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Short approach to functionalised homochiral piperidinones
Tanzh.eh:
AsymmetryVol. 5. No. 8, pp. 1463-1464,1994
Pergamon
Elsevie-r scienceLtd Printedin GreatBritain 0957-416m4 .$7.w.00
0957-4166(94)00209-6
A SHORT APPROACH TO F’UNCTIONALISED HOMOCHIRAL PIPERIDINONES Stephen A. Hermitage and Mark G. Moloney*
Because of the widespread occurrence of the piperidine ring skeleton in naturally occurring compound813,
and their importance in pharmacologically active compo~nd&~.
the preparation of such
saturated heterocycles has attracted considerable attention 7-16. However, more general methods for the preparation of substituted piperidines, which allow functionalisation at any or all positions of the heterocyclic ring with a wide variety of substituents, and in a stereocontrolled manner, are lacking17. We report here a method for the convenient preparation from S-lysine of homochiral methyl 6-oxopipecolate and it8 further conversion to more highly substituted bicyclic piperidinones via a chiral bicyclic template that permits diastemoselective functionalisation around the piperidine ring. Q-Lysine(e.e.
92%) 1 was readily convera&* to the protected (S)-a-aminoadipic acid derivative 2 by
esteritkation, N-protection, and oxidation of the co-amino function with r&benium dioxide/sodium periodate using literature procedure~‘~ in 73% yield over the three steps (Scheme 1). The preparation of a-aminoadipic acid and its derivatives has attmcted considerable attention. 20**l Adipamide 2 could be easily cyclised to the corresponding lactam in retluxing trifhroroacetic acid, to give methyl 6-oxopipecolate 3. The a-ester function was reduced to the alcohol 4 with sodium borohydride (37% yield over the two steps). The optical purity of this compound, determined from the MTPA este$* was 90% 23. This represents an efficient protected homochiral6-oxopipecolic
synthesis
of
acid, from a readily available and inexpensive starting material, previous
syntheses have generally cyclised a-aminoadipic acid directly, which is readily available but expensive.21’-a
H2N H2NL
. .. .,.
1,u, ill
C02H-BOC!HN~~eLO~CO
2Me
1
P$$$-&
R
0%
&O&OH ph8
H8
5 4 (i) (MeOhCM%, HCl, MeOH ; (ii) B-0, NaHCQ, MeoH, sonicate; (iii) RuO2. NaIO4, EtOAc. H20; (iv) TFA ; (v) NaBH,,, EtOH ; (vi) phCH(OMe~,TsOH, 8O“C.72h Treatment of lactam alcohol 4, obtained directly from the reduction step, with benmldehyde dimethyl acetal gave the bicyclic benxylidene OW acetal5 in 68% yie@. ‘H NMB spectroscopic investigations of 5 suggest that the most stable solution conformation is as shown in Scheme 1, as evidenced by n.0.e. results, and a clear W-coupling in the 2D tH COSY spectmm between He and &. 1463
S. A. HERMITAGE and M. G. MOLONEY
1464
Deprotonation of 5 with LiHMDS in THF, followed by phenylselenyl chloride (2 equivalents) gave the selenoacetal6,
which could be cleanly converted to the vinylselenide 7 in 26% over 2 steps using the
standard oxidation and elimination conditions(mCPBA). No evidence for oxidation of both phenylselenyl groups was observed. Related alkylations both in simple piperidinones28do, and in a related homochiml bicyclic lactam3 l, have been described Reaction of 7 with N,a-diphenyl nitrone gave the cycloadduct 8 as a single diastereomer in 98% yield (based on recovered starting material), in which the nitrone dipole had approached exclusively from the exe-face of the substrate with the expected regiochemistry; however, the stereochemistry at C-10 could not be established. Similar selectivity is simple lactones has been recently observed32.
5
6
7
(i) LiHMDS, THF ; (ii) 2PhSeC1,THF ; (iii) mCET3A, CH2C1, ; (iv) PhCH=ti(Ph$
’
These results demonstrate the preparation and utility of the templates 5 and 7 for the construction of substituted piperidines, and further work in this area will be reported in due course. Acknowledgements:
MGM gratefully acknowledges Zeneca for a Strategic Research Award.
