Asymmetric synthesis of conformationally constrained 4-hydroxyprolines and their applications to the formal synthesis of (+)-epibatidine

Article abstract of DOI:10.1016/S0957-4166(99)00408-5

This report describes the synthesis of enantiomerically pure (1S,3S,4R)- and (1S,3R,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acids, two new conformationally constrained 4-hydroxyprolines, using a straightforward synthetic route and starting f

Full text of DOI:10.1016/S0957-4166(99)00408-5

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3999–4007
Asymmetric synthesis of conformationally constrained
4-hydroxyprolines and their applications to the formal
synthesis of (+)-epibatidine
Alberto Avenoza,a,∗ Carlos Cativiela,b,∗ Miguel A. Fernández-Recio a and Jesús M. Peregrina a
aDepartamento de Química (Química Orgánica), Universidad de La Rioja, 26001 Logroño, Spain
bDepartmento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-C.S.I.C.,
50009 Zaragoza, Spain
Received 27 August 1999; accepted 10 September 1999
Abstract
This report describes the synthesis of enantiomerically pure (1S,3S,4R)- and (1S,3R,4R)-3-hydroxy-7-aza-
bicyclo[2.2.1]heptane-1-carboxylic acids, two new conformationally constrained 4-hydroxyprolines, using a
straightforward synthetic route and starting from (−)-8-phenylmenthyl 2-acetamidoacrylate. The easy transfor-
mation of the pure (1S,3S,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acid into (1R,4S)-N-Boc-7-
azabicyclo[2.2.1]heptan-2-one constitutes a new formal synthesis of (+)-epibatidine. © 1999 Elsevier Science Ltd.
All rights reserved.
1. Introduction
In recent years, several conformationally constrained analogues of bioactive peptides (peptidomime-
tics) have been developed with the aim of designing new pharmacological agents with more selective
properties than the original peptides.1 In order to synthesize this type of peptidomimetics, the systematic
replacement of individual amino acids with the corresponding modified amino acid is well established.2
In this context, and as a part of our research program on the synthesis of new conformationally
constrained α-amino acids,3 we have been interested in the synthesis of hydroxy-α-amino acids4 since
they open the way to the synthesis of new glycosylated hydroxyamino acids.
In particular, 4-hydroxyproline5 has received our attention due to its role as a key starting material
in the synthesis of valuable products, such as chiral phosphine ligands,6 carbapenems7 and ACE
inhibitors.8 Moreover, it is a major constituent of several different proteins (collagen, gelatin...) and other
∗
Corresponding authors.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00408-5

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A. Avenoza et al. / Tetrahedron: Asymmetry 10 (1999) 3999–4007
Figure 1. Constrained 4-hydroxyproline 1
biodegradable synthetic polymers, which are expected to be useful in biomedical applications.9 However,
and in spite of their interest, there are very few examples of restricted 4-hydroxyprolines.10
In this context, we have recently reported the racemic synthesis of the conformationally constrained α-
amino-γ-hydroxy acid rac-1, which is a derivative of 4-hydroxyproline with a 7-azabicyclo[2.2.1]heptane
skeleton11 (Fig. 1).
2. Results and discussion
We now report the synthesis of (1S,3S,4R)-1, using as starting material the iodo-1,3-oxazine 2,
obtained by iodo-oxazination of the Diels–Alder cycloadduct, synthesized by asymmetric reaction of
8-phenylmenthyl 2-acetamidoacrylate with 1,3-butadiene.12 The initial step involves ring opening of the
1,3-oxazine intermediate 2 to give compound 3 in 99% yield, by the action of trifluoroacetic acid in
water. In order to obtain 4 in good yield from 3, several conditions were investigated and the best results
were obtained with sodium carbonate in the presence of ethanol. The hydrolysis of 4 gave the required
hydroxyproline (1S,3S,4R)-1 in good yield (overall yield of 88% in three steps from 2, Scheme 1).
Scheme 1. Synthesis of constrained 4-hydroxyproline 1
Starting from enantiomerically pure (1S,3S,4R)-1 we synthesized another new conformationally cons-
trained 4-hydroxyproline, (1S,3R,4R)-9, with an overall yield of 50%, using five steps: esterification with
acetyl chloride in MeOH, protection of the amine group with (Boc)2O in the presence of diisopropyl-
amine (DIEA), Swern oxidation, subsequent reduction of the carbonyl group with sodium borohydride
and further hydrolysis (Scheme 2).
