Chromenes chiral

Dimethylchromene has also proven to be a useful substrate for the assessment of various transition metal complexes as epoxidation catalysts. Chiral Mn(III)-salen complexes are efficient <00CC615 00T417> and can be recycled when used in an ionic liquid <00CC837>. The enantioselective aziridination of a chromene has been achieved using a chiral biaryldiamine-derived catalyst (Scheme 22) <00JA7132>. 

As was mentioned previously, certain disubstituted styrene ethers can be efficiently resolved through the Zr-catalyzed kinetic resolution. As illustrated in Eq. 7, optically pure cycloheptenyl ether 64c is obtained by the Zr-catalyzed process. The successful catalytic resolution makes the parent alcohol and the derived benzyl ether derivatives 64a and 64b accessible in the optically pure form as well. However, this approach cannot be successfully applied to all the substrates shown in Table 1. Lor example, under identical conditions, cyclopentenyl susbstrate 60b is recovered in only 52% ee after 60% conversion. Cycloheptenyl substrates shown in entry 4 undergo significant decomposition under the Zr-catalyzed carbomagnesation conditions. These observations indicate that future work should perhaps be directed towards the development of a chiral metathesis catalyst that effects the chromene formation and resolves the two styrene ether enantiomers simultaneously. 

The synthetic versatility and significance of the Zr-catalyzed kinetic resolution of exocyc-lic allylic ethers is demonstrated by the example provided in Scheme 6.9. The optically pure starting allylic ether, obtained by the aforementioned catalytic kinetic resolution, undergoes a facile Ru-catalyzed rearrangement to afford the desired chromene in >99% ee [20], Unlike the unsaturated pyrans discussed above, chiral 2-substituted chromenes are not readily resolved by the Zr-catalyzed protocol. Optically pure styrenyl ethers, such as that shown in Scheme 6.9, are obtained by means of the Zr-catalyzed kinetic resolution, allowing for the efficient and enantioselective preparation of these important chromene heterocycles by a sequential catalytic protocol. 

Scheme 6.9. Tandem Zr-catalyzed kinetic resolution and Ru-catalyzed ring-opening/ring-closing metatheses afford chiral chromenes with high optical purity.

Hoveyda et al. reported a novel method for synthesizing of chromene 71 by ROM-RCM of cycloalkene 70 bearing the phenyl ether at the 3-position [Eq. (6.48)]." ° The yield is improved when the reaction is carried out under ethylene gas. In the case of cyclopentene 70a (n = 0) or cyclohexene 70b (n = 1), the yield is poor because the starting cycloalkene is in a state of equihbrium with the product and a thermodynamic product should be formed under these reaction conditions. They obtained enantiomeric ally pure cycloheptene derivative (5)-70e using zirconium-catalyzed kinetic resolution of 70e developed by their group, and chromene 71c was synthesized as a chiral form via ROM-RCM using lb [Eq. (6.49)] ... 

The only known example of asymmetric reactions in the chromene series consists in the synthesis of 155 with asymmetric induction by nitriles 156 with a chiral menthyl substituent. Compounds 155 are formed in high yields, but with low diastereomeric purity, the major stereoisomer possessing the S-configuration (96JHC27) (Scheme 57). 

An interesting reversal of chiral induction in chromium(III)-salen complexes using a tartaric derived alicyclic diamine moiety (i.e., 7) has been observed by Mosset, Saalfrank, and co-workers <99T1063>. Thus, epoxidation of the chromene 8 using catalyst 7 and an oxidant consisting of MCPBA/NMO afforded the 3S,4S epoxide 9, whereas the Jacobsen catalyst (1) provided the corresponding 3R,4R enantiomer. A mechanistic rationalization for this curious crossover has not yet been proposed. 

Katsuki has extended his earlier work on asymmetric induction using achiral catalysts such as 13. In these systems, the stereochemical bias is imbued by a chiral non-racemic axial ligand, such as (+)-3,3 -dimethyl-2,2 -bipyridine A2,A -dioxide (14), which was purified by crystallization with (5)-binaphthol. Epoxidation using these conditions resulted in good ee s and fair yields, as exemplified by the preparation of chromene epoxide 16 <99SL783>. 

Regardless of the mechanism, the chiral (salen)Mn-mediated epoxidation of unfunctionalized alkenes represents a methodology with constantly expanding generality. Very mild and neutral conditions can be achieved, as illustrated by Adam s epoxidation of chromene derivatives 12 using Jacobsen-type catalysts and dimethyldioxirane as a terminal oxidant [95TL3669]. Similarly, periodates can be employed as the stoichiometric oxidant in the epoxidation of cis- and tram-olefins [95TL319],... 

The reaction of the tetrabutylammonium salt of cAMP with 4-(bromo-methyl)-2Jf-chromen-2-one yields two products which result from axial and equatorial attack of the phosphate group. What is the isomeric relationship between the two products Determine the configuration of all the chirality centres in both products. 

