Diastereocontrolled synthesis of (-)-codonopsinine

Article abstract of DOI:10.1055/s-2003-36777

An efficient process is described for the total synthesis of the alkaloid (-)-codonopsinine. The synthetic strategy is based on the diastereoselective hydrocyanation of a 2,3-dialkoxyaldehyde derived from L-threonine followed by a reductive alkylation of

Full text of DOI:10.1055/s-2003-36777

274
LETTER
Diastereocontrolled Synthesis of (–)-Codonopsinine
Diastereocontrolled
S
y
a
nthesis of
(
n
–)-Codonops
s
inine our Haddad, Marc Larchevêque*
Laboratoire de Synthèse Organique associé au CNRS, ENSCP, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Fax +33(1)43257975; E-mail: larchm@ext.jussieu.fr
Received 11 December 2002
syn stereochemistry would be obtained by diastereocon-
trolled hydrocyanation of a diprotected dihydroxyalde-
hyde of type 5.8 We have previously reported that the
reductive alkylation of 2,3-dialkoxynitriles with alkyl
Abstract: An efficient process is described for the total synthesis of
the alkaloid (–)-codonopsinine. The synthetic strategy is based on
the diastereoselective hydrocyanation of a 2,3-dialkoxyaldehyde
derived from L-threonine followed by a reductive alkylation of the
nitrile function with a Grignard compound and sodium borohydride. Grignard reagents afforded protected aminodiols in good
yields.9 The relative stereochemistry between the oxygen
The resulting aminotriol was then cyclized into the target molecule
after selective mesylation.
at the a-position to the newly created amino function and
Key words: alkaloid, aminoalcohol, cyanohydrine, pyrrolidine
this latter group was generally established as syn; however
we recently observed that the use of aromatic Grignard
reagents reversed the diastereoselectivity to give the
aminoalcohols anti mainly.10
Codonopsinine 1 and codonopsine 2, antibiotics first iso-
lated in 1969 from Codonopsis clematidea by a Russian
group1 exhibit hypotensive pharmacological activity with
no effect on the central nervous system observed in ani-
mal tests.2 After structural characterization,1b,3 they re-
vealed to be a new class of simple pyrrolidine alkaloids
possessing 1,2,3,4,5 pentasubstituted structures. The ab-
solute configuration of the natural antibiotic 1 (Figure 1)
was determined unambiguously to be (2R,3R,4R,5R).4 In
addition, the structure of codonopsine 2 was recently con-
firmed by another group using X-ray crystallographic
analysis.5
CH3
OH
HO
OH HN
H3C
N
OMs OH
OCH3
CH3
OCH3
CN
3
O
OP
CHO
OBn
O
OBn
4
5
Despite interesting pharmacological activity and unique
structural features, to our knowledge only two syntheses
have been reported to date.6
P : protective group
Scheme 1
OH
HO
The required trialkoxynitrile 4 was synthesized very easi-
ly starting from the monoprotected dihydroxyester 7a
(Scheme 2). This latter compound was obtained by regi-
oselective opening of the (2S,3S) glycidic epoxide 6 de-
rived from L-threonine.11 The reaction of this epoxide
with benzylalcohol in the presence of lithium
perchlorate12 afforded the ester 7a exclusively.13 The free
hydroxy function of this compound was then protected as
a MOM ether and the resulting ester 7b was transformed
into the aldehyde 9 by reduction of the ester function into
the alcohol 8 with DIBAL-H followed by a Swern oxida-
tion. The hydrocyanation of the resulting aldehyde with
trimethylsilyl cyanide in the presence of MgBr2·OEt2 ac-
cording Ward et al14 and subsequent removal of the MOM
protection conducted to compound 10 which was protect-
ed as an acetonide to give the nitrile 4. This compound
was obtained in 80% yield and in a diastereomeric ratio
better than 98:2.
R
H3C
N
R = H Codonopsinine 1
R = OCH3 Codonopsine 2m
CH3
OCH3
Figure 1
We wish to describe here a new approach to the natural
codonopsinine 1 based on the stereocontrolled reductive
alkylation of a trialkoxynitrile and further cyclization of
the resulting aminotriol.
We planned to synthesize this alkaloid by cyclization of a
linear aminotriol 3 in which the appropriate alcohol would
be activated as a mesylate (Scheme 1). Such an intermedi-
ate could be obtained by a reductive alkylation of the ni-
trile 4 resulting from the condensation of an aromatic
Grignard reagent followed by in situ reduction of the in-
termediate imine.7 The required trihydroxynitrile with all
