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. Author manuscript; available in PMC: 2012 Apr 10.
Published in final edited form as: Tetrahedron Asymmetry. 2011 Apr 10;22(7):713–716. doi: 10.1016/j.tetasy.2011.04.022

Efficient, scalable asymmetric synthesis of an epoxy quinol via Noyori desymmetrization of a meso diketone

David R Clay 1, Ashley G Rosenberg 1, Matthias C McIntosh 1,*
PMCID: PMC3131412  NIHMSID: NIHMS294626  PMID: 21743778

Abstract

Epoxy quinol 1a was prepared on a multi-gram scale by Noyori transfer hydrogenative desymmetrization of the readily available meso epoxy diketone 4. Although the intrinsic enantioselectivity for the desymmetrization was modest (82:18 er at 4% conversion), a highly enantiopure product (99.6:0.4 er) could be obtained in one operation in 44% yield via kinetic resolution of the minor enantiomer with long reaction times (48 h), or in 73% yield by combination with an enzymatic resolution of a 93:7 er mixture.

1. Introduction

The trans-epoxy quinol moiety 1 is present in natural products 1b-h (Scheme 1),1 as well as being a useful synthon in complex molecule synthesis.2 Asymmetric approaches to these compounds have included whole cell oxidations of arenes to cis-arene diols,3 Baker’s yeast reduction of β-ketoesters,4 stoichiometric5 and catalytic6 asymmetric Diels-Alder reactions, asymmetric epoxidation,2a,7 use of a sulfoxide chiral auxiliary,8 enzymatic resolution of racemic9 or meso diols,10 from quinic acid,11 and by catalytic alkene isomerization of a meso bis-silyl ether.12

Scheme 1.

Scheme 1

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Over the course of our ongoing synthesis of antascomicin B 2,13,14,15 we identified parent epoxy quinol 1a as an early intermediate in the asymmetric synthesis of the C29-C34 cyclohexyl moiety (Scheme 2). We would thus need to be able to generate multi-gram quantities of 1a in an efficient manner. The existing approaches to epoxy quinols suffer from tedious and inefficient protection/deprotection and/or oxidation/reduction sequences, the use of expensive or hard to obtain starting materials, and/or lack of scalability. Thus, while racemic 1a has been prepared in 4 steps from benzoquinone,16 the reported asymmetric synthesis of the corresponding silyl ether 1i required eight steps from benzoquinone, a high enzyme loading for the desymmetrization step (lipase PS-D, 1 eq by weight), and a long reaction time (16 days).17,18

Scheme 2.

Scheme 2

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We sought a more efficient approach for preparing large quantities of 1a, which would be comparable to a short racemic synthesis.16,19 Asymmetric transfer hydrogenation offers a mild, readily scalable approach to enantiopure alcohols.20 The asymmetric reduction of meso-epoxy diketone 4 (available in two steps from benzoquinone)21 would shorten the synthesis of 1a to four steps (Scheme 3). The meso diketones have previously been desymmetrized via whole cell reductions,22 asymmetric hydride reductions,23 and asymmetric deprotonations.24 The asymmetric hydrogenation of meso diketones to keto alcohols has apparently not been explored.25

Scheme 3.

Scheme 3

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Using formic acid/trialkylamine26 as the stoichiometric reductant, we studied the effect of catalyst loading, the identity of the trialkylamine, acid:amine ratio and acid:ketone ratio on the enantioselectivity of reduction of epoxy diketone 4 using DMF as a cosolvent. The reaction was performed using using the Ru(p-cymene)[(S,S)-TsDPEN] catalyst from -10 °C to rt for approximately 16 h. The desired keto alcohol 5 was formed in 83:17 to 90:10 er (Scheme 3, Table 1). The catalyst loading, identity of the amine, acid:amine and acid:ketone ratio had relatively modest effects on the er.

Table 1.

Optimization of the reduction of diketone 4 on a 1.0 mmol scale.

entry catalyst (mol %) acid:amine ratio amine acid:ketone ratio er (5:ent-5)
1 0.4 7:1 NEt(iPr)2 5:1 83:17
2 0.8 “ “ “ 90:10
3 1.0 “ “ “ 90:10
4 1.6 “ “ “ 90:10
5 1.0 “ NEt3 “ 90:10
6 1.2 “ “ “ 90:10
7 2.0 “ “ “ 90:10
8 1.0 “ “ 10:1 83:17
9 0.2 5:2 NEt(iPr)2 3.2:1 86:14
10 0.4 “ “ 3.2:1 86:14
11 1.0 “ “ 3.2:1 86:14
12 “ “ “ 2.5:1 80:20
13 “ “ NEt3 3.2:1 87:13
14 “ “ “ 2.5:1 85:15
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In contrast to the racemic reduction of 4 with NBu4BH4, which gave ca. 6:1 dr,16 the Noyori reduction gave a single diastereomer. The absolute configuration of alcohol 4 was determined by chiral GC correlation to the compound prepared via the enzymatic desymmetrization route.

