Indole alkaloids synthesis via a selective cyclization of aminocyclopropanes

Article abstract of DOI:10.2533/chimia.2012.233

The continuous progress in medicinal chemistry requires more versatile synthetic strategies for the generation of large libraries of active compounds and their analogues. As a result, the research for new effective cyclization and cycloaddition reactions is an essential task in organic chemistry. In 2008 we developed the first catalytic formal homo-Nazarov reaction starting from activated cyclopropanes. Herein we report the extension of the catalytic formal homo-Nazarov cyclization to aminocyclopropanes. Highly diastereoselective cyclizations were obtained via an acyliminium intermediate generated through opening of the cyclopropane. An excellent control over the regioselectivity of either the C-C or C-N cyclization in the case of free indoles as nucleophilic partners was achieved. The utility of the developed methodology was demonstrated by the generation of the polycyclic scaffolds of Aspidosperma and Gonioma natural products starting from a common intermediate. Based on this method, a formal total synthesis of the alkaloid aspidospermidine and the total synthesis of the alkaloid goniomitine are presented. Finally, the scope and limitations of our methodology are discussed on an extended range of vinyl-cyclopropyl ketones with cyclic or acyclic carbamates, as well as ethers as donor groups on the cyclopropane. Schweizerische Chemische Gesellschaft.

Full text of DOI:10.2533/chimia.2012.233

Laureates: awards and Honors, sCs FaLL Meeting 2011
CHIMIA 2012, 66, No. 4 233
doi:10.2533/chimia.2012.233
Chimia 66 (2012) 233–236 © Schweizerische Chemische Gesellschaft
Indole Alkaloids Synthesis via a Selective
Cyclization of Aminocyclopropanes
Filippo De Simone§ and Jérôme Waser*
§SCS-DSM Award for best poster presentation
Abstract: The continuous progress in medicinal chemistry requires more versatile synthetic strategies for the
generation of large libraries of active compounds and their analogues. As a result, the research for new effective
cyclization and cycloaddition reactions is an essential task in organic chemistry. In 2008 we developed the first
catalytic formal homo-Nazarov reaction starting from activated cyclopropanes. Herein we report the extension
of the catalytic formal homo-Nazarov cyclization to aminocyclopropanes. Highly diastereoselective cyclizations
were obtained via an acyliminium intermediate generated through opening of the cyclopropane. An excellent
control over the regioselectivity of either the C–C or C–N cyclization in the case of free indoles as nucleophilic
partners was achieved. The utility of the developed methodology was demonstrated by the generation of the
polycyclic scaffolds of Aspidosperma and Gonioma natural products starting from a common intermediate.
Based on this method, a formal total synthesis of the alkaloid aspidospermidine and the total synthesis of the
alkaloid goniomitine are presented. Finally, the scope and limitations of our methodology are discussed on an
extended range of vinyl-cyclopropyl ketones with cyclic or acyclic carbamates, as well as ethers as donor groups
on the cyclopropane.
Keywords: Activated cyclopropanes · Alkaloids · Heterocycles · Regioselectivity · Total synthesis
(Scheme 1).[2] Different from the concert- (Scheme 2). Indeed, the presence of a het-
ed Nazarov cyclization, the cyclization of eroatom would assure a good stabilization
Introduction
vinyl-cyclopropyl ketones proceeds via a of the formed carbocation, as demonstrat-
Carbocyclic and heterocyclic scaffolds
play a key role in natural and pharmaceuti-
cal compounds.[1] Rigidified ring systems
assure a better stability and a well-defined
tridimensional arrangement of functional
groups allowing stronger and more se-
lective interactions with receptors or en-
zymes. Consequently, the development of
new efficient processes for the synthesis
of carbocycles and heterocycles is a fun-
damental task for an organic chemist.
stepwise process involving a carbocationic ed by the broad literature of donor–accep-
intermediate III.
