Synthesis of the new 7S-aminolentiginosine and derivatives

Article abstract of DOI:10.1002/adsc.200800806

The new 7S-aminolentiginosine has been synthesized by a diastereoselective 1,3-dipolar cycloaddition strategy starting from 3,4-dihydroxylat-ed pyrroline N-oxides derived from L-tartaric acid in thirteen steps. The intermediate 7S-azidolentigi-nosine unde

Full text of DOI:10.1002/adsc.200800806

UPDATES
DOI: 10.1002/adsc.200800806
Synthesis of the New 7S-Aminolentiginosine and Derivatives
Franca M. Cordero,a,* Paola Bonanno,a Sven Neudeck,a Carolina Vurchio,a
and Alberto Brandia,*
a
University of Florence, Department of Organic Chemistry “Ugo Schiff” and HeteroBioLab, via della Lastruccia 13, 50019
Sesto Fiorentino (FI), Italy
Fax : (+39)-055-457-3531; phone: (+39)-055-457-3485; e-mail: franca.cordero@unifi.it or alberto.brandi@unifi.it
Received: December 23, 2008; Published online: April 30, 2009
Dedicated to Professor Armin de Meijere on the occasion of his 70th birthday
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800806.
Abstract: The new 7S-aminolentiginosine has been
synthesized by a diastereoselective 1,3-dipolar cy-
cloaddition strategy starting from 3,4-dihydroxylat-
ed pyrroline N-oxides derived from l-tartaric acid
in thirteen steps. The intermediate 7S-azidolentigi-
nosine undergoes efficiently copper(I)-catalysed
Huisgen cycloadditions to alkynes.
amino group, which is amenable for further transfor-
mations such as, for example, the coupling with amino
acids for the synthesis of peptide conjugates.
Lentiginosine, in spite of being the least hydroxylat-
ed compound of the series and the most recent to be
studied, has shown a very promising and selective in-
hibitory activity against amyloglucosidase, higher than
that of castanospermine (2).[7] This activity seems to
depend on the peculiar trans-dihydroxy substitution
of the 5-membered ring portion of the molecule, able
to provide selective interactions with the enzyme
cavity.[8] This finding suggests that a substitution on
the six-membered ring should not hamper this favour-
able interaction and possibly furnish a handle to
Keywords: azides; 1,3-dipolar cycloaddition; imino-
sugars; pyrroline N-oxides
Polyhydroxylated indolizidine alkaloids[1] such as (À)- attach groups which could improve the interaction
swainsonine (1),[2] (+)-castanospermine (2),[3] and with the receptor. Preliminary computational studies[9]
(+)-lentiginosine (3)[4] (Figure 1) have been attracting suggest that various substituents could be favourably
vast attention since their isolation owing to their re- accommodated in the enzyme cavity.
semblance with sugars and interest in their biological
In this context we report here the successful stereo-
activities as a consequence. Their activity as glycosi- selective short synthesis of 7S-aminolentiginosine 4
dase inhibitors suggests a potential role as therapeutic (Scheme 1) applying the 1,3-dipolar cycloaddition
agents in many different pathologies such as viral in- strategy starting from a hydroxylated pyrroline N-
fections, tumour metastasis, diabetes and genetic dis- oxide 5.[10]
orders.[5]
In the search of new R protecting groups on ni-
These attractive activities have stimulated much in- trone 5 to expand the potentiality of the strategy, the
terest in the synthesis of unnatural analogues with the new (bis)benzoylated nitrone 11 was obtained in a
possibility of expanding their applications. Because of very efficient way starting from l-tartaric acid
the growing interest in glycoconjugation,[6] we consid- (Scheme 2). Benzylimide 6 was obtained by heating
ered the possibility of synthesising polyhydroxylated the benzylammonium salt of tartaric acid in refluxing
indolizidines containing a functional group, like an xylenes, with azeotropic removal of water, as recently
Figure 1. Polyhydroxylated indolizidine alkaloids.
Scheme 1. Retrosynthesis of 7S-amino-lentiginosine.
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Franca M. Cordero et al.
