696 HARADA g9 Tofenacin 20 2 Fig.9.Chiral drugs with a D on.How methylamin vridine (DMAP). 1 2)HPLC 25 图62 -11600 (R)(-)-26a,X-ray S--26 80mg injected. HO H 00- D R+25 C.DMAP CHande Fig 11.HPLC separation of CSDP esters 26a and 26b. Chirality DOI 10.1002/chir
The desired molecular tool, CSDP acid (2)-1, was synthesized by reacting (1S,2R,4R)-(2)-2,10-camphorsultam anion with 4,5-dichlorophthalic anhydride: acid (2)-1, mp 2218C from EtOH; ½a 20 D 2101.1 (c 1.375, MeOH).64 This carboxylic acid was condensed with alcohol under the conditions of 1,3-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). Various chiral drugs with a diphenylmethanol skeleton have been developed as shown in Figure 9. Among them, the absolute configurations of some drugs have remained undetermined. In addition, those drugs were prepared mostly by means of asymmetric syntheses and/or enzymatic reactions. Therefore, it is hard to obtain enantiopure drugs without purification by recrystallization. How can we determine the absolute configuration of these chiral drugs and also obtain enantiopure compounds? To solve these problems, we have applied the CSDP acid method to various diphenylmethanols as follows. To exemplify a general procedure of the CSDP acid method, we show here the results of chiral (2,6-dimethylphenyl)phenylmethanol (25). The CSP acid (2)-1 was allowed to react with (6)-25 using DCC and DMAP in CH2Cl2 yielding diastereomeric esters, which were effectively separated by HPLC on silica gel: hexane/EtOAc 5 6:1; a 5 1.25, Rs 5 1.94 (Figs. 10 and 11).66 The firsteluted ester (2)-26a obtained was recrystallized from EtOH giving prisms. A single crystal of 26a was subjected to X-ray analysis affording the ORTEP drawing as shown Fig. 9. Chiral drugs with a diarylmethanol skeleton. Fig. 10. Preparation of CSDP esters: DCC, DMAP in CH2Cl2 and recovery of enantiopure alcohol (R)-(1)-25. 66 Fig. 11. HPLC separation of CSDP esters 26a and 26b. 66 696 HARADA Chirality DOI 10.1002/chir
ABSOLUTE CONFIGURATIONS BY X-RAY AND H NMR 697 In the case of halogenated alcohols 29 and 30.their heenamntiopee )30 ws trea A=5=55作 Fg12.ORTEP draing of图-(-26a“ (entry 6).Ther )rem 26 inTHF yielded h own in.Table 2.the tooled to various supsn tiopure alce g35.37-4号 rations. the indirect chemical co ,and51-56 acid alco e 36 ar way bs ard mar dternined 10 & adopted as In the case of alcohols 27 and 28.those solved as CSDP esters, wher the primary alcoho erified (entry re a chir by 6 was 12)he s 1 and 8. and the a but it The lata o be oted that the on as e gel than the co nding CSP acid esters:s aration fac toohcrrehimgog Alcohol (3R,4R)-(+)-47 is a r the syn es in one rotationa Chirality DOI 10.1002/chin
in Figure 12, from which the absolute configuration of the alcohol part was clearly determined as R based on the absolute configuration of the camphorsultam moiety used as an internal reference. The R absolute configuration of 26a was also confirmed by the heavy atom effect of two chlorine and sulfur atoms contained. The reduction of the first-eluted ester (R)-(2)-26a with LiAlH4 in THF yielded enantiopure alcohol (R)-(1)-25. 66 Although the reduction with LiAlH4 was used here to recover the alcohol, we found later that the solvolysis with K2CO3 in MeOH as a more mild condition is also applicable to most CSDP esters. As shown in Table 2, the method using CSDP and/or CSP acids has been successfully applied to various substituted diphenylmethanols 27–33, 35, 37–42, and 51–56 (entries 2–14 and 23–28). Namely the diastereomeric esters prepared from racemic alcohols and CSDP acid (1S,2R,4R)-(2)-1 were effectively separated by HPLC on silica gel with separation factor a 5 1.10–1.34. It is known that