Natural product synthesis enol triflates

Scheme 10. Synthesis of natural product from enol triflate. (Continued)...

Luker,T. Hiemstra, H., and Speckamp, W.N. 1997. Total synthesis of desoxoprosophylline application of a lactam-derived enol triflate to natural product synthesis. J Org Chem 62, 3592-3596. 

Treatment of ketone (69) with excess amounts of t-BuMe2SiOTf and bis[(k)-l-phenylethyl]amine ((i )-BPEA) gives tricyclic silyl aldolate (70) with moderate enantioselectivity [104]. The formation of (70) can be explained by the enol silylation to (71) followed by a tandem Michael-aldol reaction. The asymmetric induction by the chiral amine occurs in the enol silylation (Scheme 9.40). The combined use of silyl triflates and amines has been applied to an intramolecular aldol reaction for natural product synthesis [105]. 

Mannich and related readions provide one of the most fundamental and useful methods for the synthesis of p-amino carbonyl compounds, which constitute various pharmaceuticals, natural products, and versatile synthetic intermediates.1271 Conventional protocols for three-component Mannich-type readions of aldehydes, amines, and ketones in organic solvents indude some severe side reactions and have some substrate limitations, espedally for enolizable aliphatic aldehydes. The dired synthesis of P-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view. Our working hypothesis was that aldehydes could read with amines in a hydro-phobic reaction fidd created in water in the presence of a catalytic amount of a metal triflate and a surfactant to produce imines, which could then read with hydrophobic silyl enolates. 

Although the coupling of aiyl halides with alkenes (commonly referred to as the Heck reaction) was first reported more than 25 years ago [ 1 ], only in the past decade has its enormous synthetic potential been realized [2], Within that time, the reaction has been extended to many substrates, including vinyl iodides and bromides and enol triflates. Moreover, the intramolecular variant has become one of the more important reactions for the formation of carbon-carbon bonds and has emerged as a premier method for the construction of quaternary carbon centers. The ability of intramolecular Heck reactions to reliably fashion carbon-carbon bonds in polyfunctional molecules has led to wide application of this reaction at the strategy level for the synthesis of complex natural products [2g],... 

The structurally novel antimitotic agent curacin A (1) was prepared with an overall yield of 2.5 % for the longest linear synthesis. Three of the four stereogenic centers were built up using asymmetric transformations one was derived from a chiral pool substrate. Key steps of the total synthesis are a hydrozirconation - transmetalation protocol, the stereoselective formation of the acyclic triene segment via enol triflate chemistry and another hydrozirconation followed by an isocyanide insertion. For the preparation of the heterocyclic moiety of curacin A (1) the oxazoline - thiazoline conversion provides efficient access to the sensitive marine natural product. 

The norephedrine-derived Masamune asymmetric aldol reaction was utilized in the total synthesis of (+)-testudinariol A (12), a triterpene marine natural product that possesses a highly functionalized cyclopentanol framework with four contiguous stereocenters appended to a central 3-alkylidene tetrahydropyran6 (Scheme 2.2f). The norephedrine-derived ester 13 was enolized with dicyclo-hexylboron triflate and triethylamine in dichloromethane and then treated with 3-benzyloxypropanal to afford the aldol adduct (14) as a 97 3 mixture of anti/syn diastereomers in 72% yield. Diastereoselectivity within the anti -manifold was 90 10. Protection of alcohol as the methoxyethoxymethyl (MEM) ether followed by conversion of the ester to an aldehyde by LiAlELt reduction and subsequent Swem oxidation gave the aldehyde 16 in 64% yield over three steps. 

The Nazarov cyclization has been featured in a variety of synthetic endeavors involving both natural and unnatural products. In the area of polyquinane natural products ( )-hirsutene (88), ( )-mod-hephene (89), ( )-silphinene (90), ( )-A 2)-capnellene (91) and ( )-cedrene, have all been prepared (Scheme 37). The synthesis of (91) is noteworthy in the iterative use of the silicon-directed Nazarov cyclization. TIk divinyl ketones were constructed by the carbonylation-coupling of enol triflates (92) and (95) with the -silylvinylstannane (Scheme 38). llie diquinane (94), obtained from Nazarov cyclization of (93), was transformed into enol triflate (95) which was coupled with the -silylvinylstaimane as before. Silicon-directed Nazarov cyclization of (96) was highly diastereoselective to provide the cis,anti,cis isomer of (16). The synthesis was completed by routine manipulations. 

Application of the external chiral boron reagent (90) in the totd synthesis of bryostatin, a natural product, is shown in Scheme 45. The convergent approach adopted involves coupling of the boron enolate derived from (111) with aldehyde (112). The reaction mediated by an achiral boron reagent (Et2BOTf) provides only a 2 1 preference for the formation of the desired isomer (115) in adduct (113). The use of chiral (2/ ,5 )-dimethylborolanyl triflate in this reaction increases the selectivity to a 6 1 preference as... 

Since the discovery of Pd-catalyzed carbonylation of aryl, vinyl, and benzyl halides by Heck in 1974, this reaction has been used for the synthesis of ester, amide, acid, and acid anhydride. We can nse enol triflate, aryl Iriflate, aniUne derivatives, and vinyl silane as the pseudo aryl or vinyl halide. This reaction has now been further extended for the synthesis of aldehyde and ketone by combination with transmetalation. These reactions have widely been used in organic syntheses, especially the syntheses of biologically active substances in the field of fine chemistry and the syntheses of natural products. 

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