Total synthesis of radicamine B and 5-epi-radicamine B

Article abstract of DOI:10.1016/j.tetlet.2011.09.043

Radicamine B 5 was synthesized from p-hydroxy benzaldehyde 7 stereoselectively using acid catalysed amido cyclisation with the help of neighbouring group participation (NGP). Without NGP both radicamine B 5 and its epimer 5-epi radicamine B 6 were obtaine

Full text of DOI:10.1016/j.tetlet.2011.09.043

Tetrahedron Letters 52 (2011) 6366–6369
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Tetrahedron Letters
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Total synthesis of radicamine B and 5-epi-radicamine B
⇑
Y. Jagadeesh, B. Venkateswara Rao
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Radicamine B 5 was synthesized from p-hydroxy benzaldehyde 7 stereoselectively using acid catalysed
amido cyclisation with the help of neighbouring group participation (NGP). Without NGP both radic-
amine B 5 and its epimer 5-epi radicamine B 6 were obtained. The key steps of the synthesis are Sharpless
asymmetric dihydroxylations and acid mediated amido cyclisation.
Received 1 August 2011
Revised 8 September 2011
Accepted 9 September 2011
Available online 21 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Iminosugars, isolated from plants or microorganisms, are consid-
ered to have a high potential therapeutic value and are of interest to
be applied in the elucidation of biological recognition processes, due
to their glycosidase inhibition properties.1 Several structurally re-
lated monocyclic and bicyclic polyhydroxy pyrrolidines have been
reported to show various biological activities, such as antibacterial,2
antiviral,3 antitumor,4 antidiabetic,5 and also acaricidal activity.6
Polyhydroxylated pyrrolidine alkaloids containing an aromatic sub-
stituent on the iminosugar ring are of a rare class found in nature (
Fig. 1), codonopsinine 1, codonopsine 2,7 and codonopsinol 38 are
examples in this unusual category, which exhibit glycosidase inhib-
itory activity. In 2001, Kusano and co-workers isolated radicamines
A 4 and B 5 from Lobelia chinensis LOUR (Campanulaceae). The plant,
L. chinensis LOUR is distributed throughout China, Taiwan, Korea and
Japan. The whole plants have been used as diuretic, antidote, hemo-
stat and as carcinostatic agents for stomach cancer in Chinese folk
medicine.9 Both the compounds 4 and 5 were found to exhibit inhib-
HO
H3C
OH
HO
OH
R
OMe
OMe
N
N
OMe
HO
CH3
CH3
R= H, codonopsinine 1
R= OMe, codonopsine 2
codonopsinol 3
HO
OH
HO
OH
HO
OH
OH
OH
OMe
N
H
N
H
N
H
OH
OH
OH
OH
5-epi-radicamine B 6
radicamine B 5
radicamine A 4
Figure 1. Some structurally related polyhydroxylated pyrrolidine compounds.
Wittig olefination followed by Sharpless asymmetric dihydroxyla-
tion to install the chirality and an intramolecular acid catalysed
amidocyclisation protocol to construct the pivotal pyrrolidine core
of the target molecule.
Reaction of compound 7 with K2CO3 and BnBr in dry DMF at 60 °C
for 12 h gave compound 8 in 91% yield.13 The aldehyde of compound
8 was submitted to the Wittig reaction with Ph3PCHCO2Et in toluene
under reflux for 4 h to give exclusively trans olefin 9 in 88% yield.14
itory activity on a
-glucosidase.10 Kusano et al. proposed the relative
stereochemistry of radicamine A 4 and B 5 as 2S, 3S, 4S, 5S. Later, Yu
and Huang11b and Ramana and co-workers11c independently syn-
thesized natural radicamines 4 and 5 at the same time and assigned
the absolute configuration as 2R,3R,4R,5R (Fig. 1).
In the past one decade a number of methods were developed for
the synthesis of radicamine B 5 from sugars and amino acids.11 In
our continued interest in the development of new and efficient
synthetic routes to some important chiral pyrrolidine compounds
and aza sugars,12 recently we have developed a stereoselective acid
mediated amido cyclisation protocol for constructing the pyrroli-
dine skeleton and applied it for the synthesis of codonopsinine
112c and codonopsinol 3.12b Herein we present the application of
the above strategy for the synthesis of radicamine B 5 starting from
simple and readily available starting material p-hydroxy benzalde-
hyde 7. Our retrosynthetic disconnections are outlined in Scheme
1. The key transformations in the proposed strategy will involve
The treatment of compound 9 with AD-mix-a at 0 °C for 24 h gave
the desired diol derivative 10 in 91% yield.15 Compound 10 on treat-
ment with 2,2-DMP in the presence of catalytic amount of p-TSA in
CH2Cl2 afforded compound 11 in 97% yield. Reduction of the ester
functionality of 11 with LAH afforded alcohol 12 in 92% yield. The
alcohol functionality of the compound 12 was oxidized to aldehyde
under Swern conditions. The resultant aldehyde on Wittig reaction
with Ph3PCHCO2Et in toluene reflux for 6 h gave the corresponding
trans olefin 13 in 83% yield, along with the cis olefin in 9:1 ratio. Fur-
ther, the compound 13 was subjected to dihydroxylation with OsO4,
we got 7:3 ratio of 14 and 15. Based on the kishi rules we assumed
that the stereochemistry of the major isomer would be as shown
in Scheme 2.16 We again tried the dihydroxylation with ‘Admix b’
which is a matched ligand based on the kishi rules, it gave as 14
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B. Venkateswara
Rao).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.043

