A concise and divergent approach to radicamine B and hyacinthacine A 3 based on a step-economic transformation

Article abstract of DOI:10.1016/j.tet.2012.01.085

Based on our recently developed step-economic methodology of reductive alkylation of lactams/amides, we have developed a two-step synthesis of azasugar radicamine B (2a) and a four-step synthesis of azasugar hyacinthacine A ₃ (5) from the common chiral building block 12. Hantzsch ester (HEH) was used as a milder hydride donor in the one-pot stereoselective reductive alkylation of lactam 12. The Wacker oxidation of fully substituted pyrrolidine derivative 2,5-trans-17 led to the synthesis of hyacinthacine A₃ (5). Compound 2,5-trans-17 could also serve as a plausible key intermediate for the synthesis of broussonetine sub-class of azasugars.

Full text of DOI:10.1016/j.tet.2012.01.085

Tetrahedron 68 (2012) 5297e5302
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A concise and divergent approach to radicamine B and hyacinthacine A3 based on
a step-economic transformation
*
Jin-Cheng Liao, Kai-Jiong Xiao, Xiao Zheng, Pei-Qiang Huang
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 October 2011
Received in revised form 29 October 2011
Accepted 8 November 2011
Available online 4 February 2012
Based on our recently developed step-economic methodology of reductive alkylation of lactams/amides,
we have developed a two-step synthesis of azasugar radicamine B (2a) and a four-step synthesis of
azasugar hyacinthacine A3 (5) from the common chiral building block 12. Hantzsch ester (HEH) was used
as a milder hydride donor in the one-pot stereoselective reductive alkylation of lactam 12. The Wacker
oxidation of fully substituted pyrrolidine derivative 2,5-trans-17 led to the synthesis of hyacinthacine A3
(5). Compound 2,5-trans-17 could also serve as a plausible key intermediate for the synthesis of
broussonetine sub-class of azasugars.
Keywords:
Step-economy
Azasugars
Ó 2012 Elsevier Ltd. All rights reserved.
Alkaloids
Glycosidase inhibitors
Hantzsch ester
1. Introduction
activity.7 Codonopsinol (3),8c a new codonopsine related alkaloid
recently isolated from the aerial parts of Codonopsis clematidea,8a
Efficiency is the major goal in contemporary organic synthesis.1
Step-economic organic synthesis is a useful tactic for this goal.2 In
this context, we have recently developed some step-economic
organic transformations that allowed one-pot access to target
molecules,3e5 one such example being the one-pot sequential
reductive alkylation of lactams/amides with Grignard and
organolithium reagents or hydrides (Scheme 1).3
also shows inhibitory activity against the a-glucosidase of yeast
and bacillus Bacillus stearothermophilus lyoph.8b Interestingly, the
unnatural analogues 1b and 2b show better inhibitory activities
against
a
-glucosidases than radicamines A (1a) and B (2a).8b
Hyacinthacines [e.g., A2 (4) and A3 (5)], a group of pyrrolizidine
azasugars9 isolated from the bulbs of Muscari armeniacum (Hya-
cinthaceae), show interesting inhibitory activities against a variety
of glycosidases. Broussonetines, a sub-class of pyrrolidine azasu-
gars [e.g., broussonetines C, D, M, O, P (6, 7, 8, 9, 10)] isolated from
the plant species Broussonetia kazinoki Siebold (Moraceae),10 ex-
hibit stronger inhibitory activity against some glycosidases than
standard azasugars.
As a continuation of our longstanding interest in the asymmetric
synthesis of bioactive alkaloids and azasugars,11 we have developed
an approach to the asymmetric syntheses of 5-epi-radicamine B
(13)11f and hyacinthacine A3 (5)9d starting from tartarimide 11
(Scheme 2). This approach, however, have some shortcomings, such
as the multi-step transformations from pyrrolidin-2-one 12 to
5-epi-radicamine B (13)11f and hyacinthacine A3 (5), and the failure
to access to the natural product of the former. Consequently, it is
necessary to develop a concise and versatile synthetic route to
these two alkaloids. We now report the efficient and divergent
syntheses of azasugars radicamine B (2a) and hyacinthacine A3 (5)
by applying the above-mentioned step-economic method of
reductive alkylation of lactams/amides (Scheme 1).3
Scheme 1. One-pot sequential reductive alkylation of lactams/amides.
Polyhydroxylated alkaloids (or azasugars) have been exten-
sively studied over the past three decades owing to the remarkable
biological properties and the potential as pharmaceuticals.6 For
example, radicamines A (1a) and B (2a, Fig. 1), isolated from Lobelia
chinensis Lour (Campanulaceae), show
a-glucosidase inhibitory
* Corresponding author. Tel.: þ86 592 2182240; fax: þ86 592 2186400; e-mail
address: pqhuang@xmu.edu.cn (P.-Q. Huang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.085

5298
J.-C. Liao et al. / Tetrahedron 68 (2012) 5297e5302
pyrrolidine 15, the one-pot reductive alkylation procedure3b was
envisioned. The challenge in this transformation is the stereo-
chemical control regarding the highly substituted ring system.
