A general strategy for the stereocontrolled preparation of diverse 8- and 9-membered Laurencia -type bromoethers

Article abstract of DOI:10.1021/ja2069449

A unique procedure to effect a ring-expanding bromoetherification process is described, wherein tetrahydrofurans and tetrahydropyrans are smoothly transformed into 8- and 9-membered bromoethers in a regio- and stereocontrolled manner through the use of BDSB (bromodiethylsulfonium bromopentachloroantimonate). These products resemble the cores of the Laurencia C15 acetogenins. In light of the generality and effectiveness of the approach, this work provides a unique strategy for their laboratory preparation and may implicate a possible biosynthesis pathway.

Full text of DOI:10.1021/ja2069449

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pubs.acs.org/JACS
A General Strategy for the Stereocontrolled Preparation of Diverse
8- and 9-Membered Laurencia-Type Bromoethers
Scott A. Snyder,* Daniel S. Treitler, Alexandria P. Brucks, and Wesley Sattler
Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, New York 10027, United States
S Supporting Information
b
Scheme 1. Structures of Selected Lauroxocane Natural Pro-
ducts, Murai’s Biomimetic Study, and an Alternative
ABSTRACT: A unique procedure to effect a ring-expanding
bromoetherification process is described, wherein tetrahydro-
furans and tetrahydropyrans are smoothly transformed into 8-
and 9-membered bromoethers in a regio- and stereocontrolled
manner through the use of BDSB (bromodiethylsulfonium
bromopentachloroantimonate). These products resemble the
cores of the Laurencia C15 acetogenins. In light of the
generality and effectiveness of the approach, this work pro-
vides a unique strategy for their laboratory preparation and
may implicate a possible biosynthesis pathway.
ome of the most fascinating halogenated natural products1
S
are the Laurencia C15 acetogenins, of which the inaugural
member, laurencin (1, Scheme 1), was first reported by Irie and
co-workers in 1965.2,3 Since then, more than 140 members have
been isolated, most containing a cyclic bromoether core ranging
in size from 4- to 12-membered.4 The lauroxocanes (including
1À4) possess an 8-membered ring system and represent the
largest subset of the family. These medium-ring bromoethers,
encompassing more than 50 natural products, have elicited much
attention not only for the synthetic challenges they provide but
also for the general question of their biogenesis.
reason, none of the 30 published total syntheses of lauroxocanes3,14
have forged their medium-sized cores through a direct bromonium-
induced reaction.15 In this communication, we show that with the
proper brominating reagent and appropriate substrates, ring ex-
pansion of oxonium species akin to 8 can lead to selective and
stereocontrolled laboratory syntheses of diverse 8- and 9-membered
bromoethers resembling the Laurencia C15 acetogenins.
Our first insight that a ring-expansion process could afford
8-membered rings derived from the discovery that hydroxyte-
trahydrofuran 9 (Scheme 2) was converted into ketone 11 rather
than bromoether 10 (a model compound resembling 2) upon
exposure to BDSB.16 Although not an 8-membered ring, its
presumed formation through a bicyclic oxonium formationÀ
hydride shift process17 suggested the materials needed for a
controlled ring-expanding bromoetherification. Specifically, if the
alcohol of 9was moved to the 4-position of the tetrahydrofuran ring
and protected as an ester or carbonate (as in 12), then a similar
rearrangement terminated by ring opening of the bicyclic oxonium
ion (i.e., 13)18 could yield an 8-exo (laurenan-like)19 bromoether
with differentiated oxygen functionalities (i.e., 14 or 15).20
Similarily, substrates with one less methylene unit between
The Murai group first showed that these rings could arise via
bromoperoxidase-catalyzed bromoetherifications of linear pre-
cursors (as in 5f6).5 The incredibly low yield of product
observed, however, may imply that direct 8-endo cyclization of
precursor 5 is an unfavorable event,6 even within the confines of
an enzyme pocket. As such, we wondered if these challenging
domains could also arise via a series of two potentially more
favorable 5-membered ring-forming steps. Specifically, if 5
underwent an initial 5-endo bromoetherification to form 7,7 a
second bromoetherification might then lead to a bicyclic oxo-
nium intermediate (i.e., 8). Such a material could then lead to
lauroxocane natural products (2, 3, 6, and others) via reactions at
the starred carbon, such as intramolecular cyclization, external
nucleophile attack, and/or elimination.8,9 Although this exact
