New asymmetric strategy for the total synthesis of naturally occurring (+)-alexine and (-)-7-epi-alexine

Article abstract of DOI:10.1016/j.tet.2008.03.029

A novel and highly convenient process is described for the asymmetric synthesis of polyhydroxylated pyrrolizidine alkaloids, (+)-alexine [(1R,2R,3R,7S,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine] and (-)-7-epi-alexine [(1R,2R,3R,7R,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine], as the potent glycosidase inhibitors by featuring the efficient and stereodefined elaboration of the functionalized pyrrolidine derivatives, which were, in turn, prepared via stereoselective manipulation of the homochiral allyl alcohol precursors derived from l-xylose.

Full text of DOI:10.1016/j.tet.2008.03.029

Tetrahedron 64 (2008) 5254–5261
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New asymmetric strategy for the total synthesis of naturally
occurring (þ)-alexine and (ꢀ)-7-epi-alexine
Masaki Takahashi a, Tetsuya Maehara a, Tetsuya Sengoku a, Norifumi Fujita b,
,
Kunihiko Takabe a, Hidemi Yoda a
*
a Department of Materials Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Naka-ku, Hamamatsu 432-8561, Japan
b Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University, Moto-oka 744, Nishi-ku, Fukuoka 819-0395, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and highly convenient process is described for the asymmetric synthesis of polyhydroxylated
pyrrolizidine alkaloids, (þ)-alexine [(1R,2R,3R,7S,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine]
and (ꢀ)-7-epi-alexine [(1R,2R,3R,7R,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine], as the potent
glycosidase inhibitors by featuring the efficient and stereodefined elaboration of the functionalized
pyrrolidine derivatives, which were, in turn, prepared via stereoselective manipulation of the homochiral
Received 21 February 2008
Received in revised form 10 March 2008
Accepted 11 March 2008
Available online 14 March 2008
allyl alcohol precursors derived from L-xylose.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
The presence of a hydroxymethyl function to the ring nitrogen
[C(3)],4c however, distinguishes these groups from the larger class
of necine bases such as dihydroxyheliotridane (6), which bear
carbon substituents at C(1). Alexines have 5 chiral centers; 7 of the
32 stereoisomers have been isolated as natural products from
plants.10,11,13 The biological potential, which varies substantially
with the number, position, and stereochemistry of the hydroxyl
groups into the pyrrolizidine skeleton, and the complexity of five
adjacent stereogenic centers have led to a large number of
subsequent papers on their synthesis.14 However, in contrast to the
synthetic endeavors on the alexines, to our knowledge, there are
only two syntheses of the parent alkaloid, alexine (1b), based on an
optical resolution method by Fleet et al.4b and our redundant
synthetic strategy.14h Thus, the method is very limited to special
ways. With these considerations in mind, we wish to describe
Polyhydroxylated monocyclic and bicyclic alkaloids can be
viewed as sugar mimics in which the ring oxygen is replaced by
nitrogen;1 the biological properties inhibiting various glycosidases
in a reversible and competitive manner2 and uses as chemothera-
peutic agents have ensured an escalating interest in synthesizing
both naturally occurring and synthetic compounds,3 since such
glycosidase inhibitors proved to have the potential to produce
antiviral, insect antifeedant, antidiabetic, and anticancer effects as
well as immune modulatory properties. Noteworthy members
among this class of compounds are polyhydroxylated pyrrolizidines
such as the alexines (1),4 represented by the parent alkaloid (1b),
australine (2) (the 7a epimer of 1b),5 and casuarine (3)6 (Fig. 1)
exhibiting viral and retroviral7 including anti-HIV8 activity together
with powerful glycosidase inhibitory properties.9 Recently, a new
series of hyacinthacines were isolated from bluebells (Hyacin-
thoides non-scripta)10 and grape hyacinths (Muscari armeniacum)11
by Asano and co-workers. Hyacinthacine B2 (4), for example, was
found to be a selective inhibitor of b-glucosidase and b-galactosi-
dase and, in addition, proved to inhibit rat intestinal lactase in
a competitive manner with an IC50 value of 3.6 mM.11 There is
a significant structural resemblance to (2R,3R,4R,5R)-2,5-dihy-
droxymethyl-3,4-dihydroxypyrrolidine, DMDP (5), known as
a strong glycosidase inhibitor occurring in some spp. Derris and
Lonchocarpus (Leguminosae).12 These are also a unique subset of
pyrrolizidine alkaloids possessing contiguous stereogenic centers.
Y
HO
OH
OH
HO
OH
H
N
H
N
H
N
X
7
5
1
HO
OH
6
2
OH
OH
3
OH
casuarine (3)
OH
OH
australine (2)
7-epi-alexine (1a):
X = H, Y = OH
alexine (1b): X = OH, Y = H
OH
OH
OH
H
N
OH
H
HO
HO
OH
HN
N
HO
OH
hyacinthacine B2 (4)
OH
DMDP (5)
dihydroxyheliotridane (6)
* 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.2008.03.029

M. Takahashi et al. / Tetrahedron 64 (2008) 5254–5261
5255
Y
intermediate, which on treatment with vinyl-Grignard reagent at
ꢀ78 ꢁC, resulted in the preparation of the fully functionalized allylic
alcohol 12a or 12b with fortunately almost complete stereo-
selectivity.18 It is reasonable to presume that the obtained product
could be12a, sincethe reactionwouldproceed simplyin terms of the
Cram’s non-chelation transition structure through the attack on the
carbonyl group from the less hindered face.
In light of the above outcome, we turned our attention to the
construction of a pyrrolizidine ring system. After protection of the
hydroxyl group of 12a with MOMCl, 13a thus obtained was
subjected to the following reactions of desilylation, mesylation,
and t-BuOK-promoted cyclization, leading to the pyrrolidine in-
termediate 14a in 82% yield (three steps). Then, 14a was regiose-
lectively hydroborated with 9-BBN to give the primary alcohol 15a
as a sole product. Compound 15a prepared in this way was, in turn,
submitted to the subsequent reactions of mesylation again and
BF3$OEt2-induced Boc-deprotection accompanied with the simul-
taneous reactions of deprotection of MOM group and nitrogen-
induced cyclization under the conditions developed in our laboratory,19
to provide the desired pyrrolizidine structure 16a directly in 84%
overall yield from 15a. Finally, removal of the three benzyl-
protecting groups in 16a was effectively conducted with 10% Pd on
carbon in the presence of HCOONH4 in MeOH at 60 ꢁC to complete
the total synthesis of 1a in 82% yield.
OH
X
H
N
Y
OR1 OR3
X
7
1
3
7a
6
2
OH
OH
OR1
5
NHR2OR1
7-epi-alexine (1a): X = H, Y = OH
(IIIa): X = H, Y = OH
alexine (1b): X = OH, Y = H
(IIIb): X = OH, Y = H
OR1 OR3
OR1
(II)
NHR2OR1
OH
OR1
3 O
OH
O
4
OH
2
HO
R1O
L-xylose
(I)
OR1
OH
Figure 2. General retrosynthesis.
herein an efficient and stereodefined asymmetric synthesis of 1b
together with its 7-epi isomer 1a by means of stereoselective
elaboration of the functionalized homochiral allyl alcohol precursor
derived from L-xylose.
In formulating the synthetic plan for 1, we recognized that the
absolute configurations at C(1) and C(2) are the same as the con-
figurations at the corresponding centers C(2) and C(3) of L-xylose
(Fig. 2). Further, we envisioned that the stereogenic center of C(7a)
would originate from the nucleophilic addition to the aminal de-
Unambiguous proof of the stereochemistry of the generated
stereocenter in 12a came, at this stage, from the comparison of its
spectral data with those of the reported value,4b resulting in the
conclusion that obtained 1a should be 7-epi-alexine {[a]2D3 ꢀ11.0 (c
1.00, H2O) [lit. [a]D20 ꢀ10.6 (c 0.56, H2O)]4b} (Scheme 2).
rivative of 2,3,5-tri-O-protected L-xylose (I), allowing the synthesis
of the amino alcohol intermediate (II). Meanwhile, the remaining
stereogenic center C(7) of 1 would have to be independently set in
an asymmetric carbon-extension reaction to provide the corre-
sponding allyl alcohol (III).
Having obtained and characterized synthetic 7-epi-alexine (1a),
we attempted the asymmetric preparation of 12b containing the
reverse stereochemistry at C(6) required to synthesize natural
(þ)-alexine (1b). The results from our survey are described in
Scheme 3. After oxidation of 12a with tetrapropylammonium per-
ruthenate(TPAP)/NMO reagent,20 we were delighted to find
through detailed investigation of stereoselective reduction that the
Luche reagent in MeOH at low temperature could effect these
reactions beneficially, bringing about the desired reduction product
12b predominantly (12a/12b¼4:96, determined by 1H NMR) in
a reverse stereoselective manner. We postulate at present that this
high stereoselective performance would be attributed to the steric
demand of the CeCl3-mediated six-membered metal-chelating
structure (Fig. 3).21 It would proceed through the preferential attack
of Hꢀ to the carbonyl function from the right face of this
six-membered model due to the shielding effect of the three large
functional groups described below.
