Stereocontrolled synthesis and cyclization of (+,-)-alpha;,alpha;'-dihydroxy-alpha;,alpha;',beta;-trimethylglutaric acid derivatives

摘要

Mendeleev Communications Electronic Version, Issue 2. 1997 (pp. 47ndash;86) Stereocontrolled synthesis and cyclization of (+,ndash;)- , '-dihydroxy- , ', -trimethylglutaric acid derivatives Igor V. Vystorop,*a Ivan I. Chervin,b Andrei N. Utienyshev,a Carlos Jaime,c Xavier Saacute;nchez-Ruiz,c Sergei M. Aldoshina and Remir G. Kostyanovsky*b a Institute of Chemical Physics in Chernogolovka, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russian Federation.Fax: +7 096 515 3588; e-mail: vystorop@icp.ac.rub N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 117977 Moscow, Russian Federation. Fax: +7 095 938 2156 c Department de Quiacute;mica, Universitat Autograve;noma de Barcelona, 08193 Bellaterra, Spain. Hydrocyanation of 3-methylpentane-2,4-dione stereospecifically gave trans,trans-iminolactone 1, whose configuration was established by X-ray diffraction of the corresponding lactone 2; the rate of cyclization of the diastereoisomeric lactonic acids 3a,b and their esters 4a,b into dilactone 5 was controlled sterically by the methyl groups with cis,cis-isomers 3b, 4b predominating; alcoholysis of 5 regiospecifically afforded ester 4b.In preceding papers1,2 we have reported the synthesis and stereochemical principles of cyclization in the series of a,a'-dihydroxy-a,a'-dialkylglutaric acids (DDG) derivatives. It was shown that an increase in the size of the alkyl substituents R by replacement of both Me groups with But groups leads to (i) a change of the stereoselectivity in the 1,3-diketone hydrocyanation from the formation of solely meso (R = Me)1 to that of solely (+,ndash;)-DDG derivatives (R = But)2 and (ii) the facilitation of the dilactone C formation from (+,ndash;)-DDG monolactones1,2 owing to an increase in the population of the conformer B, which has functional groups suitably cis-pseudoa, a-oriented for cyclization.In the present report,3 the influence of an additional b-methyl substituent upon the stereocontrolled formation and cyclization of DDG derivatives (R = Me) was investigated. Hydrocyanation of 3-methylpentane-2,4-dione (MPD) was carried out under the described4 reaction conditions (Scheme 1).The only compound obtained was the iminolactone 1. It follows that the introduction of a methyl group at the a-position of pentane-2,4-dione results in a change of the hydrocyanation stereoselectivity, as in the case of dipivaloylmethane.2 In the strong predominant keto-form of MPD (e.g. 97.2 in aqueous medium)5 the anti,anti-conformation (Scheme 1) is prefered6 due to a minimization of both the dipolendash;dipole interactions of the carbonyl groups and the nonbonded 1,2- interactions of the methyl groups. Therefore, the stereospecificity of formation of the intermediate (+,ndash;)- biscyanohydrin (+,ndash;)-BCH may be mainly attributed to the steric control of the a-methyl group upon approach of the attacking nucleophile (CNndash;) to