HENRY Nitro Aldol Condensation

Fluoromethyl ketones are one of the most widely used classes of peptidyl a-fluoroalkyl ketones, second only to trifluoromethyl ketones. Peptidyl fluoromethyl ketones are very effective as irreversible inhibitors of cysteine proteases the first reported use of a fluoromethyl ketone compound was the use of Z-Phe-Ala-CH2F as an irreversible inhibitor of cathepsin BJ2,31 Today, many lysine and arginine derivatives have been synthesized as potential inhibitors for trypsin and trypsin-like enzymesJ3 There are four basic methods for the synthesis of peptide fluoromethyl ketones (1) the reaction of HF with peptide diazomethyl ketones (Section 15.1.4.1.1), (2) a halogen-exchange reaction with a chloro-, bromo-, or iodomethyl ketone (Section 15.1.4.1.2), (3) a Henry nitro-aldol condensation reaction (Section 15.1.4.1.3), and (4) a modified Dakin-West acylation reaction (Section 15.1.4.1.4). 

The Henry nitro-aldol condensation involves the use of P-amino alcohols as the building blocks of fluoromethyl ketones. Although this method has been used extensively in the synthesis of monofluoropeptides (Table 2),19-121 it is more widely utilized as a method for synthesizing trifluoromethyl ketones and the details of the reaction will be discussed in Section 15.1.4.3.2. 

As with the Henry nitro-aldol condensation, the modified Dakin-West acylation is primarily used for synthesis of trifluoromethyl ketones, although there are several examples of its use in the synthesis of fluoromethyl ketones (Table 3).[31314 The modified Dakin-West reaction utilizes fluoroacetic anhydride (or other appropriate anhydrides) to form an anhydride, which then undergoes cyclization, activation of the a-carbon, and acylation at the a-carbon the precise details of this method will be discussed in Section 15.1.4.3.1. 

Most peptidyl a,a-difluoroalkyl ketones are actually extended chains based on statone, rather than simple difluoromethyl ketones. The statone derivatives are based on pepstatin, which is an extremely potent peptide inhibitor of aspartic proteases. The difluoro derivatives of statone take advantage of both the electronegativity of fluorine and the potential for additional interactions between the protease and structures on the leaving group side of the inhibitor. 15 This dual nature is part of what makes a,a-difluoroalkyl ketones effective inhibitors of aspartyl proteases as well as serine proteases. There are three main methods of synthesizing peptidyl a,a-difluoroalkyl ketones (1) the Reformatsky reaction with peptide aldehydes (Section 15.1.4.2.1), (2) a modified Dakin-West reaction (Section 15.1.4.2.2), and (3) a Henry nitro-aldol condensation (Section 15.1.4.2.3). 

Similar to the Dakin-West procedure previously mentioned, the Henry nitro-aldol condensation reaction is most widely used to synthesize trifluoromethyl ketones, although there are many examples of a,a-difluoroalkyl ketones synthesized by this method (Table 6)JU 12271 The method for a,a-difluoroalkyl and trifluoromethyl ketone synthesis is identical except for the final oxidation although fluoroalkyl and a,a-difluoroalkyl ketones are easily oxidized by the Sarett method (Cr03/pyridine),[12 the corresponding trifluoromethyl ketones can only be oxidized under basic conditions (0.3 M NaOH) with KMn04Jul Also, in some of the syntheses of a,a-difluoroalkyl ketones, the nitro alcohol intermediate was protected by si-lylation with /ert-butylchlorodimethylsilane. The silyl group was later removed by TosOH prior to oxidation. The full details of this method are given in Section 15.1.4.3.2. 

In this section the synthesis of fluoroalkyl (Section 15.1.4.1.3), a,a-difluoroalkyl (Section 15.1.4.2.3), and trifluoromethyl- and perfluoroalkyl ketones are discussed collectively. The second most widely used method for synthesizing peptide fluoromethyl ketones is the Henry nitro-aldol condensation reaction, which involves the use of (3-nitro alcohols to build the fluoromethyl ketones. As with the modified Dakin-West procedure, the Henry reaction has also been used to synthesize mono-, di-, tri-, and extended fluoromethyl ketones, making it another extremely versatile synthetic method.19 12 19 27 29 33 341 However, similar to the Dakin-West procedure, the products of the Henry reaction are not chiral, since an achiral carbanion is involved in the crucial carbon bond forming step. 

