Asymmetric cycloisomerization

When (R,R)-Me-Duphos, (R,R,R,R)-BICPO [9] or BINAP [10] is used, the rhodium-catalyzed asymmetric cycloisomerization of 3 affords 4 with up to >99.5% enantiomeric excess (Scheme 7 2). This methodology was applied to the synthesis of functionalized a-methylene-y-butyrolactone derivatives 6 such as (-i-)-pilocarpine 7 (Scheme 7.3) [11]. 

DFT studies of the asymmetric cycloisomerization of enyne catalysed by PtCl2 have been carried out at the B3LYP/6-31G(d,p) level.40 The formation of the cyclopropy- 0> lcarbene intermediate represents the chirality-limiting step. 

Scheme 3. Pd-catalyzed asymmetric cycloisomerization with c/s-bidentate ligands.

Rh-catalyzed Asymmetric Cycloisomerization Reaction Synthesis of (3-Oxo-2-pentylidenecyclopentyl)acetaldehyde... 

In the first asymmetric cycloisomerization reaction, the cyclopentenol derivative 82 was prepared from 80 in the presence of (—)-CAMP 81 (Scheme 5.16) [83]. The low asymmetric control (14% ee) was attributed to the reversibility of the cyc-lization. It should be noted that this reaction is not suitable for the preparation of six-membered rings. 

Recently, the transition-metal-catalyzed enanti-oselective enyne cycloisomerization has been reported.99 Cao and Zhang reported that, in the presence of catalytic amounts of [Rh(bicpo)Cl]2 and AgSbFe, the enantioselective cycloisomerization of the 1,6-enynes 50 gave the functionalized lactams 51 in good yields with high ee values (Scheme 17).99a Hatano et al. reported that, in the presence of catalytic amounts of palladium(II) and (i )-SEG-PHOS, the asymmetric cycloisomerization of the 1,6-enyne 52 gave the tetrahydrofuran derivative 53 in 99% yield with >99% ee (Scheme 18).99b It should be noted that the quaternary chiral center is constructed with extremely high ee in almost quantitative yield. 

BINAP were used, the Rh-catalyzed asymmetric cycloisomerization... 

Scheme 2-56. Rh-catalyzed asymmetric cycloisomerization of enyne 477a.

Asymmetric cycloisomerization of nitrogen-bridged 1,6-enynes occurs in the presence of a cationic rhodium complex coordinated with a chiral diene/phosphine tridentate ligand to give chiral 3-azabicyclo[4.1.0]heptenes with high enantioselectivity (Scheme 149). " ... 

Using the catalyst system based on [Ni(allyl)(cod)l [BARF] and Wilke s aza-phospholene ligand, several 1,6-dienes including diene 48 were converted to exo-methylenecyclopentanes 49 through the asymmetric cycloisomerization with enantiomeric excess of up to 91% (Scheme 28) (66). 

Inducing Asymmetry in -Elimination Pathway Apart from its racemic variants, cycloisomerization of enynes has been successfully employed in asymmetric synthesis. In the first example of an asymmetric cycloisomerization reaction, Trost et al. used a combination of palladium(O) and a chiral acid to catalyze the cycloisomerization of 1,6-enynes resulting in a rather low enantioselectivity of 33% ee for the formation of 1,4-diene (35) (Scheme 7.17(a)) [35]. Modem development of chiral phosphoric acids has allowed the reexamination of this approach. Thus, when palladium(O) and chiral (5)-TRIP were used with enyne 36 a 71% yield of diene 37 was isolated in 88% ee [36]. Under the same eon-cept, Mikami and coworkers found that cationic palladium... 

Expansion of the substrate scope on asymmetric cycloisomerization came from the advancement of rhodium catalysis. Following the same catalytic cycle, rhodium(l) complexes coordinate enynes followed by oxidative... 

SCHEME 7.37 Variations of asymmetric cycloisomerization of 1,6 dienes under nickel catalysis. 

TABLE 7.1 Dependence of Counteranions of the Catalyst on the Asymmetric Cycloisomerization of 1,6-Dienes... 

Fairlamb US (2004) Asymmetric cycloisomerization of 1,6- and 1,7-enynes by transition-metal catalysts. Angew Chem Int Ed 43 1048-1052... 

A so far unsolved problem is the development of asymmetric procedures for the above described Fe(0)-catalyzed cycloisomerizations and cycloadditions. The option to use the element of planar chirality might allow to successfully address this issue in future applications. 

Zhang s group has reported highly enantioselective cycloisomerization processes catalyzed by rhodium(i) chiral complexes (Scheme 53). For instance, (A)-BINAP gives excellent asymmetric induction in the reaction of enediyne 212 to furnish the quasi-enantiopure Alder-ene product 213.219... 

Zhang54 published the first and only account of a non-asymmetric rhodium-catalyzed Alder-ene cycloisomerization of 1,6-enynes.55 The conditions developed by Zhang and co-workers are advantageous in that, similar to the ruthenium conditions developed by Trost, selectivity for 1,4-diene products is exhibited. The rhodium conditions are dissimilar from many other transition metal conditions in that only (Z)-olefins give cycloisomerization products. 

Figure 2 Ligands for effecting asymmetric transition metal-catalyzed Alder-ene cycloisomerization.

