Chiral MacMillan

In all the reactions described so far a chiral Lewis acid has been employed to promote the Diels-Alder reaction, but recently a completely different methodology for the asymmetric Diels-Alder reaction has been published. MacMillan and coworkers reported that the chiral secondary amine 40 catalyzes the Diels-Alder reaction between a,/ -unsaturated aldehydes and a variety of dienes [59]. The reaction mechanism is shown in Scheme 1.73. An a,/ -unsaturated aldehyde reacts with the chiral amine 40 to give an iminium ion that is sufficiently activated to engage a diene reaction partner. Diels-Alder reaction leads to a new iminium ion, which upon hydrolysis af-... 

Figure 5.45 Cationic gemini amphiphiles having chiral counterions. TEM images of representative twisted ribbons formed by 16-2-16 tartrate (49 + 50) at 0.1% in water for various values of enantiomeric excess (a) 0 (racemate) (b) 0.5 (c) 1 (pure L) (d) 1 (pure L) in presence of 1 eq sodium L-tartrate. Bar = 100 nm. Reprinted with permission from Ref. 165. Copyright 1999 by Macmillan Magazines.

The Catalysis Concept of Iminium Activation In 2000, the MacMillan laboratory disclosed a new strategy for asymmetric synthesis based on the capacity of chiral amines to function as enantioselective catalysts for a range of transformations that traditionally use Lewis acids. This catalytic concept was founded on the mechanistic postulate that the reversible formation of iminium ions from a,p-unsaturated aldehydes and amines [Eq. (11.10)] might emulate the equilibrium dynamics and 7i-orbital electronics that are inherent to Lewis acid catalysis [i.e., lowest unoccupied molecular orbital (LUMO)-lowering activation] [Eq. (11.9)] ... 

In this chapter, we discuss recent (reported mainly during 2000-2005) asymmetric reactions catalyzed by chiral bases. Because practicality is an important factor in the present asymmetric catalysis, we restricted our discussion mainly to the reactions giving over 90% ee unless the conversion is novel. We notice, however, that there are many potentially useful and scientifically interesting reactions, in which enantioselectivity does not exceed the practical range at this moment. Chiral organic base (proline and cinchona alkaloids)-catalyzed reactions were discussed in Chapter 11 by Lelais and MacMillan. 

At present, most enamine-catalyzed aldol reactions are reliable only with electron-poor aromatic aldehyde acceptors, hi addition, a handful of aliphatic aldehydes (e.g. isobutyraldehyde or pivalaldehyde) are often used as acceptors. The use of unbranched aldehyde acceptors is difficult, and generally only modest yields have been obtained. In addition, unsaturated aldehydes are curiously absent from the list of commonly used acceptors. On a positive side, it should be noted that even potentially racemizing a-chiral aldehydes have been employed as acceptors. As an example, in the recent synthesis of caUipeltoside C, MacMillan and coworkers were able to employ protected Roche aldehyde 113 as a starting material (Scheme 22) [204]. 

MacMillan DWG, Lelais G (2007) History and perspective of chiral organic catalysts. In Mikami K, Lautens M (eds) New frontiers in asymmetric catalysis. WUey, Hoboken, NJ, p 313... 

In 2004, List reported that several ammonium salts including dibenzylammonium trifluoroacetate catalyzed the chemoselective 1,4 reduction of a, 5-unsaturated aldehydes with Hantszch esters as hydride sources [40]. It is assumed that substrate activation via iminium ion formation results in selective 1,4 addition of hydride. Subsequently, List [41] and MacMillan [42] reported asymmetric versions of this reaction promoted by chiral imidazoUdinone salts. In this context, several reports of this metal-free reductive process catalyzed by chiral phosphoric acids have appeared in the recent literature. 

Many of the five- and six-carbon sugars, although well known, are rare, and too expensive to be used as chiral pool starting materials. David MacMillan of Caltech in an elegant series of papers (Angew. Chem. Int. Ed. 2004,43. 2152 Science 2004,305, 1752 Angew. Chem. Int. Ed. 2004,47,6722) has demonstrated a two-step route not just to protected six-carbon carbohydrates, but also to alkyl, thio and amino derivatives of those carbohydrates. 

DFT has been used to investigate the Diels-Alder reactions of cyclopentadiene with a,/S-unsaturated aldehydes and ketones organocatalysed by MacMillan s chiral... 

The MacMillan group has also shown that cycloaddition reactions (see also Chapter 8) can be performed highly diastereo- and enantioselectively. The [3+2]-cycloaddition of nitrones and a,/i-un saturated carbonyl compounds in the presence of 20 mol% of a phenylalanine-derived imidazolidinone acid salt led to products with 99% ee [32]. An example of an enantioselective rearrangement reaction (see also Section 13.6) with 99% ee has been reported by the Fu group [33], who used 2 mol% of a planar chiral DMAP derivative as catalyst. 

A highly enantioselective Mukaiyama-Michael addition of silyl ethers, CH2= C(OSiMe3)R1, to a,/9-unsaturated aldehydes, R2CH=CHCHO, catalysed by MacMillan s chiral imidazolidinone (150), in the presence of 2,4-(N02)2C6H3C02H as an acid... 

