Isochromane, oxidation

Nanaomycin A 103 and deoxyfrenolicin 108 are members of a group of naphthoquinone antibiotics based on the isochroman skeleton. The therapeutic potential of these natural products has attracted considerable attention, and different approaches towards their synthesis have been reported [65,66]. The key step in the total synthesis of racemic nanaomycin A 103 is the chemo-and regioselective benzannulation reaction of carbene complex 101 and allylacety-lene 100 to give allyl-substituted naphthoquinone 102 after oxidative workup in 52% yield [65] (Scheme 47). The allyl functionality is crucial for a subsequent intramolecular alkoxycarbonylation to build up the isochroman structure. However, modest yields and the long sequence required to introduce the... 

Shah et al. (1994) have studied the preparation of a class of compounds called Indans, by cross-dimerization of AMS with amylenes, using an ion-exchange resin and acid-treated clay catalysts (Eqns. (12) and (13)). Indans can be subsequently converted, e.g. by acetylation, into perfumric compounds having mu.sk odour. For example, 1,1,2,3,3-pentamethylindan, the product obtained by cross-dimerization of AMS and wo-amylene (Eqn. (12)), can be reacted with propylene oxide and /7 ra-formaldehyde to give an indan type isochroman musk compound, 6-oxa-l,l,2,3,3,8-hexamethyl-2,3,5,6,7,8-hexahydro-lH-benz(f)-indene, sold as Galaxolide commercially. 

Irradiation in air of the deoxycholic acid (DCA, 157) complex of indanone leads to oxidation of both the steroid and the guest, yielding 5- 3-hydroxy-DCA, 158, and optically active 3-hydroxyindanone (241). In the presence of air, irradiation of the DCA clathrates of isochromane, 159, and indene, 161, leads to reaction with oxidation of the host and of the allylic position of the guest to a keto group (e.g., 159 — 160 and 161 — 162).The detailed mechanisms of these oxidations remain to be elucidated. 

Oxidation of dihydroisocoumarins is conveniently achieved through bromination with NBS followed by dehydrohalogenation with triethylamine (62JOC4337, 71T6171). Since the oxidation of isochromans to isochromanones proceeds readily using chromium trioxide, this method effectively constitutes a synthesis of isocoumarins from isochromans. 

A similar approach has been used to synthesize isochroman-3-ones (80JA4193). o-Bromomethylbenzyl alcohol oxidatively adds to the zerovalent complex and carbonylation and reductive elimination of the catalyst follow. The catalyst is kept active by the presence of base which absorbs the hydrogen bromide formed in the reaction. 

The Baeyer-Villiger oxidation of indan-2-one gives isochroman-3-one in good yield (49JCS1720). 

The direct oxidation of 2-(2-hydroxymethylphenyl)ethan-l-ols to isochroman-l-ones may proceed via the isochroman (61TL223). 

A Friedel-Crafts type alkylation of 1,1,2,3,3-pentamethylindane with (R)- or (.S )-ructhylcpoxide followed by acid-catalyzed condensation of the resulting alcohols with paraformaldehyde affords two diastereomeric pairs of isochro-mans 586, 587 (Scheme 127) <1999HCA1656>. Separation of the enantiomers of (4.S, 7/ /.S )-isochromans 586 is achieved by flash chromatography of their corresponding tricarbonylchromium complexes and subsequent oxidative demetallation the result of this synthetic work establishes that (4,y,71J)-isochroman is found to be responsible for the intense musk odour of the perfume galaxolide (Scheme 127) <1999HCA1656>. 

A variety of oxidative conditions can be used to effect the transformation of isochromans to dihydroisocoumarins (Equation 447). 

Oxidation of isochroman-4-ols to the corresponding isochroman-4-ones is observed during the syntheses of 4-hydro-xybenzo[c]pyran quinones <1997TL5055>, benzo[g]isochromanols <2001T9623>, and model studies towards the stephaoxocanes <2003EJ04731>. 

The first synthesis of the tetracyclic integrastatin nucleus involves a benzylic oxidation of a bridged isochroman using PDC in the presence of /-butylhydroperoxide (TBHP) <20030L4441, 20050BC756>. 

Oxidation of the chroman 1203 bearing a fused tetrahydrofuran moiety leads to the isochroman-4-one 1205 via oxidation of the quinoid-like intermediate 1204. This diketone is observed as an unwanted side-product during enantiospecific syntheses of monocerin analogues (Scheme 295) <1996T8535>. 

Isochromane-3-oae. lsochromane-3-one (2) can be prepared in 68 % yield (pure) by Baeyer-Villigcr oxidation of indane-2-one (1) with 90% hydrogen peroxide, sulfuric... 

Isochroman-5,8-diones (300) were prepared by oxidation of 5,8-dimethoxy-isochromans with AgO and nitric acid (82SC279). This system is present as a structural moiety in some natural quinones, such as eleutherin (51HCA561), kalafungin (68MI1), nanaomycins (75MI2, 75MI3 76CC320), and other compounds. 

OxyfunctionaUzations. Al-Oxides, sulfoximines (from sulfimides), isocoumarins (from isochromans), 2-hydroxyflavanes (from flavanes) are readily prepared. 

Homophthalic anhydrides can be prepared by oxidation of isochroman-3-ones which in turn can be also obtained by organolithiation reactions, as mentioned earlier. 

Cumene is prepared on a large scale from benzene and propylene as an intermediate in the synthesis of acetone and phenol. This makes it an inexpensive and readily available starting material for the production of Galaxolide . Three further electrophilic addition reactions complete the synthesis. Firstly, isoamylene is added, to form pentamethylindane, to which propylene oxide is added. Finally, treatment with formaldehyde leads, via the hemiacetal, to the isochroman. 

Benzylic oxidation. This combination oxidizes substituted toluenes to the corresponding acids and diarylmethanes (including fluorene) into ketones at room temperature in MeCN. Benzyl ethers such as phthalan and isochroman are converted to phthalide and 3,4-dihydroisocoumarin in quantitative yield. 

The hydroperoxides are the primary products of oxidation of phthalane and isochromane [202,203,284,293]. Hydroperoxide is the main product of dioxan oxidation. The decomposition occurs according to... 

Reduced Isocoumarins.- Kigelin (143 R=H) is a natural di-hydroisocoumarin its methyl ether (143 R=Me) has been synthesized in two steps from another natural compound called elemicin (allylbenzene). Cyclization with mercury(II) acetate gave the 1-isochromanol which was oxidized to (143 R=Me) with pyridinium chlorochromate.153 Isomeric with dihydroisocoumarins are the isochroman-3-ones one such compound has been synthesized by the action of hot mineral acid on 2-methoxymethylbenzyl cyanides such... 

Benzylic oxidation. Dihydroisobenzofuran and isochroman are readily converted to the lactones. Solvent effects are manifested in the cleavage of styrenes, since EtOAc favors the formation of aldehydes, whereas in THF, the major products are the benzoic acids. 

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