Oxidative spirocyclization derivatives

The other key step in the synthetic approaches to FR901483 is the elaboration of the quaternary spirocenter at C(l) (Scheme 4). Sorensen, Ciufolini, and Wardrop all use an oxidative spirocyclization of nitrogen tethered phenol derivatives, employing hypervalent iodine reagents, to generate the spirocenter at C(l). In contrast, in the other approaches the formation of the quaternary stereocenter does not coincide with the... 

Asymmetric induction has also been achieved in the cyclization of aliphatic alcohol substrates where the catalyst derived from a spirocyclic ligand differentiates enantiotopic alcohols and alkenes (Equation (114)).416 The catalyst system derived from Pd(TFA)2 and (—)-sparteine has recently been reported for a similar cyclization process (Equation (115)).417 In contrast to the previous cases, molecular oxygen was used as the stoichiometric oxidant, thereby eliminating the reliance on other co-oxidants such as GuCl or/>-benzoquinone. Additional aerobic Wacker-type cyclizations have also been reported employing a Pd(n) system supported by A-heterocyclic carbene (NHC) ligands.401,418... 

Upon oxidation, a cyclization reaction using a 4-methoxyphenyl ring-derived substrate did not form any of the fused bicyclic product. Instead, a spirocyclic product was formed in direct analogy to the chemistry of Yamamura and Swenton (Scheme 37). In general, cyclization reactions having... 

The synthesis of various heterocyclic systems via 1,3-dipolar cycloaddition reactions of 1,3-oxazolium-5-oxides (32) with different dipolarophiles was reported. The cycloaddition reactions of mesoionic 5H,7H-thiazolo[3,4-c]oxazolium-l-oxides (32), which were prepared from in situ N-acyl-(/J)-thiazolidine-4-carboxyIic acids and N,N -dicyclohexylcarbodiimide, with imines, such as N-(phenylmethylene)aniline and N-(phenylmethylene)benzenesulfonamide, gave 7-thia-2,5-diazaspiro[3,4]octan-l-one derivatives (33) and lH,3H-imidazo[ 1,5-cJthiazole derivative (35). The nature of substituents on imines and on mesoionic compounds influenced the reaction. A spirocyclic p-lactam (33) may be derived from a two-step addition reaction. Alternatively, an imidazothiazole (35) may be obtained from a typical 1,3-dipolar cycloaddition via a tricyclic adduct (34) which loses carbon dioxide and benzenesulfinic acid. [95T9385]... 

The synthesis and characterization of a new 6-phosphoverdazyl radical incorporated into a spirocyclic framework containing a cyclotriphosphazane ring has been reported <02CJC1501>. Verdazyl-3-carboxylic acid (35) was prepared by condensation of carbonic acid bis(l-methylhydrazide) (33) with glyoxylic acid, to give tetrazine (34), and subsequent oxidation with benzoquinone. The coordination chemistry of this water-soluble verdazyl derivative was explored <02CC1688>. 

This was followed by two other alternative syntheses of racemic horsfiline, one based on an oxidative rearrangement of the tetrahydro-y-carboline derivative 62 (Scheme 4) and another involving a spirocyclization between the 2-oxo-5-melhoxytryptamine derivative 63 and formaldehyde (Scheme S) [61]. 

Alkylated prolines can be incorporated into synthetic peptides as mimics for the p-turn found in the conformation of folded proteins. One such compound9 combines a spirocyclic proline derivative 77 with tyrosine. The allyl group in 74 is oxidatively cleaved to give 75 and eventually coupled to the nitrogen atom of the amide in 76 by a Mitsunobu reaction. 

Pummerer-like cyclization reactions were utilized to prepare spirocyclic oxindole derivatives <04OL1869, 04OL2849>. For example, treatment of 2-sulfenylindole 215 with an iodonium reagent in the presence of 2,6-lutidine produced thioimidate 216. Oxidation of the latter with cerium ammonium nitrate (CAN) gave spirooxindole 217. 

The synthesis of the spirocyclic core [70-77] is obviously the most difficult task, the biomimetic approach being the most frequent way of preparing it. The strategy is based on the hipervalent iodine-mediated oxidative hydroxylation of a tyrosinal derivative followed by a cis-bisepoxidation. The shortest way [75] involved the introduction of the side chain as an amide of tyrosine ethyl ester. Aranorosin was obtained after DIBAL reduction to the aldehyde, oxidation to the dienone with phenyliodosyl bis(trifluoroacetate) (PIFA) and final epoxidation (Scheme 24). 

Thus, oxidation of oxazoline derivatives of phenolic compounds 33 with IBD in trifluoroethanol leads to spirocyclic amides 34 [26]. The low yield of compound 34b is attributable to the carbamate carbonyl of 33b competing effectively with the oxazoline nitrogen to capture the electrophilic intermediate obtained by activation of the phenol (Scheme 14). 

Oxidative cyclization of 2,3-dibenzyl-2-hydroxybutanes gives the expected lignans along with an unusual spirocyclization product which is thought to be derived from the cyclooctadiene product through oxidative formation of the bridging ether followed by a 1,2-aryl shift (eq 36). ... 

