Computer-Assisted Synthetic Analysis. a Rapid Computer Method for the Semiquantitative Assignment of Conformation of Six-Membered Ring Systems

Home , Edwin Vedejs, Ralph Raphael, Retrosynthetic analysis, Substituted benzofuran, Thienobenzodiazepine

J. Org. Chem. 1980,45, 765-780 765 Computer-Assisted Synthetic Analysis. A Rapid Computer Method for the Semiquantitative Assignment of Conformation of Six-Membered Ring Systems. 2. Assessment of Conformational Energies

E. J. Corey* and N. Frank Feiner

Department of Chemistry, Harvard University, Cambridge, Massachusetts 02138

Received May 23, 1979

The description of a new semiquantitative computer-based method to be used in synthetic planning for the prediction of the conformation of six-membered ring systems is carried on in this paper through the final stages of assignment. Starting with specific geometries from preliminary assignment (i.e., chair, half-chair, boat) which are deduced from the first stage of analysis, simple empirical procedures are applied to calculate approximate conformational destablization energies of each of the preliminary (i.e.,tentative) geometries. These procedures are based upon consideration of the disposition of axial and equatorial appendages and do not rely on three- dimensional atomic coordinates. The quantification of interatomic interactions depends on seta of appendage interaction values, the derivation of which is described. Rules for identifying destabilizing interactions between appendages within the same ring and on adjoining rings are given. The destabilization energies so obtained lead to the final conformational decision. Comparisons are made between the results of the present method and those obtained both by more complex molecular mechanics calculations and by X-ray crystallographic analysis.

The importance of stereochemical factors in the analysis of complex synthetic problems cannot be exaggerated. In the accompanying paper’ we have outlined the plan of development of such an aspect of the Harvard LHASA computer program for synthetic analysis and have dis- 9 cussed the initial steps for predicting conformations of 8 10 six-membered ring systems. In this paper we provide a description of the last stages of conformational determi- bonds (to indicate specific stereorelationships at chiral nation and the implementation of a computationally ef- centers) which the chemist draws into the computer2band ficient method of execution. rendering them effectively three-dimensional (e.g., 9 and/ The preceding paper dealt with a first-order confor- or 10). Although a formal three-dimensional representa- mational analysis of six-membered ring systems wherein tion of structure is not actually generated, the information each six-membered ring was scrutinized for a number of provided by the first-order analysis is in many ways predefined configurational constraints. The results were equivalent to what would be gleaned from a 3-D repre- threefold. First, each six-membered ring system received, sentation. if possible, a preliminary conformational assignment in The conformation that is assigned during the fint-order harmony with these constraints. The assignment corre- analysis is provisional and is refined as described in this sponded to one or both of the well-defined chair (1, 2), paper to obtain a final conformational decision. Unless half-chair (3, 4), or boat (5, 6) geometries or to the flat a six-membered ring system has been found to be either geometry 7. If no such assignment could be made the ring flat, ambiguously constrained, or conformationally rigid, each of its provisionally assigned forms is examined, and, on the basis of assessment of nonbonded interatomic interactions, a total destabilization energy EDsYs is computed. This energy value is taken to reflect the tendency 3 4 of the six-membered ring to depart from its provisionally assigned conformation and, in addition, permits prediction n of the relative populations of a pair of energetically ac- 5 6 v ceptable conformers. The conformational energies given 7 by our method are only approximate, and the conformational assessment to which they lead is utilized in con- was deemed conformationally ambiguous and was dis- nection with screening out stereochemically inappropriate qualified from any further consideration. Second, each chemistry during the performance of a full antithetic six-membered ring system received a flexibility assignment analysis. The specific context of the conformational of either rigid, distortable, or flippable, reflecting, re- analysis was outlined at the outset of the accompanying spectively, negligible conformational mobility, the ability paper.’ The refinement and precision of a molecular- to deform out of the well-defined assigned geometry, or mechanics calculation3 has not been the goal of our me- the freedom to interconvert between two well-defined thod. assigned geometries. Third, for each preliminarily assigned Interatomic interactions are estimated from a consid- form, each stereoappendage attached to the six-membered eration of the disposition of the axial and equatorial ap- ring received a stereolabel of either axial or equatorial. Thus the fmt-order analysis performs an important task. This can be viewed as taking two-dimensional structures (2) (a) Corey, E. J.; Howe, W. J.; Pensak, D. A. J. Am. Chem. SOC. 8)2a 1974, 96, 7724. (b) A structure is quickly input by using an electronic (e.g., with conventional wedged and dashed stereo- drawing tablet and stylus” or via cross-hair cursor positioning of the atoms. (c) Corey, E. J.; Wipke, W. T.; Cramer, R. D., 111. J. Am. Chem. SOC.1972, 94, 421. (1) Corey, E. J.; Feiner, N. F. J. Org. Chem., preceding paper in this (3) (a) Allinger, N. L. J. Am. Chem. SOC.1977,99,8127. (b) Allinger, issue. N. L. Ado. Phys. Org. Chem. 1976,13, 1.

0022-3263/80/1945-0765$01.00/0 0 1980 American Chemical Society 766 J. Org. Chem., Vol. 45, No. 5, 1980 Corey and Feiner pendages about the ring; three-dimensional atomic coor- Table I. Set of Computational A Values dinates are not required. We have developed a series of H 0 NHd 2.0 simple empirical computational procedures for tallying the NR; 2.1 interactions, drawing on the results of inspection of F 0.2 NHR 1.3 Dreiding-type molecular models and the available exper- c1 0.4 N= 0.5 imental data. Two types of destabilizing interaction are Br 0.4 NI 0.2 differentiated: intra-ring, those between a pair of ap- I 0.4 NO, 1.1 pendages on the same six-membered ring, and inter-ring, 1.6 0.2 those between two appendages or atoms on adjoining rings. C72 na aryl 3.0 In this way a means of rapid, semiquantitative conformational analysis is achieved; the computational procedures described below require on the average only 1 s of OR 0.8 CR 3 6.0 computer time per target structure. CHR, 2.1 CH,R 1.8 Intra-ring Interactions in Chairs A monoequatorially substituted cyclohexane (1 1) or a by reasoning that, in general, axial/equatorial interactions, 1,3- or 1,4-diequatorially substituted cyclohexane (12 or unlike their 1,2-E/E counterparts, cannot be relieved in 13) is considered to have minimal through-space substit- departing from the chair: initial chair deformation leads R to increased interaction (19), while a full conformational inversion returns an equivalently disposed A/E pair (20h5 An important simplifying assumption used throughout b+ 'PR'ReR' J is that conformational effects are additive, i.e., that various 11 R 33 14 destabilizing interactions identified within a six-membered 12 ring system operate independently of each other. Thus, R' R' for example, it is assumed that the position of the equi- RI I librium between 21 and 22 can be determined simply from B 15 16 17 uent interactions and is hence assigned a total destabilization energy of zero; i.e., these ring systems are considered, 21 for all R, to be perfect chairs. In our analysis, four types of intra-ring arrangements which can destabilize the chair B are recognized. These include (1)the presence of a single axial appendage (14) and the interaction of a pair of appendages in either (2) 1,2-trans-diequatorial (15), (3) 1,3- cis-diaxial (16), or (4) 1,2-cis-axial/equatorial(17) dispo- 14 11 sition. EDR = A R EDR = (2) In practice only three of these interaction types, those the difference in the conformational energies of the systems in 14,15,and 16, are counted as actually raising the energy 23 and 24. Although the additivity principle has been of the chair conformation. No effective destabilization is shown to be not always ~alid,~J&~it is frequently usefully counted for the 1,2-cis-axial/equatorialinteraction in 17. applied7cand is felt to be a satisfactory approximation for This simplifying procedure is followed even though ap- our purposes. pendage pairs here bear the same spatial relationship as Axial Interaction. For a monosubstituted cyclohexane, do two trans-diequatorially situated appendages (15),with the negative of the free energy difference associated with a dihedral angle of separation, 4, of 60° ( it is justified its conformational equilibrium (14 + 11) is defined as the A value8 of the substituent R. In a monosubstituted cyclohexane, the greater the A value of an appendage R the greater the driving force to adopt the R-equatorial chair

(5) (a) Strictly speaking, real differences can exist between l,2-cis- Ill disubstituted cyclohexane conformers (18 vs. 20), reflecting specific ro- 111 Ill tational preferences of R and R' in their respective axial and equatorial environments.6 (b) This rationalization breaks down in the relatively uncommon instances when half-flips of chairs give well-defined boats. Thus R/R' destabilizations are tallied for boat conformers ii and iv but not for chair conformers i and iii. 18 19 20

(4) In reality cyclohexane has been shown to adopt a distorted chair conformation which serves to bring A/E substituent pairs in somewhat closer proximity (4 in i = 55O) than E/E pairs (4 in ii = 65'), resulting in enhanced A/E interactions. Cf.: (a) Aycard, J.-P.; Bodot, H.; Lau- ricella, R. Bull. SOC.Chim. Fr. 1969,3516. (b) Wohl, R. A. Chimia 1964, (6) (a) Stolow, R. D. J. Am. Chem. SOC.1964,86,2170. (b) Tichy, M.; 219. (c) Sicher, J.; Tichy, M. Collect. Czech. Chem. Commun. 1967,32, Vasickova, S.; Vitek, A.; Sicher, J. Collect. Czech. Chem. Commun. 1971, 3687. 36, 1436. (c) Eliel, E. L.; Schroeter, S. H.; Brett, T. J.; Biros, F. J.; Richer, J.-C.J. Am. Chem. SOC.1966,88, 3327. (7) (a) De Beule, H.; Anteunis, M. Tetrahedron 1974, 30, 3573. (b) Eliel, E. L.; Enanoza, R. M. J. Am. Chem. SOC.1972,94, 8072. (c) Rej, R. N.; Bacon, E.; Eadon, G. Ibid. 1979, 101, 1668. (8) Winstein, S.; Holness, N. J. J. Am. Chem. SOC.1955, 77, 5562. Computer-Assisted Synthetic Analysis J. Org. Chem., Vol. 45, No. 5, 1980 767 form. In our computation, the A value of R, AR, is thus Table 11. Reported 1,2-Diequatorial R/R considered to be the destabilization energy imparted to a Interaction Energies (kcal/mol) monosubstituted six-membered chair by an axial ap- entry R, RZ energy ref pendage (14); an equatorial appendage (11) contrib- T R R 1 F 1 0.1 13 utes a destabilization energy of zero (eq 1 and 2).9 2 c1 c1 0.7-1.4 14-17 The A values for a large number of monosubstituted 3 c1 Br 1.1-1.5 14 cyclohexanes are on record.1° We have observed that, to 4 c1 I 1.2 18 a first approximation, the A value of an appendage is 5 c1 OMe 0.5-1.2 15,17 chiefly determined by the nature of its connecting atom 6 c1 Me 0.2 14 7 Br Br 1.2-2.0 14-15 (i.e,, the atom which is bonded to the six-membered ring), 8 Br I 1.9 19 specifically by the atomic type, degree of hydrogen at- 9 Br OMe 0.4-1.0 15, 17 tachment, and hybridization of this atom. On this basis 10 Br Me 0.25 14 a relatively short list of A values that are of general use 11 I I 1.9 20 within the analysis was drawn up. This is presented in 12 OMe I 0.4-0.8 17 Table I. 13 OH OH 0.35 20,21 Estimation of Diaxial and Diequatorial Interac- 14 OH OMe 0.64 15 15 OH NHZ -0.9 22 tions. Although the conformational energies for many 16 OH NMe, -0.6 22 monoaxially substituted cyclohexanes are known, there is 17 OMe OAc 0.2-1.0 17 a surprising paucity (of energy data available in the liter- 18 OTs OTs 1.8 20 ature for pairs of interacting cyclohexane substituents. 19 OAc OAc 0.2 20 Thus it was anticipated that in many instances during a 20 SMe c1 1.2-2.2 17 21 SPh c1 0.7-0.9 23 conformational analysis the value for an unmeasured in- 22 SMe Br 1.5-2.5 17 teratomic interaction of either the 1,2-diequatorial(15) or 23 SMe OMe 0.6-1.8 17 the 1,3-diaxial (16) type would be required. Since there 24 SMe OAc 0.6-1.8 17 exists no simple method for the general estimation of the 25 SMe SMe 1.5-2.9 17 magnitudes of such interactions, we were obliged to devise 26 Me Me 0.75-0.80 14, 22 means of doing so. 27 Me OH 0.38 5, 24 Two simple approaches, which eventually had to be 28 Me C0,Et 0.2 24 29 Me co 2- 0.9 24 rejected, are as follows. First we describe an approach with 30 Me CN 0 24, 25 1,Zdiequatorial interactions. Our basis for the prediction 31 Me NHR 0.7 26 of the magnitude of these came from a simple analysis of 32 t-Bu OH 2.5 27 the destabilizing factors in monoaxially substituted cy- 33 t-Bu OMe 2.5 27 clohexanes. It is commonly believedlla that the destabi- 34 CO,H CO, R 0.3 4a lization caused by an axial substituent is due its interaction with the two sy-1,3-diaxialhydrogens on the ring (25).” used to derive an expression for approximating the magnitude of the 1,2-diequatorial intra-ring interaction as H? follows. The connecting atoms (vide supra) of a pair of 1,2-diequatorially arranged appendages bear the same spatial relationship as the terminal carbon atoms in the gauche rotamer of butane (27 and 28). The case was thus R 26 27

Each of these interactions is of the same type as that in the gauche rower of butane (26, R = Me, and 27). Thus h it was thought that the contribution to the destabilization 28 energy made by a lone axial group R, EDR, could be set E,R’R’ = g[1,2,3]= (AR f AR,)/~(4) equal to the sum of the energies of its two equivalent gauche interactions g[1,2,3] and g[1,4,5] (25); since the A made that, to a simple first approximation, the 1,2-di- value of R is a measure of this destabilization, AR was equatorial destabilization could be considered to arise from equated to this sum (eq 3). a “shared” gauche interaction between the two appendages, On the basis of this simple relationship the gauche in- in other words one whose magnitude is given by the av- teraction value (g value) of a cyclohexane appendage was erage of the g values of the two groups, i.e., 1/2(A~/2+ defined as equal to half its A value. The g value was then AR./2). A possible general expression for estimating the 1,2-diequatorial interaction energies of structural type 15 (9)In this paper EDR and EDRIR‘denote contributions to the total was thus formulated; this is given in eq 4. destabilization energy EDYysof a particular conformer made by a single To ascertain the degree to which this formula provided appendage R and a pair of appendages R/R’, respectively. energies in accord with experimental results, we plotted (10) (a) Hirsch, J. A. Top. Stereochem. 1967, I, 199. (b) Jensen, F. R.; all such data known to us, tabulated in Table 11, against Bushweller, C. H. Adu. Alicyclic Chem. 1971, 3, 139. (c) Morris, D. G. Aliphatic, Alicyclic, Saturated Heterocycl. Chem. 1973,l (Part III), 105; 1974,2,174. (d) Morris, D. G. Alicyclic Chem. 1975,3,266; 1976,4,196. (e) Brown, N. M. D.; Cowley, D. J. Ibid. 1977, 5, 191. (f) The first A (13)Hall, L. D.;Jones, D. L. Can. J. Chem. 1973,51,2914 and refer- values for phosphorus have been obtained recently Gordon, M. D.; Quin, ences therein. L. D. J. Am. Chem. SOC.1976, 98, 15. (14)Buys, H. R.; Havinga, E. Tetrahedron Lett. 1968, 3759. (11) (a) Eliel, E. L.; Allinger, N. L.; Angyal, S. J.; Morrison, G. A. (15)Subbotin, 0.A.; Sergeev, N. M.; Zefirov, N. S.; Gurvich, L. G. J. “Conformational Analysis”; Interscience: New York, 1965;p 43. (b) Ibid., Org. Chem. USSR (Engl. Transl.) 1975, 11, 2265. pp 113-4. (c) Ibid., p 11. (16)Reeves, L. W.;Stromme, K. 0. Tram. Faraday SOC.1961,57,390. (12)An alternative explanation for the equatorial bias among six- (17)(a) Zefiiov, N. S.; Gurvich, L. G. Tetrahedron 1976,32,1211.(b) membered-ring substituents hinges on the gauche H/H interaction. Cf.: Bairamov, A. A.; Mursakulov, I. G.; Guseinov, M. M.; Zefirov, N. S. J. Org. Wertz, D. H.; Allinger, N. L. Tetrahedron 1974,30,1579.Cf. also ref 17. Chem. USSR (Engl. Transl.) 1978, 14, 903. 768 J. Org. Chem., Vol. 45, No. 5, 1980 Corey and Feiner

Table 111. Reported 1,3-Diaxial R/R Interaction Energies (kcal/mol) entry R, energy ref 32,Ut R2 1 Me Me 3.7 28 2 OH OH 1.9 29 3 Me OH 1.9-2.7 29, 30 4 OAc OAc 2.0 29 5 c1 c1 5.5 29, 31 6 Me Br 2.2 29 7 Me F 0.4 29 8 Me CQ,Et 2.8-3.2 29, 30 9 Me Ph 2.9 32 10 Me CN 2.7 30 11 Me co; 3.4 30 12 CN CN 3.0 30 13 CO,CH, CO,CH, 1.7 33 14 CO,H CO, H 1.1 33 15 c0,- c0,- 4.2 33 16 NH,' c0,- -1.8 33 17 NH,' CO, H 0.5 33 18 OMe CH, R 1.9 34 5 I

Ecalcuiated Figure 1. Reported 1,2-diequatorialinteraction-energy values and ranges (Table 11) plotted against values calculated with A values (Table I) by using eq 4. The numbers in the plot correspond to the entry numbers of Table 11. The dashed line denotes ideal correspondence. All energies are in kcal/mol. I I the predicted values computed from eq 4 (Figure 1). It 4 was immediately obvious from this plot that, in spite of i, the wide range of some of the reported values, the devia- ,, tion from an ideal correspondence (indicated by the ,/ / straight line through the origin) is large. It was clear that / a reasonable approximation of 1,Zdiequatorial interactions / is not to be had through utilization of A values. I I /' 1. 17' Next we describe a simple but unsuccessful approach /' 1 I I I I to the derivation of the magnitude of 1,3-diaxial interac- I 2 3 4 tions using A values. Two cis-1,3-diaxially oriented sub- I 5l stituents on a six-membered ring (16) bear a unique and i I I 16 i 16 Ecalculated JJ Figure 2. Reported 1,3-diaxialinteraction-energy values and ranges (Table 111) plotted against values calculated with A values (Table I) by using eq 5. The numbers in the plot correspond to the entry numbers of Table 111. The dashed line denotes ideal special geometric relationship to each other: as will be correspondence. All energies are in kcal/mol. demonstrated in the ensuing discussion, this interaction will serve as an ideal geometric model for many of the less a general predictive expression for the destabilizing in- commonly considered inter-ring destabilizing arrangements teraction between a 1,3-diaxial pair, initial recourse was possible in six-membered ring systems. In order to derive made to the known conformational energy value of 3.7 kcal/mol for diaxial1,3-dimethylcyclohexane(16, R = R'

~ = CH,).28 Since this value is almost equivalent to twice (18) Pan, Y.-H.;Stothers, J. B. Can. J. Chem. 1967, 45, 2943. the A value of the methyl group itself, it was tempting to (19) Torgrimsen, T.; Klaeboe, P. Acta Chem. Scand. 1971,25, 1915. consider all l,&diaxial interactions between two six-mem- (20) Lemieux, R. U.; Lown, J. W. Can. J. Chem. 1964,42, 893. bered ring appendages as imparting destabilizations (21) Angyal, S. J.; McHugh, D. J. Chem. Ind. (London) 1956, 1147. (22) Tichy, M.; Vasickova, S.; Arakelian, S. V.; Sicher, J. Collect. roughly equal to the sum of the A values of the two ap- Czech. Chem. Commun. 1970, 35, 1522. pendages. (23) Zefirov, N. S. J. Org. Chem. USSR (Engl. Transl.) 1970,6, 1768. A potentially general expression, then, which was for- (24) Tichy, M.; Sicher, J. Collect. Czech. Chem. Commun. 1968, 33, 68. mulated to estimate the l,&diaxial component of the de- (25) LaFrance, R.; Aycard, J.-P.; Berger, J.; Bodot, H. Org. Magn. stabilization energy of structural type 16, is given in eq 5. Reson. 1976,8, 95. To our knowledge only a modest number of 1,3-diaxial (26) Vierhapper, F. W.; Eliel, E. L. J. Org. Chem. 1977, 42, 51. (27) (a) Stolow, R. D.; Groom, T.; Lewis, D. J. Tetrahedron Lett. 1969, interaction energies have been measured experimentally 913. (b) Stolow, R. D.; Gallo, A. A.; Marini, J. L. Tetrahedron Lett. 1969, 4655. (c) Stolow, R. D.; Marini, J. L. Ibid. 1971, 1449. (d) Pasto, D. J.; Rao, D. R. J. Am. Chem. SOC.1970, 92, 5151. (28) Allinger, N. L.; Miller, M. A. J. Am. Chem. SOC.1961,83, 2145. Computer-Assisted Synthetic Analysis J. Org. Chem., Vol. 45, No. 5, 1980 769 (Table 111); these data were plotted against the corre- Table IV. Set of Computational G Values sponding values predicted by eq 5 (Figure 2); again the H 0 0.5 straight line drawn through the origin represents an ideal 0.5 correspondence. Examination of this plot revealed a less F 0 0.3 0.5 than satisfactory agreement between prediction and ob- c1 0.1 Br 0.8 0.1 servation. It was once again clear that appendage A values I 1.0 cannot be reliably drawn on to provide assessment of ap- 0.3 pendage/appendage 1,3-diaxial interactions. PRZ 1.6 C- 0 We now discuss a more productive empirical approach SR 1.1 aryl 1.2 to the prediction of appendage/appendage interaction 2.7 co; 0.5 S(OZ)R 3.5 CHO 0.3 destabilization energies. We were not particularly sur- c= 0.2~.~ prised by the shortcomings of the early attempts described OR 0.2 CR, 2.5 above. The lack of a simple relationship between the CHR, 0.8 conformational bias recorded for isolated cyclohexane CH,R 0.4 appendages, as measured by their A values, and the energies of interaction recorded between pairs of cyclohexane appendages has been commented upon by several investigator~;~’,~~*~the difficulty lies in consideration of the A value as an inherent property of the appendage itself, rather than of the monosubstituted cyclohexane system for which it was measured. However, it seemed that it might be possible to utilize the energy data collected from the literature to generate empirically sets of reasonably self-consistent appendage interaction values which would be useful, to a first approximation, in predicting 1,3-diaxial and 1,2-diequatorial interactions. This proved to be the case. Our method for assessing the three basic types of intra-ring destabilization interactions defined above for six-membered chairs is as follows. Each appendage type R listed in Table I has associated with it three appendage interaction values: l(1)an A value,8AR, as defined above, for monoaxial interactions, (2) a G value,35GR, for 1,2- diequatorial interactions, and (3) a U UR, for i- 1,3-diaxial interactions. Monoaxial interactions (14) are computed as already described (eq 1). A group pair interaction is simply obtained by summing the appropriate G or U values for diequatorial (15) and diaxial (16) in- I I 1 I I teractions respectively (eq 6 and 7). The successful de- 0 1 2 3 4 5 rivation of the sets of G and U values is now described. G-VALUE Figure 3. Correlation of A (Table I) and G values (Table IV) for some appendages with carbon connecting atoms. The rela- pa tionship Gc = 0.4Ac derives from the slope of the line drawn. lection, it proved possible to use these data to extract a fairly complete set of G values by proceeding as follows. G values were first assigned to those appendages R for In order to obtain the desired G values, we used the set which R/R diequatorial interaction energies (ERIR) were of published diequatorial interaction energies collected in known (Table 11, entries 2, 7, 11, 13, 25, 26, and 34). In Table 11. Since roughly half of the appendage types which these cases GR was set equal to half of ER R or to half of had been defined (Table I) are represented in this col- the median ER/R if a range of values had been reported. Thus, for example, the G value for iodine was assigned a (29) Allinger, N. L.; Graham, J. C.; Dewhurst, B. B. J. Org. Chem. value of 1.9/2 = 1.0 (Table 11, entry 11). In this way, G 1974,39, 2615 and references cited therein. values were extracted for the following appendage types: (30) Tichy, M.; Orahovata, A.; Sicher, J. Collect. Czech. Chem. Com- C1, Br, I, OR, SR, C=, and CHR2. The assignments are mun. 1970, 35, 459. (31) Schwabe, V. K. Z. Elektrochem. 1956,60, 151. given in Table IV. The G value assigned OR (0.2) rep- (32) (a) Shapiro, B. L.; Chrysam, M. M. J. Org. Chem. 1973,38, 880. resents an arbitrary choice, for it will be noted that widely (b) Shapiro, B. L.; Johnson, M. D., Jr.; Shapiro, M. J. Ibid. 1974,39,796. divergent energy values for three OR/OR diequatorial (c) Allinger, N. L.; Tribble, M. T. Tetrahedron Lett. 1971, 3259. (33) Armitage, B. J.; Kenner, G. W.; Robinson, M. J. T. Tetrahedron interactions have been reported (Table 11, entries 13, 18, 1964, 20, 147. and 19). G values were then assigned to those appendages (34) Tavernier, D.; DePessemier, F.; Anteunis, M. Bull. Soc. Chim. R’ for which R/R’ diequatorial interaction energies were Belg. 1975, 84, 333. known, i.e., energies reported involving two different ap- (35) The term “G value” to denote the nonbonded interaction free energy of the hydroxyl group in 1,a-diequatorialrelationships was coined pendages R and R’ where R was an appendage whose G by Lemiewm value had been assigned as described above (Table 11, (36) We suggest the particular alphabetic designation “V’ in lieu of GR ER/R, the perhaps more obvious but already spoken for “A”. This derives from entries 1, 29-31). Subtracting from gave G,; the term “upright” which was originally’ used to describe what later” when a negative number resulted, a GR, value of zero was came to be known as “axial” bonds. assigned to R’. Thus G values were obtained for the fol- (37) Hassel, 0. Tidsskr. Kjemi Bergues. Metall. 1943, 3, 32; Acta lowing appendage types: F, C02-, CN, and NHR. The Chem. Scand. 1947, I, 149. (38) Barton, D. H. R.; Hassel, 0.;Pitzer, K. S.; Prelog, V. Nature assignments appear in Table IV. In order to complete the (London) 1953, 172, 1096. assignment of G values, we made the assumption that 770 J. Org. Chem., Vol. 45, No. 5, 1980 Corey and Feiner

3r------/1 Table V. Set of Computational U Values H 0 NH,' 2.0 NR, 2.1 F 0 NHR 1.3 c1 0.4 N= 0.5 Br 0.4 N- 1.2 I 0.4 NO, 1.1 ! .18 I /I :/'I ! I PR, 1.6 C- 1.2 SR 0.8 aryl 1.1 1.9 co; 2.0 S(O)R CHO 0.8 S( 0, 2.5 )R C= 0.9 OR 0.8 CR, 6.0 CHR, 2.1 CH,R 1.8

115 -1r , I / Ecalcuiated Figure 4. Reported 1,2-diequatorial interaction-energyvalues and ranges (Table 11) plotted against values calculated with G values (Table IV) by using eq 6. The numbers in the plot cor- reqwnd to the entry numbers of Table 11. The dashed line denotes ideal correspondence. All energies are in kcal/mol. within a group of appendages with the same connecting atom (vide supra) there exists a rough linear correspondence between the G and A values. Thus when the G values computed by using the technique described above for the I I I four carbon appendages CN, C02H,CH3, and C02- were 1 2 4 plotted against the corresponding A values, a satisfactory linearity was observed (Figure 3). From this plot, which tl' -IC I gives Gc = 0.4Ac, G values for aryl, CHO, CHR2, and CR3 I were obtained. Similarly, on the basis of the single G values computed above for NHR and SR, it followed that -16 GN = 0.24ANand Gs = 1.4As. This technique established -21 G values for all the remaining appendage types except Pb, E ca tcu la ted which was arbitrarily assigned a G value equal to its A Figure 5. Reported 1,3-diaxial interaction-energy values and value. Our complete set of G values appears in Table IV. ranges (Table 111) plotted against values calculated with U values In general, the use of G values to give 1,Z-diequatorial (Table V) by using eq 7. The numbers in the plot correspond to the entry numbers of Table III. The dashed line denotes ideal interaction energies appears to work satisfactorily; the correspondence. All energies are in kcal/mol. correlation achieved is illustrated in Figure 4 by using data drawn from Table 11. We have analyzed the results in There are a few instances where the A value has been terms of appendage types and found that although there modified, namely, for the appendage types F, aryl, C=, is usually very good agreement between prediction and CE, and Nr. Fluorine is apparently of very little steric observation for the pairings halogen/ halogen, halogen/ consequence in transannular appendage interaction (Table oxygen, oxygen/oxygen, sulfur/halogen, and sulfur/ 111, entry 7) and has been assigned a zero U value. We oxygen, the predicted carbon/heteroatom values are con- have also chosen to assign a somewhat reduced U value sistently high. Thus we have adopted the empirical to sp2-hybridizedcarbon and to phenyl (Table 111, entries practice of reducing to one-third all 1,2-diequatorialgauche 13 and 9); the conformational peculiarities of this latter interactions computed between carbon and heteroatom substituent have been discussed.32 On the other hand, as appendages by G-value summation. It will also be noted has been noted,30 the "small" cyano group can display from the plot in Figure 4 that zero destabilization energies significant 1,3-diaxial interaction with groups larger than have been computed for the interactions between OH and hydrogen (Table 111, entry 10). Accordingly, this group a second OR or NR appendage. As will be discussed in and the isoelectronic isocyanide have been assigned en- more detail shortly, this follows our practice of counting hanced U values. The good correlation which results when no net stabilization or destabilization for appendage pairs U values are used to predict l,&diaxial interaction energies that can hydrogen bond. is shown in Figure 5. This plot includes corrections for In contrast to the estimation of G values, obtaining a electrostatic phenomena, which will be described shortly. set of U values was a simpler task. As noted above, there Modified Intra-ring Interactions. In the assessment is a fairly direct relation between 1,3-diaxial interaction of conformational destabilization due to intra-ring inter- energies and A value, and it seemed that in most cases the actions it is important to be aware of those general U value of an appendage could be set equal to its A value. structural features which will lead to a reduction in the Our empirical U-value assignments are listed in Table V. normally computed interaction energies. Both steric Computer-Assisted Synthetic Analysis J. Org. Chem., Vol. 45, No. 5, 1980 771 modifications, which result in the partial or complete ab- Reduced axial interaction might also be anticipated for sence of one component of a 1,3-diaxial interaction, and appendages in small rings where the geometric constraints electronic factors, which lead to stabilizing interactions, tend to bend the appendage R away from the /3 syn sub- must be considered. stituents. Conformational preferences have been measured In the discussion of interatomic interactions in chairs, for the spirooxirane 32 (n = 3, R = 0)47and for the spi- the conformational destabilization caused by a lone axial roaziridine 32 (n = 3, R = NH).48 In both systems the appendage was attributed to its repulsive interaction with heteroatom was found to be axial, and A values of 0.16 and the two syn-axial hydrogens (29). In the absence of one 0.27 kcal/mol, respectively, were reported. On the basis of these results the empirical practice has been adopted of reducing the destabilizing contributions of axial substituents in spiro-coupled (32) or fused (33) small rings to one-fourth (for three-membered rings) or half (for four- /I membered rings) of their customary A value (eq 10 and 29 X 11); U and G values are likewise decremented. 30 The possibility is also recognized of instances when, = [(3 - n)/3lA~(8) because of a stabilizing electrostatic interaction between two groups, simple summation of the corresponding air of these syn-axial hydrogens, as, for example, in 3-sub- of U or G values will give an inappropriately high ED I: IR'. stituted cyclohexanones or methylenecyclohexanes (e.g., The following computational provisions have been adopted 30, X = 0 or CH2),one might thus anticipate the desta- as empirical but simple means of handling these situations. bilization caused by an axial appendage to be reduced by (i) If the two interacting groups bear opposite charges, a half. Conformational studies on such systems have pro- stabilization (i.e., a negative EDRIR')equal to half the sum vided varied results. For alkyl-group appendages the total of the appropriate U or G values is tallied.49 (ii) If the destabilization due to axial R has been found to range from two interacting groups bear the same charge, the inter- 1/2AM.efor 3-methylmethylenecyclohexane (30, R = CH3, action is computed by summing the appropriate U or G X = CH2)39to AMefor 3-methylcyclohexanone (30, R values; no extra destabilization is counted. (iii) If the = CH3, X = O).l%For polar appendages (30, R = OR or possibility for hydrogen bonding between ?he two inter- SR, X = 0),however, either an increase or decrease in axial acting groups exists, with such bonding limited to hydrogen population has been observed, depending on solvent po- bridging between elements of the set fluorine, oxygen, and larit~.~~Therefore the following computational practice nitrogen,50 no destabilizing interaction is computed. has been adopted: for axial appendages with carbon One further instance where electrostatic effects result connecting atoms the destabilization contribution is given in a conformational stabilization is exemplified by the by the A value of the appendage, diminished by times diaxial forms of tram-1,2- and -1,4-dihalocyclohexanes (34 the number, n,of @ sp2 centers (eq S).@ If the appendage and 35). In these molecules a considerably greater pro- @ has a heteroatom origin, no special effect of sp2centers X x is counted. A great deal of investigation has focused on the conformational behavior of six-membered heterocycles.41a6 In our general treatment it has not been possible to make I Y provision in the computational procedures for the variety Y of phenomena that have been observed, although a very 34 35 important feature of the analysis allows the chemist to EDsys = liz(Ax t AY) (12) specify the effect of many of these during a specific analysis; this feature is described briefly below. Hetero- portion of diaxial population than would be expected from cyclic systems are simply treated in the computation as A-value additivity considerations is often observed.51 This follows. A zero steric interaction is counted between any phenomenon has been attributed to a more favorable axial appendage and a @-situatedheteroatom in the six- electrostatic interaction between the dipoles in the diaxial membered ring. Thus in the 3-substituted tetrahydro- c~nformation.~~In our assessment of interatomic desta- pyran 31, for example, the destabilization due to axial R bilization interactions, this effect is allowed for by halving is computed as half of the A value of R (eq 9). the destabilization contribution computed for [ 1,2]- or [ 1,4]-disposed diaxial heteroatomic appendage pairs through A-value summation (eq 12). In the absence of information on other heteroatoms this procedure is restricted to halogen appendages. It remains to comment on the fact that, as a result of the complexity intrinsic in the operation of electrostatic forces of both an intramolecular and a solvent-involving nature upon the conformational behavior of six-membered ring systems, a wide variety of subtle geometric results beyond the scope of our simple general treatment can be anticipated. Descriptions detailing the operation of special (39)Lambert, J. B.; Clikeman, R. R. J. Am. Chem. SOC.1976,98,4203. (40)For one @ sp2 center (e.g., 30) EI, = 2/J~. Since the 1,3-diaxial effects of a stereoelectronic origin, such as interactions H/R interaction is given by l/gt~,it follows that the l,&diaxial orbital/R interaction is given by I/&. (41)Eliel, E. L. J. Chem. Edoc. 1975,52,762. (47)Carlson, R. G.;Behn, N. S. Chem. Commun. 1968, 339. (42)Lambert, J. B.; F'eatherman, S. I. Chem. Reu. 1975, 75, 611. (48)Buchanan, G. W.;Kohler, R. J. Org. Chem. 1974,39, 1011. (43)Blackburne, I. D.;Katritzky, A. R. Acc. Chem. Res. 1975,8,300. (49)Kung, T. C.; Gutache, C. D. J. Org. Chem. 1978,43,4069. (44)Hirsch, J. A,; Havinga, E. J. Org. Chem. 1976,41,455. (50)Morrison, R. T.;Boyd, R. N. "Organic Chemistry", 2nd ed.;Allyn (45)Robinson, M. J. T. Tetrahedron 1974,30,1971. and Bacon: Boston, 1966; pp 503-4. (46)Claus, P. K.; Rieder, W.; Vierhapper, F. W. Tetrahedron Lett. (51)Cf. ref lob, pp 185 ff. 1976, 119. (52)Wood, G.; Woo, E. P.; Miskow, M.H. Can. J. Chem. 1969,47,429. 772 J. Org. Chem., Vol. 45, No. 5, 1980 Corey and Feiner

/ Table VI. Reported Conformational Energies of / I 3- and 4-Monosubstituted Cyclohexenes (kcal/mol) 'I entry R energy ref 1 4-F 0.01 10b 2 3-C1 -0.64 61 3 441 0.2 10b 4 3-Br -0.70 61 5 4-Br 0.5-0.9 10b 6 4-1 -0.02 10b 7 4-NO, 0.2-0.3 63 8 4-CN 0 58 9 4-Ph 0.99 10b 10 4-CO,Me 0.84 63 11 4-C02Et 1.1 59 12 4-COO13 1.0 63 13 4-CH20H 0.9 60 i I 14 3-Me 0.6 58 15 4-Me 1.0 61,62 16 3-t-BU 1.0-2.7 56 teraction for either an axial (38b) or pseudoaxia15' (39) Figure 6. Reported conformational energies of 3- and 4-mOnO- appendage.lob As a first approximation, then, a desta- substituted cyclohexenes (Table VI) plotted against values calculated with A values (Table I) by using eq 13. The numbers in the plot correspond to the entry numbers of Table VI. The dashed line denotes ideal correspondence. All energies are in kcal/mol. within 4-oxycyclohexanones,53solvent effects on halo- 3 8a 38b R cyclohexanes" and 2-halo~yclohexanones,~~~~~~~~or results 39 of intramolecular hydrogen bonding,56serve to illustrate the range of these phenomena. Fortunately, due to the E,R = */~AR(13) highly interactive nature of the LHASA program, the bilization energy of two-thirds the A value of the ap- chemist is readily able to specify conformation at the outset pendage R is assigned to the monoaxially substituted of the analysis, as described in the accompanying paper,' conformers 38b and 39 (eq 13), in close analogy with the and can thereby include special conformational effects in case described above of cyclohexane systems with an ex- the antithetic analysis. ocyclic double bond (30). A small number of reported conformational preferences for monosubstituted cyclo- Intra-ring Interactions in Non-Chairs hexenes have been collected in Table VI. A plot of the In the accompanying paper,l first-order structural con- free-energy differences observed for these systems vs. the straints were described which led to well-defined and corresponding destabilizations which result from compu- conformationally mobile half-chair (36) and boat (37) tations employing eq 13 appears in Figure 6. conformations. During the second-order conformational For the half-chair three types of destabilizing interactions have been identified for pairs of appendages: 1,3- axial/pseudoaxial (40), 1,2-equatorial/pseudoequatorial (41), and 1,2-diequatorial(42). There have been very few 36 R' 31 analysis it is therefore necessary to be able to assess interatomic interactions within these ring systems. Since there are considerably less data available on the conformational behavior of half-chairs and boats, our treatment 41 of them is necessarily empirical, drawing from the examination of Dreiding-type molecular models and the computational procedures which have been developed for chairs. Half-Chairs. The conformational equilibrium for a monosubstituted cyclohexene (38a + 38b) is known to be 42 less biased against the axial conformer than is the case with EDRlR'=GR t G~f(15) its saturated analogue; this may, at least in part, be at- values published for these types of interacti~ns,~~~~~~~~~ tributed to the absence of one 1,3-diaxial hydrogen in- (57) Using Fieser molecular models, we have measured the 1,3-diaxial (53) (a) Stolow, R. D.; Giants, T. W. Chem. Commun. 1971, 528. (b) separation in the chair (d in i) and the 1,3-diaxial/pseudoaxial separation Stolow, R. D.; Groom, T. Tetrahedron Lett. 1968, 4069. in the half-chair (d in ii) both to be 125 mm. (54) (a) Bodot, H.; Dicko, D. D.; Gounelle, Y. Bull. SOC.Chim. Fr. 1967, 870. (b) Abraham, R. J.; Rossetti, Z. L. Tetrahedron Lett. 1972, 4965. (c) Abraham, R. J.; Siverns, T. M. J. Chem. Soc., Perkin Trans. 2 1972, 1587. 234 (55) (a) Jantzen, R.; Tordeux, M.; de Villardi, G.; Chachaty, C. Org. Magn. Reson. 1976,8,183. (b) Cantacuzene, J.; Jantzen, R. Tetrahedron 1970,26, 2429. (c) Cantacuzene, J.; Atlani, M. Ibid. 1970, 26, 2447. (d) (58) Aycard, J.-P.; Bodot, H. Org. Magn. Reson. 1975, 7, 226. Catacuzene, J.; Jantzen, R.; Ricard, D. Ibid. 1972,28, 717. (59) Aycard, J.-P.; Bodot, H. Can. J. Chem. 1973, 51, 741. (56) (a) Tichy, M. Adu. Org. Chen. 1965,5, 115. (b) Tichy, M. Collect. (60) Aycard, J.-P.; Geuss, R.; Berger, J.; Bodot, H. Org.Magn. Reson. Czech. Chem. Commun. 1973,38, 3631. 1973, 5, 473. Computer-Assisted Synthetic Analysis J. Org. Chem., Vol. 45, No. 5, 1980 773 certainly not enough data to develop a separate semi- Table VII. Bowsprit-Flagpole Distances, d, and Flatness empirical treatment, for appendage-pair interactions in Parameters, b, Associated with Several Boat Conformers half-chairs. Therefore, recourse has been taken to the flattening computational practice adopted for chairs: the R/R' de- boat type bond type d, A b stabilization contribution for structures 40-42 is obtained by simply adding the appropriate pair of U" or G values BISP2 2.9 0 (eq 14 and 15). Boats. We are aware of no substantial body of work cis-3 2.7 0.25 that has explored the energetics of substituted six-membered rings in boat conformations. However, in order to 0 assess conformational equilibria in systems such as 43 and SP2 2.6 0.50 44, we found it necessary to formulate empirical rules for cis-4 2.1 0.60

cis- 5 1.9 0.70

none 1.8 0.75 43 44 computing the destabilizing interactions that can take much the same spatial relationship as does a monoaxial place in these systems. appendage the two 1,3-diaxial hydrogens in the chair (25). In our analysis eight types of intra-ring arrangements Hence for conformer 45 the destabilization due R is set which can destabilize the boat are recognized. These in- equal to the A value of the appendage counted (eq 16). A clude (1) a single axial appendage on the bottom of the pair of 1,2-diequatorial appendages in the boat (47) are boat (45), (2) a single equatorial appendage on the side of arranged identically with the corresponding pair in the chair (15); the resulting destabilization is thus assigned by sq summing the appropriate G values (eq 18). Furthermore, R 7 it seems reasonable to consider both the 1,a-diequatorial 46 eclipsed (48) and the 1,2-diaxial(49) appendage-pair in- 45 EDR= '/zAR (17) teractions closely analogous the 1,3-diaxial append- EDR = AR (16) as to age-pair interaction in the chair (16). Therefore, for these two situations, as well as for the 1,3-d&al interaction (50), which is exactly the same as its chair counterpart, the R'w destabilization component due the R/R' pairing is computed through U-value summation (eq 19). For a single equatorial appendage on the side of the boat (46), which is a special instance of the 1,2-diequatorial eclipsed ar- -F7R' R rangement 48, a destabilization given by half of the A value R of R is assigned (eq 17). 50 Axial appendages on the top of the boat (51,521, however, are in unique geometrical arrangements with no close F analogy to chair systems. Therefore, in order to compute the conformational destabilizations caused by the interaction of such substituents, a simple and clearly approximate method was developed by using eq 20 and 21. The b values derive from comparing the bowsprit-flagpole distances measured by using Dreiding-type models for a number of boat types (53 and 54) against the 2.6-A 1,3- the boat (46), a pair of appendages in (3) 1,2-diequatorial (47), (4) 1,2-diequatorial eclipsed (48), (5) 1,2-diaxial (49), or (6) l,&diaxial (50) disposition, (7) a single axial appendage on the top of the boat (51), and (8) a pair of axial 53 U appendages on the top of the boat (52). 54 From inspection of Dreiding-type models it is apparent that most of these arrangements find close parallels in diaxial distance measured in the chair (55) (cf. Table VII). those already encountered in chair systems; expressions Because they are rough estimates, these b values are sub- for the resulting destabilization energies follow directly. ject to change in the face of any experimental data that Thus a single axial appendage on the bottom of a boat (45) may be forthcoming. encounters two axial hydrogen atoms, on C2 and C6, in