This nitrile was transformed into secondary amine in the
following manner: 4-methoxyphenylmagnesium bromide
in THF was reacted with nitrile 4. After completion of the
addition, the intermediate iminomagnesium compound
was treated with methanol and the resulting primary imine
Synlett 2003, No. 2, Print: 31 01 2003.
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© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Diastereocontrolled Synthesis of (–)-Codonopsinine
275
OMOM
was transiminated into secondary imine with methyl-
amine in methanol15 and reduced with sodium borohy-
dride. This transimination allowed us to access directly to
the N-methyl amine required for the synthesis of the target
molecule. The amine 11 was isolated as a 8:2 mixture of
diastereomers and in a 80% yield from nitrile 4.16
OP
CO2Et
a
c
R
CO2Et
O
OBn
OBn
8 R = CH2OH
9 R = CHO
6
7a P = H
b
d
7b P = MOM
At this stage, we were unable to determine the relative ste-
reochemistry of the aminotriol 11. The synthesis of
codonopsinine was carried on with the diastereomeric
mixture. First attempts of debenzylation by catalytic hy-
drogenation or by elimination with dimethylsulfide–bo-
ron trifluoride diethyl etherate17 failed, giving poor yields
or non-reproducible results. However, a satisfactory result
was obtained by protecting the secondary amine as its tri-
fluoroacetamide. Removal of the benzyl group was then
conducted without any problem by catalytic hydrogena-
tion of 12 using10% palladium on charcoal as catalyst.
The resulting free secondary alcohol was then trans-
formed into mesylate and the amine was deprotected by
hydrolysis with aqueous potassium carbonate. Due to the
presence of the acetonide, the cyclization was impossible
at this stage and it was necessary to remove this protection
in acidic medium to obtain codonopsinine after treatment
with potassium carbonate. The minor isomer was easily
removed and pure codonopsinine 1 was isolated in 55%
yield.18 The relative stereochemistry was established by
comparison of the 1H NMR spectrum which was identical
to the spectrum reported for the (–)-(2R,3R,4R,5R) iso-
mer,4b Melting point and rotatory power were also in
agreement with the reported values thus establishing the
relative configuration of compound 11 to be 1,2 anti.
Moreover, an accurate examination of the 1H NMR spec-
trum showed that the minor isomer was the (2S,3R,4R,5R)
epimer.
OH
O
e
f
CN
CN
O
OBn OH
BnO
10
4
COCF3
O
NR
O
N
g
i
BnO
O
HO
O
OCH3
OCH3
11 R = H
12 R = CO-CF3
13
h
OH
HO
O
HN
j
k
H3C
N
MsO
O
OCH3
CH3
OCH3
14
1
Scheme 2 (a) neat BnOH 3 equiv, LiClO4 0.5 equiv, 30 h, 60 °C,
67%; (b) MOMCl, i-Pr2EtN, 12 h; r.t., 82%; (c) DIBAL-H, toluene,
–30 °C to 20 °C, 12 h, 82%; (d) (COCl)2, DMSO, Et3N, 90%; (e) 1)
TMSCN, MgBr2–Et2O 2 equiv, CH2Cl2, 0 °C, 3 h then r.t. (15 h), 2)
10% HCl–MeOH, r.t., 12 h, 85% (two steps); (f) Dimethoxypropane,
cat. APTS, benzene azeotrope, 80 °C, 3 h, 77%; (g) cf Ref.16 (h)
(CF3CO)2O, Et3N, r.t., 16 h, 91%; (i) H2, 10% Pd/C, EtOH, r.t., 12 h,
90%; (j) MsCl, Et3N–cat. DMAP, CH2Cl2, 20 °C, 12 h, then K2CO3,
MeOH–H2O, 10 h, 80%; (k) 10% aqueous HCl–THF 1:1, 65 °C, 12
h, then K2CO3, 20 °C, 18 h, 55%.
The stereochemical outcome is consistent with a chela-
tion-controlled mechanism. Indeed, it is reasonable to
assume that the species actually reduced is not the magne-
sioimine but more likely the hydrogenated or alkylated
imine resulting from the methanolysis. A chelation of the
solvated MgBr2 magnesium atom by the oxygen in posi-
tion a or b may be postulated and the formation of the b-
chelate is probably disfavored by the steric hindrance gen-
erated by the presence of the acetonide, which increases
the distance between the b-oxygen and the nitrogen atom
(Figure 2). However, at present, we have no explanation
for the reversal of the stereochemistry when moving from
aryl to alkyl Grignard reagents. In order to rationalize
these results, further exploration of these reactions are
underway in our laboratory.
M
Me
O
N
O
H -
H
R
CH(Me)OBn
H
α-chelate
Figure 2
References
In summary, this synthesis demonstrates that the reductive
alkylation of 2,3-dialkoxynitriles allows an efficient ac-
cess to codonopsinine and could be applied to other poly-
hydroxylated pyrrolidines.
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Synlett 2003, No. 2, 274–276 ISSN 0936-5214 © Thieme Stuttgart · New York

