Enantioselective total synthesis of brevetoxin A: convergent coupling strategy and completion

Article abstract of DOI:10.1002/chem.200900777

A highly convergent, enantioselective total synthesis of brevetoxin A is reported. The development of a [X+ 2+ X] Horner-Wadsworth-Emmons/ cyclodehydration/reductive etherification convergent coupling strategy allowed a unified approach to the synthesis o

Full text of DOI:10.1002/chem.200900777

FULL PAPER
DOI: 10.1002/chem.200900777
Enantioselective Total Synthesis of Brevetoxin A: Convergent Coupling
Strategy and Completion
Michael T. Crimmins,* J. Lucas Zuccarello, Patrick J. McDougall, and J. Michael Ellis[a]
Abstract: A highly convergent, enan-
tioselective total synthesis of brevetox-
in A is reported. The development of a
clic fragments from four cyclic ether
subunits. The Horner–Wittig coupling
of the two tetracyclic fragments provid-
ed substrates that were explored for re-
ductive etherification, the success of
which delivered a late-stage tetraol in-
termediate. The tetraol was converted
to the natural product through an ex-
peditious selective oxidative process
followed by methylenation.
[X+2+X]
Horner–Wadsworth–
Emmons/cyclodehydration/reductive
etherification convergent coupling
strategy allowed a unified approach to
the synthesis of two advanced tetracy-
Keywords: asymmetric synthesis ·
convergent strategy · ladder toxin ·
polycyclic ether · total synthesis
Introduction
(Scheme 1), we recognized that a strategy of this type would
be particularly well suited for the convergent construction
of the individual BCDE and GHIJ subunits. Therefore, we
designed a unique convergent coupling strategy that relies
upon a Horner–Wadsworth–Emmons (HWE) reaction for
the union of a cyclic ether functionalized as the b-keto phos-
phonate with another as the aldehyde (Scheme 2). The re-
sulting enone intermediate would be subjected to 1,4-reduc-
tion, and an endo-selective cyclodehydration would provide
a cyclic enol ether. Stereoselective hydration of the enol
ether followed by a reductive etherification sequence would
complete the tetracyclic subunit.
In the preceding manuscript,[1] we described the develop-
ment of efficient routes to the B, E, G, and J ring subunits
7–10 of brevetoxin A (1; Scheme 1), which provided multi-
gram quantities of these key intermediates. Described
herein is the convergent coupling of these subunits through
a unified strategy to produce two advanced tetracyclic frag-
ments 5 and 6, the conversion of the tetracyclic fragments
into Horner–Wittig coupling partners 3 and 4, and the com-
pletion of 1 through the late-stage nonacycle 2.[2]
The HWE/cyclodehydration/reductive etherification strat-
egy has several pertinent advantages. The mildness and reli-
able efficiency of the HWE reaction is particularly impor-
tant for the stoichiometric coupling of advanced frag-
ments—a critical consideration in the choice of assembly
strategy. Also, the numerous methods for effecting 1,4-re-
duction of enones[4] and cyclodehydrations of d-hydroxy ke-
tones[5] bolster the potential for the success of the strategy.
Finally, the hydration and reductive etherification of enol
ethers is well known as one of the most powerful ap-
proaches for the closure of interior rings in a polycyclic
ether array.[3] Strategically, for the BCDE tetracycle 5, the B
ring aldehyde 7 would be coupled with the E ring keto phos-
phonate 11, which would derive from the E ring precursor
8[1] (Scheme 3).
Results and Discussion
Convergent coupling strategy for the synthesis of the BCDE
and GHIJ fragments: In the context of the rapidly growing
collection of synthetic strategies for the assembly of trans/
syn/trans-fused polycyclic ether arrays,[3] we were attracted
to the maximized convergency of the [X+2+X] concept,[3c]
in which two individual rings are coupled, followed by the
formation of two new, adjoining rings. Furthermore, based
upon our overarching retrosynthetic analysis of
1
[a] Prof. M. T. Crimmins, Dr. J. L. Zuccarello, Dr. P. J. McDougall,
Dr. J. M. Ellis
University of North Carolina at Chapel Hill
Department of Chemistry
Chapel Hill, NC 27599-3290 (USA)
Fax : (+1)919-962-2388
Preparation of the suitably functionalized E ring keto
phosphonate 11 was accomplished by converting primary al-
cohol 8 into iodide 12, which was displaced by cyanide to
afford nitrile 13 (Scheme 4). Partial reduction of the nitrile
E-mail: crimmins@email.unc.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900777.
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Scheme 2. Convergent coupling strategy to form tetracyclic polyether
arrays.
Scheme 3. ACTHNUTRGNEUG[N X+2+X] strategy for the BCDE tetracycle 5.
catalyst and Me2PhSiH, the enone was reduced,[8] and subse-
quent addition of pyridinium p-toluenesulfonate (PPTS) to
the reaction mixture provided enol ether 16 in a one-pot
transformation.
Scheme 1. Retrosynthetic analysis of brevetoxin A. Bn=benzyl, MOP=
methoxypropyl, PMB=p-methoxybenzyl, TBS=tert-butyldimethylsilyl,
TIPS=triisopropylsilyl, TBDPS=tert-butyldiphenylsilyl.
