Bicyclic compounds derived from tartaric acid and α-amino acids (BTAas): Synthesis of new molecular scaffolds derived from the combination of (R,R)-tartaric acid and L-serine

Article abstract of DOI:10.1002/1099-0690(200203)2002:5<873::AID-EJOC873>3.0.CO;2-V

The synthesis of the new N-Fmoc-protected dipeptide isoster methyl (1S,2S,5S,6R)-2exo-hydroxymethyl-7,8-dioxa-3-azabicyclo [3.2.1] octane-6 exo-carboxylate (BTS) has been achieved, starting from (R,R)-tartaric acid and O-benzyl-L-serine, in 11% overall yield after 9 steps. Interestingly, starting from the same α-amino acid, it was also possible to prepare the 2endo-substituted compound, formally derived from the combination of tartaric acid with D-serine. Each compound has a CH₂OH functional group at C-2, which is very useful for greater diversification of the 7,8-dioxa-3-azabicyclo [3.2.1]octane-6-carboxylate (BTAa) dipeptide isosters. The oxidation of the C-2 carbinol group in BTS, moreover, gave rise to a novel, conformationally constrained, α-amino acid that may find application in peptidomimetic synthesis.

Full text of DOI:10.1002/1099-0690(200203)2002:5<873::AID-EJOC873>3.0.CO;2-V

FULL PAPER
Bicyclic Compounds Derived from Tartaric Acid and α-Amino Acids (BTAas):
Synthesis of New Molecular Scaffolds Derived from the Combination of
(R,R)-Tartaric Acid and -Serine
L
Nicoletta Cini,[a] Fabrizio Machetti,[a] Gloria Menchi,[a] Ernesto G. Occhiato,[a] and
Antonio Guarna*[a]
Keywords: Amino acids / Nitrogen heterocycles / Peptides / Peptidomimetics
The synthesis of the new N-Fmoc-protected dipeptide isoster
the combination of tartaric acid with D-serine. Each com-
methyl (1S,2S,5S,6R)-2exo-hydroxymethyl-7,8-dioxa-3-aza- pound has a CH2OH functional group at C-2, which is very
bicyclo[3.2.1]octane-6exo-carboxylate (BTS) has been
achieved, starting from (R,R)-tartaric acid and O-benzyl-
serine, in 11% overall yield after 9 steps. Interestingly, start-
useful for greater diversification of the 7,8-dioxa-3-azabicy-
clo[3.2.1]octane-6-carboxylate (BTAa) dipeptide isosters. The
oxidation of the C-2 carbinol group in BTS, moreover, gave
L
-
ing from the same α-amino acid, it was also possible to pre- rise to a novel, conformationally constrained, α-amino acid
pare the 2endo-substituted compound, formally derived from that may find application in peptidomimetic synthesis.
Introduction
To expand the scope and applications of BTAas further,
we planned syntheses of the Bicycles derived from (R,R)-
We have recently reported the synthesis of a new class of Tartaric acid and -Serine (BTSs) (Figure 1). Moreover, the
γ-amino acids named 7-Bicycles derived from Tartaric acid free hydroxy group on the serine C-2 side chain can easily
and α-Amino acids (BTAas) (Figure 1), obtained by com- be either derivatized or transformed into other functional
bination of tartaric acid and α-amino acid derivatives.[1,2] groups, thus widening the range of compounds obtainable
These compounds, which can be thought of as dipeptide with the same scaffold. For example, oxidation of the 2-
isosters, are characterized by rigid molecular skeletons and hydroxymethyl group to a carboxylic group would produce
the presence of two side chains at positions 2 and 6, with a new, conformationally constrained, α-amino acid. In this
spatial orientations controlled by the stereochemistry of the paper we thus report on the synthesis of the BTS molecular
reagents. Because of these features, BTAas are useful com- scaffold and its transformation into the corresponding α-
pounds for the synthesis of peptidomimetics[3Ϫ5] by inser- amino acid.
tion into biologically active peptides, although other ap-
plications can be envisioned. Of the 164 different peptide
isosters that could arise from the combination of (R,R)-,
(S,S)-, and meso-tartaric acids with glycine and 20 chiral,
natural -amino acids and their  enantiomers, we have so
far prepared and used those from glycine, alanine, and
phenylalanine, and also those from unnatural phenylgly-
cine.[1,2] We have employed these compounds as monomers
for the generation of oligomers[6] and as chiral auxiliaries,[7]
and their 6endo derivatives as reverse turn inducers in pep-
tide chains.[8]
[a]
Dipartimento di Chimica Organica ‘‘U. Schiff’’ and Centro di
Studio sulla Chimica e la Struttura dei Composti Eterociclici
`
e loro Applicazioni, C.N.R., Universita di Firenze,
Polo Scientifico di Sesto Fiorentino,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
E-mail: antonio.guarna@unifi.it
Figure 1. Structure of BTAa and BTS
Eur. J. Org. Chem. 2002, 873Ϫ880
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0305Ϫ0873 $ 17.50ϩ.50/0
873

N. Cini, F. Machetti, G. Menchi, E. G. Occhiato, A. Guarna
FULL PAPER
Results and Discussion
for the next cyclization step. This was carried out
(Scheme 2) in refluxing benzene in the presence of H2SO4/
SiO2 as already described (20 min reflux before distilling off
half of the solvent).[2] After treatment of the crude reaction
mixture with Na2S2O3, necessary to remove the residual
iodinane from the previous DessϪMartin oxidation, and
subsequent chromatography, compound 8 was obtained in
57% yield. Elimination of benzyl alcohol from 6 seems not
to occur under the cyclization conditions, since neither the
formation of α,β-unsaturated aldehyde 7 nor of its cycliza-
tion corresponding products 18 and 19 (see Scheme 4) was
According to the synthetic methodology already reported
for BTAas,[2] the key intermediate for the synthesis of N-
Fmoc-BTS is the O-protected aldehyde 6 (Scheme 1). We
chose benzyl protection for both amino and hydroxy groups
in -serine derivative 2, because it can, in principle, be sim-
ultaneously removed from both groups by a single hydro-
genolysis step. Starting from O-benzyl -serine methyl ester
hydrochloride 1, the N-Bzl protected amino alcohol 3 was
obtained nearly quantitatively after N-benzoylation and Li-
AlH4 reduction. Compound 3 was treated with monome-
thyl tartrate derivative 4, in the presence of PyBrOP as a
coupling reagent and DIPEA as a base in CH2Cl2, to afford
amide 5 in 70% yield after chromatography. No epimeriz-
ation of the stereocenters in 5 occurred during the coupling
reaction. Oxidation of 5 to the corresponding aldehyde 6
was troublesome, due to the great instability of this product.
