Total Synthesis of (-)-Rhazinilam and Formal Synthesis of (+)-Eburenine and (+)-Aspidospermidine: Asymmetric Cu-Catalyzed Propargylic Substitution

Article abstract of DOI:10.1021/acs.orglett.7b02619

A total synthesis of (-)-rhazinilam and formal syntheses of (+)-eburenine and (+)-aspidospermidine that rely on a copper(I)-catalyzed asymmetric propargylic substitution as the key step are reported. A salient feature of the reaction is the asymmetric con

Full text of DOI:10.1021/acs.orglett.7b02619

Letter
pubs.acs.org/OrgLett
Total Synthesis of (−)-Rhazinilam and Formal Synthesis of
(+)-Eburenine and (+)-Aspidospermidine: Asymmetric Cu-Catalyzed
Propargylic Substitution
Andrej Shemet and Erick M. Carreira*
ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland
̈
̈
S
* Supporting Information
ABSTRACT: A total synthesis of (−)-rhazinilam and formal syntheses of (+)-eburenine and (+)-aspidospermidine that rely on
a copper(I)-catalyzed asymmetric propargylic substitution as the key step are reported. A salient feature of the reaction is the
asymmetric construction of a quaternary stereocenter in high yield and enantiomeric excess.
he monoterpene indole alkaloid (−)-rhazinilam (1) was
T
originally isolated from the plant species Rhazya stricta,
which grows wild in the desert regions of Iraq, Saudi Arabia,
and Yemen as well as northwestern regions of the Indian
subcontinent.1 Biological studies of 1 revealed cytotoxic activity
toward various cancer cell lines in the low micromolar range in
vitro,2 where it was shown to inhibit microtubule assembly and
disassembly as well as the formation of abnormal tubulin
spirals.3,4 Accordingly, (−)-rhazinilam (1) has been recognized
as a lead compound for the development of new antitumor
agents. Structurally, this natural product contains a nine-
membered lactam fused to a 5,6,7,8-tetrahydroindolizine
possessing a quaternary stereocenter.
The unique structure of rhazinilam (1), coupled with its
potent biological activity, sparked interest within the synthetic
community. In the early 1970s, Smith and co-workers disclosed
the first total synthesis of ( )-rhazinilam.5a To date, various
approaches toward the synthesis of rhazinilam (1) have been
reported in the literature.5−7 Within these approaches, the
stereocontrolled formation of the quaternary center has
typically represented a key challenge.6,8 Complex structures
such as these compel researchers to develop novel strategies
and methods for their construction. In previous asymmetric
syntheses of (−)-rhazinilam, the stereoselective formation of
the quaternary center was achieved by nucleophilic attack of a
pyrrole on various electrophilic sites (Figure 1A). Nelson and
co-workers reported a Au(I)-catalyzed addition of pyrrole to an
enantioriched allene,6b and Banwell and co-workers employed
chiral amine organocatalysis to effect conjugate addition of a
Figure 1. Structure and syntheses of (−)-rhazinilam (1).
pyrrole.6c Herein we report the development of an intra-
molecular Cu-catalyzed asymmetric propargylation using a
pyrrole as a C-nucleophile and its application to the total
Received: August 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02619
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
synthesis of (−)-rhazinilam (1) and formal syntheses of
(+)-eburenine (8) and (+)-aspidospermidine (9) (Figure 1B).
Recently, asymmetric Cu-catalyzed substitution reactions of
racemic propargyl alcohol derivatives have attracted consid-
erable attention (Scheme 1).9 Several classes of nucleophiles,
Table 1. Optimization of the Reaction Conditions
Scheme 1. Copper-Catalyzed Propargylic Substitution
b
c
d
entry
L
[Cu]
solvent
t (h) yield (%)
e.r.
