A new synthetic approach to (+)-hyacinthacine A1 and the first total synthesis and absolute configuration assignment of naturally occurring (+)-hyacinthacine A6

Article abstract of DOI:10.1002/ejoc.200700820

Naturally occurring (1S,2R,3R,7aR)-1,2-dihydroxy-3- hydroxymethylpyrrolizidine [(+)-hyacinthacine A₁ (1)] and (1S,2R,3R,5R,7aR)-1,2-dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine [(+)-hyacinthacine A₆ (2)] have been synthesized by W

Full text of DOI:10.1002/ejoc.200700820

RETRACTION
DOI: 10.1002/ejoc.200900576
A New Synthetic Approach to (+)-Hyacinthacine A1 and the First Total
Synthesis and Absolute Configuration Assignment of Naturally Occurring
(+)-Hyacinthacine A6
Isidoro Izquierdo,*[a] María T. Plaza,[a] Juan A. Tamayo,[a] and
Fernando Sánchez-Cantalejo[a]
Keywords: Alkaloids / Azasugars / Hyacinthacines / Enantioselectivity / Synthetic methods / Enzyme inhibitors
After publication of this Full Paper,[1] the authors learned, through
further NMR analysis, that the structures of products 9, 13, 14, 15
and 2 had been incorrectly deduced. As such, the names of the given
products are also incorrect. The authors therefore retract this Full
Paper and apologize for any inconvenience this may have caused.
The Authors
[1] I. Izquierdo, M.-T. Plaza, J.-A. Tamayo, F. Sánchez-Cantalejo,
Eur. J. Org. Chem. 2007, 6078–6083.
Received: May 20, 2009
Published Online: June 17, 2009
[a] Department of Medicinal and Organic Chemistry, Faculty of
Pharmacy, University of Granada,
18071 Granada, Spain
Fax: +34-958-243845
E-mail: jtamayo@ugr.es
Eur. J. Org. Chem. 2009, 3809
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3809

FULL PAPER
DOI: 10.1002/ejoc.200700820
A New Synthetic Approach to (+)-Hyacinthacine A1 and the First Total
Synthesis and Absolute Configuration Assignment of Naturally Occurring
[‡]
(+)-Hyacinthacine A6
Isidoro Izquierdo,*[a] María T. Plaza,[a] Juan A. Tamayo,[a] and
Fernando Sánchez-Cantalejo[a]
Keywords: Alkaloids / Azasugars / Hyacinthacines / Enantioselectivity / Synthetic methods / Enzyme inhibitors
Naturally occurring (1S,2R,3R,7aR)-1,2-dihydroxy-3-hy-
droxymethylpyrrolizidine [(+)-hyacinthacine A1 (1)] and
(1S,2R,3R,5R,7aR)-1,2-dihydroxy-3-hydroxymethyl-5-meth-
ylpyrrolizidine [(+)-hyacinthacine A6 (2)] have been synthe-
sized by Wittig’s methodology using aldehyde 7, prepared
unsaturated ester 8 or ketone 9, which were submitted to
internal lactamization and reductive amination, respectively,
to give the corresponding intermediate pyrrolizidin-5-one 11
and the totally protected pyrrolizidine 14. Compounds 11 and
14 were easily transformed into the above hyacinthacines 1
and 2, respectively.
from
(2R,3S,4R,5R)-3,4-bis(benzyloxy)-2Ј-O-(tert-butyldi-
phenylsilyl)-2,5-bis(hydroxymethyl)pyrrolidine (3, partially
protected DALDP), as the homochiral starting material and
the appropriated ylide to afford either the corresponding α,β-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Polyhydroxylated pyrrolidine (DMDP), piperidine
(DMJ), indolizidine (castanospermine), pyrrolizidine (alex-
ine and australine) and nortropane (calystegine B2) alka-
loids (imino- or azasugars) have increasingly gained atten-
tion because of their capacity to inhibit glycosidases. This
class of inhibitors was first discovered in plants in which
these azasugars were found to protect the plants by in-
hibiting the carbohydrate-processing enzymes of preda-
tors.[1]
3-(Hydroxymethyl)pyrrolizidines form a new class of
polyhydroxylated pyrrolizidines isolated from flowering and
leguminous plants.[2] The first examples of this family were
alexine, isolated in 1988 from Alexa leiopetala by Nash et
al.,[3] and australine, isolated in the same year from the
seeds of Castanospermum australe by Molyneux et al.[4] (see
Figure 1). More recently, a series of hyacinthacines have
been isolated from bluebells (Hyacinthoides non-scripta),[5]
grape hyacinths (Muscari armeniacum)[6] and from the bulbs
of Scilla sibirica,[7] Scilla peruviana[8] and Scilla socialis[9]
by Asano and co-workers.
Figure 1. Naturally occurring polyhydroxylated alkaloids (imino-
or azasugars).
Since the discovery of these nitrogen-containing inhibi-
tors, many medical studies have been performed to find out
if their inhibitory activity could be used in therapeutic ap-
plications. Swainsonine is one of the most widely studied
polyhydroxylated alkaloids. Clinical trials have shown that
it prevents tumour formation at new invasion sites, en-
hances antibody response to cancerous tumours and im-
proves stem cell formation in bone marrow.[10] Other studies
have shown azasugars to aid the treatment of diabetes and
HIV/AIDS.[1,11,12] Consequently, these inhibitors have enor-
mous medical potential; however, the few naturally occur-
ring iminosugars that have been isolated so far represent
only a small fraction of the possible azasugars that could
be potent medical agents.
