Total synthesis of the 5-epimers of naturally occurring (-)-hyacinthacine A5 and unnatural (+)-hyacinthacine A4

Article abstract of DOI:10.1016/j.tetasy.2007.09.014

(1R,2S,3R,5S,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 10 [(+)-5-epihyacinthacine A₅] and (1R,2S,3R,5S,7aS)-1,2-dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 17 [ent-5-epihyacinthacine A₄] have been synthesized by ei

Full text of DOI:10.1016/j.tetasy.2007.09.014

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2211–2217
Total synthesis of the 5-epimers of naturally occurring
(ꢀ)-hyacinthacine A5 and unnatural (+)-hyacinthacine A4
I
*
´
´
Isidoro Izquierdo, Marıa T. Plaza, Juan A. Tamayo and Fernando Sanchez-Cantalejo
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, Granada 18071, Spain
Received 17 July 2007; accepted 13 September 2007
Abstract—(1R,2S,3R,5S,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 10 [(+)-5-epihyacinthacine A5] and (1R,2S,3R,
5S,7aS)-1,2-dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 17 [ent-5-epihyacinthacine A4] have been synthesized by either
Horner–Wadsworth–Emmons (HWE) or Wittig methodology using aldehydes 6 and 13, prepared from (2R,3S,4R,5R)-3,4-dibenzyl-
oxy-N-benzyloxycarbonyl-20-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine
5
(partially protected DALDP) and
(2R,3S,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2,5-bis(hydroxymethyl)-20-O-pivaloylpyrrolidine 12 (partially protected DGADP),
respectively, and the appropriated ylide, followed by cyclization through an internal reductive amination process of the corresponding
intermediate pyrrolidinic ketones 7 and 14 and subsequent deprotection.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Scilla peruviana and more recently from Scilla socialis by
Asano et al.4 In addition, their scarcity in the natural
sources together with the drawbacks found during their
isolation and purification makes necessary to implement
synthetic routes to these compounds. In this context and
in the recent past years, our group have put into practice
a synthetic methodology for the preparation of the above
PHPAs.5
Several important biological process, such as intestinal
digestion, lysosomal catabolism and post-translational
modification, which are closely related to the endoplasmic
reticulum (ER) quality control and ER-associated degrada-
tion of glycoproteins are mediated by glycosidases. On the
other hand, imino or azasugars can inhibit glycosidases
because of a structural resemblance of their sugar moiety
to natural substrates and hence have enormous potential
as biochemical tools in glycolscience as well as therapeutic
agents.2 From a structural point of view, naturally occur-
ring iminosugars are classified into five classes: polyhydr-
oxylated pyrrolidines (DMDP), piperidines (DMJ),
indolizidines (castanospermine), pyrrolizidines (alexine
and australine) and nor-tropans (calystegine B2).
Of the different naturally occurring PHPAs with branching
at C(3,5) known so far, (ꢀ)-hyacinthacine A5 1, a moderate
inhibitor (IC50 = 110 lM) of amyloglucosidase from
Aspergillus niger, and (ꢀ)-hyacinthacine A4 2, both isolated
from an extract of the bulbs of S. sibirica (Liliaceae),4c
show functionalization and stereochemistry at the A-ring
(see Fig. 1) matching exactly that present in the orthogo-
nally protected derivative of 2,5-dideoxy-2,5-imino-D-altri-
tol 3 (DALDP) and 2,5-dideoxy-2,5-imino-D-galactitol 4
(DGADP), respectively, in such a way that both could be
considered as excellent homochiral starting materials for
their corresponding enantiosyntheses. To the best of our
knowledge, only one synthesis of the 5-epimer of (ꢀ)-hya-
cinthacine A4 from D-glucose has been reported6 but none
for either 1 or 2. On the other hand, stereocontrolled syn-
theses of 3 and 4, from the commercially available hexulose
D-fructose, have been recently disclosed by our group.7,8
While the presence of polyhydroxylated piperidine and
pyrrolidine alkaloids is widespread in many unrelated plant
families, polyhydroxylated pyrrolizidine alkaloids (PHPAs)
are restricted to specific ones.3 Thus, a particular kind of
these alkaloids, known as hyacinthacines, has been isolated
from bluebells (Hyacinthoides non-scripta), grape hyacinths
(Muscari armeniacum) and from the bulbs of Scilla sibirica,
q Part 10 of this series. For Part 9, see Ref. 1.
*
Herein we report the stereospecific synthesis of 5-epihyacin-
thacine A5 10 obtained from 3 in five steps (21% yield) and
Corresponding author. Tel.: +34 958 249583; fax: +34 958 243845;
e-mail: isidoro@ugr.es
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.09.014

2212
I. Izquierdo et al. / Tetrahedron: Asymmetry 18 (2007) 2211–2217
OH
OBn
Cbz
N
HO
H
N
OTBDPS
a
R
A
OH
OBn
3
HN
BnO
OBn
Me
OH
OTBDPS
Protected DALDP 3
R = CH2OH
5
(-)-Hyacinthacine A5
1
b
c
6 R = CHO
7 R = (E)-HC=CHCOMe
OBn
PivO
OH
H
Scheme 1. Chemoselective N-protection and carbon-chain lengthening at
C(50) in 3. Reagents and conditions: (a) CbzCl/Me2CO/K2CO3; (b) NMO/
OBn
OH
A
OH
HN
N
˚
TPAP/CH2Cl2/4 A MS; (c) (EtO)2P(O)CH2COCH3/NaH/THF, rt.
