Pectenotoxin-2 synthetic studies. 3. Assessment of the capacity for stereocontrolled cyclization to form the entire C1-C26 subunit based upon the double bond geometry across C15-C16

Article abstract of DOI:10.1021/jo062513f

Second-generation synthetic routes to enantiopure sulfone 21 and aldehyde 24 are described. The union of these two intermediates by means of a Julia-Kocienski coupling gave rise to a series of E-configured building blocks that did not prove amenable to tr

Full text of DOI:10.1021/jo062513f

Pectenotoxin-2 Synthetic Studies. 3. Assessment of the Capacity for
Stereocontrolled Cyclization To Form the Entire C1-C26 Subunit
Based upon the Double Bond Geometry Across C15-C16
Patrick D. O’Connor, Christopher K. Knight, Dirk Friedrich,† Xiaowen Peng,
and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210-1185
paquette.1@osu.edu
ReceiVed December 7, 2006
Second-generation synthetic routes to enantiopure sulfone 21 and aldehyde 24 are described. The union
of these two intermediates by means of a Julia-Kocienski coupling gave rise to a series of E-configured
building blocks that did not prove amenable to transannular cyclization. Alternatively, when the C15-
C16 double bond was introduced with Z-geometry by Wittig olefination, spontaneous closure to generate
a tetrahydrofuran culminated an ensuing direct dihydroxylation step. The structural assignment to 35,
1
undergirded by detailed H and 13C NMR studies, is consistent with proper transannular bonding so as
to deliver the entire C1-C26 fragment of PTX2.
Introduction
sumption of shellfish contaminated with the toxic dinoflagellates
Dinophysis fortii and Dinophysis accuminata.2 Subsequent
studies have led to the structural characterization of as many as
15 PTXs3 and to the discovery of their beneficial biological
activity. For example, PTX2 (1) exhibits nanomolar cytotoxic
capability against several human cancer cell lines4 and has the
impressive ability to interact with the acton skeleton at a unique
site.5
The pectenotoxins are characterized by exquisitely complex
structural features that consist of a pair of spiroacetals, 19
stereocenters (six are quaternary), and additional oxygenated
rings that reside in a 33-carbon macrolide ring. The majority
of the family members differ from each other in the spiro
geometry at C7 and in the oxidation state of C43.6 Following
the assignment of absolute stereochemistry to PTX1 on the basis
The pectenotoxins (PTXs) comprise an important class of
complex marine macrolides, the first members of which were
isolated and identified in 1985.1 They were of contemporary
interest because of their role in promoting the onset of severe
diarrhea, vomiting, and liver damage subsequent to the con-
† Present address: Sanofi-Aventis, 1041 U.S. Route 202/206, P.O. Box 6800,
Bridgewater, NJ 08807-0800.
(1) (a) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.; Matsumoto,
G. K.; Clardy, J. Tetrahedron 1985, 41, 1019. (b) Sasaki, K.; Wright,
J. L. C.; Yasumoto, T. J. Org. Chem. 1998, 63, 2475. (c) Daiguji, M.; Satake,
M.; James, K. J.; Bishop, A.; Mackenzie, L.; Naoki, H.; Yasumoto, T. Chem.
Lett. 1998, 653.
(2) (a) Yasumoto, T.; Oshima, Y.; Yamaguchi, M. Bull. Jpn. Soc. Sci.
Fish. 1978, 44, 1249. (b) Yasumoto, T.; Oshima, Y.; Sugawara, W.; Fukuyo,
Y.; Oguri, H.; Igarashi, T.; Fujita, N. Bull. Jpn. Soc. Sci. Fish. 1980, 46,
1405. (c) Toxic Dinoflagellate Blooms; Kat, M., Anderson, D. M., White,
A. W., Baden, D. G., Eds.; Elsevier: Amsterdam, 1985; p 215. (d) Kumagai,
M.; Yanagi, T.; Murata, M.; Yasumoto, T.; Kat, M.; Lassus, P.; Rodriguez-
Vazquez, J. A. Agric. Biol. Chem. 1986, 40, 2853. (e) Hu, T.; Doyle, J.;
Jackson, D.; Marr, J.; Nixon, E.; Pleasance, S.; Quilliam, M. A.; Walter,
J. A.; Wright, J. L. C. J. Chem. Soc., Chem. Commun. 1992, 39. (f) Toxic
Phytoplankton Blooms in the Sea; Boni, L., Poletti, A., Popei, M., Smayda,
T. J., Shimizu, Y., Eds.; Elsevier: Amsterdam, 1993; p 475. (g) Toxic
Phytoplankton Blooms in the Sea; Quilliam, M. A., Gilgan, M. W.,
Pleasance, S., Defreitas, A. S. W., Douglas, D., Fritz, L., Hu, T., Marr,
J. C., Smyth, C., Wright, J. L. C., Smayda, T. J., Shimizu, Y., Eds.;
Elsevier: Amsterdam, 1993; p 547. (h) Draisci, R.; Lucentini, L.; Giannetti,
L.; Boria, P.; Poletti, R. Toxicon 1996, 34, 923.
(3) (a) Miles, C. O.; Wilkins, A. L.; Samdal, I. A.; Sandvik, M.; Petersen,
D.; Quilliam, M. A.; Naustvoll, L. J.; Rundberget, T.; Torgenson, T.;
Hovgaard, P.; Jensen, D. J.; Cooney, J. M. Chem. Res. Toxicol. 2004, 17,
1423. (b) Miles, C. O.; Wilkins, A. L.; Hawkes, A. D.; Jensen, D. J.;
Selwood, A. I.; Beuzenberg, V.; MacKenzie, A. L.; Cooney, J. M.; Holland,
P. T. Toxicon 2006, 48, 152.
(4) Jung, J. H.; Sim, D. J.; Lee, C.-O. J. Nat. Prod. 1995, 58, 1722.
(5) (a) Spector, I.; Braet, F.; Shochet, N. R.; Bubb, M. R. Microsc. Res.
Tech. 1999, 47, 18. (b) Leira, F.; Cabado, A. G.; Vieytes, M. R.; Roman,
Y.; Alfonso, A.; Botana, L. M.; Yasumoto, T.; Malaguti, C.; Rossini, G. P.
Biochem. Pharm. 2002, 63, 1979.
(6) Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897.
