A novel and versatile method for the enantioselective syntheses of tropane alkaloids

A full account of the novel and flexible approach to hydroxylated 8-azabicyclo[3,2,1]octan-3-ones and 9-azabicyclo[3,3,1]nonan-3-ones is presented.Using keto-lactams as the starting materials,this two-step method consists of silyl enol ether formation with TBDMSOTf,lactam activation with Tf2O/DTBMP,and halide-promoted cyclization.Radical dechlorination of the resulting 1-halotropan-3-ones led to the corresponding hydroxylated tropan-3-ones,which can be hydrogenated to yield3,6-dihydroxytropanes.Starting from optically active keto-lactams,the method has been applied to the enantioselective syntheses of(+)-(1S,3S,5R,6S)-pervilleine C(6),(+)-(1S,3R,5S,6R)-valeroidine(3),(+)-(1S,3S,5R,6S)-dibenzoyloxytropane(8),and(+)-(1S,3S,5R,6S)-merredissine(9).     

Total syntheses of (+)-spiculoic acid A and (+)-zyggomphic acid, new marine natural products of polyketide origin

The total syntheses of both natural (+)-spiculoic acid A and (+)-zyggomphic acid, new cytotoxic marine natural products of polyketide origin, have been accomplished for the first time. These syntheses were achieved by the highly stereoselective and high-yielding intramolecular Diels-Alder reaction of a functionalized (E,E,E)-2,7,9-dodecanal derivative to construct the core tetrahydroindan-2-one skeleton. A stereocongener of (+)-spiculoic acid A, i.e., the (2R,5S,6R)-isomer, was also synthesized. The details of these total syntheses are described.     

Total syntheses of macrosphelides (+)-A, (−)-A and (+)-E

Total syntheses of (+)-macrosphelide A 1 (18.5% overall yield in 11 steps) and (+)-macrosphelide E 2 (23.9% overall yield in 11 steps) have been achieved via the chemoenzymatic reaction product (4R,5S)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4. The enantiomer (−)-A (1) (14.2% overall yield in 11 steps) of (+)-1 was also synthesized from the chemoenzymatic reaction product (4S,5R)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4.     

The first asymmetric synthesis of all four isomers of cis- and trans-3,4-dihydroxy-3,4-dihydromollugin

Asymmetric synthesis of all the four stereoisomers of cis-3,4-dihydroxy-3,4-dihydromollugins 4 and 6 and trans-3,4-dihydroxy-3,4-dihydromollugins 5 and 7 was achieved. The O-methoxymethyl mollugin derivatives were dihydroxylated to (−)- and (+)-cis-3,4-dihydroxy-3,4-dihydromollugin derivatives using both AD-mix-α and AD-mix-β. Deprotection of the MOM-ethers of cis-dihydroxy compounds resulted in the targeted stereoisomers (−)-(3R,4R)-cis-3,4-dihydroxy-3,4-dihydromollugin 4, (−)-(3R,4S)-trans-3,4-dihydroxy-3,4-dihydromollugin 5, (+)-(3S,4S)-cis-3,4-dihydroxy-3,4-dihydromollugin 6 and (+)-(3S,4R)-trans-3,4-dihydroxy-3,4-dihydromollugin 7. These routes were paved with difficulties, for example, incompatibility of the substrates with AD-mixes, the unexpected formation of trans-dihydroxy compounds and failures in deprotection protocols.     

Palladium-catalyzed asymmetric Diels–Alder reactions with novel chiral imino-phosphine ligands

Palladium-catalyzed asymmetric Diels–Alder reactions have been achieved with considerably high enantioselectivity by using chiral imino-phosphine ligands derived from (1S,4R)-(+)-fenchone, (1R,2R,5R)-(+)-2-hydroxy-3-pinanone derivatives, (1S,5R)-(−)-menthone, (1R,4R)-(+)-camphor, and (1S)-(+)-ketopinic acid. A mechanism for the asymmetric induction is proposed on the basis of the stereochemical outcome of the reactions.     

