The Journal of
Organic Chemistry AUGUST4, 1989
VOLUME54, NUMBER 16
. . Communications N
Molecular Clefts. 1. Synthetic Methodology for the Preparation of Analogues of Kagan's Ether Michael Harmata* and Thomas Murray Department of Chemistry, University of Missouri-Columbia,
Columbia, Missouri 65211
Received M a y 8, 1989
Summary: A synthesis of analogues of Kagan's ether 7a is reported. The procedure has reasonable generality and promises to be important in the synthesis of molecular clefts. The final step consists of an electrophilic attack of an oxonium ion on an aromatic ring, and aromatics substituted with electron-withdrawing groups do not participate in the reaction.
Sir: The investigation of molecular cavities capable of binding to as well as inducing reactions of organic substrates is a recognized field of established and growing importance.' We wish to contribute to this area by preparing and studying a series of molecular clefts that are analogues of 5,6,11,12-tetrahydro-5,ll-epoxydibenzo[a,e]cyclooctene (Kagan's ether, 7a). The parent of this family is represented by 1. Inspection of Dreiding or CPK models suggests that the terminal phenyl rings of 1 lie in virtually parallel planes and are approximately 7 A apart. This distance is nearly ideal for binding an aromatic guest or "tweezing" a base pair of DNA.2 While the cleft in 1 is relatively shallow, appropriately constructed congeners should prove interesting as hosts for aromatic guests and DNA bis-inter~alators.~ In this paper we report some of the synthetic methodology we have developed to pursue these goals. (1) (a) Dugas, H. Bioorganic Chemistry-A Chemical Approach t o Enzyme Action; Springer-Verlag: New York, 1989. (b) Bender, M. L.; Bergeron, R. J.; Komiyama, M. The Bioorganic Chemistry of Enzymatic Catalysis; Wiley: New York, 1984. (c) Rebek, J., Jr. Top. Curr. Chem. 1988,149, 189. (2) For some information on molecular tweezers, see: Zimmerman, S. C.; VanZyl, C. M.; Hamilton, G. S. J. Am. Chem. SOC.1989,111,1373. Compound 1 is a molecular tweezer. (3) (a) Gale, E. F.; Cundliffe, E.; Reynolds, P. E.; Richmond, M. H.; Waring, M. J. The Molecular Basis of Antibiotic Action; Wiley: New York, 1981, Chapter 5. (b) Wakelin, L. P. G. Med. Res. Rev. 1986,6,275.
Kagan's ether, 7a, was first prepared by Kagan and co-workers by the reaction of phenylacetaldehyde with fluorosulfonic acid in carbon tetrachloride at 0 "C (eq 11.4 FSGH, CC14, O°C I PhCHPCHO
(1)
Of
h S I , CHCla, 5OC 78
Jung later reported this transformation utilizing TMSI to effect the dehydrative cyclodimeri~ation.~X-ray data show that 7a is folded with a 9 3 O angle between the aryl rings.'b Models and other X-ray datak indicate that this angle may vary somewhat depending on substitution. Concavity and rigidity combine to make Kagan's ether a (4) (a) Kagan, J.; Chen, S.-A.;Agdeppa, D. A., Jr. Tetrahedron Lett. 1977,4469. (b) Zabel, V.; Wataon, W. H.; Kagan,J.; Agdeppa, D. A., Jr.; Chen, S.-A.Cryst. Struct. Commun. 1978,7,727. (c)Chen, J. S.; Watson, W. H.; Kagan, J.; Agdeppa, D. A., Jr.; Chen, S.-A. Acta Crystallogr., Sect. B. 1978, B4,3627. (d) Kagan, J.; Agdeppa, D. A., Jr.; Chang,A. I.; Chen, S.-A.;Hamata, M. A. Melnick, B.; Patel, G.; Poorker, C.; Singh, S. P. J. Org. Chem. 1981,46,2916. See also: (e) %ll, T.;O h a n , G. W.; Leffler, H. Angew. Chem., Znt. Ed. Engl. 1984, 23, 622. (0Lagidze, R. M.; Iremadze, N. K.; Samsoniya, G. G.; Lopatin, B. V. Izu. Akad. Nauk SSSr, Ser. Khim. 1966,1459; Chem. Abstr. 1967,66,85715~.(9) Lagidze, R. M.; Iremadze, N. K.; Samsoniya, G. 0. Soobsch. Akad. Nauk GruzSSR, XLVZI 1967,2, 309; Chem. Abstr. 1968,68,68768r. (5) (a) Jung, M. E.; Mossman, A. B.; Lyster, M. A. J. Org. Chem. 1978, 43,3698. (b) Jung, M. E.; Miller, S. J. J. Am. Chem. SOC.1981,103,1984.
