New synthetic technology for the construction of 9-membered ring cyclic ethers. Construction of the EFGH ring skeleton of brevetoxin A

Full text of DOI:10.1021/ja971219p

J. Am. Chem. Soc. 1997, 119, 8105-8106
New Synthetic Technology for the Construction of
8105
9-Membered Ring Cyclic Ethers. Construction of
the EFGH Ring Skeleton of Brevetoxin A
K. C. Nicolaou,* Z. Yang, M. Ouellette, G.-Q. Shi,
P. Ga¨rtner, J. L. Gunzner, K. A. Agrios, R. Huber,
R. Chadha, and D. H. Huang
Department of Chemistry and The Skaggs Institute
for Chemical Biology, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037
Department of Chemistry and Biochemistry
UniVersity of California, San Diego
Figure 1. Structure of brevetoxin A (1) and EFGH ring system 2.
Scheme 1. General Strategy for the Construction of
Functionalized Didehydrononacanes
9500 Gilman DriVe, La Jolla, California 92093
ReceiVed April 17, 1997
The structure of the powerful neurotoxin brevetoxin A1,2 (1,
Figure 1) still stands as a formidable synthetic challenge despite
much synthetic activity.3-5 Synthetic strategies for the con-
struction of several of its ring systems have been developed,3-5
but clearly the most challenging region of the molecule must
be its EFGH framework. The latter system contains three of
the most difficult rings to construct, namely, a didehydroox-
anonacane (E), a didehydrooxaoctacane (F), and an oxaoctacane
(G). All previous attempts at the system fall short of an
assembly of the complete EFGH framework. Herein, we report
a solution to this problem, employing a new method for the
construction of didehydrononacane systems. The reported
strategy allowed the synthesis of the functionalized EFGH ring
system 2 (Scheme 1) with complete stereochemical control of
all its stereogenic centers as well as the observation of its
unusual conformational properties1,2,5m by NMR spectroscopy.
The new strategy for the construction of the central didehy-
dronooxanacane ring (E) is outlined in Scheme 1. Thus, it was
anticipated that a tetrasubstituted didehydrooxanonacane (I)
could be derived by reduction of a 6-membered endoperoxide
(II), which in turn could be obtained from a conjugated diene
system (III) via singlet oxygen addition. The latter system was
envisioned to arise from a lactone-derived phosphate (V f IV)
via palladium coupling chemistry, according to a method
recently developed in these laboratories.6 As demonstrated
below, this strategy is both feasible and highly efficient.
Reaction of aldehyde 34 with the ylide derived from 4
(LiHMDS; for abbreviations see legends in schemes) in toluene
resulted in the stereoselective formation of 5 (84%), whose
desilylation with TBAF led to diol 6 (82%). Exposure of 6 to
the Dess-Martin reagent (1.3 equiv) resulted in selective
oxidation of the primary alcohol, furnishing aldehyde 7 (87%),
which was oxidized further to hydroxy acid 8 (96%) by the
action7 of NaClO4-NaHPO4 in the presence of 2-methyl-2-
butene in t-BuOH:H2O (5:1). Lactonization of 8 following the
Yamaguchi protocol8 then gave lactone 9 (70%). Applying our
palladium-catalyzed methodology6 for the conversion of lactones
to cyclic enol ethers, we converted 9 to 11 via 10 [(i) KHMDS-
(PhO)2POCl, 90%; (ii) vinyltri-n-butyltin-Pd(PPh3)4 cat., 96%].
System 11 was transformed to phosphonium salt 20 with the
proper stereochemistry, Via the endoperoxide 12 as summarized
in Scheme 2. Reaction of singlet oxygen with 11 gave
endoperoxide 12 as a mixture of diastereoisomers (R:â ca. 1:1
ratio, 85%). Hydrogenation of 12 in the presence of Lindlar
catalyst in MeOH furnished the corresponding diols (100%, R:â
ca. 1:1), which were converted to monosilyl ethers 13 and 14
by the action of TBSCl-imidazole (imid.) (93%). The mixture
was then oxidized with TPAP-NMO9 to furnish enone 15 in
85% yield. The latter compound was then converted stereo-
selectively to the desired R-hydroxy compound 17 by a two-
step sequence involving selective saturation of the exocyclic
double bond ([(Ph3P)CuH]6)10 (96%) and DIBAL reduction of
the carbonyl function (87%). The conversion of 17 to 20
required pivalate formation to afford 18 (94%) followed by
desilylation (TBAF, 91%), iodide formation (I2, Ph3P, imid.),
and heating with Ph3P (87% for two steps).
Coupling of the ylide derived from phosphonium salt 214
(Scheme 3, n-BuLi, HMPA) with aldehyde 2211 gave cis-olefin
23 (56%). Desilylation of 23 with TBAF resulted in the
formation of hydroxy dithioketal 24 (82%), which gave rise to
oxocene 25 (72%) upon treatment with AgClO4-NaHCO3.12
Reductive removal of the ethylthio group from 25 (Ph3SnH-
AIBN) established the desired oxocene framework 26 (81%).
