BINOLate/Ti-catalyzed asymmetric

Mikami reported a BINOL-Ti-catalyzed asymmetric intramolecular carbonyl-ene cyclization [142], giving the cyclization product with high enantiomeric excess (Scheme 14.56). The sense of asymmetric induction was found to be the same as that for the glyoxylate-ene reaction. This methodology has been successfully applied to the synthesis of analogs of vitamin D3 [143]. 

BINOLate/Ti-Catalyzed Asymmetric Ring-Opening Aminoiysis of Epoxides... 

BINOL-Ti-catalyzed carbonyl-ene reaction of glyoxylate has also been applied to the asymmetric desymmetrization of prochiral ene substrates with planar symmetry and kinetic optical resolution of racemic ether. As shown in Scheme 14.55, optically active products can be obtained with extremely high enantiomeric excesses [140]. The asymmetric desymmetrization of meso olefin derivative via BINOL-Ti-catalyzed carbonyl-ene reaction of formaldehyde, vinyl and alkynyl analogs of glyoxylates has been applied to the synthesis of isocarbocycline analogs [141]. 

The sense of asymmetric induction was the same as observed in BINOL-H-catalyzed asymmetric reactions such as carbonyl-ene reaction (55-57,59) and Mukaiyama-aldol reaction (40,41) regardless of the preparative procedure of the catalysts (/ )-BINOL-Ti catalyst produces an (/ )-alcohol product. This F-C reaction would not proceed through a six-membered transition state (A) involving a chiral Lewis acid, which has been reported to preferentially produce an orrAo-F-C-product in the reaction of phenol (19,24) or 1-naphthol (25). In sharp contrast, the para-isomer was obtained as the major product in our case. 

There have been numerous Other applications of BINOL-Ti-catalyzed ally-lation reactions in complex molecule syntheses [30, 32], In the construction of the terminal portion of mucocin, Evans documented the asymmetric addition of an allylstannane to unsaturated aldehyde 202, giving adduct 203 in 98 2 dr (Equation 14) [125]. In another example, Roush disclosed the addition of an allylstannane to aldehyde 204, en route to the synthesis of the superstolides (Equation 15) [126]. These examples underscore the Ti-cata-lyzed enantioselective allylation process as a general approach to useful, functionalized chiral fragments. 

The Ti(0 Pr)2Cl2/D-DIPT poison has also been used for the Ti(0 Pr)2Cl2/ BINOL-catalyzed asymmetric carbonyl-ene reaction with chloral (Scheme 8.8). With the Ti(0 Pr)4/D-DIPT poison in a 1 3 ratio, both the regioselectivity and the enantioselectivity of the ene product are improved. 

Scheme 8C.3. Asymmetric carbonyl-ene reaction catalyzed by BINOL-Ti complex.

The advantage of asymmetric activation of the racemic BINOL-Ti(OPr )2 complex ( 2) is highlighted in a catalytic version (Table 8C.3, entry 5) wherein high enantioselectivity (80.0% ee) is obtained by adding less than the stoichiometric amount (0.25 molar amount) of (R)-BI-NOL [42a], A similar phenomenon has been observed in the aldol [42c] and (hetero) Diels-Al-der [44] reactions catalyzed by the racemic BINOL-Ti(OPr )2 catalyst (+2). 

Scheme 8C.21. Asymmetric carbonyl addition reaction catalyzed by BINOL-Ti.

The activation of a racemic catalyst by a chiral additive was achieved by Mikami in a chiral titanium complex-catalyzed asymmetric carbonyl-ene reaction (Scheme 9.21) [39], The racemic catalyst ( )-BINOL-Ti-(0-i-Pr)2 37 (10 mol %) is activated by adding (R)-BINOL (5 mol %), and the ene product 38 with 90% ee is obtained. (R)-BINOL is selectively associated with (/f)-BIN0L-Ti-(0-i-Pr)2 to give a dimeric catalyst whose activity is kinetically calculated to be 25.6 times greater than that of the remaining (S)-BIN0L-Ti-(0-i-Pr)2. 

In our research on the asymmetric catalysis of the carbonyl-ene reaction, we found that the BINOL-Ti complexes (1) [30], prepared in situ, in the presence of 4-A molecular sieves, from diisopropoxytitanium dihalides (X2Ti(OPr )2 X = Br [31] or Cl [32]) and optically pure BiSfOL (vide infra), catalyze [33], rather than promote stoichiome-trically, the carbonyl addition reaction of allylic silanes and stannanes [34]. The addition to glyoxylate of ( )-2-butenylsilane and -stannane proceed smoothly to afford the syn product in high enantiomeric excess (Sch. 5). The s yn-product thus obtained could be readily converted to the iaetone portion of verrucaline A [35]. 

