Stereoselective Synthesis of 2,3,5-Trisubstituted Tetrahydrofurans

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Stereoselective Synthesis of 2,3,5-Trisubstituted Tetrahydrofurans Initiated by a Ti-BINOLate-Catalyzed Vinylogous Aldol Reaction Patrick Hoffmeyer, and Christoph Schneider J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Dec 2018 Downloaded from http://pubs.acs.org on December 21, 2018

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The Journal of Organic Chemistry

Stereoselective Synthesis of 2,3,5-Trisubstituted Tetrahydrofurans Initiated by a Ti-BINOLateCatalyzed Vinylogous Aldol Reaction Patrick Hoffmeyer and Christoph Schneider* Institut für Organische Chemie, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany *Email: [email protected]

ABSTRACT: The enantioselective synthesis of 2,3,5-trisubstituted tetrahydrofurans 3 has been achieved using a chiral titanium-BINOL-complex as catalyst for the vinylogous Mukayiama aldol reaction of bis(silyl) diendiolate 1 and an aldehyde. The ensuing BF3•OEt2 mediated Prins-type cyclization with a second aldehyde gave rise to 2,3,5-substituted tetrahydrofurans 3 with generally good yields and excellent stereocontrol. In this process three new σ-bonds and three new stereogenic centers were generated in a one-pot process.

Substituted tetrahydrofurans are common structural motifs found in several natural products and biologically active compounds. Therefore, in recent years, many efforts have been devoted toward the development of stereoselective methods to generate

multisubstituted

tetrahydrofurans. With regard to natural product synthesis and medicinal chemistry, ACS Paragon Plus Environment

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enantioselective processes are particularly valuable, but at the same time most challenging.1-3 The Prins cyclization using homoallyl alcohols and aldehydes has been shown to be a powerful tool for this purpose.4-8 In this context Coates and coworkers developed a diastereoselective tetrahydrofuran synthesis employing cyclic allylsiloxanes with Lewis acids, but up to this point no enantioselective modification has been reported.9 Suga et al. employed rhodium carbene complexes leading to 1,3-dipoles, to generate tetrahydrofurans with good diastereoselectivity in a cycloaddition reaction. Nevertheless, an enantioselective modification required the use of a chiral auxiliary.10 Kočovský et. al developed a two-step allylation sequence of a bifunctional allyldisilane with aldehydes to generate tetrahydrofurans diastereo- and enantioselectively. However, the substrate scope was rather limited with only a very few enantioselective examples.11 Finally, the List group was able to generate tetrahydrofurans with high enantioselectivity employing a novel Brønsted acid as chiral catalyst. The dienyl homoallylic alcohols, used, however, had to be prepared separately prior to the actual synthesis.12

We recently reported a novel Lewis acid-mediated one-pot process for the highly diastereoselective synthesis of 2,3,5-trisubstituted tetrahydrofurans employing bis(silyl) dienediolate 1 established in our group.13-17 Based upon detailed mechanistic insight which we successfully obtained using lab on chip technology we were able to develop an enantioselective version of this new process taking advantage of methodology established by Keck et al. for similar vinylogous Mukaiyama aldol reactions (VMAR) of thioester-based dienolates.18 Thus, a chiral titanium-BINOL-catalyst generated in situ from Ti(OiPr)4, R-BINOL, and B(OMe)3 effected the VMAR of 1 and benzaldehyde in diethyl ether to furnish the intermediate vinylogous aldol product 2a. That in turn was treated with BF3•OEt2 and a second equivalent of the aldehyde in ethyl acetate to give rise to tetrahydrofuran 3a with good overall yield and enantioselectivity (Scheme 1). On that basis we now report a quite generally applicable, straightforward, and enantioselective synthesis of 2,3,5-substituted tetrahydrofurans. ACS Paragon Plus Environment

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Scheme 1: Synthesis of enantioenriched tetrahydrofuran 3a under our previous conditions.