1
2
(S)-L1
(S)-L1
(S)-L1
(S)-L1
(S)-L2
(S)-L3
(S)-L4
(S)-L5
(S)-L5
(S)-L5
(S)-L5
(S)-L5
(R)-L5
A
A
A
A
A
A
A
A
B
C
B
B
B
toluene
THF
24
24
10
12
12
10
10
10
10
10
8
47
36
55
86
83
78
87
84
95
92
95
89
90
−
−
3
acetone
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
TFE
60:40
71:29
76:24
80:20
68:32
82:18
82:18
81:19
86:14
90:10
11:89
4
including alcohols, amines, and sulfides, have been used to
efficiently generate propargylic stereocenters with high levels of
enantioselectivity.10 These reactions exploit the ability of
copper acetylides A, generated from terminal propargylic
alcohol derivatives, to form copper allenylidenes B, which are
electrophilic at the carbon γ to the copper center. Indeed,
modifying copper with chiral ligands renders the subsequent γ-
attack enantioselective, thus generating the corresponding
optically active substitution products. Success has also been
found using C-nucleophiles, yet the extension of this class of
nucleophiles to substrates leading to quaternary centers still
remains limited. The sole report was by Nishibayashi in 2016,
wherein an intermolecular asymmetric Cu-catalyzed indole
propargylation was developed using racemic tertiary trifluor-
omethylated propargylic esters.11
5
6
7
8
9
10
11
e
12
TFE
26
26
ef
,
13
TFE
a
Reaction conditions: [Cu] (5 mol %) and ligand (10 mol %) in the
b
solvent (0.1 M) from −8 to 0 °C. A: (CuOTf)2·C6H6; B:
[(CH3CN)4Cu]PF6; C: [(CH3CN)4Cu]BF4. THF = tetrahydrofuran;
c
d
e
TFE = 2,2,2-trifluoroethanol. Isolated yields. At −25 °C for 26 h.
f
(R)-7 was obtained as the major enantiomer.
We saw the chemistry of copper allenylidenes as an
opportunity to design a synthetic approach to (−)-rhazinilam
that centers on a novel intramolecular Cu-catalyzed prop-
argylation of a pyrrole as the asymmetry-generating step in the
route (Figure 1B). This strategy would allow the highly efficient
construction of the 5,6,7,8-tetrahydroindolizine core while
preserving an alkyne as a useful functional group handle.
Cyclization precursor 6 was easily synthesized in four steps
from known pyrrole 12 as shown in Scheme 2.12 With 6 in
hand, we began screening reaction conditions for the planned
Cu-catalyzed asymmetric propargylation substitution.
7 was isolated in 83% yield with 76:24 e.r. (entry 5). These
promising results prompted us to further modify the
substitution pattern of the oxazoline. Hence, naphthyl-
substituted ligand L3 and trimethoxy-substituted ligand L5
were synthesized and tested. Slightly higher selectivity was
achieved with ligand L3 (entry 6), and to our delight, alkyne 7
was isolated in 84% yield with 82:18 e.r. when L5 was
employed (entry 8). The use of different copper sources such
as [(CH3CN)4Cu]PF6 and [(CH3CN)4Cu]BF4 provided
slightly higher yields in the reaction (entries 9 and 10).
Importantly, we noted that the enantioselectivity of the reaction
could be slightly improved by switching to 2,2,2-trifluoroetha-
nol as the solvent at −25 °C. Under these conditions, bicyclic
alkyne 7 was obtained in 89% yield with 90:10 e.r. (entry 12). It
should be noted that the use of activating groups other than
acetate, such as propargylic carbonates, did not lead to any
further improvement in the yield or e.r. The corresponding free
propargylic alcohol did not show any reactivity under the
optimized conditions and led only to recovery of the starting
material.
Scheme 2. Synthesis of Cyclization Precursor 6
With the optimized conditions in hand, our focus turned
toward the completion of the synthesis of (−)-rhazinilam. As
shown in Scheme 3, deprotonation of alkyne 7 and subsequent
trapping with ethyl chloroformate followed by hydrogenation
using Adam’s catalyst afforded ester 15 in 75% yield. To our
surprise, the use of standard peptide coupling reagents to
convert the free acid to amide 16 failed because of the high
nucleophilicity of the pyrrole and instead led to acylation at C3
of the pyrrole. However, the condensation of 15 with 2-
iodoaniline could be effected in 97% yield using AlMe3.
With this material in hand, we turned our attention to the
formation of the nine-membered lactam 18. In earlier
syntheses, Trauner and co-workers demonstrated that the
Initially, the combination of (CuOTf)2·C6H6 and a series of
PyBOX ligands, which were previously reported to effectively
act as ligands in Cu-catalyzed enantioselective propargylic
amination, were tested (Table 1).10a,b An initial solvent and
base screening revealed that MeOH and Hunig’s base were
̈
optimal. Furthermore, experiments employing L1−L5 allowed
the desired bicyclic alkyne 7 to be obtained in high yield, yet
only moderate levels of enantioselectivity were observed.
