Proline chiral catalysts

Catalytic Enantioselective Reduction of Ketones. An even more efficient approach to enantioselective reduction is to use a chiral catalyst. One of the most developed is the oxazaborolidine 18, which is derived from the amino acid proline.148 The enantiomer is also available. These catalysts are called the CBS-oxazaborolidines. 

These authors were also able to perform this domino process in an enantioselec-tive fashion using the Rh-proline derivative 6/2-57 (Rh2(S-DOSP)4) as chiral catalyst for the cyclopropanation [202]. Reaction of 2-diazobutenoate 6/2-56 and alkenes 6/2-55 in the presence of the catalyst 6/2-57 led primarily to the cyclopropane derivative... 

A method for highly efficient asymmetric cyclopropanation with control of both relative and absolute stereochemistry uses vinyldiazomethanes and inexpensive a-hydroxy esters as chiral auxiliaries263. This method was also applied for stereoselective preparation of dihydroazulenes. A further improvement of this approach involves an enantioselective construction of seven-membered carbocycles (540) by incorporating an initial asymmetric cyclopropanation step into the tandem cyclopropanation-Cope rearrangement process using rhodium(II)-(5 )-N-[p-(tert-butyl)phenylsulfonyl]prolinate [RhjtS — TBSP)4] 539 as a chiral catalyst (equation 212)264. 

Enantiomerically pure 3-amino alcohols which are important intermediates for many bioactive compounds can be directly synthesized by the ARO reaction of readily accessible racemic and meso epoxides with appropriate amines. Indeed, some simple and multifunctional p-amino alcohols have been obtained using this strategy by the promotion of chiral BINOL [30-32,88,89], salen [35,52], bipyridine [33,40,90-94] and proline-A,JV-dioxide based metal complexes [95]. However, none of these systems demonstrated the recyclability of the precious chiral catalyst. 

Tab. 14.3 Asymmetric cyclopropanation using rhodium prolinates as chiral catalysts.

A variety of chiral catalysts have been evaluated in intermolecular cyclopropanations of donor/acceptor carbenoid systems, but few come close to the levels of asymmetric induchon furnished by the prolinate catalysts [11, 37, 38, 40, 49]. The only system that... 

Fig. 14.3 Predictive models for asymmetric induction by (a) (R)-panto-lactone as a chiral auxiliary (b) (S)-prolinate dirhodium catalysts...

Considerable interest has been shown in developing asymmetric variants of the Si-H insertion. The chiral auxiUary (Jl)-pantolactone has performed quite well in this chemistry, as illustrated in the formation of 169 in 79% diastereomeric excess (Eq. 19) [28]. A wide variety of chiral catalysts have been explored for the Si-H insertion chemistry of methyl phenyldiazoacetate [29, 117-119]. The highest reported enantioselectivity to date was obtained with the rhodium prolinate catalyst Rh2(S-DOSP)4, which generated 170 with 85% enantiomeric excess (Eq. 20) [120]. 

In summary, the chemistry of the donor/acceptor-substituted carbenoids represents a new avenue of research for metal-catalyzed decomposition of diazo compounds. The resulting carbenoids are more chemoselective than the conventional carbenoids, which allows reactions to be achieved that were previously inaccessible. The discovery of pan-tolactone as an effective chiral auxiliary, and rhodium prolinates as exceptional chiral catalysts for this class of rhodium-carbenoid intermediate, broadens the synthetic utility of this chemistry. The successful development of the asymmetric intermolecular C-H activation process underscores the potential of this class of carbenoids for organic synthesis. 

A vast array of chiral catalysts have been developed for the enantioselective reactions of diazo compounds but the majority has been applied to asymmetric cyclopropanations of alkyl diazoacetates [2]. Prominent catalysts for asymmetric intermolecular C-H insertions are the dirhodium tetraprolinate catalysts, Rh2(S-TBSP)4 (la) and Rh2(S-DOSP)4 (lb), and the bridged analogue Rh2(S-biDOSP)2 (2) [7] (Fig. 1). A related prolinate catalyst is the amide 3 [8]. Another catalyst that has been occasionally used in intermolecular C-H activations is Rh2(S-MEPY)4 (4) [9], The most notable catalysts that have been used in enantioselective ylide transformations are the valine derivative, Rh2(S-BPTV)4 (5) [10], and the binaphthylphosphate catalysts, Rh2(R-BNP)4 (6a) and Rh2(R-DDNP)4 (6b) [11]. All of the catalysts tend to be very active in the decomposition of diazo compounds and generally, carbenoid reactions are conducted with 1 mol % or less of catalyst loading [1-3]. 

Feringa reported an enantioselective allylic oxidation of cyclohexene to optically active 2-cyclohexenyl propionate 25 by using a chiral copper complex prepared from Cu(OAc)2 and (S)-proline, as chiral catalyst (Scheme 9.14) [32], In the absence of additives, a negative NLE was observed, whereas in the presence of a catalytic amount of anthraquinone, a positive NLE (asymmetric amplification) was observed. Moreover, higher enantioselectiv-ity was attained when enantiopure (S)-proline was used. However, the role of the additive remains elusive. 

