LETTER 565

Studies towards the Total Asymmetric Synthesis of the Pentacyclic Indole

Alkaloid Arboflorine: Asymmetric Synthesis of a Key Intermediate
e a Hui-Ying Huang,b Hui Liu,a Yuan-Ping Ruan,a Pei-Qiang Huang*a
SyntheticStudiestowardsArboflorinDu,
Yu
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: [email protected]
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- from piperideine 8 by Li’s cross-dehydrogenative-cou-
scribed. The method featured the use of Ellman’s sulfinamide pling reaction (CDC)6 or the Polonovski–Potier reaction.7
chemistry for the establishment of the first chiral center, and the Compound 8, in turn, could be accessible from chiral
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
R R

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OMe
Indole alkaloids are a class of natural products widely dis- R NH2
tributed in plants that exhibit structural diversity and sig- –O
R = CO2Me NH2
nificant biological activities.1 In 2006, Kam and co- 2 3
workers reported the isolation and structure elucidation of N
arboflorine (1) as a minor alkaloid from the stem bark of N
1
the Malayan Kopsia arborea.2 A notable feature of this H
MeO2C
new alkaloid resides in that it represents a new subclass of
monoterpenoid indoles with a novel pentacyclic carbon NH2
4
skeleton. Moreover, the incorporation of a third nitrogen
atom embedded within a tryptamine–secologanin-derived Scheme 1 Possible biogenetic pathway to 1 (in part) suggested by
monoterpenoid indole is also unusual (Figure 1). Kam and co-workers

N N
H N
H

N N O
H N
H Boc
O N S
O N H EtO2C N t-Bu
H H
arboflorine (1) arboflorine (1) 5

Figure 1 Structure of arboflorine

N+ O
In continuation of our interest in the asymmetric synthesis N HN S
CN t-Bu
of bioactive alkaloids,3 in particular piperidines4 and 2-
piperidinones,5 we have embarked on the asymmetric syn-
N
thesis of arboflorine (1), and the preliminary results on the Boc OEt N
TMS O CO2Et
construction of a key intermediate are presented herein. Boc
6 7
Our approach is based on the possible biogenetic pathway O
proposed by Kam and co-workers,2 which highlighted the O S
cyclization of the key intermediate 2 (Scheme 1). In our N HN S t-Bu N
H
retrosynthetic analysis showed in Scheme 2, compound 7 t-Bu
N
9
was designed as a precursor of the key intermediate 6, +
which is similar to the proposed biogenetic intermediate N
Br
CO2Et
Boc
8 N CO2Et
SYNLETT 2011, No. 4, pp 0565–0568xx. 201 H
Advanced online publication: 27.01.2011 10
DOI: 10.1055/s-0030-1259521; Art ID: W18610ST
© Georg Thieme Verlag Stuttgart · New York Scheme 2 Retrosynthetic analysis of arboflorine
566 Y. Du et al. LETTER

synthesized by chiral directing reduction of Ellman’s sul- carboxylated product 19 in an overall yield of 86%. Treat-
finamide.8,9 ment of indole-alcohol 19 with PPh3–CBr4 in CH2Cl2
The synthesis started with the preparation of the protected proceeded chemoselectively to give the desired bromide
(RS,R)-N-tert-butanesulfinyl amine 9 by a known proce- 10 in 90% yield.
dure (Scheme 3).9 Ti(OEt)4-mediated9,10 condensation of
O
3-acetylpyridine (11) with Ellman’s (R)-sulfinamide 128 Br
afforded sulfinimine 13 in 88% yield. Reduction of sulfin- S CH2Cl2
N +
H r.t., 7 d
imine 13 with DIBAL-H in THF at –78 °C9 produced the N CO2Et
desired compound 9 in 89% yield. N H
9
10
O O
O O t-Bu S t-Bu S
O
Ti(OEt)4, THF S HN HN
+ S N
NH2 reflux, 36 h
N 88% N NaBH4, MeOH
12 13 Br– N+ N
11 0 °C, 1 h
O 70% from 9
DIBAL-H, THF S
N
–78 °C, 3 h H N N
89% N H CO2Et H CO2Et
9 20 21

Scheme 3 Synthesis of compound 9 O

N HN S
(Boc)2O, Et3N t-Bu
The synthesis of segment 10 is outlined in Scheme 4,

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DMAP, MeCN,
which started with 2-(indol-3-yl)acetic acid (14). Reduc- r.t., 4 h
91%
tion of 2-(indol-3-yl)acetic acid (14) with lithium alumi- N
CO2Et
num hydride in THF gave the corresponding alcohol 15 in Boc
8
96% yield, which was protected (TBSCl, Et3N, CH2Cl2) to
give compound 16 in 98% yield. Scheme 5 Synthesis of compound 8

