Chiral sulfide-mediated enantioselective epoxidation of aldehydes

Non-racemic epoxides were prepared via enantioselective Corey-Chaykovsky epoxidation of aromatic, heteroaromatic and cinnamic aldehydes with chiral sulfonium ylides. One-pot epoxidation using aldehydes, alkyl bromides and chiral sulfide in the presence of a base was also investigated. The chiral sulfide was easily synthesized in five steps from d -camphor through hetero Diels-Alder reaction as a key step.


Introduction
Epoxides are useful and important synthetic intermediates and found diverse applications in organic synthesis. 1Great concern focuses on development of synthetic methods for asymmetric epoxidation, as exemplified by the Sharpless, Katsuki, and Jacobsen olefin oxidations and Darzens approaches using carbonyl compounds. 2][6][7][8][9][10] The methodology involves the formation of sulfonium ylide which can be in situ generated via essentially two independent routes, viz.(i) alkylation of a sulfide, followed by deprotonation of the resulting sulfonium salt (salt method), [4][5][6][7][8][9] and (ii) coupling of a sulfide with a carbenoid (metal carbene) generated in situ from diazo compound or its precursor (e.g.tosyl hydrazone salt). 4,10The efficiency of asymmetric induction for the epoxidation undoubtedly depends largely upon chiral sulfides used.In very recent reports, efforts have been made on the synthesis of new chiral sulfides/sulfonium ylides as well as their use in not only epoxidation 11 but also aziridination 12 and cyclopropanation. 13Thus, information on a variety of new chiral sulfides and/or sulfonium ylides regarding the efficiency on yields and stereoselectivities for these reactions is necessary to understand chemistry from the synthetic and mechanistic points of view. 14The attractive advantages of exploiting natural d-camphor in asymmetric synthesis are its relatively inexpensive and easy availability, potent transformation ability, and promising asymmetric induction due to the topological differentiation efficiency apparently by virtue of the rigid framework of its derivatives. 15With this in mind, we envisioned that camphor framework-connected cyclic chiral sulfide would be of high potential as an asymmetric induction mediator in the epoxidation.In this full paper we describe our results in the enantiomeric Corey-Chaykovsky epoxidation with optimization of various factors and reaction conditions employing such camphor-derived homochiral tricyclic sulfide 1. 16