UPDATES
Scheme 2. Synthesis of (3S,4S)-4-(benzoyloxy)-1-oxido-3,4-
dihydro-2H-pyrrol-3-yl benzoate (11).
reported by Rosenberg et al.[11] N-Benzyldihydroxy-
pyrrolidine 8 was obtained by reduction of the in situ
generated borane through a slight modification of
Rosenbergꢁs procedure. In particular, 6 was treated
Scheme 3. Synthesis of the indolizidine core.
with NaBH4 and I2 at 08C and then heated at the tested, but no improvement of yield, selectivity, and
reflux temperature for 6 h to reach a full conversion. reaction times was observed.
After destroying the excess of borane with MeOH at
The minor diastereoisomer 14 derives from an exo-
room temperature, the pyrrolidine-borane adduct 7 syn approach of the dipolarophile to the C-4 BzO
was at first washed with water to remove NaI salt, substituent of the nitrone, less favoured than the
then treated with MeOH at 408C to achieve, after common exo-anti approach[7] (Figure 2). The exo ap-
benzoylation, 9 in 65% overall yield respect to 6. In proach is highly favoured, because of the encumber-
our hand, the reductive work-up procedure under ing effect of the BzO C-3 group in an endo approach.
neutral conditions resulted to be much more efficient Evidence for the assignment derives from proton
and reproducible than the acidic one previously NMR coupling constants of the bridgehead proton
used,[11] especially for large-scale preparations.
3a-H with the vicinal 4-H, 3.1 Hz in 13 compared to
The key oxidation of the C2 symmetrical pyrroli- 6.7 Hz in 14, diagnostic for a trans and a cis relation-
dine 10 was attempted by several methods, such as ship, respectively. The low diastereoselectivity can be
SeO2/H2O2,[12] and MTO/H2O2,[13] which were not sat- ascribed to the relative flatness of the benzoyl group
isfying for the reaction yields, or N-sulfonyloxaziri- exerting a lower steric hindrance compared to t-Bu
dine,[14] not practical in large-scale syntheses for the group.
cost and atom economy. It was found that oxone, re-
Cycloadducts 13 and 14 could be only partially sep-
cently employed by Font and co-workers to oxidize arated by chromatography on silica gel, unlike the
prolinol,[15] gave a very good yield (83%) also in the tert-butyl-protected adducts. Therefore, it was more
case of oxidation of 10 to nitrone 11 with a reaction convenient to carry out the next step on the isomeric
very simple and convenient.
The cycloaddition of 11 to butenol 12 (Scheme 3),
carried out in toluene at 1008C for 75 min, gave two
main cycloadducts 13 and 14, besides a third one in
traces, in 85% overall yield. The ratio of the two main
cycloadducts 13 and 14, 3.2:1, is somewhat lower than
that obtained by the cycloaddition of t-Bu-protected
nitrone to 12 (5:1), but similar to that obtained with
TBDMS-protected nitrone.[16,12b] Also microwave con-
Figure 2. Preferred transition state trajectories of the cyclo-
ditions, at different temperatures and solvents, were addition to 1-buten-4-ol (12).
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Synthesis of the New 7S-Aminolentiginosine and Derivatives
UPDATES
mixture as the corresponding diastereomeric indolizi-
dines 16 and 17 were easily separable (Scheme 3).
Mesylation of the mixture of isoxazolidine alcohols 13
and 14 produces the inner salts 15 which are not iso-
lated, but immediately reduced by H2 on Pd/C to in-
dolizidines 16 and 17 in 92% and 79% yield, from 13
and 14 respectively, after chromatographic separation.
To introduce the amino group on C-7 of indolizi-
dine 16 we chose the strategy of mesylation of the
free 7-OH and nucleophilic substitution of the mesy-
late with NaN3.[17] The reaction was performed also
on the 1,2-(bis)-t-Bu protected indolizidinetriol 18.[18]
The reaction of the mesylate of 18 with NaN3 in DMF
at 808C for 2.5 h gave a mixture of two products
(Scheme 4).
Scheme 6. Cu(I)-catalysed Huisgenꢁs cycloaddition.
4 in six steps from cycloadduct 13 and 19% overall
Besides the expected azide 20 obtained in poor yield (Scheme 5).
