A flexible approach for the asymmetric syntheses of hyacinthacines A 2, A3 and structural confirmation of hyacinthacine A 3

Article abstract of DOI:10.1039/b926741g

A concise and flexible approach for the asymmetric syntheses of polyhydroxylated pyrrolizidine alkaloids hyacinthacines A₂ and A ₃ has been developed using iterative reductive alkylation of O,O′-dibenzyltartarimide (5) as key steps. The ambiguity about the structure of synthetic hyacinthacine A₃ due to the differences in the NMR data of the synthetic material (2) and the natural product (hyacinthacine A₃) was eliminated jointly by comprehensive 1D and 2D-NMR studies, and by analysis of the ¹H and ¹³C NMR spectra of a mixed synthetic product and natural hyacinthacine A₃. The latter method also allowed a confirmation of the structure of the natural hyacinthacine A ₃, and may be useful for structural confirmation of other hydroxylated alkaloids.

Full text of DOI:10.1039/b926741g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A flexible approach for the asymmetric syntheses of hyacinthacines A2, A3 and
structural confirmation of hyacinthacine A3†
Wen-Jun Liu, Jian-Liang Ye* and Pei-Qiang Huang*
Received 22nd December 2009, Accepted 9th February 2010
First published as an Advance Article on the web 3rd March 2010
DOI: 10.1039/b926741g
A concise and flexible approach for the asymmetric syntheses of polyhydroxylated pyrrolizidine
alkaloids hyacinthacines A2 and A3 has been developed using iterative reductive alkylation of
O,O¢-dibenzyltartarimide (5) as key steps. The ambiguity about the structure of synthetic hyacinthacine
A3 due to the differences in the NMR data of the synthetic material (2) and the natural product
(hyacinthacine A3) was eliminated jointly by comprehensive 1D and 2D-NMR studies, and by analysis
of the 1H and 13C NMR spectra of a mixed synthetic product and natural hyacinthacine A3. The latter
method also allowed a confirmation of the structure of the natural hyacinthacine A3, and may be useful
for structural confirmation of other hydroxylated alkaloids.
australine,4 casuarine,5 uniflorine,6 and hyacinthacines,7–10 the
latter is an expanding group of pyrrolizidine-based iminosugars.
Introduction
Iminosugars (azasugars) are monosaccharide analogues with
nitrogen replacing the ring oxygen. Due to the structural resem-
Since the first isolation of hyacinthacine C1 from hyacinthoides
non-scripta (Hyacinthaceae),7 a number of hyacinthacines have
blance, they are considered as mimics of sugars.1 Most of them
exhibit promising glycosidase or glycosyltransferase inhibitory
activity. Because glycoside cleavage is a biologically widespread
process, glycosidase inhibitors could have many potential applica-
tions as biochemical tools, and therapeutic agents2 such as anti-
HIV, anti-diabetic, and anticancer agents. In the polyhydroxy-
pyrrolizidine class of iminosugars (Fig. 1), such as alexine,3
been isolated.8–10 Among them, hyacinthacines A1, A2 (1), A3 (2)
and B2, were isolated from the bulbs of Muscari armeniacum (Hya-
cinthaceae), which show interesting inhibitory activities against a
variety of glycosidases. For example, hyacinthacine A2 exhibits
selective inhibitory activity against amyloglucosidase Aspergillus
niger with IC50 of 8.6 and 17 mM respectively.7 The important
bioactivities exhibited by these iminosugars and the potential for
developing them as therapeutic agents, as well as the intriguing
structural features make them attractive targets, and a number
of enantioselective synthetic methods have been reported.11–15
A
common structural feature of the abovementioned iminosugars
resides in the presence of a hydroxymethyl substituent at C-3.
The 1,2-trans-diol substructure constitutes an additional feature
of some of them (e.g. australine, alexine, casuarine, uniflorine A,
and hyacinthacines A2, A3, B4, etc.).
Several syntheses of (+)-hyacinthacine A2 (1)12 and a synthesis
of (+)-hyacinthacine A3 (2)13a have been reported, which used
carbohydrates as the starting materials. While this manuscript was
in preparation, Marco and co-workers reported a stereoselective
synthesis of (+)-hyacinthacine A2, and the synthesis of (+)-
hyacinthacine A3 and its 5-epimer (in ca. 1.2 : 1 d.r.) from Garner’s
(R)-aldehyde.16 While the 1H and 13C NMR data of all the
Fig.
alkaloids.
1
Some naturally occurring polyhydroxylated pyrrolizidine
12
synthetic (+)-hyacinthacine A2 matched well with those of the
natural product,7 significant differences existed between those of
(+)-hyacinthacine A3,7,13a,16 which required a verification. As a
continuation of our interest in the synthesis of polyhydroxylated
pyrrolidines,17 we now reported a concise and flexible approach for
the syntheses of (+)-hyacinthacine A2 (1) and (+)-hyacinthacine
A3 (2) using fully protected tartarimide 5 as the chiral building
block, which is easily available from D-tartaric acid. In addition,
a comprehensive structural study by means of both 1D and 2D-
NMR techniques allowed the confirmation of the structures of
both natural and synthetic (+)-hyacinthacine A3.
