Chemoenzymatic synthesis of azacycloalkan-3-ols

Article abstract of DOI:10.1016/S0957-4166(99)00351-1

Optically active ω-bromocyanohydrins are easily synthesized through an enantioselective (R)-oxynitrilase-catalyzed reaction from their corresponding ω-bromoaldehydes. These cyanohydrins are starting materials for the preparation of medium size nitrogen heterocycles. The reduction of (R)-(+)-5- bromo-2-hydroxypentanenitrile affords, in one-pot, piperidin-3-ol. Azepan-3- ol and azocan-3-ol are readily obtained from their corresponding cyanohydrins in high enantiomeric excesses.

Full text of DOI:10.1016/S0957-4166(99)00351-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3449–3455
Chemoenzymatic synthesis of azacycloalkan-3-ols
Maria I. Monterde, Serge Nazabadioko, Francisca Rebolledo, Rosario Brieva and
Vicente Gotor ∗
Departamento de Química Orgánica e Inorgánica, Facultad de Química, Universidad de Oviedo, 33071- Oviedo, Spain
Received 27 July 1999; accepted 11 August 1999
Abstract
Optically active ω-bromocyanohydrins are easily synthesized through an enantioselective (R)-oxynitrilase-
catalyzed reaction from their corresponding ω-bromoaldehydes. These cyanohydrins are starting materials for
the preparation of medium size nitrogen heterocycles. The reduction of (R)-(+)-5-bromo-2-hydroxypentanenitrile
affords, in one-pot, piperidin-3-ol. Azepan-3-ol and azocan-3-ol are readily obtained from their corresponding
cyanohydrins in high enantiomeric excesses. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The synthesis of optically active cyanohydrins by chemical or enzymatic procedures has received
a considerable amount of attention over recent years.1 (R)-Oxynitrilase from almonds has been used
to catalyze the enantioselective addition of hydrogen cyanide to aromatic and aliphatic aldehydes2 or
aliphatic ketones,3 giving the corresponding (R)-cyanohydrins. One of the most successful procedures
for the preparation of (R)-cyanohydrins has been the use of powdered defatted almond meal as a rich
source of (R)-oxynitrilase.4
In a previous report,5 we have prepared, in high yield and enantiomeric excess, (R)-(+)-5-bromo-2-
hydroxypentanenitrile 3a and (R)-(+)-6-bromo-2-hydroxyhexanenitrile 3b through an enzymatic trans-
cyanation process catalyzed by (R)-oxynitrilase. We have also shown that cyanohydrin 3b is a suitable
starting material for the preparation of (S)-pipecolic acid and 2-substituted piperidine alkaloids.6
In this paper, we propose an approach to the synthesis of some optically active azacycloalkan-3-
ols, structures which are constituents of several bioactive compounds. In particular, piperidin-3-ol is
an attractive target because of its widespread occurrence in natural products. Medicinally important
examples containing 3-piperidinol fragments include cholinotoxic agents,7 antihypertensives and calcium
antagonists,8 2,3-oxydosqualene cyclase inhibitors,9 5-HT4 agonists,10 nootropics11 or antiarrhythmic
∗
Corresponding author. E-mail: vgs@sauron.quimica.uniovi.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00351-1

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agents.12 In view of these applications, as expected, several routes for the preparation of these compounds
have been described. The total syntheses of (S)-(−)-piperidin-3-ol have been reported from D-manitol,13
(S)-malic acid,14 or L-(+)-glutamic acid;14 nevertheless, no experimental details or yields are contained in
the first report and poor or moderated yields (10 and 37%, respectively) are reported in the second one. In
a more recent report, Cossy et al.15 have prepared (R)-(−)-N-alkylpiperidin-3-ols from 2-hydroxymethyl-
N-alkylpyrrolidines by a ring expansion. The resolution of racemic piperidin-3-ol through fractional
recrystallization16 or by enzymatic hydrolysis of several ester derivatives17 has also been described.
On the other hand, monocyclic medium ring nitrogen heterocycles are an important class of com-
pounds, especially in view of their pharmacological properties.18 However, synthetic methods for the
preparation of these compounds are, in general, very specific in each class.
In this article we describe a simple and stereoselective method for the preparation of these hydroxy-
azacycles.