With the compound 12b in hand as a main product, we
attempted the total synthesis of 1b based on the same synthetic
strategy as mentioned above. Fortunately, it has become apparent
that the major diastereomer 13b obtained from the protection of
this diastereomer mixture with MOMCl was easily separated from
13a by column chromatography on silica gel (13a: Rf¼0.45, 13b:
Rf¼0.60 hexane/EtOAc¼5:1, respectively). Then, 13b was
2. Results and discussion
As shown in Scheme 1, starting 2,3,5-tri-O-benzyl-
was initially prepared from -xylose through a three-step sequence;
L-xylose (7)
L
methyl glycosilation, benzyl protection with NaH, and hydrolysis of
the corresponding methyl furanoside.15 Nucleophilic addition of
vinylmagnesium chloride to the furanosylamine intermediate
derived from 7 with 4-methoxybenzylamine (MPM amine) gave the
labile amino alcohol 8 as a single isomer.16 For the purpose of facility
in the pyrrolizidine ring construction at the final stage together with
reducing formation of by-products,17 an attempt to obtain the N-Boc
derivative was designed and elaborated through promising treat-
ments of 8 upon replacing the MPM function via the benzoyl (Bz)
group. Thus, 8 was effected with BzCl, which on successive treat-
ment with cerium ammonium nitrate (CAN) gave rise to the amide 9
in 77% two-step yield. Compound 9 thus obtained was further
stepwiselysubmitted to protection reactions with TBSCl followed by
(Boc)2O, leading to the N-Boc amide 10. Then, chemoselective
deprotection of the Bz group in 1,1,3,3-tetramethylguanidine at
130 ꢁC yielded the pure NHBoc carbamate 11 in 98% yield without
racemization as well as thermal decomposition. The olefinic part in
11 was then cleaved via dihydroxylation to afford the aldehyde
OBn OH
OBn OH
OH
OBn
O
O
a
b
OBn
OBn
OH
OH
HO
BnO
NH OBn
NH OBn
OH
OBn
L-xylose
7
8
9
MPM
OBn OTBS
Bz
OBn OTBS
OBn
OBn OTBS
OBn
X Y
d
e
c
OBn
N
OBn
Boc
NH OBn
NH OBn
11
10
12a: X = H, Y = OH
12b: X = OH, Y = H
Bz
Boc
Boc
Scheme 1. Reagents and conditions: (a) (i) MPMNH2, MS 4 Å, toluene, reflux; (ii) CH2]CHMgCl, THF, ꢀ78 ꢁC to 0 ꢁC, 2 h; 75% (two steps); (b) (i) BzCl, CH2Cl2; 89%; (ii) CAN, MeOH;
86%; (c) (i) TBSCl, imidazole, DMF; 89%; (ii) Boc2O, Et3N, DMAP, CH2Cl2; 92%; (d) (Me2N)2C]NH, reflux, 130 ꢁC, 8 h; 98%; (e) (i) OsO4, NMO, acetone; 94%; (ii) NaIO4, THF/H2O (1:1);
(iii) CH2]CHMgCl, THF, ꢀ78 ꢁC; 95% (two steps).

5256
M. Takahashi et al. / Tetrahedron 64 (2008) 5254–5261
MOMO
MOMO
OBn OTBS
OBn
OBn
OBn OTBS
HO
Boc
HO
H
N
a
b
c
OBn
OBn
NH OBn
Boc
OH
NH OBn
Boc
HO
12a
13a
14a
OBn
MOMO
H
OBn
OBn
OBn
OBn
HO
H
N
H
N
d
e
OH
OH
N
Boc
OBn
OBn
15a
16a
7-epi-alexine (1a)
Scheme 2. Reagents and conditions: (a) MOMCl, i-Pr2NEt; 98%; (b) (i) Bu4NF, THF; 98%; (ii) MsCl, Et3N, CH2Cl2; (iii) t-BuOK, THF; 84% (two steps); (c) (i) 9-BBN, H2O2 (34.5%), 3 N
NaOH, THF; 94%; (d) (i) MsCl, Et3N, CH2Cl2; (ii) BF3$OEt2, CH2Cl2, ꢀ20 ꢁC; 84%; (e) Pd/C (10%), HCO2NH4, MeOH, reflux, 2 h; 82%.
a
OBn OTBS
OBn OTBS
X Y
6
O
OBn
OBn
3
1
b
NH OBn
NH OBn
Boc
Boc
12a: X = H, Y = OH
12b: X = OH, Y = H
17
c
MOMO
MOMO
Boc
OBn
OBn OTBS
MOMO
Boc
OBn
OBn
H
H
N
d
e
f
OBn
HO
OBn
OBn
N
Boc
HO
NH OBn
OBn
13b
14b
15b
HO
OBn
OH
H
N
H
g
OBn
OH
N
16b
alexine (1b)
OBn
OH
Scheme 3. Reagents and conditions: (a) TPAP, NMO, MS 4 Å, CH2Cl2; 92%; (b) NaBH4, CeCl3, MeOH, ꢀ45 ꢁC; 80%; (c) MOMCl, i-Pr2NEt; 4% (13a); 96% (13b); (d) (i) Bu4NF, THF; 91%;
(ii) MsCl, Et3N, CH2Cl2; (iii) t-BuOK, THF; 87% (two steps); (e) 9-BBN, H2O2 (34.5%), 3 N NaOH, THF; 97%; (f) (i) MsCl, Et3N, CH2Cl2; (ii) BF3$OEt2, CH2Cl2, ꢀ20 ꢁC; 84% (two steps); (e)
Pd/C(10%), HCO2NH4, MeOH; reflux 2 h; 83%.
desilylated with Bu4NF and the product was further treated under
the cyclization conditions to lead to the pyrrolidine derivative 14b
in 87% two-step yield. Compound 14b thus prepared was succes-
sively effected by hydroboration with 9-BBN and advantageous
BF3$OEt2-mediated cyclization again after mesylation of 15b,
providing the desired alexine tri-benzylether 16b in high yield.
Finally, debenzylation of 16b under the same reaction conditions as
mentioned above complete the total synthesis of (þ)-alexine (1b).
The spectral data of synthetic 1b, together with the optical rotation
of which matches that of the reported value {[a]2D3 þ40.4 (c 0.33,
H2O) [lit. [a]2D0 þ40.0 (c 0.25, H2O)]4a}, were completely identical to
those of the natural product.4a Compounds 1a and 1b were
obtained in 15 and 17 steps, and 21 and 16% overall yield from
overall yields, respectively. This process was substantially
performed under mild conditions through the entire sequence and
represents an easily accessible pathway to widespread pyrrolidine
and pyrrolizidine types of alkaloidal sugar mimics. Further
syntheses based on this strategy are currently underway.
4. Experimental section
4.1. General
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,
Stanford Research Systems). Fourier transform infrared (FTIR)
spectra were recorded on a Shimadzu FTIR-8200A spectrometer.
The 1H and 13C nuclear magnetic resonance (NMR) spectra oper-
ating 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 (ppm) relative to TMS as internal standard
(d¼0 ppm) for 1H NMR, and CDCl3 was used as internal standard
(d¼77.0) for 13C NMR. The 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
2,3,5-tri-O-benzyl-L-xylose (7), respectively.
3. Conclusions
In summary, an efficient and novel synthetic pathway to natural
(þ)-alexine and (ꢀ)-7-epi-alexine has been established by featur-
ing the efficient and stereodefined elaboration of the functionalized
homochiral allyl alcohols prepared from
L-xylose in excellent
Cl3
Cl
Cl
Cl
Ce
Ce
O
OBn OTBS
OBn
O
O
Bn
H
NHBoc
NH OBn
Boc
R
H
H
R=CH(OBn)CH(OTBS)CH2OBn
Figure 3. Six-membered chelation model.

M. Takahashi et al. / Tetrahedron 64 (2008) 5254–5261
5257
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-pressure 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.
4.2.2.2. Deprotection of MPM group. To a solution of the above
benzylamide (0.213 g, 0.317 mmol) in MeOH (2.7 mL) was added
cerium ammonium nitrate (CAN) (0.521 g, 0.951 mmol) slowly at
0 ꢁC and stirred for 4 h at room temperature. Then, the mixture 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 anhydride Na2SO4, and concentrated
in vacuo. The residue was purified by column chromatography
(silica gel, hexane/EtOAc¼3:2) to give the benzylamide 9 (0.150 g,
86%) as a white solid; mp 104.7–104.9 ꢁC. [a]D27 ꢀ53.0 (c 1.0, CHCl3);
4.2. Experimental procedures
IR (KBr) 3402 (O–H), 2961 (C–H), 1658 (C]O) cmꢀ1 1H NMR
;
(CDCl3) d 7.79–7.77 (m, 2H, ArH), 7.52–7.46 (m, 3H, ArH), 7.34–7.17
(m, 15H, ArH), 6.84 (d, J¼9.0 Hz, 1H, NH), 5.98 (ddd, J¼17.2,
10.4, 4.8 Hz, 1H, CH2]CH), 5.28–5.24 (m, 2H, CH2]CH), 5.02 (m,
1H, CH), 4.80 (dd, J¼10.8 Hz, 1H, PhCH2), 4.78 (dd, J¼11.0 Hz, 1H,
PhCH2), 4.68 (dd, J¼10.8 Hz, 1H, PhCH2), 4.50 (dd, J¼11.0 Hz,
1H, PhCH2), 4.49 (dd, J¼11.8 Hz, 1H, PhCH2), 4.42 (dd, J¼11.8 Hz, 1H,
PhCH2), 4.09 (m, 1H, CH), 4.04 (dd, J¼8.4, 1.8 Hz, 1H, CH), 3.68 (dd,
J¼8.4, 1.8 Hz, 1H, CH), 3.54 (dd, J¼9.5, 6.6 Hz, 1H, CH2), 3.42 (dd,
J¼9.5, 6.1 Hz, 1H, CH2), 2.47 (d, J¼7.5 Hz, 1H, OH); 13C NMR (CDCl3)
d 166.8 (C]O),138.1 (2C),138.0 (C),137.9 (C),136.3 (CH2]CH),134.4
(CH), 131.5 (2CH), 128.6 (CH), 128.4 (2CH), 128.3 (2CH), 128.1 (3CH),
127.9 (2CH), 127.8 (3CH), 127.7 (2CH), 127.6 (CH), 127.0 (CH), 115.8
(CH2]CH), 81.9 (CH), 79.5 (CH), 75.2 (2CH2), 73.1 (CH), 71.1 (CH),
69.3 (CH2), 52.1 (CH2); HRMS (ESIþ) m/z calcd for C35H37NO5þNa:
574.2569, found 574.2578. Anal. Calcd for C35H37NO5: C, 76.20; H,
6.76; N, 2.54. Found: C, 76.28; H, 6.88; N, 2.68.
4.2.1. (2S,3R,4R,5S)-1,3,4-Tris(benzyloxy)-5-(4-methoxybenzyl-
amino)hept-6-en-2-ol (8)
A solution of 7 (0.481 g, 1.144 mmol) and 4-methoxybenzyl-
amine (0.157 g,1.144 mmol) in toluene (9.5 mL) was refluxed for 8 h
in the presence of molecular sieves (4 Å, 0.5 g). Filtration and
evaporation of the volatiles gave a crude anomeric mixture of the
aminal (0.617 g) as a yellow oil, which was not purified further.
