Oximes nitrile oxide intramolecular cycloadditions

Intramolecular nitrile oxide—olefin cycloaddition of oxazolidine and thiazoli-dine oximes 407 (R = H, Me R1 =H, Me X = 0, S n = 1,2) proceed stereose-lectively, yielding tricyclic fused pyrrolidines and piperidines. Thus, 407 (n =2 R = H R1 =Me X=S) has been oxidized to the nitrile oxides with sodium hypochlorite, in the presence of triethylamine in methylene chloride, to give the isoxazolothiazolopyridine 408 in 68% yield. Reduction of 408 with lithium aluminum hydride affords mercaptomethylmethylpiperidine 409 in 24% yield (448). 

A total synthesis of the sesquiterpene ( )-illudin C 420 has been described. The tricyclic ring system of the natural product is readily quickly assembled from cyclopropane and cyclopentene precursors via a novel oxime dianion coupling reaction and a subsequent intramolecular nitrile oxide—olefin cycloaddition (463). 

Conversion of the oximes (635) to nitrile oxides (636) by treatment with chloramine-T led to an intramolecular nitrile oxide-alkene cycloaddition and formation of the derivatives (637) (Scheme... 

Keywords Intramolecular 1,3-dipolar cycloadditions. Stereoselectivity, Nitrile oxides, SUyl nitronates. Oximes, H-Nitrones, Azides, NitrUimines... 

The reaction of the a-bromo aldoxime 52e (R = R = Me) with unsaturated alcohols has been extended to the heterocyclic systems furfuryl alcohols and 2-thiophene methanol [29b]. The furanyl and thiophenyl oximes 63a-c were treated with NaOCl and the resulting heterocyclic nitrile oxides were found to undergo spontaneous intramolecular dipolar cycloaddition to produce the unsaturated tricyclic isoxazolines 64a-c in high yield (Eq. 5). In these cases, the heterocyclic ring acts as the dipolarophile with one of the double bonds adding to the nitrile oxide [30]. 

Intramolecular nitrone cycloadditions often require higher temperatures as nitrones react more sluggishly with alkenes than do nitrile oxides and the products contain a substituent on nitrogen which may not be desirable. Conspicuously absent among various nitrones employed earlier have been NH nitrones, which are tautomers of the more stable oximes. However, Grigg et al. [58 a] and Padwa and Norman [58b] have demonstrated that under certain conditions oximes can undergo addition to electron deficient olefins as Michael acceptors, followed by cycloadditions to multiple bonds. We found that intramolecular oxime-olefin cycloaddition (lOOC) can occur thermally via an H-nitrone and lead to stereospecific introduction of two or more stereocenters. This is an excellent procedure for the stereoselective introduction of amino alcohol functionality via N-0 bond cleavage. 

Oxidation of oxime 422 with aqueous sodium hypochlorite has been used to synthesize the central piperidine ring of the tricyclic system 423 in moderate yield, which presumably proceeds via an intramolecular 1,3-diploar cycloaddition of the intermediate nitrile oxide (Equation 114) <2000EJ0645>. 

Dihydro- and tetrahydrofuroisoxazoline rings were constructed by intramolecular cycloaddition of nitrile oxides or nitrones, generated from oximes . Thus, oxime 30 and sodium hypochlorite afforded furoisoxazolines 31 (equation 14). Similarly, furanyl or thienyl oximes 32 in the presence of NaOCl afforded tricyclic products 33 in 35-90% yields (equation 15). Nitrostyrenes (ArCH=CHN02) and various nucleophiles (for example, allyl mercaptan) also generated hydroximoyl chlorides which underwent similar cycloaddition leading to bicycUc tetrahydrothiophene and tetrahydrofuran derivatives ... 

Novel polycyclic heterocyclic systems including the isoxazoline ring were described. Thus, oximes 191 and 193 in the presence of sodium hypochlorite afforded heterocycles 192 or 194, respectively (equations 83 and 84). Intramolecular cycloaddition of nitrile oxide was used in the synthesis of the A-ring fragments of la,25-dihydrovitamin D3 and taxane diterpenoids, sulphur-containing isoxazoles, fluoro-substituted aminocyclopentanols and aminocyclopentitols . New gem- and vic-disubstituted effects in such cyclization reactions have been reviewed by Jung. ... 

A previous review has highlighted the following methods of ring synthesis intramolecular cyclization of oximes, nitro alkenes, and nitrones, and [4+2] cycloaddition reactions <1996CHEC-II(6)279>. In addition to that, this review includes the intramolecular cyclization of hydroxylamines, hydroxamates, hetero-Diels-Alder [4+2], 1,3-dipolar cycloaddition of nitrile oxides to alkenes, and [3+3] cycloaddition reactions. This review does not cover cycloaddition reactions of the [4+2] [3+2] and [4+2] [3+2] [3+2] types which primarily led to heterocycle-fused oxazine ring systems. 

The most widely used, and often most convenient reagents for such one-pot reactions are sodium hypochlorite (45) or hypobromite (16). These reactions are performed in the presence of an organic base (generally triethylamine) that normally enhances the yield of cycloaddition products (45). This method was employed for many intermolecular reactions (71) and also seems especially suited for intramolecular ones (72-77) as well as for the solid-phase synthesis (78) of 2-isoxazolines. Hypohalite can also be replaced by sodium broruite in combination with a catalytic amount of tri-u-butyltin chloride (79). In a related method, O-tributylstannyl oximes were treated with tert-butyl hypochlorite to produce nitrile oxides that were trapped with aUcenes or alkynes to afford the corresponding isoxazolines or isoxazoles in moderate to good yield (80). 

