Enantioselective total synthesis of (+)-ibophyllidine via an asymmetric phosphine-catalyzed [3 + 2] annulation

Article abstract of DOI:10.1039/c2sc20468a

In this study we performed the total synthesis of the terpene indole alkaloid (+)-ibophyllidine through a pathway involving asymmetric phosphine catalysis, with our novel l-4-hydroxyproline-derived chiral phosphine mediating the key [3 + 2] annulation. Hydrogenation of the [3 + 2] adduct allowed the rapid formation of the stereochemically dense pyrrolidine ring of (+)-ibophyllidine in excellent yield with exceptionally high levels of both diastereo- and enantioselectivity. We constructed the remainder of the pentacyclic skeleton through an intramolecular alkylation and an intramolecular aza-Morita-Baylis-Hillman reaction. The Royal Society of Chemistry 2012.

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EDGE ARTICLE
Enantioselective total synthesis of (+)-ibophyllidine via an asymmetric
phosphine-catalyzed [3 + 2] annulation†
*
Ian P. Andrews and Ohyun Kwon
Received 18th April 2012, Accepted 19th May 2012
DOI: 10.1039/c2sc20468a
In this study we performed the total synthesis of the terpene indole alkaloid (+)-ibophyllidine through
a pathway involving asymmetric phosphine catalysis, with our novel L-4-hydroxyproline-derived chiral
phosphine mediating the key [3 + 2] annulation. Hydrogenation of the [3 + 2] adduct allowed the rapid
formation of the stereochemically dense pyrrolidine ring of (+)-ibophyllidine in excellent yield with
exceptionally high levels of both diastereo- and enantioselectivity. We constructed the remainder of the
pentacyclic skeleton through an intramolecular alkylation and an intramolecular aza-Morita–Baylis–
Hillman reaction.
found distinctly amid the ibophyllidines is the presence of a five-
Introduction
membered pyrrolidine ring in place of the more common six-
membered piperidine. This characteristic architectural difference
presumably arises as a result of biogenetic excision of a single
carbon atom from the pandoline alkaloids through an oxidative
cleavage process.2 As a result, the five-membered D ring of the
ibophyllidines represents an uncommon synthetic challenge
among aspidospermine and pseudoaspidospermidine natural
products. Arguably, the most demanding of this family, from
a synthetic standpoint, is ibophyllidine. Originally isolated in
1976 from the plants Tabernanthe iboga and T. subsessilis, this
alkaloid contains an all-syn-pyrrolidine nucleus that places the
C20 ethyl group on the highly congested concave face of the
cupped structure.3 Despite the presence of this unique carbon
skeleton, the ibophyllidines have received considerably less
attention than their higher-carbon homologues.
The ibophyllidines comprise a small family of terpene indole
alkaloids sharing a fused pentacyclic framework, but varying in
the substitution and stereochemistry at C20 (ibophyllidine
numbering; Fig. 1). Derived biosynthetically from tryptamine
and the iridoid terpene secologanin, the ibophyllidines share the
A, B, C, and E rings that are conserved among skeletally similar
aspidospermine and pseudoaspidospermidine alkaloids of the
same origin (2, Fig. 1).1 Although high levels of variation exist
with respect to the D rings of these alkaloids, a unique variation
Of the existing strategies for constructing the ibophyllidine
skeleton, perhaps the most elegant is the use of a biomimetically
inspired Diels–Alder reaction of an in situ-generated secodine-
analogue (3, Scheme 1). First implemented by Kuehne and
Bohnert, and later by Das et al., the key cyclization in this concise
route exhibited high levels of stereospecificity with regard to the
C20 ethyl group. Cyclization was found, however, to occur via
the diene approaching opposite the C20 ethyl substituent,
generating 20-epi-ibophyllidine (4) exclusively.4,5 In an alterna-
tive strategy, the Bonjoch group attempted a key Fischer indo-
lization on a bicyclic ketone bearing all of the D ring
stereochemistry (5 / 6 + 60), but obtained poor selectivity (ratio
of 6 : 60 ¼ 1 : 4.5).6 In fact, the four reported total syntheses of
ibophyllidine have all been accomplished utilizing a singular
tactical blueprint based on a variation of Kuehne and Bohnert’s
original Diels–Alder strategy. The key cyclizations in these
routes led to A-B-C-E tetracycles (7a–d / 8a–d), as opposed to
the 20-epi-ibophyllidine (4) skeleton. This strategy allows late-
stage closure of the D ring through condensation between the C
Fig. 1 Representative ibophyllidines and the aspidospermine/pseu-
doaspidospermidine alkaloid skeleton.