tor cyclopropanes,[4] and would extend the
In 2009, we reported the development range of structures accessible. In particu-
of the first catalytic method for the homo- lar, the cyclohexylamines which could be
Nazarov reaction of vinyl-cyclopropylke- obtained through the cyclization of ami-
tonesusingacatalyticamountofaBrønsted nocyclopropanes can be found in several
acid in acetonitrile.[3] Although the discov- natural alkaloids such as aspidospermidine
ery of the new catalytic conditions for the (1), aspidofractinine (2), strychnine (3),
formal homo-Nazarov cyclization allowed vindoline (4), vindolinine (5), vinblastine
the application of our method to several (6) and vincristine (7) (Scheme 2).An ami-
unprecedented heterocyclic structures, the nocyclopropane could be used as precur-
required presence of an aromatic group sor of an iminium intermediate in the for-
to stabilize the carbocationic intermedi- mal homo-Nazarov cyclization. However,
ate still constituted a severe limitation in aminocyclopropanes with no electron-
Starting from the Nazarov reaction, the
replacement of the double-bond by a cy-
clopropane could give access to larger ring
systems via a ‘homo-Nazarov’ cyclization
terms of scope.
withdrawing groups are unstable and the
We report herein the extension of the presence of an electron-withdrawing group
methodology obtained replacing the aro- on the nitrogen would be required to pre-
matic stabilizing group by a heteroatom vent the opening of the cyclopropane ring.
Scheme 1.
ANazarov Cyclizatio
n
Mechanism of the
Nazarov and formal
homo-Nazarov reac-
tion.
H
O
OH
O
O
H
conrotatory
ring closure
H
R
1
2
1
2
1
2
R
R
R
1
2
R
R
R
R
*Correspondence: Prof. Dr. J. Waser
Ecole Polytechnique Fédérale de Lausanne
Laboratory of Catalysis and Organic Synthesis
EPFL SB ISIC LCSO
BCH 4306
CH-1015 Lausanne
Tel.: +41 21 693 93 88
Fax: +41 21 693 97 00
E-mail: jerome.waser@epfl.ch
I
II
H
BFormal Homo-Nazarov
OL
A
R
OLA
O
O
LA
2
2
2
2
ED
G
E
D
G
R
E
D
G
R
E
D
G
R
H
1
1
3
1
R
1
R
R
R
R
IV
3
3
3
III
R
R
LA
R

234 CHIMIA 2012, 66, No. 4
Laureates: awards and Honors, sCs FaLL Meeting 2011
Scheme 2. Formal
the more stable exo form 10a with cata-
O
H
O
O
N
H
A
HA
homo-Nazarov cycli-
zation of aminocyclo-
propanes and alkaloid
natural products con-
taining a cyclohexyl-
amine ring.
1
1
1
lytic BF3·OEt . This isomerization, first
X
R
X
R
X
R
introduced by 2Grieco, was proposed to oc-
R
2
N
cur via a ketene iminium salt.[6] Ester 10a
O
N
O
3
2
R
O
R
Et
R
2
was then hydrolyzed to give a single dia-
3
3
R
R
stereoisomers of carboxylic acid 11. The
H
O
O
choice of the right conditions to convert the
sensitive cyclopropane 11 into the Weinreb
amide 12 in good yield was crucial. After
a short screening of coupling reagents, we
selected 4-(4,6-dimethoxy-1,3,5-triazin-
H
H
H
N
H
H
N
N
H
N
N
N
Aspidospermidine (1)
Aspidofractinine(2)
Strychnine (3)
H
N
O C 2
O Me
Ac
Et
R
2-yl)-4-methylmorpholinium
chloride
H
O
H
O
CO2Me
CO2Me
Me
H
H
(DMTMM) since it allowed the formation
of the amide 12 in good yield and without
further purification. With these encour-
aging results in hand, we decided to syn-
Me
O
Et
Ac
N
N
MeO
O
N
MeO
Me
O
H
N
N
H
N
Et
OH
thesize the free indole cyclization precur-
N
Vindoline (4)
Vindolinine (5)
sor 14. The use of indole N-carboxylates
R=Me: Vinblastine (6)
R=C O: Vincristine (7)
pioneered by Katritzki[7] was considered
the more appropriate choice. Indeed, the
carboxy group presented the advantage to
direct selectively the lithiation on the C(2)
H
afforded enamide 9 in good yield (Scheme
benzyl-carbamoyl protecting
In this context, acylamino cyclopropanes
represent a good compromise in terms of
reactivity, since they are sufficiently elec-
tron-rich to promote the ring opening and
stabilize the formed cation as an acylimin-
ium species (I), but are stable enough to be
isolated (Scheme 2).
