Scalable synthesis of methyl ent-isocopalate and its derivatives

An efficient and convenient synthetic route was developed to prepare the tricycle diterpene intermediates 1-3 starting from commercially available (−)-sclareol. This improved approach involving four-step reactions provides large-scale (30-40 g) methyl ent-isocopalate in 61% overall yield, which could supply sufficient material for the synthesis of marine natural products containing tricyclic diterpenes.     

Total synthesis of (−)-2-epi-lentiginosine by use of chiral 5-hydroxy-1,5-dihydropyrrol-2-one as a building block

We have developed a practical synthesis of the chiral lactam as a new chiral building block for alkaloid synthesis. Lipase-catalyzed kinetic resolution of hydroxylactam 8, followed by isolation-racemization of the chiral acetoxylactam 9 provided the optically pure hydroxylactam 8 in 96.0% yield with >99% ee after five cycles of kinetic resolution-racemization process. Chemical transformation of (S)-hydroxylactam 8 furnished chiral (−)-2-epi-lentiginosine (1) in 20% yield in 10 steps with no loss of enantiomeric excess.     

Synthesis of the fungal natural product (−)-xylariamide A

The first synthesis of the fungal natural product (−)-xylariamide A 1 is reported. N,O-Bis(trimethylsilyl)acetamide induced coupling of d-tyrosine with (E)-but-2-enedioic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester 5 produced the dechloro natural product 6, which was subsequently monochlorinated using oxone and KCl to yield synthetic 1. (−)-Xylariamide A 1, (+)-xylariamide A 2 and (−)-dechloroxylariamide A 6 displayed no cytotoxic or antimicrobial activity.     

Formal synthesis of (−)-anisomycin based on stereoselective nucleophilic substitution along with 1,2-aryl migration

The stereoselective conversion of (4R)-5-hydroxy-4-(4′-methoxyphenyl)-2(E)-pentenoate 4 into the (4S)-4-hydroxy-5-(4′-methoxyphenyl)-2(E)-pentenoate 5 using the AgNO₃/MS 4 Å/MeNO₂ system was accomplished along with complete inversion at the C₄-position, and the synthesis of the intermediate (4S)-7 for the chiral synthesis of (−)-anisomycin 6 from (4S)-7 based on osmium tetroxide-catalyzed stereoselective hydroxylation was achieved.     

Synthesis of new (−)-menthylgermanium derivatives and its use in heterogeneous bimetallic catalysis

The syntheses and physical properties of tri-(−)-menthylgermanium chloride (2), tri-(−)-menthylmethylgermanium (5), and tri-(−)-menthylgermanium hydride (6) are reported. The preparation of a bimetallic catalyst derived from 5 and Pt supported on SiO₂ and its use in the enantioselective catalytic hydrogenation of acetophenone is also reported.     

Stereoselective construction of the pyrrolizidine bridgehead stereochemistry by the adjacent hydroxyl group in the synthesis of (+)-heliotridine and (−)-retronecine

Formal total synthesis of (+)-heliotridine (4) and total synthesis of (−)-retronecine (5) were accomplished by using (S)-3-acetoxysuccinimide (6) as the common starting material. The stereogenic center of 6 ended up as C-1 in both alkaloids. The chiral centers at C-7a of the alkaloids were stereoselectively constructed through the help of the adjacent functionality at C-1. The B-rings of the alkaloids were formed through α-sulfonyl radical cyclizations.     

Chemistry of xanthorrhizol: synthesis of several bisabolane sesquiterpenoids from xanthorrhizol

(−)-Xanthorrhizol (1) isolated from the rhizomes of Curcuma xanthorrhiza has been transformed to several bisabolane-type sesquiterpenoids, in a stereoselective manner. 10R- and 10S-10,11-dihydro-10,11-dihydroxyxanthorrhizols (2, 3), (−)-curcuquinone (4), (−)-curcuhydroquinone (5), helibisabonol A (7) and allylic alcohol 8 have been prepared from xanthorrhizol in optically active forms. All the routes involved a Sharpless AD to introduce the stereogenic centre at C-10.     