10.1021/jo062513f CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/02/2007
J. Org. Chem. 2007, 72, 1747-1754
1747

O’Connor et al.
implementation of Mitsunobu conditions involving 1-phenyl-
1H-tetrazole-5-thiol16 and peracid oxidation. This protocol
provided access to sulfone 10, thereby conveniently setting the
stage for Julia-Kocienski coupling17 to the previously reported
aldehyde 11.11,18 These steps were followed by regiocontrolled
cleavage of the acetal functionality with DIBAL-H15,19 to
provide the primary carbinol, which smoothly underwent
oxidation to aldehyde 13 in the presence of the Dess-Martin
periodinane reagent.20
Accommodation of 13 in the synthesis was accomplished by
homologation with methoxymethylenetriphenyl phosphorane21
in a conventional Wittig olefination. As expected, the response
of the vinyl ether so formed to two-step oxymercuration-
sodium borohydride reduction21,22 satisfactorily gave 14 in
>70% yield.
To position ourselves to produce the substituted tetrahydro-
furan 18, the time had arrived to introduce R3, the second of
the three requisite hydroxyl protecting groups. The robust
requirements for R3 prompted selection of the tert-butyldiphe-
nylsilyl option. Advantage was immediately taken of its lowered
hydrolytic reactivity, as reflected in the ensuing acetal cleavage
under acidic conditions. With diol 15 in hand, we next explored
the formation of epoxide 16 and ensuing implementation of
asymmetric dihydroxylation. Both steps proceeded uneventfully
to deliver 17 in a diastereomeric ratio of 4:1. Although the
elevated polarity characteristics of this pair of compounds
precluded their convenient separation, this was not the situation
following stereocontrolled acid-catalyzed cyclization to install
a tetrahydrofuran ring. The structural formulation of 18, which
was amenable to chromatographic purification, follows from
detailed COSY and NOESY experiments.
of X-ray crystallography,1a it has proven possible to deduce the
structures of the remaining family members by NMR and MS
techniques.
In light of the above, there have understandably been a
number of efforts targeting several PTXs. Among the more
notable achievements to date are Evans’ asymmetric synthesis
of pectenotoxins-4 and -8,7 Brimble’s targeting of the ABC
segment of PTX7,8 and Roush’s preparation of the C11-C26
fragment of PTX2,9 in addition to Murai’s successful routes to
the C8-C18 and C31-C40 components common to all
members.10-11 Our approach to the synthesis of 1 is based on
the convergent coupling of either sulfonyl tetrazole 411 or
phosphonium iodide 5 to aldehyde 6.12 These key disconnections
are illustrated in Scheme 1. Arrival at this pair of advanced
intermediates requires that decisions be made with regard to
three hydroxyl protecting groups. Subsequent to our initial effort
that gave rise to 2 with R1 ) PMB and R3 ) TBS, it was
recognized that modification of these masking functionalities
was necessary. Similar modifications of the nature of R2 were
mandated en route to 4 and 5. The integration of these changes
into the synthesis plan is detailed herein. Beyond this, our
attention was directed toward elucidating whether a trans or
cis double bond as in 2 and 3, respectively, was more ideally
suited to the crafting of ring C following appropriate regiose-
lective oxidation and intramolecular cyclization.
This routing was followed by selective protection of the
primary hydroxyl as the benzyl ether in advance of the
introduction of a second PMB group and two-step generation
of tetrazolyl sulfone 21. A final molybdate oxidation23 was
particularly efficacious in this instance.
Results and Discussion
Studies Involving the (E)-Allylic Alcohol 26. Recourse to
PMB protection at C18 in 21 required in turn that only a single
minor modification be made in the C1-C15 fragment. This
change, delineated in Scheme 3, consisted in conversion of the
previously described R-hydroxy ester 2211 to its triethylsilyl ether
23. The latter can be reproducibly reduced to aldehyde 24 with
DIBAL-H at low temperature (-90 °C). Complications resulting
from overreduction of the methyl ester functionality or the
intrinsic instability of 24 could thereby be skirted. Fortunately,
unchromatographed 24 proved to be pure enough for coupling
studies.
Second-Generation Route to Sulfone 21. The alternate route
began with the known 4-methyl-4-penten-1-ol,11 which was
directly silylated to deliver 7 in advance of asymmetric
dihydroxylation13 with AD-mix-R14 and conversion to PMP
acetal 8 by reaction with p-methoxybenzaldehyde dimethyl
acetal in the presence of pyridinium tosylate15 (Scheme 2). The
resulting mixture of diastereomers was subsequently modified
to unmask the hydroxyl group as in 9 and allow for sequential
(7) (a) Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem.,
Int. Ed. 2002, 41, 4569. (b) Evans, D. A.; Rajapakse, H. A.; Chiu, A.;
Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4573.
(8) (a) Halim, R.; Brimble, A. M.; Merten, J. Org. Lett. 2005, 7, 2659.
(b) Halim, R.; Brimble, M. A.; Merten, J. Org. Biomol. Chem. 2006, 4,
1387.
(9) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949.
(10) (a) Amano, S.; Fujiwara, K.; Murai, A. Synlett 1997, 1300. (b)
Awakura, D.; Fujiwara, K.; Murai, A. Synlett 2000, 1733. (c) Fujiwara,
K.; Kobayashi, M.; Yamamoto, F.; Aki, Y.; Kawamura, M.; Awakura, D.;
Amono, S.; Okano, A.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett.
2005, 46, 5067.
(11) Bondar, D.; Liu, J.; Mu¨ller, T.; Paquette, L. A. Org. Lett. 2005, 7,
1813.
(12) (a) Paquette, L. A.; Peng, X.; Bondar, D. Org. Lett. 2002, 4, 937.
(b) Peng, X.; Bondar, D.; Paquette, L. A. Tetrahedron 2004, 60, 9589.
(13) Kolb, H. C.; Van Nieuwenzhe, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
In our original work, the configuration of C7 was assigned
as S on the basis of anticipated stabilization arising from
operation of the anomeric effect and the result of MM3
(16) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Moreley, A. Synlett
1998, 26.
(17) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.;
Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856.
(18) Baker, R.; Brimble, M. A. Tetrahedron Lett. 1986, 27, 3311.
(19) Smith, A. B.; Hale, K. J.; Laasko, L. M.; Chen, K.; Rie´ka, A.
Tetrahedron Lett. 1989, 30, 6960.
(20) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(21) Clark, J. S.; Freeman, R. P.; Cacho, M.; Thomas, A. W.; Swallow,
S.; Wilson, C. Tetrahedron Lett. 2004, 45, 8639.
(14) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu,
D.; Zhang, X. L. J. Org. Chem. 1992, 57, 2768.
(22) Ator, M. A.; Schmidt, S. J.; Adams, J. L.; Dolle, R. E.; Kruse,
L. I.; Frey, C. L.; Barone, J. M. J. Med. Chem. 1992, 35, 100.
(23) Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6, 3849.
(15) Hale, K. J.; Cai, J. Tetrahedron Lett. 1996, 37, 4233.