Department of Chemistry and Biochemistry, University of California, Los
Angeles, 607 Charles E. Young Drive East, Los Angeles, California
90095-1569, USA. E-mail: ohyun@chem.ucla.edu
† Electronic supplementary information (ESI) available: Experimental
details and spectral data of new compounds. See DOI:
10.1039/c2sc20468a
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Scheme 1 Summary of strategies that have been used to synthesize ibophyllidine and our unique approach.
ring’s secondary amino group and a pendant ketone unit, fol-
lowed by setting of the troublesome C20 stereocenter through
hydrogenation of the resultant imine/enamine. To date, this
strategy remains the only successful one for the synthesis of
ibophyllidine, with tactical variances occurring only with respect
to the exact structure of the acyclic secodine analogue and the
method of its formation. Each of these cases, however, required
stereochemical inversion at one or more of the stereocenters at
the C/E ring juncture. First disclosed by Kuehne and Bohnert,
this approach generated the desired A-B-C-E ring system, but
required full epimerization at C3 and C7 in order to access ibo-
phyllidine (7a / 8a; Scheme 1).4 In a similar approach devel-
oped during a study aimed at advancing a common intermediate
to a number of related aspidosperma alkaloids, the synthesis still
required epimerization of the C3 and C7 centers and, in this case,
also necessitated excision of the additional carbon atom that was
positioned to allow access to other targets (7c / 8c).7 In 2007,
Kalaus et al. reported a similar tactic nearly paralleling Kuehne
and Bohnert’s studies that necessitated inversion of stereo-
chemistry at C3 after formation of the C and E rings (7d / 8d).8
Although the required stereochemical inversions were imple-
mented efficiently in each of these cases, they exemplify the
inherent challenges in controlling the relative stereochemistry
around the pyrrolidine ring of ibophyllidine.9
the synthesis of desethylibophyllidine and they do not address
the difficulties associated with the introduction of the additional
C20 stereocenter.11 Therefore, synthesis of the ibophyllidine
alkaloids, in particular ibophyllidine, with selective introduction
of the stereochemistry about the D ring as well as control over
the absolute configuration, remains a considerable challenge.
Results and discussion
As part of a research program dedicated to investigating the
reactivity of electron-deficient p systems under the influence of
nucleophilic phosphine catalysts,12 we have developed a powerful
method for the syn-selective formation of 1,2,3,5-tetrasubstituted
pyrroline rings.13 Recently, we have employed this approach with
our novel trans-L-4-hydroxyproline-derived chiral phosphine 12
to obtain products with high yields and ee’s.14,15 We suspected
that this method could be implemented to set the relative
stereochemistry between the indole nucleus and the daunting C20
ethyl group, while a subsequent diastereoselective hydrogenation
would effect formation of the third asymmetric center about the
D ring of ibophyllidine (9 + 10 / 11; Scheme 1). This unique
pathway directly addresses the challenge of D ring stereocontrol
and starkly contrasts the existing syntheses by focusing on early
stage formation of this ring with an emphasis on high diastereo-
and enantioselectivity.
Kuehne and Bohnert’s original synthesis was later modified to
prepare optically active (+)-ibophyllidine, with the absolute
configuration controlled using a bulky ferrocenyl chiral auxiliary
(7b / 8b). The key annulation resulted in a modest 5 : 1 dr with
respect to the auxiliary; to date, this synthesis has been the only
one reported for non-racemic ibophyllidine.10
In the retrosynthetic sense, we envisioned (+)-ibophyllidine (1)
as being derived from the highly functionalized all-syn-pyrroli-
dine 14 by way of intramolecular alkylation at the C3 position of
the indole followed by an aza-Morita–Baylis–Hillman reaction
onto the newly formed spirocyclic indolenine 13, to establish the
C and E rings, respectively (Scheme 2). The cyclization precursor
14 would be derived from the less-elaborated pyrrolidine 11. We
Although a number of other methods exist for building the
ibophyllidine skeleton, they have typically been employed only in
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of ibophyllidine. Having developed an efficient route toward
multigram quantities of the necessary tricycle 16, we next
investigated the hydrogenation of the pyrroline double bond.
