Polyhydroxylated pyrrolizidines. Part I: Short and highly stereocontrolled syntheses of hyacinthacines

Article abstract of DOI:10.1016/S0957-4166(01)00440-2

Two short and highly stereocontrolled syntheses for 7a-epi-hyacinthacine A₂ (7-deoxyalexine) 3 and 5,7a-diepi-hyacinthacine A₃ 4 are, respectively, reported herein. An appropriately protected polyhydroxypyrrolidine, (2R,3R,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2′-O-tert- butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 5, readily available from D-fructose, was chosen as the chiral starting material.

Full text of DOI:10.1016/S0957-4166(01)00440-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2481–2487
Polyhydroxylated pyrrolizidines. Part I: Short and highly
stereocontrolled syntheses of hyacinthacines
Isidoro Izquierdo,* Mar´ıa T. Plaza, Rafael Robles and Francisco Franco
Department of Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Received 19 September 2001; accepted 8 October 2001
Abstract—Two short and highly stereocontrolled syntheses for 7a-epi-hyacinthacine A2 (7-deoxyalexine) 3 and 5,7a-diepi-
hyacinthacine A3 4 are, respectively, reported herein. An appropriately protected polyhydroxypyrrolidine, (2R,3R,4R,5S)-3,4-
dibenzyloxy-N-benzyloxycarbonyl-2%-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 5, readily available from
D
-fructose, was chosen as the chiral starting material. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
stereocontrol. In addition, the scope of this method-
ology was explored by also synthesizing 5,7a-diepi-
hyacinthacine A3 4, another unnatural hyacinthacine
isomer.
The polyhydroxylated pyrrolizidine skeleton [1-aza-
bicyclo[3.3.0]octane] is the basic framework of a diverse
group of alkaloid sugar mimics isolated from natural
sources and can be classified into three main groups:
those with an one carbon branch at C(1) (necines),
those with the same substituent but at C(3) (alexines)1
and finally those recently isolated with such a carbon
branch both at C(3) and C(5) (hyacinthacines).2 Most
of these molecules show inhibitory activity against dif-
ferent kinds of glycoprotein-processing glycosidases and
hence have potential as chemotherapeutic agents.3 As a
consequence of this bioactivity, great efforts have been
made during the past two decades in order to achieve
either the isolation of new pyrrolizidine alkaloids from
nature or the design of stereocontrolled synthetic
routes3,4 to these compounds, or to their unnatural
isomers, which might be of interest for SAR studies.
According to the following retrosynthetic analysis for
the hyacinthacine A2 and A3 type compounds (Scheme
1), the protected 2,5-dideoxy-2,5-imino-
D-glucitol
(DGDP)6 5 prepared from
D
-fructose, can be consid-
ered an excellent chiral starting material for the synthe-
sis of such target molecules. Thus, carbon-chain
lengthening either at C(2%) or C(5%) (the original C(1)
and C(6) of D-fructose) by a suitably functionalized two
carbon fragment, followed by further cyclization, could
lead to pyrrolizidines with stereochemistry at C(7a)
belonging either to that of the alexine 1 or australine 2
series, depending on whether the above mentioned car-
bon-chain lengthening is completed at C(5%) or C(2%),
respectively, indicating that 5 has an interesting pivotal
synthetic character.
To the best of our knowledge, the first synthesis for a
hyacinthacine was that has been recently reported by
Yoda’s group5 for 7a-epi-hyacinthacine A2 (7-
deoxyalexine, 3), by using a methodology previously
applied to the synthesis of (+)-alexine.4d However, this
synthesis is impractical, having serious drawbacks in
that it is lengthy and poorly stereoselective. Thus, a
synthesis of 26 steps and separation of mixtures of
diastereomeric intermediates were necessary in order to
obtain 3. Herein, we report a new synthetic procedure
that produces 3 much more directly and with high
2. Results and discussion
Oxidation of (2R,3R,4R,5S)-3,4-dibenzyloxy-N-benzyl-
oxycarbonyl - 2% - O - tert - butyldiphenylsilyl - 2,5 - bis-
(hydroxymethyl)pyrrolidine 56 catalysed by tetra-n-
propylammonium perruthenate7 yielded the aldehyde 6
(see Section 3) which was directly treated with
(methoxycarbonylmethylene)triphenyl phosphorane to
afford methyl (E)-3-[(2%S,3%R,4%R,5%R)-3%,4%-dibenzyl-
oxy - N - benzyloxycarbonyl - 5% - tert - butyldiphenylsilyl-
oxymethylpyrrolidin-2%-yl]propenoate
7 in a highly
* Corresponding author. E-mail: isidoro@platon.ugr.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00440-2

2482
I. Izquierdo et al. / Tetrahedron: Asymmetry 12 (2001) 2481–2487
Scheme 1.
stereoselective manner. The structure of 7 was determined
on the basis of its spectroscopic data and the (E)-configu-
ration established from the J2,3 value (15.8 Hz). Catalytic
hydrogenation (10% Pd–C) of 7 afforded the saturated
and N-deprotected ester 8, which, in order to promote
the required cyclization to the indolizidine skeleton, was
heated with methanolic sodium methoxide8 to effect
internal N-acylation of the pyrrolidine moiety by the ester
group, giving the fully protected g-lactam identified as
(1R,2R,3R,7aS)-1,2-dibenzyloxy-3-tert-butyldiphenyl-
silyloxymethylpyrrolizidin-5-one 9 as the main product,
together with a small amount of the O-desilylated
derivative 10, which was also obtained after treatment of
9 with tetra-n-butylammonium fluoride dihydrate in
THF. The g-lactam 10 was reduced with borane–dimethyl
sulfide complex in THF producing the partially protected
7a-epi-hyacinthacine A2 11 in moderate yield (Scheme 2).
