Cyclizations desymmetrization

Keywords Ene reaction, Hetero-Diels-Alder reaction, Ene cyclization, Desymmetrization, Kinetic resolution. Non-linear effect. Asymmetric activation, Metallo-ene, Carbonyl addition reaction, Aldol-type reaction. Titanium, Aluminum, Magnesium, Palladium, Copper, Lanthanides, Binaphthol, Bisoxazoline, Diphosphine, TADDOL, Schiff base. 

TABLE 2.13 Selected Results of the Regioselective Monoamination-Cyclization-Desymmetrization Multienzyme Cascade ... 

R,4R)-Supellapyrone (41) is the female sex pheromone of the brown banded cockroach (Supella longipalpa). Scheme 59 summarizes Mori s synthesis of 41 [89].Enzymatic desymmetrization of meso-B to give (2R,4S)-C and Reformatsky-type cyclization of D to furnish E were the key steps. 

Recently, Krische and co-workers developed an effective protocol for the catalytic desymmetrization and parallel kinetic resolution of enone-diones via tandem conjugate addition-aldol cyclization (Scheme 66).150 This transformation, involving enantioselective rhodium-catalyzed conjugate addition methodology, enabled the formation of two C-G bonds and four contiguous stereogenic centers from simple precursors with high diastereo- and enantiocontrol. 

The kinetic resolution by etherification has also been conducted through the cyclization of epoxy aliphatic alcohols.274 In these reactions catalyzed by monomeric complex 51, the ring closure of acyclic substrates occurred with exclusive / -selectivity (Equation (74)), whereas m -openings were observed in the desymmetrization of... 

In 1992, Trost and his co-workers investigated desymmetrization of cyclic w j-o-diesters with lithium sulfonyl-methylenenitronate as a nucleophile in the presence of Trost s ligand 118, where the corresponding cyclic compounds are obtained with an excellent enantioselectivity via intramolecular cyclization (Scheme 15),103,103a Asymmetric cyclopropanation and lactone annulation are achieved according to this protocol (Scheme Nitroalkanes can also be employed as carbon-centered nucleophiles in lieu of malonates (Scheme 17). ... 

Ziegler et al. have reported the asymmetric desymmetrization approach to the synthesis of tricothecene, anguidine, via an ene cyclization (Scheme 8C.11) [31], The (2,4) ene cyclization (vide infra) of the prochiral aldehyde on silica gel gives a 1 1 diastereomeric mixture. Cyclization with purified Eu(fod)3 as Lewis acid catalyst gives an 8 1 mixture. The major isomer is a potential intermediate for the synthesis of anguidine. However, use of (+)-Eu(hfc)3, (+)-Eu(dppm)3, or (S)-BINOL-TiCl2 complex as chiral Lewis acid affords the major product with only 20-38% ee. 

Enantioselective RCM is achieved using the chiral Mo complex 79 [30]. Kinetic resolution occurred in the reaction of the racemic diene 80 catalysed by 79, and the cyclized product 81 with 93% ee was obtained, and the unreacted diene 80 (19%) of 99% ee was recovered. Also the optically active dihydrofuran 83 with 93% ee was obtained in 85% yield by enantioselective desymmetrization through RCM of triene 82 using the Mo complex 79 [30a]. 

Neri et al89 reported the desymmetrization of A-Boc-serinol 98 by the selective monoacetylation using PPL (porcine pancreas lipase) and vinyl acetate as the acylating agent in organic solvent. The mono acetylated product (R)-99 was obtained after 2 hours with 99% ee and isolated in 69% chemical yield. Traces of the diacetylated product 100 were observed. The cyclization of (R)-99 in basic medium afforded the racemic oxazolidinone 101. The latter was subjected to enzymatic hydrolysis in phosphate buffer affording (R)-... 

Olefin metathesis does not generate stereogenic centers, however, the reaction may be employed in the desymmetrization of prochiral (poly)olefins of the kinetic resolution of racemates. In the example depicted in Scheme 17, a trialkene is desymmetrized, and the preference for the cyclization reaction with one of the two symmetry-equivalent C = C double bonds leads to the enantioselective formation of the reaction product, a chiral dihydrofuran. The following principal conclusions can be drawn from this study ... 

Indium trichloride mediates the intramolecular cyclization of the prochiral allylstannyl diketone to afford the desymmetrized cis-cis cyclohexanol predominantly (Equation (36)). The use of TiCU in place of InCl3 gives the cis-trans diastereomer.213... 