2. Results and discussion
Since ω-bromocyanohydrins are suitable starting materials for the preparation of heterocycles, we
decided to extend our method of preparation of these compounds, via an (R)-oxynitrilase-catalyzed
transcyanation,5 to longer chain ω-bromocyanohydrins 3c–e (n=3–5). Firstly, we have prepared the
corresponding bromoaldehydes 1c–e by reduction of the commercially available esters or acids with
DIBA-H and, secondly, we have carried out the transcyanation process of 1c–e under the optimal
conditions found for 1a,b, that is, using (ꢀ)-2-methyl-2-hydroxyhexanenitrile 2 as the hydrogen cyanide
donor (Scheme 1). Thus, cyanohydrins (R)-3c–e were obtained in moderate yields and high enantiomeric
excess (see Experimental).
Scheme 1.
The enantiomeric excesses of (R)-3c–e were determined by derivatization with Mosher’s acid chloride
followed by 19F NMR analysis. The (R)-configuration of the cyanohydrins was assigned on the basis of
the specificity of the enzyme and by analogy with the results obtained for (R)-3a and (R)-3b.
2.1. Synthesis of (R)-1-(benzyloxycarbonyl)piperidin-3-ol
The optically active (R)-(+)-5-bromo-2-hydroxypentanenitrile 3a could be transformed by reduction
into the corresponding 1,2-aminoalcohol. Due to the presence of the leaving group at C-5 position,
the resulting amine function could undergo a nucleophilic substitution to yield piperidin-3-ol; thus
treatment of the cyanohydrin 3a with BH3·THF gives, after protection of the resulting amine with
benzylchloroformate, (R)-1-(benzyloxycarbonyl)piperidin-3-ol 4 in good yield (Scheme 2).

M. I. Monterde et al. / Tetrahedron: Asymmetry 10 (1999) 3449–3455
3451
Scheme 2.
To ensure that no racemization has occurred during the process, the enantiomeric excess of (R)-
4 was determined by derivatization with Mosher’s acid chloride followed by 19F NMR analysis. The
enantiomeric excess for (R)-4 was 96%, the same as its precursor (R)-3a.5
2.2. Synthesis of (R)-1-(benzyloxycarbonyl)azepan-3-ol and (R)-1-(benzyloxycarbonyl)azocan-3-ol
The seven-, eight-, nine- and ten-membered rings cannot be synthesized in a one-pot procedure by
the reduction of the nitrile function. Under the same conditions as for the synthesis of (R)-4, treatment
of the cyanohydrins (R)-3b–e (n=2–5, respectively) with BH3·THF and subsequent reaction with ben-
zylchloroformate yielded the open chain bromoaminoalcohols (R)-5b–e (Scheme 3). Nevertheless, the
ring closure took place easily on treatment of the protected bromoaminoalcohols (R)-6b,c with tBuOK.
Attempts to cyclize them under milder basic conditions (pyridine or NaOH/Bu4NCl) were unsuccessful.
The hydroxyl protecting group can be quantitatively removed by treatment with tetrabutylammonium
fluoride (TBAF) to obtain the heterocycles (R)-9 and (R)-10 in good yields. Attempts at cyclization of
the bromoaminoalcohols (R)-6d,e failed under all the tested conditions. Besides the previously mentioned
basic media, we attempted the nine- and ten-membered ring closures using silver perchlorate, but
unsuccessfully.
Scheme 3.
To ensure that no racemization has occurred during the processes, the enantiomeric excesses of (R)-9
and (R)-10 were determined by 1H NMR analysis of their acetyl derivatives in the presence of the chiral
shift reagent Eu(hfc)3. The enantiomeric excesses for (R)-9 and (R)-10 were 91% and 90%, the same as
their precursors (R)-3b5 and (R)-3c, respectively.
In conclusion, the reduction of the nitrile function in the (R)-ω-bromocyanohydrins permits (R)-ω-
bromo-1,2-aminoalcohols to be obtained which, depending on their chain length, are suitable starting
materials for the preparation of optically active piperidin-3-ol, azepan-3-ol and azocan-3-ol. To the best
of our knowledge, the asymmetric syntheses of the two last heterocycles have not been described before.

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3. Experimental
Melting points were taken using a Gallenkamp apparatus and were uncorrected. Optical rotations
were measured using a Perkin–Elmer 241 polarimeter and specific rotations are quoted in units of
1
10−1 deg cm2 g−1. H and 13C NMR were obtained with TMS (tetramethylsilane) as internal standard,
using a Bruker AC-300 (1H 300 MHz and 13C 75.5 MHz) spectrometer. Mass spectra were recorded
on a Hewlett–Packard 5987A and Finnigan MAT/95 spectrometers. Microanalyses were performed
on a Perkin–Elmer 240B elemental analyzer. All reagents were purchased from Aldrich Chemie.