Scheme 2. Synthesis of constrained 4-hydroxyproline 9
The stereoselective reduction of ketone 7 gave a mixture of alcohols 6 and 8 in a 15:85 ratio,
respectively. The major isomer 8 was obtained in a 79% yield after separation by column chromatography
(Scheme 2).

A. Avenoza et al. / Tetrahedron: Asymmetry 10 (1999) 3999–4007
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The enantiomeric purity of the intermediates in the synthesis of amino acids was examined by
preparation of the Mosher ester of alcohol (1S,3S,4R)-6. According to the protocol described in the
literature,13 (1S,3S,4R)-6 was coupled with (R)-(+)-methoxytrifluorophenylacetic acid [(R)-(+)-MTPA]
in the presence of DCC and DMAP to give Mosher ester 10. Analysis of the NMR spectra of ester 10
showed that the enantiomeric purity of compound (1S,3S,4R)-6 was at least 96% (only one isomer was
1
observed in the H and 19F NMR spectra). In order to be sure that compound (1S,3S,4R)-6 was almost
enantiomerically pure, we determined the cross-contamination by conversion of rac-6 into its Mosher
ester derivatives 10 and 11, coupling rac-6 in the same conditions, with (R)-(+)-MTPA (Scheme 3).
The synthesis of rac-6 was carried out using the same methodology described above for preparation of
(1S,3S,4R)-6 from (1S,3S,4R)-1, but now starting from rac-1.
Scheme 3. Determination of enantiomeric purity of 6
Next, we applied conformationally constrained 4-hydroxyproline (1S,3S,4R)-1 to an asymmetric
synthesis of (+)-epibatidine 12, a nitrogen containing chiral building block with the 7-
azabicyclo[2.2.1]heptane ring system, which constitutes a popular target for synthesis owing to its
structural novelty and relevant pharmacological profile.
Since the discovery of epibatidine14 by Daly et al. in 1992 and due to its potent non-opioid analgesic
effect, this alkaloid has been the focus of intense synthetic interest over the past 7 years, despite its
toxicity.15
Nevertheless, although there have been many reports on its total synthesis,16 there have been only a
few reports on the asymmetric synthesis17 of epibatidine 12. Many different synthetic strategies have
been developed for the preparation of this novel alkaloid and, in a number of syntheses, N-Boc-7-
azabicyclo[2.2.1]heptan-2-one 13 has been used as an advanced key intermediate in the synthesis of
epibatidine17a–c,e,i,j,18 (Scheme 4).
Scheme 4. Retrosynthesis of (+)-epibatidine 12 from chiral ketone 13
In this context, we planned to use the building block (1S,3S,4R)-1 as the key chiral precursor for the
preparation of ketone (1R,4S)-13, because it possesses the correct stereochemistry required to obtain
(1R,2R,4S)-12.
We first studied the cleavage of the methoxycarbonyl group of (1S,4R)-7, easily available from
(1S,3S,4R)-1. Treatment of (1S,4R)-7 with lithium hydroxide in aqueous MeOH gave (1S,4R)-14. The
synthesis of (1R,4S)-13 required the decarboxylation of (1S,4R)-14, so sequential formation of the acid
chloride of (1S,4R)-14 was achieved by the action of oxalyl chloride, followed by coupling with N-
hydroxy-2-thiopyridone (NHTP) to give the corresponding O-acyl thiohydroxamide. This compound
was then photolyzed with tributyltin hydride, using a 200 W tungsten lamp, to give (1R,4S)-13 in a 13%
yield from (1S,3S,4R)-1 in five steps (Scheme 5).

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A. Avenoza et al. / Tetrahedron: Asymmetry 10 (1999) 3999–4007
Scheme 5. Syntheses of chiral ketone 13. Reagents: (a) LiOH, MeOH, H2O; (b) i: (COCl)2; ii: Et3N, NHTP; iii: Bu3SnH, hν;
(c) i: HCl; ii: CbzCl, Na2CO3; (d) Campbell and Rapoport,17c two steps
In order to improve this yield, we attempted to change the Boc group for the Cbz group and using the
same strategy as that described above, (1R,4S)-13 was obtained from (1S,3S,4R)-1 in an overall yield of
37% using six steps.