Department of Chemistry and The Key Laboratory for Chemical Biology
of Fujian Province, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen, Fujian 361005, P. R. China. E-mail: pqhuang@
xmu.edu.cn; Fax: +86-592-2186400; Tel: +86-592-2180992
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of compounds 3a, 10, 1, 13a, 13b, 14, 6, 15a, 2, and natural
hyacinthacine A3 provided by N. Asano. Structural verification and
assignment for compound 2. See DOI: 10.1039/b926741g
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3a. The stereochemistry of 3a was assigned on the basis of
2D NOESY experiments on the known intermediate 10,12d and
was further confirmed by ultimate synthesis of hyacinthacine
A2 (1). The stereochemical outcome of the reductive alkylation
of 4 is consistent with our previous results.17 It is worthy of
mention that under the reaction conditions, beside the reductive
dehydroxylation, both, the N-activating group (Boc)20 and the O-
protecting group (TBS)21 were cleaved in one-pot.
Results and discussion
In view of developing a flexible approach to some of these
iminosugars, and on the basis of our previous results,17 we designed
an iterative reductive alkylation approach, which is outlined
retrosynthetically in Scheme 1.
22
Treatment of the aminol 3a with Ph3P/CCl4/NEt3 in DMF
afforded efficiently the desired cyclic product 10 in 79% yield.
Finally, subjection of 10 to catalytic hydrogenolytic conditions in
acidic medium (H2, 10%Pd/C, HCl, rt) provided hyacinthacine A2
1
(1) in 84% yield. The H and 13C NMR spectra of the synthetic
hyacinthacine A2 (1) matched the reported data.7,12 That the optical
rotation of our synthetic product {[a]2D0 +12.6 (c 1.64, H2O)} more
closely matched those reported for the synthetic materials {[a]D25
+12.5 (c 0.4, H2O);12a [a]D25 +10.5 (c 0.6, H2O);12c [a]2D5 +12.7 (c 0.13,
H2O);12b [a]2D0 +11.2 (c 0.52, H2O);12e [a]D20 +12.1 (c 0.3, H2O)16}
than the natural one ([a]D25 +20.1 (c 0.44, H2O)7} is a phenomenon
previously noted by Denmark and co-workers in their elegant
synthesis of (+)-1-epi-australine.15o
Scheme 1 Retrosynthetic analysis of hyacinthacines A2 and A3.
Having accomplished the synthesis of hyacinthacine A2, we
then turned our attention to the synthesis of hyacinthacine A3
(Scheme 3). For this purpose, but-3-en-1-yl group was selected as
a latent 2-butanon-1-yl group, required for the formation of the
pyrrolizidine ring via a third reductive alkylation.23 Thus treatment
of imide 4 with Grignard reagent 11 (THF, -30 ◦C) followed by re-
ductive dehydroxylation (BF3·OEt2, Et3SiH, CH2Cl2, -78 ◦C ~ rt)
of the tautomeric mixture 12a/12b resulted in the formation of
concomitantly N-Boc cleaved pyrrolidine 13a and its diastereomer
13b in 8 : 1 ratio. Under the Wacker oxidation conditions (O2,
PdCl2, CuCl, DMF–H2O, rt), the carbamate 14, prepared in 89%
yield by treating 13a with CbzCl under basic conditions (K2CO3,
THF–H2O, rt), was converted to methyl ketone 6 in 75% yield.
Subjection of 6 to catalytic hydrogenolytic conditions (H2, 1 atm,
10%Pd/C, MeOH, rt, 12 h)23 led, in one-pot, to the pyrrolizidine
15a and 15b in 8.3 : 1 ratio with a combined yield of 84%. Cleavage
The synthesis of imide 4 from the fully protected tartarimide 5
was described in our previous report,17 in which the stepwise reduc-
tive benzyloxymethylation (the first reductive alkylation) provided
trans-diastereomer 7a in high diastereoselectivity (d.r. = 6.5 : 1)
(Scheme 2). The synthesis of (+)-hyacinthacine A2 was first inves-
tigated, which started with the second reductive alkylation. Thus
treatment of imide 4 with Grignard reagent18 8 in dichloromethane
◦
at -30 C afforded smoothly the adduct 9a and its tautomer 9b
in 73% combined yield with the ring-opening tautomer 9a being
predominant. A partial conversion of 9a to 9b was observed
upon standing 9a at rt. Taking advantage of this tautomerism,
the tautomeric mixture 9a/9b was subjected to boron trifluoride-
mediated reductive dehydroxylation with triethylsilane,19 which
produced the aminols 3a and 3b in 54% combined yield with a
diastereomeric ratio of 7.3 : 1 in favor of the desired diastereomer
Scheme 2 Asymmetric synthesis of hyacinthacine A2.
