Synthesis of a new enantiopure bicyclic γ/δ-amino acid (BTKa) derived from tartaric acid and α-amino acetophenone

Article abstract of DOI:10.1016/S0040-4020(02)01297-8

The synthesis of a novel enantiopure γ/δ-amino acid having the 3-aza-6,8-dioxabicyclo[3.2.1]octane structure was realized by the combination of tartaric acid derivatives and α-amino acetophenone followed by a trans-acetalisation process. This amino acid,

Full text of DOI:10.1016/S0040-4020(02)01297-8

Tetrahedron 58 (2002) 9865–9870
Synthesis of a new enantiopure bicyclic g/d-amino acid (BTKa)
derived from tartaric acid and a-amino acetophenone
*
Antonio Guarna, Ilaria Bucelli, Fabrizio Machetti, Gloria Menchi, Ernesto G. Occhiato,
Dina Scarpi and Andrea Trabocchi
`
Dipartimento di Chimica Organica “U. Schiff”, Universita di Firenze and Istituto di Chimica dei Composti Organometallici—CNR,
via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italy
Received 19 July 2002; revised 16 September 2002; accepted 10 October 2002
Abstract—The synthesis of a novel enantiopure g/d-amino acid having the 3-aza-6,8-dioxabicyclo[3.2.1]octane structure was realized by
the combination of tartaric acid derivatives and a-amino acetophenone followed by a trans-acetalisation process. This amino acid, which has
a rigid skeleton and carries substituents at the 3, 5 and 7 positions of the scaffold, could find different applications in organic and
peptidomimetic synthesis. Two different synthetic strategies were studied, one of them allowing the multigram scale preparation of the amino
acid. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Recently we have reported on the synthesis of a new class of
g/d-amino acids named BTAa (Bicycles from Tartaric acid
and Amino acid) obtained by the combination of tartaric
acid and a-amino acid derivatives.1–3 These compounds
present a high degree of molecular diversity which can be
varied through modifications of the configuration of the
stereocenters and the functionalities introduced on the
scaffold by choice of suitable starting reagents. These
compounds could find different applications in organic and
peptidomimetic synthesis: for example, we have used them
as monomers for the generation of oligomers,4 as chiral
auxiliaries in asymmetric synthesis,5 and, the 7-endo
derivatives, as reverse turn inducers in peptide chains.6
The methodology we have developed for the preparation of
BTAa is based on the coupling between (R,R)-, (S,S)- or
meso-tartaric acid derivatives with various a-amino alco-
hols or a-amino aldehydes derived from the corresponding
a-amino acids.1,2 In order to expand the range of scaffolds
in our hands, we envisaged that new functionalised scaffolds
1 and 2 bearing a substituent at C-5 could be prepared
starting from a-amino ketones 5 and tartaric acid deriva-
tives (Scheme 1).
The coupling between compound 5 and tartaric acid
derivatives would lead to intermediates 3 or 4, which after
trans-acetalisation, could give the scaffold 2. Subsequent
Scheme 1.
Keywords: amino acids and derivatives; amino ketones; peptide mimetics.
*
Corresponding author. Tel.: þ39-55-4573481; fax: þ39-55-4573569; e-mail: antonio.guarna@.unifi.it
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01297-8

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A. Guarna et al. / Tetrahedron 58 (2002) 9865–9870
Scheme 2.
amide reduction would produce the desired amino acid 1
(which was named BTKa, Bicycles from Tartaric acid and
Keto-amines). This new scaffold bears three different points
of substitution and therefore should be useful for the
development of chemical libraries. As a first example, we
report here the synthesis of the compound derived from
a-aminoacetophenone and tartaric acid.
jected to the trans-acetalisation conditions developed in our
previous work,1 i.e. boiling a toluene solution of the amide
in the presence of a suspension of concentrated H2SO4
absorbed on silica gel and distilling off part of the solvent.