Solvents were distilled over an adequate desiccant and stored under nitrogen. Flash chromatography
was performed using Merck silica gel 60 (230–400 mesh).
3.1. (R)-Oxynitrilase catalyzed transcyanation of ω-bromoaldehydes. General procedure
The defatted ground almond meal (2 g) was incubated with 5 ml of 0.02 M citrate buffer (pH
5.5) in a 250 ml reaction vessel. After 15 min, 50 ml of diisopropyl ether, distilled substrate ω-
bromoaldehyde (8.4 mmol) and the (ꢀ)-2-hydroxy-2-methylhexanenitrile (1.6 g, 12.6 mmol) were added
to the suspension. The mixture was shaken at 30°C and 250 rpm in a rotatory shaker. After 24 h, the
reaction mixture was filtered and washed with CH2Cl2. The combined filtrates were concentrated in
vacuo, and the residue was purified by flash chromatography on silica gel with hexane:H2CCl2:AcOEt
(7.5:2.5:1), to give the (R)-cyanohydrin 3.
3.1.1. (R)-(+)-7-Bromo-2-hydroxyheptanenitrile (R)-3c
Colourless oil; yield 65%; [α]25 +7.8 (c=1.1, CHCl3), ee 90%; H NMR (CDCl3) δ 1.48–1.61 (m,
1
D
4H), 1.80–1.98 (m, 4H), 3.27 (br s, 1H), 3.35 (t, 2H), 4.50 (t, 1H); 13C NMR (CDCl3) δ 23.6, 27.3, 32.2,
33.5, 34.7, 61.0, 119.9; MS (EI) m/z 207 [M+(81Br), 8], 205 [M+(79Br), 8], 189 (13), 187 (13), 81 (92),
69 (45), 55 (100).
3.1.2. (R)-(+)-8-Bromo-2-hydroxyoctanenitrile (R)-3d
Colourless oil; yield 41%; [α]25 +8.8 (c=1.2, CHCl3), ee 92%; H NMR (CDCl3) δ 1.35–1.61 (m,
1
D
6H), 1.80–1.97 (m, 4H), 3.29 (br s, 1H), 3.42 (t, 2H), 4.47 (t, 1H); 13C NMR (CDCl3) δ 24.3, 27.8, 28.0,
32.4, 33.7, 34.9, 61.1, 119.9; MS (EI) m/z 221 [M+(81Br)<1], 219 [M+(79Br)<1], 176 (45), 174 (45),
150 (65), 148 (65), 69 (100).
3.1.3. (R)-(+)-9-Bromo-2-hydroxynonanenitrile (R)-3e
Colourless oil; yield 40%; [α]25 +7.7 (c=1.1, CHCl3), ee 97%; H NMR (CDCl3) δ 1.31–1.60 (m,
1
D
8H), 1.80–1.97 (m, 4H), 3.04 (br s, 1H), 3.42 (t, 2H), 4.50 (t, 1H); 13C NMR (CDCl3) δ 24.7, 28.2, 28.8
29.0, 32.9, 34.3, 35.3, 61.5, 120.4. MS (EI) m/z 235 [M+(81Br)<1], 233 [M+(79Br)<1], 164 (44), 162
(44), 109 (56), 83 (71), 55 (100).
