Synthesis of Functionalized 2,3- and 3,4-Dihydropyrans Starting from α-Hydroxycarboxylic Esters via RCM

Abstract

a-Hydroxy carboxylic acids and their derivatives are naturally occurring starting materials for the synthesis of functionalized tetrahydropyrans using ring closing metathesis and base induced epoxide rearrangement as key steps. (S)-Lactic acid methyl ester has been used as the starting material for the preparation of enantiomerically pure 6-desoxy C-glycoside precursors.Tetrahydropyrans with oxo substituents play an important role in synthetic organic chemistry, as these substructures are found in many natural products with interesting biological properties, such as annonaceous acetogenins, 1 polyether ionophores, 2 and C-glycosides. [3][4][5] The latter class of compounds has found increasing interest over the past years, because many physiologically active natural products with C-glycosidic structures have been identified, but there is also a continuous interest in the use of non-natural C-glycosides as carbohydrate mimics. 6 Thus, organic chemists have developed a variety of syntheses for these compounds, mostly starting from naturally occurring carbohydrates. Probably the most useful de novo synthesis of glycals and carbohydrates is the hetero-DielsAlder reaction of aldehydes and siloxydienes. 7,8 Metal-catalyzed or -mediated ring closure reactions are less common in this field. Among this group of reactions the ring closing metathesis of dienes 9 turned out to be a very powerful tool over the last few years. Recent examples for the utilization of olefin metathesis for the construction of di-and tetrahydropyran frameworks include the synthesis of spirocyclic dihydropyrans 10 and the utilization of carbohydrates as starting materials for fused or spiroannellated dihydropyrans and -furans. 11In this communication we wish to disclose our preliminary results on the utilization of naturally occurring a-hydroxy carboxylic acid 12 derivatives as starting materials for functionalized di-and tetrahydropyrans (Scheme 1). 13The a-allyloxy ester 2a was obtained in enantiomerically pure form and very high yield from inexpensive (S)-methyl lactate following a literature procedure. 14 Allylation of 1a with sodium hydride and allyl bromide occurs with complete racemization to give rac-2a ([a] 25 D = 0°). Reduction of the ester functionality in 2a with DIBAL-H and addition of one equivalent of vinylmagnesium chloride in a one-pot procedure yields, with good diastereoselectivity (dr = 4:1), the allylic alcohol 3a. The relative configuration of 3a is opposite to the one observed by us for very similar systems, which have been prepared via a two-step procedure, i. e. with isolation of the aldehyde. 13 Thus, it is likely that the formation of 3a via the one-pot procedure involves the intermediate formation of a chelate complex A of aluminum and the a-allyloxy aldehyde ("Cram's cyclic model") (Scheme 2). 15 Scheme 2Ring closing metathesis of 3a gives dihydropyrans 4a as an inseparable mixture of diastereomers (cis/trans = 4:1). The cis-configuration of the major diastereoisomer was elucidated by comparison of the coupling constant...

The Tandem Ring‐Closing Metathesis–Isomerization Approach to 6‐Deoxyglycals

“…[45] This reaction proceeds without racemization, in contrast to a standard Williamson ether synthesis, and gives enantiomerically pure 2. As previously reported by us, [42] 2 can be converted to 3 by a one-pot reduction of the ester function, followed by addition of vinyl magnesium chloride. However, this step proceeds with only moderate diastereoselectivity, which might result from insufficient Cram-chelate control due to competing complexation of the ether solvent.…”

“…Ethyl lactate (1) was identified as the starting material of choice, [41] because addition of a vinyl nucleophile to an appropriately O-protected lactaldehyde will either proceed via Cram-chelate control, [42,43] eventually leading to the rhodinal series, or via Felkin-Anh control, [43,44] eventually leading to the amicetal series. With a view to the synthesis of protected l-rhodinals, ethyl lactate (1) was first allylated with allyl ethyl carbonate catalyzed by Pd 0 .…”

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

“…As can be seen from the results summarized in Ta 2 give, in combination with PPh 3 as a ligand, better results, however, in the latter case unidentified by-products are observed in small amounts. It has previously been reported by Zumpe and Kazmaier that this precatalyst can be used for the selective O-allylation of Boc-protected serine methyl ester.…”

“…For instance, allylation of the corresponding sodium alkoxides with allyl bromide or iodide requires strongly basic conditions and leads to immediate racemization if, e.g., (S)-ethyl lactate is employed in the reaction. [2,20] In the case of mandelates not only racemization occurs, but a subsequent Wittig rearrangement of the primary O-allylation product is observed which gives a carbinol in preparatively useful yield (Scheme 2). [4] The same phenomenon was observed for a-hydroxy ketones such as benzoin.…”

“…[22,23] We have successfully used the latter method for a-hydroxy esters. [2,3,5] However, application of these conditions to aromatic a-hydroxy ketones [24] turned out to give less satisfactory results, because these substrates partially undergo an oxidative C À C bond cleavage under these conditions, resulting in the formation of allyl benzoate (8) as a by-product. For 3-hydroxypropiophenone (6) and substituted derivatives this side reaction becomes a serious limitation, as approximately 50% of the starting material are converted via this pathway (Scheme 2).…”