Evolution of a short route to strychnine by using the samarium-diiodide-induced cascade cyclization as a key step

Article abstract of DOI:10.1002/chem.201500094

This comprehensive report accounts the development of a highly diastereoselective samarium diiodide-induced cascade reaction of substituted indolyl ketones. The complexity-generating transformation with SmI₂ allows the diastereoselective generation of three stereogenic centers including one quaternary center in one step. The obtained tetra- or pentacyclic dihydroindole derivatives are structural motifs of many monoterpene indole alkaloids, and their subsequent transformations gave way to one of the shortest approaches towards strychnine (14 % overall yield in ten steps, or 10 % overall yield in eight steps). During the course of this report we discuss the influence of substituents on the cyclization step, plausible mechanistic scenarios for the SmI₂-induced cascade reaction, diastereoselective reductive amination, and regioselective dehydratization protocols towards the pentacyclic core structure of strychnos alkaloids.

Full text of DOI:10.1002/chem.201500094

DOI: 10.1002/chem.201500094
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Total Synthesis |Hot Paper|
Evolution of a Short Route to Strychnine by Using the Samarium
Diiodide-Induced Cascade Cyclization as a Key Step
[a, b]
[a]
Christine Beemelmanns
and Hans-Ulrich Reissig*
Dedicated to Professor Dr. Klaus Roth on the occasion of his 70th birthday
Abstract: This comprehensive report accounts the develop-
ment of a highly diastereoselective samarium diiodide-in-
duced cascade reaction of substituted indolyl ketones. The
sequent transformations gave way to one of the shortest ap-
proaches towards strychnine (14% overall yield in ten steps,
or 10% overall yield in eight steps). During the course of
this report we discuss the influence of substituents on the
cyclization step, plausible mechanistic scenarios for the SmI2-
induced cascade reaction, diastereoselective reductive ami-
nation, and regioselective dehydratization protocols towards
the pentacyclic core structure of strychnos alkaloids.
complexity-generating transformation with SmI allows the
2
diastereoselective generation of three stereogenic centers
including one quaternary center in one step. The obtained
tetra- or pentacyclic dihydroindole derivatives are structural
motifs of many monoterpene indole alkaloids, and their sub-
Introduction
a number of powerful strategies have successfully been devel-
oped to convert these compounds into highly reactive inter-
mediates, which serve as precursor in carbon–carbon and
carbon–heteroatom bond formation, cycloadditions, and cas-
Cascade or domino processes in organic chemistry refer to the
sequential formation of two and more bonds in one reaction
vessel, and represent an efficient strategy for the construction
[7]
cade reactions. Our group has a longstanding interest in
[
1]
[8]
of complex architectural features of natural products. The de-
velopment of increasingly sophisticated, but likewise simple
and scalable cascade reactions, has received considerable at-
tention from the organic chemistry community in the last de-
using the versatile electron-transfer reagent SmI2, and we de-
veloped a series of reductive (hetero)aryl–ketyl cyclization pro-
[9,10]
tocols.
By using our methodology, we were able to build
up a broad spectrum of differently substituted N-, O-, and S-
[
2]
cades. As a result, our deeper understanding of fundamental
reaction mechanisms has significantly influenced our percep-
containing carbo(poly)cyclic building blocks 1–8 suitable for
[11–13]
the application in natural product synthesis (Scheme 1).