Absolute stereochemistries and total synthesis of (+)/(−)-macrosphelides, potent, orally bioavailable inhibitors of cell-cell adhesion

In the current studies, we used the single-crystal X-ray analysis and Kakisawa-Kashman modification of the Mosher NMR method to determine the complete relative and absolute stereochemistries of the (+)-macrosphelides A (+)-1 and B (+)-2. The stereostructure of (+)-2 was determined by chemical comparison with artificial (+)-2 from (+)-1. We also report the convergent total synthesis of (+)-1 and (+)-3, as well as their antipodes, utilizing an asymmetric dihydroxylation for introduction of chirality and Yamaguchi macrocyclization to form the 16-membered trilactone macrolides.     

New S,O-acetals from (1R)-(−)-myrtenal as chiral auxiliaries in nucleophilic additions

Treatment of hydroxythiol 4 with α,α-diethoxyacetophenone at room temperature yielded a mixture of epimeric S,O-acetals 6 and 7 (1:4, 92% yield), which were efficiently separated by flash chromatography. The OTBS derivatives 8 and 9 were treated with several Grignard reagents to afford carbinols 10 and 13 respectively (85-99% yield, >95% dr). After successive hydrolysis and reduction of 10 and 13 it is possible to obtain either enantiomer of diols 16 in high optical purity (>95% er).     

Synthetic study of hetisine-type aconite alkaloids. Part 3: Total synthesis of (±)-nominine

Completion of the total synthesis of (±)-nominine (1) is described in detail. Based on the results of the preceding two papers, total synthesis of (±)-nominine was accomplished diverging from the intermediate 7. Thus, following pyrrolidine ring formation through transformation from 7 to 8, the C-ring was constructed by radical cyclization to form 10 from the enyne precursor 9. Subsequent elaboration of the C-ring, followed by formation of the azabicyclic ring system, completed a total synthesis of (±)-1. Single-crystal X-ray analysis of (±)-1 unambiguously confirmed its molecular structure and racemic crystal structure.     

Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring: first asymmetric synthesis of anesthetic (S)-ketamine with high selectivity

Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring was performed with respect to the asymmetric synthesis of anesthetic (S)-ketamine 1. Diastereoselective nucleophilic 1,2-addition reaction of phenyllithium to α-ketoxime-ether acetal 9 bearing chiral auxiliary on the α-carbonyl function gave benzyloxyamine 11 major in 83% yield with 82% de, which was converted to the corresponding amino ketone 12. However, the reaction of 2-chlorophenyllithium did not work in which this route was unavailable for the synthesis of 1. Then, an alternative strategy directed toward 1, starting with a compound having 2-chlorophenyl groups in advance, was designed in which the chiral quaternary carbon center bearing a nitrogen atom in the ring is created by the enantioselective reduction of the atropisomeric intermediate ketone 18, and the sequential allyl cyanate-to-isocyanate rearrangement with complete 1,3-chirality transfer. The first asymmetric synthesis of 1 with excellent selectivity (>99% ee) was accomplished by a short path according to the strategy.     

The total synthesis of (−)-tetrahydrolipstatin

Careful control during the bromolactonisation of β,γ-unsaturated acid 3 was required to afford regioselectively the trans-β-lactone 4 as the major diastereomer. Radical debromination of 4 followed by a three-step sequence of reactions afforded the lipase inhibitor (−)-tetrahydrolipstatin.     

Microbial transformation of (−)-Huperzine A

Five products were yielded from the transformation of (−)-Huperzine A (1) by Streptomyces griseus CACC 200300. Their structures were determined as 16-hydroxyl huperzine A (2), 14α-hydroxyl huperzine A (3), huperzine A 8α,15α-epoxide (4), 13N-formyl huperzine A (5), and 13N-acetyl huperzine A (6) on the basis of their chemical and physical data. It is the first report on the microbial transformation of (−)-Huperzine A and would facilitate further structural modification by chemo-enzymatic method.     

Radical cyclizations of acylsilanes in the synthesis of (+)-swainsonine and formal synthesis of (−)-epiquinamide

Radical cyclization of acylsilane is an useful synthetic methodology. To demonstrate the versatility of this method using the cyclization as a key step, polyhydroxylated indolizidine (+)-swainsonine was synthesized through two different bond connection approaches to construct the bicyclic skeleton. In the first approach, we used 2,3-isopropylidene-d-ribono-1,4-lactone (20) as a chiral building block to form the indolizidine skeleton through a 1,6-cyclization. In the second approach, (S)-(+)-5-oxo-2-tetrahydrofurancarboxylic acid (23) was used to construct the same ring system through a 1,5-cyclization. Starting from acid 23, we also synthesized exo-1-hydroxyquinolizidin-4-one (56), which was a synthetic intermediate in the synthesis of polyhydroxylated quinolizidine (−)-epiquinamide.     

