Versatile synthesis of the C3-C14 domain of 7-deoxyokadaic acid

Article abstract of DOI:10.1021/jo8017457

Described is a flexible synthesis of the C3-C14 domain of 7-deoxyokadaic acid that is amenable to facile structural diversification. Treatment of ynone 10 under acidic conditions led to net bis-conjugate addition of the latent diol to give the thermodynam

Full text of DOI:10.1021/jo8017457

Versatile Synthesis of the C3-C14 Domain of
7-Deoxyokadaic Acid
Timothy M. Trygstad,† Yucheng Pang,‡ and
Craig J. Forsyth*,‡
Department of Chemistry and Physical Sciences, The College
of St. Scholastica, Duluth, Minnesota 55811, and
Department of Chemistry, The Ohio State UniVersity,
Columbus, Ohio 43210
FIGURE 1. Okadaic acid and some targeted analogues.
forsyth@chemistry.ohio-state.edu
okadaic acid class of inhibitors.7 The continued development
of an empirical understanding of the essential structural differ-
ences between the binding of inhibitors to PP1 versus PP2A is
expected to facilitate the identification of novel small molecules
with enhanced levels of specificity.
ReceiVed August 05, 2008
The availability of X-ray crystallographic data for cocrystals
of okadaic acid and both PP1 and PP2A now provide a wealth
of information toward this goal.8,9 Within the similar topologies
of the PP1/PP2A active sites, where the C1-C14 portion of
okadaic acid docks, there are several likely binding interactions
involving the C10 and C13 methyl substituents of okadaic acid.
For the C10 methyl group, contacts may occur with Cys273
(3.72 Å), Glu275 (3.29 Å), and Phe275 (3.74 Å) of PP1 and
with Cys266 (3.97 Å), Arg268 (3.70 Å), and Cys269 (3.84 Å)
when bound to PP2A.9 The C13 methyl substituent has potential
interactions with Val250 (3.95 Å), Tyr 255 (4.53 Å), and Phe276
(3.72 Å) of PP1 and with Leu243 (3.47 Å) and Tyr265 (4.32
Å) of PP2A.9 These crystallographic correlations have prompted
the development of a versatile new synthetic entry to the
C3-C14 domain of okadaic acid that may vary in functional-
ization at C10, C13 (e.g., 3-5), and other sites.
The original retrosynthesis of 7-deoxyokadaic acid began with
a disconnection between C14 and C15 leading to the C1-C14
aldehyde 6 and the C15-C38 ꢀ-ketophosphonate 7 (Scheme
1).3 Compound 6 could, in turn, be prepared from the lithium
enolate of Seebach’s lactate (8)10 and the C3-C14 aldehyde
9.3 At this juncture, we planned to assemble the spiroketal from
ynone 10 via a double intramolecular hetero-Michael addition
(DIHMA) process.11 We anticipated that under thermodynamic
Described is a flexible synthesis of the C3-C14 domain of
7-deoxyokadaic acid that is amenable to facile structural
diversification. Treatment of ynone 10 under acidic condi-
tions led to net bis-conjugate addition of the latent diol to
give the thermodynamically favored spiroketal 27, a versatile
intermediate, en route to 7-deoxyokadaic acid and analogs.
Okadaic acid (1, Figure 1) is the archetypal seriene/threonine
protein phosphatase inhibitor.1 The natural product 7-deoxy-
okadaic acid (2) maintains similar protein serine/threonine
phosphatase inhibitory activity,2 whereas omission of the C7
hydroxyl group substantially simplifies synthetic access.3 Hence,
7-deoxyokadaic acid has become the primary template for our
research into the development of selective phosphatase inhibitors.
