Short Enantioselective Total Synthesis of (-)-Rhazinilam Using a Gold(I)-Catalyzed Cyclization

Article abstract of DOI:10.1021/acs.orglett.7b02210

(R)-(-)-Rhazinilam has been synthesized in nine steps and 20% overall yield. The key steps involve two metal-catalyzed processes: the enantioselective gold(I)-catalyzed cycloisomerization of an allene-functionalized pyrrole and the palladium-catalyzed hydrocarboxylation of a vinyl moiety with formate as a CO surrogate. This novel strategy represents the shortest and highest yielding enantioselective total synthesis of (-)-rhazinilam.

Full text of DOI:10.1021/acs.orglett.7b02210

Letter
pubs.acs.org/OrgLett
Short Enantioselective Total Synthesis of (−)-Rhazinilam Using a
Gold(I)-Catalyzed Cyclization
Valentin Magne, Charlotte Lorton, Angela Marinetti, Xavier Guinchard, and Arnaud Voituriez*
́
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Universite
91198 Gif-sur-Yvette, France
́ ́
Paris-Sud, Universite Paris-Saclay, 1 av. de la Terrasse,
S
* Supporting Information
ABSTRACT: (R)-(−)-Rhazinilam has been synthesized in nine steps and 20%
overall yield. The key steps involve two metal-catalyzed processes: the
enantioselective gold(I)-catalyzed cycloisomerization of an allene-functionalized
pyrrole and the palladium-catalyzed hydrocarboxylation of a vinyl moiety with
formate as a CO surrogate. This novel strategy represents the shortest and
highest yielding enantioselective total synthesis of (−)-rhazinilam.
(R)-(−)-Rhazinilam 1 has been isolated initially through
extraction procedures from Melodinus australis,1a Rhazya
stricta,1b and from Malaysian Apocynaceae.1c It was demon-
strated later that its isolation is an artifact of the extraction
procedure by which the natural precursor, dihydropyrrole 2,
was oxidized into pyrrole 1 (Figure 1).1c,d (R)-(−)-Rhazinilam
enantioselective total synthesis of (R)-(−)-rhazinilam 1 (12
steps, 16.4% overall yield, 86% ee).
With the aim of accessing (R)-(−)-rhazinilam via a robust
and efficient procedure involving a smaller number of synthetic
steps, we have envisioned the retrosynthetic approach depicted
in Figure 2.
Figure 1. Structure of (−)-rhazinilam 1 and its precursor 2.
has attracted significant attention due to its strong biological
activity, acting as an inhibitor of the tubulin−microtubule
equilibrium.2 Moreover, its complex structure represents a
highly challenging synthetic target for organic chemists.3,4 The
tetracyclic structure of 1 features indeed an all-carbon
quaternary stereogenic center, an axially chiral arylpyrrole
group, and a 9-membered lactam ring.
Due to this synthetic interest, seven asymmetric total
syntheses have been reported, giving 1 in 1.6−19.8% overall
yields, over 12−18 chemical steps.5 Among others, Zhu
recently reported an elegant strategy involving a tandem
Staudinger reduction/aza-Wittig reaction and the heteroannu-
lation of a tetrahydropyridine with bromoacetaldehyde as the
key steps.5g The enantioselective step is a palladium-(S)-
tBuPHOX catalyzed decarboxylative allylation reaction on a
cyclopentanone derivative, which generates the stereogenic
quaternary carbon center of 1. To date, this is the shortest
Figure 2. Retrosynthetic approach to (R)-(−)-rhazinilam 1.
Overall, according to our strategy in Figure 2, rhazinilam 1
would be obtained by a final macrolactamization step from
amino acid i. The carboxylic acid function will be installed by
means of a palladium-catalyzed hydrocarboxylation of olefin ii.
The aniline moiety of ii will be installed by a Suzuki cross-
coupling after iodination of the tetrahydroindolizine iii, this
bicyclic derivative being obtained via an enantioselective
gold(I)-catalyzed cycloisomerization (hydroarylation) of the
Received: July 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02210
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Organic Letters
Letter
allene-functionalized pyrrole iv. This transformation will
establish the absolute configuration of the stereogenic
quaternary carbon center of iii. This step has been inspired
by the diastereoselective gold-catalyzed 6-exo-trig hydro-
arylation reaction developed by Nelson for the synthesis of
(−)-rhazinilam,5b which involved, however, an enantioenriched
allene as the starting material. The method led to (R)-
(−)-rhazinilam in 11 steps, 19.8% overall yield, and 94% de.
With our retrosynthetic analysis in mind, we have
investigated the cycloisomerization of pyrrole 3 under gold(I)
