Imides stereoselective reductions

In another approach to the meso problem , utilization of a chiral auxiliary attached at nitrogen appears to induce very high stereoselectivity. Reduction of the optically active imide 10a (see Appendix) with tetramethylammonium triacetoxyborohydridc in acetone/ acetic acid at 25 "C gives a 4 96 mixture of the diastcreomers 11a and 12a in 87% yield44. On changing the solvent to acetonitrile/acetic acid the diastereomeric ratio is improved to < 1 99, but the yield is lower (63%). 

The Evans aldol reaction using chiral p-keto imide 23 as a dipropionate building block is also very effective for the construction of polypropionate segments in polyoxomacrolides (Scheme 2) [8]. The diastereoselective aldol reaction of 23 via different metal enolates (Ti, Sn, and B enolates) afforded three kind of aldols, syn-syn-24, anti-syn-25, and anti-anti-26, with high diastereoselectivity, respectively. The subsequent stereoselective reduction of the resulting p-hydroxy ketones 24-26 provides various types of dipropionate units. Based on this strategy, the... 

The 2b-catalyzed reduction of j or 8-keto esters provided the corresponding hydroxy esters with high enantioselectivity (Scheme 11.9) [5b], while the reduction of a-keto esters was less effective [6b, 44b, 59]. Desymmetrization of meso-imides 31 via stereoselective reduction is one of the most powerful transformations to provide products with three new chiral centers. Such transformations with good enantioselectivities were achieved by OABs-catalyzed reductions (Scheme 11.10) [60-62], The hydroxy lactams 32 obtained were easily converted into ethoxy lactams 33 by acidic ethanoly-sis, and were transformed into chiral lactones 34 by sodium borohydride reduction. 

Following the publication of work of the Merck group, Kametani et al have shown that their functionalized azetidinone can also be converted to the [3.2.0]bicyclic ring system by the carbene-insertion method (149) - (150). It has also been reported that ( )-thienamycin may be prepared by a method adaptable to large scale operation. This route involves the formation of the highly functionalized amino-alcohol (151) by stereoselective reduction, efficient carbodi-imide assisted -lactam formation, and the carbenoid-insertion reaction. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

In an effort to identify a more stereoselective route to dihydroagarofuran (15), trimethylsilylated alkyne 17 was utilized as a substrate for radical cyclization (Scheme 2). Treatment of 17 with a catalytic amount of AIBN and tri-n-butyltin hydride (1.25 equiv) furnishes a mixture of stereoisomeric vinyl silanes 18 (72% combined yield) along with an uncyclized reduction product (13% yield). The production of stereoisomeric vinyl silanes in this cyclization is inconsequential because both are converted to the same alkene 19 upon protodesiiyiation. Finally, a diastereoselective di-imide reduction of the double bond in 19 furnishes dihydroagaro-... 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

The reductive cyclization of imides is a well-established method for the construction of five-and six-membered heterocycles and works often in a stereoselective fashion [81a]. An early example utilizes the following reactions ... 

The enantioselective total synthesis of streptazolin (609), a neutral lipophilic antibiotic isolated from cultures of Streptomyces viridochromogenes, utilizes a tandem iminium ion— vinylsilane cyclization of the tartrate-derived 607 together with intramolecular acylation as a way of achieving high stereoselectivity. Heating a mixture of 570 and ( )-4-bromo-4-(tri-methylsilyl)-3-buten-l-amine (605) followed by dehydration with acetyl chloride provides the imide (606) in reproducible yields of 90%. Reduction of 606 with sodium borohydride affords 607, which is refluxed in trifluoroacetic acid to provide, after careful purification, the single bicyclic adduct 608 in 74% yield. This is then transformed in four steps to the desired streptazolin (609) [196] (Scheme 134). 

The epimeric (+)-a-allokainic acid was constructed by the unsaturated imide/ alkyne alkylative coupling of 9 with trimethylaluminum in 73% yield and 97 3 diastereoselectivity (Scheme 8.11) [33]. This was followed by silyl to carbonate protecting group transposition, stereoselective aUylic reduction, and removal of protecting groups to afford (+)-a-allokainic acid. The complementary nature of these two stereodivergent approaches allowed access to both epimeric natural products. 

The Oishi-Nakata synthesis is based on the stereoselective synthesis of the C1-C7 (106) and Cg-Cis (103) segments from the optically active syn-a-methyl-P-hydroxy imides prepared by Zn(BH4)2 reduction of the corresponding p-fceto imides. 

Wender et al. applied the Evans aldol reaction to the enantioselective synthesis of phorbol, an activator of isozymes of protein kinase C family (Scheme 8.6). Aldehyde 34 was submitted the aldol reaction to give syn adduct 35 in excellent yield. Imide 35 was transformed into ketone 36 via the Weinreb amide. Reduction of (3-hydroxyketone 36 proceeded stereoselectively to provide the l,3-5y diol, which was converted into the monoacetylated 37 by a one-pot, selective protection-deprotection procedure. Oxidation of the furan ring and rearrangement to the pyranone was followed by acetylation of the resulting hemiacetal to give 38. Treatment of 38 with l,8-diazabicyclo[5.4.0]undec-7-ene promoted [5 - - 2] cycloaddition reaction to afford tricyclic 39, which was the intermediate of phorbol 40. 

---