The synthesis started with the one-pot reductive alkylation of
the known chiral building block 123b that was easily accessible from
D
-tartaric acid.5,11f,12 Successive treatment of the CH2Cl2 solution of
lactam 12 (1.0 equiv) and DTBMP (1.2 equiv) with 1.2 equiv of Tf2O
(ꢀ78 ꢁC, 45 min), 1.0 equiv of 4-(benzyloxy)phenylmagnesium
bromide in THF (rt, 1 h), and 3.0 equiv of LiAlH4 (rt, 1 h), afforded
the desired reductive alkylation product 2,5-trans-15 and 2,5-cis-15
in 55% yield. However, the diastereoselectivity was very low
(dr¼1:1, Scheme 4). To improve stereoselectivity, Hantzsch ester
(HEH), a milder hydride donor,13 was exploited. Indeed, the dia-
stereoselectivity was improved to 1.8:1 in favor of diastereomer
2,5-trans-15 with a combined yield of 56%. The stereochemistry of
the major diastereomer was ultimately confirmed by conversion
into radicamine B (2a). Compared with the previous four-step
synthesis, this one step transformation is remarkably efficient, al-
though both the yield and the diastereoselectivity were modest.11f
Deprotection of 2,5-trans-15 under catalytic hydrogenolytic con-
ditions [H2, l atm, 20% Pd(OH)2/C, EtOH/EtOAc/HCl, rt, 15 h] gave
the hydrochloride salt of radicamine B (2a$HCl) {[
a
]
20 þ79 (c 0.25,
D
H2O); lit.7e
[a]
þ81 (c 0.25, H2O)} in 91% yield. The 1H and 13C
25
D
NMR spectral data of our synthetic product are in good agreement
with those reported.7e
Fig. 1. Structures of some bioactive polyhydroxylated pyrrolidines and azasugars.
Scheme 4. Improved synthesis of radicamine B.
Scheme 2. Our previous syntheses of 5-epi-radicamine B and hyacinthacine A3.
We next turned our attention to the synthesis of hyacinthacine
A3 (5) (Scheme 5). As depicted in Scheme 5, our retrosynthetic
analysis started with the protected form of hyacinthacine A3 (14),
which could be directly converted into hyacinthacine A3 (5) by
deprotection.9d Pyrrolizidine 14 could be accessed from pyrrolidino
ketone 16 via a stereoselective one-pot transformation reported in
the literature.9d Ketone 16 was envisioned to be formed by the
Wacker oxidation14 of olefin 2,5-trans-17. However, this conversion
appeared challenging, due to the strong Lewis basicity and good
chelating capacity of the amino group in 2,5-trans-17. The failure in
the Wacker oxidation of amino-containing olefins such as 18
(Fig. 2)15 has been reported. The presence of amino group also
causes troubles in other transition metal-catalyzed reactions such
as olefin metathesis reactions.16 Nevertheless, successful Wacker
oxidation reaction17 and olefin metathesis reactions16of amino-
containing compounds have also been reported. For example, the
olefin metathesis of compound 19 gave the desired product in high
yield.18
2. Results and discussion
We first undertook the synthesis of radicamine B (2a). Thanks to
the nice work of Yu and Huang,7c the absolute configurations of
radicamines A (1a) and B (2a) have been revised as shown in Fig. 1.
Our retrosynthetic analysis of radicamine B (2a) is depicted in
Scheme 3. For the rapid transformation of lactam 12 to 2,5-trans-
Scheme 3. Retrosynthetic analysis of radicamine B.

J.-C. Liao et al. / Tetrahedron 68 (2012) 5297e5302
5299
Compound 16 was then treated with ceric ammonium nitrite
(CAN) in a mixed solvent (MeCN/H2O¼3:1) to give the presumed
free amine A, which without purification was subjected to catalytic
hydrogenation conditions (H2, 10% Pd/C, MeOH, rt, 12 h) to produce
20
20
pyrrolizidine 14 {[
a]
ꢀ1.0 (c 1.0, CHCl3); lit.9d
[
a
]
ꢀ0.95 (c 2.0,
D
D
CHCl3)} and its diastereomer 14a (dr¼7.1:1) in a combined yield of
63%. It is worth noting that, although a one-pot transformation of
16 to hyacinthacine A3 (5) was possible, stopping the reaction at the
stage of 14 is advantageous because two diastereomers 14 and 14a
are easily separated. Thus, starting from pyrrolidinone 12, a three-
step synthesis of O-benzylated pyrrolizidine 14 was achieved with
an overall yield of 22%. This approach is four steps shorter than the
previous route9d (seven steps, 21% overall yield). Final deprotection
of pyrrolizidine 14 to complete the synthesis of hyacinthacine A3 (5)
has been described.9d
Scheme 5. Retrosynthetic analysis of pyrrolizidine 14.