A Pd(ll) catalyst system with an oxazoline ligand 44 has been described that allows the desymmetrization of meso-Z-alkyl-2-propargylcyclohexane-l,3-diols in an asymmetric cyclization-carbonylation reaction. The products which contain a chiral quaternary carbon were obtained in excellent yields with high ee s (Scheme 56) <2006T9988>. 7-Hydroxy terminal <2005JOC3099> and internal <2006TL2793> alkenes can be converted to tetrahydrofurans by Pd(0)-catalyzed carboetherification reactions combined with a coupling of aryl or vinyl halides. 

Enantioselective Intramolecular Cyclization (Sn2 reaction). The desymmetric transformation of meso-structures has been recognized as a versatile synthetic method for optically active compounds in organic enzymatic processes. The enantioselective intramolecular cyclization of the bis-phenyllithium species, which is generated by addition of butyllithium to a solution of cis-3,5-di(bromophenoxy)cyclopentene, has been attained by addition of lithium salt (1.2 equiv) of (/ )-BINOL-Me to produce a cyclopenta[fc]benzofuran with 87% ee (eq 18). ... 

Yamamoto has reported the desymmetrizing intra-molecular cyclization of the 1,3-diketone 97 for diastereoselective formation of cis-cis 98 vs. cis-trans 99. Optimized conditions with SnCU led to the jS-chelation in the synclinal arrangement 100 to give 98, whereas the use of TiCU facilitated rapid transmetalation of the organostannane yielding 99 (Scheme 5.2.22).22... 

The key-steps of our 2001 synthesis was enzymatic desymmetrization of meso-B, enzymatic enantiomer separation of ( )-B, and Reformatsky-type cyclization of E to give F. The natural supellapyrone... 

Alkylation. Acetals of enals serve as alkylating agents for t-butyl (3-keto esters using a Pd complex of BINAP. With a cationic Pd complex of (R)-BINAP intramolecular addition of arylboronic acid moiety to a sidechain ketone leads to chiral, tertiary henzylic alcohols. Heck reaction. Cyclization with desymmetrization is shown to proceed in excellent yields and ee by the formation of tetralin derivatives. ... 

A highly enantioselective intramolecular AHR of the cyclohexadienone 322 to give 324 with 96% ee in 100% conversion was carried out using the chiral phosphoamidite-type ligand (III-IO), which is monodentate. The stereogenic center was not created at the site of C—C bond formation, but instead the cyclohexadienone was desymmetrized. The use of Cy2MeN as a base gave the best result. It should be added that the carbopalladation product 323 has no jS-H syn to Pd, and hence the cyclized product 324 was formed by syn y3-H elimination after epimerization [132]. 

The F-ring of the polyether macrolide halichondrin was constructed by Pd-catalyzed selective monocyclization of 187 and 189. No dicyclization took place due to steric reasons. Desymmetrization of the meso-Aio 187 gave the tetrahydro-fiiran 188 in high yield using Trost L-1 as a chiral ligand, and cyclization of the C2 symmetric diacetate 189 afforded the desired diastereoisomeric tetrahydrofuran 190 [73]. 

Haseltine has described an enantioselective formal synthesis of pancratistatin in which the stereocontrol is driven by the aeetonide of conduritol A. The enantioselective hydrolysis (desymmetrization) of this compound was achieved with a lipase, and the aryl-cyclohexane ring bond was formed through an intramolecular cyclization of the activated benzene ring with an allylic triflate (278). Plumet reported a total synthesis of (-l-)-7-deoxypaneratistatin based on the conjugate addition of an aryl-lithium species to a bicyclic conjugated sulfone derived from furan, which enabled the efficient installation of the six stereogenic centers of the cyclohexane ring (279) (Scheme 13). 

Later, the groups of Sakai and of Tanaka and Suemune, respectively, extended the scope of the enantioselective cyclizations by employing desymmetrization of the aldehyde substrates bearing two identical terminal olefin moieties, and the cyclopentanone products with two vicinal stereo-centers, 8 or 9, could be obtained using a catalytic amount of the cationic Rh complex (5 mol%) (Table 8.2). However, if neutral Rh catalysts were employed, a high catalyst loading at 50 mol% was needed (entries 1, 2). Tanaka, Suemune, and co orkers also developed the kinetic resolution of unsymmetrical racemic diene-aldehyde 10 via a Rh-catalyzed asymmetric hydroacylation reaction (Scheme 8.5). The cyclization product could be obtained in >95% ee. ... 

Table 8.2 Enantioselective cyclization through desymmetrization approach reported by Sakai, Tanaka, and Suemune.

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