First asymmetric synthesis of pyrrolizidine alkaloids, (+)-hyacinthacine B1 and (+)-B2

Article abstract of DOI:10.1016/j.tet.2008.06.078

An enantiomerically and diastereomerically pure route has been developed for the first asymmetric synthesis of (1S,2R,3R,5R,7aR)- and (1S,2R,3R,5S,7aR)-1,2-dihydroxy-3,5-dihydroxymethylpyrrolizidine, hyacinthacine B₁ and B₂, featurin

Full text of DOI:10.1016/j.tet.2008.06.078

Tetrahedron 64 (2008) 8052–8058
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
First asymmetric synthesis of pyrrolizidine alkaloids,
(þ)-hyacinthacine B1 and (þ)-B2
Tetsuya Sengoku, Yasutaka Satoh, Manami Oshima, Masaki Takahashi, Hidemi Yoda
*
Department of Materials Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Naka-ku, Hamamatsu 432-8561, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantiomerically and diastereomerically pure route has been developed for the first asymmetric
synthesis of (1S,2R,3R,5R,7aR)- and (1S,2R,3R,5S,7aR)-1,2-dihydroxy-3,5-dihydroxymethylpyrrolizidine,
hyacinthacine B1 and B2, featuring efficient and stereodefined elaboration via the asymmetric dihy-
droxylation (AD) of the functionalized homochiral pyrrolidine derivative prepared from (S)-(ꢀ)-2-pyr-
rolidone-5-carboxylic acid.
Received 5 June 2008
Accepted 20 June 2008
Available online 25 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
stereochemistry of the hydroxyl groups into the pyrrolizidine
skeleton.9 Hyacinthacine B1 (5a) and B2 (5b), for example, were
Structurally complex alkaloidal sugar mimics with a nitrogen in
the ring have been isolated from plants and microorganisms and
inhibit various glycosidases in a reversible and competitive man-
ner.1 Since such glycosidase inhibitors have been also proved to
have the potential to produce antiviral, insect antifeedant, antidi-
abetic, and anticancer effects as well as immune modulatory
properties,1 they have held considerable interest in the context of
the synthesis of nitrogen-containing natural products. Noteworthy
members among this class of compounds are polyhydroxylated
pyrrolizidines such as the alexines,2 represented by the parent al-
kaloid (1), and australine (2),3 exhibiting viral and retroviral4 in-
cluding anti-HIV5 activities as well as powerful glycosidase
inhibitory property (Fig. 1). There is a significant structural re-
semblance to (2R,3R,4R,5R)-2,5-dihydroxymethyl-3,4-dihydroxy-
pyrrolidine, DMDP (3), known as a strong glycosidase inhibitor
occurring in some Derris spp. and Lonchocarpus (Leguminosae).6
Recently, a new series of hyacinthacines were isolated from blue-
bells (Hyacinthoides non-scripta)7 and grape hyacinths (Muscari
armeniacum)8 by Asano et al. The presence of a hydroxymethyl
function to the ring nitrogen [C(3)] distinguishes these groups from
the larger class of necine bases such as dihydroxyheliotridane (4),
which bear carbon substituents at C(1). These compounds possess
five stereogenic centers, two of which are connected with adjacent
two hydroxyl groups. In particular, the preparation both of un-
natural epimers and other structural analogs of these compounds
has created much interest since the biological activity of these
molecules varies substantially with the number, position, and
found to be selective inhibitors of
dase and the latter was, in addition, proved to inhibit rat intestinal
lactase in a competitive manner with an IC50 value of 3.6
M.8
b-glucosidase and b-galactosi-
m
While many total syntheses of hyacinthacine A series (the
structure without the hydroxyl group(s) in the left-side ring of the
pyrrolizidine framework shown in Fig. 1) have been recently
completed by several groups,10 the synthesis of hyacinthacine B
series, however, has not been achieved to date. The central feature
of this report is to describe the details of the first and expeditious
route for the stereoselective construction of hyacinthacine B1 (5a)
and B2 (5b) [stereoisomer of 5a at C(5)] via the catalytic Sharpless
asymmetric dihydroxylation starting from (S)-(ꢀ)-2-pyrrolidone-
5-carboxylic acid, thus establishing the absolute configuration of
the natural products.
In formulating the synthetic plan for 5, we recognized that the
absolute configurations at C(1), C(2), and C(3) are the same as the
configurations at the corresponding centers C(3), C(4), and C(5) of
OH
HO
OH
HO
OH
1
H
N
H
N
HO
OH
OH
OH
OH
2
HN
3
OH
OH
DMDP (3)
alexine (1)
australine (2)
OH
OH
H
H
OH
HO
H
OH
OH
N
N
N
dihydroxy-
HO
OH
HO
OH
heliotridane(4)
hyacinthacine B1 (5a)
hyacinthacine B2 (5b)
* Corresponding author. Tel./fax: þ81 53 478 1150.
E-mail address: tchyoda@ipc.shizuoka.ac.jp (H. Yoda).
Figure 1. Structures of selected polyhydroxylated alkaloids.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.078

T. Sengoku et al. / Tetrahedron 64 (2008) 8052–8058
8053
OH
1
enhancement in the selectivity together with the yield of these
reactions was fortunately observed after detailed examination
employing excess amounts of reducing agent in a dilute EtOH
solution (0.005 M) to yield 7 with predominant stereoselectivity
(95:5)15 in an almost quantitative yield. After successive reactions
of the diastereomer mixture 7 through mesylation and cyclization
with t-BuOK, it was advantageously ascertained that the major
product was the desired pyrrolidine derivative 8a and able to be
separated from the minor isomer 8b (Scheme 2)16 by column
chromatography on silica gel, which proceeded in 96% two-step
yield. Although an attempt toward the synthesis of the target
compounds employing this N-Boc 8a was initially carried out, the
results from our survey have revealed formation of an intractable
mixture on the construction of a pyrrolizidine ring accompanying
the elimination of the Boc group. Thus, upon replacing the Boc
function, the Cbz-pyrrolidine 9 was selected for further convenient
transformation of the functional groups and elaborated through the
promising four-step sequence (desilylation, NaH-assisted Boc-
elimination17 and N-Cbz protection, followed by TBS-silylation)
from 8a.
H
O
O
7a
N
OH
OH
2
OR2
*
5
3
*
HO
N
R1
HO
OH
(III)
hyacinthacine B (5)
O
O
O
3
O
4
OR2
(II)
OR2
(I)
5
O
N
R1
N
R1
R1 = electron
withdrawing function
OH
O
N
H
(S)-(-)-2-pyrrolidone-
5-carboxylic acid
O
Figure 2. General retrosynthesis.
a protected lactam (I) derived from (S)-(ꢀ)-2-pyrrolidone-5-carb-
oxylic acid (Fig. 2). Further we envisioned that the stereogenic
center of C(7a) would originate from nucleophilic addition to (I)
and successive reduction to the corresponding alcohol followed by
cyclization, allowing the synthesis of the homochiral pyrrolidine
intermediate (II). Meanwhile, the remaining stereogenic center
C(5) of 5 would have to be independently set in an asymmetric
dihydroxylation (AD) reaction of the pyrrolidine (II) to afford the
corresponding diol derivative (III).
