Synthesis of enantiopure analogues of 3-hydroxyproline and derivatives

Article abstract of DOI:10.1016/S0957-4166(02)00158-1

All four enantiomerically pure 2-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acids, novel restricted analogues of 3-hydroxyproline, are described. The synthesis starts with the Diels-Alder reaction between methyl 2-benzamidoacrylate and Danishefsky's

Full text of DOI:10.1016/S0957-4166(02)00158-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 625–632
Synthesis of enantiopure analogues of 3-hydroxyproline and
derivatives
Alberto Avenoza,a,* Jose´ I. Barriobero,a Jesu´s H. Busto,a Carlos Cativielab and Jesu´s M. Peregrinaa,*
aDepartamento de Qu´ımica, Universidad de La Rioja, Grupo de S´ıntesis Qu´ımica de La Rioja, U.A.-C.S.I.C.,
26006 Logron˜o, Spain
bDepartamento de Qu´ımica Orga´nica, Instituto de Ciencia de Materiales de Arago´n, Universidad de Zaragoza-C.S.I.C.,
50009 Zaragoza, Spain
Received 16 March 2002; accepted 25 March 2002
Abstract—All four enantiomerically pure 2-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acids, novel restricted analogues of
3-hydroxyproline, are described. The synthesis starts with the Diels–Alder reaction between methyl 2-benzamidoacrylate and
Danishefsky’s diene and uses as key steps a base-promoted internal nucleophilic displacement of the methanesulfonate group in
the cyclohexane ring, followed by a resolution method that involves formation of diastereomers and further separation by
crystallization. This synthetic route allowed us to obtain both enantiomers of the N-Boc-7-azabicyclo[2.2.1]heptan-2-ones,
valuable ketones used as precursors of (−)- and (+)-epibatidine and other more interesting analogues. © 2002 Published by
Elsevier Science Ltd.
1. Introduction
On the other hand, 7-azabicyclo[2.2.1]heptane-1-car-
boxylic acid derivatives as proline analogues constitute
a source of interesting compounds that include a novel
class of HIV-1 protease inhibitor17 and the
boroarginine thrombin inhibitor.18 Hence, the incorpo-
ration of a hydroxyl group in a predetermined position
of these systems opens the way to new families of
products of potential interest. In the main, three
research groups (those of Rapoport, Avenoza and
Cativiela) have developed the design of restricted amino
acid analogues of proline that contain the 7-azabicyc-
lo[2.2.1]heptane skeleton. For example, Rapoport and
co-workers have synthesized N-protected 2- and 3-oxo-
7-azabicyclo [2.2.1]heptane carboxylic esters 119 and 220
(interesting building blocks to obtain strained amino
acids and precursors of epibatidine) and amino acid 3,20
In recent years the synthesis and incorporation into
peptides of conformationally constrained amino acids
has become extremely important, since it represents a
great advance in the creation of peptides with valuable
physical properties and biological activity.1–4 Proline
has an enormous impact on the conformation of pep-
tides owing to its ability to form trans as well as cis
amide bonds, thus allowing the formation of turn struc-
tures. As a consequence, analogues of natural proline
have attracted significant attention. For instance, the
synthesis of hydroxyprolines5–12 has been a matter of
interest in order to incorporate such units into peptides,
since this leads to enhanced stability of the collagen
triple helix by hydrogen bonds between the hydroxyl
group and the peptide backbone. The stability of the
collagen helix depends strongly on the percentage of
prolines and hydroxyprolines present. Moreover, 4-
hydroxyproline is a common component in collagenous
protein, although its isomer 3-hydroxyproline is a rare
b-hydroxy-a-amino acid that has been found as a minor
constituent in some proteins and both isomers, i.e. cis
and trans are elements of the antibiotic teleomycin.13–16
starting from L-serine and L-glutamic acids and involv-
ing CꢀC bond formation onto the pyrrolidine ring as a
key step. On the other hand, our groups have explored
a synthetic route based on internal nucleophilic dis-
placement, by an amide group, of a leaving group in a
six-membered ring. The ring was created by a Diels–
Alder reaction between a,b-didehydro-a-amino acid
derivatives and Danishefsky’s diene. In this way, com-
pounds 2 and related derivatives21,22 (starting materials
in the synthesis of cis- and trans-4-hydroxyproline ana-
logues) have been synthesized in racemic and enantio-
pure forms. Moreover, compounds 3,23 4,24 525 and 626
* Corresponding authors. Tel.: +34-941-299655; fax: +941-299655;
e-mail: alberto.avenoza@dq.unirioja.es
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00158-1

626
A. A6enoza et al. / Tetrahedron: Asymmetry 13 (2002) 625–632
have been obtained in good yields. Our present goal is
to obtain the building block 1 as a starting material in
the synthesis of new ‘chimeras,’ combinations of con-
strained proline and serine, or strained 3-hydroxyproli-
nes (Fig. 1).
2.2. Synthesis of methyl N-Boc-2-hydroxy-7-azabicyclo-
[2.2.1]heptane-1-carboxylates (1S,2S,4R)-11 and
(1R,2R,4S)-11
Esterification of ( )-10 with acetyl chloride in MeOH
and subsequent protection of the amine group with
(Boc)2O in the presence of Na2CO3·10H2O gave the
protected alcohol ( )-11, which could be separated by
resolution methods. The strategy used to resolve the
racemic protected amino acid involved the reaction of
( )-11 with (R)-(+)-methoxytrifluorophenylacetic acid
[(R)-(+)-MTPA] in the presence of DCC and DMAP to
give (1S,2S,4R,2%R)-12 and (1R,2R,4S,2%R)-13 as a
diastereoisomeric mixture in 95% yield. These
diastereoisomers were easily separated by crystalliza-
tion, using octane as the solvent, to give crystals of the
pure isomer (1S,2S,4R,2%R)-12. The purity of this mate-
rial was determined by 19F NMR (>95%). The filtrate
was chromatographed to give the diastereoisomer
(1R,2R,4S,2%R)-13 and the purity of this compound was
also determined by 19F NMR (>95%). Hydrolysis of the
chiral ester was achieved in MeONa/MeOH and gave
enantiomerically pure isomers (1S,2S,4R)-11 and
(1R,2R,4S)-11 (Scheme 2).
