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New Total Syntheses of Strychnine.

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HIGHLIGHTS
New Total Syntheses of Strychnine
Uwe Beifus*
Strychnine (1). the active component of a notorious arrow
poison in Southeast Asia, has a mysterious history. It is a convulsant blocking postsynaptic inhibition in the spinal cord by
acting as an antagonist of the inhibitory neurotransmitter,
glycine.[21In therapeutic doses strychnine has a mildly analeptic
effect; in toxic doses it leads to uncoordinated tonic convulsions
induced by acoustic, tactile, or optical stimuli Paralysis o f the
respiratory organ results in death; 100-300 mg is the lethal dose
for an adult human.i2c1
lished the first, and so far only, enantioselective route to strychnine (l),["] and in the meantime Kuehne et al.illl and Rawal et
a1.i'21 have also completed their total syntheses. This certainly
provides ample grounds for discussing these four new syntheses.
Magnus' synthesis['] follows the retrosynthetic analysis of the
strychnos framework employed successfully by Harley-Mason
in the syntheses of several natural products in the 1960s and
1 9 7 0 ~ . [ 'The
~ ] key step in this strategy is the transannular iminium ion cyclization of a nine-membered ring for the stereoselective construction of rings D and E of the strychnos alkaloids.
Magnus follows the classical approach right from the start with
the multistep conversion of the tetracyclic amine ruc-5, which is
readily accessible from 3 and 4,into 6 (Scheme 1). A crucial step
no
1
2
A
4
3
In 1818 strychnine ( l ) , which occurs in larger amounts in the
poison nut (Stryclznos nu.^ vornic L.) and the Saint-Ignatius'sbean (Strychnos ignutii Bergius), was isolated by Pelletier and
C a ~ e n t o u [and
~ ] was one of the first alkaloids obtained in pure
form. The structure determination by chemical degradation of
the natural product, a complex structure with seven rings and
six stereogenic centers, proved to be difficult and tedious. Many
structural formulas were proposed and rejected before Robinson
et al. (1946) and Woodward et al. (1947) presented the correct
formula.r41The relative and absolute configuration was determined by X-ray crystallography a few years later.[51
The structure determination culminated with the total synthesis of 1 by Woodward et al., which was the only total synthesis
of this natural product for nearly forty years.[61Even today this
synthesis is still considered a highlight in the development of
modern organic synthesis, since at that time the deliberate design and execution of the synthesis of a molecule of this complexity was unprecedented. Despite the rapid development of
organic chemistry since then. strychnine has remained an attractive. challenging synthetic target. A number of novel approaches to the strychnos alkaloids have been
but the
molecules prepared frequently lack the functionalities required
for the construction of the seven-membered allylic ether G ring
of strychnine. Recently, almost forty years after Woodward's
synthesis, four research groups achieved the total synthesis of
strychnine. In 1992 Magnus et al. reported on the successful
conclusion of the second total synthesis of strychnine and at the
same time the first total synthesis o f the so-called WielandGumlich aldehyde 2.191Shortly afterwards Overman et al. pub[*] Dr U. Beifiiss
lnstitut fur Organische Chemie der Universitit
Tammannstrdsse 2, D-37077 (iottingen (FRG)
Telefax. Int. code + (551)39-9660
Me0,C
5
I
1
C0,Me
Me0,C
6
Scheme I . a) CICO,CH,CCl,. CH,CI,; b) NaOMe. MeOH: c) 50% aq NaOH.
CH,CI,. CIC02Me. benzyltriethylammonium chloride; d) Zn. CH,COOH. THF.
is the fl,fi,b-trichloroethylchloroformate induced fragmentation
of the tertiary amine ruc-5 to provide the expanded nine-membered ring system. One of the most remarkable steps in the
remainder of the synthesis is the construction of the F ring by
intramolecular conjugate addition. For this purpose amide 7a is
prepared and treated with sodium hydride in THF, which results
in the facile, diastereoselective transformation into rac-8. The
stereoselectivity of this 1,il-addition is attributed to the protonation of the intermediate ester enolate from the top Pace. Oxidation of ruc-8 to give the corresponding mixture o f sulfoxides is
then followed by a Pummerer reaction and HgZ+-mediated hydrolysis to furnish rac-9 (Scheme 2).