Preparation of Chiral Sulfide 1
The sulfide 1 was readily prepared from natural d-camphor in five steps in 50-60% overall yields (Scheme 1).The key step was the highly exo selective and complete π-face-selective hetero Diels-Alder reaction of 3-arylmethylenecamphorthiones 3 with methyl acrylate. 17The stereochemistry of cycloadducts 4 was unequivocally established by X-ray crystallographic analysis of 4 (Ar = Ph) and 1 H-NMR spectroscopic study. 17Although cycloadducts 4 or alcohols 5 essentially neither reacted with benzyl bromide to give sulfonium salts nor mediated epoxidation with aldehydes in the presence of a base, it was hoped that chiral sulfide 1 obtained by highly π-face-selective hydrogenation of 5 would act efficiently as a mediator in the epoxidation.Indeed, sulfide 1 worked well in the epoxidation by both methods, (A) the epoxidation of aldehydes using sulfonium salt prepared in advance and (B) the one-pot epoxidation starting from aldehyde, alkyl halide and sulfide 1 in the presence of a base.Scheme 2. For specification of the substituent R 1 , see Table 6.
Sulfonium perchlorate 7a, which was prepared by the reaction of chiral sulfide 1 with benzyl bromide and silver perchlorate, was allowed to react with aldehyde 6b (R 1 = p-NO 2 C 6 H 4 ) as a model reaction to find first a suitable base under the conditions (Table 1).In all the cases trans epoxide (trans-8b) was obtained as the major product with enantiomeric excess (ee) of 71-79 %.Among the bases used KOH seems to be the best of choice in the balance of yield and enantioselectivity.Then, we explored the same reaction in the presence of KOH to optimize reaction conditions by varying solvent, temperature and reaction time.The results are shown in Table 2.In every case high trans:cis selectivity was obtained.As the reaction temperature becomes lower (runs 2-6 and 7-10), the trans:cis selectivity and the enantioselectivity both become higher in the same solvent, as expected.As for the solvent effect on the enantioselectivity and the diastereoselectivity, higher ee's values could be attained in more polar solvents than in less polar solvents, whereas the reverse propensity was observed for the diastereoselectivity.This effect would not simply arise from solubility of the sulfonium perchlorate 7a because 7a is soluble enough in either solvent under the conditions applied.Quite recently, an excellent rationale has been proposed by Aggarwal et al. to explain origins of both of the stereoselectivities by unraveling the mechanism.10a This tendency of the solvent effect was also observed in the reaction of benzaldehyde (6a) to give epoxide 8a (Table 3).Since in more polar solvents higher enantioselectivity was obtained as described above, we further examined the reaction by adding water as a co-solvent.The results are summarized in Table 4.As the ratio water/solvent increases (runs 1-5 and 9-11), the enantioselectivity goes up, while the trans:cis ratio gradually decreases. 18At a temperature of -40 o C in MeCN-H 2 O (7:3) (runs 6 and 7), the highest ee's of 86% and 91% were achieved albeit in lower isolated yield.In the reaction in the medium of water (run 8) equally good enantioselectivity of 80 % ee was obtained, though the isolated yield was very low.The low yield may be due to sparing solubility of the aldehyde 6 and/or generated sulfonium ylide into the water, since considerable amounts of 6 unreacted was recovered.
Furthermore, effects of the counter anion of the sulfonium salts for the epoxidation were also checked.As a result, no significant differences of the yields and both the stereoselectivities were observed (Table 5).In order to examine the generality of this epoxidation, the reaction of 7a with aldehydes 6 bearing a variety of substituents (R 1 ) was performed under the conditions optimized above in terms of balance of the reactivity (yield) and the diastereo-and enantioselectivities.The results are shown in Table 6.Apparently, the electron-withdrawing substituents accelerate the reaction, whereas the electron-repelling ones retard the reaction.By using 2.0 equimolar amounts of 7a, the results could be somewhat improved (runs d and e).
It is noteworthy that chiral sulfide 1 was recovered enantiomerically pure in good yields in the cases that good isolated yields of epoxides 8 were obtained (Tables 2 -6) and could be reused.
By employing this epoxidation method, trans-oxiranylcarboxamide 10 could be synthesized in high trans : cis selectivity with fairly good enantioselectivity (Scheme 3, Table 7), which are comparable to those in recent report.5a,11e However, it was found that an electron-withdrawing group such as a nitro group in aldehyde 6 is necessary to activate the formyl group in the epoxidation with this amide-stabilized sulfonium ylide generated from salt 9.

Scheme 4
Establishing the method (A) using sulfonium salt 7 or 9 prepared beforehand, we next performed three-component one-pot epoxidation of 6 with alkyl bromide and chiral sulfide 1.A model reaction using benzaldehyde 6a (1.0 equiv), benzyl bromide (3.0 equiv) and chiral sulfide 1 (1.0 equiv) in acetonitrile under the conditions furnished the desired epoxide 8a in 72 % yield with high diastereoselectivity (trans:cis = 96:4) and with moderate enantioselectivity (56 % ee) of the trans isomer, when K 2 CO 3 was used as a base (Table 8, run 1).Cs 2 CO 3 can also be a candidate as a base.Encouraged by this result, we next screened solvents for better stereoselectivities (Table 9).Among the solvents used, the reaction in t-butyl alcohol showed the best enantioselectivity of 71 % ee of the trans isomer albeit in lower isolated yield and with somewhat decreased diastereoselectivity (run 4).The reaction in tetrahydrofuran or acetone gave only a trace amount of epoxide 8a.Acetonitrile and t-butyl alcohol can be the solvent of choice for diastereo-and enantioselectivities, whereas water-containing acetonitrile was less effective in contrast to the above results in Table 4.At a higher temperature of 83 o C the reaction was indeed accelerated (2 h, in t-BuOH) but the enantioselectivity of trans isomer was depressed to 44% ee.In order to see possibility of the catalytic process of this one-pot epoxidation, the reactions of 6a,b with benzyl bromide in the presence of varied quantities of chiral sulfide 1 were examined.The results are shown in Table 10.Obviously, degrees of the diastereo-and enantioselectivities in each reaction were not so markedly decreased by reducing the amounts of 1 added, while the reaction became slow (runs 1-4 and 5-8).The electron-withdrawing p-nitro substituent of benzaldehyde obviously accelerated the reaction and good yield of epoxide 8b was obtained.Although sub-stoichiometric amounts of sulfide 1 are necessary to obtain higher yields and stereoselectivities, a merit of this epoxidation is that after the reaction, chiral sulfide 1 was recovered optically pure in good yield and could be reused.Finally, the reactions of variously substituted aromatic aldehydes 6 and alkyl bromides were carried out in the presence of an equimolar amount (n =1.0) of 1 under the optimized reaction conditions.The epoxides 8 were obtained in fairly good yields and stereoselectivities (Table 11).From the viewpoint of enantioselectivity, it is suggested that recommended are the reactions with benzyl bromide in t-BuOH for syntheses of trans-epoxides 8a-c,e and 8g (runs 12-14, 16, and 17), whilst the reaction with p-methylbenzyl bromide in MeCN (run 10) is preferable to those of runs 4 and 15 for synthesis of trans-2-phenyl-3-p-tolyl epoxide 8d.In this one-pot method, the chiral sulfide 1 used was again virtually quantitatively recovered enantiomerically pure after the reaction and could be used repeatedly.Rationale for enantio-and diastereoselectivities