Vinylmagnesium chloride (1.48 M solution in THF, 3.1 mL,
4.576 mmol) was added dropwise to a solution of this aminal in THF
(6 mL) under nitrogen at ꢀ78 ꢁC. The reaction mixture was grad-
ually warmed to 0 ꢁC and stirred for 2 h. It was quenched by the
addition of saturated NH4Cl (5 mL) and extracted with ethyl acetate
(10ꢂ3 mL). The combined organic extracts were washed with brine
(5 mL), dried over anhydride Na2SO4, and concentrated to give the
crude amino alcohol, which was purified by column chromatog-
raphy (silica gel, hexane/EtOAc¼5:1) to give 8 (0.486 g, 75%) as
a pale yellow oil. [a]2D4 ꢀ11.7 (c 1.0, CHCl3); IR (NaCl) 2864 (C–H),
1247 (C–O) cmꢀ1; 1H NMR (CDCl3) d 7.35–7.15 (m, 17H, ArH), 6.84–
6.79 (m, 2H, ArH), 5.78 (m, 1H, CH2]CH), 5.23–5.09 (m, 2H,
CH2]CH), 4.65–4.61 (m, 3H, PhCH2 and CH), 4.60–4.30 (m, 6H,
3PhCH2), 4.09 (dd, J¼5.8, 8.3 Hz, 1H, CH), 3.84–3.40 (m, 4H, CH2 and
2CH), 3.74 (s, 3H, CH3); 13C NMR (CDCl3) d 158.9 (C), 141.0
(CH2]CH), 138.6 (C), 138.5 (C), 138.4 (C), 137.7 (CH), 130.9 (CH),
129.9 (CH), 129.6 (2CH), 128.5 (CH), 128.4 (2CH), 128.3 (CH), 128.2
(CH), 128.1 (2CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.6 (2CH),
127.5 (CH), 126.9 (CH), 117.4 (CH2]CH), 114.0 (CH), 113.8 (CH), 81.0
(CH), 75.7 (CH), 73.8 (CH2), 73.5 (CH2), 66.1 (CH2), 65.2 (CH), 58.2
(CH), 55.2 (CH3), 49.9 (CH2); HRMS (ESIþ) m/z calcd for
4.2.3. tert-Butyl benzoyl((3S,4R,5S,6S)-4,5,7-tris(benzyloxy)-6-
(tert-butyldimethylsilyloxy)hept-1-en-3-yl)carbamate (10)
4.2.3.1. Protection with TBSCl. A solution of 9 (0.230 g, 0.417 mmol),
imidazole (0.057 g, 0.834 mmol) and tert-butyldimethylsilyl
chloride (TBSCl) (0.094 g, 0.625 mmol) in DMF (0.5 mL) was stirred
for 12 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 anhydride
Na2SO4, and concentrated in vacuo. The combined organic layers
were washed with brine (5 mL), dried over anhydride Na2SO4, and
concentrated in vacuo. The residue was chromatographed (silica
gel, hexane/EtOAc¼15:1) to give the TBS-ether (0.246 g, 89%) as
a colorless oil. [a]2D7 ꢀ55.6 (c 1.0, CHCl3); IR (NaCl) 2856 (C–H), 1658
(C]O), 1253 (C–O) cmꢀ1; 1H NMR (CDCl3) d 7.77–7.73 (m, 2H, ArH),
7.47–7.43 (m, 3H, ArH), 7.28–7.22 (m, 15H, ArH), 6.77 (d, J¼9.0 Hz,
1H, NH), 5.95 (ddd, J¼16.7, 10.4, 5.0 Hz, 1H, CH2]CH), 5.26–
5.22 (m, 2H, CH2]CH), 4.95 (m, 1H, CH), 4.77 (dd, J¼10.8 Hz, 1H,
PhCH2), 4.75 (dd, J¼11.6 Hz, 1H, PhCH2), 4.64 (dd, J¼10.8 Hz,
1H, PhCH2), 4.60 (dd, J¼11.6 Hz, 1H, PhCH2), 4.42 (dd, J¼11.9 Hz, 1H,
PhCH2), 4.36 (dd, J¼11.9 Hz, 1H, PhCH2), 4.20 (m, 1H, CH), 4.05 (d,
J¼7.5 Hz, 1H, CH), 3.70 (d, J¼3.0 Hz 1H, CH), 3.65 (dd, J¼9.5, 6.0 Hz,
1H, CH2), 3.42 (dd, J¼9.5, 6.0 Hz, 1H, CH2), 0.91 (s, 9H, 3CH3), 0.10 (d,
J¼7.0 Hz, 6H, CH3); 13C NMR (CDCl3) d 166.8 (C]O), 138.7 (C), 138.3
(2C), 138.2 (C), 136.6 (CH2]CH), 134.5 (2CH), 131.4 (2CH), 128.5
(2CH), 128.3 (2CH), 128.2 (2CH), 128.1 (2CH), 127.7 (2CH), 127.6
(2CH), 127.4 (CH), 127.3 (CH), 127.3 (CH), 127.0 (CH), 115.7
(CH2]CH), 80.8 (CH), 80.7 (CH), 75.1 (CH), 74.5 (CH2), 73.2 (CH),
72.9 (CH2), 71.2 (CH2), 52.6 (CH2), 26.0 (2CH3), 25.6 (CH3), 18.2 (C),
ꢀ3.9 (CH3), ꢀ4.6 (CH3); HRMS (ESIþ) m/z calcd for C41H51NO5-
SiþNa: 688.3434, found 688.3386.
C
36H41NO5þH: 568.3063, found 568.3042.
4.2.2. N-((3S,4R,5R,6S)-4,5,7-Tris(benzyloxy)-6-hydroxyhept-1-en-
3-yl)benzamide (9)
4.2.2.1. Protection with BzCl. To
a
solution of
8
(1.663 g,
2.929 mmol) in CH2Cl2 (2 mL) was added a solution of benzoyl
chloride (1.323 g, 8.788 mmol) in CH2Cl2 (1 mL) and stirred for 3 h.
Then, the mixture was quenched by the addition of saturated aq
NaHCO3 (5 mL) and extracted with CH2Cl2 (10ꢂ3 mL). The
combined organic extracts were washed with brine (5 mL), dried
over anhydride Na2SO4, and concentrated in vacuo. The residue was
chromatographed (silica gel, hexane/EtOAc¼5:1) to give the MPM-
benzylamide (1.751 g, 89%) as a pale yellow oil. [a]2D8 ꢀ12.3 (c 1.0,
CHCl3); IR (NaCl) 3402 (O–H), 2864 (C–H), 1625 (C]O), 1247
(C–O) cmꢀ1 1H NMR (CDCl3) d 7.40–7.05 (m, 22H, ArH), 6.81–6.77
;
(m, 2H, ArH), 6.48 (m, 1H, CH), 5.78 (m, 1H, CH2]CH), 5.18–3.90 (m,
12H, CH2]CH, 4PhCH2 and 3CH), 3.77 (s, 3H, CH3), 3.78–3.48 (m,
3H, CH2 and CH), 2.65 (m, 1H, OH); 13C NMR (CDCl3) d 168.8 (C]O),
158.8 (C), 138.3 (CH2]CH), 138.0 (C), 137.2 (C), 134.5 (C), 129.4 (CH),
129.1 (CH), 128.4 (2CH), 128.3 (2CH), 128.0 (3CH), 127.9 (2CH), 127.8
(CH), 127.7 (2CH), 127.6 (2CH), 127.5 (2CH), 127.8 (3CH), 127.7 (2CH),
126.7 (CH), 126.9 (CH), 119.5 (CH2]CH), 113.7 (CH), 79.4 (CH), 77.3
(CH), 74.6 (CH2), 74.1 (CH2), 73.3 (CH2), 71.4 (CH2), 70.0 (CH), 62.6
(CH), 55.2 (CH3), 54.3 (CH2); HRMS (ESIþ) m/z calcd for
4.2.3.2. Protection with (Boc)2O. A solution of the above TBS-ether
(0.371 g, 0.557 mmol), Et3N (0.564 g, 5.571 mmol), (Boc)2O
(0.608 g, 2.786 mmol), and DMAP (0.340 g, 2.786 mmol) was stir-
red for 12 h. It was quenched by the addition of water (5 mL) and
extracted with ethyl acetate (10ꢂ3 mL). The combined organic
layers were washed with brine (5 mL), dried over anhydride
C
43H45NO6þNa: 694.3145, found 694.3131.

5258
M. Takahashi et al. / Tetrahedron 64 (2008) 5254–5261
Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, hexane/EtOAc¼20:1) to give 10
(0.392 g, 92%) as a viscous oil. [a]2D4 þ14.9 (c 0.8, CHCl3); IR (NaCl)
18.2 (C), ꢀ4.2 (CH3), ꢀ4.4 (CH3); 13C NMR (CDCl3) d (minor iso-
mer) 157.2 (C]O), 138.6 (C), 138.5 (C), 138.4 (C), 128.4 (3CH),
128.3 (3CH), 128.2 (3CH), 128.1 (3CH), 127.6 (3CH), 127.4 (2CH),
127.2 (2CH), 80.5 (C), 80.3 (CH), 76.7 (CH), 75.4 (CH), 74.1 (CH2),
72.9 (CH), 71.3 (CH2), 71.4 (CH), 71.0 (CH), 62.6 (CH), 52.3
(CH), 28.1 (CH3), 25.8 (CH3), 17.8 (CH3), ꢀ4.1 (CH3), ꢀ4.6 (CH3);
HRMS (ESIþ) m/z calcd for C39H57NO8SiþNa: 718.3751, found
718.3748.