Magnus et al. obtained both enantiomers of 9 with considerable effort by acylation of 6 with (+)-(R)-p-toluenesulfinylacetic acid and cyclization of the resulting sulfoxide 7 b, separation of the four diastereomers formed in this way. combination
of the pairs with the same absolute configurations at C-6 and
C-7, and subsequent conversion into the two enantiomers 9 and
en/-9.[9"lThe cyclization of sulfoxide 7 b yields the two products
enantiomeric at C-6 and C-7 in a 55:45 ratio. This is why this
route is not only laborious but also only insignificantly more
efficient than resolution.
HIGHLIGHTS
Me0,C
&,Me
7a
R=SPh
7b
R=pSTol
MeO&
.
-
I
R
60,Me
C0,Me
13a :
13b :
8
H
rr-CO,Me
p-CO,Me
14
R
= p-SO,C,H,OMe
+
0-
f.g
T
R
OTIPS
15
R
9
= p-S02C,H,0Me
After transformation of rac-9 into acetal ruc-I0 (Scheme 2)
rings D and E are constructed in the most critical step of the
entire synthesis. A transannular iminium ion cyclization['~' 31
provides predominantly roc-12 in 65 YOyield with remarkable
regio- and stereoseIecti~ity.['~1
It is assumed that treatment of
rar-10 with niercury(ir) acetate in acetic acid leads primarily to
the cyclic iminium ion rac-11 which then gives roc-12.
16
17
CHO
OR'
R'=TBDMS
R'=H
R = p-SO,C,H,OMe
10
Scheme 2 a) PhSCH,CO,H. his(2-oxo-3-oxazolidinyl)phosphinicacid (BOPCI),
E1,N. CHICI,. b) NaH, T H F ; c ) m-chloroperbenroic acid (MCPBA). CH,CI,,
0 C . d ) tritluoroacetic anhydride (TFAA). 2.6-di-1ert-butyl-4-methylpiperidine:
e ) HgO. C'dC'O,. T H E H,O; f) BrCH,CH,OH. 1.8-diazohicyclo[5.4.0]undec-7-ene
(DBU). C.H8: g) BH, T H F ; h) Na,CO,, MeOH, 65°C.
R
Scheme 3. a) Zn. H,SO,, MeOH; h) MeONa. MeOH; c)p-McOC,H,SO,CI,
EtNiPr,. 4-dimethylaminopyridine (DMAP). CH,CI,; d) LiBH,, THF.
f ) triisopropylsilyltrifluoromethanesull'onate
HN(CH,CH,0H)2; e) HCIO,:
(TIPSOTfj, DBU. CH,CI,. g) (EtO),P(O)CH,CN. potassium hexamethyldisilazide (KHMDS), THF, 25 'C; h) diisobutylaluminum hydride (DIBAL). CHiCIZ,
H , O t ; I) NaBH,, MeOH; J ) 2 N HCI. MeOH: k) /rr~-butyldimethylsilyltrifluoromethanesulfonate (TBDMSOTI). DBU, CH,CI,. -20 C: I ) S O , . C,H,N. DMSO. Et,N: m) pyridinr, HE
reaction furnishes the a,B-unsaturated cyanide 15 as a 2: 3 mixture of the ( Z ) and ( E ) isomers. Although the undesired ( Z )
isomer can be isolated and isomerized photochemically to give
a mixture of both isomers, this step is far from being optimal.
The next steps in the synthesis include the multistep conversion of (E)-15 into 16, subsequent cleavage of the silyl ether
protecting group, and cyclization of 17, which cannot be isolated, to provide hexacyclic 18. With the reductive removal of the
Po/
k
b,Me
HO
L
11
12
A number of steps are required for the conversion of rac-12
into the cyclic hemiacetal vac-14 (Scheme 3). This compound is
important for the rest of the synthesis, since it cannot only be
prepared from tryptamine (3) and dimethyl 2-ketoglutarate (4),
but can also be obtained readily in substantial amounts and in
enantiomerically pure form by degradation of strychnine. Once
enough of this relay hemiacetal has been secured, assembly of
the G ring can be tackled.