3. Conclusion
To conclude, by applying the method of one-pot reductive al-
kylation of lactams/amides, we have developed a two-step syn-
thesis of natural radicamine B (2a) and five-step synthesis of
hyacinthacine A3 (5) from pyrrolidin-2-one 12. The approach to
hyacinthacine A3 (5) is especially effective compared with the
previous eight-step route.9d Moreover, since compound 20 has
been designed and used by Marco and co-workers as a common
intermediate in the total synthesis of broussonetines C, D, M, O, P
(6, 7, 8, 9, and 10) (Scheme 7),10h,i the reductive alkylation product
2,5-trans-17 would serve as a valuable intermediate for the syn-
theses of this class of natural products.
Fig. 2. Two substrates tested for the Wacker oxidation and the olefin metathesis
reaction, respectively.
The synthesis started with the one-pot reductive alkylation of
the known chiral building block 12, which was treated successively
with Tf2O/DTBMP, but-3-enylmagnesium bromide, and HEH to af-
ford a mixture of separable diastereomers 2,5-trans-17 and 2,5-cis-
17 in a ratio of 2:1 with 80% combined yield (Scheme 6). The ste-
reochemistry of the major diastereomer was confirmed by con-
version into compound 14. To our delight, 2,5-trans-pyrrolidine 17
was converted to methyl ketone 16 in 73% yield under modified
Wacker oxidation conditions [O2 (1 atm), PdCl2 (0.5 equiv), CuCl
(1.1 equiv), DMF/H2O (v/v¼3:1), rt],17 in which the amount of PdCl2
was increased from the commonly used 0.1 equiv14 to 0.5 equiv.17a
The success of this reaction might be ascribed to the steric hin-
drance in 2,5-trans-pyrrolidine 17, which prevented the amino
group coordination to the palladium catalyst. In fact, the steric
hindrance also facilitated the Wacker oxidation of other amino-
containing compounds.17
Scheme 7. Marco’ general approach to broussonetines C, D, M, O, and P.
4. Experimental section
4.1. General methods
Infrared spectra were measured a Nicolet Avatar 360 FT-IR
spectrometer using film KBr pellet techniques. 1H and 13C NMR
data were acquired with spectrometer Bruker AMX 400 MHz.
Chemical shifts (d) are expressed downfield from TMS. Mass spectra
were recorded by Bruke Dalton Esquire 3000 Plus, HRFABMS spectra
were recorded on a Bruker APEX-FTMS apparatus. Tetrahydrofuran
(THF) was distilled prior to use from sodium benzophenone ketyl.
Methylene chloride (CH2Cl2) was distilled over calcium hydride
under N2. Silica gel (zhifu, 300e400 mesh) from Yantai silica gel
factory (China) was used for column chromatography. Both of the
Grignard reagents were titrated immediately before use.19
4.1.1. (2R,3R,4R,5R)-1-(4-Methoxybenzyl)-3,4-bis(benzyloxy)-2-(4-
(benzyloxy)phenyl)-5-(benzyloxymethyl)pyrrolidine
(2,5-trans-
15). Tf2O (79 L, 0.47 mmol) was added dropwise to a cooled
m
(ꢀ78 ꢁC) solution of lactam 12 (210 mg, 0.39 mmol) and 2,6-di-tert-
butyl-4-methylpyridine (96 mg, 0.47 mmol) in CH2Cl2 and the re-
sultant mixture was stirred at ꢀ78 ꢁC for 45 min. A solution of
freshly prepared 4-(benzyloxy)phenylmagnesium bromide
(0.52 M, 0.75 mL, 0.39 mmol) in THF was added dropwise to the
resultant mixture. The mixture was allowed to warm slowly to
room temperature and stirred for 1 h. Then the mixture was cooled
Scheme 6. Improved synthesis of (þ)-hyacinthacine A3.

5300
J.-C. Liao et al. / Tetrahedron 68 (2012) 5297e5302
to ꢀ78 ꢁC, and Hantzsch ester (HEH) (147 mg, 0.59 mmol) was
added in one portion. The mixture was allowed to warm slowly to
room temperature and stirred for 1 h. The mixture was concen-
trated under reduced pressure. The residue was purified by flash
chromatography on silica gel (eluent: CH2Cl2/hexane¼1:2) to afford
compound 2,5-trans-15 (100 mg, yield: 36%) and its diastereomer
(75
m
L, 0.45 mmol) was added dropwise to a cooled (ꢀ78 ꢁC) so-
lution of lactam 12 (200 mg, 0.37 mmol) and 2,6-di-tert-butyl-4-
methylpyridine (91 mg, 0.45 mmol) in CH2Cl2 and the resultant
mixture was stirred at ꢀ78 ꢁC for 45 min. A solution of freshly
prepared but-3-enylmagnesium bromide (0.29 M, 1.28 mL,
0.37 mmol) in THF was added dropwise to the resultant mixture.
The mixture was allowed to warm slowly to room temperature
and stirred for 1 h. Then the mixture was cooled to ꢀ78 ꢁC, and
Hantzsch ester (HEH) (140 mg, 0.56 mmol) was added in one
portion. After being stirred for 1 h, the mixture was concentrated
under reduced pressure. The residue was purified by flash chro-
matography on silica gel (eluent: EtOAc/hexane¼1:10) to afford
compound 2,5-trans-17 (115 mg, yield: 53%) and its diastereomer
2,5-cis-15 (55 mg, yield: 20%) (combined yield: 56%, dr¼1.8:1).