2858 (C–H), 1732 (C]O), 1674 (C]O), 1252 (C–O) cmꢀ1 1H NMR
;
(CDCl3) d 7.46–7.21 (m, 20H, ArH), 6.19 (m, 1H, CH2]CH), 5.32–5.18
(m, 2H, CH2]CH), 4.79–4.56 (m, 3H, PhCH2 and CH), 4.52–4.46 (m,
2H, PhCH2), 4.43–4.39 (m, 2H, PhCH2), 4.16 (dt, J¼10.9, 2.2 Hz, 1H,
CH), 3.76 (dd, J¼10.9, 2.2 Hz, 1H, CH), 3.67 (dd, J¼1.8, 6.3 Hz, 1H,
CH2), 3.49 (dd, J¼6.3, 9.4 Hz,1H, CH2), 0.98 (s, 9H, 3CH3), 0.92 (s, 9H,
3CH3), 0.04 (s, 6H, 2CH3); 13C NMR (CDCl3) d 173.6 (C]O), 156.3
(C]O), 139.0 (C), 138.7 (2C), 138.6 (C), 136.6 (CH2]CH), 134.5 (CH),
130.9 (2CH), 128.3 (CH), 128.2 (CH), 128.1 (3CH), 128.0 (2CH), 127.9
(2CH), 127.8 (CH), 127.7 (2CH), 127.6 (2CH), 127.5 (2CH), 127.4 (2CH),
127.3 (CH), 127.0 (CH), 120.5 (CH2]CH), 83.9 (CH), 82.8 (CH), 79.5
(C), 73.7 (CH), 73.2 (CH), 72.6 (CH2), 72.5 (CH2), 72.1 (CH2), 27.7
(CH3), 27.2 (CH3), 26.0 (CH3), 25.8 (3CH3), 18.2 (C), ꢀ4.5 (CH3), ꢀ4.7
(CH3); HRMS (ESIþ) m/z calcd for C46H59NO7SiþNa: 788.3959,
found 788.3914.
4.2.5.2. Cleavage and nucleophilic addition. To a solution of the
above diol (0.449 g, 0.645 mmol) in THF (0.9 mL) was added a
solution of sodium periodate (0.690 g, 3.226 mmol) in H2O (0.9 mL)
and stirred for 4 h. The mixture was extracted with ether
(10ꢂ3 mL) and evaporated in vacuo to give the crude aldehyde
(0.428 g) as a yellow oil, which was used without further purifi-
cation. Vinylmagnesium chloride (1.47 M solution in THF, 1.70 mL,
2.581 mmol) was added dropwise at ꢀ78 ꢁC to a solution of the
aldehyde in THF (6 mL) under nitrogen and the reaction mixture
was stirred for 3 h. It was quenched by the addition of saturated
NH4Cl (5 mL) and extracted with ethyl acetate (10ꢂ3 mL). The
combined organic extracts were washed with brine (5 mL), dried
over anhydride Na2SO4, and concentrated to give the crude amino
alcohol, which was purified by column chromatography (silica gel,
hexane/EtOAc¼9:1) to give 12a (0.424 g, 95%) as a colorless oil.
[a]2D4 ꢀ3.1 (c 1.0, CHCl3); IR (NaCl) 3443 (O–H), 1713 (C]O), 1253
(C–O) cmꢀ1; 1H NMR (CDCl3) d 7.29–7.25 (m, 15H, ArH), 5.79 (m, 1H,
CH2]CH), 5.22–5.18 (m, 3H, CH2]CH and CH), 4.85 (d, J¼10.8 Hz,
1H, PhCH2), 4.71 (d, J¼11.1 Hz, 1H, PhCH2), 4.60 (d, J¼10.8 Hz,
1H, PhCH2), 4.55 (d, J¼11.1 Hz, 1H, PhCH2), 4.44 (d, J¼12.0 Hz, 1H,
PhCH2), 4.40 (d, J¼12.0 Hz,1H, PhCH2), 4.17 (m, 1H, CH), 4.08 (m,1H,
CH), 3.66–3.60 (m, 2H, CH2 and CH), 3.48 (m, 1H, CH2), 3.35 (m,
4.2.4. tert-Butyl (3S,4R,5S,6S)-4,5,7-tris(benzyloxy)-6-(tert-
butyldimethylsilyloxy)hept-1-en-3-ylcarbamate (11)
A solution of 10 (0.255 g, 0.333 mmol) and 1,1,3,3-tetrame-
thylguanidine (0.383 g, 3.329 mmol) was stirred at 130 ꢁC for 8 h.
After concentration of the reaction mixture in vacuo, column
chromatographic purification (silica gel, hexane/EtOAc¼10:1)
gave 11 (0.216 g, 98%) as a colorless oil. [a]2D7 ꢀ37.1 (c 0.6, CHCl3);
IR (NaCl) 2858 (C–H), 1717 (C]O), 1253 (C–O) cmꢀ1 1H NMR
;
(CDCl3) d 7.30–7.21 (m, 15H, ArH), 5.85 (m, 1H, CH2]CH), 5.27–
5.14 (m, 3H, CH2]CH and CH), 4.78 (d, J¼11.6 Hz, 1H, PhCH2),
4.71 (d, J¼11.6 Hz, 1H, PhCH2), 4.60 (d, J¼10.8 Hz, 1H, PhCH2),
4.55 (d, J¼10.8 Hz, 1H, PhCH2), 4.44 (d, J¼12.0 Hz, 1H, PhCH2),
4.40 (d, J¼12.0 Hz, 1H, PhCH2), 4.11 (m, 1H, CH), 3.89 (d, J¼7.1 Hz,
1H, CH), 3.66 (dd, J¼7.8, 2.8 Hz, 1H, CH), 3.60 (m, 1H, CH2), 3.42
(dd, J¼9.5, 6.0 Hz, 1H, CH2), 1.41 (s, 9H, 3CH3), 0.90 (s, 9H, 3CH3),
0.07 (s, 6H, 2CH3); 13C NMR (CDCl3) d 155.5 (C]O), 139.0 (C),
138.4 (C), 138.3 (C), 137.3 (CH2]CH), 128.2 (3CH), 128.1 (CH),
128.0 (2CH), 127.9 (2CH), 127.8 (2CH), 127.7 (2CH), 127.6 (CH),
127.5 (CH), 127.3 (CH), 115.2 (CH2]CH), 81.0 (CH), 80.4 (C), 79.3
(CH2), 77.2 (CH), 75.2 (CH), 74.5 (CH), 72.9 (CH2), 71.3 (CH2), 53.4
(CH2), 28.4 (3CH3), 26.0 (3CH3), 18.2 (C), ꢀ3.9 (CH3), ꢀ4.6 (CH3);
HRMS (ESIþ) m/z calcd for C39H55NO6SiþNa: 684.3696, found
684.3650.
1H, CH), 1.61 (s, 9H, 3CH3), 0.91 (s, 9H, 3CH3), 0.07 (s, 6H, 2CH3); 13
C
NMR (CDCl3) d 155.7 (C]O), 138.9 (C), 138.6 (C), 138.4 (C), 135.5
(CH2]CH), 128.3 (2CH), 128.2 (2CH), 128.1 (2CH), 128.0 (2CH), 127.9
(2CH), 127.6 (3CH), 127.3 (CH), 127.2 (CH), 119.7 (CH2]CH), 80.4 (C),
80.1 (CH), 78.2 (CH), 76.8 (CH), 74.2 (CH), 73.9 (CH2), 72.9 (CH2), 71.5
(CH2), 54.5 (CH2), 28.4 (3CH3), 28.3 (3CH3),18.3 (C), ꢀ3.9 (CH3), ꢀ4.6
(CH3); HRMS (ESIþ) m/z calcd for C40H57NO7SiþNa: 714.3802, found
714.3798.
