A facile synthesis of (6S,1′S)-(+)-hernandulcin and (6S,1′R)-(+)-epihernandulcin

A facile total synthesis of (+)-hernandulcin (1) was accomplished from (−)-isopulegol in 6 steps with 15% overall yield. Epoxidation of (−)-isopulegol with m-chloroperbenzoic acid followed by opening of the epoxide 3a with prenyl Grignard afforded the tertiary alcohol 4a with correct C-6 and C-1′ stereochemistry as a major product. Oxidation of the secondary alcohol in compound 4a to the ketone 5a was accomplished in high yield by using TPAP and N-methylmorpholine N-oxide. Conversion of the ketone 5a to α,β-unsaturated ketone via organoselenium intermediate gave (+)-hernandulcin (1). This method was also successfully applied to the synthesis of (+)-epihernandulcin (2).     

Total synthesis of (+)-epiepoformin, (+)-epiepoxydon and (+)-bromoxone employing a useful chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexanecarboxylate

Enantioselective total synthesis of (+)-epiepoformin 1, (+)-epiepoxydon 2 and (+)-bromoxone 3 using a chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclo- hexanecarboxylate 6, is described. Since the synthesis afforded intermediates 18, 2 and 25, it accomplished a formal synthesis of (−)-theobroxide 19, (−)-phyllostine 22, (+)-herveynone 27 and (−)-asperpentyn 28. The usefulness of 6 for the synthesis of natural epoxycyclohexene derivatives was demonstrated.     

Stereoselective total syntheses of (+)-exo- and (−)-exo-brevicomins, (+)-endo- and (−)-endo-brevicomins, (+)- and (−)-cardiobutanolides, (+)-goniofufurone

Stereoselective total syntheses of aggregation pheromones (+)-exo-brevicomin (9a), (−)-exo-brevicomin (9b), (+)-endo-brevicomin (9c), (−)-endo-brevicomin (9d) and styryllactones (+)-cardiobutanolide (14a), (−)-cardiobutanolide (14b), and (+)-goniofufurone (19a) were achieved in good yields from enantiomerically pure highly functionalized furanoid glycal building blocks (1a-d) involving similar synthetic strategies, thus making these furanoid glycals highly useful building blocks in diversity-oriented synthesis (DOS).     

Asymmetric synthesis of the 6-cyanoindole derivatives as non-steroidal glucocorticoid receptor modulators using (+)- and (−)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate

We have successfully synthesized enantiomerically pure (+)- and (−)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate (+)-1 and (−)-1, which are key intermediates of non-steroidal glucocorticoid receptor modulators, by employing a cinchona alkaloid catalyzed addition of 6-cyanoindole to ethyl trifluoropyruvate. The optimized method can be applied to large-scale synthesis. Furthermore, using the key intermediates (+)-1 and (−)-1, enantiomerically pure glucocorticoid receptor modulators (+)-3 and (−)-3 can be synthesized (>99% ee for both compounds). The glucocorticoid receptor binding affinity was influenced by the stereogenic center at the trifluoromethyl alcohol moiety; compound (−)-3 showed a higher binding affinity compared to (+)-3.     

Total syntheses of the sesquiterpenoids (+)-trans-dracunculifoliol and (+)-4-hydroxyoppositan-7-one

Sesquiterpenoids (+)-trans-dracuncuflifoliol (1) and (+)-4-hydroxyoppositan-7-one (2) were prepared stereoselectively from enantiomerically pure (7aR)-7a-methyl-1,2,5,6,7,7a-hexahydro-4H-inden-4-one ((−)-6), whose synthesis was described herein. Conjugate addition of the organocopper (I) reagent 10 to (−)-6, followed by epimerization of the ring junction, generated 3 of the 4 contiguous chiral centers of both natural products.     

Stereocontrolled synthesis of a potent agonist of group II metabotropic glutamate receptors, (+)-LY354740, and its related derivatives

Efficient synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740: 1) and its structurally related analogs (−)-2 and (−)-3 has been accomplished starting with (1S,2R)-1-amino-2-hydroxycyclopentane- or cyclohexanecarboxylic acid (4 or 17 ) via an intramolecular cyclopropanation of α-diazo acetamide.     

Diastereoselective routes towards the austrodorane skeleton based on pinacol rearrangement: synthesis of (+)-austrodoral and (+)-austrodoric acid

Efficient routes towards the austrodorane skeleton from the labdane diterpene (−)-sclareol (22) are described. The processes, based on pinacol rearrangement, take place with complete diastereoselectivity. Utilizing these, the marine nor-sesquiterpenes (+)-austrodoral (1) and (+)-austrodoric acid (2) have been prepared from 22. Ketone 19, a key intermediate in the synthesis of rearranged cytotoxic diterpene lactones, such as norrisolide (3), has also been prepared in moderate yield.     