Me
(-)-Hyacinthacine A4
OH
2
Protected DGADP
4
Figure 1. Retrosynthesis showing the functional and stereochemical
relationship between the A-ring of hyacinthacines 1 and 2 with that of
2,5-dideoxy-2,5-iminocyclitols 3 (DALDP) and 4 (DGADP), respectively.
OBn
OBn
OBn
H
N
a,b
-H2O
OR
OBn
OPG
7
HN
Me
O
Me
a
OPG
8
A
OH
H
PG =T BDPS
OH
N
H
N
OR
OR1
Me
OH
(+)-5-Epihyacinthacine A5 10
Me
9 R = Bn; R1 = TBDPS
OH
OH
b
c
10 R = R1 = H
d
H
N
H
N
11 R = R1 = Ac
OH
OH
Scheme 2. Synthesis of (+)-5-epihyacinthacine A5 10. Reagents and
conditions: (a) Raney-nickel/H2/MeOH; (b) (i) 10% Pd–C/H2/HCl, then
Amberlite IRA-400 (OHꢀ form), (ii) TBAFÆ3H2O/THF; (c) Ac2O/DMAP
(cat.)/Py, rt; (d) MeONa (cat.)/MeOH, rt.
Me
Me
(+)-5-Epihyacinthacine A4 17
OH
OH
(-)-5-Epihyacinthacine A4
X.-P. Cao et al. (2007)
Figure 2. Some of the hyacinthacines described herein.
9. The NOE interactions are shown in Figure 3. The defi-
nite NOE effects between C(3)H–C(5)H, C(3)H–C(1)H
and Me(5)H–C(8)H were crucial in order to establish the
(S)-configuration at C-5. In addition, the rest of the NOE
interactions also confirmed the total stereochemistry of 9
and made it possible to assign the resonance signals for
H-6a,6b,7a,7b.
ent-5-epihyacinthacine A4 17 from pyrrolidine 4, in six
steps (10% yield) (Fig. 2).
2. Results and discussion
In the synthesis described herein, the starting pyrrolidine 3
was previously N-protected as its Cbz derivative 5, which
was then oxidized (NMO/TPAP) to pyrrolidinic aldehyde
6 and finally allowed to react with diethyl (2-oxoprop-
yl)phosphonate in a basic medium to afford, in a highly
stereoselective manner, 4-[(3E,20R,30R,40S,50R)-30,40-di-
benzyloxy-N-benzyloxycarbonyl-50-tert-butyldiphenylsilyl-
oxymethylpyrrolidin-20-yl]but-3-en-2-one 7, in accordance
with the J3,4 values of 16.2 and 16.1 Hz, shown by H-3 in
the mixture of rotamers9 (Scheme 1).
H
H1
7βH
H7α
H6β
H6α
Me
OBn
H2
N
OBn
OTBDPS
H5 H3
9
Figure 3. Main NOE interactions in 9.
Catalytic hydrogenation (Raney-nickel) of 7 (see Scheme 2)
unchained a tandem process consisting of concomitant car-
bon–carbon double bond hydrogenation, N-deprotection
to the saturated pyrrolidinic ketone 8, not isolated, which
subsequent intramolecular condensation gave the interme-
diate D5-pyrrolizine A that was finally hydrogenated to the
fully protected (1R,2S,3R,5S,7aR)-1,2-dibenzyloxy-3-tert-
butyldiphenylsilyloxymethyl-5-methylpyrrolizidine 9.
The surprising and highly stereoselective formation of 9,
contrary to previous results5a,b,d,g where the hydrogenation
usually proceeds in such a way that the C(7a)H and
C(5)Me result in a trans-relationship, can be attributed,
according to Figure 4, to the special shape adopted by
the intermediate D5-pyrrolizine A, where it is clearly appre-
ciated that the a-face is more favoured for hydrogen attack
than the b-face.
The stereochemistry of the new C(5) stereogenic centre was
established on the basis of extensive NOE experiments on
Removal of the protecting groups in 9 gave the target mole-
cule (+)-5-epihyacinthacine A5 10 that was also character-

I. Izquierdo et al. / Tetrahedron: Asymmetry 18 (2007) 2211–2217
2213
The absolute configuration of the new stereogenic centre
C(5) was established on the basis of the NOE effects found
(see Fig. 5). Thus, the definite NOE effects between C(3)H–
C(5)H, C(3)H–C(7a)H and Me(5)H–C(8)H were essential
in order to establish the (S)-configuration at C-5. As be-
fore, the rest of the NOE interactions also confirmed the
total stereochemistry of 15 and made it possible to assign
the resonance signals for H-6a,6b,7a,7b.
H
H1
7βH
N
H7α
H6β
H6α
Me
OBn
H2
Figure 4. Minimized structure (MOPAC) for intermediate D5-pyrrolizine
A.
OBn
OPiv
H5 H3
ized as its per-O-acetyl derivative 11, in accordance with
their analytical and spectroscopic data.
15
Figure 5. Main NOE interactions in 15.
The enantiomeric pivotal character of 4 would allow the
synthesis of looking-glass hyacinthacine 17. Thus, in a
similar synthetic route, pyrrolidine 4 was N-protected to
derivative 12, which subsequent oxidation (NMO/TPAP)
afforded the pyrrolidinic aldehyde 13 that as before was
not investigated, but used in the next step. Aldehyde 13
readily reacted with 1-triphenylphosphoranylidene-2-prop-
anone giving 4-[(3E,20S,30R,40S,50R)-30,40-dibenzyloxy-
N-benzyloxycarbonyl-50-pivaloyloxymethylpyrrolidin-20-yl]-
but-3-en-2-one (14) (see Scheme 3).