The primary amino acid sequences of the okadaic acid
receptors protein phosphatases 1 and 2A (PP1 and PP2A,
respectively) are ca. 50% conserved.4 Subtle yet significant
structural differences in and about the active sites of PP1 and
PP2A may contribute to differential sensitivities toward 7-deox-
yokadaic acid, with Ki ) 150 and 30 nM for PP1 and PP2A,
respectively.2,5,6 Differential levels of binding affinities to PP1
versus PP2A have also been reported for most members of the
(7) (a) Larsen, K.; Petersen, D.; Wilkins, A. L.; Samdal, I. A.; Sandvik, M.;
Rundberget, T.; Goldstone, D.; Arcus, V.; Hovgaard, P.; Rise, F.; Rehmann, N;
Hess, P.; Miles, C. O. Chem. Res. Toxicol. 2007, 20, 868. (b) Roberge, M.;
Tudan, C.; Hung, S. M. F.; Harder, K. W.; Jirik, F. R.; Anderson, H. Cancer
Res. 1994, 54, 6115. (c) Matsuzawa, S.; Suzuki, T.; Suzuki, M.; Matsuda, A.;
Kawamura, T; Mizuno, Y.; Kikuchi, K. FEBS Lett. 1994, 356, 272. (d) Li, Y-M.;
Casida, J. E Proc. Natl. Acad. Sci. USA 1992, 89, 11867. (e) Mackintosh, C.;
Klumpp, S. FEBS Lett. 1990, 277, 137. (f) Holmes, C. F. B.; Luu, H. A.; Carrier,
F.; Schmitz, F. J. FEBS Lett. 1990, 270, 216. (g) MacKintosh, C.; Beattie, K. A.;
Klumpp, S.; Cohen, P.; Codd, G. A. FEBS Lett. 1990, 264, 187. (h) Matsushima,
R.; Yoshizawa, S; Watanabe, M. F.; Harada, K.; Furusawa, M.; Carmichael,
W. W.; Fujiki, H Biochem. Biophys. Res. Commun. 1990, 171, 867. (i) Ishihara,
H.; Martin, B. L.; Brautigan, D. L.; Karaki, H.; Ozaki, H.; Kato, Y.; Fusetani,
N.; Watabe, S.; Hashimoto, K. Biochem. Biophys. Res. Commun. 1989, 159,
871. (j) Ohuchi, K.; Tamura, T.; Ohashi, M.; Watanabe, M.; Hirasawa, N.;
Tsurufuji, S; Fujiki, H. Biochim. Biophys. Acta 1989, 1013, 86.
† The College of St. Scholastica.
‡ The Ohio State University.
(1) (a) Tachibana, K.; Scheuer, P. J.; Tsukitani, Y.; Kikuchi, H.; Van Engen,
D.; Clardy, J.; Gopichand, Y.; Schmitz, F. J. J. Am. Chem. Soc. 1981, 103, 2469.
(b) Dounay, A. B.; Forsyth, C. J. Curr. Med. Chem. 2002, 9, 1851.
(2) Takai, A.; Murata, M.; Torigow, K.; Isobe, M.; Mieskes, G.; Yasumoto,
T. Biochem. J. 1992, 284, 539.
(3) Dounay, A. B.; Urbanek, R. A.; Sabes, S. F.; Forsyth, C. J. Angew. Chem.,
Int. Ed. 1999, 38, 2258.
(4) Huang, X.; Cheng, A.; Honkanen, R. E. Genomics 1997, 44, 336.
(5) Takai, A.; Mieskes, G. Biochem. J. 1991, 275, 233.
(6) Bialojan, C.; Takai, A. Biochem. J. 1988, 256, 283.
(8) Maynes, J. T.; Bateman, K. S.; Cherney, M. M.; Das, A. K.; Luu, H. A.;
Holmes, C. F. B.; James, M. N. G. J. Biol. Chem. 2001, 276, 44078.
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Strack, S.; Stock, J. B.; Shi, Y. Cell 2006, 127, 341.
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910 J. Org. Chem. 2009, 74, 910–913
10.1021/jo8017457 CCC: $40.75 2009 American Chemical Society
Published on Web 12/15/2008

SCHEME 1. Retrosynthesis of 7-Deoxyokadaic Acid
SCHEME 3. Synthesis of the C10-C14 Fragment
provided enantiomerically enriched 17,13 which was converted
into the internal alkyne 19 via reaction with in situ formed
1-lithio-1-butyne.15 At the stage of 19 it was found that the HKR
process had given an approximate 6.4:1 ratio of (R)-17 to (S)-
17, based on chiral column analysis against a racemic standard.16
Compound 19 was isomerized to the terminal alkyne 20 under
Brown’s strongly basic conditions.17 Attempts to accomplish
this conversion in the presence of silyl protecting groups were
unsuccessful. The secondary alcohol 20 was converted into the
TES ether 11, completing the synthesis of the C3-C9 fragment
in ca. 61% overall yield over four steps from (()-16.
SCHEME 2. Synthesis of the C3-C9 Fragment
The synthesis of the C10-C14 fragment began with the
known aldehyde 2118 (Scheme 3), which was identified via 1H
NMR spectroscopic comparison. The C12 stereogenic center
was installed via allylation19 of 21 to give the terminal alkene
22 in a 15:1 diastereomeric ratio based upon 1H NMR
spectroscopy. Subsequent protection of the secondary alcohol
22 with TESCl gave 23. Cleavage of the PMB ether of 23,
followed by TBDPS ether formation, yielded 25. These protect-
ing group manipulations became necessary for two reasons.