hypothesis has not, to the best of our knowledge, been published
before, ring expansions through oxonium formation have been
demonstrated by Braddock for the formation of the 12-mem-
bered ring obtusallenes and related marilzabicycloallenes in mod-
erate yield.10,11 Additionally, Kim and co-workers12 have published
the opposite perspective on this idea: the tricyclic oxonium ion
derived from a ring contraction of the oxocane prelaurefucin
could lead to two tetrahydrofuran-containing natural products.13
The key challenge, however, is translating these ideas into
practical laboratory syntheses of single members. Perhaps for this
Received: July 25, 2011
Published: September 16, 2011
r
2011 American Chemical Society
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Scheme 2. Inspiration of a General Approach for Controlled
8-Membered Cyclic Bromoether Synthesis
Scheme 3. Initial Explorations of 8-Membered Bromoether
Formation Using Substrates 20 and 26
the tetrahydrofuran ring and the alkene (i.e., 16) could afford the
corresponding 8-endo (lauthisan-like)19 materials (i.e., 18 and
19). Critically, if the process was fully stereocontrolled, then all
lauroxocane cores could be predictably accessed, one at a time.
Our studies began with variants of model compound 20
(Scheme 3), prepared readily through the approach of Britton
and co-workers (see Supporting Information (SI)).21 Although
attempted cyclization of the free alcohol variant (20a) failed to
produce any ring-expanded ketone, exposure of the acetylated
version (20b) to 1.2 equiv of BDSB for 5 min at À25 °C yielded
the desired 8-exo bromoether as a 3.6:1 mixture of acetate
regioisomers (i.e., 21 and 22) in 74% yield. Significantly, this
reaction process was both stereo- and regioselective, indicating
that it proceeded through only one of two facially distinct
bromonium ions and only with 5-exo attack by the tetrahydro-
furan oxygen (not the 6-endo alternative). Since the alkene is
significantly removed from the chirality of the tetrahydrofuran, a
likely possibility is that both faces are accessible, but ultimately
the more reactive bromonium ion is accessed by bromonium
transfer processes to funnel to the observed single diastereomer.22
Molecular models are drawn in the center of Scheme 3; for steric
reasons, the brominated side chain of the oxonium species likely
prefers an exo orientation with respect to the concave oxonium.
From a practical standpoint, however, the acetylated products
proved difficult to handle due to facile migration of their acetate
groups (i.e., 21H22). Pleasingly, the benzoate congener (20c)
solved this problem23 and led to higher regiochemical differen-
tiation, affording a 10:1 mixture of separable 23 and 24 in 76%
yield. Hydrolysis of these materials to the diol followed by
rebenzoylation afforded a 6.6:1 ratio of 24:23 in 90% yield,
allowing access to either monobenzoylated regioisomer in good
yield. In the interest of affording only a single product, the tert-
butoxycarbonyl (Boc) variant 20d smoothly underwent ring
expansion to carbonate 25 in 79% yield. In addition to varying
the identity of the ring-opening group, we also altered its stereo-
chemistry. We were delighted to find that all variants of 26 afforded
diastereomeric 8-exo bromoethers with similarly good yields. The
relative stereochemistries of 21À25 and 27À31 were confirmed by
X-ray diffraction of their crystalline diol derivatives (see SI). Worth
noting is that the efficiency of the cyclizations was dependent upon
the bromonium source used. While BDSB provided the optimal
yield for the synthesis of 25, TBCO (2,4,4,6-tetrabromo-2,5-
cyclohexadienone) and (coll)2BrOTf afforded a 62% and 52% yield
of 25, respectively, while NBS gave less than 10% of the desired
product, even after 48 h (the use of N,N-dimethylacetamide as a
nucleophilic promoter failed to enhance this yield).24
To evaluate the diastereocontrol needed to access the entire
range of lauroxocane natural products selectively, we next
examined 7 analogues of 20d that systematically varied the
relative stereochemistry of their C2- and C5-alkyl groups and
the position and E/Z-stereochemistry of the alkene. All
substrates possessed Boc groups to afford a single product
and were cyclized using BDSB. Although all bromoethers in
this study were prepared without regard for absolute stereo-
chemistry, each synthesis could be rendered asymmetric.21
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Table 1. Exploration of the Generality of Ring-Expansion
Scheme 4. Formation of 9-Exo and 9-Endo Ring Systemsa
a The diol derived from 49 was confirmed by X-ray.