[‡] Polyhydroxylated Pyrrolizidines, 9. Part 8: Ref.[15g]
[a] Department of Medicinal and Organic Chemistry, Faculty of
Pharmacy, University of Granada,
18071 Granada, Spain
Fax: +34-958-243845
E-mail: isidoro@ugr.es
With the aim of exploring the whole chemical space oc-
cupied by the azasugars, syntheses of these compounds have
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
6078
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6078–6083

Synthesis of (+)-Hyacinthacine A1 and (+)-Hyacinthacine A6
been and must continue to be developed. In addition, natu- the primary alcohol free for oxidation to aldehyde 7 (IR
rally occurring azasugars are present in scarce quantities in evidence: ν = 1725 cm–1 and no hydroxy absorption band)
˜
natural sources and are often difficult to be purified,[13] and by N-methylmorpholine N-oxide (NMO) catalyzed by tetra-
therefore synthetic routes to these iminosugars and ana- n-propylammonium perruthenate (TPAP) in preparation
logues are also wanted. In this context in recent years our for Wittig-chain lengthening. In the event, either methyl
group has developed a synthetic methodology involving the (triphenylphosphoranylidene)acetate or 1-(triphenylphos-
use of appropriately functionalized and protected pyrrol- phoranylidene)-2-propanone reacted with aldehyde 7 to
idines[14] as key intermediates for the preparation of more yield the corresponding α,β-unsaturated ester 8 or ketone
complex
polyhydroxylated
pyrrolizidine
alkaloids 9, respectively, as a mixture of rotamers (1H NMR evi-
(PHPAs).[15] On the other hand, such polyhydroxylated pyr- dence). As expected, only the stereoisomer with the (E) con-
rolidines have been prepared from the commercially avail- figuration was obtained in both cases (8: J2,3 = 15.6 Hz; 9:
able hexulose, -fructose. Herein, we describe our studies J3,4 = 16.0 Hz).
on (+)-hyacinthacine A1 (1) and (+)-hyacinthacine A6 (2)
which culminated in the second reported total enantioselec-
tive synthesis of 1[16] and the first total synthesis and abso-
lute configuration assignment of 2.[7]
Our retrosynthetic strategy towards PHPAs 1 and 2 is
illustrated in Figure 2 in which a simple cleavage of the
N(4)–C(5) bond in the pyrrolizidine skeleton and a Wittig-
type disconnection at either C(2)–C(3) or C(3)–C(4) of the
α,β-unsaturated pyrrolidine ester 8 and ketone 9, respec-
tively, reveals the key triorthogonally protected and
stereochemically loaded 2,5-dideoxy-2,5-imino--altritol
(DALDP, 3)[14c] as the precursor.
Scheme 1. Synthesis of α,β-unsaturated pyrrolidine ester 8 and
ketone 9 from triorthogonally protected DALDP (3). Reagents and
conditions: a) (tBuOCO)2O/DCM/TEA, r.t.; b) BzCl/DCM/TEA,
r.t.; c) TBAF·3H2O/THF, r.t.; d) NMO/TPAP/DCM/MS (4 Å), r.t.;
e) for 8 Ph3P=CHCO2Me, for 9 Ph3P=CHCOMe/MePh, 80 °C.
[** refer to H(2)–H(3) in ester 8 and H(3)–H(4) in ketone 9.].
Scheme 2 displays all the chemical transformations nec-
essary to achieve the synthesis of 1. Thus, catalytic (10%
Pd/C) hydrogenation of 8 afforded the intermediate satu-
rated pyrrolidine ester (no signals due to vinylic protons
1
were observed in the H NMR spectrum of an aliquot of
the reaction mixture) which was not further investigated but
submitted to N-deprotection in an acidic medium to afford
intermediate 10. This intermediate was subsequently treated
with base (MeONa/MeOH) to promote internal lactamiz-
ation and concomitant O-debenzoylation to afford the pyr-
Figure 2. Retrosynthesis of hyacinthacines A1 (1) and A6 (2) from
a triorthogonally protected derivative of DALDP (3).
rolizidin-5-one 11 which was completely characterized on
the basis of its analytical and spectroscopic data. Reduction
Results and Discussion
According to the above retrosynthetic analysis and based
on the results from previous studies,[15] we began the syn-
thesis (see Scheme 1) with (2R,3S,4R,5R)-3,4-bis(benzyl-
oxy)-2Ј-O-(tert-butyldiphenylsilyl)-2,5-bis(hydroxymethyl)-
pyrrolidine (3) which was chemoselectively transformed
into its N-Boc derivative 4 by treatment with di-tert-butyl
dicarbonate in dichloromethane (DCM)/triethylamine
(TEA). Conventional benzoylation of 4 to the correspond-
ing 5-(benzoyloxymethyl) derivative 5 followed by O-de-
Scheme 2. Synthesis of (+)-hyacinthacine A1 (1) from 8. Reagents
and conditions: a) 10% Pd/C, H2, balloon, r.t.; b) i. TFA/DCM,
room temp.; ii. neutralization with MeONa/MeOH; c) MeONa
(cat.)/MeOH, ∆; d) H3B·SMe2/THF, then MeOH, ∆; e) conc. HCl/
conditions of (a), then Amberlite IRA-400 (OH– form) and
silylation afforded the pyrrolidine 6, opportunely leaving chromatography on Dowex 50Wϫ8 (200–400 mesh).