First, in the synthesis of 11, the PMB protecting group aided
the alkyne migration process. Second, the presence of the PMB
protecting group facilitated the tin-mediated chelation controlled
allylation reaction leading to 12, and the subsequent conversion
to the TBDPS protecting group was preferred for terminal
differentiation post convergence with 11. Ozonolysis of 25 gave
aldehyde 12, completing the synthesis of the C10-C14 fragment
in an overall yield of ca. 50% over five steps from 21.
Completion of the synthesis of the C3-C14 domain began
with the coupling of the lithium acetylide derived from 11 with
12 to afford the propargylic alcohols 26 (Scheme 4) as a
diastereomeric mixture (epimeric at both C4 and C10). Oxida-
control the resident configurations at C4 and C12 would favor
the formation of the natural product’s C8 stereogenic center.
Intermediate 10 was prepared from the C3-C9 fragment
alkyne 11 and C10-C14 aldehyde 12, both of which were
obtained from commercially available compounds 1-butyne (13),
epichlorohydrin (14), and methyl-(R)-3-hydroxy-2-methylpro-
pionate (15). The synthesis of the C3-C9 alkyne 11 began with
protected glycidol ether 16 (Scheme 2), which was prepared as
previously described and identified via 1H NMR spectroscopic
comparison.12,13 Hydrolytic kinetic resolution (HKR)14 of 16
(13) (a) Dounay, A. B. Ph.D. Thesis, University of Minnesota, 2001, p 201.
(b) Nicolaou, K. C.; Fylaktakidou, K. C.; Monenschein, H.; Li, Y.; Weyershausen,
B.; Mitchell, H. J.; Wei, H.; Guntupalli, P.; Hepworth, D.; Sugita, K. J. Am.
Chem. Soc. 2003, 125, 15433. and compound 48 therein.
(14) Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
6776.
(15) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(16) HP Series 1100, Chiralcel OD, column no. OD00CE-AJ015, 1.0 µL
injection, 0.5 mL/min, 95:5 hexane/iPrOH, UV detection λ ) 280 nm.
(17) (a) Macaulay, S. R. J. Org. Chem. 1980, 45, 734. (b) Brown, C. A.;
Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891.
(11) (a) Wang, C.; Forsyth, C. J. Org. Lett. 2006, 8, 2997. (b) Geisler, L. K.;
Nguyen, S.; Forsyth, C. J. Org. Lett. 2004, 6, 4159. (c) Hao, J.; Forsyth, C. J.
Tetrahedron Lett. 2002, 43, 1. (d) Aiguade, J.; Hao, J.; Forsyth, C. J. Org. Lett.
2001, 3, 979.
(18) Organ, M. G.; Wang, J. J. Org. Chem. 2003, 68, 5568.
(19) (a) Harried, S. S.; Lee, C. P.; Yang, G.; Lee, T. I. H.; Myles, D. C. J.
Org. Chem. 2003, 68, 6646. (b) White, J. D.; Hong, J.; Robarge, L. A. J. Org.
Chem. 1999, 64, 6206. (c) Keck, G. E.; Park, M.; Krishnamurthy, D. J. Org.
Chem. 1993, 58, 3787.
(12) Mouzin, G.; Cousse, H.; Rieu, J. P.; Duflos, A. Synthesis 1983, 2, 117.
J. Org. Chem. Vol. 74, No. 2, 2009 911

SCHEME 4. Synthesis of the C3-C14 Domain
to various derivatives. This has been successfully employed in
the synthesis of the 10-desmethyl-7-deoxyokadaic acid analog
4. A combination of such tactics has led to 7-deoxyokadaic acid
analog 5. Potentially synergystic efforts are also underway to
probe the effects of structural variations about the terminal
C30-C38 spiroketal of okadaic acid analogs.21
Incorporation of C3-C14 structural variants into full length
okadaic acid analogs will allow comparative phosphatase
binding assays to be performed. This should contribute to an
enhanced understanding of the essential roles of the structural
moieties within the active site-occupying domain of okadaic
acid, as suggested by X-ray crystallography.