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Scheme 3 Asymmetric synthesis of hyacinthacine A3.
of the three benzyl groups of the major diastereomer 15a under
acidic catalytic hydrogenolytic conditions (H2, 1 atm, 10%Pd/C,
HCl, MeOH, rt, 4 days) finally furnished hyacinthacine A3 (2) in
88% yield. Although a one-pot transformation of the carbamate 6
to hyacinthacine A3 (2) is plausible,23 the stepwise procedure used
herein allowed an easy separation of the diastereomers (15a/15b).
data of the natural hyacinthacine A3 were in fully agreement with
those previously reported,7 and a minor difference exist in the
two H NMR spectra (cf. Table 1 and Figure 8 in ESI†). When
1
our synthetic compound (2) was mixed with about same amount
1
of the natural hyacinthacine A3, the H and 13C NMR spectra
of the mixed sample showed only one set of peaks (Fig. 2c) that
matched neither with those of the natural product nor with those
of the synthetic compound 2 (especially, in the circle range, Fig. 2)!
Nevertheless, the presence of only one set of peaks in the 1H and 13C
NMR spectra of the mixed synthetic and natural sample provided
evidence that the two compounds are the same.
To further confirm the identity of our product, the method
for the identification of polyhydroxylated pyrrolizidines recently
reported jointly by Nash and Pyne was used.28 Thus the tri-TMS
derivatives of the mixture of the natural hyacinthacine A3 and
synthetic compound were prepared. GC-MS analysis showed only
one peak at the retention time of 4.43 min with a m/z 300([M-
CH2OSiMe3]+) base ion and a m/z 388([M-CH3]+) characteristic
fragment peak on mass spectrum.7,10
1
The H and 13C NMR data of our synthetic hyacinthacine A3
(2) were in agreement with those reported by Marco and co-
workers (DdC ≤ 0.5),16 although some different 13C assignment
(at C3, C5, C8, cf. Table 2 in ESI†) were noted. However, the
magnitude of the optical rotations {[a]2D0 +7.5 (c 0.9, H2O); lit.7
[a]2D5 +19.2 (c 0.43, H2O) for the natural product; [a]2D5 +14 (c
0.55, H2O);13a [a]D25 +15.1 (c 0.35, H2O)16 for synthetic products}
1
were not consistent. In addition, some of the H and 13C NMR
data were not in accordance with those reported for the natural7
1
and another synthetic13a hyacinthacine A3. Furthermore, the H
13a,16
and 13C NMR data of all the synthetic (+)-hyacinthacine A3
did not fully match those of the natural product.7 It is worthy of
note that similar phenomena were also observed in hyacinthacines
A1,14j C3,24 and other polyhydroxylated pyrrolizidines, such as
(+)-crotanecine,25 and (-)-rosmarinecine.26 It was suggested that
the spectral data of polyhydroxylated pyrrolizidines might be
affected by pH, concentration and/or trace of elements exist in
solvents, such as potassium cation.14j,27 Thus, a comprehensive
structural study was undertaken by means of both 1D and 2D-
NMR techniques, and by comparison with an authentic sample.
The 1H-1H COSY combined with HSQC, HMBC and DEPT-
135 techniques were used to determine the complete connectivity
of carbon and hydrogen atoms. All the NMR data (cf. ESI†)
indicated that our synthetic compound (2) has the structure pro-
posed for hyacinthacine A3. The 2D NOESY experiment results
indicated that the stereochemistries at the newly formed chiral
centers at C-5 and C-7a of compound 2 are in accordance with
those proposed for hyacinthacine A3. Finally, the structure was
determined by comparison with a sample of natural hyacinthacine
A3, kindly provided by Dr N. Asano. The re-recorded 13C NMR
Thus the structure of the natural hyacinthacine A3 was con-
firmed, and the structure of our synthetic compound 2 was also
established as hyacinthacine A3. In addition, our method for
confirmation the structure of polyhydroxylated alkaloids was also
validated.
Conclusions
In summary, (+)-hyacinthacine A2 (1) and (+)-hyacinthacine A3
(2) have been synthesized from imide 4, easily available from
the known O,O¢-dibenzyltartarimide 5, in four (overall yield:
26%) and six (overall yield: 27%) steps respectively. The syntheses
demonstrated that the iterative reductive alkylation is a efficient
strategy for flexible and highly stereoselective synthesis of poly-
hydroxylated pyrrolizidines. We also demonstrated that analysis
of NMR spectra of a mixed synthetic product and authentic
sample constitutes a valuable method for the mutual confirmation
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yield, 73%), with the latter being an inseparable mixture of two
diastereomers. This mixture was used in the next step without
further separation.