4.2.6. tert-Butyl (3S,4S,5R,6R,7S)-5,6,8-tris(benzyloxy)-7-hydroxy-
3-(methoxymethoxy)oct-1-en-4-ylcarbamate (13a)
4.2.5. tert-Butyl (3S,4S,5R,6S,7S)-5,6,8-tris(benzyloxy)-7-(tert-
butyldimethylsilyloxy)-3-hydroxyoct-1-en-4-ylcarbamate (12a)
To a solution of 12a (0.151 g, 0.218 mmol) in N,N-diisopropyl-
ethylamine (0.2 mL) was added chloromethyl methyl ether
(0.035 g, 0.102 mmol) and stirred for 12 h. It was quenched by the
addition of water (5 mL) and extracted with ethyl acetate
(10ꢂ3 mL). The combined organic layers were washed with brine
(5 mL), dried over anhydride Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
hexane/EtOAc¼9:1) to give the MOM-ether 13a (0.160 g, quant.) as
a viscous oil. [a]2D7 ꢀ26.0 (c 0.8, CHCl3); IR (NaCl) 1713 (C]O), 1253
(C–O) cmꢀ1; 1H NMR (CDCl3) d 7.29–7.20 (m, 15H, ArH), 5.73 (m, 1H,
CH2]CH), 5.27–5.17 (m, 2H, CH2]CH), 5.04 (d, J¼10.0 Hz, 1H, CH2),
4.83 (d, J¼10.7 Hz, 1H, PhCH2), 4.74 (d, J¼11.8 Hz, 1H, PhCH2), 4.66
(d, J¼6.7 Hz, 1H, PhCH2), 4.61 (d, J¼11.8 Hz, 1H, PhCH2), 4.54
(d, J¼6.7 Hz, 1H, PhCH2), 4.45 (d, J¼10.7 Hz, 1H, PhCH2), 4.38 (d,
J¼10.0 Hz, 1H, CH2), 4.13–4.09 (m, 2H, 2CH), 3.98 (d, J¼7.7 Hz, 1H,
CH), 3.91 (d, J¼7.7 Hz, 1H, CH), 3.71 (dd, J¼7.7, 3.5 Hz, 1H, CH),
3.55–3.50 (m, 2H, CH2), 3.34 (s, 3H, CH3), 1.44 (s, 9H, 3CH3), 0.90 (s,
9H, 3CH3), 0.07 (d, J¼2.9 Hz, 6H, 2CH3); 13C NMR (CDCl3) d 155.7
(C]O), 138.9 (C), 138.6 (C), 138.4 (C), 135.5 (CH2]CH), 128.3 (2CH),
128.2 (3CH), 128.1 (2CH), 127.9 (2CH), 127.6 (2CH), 127.3 (CH), 127.2
(CH), 127.1 (CH), 127.0 (CH), 119.7 (CH2]CH), 93.8 (CH2), 80.2 (C),
80.0 (CH), 78.2 (CH), 76.8 (CH), 74.2 (CH), 73.9 (CH2), 72.9 (CH), 71.5
(CH2), 71.4 (CH2), 55.6 (CH3), 54.5 (CH2), 28.4 (3CH3), 28.3 (3CH3),
4.2.5.1. Dihydroxylation. To a solution of 11 (0.147 g, 0.222 mmol)
and 4-methylmorpholine N-oxide (50 wt % in H2O, 0.039 g,
0.333 mmol) in acetone (0.5 mL) was added OsO4 (0.05 M in THF,
0.06 mL, 0.003 mmol) and stirred for 12 h. Evaporation of the
volatiles gave a crude mixture, which was chromatographed
(silica gel, hexane/EtOAc¼7:3) to give the diol (0.145 g, 94%) as
a colorless oil (2.3:1 diastereomer mixture determined by 1H
NMR). IR (NaCl) 3441 (O–H), 3031 (C–H), 2858 (C–H), 1713
(C]O), 1253 (C–O) cmꢀ1 1H NMR (CDCl3) d 7.32–7.22 (m, 15H,
;
ArH), 5.22 (d, J¼9.0 Hz, 1H, NH), 4.86 (d, J¼10.8 Hz, 1H, PhCH2),
4.81 (d, J¼11.7 Hz, 1H, PhCH2), 4.62 (d, J¼11.7 Hz, 1H, PhCH2), 4.61
(d, J¼10.8 Hz, 1H, PhCH2), 4.46 (d, J¼11.9 Hz, 1H, PhCH2), 4.41 (d,
J¼11.9 Hz, 1H, PhCH2), 4.34 (d, J¼8.1 Hz, 1H, CH), 3.97 (m, 1H, CH),
3.72–3.60 (m, 5H, 2CH2 and CH), 3.50–3.48 (m, 2H, CH2), 2.39 (d,
J¼9.9 Hz, 1H, OH),1.39 (s, 9H, 3CH3), 0.90 (s, 9H, 3CH3), 0.06 (s,
6H, 2CH3); 13C NMR (CDCl3) d (major isomer) 157.2 (C]O), 138.9
(C), 138.5 (C), 138.3 (C), 128.4 (2CH), 128.3 (2CH), 128.2 (3CH),
128.1 (2CH), 127.7 (2CH), 127.5 (2CH), 127.3 (2CH), 80.7 (CH), 80.4
(C), 76.8 (CH2), 75.4 (CH), 74.3 (CH2), 73.0 (CH), 71.5 (CH2), 71.4
(CH), 71.1 (CH), 62.6 (CH), 52.5 (CH), 28.2 (3CH3), 26.0 (3CH3),

M. Takahashi et al. / Tetrahedron 64 (2008) 5254–5261
5259
18.3 (C), ꢀ3.9 (CH3), ꢀ4.4 (CH3); HRMS (ESIþ) m/z calcd for
4.2.8. (2R,3R,4R,5S)-tert-Butyl 3,4-bis(benzyloxy)-2-(benzyl-
oxymethyl)-5-((S)-3-hydroxy-1-(methoxymethoxy)-
propyl)pyrrolidine-1-carboxylate (15a)
C
42H61NO8SiþNa: 758.4064, found 758.4007.
4.2.7. (2R,3R,4R,5S)-tert-Butyl 3,4-bis(benzyloxy)-2-(benzyl-
oxymethyl)-5-((S)-1-(methoxymethoxy)allyl)pyrrolidine-1-
carboxylate (14a)
To a solution of 14a (0.863 g, 1.430 mmol) in THF (1.8 mL) was
added 9-BBN (0.5 M solution in THF, 5.7 mL, 2.85 mmol) under
nitrogen at 0 ꢁC and stirred for 12 h at room temperature. After the
mixture was quenched by the addition of H2O (0.2 mL), a solution
of 3 N aq NaOH (1.5 mL) and hydrogen peroxide solution (34.5 wt %
in H2O, 1.5 mL) was added dropwise at 0 ꢁC and stirred for further
4 h at room temperature. The mixture was quenched by the addi-
tion of water (5 mL) and extracted with ethyl acetate (20ꢂ3 mL).
The combined organic layers were washed with brine (10 mL),
dried over anhydride Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, hexane/
EtOAc¼5:1) to give the primary alcohol 15a (0.834 g, 94%) as a
viscous oil. [a]2D2 ꢀ7.0 (c 1.0, CHCl3); IR (NaCl) 3586 (O–H), 1693
4.2.7.1. Deprotection of TBSCl. To
a solution of 13a (1.285 g,
1.747 mmol) in THF (43.6 mL) was added tetrabutylammonium
fluoride (1.0 M solution in THF, 3.5 mL, 3.5 mmol) and stirred for 3 h.
The mixture was quenched by the addition of saturated NaHCO3
(5 mL) and extracted with ethyl acetate (20ꢂ3 mL). The combined
organic extracts were washed with brine (20 mL), dried over anhy-
dride Na2SO4, and concentrated to give the crude alcohol, which was
purified by column chromatography (silica gel, hexane/EtOAc¼3:1)
to give the alcohol (1.063 g, 98%) as a white solid; mp 86.3–87.0 ꢁC.
[a]2D7 ꢀ30.9 (c 1.0, CHCl3); IR (KBr) 3412 (O–H), 1715 (C]O), 1167 (C–
(C]O) cmꢀ1 1H NMR (CDCl3) d 7.39–7.22 (m, 15H, ArH), 4.75 (d,
;
O) cmꢀ1
;
1H NMR (CDCl3) d 7.29–7.20 (m, 15H, ArH), 5.73 (m, 1H,
J¼11.6 Hz, 1H, PhCH2), 4.69 (d, J¼10.1 Hz, 1H, PhCH2), 4.64
(d, J¼10.1 Hz, 1H, PhCH2), 4.59 (d, J¼11.6 Hz, 1H, PhCH2), 4.49 (d,
J¼12.3 Hz, 1H, PhCH2), 4.45 (d, J¼12.3 Hz, 1H, PhCH2), 4.43–4.39 (m,
2H, CH2), 4.15 (d, J¼2.0 Hz,1H, CH), 4.11–3.96 (m, 2H, CH), 3.88–3.86
(m, 2H, CH2), 3.76 (d, J¼9.3 Hz, 1H, CH), 3.68–3.64 (m, 2H, CH2), 3.25
(s, 3H, CH3), 2.83 (br, 1H, OH), 2.04–1.64 (m, 2H, CH2), 1.42 (s, 9H,
3CH3); 13C NMR (CDCl3) d 155.7 (C]O), 138.4 (2C), 137.6 (C), 128.3
(3CH), 128.2 (2CH), 128.1 (2CH), 128.0 (2CH), 127.7 (3CH), 127.5
(2CH), 127.3 (CH), 97.1 (CH2), 83.1 (CH2), 80.4 (C), 76.1 (CH), 75.3
(CH), 73.0 (CH2), 72.9 (CH), 72.7 (CH2), 72.2 (CH), 71.0 (CH2), 60.1
(CH2), 59.7 (CH2), 55.9 (CH3), 34.4 (CH2), 28.2 (3CH3); HRMS (ESIþ)
m/z calcd for C36H47NO8þNa: 644.3199, found 644.3198.
CH2]CH), 5.27–5.17 (m, 2H, CH2]CH), 5.03 (d, J¼10.0 Hz, 1H,
CH2), 4.82 (d, J¼10.8 Hz, 1H, PhCH2), 4.76 (d, J¼11.2 Hz, 1H, PhCH2),
4.67 (d, J¼6.8 Hz, 1H, PhCH2), 4.61 (d, J¼11.2 Hz, 1H, PhCH2), 4.56 (d,
J¼6.8 Hz, 1H, PhCH2), 4.48 (d, J¼10.8 Hz, 1H, PhCH2), 4.45 (d,
J¼10.0 Hz, 1H, CH2), 4.11 (m, 1H, CH), 3.99–3.95 (m, 3H, 3CH), 3.69
(dd, J¼8.0, 1.8 Hz, 1H, CH), 3.55 (m, 1H, CH2), 3.40 (m, 1H, CH2), 3.37
(s, 3H, CH3), 2.49 (d, J¼9.0 Hz, 1H, OH), 1.40 (s, 9H, 3CH3); 13C NMR
(CDCl3) d 156.0 (C]O), 138.4 (C), 138.1 (C), 138.0 (C), 135.3
(CH2]CH), 128.4 (CH), 128.3 (2CH), 128.2 (3CH), 127.8 (2CH), 127.7
(2CH), 127.6 (2CH), 127.5 (CH), 127.4 (CH), 127.3 (CH), 119.8
(CH2]CH), 93.9 (CH2), 80.3 (C), 79.9 (CH), 79.0 (CH), 78.1 (CH), 74.7
(CH2), 74.1 (CH2), 73.1 (CH), 71.4 (CH), 69.3 (CH2), 55.6 (CH3), 54.1
(CH2), 28.4 (3CH3); HRMS (ESIþ) m/z calcd for C36H47NO8þNa:
644.3199, found 644.3177. Anal. Calcd for C36H47NO8: C, 69.54; H,
7.62; N, 2.25. Found: C, 69.48; H, 7.57; N, 2.32.