As only a compound with an (E)-configurated double bond
as in 17 can be used for the synthesis of the G ring, the construction of the hydroxyethylidene double bond must be diastereoselective. This problem had challenged Woodward et al., and like
those pioneers Magnus et al. were also foiled: Wittig-Homer
18
2
R = p-SO,C,H,OMe
19
R=H
sulfonamide Magnus et al. arrived at their first goal, the total
synthesis of the Wieland-Gumlich aldehyde 2. The conclusion
of the total synthesis of strychnine is also within reach; the
authors succeeded in converting 2 into the natural product in a
one-step reaction with malonic acid, following the method of
Robinson et a].[* With 27 steps this synthesis is only negligibly
shorter than Woodward's 28-step synthesis from 1954. But Magnus et al. achieved an overall yield of roughly 0.03 %, which is
more than 1000 times greater than Woodward's overall yield of
0.00006%. This result would have been impossible without powerful new synthetic methods. Magnus' synthetic strategy has a
classical form, and he prepared enantiomerically pure compounds
HIGHLIGHTS
very effectively by traditional means, namely via a relay compound obtained by degradation of the natural product itself.
The third total synthesis of strychnine ( I ) , so far the only
enantioselective route to the natural product, was accomplished
by Overman et al.["] The key to their approach to 1 is the
sequential cationic aza-Cope rearrangement/Mannich cyclization, which is frequently employed with success in alkaloid synthesis. With the synthesis of akuammicine rccc-19 the authors
proved that this strategy offers an efficient route to the strychnos alkaloids.[sb"
The crucial compound in this strychine synthesis is azabicyclo[3.2.l]octane 31. which is the substrate for the aza-Cope-
AcO D
O
R
Mannich sequence (Scheme 4). In the preparation of 31, mesodiester 20 is subjected to acetylcholine esterase catalyzed hydrolysis to yield 21 with high enantiomeric purity. Eighteen ensuing
steps then provide 31 in 14% yield. The allylic carbonate obtained
from 21 is used in a palladium-catalyzed allylic substitution with
22 to furnish the cis products 23, which are reduced with high
diastereoselectivity ( > 20: 1) in accord with the Felkin-Anh
model to provide a mixture of the trans-P-hydroxy esters 24.
Subsequent s\.n elimination affords the ( E ) isomer 25 almost
exclusively (97:3). In this way Overman et al. succeeded in solving the problem of the stereoselective construction of what will
become the allylic ether double bond at C-20 of the natural
product early in the synthesis. The next important intermediate
is the a,/hmsaturated ketone 29, which is accessible by the palladium-catalyzed, carbonylative cross-coupling of vinyl stannane 27 with the triazone-protected o-iodoaniline 28. I n turn, 27
is prepared by the palladium-catalyzed Stille coupling of the
enol triflate obtained regioselectively from 26. The key step in
the transformation of 29 into 31 is the stereoselective. intramolecular aminolysis of epoxide 30, which is the product of
the substrate-controlled stereoselective epoxidation and subsequent Wittig methylenation of 29.
Now the aza-Cope-Mannich cascade must be triggered, in
other words, amine 31 must be converted into the corresponding
formaldiminiun ion 32 (Scheme 5). This is achieved by reaction
with paraformaldehyde without added acid. Intermediate 32
undergoes cationic [3.3] sigmatropic rearrangement under these
s A c oT:vco2Et
T
02Et
20 R = A c
21 R = H
O f Bu
O f Bu
/OTlPS
C02Et
h,i
d
91%
AcO
25
26
0
MeN
(N)
NMe
2.5% [Pd,(dba),], 22% Ph,As,
GO, LiCI, NMP, 70°C
80%
Me,Sn
Ot Bu
27
(CH20),, Na2S04
CH,CN, A
28
31
t
98%
X= NHCOCF,
P
70%
L
Ot Bu
29
30
Ot Bu
s'UNR2
0
Mannich
-H+
MeNKNMe
62%
P,q
HO
33
32
N
0
I
34
ur
C
2
I
H
I
t BuO v
R
2
E
t
\
\ 15:
70%
, -,"
A
C0,Me
68%
O
'H
35
7 N .
0
31
f
22
Scheme 4. a ) CICO,Me. pyridine. CH,CII. 23 C . b) rBuOCH,COCH2C02Et
(22).NaH. 1 %[Pd,(dba),]. 1 5 % P P h , . T H E ? 3 C:c)NaCNBH,,TiCI,. -7X'C:
d ) dicyclohexylcarbodiimide (DCC). CuCI. C,H,. 80 'C: e) DIBAL. CH2C12.
- 78 C. f j TIPSCI. tetrameIhylguanidine. N-methyl-2-pyrrolidone (NMP).
- 1 0 - C , gj Jones oxidation, -5',C: h) L-Selectride. PhNTf?. T H E -78 + 0 C:
i) Me&>, 1 0 % [Pd(PPh,),], LiCI. THF, 60 C ; J ) rBuO,H, Triton-8, THE
- 15 C:
k ) Ph,P=CH,.