To a cooled (-78 ◦C) solution of the tautomeric and diastereo-
meric mixture 9a and 9b (799 mg, 1.16 mmol) in anhydrous
CH2Cl2 (10 mL) were added dropwise triethylsilane (2.2 mL,
13.9 mmol) and boron trifluoride etherate (0.23 mL, 4.6 mmol)
◦
under nitrogen atmosphere. After stirring at -78 C for 6 h, the
mixture was allowed to warm up to rt and stirred overnight.
The reaction was quenched with a saturated aqueous sodium
bicarbonate solution and extracted with CH2Cl2 (3 ¥ 20 mL). The
combined extracts were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel
(1,2-dichloroethane/methanol/aq. NH3 = 100/2.5/1) to give two
diastereomers 3a and 3b (208 mg, combined yield, 54%, ratio =
1
7.3 : 1 determined by H NMR). Most of the two diastereomers
can be separated by flash chromatography on silica gel. Major
diastereomer 3a: colorless oil: [a]2D0 18.7 (c 1.4, CHCl3). IR (film):
1
3403, 3303, 3062, 3029, 2861, 1496, 1453, 1363, 1093 cm-1. H
NMR (400 MHz, CDCl3) d 1.53–1.70, 1.70–1.85 (2 m, 4H), 3.11
(dt, J = 4.0, 9.8 Hz, 1H), 3.32 (dd, J = 4.9, 9.9 Hz, 1H), 3.48–3.58
(m, 3H), 3.65 (dt, J = 4.9, 9.7 Hz, 1H), 3.72 (dd, J = 3.1, 4.0 Hz,
1H), 3.95 (dd, J = 3.0, 4.8 Hz, 1H), 4.42–4.58 (m, 6H), 7.18–7.39
(m, 15H, Ar) ppm; 13C NMR (100 MHz, CDCl3) d 30.1, 31.9,
61.7, 62.4, 62.8, 69.2, 71.6, 72.0, 73.2, 86.0, 89.7, 127.6, 127.7,
127.8, 128.4, 138.0 (2C) ppm; MS (ESI, m/z): 462 (M+H+, 100).
Anal. Calcd for C29H35NO4: C, 75.46; H, 7.64; N, 3.03. Found: C,
75.29; H, 7.76; N, 3.17.
Fig. 2 1H and 13C NMR spectra of: a) natural hyacinthacine A3 provided
by N. Asano; b) our synthetic hyacinthacine A3 (2); c) a mixture of the
natural hyacinthacine A3 and synthetic compound.
(1R,2R,3R,7aR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-
hexahydro-1H-pyrrolizine (10)
To a stirring suspension of 3a (150 mg, 0.32 mmol) and PPh3
(171 mg, 0.65 mmol) in dry DMF (3 mL), were added dry CCl4
(0.06 mL, 0.65 mmol) and dry Et3N (0.09 mL, 0.65 mmol). The
mixture was stirred at room temperature for 1 h and then quenched
with MeOH (3 mL). After stirring for 30 min, the solvent was
removed under reduced pressure, and the residue was purified by
flash column chromatography (EtOAc/PE = 1/2, 1/1) to give the
of the structure. Because the ambiguity about the structures of
synthetic compounds frequently encounters in the total synthesis
of hydroxylated alkaloids, our method may be of value in tackling
such kind of problems.
Experimental
◦
known 10 as white crystals. M.p. 48–49 C (EtOAc-P.E.) (lit.12d
◦
m.p. 47.5 C). [a]D20 -2.9 (c 0.7, CHCl3) {lit.12d [a]D20 -5 (c 1,
3-((2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-
(benzyloxymethyl)pyrrolidin-2-yl)propan-1-ol
(3a)
CHCl3)}. IR (film): 2861, 1496, 1453, 1363, 1093 cm-1. 1H NMR
(400 MHz, CDCl3) d 1.60–2.02 (m, 4H), 2.76 (td, J = 6.7, 10.6 Hz,
1H), 2.96 (td, J = 5.6, 7.3 Hz, 1H), 3.06 (td, J = 5.9, 10.5 Hz,
1H), 3.44–3.62 (m, 3H), 3.80 (dd, J1 = J2 = 5.9 Hz, 1H), 4.07
(dd, 1H), 4.50–4.75 (m, 6H), 7.20–7.36 (m, 15H) ppm. 13C NMR
(100 MHz, CDCl3) d 25.8, 31.7, 55.1, 67.4, 68.2, 71.9, 72.1, 72.6,
73.2, 85.7, 88.9, 127.4, 127.5, 127.6 (2C), 127.7, 128.2, 128.3 (2C),
138.3, 138.4, 138.5 ppm; MS (ESI, m/z): 444 (M+H+, 100).
