Stereoselective Additions of Chiral, Functionalized Organozinc Reagents to Achiral and Chiral Aldehydes: a Matched‐Mismatched Case in Organozinc Chemistry

Abstract

The additions of the enantiomerically pure organozinc reagents 17 and 33 to the THF-aldehyde 1 in the presence of the monodentate Lewis acid boron trifluoride-ether give the nonchelation-controlled addition products 7 and 36, respectively (stereoselectivity 95:5, 86: 14). These results provide a route to oligo(tetrahydr0furan)s with the relative stereochemistry trans-syn-cis. A stereodirecting effect of the chiral center in the organozinc reagent 17 is found, leading to simple diastereoselectivies in the reaction with achiral aldehydes and to a matched-mismatched case in the reaction with the chiral aldehyde 1.During our studies directed to the stereoselective synthesis of natural"] and non-natural[21 oligo(tetrahydr0fur-an)s (oligo-THFs) we used a chelation-controlled Grignard reaction as a synthetic route to THF dimers and trimers with the relative configuration tr~ns-anti-trans [~]. Cu(1)-catalyzed addition of the enantiomerically pure Grignard reagent 2 to the THF-aldehyde 1 gave the alcohol 3 with a stereoselectivity of 93:7. The acetonide functionality of 3 was stereoselectively transformed into the epoxide function of the alcohol 4. An intramolecular epoxide opening was used to close the new THF ring, thus providing the THF dimer 5 (relative configuration: trans-anti-trans). In order to realize a stereoselective synthesis of oligoTHFs with the relative configuration trans-syn-cis, it would be very eficient to use the same route as in Scheme 1, but a nonchelation-controlled addition step instead of the chelation-controlled one. This suggests the use of another organometallic reagent as the Grignard compound, i.e. we wanted to control the stereochemical outcome of the addition reaction by metal tuning. In this way the new organometallic reagent 6 should add to the THF-aldehyde 1 to give an acetonide alcohol 7. Transformation of the acetonide into the epoxide 8 and intramolecular ring closure would provide access to a THF dimer 9 with the relative configuration trans-syn-cis. Which metal is the right one, to achieve nonchelationcontrol in this particular situation? In this paper we report on synthetic studies to answer this question. The choice of the metal has to be based on the of stereoselective additions of organometallic reagents R-M to chiral a-alkoxy aldehydes of type 11, leading to the anti product 12 via a chelation-controlled pathway and to the syn product 10 via a nonchelation-controlled pathway. Introduced by CramF51, chelation control was a transition-state concept in its beginning. Nowadays, it is exper-

Acetogenins from Annonaceae

“…The strategies used are based on two different approaches, namely stereospecific synthesis of the THF part and the lactone moiety using either (i) as starting material a compound from the chiral pool (a-amino acids, sugars) or (ii) an asymmetric induction using homochiral catalysts (Sharpless epoxidation, Sharpless asymmetric dihydroxylation) and finally a coupling reaction between the two fragments. In addition to these total syntheses, numerous reports appeared in the literature dealing with the preparation of building blocks such as 2,5-disubstituted tetrahydrofurans (187,188,189,202,203,204) contiguous THF rings (205,206,207), f-methyl-y-lactones (208,209,210, 211) and a-acetonyl-y-lactones (212).…”

Synthesis and Biological Evaluation of Integrin Antagonists Containingtrans- andcis-2,5-Disubstituted THF Rings

“…After conversion of the hydroxy function of 21 into a leaving group (tosylate or mesylate), the cleavage of the acetonide provided the diols 22 a and 22 b, which reacted in an intramolecular Williamson reaction to yield the THF alcohol 23 (retention at C2, inversion at C5). [25] In the case of the mesylate 22 b the THF-ring closure occurred directly under the acidic conditions of the acetonide cleavage (see Scheme 2). The second Scheme 2.…”

“…The (S)-acetonide bromide 20 is readily available from l-malic acid [24] and has recently been used as a valuable building block for the stereoselective synthesis of 2,5-disubstituted THFs. [25,26] It was converted into the corresponding organomagnesium compound and allowed to react with the aldehyde 19, [27] which is accessible by Swern oxidation [29] of the alcohol 18. Thus, the secondary alcohol 21 was obtained in good yield as a 1:1 epimeric mixture.…”

Design, Synthesis, and Biological Evaluation of Unconventional Aminopyrimidine, Aminopurine, and Amino‐1,3,5‐triazine Methyloxynucleosides

“…Thus, treatment of 38 [35] with pyrimidines 36 or 37, under the standard conditions, afforded the deprotected nucleosides 41 and 42 in 10 and 12 % yield, respectively. Instead, analogous treatment of derivative 40 gave unprotected 42 (10 %), although in low yield.…”