0022-3263/89/1954-3761$01.50/00 1989 American Chemical Society
3762
J. Org. Chem., Vol. 54, No. 16, 1989
Communications Scheme I
I
06%
Step 1
Step 2
Step 3 4
qo 1. DlBAL
2. MeOH,H*
5
IAr
m3
+
CHzCI2, SnCI, Step-78% 5
Step 4
R4
7
v
very promising building block for the construction of chiral molecular clefts. The fact that bridged, bicyclic dibenzo-1,5-cyclooctadiene structures should serve this role has been established. Wilcox's inspiring work on Troeger's base analogues amply demonstrates this.6 We believe this generic substructure in all its carbocyclic and heterocyclic manifestations has an exciting future in bioorganic and related chemistry. Several synthetic routes to other members of the family are readily known as are applications in the area of enantiomer rec~gnition.'~~ The methodology for the synthesis of Kagan's ether analogues available at the outset of our work allowed only the preparation of symmetrical While those methods have applicability to other problems we are (6) Wilcox, C. S. Tetrahedron Lett. 1985, 5749. (b) Wilcox, C. S.; Cowart, M. D. Ibid. 1986, 5563. (c) Larson, S. B.; Wilcox, C. S. Acta CrystalZogr.,Sect. C. Cryst.-Struct. Commun. 1986, C42,224. (d) Wilcox, C. S.; Greer, L. M.; Lynch, V. J. Am. Chem. SOC. 1987, 109, 1865. (e) Sucholeiki, I.; Lynch, V.;Phan, L.; Wilcox, C. S. J. Org. Chem. 1988,53, 98. See also: (f) Weber, E.; Miiller, U.; Worech, D.; Vwle, F.; Will, G.; Kirfel, A. J. Chem. SOC.,Chem. Commun. 1986, 1t78. (g) Fukae, M.; Inazu, T. J. InclusionrPhenom. 1984,2, 223. (7) Salicylaldehyde dimers: (a) Kulkarni, V. S. Hosangadi, B. D. Synth. Commun. 1986,16,191. (b) Jones, P. R.;Langan,M. E. Ibid. 1988, 18,433. (c) Bachet, P. B.; Brassy, C.; Guidi-Morosini, C. Acta Crystallogr., Sect. C. Cryst. Struct. Commun. 1986, C42,1630. Transition metal complexes of cyclic amidines: Huasain, M. S.; Ur-Rehman, S. Inorg. Chim. Acta 1982,6U, 231. Pavine alkaloids: (a) Knabe, J. Adu. Heterocycl. Chem. 1986, 40, 105. (b) Kyke, S. F. Ibid. 1972, 14, 279. (c) Nomoto, T.; Takayama, H. J. Chem. SOC.,Chem. Commun. 1982,1113. (d) Walsh, D. A.; Lyle, R. E. Tetrahedron. Lett. 1973,3849. (e) Zinnes, H.; Zuleski, F. R.; Shavel, J., Jr. J. Org. Chem. 1968,33,3605. (0 Stermitz, F. R.; Williams, D. K. Ibid. 1973,38,1761. (g) Kaneda, T.; Sakabe, N.; Tanaka, J. Bull. Chem. Soc. Jpn. 1976,49,1263. (h) Lagidze, R. N. Iremadze, N. K.; Vaehakidze, M. Sh. Zh. Org. Khim. 1968,4,2006. (i) Leeson, P. D.; James, K.; Baker, R. J. Chem. SOC., Chem. Commun. 1989, 433. Carbocycles and miscellany: (a) Tatemitsu, H.; Ogura, F.; Nakagawa, Y.; Nakagawa, M.; Naemura, K.; Nakazaki, M. Bull. Chem. SOC. Jpn. 1976,48,2473. 6)Kaneda, T.; Katayama, C.; Tanaka, J. Zbid. 1976, 49, 1709. (c) Roberta, R. M.; Anderson, G. P., Jr.; Khalaf, A. A,; Low, C.-E. J. Org. Chem. 1971,36,3342. (d) Low, C.-E.; Roberta,R. M. Zbid. 1973,38,1909. (e) Albini, A.; Faeani, E.; Oberti, R. J. Chem. SOC.,Chem. Commun. 1981, 50. (0 Albini, A.; Faaani, E.; Oberti, R. Tetrahedron 1982,38,1027. (g) Albini, A.; F d , E.; Sulpizio, A. J. Am. Chem. SOC. 1984,106,3562, (h) Caetonguay, A.; Berger, Y. A u t . J. Chem. 1979,32, 2681.