The above finding was in accordance with the already men-
tioned results and the hydrogenation took place by the less
hindered a-face, C(7a)H and C(5)Me adopting the usual
trans-relationship, as expected on the basis of Figure 6,
where the minimized structure of intermediate D5-pyrroli-
zine B is displayed.
Cbz
N
OPiv
a
R
4
BnO
OBn
12 R = CH2OH
b
c
13 R = CHO
14 R = (E)-HC=CHCOMe
Scheme 3. Chemoselective N-protection and carbon-chain lengthening at
C(50) in 4. Reagents and conditions: (a) CbzCl/Me2CO/K2CO3; (b) NMO/
˚
TPAP/CH2Cl2/4 A MS; (c) Ph3P@CHCOCH3/MePh, 80 °C.
Figure 6. Minimized structure (MOPAC) for intermediate D5-pyrrolizine
B.
In Scheme 4 and as for 7, the catalytic hydrogenation
of 14 afforded a single isomeric pyrrolizidine identified
as (1R,2S,3R,5S,7aS)-1,2-dibenzyloxy-5-methyl-3-pivaloyl
oxymethylpyrrolizidine 15.
As for 9, removal of the protecting groups in 15 gave the
target molecule (+)-5-epihyacinthacine A4 17, after purifi-
cation through its per-O-acetyl derivative 18, in accordance
with its analytical and spectroscopic data.
OR
OBn
OBn
OPiv
H
N
H
N
a
a
OR
14
OR1
Me
Me
3. Conclusions
15 R = Bn; R1 = Piv
16 R = Bn; R1 = H
B
b
c
d
17 R = R1 = H
The first total stereospecific syntheses of two unknown hya-
cinthacines 10 and 17, both related with (ꢀ)-hyacinthacine
A5 (1) and A4 (2), were achieved, indicating that the general
methodology developed by our group is of practical use in
preparation of isomers of naturally occurring PHPAs that
would be of value in SAR studies.
b
18 R = R1 = Ac
Scheme 4. Synthesis of (+)-5-epihyacinthacine A4 17. Reagents and
conditions: (a) 10% Pd–C/H2/MeOH; (b) MeONa (cat.)/MeOH; (c) 10%
Pd–C/H2/HCl, then Amberlite IRA-400 (OHꢀ form); (d) Ac2O/DMAP
(cat.)/Py, rt.

2214
I. Izquierdo et al. / Tetrahedron: Asymmetry 18 (2007) 2211–2217
4. Experimental
lau, 230–400 mesh) and thoroughly washed with Et2O. The
combined filtrate and washings were concentrated to afford
presumably aldehyde 6. This material was used in the next
step.
Solutions were dried over MgSO4 before concentration un-
1
der reduced pressure. The H and 13C NMR spectra were
recorded with Bruker AMX-300, AM-300 and ARX-400
spectrometers for solutions in CDCl3 (internal Me4Si). IR
spectra were recorded with a Perkin–Elmer FT-IR Spec-
trum One instrument, and mass spectra were recorded with
a Hewlett–Packard HP-5988-A and Fisons mod. Platform
II and VG Autospec-Q mass spectrometers. Optical rota-
tions were measured for solutions in CHCl3 (1-dm tube)
with a Jasco DIP-370 polarimeter. TLC was performed
on precoated silica gel 60 F254 aluminium sheets and detec-
tion 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 silica gel (Merck, 7734). The non-crystalline
compounds were shown to be homogeneous by chromato-
graphic methods and characterized by NMR, MS and
HRMS.
To a well stirred suspension of sodium hydride (60%
134 mg, 3.36 mmol) in anhydrous THF (10 mL), diethyl
(2-oxopropyl)phosphonate (600 lL, 3.36 mmol) was
added and the mixture left at room temperature for
1 h, after which time a solution of aldehyde 6 in THF
(10 mL) was added. After 15 min TLC (Et2O/hexane
4:1) revealed the presence of a new compound of slightly
lower mobility. The solvent was eliminated and the resi-
due was partitioned into Et2O/water. The organic phase
was separated and concentrated to a residue that was
submitted to column chromatography with Et2O/hexane
(1:1) as eluent to give pure 7 (510 mg, 60% from 5) as
26
a colourless syrup, which had ½aꢁD ¼ þ18 (c 1, CHCl3).
IR (neat): 3032 (aromatic), 1704 and 1678 (a,b-unsatu-
rated ketone C@O and Cbz), 737 and 699 cmꢀ1 (aro-
matic). NMR data (300 MHz): 1H, d 7.60–7.10 (m, 25
0
4.1. (2R,3S,4R,5R)-3,4-Dibenzyloxy-N-benzyloxycarbonyl-
20-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrol-
idine 5
H, 5Ph), 6.42 and 6.33 (2 br dd, 1H, J2 ;4 6.3 Hz, H-4,
two rotamers), 5.92 and 5.85 (2 br d, 1H, J3,4 16.2 and
16.1 Hz, H-3, two rotamers), 5.12–3.70 (4 br m, 12H,
3CH2Ph and H-20,30,40,50,500a,500b), 2.10 and 1.90 (2 br
s, 3H, H-1,1,1, two rotamers), 1.00 and 0.93 (2 br s,
9H, CMe3, two rotamers). 13C (75 MHz), d 197.70 (C-
2), 154.57 (Cbz), 81.02 and 77.84 (C-30,40), 73.00, 72.63
and 67.16 (2CH2Ph, and Cbz), 63.10 (C-500), 62.83,
60.66 and 60.46 (C-20,50, two rotamers), 27.72 (C-1),
26.98 (CMe3) and 19.30 (CMe3). HRMS (LSIMS): m/z
776.3379 [M++Na]. For C47H51NO6NaSi 776.3383 (devi-
ation +0.3 ppm).
