Graduate Thesis Or Dissertation
 

Development of Carbenoid Eliminative Cross-coupling for the Stereocontrolled Synthesis of Trisubstituted Alkenyl Moieties Within Styrenes and 1,3-Dienes

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  • Traditional approaches for the direct preparation of alkenes are unable to fully control either the stereochemical configuration of the carbon-carbon double bond or else the regiochemistry of the substituents surrounding it. The recently introduced concept of carbenoid eliminative cross-coupling (CEXC) offers a remedy to these deficiencies by providing for a connective synthesis of alkenes that is at once both stereospecific and regiospecific. CEXC involves the conjoinment of a pair of enantioenriched sp3-hybridized carbenoids to yield an alkene by a three-step mechanism comprised of: (i) ate-complex formation, (ii) 1,2-metallate rearrangement, and (iii) β-elimination. The stereochemical outcome of a CEXC reaction is determined by the stereochemical pairing of carbenoids, either like [(R)+(R) or (S)+(S)] or unlike [(S)+(R)], and the type of elimination process employed, either syn (thermal) or anti (base mediated). Prior to the work described in this thesis, CEXC had been utilized only for the synthesis of simple trisubstituted styrene-type alkenes by the reaction of lithiated benzylic carbamates with α-carbamoyloxyalkyl boronates. Herein, the application of CEXC to the stereocontrolled synthesis of a biologically active polyfunctional styrene target (a P-glycoprotein inhibitor) is described alongside a novel extension of the methodology to access conjugated dienes (specifically 1,2,4-trisubstituted-1,3-dienes) from appropriate lithiated allylic carbamates and α-carbamoyloxyalkyl boronates. In the first project described, a P-glycoprotein inhibitor, (E)-6,7-dimethoxy-2-[3-(8-methoxychroman-4-ylidene)propyl]tetrahydroisoquinoline ((E)-74), containing an exocyclic trisubstituted alkene that links together non-trivial heterocyclic domains, was envisioned to arise via eliminative cross-coupling between two fully functionalized carbenoids, (R)-HetNCH2CH2CH(OCb)Bneo (79) [HetN = 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl, Cb = C(=O)Ni-Pr2, Bneo = B(OCH2CMe2CH2O)] and (S)-4-[(diisopropylamino)-carbonyloxy]-4-lithio-8-methoxychroman (80). Attempts to access B-carbenoid 79 via a lithiation-borylation sequence were thwarted when it was discovered that lithiation of HetNCH2CH2CH2(OCb) occurs at C1 of the heterocycle rather than adjacent to the carbamate (the related C1-lactam congener lithiated exclusively at C8 of the isoquinoline). To circumvent this regioselectivity issue, a simplified surrogate of 79 lacking the tetrahydroisoquinoline moiety, (R)-TBSOCH2CH2CH(OCb)Bneo ((R)-93), was prepared via borylation of TBSO(CH2)3OCb by treatment with (+)-sparteine/s-BuLi followed by i-PrOBneo (in Et2O, –78 °C). In a diagnostic experiment to establish the enantioselectivity of the borylation reaction, transesterification of (R)-93 with (R,R)-1,2-diphenylethane-1,2-diol (98) and NMR spectral analysis of the resulting product, revealed dr > 97:3, indicating that boronate (R)-93 was highly enantioenriched (a control experiment with (±)-98 gave dr = 50:50). CEXC between B-carbenoid 93 and the chromanyl Li-carbenoid 80 under a variety of reaction conditions proceeded with a stereorandom outcome. This fact was traced to spontaneous low-temperature (–78 °C) racemization of 4-lithio-8-methoxychroman-4-yl carbamate 80 which has unexpectedly low configurational stability. Formal replacement of the 8-MeO group in the chroman nucleus with an 8-Cl substituent suppressed racemization in the corresponding organolithium and CEXC between (R)- or (S)-4-[(diisopropylamino)carbonyloxy]-4-lithio-8-chlorochroman and B-carbenoid (R)-93 proceeded as anticipated in a stereochemically programmable manner. Under optimized conditions, the desired alkene product, (E)-4-[3-[(tert-butyldimethylsilyl)oxy]propyliden-1-yl]-8-chlorochroman ((E)-113), was obtained in 44% yield and E:Z = 97:03 by eliminative cross-coupling between (S)-112 and (R)-93 and employing a syn (thermal) elimination step (i.e., an unlike•syn type CEXC reaction). Alkene product (E)-113 was advanced to P-glycoprotein inhibitor (E)-74 in 38% overall yield by a sequence of four-steps: (i) Pd(0) catalyzed