Pectenotoxin-2 synthetic studies. 1. Alkoxide precoordination to [Rh(NBD)(DIPHOS-4)]BF4 allows directed hydrogenation of a 2,3-dihydrofuran-3-ol without competing furan production

Article abstract of DOI:10.1021/ol010302l

(equation presented) The alkoxide-directed hydrogenation shown is reported as a key step in a concise synthesis of a fully functionalized precursor to the C29-C40 F/G sector of pectenotoxin-2.

Full text of DOI:10.1021/ol010302l

ORGANIC
LETTERS
2002
Vol. 4, No. 6
937-940
Pectenotoxin-2 Synthetic Studies. 1.
Alkoxide Precoordination to
[Rh(NBD)(DIPHOS-4)]BF4 Allows Directed
Hydrogenation of a 2,3-Dihydrofuran-3-ol
without Competing Furan Production
Leo A. Paquette,* Xiaowen Peng, and Dmitriy Bondar
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received December 30, 2001
ABSTRACT
The alkoxide-directed hydrogenation shown is reported as a key step in a concise synthesis of a fully functionalized precursor to the C29−C40
F/G sector of pectenotoxin-2.
Recognition that the pectenotoxins (PTXs) are the agents
chiefly responsible for the onset of severe diarrhea and liver
damage following the ingestion of bivalves (scallops, mus-
sels, clams, etc.) has had significant dietary consequences
in Japan and Europe.1,2 From among the several known
members of the PTX family, PTX2 (1) has more recently
also attracted attention for its selective cytotoxicity proper-
ties3 and its impressive capacity for site-specific interaction
with the actin cytoskeleton.4 The structural complexity of 1
brings a large assortment of challenges to those who attempt
its synthesis. Embedded in its framework are 19 stereocenters
(of which six are quaternary), a pair of spiroacetals, and
several additional oxygenated rings housed in a 33 carbon
macrolide ring.
To the present time, only two research groups have
documented preliminary studies targeting the PTXs.5,6 For
the above reasons and in keeping with our long-standing
interest in marine toxins,7 we have initiated a synthetic effort
aimed at securing 1 in these laboratories.8 Retrosynthetically,
we envisioned 2 to constitute an advanced precursor to its
C29-C40 sector that comprises rings F and G. In this
(1) (a) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.; Matsumoto,
G. K.; Clardy, J. Tetrahedron 1985, 41, 1019. (b) Murata, M.; Sano, M.;
Iwashita, T.; Naoki, H.; Yasumoto, T. Agric. Biol. Chem. 1986, 50, 2693.
(c) Yasumoto, T.; Murata, M.; Lee, J.-S.; Torigoe, K. Mycotoxins and
Phycotoxins 1989, 88, 375. (d) Yasumoto, T.; Murata, M. Chem. ReV. 1993,
93, 1897. (e) Sasaki, K.; Wright, J. L. C.; Yasumoto, T. J. Org. Chem.
1998, 63, 2475.
(2) Ishige, M.; Satoh, N.; Yasumoto, T. Reps. Hokkaido Inst. Health
1988, 38, 15.
(3) Jung, J. H.; Sim, C. J.; Lee, C.-O. J. Nat. Prod. 1995, 58, 1722.
(4) Spector, I.; Braet, F.; Shochet, N. R.; Bubb, M. R. Microscop. Res.
Technol. 1999, 47, 18.
(5) (a) Amano, S.; Fujiwara, K.; Murai, A. Synlett 1997, 1300. (b)
Awakura, D.; Fujiwara, K.; Murai, A. Synlett 2000, 1733.
(6) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949.
(7) (a) Paquette, L. A.; Pissarnitski, D.; Barriault, L. J. Org. Chem. 1998,
63, 7389. (b) Paquette, L. A.; Barriault, L.; Pissarnitski, D. J. Am. Chem.
Soc. 1999, 121, 4542. (c) Barriault, L.; Boulet, S. L.; Fujiwara, K.; Murai,
A.; Paquette, L. A.; Yotsu-Yamashita, M. Bioorg. Medicin. Chem. Lett.
1999, 9, 2069. (d) Paquette, L. A.; Barriault, L.; Pissarnitski, D.; Johnston,
J. N. J. Am. Chem Soc. 2000, 122, 619.
(8) Liu, J.; Paquette, L. A. Unpublished work.
10.1021/ol010302l CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/19/2002