To a cooled (-30 ◦C) CH2Cl2 solution (12 mL) of the known imide
4 (822 mg, 1.59 mmol), prepared by stepwise reductive benzy-
loxymethylation of tartarimide 5,17 was added dropwise a freshly
prepared THF solution of 3-(tert-butyldimethylsiloxy)propyl
magnesium bromide (8, 12 mL, 4.7 mmol), prepared from 3-(tert-
butyldimethylsiloxy)propyl bromide (1.20 g, 4.8 mmol) and Mg
(173 mg, 7.2 mmol) in THF (12 mL), under nitrogen atmosphere.
After stirring at rt for 2 h, the reaction was quenched with a
saturated aqueous solution of NH4Cl (10 mL) and extracted
with CH2Cl2 (3 ¥ 20 mL). The combined extracts were dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography on silica
gel eluting with ethyl acetate–P.E. (1 : 9) to give two tautomers
oxooctanylcarbamate 9a and N,O-acetal 9b (799 mg, combined
Hyacinthacine A2 (1)
To a solution of pyrrolizidine 10 (120 mg, 0.28 mmol) in methanol
(10 mL) was added 10% Pd/C (50 mg). After the reaction flask
was purged with hydrogen, 10 drops of 6 N HCl were added and
the reaction mixture was stirred for 4 days at room temperature
under a hydrogen atmosphere. The catalyst was then filtered off
and washed with MeOH. The filtrates were concentrated under
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reduced pressure. The residue was transferred to a column of
DOWEX 1 ¥ 8 resin (OH-form) and eluted with deionized water to
give hyacinthacine A2 (1, 38 mg, yield, 84%) as white crystals. M.p.
10.2 Hz, 1H), 5.01 (ddd, J = 1.6, 3.4, 17.1 Hz, 1H), 5.82 (ddd,
J = 6.6, 10.2, 17.1 Hz, 1H), 7.20–7.37 (m, 15H) ppm; 13C NMR
(100 MHz, CDCl3) d 28.0, 31.4, 61.7, 64.5, 70.8, 71.2, 71.6, 73.1,
83.9, 84.9, 114.5, 127.5, 127.6, 127.7, 128.3, 128.4, 138.2 (2C),
138.3, 138.6 ppm. MS (ESI, m/z): 458 (M+H+, 100). Anal. Calcd
for C30H35NO3: C, 78.74; H, 7.71; N, 3.06. Found: C, 78.37; H,
7.52; N, 3.01.
◦
130–131 C (H2O); [a]D20 +12.6 (c 1.64, H2O) {[a]2D5 +12.5 (c 0.4,
H2O);12a [a]2D5 +10.5 (c 0.6, H2O);12c [a]D25 +12.7 (c 0.13, H2O);12b
[a]D20 +11.2 (c 0.52, H2O);12e [a]D20 +12.1 (c 0.3, H2O);16 [a]2D5 +20.1
(c 0.44, H2O)7}; IR (film): 3354, 2956, 2920, 2866, 1124 cm-1. 1H
NMR (400 MHz, D2O) d 1.67–1.96 (m, 4H), 2.66 (ddd, J = 3.9,
6.6, 9.0 Hz, 1H), 2.70 (td, J = 5.6, 11.0 Hz, 1H), 2.86 (ddd, J =
5.9, 7.1, 10.9 Hz, 1H), 3.11 (td, J = 4.4, 7.4 Hz, 1H), 3.61 (dd, 1H,
J = 6.6, 11.6 Hz, 1H), 3.66–3.77 (m, 3H) ppm; 13C NMR (D2O) d
27.3, 32.6, 57.6, 66.0, 68.8, 72.0, 80.2, 83.1 ppm; HRESIMS calcd
for [C8H15NO3 + H]+: 174.1125; found: 174.1130.
Benzyl (2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-
(but-3-enyl)pyrrolidin-1-yl carboxylate (14)