explored. Thus, compound
6
was treated with
(triphenylphosphoranylidene)acetaldehyde giving the
related (E)-a,b-unsaturated aldehyde 12, which, after
catalytic hydrogenation as above, afforded in only one
step the fully protected (1R,2R,3R,7aS)-1,2-dibenzyl-
oxy-3-tert-butyldiphenylsilyloxymethylpyrrolizidine 15.
Formation of 15 must take place according to Scheme
3, through an initial hydrogenation of 12 to the satu-
rated aldehyde 13, subsequent internal condensation to
the bicyclic enamine 14, both not isolated, and final
hydrogenation to 15. Partial deprotection of 15 to 11
and hydrogenolysis of the benzyl protecting groups in
acid medium (HCl) yielded the corresponding 7a-epi-
hyacinthacine A2 hydrochloride 16, which was con-
verted, after treatment with Amberlite IRA-400 (OH−),
into the required free base 3. The H and 13C NMR
1
spectra of 3, whose signals were assigned on the basis
of COSY and HETCOR experiments, were consistent
with data previously reported for analogous com-
pounds.2b,9,10
In order to shorten the synthesis and to improve the
total yield of 11 from 6, an alternative route was
+
,
Scheme 2. (a) TPAP/NMO/Cl2CH2/4 A MS; (b) Ph3PꢀCHCO2Me/Cl2CH2; (c) H2/10% Pd–C; (d) MeONa/MeOH; (e) n-Bu4N F;
(f) H3B:SMe2/THF.

I. Izquierdo et al. / Tetrahedron: Asymmetry 12 (2001) 2481–2487
2483
Scheme 3. (a) Ph3PꢀCHCHO/Cl2CH2; (b) H2/10% Pd–C; (c) n-Bu4N+F; (d) H2/10% Pd–C/MeOH, HCl; (e) Amberlite IRA-400
(HO− form).
Reaction of [(2%R,3%R,4%R,5%R)-3%,4%-dibenzyloxy-N-benz-
yloxycarbonyl - 5% - tert - butyldiphenyl silyloxymethyl-
pyrrolidin-2%-yl]carbaldehyde 6 with 1-triphenylphos-
phoranylidene-2-propanone gave the corresponding 4-
[(2%S,3%R,4%R,5%R)-3%,4%-dibenzyloxy-N-benzyloxycarbon-
yl-5%-tert-butyldiphenylsilyloxymethylpyrrolidin-2%-yl]-
but-3-en-2-one 17. The structure of 17 was determined
on the basis of its spectroscopic data. Nevertheless, the
configuration at the C(3)ꢁC(4) double bond (which was
irrelevant to our purposes) could not be established due
to the broadening showed by the C(3)H and C(4)H
signals, which made measurement of the coupling con-
stants impossible.
could be demonstrated by the isolation of a minute
amount of 18 from the reaction mixture, subsequent
intramolecular condensation to give the bicyclic enam-
ine 19, which was not isolated and final hydrogenation
to 20.
The stereochemistry of the new C(5) stereogenic centre
was established on the basis of extensive NOE experi-
ments. The NOE interactions are shown in Fig. 1. The
definite NOE effects between C(5)H and C(3)H,
between C(5)H and C(1)H and between C(5)H and
C(7a)H indicate that C(1)H, C(3)H, C(5)H and C(7a)H
are on the same side of the molecule. Thus, the configu-
ration at C(5) is S. Noteworthy was the high stereose-
lectivity found in the hydrogenation of 19, that can be
attributed, according to Fig. 1, to its peculiar shape,
where it is appreciated that the a-face is less hindered
for hydrogen attack than the b-face is, preferentially
affording compound 20.
Catalytic hydrogenation (10% Pd–C) of 17 afforded, in
only one step, the fully protected (1R,2R,3R,5S,7aS)-
1,2-dibenzyloxy-3-tert-butyldiphenylsilyloxymethyl-5-
methylpyrrolizidine 20. Formation of 20 must take
place as previously (Scheme 4): initial hydrogenation of
17 to the N-deprotected saturated methylketone 18, as
Scheme 4. (a) Ph3PꢀCHCOCH3/Cl2CH2/D; (b) H2/10% Pd–C; (c) n-Bu4N+F; (d) H2/10% Pd–C/MeOH, HCl; (e) Amberlite
IRA-400 (HO− form).

2484
I. Izquierdo et al. / Tetrahedron: Asymmetry 12 (2001) 2481–2487
Figure 1. Hydrogenation of intermediate enamine 19 and NOE interactions for 20.