We were particularly pleased to establish a SmI -induced cycli-
[
3]
tion of complex molecules and total synthesis. Today’s syn-
thetic chemists are in a position to build up molecules of more
or less any degree of structural complexity. Synthetic planning
of old and new target molecules is now dominated by the
2
[14,15]
zation-trapping sequence of indolyl ketones
in three con-
secutive steps. This sequence enabled the construction of
complex polycyclic dihydroindolines such as 7 (Scheme 1),
which are found in many architecturally daunting alkaloid core
structures. Our next logical aim was to use our methodology
to synthesize one of the most distinguished and historically
important members of the indole alkaloid family, strychnine,
a testing ground and yard stick for new synthetic strat-
[
3,4]
concept of step, atom, and redox economy. As already high-
[
5]
lighted by Hendrickson as early as 1975, the skeleton-forming
steps are the key points in the synthesis and should generate
the functionalities necessary to carry out all subsequent reac-
[6]
tions. One strategy to fulfill this idea of an “ideal synthesis”,
[16–18]
beside many others, is the usage of dearomatization processes
of easily available aromatic and heteroaromatic compounds.
Despite the particular stabilization of aromatic systems,
egies.
At the beginning of our first target-oriented experi-
ments, the shortest route towards strychnine was reported by
[19]
Li and Bodwell, which employs a transannular Diels–Alder re-
action with inverse electron demand. However, we sought an
even shorter and more economical cascade strategy to synthe-
size the pentacyclic dihydroindole strychnine precursors.
[
a] Dr. C. Beemelmanns, Prof. H.-U. Reissig
Institut fꢀr Chemie und Biochemie, Freie Universitꢁt Berlin
Takustrasse 3, 14195 Berlin (Germany)
[
20]
Following the retrosynthetic isostrychnine route
and
[17e]
E-mail: hans.reissig@chemie.fu-berlin.de
Rawal’s reported strychnine precursor I (Figure 1),
we envi-
[
b] Dr. C. Beemelmanns
sioned that tetracycles of type II (ABEG ring system of strych-
nine) should be easily accessible by using a modification of
Leibniz Institute for Natural Product Research and
Infection Biology e.V., Hans-Knçll-Institute (HKI)
Beutenbergstrasse 11a, 07745 Jena (Germany)
our SmI -induced cascade cyclization of the simple indole de-
2
[17o]
rivative III.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500094.
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Scheme 1. Products 1–8 generated by SmI -induced cyclizations of aryl or heteroaryl ketones.
the selective intramolecular acylation reactions. Although the
reactions were rather low-yielding and capricious, and subse-
quent transformations of products 10 and 13 are required to
receive more suitable building blocks, these results encour-
aged us to further elaborate and optimize the cascade reac-
tion. We sought to continue with a second generation of indol-
yl ketones by modifying the side chain and replacing one of
the indolyl groups with an ethoxy group that should display
better leaving-group capabilities (Scheme 2B). Candidates 15
and 17 carrying an electron-withdrawing group at C3 were our
first choice; however, to our disappointment, treatment of 15
and 17 with SmI afforded solely the cyclized spiro-lactones 11
2
and 18 in up to 77% yield; lactone 16 was apparently formed
as a side product by transesterification due to the liberated sa-
marium(III) ethoxide. In general, any additives such as HMPA
caused the formation of other unidentified side products and
resulted in lower yields of the lactones.
Figure 1. Retrosynthesis of strychnine based on a SmI
lization of simple precursor III.
2
-induced cascade cyc-
In summary, although electron-withdrawing substituents
proved to be beneficial for SmI -induced cyclizations of hetero-
2
[
10,14]
We anticipated two major synthetic challenges using precur-
sor II. First, a regioselective elimination of the tertiary hydroxyl
group was necessary to proceed with the reported Heck cycli-
zation to isostrychnine. Secondly, a diastereoselective reductive
amination protocol for the construction of the five-membered
C ring had to be established. But with successful and scalable
indolyl ketones in general,
they appeared to be disadvan-
tageous for the target cascade reaction. We assume that the
general reaction mechanism underlying these transformations
follows the “alkene-first” mechanism, or in this case, better de-
scribed as an “indole-first” mechanism, in which the first equiv-
alent of SmI initiates a single electron transfer (SET) to the
2
[9d,14d,f]
SmI -induced cyclization protocols in hand, we were confident
indole moiety (Scheme 2C).
