Regio- and stereoselective 6-exo-trig radical cyclisations onto chiral perhydro-1,3-benzoxazines: Synthesis of enantiopure 3-alkylpiperidines

Article abstract of DOI:10.1016/S0957-4166(00)00230-5

Enantiopure 3-alkyl substituted piperidines are prepared by diastereoselective 6-exo-trig cyclisation of perhydro-1,3-benzoxazines derived from (-)-(8)-amino menthol. The diastereoselective cyclisation is promoted by tributyltin hydride, and the competitive 1,5-hydrogen migration depends on the position of the acceptor double bond and the radical site. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00230-5

Tetrahedron: Asymmetry 11 (2000) 2809±2821
Regio- and stereoselective 6-exo-trig radical cyclisations onto
chiral perhydro-1,3-benzoxazines: synthesis of enantiopure
3-alkylpiperidines
Rafael Pedrosa,* Celia Andres,* Juan P. Duque-Soladana and Carlos D. Roson
Â
Departamento de Quõmica Organica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n,
Â
47011 Valladolid, Spain
Received 25 May 2000; accepted 8 June 2000
Abstract
Enantiopure 3-alkyl substituted piperidines are prepared by diastereoselective 6-exo-trig cyclisation of
perhydro-1,3-benzoxazines derived from (^)-(8)-amino menthol. The diastereoselective cyclisation is pro-
moted by tributyltin hydride, and the competitive 1,5-hydrogen migration depends on the position of the
acceptor double bond and the radical site. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Radical cyclisations are a very useful methodology for ring construction from simple to poly-
cyclic structures,1 3 and carbocyclic and heterocyclic compounds of a diverse size are usual targets
in modern radical chemistry.4,5 However, synthetic applications are somewhat constrained to the
generation of ®ve-membered rings due to the well-known behaviour of 5-hexenyl radicals in terms
of regioselectivity and stereoinduction during cyclisation.6 Formation of larger rings by radical
cyclisation is a less general synthetic pathway. In fact, ring closure is slower as the ring size
increases and, contrasting with 5-hexenyl radicals, secondary competitive processes, such as inter-
or intramolecular hydrogen abstraction,7 ring expansion8 or neophyl rearrangements9 can
appear. As a result, a loss of regio- and stereoselectivity can be expected when forming six-
membered or larger rings.
In spite of the above considerations a good choice of starting substrates may provide good results
avoiding undesired by-products. Although very few examples are known, some highly stereo-
selective 6-exo cyclisations have been reported in the syntheses of indolizidine and quinolizidine
alkaloids using alkyl radicals.10 12
* Corresponding author. E-mail: pedrosa@qo.uva.es
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00230-5

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As an extension of our previous approach13 to chiral pyrrolidines by cyclisation of 5-hexenyl
radicals, and isoquinoline or benzazepine derivatives from 6-heptenyl radicals,14 we report here
on the synthesis of enantiopure 3-alkyl piperidines by 6-exo radical ring closure on perhydro-1,3-
benzoxazines used as chiral auxiliaries.
2. Results
Preparations of perhydrobenzoxazines 3a±c were accomplished in two steps from (^)-8-amino
menthol 1.15 Condensation of 1 with 3-phenylselenopropionaldehyde a€orded quantitatively 2
which was further alkylated with allylic bromides in the presence of potassium carbonate in
re¯uxing acetonitrile.
The reaction of perhydrobenzoxazine 3a with tributyltin hydride and AIBN in re¯uxing
1
benzene was complete after 9 h. Crude H NMR analysis showed three compounds in the ratio
32:29:39 which were assigned to 4a, 5a and 6a, respectively (Table 1, entry 1). Cyclised products
4a and 5a were isolated by ¯ash chromatography and characterised as 6-exo products (Scheme 1).
Attempts to isolate 6a led to decomposition during puri®cation. This compound must arise from
a favoured intramolecular 1,5-hydrogen abstraction in which the double bond isomerisation takes
place.
Table 1
Radical cyclisations of perhydrobenzoxazines 3a±c
Scheme 1. Reagents and conditions: (i) PhSeCH2CH2CHO, CH2Cl2, rt, 3 h; (ii) BrCH2CHˆCR1R2, K2CO3, CH3CN,
re¯ux, 48 h; (iii) Bu3SnH (1.5 equiv.), AIBN (0.1 equiv.), benzene, re¯ux, 7±9 h

R. Pedrosa et al. / Tetrahedron: Asymmetry 11 (2000) 2809±2821
2811
Activation of the ole®nic acceptor (R=Ph, CO2Et) increased the chemical yield in cyclised
products 4±5 avoiding formation of undesired non-cyclic compound 6 (Table 1, entries 2 and 3).
Furthermore, an improvement in diastereoselection is encountered for cyclisation of 3b±c.
In an e€ort to improve the stereoselectivity of the cyclisation we thought that a radical centre
closer to the auxiliary would be bene®cial. To this end, homoallyl perhydrobenzoxazine 8 was
prepared by condensation of N-(3-butenyl)-8-amino menthol 715 with phenylselenoacetaldehyde16
in benzene at re¯ux.
Reaction of 8 with Bu3SnH and AIBN under dilute conditions yielded a mixture of three
compounds in the 38:16:46 ratio (1H NMR). Isolation by ¯ash chromatography a€orded 6-exo
diastereomers 9 and 10 together with the unexpected reduced perhydrobenzoxazine 11 in 80%
combined yield (Scheme 2).
Scheme 2. Reagents and conditions: (i) PhSeCH2CHO, benzene, re¯ux, 3 h (70%); (ii) Bu3SnH (1.5 equiv.), AIBN (0.1
equiv.), benzene, re¯ux, 7±9 h (80%)
Unfortunately, the open perhydrobenzoxazine 11, resulting from the competitive 1,5-hydrogen
migration, was the major compound obtained and remarkable changes in stereodi€erentiation of
the radical cyclisation were not observed. Then we turned to promote the cyclisation on sub-
strates 13a±d by changing the radical centre to the nitrogen substituent, and placing the acceptor
double bond at the acetallic carbon. The cyclisation in this type of arrangement is controlled by
the A-strain1,3 as reported for similar 5-hexenyl radical cyclisations.17
The starting benzoxazines 13a±b,d were obtained by reductive cleavage of selenylated benzoxazine
2 using borane±THF and subsequent condensation of 12 with unsaturated aldehydes in re¯uxing
benzene. Slow addition of a solution of Bu3SnH and AIBN in benzene to a solution of 13a±b in
the same solvent, at re¯ux, led to a mixture of only two products 14a±b and 15a±b corresponding
to the 6-exo diastereomers (Scheme 3, Table 2). NOESY experiments allowed the establishment
of a trans-relationship between the acetallic proton and its adjacent proton for major diastereo-
isomers 14a±d or a cis-relationship for the minor ones 15a±b.
Scheme 3. Reagents and conditions: (i) NaBH4±BF3OEt2, THF, 0ꢀC to rt, 3 h (94%); (ii) OHCCHˆCR1R2, benzene,
re¯ux, 4 h (54±80%); (iii) Bu3SnH (1.5 equiv.), AIBN (0.1 equiv.), benzene, re¯ux, 7±9 h