Eur. J. Org. Chem. 2007, 6078–6083
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6079

I. Izquierdo, M. T. Plaza, J. A. Tamayo, F. Sánchez-Cantalejo
Finally, total O-deprotection of 15 allowed us to achieve
FULL PAPER
of the lactam carbonyl group with H3B·SMe2 complex to
12 followed by its total O-debenzylation finally gave (+)- the first enantioselective synthesis of (+)-hyacinthacine A6
hyacinthacine A1 (1) which had physical and spectroscopic (2) which had analytical, spectroscopic and optical data in
data in accordance with those previously reported for the accordance with those reported for the naturally occurring
natural product.[6]
product. For example, the optical rotation of the synthetic
According to a similar protocol, but with 9, the naturally material was [α]2D6 = +15.8 (c = 0.5, water) and that of natu-
occurring (+)-(2) was synthesized for the first time (see ral (+)-hyacinthacine A6 was [α]2D6 = +16.3 (c = 0.22,
Scheme 3). Thus, catalytic hydrogenation and N-deprotec- water).[7]
tion of 9 yielded the intermediate pyrrolidine ketone 13,
intramolecular condensation gave the intermediate ∆5-pyr-
rolizine A, which was not isolated, and hydrogenation fi-
nally gave the fully protected pyrrolizidine 14, slightly con-
Conclusions
The highlights of this report are a new synthetic route to
(+)-hyacinthacine A1, the first total enantioselective synthe-
sis of naturally occurring (+)-hyacinthacine A6, its actual
configuration being (1S,2R,3R,5R,7aR), and, finally, that
partially triorthogonally protected polyhydroxylated pyr-
rolidines derived from common hexuloses, combined with
a classical Wittig methodology, are in general amenable to
the preparation of analogues and derivatives of hyacinthac-
ines that will be useful in the evaluation of the biological
and therapeutic potential of this kind of compounds.
taminated, which could be isolated in a pure state after
Zemplen debenzoylation to 15.
Experimental Section
General Remarks: Solutions were dried with MgSO4 before concen-
tration under reduced pressure. The 1H and 13C NMR spectra were
recorded with Bruker AMX-300, AM-300 and ARX-400 spectrom-
eters for solutions in CDCl3 (internal standard Me4Si). IR spectra
were recorded with a Perkin-Elmer FT-IR Spectrum One instru-
ment and mass spectra were recorded with a Hewlett-Packard HP-
5988A and Fisons mod. Platform II and VG Autospec-Q mass
spectrometers. Optical rotations were measured in CHCl3 (1-dm
tube) with a Jasco DIP-370 polarimeter. TLC was performed on
precoated silica gel 60 F254 aluminium sheets and detection was
achieved 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 chromatography was performed on sil-
ica gel (Merck 7734). All compounds were shown to be homogen-
eous by chromatographic methods and characterized by NMR, MS
and HRMS.
Scheme 3. Synthesis of (+)-hyacinthacine A6 (2) from 9. Reagents
and conditions: a) 10% Pd/C, H2, MeOH, room temp., b) i. conc.
HCl/MeOH, r.t.; ii. neutralization with MeONa/MeOH; c)
MeONa (cat.)/MeOH, r.t.; d) conc. HCl/conditions of (a), then
Amberlite IRA-400 (OH– form) and chromatography on Dowex
50Wϫ8 (200–400 mesh).
The configuration of the new stereogenic centre C-5 in 15
was determined on the basis of extensive NOE experiments,
results of which are displayed in Figure 3. Thus, the definite
NOE effects observed between 5-Me and 3-H and between
5-H and 2-H/8-H in 15, indicate the (R) configuration at C-
5. In addition, the rest of the NOE interactions also con-
firmed the complete stereochemistry of 15.
(2R,3S,4R,5R)-3,4-Bis(benzyloxy)-N-(tert-butyloxycarbonyl)-2Ј-O-
(tert-butyldiphenylsilyl)-2,5-bis(hydroxymethyl)pyrrolidine (4): Tri-
ethylamine (TEA, 510 µL, 3.66 mmol) and di-tert-butyl dicarbon-
ate (700 mg, 3.23 mmol) were added to a stirred solution of 3 in
dry dichloromethane (DCM, 20 mL) cooled in ice/water (1.25 g,
2.15 mmol), and the mixture was kept at room temperature (r.t.)
overnight. TLC (Et2O/hexane, 1:1, v/v) then revealed the presence
of a faster running compound. The reaction mixture was quenched
with methanol (MeOH, 1 mL), then supported on silica and sub-
mitted to chromatography (Et2O/hexane, 1:3, v/v) to give 4 as a
colourless syrup. Yield: 1.45 g (quantitative). [α]2D8 = +11 (c = 1).
Figure 3. Main observed NOE effects in 15 and scheme for the
hydrogenation of intermediate ∆5-pyrrolizine A.