13% yield, a new product 21 was obtained in 21%
The formation of the intermediate azides allows an-
yield to which the fragmented and pyrrole aromatized other approach for conjugating the indolizidine
structure 21 was assigned on the basis of NMR and moiety to other substrates, by running Huisgenꢁs cy-
mass spectrometry data. The product 21 must derive cloaddition to alkynes. The Cu(I)-catalysed ver-
from a Grobꢁs fragmentation-type process,[19] followed sion[20,21] of the cycloaddition confers a high chemo-
by monodeprotection and elimination/aromatization and regioselectivity to the process. To study the feasi-
of the pyrrole ring. A similar Grobꢁs-type fragmenta- bility of it two examples of the addition of azide 19 to
tion of a tosylated isoxazolidine, in a different reduc- butyn-4-ol 23, and azide 20 to ethyl propiolate 24,
ing context, was previously observed in our group.[16] were carried out (Scheme 6).
Changing the conditions of temperature and reaction
The cycloaddition of 19 to azide 23 occurs smoothly
times did not affect much the results. The finding at 808C using microwaves as the heating device and
should be ascribed to the lability of the t-Bu protect- affords good yield (75%) of the triazole 25. The reac-
ing group in connection with the sulfonate protection tion of the more reactive propiolate 20 with t-Bu-pro-
of the 7-OH during the azide substitution. The prob- tected azide 20 occurs at room temperature, more
lem, in fact, is not observed with the benzoylated in- convenient for the lability of the dipolarophile, giving
dolizidine 16. This gives the expected azide 19 in triazole 26 in 50% yield.
good 49% yield by reaction of the mesylate with
In conclusion, a short straightforward synthesis of
NaN3 in DMF at 808C for 22 h.
the new 7S-aminolentiginosine is achieved as a new
The reduction of the azide 19 with Raney Ni, and tool for the conjugation of this iminosugar with other
hydrolysis of benzoates by treatment of 22 with Am- biomolecules. The coupling could be carried out by
bersep in MeOH, affords, then, 7S-aminolentiginosine “click chemistry” by using the intermediate azide, as
it is shown in two examples. The triazole ring has, by
itself, some biomimetic character.[22] Finally, 7S-ami-
nolentiginosine is a non-natural example of an amino-
substituted sugar mimic,[23] for which a likely glycosi-
dase inhibitor activity can be foreseen.
Experimental Section
For experimental details and spectral data for all new com-
Scheme 4. Synthesis of azides 19 and 20.
pounds, see the Supporting Information.
Scheme 5. Synthesis of 7S-aminolentiginosine.
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Franca M. Cordero et al.
UPDATES
zoate (yield: 848 mg, 87%) as a white solid, which was used
in the next step without further purification.
ACHTUNGTRENNUNG
pyrrol-3-yl Benzoate (11)
A mixture of the mesylate (591 mg, 1.29 mmol) and NaN3
(209 mg, 3.2 mmol) in DMF (3.1 mL) was heated to 808C
for 22 h. The reaction mixture was diluted with EtOAc
(8 mL) and H2O (9 mL), the two phases were separated and
the aqueous phase was extracted with EtOAc (9ꢂ8 mL).
The collected organic phases were washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated under re-
duced pressure. The crude product was purified by column
chromatography on silica gel (eluent: CH2Cl2) to afford
azide 19 (yield: 296 mg, 56%) as a colorless oil. Rf =0.34;
[a]2D5: +109.70 (c 0.500, CHCl3); 1H NMR (400 MHz): d=
8.10–8.03 (m, 4H, Ph), 7.60–7.52 (m, 2H, Ph), 7.48–7.40 (m,
4H, Ph), 5.43–5.36 (m, 2H, 1-H, 2-H), 4.07–4.02 (m, 1H, 7-
H), 3.19 (d, J=11.2 Hz, 1H, 3-Ha), 2.95–2.86 (m, 2H, 3-Hb,
5-Ha), 2.55 (ddd, J=11.1, 8.4, 2.4 Hz, 1H, 8a-H), 2.42 (dt,
J=3.0, 11.6 Hz, 1H, 5-Hb), 2.13 (dm, J=13.6 Hz, 1H, 8-Ha),
1.98–1.77 (m, 3H, 6-H, 8-Hb); 13C NMR (100 MHz): d=
166.4 (s, C=O), 165.9 (s, C=O), 133.3 (d, Ph), 133.1 (d, Ph),
129.9 (d, 2C, Ph), 129.8 (d, 2C, Ph), 129.7 (s, Ph), 129.5 (s,
Ph), 128.4 (d, 2C, Ph), 128.3 (d, 2C, Ph), 81.9 (d, C-1), 77.4
(d, C-2), 61.7 (d, C-8a), 59.5 (t, C-3), 55.5 (d, C-7), 47.3 (t,
C-5), 33.2 (t, C-8), 28.6 (t, C-6); IR (CDCl3): v=2930, 2815,
2098, 1718, 1602, 1451, 1276, 1112 cmÀ1; HR-MS: m/z=
407.17102, calcd. for C22H23N4O4 [M+H]+: 407.17138; anal.