With the compound 9 in hand, we next focused our research
on the total synthesis of hyacinthacines 5a and 5b as shown in
Scheme 3. Thus, 9 was initially submitted to the catalytic Sharpless
asymmetric dihydroxylation (AD) with AD-mix-
a [(DHQ)2PHAL
ligand]18 in expectation of high enantiomeric enhancement,19
which could effect these reactions beneficially, bringing about the
desired diol product 10a with moderate stereoselectivity (10a/
10b¼71:29, determined by 1H NMR), but as an inseparable mix-
ture in 98% isolated yield. Fortunately, it has become apparent that
the major diastereomer 11a obtained after the three-step con-
version of 10, i.e., selective protection of the primary alcohol with
TBSCl and mesylation followed by cyclization, was easily separated
from 11b by column chromatography on silica gel.20 Finally, this
compound was effected by deprotection with tetrabutylammo-
nium fluoride (TBAF), which on successive treatment with tri-
fluoroacetic acid (TFA) gave rise to the desired product 5a in 92%
isolated yield.
2. Results and discussion
Our initial investigations were aimed at scrutinizing the feasi-
bility of well known acetonide-protected N-Boc lactams (I) shown
in Figure 2 for nucleophilic addition followed by stereoselective
reduction of the corresponding hydroxyl pyrrolidine intermediates.
Intrigued by previous reports regarding these reactions of the N-
Boc lactam 6 and its derivatives prepared from (S)-(ꢀ)-2-pyrroli-
done-5-carboxylic acid (Scheme 1),11 where non-stereoselective
results were obtained to achieve good yields of the open-chain
products,12 we investigated the reactivity of 6 in this nucleophilic
addition and diastereoselective reduction sequence. Whereas the
reduction of the labile hydroxyl pyrrolidine intermediate obtained
from butenyl Grignard addition to 613 with NaBH4 only in
MeOH (0.1 M solution) gave the corresponding alcohol 7 as a
non-stereoselective mixture (53:47) in 45% yield,14 remarkable
The spectral data of synthetic 5a, together with the optical ro-
26
tation of which matches that of the reported value {[
a]
þ41.9
D
(c 0.4, H2O) [lit. [
a]
þ41.3 (c 1.04, H2O)]7}, were completely iden-
D
tical to those of the natural product,7 demonstrating that the
structure attributed by Asano et al. to natural hyacinthacine B1 (5a)
was correct and the first total synthesis of 5a was accomplished.
Thus, one of the target compounds, 5a, was obtained in 24 steps
and 21% overall yield from commercially available (S)-(ꢀ)-2-
pyrrolidone-5-carboxylic acid.
O
O
O
O
O
O
ref. 11
a
O
OH
HO
O
N
H
ODPS
ODPS
ODPS
NHBoc
O
N
N
O
6
Boc
Boc
(S)-(-)-2-pyrrolidone-
5-carboxylic acid
O
O
O
O
d
ODPS
OTBS
N
Boc
N
Cbz
8a
9
+
O
HO
b
c
O
O
O
ODPS
NHBoc
ODPS
7
N
Boc
8b
Scheme 1. Reagents and conditions: (a) CH2]CH(CH2)2MgBr, THF, rt, 5 min; (b) NaBH4, CeCl3, EtOH, 0 ꢁC, 4 h, quant. (two steps); (c) (i) MsCl, Et3N, CH2Cl2; (ii) t-BuOK, THF; 91%
(8a) (two steps); 5% (8b) (two steps); (d) (i) Bu4NF, THF, quant.; (ii) NaH, THF, rt, 2 h, quant.; (iii) CbzCl, NaHCO3, MeOH; 97%; (iv) TBSCl, imidazole, DMF; 97%.

8054
T. Sengoku et al. / Tetrahedron 64 (2008) 8052–8058
O
O
O
O
O
O
O
O
SPDO
ODPS
(iiia)
N
Boc
b
ODPS
ODPS
8a
N
N
O
O
Boc
Boc
(ia)
(iia)
a
ODPS
O
N
O
O
Boc
6
b
c
ODPS
ODPS
8b
O
O
N
N
Boc
Boc
(ib)
(iib)
SPDO
ODPS
(iiib)
N
Boc
Scheme 2. Reagents and conditions: (a) (i) CH2]CHMgCl, THF, ꢀ78 ꢁC, 20 min; (ii) NaBH4, CeCl3, MeOH; 75%; (iii) MsCl, Et3N, CH2Cl2; 71%; (iv) Bu4NF, THF (separation of the two
diastereomers); (v) DPSCl, imidazole, DMF; 49% (ia) (two steps); 41% (ib) (two steps); (b) H2, Pd/C, EtOH; quant. (iia) and (iib), respectively; (c) (i) OsO4, NMO, acetone/H2O (1:1); (ii)
NaIO4, THF/H2O (1:2); (iii) NaBH4, MeOH; (iv) DPSCl, imidazole, DMF; 88% (iiia) (four steps); 86% (iiib) (four steps).
Having obtained and characterized the synthetic hyacinthacine
3. Conclusions
B1 (5a), we attempted the asymmetric dihydroxylation (AD) of 9
again with AD-mix-
b
[(DHQD)2PHAL ligand], to provide the com-
In summary, this work constitutes the first asymmetric syn-
thesis of the natural pyrrolizidine alkaloids, hyacinthacines B1 and
B2 [stereoisomer of B1 at C(5)] in 24 steps via the asymmetric
dihydroxylation (AD) of the functionalized homochiral pyrrolidine
intermediate prepared from (S)-(ꢀ)-2-pyrrolidone-5-carboxylic
acid in an overall yield of 21% and 24%, respectively, and verifies the
structure proposed in the literature for these natural products. In
addition, the concise synthetic strategy described herein represents
an easily accessible pathway to widespread pyrrolidine, pyrrolizi-
dine, and indolizidine types of natural products. Further synthetic
studies based on this strategy are currently underway and will be
reported in due course
pound 11b (11a/11b¼19:81, isolated ratio), as expected, in a reverse
stereoselective manner after the three-step treatment as men-
tioned above. This was then subjected to deprotection reactions in
the same way, resulting in the first asymmetric preparation of
27
hyacinthacine B2 (5b) {[
a]
þ42.3 (c 0.25, H2O) [lit. [
a
]
D
þ41.3
D
(c 0.36, H2O)]7} in quite high overall yield (24%) from (S)-(ꢀ)-2-
pyrrolidone-5-carboxylic acid. The spectral data as well as the op-
tical rotation of synthetic 5b were also identical21 to those of the
natural product.7
O
O
4. Experimental section
4.1. General
OTBS
N
Cbz
a
d
9
All solvents and reagents were of reagent grade quality from
Aldrich Chemical Company, Fluka, Acros or Wako Pure Chemicals
and used without any further purification. Melting points were
measured on an automated melting point system (MPA 100, Stan-
ford Research Systems). Fourier transform infrared (FTIR) spectra
were recorded on a Shimadzu FTIR-8200A spectrometer. The 1H
and 13C nuclear magnetic resonance (NMR) spectra operating at the
frequencies of 300 and 75 MHz, respectively, were measured with
a JEOL JNM-AL300 spectrometer in chloroform-d (CDCl3) unless
otherwise stated. Chemical shifts are reported in parts per million
O
O
O
O
OTBS
10a
OTBS
HO
HO
N
Cbz
N
Cbz
OH
OH
10b
b
e
O
O
H
N
H
(ppm) relative to TMS as internal standard (
d
¼0 ppm) for 1H NMR,
¼77.0) for 13C NMR. The
O
O
and CDCl3 was used as internal standard (
d
N
coupling constants are reported in hertz (Hz). Optical rotations
were measured in 1 dm path length cell of 2 mL capacity using
a JASCO Model DIP-1000 polarimeter at a wavelength of 589 nm.