The high stereoselectivity found in the hydrogenation of
intermediate ∆5-pyrrolizine A, in which 2 was the only pyr-
rolizidine detected and isolated, merits comment. The for-
mation of 2 can be attributed, according to our previous
results[15b] and Figure 3, to the particular shape of this kind
of molecule[6,17] in which the β-face is less hindered for hy-
drogen attack than the α-face, preferentially affording com-
pound 2.
IR (neat): ν = 3425 (OH), 3069 (aromatic), 1690 (C=O, Boc), 731
˜
1
and 700 cm–1 (aromatic). H NMR (400 MHz): δ = 7.70–7.27 (m,
20 H, 4 Ph), 4.83 and 4.72 (2 d, J = 12.0 Hz, 2 H, CH2Ph), 4.70–
4.61(2 d, J = 12 Hz, 2 H, CH2Ph), 4.38 (dd, J = 8, J = 9.2 Hz, 1
H), 4.15–3.55 (5 br. m, 7 H), 1.25 and 1.06 (2 s, 18 H, 2 CMe3)
ppm. 13C NMR (inter alia): δ = 79.9 and 77.7 (C-3,4), 73.1 and
72.6 (2 CH2Ph), 64.8 and 62.9 (C-2Ј,5Ј), 64.7 and 61.2 (C-2,5), 28.4
and 27.2 (2 CMe3), 19.8 (2 CMe3) ppm. HRMS (LSIMS): calcd.
6080
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6078–6083

Synthesis of (+)-Hyacinthacine A1 and (+)-Hyacinthacine A6
for C41H51NO6NaSi [M + Na]+ 704.3383; found 704.3375 (devia-
tion +1.2 ppm).
s, 3 H, OMe, 2 rotamers), 1.46 and 1.40 (2 br. s, 9 H, CMe3, 2
rotamers) ppm. 13C NMR (inter alia): δ = 166.35 and 166.29
(COPh, C-1), 147.2 (C-3), 123.8 (C-2), 72.2 (CH2Ph), 62.4, 51.8
(OMe), 28.5 (CMe3 ) ppm. HRMS (LSIMS): calcd. for
C35H39NO8Na [M + Na]+ 624.2573; found 624.2568 (deviation
+0.9 ppm).
(2R,3R,4S,5R)-2Ј-O-Benzoyl-3,4-bis(benzyloxy)-N-(tert-butyloxy-
carbonyl)-5Ј-O-(tert-butyldiphenylsilyl)-2,5-bis(hydroxymethyl)pyr-
rolidine (5): TEA (450 µL, 3.22 mmol), DMAP (50 mg) and BzCl
(272 µL, 2.34 mmol) were added to a stirred solution of 4 (1.45 g,
2.13 mmol) in dry DCM (25 mL) and the mixture was left at room
temp. overnight. TLC (Et2O/hexane, 1:1, v/v) then revealed a faster
running compound. Conventional workup of the reaction mixture
and column chromatography (Et2O/hexane, 1:3, v/v) afforded pure
5 (1.3 g, 78%) as a colourless syrup. [α]2D7 = +14 (c = 1). IR (neat):
4-[(3E,2ЈR,3ЈS,4ЈR,5ЈR)-5Ј-(Benzoyloxymethyl)-3Ј,4Ј-bis(benzyl-
oxy)-NЈ-(tert-butyloxycarbonyl)pyrrolidin-2Ј-yl]but-3-en-2-one (9):
Activated molecular sieves (4 Å) (100 mg), NMO (250 mg,
2.15 mmol) and TPAP (100 mg) were added to a stirred solution of
6 (785 mg, 1.44 mmol) in dry DCM (15 mL), and the reaction mix-
ture was kept at room temp. for 90 min. TLC (Et2O/hexane, 3:1,
v/v) then indicated the absence of the starting material and the
presence of a faster running compound. The reaction mixture was
diluted with Et2O (50 mL), filtered through a bed of silica gel 60
(Scharlau, 230–400 mesh) and thoroughly washed with Et2O. The
combined filtrate and washings were concentrated to afford pre-
sumably aldehyde 7. This material was used in the next step. 1-
(Triphenylphosphoranylidene)-2-propanone (685 mg, 2.15 mmol)
was added to a stirred solution of the above 7 in dry toluene
(20 mL) and the mixture refluxed. After 2 h, TLC (Et2O/hexane,
3:1, v/v) revealed the presence of a new compound of slightly lower
mobility. The solvent was removed, and the residue was purified
by chromatography on silica gel (Et2O/hexane, 1:5, v/v) to give pure
9 (600 mg, 71% from 6) as a colourless syrup. [α]2D6 = –30 (c = 1).
ν = 3069 and 3032 (aromatic), 1724 (COPh), 1698 (ϾNBoc),
˜
1
737 and 708 cm–1 (aromatic). H NMR (400 MHz): δ = 7.88–7.23
(4 m, 25 H,
5 Ph), 4.90–3.75 (5 m, 12 H, 2 CH2Ph,
2,2Јa,2Јb,3,4,5,5Јa,5Јb-H), 1.30 and 1.08 (2 s, 18 H, 2 CMe3) ppm.