A direct efficient diastereoselective synthesis of enantiopure 3-substituted-isobenzofuranones

Condensation of (−)-8-benzylaminomenthol with o-phthaldehyde lead to the chiral perhydro-1,3-benzoxazine 2 as single diastereoisomer. That compound reacted with different organometallics leading to 3 in excellent de. Hydrolysis of carbinols, followed by oxidation of the intermediates allowed for the synthesis of enantiopure phthalides.     

Synthetic applications of homoiodo allylsilane II. Total syntheses of (−)-andrographolide and (+)-rostratone

The first total synthesis of (−)-andrographolide (1), an ent-Labdane diterpenoid lactone from Asian medicinal herb Andrographis paniculata, was achieved via the biomimetic cyclization of an epoxy homoiodo allylsilane precursor 7. Asymmetric total synthesis of (+)-rostratone (25), an antipodal Labdane diterpenoid, was also accomplished via similar biomimetic cyclization of a readily accessible epoxy homoiodo allylsilane precursor 18.     

Efficient and highly diastereoselective preparation of a myrtenal derived bis-sulfoxide and its preliminary evaluation as chiral acyl donor

Treatment of disulfide 7 with NaIO₄ in EtOH at rt gave monosulfoxide 8 (95%), while at 50 °C it gave trans-bis-sulfoxide 6a (84%, >99% de). In contrast, treatment of 7 with MCPBA gave bis-sulfone 9 (95%). The anion of 6a reacted with benzaldehyde affording carbinol 10 (76%, >99% de). The absolute configuration of 8, 6a, and 10 was established by single crystal X-ray diffraction analyses.     

Total synthesis of (−)-funebrine via Au-catalyzed regio- and stereoselective γ-butyrolactonization of allenylsilane

The stereoselective total synthesis of (−)-funebrine from 2-butyn-1-ol was described. The crucial steps in the synthesis involved the stereoselective enolate Claisen rearrangement of the (S)-α-acyloxy-α-alkynylsilane 8, the Au-catalyzed regio- and stereoselective lactonization of the allenylsilane 7, and the Paal-Knorr pyrrole condensation using an unsymmetrical 1,4-diketone 4b.     

Synthesis, conformation and PKC isozyme surrogate binding of indolinelactam-Vs, new conformationally restricted analogues of (−)-indolactam-V

New conformationally restricted analogues of tumor promoter (−)-indolactam-V (1), indolinelactam-Vs (8, 11) and their hexyl derivatives at position 1 or 7 (9, 10, 12, 13), were synthesized from 1. (3R)-Indolinelactam-V (8) adopted a conformation similar to the twist form of 1 with a cis amide, while the conformation of (3S)-indolinelactam-V (11) was close to that of the sofa form of 1 with a trans amide. 7-Hexyl derivatives of 8 and 11 (10, 13) showed binding affinities for C1 domains of protein kinase C (PKC) isozymes compared to 1, but exhibited little selectivity among these PKC isozymes. However, introduction of the hexyl group at position 1 of 8 and 11 significantly enhanced their binding selectivity for novel PKC isozymes. The best selectivity for novel PKC isozymes was observed in (3S)-1-hexylindolinelactam-V (12) with a sofa-like conformation. These results suggest that a sofa-restricted analogue of 1 with a hydrophobic chain at an appropriate position would be a promising lead for designing agents with a high selectivity for novel PKC isozymes.     

Synthesis of indole alkaloid (−)-corynantheidol and formal synthesis of (−)-corynantheidine via one-pot asymmetric azaelectrocyclization

The highly efficient asymmetric total synthesis of indole alkaloid, (−)-corynantheidol, containing a 2,4,5-trisubstituted piperidine core, was achieved using a new version of the one-pot azaelectrocyclization reaction. The formal synthesis of (−)-corynantheidine was also achieved using the common synthetic intermediate for these corynantheines.