Better results were obtained by direct conversion of (1S,4R)-7 into (1R,4S)-13 via (1S,4R)-15. For
this purpose, (1S,4R)-7 was treated with HCl to obtain the corresponding amino acid hydrochloride,
which was then protected with CbzCl in the presence of sodium carbonate to give (1S,4R)-15. The
transformation of this compound into the required ketone (1R,4S)-13 was obtained according to the
protocol described in the literature by Campbell and Rapoport,17c and includes two steps with an overall
yield of 80%: reductive radical decarboxylation and hydrogenolysis in MeOH containing (Boc)2O. In
this way, we obtained a 49% yield of (1R,4S)-13 from (1S,3S,4R)-1 in six steps (Scheme 5).
In conclusion, we have developed the asymmetric synthesis of two conformationally constrained
4-hydroxyprolines (1S,3S,4R)-1 and (1S,3R,4R)-9 from iodo-1,3-oxazine 2. Moreover, chiral building
block (1S,3S,4R)-1 has been exploited as the precursor of chiral ketone (1R,4S)-13. This transfor-
mation constitutes a formal asymmetric synthesis of (+)-epibatidine. In addition and more impor-
tantly, taking into account that the activity of epibatidine is accompanied by high toxicity,15 N-Boc-
7-azabicyclo[2.2.1]heptan-2-one 13 has been brought further into consideration as a potential building
block for the preparation of epibatidine analogues.
3. Experimental
Solvents were purified according to standard procedures. Analytical TLC was performed using
Polychrom SI F254 plates. Column chromatography was performed using Silica gel 60 (230–400 mesh).
1
1H and 13C NMR spectra were recorded on a Bruker ARX-300 spectrometer. H and 13C NMR spectra
were recorded in CDCl3 with TMS as the internal standard and in CD3OD with TMS as the external
standard using a coaxial microtube (chemical shifts are reported in ppm on the δ scale, coupling constants
1
in hertz). The assignment of all separate signals in the H NMR spectra was made on the basis of
coupling constants, selective proton–proton homonuclear decoupling experiments, proton–proton COSY
experiments and proton–carbon HETCOR experiments. Melting points were determined on a Büchi
SMP-20 melting point apparatus and are uncorrected. Optical rotations were measured on a Perkin–Elmer
341 polarimeter in 1 and 0.5 dm cells of 1 and 3.4 mL capacity, respectively. Microanalyses were carried
out on a CE Instruments EA-1110 analyzer and are in good agreement with the calculated values. IR
spectra were recorded on a Perkin–Elmer FT-IR Spectrum 1000 spectrometer.

A. Avenoza et al. / Tetrahedron: Asymmetry 10 (1999) 3999–4007
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3.1. (10R,20S,50R)-80-Phenylmenthyl (1S,3S,4S)-3-acetoxy-1-amino-4-iodo-1-cyclohexanecarboxylate
trifluoroacetate 3
Iodo-1,3-oxazine 2 (300 mg, 0.57 mmol) was dissolved in THF:H2O (9:1) (20 mL) and trifluoroacetic
acid (72 mg, 0.63 mmol) was then added. After stirring for 5 h at rt, the reaction was quenched by
removal of the water with the addition of anhydrous Na2SO4. The remaining filtrate was evaporated
without warming the bath and the oily residue was then dissolved in Et2O and the solvent and the residual
trifluoroacetic acid distilled off in vacuo. This operation was repeated to ensure complete removal of the
trifluoroacetic acid to give compound 3 (372 mg, 99%) as a white solid. Mp 75–76°C; [α]25=+28.3
D
1
(c 1.39, CHCl3); H NMR (CD3OD): δ 0.85–1.03 (m, 4H), 1.09–1.56 (m, 12H), 1.61–1.82 (m, 4H),
0
1.90–2.21 (m, 7H), 2.22–2.32 (m, 1H, H2 a), 2.43–2.52 (m, 1H, H2e), 4.21–4.27 (m, 1H, H4e), 5.09–5.19
(m, 2H, H3e+H1 a), 7.11–7.19 (m, 1H, p-arom), 7.26–7.41 (m, 4H, m,o-arom); 13C NMR (CD3OD): δ
0
20.7 (Me), 22.0 (MeCH), 25.8 (C4), 26.4, 27.9, 28.3, 29.8, 30.6, 32.7, 35.1 (C2), 35.2, 40.8 (CMe2Ph),
0
0
42.9, 50.8 (C2 ), 59.6 (C1), 73.2 (C1 ), 80.0 (C3), 126.5, 129.6 (o,m,p-arom), 152.6 (ipso-arom), 170.8,
170.9 (COO); IR (CHCl3): 3619, 3232 (NH2), 1739 (C_O); ESI+ (m/z): 542 [m−113]+. Anal. calcd for
C27H37F3INO6: C, 49.47; H, 5.69; N, 2.14. Found: C, 49.41; H, 5.75; N, 2.00.