13C NMR (inter alia): δ = 166.2 (COPh), 80.5, 79.2 and 78.2 (C-
3,4, 2 rotamers), 72.8 and 72.4 (2 CH2Ph), 63.5 and 62.7 (C-2Ј,5Ј),
60.9 and 60.6 (C-2,5), 28.4 and 27.2 (2 CMe3), 19.4 (CMe3) ppm.
HMRS (LSIMS): calcd. for C48H55NO7NaSi [M + Na]+ 808.3646;
found 808.3650 (deviation –0.5 ppm).
(2R,3R,4S,5R)-2Ј-O-Benzoyl-3,4-bis(benzyloxy)-N-(tert-butyloxy-
carbonyl)-2,5-bis(hydroxymethyl)pyrrolidine (6): TBAF·3H2O
(500 mg, 1.59 mmol) was added to a stirred solution of 5 (1.13 g,
1.44 mmol) in THF (20 mL), and the mixture was kept at room
temp. overnight. TLC (Et2O/hexane, 1:1, v/v) then showed a new
compound of lower mobility. The mixture was neutralized with ace-
tic acid, concentrated to a residue that was dissolved in Et2O,
washed with brine, concentrated and then submitted to column
chromatography (Et2O/hexane, 1:5, v/v Ǟ Et2O) to yield pure 6
IR (neat): ν = 3063 and 3031 (aromatic), 1722 and 1699 (BzO, α,β-
˜
1
unsaturated ketone and ϾNBoc), 738 and 712 cm–1 (aromatic). H
NMR (400 MHz): δ = 7.79 (d, Jo,m = 7.2 Hz, 2 H, ortho-H, Bz),
7.49 (t, Jm,p = 7.2 Hz, 1 H, para-H, Bz), 7.32 (t, 2 H, meta-H, Bz),
7.30–7.18 (m, 10 H, 2 Ph), 6.46 (dd, J2Ј,4 = 6.0, J3,4 = 16 Hz, 1 H,
4-H), 6.08 (d, 1 H, 3-H), 4.78–3.79 (4 br. m, 10 H, 2 CH2Ph and
2Ј,3Ј,4Ј,5Ј,5ЈЈa,5ЈЈb-H), 2.00–1.90 (2 br. s, 3 H, 1-H, 2 rotamers),
1.41 and 1.32 (2 br. s, 9 H, CMe3, 2 rotamers) ppm. 13C NMR
(inter alia), δ = 197.7 (C-2), 166.1 (Bz), 155.1 (Boc), 145.9 and
144.2 (C-3,4), 81.0, 78.4, 76.9 and 75.7 (C-3Ј,4Ј, 2 rotamers), 71.6
(2 CH2Ph), 63.1 (C-5ЈЈ), 61.8 and 60.3 (C-2Ј,5Ј), 28.0 (CMe3), 27.2
(C-1) ppm. HRMS (LSIMS): calcd. for C35H39NO7Na [M + Na]+
608.2624; found 608.2621 (deviation +0.6 ppm).
(700 mg, 88%) as a colourless syrup. [α]2D9 –30 (c = 1). IR (neat): ν
˜
= 3459 (OH), 3088 and 3064 (aromatic), 1723 (COPh), 1696
(ϾNBoc), 712 and 700 cm–1 (aromatic). 1H NMR (400 MHz): δ
= 7.94–7.27 (4 m, 15 H, 3 Ph), 4.78–3.85 (7 m, 13 H, 2 CH2Ph,
2,2Јa,2Јb,3,4,5,5Јa,5Јb-H,OH), 1.50 (s, 9 H, CMe3) ppm. 13C NMR
(inter alia): δ = 166.29 and 166.16 (COPh, 2 rotamers), 155.1 and
154.3 (Boc, 2 rotamers), 81.4, 80.9 and 78.6 (C-3,4, 2 rotamers),
72.76, 72.57, 72.35 and 72.23 (2 CH2Ph, 2 rotamers), 63.54, 63.06,
61.3 and 59.6 (C-2Ј,5Ј, 2 rotamers), 61.23, 61.21, 60.99 and 59.36
(C-2,5, 2 rotamers), 28.65 and 28.63 (CMe3, 2 rotamers), 19.5
(CMe3) ppm. HRMS (LSIMS): calcd. for C32H37NO7Na
[M + Na]+ 570.2468; found 570.2466 (deviation +0.3 ppm).
(1S,2R,3R,7aR)-1,2-Bis(benzyloxy)-3-(hydroxymethyl)pyrrolizidin-
5-one (11): Compound 8 (512 mg, 0.85 mmol) in dry MeOH
(20 mL) was hydrogenated with H2 from a balloon in the presence
of 10% Pd/C (80 mg) for 2 h. TLC (Et2O/hexane, 2:1, v/v) then
Methyl 3-[(2E,2ЈR,3ЈS,4ЈR,5ЈR)-5Ј-(Benzoyloxymethyl)-3Ј,4Ј- showed the presence of a new compound of slightly lower mobility.
bis(benzyloxy)-NЈ-(tert-butyloxycarbonyl)pyrrolidin-2Ј-yl]propeno-
ate (8): Activated powdered molecular sieves (4 Å) (100 mg), N-
methylmorpholine N-oxide (210 mg, 1.77 mmol) and TPAP
(100 mg) were added to a solution of 6 (645 mg, 1.18 mmol) in
dry DCM (20 mL), and the reaction mixture was kept at room
temperature for 1 h. TLC (Et2O/hexane, 1:1, v/v) then showed a
faster running compound. The reaction mixture was diluted with
Et2O (30 mL), filtered through a bed of silica gel 60 (Scharlau,
230–400 mesh) and thoroughly washed with Et2O. The combined
filtrate and washings were concentrated to aldehyde 7 which was
dissolved in toluene (20 mL). Methyl (triphenylphosphoranyl-
idene)acetate (470 mg, 1.4 mmol) was added, and the reaction mix-
ture was refluxed for 24 h. The solvent was removed and the residue
submitted to column chromatography (Et2O/hexane, 1:5 Ǟ 2:1,
v/v) to afford syrupy 8 (420 mg, 59%, from 6). [α]3D0 = –12 (c = 1).