Finally, removal of the protecting groups in 20 gave the
target molecule 5,7a-diepi-hyacinthacine A3 4, in accor-
dance with its analytical data and 1H, 13C, and 2D
13C–1H heteronuclear shift correlation spectra.
slightly lower mobility. The reaction mixture was con-
centrated to a residue that was supported on silica gel
and chromatographed (ether/hexane, 1:2) to afford 7 (2
24
405
g, 89%) as a thick syrup: [h]2D4 −8, [h]
−21 (c 1);
film
wmax 3070 and 3035 (aromatic), 1734 and 1706 (CꢀO,
conjugated ester, and CꢀO Cbz), 1663 (CꢀC, conju-
gated), 702 and 699 cm−1 (aromatic). NMR data: H
1
3. Experimental
3.1. General
NMR, 7.61–7.19 (m, 25H, 5Ph), 6.96 (dd, 1H, J2,3
=
15.8, J2%,3=7.8 Hz, H-3), 6.02–5.85 (bd, 1H, H-2), 5.05–
3.81 (4m, 10H, 2PhCH2 and H-2%,3%,4%,5%,5¦a,5¦b). 4.62
(s, 2H, Cbz), 3.69 (s, 3H, OMe), and 1.06 (s, 9H,
CMe3); 13C NMR (inter alia), 166.35 (C-1), 155.46
(Cbz), 144.44 (C-3), 123.07 (C-2), 83.17 and 81.11
(C-3%,4%), 72.40 and 71.97 (2PhCH2 and Cbz), 67.27
(C-5¦), 64.24 and 61.38 (C-2%,5%), 51.49 (OCH3), 26.98
(CMe3), and 19.32 (CMe3). Mass spectrum (LSIMS):
m/z: 792.3336 [M++Na] for C47H51NO7NaSi 792.3333
(deviation −0.5 ppm).
Solutions were dried over MgSO4 before concentration
1
under reduced pressure. The H and 13C NMR spectra
were recorded with Bruker AMX-300, AM-300, ARX-
400, and AMX-500 spectrometers for solutions in
CDCl3 (internal 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 silica gel
60 F254 aluminium sheets and detection by charring
with H2SO4. Column chromatography was performed
on silica gel (Merck, 7734).
3.3. Methyl 3-[(2%S,3%R,4%R,5%R)-3%,4%-dibenzyloxy-5%-
tert-butyldiphenylsilyloxymethylpyrrolidin-2%-yl]-
propanoate 8
Compound 7 (1.15 g, 1.5 mmol) in methanol (30 mL)
was hydrogenated at 4 atm over 10% Pd–C (0.4 g) for
8 h. TLC (ether/hexane, 3:1) then showed a slower-run-
ning compound. The catalyst was filtered off, washed
with methanol and the filtrate and washings were con-
centrated to a residue that was subjected to column
3.2. Methyl (E)-3-[(2%S,3%R,4%R,5%R)-3%,4%-dibenzyloxy-
N-benzyloxycarbonyl-5%-tert-butyldiphenylsilyloxy-
methylpyrrolidin-2%-yl]propenoate 7
To a stirred solution of (2R,3R,4R,5S)-3,4-dibenzyloxy-
N-benzyloxycarbonyl-2%-O-tert-butyldiphenylsilyl-2,5-
bis(hydroxymethyl)pyrrolidine6 (5, 2.64 g, 3.7 mmol) in
chromatography (ether/hexane, 1:1) to yield pure
24
405
syrupy 8 (630 mg, 66%): [h]2D5 +29, [h]
+78 (c 1.1);
,
dry dichloromethane (25 mL), was added activated 4 A
film
wmax
3072 and 3033 (aromatic), 1740 (CꢀO, ester),
molecular sieves (2 g), N-methylmorpholine N-oxide
(674 mg, 5.5 mmol) and tetra-n-propylammonium per-
ruthenate (TPAP, 64 mg) and the reaction mixture was
kept at room temperature for 4 h. TLC (ether/hexane,
2:1) then indicated the absence of the starting material
and the presence of a faster-running compound. The
reaction was filtered through a bed of silica gel 60
(Merck) and thoroughly washed with dichloromethane.
The combined filtrate and washings were concentrated
to a residue, presumably [(2%R,3%R,4%R,5%R)-3%,4%-dibenz-
yloxy-N-benzyloxycarbonyl-5%-tert-butyldiphenylsilyl-
1
740 and 701 cm−1 (aromatic). NMR data: H NMR,
7.71–7.28 (m, 20H, 4Ph), 4.58 and 4.38 (2d, 2H, J=12
Hz, PhCH2), 4.51 and 4.46 (2d, 2H, J=12.5 Hz,
PhCH2), 3.96 and 3.79 (2d, 2H, J=4 Hz, H-3%,4%), 3.84
(m, 2H, H-5¦a,5¦b), 3.67 (s, 3H, OMe), 3.21 (m, 2H,
H-2%,5%), 2.47–2.29 (m, 2H, H-2a,2b), 2.04–1.94 (m, 2H,
H-3a,3b), and 1.04 (s, 9H, CMe3); 13C NMR (inter
alia), 174.05 (C-1), 84.48 and 84.03 (C-3%,4%), 71.84 and
70.99 (2PhCH2), 66.37 and 61.55 (C-2%,5%), 64.05 (C-5¦),
51.65 (OCH3), 31.77 (C-2), 29.95 (CMe3), 24.21 (C-3),
and 19.37 (CMe3). Mass spectrum (LSIMS): m/z:
638.3300 [M++1] for C39H48NO5Si 638.3302 (deviation
0.2 ppm).
oxymethylpyrrolidin-2%-yl]carbaldehyde 6 (2.5 g, 95%):
film
wmax
Cbz).
