A formal total synthesis of the sesterterpenoid (+/-)-dysidiolide and approaches to the syntheses of (+/-)-6-epi-, (+/-)-15-epi-, and (+/-)-6,15-bisepidysidiolide

A formal total synthesis of the sesterterpenoid (+/-)-dysidiolide (1), a structurally novel sponge metabolite that inhibits the cdc25A protein phosphatase, and approaches to the syntheses of (+/-)-15-epi- (34), (+/-)-6-epi- (36), and (+/-)-6, 15-bisepidysidiolide (39) are described.     

Total synthesis of (+/-)-flustramines A and C, (+/-)-flustramide A, and (-)- and (+)-debromoflustramines A

Here we describe the efficient total synthesis of the three title hexahydropyrrolo[2,3-b]indole alkaloids and debromo derivative from readily available indolin-3-ones using key domino reactions, olefination-isomerization-Claisen rearrangement (OIC), and reductive cyclization (RC). (+/-)-Flustramine C (5) was synthesized in five steps from 6-bromoindolin-3-one 9 via a key intermediate 13a. (+/-)-Flustramine A (1) has been obtained by reduction of flustramide A (6), which has been prepared in five steps from 13a. (+/-)-Debromoflustramine A (19) was provided in a similar manner from 13b. The (-)- and (+)-enantiomers of 19 were synthesized through optical resolution of (+/-)-carboxylic acid 17b using (R)-4-phenyloxazolidin-2-one.     

Determination of the enantiomers of suprofen and [2H3]suprofen in plasma by capillary gas chromatography-mass spectrometry

A method for the stereoselective assay of the (+)- and (-)-enantiomers of suprofen and [2H3]suprofen in human plasma was developed using gas chromatography-mass spectrometry-selected-ion monitoring. (+/-)-[2H7]Suprofen was used as an internal standard. The method involved diethyl ether extraction and chiral derivatization with S-(-)-1-(naphthyl)ethylamine to form diastereomeric amide. The diastereoisomers were separated on a capillary gas chromatograph-mass spectrometer. Quantitation was achieved by selected-ion monitoring of the quasi-molecular ions of the diastereoisomers. The sensitivity, specificity, accuracy and reproducibility of the method were demonstrated to be satisfactory for application to pharmacokinetic studies of suprofen enantiomers.     

Total synthesis of (+/-)-didehydrostemofoline (asparagamine A) and (+/-)-isodidehydrostemofoline

The first total syntheses of (+/-)-didehydrostemofoline (1) and (+/-)-isodidehydrostemofoline (3) are reported. The synthesis begins with the Diels-Alder reaction of readily available pyrrole 9 and ethyl (E)-3-nitroacrylate, the latter serving as a regioinverted equivalent of ketene. After hydrogenation to prevent retro-Diels-Alder reaction, the major cycloadduct is transformed to 7-azabicyclo[2.2.1]heptanol 14. Aza-Cope-Mannich reaction of the formaldiminium derivative of 14 delivers 1-azatricyclo[5.3.0.04.10]decane 15, which in 15 additional steps is converted to 1 and 3.     

Total syntheses of (+/-)-crinine, (+/-)-crinamine, and (+/-)-6a-epi-crinamine via the regioselective synthesis and Diels-Alder reaction of 3-aryl-5-bromo-2-pyrone

We have devised a new unified synthetic protocol to (+/-)-crinine, (+/-)-crinamine, and (+/-)-6a- epi-crinamine from the Diels-Alder cycloadduct of 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone with TBS vinyl ether. The requisite 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone was prepared from the C3-selective Stille coupling reaction of 3,5-dibromo-2-pyrone. Also noted is that the vinyl bromide can be used as a handle for further derivatization.     

Remarkable control of radical cyclization processes of cyclic enyne: total syntheses of (+/-)-methyl gummiferolate, (+/-)-methyl 7beta-hydroxykaurenoate, and (+/-)-methyl 7-oxokaurenoate and formal synthesis of (+/-)-gibberellin a(12) from a common synthetic precursor.

Total syntheses of (+/-)-methyl gummiferolate (13b), (+/-)-methyl 7beta-hydroxykaurenoate (14b), and (+/-)-methyl 7-oxokaurenoate (14d) and a formal synthesis of (+/-)-gibberellin A(12) (15) have been accomplished through the common synthetic precursor, (3aR,7aR)-3,3-dimethyl-7a-(2-propynyl)-3a,4,7,7a-tetrahydroisobenzofuranone (16). The homoallyl-homoallyl radical rearrangement reaction of the monocyclic enyne 25, derived from 16 in two steps, afforded the bicyclo[2.2.2]octane compound 26, which was converted to (+/-)-methyl gummiferolate (13b). In contrast, the radical cyclization of the bicyclic enyne 16 gave the tricyclic lactone 19, leading to (+/-)-methyl 7beta-hydroxykaurenoate (14b) and (+/-)-methyl 7-oxokaurenoate (14d). Transformation of 14d into lactone 20 was carried out in a single step under bromination conditions. This constitutes a formal total synthesis of gibberellin A(12) (15).     

