Total synthesis of hyacinthacine A1, a glycosidase inhibitor

Article abstract of DOI:10.1021/jo801377s

(Chemical Equation Presented) A practical and enantioselective total synthesis of hyacinthacine A₁ is achieved involving syn allylic epoxide opening with retention using Pd catalysis and "domino" hydrogenation (five steps in one pot) sequences.

Full text of DOI:10.1021/jo801377s

Total Synthesis of Hyacinthacine A1, a
Glycosidase Inhibitor
Srivari Chandrasekhar,* Bibhuti Bhusan Parida, and
Chegondi Rambabu
Organic DiVision-I, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
sriVaric@iict.res.in
ReceiVed June 24, 2008
FIGURE 1. Structures of polyhydroxylated pyrrolizidines.
these, the polyhydroxylated pyrrolizidine alkaloids (PHPAs) are
scarce in nature and also are difficult to purify from their limited
sources.9 This leaves only total synthesis as a choice to explore
SAR and for development of therapeutic agents.10
A practical and enantioselective total synthesis of hyacintha-
cine A1 is achieved involving syn allylic epoxide opening
with retention using Pd catalysis and “domino” hydrogena-
tion (five steps in one pot) sequences.
There are quite a few pyrrolizidine classes of iminosugars
known, which include hyacinthacine, alexine, australine, etc.
(Figure 1). The biological profile offered by these classes of
alkaloids attracted organic chemists to explore various synthetic
routes to have substantial number of analogues and quantities
for further studies. The noteworthy routes are the chiron
approaches starting from sugars, amino acids, and asymmetric
approaches involving chiral dihydroxylation and epoxidation.11
All these approaches, while offering advantages, also suffer from
a few drawbacks, and more efficient strategies are needed for
further exploitation of this rather new research field.
The carbohydrate-processing enzymes viz. glycosidase play
a very important role in AIDS, cancer, malaria, and diabetes.1
Inhibiting such pathways leads aids in understanding and
developing new drug candidates. It has been proven that
iminosugars can inhibit these carbohydrate enzymes because
of their resemblance to nature.2 Naturally, these classes of
compounds have attracted the attention of researchers engaged
in finding remedies for these diseases as biochemical tools in
glycolscience.3 Based on the chemical structure, the naturally
occurring iminosugars have been classified into piperidines,4
indolizidines,5 pyrrolizidines,6 pyrrolidines7 and nortropans.8 Of
The natural product hyacinthacine A1 (Figure 1), which is
isolated in less than 0.0005% from the bulbs of Muscari
armemiacum (Hyacinthaceae),12 needs to be synthesized from
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1996, 28, 643–682. (b) Liddell, J. R. Nat. Prod. Rep. 2001, 18, 441–447. (c)
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Angew. Chem., Int. Ed. 1999, 38, 750–770. (c) Asano, N.; Nash, R. J.; Molyneux,
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7826 J. Org. Chem. 2008, 73, 7826–7828
10.1021/jo801377s CCC: $40.75 2008 American Chemical Society
Published on Web 09/06/2008

