Total synthesis of the proposed structure of brevenal

Article abstract of DOI:10.1021/ja062524q

Total synthesis of the proposed structure of brevenal, a natural marine polycyclic ether product, has been accomplished. The synthesis features (i) convergent synthesis of the pentacyclic polyether skeleton using our developed Suzuki-Miyaura coupling stra

Full text of DOI:10.1021/ja062524q

Published on Web 07/11/2006
Total Synthesis of the Proposed Structure of Brevenal
Haruhiko Fuwa, Makoto Ebine, and Makoto Sasaki*
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku UniVersity,
Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan
Received April 12, 2006; E-mail: masasaki@bios.tohoku.ac.jp
Brevenal is a pentacyclic polyether natural product isolated from
gave alcohol 7, which was then converted to allylic alcohol 9 via
nitrile 8 by standard chemistry. Asymmetric epoxidation of 9 led
to hydroxyl epoxide 10 as a single stereoisomer. Oxidation and
ensuing methylenation of the resulting aldehyde gave vinyl epoxide
11. Upon treatment of 11 with DDQ, removal of the PMB group
and concomitant 6-endo ring closure smoothly took place,7 giving
rise to pyran 13 in 89% yield after TES protection. At this stage,
the stereochemistry of 12 was confirmed by NOE experiments as
shown. Pyran 13 was converted to enoate 14 in a four-step sequence.
Hydrogenation/hydrogenolysis of 14 followed by Yamaguchi
lactonization8 gave lactone 15, which was then transformed to the
AB ring enol phosphate 2.9
the red tide-forming dinoflagellate, Karenia breVis.1 Its gross
structure and relative stereochemistry have been determined based
on extensive NMR experiments. The biological profile of brevenal
is of interest in that it competitively displaces tritiated dihydrobre-
vetoxin-B ([3H]PbTx-3) from voltage-sensitive sodium channels in
a dose-dependent manner and acts as a natural brevetoxin antagonist
in vivo.1 More importantly, brevenal improved tracheal mucus
velocity in picomolar concentrations in an animal model of asthma,
and thus may be a source of agents for treating mucociliary
dysfunction associated with cystic fibrosis and other lung disorders.2
Herein, we describe the first total synthesis of the proposed structure
1 of brevenal.
The synthesis of the DE ring fragment 3 is summarized in
Scheme 3. Benzylation of the known oxepane 16,10 correspond-
ing to the D ring, followed by ozonolysis/reductive workup gave
alcohol 17. The primary alcohol of 17 was benzylated, and the
benzylidene acetal was removed to provide diol 18. One-pot tri-
flation/TBS protection11 and subsequent alkylation with allylMgBr/
CuBr12 gave olefin 19. Oxidative cleavage of the double bond,
thioacetalization of the derived aldehyde, and removal of the TBS
group led to alcohol 20. Hetero-Michael reaction with methyl
propiolate followed by hydrolysis of the thioacetal afforded
aldehyde 21, which upon exposure to SmI2 (MeOH/THF) furnished
tricyclic lactone 22 as a single stereoisomer after acidic treatment.13
DIBALH reduction and Wittig reaction, followed by oxidation,14
led to ketone 23. The C26 equatorial methyl group was introduced
by treating 23 with MeLi (THF, -78 to 0 °C), giving 24
stereoselectively (dr > 10:1).15 The C26 and C2716 stereochemistries
were confirmed by NOEs. The tertiary alcohol was silylated to give
TBS ether 25. Hydroboration, hydrogenolysis of the benzyl groups,
and ensuing acetal formation led to 26. Benzylation followed by
regioselective cleavage of the acetal moiety provided alcohol 27.
Finally, iodination followed by base treatment furnished the DE
fragment 3.
