Studies towards the total asymmetric synthesis of the pentacyclic indole alkaloid arboflorine: Asymmetric synthesis of a key intermediate

Article abstract of DOI:10.1055/s-0030-1259521

The synthesis of a plausible key intermediate for a biomimetic asymmetric synthesis of indole alkaloid arboflorine is described. The method featured the use of Ellman's sulfinamide chemistry for the establishment of the first chiral center, and the Polonovski-Potier reaction for the formation of the -aminonitrile moiety. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259521

LETTER
565
Studies towards the Total Asymmetric Synthesis of the Pentacyclic Indole
Alkaloid Arboflorine: Asymmetric Synthesis of a Key Intermediate
a
b
a
a
a
S
Y
ynthetic Studies
t
u
owards
A
rboflorin
D
u, Hui-Ying Huang, Hui Liu, Yuan-Ping Ruan, Pei-Qiang Huang*
a
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. of China
Fax +86(592)2186400; E-mail: pqhuang@xmu.edu.cn
b
School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, P. R. of China
Received 27 November 2010
2
. The a-aminonitrile 7 was envisioned to be prepared
Abstract: The synthesis of a plausible key intermediate for a bio-
mimetic asymmetric synthesis of indole alkaloid arboflorine is de-
scribed. The method featured the use of Ellman’s sulfinamide
chemistry for the establishment of the first chiral center, and the
from piperideine 8 by Li’s cross-dehydrogenative-cou-
pling reaction (CDC) or the Polonovski–Potier reaction.
Compound 8, in turn, could be accessible from chiral
6
7
Polonovski–Potier reaction for the formation of the a-aminonitrile amine 9 and indole derivative 10. Chiral amine 9 could be
moiety.
Key words: indole alkaloids, biogenetic pathway, intermediate,
Polonovski–Potier reaction, Ellman’s sulfinamide
+
N
N
N
N
H
H
OMe
R
Indole alkaloids are a class of natural products widely dis-
tributed in plants that exhibit structural diversity and sig-
nificant biological activities. In 2006, Kam and co-
NH2
R
R
2
R = CO Me
–
O
2
NH2
1
3
workers reported the isolation and structure elucidation of
N
arboflorine (1) as a minor alkaloid from the stem bark of
the Malayan Kopsia arborea. A notable feature of this
N
2
1
H
MeO2C
new alkaloid resides in that it represents a new subclass of
monoterpenoid indoles with a novel pentacyclic carbon
skeleton. Moreover, the incorporation of a third nitrogen
atom embedded within a tryptamine–secologanin-derived
monoterpenoid indole is also unusual (Figure 1).
NH2
4
Scheme 1 Possible biogenetic pathway to 1 (in part) suggested by
Kam and co-workers
N
N
H
N
H
N
O
S
N
H
N
H
Boc
EtO2C
O
N
O
N
N
H
t-Bu
H
H
arboflorine (1)
5
arboflorine (1)
Figure 1 Structure of arboflorine
N+
O
N
HN
S
In continuation of our interest in the asymmetric synthesis
3
4
CN
t-Bu
of bioactive alkaloids, in particular piperidines and 2-
5
piperidinones, we have embarked on the asymmetric syn-
N
thesis of arboflorine (1), and the preliminary results on the
construction of a key intermediate are presented herein.
Boc
N
OEt
TMS
O
CO2Et
Boc
7
6
Our approach is based on the possible biogenetic pathway
O
2
proposed by Kam and co-workers, which highlighted the
O
S
cyclization of the key intermediate 2 (Scheme 1). In our
retrosynthetic analysis showed in Scheme 2, compound 7
was designed as a precursor of the key intermediate 6,
which is similar to the proposed biogenetic intermediate
N
HN
S
t-Bu
N
H
t-Bu
N
9
+
Br
N
CO2Et
Boc
8
N
H
CO2Et
SYNLETT 2011, No. 4, pp 0565–0568
x
x.
x
x.
2
0
1
1
Advanced online publication: 27.01.2011
10
DOI: 10.1055/s-0030-1259521; Art ID: W18610ST
Scheme 2 Retrosynthetic analysis of arboflorine
©
Georg Thieme Verlag Stuttgart · New York

5
66
Y. Du et al.
LETTER
synthesized by chiral directing reduction of Ellman’s sul- carboxylated product 19 in an overall yield of 86%. Treat-
8
,9
finamide.
