Bicyclic acetals synthesis

Francke W., Schroder F., Phillipp P., Meyer H., Sinnwell V. and Gries G. (1996b) Identification and synthesis of new bicyclic acetals from the mountain pine beetle, Dendroctonus ponderosae Hopkins (Coleoptera Scolytidae). Bioorg. Med. Chem. 4, 363-374. 

Acetals result from oxidative coupling of alcohols with electron-poor terminal olefins followed by a second, redox-neutral addition of alcohol [11-13]. Acrylonitrile (41) is converted to 3,3-dimethoxypropionitrile (42), an intermediate in the industrial synthesis of thiamin (vitamin Bl), by use of an alkyl nitrite oxidant [57]. A stereoselective acetalization was performed with methacrylates 43 to yield 44 with variable de [58]. Rare examples of intermolecular acetalization with nonactivated olefins are observed with chelating allyl and homoallyl amines and thioethers (45, give acetals 46) [46]. As opposed to intermolecular acetalizations, the intramolecular variety do not require activated olefins, but a suitable spatial relationship of hydroxy groups and the alkene[13]. Thus, Wacker oxidation of enediol 47 gave bicyclic acetal 48 as a precursor of a fluorinated analogue of the pheromone fron-talin[59]. 

Many natural compounds, such as dihydroclerodin [ 17] or aflatoxin B2 [ 18,19] contain bicyclic acetal units of type furo[2,3b]furan. The synthesis of perhydrofuro[2,3fo]furans and perhydrofuro[2,3fo]pyrans was achieved by... 

In a synthesis of the immunosuppressant Sanglifehrin A, two hydroxyl groups and a ketone were mutually protected as an acetal [Scheme 1.33].60 The ketone was generated by a Wacker oxidation of the terminal alkene 33.1 whereupon it was immediately converted to the bicyclic acetal 33.2 on treatment with acid. The acetal 33.2 survived the many steps required to elaborate the complex intermediate 33.3 but its stability was to exact a price the synthesis languished on the cusp of completion until conditions were found to hydrolyse the acetal without insult to the remaining delicate functionality. Hie three functional groups were eventually reclaimed in a modest 33% yield by interrupting the hydrolysis at 50% completion. 

A recent application of the furan-carbonyl photocycloaddition involved the synthesis of the mycotoxin asteltoxin (147)." Scheme 16 shows the synthetic procedure that began with the photoaddition of 3,4-dimethylfuran and p-benzyloxypropanal to furnish photoaldol (148), which was epoxidized with MCPBA to afford the functionalized product (149) in 50% overall yield. Hydrolysis (THF, 3N HCl) provided the monocyclic hemiacetal which was protected as its hydrazone (150). Chelation-controlled addition of ethylmagnesium bromide to the latent a-hydroxy aldehyde (150) and acetonide formation produced compound (151), which was transformed through routine operations to aldehyde (152). Chelation-controlled addition of the lithium salt of pentadienyl sulfoxide (153) followed by double 2,3-sigma-tropic rearrangement provided (154) as a 3 1 mixture of isomers (Scheme 17). Acid-catalyzed cyclization of (154) (CSA/CH2CI2) gave the bicyclic acetal (155), which was transformed in several steps to ( )-asteltoxin (147). ... 

Exo- and endo-cyclic ring closure reactions using 0-nucleophiles transform oxocarbenium ions into cyclic acetals. As an example of an endocyclic cyclization, epoxide ring opening of (96) with lithium dimethyl cuprate, and subsequent treatment of the resulting alcohol with acid, smoothly gives the bicyclic acetal (97), ° a key intermediate in the total synthesis of tirandamycic acid (Scheme 47). ... 

An ingenious application of the acetal forming reaction is the synthesis of brevico-min (14)9 Carbonylation reaction of 1,3-butadiene catalyzed by Pd(OAc)2 and PPh3 produces 3,8-nonadienoate (11) which is converted to 1,6-nonadiene (12). The internal double bond is oxidized selectively with peracid and then converted to the olefinic diol 13. The oxidation of the terminal double bond with PdCl2/CuCl2 results in intramolecular attack of the 1,2-diol at the double bond to form the bicyclic acetal system of brevicomin (14) in 45% yield (Scheme 7). 