communication, we outline an effective route to 2 that
capitalizes on a new, ultramild, alkoxide-directed hydrogena-
tion protocol24 capable of skirting the flagrant tendency of
3 to experience dehydration.
Scheme 1
primary carbinol 8. The latter was protected as its MOM
derivative prior to ozonolytic degradation leading to aldehyde
10.
Concurrently, dihydrofuran 11, which is readily available
in quantity from D-mannose,13 was lithiated with tert-
butyllithium at -78 °C14 and the resulting vinyl anion was
coupled with 10 (Scheme 2). This reaction was complete
within 5 min in the cold to afford 12, which was immediately
To set the stage for proper conjoining of the two
components of 3 as indicated, the stereochemical relationship
of the hydroxyl and methyl substituents at C37 and C38,
respectively, was established by an anti aldol reaction.9
Condensation of the Z-enolate of enantiopure oxazolidinone
410 with crotonaldehyde in the presence of dibutylboron
triflate11 afforded 5 as the heavily dominant or exclusive
diastereomer depending on the reaction scale (Scheme 1).
The magnitude of JHR,Hâ (7.2 Hz) was fully congruent with
the stereochemical assignment.9 Conversion of 5 to its MOM
ether followed by reductive cleavage with sodium boro-
hydride12 then provided alcohol 6. One-carbon homologa-
tion was effected by cyanide ion displacement of the
tosylate group. Two-stage reduction of 7 made available the
protected as the SEM ether 13 in 44% overall yield.15 13
C
NMR analysis of 13 clearly revealed it to consist of two
Scheme 2
(9) (a) Raimundo, B. C.; Heathcock, C. H. Synlett 1995, 1213. (b) Yang,
J.; Cohn, S. T.; Romo, D. Org. Lett. 2000, 2, 763. (c) Walker, M. A.;
Heathcock, C. H. J. Org. Chem. 1991, 56, 5747. (d) Danda, H.; Hansen,
M. M.; Heathcock, C. H. J. Org. Chem. 1990, 55, 173.
(10) (a) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77. (b) Gage, J.
R.; Evans, D. A. Org. Synth. 1990, 68, 83.
(11) (a) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem.
Soc. 1981, 103, 3099. (b) Inoue, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
1980, 53, 174.
(12) Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998,
39, 7067.
(13) (a) Ghosh, A. K.; McKee, S. P.; Thompson, W. J. J. Org. Chem.
1991, 56, 6500. (b) Freudenberg, K.; Wolf, A. Chem. Ber. 1927, 60, 232.
(c) Ireland, R. E.; Thaisrivongs, S.; Vanier, N.; Wilcox, C. S. J. Org. Chem.
1980, 45, 48. (d) Ireland, R. E.; Norbeck, D. W.; Mandel, G. S.; Mandel,
N. S. J. Am. Chem. Soc. 1985, 107, 3285.
(14) Parker, K. A.; Su, D.-S. J. Org. Chem. 1996, 61, 2191.
938
Org. Lett., Vol. 4, No. 6, 2002

