Cyclisations aldol

The dithiadecalin (34) was used to provide the carbon backbone for C-3 to C-8 and C-9 to C-13. Compound (34) was obtained in an optically active form by a route involving an enantioselective (36% e.e.) aldol cyclisation catalyzed by (R)-proline71). 

Until 1968, not a single nonenzymic catalytic asymmetric synthesis had been achieved with an enantiomeric excess above 50%. Now, the intramolecular aldol cyclisation, catalyzed by chiral amino acids has proven to be a very useful synthetic tool. This reaction was extensively covered by two reviews 23,68). Two more papers 72 published recently, should also be cited. 

Procter utilised the conjugate reduction of a,(5-unsaturated esters to generate Sm(III) enolates for use in stereoselective aldol cyclisations (Chapter 5, Section... 

In 2002, Skrydstrup reported the diastereoselective construction of functionalised prolines using a Sml2-mediated aldol cyclisation.162 Treatment of p-lactam-derived a-benzoyloxy esters, such as 155, with Sml2 led to the generation of a Sm(III) enolate 156, aldol cyclisation and addition of the resultant samarium alkoxide to the (3-lactam carbonyl. The efficient sequential reaction gave proline derivatives, such as 157, with high diastereoselectivity and in good yield (Scheme 5.103).162 This example illustrates how the presence of a protic cosolvent does not necessarily interfere with the intramolecular aldol reaction and can in fact be crucial to the success of the cyclisation. 

The conjugate reduction of a,(3-unsaturated carbonyl compounds is a potentially useful way of accessing Sm(III) enolates that has yet to be widely exploited. Cabrera reported a cyclodimerisation sequence of a,(3-unsaturated ketones using Sml2 that involves a diastereoselective aldol cyclisation.163 For example, treatment of chalcone 158 with Sml2 generates cyclopentanol 160 in quantitative yield after chelation-controlled aldol cyclisation of Sm(III) enolate 159 (Scheme 5.104). 

Fang used similar reductive cyclisations of l,l -dicinnamoylferrocenes such as 161 to prepare 3-ferrocenophane diols 162.164 In this case, the aldol cyclisation is followed by ketone reduction in a highly diastereoselective, sequential operation (Scheme 5.105). 

Procter reported the diastereoselective spirocyclisation of unsaturated ketones 163 using Sml2-43 165 The cyclisation proceeds by conjugate reduction, Sm(III) enolate generation and chelation-controlled aldol cyclisation to give, vyrt-spirocyclic cyclopentanols 164 in good yield (Scheme 5.106). It is important... 

Perhaps the most surprising feature of the sequence is that selective reduction of one aldehyde is possible while the other survives to act as an electrophile in the later aldol cyclisation. The necessity for pre-coordination between the aldehyde and the ester carbonyl group of the alkene acceptor prior to electron transfer to the aldehyde could be responsible for this selectivity.16... 

Sonogashira coupling of alkyne 50 with aryl iodide 51 affords the diaryl alkyne 52 oxidation of which produces the 1,2-diketone 53. Hydrolysis of the acetal moiety prior to a proline-induced aldol cyclisation generates a chromanone from which the [ljbenzopyrano-[2,3-c][l]benzopyranone rotenoid system is obtained <07T11878>. 

Notice the control inherent in the aldol cyclisation. One from four possible enolates attack one of two carbonyl compounds. This is clearly thermodynamic control under these weakly basic conditions (chapter 5 ). The more highly substituted alkene (here tetra-substituted) and the most stable possible ring (i.e. 5- not 3- or 4-membered) is formed. The geometry of the alkene is of course controlled by the ring.20... 

The initial spark for proline catalysis was provided independently and simultaneously by two groups in 1971. Hajos and Parrish on the one hand (Scheme 5.1), and Eder, Sauer and Wiechert (Scheme 5.2) on the other developed an asymmetric aldol cyclisation of triketones such as 1 to bicyclic allq l ketones 2. In the former report, (S)-proline was applied at 3 mol%, a low organocatalyst loading, even to date. The quantitative cyclisation reaction was completed in the reasonable time of 20 h, and provided the product in 93.4% ee. Dehydration to enone 3 completed the synthesis of a valuable building block in steroid chemistry. 

Scheme 5.1 (S)-proline-catalysed aldol cyclisation by Hajos and Parrish.

Scheme 5.2 Aldol cyclisation by Eder, Sauer and Wiechert.

On the other hand, another cooperative catalysis approach was developed by Oh and Kim with a highly diastereo- and enantioselective domino aldol-cyclisation reaction occurring between aldehydes and methyl a-isocyanoacetate. The process employed a combination of a chiral cobalt complex derived from brucine amino diol and an achiral thiourea. The reaction was applicable to a range of aliphatic, aromatic and heteroaromatic aldehydes, providing the corresponding chiral oxazolines in good yields and diastereoselectivities of up to >90% de combined with good to excellent enantioselectivities of up to 98% ee, as shown in Scheme 7.12. 

In 2010, Shibata and co-workers developed an enantioselective enamine-trifluoropyruvate domino aldol-cyclisation reaction to yield chiral pyrroli-dones. Several commercially available derivatives of cinchona alkaloids were screened in combination with Ti(Oi-Pr)4. Hydroquinine diether ((DHQD)2AQN) was found to be the best ligand and afforded the products in high yields and enantioselectivities of up to 92% ee, as shown in Scheme 7.19. Using this system, five cyclic enamines with different protecting groups were screened with remarkable results. The enantiomers of the products were also accessible by applying the pseudoenantiomeric cinchona alkaloid. 

Scheme 7.19 Domino aldol-cyclisation reaction catalysed by chiral cinchona catatysis and titanium catalysis.

Brewster AG, Jayatissa J, Mitchell MB, Schofield A, Stood-ley RJ. Memory of chirality effects in aldol cyclisations of 1-(3-oxobutyryl) derivatives of 1-4-oxaproline and 1-proline isopropyl esters. Tetrahedron Lett. 2002 43(21) 3919-3922. 

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