Enantioselective total synthesis and absolute configuration of the alleged structure of crassinervic acid

An enantioselective synthesis of the structure reported for the natural antifungal compound, (−)-crassinervic acid (1), has been achieved starting from geraniol and p-hydroxybenzoic acid. The key chirality-inducing step is a Sharpless asymmetric epoxidation of an allylic alcohol, on the basis of which the S configuration can be assigned to the (−) natural enantiomer. The discrepancies between the spectroscopic data for synthetic and natural crassinervic acid cast some doubts on the structure assigned to the natural compound. A possible revised structure is discussed.     

Enantioselective total synthesis of the proposed structure of macrolide iriomoteolide-1b

An enantioselective total synthesis of the proposed structure of macrolide iriomoteolide-1b has been achieved by a convergent protocol, which was featured by an enantioselective organocatalytic transfer hydrogenation of enal, a Julia-Kocienski olefination to establish the C15-C16 E-olefin moiety, a Kulinkovich reaction associated with cyclopropyl-allyl rearrangement to produce allyl stannane and ytterbium triflate and carboxylic acid promoted allylation between allyl stannane and aldehyde with tertiary alcohol at the α-position. The construction of macrolide 2 was realized by the successful implementation of RCM utilizing 5 mol % Grubbs’s second generation catalyst at room temperature with E-isomer as a single product.     

Enantioselective total synthesis and structure revision of spirodihydrobenzofuranlactam 1. Total synthesis of stachybotrylactam

[reaction: see text] The enantioselective total synthesis and structure revision of spirodihydrobenzofuranlactam 1 and of its regioisomer 25 are presented. Optically pure (+)-Wieland-Miescher ketone was utilized to construct the AB bicyclic core in 10 steps. Introduction of the resorcylate D-ring unit was achieved by use of our tert-butyl ester metalation sequence. Subsequent stereoselective spirocyclization to form the C-ring was followed by regioselective ring cyanation and lactam formation to produce the pentacyclic structure 1 and its regioisomer 25.     

Enantioselective total synthesis of batzelladine F and definition of its structure

Batzelladine F (1) was synthesized in enantioselective and stereoselective fashion in 15 steps (longest linear sequence) and 1.7% overall yield from two readily available enantioenriched beta-hydroxy esters, methyl (R)-3-hydroxydecanoate and methyl (R)-3-hydroxybutyrate. Tethered Biginelli condensations are used to assemble both tricyclic guanidine fragments, with the second tethered Biginelli condensation (14 + 16 --> 17) also being employed to join the guanidine fragments. Three diastereomers of batzelladine F, 2-4, were prepared also. A combination of HPLC, optical rotation and CD spectroscopy was employed to distinguish stereoisomers 1-4, proving that 1 is the correct structure of the hexacyclic marine alkaloid batzelladine F.     

Enantioselective synthesis of chromenes

A concise approach for the synthesis of optically active chromenes is reported. The process described herein involves, as the key steps, a Sharpless-epoxidation, a selective deoxygenation, and a ring-closing metathesis.     

Enantioselective synthesis of alpha-aminopropargylphosphonates

α-Aminopropargylphosphonates have been synthesized for the first time in good yields and enantiomeric excesses (up to 81% ee) by using a copper(I)-pybox complex as the catalyst.     

Enantioselective synthesis of ansa-zirconocenes

The reaction of the chiral chelated bis-amide complex Zr{(2R,4R)-PhNCHMeCH2CHMeNPh}Cl2(THF)2 (R,R-7) with lithium ansa-bis-indenyl reagents Li2[SBI](Et2O) (8a, SBI = (1-indenyl)2SiMe2) or Li2[EBI](Et2O) (8b, EBI = 1,2-(1-indenyl)2ethane) in THF affords the corresponding ansa-zirconocenes S,S-(SBI)Zr{(2R,4R)-PhNCHMeCH2CHMeNPh} (S,S,R,R-9a) or S,S-(EBI)Zr{(2R,4R)-PhNCHMeCH2CHMeNPh} (S,S,R,R-9b) in >95% isolated yield and >99% enantiomeric excess. Compound 9b was converted to the corresponding enantiomerically pure dichloride S,S-(EBI)ZrCl2 (S,S-10b) in 91% isolated yield by reaction with HCl in Et2O. The chiral diamine (2R,4R)-HPhNCHMeCH2CHMeNHPh (R,R-5) was recovered from this reaction.     