calcd. for C22H22N4O4 (406.4): C 65.01, H 5.46, N 13.78;
found: C 64.70, H 5.08, N 13.55.
AcOH (4.34 mL) was added to a suspension of 9 (3.06 g,
7.6 mmol) in MeOH (50 mL) and THF (9 mL) at 08C.
Then, a catalytic amount of 10% Pd/C (500 mg) was added
and the mixture was stirred under a H2 atmosphere (1 atm)
overnight at room temperature. The mixture was filtered
through a short pad of Celite and concentrated under re-
duced pressure. The obtained white solid was dissolved in
AcOEt (60 mL) and washed with a saturated aqueous
Na2CO3 solution (45 mL). The aqueous solution was extract-
ed with AcOEt (2ꢂ30 mL). The combined organic phases
were washed with H2O, dried over Na2SO4, filtered and con-
centrated under reduced pressure to afford the crude
ACHTUNGTRENNUNG
(3S,4S)-4-(benzoyloxy)pyrrolidinyl benzoate (10)[19] as a pale
yellow oil (yield: 2.115 g, 89%), which was directly oxidized.
NaHCO3 (2.85 g, 33.95 mmol) was added to a stirred solu-
tion of the crude amine 10 (2.115 g, ca. 6.8 mmol) in a 4 :1
mixture of CH3CN-THF (12.5 mL) and aqueous Na2EDTA
(0.01M, 9.5 mL). The mixture was then cooled in an ice
bath and Oxoneꢃ (4.4 g, 7.15 mmol) was added portionwise
over 3 h. The mixture was stirred at 08C for 45 min and
then diluted with EtOAc (35 mL) and H2O (37 mL). The
two phases were separated and the aqueous solution was ex-
tracted with EtOAc (2ꢂ25 mL). The combined organic
phases were washed with H2O (20 mL), dried over Na2SO4,
filtered and concentrated under reduced pressure to afford
the crude pyrroline-N-oxide 11 (yield: 1.831 g, 83%) as a
white solid, that can be used in the next step without further
purification. A sample purified by chromatography on silica
gel (eluent: petroleum ether/EtOAc, 2:1) afforded analyti-
cally pure 11. Rf =0.38; m. p. 155–1588C (with decomposi-
tion); [a]2D5: =+220.53 (c 0.525, CHCl3); 1H NMR
(400 MHz): d=8.10–8.00 (m, 4H, Ph), 7.65–7.57 (m, 2H,
Ph), 7.50–7.43 (m, 4H, Ph), 7.17–7.15 (m, 1H, 5-H), 6.11–
6.09 (m, 1H, 4-H), 5.74 (dm, J=6.3, 1H, 3-H), 4.73 (dddd,
J=15.7, 6.3, 2.1, 1.2 Hz, 1H, 2-Ha), 4.07 (dddd, J=15.7, 2.1,
1.2, 0.7 Hz, 2-Hb); 13C NMR (50 MHz): d=165.4 (s, CO),
165.3 (s, CO), 133.9 (d, Ph), 133.8 (d, Ph), 130.3 (d, C-2),
129.8 (d, 4C, Ph), 128.6 (d, 4C, Ph), 128.4 (s, Ph), 128.3 (s,
Ph), 78.2 (d, C-3), 72.3 (d, C-4), 67.2 (t, C-5); IR (CDCl3):
n=1725, 1579, 1452, 1317, 1263, 1105 cmÀ1; MS (EI): m/z
(%)=325 (1, M+), 203 (10), 105 (100), 82 (11), 77 (30); anal.
calcd. for C18H15NO5 (325.31): C 66.46, H 4.65 , N 4.31;
found C 66.32, H 4.36, N 4.25.