The selective hydration of enol ether 16 in the presence
of the E-ring endocyclic olefin proved particularly challeng-
ing. Because selective hydroboration could not be achieved
under a variety of conditions, epoxidation of the electron-
rich enol ether 16 and in situ reduction of the epoxide was
explored. While dimethyldioxirane (DMDO) smoothly con-
verted the enol ether to the corresponding epoxide with ex-
cellent chemoselectivity, the epoxide proved to be extremely
unstable. Various conditions were explored, but only use of
“acetone-free” DMDO to execute the epoxidation, followed
by immediate exposure of the epoxide to iBu2AlH at low
temperature proved workable,[9] providing a mixture of dia-
stereomeric secondary alcohols. Oxidation[10] of the alcohols
produced a 3:1 mixture of ketones 17/18, revealing that the
epoxidation and in situ reduction had provided a 3:1 diaste-
to the aldehyde was followed by an aldol reaction with the
lithium carbanion of dimethyl(methylphosphonate) to pro-
duce b-hydroxy phosphonates 14 as an inconsequential mix-
ture of diastereomers. Subsequent oxidation to the keto
phosphonate[6] and ring-closing metathesis (RCM) provided
the E ring 11 in excellent yield.
For the Horner–Wadsworth–Emmons coupling of B ring 7
and E ring 11, exposure of the two fragments to aqueous
Ba(OH)2 provided a 96% yield of the desired enone 15
(Scheme 4).[7] A method was next developed to directly
access enol ether 16 from enone 15. By using the Wilkinson
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Total Synthesis of Brevetoxin A
FULL PAPER
Scheme 4. Synthesis of the BCDE tetracycle 5. Reagents and conditions: a) PPh3, I2, imidazole, C6H6, 97%; b) NaCN, DMSO, 96%; c) iBu2AlH, CH2Cl2,
08C, 84%; d) (MeO)2P(O)CH3, nBuLi, THF, ꢀ788C, 88%; e) Dess–Martin periodinane, CH2Cl2, 96%; f) [Ru(=CHPh)Cl2A(Cy3P)(sIMes)] (sIMes=1,3-
bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene), CH2Cl2, 408C, (quant.); g) 7, Ba(OH)2, THF, H2O, 96%; h) [RhCl(PPh3)3], Me2PhSiH, PhMe, 508C;
A
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
PPTS, 92%; i) DMDO, CH2Cl2, ꢀ788C; iBu2AlH; j) Dess–Martin periodinane, CH2Cl2, 67% (3:1 dr) for 2 steps; k) K2CO3, MeOH, 658C, 66% (84%
based on recovered starting material (brsm)); l) CSA, MeOH, 658C, 76%; m) BF3·OEt2, Me2PhSiH, CH2Cl2, 08C, 78%.
reomeric ratio (dr) at C12, favoring the undesired configura-
tion. This result was certainly not unexpected based on the
influence of the C8 angular methyl on the approach of elec-
trophiles to the C11–C12 enol ether double bond of 16. Ad-
ditionally, because of the 1,3-relationship of the C8 angular
methyl and the C12 substituent, it was anticipated that
major isomer 17 might be readily epimerized to 18. After in-
vestigating several bases and solvent systems, it was discov-
ered that heating the mixture of ketones at reflux in metha-
nol with potassium carbonate provided a 3:1 dr at C12, fa-
voring the desired configuration 18.[11] Furthermore, the
minor isomer could then be recovered and exposed to the
same equilibration conditions, ultimately providing an excel-
lent yield of the desired ketone 18. Heating ketone 18 at
reflux in methanol with camphorsulfonic acid (CSA) provid-
ed the desired mixed methyl ketal 19 with loss of the pri-
mary triisopropylsilyl (TIPS) protecting group,[12] and reduc-
tive etherification delivered the targeted BCDE tetracycle
5.[13]
Based upon the effectiveness of our approach to the
BCDE ring system, our vision for the synthesis of the GHIJ
fragment 20 involved analogous coupling of a G ring keto-
phosphonate with a J ring aldehyde (Scheme 5). We recog-
nized that the choice of protecting groups employed in the
GHIJ fragment synthesis would not only factor into the
overall efficiency of the total synthesis, but could also prove
critical in the success of key reactions. With preliminary ex-
periments revealing that silyl protecting groups were unsuit-
Scheme 5. ACTHNUGRTNEUNG[X+2+X] strategy for the GHIJ fragment.
able for the J ring (i.e., R1 =SiR3, Scheme 5) due to their la-
bility under the acidic conditions used in the synthesis, two
strategies were conceived. Although we were compelled by
the robustness of the protecting groups in the coupling of G
ring 21a (R2 =pivaloyl (Piv), R3 =TIPS) and J ring 22a
(R1 =Bn), we were also attracted to the expedient coupling
of G ring 21b (R2 =Bn, R3 =PMB) and J ring 22b (R1 =
Bz), in which protecting-group manipulations from G ring
intermediate 9 would be minimized. In either case, HWE
coupling would lead to an enone intermediate and subse-
quent 1,4-reduction and cyclodehydration would lead to an
enol ether poised for hydration and ultimate reductive
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M. T. Crimmins et al.
etherification to produce the desired tetracyclic fragment
20a or 20b. In the end, both protecting-group strategies
were explored as viable routes toward the completion of the
total synthesis.
The J ring alcohol 10 was used to quickly access aldehydes
22a and 22b through three-step sequences (Scheme 7). For
aldehyde 22a, protection of the primary alcohol as the
The G ring intermediate 9 (Scheme 6) was first converted
to ketophosphonate 21a through an eight-step sequence.
