Asymmetric intramolecular aldol reaction

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. 

Disubstituted cyclopentane-1,3-diones and cyclohexane-1,3-diones were used as substrates. After formation of the aldol adducts subsequent intramolecular dehydration furnished products of types 94 and 96. The asymmetric intramolecular aldol reaction proceeds with a broad variety of natural amino acids as organocata-lysts. Among these L-proline was usually found to be the most versatile. For example, conversion of the 2,2-disubstituted cyclopentane-1,3-dione 93 in the presence of L-proline gave the desired product 94 in 86.6% yield and with enantioselectivity of 84% ee [97]. This example and a related reaction with a 2,2-disubstituted cyclohexane-1,3-dione 95 are shown in Scheme 6.42. Chiral induction depends... 

The organocatalytic asymmetric intramolecular aldol reaction has also been used in the synthesis of a gibbane framework [117]. The proline-catalyzed aldol cycliza-tion of the triketone 104 into the tricyclic system 106 proceeds via the unstable ketol 105 (Scheme 6.47). For this reaction, which occurred at room temperature, a catalytic amount (10 mol%) of L-proline was used. The enone 106 was furnished in 92% yield and a single recrystallization resulted in an enantiomerically pure sample of 106. This aldol product 106 served as a useful intermediate in the synthesis of the desired gibbane framework. 

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. 

Simple dipeptides bearing a primary amino N-terminus catalyse direct asymmetric intramolecular aldol reactions in up to 99% ee.115 These simple catalysts such as L-Ala-L-Ala and L-Val-L-Phe can also promote the asymmetric formation of sugars, further suggesting a possible role in prebiotic chemistry. 

Agami C, Puchot C (1986) Kinetic analysis of dual catalysis by proline in an asymmetric intramolecular aldol reaction. J Mol Catal 38 341-343 Agami C, Puchot C, Sevestre H (1986) Is the mechanism of the proline-cata-lyzed enantioselective aldol reaction related to biochemical processes Tetrahedron Lett 27 1501-1504... 

Surprisingly, little follow-up work on this idea of small molecule asymmetric catalysis appeared for the next 25 years. In the late 1980s, Agami reported the asymmetric intramolecular aldol reaction of acyclic diketones with (S)-proline as the catalyst. It was not nntil the twenty-first centnry, however, when this notion of organocatalysts became fnlly exploited. List and Barbas ° pioneered enam-ines as catalysts for aldol and Mannich and related reactions. MacMillan has developed a variety of imininm-based catalysts prodncing large asymmetric indnction for Diels-Alder chemistry, Friedel-Crafts alkylations, Mnkaiyama-Michael and cyclopropanation " reactions. 

Impressive results have been obtained by Hajos, Wiechert and coworkers [261] in enantiosdective Robinson simulations of triketones catalyzed by ( -pro-line 1.64 (R = COOH). This type of asymmetric intramolecular aldol reaction is quite general under aminoacid catalysis [261, 775]. Asymmetric hydrocyanation of aldehydes is catalyzed by dipeptides, among which 3.4 is the most efficient. Asymmetric epoxidation of chalcone by alkaline H2O2 >s catalyzed by polyami-noacids [578, 776], but this reaction is not veiy general [777]. 

Scheme 7.69 NHC-catalyzed asymmetric intramolecular aldol reaction of achiral tricarbonyl compounds reported by Scheidt.

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. 

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]. 

Another key event in the history of organocatalytic reaction was the discovery of efficient r-proline-mediated asymmetric Robinson annulation reported during the early 1970s. The so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction (an intramolecular aldol reaction) allowed access to some of the key intermediates for the synthesis of natural products (Scheme 1.4) [37, 38], and offered a practical and enantioselective route to the Wieland-Miescher ketone [39]. It is pertinent to note, that this chemistry is rooted in the early studies of Langenbeck and in the extensive investigations work of Stork and co-workers on enamine chemistry... 

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

Bahmanyar S, Houk KN (2001a) The origin of stereoselectivity in proline-catalyzed intramolecular aldol reactions. J Am Chem Soc 123 12911-12912 Bahmanyar S, Houk KN (2001b) Transition states of amine-catalyzed aldol reactions involving enamine intermediates theoretical studies of mechanism, reactivity, and stereoselectivity. J Am Chem Soc 123 11273-11283 Bahmanyar S, HoukKN, Martin HJ, ListB (2003) Quantum mechanical predictions of the stereoselectivities of proline-catalyzed asymmetric intermolec-ular aldol reactions. J Am Chem Soc 125 2475-2479 Barbas CF 3rd, Heine A, Zhong G, Hoffmann T, Gramatikova S, Bjoernstedt R, List B, Anderson J, Stura EA, Wilson I, Lemer RA (1997) Immune versus natural selection antibody aldolases with enzymic rates but broader scope. Science 278 2085-2092... 

Enders et al. have achieved an organocatalytic asymmetric synthesis of m-substituted dihydrobenzofuranols by intramolecular aldol reaction of compounds of type 62 with proline as catalyst (Equation 143) <2006SL3399>. 

In the laboratory of J.D. White, the asymmetric total synthesis of (+)-codeine was accomplished. The Robinson annulation was the method of choice to build a phenanthrenone precursor starting from a substituted tetralone derivative. As it is usuaiiy the case, the isolation of the Michael adduct allowed the intramolecular aldol reaction to proceed cleanly and to afford a higher yield of the annulated product. 

The asymmetric Robinson annelation relies on an intramolecular aldol reaction to create the new chiral centre. More recently List19 and MacMillan20 have used proline 58 to catalyse intermolecular aldol reactions with nearly as good results. Acetone and isobutyraldehyde 89 can be condensed to give a single enantiomer of the aldol 90 in excellent yield and ee providing 30% proline is used as catalyst. 

Asymmetric Michael reactions have heen conducted with assistance of C2-symmetric malonamides derived from (5)-ptohne esters/ 2-Methyl-3,4,5,6-tetrahydropyridine and 2-cyclopentenone are condensed to afford a tricyclic alcohol. The reaction starts from Michael reaction of the endocychc enamine isomer and as the double bond shifts to the exo-cychc position an intramolecular aldol reaction follows. If the imine is hthiated, the initial Michael reaction (CuBr-catalyzed) then involves the exocyclic carbon. ... 

Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

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