A novel approach to 2,4-ethanoproline

Article abstract of DOI:10.1016/j.tetasy.2009.05.003

A novel approach to 2-azabicyclo[2.2.1]heptane-1-carboxylic acid (2,4-ethanoproline) is reported starting from (2S,4R)-4-hydroxyproline. The synthetic scheme consists of 10 steps and results in 22% total yield of the title compound. Enantiomeric purity of the product is checked by chiral stationary phase HPLC.

Full text of DOI:10.1016/j.tetasy.2009.05.003

Tetrahedron: Asymmetry 20 (2009) 1433–1436
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A novel approach to 2,4-ethanoproline
a
b,
*
Oleksandr O. Grygorenko a, , Igor V. Komarov , Carlos Cativiela
*
a Department of Chemistry, Kyiv National Taras Shevchenko University, 01033 Kyiv, Ukraine
b Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to 2-azabicyclo[2.2.1]heptane-1-carboxylic acid (2,4-ethanoproline) is reported start-
ing from (2S,4R)-4-hydroxyproline. The synthetic scheme consists of 10 steps and results in 22% total
yield of the title compound. Enantiomeric purity of the product is checked by chiral stationary phase
HPLC.
Received 26 February 2009
Accepted 1 May 2009
Available online 3 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Br
COOX3
5
4
6
Conformational restriction has been proven to be an efficient
tool in various areas of organic and medicinal chemistry, particu-
larly for drug design.1 Synthesis of constrained and rigid amino
acids has given rise to considerable interest in the last decade.2
Among the numerous rigid amino acids synthesized, proline ana-
logues are the most frequently encountered, due to the unique
properties of this proteinogenic amino acid.2,3
7
3
OH
O
1
N
O
2 H
X2
N
X2
N
O
O
X1
O
1
X1
COOX3
O
HO
Recently, we have reported the synthesis of 2-azabicy-
clo[2.2.1]heptane-1-carboxylic acid (2,4-ethanoproline) 1, a rigid
bicyclic proline analogue.4 Despite the fact that the synthetic se-
quence was short (five steps), it resulted in only 2% total yield of
the amino acid. Moreover, both enantiomers of 1 were formed in
1:1 ratio, therefore, tedious separation of diastereomeric deriva-
tives was needed. Herein we wish to report an alternative and
more practical approach to the synthesis of 2,4-ethanoproline.
O
OH
O
X2
N
N
H
X2
N
O
X1
O
O
X1
Scheme 1. Retrosynthetic analysis of 2,4-ethanoproline 1.
reductive cleavage of this protecting group during the hydrogena-
tion of the double bond, a Boc group was decided to be used in the
first steps of the synthesis, and then replaced by the Cbz protecting
group. X2 and X3 protecting groups should be orthogonal, so
methyl and tert-butyl groups (respectively) were chosen.
2. Results and discussion
The key idea of the novel retrosynthetic scheme for 2,4-etha-
noproline is a C1–C6 disconnection of the target molecule (Scheme
1). To the best of our knowledge, it is the first time this approach
has been applied to the construction of 2-azabicyclo[2.2.1]heptane
system. However, an analogous idea has been widely exploited for
the synthesis of 7-azabicyclo[2.2.1]heptane derivatives.5 Further
retrosynthetic modification led us to 4-hydroxyproline as a start-
ing material, both enantiomers of which are commercially avail-
able. The success of the approach depends critically on the choice
of the protection groups X1–X3 (Scheme 1). It has been shown pre-
viously that Cbz N-protection is optimal for the base-induced cycli-
zation step on formation of similar bicyclic cores.5 To avoid the
The synthesis is outlined in Scheme 2. (2S,4R)-4-hydroxyproline
was transformed into the protected derivative 3 by the procedures
described previously.6 Oxidation of 3 was performed with CrO3-
pyridine leading to the 4-oxoproline derivative 4.7 We have found
that Wittig–Horner olefination of 4 using LHDMS as a base gives a
better yield of 5 (85%, E/Z mixture) than Peterson olefination ap-
plied by Kondo et al. to synthesize an analogous compound.8
Hydrogenation of 5 proceeded in a diastereoselective manner
resulting in the formation of 6 (up to 84% de by NMR). Change of
protecting group in 6 was accompanied by side chain carboxylic
group deprotection necessary for the next steps and led to 7.9
Reduction of 7 via a mixed anhydride allowed alcohol 8 to be ob-
tained. At this point of the synthesis, the relative configuration at
the chiral centres of the molecule was assigned by NOESY mea-
surements (correlation between 2-CH and 4-CH of pyrrolidine moi-
ety was observed). Compound 8 was subjected to a Mitsunobu
* Corresponding authors. Tel.: +38 044 239 33 15; fax: +38 044 235 12 78
(O.O.G.); tel.: +34 976 76 12 10; fax: +34 976 76 12 10 (C.C.).
