Asymmetric Syntheses of Methyl <i>N</i>,<i>O</i>‑Diacetyl‑d‑3-<i>epi</i>-daunosaminide and Methyl <i>N</i>,<i>O</i>‑Diacetyl‑d‑ristosaminide

Ab initio asymmetric syntheses of methyl <i>N</i>,<i>O</i>-diacetyl-d-3-<i>epi</i>-daunosaminide and methyl <i>N</i>,<i>O</i>-diacetyl-d-ristosaminide, employing diastereoselective epoxidation and dihydroxylation, respectively, of alkyl (3<i>S</i>,α<i>R</i>,<i>Z</i>)-3-[<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amino]­hex-4-enoates as the key steps, are reported. The requisite substrates were readily prepared using the conjugate additions of lithium (<i>R</i>)-<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amide to methyl and <i>tert</i>-butyl (<i>E</i>)-hexa-2-en-4-ynoates followed by diastereoselective alkyne reduction. <i>syn</i>-Dihydroxylation using OsO₄ proceeded under steric control on the 4<i>Re</i>,5<i>Re</i> face of the olefin to give the corresponding diol, which subsequently underwent lactonization. Meanwhile, epoxidation using F₃CCO₃H in conjunction with F₃CCO₂H proceeded on the opposite 4<i>Si</i>,5<i>Si</i> face of the olefin under hydrogen-bonding control from the in situ formed ammonium ion. Treatment of the intermediate epoxide with concd aq H₂SO₄ promoted highly regioselective ring-opening (distal to the in situ formed ammonium moiety) to give the corresponding diol (completing overall the formal <i>anti</i>-dihydroxylation of the olefin), which then underwent lactonization under the reaction conditions. Elaboration of these diastereoisomeric lactones through hydrogenolysis, <i>N</i>-Boc protection, reduction, methanolysis, and acetate protection gave methyl <i>N</i>,<i>O</i>-diacetyl-d-3-<i>epi</i>-daunosaminide and methyl <i>N</i>,<i>O</i>-diacetyl-d-ristosaminide

Asymmetric Syntheses of Methyl <i>N</i>,<i>O</i>‑Diacetyl‑d‑3-<i>epi</i>-daunosaminide and Methyl <i>N</i>,<i>O</i>‑Diacetyl‑d‑ristosaminide

Ab initio asymmetric syntheses of methyl <i>N</i>,<i>O</i>-diacetyl-d-3-<i>epi</i>-daunosaminide and methyl <i>N</i>,<i>O</i>-diacetyl-d-ristosaminide, employing diastereoselective epoxidation and dihydroxylation, respectively, of alkyl (3<i>S</i>,α<i>R</i>,<i>Z</i>)-3-[<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amino]­hex-4-enoates as the key steps, are reported. The requisite substrates were readily prepared using the conjugate additions of lithium (<i>R</i>)-<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amide to methyl and <i>tert</i>-butyl (<i>E</i>)-hexa-2-en-4-ynoates followed by diastereoselective alkyne reduction. <i>syn</i>-Dihydroxylation using OsO₄ proceeded under steric control on the 4<i>Re</i>,5<i>Re</i> face of the olefin to give the corresponding diol, which subsequently underwent lactonization. Meanwhile, epoxidation using F₃CCO₃H in conjunction with F₃CCO₂H proceeded on the opposite 4<i>Si</i>,5<i>Si</i> face of the olefin under hydrogen-bonding control from the in situ formed ammonium ion. Treatment of the intermediate epoxide with concd aq H₂SO₄ promoted highly regioselective ring-opening (distal to the in situ formed ammonium moiety) to give the corresponding diol (completing overall the formal <i>anti</i>-dihydroxylation of the olefin), which then underwent lactonization under the reaction conditions. Elaboration of these diastereoisomeric lactones through hydrogenolysis, <i>N</i>-Boc protection, reduction, methanolysis, and acetate protection gave methyl <i>N</i>,<i>O</i>-diacetyl-d-3-<i>epi</i>-daunosaminide and methyl <i>N</i>,<i>O</i>-diacetyl-d-ristosaminide

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 Syntheses of (−)-3-<i>epi</i>-Fagomine, (2<i>R</i>,3<i>S</i>,4<i>R</i>)‑Dihydroxypipecolic Acid, and Several Polyhydroxylated Homopipecolic Acids

