Total synthesis of brevenal

Article abstract of DOI:10.1021/ja200089f

This Article describes the total synthesis of the marine ladder toxin brevenal utilizing a convergent synthetic strategy. Critical to the success of this work was the use of olefinic-ester cyclization reactions and the utilization of glycal epoxides as precursors to C-C and C-H bonds.

Full text of DOI:10.1021/ja200089f

ARTICLE
pubs.acs.org/JACS
Total Synthesis of Brevenal
Yuan Zhang, John Rohanna, Jie Zhou, Karthik Iyer, and Jon D. Rainier*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
S Supporting Information
b
ABSTRACT: This Article describes the total synthesis of the marine
ladder toxin brevenal utilizing a convergent synthetic strategy. Critical
to the success of this work was the use of olefinic-ester cyclization
reactions and the utilization of glycal epoxides as precursors to C-C
and C-H bonds.
he dinoflagellate-derived marine ladder toxin family of
natural products has presented the scientific community
cyclization to the D-ring would complete the brevenal penta-
cyclic core as 1.
T
with a number of interesting challenges. Structurally, their fused
ether architectures remain a challenge in terms of isolation,
structure elucidation, and synthesis.1 Environmentally, their role
in food poisoning and red tide events has long made them a curse
on marine life and on the fishing industry.2 Functionally, their ion
channel binding properties have made them useful tools in
biology.3 Thus, the 2005 report from the Bourdelais and Baden
laboratories that described the isolation and structure elucidation
of brevenal, a ladder toxin from the dinoflagellate Karenia brevis,
was met with considerable enthusiasm.4 In addition to its
interesting pentacyclic structure, brevenal’s impressive biological
profile included ion channel activity,5 a lack of neurotoxicity,
along with an ability to increase tracheal mucous velocity in
animal models of asthma.6 These properties have led to brevenal
receiving a significant amount of attention including from the
synthetic community where two total syntheses and one partial
synthesis have been reported.7 The initial total synthesis by the
Sasaki group also included a structural reassignment of the C(26)
stereocenter. The synthesis utilized alkyl Suzuki couplings and
required 32 steps to the brevenal core, 47 total steps (longest
linear sequence), and was completed in 0.2% overall yield. The
second synthesis was accomplished by Kadota and Yamamoto
and represented an improvement in terms of side-chain con-
struction but not with respect to the number of steps (47 steps to
the core, 57 total steps (longest linear sequence), 0.8% overall
yield). Finally, Crimmins recently reported a synthesis of the A,
B- and E-rings that centered around his asymmetric glycolate
alkylation, RCM chemistry.8
With this plan in mind, we initially targeted the generation of
the A-B bicycle. As envisioned, the formation of the A-ring
required two unprecedented reactions, OLEC to the ring itself
where a cyclic template would not be present on the cyclization
precursor and a stereoselective epoxidation, C-C bond-forming
reaction on an A-ring dihydropyran that lacked an allylic stereo-
center. Our attempts to solve these problems began with
4-hydroxybutanal derivative 6 and a Brown crotylboration reac-
tion to give 8 having the C(8) and C(9) brevenal stereocenters in
90% yield and in 95:5 er (Scheme 2).15 Extension of the olefin
and the DCC-mediated esterification using acid 10 gave cycliza-
tion precursor 11. In the conversion of olefinic ester 11 into
A-ring substrate 12, we compared enol ether-olefin RCM with
our recently developed OLEC chemistry and found OLEC to be
superior with respect to both yield and efficiency (conditions A
and B). The OLEC reaction was run on multigram scale and
delivered 12 in 88% yield. Also interesting was the comparison of
the OLEC conditions using CH3CHBr2 (condition B) with
those using CH2Br2 (condition C) and the Tebbe reagent
(condition D).16,17 The use of CH2Br2 gave a 1:1 mixture of
cyclic and acyclic enol ether in 70% yield, while the use of the
Tebbe reagent resulted in the decomposition of starting material
with no noticeable product formation.18
We next examined oxidation to the aforementioned C(11)
hydroxyl group followed by a directed C-C bond-forming
reaction to the C(12) methyl group. We were pleased to find
that the reaction of dihydropyran 12 with DMDO and AlMe3
was stereoselective, giving the desired product 16 in 66% yield
(Scheme 3).19 We envision that the C(12) angular methyl group
comes from a directed transfer of methyl as indicated by 15.