20
Compound 2,5-trans-15: colorless oil; [
a]
þ6.2 (c 0.6, CHCl3); IR
D
(film): 3062, 3030, 2918, 2851, 1610, 1510, 1454, 1245, 736,
697 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
3.36 (ddd, J¼6.5, 6.2, 3.4 Hz,
1H, H-2), 3.38 (d, J¼14.5 Hz, 1H, NCH2), 3.53 (dd, J¼9.4, 3.4 Hz, 1H,
H-6), 3.55 (d, J¼14.5 Hz, 1H, NCH2), 3.60 (dd, J¼9.4, 6.2 Hz, 1H, H-6),
3.77 (s, 3H, OCH3), 4.01 (dd, J¼6.6, 3.2 Hz, 1H, H-4), 4.03 (d,
J¼6.6 Hz, 1H, H-5), 4.16 (dd, J¼6.5, 3.2 Hz, 1H, H-3), 4.32 (d,
J¼11.7 Hz, 1H, OCH2Ph), 4.36 (d, J¼11.7 Hz, 1H, OCH2Ph), 4.45 (d,
J¼12.0 Hz, 1H, OCH2Ph), 4.48 (d, J¼11.8 Hz, 1H, OCH2Ph), 4.49 (d,
J¼12.0 Hz,1H, OCH2Ph), 4.54 (d, J¼11.8 Hz,1H, OCH2Ph), 5.06 (s, 2H,
OCH2Ph), 6.77 (d, J¼8.5 Hz, 2H, AreH), 6.94 (d, J¼8.5 Hz, 2H, AreH),
2,5-cis-17 (58 mg, yield: 27%). Compound 2,5-trans-17: colorless
20
oil; [
a
]
þ25.5 (c 1.0, CHCl3); IR (film): 2924, 2857, 1610, 1510,
D
1496, 1453, 1246, 1099, 1028, 735, 697 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): 1.50e1.60 (m, 1H, H-6), 1.70e1.80 (m, 1H, H-6), 1.88e1.98
d
(m, 1H, H-7), 2.02e2.13 (m, 1H, H-7), 3.04 (ddd, J¼8.9, 4.0, 3.6 Hz,
1H, H-5), 3.22 (ddd, J¼7.0, 4.5, 2.3 Hz, 1H, H-2), 3.50 (dd, J¼9.5,
7.0 Hz, 1H, H-10), 3.57 (dd, J¼9.5, 4.5 Hz, 1H, H-10), 3.59 (d,
J¼13.9 Hz, 1H, NCH2), 3.79 (dd, J¼3.6, 2.3 Hz, 1H, H-4), 3.80 (s, 3H,
OCH3), 3.89 (d, J¼13.9 Hz, 1H, NCH2), 3.96 (app. t, J¼2.3 Hz, 1H, H-
3), 4.45e4.50 (m, 5H, OCH2), 4.57 (d, J¼12.0 Hz, 1H, OCH2),
4.86e4.98 (m, 2H, ]CH2), 5.73 (ddt, J¼17.1, 10.3, 6.8 Hz, 1H, ¼CH),
6.81e6.84 (m, 2H, AreH), 7.24e7.32 (m, 17H, AreH) ppm; 13C NMR
7.08e7.48 (m, 24H, AreH) ppm; 13C NMR (100 MHz, CDCl3):
d 49.4,
55.2, 62.0, 67.9, 70.0, 70.9, 71.6, 72.0, 73.3, 85.1, 91.5,113.6 (2C),114.8
(2C), 127.3, 127.4 (3C), 127.5, 127.6 (2C), 127.7 (2C), 127.8 (2C), 127.9,
128.1 (2C), 128.2 (2C), 128.3 (2C), 128.5 (2C), 128.9 (2C), 129.2 (2C),
131.4, 134.2, 137.2, 138.3, 138.3, 138.5, 158.3, 158.3 ppm; MS (ESI) m/
z 706 (MþHþ, 100%); HRESIMS calcd for [C47H48NO5]þ (MþHþ):
706.3527; found: 706.3521. Compound 2,5-cis-15: colorless oil;
20
[
a]
þ3.4 (c 1.0, CHCl3); IR (film): 3061, 3031, 2916, 2849, 1609,
(100 MHz, CDCl3): d 27.7, 29.5, 50.5, 55.3, 64.2, 64.5, 69.0, 71.3,
D
1510, 1453, 1108, 735, 696 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
3.32
71.4, 73.2, 85.8, 87.2, 113.6, 114.3, 127.5, 127.5, 127.5, 127.6 (2C),
127.8 (2C), 127.9 (2C), 128.3 (4C), 128.3 (2C), 129.2 (2C), 130.5 (2C),
138.4, 138.5, 138.5, 138.7, 158.5 ppm; MS (ESI) m/z 578 (MþHþ,
(ddd, J¼6.9, 6.8, 4.3 Hz, 1H, H-2), 3.44 (d, J¼14.6 Hz, 1H, NCH2), 3.47
(dd, J¼9.4, 4.3 Hz, 1H, H-6), 3.55 (d, J¼6.5 Hz, 1H, H-5), 3.72 (dd,
J¼9.4, 6.8 Hz, 1H, H-6), 3.77 (s, 3H, OCH3), 3.80 (d, J¼14.6 Hz, 1H,
