Scheme 3. Synthesis of the F Ring THF Unit
Figure 1. Selected diagnostic NOESY cross-peaks and coupling
constants in the CDE ring fragment 3.
at least the F ring system, remained to be demonstrated. In
addition, we have previously addressed the synthesis of the
nonanomeric AB ring system of the PTXs, and the compat-
ibility of the DE ring synthesis with this sequence would be
highly desirable. Ideally, we would like to include the
nonanomeric AB spiroketal unit with the C ring building
block (the ABC + F f ABCDEF strategy, Scheme 2). To
lation5 under carefully optimized reaction conditions6 gave
access to lactone 11 with useful levels of regioselectivity
(4:1) and 98% ee.7 Repeated reaction cycles afforded gram
quantities of lactone 11.
The bishomoallylic alcohol 11 was epoxidized using a
combination of catalytic VO(acac)2 and cumene hydroper-
oxide (CHP).8 Under these conditions, the intermediate epoxy
alcohol readily cyclized to give the 2,5-trans substituted
tetrahydrofuran 12 as the major product (dr ) 5:1).9 The
stereochemistry of the product could readily be predicted
by the Kishi model.8b The stereochemistry of the product
was assigned by key NOE correlations observed in 12 and
the benzyl ether10 derivative 13 (Scheme 3).
Scheme 2. Two Different Strategies for the Construction of the
ABCDEF Ring System of PTX2 and Structures of Potential
Building Blocksa
Lactone 13 was transformed into the desired ketone 5 in a
four-step sequence (Scheme 4): (1) conversion into Weinreb
amide 14, (2) Ley oxidation11 of the secondary alcohol, (3)
Wittig olefination of the crude ketone, and (4) treatment of the
Weinreb amide with methyl magnesium chloride.
(7) A benzoate derivative was used for ee determination (see Supporting
Information).
(8) (a) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973,
95, 6136–6137. (b) Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.;
Smith-Palmer, T.; Kishi, Y. J. Am. Chem. Soc. 1978, 100, 2933–2935. (c)
Hashimoto, M.; Harigaya, H.; Yanagiya, M.; Shirahama, H. J. Org. Chem.
1991, 56, 2299–2311. For a recent review, see: (d) Hartung, J.; Greb, M.
J. Organomet. Chem. 2002, 661, 67–84.
(9) The use of CHP instead of TBHP and the presence of molecular
sieves greatly improved the reproducibility of this reaction, but no change
in the diastereoselectivity was observed.
(10) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun. 1981,
1240–1241.
(11) Griffith, W. P.; Ley, S. V.; Whitecombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625–1627.
aPg ) protecting group, M ) metal, X ) leaving group.
(12) (a) Ukaji, Y.; Kanda, H.; Yamamoto, K.; Fujisawa, T. Chem. Lett.
1990, 597–600. (b) Ruano, J. L. G.; Tito, A.; Culebras, R. Tetrahedron
1996, 52, 2177–2186.
(13) The use of excess MeTi(OiPr)3 gave finally in all cases reproducible
results.
test the viability of this strategy, the stability of the nonanomeric
AB spiroketal unit to the DE ring ketalization conditions must
be tested in a realistic system bearing the F ring.
Synthesis of the F ring building block 5 commenced with
ring opening of easily accessible γ-vinyl butyrolactone 82
with methallylsilane 93 in the presence of Meerwein’s salt
to give diene 10 in good yield as a single isomer (Scheme
3).4 In the next step, a regioselective asymmetric dihydroxy-
(14) Presumably, the presence of additional chelating groups (benzyl
ether, two THF ring units) in 17 interferes with the reaction.
(15) Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980, 807–
810.
(16) For a review of nonanomeric spiroketals, see: Aho, J. E.; Pihko,
P. M.; Rissa, T. K. Chem. ReV. 2005, 105, 4406–4440.
(17) ∼50% of the isomerization of 20 to 21 occurred within 5 min
(see Supporting Information for details). For the synthesis and charac-
terization of 20 and 21, see: Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6,
3849–3852.
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