Structural Revision of the Hancock Alkaloid (−)-Galipeine

The ¹H and ¹³C NMR data of synthetic samples of (<i>S</i>)-<i>N</i>(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 (<i>S</i>)-<i>N</i>(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 (<i>S</i>)-configuration of the alkaloid, and together, these data engender the structural revision of (−)-galipeine to (<i>S</i>)-<i>N</i>(1)-methyl-2-[2′-(3″-methoxy-4″-hydroxyphenyl)­ethyl]-1,2,3,4-tetrahydroquinoline

Asymmetric Syntheses of Nakinadine D, Nakinadine E, and Nakinadine F: Confirmation of Their Relative (<i>RS</i>,<i>SR</i>)‑Configurations and Proposal of Their Absolute (2<i>S</i>,3<i>R</i>)‑Configurations

The <i>syn</i>- and <i>anti</i>-diastereoisomeric forms of the reported structures of the marine alkaloids nakinadines D–F have been synthesized, for the first time in all cases, via an approach involving asymmetric Mannich-type (imino-aldol) reactions of methyl phenylacetate with <i>N</i>-<i>tert</i>-butylsulfinyl imines as the key steps to control the stereochemistry. Comparison of the ¹H and ¹³C NMR spectroscopic data reported for the natural materials with those acquired for these synthetic samples confirms the initially assigned relative (<i>RS</i>,<i>SR</i>)-configurations of these three alkaloids. In the absence of specific rotation (or other diagnostic) data for the natural materials, it is not possible to unambiguously assign their absolute configurations, although given the absolute (2<i>S</i>)-configurations assigned to nakinadines B and C, and the absolute (2<i>S</i>,3<i>R</i>)-configuration previously established for nakinadine A, the data herein uphold our proposal that nakinadines D–F share the absolute (2<i>S</i>,3<i>R</i>)-configuration

Asymmetric Synthesis of Substituted <i>anti</i>-β-Fluorophenylalanines

A range of substituted <i>anti</i>-β-fluorophenylalanines was produced from the corresponding enantiopure α‑hydroxy-β-amino esters using a stereospecific XtalFluor-E promoted rearrangement procedure as the key step. The requisite substrates are readily produced via aminohydroxylation of an α,β-unsaturated ester using our lithium amide conjugate addition methodology and, following rearrangement, deprotection of the resultant enantiopure β-fluoro-α-amino esters gives the corresponding enantiopure <i>anti</i>-β-fluorophenylalanines in good yield and high diastereoisomeric purity

Diastereoselective Ammonium-Directed Epoxidation in the Asymmetric Syntheses of Dihydroconduramines (+)-C-2, (−)-C-2, (+)-D-2, (+)-E-2, (+)-F-2, and (−)-F‑2

Epoxidations (40% aq HBF₄ then <i>m</i>-CPBA) of racemic <i>cis</i>-2-(<i>N</i>-benzylamino)­cyclohex-3-en-1-ol and racemic <i>cis</i>-2-(<i>N</i>,<i>N</i>-dibenzylamino)­cyclohex-3-en-1-ol proceed with very high levels of diastereoselectivity (>95:5 dr). The latter is in direct contrast to the epoxidation of the corresponding <i>trans</i>-diastereoisomer (which proceeds with essentially no selectivity), showing that the relative configuration of the substrate dramatically influences the diastereoselectivity in these instances. Meanwhile, epoxidations of enantiopure (1<i>R</i>,2<i>S</i>,α<i>R</i>)-2-[(<i>N</i>-α-methylbenzyl)­amino]­cyclohex-3-en-1-ol and (1<i>S</i>,2<i>R</i>,α<i>R</i>)-2-[(<i>N</i>-α-methylbenzyl)­amino]­cyclohex-3-en-1-ol [surrogates for the enantiomers of <i>cis</i>-2-(<i>N</i>-benzylamino)­cyclohex-3-en-1-ol] proceed with complete diastereoselectivity (>95:5 dr) under the same conditions, showing that neither the presence of the α-methyl group nor the relative configuration of the α-methylbenzyl stereocenter have an effect upon the established level of diastereoslectivity in these cases. In contrast, epoxidations of enantiopure (1<i>R</i>,2<i>S</i>,α<i>R</i>)-2-[<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amino]­cyclohex-3-en-1-ol and (1<i>S</i>,2<i>R</i>,α<i>R</i>)-2-[<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amino]­cyclohex-3-en-1-ol [surrogates for the enantiomers of <i>cis</i>-2-(<i>N</i>,<i>N</i>-dibenzylamino)­cyclohex-3-en-1-ol] proceed with lower diastereoselectivity (∼70:30 dr). Thus, the presence of the α-methyl group has a detrimental effect on the established level of diastereoselectivity in these cases (although again the relative configuration of the α-methylbenzyl stereocenter is unimportant). The diastereoselective epoxidation pathway is used to enable the asymmetric syntheses of six hitherto unknown, enantiopure dihydroconduramines (+)-C-2, (−)-C-2, (+)-D-2, (+)-E-2, (+)-F-2, and (−)-F-2 (>99% ee in each case)

