Stereoselective synthesis of an immunomodulator (+)-conagenin using dirhodium(II)-catalyzed C-H amination and chelation-controlled reductions as key steps

Article abstract of DOI:10.1055/s-2006-933145

Stereoselective synthesis of an immunomodulator (+)-conagenin from commercially available optically active methyl 3-hydroxy-2-methylpropanoate was achieved using dirhodium(II)-catalyzed C-H amination and chelation-controlled reductions as key steps. Georg

Full text of DOI:10.1055/s-2006-933145

930
LETTER
Stereoselective Synthesis of an Immunomodulator (+)-Conagenin Using
Dirhodium(II)-Catalyzed C–H Amination and Chelation-Controlled
Reductions as Key Steps
Stereoselective
a
S
ynthesis
o
k
f
an Immuno
a
modulator
y
(+)-Conagen
u
in ki Yakura,* Yuya Yoshimoto, Chisaki Ishida, Shunsuke Mabuchi
Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
E-mail: yakura@pha.u-toyama.ac.jp
Received 7 January 2006
corresponding trichloroacetyl carbamate, which was
treated with neutral alumina12 without purification to ob-
tain the precursor of C–H amination reaction 5 in quanti-
tative yield. Dirhodium(II)-catalyzed C–H amination of 5
using modified Du Bois’ conditions9 proceeded stereo-
specifically to give oxazolidinone 6. Thus, treatment of 5
with 10 mol% of dirhodium(II) tetraacetate, 4.2 equiva-
lents of phenyliodine(III) diacetate, and 6.9 equivalents of
magnesium oxide in dichloromethane under reflux for 40
hours gave the corresponding C–H amination product 6 in
64% yield based on the consumed 5 (30% of 6 and 53%
of recovered 5).13 After the NH group of oxazolidinone
was protected with tert-butoxycarbonyl (Boc) group to af-
ford 7 in 76% yield, the oxazolidinone ring-opening was
accomplished by the treatment of 7 with cesium carbonate
in methanol14 to give optically pure N-Boc-a-methyl-
serine methyl ester 2, [a]D27 +2.17 (c 1.33, CHCl3) {lit.15
[a]D18 +1.9 (c 0.54, CHCl3)}, in 79% yield.16
Abstract: Stereoselective synthesis of an immunomodulator (+)-
conagenin from commercially available optically active methyl 3-
hydroxy-2-methylpropanoate was achieved using dirhodium(II)-
catalyzed C–H amination and chelation-controlled reductions as
key steps.
Key words: conagenin, immunomodulator, dirhodium(II), C–H
amination, chelation control, reduction
(+)-Conagenin (1) was isolated from the fermentation
broths of Streptomyces roseosporus, by Ishizuka and co-
workers in 1991.1 It is a low molecular weight immuno-
modulator and stimulates activated T-cells,2 which pro-
duce lymphokines and generate antitumor effector cells.
In addition, 1 was found to improve the antitumor efficacy
of adriamycin and mitomycin C against murine leuke-
mia.3 Because of these biological activities and its unique
highly functionalized structure, 1 has attracted much at-
tention from synthetic chemists. Until now, three total
syntheses4 and a formal synthesis5 of (+)-1 have been
reported, in addition to synthesis of its analogues6 and a
partial synthesis.7 We report here the stereoselective syn-
thesis of (+)-1. Both amine 2 and carboxylic acid 3 moi-
eties were synthesized starting from commercially
available methyl 3-hydroxy-2-methylpropanoate (4)8
(Scheme 1).
O
MeO2C
i
ii
MeO2C
O
O
(R)-4
O
NH2
HN
6
5
MeO2C
iii
iv
BocHN
CO2Me
OH
O
O
N
Boc
2
7
Scheme 2 Reagents and conditions: i) CCl3CON=C=O, CH2Cl2,