Phenyl-substituted oxazoline L1 resulted in a moderate e.r. of
71:29 (entry 4). When the electron density of the ligand was
increased by methoxy substitution of the aromatic ring, alkyne
B
DOI: 10.1021/acs.orglett.7b02619
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Completion of the Total Synthesis of
(−)-Rhazinilam
Scheme 5. Formal Syntheses of (+)-Eburenine and
(+)-Aspidospermidine
formation of similar macrocycles could be achieved by Pd-
catalyzed biaryl coupling.5d,13 In line with these reports, 16 was
protected, giving 17 in 71% yield. However, Trauner’s
conditions led to isolation of the desired product in only
10% yield. Extensive screening studies were necessary to
achieve the formation of lactam 18 by palladium catalysis. The
highest yield of 18 (38%) was obtained using catalytic
Pd(OAc)2 with K2CO3 and DMA as the base and solvent,
respectively. Furthermore, it was found that the addition of
H2O (10 equiv) was crucial for this reaction to proceed, while
the use of phosphine ligands to modify Pd had minimal effect
on the reaction outcome. Deprotection occurred upon
exposure to BCl3 at −78 °C in CH2Cl2, affording
(−)-rhazinilam (1) in six steps from alkyne 7. The
spectroscopic data of the synthetic material matched those of
the natural product. Comparison of the optical rotation of the
synthetic material to that of the natural product enabled the
configurational assignment of the copper-catalyzed trans-
formation of propargylic ester 6 to indolizine 7.
(−)-Rhazinilam (1) has been recognized as the oxidative
degradation product of (+)-eburenine (8) and shares a
common central structural feature of aspidosperma alkaloids
(Scheme 4).5a In order to further exploit the novel Cu-
catalyzed propargylic substitution, we turned our attention
toward the synthesis of (+)-aspidospermidine (9) (Scheme 5).
Lithiation of alkyne 7 with n-BuLi and quenching with CO2
afforded acid 19 in excellent yield (91%). Subsequent
hydrogenation using Pd/C converted alkynoic acid 19 to its
saturated analogue 20, which readily engaged in an intra-
molecular Friedel−Crafts acylation upon treatment with
polyphosphoric acid (PPA) to form tricyclic ketone 21.
Reduction with PtO2 and H2 followed by treatment with
DMP provided pyrrolidine 22 as a single diastereomer in 25%
yield over two steps. Tricycle 22 was also prepared by Banwell,
yet that group was not successful in converting it to 9.14
However, we found that Fischer indolization could be used to
obtain 8 in 53% yield. Reduction of the indoline moiety gave
(+)-aspidospermidine (9) in 80% yield. Moreover, 8 can be
converted to (+)-vincadifformine (23) and other related
alkaloids via known procedures.15
In summary, we have developed an efficient asymmetric
copper-catalyzed intramolecular substitution of propargylic
acetate with pyrrole to enable rapid and asymmetric access to
5,6,7,8-tetrahydroindolizines bearing an all-carbon quaternary
stereocenter. The utility of this copper-catalyzed asymmetric
propargylic substitution was exemplified by a concise total
synthesis of (−)-rhazinilam (1). Additionally, formal syntheses
of (+)-eburenine (8) and (+)-aspidospermidine (9) were
achieved from alkyne 7, demonstrating the versatility of this
approach. We are currently focusing on the expansion of this
transformation in order to access other highly substituted
propargylic products in an asymmetric fashion.
ASSOCIATED CONTENT
* Supporting Information
Scheme 4. Biosynthesis of (−)-Rhazinilam
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02619.
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
Crystallographic data for rac-18 (CIF)
Crystallographic data for rac-19 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: carreira@org.chem.ethz.ch.
C
DOI: 10.1021/acs.orglett.7b02619
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(11) Tsuchida, K.; Senda, Y.; Nakajima, K.; Nishibayashi, Y. Angew.
Chem., Int. Ed. 2016, 55, 9728.
Erick M. Carreira: 0000-0003-1472-490X
Notes
(12) See the Supporting Information.
(13) Bowie, A. L.; Trauner, D. J. Org. Chem. 2009, 74, 1581.
(14) (a) Banwell, M. G.; Smith, J. A. J. Chem. Soc., Perkin Trans.1
The authors declare no competing financial interest.
2002, 2613. (b) Iyengar, R.; Schildknegt, K.; Aube,
2, 1625.
̀
J. Org. Lett. 2000,
ACKNOWLEDGMENTS
We are grateful to Dr. N. Trap (ETH Zurich) and M. Solar
■
(15) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C.
̈
Nature 2011, 475, 183.
(ETH Zurich) for X-ray crystallographic analyses. We thank the
̈
Swiss National Science Foundation for support in the form of
Grant 200020_172516.
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Org. Lett. XXXX, XXX, XXX−XXX