Polyhydroxylated pyrrolizidines. Part 2: The first total synthesis of (+)-hyacinthacine A3

Article abstract of DOI:10.1016/S0957-4166(02)00408-1

The first total synthesis for the (+)-hyacinthacine A₃ 1 in a highly stereocontrolled manner, is reported herein. An appropriately protected polyhydroxylated pyrrolidine, such as (2R,3R,4R,5R)-3,4-dibenzyloxy-N-tert-butyloxycarbonyl-2′-O-tert-

Full text of DOI:10.1016/S0957-4166(02)00408-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1581–1585
Polyhydroxylated pyrrolizidines. Part 2: The first total synthesis
†
of (+)-hyacinthacine A3
Isidoro Izquierdo,* Mar´ıa T. Plaza and Francisco Franco
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Received 11 July 2002; accepted 17 July 2002
Abstract—The first total synthesis for the (+)-hyacinthacine A3 1 in a highly stereocontrolled manner, is reported herein. An
appropriately protected polyhydroxylated pyrrolidine, such as (2R,3R,4R,5R)-3,4-dibenzyloxy-N-tert-butyloxycarbonyl-2%-O-tert-
butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 2, (DMDP protected), readily available from
D-fructose, was chosen as the
homochiral starting material. The absolute configuration of natural 1 is also unambiguously established. © 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
in stereoselectivity. Subsequently, Martin et al.5
reported on the first total synthesis of (+)-hyacinthacine
A2 from a suitably functionalized N,2-diallyl-pyrro-
The polyhydroxylated pyrrolizidine skeleton [1-aza-
bicyclo[3.3.0]octane] is the basic framework of a diverse
group of sugar mimic alkaloids isolated from natural
sources. Among them, those recently isolated1 bearing
one carbon branch both at C(3) and C(5) are known as
hyacinthacines. Most of these natural compounds show
inhibitory activity against different kinds of glyco-
protein processing glycosidases and hence their poten-
lidine, prepared from a derivative of
D-arabinose, in
which a RCM reaction was the synthetic key step for
building up the bicyclic pyrrolizidine skeleton. Simulta-
neously, our group reported6 on the short and highly
stereocontrolled syntheses of the already mentioned
(+)-7-deoxyalexine and, for the first time, (+)-5,7a-
diepi-hyacinthacine A3, from a partially protected 2,5-
tiality as new chemotherapeutic agents.2 As
a
dideoxy-2,5-imino-D
-glucitol (DGDP).7 To the best of
consequence of this bioactivity, a great deal of effort
has been devoted over the last two decades in order to
achieve either the isolation of new polyhydroxylated
pyrrolizidine alkaloids from nature or to design stereo-
controlled synthetic routes2d,3 leading to these com-
pounds, or to their unnatural isomers, which could be
of interest for SAR studies.
our knowledge no other synthesis of the natural (+)-
hyacinthacine A3 has been communicated to date.
Herein, we report on the first total enantiosynthesis of
such a compound using an adequately protected 2,5-
dideoxy-2,5-imino-
D
-mannitol (DMDP, 2),8 prepared
from -fructose, as the homochiral starting material.
D
Retrosynthesis for 1 (Scheme 1) indicates that protected
DMDP could be considered an excellent starting chiral
template for its enantiosynthesis, since carbon-chain
The first synthesis for a hyacinthacine was that reported
by Yoda’s group4 on the (+)-7a-epi-hyacinthacine A2
(7-deoxyalexine), using
a methodology previously
applied to the synthesis of (+)-alexine.3d At the same
lengthening at C(5%) (the original C-6 of
D-fructose)
time White et al.3f described the synthesis of its 2-O-
with a suitably functionalized three more carbon atoms
fragment, followed by a further cyclization, could lead
to the pyrrolizidine skeleton with the stereochemistry at
C(7a) correct for the target molecule.
benzyl derivative starting from 2,3-O-isopropylidene-D-
glyceraldehyde, via a tandem ring-closing metathesis
(RCM) and a transannular cyclization the key steps for
the construction of pyrrolizidine skeleton. However,
both methodologies are lacking in conciseness as well as
2. Results and discussion
According to Scheme 2, oxidation of (2R,3R,4R,5R)-
3,4-dibenzyloxy- N - tert -butyloxycarbonyl -2% - O - tert-
butyldiphenylsilyl - 2,5 - bis(hydroxymethyl)pyrrolidine8a
* Corresponding author. E-mail: isidoro@platon.ugr.es
† For Part 1 of the series, see: Ref. 6.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00408-1