Figure 1. 7-Azabicyclo[2.2.1]heptane-1-carboxylic acid deriva-
tives.
2. Results and discussion
2.1. Synthesis of 2-hydroxy-7-azabicyclo[2.2.1]heptane-
1-carboxylic acid hydrochloride ( )-10
The starting material for our study was the trans-
methoxycyclohexanone ( )-7, which was obtained by
Diels–Alder reaction between methyl 2-benzamidoacryl-
ate and Danishefsky’s diene.27 We have improved the
yield of this reaction to 70% by using hydroquinone as
a polymerization inhibitor and a 1:1 diene/dienophile
ratio. Reduction of ketone ( )-7 with L-Selectride® at
−78°C in THF quantitatively gave the trans alcohol.
Treatment of this alcohol with methanesulfonyl chlo-
ride in triethylamine (TEA) provided the corresponding
methanosulfonate derivative ( )-8, which was used in
the next reaction without further purification. Base-pro-
moted internal nucleophilic displacement of the
t
methanesulfonate group using BuOK in THF, thereby
yielding the 7-azabicyclo[2.2.1]heptane system of the
constrained proline analogue, gave the desired com-
pound ( )-9 in high yield. The racemic hydrochloride
amino acid ( )-10 was obtained in a 95% yield by
hydrolysis of compound ( )-9 (Scheme 1).
Scheme 2. (a) (i) AcCl, MeOH, 60°C, (ii) (Boc)2O,
Na2CO3·10H2O, THF/H2O, rt 80%; (b) (R)-(+)-MTPA,
DCC, DMAP, CH2Cl2, rt 95%; (c) separation by crystalliza-
tion from octane; (d) MeONa, MeOH, rt, 87%.
2.3. Synthesis and determination of the absolute
configurations of N-Boc-7-azabicyclo[2.2.1]heptan-2-
ones (1S,4R)-16 and (1R,4S)-16
Single crystals of the diastereoisomers (1S,2S,4R,2%R)-
12 and (1R,2R,4S,2%R)-13 could not be obtained and so
we developed a route to identify the absolute configura-
tions of the new enantiomers. Our proposal was to
derivatize the alcohols (1S,2S,4R)-11 and (1R,2R,4S)-
11 to obtain known chiral compounds. In this context,
and taking into account the significance of N-Boc-7-
azabicyclo[2.2.1]heptan-2-ones (1S,4R)- and (1R,4S)-16
as precursors of (−)- and (+)-epibatidine and related
analogues, we decided to undertake their synthesis.28–30
Scheme 1. (a) Ref. 23; (b) (i) L-Selectride®, THF, −78°C,
100%; (ii) MsCl, TEA, CH2Cl2, 35°C; (c) tBuOK, THF,
−78°C, 76% two steps; (d) 12N HCl, 120°C, 95%.

A. A6enoza et al. / Tetrahedron: Asymmetry 13 (2002) 625–632
627
2.4. Synthesis of all four 2-hydroxy-7-azabicyclo[2.2.1]-
heptane-1-carboxylic acids (1S,2S,4R)-10, (1R,2R,4S)-
10, (1S,2R,4R)-19 and (1R,2S,4S)-19
We attempted the cleavage of the methoxycarbonyl
group of the azabicyclo[2.2.1]heptane system. The acid
(1S,4R)-15 was obtained from diol (1R,2S,4R)-14 by
oxidation using Jones’ reagent. This diol was in turn
obtained from alcohol (1S,2S,4R)-11 by treatment with
NaBH4/CaCl2 in THF/EtOH. The decarboxylation of
(1S,4R)-15 was carried out by formation of the acid
chloride and subsequent coupling with N-hydroxy-2-
thiopyridone. This compound was photolyzed in the
presence of tributyltin hydride to give ketone (1S,4R)-
16 in 50% yield from (1S,4R)-15. The specific rotation
of (1S,4R)-16 was identical to that described in the
literature22 {[h]D25 (c 1.03, CHCl3)=+75.5}. The same
procedure, starting from the alcohol (1R,2R,4S)-11,
was followed to give the ketone (1R,4S)-16 (Scheme 3).
Acid hydrolysis of the methyl ester and N-Boc groups
in the compound (1S,2S,4R)-11 quantitatively gave the
required amino acid hydrochloride (1S,2S,4R)-10, in
which the alcohol group is in the endo disposition. In
order to obtain the alcohol in the exo disposition, we
synthesized the enantiopure protected ketone (1S,4R)-
17 by treatment with Dess–Martin reagent in
dichloromethane. This compound is an excellent build-
ing block for analogues of a-amino acids through fur-
ther functionalization. Rapoport and Hart obtained the
same building block, 1, with other protective groups
(N-Cbz and tert-butyl ester) in only 4% yield from
L
-serine, whereas our route gives an improved yield of
These transformations constitute a formal synthesis of
(−)- and (+)-epibatidine. In addition, and more impor-
tantly, taking into account that the activity of epiba-
13% for the enantiopure (1S,4R)-17 (from
(Scheme 4).
D,L-serine)
tidine
is
accompanied
by
high
toxicity,31
Reduction of the ketone (1S,4R)-17 with sodium boro-
hydride in the presence of CeCl3·7H2O at rt gave a
mixture of endo/exo alcohols in a 7:3 ratio in favour of
the endo compound (1S,2S,4R)-11. Surprisingly, the
use of L-Selectride® at −78°C gave only the alcohol
N-Boc-7-azabicyclo[2.2.1]heptan-2-ones (1S,4R)-16 and
(1R,4S)-16 can also be considered as potential building
blocks for the preparation of other analogues of
epibatidine.
