Polyhydroxylated pyrrolizidines. Part 3: A new and short enantiospecific synthesis of (+)-hyacinthacine A2

Article abstract of DOI:10.1016/j.tetasy.2003.09.042

(1R,2R,3R,7aR)-1,2-Dihydroxy-3-hydroxymethylpyrrolizidine (+) -Hyacinthacine A₂ 1 has been synthesized by Wittig's methodology using [(2′S,3′R,4′R,5′R)-3′,4′-dibenzyloxy- N-tert-butyloxycarbonyl-5′-tert-butyldiphenylsilyloxymethylpyrrolidin- 2′

Full text of DOI:10.1016/j.tetasy.2003.09.042

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3933–3935
Polyhydroxylated pyrrolizidines. Part 3: A new and short
ꢀ
enantiospecific synthesis of (+)-hyacinthacine A2
Isidoro Izquierdo,* Mar´ıa T. Plaza and Francisco Franco
Department of Medicinal and Organic Chemistry. Faculty of Pharmacy. University of Granada, Granada 18071, Spain
Received 2 September 2003; accepted 22 September 2003
Abstract—(1R,2R,3R,7aR)-1,2-Dihydroxy-3-hydroxymethylpyrrolizidine (+)-Hyacinthacine A2 1 has been synthesized by Wittig’s
methodology using [(2%S,3%R,4%R,5%R)-3%,4%-dibenzyloxy-N-tert-butyloxycarbonyl-5%-tert-butyldiphenylsilyloxymethylpyrrolidin-2%-
yl]carbaldehyde 3, prepared from a partially protected DMDP 2, and the appropriated ylide, followed by cyclization by an
internal reductive amination process of the resulting unsaturated aldehyde 4 and total deprotection.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
According to Scheme 1, the actual homochiral starting
material was [(2%S,3%R,4%R,5%R)-3%,4%-dibenzyloxy-N-
tert - butyloxycarbonyl - 5% - tert - butyldiphenylsilyloxy-
methylpyrrolidin-2%-yl] carbaldehyde 3, prepared from
2 by a previously described procedure,1 which was
treated with triphenylphosphoranylideneacetaldehyde
Hyacinthacine A2 1 was isolated for the first time by
Asano et al.2 from the bulbs of Muscari armeniacum
(Hyacinthaceae), and was shown to be a potent and
selective inhibitor of amyloglucosidase (Aspergillus
niger).2,3 Only two synthetic approaches have been
recently reported for 1, those by Martin et al.4 and by
Goti,5 both from commercial 2,3,5-tri-O-benzyl-
D-ara-
binofuranose, but unfortunately lacking in high
stereoselectivity.
Retrosynthesis of 1 in Figure 1, clearly shows that
functionalization and stereochemistry of this molecule
exactly match that of the homochiral starting material,
(2R,3R,4R,5R)-3,4-dibenzyloxy-N-tert-butyloxycarbon-
yl-2%-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)-
pyrrolidine,6 protected DMDP 2. With this material in
hand, only the following steps are necessary for achiev-
ing the synthesis of 1: elongation at C(5%) of the carbon-
chain of the pyrrolidine skeleton by two more carbon
atoms with the appropriate functionalization (formyl
group) and cyclization to the pyrrolizidine skeleton by
an internal reductive amination process, and finally
total deprotection.
Figure 1. Retrosynthesis of hyacinthacine A2 (1).
Scheme 1. Reagents and conditions: (a) Ph3PꢀCHCHO/MePh/
D; (b) H2/10% PdꢁC; (c) HCl, then Amberlite IRA-400 (OH−
form); (d) 10% PdꢁC/HCl then Amberlite IRA-400 (OH−
form).
ꢀ For Part 2 of the series, see Ref. 1.
* Corresponding author. Tel.: +34-958-243847; fax: +34-958-2433845;
e-mail: isidoro@ugr.es
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.042