To a well stirred solution of 37 (970 mg, 1.67 mmol) in dry
acetone (15 mL), anhydrous potassium carbonate (1.5 g)
and benzyl chloroformate (CbzCl, 330 lL, 2.34 mmol)
were added and the mixture kept at rt for 2 h. TLC
(Et2O/MeOH 20:1) then revealed the presence of a faster-
running compound. The mixture was filtered and the solid
thoroughly washed with acetone after which the filtrate and
washings concentrated to a residue that was submitted to
chromatography (Et2O/hexane 1:4 ! Et2O/MeOH 2:1) to
give
5
as colourless syrup. Yield: 800 mg (67%);
4.3. (1R,2S,3R,5S,7aR)-1,2-Dibenzyloxy-3-tert-butyldi-
phenylsilyloxymethyl-5-methylpyrrolizidine 9
25
26
½aꢁD ¼ þ6, ½aꢁ405 ¼ þ21 (c 1, CHCl3). IR (neat): 3429
(OH), 3067 (aromatic), 1699 (C@O, Cbz), 737 and
700 cmꢀ1 (aromatic). NMR data (400 MHz)9: H, d 7.70–
Compound 7 (510 mg, 0.71 mmol) in MeOH (15 mL)
was hydrogenated at 60 psi over wet Raney-nickel
(600 mg) overnight. TLC (Et2O/hexane 4:1) then showed
the presence of a new compound. The catalyst was
filtered off, washed with MeOH and the filtrate and
washings concentrated to a residue that was submitted
1
7.12 (m, 25H, 5 Ph), 5.10 and 4.85 (2 d, 2H, J 12.4 Hz,
CH2Ph), 4.78 and 4.68 (2 d, 2H, J 11.8 Hz, CH2Ph), 4.68
and 4.58 (2 d, 2H, J 12 Hz, CH2Ph), 4.35–3.60 (4 br m,
8H, H-2,20a,20b,3,4,5,50a,50b), 1.01 (s, 9H, CMe3); 13C
(100 MHz), d 155.63 (C@O, Cbz), 79.50 and 77.35 (C-
3,4), 73.04 and 72.38 (2CH2Ph), 67.18 (CH2Ph, Cbz),
64.80 and 61.13 (C-2,5), 63.58 and 62.51 (C-20,50), 26.94
(CMe3), and 19.26 (CMe3). HRMS (LSIMS): m/z
738.3226 [M++Na]. For C44H49NO6NaSi 738.3227 (devia-
tion +0.1 ppm).
to column chromatography (Et2O/hexane 2:1) to afford
25
pure syrupy 9 (260 mg, 60%), which had ½aꢁD ¼ þ31
(c 1, CHCl3). IR (neat): 3069, 3030, 738 and 700 cmꢀ1
(aromatic). NMR data (300 MHz): 1H, d 7.65–7.15 (2
m, 20H, 4Ph), 4.78 and 4.69 (2 d, 2H, J 11.8 Hz,
CH2Ph), 4.50 and 4.36 (2 d, 2H, J 12.2 Hz, CH2Ph),
4.23 (t, 1H, J1,2 = J2,3 = 3.6 Hz, H-2), 4.00 (t, 1H,
4.2. 4-[(3E,20R,30R,40S,50R)-30,40-Dibenzyloxy-N-benzyl-
oxycarbonyl-50-tert-butyldiphenylsilyloxymethylpyrrolidin-
20-yl]but-3-en-2-one 7
0
J3;8 ¼ J8;8 ¼ 9:5 Hz, H-8), 3.68 (dt, 1H, J7a,7b 5.7,
0
J1,7a = J7a,7a, = 8.5 Hz, H-7a), 3.58 (dd, 1H, J3;8 5.1 Hz,
H-80), 3.47 (dd, 1H, H-1), 2.79 (m, 1H, H-3), 2.46 (sex,
1H, J5,6b = J5,6a = J5,Me = 6.3 Hz, H-5), 1.96 (m, 1H,
H-7b), 1.71 (m, 1H, H-6a), 1.49–1.33 (m, 2H, H-
6b,7a), 1.00 (s, 9H, CMe3) and 0.73 (d, 3H, Me); 13C
(75 MHz), d 85.87 (C-1), 80.12 (C-2), 73.83 and 71.87
(2CH2Ph), 69.71 (C-3), 66.78 (C-7a), 63.33 (C-8), 62.86
(C-5), 34.84 (C-6), 29.73 (C-7), 27.05 (CMe3), 21.66
(Me) and 19.30 (CMe3). HRMS (LSIMS): m/z 606.3407
[M++H]. For C39H48NO3Si 606.3403 (deviation
ꢀ0.6 ppm).