3.2. (10R,20S,50R)-80-Phenylmenthyl (1S,3S,4R)-3-acetoxy-7-azabicyclo[2.2.1]heptane-1-carboxylate
4
Trifluoroacetate 3 (400 mg, 0.61 mmol) was dissolved in EtOH (25 mL) and Na2CO3 (1.93 g, 18.3
mmol) was then added at rt. The suspension was stirred at 30°C for 24 h and the solvent evaporated.
The residual solid was suspended in CH2Cl2, filtered off and the filtrate was evaporated to give an oil,
which was purified by column chromatography (hexane:ethyl acetate, 6:4) to give 4 (240 mg, 95%) as a
colourless oil. [α]25=+1.0 (c 2.32, CHCl3); 1H NMR (CDCl3): δ 0.79–0.92 (m, 4H), 0.97–1.14 (m, 2H),
D
0
0
1.15–1.77 (m, 14H), 1.82–1.95 (m, 2H, NH+H6 e), 2.04–2.18 (m, 5H, MeCO+H2 a+H2x), 3.48 (d, 1H,
0 0
J
J
4–5x=5.1 Hz, H4), 4.73 (dd, 1H, J3n–2n=6.9 Hz, J3n–2x=2.4 Hz, H3n), 4.89–5.01 (td, 1H, J1 –2 =10.4 Hz,
1 –6 e,6 a=4.1 Hz, H1 ), 7.08–7.17 (m, 1H, p-arom), 7.23–7.33 (m, 4H, m,o-arom); 13C NMR (CDCl3): δ
0
0
0
0
0
0
0
0
21.1 (MeCO), 21.6 (MeCH), 24.6, 25.8, 26.6, 27.4, 31.1, 32.1, 34.3 (C5, C6, C3 , C4 , C5 , MeC, Me C),
0
0
0
39.7 (CMe2Ph), 41.4 (C6 ), 42.5 (C2), 49.5 (C2 ), 60.8 (C3), 67.5 (C1), 75.1 (C1 ), 77.5 (C4), 125.0 (p-
arom), 125.4, 128.1 (m,o-arom), 151.6 (ipso-arom), 170.5, 171.8 (COO); IR (CHCl3): 3295 (NH), 1724
(C_O). APCI+ (m/z): 414.3. Anal. calcd for C25H35NO4: C, 72.61; H, 8.53; N, 3.39. Found: C, 72.48;
H, 8.57; N, 3.45.
3.3. (1S,3S,4R)-3-Hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acid hydrochloride 1
Amino ester 4 (240 mg, 0.58 mmol) was suspended in 6N HCl (15 mL). The mixture was stirred
at reflux for 14 h, the solvent evaporated and the excess of HCl removed in vacuo. The residual white
solid was dissoved in water (15 mL) and washed with CH2Cl2 (2×15 mL). The aqueous phase was
25
1
evaporated in vacuo to give 1 (106 mg, 94%) as a white solid. [α] =−12.8 (c 1.9, MeOH); H NMR
D
(CD3OD): δ 1.71–2.12 (m, 5H, H2x+H5x+H5n+H6x+H6n), 2.50 (dd, 1H, J2n–2x=13.8 Hz, J2n–3n=6.9 Hz,
H2n), 3.96–4.01 (m, 1H, H4), 4.20 (dd, 1H, J3n–2n=6.9 Hz, J3n–2x=2.1 Hz, H3n); 13C NMR (CD3OD): δ
22.9, 31.0 (C5+C6), 42.8 (C2), 66.5 (C4), 71.9 (C1), 72.1 (C3), 170.7 (COOH); IR (CHCl3): 1738 (C_O);
ESI+ (m/z): 158.4. Anal. calcd for C7H12ClNO3: C, 43.42; H, 6.25; N, 7.23. Found: C, 43.31; H, 6.33;
N, 7.15.

