Synthesis of All-Carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron-Catalyzed Kumada Cross-Coupling.

1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p-substituted arenes and alkynes. Access to all-carbon disubstituted BCPs via cross-coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3-C-disubstituted BCPs from 1-iodo-bicyclo[1.1.1]pentanes (iodo-BCPs) by direct iron-catalyzed cross-coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo-BCPs as electrophiles in cross-coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3-C-disubstituted BCPs including various drug analogues.

The Hancock Alkaloids (-)-Cuspareine, (-)-Galipinine, (-)-Galipeine, and (-)-Angustureine: Asymmetric Syntheses and Corrected 1H and 13C NMR Data.

The asymmetric syntheses of all members of the Hancock alkaloid family based upon a 2-substituted N-methyl-1,2,3,4-tetrahydroquinoline core are delineated. The conjugate addition of enantiopure lithium N-benzyl- N-(α-methyl- p-methoxybenzyl)amide to 5-( o-bromophenyl)- N-methoxy- N-methylpent-2-enamide is used to generate the requisite C-2 stereogenic center of the targets, while an intramolecular Buchwald-Hartwig coupling is used to form the 1,2,3,4-tetrahydroquinoline ring. Late-stage diversification completes construction of the C-2 side chains. Thus, (-)-cuspareine, (-)-galipinine, (-)-galipeine, and (-)-angustureine were prepared in overall yields of 30%, 28%, 15%, and 39%, respectively, in nine steps from commercially available 3-( o-bromophenyl)propanoic acid in all cases. Unambiguously corrected 1H and 13C NMR data for the originally isolated samples of (-)-cuspareine, (-)-galipinine, and (-)-angustureine are also reported, representing a valuable reference resource for these popular synthetic targets.

Structural Revision of the Hancock Alkaloid (-)-Galipeine.

The 1H and 13C NMR data of synthetic samples of (S)-N(1)-methyl-2-[2'-(3″-hydroxy-4″-methoxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline, the originally proposed structure of the Hancock alkaloid (-)-galipeine, do not match those of the natural product. Herein, the preparation of the regioisomer (S)-N(1)-methyl-2-[2'-(3″-methoxy-4″-hydroxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline is reported, the 1H and 13C NMR data of which are in excellent agreement with those of (-)-galipeine. Comparison of specific rotation data enables assignment of the absolute (S)-configuration of the alkaloid, and together, these data engender the structural revision of (-)-galipeine to (S)-N(1)-methyl-2-[2'-(3″-methoxy-4″-hydroxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline.

Asymmetric Synthesis of the Tetraponerine Alkaloids.

The asymmetric syntheses of all eight tetraponerine alkaloids (T1-T8) were achieved using the diastereoselective conjugate additions of lithium amide reagents in the key stereodefining steps. Conjugate addition of either lithium (R)-N-allyl-N-(α-methylbenzyl)amide or lithium (R)-N-(but-3-en-1-yl)-N-(α-methylbenzyl)amide to tert-butyl sorbate was followed by ring-closing metathesis of the resultant N-alkenyl ß-amino esters, reduction to the corresponding aldehydes, and reaction with tert-butyl (triphenylphosphoranylidene)acetate. Subsequent conjugate addition of the requisite antipode of lithium N-benzyl-N-(α-methylbenzyl)amide to the resultant α,ß-unsaturated esters gave a range of diamines for elaboration to T1-T8 via a sequence involving reduction of the ester moiety to give the corresponding aldehyde, olefination, tandem hydrogenation/hydrogenolysis, and cyclization upon reaction with 4-bromobutanal to give the tricyclic skeleton.

Asymmetric Syntheses of (+)-Preussin B, the C(2)-Epimer of (-)-Preussin B, and 3-Deoxy-(+)-preussin B.

Efficient de novo asymmetric syntheses of (+)-preussin B, the C(2)-epimer of (-)-preussin B, and 3-deoxy-(+)-preussin B have been developed, using the diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 4-phenylbut-2-enoate and diastereoselective reductive cyclizations of γ-amino ketones as the key steps to set the stereochemistry. Conjugate addition followed by enolate protonation generated the corresponding ß-amino ester. Homologation using the ester functionality as a synthetic handle gave the corresponding γ-amino ketone. Hydrogenolytic N-debenzylation was accompanied by diastereoselective reductive cyclization in situ; reductive N-methylation then gave 3-deoxy-(+)-preussin B as the major diastereoisomeric product. Meanwhile, the same conjugate addition but followed by enolate oxidation with (+)-camphorsulfonyloxaziridine gave the corresponding anti-α-hydroxy-ß-amino ester. α-Epimerization by oxidation and diastereoselective reduction then gave access to the corresponding syn-α-hydroxy-ß-amino ester. Homologation of both of these diastereoisomeric α-hydroxy-ß-amino esters gave the corresponding ß-hydroxy-γ-amino ketones. N-Debenzylation and concomitant diastereoselective reductive cyclization, followed by reductive N-methylation, provided the C(2)-epimer of (-)-preussin B and (+)-preussin B as the major diastereoisomeric products, respectively. The overall yields (from phenylacetaldehyde) were 19% for 3-deoxy-(+)-preussin B over seven steps, 8% for the C(2)-epimer of (-)-preussin B over nine steps, and 7% for (+)-preussin B over eleven steps.

The asymmetric syntheses of pyrrolizidines, indolizidines and quinolizidines via two sequential tandem ring-closure/N-debenzylation processes.

Concise asymmetric syntheses of (-)-lupinine, (+)-isoretronecanol, (+)-5-epi-tashiromine and (R,R)-1-(hydroxymethyl)octahydroindolizine (the azabicyclic core within stellettamides A-C) have been achieved in 8 steps or fewer from commercially available starting materials. The key steps in these syntheses involved the preparation of enantiopure ß-amino esters, upon conjugate addition of lithium (R)-N-(p-methoxybenzyl)-N-(α-methyl-p-methoxybenzyl)amide to either ζ-chloro or ζ-hydroxy substituted tert-butyl (E)-hept-2-enoate, or ε-chloro or ε-hydroxy substituted tert-butyl (E)-hex-2-enoate. Activation of the ω-substituent as a leaving group led to SN2-type ring-closure, which occurred with concomitant N-debenzylation via an E1-type deprotection step, to give the corresponding pyrrolidine or piperidine in good yield. Subsequent alkylation of these enantiopure azacycles, followed by a second ring-closure/concomitant N-debenzylation step formed the pyrrolizidine, indolizidine or quinolizidine motif, and reduction with LiAlH4 gave the target compounds in diastereoisomerically and enantiomerically pure form.

An efficient asymmetric synthesis of (-)-lupinine.

The asymmetric synthesis of (-)-lupinine was achieved in 8 steps, 15% overall yield and >99 : 1 dr from commercially available starting materials. The strategy used for the construction of the quinolizidine scaffold involved reaction of an enantiopure tertiary dibenzylamine via two sequential ring-closures which both occurred with concomitant N-debenzylation.