BINOL cyclization

The dihydropyrones are not produced directly in the initial BINOL-titanium(IV)-cat-alyzed reaction. The major product at this stage is the Mukaiyama aldol product which is subsequently cyclized by treatment with TFA [19fj. The formal cycloaddition product 3d (97% ee) obtained from a-(benzyloxy)acetaldehyde is an important intermediate for compactin and mevinolin. Scheme 4.13 outlines how the structural subunit 13 is available in three steps via this cycloaddition approach [19 fj. 

Metljylcoumarone has been prepared by the cyclization of ethyl a-phenoxyacetoacetate followed by hydrolysis and decarboxylation of the resulting ethyl 3-methylcoumarilate,3 4 by debromination and rearrangement of 3,4-dibromo-4-methyl-coumarin to 3-methylcoumarilic acid followed by decarboxylation,4-6 by cyclization of phenoxyacetone with concentrated sulfuric acid,6 and by treatment of 3-coumaranone with methyl-magnesium iodide followed by dehydration of the resulting car-binol.7... 

List and coworkers reasoned that BINOL phosphates (specific Brpnsted acid catalysis) could be suitable catalysts for an asymmetric direct Pictet-Spengler reaction [26], Preliminary experiments revealed that unsubstituted tryptamines do not undergo the desired cyclization. Introduction of two geminal ester groups rendered the substrates more reactive which might be explained by electronic reasons and a Thorpe-Ingold effect. Tryptamines 39 reacted with aldehydes 40 in the presence of phosphoric acid (5)-3o (20 moI%, R = bearing 2,4,6-triisopropyI-... 

In 2007, Hiemstra et al. established a catalytic asymmetric Pictet-Spengler reaction that proceeds via (V-sulfenyliminium ions (Scheme 15) [27], Treatment of iV-sulfenylated tryptamines 42 with aldehydes 40 and BINOL phosphate (R)-3f (5 mol%, R = 3,5-(CF3)2-CgH3) afforded tetrahydro-P-carbohnes. After completion of the cyclization the sulfenyl group was cleaved by the use of HCl. This one-pot... 

In 2007, Terada et al. extended their previously described chiral phosphoric acid-catalyzed aza-ene-type reaction of M-acyl aldimines with disubstituted enecarbamates (Scheme 28) to a tandem aza-ene-type reaction/cyclization cascade as a one-pot entry to enantioenriched piperidines 121 (Scheme 48). The sequential process was rendered possible by using monosubstituted 122 instead of a disubstituted enecarbamate 76 to produce a reactive aldimine intermediate 123, which is prone to undergo a further aza-ene-type reaction with a second enecarbamate equivalent. Subsequent intramolecular cychzation of intermediate 124 terminates the sequence. The optimal chiral BINOL phosphate (R)-3h (2-5 mol%, R = 4-Ph-C H ) provided the 2,4,6-sub-stituted M-Boc-protected piperidines 121 in good to exceUent yields (68 to > 99%) and accomplished the formation of three stereogenic centers with high diastereo- and exceUent enantiocontrol (7.3 1 to 19 1 transicis, 97 to > 99% ee(trans)) [72]. 

In 2008, the Ackennann group reported on the use of phosphoric acid 3r (10 mol%, R = SiPhj) as a Brpnsted acid catalyst in the unprecedented intramolecular hydroaminations of unfunctionaUzed alkenes alike 144 (Scheme 58) [82], BINOL-derived phosphoric acids with bulky substituents at the 3,3 -positions showed improved catalytic activity compared to less sterically hindered representatives. Remarkably, this is the first example of the activation of simple alkenes by a Brpnsted acid. However, the reaction is limited to geminally disubstituted precursors 144. Their cyclization might be favored due to a Thorpe-Ingold effect. An asymmetric version was attempted by means of chiral BINOL phosphate (R)-3( (20 mol%, R = 3,5-(CF3)2-CgH3), albeit with low enantioselectivity (17% ee). 

