A highly convergent approach toward (-)-brevenal

Article abstract of DOI:10.1021/ol1008203

Progress toward a highly convergent, asymmetric synthesis of brevenal is reported. Construction of the AB-ring and E-ring cyclic ether fragments was achieved through asymmetric alkylation/ring-closing metathesis strategies. A Horner-Wadsworth-Emmons olefination was used in a key bond-forming step to couple the advanced cyclic fragments and enable rapid access to the AB-E ring system.

Full text of DOI:10.1021/ol1008203

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2614-2617
A Highly Convergent Approach toward
(-)-Brevenal
Michael T. Crimmins,* Mariam Shamszad,† and Anita E. Mattson‡
Kenan and Caudill Laboratories of Chemistry, UniVersity of North Carolina at Chapel
Hill, North Carolina 27599
crimmins@email.unc.edu
Received April 9, 2010
ABSTRACT
Progress toward a highly convergent, asymmetric synthesis of brevenal is reported. Construction of the AB-ring and E-ring cyclic ether
fragments was achieved through asymmetric alkylation/ring-closing metathesis strategies. A Horner-Wadsworth-Emmons olefination was
used in a key bond-forming step to couple the advanced cyclic fragments and enable rapid access to the AB-E ring system.
Marine polycyclic ether natural products have received much
attention over the years due to their unique and highly
complex molecular architecture, in addition to their diverse
and potent biological activities.1 A number of bioactive
polyether natural products have been isolated from the marine
dinoflagellate Karenia breVis, the organism responsible for
toxic red tides along Florida’s Gulf Coast. The most well-
known compounds isolated from K. breVis are a family of
neurotoxins called the brevetoxins. The brevetoxins are
responsible for massive kills of fish and marine animals and
can also adversely affect humans; inhaled brevetoxins cause
respiratory irritation and breathing difficulties in sensitive
populations.2 At high concentrations, ingested brevetoxins
lead to a collection of symptoms commonly referred to as
neurotoxic shellfish poisoning (NSP).3 Brevenal (1) was
isolated in 2004 from K. breVis and has been shown to
counteract the toxic effects of the brevetoxins.4 Specifi-
cally, brevenal has been shown to competitively displace
titrated dihydrobrevetoxin-B from voltage-sensitive so-
dium channels in rat brain synaptosomes in a dose-
dependent manner, alleviating the toxic effects of the
brevetoxins in vivo.5 More importantly, picomolar con-
centrations of brevenal were found to increase tracheal
mucus velocity to the same degree as that observed with
millimolar concentrations of a sodium channel blocker,
amiloride, which is used in the treatment of the debilitating
lung disorder cystic fibrosis.6 As such, brevenal represents
a potential lead for the development of novel therapeutic
agents for the treatment of mucociliary dysfunction
associated with cystic fibrosis and other lung disorders.
To date, two syntheses of brevenal have been reported
by the laboratories of Sasaki7 and Yamamoto.8
† Current location: University of Texas at Austin, Austin, TX.
‡ Current location: Assistant Professor of Chemistry, The Ohio State
University, Columbus, OH.
(4) Bourdelais, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M.;
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Nakata, T. Chem. ReV. 2005, 105, 4314–4347.
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J.; Bossart, G. D.; Baden, D. G. Harmful Algae 2004, 3, 99–115.
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10.1021/ol1008203  2010 American Chemical Society
Published on Web 05/06/2010

