
139 (c ˆ 2.0 in CHCl3).
ˆ
119.4 (c ˆ 0.35 in CHCl3); lit[13]
ˆ
Chem. Eur. J. 2000, 6, No. 4
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663

J. Bonjoch, J. Bosch et al.
FULL PAPER
[17] For other procedures for the preparation of a-hydroxy silanes, see:
R. L. Danheiser, D. M. Fink, K. Okano, Y.-M. Tsai, S. W. Szczepanski,
J. Org. Chem. 1985, 50, 5393 ± 5396; R. J. Linderman, Y. Suhr, J. Org.
Chem. 1988, 53, 1569 ± 1572.
[18] T. D. Nelson, R. D. Crouch, Synthesis 1996, 1031 ± 1069.
[19] As racemic 2 was accessible in larger amounts than enantioenriched 2,
these initial experiments were carried out with racemic material.
[20] The constitution and relative configuration of alcohol 8 and cyclo-
propane 10 were unambiguously established from their 1H and
13C NMR data with the aid of 2D-NMR (COSY, HMQC, HMBC, and
NOESY) experiments.
[21] Although this mechanism is similar to that proposed for the [3‡2]-
annulation reactions of enones with allylic[21a] and propargylic[21b]
silanes bearing bulky trialkylsilyl groups, its operation in this case is
somewhat surprising because a-acetoxyallyl silanes react with electro-
philes by the normal addition-desilylation route.[21c] a) H.-J. Knölker,
N. Foitzik, H. Goesmann, R. Graf, Angew. Chem. 1993, 105, 1104 ±
1106; Angew. Chem. Int. Ed. Engl. 1993, 32, 1081 ± 1083; H.-J.
Knölker, N. Foitzik, C. Gabler, R. Graf, Synthesis 1999, 145 ± 151;
J. S. Panek, N. F. Jain, J. Org. Chem. 1993, 58, 2345 ± 2348; b) R. L.
Danheiser, B. R. Dixon, R. W. Gleason, J. Org. Chem. 1992, 57, 6094 ±
6097; c) J. S. Panek, M. A. Sparks, J. Org. Chem. 1989, 54, 2034 ± 2038.
[22] a) Radical cyclization: M. E. Kuehne, T. Wang, D. Seraphin, J. Org.
Chem. 1996, 61, 7873 ± 7881; b) Intramolecular Heck reaction: V. H.
Rawal, C. Michoud, R. F. Monestel, J. Am. Chem. Soc. 1993, 115,
3030 ± 3031; c) Ni(COD)2-promoted biscyclization: see ref. [11a,c,e].
[23] a) Intramolecular nucleophilic addition to an a,b-unsaturated ester:
see ref.[6b]; b) Intramolecular Heck reaction: see ref. [5b].
[24] For some examples of tandem cyclization-capture processes that
involve the trapping of s-alkyl palladium species with different
quenchers, see: a) CO as the quencher, R. Grigg, P. Kennewell, A.
Teasdale, Tetrahedron Lett. 1992, 33, 7789 ± 7792; E. Negishi, C.
Coperet, S. Ma, T. Mita, T. Sugihara, J. M. Tour, J. Am. Chem. Soc.
1996, 118, 5904 ± 5918; B. Crousse, L.-H. Xu, G. Bernardinelli, E. P.
Kündig, Synlett 1998, 658 ± 660; b) LiCN as the quencher, R. Grigg, V.
Santhakumar, V. Sridharan, Tetrahedron Lett. 1993, 34, 3163 ± 3164;
c) methyl acrylate as the quencher, G.-Z. Wu, F. Lamaty, E. Negishi, J.
Org. Chem. 1989, 54, 2507 ± 2508; d) vinylic stannanes as quenchers, B.
Burns, R. Grigg, P. Ratananukul, V. Sridharan, P. Stevenson, S.
Sukirthalingam, T. Worakun, Tetrahedron Lett. 1988, 29, 5565 ± 5568;
R. Larock, N. H. Lee, J. Org. Chem. 1991, 56, 6253 ± 6254.
[25] This alkylating agent was prepared following the Rawal protocol.[5b]
[26] G. K. Friestad, B. P. Branchaud, Tetrahedron Lett. 1995, 36, 7047 ±
7050.
[27] S. Cacchi, G. Fabrizi, F. Gasparrini, C. Villani, Synlett 1999, 345 ± 347,
and references therein.
Acknowledgements
This work was supported by DGICYT, Spain (Projects PB94 ± 0214 and
PB97 ± 0877). Financial support for DGEU, Catalonia (1997SGR-0018 and
1997SGR-00166) is also acknowledged. Thanks are also due to the AECI,
Mutis program (Spain) for a fellowship to S.G.-R.