Intramolecular heterocyclization in polyacrylonitrile 86UK62. a-Isocyano acetates, synthesis of N-heterocycles from 85YGK764. Isonitrosotosyl malonates in synthesis of N-heterocycles 80H(14)1581. Lactams, regioselective formation from bridged bicyclic ketones 81T1283. Malononitrile derivatives, synthesis of N-heterocycles condensed from ... 

Synthesis and Polymerization of Atom-Bridged Bicyclic Acetals and Ortho Esters... 

A review of the synthesis and polymerization of bicyclic acetals and orthoesters Is presented, and the relationship between ring structure and the ability to polymerize Is discussed. The highly labile bicyclic acetals and orthoesters were synthesized at high tenr-perature In dloctyl phthalate under vacuum In order to remove the monomers as soon as they form. The ability of the bicyclic monomers to polymerize falls In the same sequence as the ring strain [2.2.1] > [2.2.2] >... 

This review summarizes all the data we obtained on the synthesis and cationic ring-opening polymerization of bicyclic acetals and orthoesters, and discusses the relationship between ring-strain and poly-merlzablllty. This ties In with earlier work on the polymerlzabll-Ity of monocyclic and bicyclic lactams ( - ). A new mechanism for the propagation step In the polymerization of bicyclic orthoesters Is supported. 

A more complex example with stereochemistry comes from Schreiber s asteltoxin synthesis.16 Hydroboration of the bicyclic acetal 96 with borane itself occurs on the underside of the folded bicyclic molecule to give 97. But this is not the end of the story. The product of the hydroboration is the THF 98. 

A library of resin bound furans 294-296 with diverse appendages were prepared and oxidized. Those furans with appended diols gave bicyclic acetals 297, those with a single alcohols the hydropyrones 298 that underwent dehydration and those without a hydroxyl gave the open-chain compounds, thus generating three structural types from a common intermediate. This last diversity-oreiented example nicely illustrates the synthetic flexibility and power offered by the use of furans. It is certain that the role of furan in complex-molecule synthesis will continue to expand in many new directions. 

The understanding of the stereochemistry of bicyclic acetal polymerization has recently been advanced by the synthesis of optically active DBO enantiomers by the following procedure 41 A2) ... 

Conformationally defined bicyclic acetal template and readily differentiated hydroxyl in the 2,7-anhydro sugar analogue 241 makes this synthesis flexible enough for preparation various KDN derivatives. 

Azadirachtin (618), a terpenoid with strong antifeedant activity, possesses a unique bicyclic acetal subunit. Retrosynthetic analysis indicates that the intermediate 619 would be a suitable candidate for use in a convergent synthesis of the natural product. 

A convenient synthesis of (— )- xo-brevicomin (87) utilizes a radical chain reaction of methyl vinyl ketone with (45, 5R)-4-benzyloxymethyl-5-iodomethyl-2,2-dimethyl-l,3-dioxo-lane (209), prepared by treating the (R,R)-tartaric acid derivative 141 with triphenylpho-sphonium iodide in the presence of imidazole. Adduct 215, after acidic hydrolysis of the isopropylidene protecting group, furnishes the bicyclic acetal 216. Subsequent debenzylation and tosylation followed by methylation with lithium dimethylcuprate provides 87 in an overall yield of 17% from (R,R)-tartaric acid. The optical purity of 87 corresponds to greater than 99% ee (Scheme 50). Carrying out a similar series of transformations with ( S,5)-tartaric acid leads to ( + )-exo-brevicomin (90) [78]. 

When the methodology of stereoselective synthesis was still in its infancy, it was considered advantageous to utilize sequences of stereogenic centers available from enantiomerically pure natural products as building blocks [3, 4] this so-called chiral pool synthesis strategy is exemplified in Scheme 4.2. The bicyclic acetal structure of exo-brevicomin (31) can be ret-rosynthetically linked to the chiral ketodiol 32, which can be derived from (S,S)-(-)-tartaric acid, a readily available chiral starting material. This leads to the building block oriented bond-set depicted in intermediate 32. 

Keywords Marine natural products Spiroacetals Bicyclic acetals Total synthesis... 

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