COOH
OH TBSCl, Et3N, For the synthesis of compound 8, a CH2Cl2 solution of 9
LiAlH4, THF CH2Cl2
and 10 was stirred at room temperature for seven days to
r.t., 10 h r.t., 4 h
N 96% N 98%
give the presumed pyridinium13 20 that was reduced with
H H NaBH4 in one pot to give piperideine14 21 in 70% yield.
14 15
N-Protection [(Boc)2O, Et3N, DMAP, MeCN] of the in-
LiCHCO2Et
OTBS t-BuOCl, Cl OTBS CO2t-Bu
dole nitrogen in compound 21 produced N-Boc derivative
Et3N, THF
8 in 91% yield (Scheme 5).
–78 °C, ZnCl2, 1 h,
N 20 min N –78 °C The next task was the regioselective introduction of a cy-
H 94% from 16
16 17 ano group at C-2 of the piperideine ring of compound 8 to
OTBS give compound 7. Attempted cyanation at C-2 of piperi-
CF3COOH, CH2Cl2,
0 °C to r.t., 6 h;
OH deine 8 by Li’s CDC reaction6,15 using either CuCl, CuBr
CO2t-Bu
K2CO3, EtOH, or RuCl3 in the presence of O2, or H2O2, or t-BuOOH was
r.t., 2 h N CO2Et unsuccessful. It was found that the oxidative dehydroge-
N H
H CO2Et 86%
18
19 nation occurred more readily at the carbon a to the tert-
butanesulfinamide group than at the piperidine a-carbon.
Ph3P, CBr4,
CH2Cl2
Br We then resorted to the Polonovski–Potier reaction.7,16,17
0 °C, 2 h
However, successive treatment of compound 8 with
90% N
H
CO2Et MCPBA and NaCN gave only the corresponding sulfone
10 in 45% yield.
Scheme 4 Synthesis of compound 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
Oxidative conversion of 3-substituted indole 16 into was treated with a 4 M HCl in methanol solution9 to give
chloroindolenine 17 and use of this compound for the amine dihydrochloride salt 22 that was protected
functionalization at the carbon a to nitrogen by Kuehne’s [(Boc)2O, Et3N, MeCN] to give compound (R)-23 in 86%
method11,12 (t-BuOCl, Et3N, THF; ZnCl2, lithium ethyl yield over two steps (Scheme 6). Successive treatment of
tert-butyl malonate) provided compound 18 in 94% yield. pyridine derivative 23 with bromide 10 and NaBH4 in
Successive treatment of compound 18 with trifluoroacetic methanol afforded compound 24 in 64% yield. Treatment
acid and potassium carbonate gave the desilylated and de-

Synlett 2011, No. 4, 565–568 © Thieme Stuttgart · New York

LETTER Synthetic Studies towards Arboflorine 567

of compound 24 with (Boc)2O in the presence of Et3N and progress on the key decyanative cyclization16,19 and the
DMAP in MeCN gave fully protected compound 25 in completion of the total synthesis of arboflorine (1).
92% yield (Scheme 6).

O
Supporting Information for this article is available online at
4 M HCl, MeOH, Boc2O, Et3N,
S 1,4-dioxane MeCN http://www.thieme-connect.com/ejournals/toc/synlett.
N H2N
H 0 °C to r.t., 1 h ⋅2HCl r.t., 3 h
N 86% from 9
9 N
22
Acknowledgment
The authors are grateful to the NSF of China (No. 20832005), the
NFFTBS (No. J1030415), and the National Basic Research Pro-
N NHBoc
10, r.t., 7 d
gram (973 Program) of China (Grant No. 2010CB833200) for fi-
HN nancial support.
then NaBH4,
Boc
N MeOH
0 °C, 1 h
N
23 64% H CO2Et References and Notes
24
(1) For some recent reviews, see: (a) Kam, T.-S.; Lim, K.-H.
BocHN BocHN Alkaloids of Kopsia, In The Alkaloids: Chemistry and
Biology, Vol. 66; Cordell, G. A., Ed.; Academic Press:
MCPBA,
(Boc)2O, Et3N, K2CO3, Amsterdam, 2008, 1–111. (b) Ishikura, M.; Yamada, K.;
DMAP, MeCN N CH2Cl2 N Abe, T. Nat. Prod. Rep. 2010, 27, 1630. (c) Li, S.-M. Nat.
r.t., 3 h 0 °C, 1 h Prod. Rep. 2010, 27, 57.
92% O (2) Lim, K.-H.; Kam, T.-S. Org. Lett. 2006, 8, 1733.
(3) Huang, P.-Q. Synlett 2006, 1133.
N N (4) (a) Xiao, K.-J.; Liu, L.-X.; Huang, P.-Q. Tetrahedron:

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Boc
CO2Et
Boc
CO2Et Asymmetry 2009, 20, 1181. (b) Lin, G.-J.; Huang, P.-Q.
25 26 Org. Biomol. Chem. 2009, 7, 4491. (c) Zheng, X.; Chen, G.;
Ruan, Y.-P.; Huang, P.-Q. Sci. China, Ser. B: Chem. 2009,
TFAA, CH2Cl2; 52, 1631. (d) Yang, R.-F.; Huang, P.-Q. Chem. Eur. J. 2010,
KCN/H2O 16, 10319. (e) Xiao, K.-J.; Wang, Y.; Ye, K.-Y.; Huang,
MeCO2H, MeCO2Na, N NHBoc
buffer pH 4
+ P.-Q. Chem. Eur. J. 2010, 16, 12792.
(5) (a) Liu, L.-X.; Xiao, K.-J.; Huang, P.-Q. Tetrahedron 2009,
0 °C, 30 min CF3CO2–
74% from 25 52, 3834. (b) Fu, R.; Du, Y.; Li, Z.-Y.; Xu, W.-X.; Huang,
N P.-Q. Tetrahedron 2009, 65, 9765. (c) Fu, R.; Chen, J.; Guo,
Boc
CO2Et L.-C.; Ruan, Y.-P.; Huang, P.-Q. Org. Lett. 2009, 11, 5242.
(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.
N NHBoc
(6) (a) Li, Z.-P.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173.
CN
(b) Baslé, O.; Li, C.-J. Green Chem. 2007, 9, 1047. (c) Li,
C.-J. Acc. Chem. Res. 2009, 42, 335.
(7) (a) Grierson, D. Org. React. (N.Y.) 1990, 39, 85.
N (b) Polonovski, M. Bull. Soc. Chim. Belg. 1930, 39, 1.
Boc
CO2Et (c) Potier, P. Annu. Proc. Phytochem. Soc. Eur. 1980, 17,
28
159.
(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,
39. (c) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.;
Han, Z.; Gallon, E. Aldrichimica Acta 2005, 38, 93.
Compound 25 was subjected to Polonovski–Potier reac- (d) Daniel, M.; Stockman, R. A. Tetrahedron 2006, 62,
tion to generate 2-cyano-D3-piperideine 28. In the event, 8869.
piperideine 25 was treated with MCPBA, K2CO3 in (9) Chelucci, G.; Baldino, S.; Chessa, S.; Pinna, G. A.;
CH2Cl2 to give the N-oxide 26, which was treated with Soccolini, F. Tetrahedron: Asymmetry 2006, 17, 3163.
TFAA in CH2Cl2, and the presumed iminium intermediate (10) (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman,
27 was trapped by KCN in an aqueous AcOH–NaOAc J. A. J. Org. Chem. 1999, 64, 1278. (b) Cogan, D. A.;
Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268. (c) Davis,
buffer solution (pH 4) to afford, in one pot, the desired ni- F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
trile 28 as an inseparable diastereomeric mixture in 74% Zhang, H. J. Org. Chem. 1999, 64, 1403.
yield (Scheme 6). The diastereomeric ratio was deter- (11) (a) Kuehne, M. E.; Xu, F. J. Org. Chem. 1997, 62, 7950.
mined to be 58:42 by 1H NMR analysis.18 (b) Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.;
Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1999,
In summary, an efficient synthesis of 2-cyano-D3-piperi-
121, 11964.
deine 28, a plausible synthetic equivalent of the key inter- (12) For an alternative method, see: Johansen, M. B.; Kerr, M. A.
mediate for a biomimetic synthesis of pentacyclic indole Org. Lett. 2010, 12, 4956.
alkaloid arboflorine (1) has been disclosed. Work is in (13) Fry, E. M.; Beisler, J. A. J. Org. Chem. 1970, 35, 2809.

