11. Deprotection of silyl ether and Dess-Martin oxidation
gave aldehyde 7 in 46% overall yield for the five-step
sequence. Allylsilane 8, the coupling partner of 7 in the
proposed Hosomi-Sakurai reaction, was prepared from
aldehyde 12 in three steps: (i) dibromomethylenation,9 (ii)
Kumada-Tamao-Corriu coupling with TMSCH2MgCl, and
(iii) protodesilylation of the resulting bisallylsilane.10 The
SnCl4-promoted Hosomi-Sakurai reaction of 7 with 8 gave
the desired 13S in 47% yield and its isomer 13R in 42%
yield, which was converted to 13S in 65% yield by
Mitsunobu reaction and methanolysis of the resulting acetate.
Conversion of 13S to 6 entailed the efficient five-step
sequence of the following transformations proceeding in 76%
overall yield: 1-ethoxyethyl ether protection of the secondary
alcohol, removal of the TBDPS group and TEMPO oxidation
of the derived primary alcohol to the corresponding aldehyde,
two-carbon Wittig homologation to the (E)-R,ꢀ-unsaturated
ester, and hydrolysis of the ethoxyethyl ether.
acetylene gave (3Z,5E)-3-bromo-3,5-dienyne 16. Introduction
of the methyl group in 16 via the Kumada-Tamao-Corriu
coupling proceeded with the anticipated inversion7 of olefin
geometry, providing the desired trisubstituted dienyne 9 as
the major component of a 4:1 isomeric mixture. The terminal
TMS-acetylene unit was then converted to the corresponding
methylesterbywayofahydroboration-oxidation-esterification
sequence to give 17 in 75% overall yield. Deprotection of
the TIPS ether, introduction of diethyl methylphosphonate,
and a two-step oxidation of the primary alcohol completed
the synthesis of 5 in 32% overall yield from 17.14
The synthesis of (-)-dactylolide was completed as shown
in Scheme 4. To our delight, the HWE reaction of aldehyde
Scheme 4. Synthesis of (-)-Dactylolide
The THP ring of 14 was constructed by the intramolecular
O-Michael reaction. Originally, standard cyclization condi-
tions such as t-BuOK in THF11 gave poor yields of cyclized
products. Switching to LHMDS as a base and running the
reaction below -40 °C predominantly gave the undesired
trans isomer over the cis isomer in a 2: 1 ratio in 60-79%
yield.12 However, raising the reaction temperatures above
-10 °C resulted in the formation of thermodynamic cis
isomer (20%) rather than the trans isomer (8%), and acyclic
conjugated ester 6′ (66%) was produced by the isomerization
of the exo double bond. In the end, the optimized reaction
conditions (LHMDS 0.1 equiv, TMEDA 1.2 equiv; toluene,
rt, 30 min) provided a 1.8:1 cis/trans mixture of the two
tetrahydropyrans, readily separable by chromatography, in
94% combined yield.13 Gratifyingly, exposure of 14 to
DIBALH (3 equiv) resulted in reduction of the ester moiety
to the aldehyde with concomitant removal of the pivaloate
group to give hydroxy aldehyde 4 in 92% yield.
4 and ꢀ-ketophosphonate 5 successfully forged the C8-C9
bond in the presence of unprotected hydroxy group and
carboxylic acid moieties; seco acid 18 was thus obtained in
Preparation of ꢀ-ketophosphonate 5 is summarized in
Scheme 3. Dibromomethylenation9 of aldehyde 15 followed
by the stereoselective Sonogashira coupling with TMS-
(3) Another example of antipodal natural products of marine orgin was
reported in the case of (+)-wistarin and (-)-wistarin, see: (a) Gregson,
R. P.; Ouvrier, D. J. J. Nat. Prod. 1982, 45, 412–414. (b) Fontana, A.;
Fakhr, I.; Mollo, E.; Cimino, G. Tetrahedron: Asymmetry 1999, 10, 3869–
3872.
Scheme 3. Synthesis of C1-C8 Fragment 5
(4) Synthesis of (-)-1: (a) Hoye, T. R.; Hu, M. J. Am. Chem. Soc. 2003,
125, 9576–9577. Synthesis of (+)-1: (b) Smith, A. B., III; Safonov, I. G.;
Corbett, R. M. J. Am. Chem. Soc. 2001, 123, 12426–12427. (c) Smith, A. B.,
III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2002, 124, 11102–
11113.
(5) Synthesis of (-)-2: (a) Ding, F.; Jennings, M. P. Org. Lett. 2005, 7,
2321–2324. (b) Louis, I.; Hungerford, N. L.; Humphries, E. J.; McLeod,
M. D. Org. Lett. 2006, 8, 1117–1120. (c) Ding, F.; Jennings, M. P. J. Org.
Chem. 2008, 73, 5965–5976. Synthesis of (+)-2: (d) Smith, A. B., III;
Safonov, I. G. Org. Lett. 2002, 4, 635–637. (e) Aubele, D. L.; Wan, S.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485–3488. (f) Sanchez,
C. C.; Keck, G. E. Org. Lett. 2005, 7, 3053–3056.
(6) For an application of the reverse order approach to macrolide
synthesis, i.e., ester formation followed by intramolecular macrolactoniza-
tion, see: Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R. J. Am. Chem. Soc.
1982, 104, 2030–2031.
(7) Uenishi, J.; Matsui, K.; Ohmi, M. Tetrahedron Lett. 2005, 46, 225–
228.
(8) Vinyllithium 10 was generated from the corresponding tributylvinyl-
stanne with BuLi. The stanne, see: Uenishi, J.; Kawahama, R.; Yonemitsu,
O.; Wada, A.; Ito, M. Angew. Chem., Int. Ed. 1998, 37, 320–323.
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