Nitroso Diels-Alder reaction intramolecular

As a current example of a stereoselective intramolecular Diels-Alder reaction using nitroso dienophiles, Kibayashi s studies aimed at the enantioselective total sysnthesis of (-)-pumiliotoxin C 4-31 shall be discussed here [356, 357]. The chiral nitroso compound 4-30 derived from L-malic acid was generated in situ... 

The well-established Diels-Alder reaction between nitroso compounds and conjugated dienes has continued to be refined over the last decade. The most important advances have been in the development of chiral nitroso dienophiles useful for asymmetric synthesis and in the exploitation of the intramolecular Diels-Alder reaction in synthesis <94S1107>. 

The intramolecular /zetero-Diels-Alder reactions of 4-O-protected acyl-nitroso compounds 81, generated in situ from hydroxamic acids 80 by periodate oxidation, were investigated under various conditions in order to obtain the best endo/exo ratio of adducts 82 and 83 [65h] (Table 4.15). The endo adducts are key intermediates for the synthesis of optically active swainsonine [66a] and pumiliotoxin [66b]. The use of CDs in aqueous medium improves the reaction yield and selectivity with respect to organic solvents. 

The nitroso moiety of the N-acylnitroso function is a powerful dienophile and therefore N-acylnitroso compounds are trapped rapidly, especially in an intramolecular reaction, with a diene allowing the Diels Alder reaction to occur also in water, although N-acylnitroso compounds are short-lived in aqueous medium. 

An intramolecular hetero-Diels-Alder reaction of enantiomerically pure iV-acyl nitroso derivatives 78, prepared from hydroxamic acids 77 by oxidation on treatment with Pr4NI04 in an aqueous medium, afforded a mixture of diastereomeric pyrido[l,2-A][l,2]oxazin-8-ones 79 and 80 (Scheme 5) <1996J(P1)1113, 20000L2955,... 

A useful trick is based on the reversible preparation of the adducts of nitroso compounds with 9,10-dimelhylanthracene, e.g.. 5 they undergo a retro-Diels Alder reaction on heating, releasing the nitroso moiety which undergoes a rapid inter- or intramolecular Diels-Alder reaction2,4. 

Intramolecular acyl nitroso Diels-Alder reactions have been utilized as key steps in some elegant alkaloid total syntheses. Keck has prepared compound (104) (equation 40) which upon thermolysis gave an intermediate acyl nitroso species leading to adduct (105) as a mixture of epimers. This mixture was... 

Recently, Kibayashi s group (85JA5534) elegantly carried out the stereo-controlled total synthesis of gephyrotoxin (skin extracts of neopropical poison dart frog) based upon an intramolecular nitroso Diels-Alder reaction. The hydroxamic acid 365 was treated with tetrapropylammonium periodate... 

The methodology based on nitroso DieIs-alder reaction that proved useful in the synthesis of tropane alkaloids also seemed to open an attractive route to some other alkaloids. Compared to the intramolecular imino Diels-Alder reaction (ref. Ic) the intramolecular variant of the nitroso Diels-Alder reaction has received far less attention (refs. 6b 12), despite the enormous potential it holds for alkaloid synthesis. With this in mind we proceeded to examine the application of the intramolecular nitroso Diels-Alder cycloaddition in the synthesis of alkaloids possessing saturated nitrogen heterocyclic ring systems. 

A synthesis of the frog neurotoxin ( )-gephyrotoxin (124) uses the intramolecular Diels-Alder reaction of an acyl nitroso-compound, generated by situ periodate oxidation of the hydroxa-mic acid (121), to form the piperidine portion (122) of the molecule. After introduction of the propyl residue, reduction and protection to (123), the synthesis was completed by hydrogenation... 

The hetero-Diels-Alder reaction of steroidal dienes (156) with nitroso-aromatics are regioselective with two stereoisomers (157) and (158) produced in a 2 1 ratio (Scheme 60) The regio-, stereo-, and enantio-selectivity of 4 -I- 2-cycloadditions of nitrosoalkenes to alkenes have been extensively reviewed.The intramolecular acylnitroso Diels-Alder cycloaddition of (159) produced the bicyclic adducts (160) in high yields (Scheme 61). ... 

Finally, Kibayashi used aqueous versions of the intramolecular acyl-nitroso Diels-Alder reaction to good effect in his stereocontrolled syntheses of (-)-swainsonine (6.28) [78] and (-)-pumiliotoxin C (6.34) [79] (Schemes 1.13 and 1.14). In each case, oxazinolactam cycloadducts (cf. 6.32 and 6.38) served as key functional chiral building blocks for the remaining synthetic operations. For example, retrosynthetic analysis of the trihydroxy-indohzidine system of swainsonine (6.28) reveals that the pyrrolidine ring of this target can be formed by amine alkylation (cf. 6.29) while the vicinal diol can be installed via substrate-controlled cw-hydroxylation of a (Z)-allyl... 

SCHEME 41.39. Intramolecular nitroso Diels-Alder reaction. 

Having completed the intramolecular nitroso-Diels-Alder reaction, the shape of the bicyclic oxazinolactam 188 allowed for a diastereoselective successive addition of two nucleophiles (Scheme 41.40). The addition of methylmag-nesium bromide into 188 at 0°C because the carbonyl is activated by the N O bond, followed by sodium boro-hydride in acetic acid, delivers the cis-2,6 disubstituted piperidine precursor 190. The diastereoselectivity could be explained by the fact that the presence of the oxazino ring would force the C4a substituent of the N-alkoxypiperidi-nium unit 189 into a pseudoequatorial position, and the stereoelectronically axial attack of the hydride led diaster-eoselectively to the desired compound 190, which was eventually transformed into (-)-lepadin B 191. 

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