Cyclisation took place under these conditions to give, after
chromatography, the corresponding lactam 8a in 85% yield
and the side product 2-oxomorpholine 9a (,10%). The
latter compound derived from loss of water from the
reaction intermediate 7a. The supposed intermediate
hemiacetal 7a has not been isolated, although its formation
is reasonable taking into account that the corresponding
methyl acetal 7b is obtained during the synthesis of BTKa
using the synthetic methodology depicted in Scheme 3 (see
later). In the 1H NMR spectra of the crude reaction mixtures,
the presence of two singlets at about 5.2 and 5.0 ppm,
assigned to proton H-1 and H-7, respectively, is diagnostic
of the formation of the bicyclic skeleton. The presence of
by-product 9a is instead revealed by the presence of a
a-Amino acetophenones are easily prepared by reaction of
aliphatic and aromatic amines with commercially available
a-halo-acetophenones. Thus, a-amino acetophenone 5a
(Scheme 2) was prepared in 65% yield, by reacting
benzylamine with a-bromoacetophenone as reported in
the literature.7,8 Condensation of this amino ketone with
(R,R)-tartaric acid monomethyl ester using PyBroP as a
coupling reagent, in the presence of DIPEA in dichloro-
methane,1 furnished amide 3a in good yield (75%) after
chromatographic purification. This compound was sub-
Scheme 3.

A. Guarna et al. / Tetrahedron 58 (2002) 9865–9870
9867
Scheme 4.
singlet at about 6.0 ppm, due to the vCH proton. In the case
of compound 8a, the lactam moiety was selectively reduced
by BH3·DMS in THF at room temperature to give amino
ester 10a in 70% yield.
pure 8b in 57% yield from 5b. In the case of 8b, this was
reduced to amine 10b in 70% after chromatography. The
N-benzhydryl protecting group was then removed from
amine 10b by treatment with ammonium formate in MeOH
on 10% Pd–C, obtaining free amine 13. The hydrolysis of
the ester group was performed in 4 M HCl at room
temperature but, after 16 h, we recovered quantitatively
only product 14 as HCl salt derived from ring opening and
hydrolysis of 13. However, it was possible to obtain the
amino acid 15 by treatment of 14 with TFA in the presence
of molecular sieves. The synthesis of the amino acid 15 was
carried out in a multigram scale, starting from 80 g of 5b
and obtaining 15 as TFA salt in 37% overall yield.
Alternatively, the N-Boc protected amino acid 12 was
obtained in high yield via one pot conversion of N-Bzh
amino ester 10b into the corresponding N-Boc amino ester
11, by treatment with ammonium formate and 10% Pd–C in
the presence of (Boc)2O in refluxed methanol, followed by
hydrolysis of 11 with LiOH.
Although the yields in the coupling process between the
a-amino ketone and the tartaric acid mono methyl ester
derivative in the above process were acceptable, the strategy
is however unsuitable for a large scale preparation of the
scaffold due to the high cost of the condensation reagent
PyBroP. For this reason, we applied a less expensive
methodology to the a-amino ketones (Scheme 3) based on
the use of tartaric acid anhydride for direct condensation
followed by the two-step, acid catalysed trans-acetalisation
of the coupling product. We applied this procedure to
a-amino ketone 5b, derived from the reaction between
a-bromo-acetophenone 6 and benzhydrylamine (BzhNH2).9
The condensation of 5b with tartaric anhydride was carried
out in CH2Cl2 to give the product 4b in quantitative yield
which, dissolved in MeOH and treated with thionyl
chloride, afforded crude lactam 7b in a 9:1 mixture with
monocyclic compound 9b derived from methanol elimi-
nation. Trans-acetalisation of 7b was first carried out on this
mixture under the usual conditions, i.e. by heating a toluene
solution for about 15 min in the presence of a suspension of
H2SO4 on silica gel, and distilling off part of the solvent.
3. Conclusion
In conclusion we have realized the synthesis of a novel
enantiopure g/d-amino acid (BTKa) having the 3-aza-6,8-
dioxabicyclo[3.2.1]octane structure by combining a tartaric
acid derivative and an a-amino acetophenone. One of the
two synthetic strategies allowed the multigram scale
preparation of the amino acid. These amino acids, which
have a rigid skeleton and carries substituents at the 3, 5 and
7 position of the scaffold (and whose spatial orientation
depends on the stereochemistry of the tartaric acid used),
could find different applications in organic and peptido-
mimetic synthesis. Moreover, since a great range of these
scaffolds can be prepared by simply changing the a-amino
ketone, their use in processes of discovering biologically
active compounds based on screening of a large number of
them is also conceivable.