We initially carried out the oxidation by a Swern reaction,
with DIPEA as a base, but the major product in the crude
reaction mixture was the α,β-unsaturated aldehyde 7 in a
4:1 ratio (determined by 1H NMR analysis) with the desired
compound 6. Abstraction of the α-proton from β-benzyloxy
aldehyde 6 during the Swern oxidation should be base-as-
sisted, as already reported for similar aldehydes.[9] Aldehyde
6 could also suffer from acid sensitivity, since no traces of
6 were recovered after an attempt to separate the two alde-
hydes by chromatography on silica gel, whereas pure 7 was
obtained in 72% yield. The best method to prevent the
base-assisted elimination appeared to be the use of the
DessϪMartin reagent[10] to perform the oxidation and
avoidance of the purification of the crude aldehyde. The
oxidation of 5 was complete in 30 min at room temperature
in CH2Cl2, affording aldehyde 6 in sufficiently pure form
1
observed by H NMR analysis of the crude reaction mix-
ture. No epimerization of the stereocenters occurred in the
course of the cyclization, as observed in other cases,[2] and
lactam 8 was thus obtained as a single diastereoisomer with
the C-4 side chain in exo orientation: the presence of a sing-
let for proton 5-H in the 1H NMR spectrum was consistent
with this stereochemistry for BTAa lactams.[2] Reduction of
Scheme 1
874
Scheme 2
Eur. J. Org. Chem. 2002, 873Ϫ880

Bicyclic Compounds Derived from Tartaric Acid and α-Amino Acids (BTAas)
FULL PAPER
the amide bond (please note that the numbering system of
the BTAa skeleton changes when the lactam moiety is re-
duced to an amine) by BH3·DMS[11] in refluxing THF
(15 min) was not completely selective, since compound 9
(56% after chromatography) was obtained along with the
amino alcohol 10 (19%) derived from COOMe reduction.
A shorter reduction time improved the selectivity but
lowered the degree of conversion into 9. However, when the
reaction was instead carried out at room temperature for
20 h, the selectivity was complete, providing only 9 in 68%
yield after chromatographic purification. Complete de-
benzylation of 9 was attempted by hydrogenolysis over
Pd(OH)2. However, all experiments always furnished a 1:2.5
mixture of the desired amino alcohol 12 together with com-
pound 11, still with the OH protection. It is possible that
the initial formation of a certain amount of free amine
Scheme 3
might poison the Pd catalyst, thus preventing further O-Bzl
deprotection. Failed or only partial O-Bzl deprotection by
hydrogenolysis over Pd catalysts in the presence of amines
has been reported.[12] The mixture of compounds 11 and 12
was not separated and was directly used for the N-Fmoc
protection with Fmoc-O-succinimide in CH2Cl2. After 24 h
at room temperature, a 1:2.5 mixture of N-Fmoc-protected
compounds 14 and 13 was quantitatively obtained. Because
of the presence of the N-Fmoc protecting group, O-de-
benzylation by hydrogenation had to be avoided, and we
therefore tried a procedure reported for the deprotection of
polybenzylated sugars, based on the use of Lewis acids such
as SnCl4 and TiCl4, in which the coordination of the metal
ion to three oxygen atoms is followed by the attack of a
chloride anion at the benzylic position.[13] In our case, by
carrying out the reaction on the mixture of 13 and 14 (sep-
aration of 13 and 14 was avoided) with TiCl4 in CH2Cl2
we obtained (after 90 min at room temperature) a complete
conversion of the mixture into the target compound 14
(51% yield after chromatography). Finally, oxidation of 14
to the α-amino acid 15 was performed with PDC in DMF,
affording 15 in 50% yield after chromatography (the conver-
The benzyl alcohol elimination observed in the course of
the oxidation of 5 to give 7 was exploited in an attempt to
synthesize the 2endo epimer of BTS, which formally derives
from the combination of (R,R)-tartaric acid and -serine
(Scheme 4). Thus, aldehyde 7 was subjected to the usual
cyclization conditions, which afforded the cyclic compound
18 in 28% yield after chromatography, along with the hemi-
acetal intermediate 19 in 27% yield. The low yield of com-
pound 18 was plausibly due to the presence of an sp2 C-
4 atom, which would make the second cyclization step of
intermediate 19, which decomposes under the reaction con-
ditions, to 18 more difficult. In fact, when 19 was again
subjected to the cyclization conditions we observed only
1
48% conversion into 18 (by H NMR). This result is con-
sistent with that obtained in the cyclization of the phenyl-
glycine derivative analogue,[2] in which the slow cyclization
step of the hemiacetal intermediate resulted in its degrada-
tion in refluxing toluene. In that case, substitution of tolu-
ene with the lower boiling benzene reduced the extent of
1
sion was 87% after 24 h according to H NMR analysis of
the crude reaction mixture). A higher yield was obtained
when the reaction was carried out with the Jones oxidant,
which furnished 15 in 80% yield after 24 h at room temper-
ature.
Because of the difficulties encountered in removing the
O-benzyl group in the presence of the free amine group, we
tried a selective deprotection with lactam 8 (Scheme 3).
Thus, hydrogenolysis of 8 in the presence of 5% Pd/C in
EtOH afforded OH-deprotected compound 16 in 75% yield
after chromatography. O-Debenzylation was slower (48 h)
when Pd(OH)2 was used as catalyst in MeOH. Unfortu-
nately, the subsequent BH3 reduction of the lactam to an
amino group did not afford the amino alcohol 17 in a yield
higher than 26% under the best conditions. Successive de-
protection of the N atom by hydrogenolysis in the presence
of Pd(OH)2 and protection as the Fmoc derivative afforded
target compound 14 in 94% yield. The overall yield of 14
by this sequence was 8%, similar to the yield (11%) ob-
tained by the first methodology.
Scheme 4
Eur. J. Org. Chem. 2002, 873Ϫ880
875

N. Cini, F. Machetti, G. Menchi, E. G. Occhiato, A. Guarna
FULL PAPER
tallized from MeOH/Et2O at 0 °C. Pure 1 (5.36 g, 85%) was ob-
tained as a white solid. M.p. 164Ϫ166 °C. [α]2D0 ϭ ϩ6.9 (c ϭ 1.00,
decomposition of this intermediate. In the current case, de-
gradation of α,β-unsaturated aldehyde by heating under
acid conditions could also cause loss of starting material.
1
MeOH) (ref.[14] [α]D ϭ ϩ6.9). H NMR (DMSO): δ ϭ 7.36Ϫ7.30
(m, 5 H, OCH2Ph), 4.53 (AB, J ϭ 6.1 Hz, 2 H, OCH2Ph), 4.34 (t,
J ϭ 4.0 Hz, 1 H, 2-H), 3.85 (d, J ϭ 4.0 Hz, 2 H, 3-H2), 3.73 (s, 3
H, COOMe), 3.36 (br, 2 H, NH3ϩ).
Finally, selective hydroboration with
1 equiv. of
BH3·DMS for 3 h at room temperature failed to give com-
pound 20 in a yield higher than 10%, because of the low
degree of conversion under these conditions. Instead, one-
pot BH3 reduction and hydroboration of 18 with an excess
of BH3·DMS (3 equiv.) for 5 h at room temperature af-
forded 2endo-BTS derivative 21 as a single diastereoisomer
in 43% yield after chromatography. The presence of a doub-
let at δ ϭ 5.86 in the 1H NMR spectrum of 20, attributable
to the 5-H proton, is consistent with the 4endo stereochem-
istry of 20 (and, by extension, of the 2endo stereochemistry
of 21) derived from the completely selective exo approach
of the borane onto the double bond.
Methyl (2S)-2-(Benzoylamino)-3-benzyloxypropanoate (2): Et3N
(4.1 mL, 29.8 mmol) and benzoyl chloride (2.1 mL, 18.1 mmol)
were slowly added at 0 °C under nitrogen to a solution of 1 (3.67 g,
14.9 mmol) in dry THF (27 mL). The mixture was stirred at room
temperature for 15 h. Brine (10 mL) was added to this solution,
and the aqueous layer was extracted with Et2O and CH2Cl2 and
dried with Na2SO4. After evaporation of the solvent, compound 2
(5.0 g) was obtained as a yellow oil, used in the next step without
1
purification. H NMR (CDCl3): δ ϭ 7.79Ϫ7.74 (m, 2 H, CHmeta),
7.51Ϫ7.32 (m, 3 H, CHortho and CHpara), 7.29Ϫ7.21 (m, 5 H,
OCH2Ph), 6.99 (br. d, J ϭ 7.8 Hz, 1 H, NH), 4.92 (dt, J ϭ 7.8,
3.0 Hz, 1 H, 2-H), 4.49 (AB, J ϭ 6.3 Hz, 2 H, OCH2Ph), 3.95 (dd,
J ϭ 10.0, 3.0 Hz, 1 H, 3-H), 3.76 (dd, J ϭ 10.0, 3.0 Hz, 1 H, 3-H),
3.72 (s, 3 H, COOMe).