This mechanism is assumed
2
to tackle these challenging tasks.
to dominate the reaction process when electron-withdrawing
groups significantly lower the redox potential of the indolyl
unit. In the alternative “carbonyl-first” mechanism, the elec-
tron-rich samarium ketyl has to attack C2 of the indole, which
seems here electronically less favorable. The predominant for-
mation of lactones (intermediate VII) suggest that either the
intramolecular acylation step (pathway B) was hampered due
to the attenuation of the nucleophilicity of the samarium eno-
late V (pathway A), or that tetracyclic intermediate VI (path-
way B) was unstable and underwent retro-Claisen reaction to
spiro-lactone precursor VII (pathway C) to give 11 after proto-
nation.
Results and Discussion
Elaboration of the cascade reaction
Indolyl ketones of type III (Figure 1) were easily obtained on
a large scale by acylation of the corresponding indole deriva-
[21]
tives with 4-oxopimelic acid or 4-oxopimelic acid monoester.
Our first foray began with the SmI -induced cyclization of
2
easy accessible symmetric bisindolyl ketones
9
and 12
We successfully demonstrated that the ex-
pected cyclization proceeded to give tetracycles of type II
[
14f,22]
(Scheme 2).
We reasoned that an electron-withdrawing 2-ethoxycarbonyl
substituent should also facilitate the SET from SmI2 to the
indole moiety and stabilize the generated radical anion with
a samarium enolate substructure. However, it was not clear
(Figure 1) even in the absence of hexamethylphosphoramide
(
HMPA), which is often required to enhance the reactivity of
[
14d,23]
the samarium ketyl.
We reasoned that electron-withdraw-
ing groups at C3 of the indole enhance the cyclization process
and stabilize the assumed intermediate samarium organyl for
whether
a
non-stabilized intermediate carbanion VIII
(Scheme 3) would undergo the intramolecular acylation reac-
&
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Scheme 2. A) First and B) second generation of cascade cyclizations of indolyl ketones with electron-withdrawing substituents at C3 of the indole moiety.
C) Mechanistic view: “indole-first” mechanism leading to cyclization products 10 and 11.
tion since an intermolecular version of the cyclization-trapping
the cascade reaction and afforded a slightly higher yield of
[
14c]
[24]
sequence failed previously.
To our surprise, cyclization of in-
product 20, although the combined yield of cyclized prod-
dolyl ketone 19 (Scheme 3A) proceeded smoothly and we
were able to isolate 32% of the desired product 20, in addition
to 21% of tetracyclic diol 21, whereas spiro-lactone 22 was
only obtained in 11%. Due to the comparable reactivity of the
ketone moiety of product 20, reduction to diol 21 occurred
almost simultaneously under the applied reaction conditions.
We tested different additives and found that HMPA facilitated
ucts decreased. This may be attributed to a likewise increased
[25]
rate of (reductive) deacylation of starting material.
Based on these encouraging results, we hypothesized that
indolyl ketones without a substituent at the pyrrole subunit
should also be able to undergo the cascade cyclization pro-
cess. We first tested unsubstituted indolyl ketone 23
(Scheme 3B), which underwent the anticipated cascade reac-
2 2
Scheme 3. A) SmI -induced cascade cyclization of indolyl ketone 19 with an electron-withdrawing substituent at C2; B) SmI -induced cascade cyclization of
unsubstituted indolyl ketone 23.
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Scheme 4. A) Base-promoted benzylation of tetracyclic indoline derivative 24; B) SmI
2
-induced cascade cyclizations of indolyl ketone 23 followed by an in situ
alkylation.
tion with good efficacy yielding diastereomerically pure tetra-
required for the construction of the strychnine key precursor I
(Figure 1).
[
17o]
cyclic product 24 as major product.
We also isolated diol 25
and spiro-lactone 26 in <5 and approximately 19% yield, re-
spectively.