General route to 4a-methylhydrofluorene diterpenoids: total syntheses of (+/-)-taiwaniaquinones d and h, (+/-)-taiwaniaquinol B, (+/-)-dichroanal B, and (+/-)-dichroanone

A general and convergent route for the synthesis of the 4a-methylhydrofluorene diterpenoids has been established through a common hexahydrofluorenone intermediate (10) obtained via Pd(0)-catalyzed reductive cyclization of a substituted 2-(2-bromobenzyl) methylene cyclohexane (13). The strategy has been successfully utilized for the synthesis of (+/-)-taiwaniaquinones D (3) and H (5), (+/-)-taiwaniaquinol B (1), (+/-)-dichroanal B (7), and (+/-)-dichroanone (8).     

Electrocyclic ring-opening/pi-allyl cation cyclization reaction sequences involving gem-dihalocyclopropanes as substrates: application to syntheses of (+/-)-, (+)-, and (-)-gamma-lycorane

The readily prepared gem-dibromocyclopropanes (+/-)-13 and (+/-)-19 each engage in a silver(I)-promoted electrocyclic ring-opening/pi-allyl cation cyclization sequence to deliver the hexahydroindole (+/-)-20, which participates in a Suzuki cross-coupling reaction with arylboronic acid 3 to give the tetracyclic compound (+/-)-21. Catalytic hydrogenation of this last compound proceeds in a completely stereoselective manner to give the saturated analogue (+/-)-24, which undergoes Bischler-Napieralski cyclization on reaction with phosphorus oxychloride. The resulting lactam (+/-)-25 is then reduced with lithium aluminum hydride to give (+/-)-gamma-lycorane [(+/-)-1]. By using (-)-menthyl-derived carbamates 27 and 28, this chemistry has been extended to the synthesis of the (+)- and (-)-modifications of the title compound.     

Stereocontrolled synthesis of polyfunctionalized cis-decalins from 2-methoxyphenols: total syntheses of (+/-)-eremopetasidione, (+/-)-3 beta-angeloyloxyfuranoeremophilane, and (+/-)-3 beta-methacryloyloxyfuranoeremophilane

A four-step stereocontrolled synthesis of polyfunctionalized cis-decalins is described, involving oxidation of 2-methoxyphenol, intermolecular Diels-Alder reaction, olefination, and Cope rearrangement. Application of this efficient strategy to the total syntheses of (+/-)-eremopetasidione, (+/-)-3 beta-angeloyloxyfuranoeremophilane, and (+/-)-3 beta-methacryloyloxyfuranoeremophilane was accomplished from creosol and ethyl vinyl ketone via a common intermediate 21.     

Enzymatic synthesis of (-)- and (+)-acetoxyhexamides and (-)- and (+)-hydroxyhexamides.

The enantioselective hydrolysis of (+/-)-4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)-benzenesulfona mides 3 with lipase Amano P from Pseudomonas sp. in a water-saturated solvent gave (R)-4-(1-hydroxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 2 (39%, > 99% ee) and unchanged (S)-3 (50%, 62% ee). On the other hand, enantioselective esterification of (+/-)-2 with lipase Amano P in the presence of vinyl acetate provided (R)-3 (41%, > 99% ee) and unchanged (S)-2 (46%, 78% ee).     

Synthesis of 2-substituted (+/-)-(2r,3r,5r)-tetrahydrofuran-3,5-dicarboxylic acid derivatives

An efficient synthesis of 2-substituted (+/-)-(2R,3R,5R)-tetrahydrofuran-3,5-dicarboxylic acid derivatives has been developed. Starting from 5-norborne-2-ol, the key intermediate (+/-)-methyl 5,6-exo,exo-(isopropylidenedioxy)-2-oxabicyclo[2.2.1]heptane-3-exo-carboxylate (15) was synthesized in an efficient six-step sequence. The key transformation is the base-catalyzed methanolysis-rearrangement of (+/-)-6,7-exo,exo-(isopropylidenedioxy)-4-exo-iodo-2-oxabicyclo[3.2.1]octan-3-one (14). Further manipulation of the 3-substituent of (+/-)-methyl 5,6-exo,exo-(isopropylidenedioxy)-2-oxabicyclo[2.2.1]heptane-3-exo-carboxylate (15) followed by deprotection of the diol moiety and ring opening catalyzed by RuCl(3)/NaIO(4) gave the title compounds in good yield.     