A range of enantiopure polyhydroxylated piperidines, including (2<i>R</i>,3<i>S</i>,4<i>R</i>)-dihydroxypipecolic acid, (−)-3-<i>epi</i>-fagomine, (2<i>S</i>,3<i>S</i>,4<i>R</i>)-dihydroxyhomopipecolic acid, (2<i>S</i>,3<i>R</i>,4<i>R</i>)-dihydroxyhomopipecolic acid, and two trihydroxy-substituted homopipecolic acids, have been prepared using diastereoselective olefinic oxidations of a range of enantiopure tetrahydropyridines as the key step. The requisite substrates were readily prepared from <i>tert</i>-butyl sorbate using our diastereoselective hydroamination or aminohydroxylation protocols followed by ring-closing metathesis. After diastereoselective olefinic oxidation of the resultant enantiopure tetrahydropyridines and deprotection, enantiopure polyhydroxylated piperidines were isolated as single diastereoisomers (>99:1 dr) in good overall yield

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 (<i>S</i>)-<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)­amide to <i>tert</i>-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 β-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 <i>anti</i>-α-hydroxy-β-amino ester. α-Epimerization by oxidation and diastereoselective reduction then gave access to the corresponding <i>syn</i>-α-hydroxy-β-amino ester. Homologation of both of these diastereoisomeric α-hydroxy-β-amino esters gave the corresponding β-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

Syntheses of Dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F‑1 via Diastereoselective Epoxidation of N‑Protected 4‑Aminocyclohex-2-en-1-ols

Diastereoselective syntheses of dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1 have been achieved from N-protected 4-aminocyclohex-2-en-1-ols via two complementary procedures for epoxidation as the key step. Treatment of either <i>trans</i>- or <i>cis</i>-4-<i>N</i>-benzylaminocyclohex-2-en-1-ol with Cl₃CCO₂H and then <i>m</i>-chloroperoxybenzoic acid (<i>m</i>-CPBA) resulted in initial formation of the corresponding ammonium species, followed by epoxidation on the face syn to the ammonium moiety exclusively; chemoselective N-benzylation then provided either (1<i>RS</i>,2<i>SR</i>,3<i>RS</i>,4<i>RS</i>)- or (1<i>RS</i>,2<i>RS</i>,3<i>SR</i>,4<i>SR</i>)-2,3-epoxy-4-<i>N</i>,<i>N</i>-dibenzylaminocyclohexan-1-ol, respectively. Treatment of either <i>trans</i>- or <i>cis</i>-4-<i>N</i>,<i>N</i>-dibenzylaminocyclohex-2-en-1-ol with <i>m</i>-CPBA resulted in initial formation of the corresponding <i>N</i>-oxide, followed by epoxidation on the face syn to the hydroxyl group exclusively; reduction then provided either (1<i>RS</i>,2<i>RS</i>,3<i>SR</i>,4<i>RS</i>)- or an alternative route to (1<i>RS</i>,2<i>RS</i>,3<i>SR</i>,4<i>SR</i>)-2,3-epoxy-4-<i>N</i>,<i>N</i>-dibenzylaminocyclohexan-1-ol, respectively. In all cases, S_N2-type ring opening of these epoxides upon treatment with aqueous H₂SO₄ proceeded by nucleophilic attack with inversion at C(2) preferentially, distal to the in situ formed ammonium moiety. Hydrogenolytic N-deprotection then gave the corresponding dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1

Probing Competitive and Co-operative Hydroxyl and Ammonium Hydrogen-Bonding Directed Epoxidations

The diastereoselectivities and rates of epoxidation (upon treatment with Cl₃CCO₂H then <i>m</i>-CPBA) of a range of <i>cis</i>- and <i>trans</i>-4-aminocycloalk-2-en-1-ol derivatives (containing five-, six-, and seven-membered rings) have been investigated. In all cases where the two potential directing groups can promote epoxidation on opposite faces of the ring scaffold, evidence of competitive epoxidation pathways, promoted by hydrogen-bonding to either the in situ formed ammonium moiety or the hydroxyl group, was observed. In contrast to the relative directing group abilities already established for the six-membered ring system (NHBn ≫ OH > NBn₂), an <i>N</i>,<i>N</i>-dibenzylammonium moiety appeared more proficient than a hydroxyl group at directing the stereochemical course of the epoxidation reaction in a five- or seven-membered system. In the former case, this was rationalized by the drive to minimize torsional strain in the transition state being coupled with assistance from hydrogen-bonding to the ammonium moiety. In the latter case, this was ascribed to the steric bulk of the ammonium moiety disfavoring conformations in which hydrogen-bonding to the hydroxyl group results in direction of the epoxidation to the <i>syn</i> face. In cases where the two potential directing groups can promote epoxidation on the same face of the ring scaffold, an enhancement of epoxidation diastereoselectivity was not observed, while introduction of a second, allylic heteroatom to the substrate results in diminishment of the rate of epoxidation in all cases. Presumably, reduction of the nucleophilicity of the olefin by the second, inductively electron-withdrawing heteroatom is the dominant factor, and any assistance to the epoxidation reaction by the potential to form hydrogen-bonds to two directing groups rather than one is clearly unable to overwhelm it