Our synthetic strategy toward 1 was to build up the pentacyclic
polyether core of 1 from the AB and DE ring fragments (2 and 3,
respectively) by means of our developed Suzuki-Miyaura coupling-
based methodology (Scheme 1).3-5
Scheme 1. Synthetic Strategy
The synthesis of the AB ring fragment 2 started with Evans’
syn-aldol reaction of aldehyde 4 with oxazolidinone 5.6 Subsequent
reductive removal of the chiral auxiliary provided 1,3-diol 6 as a
single stereoisomer (Scheme 2). Protection of 6 as its p-methoxy-
benzylidene acetal followed by regioselective DIBALH reduction
Scheme 2. Synthesis of the AB Ring Fragmenta
a Reagents and conditions: (a) n-Bu2BOTf, Et3N, CH2Cl2, -78 to 0 °C; (b) NaBH4, THF/H2O, 0 °C to rt, 90% (two steps); (c) p-MeOC6H4CH(OMe)2,
PPTS, CH2Cl2, rt; (d) DIBALH, CH2Cl2, -78 to -40 °C, 94% (two steps); (e) MsCl, Et3N, CH2Cl2, 0 °C; (f) NaCN, DMSO, 60 °C, 96% (two steps); (g)
DIBALH, CH2Cl2, -78 °C, 90%; (h) Ph3PdC(Me)CO2Et, toluene, 80 °C, 97%; (i) DIBALH, CH2Cl2, -78 °C, quant.; (j) (+)-DET, Ti(Oi-Pr)4, t-BuOOH,
CH2Cl2, -40 °C, 88%; (k) SO3‚pyridine, Et3N, DMSO/CH2Cl2, 0 °C; (l) Ph3PCH3Br, NaHMDS, THF, 0 °C, 90% (two steps); (m) DDQ, CH2Cl2/H2O, rt;
(n) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 89% (two steps); (o) (Sia)2BH, THF, 0 °C; then aq. NaHCO3, H2O2, rt, 92%; (p) SO3‚pyridine, Et3N, DMSO/
CH2Cl2, 0 °C; (q) Ph3PdCHCO2Bn, toluene, 80 °C, 86% (two steps); (r) aq. HCl, THF, rt, 95%; (s) H2, Pd(OH)2/C, 2:1 THF/MeOH, rt, 90%; (t) 2,4,6-
Cl3C6H2COCl, Et3N, THF, 0 °C to rt; then DMAP, toluene, 110 °C, 98%; (u) KHMDS, (PhO)2P(O)Cl, HMPA/THF, -78 °C, 96%.
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C O M M U N I C A T I O N S
Scheme 3. Synthesis of the DE Ring Fragmenta
a Reagents and conditions: (a) NaH, BnBr, DMF, 0 °C to rt; (b) O3, MeOH/CH2Cl2, -78 °C; then NaBH4, -78 to 0 °C, 96% (two steps); (c) KOt-Bu,
BnBr, THF, rt; (d) p-TsOH, MeOH/CHCl3, rt, quant. (two steps); (e) Tf2O, 2,6-lutidine, CH2Cl2, -78 °C; then TBSOTf, -78 to 0 °C; (f) allylMgBr, CuBr,
ether, 0 °C, 85% (two steps); (g) OsO4, NMO, THF/H2O, rt; then NaIO4, rt; (h) 1,3-propanedithiol, BF3‚OEt2, CH2Cl2, -78 to 0 °C; (i) TBAF, THF, rt, 88%
(three steps); (j) methyl propiolate, NMM, CH2Cl2, rt; (k) MeI, NaHCO3, MeCN/H2O, rt, 99% (two steps); (l) SmI2, MeOH, THF, rt; then p-TsOH, toluene,
80 °C, 84% (two steps); (m) DIBALH, CH2Cl2, -78 °C; (n) Ph3PCH3Br, NaHMDS, THF, 0 °C to rt, 94% (two steps); (o) TPAP, NMO, 4 Å MS, CH2Cl2,
rt, 97%; (p) MeLi, THF, -78 to 0 °C, 97% (dr > 10:1); (q) TBSOTf, Et3N, CH2Cl2, rt, quant.; (r) 9-BBN, THF, rt; then aq. NaHCO3, H2O2, 0 °C to rt; (s)
H2, Pd(OH)2/C, MeOH, rt; (t) p-MeOC6H4CH(OMe)2, PPTS, CH2Cl2, rt, 80% (three steps); (u) KOt-Bu, BnBr, THF, rt; (v) DIBALH, CH2Cl2, -78 to -40
°C, 85% (two steps); (w) I2, PPh3, imidazole, THF, rt; (x) KOt-Bu, THF, 0 °C, 99% (two steps).