Experimental Section
Yneone 10. To a magnetically stirred, room temperature solution
of 26 (6.294 g, 7.43 mmol) in methylene chloride (74 mL) was
added NaHCO3 (9.36 g, 111.4 mmol) and Dess-Martin periodinane
(6.3 g, 14.9 mmol). After TLC indicated no remaining 26, saturated
aqueous NaHCO3 (50 mL) was added dropwise. The separated
aqueous phase was extracted with methylene chloride (3 × 25 mL),
and the combined organic phase was washed with H2O (50 mL)
and then brine (50 mL), dried over Na2SO4, filtered, and concen-
trated. The residue was purified by flash chromatography (hexanes/
ethyl acetate, 20:1, v/v) to give 10 as an oil (5.06 g, 5.98 mmol,
81%): [R]25 +0.5 (c 3.1, CHCl3); 1H NMR (500 MHz) δ
tion of alcohols 26 gave ynones (4R/S)-10. At this stage, the
minor (4R)-diastereomer resulting from the HKR of (()-16 was
chromatographically separated from (4S)-10. Subsequent imple-
mentation of the DIHMA process using the (4S)-diastereomer
of 10 provided spiroketal 27. For this, prolonged exposure to
acid was intended to assist equilibration to capture the benefit
of mutual anomeric stablization in 27. To complete the synthesis
of the 7-deoxyokadaic acid intermediate 29, ketone 27 was
subjected to Wittig olefination to yield the exo methylene
compound 28. Subsequent isomerization to the internal alkene
29 was accomplished under acidic conditions (Scheme 4).
Remarkably, none of the alternative endocyclic alkene isomer
was detected to accompany 29. This regioselective alkene
migration may reflect an enhanced acidity of the R-ketal
methylene protons and/or alkene conjugation with a transient
oxocarbenium intermediate. In any event, it places the alkene
R to the C8 spiroketal center as is observed among okadaic
acid and its congeners.
D
7.69-7.64 (m, 4H), 7.46-7.35 (m, 6H), 7.25 (d, J ) 9 Hz, 2H),
6.88 (d, J ) 9 Hz, 2H), 4.62-4.59 (m, 1H), 4.44 (s, 2H), 3.81 (s,
3H), 3.50 (d, J ) 7 Hz, 2H), 3.36 (dd, J ) 5.5, 9.5 Hz, 1H), 3.32
(dd, J ) 5.5, 9.5 Hz, 1H), 2.66 (dd, J ) 9, 15.5 Hz, 1H), 2.58 (dd,
J ) 5.5, 15.5 Hz, 1H), 2.33 (t, J ) 7 Hz, 2H), 2.04-1.96 (m, 1H),
1.72-1.48 (m, 5H), 1.07 (s, 9H), 0.96-0.88 (m, 18H), 0.83 (d, J
) 7 Hz, 3H), 0.63-0.55 (m, 12H); 13C NMR (125 MHz) δ 187.0,
159.4, 135.8, 133.8, 130.6, 129.8, 129.5, 127.9, 113.9, 94.1, 81.7,
81.0, 74.4, 73.2, 71.1, 69.7, 66.0, 55.5, 49.3, 34.2, 31.8, 27.0, 23.8,
22.9, 19.4, 14.3, 11.7, 7.1, 5.2; IR (neat) 3080-3000, 3000-2850,
2212, 1741, 1676, 1612, 1588, 1513, 1462, 1247, 1120-1060 cm-1
;
HRMS calcd for C49H76Si3O6Na (M + Na) 867.4847, found
867.4881; Rf ) 0.30 (hexanes: ethyl acetate, 8:1, v/v).
Pyranone 27. To a magnetically stirred, room temperature
solution of ynone 10 (710 mg, 845 µmol) in toluene (8.4 mL) was
added p-toluenesulfonic acid monohydrate (192 mg, 1.00 mmol).