Preparation and application of (+)-(3,3-dimethyl-2-methylenenorbornan-1-yl)methyl methanesulfonate: a new and versatile chiral fenchone analogue

The preparation of (+)-(3,3-dimethyl-2-methylenenorbornan-1-yl)methyl methanesulfonate (9) was carried out in 2 steps, dihydroxylation and mesylation, from (−)-2-methylenebornane. Hydrolysis and reduction of 9 gave a fenchyl alcohol (2) and a methylenefenchone (21), respectively. Oxidation of 9 afforded a new analogue (23) of the class of oxatricyclo compounds. Treatment of 9 with NBS resulted in a Wagner-Meerwein rearrangement to produce brominated methylenebornane derivatives (25 and 26), which are also new compounds.     

A concise synthesis of (±) and a total synthesis of (+)-epiquinamide

A total synthesis of the quinolizidine alkaloid (+)-epiquinamide 1 has been achieved starting from (−)-pipecolinic acid 3. The key step is the highly diastereoselective addition of a TBDMS-protected propargyl alcohol to a chiral aldehyde derived from 3 to give erythro alkynol 19, which is then easily transformed into the desired bicyclic skeleton.     

Regioselective routes towards 14-hydroxyabietane diterpenes. A formal synthesis of immunosuppressant (−)-triptolide from (+)-abietic acid

Two procedures to introduce an oxygenated function into the C-14 of abietane diterpenes with complete regioselectivity have been developed. Utilizing these, the synthesis of the antileishmanial quinone (−)-12-deoxyroyleanone (1) and a formal synthesis of antitumour and immunosuppressant (−)-triptonide (7) and (−)-triptolide (8) from (+)-abietic acid (13) have been carried out.     

Gold catalysis in stereoselective natural product synthesis: (+)-linalool oxide, (−)-isocyclocapitelline, and (−)-isochrysotricine

A stereoselective synthesis of the tetrahydrofuran-containing natural products (2S,5R)-(+)-linalool oxide (1), (−)-isocyclocapitelline (2), and (−)-isochrysotricine (3) is reported. Key steps are the copper-mediated S_N2′-substitution of propargyl oxiranes 7 and the gold-catalyzed cycloisomerization of dihydroxyallenes 8/17, resulting in a highly efficient center-to-axis-to-center chirality transfer. The enantioselective total synthesis of (−)-isocyclocapitelline (2) and (−)-isochrysotricine (3) allowed the elucidation of the absolute configuration of these β-carboline natural products.     

Temporary thio-derivatization in the synthesis of (+)-4-acetylbromoxone

A stereocontrolled synthesis of the marine natural products (+)-bromoxone (1) and (+)-4-acetylbromoxone (2) is reported. The sequence features the enzymatic kinetic resolution of 4-hydroxycyclohexenone (6) via its S-benzyl adduct. Thereafter, a base-mediated elimination-silylation generated an optically active (−)-4S-4-tert-butyldimethylsilyoxycyclohexenone (5), which then underwent diastereoselective epoxidation. Saegusa-Ito oxidation enabled formation of the corresponding α,β-unsaturated ketone 13. Bromination-elimination and subsequent removal of the silicon protecting group afforded (+)-bromoxone (1) which was converted into (+)-(4S,5R,6R)-4-acetoxy-2-bromo-5,6-epoxycyclohex-2-enone (2) [(+)-4-acetylbromoxone]. Using a luciferase gene reporter assay ED₅₀ for NFκB inhibition of 9 μM was determined.     

Enantioselective synthesis and absolute configuration of the sex pheromone of Hedypathes betulinus (Coleoptera: Cerambycidae)

The male-produced sex pheromone of Hedypathes betulinus was identified as a mixture of (E)-6,10-dimethyl-5,9-undecadien-2-one (geranylacetone) (1) and its respective alcohol (2) and acetate (3). Kinetic resolution of alcohol (2) promoted by CAL-B in organic media provided both, (R)-(−)-(E)-6,10-dimethyl-5,9-undecadien-2-yl acetate (3) and (S)-(+)-(E)-6,10-dimethyl-5,9-undecadien-2-ol (2) in high enantiomeric purity. Comparative GC analysis using a chiral column revealed the natural constituents as being (R)-(3) and a mixture of (R)- and (S)-(2) in a ratio of 82.3% and 17.6%, respectively.     

A synthetic strategy using Witkop's pyrroloindole for (−)-debromoflustramine B, (+)-ent-debromoflustramine B and (+)-ent-debromoflustramide B

While prenylation of (−)-Witkop's pyrroloindole (2), secured from l-tryptophan under standard N-alkylation conditions, led to a ca. 1:1 diastereoisomeric mixture of two C^3a-alkylated indolenines 3 and 4, use of phase-transfer conditions altered this to ca. 1:2. Reduction followed by N-prenylation of the resulting secondary amines gave C,N-dialkylated products. The derived separable diastereoisomeric (−)- and (+)-Barton esters 19a and 19b were then converted into (−)-debromoflustramine B and (+)-ent-debromoflustramine B, respectively. A novel reaction involving oxygen and the carbanion derived from Barton ester 19b led to (+)-ent-debromoflustramide B. Treatment of N⁸-prenylated Witkop's pyrroloindole 5 with Lewis acid (BF₃·Et₂O) uncovered a new clean intramolecular cyclisation involving the prenyl unit.     