Our retrosynthetic analysis of brevenal includes the
installation of the unsaturated side chains at both ends of
the molecule late in the synthesis (Scheme 1). The penta-
ether via a ring-closing metathesis reaction of diene 7. Stereo-
selective alkylation of glycolate 8 followed by conversion
of the oxazolidinone to the olefin would afford advanced
diene 7. The precursor to glycolate 8, enol ether 9, would
be accessed from 10 via a cyclodehydration reaction. A
Horner-Wadsworth-Emmons coupling of aldehyde 11 and
ꢀ-ketophosphonate 12 would give rise to 10.
Scheme 1. Retrosynthetic Analysis
The synthesis commenced with a monobenzylation of
commercially available 1,4-butanediol10 (13) followed by a
Jones oxidation11 to afford carboxylic acid 14 (Scheme 3).
Conversion to the methyl ester under acidic conditions
followed by displacement with lithiodimethyl methylphos-
phonate12 then furnished ꢀ-ketophosphonate 12 in excellent
yield over the four steps. The preparation of aldehyde 11
began with a highly diastereoselective “Evans” syn propi-
onate aldol addition13 between phenylalanine-derived N-
propionylthiazolidinethione 15 and aldehyde 16. The result-
ant aldol adduct 17 was protected as the trimethylsilyl (TMS)
ether, and reductive removal of the auxiliary furnished the
desired aldehyde 11.
With both aldehyde 11 and ꢀ-ketophosphonate 12 pre-
pared, efforts were directed toward the completion of the
AB-ring fragment. Enone 10 was prepared in 90% yield
under mild reaction conditions using a modified Horner-
Wadsworth-Emmons olefination.14 1,4-Reduction of 1015
followed by deprotection of the TMS group generated
hydroxy ketone 18. After screening of a variety of cyclo-
dehydration conditions, it was discovered that camphorsul-
fonic acid (CSA) in the presence of molecular sieves afforded
enol ether 9 in excellent yield. Enol ether 9 was then
transformed to thioacetal 19 via an epoxide intermediate,16
and the resulting hydroxyl group was protected as the
triethylsilyl (TES) ether. The thioethyl group was converted
to a methyl group in one pot, using Sasaki’s protocol, to
give pyran 20.17 It was found that protection of the hydroxyl
group was necessary for this reaction to proceed in high yield.
With the necessary A-ring functionality in place, construc-
tion of the B-ring then ensued. The benzyl group was cleaved
in the presence of sodium naphthalenide18 to generate alcohol
21. Swern oxidation19 of the resultant hydroxyl group,
followed by a methylene Wittig reaction,20 afforded olefin
22. The TES ether was then cleaved with CSA and ethanol
cyclic polyether core was envisioned to arise from advanced
enone 3 via an acid-catalyzed cyclodehydration to form the
D-ring (2) followed by cyclization to afford the C-ring.
Enone 3 would be made available through a Horner-
Wadsworth-Emmons coupling between AB-ring ꢀ-keto-
phosphonate 4 and E-ring aldehyde 5.
Initial efforts toward the total synthesis of brevenal focused
on the construction of AB-ring ꢀ-ketophosphonate 4. The
retrosynthesis of 4 is centered on a glycolate alkylation/ring-
closing metathesis approach, developed in our laboratory, for
the enantioselective construction of medium-ring ethers (Scheme
2).9 It was envisioned that the ꢀ-ketophosphonate functionality
Scheme 2. Retrosynthetic Plan for ꢀ-Ketophosphonate 4
(8) Takamura, H.; Kikuchi, S.; Nakamura, Y.; Yamagami, Y.; Kishi,
T.; Kadota, I.; Yamamoto, Y. Org. Lett. 2009, 11, 2531–2534.
(9) (a) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029–
2032. (b) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122,
5473–5476.
(10) Butler, C. L.; Clapp, M. J. J. Am. Chem. Soc. 1938, 60, 1472–
1473.
(11) Davis, F. A.; Kasu, P. V. N.; Sundarababu, G.; Qi, H. Y. J. Org.
Chem. 1997, 62, 7546–7547.
(12) Delamarche, I.; Mosset, P. J. Org. Chem. 1994, 59, 5453–5457.
(13) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J.
Org. Chem. 2001, 66, 894–902.
(14) Alvarezibarra, C.; Arias, S.; Banon, G.; Fernandez, M. J.; Rodriguez,
M.; Sinisterra, V. J. J. Chem Soc., Chem. Commun. 1987, 1509–1511.
(15) Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusa, T. J.
Org. Chem. 1986, 51, 537–540.
would be installed in three steps from nitrile 6. Access to the
6,7-fused system would hinge on closure of the medium-ring
(16) (a) Rainier, J. D.; Allwein, S. P.; Cox, J. M. Org. Lett. 2000, 2,
231–234. (b) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001,
66, 1380–1386.
(7) (a) Ebine, M.; Fuwa, H.; Sasaki, M. Org. Lett. 2008, 10, 2275–
2278. (b) Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.; Sasaki, M.
J. Am. Chem. Soc. 2006, 128, 16989–16999.
(17) Please see ref 7b.
(18) Philips, K. D.; Horwitz, J. P. J. Org. Chem. 1975, 40, 1856–1858.
(19) Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 4537–4538.
Org. Lett., Vol. 12, No. 11, 2010
2615

