An efficient synthesis of enantiopure (+)- and (-)-3-exo-amino-7,7-dimethoxynorbornan-2-exo-ols

Article abstract of DOI:10.1016/S0957-4166(01)00085-4

We describe the synthesis of new amino alcohols (+)- and (-)-3-exo-amino-7,7-dimethoxynorbonan-2-exo-ols. The (+)- or (-)-7,7-dimethoxy-1,4,5,6-tetrachlorobicyclo[2.2.1]hept-5-en-2-endo-ol, obtained from the enzyme catalysed transesterification of the racemate, was reduced and dechlorinated (Na/NH₃; ethanol), followed by pyridinium chlorochromate oxidation of the resultant alcohols to the corresponding ketones. After treatment with t-BuOK/BuONO, in a nitrosation reaction, α-keto oximes were obtained. Reduction over two steps with NaBH₄ and NaBH₄/NiCl₂·6H₂O followed by in situ acetylation furnished the corresponding acetamido esters, which were hydrolysed with CH₃OH/Na to produce the enantiopure amino alcohols in good yields.

Full text of DOI:10.1016/S0957-4166(01)00085-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 557–561
An efficient synthesis of enantiopure (+)- and
(−)-3-exo-amino-7,7-dimethoxynorbornan-2-exo-ols
Alexandre A. M. Lapis, Olyr C. Kreutz, Adriana R. Pohlmann and Valentim E. U. Costa*
Instituto de Qu´ımica, Universidade Federal do Rio Grande do Sul, Av. Bento Gonc¸alves, 9500,
91501-970 Porto Alegre RS, Brazil
Received 19 December 2000; accepted 29 January 2001
Abstract—We describe the synthesis of new amino alcohols (+)- and (−)-3-exo-amino-7,7-dimethoxynorbonan-2-exo-ols. The (+)-
or (−)-7,7-dimethoxy-1,4,5,6-tetrachlorobicyclo[2.2.1]hept-5-en-2-endo-ol, obtained from the enzyme catalysed transesterification
of the racemate, was reduced and dechlorinated (Na/NH3; ethanol), followed by pyridinium chlorochromate oxidation of the
resultant alcohols to the corresponding ketones. After treatment with t-BuOK/BuONO, in a nitrosation reaction, a-keto oximes
were obtained. Reduction over two steps with NaBH4 and NaBH4/NiCl2·6H2O followed by in situ acetylation furnished the
corresponding acetamido esters, which were hydrolysed with CH3OH/Na to produce the enantiopure amino alcohols in good
yields. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
A convenient method for obtaining enantiopure materi-
als is enzyme catalysed acylation.18 The enzyme
catalysed transesterification using vinyl acetate19–21 was
applied, in 1990, for the resolution of 7,7-disubstituted
A wide range of 1,2-amino alcohols have been used as
chiral building blocks in organic synthesis, as well as
chiral auxiliaries or ligands.1 In many cases, it has been
recognised that homochiral amino alcohols are versatile
reagents for the generation of enantiopure materials, as
examples: the cis-1-amino-2-indanol,2 an important
subunit in drug design and the asymmetric synthesis of
biologically active molecules, and the optically active
2-amino-1,3,4-butanetriol, a building block for the syn-
thesis of a potent HIV-protease inhibitor.3 As interme-
diates, chiral b-amino alcohols were recently used for
1,4,5,6-tetrachlorobicyclo[2.2.1]hept-5-en-2-ols
using
lipase from C. rugosa.22
In recent years, our group has synthesised23 and studied
constrained polycyclic compounds by NMR spec-
troscopy.24–27 The enantiomeric analysis of chiral poly-
cyclic derivatives by NMR using a mixture of chiral
and achiral shift reagents was reported,28,29 as well as
an approach to determine the optimal position of the
lanthanide ion in complexes formed by shift reagents
and substrates30 using the pseudocontact model. Addi-
tionally, we reported the kinetic resolution of a very
hindered secondary pentacyclic alcohol31 employing the
lipase from C. rugosa in vinyl acetate.
the
stereocontrolled
synthesis
of
tetra-
hydroisoquinolines, an important class of physiologi-
cally active alkaloids.4 Furthermore, the abundance and
crystallinity of (+)-camphor has attracted considerable
interest throughout the synthesis of enantiomerically
pure derivatives including 3-endo-amino-2-endo-bor-
nanol,5
phorquinone-3-oxime7
exo,exo-amino
alcohol,6
bridgehead-substituted
anti-(+)-cam-
In this work, we describe the efficient synthesis of
enantiopure (+)- and (−)-3-exo-amino-7,7-dimethoxy-
norbonan-2-exo-ols in six steps from (+)- and (−)-7,7-
dimethoxy-1,4,5,6-tetrachlorobicyclo[2.2.1]hept-5-en-2-
endo-ol.
