Water Overcomes Methyl Group Directing Effects in Epoxide-Opening Cascades

Abstract

Water is an effective promoter of the endo-selective opening of trisubstituted epoxides, enabling related cascades leading to a variety of substituted ladder polyether structures. When used in conjunction with a tetrahydropyran-templated nucleophile, water can overcome the powerful electronic directing effect of a methyl substituent at either site of the epoxide, making water a uniquely versatile medium and promoter for epoxide opening.In 1985 Nakanishi advanced a concise and appealing proposal for the biosynthesis of the ladder polyether family of natural products, a synthesis that culminates in a cascade of regio-and stereoselective epoxide openings (Scheme 1). 1 Our group recently reported an emulation of the Nakanishi hypothesis, wherein water serves as the superior promoter of endo-selective epoxide-opening cascades. 2 This earlier account was limited to cascades of trans-disubstituted epoxides, and we herein report that water (as solvent) is also a simple and general solution for cascades involving trisubstituted epoxides. Overcome by this method is the well documented, strong directing effect that methyl (Me) groups have on epoxide ring-opening reactions, 3 and thus enabled is the rapid assembly of multiple patterns of substituted ladder polyether subunits. An angular Me group is the only substituent other than hydrogen (H) observed at ladder polyether ring junctions, and every structure in this large family of natural products possesses at least one Me group. Nature has conceived two variations of this substitution, requiring two chemically quite different kinds of (E)-trisubstituted epoxides in the corresponding polyepoxide precursors. For example, in the hypothesized precursor (1) to brevetoxin B (Scheme 1), Me groups are observed both and 4 to the internal nucleophile; the putative cascade must tolerate both possibilities. In fact, nearly all ladders bearing more than one Me group, including the brevetoxins, maitotoxin, gambierol, and gymnocin B, are proposed to arise from similar polyepoxides bearing an "out-of-register" mixture of both distally and proximally substituted epoxides.The crux of the problem is that the Me group is generally a strong director of epoxide-opening regioselectivity, particularly under acid catalysis. Valuable methods for endo-selective opening, epitomized by those developed by the McDonald group,3a-c take advantage of this directing effect, 3 but these necessarily accommodate only Me substitution. Moreover, distal Me substitution at every epoxide is generally vital for high regioselectivity and yield. 5 The endo-selective opening of epoxides with a Me or other simple alkyl group 6 to the pendent nucleophile has not been documented except under enzyme catalysis7 or when a stronger directing group at the distal site of the epoxide was used. 8 We conjectured that tetrahydropyran (THP)-templated, water-promoted cascades might prove relatively insensitive to the electronic effects and afford a general solution to the problem of Me substitution, particularly for the challe...

Biomimetic Synthesis of Polyether Natural Products via Polyepoxide Opening

“…Extending this work further, the Jamison group demonstrated that methyl substituents on epoxides are also tolerated in aqueous cascades (Scheme 15.21b) [201,202]. Under aqueous conditions, diepoxides 279 and 280, which incorporate methyl substituents at the positions of endo attack afforded the triads 282 and 283 (Scheme 15.21b).…”

“…A methyl group on a trisubstituted epoxide can be situated in a position where its directing effect promotes endo-opening under acidic conditions (as in 273, Scheme 15.21a) or in a position that would normally promote exo-selective epoxide opening under the same conditions (as in 274, Scheme 15.21a). To incorporate methyl substituents at the ring junctions of the final products in epoxide-opening cascades, the Jamison group, in an immediate extension of their work on aqueous directing group-free endo-selective epoxide openings, prepared and evaluated cyclization reactions of templated epoxy alcohols 273 and 274, which feature both types of methyl substitution on the epoxide (Scheme 15.21a) [201,202]. Acid-catalyzed cyclizations of epoxy alcohol 273 proceeded with high endo selectivity due to the electronic effect of the methyl substituent at the endo site of attack on the epoxide.…”

“…In addition to achieving high endo selectivity, aqueous cyclizations circumvent side reactions associated with other activation conditions, such as the rearrangement of epoxide 273 to a iso-propyl ketone via 1,2-hydride shifts under acidic conditions. [201].…”

Lessons and revelations from biomimetic syntheses

“…The kinetic preference for epoxide-opening cascades lies in favor of the exo products, instead of the endo moieties of the ladder poly cyclic ethers 39 . Directing epoxide-opening cascades toward the endo products in the laboratory is made more complex by the inclusion of methyl groups at the ring junctions-seen in every member of the family 40 . This contra-Baldwin challenge, as well as the complex structures and biological activities of this class of polyethers, has enticed many to develop general methods for their preparation 11,39 .…”

Hydroxyl-Substituted Ladder Polyethers via Selective Tandem Epoxidation/Cyclization Sequence

“…5 Templating 6 allows for highly-selective THP formation without the need for directing groups, and we have reported the use of a preformed THP 7 or 1,3 dioxane 8 in water-promoted cyclizations. This approach has enabled the synthesis of THPs bearing methyl substituents at the ring junctions 9 as well as marine ladder polyether fragments via polyepoxide cascades. 7b …”