Five-membered cyclic nitronates

Dipolar cycloadditions of five-member cyclic nitrones to a,(3-unsaturated acid derivatives 99H(50)1213. 

Enantio-pure five-membered cyclic nitrones (154) and (155) were formed in a one-pot synthesis from the corresponding lactols (152) and (153) as the result of their reactions with unsubstituted hydroxylamine and by (a) subsequent treatment with MsCl and NaOH (Scheme 2.55) (310a) or by (b) subsequent treatment with TBDMSC1,12, TPP, imidazole, and tetrabutylammonium fluoride (TBAF) (310b). 

The second method (path b) involves the initial transformation of AN into nitroso acetals A containing the good leaving group Y followed by 1,3-elimination of the Si Y fragment from the above mentioned intermediate to form the target nitronates. The use of this method in the synthesis of only five-membered cyclic nitronates has been documented (see Section 3.2.1.2.1.2). However, there are no obvious obstacles to the extension of the scope of this method. 

Another approach to the synthesis of cyclic nitronates is based on cycloaddition reactions (Scheme 3.11, Eq. 2), where two bonds (C-C and C-O) are simultaneously formed. This strategy allows one to perform stereoselective processes with the use of very simple precursors. However, this approach to the synthesis of five-membered cyclic nitronates implies that reactive and very unstable nitrocarbenes are involved in the process. 

Intramolecular Cyclization of y-Functionalized AN The most commonly used procedure for the synthesis of five-membered cyclic nitronates (5) is... 

In some cases, five-membered cyclic nitronates can be prepared by the chemos-elective replacement of one of two different halogen atoms in 1,3-dihalopropanes... 

Yet another approach to the synthesis of five-membered cyclic nitronates (5) is based on the Henry condensation of a-halo-substituted aldehydes (9) with primary AN followed by cyclization of nitroaldols (Scheme 3.14, Eq. 4) to give five-membered nitronates containing the hydroxy group at the C-4 atom. 

Finally, Scheme 3.14 presents the Michael addition of bromomalonic ester to conjugated nitro olefins 10. This approach allows one to synthesize five-membered cyclic nitronates (5) doubly functionalized at the C-5 atom (Scheme 3.14, Eq. 5). 

The process shown in Scheme 3.16 is rather interesting. It should be noted that in most cases this reaction is very stereoselective with respect to the arrangement of the substituents at C-4 and C-5 atoms. In light of recent data on the possible isomerization of nitrocyclopropanes (13) to form five-membered cyclic nitronates (5) (for more details, see Section 3.2.2.1.2), low chemoselectivity of many reactions involving sulfur ylides does not seem to be so fatal. 

Unfortunately, only two attempts were made to use this approach in the synthesis of five-membered cyclic nitronates (5), and only one of them could be considered as successful. In the latter case, isomeric nitrocyclopropane was obtained as the major product. Only a-functionalized nitro alcohols are readily involved in the Mitsunobu cyclization. However, the possibility of isomerization of by-products, nitrocyclopropanes, which was mentioned in the discussion of Scheme 3.16, caused the revision of this process as a procedure for the synthesis of five-membered cyclic nitronates. (A new approach to the synthesis of initial y-nitro alcohols from readily available AN was documented in Reference 64)... 

Recently, Italian researchers have developed a new procedure for the synthesis of five-membered cyclic nitronates with the use of enantiomerically pure epoxides (65-67) and aziridines (68) as the starting substrates (15) (Scheme 3.18, see also substrate B in Scheme 3.11, Eq. 1). 

In the synthesis of five-membered cyclic nitronates (5), the problem of stereoselectivity is in preparing these products with desired relative configurations of the stereocenters at the C-4 and C-5 atoms (see Scheme 3.12). Generally, the trans configuration of these substituents is most preferable. Several procedures giving exclusively this configuration were documented (see,e.g. (50, 55, 58, 63, 68)). 

In 1981, it was demonstrated (70) that anions of nitro compounds can be involved in C,C-coupling with allyl acetates at the allylic carbon atom with the use of metal complex catalysis. For many years, this observation did not come to the attention of chemists interested in the synthesis of cyclic nitronates. However, Trost demonstrated (71) that this process can be used in the synthesis of five-membered cyclic nitronates from olefins (18) containing two acyl groups in the different allylic positions (Scheme 3.21). 

Lastly, the radical inter- and intramolecular cyclizations in the presence of one-electron oxidizing agents as a procedure for the synthesis of five-membered cyclic nitronates can be considered. Radical oxidation of a-nitro ketones (19) in the presence of disubstituted olefins under the action of Mn(OAc)3 was documented (72a) (Scheme 3.22, Eq. 1). 

Synthesis of Five-membered Cyclic Nitronates by Cycloaddition Reactions... 

Here, we have already noted that cyclopropanes (23) are structural isomers of five-membered cyclic nitronates (24). There was evidence that functionalized cyclopropane (23b) can be isomerized to give the corresponding five-membered cyclic nitronate (24b) under the action of halide anions (82) (Scheme 3.28, Eq. 1). Moreover, the in-depth study (79) demonstrated that the above mentioned... 