The synthesis started with the preparation of the protected
RS,R)-N-tert-butanesulfinyl amine 9 by a known proce-
ment of indole-alcohol 19 with PPh –CBr in CH Cl
3 4 2 2
proceeded chemoselectively to give the desired bromide
1
0 in 90% yield.
(
9
9,10
dure (Scheme 3). Ti(OEt) -mediated condensation of8
4
O
3
-acetylpyridine (11) with Ellman’s (R)-sulfinamide 12
Br
S
N
H
CH2Cl2
r.t., 7 d
afforded sulfinimine 13 in 88% yield. Reduction of sulfin-
imine 13 with DIBAL-H in THF at –78 °C produced the
desired compound 9 in 89% yield.
+
9
N
CO2Et
N
H
9
1
0
O
O
O
O
S
t-Bu
S
t-Bu
S
O
S
Ti(OEt)4, THF
reflux, 36 h
HN
HN
+
N
NH2
88%
NaBH , MeOH
N
N
4
Br–
12
13
N+
N
11
0 °C, 1 h
O
S
70% from 9
DIBAL-H, THF
78 °C, 3 h
N
–
H
N
N
H
89%
H
CO2Et
CO Et
2
N
9
20
21
Scheme 3 Synthesis of compound 9
O
S
N
HN
(Boc)2O, Et3N
t-Bu
The synthesis of segment 10 is outlined in Scheme 4,
which started with 2-(indol-3-yl)acetic acid (14). Reduc-
tion of 2-(indol-3-yl)acetic acid (14) with lithium alumi-
num hydride in THF gave the corresponding alcohol 15 in
DMAP, MeCN,
r.t., 4 h
9
1%
N
CO2Et
Boc
8
9
6% yield, which was protected (TBSCl, Et N, CH Cl ) to
3
2
2
give compound 16 in 98% yield.
Scheme 5 Synthesis of compound 8
COOH
TBSCl, Et3N,
For the synthesis of compound 8, a CH Cl solution of 9
2 2
OH
LiAlH4, THF
r.t., 10 h
CH Cl2
2
and 10 was stirred at room temperature for seven days to
r.t., 4 h
98%
13
give the presumed pyridinium 20 that was reduced with
N
96%
N
H
15
14
H
NaBH in one pot to give piperideine 21 in 70% yield.
4
14
N-Protection [(Boc) O, Et N, DMAP, MeCN] of the in-
2
3
LiCHCO2Et
CO2t-Bu
t-BuOCl,
Et3N, THF
Cl
OTBS
dole nitrogen in compound 21 produced N-Boc derivative
OTBS
8
in 91% yield (Scheme 5).
–
78 °C,
ZnCl2, 1 h,
–78 °C
N
H
20 min
N
The next task was the regioselective introduction of a cy-
ano group at C-2 of the piperideine ring of compound 8 to
give compound 7. Attempted cyanation at C-2 of piperi-
94% from 16
1
7
16
OTBS
CF3COOH, CH2Cl2,
°C to r.t., 6 h;
6,15
OH
deine 8 by Li’s CDC reaction using either CuCl, CuBr
0
CO2t-Bu
CO2Et
or RuCl in the presence of O , or H O , or t-BuOOH was
K2CO3, EtOH,
r.t., 2 h
3
2
2
2
N
CO2Et
N
unsuccessful. It was found that the oxidative dehydroge-
nation occurred more readily at the carbon a to the tert-
butanesulfinamide group than at the piperidine a-carbon.
H
H
86%
1
9
18
Ph3P, CBr4,
CH2Cl2
7,16,17
Br
We then resorted to the Polonovski–Potier reaction.
However, successive treatment of compound 8 with
MCPBA and NaCN gave only the corresponding sulfone
in 45% yield.