After obtaining bis-TIPS ether 23 through a series of pro-
Scheme 7. Completion of J ring aldehydes 22a and 22b. Reagents and
conditions: a) KH, BnBr, nBu4N+Iꢀ, THF, 08C, 88%; b) nBu4NF, THF,
99% (for 27a), 100% (for 27b); c) BzCl, Et3N, DMAP, CH2Cl2, 08C,
91%; d) TEMPO, NaOCl, KBr, CH2Cl2, H2O, 0 8C, 87% (for 22a), 70%
(for 22b). Bz=benzoyl.
benzyl ether and removal of the tert-butyldiphenylsilyl
(TBDPS) group with nBu4NF yielded alcohol 27a. Although
a host of oxidants were found to be unsuitable for alcohol
27a due to epimerization and overoxidation to the carboxyl-
ic acid, the use of TEMPO was found to reliably give alde-
hyde 22a in 87% yield.[16] Alternatively, J ring alcohol 10
was protected with benzoyl chloride in the presence of N,N’-
dimethylaminopyridine (DMAP) to provide the benzoate
ester, which was subjected to nBu4NF as before to deliver al-
cohol 27b in 91% over two steps. Once again, TEMPO
proved to be the oxidant of choice for the formation of the
sensitive aldehyde 22b.
Scheme 6. Completion of G ring keto phosphonates 21a and 21b. Re-
agents and conditions: a) TIPSOTf, 2,6-lutidine, CH2Cl2, 08C; b) LiDBB,
THF, ꢀ788C; c) PivCl, DMAP, Et3N, CH2Cl2, 90% for 3 steps; d) tri-
fluoroacetic acid (TFA), THF, H2O, 96%; e) 2,2,6,6-tetramethylpiperi-
dine 1-oxyl (TEMPO), NaOCl, KBr, CH2Cl2, H2O, 0 8C, 97%; f) NaClO2,
Me2C=CHMe, tBuOH, pH 4 buffer, 98%; g) K2CO3, MeI, DMF, 96%;
The HWE coupling of the G and J rings was first explored
for keto phosphonate 21a and aldehyde 22a (Scheme 8). As
in the BCDE synthesis, exposure to Ba(OH)2 smoothly fur-
nished enone 28a in 80% yield. Clean 1,4-reduction with
40 mol% of Strykerꢁs reagent produced the ketone and the
acetonide protecting group was swiftly removed by heating
at reflux in methanol with TFA to afford diol 29a in 88%
yield over two steps. The ketophosphonate 21b and alde-
hyde 22b were coupled and converted to the corresponding
diol 29b following the same three-step protocol, though in
slightly diminished yield.
The cyclodehydration of ketodiol 29a to form the I ring
(Scheme 9) was met with considerable resistance because
both the desired enol ether and the starting material were
observed to degrade into a complex mixture of intractable
products under even moderately acidic conditions, particu-
larly upon heating above 508C. Furthermore, conversion of
the starting material was often sluggish, indicating the need
for rigorous removal of water. It was hoped that the reac-
tion would proceed at room temperature in the presence of
strong acid and molecular sieves, but in practice, successful
reaction required increased temperature. Eventually it was
found that reaction with PPTS in benzene at 408C with
azeotropic removal of water under aspirator vacuum
h) LiCH2(O)P
(OMe)2, THF, ꢀ788C, 87% (for 21a), 89% (for 26);
i) NaH, PMBBr, nBu4N+Iꢀ, THF, 08C to RT; j) H2SiF6, CH3CN, 89% for
2 steps; k) Dess–Martin periodinane, CH2Cl2, 92%.
tecting-group manipulations, selective removal of the pri-
mary TIPS group under acidic conditions followed by a two-
step oxidation process[14] provided carboxylic acid 24 in ex-
cellent yield. Exposure to K2CO3 and MeI afforded the
methyl ester, which underwent a Claisen condensation with
lithiated dimethyl methylphosphonate to give the desired
keto phosphonate 21a. Alternatively, protection of G ring
intermediate 9 as the bis-p-methoxybenzyl (PMB) ether,
rapid removal of the TIPS group with H2SiF6,[15] and oxida-
tion of the resultant alcohol with catalytic 2,2,6,6-tetra-
ACHTUNGTRENNUNGmethylpiperidine-1-oxyl (TEMPO) revealed aldehyde 25 in
87% yield over three steps.[16] In this case, direct reaction of
the aldehyde with lithiated dimethyl(methylphosphonate)
was high yielding and oxidation of the resultant b-hydroxy-
phosphonates 26 (inconsequential mixture of diastereomers)
under Dess–Martin conditions afforded ketophosphonate
21b. Although ketophosphonate 21a required three more
steps from intermediate 9 than ketophosphonate 21b, the
overall yield was quite similar in both cases.
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Total Synthesis of Brevetoxin A
FULL PAPER
Scheme 8. HWE coupling of the G and J rings. Reagents and conditions:
a) Ba(OH)2, H2O, THF, 80%; b) [CuHACHTUNTRGNEUNG(Ph3P)]6 (40 mol%), PhMe, 95%
(from 28a), 89% (from 28b); c) TFA, MeOH, 658C, 93% (for 29a),
83% (for 29b).