catalysis (Table 1). Gold catalysis is known to be a highly
catalysis and offers interesting possibilities to our strategy. The
cycloisomerization of 3 into 4 has been investigated at first by
using 5 mol % of the achiral [Ph3PAuCl/AgOTf] catalytic
system in toluene at room temperature (entry 1 in Table 1).
The desired tetrahydroindolizine 4 could be obtained in 97%
isolated yield through 6-exo-trig hydroarylation of the allene.
We next turned our attention to the development of an
enantioselective variant of this reaction. A systematic screening
of chiral gold(I) precatalysts revealed that complexes of either
the chiral phosphoramidite I or BINAP ligands II and III,
combined with AgSbF6 as the silver salt, gave low ee’s (Table 1,
entries 2−4). Other digold(I) complexes of atropochiral
SEGPHOS-diphosphines, such as IV or V, triggered low to
moderate enantioselectivities (entries 5 and 6). The use of the
(i-Pr-MeO-BIPHEP)(AuCl)2 precatalyst VI led to a moderate
11% ee (entry 7). The first promising results were obtained
with the ((R)-DTBM-MeO-BIPHEP)(AuCl)2 precatalyst VII
(entry 8, 53% yield, 73% ee), showing the huge impact of the
phosphorus substituents of the diphosphine on the reaction
outcome. Encouraged by this result, we retained precatalyst VII
and screened different silver salts under the same reaction
conditions (toluene as the solvent, room temperature) (entries
8−12). The reaction reached 72% yield and 78% ee using silver
triflate (entry 12). Finally, a solvent screening (entries 12−16)
revealed that mesitylene is the best solvent for this reaction,
giving the chiral tetrahydroindolizine derivative 4 in 81%
isolated yield and 84% ee (entry 16). Neither decrease of the
reaction temperature to 10 °C (entry 17) nor variation of the
reaction concentration improved this result.
Table 1. Optimization of the Enantioselective Gold(I)-
Catalyzed Cycloisomerization of 3
a
b
entry
[LAuCl]
X
solvent
yield (%)
ee (%)
c
d
1
Ph3PAuCl
I
OTf
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
SbF6
PF6
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
PhCF3
97
c
2
39
83
68
61
64
44
53
66
62
84
72
64
97
73
5
2
3
II
4
III
11
2
5
IV
6
V
41
11
73
76
78
62
78
36
65
81
84
80
7
VI
8
VII
VII
VII
VII
VII
VII
VII
VII
VII
VII
9
10
11
12
13
14
15
16
BF4
After optimization of the enantioselective Au(I)-catalyzed
cyclization reaction, the first steps of the total synthesis of (R)-
(−)-rhazinilam have been performed, as shown in Scheme 1.
NTf2
OTf
OTf
OTf
OTf
OTf
OTf
Scheme 1. Synthesis of the 5,6,7,8-Tetrahydroindolizine 5
xylene
d
mesitylene
mesitylene
81
e
17
63
a
1
Yields were determined by H NMR using trimethoxybenzene as
b
internal standard. Determined by HPLC on a chiral stationary phase,
on compound 5 (see Scheme 1 for synthetic details). 5 mol % of
silver salt. Isolated yield at a 0.05 mmol scale. At 10 °C.
c
d
e
Starting from the commercially available or readily prepared
1-(3-bromopropyl)-1H-pyrrole, addition of the corresponding
Grignard reagent to pent-2-yn-1-yl methanesulfonate, in the
presence of 8 mol % of CuCN and 16 mol % of LiBr, the
conjugate nucleophilic substitution furnished the desired
pyrrole−allene substrate 3 in quantitative yield on a multigram
scale. Next, the reaction conditions described in Table 1, entry
16, being satisfactory in terms of both yield and enantiose-
lectivity, a key point in the context of this total synthesis was
the larger scale applicability of the method. Consequently, the
enantioselective gold-promoted cycloisomerization of 3 was
performed on a 1 mmol scale with the [(R)-DTBM-MeO-
BIPHEP-(AuCl)2/AgOTf] catalytic system under the opti-
powerful tool for the synthesis of polycyclic molecules via
cycloisomerization of unsaturated substrates.6 Several applica-
tions to the synthesis of complex natural products demonstrate
the maturity attained nowadays by these methods.7 Further-
more, the recent development of efficient chiral gold catalysts8
has increased significantly the synthetic potential of gold
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DOI: 10.1021/acs.orglett.7b02210
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Letter
mized conditions. The 6-exo-trig cyclization reaction afforded
the desired chiral 5,6,7,8-tetrahydroindolizine 4 in 89% yield
(156 mg) and 83% ee. Thus, the isolated yield and
enantioselectivity are approximately the same after a 20-fold
scale-up of the reaction.
knowledge, this example represents the first application of this