1748 J. Org. Chem., Vol. 72, No. 5, 2007

Pectenotoxin-2 Synthetic Studies
SCHEME 1
calculations. The latter data suggested that the lack of anomeric
stabilization in the C7R isomer amounted to approximately 5
kcal/mol. This conclusion has since been validated by experi-
mental evidence from the Brimble group, who independently
reported the synthesis of a common intermediate and assigned
its structure on the basis of NOE studies.8a Although the C7S
configuration is favored in the open chain or seco acid form,
this is not necessarily the case when the spirokal is embedded
in a macrocyclic framework. To this end, the observation by
Sasaki et al. that PTX7 equilibrates under acidic conditions to
a mixture rich in PTX6 with C7R configuration is relevant.1b
The defining experiments reported by Pihko and Aho in which
both AB ring anomers were separately synthesized under kinetic
control also bear on this issue.23
The union of aldehyde 24 with sulfone 21 through Julia
olefination proceeded uneventfully to deliver the coupling
product 25 in modest yield (Scheme 4). The relatively low
efficiency of this step is attributed to the heightened sensitivity
of 24. Subsequent deprotection of the TES ether involved the
use of acetic acid in aqueous THF. This step resulted in
quantitative conversion to the pair of diastereomeric alcohols
26 and made possible further independent advancement to epoxy
alcohol 27 and the (E)-enone 28. Whereas the Dess-Martin
periodinane can be effectively utilized in the 26 f 28 conver-
sion, all attempts to bring about the epoxidation of 28 were to
no avail. Alternate routing via 27 made it possible to access
the desired epoxy ketone 29, whose further chemical modifica-
tion in a number of directions resulted either in decomposition
or no reaction. Equally unproductive were our attempts to
remove the PMB groups in 29 for the purpose of generating 30
as a prelude to the anticipated operation of hydroxyl-initiated
transannular cyclization.
The above observations prompted subsequent consideration
of an alternative route involving Z-unsaturation across C15-
C16.
Ring Closure within the Z-Series with Generation of the
C1-C26 Sector. The alternative synthetic program commenced
with the preparation of phosphonium salt 32 via the primary
iodide 31 (Scheme 5). Once the ylide had been generated from
32, the much desired Z-configured coupling product 33 was
furnished. Once again, the propensity of aldehyde 24 to
degradation served to limit the yield of 33 to 40%. The
dihydroxylation of 33 was not successful when performed via
several methods. However, success was ultimately realized under
forcing conditions involving the use of stoichiometric amounts
of osmium tetroxide. This protocol gave rise in 37% yield to a
diastereomeric mixture of diols. The isomer depicted as 34 was
subject to spontaneous stereocontrolled transannular cyclization
with deliverance of 35 as the only fully characterized product.
The LCMS (ESI+)-derived spectrum of 35 showed one
predominant peak in the total ion current trace, which produced
no (quasi)-molecular ions. Instead, a m/z ) 1181 base peak
reconcilable with [M + Na - C6H14Si] resulting from the facile
loss of the TES protecting group was seen. Weaker ions
J. Org. Chem, Vol. 72, No. 5, 2007 1749

O’Connor et al.
SCHEME 2
SCHEME 3
corresponding to [M + NH4 - C6H14Si] at m/z ) 1176 and
[M + H - C6H14Si] at m/z ) 1159 were also observed.
A number of key NMR observations proved to be diagnostic
producing pyran rings. Instead, the 13C chemical shifts of C12
and C15 strongly suggest that a tetrahydrofuran ring had been
formed. This conclusion receives additional support from an
HMBC correlation observed between H15 and C12 (3-bond
correlation via oxygen). Importantly, the pattern of NOEs
surrounding the C12 to C15 THF ring supports the indicated
relatiVe stereochemistry at C12/C14/C15. Last, appropriate
HMBC correlations and/or NOEs confirm that all five protecting
1
of structure. Thus, the H and 13C chemical shifts of C11 and
C12 indicate that the epoxide ring has been opened. Beyond
this, the 13C shifts of C12 and C15 are not compatible with
simple epoxide opening to produce an open-chain Vic-diol or
with either one of the two alternative modes of cyclization
1750 J. Org. Chem., Vol. 72, No. 5, 2007

Pectenotoxin-2 Synthetic Studies
SCHEME 4
mmol), K2CO3 (90.476 g, 3.45 mmol), potassium osmate dihydrate
(0.004 g, 0.0115 mmol), K2S2O8 (0.313 g, 1.16 mmol), methane-
sulfonamide (0.107 g, 1.127 mmol), and NaHCO3 (0.290 g, 3.45
mmol) were suspended in t-BuOH/H2O (1:1, 20 mL), cooled to
0 °C, and stirred for 30 min. A solution of 16 (0.675 g, 1.15 mmol)
in t-BuOH (1 mL) was added by syringe pump over 1 h, and the
mixture was stirred for 16 h. Hydrogen sulfoxide was bubbled
through the mixture for 30 min or until no more precipitate was
observed. The suspension was diluted with brine (10 mL) and
extracted with EtOAc (4 × 10 mL). The combined extracts were
washed with brine, dried, evaporated, and passed through a silica
gel pad. Elution with EtOAc and removal of the solvent under
reduced pressure provided a 4:1 mixture of diols (0.60 g, 85%
combined) rich in 17, which can be separated following cyclization
to 18. For 17: colorless oil; IR (film, cm-1) 3403, 1612, 1510,
groups are in place. A compilation of these data is provided in
Table 1 (Supporting Information).
Summary. To recapitulate, the linkage of intermediates 21
and 24 in a projected synthesis of pectenotoxin-2 was thwarted
by an inability to induce 29 into transannular cyclization. In
contrast, a key element of success was realized by replacing
the Julia-Kocienski olefination with a Wittig alternative. The
introduction of a Z double bond in this manner, when followed
by proper dihydroxylation, resulted in the charting of a route
to 35. To arrive at the proper stereochemistry of PTX2 from 35
will require epimerization at C15 after generation of ketone
functionality at C14. Studies intended to follow up this lead in
addition to other avenues of molecular modification continue
to be pursued.
1
1465; H NMR (300 MHz, C6D6) δ 7.90-7.85 (m, 4H), 7.31-
7.27 (m, 6H), 7.25 (d, J ) 8.7 Hz, 2H), 6.86 (d, J ) 8.7 Hz, 2H),
4.28-4.20 (m, 2H), 4.06-3.98 (m, 2H), 3.37 (s, 3H), 3.37-3.26
(m, 2H), 2.59 (br s, 1H) 2.38-2.21 (m, 2H), 2.08-2.00 (m, 2H),
1.86-1.31 (m, 9H), 1.26 (s, 9H), 1.15 (s, 3H), 1.09 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 159.6, 136.0, 134.2, 131.8, 129.9, 129.1,
Experimental Section
(3R,4R,7S)-7-(4-Methoxybenzyloxy)-9-(tert-butyldiphenylsi-
lyloxy)-7-methyl-1-((S)-2-methyloxiran-2-yl)nonane-3,4-diol (17).