References ::
3. 4. i: I. 8. 9. 10. 11. ::: 14: 15. 16. 17. 18. :: 21. 22. 23. ?5: g 28: 29. 30. Z:
Baliah. V., Jeywaman. K. and m. L., Chem. Rev., 1983.83.379-423. pinder, AR., Nat. Prod. Rep., 1990,7.447455 and earlies nspwts. Atlvtie. A.B. and Mcuan, ED., Chem. Sot. Rev., 1984.13.245-278.
%&s,
h..
et al., Tetr&&n
iea., 1993.342593-2596.
Skiles. J.W.. et al.. Biorg. Med. Chem. Lctt.. 1993.3,773-776. Pe~,J.. Sheam, B.G., Confer. W.L. and Mathew, R.M., Tetrhedron Lett., 1991.32.7183-7186. Lu, Z-H. and Zhou, W.-S., J. Chem. Sot., Perkin Trans. 1. 1993,593-S%. Jeffad, C.W. and Wang, LB., Tetrahedron ktt.. 1993.34.2911-2914. Keck, G.E. and Fabni. A., Tetrahedron Lea., 1993.34.3223-32X Knight, D.W., Lewis. N., Share, A.C. and Haigh. D., Tetrahedron:Asym. 1993.4.625-628. Gomez-Montarey. I.. Gonzala-Muniz R. ti. R. and Garcia-Lopn, M.T., Tetruhedron Lea.. 1993.34.3593-3594. BeakP.andLee, W.K.,J.Org. Chem., 1993,58,1109-1117. Bailey, P.D., Brown. G.R.. ICabcr,F.. Reed, A. and Wilson. R.D.. Tetrahedron:Asymrnetty, 1991.2.1263-1282. Jones, RCF., Turner, I. and Howe KJ.. Tetruhedron Lett., 1993.34,6329-6332. Cabalho. E.. F&la. P.. Medank M. and Feliciano. A.S.. Tetrahedron. 1993.49.10079-10088. Royer. J. aHwon; Hi-P., Jan& Chin&a Acta. .1993; 11.3-8. oppolzer, W. and Mesifield, E., Helv. Chim. Acta, 1993,76,957. Ail-newcompounds gave satidhctory spfxtroscqic and high resolution maw spectmscopic or analytical data. Yoshihii. S.. Tanah EL-I. and N&a. Y.. Chem. Pharm. Bull.. 1987.35.2994-3001. krgmeia, S.C., Cobas. A.A. and R&&t. H., J. Org. Cheml. l!&i. 5& 2369-2376. Amaoao. R., Cardillo. G., Rcnnero. MS. and Tomasini. C., Guzz. Chlm Ital., 1993.1X3,75-8. Dale, J& and Moshez, RS.. J. Am. Chem. Sot., 1969,95,512-519. Hung, S.-B., Nelson, J.S. and Weller, D.D., Syn. Commun.. 1989.19.3485-3496. Milk, S.M. and Nutl, RF.. 1980. Brilish patent 1.569.486. Gremstein. J.P., Birnbnum, S.M. and Gtcy, MC., J. Am. Chem. Sot.. 1953,75.1994-1995. prassad KU., Rm, R.W., WtiU. FL., Vikha-Marthz, J.A. nod S&ally. A.V.. J. Med. C&m., 1976.19,492495. Crab, T.A., Jackson, D. and Pate& A.V.. Adv. Heterocycl. Chem., 1990.49.193-275. Baens. N.P.. Compexnolle, F., Toppet, S.M. and Hoonwxk G.J., Tetrahedron, 1993,49.3193-3202. Meyers. AI., Kunnen, K.B. and Still, W.C., J. Am. Chem. SOC., 1987,109,44054407. Hagen, T.J., Syn. Lea.. 1990.6366. Meyers. AL, Leiker, B.A., Aitken, R.A. and Wamex, K.T.. J. Org. Chem., 1986.51,1936-1938. F&pens. M.T., Keller. E., Lange, B.d., Zijlsha, R.WJ. and Feringa, B.L., Tetrahedion:Asynmetry. 1994.5.607-624.