Third generation of cascade cyclizations of indolyl ketones
We then studied the potential of the SmI -induced cascade
2
cyclization to be extended to an in situ-trapping sequence.
The feasibility of an intermolecular alkylation process was first
examined with tetracyclic compound 24 that was treated with
As a next logical step, we tested the crucial indolyl ketone 30,
which was easily obtained from 3-cyanomethylindole in 82%
yield (see the Supporting Information). Gratifyingly, treatment
potassium carbonate, catalytic amounts of n-Bu NI, and benzyl
of 30 with SmI /HMPA directly afforded 74% of the tetracyclic
4
2
bromide (Scheme 4A). The desired alkylation proceeded in
good yield and furnished compound 27 as a single diastereo-
mer (see IX). This experiment proves the fairly high acidity of
compound 28 accompanied by diol 31; low amounts of 24
and spiro-lactone 32 with an exo-methylene group were also
isolated (Table 1, entry 1).
[26]
the bridgehead hydrogen adjacent to the carbonyl group.
The formation of exo-methylene spiro-lactone 32 can be ra-
tionalized by a Lewis acid-assisted elimination of cyanide from
the unstabilized carbanion XI (Scheme 5) and subsequent lac-
tone formation. Dealkylated tetracyclic compound 24 is most
Subsequently, we investigated the cyclization sequence and in
situ substitution with precursor 23 by using either allyl iodide
or bromoacetonitrile as electrophiles, which were added short-
ly after decolorization of SmI to the reaction mixture (Sche-
likely formed by a subsequent SET (SmI ) to the carbonyl
2
2
[
14e–f]
me 4B).
In both reactions, the functionalized tetracycles 28
group of product XII. The generated intermediate, samarium
ketyl XIII (Scheme 5), can either undergo a reduction towards
and 29 were obtained in acceptable yields. We were particular-
ly delighted to isolate compound 28, which contains all atoms
diol 31 by a second equivalent of SmI or a reductive fragmen-
2
Table 1. Optimization of the cascade cyclization protocol of 3-(cyanomethyl)-substituted indolyl ketone 30.
[
a]
[b]
[c]
[c]
[c]
[c]
Entry
Conditions
Scale [mmol]
t [s]
Yield 28 [%]
Yield 31 [%]
Yield 24 [%]
Yield 32 [%]
1
2
RT, HMPA
RT
1
1
1
1
2
2.9
4.1
20
600
100
40
20
20
74
–
8
–
–
–
6
5
–
–
–
<5
–
5
–
–
22
4
5
[
27]
3
4
5
6
7
RT, TPPA, BrCH
RT, tBuOH, HMPA
RT, HMPA, BrCH CN
08C, HMPA, BrCH CN
RT, HMPA, BrCH CN
2
CN
45
29
77
72
41
2
2
–
11
2
40
15
5
[a] All reactions were carried out with 2.2–2.5 equiv SmI
2
in THF. [b] Time point of complete color change from purple–blue to beige–brown. [c] All yields
refer to separated and spectroscopically pure samples.
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tation under formation of an X SmCH CN species and of sa-
ketone 30 and its SmI -induced cyclization (63% yield for two
2
2
2
marium(III) enolate XIV, which after protonation affords com-
pound 24. Surprisingly, the protonation products of inter-
mediates X and XI were never detected after work up.
steps, 1.0–2.0 g scale), we started the exploration of the reduc-
[
9d]
tive amination reaction towards target structure
I
[28]
(Scheme 6).
Encouraged by the cyclization results, we investigated sever-
al other reaction conditions to optimize the formation of the
desired compound 28. We first tried to avoid the addition of
HMPA, but conversion to product 28 was not observed and
mainly starting material was re-isolated (Table 1, entry 2). Fortu-
nately, it was possible to replace HMPA with tripyrrolidino
By using our standard conditions for hydrogenations with
Raney nickel we obtained pentacyclic imine 34 in excellent
[14c]
yield (Scheme 6A).