Synlett 2011, No. 4, 565–568 © Thieme Stuttgart · New York

568 Y. Du et al. LETTER

(14) Passarella, D.; Martinelli, M.; Llor, N.; Amat, M.; Bosch, J. K2CO3 and extracted with CH2Cl2 (3 × 3 mL). The combined
Tetrahedron 1999, 55, 14995. extracts were successively washed with H2O (2 mL) and
(15) (a) Murahashi, S. I.; Komiya, N.; Terai, H. Angew. Chem. brine (1 mL), dried over anhyd Na2SO4, filtered and
Int. Ed. 2005, 44, 6931. (b) Murahashi, S. I.; Nakae, T.; concentrated in vacuo. The residue was purified by flash
Terai, H.; Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005. column chromatography on neutral Al2O3 (Rf = 0.4, eluent:
(16) (a) Grierson, D. S.; Harris, M.; Husson, H.-P. J. Am. Chem. EtOAc–n-hexane, 1:4) to give compound 28 (108 mg, 74%
Soc. 1980, 102, 1064. (b) Grierson, D. S.; Vuilhorgne, M.; from 25) as a white amorphous solid. IR (film): 3370, 2978,
Husson, H.-P. J. Org. Chem. 1982, 47, 4439. (c) Sundberg, 2934, 2216 (w, CN), 1730 (s), 1511, 1458, 1392, 1367, 1328,
R. J.; Grierson, D. S.; Husson, H.-P. J. Org. Chem. 1984, 49, 1248, 1169, 1133 cm–1. 1H NMR (400 MHz, CDCl3;
2400. diastereomeric mixture and rotamers): d = 1.25 (m, 3 H,
(17) Bonjoch, J.; Solé, D.; García-Rubio, S.; Bosch, J. J. Am. CH2CH3), 1.33 (m, 3 H, CHCH3), 1.44 [m, 9 H, C(CH3)3],
Chem. Soc. 1997, 119, 7230. 1.65 [s, 9 H, C(CH3)3], 2.08–2.18 (m, 1 H, C=CHCH2),
(18) All new compounds gave satisfactory analytical and spectral 2.26–2.44 (m, 1 H, C=CHCH2), 2.53–2.63 (m, 1 H,
data. C=CHCH2CH2), 2.70–2.95 (m, 5 H, C=CHCH2CH2,
Experimental Procedure for the Synthesis of the Key ArCH2CH2N), 4.03 (s, 2 H, CH2CO2), 4.16 (m, 2 H,
Intermediate 28: A solution of MCPBA (72%, 84 mg, 0.35 CH2CH3), 4.27 (s, 1 H, CHCN), 4.22–4.38 (m, 1 H, CHCH3),
mmol) in CH2Cl2 (1 mL) was added dropwise to a solution 4.57 (br s, 1 H, NH), 5.86, 5.89 (br s, 1 H, C=CH), 7.24 (t,
of compound 25 (138 mg, 0.25 mmol) in CH2Cl2 (1.5 mL) at J = 7.3 Hz, 1 H, ArH), 7.29 (t, J = 7.3 Hz, 1 H, ArH), 7.53
0 °C. After stirring at 0 °C for 1 h, K2CO3 (70 mg, 0.5 mmol) (d, J = 7.8 Hz, 1 H, ArH), 8.09 (d, J = 7.8 Hz, 1 H, ArH).
13
was added. After stirring for an additional 1 h at 0 °C, the C NMR (100 MHz, CDCl3; diastereomeric mixture and
mixture was filtered through celite. The residue was purified rotamers): d = 14.2, 22.4, 22.5, 25.1, 25.2, 28.1, 28.25,
by flash column chromatography on silica gel (Rf 0.18, 28.29, 28.33, 28.7, 29.6, 33.17, 33.2, 45.6, 45.65, 47.5, 52.4,
eluent: CH2Cl2–MeOH, 15:1) to give N-oxide 26 (140 mg, 55.2, 55.3, 60.8, 79.8, 80.1, 84.0, 115.7, 115.9, 116.1, 118.0,
98%), which was dissolved in anhyd CH2Cl2 (2.0 mL) and 118.1, 118.2, 122.5, 124.2, 124.449, 124.458, 129.2, 129.7,
cooled to 0 °C. TFAA (0.07 mL, 0.5 mmol) was added. After 129.8, 134.08, 134.14, 135.8, 150.4, 155.3, 170.12, 170.18.
being stirred for 30 min at 0 °C, an aqueous solution (0.5 HRMS: m/z [M + Na+] calcd for C32H44N4NaO6: 603.3159;

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mL) of KCN (65 mg, 1.0 mmol) was added, and the solution found: 603.3153.
was buffered to pH 4 by addition of AcOH and NaOAc. (19) Agami, C.; Couty, F.; Evano, G. Org. Lett. 2000, 2, 2085.
After stirring for 1 h at 0 °C, the mixture was basified with

Synlett 2011, No. 4, 565–568 © Thieme Stuttgart · New York