Synthesis of Five-membered Cyclic Nitronates from a-Halogen-substituted AN. The key step of this approach is presented in Scheme 3.1, path (b). Until recently, this synthetic route to nitronates (24) has been of no preparative interest, because only two examples, such as elimination of trimethylsilyl nitrite (75) and 1,2-dinitrophenylethane (85) from the corresponding nitroso acetals were documented. 

Since inactivated alkenes do not contain the substituent X stabilizing the positive charge in intermediate B (see Scheme 3.40), the latter can undergo a hydride shift to form a more stabilized cationic center (intermediate B in Scheme 3.42), which finally gives rise to an impurity of five-membered cyclic nitronate (24). 

The reactions of ammonia or primary amines with five-membered cyclic nitronates containing the EWG -group at the C-5 atom involve deoxygenation of the nitronate fragment, aromatization of the ring, and amidation of the ester... 

Five-membered cyclic nitronates can be subjected to aromatization by alkali (21) or dilute acids (37, 319) (Scheme 3.110). 

Trost and coworkers (71) used tin dichloride for deoxygenation of annelated five-membered cyclic nitronates (140a,b) with retention of stereocenters (Scheme 3.115). 

An analogous result was obtained by the hydrogenation of five-membered cyclic nitronate. The latter reaction afforded a-oximino-Y-hydroxypentane-1,5-dicarboxylic acid derivative (Scheme 3.116, Eq. 2) in high yield (83%) (319). 

Ozonolysis of Cyclic Nitronates This very interesting approach to cleavage of the nitronate fragment has been recently demonstrated by Linker and coworkers using two optically pure five-membered cyclic nitronates as an example (263a) (Scheme 3.118). 

The ester groups in five-membered cyclic nitronates were successfully subjected to different transformations. Treatment of nitronates containing the methoxycarbonyl groups at positions 3 and 5 with butylamine at 20°C afforded the corresponding diamides (237b) (Scheme 3.119, Eq. 2). Their yields depend dramatically on the nature of the substituent R (further transformations of these products are shown in Scheme 3.109). 

Five-membered Cyclic Nitronates In spite of the fact that five-membered cyclic nitronates are known for more than a hundred years and are classified as the most stable representative of this class of compounds, their... 

Chart 3.13 [3 + 2]Reactivity of five-membered cyclic nitronates. 

It should be noted that tetramethylethylene was involved in the [3+ 2]-cyclo-addition with five-membered cyclic nitronates (363). 

The mechanism of this reaction has not been studied in detail. However, it can be represented as a sequence of reactions. The first reaction is, in fact, [3+ 2]-cycloaddition of olefin to furoxan (161). Under severe conditions, the resulting intermediate A undergoes fragmentation to give five-membered cyclic nitronate B. The latter is involved in the usual addition reaction with an excess of olefin to form isolable bicyclic product (162) (301, 378, 379). 

In intramolecular [3+ 2]-cycloaddition reactions of five-membered cyclic nitronates, only a Si-containing tether was used (393) (Scheme 3.150, see also Scheme 3.120 and references therein). 

This process was carried out with the use of diastereomerically and enan-tiomerically pure five-membered cyclic nitronates (213). After selective silylation of the hydroxy group and intramolecular cycloaddition, these compounds give enantiomerically pure fused systems, which are similar precursors of enantiomer-ically pure hydroxyamino acids and other polyfunctional compounds possessing potential biological activity. 

In the synthesis of enantiomerically pure five-membered cyclic nitronates,... 

In addition, chiral five-membered cyclic nitronates can be prepared from optically inactive starting nitronates with the use of ligated palladium (catalyst) as a chiral inductor (71) (ee 97%). 

As mentioned above (66, 393), (see Scheme 3.150) silylation followed by intramolecular enantioselective cycloaddition with five-membered cyclic nitronates, containing the hydroxyl group at C-4, can produce chiral polycyclic structures (293), which are direct precursors of chiral hydroxyamino acids (294) and aminopolyols (295) (Scheme 3.179). 

Silylation of 3-alkyl-substituted five-membered cyclic nitronates remains virtually unknown, although one example of the successful synthesis of the corresponding nitroso acetal was documented (Scheme 3.203) 475. 

Catalytic C,C-coupling reactions with five-membered cyclic nitronates were reported (485) (Scheme 3.209). 

Recently, it has been demonstrated (495) that the [3+ 2]-cycloaddition reactions of 3-bromo-substituted six-membered cyclic nitronates (400), which are constructed from olefins (401) and l-bromo-l-nitro-2,4/-methoxyphenylethylene, with olefins (402) produce 3-vinylisoxazolines (403) or five-membered cyclic nitronates (404) in good yields (Scheme 3.221). 

The formation of five-membered cyclic nitronates (404) is explained in terms of ring-chain tautomerism of cationic intermediates A (A=A ). The presence of the alkoxy substituent (R4) at the C-6 atom could stabilize the open form (cation A7), which finally leads to the formation of functionalized five-membered cyclic nitronates (404) probably with the participation of water. 

The synthesis of 8-homocastanospermine via the 1,3-dipolar cycloaddition of five-membered cyclic nitrone derived from malic acid and unsaturated D-threo-hexaldonolactone is reported <2006CJC534>. 

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