· (MW 460.13)
(reagent used as a versatile precursor to a variety of highly substituted hydropyrans with multiple stereocenters in high enantiopurity)
Physical Data: mp 203-204.5 °C with decomposition.
Solubility: soluble in methylene chloride, THF, diethyl ether, and most organic solvents.
Form Supplied in: yellow solid; prepared in multigram scale.1
Handling, Storage, and Precautions: can be kept in a vial with a screw cap in a refrigerator for a few years. Incompatible with strong acid and strong oxidizing reagents.
Enantiocontrolled [5 + 2] Cycloadditions
The title compound 1 undergoes a novel [5 + 2] cycloaddition at 2,6-positions with various electron-deficient acyclic or cyclic alkenes in the presence of 10-120% of a Lewis acid, EtAlCl2 (1). The reactions proceed at room temperature in good-to-excellent yields with an exo selectivity [electron withdrawing group (EWG) at exo position]. Only one activating group (EWG = CHO, COOMe, COMe, CONR2, etc.) was required on the alkene. Acrylonitrile and an activated alkyne also react but with lower yields. Complex 2 is obtained in high enantiopurity (>95% ee) from enantioenriched 1 (>95%) despite an observed racemization of the starting complex in the presence of EtAlCl2.
Three general demetallation protocols have been developed to provide a number of oxa-bicyclo[3.2.1]octane rings of high enantiopurity from complex 2 (1, 2). Under acidic conditions (HCl/MeCN or TFA/CH2Cl2), protodemetallation takes place to give compound 3 with the stereocontrolled introduction of a new allylic chiral center. Upon treatment with iodine, complex 2 gives the allylic iodide 4 in a stereocontrolled fashion. Oxidative demetallation with ceric ammonium nitrate (CAN) gives the conjugated diene 5, which could be further functionalized if desired. When 2a of 97% ee is used, demetallation products 3a,4a,5a are obtained in 97% ee.
Enantiocontrolled Synthesis of 2,3,6-Trisubstituted Hydropyrans
When treated with bromine at -78 °C, briefly followed by quenching with MeMgBr or NaOMe, compound 1 gives the symmetrical trisubstituted pyranyl molybdenum complex 7,8 in 98-100% yields (3), but selective introduction of two different groups at 2,6-positions is unsuccessful.2
However, the 2-methoxy group of complex 8 can be selectively (>84:1 selective over the 6-methoxy group) removed by treating with Ph3CPF6 to give intermediate 9, which is conveniently converted into complex 10 with a nucleophile R1M. The 6-methoxy group can then be replaced by another nucleophile R2M in a two-step sequence (4). The nucleophiles R1M and R2M can be Grignard reagents, lithium reagents, enolates, cyanide, and methoxide, and the overall yields from 8 to 11 are 37-90% after four easy transformations. Highly enantiopure 11 (98% ee) is obtained starting from enantioenriched 1 (98% ee).
The method has been successfully applied to the preparation of a key intermediate 13 that has been used by Kende for the synthesis of ambruticin.3 Complex 11a is obtained from 1 (98% ee) in 83% yield with 98% ee. Demetallation of 11a under photochemical conditions followed by hydrolysis provides 13 in 78% yield and 98% ee (5).
- 1. Yin, J.; Liebeskind, L. S., J. Am. Chem. Soc. 1999, 121, 5811.
- 2. Yin, J.; Llorento, I.; Villanueva, L. A.; Liebeskind, L. S., J. Am. Chem. Soc. 2000, 122, 10458.
- 3. Kende, A. S.; Mendoza, J. S.; Fujii, Y., Tetrahedron 1993, 49, 8015.
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