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I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1581–1585
Scheme 1. Retrosynthesis of (+)-hyacinthacine A3.
isolated but observed by TLC analysis, and final hydro-
genation to 1.
The configuration of the new C(5) stereogenic center
was determined from the results of extensive NOE
experiments. The definite NOE effects (see Fig. 3)
between C(3)H and C(5)Me and between C(2)H and
C(7a)H indicated that the formers are in the a-face,
whereas the latter are in the b-face.
The high stereoselectivity found in the hydrogenation
of intermediate D5-pyrrolizine A, where 1 was the only
detected and isolated pyrrolizidine merits comment.
Formation of 1 can be attributed, according to our
previous results6 and to Fig. 3, to the particular shape
of this kind of molecule,1b where that the b-face is less
hindered for hydrogen attack that the a-face is, prefer-
entially affording compound 1.
Scheme 2. Synthesis of a,b-unsaturated pyrrolidinic ketone 4.
,
Reagents and conditions: (a) TPAP/NMO/Cl2CH2/4 A MS;
(b) NaBH4/MeOH; (c) Ph3PꢀCHCOMe/PhMe/D.
2 with N-methylmorpholine N-oxide catalyzed by tetra-
n-propylammonium perruthenate (TPAP)9 yielded the
aldehyde 3 according to its NMR spectra, where two
rotameric forms for 3 could clearly be observed [signals
for formyl group at l 9.51d (J 1.3 Hz) and 9.43d (J 2.3
Hz)]. That rotamers of 3, which are expected for N-acyl
pyrrolidines,10 and not epimers at C (5), actually exist
could be demonstrated by its sodium borohydride
reduction to starting 2. Subsequent treatment of 3 with
3. Conclusions
Finally, two important conclusions can be drawn from
the above results: that partially protected polyhydroxyl-
ated pyrrolidines, derived from common hexuloses,
together with a classical Wittig’s methodology are both
suitable for the enantiosynthesis of complex polyhy-
1-triphenylphosphoranylidene-2-propanone
afforded
(E)-4-[(2%R,3%R,4%R,5%R)-3%,4%-dibenzyloxy-N-tert-butyl-
oxycarbonyl-5%-tert-butyldiphenylsilyloxymethylpyrro-
lidin-2%-yl]but-3-en-2-one 4 in a highly stereoselective
manner. The structure of 4, which also exists as a
mixture of rotamers, was determined on the basis of its
analytical and spectroscopic data, where the E configu-
ration was established from the J3,4 value (16.2 Hz).
droxylated
pyrrolizidines
alkaloids,
and
that
(1R,2R,3R,5R,7aR) is the actual configuration for the
natural (+)-hyacinthacine A3.
4. Experimental
4.1. General
Catalytic hydrogenation (10% Pd–C) of 4 afforded the
1
protected saturated ketone 5, according to the H and
Solutions were dried over MgSO4 before concentration
13C NMR spectra of an aliquot, which showed the
absence of rotameric forms. Addition of hydrochloric
acid to the above hydrogenation reaction mixture
achieved the complete N- and O-deprotection of 5 to 6,
in order to promote the required cyclization to the
pyrrolizidine skeleton. Thus, neutralization [Amberlite
IRA-400 (OH− form)], followed by a second catalytic
hydrogenation of 6, as above, afforded (+)-
hyacinthacine A3 1, [(1R,2R,3R,5R,7aR)-1,2-dihydroxy-
3-hydroxymethyl-5-methylpyrrolizidine] in only one
step, which physical and spectroscopic data (see Figs. 1
and 2) closely matching those previously reported1b for
the natural compound. Formation of 1 must take place,
according to Scheme 3, by a subsequent internal con-
densation to the intermediate D5-pyrrolizine A, not
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). IR spectra were recorded with a Perkin–
Elmer 782 instrument and mass spectra with
a
Micromass Mod. Platform II and Autospec-Q mass
spectrometers. Optical rotations were measured for
solutions in CHCl3 (1 dm tube) with a Jasco DIP-370
polarimeter. TLC was performed on precoated E.
Merck silica gel 60 F254 aluminum sheets with detection
by employing a mixture of 10% ammonium molybdate
(w/v) in 10% aqueous sulfuric acid containing 0.8%
cerium sulfate (w/v) and heating. Column chromatogra-
phy was performed on silica gel (E. Merck, 7734). All
the compounds were shown to be homogeneous by