the C=O group of MPD and then of intermediate monocyanohydrin (MCH, Scheme 1, only R,R-enantiomers are shown).Spontaneous cyclization of (+,ndash;)-BCH into the stereoisomer 1, with a trans,trans mutual arrangement of the methyl groups, is the result of repulsive 1,2-interactions between the methyl groups and also by lesser steric hindrance from the b-methyl group upon cyclization of anti-oriented functional groups (Scheme 1).The configuration of iminolactone 1, namely, the cis-orientation of CN and OH groups as well as the preferable pseudo-e-positions of all the methyl groups, was established by an X-ray diffraction studydagger; of the corresponding lactone 2 (Figure 1).The same configuration of lactone 2 in solution was determined by NMR spectroscopyDagger; by comparison of the spinndash;spin coupling constants (3JC,H) with the dihedral angles in the crystal (Figure 1). A mixture of the diastereomeric lactonic acids 3a and 3b (ca. 3 : 2, according to the 1H NMR spectrum) was prepared by hydrolysis of 2 followed by separation by fractional crystallization from acetonendash;benzene.The preference of the isomer 3a formation from intermediate (+,ndash;)-a,a'-dihydroxy- a,a',b-trimethylglutaric acid (+,ndash;)-DTG may be caused by the steric effects of the methyl groups, as in the case of stereocontrolled cyclization of (+,ndash;)-BCH (Scheme 1). The configuration of 3a and 3b assigned (+,ndash;), was confirmed by identification of the alkaline hydrolysis products of 3a,b and 5 with the (+,ndash;)-DTG salt.Dagger; The relative rates of acid-catalysed lactonization of the diastereomeric monolactones 3a and 3b (in the presence of CF3CO2H) as well as their esters 4a and 4b (TsOH, Scheme 1) to the unsymmetrical dilactone 5 were estimated by 1H NMR through the lsquo;half-livesrsquo; of the reactants.It was found that the cis,cis-isomers 3b and 4b react 8 and 4 times faster than do the trans,trans-isomers 3a and 4a, respectively. In contrast to the (+,ndash;)-DDG derivatives, the relative acceleration of cyclization of 3b and 4b cannot be explained by an increase in the population of the conformer B (the Cohen model9 of stereopopulation control), because this conformer strongly predominates over the conformer A in 3a (90.4) and 4a (91.7) in contrast to 3b (27.8) and 4b (28.8).The populations of conformers A and B were calculated using Allingerrsquo;s MM2(91) program,10 an improved version of the MM2(77) force field,11 and confirmed by spectroscopyDagger; of 3a and 4a (3JC-1,3-H and 3JC-5,3-H). dagger; Crystal data for 2: C8H11NO3, M =169.18, monoclinic, space group P21/c, a =11.140(2), b =13.334(3), c =12.266(2)Aring;, b =86.97(3)deg;, V =1819.5(3)Aring;3, Dc =1.235gcmndash;3, Z =4.Intensities of 3840 independent reflections with I 2s(I) were collected on an automatic four-circle diffractometer KM-4 using MoKa radiation. The structure was solved by the direct method (SHELX-86 program7) and refined by full-matrix least-squares technique in anisotropic approximation for non-hydrogen