THF. 0 + 23 C: I)tetrabutylammoniiim fluoride
(TBAF). THF. - 15'C; m) methanesulfonyl chloride (MsCI). iPr,NEt. CH,CI,.
-23 C. n) LiCI. DMF, 23°C: o j NH,COCF,. NaH, DMF. 23 C ; pj NaH. C,H,.
100 C; q ) KOH. EtOH-H,O. 60 C .
65%
H
C02Me
36
u-C0,Me
37
[$-C02Me
OH
0
MeNKNMe
1
NR~=
N
''
I
vw.
Scheme 5 a) Lithium diisopropyldmide (LDA), NCCO,Me, THF. - 78 C; b) 5 %
HCI-MeOH. reflux, c ) Zn. 10% H,SO,-MeOH, reflux: d) NaOMe, MeOH. 23 C:
e) DIBAL. CHJI,. -78 ' C . f ) CH2(C02H)2.Ac,O, NaOAc, HOAc, 11O'C.
HIGHLIGHTS
far to employ the furan ring in 44 for the construction of rings
F and G in strychine. This is why Kuehne et al. relied on rue-42
in their approach to the natural product.
This entailed the lengthy and difficult successive construction
of the three missing rings F, G, and C. The synthesis of the F ring
is the least troublesome, as it succeeds in only three steps and
with 67% yield (rac-43 -+ rue-47) (Scheme 7). The key step is
the intramolecular nucleophilic ring-opening of the unisolated
epoxide rue-45; the thermodynamically controlled reaction
yields rue-46 exclusively.
reaction conditions to give 33, which contains all the structural
features that are required for the ensuing intramolecular Mannich
cyclization. At the end of the sequence 34 is obtained stereoselectively and almost quantitatively (98 % y i e l d t a n outstanding example of the efficiency and flexibility of this synthetic strategy. The cyclization product 34 is then acylated with methyl
cyanoformate. and cleavage of the triazone protecting group
affords pentacycle 35. which contains all of the C atoms required for the synthesis of the Wieland-Gumlich aldehyde 2.
The conversion of 36 into strychnine (1) by conventional means
is the concluding step in the first synthesis of this natural product
proceeding without the resolution of racemates and without
relay compounds. Overman et al. accomplish this in a total of 25
steps and with an overall yield of approximately 3 % . This first
enantioselective total synthesis is achieved in excellent yield. But
just as impressive is the underlying retrosynthetic analysis,
which is then followed by combining several modern palladiumcatalyzed reactions and the elegant aza-Cope-Mannich sequence, a distinctive feature of Overman's work.
The beginning of Kuehne's total synthesis of racemic strychnine rrrc-l I' ' I is promising, since the highly diastereoselective
construction of the tetracycle rue-42 from tryptamine 38 and
butenal39 proceeds in only one synthetic operation (Scheme 6).
The yield for this novel and efficient sequential reaction is 51 %
after cleavage of the acetal to provide aldehyde rue-43. Presumably the cyclizing Mannich reaction that leads to rm-40 is
followed by a [3,3] sigmatropic rearrangement giving rac-41,
which in turn undergoes acid-catalyzed cyclization to afford rac42. This new method also provides access to the indolenine rac44,'8'1 a compound containing all but two carbon atoms of ring
C of the target n~olecule.However. it has not been possible so
r
Me,S+I -, n BuLi
THF
H
-
D
e,,
C02Me
I
43
~
C02Me
45
+r
DEU,
65% MeOH
10h
ti
P h
PdlC,
MeOH
H2
'..
H
''",OH
67%
C0,Me
46
@
'%,,
"OH
LO,Me
47
CH,Ph
I
H
Scheme 7 .
C0,Me
OMe
39
38
9h
OMe
Ph'
w
C
O
,
M
e
H
I
L
C02Me
J
41
40
10% HCIO4
THF, 2 3 T . 5h
H
-
51 %
Schemc 6 .