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Table 2
Radical cyclisations of perhydrobenzoxazines 13a±b,d
As expected, a single diastereomer 14d was formed in the cyclisation of 13d (Table 2, entry 3) as
a result of the strong local allylic strain operating when R2ˆH, and the reduced acyclic products
were not formed for 13a±d whatever the nature of groups R1 or R2. The formation of the 1,5-
migration products from 3 and 8, and the absence of this by-product from 13, is a consequence of
the concerted six-membered transition state required for these transformations. In fact, N-axial
substituted radicals formed from 3 and 8 can easily adopt the chair-like conformations A and B
required for H-migration (Scheme 4), while the radical C, formed from 13 is unable to adopt the
correct conformation for the migration of the N,O-acetallic hydrogen, in contrast with dioxolane
and other acetals.18,19
Scheme 4.
Assuming the axial preference for the substituent at the nitrogen in all of these benzoxazines,
the exact stereochemistry of major cyclisation products 4a±c and 9 can be correctly justi®ed in
terms of the proposed model for 6-heptenyl radicals,20 whereas the formation of 14a±d is a con-
sequence of the allylic strain in the radical intermediate C.17

R. Pedrosa et al. / Tetrahedron: Asymmetry 11 (2000) 2809±2821
2813
The major cyclisation stereoisomers 4a±b and 14a,b,d, after separation by ¯ash chromato-
graphy, were transformed into enantiopure 3-alkyl piperidines in two steps (Scheme 5). Treat-
ment of 4a±b or 14a±b,d with LiAlH4 and AlCl3 in THF at 0ꢀC led to the piperidinyl menthols
16a±d in nearly quantitative yield. The menthol derivatives were converted into 3-substituted
piperidines by oxidation with PCC to the corresponding piperidinyl menthones, followed by
reaction with KOH in MeOH±THF. In this way, (R)-3-ethylpiperidine 17a21 and (S)-3-benzyl-
piperidine 17b were obtained. These products were also formed starting from 14a and 14b,
respectively. In addition, diastereomer 14d provided (S)-3-isopropylpiperidine 17d following the
same sequence.
Scheme 5. Reagents and conditions: (i) LiAlH4±AlCl3, THF, 0ꢀC, 15 min, H2O (93±96%); (ii) PCC, CH2Cl2, rt, then
KOH, MeOH±THF (42±72%)
For compound 4c, the con®guration of the stereocentre at C-3 in the piperidine ring was
assigned by transformation into piperidine 17a following the sequence depicted on Scheme 6.
Scheme 6. Reagents and conditions: (i) DIBALH, toluene, 0ꢀC, 1 h, H2O (92%); (ii) CBr4, Ph3P, CH2Cl2, 0ꢀC, 1.5 h
then Bu3SnH, AIBN, benzene, re¯ux (65%); (iii) PCC, CH2Cl2, rt, then KOH, MeOH±THF (68%)
In summary a concise, ecient protocol to access chiral 3-alkylpiperidines is described by mild
radical cyclisation.
3. Experimental
All the reactions were monitored by TLC. Preparative chromatography was performed on
silica gel (230±400 mesh) by the ¯ash technique. Melting points were measured in open capillary
tubes and are uncorrected. NMR spectra were registered on Bruker AC-300 and ARX-300

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R. Pedrosa et al. / Tetrahedron: Asymmetry 11 (2000) 2809±2821
spectrometers at 300 MHz (1H) and 75 MHz (13C DEPT). Optical rotations were obtained from a
Perkin±Elmer 241 polarimeter.
3.1. 3-Phenylselenopropionaldehyde
A solution containing diphenyldiselenide (2.0 g, 6.4 mmol) in absolute ethanol (60 mL) was
treated with sodium borohydride (0.5 g, 13 mmol) in portions. Then 3-chloropropionaldehyde
diethylacetal (2.0 mL, 11.4 mmol) was added at once and the mixture re¯uxed for 4 h. The mixture
was poured into water, extracted with ether and concentrated in vacuo. The crude acetal was
hydrolysed by stirring with 2N aqueous HCl solution (50 mL) for 18 h. Extractions with ether
and concentration yielded a residue which was puri®ed by ¯ash chromatography yielding pure
1
aldehyde (1.97 g, 81%). Yellow oil; H NMR (CDCl3): ꢀ=2.85 (dt, 2H, J=7.0 Hz, J=1.1 Hz),
3.09 (t, 2H, J=7.0 Hz), 7.20±7.50 (m, 5H), 9.71 (t, 1H, J=1.1 Hz). IR (liquid ®lm, cm^1): 2810,
2710, 1710. MS (EI, m/z): 214 (M, 34), 158 (86), 78 (100).
3.2. 2-(20-Phenylselenoethyl)-perhydro-1,3-benzoxazine 2
A mixture of (^)-8-amino menthol 115 (1.4 g, 8.4 mmol) and 3-phenylselenopropionaldehyde (1.8
g, 8.4 mmol) was stirred in dichloromethane (5 mL) at room temperature for 3 h. The solvent was
removed in vacuo yielding pure benzoxazine (3.0 g, 99%). Yellow oil; 1H NMR (CDCl3): ꢀ=0.86±
1.09 (m, 4H), 0.91 (d, 3H, J=6.5 Hz), 1.03 (s, 3H), 1.04 (s, 3H), 1.25±1.42 (m, 2H), 1.68 (m, 2H),
1.84±1.97 (m, 3H), 3.00 (t, 2H, J=7.5 Hz), 3.28 (dt, 1H, J=4.2 Hz, J=10.2 Hz), 4.37 (dd, 1H, J=5.5
Hz, J=6.1 Hz), 7.20±7.50 (m, 5H); 13C NMR (CDCl3): ꢀ=19.7, 22.2, 23.4, 25.5, 29.8, 31.3, 34.9,
36.8, 41.6, 51.2, 51.7, 74.8, 81.9, 126.6, 128.9 (2C), 130.4, 132.5 (2C). IR (liquid ®lm, cm^1): 3280, 730,
685. Anal. calcd for C19H29NOSe: C, 62.28; H, 7.98; N, 3.82. Found: C, 62.53; H, 8.14; N, 4.14.
3.3. Synthesis of perhydro-1,3-benzoxazines 3a±c
General procedure. Compounds 3a±c were prepared, as previouly described for related com-
pounds,22 by alkylation of 2 with the corresponding allylic bromide in the presence of potassium
carbonate in acetonitrile at re¯ux for 48 h.
3.4. N-Crotyl-2-(20-phenylselenoethyl)-perhydro-1,3-benzoxazine 3a
Oil, 97%; 1H NMR (CDCl3): ꢀ=0.87±1.05 (m, 3H), 0.91 (d, 3H, J=6.5 Hz), 1.12 (s, 6H), 1.32±
1.55 (m, 2H), 1.56±1.70 (m, 2H), 1.62 (dd, 3H, J=1.3 Hz, J=3.3 Hz), 1.85 (m, 1H), 1.87±2.02 (m,
2H), 2.99 (m, 3H), 3.28 (m, 2H), 4.65 (dd, 1H, J=4.7 Hz, J=7.2 Hz), 5.44 (m, 2H), 7.20±7.52 (m,
5H); 13C NMR (CDCl3): ꢀ=17.7, 20.3, 22.2, 24.3, 25.0, 26.9, 31.3, 34.7, 35.0, 41.4, 44.5, 46.2,
56.9, 75.8, 86.6, 124.4, 126.5, 128.9 (2C), 130.6, 132.5 (2C), 133.3. IR (liquid ®lm, cm^1): 730, 690.
MS (CI, m/z): 422 (M+1, 13), 264 (100), 236 (83). Anal. calcd for C23H35NOSe: C, 65.70; H, 8.39;
N, 3.33. Found: C, 65.47; H, 8.52; N, 3.16.
3.5. N-Cinnamyl-2-(20-phenylselenoethyl)-perhydro-1,3-benzoxazine 3b
20
1
Oil, 63%; ‰ꢁŠD =^31.2 (c 1.1, CH2Cl2); H NMR (CDCl3): ꢀ=0.86±1.07 (m, 3H), 0.91 (d, 3H,
J=6.3 Hz), 1.15 (s, 3H), 1.16 (s, 3H), 1.32±1.34 (m, 2H), 1.56 (m, 1H), 1.68 (m, 1H), 1.83 (m,