if the separation factor a is larger than 1.10, the two components are baseline separable, yielding pure compounds. In the case of alcohols 32, 38, 40, 51, 52, and 54–56, the CSDP acid method has been applied in a straightforward manner; the separated CSDP esters were recrystallized giving single crystals, which were subjected to X-ray crystallography (entries 7, 11, 12, 23, 24, and 26– 28). The absolute configurations of the alcohol parts were thus explicitly determined. In the case of alcohols 27 and 28, those compounds were previously enantioresolved by means of CSP acid (1S,2R,4R)-(2)-2, a similar chiral auxiliary developed by us as shown in Figures 1 and 8, and the absolute configurations of their CSP esters were determined by X-ray crystallography (entries 20 and 30 ). So, by comparison with the data, the absolute configurations of CSDP acid esters of alcohols 27 and 28 were established by chemical correlation. It should be noted that the CSDP acid esters of 27 and 28 were more effectively separated by HPLC on silica gel than the corresponding CSP acid esters: separation factor a 5 1.20–1.26 vs. 1.1 (entries 2, 20 , 3, and 30 ). In general, CSP acid esters have low solubility, possibly due to too better crystallinity, resulting in longer elution time and smaller a value in HPLC on silica gel. In addition, CSP esters were often obtained as fine needles, which were unsuitable for X-ray crystallography. Therefore CSDP acid 1 is more useful in most cases than CSP acid 2. In the case of halogenated alcohols 29 and 30, their diastereomeric CSDP esters were obtained as fine crystals, which were unsuitable for X-ray crystallography. So, as described above, the enantiopure alcohol (2)-29 recovered was converted to camphanate ester, the absolute con- figuration of which was determined by X-ray crystallography as R (entry 4, Table 2). Alcohol (2)-30 was treated in the same way, but its camphanate ester was not suitable for X-ray analysis (entry 5). The absolute configuration of (2)-30 was determined as R by the comparison of its CD spectrum with that of (R)-(2)-29. Methyl-substituted alcohol 31 could not be enantioresolved by the CSDP acid method, because of the small difference in substituent effects: Me vs. H (entry 6). Therefore, we have adopted the chemical conversion method as follows: racemic alcohol 32 with 4-Me and 40 -Br groups was effectively enantioresolved as CSDP esters, the absolute configuration of which was determined by X-ray crystallography (entry 7). The enantiopure alcohol (R)-(2)-32 obtained was reduced to remove Br atom yielding (S)-(2)- 31. Alcohols 34 and 36 are very unique chiral compounds, the chirality of which is generated by the substitution of isotopes: in the case of 34, H vs. D; in the case of 36, 12C vs. 13C. So, it is very difficult to recognize directly such an ultimately small chirality. To synthesize enantiopure alcohols 34 and 36, and to determine their absolute configurations, the indirect chemical conversion method was employed as follows. For example, deuterium-substituted/ 4-Br alcohol 35 was similarly enantioresolved as in the case of compound 29 (entry 9). The enantiopure alcohol (S)-(2)-35 obtained was reduced to remove the Br atom yielding [CD(2)270.4]-(S)-34, which exhibits a negative CD Cotton effect at 270.4 nm. In a similar way, 13C-substituted diphenylmethanol [CD(2)270]-36 was synthesized in an enantiopure form and its absolute configuration was determined as S (entry 10). Although the CSDP acid method was easily applicable to o-methoxy-substituted alcohol 38 (entry 11), o-methylsubstituted alcohol 39 could not be enantioresolved as the CSDP acid esters. So, the indirect method was adopted as