(61) Rickborn, B.; Lwo, S. Y. J. Org. Chem. 1965, 30, 2212. (62) Allinger, N. L.; Hirsch, J. A.; Miller, M. A.; Tyminski, I. J. J. Am. Chem. SOC.1968,90,5773. (63) Zefirov, N. S.; Chekulaeva, V. N.; Belozerov, A. I. Tetrahedron 55 U 1969,25, 1997. 56 57 (64) Viktorova, N. M.; Knyazev, S. P.; Zefirov, N. S.; Gavrilov, Y. D.; Nikolaev, G. M.; Bystrov, V. F. Org. Magn. Reson. 1974, 6, 236. Thus, for example, the destabilization computed for (65) Eliel, E. L. "Stereochemistry of Carbon Compounds"; McGraw- system 56 due to the lone axial methyl group is initially Hill: New York, 1962; pp 204 ff. (66) (a) Carriera, L. A.; Carter, R. 0.;Durig, J. R. J. Chem. Phys. 1973, set equal to AMe,i.e., 1.8 kcal/mol. In this particular 59, 812. (b) Paschal, J. W. J. Am. Chem. SOC.1974,96, 272. system bl = 0 (for bond a) and b2 = 0.60 (for bond c),giving 774 J. Org. Chem., Vol. 45, No. 5, 1980 Corey and Feiner a correction factor of 0.60 and hence a destabilization INTERACTION RING RING [SYS E, energy of 0.60 X 1.8 = 1.1 kcal/mol for 56. Similarly, the 3 0 energy of interaction arising from the [1,4] SMe/N02 interaction in 57, where there are no flattening bonds and hence where bl = b2 = 0.75, is found to be 1.5(0.8 + 1.1) I. 1 5A 1. 8 = 2.9 kcal/mol. 63 (2 Inter-ring Interactions

The conformation adopted by a six-membered ring will 0 0 be greatly influenced by interaction between appendages 0 518 EE 0 on the six-membered ring itself and appendages attached to a second fused ring (59); a major feature of our sec- 64 [m R-R' Figure 7. Destabilizing interatomic interactions and total conformational energies tallied for cis- and trans-decalin. As described in the text, failure to take common interactions into account leads to an inflated energy difference found between the two systems. 59 60 61 62 pendage connecting atoms (C5/C8and C1/C4)are joined;@ ond-order analysis is, therefore, the identification and thus EDsys= 0. The energy difference between cis- and estimation of inter-ring interactions. Unfortunately, there trans-decalin is therefore computed to be 3.6 kcal/mol. are little quantitative data available on interactions be- This is significantly higher than the 2.55 kcal/mol re- tween appendages subtended by different ring~.~*~,~'In portedmcas the theoretical energy difference between these order to put the assessment of such inter-ring interactions two systems. on a semiquantitative basis, we have utilized the empirical This discrepancy is due to the fact that in the compu- models developed above for intra-ring appendage repul- tation employed, in which the interaction energies of each sions. The treatment described below is divided into four ring were simply summed in order to obtain the total categories: (1) interactions within the cis-decalin cavity, destabilization for the decalin system, common interatomic (2) 1,3-diaxial-like interactions in cis- and trans-decalins, interactions were ignored; these were thereby counted (3) interactions in other fused 6/n (six-memberedln- twice. Thus, with cis-decalin (63) the destabilization at- membered) ring systems, and (4)chair/boat interactions. tributed to axial atom 5, which was viewed as involving A few simplifying assumptions govern our computation the two axial hydrogens off C1 and C,, would have been of inter-ring interactions. (i) No inter-ring interactions better described in terms of its gauche components, i.e., are computed between rings whose fusion includes any sp2 the C1/C5 and the C3/C5interactions. Similarly, the axial centers (60 and 61). (ii) No inter-ring interactions are C1 destabilization is seen to consist of the C C5 and the computed between a pair of rings whose fusion involves C1/C7gauche interactions. By computing E&4s by simply a heteroatom (62). The conformational complexities in- summing the A values of C1 and C5, one then observes that volved in such cases, whereby the character of the fusion a double counting of the C1/C5gauche interaction (worth can change through heteroatom inversion,68cannot cur- l/zAc,or 0.9 kcal/mol) results. The destabilization energy rently be properly analyzed by the program. In these of the cis-decalin system, properly computed, then works situations it is necessary for the chemist to specify out to be 3.6 - 0.9 = 2.7 kcal/mol, and the energy differ- graphically the conformation of each ring.' (iii) No in- ence found with trans-decalin (64) becomes reasonable. ter-ring interactions are computed between a pair of six- It is, therefore, the computational practice to record the membered rings if either ring is of ambiguous conforma- gauche interaction components of each destabilization tion, although if the ring pair is cis fused, an arbitrary counted and to subtract the shared interactions to arrive inter-ring interaction destabilization is assigned; this will at a total destabilization energy for a conformationally be illustrated presently. interdependent group of rings. A detailed example of this &-Decalins. Prior to describing our method for com- practice will be given below. puting interactions between cis-decalin appendages, it is Severe inter-ring interactions can take place within the necessary to consider cis-decalin itself (63) and to compare concavity of a cis-decalin system (65). Two types of po- the conformational strain obtained against that computed for trans-decalin (64) (Figure 7). In cis-decalin (63) two l,&diaxial appendage/hydrogen interactions are found in each ring. In ring 1 these are between C5 and the axial hydrogens off C1 and C,; the resulting destabilization is given by the A value of C5, Le., 1.8 kcal/mol. In ring 2 the interaction is between C1 and the axial hydrogens off C5 and C,; it is given by A', i.e., 1.8 kcal/mol. The resulting total destabilization energy, EDSYS,is thus 3.6 kcal/mol. In trans-decalin (64) there are only 1,2-diequatorial interactions, and these are not recorded because the ap-

(67) (a) Cf.: Ficini, J.; Touzin, A. M. Tetrahedron Lett. 1977, 1081. (b) Cf. ref 45. (c) Cf. ref 11, pp 226-43. (d) Laing, M.; Burke-Laing, M. E.; Bartho, R.; Weeks, C. M. Tetrahedron Lett. 1977,3839. (e) Masaki, N.; Niwa, M.; Kikuchi, T. J. Chem. Soc., Perkin Trans. 2 1975,610. (fj tentially interacting axial appendages can be identified: Rogers, D.; Williams, D. J.; Joshi, B. S.; Kamat, V. N.; Viswanathan, N. Tetrahedron Lett. 1974,63. (68) Cf.: Blackburne, I. D.; Katritzky, A. R.; Read, D. M.; Chivera, P. (69) No destabilization is counted in the analysis for any appendage J.; Crabb, T. A. J. Chem. Soc., Perkin Trans. 2 1976, 418. pair that is joined by a chain of fewer than four atoms. Computer-Assisted Synthetic Analysis J. Org. Chem., Vol. 45, No. 5, 1980 775

INTERACTION GAUCHE RING RING a “central” appendage (C1, C,) and an “edge” appendage %. 83 (El, E,). Two types of interaction are possible: (i) an appendage/ring interaction involving the C1/R2or C2/R1 atoms and (ii) an appendage/appendage interaction in- 5A 315 .5 volving the E2/C1, C1/C2, or C2/E1atoms. 11 A 3/11 .5 The appendage/ring interaction is completely analogous to the l,&diaxial interaction within the chair. Appendage C1,for example, bears the same spatial relationship to ring atom R2 as it does to ring atom Ri; the C1/Ri pairing is, in fact, assessed during examination for 1,3-diaxial intra- 7111 inJ (8’111 2.8 ring interactions. Thus, in the computation, the append- 7\11 age/ring inter-ring interaction is tallied by summing the -- U values of the appropriate connecting atoms (eq 22a and 5.4 4.6 22b). The appendage/appendage interaction is more difficult 0 to quantify. Inspection of Dreiding-type molecular models me- reveals that in such an arrangement each pair of appendage Eiyi=2.7 connecting atoms (Le., E2 and C1, C1 and C2, or C2 and El r 66 in 65) is forced exceedingly close together. We are aware 0 of no measured value for this type of interaction, although F] the possibility for such a clash, specifically for a methyl/ methyl edge/center interaction (65, E, = C1 = Me, C2 = Figure 8. Destabilizing interatomic interactions and total con- El = H), is exemplified within the D and E rings of the formational energies tallied for the two chair/chair conformers of la-methyl-cis-decalin. The conformational analysis is fully friedelin ~ystem.~~~-~In the computation, a cis-decalin described in the text. edge/center or center/center appendage/appendage interaction is empirically assigned a destabilization contri- C5/C11 interaction itself, as will be seen shortly. bution equal to the 13um of the U values of the two ap- The sole intra-ring destabilization within ring 2 involves pendages involved (eq 22~-e).~OThus for cis-decalin 65 the axial C1 appendage. As outlined above, the resulting with E, = C1 = Me and C2 = El = H, the system desta- energy, which involves the two gauche interactions CJC5 bilization energy, EDSYs,computed for the conformation and C1/C7, is obtained from the A value of C1. This is shown will be very high and will include (i) the intrinsic given in Table I as 2.1, corresponding to the CHR, clas- cis-decalin interaction (vide supra), (ii) the interaction of sification C1 has received. But it will be appreciated that the central methyl group (C,) with a 1,3-diaxial hydrogen this assignment represents an implicit counting of the CI1 (El), a 1,3-diaxial ring carbon atom (Ri),and a 1,3-diax- methyl group at a premature stage of the analysis, and it ial-like ring atom (E,), (iii) the interaction of the edge will lead to a double counting when inter-ring interactions methyl group (E,) with a 1,3-diaxial hydrogen (C,) and a are picked up. Thus, at this point, a base A value for C1, 1,3-diaxialring carbon atom (R;), and (iv) the C1/E2clash i.e., the A value for the substituent with all sp3-attached itself. groups considered to be hydrogen (in this case 1.81, is A description of our computational treatment of la- used.72 Therefore, 0.9 kcal/mol is counted for each gauche methyl-cis-decalin (66 * 67) now follows (cf. Figure 8). It interaction. is important to consider this system in some detail to Inter-ring examination will reveal an interaction between illustrate fully the subtleties involved in computing these C7 and Cll of the appendage/ring type described above. types of inter-ring interactions. The total destabilization Destabilization is recorded for ring 2 only since it com- energy for the equatorial methyl conformer 66 will be plements the entry for the C5/Clldiaxial interaction made computed at 2.7 kcal/mol, the same as that found for earlier for ring 1. The energy value is obtained by adding cis-decalin itself (63) above; as outlined in the Intra-ring the U values for C, and Cll.Again, it will be appreciated Interactions in Chairs section, the additional axial/equa- that a base U value for the ring atom (in this case C7)must torial gauche interaction between C8 and Cll is not in- be employed in this type of summation; thus a destabili- cluded in the taliy. The situation is more complex for axial zation of 1.8 + 1.8 = 3.6 kcal/mol is found. In addition, methyl conformer 67. Intra-ring interactions are first however, it will be noted from Figure 8 that among the picked up. In ring 1 these include (i) gauche interactions gauche components recorded for the C7/C11 destabilization between axial appendages C5and Cll each with C3 [the 0.9 is the Ca/C11 equatorial/axial gauche interaction worth Ga kcal/mol destabilizations each derive from the appropriate + Gll = 0.8 kcal/mol. Since 1,2-cis-axial/equatorialin- A values (1/2At,,1/2All)] and (ii) a 1,3-diaxial interaction teractions are not counted as destabilizing (cf. 171, a re- (3.6 kcal/mol) between C5 and Cll given by U5+ Ull. It duced C7/C11 destabilization energy of 2.8 kcal/mol is is important that this latter interaction be described in tallied. terms of its two gauche components as well as the “extra”71 Total destabilizations of rings 1 and 2 are thus found to be 5.4 and 4.6 kcal/mol, respectively. The energy of the (70) When appendage/appendage interactions of this type are tallied, cis-decalin system 67 is obtained by summing these values no check for double counting takes place. Clearly this would be inap- and subtracting the doubly counted gauche interactions propriate given the approximating required for assessing such interac- for C1/CBand for C1/C7, giving 8.2 kcal/mol. Therefore, tions. (71) In the computation, a 1,3-diaxial interaction (i) is viewed as being 5.5 kcal/mol separates conformers 66 and 67. composed of two gauche butane-like interactions (Cl/Cd and C,/C,) It was of interest to compare this result with the quan- analogous to a lone axial appendage interaction (e.g., C1/C5) plus an extra titative treatment of this system by the comprehensive interaction between the appendage origins themselves (Le., C1/C2).

(72) In the computation, any axial or equatorial carbon appendage that is in a ring of size less than nine-membered that is fused to the LY six-membered ring under consideration is assigned A and U values of 1.8 each and a G value of 0.4; these are its base appendage interaction values. 776 J. Org. Chem., Vol. 45, No. 5, 1980 Corey and Feiner

Table VIII. Conformational Energies (kcal/mol) for Monomethyl-cis-decalins Computed by the Method Described in This Paper and by the Molecular-MechanicsMethod of Allinger3*74 cis-decalin LHASA Allinger 0 75 3 la -Me 5.5 5.29 76 20-Me 1.8 1.68 3a-Me 3.6 3.76 recorded, as described above, this duplication will be de- 40-Me 0.9 0.46 tected and corrected. Other Fused-Ring Systems. Significant interatomic semiempirical molecular mechanics conformational anal- interactions may also take place between six-membered ysis method developed by Allinger.3*73 His computer ring systems and the appendages on smaller or larger fused program determines an energy difference between the two rings. Although it is difficult to analyze such interactions la-methyl-cis-decalin conformers 66 and 67 of 5.29 kcal/ with as much precision as has been done with decalin mol.74 A similar comparison between our treatment and systems, due to the wide range and variability of the the Allinger method for the remaining monomethyl-cis- possible spatial relationships, simple empirical ways of decalins is presented in Table VIII. Very good agreement assessing such interactions have been formulated. in all but the 40-methyl-cis-decalin case is reached. As a first approximation it is considered that there are cis- and trans-Decalins. There exists a second type no inter-ring interactions between ring systems smaller or of inter-ring interaction which may take place between larger than six-membered which are trans fused to six- pairs of appendages (R/R’) situated on opposite sides of membered rings. Cis-fused ring systems, on the other a cis- or trans-decalin fusion bond; this is illustrated with hand, must be dealt with. structures 68,69, and 70. The R and the R’ appendages In general, cis-fused rings of size other than six-membered can have the effect of positioning an appendage under the six-membered ring in much the same way that an axially oriented tert-butyl appendage disposes one of its methyl groups with respect to the ring (78 and 79). 70 68 69

R R‘ R t-I cc’71 72 E~R’R’= UR + UR~(23) EDR= 1/2AR(24) Specifically, such interactions are tallied only for rings smaller than nine-membered (i.e., 78, n I 8 and # 6) and only when they bear an appendage R (i) that is attached “a-axial” with respect to the six-membered ring [i.e., attached to that atom of the fused ring (C* in 78) that both I I is H R a to the six-membered ring and is the connecting atom of 73 74 an axial appendage] and (ii) that is syn to the six-membered ring (i.e., trans, with respect to the n-membered ring, = lI6AR(25) ED^ = 0 (26) to the appendages off the two 6/n fusion atoms). The in these systems bear the same spatial relationship to each magnitude of the extra destabilization imparted by the other as the members of a 1,3-diaxial appendage pair on presence of R in structure 78 is taken simply as the U value a cyclohexane chair. Thus the same procedures used in of R (eq 27). This is added to the destabilizing contribu- computing 1,3-diaxial-interaction destabilizations, de- tion made by axial C*. scribed above, are employed here. This simply involves For cases where there is also present a syn-axial ap- summing the U values for R and R’ (71) or utilizing the pendage off the six-membered ring (R’ in 80), a situation appropriate A value expression when R’ is replaced by a quite similar to the appendage/appendage cis-decalin hydrogen atom (72), an sp2-hybridized center (73), or a concavity arrangement (65) is encountered. In these cir- heteroatomic center (74) (eq 23-26). cumstances the destabilization energy for the append- When using these procedures for computing inter-ring age/appendage interaction is obtained by summing the U interactions, a repeated counting of 1,2-diequatorial in- values of the two appendages involved (eq 28).’O Thus, for tra-ring interactions is incurred. Thus the 1,Zdiequatorial conformation 80, with R = R’ = Me, the contributors to interactions between C2 and C4 on ring 1 and between C1 the total destabilization (kcal/mol) include the following: and C3 on ring 2 in trans-decalin 75 and those between C1 (i) axial C* (0.9),’2 (ii) axial R’ (0.9), (iii) l,&diaxial C7/R’ and C3 on ring 2 in cis-decalin 6 form part of the inter-ring (3.6),72and (iv) R/R’(3.6). Thus EDsysfor conformer 80 destabilizations just described. However, since the gauche is 9.0 kcal/mol. components of each intra-ring or inter-ring interaction are Chair/Boat Interactions. The final type of inter-ring situation which is considered involves two fused six-membered rings, with one a chair and the other held in a boat (73) The Allinger program was made available through the courtesy conformation. Due to the reduced symmetry of the boat, of Dr. D. A. Pensak, E. I. duPont de Nemours and Co. (74) As pointed out in the accompanying paper,’ the Allinger program the possible fusion arrangements are more complex than requires the precise three-dimensional coordinates of every atom in the for chair/chair pairings. Below we outline how the fused system, including each hydrogen, and the calculation requires on the chair/boat systems are handled, first describing chair/boat order of 3 min. By comparison, the computation described in these papers starta with a two-dimensional structure sketched quickly by the cis fusions and then chair/boat trans fusions. For both chemist and requires less than 1.5 s of computer time. it has been possible to describe the various structural Computer-Assisted Synthetic Analysis J. Org. Chem., Vol. 45, No. 5, 1980 777 situations in terms of the models developed above; hence, second-order analysis described in this paper, little has the computation of the destabilizing interactions that can been said to this point about ring flexibility. The signif- arise is carried out in a completely analogous manner, and icance of this parameter is now discussed briefly. no new destabilization energy equations are required. It will be recalled that each ring received one of three Four types of chair/boat cis fusions are possible, in- flexibility designations: rigid, distortable, or flippable. volving attachment of the chair to the (1) “end/bottom” Rigid rings are those found structurally constrained to a (81), (2) “end/top” (82), (3) “side/top” (83), or (4) “side/ single geometric form (one of structures 1-6) with no conformational variation allowed; for these systems second-order analysis is clearly inappropriate, and a final assignment conformation is possible immediately after the first-order analysis. Flexible six-membered rings represent the opposite situation. For such systems configurational constraint is minimal, and two well-defined conformations, bottom” (84) of the boat, as schematically illustrated. It corresponding to two chairs (1 or 2), two half-chairs (3 or was hoped that inter-ring interactions for all these situa- 4), two boats (5 or 6), or sometimes to a chair and boat (1 tions might be handled by the analytical method developed or 5), can exist. By comparison of the relative energies of for other cis-fused 6/n pairs. Here, as described above, the two geometries during the second-order analysis, the only the syn appendage subtended by that atom in the basis for a conformational decision can be reached. The n-membered ring that is “a-axial” to the six-membered third flexibility designation, distortable, accounted for ring is capable of interacting with the six-membered ring intermediate structural situations. Distortable six-mem- (78). This guide does, in fact, usefully apply to the two bered rings, like rigid systems, are limited by configura- cis-fused chair/boat systems 81 and 83 (85), but for the tional constraint to adopt a single well-defined confor- other two systems the steric arrangement is so modified mation; however, like flippable systems, they may depart that only that syn appendage subtended by the “0-axial” from this conformation. The unique aspect of distortable atom in the boat ring may interact (86). Destabilization rings is that when they leave the well-defined conforma- contributions for the appendage R in systems 85 and 86 tional form they can only enter into a distorted geometry, are computed by using eq 27.’O assumed to be of intrinsically higher energy, and they may not achieve a second well-defined form. For such ring systems a second-order analysis is crucial, for it must be determined whether the energy of the well-defined form is low enough to discourage the ring from availing itself of the distorted geometry.

a Significant Energy Difference. A significant energy 87 88 advantage for a conformer is considered to be 1.2 kcal/mol; 85 86 this corresponds to roughly a 90% preponderance of this conformer at room temperature.llC Thus conformational Two types of chair/boat trans fusions are possible, with homogeneity would be predicted, for example, for 2- the fusion involving either an end (87) or a side (88) of the methylcyclohexanone (89),where the two possible con- boat. In either case, the inter-ring appendage/appendage CH3 R interactions are almost completely analogous to those I described above for trans-decalins (69 and 70), where, it I will be remembered, two axial/axial and two equatorial/ equatorial appendage pairings are possible. For chair/boat tram fusions, however, two equatorial/equatorial pairings are possible, but only one axial/axial pairing is possible; a T b members of the other axial appendage pair are on opposite 89, R = H sides of the ring systems (X and Y in 87 and 88). For the 90,R = Ph interacting pairs, destabilization energies are obtained by formers differ in destabilization energy by AMe = 1.8 using eq 23-26. kcal/mol, but would not be expected for cis-2-methyl-5- phenylcyclohexanone (go),where EDsYs is computed at Final Conformational Assignments 2/3(3.0)- 1.8 = 0.2 kcal/mol (cf. eq 8), favoring 90a. Thus Once all the interatomic interactions associated with a definite stereaassignment corresponding to the chair each of the assigned conformations have been assessed for geometry of 89b would be made for system 89. For system each of the six-membered rings in the molecule, it is 90, however, since only a slight preponderance (i.e., about possible to address the question of final conformational a 60/40excess1lC) of the minimum-energy conformer can assignment. Two criteria must be met in order to assign be expected, no assignment of geometry or axial/equatorial a unique and well-defined conformation to a six-membered labeling would be made. These same considerations apply ring: (i) the total computed destabilization EDsYsof the to fusion composites,’ Le., to conformationally interde- lowest energy conformation must be significantly lower pendent groups of six-membered rings. Thus, for the than the energies of all other conformations considered, monomethyl-cis-decalins discussed above (Table VIII), and (ii) the destabilization of the minimum-energy con- conformational assignments can be made for the la, 2@, former must be less than an energy cutoff ualue. Both and 3a systems, where in each case EDsYs is more than 1.2 these points will be discussed presently. kcal/mol, but not for the 4P compound, where the two Ring Flexibility. First, however, it is important to conformers are found to be separated by only 0.9 kcal/mol. refocus attention on the flexibility designation which ac- The distinction between configurationally locked vs. companied the preliminary conformational assignment conformationally free well-defined geometries is important made for each six-membered ring during the first-order when the results of the analysis are applied to the evalu- analysis.’ Although it has been amply demonstrated how ation of chemical transformations in the antithetic anal- the preliminary conformation has formed the basis for the ~sis.’~Thus the six-membered rings in 91 and 89 both 778 J. Org. Chem., Vol. 45, No. 5, 1980 Corey and Feiner

91 92 RING XS RING RING 2411 RING receive unambiguous chair assignments. In 91 this as- Q 0 0 0 signment represents the only geometry available to the 2.7 1.8 3.0 6.0 ring, since through first-order analysis it is shown to be I1.35 +-’ bm -1.5 e b 1.5 rigid.’ System 89, on the other hand, is flippable, and the 1.35 1.35 3.3 7.5 ring is free to depart from the geometry of 89b; although E:’’= 2.7 E:’’= 10.8 strongly predominating in equilibrium concentration, this conformer is rapidly interconverting with 89a.65 A parallel distinction can be made between configura- 6.0 1.8 3.0 6.0 tionally vs. conformationally ambiguous ring systems, as -i.sd3”-& -1.5 1.5 exemplified by 92 and 90, respectively. System 92 is shown 7.5 1.5 3.3 7.5 during first-order analysis to be incompatible with any E:”= 9.0 E:’’= 10.8 well-defined geometry.’ Thus no axial or equatorial labels can be assigned. No A/E labels may be assigned either inlsystem 90 where the second-order analysis showed the Figure 9. Destabilizing interatomic interactions and total con- energy separation between the two chair forms to be in- formational energies tallied for the substituted cis-decalin con- significant. Only lenient stereochemical screening will be formers 93 and 94. The conformational analysis is fully described applied in transform evaluations involving both these types in the text. of systems.75 ‘/zAM, + AM,). On the basis of these data the cutoff Cutoff Energy. As stated at the ouFset the basis for energy for the chair has been assigned a value of 6.0 our method of conformational analysis is the strong kcal/mol. This energy value was also assigned as the A tendency of configurationally unconstrained six-membered value of the tert-butyl group; trans-1,3-di-tert-butyl- ring systems to adopt the well-defined chair or half-chair cyclohexane is known to exist in a twist conformation.81 conformations. If, however, the resulting interatomic ap- The activation barrier between cyclohexene and its twist pendage/appendage interactions are large enough, the geometry has been measured at about 5.3 kcal/mol.82 The energy advantage of the conformation may be lost, and the corresponding barrier for cyclohexane is 10.8 kcal/m01.~’ six-membered ring will possibly opt for an ill-defined On the basis of these values the cutoff energy for the skewed or twist geometry.76 Although a well-defined ge- half-chair has been assigned a value of 3.0 kcal/mol. This ometry may still, in fact, represent the energy minimum cutoff is also applied to chair systems with a single sp2 for such a system, our method does not permit an accurate center in the ring, on the basis that the energy barrier appraisal of this possibility. It is, therefore, the practice between the chair and twist forms in the cyclohexanone in our analysis to compare the total destabilization energy system is reported to be 2.5-3.3 k~al/mol.~~**~~~~ EDsYscomputed for a given conformation against an ar- In practice, no cutoff-energy value has been assigned to bitrary absolute standard termed the cutoff energy. If the the boat conformation. It will be remembered that boat EDsYsvalues computed for the available well-defined forms geometries are only considered in the second-order analysis are each found to exceed the cutoff value, no conforma- when the conformational possibilities are restricted to a tional assignment is made for a ring system. In principle choice between two well-defined boats (43) or between one three cutoff-energy values were required, corresponding such boat and a chair (44). Since no twisting of the ring to the chair, half-chair, and boat geometries. The deriv- from the boat form is permitted by the constraints of ation of these parameters is described below. configuration in such situations, it is not appropriate to We were led to a cutoff-energy value for the chair ge- compare the destabilization energy computed for a par- ometry by consideration of two sets of experimental data. ticular conformation against an absolute cutoff energy. Of The energy difference between the chair and twist-boat course, comparison of the destabilization energies for geometries of cyclohexane has been measured to be 5.5 available conformers with each other is still important, and kcal/m01;~~it was tempting directly to utilize this value the same significance is attached to energy differences here as the cutoff energy for all chairs. X-ray crystallographic as in the case described above. structures have been published for a number of natural A second use is also made of the cutoff-energy values; products with a common structural feature: each contains this pertains to distortable ring systems, i.e., those limited at least one conformationally independent six-membered to a single well-defined geometry but for which skewed ring in which there is a single destabilization-a syn-1,3- conformations are available. For such systems the skewed diaxial methyl/methyl interaction.7gs0 For each of these form that the six-membered ring can adopt is assigned a systems the six-membered rings were found to be just destabilization energy equal to the cutoff value of the basic commencing to depart from the chair. We compute the ring system, as defined above, without regard to the total conformational destabilization for the methyl/methyl specific substitution pattern of the ring. 1,3-diaxial interaction to be 5.4 kcal/mol (UMe + UM, + Two examples are now presented which will illustrate the utility of the cutoff energy and, in addition, amplify (75) Corey, E. J.; Feiner, N. F.; Greene, T.; Hewett, A. P. W.; Long, A. K.; Orf, H. W.; Stolow, R. D.; Vinson, J. W., unpublished results. (76) Kellie, G. M.; Riddell, F. G. Top. Stereochem. 1974, 8, 225. (81) Remijnse, J. D.; van Bekkum, H.; Wepster, B. M. Red. Trau. (77) Squillacote, M.; Sheridan, R. S.; Chapman, 0. L.; Anet, F. A. L. Chim. Pays-Bas 1974,93, 93. J. Am. Chem. SOC.1975, 97, 3244. (82) (a) Anet, F. A. L.; Haq, M. Z. J. Am. Chem. SOC.1965.87, 3147. (78) Methyl suaveolate: Manchand, P. S.; White, J. D.; Fayos, J.; (b) Jensen, F. R.; Bushweller, C. H. J. Am. Chem. SOC.1969,91,5774. Clardy, J. J. Org. Chem. 1974, 39, 2306. (83) Allinger, N. L.; Blatter, H. M.; Freiberg, L. A.; Karkoweki, F. M. (79) Stypoldione: Gerwick, W. H.; Fenical, W.; Fritsch, N.; Clardy, J. J. Am. Chem. SOC.1966,88, 2999. Tetrahedron Lett. 1979, 145. (84) Cf.: Sondheimer, F.; Klibansky, Y.; Haddad, Y. M. Y.; Summers, (80) Friedelin-like triterpenes: cf. ref 67d-f. G. H. R.; Klyne, W. Chem. Ind. (London) 1960, 902. Computer-Assisted Synthetic Analysis J. Org. Chem., Vol. 45, No. 5, 1980 779 the treatment of inter-ring interactions. The conforma- signed to serve as an adjunct in the computer-assisted tional equilibrium between systems 93 and 94 is analyzed generation of synthetic routes to complex organic mole- as follows (Figure 9). During first-order conformational cules.' The results of the conformational analysis de- analysis' flexibility assignments of flippable and distortable scribed herein are obtained sufficiently rapidly and with are made for rings 1and 2, respectively; this follows from enough reliability to be of value in LHASA. In essence the the single configurational constraint on the ring system: stereochemical information so obtained permits the the trans fusion with the five-membered ring. Thus, both screening of many organic transformations which retro- six-membered rings may adopt chair conformations in 93; synthetically remove stereocenters from a six-membered in 94 only twist geometries are available to ring 2, although ring so that a rating of acceptable or not acceptable is a chair form is possible for ring 1. generated. Thus a service comparable to that provided We first consider the unsubstituted system 93a 94a. for an organic chemist consulting a Dreiding-type molec- In conformation 93a an unsubstituted cis-decalin system ular model is performed. Various stereochemical aspects is present. Thus, as described above, following consider- of antithetic analysis by computer are currently under ation of first intra-ring and then inter-ring interactions, de~elopment'~and will be reported on in future publica- a system destabilization energy, EDsys, of 2.7 kcal/mol will tions. be computed for the pair of rings. In conformation 94a, We close by providing a number of examples of the on the other hand, the situation is quite different. In ring results of our computations for a variety of six-membered 1, a provisional chair, the monoaxial C1/H,H interaction ring systems whose conformations have been determined contributes 1.8 kcal/"ol of destabilization. Ring 2 is a by X-ray crystallographic analysis. The aphidicolin (95) twist conformer and is thus assigned its cutoff energy of 7, /\ 6.0 kcal/mol. No specific inter-ring interactions are assessed between rings 1 and 2 because, as stated at the &&& A outset of the discussion of inter-ring interaction compu- '"H tation, one of the rings is of ambiguous geometry. How- A -,A! A! ever, an arbitrary destabilization of 3.0 kcal/mol (Le., 1.5 H 'ii kcal/mol/ring) is assigned to the ring l/ring 2 system to 96'' 97 take inter-ring interatomic interactions into account. This and related 8-epiaphidicolin (96) and stemodin (97) ring practice is adopted in all such 6/6 fusion situations when systems provide interesting illustrations of the variation the conformation of one ring is not known. Thus the total of six-membered ring conformation with configurational destabilization energies for rings 1 and 2 compute at 3.3 constraint. In each system the conformation of the B ring and 7.5 kcal/mol, respectively, and for system 94a EDsys follows from the axial appendage assignments made on the = 10.8 kcal/mol. The difference in the total destabilization basis of the trans fusions identified during first-order energies between systems 93a and 94a, which is found to analysis. In systems 95 and 97 a chair geometry can be be 8.1 kcal/mol, then leads to unambiguous assignment assigned, but this is found not possible in 96. The X-ray of conformation 93a. data support these conclusions. Next we consider the monosubstituted system 93b + A number of reported systems of natural or synthetic 94b. In conformer 93b both rings are provisional chairs; origin follow, each of which can be assigned a ring flexi- intra-ring interactions are looked at first. Ring 1 will be bility designation of flippable. These include the chair == assigned a destabilization of 6.0 kcal/mol for its axial chair (C/C) systems 98-100, the half-chair 6 half-chair tert-butyl group; no destabilizing interactions are found within ring 2. Since the destabilization assigned to ring CI 1 is equal to its cutoff-energy value, the provisional assignment of the chair geometry for the ring must thus be abandoned at this stage in the computation. Therefore, OH no specific inter-ring interactions are computed between ring 1 and ring 2, and an arbitrary destabilization energy CI of 3.0 kcal/mol is assigned the ring system. Thus the total 98'' 99'O 100" destabilization energies for rings 1 and 2 are computed to be 7.5 and 1.5 kcal/mol, respectively, and EDsYsis 9.0 kcal/mol. In conformer 94b, ring 1 is a provisional chair (85) A listing of this computer program is available from one of the and ring 2 a twist. Since the tert-butyl group is now authors (E.J.C.). equatorial and hence noninteracting, this system is com- (86) Aphidicolin: Brundret, K. M.; Dalziel, W.; Hesp, B.; Jarvis, J. A. puted to have the same destabilizations as system 94a. As J.; Neidle, S. J. Chem. SOC.,Chem. Commun. 1972, 1027. + (87) 8-Epiaphidicolin: Trost, B. M.; Nishimura, Y.; Yamamoto, K. J. a result, EDsYs for the 93b 94b equilibrium is computed Am. Chem. SOC.1979, 101, 1328. to be 1.8 kcal/mol in favor of 93b. This energy difference (88) Stemodin: Manchand, P. S.; White, J. D.; Wright, H.; Clardy, J. is considered to significantly favor conformer 93b. Thus J. Am. Chem. SOC.1973, 95, 2705. a chair geometry may be assigned ring 2. Ring 1, on the (89) Violacene: Van Engen, D.; Clardy, J.; Kho-Wiseman, E.; Crews, P.; Higgs, M. D.; Faulkner, D. J. Tetrahedron Lett. 1978, 29. other hand, is not assigned a geometry since its total de- (90) Mynderse, J. S.; Faulkner, D. J.; Finer, J.; Clardy, J. Tetrahedron stabilization was found to exceed the cutoff-energy value. Lett. 1975, 2175. (91) Wratten, S. J.; Faulkner, D. J. J. Am. Chem. SOC.1977,99, 7367. (92) Trinervitriol Prestwich, G. D.; Tanis, S. P.; Springer, J. P.; Conclusions Clardy, J. J. Am. Chem. SOC.1976, 98, 6061. (93) Gardlik, J. M.; Johnson, L. K.; Paquette, L. A.; Solheim, B. A.; In this and the accompanying paper' we have formulated Springer, J. P.; Clardy, J. J. Am. Chem. SOC.1979, 101, 1615. (94) Oppositol: Hall, S. S.; Faulkner, D. J.; Fayos, J.; Clardy, J. J. Am. a number of general guidelines to enable the prediction Chem. SOC.1973, 95, 7187. of the consequences of structure on the conformation of (95) Xylomollin: Nakane, M.; Hutchinson, C. R.; Van Engen, D.; six-membered rings. The response to the effects of both Clardy, J. J. Am. Chem. SOC.1978, 100, 7079. configurational constraint and nonbonded interatomic (96) Neoconcinndiol Howard, B. M.; Fenical, W.; Finer, J.; Hirotsu, K.; Clardy, J. J. Am. Chem. SOC.1977, 99, 6440. interaction has been treated. These guidelines have been (97) Corylifuran: Burke, B. A.; Chan, W. R.; Prince, E. C.; Eickman, utilized in the preparation of a computer programa5 de- N.; Clardy, J. Tetrahedron 1976, 32, 1881. 780 J. Org. Chem. 1980,45,780-785 (HC/HC) system 101, the half-chair + boat (HC/B) system 102, and the chair,chair * chair,twist (CC/CT) fusion composite system 103. For each of these systems

ED= 5.0 $=0.8 ED=B 1.9

101" 102~~ 103"

~E~'1.4(HCIHC) >E+=Z,O (HUB) ~E~'4.6(CC'CT) is shown the conformation predicted and the computed "I. total destabilization energy (AED, kcal/mol) found to favor 106% this conformation over its well-defined alternative. In each 107" case the significant energy difference computed leads to E0=4.2 $=L4 ED=3.9B prediction of the geometry actually established by the X-ray data. Again, these assignments are supported by the X-ray data. Finally, several naturally occurring systems (104-107) are shown, each of which contains one or a pair of six- Acknowledgment. This research was assisted by a membered rings with a flexibility classification of dis- grant from the National Institutes of Health and by a tortable. For each of these is shown the total destabili- fellowship from the National Research Council of Canada. zation energy (ED,kcal/mol) computed for the single We thank Professor A. Peter Johnson, Polytechnic of well-defined chair conformation available. In each case North London, and Professor Robert D. Stolow, Tufts this number is below the appropriate energy cutoff value University, for their important contributions during the and leads to acceptance of the chair geometry shown. development of these ideas.

Indole-3-sulfonium Ylides and Related Sulfonium Salts. Chemical and Physical Properties

Kyong-Hwi Park and G. Doyle Daves, Jr.* Department of Chemistry and Biochemical Sciences, Oregon Graduate Center, Beaverton, Oregon 97005 Received November 26, 1979

Acid-base titration of the sulfonium salt-sulfonium ylide pair dimethyl(1H-indol-3-y1)sulfonium3-(dimethylsulfonio)indolide, the corresponding 2-methyl or 2-phenyl analogues, or the homologous 3-diethylsulfonium compounds resulted, in each case, in a hysteresis; i.e., titration of the sulfonium ylide with acid gave a different set of pH values from those observed upon titration of the sulfonium salt with base. In related studies comparison of ultraviolet spectra of the sulfonium salts and ylides in anhydrous dioxane and in water revealed significant differences. 'H NMR spectra of sulfonium salts in aqueous or aqueous trifluoroacetic acid solutions revealed the formation of a new species which (a) exhibited an acid-base titration hysteresis indistinguishable from that of the precursor salt, (b) exhibited ions in the mass spectra corresponding to a sulfonium salt plus a molecule of water, and (c) reverted to the precursor salt upon attempted purification. These results are consistent with covalent hydration across the highly polarized C-2, C-3 double bond of the indole ring.

We have reported that 3-(dimethylsulfonio)indolide (la), (the pKa of the conjugate acid, sulfonium salt 4a, is >11) +,/Me +/Me and (b) incorporates deuterium into the S-methyl groups when dissolved in deuteriochloroform or deuteriomethanol -;.\.Me @7J5\c!2 (requiring the intermediacy of methylidene ylide 2).l \ R - H More recently, we have made a detailed study of 13C and 1 lH NMR spectra of la, its 2-methyl (lb) and 2-phenyl (IC) 2 analogues, precursor 3-(methylthio)-lH-indoles(3), and +/Me dimethyl( 1H-indol-3-y1)sulfonium salts (4) in aprotic solvents.' In the present report, we describe the prepa- @J''M:- @J''M:- R ration of these compounds and of the related 3-(diethyl- QJ---Jl\Me QJ---Jl\Me k H su1fonio)indolide (5) and corresponding sulfonium salt 6 3 4 and studies of various aspects of their chemical and physical properties including acid-base titration phenom-

+/Et ;/Et ena, ultraviolet spectroscopy in protic and aprotic solu- \E+x- tions, 'H NMR spectra in protic solvents, and electron @J ionization and field desorption mass spectrometry. QpEtH 5 6 (1) G. D. Daves, Jr., W. R. Anderson, Jr., and M. V. Pickering, J. a, R = H;b, R = Me;c, R = Ph Chem. SOC.,Chem. Commun., 301 (1974). (2) K. H. Park, G. A. Gray, and G. D. Daves, Jr., J.Am. Chem. SOC., a stable, crystalline sulfonium ylide, (a) is unusually basic 100,7475 (1978).

0022-3263/80/1945-0780$01.00/0 0 1980 American Chemical Society Top Heterocycl Chem (2006) 6: 1–37 DOI 10.1007/7081_035 © Springer-Verlag Berlin Heidelberg 2006 Published online: 21 April 2006 Directed Synthesis of Biologically Interesting Heterocycles with Squaric Acid (3,4-Dihydroxy-3-cyclobutene-1,2-dione) Based Technology

Masatomi Ohno1 (u)·ShojiEguchi2 1Department of Advanced Science and Technology, Toyota Technological Institute, 2-12-1 Hisakata, Tempaku, 468-8511 Nagoya, Japan [email protected] 2Department of Molecular Design & Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, 464-8603 Nagoya, Japan

1 Chemistry of Squaric Acid with 3-Cyclobutene-1,2-Dione Skeleton ..... 2

2 Derivatization of Squaric Acid to 4-Hydroxy-2-Cyclobutenone Skeleton .. 3

3 Ring Transformation of the Derivatized Cyclobutenone ...... 5 3.1 VariedReactivityinRingOpeningandRingClosure...... 5 3.2 ThermalConcertedProcess...... 9 3.3 ReactiveIntermediateInducedProcess...... 21

4 Squaric Acid Bioisostere ...... 27

5ConcludingRemarks...... 32

References ...... 32

Abstract A variety of methods for organic transformation starting from squaric acid have been developed in this decade. These are based on conversion of pseudoaromatic 3,4-dihydroxy-3-cyclobutene-1,2-dione into the more reactive 4-hydroxy-2-cyclobutenone by introduction of the required (or desired) functional groups followed by key ring transformation, the rearrangement being stimulated thermally or induced by a reactive intermediate. These strategies can construct a variety of bioactive heterocycles when functional groups contain heteroatoms or heterocycles. Interestingly, squaric acid is rendered as an acid part, for example, of an amino acid, and this bioisostere concept is extended to various heterocycle-containing squaramides (3,4-diamino-3-cyclobutene-1,2-dione derivatives) as bioactive conjugate compounds. This review article covers biologically interesting heterocyclic compounds accessible with the squaric acid based technology.