Reactions were monitored by thin-layer chromatography (TLC)
using 0.25 mm Merck silica gel 60-F254 precoated silica gel plates by
irradiation with UV light and/or by treatment with a solution of
phosphomolybdic acid in methanol followed by heating. Column
chromatography was performed on Kanto Chemical silica gel 60N
eluting with the indicated solvent system. The non-crystalline
compounds were shown to be homogeneous by chromatographic
methods and characterized by NMR, IR, high resolution mass
spectra (HRMS), and microanalysis. High-performance liquid
chromatography (HPLC) was carried out using a Shimadzu Model
LC-10AD or 10AT intelligent pump and SPD-10A UV detector. HRMS
were recorded on a JEOL JMS-T100CS spectrometer. Microanalyses
were performed with a JSL Model JM 10.
TBSO
OTBS
11a
TBSO
OTBS
11b
c
f
OH
OH
H
N
H
N
OH
OH
OH
OH
HO
HO
hyacinthacine B1 (5a)
hyacinthacine B2 (5b)
Scheme 3. Reagents and conditions: (a) AD-mix-
(1:1), 0 ꢁC, 48 h; 98%; (b) (i) TBSCl, Et3N, CH2Cl2; 97%; (ii) MsCl, Et3N, CH2Cl2; 92%; (iii)
H2, Pd/C, EtOH; (11a); 69% (11b); 28%; (c) (i) Bu4NF, THF; 97%; (ii) TFA, H2O; 92%; (d)
AD-mix-b
[(DHQD)2PHAL ligand], t-BuOH/H2O (1:1), 0 ꢁC, 24 h; 98%; (e) (i) TBSCl, Et3N,
CH2Cl2; 97%; (ii) MsCl, Et3N, CH2Cl2; 92%; (iii) H2, Pd/C, EtOH; (11a); 19% (11b); 80%; (f)
(i) Bu4NF, THF; 97%; (ii) TFA, H2O; 94%.
a
[(DHQ)2PHAL ligand], t-BuOH/H2O

T. Sengoku et al. / Tetrahedron 64 (2008) 8052–8058
8055
4.2. Experimental procedures
2.09 (m, 1H, CH2), 1.88–1.66 (br, 2H, CH2), 1.50 (s, 9H, 3CH3), 1.35 (s,
3H, CH3), 1.32 (s, 3H, CH3), 1.05 (s, 9H, 3CH3); 13C NMR (CDCl3)
4.2.1. tert-Butyl (R)-2-(tert-butyldiphenylsilyloxy)-1-((4R,5R)-
5-(1-hydroxypent-4-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-
ethylcarbamate (7)
d 154.5, 138.8, 135.5, 132.8, 129.9, 129.8, 129.0, 128.2, 127.8, 125.2,
114.3, 110.9, 81.6, 80.3, 79.9, 79.4, 64.5, 62.9, 62.4, 61.8, 30.6, 28.4,
27.5, 26.8, 26.0, 24.9, 21.4, 19.1. Anal. Calcd for C33H47NO5Si: C,
To a solution of 6 (0.049 g, 0.0933 mmol) in THF (1.0 mL) was
added butenylmagnesium bromide (0.2 M solution in THF, 2.8 mL,
0.559 mmol) dropwise under nitrogen at 0 ꢁC and stirred 5 min. It
was quenched by the addition of water (5 mL) and extracted with
ethyl acetate (10ꢂ3 mL). The combined organic extracts were
washed with brine (5 mL), dried over anhydrous Na2SO4, and
concentrated to give the crude hydroxyl pyrrolidine as a pale yellow
oil, which was used without further purification. To a solution of
the above compound and powdered CeCl3 (0.037 g, 0.150 mmol)
(heated to 135–140 ꢁC for 1 h with evacuation (ca. 1.0 Torr) before
use) in EtOH (15.6 mL) was added NaBH4 (0.876 g, 23.33 mmol) at
0 ꢁC and stirred for 1 h. It was quenched by the addition of water
(2 mL) and extracted with ethyl acetate (10ꢂ3 mL). The combined
organic extracts were washed with brine (5 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography (silica gel, hexane/EtOAc¼5:1)
to give the diastereomer mixture (95:5, determined by 1H NMR) of
7 (0.031 g, 57%, Rf¼0.55, hexane/EtOAc¼3:1) as a colorless oil. IR
(NaCl) 3441 (O–H), 2858 (C–H), 1703 (C]O), 1641 (C]C), 1250 (C–
70.05; H, 8.37; N, 2.48. Found: C, 69.83; H, 8.41; N, 2.42. Compound
17
8b: [
a
]
D
ꢀ21.1 (c 1.0, CHCl3); IR (NaCl) 2858 (C-H), 1697 (C]O),
1641 (C]C), 1244 (C–O) cmꢀ1; 1H NMR (CDCl3)
d 7.66–7.62 (m, 4H,
ArH), 7.40–7.36 (m, 6H, ArH), 5.73 (dt, J¼17.0, 7.0 Hz, 1H, CH2]CH),
4.97 (dd, J¼17.0, 1.5 Hz, 1H, CH2]CH), 4.91 (d, J¼10.3 Hz, 1H,
CH2]CH), 4.75 (br, 1H, CH), 4.40 (m, 1H, CH), 4.10 (m, 1H, CH), 3.88
(m, 1H, CH2), 3.73 (dd, J¼10.3, 3.2 Hz, 1H, CH2), 3.59 (m, 1H, CH),
2.16–2.02 (m, 2H, CH2), 1.87–1.67 (m, 2H, CH2), 1.46 (s, 9H, 3CH3),
1.37 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.07 (s, 9H, 3CH3); 13C NMR
(CDCl3)
d 154.3, 137.5, 135.6, 135.5, 133.1, 132.9, 129.8, 129.7, 129.5,
127.8, 127.7, 127.6, 114.9, 111.5, 84.5, 83.9, 82.1, 81.3, 79.7, 65.6, 64.5,
63.9, 63.6, 33.3, 32.8, 30.3, 28.4, 27.3, 27.0, 26.5, 25.5, 19.2. Anal.
Calcd for C33H47NO5Si: C, 70.05; H, 8.37; N, 2.48. Found: C, 69.96; H,
8.35; N, 2.33.