4,5-Didehydro-7-silyloxymethyl-2-oxepanone and formal total syntheses of Hagen’s gland lactones and trans-kumausynes

A concise and enantiospecific route to the 2,6-dioxabicyclo[3.3.0]octan-3-one ring system from commercially available (R)-(+)- and (S)-(−)-glycidols is described. The key features involve ring closing metathesis to construct the 7-substituted-4,5-dehydro-2-oxepanone and its base-catalyzed single-step rearrangement into the 2,6-dioxabicyclo[3.3.0]octan-3-one skeleton. Using this strategy, formal total syntheses of (7R)-cis-Hagen’s gland lactones and (+)- and (−)-trans-kumausynes have been achieved.     

Absolute configuration of (−)-4-methylheptan-3-ol,a pheromone of the smaller european elm bark beetle,as determined by the synthesis of its (3R,4R)-(+)- and (3S,4R)-(+)-isomers

Nerol and geraniol were stereoselectively converted to (±)-threo- and (±)-erythro-4-methylheptan-3-ol respectively. (R)-(+)-Citronellic acid was converted to a mixture of (3R,4R)-(+)-threo- and (3S,4R)-(+)-erythro-isomers which was separable by GLC. These syntheses established the absolute configuration of the naturally occurring (?)-4-methylheptan-3-ol to be 3S,4S.     

Asymmetric total synthesis of (+)-curcutetraol and (+)-sydonol

The asymmetric total syntheses of (+)-curcutetraol and (+)-sydonol, phenolic bisabolane-type sesquiterpenoids having chiral tertiary alcohol moiety in the o-position of a phenol, were achieved in high enantiomeric excesses (99% ee). The chiral tertiary benzylic alcohol moiety of these compounds was constructed by an asymmetric synthesis using an easily available chiral aminal, (−)-(2R,5S)-2-methoxycarbonyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane. The absolute configurations of both (+)-curcutetraol and (+)-sydonol have been assumed to be S-configuration based on the stereochemical course of the well established asymmetric synthesis used in the syntheses.     

Enzymatic transesterification of pharmacologically interesting β-aminocycloalkanol precursors

Chemoenzymatic syntheses of both enantiomers of cis- and trans-2-aminocyclopentanol as well as cis- and trans-2-aminocyclohexanol, which are valuable building blocks for a plethora of ligands and pharmaceuticals have been efficiently carried out. The strategy involves the stereospecific syntheses of racemic aminocycloalkanol precursors via tagging of a phthalimide as a masking group and subsequent lipase-catalyzed kinetic resolution. Most of the lipases exhibited excellent enantioselectivity (E ? 200) in the transesterification reactions of trans-derivatives, with both N-protected (R,R)-amino acetates and (S,S)-amino alcohols being isolated in enantiopure form. With regard to cis-derivatives, lipases were also very selective, even though the biotransformations were significantly slower.     

Methyl (3R,5R)-3,5-dihydroxydecanoate in the asymmetric synthesis of Idea Leuconoe pheromone and formal syntheses of (+)-(3R,5R)-3-hydroxydecano-5-lactone, verbalactone, and Tolypothrix pentaether

A simple and efficient asymmetric synthesis of (5S,7R)-7-hydroxydodecano-5-lactone, a component of the giant danaine butterfly Idea leuconoe pheromone, and formal syntheses of (+)-(3R,5R)-3-hydroxydecano-5-lactone, verbalactone, and Tolypothrix pentaether have been accomplished starting from methyl (3R,5R)-3,5-dihydroxydecanoate. The latter is obtained from methyl 3-[(tributylstannyl)methyl]but-3-enoate using Keck allylation in the key step of the construction of its carbon skeleton.     