After significant experimentation, we found that treating the
pyrroline with RANEYꢀ Ni in THF under 200 psi of H2 yielded
the desired all-syn-pyrrolidine 11 in 80% isolated yield; we
established this relative stereochemistry through observation of
an NOE between the protons at the 3 and 5 positions of the
pyrrolidine ring.17
Having successfully established the congested stereochemical
arrangement about the ibophyllidine D ring, we then used
conventional functional group transformations to elaborate the
key pyrrolidine into the desired cyclization precursor 14 (Scheme
4). We used LiAlH4 to reduce the ester group of compound 11
and then employed Mg powder under sonication for reductive
cleavage of the tosyl amide; we treated the resulting crude amino
alcohol with chloroacetyl chloride to provide the chlor-
oacetamide 17 in 78% yield over three steps.18 Sequential Swern
oxidation of 17 and Horner–Wadsworth–Emmons olefination
proceeded in 98 and 76% yields, respectively, furnishing the
a,b-unsaturated ester 18, the Boc group of which was cleaved in
toluene under reflux in the presence of silica gel. The crude
material obtained after filtration and removal of the volatiles was
re-dissolved in acetone and reacted under Finkelstein conditions
to provide the iodide 14 in 94% over two steps.
Scheme
2 Retrosynthetic analysis of (+)-ibophyllidine based on
a phosphine-catalyzed [3 + 2] annulation.
planned for this key intermediate to be readily accessible in two
steps from the N-tosyl imine 9 and the allenoate 10 by way of an
asymmetric [3 + 2] annulation, followed by diastereoselective
hydrogenation of the resultant pyrroline double bond.
Our synthetic campaign commenced (Scheme 3) with an
exploration of the key [3 + 2] annulation between the known
allenoate 10 and the N-tosyl imine 9, prepared in 90% yield by
condensation of p-toluenesulfonamide with N-Boc-indole-3-
aldehyde (15). Next, we applied our novel P-chiral [2.2.1]bicyclic
phosphine 12, derived from trans-L-4-hydroxyproline, to the
annulation. The reaction proceeded exceedingly well, forming
the desired pyrroline in 99% yield and 99% ee after 1 h at room
temperature when employing 30 mol% of the catalyst.16
Decreasing the catalyst loading to 10 mol% had no effect on
enantioselectivity, but the reaction took 4 h to reach completion
and provided a slightly decreased yield of 93%. This practical
procedure (at 10 mol% catalyst loading) allowed the preparation
of the optically pure pyrroline 16 on a multigram scale. As an
example of the utility of this reaction, the annulation performed
on an approximately 30 g scale proceeded in 94% yield and 97%
ee. While efficiently controlling the absolute configuration of the
two newly formed stereocenters, it should also be noted that the
high diastereoselectivity of this process quickly sets the syn
relationship between the C20 ethyl group and the indole
nucleus—an inherently difficult process in the previous syntheses
With access to the cyclization precursor 14, we explored the
transformations necessary to form the C and E rings (Scheme 5).
The use of reactive haloamides to form the C ring of aspido-
sperma and related alkaloids, by way of an intramolecular
alkylation, is well established, having been first demonstrated by
Heathcock and Toczko in the synthesis of (ꢀ)-aspidospermi-
dine.19,20 Accordingly, we found that activation of the iodide with
silver trifluoromethanesulfonate, along with added base, facili-
tated the desired spirocyclization, delivering the spirocyclic
indolenine 13. For formation of the E ring, we drew inspiration
from Andrade’s recent exploits regarding a similar intra-
molecular aza-Morita–Baylis–Hillman reaction.20,21 We were
delighted to discover that addition of the highly nucleophilic and
sterically undemanding trimethylphosphine to a solution of the
Scheme 4 Elaboration of the pyrrolidine 11 to the cyclization precursor
14: (a) LiAlH4, THF, 0 ꢁC to rt; (b) Mg powder, THF–MeOH (9 : 1),
sonication; (c) chloroacetyl chloride, THF, Et3N, 0 ꢁC, 78% (three steps);
(d) oxalyl chloride, DMSO, ꢂ78 ꢁC, then Et3N, 98%; (e) methyl
diethylphosphonoacetate, NaHMDS, THF, ꢂ78 ꢁC, 76%; (f) SiO2,
toluene, reflux; (g) NaI, acetone, reflux, 94% (2 steps).
Scheme 3 Synthesis of the key pyrrolidine 11: (a) p-toluenesulfonamide,
TiCl4, Et3N, CH2Cl2, 0 ꢁC to rt, 90%; (b) allenoate 10, 10 mol% chiral
phosphine 12, benzene, 93%, 99% ee; (c) RANEYꢀ Ni, THF, H2
(200 psi), 80%.
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ring of (+)-ibophyllidine but also resulted in the first total
synthesis of (+)-ibophyllidine utilizing asymmetric catalysis. This
approach is also the first non-formal total synthesis of a complex
natural product to employ phosphine-catalyzed [3 + 2] annula-
tion between activated imines and electron-deficient allenes.