(2R)-(؉)-2-(N-Benzylamino)-3-benzyloxy-1-propanol (3):[15] A solu-
tion of 2 (5.0 g, 15.9 mmol) in dry THF (30 mL) was added drop-
wise at 0 °C and under nitrogen to a suspension of LiAlH4 (2.1 g,
55.3 mmol) in dry THF (40 mL). The mixture was refluxed for 8 h,
and was then stirred at room temperature overnight. A solution of
KOH (0.4 , 4 mL) was then slowly added to the mixture, cooled
with an ice bath, and after 5 min, 8 mL of H2O were added and
the suspension was refluxed for 30 min. The hot reaction mixture
was filtered through a Celite layer and diluted with CH2Cl2, and
the organic phase was separated and dried with Na2SO4. After
evaporation of the solvent, compound 3 (4.23 g, 98%) was obtained
Conclusion
In conclusion, we have demonstrated that, starting from
(R,R)-tartaric acid and -serine, the synthesis of the BTS
scaffold with a 2exo-CH2OH functional group is possible
by two different methodologies, in acceptable 8 and 11%
overall yields after 9 steps. Interestingly, by starting from
the same natural -amino acids, we found that it was pos-
sible to prepare the 2endo-substituted compound, formally
derived from the combination of tartaric acid with the -
serine, by exploiting the α,β-unsaturated aldehyde formed
in the Swern oxidation process. The oxidation of the C-2
carbinol group in compound 14 gave rise to a novel, con-
formationally constrained, α-amino acid 15, which may find
application in peptidomimetic synthesis.
as a yellow oil. [α]2D0 ϭ ϩ12.9 (c ϭ 1.40, CHCl3) (ref.[15] [α]D
ϭ
ϩ13.3). 1H NMR (CDCl3): δ ϭ 7.36Ϫ7.26 (m, 10 H, 2 ϫ Ph), 4.48
(s, 2 H, OCH2Ph), 3.79 (s, 2 H, NCH2Ph), 3.76Ϫ3.44 (m, 4 H, 1-
H2, 3-H2), 2.92 (m, 1 H, 2-H).
Methyl (2R,3R)-(؊)-N-Benzyl-NЈ-[(1R)-1-benzyloxymethyl-2-hy-
droxyethyl]-2,3-di-O-isopropylidenetartramate (5): A solution of 4
(2.94 g, 14.4 mmol) in dry CH2Cl2 (46 mL), PyBrOP (6.72 g,
14.4 mmol), and DIPEA (5.0 mL, 28.8 mmol) were added at 0 °C
under nitrogen to a solution of 3 (3.90 g, 14.4 mmol) in anhydrous
CH2Cl2 (50 mL; CH2Cl2 was filtered through a short pad of
Na2CO3 just before being used). The mixture was stirred at 0 °C
for 20 min and then at room temperature overnight. After evapora-
tion of the solvent, the oil obtained was dissolved in EtOAc and
filtered through a short layer of Celite. The solution was washed
with aqueous 5% KHSO4, 5% NaHCO3, and brine, and dried with
Na2SO4. After evaporation of the solvent, the crude product was
Experimental Section
General: All reactions requiring dry conditions were performed un-
der nitrogen and in anhydrous solvents. Chromatographic separa-
tions were performed under pressure on silica gel by flash-column
techniques; Rf values refer to TLC carried out on 25-mm silica gel
plates (Merck F254), with the same eluent as indicated for the col-
umn chromatography. Melting points are uncorrected. IR spectra
were recorded with a PerkinϪElmer 881 spectrophotometer in
CDCl3 solution. 1H NMR (200 MHz) and 13C NMR (50 MHz)
spectra were recorded with a Varian XL 200 instrument in CDCl3
solution. Mass spectra were carried out by EI at 70 eV on 5790A-
5970A HewlettϪPackard and QMD 1000 Carlo Erba instruments.
Electron-Spray Mass Spectra were recorded with a PE SCIEX API
purified by chromatography (EtOAc/petroleum ether, 1:2, Rf
ϭ
0.1), to yield 5 (4.61 g, 70%) as a yellow oil. [α]2D0 ϭ Ϫ39.8 (c ϭ
1
0.67, CHCl3). H NMR (CDCl3) (2:1 mixture of rotamers). Major
Rotamer: δ ϭ 7.34Ϫ7.24 (m, 10 H, 2 ϫ Ph), 5.32 (d, J ϭ 5.8 Hz, 1
H, OCHCON), 5.08 (d, J ϭ 17.2 Hz, 1 H, NCH2Ph), 4.83 (d, J ϭ
5.8 Hz, 1 H, OCHCOOMe), 4.63 (d, J ϭ 17.2 Hz, 1 H, NCH2Ph),
4.39 (s, 2 H, OCH2Ph), 3.86Ϫ3.55 (m, 5 H, CH2OH, CH2OBzl,
CHN), 3.74 (s, 3 H, OMe), 2.18 (br. s, 1 H, OϪH), 1.43 (s, 3 H,
CMe), 1.42 (s, 3 H, CMe); Minor Rotamer: δ ϭ 7.34Ϫ7.24 (m, 10
H, 2 ϫ Ph), 5.37 (d, J ϭ 5.4 Hz, 1 H, OCHCON), 5.15 (d, J ϭ
5.4 Hz, 1 H, OCHCOOMe), 4.78 (d, J ϭ 16.0 Hz, 1 H, NCH2Ph),
365 instrument. Microanalyses were carried out with
PerkinϪElmer 2400/2 elemental analyzer. Optical rotations were
determined with a JASCO DIP-370 instrument.
a
Methyl (2S)-2-Amino-3-benzyloxypropanoate Hydrochloride (1):[14]
HCl (37%, 4.2 mL) was added dropwise at 0 °C to a solution of O- 4.60 (d, J ϭ 16.0 Hz, 1 H, NCH2Ph), 4.39 (s, 2 H, OCH2Ph),
benzyl--serine (5.0 g, 25.6 mmol) in 2,2-dimethoxypropane 3.86Ϫ3.55 (m, 5 H, CH2OH, CH2OBzl, CHN), 3.77 (s, 3 H, OMe),
(25 mL) and the mixture was stirred at room temperature for 48 h.
Evaporation of the solvent gave a crude product, which was recrys-
2.18 (br. s, 1 H, OϪH), 1.45 (s, 3 H, CMe), 1.40 (s, 3 H, CMe).