Enantioselective hydrogenation of 1,6-enynes using chirally modified cationic rhodium precatalysts enables enantioselective reductive cyclization to afford alky-lidene-substituted carbocycles and heterocycles [27 b, 41, 42]. Good to excellent yields and exceptional levels of asymmetric induction are observed across a structurally diverse set of substrates. For systems that embody 1,2-disubstituted alkenes, competitive /9-hydride elimination en route to products of cycloisomerization is observed. However, related enone-containing substrates cannot engage in /9-hydride elimination, and undergo reductive cyclization in good yield (Table 22.12). 

One of the major advantages of the rhodium(I)-catalyzed Alder-ene reaction is that mild conditions are used to effect the cycloisomerization process thus increasing the likelihood of being able to facilitate an asymmetric reaction. In fact, Zhang has demonstrated convincingly that the Alder-ene reaction of enynes can indeed be performed with excellent enantioselectivity and with similar efficiency. These examples are highlighted below in chronological order. 

Asymmetric synthesis of stavudine and cordycepin, anti-HIV agents, and several 3 -amino-3 -deoxy-P-nudeosides was achieved utilizing this cycloisomerization of 3-butynols to dihydrofuran derivatives [16]. For example, Mo(CO)6-TMNO-promoted cyclization of the optically active alkynyl alcohol 42, prepared utilizing Sharpless asymmetric epoxidation, afforded dihydrofuran 43 in good yield. Iodine-mediated introduction of a thymine moiety followed by dehydroiodination and hydrolysis of the pivaloate gave stavudine in only six steps starting from allyl alcohol (Scheme 5.13). 

McDonald, F. E. Gleason, M. M. Asymmetric synthesis of nucleosides via molybdenum-catalyzed alkynol cycloisomerization coupled with stereoselective glycosylations of deoxy-furanose glycals and 3-amidofuranose glycals. J. Am. Chem. Soc. 1996, 118, 6648-6659. 

Scheme 6. Asymmetric Rh-catalyzed cycloisomerization reaction via a new procedure.

As variations of Rh-catalyzed cycloisomerization Widenhoefer and coworkers have developed asymmetric 1,6-enyne cyclization/hydrosilylation reactions by using the Rh(I)/biphemp system excellent de and ee were obtained [42]. Brum-mond et al. also discovered a rhodium(I)-catalyzed allenic Alder-ene reaction that... 

Jt-allyl complex can be generated after cyclization, as suggested by Takacs in a Fe(0)-catalyzed cyclization of polyenes. It also can be preformed if an active functional group is present in the allylic position. The palladium-catalyzed intramolecular cycloisomerization reaction of allylic acetates is an efficient method for constructing five- or six-membered rings [56, 57]. An asymmetric approach to this transformation has been studied and so far only poor enantioselectivity has been achieved (0-20% ee) [58]. Very recently, Zhang et al. also reported a Rh-catalyzed cycloisomerization involving a Jt-allylrhodium intermediate formed from an allylic halide [59]. 

In the second example, Gilbertson and colleagues have revealed that cationic Me-DuPhos-Rh catalysts effect asymmetric [4 + 2] cycloisomerization of standard dieneynes such as 70 to afford bicyclic products 71, whereupon two stereogenic centers are established with high levels of absolute stereocontrol (Scheme 13.25).70... 

Scheme 5.14 The aldol cycloisomerization by pipecolinic acid and NMI-catalyzed asymmetric intramolecular MBH reaction followed by a kinetic resolution quench .

A modification of this system was also used in intramolecular MBH reactions (also called as aldol cycloisomerization) [71, 74]. In this reaction, optically active pipecolinic acid 61 was found to be a better co-catalyst than proline, and allowed ee-values of up to 80% to be obtained, without a peptide catalyst. The inter-molecular aldol dimerization, which is an important competing side-reaction of the basic amine-mediated intramolecular MBH reaction, was efficiently suppressed in a THF H20 (3 1) mixture at room temperature, allowing the formation of six-membered carbocycles (Scheme 5.14). The enantioselectivity of the reaction could be improved via a kinetic resolution quench by adding acetic anhydride as an acylating agent to the reaction mixture and a peptide-based asymmetric catalyst such as 64 that mediates a subsequent asymmetric acylation reaction. The non-acylated product 65 was recovered in 50% isolated yield with ee >98%. 

The chemical reactions possible with silver catalysis are multiple and cover cycloadditions, cycloisomerizations, allylations, aldol reactions, and even C-H bond activation. Also, asymmetric versions are known, even though they still need to be improved.3-10... 

An asymmetric synthesis of aminocyclopentitols 134-137 has been used in the synthesis of trehazolin via free-radical cycloisomerization of enantiomerically pure, alkyne-tethered oxime ethers derived from D-mannose (Scheme 17).84 Treatment of 2,3 5,6-di-(9-isopropylidene-D-mannofuranose (128)85 with ethynylmagnesium bromide gave compound 129, which underwent sequential one-pot acid hydrolysis plus diol cleavage to give 130, oximation of which afforded the radical precursor 131, in 41% overall yield from 129. The free hydroxyl group of 131 was protected as acetate 132 and tert-butyldimethylsilyl ether 133, which were isolated as inseparable... 

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