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 (<i>R</i>)-<i>N</i>-allyl-<i>N</i>-(α-methylbenzyl)­amide or lithium (<i>R</i>)-<i>N</i>-(but-3-en-1-yl)-<i>N</i>-(α-methyl­benzyl)­amide to <i>tert</i>-butyl sorbate was followed by ring-closing metathesis of the resultant <i>N</i>-alkenyl β-amino esters, reduction to the corresponding aldehydes, and reaction with <i>tert</i>-butyl (triphenyl­phosphoranylidene)­acetate. Subsequent conjugate addition of the requisite antipode of lithium <i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amide to the resultant α,β-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

Diastereoselective Ammonium-Directed Epoxidation in the Asymmetric Syntheses of Dihydroconduramines (+)-C-2, (−)-C-2, (+)-D-2, (+)-E-2, (+)-F-2, and (−)-F‑2

Epoxidations (40% aq HBF₄ then <i>m</i>-CPBA) of racemic <i>cis</i>-2-(<i>N</i>-benzylamino)­cyclohex-3-en-1-ol and racemic <i>cis</i>-2-(<i>N</i>,<i>N</i>-dibenzylamino)­cyclohex-3-en-1-ol proceed with very high levels of diastereoselectivity (>95:5 dr). The latter is in direct contrast to the epoxidation of the corresponding <i>trans</i>-diastereoisomer (which proceeds with essentially no selectivity), showing that the relative configuration of the substrate dramatically influences the diastereoselectivity in these instances. Meanwhile, epoxidations of enantiopure (1<i>R</i>,2<i>S</i>,α<i>R</i>)-2-[(<i>N</i>-α-methylbenzyl)­amino]­cyclohex-3-en-1-ol and (1<i>S</i>,2<i>R</i>,α<i>R</i>)-2-[(<i>N</i>-α-methylbenzyl)­amino]­cyclohex-3-en-1-ol [surrogates for the enantiomers of <i>cis</i>-2-(<i>N</i>-benzylamino)­cyclohex-3-en-1-ol] proceed with complete diastereoselectivity (>95:5 dr) under the same conditions, showing that neither the presence of the α-methyl group nor the relative configuration of the α-methylbenzyl stereocenter have an effect upon the established level of diastereoslectivity in these cases. In contrast, epoxidations of enantiopure (1<i>R</i>,2<i>S</i>,α<i>R</i>)-2-[<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amino]­cyclohex-3-en-1-ol and (1<i>S</i>,2<i>R</i>,α<i>R</i>)-2-[<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amino]­cyclohex-3-en-1-ol [surrogates for the enantiomers of <i>cis</i>-2-(<i>N</i>,<i>N</i>-dibenzylamino)­cyclohex-3-en-1-ol] proceed with lower diastereoselectivity (∼70:30 dr). Thus, the presence of the α-methyl group has a detrimental effect on the established level of diastereoselectivity in these cases (although again the relative configuration of the α-methylbenzyl stereocenter is unimportant). The diastereoselective epoxidation pathway is used to enable the asymmetric syntheses of six hitherto unknown, enantiopure dihydroconduramines (+)-C-2, (−)-C-2, (+)-D-2, (+)-E-2, (+)-F-2, and (−)-F-2 (>99% ee in each case)