(Received
in UK 16 June 1994)
AsymmetryVol. 5. No. 8, pp. 1463-1464,1994
Pergamon
Elsevie-r scienceLtd Printedin GreatBritain 0957-416m4 .$7.w.00
0957-4166(94)00209-6
A SHORT APPROACH TO F’UNCTIONALISED HOMOCHIRAL PIPERIDINONES Stephen A. Hermitage and Mark G. Moloney*
Because of the widespread occurrence of the piperidine ring skeleton in naturally occurring compound813,
and their importance in pharmacologically active compo~nd&~.
the preparation of such
saturated heterocycles has attracted considerable attention 7-16. However, more general methods for the preparation of substituted piperidines, which allow functionalisation at any or all positions of the heterocyclic ring with a wide variety of substituents, and in a stereocontrolled manner, are lacking17. We report here a method for the convenient preparation from S-lysine of homochiral methyl 6-oxopipecolate and it8 further conversion to more highly substituted bicyclic piperidinones via a chiral bicyclic template that permits diastemoselective functionalisation around the piperidine ring. Q-Lysine(e.e.
92%) 1 was readily convera&* to the protected (S)-a-aminoadipic acid derivative 2 by
esteritkation, N-protection, and oxidation of the co-amino function with r&benium dioxide/sodium periodate using literature procedure~‘~ in 73% yield over the three steps (Scheme 1). The preparation of a-aminoadipic acid and its derivatives has attmcted considerable attention. 20**l Adipamide 2 could be easily cyclised to the corresponding lactam in retluxing trifhroroacetic acid, to give methyl 6-oxopipecolate 3. The a-ester function was reduced to the alcohol 4 with sodium borohydride (37% yield over the two steps). The optical purity of this compound, determined from the MTPA este$* was 90% 23. This represents an efficient protected homochiral6-oxopipecolic
synthesis
of
acid, from a readily available and inexpensive starting material, previous
syntheses have generally cyclised a-aminoadipic acid directly, which is readily available but expensive.21’-a
H2N H2NL
. .. .,.
1,u, ill
C02H-BOC!HN~~eLO~CO
2Me
1
P$$$-&
R
0%
&O&OH ph8
H8
5 4 (i) (MeOhCM%, HCl, MeOH ; (ii) B-0, NaHCQ, MeoH, sonicate; (iii) RuO2. NaIO4, EtOAc. H20; (iv) TFA ; (v) NaBH,,, EtOH ; (vi) phCH(OMe~,TsOH, 8O“C.72h Treatment of lactam alcohol 4, obtained directly from the reduction step, with benmldehyde dimethyl acetal gave the bicyclic benxylidene OW acetal5 in 68% yie@. ‘H NMB spectroscopic investigations of 5 suggest that the most stable solution conformation is as shown in Scheme 1, as evidenced by n.0.e. results, and a clear W-coupling in the 2D tH COSY spectmm between He and &. 1463
S. A. HERMITAGE and M. G. MOLONEY
1464
Deprotonation of 5 with LiHMDS in THF, followed by phenylselenyl chloride (2 equivalents) gave the selenoacetal6,
which could be cleanly converted to the vinylselenide 7 in 26% over 2 steps using the
standard oxidation and elimination conditions(mCPBA). No evidence for oxidation of both phenylselenyl groups was observed. Related alkylations both in simple piperidinones28do, and in a related homochiml bicyclic lactam3 l, have been described Reaction of 7 with N,a-diphenyl nitrone gave the cycloadduct 8 as a single diastereomer in 98% yield (based on recovered starting material), in which the nitrone dipole had approached exclusively from the exe-face of the substrate with the expected regiochemistry; however, the stereochemistry at C-10 could not be established. Similar selectivity is simple lactones has been recently observed32.
5
6
7
(i) LiHMDS, THF ; (ii) 2PhSeC1,THF ; (iii) mCET3A, CH2C1, ; (iv) PhCH=ti(Ph$
’
These results demonstrate the preparation and utility of the templates 5 and 7 for the construction of substituted piperidines, and further work in this area will be reported in due course. Acknowledgements:
MGM gratefully acknowledges Zeneca for a Strategic Research Award.
