Synthesis of the ABC Substructure of Brevenal by Sequential exo-Mode Oxacyclizations of Acyclic Polyene Precursors

Article abstract of DOI:10.1021/acs.orglett.7b02538

Exploratory studies on the sequential exo-mode oxacyclizations of acyclic polyene precursors have provided a substantial substructure of brevenal, including the fused tricyclic polyether with stereochemical patterns consistent with the AB and BC ring fusions. The synthesis of acyclic substrates featured two variations of Cr(II)/Ni(II) couplings for preparing 1,1-disubstituted allylic alcohols. A sequence of iodine-promoted cycloetherification, base-promoted intramolecular conjugate addition, and mercury-promoted cycloetherification produced the tricyclic substructure.

Full text of DOI:10.1021/acs.orglett.7b02538

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Synthesis of the ABC Substructure of Brevenal by Sequential
exo‑Mode Oxacyclizations of Acyclic Polyene Precursors
Jessica A. Hurtak and Frank E. McDonald*
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States
S
* Supporting Information
ABSTRACT: Exploratory studies on the sequential exo-mode
oxacyclizations of acyclic polyene precursors have provided a
substantial substructure of brevenal, including the fused tricyclic
polyether with stereochemical patterns consistent with the AB and
BC ring fusions. The synthesis of acyclic substrates featured two
variations of Cr(II)/Ni(II) couplings for preparing 1,1-disubstituted allylic alcohols. A sequence of iodine-promoted
cycloetherification, base-promoted intramolecular conjugate addition, and mercury-promoted cycloetherification produced the
tricyclic substructure.
used polycyclic ether natural products are best known as
potent marine neurotoxins, including brevetoxins, ciguatox-
ins, and maitotoxin. These toxins feature a regular framework of
trans-fused cyclic ethers, mostly six- and seven-membered rings,
with eight- and nine-membered rings in some of the larger and
more toxic natural products.1 Brevenal, 1 (Figure 1), a
this work, we describe sequential exo-mode oxacyclizations as a
unique strategy for fused polycyclic ether synthesis.
The origin of this idea involved a cascade of electrophile-
promoted oxacyclizations from the proposed triene triol 2,
aiming for diastereoselective formation of each new ring with
stereoinduction from an allylic oxygen substituent to provide
tricyclic polyether 3 (Figure 2).8 This synthetic scheme was
F
Figure 1. Structure of brevenal, highlighting the substructure described
in this communication.
structurally simpler pentacyclic member of this family, is a
naturally occurring nontoxic antagonist to the neurotoxic activity
of the brevetoxins and ciguatoxins.1,2 As brevenal exhibits
potential therapeutic activity for a variety of diseases associated
with ion channel activation, including cystic fibrosis,3 an efficient
and relatively short chemical synthesis of brevenal and various
analogues is an exciting prospect.
Figure 2. Proposed sequence of exo-mode oxacyclizations of triene triol
2 to form the ABC substructure of brevenal.
Sasaki reported the first synthesis of brevenal in 2006, which
corrected the stereochemical assignment of the E ring tertiary
alcohol. The synthesis was refined through three generations,
ultimately providing gram-scale quantities of brevenal.4
Yamamoto and Rainier subsequently described additional
contributions by complementary approaches.5,6 However,
these syntheses featured strategies involving sequential annula-
tion of rings, requiring both carbon−carbon and carbon−oxygen
bond-forming reactions.
Our laboratory has a longstanding interest in strategies that
form multiple cyclic ethers from polycyclization of an acyclic
carbon chain. We previously focused on endo-regioselective
polyepoxide cyclizations but uncovered consequential limita-
tions with regard to substituent patterns at the ring fusions.7 In
conceived with the expectation that the six-membered A ring
would form faster than the seven-membered B ring, and that the
acetonide protective group might slow but not prevent
oxacyclization to form the six-membered C ring.9 Model studies
showed that stage a offered a stereoselective 6-exo-oxacyclization
approach to the A ring.8 However, another model study directed
at stage b was complicated by an unexpected 8-endo-mode
pathway,10 suggesting that the proposed 7-exo electrophile-
promoted oxacyclization of 4 to form the B ring could be
Received: August 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02538
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
problematic. An alternative strategy to address stage b via
intramolecular conjugate addition of dienone 5 to bicyclic
product 6 was designed to electronically block the 8-endo-
oxacyclization pathway.11,12 This approach would require
stereoselective reduction of the ketone 6 to the allylic alcohol
7, prior to stage c to close the C ring of tricyclic product 3. We
were confident that the residual “X” and “Y” groups could be
replaced with “H” in a final step.13
Scheme 2. Sequential Stereoselective Oxacyclizations To
Form the AB Rings from the Dienoate Diol 14
Synthesis of the acyclic triene triol 2 began by linking the
known aldehyde 814 and terminal alkyne 9,15 utilizing a Cr(II)/
Ni(II) reductive coupling developed by Takai (Scheme 1),16
Scheme 1. Synthesis of Acyclic Triene Triol 2
substituted products 24 and 25.25 Notably, deiodination of the
major diastereomer 22 required higher temperature and