I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1581–1585
1583
1
Figure 1. 2D H–1H COSY for (+)-hyacinthacine A3.
of the starting material and the presence of a faster-run-
ning compound. The reaction was filtered through a
bed of Silica gel 60 (Scharlau, 230–400 mesh) and
thoroughly washed with dichloromethane. The com-
bined filtrate and washings were concentrated to a
residue, presumably [(2%S,3%R,4%R,5%R)-3%,4%-dibenzyl-
oxy-N-tert-butyloxycarbonyl-5%-tert-butyldiphenylsilyl-
oxymethylpyrrolidin-2%-yl]carbaldehyde 3 as a syrup.
NMR (300 MHz) data (inter alia), l: 9.51 (d, J2%,CHO
1.3 Hz) and 9.43 (d, J2%,CHO 2.3 Hz); 13C NMR, l:
200.47 and 200.26 (CHO). Compound 3 was dissolved
in toluene (10 mL) and 1-triphenylphosphoranylidene-
2-propanone (460 mg, 1.44 mmol) was added and the
mixture refluxed for 24 h. TLC (ether/hexane, 1:2) then
revealed the presence of a slightly slower-running com-
chromatography and characterized by NMR spec-
troscopy and FAB-HRMS with thioglycerol matrix.
4.2. (E)-4-[(2%R,3%R,4%R,5%R)-3%,4%-Dibenzyloxy-N-tert-
butyloxycarbonyl-5%-tert-butyldiphenylsilyl
oxymethylpyrrolidin-2%-yl]but-3-en-2-one 4
To a stirred solution of (2R,3R,4R,5R)-3,4-dibenzyl-
oxy-N-tert-butyloxycarbonyl-2%-O-tert-butyldiphenyl
silyl-2,5-bis(hydroxymethyl)pyrrolidine8a
2
(360 mg,
0.53 mmol) in dry dichloromethane (5 mL), were added
,
activated 4 A molecular sieve (270 mg), N-methylmor-
pholine N-oxide (92 mg, 0.79 mmol) and TPAP (19 mg)
and the reaction mixture kept at room temperature for
2 h. TLC (ether/hexane, 2:1) then indicated the absence

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I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1581–1585
1
Figure 2. 2D H–13C COSY for (+)-hyacinthacine A3.
pound. The reaction mixture was filtered and supported
on silica gel, then chromatographed (ether/hexane, 1:1)
4.3. (+)-Hyacinthacine A3 [1 (1R,2R,3R,5R,7aR)-1,2-
dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine]
to afford 4 (380 mg, quantitative) as a thick syrup: [h]D26
film
max
+16 (c 1); w
3067 and 3033 (aromatic), 1697, 1679
Compound 4 (380 mg, 0.52 mmol) in dry methanol (20
mL) was hydrogenated at 4 atm over 10% Pd–C (142 g)
for 12 h. TLC (ether/hexane, 2:1) then showed a com-
pound, presumably 5, with the same mobility. An
aliquot was concentrated and showed the following
and 1632 (CꢀO, conjugated ketone, Boc, and CꢀC
conjugated), 739 and 700 cm−1 (aromatic). H NMR
1
(300 MHz) data (inter alia): 6.70 and 6.68 (2dd, 1H,
J2%,4 7.6 and 8.7 Hz, H-4 for the two rotamers), 6.10 and
6.00 (2d, 1H, J3,4 16.2 Hz, H-3 for the two rotamers),
2.17 and 2.13 (2s, 3H, H-1,1,1 for the two rotamers),
1.33 and 1.27 (2s, 9H, Me3CO for the two rotamers),
1.06 and 1.04 (2s, 9H, Me3CSi for two rotamers). Mass
spectrum (LSIMS): m/z: 742.3537 [M++Na] for
C44H53NO6NaSi 742.3540 (deviation +0.3 ppm).
1
NMR data: H NMR, l: 7.68–7.20 (2m, 20H, 5 Ph),
4.68 and 4.58 (2d, 2H, J 12.2 Hz, CH2Ph), 4.45 and
4.42 (2d, 2H, J 12.6 Hz, CH2Ph), 4.40 (s, 1H, H-4%),
4.26 (d, 1H, J2%,3% 6.3 Hz, H-3%), 4.07 (dd, 1H, J5%,5%%a 4.7,
J5%%a,5%%b 10.5 Hz, H-5%%a), 4.00 (dd, 1H, J5%,5%%b 8.8 Hz,
H-5%), 3.78 (m, 1H, H-2%), 3.64 (bt, 1H, H-5%%b), 2.45

I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1581–1585
1585
(C-7a), 64.96 (C-3), 62.65 (C-5), 61.82 (C-8), 32.87
(C-6), 29.26 (C-7), and 16.49 (Me-5). Mass spectrum
(LSIMS): m/z: 188.1292 [M++H] for C9H18NO3
188.1287 (deviation −2.7 ppm).
Acknowledgements
The authors are deeply grateful to Ministerio de Cien-
cia y Tecnolog´ıa (Spain) for financial support (Project
PB98-1357) and for a grant (F. Franco).
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Figure 3. NOE interactions in 1 and hydrogenation pathway
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(ddd, 1H, J 6.0, J 9.5, J 16.0 Hz, H-3a), 2.35–2.17 (2 m,
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(ether–methanol–triethylamine,
1:1:0.1) yielded pure syrupy 1 (68 mg, 70% from 4):
405
[h]D25 +14, [h] +42 (c 0.55, water) [lit.1b [h]2D5 +19.2 (c
26
0.43, water)]. NMR data (400 MHz, D2O): l: 3.91 (bt,
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H-1) 3.71 (d, 2H, J3,8 4.5 Hz, H-8,8), 3.59 (dt, 1H,
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1H, H-3), 2.03–1.92 (m, 2H, H-6,7), 1.88–1.80 (m, 1H,
H-7%), 1.73–1.63 (m, 1H, H-6%), 1.24 (d, 3H, J5,Me 6.8
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