4.2.9. (1S,5R,6R,7R,7aS)-6,7-Bis(benzyloxy)-5-(benzyloxy-
methyl)hexahydro-1H-pyrrolizin-1-ol (16a)
To a solution of 15a (0.070 g, 0.112 mmol) and Et3N (0.023 g,
0.224 mmol) in CH2Cl2 (1.1 mL) was added methanesulfonyl chlo-
ride (0.020 g, 0.168 mmol) and stirred for 1 h. The mixture was
quenched by the addition of 0.5% aq HCl (3 mL) and extracted with
CH2Cl2 (10ꢂ3 mL). The combined organic extracts were washed
with brine (5 mL), dried over anhydride Na2SO4, and concentrated
to give the crude mesylate (0.079 g), which was used without fur-
ther purification. To a solution of this mesylate in CH2Cl2 (1.5 mL)
was added 0.5 mL of BF3$OEt2/CH2Cl2 (1:3) solution at ꢀ20 ꢁC and
warmed to 0 ꢁC. After the mixture was stirred for 3 h, it was
quenched by the addition of saturated aq NaHCO3 (1 mL) and
stirred for additional 2 h. It was diluted with water (5 mL) and
extracted with CH2Cl2 (10ꢂ3 mL). The combined organic extracts
were washed with brine (5 mL), dried over anhydride Na2SO4, and
concentrated in vacuo. The residue was chromatographed (silica
gel, chloroform/MeOH¼5:1) to give 16a (0.043 g, 84%) as a pale
yellow oil. [a]2D2 ꢀ1.9 (c 1.0, CHCl3); IR (NaCl) 3582 (O–H), 2863
4.2.7.2. Mesylation and cyclization. To a solution of the above al-
cohol (1.063 g, 1.710 mmol) and Et3N (0.346 g, 3.420 mmol) in
CH2Cl2 (8.6 mL) was added methanesulfonyl chloride (0.300 g,
2.621 mmol) and stirred for 12 h. The mixture was quenched by the
addition of 0.5% aq HCl (3 mL) and extracted with CH2Cl2
(20ꢂ3 mL). The combined organic extracts were washed with brine
(20 mL), dried over anhydride Na2SO4, and concentrated to give the
crude mesylate (1.197 g), which was not purified further. A solution
of this mesylate in THF (5.0 mL) was added dropwise at 0 ꢁC to
a suspension of t-BuOK (0.294 g, 2.621 mmol) in THF (1.0 mL) under
nitrogen and gradually warmed to room temperature. After the
mixture was stirred for 12 h, it was quenched by the addition of
H2O (5 mL) and extracted with ethyl acetate (10ꢂ3 mL). The com-
bined organic extracts were washed with brine (5 mL), dried over
anhydride Na2SO4, and concentrated in vacuo. The crude product
was purified by column chromatography (silica gel, hexane/
EtOAc¼9:1) to give 14a (0.863 g, 84%) as a colorless oil. [a]2D6 ꢀ51.8
(C–H), 1693 (C]O) cmꢀ1 1H NMR (CDCl3) d 7.39–7.22 (m, 15H,
;
ArH), 4.72–4.20 (m, 7H, 3PhCH2 and CH), 3.89–3.56 (m, 4H, CH2 and
2CH), 1.87–1.67 (m, 3H, CH2 and CH), 1.33–1.26 (m, 4H, CH2 and
2CH); 13C NMR (CDCl3) d 138.4 (C), 137.6 (C), 137.5 (C), 128.5 (2CH),
128.4 (2CH), 128.3 (3CH), 128.1 (2CH), 127.9 (2CH), 127.5 (2CH),
127.2 (2CH), 83.2 (CH), 81.0 (CH), 77.6 (CH), 77.2 (CH), 73.0 (CH2),
72.9 (CH2), 72.7 (CH2), 72.2 (CH), 71.0 (CH2), 68.3 (CH2), 37.2 (CH2);
HRMS (ESIþ) m/z calcd for C29H33NO4þH: 460.2488, found
460.2481.
(c 1.0, CHCl3); IR (NaCl) 2858 (C–H), 1713 (C]O), 1217 (C–O) cmꢀ1
;
1H NMR (CDCl3) d 7.34–7.22 (m, 15H, ArH), 5.73 (m, 1H, CH2]CH),
5.20–5.14 (m, 2H, CH2]CH), 4.76 (d, J¼11.8 Hz, 1H, PhCH2), 4.65 (d,
J¼11.8 Hz, 1H, PhCH2), 4.57 (d, J¼9.4 Hz, 1H, PhCH2), 4.54
(d, J¼15.8 Hz, 1H, PhCH2), 4.49 (d, J¼15.8 Hz, 1H, PhCH2), 4.44 (d,
J¼9.3 Hz, 1H, CH), 4.36 (d, J¼9.4 Hz, 1H, PhCH2), 4.28–4.24 (m, 2H,
CH), 4.02 (m, 1H, CH), 3.90 (m, 1H, CH), 3.76 (d, J¼9.3 Hz, 1H, CH),
3.74 (m, 1H, CH), 3.20 (s, 3H, CH3), 1.42 (s, 9H, 3CH3); 13C NMR
(CDCl3) d 154.9 (C]O), 138.6 (C), 136.0 (C), 135.5 (C), 128.3
(CH2]CH), 128.2 (CH), 128.1 (3CH), 128.0 (3CH), 127.8 (2CH), 127.7
(2CH), 127.6 (CH), 127.5 (CH), 127.4 (CH), 127.3 (CH), 117.8
(CH2]CH), 86.2 (CH), 83.3 (CH2), 80.4 (C), 75.3 (CH), 73.1 (CH), 72.0
(CH), 71.1 (CH), 61.1 (CH2), 60.1 (CH2), 59.7 (CH2), 55.6 (CH3), 54.1
(CH2), 28.2 (3CH3); HRMS (ESIþ) m/z calcd for C36H45NO7þNa:
626.3094, found 626.3102.
4.2.10. (1R,2R,3R,7S,7aS)-3-(Hydroxymethyl)hexahydro-1H-
pyrrolizine-1,2,7-triol (7-epi-alexine) (1a)
To a solution of 16a (0.043 g, 0.0936 mmol) and ammonium
formate (0.006 g, 0.150 mmol) in MeOH (1.0 mL) was added 10% Pd
on carbon (0.15 g) and refluxed for 2 h. The mixture was filtered
through a pad of Celite with MeOH and concentrated. Finally, the
water solution of the crude product was passed through Dowex

5260
M. Takahashi et al. / Tetrahedron 64 (2008) 5254–5261
50WX-8 (Hþ form), which was first eluted with water (20 mL), and
then with 0.7 M NH4OH (20 mL) followed by 1.4 M NH4OH (10 mL).
Alkaline fractions were concentrated in vacuo to give 1a (0.014 g,
82%) as a syrup. The spectral data of synthetic 1a thus obtained were
identical in all respects with those of the previously synthesized
compound.4b [a]D23 ꢀ11.0 (c 1.0, H2O) {lit. [a]D20 ꢀ10.6 (c 0.56, H2O)};4b
IR (NaCl) 3427 (O–H), 2862 (C–H) cmꢀ1; 1H NMR (D2O) d 4.38 (br,1H,
CH), 4.13 (t, J¼8.0 Hz, 1H, CH), 3.87–3.76 (m, 3H, CH2 and CH), 3.38
(dd, J¼3.7, 8.5 Hz, 1H, CH), 3.08 (m, 1H, CH), 2.88–2.86 (m, 2H, CH),
1.79–1.77 (m, 2H, CH); 13C NMR (D2O) d, 77.5 (CH), 75.3 (CH), 72.3
(CH), 67.0 (CH), 64.2 (CH), 59.2 (CH2), 46.7 (CH2), 34.2 (CH2); HRMS
(ESIþ) m/z calcd for C8H15NO4þH: 190.1079, found 190.1075.
4.2.12.2. Protection with MOMCl. To a solution of the above mixture
(0.035 g, 0.0507 mmol) in N,N-diisopropylethylamine (0.2 mL) was
added chloromethyl methyl ether (0.008 g, 0.102 mmol) and stirred
for 12 h. It was quenched by the addition of water (5 mL) and
extracted with ethyl acetate (10ꢂ3 mL). The combined organic
layers were washed with brine (5 mL), dried over anhydride Na2SO4,
and concentrated in vacuo. The crude products of two diastereomers
were separated by column chromatography (silica gel, hexane/
EtOAc¼9:1) to give 13a (0.002 g, 4%, Rf¼0.45, hexane/EtOAc¼5:1)
and 13b (0.036 g, 96%, Rf¼0.60, hexane/EtOAc¼5:1) as a viscous oil,
respectively. Compound 13a: see Section 4.2.6. Compound 13b: [a]D24
þ15.6 (c 0.7, CHCl3); IR (NaCl) 2872 (C–H), 1713 (C]O), 1217 (C–
O) cmꢀ1 1H NMR (CDCl3) d 7.34–7.26 (m, 15H, ArH), 5.76 (m, 1H,
;
4.2.11. tert-Butyl (4R,5R,6S,7S)-5,6,8-tris(benzyloxy)-7-(tert-
butyldimethylsilyloxy)-3-oxooct-1-en-4-ylcarbamate (17)
CH2]CH), 5.28–5.24 (m, 2H, CH2]CH), 5.04 (d, J¼13.2 Hz,1H, CH2),
4.83 (d, J¼10.8 Hz 1H, PhCH2), 4.74 (d, J¼11.8 Hz, 1H, PhCH2), 4.66
(d, J¼6.7 Hz, 1H, PhCH2), 4.61 (d, J¼11.8 Hz, 1H, PhCH2), 4.54 (d,
J¼6.7 Hz, 1H, PhCH2), 4.45 (d, J¼10.7 Hz, 1H, PhCH2), 4.38 (d,
J¼10.0 Hz,1H, CH2), 4.13–4.09 (m, 2H, CH), 3.98 (d, J¼7.7 Hz,1H, CH),
3.91 (d, J¼7.7 Hz, 1H, CH), 3.71 (dd, J¼7.7, 3.5 Hz, 1H, CH), 3.55–3.51
(m, 2H, CH2), 3.34 (s, 3H, CH3), 1.44 (s, 9H, 3CH3), 0.90 (s, 9H, 3CH3),
0.07 (d, J¼2.9 Hz, 6H, 2CH3); 13C NMR (CDCl3) d 155.5 (C]O), 139.2
(C), 138.9 (C), 138.4 (C), 136.3 (CH2]CH), 128.5 (2CH), 128.3 (2CH),
128.2 (2CH), 128.1 (2CH), 127.8 (2CH), 127.6 (2CH), 127.5 (CH), 127.3
(CH), 127.2 (CH), 119.7 (CH2]CH), 86.5 (CH2), 80.6 (C), 79.1 (CH2),
77.2 (CH), 77.0 (CH), 74.7 (CH), 74.4 (CH), 72.8 (CH), 71.1 (CH2), 71.0
(CH2), 56.1 (CH3), 54.0 (CH2), 28.4 (3CH3), 26.1 (3CH3), 18.2 (C), ꢀ3.9
(CH3), ꢀ4.5 (CH3); HRMS (ESIþ) m/z calcd for C42H61NO8SiþNa:
758.4064, found 758.4018.