4.2.3. (3aS,4R,6R,6aR)-Benzyl 4-(but-3-enyl)-6-((tert-butyl-
dimethylsilyloxy)methyl)-2,2-dimethyldihydro-3aH-
[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate (9)
O) cmꢀ1; 1H NMR (CDCl3)
d
(major isomer) 7.71–7.64 (m, 4H, ArH),
4.2.3.1. Deprotection of DPS group. A solution of 8a (0.172 g,
0.304 mmol) and tetrabutylammonium fluoride (1.0 M solution in
THF, 0.45 mL, 0.45 mmol) in THF (3 mL) was stirred for 2 h. The
mixture was quenched by the addition of saturated aq NaHCO3
(5 mL) and extracted with ethyl acetate (10ꢂ3 mL). The combined
organic extracts were washed with brine (5 mL), dried over
anhydrous Na2SO4, and concentrated to give the crude alcohol,
which was purified by column chromatography (silica gel, hexane/
7.43–7.26 (m, 6H, ArH), 5.86 (ddt, J¼17.0, 10.1, 6.8 Hz, 1H, CH2]CH),
5.08–5.01 (m, 2H, CH2]CH), 4.95 (dd, J¼10.1, 1.1 Hz, 1H, CH), 4.25
(dd, J¼10.1, 4.9 Hz,1H, CH), 4.01–3.85 (m, 2H, CH2), 3.77 (m,1H, CH),
3.73 (dd, J¼10.1, 2.4 Hz, 1H, CH), 3.00 (br, 1H, OH), 2.30 (m, 1H, CH2),
2.15 (dt, J¼14.8, 7.0 Hz,1H, CH2), 1.85 (m, 1H, CH2), 1.60 (m, 1H, CH2),
1.46 (s, 9H, 3CH3), 1.34 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.06 (s, 9H,
3CH3); 13C NMR (CDCl3)
d (major isomer) 156.0, 138.8, 135.6, 135.5,
133.2, 133.1, 129.8, 129.7, 127.7, 127.6, 114.6, 108.0, 80.8, 80.5, 75.9,
EtOAc¼1:1) to give the alcohol (0.100 g, quant., Rf¼0.46, hexane/
25
68.2, 63.9, 51.1, 33.0, 29.4, 28.3, 27.8, 26.8, 25.6, 19.3; 13C NMR
EtOAc¼1:1) as a colorless oil. [
a]
ꢀ42.2 (c 1.0, CHCl3); IR (NaCl)
D
(CDCl3)
d
(minor isomer) 155.5, 138.4, 135.6, 135.4, 133.2, 129.7,
3441 (O–H), 2858 (C-H), 1687 (C]O), 1643 (C]C), 1248
129.6, 127.7, 127.6, 114.7, 108.0, 79.8, 79.4, 74.9, 68.3, 64.0, 51.0, 34.3,
(C–O) cmꢀ1 1H NMR (CDCl3)
;
d
5.84 (ddt, J¼17.0, 10.3, 6.6 Hz, 1H,
30.1, 28.3, 27.8, 26.8, 24.8, 19.4; HRMS (ESIþ) m/z calcd for
CH2]CH), 5.04 (dd, J¼17.0, 1.4 Hz, 1H, CH2]CH), 4.96 (d,
J¼10.1 Hz, 1H, CH2]CH), 4.67 (t, J¼6.2 Hz, 1H, CH), 4.38 (br, 1H,
CH), 3.90–3.79 (m, 2H, CH2), 3.74–3.67 (m, 2H, CH2), 2.20 (dt,
J¼14.6, 7.4 Hz, 1H, CH2), 2.05 (dt, J¼14.6, 7.4 Hz, 1H, CH2) 1.93–1.72
(m, 2H, OH and CH2), 1.56–1.48 (m, 4H, CH3 and CH2), 1.46 (s, 9H,
C
33H49NO6SiþNa: 606.3227, found 606.3210.
4.2.2. (3aS,4R,6R,6aR)-tert-Butyl 4-(but-3-enyl)-6-((tert-butyl-
diphenylsilyloxy)methyl)-2,2-dimethyldihydro-3aH-
[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate (8a)
3CH3), 1.34 (s, 3H, CH3); 13C NMR (CDCl3)
d 154.8, 138.5, 114.5,
To a solution of 7 (0.060 g, 0.103 mmol) and Et3N (0.084 g,
0.824 mmol) in CH2Cl2 (1.0 mL) was added methanesulfonyl chlo-
ride (0.035 g, 0.309 mmol) at 0 ꢁC and stirred for 30 min. The
mixture was quenched by the addition of 3% aq HCl (3 mL) and
extracted with ethyl acetate (10ꢂ3 mL). The combined organic
extracts were washed with brine (5 mL), dried over anhydrous
Na2SO4, and concentrated to give the crude mesylate, which was
used without further purification. To a solution of this mesylate in
THF (2.0 mL) was added t-BuOK (0.023 g, 0.206 mmol) at 0 ꢁC and
stirred for 2 h. The mixture was quenched by the addition of water
(1 mL) and stirred for additional 2 h. It was diluted with water
(5 mL) and extracted with CH2Cl2 (10ꢂ3 mL). The combined or-
ganic extracts were washed with brine (5 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude products of
two diastereomers were separated by column chromatography
(silica gel, hexane/EtOAc/toluene¼10:1:2) to give 8a (0.053 g, 91.0%,
Rf¼0.36, hexane/EtOAc/toluene¼10:1:2) and 8b (0.003 g, 5.1%,
112.3, 81.1, 80.5, 78.4, 64.8, 62.8, 60.6, 30.5, 28.4, 26.5, 25.2. Anal.
Calcd for C17H29NO5: C, 62.36; H, 8.93; N, 4.28. Found: C, 62.56; H,
8.89; N, 4.61.
4.2.3.2. Deprotection of Boc group. To a solution of the above
alcohol (0.018 g, 0.0550 mmol) in THF (0.6 mL) was added a sus-
pension of NaH (65 wt %, 0.004 g) in THF (0.5 mL) and stirred for
2 h. It was quenched by the slow addition of water (2 mL) and
extracted with CH2Cl2 (5ꢂ3 mL). The combined organic extracts
were dried over anhydrous K2CO3 and concentrated in vacuo. The
crude product was purified by column chromatography (silica gel,
chloroform/MeOH¼20:1) to give the amino alcohol (0.013 g, quant.,
Rf¼0.27, CHCl3/MeOH¼10:1) as a white solid; mp 104.2–104.8 ꢁC.
24
[a
]
ꢀ3.7 (c 1.0, CHCl3); IR (KBr) 3441 (O–H), 2862 (C–H), 1641
D
(C]C) cmꢀ1
;
1H NMR (CDCl3)
d
5.83 (ddt, J¼17.1, 10.3, 6.6 Hz, 1H,
CH2]CH), 5.05 (ddd, J¼17.1, 3.5, 1.7 Hz, 1H, CH2]CH), 4.98 (m, 1H,
CH2]CH), 4.52 (dd, J¼5.3, 3.8 Hz,1H, CH), 4.37 (d, J¼5.3 Hz,1H, CH),
3.48 (dd, J¼8.7, 3.8 Hz, 2H, CH), 3.31–3.19 (m, 2H, CH2), 2.92 (dt,
J¼7.0, 3.8 Hz, 1H, CH), 2.76–2.45 (br, 2H, OH and NH), 2.24–2.17
(ddd, J¼14.0, 7.0, 1.1 Hz, 2H, CH2) 1.80–1.60 (m, 2H, CH2), 1.46 (s, 3H,
Rf¼0.30, hexane/EtOAc/toluene¼10:1:2) as
a
viscous oil, re-
17
spectively. Compound 8a: [
(C–H), 1699 (C]O), 1641 (C]C), 1248 (C–O) cmꢀ1; 1H NMR (CDCl3)
7.64–7.58 (m, 4H, ArH), 7.43–7.38 (m, 6H, ArH), 5.87 (m, 1H,
a]
ꢀ64.2 (c 1.0, CHCl3); IR (NaCl) 2858
D
d
CH3), 1.34 (s, 3H, CH3); 13C NMR (CDCl3)
d 138.2, 114.9, 110.9, 83.6,
CH2]CH), 5.05 (dd, J¼17.0, 1.1 Hz, 1H, CH2]CH), 4.93 (br d,
J¼9.2 Hz, 1H, CH2]CH), 4.79 (t, J¼6.4 Hz, 1H, CH), 4.69 (m, 1H, CH),
4.27–3.83 (m, 3H, CH2 and CH), 3.65 (m, 1H, CH), 2.20 (m, 1H, CH2),
82.2, 65.4, 59.8, 59.6, 31.2, 27.8, 26.1, 24.0. Anal. Calcd
for C12H21NO3: C, 63.41; H, 9.31; N, 6.16. Found: C, 63.22; H, 9.69;
N, 6.16.

