Enantioselective synthesis allylation

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]. 

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]. 

Schemes 16-19 present the details of the enantioselective synthesis of key intermediate 9. The retrosynthetic analysis outlined in Scheme 5 identified aldoxime 32 as a potential synthetic intermediate the construction of this compound would mark the achievement of the first synthetic objective, for it would permit an evaluation of the crucial 1,3-dipolar cycloaddition reaction. As it turns out, an enantioselective synthesis of aldoxime 32 can be achieved in a straightforward manner by a route employing commercially available tetronic acid (36) and the MEM ether of allyl alcohol (74) as starting materials (see Scheme 16).

Another extensively developed group of allylic boron reagents for enantioselective synthesis is derived from tartrates.42... 

The optically active propargylic and allylic alcohols thus obtained are important synthetic intermediates in the enantioselective synthesis of insect pheromones, prostaglandins, prostacyclins, and many other bioactive compounds (Scheme 6-26).53... 

Many methods have been reported for the enantioselective synthesis of the remaining PG building block, the (J )-4-hydroxy-cyclopent-2-enone. For example, the racemate can be kinetically resolved as shown in Scheme 7-28. (iS )-BINAP-Ru(II) dicarboxylate complex 93 is an excellent catalyst for the enantioselective kinetic resolution of the racemic hydroxy enone (an allylic alcohol). By controlling the reaction conditions, the C C double bond in one enantiomer, the (S )-isomer, will be prone to hydrogenation, leaving the slow reacting enantiomer intact and thus accomplishing the kinetic resolution.20... 

Related catalytic enantioselective processes It is worthy of note that the powerful Ti-catalyzed asymmetric epoxidation procedure of Sharpless [27] is often used in the preparation of optically pure acyclic allylic alcohols through the catalytic kinetic resolution of easily accessible racemic mixtures [28]. When the catalytic epoxidation is applied to cyclic allylic substrates, reaction rates are retarded and lower levels of enantioselectivity are observed. Ru-catalyzed asymmetric hydrogenation has been employed by Noyori to effect the resolution of five- and six-membered allylic carbinols [29] in this instance, as with the Ti-catalyzed procedure, the presence of an unprotected hydroxyl function is required. Perhaps the most efficient general procedure for the enantioselective synthesis of this class of cyclic allylic ethers is that recently developed by Trost and co-workers, involving Pd-catalyzed asymmetric additions of alkoxides to allylic esters [30]. 

A further enantioselective synthesis of (+)-T-4 (125), T-6 (128), T-7 (129) and T-8 (126) has been reported by Stragies and Blechert [198]. Key steps are a Pd-catalyzed domino allylation and a Ru-catalyzed metathesis ring rearrangement. Their strategy represents a general approach towards all naturally occurring tetraponerines and will be illustrated here by the description of the syntheses of (+)-T-4 (125) and (+)-T-8 (126) (Scheme 9). 

Although it was also Henbest who reported as early as 1965 the first asymmetric epoxidation by using a chiral peracid, without doubt, one of the methods of enantioselective synthesis most frequently used in the past few years has been the "asymmetric epoxidation" reported in 1980 by K.B. Sharpless [3] which meets almost all the requirements for being an "ideal" reaction. That is to say, complete stereofacial selectivities are achieved under catalytic conditions and working at the multigram scale. The method, which is summarised in Fig. 10.1, involves the titanium (IV)-catalysed epoxidation of allylic alcohols in the presence of tartaric esters as chiral ligands. The reagents for this asyimnetric epoxidation of primary allylic alcohols are L-(+)- or D-(-)-diethyl (DET) or diisopropyl (DIPT) tartrate,27 titanium tetraisopropoxide and water free solutions of fert-butyl hydroperoxide. The natural and unnatural diethyl tartrates, as well as titanium tetraisopropoxide are commercially available, and the required water-free solution of tert-bnty hydroperoxide is easily prepared from the commercially available isooctane solutions. 

Sharpless "asymmetric epoxidation" has been used in the enantioselective synthesis of several natural products, including the kinetic resolution of allylic alcohols [11] and the creation of ... 

In connection with the synthetic work directed towards the total synthesis of polyene macrolide antibiotics -such as amphotericin B (i)- Sharpless and Masamune [1] on one hand, and Nicolaou and Uenishi on the other [2], have developed alternative methods for the enantioselective synthesis of 1,3-diols and, in general, 1, 3, 5...(2n + 1) polyols. One of these methods is based on the Sharpless asymmetric epoxidation of allylic alcohols [3] and regioselective reductive ring opening of epoxides by metal hydrides, such as Red-Al and DIBAL. The second method uses available monosaccharides from the "chiral pool" [4], such as D-glucose. 

A regio-, diastereo- and enantioselective synthesis of amino acids was reported by Takemoto and coworkers. The glycine equivalent ethyl diphenylimino glycinate was used as pronucleophile (Scheme 9.14), while the Hgand was a bidentate chiral phosphite, and 3-arylaUyl diethyl phosphates were employed as allylic substrates [39, 46]. 

