First total synthesis and absolute configuration of naturally occurring (-)-hyacinthacine A7 and its (-)-1-epi-isomer

Article abstract of DOI:10.1016/j.tet.2008.03.009

A convergent synthesis of the naturally occurring alkaloid (-)-hyacinthacine A₇, a glycosidase inhibitor of the pyrrolizidine class, is described. The homochiral starting material was tri-orthogonally protected DMDP 10, derived from d-fructose. Key steps of the synthesis were the carbon-chain lengthening at C(5′) in 10 to the α,β-unsaturated pyrrolidine ketone 12 and the one-pot construction of the bicyclic pyrrolizidine system of 13 and 14. Another key step was the partial inversion of the configuration at C(1) in 13 which led, after total deprotection, not only to the naturally occurring target molecule 9 but also to its (-)-1-epi-isomer 19.

Full text of DOI:10.1016/j.tet.2008.03.009

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4613e4618
www.elsevier.com/locate/tet
First total synthesis and absolute configuration of naturally
occurring (ꢀ)-hyacinthacine A7 and its (ꢀ)-1-epi-isomer*
*
´
´
´
~
Isidoro Izquierdo , Marıa T. Plaza, Juan A. Tamayo, Vıctor Yanez,
´
Daniele Lo Re, Fernando Sanchez-Cantalejo
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Received 28 November 2007; received in revised form 3 March 2008; accepted 3 March 2008
Available online 7 March 2008
Abstract
A convergent synthesis of the naturally occurring alkaloid (ꢀ)-hyacinthacine A7, a glycosidase inhibitor of the pyrrolizidine class, is
described. The homochiral starting material was tri-orthogonally protected DMDP 10, derived from D-fructose. Key steps of the synthesis
were the carbon-chain lengthening at C(50) in 10 to the a,b-unsaturated pyrrolidine ketone 12 and the one-pot construction of the bicyclic
pyrrolizidine system of 13 and 14. Another key step was the partial inversion of the configuration at C(1) in 13 which led, after total deprotec-
tion, not only to the naturally occurring target molecule 9 but also to its (ꢀ)-1-epi-isomer 19.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
The greater part of the synthetic routes to these azasugars
starts with a carbohydrate analogue resembling, if possible,
the majority of its stereocenters. However, non-carbohydrate
approaches such as ring closing metathesis,8 cyclization of
Polyhydroxylated pyrrolizidine alkaloids (PHPAs)2 bearing
a hydroxymethyl group adjacent to the ring nitrogen [C(3),
Fig. 1] are relatively uncommon in nature, only 24 different
compounds of this sort have been isolated so far. Several
members of this class of alkaloids, including alexine (1) and
australine (2), the first ones being described,2 have been iso-
lated from leguminosae exhibit promising biological activ-
ity2,3 (e.g., 1 displays antiviral and anti-HIV activity).4 In
2000, Asano et al. reported the first isolation, from an extract
of the bulbs of Muscari Armeniacum (Hyacinthaceae), of hya-
cinthacines A1eA3 (3e5, respectively) together with those
belonging to the B and C series in 1999.5 Lately in 2002,
the same author accounted on the isolation, from an extract
of the bulbs of Scilla sibirica, of new members of this A series,
named as hyacinthacines A4eA7 (6e9, respectively).6 Many
of these alkaloids display potent glycosidase inhibitory activ-
ity, which makes them either potential drug or therapeutic lead
candidates against viral infections, cancer, and diabetes.7
H
N
OH
HO
OH
OH
HO
H
H
N
7
1
7a
A
OH
OH
OH
3
5
N
R
OH
Alexine (1)
OH
Australine (2)
OH
(1S) R = H, Hyacinthacine A1 (3)
(1R) R = H, Hyacinthacine A2 (4)
(1R) R = Me, Hyacinthacine A3 (5)
OH
OH
H
H
N
OH
OH
N
Me
R
OH
OH
R = Me, (5R) Hyacinthacine A6 (8)
R = Me, (5S) Hyacinthacine A7 (9)
Hyacinthacine A4 (6)
(1R,2S,3R,5R) Hyacinthacine A5 (7)
HO
HO
OH
OH
H
H
∗
∗
OH
OH
OH
OH
HN
HN
DALDP
DMDP
*
Part 11 of this series. For Part 10, see Ref. 1.
* Corresponding author. Tel.: þ34 958 249583; fax: þ34 958 243845.
E-mail address: isidoro@ugr.es (I. Izquierdo).
