Stereoretentive suzuki-miyaura coupling of haloallenes enables fully stereocontrolled access to (-)-Peridinin

Article abstract of DOI:10.1021/ja102721p

Stimulated by the substantial challenge of synthesizing the complex and sensitive stereogenic allene-containing core of (-)-peridinin, the first stereocontrolled coupling of haloallenes with boronic acids has been achieved. This new method and the principles that emerged during its development stand to enable the more efficient and flexible preparation of a wide range of natural products, pharmaceuticals, and intermediates that possess a stereogenic allene motif. This new reaction was harnessed to achieve the first completely stereocontrolled total synthesis of (-)-peridinin. This synthesis was accomplished using only one reaction iteratively to assemble four fully functionalized building blocks with complete stereoretention at each initial halide or boron-bearing carbon. This synthesis elevates the capacity of the iterative cross-coupling strategy to an unprecedented benchmark. Moreover, the efficient and highly modular nature of this synthesis promises to enable systematic dissection of the heretofore enigmatic structure/function relationships that underlie the protein-like antilipoperoxidant activities of this remarkable small molecule natural product.

Full text of DOI:10.1021/ja102721p

Published on Web 05/04/2010
Stereoretentive Suzuki-Miyaura Coupling of Haloallenes Enables Fully
Stereocontrolled Access to (-)-Peridinin
Eric M. Woerly, Alan H. Cherney, Erin K. Davis, and Martin D. Burke*
Howard Hughes Medical Institute, Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois at
Urbana-Champaign, Urbana, Illinois 61801
Received April 6, 2010; E-mail: burke@scs.uiuc.edu
Table 1. Development of the First Stereocontrolled SM Coupling
Deficiencies of antilipoperoxidant proteins have been associated
with atherosclerosis, rheumatoid arthritis, and cancer and may
contribute to an accelerated aging process.1 Small molecules with
the capacity to replicate the functions of these proteins could
therefore have a major positive impact on human health. In contrast
to most carotenoids,2 the C37-norcarotenoid peridinin (1)3 may exert
antilipoperoxidant activities primarily through self-preserving mech-
anisms, including catalytic quenching of 1O2 and decreasing
membrane permeability to other reactive oxygen species.4 Isolation
from natural sources is very inefficient,3b however, and the sensitive
and stereogenic allene moiety central to the structure of 1 has made
its stereoselective synthesis very challenging.5,6 As a result, the
underpinnings of these activities have been only minimally
explored.4,7 To facilitate systematic studies of such small molecules
with protein-like functions, we recently introduced a simple,
efficient, and flexible synthesis strategy that involves the iterative
cross-coupling (ICC) of bifunctional haloboronic acids masked as
the corresponding N-methyliminodiacetic acid (MIDA) boronates.8
Enabled by this ICC approach and the development of new
methodology for the highly stereoretentive Suzuki-Miyaura (SM)
cross-coupling of haloallenes, we herein report the first fully
stereocontrolled total synthesis of (-)-1.
of Chiral Haloallenes
entry
2
R
X
ligand
3
% stereoretentiona,b
1
2
3
4
5
6
7
8
(R)-2a t-Bu
(R)-2b t-Bu
(R)-2c t-Bu
(R)-2d 3-pentyl
(R)-2e n-pentyl
(R)-2c t-Bu
(R)-2c t-Bu
(R)-2c t-Bu
(R)-2c t-Bu
(R)-2c t-Bu
(R)-2c t-Bu
Cl PPh3
Br PPh3
(S)-3a
(S)-3a
(R)-3a
(R)-3b
(R)-3c
(R)-3a
(R)-3a
-78
-78
72
58
25
80
50
71
91
I
I
I
I
I
I
I
I
I
I
I
I
PPh3
PPh3
PPh3
PFur3
PCy3
Pt-Bu2Me (R)-3a
9
10
11
Po-Tol3
Pt-Bu3
XPhos
XPhos
XPhos
XPhos
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3b
(R)-3c
93
91
12c (R)-2c t-Bu
>99d
>99
85
13c (R)-2d 3-pentyl
14c (R)-2e n-pentyl
a
% stereoretention ) ee product/ee starting material (chiral GC,
average of
2 runs); negative values reflect net stereoinversion.
b Unoptimized GC yields ranged from 10 to 83%. c Hexane:THF:H2O
9:1:1 was used as solvent. d Isolated yield ) 61%.
Scheme 1
C8′/C9′ bond in 1 via a Stille coupling have been complicated by
similar issues.6 Consistent with these precedents, using conditions
similar to those reported to promote the SM coupling of achiral
haloallenes,10a the reaction of PhB(OH)2 with enantioenriched
chloro- and bromoallenes (R)-2a,b demonstrated net stereoinversion
to provide (S)-3a as the major product (Table 1, entries 1-2). In
contrast, coupling of iodoallene (R)-2c yielded (R)-3a with a
moderate 72% stereoretention (entry 3).
Building on this starting point, we tested the previously
unconfirmed hypothesis11 that maximized steric bulk at C3 of a
haloallene could promote stereoretention, presumably by disfavoring
SN2′-like OA. Specifically, we evaluated a series of substrates 2c-e
having progressively smaller R groups at C3 and indeed observed
decreased stereoretention (entries 3-5). Guided by reciprocal
logic,14 we hypothesized that bulky phosphine ligands15 would also
promote stereoretentive direct OA at the less sterically hindered