Scheme 9. Completion of GHIJ fragment 20a. Reagents and conditions:
a) PPTS, C6H6, 408C, 50 mmHg, 82% brsm; b) KNACHTNURGTNE(UNG SiMe3)2, BnBr,
Bu4N+Iꢀ, THF, 08C to RT, 92%; c) BH3·THF, THF, 08C, 91% (3:1 dr);
d) Dess–Martin periodinane, CH2Cl2, 96% (from 31), 80% (from 32);
e) DBU, CH2Cl2, 408C, 85% brsm; f) DDQ, CH2Cl2, pH 7 buffer, 89%;
g) PPTS, MeOH, 658C, 87%; h) BF3·OEt2, Et3SiH, CH2Cl2, ꢀ30 to 08C,
96%.
(ꢁ25 mmHg) smoothly produced the desired endocyclic
enol ether in good yield with minimal decomposition. Pro-
tection of the axially disposed C39 hydroxyl as its benzyl
ether with potassium hexamethyldisilazide (KHMDS) and
BnBr then yielded ether 30.
chloro-5,6-dicyanobenzoquinone (DDQ), and the resulting
hemiketal was treated with PPTS in MeOH to form mixed
methyl ketal 35. Reductive etherification mediated by
BF3·Et2O and Et3SiH then completed the GHIJ tetracycle
20a in excellent yield as a single isomer.[18]
To our surprise, the cyclodehydration of ketodiol 29b
(Scheme 10) did not proceed well under the previously em-
ployed conditions. However, treatment with P2O5 in toluene
at ꢀ308C delivered the endocyclic enol ether in good yield.
Acylation of the C39 hydroxyl with benzoyl chloride and
DMAP in pyridine with heating provided the benzoate-pro-
tected enol ether 36. Similar to before, BH3·THF was effec-
tive (95% yield) for the hydroboration of the enol ether,
but in this case, the hydration product obtained after oxida-
tive workup was an inseparable mixture of diastereomers
(2:1 dr). Other reagents for hydroboration, including 9-
The stage was then set for the critical enol ether hydra-
tion/oxidation sequence. Although selective olefin hydration
was achieved in the BCDE system through the use of
DMDO/iBu2AlH, the absence of other double bonds in the
GHIJ system allowed for hydroboration/oxidation of the I
ring enol ether 30. Although BH3·DMS was unsatisfactory,
BH3·THF allowed for a 91% yield of a 3:1 mixture of sepa-
rable diastereomers 31 and 32 after alkaline peroxide
workup.[17] The isomers were separately oxidized under
Dess–Martin conditions to the corresponding ketones 33
and 34, respectively. Whereas the minor epimer 34 was iso-
merized to the major epimer 33 with 1,8-diazabicycloundec-
7-ene (DBU) at 408C in good yield, the major epimer 33
could not be isomerized to the minor ketone 34 under iden-
tical conditions. The major isomer was therefore reasoned
to have the desired configuration at C34, since having the G
ring substituent in an equatorial position on the I ring would
be more thermodynamically favorable.
borabicycloACTHNUGRTNEUNG[3.3.1]nonane (9-BBN) and enantiopure isopino-
campheylborane (IpcBH2),[19] were probed with the inten-
tion of increasing the diastereoselectivity of the reaction,
but inferior results were obtained. Thus, the mixture of dia-
stereomers was oxidized to ketone 37 (2:1 mixture of insep-
arable epimers) under Dess–Martin conditions and exposure
To complete the GHIJ fragment, the PMB protecting
group of ketone 33 was oxidatively removed with 2,3-di-
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M. T. Crimmins et al.
coupling partners. To this end, the conversion of diol 5 to
phosphine oxide 3 (Scheme 11) commenced with protection
of diol 5 as the bis-p-methoxybenzyl ether with subsequent
Scheme 10. Completion of alternative GHIJ fragment 40. Reagents and
conditions: a) P2O5, PhMe, ꢀ308C, 80% (95% brsm); b) BzCl, DMAP,
pyridine, 608C, 95%; c) BH3·THF, THF, 08C; d) Dess–Martin periodi-
nane, CH2Cl2, 87% for 2 steps, 2:1 dr; e) DBU, CH2Cl2, 408C; f) H2,
Scheme 11. Formation of phosphine oxide 3. Reagents and conditions:
a) NaH, PMBBr, DMF, 91%; b) LiDBB, THF, ꢀ788C, 89%; c) TBSOTf,
2,6-lutidine, CH2Cl2, 08C, 96%; d) HF·pyridine, THF, 86%; e) MsCl,
Pd(OH)2, THF, 68% for
h) BF3·OEt2, Et3SiH, CH2Cl2, ꢀ30 to 08C, 95%.
2
steps; g) PPTS, MeOH, 658C, 80%;
Et3N, 0 8C; f) nBuLi, HPPh2, THF, 08C; H2O2, 94% for
g) nBu4NF, THF, 94%; h) 2-methoxypropene, PPTS, 08C, 90%.