Figure 1. Naturally occurring pyrrolizidine alkaloids of the A series and poly-
hydroxylated pyrrolidines (imino or azasugars).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.009

4614
I. Izquierdo et al. / Tetrahedron 64 (2008) 4613e4618
acetylenic sulfones with chloroamines,9 tandem inter [4þ2]/
inter [3þ2] cycloaddition process,10 triple reductive amina-
tions,11 cuprate chemistry,12 and diastereoselective syn-di-
hydroxylation13 are becoming more popular. Defenders of
non-carbohydrate synthetic strategy claim that these routes
are superior because they exhibit increased stereoselectivity
and are more efficient at introducing the amine moiety.11 If
possible, a flexible and stereocontrolled synthetic approach
taking advantage of the carbohydrate’s inherent stereochemis-
try and an efficient introduction of the amine function would
be desired.
With the aim of proving the whole chemical space occupied
by the polyhydroxylated pyrrolizidine alkaloids, syntheses of
the above compounds have been and must continue to be de-
veloped. In addition, naturally occurring azasugars are
scarcely present in the natural sources and are often difficult
to purify from them,14 and therefore, synthetic routes to these
iminosugars and analogues, are also desirable. In this context
and in the recent past years, our group have put into practice
a synthetic methodology, consisting in the use of appropriately
functionalized and orthogonally protected pyrrolidines15 as
key intermediate for the preparation of more complex
PHPAs.1,16 On the other hand, such polyhydroxylated pyrroli-
dines were prepared from the commercially available hexulose
D-fructose. Even though the preparation of the PHPAs 3 and 8,
from an appropriately protected derivative of DALDP, has
been recently disclosed by our group,16i we wander on the pos-
sibility of using the more easily available DMDP as the homo-
chiral starting material, since the configuration at the starred
carbon is the only difference in both pyrrolidines, an inversion
of such configuration at any stage of the synthetic route would
be sufficient. Thus, herein we describe our studies on hyacin-
thacine A7 (9), which culminated in the first total synthesis and
absolute configuration determination of this natural product.
9 leads to new pyrrolizidines with a stereochemistry at the A-
ring exactly matching with that existing in the tri-orthogonally
protected and stereochemically loaded 2,5-dideoxy-2,5-imino-
D-mannitol (DMDP, 10),15f a simple cleavage of N(4)eC(5)
bond in the pyrrolizidines skeleton and a Wittig-type discon-
nection at C(3)eC(4) of the a,b-unsaturated pyrrolidine
ketone 12, reveals key 10 as the precursor.
Following the above retrosynthesis, and based on results
from previous studies,16a,b we began the synthesis with
(2R,3R,4R,5R)-4-benzoyloxy-3-benzyloxy-N-benzyloxycar-
bonyl-20-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)
pyrrolidine (10, Scheme 1).15f Oxidation of 10 with N-methyl-
morpholine N-oxide (NMO) catalyzed by tetra-n-propylam-
moniumperruthenate (TPAP) yielded the aldehyde 11
according to its IR spectra (n 1710 cmꢀ1, CHO). Subsequent
treatment of 11 with 1-triphenylphosphoranylidene-2-propa-
none afforded (E)-4-[(20R,30R,40R,50R)-30-benzoyloxy-40-ben-
zyloxy-N-benzyloxycarbonyl-50-tert-butyldiphenylsilyloxy-
methylpyrrolidin-20-yl]but-3-en-2-one (12) in
a
highly
stereoselective manner. The structure of 12, which exists as
a mixture of two rotamers (w1.1:1 ratio), was determined
on the basis of its analytical and spectroscopic data, whereas
the E configuration at C(3,4) was established from the J3,4
value (16.1 Hz).
OBz
OBn
OTBDPS
O
OBz
OBn
OTBDPS
R
b
CbzN
CbzN
10 R = CH2OH
11 R = CHO
12
a
Scheme 1. Synthesis of a,b-unsaturated pyrrolidine ketone 12. Reagents and
˚
conditions: (a) TPAP/NMO/Cl2CH2/4 A MS, rt; (b) Ph3P]CHCOCH3/
MePh, 80 ꢁC.