13C NMR (CDCl3) (2:1 mixture of rotamers): δ ϭ 171.0 (s, CϭO,
876
Eur. J. Org. Chem. 2002, 873Ϫ880

Bicyclic Compounds Derived from Tartaric Acid and α-Amino Acids (BTAas)
FULL PAPER
one rotamer), 170.5 (s, CϭO, one rotamer), 169.6 (s, CϭO, one (8): A solution of 6 (2.03 g, 4.37 mmol) in benzene (70 mL) was
rotamer), 169.4 (s, CϭO, one rotamer), 138.4 (s, Ph), 137.7 (s, Ph), quickly added to a refluxing suspension of H2SO4/SiO2 (2.40 g, g/
137.4 (s, Ph), 136.6 (s, Ph), 128.6 (d, Ph), 128.3 (d, Ph), 128.2 (d, g ratio 0.36) in benzene (130 mL). The mixture was allowed to react
Ph), 127.9 (d, Ph), 127.6 (d, Ph), 127.5 (d, Ph), 127.4 (d, Ph), 127.3
(d, Ph), 126.8 (d, Ph), 126.6 (d, Ph), 113.0 (s, CMe2, one rotamer), reaction mixture was filtered through a short layer of NaHCO3,
112.7 (s, CMe2, one rotamer), 76.5 (d, OCHCON), 76.2 (d, OCH- and the solvent was evaporated. The residue was dissolved in
for 20 min and half of the solvent was then distilled off. The hot
COOMe), 73.0 (t, OCH2Ph, one rotamer), 72.8 (t, OCH2Ph, one CH2Cl2, 60 mL of saturated aqueous NaHCO3 containing 2.2 g of
rotamer), 68.9 (t, CH2OBzl, one rotamer), 68.1 (t, CH2OBzl, one Na2S2O3 was then added, and the mixture was stirred for 5 min.
rotamer), 62.4 (t, CH2OH, one rotamer), 60.9 (t, CH2OH, one rot-
The organic phase was washed with saturated aqueous NaHCO3
amer), 60.8 (d, CHN, one rotamer), 58.2 (d, CHN, one rotamer), and water, and dried with Na2SO4. After evaporation of the solv-
52.3 (q, OMe), 51.8 (t, NCH2Ph, one rotamer), 45.7 (t, NCH2Ph, ent, the crude product was purified by chromatography (EtOAc/
one rotamer), 26.2 (q, CMe, one rotamer), 26.1 (q, 2 C, CMe, both
petroleum ether, 1:2, Rf ϭ 0.26), yielding 8 (990 mg, 57%) as a
1
rotamers), 26.0 (q, CMe, one rotamer). MS m/z (%) ϭ 457 (0.3) white solid. m.p. 68Ϫ70 °C. [α]2D7 ϭ Ϫ24.4 (c ϭ 0.54, CHCl3). H
[Mϩ], 366 (3), 336 (21), 275 (0.2), 159 (10), 91 (100). IR (CDCl3): NMR (CDCl3): δ ϭ 7.34Ϫ7.09 (m, 10 H, 2 ϫ Ph), 5.90 (s, 1 H, 5-
Ϫ1
˜
ν ϭ 3440 (OϪH), 1740 (OϪCϭO), 1634 (NϪCϭO) cm
.
H), 5.06 (d, J ϭ 16.0 Hz, 1 H, NCH2Ph), 4.93 (s, 1 H, 7-H), 4.70
C25H31NO7 (457.5): calcd. C 65.63, H 6.83, N 3.06; found C 65.35, (s, 1 H, 1-H), 4.44 (s, 2 H, OCH2Ph), 4.05 (d, J ϭ 16.0 Hz, 1 H,
H 6.88, N 2.85.
NCH2Ph), 3.77 (s, 3 H, OMe), 3.65Ϫ3.32 (m, 3 H, 4-H, CH2OBzl).
13C NMR (CDCl3): δ ϭ 168.7 (s, CϭO), 165.7 (s, CϭO), 137.0 (s,
1 C, Ph), 135.8 (s, 1 C, Ph), 128.5 (d, 2 C, Ph), 128.2 (d, 2 C, Ph),
127.6 (d, 1 C, Ph), 127.4 (d, 1 C, Ph), 127.3 (d, 2 C, Ph), 127.2 (d,
2 C, Ph), 101.0 (d, 5-C), 77.6 (d, 1-C), 77.2 (d, 7-C), 73.0 (t,
OCH2Ph), 67.4 (t, CH2OBzl), 59.0 (d, 4-C), 52.4 (q, OCH3), 46.3
(t, NCH2Ph). MS m/z (%) ϭ 397 (0.4) [Mϩ], 306 (3), 215 (0.2), 91
Methyl (2R,3R)-N-Benzyl-NЈ-[(1S)-1-benzyloxymethyl-1-formylme-
thyl]-2,3-di-O-isopropylidenetartramate (6): The DessϪMartin
periodinane (2.73 g, 6.44 mmol) was added under nitrogen to a so-
lution of 5 (2.00 g, 4.37 mmol) in anhydrous CH2Cl2 (120 mL). The
reaction mixture was stirred at room temperature for 30 min, and
the homogeneous solution was then diluted with Et2O (30 mL) and
filtered quickly through a Celite layer. After evaporation of the
solvent, product 6 (2.03 g) was obtained as a white solid (decom-
poses on heating) and used directly for the next step without puri-
fication. 1H NMR (CDCl3): δ ϭ 9.38 (s, 1 H, CHO), 7.37Ϫ7.24
(m, 10 H, 2 ϫ Ph), 5.32 (d, J ϭ 6.0 Hz, 1 H, OCHCON), 5.24 (d,
J ϭ 16.0 Hz, 1 H, NCH2Ph), 4.98 (d, J ϭ 6.0 Hz, 1 H, OCH-
COOMe), 4.62 (d, J ϭ 16.0 Hz, 1 H, NCH2Ph), 4.43 (s, 2 H,
OCH2Ph), 4.07 (dd, J ϭ 8.0, 2.0 Hz, 1 H, CH2OBzl), 3.87 (m, 2
H, CH2OBzl, CHN), 3.74 (s, 3 H, OMe), 1.46 (s, 3 H, CMe), 1.41
(s, 3 H, CMe).
˜
(100), 59 (3). IR (CDCl3): ν ϭ 1753 (OϪCϭO), 1667 (NϪCϭO)
cmϪ1. C22H23NO6 (397.3): calcd. C 66.48, H 5.83, N 3.52; found
C 66.84, H 5.95, N 3.33.
(؊)-Methyl (1S,2S,5S,6R)-3-Benzyl-2exo-(benzyloxymethyl)-7,8-
dioxa-3-azabicyclo[3.2.1]octane-6exo-carboxylate (9) and
(؊)-(1S,2S,5S,6S)-3-Benzyl-2exo-(benzyloxymethyl)-6exo-hydroxy-
methyl-7,8-dioxa-3-azabicyclo[3.2.1]octane (10):
A solution of
BH3·Me2S (10 , 30 µL, 0.295 mmol) was added over 2 min under
nitrogen to a refluxing solution of 8 (350 mg, 0.88 mmol) in anhyd-
rous THF (10 mL) and the mixture was stirred for 15 min. The
mixture was then immediately cooled with an ice bath. The solvent
was evaporated and the crude product was dissolved in dioxane
(11 mL), followed by addition of TMEDA (160µL, 1.06 mmol).