8056
T. Sengoku et al. / Tetrahedron 64 (2008) 8052–8058
4.2.3.3. Protection with CbzCl. Carbobenzoxy chloride (CbzCl)
(0.012 g, 0.0686 mmol) was added to a suspension of the above
amino alcohol (0.013 g, 0.0572 mmol) and NaHCO3 (0.010 g,
0.119 mmol) in MeOH (0.6 mL) at 0 ꢁC. After the mixture was stirred
for 3 h, it was quenched by the addition of water (5 mL) and
extracted with ethyl acetate (5ꢂ3 mL). The combined organic ex-
tracts were washed with brine (3 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The combined organic extracts
were washed with brine (5 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was chromatographed (silica
79.6, 71.4, 66.6, 66.3, 64.4, 63.7, 63.6, 62.7, 61.8, 29.4, 25.8, 24.7, 23.5,
d (minor isomer) 155.2, 136.3,
128.5, 128.3, 128.1, 111.2, 81.8, 80.0, 72.0, 66.8, 66.3, 64.5, 63.7, 63.6,
18.0, ꢀ5.7, ꢀ5.8; 13C NMR (CDCl3)
62.7, 61.7, 29.8, 25.8, 24.7, 23.5, 18.0, ꢀ5.7, ꢀ5.8. Anal. Calcd for
C26H43NO7Si: C, 61.27; H, 8.50; N, 2.75. Found: C, 61.22; H, 8.37; N,
2.94.
4.2.5. (3aR,4R,6S,8aR,8bS)-4,6-Bis((tert-butyldimethylsilyloxy)-
methyl)-2,2-dimethylhexahydro-3aH-[1,3]dioxolo-
[4,5-a]pyrrolizine (11a)
gel, hexane/EtOAc¼1:1) to give the Cbz-alcohol (0.020 g, 97%,
24
Rf¼0.46, hexane/EtOAc¼1:1) as a colorless oil. [
a
]
ꢀ43.1 (c 1.0,
4.2.5.1. Regioselective protection. A mixture of the above diol 10
(0.016 g, 0.0314 mmol), Et3N (0.016 g, 0.157 mmol), and TBSCl
(0.019 g, 0.126 mmol) in CH2Cl2 (1.6 mL) was stirred for 48 h. It was
quenched by the addition of water (5 mL) and extracted with ethyl
acetate (10ꢂ3 mL). The combined organic extracts were washed
with brine (5 mL), dried over anhydrous Na2SO4, and concentrated
in vacuo. The crude product was chromatographed (silica gel,
hexane/EtOAc¼10:1) to give the diastereomer mixture of the
mono-TBS-ether (0.019 g, 97%, Rf¼0.31, hexane/EtOAc¼5:1) as
a colorless oil. IR (NaCl) 3441 (O–H), 2856 (C–H), 1692 (C]O), 1252
D
CHCl3); IR (NaCl) 3441 (O–H), 1684 (C]O), 1641 (C]C), 1246 (C–
O) cmꢀ1 1H NMR (CDCl3)
;
d
7.35–7.31 (m, 5H, ArH), 5.75 (br, 1H,
CH2]CH), 5.17 (d, J¼12.3 Hz, 1H, CH2]CH), 5.07 (d, J¼12.3 Hz, 1H,
CH2]CH), 4.92 (d, J¼10.3 Hz, 2H, PhCH2), 4.68 (br, 1H, CH), 4.43 (br,
1H, CH), 3.96–3.84 (m, 3H, CH2 and CH), 3.72 (br, 1H, CH), 2.53 (br,
1H, OH), 2.17 (m, 1H, CH2), 2.03 (m, 1H, CH2), 1.84–1.71 (m, 2H, CH2),
1.49 (s, 3H, CH3), 1.34 (s, 3H, CH3); 13C NMR (CDCl3)
d 155.1, 138.2,
136.1, 128.5,128.2,128.1, 114.5, 112.3, 81.0, 78.5, 67.1, 65.0, 62.5, 60.7,
30.4, 28.2, 26.4, 25.1. Anal. Calcd for C20H27NO5: C, 66.46; H, 7.53; N,
3.88. Found: C, 66.42; H, 7.81; N, 4.19.
(C–O) cmꢀ1 1H NMR (CDCl3)
; d 7.36–7.30 (m, 5H, ArH), 5.21–4.99
(m, 2H, 2CH), 4.71–4.62 (m, 2H, PhCH2), 4.05 (m, 1H, CH), 3.79–3.33
(m, 6H, 2CH2 and 2CH), 2.64–2.07 (br, 3H, OH and CH2), 1.84–1.65
(m, 2H, CH2), 1.49 (s, 3H, CH3), 1.48 (s, 3H, CH3), 1.33 (s, 3H, CH3),
0.89 (s, 9H, 3CH3), 0.83 (s, 9H, 3CH3), 0.06 (s, 6H, 2CH3), ꢀ0.06 (s,
4.2.3.4. Protection with TBSCl. A mixture of the Z-alcohol obtained
as noted above (0.019 g, 0.0498 mmol), imidazole (0.007 g,
0.0996 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (0.012 g,
0.0996 mmol) in DMF (0.5 mL) was stirred for 8 h. It was quenched
by the addition of water (5 mL) and extracted with ethyl acetate
(10ꢂ3 mL). The combined organic extracts were washed with brine
(5 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
The combined organic layers were washed with brine (5 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. The crude
product was purified by column chromatography (silica gel, hex-
3H, CH3), ꢀ0.08 (s, 3H, CH3); 13C NMR (CDCl3)
d (major isomer)
155.1,136.5,128.5,128.3,128.0,111.0, 81.6, 80.0, 71.9, 67.2, 67.0, 66.6,
64.7, 63.6, 63.4, 29.5, 25.9, 25.8, 24.8, 24.1, 18.3, 18.0, ꢀ5.3, ꢀ5.4,
ꢀ5.7, ꢀ5.8; 13C NMR (CDCl3)
d (minor isomer) 155.1, 136.5, 128.5,
128.3, 128.0, 111.0, 81.6, 80.3, 72.1, 67.2, 67.0, 66.6, 64.8, 63.7, 63.6,
63.4, 29.6, 25.9, 25.8, 24.8, 24.3, 18.3, 18.0, ꢀ5.4, ꢀ5.7, ꢀ5.8. Anal.
Calcd for C32H57NO7Si2: C, 61.60; H, 9.21; N, 2.24. Found: C, 61.34; H,
8.85; N, 2.48.
ane/EtOAc¼10:1) to give the TBS-ether 9 (0.023 g, 97%, Rf¼0.33,
24
hexane/EtOAc¼10:1) as a colorless oil. [
a]
ꢀ78.4 (c 1.0, CHCl3); IR
D
(NaCl) 2858 (C–H), 1697 (C]O), 1639 (C]C), 1251 (C–O) cmꢀ1
;
1H
4.2.5.2. Mesylation and cyclization. To a solution of this TBS-pro-
tected diastereomer mixture (0.025 g, 0.0401 mmol) and Et3N
(0.008 g, 0.0802 mmol) in CH2Cl2 (0.4 mL) was added meth-
anesulfonyl chloride (0.007 g, 0.0602 mmol) at 0 ꢁC and stirred for
15 min. The mixture was quenched by the addition of 3% aq HCl
(3 mL) and extracted with ethyl acetate (10ꢂ3 mL). The combined
organic extracts were washed with brine (5 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. The crude product was
chromatographed (silica gel, toluene/EtOAc¼10:1) to give the di-
astereomer mixture of the mesylate (0.026 g, 92%) as a colorless oil.
A solution of this mesylate (0.026 g, 0.037 mmol) and 5% Pd on
carbon in EtOH (4 mL) was stirred at 0 ꢁC for 0.5 h under hydrogen.