(DHQD)2PHAL (0.035 g, 0.046 mmol), K3Fe(CN)6 (0.188 g, 0.575
J. Org. Chem, Vol. 72, No. 5, 2007 1751

O’Connor et al.
SCHEME 5
128.1, 127.7, 114.0, 76.0, 74.9, 74.0, 63.2, 60.7, 56.4, 54.7, 53.3,
41.9, 35.2, 32.7, 28.5, 27.9, 27.1, 24.0, 20.7, 19.4; HRMS (ES)
calcd for m/z (M + Na)+ 643.3431, obsd 643.3428.
brine, dried, and evaporated. The residue was chromatographed
(SiO2, elution with hexane/EtOAc 10:1) to afford the monobenzyl
ether (0.067 g, 59%) as a colorless oil: IR (film, cm-1) 3397, 1381,
1
(1R,4S)-4-(4-Methoxybenzyloxy)-6-(tert-butyldiphenylsilyloxy)-
1-((2R,5R)-5-(hydroxymethyl)-5-methyl-tetrahydrofuran-2-yl)-
4-methylhexan-1-ol (18). A solution of 17 (0.501 g, 0.807 mmol)
in MeOH/CH2Cl2 1:1 (20 mL) was treated at -78 °C with
pyridinium p-toluenesulfonate (0.052 g, 0.207 mmol), stirred for 5
min, and allowed to warm to room temperature for 2 h prior to
being quenched with saturated sodium bicarbonate solution (50 mL).
The aqueous layer was extracted (EtOAc, 3 × 40 mL), the
combined organic phases were washed with brine, dried, and
evaporated, and the residue was purified by silica gel chromatog-
raphy (EtOAc/hexane 1:1) to afford pure 18 as a colorless oil (0.451
1248; H NMR (300 MHz, CDCl3) δ 7.72-7.67 (m, 4H), 7.48-
7.29 (m, 11H), 7.15 (d, J ) 8.5 Hz, 2H), 6.82 (d, J ) 8.5 Hz, 2H),
4.58 (s, 2H), 4.25-4.22 (m, 2H), 3.85-3.78 (m, 3H), 3.79 (s, 3H),
3.37-3.32 (m, 2H), 3.31-3.24 (m, 1H), 2.00-1.45 (m, 10H), 1.25
(s, 3H), 1.18 (s, 3H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
158.7, 138.5, 135.5, 134.7, 133.9, 129.5, 128.8, 128.3, 127.6, 127.5,
127.4, 113.6, 83.0, 82.9, 76.3, 75.8, 74.8, 73.3, 62.7, 60.2, 55.2;
HRMS (ES) m/z calcd for (M + Na)+ 733.3900, obsd 733.3899.
The above alcohol (1.41 g, 198 mmol) and PMBBr (0.792 g,
3.96 mmol) were dissolved in THF (40 mL) and treated with KH
(30% dispersion in mineral oil, 0.42 g, 3.17 mmol, 1.6 equiv) in
one portion. The suspension was stirred for 2 h, cooled to 0 °C,
and quenched by addition of MeOH (0.5 mL). The solution was
diluted with saturated sodium bicarbonate solution, and the aqueous
layer was extracted with EtOAc (3 × 30 mL). The combined
organic extracts were washed with brine, dried, evaporated, and
chromatographed (SiO2, elution with hexane/EtOAc 20:1) to afford
19 (1.36, 83%) as a colorless oil: IR (film, cm-1) 1377, 1243, 1055;
1H NMR (300 MHz, CDCl3) δ 7.71-7.69 (m, 4H), 7.45-7.30 (m,
11H), 7.26 (d, J ) 8.6 Hz, 2H), 7.13 (d, J ) 8.6 Hz, 2H), 6.82 (d,
J ) 8.6 Hz, 2H), 4.68 (d, J ) 11.4 Hz, 1H), 4.62 (d, J ) 2.1 Hz,
2H), 4.52 (d, J ) 11.4 Hz, 1H), 4.23-4.08 (m, 2H), 3.86-3.75
(m, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.39 (s, 2H), 3.33-3.28 (m,
1H), 1.97-1.80 (m, 4H), 1.75-1.40 (m, 6H), 1.29 (s, 3H), 1.26
(s, 3H), 1.07 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 158.9, 158.7,
138.7, 135.5, 133.9, 131.6, 131.3, 129.5, 129.4, 128.7, 128.2, 127.6,
127.4, 127.3, 113.6, 82.7, 81.8, 75.8, 73.3, 72.2, 65.8, 62.5, 60.2,
55.2, 40.7, 34.3, 29.6, 29.3, 27.8, 26.8, 24.8, 23.8, 19.1; HRMS
(ES) m/z calcd for (M + Na)+ 853.4476, obsd 853.4475.
1
g, 91%): IR (film, cm-1) 3405, 1610, 1510, 1465; H NMR (500
MHz, CDCl3) δ 7.82-7.80 (m, 4H), 7.22-7.20 (m, 8H), 6.80 (d,
J ) 8.6 Hz, 2H), 4.26-4.19 (m, 2H), 4.01 (t, J ) 7.3 Hz, 2H),
3.58-3.54 (m, 1H), 3.31 (s, 3H), 3.24-3.16 (m, 3H), 2.37 (br s,
1H), 2.08-2.02 (m, 1H), 2.01-1.92 (m, 2H), 1.69-1.19 (series of
m, 8H), 1.19 (s, 9H), 1.12 (s, 3H), 0.97 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.0, 135.5 (2C), 1.33.8, 131.5, 129.5, 128.7,
127.6, 113.6, 83.6, 83.5, 76.1, 75.8, 75.0, 68.3, 62.7, 60.3, 60.2,
55.2, 45.0, 40.7, 34.3, 33.4, 28.3, 27.5, 26.8, 24.2, 23.7, 19.1; HRMS
(ES) m/z calcd for (M + Na)+ 643.3431, obsd 643.3431.