Keywords Bioisostere · Cyclobutenone · Electrocyclic reaction · Reactive intermediate · Squaric acid 2 M. Ohno · S. Eguchi 1 Chemistry of Squaric Acid with 3-Cyclobutene-1,2-Dione Skeleton

Squaric acid (1) is categorized as an oxocarbon having a four-membered ring [1] (Fig. 1). Despite being a small molecule, it possesses unique 2π- pseudoaromaticity [2–5], which brings high acidity (pKa1 = 0.52, pKa2 = 3.48) as an organic acid, and polyfunctionality, including two hydroxyl and twocarbonylgroupsconjugatedacrossadoublebond.Peculiarhydrogen- bonded network and chelated structures in some acid derivatives have been occasionally discussed [6–12]. The unique structure is utilized in electronic devices, for example, as a donor–acceptor triad called “squaraine” (2) [1, 13– 15]. The dicationic nature of the cyclobutene ring necessary for aromatic character is combined with the donating nature of aromatic and heteroaromatic rings to produce SHG properties, for example [16]. Dimer 3 is a new candidate designed for extension of conjugation plane [17, 18]. On the other hand, the unique structure of 1 has also been applied in organic synthesis as an attractive C4-synthon. The relief of ring strain can serve as a significant driving force in its ring-transformation reaction and this is in fact accomplished by two processes. The first is conversion of the stable aromatic cyclobutenedione system to the more reactive hydroxycyclobutenone system; where required or desired substituents can be introduced into the ring system. The second is ring expansion from a four-membered ring to five ∼ seven-membered rings in either concerted or stepwise manner. This methodology has been exploited in the synthesis of various bioactive carbo- and heterocycles [19–23]. Another feature of using 1 to develop bioactive compounds is based on variation of substituents on squaric acid esters and amides, where the cyclobutenedione ring is still retained. In fact, semisquaric acid (4), which is known as moniliformin, is a primitive derivative with biological activity (mycotoxin) [24]. According to the concept, for 1 to play

Fig. 1 Squaric acid and its derivatives [1–18] Squaric Acid Based Technology 3 a role of bioisostere (e.g., semisquaric acid is considered to have similarity to pyruvic acid in structure), research has pursued the possibility of 1 as a re- placeable moiety for an acid part of natural products such as amino acids and nucleic acids, and for a certain part of pharmacoactive compounds (see later). As a synthetic tool, the use of 1 has recently been demonstrated in asymmetric reduction adopting the cyclobutenedione as a ligand with a chiral center [25, 26].

2 Derivatization of Squaric Acid to 4-Hydroxy-2-Cyclobutenone Skeleton

Squaric acid itself is almost useless for this aim because of its intrinsic aromatic stability and difficult solubility in organic solvents. Instead, its esters 5 are the most convenient compounds from which derivatization reactions start. While acid 1 and its esters are now commercially available, (cf. 1 is now produced on a commercial basis by Kyowa Hakkou Kogyo Co. Japan [27]). The esterification method for 1 is improved [28] and preparation of dimethyl squarate 5 (R = CH3)isrecordedinOrganic Synthesis [29]. There are several approaches for derivatization of squaric acid (1). The traditional major route relies on the nucleophilic reaction of the eligible esters 5 with organolithium and organomagnesium reagents; their addition to 5 is known to be sufficiently selective to give 1,2-addition products 6 (4-substituted 4-hydroxy-2-cyclobutenones) from the former and 1,4-addition products 7 (3-substituted cyclobutene-1,2-diones) from the latter [30]. When acid-catalyzed rearrangement of 6 to form 7 with one combined substituent (R1) at C-3 is followed by the repeated nucleophilic addition to combine another substituent (R2), this series of reactions gives rise to 2,4-doubly substituted 4-hydroxy-2-cyclobutenone 8 [31, 32]. Trisubstituted 4-hydroxy-2-cyclobutenone 11 can be prepared via acetal intermediates 9 and 10 [33] (Scheme 1). Organotin and copper species are also used for the derivatization of 5 by cross-coupling reactions (typically shown as 5 → 12 → 13) [34–38]. The α-carbanion generated at the position adjacent to cyclobutenedione ring is a different derivatization route via nucleophilic addition (14 → 15 → 16) [39] (Scheme 2). The derivatization method is compensated by the electrophilic addition reaction using organosilicon reagents [40–43]. Thus, the squaric acid family of derivatives, e.g., dichloride 17, methyl ester chloride 18, amide chloride 19, and diester 5 are the partners of the reactions with allylsilanes, silyl enol ethers, and silyl ketene acetals (Scheme 3). In this case, 1,2- and 1,4-addition to 20 and 21, respectively, are regulated by the substitution pattern of unsaturated organosilanes, kind of Lewis acid catalysts, and the reactivity of acid derivatives. The less congested is the reaction site, the more preferable is 1,2- 4 M. Ohno · S. Eguchi

Scheme 1 Derivatization of squaric acid: traditional nucleophilic conditions [30–33]

Scheme 2 Derivatization of squaric acid: organometallic routes via coupling reactions [34–39] addition in allylsilanes and silyl enol ethers. TiCl4 catalyzes 1,2-addition and ZnCl2 1,4-addition in silyl ketene acetals regardless of the substitution pattern. Only silyl enol ethers and silyl ketene acetals are reactive with diester 5 via 1,4-addition. In addition to the above carbonyl group activation, the acetal 10 is also a useful candidate for generating the electrophilic center under these conditions. Thus, besides typical organosilanes, azide functions can be introduced with BF3-catalysis (vide infra). Similar electrophilic Friedel–Crafts-like reactions allow the most reactive dichloride 17 to furnish 1,4-diarylcyclobutenedione derivatives [44, 45]; for example, 1,4-thieno[3,2-b]pyrrole-substituted cyclobutenedione 23 was prepared by this method and an oxygen-inserted conjugation system 24 was attained as a photochromic devise [46] (Scheme 4). Apart from these methods based on the squaric acid family, direct formation of cyclobutenedione rings by [4 + 2] and [2 + 2] cycloaddition reactions is a plausible approach to variably substituted 4-hydroxy-2-cyclobutenone systems [47–54]. Squaric Acid Based Technology 5

Scheme 3 Derivatization of squaric acid: electrophilic conditions using unsaturated organosilanes [40–43]

Scheme 4 Derivatization of squaric acid by Friedel–Crafts-like reaction: an example [46]

3 Ring Transformation of the Derivatized Cyclobutenone

3.1 Varied Reactivity in Ring Opening and Ring Closure

The intrinsic reactivity of small rings is ascribable to ring strain relief in nature, and in squaric acid chemistry it is accomplished by conversion of rather stable cyclobutene-1,2-dione to the more reactive 4-hydroxy-2- cyclobutenone [55, 56] as described in the previous section. At the same time, this conversion step fulﬁlls the regiospeciﬁc introduction of substituents required for the targeted heterocyclic structure. Thereby, the set-up four- membered ring is now subjected to directed synthesis through variable ring transformation reactions. These involve tandem ring opening and ring closure steps, which are concerted or non-concerted. The typical concerted process is 4π-electrocyclic 6 M. Ohno · S. Eguchi ring opening of cyclobutene to 1,3-butadiene. This was discussed in terms of torquoselectivity by Houk [57–64]. According to his theory, π-donor sub- – stituents(R=O,OH,NH2) prefer outward rotation while π-acceptor substituents (R = BMe2, CHO) should rotate inwardly on the thermal process (Fig. 2). Recent discovery has extended this concept; a silyl substituent accel- erates and promotes inward rotation despite the resulting steric congestion, and a stannyl substituent does similarly [65, 66].

Fig. 2 Torquoselect iv it y in 4π electrocyclic ring opening (thermal conditions) [57–64]

4-Hydroxy-2-cyclobutenone adheres to the above prediction [55–64]. In this case, it is important that the inwardly-directed substituent (i.e., OH is an outward-directing group) is capable of participating within the molecule. Moreover, a highly reactive vinylogous ketene function occurs instead of butadiene formation to assist efﬁcient ring-closure through intramolecular interaction. When an unsaturated bond is located at the 4-position, the consecutive process is thermally allowed 6π-electrocyclization (Fig. 3).

Fig. 3 Sequence of 4π–6π electrocyclic ring opening and ring closure [19–23]

This strategy is very powerful and fruitful for the directed synthesis of both carbo- and heterocycles, and successful examples have cumula- tively been reported until now [19–23]. The major contribution has come from the Moore and Liebeskind groups. Among many efforts devoted in this area, the recent typical example [polysubstituted naphthoquinone, Echinochrome A (30)] constitutes a characteristic feature for the method of directed synthesis including 26 → 27 and 28 → 29 as key steps [67]. Ferro- cenyl quinone and 5-O-methylembelin were also synthesized according to this methodology [68, 69] (Scheme 5). In the case of monosubstituted cyclobutenone 31, the adduct with lithiovinylsuofone 32 was reported to undergo an extraordinarily facile tandem 4π–6π electrocyclic process (33 → 34)at–78 ◦C to give cyclohexenone 36 [70]. The photochemical process may oblige the opposite direction on a hydroxyl group to be oriented inwardly; actually cyanohydrin 37 was reported to give butenolide 39 as a result of an intramolecular addition reaction of (Z)-hydroxyvinylketene 38 [71] (Scheme 6). Squaric Acid Based Technology 7

Scheme 5 Synthesis of echinochrome A: a typical example for 4π–6π electrocyclic ring opening and ring closure [67]

Scheme 6 Tandem 4π–6π electrocyclic concerted process at low temperature [70] and under photochemical conditions [71] 8 M. Ohno · S. Eguchi

If the substituent is allylic and hence homoconjugative, intramolecular [2 + 2] cycloaddition is progressive to form bicyclo[3.2.0]heptenone as shown in Fig. 4 [19–23]. This is the second pattern of the ring transformation based on squaric acid.

Fig. 4 Intramolecular [2 + 2] cycloaddition to bicyclo[3.2.0]heptenone [21]

The third pattern was developed by Paquette, who studied the possibility of the concerned reaction extensively and established the cascade rearrangements route [72]. The scenario of the cascade rearrangement is: 1. 1,2-Addition of a pair of alkenyl anions (either the same or different) to a squarate ester in an anti and/or syn manner 2. Charge-driven 4π conrotatory opening to coiled 1,3,5,7-octatetraene followed by 8π recyclization for anti-adduct, and straightforward oxy-Cope rearrangement for syn-adduct 3. Transannular Aldol condensation for the ﬁnal ring closure to bicycles The prototype as shown in Fig. 5 was extended to more sophisticated molecular design such as a polyquinane skeleton.

Fig. 5 Cascade rearrangements following twofold addition of alkenyl anions to squarate esters [72]

On the other hand, ring strain relief is triggered by reactive intermediates, and as a matter of fact, this is the alternative option. The reactive intermediates are carbocation, carbon radical and carbene, and their hetero-analogs. Once generated at the position adjacent to C-4, they mediate sequential ring expansion to a ﬁve-membered ring [23]. The similar story may be depicted by metal catalyses [73, 74]. Squaric Acid Based Technology 9

Fig. 6 Ring transformation induced by reactive intermediates [23]

The above ring transformation strategies have also been investigated by beginning with preparation of cyclobutenedione and cyclobutenone skeletons rather than employment of squaric acid [75–77].

3.2 Thermal Concerted Process

Thermal ring expansion of polysubstituted 4-hydroxy-2-cyclobutenones, which can be prepared from squaric acid ester (see the previous section), has been extensively studied and its synthetic value has now been conﬁrmed. The early works have been reviewed several times for the cases of cyclobutenones that have unsaturated bonds at the 4-position, such as (cyclo)alkenyl, alkynyl, and aromatic groups [19–23]. Especially, directed synthesis of heterocycles is feasible by placing heteroatoms such as nitrogen and oxygen at the appropriate position. When hetero double bonds are located at the 4-position, tandem 4π–6π electrocyclic reactions (Fig. 3) can afford six-membered heterocycles. This is the case for a C = Obondtogiveα-pyrone. Thus, treatment of cyclobutenedione [e.g., 5 (R = i-Pr)] at – 78 ◦CwithO-TBDMS-cyanohydrin/LiHMDS followed by low-temperature quench and workup directly gave α-pyrone 41, which is often found in bioactive compounds [37, 78]. A particularly interesting aspect is the ability of the intermediate 4-acylcyclobutenone 40 to rearrange to 41 at or below room temperature as most ring expansions of 4- aryl or 4-vinylcyclobutenones require heating at higher than 100 ◦C. This is attributed to greater polarization of the C = Obond(Scheme7).

Scheme 7 Synthesis of α-pyrone: tandem 4π–6π electrocyclic concerted process with aC= O function [78] 10 M. Ohno · S. Eguchi

The C = N version was realized by using azaheteroaryl substituents at the 4-position [79]. The required cyclobutenones 43 were prepared by the addition of the corresponding 2-lithioheteroaromatics (or Pd-catalyzed cross- coupling with 2-stannylheteroaromatics). The usual ring opening followed by intramolecular cyclization of the C = N bond of azaheteroaromatics onto the vinylketene end occurred faithfully to give quinolizin-4-ones 45a, imidazo[1,2-a]pyridin-5-ones 45b,andthiazolo[3,2-a]pyridin-5-ones 45c (Scheme 8).

Scheme 8 Synthesis of fused pyridones: tandem 4π–6π electrocyclic concerted process with C = N functions [79]

Furan and thiophene have also been utilized in this type of transformation as building blocks. In the same manner, prerequisite structures prepared by cross-coupling as well as traditional carbanion addition were converted ex- pectedly into benzo- and dibenzofurans and their thiophene analogs (i.e., 47 → 48) [80]. Likewise, sesquiterpene furanoquinone 51 was synthesized [81], and the total synthesis of the indolizidine alkaloid, septicine 54,wasper- formed with the key step 52 → 53 for the pyrrole case [82] (Scheme 9). Dihydropyridine is another building block. Construction of the pyri- doacridone ring system, which is found in marine alkaloids and often exhibits an array of biological activities (e.g., amphimedine), was accessible from condensation of 5 (R = i-Pr) with 1-BOC-2-lithio-1,4-dihydropyridine 55 (note: the N atom has no nucleophilicity toward the ketene group that is formed transiently upon thermolysis). Neat thermolysis of the 1,2-adduct 56 produced an oxazolone-fused dihydroquinoline 57 as a result of the expected tandem 4π–6π electrocyclizations. The subsequent removal of the protecting pyrrole group and oxidative aromatization, with loss of the oxazolone ring, afforded the aimed-at heteropolycycle 58 [83] (Scheme 10). The xanthone core is present in a large family of natural products with broad biological activities. Highly substituted xanthone systems with linear and angular fusion were designed along the cyclobutenedione route [84, 85]. First, the requisite benzopyrone-fused cyclobutenedione structure (such as 61) was constructed by addition of dithiane anion 59b of salicylaldehyde 59a to dimethyl squarate 5, followed by acid-catalyzed cyclization with elimination of methanol. The next step of adding unsaturated organolithium (61 → 62) Squaric Acid Based Technology 11

Scheme 9 Tandem 4π–6π electrocyclic concerted process with furan, thiophene, and pyrrole rings [80–82]

Scheme 10 Tandem 4π–6π electrocyclic concerted process with a dihydropyridine ring [83] occurred selectively at the carbonyl group opposite the bulky dithiane moiety. The key ring opening step (62 → 63) proceeded even at room temperature (practically reflux was applied in THF) to give the target molecule after deprotection. Another method for obtaining angularly fused xanthones was done 12 M. Ohno · S. Eguchi by successive treatment of 3-anisoylcyclobutene-1,2-dione with heteroaryl- lithium and methyl triflate and prolonged heating of the adduct (mesitylene, reflux). In a related work using 3-benzoylcyclobutene-1,2-dione, the adduct 64 having a p-dimethylaminophenyl group at the 4-position underwent unusual rearrangement to a furan derivative 66 due to participation of an allenylketene iminium ion intermediate 65 [86] (Scheme 11).

Scheme 11 Synthesis of xanthone core by tandem 4π–6π electrocyclic concerted process [84, 85] and an unusual rearrangement to form furan [86]

Alternative synthesis of six-membered oxygen-heterocycles was demonstrated in examples of chroman and pyranoquinone, which constitute a large class of biologically active natural products. Here, allenyl and alkynyl groups were utilized as the substituents at the 4-position. An approach to chroman depends on combination of the 4π–6π electrocyclic reactions and an intramolecular hetero Diels–Alder reaction [87]. The prerequisite structure was constructed by introduction of a designed alkyne 67 to 5 (R = Me) followed by F–-promoted isomerization to the allenyl function at C-4 (68 ◦ → 69). The key thermal reactions (50 C, 36 h) involving both electrocyclic ring opening of 69 and consecutive intramolecular [4 + 2] cycloaddition of o-quinone methide 70 afforded the hexahydrocannabinol analog 71 (Scheme 12). In the case of an alkynyl substituent, the targeted pyranoquinone 76 was obtained by thermolysis (toluene reﬂux 1.5 h) of the adduct 72 prepared Squaric Acid Based Technology 13

Scheme 12 Synthesis of hexahydrocannabinol analog by combination of 4π–6π electrocyclic reactions and hetero Diels–Alder reaction [87] from lithiated alkynyl glycopyranoside and 5 (R = Me), involving a more complicated route (Scheme 13). The rearrangements featuring the alkynyl substituent were envisaged to proceed via the mechanism in which ketene 73 and diradical intermediates 74 and 75 participate. The electrocyclization was succeeded by 6-exo radical cyclization and H-abstraction to lead to the quinone ring [88]. Interestingly, it was pointed out that such diradical intermediates formed during thermolysis of 4-alkynylcyclobutenones contributed

Scheme 13 Synthesis of pyranoquinone by 4π–6π electrocyclic reactions followed by cyclization of the diradical intermediate [88, 89] 14 M. Ohno · S. Eguchi

DNA cleavage (mimic of esperamicin) [89]. The related diradical mechanism was operated in the photoannulation reaction of 2-aryl-3-isopropoxy-1,4- naphthoquinone available from 5 (R = i-Pr) and was fruitful in synthesis of dimethylnaphthogeranine E [90]. Furaquinocins are a class of antibiotics composed of naphthoquinone fused with an angular ﬁve-membered oxygen ring bearing the isoprenoid side chain. After the enantio- and diastereoselective construction of dihydrobenzofuran and introduction of an unsaturated side chain via the Horner–Wadsworth–Emmons reaction, assembly of the naphthoquinone was achieved by the squaric acid based technology (addition of designed organolithium 78 to 77a/hydrolysis/heating of 79a at 110 ◦C/air oxidation/desilylation) to give furaquinocin E (80a). Different substitution patterns for biological testing were performed by changing those of squaric acid; the regioisomer (80b) of natural product E was accomplished by reversing the chemoselectivity from imine (i.e., 77a) to pristine carbonyl group (i.e., 77b) and structural isomers (80c, 80d)byplacingthesamesubstituents[91] (Scheme 14).

Scheme 14 Synthesis of furaquinocins: assembly of furanonaphthoquinone by 4π–6π electrocyclic reactions [91]

In analogy with the foregoing construction of six-membered oxygen- heterocycles, several nitrogen versions were also developed. Synthesis of benzophenanthridine and isoquinoline resembles that of 76 as shown in Scheme 13, and alkynyl substituents bearing a nitrogen atom incorporated in the side chain were applied in these reactions with a similar mechanism. For example, chelilutine analog 82 (related to antitumor NK109) was produced by the use of an N-propargylnaphtylamine block, and isoquinolinetrione 84 by the use of an N-propargylacrylamide block [92, 93] (Scheme 15). Squaric Acid Based Technology 15

Scheme 15 Synthesis of six-membered nitrogen heterocycles in analogy with the oxygen version [92, 93]

Synthetic strategy for tetrahydroquinolinequinone 87 is similar to that for 63 (Scheme 11). Fusion with a piperidine ring at C-3/C-4 by introduction of hydroxypropyl and N-benzylamino groups at these sites, and subsequent cyclization by the Mitsunobu reaction (5 → 85)wasfollowedbytheusual sequence (85 → 86 → 87) [94] (Scheme 16).

Scheme 16 Synthesis of tetrahydroquinolinequinone in analogy with the xanthone core [94]

Finally noted in this type of ring transformation is construction of porphyrin–quinone architectures. This was performed by introduction of a porphyrin residue at C-3 by the coupling reaction of 12 with some bro- moporphyrins (cf. Scheme 2) and the prescribed conversion to quinone derivatives, fascinating as potential anticancer agents [95, 96]. The electrocyclic reaction in which unsaturated substituents participate at C-2 of cyclobutenedione provides a somewhat different cyclization mode. The thermal rearrangements of 2-dienylcyclobutenones 88 and 3-(o-vinylphenyl)- cyclobutenediones 92 underwent well-precedented 4π–6π electrocyclic reactions, but within the diene moiety to phenolic intermediates 90 and 94.These were allowed to react intramolecularly to give benzofurans 91 and naphthofu- 16 M. Ohno · S. Eguchi ranones 95, respectively [97, 98]. This work represents a new aspect of squaric acid chemistry (Scheme 17).

Scheme 17 Thermal rearrangements of 2-dienylcyclobutenones and 3-(o-vinylphenyl)- cyclobutenediones [97, 98]

When the substituents of o-vinylphenyl and isobutenyl groups were placed ◦ at C-2 and C-3, respectively, such as 96,thermolysis(70 C) preferred tandem 8π–6π electrocyclic reactions between these substituents to give a tetracyclic cyclobutenone 98. This underwent the precedented ring transformation/oxidation and, ultimately, photofragmentation with expulsion of isobutylene to give angular furoquinone 99, for example, by the use of 2- lithiofuran. In the case of an alkynyl group at C-3, thermolysis gave an alkenylidenefuran [99–101] (Scheme 18).

Scheme 18 Tandem 8π–6π electrocyclic reactions of 2-(vinylphenyl)-3-isobutenylcyclo- butenone [99–101]

The cascade rearrangements following double addition of alkenyl anions to the squarate ester was initiated by Paquette from the clue of Asensio’s ﬁnd- ing that twofold addition of organolithium (MeLi, PhLi, etc.) leads to the facile electrocyclic ring opening to 1,4-diketones [102]. This expedient method for construction of complex polycycles is achieved by a simple one-pot process Squaric Acid Based Technology 17 amenable to regioselective operation, stereochemical control, self-immolative chirality transfer, 1,5-asymmetric induction, and chemical modulation [72]. In this regard, synthesis of oxa- and aza-heterotricycles was exempliﬁed in the case where 2-lithiated dihydrofuran and dihydropyrrole were used as the alkenyl anions. The stereochemical course was completely dissected on the basis of cascades as shown in Scheme 19 (see also Fig. 5) [103, 104]. Total synthesis of hypnophilin (triquinane epoxide) has proved the method to be a valuable synthetic tool [105, 106].

Scheme 19 Dissected cascade rearrangements with 2-lithiodihydrofuran as an alkenyl anion [103, 104]

A different approach to triquinane was made by Moore [107–110]. His synthetic route includes the intramolecular [2 + 2] cycloaddition of the vinylketene intermediate as shown in Fig. 4. If the bicyclo[3.2.0]heptenone from this reaction is designed to have an alkenyl-substituent at the bridge- head (i.e., 101 → 102 → 103), the next oxy-Cope rearrangement is satis- ﬁed by adding another alkenyl group (i.e., 104)togivethetriquinane106 (Scheme 20). As a matter of fact, the above preparative reaction to obtain the framework of bicyclo[3.2.0]heptenone is already in hand. Indeed, the ring closure step after electrocyclic ring opening of 4-hydroxy-2-cyclobutenone is not limited to fully conjugated systems; synthetic variants are realizable with other prox- imally placed ketenophiles. When an allyl group was located at C-4, the ketene underwent an intramolecular [2 + 2] cycloaddition reaction with this double bond to give the bicyclo[3.2.0]heptenone derivatives [111, 112]. 18 M. Ohno · S. Eguchi

Scheme 20 Different route to triquinane via oxy-Cope rearrangement of bicyclo[3.2.0] heptenone [107–110]

While an allylic portion has hitherto been introduced under usual nucleophilic conditions, allylsilanes 108 are the reagent of choice as an alternative under electrophilic conditions. The electrophilic center was generated from cyclobutenedione monoacetal 107 with BF3 catalyst, being allowed to react smoothly to give regiospeciﬁcally allylated product 109.This was obtained as a protected form and utilized directly for the following thermal ring opening to give the expected [2 + 2] cycloadducts 111 in a high yield. A triquinane framework 112 wasalsoaccessiblebythisroute from one-carbon homologation of the adduct with diazoacetate, when cy- 1 2 clopentylmethyltrimethylsilane (108,R – R = CH2CH2CH2) was employed asastartingreagent.Atricyclicoxygen-heterocycle114 was constructed by the same sequential reactions using 6-hydroxy-2-hexenyltrimethylsiane 1 2 (108,R = H, R = CH2CH2CH2OH) [42] (Scheme 21). Interestingly, reactivity of cyclobutenones having both phenyl and allyl groups at C-4 (obtained by BF3-catalyzed reaction of 4-phenyl-4-hydroxycyclobutenone with allylsilane) was judged to be competitive between the thermal [2 + 2] cycloaddition and 6π-electrocyclic ring closure under equilibrated conditions (cyclobutenone vinylketene), although inward rotation is preferred for the allyl substituent on the basis of torquoselectivity arguments [43]. The 2-chloro-4-hydroxy-2-cyclobutenone with an acylmethyl substituent at C-4 (115) was available from the electrophilic reaction of ester chloride 18 with silyl enol ether and silyl ketene acetal (Scheme 3). This was also found to be thermolabile to give a rearranged product, γ-acylmethylenetetronate 118 [113]. In this case, the cyclization occurred by choosing the hydroxyl function as a proximal ketenophile from an equilibrated mixture. Although the [2 + 2] cycloaddition mode might be a possible route to a β-lactone according to the favored outward rotation of a hydroxyl group (115 → 116a), the equilibrium could be shifted by lactonization and dehydrochlorination to thermodynamically stable (Z)-tetronate (116b → 117 → 118) (Scheme 22). Photochemistry of the same compound resulted in the formation of chlorine- Squaric Acid Based Technology 19

Scheme 21 Allylation under electrophilic conditions and thermal rearrangement to bicyclo[3.2.0]heptenone [42]

Scheme 22 Thermal and photochemical conversion of 2-chloro-4-hydroxy-2-cyclobutenone [113] retained 2(5H)-furanone 119 from the sequence of favored inward rotation of a hydroxyl group, lactonization, and 1,3-hydrogen shift. This protocol was applied to the total synthesis of antibacterial and antitumor (E)-basidalin. The precursor 120 was made by TiCl4-catalyzed addition of dichloride 17 to silyl enol ether of 3,3-dimethyl-4-penten-2-one (used as a protected form of aldehyde function). Then, the more reactive chlorine atom at C-3 was replaced with an amino group, and key ring expansion was successfully performed by heating (reﬂux, xylene/pyridine) to give tetronamide 122.ThisisformedstereospeciﬁcallyinE-form due to intramolecular hydrogen-bonding, mimicking the biogenetic route of naturally occurring 5-ylidene-2(5H)-furanone (in contrast to thermodynamically con- 20 M. Ohno · S. Eguchi trolled Z-form as observed above). Final deprotection afforded (E)-basidalin (123) [113] (Scheme 23).

Scheme 23 Synthesis of (E)-basidalin mimic to the biogenetic route [113]

For the preparation of 4-amino-2(5H)-furanone as above, the disfavored outward rotation of hydroxyl group was compensated for by adding an acid such as triﬂuoroacetic acid to assist cyclization [114]. Notably, 4-aryl-4- hydroxy-2-cyclobutenone bearing o-carboranyl substituent at C-2 also gave rise to the corresponding 2(5H)-furanone (124 → 125) rather than the usual quinone, indicating that direction of rotation is affected even by substituent at C-2 [115]. Anyhow, the product has potential utility for boron neutron therapy. Analogously, in a cyclobutenone system other than squaric acid, intramolecular addition of hydroxyl group to in situ formed ketene was also reported to give a lactone ring (126 → 127) [116] (Scheme 24).

Scheme 24 Analogous thermal rearrangements of cyclobutenones to form lactone rings [115, 116]

Dithiane and oxirane substituents at C-4 are documented to be other ketenophiles, yet the thermolytic products were not composed of the expected medium rings but of contracted rings because of further reactions under the reaction conditions [117]. Squaric Acid Based Technology 21

3.3 Reactive Intermediate Induced Process

Small ring compounds, in general, have considerable strain within the molecule and the ring strain relief is capable of driving the ring opening reactions to lead to the formation of ring expansion products. These trends are described in the foregoing thermal electrocyclic process. However, such chemical behavior is not limited to the concerted manner. As is well known, the reactive intermediate generated at the position adjacent to a strained ring induces ring opening to other transient intermediates, which are fated to fall into the ring expansion products. This scheme is represented by four- to five- membered expansion in squaric acid chemistry, and candidates of reactive intermediates range from radical and cation to carbene and nitrene (Fig. 6). For heterocycle synthesis, first investigated was the oxygen radical- mediated reaction. The cycloalkoxy radical is a fascinating intermediate suitable for 4-hydroxy-2-cyclobutenone, since it can be readily generated from a parent alcohol, and the formed oxy radical is so reactive that C – C bonds adjacent to the radical center are efficiently cleaved to produce a carbonyl and an unsaturated acyl radical (β-scission). Recyclization via addition of the radical to the radicophilic carbonyl end constitutes an effective approach to ring transformation. The action of lead tetraacetate on the alcohol is a preferable method for the aimed reaction. Thus, simple treatment of 4-hydroxy-2-cyclobutenone 128 with this reagent at room temperature gave acetoxy-substituted 2-(5H)-furanone 134 as a ring expansion product; 5-alkylidene-2-(5H)-furanone 135 was accomplished when the 4-substituent has an α-hydrogen to eliminate [118]. The outcome is explained by the sequence of β-scission of the initial 4-oxo-2-cyclobutenoxy radical 130, 5-endo-trig-cyclization of the resulting acyl radical 131,andfinalreductive elimination of lead(II) acetate from 133 (Scheme 25). The fact that the same

Scheme 25 Ring expansion to 2-(5H)-furanone induced by oxy-radical intermediate [118] 22 M. Ohno · S. Eguchi reaction took place with HgO/I2 indicated the distinct participation of a free radical mechanism. The versatility of the present furanone synthetic method was demonstrated in the stereoselective synthesis of the Z-isomer of multicolanate (139) [118] (Scheme 26). The prerequisite compound 137 was prepared by successive treatment of appropriate organomagnesium and organolithium reagents, and it was transformed smoothly with lead tetraacetate to the target molecule (the incomplete acetate product 138 was subjected to elimination reaction with DBU).

Scheme 26 Synthesis of (Z)-multicolanate by simple treatment with Pb(OAc)4 [118]

In connection with this search, the chemical behavior of the carbon- centered radical was also examined [118]. The similar hydroxycyclobutenone 140 bearing Barton’s ester at C-4 was photolyzed (W-lamp) to again give a5-endo-cyclized product, 4-cyclopentene-1,3-dione 145, prior to enol-keto tautomerization (Scheme 27).

Scheme 27 Ring expansion to 4-cyclopentene-1,3-dione induced by carbon-centered radical [118] Squaric Acid Based Technology 23

Although this ring does not include a hetero atom, biological activity is known in some derivatives. Human chymase inhibitor methyllinderone (148) was obtained from 4-alkynyl-4-hydroxycyclobutenone 146 by Shionogi’s group [119], and antimicrobial gloiosiphone A (dimethyl derivative, 151)was elaborated by Paquette with new methodology involving BF3-catalyzed ring expansion of hydroxycyclobutenone 149 having an acetal-functionalized cy- clopentenyl group at C-4 [120, 121] (Scheme 28). New routes to iodo- and silylalkylidenecyclopentene-1,3-diones have also been developed by us [122, 123].

Scheme 28 Synthesis of methyllinderone [119] and dimethyl gloiosiphone A [120, 121]

It is worth noting here the remarkable reactivity of the unsaturated acyl radical 152a. The Baldwin rule predicts that 5-endo cyclization is not favored. However, actually, this mode (131 → 132)wasfoundtobeadvan- tageous, and no product was obtained from essentially favored 5-exo cyclization (131 → 132exo). According to several calculations, the net cyclization is best explained by non-radical ring closure from ketene-substituted α-carbonyl radical 152b to the cyclized radical 153 (i.e., nucleophilic attack of OH on C = C = Owithadipolarπ-radical-stabilized transition structure 154TS) [124]. Independently, the similar chemical behavior of the ketenyl radical was reported by Pattenden [125, 126] (Scheme 29). Additional reactions involving the electron-deficient oxygen center were carried out by employing a hypervalent iodine reagent, because the facile displacement on iodine with nucleophiles (e.g., NH2 and OH) and the super- leaving ability of newly formed iodine intermediates endows the electron- deficient center of these heteroatoms. Whereas this type of rearrangement has already been found for nitrogen, the case for oxygen was provided for the first time by the reaction of 4-hydroxy-2-cyclobutenone to 2-(5H)-furanone [127]. PhI(OAc)2 is the reagent of choice, and a better result was attained in reflux- ing methanol to give the 5-methoxy-2-(5H)-furanone 158;Scheme30illus- 24 M. Ohno · S. Eguchi

Scheme 29 Preferential 5-endo cyclization and estimated unusual cyclization mode (nucleophilic attack and π-radical stabilization) [124]

Scheme 30 Ring expansion to 2-(5H)-furanone induced by electron-deficient oxygen center [127] trates a plausible mechanism. First, nucleophilic displacement on a hypervalent iodine with the hydroxyl group of the substrate 128 generates another hypervalent iodine intermediate 155, which generates an electron-deficient oxygen center susceptible to eliminative ring opening to an acyl cation intermediate 156. Second, recyclization of this acyl cation with carbonyl oxygen is a facile process for giving a furanone cation 157, which is trapped with the solvent nucleophile to give the final product 158.WithR= furyl group in 128, the product was a mixture of the usual furanone 159a and furylidenefura- none 159b (2 : 1). It should be noted here that the carbocation version of this type of ring transformation has already been substantiated in the reaction Squaric Acid Based Technology 25 of 149 → 150 (Scheme 28, by Paquette). In the 4-(2-hydroxymethylphenyl)- substituted case, eight-membered lactone 161 wasobtainedviaadifferent mechanism involving glycol cleavage of hemiacetal 160. Carbene (carbenoid)-mediated ring transformation was exemplified in the reaction of diazo-functionalized hydroxycyclobutenone 162 [129]. While furanone 165 and cyclopentenedione 166 were found to be products from the reaction of 162 depending on the decomposition conditions (acid-catalysis: TfOH, BF3 etc., metal-catalysis: Rh2(OAc)4, photolysis, thermolysis), two facts are worthy of note. In the Rh2(OAc)4-catalyzed reaction, a metalla- cyclic intermediate 169 was suggested to cause selective formation of 166; a similar one was proposed in the reaction of cyclobutenedione with ferro- cenyl chromium carbene complex, from which potentially antitumor-active ferrocenylidenefuranone was obtained despite much lower yield [128]. In thethermalreaction,anewtypeofringtransformationwasobserved;relatively stable diazoacetate derivative (162:R= Ot-Bu) underwent 8π electrocyclic ring closure (1,7-dipolar cycloaddition) and prototropy to give the 1,2-diazepinedione 172 after usual 4π-electrocyclic ring opening to di- azovinylketene intermediate 170 (Scheme 31). Seven-membered carbon ring formation based on squaric acid technology was precedented with the use of a cyclopropyl substituent [130]. Along with the carbene case, nitrene-mediated ring transformation took advantage of azido-functionalization (Ohno et al. unpublished data). Intro-

Scheme 31 Ring expansion of diazo-functionalized cyclobutenones: 1,7-dipolar cycloaddition to diazepinedione [129] 26 M. Ohno · S. Eguchi duction of an azido group was accomplished by an electrophilic substitution reaction using the acetal 173 and trimethylsilyl azide catalyzed with BF3 · Et2O. Typically, the 2-phenyl substituted case was examined for thermal decomposition. Thus, heating azide 174 for 30 min in reﬂuxing xylene gave a maleimide derivative 180 after treatment of the primary product with water. This maleimide is likely to be formed from 2-aza-2,4-cyclopentadienone 177, to which there are two possible routes, either via extrusion of nitrogen followed by nitrene-induced ring expansion (175 → 176)orviaconsecutive 4π–8π electrocyclic rearrangements followed by extrusion of nitrogen (178 → 179). More importantly, the above experiment indicates that polysubstituted 2-aza-2,4-cyclopentadienone 177 can survive even at higher temperatures. In fact, without addition of water, it could be isolated as a yel- low crystal after concentration of the solution. Whereas the parent 2-aza- 2,4-cyclopentadienone is known to be anti-aromatic (life time: ca. 2 sat ◦ 30 C) [131, 132], the observed extreme stability of 177 is attributed to dou-

Scheme 32 Ring expansion of azido-functionalized cyclobutenones: formation of stable 2-aza-2,4-cyclopentadienone and its reaction with some nucleophiles (Ohno et al. unpublished data) Squaric Acid Based Technology 27 ble resonance between the carbonyl group and both ethoxy groups. Despite such thermodynamic stability, 177 is reactive enough to give nitrogen heterocycles with some nucleophiles: maleimide acetals 181 (with alcohol), cyclic amidines 182 (with amine), a bicyclic nitrogen-heterocycle 183 (for example, with ethylenediamine), and a tetramic acid analog 184 (for example, with lithium malonate) (Scheme 32).

4 Squaric Acid Bioisostere

In the previous section, the utility of squaric acid is described from the viewpoint of developing biologically active substances, especially focusing on synthetic strategies for ring transformation to various heterocycles. The structureofcyclobutenedioneitselfisalsointriguingandoccasionallyex- ploited for studies on biologically interesting molecular design. One reason is the peculiar acidic functionality of squaric acid. Therefore, “bioisostere” with this ring investigates how the acid derivatives show their activity relative to naturally occurring products or pharmacologically interesting products. These compounds are mainly attained by functional interconversion of acid ester to acid amide (i.e., squarate to squaramide). This section deals with chemistry of biologically active cyclobutenediones bearing heterocycles at the C-2 and/or C-3 position. Amino squaric acids 186 and 188, the relatives of natural amino acids, represent an intuitive example of bioisostere, although the heterocycle is absent in these molecules. These were obtained by radical reaction of 2-stannylcyclobutenedione [133] and carbanion addition to squarate ester [134, 135] (Scheme 33).

Scheme 33 Squaric acid bioisostere: synthesis of amino squaric acid [133–135] 28 M. Ohno · S. Eguchi

A new type of modified oligonucleotides containing a squaryl group was also developed as a novel mimic of the phosphate group [136, 137]. A modified thymidine dimer derivative T3 sq5 T(189) having a squaramide linkage was synthesized by two-step substitution with 5 (R = Et) and incorporated into oligodeoxynucleotides. The DNA duplex [5 -d(CGCATsqTAGCC)- 3/5-d(GGCTAATGCG)-3]wasfoundtobedistortedatthemodified dimer site but preserved the base pairing ability. Continued work with U2 sq5 T(190) indicated unique base-pairing ability for oligonucleotides with G at the site opposite to the T of U2 sq5 T(Fig.7).Theseresultssug- gest that there is the possibility to create a new class of antisense/antigene molecules and nucleotide analogs based on squaric acid–nucleoside (base) conjugates.

Fig. 7 Structural similarity of squaric acid ester and amide and the structures of oligonu- cleotide analogs containing a squaramide linkage [136, 137]

Prior to these ﬁndings, the key coupling reaction using squarate esters [5 (R = Et) → 191 → 192] had been put into practical use by the pioneering work of Tietze. This featured use of a slight excess of amines, excellent yield, stepwise introduction of two amine components, and easy analysis by UV spectroscopy [138]. This methodology has been applied to the synthesis of (neo)glycoconjugates, in which the cyclobutene-1,2-dione skeleton is used as a linker between saccharide and protein. In a recent work hydropho- bic didecyl squarate 5 (R = C10H21) was reported to be a reagent to handle with ease for puriﬁcation, as shown in conjugation to BSA (193 → 194), for example [139] (Fig. 8). Among recent developments in glycoconjugates applied for drug im- munotherapy and so on [140], a variety of oligosaccharide–squaramide– protein (e.g., bovine, human, and chicken serum albumins) conjugates have been prepared with the Tietze’s squarate ester methodology and tested for their bioactivity [141–157]. The glycoconjugates with special functions were also documented: for example, 1,4,7,10,13-pentaazacyclopentadecane Squaric Acid Based Technology 29

Fig. 8 Tietze’s method for conjugation between two amines with squarate ester and an example for squaric decyl ester glycoside conjugation to BSA (bovine serum albu- min) [138, 139] core 195 with five squaramide-linking glycoconjugates as a high affinity pentavalent receptor-binding inhibitor for cholera toxin due to the 1 : 1 association [158, 159]; GdIII complex of inulin-1,4,7,10-tetraazacyclododecan- 1,4,7-triacetic acid conjugate 196 linked with squaramide as a contrast agent in magnetic resonance imaging [160]; anthracycline glycoside 197 with a squaramide linker as a modified antibiotic [161] (Fig. 9); cholesterol glycoside with a squaramide linker as an additive to cationic liposome for- mulation [162]; and photophore (Nakanishi diazirine)–ligand (moenomycin derivative)–biotin with a squaramide linker as a photoaffinity label [163, 164]. It is interesting that such squaramide linking was also used for networking of chitosan to form a hydrogel [165]. Along this line, pharmacologically interesting cyclobutenedione derivatives are also synthesized and screened in relation to the lead compounds. Diazabicyclic amino acid phosphonate 199 was identified as N-methyl- d-aspartate antagonist for the treatment of neurological disorders such as stroke and head trauma; this was found out from bioactive model 4-(3-phosphonopropyl)-2-piperazinecarboxylic acid (198) [166]. Bioisosteric replacement of the N-cyanoguanidine moiety of pinacidil (200) with di- aminocyclobutenedione template afforded the prototype 201 of a novel series of adenosine 5 -triphosphate-sensitive potassium channel openers with unique selectivity for bladder smooth muscle in vivo [167, 168]. In a series of very late antigen-4 integrin antagonists, incorporation of the cyclobutenedione ring as an amino acid isostere (i.e., 203) was designed in relation to existing active thioproline CT5219 (202) [169, 170]. Pibutidine hydrochloride (or IT-066) (205), developed from the lead lafudidine (204)waslaunched as a potent H2-receptor antagonist for the treatment of peptic ulcers [171– 173]. Indole-based derivative BMS-181885 (206) was recorded as a potential antimigraine agent, elicited by binding to 5-HT receptor [174] (Fig. 10). 30 M. Ohno · S. Eguchi

Fig. 9 Some squaramide-linked glycoconjugates with special functions [158–161]

In the squaraine chemistry, biologically interesting heterocyclic squarylium dyes are also being explored (Fig. 11). Potential usefulness in photo- dynamic therapy was envisioned by effective singlet oxygen generation of benzothia(selena)zole-derived squarylium dye 207 and halogenated squarylium dye [175, 176]. Some chemosensors for some metal ions were based on the red-ﬂuorophore of azacrown-appended squarylium dyes 208. Related podand-based (H-aggregation) squarylium dyes 209 were demonstrated to detect alkaline and earth-alkaline metal ions (Na+,K+,Mg2+,Ca2+) selectively [177, 178]. Carbohydrates and proteins were monitored by labeling with properly functionalized symmetric and asymmetric dyes (e.g., 210) [179– 182]. Squaric Acid Based Technology 31

Fig. 10 Some heterocyclic derivatives of squaramide designed in relation to the lead compounds [166–174]

Fig. 11 Biologically interesting squaraines conjugated with heterocycles [175–182] 32 M. Ohno · S. Eguchi 5 Concluding Remarks

Squaric acid is in principle a pseudoaromatic and therefore stable four- membered compound designated as 3,4-dihydroxy-3-cyclobutene-1,2-dione. Characteristic square planarity brings it high acidity, a peculiar network, and a donor–acceptor triad. Nevertheless, its intrinsically strained and highly oxygenated character makes it extraordinarily useful in synthesis. Once the cyclobutenedione skeleton is converted into the hydroxycyclobutenone skeleton, it can undergo further ring transformation either by thermal concerted rearrangements (chieﬂy depending on electrocyclic ring opening and ring closure) or by reactions induced by a reactive intermediate (including cation, radical, and divalent species). The directed synthesis of various heterocycles is accomplished by virtue of incorporation of heteroatom(s) on one or more of four possible sites of the four-membered ring and execution of the above ring transformation. Fortunately, the methods developed for introduction of substituents range from nucleophilic to electrophilic conditions and from ionic to radical and organometallic coupling reactions. It is evi- dent from the cumulative successes shown in this review article that squaric acid plays the role of a useful synthetic C-4 building block for construction of biologically interesting oxygen, nitrogen, and sulfur heterocycles, if combined appropriately with corresponding heteroatoms. Bioactive heterocycles can also be provided by derivatization of the cyclobutenedione ring as retained. This utilization comes from the bioisostere concept and from its versatility as a linker of bioconjugates. In these cases, a squaramide form is oftenemployedintheacidinterconversion. Conclusively, the small molecule of squaric acid is able to produce a big effect on the synthesis of biologically interesting heterocycles.