We propose herein the first utilization
of the catalytic formal homo-Nazarov cy-
clization of aminocyclopropanes in the
synthesis of a natural product. Based on
this method, a formal total synthesis of the
Aspidosperma alkaloid aspidospermidine
(1) is presented.
Moreover, the versatility of our cycli-
zation method is demonstrated by its suc-
cessful application in the total synthesis
of the natural alkaloid goniomitine (21),
accomplished in 13 linear steps with an
overall yield of 11%.
Finally, the scope and limitations of our
methodology are investigated for a wide
range of vinyl-cyclopropyl ketones.
3).[6] The
position of indole and to protect the indole
nitrogen at the same time. Furthermore,
the obtained carboxy indole is labile and
underwent decarboxylation upon work
up to give directly the unprotected prod-
uct. Nevertheless, the literature about this
method included only examples with more
simple substrates. Using isolated and re-
crystallized indole-N-carboxylic acid 13
we were pleased to isolate the precursor
14 for the formal homo Nazarov cycliza-
tion in good yield.
group was chosen due to its tolerance to-
wards acidic conditions and its easy re-
moval under mild conditions (for example
via hydrogenation), as well as in order to
obtain the desired electron-density on the
nitrogen.
It was important to finely tune the prop-
erties of the catalyst and the reaction time
in order to obtain reproducible yield for
the cyclopropanation of 9. On preparative
scale, a diasteromeric mixture (1:1 dr) of
cyclopropane ethyl esters 10a,b was ob-
tained using copper (i) triflate and ethyl di-
azoacetate in a reproducible 76% of yield.
Endo ester 10b was then isomerized into
Surprisingly, when we attempted the
cyclization of 14 using our standard con-
ditions for the formal homo-Nazarov re-
action, two different compounds were
Scheme 3. Synthesis
of indole-substituted
cyclopropane 14.
Cbz
N
Cbz
N
Cbz
N
H
N
a) BuLi, CbzCl
EtI, 67%
Cu(I) cat,
H
O
O
O
BF •Et O
N2CHCO2Et,
76%
3
2
b) NaB 4
H
95%
EtO
EtO
Et
Et
Et
c) H2SO4
8
9
10a-b
10a
93% overall
dr: 1:1
NaO
H
95%
D MM
MT
Cbz
N
Cbz
N
Cbz
N
N
O
13 C
OOH
H
Et
H
MeN CH3•HCl,
H
O
O
O
Formal Total Synthesis of
Aspidospermidine
93%
t
BuLi, LiCl
67%
O N
Me
HO
H
N
Et
Et
Me
14
12
11
When considering potential targets for
the formal homo-Nazarov cyclization of
aminocyclopropanes, we decided to at-
tempt first a synthesis of the Aspidosperma
alkaloid aspidospermidine (1). We select-
ed this alkaloid, isolated from the bark of
Aspidosperma quebracho blanco and other
species native of South America,[5] since
it is the simplest natural product contain-
ing the tetracyclic scaffold also present in
many more complex alkaloids. A new con-
vergent approach to the total synthesis of
Aspidosperma alkaloids would give access
to a wide range of potentially bioactive nat-
ural compounds and synthetic analogues.
Starting from commercially available
δ-valerolactam (8), a sequence of protec-
tion, alkylation, reduction and dehydration
Scheme 4.
O
TsO
H
O
Et
H
N
Et
H
N
Cyclization of cy-
clopropane 14 and
determination of the
relative configuration
of cis-17 and cis-18.
H ,Pd/C
20 mol %
N
2
HN
14
Cbz
Et
H
Et
H
EtO
H
CH3C
N
N
N
O
O
74%
quant.