R. Pedrosa et al. / Tetrahedron: Asymmetry 11 (2000) 2809±2821
2815
1H), 1.87±2.05 (m, 2H), 2.99 (dt, 2H, J=3.0 Hz, J=7.4 Hz), 3.27±3.35 (m, 2H), 3.53 (dd, 1H,
J=5.8 Hz, J=18.1 Hz), 4.71 (dd, 1H, J=4.8 Hz, J=7.3 Hz), 6.23 (dt, 1H, J=5.4 Hz, J=15.9
Hz), 6.43 (d, 1H, J=15.9 Hz), 7.17±7.56 (m, 10H); 13C NMR (CDCl3): ꢀ=20.5, 22.2, 24.4, 25.0,
26.9, 31.3, 34.7, 35.0, 41.4, 44.8, 46.4, 57.1, 75.9, 86.5, 126.1 (2C), 126.6, 126.9, 128.4 (2C), 128.9
(3C), 130.4, 132.7 (3C), 137.5. IR (liquid ®lm, cm^1): 730, 690. Anal. calcd for C28H37NOSe: C,
69.69; H, 7.73; N, 2.90. Found: C, 69.52; H, 7.51; N, 3.08.
3.6. N-(3-Ethoxycarbonyl-2-propenyl)-2-(20-phenylselenoethyl)-perhydro-1,3-benzoxazine 3c
20
1
Oil, 84%; ‰ꢁŠD =^27.8 (c 1.2, CH2Cl2); H NMR (CDCl3): ꢀ=0.85±1.07 (m, 3H), 0.90 (d, 3H,
J=6.5 Hz), 1.05 (s, 3H), 1.16 (s, 3H), 1.23±1.33 (m, 1H), 1.30 (t, 3H, J=7.1 Hz), 1.42 (m, 1H),
1.57 (m, 1H), 1.69 (m, 1H), 1.71±1.93 (m, 3H), 2.90±3.00 (m, 2H), 3.27 (dt, 1H, J=3.9 Hz,
J=10.6 Hz), 3.33 (dd, 1H, J=1.9 Hz, J=4.3 Hz), 3.50 (ddd, 1H, J=1.8 Hz, J=4.7 Hz, J=19.8
Hz), 4.18 (q, 2H, J=7.1 Hz), 4.71 (dd, 1H, J=4.2 Hz, J=7.7 Hz), 6.04 (dt, 1H, J=1.5 Hz,
J=15.5 Hz), 6.98 (dt, 1H, J=4.5 Hz, J=15.5 Hz), 7.20±7.56 (m, 5H); 13C NMR (CDCl3):
ꢀ=14.2, 20.9, 22.2, 24.3, 24.9, 26.7, 31.3, 34.5, 34.9, 41.3, 43.6, 45.9, 57.0, 60.1, 76.0, 86.1, 120.8,
126.7, 128.9 (2C), 130.2, 132.8 (2C), 151.1, 166.8. IR (liquid ®lm, cm^1): 1670, 730, 690. Anal.
calcd for C25H37NO3Se: C, 62.75; H, 7.79; N, 2.93. Found: C, 62.98; H, 7.92; N, 3.14.
3.7. Radical cyclisation of perhydrobenzoxazines 3a±c
General method: To a solution of the corresponding benzoxazine 3a±c (1.5 mmol) in re¯uxing
benzene (70 mL) was injected (5±7 h, syringe pump) a solution of tributyltin hydride (0.66 mL,
2.2 mmol) and AIBN (24 mg) in benzene (25 mL). The re¯ux was maintained until disappearance
of starting compound (TLC). Then, the solvent was removed and the residue was puri®ed by ¯ash
chromatography on silica gel.
3.8. Compound 4a
Colourless oil, 16%; 1H NMR (CDCl3): ꢀ=0.84±0.99 (m, 3H), 0.87 (t, 3H, J=7.6 Hz), 0.89 (d,
3H, J=6.3 Hz), 1.11 (s, 3H), 1.17 (s, 3H), 1.03±1.87 (m, 12H), 2.52 (t, 1H, J=10.2 Hz), 2.70 (d,
1H, J=9.1 Hz), 3.44 (dt, 1H, J=4.0 Hz, J=10.4 Hz), 4.72 (t, 1H, J=3.3 Hz); 13C NMR
(CDCl3): ꢀ=11.4, 20.9, 22.2, 24.9, 25.1, 26.9, 27.2, 30.8, 31.3, 35.0, 37.9, 41.3, 43.7, 45.9, 56.0,
75.9, 81.7. IR (liquid ®lm, cm^1): 1450, 735, 690. Anal. calcd for C17H31NO: C, 76.92; H, 11.77;
N, 5.28. Found: C, 77.11; H, 11.94; N, 5.43.
3.9. Compound 4b
1
Colourless oil, 57%; H NMR (CDCl3): ꢀ=0.90±1.04 (m, 2H), 0.92 (d, 3H, J=6.6 Hz), 1.05±
1.16 (m, 1H), 1.06 (s, 3H), 1.14 (s, 3H), 1.35±1.61 (m, 6H), 1.70 (m, 1H), 1.76±1.93 (m, 3H), 2.50
(dd, 1H, J=7.9 Hz, J=13.4 Hz), 2.61 (dd, 1H, J=6.7 Hz, J=13.6 Hz), 2.63 (t, 1H, J=3.3 Hz),
2.69 (dd, 1H, J=4.1 Hz, J=10.6 Hz), 3.45 (dt, 1H, J=4.1 Hz, J=10.6 Hz), 4.70 (t, 1H, J=3.3
Hz), 7.13±7.28 (m, 5H); 13C NMR (CDCl3): ꢀ=20.6, 22.3, 25.1 (2C), 26.9, 30.7, 31.3, 35.0, 38.2,
40.9, 41.4, 44.0, 46.1, 55.8, 75.8, 81.7, 125.6, 128.1 (2C), 129.0 (2C), 140.7. IR (liquid ®lm, cm^1):
1445, 740, 695. Anal. calcd for C22H33NO: C, 80.68; H, 10.16; N, 4.28. Found: C, 80.53; H, 10.29;
N, 4.41.

