Au(I)-catalyzed annulation of enantioenriched allenes in the enantioselective total synthesis of (-)-rhazinilam

Article abstract of DOI:10.1021/ja0629110

Highly stereoselective Au(I)-catalyzed pyrrole additions to enantioenriched allenes afford a unique entry to optically active heterocycles. Asymmetric quaternary carbons can be installed with concurrent heterocycle annulation utilizing this methodology. The enantioenriched allenes are conveniently obtained by catalytic asymmetric acyl halide-aldehyde cyclocondensations and S_N2′ ring opening of the resulting enantioenriched β-lactones. An enantioselective total synthesis of (-)-rhazinilam highlights the potential utility of this reaction technology in target-oriented synthesis. Copyright

Full text of DOI:10.1021/ja0629110

Published on Web 07/22/2006
Au(I)-Catalyzed Annulation of Enantioenriched Allenes in the Enantioselective
Total Synthesis of (-)-Rhazinilam
Zuosheng Liu, Andrew S. Wasmuth, and Scott G. Nelson*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received April 26, 2006; E-mail: sgnelson@pitt.edu
The utility of allenes in metal-catalyzed addition reactions has
made these intermediates increasingly popular for an array of
synthesis activities. In this context, allenes parallel closely alkynes
in their reactivity toward metal-mediated nucleophilic additions.1
However, unlike alkyne substrates, allenes offer the potential for
relaying the associated axial chirality to ensuing bond constructions.2
For example, allene chirality is faithfully translated to tertiary
carbinol stereocenters during Ag(I)-catalyzed cyclization of enan-
tioenriched allene acetic acid derivatives 1 (eq 1).3
Figure 1. Allene templates for asymmetric annulation reactions.
Scheme 1 a
On the basis of this precedent, a strategy for enantioselective
annulative quaternary carbon construction would evolve from
engaging latent carbon-based nucleophiles tethered at the allene
terminus in similar metal-catalyzed allene additions. The enantio-
selective total synthesis of (-)-rhazinilam (2) reported herein
demonstrates the success of this reaction design using Au(I)-
catalyzed pyrrole-allene additions (Figure 1).
Scrutinizing (-)-rhazinilam’s structure revealed the tetahydroin-
dolizine ring system and the chiral quaternary carbon as the key
architectural features of the natural product.4 While atropisomerism
about the C12-C13 biaryl bond warranted appropriate consideration,
i
a Conditions: (a) 5 mol % of 7, Pr2NEt, -78 °C; (b) 8, 10 mol % of
a synthesis strategy relying on late-stage lactamization after C5
stereocenter installation would ensure the correct atropisomer about
the biaryl axis.4a To implement this strategy, we envisioned
tetrahydroindolizine construction proceeding with concurrent instal-
lation of the quaternary carbon stereocenter. Specifically, intramo-
lecular pyrrole addition to a metal-activated allene 3 constituted
an expedient entry to the tetrahydroindolizine unit 4 provided
efficient translation of allene chirality to the incipient quaternary
carbon was realized. SN2′ ring opening of optically active â-lactone
5 would provide an especially concise synthesis of the requisite
enantioenriched pyrrole-substituted allene 6.
i
CuCN, -78 °C; (c) (i) 10 mol % of AgNO3, Pr2NEt; (ii) DBU; (d)
TMSCHN2, C6H6/MeOH; (e) 20 mol % of (MeCN)2PdCl2, CH2Cl2.
12 of rhazinilam (37% ee, 92%). However, in addition to the high
catalyst loadings, this reaction pathway was compromised by the
poor enantioselectivity accompanying Pd(II) catalysis.
On the basis of these observations, elucidating catalyst systems
that would effectively translate allene chirality to the annulation
process was essential for realizing our synthesis strategy. Substrate-
directed catalyst association to the allene π-orbital syn to the pendant
carboxylate ester was envisioned as a mechanism for ensuring