Resolution and conformational analysis of diastereoisomeric esters of cis- and trans-2-(aminomethyl)-1-carboxycyclopropanes

(1R,2S)-, (1S,2R)-, (1R,2R)- and (1S,2S)-2-(Aminomethyl)-1-carboxycyclopropanes, conformationally restricted analogues of the neurotransmitter γ-aminobutyric acid (GABA), have been resolved by chromatographic separation of the corresponding diastereoisomeric esters which were formed between the cis- and trans-2-(acetamidomethyl)-1-carboxycyclopropanes with (R)-(−)-pantolactone. ¹H NMR, semi-empirical conformational analysis, ab initio (DFT) structure and NMR shielding tensor calculations of the cis-diastereoisomers allowed the absolute configuration assignments of the cis-amino acids.     

BF3-induced cyclobutane-opening of verbenone and its deconjugate homolog. Efficient preparation of o-mentha-1,8-dien-3-one and o-menth-1-en-3-one in optically active forms

Starting with (+)-verbenone, readily obtainable from (+)-nopinone, enantioselective preparation of (S)-(+)-4-isopropenyl-, (S)-(−)-4-isopropyl- and (R)-(+)-4-(1-acetoxy-1-methylethyl)-3-methyl-2-cyclohexen-1-ones was accomplished with little loss of stereochemical integrity via BF₃-induced cyclobutane-opening of (+)-4-(methylene)nopinone. As we have developed an efficient chemical transformation of (+)-nopinone into (−)-verbenone, the present syntheses of the above cyclohexenones are formal syntheses of their enantiomers from (+)-nopinone.     

Stereoselective synthesis of 3,4,5,6-tetrahydroxycyclohexyl β-amino acid derivatives

Stereoselective syntheses of racemic (1S,2R,3R,4R,5S,6R)- and (1S,2R,3R,4S,5S,6R)-3,4,5,6-tetrahydroxy derivatives of 2-aminocyclohexanecarboxylic acid have been achieved by a stereospecific Diels-Alder reaction between furan and maleic anhydride, a Curtius rearrangement and hydroxylation reactions.     

Photoinduced electron transfer-initiated asymmetric cyclization of N-benzoyl-α-dehydronaphthylalanine alkyl esters carrying chiral and bulky auxiliaries

The irradiation of the title compounds [(Z)-1] having (S)-(+)-sec-butyl, (−)-mentyl and related chiral auxiliaries in methanol and 1,2-dichloroethane containing 2-(diethylamino)ethanol afforded chiral auxiliary-substituted (4S,5S)-, (4R,5R)-, (4R,5S)- and (4S,5R)-4,5-dihydrooxazole derivatives (2) along with (E)-1. It was found that the photoinduced electron transfer-initiated cyclization of 1 gives either of the two diastereomers for cis-2 and trans-2 in diastereomeric excess whose value varies from 6% to 81% depending on solvent and chiral auxiliary.     

Carbocyclic nucleosides from enantiomeric, α-pinane-based aminodiols

Starting from (1R,2S,3S,5R)- and (1S,2R,3R,5S)-6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,2’-oxiran]-3-ol (?)-8 and (+)-8, two comparative syntheses were developed for pinane-based chiral carbocyclic nucleosides. The regioselective ring opening of the spiro-oxirane ring of (?)-8 and (+)-8 with NaN₃ resulted in azidodiols (?)-9 and (+)-9. Catalytic reduction of (?)-9 and (+)-9 furnished chiral aminodiols (?)-10 and (+)-10, which were transformed by linear synthesis to purine-type nucleosides 16–18 through pyrimidine intermediates. Regioselective ring opening of the oxirane ring of (?)-8 and (+)-8 resulted in adenine-, cytosine- and uracil-based carbocyclic nucleosides 19–21 in a single-step synthesis.     