SCHEME 1. Retrosynthesis of Hyacinthacine A1
SCHEME 4
SCHEME 2
The protection of the syn-azido alcohol 3 as MOM ether 10
was achieved using MOMCl and diisopropylethylamine (DI-
PEA), which followed selective acidic hydrolysis of the iso-
propylidine group in the presence of MOM ether using PPTS
in MeOH to realize diol 11. The selective blocking of the
primary alcohol group was rather routine under silylation
conditions (TBSCl, imidazole) to obtain 12 in 78% yield. The
prerequisite for the most critical domino reaction to generate
the bicyclic pyrrolizidone moiety was to make the free secondary
alcohol as mesyl ester which was performed by exposing 12 to
MsCl and Et3N at -10 °C for 10 min. The resulting mesylate
13 when subjected to hydrogenation (10% Pd-C/H2, EtOH)
followed by filtration, and the filtrate was refluxed in the
presence of K2CO3 (diluted with 0.2 mL of H2O) resulting in a
cascade of transformations which include reduction of azide to
amine followed by a SN2 displacement of mesylate to generate
the pyrrolidine intermediate, which in turn underwent an
intramolecular amidation with the ester to furnish the pyrrolizi-
done 2 in 65% yield (five steps). The concomitant olefin
reduction and hydrogenolysis of benzyl ether were obvious. The
resulting 2 on hydrolysis of MOM ether and silyl ether with
PTSA and further reduction of amide functionality with LAH
completes the total synthesis of hyacinthacine A1, 1a, in 58%
yield over two steps (Scheme 4).
SCHEME 3. Syn Opening of Epoxide with TMSN3 and
Pd(PPh3)4
simple and readily accessible chemicals so that analoging can
done efficiently for glycosidase inhibition and related studies
(Scheme 1).
The known R-benzyloxy alcohol 5 (obtained from (+)-DET
6)13 on a very straightforward IBX oxidation followed by Wittig
olefination with ethoxycarbonylmethylenetriphenylphosphorane
produced the (E)-R,ꢀ-unsaturated ester 7. This on DIBALH
reduction yielded allyl alcohol 8, which underwent a mismatched
Sharpless asymmetric epoxidation with D-(-)-DET to furnish
epoxy alcohol 9 in more than 98% de and ee.14 Further homo-
logation was achieved by a one-pot, two-step protocol (IBX,
EtOAc followed by PPh3dCHCO2Et) to furnish R,ꢀ-unsaturated
γ,δ-epoxy ester 4 in 90% yield for two steps (Scheme 2).15
The desired azido group was introduced with retention of
configuration taking advantage of the neighboring olefin group
via π-allyl Pd complex (Scheme 3).16 This represents first
application of this novel methodology in a total synthesis of
natural product.
In conclusion, the synthesis of hyacinthacine A1 is achieved
starting from L-(+)-DET. The key steps are the azido group
introduction with retention of configuration while opening
epoxide and the domino-pyrrolizidone construction in one
stroke. Also, the appropriate choice of Sharpless asymmetric
epoxidation and chiral synthon and epoxide opening will provide
various stereo analogs which is a noteworthy feature of present
strategy.
Experimental Section
(4R,5S,6S,E)-Ethyl 4-Azido-6-(benzyloxy)-6-((S)-2,2-dimethyl-
1,3-dioxolan-4-yl)-5-hydroxyhex-2-enoate (3). To a stirred solution
of (E)-R,ꢀ-unsaturated γ,δ-epoxy ester 4 (4.34 g, 11.98 mmol) in
THF (60 mL) were added TMSN3 (3.2 mL, 23.97 mmol) and
Pd(PPh3)4 (1.38 g, 1.19 mmol) under N2 atmosphere, and the
mixture was stirred for 12 h at rt. Then 10% citric acid in methanol
(10 mL) was added to the reaction mixture, which was stirred at 0
°C for 1 h, solid NaHCO3 (10 g) was added and the mixture stirred
for 15 min and filtered, methanol was completely removed in vacuo
at 30 °C, and the mixture was purified through silica gel chroma-
(13) (a) Steuer, B.; Wehner, V.; Lieberknecht, A.; Jager, V. Org. Synth. 1997,
74, 1–12. (b) Fujita, K.; Nakai, H.; Kobayashi, S.; Inoue, K.; Nojima, S.; Ohno,
M. Tetrahedron Lett. 1982, 23, 3507–3510.
(14) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.
(15) More, J, D.; Finney, N. S. Org. Lett. 2002, 4, 3001–3003.
(16) Miyashita, M.; Mizutani, T.; Tadano, G.; Iwata, Y.; Miyazawa, M.;
Tanino, K. Angew. Chem., Int. Ed. 2005, 44, 5094–5097.
J. Org. Chem. Vol. 73, No. 19, 2008 7827