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A. Avenoza et al. / Tetrahedron: Asymmetry 10 (1999) 3999–4007
3.4. Methyl (1S,3S,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylate hydrochloride 5
Acetyl chloride (243.3 mg, 3.1 mmol) was added dropwise to methanol (10 mL) at 0°C. After stirring
for 10 min, the amino acid hydrochloride 1 (200 mg, 1.03 mmol) was added. The resulting solution
was stirred at 60°C for 12 h. The solvent was removed, the residual oil suspended in Et2O (20 mL)
and the solvent evaporated again. After repeating twice more, 5 (213 mg, 100%) was obtained pure as
a white solid. [α]25=−12.0 (c 1.91, MeOH); 1H NMR (CD3OD): δ 1.74–1.86 (m, 1H, H6n), 1.91–2.19
D
(m, 4H, H2x+H5x+H5n+H6x), 2.54 (dd, 1H, J2n–2x=13.5 Hz, J2n–3n=5.7 Hz, H2n), 3.86 (s, 3H, COOMe),
4.01–4.07 (m, 1H, H4), 4.20–4.27 (m, 1H, H3n); 13C NMR (CD3OD): δ 22.8 (C6), 31.0 (C5), 42.8 (C2),
53.8 (COOMe), 66.7 (C4), 71.6 (C1), 71.9 (C3), 169.5 (COOMe); IR (CHCl3): 1755 (C_O); ESI+ (m/z):
172.3 [m−Cl]+. Anal. calcd for C8H14ClNO3: C, 46.27; H, 6.80; N, 6.75. Found: C, 45.94; H, 6.71; N,
6.83.
3.5. Methyl (1S,3S,4R)-N-(tert-butoxycarbonyl)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylate 6
Hydrochloride 5 (330 mg, 1.6 mmol) was dissolved in dry acetonitrile (25 mL) under an argon
atmosphere. (Boc)2O (454 mg, 2.08 mmol) and DIEA (516 mg, 4 mmol) were added to the mixture.
After stirring at 50°C for 24 h, the solvent was removed and the residual solid dissolved in CH2Cl2.
The resulting suspension was washed with a saturated NaCl solution (30 mL) and a saturated NaHCO3
solution (2×30 mL), dried and the solvent evaporated to give an oil, which was purified by column
chromatography (hexane:ethyl acetate, 4:6) to give 6 (367 mg, 85%) as a colourless oil. [α]25=−33.1 (c
D
1.84, CHCl3); 1H NMR (CDCl3): δ 1.40–1.44 (m, 10H, CMe3+H5n), 1.49–1.54 (m, 1H, H6n), 1.78–1.92
(m, 1H, H5x), 1.94–2.02 (m, 2H, H2x+H6x), 2.13 (dd, 1H, J2n–2x=12.9 Hz, J2n–3n=6.9 Hz, H2n), 2.32–2.46
(br s, 1H, OH), 3.78 (s, 3H, COOMe), 3.89–3.96 (dd, 1H, J3n–2n=6.9 Hz, J3n–2x=2.1 Hz, H3n), 4.20 (d, 1H,
J
4–5x=6.6 Hz, H4); 13C NMR (CDCl3): δ 23.9 (C5), 27.9 (CMe3), 30.9 (C6), 46.4 (C2), 52.1 (COOMe),
66.1 (C4), 67.9 (C1), 73.3 (C3), 81.1 (CMe3), 156.8 (NCOO), 170.8 (COOMe); IR (CHCl3): 3599 (OH),
1742 (OC_O), 1702 (NC_O); ESI+ (m/z): 294.3 [m+Na]+. Anal. calcd for C13H21NO5: C, 57.55; H,
7.80; N, 5.16. Found: C, 57.48; H, 7.78; N, 5.22.