NCH2), 3.81 (dd, J¼6.5, 4.4 Hz, 1H, H-4), 3.98 (dd, J¼6.9, 4.4 Hz, 1H,
H-3), 4.28 (d, J¼11.7 Hz, 1H, OCH2Ph), 4.33 (d, J¼11.7 Hz, 1H,
OCH2Ph), 4.40 (d, J¼12.0 Hz, 1H, OCH2Ph), 4.45 (d, J¼12.0 Hz, 1H,
OCH2Ph), 4.53 (d, J¼11.9 Hz, 1H, OCH2Ph), 4.59 (d, J¼11.9 Hz, 1H,
OCH2Ph), 5.07 (s, 2H, OCH2Ph), 6.75 (d, J¼8.6 Hz, 2H, AreH), 6.94 (d,
J¼8.6 Hz, 2H, AreH), 7.06 (d, J¼8.6 Hz, 4H, AreH), 7.18e7.47 (m,
100%); HRESIMS calcd for [C38H43NO4]þ: 578.3265; found:
20
578.3275. Compound 2,5-cis-17: a colorless oil; [
a]
ꢀ25.0 (c 1.0,
D
CHCl3); IR (film): 2918, 2856, 1610, 1511, 1453, 1248, 1098, 1028,
736, 697 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
1.56e1.68 (m, 1H, H-
6), 1.76e1.86 (m, 1H, H-6), 1.86e1.93 (m, 2H, H-7), 2.95 (ddd, J¼9.6,
8.5, 4.5 Hz, 1H, H-5), 3.07e3.10 (m, 1H, H-2), 3.10 (dd, J¼8.9, 4.4 Hz,
1H, H-10), 3.30 (app. t, J¼8.9 Hz, 1H, H-10), 3.62 (d, J¼13.6 Hz, 1H,
NCH2), 3.76 (dd, J¼6.9, 4.5 Hz, 1H, H-4), 3.82 (s, 3H, OCH3),
3.88e3.90 (m, 1H, H-3), 3.92 (d, J¼13.6 Hz, 1H, NCH2), 4.24 (d,
J¼12.0 Hz, 1H, OCH2), 4.26 (d, J¼12.1 Hz, 1H, OCH2), 4.39 (d,
J¼12.1 Hz, 1H, OCH2), 4.46 (d, J¼12.0 Hz, 1H, OCH2), 4.48 (d,
J¼12.2 Hz, 1H, OCH2), 4.57 (d, J¼12.2 Hz, 1H, OCH2), 4.90e4.98 (m,
2H, ¼CH2), 5.78 (ddt, J¼16.8, 10.3, 6.5 Hz, 1H, ¼CH), 6.78e6.83 (m,
2H, AreH), 7.26e7.36 (m, 17H, AreH) ppm; 13C NMR (100 MHz,
20H, AreH) ppm; 13C NMR (100 MHz, CDCl3):
d 54.2, 55.2, 62.9,
70.0, 70.1, 70.4, 72.1, 72.3, 73.3, 82.8, 89.3, 113.3 (2C), 114.7 (2C),
127.3, 127.4 (2C), 127.5 (2C), 127.5 (3C), 127.6 (4C), 127.9, 128.2 (2C),
128.2 (3C), 128.5 (2C), 129.3 (2C), 129.7, 130.6 (2C), 134.2, 137.2,
138.2, 138.6, 138.7, 158.2, 158.5 ppm; MS (ESI) m/z 706 (MþHþ,
100%); HRESIMS calcd for [C47H48NO5]þ (MþHþ): 706.3527; found:
706.3538.
CDCl3):
d 27.2, 30.7, 55.2, 57.5, 65.9, 68.5, 70.7, 71.3, 72.0, 72.9, 81.9,
4.1.2. (2R,3R,4R,5R)-3,4-Dihydroxy-2-(hydroxymethyl)-5-(4-
hydroxyphenyl) pyrrolidine (radicamine B) hydrochloride salt
(2a). Compound 2,5-trans-15 (60 mg, 0.08 mmol) was dissolved in
EtOAc (1 mL) containing concentrated HCl (0.1 mL, 16.7 mmol) and
then 20% Pd(OH)2/C (30 mg) was added. The mixture was stirred
under a hydrogen atmosphere (1 atm, balloon) at room tempera-
ture for 15 h. After the catalyst was filtered off, the filtrate was
concentrated under reduced pressure, affording radicamine B hy-
drochloride salt 2a (20 mg, yield: 91%) as a white solid. Mp >145 ꢁC
82.4, 113.5, 114.2, 127.4 (2C), 127.5 (2C), 127.6 (4C), 128.0 (2C), 128.2
(2C), 128.3 (2C), 128.3 (2C), 130.5 (2C), 131.1, 138.2, 138.6, 138.6,
138.9, 158.7 ppm; MS (ESI) m/z 578 (MþHþ, 100%); HRESIMS calcd
for [C38H43NO4]þ (MþHþ): 578.3265; found: 548.3267.
