A radical approach for the construction of the tricyclic core of stemoamide

Article abstract of DOI:10.1055/s-2004-837197

A rapid synthesis of (±)-9,10-bis-epi-stemoamide is presented. Three of the four contiguous Stereocenters of this compound were set in a diastereoselective radical 7-exo-trig cyclization, which also allowed the construction of the tricyclic core of the mo

Full text of DOI:10.1055/s-2004-837197

LETTER
349
A Radical Approach for the Construction of the Tricyclic Core of Stemoamide
C
onstructionof th
i
T
ric
y
c
e
o
o
Stemoamid
l
e
as Bogliotti, Peter I. Dalko, Janine Cossy*
Laboratoire de Chimie Organique associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
E-mail: Janine.Cossy@espci.fr
Received 30 September 2004
Abstract: A rapid synthesis of ( )-9,10-bis-epi-stemoamide is pre-
sented. Three of the four contiguous stereocenters of this compound
were set in a diastereoselective radical 7-exo-trig cyclization, which
also allowed the construction of the tricyclic core of the molecule.
R
R
O
C
O
7-exo-trig
N
N
O
A
O
B
O
O
Key words: radical cyclization, metathesis, stereoselective syn-
thesis
H
A
R = H
R = Me
RCM
PhS
R
O
Stemoamide (Figure 1) is the structurally simplest
member of the large number of biologically active
Stemonaceae alkaloids, which were obtained by extrac-
tion of the roots and rhizome of the Stemona and
Croomina species. In traditional Chinese and Japanese
folk medicine this extract is used for the treatment of res-
piratory diseases such as bronchitis, pertussis and tubercu-
losis and it has also been utilized as insecticide and
antihelmintic.1 To date more than forty biologically active
alkaloids were isolated and characterized, few of them
were prepared also by synthesis.2 While there is a consid-
erable amount of synthetic work in acceding to the racem-
ic and optically active stemoamide,1 little attention has
been given to prepare synthetic analogs.3e,f,4 In this com-
munication we describe a short synthesis of the ( )-9,10-
bis-epi-stemoamide using a radical cyclization as the key
step.
N
O
O
H
B
O
1
Scheme 1
magnesium bromide to the hemiacetal afforded the corre-
sponding diol,6 which was converted selectively to the
mono-protected alcohol 2 in two steps (TBSCl/imidazole
followed by selective desilylation with NH4F). This easily
scalable sequence allowed the preparation of a multigram
quantity of 2.
The C-ring of stemoamide was introduced with a Mit-
sunobu-type substitution of the primary alcohol with
succinimide followed by selective reduction of one of the
carbonyl functionality using superhydride (LiBEt3H,
THF, –78 °C) producing 3 in 87% yield. Preliminary stud-
ies indicated that thioaryl ethers are convenient sources of
radicals from pyrrolidinones, thus thiophenyl derivative 4
was selected for further studies. Intermediate 4 was pre-
pared by treatment of 3 with PhSH in the presence of
APTS7 and, under these acidic conditions, the silyl pro-
tecting group was also cleaved (91%, overall yield).
1
Me
O
Me
10
O
O
3
H
N
N
9
8
O
O
O
H
H
9,10-bis-epi-Stemoamide
(–)-Stemoamide
Figure 1
1) HCl (0.2 N)
MgBr
A retrosynthetic analysis of the tricyclic core of stemo-
amide is depicted in Scheme 1. The radical intermediate
for the key cyclization reaction should be generated from
the corresponding thiophenyl derivative.5,7 The a,b-unsat-
urated lactone A could be prepared by ring-closing
metathesis (RCM), and the unsaturated compound B
should be easily accessible from dihydrofuran 1.
2)
THF
then APTS/MeOH
OH
OTBS
O
1
3) TBSCl, imidazole, DMF, 93%
4) NH4F, MeOH, ∆, 15 h, 68%
2
1) Succinimide, DIAD,
PPh3, THF, 90%
2) LiBEt3H, THF –78 °C
87%
O
O
The synthesis of the advanced intermediate 4 from dihy-
drofuran 1 is depicted in Scheme 2. Acid-catalyzed hydra-
tion of dihydrofuran, followed by addition of vinyl
PhSH,
APTS
N
N
91%
OH
OTBS
PhS
HO
SYNLETT 2005, No. 2, pp 0349–0351
0
1.
0
2.
2
0
0
5
4
3
Advanced online publication: 17.12.2004
DOI: 10.1055/s-2004-837197; Art ID: G37304ST
Scheme 2
© Georg Thieme Verlag Stuttgart · New York