3.6. Methyl (1S,4R)-N-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-3-one-1-carboxylate 7
To a solution of oxalyl chloride (145.6 mg, 1.14 mmol) in CH2Cl2 (20 mL) at −78°C was added
dropwise DMSO (149 mg, 1.91 mmol). After 10 min stirring at −78°C, alcohol 6 (260 mg, 0.95 mmol)
in CH2Cl2 (5 mL) was added to the solution. The reaction mixture was stirred, at −78°C, for 20 min
and then Et3N (388 mg, 3.83 mmol) was added. The solution was allowed to warm to rt. After 1 h
stirring, the reaction was quenched by addition of water (20 mL). The aqueous phase was extracted with
CH2Cl2 (2×15 mL) and the combined organic layers were dried. The solvent was evaporated to give
an oil, which was purified by column chromatography (hexane:ethyl acetate, 6:4) to give 7 (234 mg,
91%) as a colourless oil. [α]25=−58.8 (c 1.48, CHCl3); 1H NMR (CDCl3): δ 1.40 (s, 9H, CMe3), 1.66
D
(ddd, 1H, J5n–5x=13.2 Hz, J5n–6n=9.0 Hz, J5n–6x=4.3 Hz, H5n), 1.87 (ddd, 1H, J6n–6x=12.3 Hz, J6n–5n=9.0
Hz, J6n–5x=4.5 Hz, H6n), 2.10–2.23 (m, 1H, H5x), 2.30 (d, 1H, J2n–2x=17.7 Hz, H2n), 2.31–2.42 (m, 1H,
H6x), 2.85 (dd, 1H, J2x–2n=17.7 Hz, J2x–6x=2.7 Hz, H2x), 3.83 (s, 3H, COOMe), 4.34 (d, 1H, J4–5x=5.7
Hz, H4); 13C NMR (CDCl3): δ 23.7 (C5), 27.9 (CMe3), 31.8 (C6), 47.1 (C2), 52.6 (COOMe), 67.0 (C4),
68.4 (C1), 82.2 (CMe3), 155.5 (NCOO), 169.3 (COOMe), 207.2 (C3); IR (CHCl3): 1766, 1747, 1710
(NC_O, OC_O, C_O); ESI+ (m/z): 270.3. Anal. calcd for C13H19NO5: C, 57.98; H, 7.11; N, 5.20.
Found: C, 57.29; H, 7.18; N, 5.23.

A. Avenoza et al. / Tetrahedron: Asymmetry 10 (1999) 3999–4007
4005
3.7. Methyl (1S,3R,4R)-N-(tert-butoxycarbonyl)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylate
8
To a solution of ketone 7 (240 mg, 0.89 mmol) in dry MeOH (25 mL) at −78°C was added NaBH4
(168 mg, 4.45 mmol). After stirring at −78°C for 1 h, the reaction was quenched with the addition of
water (10 mL) and then the solvent was evaporated. The residual solid was dissolved in CH2Cl2 (40 mL),
washed with a saturated NaCl solution (20 mL) and a saturated NaHCO3 solution (2×20 mL), dried and
the solvent was evaporated to give an oil, which was purified by column chromatography (hexane:ethyl
acetate, 6:4) to give 6 (34 mg, 14%) and 8 (191 mg, 79%) as colourless oils. [α]25=−9.2 (c 1.27, CHCl3);
D
1H NMR (CDCl3): δ 1.36–1.44 (m, 10H, CMe3+H2n), 1.69–1.86 (m, 2H, H5x+H6n), 2.10–2.27 (m, 2H,
H5n+H6x), 2.28–2.50 (br s, 1H, OH), 2.50–2.62 (m, 1H, H2x), 3.76 (s, 3H, COOMe), 4.21 (‘t’, 1H,
J
4–5x=J4–3x=4.6 Hz, H4), 4.38–4.46 (m, 1H, H3x); 13C NMR (CDCl3): δ 20.7 (C5), 27.9 (CMe3), 32.8
(C6), 42.7 (C2), 52.1 (COOMe), 63.0 (C4), 69.3 (C3), 69.4 (C1), 81.1 (CMe3), 156.2 (NCOO), 171.1
(COOMe); IR (CHCl3): 3606 (OH), 1741 (OC_O), 1701 (NC_O); ESI+ (m/z): 310.3 [m+K]+. Anal.
calcd for C13H21NO5: C, 57.55; H, 7.80; N, 5.16. Found: C, 57.42; H, 7.83; N, 5.19.