2 steps;
to DBU increased the diastereomeric ratio to 6:1. At this
point, it was postulated that removal of one or more of the
hydroxyl protecting groups might allow for separation of the
epimers. Although we favored selective removal of the
PMB groups with DDQ at this juncture to access the target-
ed tetracycle 20b (Scheme 5), the resulting diols remained
an inseparable mixture. On the other hand, hydrogenolysis
of both PMB groups and the benzyl group by using the
Pearlman catalyst led to triol 38,[20] from which the minor,
undesired isomer 34-epi-38 was easily removed by chroma-
tography. Ketalization with PPTS in MeOH led to mixed
methyl ketal 39 and reductive etherification under condi-
tions used before accomplished a shortened synthesis of the
GHIJ fragment 40 in excellent yield.
reductive cleavage of the benzyl ethers with lithium di-tert-
butyl diphenyl (LiDBB) to form diol 41. Protection of the
diol as the bis-tert-butyldimethylsilyl (TBS) ether and selec-
tive cleavage of the primary TBS ether with HF·pyridine af-
forded alcohol 42. Smooth transformation to phosphine
oxide 43 was then accomplished through mesylation of the
alcohol, nucleophilic displacement of the mesylate to pro-
vide the phosphine, and finally, oxidative workup of the
phosphine with H2O2.[2,21] Cleavage of the silyl ether 43 with
nBu4NF and formation of the methoxypropyl (MOP) acetal
delivered the required phosphine oxide 3 in high yield.[22]
For the GHIJ fragment, tetracycle 20a was treated with
nBu4NF and the resultant secondary alcohol was oxidized to
ketone 44 under Dess–Martin conditions (Scheme 12). Re-
action of ketone 44 with ZnACHTNUTRGNENG(U OTf)2 and EtSH produced the
Coupling of the BCDE and GHIJ fragments and completion
of 1: The planned approach for the completed total synthe-
sis of 1 focused on an endgame that would exploit the selec-
tive manipulation of nonacycle 2 (see above, Scheme 1).
Nonacycle 2 would derive from a stereoselective Horner–
Wittig coupling[21] of phosphine oxide 3 and aldehyde 4,
which found precedent in the strategy previously reported
by Nicolaou and co-workers.[2] We recognized that the di-
thioketal moiety of aldehyde 4 offered versatility because it
could serve as a stabilized precursor to a mixed ketal (2,
X=OMe) or lead to a mixed S,O-ketal (2, X=SO2Et) in
the event that formation or reductive etherification of the
less-activated nonacycle proved to be problematic.
dithioketal[23] and reductive cleavage of the pivaloate ester
delivered alcohol 45. Although most conditions proved to
be unsuitable for the subsequent oxidation of the primary
alcohol to dithioketal aldehyde 46 due to undesired oxida-
tion of the dithioketal, the use of stoichiometric nPr4NRuO4
cleanly provided the desired aldehyde.[24]
As for the alternative GHIJ tetracycle 40, the primary hy-
droxyl was selectively protected as the TBS ether
(Scheme 13) and the remaining secondary hydroxyl was oxi-
dized under buffered Dess–Martin conditions to afford
ketone 47. Removal of the silyl protecting group with
H2SiF6 provided the hydroxy ketone and exposure to Zn-
AHCTUNGTRENNG(UN OTf)2 in 1:1 EtSH/CH2Cl2 reliably gave dithioketal 48. As
The next task became the manipulation of the tetracyclic
fragments 5 and 20a or 40 to the required Horner–Wittig
before, reaction with one equivalent of nPr4NRuO4 deliv-
ered aldehyde 49 in good yield.
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Total Synthesis of Brevetoxin A
FULL PAPER
Having both phosphine oxide 3 and aldehydes 46 and 49
in hand, we then explored their assembly under Horner–
Wittig conditions (Scheme 14).[2,21] After some experimenta-
tion, addition of three equivalents of lithium diisopropyl-
AHCTUNGTREGaNNUN mide (LDA) to a solution of phosphine oxide 3 and alde-
hyde 46 at ꢀ788C was found to produce 63% of the
Horner–Wittig adduct. It is noteworthy that no epimeriza-
tion of aldehyde 46 was observed despite the presence of su-
perstoichiometric base.[25] Exposure of the intermediate hy-
droxyphosphine oxide to KNACHTNUGTRNEUNG(SiMe3)2 provided the desired
Z-olefin 50 in 74% yield. In contrast, when phosphine oxide
3 and aldehyde 49 were reacted in the presence of three
equivalents of LDA, the desired Wittig adduct was obtained
in only 28% yield, along with an additional 14% of adduct
in which the primary benzoate ester had been cleaved.
Scheme 12. Preparation of aldehyde 46. Reagents and conditions:
a) nBu4NF, THF, 08C, 94%; b) Dess–Martin periodinane, CH2Cl2, 95%;
c) ZnACHTUNGTRENNUNG(OTf)2, EtSH, CH2Cl2, 97%; d) LiAlH4, Et2O, 0 8C, 85%;
Treatment of the Wittig adducts with KNACHTUNTGRNEUNG(SiMe3)2 was also
e) nPr4NRuO4, 4 ꢂ MS, CH2Cl2, 75%.
complicated by the loss of benzoate protecting groups and
unidentified degradation, producing olefins 51 and 52 in an
unacceptable 32% combined yield. Further attempts to
identify cleaner elimination conditions by altering the base,
solvent, and temperature were unsuccessful.
After carrying out the effective coupling of the BCDE 3
and GHIJ 46 fragments, we focused on mixed methyl ketal
54 as a precursor to the targeted nonacycle 55 (Scheme 14).