efficient chirality transfer by forcing nucleophilic attack opposite
the activating metal (3, Figure 1). Poor enantioselection achieved
under Pd(II) catalysis was ascribed to the limited Lewis acidity of
PdCl2 and the resulting lability of the directing Lewis acid-base
contact. The further erosion of enantioselectivity observed for the
Pd(II)-catalyzed cyclization of allene 13 (16% ee) lacking a Lewis
basic directing group provided confirmatory evidence for this
hypothesis. This analysis suggested that the most successful catalysts
would express both hard and soft Lewis acid characteristics required
for simultaneous association with both the ester carbonyl and allene
π-system, respectively.
Considering the pivotal nature of the putative pyrrole-allene
cyclization in our synthesis design, preliminary investigations
focused on validating this transformation as a conduit to rhazinilam.
Toward this goal, â-lactone 5 (97% ee, 79%) was prepared by the
Al(III)-catalyzed acyl halide-aldehyde cyclocondensation (AAC)
i
of 2-pentynal (6) and acetyl bromide (5 mol % of 7, Pr2NEt)
(Scheme 1).5 Copper(I)-catalyzed SN2′ ring opening of 5 with the
pyrrole-substituted Grignard reagent 86 provided the enantioenriched
allene 9 (88%). Assaying the optical purity of 9 required conversion
i
to unsaturated δ-lactone 10 (10 mol % of AgNO3, Pr2NEt, then
DBU) and confirmed only modest stereochemical erosion had
accompanied â-lactone ring opening (91% ee, 83%). The proclivity
of Pd(II) complexes for activating alkenes as electrophiles inspired
our initial decision to explore Pd-based annulation catalysts. Thus,
reacting allene 11 with Cl2Pd(CH3CN)2 (20 mol %) promoted 6-
endo-trig cyclization to directly afford the tetrahydroindolizine core
To expedite ensuing investigations, the 3,4-cis-disubstituted
â-lactone 14 was selected as the allene precursor in preference to
5, thereby eliminating the need for repetitive allene f lactone
conversion to assay SN2′ stereoselection (Scheme 2). Thus, â-lac-
9
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10.1021/ja0629110 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
olefin cleavage (72%), Horner-Wittig homologation, and catalyzed
dihydrogenation (95% over two steps) afforded ester 19 with the
C5 tether correctly formatted for eventual lactamization. Biaryl bond
construction proceeded by regioselective pyrrole iodination (89%)4c
and ensuing Suzuki-Miyaura cross-coupling of iodide 20 with
N-Boc aniline boronic ester 21 using Buchwald’s SPhos ligand (2.5
mol % of Pd2(dba)3, 10 mol % of SPhos, K3PO4, aq THF) to afford
the 3-aryl pyrrole 22 (86%).14 Chemoselective ester saponification
and aniline N-deprotection (93% for two steps) preceded HATU-
mediated lactamization of the resulting amino acid to deliver 10-
(carbomethoxy)rhazinilam 23 (74% over three steps). Pyrrole
decarboxylation (NaOH; HCl, 50 °C) then provided synthetic (-)-
rhazinilam (2) in 96% yield (94% ee).
Asymmetric Au(I)-catalyzed pyrrole additions to enantioenriched
allenes afford a unique entry to optically active heterocycles.
Trisubstituted allenes provide convenient templates for heterocycle
annulation with concomitant asymmetric quaternary carbon con-
struction. An enantioselective total synthesis of (-)-rhazinilam
highlights the potential utility of this reaction technology in target-
oriented synthesis.
Scheme 3 a
Acknowledgment. Support from the National Institutes of
Health (R01 GM63151), the Bristol-Myers Squibb Foundation, and
the Merck Research Laboratories is gratefully acknowledged.
Supporting Information Available: Experimental procedures and
1
representative H and 13C spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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yield (84% de).9,10 Evaluating reaction efficiency as a function of
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