Unusual conversion of perfluoromethylepoxycyclopentane into a linear β-aminovinylketone by CC bond cleavage

2,3,3,4,4,5,5-Heptafluoro-1-trifluoromethyl-1,2-epoxycyclopentane reacted with 2-isopropyl-acetophenone imine giving 2,3,3,4,4,5,5-heptafluoro-2-trifluoromethyl-1-(2′-isopropylimino-2′-phenylethane) cyclopentan-1-ol, which in its turn underwent an intramolecular rearrangement yielding the linear 4,4,5,5,6,6,7,8,8,8-decafluoro-1-isopropylamino-oct-1-en-3-one, being characterized by X-ray structural analysis (triclinic, P-1, a=920.5(2), b=1027.9(3), c=1127.4(3) pm, α=110.99, β=105.68°, γ=96.75°).     

Constrained cycloalkyl analogues of glutamic acid: stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and its 6-phosphonic acid analogue

A new stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2.6-dicarboxylic acid (LY354740) 1, a potent and selective 2mGluR agonist, has been accomplished in four steps with an overall yield of 27% starting from the enantiopure (+)-(R)-2-(p-tolylsulfinyl)cyclopent-2-enone 3. The key steps include asymmetric cyclopropanation of 3 with (dimethylsulfuranylidene)acetate (EDSA) and removal of the chiral p-tolylsulfinyl auxiliary from the cycloadduct ent-4c upon treatment with iso-propylmagnesium chloride. The stereoselective hydantoin formation from the bicyclic ketone 6 formed (Bucherer–Bergs reaction) and subsequent hydrolysis completed the synthesis of 1. The same reaction sequence has been applied in the first synthesis of enantiopure (+)-2-amino-6-phosphonobicyclo[3.0.1]hexane-2-carboxylic acid 2, a structural 6-phosphono analogue of 1. The starting bicyclic ketophosphonates 9–11 have been obtained by asymmetric cyclopropanation of (?)-(S)-3 with phosphoryl sulfonium ylides, producing only two endo-isomers. The major endo-isomer (+)-11a containing the 6-diisopropoxyphosphoryl group has been converted in three steps into (+)-endo-2 in 46% overall yield.     

(+)-Neplanocin F, 2′-fluoroneplanocin, and a 6′-isoneplanocin via a common versatile cyclopentenol precursor

Reductive (diisobutylaluminum hydride) ring opening of an acetal protected cyclopentenol has provided a precursor adaptable to uniquely substituted carbocyclic nucleosides. To illustrate the broad implication of this process the preparation of unnatural (+)-neplanocin F, an ara-like 2′-fluoroneplanocin, and a 6′- isomeric l-like neplanocin analog is described.     

Synthesis of thienamycin-like 2-iso-oxacephems with optional stereochemistry

All four trans-stereoisomers of 7-(1-hydroxyethyl)-2-iso-oxacephem-4-carboxylic acids, which are the 2-iso-oxacephem analogues of Thienamycin, have been synthesized. (αR,6R,7R)- and (αS,6S,7S)-7-(1-hydroxyethyl)-3-methyl-2-iso-oxacephem-4-carboxylic acids have been prepared starting from l- and d-threonine, the configuration at the α-position was inverted by using Mitsunobu reactions providing the (αS,6R,7R)- and (αR,6S,7S)-diastereomers of the compounds above. A synthetic route to the cis-annelated analogues was also worked out.     

Sequential cyclizations of 2-isothiocyanatobenzonitrile and 2-isocyanatobenzonitrile with α-aminoketones

Pharmacologically relevant 5-thioxo-6H-imidazo[1,2-c]quinazolines and 5-oxo-6H-imidazo[1,2-c]quinazolines were prepared by sequential reactions of α-aminoketones with 2-isothiocyanatobenzonitrile and 2-isocyanatobenzonitrile, respectively.     

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.     

Spectaline and iso-6 cassine,two new piperidin 3-ol alkaloids from the leaves of cassia spectabilis

From the leaves of an african leguminosae: Cassia spectabilis DC, we have isolated two unprecedented piperidin 3-ol alkaloids. By spectral data, their structures were elucidated as follows (+)Spectaline(l): 2(S)-methyl 6(R)-(13'-oxotetradecyl)piperidin 3(S)-ol and (-)iso-6-cassine(2) 2(R)-methyl 6(R)-(11'-oxodecyl) piperidin 3(R)-ol.     