Ziegler et al. have reported the asymmetric desymmetrization approach to the synthesis of tricothecene, anguidine, via an ene cyclization (Scheme 8C.11) [31], The (2,4) ene cyclization (vide infra) of the prochiral aldehyde on silica gel gives a 1 1 diastereomeric mixture. Cyclization with purified Eu(fod)3 as Lewis acid catalyst gives an 8 1 mixture. The major isomer is a potential intermediate for the synthesis of anguidine. However, use of (+)-Eu(hfc)3, (+)-Eu(dppm)3, or (S)-BINOL-TiCl2 complex as chiral Lewis acid affords the major product with only 20-38% ee. 

Mikami et al. reported the first examples of catalytic asymmetric intramolecular carbonyl-ene reactions of types (3,4) and (2,4), using the BINOL-derived titanium complex (1) [46,49], The catalytic 7-(2,4) carbonyl-ene cyclization gives the corresponding oxepane with high enantiopurity, and the gem-dimethyl groups are not required (Scheme 8C.I8). In a similar catalytic 6-(3,4) ene cyclization, tran.v-tetrahydropyran is preferentially obtained with high enantiopurity (Scheme 8C. 19), The sense of asymmetric induction is the same as that observed for the glyoxylate-ene reaction, that is, (R)-BINOL-Ti catalyst provides (R)-alcohol. Therefore, the... 

Scheme 8C.18. Asymmetric 7-(2,4) carbonyl-ene cyclization catalyzed by BINOL-Ti complex.

Synthesis of imidazole-2-carboxaldehyde has previously been reported by manganese dioxide oxidation of the corresponding car-binol,4 by acid-promoted cyclization of 7V-(2,2-diethoxyethyl)-2,2-... 

A series of dibenzofuran-l,4-diones illustrated in the following scheme were constructed via a DDQ-mediated intramolecular oxidative cyclization of quinone-arenols <070L2807>. Dibenzo[b] furans were also found to be made from 2//-pyran-2-ones and 6,7-dihydro-577-benzo[Z>]furan-4-one <07T1610>. The asymmetric synthesis of chiral furo-fused BINOL derivatives was achieved via copper(II)-mediated oxidative coupling from naphthofuranol in the presence of chiral phenylethylamine <07TL317>. 

Cationic Cyclization. A cationic cyclization of BINOL-derived neryl ether has been accomplished with an organoalu-minum triflate catalyst. Limonene is obtained in 54% yield and... 

Ene Cyclization. An intramolecular (3,4)-ene reaction of unsaturated aldehydes has been accomplished with the BINOL-... 

Ene Cyclization, " The asymmetric catalysis of the intramolecular carbonyl-ene reaction not only of type (3,4) but also (2,4) employs the BINOL-derived titanium complexes [(I )-BINOL-TiX2 X = C104 or OTf], modified by the perchlorate and trifluoromethanesulfonate ligands. The tmns-... 

Enantioselective Polyene Cyclization Catalyzed SnCU-BINOL Derivatives. Non-enzymatic enantioselective polyene cyclizations are very attractive alternatives to the multistep synthesis from naturally occurring chiral synthons. The authors have succeeded in the first enantioselective biomimetic cyclization of polyprenoids catalyzed by LBA. (—)-Ambrox is the most important commercial substitute for ambergris, due to its unique olfactory and fixative properties. The successful preparation of (—)-ambrox has been achieved by the enantioselective cyclization of homofamesol promoted by (/ )-BINOL-Me-SnCl4, although the enantioselectivity and diastereoselectivity is moderate (eq 10). 

Cyclization of the more reactive o-geranylphenol with (/ )-BINOL-SnCLt gives the frani-fused tricyclic compound as a major diastereomer (36% ee, 84% ds) in good yield (eq 11). The enantioselectivity is improved to 50% ee by using (/ )-BINOL-Me-SnCU. The monobenzoyl ester of (/ )-BINOL [(/ )-BINOL-Bzj-SnCU complex is the most effective for controlling the absolute and relative stereochemistries (54% ee, 95% ds). 

Enantioselective Intramolecular Cyclization (Sn2 reaction). The desymmetric transformation of meso-structures has been recognized as a versatile synthetic method for optically active compounds in organic enzymatic processes. The enantioselective intramolecular cyclization of the bis-phenyllithium species, which is generated by addition of butyllithium to a solution of cis-3,5-di(bromophenoxy)cyclopentene, has been attained by addition of lithium salt (1.2 equiv) of (/ )-BINOL-Me to produce a cyclopenta[fc]benzofuran with 87% ee (eq 18). ... 