4.1.4. 4-((2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)-1-
(4-methoxybenzyl)pyrrolidin-2-yl)butan-2-one (16). To a solution
of olefin 2,5-trans-17 (49 mg, 0.085 mmol) in DMF (1.5 mL) and
H2O (0.5 mL) were added CuCl (9.3 mg, 0.094 mmol) and PdCl2
(7.5 mg, 0.043 mmol) and the resulting suspension was stirred
under an oxygen atmosphere (1 atm, balloon) at room tempera-
ture for 6 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. The
residue was purified by flash chromatography on silica gel (elu-
(dec) [lit.7g mp >150 ꢁC (dec)]; [
a
]
D
þ79 (c 0.25, H2O) {lit.7e
[a]
20
25
D
þ81 (c 0.25, H2O)}; IR (film): 3329, 2933, 1618, 1513, 1254,
832 cmꢀ1; 1H NMR (400 MHz, D2O):
d
3.57 (ddd, J¼7.8, 5.7, 3.9 Hz,
1H, H-2), 3.81 (dd, J¼12.6, 5.7 Hz, 1H, H-6), 3.86 (dd, J¼12.6, 3.9 Hz,
1H, H-6), 4.08 (dd, J¼7.8, 7.5 Hz, 1H, H-3), 4.31 (d, J¼10.1 Hz, 1H, H-
5), 4.38 (dd, J¼10.1, 7.5 Hz, 1H, H-4), 6.86 (d, J¼8.3 Hz, 2H, AreH),
7.32 (d, J¼8.3 Hz, 2H, AreH) ppm; 13C NMR (100 MHz, D2O):
d
58.2,
ent: EtOAc/hexane¼1:5) to give 16 (37 mg, yield: 73%) as a col-
20
61.6, 62.8, 73.6, 77.1, 116.2, 122.9, 130.2, 157.1 ppm; MS (ESI) m/z 226
(MꢀClꢀ, 100%); HRESIMS calcd for [C11H16NO4]þ (MꢀClꢀ):
226.1074; found: 226.1079.
orless oil. [
a
]
þ12.0 (c 1.0, CHCl3); IR (film): 2921, 2851, 1712,
D
1610, 1511, 1453, 1364, 1246, 1097, 1028, 737, 698 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): 1.68e1.77 (m, 1H, H-6), 1.92e1.98 (m, 1H, H-
d
6), 2.00 (s, 3H, CH3), 2.30 (ddd, J¼17.5, 9.3, 6.0 Hz, 1H, H-7), 2.42
(ddd, J¼17.5, 9.5, 5.5 Hz, 1H, H-7), 3.02 (ddd, J¼7.3, 4.8, 4.4 Hz, 1H,
H-5), 3.25 (m, 1H, H-2), 3.49 (dd, J¼9.2, 7.3 Hz, 1H, H-10), 3.56
4.1.3. (2R,3R,4R,5R)-1-(4-Methoxybenzyl)-3,4-bis(benzyloxy)-2-
(benzyloxymethyl)-5-(but-3-enyl) pyrrolidine (2,5-trans-17). Tf2O

J.-C. Liao et al. / Tetrahedron 68 (2012) 5297e5302
5301
(dd, J¼9.2, 4.4 Hz, 1H, H-10), 3.59 (d, J¼14.1 Hz, 1H, NCH2), 3.70
Supplementary data
(dd, J¼4.8, 1.9 Hz, 1H, H-4), 3.79 (s, 3H, OCH3), 3.83 (d, J¼14.1 Hz,
1H, NCH2), 3.98 (app. t, J¼1.9 Hz, 1H, H-3), 4.38e4.46 (m, 4H,
OCH2), 4.49 (d, J¼11.9 Hz, 1H, OCH2), 4.53 (d, J¼12.0 Hz, 1H,
OCH2), 6.83 (d, J¼8.5 Hz, 2H, AreH), 7.21 (d, J¼8.5 Hz, 2H, AreH),
7.25e7.34 (m, 15H, AreH) ppm; 13C NMR (100 MHz, CDCl3):
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.01.085. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
d
22.9, 29.7, 29.8, 38.8, 50.2, 55.3, 63.6, 64.5, 68.1, 71.3, 73.3, 85.2,
87.3, 113.7 (2C), 127.5, 127.6, 127.6 (3C), 127.9 (3C), 128.3 (4C),
128.3 (3C), 129.2 (2C), 131.4, 138.3, 138.3, 138.4, 158.5, 208.6 ppm;
MS (ESI) m/z 594 (MþHþ, 100%); HRESIMS calcd for [C38H43NO5]þ
(MþHþ): 594.3214; found: 594.3211.
