Ambient-Pressure Asymmetric Preparation of S,S-DICHED, a C ₂-Symmetrical Director for Matteson Reactions

◊ These authors contributed equally to this work.

Abstract

A synthesis of S,S-DICHED (dicyclohexylethane-1,2-diol), a C ₂-symmetrical chiral director for Matteson homologations, is described. It relies on the insertion of lithiated S-2-cyclohexyloxirane into cyclohexylboronic acid pinacol ester and proceeds in three linear steps from readily available starting materials. No step requires chromatography or any specialized equipment.

Key words

DICHED - DIPED - Matteson reaction - lithiated epoxide - ­chiral director

DICHED (dicyclohexylethane-1,2-diol, 1) and DIPED (diisopropylethane-1,2-diol) are C ₂-symmetrical, highly effective chiral directors for Matteson's diastereoselective homo­logation of corresponding boronic esters.[1] S,S-DICHED (SS-1) is commercially available in enantiomerically pure form but rather expensive. Preparation of scalemic DICHED was first described by Hoffmann and co-workers.[2] It requires Sharpless bishydroxylation of trans-stilbene and subsequent hydrogenation, which was achieved with Rh/Al₂O₃ at 60–70 atm H₂. Matteson et al. developed a reduction protocol that proceeds via a concentrated solution of the corresponding methoxy borate, which only requires 10–11 atm H₂.[3] The high cost of RhCl₃, as well as the inconvenience of the high-pressure hydrogenation procedures[4] led us to explore alternative routes, the best of which is shown in Scheme [1]. It was based on the work of Aggarwal et al., who first described the insertion of lithiated epoxides (similar to 8) into pinacol boronates.[5]

Scheme 1 (A) Synthesis of S,S-DICHED (SS-1). (B) Mechanism of A­ggarwal homologation with lithiated epoxides and suggested explanation for the need for two equivalents of 6.[7] (C) Application of SS-1 in a short Matteson sequence showed no double stereodifferentiation, but confirmed the absolute configuration of SS-1.

For our synthesis of S,S-DICHED (SS-1), enantiomerically pure cyclohexyloxirane 5 was prepared as reported by Ortiz-Marciales et al. [6] by brominating ketone 2 and submitting the crude product 3 to a CBS-type reduction and cyclization using catalyst 4. Scale up of the procedure to multi­gram levels was straightforward, as bromide 3 could be used directly after aqueous workup and oxirane 5 was distilled at 56–65 °C at 14 mbar.

To convert oxirane 5 into DICHED, lithiation with LiTMP in the presence of two equivalents of cyclohexylpinacol boronate 6 had to be carried out at 0 °C for two hours. The ­chiral carbenoid 8 and boronate 6 form ate complex 9 that undergoes a 1,2-rearrangement to α-alkoxyboronate 10. Aggarwal's original procedure for this type of reaction[5] employed –30 °C, but 5 did not react with LiTMP under these conditions (as confirmed by in situ quench with TMSCl). Initially we allowed the reaction mixture to reach room temperature to facilitate the 1,2-rearrangement. However, on warmer days competing β-elimination (of 10 to 1,2-­dicyclohexylethylene) was observed. This problem was completely avoided by using a p-xylene/solid CO₂ cooling bath (13 °C). The reaction was then completed by H₂O₂/NaOH oxidation at 0 °C. Attempts to reduce the required amount of boronate 6 led to significant losses in yield.[7] However, as 6 can be readily made on a large scale (see Supporting Information), the need for two equivalents of 6 is of little preparative concern.

The de of the reaction was excellent and no formation of the undesired meso-diol was observed by ¹H NMR analysis of the crude product. The enantiomeric purity of the product was assessed after derivatization with (S)-OAc-mandelic acid (SS-1 → 7) and was usually >95% ee. On occasions when slightly less pure batches of catalyst 4 were used, the ee dropped to 89–91%. Such material could, however, be enantiomerically enriched afterwards by recrystallization from EtOH (0.75 g/mL) or by column chromatography after conversion into 7 (see Supporting Information). The absolute configuration of SS-1was confirmed after using its boronic ester derivative 11 [8] in a short homologation sequence to yield 12 (Scheme [1], C). Conversion into 13 delivered a product of which both diastereomers are known.[9] Interestingly 13 had a de of only 80%, although the sequence started with highly pure material (>95% ee). This could indicate that the double stereodifferentiation discovered by Matteson[1] did not occur in this case, probably due to the high migration tendency of the newly introduced vinyl group.[10]

In the context of this work, we also looked at Matteson's synthesis of DIPED from tartaric acid,[11] which we were able to modify, so that the use of a pyrolysis oven was avoided and the expensive rhodium catalyst could be replaced by Raney nickel (see Supporting Information). Nevertheless the enantioselective synthesis of S,S-DICHED[12] (Scheme [1]), emerged as advantageous, as it creates a nonvolatile product (unlike DIPED), does not require expensive transition metals or chromatography and can be conducted without the use of high pressure or other specialized equipment. Its disadvantage is the need for the potentially toxic intermediates 3 and 5, for which we recommend careful handling. Accordingly annotated procedures are given in the Supporting Information.