During an attempted purification by
column chromatography on silica gel, we realized that 34
easily tautomerizes to its enamine form. This imine–enamine
isomerization was then exploited to prepare protected enam-
ine derivatives 35 and 36, which could subsequently be used
to prepare similar strychnine precursors as reported by Bod-
[
27]
phosphoric acid triamide (TPPA), giving lower, but still ac-
ceptable yields (Table 1, entry 3). In another attempt, tBuOH
was added as proton source to act as a buffer under the gen-
erated basic reaction conditions (Table 1, entry 4), but this re-
sulted only in 29% of 28 together with a mixture of unidenti-
fied side-products. We then reasoned that we could suppress
or reverse the formation of dealkylated product 24 by subse-
quent addition of the respective alkylating reagents analo-
[19]
well and Li. We tested different dehydrating methods, which
all resulted in the exclusive formation of the desired thermody-
namically favored conjugated dienes 37 and 38. Changing the
protection group of the secondary amine had no effect on the
regioselectivity of the elimination process, with yields ranging
from 80–90% for the two-step method, and 66–80% for the
[14e]
[29]
gously to our previously reported trapping experiments.
described one-pot method. Subsequent treatment of dienes
Performing the reaction under standard conditions, but adding
either bromo or iodo acetonitrile to the reaction after decolori-
37 or 38 with NaCNBH afforded protected amines 39 and 40
3
as single diastereomers in 78 and 40% yield, respectively. The
1
zation of the SmI solution, increased the overall yield of the
H NMR spectroscopic data of compound 39 were in full ac-
2
target compound 28 to 77%, whereas the side-product 24
was formed in less than 5% yield (Table 1, entry 5). Subse-
quently, we tried to scale up the reaction.
cordance with the data reported by Bodwell and Li who ach-
ieved the synthesis of this compound through their Diels–
[19]
Alder route (Scheme 6B). However, careful NOE and NOESY
experiments revealed a cis orientation of the bridgehead pro-
tons (H-11b and H-13a, XVI, Scheme 6A), and not the required
trans orientation for a strychnine synthesis. This unexpected
diastereoselectivity of the reduction step can only be explained
by the essentially planar geometry of amino dienes 37 and 38
(see conformation XV, Scheme 6A) and the resulting iminium
species. The attack of the hydride reagent occurs exclusively
from the top-face of the molecule, rather than from the more
shielded bottom-side. Although Bodwell’s synthetic precursor
42 lacks the carbonyl group in ring G (Scheme 6B), a very simi-
lar geometry of the amino diene moiety can be expected and
the described subsequent reduction with sodium borohydride
to 43 proceeds most likely in an analogous fashion from the
top-side of the molecule. Since compounds 43 and 39 do not
have the required configuration at the crucial bridgehead posi-
tion C13a, these intermediates cannot be suitable precursors
for strychnine. Hence, the claim of a formal total synthesis by
the Bodwell group has been disproved. Due to the structure
However, an increase in the reaction volume (Table 1, en-
tries 6 and 7) resulted only in lower yields of 28 and side-prod-
uct formation became more dominant, possibly due to slow
distribution of the components and increased local reaction
heat. Since the carbonyl groups of indolyl ketone 30 and that
of product 28 show similar reactivity upon exposure to SmI2,
this arising competition limits the ability to scale up the cycli-
zation reaction. We were further able to apply this method to
a number of differently substituted indolyl ketones that will be
reported in due course. In summary, the results involving the
third generation approach reveal that by understanding the
nature of the SmI -induced cascade cyclization process, we
2
were able to improve and optimize the reaction conditions.
Formal total synthesis of strychnine
By using our short and practical synthesis of tetracyclic com-
pound 28, which just involves an N-acylation step to indolyl
2
Scheme 5. Intermediates involved in the SmI -mediated cascade reaction of indolyl ketone 30.