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3.10. Compound 4c
1
Colourless oil, 57%; H NMR (CDCl3): ꢀ=0.88±1.04 (m, 2H), 0.91 (d, 3H, J=6.4 Hz), 1.06±
1.13 (m, 1H), 1.09 (s, 3H), 1.13 (s, 3H), 1.24 (t, 3H, J=7.0 Hz), 1.26±1.63 (m, 7H), 1.76 (m, 1H),
1.83 (m, 1H), 1.90±2.10 (m, 1H), 2.20±2.30 (m, 2H), 2.62±2.70 (m, 2H), 3.44 (dt, 1H, J=4.0 Hz,
J=10.1 Hz), 4.11 (q, 2H, J=7.0 Hz), 4.66 (t, 1H, J=3.5 Hz); 13C NMR (CDCl3): ꢀ=14.2, 19.8,
22.2, 25.0, 25.5, 26.8, 30.3, 31.3, 33.1, 34.9, 39.0, 41.2, 44.4, 45.7, 55.8, 60.2, 75.7, 81.7, 172.8. IR
(liquid ®lm, cm^1): 1730, 1070, 1030. Anal. calcd for C19H33NO3: C, 70.55; H, 10.28; N, 4.33.
Found: C, 70.42; H, 10.41; N, 4.24.
3.11. Compound 5a
Colourless oil, 15%; 1H NMR (CDCl3): ꢀ=0.86±0.99 (m, 2H), 0.89 (t, 3H, J=7.3 Hz), 0.91 (d,
3H, J=6.5 Hz), 0.92 (s, 3H), 1.02±1.17 (m, 1H), 1.16 (s, 3H), 1.17±1.64 (m, 8H), 1.66±1.94 (m,
5H), 2.98 (dt, 1H, J=2.6 Hz, J=11.3 Hz), 3.35 (dt, 1H, J=4.3 Hz, J=10.6 Hz), 3.90 (dd, 1H,
J=3.4 Hz, J=9.6 Hz); 13C NMR (CDCl3): ꢀ=11.3, 11.5, 22.1, 25.0, 25.7, 27.1, 29.1, 31.1, 32.7,
34.6, 37.8, 41.4, 49.1, 49.9, 55.7, 74.1, 85.4. IR (liquid ®lm, cm^1): 1590, 730, 690. Anal. calcd for
C17H31NO: C, 76.92; H, 11.77; N, 5.28. Found: C, 76.79; H, 11.96; N, 5.09.
3.12. Compound 5b
Colourless oil, 34%; 1H NMR (CDCl3): ꢀ=0.88±1.09 (m, 3H), 0.92 (d, 3H, J=6.5 Hz), 0.93 (s,
3H), 1.10 (s, 3H), 1.28±1.56 (m, 4H), 1.64±1.74 (m, 3H), 1.83±1.96 (m, 4H), 2.43 (dd, 1H, J=7.2
Hz, J=13.5 Hz), 2.58 (dd, 1H, J=6 Hz, J=13.5 Hz), 3.00 (dd, 1H, J=2.0 Hz, J=8.0 Hz), 3.36
(dt, 1H, J=4.3 Hz, J=10.5), 3.96 (dd, 1H, J=3.5 Hz, J=9.4 Hz), 7.14±7.31 (m, 5H); 13C NMR
(CDCl3): ꢀ=11.5, 22.1, 25.0, 25.7, 29.0, 31.1, 32.6, 34.7, 37.9, 40.8, 41.4, 49.0, 49.8, 55.7, 74.2,
85.2, 125.8, 128.1 (2C), 128.9 (2C), 140.3. IR (liquid ®lm, cm^1): 1600, 730, 697. MS (CI, m/z): 356
(M++1, 13), 328 (100). Anal. calcd for C22H33NO: C, 80.68; H, 10.16; N, 4.28. Found: C, 80.51;
H, 10.32; N, 4.46.
3.13. Compound 5c
Colourless oil, 34%; 1H NMR (CDCl3): ꢀ=0.88±1.10 (m, 4H), 0.91 (d, 3H, J=6.5 Hz), 0.92 (s,
3H), 1.14 (s, 3H), 1.25 (t, 3H, J=7.1 Hz), 1.30±1.93 (m, 10H), 2.18 (m, 1H), 2.20 (m, 1H), 3.04
(dt, 1H, J=2.6 Hz, J=11.2 Hz), 3.35 (dt, 1H, J=4.2 Hz, J=10.5 Hz), 3.94 (dd, 1H, J=3.4 Hz,
J=9.2 Hz), 4.1 (q, 2H, J=7.1 Hz); 13C NMR (CDCl3): ꢀ=11.9, 14.2, 22.0, 25.0, 25.5, 29.1, 31.0,
32.0, 33.1, 34.5, 39.0, 41.2, 48.5, 49.4, 56.0, 60.2, 74.2, 84.9, 172.3. IR (liquid ®lm, cm^1): 1630,
1170. Anal. calcd for C19H33NO3: C, 70.55; H, 10.28; N, 4.33. Found: C, 70.70; H, 10.12; N, 4.45.
3.14. N-(3-Butenyl)-2-(phenylselenomethyl)-perhydro-1,3-benzoxazine 8
Condensation of N-(3-butenyl)-8-amino menthol 715 (5 g, 22 mmol) with phenylselenoacet-
aldehyde16 (6.5 g, 33 mmol) was carried out in benzene at re¯ux for 24 h. Filtration on Kieselguhr
and removal of the solvent a€orded 6.3 g (70%) of product. Yellow oil, ‰ꢁŠ2D0=^43.7 (c 1.0,
CH2Cl2). 1H NMR (CDCl3): ꢀ=0.85±1.06 (m, 3H), 0.88 (d, 3H, J=6.4 Hz), 1.09 (s, 3H), 1.13 (s,
3H), 1.28±1.47 (m, 2H), 1.58 (m, 1H), 1.65 (m, 1H), 1.84 (m, 1H), 2.19 (q, 2H, J=7.8 Hz), 2.53