In later work, Mioskowski and co-workers (320) used cyclohexenone 160 to prepare oxime 161 as part of a twofold nitrile oxide strategy to synthesize the basic taxol ring system. Cycloaddition of 161 was effected by means of sodium hypochlorite and gave tricyclic isoxazoline 162, which feamres rings A and C of taxol (320) (Scheme 6.79). Nagaoka and co-worker tried to apply a related intramolecular cycloaddition toward the synthesis of the taxane A/B ring but this approach failed, producing only the oxime derivative (248) (see Scheme 6.44, Section 6.3.1). 

An intramolecular nitrile oxide cycloaddition also served as the key step in the stereoselective assemblage of the skeleton of angular triquinane sesquiterpenes of the isocomene series. Tetracyclic isoxazoline 203 was obtained from oxime 202 [derived from tetrahydroindandione 201] and on treatment with sodium hypochlorite... 

Intramolecular cycloaddition of the nitrile oxide intermediate generated from the unsaturated oxime 221 was used for an evenmal synthesis of la,2p,25-trihydroxy-vitamin D3 (262) (Scheme 6.90). Oxime 221, prepared from tri-O-isopropyhdene-d-mannitol (220), was processed as usual to give isoxazoline 222 in good yield and with excellent stereoselectivity. Conversion of 222 to the aldol 223 proceeded in the normal manner and further elaboration gave the desired diene intermediate 224 (262). 

The sesquiterpene skeleton has also been assembled by the intramolecular nitrile oxide cycloaddition sequence. Oxime 238 (obtained from epoxy silyl ether 237), on treatment with sodium hypochlorite gave isoxazoline 239, which was sequentially hydrolyzed and then subjected to the reductive hydrolysis conditions-cyclization sequence to give the furan derivative 240 (330) (Scheme 6.93). In three additional steps, compound 240 was converted to 241. This structure contains the C11-C21 segment of the furanoterpene ent-242, that could be obtained after several more steps (330). 

A stereoselective synthesis of testosterone (261) was advanced by Fukumoto and co-workers (331), where ring B was joined to the C/D part by an intramolecular nitrile oxide cycloaddition. The key nitrile oxide dipole was generated in situ from oxime 258, which in turn was derived from the optically active tetrahydroin-danone 257. Tetracyclic isoxazoline (259) was obtained as a single stereoisomer... 

Further examples of intramolecular 1,3-dipolar cycloadditions (cf. Section 10.21.9.2.2(ii)) include the synthesis of an isoxazolidine from nitrone 193 (Equation 128) <1997J(P1)1805>, and a pyrazolo heterocycle from the nitrile oxide generated in situ from the oxime 194 (Equation 129) <1999TL3535>. 

N. P. Peet, E. W. Huber, and R. A. Farr, Diastereoselectivity in the intramolecular nitrone, oxime, and nitrile oxide cycloaddition reactions, Tetrahedron 47 7537 (1991). 

Cyclization of nitrile oxides with a four-atom intervening chain to the alkene always leads to 5,6-fused bicylic isoxazolines possessing a bridgehead C—N double bond. This is in contrast to nitrone cycliza-tions where competition to form bridged bicyclic isoxazolidines is observed. The alkenyl oximes (73) and (74) cyclize in typical fashion via nitrile oxide intermediates (Scheme 21).33a>36 The stereochemistry of cyclization here was studied both experimentally and by calculation. The higher stereoselectivity observed with the (Z)-alkene is typical. (Z)-Alkenes cycloadd much slower than ( >alkenes in intermole-cular reactions this is attributed to greater crowding in the transition state. Thus, intramolecular cycloaddition of (Z)-alkenes depends on a transition state that is heavily controlled by steric factors. 

Nitrile oxide 75, generated in situ from oxime 74, gives intramolecular 1,3-dipolar cycloaddition affording a mixture of inseparable oxocane 76 and oxonane 77 in a ratio of 1 1.4 (Scheme 11). Hydrogenation of these isoxazolines with Raney nickel leads to keto alcohols 78 and 79, which can be separated by chromatography <2006SL1205>. 

Modifying the aldehyde function in the pyrroles 1162 into 1,3-dipoles 1163 (nitrone) and 1167 (nitrile oxide) furnished tricyclic heterocycles 1164 and 1168 via intramolecular 1,3-dipolar cycloaddition reactions (Scheme 226) <2000T3013>. None of the isomeric bridged product 1165 is produced despite the preference for that regiochem-istry in the intermolecular reaction. Generated in situ (from the oximes 1166) nitrile oxides 1167 cyclized spontaneously to the dihydroisooxazole 1168 in quantitative yield at room temperature. 

Macrocyclization of an unsaturated nitrile oxide (10, 309).1 Reaction of the co-nitroalkene 1 with p-chlorophenyl isocyanate results in a nitrile oxide intermediate that undergoes an intramolecular [3 + 2] cycloaddition to give 2. The yield is considerably higher than that obtained by oxidation of the corresponding unsaturated oxime. The product is converted in several steps to the may tans inoid 3. 

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