A somewhat different approach to catalyst separation has been devised by engineering the chiral salen catalyst to have built-in phase-transfer capability, as exemplified by the Mn(III) complex 10 <02TL2665>. Thus, enantioselective epoxidation of chromene derivatives (e.g. 11) in the presence of 2 mol% catalyst 10 under phase transfer conditions (methylene chloride and aqueous sodium hypochlorite) proceeded in excellent yield and very good ee s. The catalyst loading could be reduced to about 0.4% with only marginal loss of efficiency. 

A-Aminophthalimide (118) can also be added to olefins in an asymmetric fashion. Thus, reaction of A -enoyl oxazolidinone 122 with 118 and lead tetraacetate in the presence of the camphor-derived chiral ligand 120 provides aziridine 123 in 83% yield and with 95% ee <020L1107>. Other useful chiral ligands include imine 121, derived from the condensation of 2,2 -diamino-6,6 -dimethylbiphenyl with 2,6-dichlorobenzaldehyde. The corresponding monometallic Cu(I) complex was found to be very efficient in chiral nitrogen transfer onto chromene derivative 124 using (Ar-(p-toluenesulfonyl)imino)phenyliodinane (PhI=NTs) to provide aziridine 125 in 87% yield and 99% ee <02JOC3450>. 

The cyclohexadienone 10 undergoes an intramolecular asymmetric Heck reaction in the presence of a chiral monodentate phosphoramidate ligand to give the benzo[c]chromene derivative 11 with excellent enantioselectivity and conversion <02JA184>. 

Mannschreck e/a/.189-193 have studied the preparation, separation, and thermal and photo racemization of the chiral chromenes and spiropyrans shown in Figure 1.6. 

Figure 1.6. Some chiral spiropyrans and chromenes that have been resolved.

K. Otocan, L. Loncar, M. Mintas, T. Trotsch and A. Mannschreck, Chiral chromenes synthesis, separation of enantiomers and barriers to racemization, Croat. Chim. Acta, 66, 209-219 (1993). 

Kinetic resolntion of cyclic allylic ethers can be performed by asymmetric Zr-catalyzed carbomagnesation. Six-, seven-or eight-membered ethers can readily be resolved by the Zr-catalyzed protocol (with ee between 81 to 99%). As an example, the tandem Zr-catalyzed kinetic resolution followed by a Ru-catalyzed ring-opening/ring-closing metathesis affords chiral chromenes with high optical purity (ee > 99%). ... 

No racemisation is observed during the Pt(IV)-catalysed cyclisation of chiral propargyl ethers to chromenes. The PtCU catalyst appears to activate selectively the triple bond to nucleophilic attack by the arene and enables this well-established route to chromenes to be carried out under mild, neutral conditions and with a variety of substrates (Scheme 12) <03T8859>. A Pt-catalysed 6-endo hydroarylation of an alkynone combined with an intramolecular Michael addition are the key steps in a synthesis of the rotenoid deguelin <030L4053>. 

Katsuki and co-workers have investigated asymmetric epoxidation reactions mediated by achiral Mn(salen) complexes in the presence of chiral additives the combination of tetramethyl diamine-derived complex 37 and (—)-sparteine 38 can mediate the oxidation of chromenes with up to 73% ee (Table 2, entry 1) however, the yields were low <1997T9541>. More successful was ethylene diamine-derived complex 39, which promoted the asymmetric epoxidation of several chromenes in good to excellent yields and good levels of ee in combination with chiral... 

Table 2 Chromene oxidations in the presence of chiral additives...

Recently, Wong and Shi have examined the effect of substitution in the 6- or 8-position in the asymmetric epoxidation of chromenes by chiral dioxiranes derived from ketones 52 and 53. Up to 93% ee was achieved, with higher ee s obtained when substrates are substituted at the 6-position <2006JOC3973>. 

Due to the demand for inexpensive anti-HIV agents, several reactions for the synthesis of Indinavir (70, an HIV protease inhibitor of Merck Co.) have been reported. Enantioselective epoxidation of simple alkenes with bleach is achievable in the presence of the Mn " complex 69 possessing a well-designed chiral salen ancillary [69]. Scheme 20 exemplifies its application to the synthesis of Indinavir (70), by way of indene oxide (68) in 88 % ee [69]. This method is also useful for the asymmetric synthesis of a chromene epoxide in 97 % ee serving as an intermediate for Lemakalim, a K" -channel opening agent [70]. 

Dimethyl-2//-chromenes have been epoxidized enantioselectively with DMD in the presence of chiral Mn(III)salen catalysts <95TL3669>. 

G. Harie, A. Samat, R. Guglielmetti, I. Van Parys, W. Saeyens, D. De Keukeleire, K. Lorenz, and A. Mannschreck, Chiral 2-aryl-2-methyl-[27/]-chromenes Synthesis, characterization of enantiomers and barriers to thermal racemization, Helv. Chim.Acta80, 1122-1132 (1997). 

---