Intramolecular desymmetrization

Iwabuchi et al. developed an intramolecular desymmetrization approach for the conversion of the cyclohexanone 93 into the bicyclic 94 using the silylated hydroxyproline 95 as an enamine-catalyst 87). Using 25 mol% of 95, the product 94 was obtained in good yield and excellent stereoselectivity and was employed... 

In contrast to the early report of intramolecular desymmetrization reactions [6], the intramolecular ring-closing reactions of achiral substrates via enamine catalysis were not disclosed until the beginning of the twenty-first century. In 2003, list reported the first highly stereoselective intramolecular aldol reaction of achiral dicarbonyl compounds. Cyclic aldol products 6a-< were delivered from heptanedials 5 with excellent diastereo- and enantioselectivity by the catalysis of L-proline (Scheme 36.2). The cyclization of ketoaldehyde 7 afforded alcohol 8 as a 2 1 diastereomeric mixture but with 99% ee. This strategy could provide P hydroxyl carbonyl derivatives that are of potential applications in organic synthesis [7aj. 

An impressive application of the (salen) Co-catalyzed intramolecular ARO of meso-epoxy alcohols in the context of total synthesis was reported recently by Danishefsky [33], Enantioselective desymmetrization of intermediate 9 by use of the cobalt acetate catalyst 8 at low temperatures afforded compound 10, which was obtained in 86% ee and >86% yield (Scheme 7.18). Straightforward manipulation of 10 eventually produced an intermediate that intersected Danishefsky s previ-... 

The addition of large linear blocks to dendrons with opposite polarity creates a desymmetrized structure predisposed to sequester insoluble components by aggregation rather than intramolecular hydrogen-bonding. Amphiphilic, linear-dendritic diblock (AB) and triblock (ABA) copolymers self-assemble into multimolecular micelles with CMC values that are well below those of low molecular weight surfactants. Typically, a hydrophilic linear block such as PEG is attached to the focal point... 

In 1992, Trost and his co-workers investigated desymmetrization of cyclic w j-o-diesters with lithium sulfonyl-methylenenitronate as a nucleophile in the presence of Trost s ligand 118, where the corresponding cyclic compounds are obtained with an excellent enantioselectivity via intramolecular cyclization (Scheme 15),103,103a Asymmetric cyclopropanation and lactone annulation are achieved according to this protocol (Scheme Nitroalkanes can also be employed as carbon-centered nucleophiles in lieu of malonates (Scheme 17). ... 

Brase reported an intramolecular asymmetric Heck-intermolecular Heck cascade reaction of l,3-bis(enolnonaflates) 131 to the highly congested bicyclic compound 132 [122] (Scheme 5). Although the level of asymmetric induction is low (up to 52% ee), this result shows that the concept of two leaving groups in the desymmetrization reaction can be applied. 

Scheme 8E.6. Desymmetrization of meso-2-ens-1,4-diols by intramolecular alkylation.

A desymmetrization of cyclohexa-2,5-dienes (22) and (24), obtained by Birch reductive alkylation, through a diastereoselective intramolecular hydroamination led with high selectivity to the corresponding bicyclic allylic amines (23) and (25) (Scheme 6).19... 

The desymmetrization of dicarbonate 206 was initiated by the addition of one equivalent of N-(3-butenyl) nosylamide 207 under palladium catalysis in the presence of Trost s chiral diphosphine ligand 205. When the first allylic substitution was completed, the reaction was warmed and the resulting intermediate 208 was treated in situ with one equivalent of a second nosylamide 209. Product 210 resulting from this double substitution reaction was submitted to a tandem intramolecular ROM/RCM to furnish key precursor 211, which was engaged in the final cyc-lization step by the reduction of the double bonds, followed by the HCl-promoted domino deprotection of the acetal and aminal formation. 

An alternative concept is asymmetric desymmetrization of a prochiral molecule of type 83. The starting materials 83 have three keto groups and one carbon atom bearing at least three substituents. A prerequisite is the presence of a prochiral carbon atom with two identical substituents bearing a keto functionality (Scheme 6.39, Eq. (2)). This type of asymmetric intramolecular aldol reaction proceeds with formation of cyclic ketols of type 84 with two stereogenic centers. Dehydration can subsequently be performed, leading to optically active enones of type 85. The two types of intramolecular aldol reaction are shown conceptually in Scheme 6.39. 

The intramolecular aldol reaction of triketones with asymmetric desymmetrization has been known for a long time. When Eder, Sauer, and Wiechert [97, 98], and in parallel Hajos and Parrish [99-101] reported this reaction in the early 1970s it was the first example of an asymmetric catalytic aldol reaction, and one of the first examples of an organocatalytic asymmetric synthesis [104]. 

