Diastereoselectivity alkylation reactions

Six-Membered Ring (exo-Cyclic). The diastereoselective alkylation reactions of exo-cyclic enolates involving 1,2-asymmetric inductions are anti-inductions. In Scheme 2-2, there are two possible enolate chair conformations in which the two possible transition-state geometries lead to the major diaster-eomer 9e (where the substituent takes the equatorial orientation). However, for the case in which R = methyl and X = alkoxyl or alkyl, one would expect the... 

The diastereoselective alkylation reaction of endo-cyclic five-membered ring enolates exhibits good potential for both 1,3- and 1,2-asymmetric induction. In Scheme 2-6, the factor controlling the alkylation transition state is steric rather than stereoelectronic, leading to an auh-induction.13... 

Scheme 2-8. Diastereoselective alkylation reactions in the norbornyl ring system.

TABLE 2-5. Diastereoselective Alkylation Reaction of the Lithium Enolates Derived from Imides 22 and 23... 

An internal diastereoselective alkylation reaction leading to cyclopropane formation 24 has been reported40. Although the 2-oxazolidinone moiety employed was not chiral, it should be possible to perform this reaction using a chiral auxiliary of the oxazolidinone type. 

Amides prepared from both enantiomers of 10,10-dimethyl-4-aza-3-thiatricyclor5.2.1.01,5ldecane 3,3-dioxide (bornane-10,2-sultam) can be used in diastereoselective alkylation reactions to give high chemical yields and high diastereomeric ratios of monoalkylation products5,6,10,16-19. 

A special case of diastereoselective alkylation reaction via azaenolates is the intramolecular cyclization of metalated 4,5-dihydro-2-(5-iodohexyl)-4,4-dimethyloxazole which furnishes the thermodynamically less favored cri-2-methylcyclopentanecarboxylic acid derivative 8 preferentially32. 

Chiral glycine enolate synthons have been employed in diastereoselective alkylation reactions [15]. A complementary approach to the synthesis of a-amino acids is the electrophilic amination of chiral enolates developed by Evans [16]. Lithium enolates derived from A-acyloxazolidinones 38, reacted readily with DTBAD to produce the hydrazide adducts 39 in excellent yields and diastereoselectivities (Scheme 18). Carboximides 38 were obtained by A-acylation of (S)-4-(phenylmethyl)-2-oxazoli-dinone and the lithium-Z-enolates of 38 were generated at -78 °C in THF under inert atmosphere using a freshly prepared solution of lithium diisopropylamide (LDA, 1.05 equiv.) [17]. 

The structurally novel bicyclic oxazinone was prepared based on D-glucopyranose. The lithium enolates of these compounds undergo highly diastereoselective alkylation reactions with reactive alkyl halides, in modest yields. Use of the phosphazene P4 base enhanced the yields of these processes, suggesting that metal enolate aggregation is at least partly... 

Recently, many research groups have focused their efforts oti the development of stereoselective routes leading to optically pure aminophosphinic acids. With this aim, Yamagishi and co-workers recently devised a practical methodology for the preparation of optically pure A-protected 1,1-diethoxyethyl(aminomethyl) phosphinates (12) [39] and their participation in diastereoselective alkylation reactions [40] which were first studied several years ago by McCleery and Tuck [41] (Scheme 4). In particular, they managed to obtain on a gram-scale and 99 % enantiomeric excess (ee) compound 11, after addition of paraformaldehyde to l,l-diethoxyethyl-//-phosphinate (10) and subsequent lipase-catalyzed resolution of the resulting racemic alcohol. Conversion of 11 to substrate 12 in four steps afforded a valuable substrate suitable for lithium bis(trimethylsilyl)amide (LHMDS)-promoted alkylation performed in a diastereoselective fashion (dr = 10 1) (Scheme 4). 

With this piece synthesized, the opportunity to install the stereo-genic center in 27 selectively through a diastereoselective alkylation reaction was now at hand. For this purpose, the Winkler group decided to enlist a widely applicable and useful method developed by Andrew Myers and co-workers at Harvard University for the synthesis of a-amino acids in which pseudoephedrine glycinamide (41), an inexpensive and commercially available material, serves as a chiral auxiliary capable of controlling the selectivity of nucleophile addition. Indeed, this synthetic technology proved highly efficacious as treatment of 41 with two equivalents of LDA in the presence of LiCl in THF at — 78°C, followed by the slow addition... 

Scheme 4.5 Diastereoselective alkylation reactions of pseudoephedrine-based auxiliaries 21. Cleavage of the auxiliary and model 29 for the stereochemical outcome.

A number of optically active, heteroatom-substituted carboxylic acid derivatives are excellent substrates for diastereoselective alkylation reactions. The ready availability of such chiral a-, (3-, and y-heteroatom-substituted carboxylic acid derivatives from the chiral pool and, more recently, through the implementation of catalytic, enantioselective methods (such as enantio-selective reduction of / keto esters Chapter 2, Section 2.7) makes this class of alkylations useful for the construction of stereochemically complex systems, particularly those containing quaternary stereogenic centers [54]. Key pioneering experiments in this area were disclosed independently by See-bach [55] and Prater [56]. 