7S-Aminolentiginosine (4)
(1S,2S,7S,8aS)-7-Amino-2-(benzoyloxy)octahydro-1-indo-
lizinyl benzoate (22): A water suspension of activated
Raney-Ni was added dropwise to a solution of 19 (250 mg,
0.615 mmol) in MeOH (6 mL). The mixture was stirred at
room temperature for 1 h, filtered through a short pad of
Celite and concentrated under reduced pressure. The resi-
due was diluted with CH2Cl2, dried over Na2SO4, filtered
and concentrated under reduced pressure to give 22 (yield:
150 mg, 64%) as a pale yellow solid, that was directly depro-
1
tected without further purification. H NMR (400 MHz): d=
8.10–8.00 (m, 4H, Ph), 7.59–7.51 (m, 2H, Ph), 7.47–7.38 (m,
4H, Ph), 5.42 (br dd, J=6.2, 3.0 Hz, 1H, 2-H), 5.26 (dd, J=
7.9, 3.0 Hz, 1H, 1-H), 3.56–3.51 (m, 1H, 7-H), 3.14 (br d, J=
11.2 Hz, 1H, 3-Ha), 3.03 (dd, J=11.2, 6.7 Hz, 1H, 3-Hb),
2.89–2.76 (m, 2H, 5-Ha, 8a-H), 2.74–2.62 (m, 1H, 5-Hb), 2.28
(br d, J=14.3 Hz, 1H, 8-Ha), 1.93–1.85 (m, 2H, 6-H), 1.85–
1.74 (m, 1H, 8-Hb); 13C NMR (50 MHz): d=166.0 (s, C=O),
165.6 (s, C=O), 133.2 (d, Ph), 133.1 (d, Ph), 129.7 (d, 4C,
Ph), 129.4 (s, Ph), 129.3 (s, Ph), 128.3 (d, 2C, Ph), 128.2 (d,
2C, Ph), 82.1 (d, C-1), 77.2 (d, C-2), 60.3 (d, C-8a), 59.1 (t,
C-3), 45.8 (t, C-5), 45.6 (d, C-7), 32.0 (t, C-8), 27.9 (t, C-6);
HR-MS: m/z=381.18190, calcd. for C22H25N2O4 [M+H]+:
381.18088.
(1S,2S,7S,8aS)-7-Aminooctahydro-1,2-indolizinediol
(4): Ambersep 900-OH was added to a solution of crude 22
(128 mg, 0.33 mol) in MeOH (5 mL) and the mixture was
maintained at room temperature for 2 h under gentle mag-
netic stirring. The reaction mixture was filtered through
cotton wool and concentrated under reduced pressure to
give 4 (yield: 38 mg, 0.22 mmol, 66%). [a]2D4: À16.666 (c 0.27,
MeOH); 1H NMR (CD3OD, 400 MHz): d=3.97 (ddd, J=
(1S,2S,7S,8aS)-7-Azido-2-(benzoyloxy)octahydro-1-
indolizinyl Benzoate (19)
Methanesulfonyl chloride (MsCl, 0.327 mL, 4.24 mmol) was
added dropwise to a solution of 16 (809 mg, 2.12 mmol) and
triethylamine (1.462 mL, 10.5 mmol) in CH2Cl2 (3 mL) at
08C. The mixture was stirred under nitrogen at room tem-
perature for 2 h and the resulting suspension was diluted
with CH2Cl2 (9 mL) and H2O (9 mL). The two phases were
separated and the aqueous phase extracted with CH2Cl2 (2ꢂ
9 mL). The collected organic phases were washed with
brine, dried over Na2SO4 and concentrated under reduced
presure. The crude product was filtered through a short pad
of silica gel (eluent: EtOAc/petroleum ether, 1:1) and evap-
oration of the solvent afforded (1S,2S,7R,8aS)-1-(benzoyl-
A
ben-
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Synthesis of the New 7S-Aminolentiginosine and Derivatives
UPDATES
7.2, 3.5, 1.5 Hz, 1H, 2-H), 3.60 (dd, J=8.4, 3.5 Hz, 1H, 1-H),
3.29–3.24 (m, 1H, 7-H), 2.85 (dd, J=10.6, 1.5 Hz, 1H, 3-Ha),
2.76 (ddd, J=11.4, 4.7, 2.6 Hz, 1H, 5-Ha), 2.63 (dd, J=10.6,
7.2 Hz, 1H, 3-Hb), 2.37 (dt, J=2.9, 12.4 Hz, 1H, 5-Hb), 2.18
(ddd, J=11.6, 8.4, 2.7 Hz, 1H, 8a-H), 1.92 (dq, J=13.3,
2.4 Hz, 1H, 8-Ha), 1.84 (br dt, J=4.4, 13.1 Hz, 1H, 6-Ha),
1.63–1.54 (m, 2H, 6-Hb, 8-Hb); 13C NMR (CD3OD,
100 MHz): d=85.1 (d, C-1), 77.8 (d, C-2), 64.1 (d, C-8a),
62.6 (t, C-3), 48.2 (t, C-5), 45.2 (d, C-7), 35.9 (t, C-8), 32.2 (t,
C-6); HR-MS: m/z=173.1290, calcd. for C8H17N2O2 [M+
H]+: 173.1294.