Acknowledgements
This study was supported by the NIH (O.K.: R01GM071779 and
P41GM081282), the NSF (equipment grant CHE-1048804), and
the National Center for Research Sources (S10RR025631).
Notes and references
Scheme 5 Completing the synthesis of (+)-ibophyllidine: (a) AgOTf,
Et3N, toluene, 0 ꢁC to rt; (b) Me3P, benzene–MeOH (14 : 1), 80% (two
steps); (c) Lawesson’s reagent, benzene, reflux; (d) RANEYꢀ Ni,
THF, H2 (200 psi), 90% (two steps); (e) Dess–Martin periodinane,
CH2Cl2, 51%.
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indolenine 13 in benzene, with methanol as an additive,
promoted the desired intramolecular aza-Morita–Baylis–Hill-
man reaction, yielding the desired pentacycle 19 in 80% yield over
two steps.22,23
With the pentacyclic framework in place, all that remained was
reduction of the lactam and migration of the double bond into
conjugation with the indoline nitrogen atom. Although we failed
in our cursory attempts to isomerize the olefinic bond of 19 to
form the desired vinylogous urethane, we found that thioamide
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droibophyllidine (20) as a single diastereoisomer.24,25 We sus-
pected that oxidation of the indoline unit of 20 to the
corresponding indolenine would result in facile tautomerization
to (+)-ibophyllidine. To this end, we investigated a number of
oxidants [DDQ,26 Pd/C,27 (PhSeO)2,28 tert-butyl hypochlorite,29
MnO2,30 N-tert-butylbenzenesulfinimidoyl chloride,31 IBX,32
PhIO33], but none resulted in any detectable (+)-ibophyllidine.
Oxidation under Swern conditions provided some of the target
structure, but it was isolated in low yield as the minor component
of an inseparable mixture with an unidentified side product.34
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Martin periodinane led to formation of (+)-ibophyllidine in 51%
yield,35 with spectroscopic data consistent with those reported in
the literature.3,8,10
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Conclusions
We have completed the first enantioselective total synthesis of
(+)-ibophyllidine in 15 steps and 13% overall yield from N-Boc-
indole-3-aldehyde. The key transformation is our recently
developed asymmetric [3 + 2] annulation, here performed
between 4-ethyl-2,3-butadienoate and the N-tosyl-aldimine
derived from N-Boc-indole-3-aldehyde. Diastereoselective
hydrogenation of the [3 + 2] adduct provided rapid access to the
synthetically challenging all-syn-pyrrolidine ring of ibophylli-
dine, with exceptional levels of stereochemical control. Our
strategy not only circumvents some of the difficulties typically
associated with constructing the stereochemistry around the D
13 (a) X.-F. Zhu, C. E. Henry and O. Kwon, Tetrahedron, 2005, 61, 6276;
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14 Full disclosure of the chiral phosphine 12, including its preparation
and the substrate scope of [3 + 2] annulations between N-sulfonyl
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23 Before deciding on the Morita–Baylis–Hillman strategy, we
attempted to form the E ring through a Mannich reaction. Using
either a fully saturated ester side chain or a more reactive b-
ketoester, we were unable to facilitate the desired Mannich
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16 The chiral phosphine 12 performed better than the typically employed
tri-n-butylphosphine. Although the [3 + 2] annulation using 20 mol%
tri-n-butylphosphine proceeded faster than the one mediated by 12,
consuming the imine within 30 min, the pyrroline was isolated in
only 78% yield. Increasing the tri-n-butylphosphine loading to 50
mol% resulted in the desired pyrroline being isolated in 80% yield.
17 See the ESI† for a discussion of the hydrogenation, including the
various conditions employed and the optimization of the reaction
using RANEYꢀ Ni.
18 During various trials, we observed the formation of some of the bis-
acylation product derived from N- and O-acylation. In these
instances, the O-acetyl group could be selectively cleaved in
quantitative yield through treatment with a methanolic suspension
of K2CO3 (see ESI† for details).
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fragmentation product, with no observed formation of the
pentacycle 19. We suspect that the added steric bulk adjacent to the
enoate double bond prohibited addition of DBU in favor of
deprotonation at the C3 position of the pyrrolidine ring, followed
by C ring fragmentation and restoration of the aromatic indole
nucleus (see ESI† for details). Although we also screened other
amines known to catalyze Morita–Baylis–Hillman reactions, none
led to the desired pentacycle, with fragmentation being the
dominant pathway in each case.
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