Enantiospecific synthesis of (−)-2-hydroxy-exo-brevicomin

An enantiospecific synthesis of (−)-2-hydroxy-exo-brevicomin was achieved from l-(+)-tartaric acid in high yield. The key step involves a very highly diastereoselective reduction of a keto Weinreb amide.     

Enantiospecific synthesis of (-)-trachyspic acid

The enantiospecific synthesis of (-)-trachyspic acid () is presented. This has allowed for the assignment of the absolute configuration of natural (+)-trachyspic acid as 3S,4S,6S.     

Enantiospecific total synthesis of (-)-4-thiocyanatoneopupukeanane

Enantiospecific synthesis of the natural enantiomer of the marine sesquiterpene (-)-4-thiocyanatoneopupukeanane (6) is described. The bicyclo[2.2.2]octanecarboxylate 14, obtained from (R)-carvone via Michael-Michael reaction, was transformed into neopupukeananedione 12 by employing rhodium acetate catalyzed intramolecular C-H insertion of the diazo ketones 16 or 19 as the key reaction. Regioselective deoxygenation of the C-2 ketone transformed the dione 12 into neopupukean-4-one 10. Alternately, the keto ester 18 was also transformed into neopupukean-4-one 10 via regioselective deoxygenation of the ketone in 18 followed by intramolecular rhodium carbenoid C-H insertion of the diazo ketone 31. Finally, neopupukean-4-one 10 was transformed into (-)-4-thiocyanatoneopupukeanane 6 via the alcohol 32 and the mesylate 33.     

Enantiospecific synthesis of carbapentostatins

In this paper we describe enantioselective syntheses of (+)-carbapentostatin (8) and its cyclopentyl analogue 12b. A new and efficient one-pot, two-step preparation of aldehyde 15 has been developed, based on the borane reduction of N-Pf-protected L-aspartic acid gamma-methyl ester (13) and Swern oxidation of the resulting alcohol. Homologation to diester 18 and ring formation by Dieckman cyclization, followed by reduction and dehydration steps, afford the 4-amino-1-cyclopentenemethanol derivative 22. Hydroboration and oxidation transform this compound stereospecifically into aminocyclopentanol 26, the key aminocyclitol component for an asymmetric synthesis of (+)-carbapentostatin.     

Enantiospecific synthesis of angular triquinanes

The enantiospecific synthesis of angular triquinanes has been developed starting from the readily available (S)-campholenaldehyde. Two alternate strategies have been used, one employing a Johnson’s orthoester Claisen rearrangement followed by an intramolecular cyclopropanation and regioselective cyclopropane ring cleavage, and a second one based on a RCM reaction.     

Enantiospecific synthesis of 1-azafagomine

For the first time the two enantiomeric forms of the glycosidase inhibitor 1-azafagomine have been synthesised starting from D- and L-xylose. D-Xylose was converted to the 2,3,5-tribenzylfuranose, which upon reductive amination with tert-butyl carbazate gave the protected 1-hydrazino-1-deoxypentitol in high yield. N-acetylation, mesylation of the 4-OH, removal of the Boc group, cyclisation and deprotection gave (+)-1-azafagomine ((+)-1). By a similar sequence of reactions, L-xylose was converted to (-)-1-azafagomine ((-)-1). Enzymatic and other routes to optically pure 1-azafagomine were also studied. Compound (-)-1 is a potent competitive glycosidase inhibitor, while (+)-1 has no biological activity. The inhibition of almond beta-glucosidase by (-)-1 was found to be slow owing to a slow binding step of inhibitor to enzyme, with no subsequent conformational rearrangement. The rate constants for binding and release were found to be 3.3 x 10(4)M(-1)s(-1) and 0.011 s(-1), respectively, yielding Ki = 0.33 microM.     

Enantiospecific total synthesis of aciphyllene

Enantiospecific total synthesis of the sesquiterpene aciphyllene and its three epimers have been described starting from the readily available monoterpene (R)-limonene employing an intramolecular type II carbonyl ene reaction as the key step.     

Enantiospecific synthesis of norcoronamic acids

The synthesis of enantiomerically pure norcoronamic acids, starting from enantiomerically pure 1,2-propanediols, is described.     

Enantiospecific synthesis of (+)-hernandulcin

The sesquiterpene (+)-hernandulcin has been enantiospecifically synthesized starting from (−)-neoisopulegol in seven steps and in 25% overall yield.     

Enantiospecific total synthesis of lairdinol A

The synthesis of lairdinol A, a component of the host-selective phytotoxin depsilairdin, was achieved in 12 steps (18% overall yield) without the use of protecting groups starting with the Diels-Alder reaction of (R)-carvone with 3-trimethylsilyloxy-1,3-pentadiene. The key step established the trans ring fusion by preferential epoxidation of a trans-fused enone in an equilibrating mixture of the cis-fused and trans-fused diastereomers (i.e., equivalent to a dynamic kinetic resolution of these isomers). The synthesis confirms the absolute configurations of lairdinol A and its enantiomer, cyperusol C.     

Enantiospecific total synthesis of (−)-crotanecine

Crotanecine is the necine base component of a number of pyrrolizidine alkaloids. This necine subunit is an amino triol bearing a primary allylic alcohol characterized by an all-cis relationship of its stereocenters. The synthesis of crotanecine has been accomplished using simple yet versatile ring construction approach using ribose as chiral starting point.     