In light of the fact that we had previously utilized substrates
having pendant acetals in the Me3Al epoxide opening reactions,20
the generation of methyl ether 17 was somewhat surprising to us.
From a general interest in the synthesis and ion channel
binding properties of the ladder toxins, we also became interested
in brevenal.9,10 Influenced a great deal by methodology that
enables the cyclizations of olefins having pendant esters,11-13
we settled upon the strategy illustrated in Scheme 1 that called
for the coupling of A-B bicyclic alcohol 4 with E-ring acid 5
and olefinic-ester cyclization (OLEC) to the brevenal C-ring
2.14 Incorporation of the C(19) angular methyl group and
Received: January 6, 2011
Published: February 15, 2011
r
2011 American Chemical Society
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Scheme 1. OLEC Plan to Brevenal
Scheme 2. Brevenal A-Ringa
a We believe that the lower yield in entry C is due to the instability of the acyclic enol ether to purification.
While the fact that 16 and 17 are readily separable makes this
process workable, the generation of 17 is obviously not ideal.
Although we have dedicated a considerable amount of time and
effort in attempts to overcome the formation of 17, to date we
have not been able to find conditions or substrates that are more
effective than those shown.21
Having established the brevenal A-ring, we next targeted the
B-ring and subjected 16 to a two-step cyclization protocol
involving the initial generation of a cyclic mixed acetal and the
subsequent elimination of methanol to give 18 (Scheme 4).22
This sequence was superior to our previously reported one-step
reaction using PPTS and pyridine due to the sensitive nature of
18 to PPTS at 130 °C.23 DMDO epoxidation and in situ coupling
with allyl Grignard gave allyl oxepane 19 in 87% yield as a 10:1
mixture of diastereomers.24,25
and Rubottom oxidation introduced the C(14) hydroxyl group
as a 6:1 mixture favoring the desired diastereomer 20.26 In a
fashion similar to Sasaki’s findings with a related substrate,7a the
i-Bu2AlH reduction of 20 delivered the C(14), C(15) diol
corresponding to 21 as the major product. It turns out that a
free alcohol is required for the synthesis of 21. When a C(14)
TES ether was used in the reduction, the undesired C(15)
stereoisomer was isolated as the major product. Treatment of
the diol with Bu2SnO and benzyl bromide gave A,B coupling
precursor 21 as the major product.27 Worthy of mention here is
that all of the stereocenters in 21 arose from substrate-controlled
diastereoselective reactions once the C(8) and C(9) stereocen-
ters had been established (Scheme 2).
With 21 in hand, we next targeted the synthesis of the brevenal
E-ring (Scheme 6). From olefinic-ester 22, which is available
in four steps from L-glyceraldehyde acetonide,28 OLEC success-
fully gave oxepene 23 in 66% yield along with 22% of the
The completion of our synthesis of the brevenal A-B ring
system is illustrated in Scheme 5. Oxidation of the C(15) alcohol
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Scheme 3. Epoxidation-Directed Addition to the A-Ring
protecting group from TES to PMB, oxidative fragmentation
of the alkene afforded the E-ring coupling precursor 29.
With the synthesis of both of the precursors completed, we
were prepared to examine their utility in the generation of the
remainder of brevenal. Esterification of E-ring acid 29 using A,B-
alcohol 21 and the Yamaguchi acid chloride gave ester 30
(Scheme 7).33 Despite the presence of a number of potential
coordination sites, the Ti OLEC chemistry was impressive here
giving C-ring enol ether 31 in 83% yield.
Our initial attempts to incorporate the C(19) angular methyl
group are outlined in Schemes 8 and 9. From 31, our initial plan
was to utilize the oxidation, AlMe3 protocol. On the basis of a
related reaction that had been successful in our hemibrevetoxin B
synthesis, we had hoped that the C(14) ether would control the
facial selectivity in the epoxidation reaction and, as a conse-
quence of the mechanism (see Scheme 3), the stereoselective
incorporation of the C(19) angular methyl group. In the event,
exposure of a CH2Cl2 solution of the epoxide from 31 to AlMe3
resulted in the generation of ketone 33. Presumably 33 comes
from a pinacol-type rearrangement of the intermediate epoxide,
that is, 32.34
Scheme 4. Brevenal’s B-Ring
The choice of solvent proved important in overcoming the
generation of 33. When the epoxide opening reaction was carried
out in toluene rather than CH2Cl2, we isolated 34 having the
desired connectivity but as a mixture of C(18) and C(19)
diastereomers (Scheme 9).35 While the observed solvent effect
is certainly interesting, that 34 was isolated as an inseparable
mixture of diastereomers as a result of the poor selectivity in the
epoxidation reaction made this approach untenable and forced us
to modify our strategy.