350
N. Bogliotti et al.
LETTER
In order to test the radical cyclization, the synthesis of the tion provided lactone 9 in 56% (conversion 68%). The
nor-C(10) stemoamide from derivative 6 was first consid- radical cyclization of 9 was achieved with Bu3SnH, AIBN
ered (Scheme 3).7 The requisite a,b-unsaturated lactone (cat.) in refluxing benzene, and afforded the tricyclic
(stemoamide A-ring) was assembled in 2 steps from the compound 10 in a non-optimized 20% yield as a single
corresponding allylic alcohol 4 by esterification using an diastereoisomer.11 It is worth noting that we were not able
excess of acryloyl chloride and Hünig’s base followed by to isolate other diastereomers in this cyclization reaction.
a ring-closing metathesis (RCM). In this latter reaction, The stereochemistry of the newly formed centers in 10
Grubbs’ catalysts first and second generation8 afforded 6 was assigned on the basis of 1H NMR coupling constants
1
only in moderate yields (around 50%) from the unsaturat- and by comparison with the H NMR and 13C NMR
ed compound 5 while Hoveyda’s catalyst9 I afforded 6 in spectrum described in the literature.3e
good yield (81%).
O
CO2H
O
O
O
N
N
DCC, DMAP
CH2Cl2
Cl
OH
O
O
N
4
PhS
PhS
Hünig's base
CH2Cl2, –78 °C
93%
4
8
O
98%
PhS
5
O
N
N
cat. II (10 mol%) Mes
Mes
Cl
Cl
CH2Cl2, ∆
Conv = 68%
56%
Ru
cat I (10 mol%)
CH2Cl2, ∆
N
N
Mes
Mes
Cl
81%
Cy3P
Ru
II
Cl
ArS
i-PrO
PhS
Me
Me
O
Bu3SnH
H
H
H
I
AIBN (cat.)
N
N
N
O
O
O
O
O
O
PhH, 80 °C
20%
O
6
O
9
10
Scheme 3
Scheme 5
The radical cyclization of 6 was realized in benzene under
high dilution conditions (5.6 mM) at reflux temperature
by slow addition of a Bu3SnH solution (0.2 M) and AIBN
(cat.) (Scheme 4).10 The reaction afforded a 5:1 mixture of
two diastereomers in 41% yield. The structure of the two
isomers was assigned by analyzing the 1H NMR coupling
constants of 7a and 7b.
In this radical cyclization, the cis-fused AB ring of the
epi-stemoamide was formed according to a 7-exo-trig pro-
cess. The relative trans-stereochemistry of the methyl
substituent at C(10) and the hydrogen Ha can be the con-
sequence of a kinetic control with preferred reduction of
the radical from the endo face. The unfavorable 1,3-inter-
action between the methyl at C(10) and the hydrogen Ha
in the transition state renders intermediate C energetically
less favorable (Figure 2).
PhS
Bu3SnH
AIBN (cat.)
N
O
Bu3SnH
PhH, 80 °C
41%
O
O
6
Ha
Ha
O
O
N
N
Me
10
•
O
H
H
O
H
Me
10
H
H
H
•
N
N
O
O
O
O
O
H
H
O
+
O
O
C
D
H
H
Figure 2
7b
7a
dr = 5 : 1
In summary, a diastereoselective synthesis of the ( )-
9,10-bis-epi-stemoamide was realized in 10 steps. The
sequence was based on a 7-exo-trig radical cyclization,
which allowed the control of three of the four contiguous
stereocenters of the molecule. The synthesis of (–)-ste-
moamide is underway in the laboratory and will be report-
ed in due time.
Scheme 4
In the aim of synthesizing stemoamide, the methacrylate
8 was prepared by condensation of the parent alcohol with
methacrylic acid (Scheme 5). The ring-closing metathesis
was more suitable with Grubbs’ catalyst II and the reac-
Synlett 2005, No. 2, 349–351 © Thieme Stuttgart · New York

LETTER
Construction of the Tricyclic Core of Stemoamide
351
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(11) 9,10-bis-epi-Stemoamide (10):
To a stirred solution of 9 (48 mg, 0.15 mmol) and AIBN (5
mg, 0.03 mmol) in degassed benzene (30 mL) at reflux, a
solution of Bu3SnH (100 mL, 0.37 mmol) in benzene (3 mL)
was added over 4 h via a syringe pump. The crude mixture
was treated with a sat. aq solution of KF, extracted by
CH2Cl2, dried over MgSO4, filtered, concentrated under
reduced pressure, and purified by chromatography on silica
gel (gradient: CH2Cl2 then CH2Cl2–MeOH 95:5) to afford
compound 10 (6.7 mg, 0.03 mmol, 20%) as a single
diastereomer. 1H NMR (300 MHz, CDCl3): d = 1.39 (d,
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2.78 (ddd, J = 13.9, 10.4, 3.4 Hz, 1 H), 3.63 (dd, J = 9.0, 7.2
Hz, 1 H), 4.18 (dt, J = 13.9, 4.5 Hz, 1 H), 4.62 (ddd, J = 10.6,
7.9, 3.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 15.9,
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177.9. MS (EI, 70eV): m/z (%) = 224 (12) [MH+], 223 (87)
[M+], 208 (41), 180 (44), 98 (100), 97 (59).
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Synlett 2005, No. 2, 349–351 © Thieme Stuttgart · New York