Scheme 5
Recently, mechanisms of carbonyl epoxidation with sulfonium ylide based on computational studies have been proposed by Aggarwal et al. 14a and Koskinen et al.. 14b On the basis of their proposal, the predominant formation of (S,S)-trans-stilbene oxides observed in the epoxidation with the sulfonium ylide derived from chiral sulfide 1 can essentially be explained as illustrated in Scheme 5. (i) The sulfonium ylide adopts two dominant conformations in which the filled orbital on the ylide carbon is orthogonal to the sulfur lone pair.(ii) The conformation having the R 2 group in an equatorial position is favored over the other one with an axial R 2 group due to steric repulsion between the R 2 group and the diaxial protons in the thiane ring.(iii) The aldehyde attacks the ylide carbon preferably from the less hindered Si face with an arrangement of the aldehyde as to be attacked from the Re face or the Si face in a manner of cisoid ([2+2]) or gauche addition with coulombic interaction to form the cisoid betaines.The former (Si-Re) cisoid betaine forms the anti-transoid betaine via the rotation around the C-C bond.The internal nucleophilic substitution with trans elimination of sulfide 1 leads to a stereoselective formation of (S,S)-trans-epoxides, while the syn-transoid betaine formed from the syn-cisoid betaine (Si-Si) leads to (S,R)-cis-epoxide.The higher becomes the activation barrier in the tortional rotation step from the syn-cisoid (Si-Si) to the syn-transoid betaine, the greater increases the degree of reversibility to the starting materials; thus, it leads to high trans selectivity.The distribution of these key species involved in the pathways is significantly influenced by the factors such as substituents (electronic property, steric hindrance) and solvents (charge solvation).† Although the sense of asymmetric induction and diastereoselectivity could be thus explained, the observed enantioselectivity was not so high than that expected.This is ascribable most likely to partial release of controlling the ylide conformation as the factor (ii), 11c nevertheless, much better enantioselectivity was observed in the imino Corey-Chaykovsky aziridination by the use of the same ylides derived from sulfide 1. 12a It is also noteworthy that a simple, relatively less congested C 2 -symmetric sulfide (2,5-dimethylthiolane, 2,5-diethylthiolane) is an efficient catalyst for the epoxidation via the ylide route. 6

Conclusions
The present study demonstrates diastereo-and enantioselective synthesis of optically active epoxides via the Corey-Chaykovsky reaction.Although the stereoselectivities observed were moderate to good, the methods are promising because of the easy and simple but efficient preparation of the chiral sulfide with good crystallinity and the feasible introduction of a variety of substituents to the tetrahydrothiopyran ring to tune up the stereoselectivities by further manipulation.Moreover, the chiral sulfide can be recovered optically pure and essentially quantitatively and reused.