To a stirring solution of 13a (334 mg, 0.73 mmol) and anhydrous
K2CO3 (110 mg, 0.80 mmol) in THF (4 mL) and H2O (4 mL) was
added benzyl chloroformate (0.11 mL, 0.73 mmol). After stirring
at rt for 1.5 h, the solvent was removed under reduced pressure,
and the residue was purified by flash column chromatography
(EtOAc/P.E. = 1/14) to give 14 (385 mg, yield, 89%) as a colorless
oil: [a]2D0 -36.9 (c 7.2, CHCl3). IR (film): 2924, 1702, 1587, 1496,
1406, 1347, 1091 cm-1. 1H NMR (400 MHz, CDCl3, two rotamers,
M1: M2 = 1 : 1) d 1.71–2.21 (m, 8H), 3.43–3.51 (m, 2H), 3.73 (dd,
J = 4.1, 8.9 Hz, 2H), 3.78–3.85 (m, 3H), 3.89 (dd, J = 2.5, 11.2 Hz,
1H), 4.05 (dd, J = 4.2, 8.7 Hz, 1H), 4.11–4.18 (m, 3H), 4.25 (dd,
J = 4.0, 10.4 Hz, 1H), 4.30–4.50 (m, 9H), 4.56–4.67 (m, 3H),
4.85–5.08 (m, 6H), 5.12–5.22 (m, 2H), 5.61 (m, 1H), 5.81 (m, 1H),
7.13–7.38 (m, 40H) ppm. 13C NMR (100 MHz, CDCl3) mixture of
two rotamers: d 29.0, 30.4, 30.8, 62.6, 62.9, 64.0, 64.4, 66.8, 66.9,
67.8, 68.8, 70.9, 71.0, 71.2, 72.9, 73.0, 82.0, 83.1, 83.3, 84.3, 115.0,
127.5, 127.5, 127.7, 128.0, 128.1, 128.3 (2C), 128.4, 128.5, 136.6,
137.6, 137.9, 138.3, 138.5, 154.2, 154.6 ppm. MS (ESI, m/z): 592
(M+H+, 100). Anal. Calcd for C38H41NO5: C, 77.13; H, 6.98; N,
2.37. Found: C, 77.07; H, 7.26; N, 2.41.
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-(but-3-
enyl)pyrrolidine (13a)
To a stirring solution of 4 (640 mg, 1.23 mmol) in THF (12 mL)
was ad◦ded a solution of 4-butenyl magnesium bromide in THF
at -30 C, which was prepared from 4-bromo-1-butene (0.4 mL,
4.0 mmol) and Mg (145 mg, 6.0 mmol) in THF (8 mL) at rt.
The mixture was stirred at the same temperature for 2 h before
quenching with a saturated aqueous solution of NH4Cl (5 mL)
and extracted with CH2Cl2 (3 ¥ 20 mL). The combined extracts
were dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel eluting with ethyl acetate–P.E. (1 : 11)
to give a mixture of 12b (two diastereomeric mixture) and its ring-
opening tautomer 12a (425 mg, combined yield, 60%), which was
used in the next step without further separation.
To a cooled (-78 ◦C) solution of diastereomeric and tautomeric
mixture 12a and 12b (425 mg, 0.74 mmol) in anhydrous CH2Cl2
(8 mL) were added dropwise triethylsilane (1.8 mL, 11.1 mmol) and
boron trifluoride etherate (0.5 mL, 2.96 mmol) under nitrogen at-
mosphere. After stirring at -78 ◦C for 6 h, the mixture was allowed
to warm up to rt and stirred overnight. The reaction was quenched
with a saturated aqueous sodium bicarbonate and extracted with
CH2Cl2 (3 ¥ 15 mL). The combined extracts were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (1,2-dichloroethane/NH3·H2O =
100/1) to give two diastereomers 13a and 13b in 8 : 1 ratio (301 mg,
combined yield, 89%). Major product 13a: pale yellow oil. [a]D20
19.4 (c 4.0, CHCl3). IR (film): 3336, 3030, 2921, 1599, 1453, 1384,
Benzyl (2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-
(3-oxobutyl)pyrrolidin-1-yl-carboxylate (6)
To a stirring solution of olefin 14 (277 mg, 0.47 mmol) in DMF
(7.5 mL) and H2O (2.5 mL) were added CuCl (50 mg, 0.52 mmol)
and PdCl2 (35 mg, 40 mol%), and the resulting suspension was
stirred under oxygen atmosphere at 1 atm and at room temperature
for 24 h. The insoluble materials were removed by filtration,
and washed with CH2Cl2. The filtrate was dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure to give a
residue, which was chromatographed on silica gel (EtOAc/P.E. =
1/8) to give 6 (214 mg, yield, 75%) as a colorless oil. [a]2D0 -38.6
(c 4.0, CHCl3). IR (film): 3030, 2925, 1698, 1435, 1348, 1091 cm-1.
1H NMR (400 MHz, CDCl3, two rotamers, M: m = 1.24: 1) d
1.87–2.48 (m, 14 H), 3.40 (d, J = 8.9 Hz, 1H), 3.46 (d, J = 8.9 Hz,
1H), 3.72 (dd, J = 4.1, 8.9 Hz, 1H), 3.75–3.79 (m, 3H), 3.83 (dd,
J = 3.2, 9.5 Hz, 1H), 4.05 (dd, J = 4.1, 8.9 Hz, 1H), 4.12–4.18 (m,
3H), 4.26 (dd, J = 4.0, 10.4 Hz, 1H), 4.30–4.49 (m, 9H), 4.55–4.66
(m, 3H), 5.03 (d, J = 12.2 Hz, 1H), 5.04 (d, J = 12.3 Hz, 2H), 5.15
(d, J = 12.3 Hz, 2H), 5.20 (d, J = 12.2 Hz, 2H), 7.16–7.39 (m,
40H) ppm. 13C NMR (100 MHz, CDCl3, mixture of two rotamers)
d 25.1, 26.1, 29.3, 29.5, 40.5, 40.8, 62.7, 63.1, 63.9, 64.2, 66.9, 67.0,
67.6, 68.6, 70.9, 71.0, 71.2, 72.9, 73.0, 81.6, 82.7, 83.7, 84.6, 127.5
(2C), 127.6, 127.7, 128.0, 128.1, 128.3, 128.4, 128.5, 136.4, 136.5,
137.5, 137.7, 138.2, 138.4, 154.3, 154.5, 208.0 (2C) ppm. MS (ESI,
m/z): 608 (M+H+, 100). Anal. Calcd for C38H41NO6: C, 75.10; H,
6.80; N, 2.30. Found: C, 75.04; H, 6.63; N, 2.37.