Catalytic hydrogenation (10% Pd/C)ecyclization of 12 af-
forded, in only one step, a mixture of the fully protected
(1R,2R,3R,5S,7aR)-(13) and (1R,2R,3R,5R,7aR)-1-benzoyl-
oxy-2-benzyloxy-3-tert-butyldiphenylsilyloxymethyl-5-meth-
ylpyrrolizidine (14). According to Scheme 2, formation of 13
and 14 must take place as follows: catalytic hydrogenation
converted 12 into the N-deprotected saturated pyrrolidine
ketone A, an intramolecular condensation reaction gave the
2. Results and discussion
Our retrosynthetic pathway toward PHPA 9 is illustrated in
Figure 2, in which an inversion of the configuration at C(1) in
Inversion at C(1) and
protecting groups removal
OH
OBz
H
N
H
N
1
A
OH
OBn
OBz
OBz
OBn
H
N
Me
Me
a
-H2O
OH
OTBDPS
5-Epihyacinthacine A3 (13)
tri-orthogonally protected
OBn
12
HN
(-)-Hyacinthacine A7 (9)
O
Me
OPG
OPG
OBn
A
B
Cyclization
a
OBz
OBz
H
OBz
O
H
N
OBz
OBn
OTBDPS
4
5'
HO
PG = TBDPS
OBn
OPG
+
OBn
3
N
CbzN
CbzN
2'
Me
Me
OPG
14
OTBDPS
13
10
12
Chain lengthening at C(5')
Scheme 2. Synthesis of totally protected derivatives of 5-epi-hyacinthacine A3
(13) and hyacinthacine A3 (14) from 12. Reagents and conditions: (a) 10%
Pd/C/H2, 60 psi, rt.
Figure 2. Retrosynthesis of (ꢀ)-hyacinthacine A7 (9) from a tri-orthogonally
protected derivative of DMDP (10).

I. Izquierdo et al. / Tetrahedron 64 (2008) 4613e4618
4615
H7α
H7β
H
H7β
H7α
H6α
H6β
HO
H7a
H
H
7αH
H
1 OBz
OBn
H2
OPG
H7α
H6α
H6β
H7β
H6α
H6β
1 OBz
1 OH
OBn
H2
OH
H7β
H6α
H6β
H7a
H1
OBn
H2
OH
H
N
OBn
N
H2
N
N
OPG
Me
H5
H5
H5
Me
H3
18
Me H3
H3
Me H3
H
PG = TBDPS
17
13
14
Figure 4. Main observed NOE effects in compounds 17 and 18.
Figure 3. Main observed NOE effects in compounds 13 and 14.
intermediate D5-pyrrolizine B, not isolated, which is finally
hydrogenated to afford a mixture of 13 and 14 in w1:1 ratio,
easy and successfully separated by chromatographic means.
The configuration of the new stereogenic center C(5) in 13
and 14, was established on the basis of extensive NOE exper-
iments and results are displayed in Figure 3. Thus, the definite
NOE effects between C(3)H and C(5)H, C(5)H and C(7a)H,
and Me(5)H with C(2)H and C(8)H in 13, indicate the S con-
figuration at C(5). Whereas, the NOE effects between C(3)H
and Me(5)H, and C(5)H with C(2)H and C(8)H in 14, indicate
the R configuration for that stereogenic center. In addition, the
rest of the NOE interactions also confirmed the total stereo-
chemistry of 13 and 14.
between H(1)eH(3,7a), Me(5)eH(7a,8) indicating, respec-
tively, their a and b-disposition in 17, whereas the NOE ef-
fects between H(1)eH(2,7a,8), Me(5)eH(8) in 18 confirm
the b-disposition for all of them.
Finally, catalytic hydrogenolysis with H2 and 10% Pd/C
convert 17 and 18 to (ꢀ)-1-epi-hyacinthacine A7 (19) and
(ꢀ)-hyacinthacine A7 (9), respectively, in accordance with
their analytical and spectroscopic data, confirming that
1S,2R,3R,5S,7aR are the actual absolute configurations of the
stereogenic centers in natural product 9. PHPA 19 is currently
being evaluated for its ability to inhibit carbohydrate-process-
ing enzymes.
Conversion of 13 into the target molecule 9 (see Scheme 3)
was achieved as follows: conventional debenzoylation of 13
afforded pyrrolizidine 15 that was Swern oxidized to the inter-
mediate ketone A, not isolated, but NaBH4 reduced to yield
a mixture of starting 15 and the inversion product 16 that
was separated by chromatography. Compounds 15 and 16
were, respectively, O-desylilated to afford the corresponding
17 and its C(1) inversion product 18. Attempt to generate 16
from 15 stereospecifically by using Mitsunobu hydroxyl inver-
sion17 failed.
3. Conclusions
In summary, the first stereoselective synthesis of naturally
occurring (ꢀ)-hyacinthacine A7 as well as that of its
(ꢀ)-1-epi-isomer have been achieved starting from a tri-
orthogonally protected derivative of DMDP. The inherent chi-
rality of DMDP is in part realized in the target alkaloids, the
required carbon-chain lengthening was easily completed
through a Wittig olefination reaction, and the pyrrolizidine
structure was installed through an one-pot intramolecular
reductive amination process. This route will provide an easy
access to many other PHPAs that will be useful tools for
SAR studies in glycobiology.