C (187 mg) and reacted under H2 atmosphere (1 Atm) over-
night. The reaction mixture was filtered through a short pad
of Celite and concentrated under reduced pressure. The
crude product was dissolved in CH2Cl2 (7 mL) and washed
with a saturated aqueous NaHCO3 solution (7 mL). The
aqueous solution was extracted with CH2Cl2 (3ꢂ10 mL) and
the combined organic phases washed with H2O (20 mL),
dried over Na2SO4, filtered and concentrated under reduced
pressure to give crude (1S,2S,7R,8aS)-1,2-di-tert-butoxyocta-
hydro-7-indolizinol (18; yield: 970 mg, 96%) as a yellow
waxy solid, which was used in the next step without further
purification.
Methanesulfonyl chloride (0.52 mL, 6.73 mmol) was
added dropwise to a solution of 18 (960 mg, 3.36 mmol) and
triethylamine (2.34 mL, 16.8 mmol) in CH2Cl2 (4.8 mL) at
08C. The mixture was stirred under nitrogen at room tem-
perature for 2 h and the resulting suspension was diluted
with CH2Cl2 (15 mL) and H2O (15 mL). The two phases
were separated and the aqueous phase extracted with
CH2Cl2 (2ꢂ15 mL). The collected organic phases were
washed with brine (3ꢂ10 mL), dried over Na2SO4 and con-
centrated under reduced pressure. The crude (1S,2S,7R,8aS)-
(1S,2S,7R,8aS)-2-(Benzoyloxy)-7-[4-(2-hydroxyethyl)-
1H-1,2,3-triazol-1-yl]octahydro-1-indolizinyl Benzoate
(25)
In a microwave reaction tube were added a mixture of azide
19 (60 mg, 0.148 mmol) and 97% pure 3-butyn-1-ol (23,
0.013 mL, 0178 mmol) in a 1:1 mixture of water and t-BuOH
(0.6 mL), copper powder (4 mg, 0.06 mmol) and copper sul-
fate (16 mg. 0.1 mmol). The mixture was stirred for 30 min
at 808C, using an irradiation power of 100 W. Then, other
two portions of 23 (0.013 mL) were added and the mixture
was heated at 808C for 30 min after each addition. The reac-
tion mixture was concentrated under reduced pressure, then
diluted with CH2Cl2, dried over Na2SO4, filtered and con-
centrated. The crude product was purified by chromatogra-
phy on silica gel (eluent: EtOAc/MeOH, 14:1) to afford an-
alytically pure triazole 25 (yield: 53 mg, 75%). Rf =0.26;
[a]2D2: +115.39 (c 1.23, CHCl3); 1H NMR (400 MHz): d=
8.10–8.06 (m, 2H, Ph), 8.04–8.01 (m, 2H, Ph), 7.59–7.54 (m,
2H, Ph), 7.46–7.41 (m, 5H, Ph, triazole), 5.46–5.39 (m, 2H,
1-H, 2-H), 4.80–4.74 (m, 1H, 7-H), 3.99–3.92 (m, 2H,
CH2OH), 3.22 (d, J=11.2 Hz, 1H, 3-Ha), 3.01 (ddd, J=11.3,
4.7, 2.4 Hz, 1H, 5-Ha), 2.96 (dd, J=11.2, 6.7 Hz, 1H, 3-Hb),