R. Pedrosa et al. / Tetrahedron: Asymmetry 11 (2000) 2809±2821
2817
(m, 1H), 2.76 (m, 1H), 3.08 (m, 2H), 3.41 (dt, 1H, J=4.0 Hz, J=10.5 Hz), 4.77 (dd, 1H, J=5.4
Hz, J=6.9 Hz), 4.98 (m, 2H), 5.73 (ddt, 1H, J=6.8 Hz, J=10.3 Hz, J=17.1 Hz), 7.18±07.50 (m,
5H); 13C NMR (CDCl3): ꢀ=20.3, 22.1, 25.0, 26.6, 31.2, 31.4, 34.9, 38.6, 41.1, 42.6, 45.8, 57.1,
76.2, 87.0, 115.4, 126.5, 128.9 (2C), 131.1, 132.1 (2C), 136.4. IR (liquid ®lm, cm^1): 1650, 740, 700.
Anal. calcd for C22H33NOSe: C, 65.01; H, 8.18; N, 3.45. Found: C, 65.19; H, 8.32; N, 3.29.
3.15. Compound 9
Colourless oil, 30%; 1H NMR (CDCl3): ꢀ=0.85±0.99 (m, 2H), 0.86 (d, 3H, J=6.4 Hz), 0.92 (d,
3H, J=6.6 Hz), 1.01±1.15 (m, 1H), 1.12 (s, 3H), 1.20 (s, 3H), 1.20±1.32 (m, 2H), 1.34±1.59 (m,
3H), 1.70 (m, 2H), 1.80 (m, 2H), 1.90 (m, 1H), 2.79 (dt, 1H, J=3.9 Hz, J=11.5 Hz), 2.92 (dt, 1H,
J=2.9 Hz, J=11.5 Hz), 3.46 (dt, 1H, J=4.0 Hz, J=10.5 Hz), 4.82 (t, 1H, J=3.0 Hz); 13C NMR
(CDCl3): ꢀ=21.3, 21.6, 22.2, 24.6, 25.1, 27.1, 31.3, 34.3, 35.0, 39.5, 39.8, 41.3, 43.5, 55.0, 76.0,
81.8. IR (liquid ®lm, cm^1): 1460, 975. MS (CI, m/z): 252 (M++1, 100), 177 (40), 131 (22). Anal
calcd for C16H29NO: C, 76.44; H, 11.63; N, 5.57. Found: C, 76.71; H, 11.74; N, 5.49.
3.16. Compound 10
White solid, 13%, mp 68±70ꢀC (hexane); H NMR (CDCl3): ꢀ=0.87±0.99 (m, 2H), 0.90 (d,
1
3H, J=2.1 Hz), 0.91 (s, 3H), 0.92 (d, 3H, J=1.6 Hz), 0.99±1.12 (m, 1H), 1.15 (s, 3H), 1.13±1.50
(m, 5H), 1.55±1.72 (m, 3H), 1.81±1.93 (m, 2H), 2.11 (dt, 1H, J=2.4 Hz, J=11.9 Hz), 3.00 (dt,
1H, J=3.3 Hz, J=11.5 Hz), 3.35 (dt, 1H, J=4.3 Hz, J=10.5 Hz), 3.90 (dd, 1H, J=3.5 Hz,
J=9.5 Hz); 13C NMR (CDCl3): ꢀ=11.3, 21.7, 22.1, 25.0, 25.8, 29.8, 31.1, 34.1, 34.7, 41.4, 41.5,
42.6, 50.1, 55.6, 74.1, 84.7. IR (liquid ®lm, cm^1): 1445. MS (CI, m/z): 252 ( M++1, 80), 177 (45),
103 (100). Anal calcd for C16H29NO: C, 76.44; H, 11.63; N, 5.57. Found: C, 76.59; H, 11.74; N,
5.48.
3.17. N-(30-Phenylselenopropyl)-8-amino menthol 12
To a mixture of sodium borohydride (1.65 g, 43.5 mmol) and BF3±OEt2 (8.9 mL, 72.5 mmol) in
dry THF (100 mL), at 0ꢀC under an Ar atmosphere, was slowly added a solution of benzoxazine
2 (10.6 g, 29.0 mmol) in THF, and the system was stirred at room temperature for 3 h. After this
time, excess of methanol was added, and the solvents were eliminated under vacuum. The residue
was treated with a 24% sodium hydroxide solution at re¯ux. Extractions with chloroform and
removal of the solvent yielded 10.0 g (94%) of the titled amino menthol. Pale yellow oil,
20
1
‰ꢁŠD =^14.6 (c 2.0, CH2Cl2); H NMR (CDCl3): ꢀ=0.85±1.04 (m, 3H), 0.90 (d, 3H, J=6.6 Hz),
1.06 (s, 3H), 1.08 (s, 3H), 1.19±1.29 (m, 2H), 1.43 (m, 1H), 1.59±1.71 (m, 2H), 1.76±1.94 (m, 3H),
2.60±2.70 (m, 2H), 2.92 (t, 2H, J=6.2 Hz), 3.58 (dt, 1H, J=4.0 Hz, J=10.5 Hz), 7.20±7.50 (m,
5H); 13C NMR (CDCl3): ꢀ=21.4, 22.1, 25.4, 25.6, 26.0, 30.7, 31.0, 34.9, 40.6, 44.4, 49.5, 56.8,
72.5, 126.8, 129.0 (2C), 129.9, 132.7 (2C). IR (liquid ®lm, cm^1): 3320, 1600, 760, 710. Anal. calcd
for C19H31NOSe: C, 61.94; H, 8.48; N, 3.80. Found: C, 62.12; H, 8.67; N, 3.96.
3.18. N-Phenylselenopropyl-2-(10-propenyl)-perhydro-1,3-benzoxazine 13a
Pale yelow oil, 60%; 1H NMR (CDCl3): ꢀ=0.84±1.18 (m, 3H), 0.90 (d, 3H, J=6.5 Hz), 1.05 (s,
3H), 1.11 (s, 3H), 1.22±1.44 (m, 2H), 1.57±1.94 (m, 5H), 1.67 (dd, 3H, J=1.5 Hz, J=6.5 Hz), 2.41