After filtration through a pad of Celite with EtOH and concentra-
tion, the crude products of two diastereomers were separated by
column chromatography (silica gel, hexane/EtOAc¼5:1) to give 11a
(0.0121 g, 69%, Rf¼0.53, hexane/EtOAc¼5:1) and 11b (0.005 g, 28%,
NMR (CDCl3) 7.35–7.26 (m, 5H, ArH), 5.78 (m, 1H, CH2]CH), 5.21–
d
4.91 (m, 4H, CH2]CH and 2CH), 4.71–4.64 (m, 2H, PhCH2), 4.10 (m,
1H, CH), 3.84–3.72 (m, 2H, CH2), 3.59 (br d, J¼9.9 Hz, 1H, CH), 2.16–
2.02 (m, 3H, CH2), 1.73 (m, 1H, CH2), 1.48 (s, 3H, CH3), 1.34 (s, 3H,
CH3), 0.84 (s, 9H, 3CH3), ꢀ0.06 (s, 3H, CH3), ꢀ0.08 (s, 3H, CH3); 13
C
NMR (CDCl3)
d 155.0, 138.7, 136.6, 128.5, 128.2, 128.0, 114.4, 110.9,
81.7, 79.8, 66.9, 66.5, 64.7, 63.7, 63.0, 62.0, 30.5, 28.9, 27.2, 26.0, 25.8,
24.9, 18.0, ꢀ5.7, ꢀ5.8. Anal. Calcd for C26H41NO5Si: C, 65.65; H, 8.69;
N, 2.94. Found: C, 65.80; H, 8.36; N, 3.15.
4.2.4. (3aR,4R,6R,6aS)-Benzyl 4-((tert-butyldimethylsilyloxy)-
methyl)-6-((S)-3,4-dihydroxybutyl)-2,2-dimethyldihydro-
3aH-[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate (10)
To a stirred solution of AD-mix-a (0.059 g) and (DHQ)2PHAL
(0.0032 g, 0.00416 mmol) in t-BuOH (0.23 mL) and water (0.23 mL)
was added 9 (0.020 g, 0.042 mmol) at 0 ꢁC and stirred for 48 h at
the same temperature. Powdered NaHSO3 (0.052 g, 0.500 mmol)
was added and the mixture was extracted with CH2Cl2 (5ꢂ3 mL).
The combined organic layers were dried over anhydrous Na2SO4
and concentrated in vacuo. The crude product was purified by
column chromatography (silica gel, hexane/EtOAc¼1:1) to give the
diastereomer mixture of the diol 10 (0.021 g, 98%, Rf¼0.44, hexane/
EtOAc¼1:2) as a colorless oil. IR (NaCl) 3441 (O–H), 2858 (C–H),
Rf¼0.36, hexane/EtOAc¼5:1) as a colorless oil, respectively. Com-
24
pound 11a: [
a
]
þ6.1 (c 1.0, CHCl3); IR (NaCl) 2856 (C–H), 1256 (C–
D
O) cmꢀ1
;
1H NMR (CDCl3)
d
4.72 (d, J¼5.3 Hz, 1H, CH), 4.50 (t,
J¼5.3 Hz, 1H, CH), 3.65–3.60 (m, 2H, CH2), 3.51–3.27 (m, 5H, CH2
and 3CH), 2.15–2.02 (m, 2H, CH2), 1.89 (m, 1H, CH2), 1.58–1.44 (m,
4H, CH3 and CH2), 1.31 (s, 3H, CH3), 0.89 (s, 18H, 6CH3), 0.05 (s, 6H,
2CH3), 0.04 (s, 6H, 2CH3); 13C NMR (CDCl3)
d,111.5, 86.1, 83.4, 70.2,
68.9, 68.5, 66.9, 65.7, 29.7, 26.7, 26.0, 25.9, 25.8, 23.8, 23.6, 18.3,
1690 (C]O), 1250 (C–O) cmꢀ1; 1H NMR (CDCl3)
d
7.35–7.30 (m, 5H,
ꢀ5.2, ꢀ5.3, ꢀ5.4. Anal. Calcd for C24H49NO4Si2: C, 61.09; H, 10.47; N,
25
ArH), 5.19 (dd, J¼12.1, 1.7 Hz, 1H, CH), 5.03 (d, J¼12.1 Hz, 1H, CH),
4.73–4.64 (m, 2H, PhCH2), 4.11 (m, 1H, CH), 3.81–3.47 (m, 6H, 2CH2
and 2CH), 3.09 (br, 1H, OH), 2.84 (br, 1H, OH), 2.50–2.09 (m, 2H,
CH2), 1.80–1.66 (m, 2H, CH2), 1.51 (s, 3H, CH3), 1.35 (s, 3H, CH3), 0.84
(s, 9H, 3CH3), ꢀ0.06 (s, 3H, CH3), ꢀ0.08 (s, 3H, CH3); 13C NMR
2.97. Found: C, 60.98; H, 10.42; N, 3.11. Compound 11b: [
a
]
ꢀ3.6 (c
D
0.7, CHCl3); IR (NaCl) 2856 (C–H), 1256 (C–O) cmꢀ1
(CDCl3)
;
1H NMR
d
4.70 (d, J¼6.2 Hz, 1H, CH), 4.47 (t, J¼6.2 Hz, 1H, CH), 3.75
(dd, J¼10.1, 6.2 Hz, 1H, CH2), 3.67–3.56 (m, 2H, CH2 and CH), 3.52–
3.43 (m, 3H, CH2 and CH), 3.26 (ddd, J¼12.5, 6.2, 6.2 Hz, 1H, CH),
1.95–1.78 (m, 2H, CH2), 1.78–1.61 (m, 2H, CH2), 1.51 (s, 3H, CH3), 1.32
(CDCl3) d (major isomer) 155.2, 136.3, 128.5, 128.4, 128.2, 111.2, 82.0,

T. Sengoku et al. / Tetrahedron 64 (2008) 8052–8058
8057
(s, 3H, CH3), 0.89 (s, 18H, 6CH3), 0.06 (s, 6H, 2CH3), 0.05 (s, 6H,
2CH3); 13C NMR (CDCl3)
111.5, 86.7, 81.4, 68.0, 65.1, 64.8, 63.3, 61.3,
30.7, 26.0, 25.9, 24.2, 23.1, 18.2, ꢀ5.2, ꢀ5.3, ꢀ5.4. Anal. Calcd for
24H49NO4Si2: C, 61.09; H, 10.47; N, 2.97. Found: C, 61.20; H, 10.18;
5.1, 3.9 Hz, 1H, CH), 2.09–1.90 (m, 3H, CH2), 1.81 (m, 1H, CH2); 13C
d
NMR (D2O) d 79.9, 75.8, 72.0, 67.4, 66.7, 66.2, 65.4, 34.2, 26.9; HRMS
(ESIþ) m/z calcd for C9H17NO4þH: 204.1236, found 204.1227.
C
N, 2.65.
Acknowledgements
4.2.6. (1S,2R,3R,5R,7aR)-3,5-Bis(hydroxymethyl)hexahydro-
1H-pyrrolizine-1,2-diol (hyacinthacine B1) (5a)
This work was supported in part by a Grant-in-Aid for Scientific
Research from Japan Society for the Promotion of Science. We
acknowledge Nanotechnology Network Project (Kyushu-area
Nanotechnology Network) of the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
4.2.6.1. Deprotection of bis-TBS group. A solution of 11a (0.038 g,
0.0805 mmol) and tetrabutylammonium fluoride (1.0 M solution in
THF, 0.18 mL, 0.18 mmol) in THF (0.8 mL) was stirred at 0 ꢁC for 6 h.