and
2-norbonanones and 2-norbonanoximes.8 Bicyclic
amino alcohol derivatives are stereochemically con-
strained compounds and are interesting systems for use
as chiral auxiliaries,9–13 synthetic intermediates and chi-
ral ligands for asymmetric synthesis.9,15–17
2. Results and discussion
( ) - 7,7 - Dimethoxy - 1,4,5,6 - tetrachlorobicyclo[2.2.1]-
hept-5-en-2-endo-ol, obtained from the Diels–Alder
* Corresponding author. E-mail: valentim@iq.ufrgs.br
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00085-4

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A. A. M. Lapis et al. / Tetrahedron: Asymmetry 12 (2001) 557–561
reaction of 1,2,3,4-tetrachloro-5,5-dimethoxycyclopen-
tadiene and vinyl acetate followed by acid hydrolysis
mixtures (endo–endo, endo–exo and exo–exo) were
always obtained. Hence, we decided to proceed with the
reduction of a-keto oxime (+)-4 or (−)-4 in two steps.
Firstly, NaBH4 reduction afforded the hydroxy oximes
(+)-5 and (−)-5, respectively, and then, in a second step,
(sulfuric
acid/methanol),
was
subjected
to
transesterification22 with vinyl acetate and lipase from
Candida rugosa, over 7 days. The enantiomeric purity
of the products was determined by chiral gas chro-
matography (alcohol: e.e. 98%; acetate: e.e. 99%). The
acetate was hydrolysed (sulfuric acid/methanol) to fur-
nish the corresponding alcohol (+)-1. The absolute
configuration of each product (−)-1 and (+)-1 was
assigned as (1R,2S,4S) and (1S,2R,4R), respectively, by
comparison of the specific rotation measurements
reported by Berger et al.22 The pure alcohols (−)-1 and
(+)-1 were then reduced and dechlorinated using the
reductive system Na/NH3 liq./ethanol (Scheme 1) to
afford (−)-2 or (+)-2.
these
oximes
were
reduced
using
NaBH4/
NiCl2·6H2O.6,33 This methodology proved to be
efficient in the reduction of the hydroxy oxime (+)-5 or
(−)-5. However, direct extraction and purification of
product exo,exo-(+)-7 or (−)-7 afforded the amino alco-
hol in poor yields. To overcome this, an in situ acetyla-
tion of (+)-7 or (−)-7 was carried out after the hydroxy
oxime reduction, producing (+)-6 or (−)-6 in good yield
and purity (Scheme 1). Finally, the acetamido esters
exo,exo-(+)-6 or (−)-6 were treated with Na/MeOH to
provide the enantiomerically pure amino alcohols
exo,exo-(+)-7 or (−)-7 in high 88% yields.
The dechlorinated alcohols (−)-2 or (+)-2 were oxidised
by treatment with pyridinium chlorochromate (PCC)32
giving the corresponding ketones (+)-3 and (−)-3,
respectively. In the Roy camphor nitrosation reaction,7
the ketones (+)-3 or (−)-3 were treated with the t-
BuOK/BuONO system, furnishing the a-keto oximes
(+)-4 and (−)-4, each one, with a diasteriomeric ratio of
(E)-/(Z)-configurations of 4:1.
The exo,exo-configuration of amino alcohol 7 was
assigned by NOESY NMR experiment. The interac-
tions between the a-hydrogen of alcohol and amine
groups, at positions 2 and 3, with the hydrogens at
positions 5 and 6 of the ring were observed. The chiral
gas chromatography analysis has showed that all inter-
mediates as well as the amino alcohols (+)-7 or (−)-7
maintained the enantiomeric excess (98 and 99%,
respectively) in the course of this synthetic route.
Despite earlier work reporting the reduction of bicyclic
a-keto oxime derivatives to their respective endo–endo
and exo–exo amino alcohols by treatment with LiAlH4
or amino alcohols (exo–exo) by reaction with
NaBH4,12–14 followed by hydrogenation with H2/PtO2,
we observed that these methods were not efficient to
reduce the a-keto oxime (+)-4 or (−)-4 as stereoisomeric
Table 1 shows the specific rotation values of com-
pounds 2–7. For compounds 4 and 5, these values
correspond to the diasteriomeric mixtures of oximes
(E)/(Z) (4:1 and 6:4, respectively).