1
1362, 1095 cm-1. H NMR (400 MHz, CDCl3) d 1.52–1.72 (m,
2H), 2.02–2.22 (m, 2H), 3.11 (td, J = 5.4, 8.1 Hz, 1H), 3.39 (m,
1H), 3.51 (m, 2H), 3.71 (dd, J = 3.1, 8.0 Hz, 1H), 3.87 (dd, J =
3.1, 4.0 Hz, 1H), 4.48–4.57 (m, 6H), 4.95 (m, 1H), 5.02 (ddd, J =
1.6, 3.4, 17.1 Hz, 1H), 5.81 (tdd, J = 6.6, 10.2, 17.1 Hz, 1H), 7.20–
7.41 (m, 15H) ppm; 13C NMR (100 MHz, CDCl3) d 31.0, 33.3,
61.4, 61.8, 70.5, 71.7, 73.2, 86.3, 89.7, 114.7, 127.6 (2C), 127.7,
127.8, 128.3, 138.2, 138.3 ppm. MS (ESI, m/z): 458 (M+H+, 100).
Minor product 13b: pale yellow oil. [a]2D0 37.0 (c 2.2, CHCl3). IR
1
(film): 3336, 3030, 2921, 1599, 1453, 1384, 1362, 1095 cm-1. H
NMR (400 MHz, CDCl3) d 1.66–1.80 (m, 2H), 2.00–2.21 (m, 2H),
3.14 (dt, J = 3.9, 7.0 Hz, 1H), 3.27 (ddd, J = 3.8, 5.5, 5.5 Hz,
1H), 3.55 (dd, J = 5.4, 9.4 Hz, 1H), 3.59 (dd, J = 5.7, 9.4 Hz,
1H), 3.74 (d, J = 3.9 Hz, 1H), 3.82 (d, J = 3.8 Hz, 1H), 4.36
(d, J = 11.9 Hz, 1H), 4.47–4.56 (m, 5H), 4.94 (ddd, J = 1.2, 3.3,
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(1R,2R,3R,5R,7aR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-5-
methyl-hexahydro-1H-pyrrolizine (15a)
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Gu and T. M. Block, in Iminosugars, P. Compain and O. R. Martin,
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Fan, in Iminosugars, P. Compain and O. R. Martin, Ed., John Wiley
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2007, Chap. 14, pp. 327-455; (c) H Fiaux, F. Popowycz, S. Favre, C.
Schuetz, P. Vogel, S. Gerber-Lemaire and L. Juillerat-Jeanneret, J. Med.
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Carmona and P. Vogel, Curr. Drug Metab., 2004, 5, 329–361.
4 (a) R. J. Molyneux, M. Benson, R. Y. Wong, J. E. Tropea and A. D.
Elbein, J. Nat. Prod., 1988, 51, 1198–1206. epi-australines: (b) A. Kato,
E. Kano, I. Adachi, R. J. Molyneux, A. A. Watson, R. J. Nash, G. W. J.
Fleet, M. R. Wormald, H. Kizu, K. Ikeda and N. Asano, Tetrahedron:
Asymmetry, 2003, 14, 325–331.
Compound 6 (60 mg, 0.10 mmol) in MeOH (5 mL) was hy-
drogenated over 10% Pd/C (30 mg) for 12 h. The catalyst was
filtered off, washed with MeOH, and the filtrate and washings
were concentrated to give a residue that was submitted to column
chromatography (EtOAc/PE = 1/1) to afford 15a (37 mg, yield,
84%) as a colorless oil. [a]D20 -0.95 (c 2.0, CHCl3). IR (film) 2963,
1
2857, 1601, 1451, 1360, 1259, 1070 cm-1. H NMR (400 MHz,
CDCl3) d 1.17 (d, J = 6.8 Hz, 3H), 1.44–1.52 (m, 1H), 1.68–
1.75 (m, 1H), 1.78–1.91 (m, 2H), 3.24–3.31 (m, 2H), 3.45–3.51
(m, 2H), 3.54–3.60 (m, 1H), 3.76 (t, J = 4.0 Hz, 1H), 4.06 (t,
J = 4.1 Hz, 1H), 4.45–4.60 (m, 6H), 7.20–7.35 (m, 15H) ppm. 13
C
NMR (100 MHz, CDCl3) d 17.2, 29.1, 32.5, 57.6, 61.0, 68.8, 71.5,
71.9, 73.1, 73.2, 86.9, 88.2, 127.4 (2C), 127.5, 127.6, 127.7, 128.2,
128.3 (2C), 138.4, 138.6 ppm. HRESIMS calcd for [C30H35NO3 +
H]+: 458.2690; found: 458.2708.