Table 1. Summary of Hydrogenation Experiments Performed on 14 and 15a
run
substrate
catalyst
base
solvent
products
1
2
3
4
5
6
7
8
9
14
14
14
14
15
15
15
15
14
14
14
Rhb
10% Pd/C
Irc
Rhb
Rhb
Rhb
Rhb
Rhb
Irc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
THF
THF
CH2Cl2
THF
THF
16 (54%); 18 (11%); 14 (25%)
complex mixture
16 (84%)
17 (46%); 18 (3%); 14 (46%)
epi-17 (50%); 15 (20%)
epi-16 (67%); epi-18 (19%)
epi-17 (7%); epi-18 (53%); 15 (10%)
epi-17 (41%); 15 (20%)
16 (89%)
(i-Pr)2NEt
(i-Pr)2NEt
KH
KH
10
11
Rhb
Rhb
NaH
NaH
18 (43%); 14 (57%)
18 (68%); 14 (20%)d
THF
a For the general hydrogenation conditions, consult the text. b As [Rh(NBD)(DIPHOS-4)BF4. c As Ir(COD)(py)(PCy3)PF6. d Run 10 was allowed to proceed
for 3 days.
diastereomers. Although their chromatographic separation
could not be achieved at this stage, it proved to be readily
accomplished following chemoselective desilylation. The
ratio of 14 to 15 was 5:1. The absolute configuration of either
SEM ether could not be ascertained. However, since this
unidentified chiral center was to be oxidized to the ketone
level in one of the final steps of the synthesis, both
intermediates are serviceable. For convenience, the major
isomer 14, arbitrarily assigned the â configuration,16 was
utilized for much of the ensuing chemistry.
The stage was now set for a hydroxyl-directed hydrogena-
tion17 to establish the third chiral center in the tetrahydrofuran
ring of 2. However, when a 2% solution of 14 in CH2Cl2
18
was stirred with 20 mol % [Rh(NBD)(DIPHOS-4)]BF4
under 800 psi of hydrogen for 17 h, the major product was
the furan 16 (run 1, Table 1).
At this point, our attention was drawn to the very early
work of Thompson and McPherson who demonstrated that
the capacity of Wilkinson’s catalyst for π-facial discrimina-
tion could be significantly enhanced by coValent bonding
between an alkoxide and the rhodium center.20 When these
conditions were applied to 14, no reduction was observed.
We were therefore led to examine the merits of ionic com-
plexation between alkali metal salts of 14/15 and the cationic
catalyst [Rh(NBD)(DIPHOS-4)]BF4. In THF solution, the
potassium salt of 15 was transformed into a product mixture
consisting predominantly of epi-18 (53%, run 7). None of
this product was formed in CH2Cl2 (run 8). Alternative use
of the sodium salt as in run 10 gave only 18. Excellent repro-
ducibility and efficiency were ultimately achieved with so-
dium hydride (1.05 equiv) in THF when the reaction time
was extended to 3 days. As before, NOESY analysis of the
PMB derivative 20 provided a desirable stereochemical con-
firmation. We strongly endorse the adoption of these mild,
basic conditions in difficult cases such as that faced here.
The readiness with which water was eliminated was
exacerbated when recourse was made to Ir(COD)(py)(PCy3)-
19
PF6 (run 3). As expected, the response of 15 was closely
comparable, and a switch to THF as the solvent was not
beneficial (run 6). The complication was attributed to the
Lewis-acidic nature of these catalysts, and recourse was
therefore made to the inclusion of 2-3 equiv of Hu¨nig’s
base in the reaction medium from the outset (runs 4 and 5).
While this ploy halted furan formation, the reputed hydroxyl-
directing capability of these catalysts did not surface. Thus,
17 and epi-17 were isolated in 46-50% yield as the major
products. The stereochemical assignment to 17 was convinc-
ingly established by conversion to 19 (NaH, PMBBr) and
NOESY analysis in CDCl3. In this solvent system, H5R and
H5â were cleanly differentiated and their spatial relationship
to H4 and H6 easily ascertained.
(15) Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.
(16) This assignment is in line with predominant adherence to the Cram
chelate transition state during 1,2-addition to the R-chiral, R-oxygenated
aldehyde 10.
(17) (a) For a review, see: Brown, J. M. Angew. Chem., Int. Ed. Engl.
1987, 26, 190. (b) Smith, M. E. B.; Derrien, N.; Lloyd, M. C.; Taylor, S.
J. C.; Chaplin, D. A.; McCague, R. Tetrahedron Lett. 2001, 42, 1347.
(18) (a) Evans, D. A.; Morrissey, M. M. J. Am. Chem. Soc. 1984, 106,
3866. (b) Brown, J. M.; Naik, R. G. J. Chem. Soc., Chem. Commun. 1982,
348.
(19) (a) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
(b) Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072.
Org. Lett., Vol. 4, No. 6, 2002
939

the diol to silica gel-supported sodium periodate21 (Scheme
3). Wadsworth-Horner-Emmons homologation22 of 21 and
exposure of 22 to DDQ oxidation23 efficiently secured 2
ready for eventual conversion to pectenotoxin-2.24
Scheme 3
Acknowledgment. This research was financed in part by
unrestricted grants from the Eli Lilly Company and Aventis
Pharmaceuticals, Inc.
Supporting Information Available: Copies of the 300
1
or 500 MHz H NMR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL010302L
(21) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622.
(22) Wadsworth, W. S., Jr. Org. React. 1977, 25, 73.
(23) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885.
(24) Protocol for Alkoxide-Directed Hydrogenation. To a slurry of
sodium hydride (3.9 mg of 60% in oil, 0.098 mmol, 1.05 equiv) in
deoxygenated THF (0.50 mL) was added a solution of 14 (50 mg, 0.093
mmol) in the same solvent (0.50 mL). The contents of the vial were stirred
for 10 min before a solution of [Rh(NBD)(DIPHOS-4)]BF4 (13.5 mg, 20
mol %) in deoxygenated THF (1.5 mL) was quickly introduced. The vial
was placed in a Parr autoclave, flushed with argon, and pressurized to 800-
900 psi of hydrogen. After overnight stirring (17 h), the pressure was
released and the reaction mixture was subjected directly to chromatography
on silica gel (elution with 2:1 hexanes/ethyl acetate).
Completion of the route to 2 involved hydrolytic cleavage
of the acetonide with aqueous acetic acid and exposure of
(20) Thompson, H. W.; McPherson, E. J. Am. Chem. Soc. 1974, 96,
6232.
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Org. Lett., Vol. 4, No. 6, 2002