The mixture was concentrated to give the crude product, which was
purified by column chromatography (silica gel, chloroform/
References and notes
1. (a) Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497; (b) Fellows, L. E.; Kite, G. C.;
Nash, R. J.; Simmonds, M. S. J.; Scofield, A. M. In Plant Nitrogen Metabolism;
Poulton, J. E., Romero, J. T., Conn, E. E., Eds.; Plenum: New York, NY, 1989; p 395;
(c) Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319; (d) Iminosugars as
Glycosidase Inhibitors: Norjirmycin and Beyond; Stu¨ tz, A. E., Ed.; Wiley-VCH:
Weinheim, 1999; (e) Iminosugars: From Synthesis to Therapeutic Applications;
Philippe Compain, P., Martin, O. R., Eds.; Wiley-VCH: Weinheim, 2007.
2. Isolation: Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.; Derome, A. E.;
Hamor, A. E.; Scofield, A. M.; Watkin, D. J. Tetrahedron Lett. 1988, 29, 2487.
3. Isolation: Molyneux, R. J.; Benson, M.; Wong, R. Y.; Tropea, J. E.; Elbein, A. D.
J. Nat. Prod. 1988, 51, 1198.
MeOH¼10:1) to afford the diol (0.019 g, 97%, Rf¼0.22, CHCl3/
25
MeOH¼10:1) as a colorless oil. [
a
]
þ4.1 (c 0.6, CHCl3); IR (NaCl)
D
3485 (O–H), 2874 (C–H) cmꢀ1
; d 4.56 (dd,
1H NMR (CDCl3)
J¼10.4, 5.7 Hz, 1H, CH), 4.50 (dd, J¼5.7, 1.5 Hz, 1H, CH), 3.74 (m, 1H,
CH), 3.68 (dd, J¼15.3, 9.2 Hz, 1H, CH2), 3.58 (dd, J¼10.2, 3.5 Hz, 1H,
CH2), 3.48–3.35 (m, 3H, CH2 and 2CH), 3.44 (dd, J¼15.3, 6.5 Hz,
1H, CH2), 2.93–2.56 (br, 2H, 2OH), 2.21–2.09 (m, 2H, CH2), 1.96 (m,
1H, CH2), 1.65 (m, 1H, CH2), 1.50 (s, 3H, CH3), 1.30 (s, 3H, CH3); 13C
NMR (CDCl3) d 112.1, 85.2, 82.7, 70.8, 67.2, 66.6, 65.8, 62.8, 28.7, 26.8,
24.3, 24.0. Anal. Calcd for C12H21NO4: C, 59.24; H, 8.70; N, 5.76.
Found: C, 59.16; H, 9.07; N, 5.53.
4. Elbein, A. D.; Tropea, J. E.; Molyneux, R. J. U.S. Pat. Appl. US 289,907, 1989 (Appl.
No. US 1988-289907); Chem. Abstr 1990, 113, 91444p.
5. Fellows, L. E.; Nash, R. J. PCT Int. Appl. WO GB APPLE. 7,951, 1989 (Appl. No. PCT/
GB1990/000538); Chem. Abstr. 1991, 114, 143777s.
6. Fellows, L. E. Pestic. Sci. 1986, 17, 602.
4.2.6.2. Deprotection of acetal. To a solution of the above diol
(0.013 g, 0.0534 mmol) in H2O (0.5 mL) was added trifluoroacetic
acid (0.5 mL) at 0 ꢁC and stirred for 24 h. The mixture was con-
centrated to give the crude product. Finally, the water solution
of the crude product was passed through Dowex 50WX-8 (Hþ
form), which was first eluted with water (20 mL), and then with
0.7 M NH4OH followed by 1.4 M NH4OH. Fractions were concen-
trated in vacuo to give 5a (0.011 g, 92%, Rf¼0.45, MeOH/H2O/
NH4OH¼20:2:1) as a colorless oil. The spectral data of synthetic
7. 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.
8. 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; Recently, the
search in the same group for hyacinthacines in the hyacinthaceae has led to the
isolation from Scilla socialis bulbs of new 11 hyacinthacines, see: Kato, A.; Kato,
N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.; Kuriyama, C.; Ikeda, K.; Asano, N.;
Nash, R. J. J. Nat. Prod. 2007, 70, 993 and references cited therein.
9. (a) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5546; (b) Ikota, N.;
Nakagawa, H.; Ohno, S.; Noguchi, K.; Okuyama, K. Tetrahedron 1998, 54, 8985;
(c) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem. Soc. 1998, 120, 7359; (d)
Denmark, S. E.; Martinborough, E. A. J. Am. Chem. Soc. 1999, 121, 3046; (e)
Denmark, S. E.; Hurd, A. R. J. Org. Chem. 2000, 65, 2875; (f) Denmark, S. E.;
Herbert, B. J. Org. Chem. 2000, 65, 2887; (g) Yoda, H.; Katoh, H.; Takabe, K.
Tetrahedron Lett. 2000, 41, 7661; (h) Denmark, S. E.; Cottell, J. J. J. Org. Chem.
2001, 66, 4726; (i) Donohoe, T. J.; Sintim, H. O. Org. Lett. 2004, 6, 2003; (j) Tang,
M.; Pyne, S. G. Tetrahedron 2004, 60, 5759.
10. (a) Rambaud, L.; Compain, P.; Martin, O. R. Tetrahedron: Asymmetry 2001, 12,
1807; (b) Izquierdo, I.; Plaza, M. T.; Robles, R.; Franco, F. Tetrahedron: Asymmetry
2001, 12, 2481; (c) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry
2002, 13, 1581; (d) Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003,
35; (e) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti, A. Tetrahedron Lett.
2003, 44, 2315; (f) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry
2003, 14, 3933; (g) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry
2004, 15, 1465; (h) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A. Tetrahedron: Asym-
metry 2004, 15, 3635; (i) Desvergnes, S.; Py, S.; Vallee, Y. J. Org. Chem. 2005, 70,
1459; (j) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2005, 7, 2587; (k) Do-
nohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem. 2005, 70, 7297; (l) Iz-
quierdo, I.; Plaza, M. T.; Yanez, V. Tetrahedron: Asymmetry 2005, 16, 3887; (m)
Dewi-Wuelfing, P.; Blechert, S. Eur. J. Org. Chem 2006, 1852; (n) Izquierdo, I.;
Plaza, M. T.; Tamayo, J. A.; Rodriguez, M.; Martos, A. Tetrahedron 2006, 62, 6006;
(o) Zhou, L.; Chen, J.; Cao, X.-P. Synthesis 2007, 1359; (p) Donohoe, T. J.; Thomas,
R. E. Chem. Rec. 2007, 7, 180; (q) Calveras, J.; Casas, J.; Parella, T.; Joglar, J.; Clapes,
P. Adv. Synth. Catal. 2007, 349, 1661; (r) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.;
Sanchez-Cantalejo, F. Tetrahedron: Asymmetry 2007, 18, 2211; (s) Izquierdo, I.;
Plaza, M. T.; Tamayo, J. A.; Sanchez-Cantalejo, F. Eur. J. Org. Chem. 2007, 6078; (t)
Kaliappan, K. P.; Das, P. Synlett 2008, 841; (u) Reddy, P. V.; Veyron, A.; Koos, P.;
Bayle, A.; Greene, A. E.; Delair, P. Org. Biomol. Chem. 2008, 6, 1170; (v) Izquierdo,
hyacinthacine B1 (5a) thus obtained were identical in all respects
26
with those of the reported natural product.7 [
a
]
D
þ41.9 (c 0.4, H2O)
{lit. [
a
]
þ41.3 (c 1.04, H2O)7}; IR (NaCl) 3335 (O–H), 2874 (C–
H) cmꢀ1D; 1H NMR (D2O)
d
3.94–3.90 (m, 2H, 2CH), 3.72 (dd, J¼11.2,
3.8 Hz, 1H, CH2), 3.59 (dd, J¼11.2, 6.2 Hz, 1H, CH2), 3.55 (m, 1H, CH),
3.53 (dd, J¼11.2, 6.6 Hz, 1H, CH2), 3.42 (dd, J¼11.2, 5.9 Hz, 1H, CH2),
3.03 (m, 1H, CH), 2.90 (m, 1H, CH), 2.07–1.90 (m, 2H, CH2), 1.77 (m,
1H, CH2), 1.51 (m, 1H, CH2); 13C NMR (D2O)
d 78.1, 74.9, 72.2, 72.0,
69.5, 67.3, 65.9, 32.2, 25.3; HRMS (ESIþ) m/z calcd for C9H17NO4þH:
204.1236, found 204.1223.