Despite the disappointing result to 34, we felt that the facility
of both epoxide and oxocarbenium ion formation was advanta-
geous. To overcome the lack of selectivity in the C-C bond-
forming reaction, we set out to identify conditions where the
stereochemical outcome of the C(19) C-C bond formation
would be decoupled from the stereochemistry of the C(18),
C(19) epoxide. That is, we felt that if we were able to generate an
oxocarbenium ion that was analogous to 32 but that had the
adjacent alkoxide masked with a nontransferable group, the lack
of selectivity in the C(19) bond formation might be overcome.
Largely driving these efforts was the overwhelming propensity
for axial addition to oxocarbenium ions in six-membered rings.36
Although precedent for the proposed reaction sequence
existed,37 to the best of our knowledge the precedent was not
extensive. Thus, before carrying out the chemistry on our
brevenal substrate, we opted to initially explore the proposed
chemistry with model bicyclic enol ether 35. Enol ether 35 was
chosen largely because we had previously demonstrated that its
DMDO epoxidation chemistry was not selective.25 In the event,
when the epoxide from 35 was exposed to a mixture of TESOTf
and ZnMe2,38 we isolated C,C-ketal 38 having the expected
mixture of silyl ether diastereomers but as a single stereoisomer at
the newly formed 3° ether center (Scheme 10). Through the use
of NOE correlation experiments, we subsequently showed that
the methyl group was in the desired axial position.
Scheme 5. Completion of Brevenal’s A-B Ring Precursor
corresponding acyclic enol ether. The acyclic enol ether bypro-
duct could be converted into 23 using the Grubbs second
generation catalyst 13, but the conversion was relatively low,
that is, 35%, and included varying quantities of the corresponding
dihydropyran from olefin isomerization and cyclization.29 Oxida-
tion of 23 and in situ reduction using i-Bu2AlH gave 24 as a single
diastereomer.30 Mechanistically, we believe that the epoxide
oxygen atom directs the reduction in a fashion similar to the
analogous reaction with Me3Al, for example, 15, Scheme 3.19
Oxidation of the C(26) alcohol to the corresponding ketone and
addition of MeMgBr in toluene gave a 7:1 mixture of 3° alcohol
25.7,31 Silyl ether formation, hydrolysis of the benzylidene acetal,
and conversion of the C(21) alcohol into the corresponding
homoallyl derivative gave 27.32 After switching the C(23)
Having established the ability to generate oxocarbenium ions
in the model substrate, we were prepared to examine the reaction
in brevenal substrate 31 (Scheme 11). Unfortunately, the treat-
ment of the epoxide from 31 with TESOTf and ZnMe2 was
capricious, giving trace amounts of the desired product 40 along
with other oxidized material that included methanol adduct 39.
As has been proposed by Wei for a related transformation, we
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Scheme 6. Synthesis of Brevenal’s E-Ring Precursor
Scheme 7. Coupling to Brevenal’s C-Ring
Scheme 8. Pinacol-Type Rearrangement of 31
Scheme 9. Me3Al Addition to 31
Scheme 10. Oxocarbenium Ions from Glycal Epoxides
believe that 39 comes from the oxidation of ZnMe2 by the
epoxide from 31 and the subsequent transfer of methoxide to the
epoxide.39
Having failed to directly introduce the C(19) angular methyl
group into 31, we decided to examine a stepwise solution to the
problem. In contrast to the results from the reaction of ZnMe2,
the addition of EtSH to the epoxide from 31 worked well, giving a
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Scheme 11. Attempted Generation of 40
Scheme 12. C(19) Methyl Incorporation
Scheme 13. Attempts at Brevenal’s D-Ring
mixture of C(18) alcohol diastereomers 41 in 89% yield
(Scheme 12).40 The stereoselective introduction of the C(19)
methyl group was finally accomplished by subjecting the TES
ether analogue of 41 to Kadota’s recently reported conditions,
Me2Zn and Zn(OTf)2, to give 42.41 Removal of the TES group
and oxidation gave ketone 43 as a single diastereomer in 81%
yield for the five steps following oxidative removal of the PMB
ether. A harbinger of future problems with the reductive cycliza-
corresponding sulfone using either homolytic or heterolytic
reaction conditions failed miserably. These reactions led to either
the recovery of 44 or its conversion into intractable mixtures.
