Enantioselective synthesis of a potential key intermediate for the total synthesis of fumagillin

Key intermediate, 7, of a projected total synthesis of the anti-angiogenesis compound Fumagillin 1 and the semi-synthetic analogue TNP-470 2, has been prepared in enantiomerically pure form by employing an early nucleophilic addition ring closure [NARC] sequence to construct the cyclohexene backbone.     

Formal enantioselective synthesis of (+)-vincamine. The first enantioselective route to (+)-3,14-epivincamine and its enantiomer

A formal synthesis of (+)-vincamine (1) from (S)-(+)-2-ethyl-2-(2-methoxycarbonylethyl) cyclopentanone (6a) is described. This intermediate had previously been obtained by our research group in 90% ee through d'Angelo's deracemizing alkylation of the chiral imine 7, easily prepared from (R)-(+)-α-methylbenzylamine and 2-ethyl cyclopentanone with methyl acrylate. A potencial advanced intermediate for the synthesis of (+)-4, an epimer of (+)-1 at positions C-3 and C-14, has also been prepared from 6a.     

Tandem radical cyclization-based strategy for the synthesis of oxa- and aza-cages: a case of fragmentation versus cyclization

A new strategy for the synthesis of oxa- and aza-cage compounds based on tandem radical cyclizations is described. The iodides 1 lead to oxa-cages 3 after two tandem radical cyclizations. The ester 10aa on reaction with n-Bu₃SnH and AIBN gives rise to the oxa-cage 12aa after two tandem 5-exo-trig cyclizations. On the other hand, reaction of the ketones 17aa and 21 under similar conditions furnished the oxa-cages 20aa and 23, respectively, via a double 5-exo-trig tandem radical cyclization followed by fragmentation.     

Total synthesis of 1-deoxy-7,8a-di-epi-castanospermine and formal synthesis of pumiliotoxin-251D

A concise and efficient synthesis of (6R,7S,8R,8aS)-6,7,8-trihydroxyindolizidine (1-deoxy-7,8a-di-epi-castanospermine) 2 is described. The synthesis employs cross metathesis in building the key intermediate 9 and is used effectively in constructing indolizidine skeleton for the total synthesis of 1-deoxy-7,8a-di-epi-castanospermine and also for the bicyclic framework of pumiliotoxin 251D 12, 13. The indolizidine skeleton is achieved in one pot sequence of transformations such as deprotection of Cbz group, reduction of double bond, and cyclization. The configurational and conformational structures of compound 10 are unambiguously confirmed by X-ray analysis.     

A new total synthesis of (±)-oestrone

A conceptually new total synthesis of oestrone, based on a novel cascade of radical cyclisations from the iodo aryl vinylcyclopropane 2, via 10, 15, 16 and 17, leading to the intermediate trans,anti,trans-oestradiol derivative 11 in one step, is described. Oxidation of 11, followed by demethylation of the resulting aryl methyl ether 18 then gives (±)-oestrone 1.     

Asymmetric synthesis of macrolactin analogue

Total asymmetric synthesis of macrolactin A analogue was accomplished by the convergent strategy. Rapid access to advanced intermediate 16 through isomerization of ynone to (E,E)-conjugated dienone is a key step of this synthesis. Overall, control of all of the four stereocenters was achieved by means of asymmetric and diastereoselective reactions without using any chiral natural sources.     

An approach to the synthesis of isolongifolene

An efficient synthesis of 7, 7-dimethyltricyclo [6.2.1.0^1,6] undeca-2, 5-dien-4-one 2, an advanced intermediate for the synthesis of the tricyclic sesquiterpene isolongifolene 1, has been carried out utilising Ar₁-5 participation reaction as the key step.     

The efficient synthesis of carbodiimides using a titanium imido complex

An efficient rt synthesis of carbodiimides or ureas from the combination of a titanium imido complex 2 and a range of 12 aryl and aliphatic isocyanates is described. Control experiments suggest that carbodimide formation is via heterocumulene metathesis through a transient intermediate η²-ureato-N,O metallacycle 8.     

