Enantioselectivity synthesis

The target molecule above contains a chiral center. An enantioselective synthesis can therefore be developed We use this opportunity to summarize our knowledge of enantioselective reactions. They are either alkylations of carbanions or addition reactions to C = C or C = 0 double bonds ... 

The wM-diacetate 363 can be transformed into either enantiomer of the 4-substituted 2-cyclohexen-l-ol 364 via the enzymatic hydrolysis. By changing the relative reactivity of the allylic leaving groups (acetate and the more reactive carbonate), either enantiomer of 4-substituted cyclohexenyl acetate is accessible by choice. Then the enantioselective synthesis of (7 )- and (S)-5-substituted 1,3-cyclohexadienes 365 and 367 can be achieved. The Pd(II)-cat-alyzed acetoxylactonization of the diene acids affords the lactones 366 and 368 of different stereochemistry[310]. The tropane alkaloid skeletons 370 and 371 have been constructed based on this chemoselective Pd-catalyzed reactions of 6-benzyloxy-l,3-cycloheptadiene (369)[311]. 

The catalytic oxidative carbonylation of allene with PdCb and CuCh in MeOH affords methyl a-methoxymethacrylate (559)[499]. The intramolecular oxidative aminocarbonylation of the 6-aminoallene 560 affords the unsaturated J-amino ester 561. The reaction has been applied to the enantioselective synthesis of pumiliotoxin (562)[500]. A similar intramolecular oxycarbonyla-tion of 6-hydroxyallenes affords 2-(2-tetrahydrofuranyl)acrylates[501]. 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

Enantioselective synthesis of tryptophans has been accomplished via alkylation of 2,5-diethoxy-3,6-dihydropiperazines by the method developed by Schbllkopf[18]. For example, I> - -)-6-methoxytryptophan ethyl ester was prepared using l-(phcnylsulfonyl)-3-(bromomethyl)-6-methoxyindolefor alkyl-ationfl 9],... 

Enantiomers (Section 7 1) Stereoisomers that are related as an object and its nonsupenmposable mirror image Enantioselective synthesis (Section 27 4) Reaction that converts an achiral or racemic starting material to a chiral product in which one enantiomer is present in excess of the other... 

Despite the progress made in the stereoselective synthesis of (R)-pantothenic acid since the mid-1980s, the commercial chemical synthesis still involves resolution of racemic pantolactone. Recent (ca 1997) synthetic efforts have been directed toward developing a method for enantioselective synthesis of (R)-pantolactone by either chemical or microbial reduction of ketopantolactone. Microbial reduction of ketopantolactone is a promising area for future research. 

Depending on the stereoselectivity of the reaction, either the or the 5 configuration can generated at C-2 in the product. This corresponds to enantioselective synthesis of the d md L enantiomers of a-amino acids. Hydrogenation using chiral catalysts has been carefully investigated. The most effective catalysts for the reaction are ihodiiun... 

The frequent use of chiral controller or auxiliary groups in enantioselective synthesis (or diastereoselective processes) obviously requires the addition of such units retrosynthetically, as illustrated by the antithetic conversion 34 =i> 35. 

Methodology for the enantioselective synthesis of a broad range of chiral starting materials, by both chiral catalytic and controller-directed processes, is rapidly becoming an important factor in synthesis. The varied collection of molecules which are accessible by this technology provides another type of chiral S-goal for retrosynthetic analysis. 

The first synthesis of the potent antitumor agent maytansine was carried out by the elaboration of aldehyde D, an intermediate in the enantioselective synthesis of (-)-A/-methylmaysenine (Ref. 1,2), using enantioselective and diastereoselective steps. 

Diisocyanoadociane, a novel marine-derived diterpenoid, was analyzed retrosynthetically using the intramolecular Diels-Alder transform as T-goal concurrently with topological and stereochemical guidance. The enantioselective synthesis outlined below allowed assignment of absolute configuration. 