((3S,6R)-3,6-Bis(4-methoxybenzyloxy)-6-((2R,5R)-5-(benzyl-
oxymethyl)-5-methyl-tetrahydrofuran-2-yl)-3-methylhexyloxy)-
(tert-butyl)diphenylsilane (19). Diol 18 (0.10 g, 0.16 mmol) was
dissolved in THF (5 mL), cooled to -30 °C, and treated with
KHMDS (0.5 M in toluene, 0.64 mL, 0.32 mmol). The solution
was stirred for 45 min, warmed to -10 °C, and treated with benzyl
bromide (0.02 mL, 0.17 mmol) via syringe pump over 16 h. The
reaction mixture was quenched by the addition of saturated sodium
bicarbonate solution, the aqueous layer was extracted with EtOAc
(3 × 10 mL), and the combined organic phases were washed with
(3S,6R)-3,6-Bis(4-methoxybenzyloxy)-6-((2R,5R)-5-(benzyl-
oxymethyl)-5-methyl-tetrahydrofuran-2-yl)-3-methylhexan-1-
1752 J. Org. Chem., Vol. 72, No. 5, 2007

Pectenotoxin-2 Synthetic Studies
ol (20). A solution of 19 (1.36 g, 1.20 mmol) in THF (20 mL) was
cooled to 0 °C and treated with TBAF (1.0 M in THF, 2.52 mL)
dropwise by syringe. The stirred solution was allowed to warm to
room temperature and after 16 h was diluted with brine and
extracted with EtOAc (3 × 20 mL) prior to drying and evaporation.
The crude residue was chromatographed (SiO2, hexanes/EtOAc 4:1)
to afford the alcohol (0.96 g, 99%) as a colorless oil: IR (film,
material, quenched with 1 M NaHCO3 (30 mL), and extracted with
CH2Cl2 (3 × 30 mL). The combined organic fractions were pooled
and dried, and the solvent was evaporated to leave an oil that was
further purified by silica gel chromatography (hexane/EtOAc 10:
1) to give 23 as a transparent oil (2.5 g, 100%): IR (film, cm-1
)
1
1759, 1460, 1428; H NMR (300 MHz, CDCl3) δ 7.66-7.63 (m,
4H), 7.45-7.34 (m, 6H), 4.42 (d, J ) 4.3 Hz, 0.25H), 4.40 (d, J )
4.3 Hz, 0.25H), 4.33 (t, J ) 6.3 Hz, 0.5H), 3.77-3.62 (m, 2H),
3.733 (s, 1.5H), 3.730 (s, 1.5H), 3.60 (d, J ) 4.8 Hz, 1H), 3.55-
3.49 (m, 1H), 2.75 (d, J ) 8.0 Hz, 0.5H), 2.70 (d, J ) 8.0 Hz,
0.5H), 2.22-1.99 (m, 2H), 1.90-1.51 (m, 11H), 1.34 (d, J ) 5.8
Hz, 3H), 1.04 (s, 9H), 1.01-0.91 (m, 12H), 0.70-0.59 (m, 6H);
13C NMR (75 MHz, CDCl3) δ 173.7, 135.5 (2C), 133.9, 129.5,
127.6 (2C), 106.50, 106.46, 75.15, 75.08, 71.63, 71.60, 69.9, 69.6,
66.1, 65.3, 64.2, 59.4, 51.9, 44.0, 43.9, 40.8, 37.3, 32.78, 32.72,
28.14, 28.11, 26.9, 20.4, 19.3, 17.2, 12.98, 12.93, 6.8, 6.7, 4.6, 4.5;
HRMS (ES) m/z calcd for (M + Na)+ 733.3932, obsd 733.3929.
Controlled Reduction of 23. A stirred solution of 23 (208 mg,
293 µmol) in toluene (10 mL) was cooled to -90 °C, treated with
a 1.1 M solution of DIBAL-H (1.5 mL, 1.7 mmol), and stirred for
1.5 h before being quenched with MeOH (1 mL, 24 mmol). A
saturated solution of Rochelle’s salt (20 mL) was added, and the
mixture was allowed to warm to 0 °C, stirred for 0.5 h, and extracted
with EtOAc (4 × 30 mL). The combined organic fractions were
washed with brine, dried, and filtered through a short plug
containing basic alumina (activity 1). The solvent was removed in
vacuo to give 24 as an oil that was used without further
1
cm-1) 3432, 1641, 1372, 1243; H NMR (300 MHz, CDCl3) δ
7.37-7.26 (m, 7H), 7.21 (d, J ) 8.6 Hz, 2H), 6.85 (d, J ) 8.6 Hz,
4H), 4.71 (d, J ) 11.4 Hz, 1H), 4.61 (d, J ) 2.0 Hz, 2H) 4.54 (d,
J ) 11.4 Hz, 1H), 4.33 (d, J ) 10.5 Hz, 1H), 4.29 (d, J ) 10.5
Hz, 1H), 4.16-4.09 (m, 1H), 3.89-3.69 (m, 2H), 3.79 (s, 3H),
3.78 (s, 3H), 3.38 (s, 2H), 3.36-3.32 (m, 1H), 3.06-3.00 (m, 1H),
1.99-1.88 (m, 4H), 1.79-1.44 (m, 6H), 1.29 (s, 3H), 1.26 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 159.0, 158.9, 138.6, 131.1, 130.9,
129.5 (2C), 128.9, 128.2 (2C), 127.4 (2C), 113.8 (2C), 82.8, 81.6,
81.4, 78.5, 76.5, 73.3, 63.0, 59.5, 55.2; HRMS (ES) m/z calcd for
(M + Na)+ 615.3298, obsd 615.3307.
5-((3S,6R)-3,6-Bis(4-methoxybenzyloxy)-6-((2R,5R)-5-(benz-
yloxymethyl)-5-methyl-tetrahydrofuran-2-yl)-3-methylhexylsul-
fonyl)-1-phenyl-1H-tetrazole (21). To a stirred solution of 20
(0.401 g, 0.675 mmol) in THF (10 mL) were added triphenylphos-
phine (0.193 g, 0.742 mmol) and 1-phenyl-1H-tetrazole-5-thiol
(0.137 g, 0.773 mmol). After 5 min, the solution was cooled to
0 °C. Diisopropyl azodicarboxylate (0.137 g, 0.681 mmol) was
added dropwise via syringe, and the mixture was stirred for 1 h,
allowed to warm to room temperature, stirred for 5 h, and quenched
with saturated sodium bicarbonate solution. The aqueous layer was
extracted with EtOAc (3 × 30 mL). The combined organic extracts
were washed with brine, dried, evaporated, and chromatographed
(SiO2, elution with hexane/EtOAc 20:1) to afford the sulfide (0.423
g, 83%) as a colorless oil: IR (film, cm-1) 1730, 1611, 1512, 1457;
1H NMR (300 MHz, CDCl3) δ 7.87-7.50 (m, 5H), 7.35-7.25 (m,
9H), 6.87-6.83 (m, 4H), 4.71 (d, J ) 11.5 Hz, 1H), 4.61 (d, J )
1.9 Hz, 2H), 4.54 (d, J ) 11.5 Hz, 1H), 4.33 (s, 2H), 4.16-4.09
(m, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.49-3.33 (m, 5H), 2.14-
1.91 (m, 4H), 1.84-1.45 (m, 6H), 1.28 (s, 3H), 1.26 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 158.9, 158.8, 154.5, 138.7, 133.7, 131.3,
131.2, 130.9 (2C), 129.7 (2C), 129.6, 129.1 (2C), 129.0, 128.3 (2C),
127.4 (2C), 123.7 (2C), 113.7 (2C), 113.6 (2C), 82.8, 81.8, 81.4,
76.5, 73.3, 72.4, 63.1, 55.2, 55.2, 38.0, 34.3, 33.9, 28.2, 28.1, 24.6,
23.1, 21.9; HRMS (ES) m/z calcd for (M + Na)+ 775.3505, obsd
775.3510.