To a solution of 12a (0.010 g, 0.0145 mmol), molecular sieves
(4 Å, 0.002 g) and NMO (97%, 0.003 g, 0.0216 mmol) in CH2Cl2
(0.20 mL) was added TPAP (0.002 g, 0.00569 mol) and stirred for
12 h. The mixture was filtered through a pad of Celite with CH2Cl2
and concentrated. The residue was chromatographed (silica gel,
hexane/EtOAc¼20:1) to give 17 (0.009 g, 92%) as a colorless oil.
[a]2D5 ꢀ14.0 (c 0.4, CDCl3); IR (NaCl) 3032 (C–H), 2961 (C–H), 1717
(C]O), 1658 (ArH), 1614 (C]O), 1254 (C–O) cmꢀ1; 1H NMR (CDCl3)
d 7.29–7.21 (m, 15H, ArH), 6.62 (dd, J¼17.2, 10.4 Hz, 1H, CH2]CH),
6.11 (d, 1H, J¼17.2 Hz, CH2]CH), 5.70 (d, J¼7.0 Hz, 1H, NH), 4.70 (d,
J¼11.0 Hz, 1H, PhCH2), 4.65 (d, J¼3.0 Hz, 1H, CH), 4.61 (d, J¼11.0 Hz,
1H, PhCH2), 4.37–4.35 (m, 3H, PhCH2), 4.25 (t, J¼3.0 Hz, 1H, CH2),
4.02 (m, 1H, CH), 3.79 (dd, J¼10.1, 3.1 Hz, 1H, CH2), 3.48 (t, J¼4.2 Hz,
1H, CH), 3.35 (dd, J¼11.0, 7.0 Hz, 1H, CH2), 1.44 (s, 9H, 3CH3), 0.88 (s,
9H, 3CH3), 0.03 (d, J¼1.1 Hz, 6H, 2CH3); 13C NMR (CDCl3) d 197.6
(C]O), 152.8 (C]O), 139.2 (C), 138.9 (C), 138.4 (C), 135.3 (CH2]CH),
128.8 (2CH), 128.5 (CH), 128.3 (CH), 128.2 (2CH), 128.1 (CH), 128.0
(2CH), 127.8 (CH), 127.6 (2CH), 127.5 (CH), 127.3 (CH), 127.2 (CH),
119.7 (CH2]CH), 86.5 (CH), 80.6 (C), 77.2 (CH), 77.0 (CH), 74.7 (CH),
72.8 (CH2), 71.0 (CH2), 56.1 (CH2), 54.0 (CH2), 28.4 (3CH3), 26.1
(3CH3), 18.2 (C), ꢀ4.3 (CH3), ꢀ4.5 (CH3); HRMS (ESIþ) m/z calcd for
The same procedure gave the desilylated compound, pyrrolizi-
dines 14b, 15b, 16b, and (þ)-alexine (1b) from the corresponding
MOM-ether 13b (yields are given in Scheme 3). The spectral data of
synthetic 1b thus obtained were identical in all respects with those
of the natural4a and synthesized compound.4b
4.2.12.2.1. Desilylated compound of 13b. [a]2D5 þ6.5 (c 0.3, CHCl3);
IR (NaCl) 3412 (O–H), 2872 (C–H),1715 (C]O),1028 (C–O) cmꢀ1; 1H
NMR (CDCl3) d 7.32–7.24 (m,15H, ArH), 5.73 (m,1H, CH2]CH), 5.25–
5.21 (m, 2H, CH2]CH), 5.00 (d, J¼10.0 Hz, 1H, CH2), 4.82 (d,
J¼10.8 Hz, 1H, PhCH2), 4.76 (d, J¼11.2 Hz, 1H, PhCH2), 4.67
(d, J¼6.8 Hz, 1H, PhCH2), 4.61 (d, J¼11.2 Hz, 1H, PhCH2), 4.56 (d,
J¼6.8 Hz, 1H, PhCH2), 4.48 (d, J¼10.8 Hz, 1H, PhCH2), 4.45 (d,
J¼10.0 Hz, 1H, CH2), 4.11 (m, 1H, CH), 4.01–3.93 (m, 3H, 3CH), 3.69
(dd, J¼8.0,1.8 Hz,1H, CH), 3.55 (m,1H, CH2), 3.40(m,1H, CH2), 3.37 (s,
3H, CH3), 2.49 (d, J¼9.0 Hz, 1H, OH), 1.40 (s, 9H, 3CH3); 13C NMR
(CDCl3) d 155.6 (C]O),138.7 (C),138.5 (C),138.1 (C),135.9 (CH2]CH),
128.4 (2CH), 128.3 (3CH), 128.2 (3CH), 128.0 (3CH), 127.9 (CH), 127.7
(CH), 127.6 (CH), 127.5 (CH), 119.6 (CH2]CH), 86.3 (CH2), 80.6 (C),
79.3 (CH), 78.1 (CH), 77.2 (CH), 74.9 (CH), 74.1 (CH), 73.1 (CH2), 71.4
(CH2), 69.2 (CH2), 56.1 (CH3), 53.7 (CH2), 28.3 (3CH3); HRMS (ESIþ)
m/z calcd for C36H47NO8þNa: 644.3199, found 644.3168.
C
40H55NO7SiþNa: 712.3646, found 712.3688.
4.2.12. tert-Butyl (3S,4S,5R,6R,7S)-5,6,8-tris(benzyloxy)-7-hydroxy-
3-(methoxymethoxy)oct-1-en-4-ylcarbamate (13b)
4.2.12.1. Reduction with the Luche reagent. To a solution of 17
(0.010 g, 0.0145 mmol) and powdered CeCl3 heptahydrate (0.016 g,
0.0435 mmol) in MeOH (0.15 mL) was added NaBH4 (0.002 g,
0.0435 mmol) at ꢀ45 ꢁC and stirred for 2 h. It was quenched by the
addition of saturated NaHCO3 (2 mL) and extracted with ethyl
acetate (10ꢂ3 mL). The combined organic extracts were washed
with brine (5 mL), dried over anhydride Na2SO4, and concentrated
in vacuo. The crude product was purified by column chromatog-
raphy (silica gel, hexane/EtOAc¼9:1) to give the diastereomer
mixture of 12 (0.008 g, 80%) as a colorless oil. IR (NaCl) 3443 (O–H),
1713 (C]O), 1253 (C–O) cmꢀ1
;
1H NMR (CDCl3) d (major isomer)
4.2.12.2.2. Compound 14b. [a]2D4 ꢀ13.7 (c 0.5, CHCl3); IR (NaCl)
7.29–7.24 (m, 15H, ArH), 5.93 (m, 1H, CH2]CH), 5.26–5.23 (m, 3H,
CH2]CH and CH), 4.85 (d, J¼10.8 Hz, 1H, PhCH2), 4.71 (d, J¼11.1 Hz,
1H, PhCH2), 4.60 (d, J¼10.8 Hz, 1H, PhCH2), 4.55 (d, J¼11.1 Hz, 1H,
PhCH2), 4.44 (d, J¼12.0 Hz, 1H, PhCH2), 4.40 (d, J¼12.0 Hz, 1H,
PhCH2), 4.17 (m, 1H, CH), 4.08 (m, 1H, CH), 3.65–3.61 (m, 2H, CH2
and CH), 3.48 (m, 1H, CH2), 3.35 (m, 1H, CH), 1.61 (s, 9H, 3CH3), 0.91
(s, 9H, 3CH3), 0.07 (s, 6H, 2CH3); 13C NMR (CDCl3) d (major isomer)
155.7 (C]O), 138.9 (C), 138.6 (C), 138.4 (C), 135.5 (CH2]CH), 128.3
(2CH), 128.2 (2CH), 128.1 (2CH), 128.0 (2CH), 127.9 (2CH), 127.6
(2CH), 127.3 (2CH), 127.2 (CH), 119.7 (CH2]CH), 80.1 (C), 79.1 (CH2),
78.2 (CH), 77.2 (CH), 74.2 (CH), 72.9 (CH), 71.5 (CH2), 71.4 (CH2), 55.6
(CH2), 54.5 (CH2), 28.4 (3CH3), 28.3 (3CH3),18.3 (C), ꢀ3.9 (CH3), ꢀ4.6
(CH3); HRMS (ESIþ) m/z calcd for C40H57NO7SiþNa: 714.3802, found
714.3772.
2872 (C–H), 1713 (C]O), 1217 (C–O) cmꢀ1 1H NMR (CDCl3)
;
d 7.36–7.01 (m, 15H, ArH), 5.93 (m, 1H, CH2]CH), 5.21–5.14 (m,
2H, CH2]CH), 4.74–4.45 (m, 8H, 3PhCH2 and CH2), 4.37–4.16 (m,
4H, 4CH), 3.91–3.65 (m, 3H, CH2 and CH), 3.24 (s, 3H, CH3), 1.43
(s, 9H, 3CH3); 13C NMR (CDCl3) d 154.6 (C]O), 138.5 (C), 138.3
(C), 138.2 (C), 136.9 (CH2]CH), 128.3 (2CH), 128.0 (3CH), 127.8
(CH), 127.7 (2CH), 127.6 (2CH), 127.5 (2CH), 127.3 (CH), 127.2 (CH),
127.0 (CH), 118.1 (CH2]CH), 94.9 (CH), 86.5 (CH2), 80.2 (C), 77.2
(CH), 76.2 (CH), 74.9 (CH), 73.1 (CH), 73.0 (2CH2), 72.5 (CH2), 60.5
(CH3), 55.8 (CH2), 28.4 (3CH3); HRMS (ESIþ) m/z calcd for
C36H45NO7þNa: 626.3094, found 626.3063.
4.2.12.2.3. Compound 15b. [a]2D5 þ9.4 (c 0.8, CHCl3); IR (NaCl)
3584 (O–H), 2872 (C–H),1693 (C]O) cmꢀ1; 1H NMR (CDCl3) d 7.32–

M. Takahashi et al. / Tetrahedron 64 (2008) 5254–5261
5261
Nash, R. J.; Fellows, L. E.; Kang, M. S.; Tyms, A. S. Antivir. Chem. Chemother. 1992,
3, 273.