H
H
N
H
N
Cbz
cis-15
cis-16
cis-17
cis-18
ratio 1.6 :1
cis-18
cis-17
cis-17
1
H
2 a
1
H
1
H
c
H
H
n
H
b
2
H
H
f
H
N
H
C
H
2
d
o 3
H m
H
1
l
i
H
N
2
H
e
H
g
h
H
H
O
Importantcorrelations NOESY:
f
a
1
f
n
f
o
f
e
1
f
m
H -H ;H-H ;H-H ;H-H ;H-H .

Laureates: awards and Honors, sCs FaLL Meeting 2011
CHIMIA 2012, 66, No. 4 235
isolated. NMR and X-ray analysis carried goniomitine scaffold cis-16 was obtained
out after separation of the two cyclization with high yield and diastereoselectivity.
Moreover, in both the cyclization
mechanism, the regioisomers were ob-
products and removal of the Cbz protect-
One of the possible explanations for tainedaspurediastereoisomers.Qualitative
ing group allowed the identification of the the observed selectivity could lie in the analysis of the possible transition states
desired product cis-15 derived from the hard/soft properties of the generated enol suggested that a classical Fürst-Plattner
attack on indole at the C(3) position and intermediates which allowed the selective stereocontrol could be the basis for the
the compound cis-16 resulting from cy- formation of either the kinetic or the ther- high stereoselectivity observed for this
clization on the N(1) position in a ratio modynamic product. When the aminocy- particular cyclization.[10]
of 1.6:1 (Scheme 4). The isolation of free
clopropane is activated with Cu(OTf)2 the
amine cis-17 accomplished the successful formed copper-bound enolate would have
formal total synthesis of aspidospermi- a ‘soft’ character, which could favor the at- Total Synthesis of Goniomitine
dine (1), since this intermediate had been tack of the acyl iminium on the softer C(3)
reported in the synthesis by Wenkert and indole position. Proton-transfer and rearo-
In order to finish the total synthesis of
Hudlicky.[8]
matization of the cyclization product lead goniomitine, we considered a more con-
to the more stable thermodynamic product vergent approach starting from the cycli-
cis-15. Moreover, the polar solvent is fun- zation precursor 19. Cyclopropane 19 was
damental to stabilize the charged iminium obtained from the addition of a bislithiated
Selective Cyclization
intermediate so that the charge-controlled salt of TIPS-protected and N-carboxylated
In order to improve the selectivity to- reaction with the nitrogen becomes slower tryptophol on Weinreb amide 12.
wards C–C cyclization, we tested several compared with the attack from the carbon
The indole 19 was then cyclized in
presence of catalytic p-toluenesulfonic
On the other hand, the use of TsOH acid in dichloromethane (Scheme 6). The
combinations of acid catalysts and sol- atom.
vents (Scheme 5). We were pleased to note
that softer Lewis acid such as copper salts would generate a hard enol which could presence of the alkyl chain at C(3) had no
increased dramatically the regioselectiv- lead to the attack of the iminium on the negative influence on the cyclization rate,
ity toward the C–C cyclization allowing harder N(1) position of indole. The non-
the formation of the desired cyclic com- coordinating effect of methylene chloride, good yield as a pure diastereoisomer.
pound cis-15 as a pure diastereoisomer would hence favor a fast charge-controlled The carbonyl group was then reduced
and the desired product 20 was obtained in
in good yield. The N-cyclization product
attack on the harder nitrogen. The formed with sodium borohydride and the resulting
cis-16 was also highly interesting, since intermediate, through deprotonation and alcohol acetylated in order to facilitate the
it represented the tetracyclic core of go- tautomerization would yield the kinetic cleavage of the C–O bond. The acetate and
niomitine (21). Considering the rarity of product cis-16.
the benzyl carbamate were cleaved during
In order to confirm this hypothesis, hydrogenolysis and the deprotection of the
this scaffold in nature, the few examples
of reported synthetic approaches[9] and the we analyzed the interconversion of the primary alcohol using TBAF finally gave
absence of any information on its bioactiv- two cyclic compounds under the reaction goniomitine (21) in 77% overall yield from
ity, we decided to optimize the cyclization conditions used to obtain the opposite re- 20.
towards the formation of the N(1) cycliza- gioisomer. In presence of copper triflate in
The total synthesis of goniomitine (21)
tion product. During the screening of sev- acetonitrile, it was possible to convert the was accomplished in a linear sequence of
eral different solvents we were delighted cyclic compound cis-16 into the regioiso- 13 steps with an overall yield of 11%.[11]
to find a remarkable switch of selectivity mer cis-15, while no interconversion was This synthesis represents up to date the
when p-toluenesulfonic acid was tested observed when cis-15 was submitted to p- most efficient way to obtain goniomitine
in dichloromethane. The formation of the
toluenesulfonic acid in dichloromethane.