The benzylidene group was cleaved from 26 by hydrogenolysis
(Pd/C, H2, 94%), and the resulting diol (27) was selectively
silylated with TBSCl-imid. to afford 28 (90%). Compound 28
was then oxidized with TPAP-NMO9 to furnish ketone 29
(89%), the conversion of which to dithioketal 30 was achieved
with EtSH-Zn(OTf)2 (80%). Finally, desilylation of 30 with
(1) Shimizu, Y.; Chou, H.-N.; Bando, H.; Duyne, G. V.; Clardy, J. C. J.
Am. Chem. Soc. 1986, 108, 514.
(2) (a) Pawlak, J.; Tempesta, M. S.; Golik, J.; Zagorski, M. G.; Lee, M.
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M. S. J. Org. Chem. 1988, 53, 4158.
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C.-K.; Duggan, M. E.; Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321.
(c) Nicolaou, K. C.; Prasad, C. V. C.; Ogilvie, W. W. J. Am. Chem. Soc.
1990, 112, 4988. (d) Nicolaou, K. C.; McGarry, D. G.; Somers, P. K.; Kim,
B. H.; Ogilvie, W. W.; Yiannikouros, G.; Prasad, C. V. C.; Veal, C. A.;
Hark, R. R. J. Am. Chem. Soc. 1990, 112, 6263. (e) Curtis, N. R.; Holmes,
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Tetrahedron 1995, 51, 145. (h) Fujiwara, K.; Tsunashima, M.; Awakura,
D.; Murai, A. Tetrahedron Lett. 1995, 36, 8263. (i) Pirrung, F. O. H.;
Hiemstra, H.; Speckamp, W. N.; Kaptein, B.; Schoemaker, H. E. Synthesis
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(11) Aldehyde 22 was prepared from triacetyl-D-glucal by standard
methods. See the Supporting Information.
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S0002-7863(97)01219-5 CCC: $14.00 © 1997 American Chemical Society

8106 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Communications to the Editor
Scheme 2. Construction of the E ring phosphonium salt 20a
Figure 2. Crystal structure of E ring system.
Scheme 4. Synthesis of EFGH Ring System 2a
a Reagents and conditions: (a) 1.0 equiv of 20, 1.05 equiv of n-BuLi,
THF, -78 °C; then 4.0 equiv of HMPA, 1.2 equiv of 32, -78 °C, 1
h; then 25 °C, 8 h, 77%; (b) 1.05 equiv of DIBAL, CH2Cl2, -78 °C,
84%; (c) 2.5 equiv of AgClO4, 10.0 equiv of NaHCO3, 4 Å MS, silica
gel, MeNO2, 25 °C, 1 h, 81%; (d) 15 equiv of Ph3SnH, 0.1 equiv of
AIBN, toluene, ∆, 80%. TPAP ) tetra-n-propylammonium perruth-
enate; NMO ) 4-methylmorpholine N-oxide; DIBAL ) diisobutyl-
aluminum hydride.
a Reagents and conditions: (a) 1.2 equiv of 4, 1.2 equiv of LiHMDS
in THF, toluene, 0 °C; then 1.0 equiv of 3, 8 h, 84%; (b) 2.4 equiv of
TBAF, THF, 25 °C, 7 h, 82%; (c) 1.3 equiv of Dess-Martin reagent,
CH2Cl2, 25 °C, 87%; (d) 3.0 equiv of NaClO2, 1.2 equiv of NaH2PO4,
5.0 eqiuv of 2-methyl-2-butene, t-BuOH:H2O (5:1), 25 °C 96%; (e)
1.2 equiv of trichlorobenzoyl chloride, 1.3 equiv of Et3N, THF, 0 °C;
then 6.0 equiv of 4-DMAP, benzene, 80 °C, 1 h, 70%; (f) 2.0 equiv of
KHMDS, 2.0 equiv of (PhO)2POCl, HMPA, THF, -78 °C, 90%; (g)
1.5 equiv of n-Bu3SnCHdCH2, 0.05 equiv of Pd(PPh3)4, 3.0 equiv of
LiCl, THF, 80 °C, 95%; (h) 0.045 equiv of meso-tetraphenylporphine,
CCl4, O2, hV, 0 °C, 85%; (i) H2, Lindlar catalyst, MeOH, 25 °C, 100%;
(j) 1.05 equiv of TBSCl, 1.2 equiv of imid., CH2Cl2, 25 °C, 93%; (k)
TPAP, NMO, CH2Cl2, 25 °C, 1 h, 85%; (l) 2.0 equiv of [(Ph3P)CuH]6,
benzene, 25 °C, 5 h, 96%; (m) 1.05 equiv of DIBAL, CH2Cl2, -78
°C, 2 h, 87%; (n) 3.0 equiv of PivCl, 4.0 equiv of 4-DMAP, CH2Cl2,
25 °C, 94%; (o) 1.5 equiv of TBAF, THF, 25 °C, 91%; (p) 2.0 equiv
of imid., 2.0 equiv of Ph3P, 1.05 equiv of I2, CH2Cl2, 25 °C; (q) 10.0
equiv of Ph3P, fusion (90 °C), 3 h, 87% for tw steps. LiHMDS )
lithium bis(trimethylsilyl)amide; TBAF ) tetra-n-butylammonium
fluoride; 4-DMAP ) 4-(dimethylamino)pyridine; KHMDS ) potassium
bis(trimethylsilyl)amide; HMPA ) hexamethylphosphoramide; TBS )
tert-butyldimethylsilyl.