8. 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.
7.28 (m, 15H, ArH), 4.68 (d, J¼13.8 Hz, 1H, PhCH2), 4.60 (d,
J¼13.2 Hz, 1H, PhCH2), 4.59 (d, J¼13.8 Hz, 1H, PhCH2), 4.60 (d, J¼
13.2 Hz, 1H, PhCH2), 4.53 (d, J¼11.6 Hz, 1H, PhCH2), 4.51 (d,
J¼11.6 Hz, 1H, PhCH2), 4.49–4.45 (m, 2H, CH2), 4.25 (t, J¼5.1 Hz, 1H,
CH2), 4.15 (m, 1H, CH2), 4.10 (t, J¼6.8 Hz, 1H, CH2), 4.00 (dd, J¼11.1,
7.2 Hz, 1H, CH), 3.66–3.56 (m, 5H, CH2 and 3CH), 3.33 (s, 3H, CH3),
2.83 (br, 1H, OH), 1.91–1.87 (m, 2H, CH2), 1.42 (s, 9H, 3CH3); 13C NMR
(CDCl3) d 154.6 (C]O), 138.5 (C), 138.3 (C), 137.9 (C), 136.9
(CH2]CH), 128.3 (2CH), 128.2 (2CH), 128.1 (CH), 128.0 (CH), 127.9
(CH), 127.8 (3CH), 127.7 (2CH), 127.6 (2CH), 127.5 (CH), 118.1
(CH2]CH), 94.2 (CH), 80.1 (C), 78.8 (CH2), 78.6 (CH2), 77.2 (CH), 73.1
(CH2), 73.0 (CH), 72.5 (CH), 70.1 (CH), 69.1 (CH), 60.5 (CH2), 55.8
(CH2), 37.2 (CH2), 28.4 (3CH3); HRMS (ESIþ) m/z calcd for
9. (a) Tropea, J. E.; Molyneux, R. J.; Kaushal, G. P.; Pan, Y. T.; Mitchell, M.; Elbein, A.
D. Biochemistry 1989, 28, 2027; (b) Winchester, B.; Aldaher, S.; Carpenter, N. C.;
di Bello, I. C.; Choi, S. S.; Fairbanks, A. J.; Fleet, G. W. J. Biochem. J. 1993, 290, 743.
10. 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.
11. 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.
12. Fellows, L. E. Pestic. Sci. 1986, 17, 602.
13. (a) Nash, R. J.; Fellows, L. E.; Girdhar, A.; Fleet, G. W. J.; Peach, J. M.; Ramsden,
N. G.; Hegarty, M. P.; Scofield, A. M. Phytochemistry 1990, 29, 111; (b) Yama-
shita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Fleet, G.
W. J.; Asano, N. J. Nat. Prod. 2002, 65, 1875; (c) Yasuda, K.; Kizu, H.; Yamashita,
T.; Kameda, Y.; Kato, A.; Nash, R. J.; Fleet, G. W. J.; Asano, N. J. Nat. Prod. 2002,
65, 198.
C
36H47NO8þNa: 644.3199, found 644.3235.
4.2.12.2.4. Compound 16b. [a]2D3 þ1.8 (c 0.7, CHCl3); IR (NaCl)
3584 (O–H), 2872 (C–H), 1693 (C]O), 1365 (C–O) cmꢀ1 1H NMR
;
(CDCl3) d 7.39–7.22 (m, 15H, ArH), 4.72–4.20 (m, 7H, 3PhCH2 and
CH), 3.89–3.51 (m, 4H, CH2 and 2CH),1.99–1.95 (m, 3H, CH2 and CH),
1.33–1.26 (m, 4H, CH2 and 2CH); 13C NMR (CDCl3) d 138.4 (C), 137.6
(C), 137.3 (C), 128.5 (2CH), 128.4 (2CH), 128.3 (2CH), 128.2 (3CH),
128.1 (CH), 128.0 (CH), 127.9 (2CH), 127.5 (2CH), 77.6 (CH), 77.2 (CH),
73.0 (CH2), 72.9 (CH2), 72.7 (CH2), 72.2 (CH), 73.0 (CH), 68.3 (CH),
62.7 (CH2), 47.2 (CH2), 37.2 (CH2); HRMS (ESIþ) m/z calcd for
14. Recent syntheses: (a) Choi, S.; Bruce, I.; Fairbanks, A. J.; Fleet, G. W. J.; Jones, A.
H.; Nash, R. J.; Fellows, L. E. Tetrahedron Lett. 1991, 32, 5517; (b) Ikota, N.
Tetrahedron Lett. 1992, 33, 2553; (c) Pearson, W. H.; Hembre, E. J. J. Org. Chem.
1996, 61, 5546; (d) Hall, A.; Meldrum, K. P.; Therond, P. R.; Wightman, R. H.
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C
29H33NO4þH: 460.2488, found 460.2497.
4.2.12.2.5. Alexine (1b). Mp 161.7–163.2 ꢁC; (lit. mp 162–
163 ꢁC);4a [a]2D3 þ40.4 (c 0.3, H2O) {lit. [a]D20 þ40.0 (c 0.25, H2O)};4a
IR (KBr) 3425 (O–H), 2858 (C–H) cmꢀ1; 1H NMR (D2O) d 4.47 (m,1H,
CH), 4.21 (d, J¼6.2 Hz, 1H, CH), 3.77–3.75 (m, 2H, CH2), 3.69 (d, 1H,
J¼6.2 Hz, 1H, CH), 3.55 (dd, J¼8.5, 3.7 Hz, 1H, CH), 3.00–2.96 (m, 3H,
CH), 2.08 (m, 1H, CH), 1.85 (m, 1H, CH); 13C NMR (D2O) d 77.2 (CH),
75.3 (CH), 71.2 (CH), 69.8 (CH), 64.2 (CH), 59.2 (CH2), 45.5 (CH2),
34.8 (CH2); HRMS (ESIþ) m/z calcd for C8H15NO4þH: 190.1079,
found 190.1077.
15. (a) Augestad, I.; Berner, E. Acta Chem. Scand. 1954, 8, 251; (b) Kawana, M.;
Kuzuhara, H.; Emoto, S. Bull. Chem. Soc. Jpn. 1981, 54, 1492.
16. The addition of organometallic compounds to glycosylamines introduced by
Nicotra et al.16a is an efficient and versatile method to obtain functionalized
pyrrolidines. The synthetic applications of this reaction have been demon-
strated both by our group14h,16b,c and by others16d–f for the synthesis of
glycosidase or glycosyltransferase inhibitors. (a) Lay, L.; Nicotra, F.; Paganini, A.;
Pangrazio, C.; Panza, L. Tetrahedron Lett. 1993, 34, 4555; (b) Yoda, H.; Yamazaki,
H.; Kawauchi, M.; Takabe, K. Tetrahedron: Asymmetry 1995, 6, 2669; (c) Yoda, H.;
Asai, F.; Takabe, K. Synlett 2000, 1001; (d) Hashimoto, M.; Terashima, S. Chem.
Lett. 1994, 1001; (e) Behr, J.-B.; Mvondo-Evina, C.; Phung, N.; Guillerm, G.
J. Chem. Soc., Perkin Trans. 1 1997, 1597; (f) Dondoni, A.; Perrone, D. Tetrahedron
Lett. 1999, 40, 9375; The absolute configuration of the newly created
stereogenic center of 8 was easily characterized to be S after derivatization to
the corresponding vinyl lactam 18 as shown below.
Acknowledgements
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.
OBn OH
BnO
Hb
OBn
PCC, MS4A
CH2Cl2
OBn
References and notes
Ha
O
N
NH OBn
1. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645; (b) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199.
2. (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. Plant Nitrogen Metabolism;
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(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.
MPM
8
18
MPM
Ja,b=11.7 Hz
The observed vicinal coupling constant (Ja,b) of protons (Ha,Hb) was 11.7 Hz,
which indicates the lactam 18 occupies the cis-relation.16a,b
17. Initially we investigated the direct pyrrolizidine ring formation employing the N-
benzylated derivative of 15a via the quaternary ammonium salt, however, these
reactions resulted in the formation of a complex mixture including N-mesylated
compounds and gave the desired product 16a in very low yield (10w15%).
18. Determined by 13C NMR analysis. Only trace amounts of minor stereoiso-
mer were detected. The configuration of the newly generated stereocenter
of the product was exactly determined to be R, and hence the obtained
compound was 12a, by comparing its 1H and 13C NMR spectral data with
those of the reported value4b after completion of the synthesis of 7-epi-
alexine 1a.
3. Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J.
Phytochemistry 2001, 56, 265.
4. The first pyrrolizidine alkaloid found with a carbon substituent at C-3. (a)
Isolation: 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; (b)
Synthesis: Fleet, G. W. J.; Haraldsson, M.; Nash, R. J.; Fellows, L. E. Tetrahedron
Lett. 1988, 29, 5441; (c) For a recent review, see: Pyne, S. G.; Tang, M. Curr. Org.
Chem. 2005, 9, 1393.
5. Isolation: Molyneux, R. J.; Benson, M.; Wong, R. Y.; Tropea, J. E.; Elbein, A. D.
J. Nat. Prod. 1988, 51, 1198.
6. Isolation: Nash, R. J.; Thomas, P. I.; Waigh, R. D.; Fleet, G. W. J.; Wormald, M. R.;
Lilley, P. M. D.; Watkin, D. J. Tetrahedron Lett. 1994, 35, 7849.
19. (a) Yoda, H.; Oguchi, T.; Takabe, K. Tetrahedron Lett. 1997, 38, 3283; (b) Yoda, H.;
Kawauchi, M.; Takabe, K. Synlett 1998, 137.
20. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
21. The same type of transition metal halide-promoted six-membered chelating
reactions have been already demonstrated in this laboratory with high
stereoselectivity, see: Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996,
37, 5531.
7. (a) Elbein, A. D.; Tropea, J. E.; Molyneux, R. J. US Pat. Appl. US 289,907, 1989
(Appl. No. US 1988-289907); Chem. Abstr. 1990, 113, 91444 p; (b) Taylor, D. L.;