To a stirred solution of 5 (800 mg, 1.12 mmol) in dry
CH2Cl2 (25 mL) were added activated 4 A molecular sieves
˚
(0.5 g), N-oxide-N-methylmorpholine (NMO, 196 mg,
1.68 mmol) and tetra-n-propylammonium perruthenate
(TPAP, 40 mg) after which the reaction mixture was kept
at rt for 60 min. TLC (Et2O/hexane 4:1) then indicated
the absence of the starting material and the presence of a
faster-running compound. The reaction was diluted with
Et2O (50 mL), filtered through a bed of Silica gel 60 (Schar-

I. Izquierdo et al. / Tetrahedron: Asymmetry 18 (2007) 2211–2217
2215
4.4. (1R,2S,3R,5S,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-
methylpyrrolizidine [(+)-5-epihyacinthacine A5, 10]
(2 d, 2H, J 12.3 Hz, CH2Ph), 4.76 and 4.55 (2 d, 2H, J
11.7 Hz, CH2Ph), 4.69 and 4.67 (2 d, 2H, J11.2 Hz, CH2Ph),
4.50–3.72 (4 m, 8H, H-2,20a,20b,3,4,5,50a,50b), 1.07 (s, 9H,
CMe3); 13C (75 MHz), d 178.17 (C@O, Piv), 78.82 (C-3,4),
73.76 (2 CH2Ph), 67.72 (CH2Ph, Cbz), 63.39 and 62.97
(C-2,5), 60.0 and 57.96 (C-20,50), 29.78 (CMe3) and 27.27
(CMe3). HRMS (LSIMS): m/z 584.2621 [M++Na]. For
C33H39NO7Na 584.2624 (deviation +0.6 ppm).
A solution of 9 (250 mg, 0.41 mmol) in MeOH (20 mL) was
acidified (concd HCl) and hydrogenated (10% Pd–C,
80 mg) at 60 psi for 14 h. The catalyst was filtered off,
washed with MeOH and the filtrate and washings neutral-
ized with Amberlite IRA-400 (OHꢀ form) and concen-
trated. 1H NMR of the residue showed the absence of
benzyl group and that the TBDPS group still remain.
The residue was dissolved in THF (10 mL) and treated with
a solution of TBAFÆ3H2O (200 mg, 0.63 mmol) in the same
solvent (5 mL) at rt for 4 h. TLC (Et2O/MeOH/NH4OH
4:1:1) then revealed a new compound. The solvent was
removed and the residue submitted to chromatography
(Et2O/MeOH 5:1) to afford pure 10 (66 mg, 86%), which
4.6. 4-[(3E,20S,30R,40S,50R)-30,40-Dibenzyloxy-N-benzyl-
oxycarbonyl-50-pivaloyloxymethylpyrrolidin-20-yl]but-3-en-
2-one 14
To a stirred solution of 12 (1.35 g, 2.41 mmol) in dry DCM
˚
(20 mL) were added activated 4 A MS (0.5 g), NMO
(425 mg, 3.6 mmol) and TPAP (100 mg) after which the
reaction mixture was kept at rt for 60 min. TLC (Et2O/hex-
ane 1:1) then indicated the absence of the starting material
and the presence of a faster-running compound. The reac-
tion was diluted with ether (30 mL), filtered through a bed
of Silica gel 60 (Scharlau, 230–400 mesh) and thoroughly
washed with ether. The combined filtrate and washings
28
28
had ½aꢁD ¼ þ12, ½aꢁ405 ¼ ꢀ30 (c 1, MeOH). NMR data
(300 MHz, MeOH-d4): 1H,
J2,3 = 4.2 Hz, H-2), 3.75 (dd, 1H, J3,8 7.9, J8;8 10.7 Hz,
d
4.13 (t, 1H, J1,2 =
0
0
H-8), 3.67 (dd, 1H, J1,7a 7.7 Hz, H-1), 3.53 (dd, 1H, J3;8
5.1 Hz, H-80), 3.39 (dt, 1H, J7a,7 7.5, J7a;7 5.9 Hz, H-7a),
0
0
0
2.81–2.74 (m, 2H, H-3,5), 1.99 (ddt, 1H, J6 ;7 7.2, J7;7
0
0
12.8 Hz, H-7), 1.87 (dq, 1H, J5;6 ¼ J6;7 ¼ J6;7 ¼ 5:3, J6;6
were concentrated to presumably aldehyde 13 (1.19 g,
25
12 Hz, H-6), 1.85 (ddt, 1H, J6 ;7 8.0 Hz, H-70), 1.4 (br
88%); ½aꢁD ¼ ꢀ9 (c, 0.85). IR (neat): 3068 and 3032
0
0
dq, 1H, J5;6 8.0 Hz, H-60) and 0.85 (d, 3H, J5,Me 6.3 Hz,
(aromatic), 1735 (CHO), 1710 (C@O), 735 and 710 cmꢀ1
0
Me); 13C (75 MHz), d 79.30 (C-1), 75.19 (C-2), 70.77 (C-
3), 69.83 (C-7a), 64.48 (C-5), 62.31 (C-8), 34.95 (C-6),
29.96 (C-7) and 21.21 (Me).
(aromatic). This material was used in the next step.
To a solution of 13 (1.19 g, 2.12 mmol) in dry toluene
(20 mL) was added 1-triphenylphosphoranylidene-2-prop-
anone (1.07 g, 3.36 mmol) and the mixture was heated at
100 °C for 3 h. TLC (ether/hexane 2:1) then revealed the
presence of a slightly slower-running compound. The reac-
tion mixture was filtered and supported on silica gel, then
chromatographed (ether/hexane 1:2) to afford 14 (730 mg,
Conventional acetylation of 10 afforded the corresponding
27
tri-O-acetyl derivative 11 as a syrup, which had ½aꢁD þ 10,
27
½aꢁ405 ¼ þ32 (c 1, CHCl3). IR (neat): 1747 cmꢀ1 (C@O, ace-
1
tate). NMR data (300 MHz): H, d 5.45 (t, 1H, H-2), 4.89
(dd, 1H, J1,2 4.5, J1,7a 6.9 Hz, H-1), 4.12 (dd, 1H, J3,8 7.5.