tography (12% EtOAc/petroleum ether) to yield syn-azido alcohol
mg, 0.11mmol) dissolved in MeOH (3 mL) was added PTSA (cat.)
and the mixture stirred for overnight at rt. After complete
disappearance of the starting material (TLC monitored) and
subsequent deprotection of TBS as well as MOM (as evidenced
from mass spectum during course of reaction), solid NaHCO3 was
added, the mixture stirred for 15 min and filtered, and MeOH was
removed from the reaction mixture in vacuo. To that crude mass
dissolved in THF (2 mL) was added dropwise a suspension of LAH
(13 mg, 0.34 mmol) in THF (1 mL) at 0 °C and the mixture refluxed
for 2 h. Then the reaction was quenched with 0.1 mL of water, 0.1
mL of 10% NaOH, and then 0.2 mL of water and stirred for 6 h at
rt. The resulting mixture was filtered through Celite and washed
with EtOAc (3 × 2 mL). The filtrate was dried over anhydrous
Na2SO4. Evaporation of solvent in vacuo afforded a residue that
was retained on a column packed with Dowex 50W × 8 (200-400
mesh). The column was washed with MeOH, water, and then with
1 N NH4OH to afford pure 1a (11.6 mg, 58%): [R]25D ) +33.5 (c
1
3 (4.85 g, 80%): [R]25 ) -47.6 (c 1.7, CHCl3); H NMR (300
D
MHz, CDCl3) δH (ppm) 7.38-7.34 (m, 5H), 6.95 (dd, J ) 15.1,
6.7 Hz, 1H), 6.07 (d, J ) 15.1 Hz, 1H), 4.75 (d, J ) 11.3 Hz, 1H),
4.61 (d, J ) 11.3 Hz, 1H), 4.38-4.29 (m, 1H), 4.24-4.14 (m,
3H), 4.02 (dd, J ) 8.3, 6.0 Hz, 1H), 3.85 (t, J ) 8.3 Hz, 1H),
3.81-3.72 (m, 1H), 3.62 (dd, J ) 8.3, 5.2 Hz, 1H), 2.74 (d, J )
5.2 Hz, 1H), 1.44 (s, 3H), 1.34 (s, 3H), 1.30 (t, J ) 7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3) δC (ppm) 165.7, 141.9, 137.7, 128.7,
128.4, 128.3, 125.0, 109.5, 77.7, 76.7, 74.4, 73.2, 66.0, 62.7, 61.0,
26.4, 25.2, 14.3; IR (neat) νmax 3450, 2985, 2932, 2104, 1720, 1656,
1455, 1373, 1249, 1180, 1064, 984 cm-1; MS (ESI) m/z 428 (100)
[M + Na]+; HRMS (ESI) [M + Na]+ C20H27N3O6Na calcd
428.1797, found 428.1795.
(5R,6R,7S,7aR)-5-((tert-Butyldimethylsilyloxy)methyl)-6-hy-
droxy-7-(methoxymethoxy)hexahydropyrrolizin-3-one (2). To
the mesyl ester 13 (300 mg, 0.49 mmol) in EtOH (7 mL) was added
10% Pd/C (50 mg) and the mixture stirred under H2 (1 atm) at rt
for 12 h. Then the reaction mixture was filtered through Celite and
washed with EtOH (3-5 mL) and K2CO3 (344 mg, 2.49 mmol),
water (0.2 mL) was added to the filtrate, and the mixture was
refluxed for 2 h. Then it was concentrated in vacuo to remove
solvents. The crude mass was chromatographed through silica gel
(12% acetone/petroleum ether) to afford bicyclic lactam 2 (111 mg,
0.2, CH3OH) [lit.12 [R]25 ) +38.2, c 0.23, H2O]; H NMR (300
1
D
MHz, CDCl3 + CD3OD) δH (ppm) 3.86-3.80 (m, 2H), 3.75-3.64
(m, 2H), 3.57-3.45 (m, 1H), 3.17-3.12 (m, 1H), 2.85 (m, 1H),
2.83-2.75 (m, 1H), 2.10-2.02 (m, 1H), 1.98-1.82 (m, 1H),
1.77-1.61 (m, 2H); 13C NMR (75 MHz, CDCl3 + CD3OD) δC
(ppm) 75.3, 72.4, 71.5, 70.02, 60.73, 57.27, 27.3, 25.0; IR (neat)
νmax 3398, 2932, 2850 cm-1; MS(ESI) m/z 174 (100) [M + H]+;
HRMS (ESI) [M + H]+ C8H16NO3 calcd 174.1130, found 174.1127.
65%) as a white solid: mp 90-92 °C; [R]25 ) -30.1 (c 0.7,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δH (ppm) 4.82 (d, J ) 6.7
Acknowledgment. B.B.P. and C.R. thank the Council of
Scientific and Industrial Research (CSIR), New Delhi, for a
research fellowship and the Director, Indian Institute of Chemi-
cal Technology (IICT), for research facilities.
Hz, 1H), 4.71 (d, J ) 6.7 Hz, 1H), 4.57-4.47 (m, 1H), 4.01-3.91
(m, 3H), 3.86 (dd, J ) 10.5, 2.2 Hz, 1H), 3.54-3.48 (m, 1H), 3.44
(s, 3H), 3.33 (m, 1H), 2.67-2.52 (m, 1H), 2.38 (ddd, J ) 12.8,
9.8, 3.0 Hz, 1H), 2.26-2.11 (m, 1H), 2.10- 1.97 (m,1H), 0.88 (s,
9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δC
(ppm) 176.4, 97.7, 79.9, 75.4, 62.8, 61.3, 61.0, 56.2, 32.8, 25.8,
19.1, 18.1, -5.4, -5.5; IR (KBr) νmax 3389, 2927, 2856, 1675,
1436, 1415, 1215, 1121, 1032, 966 cm-1; MS (ESI) m/z 368 (100)
[M + Na]+; HRMS (ESI) [M + H]+ C16H32NO5Si calcd 346.2049,
found 346.2067.
Supporting Information Available: Experimental proce-
dures, melting points, specific rotation, spectral data (1H NMR,
1
13C NMR, IR, MS, HRMS), and copies of H NMR and 13C
NMR for all compounds described in the paper. This material
is available free of charge via the Internet at http://pubs.acs.org.
(1S,2R,3R,7aR)-3-(Hydroxymethyl)hexahydro-1H-pyrrolizine-
1,2-diol [(+)-Hyacinthacine A1] (1a). To bicyclic lactam 2 (40
JO801377S
7828 J. Org. Chem. Vol. 73, No. 19, 2008