Scheme 3. (a) NaBH4, CaCl2, THF/EtOH, 0°C to rt, 99%; (b) Jones’ reagent, acetone, 0°C to rt, 90%; (c) (i) (COCl)2, DMF,
dichloroethane, rt, (ii) N-hydroxy-2-thiopyridone, TEA, THF, 0°C to rt, (iii) Bu3SnH, hw, THF, 50% three steps.
Scheme 4. (a) 6N HCl, 60°C, 100%; (b) Dess–Martin reagent, CH2Cl2, rt, 89%; (c) L-Selectride®, THF, −78°C, 76%; (g) 6N HCl,
85°C, 100%.

628
A. A6enoza et al. / Tetrahedron: Asymmetry 13 (2002) 625–632
(1S,2R,4R)-18 with the hydroxy group in the exo dispo-
sition. Generally, reductions of similar substrates with
L-Selectride® give endo isomers28 and we believe that the
influence of the methyl ester group in position 1 is critical
tothisselectivity. Hydrolysisofthealcohol(1S,2R,4R)-18
led to the synthesis of the amino acid hydrochloride
(1S,2R,4R)-19, which possesses the hydroxy group in the
exo disposition (Scheme 4).
( )-7 (2.49 g, 8.16 mmol) was dissolved in dry THF (100
mL) and L-Selectride® (14.7 mL of a 1 M solution in THF,
14.7 mmol) was added dropwise at −78°C under an inert
atmosphere. After 4 h stirring at the same temperature,
the reaction was quenched by the addition of saturated
aqueous NH4Cl (50 mL). The resulting mixture was
allowed to warm up to rt and washed with EtOAc (5×100
mL). The combined organic layer was dried over anhy-
drous Na2SO4. Evaporation of the solvent gave a residue
that was chromatographed on silica gel, eluting with
EtOAc, to give 2.51 g of the trans alcohol as a white solid
(100%). The alcohol was dissolved in dry CH2Cl2 (80 mL)
under an inert atmosphere and TEA (2.84 mL, 20.4 mmol)
and methanesulfonyl chloride (0.95 mL, 12.2 mmol) were
added to the solution at 0°C. The solution was stirred at
35°Covernight. Themixturewaswashedwithwater(2×50
mL), saturated aqueous NaHCO3 (50 mL) and brine. The
combined organic layers were dried over anhydrous
Na2SO4 and filtered. After evaporation of the solvent, the
residue (3.02 g) was used in the next reaction without
further purification. In order to characterize the mesylate,
a small portion of the residue was chromatographed on
a silica gel column, eluting with hexane/EtOAc (1:9), to
give compound ( )-8. Mp: 142°C. Anal. calcd for
C17H23NO7S; C, 52.97; H, 6.01; N, 3.63; S, 8.32. Found
C, 52.78; H, 6.15; N, 3.81; S, 8.24%. IR (CH2Cl2, cm−1):
3411 (NH); 1732 (COO); 1662 (CON). 1H NMR (CDCl3):
l 2.03–2.25 (m, 4H); 2.43–2.49 (m, 1H); 2.63–2.68 (m,
1H); 3.05 (s, 3H, CH3SO2); 3.35 (s, 3H, CH3O); 3.86 (s,
3H, CH3OCO); 4.32 (dd, 1H, Ja–e=4.8 Hz, Ja–a=10.8 Hz,
H2); 4.80–4.90 (m, 1H, H4); 7.31 (br s, 1H, NH); 7.41–7.52
(m, 3H, arom), 7.75–7.80 (m, 2H, arom). 13C NMR
(CDCl3): l 26.4, 28.5, 33.0 (C3, C5, C6); 38.6 (CH3SO2);
53.1 (CH3OCO); 58.3 (CH3O); 63.3 (C1); 77.1 (C2, C4);
126.9, 128.7, 131.8, 134.6 (arom); 166.9; 172.1 (COO,
CON).
Anidenticalprocedurewasusedtoobtainthecorrespond-
ing enantiomers (1R,2R,4S)-10 and (1R,2S,4S)-19 from
alcohol (1R,2R,4S)-11. The specific rotations measured
for these compounds were in agreement with the isomers
previously synthesized, but with opposite signs (Scheme
4).
3. Conclusions
In conclusion, we have developed a versatile route to
synthesize, for the first time to the best of our knowledge,
all four conformationally constrained analogues of 3-
hydroxyproline that incorporate the 7-azabicyclo
[2.2.1]heptane skeleton: (1S,2S,4R)-10, (1R,2R,4S)-10,
(1S,2R,4R)-19 and (1R,2S,4S)-19. Moreover, we have
improved the yield in the synthesis of building block 1,
reported earlier by Rapoport, and obtained compounds
(1S,4R)-17 and (1R,4S)-17. This synthetic route also
allows both enantiomers of the N-Boc-7-azabicyclo-
[2.2.1]heptan-2-ones (1S,4R)-16 and (1R,4S)-16 to be
obtained, and these are valuable building blocks for the
synthesis of epibatidine analogues.
4. Experimental
4.1. General procedures
4.1.2. Methyl N-benzoyl-7-azabicyclo[2.2.1]heptane-endo-
2-methoxy-1-carboxylate ( )-9. To a solution of ( )-8
(3.14 g, 8.16 mmol) in dry THF (100 mL) was added a
1 M solution of tBuOK in THF (9.8 mL, 9.8 mmol) under
an inert atmosphere at −78°C. After stirring for 15 min
at −78°C, the reaction was warmed up to rt and stirred
at this temperature for 20 h. The reaction was quenched
by the addition of saturated aqueous NH4Cl (15 mL) and
stirred for 15 min. The THF was evaporated and the
resulting mixture was extracted with EtOAc (4×100 mL).