Molecular structures and ab initio molecular orbital calculations of the optically active derivatives of 1-aminocyclopropane-1-carboxylic acid

The novel optically active derivatives of 2,2′-disubstituted-1-aminocyclopropane-1-carboxylic acid (−)-2 and (+)-3 were synthesised from the spiro-azlactone (+)-1. Oxidation of the diol moiety of (+)-3 gave by ring enlargement the racemic mixture of 2,3-dihydrofuran derivative (±)-6. This conversion is explained by stepwise rearrangement of the initially formed tetrasubstituted cyclopropanecarbaldehyde 4 through zwitterionic's reactive intermediate 5. The formation of (±)-6 is preferred energetically as established by ab initio calculations of the ground states and possible intermediates for that rearrangement. The crystal structure and absolute configuration of the compounds (+)-1, (−)-2, (+)-3 and (−)-7 were determined by single-crystal X-ray diffraction method. All four compounds possess Z-configuration of the cyclopropane ring. The dioxolane ring in the structures (+)-1 and (−)-2 adopts half-chair conformation, while the cyclopropane ring and geminally substituted groups in the structures (−)-2, (+)-3 and (−)-7 possess the anticlinal conformation. The molecules of the compound (+)-1 are connected by very weak intermolecular hydrogen bond of C-H?O type. In the compounds (−)-2, (+)-3 and (−)-7inter- and intramolecular hydrogen bonds of N-H?O type were observed. The spiro-compound (+)-1 exhibited a more pronounced inhibitory activity against the proliferation of murine leukemia and human T-lymphocytes cells than other type of tumor cell lines and normal human fibroblast cells.     

A biomimetic total synthesis of (+)-intricarene

An asymmetric synthesis of the furanocembrane (−)-bipinnatin J (3a) found in gorgonian corals is described. Treatment of 3a with VO(acac)₂-^tBuOOH, followed by acetylation, gave acetoxypyranone 15. When 15 was heated in the presence of DBU, it underwent a transannular oxidopyrylium-alkene [5+2] cycloaddition producing the polycyclic diterpene (+)-intricarene 1, isolated from the coral Pseudopterogorgia kallos. The total synthesis of intricarene 1 mimics its most likely biosynthesis via oxidation of bipinnatin J (3a) in vivo.     

First enantiospecific synthesis of marine nor-sesquiterpene (+)-austrodoral from (−)-sclareol

A short and efficient synthesis of the rearranged nor-sesquiterpenes (+)-austrodoral (1) and (+)-austrodoric acid (2), recently isolated from the Antarctic marine mollusk Austrodoris kerguelenensis, from diterpene (−)-sclareol (4) is reported. The key step of the sequence is the pinacol rearrangement of the drimanetriol 11.     

Synthesis of the marine furanoditerpene (−)-marginatone

A synthesis of the marine labdane furanoditerpene (−)-marginatone 1 has been accomplished by a short sequence of reactions starting from (+)-coronarin E 5. The key step is the stereocontrolled-intramolecular electrophilic cyclisation of the (+)-dihydrocoronarin E 6, to the tetracyclic marginatane skeleton 7, which is subsequently functionalized by allylic oxidation to give 1. As (+)-coronarin E 5 was previously synthesized from (−)-sclareol 10, the herein reported preparation constitutes the first formal total synthesis of (−)-marginatone 1, by which its absolute configuration has been confirmed.     

Asymmetric synthesis of (+)-1-deoxynojirimycin and (+)-castanospermine

Asymmetric total syntheses of (+)-1-deoxynojirimycin (1) and (+)-castanospermine (2) are described. Starting from diene 3, the required absolute stereochemistry is introduced by an asymmetric hydroxylation followed by epoxidation. An intramolecular cyclization of amine 17 gives access to the corresponding tetrasubstituted piperidine 18, which is a precursor to compounds 1 and 2. (+)-Deoxynojirimicyn (1) was obtained in 36% yield over 11 steps from diene 3, while (+)-castanospermine (2) was achieved in 13% after 19 steps from the same starting material.     

New total synthesis of (+)-cystothiazole A based on palladium-catalyzed cyclization-methoxycarbonylation

Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpenta-4-yne-1,2-diol (6) derived from (2R,3S)-epoxy butanoate 7 followed by methylation gave the tetrahydro-2-furylidene acetate (−)-10, which was converted to the left-half aldehyde (+)-3. A Wittig reaction between (+)-4 and the phosphoranylide derived from the bithiazole-type phosphonium iodide 4 using lithium bis(trimethylsilyl)amide afforded the (+)-cystothiazole A (2).