E-mail addresses: gregor@univ.kiev.ua (O.O. Grygorenko), cativiela@unizar.es (C.
Cativiela).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.05.003

1434
O. O. Grygorenko et al. / Tetrahedron: Asymmetry 20 (2009) 1433–1436
HO
HO
HO
.
HCl
O
CrO3/py
66%
SOCl2/MeOH
100%
Boc2O/TEA
100%
O
O
OH
N
N
H
N
H
O
O
O
Boc
3
2
CO2t-Bu
CO2t-Bu
t-BuO
OMe
OMe
O
P
O
H2/Pd-C
1.TFA
O
O
O
LHMDS
85%
96%
2.Cbz-Cl/K2CO3
100%
N
N
N
O
O
O
O
O
Boc
Boc
5
Boc
4
6
CO2H
Br
OH
KHMDS
CBr4/PPh3
1. i-BuOC(O)Cl/TEA
4
O
O
O
90%
96%
75% e.e.
2. NaBH4
57%
N
2
N
N
O
Cbz
Cbz
Cbz
7
8
9
HCl/H2O
85%
N
N
H2
Cl-
+
O
O
O
Cbz
OH
.
10a (1R,4S)
1a HCl (1R,4S)
Scheme 2. Synthesis of 2,4-ethanoproline 1.
reaction to give the bromide 9. Cyclization of 9 induced by KHMDS
resulted in an excellent yield of the desired 2,4-ethanoproline
derivative 10a, which was transformed into the amino acid 1a
(as the hydrochloride) by acidic hydrolysis.
under UV light (254 nm), iodine vapour or ninhydrin chromatic
reaction whichever was appropriate. Column chromatography
was performed using Merck silica gel (40–60
lm). The solvents
used as HPLC mobile phases were of chromoscan grade. IR spectra
To establish the enantiomeric purity of the product, compound
10a was analyzed by chiral stationary phase HPLC. As the refer-
ence, we used a sample of a single enantiomer of 2,4-ethanoproline
1b (1S,4R) with the known configuration obtained previously.4
Standard methods were used to synthesize N-Cbz-protected
methyl ester 10b from this sample to compare with 10a. It has
been found that 10a obtained by the novel method had moderate
enantiomeric purity (75% ee) Nevertheless, good chromatographic
separation of the enantiomers has been achieved at analytical
scale.
It is interesting to note, that the synthetic approach to 2,4-eth-
anoproline described above is stereoselective, despite the fact, that
both the stereogenic centres of the starting (2S,4R)-hydroxyproline
were racemized at the corresponding steps. The stereoselectivity is
ensured by sequential 1,3-induction of chirality during the synthe-
sis, which is rather efficient in the conformationally restricted pyr-
rolidine core.
were registered on a Mattson Genesis FTIR spectrophotometer;
m
max is given for the main absorption bands. 1H and 13C NMR spec-
tra were recorded on a Varian Unity-300 or a Bruker ARX-300
instrument in CDCl3, using the residual solvent signal as the inter-
nal standard; chemical shifts (d) are given in parts per million and
coupling constants (J) are given in hertz. Optical rotations were
measured at room temperature using a PerkinElmer 241 Polarim-
eter-C in a 10-cm cell of 1-mL capacity. High-resolution mass spec-
tra were obtained on a high-resolution VG-autospectrometer. HPLC
was carried out using a Waters HPLC system equipped with a
Waters 600-E pump and a Waters 991 photodiode array detector.