The organic layer was dried over anhydrous Na2SO4,
filtered and evaporated to give a residue, which was
purified by silica gel column chromatography, eluting
with hexane/EtOAc (1:1), to give ( )-9 (1.80 g, 76% from
ketone( )-7)asacolorlessoil. Anal. calcdforC16H19NO4;
C, 66.42; H, 6.62; N, 4.84. Found C, 66.32; H, 6.79; N,
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). H and 13C NMR spectra
1
1
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 D2O with TMS as the
external standard using a coaxial microtube (chemical
shifts are reported in ppm on the l scale, coupling
constants in Hz). The assignment of all separate signals
in the 1H NMR spectra was made on the basis of coupling
constants, selective proton–proton homonuclear decou-
pling experiments, proton–proton COSY experiments
and proton–carbon HETCOR experiments. Melting
points were determined on a Bu¨chi SMP-20 melting point
apparatus and are uncorrected. Optical rotations were
measured on a Perkin–Elmer 341 polarimeter in 1.0 and
0.5 dm cells of 1.0 and 3.4 mL capacity, respectively.
Microanalyses were carried out on a CE Instruments
EA-1110 analyser and are in good agreement with the
calculated values. IR spectra were recorded on a Perkin–
Elmer FT-IR spectrum 1000 spectrophotometer.
1
4.77%. IR (CH2Cl2, cm−1): 1737 (CO), 1648 (CON). H
NMR (CDCl3): l 1.30 (dd, 1H, J3n–2x=12.6 Hz, J3n–3x
=
30 Hz, H3n); 1.61–1.78 (m, 2H, H5x, H5n); 2.24–2.29 (m,
1H, H6n); 2.30–2.60 (m, 2H, H3x, H6x); 3.34 (s, 3H, CH3O);
3.84 (s, 3H, CH3OCO); 4.15–4.22 (m, 1H, H4); 4.31–4.38
(m, 1H, H2x); 7.36–7.50 (m, 3H, arom); 7.61–7.66 (m, 2H,
arom). 13C NMR (CDCl3): l 2.22 (C6); 30.8 (C5); 37.8
(C3); 52.6 (CH3OCO); 58.0 (CH3O); 62.1 (C4); 70.2 (C1);
82.8 (C2); 128.4, 128.6, 131.6, 134.0 (arom); 171.2, 172.3
(COO, CON).
4.1.1. Methyl 1-benzamido-c-4-methanesulfonyloxy-c-2-
methoxycyclohexane-r-1-carboxylate ( )-8. Compound

A. A6enoza et al. / Tetrahedron: Asymmetry 13 (2002) 625–632
629
4.1.5. Methyl N-(tert-butoxycarbonyl)-2-[2%-methoxy-2%-
(trifluoromethyl)phenylacetyloxy] - 7 - azabicyclo[2.2.1]-
heptane-1-carboxylates (1S,2S,4R,2%R)-12 and (1R,2R,
4S,2%R)-13. To a solution of alcohol ( )-11 (410
mg, 1.51 mmol), DCC (373 mg, 1.81 mmol) and
DMAP (9 mg, 0.07 mmol) in dry CH2Cl2 (10 mL) at
0°C was slowly added a solution of (R)-(+)-MTPA
(424 mg, 1.81 mmol) in dry CH2Cl2 (10 mL). The
mixture was stirred at 0°C for 1 h and the reac-
tion was warmed to rt and stirred at this temperature
for 18 h. The resulting white suspension was filtered
to remove the N,N%-dicyclohexylurea. The filtrate was
concentrated in vacuo to give a white slurry and
diethyl ether was added. The resulting suspension was
filtered to remove the N-acyl-N%-cyclohexylurea and
the solvent was evaporated. The residue was purified
by column chromatography, eluting with hexane/
EtOAc (7:3), to give the mixture of (1S,2S,4R,2%R)-12
and (1R,2R,4S,2%R)-13 as a colorless oil (700 mg,
95%). The diastereoisomers were separated by crystal-
lization from octane to give (1S,2S,4R,2%R)-12 (331
mg, 45%) as a white solid of high purity. The mother
liquor containing (1R,2R,4S,2%R)-13 was purified by
column chromatography, using hexane/EtOAc (8:2) as
an eluent, to give (1R,2R,4S,2%R)-13 as a colorless
oil (330 mg, 45%). The purity of the products was
determined by 19F NMR (>95%). (1S,2S,4R,2%R)-12:
Mp: 88°C. [h]2D5=+45.3 (c 1.09, MeOH). Anal. calcd
for C23H28F3NO7: C, 56.67; H, 5.79; N, 2.87. Found:
C, 56.73; H, 5.82; N, 2.92%. IR (CH2Cl2, cm−1) 1748
(COO); 1704 (CON). 1H NMR (CDCl3): l 1.36
(dd, 1H, J3n–3x=13.2 Hz, J3n–2x=3.0 Hz, H3n); 1.41
(s, 9H, C(CH3)3); 1.45–1.58 (m, 1H); 1.87–2.25 (m,
3H); 2.45–2.60 (m, 1H, H3x); 3.51 (s, 3H, OCH3);
3.76 (s, 3H, CH3OCO); 4.32 (‘t’, 1H, J4–3x=J4–5x=5.1
Hz, H4); 5.58 (ddd, 1H, J2x–3x=10.2 Hz, J2x–3n=3.0
Hz, J2x–6x=1.5 Hz, H2x); 7.35–7.45 (m, 3H, arom);
7.47–7.55 (m, 2H, arom). 13C NMR (CDCl3): l 25.6
(C6); 28.0 (C(CH3)3); 28.8 (C5); 36.8 (C3); 52.4
(CH3OCO); 55.3 (OCH3); 59.5 (C4); 70.5 (C(CH3)3);
76.7 (C2); 81.5 (C1); 121.3 (C(CF3)); 125.1 (CF3);
127.4, 128.4, 129.7, 131.9 (arom); 155.6 (COOC-
(CH3)3); 165.7, 169.2 (COOCH3, COO). 19F NMR
4.1.3. endo-2-Hydroxy-7-azabicyclo[2.2.1]heptane-1-car-
boxylic acid hydrochloride ( )-10. Compound ( )-9
(614 mg, 2.12 mmol) was suspended in 12N HCl (25
mL) and the mixture was heated at 120°C for 7 days.