atoms.H atoms were defined in the difference Fourier synthesis. The final value of R-factor is 0.044. The characteristic feature of crystal packing of 2 is the presence of centrosymmetric dimer associates of R,R- and S,S-enantiomers (Figure 1), linked by intermolecular hydrogen bonds (IMHB): (i) O(2)middot;middot;middot;H(2a)=2.03Aring;, O(2)middot;middot;middot;O(3a)=2.858Aring;, C(1)=O(2)middot;middot;middot;H(2a) = 154.5deg;, O(2)middot;middot;middot;H(2a)ndash;O(3a)=171.6deg;, E1 =ndash;2.4kcalmolndash;1; (ii) O(2a)middot;middot;middot;H(2)=2.00Aring;, O(2a)middot;middot;middot;O(3) = 2.842 Aring;, C(1a)=O(2a)middot;middot;middot;H(2)=154.4deg;, O(2a)middot;middot;middot;H(2)ndash; O(3)=172.6deg;, E2 =ndash;2.7kcalmolndash;1.The IMHB energies (E1 and E2) (1 cal=4.184J) were calculated by a reported method.8 Atomic coordinates, thermal parameters, and bond lengths and angles have been deposited at the Cambridge Crystallographic Data Centre (CCDC).See Notice to Authors, Mendeleev Commun., 1997, Issue 1. Any request to the CCDC for this material should quote the full literature citation and the reference number 1135/14. a a a a b O R R O HO CO2R' O R R O HO CO2R' O O R R O H+ O A B C R = Me, But; R' = H, MeMendeleev Communications Electronic Version, Issue 2. 1997 (pp. 47ndash;86) Dagger; Spectroscopic data IR (CHCl3) nmax/cmndash;1, 1H NMR (400.13MHz), 13C NMR (100.62MHz) (data in square brackets were obtained under conditions of {4-Me}), d/ppm, J/Hz for 1: yield 36.2; mp 149ndash;150 deg;C (from diethyl ether); IR: 1708 (C=N); 1HNMR (CDCl3) d 1.31 (3H, d, 3J 7.0, 3-Me), 1.48 (3H, s, 2-Me), 1.75 (3H, s, 4-Me), 1.98 (1H, q, 3-H). For 2: yield 83.5; mp 81ndash;82 deg;C (from benzene); IR: 1798 (C=O); 1H NMR (CDCl3) d 1.35 (3H, d, 3J 7.0, 3-Me), 1.46 (3H, s, 2-Me), 1.81 (3H, s, 4-Me), 2.06 (1H, q, 3-H); 13C NMR (CHCl3) d 7.03 dq (3-Me, 1J 128.6, 2J 4.4), 20.99 dq (2-Me, 1J 127.9, 3J3-H 2.5), 24.56 dq (4-Me, 1J 131.5, 3J3-H 4.4), 49.93 dm (C-3, 1J 130.8, J 3.6), 73.32 m (C-2, J 4.4), 78.03 m (C-4, J 5.1, dq, 2J 4.4, 3J 5.8), 117.02 dq (C-5, 3J3-H 8.7, 3J4-Me 4.4 d, 3J3-H 8.7), 175.50 q (C-1, 3J2-Me 4.4, 3J3-H 0.5).For 3a: yield 25; mp 119ndash;120 deg;C (from acetonendash;benzene); IR: 1786 C(1)=O, 1718 C(5)=O; 1H NMR (2H6acetone) d 1.14 (3H, d, 3J 7.3, 3-Me), 1.35 (3H, s, 2-Me), 1.61 (3H, s, 4-Me), 2.27 (1H, q, 3-H); 13C NMR (2H6acetone) d 7.20 dq (3-Me, 1J 127.9, 2J 4.4), 21.96 dq (Me, 1J 127.9, 3J3-H 3.6), 22.52 dq (Me, 1J 129.3, 3J3-H 5.1), 50.21 dm (C-3, 1J 130.0, J 4.4), 73.35 m (C-2, J 4.4), 84.76 m (C-4, J 5.1), 172.95 dq (C-5, 3J3-H 7.3, 3J4-Me 4.0), 176.61 q (C-1, 3J2-Me 4.4, 3J3-H 0.5).For 3b: yield 21; mp 148ndash;149 deg;C (from acetonendash;benzene); IR: 1784 C(1)=O, 1734 C(5)=O; 1H NMR (2H6acetone) d 1.11 (3H, d, 3J 7.3, 3-Me), 1.34 (3H, s, 2-Me), 1.50 (3H, s, 4-Me), 2.76 (1H, q, 3-H); 13C NMR (2H6acetone) d 9.13 dq (3-Me, 1J 127.2, 2J 3.6), 19.00 dq (2-Me, 1J 129.3, 3J3-H 2.9), 20.27 dq (4-Me, 1J 127.9, 3J3-H 2.4), 46.62 dm (C-3, 1J 133.0), 75.04 m (C-2, J 5.1, J 