Despite the rarity of the conversion of 7-hydroxy ketones or
ketals to eight-membered cyclic ketals found in the litera-
ture, we believed that the formation of mixed ketal 54
should be possible due to the structural preorganization ap-
pearing in olefin 50. Specifically, we expected the C24–C25
Z olefin, along with the conformational constraints about
the C21–C22 and C26–C27 bonds, to facilitate the required
cyclization event. In addition, based upon the reported use
of (F3CCO2)2IPh in alcoholic solvent to convert dithioketals
to dialkoxy ketals,[26] we presumed that treating olefin 50
with the hypervalent iodine reagent in MeOH would lead to
the dimethyl ketal 53 or to mixed ketal 54 directly. In the
event, treatment of olefin 50 with (F3CCO2)2IPh in MeOH
Scheme 13. Preparation of aldehyde 49. Reagents and conditions:
a) TBSCl, imidazole, CH2Cl2, 94%; b) Dess–Martin periodinane, pyri-
dine, CH2Cl2, 87%; c) H2SiF6, CH3CN, H2O, 97%; d) ZnACHTNUGRTNEUNG(OTf)2, EtSH,
CH2Cl2, 87%; e) nPr4NRuO4, 4 ꢂ MS, CH2Cl2, 75%.
Scheme 14. Coupling of tetracyclic fragments 3 and 46. Reagents and conditions: a) LDA, THF, ꢀ788C, 63% (from 3+46), 42% (from 3+49); b) KN-
(SiMe3)2, DMF, 74% (for 50), 32% (for 51 and 52, combined yield); c) (F3CCO2)2IPh, MeOH; d) PPTS, CH(OMe)3, PhMe, 508C, 80% for 2 steps.
A
ACHTUNGTRENNUNG
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M. T. Crimmins et al.
rapidly removed the MOP protecting group and led to a
mixture of the expected ketal products in a 4:1 ratio, favor-
ing the dimethyl ketal 53.[27] Upon exposure of the crude
mixture to PPTS, an 80% overall yield of mixed methyl
ketal 54 was obtained.
In view of our previous successes in the reductive etherifi-
cation of precursors to the BCDE and GHIJ fragments (see
above, Schemes 4, 9, and 10), it was anticipated that treat-
ment of ketal 54 with an appropriate Lewis acid in the pres-
ence of a trialkylsilane would deliver the expected nonacy-
cle 55. Despite extensive screening of Lewis acids
(BF3·OEt2, TiCl4, trimethylsilyl trifluoromethanesulfonate
(TMSOTf)), solvents, and silanes (Et3SiH, Me2PhSiH), only
traces of the desired product 55 were observed. Instead, hy-
drolysis of the ketal and intractable decomposition were re-
peatedly observed.[28] Drying agents (4 ꢂ molecular sieves,
BaO) were investigated in an effort to suppress hydrolysis,
but under these conditions, cleavage of the central oxocene
(producing the C27 methyl ether) was the major product.
This result indicated that the kinetically preferred mode of
ꢀ
C X bond cleavage for the methyl ketal substrate involved
good nO!s*C27 orbital overlap (Scheme 15), leading to a
ꢀ
O
ring-opened oxocarbenium ion that is intercepted by silane.
We reasoned that the precedented sulfone leaving group[2,29]
Scheme 16. Closure of the A and F rings. Reagents and conditions:
a) PPTS, MeOH, 08C, 96%; b) AgClO4, NaHCO3, 4 ꢂ MS, MeNO2,
65%; c) m-CPBA, CH2Cl2, 08C, 74%; d) BF3·OEt2, Et3SiH, CH2Cl2, ꢀ78
ꢀ
Scheme 15. Favored modes of C X bond cleavage for methoxy ketal and
sulfone substrates.
to 08C, 85%; e) TEMPO, PhIACTHUNGTRNEGN(U OAc)2, CH2Cl2, 83%.
cleavage of the benzyl ethers with LiDBB[31] delivered tet-
raol 61, which was exposed to PhI(OAc)2 and catalytic
would circumvent this unwanted stereoelectronic effect,
since the absence of lone pair electrons on sulfur would
ACHTUNGTRENNUNG
TEMPO to selectively form the A-ring lactone and the C44
aldehyde, while leaving the axially-disposed C39 secondary
alcohol untouched.[30] The unpurified decacyclic aldehyde 62
was treated with Eschenmoserꢁs salt in the presence of
Et3N[2, 32] to complete the synthesis of 1.[33] Synthetic 1 was
identical in all respects (1H and 13C NMR and IR spectros-
copies, mass spectrometry, and [a]D) to an authentic sam-
ple.[2a,d,34]
render the n!s*C27 interaction inoperative. Instead, the
ꢀ
O
required mode of bond cleavage should be favored
(Scheme 15). The increased lability of the sulfinate leaving
group relative to the methoxide nucleofuge was also expect-
ed to facilitate the desired reactivity.
Turning our attention to the reductive etherification of
sulfone 58 (Scheme 16), the MOP acetal was removed from
olefin 50 under acidic conditions, and the resulting hydroxy
dithioketal 56 was treated with AgClO4 to provide the
mixed S,O-ketal 57.[2] Subsequent oxidation with m-CPBA
led to sulfone 58 and reductive etherification with concomi-
tant removal of the PMB protecting groups was smoothly
accomplished to give diol 59 in 85% yield. Whereas the A
ring lactone 60 was readily accessible in 83% yield from
Conclusion
The second total synthesis of 1 has been accomplished in a
highly convergent, enantioselective fashion. The synthesis
hinges on the selective oxidation of a late-stage nonacyclic
tetraol. Access to the key tetraol intermediate was explored
through the rare cyclization of a medium-ring mixed methyl
ketal, which was assessed as a substrate for oxocene-forming
reductive etherification. In the end, a sulfone-based ap-
diol 59 through exposure to PhIACTHNUTRGNENUG(OAc)2 and catalytic
TEMPO,[30] clean debenzylation was not observed under a
variety of conditions. Nevertheless, compound 1 was ac-
cessed in three steps from diol 59 (Scheme 17). Reductive
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Total Synthesis of Brevetoxin A
FULL PAPER
[3] a) K. C. Nicolaou, M. O. Frederick, R. J. Aversa, Angew. Chem.