The mixture was left to react at room temperature for 30 min, the
solvent was then evaporated, and the residue was suspended in di-
ethyl ether and carefully filtered through a short Celite layer. After
evaporation of the solvent, a mixture of product 9 and amino alco-
hol 10 (3:1) was obtained. Purification by chromatography (EtOAc/
petroleum ether, 1:2) gave pure 9 (190 mg, 56%, Rf ϭ 0.53) and 10
(60 mg, 19%, Rf ϭ 0.23). Compound 9 was also prepared from 8
(350 mg, 0.88 mmol) in anhydrous THF (10 mL) as described
above, by adding a 10  BH3·DMS solution at room temperature
and stirring for 20 h. Compound 9: [α]2D6 ϭ Ϫ31.7 (c ϭ 1.23,
CHCl3). 1H NMR (CDCl3): δ ϭ 7.32Ϫ7.23 (m, 10 H, 2 ϫ Ph), 5.73
(d, J ϭ 1.8 Hz, 1 H, 1-H), 4.69 (s, 1 H, 6-H), 4.55 (s, 1 H, 5-H),
4.48 (s, 2 H, OCH2Ph), 3.84 (d, J ϭ 15.4 Hz, 1 H, NCH2Ph), 3.73
(s, 3 H, OMe), 3.64 (m, 2 H, CH2OBzl), 3.51 (d, J ϭ 15.4 Hz, 1
H, NCH2Ph), 3.11 (m, 1 H, 2-H), 2.81 (dd, J ϭ 12.1, 1.4 Hz, 1 H,
4-H), 2.48 (dd, J ϭ 12.2, 1.4 Hz, 1 H, 4-H). 13C NMR (CDCl3):
δ ϭ 171.5 (s, CϭO), 138.4 (s, 1 C, Ph), 137.9 (s, 1 C, Ph), 128.3 (d,
2 C, Ph), 128.2 (d, 4 C, Ph), 127.5 (d, 1 C, Ph), 127.3 (d, 2 C, Ph),
127.1 (d, 1 C, Ph), 102.4 (d, 1-C), 76.9 (d, 6-C), 75.6 (d, 5-C), 73.2
(t, OCH2Ph), 64.3 (t, CH2OBzl), 60.4 (d, 2-C), 57.4 (t, 4-C), 52.2
(q, OMe), 49.6 (t, NCH2Ph). MS m/z (%) ϭ 325 (0.8), 234 (20), 91
Methyl (2R,3R)-(؊)-N-Benzyl-NЈ-(1-formylvinyl)-2,3-di-O-isoprop-
ylidenetartramate (7): A solution of (COCl)2 (378 µL, 4.40 mmol)
in dry CH2Cl2 (10 mL) was cooled to Ϫ60 °C under nitrogen, and
anhydrous DMSO (590 µL, 8.31 mmol) was added slowly at such
a rate as to keep the temperature constant. After 5 min, a solution
of 5 (1.77 g, 3.87 mmol) in dry CH2Cl2 (12 mL) was added drop-
wise, maintaining the temperature at Ϫ60 °C. The mixture was
stirred for 15 min, DIPEA (2.77 mL, 15.9 mmol) was then added,
and after 10 min the reaction mixture was left to warm to room
temperature, followed by addition of water (15 mL). The organic
phase was washed with water and dried with Na2SO4, and after
evaporation of the solvent a mixture of 7 and 6 (4:1) was obtained.
Purification by chromatography (Et2O/petroleum ether, 2:1, Rf ϭ
0.25) gave only 7 (968 mg, 72%) as a yellow oil. [α]2D0 ϭ Ϫ14.2 (c ϭ
0.31, CHCl3). 1H NMR (CDCl3): δ ϭ 9.36 (s, 1 H, CHO),
7.32Ϫ7.16 (m, 5 H, Ph), 6.10 (s, 1 H, CϭCH2), 5.97 (s, 1 H, Cϭ
CH2), 5.17 (d, J ϭ 5.2 Hz, 1 H, OCHCON), 4.77Ϫ4.64 (m, 3 H,
NCH2Ph, OCHCOOMe), 3.73 (s, 3 H, OMe), 1.38 (s, 3 H, CMe),
1.36 (s, 3 H, CMe). 13C NMR (CDCl3): δ ϭ 188.5 (d, CHO), 170.7
(s, CϭO), 168.7 (s, CϭO), 146.2 (s, CϭCH2), 136.1 (s, 1 C, Ph),
128.6 (d, 2 C, Ph), 128.6 (d, 1 C, Ph), 127.9 (d, 2 C, Ph), 113.5 (s,
CMe2), 113.5 (t, CϭCH2), 76.7 (d, OCHCON), 76.5 (d, OCH-
COOMe), 52.6 (q, OCH3), 51.3 (t, NCH2Ph), 26.4 (q, CMe), 25.9
(q, CMe). MS m/z (%) ϭ 347 (0.3) [Mϩ], 159 (12), 91 (100), 59 (15).
IR (CDCl3): ν˜ ϭ 1750 (OϪCϭO), 1707 (H-CϭO), 1667 (NϪCϭO)
cmϪ1. C18H21NO6 (347.4): calcd. C 62.23, H 6.09, N 4.03; found
C 62.58, H 6.45, N 4.34.
(100), 59 (3). IR (CDCl3): ν ϭ 1757 (OϪCϭO) cmϪ1. C22H25NO5
˜
(383.4): calcd. C 68.92, H 6.57, N 3.65; found C 68.56, H 6.59, N
3.38. Compound 10: [α]2D5 ϭ Ϫ41.9 (c ϭ 0.43, CHCl3). 1H NMR
(CDCl3): δ ϭ 7.34Ϫ7.23 (m, 10 H, 2 ϫ Ph), 5.56 (d, J ϭ 1.6 Hz, 1
(؊)-Methyl (1R,4S,5S,7R)-3-Benzyl-4exo-(O-benzylhydroxy- H, 1-H), 4.48 (s, 2 H, OCH2Ph), 4.35 (t, J ϭ 5.1 Hz, 1 H, 6-H),
methyl)-2-oxo-6,8-dioxa-3-azabicyclo[3.2.1]octane-7exo-carboxylate 4.17 (s, 1 H, 5-H), 3.85 (d, J ϭ 13.6 Hz, 1 H, NCH2Ph), 3.65 (m,
Eur. J. Org. Chem. 2002, 873Ϫ880
877

N. Cini, F. Machetti, G. Menchi, E. G. Occhiato, A. Guarna
FULL PAPER
2 H, CH2OBzl), 3.55 (m, 2 H, CH2OH), 3.50 (d, J ϭ 13.6 Hz, 1 4.64Ϫ4.21 (m, 5 H ϩ 5 H), 3.91Ϫ3.24 (m, 5 H ϩ 5 H), 3.79 (s, 3
H, NCH2Ph), 3.09 (m, 1 H, 2-H), 2.77 (dd, J ϭ 11.7, 1.8 Hz, 1 H, H, OMe minor rotamer), 3.75 (s, 3 H, OMe major rotamer), 1.92
4-H), 2.34 (dd, J ϭ 11.7, 1.8 Hz, 1 H, 4-H), 2.63 (br. s, 1 H, OϪH). (br. s, 1 H, OϪH). 13C NMR (CDCl3) (3:2 mixture of rotamers):
13C NMR (CDCl3): δ ϭ 138.7 (s, 1 C, Ph), 138.0 (s, 1 C, Ph), 128.4 δ ϭ 170.3 (s, CϭO), 156.0 (s, NCϭO, one rotamer), 155.8 (s, NCϭ
(d, 2 C, Ph), 128.3 (d, 2 C, Ph), 128.2 (d, 2 C, Ph), 127.6 (d, 1 C, O, one rotamer), 143.5 (s, 2 C), 141.3 (s, 2 C), 127.7 (d, 2 C), 127.2
Ph), 127.5 (d, 2 C, Ph), 127.0 (d, 1 C, Ph), 101.3 (d, 1-C), 77.9 (d, (d, 2 C), 124.6 (d, 2 C), 119.9 (d, 2 C), 100.9 (d, C-1, one rotamer),
6-C), 74.6 (d, 5-C), 73.3 (t, OCH2Ph), 64.8 (t, CH2OBzl), 64.2 (t, 100.2 (d, C-1, one rotamer), 75.5 (d, C-6, one rotamer), 75.3 (d, C-
CH2OH), 60.9 (d, 2-C), 57.7 (t, 4-C), 49.6 (t, NCH2Ph). MS m/z 5), 75.1 (d, C-6, one rotamer), 67.2 (t, CH2OCO, one rotamer),
(%) ϭ 355 (0.4) [Mϩ], 324 (2), 234 (90), 173 (2.5), 91 (100), 59 (3). 67.1 (t, CH2OCO, one rotamer), 60.5 (t, CH2OH, one rotamer),
IR (CDCl3): ν˜ ϭ 3591 (OϪH) cmϪ1. C21H25NO4 (355.4): calcd. C
70.96, H 7.09, N 3.94; found C 70.98, H 7.45, N 3.96.