26
26
J8;8 11.0 Hz, H-8), 4.06 (dd, 1H, J3;8 6.9 Hz, H-80), 3.64 (br
q, J2,3 6.7 Hz, H-3), 3.21 (dt, 1H, J 5.2, J 7.1 Hz, H-7a),
83%) as a thick syrup; ½aꢁD ¼ ꢀ1, ½aꢁ405 ¼ ꢀ116 (c 1,
CHCl3). IR (neat): 3065 and 3032 (aromatic), 1713, 1677
and 1633 (C@O Piv, C@O conjugated ketone, Cbz and
C@C conjugated), 737 and 698 cmꢀ1 (aromatic). NMR
data (400 MHz): 1H, d 7.45–7.20 (m, 15H, 3 Ph), 6.88
0
0
0
2.80 (sex, 1H, J5;6 ¼ J5;6 ¼ J5;Me ¼ 6:2 Hz, H-5), 2.03,
1.97 and 1.96 (3 s, 9H, 3 Ac), 2.08–1.85 (m, 2H, H-6,7),
1.62–1.42 (m, 2H, H-60,70) and 1.05 (d, 3H, Me); 13C
(75 MHz), d 170.75, 170.30, and 170.10 (3 MeCO), 76.59
(C-1), 73.23 (C-2), 66.33 (C-7a), 64.24 (C-3), 63.44 (C-8),
63.02 (C-5), 34.04 (C-6), 29.11 (C-7), 21.67 (Me), 20.88,
20.80 and 20.71 (3 MeCO). HRMS (LSIMS): m/z
336.1422 [M++Na]. For C15H23NO6Na 336.1423 (devia-
tion +0.3 ppm).
0
(dd, 1H, J2 ;4 7.1, J3,4 16.2 Hz, H-4), 6.51–5.91 (2 br m,
1H, H-3,4 two rotamers), 5.30–4.00 (4 br m, 12H, 3CH2Ph
and H-20,30,40,50,500a,500b, two rotamers), 2.10 (br s, 3H, H-
1,1,1), 1.18 and 1.17 (2 s, 9H, CMe3, two rotamers). 13C
(100 MHz), d 198.60 (C-2), 178.13 (CO, Piv), 80.27 and
77.85 (C-30,40), 73.60, 73.22 and 67.57 (2CH2Ph and
Cbz), 52.81 (C-500), 60.80 and 58.09 (C-20,50), 30.39
and 29.76 (C-1, two rotamers), 27.88 and 27.28 (CMe3,
two rotamers). HRMS (LSIMS): m/z 622.2777 [M++Na].
For C36H41NO7Na 622.2781 (deviation +0.6 ppm).
4.5. (2R,3S,4R,5S)-3,4-Dibenzyloxy-N-benzyloxycarbonyl-
2,5-bis(hydroxymethyl)-20-O-pivaloylpyrrolidine 12
To a well stirred solution of 48 (1.63 g, 3.82 mmol) in dry
acetone (15 mL), anhydrous potassium carbonate (1 g)
and benzyl chloroformate (820 lL, 5.73 mmol) were added
and the mixture kept at rt for 12 h. TLC (Et2O) then
revealed the presence of a faster-running compound. The
mixture was filtered and the solid thoroughly washed with
acetone and the filtrate and washings concentrated to a resi-
due that was submitted to chromatography (Et2O/hexane,
4.7. (1R,2S,3R,5S,7aS)-1,2-Dibenzyloxy-5-methyl-3-piva-
loyloxymethylpyrrolizidine 15
Compound 14 (1.1 g, 1.84 mmol) in dry MeOH (15 mL)
was hydrogenated at 60 psi over 10% Pd–C (100 mg) for
24 h. TLC (ether/hexane 4:1) then showed the presence of
a new compound of lower mobility. The catalyst was fil-
tered off, washed with MeOH and the filtrate and washings
concentrated to a residue that was submitted to column
1:2 ! 1:1) to give 12 as colourless syrup. Yield: 1.45 g
23
(68%), ½aꢁD ¼ þ22 (c 1, CHCl3). IR (neat): 3441 (OH),
3065 and 3032 (aromatic), 1724 and 1699 (C@O, Piv and
chromatography (ether/hexane 1:1) to afford pure syrupy
25
Cbz), 737 and 697 cmꢀ1 (aromatic). NMR data
15 (435 mg, 52%), which had ½aꢁD ¼ ꢀ27 (c 1, CHCl3).