Despite the structural relationship between ginkgolide B and bilobalide, retrosynthetic analysis of the latter produced a totally different collection of sequences. A successful synthesis of bilobalide was implemented using a plan which depended on stereochemical and FG-based strategies. A process for enantioselective synthesis was based on an initial enantioselective Diels-Alder step in combination with a novel annulation method. 

The hydroxydiene A could be obtained by enantioselective CBS reduction of dienone B in 90% ee, which led to an enantioselective synthesis of the natural occurring form of forskolin. 

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

Enantioselective synthesis with lithium/(-)-sparteine carbanion pairs 97AG(E)2282. 

Enantioselective synthesis of bioactive 0-heterocycles related to plant protection and physiology 98YGK884. 

Enantioselective synthesis and transformations of oxirane and aziridine derivatives 99PAC423. 

The enantioselective synthesis of the V-benzyl-substituted /3-lactam 274a (NR2 = PhCH2NH), a precursor for carbapenem antibiotics, was described starting from the chiral synthon 5(R)-menthyloxy-2(5//)-furanone 170 (Scheme 71)... 

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

The high enantioselectivity of the exo product opens up a new and readily accessible route to an enantioselective synthesis of interesting isoquinoline alkaloids (Scheme 6.15) [35]. The tricyclic isoxazolidine exo-15b was obtained from the 1,3-dipolar cydoaddition reaction as the pure exo isomer and with 58% ee [34]. As shown in Scheme 6.15 the exo product from the 1,3-dipolar cydoaddition was converted into 17 in two steps without racemization at the chiral center. In addition to the illustrated synthesis, the 6,7-dimethoxy-derived isoxazolidine exo-15b is a very useful precursor for the synthesis of naturally occurring isoquinoline alkaloids [36-40]. 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

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. 

On that basis, crystallization is often used in combination with other enantiose-lective techniques, such as enantioselective synthesis, enzymatic kinetic resolution or simulated moving bed (SMB) chromatography [10, 11]. In general, when referring to crystallization techniques, the aim is to obtain an enantiomeric enrichment in the crystallized solid. However, the possibility of producing an enrichment in the mother liquors [12, 13], even if this is not a general phenomenon [14], must be taken into account. 

The second system studied was the separation of the chiral epoxide enantiomers (la,2,7,7a-tetrahydro-3-methoxynaphth-(2,3b)-oxirane Sandoz Pharma) used as an intermediate in the enantioselective synthesis of optically active drugs. The SMB has been used to carry out this chiral separation [27, 34, 35]. The separation can be performed using microcrystalline cellulose triacetate as stationary phase with an average particle diameter greater than 45 )tm. The eluent used was pure methanol. A... 

To get around this problem, pharmaceutical companies attempt to devise methods of enantioselective synthesis, which allow them to prepare only a single enantiomer rather than a racemic mixture. Viable methods have already been developed for the preparation of (5)-ibuprofen, which is now being marketed in Europe. We ll look further into enantioselective synthesis in the Chapter 19 Focus On. 

Several approaches to enantioselective synthesis have been taken, but the most efficient are those that use chiral catalysts to temporarily hold a substrate molecule in an unsymmetrical environment—exactly the same strategy that nature uses when catalyzing reactions with chiral enzymes. While in that unsymmetrical environment, the substrate may be more open to reaction on one side than on another, leading to an excess of one enantiomeric product over another. As an analog)7, think about picking up a coffee mug in your... 

Two methods are used in practice to obtain enantiomerically pure amino acids. One way is to resolve the racemic mixture into its pure enantiomers (Section 9.8). A more direct approach, however, is to use an enantioselective synthesis to prepare only the desired 5 enantiomer directly. As discussed in the Chapter 19 Focus Oil, the idea behind enantioselective synthesis is to find a chiral reaction catalyst that will temporarily hold a substrate molecule in an unsymmetrical environment. While in that chiral environment, the substrate may be more... 

Enantioselective synthesis (Chapter 19 Focus On) A reaction method that yields only a single enantiomer of a chiral product starting from an achiral substrate. 

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