0
°C, 2 h
0%
N
H
CO2Et
9
10
At this stage, modification of our synthetic plan by substi-
tution of the sulfoxide group of tert-butanesulfinamide by
a Boc group was indicated. For this purpose, compound 9
was treated with a 4 M HCl in methanol solution to give
amine dihydrochloride salt 22 that was protected
Scheme 4 Synthesis of compound 10
Oxidative conversion of 3-substituted indole 16 into
chloroindolenine 17 and use of this compound for the
functionalization at the carbon a to nitrogen by Kuehne’s
9
[
(Boc) O, Et N, MeCN] to give compound (R)-23 in 86%
1
1,12
2 3
method
(t-BuOCl, Et N, THF; ZnCl , lithium ethyl
3 2
yield over two steps (Scheme 6). Successive treatment of
tert-butyl malonate) provided compound 18 in 94% yield.
Successive treatment of compound 18 with trifluoroacetic
acid and potassium carbonate gave the desilylated and de-
pyridine derivative 23 with bromide 10 and NaBH in
4
methanol afforded compound 24 in 64% yield. Treatment
Synlett 2011, No. 4, 565–568 © Thieme Stuttgart · New York

LETTER
Synthetic Studies towards Arboflorine
567
of compound 24 with (Boc) O in the presence of Et N and progress on the key decyanative cyclization16,19 and the
2
3
DMAP in MeCN gave fully protected compound 25 in completion of the total synthesis of arboflorine (1).
9
2% yield (Scheme 6).
Supporting Information for this article is available online at
O
4
M HCl, MeOH,
Boc2O, Et3N,
MeCN
http://www.thieme-connect.com/ejournals/toc/synlett.
1
,4-dioxane
S
H2N
⋅2HCl
N
H
0
°C to r.t., 1 h
r.t., 3 h
86% from 9
N
N
9
Acknowledgment
22
The authors are grateful to the NSF of China (No. 20832005), the
NFFTBS (No. J1030415), and the National Basic Research Pro-
gram (973 Program) of China (Grant No. 2010CB833200) for fi-
nancial support.
N
NHBoc
1
0, r.t., 7 d
HN
Boc
then NaBH4,
MeOH
0
N
°C, 1 h
4%
23
N
6
References and Notes
H
CO2Et
24
(
1) For some recent reviews, see: (a) Kam, T.-S.; Lim, K.-H.
Alkaloids of Kopsia, In The Alkaloids: Chemistry and
Biology, Vol. 66; Cordell, G. A., Ed.; Academic Press:
Amsterdam, 2008, 1–111. (b) Ishikura, M.; Yamada, K.;
Abe, T. Nat. Prod. Rep. 2010, 27, 1630. (c) Li, S.-M. Nat.
Prod. Rep. 2010, 27, 57.
BocHN
BocHN
MCPBA,
K2CO3,
CH2Cl2
(
Boc)2O, Et3N,
DMAP, MeCN
N
N
r.t., 3 h
0 °C, 1 h
O
92%
(2) Lim, K.-H.; Kam, T.-S. Org. Lett. 2006, 8, 1733.
(
(
3) Huang, P.-Q. Synlett 2006, 1133.
4) (a) Xiao, K.-J.; Liu, L.-X.; Huang, P.-Q. Tetrahedron:
Asymmetry 2009, 20, 1181. (b) Lin, G.-J.; Huang, P.-Q.
Org. Biomol. Chem. 2009, 7, 4491. (c) Zheng, X.; Chen, G.;
Ruan, Y.-P.; Huang, P.-Q. Sci. China, Ser. B: Chem. 2009,
52, 1631. (d) Yang, R.-F.; Huang, P.-Q. Chem. Eur. J. 2010,
N
N
CO2Et
CO2Et
Boc
Boc
26
25
TFAA, CH2Cl2;
KCN/H2O
MeCO2H, MeCO2Na,
buffer pH 4
1
6, 10319. (e) Xiao, K.-J.; Wang, Y.; Ye, K.-Y.; Huang,
N
NHBoc
+
P.-Q. Chem. Eur. J. 2010, 16, 12792.
(
5) (a) Liu, L.-X.; Xiao, K.-J.; Huang, P.-Q. Tetrahedron 2009,
52, 3834. (b) Fu, R.; Du, Y.; Li, Z.-Y.; Xu, W.-X.; Huang,
P.-Q. Tetrahedron 2009, 65, 9765. (c) Fu, R.; Chen, J.; Guo,
L.-C.; Ruan, Y.-P.; Huang, P.-Q. Org. Lett. 2009, 11, 5242.