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pubs.acs.org/JACS

Furans as Versatile Synthons: Total Syntheses of Caribenol A and Caribenol B Hong-Dong Hao and Dirk Trauner* Department of Chemistry and Center for Integrated Protein Science, Ludwig-Maximilians-UniversitatMü ̈nchen, Butenandtstrasse 5-13, 81377 München, Germany

*S Supporting Information

ABSTRACT: Two complex norditerpenoids, caribenols A and B, were accessed from a common building block. Our synthesis of caribenol A features the diastereoselective formation of the seven-membered ring through a Friedel−Crafts triflation and a late-stage oxidation of a furan ring. The first synthesis of caribenol B was achieved using an intramolecular organocatalytic α-arylation. An unusual intramolecular aldol addition was developed for the assembly of its cyclopentenone moiety, and the challenging trans-diol moiety was installed through a selective nucleophilic addition to a hydroxy 1,2-diketone. Our overall synthetic strategy, which also resulted in a second-generation synthesis of amphilectolide, confirms the usefulness of furans as powerful nucleophiles and versatile synthons.

■ INTRODUCTION Furans teeter on the edge of aromaticity and can behave both as arenes and as very electron-rich dienes. As such, they can undergo a wide variety of chemical transformations, including electrophilic substitutions, metalations, cycloadditions, and oxidations (Scheme 1). If extended to furyl carbinols, their synthetic

Scheme 1. Furans and Furyl Carbinols as Powerful Synthons

Figure 1. Natural products isolated from Pseudopterogorgia elisabethae.

that have shown biological activity against Mycobacterium tuberculosis H37Rv and antiplasmodial activity. The caribenols A and B became attractive targets for the synthetic community due to their intriguing biological activities as well as their unique skeletons.2i Caribenol A was shown to possess a caged structure and tricarbocyclic ring system with − six stereocenters. Its first synthesis by Yang and co-workers3a c − power is increased even more, allowing for Piancatelli rearrange- was based on an intramolecular Diels Alder reaction and a ments and Achmatowicz reactions with subsequent cyclo- late-stage oxidation to install the hydroxy butenolide moiety. additions to access carbocyclic systems. Often associated with More recently, Luo and co-workers reported an approach to 3d − asignificant increase in molecular complexity, these trans- caribenol A that hinges on a Cope rearrangement and a C H formations have been extensively exploited in the total synthesis insertion reaction. 1 Some years ago, our group launched a program aimed at of complex target molecules. fi Many of the functional groups and ring systems accessible a uni ed synthesis of the Pseudopterogorgia terpenoids. To this from furans can be found in natural products isolated from end, we developed a scalable synthesis of furan building block 7 the Caribbean sea plume Pseudopterogorgia. These include diterpenes and norditerpenes with novel carbon skeletons,2 Received: January 8, 2017 such as aberrarone, caribenol A, and caribenol B (Figure 1) Published: February 20, 2017

Scheme 2. Previous Work toward Natural Products Total Scheme 4. Revised Retrosynthetic Analysis of Caribenol A Syntheses Using Furan Building Block 7

reductive transposition method.11 A subsequent cross-metathesis from (−)-β-citronellol, which could be converted into two and transformation of the resulting methyl ester to an Evans 4 natural products: sandresolide B and amphilectolide oxazolidine afforded 18. Diastereoselective conjugate addition (Scheme 2). We now provide an account of our syntheses of promoted by TMSCl and HMPA12 then gave alkene 19, which caribenols A and B as well as a second-generation synthesis was converted into 20 through alcoholysis13 and Weinreb of amphilectolide. They are also based on furan 7 and required amide14 formation. The requisite cyclopentenone 13 was then the development and application of a new methodology that constructed through Grignard addition and a clean ring-closing 5 exploits the special reactivity of furans. metathesis,15 which preserved the stereochemical integrity at C(3). The relative configuration of 13 was verified by X-ray ■ RESULTS AND DISCUSSION diffraction (see Supporting Information). Our initial synthetic strategies toward caribenol A focused on With enone 13 at hand, we proceeded to investigate the Pauson−Khand reactions6 and gold-catalyzed cycloisomeriza- closure of the seven-membered ring. A variety of Lewis and tions7 to forge the 5−7−6 ring system of the target molecule Brønsted acids failed to afford the desired tetracycle 12 in (Scheme 3). Although allene 8 underwent a clean allenic appreciable amounts (see Supporting Information for details). However, exposure of enone 13 to our Friedel−Crafts triflation Scheme 3. Failed Attempts toward Caribenol A conditions led to clean formation of the vinyl triflate 21 as a single diastereomer.9 The hydrolysis of 21 to the corresponding cyclopentanone 12 was not trivial, but after screening several conditions we found that TMSOK in THF16 smoothly achieved this transformation. The structure of 12 was verified by X-ray diffraction (see Supporting Information). With the core structure of caribenol A in hand, the stage was now set to add the missing methyl group and introduce the double bond in the correct position. Using standard conditions (KHMDS, Comins’ reagent), we again arrived at the undesired isomer 21. Presumably, this was due to a directing effect of the furan oxygen. Consequently, oxidation of the furan ring was first effected using peracetic acid17 to provide butenolide 22, an intermediate Pauson−Khand reaction, the procedure suffered from low in Yang’s synthesis of caribenol A.18 Using Barton’s protocol for yields and was difficult to scale up due to the instability of 8. vinyl iodide formation followed by Stille coupling, synthetic Enyne 10, on the other hand, provided the unwanted 6−7−6 caribenol A was obtained and found to be identical in all respects isomer 11, which bears a quaternary carbon with the correct with the natural product (see Supporting Information). absolute configuration. Extensive efforts to reverse the regio- We next turned our attention to caribenol B, which features a selectivity of this Au-mediated process proved unsuccessful fully substituted cyclopentenone ring containing a trans-1,2-diol (for the details on the synthesis of 8 and 10, see the Supporting moiety. This is a rare structural motif in natural products19 Information). due to its instability under either acidic or basic conditions. We On the basis of these results and considering the high initially attempted to access this challenging dihydroxycyclo- nucleophilicity8 of the furan ring, we next explored our pentenone from a furan through the Piancatelli rearrangement Friedel−Crafts triflation9 for construction of the carbotricyclic or an Achmatowicz reaction20 with subsequent ring contraction framework. Our corresponding retrosynthetic analysis is shown (Scheme 6). Retrosynthetic analysis of acetal 23 identified in Scheme 4. It calls for the elaboration of cyclopentenone 13 furfural 24 as a key intermediate. It could be traced back to from furan building block 7. Following closure of the seven- aldehyde 25 and, via α-arylation, to aldehyde 26, which could membered ring, 12 would be converted into caribenol A via be easily accessed from our previously used ester 14. cross coupling and oxidation of the furan ring (Scheme 4). Our synthesis commenced with hydrogenation and DIBAL-H Toward cyclopentenone 13, furan 7 was first converted to reduction of 14. The resulting aldehyde 26 was subjected to the allylic alcohol 15 by Swern oxidation, Wittig olefination, and radical cation cyclization21 catalyzed by 28, which, after in situ DIBAL-H reduction in excellent yield (Scheme 5). The terminal reduction, afforded the stable primary alcohol 29, Scheme 7. alkene 1610 was then made from 15 using Myers’ allylic The cyclization proved to be highly diastereoselective (dr 20:1)

4118 DOI: 10.1021/jacs.7b00234 J. Am. Chem. Soc. 2017, 139, 4117−4122 Journal of the American Chemical Society Article

a Scheme 5. Total Synthesis of Caribenol A

a − ° − ° Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2, 78 C, then NEt3, 78 C. (b) Methyl (triphenylphosphoranylidene)acetate, toluene, ° − ° − 85 C (86% over two steps). (c) DIBAL-H, CH2Cl2, 78 to 0 C (92%). (d) Ph3P, DEAD, IPNBSH, THF, then HFIP, H2O. (e) Hoveyda Grubbs ° catalyst second generation (7 mol %), methyl acrylate (20 equiv), CH2Cl2, rt (63% over two steps). (f) TMSOK, THF, 50 C (94%). (g) Piv-Cl, − ° − ° NEt3, 78 to 0 C (85%). (h) Isopropenylmagnesium bromide (4.5 equiv), CuCN (2.25 equiv), Et2O, then HMPA, 78 C, then 18, TMSCl, THF, − ° ° · ° 78 C (86%). (i) Sm(OTf)3, MeOH, 50 C (88%). (j) HNMe(OMe) HCl (10 equiv), Me2AlCl (10 equiv), 0 C to rt (86%). (k) Vinylmagnesium bromide (5 equiv), THF, 0 °C (94%). (l) Hoveyda−Grubbs catalyst second generation (10 mol %), toluene, reﬂux (77%). (m) 2,6-Di-tert- ° butylpyridine (2 equiv), Tf2O (3 equiv), CH3CN. (n) TMSOK, THF, 50 C (53% over two steps). (o) CH3CO3H (2.2 equiv), NaOAc (2.3 equiv), ° CH2Cl2 (72%). (p) N2H4 (2 equiv), Et3N (3 equiv), EtOH, 50 C, then I2 (2 equiv), TMG (3 equiv) (56%). (q) Me4Sn (2 equiv), AsPh3 (20 mol %), ° ′ ﬂ Pd(PPh3)4 (5 mol %), NMP, 60 C(33%).IPNBSH=N-isopropylidene-N -2-nitrobenzenesulfonyl hydrazine, HFIP = hexa uoroisopropanol, TMG = tetramethylguanidine, NMP = N-methyl-2-pyrrolidone.

Scheme 6. Retrosynthetic Analysis of Caribenol B Scheme 7. Organocatalytic α-Arylation and Second- a Generation Synthesis of Amphilectolide

when the matched enantiomer22 of the catalyst was used. The configuration of the newly formed stereocenter23 at C(3) was fi con rmed by transformation of 29 into amphilectolide. The a Reagents and conditions: (a) Rh(PPh3)3Cl (10 mol %), H2 balloon, spectra of the natural product were identical in all respects to ° − ° those previously reported.2d,3d,4 THF, 50 C (98%). (b) DIBAL-H, CH2Cl2, 78 C. (c) (2R,5R)- (+)-2-tert-Butyl-3-methyl-5-benzyl-4-imidazolidinone trifluoroacetic With these results in mind, we proceeded to pursue caribenol acid salt (40 mol %), CAN (2.2 equiv), H2O (2 equiv), DME, B. Furan 29 was subjected to Vilsmeier−Haack conditions, − ° 20 C, 18 h, then MeOH, NaBH4 (15 equiv) (66% over three steps). in the course of which the primary alcohol was also formylated, (d) CH3CO3H, NaOAc, CH2Cl2 (95%). (e) NaBH4, EtOH (82%). to provide furfural 31, Scheme 8. Exposure to DIBAL-H, (f) TPAP (5 mol %), NMO, CH2Cl2 (60%). (g) n-BuLi, iso- subsequent DMDO oxidation, and protection then yielded propyltriphenylphosphonium iodide, THF (45%).

4119 DOI: 10.1021/jacs.7b00234 J. Am. Chem. Soc. 2017, 139, 4117−4122 Journal of the American Chemical Society Article

Scheme 8. Attempted Achmatowicz Reaction and Ring chain at this stage by this method proved critical. Furan 37 a Contraction was then formylated, and the resulting aldehyde was homologated by Van Leusen reaction27 to nitrile 38. Oxidation with DMDO28 presumably gave a cyanoketone 39, which underwent the desired aldol cyclization to yield the tertiary alcohol 40. The diastereoselectivity of this addition is presumably governed by the adjacent isobutenyl group. The structure of 40 was confirmed by single-crystal X-ray diffraction (see Supporting Information).29 Hydroxylation of 40 using DMDO afforded the cyanohydrin 41, which was then treated with AgNO3 and 2,6-lutidine30,31 to provide diketone 42 as the penultimate intermediate. To our delight, 42 underwent a diastereoselective Grignard addition,32 which afforded caribenol B as a single diastereomer. In summary, we achieved an asymmetric synthesis of caribenol A and the first total synthesis of caribenol B. Both of our syntheses are highly stereoselective and protecting group free.33 The nucleophilicity of furans was critical to the success of our program, as they were used in a Friedel−Crafts triflation and an intramolecular organocatalytic α-arylation. A novel strategy for aReagents and conditions: (a) POCl , DMF (70%). (b) DIBAL-H, the conversion of furfurals into cyclopentenones and a mild 3 method for the hydrolysis vinyl triflates were also developed. CH2Cl2 (90%). (c) DMDO, CH2Cl2 (88%). (d) PPTS, MeOH (100%). (e) TBSCl, imidazole, CH2Cl2 (93%). The scope of the gold-catalyzed cycloisomerization shown in Scheme 3 is under active investigation in our laboratories, and results will be reported in due course. dihydropyran 34 in excellent yield. Unfortunately, 34 could not be converted into cyclopentenone 35 via retro-6π- ■ ASSOCIATED CONTENT 24 electrocylization and aldol closure despite literature precedence * and extensive efforts from our side (see Supporting Information S Supporting Information for details). Consequently, we modified our synthetic strategy The Supporting Information is available free of charge on the to provide a better nucleophile for the aldol-type ring closure25 ACS Publications website at DOI: 10.1021/jacs.7b00234. (for a detailed evolution of our synthetic strategy for caribenol B, (CIF) see the Supporting Information). Our ultimately successful synthetic route toward caribenol B (CIF) is shown in Scheme 9. It commenced with oxidative cyclization Experimental procedures and data (PDF) 26 25 of aldehyde . The resulting unstable aldehyde was (CIF) immediately subjected to Julia−Kocienski olefination to install the isobutenyl side chain in one pot.26 Installation of this side (CIF)

a Scheme 9. Total Synthesis of Caribenol B

a − ° Reagents and conditions: (a) DIBAL (1.2 equiv), CH2Cl2, 78 C. (b) (2R,5R)-(+)-2-tert-Butyl-3-methyl-5-benzyl-4-imidazolidinone ﬂ − ° − ° tri uoroacetic acid salt (40 mol %), CAN (2.2 equiv), H2O (2 equiv), DME, 20 C, 18 h. (c) LiHMDS (12 equiv), 36 (12 equiv), 78 C, ° 1 h, then 0 C (1 h), rt (30 min) (26% over three steps). (d) POCl3 (1.5 equiv), DMF (79%). (e) Tos-MIC (3 equiv), t-BuOK (4.5 equiv), THF, − ° ° 50 C, then MeOH, 65 C (57%). (f) DMDO (1 equiv), K2CO3 (2 equiv), Na2SO4,CH2Cl2 (77%). (g) DMDO (2 equiv), K2CO3 (2 equiv), Na2SO4,O2 balloon, CH2Cl2 (54%). (h) AgNO3 (10 equiv), 2,6-lutidine (10 equiv), CH3CN. (i) MeMgBr (3 equiv), Et2O (45% over two steps).

4120 DOI: 10.1021/jacs.7b00234 J. Am. Chem. Soc. 2017, 139, 4117−4122 Journal of the American Chemical Society Article ■ AUTHOR INFORMATION (c) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2004, 2004, 3377. For recent synthetic applications, see: (d) Kawamura, S.; Chu, H.; Corresponding Author * Felding, J.; Baran, P. S. Nature 2016, 532, 90. (e) McKerrall, S. J.; E-mail: [email protected] Jørgensen, L.; Kuttruff, C. A.; Ungeheuer, F.; Baran, P. S. J. Am. Chem. ORCID Soc. 2014, 136, 5799. (f) Jørgensen, L.; McKerrall, S. J.; Kuttruff, C. A.; Dirk Trauner: 0000-0002-6782-6056 Ungeheuer, F.; Felding, J.; Baran, P. S. Science 2013, 341, 878. (g) Williams, D. R.; Shah, A. A. J. Am. Chem. Soc. 2014, 136, 8829. Notes (h) Lv, C.; Yan, X. H.; Tu, Q.; Di, Y. T.; Yuan, C. M.; Fang, X.; Ben- fi The authors declare no competing nancial interest. David, Y.; Xia, L.; Gong, J. X.; Shen, Y. M.; Yang, Z.; Hao, X. J. Angew. Chem., Int. Ed. 2016, 55, 7539. (i) Wen, B.; Hexum, J. K.; Widen, J. C.; ■ ACKNOWLEDGMENTS Harki, D. A.; Brummond, K. M. Org. Lett. 2013, 15, 2644. (j) Grillet, We thank the Deutsche Forschungsgemeinschaft (SFB 749) for F.; Huang, C. F.; Brummond, K. M. Org. Lett. 2011, 13, 6304. financial support. Dr. Peter Mayer is acknowledged for X-ray (k) Brummond, K. M.; Gao, D. Org. Lett. 2003, 5, 3491. (7) For recent reviews about gold catalysis in total synthesis, see: analyses. We thank Felix Hartrampf, Giulio Volpin, Dr. Julius R. (a) Pflasterer,̈ D.; Hashmi, A. S. Chem. Soc. Rev. 2016, 45, 1331. Reyes, and Dr. Bryan Matsuura (all LMU Munich) for helpful (b) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028. discussions during the preparation of this manuscript and Irina (c) Zhang, Y.; Luo, T. P.; Yang, Z. Nat. Prod. Rep. 2014, 31, 489. Albrecht for early contribution to the project. (d) Fürstner, A. Acc. Chem. Res. 2014, 47, 925. For cycloisomerization of 1,5-enyes by gold catalysis, see: (e) Luzung, M. R.; Markham, J. P.; ■ REFERENCES Toste, F. D. 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4121 DOI: 10.1021/jacs.7b00234 J. Am. Chem. Soc. 2017, 139, 4117−4122 Journal of the American Chemical Society Article

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4122 DOI: 10.1021/jacs.7b00234 J. Am. Chem. Soc. 2017, 139, 4117−4122 Tetrahedron 67 (2011) 7195e7210

Contents lists available at ScienceDirect

Tetrahedron

journal homepage: www.elsevier.com/locate/tet

Tetrahedron report number 945 Indole synthesis: a review and proposed classiﬁcation

Douglass F. Taber a,*, Pavan K. Tirunahari b a Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA b Accel Synthesis, Inc., Garnet Valley, PA 19060, USA article info

Article history: Received 1 June 2011 Available online 21 June 2011

Contents

1. Introduction ...... 7195 2. Type1 ...... 7196 3. Type2 ...... 7198 4. Type3 ...... 7199 5. Type4 ...... 7200 6. Type5 ...... 7201 7. Type6 ...... 7204 8. Type7 ...... 7205 9. Type8 ...... 7206 10. Type9 ...... 7207 11. Conclusions ...... 7208 Acknowledgements ...... 7208 References and notes ...... 7208 Biographical sketch ...... 7210

1. Introduction has been to be illustrative, not exhaustively inclusive. It is apparent, however, that every indole synthesis must fit one or the other of the The indole alkaloids, ranging from lysergic acid to vincristine, nine strategic approaches adumbrated here. The web of scientific have long inspired organic synthesis chemists. Interest in de- citations unites and organizes the world-wide research effort. It is veloping new methods for indole synthesis has burgeoned over the our intention that the system put forward here for classifying in- past few years. These new methods have been fragmented across dole syntheses will be universally understood. As authors conceive the literature of organic chemistry. In this review, we present of new approaches to the indole nucleus, they will be able to a framework for the classification of all indole syntheses. classify their approach, and so readily discover both the history and As we approach the classification of routes for the preparation of the current state of the art with that strategy for indole construc- indoles, we are mindful that the subject has occupied the minds of tion. In addition to avoiding duplication, it is also our hope that organic chemists for more than a century. There have been many efforts will then be directed toward the very real challenges that reviews of indole synthesis.1 We were also aware that much more remain to be overcome. It is noteworthy that, in the most recent could be said than we have written. We have only briefly covered year we have covered, 2009, significant new contributions were the conversion of indolines into indoles, and the reduction of reported for each of these nine strategies. We have highlighted oxindoles to indoles. We have not covered the extensive literature these at the end of each section. on the modification of existing indoles. Throughout, our interest There are four bonds in the five-membered indole ring. In classifying methods for synthesis (Fig. 1), we have focused on the last bond formed. We have also differentiated, in distinguishing Type 1 versus Type 2 and Type 3 versus Type 4, between forming * Corresponding author. E-mail address: [email protected] (D.F. Taber).

H Type 1 synthesis (Scheme 1e17) involves aromatic CeH functionalization. Although CeH activation is thought of as a modern X N topic, the venerable Fischer indole synthesis (still under active H e Type 1 development, Schemes 1 3) falls under this heading. Paul N Fischer R. Brodfuehrer and Shaopeng Wang of Bristol-Myers Squibb de- Type 2 H Type 9 scribed2 the convenient (Scheme 1) reaction of an aryl hydrazine 1 Mori Kanematsu with dihydropyran 2 to give the 3-hydroxypropylindole 3. Stephen L. Buchwald of MIT developed3 an elegant (Scheme 2) amination of N N aryl iodides to give Boc-protected aryl hydrazines, such as 4. Acid- H H mediated condensation of 4 with the ketone 5 delivered the indole Type 3 Type 8 Hemetsberger N van Leusen 6. The condensation of 4 and 5 proceeded with high regiose- Indole H lectivity. Norio Takamura of Musashino University, Tokyo pre- sented4 a complementary approach (Scheme 3), the addition of an a N aryllithium 8 to an -diazo ester 7, followed by acid-mediated cy- X O clization. The ester of 9 is easily manipulated, and can also be re- Type 4 Type 7 moved altogether. Several other useful variations on the Fischer Buchwald Nenitzescu 5e7 NH2 N indole synthesis have been reported. Type 5 Type 6 SO2NHMe SO NHMe Sundberg Madelung 2 OH + ZnCl2 N H O N Fig. 1. The nine types of indole synthesis. H 12NH2 3 a bond to a functionalized aromatic carbon, and forming a bond to Scheme 1. an aromatic carbon occupied only by an H. Type 5 has as the last step CeN bond formation, while with Type 6 the last step is CeC bond formation. In Type 7, the benzene ring has been derived from Br O Br an existing cyclohexane, and in Type 8, the benzene ring has been MeO MeO built onto an existing pyrrole. Finally, in Type 9, both rings have + p-TsOH been constructed. Br N Boc Br N There are several name reactions associated with indole syn- H 4 NH2 5 6 thesis. We have tried to note these in context, and to group examples of a particular name reaction together. For convenience, the Scheme 2. ‘name reaction’ indole syntheses mentioned in this review are:

Bartoli indole synthesisdType 1 Ph CO Et Li MeO Bischler indole synthesisdType 5 Ph 2 d + CO2Et Fischer indole synthesis Type 1 N2 N d MeO H Hemetsberger indole synthesis Type 3 7 89 Julia indole synthesisdType 5 Larock indole synthesisdType 5 Scheme 3. LeimgrubereBatcho indole synthesisdType 5 Indoles can also be formed by acid-mediated cyclization of al- Madelung indole synthesisdType 6 dehydes. Richard J. Sundberg of the University of Virginia described8 Nenitzescu indole synthesisdType 7 the preparation from 10 (Scheme 4) and cyclization of acetals, such Reissert indole synthesisdType 5 as 11 to give the indole 12. The Bischler indole synthesis9a,b is a var- Sundberg indole synthesisdType 5 iation on this approach. Chan Sik Cho and Sang Chul Shim of Kyungpook National University, Taegu devised9c a route to indoles While it might be sufﬁcient to merely label the nine strategies (Scheme 5) based on Ru-mediated addition of an aniline 13 to an 1e9, for ease of recollection we have also associated each strategy epoxide 14. An interesting oxidationereduction cascade led to the 2- with the name of an early or well-known practitioner. The division alkyl indole 15, probably via a Bischler-like tautomerization. of strategies is strictly operational. Thus, the Fischer indole synthesis is classiﬁed as Type 1, AreH to C2, since that is the way it is carried out, even though the last bond formed, as the reaction EtO OEt proceeds, is in fact N to C1. H TiCl4 N N N 10 Ms 11 Ms 12 Ms 2. Type 1 Scheme 4.

O H Cl Ru cat. Cl + Ph N N NH2 N H H H 13 14 15

Fischer strategy Scheme 5. D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7197

Other transition-metal-mediated protocols for indole synthesis O CO2Et have been developed. In a variant on the Bartoli indole synthesis, O 2-ClPy + Kenneth M. Nicholas of the University of Oklahoma reported10 the OEt 2,6-Cl2Py N N H N2 Tf O Ru-catalyzed reductive coupling of a nitrosoaromatic, such as 16 Br 2 H Br (Scheme 6) with an alkyne 17 to give the indole 18. Akio Saito and 30 31 32 Yuji Hanzawa of Showa Pharmaceutical University described11 the Scheme 11. Rh-catalyzed cyclization of 19 (Scheme 7)to20. The reaction was thought to proceed via the allene 21. Indoles, such as 35 (Scheme 12) can also be prepared from Ph Ph oxindoles, such as 34, prepared from 33. Wendell Wierenga, then at Ru cat. 16 + Upjohn, optimized both the Gassman synthesis of oxindoles from CO anilines, and the subsequent reduction. This is a net Type 1 NO N H H synthesis. 16 17 18 Cl Cl Cl Scheme 6. SMe O2N O2N O2N BH3 O N NH2 N H H MeO Cl Cl Cl MeO 33 34 35 Rh cat. N N Scheme 12. Ar 19 20 N Samir Z. Zard of Ecole Polytechnique described17 the cyclization 21 (Scheme 13) of allyl anilines, such as 36 to the indoline 38 using 37. As indolines can be converted into indoles by oxidation18 or by Scheme 7. base-mediated elimination of an N-sulfonyl group19 this is also a net Type 1 indole synthesis. Several other Type 1 indole syntheses have been described. In the examples cited so far, only one regioisomeric aryl H could be substituted. In an ortho-metalation approach, Francis Johnson of 12 O OEt SUNY Stony Brook showed that (Scheme 8) the anion from cy- S O clization of 22 could be alkyated with an electrophile, such as 23 to N N O O give the indole 24. Darrell Watson and D.R. Dillin at the University MeO 37 of Mary Hardin-Baylor reported13 a photochemical route (Scheme O MeO 9) to indoles. Irradiation of 25 in an oxygen atmosphere led to 26. N cat. lauroyl peroxide When the photolysis was carried out under nitrogen, the product Ms N € € 14 was 27. Frank Glorius of the Universitat Munster devised a related 36 38 Ms catalytic oxidation of enamines, such as 28 (Scheme 10) to the indole 29. Just recently, Yan-Guang Wang of Zhejian University, Scheme 13. 15 Hangzhou described the coupling (Scheme 11) of a wide range of In 2009, four interesting new examples of Type 1 indole syn- anilides, such as 30 with ethyl diazoacetate 31 to give the indole 32. thesis were described. It had been thought that the cyclization of an acetal (Scheme 4) to the indole would only work with electron-rich aromatic rings. Dali Yin of the Institute of Materia Medica, Beijing20 MeO n observed that 39 (Scheme 14), readily prepared by sequential dis- H -BuLi x 4; MeO placement on the corresponding diﬂuorodintrobenzene, smoothly O OCl cyclized to 40. N 23 N CH2CF3 22 24 H H N N

Scheme 8. O2N O2N OEt TFA N N OEt NO O 39 2 NO2 40

O Scheme 14. hν N Following up on the work of Glorius (Scheme 10), Ning Jiao of O2 N N 21 25 26 27 Peking University found that, under oxidizing conditions, an aniline derivative, such as 41 (Scheme 15) could be condensed with Scheme 9. the diester 42 to give the indole 43. Note that the cyclization proceeded with high regioselectivity. The product was easily hydro- lyzed and decarboxylated to give the 2,3-unsubstituted indole.

CO Me MeO C CO Me CO Me Cu(OAc) 2 2 2 2 2 42 cat. Pd(OAc) CO2Me MeO N 2 NH Pd cat. MeO N 2 N O H 28 H CO2Me 29 H 41 2 43

Scheme 10. Scheme 15. 7198 D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210

Akio Saito and Yuji Hanazawa of Showa Pharmaceutical Uni- This approach has been extended in several directions. John versity published22 a full account of the Rh-mediated cyclization of E. Macor at Pﬁzer found26 that cyclization of the dibromide 53 to 54 propargylaniline derivatives, such as 44 (Scheme 16) that they (Scheme 20) was more efﬁcient than cyclization of the corre- developed. This reaction is apparently proceeding via rearrange- sponding monobromide. Note that the potentially labile allylic ment to an intermediate o-allenylaniline, that then cyclizes to the carbamate survived the Pd reaction conditions. Haruhiko Fuwa and product, 45. Makoto Sasaki of Tohoku University devised27 the conversion of the N-acetyl aniline 55 (Scheme 21) into the enol phosphonate 56. Consecutive Suzuki coupling followed by Heck cyclization de- MeO MeO livered the indole 57. Rh cat. N Cbz N (F C) CHOH H H 3 2 O N N N O 44 45 S Cbz N O S Br O Pd cat.

Scheme 16. N Et3N N Br H 53 OCF 54 Br Erik J. Sorensen of Princeton University uncovered23 a route to 3 indoles (Scheme 17) based on an interrupted Ugi reaction, the Scheme 20. combination of 46 and tert-butyl isocyanide to give the amino- indole 48. The acid 47 was particularly effective at mediating this Br Br reaction. B(OH)2 + O OPh N O N O MeO F CSO P H 55 Boc 56 Boc P(OPh) 3 2 N OPh MeO N 2 47 O cat. H Ph t Pd cat. Ph -BuNC N MeO N MeO N H 46 Ph 48 57 Boc

Scheme 17. Scheme 21.

3. Type 2 Morten Jørgensen of H. Lundbeck A/S, Denmark took advan- 28 X tage of the more facile oxidative addition of aryl iodides compared to aryl bromides to accomplish sequential N-arylation and Heck cyclization, converting 58 (Scheme 22) into the indole 59. Lutz N € € H Ackermann of the Ludwigs-Maxmilian-Universitat Munchen effected29 regioselective Ti-mediated hydroamination of the alkyne Mori strategy 61 (Scheme 23) with the aniline 60. Pd-mediated cyclization of the nucleophilic enamine so formed gave the indole 62.

In a landmark paper in 1977, Miwako Mori, working with Yoshio 24 ﬁ Ban at Hokkaido University, reported the rst intramolecular OMe OMe Heck cyclization, converting the 2-bromoaniline derivative 49 Br H2N (Scheme 18) into the N-acetyl indole 50 with a Pd catalyst. In 1980, 25 Pd cat Louis S. Hegedus at Colorado State University showed that iodides I N were superior to bromides for the cyclization, and that free amines, 58 59 H such as 51 (Scheme 19) were compatible with the reaction condi- Scheme 22. tions, forming 52.

Ph Ph CO Me 1. 61 2 CO2Me Cl Br Pd cat. TiCl4 N TMEDA NH2 2. Pd cat. N N H 49 50 60 62 O O Scheme 23. Scheme 18.

Indoles can also be prepared by free radical cyclization. Athel- stan L. J. Beckwith of the University of Adelaide cleverly employed30 the nitroxide 64 (Scheme 24) to effect ﬁrst reduction, to facilitate loss of N from the diazonium salt 63, then radical cyclization, then Ι 2 Pd cat. radical-radical coupling with the nitroxide, followed by loss of the Et N amine to give the indole aldehyde 65. Richard P. Hsung, now at the N 3 N University of Wisconsin, demonstrated31 that a more conventional 51 H 52 H reductive cyclization of the allenylaniline 66 to form 67 (Scheme Scheme 19. 25) was also effective. D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7199

the Pd-mediated arylation of the anion derived from 78 (Scheme O H 30). Depending on the reaction conditions, the dominant product N could be either the indoline, or the indole 79. N2 64 O CO2Me N I CO2Me N Pd cat. 63 65 O N K2CO3 N O phenol 78 79 Scheme 24. Scheme 30.

I Bu3SnH Among the several Type 2 indole syntheses reported in 2009, AIBN two were particularly interesting. Sandro Cacchi of the Universita N N 66 67 degli Studi ‘La Sapienza‘, Roma, prepared37 the enaminone 80 Boc Boc (Scheme 31) by condensation of the iodoaniline with the acetylenic Scheme 25. ketone. On exposure to a Cu catalyst, 80 cyclized to the indole 81. O Ph Lanny S. Liebeskind of Emory University showed32 that ortho- I bromo allyl anilines, such as 68 (Scheme 26) could, on trans- Cu cat. metalation, be induced to cyclize to the indoline anion. The anion N N H could be trapped with a variety of electrophiles. The product 80 Ph O 81 H indoline was readily oxidized to the indole 69. Professor Buchwald generated33 from 70 (Scheme 27) a zirconocene benzyne complex Scheme 31. that inserted into the pendent alkene. Iodination delivered the 38 indoline 71, that via elimination and bromination was carried on to Luc Neuville and JZhu of CNRS Gif-sur-Yvette assembled the indole 72. (Scheme 32) the amide 82 by a four-component coupling. With the proper choice of ligand, 82 could be cyclized to 83. The con- MeO Br t 1. -BuLi; MeO N version of an oxindole into the indole is described in the preceding section. N N N 68 69 2. chloranil I cat. Pd(dba)2 O Scheme 26. N O BINAP N O O

Br N N H H Cl I I I 82 83 Cp Zr Br 2 1. DBU Scheme 32. tert-BuLi; 2. NBS N N N I 4. Type 3 70 2 71 72

Scheme 27. N Brian M. Stoltz of Caltech added34 the anion derived from 74 H

(Scheme 28) to the benzyne derived from 73 to give the indoline 75. Hemetsberger strategy The authors did not oxidize 75 to the corresponding indole, but this should be straightforward. The lead Type 3 approach is the Hemetsberger39 indole syn- 40 MeO MeO thesis, as, for instance, employed by John K. MacLeod of Australia F TMS National University in his synthesis (Scheme 33)ofcis-trikentrin A. CO2Me The aldehyde 84 was homologated to the azido ester 85, that was OTf Boc N then heated to convert it into the indole 86. N CO2Me 73 H 74 75 Boc H Scheme 28. CO Et O 2 N3 CO2Et 35 N3 As described by Brigitte Jamart-Gregoire of the Universitede EtONa Nancy, a benzyne was also the intermediate in the cyclization of the 84 85 anion derived from 76 (Scheme 29) to the indole 77. Daniel Soleof the Universitat de Barcelona effected36 the conceptual alternative, CO2Et N Cl H 86 NaNH2 t-BuONa Scheme 33. N N H The thermal conversion of azido styrenes, such as 85 into the 76 H 77 indole had been shown39 to proceed by way of the azirine. We Scheme 29. therefore developed41 a general method for the conversion of an a- 7200 D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 aryl ketone, such as 87 (Scheme 34) into the azirine 88. Thermolysis The cyclic heptadepsipeptide HUN-7293 contains the N- of the azirine gave the indole 89. Subsequently, Koichi Narasaka of methoxy tryptophan 104 (Scheme 38). To prepare 104, Dale L. the University of Tokyo demonstrated42 that Rh triﬂuoroacetate Boger of Scripps/La Jolla took advantage48 of the Kikugawa oxindole catalyzed the conversion of azirines, such as 88 into indoles at room synthesis to convert 101 into 102. Reduction followed by acid- temperature. Tom G. Driver of the University of Illinois, Chicago catalyzed condensation with the enamide 103 then delivered 104. later found43 that the same catalyst converted azido styrenes, such O 1. t-BuOCl as 85 (Scheme 33) into the indole, also at room temperature. O N 2. AgOAc O HOMe N 101 102 OMe NH2OH; N CO2H MsCl; DBU 1. LiAlH4 Br Br 87 88 NHAc 2.H+/ CO2H N 103 NHAc 104 OMe Br N H 89 Scheme 38.

Scheme 34. In 2009, Vy M. Dong of the University of Toronto found49 that CO 44 Kang Zhao of Tianjin University established that PIFA oxidation could serve (Scheme 39) as the reductant for the cyclization of a b- of an enamine, such as 92 (Scheme 35), prepared from 90 and 91, nitro styrene 105 to the indole 106. Jin-Quan Yu, also of Scripps/La offered a convenient route to the N-aryl indole 93.Thiscyclization Jolla, developed50 an oxidant that enabled the Pd-mediated cycli- may likely also be proceeding by way of the intermediate azirine. zation of 107 (Scheme 40) to the indole 108. CN Cl NH2 CN R2 91 HN Pd cat. O F F NO2 90 CN 92 CO N Cl 105 106 H F N PIFA Scheme 39.

93 Br Cl Br H Pd cat. N Scheme 35. Tf ox. N H. Person of the Universite de Rennes found45 that exposure of a b- 107 108 Tf nitro styrene 94 (Scheme 36)toanisonitrile95 led to the N-hydroxy Scheme 40. indole 96. Glen A. Russell of Iowa State University reported46 a related reductive cyclization of a b-nitro styrene with triethyl phosphite. 5. Type 4 H N O 95 CO2Me NC N CO2Me X NO2 N O2N O2N 94 96 OH Buchwald strategy

Scheme 36. The development of transition-metal-mediated aryl halide amination opened the way to Type 4 indole synthesis. In 1998, The coupling of a phenol 97 (Scheme 37) with a diazonium salt Stephen L. Buchwald of MIT reported51 that on exposure to ben- 98 is a well-known process. Masato Satomura of Fuji Photo Film Co. zylamine in the presence of a Pd catalyst, the dibromide 109 discovered47 that exposure of the adduct 99 to mild acid led to (Scheme 41) smoothly cyclized to the indoline 110. Ammonium cyclization to the indole 100. The NeN bond was readily cleaved by formate in the presence of Pd/C converted 110 into the indole 111. Raney nickel to give the free amine.

N2 HO Ph HO 98 Br NH N 2 N Pd cat. N 97 99 Br 109 Ph 110 HO H+ N HCO2NH4 100 N Pd/C N 111 H H

Scheme 37. Scheme 41. D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7201

In the course of a synthesis of the duocarmycins, Tohru N O CO Et 52 H N 2 N Fukuyama of the University of Tokyo employed a similar ap- O N 2 O2N S proach, cyclizing 112 (Scheme 42)to113. By that time, the Cu 1. NH2 catalysts for aryl halide amination had been developed. Cl 2. SOCl2 Cl Cbz 122 123 H N CO2Me MeO O2N Cu cat. MeO CO2Me NH2 SH MeO N N K2CO3 124 MeO Br MeO Cbz MeO 112 113

Scheme 42. Scheme 46. In 2009, Qian Cai and Ke Ding of the Institute of Biological 57 Jose Barluenga of the University of Oviedo took advantage53 of Chemistry, Guangzhou described (Scheme 47) the CuI-mediated the greater reactivity of an aryl bromide compared to the chloride condensation of the isocyano ester 126 with o-halo aromatic ke- as he developed the convergent coupling of 114 (Scheme 43) with tones and aldehydes, such as 125 to give directly the corresponding 58 115 to give the indole 116. For this coupling, a Pd catalyst was indole 127. Stuart L. Schreiber of Harvard University took a related required. approach, cyclizing 128 (Scheme 48), prepared via the corresponding aziridine, to the indole 129. Ph N NC Br Br CO2Et Br NaOt-Bu O 126 + CO2Et CuI BnO Cl Pd cat. Br N H 114 115 OMe 125 127

Scheme 47.

OMe I OMe N BnO CO2Me Ph 116 CO2Me N CuI N Scheme 43. H 128 129

Alexander V. Karchava of Moscow State University devised54 Scheme 48. a route to indoles from ortho-bromophenylacetic acid esters, such as 117 (Scheme 44). Formylation followed by condensation with an amine 118 set the stage for the Cu-mediated intramolecular ami- 6. Type 5 nation to give the indole 119.

CO Me CO2Me 2 NH 1. NaH/Me formate 2

2. N Sundberg strategy Br NH 2 In 1969, Richard J. Sundberg of the University of Virginia 117 118 119 3. Cu cat. reported59 that ortho-azido styrenes, such as 130 (Scheme 49)were converted on thermolysis into the corresponding indole 131.He Scheme 44. later found60 that heating ortho-nitro styrenes, such as 132 Phenols, under photolysis, can activate meta-substituted halides (Scheme 50) with P(OEt)3 also delivered the indole. Aryl migration for nucleophilic displacement. Nien-chu C. Yang of the University of dominated over alkyl migration, leading to 133. Recently, Tom G. 55 Chicago devised an indoline synthesis based on this effect, irra- Driver of the University of Illinois, Chicago showed61 that the azide diating 120 (Scheme 45) to give 121. version of the Sundberg indole synthesis could be carried out at lower temperature with a Rh catalyst. H

MeO2C N CO2Me O hν N N MeOH N 3 H HO Cl HO 130 131 120 121 O Scheme 49. Scheme 45.