Y. Jagadeesh, B. Venkateswara Rao / Tetrahedron Letters 52 (2011) 6366–6369
6367
O
OAc OAc
OH
HO
cyclisation with
NGP
H
OAc
N
H
OAc NHCOR'
HO
p-hydroxy benzaldehyde 7
RO
RO
OH
HO
radicamine B 5
O
OH
Sharpless asymmetric
dihydroxylations
Wittig olefinations
cyclisation without
NGP
OH
NHCOR'
O
OH
HO
O
OH
O
OEt
N
H
O
OH
OH
HO
RO
5-epi-radicamine B 6
Scheme 1. Retrosynthetic pathway.
O
OH
O
O
O
b
c
a
H
OEt
H
OEt
OH
HO
BnO
BnO
BnO
7
8
10
9
O
O
O
O
O
f
e
d
OEt
OH
OEt
O
O
BnO
O
11
BnO
BnO
12
13
O
OH
O
O
OH
O
g
OEt
OEt
O
OH
O
15
OH
BnO
BnO
14
Scheme 2. Reagents and conditions: (a) BnBr, K2CO3, TBAI, DMF, 60 °C, 12 h, 91%; (b) Ph3PCHCO2Et, toluene, reflux, 4 h, 88%; (c) AD-mix-a, CH3SO2NH2, tBuOH:water, 24 h,
91%; (d) 2,2-DMP, p-TSA, CH2Cl2, 12 h, 97%; (e) LiAlH4, THF, 0 °C to rt, 3 h, 92%; (f) (i) (COCl)2, DMSO, CH2Cl2, ꢀ78 °C (ii) Ph3PCHCO2Et, toluene, reflux, 6 h, 83%; (g)
(DHQ)2PHAL, OsO4, K2CO3, K3Fe(CN)6, CH3SO2NH2, tBuOH:water, 92%.
and 15 in 19:1 ratio. In order to get the required isomer 15 in excess,
we utilized ‘Admix
’ for dihydroxylation.16a Initially we tried with
1 mol % which gave us 14 and 15 in 4:6 ratio. The poor de is because
of the unmatched nature of ‘Admix ’ with the substrate. To improve
the ratio further in favour of 15, we utilized excess ligand (4 mol %)
which gave us the separable products 14 and 15 in 1:5.5 ratio, as per
our earlier observation.12c
The diol 15 on further treatment with thionyl chloride/Et3N in
CH2Cl2 afforded the cyclic sulfite, which was immediately treated
with sodium azide in dry DMF, to undergo stereoselective ring
opening with azide to give the azido alcohol 16 in 84% yield.17
Reduction of the azido functionality with TPP/ethanol gave amine,
which was immediately treated with CbzCl/Na2CO3 in ethanol to
afford the fully protected compound 17 in 76% yield. The ester
functionality of compound 17 was reduced under LiBH4 conditions
to give the diol 18 in 78% yield. Treatment of compound 18 with
TFA:CH2Cl2 (1:1) for 4 h at room temperature gave directly diaste-
reomeric cyclic pyrrolidine compounds 19 and 20 (1.3:1) in 78%
yield (Scheme 3). The formation of cyclic compounds 19 and 20
from 18 can be explained through intramolecular SN1 reaction
where the acetonide deprotection followed by intramolecular cyc-
lisation is taking place simultaneously. It seems plausible to sug-
gest that the N-nucleophilic attack on the sp2 carbon of the
stabilised benzylic carbocation yielded diastereomeric cyclic pyrr-
oilidine compounds 19 and 20 (1.3:1).12b
a
a
To get complete stereoselectivity in cyclisation we required tet-
raacetyl derivative as per our earlier observation.12c Keeping this
in mind, we planned for tetraacetate derivative 21 from the diol
compound 18. When compound 18 was subjected to mild acidic
conditions (80% acetic acid in water) it gave the corresponding tetrol
derivative as a single product, which on acetylation with acetic
anhydride in the presence of Et3N afforded tetraacetyl derivative
21 in 67%. Treatment of compound 21 with trifluoroacetic acid in
CH2Cl2 (1:3) indeed afforded the cyclic triacetyl derivative 22 as an
exclusive isomer in 90% yield. The stereoselective formation of pyr-
rolidine compound 22 from 21 can be explained through intramo-
lecular SN1 reaction via resonance-stabilized benzylic carbocation.
The benzylic carbocation can be further stabilized by the neighbour-
ing acetoxy group to give a trans dioxolane carbocation (acetoxoni-
um ion) intermediate, thereby further facilitating the approach of