(21) as a racemic mixture. Moreover our
convergent approach could be applied to
introduce a broad structural diversity on
the indole and piperidine moiety.
Scheme 5. Regio-
and diastereoselec-
tive cyclization of
aminocyclopropane
14.
Cbz
N
cis-15 : cis-16
Catalyst Solvent
O
1.6
7
:
:
:
1
1
21
TsOH CH3C
N
Cu(OTf) CH3CN
HN
2
Scope Extension
Et
14
1
TsOH CH2Cl2
With the optimized conditions for the
regioselective cyclization in hand, we de-
cided to synthesize a further series of sub-
strates in order to extend the scope of this
new reaction (Scheme 7). Modifications of
the hetero-aromatic part of the molecule
were first considered. Using the conditions
optimized for the cyclization of aminocy-
clopropane 14, we were pleased to observe
Cu(OTf)
CH2Cl2,2rt
15 min
TsOH
80%
85%
CH3CN, rt
15 min
H
N
O
Cu(OTf)
CH2Cl2,2rt
N
Et
Cbz
H
N
H
Et
48h
>90%
Cbz N
O
a high yielding cyclization with a complete
control on the regiochemistry for methoxy-
indoles 22a and 22b. When pyran was used
cis-15
cis-16
as nucleophile (23), the cyclization prod-
uct 29 was obtained using p-toluenesulfon-
ic acid as catalyst in acetonitrile.
Scheme 6. Total syn-
thesis of goniomitine
(21).
Cbz
N
H
N
N
Cbz
Et
Et
a) NaBH4;b)Ac O;
O
c) H ,Pd; d) T 2
B
AF
H
H
TsOH, DCM
N
N
2
The scope was then extended to acy-
clic aminocyclopropanes (24 and 25) and
HN
93%
Et
O
77% overall
OTIPS
an oxycyclopropane (26).[12] For N-methyl
O
H
OTIP
S
19
20
(±)-Goniomitine(21)
indole 24, cyclization was successful, but a

236 CHIMIA 2012, 66, No. 4
Laureates: awards and Honors, sCs FaLL Meeting 2011
Scheme 7. Extension
of the cyclization
scope.
not limited to the formal homo-Nazarov
process, and further applications in other
type of cyclization or intermolecular an-
nulation reactions can be expected in the
future.[13]
O
O
Et
29
78%
CbzN
N
O
N
Cbz
Et
Me
N
TsOH,
H3CN,
rt
H
N
C
Received: January 13, 2012
R
O
TsO
H
Cbz
O
28a-b
86-92%
Cbz Bn
30
CH3CN,
N
CH3CN, rt
[1] J. Clardy, C. Walsh, Nature 2004, 432, 829.
[2] a) W. S. Murphy, S. Wattanasin, Tetrahedron
O
T
FA,
89%
O
Me
N
Et
23
Cbz
N
Lett. 1980, 21, 1887; b) O. Tsuge, S. Kanemasa,
T. Otsuka, T. Suzuki, Bull. Chem. Soc. Jpn.
1988, 61, 2897; c) F. De Simone, J. Waser,
Chimia 2009, 63, 162.
rt
O
Bn
N
O
Cu(OTf)
2
H
R
24
O
N
CH2Cl2,
X
1
Cbz
H
N
R
Et
rt
5
22a-b
4
R
3
2
[3] F. De Simone, J. Andres, R. Torosantucci, J.
Waser, Org. Lett. 2009, 11, 1023.