follows: o-hydroxymethyl-substituted alcohol 40 was enantioresolved as CSDP esters, where the primary alcohol moiety was esterified (entry 12). Enantiopure alcohol (R)- (1)-40 was then converted to the target compound (R)- (2)-39. It should be noted that the absolute configuration of alcohol 39 was once estimated on the basis of asymmetric reaction mechanism, but it was revised later by this study. The data of alcohols 41 and 42 indicate that the HPLC separation as CSDP esters is easier for silyl ethers (entries 13 and 14). The CSDP acid method was applicable to benzyl alcohols 43–46 and naphthalene alcohols 47–49, the CSDP esters of which were effectively separated by HPLC on silica gel with a 5 1.11–1.38 (entries 15–21). In addition, except the case of 45, the absolute configurations of their CSDP esters were determined by X-ray crystallography. Alcohol (3R,4R)-(1)-47 is a key compound for the synthesis of a light-powered chiral molecular motor [CD(2)237.2]-(2)-59a, which rotates in one rotational Fig. 12. ORTEP drawing of CSDP ester (R)-(2)-26a. 66 ABSOLUTE CONFIGURATIONS BY X-RAY AND 697 1 H NMR Chirality DOI 10.1002/chir
69 HARADA NO S)(--27 (R)-(-28 (R--29 HO (S--31 （R-)32 (R(-+33 HO H 1CD-270.41-3435 1CD-270-(S-36((-)37 CHaO HO H HO H CHa O☆ ((-→38 (R)-)39 (R-(+40 网R=TBDS HO H (-(-43 (⑤(-)44 (R)-(+)-45 (R)-(+)46 ⊙Oon 9 HO ⊙O HO 3R.4-+)-47 (1R,2S-(+148 (1S.4R-49 ⊙Om (aR,aR)-→50 HO H HOH C c (R(-51 (R-()52 (R)-53 ChiraiyDO110.1002/chir
TABLE 2. Enantioresolution of alcohols by HPLC on silica gel using (1S,2R,4R)-(2)-CSDP acid 1, and determination of their absolute configurations by X-ray crystallography 698 HARADA Chirality DOI 10.1002/chir
ABSOLUTE CONFIGURATIONS BY X-RAY AND 'H NMR 69g TABLE2.Continued HO H oCO (6(-)54 Me0(5)55 +-56 (15.25(+)57 59-58 Entry Alcoho Solvent ab X-ray SP FaKHarnbNiLnpubishedih -5/1 y(Ist.Fr.) 53 Fujita K.Harada N (lst.Fr) o 33456789012314151671890234567890 57776880900132853784411431441561118140012854558678 Fujita K.Harad y(Ist,Fr.) =5 n (n 69 TiH.Harada N.upublished data (2nd.Fr.) unpublished data 1R.2R 4444558 @where f:and 1 tion times o对hei ctions,respectively,and to is the reten t-and seo d-eluted the bas level respe ih()-()-CSPacid 2 y al moiety Chirality DOI10.12/chir
TABLE 2. Continued Entry Alcohol Solventa ab Rs c X-rayd Abs.Config. First Fr. Ref. 1 25 H/EA 5 6/1 1.25 1.94 y (1st, Fr.) R 66 2 27 H/EA 5 4/1 1.20 0.91 – S Fujita K, Harada N. unpublished data. 20e 27 H/EA 5 4/1 1.1 1.3 y (1st, Fr.) S 67 3 28 H/EA 5 5/1 1.26 1.37 – R Fujita K, Harada N. unpublished data. 30e 28 H/EA 5 5/1 1.1 1.6 y (1st, Fr.) R 67 4 29 H/EA 5 8/1 1.1 1.3 y f R 29 5 30 H/EA 5 6/1 1.17 0.95 – R Fujita K, Harada N. unpublished data. 6 31 H/EA 5 7/1 – – – – 67 7 32 H/EA 5 8/1 1.18 0.83 y (1st, Fr.) R 67 8 33 H/EA 5 4/1 1.1 1.0 – R Fujita K, Harada N. unpublished data. 9 35 H/EA 5 8/1 1.21 1.07 y f S 29 10 37 H/EA 5 4/1 1.27 1.20 y f S 68 11 38 H/EA 5 5/1 1.12 1.01 y (1st, Fr.) S 69 12 40 H/EA 5 4/1 1.14 0.91 y (2nd, Fr.)g R 69,70 13 41 H/EA 5 10/1 1.26 1.03 – R 69 14 42 H/EA 5 6/1 1.26 1.29 – R Taji H, Harada N. unpublished data. 15 43 H/EA 5 5/1 1.16 1.11 y (1st, Fr.) S 71 16 44 H/EA 5 5/1 1.12 0.87 y (1st, Fr.) S 71 17 45 H/EA 5 2/1 1.11 0.88 – R 71 18 46 H/EA 5 2/1 1.38 1.19 y (1st, Fr.) R 71 19 47 H/EA 5 7/1 1.18 1.06 y (2nd, Fr.) 3R,4R 27,64 20 48 H/EA 5 7/1 1.23 1.27 y (1st, Fr.), y (2nd, Fr.) 1R,2S Koumura N, Harada N. unpublished data. 21 49 H/EA 5 10/1 1.30 1.74 y (1st, Fr.) 1S,4R 64 22 50 H/EA 5 3/1 1.2 1.6 y (2nd, Fr.) aR,aR 72,73 23 51 H/EA 5 5/1 1.34 2.37 y (1st, Fr.) R 74 24 52 H/EA 5 5/1 1.16 1.22 y (1st, Fr.), y (2nd, Fr.) R 74 25 53 H/EA 5 5/1 1.11 1.33 – R 74 26 54 H/EA 5 4/1 1.21 2.50 y (1st, Fr.) S 74 27 55 