C1. In fact, in contrast to smaller ligands (entries 3, 6-8), >90%
stereoretention was observed for phosphine ligands having cone
angles >180° (entries 9-11).16 With air-stable XPhos,15a optimiza-
tion of solvent led to >99% stereoretention and 61% isolated yield
(entry 12). Substantial improvements in stereoretention were also
observed for couplings with 2d and 2e under these optimized
conditions (entries 13 and 14).
Guided by the ICC strategy,8 we applied only SM transforms to
retrosynthesize 1 into four building blocks, BB1-BB4, having all
of the required functionality preinstalled in the correct oxidation
states and with the desired stereochemical relationships (Scheme
1). We recognized, however, that the disconnection between C8′/
C9′ corresponded to a stereoretentive SM coupling with a haloal-
lene. Albeit potentially very useful in the preparation of many
natural products,9 this was an unprecedented transformation10 that
first required development.
In related Negishi couplings,11 chloro- and bromoallenes yield
products representing net stereochemical inversion, whereas the
corresponding iodoallenes tend to favor stereoretention. These
results were attributed to two competing mechanisms involving
direct oxidative addition (OA) at C-X or indirect SN2′-like OA12
followed by a suprafacial 1,3 shift of Pd.13 Attempts to form the
Collectively, these findings revealed that maximized stereore-
tention in the SM coupling of chiral haloallenes can best be achieved
using allenyl iodide substrates having steric bulk at C3 in combina-
tion with sterically bulky phosphine ligands. Guided by these
9
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C O M M U N I C A T I O N S
Scheme 2
boronic acid proved to be unstable; thus a new tactic was
developed to promote the next cycle of B-activation and
coupling. Specifically, in a novel transformation, 13 was directly
converted into the corresponding pinacol ester, which was an
effective intermediate for B-selective coupling with BB3. The
resulting highly complex heptaenyl MIDA boronate 14 was stable
to chromatography and storage. Conversely, attempts to isolate
the heptaenyl boronic acid derived from 14 or to utilize the
corresponding pinacol ester were not fruitful. To solve this
challenging problem, we hybridized the principles established
above for allenyl halide coupling (Table 1) with in situ release
of the unstable boronic acid8d,b derived from MIDA boronate
14 to promote the final union with BB4 in good yield and with
complete stereoretention. Global desilylation concluded, to the
best of our knowledge, the first completely stereocontrolled total
synthesis of (-)-peridinin.
Scheme 3
Scheme 4
This efficient and highly modular pathway to 1 stands to facilitate
systematic dissection of the structure/function relationships that
underlie the self-preserving antilipoperoxidant activities of this small
molecule natural product.
Acknowledgment. We thank the NIH (GM090153) for funding
and DSM for a gift of (-)-actinol. M.D.B. is an HHMI Early Career
Scientist, Beckman Young Investigator, and Sloan Fellow. E.M.W.
is an NSF and Eli Lilly Graduate Fellow.
general principles, we designed BB46b for peridinin (Scheme 1) to
include both an allenyl iodide and a sterically bulky, yet still easily
removable, TMS ether at C5′.
Supporting Information Available: Procedures, complete ref 1a,
and spectral and crystallographic data (.cif). This material is available
free of charge via the Internet at http://pubs.acs.org.
Preparation of the remaining building blocks was enabled by
some highly favorable features of the MIDA boronate platform.8
Specifically, following a hydroboration of alkyne 45b to give pinacol
ester 5, a direct transesterification to form the air-stable MIDA
boronate BB1 was achieved (Scheme 2).17 This direct transesteri-
fication from a boronic ester to a MIDA boronate avoids the
intermediacy of unstable boronic acids. The unique compatibilities
of the MIDA boronate functional group with a wide range of
reaction conditions8c and chromatography8 were utilized to prepare
the final two building blocks. Specifically, propynyl MIDA boronate
6 (Supporting Information) underwent highly regio- and stereo-
controlled molybdenum-catalyzed hydrostannylation18 to yield bis-
metalated olefin 7 (Scheme 3). A subsequent metal and halide
selective coupling between 7 and lactone 819 provided BB2 as a
single stereoisomer.20 The final building block BB3 was prepared
via initial bromination of commercially available 9 followed by
regio- and stereoselective elimination to generate the novel trisub-
stituted bromoalkenyl MIDA boronate 10 as a single stereoisomer20
(Scheme 4). Two cycles of our recently developed methodology8e
for stereospecific metal-selective cross-coupling with bis-metalated
olefin 1121 followed by stereoretentive iododegermylation22 pro-
vided BB3.
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9
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C O M M U N I C A T I O N S
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