3.2. (S)-1-tert-Butoxycarbonyl-4-oxoproline methyl ester 47
To a solution of pyridine (20 ml) in dichloromethane (50 ml),
powdered chromium(VI) oxide (11.4 g) was slowly added upon
stirring at 0 °C. The mixture was stirred for 0.5 h, and solution of
3.11 g of 3 in dichloromethane (40 ml) was added. The resulting
mixture was stirred at ambient temperature overnight. The solu-
tion was decanted from the slurry formed, and the residue was
washed thoroughly with dichloromethane. The combined organic
phases were washed with saturated sodium bicarbonate, aqueous
citric acid and brine, dried over magnesium sulfate and evaporated.
The residue was chromatographed (hexane–ethyl acetate (1:1) as
an eluent) to give 1.98 g (66%) of 4 as colourless oil. For spectral
and physical data, see Ref. 7.
The synthesis allows the title compound to be obtained in 22%
yield (10 steps, 75% ee) starting from 4-hydroxyproline. It should
be noted that both enantiomers of 2,4-ethanoproline can be pre-
pared, as both (2S,4R)- and (2R,4S)-4-hydroxyproline are commer-
cially available.
3. Experimental
3.1. General
All reagents were purchased from the Aldrich Chemical Co. and
were used without further purification. Solvents were dried, when
necessary, by standard methods. The progress of the reactions was
monitored by thin layer chromatography (TLC) on Merck 60 F240
precoated silica gel polyester plates, and products were visualized
3.3. (S)-1-tert-Butyl 2-methyl 4-(2-tert-butoxy-2-oxoethylidene)-
pyrrolidine-1,2-dicarboxylate 5
To
a solution of tert-butyl P,P-dimethylphosphonoacetate
(1.48 ml, 7.5 mmol) in absolute THF, 7.5 ml of 1.0 M LHMDS solu-

O. O. Grygorenko et al. / Tetrahedron: Asymmetry 20 (2009) 1433–1436
1435
tion in THF was added under argon atmosphere upon stirring. The
resulting mixture was stirred for 0.5 h, and then it was slowly
added to a solution of 1.65 g of 4 in absolute THF at 0 °C. The mix-
ture was stirred at 0 °C for 15 min, at ambient temperature for
45 min, and was then quenched with saturated aqueous ammo-
nium chloride. THF was removed in vacuo, and the residue was di-
luted with water and extracted with ethyl acetate. The combined
organic extracts were dried over magnesium sulfate and evapo-
rated. The residue was passed through short silica gel column (hex-
ane–ethyl acetate (2:1) as an eluent) to give 1.97 g (5.8 mmol, 85%)
of 5 as yellowish oil. The compound is a mixture of E/Z isomers,
both appearing as mixtures of E/Z rotamers at the amide bond. IR
(cmÀ1): 1750, 1707. HRMS (m/z): calcd for C17H27NNaO6
364.1730, found 364.1716. 1H NMR (CDCl3, d): 5.70–5.78, 5.56–
5.59 (2m, 1H, C@CH), 4.95–5.03, 4.42–4.62 (2m, 2H), 4.22–4.26
(m, 1H), 3.72 (br s, 3H, COOCH3), 3.29–3.33, 2.98–3.16, 2.73–2.78
(3m, 2H), 1.41–1.48 (m, 18H, COOC(CH3)3). 13C NMR (CDCl3, d):
173.1, 172.6, 168.8, 165.4, 165.4 and 165.0 (COOt-Bu), 155.7,
154.8, 154.4 and 153.8 (COOMe), 136.5 and 136.4 (C@CH), 121.6,
121.4, 116.3 and 115.9 (C@CH), 80.7, 80.6, 80.5 and 80.2
(COOC(CH3)3), 66.8, 66.4, 59.3, 58.7, 57.5, 57.1, 52.4 and 52.3
(COOCH3 and 2-CH), 55.3, 55.0, 52.0 and 50.9 (5-CH2), 37.7, 37.0,
36.2 and 35.3 (3-CH2), 28.5, 28.4, 28.2 and 28.1 (COOC(CH3)3).