Similarly, nitro groups can activate para-substituted halides for nucleophilic displacement. Douglas C. Neckers of Bowling Green P(OEt)3 State University observed56 that exposure to a primary amine N converted the thiadiazole 123 (Scheme 46), prepared from 122, into NO2 H 132 133 the indole-2-thiol 124. The reaction is thought to be proceeding by way of the alkyne thiol. Scheme 50. 7202 D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210

Benzylic methyl groups are acidic enough to be deprotonated, MeO C MeO2C 2 N N especially when there is an ortho-nitro group. This is the basis for 1. NPIF the Reissert indole synthesis62 (134 to 135, Scheme 51) and the 2. TiCl LeimgrubereBatcho indole synthesis63 (136 to 138, Scheme 52). 3 TBSO N I I 147 H 148 1. (CO2Me)2 t-BuOK Scheme 56. CO Me 2. SnCl 2 Cl NO 2 Cl N 2 H 134 135 O CO2Et Scheme 51. CO2Et CH3O 1. /Fp CH O H N2 3

2. H2 -Pd/C OMe NO N 2 H OMe N 137 OMe 1. 149 150 OMe Scheme 57. 2. H -Pd/C NO 2 N 2 H 136 138 As demonstrated69 by Ken-ichi Fujita and Ryohei Yamaguchi of Scheme 52. Kyoto University, in situ oxidation of the alcohol 151 (Scheme 58) Amos B. Smith III of the University of Pennsylvania took ad- led to the indole 152. With added 2-propanol, an alcohol with an vantage64 of the acidity of 139 (Scheme 53). Double deprotonation ortho-nitro group was also converted into the indole. followed by condensation with 140 delivered the indole 141. MeO OH MeO Ir cat OH N NH2 H 2xn-BuLi; 151 152 O NH N Scheme 58. 140 H O 139 SiMe3 141

Scheme 53. Hironao Sajiki and Kosaku Hirota of Gifu Pharmaceutical Uni- versity showed70 that reduction of an ortho-amino nitrile, such as Donal F. O’Shea of University College Dublin demonstrated65 153 (Scheme 59) delivered the indole 154, presumably by trapping that an alkyllithium ﬁrst deprotonated 142 (Scheme 54), and then of the intermediate imine. It may well be that an ortho-nitro sub- added to the pendent alkene. Benzonitrile 143 was added to the stituent would work as well, but such a transformation was not resulting carbanion to give the indole 144. included in this report.

CN H2 NH Pd - C N 2 H CH O n CH O 3 2x -BuLi; 3 153 154 Ph Ph-CN NH N Scheme 59. 143 Boc 142 Boc 144

Scheme 54. K. C. Nicolaou of Scripps/La Jolla prepared71 the enone 155 (Scheme 60) from the intermediate in the Bischler indole synthesis. It is clear that any synthetic route to ortho-amino or ortho-nitro Reduction of 155 gave an intermediate that reacted with mild nu- a-aryl ketones or aldehydes can be used to prepare indoles. Joseph cleophiles, such as the allylsilane 156 to give the indole 157. F. Bunnett of the University of California, Santa Cruz observed66 that, under SRN1 conditions, acetone enolate displaced the bromide of 145 (Scheme 55), leading to the indole 146. Viresh H. Rawal Br 67 of the University of Chicago arylated the silyl enol ether 147 CO Me SiMe3 2 156 (Scheme 56) with an ortho-nitrophenyl iodinium salt (NPIF) to give, CO Me O 2 . N after reduction, the indole 148. M. Mahmoun Hossain of the Uni- NO2 SnCl2 2H2O 68 OH versity of Wisconsin, Milwaukee inserted ethyl diazoacetate into 155 157 the aldehyde 149 (Scheme 57), converting it, via reduction, into the indole 150. Scheme 60.

Br In 1986, Sylvestre A. Julia of the Ecole Normale Superieure, Paris hν reported72 that sulﬁnamides, such as 159 (Scheme 61), readily NH N 2 H prepared from the aniline 158, were converted by heating into the 145 146 indole 161 via 160. It is striking that the Julia indole synthesis has Scheme 55. been little used since it was reported. D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7203

MeO Br Br 1. SOCl2 /im MeO Et3B 2. S NH2 N O MgBr Pd cat 158 159 N H NH 2 H 171 172 O MeO S MeO Scheme 65. N NH2 160 161 H

Scheme 61. S S The preparation of indoles from ortho-haloanilines by conden- 174 sation with an alkyne goes back at least to 1963, when C. E. Castro of N 73 NH the University of California, Riverside, observed (Scheme 62) that Ts coupling of 162 with 163 led not to the diaryl alkyne, but to the 173 Ts 175 indole 164. Scheme 66. I Cu Ph 163 Ph N NH2 H Bu3SnH 162 164 Br N AIBN N Scheme 62. 176 Ph 177 Ph

In 1985, Edward C. Taylor of Princeton University and Alexander Scheme 67. McKillop of the University of East Anglia showed74 that Pd was effective at cyclizing ortho-alkynylanilines to the corresponding Toyohiko Aoyama of Nagoya City University reacted81 ortho- indole. This led to the 1989 report75 by J. K. Stille of Colorado State acylanilines, such as 178 (Scheme 68) with lithio TMS diazo- University that the two-step coupling described by Castro (Scheme methane 179 to give an alkylidene carbene, that inserted into the 62) could be carried out at much lower temperature using Pd ca- adjacent NH to give the indole 180. Bartolo Gabriele of the Uni- talysis. With this precedent, in 1991 Richard C. Larock of Iowa State versita della Calabria added82 acetylides, such as 182 (Scheme 69) University disclosed76 that, using Pd catalysis (Scheme 63), internal to ortho-acylanilines, such as 181 to give alkynyl alcohols, that alkynes, such as 166 could be condensed with an ortho-iodoaniline underwent carbonylative cyclization with Pd catalysis to give the 165 under Pd catalysis to give the 2,3-disubstituted indole 167 with indole 183. high regiocontrol. One of the advantages of the Larock indole synthesis is the malleability of the 2-silyl substituent on the SiMe3 product indole. 179 O N2

I SiMe3 NH N 166 SiMe3 Ts Ts N 178 180 NH2 Pd cat. H 165 167 Scheme 68.

Scheme 63.

SiMe3 More recently, (the late) Keith Fagnou of the University of Ot- tawa demonstrated77 that Rh catalysis could effect ortho function- 182 O CO2Me alization of acetanilides, such as 168 (Scheme 64). Subsequent 1. coupling with internal alkynes, such as 169 led to the indole 170 NH2 2. Pd cat. N with high regiocontrol. 181 MeOH/CO 183 H

Ph Scheme 69. 169 H Ph MeO N Rh cat. MeO N 8:1 Cu(OAc)2 O 168 O 170 In 2009, Hideo Nagashima of Kyushu University reported83 that Scheme 64. an o-nitrophenyl acetonitrile 184 could indeed (Scheme 70)be reductively cyclized to the indole 185. Yanxing Jia of Peking Uni- versity prepared84 188, a key intermediate in the synthesis of Several other ﬂexible routes to indoles have been developed. (À)-cis-clavicipitic acid, by selective condensation of the aldehyde 78 Mark Lautens of the University of Toronto established that ortho 187 (Scheme 71) with the iodoaniline 186. dihaloalkylidene anilines, such as 171 (Scheme 65) could be condensed with alkyl, alkenyl or aryl boranes or boronic acids to give the 2-substituted indole, in this case 172. Kentaro Okuma of 79 Fukuoka University found that the sulfonium salt 174 (Scheme CN H2 66) effected cyclization of an ortho alkenyl aniline, such as 173 to NH Pt cat. N the indole 175. Jeffrey N. Johnston, now at Vanderbilt University, 2 H 184 185 effected80 free radical reductive cyclization of halides, such as 176 (Scheme 67), to give the indole 177. Scheme 70. 7204 D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210

H George A. Kraus of Iowa State University described91 a concep- O MeO2C tually related cyclization (Scheme 76). Condensation of an aldehyde N(Boc)2 198 with the aniline 197 gave the imine, that on exposure to strong MeO C Cl Cl 2 base gave the indole 199. Gary A. Sulikowski, now at Vanderbilt I 187 N(Boc)2 University, showed92 that cyclization of the carbene derived from Pd cat. N 200 (Scheme 77) proceeded to give 201 with high regiocontrol. NH2 186 188 H

Scheme 71. PPh3 H 198 Sandro Cacchi of the Universita ‘La Sapienza‘, Rome, extended85 /H+ the Gabriele approach, cyclizing (Scheme 72) the propargylic car- 1. O bonate 189 to 190. This transformation may be proceeding by way t NH2 2. -BuOK of the intermediate allene. Two related approaches to indole syn- N 197 H 199 thesis86,87 also appeared. Scheme 76. OCO2Et

Pd cat. CO2CH3 CO2CH3 H CO/MeOH N CO Me N Rh cat. N 2 2 H 189 190 N N O CF3 O 200 201 O Scheme 72. N O N Ts Ts O Tao Pei of Merck Rahway developed88 a powerful new approach Scheme 77. to substituted indoles, based on the addition (Scheme 73)ofan organometallic to a chloro ketone 191. The conversion into 192 Bond formation in the opposite direction has also been de- 93 proceeded by 1,2-migration of the arene with nucleophilic dis- veloped. William D. Jones reported that a Ru complex catalyzed placement of chloride. the conversion of the isonitrile 202 (Scheme 78) into the indole 203. This reaction may be proceeding by way of the Ru vinylidene O complex. Cl MgBr Ru cat. NH N 2 H Cl 191 Cl 192 N N C H Scheme 73. 202 203

7. Type 6 Scheme 78.

Charles D. Jones of Lilly described94 an anionic cyclization in this N direction, converting 204 (Scheme 79) into 205. Yoshinori Naka- mura of the Tanabe Seiyaku Co. contributed95 the Rh-mediated Madelung strategy coupling of the diazophosphonate 207 (Scheme 80)toanortho- acylaniline, such as 206, to give, after cyclization, the indole 208. fi The Madelung indole synthesis, as exempli ed by the cycliza- Note that, in the cyclization of 209 (Scheme 81) developed96 by tion (Scheme 74)of193 to 194, was originally carried out at Rodney W. Stevens of Pfizer Nagoya, re-aromatization to the indole elevated temperature with bases, such as NaNH2. Willam J. Houli- 210 was achieved by elimination of arenesulfinate. han of Sandoz, Inc. (now Novartis) showed89 that, with BuLi, the cyclization of 193 to 194 was facile below room temperature. D. N. Reinhoudt of the University of Twente found90 that phenyl- acetonitriles, such as 195 (Scheme 75) could be cyclized under even O MeONa CO Me milder conditions, to form 196. N 2 N CO2Me Ts MeO MeO 204 Ts 205 O 3 n-BuLi Scheme 79. Ph N Ph N 193 H 194 H

Scheme 74. O

N2 P(OEt)2 CN /Rhcat CN 1. CO2Et O 1. NaH/TMSCl O 207 CO2Me t N 2. -BuOK N NH2 2. DBU N Ts 195 H 196 H 206 208

Scheme 75. Scheme 80. D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7205

CO2Me 8. Type 7 CO2Me DBU Ph Ph N N O 209 210 Ts O H O Scheme 81. Nenitzescu strategy Type 7 includes all routes to indoles from cycloalkane de- In 1994, Tohru Fukuyama, now at the University of Tokyo, dis- rivatives. The earliest such approach is the Nenitzescu indole syn- closed97a the cascade radical cyclization of the isonitrile 211 (Scheme thesis, exempliﬁed (Scheme 87) in a modern manifestation102 by 82) to the indole 212. Later, he applied97b a variant of this cyclization Daniel M. Ketcha of Wright State University and Lawrence J. Wilson in the total synthesis of a complex indole alkaloid. Jon D. Rainier, now of Procter & Gamble. The combination of the benzoquinone 221 at the University of Utah, has explored97c related radical cyclizations. with the resin-bound enamine 222 gave, after release from the OBn resin, the indole 223. OBn

Bu3SnH NHBn /AIBN; H+ O O P NH O N 2 N N ; HO 222 H 211 C 212 H TFA N Scheme 82. O Bn 221 223 Alois Furstner€ of the Max-Planck-Institute Mulheim€ devel- oped98a,b a reductive coupling of acyl anilides, such as 213 to give Scheme 87. 214 (Scheme 83). In the presence of a silyl chloride, the reaction was Michael A. Kerr of the University of Western Ontario developed103 98c catalytic in Ti. Bruce C. Lu of Boehringer Ingelheim employed this (Scheme 88) a complementary protocol for the conversion of a ben- reductive coupling in a combinatorial route to indoles. zoquinone into the indole. DielseAlder cycloaddition of the imine Ph 224 to the diene 225 gave the adduct 226. Protection followed by Ph oxidative cleavage and condensation delivered the indole 227. O TiCl3 H Zn N Ts H N NTs N H 213 214 CH O O 3 225 CH3O

Scheme 83. O 224 O OH 226 In 2009, Professor Doyle reported99 an alternative (Scheme 84) H diazo-based approach to indoles, Lewis acid-mediated cyclization TfO of 215 to 216.

CO2Me CO2Me N Ts N2 Zn(OTf)2 CH3O Ph 227 N Ph N 215 216 H Scheme 88.

Scheme 84. Fused pyrroles, such as 231 (Scheme 89) and 235 (Scheme 90) Churl Min Seong of the Korea Research Institute of Chemical are readily aromatized. Brian L. Pagenkopf of the University of Technology described100 the facile cyclization (Scheme 85)ofano- Western Ontario established104 a pyrrole synthesis from cyclo- cyano N-benzyl aniline 217 to the indole 218. Andrew D. Hamilton hexanone, by cyclopropanation of the enol ether 228 followed by employed101 a related protocol (Scheme 86), the cyclization of 219 condensation with the nitrile 230. The aromatization of 231 to 232 to 220. was accomplished by heating with Pd/C in mesitylene. OAc CN NaH/DMF; Ph CO2Et N Ac2O CO Et N OMe 2 O Bn 229 217 Ph 218 N 1. N2 N Scheme 85. O 2. Bn H 228 N 231

Br OAc NC 230 HOAc/ CO2H CO2Et NaOAc O Bn H N Pd-C N N MeO O N CO2Me 219 220 H 232

Scheme 86. Scheme 89. 7206 D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210

NO 9. Type 8 Ph 2 O Ph O O 1. 234

2. BnNH2 N 233 235 Bn AcO Ph N H Ac2O

O2 N van Leusen strategy 236 Bn Type 8 indole syntheses include all those that proceed by way of Scheme 90. the preformed N-containing ﬁve-membered ring. In 1986, Albert M. van Leusen of Groningen University established110 a route to highly Teruhiko Ishikawa and Seiki Saito of Okayama University con- substituted indoles, based on the condensation of isonitriles, such densed105 (Scheme 90) cyclohexane-1,3-dione 233 with the nitro- as 245 (Scheme 94) with unsaturated ketones, such as 246 to give alkene 234, leading after exchange with benzylamine to the pyrrole the 2,3-bisalkenylpyrrole 247. Heating followed by aromatization 235. Aromatization gave the 4-oxygenated indole 236. Chihiro with DDQ completed the synthesis of the indole 248. Kibiyashi of the Tokyo College of Pharmacy reported106 a related Ph O approach to 4-oxygenated indoles. Ts NC Michel Pfau of ESPCI Paris devised107 an intriguing protocol for O Ph indole construction, starting with the benzyl imine of the monop- 246 rotected cyclohexane-1,4-dione 237 (Scheme 91). Metalation of the N H imine followed by condensation with maleic anhydride 238, with 245 247 methanol workup, delivered the lactam 239. Exposure of 239 to O POCl3 effected aromatization to the 5-methoxyindole 240. Ph CO2Me DDQ O MeO 1. BnNH2 N O O H N 248 O 2. 237 O O 239 Bn Scheme 94. O 238

CO2Me Hiroyuki Ishibashi of Kyoto Pharmaceutical University demon- POCl MeO 3 strated111 (Scheme 95) a route to 4-substituted indoles from pyrrole N itself. Condensation of 249 with the chlorosulﬁde followed by sa- 240 Bn poniﬁcation and intramolecular FriedeleCrafts acylation delivered the versatile intermediate 250. Oxidation gave the indole 251. The Scheme 91. addition of nucleophiles to 250 followed by dehydration gave the 4- alkylindole (not illustrated). In 2009, Yong-Qiang Tu of Lanzhou University described108 the ArS ring expansion (Scheme 92)of241 to 242. The aromatization of 242 O to the indole should be facile. Tsutomu Inokuchi of Okayama Uni- Cl CO Et 109 2 versity showed that reduction (Scheme 93) of the Michael ad- N duct 243 followed by aromatization delivered the indole 244. Bs N ArS Bs 249 250 OH TBSO MCPBA Ph Au cat. N NPhTh Ph N N 251 Bs 241 242 NPhTh Scheme 95. Scheme 92.

Pedro Mancini of the Universidad Nacional de Litoral showed112 Ph that nitropyrroles, such as 252 (Scheme 96) were effective Diel- Ph seAlder dienophiles. Regiocontrol was poor with isoprene, NO2 whereas addition to the more activated diene 253 proceeded to Zn/NH4Cl MeO O give the 5-hydroxyindole 254 with complete regiocontrol. MeO N O 242 243 Ph CO Me 1. Ac O 2 CO2Me 2 OTMS HO 2. DDQ + N O2N MeO N N O Ts 244 252 OMe 253 254 Ts

Scheme 93. Scheme 96. D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7207

Edwin Vedejs of the University of Michigan optimized113 the N Ph acetic anhydride-mediated cyclization of the Stobbe condensation Pt cat. H N product 255 (Scheme 97) to the indole 256. Although this cyclization had been reported earlier, Vedejs found that the conditions 265 H 266 Ph originally described also delivered substantial quantities of an O O indolizidine by-product. 267 HOOC OH Ac O N 2 268 MeO C Ph 2 N N H MeO2C 255 256 H Scheme 101.

Scheme 97. 10. Type 9

Masanobu Hidai of the University of Tokyo developed114 the Pd- catalyzed cyclocarbonylation of the allylic acetate 257 (Scheme 98) to the 4-acetoxyindole 258. It seems likely that a more highly substituted version of 257 would cyclize with equal facility. Kanematsu strategy OAc The least developed approach to indoles is Type 9, the simul- Ac2O/CO taneous construction of both rings of the indole. This route was AcO 119 N pioneered in 1986 by Ken Kanematsu of Kyushu University. Pd. cat N Homologation of 269 (Scheme 102) to the allene led to the intra- 257 OMe 258 OMe molecular DielseAlder cyclization product, that was readily aro- Scheme 98. matized to the indole 270.

1. CH2=O/CuBr iPr2NH Alan R. Katrizky of the University of Florida devised115 an ap- Cl Ar 2. DDQ N proach to indoles with more highly substituted benzene rings. O N Ar Addition of the benzotriazolyl anion 259 (Scheme 99) to an enone, O OO such as 260 followed by acid-catalyzed dehydrative cyclization Cl 269 270 delivered the indole 261. H

Scheme 102. N Li O N Ph N Three related approaches have been put forward since that time. 120 + N Michael J. Martinelli, then at Lilly, established that acetic N Ph Bs anhydride-mediated decarboxylation of 271 (Scheme 103) led to 259 260 261 Bs a 1,3-dipole, that added in an intramolecular fashion to the alkyne, delivering the dihydro indole 272. In a complementary approach, A. Scheme 99. Stephen K. Hashmi of Ruprecht-Karls-Universitat€ Heidelberg 121 found that with catalytic AuBr3, 273 (Scheme 104) cyclized ef- 116 ﬁciently to 274. As outlined earlier in this review, both 272 and 274 Naoki Asao of Tohoku University found that AuBr3 was an would be readily aromatized to the corresponding indoles. effective catalyst for the cyclocondensation (Scheme 100)of262 with 263 to give the indole 264. F. Dean Toste of the University of 117 SiMe O California, Berkeley uncovered a related Au-catalyzed cyclization 3 Ac O O 2 leading to indoles. Bn

N CO2H N OMe 271 272 Bn O Ph Ph O Scheme 103. 263

cat. AuBr3 N CHO N Ts N cat. AuCl3 Ts 262 264 Ts O N HO Ts Scheme 100. 273 274

Scheme 104.

In 2009, Chi-Meng Che of the University of Hong Kong118 described (Scheme 101) the Pt-mediated intramolecular hydroamination of the alkyne 265. Condensation of the cyclic enamine In 2009, Peter Wipf of the University of Pittsburgh described122 266 so prepared with a b-diketone 267 proceeded with high the intramolecular DielseAlder cyclization (Scheme 105) of the regioselectivity to give the indoline 268. For the aromatization of allylic alcohol 275. Microwave heating led directly to the doubly a similar N-benzyl indoline, see Scheme 41. aromatized product 276. 7208 D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210

Ph 34. Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, OH 1558e1559. microwave 35. Caubere, C.; Caubere, P.; Renard, P.; Bizot-Espiart, J.-G.; Jamart-Gregoire, B. N O Tetrahedron Lett. 1993, 34, 6889e6892. Boc N 36. Sole, D.; Serrano, O. J. Org. Chem. 2008, 73,2476e2479. H 275Ph 276 37. Bernini, R.; Cacchi, S.; Fabrizi, G.; Filisti, E.; Sferrazza, A. Synlett 2009, 1480e1484. Scheme 105. 38. Erb, W.; Neuville, L.; Zhu, J. J. Org. Chem. 2009, 74,3109e3115. 11. Conclusions 39. Hemetsberger, H.; Knittel, D.; Weidmann, H. Monatsh. Chem. 1970, 101, 161e165. 40. MacLeod, J. K.; Monahan, L. C. Tetrahedron Lett. 1988, 29,391e392. In this review, we have tried to be inclusive, but certainly not 41. Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058e1059. comprehensive. We hope that the scheme outlined here for the 42. Chiba, S.; Hattori, G.; Narasaka, K. Chem. Lett. 2007, 36,52e53. classification of synthetic routes to indoles will be useful to future 43. 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Biographical sketch

Douglass F. Taber was born in 1948 in Berkeley, California. He earned a B.S. in Chem- Pavan K. Tirunahari was born in Warangal, A.P, India in 1968. He received his Bachelor istry with Honors from Stanford University in 1970, and a Ph.D. in Organic Chemistry of Science and Master of Science degrees from Osmania University, Hyderabad. He then from Columbia University in 1974 (G. Stork). After a postdoctoral year at the University joined the group of Dr. B. G. Hazra at National Chemical Laboratory, Pune, Maharastra. of Wisconsin (B.M. Trost), Taber accepted a faculty position at Vanderbilt University. He He received his Ph.D degree in Organic Chemistry from the University of Pune. He did moved to the University of Delaware of Delaware in 1982, where he is currently Pro- his postdoctoral studies in the group of Professor James. P. Morken at the University of fessor of Chemistry. Taber is the author of more than 200 research papers on organic North Carolina. Currently he is working at Accel Synthesis, Inc., Garnet Valley, PA. His synthesis and organometallic chemistry. He is also the author of the weekly Organic research interests include process research, synthetic methodologies, medicinal chem- Highlights published at http://www.organic-chemistry.org/. istry, and pharmacology. JOCSynopsis

pubs.acs.org/joc

Synthesis of Saturated N‑Heterocycles Cam-Van T. Vo and Jeﬀrey W. Bode* Laboratorium für Organische Chemie, ETH Zürich, Vladimir Prelog Weg 1-5, Zürich, Switzerland 8093

ABSTRACT: Saturated N-heterocycles are prevalent in biologically active molecules and are increasingly attractive scaﬀolds in the development of new pharmaceuticals. Unlike their aromatic counterparts, there are limited strategies for facile construction of substituted saturated N-heterocycles by convergent, predictable methods. In this Synopsis, we discuss recent advances in the synthesis of these compounds, focusing on approaches that oﬀer generality and convenience from widely available building blocks.

he last three decades have witnessed the remarkable success would be direct sp3 C−H functionalization. This transformation T of metal-catalyzed cross-coupling reactions in organic could allow access to a variety of N-heterocycles from the readily chemistry.1 Over the years, extensive improvements have been available unsubstituted starting materials. To date, most reports made in the development of ligands, metals, reaction conditions, have focused on functionalization of the C−H bond adjacent to and building block availability, making this method one of the nitrogen.7 most useful tools to append aromatic rings into a molecule.2 With α-Lithiation with Diamine Ligands. In 1989, Beak and Lee this powerful tool, it is not surprising to observe an increase of reported the pioneering α-functionalization of N-heterocycles by aromatic ring count in the new bioactive small molecules.3 However, lithiation.8 This process involved α-deprotonation with an limitations in solubility, pharmacokinetics, and bioavailability of alkyllithium/diamine complex to generate the dipole-stabilized high-aromatic-ring-count molecules are now well recognized, carbanion, followed by the addition of electrophiles to provide leading scientists to favor saturated building blocks, especially α-substituted derivatives (Figure 2). An asymmetric version was saturated N-heterocycles (Figure 1).4 Unlike their aromatic

Figure 1. Saturated N-heterocycles. Figure 2. α-Lithiation with diamine ligands and addition to electrophiles. counterparts, they cannot be easily prepared by cross-coupling 9 reactions.5,6 In this Synopsis, recent advances in the construction of later developed with the use of the chiral diamine (−)-sparteine. saturated N-heterocycle synthesis, especially the facile synthesis of Extensive work on ligand design and reaction condition common 5−7-membered N-heterocycles, will be reviewed. optimization performed by O’Brien and others enabled access the opposite enantiomers of α-substituted N-heterocycles by ■ SYNTHESIS OF SATURATED N-HETEROCYCLES using enantiomeric (+)-sparteine surrogates.10 The chiral CONTANING ONE HETEROATOM Functionalization of Saturated N-Heterocycles. The most Received: January 18, 2014 eﬃcient construction of substituted saturated N-heterocycles Published: March 11, 2014

© 2014 American Chemical Society 2809 dx.doi.org/10.1021/jo5001252 | J. Org. Chem. 2014, 79, 2809−2815 The Journal of Organic Chemistry JOCSynopsis organolithium complex was configurationally stable at low temperature and added to the electrophile with the retention of stereochemistry. The method was successfully used in the asymmetric synthesis of more complex structures such as (−)-indolizidine 167B,12 (+)-L-733,060.11 Sparteine-mediated α-functionalization was most successful with N-Boc-pyrrolidine. Asymmetric functionalization of N-Boc-piperidine was computationally calculated to proceed with lower enantioselectivity and with a higher activation barrier compared to that of N-Boc-pyrrolidine.13 Because of the instability of lithium complex at higher Figure 4. Directed C−H activation by Sames et al. temperatures (>−30 °C), the scope of the electrophiles was limited to more reactive examples, such as benzophenone, CO2, 14 ffi Me2SO4, and TMSCl. To expand the electrophile scope, Other limitations include the di culty of removing the directing transmetalation of the lithium complex to other metals such as group and overarylation on unsubstituted N-protected cyclic 25 copper and zinc was used to generate more stable organometallic amines. complexes. Dieter et al. developed a method involving the With the unique reactivity of tantalum−amidate complex for transmetalation of the lithium complex to copper followed by activating the C−H bonds adjacent to nitrogen, Schafer and co- trapping with less reactive electrophiles such as vinyl iodide, workers recently developed a new route for the synthesis of α,β-unsaturated ketones, and propargyl mesylates.15 In 2006, α-substituted, unprotected piperidines, piperazines, and aze- 26 Campos and co-workers successfully generated the configura- panes (Figure 5). In this transformation, the Ta−amidate tionally stable organozinc via the transmetalation of the lithium complex to ZnCl2, followed by Negishi coupling reaction to access a variety of enantioenriched 2-arylpyrrolidines.16 They further utilized this method in the kilogram-scale synthesis of 2-arylpyrrolidines 1, a precursor of glucokinase activator 2 in 64% yield and 91% ee (Figure 3).17 The transformation was also

Figure 5. Direct C−H activation by Schafer et al.

complex selectively activates sp3 C−H bond by β-hydrogen abstraction forming tantallaaziridine complex 3, which undergoes alkene insertion leading to the formation of the α-alkylated cyclic amine. Radical-Based C−H Functionalization. The pioneering work of Curran and Snieckus in 1990 on the formation of α-amino Figure 3. Lithiation, transmetalation, and cross-coupling. carbon-centered radicals via 1,5-hydrogen transfer inspired other research groups to develop radical-based α-functionalization of cyclic amines.27 Nakamura and co-workers developed an iron- applied for the preparation of 2-arylpiperidines18 and recently for catalyzed C−C bond formation at the α-position of acyclic and the selective β-arylation of piperidine.19,20 cyclic amines with Grignard or zinc reagents.28 The reactions Metal-Catalyzed C−H Functionalization. The major con- proceeded under mild conditions in the presence of an iron cerns in sp3 C−H activation are reactivity and selectivity.21 catalyst to provide α-aryl pyrrolidines, piperidines, and azepanes. 3 − α Cleavage of sp C H bonds is kinetically and thermodynamically Other methods to generate -amino radicals including BEt3/O2 unfavorable. Among C−H bonds in the cyclic amines, the bonds (or air) or light in the presence of organic photosentitizer were adjacent to heteroatoms are more reactive. With the appropriate developed by Yoshimitsu29 and Hoﬀmann (Figure 6).30 The directing groups, activation of the C−Hbondnextto later method allowed accessing a highly functionalized proline 4, heteroatoms could be achieved selectively. Murai and co-workers an important precursor in the total synthesis of (±)-kainic acid reported the reaction of N-2-pyridyl cyclic amines with alkenes in (5). In 2011, MacMillan reported the photoredox α-amino C−H α the presence of the low-valent metal Ru3(CO)12 to access arylation. The -amino radical was generated under photoredox α-alkylated saturated cyclic amines.22 The reactions proceeded conditionsandtrappedwithelectron-deﬁcient arenes or well with N-2-pyridylpyrrolidines and piperidines and a range of heteroarenes as radical coupling partners (Figure 7).31 mono- and disubstituted alkenes. Based on the same concept, the Redox-Neutral C−H Functionalization. Another approach to research groups of Sames23 and later Maes developed sp3 C−H the functionalization of saturated N-heterocycles is intra- bond arylation of pyrrolidines and piperidines, using aryl molecular redox-neutral C−H functionalization. The trans- boronate esters as coupling partners (Figure 4).24 This approach formation is related to the generation of an electrophile/ was, however, not successful for larger ring N-heterocycles. nucleophile pair via intramolecular hydride shift or iminium

2810 dx.doi.org/10.1021/jo5001252 | J. Org. Chem. 2014, 79, 2809−2815 The Journal of Organic Chemistry JOCSynopsis

Figure 6. Radical-based C−H functionalization.

N-Phenyl carboxaldehyde is critical for the reaction success. It serves as a hydride acceptor and directs the addition of Grignard reagents at the α-position. The redox-neutral C−H functionalization and N-alkylation of cyclic amines has been recently developed by Seidel and co- workers (Figure 9). Cyclic iminium ions were generated by the acid-catalyzed iminium isomerization33 and trapped by various nucleophiles. Relatively bulky and/or electron-deficient aryl aldehydes were used to prevent the addition of nucleophiles to the acyclic iminium ions. α-Cyanation,34 α-alkynylation35 − Figure 7. Photoredox C H functionalization by MacMillan et al. α-phosphonation,36 and α-arylation37 were developed with trimethylsilyl cyanide, copper acetylides, phosphites, and isomerization. In 2012, Maulide and co-workers reported the electron-rich arenes as nucleophiles. The reactions worked well functionalization at α-position of acyclic and cyclic amines with 32 with pyrrolidine and larger ring sizes (piperidine and azepane). Grignard reagents (Figure 8). A variety of commercially With more challenging substrates, such as morpholine, the regioselectivity eroded and the adduct of nucleophile and acyclic iminium ion was generated as the major product. Direct functionalization of saturated N-heterocycles is conceptually ideal but is not yet a general approach. Lithiation, followed by the addition of an electrophile or metal-catalyzed cross-coupling reaction, is currently the most reliable method but still suffers from laborious conditions and is largely restricted to the construction of α-functionalized pyrrolidines and piperidines. Other classes of saturated N-heterocycles with different ring sizes or additional heteroatoms are not accommodated. Metal-Mediated Hydroamination and Arylamination. The concept of transforming an acyclic amine into a cyclic amine in an atom-economic fashion has motivated many researchers. Intramolecular hydroamination or arylamination of an alkene or alkyne with pendant amine functional group delivers α-substituted cyclic amine. Palladium-catalyzed alkene arylamination and hydroamination have emerged as useful methods to Figure 8. Redox C−H functionalization via 1,5-hydride shift by Maulide α 32 prepare -substituted pyrrolidines and other N-heterocycles et al. (Figure 10). Readers can find the updated and detailed reviews in recent publications.38 available Grignard reagents (alkyl, aryl, alkenyl, and allylic) and Schafer and co-workers reported an asymmetric synthesis of alkynyl trifluoroborates were employed to form α-substituted substituted morpholines and piperazines (Figure 11).39 A pyrrolidines. This procedure was sensitive to the nature of titanium−amidate complex catalyzed the regioselective hydro- amines; it worked well with pyrrolidines but poorly with others. amination with oxygen- and nitrogen-containing aminoalkynes,

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− Figure 9. Redox C−H functionalization via iminium isomerization by Seidel et al.33 37

Figure 12. C−H amination by Betley and Hennessey.40

concern. More activated C−H bonds at benzylic, allylic, or tertiary carbon positions react preferentially. Ring size also plays an important role in the cyclization. In many cases, it is not Figure 10. Palladium-catalyzed alkene arylamination and hydro- simple to rationalize the dominant factor in determining the amination. product outcome. ■ SYNTHESIS OF SATURATED N-HETEROCYCLES WITH ADDITIONAL HETEROATOMS Cyclization. While direct functionalization and hydro/carbo- amination are often used for the preparation of N-heterocycles with one heteroatom, cyclization is more commonly used for constructing cyclic amines with additional heteroatoms. Nucleophilic substitution of amino alcohols/thiols/amines with dihalo derivatives is frequently employed for preparing morpholines, thiomorpholines, or piperazines.42 The intrinsic Figure 11. Hydroamination and reduction by Schafer et al.39 limitation of this approach is low yield due to the competing elimination reactions. A multiple-step synthesis such as alkylation followed by enantioselective reduction using Noyori−Ikariya followed by lactamization and reduction,43 reductive amination,44 or catalyst to generate substituted morpholines and piperazines in ring-closing metathesis followed by reduction could finally deliver high yield and with good enantioselectivity. the desired products.45 In addition to the lengthy synthesis, the In 2013, Betley and Hennessey reported the iron-catalyzed sp3 complexity of the final products in these procedures is derived from C−H bond amination of organoazides for the synthesis of the initial starting materials N-heterocycles (Figure 12).40 Inspired by the heme-iron activity Nucleophilic Substitution. To minimize the side reactions in Nature, they developed the iron dipyrrinato catalyst 6, which caused by strongly basic conditions of substitution reactions, mimics the electronic structure of the well-known cytochrome Aggarwal and co-workers developed a softer electrophile, a vinyl P450 reactive iron-oxo intermediate.41 In this transformation, the sulfonium salt, instead of dihalo compounds to provide a range of Fe(II) catalyst reduces the azide to generate an Fe(III) radical N-protected mono-/disubstituted morpholines, thiomorpho- imido, which either undergoes direct C−H insertion or hydrogen lines, and piperazines in good yields (Figure 13).46 The vinyl abstraction and radical rebound to afford the Fe(III) product. selenium salt was also used for the same purpose.47 The removal Catalyst turnover was achieved by in situ N-Boc protection. Like of the protecting group on nitrogen, N-tosyl in most cases, was other sp3 C−H bond functionalization methods, selectivity is a unfortunately problematic.

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Figure 16. One-step synthesis of 3-thiomorpholines.

Scheme 1. Proposed Mechanism Figure 13. Vinyl sulfonium salts for N-heterocycle synthesis by Aggarwal et al.46

Ring Transformations. Ring transformations have not been often employed for the preparation of substituted N-heterocycles. In most cases, the substituents on N-heterocycles are set prior to the ring transformation. The synthesis of substituted morpholines, thiomorpholines, and piperazines via the Lewis acid catalyzed ring expansion of 3-oxetanone-derived spirocycles was recently reported by Carreira and co-workers (Figure 14).48 carbon-centered radical followed by 6-endo-trig cyclization to deliver the product (Scheme 1). The generation of the sulfur-stabilized carbon-centered radical followed by cyclization to form the stable aminyl radical was key to the successful thiomorpholine formation. Based on the assumptions that other heteroatoms such as oxygen and nitrogen could also stabilize the primary radical, a family of SnAP reagents to access other ring sizes and types of saturated N-heterocycles including morpholines, piperazines, diazepanes, and others has been developed (Figures 17 and 18).50,51 The

Figure 14. Ring expansion of 3-oxetanone by Carreira et al.48

The elegance of the transformation lies in that changing heteroatom-substituted amino compound 7 will lead to the formation of diﬀerent substituted N-heterocycles. SnAP Reagents: Conversion of Aldehydes into Satu- rated N-Heterocycles. (SnAP = Tin (Sn) Amine Protocol). In 2013, our group introduced SnAP reagents for the conversion of aldehydes into N-unprotected 3-thiomorpholines.49 The transformation involves an intramolecular C−C bond-forming radical addition of an imine bearing a pendant organostannane (Figure 15).

Figure 15. SnAP reagent concept. Figure 17. SnAP reagents for the synthesis of substituted morpholines Aminotributylstannane 8 (SnAP TM) was condensed with and piperazines and selected examples prepared. aldehyde to aﬀord the corresponding imine, which was cyclized with a stoichiometric amount of Cu(OTf)2 to provide N-unprotected 3-thiomorpholine. The reaction accepted an outstanding scope reactions were not sensitive to the heteroatom type and of aldehydes including aryl, heteroaryl, and alkyl aldehydes retained similar reactivity toward a wide range of aldehydes (Figure 16). under a single reaction protocol. Air- and moisture-stable SnAP Preliminary mechanistic studies invoked a copper-mediated reagents were prepared on a multigram scale from inexpensive oxidation of the carbon−tin bond to generate the sulfur-stabilized starting materials.

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Ph.D. studies in the research group of Prof. Jeﬀrey W. Bode at the University of Pennsylvania in 2008 and moved to ETH−Zürich, Switzerland in 2010.

Prof. Jeffrey W. Bode studied at Trinity University in San Antonio, TX. Figure 18. SnAP reagents for the synthesis of medium ring Following doctoral studies at the California Institute of Technology and − ̈ N-heterocycles and selected examples prepared. ETH Zurich and postdoctoral research at the Tokyo Institute of Technology, he began his independent academic career at UC−Santa Barbara in 2003. He moved to the University of Pennsylvania as an ■ CONCLUSION − ̈ Associate Professor in 2007 and to ETH Zurich, Switzerland, as a full The recent shift of interest toward saturated N-heterocycles and Professor in 2010. Since 2013, he is also a Principal Investigator and their poor commercial availability raise the need for synthetic Visiting Professor at the Institute of Transformative Biomolecules methods that could offer generality and proceed from readily (WPI-ITbM) at Nagoya University. available building blocks. Despite extensive efforts, few methods provide facile access to a variety of substituted saturated ACKNOWLEDGMENTS N-heterocycles. Most still require a nitrogen protecting group, ■ which are often difficult to remove. Lithiation and trans- This research topic was supported by an ETH Research Grant metalation, followed by metal-catalyzed coupling reactions, are (ETH-12 11-1) and the European Research Council (ERC the most effective approaches but are laborious and restricted to Starting Grant No. 306793 − CASAA). the preparation of α-functionalized pyrrolidines and piperidines. For the synthesis of other classes of saturated N-heterocycles ■ REFERENCES with additional heteroatoms or different ring sizes, several approaches have been recently reported, focusing on simplicity (1) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; ff Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062. and generality to obtain di erently substituent patterns of (2) Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, N-heterocycles. 2nd ed.; Wiley−VCH Verlag: Weinheim, 2004. (3) Ritchie, T. J.; Macdonald, S. J. F. Drug Discovery Today 2009, 14, ■ AUTHOR INFORMATION 1011. Corresponding Author (4) (a) Ritchie, T. J.; Macdonald, S. J. F.; Young, R. J.; Pickett, S. D. *E-mail: [email protected]. Drug Discovery Today 2011, 16, 164. (b) Lovering, F.; Bikker, J.; Notes Humblet, C. J. Med. Chem. 2009, 52, 6752. (c) Leeson, P. D.; St-Gallay, The authors declare no competing financial interest. S. A.; Wenlock, M. C. MedChemComm 2011, 2, 91. (d) Feher, M.; Schmidt, J. M. J. Chem. Inf. Comput. Sci. 2002, 43, 218. Biographies (5) Reviews on cross-coupling reactions of aromatic N-heterocycles: (a) Maes, B. W. In Microwave-Assisted Synthesis of Heterocycles; Eycken, E., Kappe, C. O., Eds.; Springer : Berlin, Heidelberg, 2006; Vol. 1, p 155. (b) Slagt, V. F.; de Vries, A. H. M.; de Vries, J. G.; Kellogg, R. M. Org. Process Res. Dev. 2009, 14, 30. (c) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417. (d) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (6) General references on saturated N-heretocycle synthesis: (a) Eicher, T.; Hauptmann, S.; Speicher, A. Chemistry of Heterocycles: Structure, Reactions, Synthesis, and Applications; Wiley: Somerset, NJ, 2013. (b) Wolfe, J. P. Synthesis of Heterocycles via Metal-Catalyzed Reactions That Generate One or More Carbon−Heteroatom Bonds; Springer: Berlin, Heidelberg, 2013. (c) Royer, J., Ed. Asymmetric Synthesis of Nitrogen Heterocycles; Wiley-VCH Verlag: Weinheim, 2009. (d) Huang, Y.; Khoury, K.; Dömling, A. In Synthesis of Heterocycles via Multicomponent Reactions I; Orru, R. V. A., Ruijter, E., Eds.; Springer: Berlin, Heidelberg, 2010; Vol. 23, p 85. (e) Schnurch, M.; Cam-Van T. Vo completed her undergraduate studies at the University Dastbaravardeh, N.; Ghobrial, M.; Mrozek, B.; D. Mihovilovic, M. of Medicine and Pharmacy, Ho Chi Minh city, Vietnam. She started her Curr. Org. Chem. 2011, 15, 2694.