1739 (CꢀO, aldehyde) and 1706 cm−1 (CꢀO,
To
a
solution of
6
(2.1 g, 2.9 mmol) in dry
3.4. (1R,2R,3R,7aS)-1,2-Dibenzyloxy-3-tert-
dichloromethane (15 mL) was added (methoxycar-
bonylmethylene)triphenylphosphorane (1.34 g, 4 mmol)
and the mixture was left at room temperature
overnight. TLC (ether/hexane, 2:1) then revealed the
absence of 6 and the presence of a new compound with
butyldiphenylsilyloxymethylpyrrolizidin-5-one 9
A stirred solution of 8 (630 mg, 1 mmol) in a 0.1 M
sodium methoxide solution in anhydrous methanol (20
mL) was heated under reflux for 10 h. TLC (ether) then

I. Izquierdo et al. / Tetrahedron: Asymmetry 12 (2001) 2481–2487
2485
showed mainly a slower-running product. The mixture
was concentrated to a residue that was dissolved in
ether (15 mL) and washed with water (2×10 mL), then
concentrated. Column chromatography (ether/hexane,
3:2) of the residue gave syrupy 9 (430 mg, 71%): [h]D25
mixture was allowed to reach room temperature and
maintained for an additional 6 h. Methanol (1 mL) was
added and the reaction mixture was stirred under reflux
for 2 h, then concentrated and repeatedly co-distilled
with methanol. Column chromatography (ether/
26
film
+8, [h]
+23 (c 1.1); wmax
3074, 3050, and 3032
methanol/triethylamine, 5:1:0.5) of the residue afforded
405
(aromatic), 1693 (CꢀO, lactam), 737 and 700 cm−1
26
pure 11 (55 mg, 26%) as a clear syrup: [h]2D6 +9, [h]
405
1
(aromatic). NMR data: H NMR, 7.66–7.58 and 7.40–
+26.5 (c 0.8). NMR data: 1H NMR, 7.40–7.30 (m, 10H,
Ph), 4.58 and 4.52 (2d, 2H, J=11.8 Hz, PhCH2), 4.49
(s, 2H, PhCH2), 3.98 (dd, 1H, J1,2=3, J1,7a=6.7 Hz,
H-1), 3.87 (dd, 1H, J2,3=5.8 Hz, H-2), 3.83 (dd, 1H,
7.14 (t and m, 20H, 4Ph), 4.80 (dd, 1H, J3,8a=4.4,
J8a,8b=9.7 Hz, H-8a), 4.67 and 4.50 (2d, 2H, J=11.9
Hz, PhCH2), 4.45 (s, 1H, H-2), 4.42 and 4.24 (2d, 2H,
J=12.1 Hz, PhCH2), 4.26 (m, 1H, H-7a), 3.83 (dd, 1H,
J3,8a=4.4, J8a,8b=11.4 Hz, H-8a), 3.76 (dd, 1H, J3,8b=
J
3,8b=10.4 Hz, H-3), 3.65 (d, 1H, J1,7a=3.7 Hz, H-1),
6.2 Hz, H-8b), 3.45 (q, 1H, H-7a), 3.38 (bs, 1H, HO),
3.02 (dt, 1H, H-3), 2.81 and 2.26 (2 m, 2H, H-5,5%),
2.03–1.72 (2 m, 4H, H-6,6%,7,7%); 13C NMR, 138.07,
137.97, 128.47, 128.44, 127.81, 127.77 and 127.70 (Ph),
86.87 (C-1), 83.05 (C-2), 72.07 and 72.02 (2PhCH2),
67.26 and 65.97 (C-3,7a), 61.42 (C-8), 47.45 (C-5), 26.81
(C-6), and 22.83 (C-7). Mass spectrum (LSIMS): m/z:
354.2071 [M++1] for C22H28NO3 354.2069 (deviation
−0.4 ppm).
3.58 (t, 1H, H-8b), 2.63 (ddd, 1H, J6,7=11.8, J6,7%=8.4,
J6,6%=16.4 Hz, H-6), 2.42 (dd, 1H, J6%,7%=9 Hz, H-6%),
2.18 (tt, 1H, H-7), 1.85 (dt, 1H, J7,7%=11.8 Hz, H-7%)
and 1.11 (s, 9H, CMe3); 13C NMR (inter alia), 172.54
(C-5), 86.18 (C-2), 78.21 (C-1), 71.34 and 71.19
(2PhCH2), 65.47 (C-7a), 61.20 (C-3), 60.29 (C-8), 36.61
(C-6), 27.10 (CMe3), 19.77 (C-7), and 19.42 (CMe3).
Mass spectrum (LSIMS): m/z: 628.2861 [M++Na] for
C38H43NO4NaSi 628.2859 (deviation −0.3 ppm).