60.1 (t, CH2OH, one rotamer), 57.1 (d, C-2, one rotamer), 57.0 (d,
C-2, one rotamer), 52.6 (q, OMe), 47.4 (d, CH of FMOC, one
rotamer), 47.2 (d, CH of FMOC, one rotamer), 45.3 (t, C-4, one
rotamer), 44.8 (t, C-4, one rotamer). ESI-MS: m/z ϭ 426 [Mϩ·H],
Methyl (1S,2S,5S,6R)-2exo-(Benzyloxymethyl)-7,8-dioxa-3-azabicy-
clo[3.2.1]octane-6exo-carboxylate (11) and Methyl (1S,2S,5S,6R)-2-
exo-hydroxymethyl-7,8-dioxa-3-azabicyclo[3.2.1]octane-6exo-
carboxylate (12): A solution of 9 (190 mg, 0.496 mmol) in MeOH
(7 mL) was added to a suspension of 20% Pd(OH)2/C (32 mg) in
ϩ
˜
448 [M ·Na]. IR (CDCl3): ν ϭ 3600 (OϪH), 1740 (OϪCϭO), 1692
(OϪCO-N) cmϪ1. C23H23NO7 (425.4): calcd. C 64.93, H 5.45, N
3.29; found C 64.46, H 5.74, N 2.88.
MeOH (6 mL). The reaction mixture was left under H2 overnight at (؉)-(1S,2S,5S,6R)-3-(9-Fluorenylmethoxycarbonyl)-6exo-meth-
room temperature and the catalyst was then removed by filtration oxycarbonyl-7,8-dioxa-3-azabicyclo[3.2.1]octane-2exo-carboxylic
through a Celite layer and washed with MeOH. The solution was Acid (15). ؊ Method A: Pyridinium dichromate (PDC, 154 mg,
filtered through a column filled with Amberlyst A-21 beads to af- 0.409 mmol) was added at 0 °C under nitrogen to a solution of 14
ford, after evaporation of the solvent, a 2.5:1 mixture of 11 and 12
(50 mg, 0.117 mmol) in dry DMF (1 mL). After the mixture had
(150 mg, quantitative yield), which was used without separation for been stirred at room temperature for 24 h, water (10 mL) was ad-
1
the next step. H NMR (CDCl3) (2.5:1 mixture of 11 and 12): δ ϭ
7.32Ϫ7.24 (m, 5 H, Ph), 5.70 (br, 1 H, NϪH), 5.59 (s 1 H, 1-H), Na2SO4. After purification by chromatography (CH2Cl2/MeOH,
5.45 (s, 1 H, 1-H), 4.73 (s, 1 H, 6-H), 4.65 (s, 1 H, 6-H), 4.51 (s, 4 H, 20:1), pure 15 (26 mg, 50%, Rf ϭ 0.14) was obtained. Method B:
ded, and the solution was extracted with Et2O and dried with
5-H, OCH2Ph), 3.75 (s, 6 H, OMe), 3.62Ϫ3.45 (m, 4 H, CH2OH, Jones’ reagent (82.5 mg of CrO3, 150 µL of H2SO4, 1.1 mL of H2O)
CH2OBzl), 3.23 (dd, J ϭ 13.1, 2.2 Hz, 1 H, 4-H), 3.08 (m, 1 H, 4- was added at 0 °C to a solution of 14 (50 mg, 0.117 mmol) in acet-
H), 2.91 (t, J ϭ 7.0 Hz, 1 H, 2-H), 2.75Ϫ2.63 (m, 3 H, 2-H, 4-H), one (1 mL). The mixture was stirred at room temperature for 24 h,
2.44 (br, 1 H, OϪH). Compound 12 can be prepared according to
the procedure described above, starting from 17 (45 mg,
and 2-propanol (5 mL) was added. After filtration through a short
Celite layer, the solvent was evaporated. Pure product 15 (40 mg,
0.153 mmol). After evaporation of the solvent, 12 (30 mg) was ob- 80%, Rf ϭ 0.14) was obtained by chromatography according to
1
1
tained in quantitative yield and used directly for the next step. H
NMR (CDCl3): δ ϭ 5.45 (s, 1 H, 1-H), 4.65 (s, 1 H, 6-H), 4.51 (s, mixture of rotamers): δ ϭ 7.72Ϫ7.68 (m, 2 H ϩ 2 H), 7.53Ϫ7.45
1 H, 5-H), 3.75 (s, 3 H, OMe), 3.62Ϫ3.45 (m, 2 H, CH2OH), 3.08 (m, 2 H ϩ 2 H), 7.38Ϫ7.24 (m, 4 H ϩ 4 H), 6.02 (s, 1 H, 1-H,
(m, 1 H, 4-H), 2.75Ϫ2.63 (m, 2 H, 2-H, 4-H), 2.41 (br. s, 1 H, minor rotamer), 5.96 (s, 1 H, 1-H, major rotamer), 4.73Ϫ4.10 (m,
Method A. [α]2D3 ϭ ϩ8.4 (c ϭ 0.22, CHCl3). H NMR (CDCl3, 2:1
OϪH).
5 H ϩ 5 H), 3.88 (m, 1 H ϩ 1 H), 3.76 (s, 3 H, OMe, minor
rotamer), 3.75 (s, 3 H, OMe, major rotamer), 3.56Ϫ3.45 (m, 2 H
ϩ 2 H). 13C NMR (CDCl3, 2:1 mixture of rotamers): δ ϭ 170.9 (s,
CϭO, one rotamer), 170.1 (s, CϭO, one rotamer), 169.1 (s), 156.1
(s, NCϭO, one rotamer), 155.7 (s, NCϭO, one rotamer), 143.4 (s,
2 C), 141.4 (s, 2 C), 127.8 (d, 2 C), 127.1 (d, 2 C), 124.7 (d, 2 C),
120.0 (d, 2 C), 100.1 (d, C-1, one rotamer), 99.6 (d, C-1, one rot-
amer), 75.6 (d, C-6), 75.2 (d, C-5), 69.7 (t, CH2OCO, one rotamer),
67.8 (t, CH2OCO, one rotamer), 59.1 (d, C-2, one rotamer), 58.8
(d, C-2, one rotamer), 52.7 (q, OMe), 47.2 (d, CH of FMOC, one
rotamer), 47.1 (d, CH of FMOC, one rotamer), 45.8 (t, C-4, one
(؉)-Methyl (1S,2S,5S,6R)-3-(9-Fluorenylmethoxycarbonyl)-2exo-
hydroxymethyl-7,8-dioxa-3-azabicyclo[3.2.1]octane-6exo-carb-
oxylate (14): FMOC-O-Su (383 mg) was added at 0 °C to a stirred
solution of the mixture of 11 and 12 (150 mg) in CH2Cl2 (15 mL).