upon stirring at À20 °C. The resulting mixture was stirred at
À20 °C for 1 h, and a solution of 3.37 g of sodium borohydride in
water (40 ml) was added carefully. The mixture was warmed to
room temperature and stirred for 1 h, and was then quenched with
saturated sodium bicarbonate. THF was removed in vacuo, and the
residue was diluted with water and was extracted with ethyl ace-
tate. The combined organic extracts were dried over magnesium
sulfate and evaporated. The residue was chromatographed (ethyl
acetate as an eluent) to give 2.54 g (57% yield) of 8 as colourless
oil. Spectral data for the major (cis-) diastereomer are given. The
compound is a mixture of E/Z rotamers at the amide bond. IR
(cmÀ1): 3466, 1747, 1705. HRMS (m/z): calcd for C16H21NNaO5
(M+Na) 330.1312, found 330.1300. 1H NMR (CDCl3, d):7.28–7.36
(m, 5H, C6H5), 5.17 (d, J = 12.4 Hz, 1H, CH2Ph), 5.08 (d, J = 12.4 Hz,
0.5H, CH2Ph), 5.00 (d, J = 12.3 Hz, 0.5H, CH2Ph), 4.31 (dd,
J = 8.7 Hz and 8.0 Hz, 0.5H, 2-CH), 4.28 (dd, J = 8.8 Hz and 7.9 Hz,
0.5H, 2-CH), 3.89 (dd, J = 10.4 Hz and 7.4 Hz, 0.5H, 5-CH2), 3.82
(dd, J = 10.2 Hz and 7.6 Hz, 0.5H, 5-CH2), 3.74 (s, 1.5H, COOCH3),
3.64 (m, 2H, CH2CH2OH), 3.53 (s, 1.5H, COOCH3), 3.11 (t,
J = 10.2 Hz, 1H, 5-CH2), 2.48 (m, 1H, 3-CH2), 2.31 (m, 1H, 4-CH),
1.78 (br s, 1H, OH), 1.65 (m, 2H, CH2CH2OH), 1.61 (m, 1H, 3-CH2).
13C NMR (CDCl3, d): 173.4 and 173.3 (NC(O)OCH2Ph), 154.8 and
154.2 (COOCH3), 136.6 and 136.4 (ipso-C6H5), 128.5, 128.4, 128.1,
128.0, 127.9 (o-, m- and p-C6H5), 67.2 (OCH2Ph), 61.1 (CH2OH),
59.3 and 59.0 (COOCH3), 52.5, 52.3, 52.2, 52.1, 37.2, 36.3, 35.8,
35.4, 35.3, 35.1.
3.4. (2S,4R)-1-tert-Butyl 2-methyl 4-(2-tert-butoxy-2-oxoethyl)-
pyrrolidine-1,2-dicarboxylate 6
A mixture of 1.82 g of 5 dissolved in methanol and 0.18 g of 10%
palladium on charcoal was stirred under atmospheric pressure of
hydrogen for 1 h, and was then filtered over Celite and evaporated
to dryness to give 96% yield of 6 as colourless oil. The de of the
product 6 (as well as in the case of 7–9) is 84% by NMR. For spec-
troscopic and physical data, see Ref. 8.
3.7. (2S,4R)-1-Benzyl 2-methyl 4-(2-bromoethyl)pyrrolidine-
1,2-dicarboxylate 9
To a solution of 1.20 g of 8 and 1.80 g of tetrabromomethane in
10 ml of absolute dichloromethane, a solution of 1.42 g of triphen-
ylphosphine in dichloromethane was added dropwise under an ar-
gon atmosphere upon stirring at À10 °C. The resulting mixture was
slowly warmed to room temperature over 4 h, and was then evap-
orated and chromatographed (hexane–ethyl acetate (2:1) as an
eluent) to give 1.31 g (90%) of 9 as colourless oil. Spectral data
for the major (cis-) diastereomer are given. The compound is a mix-
ture of the rotamers at the amide bond. IR (cmÀ1): 1748, 1708.
HRMS (m/z): calcd for C16H20BrNNaO4 (M+Na) 392.0468, found
392.0473. (M+2) isotope peak characteristic for bromine is present.