7.3), 82.94 m (C-4 dq, 2J 4.4, 3J 4.4), 173.10 dq (C-5, 3J3-H 4.4, 3J4-Me 4.4 d, 3J3-H 4.4), 176.67 dq (C-1, 3J3-H 4.4, 3J2-Me 4.0).For 4a: yield 86; mp 71ndash;72 deg;C (from light petroleum); IR: 1788 C(1)=O, 1728 C(5)=O; 1H NMR (CDCl3) d 1.07 (3H, d, 3J 7.0, 3-Me), 1.42 (3H, s, 2-Me), 1.64 (3H, s, 4-Me), 2.10 (1H, q, 3-H), 3.83 (3H, s, OMe).For 4b: yield 84; mp 88ndash;89 deg;C (from light petroleum); IR: 1786 C(1)=O, 1742 C(5)=O; 1H NMR (CDCl3) d 1.11 (3H, d, 3J 7.0, 3-Me), 1.40 (3H, s, 2-Me), 1.53 (3H, s, 4-Me), 2.79 (1H, q, 3-H), 3.79 (3H, s, OMe). For 5: yield 55, mp 48ndash;49 deg;C (from diethyl ether); IR: 1823 (C=O), 1808 (C=O); 1HNMR (CDCl3) d 1.09 (3H, d, 3J 6.7, 7-Me), 1.58 (3H, s, 4-Me), 1.63 (3H, s, 1-Me), 2.52 (1H, q, 7-H); 13C NMR (CDCl3) d 6.07 dq (7-Me, 1J 128.6, 2J 2.9), 10.88 q and 10.98 q (1-Me and 4-Me, 1J 129.3 and 1J 129.3), 54.96 m (C-7, 1J 135.2), 86.49 m and 88.70 m (C-1 and C-4), 170.77 q (C-3, 3J4-Me 4.4 s, 3J7-H 0.3), 170.87 dq (C-6, 3J7-H 7.3, 3J1-Me 4.4).(+,ndash;)-DTG salt from 3a,b and 5; 1H NMR (D2Ondash;KOH) d 0.93 (3H, d, 3J 7.0, b-Me), 1.23 and 1.32 (3H and 3H, 2s, a-Me and a'-Me), 2.45 (1H, q, b-H). Compounds 1ndash;5 gave satisfactory elemental analyses. On the other hand, by comparison of the MM2 models of the B conformer of 3a (or 4a), 3b (or 4b) and 5, the reaction rate enhancement observed for isomers 3b, 4b may be explained as follows.Firstly, the proximity of the reacting atoms the nonbonded O(3)ndash;C(5) distance is smaller in 3b, 4b (2.88 Aring;) compared to 3a (3.04 Aring;) and 4a (3.06 Aring;) (the Menger12 postulate of proximity factor). Secondly, the cyclization of 3b (or 4b), with the formation of the cycle C of 5, probably proceeds via a less sterically hindered diastereomeric transition state (or tetrahedral intermediate) compared to that for 3a (or 4a) cyclization, leading to a more strain cycle D closure (Scheme 1).This is confirmed by a decreasing in both the non-bonded contacts between the carbon atoms of the vicinal methyl groups (3.21 and 3.22 Aring;) and the torsional strain of the Cndash;Me bonds {jMendash;C(1)ndash;C(7)ndash;Me = 60.3deg;; jMendash;C(4)ndash; C(7)ndash;Me = ndash;60.5deg;} in 5 compared to that for 3b {2.92 and 2.94 Aring;; jMendash;C(2)ndash;C(3)ndash;Me) = 35.5deg;, jMendash;C(3)ndash;C(4)ndash; Me=ndash;30.5deg;} and in contrast with that for 3a (3.30 and 3.39 Aring;; ndash;77.2deg;, 84.2deg;). Moreover, the van der Waals 1,2-interactions between the methyl groups results in the increase of B conformer puckering of the g-lactone ring of 3b and 4b (ring-puckering amplitude13 tm is 35.1deg;) unlike that of 3a (33.5deg;) and 4a (32.9deg;). This is one cause of the enforced proximity of the reacting centres in 3b, 4b.Interestingly, alcoholysis of the dilactone 5 proceeds with only a ring C opening (Scheme 1) which is probably due to a steric control of the bridged 7-Me group. Thus, the relative acceleration of cyclization of (+,ndash;)-DTG monolactones is observed for the e,a,e-B-form (pseudo-e,a,eorientation of the methyl groups), contrary to what might be Figure 1 The structure of dimer associate of lactone 2 (dotted lines indicate possible H-bonds).Selected dihedral angles (deg;) in molecules I and Ia respectively: C(1)C(2)C(3)H(1) 79.9 and ndash;75.5, C(6)C(2)C(3)H(1) ndash;43.9 and 47.8, C(5)C(4)C(3)H(1) 165.8 and ndash;162.6, C(8)C(4)C(3)H(1) 40.4 and ndash;37.3. H(1a) C(8a) C(7a) C(3a) C(4a) O(1a) C(2a) O(2a) C(6a) C(1a) C(5a) N(a) H(2a) O(3a) H(2) N O(3) C(5) C(6) O(2) C(1) C(2) O(1) C(4) C(3) C(7) H(1) C(8) I Ia O O HO CO2R Me Me H Me O Me Me O HO CO2R H Me O Me HO CN X Me H Me Me Me OH NC H Me O Me Me OH NC H Me CN OH Me Me OH HO2C H Me CO2H OH O Me Me O HO CO2R Me H O O HO CO2R Me Me Me H H Me Me Me O O i, ii iii iv v vi HCN ndash;HCN v' O O Me O O Me H Me C D D C MCH (+,ndash;)-BCH 1 X=NH 2 X = O A B 3a R = H (+,ndash;)-DTG 5 A B 3b R = H Scheme 1 Reagents and conditions: i, KCNndash;H2O, ndash;10deg;C; ii, aq.HCl (34), ndash;15 to ndash;10 deg;C; iii, aq. HCl (10), 6 h, 20 deg;C; iv, aq. HCl (25), 3 h, reflux; then CH2N2ndash;diethyl ether; v,v', CF3COOH or TsOHndash;toluene, reflux; vi, MeOH, 0.5 h, 50deg;C. 1 2 3 4 5 1 2 3 4 5 6 7 b MPD 4a R=Me 4b R=Me 1 2 3 4 5 aMendeleev Communications Electronic Version, Issue 2. 1997 (pp. 47ndash;86) expected for the e,e,e-B-form on the basis of previous studies.1,2 This work was supported by the Russian Foundation for Basic Research (grant no. 94-03-08730) and the International Science Foundation (grant no. MCO 300). References 1 R. G. Kostyanovsky, V. P. Leshchinskaya, Yu. I. Elrsquo;natanov, A. E. Aliev and I. I. Chervin, Izv.Akad. Nauk SSSR, Ser. Khim., 1989, 408 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1989, 38, 355). 2 I. V. Vystorop, Yu. I. Elrsquo;natanov and R. G. Kostyanovsky, Izv. Akad. Nauk, Ser. Khim., 1992, 1591 (Bull. Russ. Acad. Sci., Div. Chem. Sci., 1992, 41, 1227). 3 I. V. Vystorop, C. Jaime, X. Sanchez-Ruiz, I. I. Chervin and R. G. Kostyanovsky, Book of Abstracts of the 13th IUPAC Conference on Physical Organic Chemistry, Inchon, Korea, 1996, p. 126. 4 N. D. Zelinsky and L. A. Chugaev, Chem. Ber., 1895, 28, 2940. 5 C. K. Ingold, Structure and Mechanism in Organic Chemistry, Cornell University Press, Ithaca and London, 1969, ch.XI. 6 G. K. Schweitzer and E. W. Benson, J. Chem. Eng. Data, 1968, 13, 452. 7 G. M. Sheldrick, SHELX86, Program for Crystal Structure Determination, University of Cambridge, UK, 1986. 8 G. V. Timofeeva, N. Yu. Chernikova and P. M. Zorkii, Usp. Khim., 1980, 49, 966 (Russ. Chem. Rev., 1980, 49, 509). 9 S. Milstien and L. A. Cohen, J. Am. Chem. Soc., 1972, 94, 9158. 10 Version MM2(91) program is available from QCPE, University of Indiana, Bloomington, IN 47405, USA. 11 N. L. Allinger, J. Am. Chem. Soc., 1977, 99, 8127. 12 F. M. Menger, Acc. Chem. Res., 1985, 18, 128. 13 N. S. Zefirov and V. A. Palyulin, Dokl. Akad. Nauk SSSR, 1980, 252, 111 Dokl. Chem. (Engl. Transl.), 1980, 252, 207. Received: Moscow, 11th October 1996 Cambridge, 4th December 1996; Com. 6/07094I