Scheme 1. (i) Na, NH3 liq., ethanol; (ii) PCC; (iii) t-BuOK, BuONO; (iv) NaBH4, (v) a. NaBH4, NiCl2·6H2O, b. Ac2O; (vi) Na,
MeOH.

A. A. M. Lapis et al. / Tetrahedron: Asymmetry 12 (2001) 557–561
559
Table 1. Specific rotation values of compounds 2–7 (ethyl
duce 3.0 g (17.4 mmol) of a yellow oil, corresponding to
alcohol (−)-2 (yield: 72%). FTIR (film): w (cm−1): 3409
acetate)
1
(C-OH). H NMR (200 MHz, CDCl3): l 0.98 (m, 1H),
Compound
[h]2D0
c (g/100 mL)
1.88 (m, 2H), 2.12 (m, 3H), 3.05 (s, 3H), 3.09 (s, 3H),
4.3 (m, 1H). 13C NMR (50 MHz, CDCl3): l 17.5 (CH2),
27.6 (CH2), 38.4 (CH2), 38.5 (CH), 43.8 (CH), 50.0
(CH3), 50.48 (CH3), 70.1 (CH), 114.1.
(−)-2
(+)-2
(−)-3
(+)-3
(−)-4
(+)-4
(−)-5
(+)-5
(−)-6
(+)-6
(−)-7
(+)-7
−1
+1
3.07
3.07
1.88
1.88
1.00
1.00
1.52
1.52
1.04
1.04
1.04
1.04
−53
+55
−52a
+53a
−39b
+40b
−15
+14
−26
+26
4.3. (+)-7,7-Dimethoxynorbornan-2-one (+)-332
The alcohol (−)-2 (0.31 g, 1.8 mmol) was dissolved in of
dry methylene chloride (40 mL) under stirring. To this
solution was added small portions of pyridinium
chlorochromate (PCC, 775 mg, 3.6 mmol) at 0°C. The
suspension was stirred at room temperature for an
additional 4 h. Ethyl ether (20 mL) was added and a
black precipitate formed, which was filtered off with a
small column fitted with silica gel and eluted with ethyl
ether. The organic solution was concentrated producing
of a yellow oil of the pure ketone (+)-3 (290 mg, 1.7
mmol, 95%). FTIR (film): w (cm−1): 1755 (CꢀO). 1H
NMR (200 MHz, CDCl3): l 1.42 (m, 2H), 1.8 (s, 1H),
1.95 (m, 2H), 2.38 (m, 1H), 2.47 (m, 2H), 3.21 (s, 3H),
3.24 (s, 3H). 13C NMR (50 MHz, CDCl3): l 21.2 (CH2),
25.9 (CH2), 38.1 (CH), 44.0 (CH2), 49.9 (CH3), 50.8
(CH3), 52.6 (CH), 111.5 (C), 212.7 (C).
a Ratio (E)/(Z): 4:1.
b Ratio (E)/(Z): 6:4.
3. Conclusions
In summary, new enantiomerically pure amino alcohols
(+)- and (−)-3-exo-amino-7,7-dimethoxynorbonan-2-
exo-ols were easily obtained from dimethoxy-tetra-
chlorobicyclo[2.2.1]heptenol by simple procedures with
good yields. This constitutes an effective and conve-
nient synthetic approach for the preparation of new
chiral auxiliaries, synthons and building blocks.