The same procedure gave the pyrrolizidine 11b and hyacintha-
cine B2 (5b) from the corresponding Cbz-pyrrolidine 9 via the AD
reaction employing AD-mix-b (yields are given in Scheme 2). The
spectral data of synthetic hyacinthacine B2 (5b) thus obtained were
identical in all respects21 with those of the natural product.7
TBS-deprotected diol of 11b (pale yellow oil, Rf¼0.35, CHCl3/
25
MeOH¼1:1): [
a
]
D
þ10.7 (c 0.2, CHCl3); IR (NaCl) 3416 (O–H), 2853
(C–H) cmꢀ1
;
1H NMR (CDCl3)
d 4.59–4.55 (m, 2H, CH), 3.83 (dd,
J¼12.3, 3.3 Hz, 1H, CH2), 3.76 (m, 1H, CH), 3.68 (dd, J¼12.3, 5.3 Hz,
1H, CH2), 3.65–3.62 (m, 2H, CH2), 3.45 (ddd, J¼12.3, 7.1, 3.3 Hz, 1H,
CH), 3.32 (dd, J¼12.3, 8.8 Hz, 1H, CH), 2.81–2.22 (br, 2H, 2OH), 2.08
(m, 1H, CH2), 1.93–1.76 (m, 3H, CH2), 1.55 (s, 3H, CH3), 1.40 (s, 3H,
ˇ
I.; Plaza, M. T.; Tamayo, J. A.; Ya´nez, V.; L.-Re, D.; S.-Cantalejo, F. Tetrahedron
2008, 64, 4613.
CH3); 13C NMR (CDCl3)
d 112.2, 85.6, 81.4, 66.5, 63.4, 62.7, 62.3, 62.0,
11. (a) Ikota, N. Chem. Pharm. Bull. 1993, 41, 1717; Ikota, N. Chem. Pharm. Bull. 1992,
40, 1925; (b) Smith, A. B.; Salvatore, B. A.; Hull, K. G.; Duan, J. J.-W. Tetrahedron
Lett. 1991, 32, 4859; (c) Hamada, Y.; Tanada, Y.; Yokokawa, F.; Shioiri, T. Tetra-
hedron Lett. 1991, 32, 5983.
12. (a) Ikota, N. Tetrahedron Lett. 1992, 33, 2553; (b) Yoda, H.; Oguchi, T.; Takabe, K.
Tetrahedron: Asymmetry 1996, 7, 2113.
13. The reaction of 6 with Grignard reagent was undesirably accompanied with the
formation of the corresponding N–H lactam derived from Boc-elimination, see:
Ginovannini, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem 1989, 54, 228.
14. The diastereomeric ratio of 7 was easily estimated by 1H NMR analysis as
shown in the text.
29.8, 25.5. 23.9, 23.8. Anal. Calcd for C12H21NO4: C, 59.24; H, 8.70; N,
5.76. Found: C, 59.04; H, 8.80; N, 5.70.
Hyacinthacine B2 (5b) (colorless oil, Rf¼0.41, MeOH/H2O/
27
NH4OH¼6:2:1): [
a
]
D
þ42.3 (c 0.25, H2O) {lit. [
a
]
;
þ41.3 (c 0.36,
D
H2O)7}; IR (NaCl) 3354 (O–H), 2887 (C–H) cmꢀ1
1H NMR (D2O)
d
4.11 (dd, J¼8.3, 4.2 Hz, 1H, CH), 4.09 (dd, J¼6.0, 4.2 Hz, 1H, CH),
3.89 (dd, J¼11.9, 3.8 Hz, 1H, CH2), 3.85–3.78 (m, 3H, CH2 and CH),
3.73 (dd, J¼11.9, 5.1 Hz, 1H, CH2), 3.43 (m, 1H, CH), 3.37 (ddd, J¼8.4,

8058
T. Sengoku et al. / Tetrahedron 64 (2008) 8052–8058
15. The absolute configuration of the newly generated stereogenic center of the
major product could not be determined at the present stage, however, it was
easily predictable to be S with the aid of the thermodynamically more stable
Cram’s non-chelation model including the coordination of CeCl3 to the carbonyl
oxygen in a dilute EtOH solution.
16. As shown in Scheme 2, the absolute configurations of the newly generated
stereogenic centers in 8a and 8b were unambiguously characterized to be R and
S, respectively, by detailed comparison of their 1H and 13C NMR spectral data to
those of iia and iib derived from the vinyl substituted pyrrolidines ia and ib via
hydrogenation. In turn, these two compounds ia and ib were also obtained
from the N-Boc lactam 6 based on the same synthetic procedure as that of 8a
and 8b described in the text.12a On the other hand, in order to determine the
absolute configurations of ia and ib, those were independently converted to iiia
and iiib and estimated to have the depicted stereochemistries, respectively,
based on its symmetrically spectral data of iiib.
17. Intrigued by hitherto known procedures such as in acidic media regarding the
Boc-elimination, where an inseparable mixture was obtained due to the pres-
ence of the acid-labile acetonide group, we investigated an alternative method
and were surprised to find that NaH could effect prominently to eliminate the
Boc function smoothly after desilylation of 8a, finally leading to the desired
Cbz-containing substrate 9. It is of great importance to note that the Boc-
elimination with NaH in this case requires the presence of the neighboring
hydroxyl group. The reason for such an unusual elimination reaction has not
been yet clarified.
18. (a) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.; Sharpless, K. B.
J. Org. Chem. 1993, 58, 3785; (b) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang,
Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
19. (a) Behr, J.-B.; Erard, A.; Guillerm, G. Eur. J. Org. Chem. 2002, 1256; (b) Takahata,
H.; Kubota, M.; Momose, T. Tetrahedron: Asymmetry 1997, 8, 2801 Simple OsO4-
catalyzed dihydroxylation reactions carried out on 9 gave the non-stereo-
selective results.
20. The absolute stereochemistry of the newly created asymmetric carbon of 11a
derived from the AD reaction of
9 was unambiguously determined after
completion of the total synthesis of 5a based on its spectral data together with
the mechanistic proof of the AD reaction pathway reported to date.18
21. The obtained chemical shifts and coupling constants of 1H NMR of synthetic
(5b) were completely in accord with the reported values of the natural prod-
uct,7 while the slight difference (0.5–2 ppm) of the chemical shifts of 13C NMR
spectra was observed. It is, however, generally known that variation in solvent
(ionic strength, hydrogen bonding, metal ion chelation) can exert discrepancies
in NMR spectra of polyhydroxylated alkaloids, see: Wormald, M. R.; Nash, R. J.;
Hrnciar, P.; White, J. D.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
1998, 9, 2549.