Experimental Section
General Procedures.Melting points are uncorrected.Analytical TLC was carried out on Merk silica gel 60 F254 plates.Visualization was performed with UV light, p-anisaldehyde/sulfuric acid, phosphomolybdic acid, and/or KMnO 4 .Column chromatography was conducted on silica gel (100-200 mesh) or on alumina (100-200 mesh).IR spectra were recorded on a Hitachi Model 270-30 instrument. 1 H NMR and 13 C NMR spectra were measured at 100, 270 and/or 500 MHz for 1 H, and at 25, 67.8 and/or 125.65 MHz for 13 C using JEOL JNM-FX 100, JEOL JNM-EX 270 and JEOL JNM-LA 500 spectrometers.Chemical shifts from tetramethylsilane (TMS) as an internal standard are given in ppm and coupling constants, J, in Hz.Mass spectra (EI or FAB) were obtained with a Hitachi Model M-80B double focusing mass spectrometer with a data processing system M-0101.Elemental combustion microanalyses were performed on a Perkin-Elmer 2400 CHNS/O Elemental Analyzer.Optical rotations were recorded on a Nippon Bunko Model DIP-370 digital Polarimeter and are reported in units of 10 -1 degcm 2 g -1 .Enantiomeric excesses and ratios of trans and cis isomers were determined by HPLC measurement using † Aggarwal et al. proposed a general rationalization for the origins of diastereo (trans vs. cis)and enantioselectivities including their dependence on substituents and solvents in the sulfur ylide-carbonyl epoxidation.For further discussion, see literature 10a,14a .chiralcel OD, AD and AS columns (0.5-20 % i-PrOH-hexane, 0.3-5 % EtOH-hexane) on a Millipore-Waters 996 instrument or Shiseido Model S-MicroChrom instrument.
Column chromatography conditions and chiral HPLC analyses conditions and data for various epoxides are listed below.
Scheme 3 0 equiv.6a, 3.0 equiv.benzyl bromide and 1.0 equiv. 1 in the presence of a base (3.0 equiv.).b Isolated yields.In square brackets, yields based on consumed amounts of benzaldehyde 6a.c Determined by HPLC [Chiralcel OD, i-PrOH-hexane (1:100)].The absolute configuration was assigned [S,S] by comparison of the sign (-) of specific rotation with the literature data.d For 1 day.

a
Reactions were carried out in the presence of K 2 CO 3 (3.0equiv.) at room temperature for 4 days using 1.0 equiv.6a, 3.0 equiv.benzyl bromide and 1.0 equiv.1. b Isolated yields.In square brackets, yields based on consumed amounts of benzaldehyde 6a.c Determined by HPLC [Chiralcel OD, i-PrOH-hexane (1:100)].The absolute configuration was assigned [S,S] by comparison of the sign (-) of specific rotation with the literature data.d For 1 week.

a
Reactions were carried out at room temperature (22-25 o C) using 1.0 equiv.6 and 3.0 equiv.alkyl bromide in the presence of K 2 CO 3 (3.0equiv.)as a base.b Isolated yields.In square brackets, yields based on consumed amounts of aldehyde 6. c Determined by HPLC [Chiralcel OD or AD, i-PrOH-hexane (1:20-200) or EtOH-hexane (1:20-50)].The absolute configuration of trans isomers was assigned [S,S] by comparison of the sign (-) of specific rotation with the literature data or by assumption.d ortho-O-benzylated epoxide was obtained.

Table 2 .
Epoxidation of 6b (R 1 = p-NO 2 C 6 H 4 ) with 7a to afford 8b under various reaction conditions a

Table 2 .
Continued a KOH (1.2 equiv) was used as a base.b Isolated yields.In square brackets yields based on consumed amounts of 6b.c Determined by HPLC [Chiralcel OD, i-PrOH-hexane (1:30)].

Table 3 .
Effects of solvent in epoxidation of 6a (R 1 =Ph) with 7a to afford 8a a

Table 4 .
Effects of water added as a co-solvent in epoxidation of 6b (R 1 = p-NO 2 C 6 H 4 ) with 7a to afford 8b a

Table 6 .
Epoxidation of 6 bearing a variety of substituents with 7a to afford 8 a a Reactions were carried out in t-BuOH at room temperature (22-25 o C) using KOH (1.2 equiv.)as a base.bIsolatedyields.cDeterminedby HPLC [Chiralcel OD or AD, i-PrOH-hexane (1:20-200) or EtOH-hexane (1:20-300)].The absolute configuration of trans isomers was assigned by comparison of the (-) sign of specific rotation with literature data or by assumption.dInparentheses values taken from run 7 in Table4.e In square brackets values when 2.0 equiv.7a was used.

Table 8 .
Effects of base in one-pot epoxidation to afford 8a a Reactions were carried out in MeCN at room temperature for 4 days using 1.

Table 9 .
Effects of solvent in one-pot epoxidation to afford 8a a

Table 10 .
Dependence on stoichiometry of chiral sulfide 1 in one-pot epoxidation of 6a,b to afford 8a,b a Reactions were carried out in the presence of K 2 CO 3 (3.0equiv.) in MeCN at room temperature using 1.0 equiv.6a,b, 3.0 equiv.benzyl bromide and n equiv.1. b Isolated yields.In square brackets, yields based on consumed amounts of benzaldehyde 6a.c Determined by HPLC [Chiralcel OD, i-PrOH-hexane (1:50-100)].The absolute configuration was assigned [S,S] by comparison of the sign (-) of specific rotation with the literature data.