Asymmetric Syntheses of APTO and AETD: the β‑Amino Acid Fragments within Microsclerodermins C, D, and E

Efficient asymmetric syntheses of APTO and AETD, the highly functionalized β-amino acid fragments within microsclerodermins C, D, and E, are reported. The conjugate addition of lithium (<i>R</i>)-<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amide to <i>tert</i>-butyl (<i>E</i>,<i>E</i>)-7-(triisopropylsilyloxy)­hepta-2,4-dienoate and in situ enolate oxidation with (−)-camphorsulfonyloxaziridine, diastereoselective dihydroxylation of a 2,3-<i>syn</i>-γ,δ-unsaturated-α-hydroxy-β-amino ester derivative under Donohoe conditions, and a Julia–Kocieński olefination were used as the key steps

Asymmetric Syntheses of APTO and AETD: the β‑Amino Acid Fragments within Microsclerodermins C, D, and E

Efficient asymmetric syntheses of APTO and AETD, the highly functionalized β-amino acid fragments within microsclerodermins C, D, and E, are reported. The conjugate addition of lithium (<i>R</i>)-<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amide to <i>tert</i>-butyl (<i>E</i>,<i>E</i>)-7-(triisopropylsilyloxy)­hepta-2,4-dienoate and in situ enolate oxidation with (−)-camphorsulfonyloxaziridine, diastereoselective dihydroxylation of a 2,3-<i>syn</i>-γ,δ-unsaturated-α-hydroxy-β-amino ester derivative under Donohoe conditions, and a Julia–Kocieński olefination were used as the key steps

Asymmetric Syntheses of 3‑Deoxy-3-aminosphingoid Bases: Approaches Based on Parallel Kinetic Resolution and Double Asymmetric Induction

The asymmetric syntheses of a range of <i>N</i>- and <i>O</i>-protected 3-deoxy-3-aminosphingoid bases have been achieved using two complementary approaches. dl-Serine was converted to a racemic <i>N</i>,<i>N</i>-dibenzyl-protected γ-amino-α,β-unsaturated ester which was resolved using a parallel kinetic resolution (PKR) strategy upon reaction with a pseudoenantiomeric mixture of lithium (<i>R</i>)-<i>N</i>-benzyl-<i>N</i>-(α-methyl­benzyl)­amide and lithium (<i>S</i>)-<i>N</i>-3,4-dimethoxybenzyl-<i>N</i>-(α-methyl­benzyl)­amide, giving the corresponding enantio- and diastereoisomerically pure β,γ-diamino esters. Alternatively, elaboration of l-serine gave the corresponding enantiopure <i>N</i>,<i>N</i>-dibenzyl-protected γ-amino-α,β-unsaturated ester, and doubly diastereoselective conjugate addition of the antipodes of lithium <i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amide was found to proceed under the dominant stereocontrol of the lithium amide reagent in both cases, thus augmenting the accessible range of β,γ-diamino esters. Both of these protocols were expanded to include in situ oxidation of the enolate formed upon conjugate addition, giving access to the corresponding α-hydroxy-β,γ-diamino esters. Elaboration of these β,γ-diamino and α-hydroxy-β,γ-diamino esters gave the protected forms of the 3-deoxy-3-aminosphingoid base targets

Asymmetric Synthesis of (−)-Martinellic Acid

A high-yielding total asymmetric synthesis of (−)-martinellic acid is reported. The conjugate addition of lithium (<i>R</i>)-<i>N</i>-allyl-<i>N</i>-(α-methyl-4-methoxybenzyl)amide to <i>tert</i>-butyl (<i>E</i>)-3-[2′-(<i>N</i>,<i>N</i>-diallylamino)-5′-bromophenyl]propenoate and alkylation of the resultant β-amino ester have been used as the key steps to install the C(9b) and C(3a) stereogenic centers, respectively, and a highly diastereoselective Wittig reaction/intramolecular Michael addition was then used to create the C(4) stereogenic center within this tricyclic molecular architecture