–
0
°C, 30 min
3 2
CF CO
7
4% from 25
N
CO2Et
Boc
(
d) Fu, R.; Ye, J.-L.; Dai, X.-J.; Ruan, Y.-P.; Huang, P.-Q.
27
J. Org. Chem. 2010, 75, 4230. (e) Zheng, X.; Zhu, W.-F.;
Huang, P.-Q. Sci. China, Ser. B: Chem. 2010, 53, 1914.
6) (a) Li, Z.-P.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173.
(
(
N
NHBoc
(
b) Baslé, O.; Li, C.-J. Green Chem. 2007, 9, 1047. (c) Li,
CN
C.-J. Acc. Chem. Res. 2009, 42, 335.
7) (a) Grierson, D. Org. React. (N.Y.) 1990, 39, 85.
(
b) Polonovski, M. Bull. Soc. Chim. Belg. 1930, 39, 1.
(c) Potier, P. Annu. Proc. Phytochem. Soc. Eur. 1980, 17,
59.
N
CO2Et
Boc
1
28
(
8) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
Scheme 6 Synthesis of the key intermediate 28
2002, 35, 984. (b) Ellman, J. A. Pure Appl. Chem. 2003, 75,
3
9. (c) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.;
Han, Z.; Gallon, E. Aldrichimica Acta 2005, 38, 93.
d) Daniel, M.; Stockman, R. A. Tetrahedron 2006, 62,
869.
Compound 25 was subjected to Polonovski–Potier reac-
(
8
3
tion to generate 2-cyano-D -piperideine 28. In the event,
piperideine 25 was treated with MCPBA, K CO in
(9) Chelucci, G.; Baldino, S.; Chessa, S.; Pinna, G. A.;
Soccolini, F. Tetrahedron: Asymmetry 2006, 17, 3163.
10) (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman,
J. A. J. Org. Chem. 1999, 64, 1278. (b) Cogan, D. A.;
Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268. (c) Davis,
F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
11) (a) Kuehne, M. E.; Xu, F. J. Org. Chem. 1997, 62, 7950.
(b) Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.;
Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1999,
2
3
CH Cl to give the N-oxide 26, which was treated with
2
2
(
TFAA in CH Cl , and the presumed iminium intermediate
2
2
2
7 was trapped by KCN in an aqueous AcOH–NaOAc
buffer solution (pH 4) to afford, in one pot, the desired ni-
trile 28 as an inseparable diastereomeric mixture in 74%
yield (Scheme 6). The diastereomeric ratio was deter-
(
(
1
18
mined to be 58:42 by H NMR analysis.
3
In summary, an efficient synthesis of 2-cyano-D -piperi-
deine 28, a plausible synthetic equivalent of the key inter-
mediate for a biomimetic synthesis of pentacyclic indole
alkaloid arboflorine (1) has been disclosed. Work is in
121, 11964.
12) For an alternative method, see: Johansen, M. B.; Kerr, M. A.
Org. Lett. 2010, 12, 4956.
(13) Fry, E. M.; Beisler, J. A. J. Org. Chem. 1970, 35, 2809.
Synlett 2011, No. 4, 565–568 © Thieme Stuttgart · New York

5
68
Y. Du et al.
LETTER
(
(
14) Passarella, D.; Martinelli, M.; Llor, N.; Amat, M.; Bosch, J.
Tetrahedron 1999, 55, 14995.
K CO and extracted with CH Cl (3 × 3 mL). The combined
2
3
2
2
extracts were successively washed with H O (2 mL) and
2
15) (a) Murahashi, S. I.; Komiya, N.; Terai, H. Angew. Chem.
Int. Ed. 2005, 44, 6931. (b) Murahashi, S. I.; Nakae, T.;
Terai, H.; Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005.
16) (a) Grierson, D. S.; Harris, M.; Husson, H.-P. J. Am. Chem.