42
R= CH(OMe),
43
R=CHO
44
In contrast to Magnus and Overman, who directed their syntheses towards the Wieland-Gumlich aldehyde me-2 and its
straightforward conversion into strychnine rue-1, Kuehne focused on the synthesis of isostrychnine rue-53 (Scheme 8) and
had to rely on the isostrychnine-strychnine transformation,
which Woodward had already recognized as being exceptionally
difficult. First, ring C i s assembled. The key step is the intramolecular Claisen reaction of the acetamido ester rue-48 to give ketolactam rac-49. Although the overall yield for the construction of
the C ring is good (ruc-47 -+ vac-51), the eight steps are relatively laborious. In the next part of the synthesis Kuehne. like Magnus. learned by experience that the (E)-selective construction of
the allylic ether group at C-20, which is critical for closure of the
G ring, is not possible at such a late stage in the synthesis. Wittig
olefination of rue-51 provides a 1 :1 mixture of the ( E ) and (Z)
isomers of rac-52, which can be enriched by irradiation in favor
of the required (E)-acrylic ester (8 : 1). The reduction of (E)-ruc52 to isostrychnine rue-53 is straightforward; as expected, however, the last step of the synthesis, the problematic conversion of
52 to isostrychnine rac-53 is straightforward ; as expected, however, the last step of the synthesis, the problematic conversion of
isostrychnine rue-53 into strychnine rue-1, could not be solved in
HIGHLIGHTS
7
N
LiN(SiMe,),
THF. 66%
47
c
',,,,OH
06
60,Me
48
OH
o
c
,,,,,,,OAc
(48-50)
64%
d'e
0
0
49
OAc
50
formally achieves the synthesis of the natural product-albeit in
racemic form-in only 15 steps and with almost 10% yield.
which is on the order of the results of Overman and Kuehne.
Whether the four new total syntheses represent afundamrntul
improvement over Woodward's strychnine synthesis and the
extent of this improvement can certainly be debated. However,
it cannot be contested that Overman et al. accomplished the first
and only enantioselective synthesis of the natural product. and
that Kuehne and Rawal with their respective 17- and 15-step
syntheses devised approaches with markedly fewer reaction
steps than Woodward's 28-. Magnus' 21-. and Overman's 25step syntheses. The considerable improvement in the overall
yields relative to that of the first total synthesis is also noteworthy.
Whereas Magnus improved the yield by a factor 1000, Overman, Kuehne, and Rawal upped the overall yield by a factor of
52
51
54
i
28%
87%
56
55
1
,CO,Me
rr?
53
Scheme 8 a ) NaBH,CN. HOAc. 23 C ; h) Ac,O. pyi-idiiie. c) NaOMe, MeOH.
0 C: d) NaBH,, MeOH; e)Ac,O. pyridine. f) DBU. dioxane-H,O. 100°C:
g) Swerii oxidation: h) (EtO),P(O)CH,CO,Me. KN(SiMe,),. THF. 23 C. 7 h:
i) hi.: j ) DIBAL. BF, . Et,O. - 7 8 - C .
57
58
N -CO,Me
a satisfactory manner: strychnine ruc-1 was isolated in only 28%
yield in addition to 61 % unreacted starting material. One could
argue that not every step in Kuehne's synthesis proceeds with
the desired selectivity and yield and that the synthesis is not
enantioselective. Yet it should be stressed that this synthesis,
designed around a new and efficient key sequence, is one of the
shortest routes to strychnine rac-1 with 17 steps and an overall
yield of roughly 2%. The efficiency of the synthesis could also
be improved by avoiding the isostrychnine- strychnine conversion and the consequent time-consuming assembly of the C ring.
A strategy combining the advanrages of both the intramolecular Diels-Alder reaction and the intramolecular Heck reaction
was successfully tested in Rawal's synthesis of rac-1 .[121 Heating
precursor ruc-59. which is prepared from 54 in eight steps. to
185°C provides tetracycle rue-60 in 99% yield as the sole
product of the Diels-Alder reaction (Scheme 9). The rapid construction of the C ring by intramolecular amide formation in only
two steps is also remarkable. Allylation of ruc-61 with 62 furnishes roc-63. Subsequent intramolecular Heck reaction leads to the
diastereoselective ring closure providing the bridged piperidine
system with retention of the stereochemistry at the double bond
of the vinyl iodide. Deprotection concludes this hitherto shortest
synthesis of racemic isostrychnine ruc-53 which has 14 steps and
a 35 YOyield. But Rawal et al. are confronted with the problem of
the inefficient final transformation to give rac-1. If one assumes
Kuehne's reported yield of 2 8 % for this
then Rawal
1148
('
VCH Verlopsprsi~ll.r~huft
nrhH, D-694Sl Wr~inhe;r?i.1994
C&+3, 185'C
99 %
Me0,C
I
C0,Me
Me0,C
59
60
61
63
62
53
Scheme 9. a) BrCH,CH,Br. 50% NaOH, CH,CN. nBu,NBr, 23 ' C ; h) DIBAL.