OH
H
OR
N
Me
OR1
4. Experimental
15 R = Bn; R1 = PG
17 R = Bn; R1 = H
19 R = R1 = H
R
c
d
H
N
R1
OBn
a
4.1. General procedures
b
13
Me
Solutions were dried over MgSO4 before concentration un-
1
OH
H
OPG
der reduced pressure. The H and 13C NMR spectra were re-
e
15 R = OH; R1 = H
A R = R1 = >O
OR
N
corded with Bruker AMX-300, AM-300, ARX-400, and
AMX-500 spectrometers for solutions in CDCl3 (internal
Me4Si). Splitting patterns are designated as follows: s, singlet;
d, doublet; t, triplet; q, quartet; quint, quintet; sex, sextet; m,
multiplet, and br, broad. IR spectra were recorded with a Per-
kineElmer FT-IR Spectrum 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 rotations were measured for solutions in CHCl3 (1-
dm tube) with a Jasco DIP-370 polarimeter. TLC was devel-
oped on precoated silica gel 60 F254 aluminum sheets and de-
tection 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 per-
formed on silica gel (Merck, 7734). The non-crystalline
Me
OR1
PG = TBDPS
16 R = Bn; R1 = PG
18 R = Bn; R1 = H
9 R = R1 = H
c
d
Scheme 3. Synthesis of 19 and 9 from 13. Reagents and conditions: (a)
MeONa (cat.)/MeOH, 0 ꢁC/rt; (b) (i) Swern oxidation, (ii) NaBH4/MeOH,
0 ꢁC; (c) TBAF$3H2O/THF, rt; (d) 10% Pd/C/H2/HCl/MeOH then Amberlite
IRA-400 (OHꢀ form); (e) (i) BzOH/DEAD/Ph3P/THF, rt, (ii) MeONa (cat.)/
MeOH.
Structural elucidations of 17 and 18 were based on their an-
alytical and spectroscopic data. Thus, exhaustive NOE exper-
iments on such compounds (see Fig. 4) demonstrated their
whole stereochemistry, being on interest those existing effects

4616
I. Izquierdo et al. / Tetrahedron 64 (2008) 4613e4618
compounds were shown to be homogeneous by chromato-
graphic methods and characterized by NMR and HRMS.
two new compounds. The catalyst was filtered off, washed
with MeOH, and the filtrate and washings were concentrated
to a residue that was submitted to column chromatography
(1:2, Et2O/hexane) to afford first pure syrupy 13 (407 mg,
44%), which had [a]2D7 ꢀ9 (c 1); n (neat): 3070 and 3048 (aro-
4.2. (E)-4-[(20R,30R,40R,50R)-30-Benzoyloxy-40-benzyloxy-N-
benzyloxycarbonyl-50-tert-butyldiphenylsilyloxymethyl-
pyrrolidin-20-yl]but-3-en-2-one (12)
1
matic), 1721 (C]O, Bz), 739 and 701 cmꢀ1 (aromatic). H
NMR data (400 MHz): d 7.98e7.29 (5m, 20H, 4Ph), 5.37 (t,
1H, J1,2¼J1,7a¼2.8 Hz, H-1), 4.84 and 4.62 (2d, 2H,
J¼12.1 Hz, CH2Ph), 4.35 (t, 1H, J2,3¼2.8 Hz, H-2), 3.76 (t,
To a stirred solution of (2R,3R,4R,5R)-4-benzoyloxy-3-ben-
zyloxy-N-benzyloxycarbonyl-20-O-tert-butyldiphenylsilyl-2,5-
bis(hydroxymethyl)pyrrolidine15f (10, 1.46 g, 2 mmol) in dry
0
0
1H, J3,8¼J8,8 ¼10.2 Hz, H-8), 3.72 (dd, 1H, J3,8 ¼6.3 Hz, H-
˚
0
DCM (20 mL) were added activated 4 A MS (1 g), NMO
80), 3.63 (dt, 1H, J7,7a¼J7 ,7a¼7.7 Hz, H-7a), 3.30e3.25 (m,
(350 mg, 3 mmol), and TPAP (100 mg) and the reaction mix-
ture was kept at rt for 3 h. TLC (Et2O) then indicated the
absence of the starting material and the presence of a faster-
running compound. The reaction was diluted with Et2O
(30 mL), filtered through a bed of Silica gel 60 (Scharlau,
230e400 mesh), and thoroughly washed with Et2O. The com-
bined filtrate and washings were concentrated to presumably
aldehyde 11 (1.29 g, 89%); n (neat): 3068 and 3032 (aro-
matic), 1738 (CHO), 1724 and 1710 (C]O, Bz and Cbz),
740 and 700 cmꢀ1 (aromatic). This material was used in the
next step.