We then increased the reaction scale to 10 mmol (Table 2). A solvent survey indicated that acetonitrile was the optimal cosolvent for the reduction (entries 1-5). Changing the formic acid/ketone ratio from 3:1 to 1:1 resulted in a significant improvement in er (entries 3 and 6). However, a steady decrease in enantioselectivity was observed upon increasing the reaction scale beyond 10 mmol (entries 6-9). We were ultimately able to achieve a 93:7 er in the reduction on a 60 mmol scale in 85% yield. Chiral GC analysis at 4% conversion under the optimized conditions revealed a modest intrinsic enantioselectivity (82:18 er), which is, however, comparable to other dialkyl ketone transfer hydrogenations.25,27

Table 2.

Optimization of the scale-up of reduction of diketone 4.

entry solvent acid:ketonea scale (mmol) conc (M) er (5:ent-5)
1 None 3:1 10 “ 80:20
2 DMF “ “ 0.5 80:20
3 MeCN “ “ “ 82:18
4 THF “ “ “ 70:30
5 CH2Cl2 “ “ “ 70:30
6 MeCN 1:1 “ 0.15 90:10
7 “ “ 30 “ 82:18
8 “ “ 60 “ 79:21
9 “ “ 120b “ 77:23
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a

Molar ratio.

b

Reaction did not proceed to completion.

As expected, increasing the reaction time of the reduction resulted in material with a significantly improved er (99.6:0.4 at 48 h) as a consequence of the kinetic resolution of the minor enantiomer, although the isolated yield dropped to 44%. Alternatively, a 93:7 er mixture (12 h reaction time) could be enriched via enzymatic resolution with Amano lipase PS-IM to 99.5:0.5 er in an overall 73% yield.

To complete the preparation of epoxyquinol 1a, we employed the Taylor variation19 of the Lubineau procedure16 for the retro-Diels-Alder reaction of 5 to 1a. Heating 10 g of keto alcohol 5 at 210 °C in diphenyl ether afforded the desired epoxy quinol 1a in 80% yield.

3. Conclusion

In conclusion, we have prepared epoxy quinol 1a in 4 steps from benzoquinone in a concise manner with a synthetically useful yield and high enantiopurity.

4. Experimental

Method A (93:7 er)

At first, Ru(p-cymene)[(S,S)-TsDPEN] (0.25 g, 0.39 mmol, 0.65 mol %) and epoxy diketone 4 (11.4 g, 60 mmol) were added to a solution of formic acid (3.85 mL), triethylamine (14.3 mL) and acetonitrile (500 mL) at -10 °C. The reaction mixture was allowed to slowly warm to rt and stirred for ca. 16 h. The mixture was concentrated in vacuo and then stirred for ca. 16 h in 30/70 ethyl acetate/hexanes (300 mL) with activated charcoal (10 g). The mixture was filtered through a plug of Celite with 30/70 ethyl acetate/hexanes and concentrated in vacuo. At this point, the residue could be purified by flash chromatography (20/80 ethyl acetate/hexanes) to give keto alcohol 5 as colorless crystals (9.8 g, 85%, er 93:7). Spectroscopic data matched those previously reported.16

Method B (99.6:0.4 er)

As in Method A, but the reaction mixture was allowed to stir for 48 h at rt. Flash chromatography (20/80 ethyl acetate/hexanes) gave keto alcohol 5 as colorless crystals 5.1 g, 44%, er 99.6:0.4).

Method C (99.5:0.5 er)

Prior to chromatography, the residue from Method A was purified by enzymatic resolution: vinyl acetate (1.34 mL, 1.26 g, 14.6 mmol), Lipase PS-IM (1.4 g), and keto alcohol 7 (10 g, 52 mmol, 93:7 er) were added to a solution of THF (100 mL) and NEt3 (10 mL) and stirred at rt for 4 d. The reaction mixture was filtered through a plug of Celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 20/80 ethyl acetate/hexanes to give epoxy keto alcohol 5 as colorless crystals (8.5 g, 73% from 4, 99.5:0.5 er). The alcohol could be further crystallized to enantiopurity from diethyl ether.

The experimental procedure for the retro-Diels-Alder is as follows. A solution of keto epoxide 5 (10 g, 52 mmol) in diphenyl ether (200 mL) was heated under nitrogen at 210 °C for 2 h. Upon cooling to rt, the mixture was loaded directly on a silica gel column. Hexanes were used to elute the diphenyl ether, followed by 20/80 EtOAc/hexanes to give epoxy quinol 1a as white crystals (5.2 g, 42 mmol, 80%); mp 84-86 °C; [α]D19 = +3.8 (c 1.65, CH2Cl2). Spectroscopic data matched those previously reported.16

Scheme 4.

Scheme 4

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Scheme 5.

Scheme 5

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Acknowledgments

NSF (CHE0616154, CHE0911638), NIH (RR15569) and the Arkansas Biosciences Institute; David T. Williams and Andrew S. Gibson, University of Arkansas, for supporting experiments.

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