Enantioselective total synthesis isolation

The first enantioselective total synthesis of the sesquiterpenoid heliannuol D 56 has been reported by Shishido and co-workers. The key step was a base-mediated (NaOH) intramolecular cyclisation of the phenolic epoxide mixture 55 (R1 = MOM, R2 = H and R1 = H, R2 = MOM). Heliannuol D (and the eight-membered congener, heliannuol A) is an allelopathic agent isolated from cultivated sunflowers (Helianthus annuus L.SH-222) <00JCS(P 1)1807>. 

The full structure and absolute configuration of FR 900848 104 has been determined to be (6R,8S,9R,11S,12S,14R,15S,17R) from X-ray crystallographic study [133]. Strategies for its enantioselective total synthesis are based on an iterative cyclopropanation [134], and on the use of chiral auxiliaries [135]. It has also been prepared by fermentation and isolated from cultures of Streptoverticillium fervens to be considered as an agrochemical microbicide [136]. 

Adociasulfates 1-6 (380-385) were isolated from a Haliclona (aka Adocia) sp. from Palau and were all inhibitors of kinesin motor proteins [331]. Adociasulfate 2 (381) had earlier been shown to inhibit the activity of the motor protein kinesin by interference with its binding to microtubules [332], An Adocia sp. from the Great Barrier Reef contained adociasulfates 1 (380), 7 (386) and 8 (387), which inhibit vacuolar H -ATPase [333]. Adociasulfates 5 (384) and 9 (388) were obtained from Adocia aculeata from the Great Barrier Reef [334], The structure of adociasulfate 1 (380) was confirmed by an enantioselective total synthesis [335]. Adociasulfate 10 (389) from Haliclona sp. from Palau also inhibits the kinesin motor proteins [336]. 

Corey and Wu utilized PIDA oxidation leading to the quinone monoacetal (126) for the initial step of enantioselective total synthesis of miroestrol (4), which is the folk medicine of southeast Asia, isolated from Pueraria mirifica (Thai kwao keur) [86] (Scheme 5). 

S. Ito et al. utilized the aza-Claisen rearrangement of carboxamide enolates for the enantioselective total synthesis of (-)-isoiridomyrmecin, which is a constituent of Actinidia polygama and exhibits unique bioactivity. The rearrangement of the (S,S) stereoisomer was conducted under standard conditions, and the product was isolated as a single [R,R) stereoisomer in 77% yield. 

The first enantioselective total synthesis of the 7,3 -linked naphthylisoquinoline alkaloid (-)-ancistrocladidine was accomplished by J.C. Morris and co-workers. The key steps of the synthesis were the Pinhey-Barton ortho-arylation and the Bischier-Napieralski cyclization. The natural product was isolated from the 1 1 mixture of atropisomers by recrystallization from toluene/petroleum ether. 

The first enantioselective total synthesis of tetracyclic sesquiterpenoid (+)-cyclomyltaylan-5a-ol, isolated from a Taiwanese liverwort, was accomplished by H. Hagiwara and co-workers. They started out from Hajos-Parrish ketone analogue, (S)-(+)-4,7a-dimethyl-2,3,7,7a-tetrahydro-6/-/-indene-1,5-dione, that could be synthesized from 2-methylcyclopentane-1,3-dione and ethyl vinyl ketone in an acetic acid-catalyzed Michael addition followed by an intramolecular aldol reaction. The intramolecular aldol reaction was carried out in the presence of one equivalent (S)-(-)-phenylalanine and 0.5 equivalent D-camphorsulfonic acid. The resulting enone was recrystallized from hexane-diethyl ether to yield the product in 43% yield and 98% ee. Since the absolute stereochemistry of the natural product was unknown, the total synthesis also served to establish the absolute stereochemistry. 

The enantioselective total synthesis of the 13-membered macrolide fungal metabolite (+)-brefeldin A was accomplished using a triple chirality transfer process and intramolecular nitrile oxide cycloaddition in the laboratory of D. Kim. To set the correct stereochemistry at C9, the stereoselective ortho ester Claisen rearrangement was applied on a chiral allylic alcohol precursor. The rearrangement was catalyzed by phenol and it took place at 125 °C in triethyl orthoacetate to give 84% isolated yield of the desired diester. 

The first enantioselective total synthesis of (-)-tejedine was completed by P.E. Georghiou using a chiral auxiliary-assisted diastereoselective Bischler-Napieralsid cycHzation as one of the key steps.The chiral auxiliary was the commercially available (S)-a-methylbenzylamine, which was coupled to the substrate using the original Schotten-Baumann acylation conditions. The acid chloride was reacted with the chiral amine in a solvent mixture containing aqueous sodium hydroxide and dichloromethane and the desired amide was isolated in excellent yield. 

The enantioselective total synthesis of the cyclooctanoid natural product (+)-epoxydictymene was accomplished in the laboratory of L.A. Paquette. The entire tricyclic framework was constructed by the application of a Claisen rerrangement via a chairlike transition state. The precursor for this / 3,37-sigmatropic rearrangement was obtained by treating a lactone precursor with the solution of the Tebbe reagent in the presence of pyridine. The corresponding enol ether was formed in almost quantitative yield, and immediately after isolation it was treated with triisobutylaluminum to effect the Claisen rearrangement. 