Synthesis of the trichloroacetamide derivative of enantio-iso-ADDA methyl ester

The divergent syntheses of the trichloroacetamide derivatives of (2S,3R,8R,9R,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-decadenoic acid (enantio-iso-ADDA), and (2R,3R,8R,9R,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-decadenoic acid (enantio-ADDA), have been achieved. Our approach takes advantage of highly efficient non-aldol aldol, palladium catalysed aza-Claisen and cross-metathesis methodologies.     

Stereoselective synthesis of tetrahydroisoquinoline alkaloids: (−)-trolline, (+)-crispin A, (+)-oleracein E

Tetrahydroisoquinoline alkaloids, (S)-(−)-trolline, (R)-(+)-crispin A, and (R)-(+)-oleracein E, have been synthesized stereoselectively from the both enantiomers of common intermediate (S)-4 and (R)-4. The key step in the synthesis include a stereoselective Bi(OTf)₃-catalyzed intramolecular 1,3-chirality transfer reaction of chiral non-racemic amino allylic alcohols (S)-6 and (R)-6 to construct both enantiomers of (E)-1-propenyl tetrahydroisoquinoline 4.     

A new synthesis of (−)-thioambrox and its 8-epimer

This new and straightforward synthesis of (−)-thioambrox 2, a sulphur compound whose odour resembles ambergris, starts from sclareolide 4. The stereoselectivity of the final cyclization is independent of the catalyst selected, and compound 2 is always favoured over (+)-iso-thioambrox 3. With hydrochloric acid as catalyst, the cyclization is unexpectedly stereospecific to give 2 in high yield at room temperature.     

Synthesis of the 6′-iso analogues of neplanocin A and 5′-homoneplanocin A

An efficient synthesis of 6′-isoneplanocin A and 6′ -isohomoneplanocin A is reported. The key steps in the synthesis include an enyne metathesis and a regioselective oxidation.     

Microwave-assisted regioselective synthesis and isomerization of 6-O-vanillyl- and 6-O-iso-vanillyl hexoses and studies of their activities as radical scavengers by EPR spectroscopy

Four 6-O-substituted saccharides, namely 6-O-vanillyl-d-glucose 1, 6-O-vanillyl-d-mannose 2, 6-O-iso-vanillyl-d-glucose 3 and 6-O-iso-vanillyl-d-mannose 4 have been synthesized. Synthesized saccharide derivatives have been subsequently used in Mo(VI)-catalyzed stereospecific isomerizations yielding compounds with potential radical scavenging activity. In order to accelerate intramolecular isomerization rates and conversions microwave irradiation was used. Synthesized products were obtained with excellent stereoselectivity in good conversions and were tested by EPR spectroscopy for radical scavenging activity.     

Determination of absolute configuration using vibrational circular dichroism spectroscopy: the chiral sulfoxide 1-thiochroman S-oxide

We have determined the absolute configuration of the chiral sulfoxide 1-thiochroman S-oxide 1 using vibrational circular dichroism (VCD) spectroscopy. The VCD spectrum of a CCl₄ solution of 1 was analyzed using density functional theory (DFT), which predicts three stable conformations of 1, separated by <1 kcal/mol. The VCD spectrum predicted using the DFT/GIAO methodology for the equilibrium mixture of the three conformations of (S)-1 is in excellent agreement with the experimental spectrum of (+)-1. The absolute configuration of 1 is therefore (R)-(−)/(S)-(+). (+)-1 and (−)-1 of high enantiomeric excess (e.e.) were synthesized in high yields via asymmetric oxidation of 1-thiochroman 2 using Ti(iso-PrO)₄/(R,R)-1,2-diphenylethane-1,2-diol/H₂O/tert-butyl hydroperoxide and Ti(iso-PrO)₄/l-diethyl tartrate/H₂O/cumene hydroperoxide, respectively.     

Facile enantiospecific synthesis of (+)-iso-cladospolide B

Enantiospecific synthesis of bio-active butenolide (+)-iso-cladospolide B from d-(?)-tartaric acid in a short synthetic sequence is presented. Pivotal reaction sequence includes cross metathesis of an alkene and Wittig olefination.     