3.7. (E)-3-[(2%S,3%R,4%R,5%R)-3%,4%-Dibenzyloxy-N-benzyl-
oxycarbonyl-5%-tert-butyldiphenylsilyloxymethylpyrrol-
idin-2%-yl]propenal 12
Eluted second was a small amount (18 mg) of desilyl-
ated
9
[(1R,2R,3R,7aS)-1,2-dibenzyloxy-3-hydroxy-
methylpyrrolizidin-5-one, 10] as a clear thick syrup:
[h]2D4 +53 (c 1.2); wmax
3310 (OH), 3090, 3062, and
To a solution of 6 (310 mg, 0.43 mmol) in dry
dichloromethane (4 mL) was added (triphenylphospho-
ranylidene) acetaldehyde (180 mg, 0.59 mmol) and the
mixture left at room temperature for 36 h. TLC (ether/
hexane, 2:1) then revealed the presence of a slower-run-
ning compound. The reaction mixture was supported
on silica gel and chromatographed (ether/hexane, 1:1)
to afford 12 (140 mg, 44%) as a thick syrup: [h]2D6 +1,
film
3033 (aromatic), 1669 (CꢀO, lactam), 737 and 697 cm−1
1
(aromatic). NMR data: H NMR, 7.40–7.25 (m, 10H,
2Ph), 4.52 and 4.45 (2d, 2H, J=12 Hz, PhCH2), 4.51
and 4.47 (2d, 2H, J=13 Hz, PhCH2), 4.28 (dt, 1H,
J
7,7a=J7%,7a=8, J1,7a=3.8 Hz, H-7a), 4.20 (bs, 1H, OH),
3.86 (dd, 1H, J3,8a=9.6, J8a,8b=12 Hz, H-8a), 3.74 (dd,
1H, J3,8b=2.3 Hz, H-8b), 3.78–3.69 (m, 2H, H-2,3),
3.65 (d, 1H, H-1), 2.72 (m, 1H, H-6), 2.57 (ddd, 1H,
25
film
[h] +12 (c 1); wmax 3071 and 3030 (aromatic), 1708,
405
J
6%,7=2.1, J6%,7%=9.6, J6,6%=16.6 Hz, H-6%), 2.29 and 1.97
1690 and 1647 (CꢀO, conjugated aldehyde, Cbz, and
(2 m, 2H, H-7,7%); 13C NMR, 174.61 (C-5), 137.26,
137.12, 128.69, 128.67, 128.21, 128.18, and 127.72 (Ph),
86.56 (C-2), 78.33 (C-1), 71.76 and 71.65 (2PhCH2),
65.92 and 65.28 (C-3,7a), 63.81 (C-8), 35.88 (C-6), and
19.09 (C-7). Mass spectrum (LSIMS): m/z: 390.1681
[M++Na] for C22H25NO4Na 390.1681 (deviation 0.0
ppm).
CꢀC conjugated), 739 and 697 cm−1 (aromatic). NMR
1
data: H NMR, 9.25 (bs, 1H, H-1), 7.65–7.15 (m, 25H,
5Ph), 6.75 and 6.20 (2bs, 2H, H-2,3), 5.05–3.90 (4m,
12H, 3PhCH2 and H-2%,3%,4%,5%,5¦a,5¦b), and 1.09 (s, 9H,
CMe3); 13C NMR (inter alia), 193.46 (C-1), 133.68
(C-3), 129.92 (C-2), 83.00 and 80.05 (C-3%,4%), 72.41 and
72.02 (2PhCH2 and Cbz), 67.41 (C-5¦), 64.13 and 61.00
(C-2%,5%), 27.03 (CMe3), and 19.40 (CMe3). Mass spec-
trum (LSIMS): m/z: 762.3225 [M++Na] for
C46H49NO6NaSi 762.3227 (deviation 0.3 ppm).
3.5. O-Desilylation of 9
Compound 9 (460 mg, 0.76 mmol) in THF (3 mL) was
treated with a solution of tetra-n-butylammonium
fluoride dihydrate (480 mg, 1.5 mmol) in the same
solvent (3 mL) for 6 h. TLC (ether/hexane, 2:1) then
showed the presence of 10. The reaction mixture was
concentrated and the residue partitioned in ether/water.
The organic phase was separated and concentrated.
Column chromatography (ether) of the residue yielded
pure 10 (235 mg, 81%).
3.8. (1R,2R,3R,5S,7aS)-1,2-Dibenzyloxy-3-tert-
butyldiphenylsilyloxymethylpyrrolizidine 15
Compound 12 (300 mg, 0.4 mmol) in methanol (50 mL)
was hydrogenated at 4 atm over 10% Pd–C (0.2 g) for
7 h. TLC (ether/methanol/triethylamine, 20:1:0.2) then
showed a slower-running compound. The catalyst was
filtered off, washed with methanol and the filtrate and
washings concentrated to a residue that was subjected
to column chromatography (ether/methanol/triethyl-
amine, 20:1:0.2) to yield pure syrupy 15 (106 mg, 45%):
3.6. (1R,2R,3R,7aS)-1,2-Dibenzyloxy-3-hydroxy-
methylpyrrolizidine 11
1
[h]2D6 −8 (c 1.2). NMR data: H NMR, 7.73–7.15 (m,
To a stirred and cooled (ice-water) solution of 10 (220
mg, 0.5 mmol) in anhydrous THF (4 mL) was added a
borane–dimethyl sulfide complex solution in the same
solvent (10 M, 250 mL) under argon. After 30 min, the
20H, 4Ph), 4.58 and 4.44 (2d, 2H, J=11.8 Hz, PhCH2),
4.48 (s, 2H, PhCH2), 3.97 (dd, 1H, J1,2=2.8, J1,7a=6.4
Hz, H-1), 3.93–3.88 (m, 2H, H-8a,8b), 3.85 (dd, 1H,
J2,3=5.5 Hz, H-2), 4.46 (m, 1H, H-7a), 3.12–3.00 (m,

2486
I. Izquierdo et al. / Tetrahedron: Asymmetry 12 (2001) 2481–2487
2H, H-3,5), 2.70 (m, 1H, H-5%), 2.01–1.74 (m, 4H,
H-6,6%,7,7%), and 1.06 (s, 9H, CMe3); 13C NMR, 138.30,
135.73, 135.71, 133.43, 129.74, 128.56, 128.37, 127.77,
127.73 and 127.55 (Ph), 86.68 (C-2), 83.11 (C-1), 72.01
and 71.84 (2PhCH2), 67.75 (C-3), 66.40 (C-7a), 63.51
(C-8), 48.62 (C-5), 27.15 (C-6), 26.93 (CMe3), 22.76
(C-7) and 19.28 (CMe3). Mass spectrum (LSIMS): m/z:
592.3248 [M++1] for C38H46NO3Si 592.3247 (deviation
−0.2 ppm).