(8) (a) Naemura, K.; Fukunaga, R. Chem. Lett. 1985,1651. (b) Naemura, K.; Fukunaga, R.; Yamanaka, M. J. Chem. Soc., Chem. Commun. 1985, 1560.
pursuing, for our present purposes we desired a route that would allow more control over the introduction of functionality, particularly with respect to the aromatic systems present in the final product. Our synthesis is shown in Scheme I. Yields for the various steps are tabulated in Table I. The synthesis begins with the alkylation of l-carbomethoxy-2-indanone, readily available from the Dieckmann condensation of dimethyl o-phenylenedia~etate.~ Thus,treatment of a benzene solution of 2 with DBU gave a deep purple solution of the corresponding anion. Alkylation with the appropriate benzylic halide gave 3 in generally good yields.1° Decarboxylation of adducts 3 proved to be problematic. Standard decarboxylation procedures consistently gave low yields and/or extensive decomposition.'l We eventually found that 48% HBr in hot acetic acid served quite well to effect this transformation.12 At this point, what would become the oxygen bridge was added via a Baeyer-Villiger oxidation of indanones 4. Peracid oxidation13was not particularly useful, but 90% H20zin the presence of acetic anhydride and sulfuric acid produced the desired lactones 6 in good yield.14 We have not experienced any problems with this reaction, even on gram-scale preparations of 5. Reduction of the lactone to lactol with DIBAL and acetal formation with acidic methanol gave 6 in good yield. The final step consisted of a tin tetrachloride induced formation of oxonium ion 8 (CHZCl2,-78 "C), which closes via a Fried(9) Ali, E.; Owen, L. N. J. Chem. SOC.1968, 1066. (IO) Ono, N.; Ycahimura, T.; Saito, T.; Tamura, R.; Tanikaga, R.; Kaji, A. Bull. Chem. SOC.Jpn. 1979,52, 1716. (11) Numerous attempts to decarboxylate 3a or the corresponding
ethyl ester failed or proceeded poorly. Among reactions attempted were: (1) 3 equiv of TMSC1; 3 equiv of NaI; acetonitrile, reflux. (2) 3 equiv of LiCl; DMSO, 100 "C. (3) PhSLi; THF/HMPA; -20 to 25 'C. (4) 1.5 equiv of NaCN; acetonitrile, 25 O C . (5) 3 equiv of NaCN DMF, 35 OC. (6) 3 equiv of NaCN, HMPA/HIO, 25 OC, 42% 4a. (7) 3 equiv of NaCN HMPA, 75 O C , 30% 4a. (8) 3 equiv of NaCN HMPA, 25 OC, 38% 4a. (9) 2 equiv of LiCI; HMPA, 25-65 OC. (IO) 2 equiv of NaI; HMPA, 55
OC. (12) Mayer, R. In Newer Methods of Preparative Organic Chemistry; Foerst, W., Ed.; Academic: New York, 1963; Vol. 2, pp 101-131. (13) Peracids such aa mCPBA, peracetic and trifluoroperacetic acid effected the desired reaction, but only in relatively low yield and not very cleanly. (14) Markgraf, J. H.; Basta,S. J. Synth. Commun. 1972,2, 139.