3.8. (1S,3R,4R)-3-Hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acid hydrochloride 9
Alcohol 8 (192 mg, 0.70 mmol) was suspended in 6N HCl (12 mL). The mixture was stirred at reflux
for 16 h, the solvent evaporated and the excess of HCl removed in vacuo. The residual white solid was
dissolved in water (12 mL) and washed with CH2Cl2 (2×10 mL). The aqueous phase was evaporated
in vacuo to give 9 (112 mg, 82%) as a white solid. [α]25=+2.5 (c 1.23, MeOH); 1H NMR (CD3OD): δ
D
1.74 (dd, 1H, J2n–2x=13.6 Hz, J2n–3x=3.4 Hz, H2n), 1.91–2.04 (m, 1H, H5x), 2.12–2.21 (m, 2H, H6x+H6n),
2.43–2.62 (m, 2H, H5n+H2x), 4.10 (‘t’, 1H, J4–3x=J4–5x=4.6 Hz, H4), 4.48–4.57 (m, 1H, H3x); 13C NMR
(CD3OD): δ 20.3 (C5), 31.7 (C6), 40.5 (C2), 62.5 (C4), 68.4 (C3), 73.4 (C1), 170.9 (COOH); IR (CHCl3):
1737 (C_O); ESI+ (m/z): 158.4. Anal. calcd for C7H12ClNO3: C, 43.42; H, 6.25; N, 7.23. Found: C,
43.48; H, 6.21; N, 7.28.
3.9. (1S,3S,4R,20R)- and (1R,3R,4S,20R)-Methyl N-(tert-butoxycarbonyl)-3-(20 -methoxy-20-(trifluoro-
methyl)phenylacetyloxy)-7-azabicyclo[2.2.1]heptane-1-carboxylates 10 and 11
To a solution of alcohol rac-6 (160 mg, 0.59 mmol), DCC (129 mg, 0.62 mmol) and DMAP (8 mg,
0.065 mmol) in dry CH2Cl2 (6 mL) was added a solution of (R)-(+)-MTPA (157 mg, 0.67 mg) in dry
CH2Cl2 (4 mL). After stirring the mixture at rt for 6 h, the resulting white suspension was filtered to
remove the N,N0-dicyclohexylurea. The filtrate was concentrated in vacuo to give a white slurry, to which
Et2O was added. The resulting suspension was filtered to remove the N-acyl-N0-cyclohexylurea and the
solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate, 7:3)
1
to give 10+11 (187 mg, 65%) as an oil in a 1:1 ratio; H NMR (CDCl3): δ 1.31 (s, 9H, CMe3), 1.34
0
0
(s, 9H, CMe3 ), 1.43–1.71 (m, 4H), 1.89–2.36 (m, 8H), 3.53 (s, 3H, OMe), 3.57 (s, 3H, OMe ), 3.78 (s,
0
0
3H, COOMe), 3.79 (s, 3H, COOMe ), 4.37–4.43 (m, 1H, H4), 4.47–4.53 (m, 1H, H4 ), 4.98–5.04 (m,
2H, H3+H3 ), 7.35–7.60 (m, 10H, arom); C NMR (CDCl3): δ 24.5 (C5+C5 ), 27.9 (CMe3+CMe3 ),
31.7 (C6+C6 ), 42.1 (C2), 42.6 (C2 ), 52.3, 52.4 (COOMe), 55.4, 55.5 (OMe), 62.7 (C4), 63.0 (C4 ), 67.5
13
0
0
0
0
0
0
0
0
(C1+C1 ), 77.5 (C3), 77.8 (C3 ), 81.1, 81.2 (CMe3), 121.2 (C(CF3)), 125.0 (CF3), 127.3, 127.4, 128.4,
129.6, 131.8 (arom), 155.1 (NCOO), 166.5, 166.6 (RCOO), 170.0 (COOMe); IR (CHCl3): 3599 (OH),
1742 (OC_O), 1702 (NC_O); ESI+ (m/z): 388.3 [m−101]+. Anal. calcd for C23H28F3NO7: C, 56.67; H,
5.79; N, 2.87. Found: C, 56.52; H, 5.72; N, 2.91.

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A. Avenoza et al. / Tetrahedron: Asymmetry 10 (1999) 3999–4007
3.10. (1S,4R)-N-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-3-one-1-carboxylic acid 14
LiOH·H2O (318 mg, 7.6 mmol) was added to a solution of ketone 7 (204 mg, 0.76 mmol) in a mixture
MeOH:H2O, 3:2 (30 mL). The reaction mixture was stirred under reflux (70°C) for 12 h and the solvent
was evaporated. The residual white solid was dissolved in water and washed with CH2Cl2 (2×20 mL).
