Biotin nitrile oxide intramolecular cycloadditions

As was mentioned earlier, furoxans are often encountered as unwanted byproducts in nitrile oxide cycloadditions. There are, however, some efforts to exploit this facile C C forming dimerization for synthesis. In one case, an intramolecular hw(nitrile oxide) cycloaddition was used for a synthesis of biotin (322a). More recently, the intramolecular dimerization was employed for the construction of medium- and large-size rings. This was feasible if one of the two nitrile oxide functionahties was relatively hindered and stable (see Section 6.1.4). Unsymmetrical... 

Few examples of total syntheses have been reported that involve an intramolecular nitrile oxide cycloaddition and ensuing reduction to an aminoalcohol. The very first example was reported by Confalone et al. (334) and involved a synthesis of the naturally occurring vitamin biotin (287). The nitro precursor 284 was easily prepared from cycloheptene. When treated with phenyl isocyanate-triethylamine, cycloaddition led to the all-cis-fused tricyclic isoxazoline 285 with high stereoselectivity (Scheme 6.102). Reduction with LiAlFLj afforded aminoalcohol 286 as a... 

Nitrile oxide J -I- 2 cycloaddition.1 A key step in a recent stereospecific synthesis of biotin (6) from cycloheptene (1) is an intramolecular [3 + 2]cyclo-addition of a nitrile oxide (a), obtained by dehydration of a primary nitro compound (3), preferably with phenyl isocyanate. This cycloaddilion is more efficient than the well-known olefinic nitrone cycloaddition. The carbon atoms in 6 derived from cycloheptene are marked with asterisks. 

An isoxazoline intermediate generated by the intramolecular [3 + 2] dipolar cycloaddition reaction of a nitrile oxide has served as a valuable intermediate in the preparation of biotin... 

The application of intramolecular dipolar cycloaddition reactions to the synthesis of complex natural products has recently come to be recognized as a very powerful synthetic tool, one equally akin to the intramolecular Diels-Alder reaction in its potential scope of application.69 This is particularly the case with nitrile oxides and the 1NOC reaction has been extensively utilized in total synthesis.70 The intramolecular nitrile oxide cycloaddition (INOC) generally displays exceptional regio- and stereo-chemical control which undoubtedly accounts for the popularity of this reaction. Internal cycloadditions of nitrile oxides have been found to offer a powerful solution to many problems in complex natural product synthesis.48 For example, Confalone and coworkers have utilized the INOC reaction for the stereospecific synthesis of the key amino alcohol (60), which was converted in five subsequent steps to ( )-biotin (61 Scheme 14).71... 

We shall end this section with a beautiful illustration of an intramolecular 1,3-dipolar cycloaddition of a nitrile oxide that was used in the synthesis ofthe vitamin biotin. Starting at the beginning of the synthesis will allow you to revise some reactions from earlier chapters. The starting material is a simple cyclic allylic bromide that undergoes an efficient 5 2 reaction with a sulfur nucleophile. In fact, we don t know (or care ) whether this is an 5 2 or S 2 reaction as the product of both reactions is the same. This sort of chemistry was discussed in Chapter 23 if you need to check up on it. Notice that it is the sulfur atom that does the attack—it is the soft end of the nucleophile and better at Sn2 reactions. The next step is the hydrolysis ofthe ester group to reveal the thiolate anion. 

Nitrile oxides are considerably more reactive than nitrones, and nitrile oxide dimerization is a prominent side reaction that can effectively compete with dipolar cycloaddition. To overcome this obstacle, nitrile oxides are typically generated in situ under conditions that lead to their participation in 1,3-dipolar cycloaddition reactions. The resulting isoxazolines constitute a versatile class of heterocycles, which are amenable to extensive manipulation. Confalone s synthesis of biotin (16) includes clever use of an intramolecular nitrile oxide cycloaddition reaction [46] that sei-ves to install the requisite relative configuration as well as the necessary side chain (Scheme 18.4) [47]. 

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