1H, H-3), 3.24e3.16 (m, 1H, H-5), 2.21e2.13 (m, 1H, H-7),
2.04e1.91 (m, 2H, H-6,70), 1.46e1.38 (m, 1H, H-60), 1.04
(s, 9H, CMe3), and 1.03 (d, 3H, J5,Me¼6.0 Hz, Me). 13C
(100 MHz, inter alia): d 166.18 (COPh), 86.60 (C-2), 83.62
(C-1), 72.05 (CH2Ph), 71.29 (C-3), 70.44 (C-7a), 66.15 (C-
8), 63.18 (C-5), 34.30 (C-6), 30.80 (C-7), 27.00 (Me and
CMe3), and 21.90 (CMe3). HRMS (LSIMS): m/z 620.3190
[MþþH]. For C39H46NO4Si 620.3196 (deviation þ1.0 ppm).
Eluted second was 14 (360 mg, 40%) as a colorless syrup,
which had [a]2D7 ꢀ31 (c 1.2); n (neat): 3070 and 3048 (aro-
1
matic), 1720 (C]O, Bz), 736 and 709 cmꢀ1 (aromatic). H
To a solution of 11 (1.29 g, 1.8 mmol) in dry toluene
(30 mL) was added 1-triphenylphosphoranylidene-2-propanone
(1.6 g, 5 mmol) and the mixture was heated at 80 ꢁC overnight.
TLC (1:1, Et2O/hexane) then revealed the presence of a slightly
slower-running compound. The reaction mixture was filtered
and supported on silica gel, then chromatographed (2:3, Et2O/
NMR (300 MHz): d 8.10e7.32 (5m, 20H, 4Ph), 5.53 (t, 1H,
J1,2¼J1,7a¼1.7 Hz, H-1), 4.88 and 4.82 (2d, 2H, J¼12.0 Hz,
CH2Ph), 4.42 (br s, 1H, H-2), 3.82 (dd, 1H, J3,8¼6.0 Hz,
0
J8,8 ¼10.0 Hz, H-8), 3.76 (m, 1H, H-7a), 3.74 (t, 1H,
0
0
J3,8 ¼10.0 Hz, H-8 ), 3.45 (ddd, 1H, J2,3¼2.1 Hz, H-3), 3.29
(dq, 1H, H-5), 2.17e1.98 (m, 2H, H-7,70), 1.98e1.82 (m,
1H, H-6), 1.68e1.55 (m, 1H, H-60), 1.23 (d, 3H, J5,Me¼6 Hz,
Me), and 1.17 (s, 9H, CMe3). 13C NMR (75 MHz, inter alia):
d 166.08 (COPh), 87.05 (C-2), 82.10 (C1), 72.03 (CH2Ph),
70.11 (C-7a), 67.02 (C-8), 64.59 (C-3), 59.18 (C-5), 31.69
(C-6), 28.95 (C-7), 27.12 (Me and CMe3), and 19.47
(CMe3). HRMS (LSIMS): m/z 642.3018 [MþþNa]. For
C39H45NO4SiNa 642.3016 (deviation ꢀ0.4 ppm).
hexane) to afford 12 (1.21 mg, 78%) as a thick syrup; [a]D28
28
þ6, [a]
þ22 (c 1.3); n (neat): 3069 and 3033 (aromatic),
405
1710 and 1681 (C]O Bz, C]O conjugated ketone, and
Cbz), 739 and 700 cmꢀ1 (aromatic). 1H NMR (400 MHz):
d 7.90e7.10 (3m, 25H, 5 Ph), 6.80 and 6.72 (2dd, 1H,
0
J2 ,4¼7.4 and 7.8 Hz, H-4, two rotamers), 6.29 and 6.10 (2d,
1H, J3,4¼16.1 Hz, H-3, two rotamers), 5.33 (br d, 1H,
J¼5.1 Hz, H-30), 5.26 and 4.87 (2d, 2H, J¼12.1 Hz, CH2Ph),
5.05 and 4.94 (2d, 2H, J¼12.2 Hz, CH2Ph), 4.79e4.34 (2br
m, 5H, CH2Ph and H-40,500a,500b, two rotamers), 4.31 and 4.11
(2dd, 1H, J¼4.8, 9.5 Hz, H-20, two rotamers), 3.67 and 3.62
(2br t, 1H, J¼10.2 Hz, H-50, two rotamers), 2.20 and 2.02
(2br s, 3H, H-1,1,1, two rotamers), 1.03 and 0.97 (2s, 9H,
CMe3, two rotamers). 13C NMR (100 MHz, inter alia):
d 198.01 (C-2), 165.36 (COPh), 154.41 and 154.21 (CO, Cbz,
two rotamers), 82.84, 82.10, 80.66 and 79.65 (C-30,40, two ro-
tamers), 71,74 and 71.60 (CH2Ph, two rotamers), 67.40 (Cbz),
65.92 and 65.52 (C-20,50), 62.28 and 61.55 (C-500, two rotamers),
27.23 (C-1), 26.92 (CMe3), and 19.34 and 19.23 (CMe3, two ro-
tamers). HRMS (LSIMS): m/z 790.3166 [MþþNa]. For
C47H49NO7SiNa 790.3176 (deviation þ1.3 ppm).