Asymmetric synthesis of (1R,2S,3R)-3-methylcispentacin and (1S,2S,3R)-3-methyltranspentacin by kinetic resolution of tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate

Conjugate addition of lithium dibenzylamide to tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate occurs with high levels of stereocontrol, with preferential addition of lithium dibenzylamide to the face of the cyclic alpha,beta-unsaturated acceptor anti- to the 3-methyl substituent. High levels of enantiorecognition are observed between tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate and an excess of lithium (+/-)-N-benzyl-N-alpha-methylbenzylamide (10 eq.) (E > 140) in their mutual kinetic resolution, while the kinetic resolution of tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate with lithium (S)-N-benzyl-N-alpha-methylbenzylamide proceeds to give, at 51% conversion, tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate consistent with E > 130, and in 39% yield and 99 +/- 0.5% de after purification. Subsequent deprotection by hydrogenolysis and ester hydrolysis gives (1R,2S,3R)-3-methylcispentacin in > 98% de and 98 +/- 1% ee. Selective epimerisation of tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate by treatment with KO'Bu in 'BuOH gives tert-butyl (1S,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate in quantitative yield and in > 98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving (1S,2S,3R)-3-methyltranspentacin hydrochloride in > 98% de and 97 +/- 1% ee.     

Total Synthesis of the Four Enantiomerically Pure Diasteroisomers of the Phytoprostanes E1Type II and of the 15-E2t-Isoprostanes

Syntheses of the four enantiomerically pure diastereoisomers of the phytoprostanes E1 type II and 15-E2t-isoprostanes (1-4) are described. The key steps included the preparation of the Fre?manis (+/-)-hydroxycyclopentenone 5, enzymatic resolution of this racemic hydroxycyclopentenone, Wittig and Horner-Wadsworth-Emmons (HWE) coupling reactions and finally enantioselective reductions.     

Stereoselective syntheses of (+/-)-komaroviquinone and (+/-)-faveline methyl ether through intramolecular Heck reaction

[reaction: see text] An efficient, flexible, and stereoselective convergent route for constructing the trans-10-hydroxy-1,1-dimethyloctahydrodibenzo[a,d]cyclohepten-7-ones (5a-c) was achieved via intramolecular Heck reaction. This strategy has been successfully implemented for the syntheses of (+/-)-komaroviquinone (3) through (+/-)-coulterone dimethyl ether (5c) and (+/-)-faveline methyl ether (1a).     

Configurational studies on 2-[∝-(2-ethoxyphenoxy)benzyl] morpholine fce 20124

The relative configuration of the two diastereoisomers of (±)2-[?-(2-ethoxyphenoxy)benzyl] morpholine is determined by a synthesis involving regio and stereo specific reactions. (RS,RS) diastereoisomer FCE 20124 was separated into its (+) and (-) enantiomers both by crystallization of the optically active mandelate salt and by a multi-step synthesis from (+)-(2S,3R)-3-phenylglycidic acid.     

Flow-through partial-filling affinity capillary electrophoresis using a crossreactive antibody for enantiomeric separations

It is demonstrated that the separation of diastereoisomers and enantiomers can be accomplished by the flow-through partial-filling affinity CE using a crossreactive mAb. This approach revealed differences in the binding strength of the (+/-)-cis- and (+/-)-trans-benzo[a]pyrene tetrols with the anti-polycyclic aromatic hydrocarbon mAb and demonstrated that (+)-enantiomers are more strongly immunocomplexed than their (-)-counterparts. It is proposed that crossreactive monoclonal antibodies (i.e. mAb raised against achiral molecule and possessing limited selectivity) could be effectively utilized for specific stereoisomeric differentiation and chiral separations.     

Biomimetic synthesis of (+/-)-pinnatal and (+/-)-sterekunthal A

Concise biomimetic syntheses of the antimalarial naphthoquinones (+/-)-pinnatal and (+/-)-sterekunthal A are described.     

Wittig rearrangement of 1-[(1E)-3-(Benzyloxy)prop-1-en-1-yl]adamantane

Wittig rearrangement of an allyl benzyl ether containing an adamantane fragment has been studied. 1-[(1E)-3-(Benzyloxy)prop-1-en-1-yl]adamantane reacts with butyllithium to give [2,3]- and [1,2]-rearrangement products. The [2,3]-rearrangement product is a mixture of threo and erythro diastereoisomers, the latter prevailing.     

A two-directional synthesis of (+/-)-perhydrohistrionicotoxin

An entirely two-directional synthesis of (+/-)-perhydrohistrionicotoxin is presented, utilizing a tandem oxime formation/Michael addition/[3 + 2] cycloaddition as the key step. This approach also constitutes formal syntheses of (+/-)-histrionicotoxin and (+/-)-histrionicotoxin 235A.     

Total synthesis of (S)-(+)-curcudiol, and (S)-(+)- and (R)-(-)-curcuphenol.

A highly enantioselective synthesis of the versatile chiral synthons possessing one stereogenic center, (S)- and (R)-4-aryl-5-hydroxy-(2E)-pentenoate (3) was achieved based on the enzymatic reaction of (+/-)-3 with commercially available lipases MY-30 or OF-360 from Candida rugosa. Application of (S)-3 and (R)-3 to the total syntheses of(S)-curcuphenol (1), (S)-curcudiol (2), and (R)-curcuphenol (1), respectively, is described.