Roche ester

For the syntheses of a large number of deoxypolypropionates requiring a,o -diheterofunctional intermediates, a couple of novel protocols, that are complementary with the conventional protocol using so-called Roche ester, have been developed (Scheme 33).199,200 More recently, the combined use of the ZACA reaction and the lipase-catalyzed kinetic resolution via selective acetylation has been shown to be practically attractive for the synthesis of enantio-merically pure compounds that cannot be readily purified by ordinary chromatography or recrystallization199,201 (Scheme 34). 

The diene fragment in the form of iodide 87 was synthesized from commercially available (+)-Roche ester 90 by tritylation, LAH reduction, and Swern... 

In two studies toward the total synthesis of natural products it could be shown that the a,jS-unsaturated esters derived from the vinylogous Mukaiyama aldol reactions can be further functionalized into advanced intermediates. The C1-C7 segment of oleandolide commences with the VMAR of aldehyde 68 derived from the Roche ester. The so-generated stereo-triad was protected as PMB ether and the ester 76 was reduced to the allylic alcohol. Sharpless asym-... 

As outlined in Scheme 22, the synthesis of the C1-C6 subunit 95 commenced with the anti aldol reaction of the ethyl ketone 100, prepared in three steps from Roche ester 18, and acetaldehyde, with in situ reduction to give diol 103 (>30 ldr) [130, 132-136, 145, 146], Completion of 103 then required a series of protecting group manipulations... 

The Paterson second-generation approach substantially reduced the total number of steps required to complete discodermolide. Notably, the use of chiral reagents and auxiliaries was completely eliminated, relying solely on substrate control to configure all the remaining stereocentres from the ubiquitous Roche ester (18), achieving a more cost-effective route. 

As shown in Scheme 36, the Novartis group s large-scale (20-25kg) preparation of Smith s common precursor 31 began with the established Evans aldol reaction between the Roche ester-derived aldehyde 32 and the propionimide 33 [65],... 

Another synthetic application of Roush s crotylboration methodology using a (Z)-crotylboronate can be found in the formal synthesis of (+)-discodermolide (75)29 (Scheme 3.1z). The aldehyde (S)-67, which was prepared from the Roche ester, reacted with (Z)-crotylboronate (S,S)-43Z to give the syn-homoallylic alcohol 76. Silylation of alcohol and oxidative cleavage of the alkene 77 provided the aldehyde 78, from which the final product (75) can be synthesized according to a known procedure.30... 

Slight detours from Fiirstner s synthesis were required in the elaboration of the intermediate aldehyde from Roche ester. Actually, a two-step procedure was found to be more reliable since the primary alcohol 19 could be stored for an extended period of time and oxidized at the last minute in a very rapid... 

The Seebach aglycone synthesis is also independently based on the aldol coupling of the dialdehydic diolide 282 and the ethyl ketone 288, which are prepared by the use of chiral building blocks, Roche ester 285 or diethyl (S)-malate (286) and ethyl (R)-3-hydroxybutyrate (287). 

In 2008, MacMillan and co-workers [13] reported the first total synthesis and structure revision of callipeltoside C (38), a cytotoxic marine macrolide, with amino acid proline as a suitable organocatalyst for the construction of three key intermediates. This elegant synthesis (18 steps, 12% overall yield) demonstrated the power of organocatalysis with unprecedented level of ease and efficiency, which involved a proline-catalyzed double diastereo-differentiating aldol reaction between propionaldehyde 18 and the Roche ester-derived aldehyde 28 to achieve 29 (12 1 dr, 99% ee), an organocatalytic a-oxyamination to afford 32 (99% ee), and proline-... 

For the synthesis of a,(o-diheterofunctional deoxypolypropionates, silyl-protected 2-methyl-4-penten-l-ols were initially prepared in four steps from the so-caUed Roche ester [244]. However, a couple of more efHcient and potentially economical protocols based on the ZACA reaction of styrene [30] and aUyl alcohol [164] have been developed, as shown in Scheme 3.96 and Scheme 3.97. 

In contrast, O-protection of allyl alcohols (TBSO, PhO, AcO, TMS) or use of allyl acetals enhances the regioselectivity, and P-hydroxy aldehydes can be formed with good or even excellent enantioselectivity (83-97%) [49]. This method allows the inexpensive production of the so-called Roche aldehyde, which is commonly prepared from the Roche ester via a more expensive pathway (Scheme 4.77) [43, 50]. The linear aldehyde could be removed from the branched one by flash chromatography to obtain the chiral aldehyde with no loss of enantioselectivity [51]. 

As with other P(III) compounds, the binaphthol (BINOL) derivatives have been by far the most successful for a wide range of synthetic methods. Several reviews and reports have been published on the incorporation of BINOL-derived phosphoramidites in rhodium-catalysed asymmetric hydrogenations Novel chiral phosphine-phosphoramidite ligands, HY-Phos (61) and THNAPhos (62), have also been successful in rhodium-catalysed asymmetric hydrogenations. Asymmetric synthesis of the Roche ester and its derivatives (63) by rhodium-INDOLPHOS-catalysed hydrogenation was reported and a number of other BINOL-derivered phosphoramidates have been employed in iridium-catalysed hydrogenations and allylic alkyla-... 

Stueckler, C., Winkler, C.K., Bonnekessel, M., and Faber, K. (2010) Asymmetric synthesis of (R)-3-hydroxy-2-methylpropanoate ( Roche Ester ) and derivatives via biocatalytic C=C-bond reduction. Adv. Synth. Catal., 352, 2663-2666. 

Baylis-Hillman adducts are readily available building blocks, which upon stereoselective OYE-catalyzed reduction afford synthetically important chiral products [42]. The first example to be reported involves the formation of the Roche ester (4a) from the Baylis-Hillman adduct 3a especially the allyl and benzyl ethers (3b and 3c, respectively) can be reduced stereoselectively using several different OYEs, with results (99% ee) rivaling and surpassing synthetic catalysts (Eigure 5.6) [42]. 

In order to put this synthetic strategy on a more general basis, the Roche ester (3a) and structurally different Baylis-Hillman adducts 5 and 6 were tested, first using Pichia stipitis OYE 2.6 (WT) as the biocatalyst that led to excellent results in high... 

Figure S.6 OYE-catalyzed reduction of the Roche ester (3a) and O-protected forms 3b and 3c leading to chiral products 4a-c [42],...

Figure 13.19 Stereocomplementary strategies to Roche ester derivatives.

---