References and notes
1. Li, C.-J.; Trost, B. M. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 13197e13202.
2. (a) Wender, P. A.; Miller, B. L. In Organic Synthesis: Theory and Applications;
Hudlicky, T., Ed.; JAI: Greenwich, CT, 1993; Vol. 2, pp 27e66; (b) Wender, P. A.;
Handy, S. T.; Wright, D. L. Chem. Ind. (London) 1997, 765e769; (c) Wender, P. A.;
Bi, F. C.; Gamber, G. G.; Gosselin, F.; Hubbard, R. D.; Scanio, M. J. C.; Sun, R.;
Williams, T. J.; Zhang, L. Pure Appl. Chem. 2002, 74, 25e31; (d) Wender, P. A.;
Croatt, M. P.; Witulski, B. Tetrahedron 2006, 62, 7505e7511.
3. (a) Xiao, K.-J.; Luo, J.-M.; Ye, K.-Y.; Wang, Y.; Huang, P.-Q. Angew. Chem., Int.
Ed. 2010, 49, 3037e3040; (b) Xiao, K.-J.; Wang, Y.; Ye, K.-Y.; Huang, P.-Q.
Chem.dEur. J. 2010, 16, 12792e12796; For a related method, see: (c) Xiang,
S.-H.; Xu, J.; Yuan, H.-Q.; Huang, P.-Q. Synlett 2010, 1829e1832.
4.1.5. (3R,4R,6R,7R,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-3-
methyl-hexahydro-1H-pyrrolizine (14). To a solution of 16 (160 mg,
0.27 mmol) in MeCN (30 mL) and H2O (10 mL) was added ceric
ammonium nitrate (2.96 g, 2.60 mmol) at 0 ꢁC. After stirring at the
same temperature for 1 h, the mixture was allowed to warm to
room temperature and stirred for 16 h. The reaction was quenched
with saturated aqueous NaHCO3 solution (30 mL) and the resulting
mixture was extracted with EtOAc (3ꢂ20 mL). The combined or-
ganic layers were washed with brine (10 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was used in the next step without further purification. The
residue was dissolved in MeOH (5 mL) and was hydrogenated in the
presence of Pd/C (10% Pd, 16 mg) under a hydrogen atmosphere
(1 atm, balloon) for 12 h. The resulting mixture was filtered and
washed with MeOH, and the filtrate was concentrated under re-
duced pressure. The residue was purified by flash chromatography
on silica gel (eluent: EtOAc/hexane¼1:1) to afford compound 14
(68 mg, yield: 55%) and its diastereomer 14a (10 mg, yield: 8%).
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182e190; (b) Ganem, B. Acc. Chem. Res. 1996, 29, 340e347; (c) Legler, G. In
€
Iminosugars as Glycosidase Inhibitors; Stutz, A. E., Ed.; Wiley-VCH: New York, NY,
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2362e2368; (b) Shibano, M.; Tsukamoto, D.; Kusano, G. Heterocycles 2002, 57,
1539e1553; For selected asymmetric syntheses of radicamine B, see: (c) Yu, C.-
Y.; Huang, M.-H. Org. Lett. 2006, 8, 3021e3024; (d) Gurjar, M. K.; Borhade, R. G.;
Puranik, V. G.; Ramana, C. V. Tetrahedron Lett. 2006, 47, 6979e6981; (e) Merino,
P.; Delso, I.; Tejero, T.; Cardona, F.; Goti, A. Synlett 2007, 2651e2654; (f) Liu, C.;
Gao, J.; Yang, G.; Wightman, R. H.; Jiang, S. Lett. Org. Chem. 2007, 4, 556e558; (g)
Merino, P.; Delso, I.; Tejero, T.; Cardona, F.; Marradi, M.; Faggi, E.; Parmeggiani,
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Zhan, H. Chin. J. Synth. Chem. 2010, 18, 462e464; (j) Shankaraiah, G.; Kumar, R.
S. C.; Poornima, B.; Babu, K. S. Tetrahedron Lett. 2011, 52, 4885e4887; (k)
Mallesham, P.; Vijaykumar, B. V. D.; Shin, D.-S.; Chandrasekhar, S. Tetrahedron
Lett. 2011, 52, 6145e6147.
8. For isolation of codonopsinol, see: (a) Ishida, S.; Okasaka, M.; Ramos, F.; Ka-
shiwada, Y.; Takaishi, Y.; Kodzhimatov, O. K.; Ashurmetov, O. J. Nat. Med. 2008,
62, 236e238; For syntheses of codonopsinol, see: (b) Tsou, E.-L.; Chen, S.-Y.;
Yang, M.-H.; Wang, S.-C.; Cheng, T.-R. R.; Cheng, W.-C. Bioorg. Med. Chem. 2008,
16, 10198e10204; For recent total synthesis of (-)-Codonopsinol, see: (c) Ja-
gadeesh, Y.; Reddy, J. S.; Rao, B. V.; Swarnalatha, J. L. Tetrahedron 2010, 66,
1202e1207.
