Stoichiometric chiral reagents

Catalytic kinetic resolution can be the method of choice for the preparation of enantioenriched materials, particularly when the racemate is inexpensive and readily available and direct asymmetric routes to the optically active compounds are lacking. However, several other criteria-induding catalyst selectivity, efficiency, and cost, stoichiometric reagent cost, waste generation, volumetric throughput, ease of product isolation, scalability, and the existence of viable alternatives from the chiral pool (or classical resolution)-must be taken into consideration as well... 

I.5.2.I.I.4. Conjugate Addition of Chiral Organometallic Reagents External Stoichiometric Chiral Ligands... 

This reaction is very sensitive to water because in the presence of water and a metal salt (such as copper salt) the thioacetal tends to decompose, and this may reduce the amount of thioacetal available for epoxidation. When water is excluded from all the reagents, the reaction can be carried out in the presence of a catalytic amount of thioacetal. Otherwise, a stoichiometric amount of thioacetal compound is required. Scheme 4 53 summarizes the epoxidation of aldehydes using 138 as the chiral-inducing reagent. Excellent enantioselectivities are obtained in most cases. 

Asymmetric catalytic osmylation.s Chiral cinchona bases are known to effect asymmetric dihydroxylation with 0s04 as a stoichiometric reagent (10, 291). Significant but opposite stereoselectivity is shown by esters of dihydroquinine (1) and of dihydroquinidine (2), even though these bases are diastereomers rather than enantiomers. 

Conversely, Charette and coworkers have shown that the chiral phosphate 23 could be used in catalytic amounts for the cyclopropanation of protected allylic alcohols (equation 97) . This was made possible by using DME as the additive to slow down the background cyclopropanation process, leading to racemic cyclopropane (Pathway A). Bis(iodomethyl)zinc was used as the stoichiometric reagent to regenerate the reactive iodomethylzinc phosphate (Pathway B). Excellent enantioselectivities were observed using this protocol however, the scope of the reaction is still quite limited. 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

Narasaka reported a highly enantioselective Diels-Alder reaction between isoprene and a fumaric acid derivative 17 using a catalytic amount of a chiral titanium reagent prepared from tartrate-derived chiral 1,4-diol 18 and TiCI2(0-/-Pr)2 [27]. When a stoichiometric amount of the partially resolved chiral diol (25% ee) was used, the corresponding cycloadduct 19 with 83% ee was obtained (Scheme 9.12). In this reaction, white precipitate was formed, which proved to... 

If the latter reaction proceeds through a closed transition state (e.g., 5 in Scheme 7.2), good diastereocontrol can be expected in the case of trans- and cis-CrotylSiCl3 (2b/2c) [14, 15]. Here, the anh-diastereoisomer 3b should be obtained from trans-crotyl derivative 2b, whereas the syn-isomer 3c should result from the reaction of the cis-isomer 2c (Scheme 7.2). Furthermore, this mechanism creates an opportunity for transferring the chiral information if the Lewis base employed is chiral. Provided that the Lewis base dissociates from the silicon in the intermediate 6 at a sufficient rate, it can act as a catalyst (rather than as a stoichiometric reagent). Typical Lewis bases that promote the allylation reaction are the common dipolar aprotic solvents, such as dimethylformamide (DMF) [8,12], dimethyl sulfoxide (DMSO) [8, 9], and hexamethylphosphoramide (HMPA) [9, 16], in addition to other substances that possess a strongly Lewis basic oxygen, such as various formamides [17] (in a solution or on a solid support [7, 8, 18]), urea derivatives [19], and catecholates [10] (and their chiral modifications [5c], [20]). It should be noted that, upon coordination to a Lewis base, the silicon atom becomes more Lewis acidic (vide infra), which facilitates its coordination to the carbonyl in the cyclic transition state 5. 

Several methods promoted by a stoichiometric amount of chiral Lewis acid 38 [51] or chiral Lewis bases 39 [52, 53] and 40 [53] have been developed for enantioselective indium-mediated allylation of aldehydes and ketones by the Loh group. A combination of a chiral trimethylsilyl ether derived from norpseu-doephedrine and allyltrimethylsilane is also convenient for synthesis of enan-tiopure homoallylic alcohols from ketones [54,55]. Asymmetric carbonyl addition by chirally modified allylic metal reagents, to which chiral auxiliaries are covalently bonded, is also an efficient method to obtain enantiomerically enriched homoallylic alcohols and various excellent chiral allylating agents have been developed for example, (lS,2S)-pseudoephedrine- and (lF,2F)-cyclohex-ane-1,2-diamine-derived allylsilanes [56], polymer-supported chiral allylboron reagents [57], and a bisoxazoline-modified chiral allylzinc reagent [58]. An al-lyl transfer reaction from a chiral crotyl donor opened a way to highly enantioselective and a-selective crotylation of aldehydes [59-62]. Enzymatic routes to enantioselective allylation of carbonyl compounds have still not appeared. 