4.4. (1R,2R,3R,5S,7aR)-2-Benzyloxy-3-tert-butyldiphenyl-
silyloxymethyl-1-hydroxy-5-methylpyrrolizidine (15)
To an ice-water cooled and stirred solution of 13 (580 mg,
0.94 mmol) in anhydrous MeOH (10 mL) was added 1 M
MeONa in the same solvent (0.5 mL) and the reaction mixture
was allowed to reach room temperature and left for 12 h. TLC
(2:1, Et2O/hexane) then showed a slower-running compound.
The mixture was neutralized with acetic acid, concentrated
to a residue that was submitted to column chromatography
(2:1, Et2O/hexane/Et2O) to yield pure 15 (430 mg, 89%)
as a colorless syrup, which had [a]2D8 14 (c 1); n (neat): 3319
(OH), 3070, 739 and 701 cmꢀ1 (aromatic). 1H NMR
(300 MHz): d 7.78e7.26 (3m, 15H, 3Ph), 4.65 and 4.59 (2d,
2H, J¼11.9 Hz, CH2Ph), 4.09 (t, 1H, J1,2¼J1,7a¼3.7 Hz, H-
1), 3.97 (t, 1H, J2,3¼3.9 Hz, H-2), 3.86 (dd, 1H, J3,8¼5.6,
4.3. (1R,2R,3R,5S,7aR)-(13) and (1R,2R,3R,5R,7aR)-1-
Benzoyloxy-2-benzyloxy-3-tert-butyldiphenylsilyloxymethyl-
5-methylpyrrolizidine (14)
J8,8 ¼10.5 Hz, H-8), 3.80 (dd, 1H, J3,8¼5.5 Hz, H-80), 3.68
0
0
(dt, 1H, J7,7a¼J7 ,7a¼7.8 Hz, H-7a), 3.23 (dquint, 1H, J¼6.4,
Compound 12 (1.14 g, 1.48 mmol) in dry MeOH (30 mL)
was hydrogenated at 60 psi over 10% Pd/C (200 mg) for
24 h. TLC (2:1, Et2O/hexane) then showed the presence of
7.0 Hz, H-5), 3.14 (br q, 1H, H-3), 2.18e2.01 (m, 2H, H-
6,7), 1.87e1.74 (m, 1H, H-70), 1.54e1.47 (m, 1H, H-60),
1.15 (d, 3H, J5,Me¼6.3 Hz, Me), and 1.10 (s, 9H, CMe3).

I. Izquierdo et al. / Tetrahedron 64 (2008) 4613e4618
4617
13C NMR (75 MHz, inter alia): d 89.53 (C-2), 80.89 (C-1),
72.26 (CH2Ph), 71.98 (C-3), 71.79 (C-7a), 66.75 (C-8),
64.03 (C-5), 33.87 (C-6), 29.68 (C-7), 27.08 (CMe3),
21.29 (Me), and 19.39 (CMe3). HRMS (LSIMS): m/z
516.2933 [MþþH]. For C32H42NO3Si 516.2934 (deviation
þ0.1 ppm).
H-1), 3.64 (dd, 1H, J3,8¼3.6 Hz, J8,8 ¼10.8 Hz, H-8), 3.58e
3.53 (m, 2H, H-7a,80), 2.95e2.86 (2m, 2H, H-3,5), 2.36 (br
s, 1H, OH), 2.18e2.10 (m, 1H, H-7), 2.04e1.97 (m, 1H, H-
6), 1.78e1.71 (m, 1H, H-70), 1.55e1.45 (m, 1H, H-60), 1.06
(d, 3H, J5,Me¼6.0 Hz, Me). 13C (100 MHz), d 137.75,
128.86, 128.42, and 128.10 (Ph), 84.03 (C-2), 73.26
(CH2Ph), 70.00 (C-1), 67.84 and 67.49 (C-3,7a), 63.14 (C-
5), 60.85 (C-8), 36.19 (C-6), 23.15 (C-7), and 21.55 (Me).
HRMS (EI): m/z 277.1667 [Mþ]. For C16H23NO3 277.1678
(deviation ꢀ4.0 ppm).