The catalyst was filtered off, washed with MeOH, and the filtrate
and washings were concentrated to a residue that was dissolved in
DCM (8 mL) and cooled (ice/water). TFA (8 mL) was added to
this stirred solution and the mixture left for 1.5 h. TLC (Et2O/hex-
ane, 2:1, v/v) then revealed a non-mobile compound. The solvent
was removed and the residue co-distilled with toluene to give a new
residue which was dissolved in MeOH and basified by addition of
2  MeONa/MeOH and refluxed for 2 h. TLC (Et2O/MeOH, 20:1,
v/v) showed a slower running compound. The reaction mixture was
neutralized and submitted to column chromatography (Et2O/
MeOH, 20:1 Ǟ 10:1, v/v) to afford pure 11 (270 mg, 86% from 8)
as a colourless syrup. [α]2D7 = –6, [α]27 = –10 (c = 1). IR (neat): ν
˜
405
= 3365 (OH), 3031 (aromatic), 1667 (C=O lactam), 739 and
698 cm–1 (aromatic). 1H NMR (500 MHz): δ = 7.40–7.28 (m, 10 H,
2 Ph), 4.66 and 4.63 (2 d, J = 12.0 Hz, 2 H, CH2Ph), 4.61 and 4.50
(2 d, J = 11.9 Hz, 2 H, CH2Ph), 4.21 (br. q, 1 H, 7a-H), 3.93 (dd,
IR (neat): ν = 1723, 1715, 1699 and 1662 (PhCO, α,β-unsaturated
˜
ester, ϾNBoc and C=C), 738, 712 and 700 cm–1 (aromatic). 1H
J3,8 = 2.6, J8,8Ј = 12.0 Hz, 1 H, 8-H), 3.86 (dd, J1,2 = 5.5, J2,3 =
NMR (400 MHz): δ = 7.94–7.27 (3 m, 15 H, 3 Ph), 6.81 (dd, J2,3 3.0 Hz, 1 H, 2-H), 3.83 (m, 1 H, 3-H), 3.68 (dd, J3,8Ј = 7.9 Hz, 1
= 15.6, J2Ј,3 = 5.6 Hz, 1 H, 3-H), 5.96 (d, 1 H, 2-H), 4.72–3.73 (br. H, 8Ј-H), 3.51 (dd, J1,7a = 7.9 Hz, 1 H, 1-H), 2.68 (ddd, J6,6Ј
m, 10 H, 2 CH2Ph and 2Ј,3Ј,4Ј,5Ј,5ЈЈa,5ЈЈb-H), 3.68 and 3.60 (2 br. 16.7 Hz, 1 H, 6-H), 2.44 (dd, J6Ј,7Ј = 8.9, J6Ј,7 = 0 Hz, 1 H, 6Ј-H),
=
Eur. J. Org. Chem. 2007, 6078–6083
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6081

I. Izquierdo, M. T. Plaza, J. A. Tamayo, F. Sánchez-Cantalejo
FULL PAPER
2.28 (br. dt, J6,7 = J7,7a = 7.8, J7,7Ј = 12.3 Hz, 1 H, 7-H), 1.74 (tt,
J6,7Ј = 12.3, J7Ј,7a = 9.2 Hz, 1 H, 7Ј-H) ppm. 13C NMR (inter alia):
δ = 174.5 (C-5), 81.9 (C-2), 81.0 (C-1), 72.5 and 72.4 (2 CH2Ph),
65.6 (C-7a), 64.7 (C-3), 63.0 (C-8), 35.7 (C-6), 26.9 (C-7) ppm.
and an aliquot was concentrated to afford the intermediate satu-
rated ketone (IR evidence). The reaction mixture was then acidified
with conc. HCl (0.2 mL) and left at room temp. for 72 h. Neutral-
ization of the reaction mixture with 2  MeONa/MeOH and subse-
HRMS (LSIMS): calcd. for C22H25NO4Na [M + Na]+ 390.1681; quent hydrogenation in the presence of 10% Pd/C (100 mg) for 12 h
found 390.1675 (deviation +1.7 ppm).