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Scheme 6. A) Reduction of the cyanomethyl-substituted tetracyclic compound 28 with Raney nickel and related reductive amination procedures; B) Bodwell’s
[
19]
synthetic strategy towards key compound 39.
revision of compounds 39 and 43, we were compelled to find
an alternative synthetic strategy.
lease of stoichiometric amounts of water during imine forma-
tion caused partial catalyst inactivation. This assumption was
supported by the fact that the reduction of isolated imine 34
to amine 47 was accomplished in only 1–2 d by using a fresh
load of 100 wt% Raney nickel.
We continued to investigate the reduction of 28 with Raney
nickel in the presence of tert-butoxycarbonyl (Boc) anhydride
to determine how fast the formation of the free amine and the
condensation reaction proceed (Scheme 7A). After a reaction
time of one day, a mixture of protected primary amine 44, pro-
tected pentacyclic enamine derivative 45 and small amounts
of pentacyclic compound 46 were isolated. These results were
intriguing for several reasons: First, again they showed that
the exhaustive reduction of the cyano group was fast; second-
ly, subsequent reduction of the imine to a pentacyclic amine
was possible, but it presumably requires longer reaction times.
To gain more insight into the reactivity and diastereoselec-
tivity of the reduction, compounds 35, 36, and 45 were then
selectively reduced under acidic conditions with sodium cyano-
borohydride to the corresponding protected amines 46, 48,
and 49. In complimentary experiments, the treatment of sec-
ondary amine 47 with mesyl chloride, Boc anhydride, or
methyl chlorocarbonate afforded compounds 46, 48, and 49 in
[30]
even better overall yields. Comparison of the obtained NMR
data revealed that independent from the selected protecting
group and reduction method, the transfer of the hydride exclu-
sively proceeds from the back-side of the congested molecule,
affording the correct configuration at position C13a in all
cases. The next challenge was to find a suitable protocol for
the regioselective conversion of the tertiary alcohol into an
olefin with the double bond located in ring E. In a first at-
tempt, amines 48 and 49 were treated with Burgess’s reagent
(Table 2, entries 1 and 4), which after 2 h yielded a mixture of
the three possible regioisomeric compounds 50–52 (entry 1),
1
Although the H NMR spectroscopic and NOE data of 46 were
quite complex due to the broadening effect of the carbamate
group and two dominant rotamers, the relative configuration
was assigned as depicted in Scheme 7 (see XVII).
The observed high diastereoselectivity of the hydrogenation
reaction results most likely from the steric bulkiness of the ter-
3
tiary hydroxyl group at the sp -hybridized bridgehead carbon
and the strained geometry of ring C, which should disfavor the
hydrogenation from the top-face of the molecule. We then ex-
posed compound 28 to Raney nickel for three days in the ab-
sence of any protecting reagent (Scheme 7A) and obtained
almost quantitatively fully reduced amine 47. Subsequent ex-
periments also revealed that this reduction was strongly de-
pending on the quality of the Raney nickel, and that the re-
[17o,31]
and 53–55, respectively (entry 4) in good overall yield.
Screening of different reaction conditions such as solvent
and temperature failed to improve the regioselectivity, and re-
sulted in most cases in lower yields. We then turned our atten-
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Scheme 7. A) Reduction of tetracyclic compound 28 with Raney nickel. B) Formation of protected secondary amines.
Table 2. Investigation of different dehydratization methods towards Rawal’s strychnine precursor 50.