0
4.5. (1R,2R,3R,5S,7aR)-(17) and (1S,2R,3R,5S,7aR)-
2-Benzyloxy-1-hydroxy-3-hydroxymethyl-5-
methylpyrrolizidine (18)
To a stirred and cooled (ꢀ78 ꢁC) solution of 2 M oxalyl
chloride (462 mL, 0.92 mmol) in anhydrous DCM (10 mL)
was added DMSO (126 mL, 1.77 mmol) dropwise under argon
and the mixture maintained for 30 min. A solution of 15
(400 mg, 0.78 mmol) in the same solvent (5 mL) was added
and the reaction mixture was left at ꢀ78 ꢁC for 60 min.
TEA (322 mL, 2.3 mmol) was added and after 2 h at
ꢀ50 ꢁC, TLC (Et2O) then showed a faster-running compound.
The reaction was allowed to reach room temperature and then
water (15 mL) was added. The aqueous layer was removed
and extracted with DCM. The combined organic extracts
were washed with brine and concentrated to afford a residue
that was subjected to flash chromatography (Et2O) to afford
the corresponding pyrrolizidin-1-one (360 mg, 90%) (n
(neat): 1755 cmꢀ1 (CO)) that was subsequently treated with
NaBH4 (41 mg, 1.1 mmol) in anhydrous MeOH (20 mL) at
0 ꢁC for 30 min. TLC (EtOAc) then showed two lower-run-
ning compounds. After work-up, column chromatography
(1:1, Et2O/hexane) afford syrupy 15 (100 mg, 29%) and 16
(160 mg, 46%), which were separately O-desilylated.
4.6. (1R,2R,3R,5S,7aR)-1,2-Dihydroxy-3-hydroxymethyl-
5-methylpyrrolizidine [19, (ꢀ)-1-epi-hyacinthacine A7]
A solution of 17 (35 mg, 0.126 mmol) in MeOH (10 mL)
was acidified (concd HCl) and hydrogenated (10% Pd/C,
40 mg) at 70 psi for 12 h. The catalyst was filtered off, washed
with MeOH and the filtrate and washings neutralized with
Amberlite IRA-400 (OHꢀ form) and concentrated to afford
pure 19 (15 mg, 63%) as a colorless thick syrup, which had
[a]2D9 ꢀ162 (c 0.5, H2O). H NMR (500 MHz, MeOH-d4):
1
d
3.85 (t, 1H, J1,2¼J2,3¼7.4 Hz, H-2), 3.69 (t, 1H,
J1,7a¼7.4 Hz, H-1), 3.66 (dd, 1H, J3,8¼4.3 Hz, H-8), 3.59
0
0
0
(dd, 1H, J3,8 ¼5.2 Hz, J8,8 ¼11.1 Hz, H-8 ), 3.30 (q, 1H,
0
J7,7a¼J7 ,7a¼7.4 Hz, H-7a), 3.04 (br sex, 1H, J5,6
¼
0
J5,6 ¼J5,Me¼6.3 Hz, H-5), 2.72 (dt, 1H, H-3), 2.09 (ddt, 1H,
J¼4.8, 7.4, 12.5 Hz, H-7), 2.01 (ddt, 1H, J¼5.6, 7 Hz, H-6),
1.75 (m, 1H, H-70), 1.48 (br dq, 1H, J¼8.5, 12.4 Hz, H-60),
and 1.10 (d, 3H, Me). 13C NMR (125 MHz): d 85.74 (C-1),
83.06 (C-2), 75.00 (C-3), 72.41 (C-7a), 67.28 (C-5), 66.51
(C-8), 37.48 (C-6), 33.28 (C-7), and 23.87 (Me). HRMS
(EI): m/z 187.1199 [Mþ]. For C9H17NO3 187.1208 (deviation
ꢀ4.8 ppm).
Compound 15 (100 mg, 0.19 mmol) in THF (10 mL) was
treated at rt with TBAF$3H2O (68 mg, 0.21 mmol) for 12 h.
TLC (EtOAc) then revealed a slower-running compound.
The reaction mixture was supported on silica gel and submit-
ted to chromatography (Et2O/3:1, Et2O/MeOH) to afford
pure 17 (45 mg, 85%), which had [a]2D6 36 (c 1); n (neat):
3340 (OH), 737 and 698 cmꢀ1 (aromatic). 1H NMR
(400 MHz): d 7.34e7.28 (m, 5H, Ph), 5.05 (br s, 2H, OH-
1,8), 4.68 and 4.58 (2d, 2H, J¼11.6 Hz, CH2Ph), 4.04 (t,
1H, J1,2¼J1,7a¼3.6 Hz, H-1), 3.94 (t, 1H, J2,3¼3.6 Hz, H-2),
3.77e3.55 (m, 3H, H-7a,8,80), 3.20e3.10 (m, 2H, H-3,5),
2.20e2.12 (m, 1H, H-7), 2.02e1.95 (m, 1H, H-6), 1.82e
1.72 (m, 1H, H-70), 1.57e1.46 (m, 1H, H-60), and 1.19 (d,
3H, J5,Me¼6.3 Hz, Me). 13C NMR (100 MHz): d 138.14,
128.76, 128.11, and 127.84 (Ph), 89.03 (C-2), 80.54 (C-1),
72.77 (C-7a), 72.59 (CH2Ph), 71.29 (C-3), 64.28 (C-5),
61.82 (C-8), 34.14 (C-6), 30.33 (C-7), and 20.01 (Me).