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I. Izquierdo et al. / Tetrahedron: Asymmetry 14 (2003) 3933–3935
to afford (E,Z)-3-[(2%R,3%R,4%R, 5%R)-3%,4%-dibenzyloxy-
N-tert-butyloxycarbonyl-5%-tert-butyldiphenylsilyloxy-
methyl pyrrolidin-2%-yl]prop-2-enal 4.
Jasco DIP-370 polarimeter. TLC was performed on
precoated silica gel 60 F254 aluminum sheets and detec-
tion by employing a mixture of 10% ammonium molyb-
date (w/v) in 10% aqueous sulfuric acid containing
0.8% cerium sulfate (w/v) and heating. Column chro-
matography was performed on silica gel (Merck, 7734).
The structure of 4, which exists as a mixture of
1
rotamers,1 was determined on the basis of its H NMR
data, where complex signals between l 9.58–9.43 (H-1)
and l 7.10–6.00 (H-2,3) were observed.
2.1. (E,Z)-3-[(2%R,3%R,4%R,5%R)-3%,4%-Dibenzyloxy-N-
tert-butyloxycarbonyl-5%-tert-butyldiphenylsilyloxy-
methyl pyrrolidin-2%-yl]prop-2-enal 4
Catalytic hydrogenation (10% PdꢁC) of 4 afforded the
protected saturated aldehyde 5, according to the 1H
NMR spectra of an aliquot, which also showed the
absence of rotameric forms (H-1 as a triplet at l 9.52).
Addition of hydrochloric acid to the above hydrogena-
tion reaction mixture caused the total N- and O-depro-
tection of 5 to 6, in order to promote the required
cyclization to the pyrrolizidine skeleton. Thus, neutral-
ization [Amberlite IRA-400 (OH− form)], followed by a
new catalytic hydrogenation of 6, as above, afforded a
complex mixture, probably the intermediate D5-
pyrrolizine A together with some debenzylation prod-
ucts. Continuing the hydrogenation process, but in acid
medium, the required (+)-hyacinthacine A2 1,
(1R,2R,3R,7aR)-1,2-dihydroxy-3-hydroxymethylpyrro-
lizidine, was finally achieved, after neutralization. The
physical and spectroscopic data of 1 (see Fig. 2) closely
matched those previously reported for a natural2 and
synthetic sample.4
A solution of 31 (1.26 g, 1.86 mmol) in dry toluene (20
mL) was added triphenylphosphoranilydeneacetalde-
hyde (0.8 g, 2.51 mmol) and the mixture was heated at
100°C for 12 h. TLC (ether/hexane 2:1) then revealed
the presence of a new compound of lower mobility. The
solvent was eliminated and the residue supported on
silica gel and submitted to column chromatography
with ether/hexane (1:2) as eluent to give pure 4 (0.8 g,
57%) as a pale yellow syrup that was not investigated
1
but used in the next step. H NMR (300 MHz) inter
alia: l=9.58–9.43 (m, 1H, H-1), 7.10–6.70 (2m, H-3 for
E,Z isomers), 6.40–6.00 (m, H-2 for E,Z isomers), 1.25
and 1.35 (2s, CMe3, N-Boc), 1.09 and 1.08 (2s, CMe3,
OTBDPS).
2.2. (1R,2R,3R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-
pyrrolizidine (+)-Hyacinthacine A2, 1
2. Experimental
Compound 4 (0.8 g, 1.13 mmol) in methanol (20 mL)
was hydrogenated at 60 psi over 10% PdꢁC (280 mg)
for 30 min. TLC (ether/hexane 2:1) then showed the
presence of a new compound 5 of slightly lower mobil-
ity. An aliquot was concentrated and showed the fol-
lowing 1H NMR (300 MHz): l=9.52 (t, H-1),
7.70–7.10 (m, Ph), 4.80–3.50 (m, H-2%,3%,4%,5%,5%%a,5%%b
and PhCH2), 2.50–1.50 (m, H-2a,2b,3a,3b), 1.29 (s,
OCMe3) and 1.07 (s, SiCMe3).
Solutions were dried over MgSO4 before concentration
1
under reduced pressure. The H and 13C NMR spectra
were recorded with Bruker AMX-300, AM-300, and
ARX-400 spectrometers for solutions in CDCl3 (inter-
nal Me4Si). Mass spectra ware recorded with a
Hewlett–Packard HP-5988-A and Fisons mod. Plat-
form II and VG Autospec-Q mass spectrometers. Opti-
cal rotations were measured in H2O (1 dm tube) with a
The reaction mixture was acidified with a few drops of
conc. HCl and left at rt for 24 h, this caused the
removal of the Boc and TBDPS protecting groups
[TLC (ether/hexane 2:1) revealing a non mobile com-
pound]. The catalyst was filtered off, washed with
methanol and the filtrate and washings neutralized with
Amberlite IRA-400 (OH− form). A new hydrogenation
as above under the presence of acid medium over 10%
PdꢁC (200 mg) for 12 h, gave a slightly mobile com-
pound [TLC (ether/methanol/triethylamine 1:1:0.1)].
Finally pure 1 (50 mg, 26% from 4) was isolated after
neutralization and column chromatography (ether/
methanol/TEA 2:1:0.1“ether/methanol/TEA 1:1:0.1),
which had [h]D25=+10.5 (c 0.6, H2O) [lit.2 [h]2D5=+20.1 (c
0.44, H2O); lit.4 [h]D25=+12.5 (c 0.6, H2O); lit.5 [h]2D5=
1
+12.7 (c 0.13, H2O). NMR data (400 MHz, D2O): H,
l 3.79–3.71 (m, 3H, H-1,3,8), 3.63 (dd, 1H, J3,8% 6, J8,8%
12.1 Hz, H-8%), 3.37 (m, 1H, H-7a), 3.04 (broad dt, 1H,
J5a,5b 11.7, J5b,6a=J5b,6b=6.5 Hz, H-5b), 2.93–2.85 (m,
2H, H-3,5a), 1.96–1.72 (m, 4H, H-6a,6b,7a,7b); 13C, l
81.09 (C-1), 77.72 (C-2), 71.47 (C-3), 69.42 (C-7a),
62.24 (C-8), 57.05 (C-5), 31.19 (C-7), and 26.32 (C-6).
Figure 2. HMQC (D2O) spectrum for (+)-Hyacinthacine A2.

I. Izquierdo et al. / Tetrahedron: Asymmetry 14 (2003) 3933–3935
3935
Acknowledgements
2. Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.;
Kato, A.; Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet, G.
W. J. Tetrahedron: Asymmetry 2000, 11, 1–8.
3. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W.
J. Tetrahedron: Asymmetry 2000, 11, 1645–1680; (b) Wat-
son, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.;
Nash, R. J. Phytochemistry 2001, 56, 265–295.
The authors are deeply grateful to Ministerio de Cien-
cia y Tecnolog´ıa (Spain) for financial support (Project
PPQ2002-01303) as well as for a grant (F. Franco).
4. Rambaud, L.; Compain, P.; Martin, O. R. Tetrahedron:
Asymmetry 2001, 12, 1807–1809.
5. Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti,
A. Tetrahedron Lett. 2003, 44, 2315–2318.
References
6. Izquierdo, I.; Plaza, M.-T.; Franco, F. Tetrahedron: Asym-
1. Izquierdo, I.; Plaza, M.-T.; Franco, F. Tetrahedron: Asym-
metry 2002, 13, 1581–1585.
metry 2002, 13, 1503–1508.