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Mitigating Heterocycle Metabolism in Drug Discovery David J. St. Jean, Jr., and Christopher Fotsch* Department of Therapeutic Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States ■ INTRODUCTION and nowhere else on the molecule. This allowed us to eliminate In the past few decades, drug metabolism research has played examples where a change made to a compound away from the − fl an ever increasing role in the design of drugs.1 3 In vitro heterocycle may have in uenced the metabolism. metabolism assays4 have become an integral part of the routine The data that we included in this review is predominantly profiling of compounds made in drug discovery.5 The data from from in vitro microsomal stability studies. However, we have these assays have allowed medicinal chemists to focus their included some data from bioactivation studies and in vivo PK efforts on compounds with improved metabolic stability.6 studies to provide additional information about the overall fi metabolic profile. In several instances, the compound with the Detailed metabolite identi cation studies are also done more fi routinely, which provide information on how to strategically improved metabolic pro le also became the lead compound in replace or block metabolically labile sites.7 Additionally, in vivo the paper, so we felt that including the data on the intended PK studies are regularly conducted in drug discovery, which target was informative even though this is not a discussion − 4 point for the review. Of course, in some examples when the helps to build in vitro in vivo PK relationships. The positive fi influence that these advances in PKDM sciences have had on heterocycle was modi ed to improve metabolic stability, the drug discovery is reflected in the fact that fewer drug candidates activity at the intended biological target diminished. However, fail in the clinic for PKDM related issues.8 This suggests that we felt that these examples of improved metabolic stability would still be of value to the reader. In the discussion below, we medicinal chemists are successfully integrating the data fi generated by their PKDM colleagues into the design of have organized the review by rst discussing saturated compounds with fewer metabolic liabilities. heterocycles and then heteroaromatic compounds. Within Extensive data from metabolism studies have allowed each section we have organized the discussion by ring size. medicinal chemists to develop general principles for reducing ■ SATURATED HETEROCYCLES compound metabolism. These methods include, but are not Saturated heterocycles are most prone to metabolism at the limited to, reducing lipophilicity, altering sterics and electronics, 16,23 introducing a conformational constraint, and altering the position adjacent to or directly on the heteroatom. stereochemistry of their compounds. While no single method Therefore, strategies used to reduce metabolism of these is able to solve every metabolic problem, these principles do rings involve techniques to block the site of metabolism, change give medicinal chemists guidance on how to improve the the electronics of the ring, or reduce the hydrophobicity of the fi ring. Since lipophilicity and charge influence metabolism, we metabolic liabilities of their compounds. If the speci c site of 24 25,26 metabolism is known, medicinal chemists block the site, have tabulated the cLogP, cLogD7.4, and pKa for some of typically with a fluorine, or replace the metabolically labile the more common saturated heterocycles (Table 1). group with a bioisostere.9 While several authors have reviewed Saturated Four-Membered Rings. Of the saturated these techniques for reducing metabolism,5,10,11 there is no heterocycles containing one heteroatom, azetidine and oxetane review that summarizes different approaches to improving the are among the least lipophilic, so one would expect these rings metabolic stability of heterocycles. In this review, we summarize to be least likely to undergo metabolism when compared to examples where changes were made at or near the heterocycle their larger ring counterparts. In fact, in some of the examples to improve metabolic stability. By summarizing these examples, show below, the azetidine and oxetane ring analogues were we hope to provide a useful guide to medicinal chemists as they more metabolically stable than analogues containing a larger attempt to improve the metabolic profile of their own ring (see Figures 5, 8, 12, and 14). However, there are some heterocyclic compounds. reports where the four-membered saturated heterocycle was fi The majority of the examples that are included in this review modi ed to improve metabolic stability. For example, in their came from searching the online open access database work on histamine receptor 3 (H3R) inverse agonists for the CHEMBL.12 In addition to having pharmacology data on treatment of obesity, Pierson et al. found that the derivative compounds from the medicinal chemistry literature, CHEMBL containing the oxetane 1 was less metabolically stable in rat liver microsomes (RLM) than the cyclobutyl analogue (2) (see has over 120 000 points of data on the ADMET properties of 27 compounds. With the help of the visualization software Figure 1). While the oxetane analogue 1 was less lipophilic Spotfire, we were able to cull examples from the CHEMBL than cyclobutyl analogue 2, the pKa of the adjacent piperidine ADMET data that focused on heterocycles. We also identified ring was >9 for analogue 2, while the oxetane analogue 1 had a ff examples from papers that cite leading reviews in the drug pKa = 6.4. This pKa di erence may explain why the cyclobutyl − metabolism field13 18 and were present in other recent reviews analogue 2 is more stable, since at physiological pH, this − on drug metabolism.19 22 The main criteria that we placed on the examples selected for this review was that the change made Received: March 12, 2012 to improve metabolism had to occur at or near the heterocycle Published: April 25, 2012

Table 1. cLogP, cLogD , and pK Values for More Another example where the oxetane was removed to improve 7.4 da Common Saturated Heterocycles the metabolic stability of the compound was found in the aldosterone synthase inhibitors from Adams et al. (see Figure 28 2). Analogue 3 had IC50 < 10 nM, but the isobutyl group was

Figure 2. In vitro potency and PK properties of selected aldosterone synthase inhibitors.28

heavily metabolized. To mitigate this metabolism, the isobutyl group was replaced with a substituted oxetane (4), a compound with a more than 10-fold increase in metabolic stability. However, the metabolic stability was improved even further by replacing the oxetane ring with a tert-hydroxyl group (5). The decrease in cLogD7.4 correlates with the improvement in metabolic stability for these three analogues. Saturated Five-Membered Rings. In their factor Xa (FXa) program, Zbinden et al. added either a ﬂuorine or hydroxyl group to a pyrrolidine ring in an attempt to improve metabolism (Figure 3).29 The RLM clearance of pyrrolidine

a b c d ⇆ + See ref 24. See ref 25. See ref 26. pKa refers to the Het HetH equilibrium.

compound would be fully protonated and more polar than the Figure 3. In vitro potency and PK properties of selected FXa oxetane analogue. inhibitors.29

analogue 6 was only slightly improved by adding a ﬂuorine to the ring (analogue 7). However, when a hydroxyl group was added (8), the metabolic stability in RLM signiﬁcantly improved probably because this compound was more polar than the other two. Unfortunately, analogue 8 had high rat in vivo clearance. After additional in vivo PK studies, Zbinden et al. found that 50% of 8 was cleared by the kidney unchanged. Dragovich et al. also provided an example where replacing a pyrrolidine with a more polar ring improved metabolism. In their work on hepatitis C virus (HCV) NS5B inhibitors (Figure 30 Figure 1. In vitro potency and PK properties of selected H3R inverse 4) pyrrolidine analogue 9, while potent against the intended antagonists. The log D7.4 and pKa values were experimentally target, had a short half-life of 10 min in human liver determined by Pierson et al.27 microsomes (HLM). Replacement of the pyrrolidine with the

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Interestingly, the most stable piperidine analogue 17 had a higher cLogD7.4 than 14, suggesting that clearance was not driven entirely by the lipophilicity of the compound. Saturated Six-Membered Ring Heterocycles. To improve the metabolism of their piperidine analogues, Wan et al. employed a strategy of substituting the piperidine with a fluorine or adding polar groups to the ring (Figure 7).33 In their 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) program, they found that their compound containing the unsubstituted piperidine, 18, had a t1/2 of 6 min in mouse liver microsomes (MLM). The analogues with polar groups added to the ring were all more stable in MLM, with 4-fluoro Figure 4. In vitro potency and in vitro PKDM profile for selected analogue (20), thiomorpholine 1,1-dioxide (22), 4-carboxyl HCV NS5B polymerase inhibitors.30 (23) having MLM t1/2 > 30 min. Analogues 22 and 23 are the fi least lipophilic of this set of compounds, which may explain morpholine ring (10) lowered the cLogD7.4 and signi cantly why they have better metabolic stability than analogues 18, 19, improved the metabolic stability. and 21. The improved metabolic stability of the 4- Other groups have demonstrated that changing the ring size fluoropiperidine analogue 20 suggests that the fluorine atom of the pyrrolidine can reduce metabolism. For example, in their may have blocked a site of metabolism that was present on serotonin receptor subtype 2C (5-HT2C) agonist program, Fish parent compound 18. Carboxyl analogue 23 was also efficacious et al. changed the pyrrolidine in one of their analogues to a β 31 in an in vivo PD model that measured 11 -HSD1 inhibition in piperidine and an azetidine (Figure 5). The piperidine epididymal fat (40% inhibition at 10 mg/kg, po). In their anticancer program on aurora kinase inhibitors, Kerekes and co-workers improved the PK profile of their analogues containing piperidine by adding fluorine atoms and altering the ring size (Figure 8).34 One of their more advanced compounds in the paper contained a 4-fluoropiperidine (24), which had a rat oral AUC of 2.2 μM·h. To further improve the PK, the 4,4-difluoro analogue (25) was prepared, but it had a lower rat oral AUC. The five- and four-membered ring difluoro analogues 26 and 27, respectively, had higher oral AUC than the six-membered ring analogue 25. The four-membered ring analogue 27 had the highest oral AUC, but Kerekes et al. Figure 5. In vitro potency and in vitro PKDM profile for selected 5- discovered that the azetidine ring was prone to nucleophilic HT2C agonists. The log D7.4 values were experimental determined by fi Fish et al.31 ring-opening. Turning to the ve-membered ring analogue 26, Kerekes et al. discovered that a major route of metabolism in human and monkey hepatocytes was oxidation of the benzylic analogue 12 showed a slight improvement in HLM stability position adjacent to the isothiazole ring. To circumvent this over the pyrrolidine 11, while the azetidine analogue 13 was the problem, they deuterated the benzylic position of the 3,3- most stable. The position of the chloride on the phenyl ring difluoropyrrolidine, which led to a compound (28) that had was also modified on azetidine analogue 13 so that change may fl superior rat iv clearance, oral AUC, and bioavailability. This have also in uenced the metabolic stability. compound was advanced into a mouse tumor xenograft PD Pescatore et al. also prepared six-membered ring analogues of assay, where it reduced the phosphorylation of histone H3 their pyrrolidine containing compound to improve metabolism (HH3) in the tumor by ∼80% after being dosed orally at 100 (Figure 6).32 In their anticancer program on histone mg/kg. The addition of deuterium atoms to mitigate deacetylase 1 (HDAC1) inhibitors, the analogue that contained metabolism takes advantage of the kinetic isotope effect, a pyrrolidine ring, 14, had a RLM intrinsic clearance (CLint)of − −1 −1 which increase the energy required to fragment the carbon >500 μL min mg . By replacing this group with various 35 deuterium bond. This approach of incorporating deuterium piperidine analogues, they identified a compound with a greater to improve metabolism has gained renewed interest among than 7-fold improvement in RLM stability (see compound 17). medicinal chemists in the past few years.36 Another example where fluorine atoms were added to the piperidine ring was reported by Gleave et al. (Figure 9).37 In their cannabinoid receptor 2 (CB2) agonist program, they had tested the metabolic stability in RLM for a piperidine containing analogue (29) and its 4,4-difluoro derivative (30). There was very little improvement in the RLM metabolic stability for the 4,4-difluoro analogue. However, when the piperidine ring was replaced with the more polar morpholine ring (31), the metabolic stability improved by 10-fold in RLM. This trend in improved metabolic stability followed the reduction in cLogD7.4. Figure 6. In vitro potency and RLM data for selected HDAC1 Peglion and co-workers were able to improve the metabolic inhibitors.32 stability of their analogue containing a piperidine by adding a

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Figure 7. In vitro potency and PK properties of selected 11β-HSD1 inhibitors. PK experiments were conducted with C57B6 mice at 2 mg/kg (iv) and at 10 mg/kg (for 23) or 30 mg/kg (for 19) (po).33

34 ≤ ≤ Figure 8. Rat PK of selected aurora kinase inhibitors. All compounds had IC50 at Aurora A and Aurora B of 4 and 13 nM, respectively. The po AUC was determined in SD rats from 0−6 h after a 10 mg/kg oral dose. The iv PK was run at 10 mg/kg and % F determined from 30 mg/kg po.

Figure 10. In vitro potency and metabolic stability for selected 5-HT1A Figure 9. In vitro potency and metabolic stability of selected CB2 38 agonists.37 receptor agonists. The metabolic bioavailability prediction (MF%) was determined from the stability of test compound (concentration of 0.1 μM) in human liver microsomes where MF% = 100% is equal to 38 no metabolism. nitrogen (Figure 10). In their 5-HT1A agonist program for the treatment of anxiety and depression, the 1,2,3,6-tetrahydropyr- idine analogue (32) and the piperidine analogue (33) both had poor metabolic stability (MF% of 8 and 7, respectively). The piperidine analogues reported by Qiao et al. from their However, the corresponding piperazine (34) was nearly 10-fold erythropoietin-producing hepatocellular carcinoma receptor more metabolically stable than the piperidine analogue. The type B3 (EphB3) inhibitor program illustrate how the position ff ff 39 di erence in cLogD7.4 of compounds 33 and 34 is small, so the of the nitrogen atom can a ect metabolism (Figure 11). Their improved metabolic stability observed with compound 34 1-substituted piperidine analogue 35 was significantly less stable cannot be explained by a reduction in lipophilicity. Perhaps the in MLM than the analogue with the 4-substituted piperidine C-4 position of the piperidine in compound 33 is a site for (36). This change in the position of the nitrogen lowered the metabolism, which would be blocked by the piperazine cLogD7.4 and produced an analogue with a more basic nitrogen, nitrogen in analogue 34. This piperazine analogue was active which may have contributed to the improvement in metabolic in a rodent ultrasonic vocalization test, which is an animal stability. This compound, named LDN-21190439 (36), was one model for anxiety. of their lead compounds for their EphB3 inhibitor program.

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Figure 13. In vitro potency and metabolic stability of selected CB2 41 Figure 11. In vitro potency and metabolic stability of selected EphB3 agonists. 39 inhibitors. Half-life and CLint were determined in MLM.

An example where a piperazine ring was modiﬁed to improve metabolism was found in the report from Cramp et al. on their H4R antagonists (Figure 12).40 N-Methylpiperazine analogue

Figure 14. In vitro potency and metabolic stability of selected γ- 42 secretase inhibitors. The log D7.4 was determined experimentally by Stepan et al. using the method of Lombardo et al.43

increased metabolic stability was most likely a result of the Figure 12. In vitro potency and RLM stability for selected human reduction in log D7.4. However, they also suggest that the H4R inverse agonists. The percent remaining in RLM was measured − after a 10 min incubation.40 reduced C H bond reactivity of the oxetane ring compared to the THP and THF rings may have also contributed to the 37 was found to undergo rapid N-dealkylation in RLM, so a improved metabolic stability. The position of the oxygen atom in the ring can also affect number of analogues were prepared to circumvent this − problem. The bridged piperazine analogue 38 had a similar the metabolism of a THP ring. In their work on C C fi chemokine receptor type 5 (CCR5) receptor antagonists cLogD7.4, but the RLM was signi cantly improved, suggesting that the increase in sterics surrounding the site of metabolism containing THP rings (Figure 15), Rotstein et al. found that may have been responsible for the lower turnover. Another bridged piperazine analogue (39) had similar stability to 38, but the analogue containing the 5,6-ring (40) was completely eliminated by RLM. Interestingly, the analogues containing the exocyclic aminomethyl group, pyrrolidine 41 and azetidine 42, were the most metabolically stable in this set. The large reduction in cLogD7.4 may explain why these two analogues were more stable than the other compounds in this series. Turning to examples with a THP ring, Omura and co- workers were able to improve the metabolic stability of their CB2 agonist by adding a hydroxyl group to the 4-position of 41 Figure 15. In vitro potency and metabolic stability of selected CCR5 the THP ring (Figure 13). The hydroxylated THP analogue 44 44 was nearly 6-fold more metabolically stable in HLM than receptor antagonists. the unsubstituted THP analogue 43. While 44 was less potent than the parent THP analogue, the principle of having a tertiary alcohol at that position to improve metabolic stability was the 4-substituted-THP analogue was 4-fold more stable in applied to the lead compound in their paper (45), which had an HLM than the 2-substituted-THP derivative (cf., 49 vs 50).44 HLM t1/2 of >120 min and was nearly as potent as 43. These two regiochemical isomers share nearly identical Another example with THP rings was illustrated in the γ- properties except for the position of the oxygen in the THP secretase inhibitor program from Stepan et al. (Figure 14).42 In ring, so the metabolic differences cannot be explained by large this paper they showed that decreasing the ring size of the THP difference in physical properties. The 4-THP analogue 50 was in their inhibitors improved the metabolic stability. Stability in advanced into rat, dog, and monkey PK and also had IC50 = HLM improved going from the THP (46) to THF (47) to the 0.18 nM in a PBMC (peripheral blood mononuclear cell) viral oxetane analogue (48). The authors point out that the replication assay.

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Saturated Seven-Membered Ring Heterocycles. Seven- membered ring heterocycles are generally more lipophilic than their smaller ring counterparts, so methods for improving the metabolic stability of these rings typically involve reducing the ring size. For example, in the H3R inverse agonists work from Pierson et al., they found that their analogue containing an azepane ring (51) had a RLM clearance (CL) of 55 μL min−1 mg−1 (Figure 16).27,45 Replacing the ring with diﬂuoropiper-

Figure 18. In vitro potency and metabolic proﬁle for selected 5- 47 HT1A,B,D receptor ligands. Rat in vivo PK was determined after 1 mg/kg dosing iv.

similar stability in RLM, 61 had lower in vivo rat clearance. In this set of compounds there is no correlation of cLogD7.4 with metabolic stability, suggesting the ring size had more of an inﬂuence on metabolism. In their work on FXa inhibitors for the treatment of Figure 16. In vitro potency and PK properties of selected H3R inverse thrombotic disease, Fujimoto et al. had an analogue that agonists. In vivo PK experiments were run with Wistar rats at 1 mL/kg contained the seven-membered ring caprolactam (62) (Figure (iv) and 4 mL/kg (po). The log D7.4 values were experimentally 48 determined by Pierson et al.27,45 19). The metabolic stability was progressively improved by idine rings (52, 54) or morpholine (53) produced analogues with improved metabolic stability. In this case, a combination of reducing ring size and adding ﬂuorine atoms or polarity was used to reduce the metabolism. Zhang and co-workers gave an example of improving the metabolic stability of a seven-membered 1,4-oxazepane ring (Figure 17). In their adenosine type 2A (A2A) receptor

Figure 19. In vitro potency and metabolic stability for selected FXa inhibitors. The percent eliminated data were determined after 20 min incubations with NADPH and LM. The log D7.4 data were determined experimentally by Fujimoto et al.48 (MoLM = monkey liver microsomes).

replacing this ring with the six- and five-membered ring lactams (63 and 64). The six-membered ring cyclic urea analogue 65 had the best metabolic stability of this set and was advanced into the clinic as TAK-422.48 The reduction in metabolism Figure 17. In vitro potency and metabolic stability for selected human follows the trend of reduced lipophilicity for this set of 46 A2A receptor antagonists. compounds as noted by the reduction in cLogD7.4. In their anticancer program, Tsou et al. prepared a mammalian target of rapamycin (mTOR) inhibitor containing antagonist program for Parkinson’s disease, they found that an aza-bicyclo seven-membered ring (66) (Figure 20).49 This reducing the ring size of the 1,4-oxazepane in analogue 55 with compound was rapidly metabolized by both phase I and phase either a morpholine (56)oranN-methylpiperazine ring (57) II metabolism in MLM. However, reducing the ring size of the greatly improved metabolic stability.46 seven-membered ring with either a morpholine or N- Ward et al. showed how the metabolic stability of a 1,4- methylpiperazine ring led to analogues (67 and 68) with diazepane was improved by reducing the ring size (Figure greatly improved metabolic stability. Since in vivo studies for 47 18). In their 5-HT1 receptor ligand program, the metabolism mTOR inhibitors typically involve the use of nude mice, the of the analogue containing the 1,4-diazepane (58) was greatly MLM studies were conducted with microsomes from this improved by replacing the ring with piperidine rings (59, 61) strain, although a recent report from Martignoni et al.50 showed or a piperazine ring (60). While the N-methylpiperazine that there are no significant metabolic differences between derivative (60) and N-methylpiperidine derivative (61) had MLM from normal (CD-1) mice and nude mice.

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with the saturated heterocycles, we have tabulated some of the calculated and measured physical properties for some of the more common ﬁve-membered ring heterocycles (Table 2). In

Table 2. cLogP, cLogD ,pK , and Ionization Potentials for 7.4 a c Some Common Five-Membered Ring Heteroaromatics

Figure 20. In vitro potency and metabolic stability for selected mTOR inhibitors. MLM studies were conducted with MLM from nude mice. Phase I metabolism studies were conducted with NADPH, while phase I/II studies were conducted with both NADPH and uridine 5′- diphosphoglucuronic acid (UDPGA).49

Mastalerz et al., in their work on human epidermal growth factor receptor 2/epidermal growth factor receptor (HER2/ EGFR) dual inhibitors for the treatment of cancer, tried to improve the metabolic stability of their analogue containing a 1,4-diazepane (69) by adding polar groups to the ring (Figure 21).51 However, adding a hydroxyl or carbonyl to the 1,4-

Figure 21. In vitro potency and metabolic stability of selected dual EGFR/HER2 inhibitors.51

a b c ⇆ + diazepane (70 and 71) ring gave analogues that were both See ref 24. See ref 25. pKa refers to the Het HetH equilibrium. ⇆ metabolically less stable than the parent analogue 69. For the triazoles and tetrazole, the second pKa refers to the HetH Ultimately, the analogue with the best microsomal stability Het− equilibrium. was the six-membered piperazine analogue 72. Here again, reducing the ring size improved metabolic stability. addition to cLogP, cLogD7.4, and pKa, we have included the ionization potential (IP) as a measure of the electron-rich ■ HETEROAROMATIC COMPOUNDS nature of the ring. As elegantly summarized in the review by Five-Membered Heteroarenes. Five-membered hetero- Dalvie et al.,13 all of these properties can influence the arenes are commonly used in medicinal chemistry programs metabolic stability of five-membered heteroarenes. and are used as bioisosteres for carboxamides, esters, and Geng et al. in their work on glutamate racemase (MurI) carboxylic acids.9 However, because of the electron-rich nature inhibitors for H. pylori found that adding nitrogen atoms to the of the ring, they are prone to undergo oxidative metabolism, electron-rich thiophene and furan rings significantly improved which leads to electrophilic species.13 The inherent electro- metabolic stability (Figure 22).52 The high intrinsic clearance in philicity of these metabolites is thought to be in part both HLM and MLM of their thiophene analogue 73 was responsible for the idiosyncratic toxicity of some drugs mitigated by replacing the ring with either a thiazole (74)or containing five-membered heteroarenes.18,19 That being said, isothiazole (75), and the metabolic stability was improved medicinal chemists have identified methods for reducing the when the furan on analogue 76 was replaced with an oxazole metabolism of these rings by adding another nitrogen to the (77). The more metabolic stable analogues were all more polar ring, blocking a potential site of metabolism with a fluorine, or than the analogue 73. replacing the ring with another heterocycle. Examples of each In their CB2 agonist program, Riether et al. improved the of these methods as well as others are summarized below. As metabolic stability of their compound that contained a thiazole

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In their antithrombocytopenia program, Kalgutkar et al. found that their thrombopoietin (Tpo) receptor agonist containing a thiazole (81) underwent amide hydrolysis to form an intermediate (84), which was prone to bioactivation and attack of nucleophiles at the C-5 position (Figure 24).54 However, incorporation of a fluorine (82) or nitrogen (83)at the C-5 position of the thiazole prevented the bioactivation pathway from occurring. The rat in vivo PK for these two new analogues was also better than the parent compound. Interestingly, the cLogD7.4 of the two new compounds was higher than the parent compound. Nevertheless, the strategic Figure 22. In vitro potency, HLM, and MLM data for selected MurI blocking of the site of bioactivation mitigated the formation of inhibitors.52 the reactive intermediates. In a recent report from Obach et al., they found that the 53 metabolic profile of a thiazole ring dramatically changed when ring (analogue 78, Figure 23), by replacing it with isoxazole 55 rings (analogues 79 and 80). A decrease in lipophilicity cannot the ring was substituted with a methyl group (Figure 25). The cyclooxygenase (COX-1/2) inhibitors sudoxicam (86) and meloxicam (87) have the same structure except that meloxicam has a methyl group at the C-5 position of the thiazole ring. P450 mediated oxidation of sudoxicam occurred to form a reactive epoxide 88, which after hydrolysis produced the protoxin acylthiourea 89. In contrast, the major route of metabolism for meloxicam involved oxidation of the methyl group to give metabolites 90 and 91, which did not form reactive species. The protoxin acylthiourea 89, formed during the metabolism of sudoxicam, may in part be responsible for the hepatotoxicity observed with sudoxicam.56 Meloxicam, on the other hand, is not metabolized to a protoxin and has not been associated with hepatotoxicity.57,58 As pointed out in the previous example, the C-5 position is a “soft spot” for bioactivation of the thiazole ring, so the methyl group on meloxicam serves the purpose of blocking this site as well as 53 Figure 23. In vitro potency and HLM data for select CB2 agonists. providing an alternative site for metabolism. μ All compounds displayed weak activity against CB1 (EC50 >20 M). In the work by Ioannidis and co-workers on Janus kinase 2 Rat in vivo PK experiments were performed using Wistar rats at 1 (JAK2) inhibitors, they showed that the metabolic stability was μmol/kg (iv) and 10 μmol/kg (po). better for their analogue containing a pyrazole (93) rather than a thiazole ring (92) (Figure 26).59 While the difference in cLogD7.4 between these two rings cannot explain the explain why isoxazole analogues 79 and 80 were more improvement in metabolism, pyrazole rings are known to be metabolically stable than thiazole analogue 78, since the relatively stable to metabolism compared to other five- 13 cLogD7.4 is higher for analogues 79 and 80. If metabolism membered ring heteroaromatic compounds. occurs on the five-membered heteroarene, the improved Another example where the pyrazole ring was employed to metabolic stability of 79 and 80 might be explained by the improve metabolic stability was illustrated in the work from fact that the isoxazole ring is less electron-rich than the thiazole Tremblay et al. in their Hedgehog (Hh) pathway antagonists ring, as noted by the higher ionization potential for isoxazole. for the treatment of cancer (Figure 27).60 Compound 94 was

Figure 24. In vivo PK data for selected Tpo receptor antagonists. NuH is protein nucleophile or glutathione (GSH). In vivo PK was measured in male SD rats (1 mg/kg iv, 5 mg/kg po).54

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Figure 25. Metabolism of sudoxicam and meloxicam.55

Another example of a compound containing a pyrazole was found in the work on glycine transporter 1 (GlyT1) inhibitors from Thomson and co-workers (Figure 28).63 The pyrazole

Figure 28. In vitro potency and LM data for selected GlyT1 receptor 63 Figure 26. In vitro potency and RLM stability for selected JAK2 antagonists (%TO = percent turnover). inhibitors.59 ring analogue 98 was replaced with a 1,2,3-triazole ring (99), which had little eﬀect on improving dog liver microsomes (DLM) and HLM stability, but it had improved RLM stability. The improved RLM stability might be explained by the lower lipophilicity of analogue 99. Nietz and co-workers, in their work on c-Jun N-terminal kinase 3 (JNK3) inhibitors, also compared the microsomal stability of analogues containing a pyrazole with various triazoles (Figure 29).64 The pyrazole analogue 100 had poor

Figure 27. In vitro potency and HLM data for selected orally active Hh pathway antagonists. In vivo PK experiments were conducted with SD rats (iv dose of 1 mg/kg, po dose of 5 mg/kg).60 one of the initial leads in their program, but in monkey PK α β Figure 29. In vitro potency, MLM, and glucuronidation data for select studies, the , -unsaturated ketone present in 94 underwent JNK inhibitors.64 metabolism to give the corresponding saturated alcohol. Part of the strategy to circumvent this problem was to reduce the double bond and replace the ketone with five-membered metabolic stability in MLM. Replacing the pyrazole central core heteroarenes. The pyrazole containing analogue 97 showed a with a triazole had differing effects on metabolism, depending dramatic improvement in metabolic stability (HLM t1/2 = 120 on which regioisomer of the triazole ring was used. Two min), but the isoxazole analogue 95 and 1,2,5-oxadiazole analogues containing the 1,2,3-triazole (101, 102) showed an analogue 96 were less metabolically stable. A decrease in improvement in MLM stability, but the 1,2,4-triazole analogue lipophilicity cannot explain the improvement in metabolic 103 was the most metabolically stable. Why the 1,2,4-triazole stability, since the most metabolically stable compound 97 had analogue 103 was more stable than 1,2,3-triazole analogues is ffi ff the highest cLogD7.4. If metabolism occurred on the isoxazole di cult to explain, especially since there was little di erence in ring of analogue 95, the decrease in metabolic stability might be the lipophilicity between analogues 100 and 103. Since some explained by the potential for this ring to undergo metabolically triazoles are CYP P450 inhibitors,13 the improved metabolic mediated ring cleavage, which is precedented in the literature.61 stability of 101−103 might be explained by their ability to The poor metabolic stability of analogue 96 is less easily inhibit these metabolizing enzymes. Unfortunately, CYP P450 explained, since little has been reported on the metabolism of inhibition data were not disclosed for this set of compounds. 1,2,5-oxadiazole rings.62 Triazole containing compounds are also known to undergo

6010 dx.doi.org/10.1021/jm300343m | J. Med. Chem. 2012, 55, 6002−6020 Journal of Medicinal Chemistry Perspective elimination through glucuronidation,13 but analogues 101 and to replace it with a six-membered heteroaromatic ring, which 102 were both relatively stable in a glucuronidation assay. tends to be more electron poor than a five-membered Another example where the position of three heteroatoms in heteroarene. Eastwood et al. illustrated this method in their fi ff the ring had a signi cant e ect on metabolism was reported by A2B receptor antagonists program where they replaced a furan Barber et al. on the CCR5 program for HIV (Figure 30).65 ring for a pyridine ring (Figure 32).69 The metabolic stability of

Figure 32. In vitro potency and microsomal stability for selected A2B receptor antagonists.69 Figure 30. In vitro potency and HLM data for selected CCR5 antagonists. The log D7.4 values were experimentally determined by Barber et al.65 the furan analogue 111 was improved in RLM when the ring was replaced with a pyridine to give analogue 112. While the Their analogue with the 1,2,4-oxadiazole 104 was less improvement in metabolic stability was modest, it eliminated metabolically stable than the 1,3,4-oxadiazole analogue 105 in the potential for bioactivation that might have occurred with HLM. Compound 105 is more polar than analogue 104, which the furan. may explain the improvement in metabolic stability. Also, if the Six-Membered Heteroarenes. Six-membered heteroaryl five-membered ring on compound 104 is the site of groups are often used to replace aryl groups to improve the metabolism, the 1,2,4-oxadiazole ring may undergo metabolic physical properties and metabolic stability of a drug.9,21 N−O ring-opening, which is precedented in the literature.13,66 However, six-membered heteroaryl groups may also be Without an N−O bond, the 1,3,4-oxadiazole ring on 105 would metabolized at either the carbon or heteroatom. Strategies for not undergo this route of metabolism.67 improving the metabolic stability of these rings often involve In their work on dipeptidyl peptidase IV (DPP-4) inhibitors substituting or replacing the site of metabolism on the ring. for the treatment of type 2 diabetes, Nordhoff et al. determined Also, adding an additional nitrogen to the ring can serve to fi the metabolic stability of a number of three-heteroatom ve- replace the site of metabolism, lower the LogD7.4, and decrease membered heterocycles (Figure 31).68 The orientations of the the basicity of the ring. Table 3 summarizes some of the physical properties for common six-membered ring heteroarenes. Six-Membered Heteroarenes. One Nitrogen. In their anticancer program on FMS-like receptor tyrosine kinase 3 (FLT3) inhibitors, Ishida showed how the metabolism of an analogue containing a pyridine was improved by blocking the site of metabolism or adding a nitrogen to the ring (Figure 33).70 Metabolism studies on a related analogue suggested that

Table 3. cLogP, cLogD , and pK for Some Common Six- 7.4 ca Membered Ring Heteroaromatics Figure 31. In vitro potency and LM data for selected DPP-4 inhibitors.68 heteroatoms within these rings were important factors for metabolic stability. The lower lipophilicity of the 1,3,4- oxadiazole analogue 108 might explain why it was more metabolically stable than the 1,2,4-oxadiazole analogues 106 and 107. Also, as pointed out in the previous example,65 if the five-membered heteroarene is the site of metabolism, the 1,2,4- oxadiazole analogues might be susceptible to metabolic ring- opening. The improvement in metabolic stability of the 1,2,4- triazole analogue 110 over the 1,2,3-triazole analogue 109 might in part be explained by the slight decrease in lipophilicity of analogue 110. All of the previous examples involved replacing one five- membered heteroarene for another. However, another strategy fi a b c ⇆ + for reducing the metabolism of a ve-membered heteroarene is See ref 24. See ref 25. pKa refers to the Het HetH equilibrium.

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Figure 33. In vitro potency and metabolic stability of selected FLT3 inhibitors70 (MOLM-13 cells are from the human acute myeloid leukemia cell line). the 2-position of the pyridine ring on analogue 113 was a major Figure 35. In vitro potency and metabolic stability of selected MMP- site of metabolism. To circumvent this problem, they blocked 13 inhibitors.72 %QH is the percent of hepatic clearance. the 2-position with a methyl group (114), but it showed no improvement in metabolic stability. However, the 2-pyridone serine/threonine protein kinase type 2 (ROCK2) inhibitors and pyridine N-oxide analogues 115 and 116, respectively, had reported by Morwick et al. their initial lead compound better metabolic stability than 113. In addition, the analogue contained a pyridine (127), but it had poor metabolic stability that contained a pyrimidine (117) had improved metabolic (Figure 36).73 Through SAR (structure−activity relationship) stability. Analogues 115−117 increased the polarity of the ring and decreased the electron density at the C-2 position as a means for improving metabolic stability. Bailey and co-workers employed the strategy of reducing the polarity of the pyridine ring to improve the metabolic stability of their acid pump antagonist (APA) 118 (Figure 34).71 The

Figure 36. In vitro potency and metabolic stability of selected ROCK2 inhibitors.73

studies, Morwick et al. found that the 4- and 3-piperidinyl analogues 128 and 129 had a significant increase in HLM stability compared to the parent pyridine analogue. The added polarity of the more basic piperidine rings may explain the improvement in metabolic stability. An example of how metabolite identification studies can be Figure 34. In vitro potency and metabolic stability for selected 71 used to design around metabolism issues on pyridines was APAs. illustrated by Ceccarelli and co-workers (Figure 37).74 Compound 130 was a lead in their metabotropic glutamate metabolic stability of 118 was improved by over 5-fold when receptor type 5 (mGlu5) antagonist program, but it was readily the pyridine was replaced with the more polar pyrimidinone metabolized by microsomes. Metabolite identification studies (119) or a pyridin-4-one (120) ring. Analogue 120 had the revealed that the oxidation products on the upper ring were the best overall profile with respect to potency and metabolic major metabolites (analogues 131 and 132), whereas stability, so it was advanced into a rat acid secretion model metabolism on the lower ring was minor. Ceccarelli et al. where it was efficacious at 1 mg/kg, po. prepared the two major metabolites and found that the added The report by Gao et al. on matrix metalloproteinase 13 polarity of the hydroxyl groups improved the metabolic stability (MMP-13) inhibitors for rheumatoid and osteoarthritis of these compounds, but the activity at mGlu5 suffered, so they provided another example where a pyrimidine analogue was focused on preparing analogues that were designed to block the more metabolically stable than its pyridine congener (Figure sites of metabolism. Analogue 133 had a nitrogen at the site 35).72 The pyrimidine analogue 125 was marginally more where metabolism was occurring on the upper ring of the metabolically stable than the corresponding pyridine analogue parent compound, which led to an improvement in RLM. 123. However, for the analogues where R1 = C(OH)Me2, the Compound 134 had the lower pyridine ring replaced with a metabolic stability of the pyrimidine analogue 126 was pyrimidine, which also led to an improvement in RLM. They significantly better than the pyridine analogue 124. The also removed the methyl group on the upper ring that was increased polarity that the pyrimidine ring provides may being metabolized and added a fluorine atom at another site of account for the improved metabolic stability of these analogues. metabolism. This led to compound 135, which was slightly less Another approach that has been used to improve the stable in RLM than parent compound 130. However, by metabolic stability of compounds containing pyridines is to replacing the lower pyridine ring on 135 for a pyrimidine ring, saturate the ring. In the Rho-associated coiled-coil containing they obtained analogue 136, which had virtually no RLM

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Figure 37. In vitro potency and metabolic stability of selected mGlu5 antagonists.74 Arrows indicate sites of oxidation observed on metabolites generated with HLM.

Figure 38. GPR119 agonists containing 5-substituted pyrimidines: propensity for GSH adduct formation.75,76 turnover and was orally active in their in vivo model for anxiety paper to be an important analogue for understanding the (MED = 3 mg/kg, po). conformational preferences of GPR119 agonism.76 Six-Membered Heteroarenes: Two Nitrogens. While Another example of how GSH conjugation was reduced on a the strategy of adding a nitrogen to a pyridine ring can be a six-membered heterocycle containing two nitrogens was useful for reducing metabolism, there are examples when the illustrated in a report on corticotropin-releasing factor-1 fi heterocycle with two nitrogens has to be modi ed to improve receptor (CRF1) antagonists containing a pyrazin-2(1H)-one metabolism. For example, in their anti-diabetes program on G- (Figure 39). Hartz et al. initially reported on lead compound protein-coupled receptor 119 (GPR119) agonists, Kalgutkar et 141, which was orally efficacious in a rodent model of anxiety al. observed that the pyrimidine compound 137 underwent but displayed high rat iv clearance.77 Metabolite identification metabolic activation and GSH conjugation to give two major studies indicated that the peripheral methoxy groups were the metabolites 138 and 139 (Figure 38).75 The authors proposed main sites of metabolism, and oxidation on the pyrazin-2(1H)- that the GSH adducts formed through a nucleophilic aromatic one was negligible. Further SAR studies on this series, directed substitution reaction onto the pyrimidine. The negatively at replacing or removing the metabolically labile methoxy charged Meisenheimer complex that forms in the proposed groups, led them to BMS-66505378 (142), a compound that mechanism would be stabilized by the 5-cyano group on the had a 10-fold improvement in rat iv clearance.79 Additional pyrimidine ring. Kalgutkar et al. reasoned that if they added a metabolite ID studies on 142 revealed that the pyrazin-2(1H)- group to the pyrimidine ring that destabilized the Meisen- one was susceptible to oxidation and GSH conjugation.78 The heimer complex, they should reduce the formation of GSH suggested intermediate that led to pyrazin-2(1H)-one metab- adducts. To that end, they prepared the 5-methylpyrimidine olism was the chloroepoxide 146, which after hydrolysis or derivative 140 that, upon incubation with HLM, GSH, and reaction with GSH led to the observed oxidized metabolites NADPH, did not form GSH adducts. Presumably, the 5-methyl 149 and 150 and GSH adducts 147 and 148. Metabolism was group destabilizes the buildup of charge on the pyrimidine that also observed on the arylamine portion of 142 but to a lesser would be necessary for the Meisenheimer complex to form. extent. Replacing the chloride on the pyrazin-2(1H)-one ring While the biological activity of the 5-cyano analogue was not with a bromide gave compound 143, which in metabolism disclosed, the 5-methylpyrimidine was reported in another studies with RLM showed slightly less oxidation and GSH

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77−79 Figure 39. CRF1 antagonists containing pyrazin-2(1H)-ones: propensity for ring oxidation and GSH adduct formation. A single bracket on the structure of the metabolites indicates that the regiochemistry has not been assigned. Arrows indicate sites of metabolism. conjugation. The 5-methyl analogue 144 showed a significant therapies for major depressive disorder, Bannwart et al. increase in GSH adduct formation on the pyrazin-2(1H)-one described the optimization of novel triple reuptake inhibitors ring over the 5-chloro analogue, while the 5-cyano analogue (TRI) that contained a benzothiophene (151, Figure 40).82 145 had negligible metabolism at the pyrazin-2(1H)-one ring. The trend in the amount of metabolism observed on the pyrazin-2(1H)-one ring can in part be explained by the inductive effects of the substituents at the 5-positon. The electron withdrawing 5-cyano group makes the double bond less prone to oxidation, while the electron rich 5-methyl group makes it more susceptible to oxidation. Bromide and chloride are considered to be less electron withdrawing than the cyano group,80,81 which might explain why the 5-bromo and 5-chloro analogues show more metabolism on the pyrazin-2(1H)-one ring than 145. Analogues 142 and 143 differ from 144 and 145 by the stereochemistry of the α-methyl group. How this subtle Figure 40. Monoamine reuptake Ki values and in vitro metabolism data for selected TRI.82 SERT, NET, DAT are the serotonin change influenced the metabolism cannot be determined, since α transporter, norepinephrine transporter, and dopamine transporter, analogues with the same -methyl stereochemistry were not respectively. reported. Nevertheless, the trend in GSH conjugation of the pyrazinone ring for analogues 142−145 is consistent with the electronic withdrawing properties of the substituent on the 5- The metabolic stability of analogue 151 was improved by position. From the standpoint of potency, metabolism, and rat replacing the ring with either an azaindole ring (152)or PK, the 5-cyano analogue (145, BMS-72170978) was the most indazole ring (153). Both changes led to analogues that were promising lead in this report, but further development of this less lipophilic than analogue 151, which may explain the compound has not yet been disclosed. improved metabolic stability. In addition, if the benzothiophene ring on compound 151 is the site of metabolism, it may be FUSED BICYCLIC HETEROAROMATICS prone to oxidation on the phenyl ring and/or sulfur atom, ■ which is precedented in the literature.13 Analogues 152 and As with the heteroaromatic rings discussed above, the strategies 153 may have better stability than 151, since the metabolically for reducing the metabolism of fused bicyclic heteroaromatics labile benzothiophene was replaced with an azaindole and involve blocking the sites of metabolism and reducing the indazole, respectively. While the indazole containing analogue electron density of the ring by attaching polar groups or adding 153 had the best metabolic stability in this set of compounds, it heteroatoms to the ring. For example, in their work on had the undesired attribute of being a CYP2D6 inhibitor.

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Figure 41. In vitro activity and rat liver microsomal proﬁles for selected α7 nAChR agonists. RLM data are expressed as percent parent remaining after 1 h.83 The reactive metabolite assay (RMA) was conducted in the presence of HLM and GSH-EE.

Figure 42. SAR of selected AR antagonists toward oxidation by AO. A “yes” indicates that qualitative formation was observed in human S9 fraction (HS9) without NADPH which suggests AO oxidation. HLM is measured as extraction ratio (ER). cLogP values in this ﬁgure are those reported by Linton et al.84

Figure 43. In vitro activity and in vivo PK parameters for selected PDE4 inhibitors.87 The potency data are reported as the inhibition of LPS induced TNF-α production in human whole blood (hWB).

