Acyclic diastereoselection reductions

Stereoselectivity in reductions of acyclic oximes depends on the configuration of C=N bond. ( )-Isomer of oxime 89 produced syn-hydroxylamine 90 in excellent stereoselectivity in reaction with phenyldimethylsilane-trifluroacetic acid while giving anti-product in the reaction with lithium aluminium hydride. Stereoselectivity in reductions of (Z)-isomers of 89 was substantially lower in both cases (equation 62) . It can be assumed that the rules of stereoselectivity established in diastereoselective reduction of ketones can be applied to reduction of oximes as well. 

Diastereoselective reduction of acyclic a, -dialkoxy ketones.3 Reduction of the ketone 2 with this hydride results in the alcohol 3 with high syn-selectivity (97 3). The same syn-selectivity is observed with lithium trisiamylborohydride, but the yield is lower. The product was used for a synthesis of (+ )-4, a pheromone of a species of ants. 

The development of reliable methods for the diastereoselective reduction of carbonyl compounds in a wide range of acyclic systems has been an area of explosive growth in recent years. This was prompted by the requirements of modem total synthesis in which redundant diastereoisomers are avoid, - together with enhanced theoretical understanding of stereoselectivity which allows rationalization of the results. 

The reduction of cyclic imines and oximes follows a trend similar to that of corresponding ketones. However, the tendency for attack from the most hindered side is in these cases attenuated. 4.5. 87 jn the case of oximes, while NaBFLt-MoOs attacks from the axial side, NaBH4-NiCl2 attacks from the equatorial side. An example of diastereoselective reduction of acyclic chiral imines is represented by the one-pot transformation of a-alkoxy or a,/8-epoxynitriles into anti vicinal amino alcohols (eq 17) or epoxyamines. The outcome of these reductions was explained on the basis of a cyclic chelated transition state. ... 

Three of many examples of directed hydrogenation are shown in Equations 15.15-15.17. Equation 15.15 shows the reduction of a homoaUylic alcohol, which was one of the substrates first used to demonstrate this effect. Equation 15.16 shows a more complex substrate in which the diastereoselective reduction by Crabtree s catalyst is directed by the amide function as part of tlie synthesis of pulmitoxins. Equation 15.17 shows that the addition of hydrogen can be directed to a hindered face of a bicyclic system. In this case, the cationic rhodium system qf Brown, as well as Crabtree s catalyst, led to hi selectivity. Many other reactions occur with high selectivity in the presence of Brown s cationic rhodium system. Diastereoselective additions to acyclic systems, along with a rationalization for the selectivity in these types of substrates, can be found in the review by Evans. ... 

Atazanavir 21 (Figure 4.23) is an acyclic aza-peptidomimetic, a potent HIV protease inhibitor [44, 45] approved by the FDA for the treatment of acquired immunodeficiency syndrome (AIDS). An enzymatic process was developed to prepare (lS,2i )-[3-chloro-2-hydroxy-l-(phenylmethyl) propyljcarbamic acid, 1,1-dimethylethyl ester 81, a key chiral intermediate in the S5mthesis of atazanavir. The diastereoselective reduction of (lS)-[3-chloro-2-oxo-l-(phenylmethyl)propyl] carbamic acid, 1,1-dimethylethyl ester 82 was carried out using Rhodococcus erythropolis to afford 81 with a >90% yield and with a diastereomeric purity of >98% and an ee of 99.4% [111],... 

The cathodic reduction of ketones ( )-RCHMeC(0)R (R = Ph, R = Ph, Me R = cyclohexyl, R = Me) afforded mixtures of diastereomeric alcohols. The origin of the diastereoselectivity, which depends on R and R and the electrolysis conditions, is discussed [333]. Acyclic and cyclic ketones with a chiral center in the fi-position yielded diastereomers in a ratio different from that obtained by LiAlH4-reduction [334]. 

Stereoselective reduction of acyclic a-bromo esters.3 Highly diastereoselective radical reduction of a-bromo esters obtains when an electronegative group (F or OCH3) is present at the P-position, particularly at low temperatures. 