1
Analysis of the reaction mixture by H NMR spectroscopy
revealed the presence of two major products in a 3:2 ratio, of
which one was scaffold 8b and the other the corresponding
monocyclic compound 9b. The formation of 9b during the
acid-catalysed reaction could be accounted for by the
equilibrium shown in Scheme 4, in which the cation 16 is
supposed to be the common intermediate between 9 and 8.
The 3:2 ratio is the equilibrium composition, since after
heating pure 8b (obtained after chromatography) in toluene
in the presence of H2SO4 on silica gel, the same 8b/9b
mixture in 3:2 ratio is obtained. A better result in the
cyclisation process was obtained by treating the 9:1 mixture
of 7b/9b with a 1:1 mixture of TFA and dichloromethane, at
2108C for 3 h. After that time, the analysis of the reaction
mixture revealed the presence of scaffold 8b in a 9:1 ratio
with 9b, suggesting that under these conditions, in any case,
further methanol elimination from 7b does not occur.
Chromatography of the crude reaction mixture afforded then
4. Experimental
4.1. General
Melting points are uncorrected. Chromatographic separations

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A. Guarna et al. / Tetrahedron 58 (2002) 9865–9870
were performed under pressure on silica gel using flash-
column techniques; Large scale purifications were per-
formed with Biotage Inc. apparatus with a prepacked
cartridge system flash 75i Me 15 cm column. Rf values
refer to TLC carried out on 25-mm silica gel plates (Merck
F254), with the same eluant indicated for column chroma-
tography. 1H and 13C NMR spectra were recorded in CDCl3
at 200 and 50.33 MHz, respectively, unless otherwise
stated. EI mass spectra were carried out at 70 eV ionising
voltage. IR spectra were recorded with a FT-IR-1600
Perkin–Elmer spectrophotometer. Microanalyses were
carried out with a Perkin–Elmer 240 C instrument. Optical
rotations were measured with JASCO DIP-360 digital
polarimeter. THF was distilled from Na/benzophenone.
CH2Cl2 was distilled from CaH2. All reactions requiring
anhydrous conditions were performed in oven-dried glass-
ware. Acid silica gel (H2SO4/SiO2) was prepared as
reported.1
1752, 1701, 1655, 1449 cm21. Anal. calcd for C23H25NO6
(411.45): C, 67.14; H, 6.12; N, 3.40. Found: C, 67.44; H,
6.32; N, 3.16.
4.1.4. (2R,3R) 2,3-Diacetoxy-N-benzhydryl-N-(2-oxo-2-
phenyl-ethyl)-succinamic acid (4b). Di-O-acetyl-L-tartaric
anhydride (57.3 g, 265.4 mmol) was added portionwise to a
cooled (08C) stirred solution of 2-(benzhydryl-amino)-1-
phenyl-ethanone (5b, 80 g, 265.4 mol) in anhydrous CH2Cl2
(2 L) and then the reaction mixture was allowed to warm to
308C. After 16 h the mixture was concentrated and CH2Cl2
was evaporated off from the residue. The amide 4b (137 g,
100%) was thereby obtained as a viscous oil and resulted
sufficiently pure to be used in the next step without further
purification. A sample for elemental analysis was obtained
by flash chromatography on silica gel (eluent EtOAc/
petroleum ether 1:1, Rf 0.25).
White solid. Mp 99–1008C. [a]2D5¼21.1 (c 1, CHCl3). H
1
4.1.1. 2-Benzylamino-1-phenyl-ethanone hydrobromide
(5a). This compound was prepared in 65% yield according
to the known procedure.7
NMR d (mixture of rotamers) 7.85–7.00 (m), 6.91 (s), 6.66
(s), 6.20–6.16 (m), 6.14–5.90 (m), 5.80–5.77 (m), 5.64–
5.55 (m), 5.50–5.40 (m), 5.32–5.26 (m), 5.20–5.16 (m),
5.04–4.82 (m), 4.80–4.76 (m), 4.60–4.50 (m), 4.40–4.20
(m), 4.98 (br s), 4.89 (br s), 4.53 (br s), 4.38 (br s). 13C NMR
d (mixture of rotamers, aromatic signals not reported) 193.8,
191.3, 170.7, 170.2, 170.0, 169.9, 169.2, 168.1, 167.0, 70.7,
69.9, 69.4, 66.2, 64.7, 62.9, 51.4, 50.8, 20.6, 20.4, 20.0. MS
m/z (%): 300 (3), 224 (16), 166 (100), 105 (44). IR (CDCl3)
1751, 1222 cm21. Anal. calcd for C29H27NO8 (517.17): C,
67.30; H, 5.26; N, 2.71. Found: C, 67.44; H, 5.04; N, 2.90.