Scheme 4. Synthesis of the Pentacyclic Polyether Corea
a Reagents and conditions: (a) 9-BBN, THF, rt; then 3 M aq. Cs2CO3, Pd(PPh3)4, DMF, 50 °C; (b) BH3‚SMe2, THF, 0 °C to rt; then aq. NaHCO3, H2O2,
0 °C to rt, 84% (two steps); (c) TPAP, NMO, 4 Å MS, CH2Cl2, 0 °C, 98%; (d) LHMDS, TMSCl, Et3N, THF, -78 °C; (e) OsO4, NMO, THF/H2O, rt, 87%
(two steps); (f) DIBALH, THF, -78 °C, 76% (diastereomer: 7%; 31: 12%); (g) TESOTf, Et3N, CH2Cl2, 0 °C; (h) DDQ, CH2Cl2/pH 7 buffer, rt; (i) TPAP,
NMO, 4 Å MS, CH2Cl2, 0 °C, 88% (three steps); (j) EtSH, Zn(OTf)2, THF, rt, 79%; (k) TBSOTf, Et3N, CH2Cl2, 0 °C, 97%; (l) mCPBA, CH2Cl2, -78 °C;
then AlMe3, -78 to 0 °C, 92%.
Scheme 5. Completion of the Total Synthesisa
a Reagents and conditions: (a) LiDBB, THF, -78 °C, 99%; (b) TBSOTf, Et3N, CH2Cl2, 0 °C, 98%; (c) TBAF, AcOH, THF, rt, 78% after three recycles;
(d) Dess-Martin periodinane, CH2Cl2, rt; (e) Bestmann reagent, K2CO3, MeOH, rt; (f) n-BuLi, THF/HMPA, -78 °C; then MeI, rt, 99% (three steps); (g)
HF‚pyridine, THF, 0 °C to rt, 96%; (h) TESOTf, Et3N, CH2Cl2, 0 °C, 99%; (i) PhMe2SiLi, CuCN, THF, -78 to 0 °C; (j) NIS, CH3CN/THF, 0 °C to rt, 99%
(two steps); (k) 42, Pd2(dba)3, Ph3As, CuTC, 1:1 DMSO/THF, rt, 63%; (l) TBDPSCl, imidazole, DMF, 0 °C; (m) PPTS, 4:1 CH2Cl2/MeOH, 0 °C, 74% (two
steps); (n) SO3‚pyridine, Et3N, DMSO/CH2Cl2, 0 °C; (o) BrPh3PCH2CH2CH2SePh, n-BuLi, THF/HMPA, -78 °C to rt, 97% (two steps); (p) H2O2, NaHCO3,
THF, rt, 77%; (q) TASF, DMF/THF, 0 °C to rt, 79%; (r) MnO2, CH2Cl2, rt, quant.
