Asymmetric Catalytic Desymmetrization

Desymmetrization of an achiral, symmetrical molecule by a catalytic process is a potentially powerful but relatively unexplored concept in asymmetric synthesis. Although the capacity of enzymes to differentiate between enantiotopic functional groups is well known [62], there has been little investigation of non-enzymatic catalysts with similar capacity, particularly for carbon-carbon bond forming processes. The desymmetrization by the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides efficient access to remote [63] and internal [64] asymmetric induction which is otherwise difficult to achieve (Sch. 17) [65]. The (lR,5S)-syn product is obtained in 99 % ee with more than 99 % diastereoselectiv-ity. The diene thus obtained can be transformed to a more functionalized compound both regioselectively and diastereoselectively. 

---

The BINOL-Ti catalyst can also be used for the carbonyl-ene reaction with formaldehyde or vinyl and alkynyl analogues of glyoxylates in an asymmetric catalytic desymmetrization (vide infra) approach to the asymmetric synthesis of isocarbacycline analogues (Scheme 7) [31a, 31b]. 

Formal hydration of the double bond appeared by the hydroboration-oxidation sequence. Desymmetrization reactions with catalytic asymmetric hydroboration are not restricted to norbornene or nonfunctionalized substrates and can be successfully applied to meso bicyclic hydrazines. In the case of 157, hydroxy derivative 158 is formed with only moderate enantioselectivity both using Rh or Ir precatalysts. Interestingly, a reversal of enantioselectivity is observed for the catalytic desymmetrization reaction by exchanging these two transition metals. Rh-catalyzed hydroboration involves a metal-H insertion, and a boryl migration is involved when using an Ir precatalyst (Equation 17) <2002JA12098, 2002JOC3522>. 

Unlike kinetic resolution, catalytic desymmetrization and asymmetrization can afford enantiopure products in theoretical yields of 100 % and are more generally applicable than DKR or deracemization techniques. 

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]. 

In comparison with the asymmetric epoxide-opening reactions described above in Section 9.4, catalytic desymmetrizations of meso-aziridines have relatively limited precedence [151]. Kanai and Shibasaki have disclosed a number of promising results obtained with lanthanide complexes of the chiral phosphinoxide ligand 193 (Scheme 9.24) [152, 153]. These efforts were showcased in the desymmetrization of meso-aziridine 192 with TMSN j to provide azide 194 in 96% yield and 91 % ee. Adduct 194 was subsequently converted into the anti-influenza drug oseltamivir phosphate (Tamiflu, 195) [153]. 

An area in which catalytic olefin metathesis could have a significant impact on future natural product-directed work would be the desymmetrization of achiral molecules through asymmetric RCM (ARCM) or asymmetric ROM... 

The catalytic enantioselective desymmetrization of meso compounds is a powerful tool for the construction of enantiomerically enriched functionalized products." Meso cyclic allylic diol derivatives are challenging substrates for the asymmetric allylic substitution reaction owing to the potential competition of several reaction pathways. In particular, S 2 and 5n2 substitutions can occur, and both with either retention or inversion of the stereochemistry. In the... 

Related catalytic enantioselective processes [115] Two catalytic procedures for asymmetric addition of cyanides to meso epoxides have been reported [116]. One is the result of work carried out in these laboratories, shown in Eq. 6.24, promoted by Ti-peptide chiral complexes, while the other, developed by Jacobsen and Schaus, is a Yb-catalyzed enantioselective reaction that is effected in the presence of pybox ligands (Eq. 6.25) [117]. Although the Shibasaki method (Eq. 6.21) is not as enantioselective as these latter methods, it has the advantage that it accomplishes both the epoxidation and subsequent desymmetrization in a single vessel. 

In addition to its utility in the enantioselective formation of C-0 bonds (cf. Scheme 15), Trost s chiral ligand 102 has been used in the catalytic asymmetric synthesis of C-N bonds. An impressive application of this protocol is in the enantioselective total synthesis of pancrastatin by Trost (Scheme 17) H9i Thus, Pd-catalyzed desymmetrization of 112 leads to the formation of 113 efficiently and in > 95 % ee. The follow-up use of the N3 group to fabricate the requisite cyclic amide via isocyanate 117 demonstrates the impressive versatility of this asymmetric technology. 

This section will only discuss examples of catalytic kinetic resolution, DKR, desymmetrization and asymmetrization. Deracemization will not be considered because, although an important developing technology, examples of its application to the production of chiral late-stage intermediates in API production have yet to appear. 

Nugent, W. A. (1998) Desymmetrization of meso-epoxides with halides A new catalytic reaction based on mechanistic insight, J. Am. Chem. Soc., 120 7139-7140. Bruns, S. Haufe, G. (1999) Catalytic asymmetric ring opening of epoxides to chlorohydrins with mild chloride donors and enantiopure titanium complexes.. 

RECENT ADVANCES IN CATALYTIC ASYMMETRIC DESYMMETRIZATION REACTIONS... 

RECENT ADVANCES IN CATALYTIC ASYMMETRIC DESYMMETRIZATION Q TTio1< nimlnrh. ZrT l. OH... 

Catalytic asymmetric desymmetrization as a field is still growing, with new applications appearing weekly. It is evident that advances in this subfield have kept in step with advances in catalysis as a whole. Some spectacular successes have been reported in recent years, and this strategy has been applied to many new reactions. Willis mentions in conclusion to his 1999 review of this field that desymmetrization reactions involving catalytic enantioselective construction of C—C bonds are... 

Oxidative kinetic resolution of secondary alcohols mediated with a catalytic amount of optically active binaphthyl-type iV-oxyl has been performed with high selectivity". Also, it has mediated oxidative asymmetric desymmetrization of primary alcohols with good selectivity (equation 25)". ... 

Lastly, Antilla has disclosed a novel asymmetric desymmetrization of a wide range of aliphatic, aromatic, and heterocyclic meso-aziridines with TMS-N3 promoted by 11 and related 12 (Scheme 5.31) [56]. Uniquely, this is one of only several reports of electrophilic activation of nonimine substrates by a chiral phosphoric acid. Mechanistic studies suggest that silylation of 11 or 12 by displacement of azide generates the active catalytic species A. Consequently, the aziridine is activated through coordination of it carbonyl with chiral silane A to produce intermediate B. Nucleophilic ring opening by azide furnishes the desymmetrized product and regenerates 11 or 12. 

---