hydrocarboxylation method in total synthesis.
The end-game procedure (Scheme 3) starts with a carefully
optimized procedure, enabling the saponification, the HCl-
After the efficient formation of this key intermediate
displaying the required all-carbon quaternary stereogenic
center, the pyrrole ring was stabilized by introduction of a
methyl carboxylate function, according to the literature
strategy.5a,b The tetrahydroindolizine ester 5 was obtained in
94% yield via the two-step, one-pot procedure in Scheme 1. It
proved to be easier to handle and more stable toward oxidation
than its unsubstituted precursor 4. Consequently, the
enantioselectivities were measured at this stage using HPLC
with a chiral stationary phase.
Scheme 3. Total Synthesis of (−)-Rhazinilam 1
The following three steps of the total synthesis of (R)-
(−)-razinilam are displayed in Scheme 2. To install the aniline
Scheme 2. Synthesis of Intermediate 8
catalyzed decarboxylation of the pyrrole−methyl ester protect-
ing group and the removal of the formamide moiety of
compound 8 to recover the amino acid 9 in a simple operation.
Toward this goal, the ester 8 was reacted in methanol in the
presence of sodium hydroxide and then the mixture was
acidified to promote decarboxylation. Under these reaction
conditions, esterification of the propanoic side chain also
occurred. Additional exposure to a potassium hydroxide
solution finally furnished the desired carboxylic acid 9. The
final lactamization step was then accomplished using classical
conditions (EDC, HOBt, TEA), which led to (−)-rhazinilam 1
in 45% yield over the last two steps.14
Thus, the strategy developed in this study (Schemes 1−3)
proceeds in nine chemical steps and affords (−)-rhazinilam in
20% overall yield. The key gold(I)-catalyzed enantioselective 6-
exo-trig cyclization of substrate 3 yields the tetrahydroindolizine
4 in 89% yield and 83% enantiomeric excess. (−)-Rhazinilam is
obtained then, with the same enantiomeric excess, through the
seven-step sequence described. This novel synthetic pathway is
to date the shortest enantioselective total synthesis of
(−)-rhazinilam.
moiety, a regioselective electrophilic iodination of 5 was first
carried out, leading to 6 in 75% yield. A Suzuki−Miyaura
coupling between 6 and the N-unprotected 2-aminophenylpi-
nacol boronate was next performed. The reaction was carried
out with [Pd(OAc)2/SPhos] (SPhos = 2-dicyclohexylphosphi-
no-2′,6′-dimethoxybiphenyl) as the catalyst, K3PO4 as the base,
in DMSO at 120 °C for 4 h. It delivered the known5a coupling
product 7 in 75% yield. Changing either the palladium
precursor or the phosphine ligand [PdCl2SPhos2, Pd(PPh3)4]
or the base (NaHCO3, Na2CO3, Cs2CO3) did not improve the
isolated yield.9
The next step, namely the palladium-catalyzed hydro-
carboxylation of the vinyl moiety of 7 to create the propanoic
acid unit, was undertaken under Pd catalysis using the very
efficient and robust reaction conditions developed by Shi.10
Our attention was attracted by Shi’s method since it uses a
formate as a user-friendly CO surrogate instead of the toxic and
difficult to handle CO gas, as in the Sames approach.5a
Furthermore, if a number of methods have been developed for
the carbonylation of aryl and alkene groups on simple
substrates,11 applications of this key reaction to the synthesis
of complex natural products remain rare.12 Accordingly, the
reaction of 7 with stoichiometric amounts of formic acid and
phenyl formate, in the presence of a catalytic amount of
[Pd(OAc)2/dppf] (dppf = 1,1′-ferrocenediyl-bis(diphenyl-
phosphine) in toluene, afforded the desired propanoic acid 8
in 95% yield as its formamide adduct.13 To the best of our
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02210.
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: arnaud.voituriez@cnrs.fr.
ORCID
Arnaud Voituriez: 0000-0002-7330-0819
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the support of the Institut de Chimie des
Substances Naturelles (ICSN) and the Centre National de la
Recherche Scientifique (CNRS).
C
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Org. Lett. XXXX, XXX, XXX−XXX

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of the product 1 were consistent with previously reported data of (R)-
(−)-rhazinilam (ref 5). The enantiomeric excess of compound 1 was
measured by HPLC on a chiral stationary phase (see the Supporting
Information).
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