2008, 120, 7292; Angew. Chem. Int. Ed. 2008, 47, 7182; b) H. Fuwa,
M. Sasaki, Curr. Opin. Drug Discovery Dev. 2007, 10, 784; c) M.
Inoue, Chem. Rev. 2005, 105, 4379; d) T. Nakata, Chem. Rev. 2005,
105, 4314; e) I. Kadota, Y. Yamamoto, Acc. Chem. Res. 2005, 38,
423; f) M. Sasaki, H. Fuwa, Synlett 2004, 1851; g) P. A. Evans, B. De-
louvriꢄ, Curr. Opin. Drug Discovery Dev. 2002, 5, 986; h) F. P.
Marmsꢃter, F. G. West, Chem. Eur. J. 2002, 8, 4346; i) Y. Mori,
Chem. Eur. J. 1997, 3, 849; j) E. Alvarez, M.-L. Candenas, R. Pꢄrez,
J. L. Ravelo, J. D. Martꢅn, Chem. Rev. 1995, 95, 1953.
[4] P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis
Vol. 9, 1st ed., Oxford, New York, 1992, p. 63.
[5] For example, see: a) K. J. Hale, J. Q. Cai, Tetrahedron Lett. 1996, 37,
4233; b) D. A. Evans, P. H. Carter, E. M. Carreira, J. A. Prunet,
A. B. Charette, M. Lautens, Angew. Chem. 1998, 110, 2526; Angew.
Chem. Int. Ed. 1998, 37, 2354; c) G. E. Keck, A. P. Truong, Org.
Lett. 2005, 7, 2149.
[6] Attempts to prepare the ester from the iodide or nitrile for a subse-
quent Claisen condensation with the lithiated phosphonate proved
less reliable than the aldol approach.
[7] a) C. Alvarez-Ibarra, S. Arias, G. Banon, M. J. Fernandez, M. Rodri-
guez, V. Sinisterra, J. Chem. Soc. Chem. Commun. 1987, 1509; b) I.
Paterson, K. S. Yeung, J. B. Smaill, Synlett 1993, 774.
[8] I. Ojima, T. Kogure, Organometallics 1982, 1, 1390.
[9] a) H. W. B. Johnson, U. Majumder, J. D. Rainier, J. Am. Chem. Soc.
2005, 127, 848; b) M. Gibert, M. Ferrer, F. SanchezBaeza, A. Messe-
guer, Tetrahedron 1997, 53, 8643.
Scheme 17. Completion of 1. Reagents and conditions: a) LiDBB, THF,
ꢀ788C, 86%; b) TEMPO, PhI
CH2Cl2, 48% for 2 steps.
(OAc)2, CH2Cl2; c) H2C=NMe2+Iꢀ, Et3N,
ACHTUNGTRENNUNG
[10] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
[11] DBU, LiOMe, NaOMe, and imidazole resulted in either slow epime-
rization or significant decomposition products.
[12] A minor amount of inconsequential cleavage of the PMB ether was
also observed, and was carried through the reductive etherification
with the major product 19 to produce the same end product 5.
[13] a) M. T. Crimmins, P. J. McDougall, J. M. Ellis, Org. Lett. 2006, 8,
4079; b) M. T. Crimmins, P. J. McDougall, K. A. Emmitte, Org. Lett.
2005, 7, 4033.
[14] B. S. Bal, W. E. Childers Jr, H. W. Pinnick, Tetrahedron 1981, 37,
2091.
[15] A. S. Pilcher, D. K. Hill, S. J. Shimshock, R. E. Waltermire, P. De-
Shong, J. Org. Chem. 1992, 57, 2492.
[16] a) V. A. Golubev, E. G. Rozantsev, M. B. Neiman, Izv. Akad. Nauk
SSSR Ser. Khim. 1965, 1927; V. A. Golubev, E. G. Rozantsev, M. B.
Neiman, Chem. Abstr. l966, 64, 11164e; b) E. G. Rozantsev, V. D.
Sholle, Synthesis 1971, 401; c) P. L. Anelli, C. Biffi, F. Montanari, S.
Quici, J. Org. Chem. 1987, 52, 2559; d) P. L. Anelli, F. Montanari, S.
Quici, Org. Synth. 1990, 69, 212.
proach proved to be a superior path to the nonacyclic tet-
raol. A Horner–Wittig olefination of two advanced tetracy-
clic subunits assembled the eventual tetraol precursor, with
the tetracyclic units being constructed through a common
[X+2+X] strategy by using a HWE coupling and subse-
quent cyclodehydration/reductive etherification protocol.
Each of the monocyclic units for the construction of the tet-
racyclic BCDE and GHIJ units was prepared from a RCM
of an acyclic diene precursor with stereodefined ether link-
ages. Enolate methodologies developed in our laboratory
were exploited to introduce 8 of the 22 stereocenters present
within 1.
Acknowledgements
[17] For other examples showing the importance of borane-mediated
regio- and stereoselective hydration of enol ethers in polycyclic
ether synthesis, see ref. [3d] and a) K. Sato, M. Sasaki, Angew.
Chem. 2007, 119, 2570; Angew. Chem. Int. Ed. 2007, 46, 2518; b) H.
Fuwa, M. Ebine, A. J. Bourdelais, D. G. Baden, M. Sasaki, J. Am.