The mixture was stirred 1 d before saturated aqueous NaHCO3 (2
mL) was added. The mixture was diluted with diethyl ether (10
mL) and the aqueous phase was separated. The organic phase was
washed with H2O (10 mL), then brine (10 mL), dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash
chromatography (hexanes: ethyl acetate, 4:1, v/v) to give 27 as a
colorless oil (451 mg, 731 µmol, 87%): [R]D24 -36 (c 3.3, CHCl3);
1H NMR (500 MHz) δ 7.65 (d, J ) 8 Hz, 4H), 7.44-7.35 (m,
6H), 7.18 (d, J ) 8.5 Hz, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 4.39 (d,
J ) 2.5 Hz, 2H), 3.92-3.90 (m, 1H), 3.81 (s, 3H), 3.69 (t, J ) 4.5
Hz, 1H), 3.70 (dd, J ) 5.5, 10 Hz, 1H), 3.65-3.60 (m, 1H), 3.28
(d, J ) 5 Hz, 2H), 2.42 (t, J ) 13 Hz, 2H), 2.34 (d, J ) 14 Hz,
1H), 2.25 (dd, J ) 11.5, 14.5 Hz, 1H), 1.95-1.85 (m, 1H),
1.75-1.65 (m, 2H), 1.46-1.41 (m, 2H), 1.29-1.20 (m, 2H), 1.05
(s, 9H), 0.97 (d, J ) 7 Hz, 3H); 13C NMR (125 MHz) δ 206.6,
159.2, 135.8, 133.8, 130.8, 129.8, 129.2, 127.8, 113.8, 99.2, 73.0,
72.8, 70.0, 69.7, 65.2, 55.4, 52.0, 44.4, 41.2, 34.7, 27.1, 26.7, 19.4,
18.7, 13.3; IR (neat) 3070, 3048, 3000-2850, 1726, 1612, 1588,
1513, 1464, 1428, 1248, 1110-1000, 823, 741, 705 cm-1; HRMS
calcd for C37H48SiO6Na (M + Na) 639.3112, found 639.3106; Rf
) 0.35 (hexanes/ethyl acetate, 4:1, v/v).
The synthesis of the C3-C14 domain was thus completed
in an overall yield of ca. 23% over 10 steps from 21. The
assignment of relative configuration at the spiroketal center of
29 was made via conversion into a C3,C14-diol, a known
compound obtained from an intermediate used in the total
synthesis of 2.20 Comparison of the H NMR spectral data
1
indicated identical relative stereochemistry at C4, C8, C12, and
C13, as well as the location of the alkene at C9 between 29
and the natural product 7-deoxyokadaic acid.
The advantages of this new route to the functionalized
C3-C14 spiroketal domain of 2 are its efficiency and its
applicability to readily access several analogs with only minor
changes to the overall synthetic route. For instance, 13-
desmethyl-7-deoxyokadaic acid analog 3 has been obtained by
a simple change of starting material 21 to 1,3-propanediol with
essentially the same reaction sequence to assemble a C10-C14
intermediate. Similarly, employing the identical synthetic route
to spiroketal 27, the versatile C10 ketone could provide access
Exocyclic Alkene 28. To a magnetically stirred, 0 °C solution
of methyltriphenylphosphonium bromide (72 mg, 202 µmol) in THF
(20) Dounay, A. B. Thesis, University of Minnesota, 2001, pp 24-25; 1H
NMR spectra, ABD-II-233 and ABD-II-238.
(21) Forsyth, C. J.; Wang, C. Bioorg. Med. Chem. Lett. 2008, 18, 3043.
912 J. Org. Chem. Vol. 74, No. 2, 2009

(2 mL) was added n-BuLi (73 µL of a 2.5 M solution in hexanes,
182 µmol). After 5 min, the mixture was allowed to warm to room
temperature and stirred for 2 h before a solution of 27 (25 mg,
40.5 µmol) in THF(1 mL) was added. The mixture was stirred 1 h
before saturated aqueous NH4Cl (4 mL) was added. The separated
aqueous phase was extracted with ethyl acetate (3 × 1 mL), and
the combined organic phase was dried over Na2SO4, filtered, and
concentrated. The residue was purified by flash chromatography
(hexanes/ethyl acetate, 10:1, v/v) to give 28 as a colorless oil (21
mg, 34 µmol, 84%): [R]24D -30 (c 3, CHCl3); 1H NMR (500 MHz)
δ 7.69 (d, J ) 6.5 Hz, 4H), 7.45-7.36 (m, 6H), 7.23 (d, J ) 9 Hz,
2H), 6.87 (d, J ) 9 Hz, 2H), 4.81 (s, 1H), 4.78 (s, 1H), 4.50 (d, J
) 7 Hz, 1H), 4.44 (d, J ) 7 Hz, 1H), 3.88 (dd, J ) 4.5, 9.5 Hz,
1H), 3.82 (s, 3H), 3.64 (dd, J ) 7, 10 Hz, 1H), 3.63-3.60 (m,
1H), 3.58-3.54 (m, 1H), 3.34 (t, J ) 4.5 Hz, 2H), 2.32-2.28 (m,
2H), 2.13 (d, J ) 13 Hz, 1H), 1.97, (t, J ) 13 Hz, 1H), 1.85-1.82
(m, 1H), 1.72-1.68 (m, 1H), 1.68-1.62 (m, 1H), 1.55-1.51 (m,
1H), 1.46-1.41 (m, 2H), 1.30-1.23 (m, 1H), 1.09 (s, 9H), 1.02
(d, J ) 7 Hz, 3H); 13C NMR (125 MHz) δ 159.1, 142.4, 135.9,
134.1, 131.2, 129.7, 129.2, 127.7, 113.8, 110.2, 97.1, 73.0, 72.9,
70.8, 69.6, 65.8, 55.4, 44.8, 41.4, 37.4, 35.2, 27.2, 27.1, 19.5, 18.8,
13.6; IR (neat) 3072, 3000-2850, 1656, 1614, 1588, 1513, 1463,
1429, 1247, 1120-1000, 910, 823, 770 cm-1; HRMS calcd for
C38H50SiO5Na (M + Na) 637.3320, found 637.3326; Rf ) 0.34
(hexanes/ethyl acetate, 8:1, v/v).