The solvent was evaporated in vacuo, the residue was
dissolved in water, washed with diethyl ether (3×10
mL) and the aqueous layer was evaporated to give
390 mg of the amino acid hydrochloride ( )-10 (95%).
Anal. calcd for C7H12ClNO3: C, 43.42; H, 6.25; N,
1
7.23. Found: C, 43.58; H, 6.32; N, 7.38%. H NMR
(D2O): l 1.48 (dd, 1H, J3n–2x=14.1 Hz, J3n–3x=3.6
Hz, H3n); 1.80–2.15 (m, 3H); 2.40–2.50 (m, 1H, H3x);
2.55–2.65 (m, 1H); 4.13 (‘t’, 1H, J4–3x=J4–5x=5.1 Hz,
H4); 4.53–4.60 (m, 1H, H2). 13C NMR (D2O): l 24.3,
29.8, 38.6 (C3, C5, C6); 61.3 (C4); 72.7 (C2); 76.2 (C1);
173.6 (COO).
4.1.4. Methyl N-(tert-butoxycarbonyl)-endo-2-hydroxy-
7-azabicyclo[2.2.1]heptane-1-carboxylate ( )-11. Acetyl
chloride (0.57 mL, 8.1 mmol) was added dropwise to
MeOH (30 mL) at 0°C. The mixture was stirred for
10 min and the amino acid hydrochloride ( )-10 (521
mg, 2.7 mmol) was added. The resulting solution was
stirred at 60°C for 12 h. The solvent was removed,
the residual oil suspended in diethyl ether (20 mL)
and the solvent was evaporated again. This process
was repeated twice more and the corresponding pure
methyl ester hydrochloride was obtained as a solid
(560 mg, 100%). 1H NMR (D2O): l 1.55 (dd, 1H,
J
3n–3x=14.1 Hz, J3n–2x=3.6 Hz, H3n); 1.90–2.20 (m,
3H); 2.45–2.55 (m, 1H, H3x); 2.60–2.73 (m, 1H); 3.84
(s, 3H, CH3OCO); 4.23 (‘t’, 1H, J4–3x=J4–5x=5.1 Hz,
H4); 4.63 (ddd, 1H, J2x–3x=10.5 Hz, J2x–3n=3.6 Hz,
J
2x–6x=1.8 Hz, H2x). 13C NMR (D2O): l 24.5, 29.9
(C5, C6); 38.7 (C3); 56.4 (CH3OCO); 61.7 (C4); 72.8
(C2); 76.0 (C1); 171.9 (COO). The hydrochloride (380
mg, 1.8 mmol) was dissolved in water (10 mL) and
Na2CO3·10H2O (1.06 g, 3.7 mmol) was added. A
solution of (Boc)2O (524 mg, 2.4 mmol) in THF (40
mL) was added to the mixture. The mixture was vig-
orously stirred at rt for 15 h, saturated aqueous NaCl
(40 mL) was added and the resulting mixture was
extracted with EtOAc (4×40 mL). The organic layer
was dried, filtered and evaporated to give a residue,
which was purified by column chromatography, elut-
ing with hexane/EtOAc (1:1), to give ( )-11 (400 mg,
80%) as a white solid. Mp: 95°C. Anal. calcd for
C13H21NO5: C, 57.55; H, 7.80; N, 5.16. Found: C,
57.47; H, 7.70; N, 5.22%. IR (CH2Cl2, cm−1) 3591
(CDCl3):
l
−72.06. (1R,2R,4S,2%R)-13: [h]2D5=−7.4
(c 1.07, MeOH). Anal. calcd for C23H28F3NO7: C,
56.67; H, 5.79; N, 2.87. Found: C, 56.49; H, 5.62;
N, 2.78%. IR (CH2Cl2, cm−1) 1747 (COO); 1704
(CON). 1H NMR (CDCl3): l 1.36 (dd, 1H, J3n–3x
=13.5 Hz, J3n–2x=3.0 Hz, H3n); 1.34–1.48 (m, 10H,
C(CH3)3, H5n); 1.86–2.01 (m, 1H, H5x); 2.02–2.15
(m, 1H, H6); 2.16–2.28 (m, 1H, H6); 2.46–2.59
(m, 1H, H3x); 3.52 (s, 3H, OCH3); 3.81 (s, 3H,
CH3OCO); 4.30 (‘t’, 1H, J4–3x=J4–5x=5.1 Hz, H4);
5.52–5.60 (m, 1H, H2x); 7.38–7.46 (m, 3H, arom);
7.47–7.56 (m, 2H, arom). 13C NMR (CDCl3): l 26.4
(C6); 28.0 (C(CH3)3); 28.6 (C5); 37.2 (C3); 52.4
(CH3OCO); 55.3 (OCH%3); 59.5 (C4); 70.2 (C(CH3)3);
76.1 (C2); 81.6 (C1); 121.4 (C(CF3)); 125.2 (CF3);
127.4, 128.4, 129.7, 131.9 (arom); 155.6 (COOC-
(CH3)3); 165.8, 169.3 (COOCH3, COO). 19F NMR
(CDCl3): l −71.82.
1
(OH); 1734 (COO); 1700 (CON). H NMR (CDCl3):
l 1.26 (dd, 1H, J3n–3x=12.9 Hz, J3n–2x=3.9 Hz, H3n);
1.41 (s, 9H, C(CH3)3); 1.56–1.64 (m, 1H, H5); 1.93–
2.00 (m, 2H, H5, H6); 2.27–2.35 (m, 1H, H3x); 2.45–
2.55 (m, 1H, H6); 3.82 (s, 3H, CH3OCO); 4.21 (‘t’,
1H, J4–3x=J4–5x=5.1 Hz, H4); 4.59 (ddd, 1H, J2x–3x
=
10.5 Hz, J2x–3n=3.9 Hz, J2x–6x=1.5 Hz, H2x). 13C
NMR (CDCl3): l 25.8 (C6); 28.1 (C(CH3)3); 29.6
(C5); 37.7 (C3); 52.5 (CH3OCO); 59.9 (C4); 71.3
(C(CH3)3); 73.0 (C2); 81.1 (C1); 156.4 (COOC(CH3)3);
171.8 (COOCH3).