1
(300 MHz): H, d 7.30–7.27 (m, 15H, 3 Ph), 5.14 and 5.02
IR (neat): 3064, 3030 (aromatic), 1724 (C@O, Piv), 734

2216
I. Izquierdo et al. / Tetrahedron: Asymmetry 18 (2007) 2211–2217
and 697 cmꢀ1 (aromatic). NMR data (400 MHz): 1H, d
7.40–7.24 (m, 10H, 2 Ph), 4.69 and 4.65 (2 d, 2H, J
12.5 Hz, CH2Ph), 4.61 and 4.53 (2 d, 2H, J 12.0 Hz,
J1,2 6.2, J2,3 7.3 Hz, H-2), 5.18 (dd, 1H, J1,7a 3.9 Hz, H-
0
1), 4.30 (dd, 1H, J3,8 4.8, J8;8 11.1 Hz, H-8), 4.16 (dd,
1H, J3;8 8.1 Hz, H-80), 2.82 (dt, 1H, H-3), 2.69 (ddd, 1H,
0
0
CH2Ph), 4.53 (dd, 1H, J3,8 7.2, J8;8 11.4 Hz, H-8), 4.32
J 3.9, J 6.2, J 10.1 Hz, H-7a), 2.40 (br sex, 1H,
(dd, 1H, J3;8 4.3 Hz, H-80), 4.20 (dd, 1H, J1,2 5.4, J2,3
J5;6 ¼ J5;6 ¼ J5;Me ¼ 6:2 Hz, H-5), 2.13, 2.06 and 2.02 (3
0
0
7.5 Hz, H-2), 3.78 (br t, 1H, J1,7a 3.9 Hz, H-1), 2.70 (m,
1H, H-3), 2.51 (m, 1H, H-7a), 2.41 (sex, 1H,
s, 9H, 3Ac), 1.72–1.63 and 1.61–1.48 (2 m, 4H, H-
6,60,7,70) and 1.23 (d, 3H, Me).
J
5,6b = J5,6a = J5,Me = 6.1 Hz, H-5), 2.11 (m, 1H, H-6b),
1.91 (dq, 1H, J 7.3, J 10.9 Hz, H-7b), 1.68 (m, 1H,
H-6a), 1.50 (m, 1H, H-7a), 1.30 (d, 3H, Me), 1.18 (s, 9H,
CMe3); 13C (100 MHz), d 178.47 (CO, Piv), 84.27 (C-2),
77.55 (C-1), 77.13 and 76.71 (2CH2Ph), 71.25 (C-7a),
63.87 (C-8), 61.51 (C-3), 56.33 (C-5), 35.86 (C-6), 27.45
(CMe3), 20.88 (C-7) and 20.54 (Me). HRMS (LSIMS):
m/z 452.2808 [M++H]. For C28H38NO4 452.2801 (devia-
tion ꢀ1.6 ppm).
Compound 18 was submitted to Zemplen deacetylation to
give pure 17 as a colourless syrup (40 mg, 83%), which had
27
22
½aꢁD ¼ þ10 (c 1, MeOH) {Lit.6 ½aꢁD ¼ ꢀ10 (c 1, MeOH)
for the enantiomer}. IR (neat): 3200 cmꢀ1 (OH). NMR
1
data (400 MHz, MeOH-d4): H, d 4.85 (dd, 1H, J1,2 4.9,
J2,3 8.4 Hz, H-2), 4.23 (br d, 1H, H-1), 3.88 (dd, 1H, J3,8
2.6, J8;8 12.9 Hz, H-8), 3.91 (dd, 1H, J3;8 3.8 Hz, H-80),
0
0
3.79 (m, 1H, H-7a), 3.69 (m, 1H, H-3), 3.57 (br sex, 1H,
0
J5;6 ¼ J5;6 ¼ J5;Me ¼ 6:3 Hz, H-5), 2.63 (m, 1H, H-6),
4.8. (1R,2S,3R,5S,7aS)-1,2-Dibenzyloxy-3-hydroxymethyl-
5-methylpyrrolizidine 16
2.19–1.93 (m, 3H, H-60,7,70) and 1.56 (d, 3H, Me); 13C
(100 MHz), d 76.87 (C-2), 75.10 (C-7a), 66.95 (C-1), 66.39
(C-3), 61.65 (C-5), 57.83 (C-8), 34.69 (C-6), 18.88 (C-7)
and 16.88 (Me). HRMS (LSIMS): m/z 188.1290 [M++H].
For C9H18NO3 188.1287 (deviation –1.9 ppm).
A solution of 15 (410 mg, 0.91 mmol) in anhydrous MeOH
(10 mL), was treated with 2 M MeONa in the same solvent
(1 mL) for 12 h at room temperature. TLC (ether/MeOH
10:1) then showed the presence of a compound of lower
mobility. The reaction mixture was concentrated and
the residue submitted to column chromatography
Acknowledgments
´
The authors are deeply grateful to Ministerio de Educacion
(ether ! ether/MeOH 10:1) to yield 16 as a colourless syr-
26
y Ciencia (Spain, Project Ref. CTQ2006-14043) and Junta
up (140 mg, 42%) which had ½aꢁD ¼ ꢀ26 (c 1, CHCl3). IR
´
(neat): 3395 (OH), 3062, 3030, 735 and 697 cmꢀ1 (aro-
de Andalucıa (Group CVI-250) for financial support, and
1
´
´
´
Fundacion Ramon Areces for a grant (F. Sanchez-
matic). NMR data (400 MHz): H, d 7.36–7.20 (m, 10H,
Cantalejo).