Acknowledgment

We thank the Science Support Center of the University of Duisburg and Essen for financial support and Prof. Dr. C. Schmuck for fruitful discussions.

• References and Notes


Recent reviews:
• 1a Matteson DS. J. Org. Chem. 2013; 78: 10009
• 1b Thomas SP. French RM. Jheengut V. Aggarwal VK. Chem. Rec. 2009; 9: 24

Original articles:
• 1c Matteson DS. Majumdar D. J. Am. Chem. Soc. 1980; 102: 7588
• 1d Matteson DS. Ray R. J. Am. Chem. Soc. 1980; 102: 7590
• 1e Tripathy PB. Matteson DS. Synthesis 1990; 200
• 2a Hoffmann RW. Ditrich K. Köster G. Stürmer R. Chem. Ber. 1989; 122: 1783
• 2b Sharpless KB. Amberg W. Bennani YL. Crispino GA. Hartung J. Jeong KS. Kwong HL. Morikawa K. Wang ZM. J. Org. Chem. 1992; 57: 2768
• 3 Hiscox WC. Matteson DS. J. Org. Chem. 1996; 61: 8315
• 4 Ref. 3 reports problems with overreduction when using the procedure described in ref. 2. Our attempts to run the procedure in ref. 3 on 0.5–2 g scales required some dilution, leading to mixtures of starting material and (partially) hydrogenated product. Ref. (3) also describes RhCl₃ recovery.
• 5a Vedrenne E. Wallner OA. Vitale M. Schmidt F. Aggarwal VK. Org. Lett. 2009; 11: 165

Also see:
• 5b Alwedi E. Zakharov LN. Blakemore PR. Eur. J. Org. Chem. 2014; 6643
• 6 Huang K. Wang H. Stepanenko V. De Jesús M. Torruellas C. Correa W. Ortiz-Marciales M. J. Org. Chem. 2011; 76: 1883
• 7 We initially thought that the 1,2-rearrangement/epoxide opening had to be facilitated by a Lewis acid, the role of which could be fulfilled by excess boronate. However, attempts to replace it with ZnCl₂ or TMSCl (added after LiTMP) resulted in lower conversions of 5 and thus lower yields. The formation of an ate complex of type 10 after the 1,2-rearrangement would explain this observation if the rearrangement occurs as fast/faster than the formation of 9.
• 8 Singh RP. Matteson DS. J. Org. Chem. 2000; 65: 6650
• 9 Struth FR. Hirschhäuser C. Eur. J. Org. Chem. 2016; 958
• 10 Based on our previous studies (ref. 9) we expected a de of 80% for the homologation of 11 with LiCHX₂ under the employed conditions. However, we did expect the de to increase again after substitution with vinyl Grignard (→ 12) due to the double stereodifferentiation discovered by Matteson for this type of chiral director (ref. 1e). See Supporting Information for further discussion.
• 11 Matteson DS. Beedle EC. Kandil AA. J. Org. Chem. 1987; 52: 5034
• 12 Procedure for the Preparation of SS -1 Immediately before the reaction, LiTMP was prepared in a separate flask by addition of n-BuLi (2 equiv, 1.6 M in hexanes) to a solution of dry tetramethylpiperidine (2 equiv) in dry THF (1 L/mol of LiTMP) at 0 °C. The LiTMP solution was stirred for 0.5 h at r.t., transferred into a dropping funnel and added dropwise to a solution of epoxide 5 (1 equiv) and boronate 6 (2 equiv) in THF (1 L/mol of 6) with cooling in an ice bath (0 °C). Afterwards the reaction mixture was stirred for 0.5 h at 0 °C and 1.5 h at 13–14 °C (p-xylene/dry ice bath). The reaction mixture was cooled to 0 °C before aq. NaOH (2 M, 3.5 equiv) and aq. H₂O₂ (30%, 10 equiv) were added simultaneously. After stirring for 30 min aq. Na₂S₂O₅ (2 M) was added over the course of 15 min at the same temperature. Stirring was continued for 5 min before Et₂O and H₂O were added and the phases were separated. The aqueous layer was re-extracted with Et₂O, and the combined organic layers were washed with sat. aq. NH₄Cl, brine and aq. NaOH (1 M). The organic phase was dried over MgSO₄, filtered, and the solvent was removed in vacuo to yield a yellow solid. Recrystallization from EtOH or chromatography on silica (CyHex/EtOAc, 9:1) yielded SS-1 in 55–60% yield. R_f = 0.28 (CyHex/EtOAc, 4:1). ¹H NMR (300 MHz, CDCl₃): δ = 3.45–3.25 (m, 2 H), 1.95–1.42 (m, 12 H), 1.34–0.95 (m, 10 H). ¹³C NMR (75 MHz, CDCl₃): δ = 75.1, 40.4, 29.6, 28.2, 26.4, 26.2, 26.1. ¹H NMR and ¹³C NMR data were consistent with those previously reported by: Scott MS. Lucas AC. Luckhurst CA. Prodger JC. Dixon DJ. Org. Biomol. Chem. 2006; 4: 1313