1
White solid. Mp 203–2048C. H NMR (DMSO-d6) d 9.42
(br, 1H), 8.00 (d, J¼1.4 Hz, 2H), 7.82–7.40 (m, 8H), 4.86
(s, 2H), 4.25 (s, 2H). 13C NMR (DMSO-d6) d 192.2 (s),
134.8 (s), 133.6 (s), 131.6 (d), 130.2 (d), 129.1 (d), 128.8
(d), 128.5 (d), 128.2 (d), 51.9 (t), 50.2 (t). IR (KBr):
1684 cm21. Anal. calcd for C15H15NO·HBr (306.20): C,
58.84; H, 5.27; N, 4.57. Found: C, 58.44; H, 5.36; N, 4.27.
4.1.2. 2-(Benzhydryl-amino)-1-phenyl-ethanone (5b).
This compound was prepared in 82% yield according to
the known procedure and its analytical and spectroscopical
data were identical to those reported by Marchand-
Brynaert.9
4.1.5. (1R,5S,7R)-3-Benzyl-2-oxo-5-phenyl-6,8-dioxa-3-
azabicyclo[3.2.1]octane-7-exo-carboxylic acid methyl
ester (8a). A solution of 3a (1.65 g, 4.00 mmol) in toluene
(40 mL) was quickly added to a refluxing suspension of
H2SO4/SiO2 (30% w/w, 700 mg) in toluene (60 mL). The
mixture was allowed to react for 15 min, and afterwards,
one-third of the solvent was distilled off. The hot reaction
mixture was filtered through a short layer of NaHCO3, and
after evaporation of the solvent, the crude product was
purified by chromatography on silica gel (EtOAc/petroleum
ether 1:4, Rf 0.3) affording pure 8a (1.20 g, 85%).
4.1.3. (4R,5R) 5-[Benzyl-(2-oxo-2-phenyl-ethyl)-carba-
moyl]-2,2-dimethyl-[1,3]dioxolane-4-carboxylic acid
methyl ester (3a). To
a solution of 5a (1.20 g,
5.33 mmol) in anhydrous CH2Cl2 (10 mL) (CH2Cl2 was
filtered through a short pad of anhydrous Na2CO3 just
before being used) were added, under a nitrogen atmos-
phere, (R,R)-tartaric acid monomethyl ester (2.49 g,
5.33 mmol), and DIPEA (2.73 mL, 16.0 mmol). The
mixture was stirred at room temperature for 2 h, then the
solvent was removed to give an oil that was dissolved in
EtOAc. This solution was washed with aqueous 5% KHSO4,
5% NaHCO3, and brine and dried over Na2SO4. After
evaporation of the solvent, the crude product obtained was
purified by chromatography on silica gel (EtOAc/petroleum
ether 1:3, Rf 0.32), yielding 3a (1.64 g, 75%).
White solid. Mp 122–1248C. [a]2D5¼264.3 (c 0.8, CHCl3).
1H NMR d 7.62–7.59 (m, 2H), 7.41–7.24 (m, 8H), 5.16 (s,
1H), 4.92 (s, 1H), 4.64 (part A of AB system, J¼15.0 Hz,
1H), 4.52 (part B of AB system, J¼15.0 Hz, 1H), 3.74 (s,
3H), 3.59 (part A of AB system, J¼12.0 Hz, 1H), 3.40 (part
B of AB system, J¼12.0 Hz, 1H). 13C NMR d 169.0 (s),
165.4 (s), 135.3 (s), 129.5 (d), 128.8 (d), 128.3 (d), 127.9
(d), 127.8 (d), 125.4 (d), 107.7 (s), 79.1 (d), 78.4 (d), 55.5
(t), 52.6 (q), 48.6 (t). IR (CDCl3): 1762, 1673, 1601 cm21
.
