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. 2022 Aug 26;24(33):6208-6212.
doi: 10.1021/acs.orglett.2c02516. Epub 2022 Aug 16.

Synthesis of Tertiary Amines through Extrusive Alkylation of Carbamates

Guoliang Zhang  1 , David Favela  1 , Winston L Chow  1 , Rishab N Iyer  1 , Alexander J Pell  1 , David E Olson  1   2   3
Affiliations

Synthesis of Tertiary Amines through Extrusive Alkylation of Carbamates

Guoliang Zhang et al. Org Lett. .

Abstract

Basic amines are key elements of many biologically active natural products and pharmaceuticals. Given their inherent reactivity, it is often necessary to protect basic amines during target-directed synthesis, which results in wasteful protection/deprotection sequences. We report a step-economical approach enabling the protection of secondary amines as carbamates prior to their conversion to tertiary amines via the formal extrusion of CO2. This method is applied to the synthesis of iboga alkaloids (±)-conodusine A and (±)-conodusine B.

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Figures

Figure 1.
Figure 1.
Protection/deprotection sequences increase the overall step-counts of syntheses involving basic amines. In contrast, amine acylation followed by extrusive alkylation provides a more step-economical strategy for attenuating amine reactivity prior to C–N bond formation. PG = protecting group, RA = reductive amination, EA = extrusive alkylation.
Figure 2.
Figure 2.
Distinct products of TMSI-mediated carbamate deprotection are produced following acidic and basic quenches. An acidic quench yielded 4 and 5a in 66% and 0% yield, respectively. A basic quench yielded 4 and 5a in 73% and 13% yield, respectively.
Figure 3.
Figure 3.
The extrusive alkylation of carbamates exhibits broad substrate scope and functional group tolerability. aProduct 5s was derived from enantiopure proline methyl ester, and no epimerization was observed by chiral LC-MS during carbamate formation or extrusive alkylation.
Scheme 1.
Scheme 1.. Total Synthesis of Conodusine A and Ba
aConditions: (a) CO(OCCl3)2, Et3N, DCE, 0°C, then C5H5N, NaBH4 (unpurified) (b) neat, 80°C; 40% over 2 steps (c) TMSI, CH3CN, 120°C MW, then K2CO3, H2O, RT; 87%. (d) PhNMe3Br3, DCM (unpurified), then 10% Pd(PPh3)4, NaCO2H, DMSO, 63% over 2 steps (combined yield of the two epimers) (e) CH3NH(OMe), MeMgBr, THF, 0°C; 11 = 65%; 12 = 57%.
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