C,H,. -78 C, H,Oi: c)BnNH,, Et,O; d)Me,SiCI. Nal. DMF. 60 C .
e)CICO,Me. acetone. 23-C. f ) lo% , P d C . HCO,NH,, MeOH; g) 23°C.
ti) CIC02Me. PhNEt,: I ) Me,SiI. CHCI,. 61 C, 5 h:]) MeOH. 65 ' C , 6 h: k ) DMF.
acetone. K,CO,: 1) Pd(OAc),. Bu,NCI. DMF, K,CO,. 70°C. 3 h . m) 2 N HCI.
THF.
0 5 7 0 - 0 X 3 3 , ' 9 4 ~ 1 1 1 1 - 1 ~6410.00+
~~
.35~0
A n g r w . Chern. hf.
Ed. Enpl. 1994, 33. No. 1 1
HIGHLIGHTS
100000! These impressive numbers cannot be attributed solely
to improved synthetic methods and modern reagents, but emphasize the importance that sequential reactions" 'I have achieved
in the construction of complex natural products.
The four new total syntheses demonstrate that some of the
difficulties in the synthesis of strychnine, such as the diastereoselective construction of the double bond at C-20, can now be
solved elegantly, but that others like the isostrychnine-strychnine conversion remain unsolved. Thus it can be expected that
the search for improved solutions for the efficient synthesis of
strychnine and stychnos alkaloids will continue.
German version: Angew. Clrmi. 1994. 106, 1204
[I] L . Leuin. Die / ' / d @ / r ~ . J. A. Barth. Leipzig. 1923.
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365: b) E. Teuscher. U . Lindequist. Biogcne Giffe, Gustav Fischer, Stuttgart.
1987: c ) Allgwrcinc rind spciielle Pharnrakolugie und To.~rko/ogre(Ed. : W.
Forth). 5th ed.. Bibliographisches lnstitut & F. A. Brockhaus. Mannheim.
1987.
[3] P. J. Pelletier. J B. Caventou, Ann. Cliirn. P / i m 1818, if. 323.
[4]r l ) H. T Opensliaw. R. Rohinson. Nafure 1946, 157. 438; b) R. B. Woodward.
W. J. Brehrn. A. L. Nelson. J. A m . Client. Sot.. 1947. 69. 2250.
[ j ] a ) .I H Robertson. C . A. Beebers, Acru CrysruNogr. 1951. 4. 270; b) C . Bokhocen. J. C. Schoone. J. M. Bijvoet. ihirl. 1951.4,275: c) A. F. Peerdeman, J?;d.
1956. '1. 824.
[6] a ) R B Woodward, M. P. Caw, W. D . Ollis, A. Hunger, H. U . Daeniker. K.
Schenkci-. J. h i . CIi(wi7.So(.1954. 76, 4749; h) Te/ra/ierlrun 1963. 19, 247.
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Srtwo\r/c,~rii.e .S>.irrhrsi.! / P a r / '41 (Ed.: Atta-ur-Rahman). Elsevier, Amster-
dam, 1988. p. 31 : b) G . Massiot, C. Delaude in T h A/kuIuid\, El/,34 (Ed.: A.
B r o w ) . Academic Press, New York. 1988, p. 211
[XI a) J. Bonjoch, D. Sole. J. Bosch. J. Am Chem Suc. 1993. liS. 2064: b) M.
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!hid. 1990. 5.5. 6299, d ) G . A. Kraus. D. Bougie. S ~ n k r r1992. 279: e ) R. L.
Parsons, J. D . Berk, M. E. Kuehne, J. Or,?. Cliern. 1993, SX. 7482: f ) M. E.
Kuehne, D. A. Frasier, T. D. Spitzer. ;hid 1991. 56, 2696: g) S. R. Angle, J. M .
Fevig, S. D. Knight, R . W. Marquis. Jr.. L. E. Overman. J. A m . Chew. S u . .
1993. 115.3966; h) J. M. Fevig. R. W Marquis. Jr., L. E. Overman, ;hid. 1991.
113. 5085: i)V. H. Rawal, C. Michoud. R. F. Monestel, rhid. 1993. 115. 3030;
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[14] Typically rar-12 was obtained in 50% yield [9h]
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[I61 The authors do not give a yield for the conversion ofisostrychnine rm-53 into
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