dry dichloromethane (8 mL) was added 1-triphenylphos
phoranylidene-2-propanone (820 mg, 2.58 mmol) and
the mixture stirred under reflux for 36 h. TLC (ether/
hexane, 2:1) then revealed the presence of a slightly
more polar compound. The reaction mixture was
filtered and supported on silica gel, then chro-
matographed (ether/hexane, 2:3) to afford 17 as a thick
27
film
syrup (770 mg, 81%): [h]
−2.5 (c 1.8); wmax
3065
435
and 3038 (aromatic), 1708, 1679 and 1633 (CꢀO, conju-
gated ketone, Cbz, and CꢀC conjugated), 740 and 698
1
3.9. O-Desilylation of 15
cm−1 (aromatic). NMR data: H NMR, 7.65–7.22 (m,
25H, 5Ph), 6.70 and 6.12 (2bs, 2H, H-4,3), 5.09–3.96
(6m, 12H, 3PhCH2 and H-2%,3%,4%,5%,5¦a,5¦b), 2.05 (bs,
3H, H-1,1,1), and 1.08 (s, 9H, CMe3); 13C NMR (inter
alia), 198.26 (C-2), 155.50 (Cbz), 83.50 and 80.82 (C-
3%,4%), 72.37 and 71.91 (2PhCH2 and Cbz), 67.33 (C-5¦),
64.47 and 61.88 (C-2%,5%), 27.02 (CMe3), 26.77 (C-1),
and 19.41 (CMe3). Mass spectrum (LSIMS): m/z:
776.3389 [M++Na] for C47H51NO6NaSi 776.3383 (devi-
ation 0.7 ppm).
Compound 15 (57 mg, 0.1 mmol) was O-desilylated
with tetra-n-butylammonium fluoride dihydrate (56 mg,
0.17 mmol) as above to give, after work-up and column
chromatography, pure 11 (20 mg, 59%).
3.10. (1R,2R,3R,7aS)-1,2-Dihydroxy-3-hydroxy-
methylpyrrolizidine hydrochloride 16 and the free base
7a-epi-hyacinthacine A2 3
To a solution of 11 (70 mg, 0.2 mmol) in methanol (15
mL) were added 10% Pd–C (50 mg) and conc. HCl (one
drop). The mixture was hydrogenated at 4 atm
overnight. TLC (methanol/triethylamine, 4:0.1) then
3.12. (1R,2R,3R,5S,7aS)-1,2-Dibenzyloxy-3-tert-
butyldiphenylsilyloxymethyl-5-methylpyrrolizidine 20
showed (phosphomolybdic acid)
product. Work-up of the reaction mixture as above
gave a residue that was percolated (methanol/triethyl-
a slower-running
Compound 17 (460 mg, 0.62 mmol) in dry methanol (30
mL) was hydrogenated at 4 atm over 10% Pd–C (170
mg) for 24 h. TLC (ether/hexane, 1:2) then showed a
less polar compound. The catalyst was filtered off,
washed with methanol and the filtrate and washings
were concentrated to a residue that was submitted to
column chromatography (ether/hexane, 1:3) to yield
27
577
amine, 4:0.1) to yield 16 (38 mg, 93%) as a foam: [h]
1
+17 (c 1.5, methanol). NMR (D2O) data: H NMR,
4.37 (q, 1H, J7a,7a=J7b,7a=8 Hz, H-7a), 4.28 (dd, 1H,
J
1,2=6.5, J1,7a=8 Hz, H-1), 4.06 (dd, 1H, J2,3=9.2 Hz,
H-2), 4.01 (dd, 1H, J3,8a=4.4, J8a,8b=13.3 Hz, H-8a),
3.92 (dd, 1H, J3,8b=9.2 Hz, H-8b), 3.64 (dt, 1H, H-3),
3.56 (ddd, 1H, J5a,6b=2.4, J5a,6a=6.7, J5a,5b=11.2 Hz,
H-5a), 3.28 (dt, 1H, J5b,6b=6, J5b,6a=11.3 Hz, H-5b),
and 2.22–1.80 (2 m, 4H, H-6a,6b,7a,7b); 13C NMR,
74.19 and 73.78 (C-1,2), 67.32 and 65.39 (C-3,7a), 57.32
(C-8), 50.00 (C-5), 25.53 and 24.16 (C-6,7). Mass spec-
trum (LSIMS): m/z: 174.1126 [M++1] for C8H16NO3
174.1130 (deviation −2.6 ppm).
film
pure syrupy 20 (230 mg, 60%): [h]2D8 +15 (c 1); wmax
3069 and 3033 (aromatic), 737 and 698 cm−1 (aromatic).