gave, after removal of the catalyst and column chromatography
(Et2O/hexane, 1:3 Ǟ Et2O), compound 14 (150 mg), slightly con-
taminated. Finally, Zemplen debenzoylation of 14 with 2 
MeONa/MeOH (0.5 mL) for 12 h followed by column chromatog-
raphy (Et2O/hexane, 1:1 Ǟ 2:1, v/v) afforded pure 15 (90 mg, 24%
(1S,2R,3R,7aR)-1,2-Bis(benzyloxy)-3-(hydroxymethyl)pyrrolizidine
(12): An H3B·SMe2 complex solution in anhydrous THF (10 ,
670 µL) was added dropwise to a stirred solution of 11 (247 mg,
0.67 mmol) in anhydrous THF (10 mL) under argon and the mix-
ture left at room temp. for 1.5 h. TLC (Et2O/MeOH, 5:1, v/v) then
revealed the absence of 11 and the presence of a faster running
compound, presumably the borane–amine complex. MeOH (1 mL)
was cautiously added, and the reaction mixture was concentrated
to a residue which was dissolved in MeOH (5 mL) and refluxed
for 12 h, by which time the borane–amine complex was no longer
observed by TLC. The reaction mixture was concentrated, and the
residue was purified by chromatography on silica gel (Et2O/MeOH,
15:1, v/v Ǟ Et2O/MeOH/NH4OH, 5:1:0.5, v/v) to give pure 12
(140 mg, 59%) as a colourless viscous syrup. [α]2D9 = +91 (c = 1,
from 9) as a syrup. [α]2D4 = +35 (c = 1). IR (neat): ν = 3441 (OH),
˜
1
3063, 3031, 736 and 697 cm–1 (aromatic). H NMR (500 MHz): δ
= 7.36–7.26 (m, 10 H, 2 Ph), 4.79 and 4.57 (2d, J = 11.8 Hz, 2 H,
CH2Ph), 4.60 and 4.58 (2d, J = 12.5 Hz, 2 H, CH2Ph), 4.20 (dd,
J1,2 = 6.0, J2,3 = 3.7 Hz, 1 H, 2-H), 3.71 (dd, J3,8 = 3.2, J8,8Ј
=
11.0 Hz, 1 H, 8-H), 5.53 (m, 2 H, 1,8Ј-H), 3.16 (dt, J = 6, J =
9.8 Hz, 1 H, 7a-H), 2.78 (br. s, 1 H, 3-H), 2.56 (br. sext, J5,6 = J5,6Ј
= 6.0 Hz, 1 H, 5-H), 2.21 (m, 1 H, 6-H), 1.79 (m, 1 H, 7-H), 1.78
(m, 1 H, 6Ј-H), 1.44 (m, 1 H, 7Ј-H), 1.13 (d, JMe,5 = 6.0 Hz, 3 H,
Me) ppm. 13C NMR: δ = 138.7, 128.5, 128.18 and 127.75 (CH2Ph),
85.3 (C-2), 80.2 (C-1), 73.1 and 72.1 (2 CH2Ph), 72.7 (C-7a), 67.7
(C-3), 61.9 (C-8), 54.9 (C-5), 37.3 (C-6), 25.3 (C-7), 21.2 (Me) ppm.
HRMS (LSIMS): calcd. for C23H30NO3 [M + H]+ 368.2226; found
368.2227 (deviation –0.4 ppm).
MeOH). IR (neat): ν = 3330 (OH), 3031, 737 and 698 cm–1 (aro-
˜
1
matic). H NMR (500 MHz, [D4]MeOH): δ = 7.37–7.22 (m, 10 H,
2 Ph), 4.58 and 4.51 (2 d, J = 11.5 Hz, 2 H, CH2Ph), 4.57 and 4.53
(2 d, J = 11.8 Hz, 2 H, CH2Ph), 3.86 (dd, J1,2 = 5.1, J2,3 = 8.4 Hz,
1 H, 2-H), 3.82 (dd, J3,8 = 4.1, J8,8Ј = 12.1 Hz, 1 H, 8-H), 3.75 (dd,
J3,8Ј = 8.0 Hz, 1 H, 8Ј-H), 3.74 (dd, 1 H, 1-H), 3.57 (dt, J1,7a = 3.1,
J7a,7 = J7a,7Ј = 8.0 Hz, 1 H, 7a-H), 3.43 (dt, 1 H, 3-H), 2.89 (ddd,
J = 6.7, J = 2.4, J5,5Ј = 9.5 Hz, 1 H, 5-H), 2.79 (dt, J = 9.8, J =
5.6 Hz, 1 H, 5Ј-H), 2.09 (ddt, J = 2.4, J = 7.4, J7,7Ј = 12.6 Hz, 1
H, 7-H), 1.85 (m, 1 H, 6-H), 1.70 (m, 1 H, 6Ј-H), 1.42 (ddt, J =
7.7, J = 10.6 Hz, 1 H, 7Ј-H) ppm. 13C NMR (inter alia): δ = 85.2
(C-1), 82.4 (C-2), 75.9 and 75.5 (2 CH2Ph), 72.1 (C-7a), 68.7 (C-
3), 63.6 (C-8), 51.6 (C-5), 33.9 (C-7), 30.3 (C-6) ppm. HRMS
(LSIMS): calcd. for C22H28NO3 [M + H]+ 354.2069; found
354.2068 (deviation +0.2 ppm).