In the course of examining the chemistry of oxazolidines, Meyers developed diastereoselective alkylation reactions of fused, bicyclic lactams such as 91 (Scheme 3.15). The approach is particularly useful for the construction of a large array of molecules containing quaternary stereogenic centers [68]. The starting bicyclic lactams are readily prepared by condensation of chiral /3-amino alcohols such as 89 with keto acids 90 to give 91, which subsequently participates in diastereoselective alkylation reactions. Hydrolysis... 

In parallel with the interest in -oxa-substituted carbanions, there has been much interest in their -aza-substituted counterparts. In this regard, Meyers pioneered the preparation of substituted carbamine carbanions (Scheme 13.8) [51-53] and recognized the power of a methodology based on such intermediates for the synthesis of a wide range of alkaloids. The ability of formamidine derivatives of tetrahydroisoquinoline (cf. 50) to participate effectively in metalation with LDA had already been demonstrated. The use of optically active, silylated l-phenyl-2-aminopropane-l,3-diol as a chiral auxiliary was shown to lead to the configurationally stable organolithium species 51, which took part in diastereoselective alkylation reactions. When l-bromo-4-chlorobutane was employed as the electrophile, the sequence provided access to benzoquinolizine 52 in 90 % ee and 70 % overall yield [51]. 

In this transformation, condensation of 4-tert-butylcyclohexanone with 112 afforded olefin 114 in 90 % optical purity. In addition, these chiral phosphorus reagents were also shown to undergo diastereoselective alkylation reactions. 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

Various diastereoselective Michael reactions are based on y-bromo-, y-alkyl-, or y-alkoxy-2(5//)-furanones following the trans-face selectivity shown in Section 1.5.2.3.1.2. Thus the lithium enolates of esters such as ethyl propanoate, ethyl a-methoxyacetate and ethyl a-phenylacetate add to methoxy-2(5/f)-furanone with complete face selectivity269-273 (see Section 1.5.2.4.4.2.). 

Scheme 4.37. Diastereoselective aldol reactions of an alkyl zirconocene.

The availability of oxepins that bear a side chain containing a Lewis basic oxygen atom (entry 2, Table 6.4) has further important implications in enantioselective synthesis. The derived alcohol, benzyl ether, or methoxyethoxymethyl (MEM) ethers, in which resident Lewis basic heteroatoms are less sterically hindered, readily undergo diastereoselective uncatalyzed alkylation reactions when treated with a variety of Grignard reagents [17]. The examples shown below (Scheme 6.7) demonstrate the excellent synthetic potential of these stereoselective alkylations. 

The diastereoselective alkylation of dialkyl malates has been frequently used in the past [65]. However, according to the original procedure [63] (dialkyl malate, base, -78 -20 °C, then -78 °C, electrophile, then -78 0 °C, 16 h), the alkylation proceeded in average yields of about 50-60% and in diastereoselectivities in the range of 9 1 anti / syn. In our hands, application of this procedure to the reaction of benzyl bromide 23 with dimethyl malate 106 produced the alkylated compounds in only 20% yield. The yield of the alkylation was easily improved (>75%) when the ester was deprotonated with LHMDS in the presence of the electrophile at -78 °C and the reaction mixture was allowed to warm to 10 °C (Scheme 26 and Table 2). 

It has been demonstrated that in Bi(OTf)3-catalyzed alkylation reactions the optical activity of enantiopure benzyl alcohols is lost and a racemic product is isolated. This can be explained by a SA-l-type reaction mechanism and the existence of a carbocationic intermediate. However, diastereoselective substitutions of benzyl alcohols with a chiral centre in close neighborhood to the electrophilic carbon should be feasible (Scheme 23). 

Clavepictines A and B were prepared using a variety of effective reactions on the piperidine ring, such as a silver-promoted cyclization of an aminoallene intermediate, diastereoselective alkylation, and cross coupling of an enol triflate <99JA10012>. 

The last two examples in Table 2 present a useful one-pot aldol - alkylation reaction which can be carried out in high yield and with the usual — 95 5 diastereoselectivity to give the racemic products16 ... 

One of the most important factors for successful diastereoselection in chiral amide enolate alkylation reactions is the presence of strongly chelated ionic intermediates1 3. The chelation serves the purpose of locking the chiral auxiliary in a fixed position relative to the enolate. The metal counterion is chelated between the enolate oxygen and an additional polar group, anionic, carbonyl or ether oxygen attached to the chiral auxiliary. 

If the above reaction sequence is conducted with the /(-lactam containing a C(R R2)COOR3 group in the 1-position, rather than the methyl group, then diastereoselective alkylation in the 3-position of the lactam ring, followed by Birch reduction, gives a dipeptide. This has been exemplified in the synthesis of (5)-a-methylphenylalanyl-(7 )-a-allylalanineS-1... 

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