It is worthy of note that - similarly to the proline catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process in which two stereogenic centers are formed in one step, although using non-chiral starting materials (Scheme 5.16) [22, 23, 26, 27, 28]. In these reactions substituted acetone or acetaldehyde derivatives, rather than acetone, serve as donor. In contrast with the anti diastereoselectivity observed for the aldol reaction (Section 6.2.1.2), the proline-catalyzed Mannich reaction furnishes products with syn diastereoselectivity [23]. A proline-derived catalyst, which led to the formation of anti Mannich products has, however, been found by the Barbas group [29]. 

In addition to the many intermolecular asymmetric (organo)catalytic aldol reactions, analogous intramolecular syntheses are also possible. In this connection it is worthy of note that the first example of an asymmetric catalytic aldol reaction was an intramolecular reaction using an organic molecule, L-proline, as chiral catalyst. This reaction - which will be discussed in more detail below - is the so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction [97-101], which was discovered as early as the beginning of the 1970s. 

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. 

The indium trichloride-catalyzed Mukaiyama aldol reaction of 3-aminoketoesters with various silylenolethers gave under solvent-free conditions 1,3-amino alcohols with high stereoselectivity [36], Several Robinson annelation reactions have been carried out enantio-selectively using (S)-proline as a chiral catalyst [37]. Remarkably, the enantioselectivity was distinctly higher in the absence of solvent than in DMSO. 

In conclusion, the aldol reaction with L-proline as an enzyme mimic is a successful example for the concept of using simple organic molecules as chiral catalysts. However, this concept is not limited to selected enzymatic reactions, but opens up a general perspective for the asymmetric design of a multitude of catalytic reactions in the presence of organocatalysts [1, 3]. This has been also demonstrated by very recent publications in the field of asymmetric syntheses with amino acids and peptides as catalysts. In the following paragraphs this will be exemplified by selected excellent contributions. 

In conclusion, the recent contributions by several groups in the field of asymmetric syntheses with amino acids and short-chain peptides as efficient chiral catalysts appear to be very interesting for chemists from academia as well as from industry. In addition, those new syntheses are promising alternatives to existing asymmetric technologies. Without any doubts it is surprising to observe that a simple amino acid molecule - as shown in case of proline - can in principle act like an enzymatic system, thus representing an efficient enzyme mimic. 

A number of methods have been used to stereoselectively introduce a hydroxy group adjacent to a ketone. Epoxidation of an enol ether or ester can be used (see Chapter 10). Chiral auxiliaries have also been used to lead to the introduction of the hydroxy group.213 Another method is the reaction of nitrosobenzene with an aldehyde in the presence of L-proline as catalyst (Scheme 9.37).214... 

In particular, reduction of unsymmetric ketones to alcohols has become one of the more useful reactions. To achieve the selective preparation of one enantiomer of the alcohol, chemists first modified the classical reagents with optically active ligands this led to modified hydrides. The second method consisted of reaction of the ketone with a classical reducing agent in the presence of a chiral catalyst. The aim of this chapter is to highlight one of the best practical methods that could be used on an industrial scale the oxazaborolidine catalyzed reduction.1 1 This chapter gives an introductory overview of oxazaborolidine reductions and covers those of proline derivatives in-depth. For the oxazaborolidine derivatives of l-amino-2-indanol for ketone reductions see Chapter 17. 

Groger, H. Wilken, J. The Application of L-Proline as an Enzyme Mimic and Further New Asymmetric Syntheses using Small Organic Molecules as Chiral Catalysts, Angew. Chem. Ira. Ed. 2001,40, 529-532. 

A number of other chiral catalysts have been reported, among them the proline (111), lithium amides (112) and the tetrahydrofiirylamine (113). Hie optical yields of the products isolated, however, are only moderate at best. Hie use of optically active 2-methyltetrahydrofuran in Grignard reactions has also been reported however, minimal induction is observed. ... 

A combination of isopropanol and an alkali hydroxide or alkoxide together with Ru or Ir catalyst and a chiral ligand constitutes the reduction system. The ligands include proline, chiral cfr-l-amino-2-indanols, and the following 74, ° 75, 76, 77. f5)-Propargylic alcohols (>97% ee) are produced when the ketones are treated with the ruthenium complex 2 in isopropanol (without added base). ... 

In this respect, the use of water as a solvent for enantioselective reaction has been explored. In 2006 Barbas and co-workers developed an efficient proline-derived chiral catalyst (Scheme 5.5) for aldol condensation in water with high reactivity, diastereoselectivity and enantioselectivity. 

A selection of the most efficient formamide catalysts based on amino acids is shown in Figures 4.1 and 4.2 representative examples of enantioselective hydro silylation are listed in Tables 4.1 4.7. The proline derived anilide 16 and its naphthyl analogue 17, introduced by Matsumura as the first chiral catalysts [10], exhibited moderate enantioselectivity in the reduction of aromatic ketimines with trichloro silane at 10mol% catalyst loading (Table 4.1, entries 1 and 2). The formamide... 

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