proceeded less cleanly than for the minor diastereomer 23.
Structural assignments of the respective diastereomers 24 and 25
were made by comparing cross-ring NOE effects (Figure 3). In
addition, the trans-ring fusion of the AB rings of the major
diastereomer was unambiguously confirmed by an X-ray crystal
structure of the primary alcohol derivative 26.26
Figure 3. Crystal structure of trans-fused polycyclic product 26; cross-
ring NOE correlations of trans- and cis-fused polycyclic ethers 24 and 25.
A similar sequential oxacyclization process was applied to the
triene triol substrate 2 (Scheme 3) to produce compounds 27
which gave superior results compared to Nozaki−Hiyama−Kishi
(NHK) coupling with the corresponding vinylic halide.17 Dess-
Martin periodinane oxidation of the diastereomeric mixture of
allylic alcohols provided the enone 10, which underwent highly
stereoselective ketone reduction promoted by chiral oxazabor-
olidine, favoring the (S)-alcohol 11.18 Attempts to selectively
oxidize the primary alcohol of diol 12 resulted instead in the
lactone 13, with PhI(OAc)2 and catalytic TEMPO providing the
best yields.19 DIBAL-H reduction of lactone 13 concurrently
unmasked the primary alcohol and converted the lactone to a
cyclic hemiacetal, which underwent Wittig olefination to produce
diene diol 14. This compound was more easily purified after silyl
ether protection of both primary and secondary alcohols to
isolate the (Z)-enoate 15. NHK coupling of the derived aldehyde
17 with vinylic iodide 1820 proceeded in modest yield and only
worked on small scale, limiting the availability of triene triol 2.21
For this reason, formation of the A and B rings was explored
with diene diol 14. Iodocyclization (stage a) proceeded with
good diastereoselectivity (85:15 dr), favoring pyran 20 (Scheme
2).22 As diastereomers 20 and 21 arising from iodocyclization
were inseparable at this stage, we carried the mixture forward
through the conjugate addition step (stage b), with each
diastereomer giving the corresponding polycyclic products 22
and 23, which were separated at this stage.23,24 Each individual
diastereomer was deiodinated into the corresponding methyl-
Scheme 3. Sequential Oxacyclizations To Form the AB trans-
Fused Rings from Triene Triol 2
and 28 (corresponding to the generic structures 5 and 6; see
Figure 2). Iodocyclization of 2 followed by chemoselective
oxidation of the doubly allylic alcohol produced the iodomethyl-
substituted dienone 27,27 which underwent intramolecular
conjugate addition to form the trans-fused bicyclic enone 28
with high diastereoselectivity.
Given the difficulties in the NHK reaction producing substrate
2, we augmented our supply of compound 28 from aldehyde 22
B
DOI: 10.1021/acs.orglett.7b02538
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(Scheme 4). In this case, the NHK coupling with vinylic iodide
18 proceeded reproducibly and with better yield, providing
sterically blocked than in compound 22, which underwent
deiodination to 24 (see Scheme 2). Perhaps the diminished
reaction rate of trans-fused iodomethyl 22 relative to the cis-fused
diastereomer 23 should have warned us that late-stage
deiodination might be troublesome. Nonetheless, this route
demonstrates viable methods for acyclic substrate synthesis,
establishes conditions for diastereo- and regioselective con-
struction of three of the five rings of brevenal, and will provide
sufficient background for exploring and inventing catalytic
methods for these oxacyclizations.
Scheme 4. Alternative Synthesis of Enone 28 via Bicyclic
Aldehyde 29 and Stereoselective Synthesis of Allylic Alcohol
30
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02538.
Experimental details and characterization data (PDF)
NMR spectra of selected compounds (PDF)
X-ray data for 26 (CIF)
bicyclic enone 28 after oxidation. Upon exploring conditions for
the stereoselective reduction of enone 28, we observed that the
Luche reduction proceeded with high diastereoselectivity
favoring the S-isomer 30 (97:3 dr at −78 °C; 83:17 dr at −40
°C).28
The acetonide-protected oxygen of 30 was not sufficiently
nucleophilic to form the C ring by electrophilic cyclization
methods.29 Fortunately, the acetonide protective group was
rapidly and relatively cleanly hydrolyzed upon brief treatment
with trifluoroacetic acid/water to afford the alkenyl triol substrate
31, for exploring stage c, namely, forming the C ring of brevenal
(Scheme 5). Despite our earlier successes with the iodocycliza-
X-ray data for 36 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: frank.mcdonald@emory.edu.
ORCID
Frank E. McDonald: 0000-0002-6612-7106
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Scheme 5. Preparation of Tricyclic Polyethers 32 and 33 from
Alkenyl Triol 31
■
This contribution is dedicated to Prof. Paul A. Wender on the
occasion of his 70th birthday. This material is based upon work
supported by the National Science Foundation under CHE-
1362249 and using NMR instrumentation supported by Grant
CHE-1531620. Dr. John Bacsa provided crystallographic analysis
of compounds 26 and 36 in the Emory X-ray Crystallography
Center. Prof. Simon Blakey (Emory University) provided the use
of a glovebox for the Cr(II)-promoted couplings. Dr. Kristen L.
Stoltz and Mr. Xiang Liu (Emory University) assisted in early
stages of this project.
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D
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Org. Lett. XXXX, XXX, XXX−XXX