PERKIN Desymmetrisation of meso difuryl alcohols, diols and their derivatives: complementary directed and undirected asymmetric dihydroxylation reactions Robert Hodgson,a Tahir Majid b and Adam Nelson*a a School of Chemistry, University of Leeds, Leeds, UK LS2 9JT 1 b Aventis Pharma US, Route 202-206, Bridgewater, New Jersey 08807, USA Received (in Cambridge, UK) 22nd May 2002, Accepted 31st May 2002 First published as an Advance Article on the web 27th June 2002 Asymmetric reactions (for example, asymmetric epoxidation and asymmetric dihydroxylation) were examined for the desymmetrisation of the meso substrates 1,1-difuran-2-ylmethanol, N-(1,1-difuran-2-ylmethyl)-4-methylbenzene- ؒ sulfonamide, (R,S)-1,4-difuran-2-ylbutane-1,4-diol and the derivatives of these compounds. The complex OsO4 (S,S)- S )-1,2-diphenyl-N,N Ј-bis(2,4,6-trimethylbenzyl)ethane-1,2-diamine was found to be an effective reagent for the desymmetrisation of meso-1,2-bis(3,6-dihydro-3-hydroxy-2H-pyran-2-yl)ethanes and the corresponding di-p- methoxybenzoates by asymmetric dihydroxylation. The stereochemical outcome of this process depends critically on the relative stereochemistry and substitution of the substrate, and can occur anti to, or be directed by, an allylic alcohol or p-methoxybenzoyloxy functional group. Introduction The enantioselective desymmetrisation of meso compounds is one of the most powerful strategies for asymmetric synthesis.1 This strategy uses a chiral reagent to differentiate between enantiotopic functional groups in the starting material: pro- vided that the discrimination between these groups is suf- ficiently effective, the products of the reaction may be obtained in excellent yield and with high enantiomeric excess.† In this paper, we describe some methods for the desym- metrisation of meso difurans (for example 1 and 4) and closely related derivatives of these compounds (Scheme 1). At the start of our investigation, we planned to differentiate between the enantiotopic rings of the difurans 1 using a chiral oxidising agent; we envisaged that the enantiomerically enriched products of the reaction, for example 2b, might be of value in the synthesis of pipecolinic acid derivatives 3b. Polyhydrox- ylated pipecolinic acid derivatives such as 3b have value as potent and specific inhibitors of glycosidases.3 Alternatively, desymmetrisation of the diol 4, or one of its meso derivatives, was expected, after functionalisation, to give enantiomerically enriched functionalised tetrahydropyrans (THPs) 5; these compounds might be intermediates in the synthesis of C-linked glycosyl amino acids 4 of general structure 6. Scheme 1 Results and discussion Synthesis of meso starting materials double oxidative ring expansion 8 to give the insoluble dipyr- The difuryl alcohol 5 8 and the difuryl sulfonamide 10 were syn- anone 14. The dipyranone 14 was isolated by filtration of the thesised by addition of 2-lithiofuran (11), prepared by lithiation reaction mixture and was obtained as a 75 : 25 mixture of meso of furan, to furfural (7) and its N-tosylimine 6 (9) respectively and unsymmetrical isomers. We investigated the protection of (Scheme 2). the bis-hemiacetal 14 under two different reaction conditions. Treatment of a solution of the meso diol 7 4 in dichloro- Treatment of 14 with trimethyl orthoformate and 20 mol% methane with a 5.0 M solution of tert-butyl hydroperoxide in boron trifluoride in methanol gave the tricycle 15 as a mixture decane and catalytic vanadyl acetylacetonoate resulted in a of diastereoisomers; in contrast, the same reaction in dichloro- methane gave the required diacetals 12 as a 75 : 25 mixture of anomers in >98% yield, from which the required meso † In contrast, a classical resolution or kinetic resolution can only give ffi diastereoisomer could be crystallised in 52% yield (Scheme 3). up to a 50% yield of enantiomerically pure product. The e ciency of a 9 dynamic kinetic resolution 2 can, however, approach that of a perfect Luche reduction of the dipyranone 12 (75 : 25 mixture enantioselective desymmetrisation reaction. of anomers) gave the diol 13 from which the required isomer DOI: 10.1039/b204904j J. Chem. Soc., Perkin Trans. 1, 2002, 1631–1643 1631 This journal is © The Royal Society of Chemistry 2002 as 12.12 Unfortunately, the dipyrandione 18, synthesised by Jones’ oxidation of 14,12 was extremely insoluble in most organic solvents, and attempted Luche reduction followed by in situ acetylation (Ac2O, pyridine) gave mainly the dienol diacetate 19 (94% yield). In any case, 18 existed as a mixture of keto and enol tautomers, indicating that the valuable 1,4-syn stereochemical relationship present in 14 had not been pre- served. Scheme 2 The diol meso-13 was converted into other meso substrates for the desymmetrisation studies (Scheme 4). Most simply, Scheme 3 meso-13 was obtained in 41% yield by crystallisation. In a separate experiment, Luche reduction of the dipyranone meso- 12 gave the diol meso-13 in >98% yield. In the context of two- directional stereoselective functionalisation,10 the isolation of meso-13 in >98% yield as a >99 : 1 mixture of diastereoisomers must reflect a >99.5 : 0.5 diastereo- and regioselectivity for the reduction of each of the enones. In an attempt to reverse the sense of diastereoselectivity of Scheme 4 the reduction 12 13, we screened a range of reducing agents in the reduction of meso-12; for example, CBS reduction (BH3, meso-13 was protected as its p-methoxybenzoyl diester 20. 