The solution was stirred for 10 min at 0 °C and then for 24 h at
room temperature. The reaction mixture was then washed with
water (4 ϫ15 mL) and dried with Na2SO4. After evaporation of
the solvent, a 2.5:1 mixture of 13 and 14 (265 mg) was obtained.
TiCl4 (1 , 64 µL) in CH2Cl2 was added to a solution of this mix-
ture in dry CH2Cl2 (11 mL) and the resulting reaction mixture was
stirred at room temperature for 90 min. A saturated aqueous
NaHCO3 solution (10 mL) was then added. After separation, the
aqueous phase was extracted with CH2Cl2 and the combined or-
ganic phases were washed with brine and dried with Na2SO4. Pure
rotamer), 45.2 (t, C-4, one rotamer). ESI-MS: m/z ϭ 440 [Mϩ·H],
ϩ
˜
462 [M ·Na]. IR (CDCl3): ν ϭ 3500 (OϪH), 1756 (OϪCϭO), 1731
(OϪCϭO), 1710 [O-(CϭO)ϪN] cmϪ1. C23H21NO8 (439.4): calcd.
C 62.87, H 4.82, N 3.19; found C 63.11, H 4.98, N 2.95.
14 (117 mg, 51%, Rf ϭ 0.13) was obtained by chromatography (؊)-Methyl (1R,4S,5S,7R)-3-Benzyl-4exo-hydroxymethyl-2-oxo-6,8-
(CH2Cl2/MeOH, 40:1) as a white foamy solid. Compound 14 was dioxa-3-azabicyclo[3.2.1]octane-7exo-carboxylate (16): A solution
also prepared by starting from 12 as follows: FMOC-O-Su of 8 (350 mg, 0.881 mmol) in EtOH (15 mL) was added to a sus-
(101 mg, 0.229 mmol) was added at 0 °C to a stirred solution of 12
(30 mg, 0.148 mmol) in CH2Cl2 (5 mL). The solution was stirred
for 10 min at 0 °C and then for 24 h at room temperature. The
reaction mixture was washed with water (4ϫ5 mL) and dried with
Na2SO4. Purification by chromatography as above gave 14 (59 mg,
pension of 5% Pd/C (170 mg) in EtOH (15 mL). The reaction mix-
ture was left under H2 overnight at room temperature and the cata-
lyst was then removed by filtration through a layer of Celite and
washed with EtOH. The solution was filtered through a column
filled with Amberlyst A-21 beads to give, after evaporation of the
Rf ϭ 0.13) in 94% yield. [α]2D2 ϭ ϩ5.2 (c ϭ 0.25, CHCl3). 1H NMR solvent, pure 16 (203 mg, 75%) as a colorless oil. [α]2D5 ϭ Ϫ56.1
(CDCl3, 3:2 mixture of rotamers): δ ϭ 7.76 (d, J ϭ 8.0 Hz, 2 H ϩ (c ϭ 1.13, CHCl3). 1H NMR (CDCl3): δ ϭ 7.31Ϫ7.11 (m, 5 H,
2 H), 7.55 (d, J ϭ 8.0 Hz, 2 H ϩ 2 H), 7.43Ϫ7.24 (m, 4 H ϩ 4 H), Ph), 5.88 (s, 1 H, 5-H), 5.06 (d, J ϭ 14.0 Hz, 1 H, NCH2Ph), 4.91
5.69 (s, 1 H, 1-H minor rotamer), 5.60 (s, 1 H, 1-H major rotamer), (s, 1 H, 1-H), 4.68 (s, 1 H, 7-H), 4.05 (d, J ϭ 14.0 Hz, 1 H,
878
Eur. J. Org. Chem. 2002, 873Ϫ880

Bicyclic Compounds Derived from Tartaric Acid and α-Amino Acids (BTAas)
FULL PAPER
NCH2Ph), 3.73 (s, 3 H, OMe), 3.76Ϫ3.63 (m, 2 H, CH2OH), 3.23 a solution of 18 (70 mg, 0.242 mmol) in dry THF (2 mL). The solu-
(dd, J ϭ 6.0, 4.0 Hz, 1 H, 4-H). 13C NMR (CDCl3): δ ϭ 169.2 (s,
tion was stirred at room temperature for 3 h, and then H2O (2 mL),
CϭO), 166.3 (s, CϭO), 135.8 (s, 1 C, Ph), 128.8 (d, 2 C, Ph), 127.8 NaOH (30 µL), 35% H2O2 (30 µL) were added successively, and
(d, 1 C, Ph), 127.4 (d, 2 C, Ph), 101.6 (d, 5-C), 77.7 (d, 1-C), 77.4 the resulting mixture was heated at 50 °C for 1 h. Brine (20 mL)
(d, 7-C), 60.5 (d, 4-C), 59.8 (t, CH2OH), 52.8 (q, OCH3), 46.4 (t, was added and the mixture was extracted with CH2Cl2 and the
NCH2Ph), 2.90 (br. s, 1 H, OϪH). MS: m/z (%) ϭ 307 (6) [Mϩ], organic phase was dried with anhydrous Na2SO4. After solvent
276 (4), 216 (3), 91 (100), 59 (6). IR (CDCl3): ν˜ ϭ 3471 (OϪH), evaporation, the crude product was purified by chromatography
1752 (OϪCϭO), 1660 (NϪCϭO) cmϪ1. C15H17NO6 (307.2): calcd. (EtOAc/petroleum ether, 2:3, Rf ϭ 0.10) to afford pure 20 (10 mg,
C 58.65, H 5.58, N 4.56; found C 59.01, H 5.63, N 4.29.
10%) and starting material 18 (26 mg, 13%). [α]2D0 ϭ Ϫ6.13 (c ϭ
0.31, CH2Cl2). 1H NMR (CDCl3): δ ϭ 7.35Ϫ7.15 (m, 5 H, Ph),
5.86 (d, J ϭ 3.1 Hz, 1 H, 5-H), 5.37 (d, J ϭ 15.4 Hz, 1 H,
NCH2Ph), 5.03 (s, 1 H, 1-H), 4.71 (s, 1 H, 7-H), 4.00 (d, J ϭ
15.4 Hz, 1 H, NCH2Ph), 3.80 (s, 3 H, OMe), 3.80Ϫ3.74 (m, 2 H,
CH2OH), 3.40 (m, 1 H, 4-H), 1.77 (br. s, 1 H, OϪH). MS: m/z
(%) ϭ 307 (11) [Mϩ], 276 (8), 216 (8), 91 (100), 59 (5). IR (CDCl3):
(؊)-Methyl (1S,2S,5S,6R)-3-Benzyl-2exo-hydroxymethyl-7,8-dioxa-
3-azabicyclo[3.2.1]octane-6exo-carboxylate (17): This compound
was prepared according to the synthesis of 9, starting from 16
(180 mg, 0.586 mmol). After chromatography (EtOAc/petroleum
ether, 1:1, Rf ϭ 0.26), pure 17 (45 mg, 26%) was obtained as a
yellow oil. [α]2D5 ϭ Ϫ62.4 (c ϭ 0.91, CDCl3). 1H NMR (CDCl3):
δ ϭ 7.31Ϫ7.24 (m, 5 H, Ph), 5.72 (s, 1 H, 1-H), 4.74 (s, 1 H, 6-H),
4.64 (s, 1 H, 5-H), 3.88 (d, J ϭ 13.4 Hz, 1 H, NCH2Ph), 3.92Ϫ3.72
(m, 2 H, CH2OH), 3.75 (s, 3 H, OMe), 3.68 (d, J ϭ 13.4 Hz, 1 H,
NCH2Ph), 3.09 (m, 1 H, 4-H), 2.87 (m, 1 H, 2-H), 2.58 (m, 1 H,
4-H). 13C NMR (CDCl3): δ ϭ 171.5 (s, CϭO), 138.2, (s, 1 C, Ph),
128.4 (d, 4 C, Ph), 127.2, (d, 1 C, Ph), 103.1 (d, 1-C), 77.2 (d, 6-
C), 75.8 (d, 5-C), 61.1 (d, 2-C), 59.1 (t, CH2OH), 57.4 (t, 4-C), 52.5
(q, OCH3), 50.8 (t, NCH2Ph). MS m/z (%) ϭ 276 (8), 216 (3), 91
(100), 59 (10). IR (CDCl3): ν˜ ϭ 3614 (OϪH), 1743 (OϪCϭO)
cmϪ1. C15H19NO5 (293.2): calcd. C 61.45, H 6.53, N 4.78; found
C 61.74, H 6.51, N 4.53.