2.94 (t, J=5.7 Hz, 2H, CH2CH2OH), 2.75–2.67 (m, 2H, 8-
Ha, 8a-H), 2.63 (dt, J=2.9, 11.8 Hz, 1H, 5-Hb), 2.57 (br s,
1H, OH), 2.43–2.27 (m, 2H, 6-H), 2.22 (ddd, J=14.5, 11.8,
4.4 Hz, 1H, 8-Hb); 13C NMR (100 MHz): d=166.3 (s, C=O),
166.0 (s, C=O), 145.4 (s, triazole), 133.3 (d, Ph), 133.2 (d,
Ph), 129.8 (d, 4C; Ph), 129.6 (s, Ph), 129.3 (s, Ph), 128.4 (d,
2C, Ph), 128.3 (d, 2C, Ph), 121.0 (d, triazole), 82.1 (d, C-1),
77.4 (d, C-2), 61.6 (t, CH2OH), 61.5 (d, C-8a), 59.3 (t, C-3),
53.8 (d, C-7), 47.6 (t, C-5), 33.5 (t, C-8), 29.2 (t, C-6), 28.6 (t,
CH2CH2OH); IR (CDCl3): v=3627, 3456 br, 2957, 2836,
1718, 1603, 1451, 1280, 1113 cmÀ1; HR-MS: m/z=477.21325,
calcd. for C26H29N5O4 [M+H]+: 477.21325; anal. calcd. for
C26H28N4O5 H2O (494.5): C 63.15, H 6.11, N 11.33; found: C
63.37, H 6.01, N 11.25.
1,2-di-tert-butoxyoctahydro-7-indolizinyl
methanesulfonate
(yield: 1.2 g, 98%) was obtained as an orange oil and was
used in the next step without further purification.
A mixture of the mesylate (1.2 g, 3.3 mmol) and NaN3
(429 mg, 6.6 mmol) in DMF (7.9 mL) was heated at 408C
for 4 h and then at 808C for 2.5 h. The reaction mixture was
diluted with H2O (25 mL) and extracted with petroleum
ether (3ꢂ30 mL). The collected organic phases were washed
with brine, dried over anhydrous Na2SO4, filtered and con-
centrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (eluent:
petroleum ether/EtOAc, initially 19:1 then 4:1) to afford
(1S,2S,7S,8aS)-7-azido-1,2-ditert-butoxyoctahydroindolizine
(20; yield: 129 mg, 0.42 mmol, 13%) as a pale yellow waxy
solid and compound 21 (yield: 138 mg, 0.7 mmol, 21%) as a
brown oil. Data for 20: Rf =0.11 (eluent: petroleum ether/
EtOAc, 8:2); 1H NMR (400 MHz): d=3.99 (quintet, J=
3.0 Hz, 1H, 7-H), 3.81 (ddd, J=7.0, 4.0, 1.6 Hz, 1H, 2-H),
3.60 (dd, J=8.5, 3.9 Hz, 1H, 1-H), 2.89 (ddd, J=10.1,
1.4 Hz, 1H, 3-Ha), 2.75 (ddd, J=11.1, 4.6, 2.2 Hz, 1H, 5-Ha),
2.49 (dd, J=10.1, 7.1 Hz, 1H, 3-Hb), 2.22 (dt, J=2.9,
11.8 Hz, 1H, 5-Hb), 2.11–1.97 (m, 2H, 8-Ha, 8a-H), 1.87
(dddd, J=14.1, 12.4, 4.6, 3.4 Hz, 1H, 6-Ha), 1.73 (d quintet,
J=14.1, 2.5 Hz, 1H, 6-Hb), 1.59–1.46 (m, 1H, 8-Hb), 1.19 (s,
9H, t-Bu), 1.17 (s, 9H, t-Bu); 13C NMR (100 MHz): d=83.4
(d, C-1); 76.8 (d, C-2), 73.7 (s, t-Bu), 73.6 (s, t-Bu), 61.7 (t,
C-3), 61.0 (d, C-8a), 55.9 (d, C-7), 47.9 (t, C-5), 32.7 (t, C-8),
29.3 (q, 3C, t-Bu), 28.8 (q, 3C, t-Bu), 28.7 (t, C-6); HR-MS:
m/z=311.24415, calcd. for C16H31N4O2 [M+H]+: 311.24415.