In our first attempts to broaden the scope of this process the enantiomeric ratios often happened to be significantly lower when we repeated the experiment. After extensive optimization we found that in our VMAR of bis(silyl) dienediolate 1 and aldehydes the B(OMe)3 additive which was used in order to increase the reactivity of the catalyst had a detrimental effect on enantioselectivity. When we omitted it completely and ran the reaction under otherwise identical conditions just without B(OMe)3, the reaction became very reproducible and also the yield increased substantially from 65% to 86%. In addition, extending the reaction time at -78°C from 0.5 h to 5 h ensured that the vinylogous aldol reaction proceeded to completion at low temperature and gave rise to an improved enantiomeric ratio of 94:6 (Table 1). Other chiral ligands with substituents in the BINOL-backbone and other solvents displayed diminished reactivity and enantioselectivity in this reaction. The reason for this improvement is not entirely clear at the moment. Considering Yamamoto´s observation of a Brønsted assisted Lewis acid catalyst prepared from BINOL and B(OMe)3 in situ for Diels-Alder and Aldol reactions,19 however, suggests that this catalyst might have been formed in varying amounts as well and eventually foiled our VMAR. As a control experiment this very catalyst was employed in the THF synthesis on purpose yielding the desired product in only 22% yield and with 63:37 e.r.; thus, the undesired formation of this catalyst during the

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reaction might be a reasonable explanation for the lowered e.r. when using B(OMe)3 as an additive. Table 1: Substrate scope with different aldehydes[a-c]

[a] Reaction conditions: 1 (1.50 mmol), aldehyde (0.75 mmol), BF3•OEt2 (0.75 mmol) in Et2O. [b] Yields refer to chromatographically pure material over two steps. [c] Diastereomeric ratios ACS Paragon Plus Environment

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determined by 1H-NMR spectroscopy on crude products, enantiomeric ratios determined by HPLC-analysis on chiral stationary phases.

With the optimized conditions in hand, the scope of the reaction was investigated for the synthesis of 2,5-identically substituted tetrahydrofurans. Therefore, several aromatic and heteroaromatic aldehydes were subjected to the reaction and delivered the products 3a-3f with good chemical yields and generally good diastereo- and enantiocontrol (Table 1). We then turned to the synthesis of tetrahydrofurans with different 2- and 5-substituents which required the use of different aldehydes for the VMAR- and the Prins reaction. Here, aromatic aldehydes were found to be most suitable as substrates for the VMAR and provided tetrahydrofurans with generally good yields and enantioselectivities irrespective of the nature of the second aldehyde used for the Prins reaction (e. g. 3g, 3i, 3j, 3l-3o). Although yields for heteroaromatic aldehydes were also good, the enantioselectivity was somewhat lower. Aliphatic aldehydes tend to give slightly poorer results as substrates for the VMAR as documented by tetrahydrofurans 3h and 3k. Alpha-branched aliphatic aldehydes showed a significant loss in yield and enantioselectivity. In cases of less satisfactory diastereoselectivity the diastereomers could be easily separated by column chromatography with silyl-end-capped silica gel.20 Tetrahydrofuran 3n could be recrystallized from hexane:MTBE:CH2Cl2 (12:1:1, v:v:v) to give crystals of >99% ee suitable for X-ray crystallographic analysis for the determination of the absolute configuration which was used for all other products by analogy (see the SI for details).

In summary, we have developed a highly diastereo- and enantioselective synthesis of trisubstituted tetrahydrofurans based upon a sequence comprising a vinylogous Mukaiyamaaldol and Prins reaction. A chiral titanium-BINOL catalyst prepared easily in situ was employed to control the enantioselectivity of the reaction effectively. Different commercially available ACS Paragon Plus Environment


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aromatic, aliphatic and heteroaromatic aldehydes along with the readily available bis(silyl) dienediolate nucleophile 1 were employed in this process successfully and delivered the products in generally good yields. Key to the success of this process was a modification of the original procedure for the VMAR by leaving out the B(OMe)3 additive.

Experimental Section:

General Methods. All reactions were carried out in oven dried glassware under an Aratmosphere unless otherwise noted. Solvents were distilled from the indicated drying reagents: dichloromethane

(CaH2),

diethyl

ether

(Na,

benzophenone)

tetrahydrofuran

(Na,

benzophenone). Other solvents were of technical grade and distilled from the indicated drying reagents: dichloromethane (CaH2), methyl-tert-butylether (KOH), n-hexane (KOH). Ethyl acetate (Acros Organics, extra dry, with molecular sieves, water

Stereoselective Synthesis of 2,3,5-Trisubstituted Tetrahydrofurans

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