With efficient routes to 8 and 9 in hand, we next
examined the coupling of 8 and 9 through the 1,4-syn aldol
reaction (Table 1). The aldol addition of 9 to 8 (c-Hex2BCl,
Et3N, Et2O)14 provided the desired β-hydroxy ketone 15
(55%), but with poor stereoselectivity (dr = 1.5:1, entry 1).
The 1,4-syn aldol reaction of 8 and 9 at ꢀ78 °C in the
presence of (ꢀ)-Ipc2BCl14 improved the stereoselectivity of
the reaction (dr = 3:1, entry 2). Surprisingly, a higher
reaction temperature and prolonged reaction time further
improved the stereoselectivity of the 1,4-syn aldol reaction
(dr = 9:1, entry 4).15 Despite the broad utility, the 1,4-syn
aldol reaction has rarely been applied in the stereoselective
synthesis of natural products.15,16
tandem oxidation/oxa-Michael reaction (Scheme 4). The
tandem oxidation/oxa-Michael reaction20,21 of 5 (MnO2,
CH2Cl2, 25 °C, 8 h) stereoselectively provided the desired
2,6-cis-tetrahydropyran aldehyde 20 with excellent yield
and stereoselectivity (90%, dr >20:1).11 One-carbon
homologation of aldehyde 20 was achieved by the Best-
mann reagent.22
Scheme 4. Synthesis of 2,6-cis-Tetrahydropyran Aldehyde 20
through the Tandem Oxidation/Oxa-Michael Reaction
1,3-anti Reduction,17 PMB-acetal protection, and DI-
BAL-reduction provided a mixture of 18 and 180 (3:1,
Scheme 3).11,18 MOM-protection, acetonide deprotection,
and epoxide formation19 set the stage for the installation of
the second 2,6-cis-tetrahydropyran moiety.
Scheme 3. Synthesis of Epoxide 6
Having successfully assembled both the 2,6-cis-tetrahy-
dropyran moieties in 1, we embarked on the final stage of
the synthesis of 1 (Scheme 5). The Suzuki coupling
reaction23 of alkyne 4 with triflate 324 provided the
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(22) Roth, G. J.; Liepold, B.; Muller, S. G.; Bestmann, H. J. Synthesis
2004, 59–62.
The coupling reaction of epoxide 6 and dithiane 720
proceeded smoothly to provide allyl alcohol 5 for the key
(23) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483. (b)
Soderquist, J. A.; Matos, K.; Rane, A.; Ramos, J. Tetrahedron Lett.
1995, 36, 2401–2402. (c) Furstner, A.; Seidel, G. Tetrahedron 1995, 51,
11165–11176. (d) Furstner, A.; Nikolakis, K. Liebigs Ann. 1996, 2107–
2113.
€
€
(24) Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.;
Yonehara, M.; Hiroya, K.; Sakamoto, T. Org. Lett. 2006, 8, 5517–5520.
(25) The Sonogashira reaction of alkyne 23 and triflate 3 provided
only the homocoupling product of 23. Other coupling reactions (the
Negishi, the Stille, and the Heck reaction) did not provide the desired
coupling product.
(13) Koert, U.; Wagner, H.; Pidun, U. Chem. Ber. 1994, 127, 1447–1457.
(14) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,
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(15) Paterson, I.; Oballa, R. M. Tetrahedron Lett. 1997, 38, 8241–8244.
(16) Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.; Campos, K. R. J.
Am. Chem. Soc. 1999, 121, 6816–6826.
(17) Evans, D. A.; Chapman, K. T.; Carreira, E. H. J. Am. Chem.
Soc. 1988, 110, 3560–3578.
(18) The configuration of the C9 stereocenter of 18 was determined
using the Kakisawa’s procedure, see: Ohtani, I.; Kusumi, T.; Kashman,
Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096.
(19) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203.
(20) Kim, H.; Park, Y.; Hong, J. Angew. Chem., Int. Ed. 2009, 48,
7577–7581.
(21) (a) Kim, H.; Hong, J. Org. Lett. 2010, 12, 2880–2883. (b) Lee, K.;
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