3.2. (R)-(−)-1-Benzyloxycarbonylpiperidin-3-ol (R)-4
To a vigorously stirred solution of the bromocyanohydrin (R)-3a (1.4 g, 7.8 mmol) in 200 ml of dry
THF at 0°C, were added dropwise 47 ml of a 1 M solution of BH3·THF. The resulting mixture was
allowed to warm to rt and stirred for 6 h. Then 47 ml of 6 N HCl were added and the organic solvent
was removed under reduced pressure. The resulting solution was cooled to 0°C and adjusted to basic pH
by addition of NaOH pellets. The aqueous phase was extracted with CH2Cl2 (3×50 ml) and the solvent

M. I. Monterde et al. / Tetrahedron: Asymmetry 10 (1999) 3449–3455
3453
of the combined organic fractions was almost completely removed under reduced pressure. Without any
further purification 10 ml of distilled H2O and Na2CO3 (82.8 mg, 7.8 mmol) were added to the resulting
mixture, cooled to 0°C and benzylchloroformate (1.1 ml, 7.8 mmol) was added dropwise and stirred for
6 h. Then, the mixture was extracted with CH2Cl2 (3×50 ml) and the combined organic fractions were
dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash
chromatography on silica gel with hexane:AcOEt (7:3), to give the piperidin-3-ol (R)-4 as a colourless
oil in 40% yield. [α]25 −11.9 (c=1.0, CHCl3), ee 96%; 1H NMR (CDCl3) δ 1.54 (m, 1H), 1.92 (m, 3H),
D
3.16 (m, 1H), 3.51 (m, 1H), 3.79 (m, 2H), 4.00 (m, 1H), 5.11 (s, 2H), 5.12 (br s, 1H), 7.35, (s, 5H); 13
C
NMR (CDCl3) δ 25.7, 28.3, 44.7, 66.5, 67.9, 77.7, 127.9, 128.3, 136.4, 157.6; MS (EI) m/z 235 (M+,
23), 191, (26), 144 (40), 91 (74), 71 (100); HRMS calcd for C13H17NO3 235.1207, found 235.1208.
3.3. (R)-(−)-Benzyl N-(6-bromo-2-hydroxyhexyl)carbamate (R)-5b
The title compound was prepared as described for (R)-4. White solid; yield 75%; mp 50–52°C; [α]25
D
1
−8.5 (c=1.0, CHCl3), ee 91%; H NMR (CDCl3) δ 1.45 (m, 4H), 1.83 (m, 2H), 2.51 (br s, 1H), 3.07
(m, 1H), 3.34 (m, 1H), 3.42 (t, 2H), 3.73 (s, 1H), 5.09 (s, 2H), 5.34 (br s, 1H), 7.37 (s, 5H); 13C NMR
(CDCl3) δ 24.0, 32.4, 33.4, 33.5, 46.8, 66.8, 70.9, 128.0, 128.1, 128.4, 136.8, 157.1; MS (EI) m/z 331
[M+(81Br)<1], 329 [M+(79Br)<1], 165 (34), 108 (32), 104 (95), 91 (100); HRMS calcd for C14H20BrNO3
329.0625, found 329.0626. Anal. calcd for C14H20BrNO3: C, 50.92; H, 6.10; N, 4.24, found: C, 51.10;
H, 6.17; N, 4.18.
3.4. (R)-(−)-Benzyl N-(7-bromo-2-hydroxyheptyl)carbamate (R)-5c
The title compound was prepared as described for (R)-4. White solid; yield 78%; mp 55–58°C; [α]25
D
1
−4.6 (c=1.0, CHCl3), ee 90%; H NMR (CDCl3) δ 1.43 (m, 6H), 1.82 (m, 2H), 2.64 (br s, 1H), 3.11
(m, 1H), 3.33 (m, 1H), 3.41 (t, 2H), 3.69 (s, 1H), 5.10 (s, 2H), 5.32 (br s, 1H), 7.36 (s, 5H); 13C NMR
(CDCl3) δ 24.52, 27.91, 32.5, 33.7, 34.28, 46.8, 66.8, 70.9, 128.0, 128.4, 136.2, 157.0; FABS m/z 346
[(M+1)+(81Br), 15], 344 [(M+1)+(79Br), 15], 91 (100). Anal. calcd for C15H22BrNO3: C, 52.48; H, 6.17;
N, 4.08; found: C, 52.55; H, 6.48; N, 4.02.
3.5. (R)-(−)-Benzyl N-(8-bromo-2-hydroxyoctyl)carbamate (R)-5d
The title compound was prepared as described for (R)-4. White solid; yield 77%; mp 57–59°C; [α]25
D
1
−8.8 (c=0.9, CHCl3), ee 92%; H NMR (CDCl3) δ 1.43 (m, 8H), 1.86 (m, 2H), 2.49 (br s, 1H), 3.06
(m, 1H), 3.34 (m, 1H), 3.41 (t, 2H), 3.69 (s, 1H), 5.10 (s, 2H), 5.32 (br s, 1H), 7.35 (s, 5H); 13C NMR
(CDCl3) δ 25.1, 27.8, 28.5, 32.5, 33.8, 34.3, 46.8, 66.7, 71.0, 127.9, 127.9, 128.3, 136.1, 156.9; MS (EI)
m/z 359 [M+(81Br)<1], 357 [M+(79Br)<1], 165 (31), 108 (29), 91 (100). Anal. calcd for C15H22BrNO3:
C, 53.79; H, 6.49; N, 3.92; found: C, 53.59; H, 6.88; N, 3.90.