Chem. Soc. 2006, 128, 16989.
Financial support of this work by the National Institute for General Med-
ical Sciences (GM60567) is acknowledged with thanks. We are also grate-
ful to Professor Daniel Baden and Andrea J. Bourdelais at the University
of North Carolina at Wilmington for providing an authentic sample of
brevetoxin A for comparison purposes.
[18] M. T. Crimmins, J. L. Zuccarello, P. A. Cleary, J. D. Parrish, Org.
Lett. 2006, 8, 159.
[19] H. C. Brown, A. K. Mandal, N. M. Yoon, B. Singaram, J. R. Schwier,
P. Jadhav, J. Org. Chem. 1982, 47, 5069.
[20] W. M. Pearlman, Tetrahedron Lett. 1967, 8, 1663.
[1] M. T. Crimmins, J. M. Ellis, K. A. Emmitte, P. A. Haile, P. J. McDou-
gall, J. D. Parrish, J. L. Zuccarello, Chem. Eur. J. 2009, 9223–9234.
[2] a) K. C. Nicolaou, Z. Yang, G.-Q. Shi, J. L. Gunzner, K. A. Agrios,
P. Gꢃrtner, Nature 1998, 392, 264; b) K. C. Nicolaou, M. E. Bunnage,
D. G. McGarry, S. Shi, P. K. Somers, P. A. Wallace, X.-J. Chu, K. A.
Agrios, J. L. Gunzner, Z. Yang, Chem. Eur. J. 1999, 5, 599; c) K. C.
Nicolaou, P. A. Wallace, S. Shi, M. A. Ouellette, M. E. Bunnage,
J. L. Gunzner, K. A. Agrios, G.-q. Shi, P. Gꢃrtner, Z. Yang, Chem.
Eur. J. 1999, 5, 618; d) K. C. Nicolaou, G.-q. Shi, J. L. Gunzner, P.
Gꢃrtner, P. A. Wallace, M. A. Ouellette, S. Shi, M. E. Bunnage,
K. A. Agrios, C. A. Veale, C.-K. Hwang, J. Hutchinson, C. V. C.
Prasad, W. W. Ogilvie, Z. Yang, Chem. Eur. J. 1999, 5, 628; e) K. C.
Nicolaou, J. L. Gunzner, G.-q. Shi, K. A. Agrios, P. Gꢃrtner, Z.
Yang, Chem. Eur. J. 1999, 5, 646.
[21] a) L. Horner, H. Hoffmann, H. G. Wippel, G. Klahre, Chem. Ber.
1959, 92, 2499; b) A. D. Buss, S. Warren, J. Chem. Soc. Perkin Trans.
1 1985, 2307, and references therein; c) For the use of LDA in
Horner–Wittig reactions, see: C. Earnshaw, C. J. Wallis, S. Warren, J.
Chem. Soc. Perkin Trans. 1 1979, 3099.
[22] Attempts to prepare the phosphine oxide with the C21 hydroxyl or
MOP acetal directly were hampered by purification difficulties and
lower yields, respectively.
[23] E. J. Corey, K. Shimoji, Tetrahedron Lett. 1983, 24, 169.
[24] a) W. P. Griffith, S. V. Ley, G. P. Whitcombe, A. D. White, J. Chem.
Soc. Chem. Commun. 1987, 1625; b) W. P. Griffith, S. V. Ley, Aldri-
chimica Acta 1990, 23, 13.
Chem. Eur. J. 2009, 15, 9235 – 9244
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M. T. Crimmins et al.
[25] A control experiment verified that aldehyde 46 was not significantly
epimerized in the presence of LDA (3 equiv) at ꢀ788C for up to
20 min. Since the addition of lithiated 3 into aldehyde 46 is nearly
instantaneous at ꢀ788C, formation of Horner–Wittig adduct is ki-
netically faster than epimerization of aldehyde 46.
[26] G. Stork, K. Zhao, Tetrahedron Lett. 1989, 30, 287.
[27] The 4:1 ratio of products appears to be the kinetic ratio, since resub-
jecting either of the isolated ketal products to the (CF3CO2)2IPh/
MeOH conditions did not cause equilibration.
[30] T. M. Hansen, G. J. Florence, P. Lugo-Mas, J. H. Chen, J. N. Abrams,
C. J. Forsyth, Tetrahedron Lett. 2003, 44, 57.
[31] a) P. K. Freeman, L. L. Hutchinson, J. Org. Chem. 1980, 45, 1924;
b) R. E. Ireland, M. G. Smith, J. Am. Chem. Soc. 1988, 110, 854.
[32] J. Schreiber, H. Maag, N. Hashimoto, A. Eschenmoser, Angew.
Chem. 1971, 83, 355; Angew. Chem. Int. Ed. Engl. 1971, 10, 330.
[33] M. T. Crimmins, J. L. Zuccarello, J. M. Ellis, P. J. McDougall, P. A.
Haile, J. D. Parrish, K. A. Emmitte, Org. Lett. 2009, 11, 489.
[34] See the Supporting Information for details.
[28] The use of iBu2AlH also failed to bring about the intended reduc-
tion.
[29] K. C. Nicolaou, C. V. C. Prasad, C.-K. Hwang, M. E. Duggan, C. A.
Veale, J. Am. Chem. Soc. 1989, 111, 5321.
Received: March 25, 2009
Published online: August 4, 2009
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Chem. Eur. J. 2009, 15, 9235 – 9244