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C O M M U N I C A T I O N S
With the requisite fragments in hand, the crucial fragment
coupling and subsequent ring closing events were executed, as
depicted in Scheme 4. Stereoselective hydroboration of the DE ring
exocyclic enol ether 3 with 9-BBN delivered the corresponding
alkylborane, which was in situ reacted with the AB ring enol
phosphate 2 [Cs2CO3, Pd(PPh3)4] to afford the cross-coupled product
28. Hydroboration of 28 with BH3‚SMe2 generated alcohol 29 as
a single stereoisomer, which was then oxidized14 to ketone 30. The
stereochemistries of C16 and C18 were confirmed by NOE
experiments. Conversion to the corresponding enol silyl ether
followed by dihydroxylation delivered R-hydroxy ketone 31 as a
single stereoisomer. Subsequent DIBALH reduction afforded diol
32 in good selectivity (dr ) ca. 10:1).15 Protection as the TES ethers,
removal of the PMB group, and ensuing oxidation provided ketone
33. Exposure of 33 to EtSH/Zn(OTf)2 in THF effected deprotection
of the TES groups and concomitant mixed thioacetal formation to
furnish 34 in 79% yield. After TBS protection, oxidation with
mCPBA at -78 °C followed by in situ treatment with excess AlMe3
resulted in one-pot oxidative activation of the sulfide and stereo-
selective methylation, giving rise to pentacyclic polyether 36 as a
single stereoisomer in excellent yield.17 The stereochemistry of 36
achieved by CuTC-mediated modified Stille reaction. Continuous
efforts toward structural determination and total synthesis of
brevenal are underway and will be reported in due course.
Acknowledgment. We thank Prof. D. G. Baden and Dr. A. J.
Bourdelais for providing copies of 1H and 13C NMR of an authentic
sample of brevenal, and Mr. R. Watanabe (Tohoku University) for
NMR measurements. This work was financially supported by the
Naito Foundation, a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan, and JSPS (postdoctoral fellowship for H.F.).
Supporting Information Available: Experimental procedures,
spectroscopic data, and copies of 1H and 13C NMR spectra for
compounds 29, 36, 43, and synthetic 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
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(15) For stereochemical confirmation, see Supporting Information.
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3
was confirmed by NOEs and JH,H as shown.
Having constructed the polycyclic ether skeleton, we next turned
our attention to introduction of the left-hand side chain. The benzyl
group of 36 was replaced with the TBS ether, and selective
deprotection of the TBDPS group18 produced alcohol 38 (Scheme
5). Oxidation,19 Bestmann alkynylation,20 and subsequent methy-
lation led to alkyne 39. At this stage, the robust TBS groups were
replaced with the TES groups. Treatment of 40 with Fleming’s
silylcuprate reagent (PhMe2SiLi, CuCN)21 effected syn-selective
silylcupration of the internal alkyne (regioselectivity ) ca. 9:1).
Subsequent iododesilylation with NIS22 afforded vinyl iodide 41
(E:Z ) ca. 6:1).15 Stille coupling23 of 41 with vinyl stannane 42
was best accomplished by using the Pd2(dba)3/Ph3As catalyst system
in the presence of copper(I) thiophene-2-carboxylate (CuTC),24
giving allylic alcohol 43 in 63% yield as a single isomer.15 After
conversion to alcohol 44, oxidation and Wittig reaction, followed
by peroxide treatment,25 afforded diene 45. Finally, global depro-
tection of the silyl groups followed by selective oxidation of the
1
C1 alcohol with MnO2 furnished synthetic 1. Unfortunately, H
and 13C NMR data for 1 were not identical to those reported for
the natural sample. Especially, the observed chemical shifts around
the DE ring of 1 significantly deviated from those reported for the
natural product. Additionally, we observed a set of intense cross-
peaks between 26-Me and 27-H in a ROESY spectrum of 1, while
such a correlation has not been reported for the natural brevenal
(for details, see Supporting Information). On the basis of these NMR
variations, along with the proposed biosynthetic pathway for marine
polycyclic ethers,26 we think that the correct structure of brevenal
is most likely represented by the C26 epimer of the originally
proposed 1.
In conclusion, we have accomplished the first total synthesis of
the proposed structure of brevenal. The pentacyclic polyether core
was constructed in a highly convergent and stereocontrolled manner
based on our Suzuki-Miyaura coupling strategy. Stereoselective
synthesis of the left-hand multi-substituted dienal side chain was
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9650 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006