Nitro-aldol condensations

A trifold anionic/pericyclic domino reaction was used for the synthesis of the dioxapyrrolizidine 2-655 combining a nitro aldol condensation, SN-type cyclization, SN-type etherification, and an intramolecular 1,3-dipolar cyclization as described by Rosini and coworkers (Scheme 2.148) [339]. 

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... 

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 ...

Nitro-Aldol Condensation. A BINOL-derived lanthanide complex has been used as an efficient catalyst for the nitro-aldol reaction (eq 27). Interestingly enough, the presence of water and LiCl in the reaction mixture is essential to obtain the high level of asymmetric induction and chemical yield. 

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]. 

A reverse option of the nitro-aldol condensation is available, as in the synthesis of the C-ana-log of 8-D-Gal-(1 6)-D-Glc, also called aUolactose, viewed by the authors as a potential inducer of the Lac repressor protein that is not susceptible to /3-galactosidase cleavage [49] (O Scheme 17). 

The 2,4,6-triphenylpyrylium ion reacts with nitromethane to give the dienone 39. This is followed by an intramolecular nitro-aldol condensation forming 2,4,6-triphenylnitrobenzene 40. By way of the ring-opened phosphorane 41, action of phosphorylidene produces the 2-substituted 1,3,5-triphenyl-benzene 42 ... 

A synthesis of sinefungin has been described, using a nitro-aldol condensation between a dialdose derived from adenosine and an -nitro-aminoacid derivative to build the required Cj Q-carbon skeleton... 

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