1
purification: IR (film, cm-1) 1736, 1454, 1108; H NMR (300
MHz, CDCl3) δ 9.65 (d, J ) 1.3 Hz, 0.5H), 9.60 (d, J ) 1.6 Hz,
0.5H), 7.66-7.63 (m, 4H), 7.45-7.35 (m, 6H), 4.18-4.12 (m, 1H),
3.77-3.35 (m, 4H), 2.81 (d, J ) 8.0 Hz, 0.5H), 2.68 (d, J ) 8.0
Hz, 0.5H), 2.24-2.16 (m, 1H), 2.03-1.44 (m, 12H), 1.35 (d, J )
2.7 Hz, 3H), 1.04 (s, 9H), 1.00-0.911 m, 12H), 0.69-0.58 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 203.2, 135.6 (2C), 129.5 (2C),
127.6 (2C), 106.5, 75.7, 75.3, 75.1, 68.0, 65.2, 65.1, 59.4, 59.2,
41.8, 40.8, 37.3, 32.7, 28.2, 28.1, 26.8 (3C), 20.4, 19.3, 18.4, 17.7,
12.9, 6.7 (3C), 4.7 (3C); HRMS (ES) m/z calcd for (M + Na)+
703.3826, obsd 703.3815.
The aldehyde is exceptionally unstable, and upon standing
overnight at room temperature will completely decompose.
Julia-Kocienski Coupling of 21 to 24. Sulfone 21 (0.095 g,
0.121 mmol) and aldehyde 24 (0.123 g, 0.181 mmol) were dissolved
in DME (6 mL) and cooled to -70 °C. KHMDS (0.5 M in toluene,
0.256 mL, 0.128 mmol) was added dropwise via syringe. After 30
min, the mixture was warmed to 0 °C, stirred for an additional 30
min, quenched with saturated ammonium chloride solution, stirred
for 10 min longer, and diluted with saturated sodium bicarbonate
solution. The aqueous layer was extracted with EtOAc (3 × 30
mL), the combined organic extracts were washed with brine, dried,
and evaporated, and the residue was chromatographed (SiO2, elution
with hexane/EtOAc 20:1) to afford 25 (0.065 g, 43%) as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 7.66-7.64 (m, 4H), 7.43-
7.21 (m, 15H), 6.84 (d, J ) 8.4 Hz, 4H), 5.66-5.56 (m, 2H), 4.69
(d, J ) 11.4 Hz, 1H), 4.60 (d, J ) 1.9 Hz, 2H), 4.53 (d, J ) 11.4
Hz, 1H), 4.29 (s, 2H), 4.12-4.08 (m, 1H), 3.79 (s, 3H), 3.78 (s,
3H), 3.78-3.51 (m, 5H), 3.37-3.29 (m, 3H), 2.68 (d, J ) 8.0 Hz,
0.5H), 2.66 (d, J ) 9.3 Hz, 0.5H), 2.35-1.39 (m, 22H), 1.32 (d,
J ) 7.1 Hz, 3H), 1.26 (s, 3H), 1.25 (s, 3H), 1.04 (s, 9H), 0.99-
0.84 (m, 12H), 0.64-0.56 (m, 6H); 13C NMR (75 MHz, CDCl3) δ
158.9, 158.7, 138.7, 136.1, 135.6, 134.0, 133.9, 131.7, 131.3, 129.5,
129.4, 129.3, 128.8, 128.2, 127.5, 127.4, 127.3, 125.9, 125.7, 113.6,
113.5, 106.4, 106.3, 82.7, 81.8, 81.7, 81.6, 77.2, 76.6, 76.5, 75.4,
75.2, 73.3, 72.2, 71.6, 71.6, 71.1, 70.7, 66.0, 65.3, 64.4, 62.8, 59.9,
59.7, 55.2, 55.2, 47.7, 41.4, 41.3, 40.8, 37.3, 34.3, 33.6, 32.8, 32.7,
31.9, 29.7, 29.6, 29.3, 28.2, 28.1, 28.0, 27.9, 26.9 (3C), 24.8, 24.4,
23.5, 23.4, 22.6, 20.5, 20.4, 19.2, 17.8, 17.3, 6.9 (3C), 4.9 (3C);
HRMS (ES) m/z calcd for (M + Na)+ 1261.7171, obsd 1261.7125.
Desilylation of 25. A solution of 25 (0.005 g, 0.0043 mmol) in
THF/H2O/AcOH (11:3:5, 1 mL) was stirred for 6 h and quenched
Ammonium molybdate trihydrate (0.018 g, 0.0148 mmol) was
added to a stirred, 0 °C solution of hydrogen peroxide (0.042 mL,
30% in H2O). After 15 min, the yellow solution was introduced
dropwise by syringe to a solution of the above sulfide (0.112 g,
0.148 mmol) in absolute EtOH (2 mL) at room temperature. After
16 h, the reaction mixture was diluted with water (5 mL), the
aqueous layer was extracted (EtOAc, 3 × 10 mL), and the combined
organic layers were dried and evaporated. The crude residue was
passed through a pad of silica (elution with 10% EtOAc in hexane)
to afford 21 as a colorless oil (0.115 g, 99%): IR (film, cm-1
)
1
1729, 1609, 1515, 1457; H NMR (300 MHz, CDCl3) δ 7.70-
7.55 (m, 5H), 7.37-7.20 (m, 9H), 6.86 (d, J ) 8.6 Hz, 2H), 6.84
(d, J ) 8.6 Hz, 2H), 4.70 (d, J ) 11.4 Hz, 1H), 4.60 (d, J ) 1.4
Hz, 2H), 4.52 (d, J ) 11.4 Hz, 1H), 4.29 (s, 2H), 4.16-4.08 (m,
1H), 3.82-3.75 (m, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.38 (s, 2H),
3.34-3.31 (m, 1H), 2.24-1.90 (m, 4H), 1.80-1.39 (m, 6H), 1.27
(s, 3H), 1.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.9, 158.9,
153.2, 138.6, 132.9, 131.3, 131.0, 130.6, 129.5 (2C), 129.4 (2C),
128.9, 128.8 (2C), 128.2 (2C), 127.4 (2C), 127.3 (2C), 113.7 (2C),
113.6 (2C), 82.8, 81.6, 81.0, 76.4, 73.2, 72.3, 63.0, 55.1, 55.1, 51.8,
34.2, 33.9, 30.4, 27.8; HRMS (ES) m/z calcd for (M + Na)+
807.3404, obsd 807.3398.