6368
Y. Jagadeesh, B. Venkateswara Rao / Tetrahedron Letters 52 (2011) 6366–6369
O
OH
O
O
OH
O
O
OH
O
a
b
OEt
OEt
OEt
O
NHCBz
O
N3
O
OH
BnO
BnO
d
BnO
c
15
17
16
O
OH
HO
OH
HO
OH
OH
NHCBz
OH
OH
O
BnO
HN
Cbz
HN
Cbz
BnO
BnO
18
OH
OH
HO
HO
N
N
CBz
CBz
OH
OH
BnO
BnO
19
20
Scheme 3. Reagents and conditions: (a) (i) SOCl2, Et3N, CH2Cl2, 0 °C to rt, 30 min; (ii) NaN3, DMF, 80 °C, 2 h, 84%; (b) (i) TPP, ethanol, 0 °C to rt, 6 h; (ii) CbzCl, Na2CO3, ethanol,
0 °C to rt, 8 h, 76%; (c) LiCl, NaBH4, ethanol, THF, 0 °C to rt, 3 h, 78%; (d) TFA:CH2Cl2 (1:1), 0 °C to rt, 4 h, 78%.
OAc OAc
O
H3C
O
OH
OAc OAc
b
a
O
OH
NHCBz
NHCBz
OAc
OAc NHCBz
O
BnO
BnO
BnO
BnO
21
18
OH
O
HO
OAc
OH
O
AcO
HO
c
d
e
5
N
N
N
O
CBz
22
OAc
HO
BnO
O
24
23
Scheme 4. Reagents and conditions: (a) (i) 80% aq AcOH, rt, 8 h, 94%; (ii) Ac2O, Et3N, CH2Cl2, DMAP, 0 °C to rt, 4 h, 67%; (b) TFA:CH2Cl2 (1:3), 0 °C to rt, 4 h, 90%; (c) K2CO3,
MeOH, 0 °C to rt, 1 h, 84%; (d) PdCl2/H2 MeOH, 12 h, 84%; (e) (i) 6 N HCl soln, ethanol, reflux, 3 h, 80%; (ii) DOWEX 5WX8-200, 30% ammonia solution.
the N-nucleophile preferentially from the opposite face and giving
stable 2,5-trans-substituted pyrrolidine. The triacetyl compound
22 on deacetylation with K2CO3 in methanol gave interestingly the
bicyclic carbamate 23 in 84% yield instead of the corresponding N-
Cbz triol compound. The O-benzyl group in compound 23 was
deprotected by catalytic hydrogenation to give compound 24 in
84% yield. This on treatment with 6 N HCl in ethanol at reflux gave
the hydrochloride salt of radicamine B 5.18 The spectral and analyt-
ical data of the hydrochloride salt of radicamine B 5 were in excellent
agreement with the reported values.11d When the compound 5
passed through DOWEX W8-200 exchange resin column with 30%
NH3 solution afforded 519 as the free base (Scheme 4), whose phys-
ical and spectroscopic data were also identical with the reported
values.9a
transferred to 5-epi-radicamine B 620 on hydrogenation in 80%
yield (Scheme 5), whose spectral data were also in excellent agree-
ment with the reported values.21
In conclusion, the stereoselective synthesis of radicamine B 5
and its epimer 5-epi radicamine B 6 was achieved from p-hydroxy
benzaldehyde with simple reaction sequences and intramolecular
SN1 cyclisation strategy as the key step. This further confirms our
earlier proposed mechanism where the acetate is participating as
the neighbouring group during the amido cyclisation reaction.
Acknowledgements
Y.J. thanks CSIR, New Delhi for the research fellowship. The
authors also thank Dr. J. S. Yadav for his support and encourage-
ment. We also thank DST (SR/S1/OC-14/2007), New Delhi for finan-
cial support.
The cyclised compound 19 on hydrogenation also gave radic-
amine 5 in 80% yield. In a similar way, the minor isomer 20 was
OH
OH
HO
HO
a
a
;
20
19
N
H
6
N
H
5
OH
OH
HO
HO
Scheme 5. Reagents and conditions: (a) PdCl2/H2, MeOH, 12 h, 80%.