The indolizidine alkaloid (+ )-monomorine I (373), isolated from Pharaoh s ant Mono-morium pharaonis, is the first example of an indolizidine alkaloid found in the animal kingdom. One enantioselective total synthesis of 373 exploits an asymmetric cycloaddition of nitrone 370 to the chiral allylic ether 369, which is prepared from 349. The conversion of 349 to a tosylate followed by treatment with -propylmagnesium bromide in the presence of... 

The enantioselective total synthesis of streptazolin (609), a neutral lipophilic antibiotic isolated from cultures of Streptomyces viridochromogenes, utilizes a tandem iminium ion— vinylsilane cyclization of the tartrate-derived 607 together with intramolecular acylation as a way of achieving high stereoselectivity. Heating a mixture of 570 and ( )-4-bromo-4-(tri-methylsilyl)-3-buten-l-amine (605) followed by dehydration with acetyl chloride provides the imide (606) in reproducible yields of 90%. Reduction of 606 with sodium borohydride affords 607, which is refluxed in trifluoroacetic acid to provide, after careful purification, the single bicyclic adduct 608 in 74% yield. This is then transformed in four steps to the desired streptazolin (609) [196] (Scheme 134). 

The Fustero group recently also applied this strategy for the enantioselective total synthesis of (-i-)-angustureine (308) 289). (Scheme 70) Angustureine (308) is a tetrahydroquinoline alkaloid isolated from the bark of the Venezuelan shrubby tree Galipea officinalis 291). Carrying out the iminium-catalyzed intramolecular... 

Another interesting example of an oxidative phenolic coupling reaction was reported by Koga and coworkers in 1977 (Eq. 12.54-2, Scheme 12.54) [192], Exposure of chiral ester 312 to three equivalents of Mn(acac)3 in acetonitrile allowed the isolation of adduct 313 in 49% isolated yield. Koga s efforts resulted in the first enantioselective total synthesis of the biologically highly interesting Amaryllidaceae alkaloid. 

Another interesting example of selective relay alkene RCM in the presence of multiple alkene and alkyne moieties was disclosed by Crimmins et al. [63]. Mucocin (60) was isolated from the leaves of Rollinia mucosa and showed potent antitumor activity [64]. Crimmins and coworkers described an enantioselective total synthesis of (-)-mucocin in 2006 (Fig. 19). In this study they highlighted a key step using selective relay alkene RCM to form the five-membered cyclic ether. 

Sakurai J, Kikuchi T, Takahashi O, Watanahe K, Katoh T. Enantioselective total synthesis of (-l-)-stachyflin a potential anti-influenza A vims agent isolated from a microorganism. Eur. J. Org. Chem. 2011 (16) 2948-2957. 

An enantioselective total synthesis including an HNL-catalyzed step of the pheromone vittatalactone, a novel P-lactone originally isolated from feeding male striped cucumber beetles, Acalymma vittatum was recently published. PaHNL catalyzes with high enantioselectivity (>96% ee) the formation of the (R)-cyanohydrin from crotonaldehyde 9 a key step in the synthesis of one of the two main building blocks 11 (Scheme 28.5). ... 

Application of ATH in Stereoselective Synthesis Murlcatacln can be isolated as a scalemic mixture from the seeds of Annona muricata Muricatacin and epi-muricata-cin showed anti-proliferative activity against certain cell Unes. The enantioselective total synthesis of a potent cytotoxic agent (- -)- p/-muricatacin was reported by Kumarasw-amy et employing Noyori catalytic asymmetric transfer hydrogenation of benzyl 128 to (15,25)-1,2-diphenylethane-1,2-diol, which subsequently reacted with 129 to produce a key chiral intermediate 130 (Scheme 30.26). 

This protocol is particularly useful in the synthesis of the class of polychlorinated marine natural product known as chlorosulfolipids, which are believed to be responsible for seafood poisoning. ° With this protocol, Vanderwal et al. succeeded in the enantioselective total synthesis of maUiamensilipin A 11, a protein tyrosine kinase inhibitor isolated from alga Poterioochromonas malhamen-sis The enantioselective synthesis of (+)-danicalipin A 14, another chlorosulfolipid isolated from the alga Ochro-monas danica by Umezawa et al. also used this strategy as a key step (Scheme 42.5). 

Snyder SA, Tang ZY, Gupta R. Enantioselective total synthesis of (—)-napyradiomycin A1 via asymmetric chlorination of an isolated olefin. J. Am. Chem. Soc. 2009 131(16) 5744-5745. 

When chiral, drugs and other molecules obtained from natural sources or by semisynthesis usually contain one of the possible enantiomeric forms. However, those obtained by total synthesis often consist of mixtures of both enantiomers. In order to develop commercially the isolated enantiomers, two alternative approaches can be considered (i) enantioselective synthesis of the desired enantiomer or (ii) separation of both isomers from a racemic mixture. The separation can be performed on the target molecule or on one of its chemical precursors obtained from conventional synthetic procedures. Both strategies have their advantages and drawbacks. 

---