The synthetic utility of the vinylic sulfide and selenide approach is exemplified by the synthesis of enantio-pure (i )-(-)-ipsdienol, an insect aggregation pheromone (Sch. 13) [54], Kabat and Uskokovic have demonstrated the asymmetric catalytic synthesis of la,25-dihydroxyvitamin D3 (la,25(OH)2D3) A-ring synthon by means of a glyoxylate-ene reaction catalyzed by BINOL-Ti complex (1) (Sch. 14) [55]. 

Figure 1. (+)-NLE in the asymmetric glyoxalate-ene reaction catalyzed by the BINOL-Ti complex.

Keck also investigated asymmetric catalysis with a BINOL-derived titanium complex [102,103] for the Mukaiyama aldol reaction. The reaction of a-benzyloxyalde-hyde with Danishefsky s dienes as functionalized silyl enol ethers gave aldol products instead of hetero Diels-Alder cycloadducts (Sch. 40) [103], The aldol product can be transformed into hetero Diels-Alder type adducts by acid-catalyzed cyclization. The catalyst was prepared from BINOL and Ti(OPr )4, in 1 1 or 2 1 stoichiometry, and oven-dried MS 4A, in ether under reflux. They reported the catalyst to be of BINOL-Ti(OPr% structure. 

The Lewis acid-catalyzed conjugate addition of silyl enol ethers to a,y3-unsaturated carbonyl derivatives, the Mukaiyaraa Michael reaction, is known to be a mild, versatile method for carbon-cabon bond formation. Although the development of catalytic asymmetric variants of this process provides access to optically active 1,5-dicarbonyl synthons, few such applications have yet been reported [108], Mukiyama demonstrated asymmetric catalysis with BINOL-Ti oxide prepared from (/-Pr0)2Ti=0 and BINOL and obtained a 1,4-adduct in high % ee (Sch. 43) [109]. The enantioselectiv-ity was highly dependent on the ester substituent of the silyl enol ether employed. Thus the reaction of cyclopentenone with the sterically hindered silyl enol ether derived from 5-diphenylmethyl ethanethioate proceeds highly enantioselectively. Sco-lastico also reported that reactions promoted by TADDOL-derived titanium complexes gave the syn product exclusively, although with only moderate enantioselectiv-ity (Sch. 44) [110]. 

The Diels-Alder reaction of methacrolein with 1,3-dienol derivatives can also be catalyzed by the BINOL-derived titanium complex, although the catalyst must be freed from molecular sieves (MS) to give the endo adduct with high enantioselectivity (Sch. 50) [131], because MS act as achiral catalysts in the Diels-Alder reaction. The asymmetric Diels-Alder reaction catalyzed by the MS-free (MS-(-)) BINOL-Ti complex (L) can be applied naphthoquinone derivatives as dienophiles to provide entry to the asymmetric synthesis of tetra- and anthracyclinone [132] aglycones (Sch. 51). The sense of asymmetric induction is exactly the same as that observed in the presence of MS in the asymmetric catalytic reactions described above. 

Table 4. NLE in the asymmetric Diels-Alder reaction of 1-acetoxy-l,3-butadiene and methacrolein catalyzed by MS-free BINOL-Ti ( ).

In the Diels-Alder reaction of glyoxylates with the Danishefsky diene (Sch. 53), asymmetric activation of (f )-BINOL-Ti(OPr )2 (2) by (/ )-BINOL is essential if enantioselectivity is to be higher than that achieved by use of the enantio-pure BINOL-Ti catalyst (5 % ee) [78], Effects of the torsional angles of 2,2 -biaryldiol ligands have been examined in the asymmetric Diels-Alder reaction of acrylate catalyzed by titanium complexes [133]. 

Marshall subsequently demonstrated that the efficiency of the crotylation reactions catalyzed by CAB catalyst 459b could be improved by using the more reactive crotylstannanes and employing two equivalents of (CF3C0)20 to aid catalyst turnover [310]. In a comparative study of the catalytic asymmetric allylation and crotylation reactions of cyclohexane carboxaldehyde with allyl- and crotylstannanes 98 and 10, Marshall demonstrated the complementarity between the BINOL-Ti(0-i-Pr)4 catalyst 451 and the CAB catalyst 459b (Table 11-29). 

Tagliavini and Umani-Ronchi found that chiral BINOL-Zr complex 9 as well as the BINOL-Ti complexes can catalyze the asymmetric allylation of aldehydes with allylic stannanes (Scheme 9) [27]. The chiral Zr catalyst 9 is prepared from (S)-BINOL and commercially available Zr(0 Pr)4 Pr0H. The reaction rate of the catalytic system is high in comparison with that of the BINOL-Ti catalyst 4, however, the Zr-catalyzed allylation reaction is sometimes accompanied by an undesired Meerwein-Ponndorf-Verley type reduction of aldehydes. The Zr complex 9 is appropriate for aromatic aldehydes to obtain high enantiomeric excess, while the Ti complex 4 is favored for aUphatic aldehydes. A chiral amplification phenomenon has, to a small extent, been observed for the chiral Zr complex-catalyzed allylation reaction of benzaldehyde. 

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