2Ph), 4.72 and 4.69 (2 d, 2H, J 12.4 Hz, CH2Ph), 4.65
and 4.45 (2 d, 2H, J 12.1 Hz, CH2Ph), 4.18 (dd, 1H, J1,2
4.6, J2,3 8.2 Hz, H-2), 3.85 (t, 1H, J1,7a 3.9 Hz, H-1), 3.82
References
0
0
(dd, 1H, J3,8 3.0, J8;8 11.2 Hz, H-8), 3.75 (dd, 1H, J3;8
5.2 Hz, H-80), 3.07 (ddd, 1H, H-3), 2.85 (ddd, 1H, J 3.8,
J 5.8, J 9.6 Hz, H-7a), 2.71 (br sex, 1H, J5,6b = J5,6a
´
1. Izquierdo, I.; Plaza, M.-T.; Tamayo, J. A.; Sanchez-Cantalejo,
=
F. Eur. J. Org. Chem. 2007, doi:10.1002/ejoc.200700820.
2. Asano, N. Glycobiology 2003, 13, 93R–104R.
3. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645–1680; (b) Watson, A.
A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265–295.
J5,Me = 6.3 Hz, H-5), 2.05 (m, 1H, H-6b), 1.90 (dq, 1H, J
7.2, J 10.5 Hz, H-7b), 1.66 (m, 1H, H-6a), 1.57 (m, 1H,
H-7a) and 1.26 (d, 3H, Me); 13C (100 MHz), d 83.37 (C-
2), 73.66 (C-1), 73.39 and 72.58 (2CH2Ph), 68.33 (C-7a),
60.51 (C-3), 60.34 (C-8), 56.49 (C-5), 35.03 (C-6), 21.42
(C-7) and 20.06 (Me). HRMS (LSIMS): m/z 390.2038
[M++Na]. For C23H29NO3Na 390.2045 (deviation
+1.9 ppm).
4. (a) Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae, T.;
Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Wormald,
M. R.; Fleet, G. W. J.; Asano, N. Carbohydr. Res. 1999, 316,
95–103; (b) 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; (c)
Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A.
A.; Nash, R. J.; Fleet, G. W. J.; Asano, N. J. Nat. Prod. 2002,
65, 1875–1881; (d) Kato, A.; Kano, E.; Adachi, I.; Molyneux,
R. J.; Whatson, A. A.; Nash, R. J.; Fleet, G. W. J.; Wormald,
M. R.; Kizu, H.; Ikeda, K.; Asano, N. Tetrahedron: Asymme-
try 2003, 14, 325–331; (e) Asano, N.; Ikeda, K.; Kasahara, M.;
Arai, Y.; Kizu, H. J. Nat. Prod. 2004, 67, 846–850; (f) Kato,
A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.;
Kuriyama, Ch.; Ikeda, K.; Asano, N.; Nash, R. J. J. Nat.
Prod. 2007, 70, 993–997.
5. (a) Izquierdo, I.; Plaza, M.-T.; Robles, R.; Franco, F.
Tetrahedron: Asymmetry 2001, 12, 2481–2487; (b) Izquierdo,
I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry 2002,
13, 1581–1585; (c) Izquierdo, I.; Plaza, M.-T.; Franco, F.
Tetrahedron: Asymmetry 2003, 14, 3933–3935; (d) Izquierdo,
I.; Plaza, M.-T.; Franco, F. Tetrahedron: Asymmetry 2004,
15, 1465–1469; (e) Izquierdo, I.; Plaza, M.-T.; Tamayo, J. A.
4.9. (1R,2S,3R,5S,7aS)-1,2-Dihydroxy-3-hydroxymethyl-5-
methylpyrrolizidine [(+)-5-epihyacinthacine A4, 17]
Compound 16 (130 mg, 0.35 mmol) was dissolved in dry
MeOH (15 mL) and hydrogenated (10% Pd–C, 100 mg)
in an acid medium (concd HCl, four drops) at 60 psi for
24 h. TLC (ether/MeOH/NH4OH 4:1:0.1) then showed
the presence of a more polar compound. The catalyst was
filtered off, washed with MeOH and the filtrate and wash-
ings neutralized with Amberlite IRA-400 (OHꢀ form) then
concentrated to a residue that was submitted to column
chromatography (ether/MeOH/TEA 5:1:0.1) to afford 17
(67 mg, quantitative), which was slightly contaminated.
Conventional acetylation of 17 in pyridine (2.5 mL) with
acetic anhydride (1.5 mL) and DMAP (20 mg) gave the
tri-O-acetyl derivative 18 (80 mg, 78%) with had 1H
NMR spectrum (400 MHz) as follows: d 5.61 (dd, 1H,

I. Izquierdo et al. / Tetrahedron: Asymmetry 18 (2007) 2211–2217
2217
´
Tetrahedron 2005, 61, 6527–6533; (f) Izquierdo, I.; Plaza,
M.-T.; Tamayo, J. A. J. Carbohydr. Chem. 2006, 25, 281–295;
I.; Plaza, M.-T.; Rodrıguez, M.; Franco, F.; Martos, A.
Tetrahedron 2006, 62, 1904.
´
´
(g) Izquierdo, I.; Plaza, M.-T.; Tamayo, J. A.; Rodrıguez, M.;
8. Izquierdo, I.; Plaza, M.-T.; Rodrıguez, M.; Tamayo, J. A.;
Martos, A. Tetrahedron 2006, 62, 6006–6011.
6. Zhou, L.; Chen, J.; Cao, X.-P. Synthesis 2007, 1359–1365.
Martos, A. Tetrahedron 2006, 62, 2693–2697.
9. All the compounds bearing the N-Cbz functionality show
broad resonance signals in the 1H NMR and 13C NMR
spectra.
´
7. (a) Izquierdo, I.; Plaza, M.-T.; Rodrıguez, M.; Franco, F.;
Martos, A. Tetrahedron 2005, 61, 11697–11704; (b) Izquierdo,