Paterson chiral ketone

One special case involves the a-methyl substituted chiral ketones (5)-168 and (7 )-168 developed by Paterson et al. 

SCHEME 10.36. Syw-aldol reactions of Paterson and Tillyer s chiral ketone (5)-168 - derived tin enolate 169. 

Paterson I, Florence GJ, Gerlach K, Scott J. Total synthesis of the antimicrotubule agent (+)-Discodermolide using boron-mediated aldol reactions of chiral ketones. Angew. Chem. Int. Ed. 2000 39 377-380. 

Paterson has reported an analogous set of chiral ketones (cf 188), readily available from malic acid, for the diastereoselective preparation of polyketide fragments (Scheme 4.20) [95]. After conversion of 188 into boron enolate... 

In 2003, Paterson and co-workers reported a second-generation strategy for the synthesis of discodermolide, which aimed to eliminate the use of all chiral reagents and auxiliaries, and reduce the total number of synthetic steps (Scheme 24) [58, 59], These specific aims were achieved by employing an unprecedented aldol coupling at C5-C6 between C1-C5 aldehyde 118 and the advanced C6-C24 methyl ketone 119 and utilising diol 120 as a common precursor for the synthesis of the three subunits 118, 121 (C9-C16) and 98 (C17-C24). 

When we discussed how -enolates of ethyl ketones such as 207 gave 1,3-control in the aldol reaction, we noted that there was 1,4-control too. Paterson did the same reaction on the corresponding methyl ketones and found that the lithium enolate (M = Li in 234) was unselective. The boron enolate with an achiral group 9 (M = dicyclohexyl-B) was selective giving 88 12 syn anti-235 in 84% yield but with a chiral group [M = (-)-(Ipc)2B] the stereoselectivity was significantly better35 (92 8). 

We have already collected some powerful tools for use in stereocontrolled aldol reactions, but we have not finished. We shall see now in Paterson s synthesis of (+)-discodermolide, how reagent control is used not to enhance the intrinsic substrate selectivity, but to overturn it. The aldol reaction is undoubtedly one of the most powerful ways of making carbon-carbon bonds and nature thinks so too. There are numerous natural products that are replete with 1,3 related oxygen functionality. Many of these are acetate or propionate-derived in nature. The methods detailed above developed from studies into the syntheses of these natural products. The manipulations of chiral ethyl ketones of this kind are of particular interest when it comes to natural products that are polypropionate-derived. 

Paterson et have prepared the enolate of 3-pentanone, an achiral ketone, with (-( )- or (-)-IpcaBOTf and have found that its aldol reactions with various aldehydes proceed with high syn.anti ratios (>9 1) and respectable enantioselectivities (5 1-20 1) (Scheme 44). High degrees of asymmetric induction are noted with unhindered aldehydes, llie combination of the chiral ethyl ketone (104) and (-t-)-Ipc2BOTf constitutes a matched pair, which enhances the diastereofacial selectivity of the resulting enolate (compared to that obtained with an achiral boron reagent), and provides via aldol reactions high... 

In addition to their usefulness for the asymmetric addition of achiral aldehydes, it will be seen in the section 5.2.3 that the Paterson strategy is particularly useful for the aldol addition of chiral fragments such as the large, polyfunctional ketone and aldehyde fragments needed for convergent macrolide synthesis. 

Impressively short is a total synthesis by Ian Paterson [281], who uses a lactate ester as chiral auxiliary. This is subsequently converted into a ketone via a Grignard reaction with its Weinreb amide. The boron-mediated aldol reaction, after an oxidative work-up, gives the aldol with a diastereoselectivity of >98 %. Since also the reaction with propionaldehyde shows the same diastereoselectiv-... 

I. Paterson Aldol Condensations of Ketones Using Chiral Boron Reagents ... 

The chiral pool refers to readily available optically active natural products, some of which are commercially used in quantities of 10 -10 tonnes per year [5], Among them, the most inexpensive compounds are a-amino acids, like monosodium L-glutamate, or carbohydrates, like dextrose or sorbitol. The success of the second method depends on the availability of particular catalysts. One rather special example, how efficient stereoselective synthesis can work, is the syn-selective aldol reaction followed by a stereoselective alkene hydroboration and ketone reduction (Figure 1.8) which were used by Paterson et aJ. [26] to synthesize intermediates for the antibiotic oleandomycin. According to Paterson et al., four new stereocenters are formed in only two synthetic steps [9]. For the purpose of separating racemic mixtures... 

The strength of the Paterson approach is clearly due to the fact that this method is highly efficient for aldol additions of ketones with a chiral skeleton to chiral or achiral aldehydes, in the course of which the diisopinocampheylborane eno-lates exhibit distinct stereocontrol. An illustrative example thereof is shown in Scheme 4.67 by the stereodivergent aldol addition of enantiomerically pure ketone... 

Paterson 1, Lister MA, McClure CK. Enantioselective aldol condensations the use of ketone boron enolates with chiral... 

Paterson I, Wallace DJ, Velazquez SM. Studies in polypropionate synthesis high -rr-face selectivity in syn and anti aldol reactions of chiral boron enolates of lactate-derived ketones. Tetrahedron Lett. 1994 35 9083-9086. 

Paterson I, Goodman JM, Isaka M. Aldol reactions in polypropionate synthesis high rr-face selectivity of enol hori-nates from a-chiral methyl and ethyl ketones under substrate control. Tetrahedron Lett. 1989 30 7121-7124. 

Paterson I, Tillyer RD. High rr-face selectivity in anti aldol reactions of E-enol borinates from chiral alkoxy-methyl ketones stereocontrolled synthesis of a C24—C32 polyol subunit of rapamycin. J. Org. Chem. 1993 58 4182 184. 

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