Acetoxy ether

A more general route to 4-acetoxy-l,3-dioxanes utilizes the reductive acylation of l,3-dioxane-4-ones [46] (Scheme 21). l,3-Dioxane-4-ones 126 are prepared from the corresponding -hydroxy carboxylic acids. Low temperature reduction with DIBALH generates a diisobutylaluminum hemiacetal (127) which undergoes acylation in situ with AC2O in the presence of pyridine and DMAP. This method allows for the preparation of a wide range of 4-acetoxy-l,3-dioxanes, without the problem of a-epimerization. This method also represents a general approach to acylic a-acetoxy ethers, which are themselves useful synthetic intermediates [47,48]. 

Treatment of the a-acetoxy ether 322 with trimethylsilyl bromide affords the axial 4-bromotetrahydropyran 323 (Equation 137). This axial selective Prins cyclization can also be conducted in the presence of acetyl bromide, but use of SnBr4 affords equatorial 4-bromotetrahydropyrans and hence the all ry -product <2004JA9904>. 

The enantioselective synthesis of the C(18)-C(25) segment of lasanolide A 324 can be achieved via an oxonia-Cope-Prins cascade cyclization of a-acetoxy ether 325. The in situ reduction of the oxocarbenium ion intermediate 326 with Bu3SnH prevents the formation of a tetrahydropyran 4-one side product (Scheme 81) <20050L1589>. 

Yamamoto and co-workers reported an exquisite approach to the CDEFG ring system of gambierol (a polycyclic ether natural product) via intramolecular allylation of an a-acetoxy ether followed by RCM <01 JA6702> (Scheme 48). 

Kadota, I., Ohno, A., Matsuda, K., and Yamamoto, Y. 2002. Convergent synthesis of polycyclic ethers via the intramolecular allylation of alpha-acetoxy ethers and subsequent ring-closing metathesis. Journal of the American Chemical Society 124, 3562-3566. 

PREPARATION OF a-ACETOXY ETHERS BY THE REDUCTIVE ACETYLATION OF ESTERS endo-l-BORNYLOXYETHYL... 

The a-acetoxy ether elutes with an Rj of 0.32 on Merck silica gel in 5% (v/v) ethyl ether in hexanes (product stains yellow-green in an acidic solution of p-anisaldehyde). 

On treatment with diethylaluminum trimethylsilylacetylide in the presence of BF3 OEt2, a-acetoxy ether 94 gave the rran5-l,3-dioxane 95 in good yield with excellent stereoselectivity, as reported by Rychonovsky and Dahanukar [91]. The trans alkyne adduct has the configuration expected from axial addition to a cyclic oxonium ion (Sch. 59). 

In the laboratory of R.D. Rychnovsky, the segment-coupling Prins cyciization was utilized for the total synthesis of (-)-centrolobine. This approach avoided the common side reactions, such as side-chain exchange and partial racemization by reversible 2-oxonia Cope rearrangement, associated with other Prins cyciization reactions. The substrate -acetoxy ether was subjected to SnBr4 in DCM, which brought about the formation of the all-equatorial tetrahydropyran in good yield. 

Dahanukar, V.H. and Rychnovsky, S.D., General synthesis of alpha-acetoxy ethers from esters by DIBALH reduction and acetylation, J. Org. Chem., 61, 8317, 1996. 

Kopecky, D.J. and Rychnovsky, S.D., Preparation of alpha-acetoxy ethers by the reductive acetylation of esters endo-l-bomyloxyethyl acetate, Org. Synth., 80, 177, 2003. 

Scheme 73 AUylation of a-acetoxy ethers to functionalize either side of the B ring fragment of leucascandrolide A [78, 79]...

Reductive acetylation/alkylation has also provided access to advanced bis-THP intermediates of the type 284 in several reported pursuits of leucascandrolide A (Scheme 74) [76, 117, 131]. These complex examples highlight the remarkable functional group tolerance of this reaction type. The elaborate a-acetoxy ethers 283 demonstrate that a number of protecting groups (benzyl, silyl derivatives, and esters) survive the reaction conditions. Unsaturated silyl enol ethers (i.e., 281 and 282) are effective nucleophiles and provide advanced intermediates like 284 in excellent yields and diastereoselectivities (80-90 %, dr > 25 1 for all cases). A similar strategy, coupled with ring-closing metathesis, was also used by Cossy and coworkers for this natural product (Scheme 60) [108]. 

The rapid and highly convergent assembly of the bis-THP fragment 287 in Evans and Andrews synthesis of leucascandrolide A relied on a reductive acetylation/ alkylation strategy (Scheme 75) [132]. Treatment of a-acetoxy ether 285 with... 

Scheme 74 Complex alkylations of a-acetoxy ethers employing silyl enol ether nucleophiles in the context of leucascandrolide A [76, 117, 131]...

Scheme 75 Convergent strategy to bis-THP fragment of leucascandrolide A through a-acetoxy ether alkylation/conjugate addition sequence [132]...

The A ring of the cytotoxic macrolide phorboxazole family of natural products has also proven to be accessible through a number of reductive acetylation/alkylation protocols (Scheme 76) [88, 91, 129]. These examples employ sUyl enol ethers and thioacetate nucleophiles 288a-288c and a-acetoxy ether derivatives 289 to access... 

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