Graduate Thesis Or Dissertation
 

Stereocontrolled Synthesis of Allenes by Eliminative Cross-Coupling of Carbenoids

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  • The bimolecular reaction of two carbenoid species resulting in the formation of a carbon-carbon double bond (pi-system), referred to herein as carbenoid eliminative cross-coupling (CEXC), involves a series of three fundamental steps: (i) ate-complex formation (transmetalation), (ii) 1,2-metalate rearrangement, and (iii) beta-elimination. All three steps are stereospecific and so the stereochemical outcome of a CEXC transformation is in principle programmed by defining the stereochemical configurations of the two reacting carbenoid species and by controlling the mode of beta-elimination (syn or anti). Herein, studies exploring the CEXC concept for the stereocontrolled generation of allenes by the combination of an sp3-hybridized alkyl-type carbenoid [with defined absolute stereochemical configuration, (R) or (S)] with an sp2-hybridized alkylidene-type carbenoid [with defined relative stereochemical configuration, (E) or (Z)] are described. In the first approach to allenic systems studied (Chapter 2), configurationally stable sp3-hybridized alkyl carbenoids with nucleophilic character ('Hoppe-type' C-lithiated N,N-diisopropyl O-alkyl carbamates) were combined with a variety of sp2-hybridized alkylidene carbenoids with potential electrophilic character generated in situ by carbometalation of alkyne precursors possessing a terminal nucleofugal group (e.g., RCCX, X = S(O)nR´ n = 1 or 2). Alkylidenes generated from alkynyl sulfones by carbo-zincation, -alumination, and -zirconation, did not result in allene formation; however, experiments involving the corresponding copper(I) alkylidene species led to the desired allenes albeit with poor stereochemical fidelity. For example, carbocupration of (4-methoxyphenyl)ethynyl 4-tolyl sulfone with n-BuCu (generated by addition of n-BuLi to CuI) at –78 °C in Et2O, gave a putative Cu(I) alkylidene [(E)-ArBuC=CTsCu] that was combined with lithiated carbamate (R)-PhCMe(Li)OCb [Cb = CON(i-Pr)2] to lead, after warming to rt (16 h), to the anticipated allene product, 4-(4-methoxyphenyl)-2-phenylocta-2,3-diene, in modest yield (38%) but with low enantiomeric excess (17% ee, absolute configuration of major enantiomer not determined). An otherwise identical experiment involving the same Cu(I) alkylidene and the nucleophilic enantioenriched alkyl carbenoid generated by s-BuLi•(+)-sparteine mediated lithation of Ph(CH2)3OCb (Et2O, –78 °C), afforded 5-(methoxyphenyl)-1-phenylnona-3,4-diene in 45% yield and 8% ee. In the second and more successful approach to allenes investigated (Chapter 4), the polarity of the reacting carbenoid systems was inverted and nucleophilic cuprate-based alkylidenes, generated by carbocupration of thioalkynes followed by metalate formation [i.e., RCCSMe + R´Cu to RR´C=CS(Me)Cu to RR´C=CS(Me)CuBuLi], were combined with alpha-carbamoyloxyalkylboronates [RCH(OCb)Bneo, Bneo = B(OCH2CMe2CH2O)] representing shelf-stable electrophilic alkyl carbenoids. In a representative example of the optimized process identified, addition (Et2O-PhMe, –78 °C) of (R)-Ph(CH2)CH(OCb)Bneo to the putative cuprate [(E)-PhBuC=C(SMe)Cu•BuLi] generated in situ by addition of n-BuCu and then n-BuLi to PhCCSMe, gave, after warming to rt and a short period of heating (75 °C, 30 min), allene (aR)-1,5-diphenylnona-3,4-diene in 57% yield and 84% ee. The absolute stereochemical configuration of the allene product suggests a predominantly anti-mode elimination stage. A range of different trisubstituted allenes were generated by this process [RR´C=C=CH(CH2)2Ph, R = various aryl, alkyl; R´ = Me, n-Bu, i-Pr) but efficacy and stereochemical fidelity were highly substrate dependent (15 examples, 30-88% yield, 10-95% ee).
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