Silylation of 22. To a stirred solution of 22 (2.09 g, 3.50 mmol)
in (50 mL) at 0 °C were added diisopropylamine (4.5 mL, 31 mmol)
and triethylsilyl chloride (2.11 g, 14.0 mmol). The mixture was
stirred until TLC showed complete consumption of the starting
J. Org. Chem, Vol. 72, No. 5, 2007 1753

O’Connor et al.
with saturated sodium bicarbonate solution. The aqueous phase was
extracted with EtOAc (3 × 30 mL). The combined organic extracts
were washed with brine, dried, and evaporated. The residue was
chromatographed (SiO2, elution with hexane/EtOAc 20:1) to afford
26 (0.0045 mg, 99%) as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.66-7.63 (m, 6H), 7.45-7.22 (m, 13H), 6.85 (d, J )
8.5 Hz, 4H), 5.78-5.66 (m, 1H), 5.57-5.46 (m, 1H), 4.68 (d, J )
11.4 Hz, 1H), 4.60 (d, J ) 2.1 Hz, 2H), 4.53 (d, J ) 11.4 Hz, 1H),
4.30 (s, 2H), 4.13-4.07 (m, 1H), 3.784 (s, 3H), 3.777 (s, 3H), 3.79-
3.65 (m, 3H), 3.62 (dd, J ) 4.8, 10.1 Hz, 2H), 3.52 (dd, J ) 6.1,
10.1 Hz, 2H), 3.37 (s, 2H), 3.37-3.30 (m, 1H), 2.92 (d, J ) 8.1
Hz, 0.5H), 2.71 (d, J ) 8.1 Hz, 0.5H), 2.36-2.14 (m, 2H), 1.98-
0.90 (series of m, 21H), 1.26 (s, 6H), 1.25 (s, 3H), 1.04 (s, 9H),
0.97 (d, J ) 6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.9,
158.8, 138.7, 136.1, 135.6, 134.0, 133.9, 131.3, 135.5 (4C), 135.2,
134.5, 133.9, 133.8, 131.6, 131.2, 129.4, 129.3, 128.8, 128.2, 127.6
(4C), 127.5, 127.4, 127.2, 126.8, 113.7, 113.6, 106.5, 106.4, 82.8,
81.7, 81.5, 77.2, 76.6, 75.5, 75.1, 73.3, 72.2, 71.6, 71.5, 69.9, 69.3,
66.0. 64.5, 63.4, 62.9, 62.8, 60.7, 60.3, 55.2, 55.2, 45.0, 44.2, 41.4,
41.3, 40.7, 37.4, 37.3, 34.3, 33.6, 32.8, 32.7, 31.9, 29.7, 22.7, 20.5,
19.2, 16.9; HRMS (ES) m/z calcd for (M + Na)+ 1147.6307, obsd
1147.6289.
Epoxidation and Oxidation of 26. A solution of 26 (0.010 g,
0.0088 mmol) in CH2Cl2 (0.5 mL) was cooled to 0 °C and treated
with MCPBA (0.006 g, 0.035 mmol). After 3 h, the reaction mixture
was quenched with saturated sodium bicarbonate and saturated
sodium thiosulfate solutions. The mixture was stirred for 2 h and
the aqueous layer was extracted with EtOAc (3 × 30 mL). The
combined organic extracts were washed with brine, dried, and
evaporated. The residue was dissolved in CH2Cl2 (1 mL), treated
with pyridine (28 mg, 0.035 mmol) and Dess-Martin periodinane
(0.011 g, 0.026 mmol), and stirred for 20 min. The suspension was
diluted with CH2Cl2 (0.5 mL) and passed through a silica gel pad
eluting with hexanes/EtOAc (20:1, 20 mL then 4:1, 100 mL). The
latter fractions, which contained the epoxy ketone, were chromato-
graphed (SiO2, hexanes/EtOAc 20:1) to afford a 1:1 mixture of
diastereomeric epoxy ketones 29 (6.0 mg, 59%) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.67-7.60 (m, 4H), 7.46-7.22 (m,
15H), 6.87 (d, J ) 8.5 Hz, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 4.72-
4.65 (m, 1H), 4.59 (d, J ) 2.0 Hz, 2H), 4.55-4.48 (m, 1H), 4.33-
4.24 (m, 2H), 4.14-4.05 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.81-
3.66 (m, 2H), 3.63 (dd, J ) 4.8, 10.0 Hz, 1H), 3.52 (dd, J ) 6.2,
10.0 Hz, 1H), 3.38 (s, 2H), 3.36-3.29 (m, 1H), 3.27-3.21 (m,
1H), 2.72-2.52 (m, 2H), 2.25-0.90 (m, 23H), 1.28 (s, 9H), 1.05
(s, 9H), 0.93 (d, J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
204.0, 159.0, 158.9, 138.7, 135.6, 135.5, 134.4, 134.0, 133.9, 131.3,
131.2, 129.5, 129.4, 129.3, 128.9, 128.3, 127.6, 127.5, 127.4, 113.7,
113.6, 106.5, 82.8, 81.9, 81.5, 77.2, 76.6, 76.1, 75.1, 75.0, 73.3,
72.5, 71.6, 66.0, 64.0, 63.0, 59.3, 58.1, 58.0, 55.3, 55.2, 46.1, 41.0,
40.7, 37.2, 34.3, 34.0, 32.8, 31.9, 29.7, 29.6, 29.3, 28.1, 28.0, 26.8,
24.9, 23.8, 22.6, 20.4, 19.3, 17.5; HRMS (ES) m/z calcd for (M +
Na)+ 1161.6099, obsd 1161.6105.