2818
R. Pedrosa et al. / Tetrahedron: Asymmetry 11 (2000) 2809±2821
(ddd, 1H, J=5.8 Hz, J=9.5 Hz, J=14.9 Hz), 2.73 (ddd, 1H, J=7.5 Hz, J=9.1 Hz, J=16.4 Hz),
2.82 (dt, 2H, J=2.6 Hz, J=7.2 Hz), 3.42 (dt, 1H, J=4.0 Hz, J=10.5 Hz), 4.76 (d, 1H, J=6.5
Hz), 5.46 (ddd, 1H, J=1.7 Hz, J=6.4 Hz, J=15.4 Hz), 5.79 (dq, 1H, J=6.5 Hz, J=15.4 Hz),
7.20±7.52 (m, 5H). IR (liquid ®lm, cm^1): 730, 690. Anal. calcd for C23H35NOSe: C, 65.70; H,
8.39; N, 3.33. Found: C, 65.88; H, 8.21; N, 3.51.
3.19. N-Phenylselenopropyl-2-styrylperhydro-1,3-benzoxazine 13b
20
1
Pale yellow oil, 80%; ‰ꢁŠD =^37.0 (c 1.0, CH2Cl2); H NMR (CDCl3): ꢀ=0.86±1.01 (m, 2H),
0.94 (d, 3H, J=6.6 Hz), 1.04±1.21 (m, 1H), 1.15 (s, 3H), 1.16 (s, 3H), 1.36±1.52 (m, 2H), 1.61±
1.76 (m, 2H), 1.77±1.87 (m, 2H), 1.94 (m, 1H), 2.53 (ddd, 1H, J=6.1 Hz, J=8.8 Hz, J=14.8 Hz),
2.70±2.90 (m, 3H), 3.52 (dt, 1H, J=4.0 Hz, J=10.5 Hz), 5.05 (d, 1H, J=5.5 Hz), 6.17 (dd, 1H,
J=5.5 Hz, J=16.1 Hz), 6.65 (d, 1H, J=16.1 Hz), 7.10±7.40 (m, 10H); 13C NMR (CDCl3):
ꢀ=18.3, 22.2, 25.1, 25.4, 26.7, 31.3, 33.7, 34.9, 41.3, 44.1, 46.9, 56.8, 75.4, 87.6, 126.4, 126.6,
127.6, 128.5, 128.8, 129.0, 130.6, 132.1, 132.4, 136.6. IR (liquid ®lm, cm^1): 735, 690. Anal. calcd
for C28H37NOSe: C, 69.69; H, 7.73; N, 2.90. Found: C, 69.82; H, 7.58; N, 3.17.
3.20. N-Phenylselenopropyl-2-(20methylpropenyl)-perhydro-1,3-benzoxazine 13d
20
1
Pale yellow oil, 54%; ‰ꢁŠD =^14.9 (c 1.0, CH2Cl2); H NMR (CDCl3): ꢀ=0.85±1.03 (m, 2H),
0.92 (d, 3H, J=6.5 Hz), 1.07±1.14 (m, 1H), 1.12 (s, 3H), 1.13 (s, 3H), 1.27±1.38 (m, 1H), 1.46 (m,
1H), 1.62±1.93 (m, 5H), 1.69 (d, 3H, J=1.1 Hz), 1.70 (d, 3H, J=1.1 Hz), 2.45 (ddd, 1H, J=5.7
Hz, J=9.2 Hz, J=14.8 Hz), 2.70±2.90 (m, 3H), 3.47 (dt, 1H, J=4.2 Hz, J=9.4 Hz), 5.10 (d, 1H,
J=7.1 Hz), 5.22 (dt, 1H, J=1.4 Hz, J=7.1 Hz), 7.20±7.50 (m, 5H); 13C NMR (CDCl3): ꢀ=17.3,
18.4, 21.8, 24.7, 25.0, 25.4, 26.4, 30.9, 33.5, 34.5, 41.0, 43.6, 46.7, 56.3, 75.0, 84.0, 123.9, 126.0,
128.5, 130.4, 131.6, 136.0. IR (liquid ®lm, cm^1): 1640, 730, 690. Anal. calcd for C24H37NOSe: C,
66.34; H, 8.58; N, 3.22. Found: C, 66.51; H, 8.67; N, 3.09.
3.21. Compound 14a
1
48%; H NMR (CDCl3): ꢀ=0.84±1.13 (m, 3H), 0.87 (t, 3H, J=7.4 Hz), 0.91 (d, 3H, J=6.5
Hz), 0.94 (s, 3H), 1.15 (s, 3H), 1.25±1.95 (m, 12H), 2.18 (dt, 1H, J=3.0 Hz, J=11.1 Hz),
2.90±3.10 (m, 1H), 3.31 (dt, 1H, J=4.3 Hz, J=10.6 Hz), 3.70 (d, 1H, J=7.5 Hz); 13C NMR
(CDCl3): ꢀ=11.3, 12.7, 22.1, 24.5 (2C), 25.1 (2C), 26.1, 27.6, 31.1, 34.7, 41.3, 42.8, 49.0, 56.0,
74.5, 89.0. Anal. calcd for C17H31NO: C, 76.92; H, 11.77; N, 5.28. Found: C, 76.78; H, 11.62; N,
5.42.
3.22. Compound 14b
55%; 1H NMR (CDCl3): ꢀ=0.87±1.05 (m, 2H), 0.91 (d, 3H, J=6.5 Hz), 0.92 (s, 3H), 1.07±1.20
(m, 1H), 1.15 (s, 3H), 1.25±1.72 (m, 8H), 1.84 (m, 1H), 1.91±2.01 (m, 1H), 2.20 (dt, 1H, J=2.5
Hz, J=10.7 Hz), 2.34 (dd, 1H, J=9.5 Hz, J=13.2 Hz), 2.93±3.05 (m, 1H), 3.17 (dd, 1H, J=4.0
Hz, J=13.2 Hz), 3.34 (dt, 1H, J=4.1 Hz, J=10.5 Hz), 3.77 (d, 1H, J=7.4 Hz), 7.13± 7.28 (m,
5H); 13C NMR (CDCl3): ꢀ=13.0, 22.2, 24.5, 25.1, 26.1, 27.6, 31.2, 34.8, 38.1, 41.3, 42.8, 43.2,
49.0, 56.1, 74.5, 88.3, 125.5, 127.9 (2C), 129.4 (2C), 140.9. Anal. calcd for C22H33NO: C, 80.68; H,
10.16; N, 4.28. Found: C, 80.49; H, 10.29; N, 4.07.