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of common cutworm (Spodoptera litura)

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of Spodoptera litura was carried out. Substrate was converted to three new terpenoids, (+)-(1R,2S)-10-hydroxyfenchol, (+)-(1R,2R,3S)-8-hydroxyfenchol and (−)-(1S,2S,6S)-6-exo-hydroxyfenchol, and one known terpenoid, (−)-(1R,2R,3R)-9-hydroxyfenchol. These structures were established by NMR, IR, specific rotation and mass spectral studies.     

Stereospecific synthesis and hydrolysis of optically active diaryl(acylamino)(acyloxy)spiro-λ4-sulfanes and related cyclic diaryl(acylamino)sulfonium salts

The stereospecific synthesis of diaryl(acylamino)(acyloxy)spiro-λ⁴-sulfanes (S)-(+)-2, (R)-(+)-5, (S)-(+)-8, and their conversion into related diaryl(acylamino)sulfonium tetrafluoroborates (R)-(+)-3, (S)-(+)-6, (R)-(+)-9, respectively, is described. The enantiomers of spiro-λ⁴-sulfanes (S)-(+)-2, (R)-(+)-5 and (S)-(+)-8 were prepared by dehydration of the corresponding optically active sulfoxide–carboxylic acids (R)-(+)-1, (R)-(−)-4 and (S)-(+)-7, respectively, which were obtained from the racemic forms by diastereoisomeric salt separation with homochiral organic bases. The stereomechanism of the hydrolysis reaction of spiro-λ⁴-sulfanes and sulfonium tetrafluoroborates that depends on pH, the nature of the axial heteroatom, the size of the spiro rings and carboxyl neighbouring group participation is also discussed.     

Enantioselective syntheses of isoprostane and iridoid lactones intermediates by enzymatic transesterification

Crude Pseudomonas cepacia lipase (Amano PS-30) is a suitable biocatalyst for the kinetic resolution of the 1,2-cis-disubstituted cyclopentanoid building block (3aR*,4R*,6aS*)-(±)-4-hydroxymethyl-3,3a,4,6a-tetrahydrocyclopenta[b]furan-2-one through enantioselective transesterification. Enantiomerically enriched acetic acid (3aS,4S,6aR)-(+)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-4-yl methyl ester was utilized in a formal synthesis of the iridoids (+)-isoiridomyrmecin and (−)-teucriumlactone.     

Synthesis and Absolute Configuration of Naturally Occurring Dactyloxene-B and -C

Natural (+)-dactyloxene-B (12) and -C (13) have been synthesized starting from (+)-trans-2, 5, 6-trimethyl-l-cyclohexene-l-carbaldehyde (1) which is shown to have the (5S, 6R)-configuration by chemical correlation with (+)-(2R, 3S, 6S)-2, 3, 6-trimethylcyclohexanone. The absolute configurations are therefore (2R, 5R, 9S, 10R) for (+)-dactyloxene-B and (2R, 5S, 9S, 10R) for (+)-dactyloxene-C.     

Diastereoselective synthesis of new polyhydroxylated indolizidines from (l)-glutamic acid

A diastereoselective synthesis of two new swainsonine's analogues 1a and 1b with the piperidine ring fused to a phenyl nucleus at C6-C7, namely (1R, 2S, 10R, 10aR)-(+)-1,2,10-trihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f] indolizine (1a) and (1S, 2R, 10R, 10aR)-(+)-1,2,10-trihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f] indolizine (1b), is described. Throughout this work, the effectiveness of the tricyclic indolizidine dione 5, readily available in three steps from the cheap l-glutamic acid, as an attractive platform for chemo- and stereodivergent transformations is illustrated. The key steps involved totally diastereoselective ketone reduction of compound 5 and catalytic cis-dihydroxylation of the unsaturated amide 10. The synthetic strategy also allowed for the diastereoselective synthesis of benzoanalogues of the 1,8a-di-epi-lentiginosine 3a ((1R, 2S, 10aR)-(+)-1,2-dihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f]indolizine) and 2,8a-di-epi-lentiginosine 3b ((1S, 2R, 10aR)-(+)-1,2-dihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f]indolizine).