H/EA 5 5/1 1.16 1.42 y (1st, Fr.) S 75 28 56 H/EA 5 4/1 1.15 1.34 y (1st, Fr.) S 75 29 57 H/EA 5 10/1 1.17 1.79 y (2nd, Fr.) 1R,2R 28 30 58 H/EA 5 4/1 1.27 1.49 y h S 51 a H 5 n-hexane, EA 5 ethyl acetate. b Separation factor a 5 (t2 2 t0)/(t1 2 t0) where t1 and t2 are the retention times of the first- and second-eluted fractions, respectively, and t0 is the retention time of an unretained compound (void volume marker). c Resolution factor Rs 5 2(t2 2 t1)/(W1 1 W2) where W1 and W2 are the band-widths of the first- and second-eluted fractions at the base-line level, respectively. d y: yes. e The case of esters with (1S,2R,4R)-(2)-CSP acid 2. f X-ray analysis of camphanate ester. g CSDP ester of the primary alcohol moiety. h X-ray analysis of 4-bromobenzoate. ABSOLUTE CONFIGURATIONS BY X-RAY AND 699 1 H NMR Chirality DOI 10.1002/chir
HARADA s-CD(27)50 6R7 figuration could be dete absol hirality method. se of alcohols 51. 52.and 54.the X-ray crystallography s2SMME9e257s6a (M.M0-(E-CD(+)239.060 ework of these compounds t 2s2S9-MMCDe270.061 -()7was ne y X-ray e stereochems59a has two methygo the e mtor ad recr c Chirality DOI 10.1002/chir
direction by the use of light energy (see Fig. 13). cis-Olefin [CD(2)238.0]-59c is one of the motor rotation isomers. The molecular framework of these compounds takes a twisted structure, the absolute configuration of which is defined as (P,P) or (M,M). Compound [CD(1)239.0]-60 also takes a similar twisted structure, and therefore it shows a strong positive CD band at 239.0 nm. To determine the absolute configuration of [CD(1)239.0]-60, we have adopted the next strategy. Enantiopure alcohol (3R,4R)-(1)-47 was prepared by the CSDP acid method, and its absolute configuration was determined by X-ray crystallography. Starting from (3R,4R)-(1)-47, chiral molecular motors [CD(2)237.2]-(2)-59a and [CD(2)238.0]- 59c were synthesized, and a single crystal of (2)-59a was subjected to X-ray analysis. As compound (2)-59a contains no heavy atoms, X-ray analysis provided the relative stereochemistry, but not the absolute configuration. However, compound (2)-59a has two methyl groups at chiral positions, i.e., (3R,30 R) configuration, which can be used as internal references of absolute configuration. We have thus determined the absolute sense of helicity of (2)-59a as (P,P). So, the chirality of the molecular motor is expressed as (3R,30 R)-(P,P)-(E)-[CD(2)237.2]-(2)-59a. As the CD spectrum of [CD(1)239.0]-60 is almost mirror image of (3R,30 R)-(P,P)-(E)-[CD(2)237.2]-(2)-59a, the absolute helicity of [CD(1)239.0]-60 was determined as (M,M)-(E). This is another unique example of the use of internal reference in X-ray crystallography. Ternaphthalene-dimethanol 50 is an interesting compound having three naphthalene chromophores in chiral positions. Therefore, it was expected that it would show intense exciton-coupled CD, from which its absolute con- figuration could be determined. The CSDP esters of 50 were separable with a 5 1.2 (entry 22), and the absolute configuration of the second-eluted fraction was determined by X-ray crystallography. The (aR,aR) configuration of (2)-50 agreed with the assignment by the CD exciton chirality method. Various fluorinated diphenylmethanols 51–54 were also enantioresolved as CSDP esters (entries 23–26). In the case of alcohols 51, 52, and 54, their absolute configurations were determined by X-ray crystallography. MetaFig. 13. Synthesis of a light-powered chiral molecular motor 59a and determination of its absolute configuration. Fig. 14. A new model of light-powered chiral molecular motor 61a: (a) synthesis and (b) X-ray stereostructure of racemic motor (6)-61a. 700 HARADA Chirality DOI 10.1002/chir