From all of these studies, it became clear that the presence of the
C(19) angular methyl group was significantly inhibiting our
efforts to the brevenal C-ring.
We also examined the reductive cyclization of ketone 46
where the reduction would take place at the D,E-ring junction
and C(23).44 In contrast to the related reaction with 44, the
homolytic reduction of thioketal 47, while sluggish, was success-
ful, resulting in oxepane 48 as a single diastereomer (Scheme 14).
Removal of the benzyl groups and conversion of the resulting
alcohols into the corresponding TBS ethers gave pentacycle 49, a
compound that had been reported previously by Sasaki during
his brevenal work.7 Unfortunately, our spectroscopic data for 49
did not match that previously reported. While not definitively
established, we presume that pentacycle 49 differs from the
brevenal core at C(23).
1
tion of 43 was that it existed exclusively (by H NMR) as the
hydroxy ketone tautomer and not as the corresponding
hemiketal.
As mentioned above, the generation of the brevenal D-ring
from 43 required a reductive cyclization reaction. To this goal,
attempts to convert 43 directly into 45 using TMSOTf and
Et3SiH resulted in decomposition with no discernible product
formation (Scheme 13).42 A more conservative approach invol-
ving the generation of mixed ketal 44 was more successful but still
required the initial conversion of the ketone into the correspond-
ing dithioketal followed by a AgClO4 catalyzed cyclization to give
44.43 Unfortunately, attempts to reduce the thioketal or the
The effectiveness of the OLEC approach to the ladder toxins is
at least partly due to the fact that the coupling involves an
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Scheme 14. C(23)-Epi-brevenal Core
Scheme 15. Brevenal Retrosynthesis-2
esterification reaction and, as a result, the ease with which
coupling partners can be swapped out. Thus, while our lack of
success in converting C-ring precursors 43 and 46 into the
brevenal core was disappointing, we realized that we could easily
modify the strategy by coupling an A,B-acid with an E-ring
alcohol as represented by the coupling of 53 with 54 to give 52
(Scheme 15). Obviously, this new strategy required OLEC to the
D-ring oxepene, that is, 51.
While OLEC to the D-ring would certainly be more challeng-
ing than the analogous reaction to the C-ring, other aspects of the
new strategy were considered to be advantageous. The late stage
introduction of the C(19) angular methyl group and the late
stage acid-mediated cyclization to the C-ring would help us to
overcome some of the more problematic transformations in our
previous efforts.
With the preceding line of thought as background, we utilized
Shiina’s esterification conditions and anhydride 57 to couple
olefinic-alcohol 56 with acid 55 to give 58 (Scheme 16).45
Yamaguchi conditions were not as effective here. After optimiza-
tion of the cyclization conditions, we were pleased to be able to
generate oxepene 59 in 30% yield from the OLEC reaction of 58.
Acyclic enol ether 60 was the major product here, and we were
pleased to find that it could be recycled using the Grubbs second
generation catalyst, that is, 13 (Scheme 2), and ethylene at
elevated temperatures. This gave an additional 35% of cyclic
material that consisted of a 5:1 mixture of 59 and the
corresponding dihydropyran (65% overall yield of 59).46 Be-
cause they proved to be important, the OLEC cyclization
conditions are worthy of mention here. As currently employed,
these reactions require the generation of Ti(III) prior to the
addition of substrate and CH3CHBr2.47 Interestingly, when
dibromoethane and 58 were added to the reduced Ti reagent
at room temperature and subsequently slowly warmed to
reflux over 15 min, only acyclic enol ether was observed.
When dibromoethane and 58 were added to reagent at room
temperature and warmed to reflux over 2 min, a 30% yield of
59 was isolated. While we do not understand the importance
of the temperature on the reaction, it appears to point to the
presence of multiple Ti species and their differential reactivity
with 58.
With the D-ring in hand, we targeted the generation of the
C-ring. To this goal, the oxidation-reduction reaction of 59 gave
ketone 61 in 65% overall yield following oxidation of the
2° alcohol (Scheme 17). In contrast to the oxidation of 31
(Scheme 9), the DMDO oxidation of 59 gave the corresponding
epoxide as a single diastereomer. On the basis of DFT calcula-
tions in a model oxepene, we believe that the high diastereos-
electivity in the generation of the C(18) stereocenter is a result of
unfavorable torsional interactions between the C(20) pseudoax-
ial hydrogen atom and DMDO during the transition state that
would lead to the C(18) epimer of 61.48 The synthesis of 61
intercepts the same intermediate in Sasaki’s synthesis of brevenal.