(1S,2R,3R,5R,7aR)-1,2-Dihydroxy-3-(hydroxymethyl)-5-methylpyr-
rolizidine [(+)-Hyacinthacine A6 (2)]: A solution of 15 (70 mg,
0.19 mmol) in MeOH (15 mL) was acidified (conc. HCl, five drops)
and hydrogenated (413 kPa H2) in the presence of 10 % Pd/C
(50 mg) for 48 h. The catalyst was filtered off, washed with MeOH,
and the filtrate and washings were neutralized with Amberlite IRA-
400 (OH– form) and concentrated to a residue that was retained
on a column of Dowex 50Wϫ8 (200–400 mesh). The column was
thoroughly washed with MeOH, water and then with 1  NH4OH
to afford pure 2 (34 mg, 96%) as a colourless viscous syrup. [α]2D6
= +15.8 (c = 0.5, water) {ref.[7] [α]2D6 = +16.3 (c = 0.22, water)}. 1H
NMR (300 MHz, D2O): δ = 4.11 (t, J1,2 = J2,3 = 6.2 Hz, 1 H, 2-
H), 3.82 (dd, J3,8 = 5.0, J8,8Ј = 11.7 Hz, 1 H, 8-H), 3.91 (br. t, 1 H,
1-H, 3.67 (dd, J3,8Ј = 6.2 Hz, 1 H, 8Ј-H), 2.79 (dt, J1,7a = 6.5, J7a,7α
(1S,2R,3R,7aR)-1,2-Dihydroxy-3-(hydroxymethyl)pyrrolizidine [(+)-
Hyacinthacine A1 (1)]: Compound 12 (120 mg, 0.34 mmol) in
MeOH (15 mL) and conc. HCl (five drops) was hydrogenated
(482 kPa H2) in the presence of 10% Pd/C (50 mg) for 20 h. The
catalyst was filtered off, washed with MeOH, and the combined
filtrate and washings were treated with Amberlite IRA-400 resin
(OH– form). Evaporation of the solvent afforded a residue that
was retained on a column of Dowex 50Wϫ8 (200–400 mesh). The
column was thoroughly washed with MeOH, water and then with
1  NH4OH to afford pure 1 (55 mg, 93%) as a colourless viscous
syrup. [α]2D7 = +47 (c = 0.65, water) {ref.[6] [α]D +38.2 (c = 0.23,
water); ref.[16b] [α]2D0 = +45 (c = 0.23, water)}. 1H NMR (500 MHz,
[D4]MeOH): δ = 3.88 (dd, J1,2 = 5.5, J2,3 = 9.0 Hz, 1 H, 2-H), 3.84
(dd, J3,8 = 4.1, J8,8Ј = 12.1 Hz, 1 H, 8-H), 3.81 (dd, J3,8Ј = 8.0 Hz,
1 H, 8Ј-H), 3.76 (dd, 1 H, 1-H), 3.39 (dt, J1,7a = 2.4, J7a,7 = J7a,7Ј
= 7.9 Hz, 1 H, 7a-H), 3.21 (dt, 1 H, 3-H), 2.91 (ddd, J = 2.1, J =
9.0 Hz, 1 H, 5-H), 2.79 (dt, J5,5Ј = 9.8, J = 5.8 Hz, 1 H, 5Ј-H), 2.14
(ddt, J = 2.5, J = 7.6, J7,7Ј = 12.6 Hz, 1 H, 7-H), 1.87 (m, 1 H, 6-
H), 1.69 (m, 1 H, 6Ј-H), 1.50 (ddt, J = 7.6, J = 10.4 Hz, 1 H, 7Ј-
H) ppm. 13C NMR: δ = 76.9 (C-1), 72.5 (C-2), 72.1 (C-7a), 67.1
(C-3), 60.9 (C-8), 49.1 (C-5), 30.9 (C-7), 27.4 (C-6) ppm. HRMS
(LSIMS): calcd. for C8H15NO3 [M]+ 173.1052; found 173.1050 (de-
viation +0.8 ppm).
= J7a,7β = 9.4 Hz, 1 H, 7a-H), 2.59 (br. sext, J5,6α = J5,6β = J5,Me
6.7 Hz, 1 H, 5-H), 2.47 (br. q, 1 H, 3-H), 2.25 (br. dq, J6β,7α
=
=
J6β,7β = 8.2, J6α,6β = 12.0 Hz, 1 H, 6β-H), 1.81 (m, 1 H, 7β-H), 1.63
(m, 1 H, 6α-H), 1.41 (br. dq, J6α,7α = 7.6, J7α,7β = 10.8 Hz, 1 H,
7α-H), 1.12 (d, 3 H, Me) ppm. 13C NMR: δ = 77.0 (C-2), 74.1 (C-
7a), 70.9 (C-1), 69.8 (C-3), 61.8 (C-8), 56.2 (C-5), 35.9 (C-6), 23.3
(C-7), 19.6 (Me) ppm. HRMS (LSIMS): calcd. for C9H17NO3Na
[M + Na]+ 210.1106; found 210.1103 (deviation +1.1 ppm).
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for compounds 1, 2, 11 and 12 and
1
1
2D H-1H and H-13C COSY spectra for compounds 1 and 2.
Acknowledgments
The authors are deeply grateful to the Ministerio de Educación y
Ciencia (Project Ref. No. CTQ2006-14043) and the Junta de Anda-
lucía (Group CVI-250) for financial support and the Fundación
Ramón Areces for a grant (F. S.-C.).
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6082
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6078–6083

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Received: September 4, 2007
Published Online: November 2, 2007
Eur. J. Org. Chem. 2007, 6078–6083
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6083