MS (m/z, %): 353 (Mþ, ,1), 294 (7), 120 (56), 105 (100),
91 (98), 77 (28). Anal. calcd for C20H19NO5 (353.37): C,
67.98; H, 5.42; N, 3.96. Found: C, 68.16; H, 5.64; N, 3.66.
1
Colourless oil. [a]D22¼28.8 (c 1.31, CHCl3). H NMR d
(mixture of rotamers) 7.90–7.85 (m, 2H), 7.61–7.22 (m,
8H), 5.39 (d, J¼5.1 Hz, 1H), 5.11 (d, J¼5.1 Hz, 1H), 4.88–
4.64 (m, 4H), 3.80 and 3.78 (s, 3H), 1.52 and 1.49 (s, 3H),
1.35 and 1.31 (s, 3H). 13C NMR d (mixture of rotamers)
193.8, 193.3, 170.9, 168.8, 136.3, 135.9, 135.0, 133.8,
133.6, 128.8, 128.7, 128.6, 128.4, 127.9, 127.7, 127.4,
113.3, 113.1, 77.6, 76.4, 76.3, 52.6, 52.1, 51.6, 51.3, 50.5,
26.3, 26.2, 25.9. MS m/z (%): 396 (1), 352 (2), 306 (5), 292
(23), 120 (45), 91 (100). IR (CDCl3) 3034, 2982, 2956,
4.1.6. (1R,5S,7R)-3-Benzhydryl-2-oxo-5-phenyl-6,8-
dioxa-3-aza-bicyclo[3.2.1]octane-7-exo-carboxylic acid
methyl ester (8b) and (4-benzhydryl-3-oxo-6-phenyl-
3,4-dihydro-2H-[1,4]oxazin-2-yl)-hydroxy-acetic acid
methyl ester (9b). Thionyl chloride (16 mL, 219 mmol)
was added dropwise to a cooled (08C) stirred solution of
crude product 4b (137 g) in CH3OH (1.6 L) and then the

A. Guarna et al. / Tetrahedron 58 (2002) 9865–9870
9869
reaction mixture was heated at 608C. After 2 h the volatile
were removed under reduced pressure and the resulting
residue was dissolved in a 1:1 mixture of CH2Cl2–TFA
(720 mL). The mixture was cooled at 2108C and allowed to
react for 3 h. The reaction mixture was concentrated under
reduced pressure and the residue washed with Et2O. The
residue oil was chromatographed over a short pad of silica
gel (EtOAc/petroleum ether 1:4). The first fraction (Rf 0.34)
containing pure 8b (65.0 g, 57% yield from 5b) was
followed by a second fraction (Rf 0.1) containing 9b
(7.8 g, 7% yield from 5b).
4.1.8. (1S,5S,7R)-3-Benzhydryl-5-phenyl-6,8-dioxa-3-
aza-bicyclo[3.2.1]octane-7-exo-carboxylic acid methyl
ester (10b). Amide 8b (11.0 g, 25.6 mmol) was reduced
as reported for 8a to afford after chromatography purifi-
cation (EtOAc/petroleum ether 1:8, Rf 0.30) 7.4 g of 10b
(70%).
White solid. Mp 101–1028C. [a]2D5¼212.0 (c 1.0, CHCl3).
1H NMR d 7.62–7.57 (m, 2H), 7.48–7.43 (m, 3H), 7.36–
7.15 (m, 10H), 5.14 (s, 1H), 4.83 (s, 1H), 4.46 (s, 1H), 3.77
(s, 3H), 3.17 (d, J¼11.4 Hz, 1H), 2.91 (d, J¼10.6 Hz, 1H),
2.53 (d, J¼10.6 Hz, 1H), 2.43 (d, J¼11.4 Hz, 1H). 13C
NMR d 171.7 (s), 141.5 (s), 141.1 (s), 137.4 (s), 128.9 (d),
128.7 (d), 128.6 (d), 128.1 (d), 127.9 (d), 127.8 (d), 127.3
(d), 127.2 (d), 125.7 (d), 108.8 (s), 78.4 (d), 77.2 (d), 75.1
(d), 58.7 (t), 53.2 (t), 52.4 (q). MS m/z (%) 414 (Mþ21, 2),
293 (7), 167 (100), 105 (26), 91 (7), 77 (15). IR (CDCl3)
3073, 3030, 2957, 2814, 1757, 1731 cm-1. Anal. calcd for
C26H25NO4 (415.48): C, 75.16; H, 6.06; N, 3.37. Found: C,
74.93; H, 5.90; N, 3.60.
