Synthesis of 2,6-trans-disubstituted 5,6-dihydropyrans from (Z)-1,5-syn-endiols

Abstract

Certain (Z)-1,5-syn-diols 2 may be converted into 2,6-trans-5,6-dihydropyrans by using phosphonium salt 4 or phosphorane 5 as dehydrating agents. A more general four step procedure converts the (Z)-1,5-syn-endiols into enantiomeric dihydropyrans ent-3 via regioselective silylation of the allylic alcohol unit followed by mesylate formation and base-promoted nucleophilic displacement.Page 1 of (page number not for citation purposes) 6 FindingsWe recently reported a one-pot double allylboration reaction sequence which provides (Z)-1,5-syn-endiols from simple aldehyde starting materials with excellent diastereo-and enantioselectivity.[1] In connection with an ongoing natural product synthesis project, we were interested in developing methods to transform diols 2 into dihydropyrans 3 or the enantiomeric dihydropyrans ent-3 through complementary, regioselective cyclodehydration processes (Scheme 1).2,6-Disubstituted dihydropyrans are common structural elements of many biologically active natural products. [2,3] A number of methods have been developed to synthesize substituted dihydropyrans including: (i) hetero-Diels-Alder cycloadditions, [4][5][6][7] (ii) electrophile-initiated alkylation of glycals, [8][9][10][11] (iii) ring closing metathesis, [12,13] (iv) vinylsilane cyclization of oxocarbenium ions, [14] and (v) The challenge of synthesizing dihydropyrans 3 or ent-3 from 1,5-diols such as 2 lies in the differentiation of the two hydroxyl groups. Selective activation of the allylic alcohol in 2 as a leaving group followed by nucleophilic attack by the homoallylic alcohol will lead to dihydropyran 3. However, activation of the homoallylic alcohol followed by nucleophilic attack by the allylic alcohol will provide the enantiomeric dihydropyan ent-3. Cyclic ethers of various ring size have been synthesized by the cyclodehydration of diols through the use of oxyphosphonium salts and phosphorane reagents. [18][19][20][21][22][23] We reasoned that because the rate determining step of these cyclizations is believed to be the nucleophilic substitution step, selective formation of 3 should be possible owing to the superior leaving group ability of the activated allylic hydroxyl. [21] Diol 2a (R 1 = R 2 = CH 2 CH 2 Ph) was used initially in the development of a suitable cyclodehydration protocol (Figure 1). Because the R 1 and R 2 substituents of 2a are identical, steric effects on the activation of the two hydroxyl groups are eliminated. Therefore, the enantioselectivity of the ring closing step will depend only on the relative rates of the competing cyclization processes leading to 3a and ent-3a. Initial attempts at cyclization of 2a using Ph 3 P and diethyl azodicarboxylate or Ph 3 P-CCl 4 were low yielding (entries 1, 2).[22] Interestingly, small amounts of the 2,6-cis-disubstituted dihydropyran 6a were detected under these conditions, suggesting the intervention of a competitive double inversion process or a carbocationmediated cyclization process. In order to avoid the presence of nucleophilic counter ions, w...

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

“…In our case we were not able to remove stoichiometric amounts of OP(OEt) 3 (which is more hydrophilic than OP(OiPr) 3 ) through an aqueous work up (without saponification). Moreover, pentavalent P(OEt) 5 prepared from P(OEt) 3 with diethylperoxide and ethylbenzenesulfonate, respectively, in an additional step, was reported to effect cyclodehydration of diols to furans and pyrans [47–48] (for recent examples for cyclodehydration protocols see [49–50]). Thereby, the volatile products were separated from O=P(OEt) 3 through distillation.…”

Concerning the Selective Protection of (Z)-1,5-syn-Ene-diols and (E)-1,5-anti-Ene-diols as Allylic Triethylsilyl Ethers

“…In order to apply this method to the synthesis of structurally complex targets, including natural products, it is sometimes necessary to differentiate the two alcohols that result from the one-pot double allylboration reaction . We have previously reported that the allylic alcohol unit of 2 can be selectively protected with modest chemoselectivity as TBS ethers . We have examined this reaction in greater depth and report herein that optimal selectivity (≥95:5) is achieved by treating sterically unbiased diols 2 and 4 with triethylsilyl chloride (TES-Cl), imidazole, and catalytic DMAP in 1:1 CH 2 Cl 2 −DMF at −78 °C.…”

2-[1-(4-Bromophenyl)-3-hydroxy-3-(4-methoxyphenyl)propyl]cyclohexanol

“…For the biological properties of 1,5-diols, see: Flamme & Roush (2005); Hansen et al (2003); Huang et al (2009); Oger et al (2010). For details of the synthesis, see: Ceylan & Gezegen (2008); Gezegen et al (2010).…”