No 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...

J. Am. Chem. SOC.SnCI, (0.1 mL, 0.9 mmol) to give, after purification by flash chromatography (1:2 EtOAc-hexane), 249 mg (58%) of the tetrahydrofuran (2S)-2Se, which was contaminated to the extent of 10% by the acetyl epimer. This mixture was used without further purification in the following reaction. (-)-(2S,3R ,SS)-l-[Tetrahydro-2-methyl-5-(bydroxymethyl)-3furanyllethnnone ((-)-33).A solution of KOH (183 mg, 3.26 mmol). a 569-mg (2.17-mmol) sample of the optically active mixture of 3acetyltetrahydrofurans described in the previous procedure, and MeOH ( 5 mL) was maintained at 23 OC for 3 h. Saturated aqueous NH4Cl (20 mL) was then added, and the mixture was concentrated to remove MeOH. The resulting aqueous suspension was saturated with NaCl and extracted with CH2Cl2 (5 X 20 mL). The combined CH2C12 extracts were dried (NaIS04) and concentrated. The residue was purified by flash chromatography (150 MeOH-CH2CI2) to provide 210 mg (61%) of the tetrahydrofuran (-)-33 (95% pure by IH NMR analysis) as a colorless oil: [a]D-21.1 (c 1.1, MeOH); 'H NMR (500 MHz, CDCI,) 6 4.1 1-4.08 (m, 2 H, 2 CH), 3.77-3.74 (m, I H, CH320H), 3.53-3.51 (m, 1 H, CHIOH), 2.79 (ddd, J = 7.5, 2.3, 5.3 Hz, H(3)), 2.20 (s, 3 H, CH'CO), 2.21-2.00 (m, 2 H, CHI), 1.92 (br s, 1 H, OH), 1.34 (d, J = 58.8, 31.2, 30.1, 20.5; IR (film) 3411, 2875, 1708, 1702, 1096. 1040cm-I; MS (CI) m/r 159.1040 (159.1021 calcd for C8Hl4O3, MH). (-)-2,5-Anhydro-l,4-dideoxy-~-dbo-hexitol ((-)-34). A mixture of the ketone (-)-33 (73 mg, 0.46 mmol), 3.4-dinitroperoxybenzoic acid (630 mg, 2.77 mmol), 2.0 mg of tert-butyl 4-hydroxy-5-methylphenyl sulfide, and CHIClz (IO mL) was heated at reflux for 3 h. The mixture was then poured into saturated aqueous Na2S0, (20 mL) and extracted with CHIC12 (20 mL). The CHICIz extract was washed with saturated aqueous NaHCO, (20 mL), dried (Na2S04), and concentrated. The residue was purified by flash chromatography (1:l EtOAc-hexane) to provide 51 mg (64%) of the 3-acetate (95% pure by 'H NMR analysis) as a colorless oil: [ a ] D -I 1.8 (c 1.6, CHCI,); cm-I; MS (CI) m/r 175.0969 (175.0970 calcd for CBHII04. MH). 6.1 Hz, CH3); "C NMR (125 MHz, CDCI,) 6 208.0, 78.77, 77.6, 64.5, 1991, 113, 5365-5378 5365Sodium metal (7 mg, 0.3 mmol) dissolved in MeOH (1 mL) was added to a solution of a 36.0-mg (0.21-mmol) sample of the 3-acetate and MeOH (3 mL), and the resultant solution was maintained at 23 OC for 30 min. The solution was then poured into saturated aqueous NHICl (20 mL), and the mixture was concentrated to remove MeOH. The resulting aqueous suspension was saturated with NaCl and extracted with CH2Cl2 (3 X 10 mL). The combined CH2C12 extracts were dried (Na2S04) and concentrated, and the residue was purified by flash chromatography (EtOAc) to provide 26 mg (97%) of the diol (-)-34 (90% pure by 'H NMR) as a colorless oil: [ a ] D -17.2 (c 1.29, EtOAc) (lit.32 [ a ] D -16.9 (c 1.14, EtOAc)); 'H NMR (300 MHz, CD30D) 6 4.20-4.09 (m, 1 H, H(5)), 3.92-3.88 (m, 1 H), 3.84-3.76 (m, 1 H), 3.58 (dd, J = 11.6, 3.9 Hz, 1 H, H(6)), 3.49 (dd, J = ...

Ring-Enlarging Furan Annulations Summary: Substituted cycloheptatetrahydrofurans and octahydrobenzofurans are formed with high levels of stereocontrol by acid-promoted rearrangement of acetals derived from l-alkenyl-2-hydroxycyclohexanols and 1alkenyl-2-hydroxycyclopentanols, respectively. In some cases, these bicyclics can be prepared by the direct reaction of an allylic diol precursor and an aldehyde.Sir: We have reported that stereochemically complex tetrahydrofurans can be prepared in useful yields by acid-catalyzed rearrangement of allylic acetals.2 In order to extend this new tetrahydrofuran synthesis to more complex ring systems, we recently investigated the related rearrangement of cyclic allylic diols and acetals. Our expectation was that rearrangement in cyclic systems would result in an unusual annulation reaction in which elaboration of a new tetrahydrofuran ring would be coupled with a one-carbon ring-enlargement of the starting carbocyclie ring (see eq 1). Conceptually related "ring-enlarging" pyrrolidine annulation reactions had been developed earlier in our laboratories for the synthesis of pyrrolidine-containing heterocycles and complex alkaloids.3 In this paper, we report that a variety of substituted cis-fused octahydrobenzofurans 3 ( = 1) and cycloheptatetrahydrofuans 3 ( = 2) can be prepared in a steréocontrolled fashion as outline in eq 1.In order to investigate the rearrangement in both stereochemical series, the cis and trans allylic diols 4 (35%) and 5 (34%) were prepared (CH2-CHMgBr, 25 °C, THF)

It is hypothesized that buffers capable of forming a Schiff base with the PLP of gamma-aminobutyric acid aminotransferase (GABA-AT) may lead to denaturation and inactivation of the enzyme. On the basis of this hypothesis three new methods for the selective destruction of GABA-AT in GABAse (a commercial bacterial source of a mixture of GABA-AT and succinic semialdehyde dehydrogenase [SSDH]) and from pig brain are described: (1) dialysis against a primary or secondary amine buffer; (2) gel filtration with a primary or secondary amine buffer as eluent; (3) inactivation with gabaculine followed by dialysis or gel filtration with pyrophosphate buffer. The SSDH activity in GABAse, which remains unchanged by all of these methods, may then be used in a coupled assay to measure the activity of GABA-AT from different sources. These results also suggest that the use of primary and secondary amine buffers should be avoided when inhibitors are being tested with GABA-AT.