Compound 8b. White solid. Mp 62–638C. [a]2D5¼23.6 (c
1.0, CHCl3). 1H NMR d 7.60–7.53 (m, 2H), 7.40–7.28 (m,
10H), 7.24–7.17 (m, 3H), 7.07 (s, 1H), 5.22 (s, 1H), 5.02 (s,
1H), 3.75 (s, 3H), 3.41 (part A of AB system, J¼12.4 Hz,
1H), 3.29 (part B of AB system, J¼12.4 Hz, 1H). 13C NMR
d 168.9 (s), 165.5 (s), 137.5 (s), 137.1 (s), 135.4 (s), 129.5
(d), 129.3 (d) 128.7 (d), 128.6 (d), 128.3 (d), 128.0 (d), 127.7
(d), 127.6 (d), 125.4 (d), 107.9 (s), 79.3 (d), 78.7 (d), 58.8
(d), 52.7 (t), 52.5 (q). MS m/z (%): 429 (Mþ, 71), 370 (2),
311 (2), 167 (100), 152 (27), 105 (31), 77 (16). IR (CDCl3)
3064, 3034, 2596, 1761, 1667 cm21. Anal. calcd for
C26H23NO5 (429.46): C, 72.71; H, 5.40; N, 3.26. Found:
C, 72.69; H, 5.36; N, 3.59.
4.1.9. (1S,5S,7R)-5-Phenyl-6,8-dioxa-3-aza-bicyclo-
[3.2.1]octane-7-exo-carboxylic acid trifluoro acetate
(15). To a degassed solution of benzhydryl aminoester
10b (7.4 g, 17.8 mmol) in MeOH (200 mL) were added
ammonium formate (6.7 g, 107 mmol), and 10% Pd/C
(3.0 g). The resulting suspension was heated to reflux under
N2. After 1 h the mixture was cooled, filtered through a short
pad of Celite and rinsed with MeOH. The filtrate was
concentrate and the residue clear oil. 13: 1H NMR d 7.65–
7.60 (m, 2H), 7.46–7.38 (m, 3H), 4.87 (s, 1H), 4.75 (s, 1H),
3.75 (s, 3H), 3.39–3.28 (m, 2H), 3.04–2.90 (m, 2H). MS
m/z (%) 249 (Mþ, 2), 190 (13), 127 (66), 105 (74), 104
(100), 77 (99). dissolved in 4 M HCl (700 mL), washed with
petroleum ether (3£200 mL) and stirred at room tempera-
ture. After 16 h the mixture was concentrated and the
residue. 14: 13C NMR (D2O) d 192.6 (s), 174.4 (s), 135.0 (s),
128.7 (d, 2C), 128.5 (d, 2C), 127.8 (d), 71.5 (s), 67.0 (d),
52.4 (t), 49.6 (t)] dissolved in TFA (100 mL) and stirred at
Compound 9b. White solid. Mp 120–1218C. [a]2D0¼26.0 (c
6.3, CHCl3). 1H NMR d 7.40–7.20 (m, 15H), 7.16 (s, 1H),
5.99 (s, 1H), 5.08 (d, J¼2.0 Hz, 1H), 4.99 (d, J¼2.0 Hz,
1H), 3.90 (s, 3H). 13C NMR d 172.0 (s), 161.6 (s), 138.9 (s),
138.1 (s), 137.9 (s), 132.1 (s), 128.8 (d), 128.7 (d), 128.6 (d),
128.4 (d), 128.3 (d), 128.1 (d), 128.0 (d), 127.8 (d), 123.6
(d), 103.0 (d), 78.2 (d), 71.9 (d), 60.0 (d), 53.1 (q). MS m/z
(%): 429 (Mþ, 4), 210 (15), 167 (100), 152 (36), 105 (27),
77 (18). IR (CDCl3) 3534, 3062, 3027, 2949, 1744,
1678 cm21. Anal. calcd for C26H23NO5 (429.46): C,
72.71; H, 5.40; N, 3.26. Found: C, 72.93; H, 5.41; N, 3.03.