4.4. (+)-3-Hydroxyimino-7,7-dimethoxynorbornan-2-one
(+)-4
A solution of (+)-3 (400 mg, 2.35 mmol) in dry THF
(0.5 mL) was added to a magnetically stirred solution
of t-BuOK (0.31 g, 2.82 mmol) in dry THF (1.5 mL) at
−30°C under an inert gas atmosphere. The mixture was
stirred at −30°C for 10 min, treated with BuONO (0.29
g, 2.82 mmol), and stirred at room temperature for 12
h. The solvent was evaporated and the residue was
diluted in water (40 mL). The aqueous phase was
extracted with ethyl ether (3×30 mL). The aqueous
phase was acidified with 5% aqueous HCl (pH 4) and
extracted with ethyl ether (3×30 mL). After solvent
evaporation, a yellow oil was obtained corresponding
to a mixture of the anti (80%) and syn (20%) forms of
the oxime (+)-4 (yield: 400 mg, 2.01 mmol, 85%). Pure
anti-oxime was obtained when the mixture was stirred
under reflux for several days in ethyl acetate. FTIR
(film): w (cm−1): 3315 (OH), 1748 (CꢀO), 1644 (CꢀN). l
1H NMR (200 MHz, CDCl3): l 1.63 (m, 2H), 2.09 (m,
2H), 2.88 (m, 1H), 3.22 (s, 3H), 3.27 (s, 3H), 3.78 (m,
1H). 13C NMR (50 MHz, CDCl3): l 22.3 (CH2), 23.5
(CH2), 41.7 (CH), 49.8 (CH3), 51.6 (CH3), 53.2 (CH),
109.5 (C), 157.5 (CꢀNOH), 198.19 (CꢀO). HRMS
found: m/z 199.0849; calcd for C9H13NO4[M]+:
199.0844
4. Experimental
4.1. General
NMR spectra were recorded on Varian VXR-200 or
Inova 300 spectrometers at magnetic fields of 4.7 and
7.05 T at 22°C. Chemical shifts are expressed in l
(ppm) relative to TMS as an internal standard. Infrared
spectra were recorded using a FTIR-Mattson 3020
spectrometer. Products were analysed by GC on a
SHIMADZU chromatograph model GC-171 and
Varian Model star 3400 CX chromatograph both
equipped with FID using BETA-DEX™ 120 column
(30 m×0.22 mm (i.d.)×1.25 mm). Optical rotations were
measured with a Perkin–Elmer polarimeter model 341
with a 1 cm cell at 20°C. HRMS spectra were obtained
on a Jeol AX500 spectrometer.
The descriptions of the experimental procedures are the
same for synthesis to the respective ( ), (−) and (+)
products.
4.2. (−)-7,7-Dimethoxynorbornan-2-endo-ol (−)-232
A solution of the alcohol (−)-122 (7.43 g, 24.2 mmol) in
dry ethanol (4.2 mL, 71.6 mmol) and dry THF (45 mL)
was added in small portions to a solution of sodium
(5.12 g, 0.22 mol) in ammonia (230 mL) at −78°C,
under vigorous stirring for 0.5 h. Then, the mixture was
treated with of saturated aqueous ammonium chloride
solution (50 mL). The ammonia was evaporated and
the usual ethereal extraction sequence followed to pro-
4.5. (+)-3-exo-Hydroxy-7,7-dimethoxynorbornan-2-one
oxime (+)-5
A diastereomeric mixture of the keto oxime (+)-4 (700
mg, 3.5 mmol) was dissolved in of methanol (20 mL).
The solution was cooled at 0°C and small portions
powdered sodium borohydride (150 mg, 4.0 mmol)
were added with stirring. The solution was warmed up

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A. A. M. Lapis et al. / Tetrahedron: Asymmetry 12 (2001) 557–561
to room temperature and stirred for an additional 3 h.
The solvent was removed using a rotatory evaporator
and water (15 mL) was added to the residue. The
solution was acidified with HCl 5% (pH 4). Three
extractions with chloroform produced of a pale yellow
oil (660 mg, 3.28 mmol, 93%) corresponding to a
mixture of anti (60%) and syn (40%) hydroxy oxime
(+)-5. FTIR (film): w (cm−1): 3328 (OH), 1643 (CꢀN). l
1H NMR (200 MHz, CDCl3): l 1.31 (m, 2H and 2H),
2.01 (m, 2H and 2H), 2.37 (m, 2H), 2.85 (m, 1H) 3.29
(m, 6H and 6H), 3.54 (m, 1H), 4.11 (s, 1H, anti ), 4.42
(s, 1H, syn), 9.45 (bs, 2H). 13C NMR (50 MHz,
CDCl3): l 22.4 (CH2), 22.6 (CH2), 22.8 (CH2), 24.4
(CH2), 40.6 (CH), 44.4 (CH), 44.8 (CH), 50.1 (CH3),
51.1 (CH3), 51.2 (CH3), 72.6 (CH, syn), 74.9 (CH,
anti ), 112.8 (C, syn), 113.2 (C, anti ), 164.93 (CꢀNOH,
anti ), 164.97 (CꢀNOH, syn). HRMS found: m/z
201.0975; calcd for C9H15NO4[M]+: 201.1001
3H), 3.31 (s, 3H), 3.63 (d, J=7.5 Hz, 1H). 13C NMR
(50 MHz, CDCl3): l 23.3 (CH2), 24.7 (CH2), 43.7 (CH),
44.9 (CH), 49.9 (CH3), 51.2 (CH3), 56.9 (CH), 73.9
(CH), 114.6 (C). HRMS found: m/z 188.1276; calcd for
C9H8NO3 [M]+: 188.1287.
Acknowledgements
We thank CNPq and FAPERGS for financial support
and CNPq for scholarships to A.A.M.L. and O.C.K.
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