The aqueous phase was acidified and extracted with CH2Cl2 (2×20 mL). The organic phase was dried
and the solvent evaporated to give 14 (161 mg, 83%) as a white solid. Mp 147–148°C. [α]25=−33.5 (c
D
1.46, CHCl3); 1H NMR (CDCl3): δ 1.42 (s, 9H, CMe3), 1.71 (ddd, 1H, J5n–5x=12.9 Hz, J5n–6n=9.0 Hz,
J
5n–6x=4.2 Hz, H5n), 1.92–2.05 (m, 1H, H6n), 2.11–2.24 (m, 1H, H5x), 2.35–2.46 (m, 2H, H2n+H6x), 2.87
(dd, 1H, J2x–2n=18.0 Hz, J2x–6x=2.4 Hz, H2x), 4.37 (d, 1H, J4–5x=8.7 Hz, H4), 10.33 (br s, 1H, COOH);
13C NMR (CDCl3): δ 23.7 (C5), 27.8 (CMe3), 31.7 (C6), 47.0 (C2), 67.0 (C4), 68.4 (C1), 82.7 (CMe3),
155.6 (NCOO), 173.8 (COOH) 207.1 (C3); IR (CHCl3): 1764, 1712 (C_O); ESI− (m/z): 154.1. Anal.
calcd for C12H17NO5: C, 56.46; H, 6.71; N, 5.49. Found: C, 56.60; H, 6.80; N, 5.42.
3.11. (1R,4S)-N-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one 13
A mixture of Et3N (257 mg, 2.54 mmol), N-methyl-2-chloropyridinium iodide (324 mg, 1.26 mmol)
and N-hydroxy-2-thiopyridone (203 mg, 1.59 mmol) was added to a solution of acid 7 (270 mg, 1.06
mmol) in dry CH2Cl2 (20 mL). After stirring under reflux for 12 h, the solvent was evaporated to give an
oil, which was purified by a filtration with silica gel (hexane:ethyl acetate, 1:1) to give a protected acid
derivative, which was dissolved in dry CH2Cl2 (10 mL) under an argon atmosphere. Bu3SnH (617 mg,
2.12 mmol) was then added and the mixture was irradiated for 2 h using a tungsten lamp (200 W), with
external cooling to keep the reaction mixture at rt. The solvent was evaporated to give an oil, which was
purified by column chromatography (hexane:ethyl acetate, 9:1) to give 13 (45 mg, 20%) as a colourless
oil. [α]25=−75.5 (c 1.00, CHCl3). Anal. calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C,
D
62.68; H, 8.08; N, 6.52. Spectral data were identical to those reported in the literature.17b
3.12. (1S,4R)-N-(Benzyloxycarbonyl)-7-azabicyclo[2.2.1]heptan-3-one-1-carboxylic acid 15
Ketone 7 (200 mg, 0.74 mmol) was suspended in 6N HCl (15 mL). The mixture was stirred under
reflux for 14 h, the solvent evaporated and the excess of HCl removed in vacuo. The residual white
solid, without purification, was dissolved in water (12 mL) at 0°C. Na2CO3 (258 mg, 2.44 mmol) and
benzyloxycarbonyl chloride (164 mg, 0.96 mmol) was added at 0°C. After stirring at 35°C for 36 h, ice
water (10 mL) was added and the mixture washed with CH2Cl2 (2×20 mL). The aqueous phase was
acidified to pH 3 using 2N HCl and extracted with CH2Cl2 (2×20 mL). The organic phases were dried
and the solvent evaporated to give 15 (220 mg, 80%) as a colourless oil. [α]25=−43.3 (c 1.30, CHCl3).
D
Anal. calcd for C15H15NO5: C, 62.28; H, 5.23; N, 4.84. Found: C, 62.35; H, 5.20; N, 4.79. Spectral data
were identical to those reported in the literature.17c
Acknowledgements
This work was supported by the Dirección General de Enseñanza Superior (project PB97-0998-C02-
02) and the Universidad de La Rioja (project API-99/B02). M.A. Fernández-Recio thanks the Ministerio
de Educación y Ciencia for a doctoral fellowship.

A. Avenoza et al. / Tetrahedron: Asymmetry 10 (1999) 3999–4007
4007
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