Stereoselective and versatile approach for the synthesis of gossyplure and its components

Efficient synthetic routes to gossyplure and its components (1a and 1b) were formulated. The three key units viz the alkynol 3, the bromide 5, and the alkanal 13 were derived from easily accessible starting materials. Alkylation of 3 with 5, and subsequent semihydrogenation followed by oxidation, provided the C₁₁-alkenal 8 which was subjected to a stereocontrolled Wittig reaction with a C₅-phosphonium salt, to yield directly the desired pheromone (1a + 1b). The synthesis of its individual components involved the manipulation via an acetylenic intermediate, viz the alkynol 14 which was obtained through alkylation of 3. A sequence of well-established reactions on 14, then provided the corresponding (E)- and (Z)-alkenylphosphonium salts which upon a (Z)-specific Wittig olefination with the C₇-aldehyde (13), led to the stereoselective synthesis of 1a and 1b.     

A novel convergent synthesis of the potent antiglaucoma agent travoprost

The 16-(3-trifluoromethyl)phenoxy PGF_2α analogue travoprost (8a) has potent topical ocular activity. A novel convergent synthesis of 13,14-en-15-ol PGF_2α analogues was developed employing Julia–Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone (5Z)-(+)-15 with a new enantiomerically pure aldehyde ω-chain synthon (S)-(?)-16a. Subsequent hydrolysis of protecting groups and final esterification of fluprostenol (7a) yielded travoprost (8a). The main advantages are the preparation of high purity travoprost (8a) and the application of comparatively cheap reagents. The novel convergent strategy allows the synthesis of a whole series of 13,14-en-15-ol PGF_2α analogues from a common and structurally advanced prostaglandin intermediate 15. The preparation and identification of two synthetic impurities, 15-epi isomer (8b) of travoprost and a new prostaglandin related ester (5Z)-(+)-18, are also described.     

Progress toward the total synthesis of 9β-hydroxyvertine: Construction of an advanced quinolizidine intermediate

Progress toward the total synthesis of 9β-hydroxyvertine 2 is described. Our approach involves a Petasis borono-Mannich reaction to assemble a key intermediate A, securing the correct configuration at H-9 and H-10 in the final targeted molecule. Subsequent formation of the quinolizidine framework B allowed the synthesis of an advanced intermediate containing all but the lactone moiety of 2. Our unsuccessful attempts at introducing this lactone feature are also described.     

New synthesis of glycolipid immunostimulants RC-529 and CRX-524

An efficient and scalable synthesis of the potent vaccine adjuvant RC-529 (3) and TLR4 agonist CRX-524 (4) is described in eight steps from 1,3,4,6-tetra-O-acetyl-2-amino-2-benzyloxycarbonyl-2-deoxy-β-d-glucopyranose (10c) in ca. 25% overall yield. The synthesis features the strategic use of the N-Cbz group for β-glycosylation and the selective N,N,O-triacylation of common advanced intermediate 15 with (R)-3-tetradecanoyloxy or decanoyloxytetradecanoic acid (8, 9) late in the synthesis. A new method for preparing and enhancing the enantiopurity of (R)-3-hydroxytetradecanoic acid (6), a key component of 3 and 4 as well as bacterial lipid A, is also described.     

Stereoselective synthesis of chiral β-amino trifluoromethyl alcohol: development of a manufacturing process for a key intermediate in the production of a novel elastase inhibitor,AE-3763

We have successfully synthesized chiral β-amino trifluoromethyl alcohol (2S,3S)-7a, which is a key intermediate in the production of AE-3763, by stereoselective reduction of N-Cbz-protected 5-hydroxy-5-(trifluoromethyl)-1,3-oxazolidine 4 prepared from L-valine in 3 steps followed by alkaline hydrolysis. This new method can be applied to the industrial-scale synthesis of AE-3763.     

Recent results in the free radical mediated synthesis of enantiomerically pure,highly functionalized carbocycles from carbohydrates

The free radical cyclization strategy applied to precursors 1, 2 and 14 shows the power and the state of art of this ring closing method for the stereocontrolled synthesis of enantiomerically pure, highly functionalized carbocycles from carbohydrates. The tributyltin hydride mediated free radical cyclization of alkyne tethered N,N-diphenylhydrazones (1) and oxime ethers (2) give the stannylated aminocyclopentitol derivatives 4 and 11, respectively, in moderate yield and with complete stereoselectivity. The 6-exo-trig cyclization of aldehyde/oxime ether 14 derived from D-glucose has been revisited using tributyltin hydride as a reagent. This new protocol shows a superior stereoselection compared with the previous results obtained with samarium diiodide. In summary, an efficient protocol has been set up for the synthesis of enantiomerically pure, polyhydroxy aminocyclohexane derivatives, which are difficult to obtain by other methodologies.     