Enantioselective synthesis of silanol

An enantioselective nucleophilic substitution reaction of achiral dialkoxysilane has been developed. The reaction proceeds with efficient stereocontrol on the silicon chirality center to give the enantioenriched silyl ether, which can be converted to the silanol without loss of enantiopurity. We have analyzed the steric course of the reaction by using DFT calculations and propose a transition state model to explain the observed enantioselectivity.     

Enantioselective synthesis of aminobenzazepinones

Enantioselective synthesis of constrained trans-aminobenzazepinone utilizing palladium-mediated Jeffery-Heck reaction and rhodium(II) catalyzed asymmetric hydrogenation as key steps are described. Diverse functional groups such as alkyl, aryl, basic or amino acid moieties were introduced with minimal racemization.     

Enantioselective synthesis of levomilnacipran

A novel approach for the asymmetric synthesis of the active (1S,2R)-enantiomer of the antidepressant milnacipran is reported. The two stereogenic centers borne by the cyclopropane ring were sequentially installed starting from phenylacetic acid.     

Enantioselective synthesis on the solid phase

Organic transformations on substrates which are immobilized on an insoluble, polymeric carrier have found broad application in compound collection synthesis. In contrast to other synthetic methodologies in solid-phase organic synthesis, reactions that afford non-racemic products are strikingly under-represented. Not only does the introduction of stereoinformation on immobilized, achiral starting materials provide enantioenriched products which can be of value for biological testing, but it also opens up new perspectives for accessible structures. This feature article gives an overview of successful enantioselective transformations on a solid support. Critical differences in the corresponding solution-phase protocols are highlighted, and applications to the generation of compound collections are particularly mentioned.     

Enantioselective synthesis of the bottom-half of chlorothricolide

The first enantioselective synthesis of a chlorothricolide intermediate is described. The synthesis features the intramolecular Diels-Alder reaction of tetraene 3.     

Enantioselective synthesis of stephacidin B

We describe an enantioselective synthetic route to the antiproliferative alkaloid stephacidin B (1) proceeding in 18 steps and 4.0% yield from 4,4-(ethylenedioxy)-2,2-dimethylcyclohexanone (3). Key features of the synthetic sequence include the use of the Corey-Bakshi-Shibata (CBS) reduction to introduce asymmetry early in the synthetic route, use of the novel electrophile N-(tert-butoxycarbonyl)-5-(isopropylsulfonyloxymethyl)-2,3-dihydropyrrole in a stereoselective enolate alkylation, a diastereoselective Strecker-type addition of hydrogen cyanide to an N-Boc enamine substrate in the solvent hexafluoroisopropanol, platinum-catalyzed nitrile hydrolysis under neutral conditions, cyclization of an acylamino radical intermediate to form the diketopiperazine core of stephacidin B, and implementation of a convergent procedure for introduction of the key 3-alkylidene-3H-indole 1-oxide functional group in the final stage of the route to prepare the structure 2, previously proposed to be the fungal metabolite avrainvillamide (17 steps, 4.2% yield). We observed that synthetic (-)-2 dimerized in the presence of triethylamine to form (+)-stephacidin B (>95%). We also obtained evidence that 2 can form 1 under mild conditions, and that 2 reacts with nucleophiles, such as methanol, by conjugate addition.     

Enantioselective total synthesis of lycopodine

The first enantioselective total synthesis of lycopodine has been completed. Key steps include a highly diastereoselective organocatalyzed cyclization of a keto sulfone to establish the key C7 and C8 stereocenters and a tandem 1,3-sulfonyl shift/intramolecular Mannich cyclization to form the tricyclic core.     

Enantioselective synthesis of trifluoromethyl-substituted cyclopropanes

The reaction of 1-aryl-2,2,2-trifluorodiazoethanes with alkenes, catalyzed by the adamantylglycine-derived dirhodium complex Rh2(R-PTAD)4, generates trifluoromethyl-substituted cyclopropanes with high diastereoselectivity (>94%) and enantioselectivity (88->98%).