ν˜ ϭ 3468 (OϪH), 1756 (OϪCϭO), 1670 (NϪCϭO) cmϪ1
.
C15H17NO6 (307.2): calcd. C 58.65, H 5.58, N 4.56; found C 58.99,
H 5.73, N 3.89.
(؊)-Methyl (1S,2R,5S,6R)-3-Benzyl-2endo-hydroxymethyl-7,8-di-
oxa-3-azabicyclo[3.2.1]octane-6exo-carboxylate (21): BH3·Me2S in
THF (10 , 23.5 µL, 0.235 mmol) was added at 0 °C to a solution
of 18 (70 mg, 0.242 mmol) in dry THF (2 mL). The solution was
stirred at room temperature for 5 h, ethanol (2 mL), NaOH (30
µL), and 35% H2O2 (30 µL) were then added successively, and the
resulting mixture was heated at 50 °C for 1 h. Water (20 mL) was
then added and the mixture was extracted with Et2O (15 mL). The
organic phase was washed successively with water and brine, and
dried with anhydrous Na2SO4. After solvent evaporation, pure 21
(30 mg, 43%) was obtained as an oil. [α]2D5 ϭ Ϫ78.1 (c ϭ 0.63,
CDCl3) Ϫ 1H NMR (CDCl3): δ ϭ 7.45Ϫ7.24 (m, 5 H, Ph), 5.65
(s, 1 H, 1-H), 4.64 (s, 1 H, 6-H), 4.60 (s, 1 H, 5-H), 4.11 (d, J ϭ
13.2 Hz, 1 H, NCH2Ph), 3.81Ϫ3.73 (m, 2 H, CH2OH), 3.73 (s, 3
H, OMe), 3.20 (d, J ϭ 13.2 Hz, 1 H, NCH2Ph), 2.70 (m, 1 H, 4-
H), 2.55Ϫ2.45 (m, 2 H, 4-H, 2-H), 2.00 (br. s, 1 H, OϪH). 13C
NMR (CDCl3): δ ϭ 171.0 (s, CϭO), 137.4 (s, 1 C, Ph), 128.8 (d, 2
C, Ph), 128.4 (d, 2 C, Ph), 127.3 (d, 1 C, Ph), 103.7 (d, 1-C), 77.1
(d, 6-C), 75.6 (d, 5-C), 69.2 (t, CH2OH), 62.8 (d, 2-C), 60.2 (t, 4-
C), 56.9 (t, NCH2Ph), 53.2 (q, OCH3). MS: m/z (%) ϭ 293 (3)
[Mϩ], 276 (4), 262 (74), 234 (20), 216 (6), 105 (10), 91 (100). IR
(CDCl3): ν˜ ϭ 3459 (OϪH), 1752 (OϪCϭO) cmϪ1. C15H19NO5
(293.2): calcd. C 61.42, H 6.53, N 4.78; found C 61.08, H 6.94,
N 4.51.
(Ϫ)-Methyl
(1R,5S,7R)-3-Benzyl-4-methylene-2-oxo-6,8-dioxa-3-
solution of
azabicyclo[3.2.1]octane-7exo-carboxylate (18):
A
7
(608 mg, 1.75 mmol) in benzene (45 mL) was quickly added to a
refluxing suspension of H2SO4/SiO2 (523 mg) in benzene (50 mL).
The mixture was allowed to react for 20 min and then half of the
solvent was distilled off. The hot reaction mixture was filtered
through a short layer of NaHCO3 and the solvent was evaporated.
The residue was purified by chromatography (EtOAc/petroleum
ether, 1:3, Rf ϭ 0.30) to yield 18 (140 mg, 28%) as a colorless oil
and 19 (145 mg, 27%) as a yellow oil. Compound 18: [α]2D7 ϭ Ϫ68.3
(c ϭ 0.86, CHCl3). 1H NMR (CDCl3): δ ϭ 7.31Ϫ7.11 (m, 5 H,
Ph), 5.92 (s, 1 H, 5-H), 5.15 (s, 1 H, 1-H), 4.85 (AB, J ϭ 7.9 Hz, 2
H, NCH2Ph), 4.79 (s, 1 H, 7-H), 4.42 (d, J ϭ 2.6 Hz, 1 H, Cϭ
CH2), 4.36 (d, J ϭ 2.6 Hz, 1 H, CϭCH2), 3.81 (s, 3 H, OMe). 13C
NMR (CDCl3): δ ϭ 168.7 (s, CϭO), 165.1 (s, CϭO), 140.3 (s, 4-
C), 135.2 (s, 1 C, Ph), 128.8 (d, 2 C, Ph), 127.5 (d, 1 C, Ph), 126.4
(d, 2 C, Ph), 102.5 (d, 5-C), 94.4 (t, CϭCH2), 78.3 (d, 1-C), 76.7
Acknowledgments
(d, 7-C), 52.9 (q, OCH3), 44.0 (t, NCH2Ph). MS m/z (%) ϭ 289
ϩ
˜
(25) [M ], 230 (4), 198 (4), 91 (100), 59 (9). IR (CDCl3): ν ϭ 1759
We thank the MURST, the University of Florence (COFIN 2000),
and the Consiglio Nazionale delle Ricerche (CNR) for financial
support. Mr. Sandro Papaleo and Mrs. Brunella Innocenti are
acknowledged for their technical support.
(OϪCϭO), 1694 (NϪCϭO), 1643 (CϭC) cmϪ1. C15H15NO5
(289.3): calcd. C 62.30, H 5.23, N 4.84; found C 62.04, H 5.65, N
4.50. Compound 19: 1H NMR (CDCl3) (2:1 mixture of epimers):
δ ϭ 7.40Ϫ7.15 (m, 5 H ϩ 5 H), 5.59 (s, 1 H, OϪCHOH, minor
epimer), 5.50 (s, 1 H, OϪCHOH, major epimer), 5.05Ϫ4.30 (m, 4
H ϩ 4 H), 4.94 (d, J ϭ 15.8 Hz, 1 H, NCH2Ph), 4.40 (d, J ϭ
15.8 Hz, 1 H, NCH2Ph), 3.87 (s, OMe, minor epimer), 3.85 (s,
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