276
M. Haddad, M. Larchevêque
LETTER
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A 0.5 M solution of 4-methoxyphenylmagnesium bromide
in THF (8 mL, 4.0 mmol) was added dropwise via a syringe
through a septum and the reaction was allowed to warm to
room temperature. Stirring was continued for 4 h before
being cooled to –13 °C. Anhydrous methanol (5 mL) and a
1:1 (v/v)solution of methylamine in anhydrous methanol (5
mL) were added successively and the mixture was stirred for
45 min at room temperature. Sodium borohydride (254 mg,
6.7 mmol) was then added. The resultant mixture was stirred
overnight and water (50 mL) was added. The mixture was
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layers were washed with brine. After the usual work-up, the
residue was subjected to column chromatography (CH2Cl2
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(18) Selected data: 14: [α]D20 –13.1 (c = 1.43, CH2Cl2); 1H NMR
(200 MHz, CDCl3): δ (ppm) 1.28–1.38 (m, 9 H), 1.60 (m, 1
H), 2.22 (s, 3 H), 3.06 (s, 3 H), 3.61 (d, 1 H, J = 5.2 Hz), 3.78
(s, 3 H), 3.88 (dd, 1 H, J = 3.4 Hz, 7.8 Hz), 4.19 (dd, 1 H, J
= 5.2 Hz, 7.8 Hz), 4.58 (dq, 1 H, J = 3.4 Hz, 6.4 Hz), 6.88
and 7.22 (AB system, 2 H, J = 8.6 Hz). 13C (50 MHz,
CDCl3): δ (ppm) 18.1, 26.6, 27.1, 27.8, 34.0, 38.5, 55.1,
78.0, 79.3, 80.0, 80.7, 109.3, 113.8, 129.0, 130.6, 159.0. MS
(CI, NH3) m/z (%) = 374 (MH+, 100%).
1: mp: 170–171 °C: lit. 172.5–173.5 °C.4b [α]D20 –10.5 (c =
1.1, MeOH): lit. +12.5 (c 2.55, MeOH) for the enantiomer.4b
1H NMR (400 MHz, DMSO): δ (ppm) 1.18 (d, 3 H, J = 6.4
Hz), 2.00 (s, 3 H), 3.13 (dq, 1 H, J = 4.1 Hz, 6.7 Hz), 3.58 (d,
1 H, J = 6.3 Hz), 3.69 (t, 1 H, J = 4.1 Hz), 3.78 (s, 3 H), 3.96
(dd, 1 H, J = 4.0 Hz, 6.4 Hz), 6.91 and 7.28 (AB system, 4
H, J = 8.8 Hz). 13C (50 MHz, DMSO): δ (ppm) 13.5, 35.0,
55.6, 65.6, 74.3, 84.7, 86.0, 114.7, 130.8, 133.0, 160.7. MS
(EI) m/z (%) = 237 (11), 222 (5), 176 (100), 162 (26), 121
(23).
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(16) Experimental procedure for 11: Nitrile 4 (0.70 g, 2.68 mmol)
was placed in anhydrous Et2O (40 mL) and cooled to –13 °C.
Synlett 2003, No. 2, 274–276 ISSN 0936-5214 © Thieme Stuttgart · New York