Synthons asymmetric syntheses

Chemistry of enols and enolates ch20. What are synthons Asymmetric synthesis ch41... 

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204). 

The synthesis of f-i-i-crotanecine is accomplished in 10 steps in a 10.2% overall yield, as shown in Scheme 8.42. The key step in the asymmetric synthesis is a Lewis acid-promoted, tandem inter [4-i-2 /intra [3-i-2 cycbaddidon between a ffumaroyloxyxiitroalkene and chiral fi-silylvinyl ether, in which the snbsdtuted silanes are used as hydroxy synthons. ... 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

Amidjojo, M. and Weuster-Botz, D. (2005) Asymmetric synthesis of the chiral synthon ethyl (S)-4-chloro-3-hydroxybutanoate using Lactobacillus kefir. Tetrahedron Asymmetry, 16 (4), 899-901. 

As previously mentioned, the optically pure synthons (+)- and (—)-156 can be used in the asymmetric synthesis of many important intermediates via... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

Reactions catalyzed by enzymes or enzyme systems exhibit far greater specificities than more conventional organic reactions. Among these specificities which enzymatic reactions possess, stereospecificity is one of the most excellent. To overcome the disadvantage of a conventional synthetic process, i.e., the troublesome resolution of a racemic mixture, microbial transformation with enzymes possessing stereospecificities has been appHed to the asymmetric synthesis of optically active substances [1-10]. C3- and C4-synthetic units (synthons, building blocks), such as epichlorohydrin (EP), 2,3-dichloro-l-propanol (2,3-DCP), glycidol (GLD), 3-chloro-l,2-propanediol (3-CPD), 4-chloro-... 

A new stereocenter is formed when a synthon 143 with umpoled carbonyl reactivity (d reactivity) is introduced into aldehydes or imines. The enantioselective variant of this type of reaction was a longstanding problem in asymmetric synthesis. The very large majority of a-hetero-snbstitnted carbanions which serve as eqnivalents for synthons like 142 and 143 lead to racemic products with aldehydes or imines. However, enantiomerically pnre acylions and a-hydroxy carboxylic acids or aldehydes (144 and ent-144, respectively) as well as a-amino acids and aldehydes (145 and ent-145) are accessible either by nsing chiral d reagents or by reacting the components in the presence of chiral additives (Scheme 18). 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

Rhodium-catalyzed allylic alkylation provides an expeditious entry into a variety of useful synthons for asymmetric synthesis. For example, the application of this reaction to a range of enantiomerically enriched allylic carbonates with the sodium salt of methyl phenylsulfonylacetate provides products that represent important synthons for target-directed synthesis (Tab. 10.1) [17]. 

The first asymmetric synthesis of (-)-monomorine I, an enantiomer of the natural alkaloid, by Husson and co-workers starts with the chiral 2-cyano-6-oxazolopiperidine synthon (385) prepared from (-)-phenylglycinol (384), glu-taraldehyde (383), and KCN (443). Alkylation of 385 with an iodo ketal led to the formation of a single product (386). The cyano acetal (386) was treated with silver tetrafluoroborate and then zinc borohydride to afford a 3 2 mixture of C-6 epimeric oxazolidine (387) having the (2S) configuration. Reaction of 387 with... 

With (2) and furan at 0°C a yield of 50% could be achieved with an exo-endo ratio close to 1 but a very high diastereoisomeric excess (>98 d.e.) for each adduct. The accompanying scheme shows how the endo adduct (4) led to the oxanorbornenone (5), a useful synthon in asymmetric synthesis of sugars. 

One application of lactone 140 as a chiral synthon may be found in the asymmetric synthesis of (+)-12b-epidevinylantirhine (143), a cleaved product of geissoschizol (Scheme 28) [62-63]. Treatment of 140 with tryptamine in hot toluene afforded 142, which cyclized to lactam 142 by mesylation and an Sn2 displacement. Hie Bischler-Napieralski reaction of 142, followed by reduction of the resulting iminium salt with NaBH4, produced stereoselectively, the indolo[2,3-a]quinolizine as a single isomer, which was further reduced with DIBAL to give (+)-12b-epidevinylantirhine (143). 

Our strategy was to apply the P-Lactam Synthon Method (P-LSM)47-49 developed in these laboratories for (i) the asymmetric synthesis of the (2 R,3 S)-N-ben-zoyl-3-phenylisoserine moiety with excellent enantiomeric purity in high yield, and (ii) the ring-opening coupling of A-acyl-P-lactams with DAB (3). 

D-Proline (16) is an unnatural amino acid and an important chiral synthon for the synthesis of a variety of biologically active compounds. There are few chemical methods for asymmetric synthesis of this compound. Almost all processes for the production of D-proline at scale are based on resolution of d/-prolinc, and most of them involve the racemization of L-proline (17). 

In seeking ways to capitalize on this particular advantage that photochemistry enjoys over ground-state chemistry, it would be desirable to be able to carry out the A — B transformation enantioselectively. Aside from the intellectual challenge posed by such a problem, the preparation of theoretically interesting, highly strained compounds in optically pure form could be of considerable interest in subsequent mechanistic studies of the chemical behavior of such species as well as in their use as synthons in total syntheses. The present volume, as well as a number of recent review articles and symposia [1], attest to the growing interest in the field of photochemical asymmetric synthesis. 

The use of chiral ligands to facilitate asymmetric synthesis with these TMM synthons is difficult because the bond-formation process occurs away from the metal center. None the less, an enantioselective synthesis using a Tsuji TMM synthon has been achieved with a catalyst containing a chiral phosphine ligand (equation 133). While the enantiomeric excess is not very high in this case, the fact that one can achieve asymmetric induction at all is quite remarkable. 

A very short asymmetric synthesis of the bryostatin C1-C9 segment was achieved by use of three sequential 3f-promoted aldol reactions under reagent control [43f]. This synthetic methodology is based on the direct asymmetric incorporation of two acetate and one isobutyrate synthones into a framework (Sch. 1). 

The asymmetric synthesis of a-hydroxymethyl carbonyl compounds is currently the subject of considerable interest because of their versatility as dual-function chiral synthons. There have been no reports of successful enantioselective hydroxymethylations of prochiral metal enolates with formaldehyde because of the instability and small steric size of gaseous formaldehyde. The author and Yamamoto et al. developed the enantioselective alkoxymethylation of silyl enol ethers by introducing suitable carbon-electrophiles in place of the activated-protons of LBA [142]. 

Process options for the production of homochiral compounds are summarized in Fig. 2. The three basic routes are separation of racemic mixture, synthesis using a naturally occurring chiral synthon, and asymmetric synthesis using a prochiral intermediate. Historically, the efficiency of asymmetric synthesis has been capricious in terms of chemical and optical yield. Hence, from a practical, commercial process perspective, resolution via diastereomer crystallization has remained important for many commercial scale processes, for example, diltiazem. 

Another reaction of heteroatom oxidation is that of S-oxidation, which leads to the synthesis of sulfoxides, a reaction not very common in the plant cell biochemical factory. Enantiomerically pure sulfoxides are important chiral synthons in asymmetric synthesis, in particular in enantio-selective carbon-carbon bond formation [77]. The sulfoxide functional group is involved in different biological activities, and optically pure sulfoxides are of great pharmaceutical interest [82]. However, plant peroxidases, such as horseradish peroxidase, catalyze the enantio-selective sulfoxidation of alkyl aryl sulfides ... 

Evans, D. A. Studies in asymmetric synthesis. The development of practical chiral enolate synthons. Aldrichimica Acta 1982,15, 23-32. 

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