In 1986, Evans and colleagues introduced tetramethylammonium triacetoxyboro-hydride, a mild reducing reagent for the highly diastereoselective synthesis of 1,3-anft-diols from acyclic (3-hydroxy ketones1 (Scheme 4.2a). The reaction, commonly called the Evans-Chapman-Carreira reduction, is typically carried out in a 1 1 mixture of anhydrous acetic acid and acetonitrile, as the reaction needs to be run at low temperature in the presence of acetic acid. An important observation is that the anti -diastereoselectivity is realized regardless of the stereochemistry of the a-alkyl substituent Both anti - and. vvn-a.-methyl-(3-hydroxy... 

The most remarkable feature of this method is that even acyclic enamines undergo reductive alkylation with good diastereoselectivity. The reaction of propiophenone enamines 31-33 with primary carbon-centered radicals substituted by different electron-... 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

The reduction of a series of chiral acyclic ketones, lacking polar functional groups, with a range of lithium, sodium and potassium alumino- and boro-hydrides was investigated in various solvents under different reaction conditions. The changes in steric bulk of the reagents and reaction medium enabled a semiempirical scale for the effective size of the reagent to be applied to the stereochemical analysis of the observed diastereoselectivity. ... 

A more versatile reducing agent is samarium diiodide, which promotes chemoselective cyclizations of functionalized keto aldehydes in a stereodefined manner to form 2,3-dihydrocyclopentane carboxylate derivatives in good yields and with diastereoselectivities of up to 200 1 (equation 38)7 The reaction proceeds via selective one-electron reduction of the aldehyde component and subsequent nucleophilic attack on the ketone moiety. Stereochemical control is established by chelation of the developing diol (19) with Sm " " which thereby selectively furnishes cis diols (equation 39). The stereoselective M/-cyclization of 1,5-diketones to cis cyclopentane-1,2-diols using TiCU/Zn has been used to prepare stereodefined sterically hindered acyclic 1,2-diols when a removable heteroatom, such as sulfur or selenium, is included in the linking chain (equation 40). 

Dioh. Acyclic 2-hydroxyketones and a-diketones undergo ultrasound-assisted reduction with LilnH (prepared from InBrj and LiH) in a highly diastereoselective manner. For example, benzoin is converted to the meso-diol exclusively. 

Any explanation of facial selectivity must account for the diastereoselection observed in reactions of acyclic aldehydes and ketones and high stereochemical preference for axial attack in the reduction of sterically unhindered cyclohexanones along with observed substituent effects. A consideration of each will follow. Many theories have been proposed [8, 9] to account for experimental observations, but only a few have survived detailed scrutiny. In recent years the application of computational methods has increased our understanding of selectivity and can often allow reasonable predictions to be made even in complex systems. Experimental studies of anionic nucleophilic addition to carbonyl groups in the gas phase [10], however, show that this proceeds without an activation barrier. In fact Dewar [11] suggested that all reactions of anions with neutral species will proceed without activation in the gas phase. The transition states for reactions such as hydride addition to carbonyl compounds cannot therefore be modelled by gas phase procedures. In solution, desolvation of the anion is considered to account for the experimentally observed barrier to reaction. 

Reductive alkylations via a radical pathway have been performed on enamines of cyclic and acyclic ketones. In both cases the diastereoselectivity was high. Reductive alkylations via a radical pathway have been performed on enamines of and acyclic ketones. In both cases the diastereoselectivity was high, leading to cis products preferentially in the case of the cyclic derivatives and to ul substituted amines in the case of linear systems (Scheme 143),... 

Aside from the well-documented ability of the Luche reduction to provide stereocontrol in cyclic systems, acyclic stereocontrol is also viable through this process.39-41 A notable example of this was demonstrated in the synthesis of (+)-cannabisativine, a unique natural product found in the common marijuana plant.42 This synthesis necessitated a stereoselective Luche reduction to produce the diol 36 as a single diastereomer. The reaction proceeded in 96% yield and with 95% de. The pronounced diastereoselectivity can be attributed to Cram s rule, in which the hydride ion is delivered from the least sterically hindered side of the intermediate 34. Reduction via the chelated intermediate 35 would also account for the observed stereochemical outcome. 

The Felkin-Ahn and Cram models are best applied to acyclic systems. Problems arise when any of these models are used to predict the products generated by the reduction of cyclic ketones. These problems will be analyzed and new models for predicting diastereoselectivity in the reduction of cyclic molecules will be discussed in Section 4.7.C. 

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