630
A. A6enoza et al. / Tetrahedron: Asymmetry 13 (2002) 625–632
4.1.6. Methyl N-(tert-butoxycarbonyl)-2-hydroxy-7-
azabicyclo[2.2.1]heptane-1-carboxylate (1S,2S,4R)-11.
Compound (1S,2S,4R,2%R)-12 (546 mg, 1.12 mmol) was
dissolved in MeOH (35 mL) and MeONa (30 mg, 0.56
mmol) was added. The mixture was stirred for 1 day at
rt and a further quantity of MeONa (30 mg, 0.56
mmol) was added. The reaction mixture was stirred at
rt for 3 days, quenched with Dowex 50W X8 and
filtered. The residue was purified by column chro-
matography, using hexane/EtOAc (7:3) as eluent, to
give (1S,2S,4R)-11 (265 mg, 87%) as a white solid.
[h]2D5=+10.6 (c 1.00, MeOH).
extracted with CHCl3/2-propanol (4:1) (4×20 mL). The
combined organic layers were dried and concentrated.
The residual white solid (211 mg, 90%) was identified
by NMR. Mp: 145°C. [h]2D5=+1.8 (c 0.97, CHCl3). IR
(CH2Cl2, cm−1): 1779, 1750, 1713 (COO, CO, CON). 1H
NMR (CDCl3): l 1.40 (s, 9H, C(CH3)3); 1.57–1.72 (m,
1H, H5n); 1.76–1.92 (m, 1H, H6n); 1.93–2.09 (m, 1H,
H5x); 2.15 (d, 1H, J3n–3x=17.4 Hz, H3n); 2.22–2.36 (m,
1H, H6x); 2.56–2.71 (m, 1H, H3x); 4.55–4.65 (m, 1H,
H4); 10.66–11.04 (br s, 1H, COOH). 13C NMR
(CDCl3): l 25.9 (C6); 27.8 (C(CH3)3); 28.2 (C5); 44.8
(C3); 57.1 (C4); 75.9 (C(CH3)3); 82.9 (C1); 155.8
(COOC(CH3)3); 171.2 (COO); 204.3 (C2).
4.1.7. Methyl N-(tert-butoxycarbonyl)-2-hydroxy-7-
azabicyclo[2.2.1]heptane-1-carboxylate (1R,2R,4S)-11.
Compound (1R,2R,4S,2%R)-13 (500 mg, 1.02 mmol)
was dissolved in MeOH (35 mL) and MeONa (27 mg,
0.51 mmol) was added. The mixture was stirred for 1
day at rt and a further quantity of MeONa (27 mg, 0.51
mmol) was added. The mixture was stirred for 3 days at
rt, quenched with Dowex 50W X8 and filtered. The
residue was purified by column chromatography, using
hexane/EtOAc (7:3) as eluent, to give (1R,2R,4S)-11
(241 mg, 87%) as a white solid. [h]2D5=−10.3 (c 0.99,
MeOH).
4.1.11.
N-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]-
heptan-2-one-1-carboxylic acid (1R,4S)-15. As described
for (1S,4R)-15, compound (1R,4S)-15 (237 mg, 90%)
was obtained starting from (1S,2R,4S)-14 (250 mg, 1.03
mmol). [h]2D5=−2.0 (c 1.05, CHCl3).
4.1.12.
N-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]-
heptan-2-one (1S,4R)-16. To a suspension of acid
(1S,4R)-15 (196 mg, 0.77 mmol) in dichloroethane (13
mL) was added DMF (7 mL, 0.08 mmol) followed by
oxalyl chloride (170 mL, 1.92 mmol). The mixture was
stirred for 3 h at rt and evaporated to dryness. The
residue was dissolved, in the dark, in THF (10 mL) and
cooled to 0°C. N-Hydroxypyridine-2-thione (180 mg,
1.62 mmol) and TEA (240 mL, 1.69 mmol) were then
added. The mixture was stirred for 2 h at rt and filtered.
The residue was washed with cool THF and the solvent
was evaporated, with protection from light, to give a
yellow compound, which was used in the next step
without purification. The yellow solid was dissolved in
THF (30 mL) and Bu3SnH (410 mL, 1.54 mmol) was
added. The mixture was irradiated with a 200 W tung-
sten lamp at rt for 4 h. The solvent was removed and
the residue was dissolved in CH3CN (30 mL) and
extracted with hexane (4×30 mL). The CH3CN layer
was evaporated and the residue was purified by column
chromatography, using hexane/EtOAc (8:2), to give
(1S,4R)-16 as a colorless oil (82 mg, 50%). [h]2D5=+75.5
(c 1.03, CHCl3). Anal. calcd for C11H17NO3: C, 62.54;
H, 8.11; N, 6.63. Found: C, 62.49; H, 8.18; N, 6.72%.
4.1.8.