Scheme 5 Synthesis of Fluoro Ketones by a Henry Nitro-Aldol Condensation 12 ...

Kambe and Yasuda19 discovered the effectiveness of the fluoride as a Henry reaction catalyst. Since then, the use of diverse fluorides is a common method to catalyze nitro aldol condensations, since they provide mild conditions that are particularly convenient for sensitive products as carbohydrates. The most common fluorides are potassium fluoride20 and tetrabutyl ammonium fluoride.21 A recent example relates to the TBAF catalyzed addition of nitroethanol to the D-glucose derivative 18, to give nitro sugars 19 (Scheme 8).22... 

The syntheses of d- and L-2-amino-2-deoxy-arabinose and of l,4-dideoxy-l,4-imino-D-lyxitol 94 have been achieved via the nitro-aldol condensation (Henry s reaction) of 2-O-benzyl-D-glyceraldehyde (R)-25 and the diethyl acetal of nitroacetaldehyde (Scheme 13.39), which gives a 88 12 mixture of the arahino and nZ 6>-adducts. Their reduction and subsequent protection of the amines thus obtained, and then selective tosylation of the primary alcohol and hydrogenolysis, gives 93, which is subsequently converted into 94 [80]. 

Henry reaction Aldol condensation between nitroalkanes and carbonyl compounds to form 3-nitro alcohols. 202... 

Thus, various kinds of bases are effective in inducing the Henry reaction. The choice of base and solvent is not crucial to carry out the Henry reaction of simple nitroalkanes with aldehydes, as summarized in Table 3.1. In general, sterically hindered carbonyl or nitro compounds are less reactive not to give the desired nitro-aldol products in good yield. In such cases, self-condensation of the carbonyl compound is a serious side-reaction. Several modified procedures for the Henry reaction have been developed. 

When aliphatic nitro compounds are used instead of aldehydes or ketones, no reduction occurs, and the reaction has been referred to as a Tollens reaction (see 16-43). However, the classical condensation of an aliphatic nitro compound with an aldehyde or ketone is usually called the Henry reaction or the Kamlet reaction, and is essentially a nitro aldol reaction. A variety of conditions have been reported, including the use of a silica catalyst, Mg—A1 hydrotalcite, a tetraalkylam-monium hydroxide,proazaphosphatranes, " or an ionic liquid.A solvent free Henry reaction was reported in which a nitroalkane and an aldehyde were reacted on KOH powder. Potassium phosphate has been used with nitromethane and aryl aldehydes. The Henry reaction has been done using ZnEt2 and 20%... 

The nitro group, as one of the many functional groups with a strong electron-withdrawing effect, plays an extremely important role in the reactivity of the sugar molecule no matter where it is located. The anomeric nitrates introduced by Vasella [53] are particularly useful reactive synthons for introducing additional functionalities via formation of the C-C bond by Henry aldol condensation [54] followed by a radical denitration. 

The Henry reaction or the nitroaldol is a classical reaction where the a-anion of an alkyinitro compound reacts with an aldehyde or ketone to form a p-nitroalcohol adduct. Over the decades, the Henry reaction has been used to synthesize natural products and pharmaceutical intermediates. In addition, asyimnetric catalysis has allowed this venerable reaction to contribute to a plethora of stereoselective aldol condensations. Reviews (a) Ballini, R. Bosica, G. Fiorini, D. Palmieri, A. Front. Nat. Prod. Chem. 2005, 1, 37-41. (b) Ono, N. In The Nitro Group in Organic Synthesis Wiley-VCH Weinheim, 2001 Chapter 3 The Nitro-Aldol (Henry) Reaction, pp. 30-69. (c) Luzzio, F. A. Tetrahedron 2001, 57, 915-945. 

Michael condensations, together with the Diels-Alder cycloaddition and the aldol reactions, are the most powerful and useful bond-fonning reactions in synthetic organic chemistry. Like the nitro-aldol (Henry) additions, nitroalkanes are particularly appropriate reagents in Michael reactions they act as a-hydrogen donors. Nitroalkanes react easily with typical Michael acceptors such as a,p-unsaturated aldehydes or ketones under base or Lewis acid catalysis. ... 

Nitroalkanes having an a-hydrogen atom undergo aldol-type condensation with aldehydes and ketones in the presence of a base to give p-hydroxy nitro compounds or nitroethylene compounds. The reaction is known as the Henry reaction " or nitroaldol reaction. 

---