1
NMR data: H NMR, 7.77–7.73, 7.48–7.29, and 7.21–
7.19 (3m, 20H, 4Ph), 4.59 and 4.56 (2d, 2H, J=13.1
Hz, PhCH2), 4.47 and 4.37 (2d, 2H, J=11.7 Hz,
PhCH2), 3.99 (d, 1H, J1,2=0, J2,3=3.1 Hz, H-2), 3.98
(dd, 1H, J3,8=5.7 Hz, H-8), 3.79 (dd, 1H, J3,8%=6.7,
J8,8%=10.3 Hz, H-8%), 3.62 (d, 1H, J1,7a=3.8 Hz, H-1),
2.91 (bdt, 1H, J7,7a=5, J7%,7a=10 Hz, H-7a), 2.60 (bq,
1H, H-3), 2.45 (bsex, 1H, J5,6=J5,6%=6.4 Hz, H-5), 2.20
(m, 1H, H-6), 1.86 (m, 1H, H-7), 1.72 (m, 1H, H-6%),
1.54 (m, 1H, H-7%), 1.15 (d, 3H, J5,Me=6 Hz, Me-5),
and 1.13 (s, 9H, CMe3); 13C, 138.71, 135.76, 135.71,
133.81, 133.72, 129.67, 128.42, 128.32, 128.00, 127.73,
127.61, and 127.51 (Ph), 93.17 (C-2), 78.38 (C-1), 72.89
(C-7a), 71.61 and 71.58 (2PhCH2), 68.63 (C-3), 66.35
(C-8), 56.05 (C-5), 36.86 (C-6), 27.02 (CMe3), 21.01
(Me-5), 20.03 (C-7), and 19.36 (CMe3). Mass spectrum
(LSIMS): m/z: 606.3405 [M++1] for C39H47NO3Si
606.3403 (deviation −0.2 ppm).
Compound 16 (35 mg, 0.17 mmol) in methanol (3 mL)
was deionized using Amberlite IRA-400 resin (OH−
form). Evaporation of the solvent gave pure 3 (22 mg,
76%) as a thick syrup: [h]2D6 +10 (c 1, methanol). NMR
1
(D2O) data: H NMR, 4.11 (t, 1H, J1,2=J1,7a=6.6 Hz,
H-1), 3.89 (dd, 1H, J2,3=9.1 Hz, H-2), 3.85 (m, 2H,
H-8a,8b), 3.81 (q, 1H, J7a,7a=J7b,7a=7 Hz, H-7a), 3.18
(ddd, 1H, J3,8a=5.5, J3,8b=8 Hz, H-3), 3.09 (ddd, 1H,
J5a,6b=2.2, J5a,6a=6.6, J5a,5b=9.4 Hz, H-5a), 2.89 (dt,
1H, J5b,6b=6, J5b,6a=10 Hz, H-5b), 2.00–1.93 and 1.78–
1.67 (2 m, 2H, H-6a,6b), and 1.89–1.84 (m, 2H, H-
7a,7b); 13C, 76.35 (C-1), 76.04 (C-2), 65.38 (C-7a), 65.01
(C-3), 59.01 (C-8), 48.67 (C-5), 25.80 (C-7), and 24.32
(C-6). Mass spectrum (LSIMS): m/z: 174.1126 [M++1]
for C8H16NO3 174.1130 (deviation 2.3 ppm).
3.13. O-Desilylation of 20
Compound 20 (290 mg, 0.47 mmol) was O-desilylated
with tetra-n-butylammonium fluoride dihydrate (240
mg, 0.75 mmol) for 6 h as above to give, after work-up
and column chromatography (ether/hexane, 1:1) pure
(1R,2R,3R,5S,7aS)-1,2-dibenzyloxy-3-hydroxymethyl-
5-methylpyrrolizidine 21 as a colourless syrup (145 mg,
3.11. 4-[(2%S,3%R,4%R,5%R)-3%,4%-Dibenzyloxy-N-benzyl-
oxycarbonyl-5%-tert-butyldiphenylsilyloxymethylpyrrol-
idin-2%-yl]but-3-en-2-one 17
To a solution of 6 (from 5, 1 g, 1.39 mmol as above) in

I. Izquierdo et al. / Tetrahedron: Asymmetry 12 (2001) 2481–2487
2487
85%): [h]2D9 +59 (c 1.7). NMR data: 1H NMR, 7.36–7.28
Acknowledgements
(m, 10H, 2Ph), 4.58 and 4.52 (2d, 2H, J=12.3 Hz,
PhCH2), 4.46 and 4.43 (2d, 2H, J=11.8 Hz, PhCH2),
4.22 (d, 1H, J2,3=5.5 Hz, H-2), 3.82 (dd, 1H, J3,8=3.2
Hz, J8,8%=11 Hz, H-8), 3.66 (bt, 1H, H-8%), 3.60 (bd,
1H, J1,7a=3.9 Hz, H-1), 3.04 (bs, 1H, H-7a), 2.91 (bs,
1H, H-3), 2.58 (bs, 2H, H-5, HO-8), 2.22 (m, 1H, H-6),
1.87 (m, 1H, H-7), 1.71 (m, 1H, H-6%), 1.55 (m, 1H,
H-7%), and 1.20 (d, 3H, J5,Me=6.1 Hz, Me-5); 13C
NMR, 138.30, 137.94, 128.53, 128.47, 128.04, 127.88,
127.84, 127.77, and 127.68 (Ph), 91.82 (C-2), 77.78
(C-1), 72.85 (C-7a), 71.96 and 71.44 (2PhCH2), 67.31
(C-3), 61.15 (C-8), 55.65 (C-5), 36.85 (C-6), 20.35 (Me-
5), and 19.78 (C-7). Mass spectrum (LSIMS): m/z:
368.2221 [M++1] for C23H30NO3 368.2226 (deviation
1.1 ppm). Anal. calcd for C23H29NO3: C, 75.17; H, 7.95;
N, 3.81. Found: C, 74.89; H, 8.16; N, 4.28%.