Another report containing examples of fused 5,6 hetero- reactive metabolite assay, but the added polarity of the pyridyl aromatic rings was published by Wishka et al. in their work on group did not improve the metabolic stability of the compound. agonists for the α7 neuronal nicotinic acetylcholine receptor A paper containing the 5,6-heteroaromatic ring system, (α7 nAChR) (Figure 41).83 The indole ring on analogue 154 imidazopyrimidine, was published by Linton et al. from their was replaced with a benzofuran ring (155), which improved androgen receptor (AR) antagonist program for prostate cancer metabolic stability. However, benzofuran analogue 155 was (Figure 42).84 Although the lead compound 158 had desirable positive in the reactive metabolite assay, indicating that an rat PK, this compound was metabolized on the imidazopyr- electrophilic metabolite was being formed. Additional metab- imidine ring by aldehyde oxidase (AO). Unlike CYP P450s, AO olite identification studies with analogue 155 suggested that a delivers an oxygen atom as a nucleophile and is known to add glutathione ethyl ester (GSH-EE) adduct had formed on the to electron-deficient carbons in N-heterocycles.20,85,86 To phenyl ring of the benzofuran. The authors mentioned that the decrease the amount of metabolism by AO, Linton et al. position of the carboxamide on the phenyl ring of 155 may prepared an analogue with one less nitrogen in the ring to have had an influence on bioactivation, since the regioisomeric increase the electron density of the ring, which resulted in benzofuran analogue 156, which had a para-substituted analogue 159 that was no longer a substrate for AO. While the carboxamide, was negative in the reactive metabolite assay. oxidation through AO was minimized, CYP P450-mediated The related furopyridine analogue 157 was also negative in the metabolism increased, which was thought to be due to the

6015 dx.doi.org/10.1021/jm300343m | J. Med. Chem. 2012, 55, 6002−6020 Journal of Medicinal Chemistry Perspective higher lipophilicity of 159. To modify the electronics of the The position of the heteroatoms in five-membered imidazopyrimidine ring, they also prepared analogues with heteroarenes also influences metabolism. In two examples,65,68 various substituents at the 6-position (160−162). However, analogues containing the 1,2,4-oxadiazole were less stable than these compounds were all substrates of AO, even though their their 1,3,4-oxadiazole congeners. A recent review comparing the electronic properties and lipophilicity differed significantly. On HLM CL of 1,2,4- and 1,3,4-oxadiazole congeners confirms the the other hand, AO oxidation was eliminated when the 7- fact that 1,3,4-oxadiazoles tend to be more metabolically position was substituted with either a methoxy (163)or stable.88 Also, in the case of the triazole, there were two morpholine group (164), suggesting that this was the site of examples where the 1,2,4-triazole analogues were more stable AO oxidation on compound 158. This last example illustrates than their 1,2,3-triazole congeners.64,68 that, in some cases, making a N-heterocycle too electron Another method used to improve the metabolic profile of a deficient to avoid CYP P450 mediated oxidation may make it five-membered heteroarene was to install a group that served as more prone to AO oxidation. an alternative site for metabolism. This was illustrated in the An example of a 6,6-heteroaromatic system was reported by work by Obach where they showed that on meloxicam the main Lunniss et al. in their phosphodiesterase 4 (PDE4) inhibitor site of metabolism was the methyl group which spared the program (Figure 43).87 The compound containing a quinoline thiazole ring from oxidative ring-opening that was seen with 55 (165) had acceptable PK parameters in rat and dog, but they sudoxicam. This was discovered retrospectively, but adding a discovered that an oxidized analogue 166 was formed in decoy group to prevent the formation of reactive metabolites monkey hepatocytes. This metabolite was synthetically could be a useful strategy for preventing the bioactivation of prepared and was found to be more stable than the parent other compounds containing a five-membered heteroarene. compound in monkey PK studies. To further improve the For six-membered ring heteroarenes adding polar groups, metabolic stability of compound 165, the quinoline ring was fluorine atoms, or inserting nitrogens into the ring helps to replaced with a cinnoline to give analogue 167. The added decrease metabolism. Attaching electron withdrawing groups nitrogen in the cinnoline ring blocked the metabolic site of the and adding nitrogen atoms to the ring generally had the fi ff quinoline and lowered the electron density of the ring. bene cial e ect of making these compounds less prone to metabolism. However, in some instances, an electron deficient ■ CONCLUSIONS ring was more prone to nucleophilic attack by GSH as demonstrated by Kalgutkar et al. in their work with the In this review, we have given specific examples where the GPR119 agonist containing a 4-cyanopyrimidine.75 Also, metabolic profile of the compound was improved by modifying Linton et al. found that the electron deficient imidazopyr- the molecule at or near the heterocycle. In several of the imidine, while relatively stable to CYPs, was susceptible to examples discussed above, metabolite identification studies nucleophilic oxygen attack mediated by AO.84 pointed to the heterocycle as the site of metabolism, and direct Heterocycles are a broad class of compounds, covering a modification of the heterocycle led to an increase in metabolic diverse set of ring systems with various types of heteroatoms. stability. However, in the many of the other examples, the site The heterocyclic compounds illustrated in this review cover of metabolism was not elucidated and may have occurred away only a small subset of this broad class of compounds, but the from the heterocycle. So the effectthatchangingthe general principles of lowering lipophilicity and blocking sites of heterocycle had on improving metabolism may have been metabolism should serve as a useful starting point for solving indirect. Nonetheless, whether the change made to the metabolic issues on other heterocycles. Changing the ring size heterocycle had a direct or indirect effect on metabolism, or the arrangement of the heteroatoms has also been used to there is still value in examining the general trends used for improve metabolism, but the generality of these trends is less improving the metabolism that emerge from this review. clear and their applicability to other heterocycles deserves For saturated heterocyclic rings, adding fluorine atoms, polar further investigation. In the end, a certain amount of groups, or reducing the ring size helps to reduce metabolism. experimentation is necessary to understand the best way to Fluorine atoms served to lower the electron density of the ring improve the metabolism of any particular heterocycle. Knowing as well as block potential sites of metabolism. Polar groups were the identity of the metabolites can greatly facilitate this either appended to the ring or incorporated into the ring to endeavor. The examples in this review should provide give compounds with lower lipophilicity. In some cases adding medicinal chemists with a foundation for understanding a polar group had a detrimental effect on metabolism, as was techniques used to solve the issues of heterocycle metabolism. illustrated by the example from Mastalerz et al., where the hydroxyl and lactam diazepane analogues were less metabol- ■ AUTHOR INFORMATION 51 ically stable than the unsubstituted diazepane derivative. Corresponding Author Reducing the ring size generally improved metabolic stability. *Telephone: 805-447-7746. Fax: 805-480-1337. E-mail: However, there were some exceptions in examples with [email protected]. pyrrolidine rings where the larger piperidine analogue was found to be more metabolically stable.31,32 Notes fi For five-membered heteroarenes, adding one or more The authors declare no competing nancial interest. heteroatoms usually results in an increase in polarity and a ring with lower electron density, which helps to reduce Biographies metabolism. For example, we found several examples where the David J. St. Jean, Jr. received his BA from Goucher College, MD, more reactive thiophene, furan, and thiazole rings were replaced working under the direction of Prof. David Horn. In 1999, he with less electron rich rings like isoxazoles, thiadiazole, matriculated to the University of Pennsylvania where he received his oxadiazoles, pyrazoles, and triazoles that led to analogues Ph.D. in Organic Chemistry under the supervision of Prof. Gary with lower metabolism. Molander. David’s research focused on the development of novel

6016 dx.doi.org/10.1021/jm300343m | J. Med. Chem. 2012, 55, 6002−6020 Journal of Medicinal Chemistry Perspective methods utilizing samarium(II) iodide as well as the total synthesis of (4) Jang, G. R.; Harris, R. Z.; Lau, D. T. Pharmacokinetics and its role deacetoxyalcyonin acetate. Since 2004, he has been a medicinal in small molecule drug discovery research. Med. Res. Rev. 2001, 21, − chemist at Amgen where he currently holds the title of Principal 382 396. Scientist. (5) Thompson, T. N. Optimization of metabolic stability as a goal of modern drug design. Med. Res. Rev. 2001, 21, 412−449. Christopher Fotsch is a Director of Research in the Department of (6) Pritchard, J. F.; Jurima-Romet, M.; Reimer, M. L. J.; Mortimer, E.; Therapeutic Discovery at Amgen, Inc. He received his Ph.D. in Rolfe, B.; Cayen, M. N. A guide to drug discovery: making better Organic Chemistry from the University of California, Irvine under the drugs: decision gates in non-clinical drug development. Nat. Rev. Drug direction of Professor A. Richard Chamberlin, and he was a NIH Discovery 2003, 2, 542−553. Postdoctoral Fellow in the laboratory of Professor Chi-Huey Wong at (7) Shu, Y.-Z.; Johnson, B. M.; Yang, T. J. Role of biotransformation The Scripps Research Institute, CA. At Amgen, he has led medicinal studies in minimizing metabolism-related liabilities in drug discovery. − chemistry programs in the fields of oncology, neurosciences, and AAPS J. 2008, 10, 178 192. (8) Kola, I.; Landis, J. Opinion: Can the pharmaceutical industry metabolic disorders. His research interests include the discovery of reduce attrition rates? Nat. Rev. Drug Discovery 2004, 3, 711−716. novel therapies for unmet medical needs, structure-based drug design, (9) Meanwell, N. A. Synopsis of some recent tactical application of and enzyme-catalyzed organic synthesis. bioisosteres in drug design. J. Med. Chem. 2011, 54, 2529−2591. (10) Kerns, E. H.; Di, L. 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6020 dx.doi.org/10.1021/jm300343m | J. Med. Chem. 2012, 55, 6002−6020 An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Marcus Baumann*, Ian R. Baxendale*, Steven V. Ley* and Nikzad Nikbin*

Review Open Access

Address: Beilstein J. Org. Chem. 2011, 7, 442–495. Innovative Technology Centre, Department of Chemistry, University of doi:10.3762/bjoc.7.57 Cambridge, Lensfield Road, CB2 1EW Cambridge, UK Received: 10 December 2010 Email: Accepted: 22 March 2011 Marcus Baumann* - [email protected]; Ian R. Baxendale* - Published: 18 April 2011 [email protected]; Steven V. Ley* - [email protected]; Nikzad Nikbin* - [email protected] Editor-in-Chief: J. Clayden

* Corresponding author © 2011 Baumann et al; licensee Beilstein-Institut. License and terms: see end of document. Keywords: five-membered rings; heterocycles; medicinal chemistry; pharmaceuticals; synthesis

Abstract This review presents a comprehensive overview on selected synthetic routes towards commercial drug compounds as published in both journal and patent literature. Owing to the vast number of potential structures, we have concentrated only on those drugs containing five-membered heterocycles and focused principally on the assembly of the heterocyclic core. In order to target the most representative chemical entities the examples discussed have been selected from the top 200 best selling drugs of recent years.

Introduction Over the past few decades organic chemistry has seen to complex natural products, only a limited repertoire of syn- tremendous progress and this has enabled the synthetic chemist thetic transformations are utilised for their construction. to assemble virtually any molecular structure imaginable given Furthermore, many of the modern pioneering developments in reasonable time and sufficient resources. A steady increase in organic synthesis including new highly selective and mild bond architectural complexity and the incorporation of more diverse forming reactions such as metathesis and C–H activation, asym- molecular functionality has been a notable feature of pharma- metric transformations as well as polymer- and technology- ceutical research and development. This general trend has assisted syntheses are underused. emerged as a consequence of the better understanding of the genome and has resulted in many highly specific therapeutic In order to evaluate the validity of this hypothesis we decided to targets being elucidated. investigate the syntheses of the best-selling pharmaceutical substances focusing not only on the type of transformations However, even today it might be argued that because of the involved but more importantly on the way the heterocyclic perceived simpler structures of drug molecules when compared components were assembled. Aromatic and non-aromatic

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heterocyclic rings are a predominant architectural constant of In order to illustrate the diversity of synthetic methods used by pharmaceuticals and allow for variable interactions with the the pharmaceutical industry to generate heterocycle containing biological target which are not possible using simpler molecules we decided in the first part of this review to focus carbocyclic motifs. Based on our observations, we will mainly on five-membered aromatic heterocycles represented moreover be able to evaluate the degree these privileged within the top 200 best selling drugs [1,2]. This review abstracts structures utilise innovative and challenging synthetic information available from many literature sources including strategies. In addition, it will be possible to establish which patents to provide a selection of the most commonly used routes reactions are most frequently employed and which ones are in drug synthesis. Different heterocyclic structures will be intro- surprisingly rare or notably absent. Furthermore, from this duced and discussed in individual subsections. In Table 1 a study it will be possible to judge whether novel methods summary of these structures is shown. We believe that this and transformations developed within the academic article will give an enlightening overview of both the classical community are commonly applied in the later stages of drug heterocycle syntheses as well as interesting but less used trans- research. formations.

Table 1: Heterocylic structures discussed in this review.

Name Label Structure Heterocycle core

atorvastatin 1 pyrrole Figure 1

sunitinib 36 pyrrole Scheme 7

sumatriptan 49 indole Scheme 9

zolmitriptan 50 indole Scheme 9

naratriptan 69 indole Scheme 15

rizatriptan 76 indole Scheme 17

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Table 1: Heterocylic structures discussed in this review. (continued)

eletriptan 87 indole Scheme 20

fluvastatin 2 indole Scheme 25

ondansetron 119 indole Scheme 27

tadalafil 132 indole Scheme 28

carvedilol 136 carbazole Figure 4

carbazole etodolac 153 Scheme 31 (analogue)

losartan 157 imidazole Figure 5

olmesartan 158 imidazole Scheme 36

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Table 1: Heterocylic structures discussed in this review. (continued)

ondansetron 119 imidazole Scheme 37

esomeprazole 190 benzimidazole Scheme 39

pantoprazole 193 benzimidazole Scheme 40

candesartan 204 benzimidazole Scheme 41

telmisartan 217 benzimidazole Scheme 43

zolpidem 227 imidazopyridine Scheme 45

celecoxib 235 pyrazole Figure 7

pazopanib 246 indazole Scheme 50

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Table 1: Heterocylic structures discussed in this review. (continued)

anastrozole 257 1,2,4-triazole Scheme 51

rizatriptan 76 1,2,4-triazole Scheme 51

letrozole 256 1,2,4-triazole Scheme 51

sitagliptin 275 1,2,4-triazole Scheme 55

maraviroc 286 1,2,4-triazole Scheme 57

alprazolam 297 1,2,4-triazole Scheme 58

itraconazole 307 1,2,4-triazole Figure 9

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Table 1: Heterocylic structures discussed in this review. (continued)

rufinamide 315 1,2,3-triazole Scheme 61

valsartan 319 tetrazole Scheme 62

losartan 157 tetrazole Scheme 63

cilostazole 325 tetrazole Scheme 64

cefdinir 329 thiazole Figure 11

ritonavir 337 thiazole Scheme 66

pramipexole 345 thiazole Scheme 67

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Table 1: Heterocylic structures discussed in this review. (continued)

famotidine 352 thiazole Scheme 69

febuxostat 359 thiazole Scheme 70

ziprasidone 367 thiazole Scheme 71

ranitidine 377 furan Scheme 73

nitrofurantoin 382 furan Scheme 74

amiodaron 385 furan Scheme 76

raloxifene 392 thiophene Scheme 77

olanzapine 399 thiophene Scheme 79

clopidogrel 420 thiophene Scheme 81

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Table 1: Heterocylic structures discussed in this review. (continued)

timolol 432 thiadiazole Figure 14

tizanidine 440 thiadiazole Scheme 85

leflunomide 446 isoxazole Scheme 86

sulfamethoxazole 447 isoxazole Scheme 87

risperidone 454 benzoisoxazole Scheme 88

Review Pyrroles Pyrrole, a five-membered nitrogen containing heterocycle is present in some of the most common biologically important molecules, i.e., chlorophyll and haem. However, while the pyrrole ring is not widely represented in pharmaceutical compounds, the core structure of atorvastatin (1, Lipitor; Figure 1), the best-selling drug substance of the last few years, does contain a penta-substituted pyrrole ring. This drug is an example of a competitive HMG-CoA-reductase inhibitor belonging to the 7-substituted 3,5-dihydroxyheptanoic acid family. In atorvastatin this important syn-1,3-diol moiety is connected to the other functional constituents through a fully substituted pyrrole ring instead of the more elaborate systems which are encountered in other members of this family.

The initial synthesis of atorvastatin was reported by the Warner–Lambert company [3]. From structure–activity relationship (SAR) studies it was found that the addition of substituents at the 3- and 4-position of the pyrrole scaffold significantly increases potency when compared to the more classical 2,5-disubstituted pyrroles. This study culminated in the Figure 1: Structures of atorvastatin and other commercial statins. discovery of atorvastatin which has a five times greater potency

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then the initial lead, the fungal metabolite compactin (5, In order to prepare the 5-isopropylpyrrole derivative 16 a more Figure 2). efficient [3 + 2] cycloaddition of an acetylene component with an amido acid 13 was developed. Unfortunately, reacting ethyl phenylpropiolate with the corresponding amido acid in hot acetic anhydride afforded a 4:1 mixture of regioisomers with the major product being the undesired regioisomer (Scheme 2).

However, the analogous reaction with isomer 19 was found to be completely regiospecific leading to the formation of the desired product 16 albeit in only moderate yield (Scheme 3).

By modification of the coupling partners a more defined dipolar [3 + 2] cycloaddition between N,3-diphenylpropynamide (22) Figure 2: Structure of compactin. and an in situ generated mesoionic species 21 furnished the desired product 23 regiospecifically [4] (Scheme 4). Although it was possible to construct such fully substituted pyrrole rings by ZnCl2-catalysed condensation reactions A further synthetic approach was based on the classical between a functionalised enamine 6 and simple benzoin (7), this Paal–Knorr cyclocondensation of a highly substituted 1,4- method proved to be less successful for more complex pyrroles diketone with a primary amine bearing a masked aldehyde func- of which atorvastatin was an example (Scheme 1). tionality. The 1,4-diketone component, which can be accessed via a 3-step sequence [5] starting from aniline, was refluxed with 3-aminopropionaldehyde diethylacetal 32 in toluene under mildly acidic conditions to afford the fully substituted pyrrole motif in 81% isolated yield following crystallisation [6]. The key transformation in this sequence is a thiazolium-mediated Stetter reaction between 4-fluorobenzaldehyde (29) and an advanced Michael acceptor obtained from an initial Knoeven- agel condensation (Scheme 5).

In order to improve the overall yield as well as the convergency, the industrial route [7] introduced the fully elaborated side chain 34 by condensation with the previously described 1,4- Scheme 1: Synthesis of pentasubstituted pyrroles. diketone 31 (Scheme 5 and Scheme 6). The desired atorvastatin

Scheme 2: [3 + 2] Cycloaddition to prepare 5-isopropylpyrroles.

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Scheme 3: Regiospecific [3 + 2] cycloaddition to prepare the pyrrole scaffold.

Scheme 4: Formation of the pyrrole core of atorvastatin via [3 + 2] cycloaddition.

Scheme 5: Formation of pyrrole 33 via the Paal–Knorr reaction.

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structure was then obtained in only three additional steps via acetal cleavage, ester hydrolysis and formation of the calcium salt.

Figure 3: Binding pocket of sunitinib in the TRK KIT.

Scheme 6: Convergent synthesis towards atorvastatin. Structurally, this medication consists of a complex pyrrole- substituted 2-indolinone core which can be prepared by a late Sunitinib (36, Sutent) is Pfizer’s novel receptor tyrosine kinase stage aldol condensation between a 2-indolinone fragment 42 inhibitor (RTK) approved in 2006 by the FDA for the treatment with the corresponding pyrrole aldehyde 41 (Scheme 7). The of both renal cell carcinoma and gastrointestinal stromal oxime functionality in compound 38, which is obtained by tumors. This drug has been suggested as a second-line therapy nitrosation of tert-butyl acetoacetate (37) [9], is reduced by zinc for patients developing mutation-related resistance to other to give an unstable aminoketone intermediate. Subsequent cancer medications such as imatinib (Gleevec). Sunitinib binds enamine formation and ring closure affords the fully substi- to the inactivated, auto-inhibited conformation of the KIT tuted pyrrole ring 40. Selective deprotection of the tert-butyl kinase by partially occupying the space normally filled by the ester with concomitant decarboxylation yields ethyl 2,4- ADP’s adenine in the phosphorylated protein. The indolinone dimethylpyrrole-3-carboxylate which can be formylated at the section is located in a deeper pocket with the heteroatoms being free ring position by trimethyl orthoformate to yield the fully involved in H-bonding glutamate and tyrosine residues whilst elaborated pyrrole aldehyde (41). The aforementioned aldol the pyrrole ring and the diethylaminoethyl appendage are condensation unites both key fragments: Ester hydrolysis and exposed to the solvent environment [8] (Figure 3). amide formation complete the synthesis (Scheme 7).

Scheme 7: Synthesis of sunitinib.

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An attractive alternative synthesis of sunitinib introduces the drugs, with five of these belonging to the triptan family of anti- amide side chain earlier by ring opening of 4-methyleneoxetan- migraine treatments. The classical Fischer indole synthesis is 2-one (43) with N,N-diethylethane-1,2-diamine (44) [10]. The usually reported as one of the first choice routes to prepare resulting β-keto amide 45 is then converted to the analogous these scaffolds. Drugs such as GSK’s serotonin receptor modu- pyrrole by condensation with the previously mentioned oxime lators sumatriptan (49, Imitrex) and zolmitriptan (50, Zomig) 38 under reductive conditions. Deprotection and decarboxyl- use the Fischer indole synthesis at a late stage in order to form ation of the remaining tert-butyl ester produces the desired the desired compound albeit in only low to moderate yields pyrrole intermediate, which upon treatment with Vilsmeier (Scheme 9). reagent undergoes a formal acylation. This product is not isolated but reacted directly with 41 in an aldol condensation to However, in sumatriptan the indole product resulting from the yield sunitinib (Scheme 8). Fischer synthesis can still react further which leads to the formation of by-products and significantly reduced yields. One Indoles way to minimise this was to protect the nitrogen of the sulfon- The neuroamine transmitter serotonin contains an indole ring, amide group prior to indole formation [11]. This leads not only so it is not surprising that indoles are a recurring theme in many to an increased yield in the indole forming step (to 50%) but drugs affecting central nervous system (CNS) function also facilitates chromatographic purification. The dimethyl- including antidepressants, antipsychotics, anxiolytics and anti- amino group can be present from the beginning of the synthesis migraine drugs, as well as psychedelic agents. Indole is also one or can be introduced via displacement of chloride or reduction of the best represented heterocyclic motifs present in the top of a cyano moiety. Alternatively, the dimethyl ethylene amine selling pharmaceuticals, being found in eight of the top 200 side chain can be introduced in position 3 via a Friedel–Crafts-

Scheme 8: Alternative synthesis of sunitinib.

Scheme 9: Key steps in the syntheses of sumatriptan and zolmitriptan.

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Scheme 10: Introduction of the N,N-dimethylaminoethyl side chain. type acylation. The resulting acid chloride is transformed in situ All the reported methods for the synthesis of sumatriptan begin to the corresponding amide which on reduction with lithium with the sulfonamide group already present on the aromatic ring aluminium hydride affords sumatriptan (Scheme 10) [12]. and several routes are possible to introduce this functional group. The scalable route to the sulfonamides inevitably In the standard Fischer indole synthesis a hydrazine, which is involves the preparation of the sulfonyl chloride intermediate most commonly derived from the corresponding diazonium salt, which is then trapped with the desired amine. The sulfonyl is reacted with a suitable carbonyl compound. Alternatively, the chloride can also be prepared from the corresponding hemithio- Japp–Klingemann reaction can be used to directly couple the acetal 61 by treatment with NCS in wet acetic acid diazonium salt with a β-ketoester to obtain a hydrazone which (Scheme 12). This efficient oxidation produces only methanol can then undergo indole ring formation (Scheme 11) [13]. and formaldehyde as by-products [15].

As can be seen from Scheme 11 the indole 59 prepared via the Another possible approach is based on the direct displacement Japp–Klingemann reaction is substituted at position 2 by an of a benzylic chloride by sodium sulfite and subsequent sulfon- ester group which prevents reaction with electrophiles, thereby amide formation as shown in Scheme 13 [16]. reducing the amount of undesired by-products. A simple sequence of hydrolysis and decarboxylation then affords suma- A more recent method utilises a palladium-catalysed Negishi triptan [14]. coupling to access a diverse library of benzylic sulfonamides,

Scheme 11: Japp–Klingemann reaction in the synthesis of sumatriptan.

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Scheme 12: Synthesis of the intermediate sulfonyl chlorides 62 and 63. Scheme 14: Negishi-type coupling to benzylic sulfonamides.

An analogous Heck reaction approach has also been employed to introduce a homologous side chain as demonstrated during the assembly of the antimigraine drug naratriptan (69, Amerge, Scheme 15) [18].

Another related antimigraine drug developed by GSK is zolmitriptan (Zomig, 50). The indole ring and its substitution at the 3-position are identical to that of sumatriptan, however, the sulfonamide side chain has been replaced by an oxazolinone ring. The original synthesis utilised 4-nitro-L-phenylalanine (73) as the precursor for the oxazoline moiety (Scheme 16) Scheme 13: Alternative introduction of the sulfonamide. [19]. The resulting Fischer indole synthesis is similar to that used for sumatriptan (Scheme 9). all prepared in high yields. As this route employs sulfonamide- stabilised anions the preparation and handling of unstable More recent reports [20] deal with improvements to both these sulfonyl chloride intermediates is therefore circumvented syntheses making them more economic and environmentally (Scheme 14) [17]. benign. For example, the three steps to zolmitriptan, namely,

Scheme 15: Heck reaction used to introduce the sulfonamide side chain of naratriptan.

Scheme 16: Synthesis of the oxazolinone appendage of zolmitriptan.

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diazonium salt formation, its subsequent reduction and Fischer circumvents the formation of such dimeric impurities involves indole synthesis can all be carried out in aqueous media without the reduction of the intermediate diazonium salt with sodium the need for intermediate isolation. It has also been demon- sulfite and hydrochloric acid to form an easily isolable and crys- strated that the reduction of the initially formed diazonium salt talline phenylhydrazine sulfonic acid 81. The subsequent can be accomplished by using sodium metabisulfite (Na2S2O5) Fischer indole synthesis can then be performed cleanly at much rather than using the more toxic stannous chloride or the less lower temperatures (Scheme 18) and yields pure rizatriptan as water soluble and more expensive sodium sulfite. its benzoate salt [23]. In addition, the use of precursor 82, already possesing the desired dimethylamino group, simplifies Preparation of the indole ring system in the antimigraine drug the reaction sequence and tunes the reactivity of the amine rizatriptan (76, Maxalt) makes use of the Grandberg variation of preventing it from participating in many side reactions. the Fischer indole synthesis as the final stage reaction to form the tryptamine-type moiety, via formation and re-opening of a The indole core of rizatriptan can also be prepared by a pal- tricyclic intermediate [21,22]. Although not a high yield ladium-catalysed coupling first reported by Larock [24]. The process, this one pot sequence establishes the indole ring and iodoaniline derivative 84 required for this approach can be the pendant primary amine group in a single operation readily synthesised from triazolomethyl aniline 83 by treatment (Scheme 17). with iodine monochloride in aqueous methanol. The bis-TES- protected butynol 85 was found to be the most efficient coup- However, the main disadvantage of this process is the need for ling partner and led smoothly to the desired indole 86. high temperatures which leads to the formation of dimeric Subsequent removal of the TES-groups and introduction of a di- impurities and results in the requirement for extensive methylamino moiety furnishes the desired drug compound [25- chromatographic purification. An improved process which 27] (Scheme 19).

Scheme 17: Grandberg indole synthesis used in the preparation of rizatriptan.

Scheme 18: Improved synthesis of rizatriptan.

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indole ring on larger scale, ethylmagnesium bromide and the corresponding acid chloride 89 are added concurrently from two different sides of the reactor to stop these reagents reacting with each other. This method of adding the reagents circumvents the necessity to isolate the magnesium salt of the indole and increases the yield from 50 to 82%. The carbonyl group of the proline side chain is then reduced simultaneously with the complete reduction of the Cbz-group to a methyl group with lithium aluminium hydride. Finally, the sulfonate side chain is introduced via a Heck-type coupling similar to that of naratriptan (Scheme 15), followed by hydrogenation of the double bond to afford eletriptan (Scheme 20).

A rather ingenious Mitsunobu coupling reaction has been used to create a highly functionalised substrate 96 for an intramolecular Heck reaction resulting in a very short and Scheme 19: Larock-type synthesis of rizatriptan. succinct synthesis of eletriptan and related analogues 97 [29] (Scheme 21). Eletriptan (87, Relpax) is yet another indole-containing antimigraine drug. A process route for the synthesis of eletriptan Interestingly, it was found that the most obvious approach, the published by Pfizer starts from a preformed bromo-indole 88 direct Fischer indole synthesis, to prepare the core of eletriptan [28] (Scheme 20). In order to perform the acylation of the as shown in Scheme 22 is not successful [30]. This is believed

Scheme 20: Synthesis of eletriptan.

Scheme 21: Heck coupling for the indole system in eletriptan.

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Scheme 22: Attempted Fischer indole synthesis of elatriptan.

Scheme 23: Successful Fischer indole synthesis for eletriptan. to be due to the instability of the phenyl hydrazine species 98 under the relatively harsh reaction conditions required to promote the cyclisation.

However, this problem could be avoided by using an acid-labile oxalate protected hydrazine 104 as depicted in Scheme 23. The yield of this step can be further improved up to 84% if the corresponding calcium oxalate is used.

The Bischler–Möhlau reaction is an alternative indole synthesis employing an α-bromo ketone and an excess of aniline to give a 2-arylindole derivative 110 [31] (Scheme 24). For a long time this procedure has received little attention due to the requirement for rather extreme reaction conditions. However, the use of microwave radiation in combination with Lewis acid catalysis allows the reaction to be conducted much more efficiently [32]. This gives mid range yields (50–70%) of the 2-arylindoles over the two step sequence and tolerates a selection of functional groups on the aniline ring.

Fluvastatin (2, Lescol), a HMG-CoA reductase inhibitor was initially prepared by a Fischer indole synthesis [33] (Scheme 25). However, in the development stages it was decided that a Bischler–Möhlau type reaction could be used Scheme 24: Mechanistic rationale for the Bischler–Möhlau reaction. instead. In this case a ZnCl2-mediated Bischler-type indole syn-

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Scheme 25: Bischler-type indole synthesis used in the fluvastatin sodium synthesis. thesis [34] is used with stoichiometric amounts of the aniline cially available (D)-tryptophan methyl ester to form the which leads to the required 3-substituted indole core 116 at an indolopiperidine motif 135 via a Pictet–Spengler reaction fol- early stage in the synthesis. A novel way to introduce a formyl lowed by a double condensation to install the additional substituent at the 2-position of the indole was subsequently diketopiperazine ring (Scheme 28) [38,39]. developed to aid the introduction of the syn-diol pendant side- chain. To achieve the high levels of cis selectivity required from the Pictet–Spengler reaction, an extensive investigation of solvents A completely different strategy was used in the synthesis of the and the influence of additives was undertaken [40]. It was iden- serotonin 5-HT3 receptor antagonist ondansetron (119, Zofran). tified that the use of a specific 23 mol % of benzoic acid signifi- In this synthesis a palladium-catalysed intramolecular Heck- cantly increased the cis/trans ratio from a base level of 55:45 to reaction was used to build the tricyclic indole core in a short 92:8 (16 h reaction time at ambient temperature) in an overall and concise sequence (Scheme 26) [35,36]. yield of 86%. It was also determined that more polar solvents such as acetonitrile and nitromethane preferentially solvated the Alternatively, a direct Fischer indole synthesis between phenyl- trans product and thereby allowed the isolation of the cis com- methyl hydrazine and a cyclic 1,3-dione derivative could be pound by precipitation. It was also shown that by heating the utilised to prepare the desired fully substituted tricyclic core of reaction mixture under reflux the product distribution could be ondansetron (Scheme 27) [37]. driven to the thermodynamically more favoured cis isomer having both the ester and the piperonyl moiety in equatorial A different approach was used in the synthesis of the phospho- positions. Hence, after heating under reflux for 8 h the cis/trans diesterase inhibitor tadalafil (132, Cialis) starting from commer- ratio was found to be 99:1 and the product could be isolated in

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Scheme 26: Palladium-mediated synthesis of ondansetron.

Scheme 27: Fischer indole synthesis of ondansetron.

Scheme 28: Optimised Pictet–Spengler reaction towards tadalafil.

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an overall yield of 91%. This work represents an impressive Since carbazoles are similar to indoles, analogous methods can example of a well considered and executed process optimisa- be used for their synthesis. The key intermediate for carvedilol tion study. is 4-hydroxy-9H-carbazole (141) [42]. In analogy to the Fischer indole synthesis, cyclohexane-1,3-dione monophenyl hydrazone Carbazoles 139 is prepared via condensation of phenylhydrazine (138) with Carvedilol (136, Coreg) is a general non-selective β-blocker, 1,3-cyclohexanedione (121, Scheme 29). This compound can used in the treatment of mild to moderate congestive heart then undergo an acid catalysed Fischer indole synthesis to yield failure. The structure comprises of a core carbazole ring that tetrahydro-4-oxocarbazole 140. Various methods have been plays an important role in its increased activity. described to dehydrogenate this intermediate including the use of bromine, sulfur, LiCl/CuCl, lead dioxide, chloranil or pal- The cardioprotective effect of β-adrenergic blockers is attri- ladium on charcoal. However, the need to use these reagents in buted to their ability to reduce the myocardial workload by equal stoichiometry or even excess has led to the search for a reducing the system’s requirement for oxygen. However, the new approach. It was found that a catalytic quantity of Raney activity of carvedilol is greater when compared to other nickel in an aqueous potassium hydroxide solution gives the members of the β-blocker family such as propranolol (137, desired 4-hydroxy compound 141 cleanly and in high conver- Figure 4) implying that carvedilol has an additional antioxidant sion (Scheme 29). mode of action. It has been proposed that the carbazole ring may be involved in scavenging oxygen radicals thereby Alternative routes to this key intermediate such as Ullmann- accounting for reduced myocardial damage [41]. type reactions have also been reported, however, these usually rely on longer reaction sequences and require more expensive starting materials (Scheme 30) [42,43].

Etodolac (153, Lodine) is a racemic non-steroidal anti-inflammatory tetrahydrocarbazole derivative used to treat inflammation and prescribed for general pain relief. Two general routes have been described for the preparation of this drug. In the first route the hydrazine 149 is prepared via the reduction of diazonium salt 148 with tin(II) chloride and subjected to a Fischer indole reaction with aldehyde 150. The resulting indole is then condensed with ethyl 3-oxopropanoate followed by saponification of the ester to yield etodolac (Scheme 31) [44].

The second described route [45,46] is similar but starts with a Figure 4: Structures of carvedilol 136 and propranolol 137. more readily available carbonyl surrogate; 2,3-dihydrofuran

Scheme 29: Synthesis of the carbazole core of carvedilol.

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Scheme 30: Alternative syntheses of 4-hydroxy-9H-carbazole.

Scheme 31: Convergent synthesis of etodolac.

154. The Fischer indole reaction provides a primary alcohol temporary silyl mask was found beneficial as it circumvents the which is TMS-protected and condensed with methyl need for chromatographic purification. Finally, simple saponi- 3-oxopentanoate under Lewis acid conditions. The use of the fication furnishes etodolac (Scheme 32).

Scheme 32: Alternative synthesis of etodolac.

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Extensive biological studies have found that the majority of the were of a peptidic nature, suffered from poor bioavailability and reactivity of etodolac is derived from the (S)-(+)-enantiomer. also showed some agonistic activities. The first non-peptide The resolution of the racemate can be readily accomplished antagonists were developed in the early 80’s. Although these using cinchonine or the glucose derivative N-methyl-D- compounds were selective for the AT2 receptor, they bound glucamine. The latter provides the pure (S)-(+)-enantiomer in only weakly to their target protein. On examining the 25.3% yield (>96% de) after two crystallisations. In addition, angiotensin II amino acid sequence, researchers took notice of the racemisation of the undesired enantiomer via methyl ester an acidic residue on the NH2 terminus. Consequently, a formation and treatment with sodium hydroxide was found to carboxylic acid moiety was added to the designed ligand be feasible allowing efficient recycling of this material [47]. improving affinity for the AT2 receptor. However, the polar nature of the carboxylic acid group caused this compound to Imidazoles suffer from poor absorption and low bioavailability. At this Imidazole is an important biological building block being stage a classical bioisostere exchange, i.e., replacing a present in the amino acid histidine and possessing inherent cata- carboxylic acid group with a tetrazole ring, was performed lyst and acid–base functionality. An imidazole ring is also a which resulted in increased lipophilicity [48] and the develop- component of the biogenic amine histamine. It is interesting to ment of the orally active losartan. note that the imidazole ring does not however appear in the most common H1 and H2 antagonists, presumably due to its In the absence of a crystal structure, mutation studies have metabolic vulnerability, with cimetidine being an exception. shown that the AT2 antagonists such as losartan bind to an The use of such compounds has now been almost completely active site located within the membrane-bound part of the superseded by the prescription of alternative proton pump receptor, which is different to that of the peptide agonist. inhibitors such as esomeprazole. Further studies led to the discovery of valsartan, where the imidazole ring of losartan is replaced by an N-acylated amide Imidazole containing drugs can be subdivided into two classes: which is suggested to mimic the C-terminus of angiotensin II monocyclic imidazoles and benzimidazoles. The former is [49]. represented by three drugs targeting hypertension losartan (157, Cozaar), olmesartan (158, Benicar), eprosartan (159, Eprozar) The imidazole ring of losartan, an antihypertensive and as well as nausea (ondansetron (119, Zofran)) (Figure 5). All of angiotensin II blocker is formed in a condensation reaction these drugs aptly highlight a different synthetic approach to the between valeroamidine 160 and dihydroxyacetone [50]. It was imidazole core. Early antagonists of the angiotensin II receptor found that direct chlorination of the imidazole 162 also forms the dichlorination product 164 (as shown in Scheme 33) with formaldehyde as a by-product which proved difficult to suppress and made purification of the reaction mixture problematic. Hence, a sequence involving silyl protection, chlorination and deprotection was established which gave the desired product in 90% overall yield (Scheme 33).

Alternatively, glycine can be reacted with methyl pentan- imidate 169 to form the corresponding amidine 171 in high yield. Cyclisation, followed by a Vilsmeier-type reaction then furnishes the key chloroimidazolyl building block 172 in good yield (Scheme 34) [51].

More recently, Zhong and co-workers [52] reported a highly efficient one-pot procedure starting from N-acylated α-aminoni- triles 173. The desired 2,4,5-trisubstituted imidazole core 178 is formed in high yield in the presence of carbon tetrachloride and triphenylphosphine (Scheme 35). Mechanistic studies showed that the related imidoyl compounds do not themselves undergo ring closure to form imidazoles and it was therefore proposed that the reaction between carbon tetrachloride and triphen- Figure 5: Structures of imidazole-containing drugs. ylphosphine to generate dichlorotriphenylphosphorane and

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Scheme 33: Synthesis of functionalised imidazoles towards losartan.

Scheme 34: Direct synthesis of the chlorinated imidazole in losartan.

(dichloromethylene)triphenylphosphorane was pivotal. The the tetrazole containing biphenyl appendage, followed by ester amidonitrile substrate 173 can then react with both species to hydrolysis and alkylation of the resulting carboxylate with form seven-membered cyclic intermediate 175 which collapses 4-(chloromethyl)-5-methyl-2-oxo-1,3-dioxole to yield to form the imidazole compound. olmesartan (Scheme 36).

The structurally related imidazole core of olmesartan is formed The imidazole motif present in ondansetron (119), a prototypic in a different fashion (Scheme 36). Condensation between 5-HT3 receptor antagonist, is incorporated into the molecule by diaminomaleonitrile and trimethyl orthobutyrate furnishes the substitution of a trimethylammonium functionality of an trisubstituted imidazole 181 in high yield [53,54]. Acid-medi- advanced intermediate 188 by 2-methylimidazole (187, ated nitrile hydrolysis followed by esterification results in the Scheme 37) [55]. Alternatively, this substitution can be corresponding diester unit 182. Treatment of 182 with four performed on a cyclohexenone derivative prior to the Fischer equivalents of methylmagnesium chloride in a mixture of indole synthesis (Scheme 27) [38]. The required imidazole 187 diethyl ether and dichloromethane selectively provides tertiary itself can be prepared via a variety of methods. For example, a alcohol 183. In subsequent steps this imidazole is alkylated with process involving acetaldehyde, glyoxal and ammonium

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Scheme 35: Synthesis of trisubstituted imidazoles.

Scheme 36: Preparation of the imidazole ring in olmesartan.

Scheme 37: Synthesis of ondansetron. carbonate furnishes the desired compound in an excellent 95% Elz and Heil [57] prepared the 1,2,3,9-tetrahydro-4H-carbazol- yield (Scheme 37). Also, a condensation reaction between 4-one (140) by the reaction of phenylhydrazine (138) with ethylenediamine and acetic acid catalysed by γ-Al2O3 at high cyclohexan-1,3-dione (Scheme 38). Classical N-methylation temperatures gives 2-methylimidazole (187) in approximately with dimethyl sulfate followed by introduction of an exocyclic 90% yield [56]. double bond using paraformaldehyde in DMF under acidic

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Scheme 38: Alternative route to ondansetron and its analogues. conditions furnishes the Michael acceptor 189, which then In a similar strategy, the benzimidazole structure 210 in the undergoes conjugate addition with various amines (Scheme 38). angiotensin II antagonist candesartan (204, Atacand) is formed This route has been used to prepare several ondansetron from an advanced diaminobenzene derivative, which in turn is analogues based on different amine components. prepared by a tin-mediated nitro reduction to form a highly substituted diaminobenzene (Scheme 41). This general strategy Benzimidazoles involving initial alkylation of 207 is often employed to control Nearly all benzimidazole containing drugs such as the regioselectivity of the imidazole formation. The benzimida- esomeprazole (190, Nexium), omeprazole (191, Prilosec), zole ring is then assembled by treating this diamine with lansoprazole (192, Prevacid), pantoprazole (193, Protonix) and tetraethyl orthocarbonate under Lewis acid conditions. The syn- rabeprazole (194, Aciphex) are proton pump inhibitors. The thesis is concluded by installation of the tetrazole ring and common feature in their synthesis is the double condensation of acetal side chain, the latter is cleaved under physiological a 1,2-diaminobenzene with potassium ethylxanthate (196) [58]. conditions, making candesartan a pro-drug in the same way as A typical synthesis of the methoxybenzimidazole system olmesartan [62]. This synthesis of the benzimidazole precursor present in esomeprazole (omeprazole) and lansoprazole is makes use of a 1,2,3-trisubstituted nitrophthalic acid 205, which shown in Scheme 39. For esomeprazole the subsequent steps had to be selectively monoesterified and subjected to a Curtius involve an S-alkylation as well as an asymmetric oxidation of rearrangement, which is cumbersome when the reaction is the newly formed thioether [59,60]. scaled up. Alternative routes to such trisubstituted benzenes include directed ortho-lithiation of 1,3-disubstituted benzenes Additional structural diversity in the aniline component can be followed by trapping of the anion with a nitrogen electrophile introduced by protection, nitration, deprotection and reduction [63]. As a result a new route to access the key building block of the starting amine compound 201. Scheme 40 for instance has been proposed which makes use of a less widely utilised shows this in the synthesis of the benzimidazole core of panto- acid catalysed rearrangement of methyl N-nitroanthranilate prazole [61]. (212) which is obtained by N-nitration of methyl anthranilate (211, Scheme 42). Alkylation of the intermediate with the The benzimidazole ring in rabeprazole (194, Figure 6) is only biphenylmethyl bromide 208 under mildly basic conditions substituted at position 2 and can be easily prepared by the same yields adduct 213. Upon treatment of this compound with 80% procedure. aqueous sulfuric acid a rearrangement to furnish a mixture of the 3- and 5-nitro derivatives occurs, which unfortunately at this stage, could not be separated by crystallisation. However, when this mixture was subjected to catalytic hydrogenation with Raney nickel a separable mixture of the corresponding diaminobenzoates was obtained (Scheme 42) [64].

Telmisartan (217, Micardis) is a well known angiotensin II receptor antagonist used in the treatment of hypertension and, heart and bladder diseases. Its pharmacophore consists of two linked benzimidazoles and a biphenyl unit (Scheme 43). As Figure 6: Structure of rabeprazole 194. shown previously, such benzimidazoles can be formed through

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Scheme 39: Proton pump inhibitors and synthesis of esomeprazole.