Desymmetrization via proline-catalyzed asymmetric intramolecular aldol reaction can, however, also be performed with acydic diketones of type 109 as has been reported by the Agami group [106], In the first step a prochiral acyclic diketone reacts in the presence of L-proline as catalyst (22-112 mol%) with formation of the aldol adduct 111 (Scheme 6.49). In this step reaction products with two stereogenic centers, 110, are formed. These chiral hydroxyketones 110 are subsequently converted, via dehydration, into the enones 111, by treatment with p-toluenesulfonic acid. 

In conclusion, there have been many reports of the high synthetic potential of the intramolecular aldol reaction in the enantioselective construction of cyclic enones. In particular the proline-catalyzed desymmetrization of triketones has been widely used for formation of optically active bicyclic systems which are versatile building blocks for steroids and other biologically active compounds. 

In related investigations, the group of Rovis examined the effect of pre-existing stereocenters in the intramolecular asymmetric Stetter reaction [43]. The same group also exploited the concept of desymmetrization for the asymmetric synthesis of hydrobenzofuranones in an intramolecular Stetter reaction [44]. 

Indium trichloride mediates the intramolecular cyclization of the prochiral allylstannyl diketone to afford the desymmetrized cis-cis cyclohexanol predominantly (Equation (36)). The use of TiCU in place of InCl3 gives the cis-trans diastereomer.213... 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

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). ... 

Scheme 5.2.22 Desymmetrization of 1,3-diketone 97 via intramolecular allylatlon 5.2.6 Reactions of 7-(Alkoxy)allylstannanes...

Elegant use of a desymmetrization protocol has recently been reported as a key step in a total synthesis of (-i-)-cocaine [66]. In this case, submitting a meso-dialde-hyde to a prohne-catalyzed (20 mol%) intramolecular enol-exo-aldol reaction afforded a 1 1 mixture of the axial-equatorial aldol product in excellent yield (91%). A few concluding final steps - amongst others a chromatographic separation of... 

Alkylation. Acetals of enals serve as alkylating agents for t-butyl (3-keto esters using a Pd complex of BINAP. With a cationic Pd complex of (R)-BINAP intramolecular addition of arylboronic acid moiety to a sidechain ketone leads to chiral, tertiary henzylic alcohols. Heck reaction. Cyclization with desymmetrization is shown to proceed in excellent yields and ee by the formation of tetralin derivatives. ... 

A number of useful enantioselective syntheses can be performed by attaching a chiral auxiliary group to the selenium atom of an appropriate reagent. " Examples of such chiral auxiliaries include (49-53). Most of the asymmetric selenium reactions reported to date have involved Inter- or intramolecular electrophilic additions to alkenes (i.e. enantioselective variations of processes such as shown in equations (23) and (15), respectively) but others include the desymmetrization of epoxides by ringopening with chiral selenolates, asymmetric selenoxide eliminations to afford chiral allenes or cyclohexenes, and the enantioselective formation of allylic alcohols by [2,3]sigmatropic rearrangement of allylic selenoxides or related species. 

An efficient desymmetrization in me50-epoxides of type 209 by 5ec-alkyllith-ium/(-)-sparteine was found by Hodgson et al. [see Eq. (66)] [123-125]. The intermediate lithiooxirane 210 usually undergoes carbenoid formation and intramolecular C-H insertion reactions (see Hodgson et al, in this volume) however, very recently it could be trapped by external electrophiles with stereoretention at low temperatures [126]. 

C-H bonds. This strategy has been used in an intramolecular fashion for the oxidation of hydrocarbons (eq 49) and steroids. Fructose-derived ketone 5 has also been used for this purpose in an intermolecular reaction for the desymmetrization and kinetic resolution of 1,2-diols to a-hydroxy ketones (eq 50). There has also been a report of the direct oxidation of hydrocarbons to ketones and lactones by Mn-porph)rin complexes with Oxone. ... 

A highly enantioselective intramolecular AHR of the cyclohexadienone 322 to give 324 with 96% ee in 100% conversion was carried out using the chiral phosphoamidite-type ligand (III-IO), which is monodentate. The stereogenic center was not created at the site of C—C bond formation, but instead the cyclohexadienone was desymmetrized. The use of Cy2MeN as a base gave the best result. It should be added that the carbopalladation product 323 has no jS-H syn to Pd, and hence the cyclized product 324 was formed by syn y3-H elimination after epimerization [132]. 

---