r.t., 1 h, then neutral Al2O3 (quant); ii) 10 mol% Rh2(OAc)4, 4.2 equiv
PhI(OAc)2, 6.9 equiv MgO, CH2Cl2, reflux, 40 h (64% based on
consumed 5); iii) Boc2O, Et3N, DMF, r.t., 12 h (76%); iv) Cs2CO3,
MeOH, r.t., 1 h (79%).
BocHN
CO2Me
OH
OH OH
H
2
N
CO2H
OH
MeO2C
+
OH
O
OAc OAc
(R)-4 or (S)-4
(+)-conagenin (1)
CO2H
The next subject is the stereoselective synthesis of carbox-
ylic acid moiety 3 and its precursor 16, which have al-
ready been used as key intermediates for 1 by the
Hatakeyama group4a and the Ichikawa group.4c From the
perspective of applicability to synthesis of a wide range of
analogues, we chose a stepwise procedure for 16 from
methyl 3-hydroxy-2-methylpropanoate using stereoselec-
tive reductions (Scheme 3). p-Methoxybenzyl (PMB)
ether 8, which was prepared from (S)-4 according to
modified Mukaiyama protocol17 using 2-PMBoxy-3-ni-
tropyridine, was hydrolyzed using lithium hydroxide, fol-
lowed by treatment with two equivalents of phenyllithium
to afford phenyl ketone 9 in 72% yield. Chelation-con-
trolled reduction of PMBoxy-ketone 9 was accomplished
3
Scheme 1
Synthesis of a-methylserine moiety 2 was achieved
quickly from 4 based on Du Bois’ stereospecific dirhodi-
um(II)-catalyzed C–H amination reaction9–11 as a key step
(Scheme 2). Reaction of (R)-4 with trichloroacetyl iso-
cyanate in dichloromethane at room temperature gave the
SYNLETT 2006, No. 6, pp 0930–0932
0
4.
0
4.
2
0
0
6
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-933145; Art ID: U00406ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Synthesis of an Immunomodulator (+)-Conagenin
931
using zinc borohydride according to Nakata’s procedure18 Finally, conversion to conagenin was accomplished using
to afford syn-alcohol 10 in 94% yield as a major isomer. a modification of Ichikawa’s procedure4c (Scheme 4).
The ratio of syn- and anti-isomers was determined accord- Thereby, condensation of 2 and 3 proceeded using 1,3-di-
1
ing to the H NMR spectrum of the mixture to be 19:1. cyclohexylcarbodiimide (DCC) in the presence of 1-hy-
The stereochemistry of 10 was determined by the com- droxybenzotriazole (HOBt) in CH2Cl2 to give ester 17 in
parison of spectroscopic data of the corresponding diol, 89% yield, which was deprotected by trifluoroacetic acid,
which was obtained by deprotection of 10 with 2,3- followed by O–N intramolecular acyl migration using so-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), to those dium bicarbonate gave diacetylconagenin methyl ester 18
of the known authentic sample.18,19 Treatment of 10 with in 81% yield. Deprotection was carried out under basic
DDQ in the presence of molecular sieves 3 Å in anhy- conditions to afford (+)-conagenin (1), mp 154–157 °C,
27
drous dichloromethane, followed by diisobutylaluminum [a]D28 +56.6 (c 0.20, MeOH) {lit.1 mp 159–161 °C, [a]D
hydride (DIBAL-H) reduction of the resultant benzyl- +55.4, lit.4c mp 153–155 °C, [a]D +56.8 (c 0.44,
20
idene acetal gave rise to the primary alcohol 11 in 55% MeOH)}, in 71% yield. Spectroscopic data of 1 were
yield in two steps. Dess–Martin periodinane oxidation of identical to those of the reported sample.4c
11 produced 12 in 85% yield. Methylation of 12 with
OAc OAc
methyllithium in diethyl ether afforded a 4:1 mixture of
two diastereomers20 of secondary alcohol 13 in 91% yield,
