Investigation of the Deprotonative Generation and Borylation of Diamine-Ligated α-Lithiated Carbamates and Benzoates by in Situ IR spectroscopy

Abstract

Diamine-mediated α-deprotonation of O-alkyl carbamates or benzoates with alkyllithium reagents, trapping of the carbanion with organoboron compounds, and 1,2-metalate rearrangement of the resulting boronate complex are the primary steps by which organoboron compounds can be stereoselectively homologated. Although the final step can be easily monitored by 11B NMR spectroscopy, the first two steps, which are typically carried out at cryogenic temperatures, are less well understood owing to the requirement for specialized analytical techniques. Investigation of these steps by in situ IR spectroscopy has provided invaluable data for optimizing the homologation reactions of organoboron compounds. Although the deprotonation of benzoates in noncoordinating solvents is faster than that in ethereal solvents, the deprotonation of carbamates shows the opposite trend, a difference that has its origin in the propensity of carbamates to form inactive parasitic complexes with the diamine-ligated alkyllithium reagent. Borylation of bulky diamine-ligated lithiated species in toluene is extremely slow, owing to the requirement for initial complexation of the oxygen atoms of the diol ligand on boron with the lithium ion prior to boron–lithium exchange. However, ethereal solvent, or very small amounts of THF, facilitate precomplexation through initial displacement of the bulky diamines coordinated to the lithium ion. Comparison of the carbonyl stretching frequencies of boronates derived from pinacol boronic esters with those derived from trialkylboranes suggests that the displaced lithium ion is residing on the pinacol oxygen atoms and the benzoate/carbamate carbonyl group, respectively, explaining, at least in part, the faster 1,2-metalate rearrangements of boronates derived from the trialkylboranes.

Synthesis of the C18-C27 fragment of georatusin

“…Alcohol 8 was then converted into carbamate 9 using established conditions. 21,22 Fragment coupling of the resulting carbamate 9 with C2-symmetric 1,3-bis(boronic ester) 3 via the lithiation-borylation protocol gave the desired mono-product 10 in 17% yield (Scheme 3). a. CbCl, Et3N, C2H4Cl2, 70 °C, o/n, 94%; b. sBuLi, (+)-sparteine, Et2O, −78 °C, 5 h, then 3, MgBr2•OEt2, Et2O, −78 °C to Δ, o/n, 17%, dr ≥ 95:5 (Cb=N,N-diisopropylcarbamoyl).…”

“…The use of different bases did not lead to lithiation or in the case of iPrLi only to moderate yields. Therefore, we switched to the corresponding TIB ester 11 21,22 which could be completely lithiated under the standard conditions. With an effective lithiation strategy in hands, we again performed the fragment coupling and obtained the desired 1,4-bis(boronic ester) 10 in 41% yield.…”

“…23,24 Then, the (R)-Roche ester (18) was transformed into iodide 19 in a known three step sequence. 25 A literature known sequence consisting of Myers alkylation and reductive removal of the auxiliary gave us the corresponding alcohol 26 which was then converted into middle fragment 13 using a Mitsunobu reaction 22 (Scheme 5). a. TBSCl, imid., CH2Cl2, 0 °C to rt, 2.5 h, 95%; b. DiBAl-H, CH2Cl2, −78 °C to −40 °C, 3.5 h, 92%; c. I2, PPh3, imid., CH2Cl2, 0 °C to rt, 2.5 h, 82%; d. LDA, LiCl, 19, THF, −78 °C to rt, o/n, dr ≥ 95:5; e. LDA, BH3•NH3, THF, 0 °C to rt, 4.5 h, 81% o2s; f. DIAD, TIBOH, PPh3, THF, 0 °C to rt, o/n, 87% (TBS=tert-Butyldimethylsilyl, imid=imidazole, LDA=lithium diisopropylamide).…”

“…So, a two-step sequence of TIPS-protection and selective TBS-deprotection led to primary alcohol 22 (Scheme 6). With alcohol 22 in hands, next in line was another TIB-esterification 22 but unfortunately the best result we could achieve was a yield of 31% (Table 3). Higher temperatures for the Mitsunobu reaction as well as usage of TIB chloride led to decomposition.…”

The Total Synthesis of Chondrochloren A

“…[9] The configuration was confirmed at this point through an X-ray analysis of the TBS-protected secondary alcohol 16. Reductive removal of the chiral auxiliary and introduction of the TIB-group via a Mitsunobu reaction [10] provides the C7-C14 segment (3) of chondrochloren A (1) in 42 % yield over 7 steps ready to undergo a 1,2metallate rearrangement for coupling with the middle segment 12 (Scheme 4).…”