(1S,2S,7S,8aS)-7-Azido-1,2-di-tert-
butoxyoctahydroindolizine (20)
Ethyl 1-[(1S,2S,7S,8aS)-1,2-Di-tert-butoxyoctahydro-
7-indolizinyl]-1H-1,2,3-triazole-4-carboxylate (26)
Cold freshly distilled MsCl (0.3 mL, 3.87 mmol) was added
dropwise to
butoxyhexahydropyrrolo
a
solution of 2-[(2S,3aS,4S,5S)-4,5-di-tert-
[1,2-b]isoxazol-2-yl]ethanol (1.6 g,
U
Copper podwer (3.6 mg, 0.06 mmol) and copper sulfate
(28.3 mg. 0.177 mmol) were added to a mixture of azide 20
(70 mg, 0.22 mmol) and ethyl propiolate (24, 0.039 mL,
0.38 mmol) in a 1:1 mixture of water and t-BuOH (1 mL)
cooled at 08C. The reaction mixture was stirred at room
temperature overnight then concentrated, diluted with
CH2Cl2, dried over Na2SO4, filtered, concentrated. The
3.52 mmol) and NEt3 (0.69 mL, 4.93 mmol) in CH2Cl2 (dis-
tilled over P2O5, 16.4 mL) at 08C under N2. The mixture was
stirred for 1 h at 08C, and concentrated under reduced pres-
sure. The residue was diluted with THF (9 mL) and recon-
centrated for two times. The residue was dissolved in
MeOH (42 mL), treated with a catalytic amount of 10% Pd/
Adv. Synth. Catal. 2009, 351, 1155 – 1161
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Franca M. Cordero et al.
UPDATES
crude product was purified by chromatography on silica gel
(eluent: initially petroleum ether/EtOAc, 4:1, then EtOAc/
MeOH, 10:1) to afford 26 (yield: 52 mg, 50%) as a pale
yellow solid. Rf =0.16 (EtOAc); 1H NMR (400 MHz): d=
8.18 (s, 1H, triazole), 4.91–4.86 (m, 1H, 7-H), 4.43 (q, J=
7.1 Hz, 2H, CH2CH3), 3.80 (ddd, J=7.0, 3.9, 1.5 Hz, 1H, 2-
H), 3.66 (dd, J=7.7, 3.9 Hz, 1H, 1-H), 2.96–2.88 (m, 2H, 3-
Ha, 5-Ha) 2.60–2.54 (m, 1H, 8-Ha), 2.48 (dd, J=10.2, 7.0 Hz,
1H, 3-Hb), 2.46–2.40 (m, 1H, 6-Ha), 2.35–2.22 (m, 2H, 5-Hb,
6-Hb), 2.02–1.91 (m, 2H, 8-Hb, 8a-H), 1.42 (t, J=7.1 Hz; 3H,
CH2CH3); 1.20 (s, 9H, t-Bu), 1.17 (s, 9H, t-Bu); 13C NMR
(100 MHz): d=160.7 (s, CO), 139.7 (s, triazole), 126.6 (d, tri-
azole), 83.6 (d, C-1); 76.7 (d, C-2), 74.0 (s, t-Bu), 73.9 (s, t-
Bu), 61.7 (t, C-3), 61.3 (t, OCH2), 60.8 (d, C-8a), 54.8 (d, C-
7), 48.0 (t, C-5), 33.2 (t, C-8), 29.3 (q, 3C, t-Bu), 28.8 (q, 3C,
t-Bu), 28.6 (t, C-6), 14.5 (dq, CH3); HR-MS: m/z=
409.28182, calcd. for C21H37N4O4 [M+H]+: 409.28093.
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Acknowledgements
The Ministry of Research and University (MiUR-Rome,
Italy) is acknowledged for financial support (PRIN project).
S. N., on leave from the University of Gçttingen (Germany),
acknowledges the receipt of a Sokrates student exchange fel-
lowship.
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