4.1.7. (1S,5S,7R)-3-Benzyl-5-phenyl-6,8-dioxa-3-aza-
bicyclo[3.2.1]octane-7-exo-carboxylic acid methyl ester
(10a). To a solution of 8a (4.43 g, 12.6 mmol) in anhydrous
THF (85 mL) cooled at 08C was added dropwise 10 M
BH3·Me2S (2.39 mL, 23.9 mmol). The reaction mixture was
stirred at room temperature for 16 h and then EtOH (3 mL),
3 M NaOH (3 mL) and H2O (100 mL) were added suc-
cessively. The mixture was extracted with Et2O
(3£100 mL) and the combined organic phase concentrated
obtaining a crude oil that after chromatography (EtOAc/
petroleum ether 1:3, Rf 0.30) furnished 2.99 g of 10a
(70%).
˚
room temperature in the presence of 4 A molecular sieves.
After 1 h the mixture was concentrated and the residue was
washed with Et2O obtaining pure 15 (6.0 g, 95% combined
yield from 10b).
White solid. Mp 1708C (dec). [a]2D5¼þ1.1 (c 1.0, EtOH). 1H
NMR (D2O) d 7.52–7.48 (m, 2H), 7.36–7.32 (m, 3H), 5.04
(s, 1H), 4.85 (s, 1H), 3.45 (m, 4H); 13C NMR (DMSO-d6) d
171.6 (s), 136.6 (s), 130.4 (d), 129.1 (d), 126.6 (d), 106.4 (s),
76.7 (d), 76.5 (d), 48.7 (t), 44.3 (t). MS m/z (%): 235 (Mþ,
12), 190 (7) 114 (94), 105 (100); IR (KBr) 3033, 2826, 1682,
1207, 1139 cm21. Anal. calcd for C14H14F3NO6 (349.26):
C, 48.14; H, 4.04; N, 4.01. Found: C 48.04; H, 4.16; N, 3.80.
White solid. Mp 988C. [a]2D5¼þ13.0 (c 1.0, CHCl3). H
1
NMR d 7.72–7.58 (m, 2H), 7.52–7.19 (m, 8H), 5.00 (s,
1H), 4.86 (s, 1H), 3.74 (part A of AB system, J¼13.2 Hz,
1H), 3.61 (part B of AB system, J¼13.2 Hz, 1H), 3.78 (s,
3H), 3.16 (d, J¼11.2 Hz, 1H), 2.93 (d, J¼11.2 Hz, 1H), 2.63
(d, J¼11.2 Hz, 2H). 13C NMR d 171.6 (s), 137.3 (s), 128.9
(d), 128.7 (d), 128.3 (d), 128.1 (d), 127.2 (d), 125.6 (d),
107.9 (s), 78.4 (d), 77.6 (d), 61.4 (t), 60.2 (t), 54.0 (t), 52.3
(q). IR (CDCl3): 1757, 1733 cm21. MS (m/z, %): 339 (Mþ,
2), 280 (13), 218 (78), 158 (100), 105 (83), 91 (100), 77
(73). Anal. calcd for C20H21NO4 (339.39): C, 70.78; H,
6.24; N, 4.13. Found: C, 70.98; H, 6.06; N, 3.94.
4.1.10. (1S,5S,7R)-3-(tert-Butoxycarbonyl)-5-phenyl-6,8-
dioxa-3-aza-bicyclo[3.2.1]octane-7-exo-carboxylic acid
methyl ester (11). To a degassed solution of benzhydryl
aminoester 10b (16.5 g, 39.7 mmol) in MeOH (660 mL)
were added ammonium formate (17.5 g, 278 mmol),
(Boc)2O (26.3 g, 119 mmol) and 10% Pd/C (6.6 g). The
resulting suspension was heated to reflux under N2. After
1 h the mixture was cooled, filtered through a short pad of
Celitew and rinsed with MeOH. The filtrate was concentrate
and the residue was purified by silica gel chromatography

9870
A. Guarna et al. / Tetrahedron 58 (2002) 9865–9870
eluting with EtOAc/petroleum ether 1:1, Rf 0.3, to give 11
(13.0 g, 94%).