HRMS (EI): m/z 277.1666 [Mþ]. For C16H23NO3 277.1678
(deviation ꢀ4.3 ppm).
4.7. (1S,2R,3R,5S,7aR)-1,2-Dihydroxy-3-hydroxymethyl-
5-methylpyrrolizidine [9, (ꢀ)-hyacinthacine A7]
A solution of 19 (45 mg, 0.16 mmol) in MeOH (10 mL)
was debenzylated with 10% Pd/C (40 mg) as above to afford
pure 9 (23 mg, 76%) as a colorless thick syrup, which had
[a]2D9 36.4 (c 1, MeOH), [a]D28 ꢀ34 (c 1, H2O) [lit.6 [a]D
ꢀ51.8 (c 0.45, H2O)]. 1H NMR (500 MHz, MeOH-d4):
d 4.10 (dd, 1H, J1,2¼3.8 Hz, J2,3¼9.3 Hz, H-2), 3.95 (t, 1H,
J1,7a¼3.6 Hz, H-1), 3.92 (m, 1H, H-7a), 3.85 (dd, 1H,
0
0
J3,8¼3.7 Hz, H-8), 3.73 (dd, 1H, J3,8 ¼4.8 Hz, J8,8 ¼11.6 Hz,
H-80), 3.32 (m, 1H, H-5), 3.13 (m, 1H, H-3), 2.29 (m, 1H,
H-7a), 2.17 (m, 1H, H-6a), 1.91 (m, 1H, H-7b), 1.67 (m,
1H, H-6b), and 1.29 (d, 3H, J5,Me¼6.4 Hz, Me). 13C NMR
(125 MHz): d 78.78 (C-2), 75.08 (C-1), 73.71 (C-3), 72.38
(C-7a), 69.55 (C-5), 63.88 (C-8), 38.43 (C-6), 25.94 (C-7),
and 21.20 (Me). HRMS (EI): m/z 187.1214 [Mþ]. For
C9H17NO3 187.1208 (deviation þ3.2 ppm).
Compound 16 (160 mg, 0.31 mmol) in THF (10 mL) was
treated at rt with TBAF$3H2O (110 mg, 0.34 mmol) overnight.
Work-up and column chromatography as above afforded pure
18 (56 mg, 65%), which had [a]2D5 57 (c 1); n (neat): 3401
Acknowledgements
1
(OH), 737 and 698 cmꢀ1 (aromatic); H NMR (400 MHz):
d 7.38e7.30 (m, 5H, Ph), 4.60 (s, 2H, CH2Ph), 4.05 (dd,
1H, J1,2¼3.6 Hz, J2,3¼8.8 Hz, H-2), 3.89 (t, 1H, J1,7a¼3.2 Hz,
Major support for this project was provided by Ministerio
´
de Educacion y Ciencia of Spain (Project Ref. No.

4618
I. Izquierdo et al. / Tetrahedron 64 (2008) 4613e4618
Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077e3092; (c) Mroczek,
T.; Glowniak, K. Proc. Phytochem. Soc. Eur. 2002, 47, 1e46; (d) Bols,
M.; Lillelund, V. H.; Jensen, H. H.; Liang, X. Chem. Rev. 2002, 102,
515e553; (e) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773e781; (f) Fu,
P. P.; Xia, Q.; Lin, G.; Chou, M. W. Drug Metab. Rev. 2004, 36, 1e55;
(g) Pyne, S. G.; Tang, M. Curr. Org. Chem. 2005, 9, 1393e1418; (h)
CTQ2006-14043). Additional support was provided by Junta
´
de Andalucıa (Group CVI-250) and Fundacion Ramon Areces
for a grant (F.S-.C.).
´
´
Supplementary data
´
Pearson, M. S. M.; Mathe-Allainmat, M.; Fargeas, V.; Lebreton, J.
1H and 13C NMR spectra for compounds 9, 13, 14, 17e19,
homo and heteronuclear 2D-NMR spectra for compounds 9
and 19 (16 pages). Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2008.03.009.
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