R. Pedrosa et al. / Tetrahedron: Asymmetry 11 (2000) 2809±2821
2819
3.23. Compound 14d
Colourless oil, 40%; 1H NMR (CDCl3): ꢀ=0.78 (d, 3H, J=6.9 Hz), 0.80±1.20 (m, 2H), 0.87 (d,
3H, J=8.5 Hz), 0.90 (s, 6H), 0.94 (d, 3H, J=9.2 Hz), 1.22±1.72 (m, 10H), 1.86±1.93 (m, 1H),
2.09±2.19 (m, 2H), 2.99±3.02 (m, 1H), 3.30 (dt, 1H, J=4.2 Hz, J=10.5 Hz), 3.87 (d, 1H, J=8.0
Hz); 13C NMR (CDCl3): ꢀ=12.8, 13.7, 17.2, 21.1, 22.1, 25.1, 25.8, 26.8, 27.8, 31.1, 34.6, 41.2,
42.9, 46.5, 48.9, 55.0, 74.6, 86.8. Anal. calcd for C18H33NO: C, 77.36; H, 11.90; N, 5.01. Found:
C, 77.23; H, 12.02; N, 4.89.
3.24. Compound 15a
30%; 1H NMR (CDCl3): ꢀ=0.87 (t, 3H, J=7.4 Hz), 0.91 (d, 3H, J=6.5 Hz), 1.11 (s, 3H), 1.18
(s, 3H), 2.73 (dt, 1H, J=4.1 Hz, J=10.6 Hz), 2.84 (dt, 1H, J=3.2 Hz, J=12.2 Hz), 3.35 (dt, 1H,
J=4.0 Hz, J=10.4 Hz), 4.62 (d, 1H, J=1.5 Hz). Anal. calcd for C17H31NO: C, 76.92; H, 11.77;
N, 5.28. Found: C, 76.83; H, 11.54; N, 5.37.
3.25. Compound 15b
Colourless oil, 39%; 1H NMR (CDCl3): ꢀ=0.86±1.00 (m, 2H), 0.91 (d, 3H, J=6.3 Hz), 1.03 (s,
3H), 1.05 (s, 3H), 1.05±1.15 (m, 1H), 1.34±1.61 (m, 6H), 1.70 (m, 2H), 1.75±1.85 (m, 1H), 1.92 (m,
1H), 2.51 (dd, 1H, J=7.5 Hz, J=13.2 Hz), 2.66 (dd, 1H, J=8.0 Hz, J=13.2 Hz), 2.70±2.75 (m,
1H), 2.85 (dt, 1H, J=3.0 Hz, J=11.0 Hz), 3.25 (dt, 1H, J=4.0 Hz, J=10.4 Hz), 4.41 (d, 1H,
J=2.7 Hz), 7.13±7.28 (m, 5H); 13C NMR (CDCl3): ꢀ=21.9, 22.5, 25.0, 25.1, 25.8, 27.5, 31.7, 35.2,
39.0, 40.0, 41.5, 43.0, 43.8, 56.2, 76.3, 83.2, 125.7, 128.0 (2C), 129.1 (2C), 141.0. IR (liquid ®lm,
cm^1): 1600, 745, 695. Anal. calcd for C22H33NO: C, 80.68; H, 10.16; N, 4.28. Found: C, 80.57; H,
10.02; N, 4.17.
3.26. Reduction of 4a±b and 14a±d to 16a±d
General procedure. To a mixture of LiAlH4 (0.60 g, 15.8 mmol) and AlCl3 (0.70 g, 5.25 mmol)
in anhydrous THF (40 mL) was slowly added a solution of the corresponding adduct 4a±b or
14a±d (3.10 mmol) in THF (20 mL), at 0ꢀC under argon. The solution was stirred for 15 min at this
temperature, and quenched by addition of H2O. The solids were separated by ®ltration, and the
residue was washed with EtOAc. The organic layer was dried over anhydrous MgSO4, the solvents
were eliminated in vacuo, and the residue was puri®ed by recrystallisation or chromatography.
3.27. Compound 16a
Colourless solid, 94%, mp 55±57ꢀC (hexane); ‰ꢁŠ2D0=^19.4 (c 1.0, CH2Cl2); 1H NMR (CDCl3):
ꢀ=0.72±1.04 (m, 3H), 0.83 (t, 3H, J=7.5 Hz), 0.88 (s, 3H), 0.90 (d, 3H, J=6.4 Hz), 1.05±1.23 (m,
3H), 1.14 (s, 3H), 1.24±1.53 (m, 5H), 1.37 (m, 1H), 1.62 (m, 3H), 1.88 (m, 2H), 3.10 (d, 1H,
J=10.7 Hz), 3.22 (d, 1H, J=10.7 Hz), 3.59 (dt, 1H, J=4.0 Hz, J=10.1 Hz), 8.70 (br. s, 1H); 13C
NMR (CDCl3): ꢀ=11.3, 18.2, 20.9, 22.0, 25.6, 25.7, 27.6, 30.8, 30.9, 35.1, 39.1, 44.6, 46.5, 46.6,
51.3, 60.3, 72.2. IR (Nujol dispersion, cm^1): 3120, 1180, 740.