References ::
3. 4. i: I. 8. 9. 10. 11. ::: 14: 15. 16. 17. 18. :: 21. 22. 23. ?5: g 28: 29. 30. Z:
Baliah. V., Jeywaman. K. and m. L., Chem. Rev., 1983.83.379-423. pinder, AR., Nat. Prod. Rep., 1990,7.447455 and earlies nspwts. Atlvtie. A.B. and Mcuan, ED., Chem. Sot. Rev., 1984.13.245-278.
%&s,
h..
et al., Tetr&&n
iea., 1993.342593-2596.
Skiles. J.W.. et al.. Biorg. Med. Chem. Lctt.. 1993.3,773-776. Pe~,J.. Sheam, B.G., Confer. W.L. and Mathew, R.M., Tetrhedron Lett., 1991.32.7183-7186. Lu, Z-H. and Zhou, W.-S., J. Chem. Sot., Perkin Trans. 1. 1993,593-S%. Jeffad, C.W. and Wang, LB., Tetrahedron ktt.. 1993.34.2911-2914. Keck, G.E. and Fabni. A., Tetrahedron Lea., 1993.34.3223-32X Knight, D.W., Lewis. N., Share, A.C. and Haigh. D., Tetrahedron:Asym. 1993.4.625-628. Gomez-Montarey. I.. Gonzala-Muniz R. ti. R. and Garcia-Lopn, M.T., Tetruhedron Lea.. 1993.34.3593-3594. BeakP.andLee, W.K.,J.Org. Chem., 1993,58,1109-1117. Bailey, P.D., Brown. G.R.. ICabcr,F.. Reed, A. and Wilson. R.D.. Tetrahedron:Asymrnetty, 1991.2.1263-1282. Jones, RCF., Turner, I. and Howe KJ.. Tetruhedron Lett., 1993.34,6329-6332. Cabalho. E.. F&la. P.. Medank M. and Feliciano. A.S.. Tetrahedron. 1993.49.10079-10088. Royer. J. aHwon; Hi-P., Jan& Chin&a Acta. .1993; 11.3-8. oppolzer, W. and Mesifield, E., Helv. Chim. Acta, 1993,76,957. Ail-newcompounds gave satidhctory spfxtroscqic and high resolution maw spectmscopic or analytical data. Yoshihii. S.. Tanah EL-I. and N&a. Y.. Chem. Pharm. Bull.. 1987.35.2994-3001. krgmeia, S.C., Cobas. A.A. and R&&t. H., J. Org. Cheml. l!&i. 5& 2369-2376. Amaoao. R., Cardillo. G., Rcnnero. MS. and Tomasini. C., Guzz. Chlm Ital., 1993.1X3,75-8. Dale, J& and Moshez, RS.. J. Am. Chem. Sot., 1969,95,512-519. Hung, S.-B., Nelson, J.S. and Weller, D.D., Syn. Commun.. 1989.19.3485-3496. Milk, S.M. and Nutl, RF.. 1980. Brilish patent 1.569.486. Gremstein. J.P., Birnbnum, S.M. and Gtcy, MC., J. Am. Chem. Sot.. 1953,75.1994-1995. prassad KU., Rm, R.W., WtiU. FL., Vikha-Marthz, J.A. nod S&ally. A.V.. J. Med. C&m., 1976.19,492495. Crab, T.A., Jackson, D. and Pate& A.V.. Adv. Heterocycl. Chem., 1990.49.193-275. Baens. N.P.. Compexnolle, F., Toppet, S.M. and Hoonwxk G.J., Tetrahedron, 1993,49.3193-3202. Meyers. AI., Kunnen, K.B. and Still, W.C., J. Am. Chem. SOC., 1987,109,44054407. Hagen, T.J., Syn. Lea.. 1990.6366. Meyers. AL, Leiker, B.A., Aitken, R.A. and Wamex, K.T.. J. Org. Chem., 1986.51,1936-1938. F&pens. M.T., Keller. E., Lange, B.d., Zijlsha, R.WJ. and Feringa, B.L., Tetrahedion:Asynmetry. 1994.5.607-624.
(Received
in UK 16 June 1994)