The authors are deeply grateful to Ministerio de Educa-
cio´n y Cultura (Spain) for financial support (Project
PB98-1357) and for a grant (F.F.).
References
1. Some 7-deoxyalexines are also named as hyacinthacines
(see Ref. 4).
2. (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. Tetra-
hedron: Asymmetry 2000, 11, 1–8.
3.14. (1R,2R,3R,5S,7aS)-1,2-Dihydroxy-3-hydroxy-
methyl-5-methylpyrrolizidine (5,7a-diepi-hyacinthacine
A3, 4)
3. (a) Ostrander, G. K.; Scribner, N. K.; Rohrschneider, L.
R. Cancer Res. 1988, 48, 1091–1094; (b) Ratner, L. AIDS
Res. Hum. Retroviruses 1992, 8, 165–173; (c) For a recent
review: Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet,
G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645–1680.
4. (a) Casiraghi, G.; Zanardi, F.; Rassu, G.; Pinna, L. Org.
Prep. Proc. Int. 1996, 28, 643–682; (b) Denmark, S. E.;
Hurd, A. R. J. Org. Chem. 2000, 65, 2875–2886; (c)
Denmark, S. E.; Herbert, B. J. Org. Chem. 2000, 65,
2887–2896; (d) Yoda, H.; Katoh, H.; Takabe, K. Tetra-
hedron Lett. 2000, 41, 7661–7665 and references cited
therein.
To a solution of 21 (113 mg, 0.31 mmol) in methanol
(25 mL) were added 10% Pd–C (80 mg) and conc. HCl
(two drops). The mixture was hydrogenated at 4 atm
overnight. TLC (ether/methanol/triethylamine, 5:1:0.2)
then showed (phosphomolybdic acid) the presence of a
new compound. The catalyst was filtered off, thor-
oughly washed with methanol and the combined filtrate
and washings were deionized with Amberlite IRA-400
resin (OH− form, 2 mL of wet resine). Evaporation of
the solvent and column chromatography (ether/
methanol/triethylamine, 5:1:0.2) gave pure 4 (50 mg,
83%) that crystallized on standing, mp 83–85°C: [h]D28
+38 (c 0.9, methanol). NMR (MeOH-d4) data: 1H
NMR, 4.09 (d, 1H, J2.3=4.7 Hz, H-2), 3.76 (dd, 1H,
5. Yoda, H.; Asai, F.; Takabe, K. Synlett 2000, 1001–1003.
6. Izquierdo, I.; Plaza, M.-T.; Robles, R.; Franco, F. Car-
bohydr. Res. 2001, 330, 401–408.
J
3,8=4.1, J8,8%=11.2 Hz, H-8), 3.71 (dd, 1H, J3,8%=3.6
7. Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23,
13–19.
8. Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61,
5546–5556.
9. Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.;
Derome, A. E.; Hamor, T. A.; Scofield, A. M.; Watkin,
D. J. Tetrahedron Lett. 1988, 29, 2487–2490.
10. Wormald, M. R.; Nash, R. J.; Hrnciar, P.; White, J. D.;
Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
1998, 9, 2549–2558.
Hz, H-8%), 3.58 (d, 1H, J1,7a=3.8 Hz, H-1), 2.87 (ddd,
1H, J7,7a=6.4, J7%,7a=10.2 Hz, H-7a), 2.45 (bsex, 1H,
H-5), 2.29–2.19 (m, 1H, H-6), 2.21 (q, 1H, H-3), 1.71–
1.61 (m, 2H, H-6%,7), 1.51–1.43 (m, 1H, H-7%), and 1.19
(d, 3H, J5,Me=6.1 Hz, Me-5); 13C NMR, 88.16 (C-2),
75.38 (C-1), 74.60 (C-7a), 71.39 (C-3), 62.74 (C-8),
57.24 (C-5), 38.02 (C-6), 20.97 (Me-5), and 20.14 (C-7).
Anal. calcd for C9H17NO3: C, 57.73; H, 9.15; N, 7.48.
Found: C, 58.06; H, 8.88; N, 7.78%.