[
a]
[a]
[a]
Entry
R
Conditions
Product, yield [%]
Product, yield [%]
Product, yield [%]
1
2
3
4
48, CO
48, CO
48, CO
49, Ms
2
2
2
Me
Me
Me
Burgess’s reagent, toluene, 708C, 2 h
50, 37
50, 63
50, 85
53, 37
51, 25
51, 12
51, 4
54, ꢀ20
52, 18
52, 13
52, –
55, ꢀ20
[
b]
1) MsCl, DMAP , NEt
Martin’s sulfurane, NEt
Burgess’s reagent, toluene, 708C, 2 h
3
, 08C; 2) DBU, RT, 24 h
3
, DMF, À108C, 1 h
[a] Yields refer to separated and spectroscopically pure samples. [b] DMAP=4-dimethylaminopyridine.
tion to the methanesulfonyl chloride (MsCl)/1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU)-mediated elimination procedure
and found that the desired regioisomer was preferentially
formed (Table 2, entry 2). The best yield and selectivity, howev-
er, was obtained by applying the highly reactive
Ph S[OC(CF ) Ph] (Martin’s sulfurane) at lower reaction temper-
again that compound 50 is not identical with Bodwell’s and
Li’s compound 39 as clearly demonstrated by comparison of
the NMR data.
We then applied the dehydration protocol to N-alkylated
compounds 57 and 61 (Scheme 8A), which were obtained in
85 and 79% yield by simple alkylation of reduction product 47
with bromide 56 and tosylate 60, respectively. Despite the use
of low temperatures and longer reaction times, we observed
no significant regioselectivity in these elimination reactions, re-
gardless of the length of the N-alkyl side chain. We assume
that elimination occurs in an anti-fashion and therefore the
higher steric bulkiness of the N-alkyl group should not play an
important role. The lacking selectivity may therefore be attrib-
uted to an increased electron-donating effect of the N-sub-
2
3 2
2
[
32]
atures (Table 2, entry 3). Under the optimized conditions up
to 85% of isomer 50 was isolated and easily separated from its
isomer 51 (formed in 4%), whereas regioisomer 52 was not
observed under these conditions. The preferential formation of
regioisomer 50 may be explained by the lower reaction tem-
peratures, the suitable geometry with an antiperiplanar align-
ment of the CÀH bond (in ring E) and the CÀOX moiety func-
tioning as leaving group (XVIII, Table 2). It should be noted
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Scheme 8. A) Shortened approach, and B) original synthetic strategy towards Rawal’s strychnine precursor 64. [*]=the calculation of the total yield of strych-
nine (72%) is based on 62% recovered isostrychnine; for details, see refs. [17d] and [34].
stituents that should decrease the acidity of the hydrogen in
ring E. Since regioisomers 58/59 or 62/63 are easily separable
by using column chromatography, this protocol allowed us an
easy excess to reasonable quantities of strychnine precursor
[
17e]
62. Similar to the seminal protocol reported by Rawal,
we
converted carbamate 50 into 62 by TMSI-induced deprotection
and subsequent base-promoted alkylation procedure by using
tosylate 60 in 65% over two steps (Scheme 8B). Comparison
of our 1D- and 2D NMR data of strychnine precursor 62 with
the reported published values revealed a perfect match, con-
firming the identity of the compound and hence establishing
our formal total synthesis of strychnine. In a last step, we trans-
formed pentacyclic compound 62 to tert-butyldimethylsilyl
(
TBS)-protected isostrychnine 64 in 68% yield using the report-
[
33]
ed Heck reaction conditions. Again, the matching spectro-
scopic data of 64 further demonstrated the perfect concord-
ance of Rawal’s and our approach to strychnine. The abbreviat-
ed route using Martin’s sulfurane in the elimination reaction of
intermediate 61 allowed us to shorten the synthesis of TBS-
protected isostrychnine 64 to only six steps starting from com-
mercially available 3-indolyl acetonitrile with an overall yield of
Figure 2. Summary of the cascade cyclization and of our approach to strych-
nine.
[
34]
13.5%. During the entire sequence, only the TBS group of
the side chain served as a protecting group.
cyclization and of in situ functionalizations. The reaction mech-
anisms were discussed in detail on various occasions to help
us to understand and improve the processes involved.