methanolysis of the C8-Cl atom, (ii) desilylation of the side-chain TBS ether, (iii) chlorination of the resulting free hydroxyl-group, and (iv) amination of the resulting alkyl chloride with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. The higher-energy geometrical isomer of the P-glycoprotein inhibitor, (Z)-74, was obtained in an analogous fashion via CEXC product (Z)-113 which was generated by an unlike•anti eliminative cross-coupling between (S)-112 and (R)-93 (45% yield, E:Z = 12:88). In the second project described, the use of allylic carbamates as precursors to Li-carbenoids for CEXC toward 1,3-dienes introduced the added complication of α- (desired) versus γ- (undesired) regioselectivity in lithiation / transmetallation sequences. To establish proof-of-principle for conjugated diene synthesis, 4,7-dimethyl-1-phenylocta-3,5-diene was targeted in all four of its isomeric variations by CEXC between stereodefined-carbenoids-i-PrCH=CHC(OCb)(Li)CH3 (132a) and Ph(CH2)2CH(OCb)(Bneo) (159). Diene (3Z,5E)-160 was obtained in 72% yield and (3E,5E):(3Z,5E) = 5:95 by an unlike•anti eliminative cross-coupling between Li-carbenoid (E,S)-132a (obtained by direct lithiation of the corresponding carbamate with s-BuLi in the presence of TMEDA in Et2O at –78 °C) and B-carbenoid (R)-159. The carbenoids were combined in Et2O at –78 °C and following warming to rt, anti¬-elimination was effected by addition of NaOH and MeOH. An attempt to generate (3E,5E)-160 by an otherwise identical CEXC terminated by a thermal syn elimination step (85 °C in PhMe), gave the diene in a good yield (55%) but with low stereoselectivity (3E,5E):(3Z,5E) = 60:40. The origin of poor stereocontrol was attributed to unwanted anti elimination caused by adventitious basic species present in the reaction mixture. Addition of trimethylborate to this unlike•syn CEXC process prior to thermolysis effectively sequestered the basic species and meant that syn elimination now proceeded without competing anti elimination. By use of this simple device, (3E,5E)-160 was obtained in 73% yield and with excellent stereoselectivity of (3E,5E):(3Z,5E) = 97:3. Interestingly, it was discovered that stereochemical like combinations of Li-carbenoid (E,R)-132a and B-carbenoid (R)-159 gave only very low yields (≤15%) of diene 160 no matter what type of elimination process was attempted. Evidentally, in this case a significant stereochemical mis-matching effect is manifested that resists eliminative cross-coupling from occurring; experiments involving different stereochemical combinations of scalemic and racemic carbenoids supported this hypothesis. The remaining two stereoisomers of the model diene, (3E,5Z)-160 [48% yield, (3E,5Z):(3Z,5Z) = 96:4] and (3Z,5Z)-160 [44% yield, (3E,5Z):(3Z,5Z) = 16:84], were obtained by using unlike combinations of Li-carbenoid (Z,S)-132a and B-carbenoid (R)-159 with either syn [with added protective B(OMe)3] or anti elimination protocols, respectively. Notably, in all four cases above, isomerization of the pre-existing 1,2-disubstituted alkene within Li-carbenoid 132a was not observed to occur. Further to the successful preparation of two additional related conjugated dienes (4-methyl-1-phenylhepta-3,5-diene and 4,7,7-trimethyl-1-phenylocta-3,5-diene) with comparable results, the sterically non-biased trisubstituted alkene moiety of 3-(3-phenylpropyliden-1-yl)cyclohexene was likewise generated by CEXC. For this purpose, B-carbenoid (R)-159 was engaged with (R)- or (S)-3-lithio-3-[(diisopropylamino)carbonyloxy]cyclohexene (132e) and the process terminated by syn (thermal) elimination. In this manner, (3E,5Z)-166 was obtained in 45% yield with E:Z = 90:10 by the unlike•syn CEXC reaction and (3Z,5Z)-166 in 42% yield with E:Z = 13:87 by the like•syn CEXC reaction. Finally, demonstrating that CEXC can be applied to the synthesis of diene moieties within molecules possessing ancilliary stereogenic centers, a model diene representing the C6-C12 domain of the cytotoxic polyketide callystatin A was prepared in either natural (6E,8Z)-configuration [31% yield, (6E,8E):(6E,8Z) = 1:99] or unnatural (6E,8E)-configuration [57% yield, (6E,8E):(6E,8Z) = 99:1] using unlike stereochemical pairings of the relevant carbenoids and anti or syn elimination, respectively.
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