Scheme 40: Synthesis of benzimidazole core pantoprazole. the condensation reaction of a 1,2-diaminobenzene and a suit- consequently significantly lower yields. Another obvious draw- able functionalised carbonyl compound. However, in the case of back of the initially described route [65] when considering scale telmisartan other inherent functionalities such as an ester are up, is the number of sequential steps in the synthesis (8 steps, present which leads to the formation of several by-products and 21% overall yield) (Scheme 43).

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Scheme 41: Synthesis of candesartan.

Scheme 42: Alternative access to the candesartan key intermediate 216.

Hence an improved synthesis was sought [66]. This revised imidazole nitrogen with the required biphenyl derivative 223 in route utilised a palladium-mediated reduction of the highly basic media yields the methyl ester 226 which is isolated, after substituted nitrobenzene derivative 219 to afford aniline 224 work-up and solvent removal, as the hydrochloride salt in 85% which under basic conditions ring closes to the corresponding yield. HPLC analysis showed a purity of >99.5% which is by benzimidazole 225. Under the same reaction conditions, the far superior to the previously reported synthesis [65]. Finally, hydrolysis of the methyl ester also occurs which allows the hydrolysis of the methyl ester provides telmisartan in an overall introduction of the second imidazole group in the subsequent yield of about 50% compared to 21% as previously obtained condensation step. Sterically directed alkylation of the free (Scheme 44).

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Scheme 43: .Medicinal chemistry route to telmisartan.

Scheme 44: Improved synthesis of telmisartan.

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Imidazopyridine an intermediate imine to which is added a terminal alkyne in the Zolpidem (227) is a non-benzodiazepine hypnotic, and is part of presence of copper(I) chloride. A copper(II) triflate catalyst is the imidazopyridine class of pharmaceuticals. It is an agonist then used to promote a Lewis acid promoted 5-exo-dig for the target receptor of γ-aminobutyric acid (GABA), an heteroannulation to furnish, after chromatography, the bicyclic inhibitory neurotransmitter. Zolpidem binds to GABA receptors structure in good overall isolated yield (Scheme 46). at the same site as typical benzodiazepines. This drug is preferred to benzodiazepines for long term use since benzo- Despite this synthesis being much shorter and convergent it has diazepines lead to a higher tolerance as well as physical depend- some limitations since the entire procedure needs to be ence. The standard route to this scaffold is the cyclocondensa- performed in a glove box and has consequently only been tion of a functional 2-aminopyridine with an α-bromo-carbonyl reported on small scale. compound [67,68]. In the case of zolpidem, the amide moiety in the 3-position of the ring system is introduced via a Pyrazole Friedel–Crafts/Mannich-type alkylation starting either from Selective inhibitors of cyclooxygenase-2 (COX-2) are widely formaldehyde and dimethylamine or 2,2-dimethoxy-N,N- used for their anti-inflammatory effects and have shown less dimethylacetamide (Scheme 45). gastrointestinal side effects when compared to other anti- inflammatory agents, notably non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, which inhibit both COX-1 and COX-2. The central ring is usually a five- membered aromatic system, which is diaryl-substituted with a (Z)-stilbene-like linking structure. A polar sulfonamide group or biologically equivalent unit is usually present at the para-position of one of the aryl rings and is believed to promote binding to a hydrophilic pocket close to the active site of COX-2. Cele- coxib (235, Celebrex, Figure 7) belongs to the group of selective COX-2 inhibitors acting on the prostaglandin G/H synthase 2 as well as 3-phosphoinositide-dependent protein kinase 1 and is marketed by Pfizer. Interestingly, celecoxib has also been approved for familial adenomatous polyposis demon-

Scheme 45: Synthesis of zolpidem.

In a recent study a more straightforward and general copper- catalysed three component coupling leading to imidazopyridines has been reported [69]. For this reaction 2-amino-5- methylpyridine (228) was condensed with an aldehyde to form Figure 7: Structure of celecoxib.

Scheme 46: Copper-catalysed 3-component coupling towards zolpidem.

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strating its ability to induce apoptosis in certain cancer cell lines natively, in order to circumvent the regioselectivity issue, other [70]. As this activity is not shared with all COX-2 inhibitors, it pyrazole syntheses have been used. For example, the substi- is believed that the structural features such as the polar sulfon- tuted aryl hydrazine 237 can be reacted with trifluoromethyl amide group, the lipophilic tolyl moiety and the trifluoro- butynone in a one pot reaction. A Michael addition/cyclisation methylated pyrazole core with its negative electrostatic poten- sequence renders only the desired regioisomer of the pyrazole tial play a key role in apoptosis induction. Consequently, the [74]. However, preparation of the alkyne intermediates involves anti-inflammatory and apoptosis inducing properties of cele- a number of steps and often requires extensive column chroma- coxib are assumed to result via different modes of action. tography, which makes it an unattractive method for synthesis on a larger scale (Scheme 48). In a recent study [71], celecoxib has also been shown to be a rapid, freely reversible, competitive inhibitor of COX-1. This result was supported by X-ray crystallographic evidence, where celecoxib was shown to bind to one subunit of the COX-1- dimer, implying that drugs like aspirin then bind to the other monomer of the same enzyme consequently slowing down the irreversible acetylation of a serine residue by aspirin itself. This finding is relevant as aspirin is clinically used in combination with celecoxib to attenuate its cardiovascular side effects. Based on this in vitro study, it is suggested that the cardioprotective effects of low-dose aspirin on COX-1 might be reduced when administered with celecoxib. Further studies are currently underway to elucidate the full sympathetic action of co-admin- Scheme 48: Alternative synthesis of celecoxib. istration.

The common synthetic route to the diarylpyrazole ring of cele- A novel 1,3-dipolar cycloaddition between a nitrile imide 244 coxib (235) is a direct condensation of the 1,3-dicarbonyl com- and an appropriately substituted olefin 245 has also been used pound 236 and the substituted hydrazine 237 [72,73] to obtain the corresponding trisubstituted pyrazole [75]. The (Scheme 47). final synthesis and its dipole precursor are represented in Scheme 49. The immediate downside to this approach is the generation of regioisomeric mixtures. However, this is often of minor Since this is a LUMO-dipole/HOMO-dipolarophile controlled concern. In the commercial process only 2–5% of the unwanted reaction, an electron-rich alkene is required. Therefore, when regioisomer is produced, with the purified pyrazole being the morpholine derived enamine 245 was used the desired obtained by crystallisation. It has been claimed that minimising 1,3,5-substituted pyrazole was formed with 100% regiose- the diketone’s exposure to water prior to its reaction with the lectivity (Scheme 49). This high regioselectivity is only hydrazine significantly reduces the formation of the unwanted obtained when a 1,1-disubstituted enamine is used, the corres- regioisomer by avoiding the formation of a hydrate at the car- ponding 1,2-disubstituted enamine yields mainly the other bonyl bearing the more electronegative CF3-group. Alter- regioisomer.

Scheme 47: Preparation of celecoxib.

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Scheme 49: Regioselective access to celecoxib.

Indazole be methylated entirely regioselectively with either Meerwein’s Pazopanib (246, Votrient) is a new potent multi-target tyrosine salt, trimethyl orthoformate or dimethyl sulfate. A tin-mediated kinase inhibitor for various human cancer cell lines. Pazopanib reduction of the nitro group unmasks the aniline which under- is considered a promising replacement treatment to imatinib and goes nucleophilic aromatic substitution to introduce the sunitinib and was approved for renal cell carcinoma by the FDA pyrimidine system with the formation of 253. Methylation of in late 2009. The indazole system is built up via diazotisation the secondary amine function with methyl iodide prior to a and spontaneous cyclisation of 2-ethyl-5-nitroaniline (247) second SNAr reaction with a sulfonamide-derived aniline using tert-butyl nitrite. The resulting indazole structure 249 can affords pazopanib (Scheme 50) [76,77].

Scheme 50: Synthesis of pazopanib.

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Scheme 51: Syntheses of anastrozole, rizatriptan and letrozole.

1,2,4-Triazole the corresponding benzyl bromide component first with Although many common antifungal drugs contain at least one 4-amino-1,2,4-triazole (266) to form a quaternary ammonium 1,2,4-triazole ring, barely any of these drugs are represented in salt. The latter can be deaminated to give anastrozole with no the top 200 drugs based on the value of sales. This observation isomeric impurities (Scheme 52) [79]. obviously reflects more the price differential of the drug class rather than the utility of the heterocycle. In general, the triazole containing drugs belong to two groups of therapeutic agents: selective and non-steroidal aromatase inhibitors which are used in the treatment of early and advanced breast cancer in postmenopausal women, e.g., letrozole (256, Femara) and anastrozole (257, Arimidex) and 5-HT1 agonist triptan drugs such as rizatriptan (76, Maxalt) which are prescribed for migraine head- aches. The large scale syntheses of all these compounds use the commercially available 1,2,4-triazolyl sodium salt 258 in an alkylation reaction with the corresponding benzyl bromide derivative as the key step (Scheme 51) [78].

One major problem with this route towards anastrozole (257) (Scheme 51) is the formation of the non-desired regioisomer, which is often produced in between 10–20% and must be removed by means of crystallisation which results in a major loss of material [79]. In order to circumvent the formation of the Scheme 52: Regioselective synthesis of anastrozole. undesired regioisomer, a strategy that is often used is to react

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Scheme 53: Triazine-mediated triazole formation towards anastrozole.

Other synthetic routes to 1,2,4-triazoles have also been blood glucose levels in diabetes type II patients. Structurally, reported. For example, the desired triazole ring of anastrozole this novel antihyperglycaemic consists of a fluorinated β-amino can be obtained by reacting an appropriately substituted acid which is coupled to a trifluoromethylated triazolo- hydrazine hydrochloride salt 269 with triazine (270) piperazine (Scheme 55). In SAR studies this fused heterocycle (Scheme 53) [80]. was found to be more metabolically stable compared to earlier leads that contained a simple piperazine ring. Furthermore, the It has been proposed that this novel transformation occurs by a triazolopiperazine is not only involved in a tight H-bond two step process: Initially, a molecule of triazine undergoes network within the active site of DPP-IV, but also in π-stacking condensation and ring cleavage with the hydrazine to generate with the aromatic ring of a nearby phenylalanine residue, whilst formamidrazone 271 which then immediately reacts with a the trifluoromethyl group interacts with serine and arginine second molecule of triazine to yield the 1,2,4-triazole [81]. residues in a lipophilic pocket (Figure 8) [83]. Hence, in this case the triazine can be considered as a formamide donor. In the discovery chemistry route [84] the heterocycle core was

prepared from a SNAr reaction between chloropyrazine (276) Rizatriptan (76) has also been prepared by both the above and excess hydrazine. Subsequent treatment of the substituted mentioned procedures, i.e., via the pre-made triazole or by treat- intermediate with trifluoroacetic anhydride furnished the corres- ment of a hydrazine hydrochloride salt with triazine ponding bis-hydrazide 278 which underwent cyclisation at elev- (Scheme 54) [82]. Indeed, the latter protocol has been further ated temperatures in the presence of polyphosphoric acid. expanded to make use of additional formamide surrogates such Finally, the partial hydrogenation of triazolopyrazine derivative as a formamidinium salt 273 or Gold’s reagent (274) 279 with palladium on carbon gave the core triazolopiperazine (Scheme 54). 280. This was then coupled with carboxylic acid unit 281 under standard peptide bond forming conditions and subjected to pal- Sitagliptin (275, Januvia) is a recently developed oral anti- ladium catalysed debenzylation to liberate the free amine func- diabetic drug which belongs to the dipeptyl peptidase DPP-IV tionality of sitagliptin (275) (Scheme 55). inhibitor class. The inhibition of DPP-IV leads to increased incretin levels and the inhibition of glucagon release. An inherent problem with this synthesis was the necessity for Consequently, insulin secretion increases leading to decreased excess hydrazine in the first step of the sequence in addition to a

Scheme 54: Alternative routes to 1,2,4-triazoles.

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Scheme 55: Initial synthetic route to sitagliptin.

Scheme 56: The process route to sitagliptin key intermediate 280.

A novel and very promising HIV treatment is Pfizer’s maraviroc (286, Celsentri). HIV uses a member of the G-protein Figure 8: Binding of sitagliptin within DPP-IV. coupled receptor family called CCR-5 as an anchor to attach itself to white blood cells such as T-cells and macrophages fol- requirement for an expensive and only moderately efficient pal- lowed by viral fusion and entry into white blood cells. Mara- ladium reduction in the penultimate step. Furthermore, the viroc blocks this pathway by acting as an antagonist for the chloropyrazine starting material also proved to be unstable CCR-5 receptor hence disrupting HIV life cycle. The structural under a series of reaction conditions and gave rise to numerous features of this molecule are a geminal difluorocyclohexyl by-products. An improved route was developed for the com- carboxamide which is linked to a β-aminoacid, and a tropinone- pounds large scale manufacture. The refined process route type unit bound to a 1,2,4-triazole ring. Relatively simple and (Scheme 56) starts with a sequential bis-acylation of hydrazine straightforward chemical transformations are used to assemble with ethyl trifluoroacetate and chloroacetyl chloride [85]. The the main fragments of maraviroc such as amide bond formation resulting hydrazide 283 was then subjected to cyclodehydration and reductive amination (Scheme 57) [86]. The triazole ring using phosphoryl chloride to give a chloromethyl oxadiazole incorporation is achieved at an early stage by N-acylation of the derivative 284. In a cleverly staged transformation, this com- tropinone fragment 287 with 2-methylpropanoyl chloride (288). pound was treated with diaminoethane to yield the piperazine The resulting amide 289 is then converted to the corresponding ring 285, which, on heating under reflux in methanol, under- imidoyl chloride 290 using phosphorous pentachloride in goes a further condensation with the attached hydrazide to dichloromethane (which proved to be superior to phosphoryl furnish the desired triazolopiperazine ring 280 directly. chloride) followed by condensation with acetic hydrazide (291).

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Scheme 57: Synthesis of maraviroc.

It was found that the dryness of the acetic hydrazide was crucial cological profile of these drugs. A representative of this com- in order to minimise the hydrolysis of the starting amide 289. pound class is alprazolam (297, Xanax) which contains a 1,2,4- triazole fused to the benzodiazepine core. The synthesis of this Benzodiazepines are a well known class of compounds with a molecule [87,88] (Scheme 58) can be accomplished in a short wide range of CNS-related activities. Moreover, the attachment sequence of steps starting by acylation of 2-amino-5-chloroben- of a third ring has been found to impact greatly on the pharma- zophenone (298) with chloroacetyl chloride (281) to give the

Scheme 58: Synthesis of alprazolam.

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amide derivative 299. The latter undergoes an interesting ring closure reaction in the presence of hexamine and ammonium chloride and the resulting seven membered lactam 300 can then be converted into its thioamide analogue 301 with P2S5 in pyridine. Finally, the reaction of 301 with acetyl hydrazide (291) catalysed by acetic acid furnishes the triazole ring fused to the benzodiazepine core.

Another approach [89] makes use of 1,4-benzodiazepine-N- nitrosamidine 302 as the starting material which when treated with acetyl hydrazide (291) undergoes the final ring closure. This procedure can also be employed to prepare the related series of imidazobenzodiazepines if TosMIC (303) or the aminopropanol 304 are used as nucleophiles (Scheme 59).

Triazole containing antifungal compounds (Figure 9) are a well known group of pharmaceuticals but only a few members are represented in the list of best selling drugs, e.g., itraconazole (307, Sporanox), ravuconazole (308, BMS-207147) and Figure 9: Structures of itraconazole, ravuconazole and voriconazole. voriconazole (309, Vfend).

All members of this class share a common biological activity nucleophilic substitution. However, due to the previously being inhibitors of fungal cytochrome P-450 oxidase-mediated discussed regioselectivity issues, extensive chromatographic synthesis of ergosterol. Itraconazole, marketed by Janssen purification was required following this step. In the latter stages Pharmaceuticals, consists of two triazole subunits as well as a of the synthesis, the elaborated aniline derivative 310 was central diarylpiperazine unit (Figure 9). In one synthesis of trapped with phenyl chloroformate to form the corresponding itraconazole [90] 1,2,4-triazole was introduced via direct carbamate which was then converted into triazolone 314 by a

Scheme 59: The use of N-nitrosoamidine derivatives in the preparation of fused benzodiazepines.

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Scheme 60: Synthesis of itraconazole. double condensation reaction with hydrazine and formamidine. Finally, simple attachment of an isobutyl group completes the synthesis (Scheme 60).

1,2,3-Triazole Rufinamide (315, Inovelon) is Novartis’ new CNS-active compound used in the treatment of epilepsy. The common route [91,92] to the triazole ring present in this compound involves the reaction of 2,6-difluorobenzyl azide (316) with 2-chloro acrylonitrile 317 at temperatures around 80 °C in aqueous medium (Scheme 61). This transformation, which can be described either as a conjugate addition–elimination sequence or as a [3 + 2] cycloaddition followed by elimination was found to work best in a biphasic system, where the resulting HCl was Scheme 61: Synthesis of rufinamide. retained in the aqueous phase thereby reducing overall amounts of polymerisation of the 2-chloroacrylonitrile starting material. In the final step the nitrile group is quantitatively hydrolysed substituted with the less toxic and less expensive methyl under basic conditions to the primary amide. 3-methoxyacrylate. After thermal cycloaddition, the methyl ester is converted to the corresponding amide by the addition of Apart from this patented route, an improved approach has methanolic ammonia. Overall, this process can be performed as recently been described [93]. In this work it was shown that the a single pot procedure on a multi-gram scale to afford rufin- highly toxic and flammable 2-chloroacrylonitrile can be readily amide in a similarly high yield and generating less waste.

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Tetrazole The tetrazole motif as a bioisostere for a carboxyl group is a well documented structural replacement represented by five angiotensin II antagonists in the top selling 200 drugs. In order to generate the tetrazole ring, a nitrile is reacted with an azide, most commonly tributyltin azide. This is illustrated by the Novartis/Ciba-Geigy synthesis of valsartan (319, Diovan), where the tetrazole ring is constructed in the last step of the sequence (Scheme 62) [49].

Scheme 63: Early stage introduction of the tetrazole in losartan.

hydrazoic acid delivered as a 10% solution in benzene [95,96]. Scheme 62: Representative tetrazole formation in valsartan. Subsequent alkylation under Williamson conditions provides the final compound 325 in good yield (Scheme 64).

The same approach is repeated in other angiotensin AT2 antagonists, such as olmesartan (158), candesartan (204) or irbesartan Thiazole (321) (Figure 10). The first example of a thiazole in the top 200 drugs listings is cefdinir (329, Omnicef, Figure 11), a semi-synthetic third The tetrazole ring has also been introduced at the beginning of generation cephalosporin which is administered orally and has the synthesis, however, the heterocyclic ring, which has to be an extended antibacterial activity against both gram-positive carried through all subsequent steps, often requires protection. and gram-negative bacteria. The main feature of cefdinir is that One common protecting group is the trityl group as used in the it shows excellent activity against Staphylococcus species [97]. synthesis of losartan (157) (Scheme 63) [51,94]. The thiazole ring in cefdinir shows that the heterocyclic structure in a drug not only affects its pharmacodynamic properties The tetrazole ring also appears in cilostazol (325, Pletal) which but can also influence its kinetics. It is believed that in the is a selective PDE3 phosphodiesterase inhibitor used as a digestive tract iron(II) ions form chelate complexes with the platelet aggregation inhibitor. The tetrazole ring 327 is prepared thiazole ring and the oxime nitrogen atom and hence reduce the via the reaction of an in situ generated imidoyl chloride and bioavailability of cefdinir [98].

Figure 10: Structure of tetrazole containing olmesartan, candesartan and irbesartan.

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Scheme 64: Synthesis of cilostazol.

The convergent semi-synthesis of cefdinir can be achieved by coupling 7-amino-3-vinyl-3-cephem-4-carboxylic acid ester 335 with an advanced carboxylic acid derivative 334 which contains the elaborated thiazole motif (Scheme 65). This heterocyclic acid can itself be obtained from ethyl acetoacetate which is converted to an oxime 330 and α-chlorinated prior to a Hantzsch-type thiazole synthesis with thiourea in ethanol and N,N-dimethylaniline as the base [99]. Simultaneous trityl protection of the oxime and primary amine furnishes the desired coupling partner 334 in good overall yield. Hydroxide promoted ester hydrolysis was followed by treatment with phosphoryl chloride and the resulting acyl chloride coupled with the biologically derived lactam 335. All three trityl protecting groups Figure 11: Structure of cefdinir. are simultaneously cleaved with TFA to furnish cefdinir 329.

Scheme 65: Semi-synthesis of cefdinir.

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Scheme 66: Thiazole syntheses towards ritonavir.

The HIV-1 protease inhibitor ritonavir (337, Norvir, Scheme 66) consists of two differently substituted thiazole rings, which are introduced at the later stages in the synthesis of this peptidomimetic antiviral compound. Interestingly, ritonavir itself is a result of further improvements on earlier candidates for the treatment of AIDS. A lead compound (344, A-80987) was also described by Abbott bearing pyridine rings on both ends of the peptidomimetic structure, which resulted in good bioavailability as required for orally administered drugs, but this compound had an insufficient plasma half-life. This was ascribed to the more electron-rich nature of the pyridine rings when compared to many other nitrogen containing heterocycles leading to a higher metabolic susceptibility. Consequently, the Scheme 67: Synthesis towards pramipexole. pyridine rings were replaced with less electron-rich thiazoles which resulted in both good bioavailability and a long plasma half-life. In addition, H-bonding of the 5-substituted thiazole to elemental sulfur to give the α-thioketone 351 (Scheme 68). This the backbone of Asp-30 of the HIV-1 protease is reported to be in turn can be treated with cyanamide to furnish the racemic crucial with other substitution patterns showing reduced thiazole 345 [103]. Resolution with (+)-ditoloyl-D-tartrate potency. The thiazole on the left-hand side is derived from the allows isolation of the desired S-enantiomer after treatment of condensation between 2-methylpropane thioamide 338 and the diastereomeric salt with sodium carbonate. dichloroacetone 339 [100], whilst the other thiazole is obtained from the inexpensive 2,4-thiazolidinedione (341, Scheme 66) Famotidine (352, Pepcidine) is an H2-receptor antagonist [101]. similar to cimetidine which inhibits many isoenzymes of the hepatic CYP450 system and has the additional side effect of

The dopamine D2-agonist pramipexole (345, Mirapex) consists increasing the amount of gastric bacteria such as nitrate reduc- of a fused bicyclic tetrahydrobenzothiazole motif, which is also ing bacteria. The structure of this ulcer therapeutic is very prepared by a Hantzsch-type condensation between an α-brom- interesting and consists of a thiazole substituted guanidine and a inated protected form of 4-aminocyclohexanone 346 and sulfamoyl amidine. Although famotidine is orally administered, thiourea. Following deprotection, resolution with L-(+)-tartaric its solubility and hence bioavailability under acidic conditions, acid gives access to the S-enantiomer which undergoes as found in the stomach, is relatively low. Recent reports have reductive amination and can be isolated as the dihydrochloride appeared that describe famotidine as a good ligand for various salt (Scheme 67) [102]. transition metals including copper and cobalt forming tetradentate {N,N,S,N}-coordination spheres as shown by single Alternatively, the thiazole ring can be made in a one pot reac- X-ray analysis [104]. It therefore seems feasible that certain tion from the corresponding enamine 350, which is reacted with common bioavailable cations might be involved in the absorp-

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to the imidate and subsequently coupled with sulfamide to yield famotidine (Scheme 69).

A final example of a thiazole containing drug is given in the novel xanthine oxidase inhibitor febuxostat (359, Uloric) which was approved by the FDA in 2009. This inhibitor works by blocking xanthine oxidase in a non-competitive fashion. Consequently, the amount of the oxidation product uric acid is reduced. Thus it is an efficient treatment for hyperuricemia in gout. In order to prepare febuxostat first a synthesis of the non- commercial 4-isobutoxy-1,3-dicyanobenzene building block (363), has to be conducted. An elegant way of achieving this was shown through the reaction of 4-nitrocyanobenzene (360) with potassium cyanide in dry DMSO followed by quenching with isobutyl bromide under basic conditions (Scheme 70). It is suggested that a Meisenheimer-complex intermediate 361 is Scheme 68: Alternative route to pramipexole. initially formed, which after rearomatisation, undergoes nucleophilic aromatic substitution of the nitro group by the DMSO tion and activation of this thiazole containing compound. The solvent [107]. Upon hydrolysis and O-alkylation the desired synthesis of the thiazole ring [105,106] can be accomplished 4-isobutoxy-1,3-dicyanobenzene (363) is obtained in good again by condensation of thiourea with dichloroacetone 340. overall yield. Subsequently, the less hindered nitrile is Alkylation of the isothiourea sulfur with 3-chloropropionitrile converted to the corresponding thioamide 365 in an intriguing (354) and hydrolysis results in the formation of the substitution reaction using thioacetamide (364). The thiazole ring is then product 355. Functionalisation of the resulting 2-amino group formed by condensation with chloroacetoacetate 366 followed on the thiazole ring using benzoyl isothiocyanate generates the by ester hydrolysis (Scheme 70). guanidine precursor 357. A standard sequence of methylation and exchange with ammonia simultaneously cleaves the Ziprasidone (367, Geodon), is an atypical antipsychotic used to benzoyl group and unmasks the guanidine unit 358. At the other treat schizophrenia as well as mania and related bipolar disorder peripheral of the molecule the nitrile functionality is converted (Scheme 71). The exact pharmacological effect of ziprasidone

Scheme 69: Synthesis of famotidine.

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Scheme 70: Efficient synthesis of the hyperuricemic febuxostat. is not simple to understand as it affects many subtypes of hydrochloride-salt, the nucleophilic aromatic substitution step dopamine, adrenergic and serotonin receptors. However, like (370→371) was poor and gave only 38% of the desired product many antipsychotic drugs its main therapeutic activity is prob- [110]. Therefore an improved process was developed involving ably due to its antagonistic action on dopamine receptors. The the oxidative coupling of piperazine with bis(2-cyano- molecule comprises of a 1,2-benzisothiazole core, which is phenyl)disulfide (368) at elevated temperatures [109]. Due to readily prepared from commercially available the use of DMSO as a co-solvent and oxidant, each equivalent benzo[d]isothiazol-3(2H)-one (369), a saccharin derivative of the disulfide component was then converted into two equiva- [108]. The corresponding chloroimidate 370 formed by treat- lents of the product making the process more economically effi- ment of compound 369 with phosphoryl chloride is reacted with cient. The final union was accomplished using standard Finkel- excess piperazine to afford intermediate 371 (Route A) [109]. stein alkylation conditions furnishing ziprasidone in 90% yield Although this route enabled the synthesis of ziprasidone as its (Scheme 71) [111].

Scheme 71: Synthesis of ziprasidone.

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Furan cysteamine hydrochloride (380) which leads to replacement of Mometasone (373, Nasonex) is one of the few examples the hydroxyl functionality. Finally, coupling of amine 379 with amongst the top selling pharmaceutical drugs that contains a N-methyl-1-methylthio-2-nitroethenamine (381) furnishes rani- furan ring. Simple furan structures are not normally viable tidine (Scheme 73) [112]. because of their propensity for rapid metabolism by various oxidation mechanisms. Mometasone is a moderately potent gluco- corticoid used for the treatment of inflammatory skin disorders, asthma and allergic rhinitis. Because it is delivered topically or is inhaled, it is not subject to rapid metabolism. Structurally, it consists of a chlorinated dexamethasone core which is esteri- fied with 2-furoic acid at the 17-position (373, Figure 12).

Figure 12: Structure of mometasone.

Scheme 73: Synthesis of ranitidine from furfuryl alcohol. 2-Furoic acid (375) can be obtained via a Cannizzaro-type disproportionation of furfural (374) which is industrially produced from corncobs: Annual production ca. 450,000 tons. In addition, the antibiotic nitrofurantoin (382, Macrobid) used Corncobs contain hemicelluloses which degrade to xylose under in the treatment of urinary infections is based on a nitrofurfural acidic conditions. Upon strong heating, xylose is converted to building block which can be obtained by nitration of furfural furfural, which can be distilled from the biomass (Scheme 72). (374) [113]. The isolated derivative, acetal 383, can be converted to nitrofurantoin via condensation with amino- hydantoin 384 which itself is obtained from cyclisation of semi- carbazidoacetic acid under acidic conditions (Scheme 74) [114].

Scheme 72: Industrial access to 2-furoic acid present in mometasone.

The furfuryl alcohol (376) obtained in the abovementioned disproportionation (Scheme 72) is also a key starting material for the peptic ulcer therapeutic ranitidine (377, Zantac). In the Scheme 74: Synthesis of nitrofurantoin. synthesis of this H2-receptor antagonist, furfuryl alcohol is subjected to a Mannich reaction with paraformaldehyde and dimethylamine hydrochloride. The resultant (5-((dimethyl- Amiodarone (385, Cordarone) is an antiarrhythmic drug amino)methyl)furan-2-yl)methanol (378) is then treated with containing a benzofuran ring system. It is one of the most

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effective antiarrhytmic drugs. Although it is considered a class III antiarrhytmic with its mode of action being principally the blocking of potassium channels, it is anticipated that it is also capable of targeting additional sodium and calcium channels. This might explain its general effectiveness, but could also account for its potentially dangerous side effects. The basic benzofuran framework is commonly prepared by alkylation of salicylic aldehyde (386) with chloroacetic acid (387) to give the dihydrobenzofuran carboxylic acid which after intramolecular condensation readily decarboxylates (Scheme 75).

Scheme 75: Synthesis of benzofuran.

Scheme 76: Synthesis of amiodarone. A more recent synthesis of amiodarone reports the cyclisation of α-phenoxyhexanal 389 under acidic conditions to yield the substituted benzofuran 390 (Scheme 76). A Friedel–Crafts acyl- Zyprexa). The former, which is a benzo[b]thiophene, is widely ation next introduces the aryl ring at the 3-position. Demethyl- used as an oral selective estrogen receptor modulator displaying ation, iodination and a final alkylation with a diethylamino- estrogenic actions on bone (prevention of osteoporosis) and ethane fragment yields amiodarone [115-117]. anti-estrogenic actions on breast and uterus, especially in the postmenopausal women [118]. The synthesis of the Thiophene benzo[b]thiophene core 396 was accomplished by condensing Considering the fact that thiophene is a classical bioisostere for 3-mercaptoanisole (393) with 4-methoxyphenacyl bromide a benzene ring it is not surprising that it is encountered in many (394) firstly under basic conditions to affect the SN2 displace- therapeutically active agents. Amongst the drugs containing a ment followed by dehydration with polyphosphoric acid at elev- thiophene ring are raloxifene (392, Evista) and olanzapine (399 ated temperatures (Scheme 77) [119]. Further transformations

Scheme 77: Synthesis of raloxifene.

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on this scaffold include the introduction of the carbonyl at the the thienobenzodiazepine 408. Substitution of the pendant 3-position via a Friedel–Crafts acylation and deprotection, amine group with excess N-methylpiperazine (409) then affords yields raloxifene. olanzapine in modest overall yield (Scheme 79) [121].

A non-classical approach to this same benzo[b]thiophene core In a similar process the malononitrile was replaced with the less 398 is outlined in Scheme 78 [120]. The vinylic sulfoxide 396 toxic methyl cyanoacetate (410) to give the alternative com- undergoes a formal electrophilic cyclisation under the acidic pound 411 (Scheme 80). The previously used nucleophilic conditions followed by aromatisation to furnish the desired substitution was repeated to furnish the methyl ester analogue intermediate in high yield. 412. Then, in order to avoid the use of the strongly acidic reduction and cyclisation conditions employed in Scheme 79 (407→408), a milder palladium catalysed hydrogenation was used. Finally, a one pot intramolecular amide formation fol-

lowed by a TiCl4-mediated reaction to introduce the amidine function yields olanzapine (Scheme 80) [122].

Three additional thiophene-containing drugs are duloxetine (414, Cymbalta), tiotropium (415, Spiriva) and Cosopt [dorzol- Scheme 78: Alternative access to the benzo[b]thiophene core of amide (416) (Figure 13) and its second active ingredient timolol raloxifene. (see also Scheme 84)]. However, the syntheses of all three compounds use simple thiophene starting materials, viz. the Another atypical antipsychotic drug which has been long estab- carboxylic acid 417, for duloxetine [123], or a Grignard reagent lished as a top-selling pharmaceutical is olanzapine (399) which (418) for tiotropium [124] and thiophene-2-thiol (419) for was first introduced to the market by Eli Lilly in 1996. The dorzolamide [125]. thiophene unit is synthesised by a multi-component reaction between malononitrile, elemental sulfur and propionaldehyde One of the most successful platelet aggregation inhibitors (400) in the presence of triethylamine. This Gewald-type currently on the market is clopidogrel (420, Plavix) which is a thiophene synthesis is thought to proceed via an initial chiral tetrahydrothieno[3,2-c]pyridine derivative (Scheme 81). Knoevenagel reaction (400→402) followed by the addition of In the favoured synthetic route this tricyclic motif is prepared the sulfur into the nitrile to form thiocyanate 403 which then by a nucleophilic substitution of α-bromo 2-chlorophenyl aceto- ring closes to the aminothiophene product 405. This species is nitrile (421) with a secondary amine 422. Subsequent hydro- then employed in a nucleophilic aromatic substitution with lysis of the secondary nitrile under phase transfer conditions 2-fluoronitrobenzene (406) to give the coupled product 407. delivers the free acid which is converted to the methyl ester Reduction of the nitro functionality produces the corresponding 424. In order to obtain the desired S-enantiomer, a classical aniline that readily undergoes ring closure to furnish ultimately resolution with ca. 0.5 equiv of L-camphorsulfonic acid

Scheme 79: Gewald reaction in the synthesis of olanzapine.

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Scheme 80: Alternative synthesis of olanzapine.

Scheme 81: Synthesis of clopidogrel.

methane. Reduction of the nitro olefin function to the corresponding alkylamine followed by reaction with formaldehyde gave the corresponding imine 426 [127]. Treatment of the latter with hydrochloric acid initiates a Pictet–Spengler reaction to Figure 13: Access to simple thiophene-containing drugs. furnish the desired heterocycle in high overall yield (Scheme 82). (L-CSA) in toluene is used. The desired enantiomer 420 is collected as a crystalline salt in greater than 98% ee and 88% of the expected yield (Scheme 81) [126]. The remaining material can be easily epimerised under mildly basic conditions.

Although the tetrahydrothieno[3,2-c]pyridine structure 422 is now readily available on a large scale from various commercial sources, it was originally synthesised in a variety of ways. The most straightforward route was from thiophene-2-carbaldehyde Scheme 82: Pictet–Spengler reaction in the preparation of tetrahydrothieno[3,2-c]pyridine (422). (425) which was subjected to a Henry reaction with nitro-

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This key compound can also be accessed by assembling the Thiadiazole thiophene ring. In this scenario N-protected 4-piperidone 427 is Cosopt, an ophthalmic medication, consists of the two active subjected to Vilsmeier conditions to produce the reactive ingredients dorzolamide (416; Figure 13), a carboanhydrase chloroaldehyde species 428 which, upon treatment with ethyl inhibitor used as an anti-glaucoma agent, and timolol (432; mercaptoacetate (429), cyclises to the heterocyclic structure Figure 14) a β-adrenergic receptor blocker used to lower intra- although in only low isolated yield. Simple base hydrolysis of ocular pressure by reduction of aqueous humour production. In the ester followed by decarboxylation generates the desired pro- a recent report an X-ray co-crystal structure of timolol within duct (Scheme 83) [128]. the β2-adrenergic receptor was disclosed [129]. An overlay of

Scheme 83: Alternative synthesis of key intermediate 422.

Figure 14: Co-crystal structures of timolol (left) and carazolol (right) in the β-adrenergic receptor.

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this structure with a previous one showing the position of access to the other enantiomer of timolol. Under basic condi- carazolol (433), an analogue of the previously mentioned tions the chlorohydrin 438 can be converted to the corres- carvedilol (136) β-blocker, shows the binding of these ponding epoxide which can be ring opened by tert-butyl amine molecules (Figure 14). Additionally, this data nicely exempli- to furnish timolol (Scheme 84). fies the stronger binding of timolol, as its morpholine group is involved in an extra hydrogen-bonding network with nearby A related heterocyclic structure can be found in the skeletal amino acids (Asn, Tyr, Ser) and the thiadiazole motif itself muscle relaxant tizanidine (440, Zanaflex). This substituted protrudes deeper into the actual binding pocket when compared 2,1,3-benzothiadiazole 442 can be prepared by the reaction of with the carbazole system of carazolol which results in stronger an aromatic diamine 441 on heating with thionyl chloride in the interactions. presence of DMF. Selective nitration followed by an iron-mediated reduction affords the corresponding aniline 443 which Whilst the synthesis of the thiophene-containing component partakes in a nucleophilic substitution of 2-chloro-3,4- (dorzolamide) of Cosopt starts from 2-mercaptothiophene and dihydroimidazole (generated in situ from the reaction of the elaborates the thienothiopyran motif in a linear multi-step urea 444 and phosphoryl chloride). Removal of the acetate fashion, the thiadiazole ring of timolol is prepared from an group under basic conditions furnishes tizanidine (Scheme 85) acyclic precursor (Scheme 84). The active pharmaceutical [132]. ingredient (API) timolol is prepared via a biocatalytic asymmetric reaction which permits selective access to both enan- Isoxazoles and benzisoxazole tiomers [130]. Starting from 3,4-dichloro-1,2,5-thiadiazole The isoxazole ring is a common heterocyclic motif represented (435), which can be prepared from cyanogen (434) and sulfur by several of the top-selling small molecule pharmaceuticals. dichloride [131], the two chlorides are differentiated by sequen- This ring structure is often encountered as a surrogate of other tial substitution reactions using morpholine and sodium nitrogen containing heterocycles such as pyrazoles, pyridines or hydroxide. The resulting hydroxyl in compound 436 is pyrimidines [133]. Two specific drugs containing this structure alkylated with dichloroacetone to yield a carbonyl compound are leflunomide (446, Arava) and sulfamethoxazole (447, 437 susceptible to enzymatic reduction with baker’s yeast. The Bactrim). levorotatory enantiomer thus obtained can be subjected to Mitsunobu conditions with benzoic acid as the nucleophile and Leflunomide is a pyrimidine synthase inhibitor of the DMARD- leads to clean inversion of the stereocentre which thus gives type (disease-modifying anti-rheumatic drug) marketed by

Scheme 84: Synthesis of timolol.

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resulting ethyl ethoxymethylene acetoacetate (448) is next condensed with hydroxylamine hydrate in methanol to yield ethyl 5-methylisoxazole-4-carboxylate (449). The ethyl ester is hydrolysed under acidic conditions and the carboxylic acid activated with thionyl chloride in DMF for amide formation with 4-trifluoromethylaniline (450) (Scheme 86).

A related condensation between (E)-4-(dimethylamino)but-3- en-2-one (451) and hydroxylamine is used in the synthesis of bactriostatic antibiotic sulfamethoxazole (447) to yield the equivalent 5-methylisoxazole (452) (Scheme 87). This basic unit is then nitrated with a mixture of ammonium nitrate in trifluoroacetic anhydride 240, which is presumed to form the active trifluoroacetyl nitrate, and converted to the 3-amino-5- methylisoxazole (453) in a aluminium-amalgam mediated reduction [135,136]. Sulfonamide formation with the sulfonyl chloride 454 yields the antibiotic agent 447 (Scheme 87).

The most prescribed therapeutic for schizophrenia is the Scheme 85: Synthesis of tizanidine 440. benzisoxazole containing antipsychotic risperidone (455, Risperdal). For this molecule the benzisoxazole ring is formed Sanofi-Aventis. Unlike NSAIDs, which only deal with symp- via an intramolecular nucleophilic aromatic substitution toms of rheumatoid arthritis, DMARDs target the cause of it. between an in situ generated oxime 459 and the adjacent DMARDs are not necessarily structurally or mechanistically aromatic ring [137]. The precursor carbonyl derivative 458 related. The effect of leflunomide is possibly due to its regula- arises from a Friedel–Crafts acylation of the difluoroaromatic tion of the immune system via affecting lymphocytes. Its syn- 457 (the acetate N-protecting group is presumably lost in the thesis [134] is relatively straightforward starting with a work up). Finally, alkylation of the piperidine ring under Knoevenagel condensation of ethyl acetoacetate (39) and Finkelstein conditions is used to complete the synthesis of triethyl orthoformate in the presence of acetic anhydride. The risperidone (Scheme 88).

Scheme 86: Synthesis of leflunomide.

Scheme 87: Synthesis of sulfamethoxazole.

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Scheme 88: Synthesis of risperidone.

Conclusion potential heavy metal contamination. In addition, these reac- Having collected data with respect to many different reported tions are usually accompanied by the release of heat due to syntheses of drugs containing heteroaromatic five-membered exothermic reaction profiles which might result in difficult to rings, a number of observations can be drawn. For instance, it control and therefore undesired chemical processes. was established that the most common transformations used are indeed condensations and nucleophilic substitution reactions An additional comment should be made about the time frame of (Figure 15) [138,139]. This can be rationalised by considering new reaction uptake within the process environment. For certain that only small molecular weight by-products such as water or reaction types such as metathesis and C–H activation, which hydrogen chloride/bromide are generated, which are benign and obviously offer significant synthetic potential, it could be can be easily removed. Other well represented transformations argued that the length of time required for these reactions to include reductions, amide and ester formations, rearrangements evolve from research tools to production processes are outwith and saponifications, which can be performed in an atom- the pipeline development times of the drugs under discussion. A economic manner based on numerous well established proto- significant body of the literature representing the synthesis of cols. On the other hand, other robust transformations such as these drugs date back many years to origins in the late seven- oxidations, nucleophilic aromatic substitutions, olefinations, ties and early eighties. Consequently, it is probably not unex- cycloadditions and metal-mediated transformations appear to be pected to see the absence of many of the ‘newer’ chemical rarely used. The reasons for this might be the need for stoi- methodologies. chiometric reagents leading to large amounts of waste as well as Interestingly, the above-mentioned classes of chemical reactions are most widely applied to a limited number of heterocyclic cores with indoles, triazoles and benzimidazoles being the most prominent examples to date (Figure 16). It can be postulated that this is likely due to two possible factors; 1) the utilisation of so-called ‘me-too drug’ approaches by pharmaceutical companies or 2) the fact that these are privileged structures which avoid the limitations of many other aromatic heterocycles in biological systems such as toxicity. However, the more recent trend seems to indicate a move towards more diverse scaffolds. This might be ascribed to the massive efforts of the pharmaceutical industry to find new drug classes, but could also be an indication of the patenting approaches used to protect more comprehensively these new developments. Figure 15: Relative abundance of selected transformations. Furthermore, this move towards novel heterocyclic structures

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also allows for more flexible substitution patterns permitting Acknowledgements extensive SAR studies through efficient high throughput screen- We gratefully acknowledge financial support from the ings commonly used today. Cambridge European Trust and the Ralph Raphael Studentship Award (to MB), the EPSRC (to NN), the Royal Society (to IRB) and the BP endowment (to SVL).

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