Conclusion
We could also improve the cyclization protocol for the most
important tetracyclic intermediate 28, which was finally con-
verted into TBS-protected isostrychnine. It should also be
The approach to strychnine reported here clearly demonstrates
the impressive potential of the SmI -induced cascade reactions
2
and the applicability of the reductive dearomatization process-
es to rapidly construct fairly complex structures in an atom
economically fashion. New aspects of our work include the ex-
noted in this context that during the SmI -induced cyclization
2
of compound 30 to 28, the very first and crucial stereogenic
centers are generated. A conceivable enantioselective version
of this step may therefore not only establish the correct rela-
ploration of the reaction scope of the SmI -induced cascade
2
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Full Paper
tive configuration, but also the absolute configuration of tetra-
cyclic intermediate 28 and all subsequent products. It was also
necessary to optimize the reductive amination forming ring C
of strychnine. During these investigations we discovered that
a reported formal total synthesis of strychnine is unlikely to
generate the correct configuration at this subunit. By finding
a highly regioselective dehydratization method with Martin’s
sulfurane, we prepared the required pentacyclic compound 50
in excellent overall yield. We could thus minimize the use of
protecting groups and were able to reduce the necessary syn-
thetic steps starting from commercially available starting mate-
rials from ten (overall yield 14%) to eight (overall yield 10%) in
the longest linear sequence to strychnine. Figure 2 summarizes
our general strategy to prepare the crucial tetracyclic com-
pounds by the reductive cascade cyclization process and the
subsequent steps to the hexacyclic isostrychnine skeleton.
Classics in Total Synthesis III: Further Targets, Strategies, Wiley-VCH, Wein-
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Spain, D. J. Procter, Chem. Soc. Rev. 2013, 42, 9155–9183; h) M. Szostak,
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039.
Support of this work by the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie, the Studienstif-
tung des Deutschen Volkes (fellowships for C.B.), and Bayer
HealthCare is most gratefully acknowledged. We want to thank
Prof. V. Rawal for providing the original Supporting Informa-
tion, experimental procedures, and 1D spectra. We also thank
Prof. T. Bach (Technische Universitꢁt Mꢂnchen) for his sugges-
tion to try Martin’s sulfurane. We are grateful to Dr. R. Zimmer
and C. Bentz for their comprehensive assistance during the
preparation of this manuscript. The help of C. Groneberg for
HPLC separations and the NMR service team of Dr. A. Schꢁfer
for numerous NOE experiments is also gratefully acknowl-
edged. The picture of nux vomica is a courtesy of H. Zell
[
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strychnine.
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favored cis elimination.
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Received: January 9, 2015
SmI
2
; it is therefore required for many ketyl coupling reactions, see:
Published online on && &&, 2015
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ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
&
Total Synthesis
C. Beemelmanns, H.-U. Reissig*
& – &&
&
Evolution of a Short Route to
Strychnine by Using the Samarium
Diiodide-Induced Cascade Cyclization
as a Key Step
Poisonous cascade: This comprehen-
sive report details the development of
a highly diastereoselective samarium
diiodide-induced cascade reaction of
substituted indolyl ketones. The trans-
formation of our key cascade product
gave way to one of the shortest ap-
proaches towards strychnine (see
scheme; 14% overall yield in ten steps,
or 10% overall yield in eight steps).
Step by step uphill to deadly
complexity….. A samarium
diiodide mediated cascade
cyclization allows one of the most
efficient synthetic approaches to
the legendary alkaloid strychnine.
Two six-membered rings and three
stereogenic centers including
a quaternary center were generated
in the key step. All selectivity
problems encountered in the
preparation of the crucial strychnine
precursor isostrychnine were
elegantly by-passed leading to one
of the shortest syntheses of these
complex alkaloid skeletons reported
to date. More details of this
research are provided in the Full
Paper by C. Beemelmanns and H.-U.
Reissig on p. &&ff.
Chem. Eur. J. 2015, 21, 1 – 11
www.chemeurj.org
11
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