3.6. (R)-(−)-Benzyl N-(9-bromo-2-hydroxynonyl)carbamate (R)-5e
The title compound was prepared as described for (R)-4. White solid; yield 30%; mp 70–72°C; [α]25
D
1
−5.6 (c=1.0, CHCl3), ee 97%; H NMR (CDCl3) δ 1.28–1.59 (m, 10H), 1.90 (m, 2H), 2.29 (br s, 1H),
3.10 (m, 1H), 3.34 (m, 1H), 3.43 (t, 2H), 3.71 (s, 1H), 5.12 (s, 2H), 5.23 (br s, 1H), 7.35 (s, 5H); 13C
NMR (CDCl3) δ 25.3, 28.0, 28.5, 25.3, 32.6, 33.9, 34.6, 46.9, 66.8, 71.2, 128.0, 128.1, 128.5, 136.3,

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M. I. Monterde et al. / Tetrahedron: Asymmetry 10 (1999) 3449–3455
157.0; MS (EI) m/z 373 [M+(81Br), 3], 371 [M+(79Br), 3], 330 (9), 328 (10), 266 (5), 264 (6), 238 (5),
236 (5), 194 (34), 104 (70), 91 (100).
3.7. (R)-(−)-Benzyl N-[6-bromo-2-(tert-butyldimethylsilyloxy)hexyl]carbamate (R)-6b
A solution of compound (R)-5b (300 mg, 0.87 mmol), tert-butyldimethylsilyl chloride (263 mg, 1.7
mmol), imidazole (178 mg, 2.6 mmol) and a catalytic quantity of 4-(dimethylamino)pyridine (DMAP)
in dry CH2Cl2 (8 ml) under N2 atmosphere was stirred for 24 h at rt. Then, 15 ml of a saturated solution
of NH4Cl were added and the resulting mixture was extracted with CH2Cl2 (3×10 ml). The combined
organic fractions were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude
residue was purified by flash chromatography on silica gel (hexane:AcOEt 9:1) to afford the compound
(R)-6b as a colourless oil in a 90% yield; [α]25 −1.7 (c=1.0, CHCl3), ee 91%; 1H NMR (CDCl3) δ 0.09
D
(s, 6H), 0.88 (s, 9H), 1.45 (m, 4H), 1.84 (m, 2H), 3.19 (m, 2H), 3.39 (t, 2H), 3.76 (s, 1H), 4.98 (br s,
1H), 5.10 (s, 2H), 7.36 (s, 5H); 13C NMR (CDCl3) δ −4.7, −3.6, 17.9, 23.8, 25.7, 32.6, 33.5, 33.8, 46.2,
66.6, 70.8, 128.1, 128.4, 136.4, 156.4; MS (EI) m/z 445 [M+(81Br), 20], 443 [M+(79Br), 20], 388 (63),
386 (65), 344 (65), 342 (65), 283 (74), 281 (74), 131 (30), 115 (33), 91 (100).
3.8. (R)-(−)-Benzyl N-[7-bromo-2-(tert-butyldimethylsilyloxy)heptyl]carbamate (R)-6c
The title compound was prepared as described for (R)-6b. Colourless oil; yield 90%; [α]25 −2.1
D
1
(c=0.9, CHCl3), ee 90%; H NMR (CDCl3) δ 0.07 (s, 6H), 0.88 (s, 9H), 1.42 (m, 6H), 1.86 (m, 2H),
3.20 (m, 2H), 3.39 (t, 2H), 3.76 (s, 1H), 4.99 (br s, 1H), 5.12 (s, 2H), 7.37 (s, 5H); 13C NMR (CDCl3) δ
−4.0, 17.9, 24.3, 25.7, 28.5, 32.5, 33.7, 34.6, 46.2, 66.6, 70.9, 128.0, 128.4, 136.4, 156.4; MS (EI) m/z
459 [M+(81Br), 4], 457 [M+(79Br), 4], 402 (45), 400 (45), 295 (58), 293 (58), 91 (100).