(+)-Hyacinthacine A3 (2)
To a solution of pyrrolizidine 15a (25 mg, 0.05 mmol) in methanol
(5 mL) was added 10% Pd/C (10 mg). After the reaction flask was
purged with hydrogen, a few drops of HCl (6 N) were added and
the reaction mixture was stirred for 4 days at room temperature
under an atmosphere of hydrogen. The catalyst was then filtered
off and washed with MeOH. The filtrates were concentrated under
reduced pressure, transferred to a column of DOWEX 1 ¥ 8 resin
(OH- form) and eluted with deionized water to give pyrrolizidine
2 (9.0 mg, yield, 88%) as a colorless oil. [a]2D0 +7.5 (c 0.9, H2O)
{lit.7 [a]2D5 +19.2 (c 0.43, H2O) for the natural product; [a]2D5 +14 (c
0.55, H2O);13a [a]D25 +15.1 (c 0.35, H2O)16 for a synthetic products}.
IR (film) 3360, 2954, 2910, 2853, 1116 cm-1. 1H NMR (600 MHz,
D2O) d 1.20 (d, J = 6.8 Hz, 2H, CH3), 1.61 (m, 1H, H-6), 1.78 (m,
1 H, H-7), 1.89 (m, 1 H, H-6¢), 1.93 (m, 2 H, H-6¢, H-7¢), 3.09 (dt,
J = 8.0, 5.3 Hz, 1H, H-3), 3.22 (m, 1H, H-5), 3.27 (m, 1H, H-7a),
3.69 (d, J = 5.0 Hz, 2H, H-8), 3.71 (t, J = 7.5 Hz, 1H, H-1), 3.91
(br t, J = 7.8 Hz, 1H, H-2) ppm. 13C NMR (125 MHz, D2O) d
18.4, 30.7, 34.8, 60.4, 64.4, 66.1, 70.1, 81.5, 83.3 ppm. HRESIMS
calcd for [C9H17NO3 + H]+: 188.1281; found: 188.1278.
5 R. J. Nash, P. I. Thomas, R. D. Waigh, G. W. J. Fleet, M. R. Wormald,
P. M. de Q. Lilley and D. J. Watkin, Tetrahedron Lett., 1994, 35, 7849–
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8 T. Yamashita, K. Yasuda, H. Kizu, Y. Kameda, A. A. Watson, R. J.
Nash, G. W. J. Fleet and N. Asano, J. Nat. Prod., 2002, 65, 1875–1881.
9 N. Asano, K. Ikeda, M. Kasahara, Y. Arai and H. Kizu, J. Nat. Prod.,
2004, 67, 846–850.
10 A. Kato, N. Kato, I. Adachi, J. Hollinshead, G. W. J. Fleet, C. Kuriyama,
K. Ikeda, N. Asano and R. J. Nash, J. Nat. Prod., 2007, 70, 993–997.
11 For reviews, see: (a) J. P. Michael, Nat. Prod. Rep., 2005, 22, 603–626;
(b) J. R. Liddell, Nat. Prod. Rep., 2002, 19, 773–781; (c) J. R. Liddell,
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Acknowledgements
The authors are grateful to the NSF of China (20832005,
20602028) and the National Basic Research Program (973 Pro-
gram) of China (Grant No. 2010CB833206) for financial support.
We are indebted to Dr N. Asano for kindly providing us with a
sample of natural hyacinthacine A3 for comparison.
12 For the asymmetric synthesis of hyacinthacine A2, see: (a) L. Rambaud,
P. Compain and O. R. Martin, Tetrahedron: Asymmetry, 2001, 12, 1807–
1809; (b) F. Cardona, E. Faggi, F. Liguori, M. Cacciarini and A. Goti,
Tetrahedron Lett., 2003, 44, 2315–2318; (c) I. Izquierdo, M. T. Plaza
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(e) P. Dewi-Wu¨lfing and S. Blechert, Eur. J. Org. Chem., 2006, 1852–
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13 For the asymmetric synthesis of hyacinthacine A3, see: (a) I. Izquierdo,
M. T. Plaza and F. Franco, Tetrahedron: Asymmetry, 2002, 13, 1581–
1585. For asymmetric synthesis of epimers of hyacinthacine A3, see:
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Org. Biomol. Chem., 2010, 8, 2085–2091 | 2091
©