Stereocontrolled preparation of tetrahydrofurans by acid-catalyzed rearrangement of allylic acetals

Abstract

Previous investigations in our laboratories have shown that acid-catalyzed rearrangements of 5-alkenyloxazolidines 1 (X = NR) and similar precursors can be profitably employed to prepare substituted pyrrolidines and complex alkaloids.1 In this communication we report that a related rearrangement of allylic acetals (eq 1, X = 0) allows highly substituted tetrahydrofurans to be readily assembled in a stereo-and enantioselective fashion. A key feature of this new tetrahydrofuran synthesis is the use of a carbon-carbon bond-forming reaction to establish the stereochemistry of the cyclic ether product. This approach differs markedly from most other syntheses of complex tetrahydrofurans which typically involve carbon-oxygen bond formatiom2The method can be illustrated by the reaction of acetoin (3hydroxy-2-butanone) with vinylmagnesium bromide (2.5 equiv, 25 "C, THF) to give a mixture of allylic diols (-1 : l ) that was subsequently converted (catalytic HCI, MgS04, 25 "C) to the benzylidene acetal 3a in 72% overall yield. Exposure of this mixture of stereoisomeric acetals to 1.1 equiv of SnCI, in CH2CI2 (-70 "C --10 "C, 2 h, quench at -70 "C with 5-10 equiv of Et3N) gave tetrahydrofuran 4a3s4 in 58% yield after rapid pu-CH, (21 R'CHO "Jct-.. C H I 0 (1) CH2CHMgBi a R =CH, R5 =PI. 4 5rification on silica gel. The stereostructure of 4a followed from its rapid epimerization in methanolic K O H (1 N, 25 "C) to Sa3 and from the strong N O E observed between the cis-methine hydrogens at C-2 and C-5 of both acetyl epimers. If the rearrangement of 3a was allowed to warm to room temperature before quenching with excess Et3N, the trans epimer 5a could be isolated directly in 85% yield. Allylic acetals derived from aliphatic aldehydes and aliphatic enals rearranged similarly under identical conditions: e.g., 3b -4b (73%), 3c -4c (70%).3s4 To obtain the all cis kinetic product it was again necessary to not allow the reaction mixture to warm above -10 "C prior to quenching at -70 "C with excess Et,N. In the case of 3b, the allylic diol stereoisomers were separated, and the derived acetaldehyde acetals were individually rearranged to afford, after epimerization of the acyl group, 5b as the sole tetrahydrofuran product (73% from the 4R*,5R* diastereomer, 82% from the 4R*,5S* dia~tereomer).~ The scope of this new tetrahydrofuran synthesis is illustrated further by the conversions summarized in eq 3 and 4. Ketals 6a6 and 6b rearranged cleanly in the presence of SnCI, (1 equiv, -78"Croom temperature) to give tetrahydrofurans 7a3 (77%) and7b3 (94%) as the only detectable cyclic products. When a ketal is employed as the rearrangement "initiator", the alkene must be more nucleophilic than a simple terminal vinyl group. For example, attempted rearrangement of 6c6 in the presence of a variety of acid catalysts resulted in predominant fragmentation to produce (E)-3-butyl-3-penten-2-one (vide infra). The stereospecific (>97%) conversions of acetals 8a and 8b to tetrahydrofurans 9a3and 9b3 (1 .O equiv of SnCI,, -78 "C -0 "C; 90% and 73% yields...

Automatic mapping of atoms across both simple and complex chemical reactions

“…The example in a , illustrates the consequences of applying reaction heuristic [s] (see Fig. 2) in various places of the same substrate 1 in the Prins-Pinacol rearrangement 39,52 . In the top row, the heuristic is properly applied to the substrate (the substructure of the substrate recognized by the heuristic is marked orange) producing intermediate 2, which is then correctly mapped into product 3 with overall score = 3.5 (3 for disconnecting bonds 5–11, 3-H, and 7-H plus 0.5 for using the heuristic).…”

Molecular rearrangements in the construction of complex molecules

“…In his initial studies, Mark Hopkins was able to show that this construction of tetrahydrofurans is viable, and, under properly chosen conditions, proceeds with high stereoselectivity 88. Many aspects of the scope and limitations of this synthesis of tetrahydrofurans were defined over the next decade by the efforts of a number of my former co-workers 89–92.…”

Tandem C–H oxidation/cyclization/rearrangement and its application to asymmetric syntheses of (−)-brussonol and (−)-przewalskine E

“…This approach involves simpler initiation and substrate preparation as well as milder reaction conditions than a similar acetal rearrangement under acidic conditions via alkoxy release reported by Overman's group 51 52 53 54 55 56 57 58 . Notably, we nearly always obtained the desired product with a benzoxa[3.2.1]octane framework as a single diastereomer ( Fig.…”