Formation of Iodide 31. To a stirred solution of 20 (150 mg,
247 µmol) in benzene (5 mL) at 0 °C were added triphenylphos-
phine (129 mg, 494 µmol), imidazole (33 mg, 494 µmol), and iodine
(125 mg, 494 µmol). The mixture was allowed to warm to room
temperature, and stirring was continued for 1 h. The crude mixture
was passed through a silica plug and eluted with hexane/EtOAc
(1:1, 80 mL). The solvent was removed in vacuo to furnish 31 as
a colorless oil (119 mg, 67%): IR (film, cm-1) 1454, 1302, 1032;
1H NMR (300 MHz, CDCl3) δ 7.37-7.18 (m, 9H), 6.86 (d, J )
8.7 Hz, 2H), 6.85 (d, J ) 8.7 Hz, 2H), 4.69 (d, J ) 11.4 Hz, 1H),
4.61 (d, J ) 1.6 Hz, 2H), 4.52 (d, J ) 11.4 Hz, 2H), 4.29-4.191
(m, 2H), 4.14-4.06 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.37 (s,
2H), 3.36-3.28 (m, 1H), 3.22-3.13 (m, 2H), 2.29-1.38 (m, 10H),
1.26 (s, 3H), 1.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.1,
158.9, 131.2, 129.5, 128.8 (2C), 128.3 (2C), 127.4 (2C), 113.6 (2C),
82.8, 81.6, 81.3, 78.1, 73.4, 72.4, 63.0, 55.3 (2C), 44.0, 34.3, 33.7,
27.8, 24.9, 24.5, 22.8, -0.23; HRMS (ES) m/z calcd for (M +
Na)+ 725.2315, obsd 725.2311; [R]20 +10.6 (c 1.7, CHCl3).
D
Wittig Coupling of 24 with 32. The iodide (217.0 mg, 0.302
mmol) was dissolved in 3 mL of CH3CN at room temperature. PPh3
(793.0 mg, 3.02 mmol) and i-Pr2NEt (111.0 mg, 0.902 mmol) were
added. The mixture was heated at 90 °C for 48 h, and CH3CN was
removed by rotary evaporation. The residue was purified by column
chromatography (silica gel, CH2Cl2/MeOH 95:5) to afford 32 (207
mg, 70%), which was used directly.
To a stirred solution of 32 (207 mg, 211 µmol) in toluene (1.5
mL) at -78 °C was added a 0.6 M toluene solution of KHMDS
(360 µL, 216 mmol), and the mixture was stirred at -78 °C for
0.5 h. A solution of 24 (216 mg, 317 µmol) was added slowly via
syringe, and the mixture was stirred for 0.5 h prior to warming to
room temperature and stirring for a further 1 h. The reaction mixture
was quenched with 1 M NH4Cl (20 mL) and extracted with ether
(3 × 50 mL). The pooled organic fractions were washed with brine,
dried, and concentrated in vacuo, giving a brown oil that was further
purified by silica gel chromatography (hexane/EtOAc 6:1) to give
33 as a colorless oil (69 mg, 26%): IR (film, cm-1) 1512, 1346,
1
1085; H NMR (300 MHz, CDCl3) δ 7.67-7.60 (m, 4H), 7.41-
7.18 (m, 15H), 6.87-6.81 (m, 4H), 5.57-5.39 (m, 2H), 4.69 (d,
J ) 11.4 Hz, 1H), 4.60-4.48 (m, 3H), 4.28-4.21 (m, 3H), 4.14-
4.06 (m, 1H), 3.79-3.77 (m, 6H), 3.76-3.60 (m, 2H), 3.56-3.48
(m, 1H), 3.38-3.28 (m, 3H), 3.22-3.13 (m, 1H), 2.77 (d, J ) 8.0
Hz, 0.6H), 2.70 (d, J ) 8.0 Hz, 0.4H), 2.40-0.90 (m, 38H), 0.63-
0.55 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 159.0, 138.7, 135.6,
134.0, 131.5, 131.2, 129.51, 129.49, 129.4, 128.91, 128.89, 128.8,
127.4, 113.6, 106.4, 81.3, 76.6, 75.4, 72.3, 66.1, 63.0, 60.0, 55.2,
40.8, 37.3, 34.4, 28.2, 28.12, 28.09, 27.9, 26.8, 24.9, 24.5, 23.7,
20.4, 19.3, 18.3, 13.0, 6.9; HRMS (ES) m/z calcd for (M + Na)+
1261.7171, obsd 1261.7229; [R]20 +9.2 (c 2.0, CHCl3).
D
Dihydroxylation of 33 with Spontaneous Cyclization. To a
stirred solution of 33 (26.0 mg, 0.021 mmol) in acetone (0.9 mL)
and H2O (0.3 mL) were added OsO4 (10.3 mg, 0.0405 mmol) and
NMO (20.0 mg, 0.148 mmol) at room temperature. The mixture
was stirred for 24 h before being diluted with saturated Na2S2O3
solution, stirred for 0.5 h, and extracted with EtOAc (4 × 20 mL).
The combined organic layers were washed with brine, dried, and
concentrated to give crude product (30 mg). The major component
was purified by chromatography on silica gel (hexane/EtOAc 5:1
with 1% ethanol) to give pure 35 (5 mg) as a colorless oil. See
text for spectral analysis.
Oxidation of 26. Alcohol 26 (10 mg, 8.8 µmol) was dissolved
in CH2Cl2 (0.5 mL), treated with pyridine (28 mg, 0.035 mmol)
and Dess-Martin periodinane (0.011 g, 0.026 mmol), and stirred
for 20 min. The suspension was diluted with CH2Cl2 (0.5 mL) and
passed through a silica gel pad eluting with hexane/EtOAc (20:1,
20 mL then 4:1, 100 mL). The latter fractions contained 28 (0.008
g, 80%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.65-
7.62 (m, 4H), 7.41-7.21 (m, 15H), 6.93-6.86 (m, 1H), 6.844 (d,
J ) 8.4 Hz, 2H), 6.840 (d, J ) 8.5 Hz, 2H), 6.21 (d, J ) 15.8 Hz,
1H), 4.68 (d, J ) 11.4 Hz, 1H), 4.59 (d, J ) 1.8 Hz, 2H), 4.51 (d,
J ) 11.4 Hz, 1H), 4.13-4.07 (m, 2H), 3.784 (s, 3H), 3.779 (s,
3H), 3.78-3.65 (m, 3H), 3.61 (dd, J ) 4.8, 10.0 Hz, 1H), 3.50
(dd, J ) 6.2, 10.0 Hz, 1H), 3.36 (s, 2H), 3.35-3.30 (m, 1H), 2.73-
2.69 (m, 3H), 2.52-0.90 (m, 21H), 1.25 (s, 6H), 1.24 (s, 3H), 1.03
(s, 9H), 0.96 (d, J ) 6.7 Hz, 3H); HRMS (ES) m/z calcd for (M +
Na)+ 1145.6150, obsd 1145.6183.
Supporting Information Available: Experimental details for
the preparation of 9-16 inclusive, table of partial NMR assignments
1
for 35, and H NMR spectra for all new compounds described
herein. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO062513F
1754 J. Org. Chem., Vol. 72, No. 5, 2007