9. For isolation and bioactivity of hyacinthacines A2 and A3, see: (a) 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, 1e8; For recent
asymmetric syntheses of hyacinthacine A3, see: (b) Izquierdo, I.; Plaza, M. T.;
Franco, F. Tetrahedron: Asymmetry 2002, 13, 1581e1585; (c) Ribes, C.; Falomir,
E.; Carda, M.; Marco, J. A. Tetrahedron 2009, 65, 6965e6971; (d) Huang, P.-Q.;
Liu, W.-J.; Ye, J.-L. Org. Biomol. Chem. 2010, 8, 2085e2091; (e) Hu, X.-G.; Jia, Y.-
M.; Xiang, J.; Yu, C.-Y. Synlett 2010, 982e986; For syntheses of diastereomers,
see: (f) Kaliappan, K. P.; Das, P. Synlett 2008, 841e844; (g) Hu, X.-G.; Jia, Y.-M.;
Xiang, J.-F.; Yu, C.-Y. Synlett 2010, 982e986.
10. For isolation and bioactivity of broussonetines, see: (a) Shibano, M.; Kitagawa,
S.; Kusano, G. Chem. Pharm. Bull. 1997, 45, 505e508; (b) Shibano, M.; Tsuka-
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2000, 48, 1281e1284; (c) Shibano, M.; Tsukamoto, D.; Kusano, G. Heterocycles
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P, see: (e) Yoda, H.; Shimojo, T.; Takabe, K. Tetrahedron Lett. 1999, 40,
1335e1338; (f) Perlmutter, P.; Vounatsos, F. J. Carbohydr. Chem. 2003, 22,
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Biomol. Chem. 2009, 7, 1355e1360; (i) Ribes, C.; Falomir, E.; Murga, J.; Carda, M.;
Marco, J. A. Tetrahedron 2009, 65, 10612e10616.
20
20
Compound 14: colorless oil; [
a
]
ꢀ1.0 (c 1.0, CHCl3) {lit.9d
[a]
D
D
ꢀ0.95 (c 1.0 CHCl3)}; IR (film): 2963, 2857, 1601, 1451, 1360, 1259,
1070 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
1.09 (d, J¼6.7 Hz, 3H, CH3),
1.32e1.47 (m, 1H, H-2), 1.56e1.67 (m, 1H, H-1), 1.68e1.83 (m, 2H, H-
1, H-2), 3.11e3.27 (m, 2H, H-3, H-5), 3.37e3.43 (m, 2H, H-8),
3.45e3.52 (m, 1H, H-7a), 3.68 (t, J¼4.0 Hz, 1H, H-7), 3.98 (t,
J¼4.0 Hz, 1H, H-6), 4.37e4.52 (m, 6H, OCH2), 7.12e7.26 (m, 15H,
AreH) ppm; 13C NMR (100 MHz, CDCl3):
d 17.3, 29.2, 32.6, 57.7, 61.0,
68.8, 71.5, 71.9, 73.2, 73.2, 86.9, 88.2, 127.5, 127.5, 127.5, 127.6 (2C),
127.7 (2C), 127.7 (2C), 128.3 (2C), 128.3 (2C), 128.3 (2C), 138.4, 138.6
(2C) ppm; MS (ESI) m/z 458 (MþHþ, 100%); HRESIMS calcd for
[C30H35NO3]þ (MþHþ): 458.2690; found: 458.2708. Compound
20
14a: colorless oil; [
a]
þ5.2 (c 0.75, CHCl3). IR (film): 2958, 2842,
D
1611, 1432, 1354, 1263, 1052 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
1.03 (d, J¼6.3 Hz, 3H, CH3), 1.33e1.46 (m, 1H, H-2), 1.57e1.68 (m,
1H, H-1), 1.85e1.94 (m, 1H, H-2), 1.99 (m, 1H, H-1), 2.92e3.00 (m,
1H, H-3), 3.01e3.09 (m, 1H, H-5), 3.43e3.48 (m, 2H, H-8),
3.48e3.57 (m, 1H, H-7a), 3.78 (t, J¼4.0 Hz, 1H, H-7), 4.04 (t,
J¼4.0 Hz, 1H, H-6), 4.43 (d, J¼11.9 Hz, 1H, OCH2), 4.46e4.50 (m, 3H,
OCH2), 4.49 (d, J¼11.8 Hz, 1H, OCH2), 4.54 (d, J¼11.8 Hz, 1H, OCH2),
7.12e7.31 (m, 15H, AreH) ppm; 13C NMR (100 MHz, CDCl3):
d 22.8,
29.7, 32.0, 62.5, 68.1, 68.5, 71.7, 72.2, 72.2, 73.3, 87.0, 89.5, 127.4,
127.4, 127.6, 127.6 (2C), 127.7 (2C), 127.7 (2C), 128.2 (2C), 128.3 (2C),
128.3 (2C), 138.4, 138.5 (2C) ppm; MS (ESI) m/z 458 (MþHþ, 100%);
HRESIMS calcd for [C30H35NO3]þ (MþHþ): 458.2690; found:
458.2707.
Acknowledgements
The authors are grateful to the National Basic Research Pro-
gram (973 Program) of China (Grant No. 2010CB833200), the NSF
of China (20832005, 21072160), the Fundamental Research
Funds for the Central Universities of China (Grant No.
201112G001) and Scholarship Award for Excellent Doctoral Stu-
dent granted by Ministry of Education of China (2010) for fi-
nancial support.
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5302
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