Acknowledgements
`
We thank MURST and Universita di Firenze (COFIN
2000–2002), Consiglio Nazionale delle Ricerche (CNR),
White solid. Mp 68–698C. [a]2D5¼þ43.5 (c 1.45, CHCl3).
1H NMR d 7.70–7.60 (m, 2H), 7.48–7.35 (m, 3H), 4.85 and
4.80 (rotamers, br s, 1H), 4.71 and 4.68 (rotamers, br s, 1H),
4.20–4.04 (m, 1H), 4.02–3.90 (m, 1H), 3.71 (s, 3H), 3.42–
3.10 (m, 2H), 1.44 (s, 9H). 13C NMR d 170.8 (s), 155.3 (s),
136.5 (s), 129.3 (d, 2C), 128.3 (d, 2C), 125.6 (d), 106.8 (s),
80.6 (s), 77.3 (d), 76.8 (d), 52.4 (q), 51.8 (t), 45.4 (t), 28.3 (q,
3C). MS m/z (%): 349 (Mþ, ,1), 293 (18), 276 (9), 104
(99), 56 (100). IR (CDCl3) 3018, 2980, 2927, 1759, 1690,
1415 cm21. Anal. calcd for C18H23NO6 (349.38): C, 61.88;
H, 6.64; N, 4.01. Found: C, 61.68; H, 6.44; N, 4.14.
`
and CINMPIS (Universita di Bari) for financial support. Mr
Giovanni Indiani is acknowledged for carrying out several
steps of the synthesis. Mr Sandro Papaleo and Mrs Brunella
Innocenti are acknowledged for their technical support.
References
1. Guarna, A.; Guidi, A.; Machetti, F.; Menchi, G.; Occhiato,
E. G.; Scarpi, D.; Sisi, S.; Trabocchi, A. J. Org. Chem. 1999, 64,
7347–7364.
4.1.11. (1S,5S,7R)-3-(tert-Butoxycarbonyl)-5-phenyl-6,8-
dioxa-3-aza-bicyclo[3.2.1]octane-7-exo-carboxylic acid
(12). The Boc-protected amino ester 11 (10.0 g,
28.6 mmol) was dissolved in MeOH (60 mL) and LiOH
(1.29 g, 31 mmol) was added. The mixture was stirred at
room temperature for 16 h diluted with H2O (35 mL) and
washed with Et2O. The aqueous phases were adjusted to pH
4 with 5% HCl and then extracted with CH2Cl2 (3£40 mL).
The organic extracts were dried over Na2SO4, concentrated
and put under high vacuum to yield 9.2 g (98%) of acid 12.
2. Guarna, A.; Cini, N.; Machetti, F.; Menchi, G.; Occhiato, E. G.
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White solid. Mp 129–1308C. [a]2D5¼þ57.3 (c 0.98, CHCl3).
1H NMR (CD3OD) d 7.72–7.60 (m, 2H), 7.45–7.38 (m,
3H), 4.94 (s, 1H), 4.74 (s, 1H), 4.18–3.95 (m, 2H), 3.45–
3.04 (m, 2H), 1.50 (s, 9H). 13C NMR (CD3OD) d 173.6 (s),
156.9 (s), 138.2 (s), 130.1 (d, 2C), 129.1 (d, 2C), 126.8 (d),
108.2 and 107.8 (rotamers, s), 82.0 (s), 78.6 (d), 78.0 (d),
53.1 and 51.8 (rotamers, t), 48.0 and 46.7 (rotamers, t), 28.3
(q, 3C). MS m/z (%): 279 (7), 262 (5), 234 (4), 105 (100), 77
(42), 57 (100). IR (CDCl3) 1776, 1692 cm21. Anal. calcd
for C17H21NO6 (335.35): C, 60.89; H, 6.31; N, 4.18. Found:
C, 61.18; H, 6.32; N, 4.37.
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306. Chem. Abstr. 1947, 41, 2706a.
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Trans. 1 1987, 1841–1843.
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´ ´
Belmans, M.; Kemps, L.; Ceresiat, M.; Marchand-Brjnaert, J.
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