Endocyclic Alkene 29. To a magnetically stirred, room tem-
perature solution of 28 (88.4 mg, 144 µmol) in isopropyl alcohol
(1.44 mL) was added p-toluenesulfonic acid monohydrate (8.2 mg,
43 µmol). The mixture was heated to 60 °C and allowed to stir for
ca. 1 h before saturated aqueous NaHCO3 (2 mL) was added. The
mixture was allowed to cool to room temperature and then diluted
with diethyl ether (2 mL). The aqueous layer was removed, and
the organic phase was washed with H2O (2 mL) and then brine (2
mL), dried over Na2SO4, filtered, and concentrated. The residue
was purified by flash chromatography (hexanes/ethyl acetate. 50:
1, then 35:1, then 20:1 v/v) to give 29 (36 mg, 58.5 µmol, ca. 41%)
and 28 (35.2 mg, 57.2 µmol, ca. 40%), both as colorless oils. Data
for 29: [R]24 -36 (c 2.8, CHCl3); 1H NMR (500 MHz) δ
D
7.69-7.67 (m, 4H), 7.42-7.34 (m, 6H), 7.17 (d, J ) 8 Hz, 2H),
6.84 (d, J ) 8 Hz, 2H), 5.34 (s, 1H), 4.37 (d, J ) 7 Hz, 1H), 4.33
(d, J ) 7 Hz, 1H), 4.00 (dd, J ) 4.5, 10 Hz, 1H), 3.81 (s, 3H),
3.77-3.73 (m, 1H), 3.72-3.68 (m, 1H), 3.55 (dd, J ) 7.5, 9.5 Hz,
1H), 3.32 (dd, J ) 4.5, 20 Hz, 1H), 3.25 (dd, J ) 5, 20 Hz, 1H),
1.94-1.89 (m, 2H), 1.81 (dd, J ) 3, 17 Hz, 2H), 1.70 (s, 3H),
1.58-1.52 (m, 2H), 1.51-1.41 (m, 2H), 1.30-1.26 (m, 1H), 1.08
(s, 9H), 1.03 (d, J ) 7 Hz, 3H); 13C NMR (125 MHz) δ 159.2,
136.1, 135.9, 134.2, 130.9, 129.7, 129.6, 127.7, 124.9, 113.8, 94.9,
73.4, 72.8, 69.2, 68.6, 66.4, 55.4, 41.1, 35.1, 33.2, 27.5, 27.1, 23.2,
19.5, 18.7, 13.6; IR (neat) 3069, 3049, 3000-2850, 1740, 1613,
1587, 1513, 1463, 1428, 1247, 1110-990, 823, 704 cm-1; HRMS
calcd for C38H50SiO5Na (M + Na) 637.3325, found 637.3286; Rf
) 0.31 (hexanes/ethyl acetate, 8:1, v/v).
Acknowledgment. This publication was made possible by
grant number ES10615 from the National Institute of Environ-
mental Health Sciences (NIEHS), NIH, and generous unre-
stricted funding from The Ohio State University. Its contents
are solely the responsibility of the authors and do not necessarily
represent the official views of the NIEHS, NIH. We thank Dr.
A. B. Dounay (Pfizer) for the acquisition of spectral correlation
data.
Supporting Information Available: Experimental proce-
dures, characterization data, 1H NMR and 13C NMR spectra for
previously unreported compounds, HPLC trace for compound
19, and comparative 1H NMR spectra.20 This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8017457
J. Org. Chem. Vol. 74, No. 2, 2009 913