Several other groups have reported effective dioxirane systems employing Oxone as the terminal oxidant. For example, Armstrong et al. have developed a spirocyclic iV-carbethoxy-azabicyclo[3.2.1]octanone precatalyst, which affords up to 91.5% ee in the epoxidation of stilbenes (eq 102). Shing et al. have developed an arabinose-derived ketone and employed this in the enantioselective synthesis of the Taxol side chain however, enantioselectivities for the epoxidation were only up to 68% (eq 103). Bortolini et al. have also described the epoxidation of alkenes with the stoichiometric keto bile acid-Oxone system, a range of ee values were observed over several substrate types but up to 98% was observed for the epoxidation of tran -stilbene, although the yield was only 50% (eq 104). ... 

The difunctionality of NH2 moiety in the methylhydrazine derivatives has also been underlined by the reaction of (156) with trimethylorthobenzoate to afford the l-phospha-2,3,5,6-tetrazine derivative (163), which on oxidation with benzoquinone can be transformed to the radical species (164). EPR and ENDOR spectroscopic experiments clearly point to a spin polarization through the spirocyclic phosphorus atom to the other phosphorus and nitrogen nuclei in the phosphazene ring of (164). ... 

Several years later, Liu and coworkers reported another synthesis of cephalotaxine 172 that relied on a distinct [2,3]-Stevens rearrangement fScheme 1 S.4QL ° Proline derivative 173 was transformed into ammonium ylide 174 in the presence of allyl bromide and K2CO3. This zwitterion rearranged to a-allyl aminoester 175. Hydration of the olefin and reduction of the ester furnished diol 176, which was converted to aminoketone 177 via oxidation and aldol condensation. The assembly of this spirocyclic intermediate represented a formal synthesis of cephalotaxine 172. ... 

Naphthol derivatives with an acrylic pendant (251) undergo a conjugate addition of Grignard reagents, catalysed by Cu(I)-(254). The resulting magnesium enolate (252) can be oxidatively coupled in situ by copper(II) to afford spirocyclic cyclohexenones (253) in >20 1 dr and <94%... 

Tri- and tetra-peptide analogues incorporating an a-atnino acid at the anomeric position, e.g. 33, were synthesized by way of a novel oxidative ting contraction of 2-amino-2-deoxy-heptonic acid derivative 31 to give heptulosonic acid glycosylamine 32 and its anomer (Scheme 6). The spirocyclic diketopiperazine 35 was obtained from 34 it could be 0-deprotected under acidic conditions then anomerized to the thermodynamically favoured C-2 q>imer with strong base. See also reference 3 for a general route to anomeric a-amino acids. 

An improved conversion of isoxazoline derivative 36 into bis-spiroketal 37, a building block used by Fiirstner et al. in the total synthesis of the methyl ester of macrolide spirastreUolide A, was reported. In particular, Mo(MeCN)3(CO)3 was found to induce N—O bond cleavage at lower temperature than Mo(CO)6 (50 vs 90 °C) and the subsequent treatment of the crude mixture with trimethylamine Af-oxide allowed the isolation of a product free of metal contaminants. Next, simultaneous removal of silyl ethers and the cyanohydrin moiety with TASF afforded an intermediate trihydroxy diketone that smoothly underwent bis-spirocyclization in the presence of a catalytic amount ofPPTS (13CEJ3596). 

Intramolecular radical dearomatization has been examined as a route to spirocyclic ring systens. Spiro[4.5]decane derivatives have been obtained fi-om a tand radical addition process initiated by Mn(OAc)j (Scheme 15.9) [21]. Yields of spirocyclic products were highest when substituents on the intermediate cyclohexadienyl radical (e.g., OMe in 26) could promote subsequent oxidation to stable cyclohexadiene products via cation 27. Related ring systens have been prepared undo-... 

Arene oxidation leading to direct C—C bond formation allows rapid assembly of complex and ste-reochemically rich carbocyclic ring systems. Crucial to the success of this approach is the identification of carbon nucleophiles that are stable in the presence of oxidation agents typically used to effect arene dearomatization. Enolates and enol ethers are problematic as these species undergo rapid oxidation under mild conditions [62]. Stabilized enolates (such as those derived from activated methylenes) exhibit greater compatibility with oxidation conditions and have been used as nucleophilic participants in intramolecular oxidative dearomatizations initiated by [Fe(CN)g] and PIDA to afford spirocyclic cyclohexadienones [63, 64]. Detailed mechanisms for these reactions have not been defined so it is unclear whether bond formation occurs through ionic or radical intermediates. 

For example, a variety of natural products bearing spirocyclic systems exist, and many of them are biosynthetically formed by oxidative spiroannulation processes. Hypervalent iodine(III) reagents are thus considered as one of the most effective oxidants for these oxidation processes. Several efficient methods for PIFA-induced spiroannulation reactions of phenols [48, 49] towards the total synthesis of discorhabdin alkaloids [50, 51] and their oxa-analogues have been published [52, 53], which were accomplished via hypervalent iodine oxidation of phenols or (9-trimethylsilylated phenol derivatives to the azacarbocyclic spirodienones as a key step (Scheme 8). 

Some A -iodane derivatives are very useful oxidizing reagents in organic synthesis, e.g., 2-iodoxy-benzoic acid (IBX) and the Dess-Martin reagent (DMP) effectively convert primary and secondary alcohols to aldehydes and ketones, respectively [104]. Also directional preferences of short contacts observed in the sohd between electron rich sites and iodine of some A -iodane derivatives are nicely consistent with an asymmetric electron density distribution on iodine resulting in the presence of most positive regions on the covalent bonds extensions, and the preferential entrance of nucleophiles in these regions [105]. For instance, the o-hole model predicts that in the spirocyclic compound shown in Fig. 17, the electrostatic... 

---