Figure 3. NOE correlations (1H ROSEY) of selected protons in 2.
ring closure of 34 under the standard AgClO4-NaHCO3
conditions12 led to 35 (81% yield), from which the ethylthio
group was removed by reaction with Ph3SnH-AIBN to afford
the desired EFGH ring system 2 in 80% yield.
The framework of 2 was established by 1H-COSY, 1H
1
ROESY, H-13C HMQC, and HMBC NMR, as well as by
X-ray crystallographic techniques (Supporting Information).
Thus, the stereochemistry around ring E was confirmed by X-ray
analysis of intermediate E (mp 144-145 °C, EtOAc-hexane)
obtained from 17 by desilylation followed by acetonide forma-
tion (Figure 2). The relationship between the tri-O-acetyl-D-
glucal-derived stereocenters C9,C13 and C8,C17 was deduced
from 1H ROESY experiments. Indeed, the 1H ROESY experi-
ment (Figure 3) revealed a strong NOE between H-8 (δ 4.08)
and H-9 (δ 3.09) indicating a syn relationship between these
protons. The absence of NOE between H-8 (δ 4.08) and H-17
(δ 3.33) and between H-9 (δ 3.09) and H-13 (δ 2.99) supported
trans relationships at these fusions. Further study using
E.COSY techniques demonstrated that the coupling constant (J)
between H-8 and H-17 is 10.0 Hz, supporting a trans arrange-
ment between these two protons. Additional NOE correlations
were in support of structure 2 (see Figure 3).
Scheme 3. Construction of GH Ring Aldehyde 32a
a Reagents and conditions: (a) 1.0 equiv of 21, 1.05 equiv of n-BuLi,
-78 °C, then 4.0 equiv of HMPA, 1.2 equiv of 22, 8 h, 56%; (b) 1.2
equiv of TBAF, THF, 25 °C, 0.5 h, 82%; (c) 3.0 equiv of AgClO4,
10.0 equiv of NaHCO3, 4 Å MS, silica gel, MeNO2, 25 °C, 2.5 h, 72%;
(d) 4.0 equiv of Ph3SnH, toluene, AIBN, 110 °C, 2 h, 81%; (e) Pd-
C/H2, MeOH, 25 °C, 17 h, 94%; (f) 1.1 equiv of TBSCl, 1.2 equiv of
imid., CH2Cl2, 25 °C, 90%; (g) 0.05 equiv of TPAP, 1.5 equiv of NMO,
CH2Cl2/MeCN (1:1), 25 °C, 89%; (h) 15 equiv of EtSH, CH2Cl2, 0.2
equiv of Zn(OTf)2, 25 °C, 4 h; (i) 0.05 equiv of CSA, MeOH:CH2Cl2
(1:1), 1 h, 87%; (j) 3.0 equiv of SO3‚pyr, DMSO, Et3N, CH2Cl2, 0 °C,
2 h, 89%. AIBN ) 2,2′-azobisisobutyronitrile; CSA ) 10-camphor-
sulfonic acid; DMSO ) dimethyl sulfoxide; MS ) molecular sieves.
The described chemistry provides the basis for the final
approach toward brevetoxin A (1).
Acknowledgment. We thank Dr. G. Siuzdak for Mass spectroscopic
assistance. This work was supported by the National Institute of Health
and The Skaggs Institute for Chemical Biology, fellowships from the
George E. Hewitt Foundation (R.H.), the Austrian Science Foundation
(an Erwin Schro¨dinger Postdoctoral Fellowship to P.G.), and the
American Chemical Society (J.L.G.) and grants from Merck, DuPont-
Merck, Schering Plough, Hoffmann La Roche, and Amgen.
CSA in MeOH-CH2Cl2 (87%), followed by SO3‚pyr (pyr )
pyridine) oxidation, yielded aldehyde 32 (89%) via alcohol 31.
With fragments 20 and 32 at hand, the construction of the
targeted system 2 proceeded smoothly and expediently, as shown
in Scheme 4. Thus, Wittig coupling (n-BuLi, HMPA) of 20
and 32 furnished, stereoselectively and in high yield (77%), cis-
olefin 33 from which the pivalate group was removed by DIBAL
reduction, furnishing hydroxy dithioketal 34 (84%). Finally,
Supporting Information Available: A scheme for the synthesis
of compound 22, procedures for the preparation of compounds 12-
14, 16, 17, 25, 26, 32, 33, 35 and 2, a listing of selected data for the
above compounds, NMR spectra for compound 2, and X-ray crystal-
lographic data for compound E (39 pages). See any current masthead
page for ordering and Internet access instructions.
JA971219P