Spectalinine and iso-6-carnavaline,two unprecedented piperidine alkaloids from the seeds of cassia spectabilis

Along with the alkaloïds (+)spectaline (1) and (?)iso-6-cassine (2), two new piperidinol alkaloïds have been isolated from the seeds of Cassia spectabilis DC. They have been shown to possess structures 3 and 4 through chemical and spectral studies.     

Copper mediated scalemic organolithium reagents in alkaloid syntheses

Scalemic 2-pyrrolidinylcuprates generated via asymmetric deprotonation of N-Boc-pyrrolidine followed by treatment with THF soluble CuCN·2LiCl react with ω-functionalized vinyl halides to afford 2-alkenyl-N-Boc-pyrrolidines. N-Boc deprotection and cyclization via intramolecular N-alkylation generates the pyrrolizidine or indolizidine skeletons. Subsequent functional group manipulation affords enantioenriched (+)-heliotridane, (+)-isoretronecanol, a formal synthesis of (+)-laburnine, (+)-(R)-2,3,5,7a-tetrahydro-1H-pyrrolizine, (R)-1,2,3,5,6,8a-hexahydroindolizine, (+)-ent-δ-coniceine, (+)-tashiromine and (+)-5-epitashiromine.     

New natural products in the discorhabdin A- and B-series from New Zealand-sourced Latrunculia spp. sponges

A survey of the secondary metabolite chemistry profiles of New Zealand sponges of the genus Latrunculia has yielded new members of the discorhabdin A- and B-type families. The structure elucidation of (+)-(6R,8S)-1-thiomethyldiscorhabdin G^∗/I (5) and both enantiomers of 16a,17a-dehydrodiscorhabdin W (6) are reported. Absolute configurations were assigned by comparison with a dataset of recently reported electronic circular dichroism spectra of discorhabdin alkaloids. A stereochemical correction of the recently reported natural product (+)-3-dihydrodiscorhabdin A from (3S,5R,6S,8S)-(7) to the C3-epimeric (+)-(3R,5R,6S,8S)-(8) and assignment of absolute configuration is also presented. Semi-synthesis of (+)-(3S,5R,6S,8S)-(7) from (+)-discorhabdin A provided further evidence for this structure revision. Cytotoxicity data is reported for 5-8.     

Cytotoxic cembranoids from the Red Sea soft coral, Sarcophyton auritum

Chemical investigation of the Red Sea soft coral Sarcophyton auritum led to the isolation and structure elucidation of two new diterpene cembranoids; 2-epi-sarcophine (2) and (1R,2E,4S,6E,8R,11R,12R)-2,6-cembradiene-4,8,11,12-tetrol (4), as well as two known diterpene cembranoids, reported for the first time from this species, namely sarcophine (1) and (+)-7α,8β-dihydroxydeepoxysarcophine (3). Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The isolated cembranoids were found to display high cytotoxicity against HepG2 (liver cancer cell line) and MCF-7 (breast cancer cell line).     

A structure and an absolute configuration of (+)-alternamin, a new coumarin from Murraya alternans having antidote activity against snake venom

(+)-Alternamin (1), a new dihydrofuranocoumarin, was isolated from the aerial parts of Murraya alternans (Kurz) Swingle. The analysis 2-D NMR correlation of (+)-1 led to either of linear dihydrofuranocoumarin (2A, 2C) or angular one (2B). An IR and a vibrational circular dichroism (VCD) studies were conducted to distinguish the structure and to assign the absolute configuration. By comparison of the observed spectra with the calculated spectra for (S)-2A, (S)-2B, and (R)-2C, the molecular structure of (+)-1 was determined to be (S)-(+)-5,8-dimethoxymarmesin. The compound exhibited antidote activity against snake venom from Trimeresurus flavoviridis, affording experimental support for the pharmacological use of M. alternans.     

Stereoselective total synthesis of (+)-cardiobutanolide and (+)-3-epi-cardiobutanolide from diacetone d-glucose

A chiron approach starting with 3-O-benzyl-1,2-O-isopropylidene-α-d-xylo-pentodialdo-1,4-furanose utilizing a Grignard reaction, Mitsunobu stereoinversion, ethyl diazoacetate addition, and selective reduction of the ketone is employed as a key step for the total synthesis of (+)-cardiobutanolide described; a similar strategy is also reported for the first total synthesis of (+)-3-epi-cardiobutanolide.