Diphenyl-BINOL-derived chiral aluminum reagents are prepared in situ by addition of Ethylaluminum Dichloride or Diethylaluminum Chloride to 3,3 -diphenyl-BINOL. These chiral aluminum reagents promote the enantioselective Diels-Alder reaction of cyclopentadiene with the oxazolidone dienophile (eq 14). Endo products are obtained with a high level of asymmetric induction (>90% ee) however, a stoichiometric amount of the Lewis acid is required. The preparation and use of a C3 symmetric BINOL-derived boronate has been reported (eq 15). BINOL-B(OAr)3 complexes have recently been developed for the asymmetric Diels-Alder reaction with imines (eq 16). ... 

Chiral Lewis Acid. These chiral titanium reagents are widely used as chiral Lewis acid catalysts. The Diels-Alder reaction of methyl acrylate and cyclopentadiene affords the endo adduct in moderate enantioselectivity when a stoichiometric amount of the chiral titanium reagent (5) is employed (eq 6). Use of 3-(2-alkenoyl)-l,3-oxazolidin-2-ones as dienophiles greatly improves the optical purity of the cycloadduct when the 2-phenyl-2-methyl-1,3-dioxolane derivative (6) is used as a chiral ligand. Most importantly, the reaction proceeds with the same high enantioselectivity for the combination of various dienophiles and dienes even when 5-10 mol % of the chiral titanium reagent is employed in the presence of molecular sieves 4A (eqs 7 and 8). ... 

By using a stoichiometric amount of the chiral titanium reagent prepared by mixing chiral diol, Titanium IV) Chloride, and titanium tetraisopropoxide, the asymmetric [2 + 2] cycloaddition reaction of 1,4-benzoquinones and styrenes gives the corresponding cyclobutane derivatives with high optical purity. These rearrange to 2,3-dihydrobenzofuran derivatives on mild acid treatment (eq 13). ... 

The asymmetric intramolecular ene reaction of 1,3-oxazolidin-2-one derivatives of a diene carboxylic acid is also promoted by a stoichiometric amount of the chiral titanium reagent (6) to give cyclopentane or cyclohexane derivatives with high optical purity (eq 14). ... 

Chiral B(III) Lewis Acids 163 5.4.1 Chiral Lewis Acids as Stoichiometric Reagents... 

In the presence of a Zr complex of (J )-6,6 -dibromo-BINOL, A -(2-hydroxyphenyl)-aldimines participate in asymmetric hetero-Diels-Alder reactions It is an improvement to the reactions involving stoichiometric chiral boron reagents. 

The most preparatively useful enantioselective allylation of aldehydes in this domain involves dialkoxyallylchromium (III) complexes. These stoichiometric reagents are prepared by treatment of CrCl2 with lithium alkoxides of chiral alcohols [151]. From a variety of chiral modifiers, the iV-benzoyl-L-prolinol derivatives are found to give the best yields and enantioselectivities (Scheme 10-84). 

With a parallel kinetic resolution, the two reactions should not interfere with one another. In the example above, both reactions were acylations but the use of stoichiometric reagents meant that the right acylating group was attached to the right enantiomer. Even here, Vedejs does not rule out a small amount of leakage between the paths (once the chiral DMAP is liberated it can get in on the act with the other pathway). A PKR becomes more difficult if, in addition to the reactions being related, they are also catalytic. 

Asymmetric allyation of carbonyl compounds to prepare optically active secondary homoallyhc alcohols is a useful synthetic method since the products are easily transformed into optically active 3-hydroxy carbonyl compounds and various other chiral compounds (Scheme 1). Numerous successful means of the reaction using a stoichiometric amount of chiral Lewis acids or chiral allylmetal reagents have been developed and applied to organic synthesis however, there are few methods available for a catalytic process. Several reviews of asymmetric allylation have been pubHshed [ 1,2,3,4,5] and the most recent [5] describes the work up to 1995. This chapter is focussed on enantioselective allylation of carbonyl compounds with allylmetals under the influence of a catalytic amount of chiral Lewis acids or chiral Lewis bases. Compounds 1 to 19 [6,7,8,9,10,11,12,... 

The first example of chiral Lewis base-catalyzed allylation of carbonyl compounds was shown by Denmark et al. [35]. They surveyed a variety of achiral and chiral Lewis bases as stoichiometric reagents to promote the addition of al-lyltrichlorosilane to benzaldehyde and found that the chiral phosphoramide 14 was a superior chiral promoter. When crotyltrichlorosilane was employed, the diastereoselectivity anti/syn) of the product was dependent on the geometry of the crotylsilane. Based on the stereochemical outcome, the reaction was proposed to proceed via closed transition structures involving hexacoordinate siH-conates. The potential for catalysis was proved using a 25 mol % of 14 at -78 °C and a moderate enantiomeric excess was obtained (Scheme 13). 

---