Communications
J. Org. Chem., Vol. 54, No. 16, 1989 3763 Table I step 1
step 2
yields,' % step 3
step 4
step 5
a
69-73
73-89
59
66-69
67
b
84
77
66
82
96
57
46
73
entry
aryl group
M. C
d
61
57
40
44
60
e
39
60
36
81
91
f
78
66
60
49
0
Me0
Br
OAll yields are for products purified by chromatography or recrystallization.
al4raft.a alkylation to give Kagan's ether 7a and analogues 7b-e.16
While the methodology promises to have good generality, one problem was noted in the attempted synthesis of 7f. The preparation of 3f-f were straightforward. However, we have not yet been able to achieve the cyclization of 6f to form 7f. We were able to show that 6f had, in fact, been prepared. Treatment of 6f with nBusSnH and AIBN in refluxing benzene and reaction of the product with SnC14under our standard conditions gave 7a in 26% yield after chromatography as well as unreacted 6f (eq 2, no optimization attempted). Apparently the deactivating effect of the bromine substituent is sufficient to thwart the cyclization step, at least under the reactions conditions tried thus far. Efforts to overcome this problem are still in progress.16 1. (nBu)&H 2. SnCI,
6+
c 7a
(2)
"
(15) We have not explored Lewis acid variations extensively. However, treatment of 6a with BF,.EBO led to multiple product formation.
In conclusion, we have developed methodology for the preparation of unsymmetrical analogues of Kagan's ether. These structures provide a rigid, chiral framework for the construction of more intricate molecular clefts for use in molecular recognition, biomimetic chemistry, and preparation of new materials. Efforts to explore the chemistry of Kagan's ether and its analogues, establish substituent-structure relationships, and prepare 1 and its congeners are in progress and will be reported in due c~urse.~'J~ Acknowledgment. We are grateful to the National Science Foundation for partial support of the NMR (Grant PCM-8115599) and MS (Grant PCM-8117116) facilitates at the University of Missouri. Thanks to Dr. Hanna Gracz for acquisition of high-field NMR data. We gratefully acknowledge Dr. Charles L. Barnes for assistance in deciphering X-ray data. Supplementary Material Available: General experimental procedures for the preparation of 3a-7a as well as 'H NMR spectra for 7b-e (9 pages). Ordering information is given on any current masthead page.
(16)Some conditions tried were: (1)1.1 equiv of BF,.EkO; CH2C12, -78 OC. (2) 1.1 equiv of SnC4; CH2C12,-78 to 25 O C . (3)1.1 equiv of EBAlC1; CH2C12,-78 to 25 "C. (4)excess PPA; 25 OC. (5)1.1 equiv of Ti&; CH2C12,-78 to 25 "C. (6)1.1 equiv of AlCl,; CH2C12,-78 to 25 OC. (17)Intermediates 3,6,and 7 have been characterized by IR, NMR, and microanalysis or exact mass measurement. In general, 4 and 6 were characterized only by NMR and/or IR spectroscopy. (18)This work was presented in part a t the 23rd Annual Midwest Regional Meeting of the American Chemical Society, Iowa City, IA, November 16-18,1988;Paper No. 154.