First synthesis of polyoxin M

Chiral enolate derived from (4R)-4-tert-butyldiphenylsilyloxymethyl-4-butanolide 10 with lithium hexamethyldisilyazide (LiHMDS) was treated with trisyl azide, followed by addition of TMSCl to give (2S,4R)-2-azido-4-[(tert-butyldiphenylsilyloxy)methyl]-4-butanolide 8 (53%), from which the first total synthesis of polyoxin M (1) was achieved in overall 3.2% yield (13 steps) from d-glutamic acid. Moreover, the synthesis of the reported synthetic intermediate (2S,4R)-4-hydroxyornithine congener 6 for biphenomycins A and B was also achieved in overall 4.1% yield (12 steps) from d-glutamic acid.     

The first enantioselective synthesis of imino-deoxydigitoxose and protected imino-digitoxose by using l-threonine aldolase-catalyzed aldol condensation

The first enantioselective synthesis of protected imino-digitoxose (?)-16 was attained starting with a synthetic intermediate of polyoxin C prepared by the l-threonine aldolase-catalyzed aldol condensation of (2S,3S)-2,3-O-isopropyriden-4-penten-1-al 8 and glycine. The strategy took advantage of an intramolecular nucleophilic attack by a Cbz-protected amino group on the hemiacetal carbon, a side reaction in the synthesis of natural products, for the formation of the piperidine ring of the imino-sugar. Imino-deoxydigitoxose (+)-18 was also synthesized from (?)-16 by reduction and acid hydrolysis.     

A new and short enantioselective synthesis of (R)-pantolactone

Dihydro-4,4-dimethyl-2(3H)-furanone 6, the key intermediate to (R)-pantolactone 2, has been synthesized in two steps via the radical cyclization of bromoether 5. Silyl enol ether 7, prepared from 6, on Sharpless asymmetric dihydroxylation gave (R)-pantolactone 2 in moderate yield and excellent enantioselectivity.     

Natural product synthesis from (8aR)- and (8aS)-bicyclofarnesols: synthesis of (+)-wiedendiol A, (+)-norsesterterpene diene ester and (−)-subersic acid

Both enantiomers (8aR)-7 and (8aS)-7 of bicyclofarnesol were synthesized from the enzymatic resolution products (1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-5 (98% ee) and acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aS)-6 (>99% ee), respectively. The formal synthesis of (+)-wiedendiol 1 was achieved via a coupling reaction of an ate complex derived from 1,2,4-trimethoxybenzene with allyl bromide (8aS)-8 derived from (8aS)-7. The total synthesis of (+)-norsesterterpene diene ester 2 was achieved, based on the synthesis of (13E,10S)-α,β-unsaturated aldehyde 12, derived from (8aS)-7, followed by the selective construction of the (3E,5E)-diene moiety including a C(2)-stereogenic centre in (+)-2. The total synthesis of (−)-subersic acid 3 was carried out based on a Stille coupling between allyl trifluoroacetate congener 25c, derived from (8aR)-7, corresponding to the diterpene part, and aryl stannane congener 26 in the presence of Pd catalyst and CuI as an additive.     

Approaches to the total synthesis of phomactins

The macrocyclic triene 34, an advanced intermediate for synthesis of phomactins, has been synthesized using the 2,3-Wittig rearrangement of the propargylic ether 21 as a key step.     

A concise formal stereoselective total synthesis of （-）-swainsonine

A short formal stereoselective synthesis of （-）-swainsonine （1） is described. Our synthesis started with the versatile building block （R）-3-benzyloxyglutarimide 5. Through controlled regioselective reduction, Ley＇s-sulfone chemistry （N-α-sulfonylation and ZnCl2-catalyzed N-α-amidovinylation）, an RCM reaction, and an amide reduction, the synthesis of unsaturated indolizidine （8R,8aS）-3 has been achieved in five steps. The indolizidine （8R,8aS）-3 is an advanced intermediate toward the synthesis of （-）-swainsonine （1）.