10 mol% 16), conditions known to favour 1,2-reduction of In the other diastereomeric series, the diesters 21 and 22 were enones,11 gave the same meso diol 13 in 94% yield as well as the prepared by reaction of the corresponding dimesylate with unsymmetrical hydroxyketone 17 (4% yield). Clearly the stereo- caesium acetate ( 21) and caesium p-methoxybenzoate chemical control exerted by the substrate 12 overpowers the ( 22).13 Hydrolysis of the diacetate 21 gave the diol 23 which reagent control offered by the chiral catalyst. The enantiomeric was silylated to give the tert-butyldimethylsilyl ether 24. The excess of 17 was not determined. The Luche reduction of diol 23 was also prepared from meso-13 in 36% yield by treat- ketoesters similar to 18 is known to proceed with comple- ment of its dimesylate with potassium superoxide and 18- mentary (syn) stereoselectivity to the reductions of enones such crown-6 in DMSO.14 1632 J. Chem. Soc., Perkin Trans. 1, 2002, 1631–1643 Table 1 Desymmetrisation of the difurans 8 and 10 Entry Starting material Reaction conditions Product Yield (%) Њ a 1a 8 m-CPBA, CH2Cl2, 0 C 25 48 a 1b 8 NBS, NaOAc, THF–H2O 25 44 bc 1c 8 Oxone, NaHCO3, acetone–H2O – ϩ f i d 1d 8 ( )-DET , 3 Å molecular sieves, CH2Cl2, Ti(O Pr)4, – – tBuOOH Њ e 2a 10 m-CPBA, CH2Cl2, 0 C 26 29 2b 10 NBS, NaOAc, THF–H2O 27 50 ϩ i dc 2c 10 ( )-DET, 3 Å molecular sieves, CH2Cl2, Ti(O Pr)4, – tBuOOH a Isolated as a 75 : 25 mixture of anomers. b Analysis of the crude reaction mixture by 300 MHz 1H NMR showed that only starting material was present. c A quantitative yield of starting material was recovered. d Analysis of the crude reaction mixture by 300 MHz 1H NMR showed that only the starting material and diethyl tartrate were present. e Analysis of the crude reaction mixture by 300 MHz 1H NMR showed it consisted of a 47 : 53 mixture of the pyranone 26 and the pyridine 27. f DET = diethyl tartrate. Investigations into desymmetrisations by Sharpless asymmetric not successful; some representative experiments are shown in oxidation Table 1 (entries 1d and 2c). An alternative strategy was to delay the key desymmetris- At the outset of our synthetic studies, we investigated the ation step to a later stage, again using the Sharpless asymmetric desymmetrisation of the difurans 8 and 10 (Scheme 5); our epoxidation reaction to induce asymmetry (Scheme 6). This Scheme 5 results are summarised in Table 1. In the first instance, the difuryl alcohol 8 and the difuryl sulfonamide 10 were reacted with achiral oxidants (entries 1a–c and 2a–b, Table 1). Treat- ment of 8 and 10 with m-CPBA gave the expected products 25 and 26, albeit in poor yield. The sensitivity of the piperidinone product 26 to the reaction conditions was revealed by the observation of the unexpected byproduct 27 (entries 1a and 2a, Scheme 6 Table 1). In an attempt to optimise the yield of the reaction, 8 and 10 were reacted under alternative reaction conditions using approach has previously been exploited in the desymmetris- N-bromosuccinimide as the oxidant: this modification did ation of complex meso bis-allylic alcohols.18 Accordingly, a 75 : not improve the yield of the pyranone 25 and, in fact, the yield 25 mixture of meso and unsymmetrical diols 13 was reacted of the unexpected byproduct 27 was increased. We account under standard Sharpless asymmetric epoxidation conditions for the formation of the pyridine 27 by aromatisation of the (Scheme 6).19 After 9 days reaction, a 14% yield of the enone 29 piperidinone 26 to give the pyridinium derivative 28, a com- was isolated as a single anomer together with 75% recovered pound which is analogous to the acylated DMAP complexes 15 starting material (87 : 13 mixture of anomers). The hydroxy which are intermediates in many acylation reactions; inter- ketone 29 was, however, shown to have >90% ee by conversion molecular N O transfer of the tolylsulfonyl group would into the corresponding (R)-Mosher’s ester 30. The sluggish give the aryl tosylate 27. Recently, a related ring expansion has nature of the oxidation reaction was not surprising in view of been reported in which 2-acylfurans are converted into the earlier studies involving cyclohexenols,‡ particularly since 13’s corresponding 3-hydroxypyridines.5 hydroxy groups are conformationally locked in pseudo equa- torial positions and are unable to direct the epoxidation reagent.