Graduate Thesis Or Dissertation
 

Stereospecific Synthesis of Stereotriad Motifs and Alkenes Using Enantioenriched sp³-Hybridized Carbenoids

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  • Enantioenriched sp³-hybridized carbenoid reagents CR1R2MX (X = nucleofuge, M = electrofuge) of different types were investigated for the synthesis of polysubstituted alkyl chains by iterative stereospecific reagent-controlled homologation (StReCH) and for the stereospecific connective synthesis of alkenes by eliminative cross-coupling. In the first part, putative enantioenriched α-chloroalkyllithiums (CHRLiCl) were employed for double and triple StReCH of B-alkyl boronic esters to synthesize molecules containing multiple contiguous stereogenic centers. The StReCH process proceeds by a pair of fundamental steps both of which are inherently stereospecific: (i) electrophilic substitution, and (ii) 1,2-metallate rearrangement. In the main finding, all distinct diastereoisomers of a contiguous stereotriad motif were separately targeted by triple chain extension of B-phenethyl boronic esters using four unique presentation sequences of enantiomorphs of 1-[²H]-1-chloro-2-(1,3-dioxolan-2-yl)ethyllithium. The (R)- or (S)-configured chloroalkyllithium reagents were generated by sulfoxide-lithium exchange from the appropriate scalemic p-tolyl chloroalkyl sulfoxides using phenyllithium (THF, -78 °C). Stereotriad synthesis was accomplished in a single reaction vessel [7-19% yield, typical dr ≥ 74 (target):26 (Σ all other isomers)] and implemented by a simple algorithm consisting of reagent charging and temperature cycling events. In the second part, enantioenriched lithiated carbamates [CArR²Li(O₂CNiPr₂)] were combined with enantioenriched α-carbamoyloxyboronates [CHR³[B(OR)₂](O₂CNiPr₂)] to achieve alkene synthesis by a cross-coupling process involving a sequence of three stereospecific fundamental steps: (i) electrophilic substitution, (ii) 1,2-metallate rearrangement, and (iii) β-elimination. By this sequence, stereochemical information encoded within the two carbenoid building blocks is translated into any desired configuration of the targeted alkene [(E)- or (Z)-isomer] as determined by choice of carbenoid stereochemical pairing, either like [i.e., (R) + (R) or (S) + (S)] or unlike [i.e., (R) + (S)], and elimination mechanism type (syn or anti). Herein, the eliminative cross-coupling concept was established for the synthesis of two exocyclic olefin systems, α-alkylidenyltetralins and α-alkylidenylindanes. For example, a like combination of (S)-α-[(diisopropylamino)carbonyloxy]-α-lithioindane (97% ee) with (S)-2-[1-[(diisopropylamino)carbonyloxy]-3-phenylpropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (97% ee) in diethyl ether at –78 deg C lead to (E)-(3-phenylpropylidenyl)-indane in 50% yield and E:Z > 98:2 after warming to rt and treatment with NaOMe. By contrast, the analogous unlike eliminative cross-coupling reaction (i.e., (R)-lithiated carbamate with (S)-boryl carbamate) gave (Z)-(3-phenylpropylidenyl)-indane in 25% yield and E:Z = 14:86.
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