Soc. 1980, 102, 1064. (b) Grierson, D. S.; Vuilhorgne, M.;
Husson, H.-P. J. Org. Chem. 1982, 47, 4439. (c) Sundberg,
R. J.; Grierson, D. S.; Husson, H.-P. J. Org. Chem. 1984, 49,
brine (1 mL), dried over anhyd Na SO , filtered and
2
4
concentrated in vacuo. The residue was purified by flash
column chromatography on neutral Al O (R = 0.4, eluent:
2
3
f
(
EtOAc–n-hexane, 1:4) to give compound 28 (108 mg, 74%
from 25) as a white amorphous solid. IR (film): 3370, 2978,
2934, 2216 (w, CN), 1730 (s), 1511, 1458, 1392, 1367, 1328,
–
1 1
1248, 1169, 1133 cm . H NMR (400 MHz, CDCl ;
3
2
400.
diastereomeric mixture and rotamers): d = 1.25 (m, 3 H,
(
(
17) Bonjoch, J.; Solé, D.; García-Rubio, S.; Bosch, J. J. Am.
Chem. Soc. 1997, 119, 7230.
CH CH ), 1.33 (m, 3 H, CHCH ), 1.44 [m, 9 H, C(CH ) ],
2
3
3
3 3
1.65 [s, 9 H, C(CH ) ], 2.08–2.18 (m, 1 H, C=CHCH ),
3
3
2
18) All new compounds gave satisfactory analytical and spectral
2.26–2.44 (m, 1 H, C=CHCH ), 2.53–2.63 (m, 1 H,
2
data.
C=CHCH CH ), 2.70–2.95 (m, 5 H, C=CHCH CH ,
2
2
2
2
Experimental Procedure for the Synthesis of the Key
Intermediate 28: A solution of MCPBA (72%, 84 mg, 0.35
mmol) in CH Cl (1 mL) was added dropwise to a solution
ArCH CH N), 4.03 (s, 2 H, CH CO ), 4.16 (m, 2 H,
2 2 2 2
CH CH ), 4.27 (s, 1 H, CHCN), 4.22–4.38 (m, 1 H, CHCH ),
2
3
3
4.57 (br s, 1 H, NH), 5.86, 5.89 (br s, 1 H, C=CH), 7.24 (t,
J = 7.3 Hz, 1 H, ArH), 7.29 (t, J = 7.3 Hz, 1 H, ArH), 7.53
(d, J = 7.8 Hz, 1 H, ArH), 8.09 (d, J = 7.8 Hz, 1 H, ArH).
2
2
of compound 25 (138 mg, 0.25 mmol) in CH Cl (1.5 mL) at
2
2
0
°C. After stirring at 0 °C for 1 h, K CO (70 mg, 0.5 mmol)
2 3
1
3
was added. After stirring for an additional 1 h at 0 °C, the
mixture was filtered through celite. The residue was purified
C NMR (100 MHz, CDCl ; diastereomeric mixture and
3
rotamers): d = 14.2, 22.4, 22.5, 25.1, 25.2, 28.1, 28.25,
28.29, 28.33, 28.7, 29.6, 33.17, 33.2, 45.6, 45.65, 47.5, 52.4,
55.2, 55.3, 60.8, 79.8, 80.1, 84.0, 115.7, 115.9, 116.1, 118.0,
118.1, 118.2, 122.5, 124.2, 124.449, 124.458, 129.2, 129.7,
129.8, 134.08, 134.14, 135.8, 150.4, 155.3, 170.12, 170.18.
by flash column chromatography on silica gel (R 0.18,
f
eluent: CH Cl –MeOH, 15:1) to give N-oxide 26 (140 mg,
2
2
9
8%), which was dissolved in anhyd CH Cl (2.0 mL) and
2 2
cooled to 0 °C. TFAA (0.07 mL, 0.5 mmol) was added. After
being stirred for 30 min at 0 °C, an aqueous solution (0.5
mL) of KCN (65 mg, 1.0 mmol) was added, and the solution
was buffered to pH 4 by addition of AcOH and NaOAc.
After stirring for 1 h at 0 °C, the mixture was basified with
+
HRMS: m/z [M + Na ] calcd for C H N NaO : 603.3159;
3
2
44
4
6
found: 603.3153.
(19) Agami, C.; Couty, F.; Evano, G. Org. Lett. 2000, 2, 2085.
Synlett 2011, No. 4, 565–568 © Thieme Stuttgart · New York

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