[1] R. B. Woodward, M. P. Cava, W. D. Ollis, A. Hunger, H. U. Daeniker,
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[3] K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis, VCH,
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[7] For other significant efforts in this field that have not culminated in
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Mortimore, J. Am. Chem. Soc. 1996, 118, 9804 ± 9805; b) K. Shin, K.
Ogasawara, Heterocycles 1999, 50, 427 ± 431.
[8] For a preliminary account of our synthesis of ( )-strychnine, see: D.
Â
Â
Sole, J. Bonjoch, S. García-Rubio, E. Peidro, J. Bosch, Angew. Chem.
1999, 111, 408 ± 410; Angew. Chem. Int. Ed. Engl. 1999, 38, 395 ± 397.
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The Alkaloids, Vol. 48 (Ed.: G. A. Cordell), Academic Press, New
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[28] S. Bräse, A. de Meijere in Metal-catalyzed Cross-coupling Reactions
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tions (Eds.: F. Diederich, P. J. Stang), Wiley-VCH, 1998, pp. 231 ± 269.
[29] Formation of 1,4-conjugate addition products in the Heck reaction
with electron deficient olefins has also been explained by solvolysis of
the palladium enolate. R. Benhaddou, S. Czernecki, G. Ville, J. Org.
Chem. 1992, 57, 4612 ± 4616; S. E. Denmark, M. E. Schnute, J. Org.
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[10] The numbering system and ring labeling based on the biogenetic
interrelationship of indole alkaloids is used throughout this paper: J.
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Â
[11] a) J. Bonjoch, D. Sole, J. Bosch, J. Am. Chem. Soc. 1993, 115, 2064 ±
Â
2065; b) D. Sole, J. Bonjoch, J. Bosch, J. Am. Chem. Soc. 1995, 117,
Â
11017 ± 11018; c) D. Sole, J. Bonjoch, J. Bosch, J. Org. Chem. 1996, 61,
Â
4194 ± 4195; d) D. Sole, J. Bonjoch, S. García-Rubio, R. Suriol, J.
Â
Bosch, Tetrahedron Lett. 1996, 37, 5213 ± 5216; e) J. Bonjoch, D. Sole,
S. García-Rubio, J. Bosch, J. Am. Chem. Soc. 1997, 119, 7230 ± 7240.
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alkoxypropargylic silanes with electrophiles.
[30] G. E. Stokker, Tetrahedron Lett. 1987, 28, 3179 ± 3182; S.-I. Murahashi,
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Â
Â
related processes, see: D. Sole, Y. Cancho, A. Llebaria, J. M. Moreto,
A. Delgado, J. Org. Chem. 1996, 61, 5895 ± 5904.
[33] Although HCOOH and several formate salts have been employed as
hydride sources in the Pd-catalyzed conjugate addition of aryl iodides
to a,b-unsaturated carbonyl compounds,[33a] we could not use them
because it is well-known that, in the presence of Pd catalysts, they
reduce aromatic nitro groups.[33b] a) S. Cacchi, G. Palmieri, Synthesis
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Â
[34] a) D. Sole, J. Bonjoch, Tetrahedron Lett. 1991, 32, 5183 ± 5186; b) D.
Â
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[35] This ester is also an intermediate in the Overman synthesis of
strychnine.[6c]
664
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Chem. Eur. J. 2000, 6, No. 4

Total Synthesis of ( )-Strychnine
655±665
[36] Similar trends are observed in related esters embodying rings
ABCE[36a] and ABCDE[36b] of Strychnos alkaloids. a) M.-L. Bennasar,
M. Alvarez, R. Lavilla, E. Zulaica, J. Bosch, J. Org. Chem. 1990, 55,
1156 ± 1168; b) see ref. [6a].
[39] This ee value is in agreement with the purity of ( )-18 and a-(S)-
methylbenzylamine (96% ee) and is very similar to that obtained
(89% ee) in our enantioselective synthesis of ( )-tubifolidine from
the same azabicyclo ( )-18.[11e]
[37] The chemical shifts of our synthetic sample were coincident with those
reported from a natural sample of the Wieland ± Gumlich aldehyde:
[40] To facilitate the comparison with data corresponding to related
polycyclic compounds, the biogenetic numbering[10] is used in the
NMR assignments.
Â
Â
G. Massiot, B. Massoussa, M.-J. Jacquier, P. Thepenier, L. Le Men-
Olivier, C. Delaude, R. Verpoorte, Phytochemistry 1988, 27, 3293 ±
3304.
[41] R. K. Duke, R. W. Richards, J. Org. Chem. 1984, 49, 1898 ± 1904.
[38] Starting from racemic 14 we also completed the synthesis of racemic
Wieland ± Gumlich aldehyde.
Received: May 11, 1999 [F1778]
Chem. Eur. J. 2000, 6, No. 4
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665