A symmetric activation is also observed in the combination of (/f)-BINOL and Zr(0 Bu)4, which promotes enantioselective synthesis of homoallylic alcohols (Scheme 8.13). A 2 1 ratio of (/ )-BINOL and Zr(0 Bu)4 without any other chiral source affords the homoallylic alcohol product in 27% ee and 44% yield. Addition of (7 )-(+)-a-methyl-2-naphthalenemethanol ((/ )-MNM) leads to higher enantiomeric excess (53% ee) than those using only (7 )-BINOL. Therefore, (7 )-MNM can act as a chiral activator a higher ee can be achieved via activation of the allylation of benzaldehyde by addition of (7 )-MNM as a product-like activator. 

Another enantioselective synthesis, shown in Scheme 13.17, is based on enantiose-lective reduction of bicyclo[2.2.2]octane-2,6-dione by baker s yeast.129 The enantiomeri-cally pure intermediate is then converted to the lactone intermediate by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group is then introduced stereoselec-tively from the exo face of the bicyclic lactone in step C-l. A final crucial step in this synthesis is a [2,3] sigmatropic rearrangement to complete sequence D. 

Scheme 17 illustrates enantioselective synthesis of a-amino acids by phase-transfer-catalyzed alkylation (46). Reaction of a protected glycine derivative and between 1.2 and 5 equiv of a reactive organic halide in a 50% aqueous sodium hydroxide-dichloromethane mixture containing 1-benzylcinchoninium chloride (BCNC) as catalyst gives the optically active alkylation product. Only monoalkylated products are obtained. Allylic, benzylic, methyl, and primary halides can be used as alkylating agents. Similarly, optically active a-methyl amino acid derivatives can be prepared by this method in up to 50% ee. 

A cationic Ir complex possessing phosphanodihydrooxazole 26 is usable for asymmetric hydrogenation of allylic alcohols. (E)-2-Methyl-3-phenyl-2-propen-l-ol can be converted in CH2C12 containing 1 mol % of the Ir complex to the saturated product in 95% yield and 96% ee (Scheme 1.26) [141]. The process is used in the enantioselective synthesis of the artificial fragrance filial. 

The key step is the synthesis of the metathesis precursor, which was required in both the cis- and trans- configurations. The cz .v-configuration was obtained via enantioselective domino allylic alkylations (Scheme 6, 15a and 15b). For the rra/zs-configuation, an allylic alkylation was used to introduce the first amine, but the second amine was introduced via the Mitsunobu reaction25 to achieve an inversion of the stereocentre (Scheme 6,16a and 16b). 

Allylic C-H insertions have been used in key steps of the enantioselective synthesis of the pharmaceuticals (+)-ceitedil (26) [21] and (+)-indatraline (27) [22] (Scheme 11). The allylic C-H insertion reaction is an exciting alternative to the Claisen rearrangement as a rapid method for the synthesis of y,c>-unsaturated ester [23 ]. Similarly, the allylic C-H insertion with vinyl silyl ethers generates protected 1,5-dicarbonyl compounds, a complimentary reaction to the Michael addition [24]. Both types of C-H insertion can be achieved with high diastereoselectiv-ity and enantioselectivity [23, 24]. 

Attempted allylic C-H insertion by vinyldiazoacetates results in an even more complicated transformation, a combined C-H activation/Cope rearrangement [27]. These reactions tend to proceed with very high enantioselectivity as illustrated in a short enantioselective synthesis of the antidepressant (+)-sertraline (33) [27a]. Recent studies have shown that this reaction is both highly diastereose-lective and enantioselective [27b],... 

Evans et al. have recently demonstrated a highly enantioselective synthesis of allyl amines 52 from enantiomerically pure carbonates 51 catalyzed by rhodium complexes (Eq. (13)) [33], The reaction proceeds with excellent regioselectivities, and the allyl amines are isolated in high yields and with a high degree of conservation of the optical purity. The scope of this reaction is demonstrated by the synthesis of, e.g., optically active nitrogen-containing heterocycles. 

Zacchino, S.A. and Badano, H. (1991) Enantioselective synthesis and absolute configuration assignment of erythro-(3,4-methylenedioxy-7-hydroxy-1 -allyl-3, 5 -dimethoxy)-8-0-4 -neolignan and its acetate, isolated from nutmeg (Myristica fragrans). Journal of Natural Products 54(1), 155-1 60. 

A sequence of allylation, epoxidation and an acid-mediated 6-exo cyclisation converts salicylaldehydes into 2-hydroxymethyl-2-methyl-27/-[l]benzopyrans. A bicyclic chroman arising from attack of the hydroxymethyl group on the intermediate benzylic cation has been isolated <02SL322>. A twelve-step enantioselective synthesis of a 2-hydroxymethyl-2-methylchroman with an overall yield of 48% uses related methodology and introduces the chirality through an asymmetric Sharpless epoxidation <02JCS(P1)496>. 

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