A Novel Transition Metal-Catalyzed Route to Functionalized Dihydropyrans and Tetrahydrooxepines

Abstract

A straightforward route for the synthesis of α,α'-disubstituted dihydropyrans and tetrahydrooxepines has been developed involving Pd-and Ru-catalyzed reactions.2,6-Disubstituted dihydropyrans 1 and 2 (n = 1) occur frequently in nature as a structural unit in a wide range of natural products. 1 In addition, these compounds could serve as useful building blocks for the synthesis of biologically active saturated oxygen heterocycles via functionalization of the double bond. Examples include (poly)cyclic ethers, 2 but also modified carbohydrates and 2-carboxyl-substituted tetrahydropyrans with antibacterial activity such as KDO. 3 More specifically, dihydropyrans 2 (R 1 = OMe) have recently been used as intermediates in the synthesis of mevinolin and compactin. 4,5 In conjunction with previous work in our group on vinylsilane-terminated formation of dihydropyrans via oxycarbenium ions, 6 we set out to explore a novel entry into this compound class, which would enable us to vary the side chains and would also give facile access to enantiopure heterocycles. Moreover, the methodology outlined in this paper is not restricted to six-membered ring formation, but can also be applied to form the corresponding seven-membered rings. Especially the latter aspect provides a significant benefit compared to previously established methods for forming such rings via hetero Diels-Alder reactions. 5,7 A short retrosynthetic outline of our route is shown in Scheme 1. Scheme 1The target compounds 1 and 2 should be accessible via the allylic acetal 3, which contains (i) a terminal olefin function that can be used as a handle for ring-closing metathesis 8,9 and (ii) an acetal function to enable later modification of the system via oxycarbenium ion chemistry.The first sequence (Scheme 2) commenced with anhydrous methyl glyoxylate (5), 10 which upon treatment with BF 3 ·OEt 2 and allyltrimethylsilane led to methyl 2-hydroxy-4-pentenoate (6). Initially, attempts were made to convert 6 into the desired allylic acetal under acid-catalyzed conditions with acrolein derivatives, but without much success. Therefore, we turned our attention to other strategies, involving the use of 1-methoxy-1,2-propadiene, 11 which upon electrophilic activation and subsequent reaction with the secondary alcohol might give rise to the desired product. Several methods have been published describing activation of allenes towards coupling with oxygen nucleophiles (including N-bromosuccinimide, HgCl 2 ), 11 but these routes are not attractive in view of the stoichiometric use of the reagents. At this point, a publication of Alper and coworkers appeared, 12 who obtained a similar acetal as a byproduct in Pd(II)-catalyzed annulation reactions with substituted allenes. Application of their conditions and further optimization (Pd(OAc) 2 (cat.), Ph 2 P(CH 2 ) 3 PPh 2 (dppp), excess of 1-methoxy-1,2-propadiene, Et 3 N, MeCN, 80 °C in a sealed tube) led to a virtually quantitative yield of the desired acetal 7. 13 Not surprisingly, 7 was obtained as a ca. 1:1 mixture of diaste...

Ringschlussmetathese: ein Schlüssel zur Arensynthese

“…[25] Uns gelang die Synthese von acyclischen Dien-Vorstufen (30, 33) über eine Palladium(ii)-katalysierte Kupplung eines Alkohols (oder eines Sulfonamids) mit Methoxyallen in guter Ausbeute (Schema 7). [26][27][28][29] Die RCM der gemischten Acetale (30) und Aminale (33) mithilfe des Grubbs-Katalysators der zweiten Generation 7 und die nachfolgende Umsetzung der Zwischenprodukte mit TFA zur Eliminierung von Methanol führte in guten Gesamtausbeuten zu den substituierten Furan-(31) und Pyrrolderivaten (34). Es sollte erwähnt werden, dass Rutjes et al zuvor über die Bildung von N-Tosylpyrrol infolge einer ähnlichen Abbaureaktion eines entsprechenden RCM-Intermediats an Kieselgel berichtet hatten.…”

Palladium‐Catalyzed O‐Allylation of α‐Hydroxy Carbonyl Compounds

“…Examples 11c, d, e illustrate that the rapid assembly of substrates for ring closing metathesis reactions is possible using the Pd-catalyzed allylation reaction. Precursors 10c [45] and 10e [46] have been prepared in one step by addition of allyl-or allenylmetal compounds to ethyl glyoxalate. Ester 10d is available in one step from dimethyl malate via a highly diastereoselective enolate allylation, using a method described by Seebach et al [47] The ratio of diastereomers observed for 10d is not altered during the O-allylation.…”

“…Optical purities were determined by HPLC using a HP-LC-1050 system equipped with a Daicel Chiralcel OD column. The following compounds were prepared according to procedures described in the literature: 10c, [45] 10d, [47] 10e, [46] 10g, [49] 10h, [56] 10i, [3] 10j, [57] Pd 2 (dba) 3 · CHCl 3 , [58] [Pd(h 3 -C 3 H 5 )Cl] 2 , [59] and [Pd(PPh 3 ) 4 ]. [58] Screening Experiments for Different Pd-Precatalysts…”

“…Rac-2-Allyloxypent-4-enoic acid ethyl ester (11c): Obtained from 10c [45] (144 mg, 1.0 mmol) as a colorless liquid; yield: 158 mg (84%).…”

Bioorganic Studies Utilizing Rationally Designed Synthetic Molecules: Absolute Configuration of Ciguatoxin and Development of Immunoassay Systems

“…Protecting group manipulation and stereoselective allylation using Spilling's protocol 49 gave the C-glycoside 54. The acidsensitive A-ring, containing a (2S)-3-butene-1,2-diol side- 50 Palladium-catalyzed acetalization of secondary alcohol 54 with 1-phenoxy-1,2-propadiene according to the Rutjes's procedure 51 yielded a mixture of allylic acetals, 55 and 56, in 45 and 32% yields, respectively. After separation, the undesired isomer 56 was epimerized by treatment with palladium catalyst and phenol to produce the desired 55.…”