Y. Jagadeesh, B. Venkateswara Rao / Tetrahedron Letters 52 (2011) 6366–6369
6369
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Supplementary data
Supplementary data associated with this Letter can be found, in
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18. Spectral data of radicamine B salt (5ꢁHCl): ½a D28
ꢂ
+84.27 (c 1.24, MeOH) {lit.11d
½ ꢂ +74 (c 0.1, H2O)}; IR (neat) mmax: 3500–3000 (broad band), 1609, 1517,
a 2D5
1363, 1230, 828 cmꢀ1 1H NMR (500 MHz, D2O): d 3.58 (m, 1H), 3.78–3.87 (m,
;
2H), 4.08 (t, J = 7.7 Hz, 1H), 4.32 (d, J = 9.9 Hz, 1H), 4.37 (dd, J = 7.2, 9.9 Hz, 1H),
6.87 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H) ppm; 13C NMR (75 MHz, D2O) d
58.2, 61.6, 62.8, 73.7, 77.1, 116.2, 122.9, 130.2, 157.1 ppm; ESI/MS (m/z): 226.
19. Spectral data of radicamine B (5): ½a D28
ꢂ
+68.05 (c 0.37, MeOH) {lit.9a a 2D0
½ ꢂ +72 (c
0.1, H2O)}; IR (neat) mmax: 3500–3000 (broad band), 2363, 1515, 1246, 1038,
6. Tsuchiya, K.; Kobayashi, S.; Harada, T.; Kurokawa, T.; Nakagawa, T.; Shimada,
N.; Kobayashi, K. J. Antibiot. 1995, 48, 626.
830 cmꢀ1 1H NMR (500 MHz, D2O): d 3.27 (m, 1H), 3.67 (dd, J = 6.5, 12.1 Hz,
;
1H), 3.73 (dd, J = 4.7, 12.1 Hz, 1H), 3.91–3.96 (m, 2H), 4.11 (dd, J = 7.4, 9.0 Hz,
1H), 6.86 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H) ppm; 13C NMR (75 MHz,
D2O) d 64.2, 65.9, 79.3, 83.6, 118.4, 131.8, 131.9, 158.5 ppm; ESI/MS (m/z): 226
(M++H); HRMS (ESI): calcd for C11H16NO4 226.1079. Found 226.1090.
7. (a) Matkhalikova, S. F.; Malikov, V. M.; Yunusov, S. Y. Khim. Prir. Soedin 1969, 5,
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20. Spectral data of 5-epi radicamine B (6): ½a D28
ꢂ
+49.6 (c 0.89, MeOH) {lit.21 a 2D0
½ ꢂ
+47.7 (c 0.3, H2O)}; IR (neat) m ;
max: 3825, 2930, 1519, 1234, 1075, 834 cmꢀ1 1H
NMR (500 MHz, D2O); d 3.49–3.68 (m, 2H), 3.86 (psuedo t, J = 8.5 Hz, 1H), 3.96
(dd, J = 4.7, 12.4 Hz, 1H), 4.12 (s, 1H), 4.31 (s, 1H), 6.88 (d, J = 8.2 Hz, 2H), 7.32
(d, J = 8.2 Hz, 2H) ppm; 13C NMR (75 MHz, D2O): d 59.4, 64.5, 67.3, 75.9, 76.4,
115.7, 121.8, 129.7, 156.2 ppm; ESI/MS (m/z): 226 (M++H); HRMS (ESI): calcd
for C11H16NO4 226.1079. Found 226.1087.
21. Zhou, X.; Liu, W.-J.; Ye, J.-L.; Huang, P.-Q. Tetrahedron 2007, 63, 6346.