3.9. (R)-(−)-1-(Benzyloxycarbonyl)-3-(tert-butyldimethylsilyloxy)azepane (R)-7
To a stirred solution of compound (R)-6b (163 mg, 0.37 mmol) in 25 ml of dry THF under N2
t
atmosphere at rt was added, in small portions, BuOK (7.2 mg, 0.64 mmol). The resulting mixture was
stirred for 15 h. Then, 15 ml of a saturated solution of NH4Cl were added and the resulting mixture was
extracted with AcOEt (3×20 ml). The combined organic fractions were dried over Na2SO4, filtered and
evaporated under reduced pressure. The crude residue was purified by flash chromatography on silica gel
(hexane:AcOEt 9.5:0.5) to afford the compound (R)-7 as a colourless oil in a 50% yield; [α]25 −13.7
D
1
(c=1.0 CHCl3), ee 91%; H NMR (CDCl3) δ −0.01 (d, 3H), 0.11 (d, 3H), 0.90 (d, 9H), 1.78 (m, 6H),
2.88 (q, 1H), 3.05 (m,1H), 3.82 (m, 2H), 3.95 (m, 1H), 5.15 (s, 2H), 7.36 (s, 5H); 13C NMR (CDCl3) δ
−5.0, 17.9, 20.5, 25.6, 27.2, 36.9, 47.4, 53.6, 66.9, 70.6, 127.5, 128.0, 128.3, 136.8, 155.9; MS (EI) m/z
363 (M+<1), 306 (76), 262 (45), 91 (100) (M+2+<1); HRMS calcd for C20H33NSiO3 363.2222, found
363.2229.
3.10. (R)-(−)-1-(Benzyloxycarbonyl)-3-(tert-butyldimethylsilyloxy)azocane (R)-8
The title compound was prepared as described for (R)-7. Colourless oil; yield 30%; [α]25 −15.6
D
1
(c=1.0, CHCl3), ee 90%; H NMR (CDCl3) δ −0.05 (d, 3H), 0.13 (d, 3H), 0.91 (d, 9H), 1.71 (m, 8H),
2.7 (q, 1H), 2.9 (m, 1H), 3.68 (m, 1H), 3.88 (m, 1H), 4.05 (m, 1H), 5.17 (s, 2H), 7.36 (s, 5H); 13C NMR
(CDCl3) δ −5.0, 18.0, 21.1, 25.7, 26.4, 27.2, 34.2, 49.3, 52.7, 67.1, 69.6, 127.5, 128.2, 128.4, 136.6,
155.9; MS (EI) m/z 377 (M+, 5) 362 (17), 320 (13), 91 (100).

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3455
3.11. (R)-(−)-1-(Benzyloxycarbonyl)azepan-3-ol (R)-9
To a stirred solution of compound (R)-8 (400 mg, 1.1 mmol) in 25 ml of dry THF under N2 atmosphere
at rt was added dropwise a solution of 1 M tetrabutylammonium fluoride (1.33 ml). The resulting mixture
was stirred for 5 h. After removal of the solvent under reduced pressure, the crude residue was purified
by flash chromatography on silica gel (hexane:AcOEt 3:2) to yield the compound (S)-9 as a colourless
oil in a quantitative yield; [α]25 −13.5 (c=1.0, CHCl3), ee 91%; 1H NMR (CDCl3) δ 1.3–1.8 (m, 6H),
D
3.25 (m, 2H), 3.42 (m, 1H), 3.65 (m, 2H), 3.97 (br s, 1H), 5.15 (s, 2H), 7.36 (s, 5H); 13C NMR (CDCl3)
δ 20.8, 28.4, 35.6, 48.1, 53.4, 67.2, 70.5, 127.6, 127.8, 127.9, 128.4, 136.5, 157.6; MS (EI) m/z 249 (M+,
1.5), 114 (18), 91 (100).
3.12. (R)-(−)-1-(Benzyloxycarbonyl)azocan-3-ol (R)-10
The title compound was prepared as described for (R)-9. Colourless oil; quantitative yield; [α]25 −2.6
D
(c=1.1, CHCl3), ee 90%; 1H NMR (CDCl3) δ 1.25–1.82 (m, 8H), 3.03 (m, 1H), 3.30 (m, 1H), 3.81 (m,
3H), 4.29 (br s, 1H), 5.18 (s, 2H), 7.36 (s, 5H); 13C NMR (CDCl3) δ 22.4, 26.6, 26.8, 32.7, 49.3, 53.5,
67.5, 70.9, 127.7, 128.0, 128.4, 136.4, 158.2; MS (EI) m/z 263 (M+, 1.5), 128 (61), 91 (100).
Acknowledgements
Financial support of this work by CICYT (Project BIO-98-0770) is gratefully acknowledged.
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