which was oxidized with Dess–Martin periodinane to
provide methyl ketone 14. Then chelation-controlled
reduction of 14 was examined. In contrast to reduction of
9, unfortunately, reduction of PMBoxy-ketone 14 with
zinc borohydride in diethyl ether occurred with low level
of diastereoselectivity (2:1)20 to give 13. However, zinc
borohydride reduction of the hydroxy-ketone 15, which
was obtained by deprotection of 14 with DDQ in dichloro-
methane, afforded stereoselectively (>50:1) the known
diol 16, [a]D27 +35.4 (c 1.06, CHCl3) {lit.4a [a]D24 +35.5 (c
0.46, CHCl3), lit.4c [a]D18 +41.0 (c 1.05, CHCl3)}, in 83%
yield. According to the reported procedure,4a,c protection
of both hydroxy groups of 16 as acetates and oxidation of
phenyl group with ruthenium tetraoxide afforded the
carboxylic acid moiety 3 in 86% yield in two steps.
i
ii
O
+
2
3
HN
Boc
CO2Me
O
17
OAc OAc
OH OH
H
H
N
CO2Me
OH
N
CO2H
OH
iii
O
O
18
1
Scheme 4 Reagents and conditions: i) DCC, HOBt, DMAP,
CH2Cl2, r.t., 1.5 h (89%); ii) CF3CO2H, CH2Cl2, r.t., 4 h then aq
NaHCO3, THF, r.t., 10 h (81%); iii) 1 M K2CO3–MeOH (1:3), r.t.,
2 h (71%).
In summary, the convergent total synthesis of (+)-1 was
accomplished starting from commercially available
methyl 3-hydroxy-2-methylpropanoate 4. Amine moiety
2 was synthesized using C–H amination reaction as a key
step. Carboxylic acid moiety 3 was prepared based on
chelation-controlled reductions with zinc borohydride.
O
i
ii, iii
CO2Me
(S)-4
PMBO
PMBO
Ph
vii
8
9
References and Notes
OH
OPMB
(1) Yamashita, T.; Iijima, M.; Nakamura, H.; Isshiki, K.;
Naganawa, H.; Hattori, S.; Hamada, M.; Ishizuka, M.;
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iv
v, vi
PMBO
OPMB
Ph
HO
Ph
10
11
OH OPMB
O
OPMB
ix
viii
OHC
Ph
Ph
Ph
12
13
14
O
OH
OH OH
OAc OAc
CO2H
x
xi
xii, xiii
Ph
Ph
15
16
3
Scheme 3 Reagents and conditions: i) 2-PMBoxy-3-nitropyridine,
PPTS, CH2Cl2, reflux, overnight (87%); ii) LiOH, H2O, r.t., 4 h; iii)
PhLi, Et2O, 0 °C, 30 min (72% in 2 steps); iv) Zn(BH4)2, Et2O, 0 °C,
30 min (94%); v) DDQ, 3 Å MS, CH2Cl2, r.t., 1 h (65%); vi) DIBAL-
H, CH2Cl2, –80 °C, 1 h (84%); vii) Dess–Martin periodinane, CH2Cl2,
r.t., 30 min (85%); viii) MeLi, Et2O, –80 °C, 30 min (91%); ix) Dess–
Martin periodinane, CH2Cl2, r.t., 30 min (quant); x) DDQ, CH2Cl2,
r.t., 1 h (81%); xi) Zn(BH4)2, Et2O, 0 °C, 30 min (83%); xii) Ac2O,
pyridine, DMAP, r.t. 30 min (86%); xiii) cat. RuCl3, H5IO6, MeCN–
CCl4–H2O, r.t., 18 h (quant).
Synlett 2006, No. 6, 930–932 © Thieme Stuttgart · New York

932
T. Yakura et al.
LETTER
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dirhodium(II) catalysts, hypervalent iodine reagents,
solvents] gave poorer yields of cyclization product.
Development of an alternative route using C–H amination
has been investigated and will be reported.
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obtained in the condensation of 2 and 3 would reveal that the
dirhodium(II)-catalyzed C–H amination of 5 proceeded
exclusively with retention of configuration, as Espino and
Du Bois have reported.9
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(19) Diol, [a]D27 +56.1 (c 0.75, CHCl3) {lit. [a]D20 +52.6 (c 0.57,
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(20) The stereochemistries of neither diastereomer were
determined.
Synlett 2006, No. 6, 930–932 © Thieme Stuttgart · New York