unprotected alcohol precursors to 42 and 45 produced 44 and
47 in near quantitative yield. Despite the failure of these
substrates, the desired products (i.e., 43 and 46) have the same
stereochemical relationship as only one known Laurencia natural
product. By contrast, the other 6 frameworks produced model at
least 28 different isolates and one core (i.e., 25) that has not been
observed in nature.27 As such, these collated results illustrate the
potential of the approach for controlled lauroxocane synthesis
through a direct bromonium-induced process.
As a final exploration of reaction scope for this study, we
evaluated its feasibility for 9-membered ring formation, as at least
10 naturally occurring lauroxonanes (9-membered bromoethers)
have been isolated to date. Pleasingly, both substrates investi-
gated (i.e., tetrahydrofuran 48 and tetrahydropyran 50, Scheme 4)
led to the expected products upon reaction with BDSB, yielding
one 9-exo and one 9-endo product (i.e., 49 and 51).28 We expect
that diastereomeric 9-membered products, and potentially larger
rings, could arise from similar processes.
In conclusion, a novel procedure for bromonium-induced ring
expansion effected by BDSB has afforded access to medium-sized
cyclic bromothers resembling those of the Laurencia acetogenins.
This process is fast, regio- and stereoselective, and has been
demonstrated to produce seven stereochemically distinct
8-membered bromoethers as well as two 9-membered deriva-
tives. Additionally, its overall generality may shed new light on
potential biosynthetic pathways that should be considered for the
family. Current work is directed toward applying this approach to
natural product syntheses exploring the range of ring sizes and
stereochemistries accessible.
As shown in Table 1, stereoisomers of 20d (32, 34, and 36)
stereoselectively afforded the expected 8-exo bromoether
products after only 10 min. Of the analogous substrates shor-
tened by one methylene (38, 40, 42, and 45), only E-alkenes 38
and 40 underwent ring expansion to 8-endo bromoether
products.25 The two cis-disposed materials (42 and 45) instead
gave bicycles 44 and 47 as the predominant products. 5-Endo
haloetherifications are often significantly slower with Z-alkene
substrates;26 here, that suggests substrates 42 and 45 failed
due to side reactions achieving competitive reaction rates. For
example, the Boc group may have been deprotected under the
acidic conditions (BDSB is a Lewis acid at both sulfur and
bromine and could react with trace water to form HBr and
Et2SOH+), thereby enabling the resulting alcohol to attack the
bromonium intermediate preferentially. This hypothesis is
supported by the observation that BDSB cyclization of the
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, copies of spectral data, and characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
sas2197@columbia.edu
’ ACKNOWLEDGMENT
We thank Dr. Y. Itagaki for assistance with mass spectrometry,
the NSF (CHE-0619638) for an X-ray diffractometer, and Prof.
Gerard Parkin and Mr. Aaron Sattler for initial crystallographic
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evidence of 8-membered ring formation. Financial support was
provided by Columbia University, the NSF (CAREER Award
CHE-0844593 and predoctoral fellowships to D.S.T. and A.P.B.),
the ACS Petroleum Research Fund (47481-G), the Camille and
Henry Dreyfus Foundation (New Faculty Award to S.A.S.),
Bristol-Myers Squibb, and Eli Lilly. This paper is dedicated to
Prof. K. C. Nicolaou on the occasion of his 65th birthday.
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