Scheme 3. Synthesis of AB-Ring ꢀ-Ketophosphonate 4
to give alcohol 23. At this point, our glycolate alkylation/ring-
closing metathesis strategy was applied to construct the seven-
membered B-ring. Alcohol 23 was transformed to the glycolic
acid in the presence of sodium hydride and bromoacetic acid.
In one pot, the resultant acid was converted to the mixed pivalic
anhydride and treated in situ with the lithium salt of (R)-4-
isopropyl-2-oxazolidinone to produce acyl oxazolidinone 8.
Treatment of the sodium enolate of 8 with bromoacetonitrile
resulted in a highly diastereoselective glycolate alkylation21 to
furnish the nitrile. The modest yield associated with this reaction
is attributed to the formation of an unidentifiable byproduct
formed during the enolization process. All attempts to optimize
this reaction, however, were unsuccessful. The oxazolidinone
was then reductively cleaved to reveal alcohol 25. Oxidation
of 25 to the aldehyde under Swern conditions occurred in high
yield. Initially, the resulting aldehyde was subjected to a
methylene Wittig reaction using an ylide generated in situ from
potassium tert-butoxide and methyltriphenylphosphonium bro-
mide. The presence of the nitrile, however, facilitated an
elimination reaction under these rather basic conditions, thus
regenerating alcohol 23. To circumvent this undesired elimina-
tion, the methylenation reaction was performed using crystal-
lized, salt-free methylene triphenylphosphorane, thereby giving
rise to the desired diene 7.22 B-Ring formation was achieved
upon exposure of 7 to Grubbs’ second generation catalyst,23
affording bicycle 26 in 94%. Dihydroxylation of the resultant
olefin occurred readily to furnish the desired diol as a single
diastereomer. Subsequent protection of the diol afforded
advanced acetonide 6. Diisobutylaluminum hydride easily
reduced the nitrile to the aldehyde. In two steps, 6 was converted
to ꢀ-ketophosphonate 4 to complete the AB-ring fragment with
27 steps in the longest linear sequence. The stereochemistry
was confirmed by NOESY analysis.
With the AB-ring ꢀ-ketophosphonate in hand, efforts then
focused on the synthesis of the E-ring aldehyde (5, Scheme 4).
An asymmetric aldol addition, originally reported by Kobayashi
and co-workers,24 between oxazolidinone 27 and aldehyde 28
was used to prepare aldol adduct 29. The auxiliary was
converted to the methyl ester, and the free hydroxyl group was
protected as the TES ether to give ester 30. Conversion of 30
to aldehyde 31 was carried out using a two-step reduction-
(22) (a) Schmidba, H.; Vornberg, W.; Stuhler, H. Chem. Ber. 1972, 105,
1084. (b) Larionov, O. V.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 2954–
2955.
(23) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
(20) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654–1666.
(21) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2,
2165–2167.
(24) Murata, Y.; Kamino, T.; Hosokawa, S.; Kobayashi, S. Tetrahedron
Lett. 2002, 43, 8121–8123.
2616
Org. Lett., Vol. 12, No. 11, 2010

Scheme 4
.
Synthesis of Aldehyde 5
Scheme 5. Coupling of the Fragments and Proposed Endgame
of the fragments and completing brevenal (Scheme 5).
ꢀ-Ketophosphonate 4 and aldehyde 5 were joined through a
barium hydroxide mediated Horner-Wadsworth-Emmons
reaction to provide advanced enone 3 in excellent yield. In
order to complete the total synthesis of brevenal, we envision
the closure of the D-ring via an acid-catalyzed cyclodehy-
dration. Manipulation of the resulting enol ether (2) to give
ketone 40 followed by formation of the C-ring via acetal-
ization will give the pentacyclic polyether core (41). Instal-
lation of the left- and right-hand side chains will then furnish
brevenal (1).
In summary, a highly convergent approach toward the total
synthesis of brevenal has been reported. Two key cyclic ether
fragments have been constructed utilizing our asymmetric
glycolate alkylation/ring-closing metathesis approach. Frag-
ment coupling has been carried out in excellent yield, and
efforts to complete the carbon framework and elaborate the
side chains are ongoing.
oxidation sequence. After generation of a terminal olefin from
the aldehyde functionality through a Wittig reaction, the TES
group was removed to furnish alcohol 32. Alkylation of 32 with
bromoacetic acid followed by coupling with a valine-derived
oxazolidinone enabled isolation of glycoyl oxazolidinone 34.
Generation of the sodium enolate of 34 followed by alkylation
with bromoacetonitrile introduced the third stereogenic center
with excellent diastereoselectivity (95:5 dr). Reductive removal
of the auxiliary then furnished alcohol 35, and the resultant
hydroxyl group was easily oxidized to aldehyde 36 under Swern
conditions. Treatment of 36 with divinyl zinc installed the
second olefin as a mixture of diastereomers (37). Exposure of
this diastereomeric mixture to Grubbs’ second generation
catalyst enabled the isolation of cyclic ethers 38 and 39. The
undesired diastereomer 38 could be converted to 39 via a two-
step oxidation/reduction sequence. Protection of 39 as a TES
ether and reduction of the nitrile generated E-ring aldehyde 5
in 16 steps from 27.
Acknowledgment. Financial support from the National
Institute of General Medical Sciences (GM60567) is grate-
fully acknowledged.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
With both the AB-ring ꢀ-ketophosphonate and E-ring
aldehyde prepared, attention was directed toward coupling
OL1008203
Org. Lett., Vol. 12, No. 11, 2010
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