in 1966.9 Recently, G. J. Mena-Rejon reported that 1 shows
antimicrobial activity against Staphylococcus aureus.10 We
report here an asymmetric total synthesis of 1 via a dia-
stereoselective Pd(II)-catalyzed cyclization strategy. This
cyclization reaction would be attractive as a means to
synthesize other 2,6-disubstituted piperidine alkaloids.
Scheme 1 outlines our synthetic strategy. The target
compound 1 would be derived from the cyclization product
Scheme 2a
Scheme 1
a Reagents and conditions: (a) n-BuLi, (HCHO)n, 71%. (b) Na,
NH3, reflux, 76%. (c) BnBr (1.5 equiv), NaH (2.2 equiv), n-Bu4NI
(0.2 equiv), 56%. (d) Ti(Oi-Pr)4, TBHP, L-(+)-DET, 90%. (e) (i)
MsCl, Et3N; (ii) HClO4, 60 °C, 90%. (f) K2CO3, MeOH, 89%. (g)
MOMCl, i-Pr2NEt, 99%. (h) LiAlH4, THF, 50 °C, 96%. (i) p-TsCl,
pyridine, 96%. (j) NaN3, DMF, 50 °C, 47%. (k) PPh3, H2O, 81%.
(l) Boc2O, Et3N, 81%. (m) Na/NH3, 90%.
17a by hydroboration-oxidation of the vinyl group and chain
elongation using Wittig reaction. The 2,6-dialkylated
piperidine ring of 17a would be formed by Pd(II)-catalyzed
intramolecular N-alkylation. It was expected that the N-
alkylation would proceed via an intermediate π-allyl pal-
ladium complex. The key intermediate allylic amino alcohol
16 would be synthesized via a multistep procedure from 1,5-
hexadiyne (4).
As shown in Scheme 2, the key intermediate allylic amino
alcohol 16 was constructed as follows. The trans,trans-diene-
diol 5 was prepared using Rosenblum’s procedure in 51%
yield.11 Monobenzylation of 5 with benzyl bromide, NaH,
and a catalytic amount of tetrabutylammonium iodide gave
6 in 56% yield. Sharpless asymmetric epoxidation of 6 with
L-(+)-diethyl tartrate gave epoxide 7 in 90% yield,12 which
showed >98% ee by 1H NMR analysis of the corresponding
Mosher ester derivative.13 The hydroxyl group of 7 was
converted into a mesylate, which was then treated with
perchloric acid to afford dihydroxy sulfonate 8.14 Treatment
with potassium carbonate gave terminal epoxide 9 in 89%
yield. The secondary hydroxyl group of 9 was protected as
a MOM ether to give 10. Regioselective reduction of 10 with
LiAlH4 and subsequent tosylation of the resulting secondary
hydroxyl group of 11 gave tosylate 12 in 96% yield.
Transformation of 12 into azide 13 was achieved in 47%
yield by using NaN3 in DMF. Reduction of azide 13 with
PPh3-H2O afforded amine 14, and subsequent protection
of the amino group with tert-butoxycarbonyl group afforded
15 in high yield. Removal of the benzyl group of 15 with
Na in liquid ammonia afforded 16.
Allyl alcohol 16 was teated with 5 mol % PdCl2 in THF
at room temperature to afford cyclized mixtures 17a and 17b
in 69% yield; the ratio of 17a and 17b was >49:1 (Scheme
3).
Switching the catalyst in the above conditions to Cl2Pd-
(CH3CN)2 gave 17a and 17b in 51% yield (the ratio of 17a
and 17b was also >49:1). On the other hand, Pd(II) with
bigger ligands such as dppf and PPh3 did not give any
cyclized product. The stereoselective formation of 17a could
be explained by assuming that the cyclization proceeds via
transition state A. The chelation effect between the palladium
and oxygen atoms of the allyl alcohol is important. This
tendency may also be counterbalanced by the chelation effect
(9) Rice, W. Y.; Coke, J. L. J. Org. Chem. 1966, 31, 1010.
(10) Peraza, P. S.; Vallado, M. R.; Loeza, W. B.; Mena-Rejo´n, G. J.;
Quijano, L. Fitoterapia 2000, 71, 690.
(11) Lennon, P.; Rosenblum. J. Am. Chem. Soc. 1983, 105, 1233.
(12) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(13) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
(14) Behrens, C. H.; Ko, S. Y.; Sharpless, K. B.; Walker, F. J. J. Org.
Chem. 1985, 50, 5687.
28
Org. Lett., Vol. 5, No. 1, 2003