In order to test the iminium-activation strategy, MacMillan first examined the capacity of various amines to enantioselectively catalyze the Diels-Alder reaction between dienes and a,/ -unsaturated aldehyde dienophiles [6]. Preliminary experimental findings and computational studies proved the importance of four objectives in the design of a broadly useful iminium-activation catalyst (1) the chiral amine should undergo efficient and reversible iminium ion formation (2) high... 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

In line with the mechanistic rationale of LUMO-lowering iminium activation, MacMillan hypothesized that intermediate 2, generated from the secondary amine 1 and an a,/f-un saturated aldehyde, could be activated towards cydoaddi-tion with an appropriate diene (Scheme 3.1). The Diels-Alder reaction would form iminium ion cydoadduct 5 that, in the presence of water, would hydrolyze to yield the enantioenriched product 6 and regenerate the chiral imidazolidinone catalyst 1. 

Nicewicz and MacMillan merged later photoredox catalysis and asymmetric organocatalysis to an efficient approach to the otherwise difficult asymmetric a-alkylation of aldehydes 118 by activated alkyl bromides 117 (Fig. 30) [183]. The concept of face differentiation at the a-position of aldehydes via chiral enamines 121 provides the basis for the method. This allows the formation of functionalized... 

Alder reactions, 1,3-dipolar cycloadditions (Jen et al. 2000), and conjugate additions of electron rich aromatic and heteroaromatic compounds can be catalyzed using chiral amino acid derived imidazolidinones as catalysts (Scheme 17 Eqs. 35-38 Paras and MacMillan 2001, 2002 Austin and MacMillan 2002 Brown et al. 2003b). In addition, highly enantioselective epoxidations (Marigo et al. 2005b) and cyclopropana-tions (Kunz and MacMillan 2005) have recently been developed. 

In iminium catalysis, both we and the group of MacMillan had observed a strong counteranion effect on the yield and enantioselectivity of the reactions. Inspired by recent use of chiral phosphoric acid derivatives... 

We thought to start with the metal-free biomimetic transfer hydrogenation of a,(-)-unsaturated aldehydes as a model reaction which has been earlier discovered in our laboratory and independently in that of MacMillan et al. (Scheme 24). We have prepared a large number of ammonium salts as crystalline solids by mixing different primary and secondary amines with a chiral phosphoric acid. In particular, the ammonium salts of sterically hindered chiral phosphoric acids could catalyze... 

Significantly, the previously developed chiral amine based catalysts that we and MacMillan and co-workers have studied have not been of use for sterically nonhindered aliphatic substrates. For example, citral (29), of which the hydrogenation product citronellal (30) is an intermediate in the industrial synthesis of menthol and used as a perfume ingredient, could not readily be used (Scheme 26, Eq. 41). We could... 

Independently, MacMillan et al. developed an efficient catalyst system that is based on a chiral secondary amine (Tuttle et al. 2006). 

Ahrendt KA, Borths CJ, MacMillan DWC (2000) New strategies for organic catalysis The first highly enantioselective organocatalytic Diels-Alder reaction. J Am Chem Soc 122 4243-4244 Akiyama T (2004) Preparation of chiral Bronsted catalysts in asym. synthesis and asym. Mannich, aza-Diels-Alder reaction, hydrophosphorylation therewith. PCT Int Appl WO 200409675, 2004-11-11... 

Kunz RK, MacMillan DWC (2005) Enantioselective organocatalytic cyclopro-panations. The identification of a new class of iminium catalyst based upon directed electrostatic activation. J Am Chem Soc 127 3240-3241 Lacour J, Hebbe-Viton V (2003) Recent developments in chiral anion mediated asymmetric chemistry. Chem Soc Rev 32 373-382 Li X, List B (2007) Catalytic asymmetric hydrogenation of aldehydes. Chem Commun 17 1739-1741... 

Another chiral organic catalyst of major success is MacMillan s catalyst, 18, that has found widespread use in a number of relevant processes (MacMillan 2000). Immobilized versions of these catalysts for the enantioselective Diels-Alder cycloaddition of dienes with unsaturated aldehydes were developed on soluble (Benaglia et al. 2002) and insoluble supports (equation a, Scheme 7) (Benaglia 2006). 

Figure 4 (A) Atomically resolved scanning tunneling microscopy (STM) of a SWNT in the surface of a rope revealing chiral-twist. (Reprinted with permission from Ref 15. 1998 Macmillan Magazines Ltd (www.nature.com).) (B) STM images of SWNTs produced by arc-discharge method (a) chiral nanotube with angle 7°, (b) zigzag nanotube, and (c) armchair nanotube. The tube axis is shown with dashed arrows. (Reprinted with permission Ref. 16. 1998 Macmillan Magazines Ltd)...

A polymer-supported version of MacMillan s catalyst 114 has been developed by anchoring a tyrosine-derived imidazohdin-4 -one via a spacer to the monomethyl ether of PEG (Scheme 3.32) [62]. The reaction of N-benzyl-C-phenyl nitrone 115 with acrolein 116 proceeded in the presence of PEG-supported chiral imidazolidi-none and acid in wet nitromethane to give the isoxazolidine 117. The supported catalysts behaved very similarly to their nonsupported counterparts in terms of enantioselectivity, but were somewhat less efficient in terms of chemical yield. 

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