1H NMR (CDCl3, d): 7.27–7.37 (m, 5H, C6H5), 5.18 (d, J = 12.4 Hz, 1H,
OCH2Ph), 5.09 (d, J = 12.3 Hz, 0.5H, OCH2Ph), 5.01 (d, J = 12.4 Hz,
0.5H, OCH2Ph), 4.34 (t, J = 8.1 Hz, 0.5H, 2-CH), 4.31 (t, J = 8.2 Hz,
0.5H, 2-CH), 3.91 (dd, J = 10.3 Hz and 7.3 Hz, 0.5 H, 5-CH2), 3.83
(dd, J = 10.0 Hz and 7.5 Hz, 0.5H, 5-CH2), 3.75 and 3.54 (2s, 3H,
COOCH3), 3.37 (m, 2H, CH2Br), 3.13 (t, J = 9.9 Hz, 1H, 5-CH2),
2.37–2.54 (m, 2H), 1.96 (m, 2H), 1.62 (m, 1H). 13C NMR (CDCl3,
d): 173.3 and 173.2 (NC(O)OCH2Ph), 154.7 and 154.2 (COOCH3),
136.6 and 136.5 (ipso-C6H5), 128.6, 128.5, 128.2, 128.2, 128.1,
128.0 (o-, m- and p-C6H5), 67.4, 67.3, 59.2 and 59.0 (COOCH3),
52.5, 52.2, 51.9, 51.5, 37.2, 36.5, 35.5, 35.5, 31.3.
3.5. 2-((3R,5S)-1-(Benzyloxycarbonyl)-5-(methoxycarbonyl)-
pyrrolidin-3-yl)acetic acid 79
In a mixture of trifluoroacetic acid (25 ml) and dichloromethane
(30 ml) 6.04 g (17.6 mmol) of 6 was dissolved and stirred for 1.5 h,
and was then evaporated to dryness. The residue was dissolved in
50 ml of water, and 12.3 g of potassium carbonate was carefully
added followed by 2.5 ml of Cbz-chloride at 0 °C upon stirring.
The mixture was stirred for 5 h at ambient temperature, and was
then washed with dichloromethane, acidified with 1 N hydrochlo-
ric acid to pH 1–2 and extracted with ethyl acetate. The combined
organic extracts were dried over magnesium sulfate and were
evaporated to give 5.62 g (100% yield) of 7 as colourless oil. Spec-
tral data for the major (cis-) diastereomer are given. The compound
is a mixture of E/Z rotamers at the amide bond. IR (cmÀ1): 3150,
1738, 1728. HRMS (m/z): calcd for C16H18NO6 (MÀH) 320.1140,
found 320.1128. 1H NMR (CDCl3, d): 7.99 (br s, 1H, COOH), 7.28–
7.37 (m, 5H, C6H5), 5.01–5.20 (m, 2H, OCH2Ph), 4.37 (t, J = 8.0 Hz,
0.5H, 2-CH), 4.32 (t, J = 7.9 Hz, 0.5H, 2-CH), 3.92 (m, 1H, 5-CH2),
3.75 (s, 1.5H, COOCH3), 3.55 (s, 1.5H, COOCH3), 3.19 (m, 1H, 5-
CH2), 2.58 (m, 2H, 3-CH2 and 4-CH), 2.49 (CH2COOH), 1.69 (m,
1H, 3-CH2). 13C NMR (CDCl3, d): 177.2 and 177.1, 173.2 and
173.1, 155.1 and 154.6 (COOCH3), 136.2 and 136.0 (ipso-C6H5),
128.6, 128.6, 128.3, 128.3, 128.2 and 128.1 (o-, m- and p-C6H5),
67.8, 59.1, 58.9, 52.6, 52.4, 52.2, 51.8, 36.9, 36.8, 36.6, 35.6, 34.5,
33.9.
3.8. (1R,4S)-2-Benzyl 1-methyl 2-azabicyclo[2.2.1]heptane-1,2-
dicarboxylate 10a
To a solution 0.95 g of 9 in freshly distilled absolute THF (10 ml),
6.4 ml of 0.5 M KHMDS in toluene was added slowly over 20 min
under an argon atmosphere at À78 °C. The mixture was stirred un-
der the following conditions: at À78 °C for 1 h, À78 °C to À40 °C for
1 h, at À40 °C for 2.5 h, À40 °C to rt for 1 h and at rt for 1 h, and was
then cooled to 0 °C and quenched with saturated ammonium chlo-
ride. THF was removed in vacuo, and the residue was diluted with
water and extracted with ethyl acetate. The combined organic ex-
tracts were dried over magnesium sulfate and evaporated. The res-
idue was chromatographed (hexane–ethyl acetate (2:1) as an
3.6. (2S,4R)-1-Benzyl 2-methyl 4-(2-hydroxyethyl)pyrrolidine-
1,2-dicarboxylate 8
To a solution of 4.76 g of 7 and 4.2 ml of triethylamine in dry
THF (40 ml), 2.3 ml of isobutyl chloroformate was added dropwise

1436
O. O. Grygorenko et al. / Tetrahedron: Asymmetry 20 (2009) 1433–1436
eluent) to give 0.70 g (96% yield) of 10a as a colourless oil. The
hexane–chloroform–2-propanol (85:5:10) as an eluent (flow rate:
1 mL/min) with UV monitoring performed at 248 nm. The capacity
compound is a mixture of the rotamers at the amide bond.