Enantiospecific synthesis of tetrasubstituted δ-lactones

For investigations concerning the selectivity of polyketide synthases (PKSs) which have been rationally engineered through genetic techniques the synthesis of substituted δ-lactones is of great importance. An enantiospecific route towards eight of the possible sixteen stereoisomers was developed which is also readily adaptable for the introduction of alkyl modifications and isotopic labels.     

Enantiospecific synthesis of a glycoside of d-epi-purpurosamine

2-Propyl d-epi-purpurosaminide dihydrochloride 14 and its di-N-acetylated derivative 15 were synthesized by an enantiospecific sequence which involves the 2-propyl 6-O-acetyl-3,4-dideoxy-α-d-erythro-hex-3-enopyranosid-2-ulose 2 as the key precursor. The first approach through the saturated diol 4, prepared by reduction of the enone system of 2, was unsuccessful as the C-2 position of 2,6-di-O-sulfonyl derivatives 5 and 6 resisted substitution by azide. Therefore, an alternative sequence starting from the allylic alcohol 3, also derived from 2, was developed. In this case, the 2,6-di-O-tosyl derivative 9 gave the expected 2,6-diazide 10 with additional unwanted rearrangement of the double bond to the 2-propyl 4,6-diazido-2,3,4,6-tetradeoxy-α-d-threo-hex-2-enopyranoside 11 isomer. However, the ditriflate derivative 13, analogous to 9, underwent substitution to afford the diazide 10 in good yield. Upon reduction of the azide functions and saturation of the double bond of 10 by catalytic hydrogenation under acidic conditions, the dihydrochloride salt 14 was obtained as a crystalline product (43% overall yield from 3).     

Enantiospecific total synthesis of (-)-polyoxamic acid using 2,3-aziridino-gamma-lactone methodology

The non-natural enantiomer of polyoxamic acid was synthesized in six steps from 2,3-aziridino-gamma-lactone 7 with an overall yield of 10%. The key step of the strategy is a deprotection-protection sequence on the nitrogen atom of the aziridine ring required for aziridine activation toward nucleophilic ring opening.     

Enantiospecific synthesis of β-lactams via cycloaddition

Enantiospecific synthesis of variously substituted cis-β-lactams can be achieved by the annelation of Schiff bases from optically active ketal aldehydes derived from D-threonine. Similar annelation of Schiff bases from the triphenylsilyl ether of D-threonine ester and cinnamaldehyde leads to cis-β-lactams with high diastereofacial selectivity.     

Enantiospecific synthesis of the phospholipase A2 inhibitor (-)-cinatrin B

The first enantiospecific synthesis of phospholipase A2 (PLA2) inhibitor (-)-cinatrin B (2) from the D-arabinose derivative 9 is described. The spirolactone system was formed by an Ireland-Claisen rearrangement of the allyl ester 8 followed by hydrolysis and stereoselective iodolactonization. The stereoselectivity of the rearrangement was controlled by the asymmetry in the allylic alcohol fragment. Ester (S)-8 gave the desired rearrangement product 7 and the epimer 13 in high yield as a 73:27 ratio, respectively. The final stereocenter at C2 was introduced via a chelation-controlled addition of the Grignard reagent derived from trimethylsilylacetylene to alpha-hydroxy ketone 6. Transformation of the terminal alkyne into the methyl ester 21 followed by acetal hydrolysis and selective lactol oxidation afforded cinatrin B methyl ester (22). Base hydrolysis and acid-induced relactonization then gave (-)-cinatrin B (2).     

Arachidonate epoxygenase: Total synthesis of both enantiomers of 8,9- and 11,12-epoxyricosatrienoic acid

Both enantiomers of the epoxygenase metabolites 8,9- and 11,12-epoxyeicosatrienoic acid (EET) were synthesized by a convergent strategy utilizing dimethyl D- or L-malate and erythrospecific epoxidation.     

Enantiospecific synthesis of optically active cyclohexylidene bromomethanes

Optically pure cyclohexylidene bromomethanes were prepared by stereospecific bromination alpha to a chiral sulfoxide, followed by the stereospecific pyrolytic elimination of the sulfoxide moiety.     

Enantiospecific total synthesis of 15-hydroxy-5-(methoxymethoxy)crinipellin-9-one

Enantiospecific total synthesis of the crinipellin mentioned in the title was accomplished. In the present synthesis cyclopentane ring in campholenaldehyde was identified as the B-ring, two intramolecular rhodium carbenoid CH insertion reactions were employed for the construction of the A and C rings, and an intramolecular Michael addition reaction was utilized for the construction of the D-ring of crinipellin.     

Enantiospecific total synthesis of (-)-megaphone by a highly controlled consecutive 1,4- and 1,3-asymmetric induction

Enantiospecific total synthesis of (-)-megaphone (1) is reported. The key synthetic tactic is the use of (4$\text{S}$)-2$\text{Z}$-ethylidene-4-trityloxymethyl-butan-4-olide (6) to both establish the relative and absolute stereochemistry of the contiguous tertiary and quaternary carbon centers by a highly controlled 1,4- and 1,3-asymmetric induction and construct the 4-methoxy-6,6-dialkyl-cyclohexenone portion of 1.