As a test of the intermediacy of the divinyl dichloride (44) in the solvolysis of dichlorocyclopropylcar-binols, Hiyama prepared the homoallylic alcohols (48) by additirai of l,l-cyclic ketones. Treatment of (48) with trifluoroacetic acid produced the cyclopentenones in very good yield (equation 31). This reaction presumably proceeds by dehydration to the divinyl dichloride followed by a similar ionization-cyclization sequence, foterestingly the regioisomeric dichloride also underwent closure to a cyclopentenone. ... 

Yamamoto et al. [42] reported a highly enantioselective ene cyclization with a chiral zinc reagent as Lewis acid catalyst. Cyclization of 3-methylcitronellal 57 by at least 3 equiv. catalyst prepared in-situ from (i )-l,T-bi-2-naphthol (BINOL) 58 and Mc2Zn afforded the frans-cyclohexanol 59 in 86 % yield with 88 % ee as the sole product (Sch. 23). Reducing the amounts of the chiral zinc catalyst reduced both the chemical yield and the enantioselectivity. 

The system was also applicable to the cyclization of citronellal 54. Treatment of (f )- and (5)-citronellal with the chiral zinc reagent derived from (/ )- and (5)-BINOL 58 afforded the exclusive formation of /- and d-isopulegol 55, respectively. The asymmetric induction is totally controlled by the C-3 chiral center on the substrates and is independent of the chirality of the BINOL. 

Enantioselective Polyene Cyclization Catalyzed by SnCl4 BINOL Derivatives... 

Cyclization of the more reactive o-geranylphenol with the (f )-BINOL-SnCl4 complex in dichloromethane at -78 °C was complete within 1 day, and the tran -fused tricyclic compound was obtained as a major diastereomer (84 % ds) in good yield (Eq. 99). The optical yield, however, was only 36 % ee. The enantioselectivity was improved to 50 % ee by using the (f )-BINOL-Me-SnCl4 complex. Finally, we found that the monobenzoyl ester of the (i )-BINOL ((f )-BINOL-Bz)-SnCl4 complex enabled the most effective control of the absolute and relative stereochemistries (54 % ee, 95 % ds). It seems that the stereoselectivity depends on the activity of LBA, which decreased in the order BINOL-SnCU, BINOL-Me-SnCl4, and BINOL-Bz-SnCU. 

Asymmetric catalysis of ene reactions was initially investigated for the intramolecular examples, because intramolecular versions are much more facile than their inter-molecular counterparts. The first reported example of an enantioselective 6-(3,4) car-bonyl-ene cyclization employed a BINOL-derived zinc reagent [81]. This, however, was successful only when excess zinc reagent (at least 3 equiv.) was used. An enantioselective 6-(3,4) olefin-ene cyclization has also been developed which uses a stoichiometric amount of a TADDOL-derived chiral titanimn complex (Sch. 26) [82]. In this ene reaction, a hetero Diels-Alder product was also obtained, the periselectivity depending critically on the solvent system employed. In both cases, geminal disubstitution is required of high ee are to be obtained. Neither reaction, however, constitutes an example of a truly catalytic asymmetric ene cyclization. 

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. 

Few examples have been reported demonstrating enantioselective cyclization methodology. One known example, however, is similar to the diastereoselective cyclization of 175, which uses a menthol-derived chiral auxiliary and a bulky aluminum Lewis acid (see Eq. (13.55)). The enantioselective variant simply utilizes an achiral template 188 in conjunction with a bulky chiral binol-derived aluminum Lewis acid 189 (Eq. (13.59)) [75]. Once again the steric bulk of the chiral aluminum Lewis acid complex favors the s-trans rotamer of the acceptor olefin. Facial selectivity of the radical addition can then be controlled by the chiral Lewis acid. The highest selectivity (48% ee) was achieved with 4 equivalents of chiral Lewis acid, providing a yield of 63%. 

---