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Scheme 16. Subunit Coupling Part 2
Scheme 17. Completion of the D-ring and Thioketal
Formation
Scheme 18. Brevenal’s Pentacyclic Core
corresponding 1° alcohol. Parikh-Doering oxidation and Wittig
coupling using phosphonium salt 64 gave the corresponding
Z-alkene and 65 following oxidative elimination of the phenyl
selenide.49 As has been reported previously,50 the selective
removal of the 1° TBDPS group in the presence of the 2° and
3° TBS groups was accomplished using buffered TBAF. Oxida-
tion of the resulting 1° alcohol and Horner-Emmons reaction
with the lithium salt of phosphonate 66 gave 67 in 85% yield for
the two steps. Completion of brevenal was accomplished through
In contrast to pentacycle 54, the spectral data (1H, 13C, IR, MS,
[R]20D) matched that reported previously.7
Having succeeded in synthesizing 61, we were finally prepared
to complete the synthesis of the C-ring and thus the brevenal
pentacyclic core. In contrast to our attempts with 48, the
cyclization of 61 to give the C-ring was uneventful. Impressively,
when 61 was subjected to Zn(OTf)2 and EtSH, we were able to
remove both TES groups and effect cyclization to generate the
desired C(19) thioketal 62 after the generation of the C(14) TBS
ether.
The completion of the brevenal core required the incorpora-
tion of the C(19) angular methyl group. This task was accom-
plished using the Kadota methodology and resulted in the
brevenal core structure as 63 in 94% yield (Scheme 18).
Our total synthesis of brevenal was completed using a
modification of Yamamoto and Kadota’s end game protocol
for the incorporation of the side chains.7c These efforts began
with the E-ring side chain (Scheme 19). Yamamoto and Kadota
had utilized hydrogenolysis to remove the C(30) benzyl ether. In
our hands, reductive conditions were higher yielding giving the
HF pyridine removal of the TBS ethers, i-Bu2AlH reduction of
3
the ester, and selective oxidation of the resulting allylic alcohol.
Yamamoto and Kadota had carried out the reduction of the ester
prior to the removal of the TBS groups using TBAF. In our
hands, the allylic alcohol reduction product was unstable to the
chromatography that was required after the TBAF deprotection
step. Our spectral data for brevenal matched that reported
previously.
In conclusion, we have carried out the total synthesis of
brevenal utilizing OLEC chemistry to both build the A,B- and
E-rings and carry out their convergent coupling. From our
perspective, our synthesis compares favorably with other efforts
toward this molecule: it required 28 steps to the core from 1,4-
butanediol and 38 steps to brevenal (longest linear sequence,
0.99% overall yield). The synthesis has not only enabled us to
further explore and optimize the OLEC reactions, but it has also
led to a better understanding of the use of glycal epoxides in a
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Scheme 19. Brevenal Completion
complex setting. We believe that this work will lead to a better
understanding of brevenal’s impressive biological properties
including its ion channel activity. These latter studies will be
reported in due course.
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’ ASSOCIATED CONTENT
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spectroscopic data for 8, 9, 11, 12, 16-19, 21-31, 55, 56, 58,
59, 61, 63, 65, 67, and brevenal. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
rainier@chem.utah.edu
’ ACKNOWLEDGMENT
We are grateful to the National Institutes of Health for support
of this work (GM56677). We would like to thank the support
staff at the University of Utah and especially Dr. Dennis Edwards
(NMR) and Dr. Jim Muller (mass spectrometry) for help in
obtaining data. We would also like to thank Dr. Henry W. B.
Johnson for carrying out preliminary studies.
(8) Crimmins, M. T.; Shamszad, M.; Mattson, A. E. Org. Lett. 2010,
12, 2614–2617.
(9) See ref 3d and: (a) Cuypers, E.; Abdel-Mottaleb, Y.; Rainier,
J. D.; Tytgat, J. Toxicon 2008, 51, 974–983. (b) Cao, Z.; George, J.;
Gerwick, W. H.; Baden, D. G.; Rainier, J. D.; Murray, T. F. J. Pharmacol.
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T. F. J. Pharmacol. Exp. Ther. 2007, 323, 174–179.
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