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R. Pedrosa et al. / Tetrahedron: Asymmetry 11 (2000) 2809±2821
3.28. Compound 16b
Colourless liquid, 96%; ‰ꢁŠ2D0=^19.6 (c 2.0, CH2Cl2); 1H NMR (CDCl3): ꢀ=0.81±1.14 (m, 4H),
0.87 (s, 3H), 0.89 (d, 3H, J=6.6 Hz), 1.06 (s, 3H), 1.38±1.84 (m, 9H), 1.90±2.02 (m, 2H), 2.44 (dd,
1H, J=6.6 Hz, J=13.3 Hz), 2.49 (dd, 1H, J=4.9 Hz, J=13.3 Hz), 3.09 (m, 1H), 3.23 (m, 1H),
3.56 (dt, 1H, J=4.3 Hz, J=10.3 Hz), 7.00±7.30 (m, 5H); 13C NMR (CDCl3): ꢀ=18.2, 20.9, 22.1,
25.6, 25.8, 30.9, 31.1, 35.1, 39.2, 41.5, 44.6, 46.5 (2C), 51.4, 60.4, 72.2, 125.8, 128.1 (2C), 129.0
(2C), 140.0. IR (liquid ®lm, cm^1): 3125, 1180, 740.
3.29. Compound 16d
Pale yellow liquid, 93%; ‰ꢁŠ2D0=^21.0 (c 4.0, CH2Cl2); 1H NMR (CDCl3): ꢀ=0.73±0.99 (m, 4H),
0.74 (d, 3H, J=6.6 Hz), 0.76 (d, 3H, J=6.0 Hz), 0.77 (s, 3H), 0.78 (d, 3H, J=6.0 Hz), 1.00 (s, 3H),
1.12±1.73 (m, 10H), 1.81 (m, 2H), 3.00 (d, 1H, J=9.3 Hz), 3.10 (d, 1H, J=10.7 Hz), 3.47 (dt, 1H,
J=3.9 Hz, J=10.1 Hz), 8.70 (s, 1H); 13C NMR (CDCl3): ꢀ=13.5, 18.1, 20.1, 20.8, 21.9, 25.7, 26.9,
27.7, 30.8, 31.4, 35.0, 43.4, 44.5, 46.5 (2C), 49.2, 60.3, 72.1. IR (liquid ®lm, cm^1): 3120, 1185, 740.
3.30. Synthesis of enantiopure 3-alkyl-substituted piperidines 17a±d
The ®nal 3-akylpiperidines were isolated by oxidation and elimination of the menthol template
by succesive treatment with PCC and KOH solution in MeOH±THF, as previously described.15
3.31. (R)-3-Ethylpiperidine 17a hydrochloride21
Colourless solid, 70% from 16a, mp 163±165ꢀC (benzene); ‰ꢁŠD20=+3.0 (c 0.8, MeOH) [lit.21
1
[ꢁ]D=+3.2 (c 1.0, EtOH)]. H NMR (CDCl3): ꢀ=0.85 (t, 3H, J=6.7 Hz), 0.90±1.00 (m, 1H),
1.10±1.30 (m, 2H), 1.70±2.00 (m, 4H), 2.40 (q, 1H, J=11.8 Hz), 2.68 (q, 1H, J=11.0 Hz), 3.35 (t,
2H, J=13.2 Hz), 9.20 (br. s, 1H), 9.60 (br. s, 1H); 13C NMR (CDCl3): ꢀ=10.5, 22.0, 26.5, 28.4,
34.6, 44.2, 48.8.
3.32. (S)-3-Benzylpiperidine 17b
This piperidine was characterised as N-tosylamide. White solid, 42% from 16b, mp 121±122ꢀC
20
1
(Et2O); ‰ꢁŠD =+71.9 (c 1.0, CH2Cl2); H NMR (CDCl3): ꢀ=0.80±1.00 (m, 1H), 1.50±1.75 (m,
3H), 1.80±2.00 (m, 1H), 2.14 (dd, 1H, J=10.3 Hz, J=10.9 Hz), 2.30±2.50 (m, 2H), 2.44 (s, 3H),
2.62 (dd, 1H, J=6.6 Hz, J=13.5 Hz), 3.50±3.60 (m, 2H), 7.14 (d, 2H, J=8.1 Hz), 7.20±7.40 (m,
5H), 7.63 (d, 2H, J=8.1 Hz); 13C NMR (CDCl3): ꢀ=21.5, 24.2, 29.5, 37.3, 40.0, 46.7, 51.5, 126.1,
127.6 (2C), 128.3 (2C), 129.0 (2C), 129.6 (2C), 133.1, 139.3, 143.3. Anal. calcd for C19H23NO2S:
C, 69.27; H, 7.04; N, 4.25. Found: C, 69.41; H, 7.18; N, 4.09.
3.33. (S)-3-Isopropylpiperidine 17d hydrochloride
20
White solid, 72% from 16d, mp 118±119ꢀC (acetone); ‰ꢁŠD =+8.4 (c 1.2, CHCl3); H NMR
(CDCl3): ꢀ=0.91 (d, 3H, J=4.0 Hz), 0.92 (d, 3H, J=4.0 Hz), 1.10±1.30 (m, 1H), 1.54 (m, 1H),
1.70±2.00 (m, 4H), 2.56 (t, 1H, J=12.3 Hz), 2.73 (dt, 1H, J=4.0 Hz, J=12.5 Hz), 3.43 (t, 2H,
1
13
J=9.0 Hz), 9.40 (br. s, 1H), 9.70 (br. s, 1H); C NMR (CDCl3): ꢀ=18.9, 19.4, 22.2, 25.6, 30.6,

R. Pedrosa et al. / Tetrahedron: Asymmetry 11 (2000) 2809±2821
2821
39.0, 44.1, 47.3. Anal. calcd for C8H18NCl: C, 58.86; H, 11.12; N, 8.59. Found: C, 58.64; H,
11.31; N, 8.42.
3.34. Reduction and deoxygenation of compound 4c
To a solution of diastereomer 4c (32 mg, 0.1 mmol) in dry toluene, cooled to 0ꢀC under an
argon atmosphere, was added a solution of DIBALH (0.8 mL, 1 M in toluene) and the mixture
was stirred for 1 h. The reaction was poured into water and extracted with ethyl acetate. The
organic layer was dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo,
yielding 26 mg (92%) of 18 as a colourless oil: 1H NMR (CDCl3): ꢀ=0.85±1.02 (m, 4H), 0.88 (s,
3H), 0.89 (d, 3H, J=6.0 Hz), 1.14 (s, 3H), 1.27 (m, 3H), 1.33±1.82 (m, 9H), 1.83±2.02 (m, 2H),
3.18 (dd, 2H, J=10.8 Hz, J=25.6 Hz), 3.50±3.70 (m, 3H), 9.0 (br. s, 1H); 13C NMR (CDCl3):
ꢀ=18.4, 20.9, 22.0, 25.6, 29.6, 30.9, 31.4, 34.5, 35.0, 37.7, 44.5, 46.5 (2C), 51.5, 60.2, 60.8, 72.2.
This product was treated with triphenylphosphine (0.14 mmol, 36 mg) and carbon tetrabromide
(0.11 mmol, 38 mg) in dichloromethane at 0ꢀC for 1.5 h. Filtration of the mixture and solvent
removal a€orded an oil which was subsequently reduced with tributyltin hydride (38 mL, 0.138
mmol) and AIBN (cat.) in benzene at re¯ux (4 h). Acid±base workup yield pure piper-
idinylmenthol 16a (65%).
Acknowledgements
We gratefully thank the Spanish DGES (Proyect PB98-0361) for ®nancial support and the
Ministerio de Educacion y Cultura for predoctoral fellowships (J.P.D.-S. and C.D.R.).
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