N-(tert-Butoxycarbonyl)-2-hydroxy-1-hydroxy-
methyl-7-azabicyclo[2.2.1]heptane (1R,2S,4R)-14. To a
suspension of methyl ester (1S,2S,4R)-11 (320 mg, 1.18
mmol) and CaCl2 (262 mg, 2.36 mmol) in EtOH/THF
(6:4, 10 mL) at 0°C, was added NaBH4 (179 mg, 4.72
mmol). The suspension was stirred at rt for 3 h. The
mixture was diluted with EtOAc (20 mL) and extracted
with 5% aqueous K2CO3 (30 mL), 0.5N HCl (30 mL),
and brine (30 mL). The organic layer was dried, filtered
and evaporated to give pure diol (1R,2S,4R)-14 as a
white solid (240 mg, 99%). Mp: 125°C. [h]2D5=+14.7 (c
1.00, MeOH). Anal. calcd for C12H21NO4; C, 59.24; H,
8.70; N, 5.76. Found C, 59.38; H, 8.80; N, 5.81%. IR
(CH2Cl2, cm−1): 3610, 3400 (OH); 1668 (CON). 1H
NMR (CDCl3): l 1.05–1.15 (m, 1H, H3n); 1.32–1.43 (m,
10H, C(CH3)3, H6); 1.47–1.58 (m, 1H, H5); 1.63–1.79
(m, 1H, H5); 2.03–2.23 (m, 2H, H3x, H6); 3.73–3.98 (m,
2H, CH2OH); 4.10 (‘t’, 1H, J4–3x=J4–5x=5.1 Hz, H4);
4.18–4.30 (m, 2H, H2, OH); 4.97–5.43 (br s, 1H, OH).
13C NMR (CDCl3): l 23.7 (C6); 28.4 (C(CH3)3); 29.7
(C5); 38.0 (C3); 58.5 (C4); 60.0 (CH2OH); 69.7 (C2); 71.4
(C(CH3)3); 80.5 (C1); 155.2 (COOC(CH3)3).
IR (CH2Cl2, cm−1) 1760 (CO); 1690 (CON). H NMR
1
(CDCl3): l 1.44 (s, 9H, C(CH3)3); 1.50–1.68 (m, 2H);
1.92–2.08 (m, 2H); 2.00 (d, 1H, J3n–3x=17.4 Hz, H3n);
2.46 (dd, 1H, J3x–3n=17.4 Hz, J3x–4=5.1 Hz, H3x);
4.21–4.27 (m, 1H, H1); 4.52–4.57 (m, 1H, H4). 13C
NMR (CDCl3): l 24.5, 27.6 (C5, C6); 28.3 (C(CH3)3);
45.3 (C3); 56.1 (C4); 64.0 (C1); 80.9 (C(CH3)3); 155.2
(COOC(CH3)3); 209.7 (C2).
4.1.9.
N-(tert-Butoxycarbonyl)-2-hydroxy-1-hydroxy-
methyl-7-azabicyclo[2.2.1]heptane (1S,2R,4S)-14. As
described for (1R,2S,4R)-14, compound (1S,2R,4S)-14
(300 mg, 99%) was obtained starting from (1R,2R,4S)-
11 (337 mg, 1.24 mmol). [h]2D5=−14.2 (c 1.00, MeOH).
4.1.13.
N-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]-
heptan-2-one (1R,4S)-16. As described for (1S,4R)-16,
compound (1R,4S)-16 (83 mg, 50%) was obtained start-
ing from (1R,4S)-15 (200 mg, 0.78 mmol). [h]2D5=−75.5
(c 1.02, CHCl3).
4.1.10.
N-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]-
heptan-2-one-1-carboxylic acid (1S,4R)-15. A 2.5-fold
excess of Jones’ reagent was added dropwise to a
solution of (1R,2S,4R)-14 (225 mg, 0.92 mmol) in
acetone (15 mL) at 0°C over 5 min. The mixture was
stirred at 0°C for 1 h and for a further 4 h at rt. The
excess Jones’ reagent was quenched with 2-propanol.
The mixture was then diluted with water (15 mL) and
4.1.14.
2-Hydroxy-7-azabicyclo[2.2.1]heptane-1-car-
boxylic acid hydrochloride (1S,2S,4R)-10. Compound
(1S,2S,4R)-11 (20 mg, 0.07 mmol) was suspended in 6N
HCl (3 mL) and the mixture was heated at 60°C for 24

A. A6enoza et al. / Tetrahedron: Asymmetry 13 (2002) 625–632
631
h. The solvent was evaporated in vacuo, the residue was
dissolved in water, washed with diethyl ether (2×10 mL)
and the aqueous layer was evaporated to give 14 mg of
the amino acid hydrochloride (1S,2S,4R)-10 (100%).
[h]2D5=+31.0 (c 1.00, H2O).
C(CH3)3); 1.43–1.55 (m, 1H, H6); 1.69–1.90 (m, 3H,
H3x, H3n, H5x); 2.09–2.22 (m, 1H, H6); 3.61 (d, 1H,
J
OH–2n=1.8 Hz, OH); 3.83 (s, 3H, CH3OCO); 4.13–4.20
(m, 1H, H2n); 4.31 (t, 1H, J4–3x=J4–5x=4.8 Hz, H4). 13C
NMR (CDCl3): l 28.2 (C(CH3)3); 28.8 (C5); 30.6 (C6);
39.7 (C3); 52.5 (CH3OCO); 57.3 (C4); 70.9 (C(CH3)3);
75.7 (C2); 80.8 (C1); 156.5 (COOC(CH3)3); 171.9
(COO).
4.1.15.
2-Hydroxy-7-azabicyclo[2.2.1]heptane-1-car-
boxylic acid hydrochloride (1R,2R,4S)-10. As described
for (1S,2S,4R)-10, compound (1R,2R,4S)-10 (15 mg,
100%) was obtained starting from (1R,2R,4S)-11 (21
mg, 0.08 mmol). [h]2D5=−31.3 (c 1.07, H2O).
4.1.19. Methyl N-(tert-butoxycarbonyl)-2-hydroxy-7-
azabicyclo[2.2.1]heptane-1-carboxylate (1R,2S,4S)-18.
As described for (1S,2R,4R)-18, compound (1R,2S,4S)-
18 (65 mg, 76%) was obtained starting from (1R,4S)-17
(85 mg, 0.31 mmol). [h]2D5=+3.7 (c 0.57, MeOH).