[4] a) H. U. Reissig, R. Zimmer, Chem. Rev. 2003,
R
R R
R
H
Et
O
H
N
O
Cbz N
H
O
R
N
27a-b
Bn
TsOH,
H3CN,
rt
103, 1151; b) F. Gnad, O. Reiser, Chem. Rev.
2003, 103, 1603; c) M. Yu, B. L. Pagenkopf,
Tetrahedron 2005, 61, 321; d) C. A. Carson,
M. A. Kerr, Chem. Soc. Rev. 2009, 38, 3051; e)
F. De Simone, J. Waser, Synthesis 2009, 3353;
f) T. P. Lebold, M. A. Kerr,. Pure Appl. Chem.
2010, 82, 1797.
N
88-95%
26
C
25
Cbz
a R=4-OMe
b R=5-OMe
BF ·Et O,
3
2
Cu(OTf) ,
CH3CN2,
rt
HO
CH2CH2,
rt
N
O
O
H
N
O
31
O
N
75%
[5] G. Fraude, Berichte 1878, 11, 2189.
[6] P. A. Grieco, M. D. Kaufman, J. Org. Chem.
33
65%
32
70%
N
Cbz Bn
1999, 64, 7586.
[7] A. R. Katritzky, K. Akutagawa, Tetrahedron
Lett. 1985, 26, 5935.
[8] E. Wenkert, T. Hudlicky, J. Org. Chem. 1988,
eral successful applications in the synthe-
sis of complex polycyclic scaffolds and the
total synthesis of natural products.
milder acid (TFA) had to be used to prevent
53, 1953.
formation of side products via hydrolysis
and elimination to give a carbazole. In the
case of unprotected indole 25, cyclization
on either C(3) or N(1) could be again ob-
tained in dependence on the choice of cata-
lyst. Oxycyclopropane 26 gave N(1) cycli-
zation product 33 exclusively, but required
the use of a stronger Lewis acid.
[9] a) C. Hashimoto, H. P. Husson, Tetrahedron
Lett. 1988, 29, 4563; b) S. Takano, T. Sato, K.
Inomata, K. Ogasawara, J. Chem. Soc. Chem.
Commun. 1991, 462; c) G. Lewin, C. Schaeffer,
Nat. Prod. Lett. 1995, 7, 227; d) G. Lewin,
C. Schaeffer, P. H. Lambert, J. Org. Chem.
1995, 60, 3282; e) G. Lewin, C. Schaeffer, R.
Hocquemiller, E. Jacoby, S. Leonce, A. Pierre,
G. Atassi, Heterocycles 2000, 53, 2353; f) C. L.
In a broader sense, our method allowed
access to iminiums under mild conditions
based on the release of ring strain and
cross polarization. When considering the
utility of such reactive intermediate in the
synthesis of complex structure, the formal
homo-Nazarov cyclization is expected to
be broadly applicable for the synthesis of
other natural and synthetic bioactive com-
pounds. Moreover, the development of
an asymmetric cyclopropanation method
would allow an asymmetric entry into im-
portant building blocks for the synthesis of
natural products.
Morales, B. L. Pagenkopf, Org. Lett. 2008, 10,
157; g) M. Mizutani, F. Inagaki, T. Nakanishi,
C. Yanagihara, I. Tamai, C. Mukai, Org. Lett.
2011, 13, 1796.
Conclusion
[10] F. De Simone, J. Gertsch, J. Waser, Synlett
2011, 589.
In conclusion, we have developed the
first catalytic formal homo-Nazarov re-
action and discovered also other types of
cyclizations for donor–acceptor activated
[11] F. De Simone, J. Gertsch, J. Waser, Angew.
Chem. Int. Ed. 2010, 49, 5767.
[12] F. De Simone, T. Saget, F. Benfatti, S. Almeida,
J. Waser, Chem. Eur J. 2011, 17, 14527.
[13] a) F. De Nanteuil, J. Waser, Angew. Chem.,
The principle of cyclopropane activa-
cyclopropanes. The versatility of our meth-
Int. Ed. 2011, 50, 12075. b) F. Benfatti, F. De
tion discovered in this project are certainly
odology has been showcased through sev-
Nanteuil, J. Waser, Org. Lett. 2012, 14, 386.