[a
]
D = +5.0 (c 0.034, CHCl3). IR (cmÀ1): 1744, 1704. HRMS (m/z):
(k), selectivity (
a) and resolution (Rs) factors are defined as follows:
calcd for C16H19NNaO4 (M+Na) 312.1206, found 312.1204. 1H
NMR (CDCl3, d): 7.26–7.37 (m, 5H, C6H5), 4.97–5.22 (m, 2H,
OCH2Ph), 3.80 and 3.39 (2s, 3H, COOCH3), 3.53 (br s, 1H, exo-3-
CH2), 3.40 (d, J = 9.1 Hz, 0.5H, endo-3-CH2), 3.30 (d, J = 9.3 Hz,
0.5H, endo-3-CH2), 2.58 (s, 1H, 4-CH), 2.17 (td, J = 12.5 Hz and
5.2 Hz, 1H, endo-5-CH2), 2.03 (m, 1H, 7-CH2), 1.95–2.11 (m, 1H,
6-CH2), 1.86 (tddd, J = 12.3 Hz, 6.9 Hz, 4.5 Hz and 1.4 Hz, 1H, exo-
5-CH2), 1.77 (d, J = 9.5 Hz, 7-CH2), 1.51 (m, 1H, 6-CH2). 13C NMR
(CDCl3, d): 176.2 and 171.6 (NC(O)OCH2Ph), 154.8 (COOCH3),
136.8 and 136.3 (ipso-C6H5), 128.5, 128.3, 128.2, 128.1, 128.0,
127.9 (o-, m- and p-C6H5), 69.6 and 69.4, 67.4 and 67.0, 55.9 and
55.1, 52.4 and 52.0, 44.6 and 43.6, 31.8 and 37.4, 32.3 and 31.4,
28.0 and 27.8.
k = (Rt À Rt0)/Rt0,
a
= k1/k2, and Rs = 1.18(Rt2 À Rt1)/(w2 + w1), where
subscripts 1 and 2 refer to the first and second eluted enantiomers,
w1 and w2 denote their half-height peak widths; Rt1 and Rt2 denote
the retention times, and Rt0 is the dead time. A sample of 10b pre-
pared from 1b as described above was used as a reference.Resolu-
tion parameters: Rt(10a) = 17.5 min, Rt(10b) = 12.6 min, Rs = 5.4,
a
= 1.5. Ee = 75%.
Acknowledgements
This work was carried out with the financial support from the
Ministerio de Educacion y Ciencia—FEDER (Project CTQ2007-
62245), Gobierno de Aragon (group E40) and INTAS (YSF 06-
1000019-5985).
3.9. (1R,4S)-2-Benzyl 1-methyl 2-azabicyclo[2.2.1]heptane-1,2-
dicarboxylate 10b
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water and brine, dried over magnesium sulfate and evaporated in
vacuo. The residue was purified by column chromatography (hex-
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a colourless oil. [
and physical data are the same as those in the case of compound
a
]
D = À7.3 (c 0.012, CHCl3). All the other spectral
10a.
3.10. (1R,4S)-2-Azabicyclo[2.2.1]heptane-1-carboxylic acid 1a
Compound 10a (194 mg) was refluxed in 5 ml of 3 N hydrochlo-
ric acid for 14 h, and then washed with dichloromethane and evap-
orated to dryness to give 101 mg (85%) of 1a hydrochloride as a
white solid. Further purification of the product can be performed
as described elsewhere.4 For spectral and physical data, see Ref. 4.
3.11. HPLC analysis of 10a
9. Pelliciari, R.; Arenare, L.; De Caprariis, P.; Natalini, B.; Marinozzi, M.; Galli, A. J.
Chem. Soc., Perkin Trans. 1 1995, 1251–1257.
HPLC analysis of 10a was carried out by injections of 20 lL of
7 g/ml solution onto 150 Â 4.6 mm ChiralPack ICÒ column using