4.1.16. Methyl N-(tert-butoxycarbonyl)-7-azabicyclo
[2.2.1]heptan-2-one-1-carboxylate (1S,4R)-17. Dess–
Martin periodinane (162 mg, 0.38 mmol) was added to
a solution of alcohol (1S,2S,4R)-11 (80 g, 0.29 mmol)
in CH2Cl2 (10 mL) and the reaction mixture was stirred
at rt for 18 h. 1N Na2S2O3 (10 mL) was added to the
reaction and, after stirring for 10 min, the mixture was
extracted with CH2Cl2 (3×10 mL). The combined
organic layers were washed with 5% aqueous NaHCO3
(20 mL) and brine (20 mL). The organic layer was dried
over Na2SO4 and evaporated. The mixture was purified
by column chromatography, using hexane/EtOAc (7:3),
to give (1S,4R)-17 as a white solid (70 mg, 89%). Mp:
97°C. [h]2D5=−7.2 (c 1.11, MeOH). Anal. calcd for
C13H19NO5: C, 57.98; H, 7.11; N, 5.20. Found: C,
57.69; H, 7.16; N, 5.28%. IR (CH2Cl2, cm−1) 1777 (CO);
4.1.20.
2-Hydroxy-7-azabicyclo[2.2.1]heptane-1-car-
boxylic acid hydrochloride (1S,2R,4R)-19. Alcohol
(1S,2R,4R)-18 (50 mg, 0.18 mmol) was suspended in
6N HCl (5 mL). The mixture was stirred at 85°C for 24
h, the solvent evaporated and the excess HCl removed
in vacuo. The residual white solid was dissolved in
water (10 mL) and washed with diethyl ether (2×10
mL). The aqueous phase was evaporated to give
(1S,2R,4R)-19 as a white solid (35 mg, 100%). [h]2D5=
−7.1 (c 1.06, H2O). Anal. calcd for C7H12ClNO3: C,
43.42; H, 6.25; N, 7.23. Found: C, 43.57; H, 6.15; N,
1
7.30%. H NMR (D2O): l 1.67–1.79 (m, 1H); 1.85–2.10
(m, 4H); 2.32 (dd, 1H, J3n–3x=14.4 Hz, J3n–2n=7.5 Hz,
H3n); 4.23 (t, 1H, J4–3x=J4–5x=5.1 Hz, H4); 4.38 (d, 1H,
1
1742, 1710 (COO, CON). H NMR (CDCl3): l 1.43 (s,
9H, C(CH3)3); 1.59–1.72 (m, 1H, H5n); 1.81–1.93 (m,
J
2n–3n=7.5 Hz, H2n). 13C NMR (D2O) l 27.8, 28.7 (C5,
1H, H6n); 1.97–2.11 (m, 1H, H5x); 2.15 (d, 1H, J3n–3x
17.7 Hz, H3n); 2.25–2.39 (m, 1H, H6x); 2.66 (dd, 1H,
=
C6); 41.4 (C3); 59.5 (C4); 74.5 (C2); 79.4 (C1); 172.7
(COOH).
J
3x–3n=17.7 Hz, J3x–4=5.1 Hz, H3x); 3.84 (s, 3H,
CH3OCO); 4.62 (t, 1H, J4–3x=J4–5x=5.1 Hz, H4). 13C
NMR (CDCl3): l 25.7 (C6); 27.9 (C(CH3)3); 28.2 (C5);
44.8 (C3); 52.6 (CH3OCO); 57.0 (C4); 76.1 (C(CH3)3);
82.0 (C1); 155.6 (COOC(CH3)3); 166.8 (COO); 204.4
(C2).
4.1.21.
2-Hydroxy-7-azabicyclo[2.2.1]heptane-1-car-
boxylic acid hydrochloride (1R,2S,4S)-19. As described
for (1S,2R,4R)-19, compound (1R,2S,4S)-19 (28 mg,
100%) was obtained starting from (1R,2S,4S)-18 (40
mg, 0.15 mmol). [h]2D5=+6.7 (c 0.84, H2O).
4.1.17. Methyl N-(tert-butoxycarbonyl)-7-azabicyclo
[2.2.1]heptan-2-one-1-carboxylate
(1R,4S)-17.
As
Acknowledgements
described for (1S,4R)-17, compound (1R,4S)-17 (88
mg, 89%) was obtained starting from (1R,2R,4S)-11
(100 mg, 0.37 mmol). [h]2D5=+7.0 (c 0.98, MeOH).
We thank the Comisio´n Interministerial de Ciencia y
Tecnolog´ıa (CICYT) and the Comisio´n Euopea (project
2FD97-1530), the Gobierno de La Rioja (project
ANGI-2001) and the Universidad de La Rioja (project
API-01/B02). J.I.B. thanks the Comunidad Auto´noma
de La Rioja for a doctoral fellowship.
4.1.18. Methyl N-(tert-butoxycarbonyl)-2-hydroxy-7-
azabicyclo[2.2.1]heptane-1-carboxylate (1S,2R,4R)-18.
To a solution of ketone (1S,4R)-17 (70 mg, 0.26 mmol)
in dry THF (10 mL) at −78°C was added L-Selectride®
(310 mL of 1 M solution in THF, 0.31 mmol). The
reaction mixture was stirred at −78°C for 2 h and then
quenched by the addition of saturated aqueous NH4Cl
(8 mL). The resulting mixture was allowed to warm to
rt, diluted with water and the residue washed with
EtOAc (3×20 mL). The combined organic layers were
dried, filtered, and the solvent was evaporated to give
an oil, which was purified by column chromatography,
using hexane/EtOAc (1:1), to give (1S,2R,4R)-18 as a
colorless oil (54 mg, 76%). [h]2D5=−3.4 (c 0.87, MeOH).
Anal. calcd for C13H21NO5: C, 57.55; H, 7.80; N, 5.16.
Found: C, 57.68; H, 7.67; N, 5.28%. IR (CH2Cl2, cm−1)
3539 (OH); 1723, 1702 (COO, CON). 1H NMR
(CDCl3): l 1.20–1.34 (m, 1H, H5n); 1.38 (s, 9H,
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