Synthesis of (±)-coerulescine and a formal synthesis of (±)-horsfiline

Article abstract of DOI:10.1016/j.tetlet.2005.10.015

A straightforward synthesis of (±)-coerulescine and (±)-horsfiline has been established from 3-formyl-3-phenylpyrrolidine employing 4-hydroxypiperidine as the starting material. There are two remarkable steps for the synthesis of (±)-coerulescine and (±)-horsfiline. One is the rapid access to produce 3-formyl-3-phenylpyrrolidine by Lewis acid-catalyzed rearrangement of 3,4-dihydroxy-4-phenylpiperidine. The other key step is an intramolecular electrophilic cyclization from 3-benzylcarbamoyl-3- phenylpyrrolidine to the 3,3-spirocyclic 2-oxindole ring skeleton.

Full text of DOI:10.1016/j.tetlet.2005.10.015

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 8463–8465
Synthesis of ( )-coerulescine and a formal synthesis of
( )-horsfiline
Meng-Yang Chang,a,* Chun-Li Paib and Yung-Hua Kunga
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
Received 22 September 2005; revised 5 October 2005; accepted 7 October 2005
Abstract—A straightforward synthesis of ( )-coerulescine and ( )-horsfiline has been established from 3-formyl-3-phenylpyrrol-
idine employing 4-hydroxypiperidine as the starting material. There are two remarkable steps for the synthesis of ( )-coerulescine
and ( )-horsfiline. One is the rapid access to produce 3-formyl-3-phenylpyrrolidine by Lewis acid-catalyzed rearrangement of 3,4-
dihydroxy-4-phenylpiperidine. The other key step is an intramolecular electrophilic cyclization from 3-benzylcarbamoyl-3-phenyl-
pyrrolidine to the 3,3-spirocyclic 2-oxindole ring skeleton.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
MeO
5
1
The derivatives of spiropyrrolidinyl-oxindole skeleton
NH
NH
O
3a
alkaloid are represented in nature such as spirotryprosta-
3 2
1
tinsA and B, elacomine,2 and strychnophylline.3 Typi-
O
N
cally, they are biosynthesized from tryptamine or
tryptophan derivativesand are characterized by a
spiro-fused ring at the C-3 position.4 The majority of
these natural products have interesting biological activi-
tiesand pharmacological propertie.s Among them, co-
erulescine (1) and horsfiline (2) represent the simplest
prototype membersof thisusbfamily. Recently, co-
erulescine (1) was isolated from the blue canary grass
Phalaris coerulescens.5a,b Horsfiline (2) was first isolated
in 1991 by Bodo and co-workersfrom Malaysian medi-
cal plant Horsfildea superba Warb. (Myristicaceae) and
used as a source of intoxicating snuffs.5
N
N
Cbz
Me
Me
coerulescine (1)
horsfiline (2)
3a
Figure 1.
oxidantspromoted oxidative rearrangement (e.g., lead
tetraacetate,5b sodium tungstate,7j tert-butylhypochlo-
rite,7h and N-bromosuccinimide7b), Mannich reaction,7c
ring-expansion reaction,7f,i 1,3-dipolar [3+2] cycloaddi-
tion,7d,g,l intramolecular radical cyclization,7a,m–p and
asymmetric nitroolefination reaction.7e All of them find
application on specific substrates for the construction
of the 3,3-spirocyclic oxindole-derived alkaloids. Here,
we report that a new synthetic study toward ( )-
coerulescine (1) and ( )-horsfiline (2) from 1-benzyloxy-
carbonyl-4-phenyl-1,2,5,6-tetrahydropyridine (3a) as
shown in Figure 1.
The unique 3,3-spirocyclic oxindole structural features
with the quaternary center and potential biological
applicationsprompted the development of numerous
strategies toward the synthesis of coerulescine (1)
and horsfiline (2) from synthetic chemists.6,7 Basically,
the adopted strategies can be summarized in several
Keywords: Coerulescine; Horsfiline; 4-Hydroxypiperidine; Lewis acid
catalyzed rearrangement; 3-Formyl-3-phenylpyrrolidine; 3,4-Dihy-
droxy-4-phenylpiperidine.
2. Results and discussion
*
The retrosynthetic analysis of ( )-coerulescine (1) and
( )-horsfiline (2) ishsown in Scheme 1. A remarkable
Corresponding author. Tel.: +886 7 5919464; fax: +886 7 5919348;
e-mail: mychang@nuk.edu.tw
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.015

8464
M.-Y. Chang et al. / Tetrahedron Letters 46 (2005) 8463–8465
block in the synthesis of various potential biological
compounds.10,11 In view of the experimental simplicity,
we chose compound 3a as the model substrate to synthe-
size compound 5a in a moderate scale (0.1 mol). The
simple two-step procedure of dihydroxylation and Lewis
acid-catalyzed rearrangement reaction also provided
enough amountsof material 5a in the synthesis of ( )-
coerulescine (1) and ( )-horsfiline (2) in 73% yield.
Bn
N
coerulescine (1)
horsfiline (2)
CHO
3a
O
N
N
Cbz
Cbz
4
5a
Scheme 1.
When 3-benzyloxy-1-benzyloxycarbonyl-4-hydroxy-4-
phenyl piperidine (8d) (prepared from monobenzylation
of diol 8a) wastreated with boron trifluoride etherate,
the sole 3-formyl-3-phenylpyrrolidine 5a was still iso-
lated in quantitative yield. The conversion of 8a–d to
5a–c ispinacol to pinacolone rearrangement. For pro-
viding aldehyde 5a, the similar reaction had been inves-
tigated on N-substituted 4-aryl-3,4-epoxypiperidines.10
According to the report,10a different N-substitutents
(methyl or carbamate functional group) can affect the
distribution of products.
two-step transformation is described as follows. One is
the rapid access to produce 3-formyl-3-phenylpyrrol-
idine 5a by rearrangement of 3,4-dihydroxy-4-phenyl-
piperidine. The other step is an intramolecular
electrophilic cyclization8 from 3-benzylcarbamoyl-3-
phenylpyrrolidine to the 3,3-spirocyclic 2-oxindole skele-
7e
ton 4 (a FujiÕsintermediate of horsfiline).
The synthesis began from compounds 5a–c asshown in
Scheme 2. Compounds 5a–c were prepared by six-step
standard protocol from the commercially available 4-
hydroxypiperidine (6): (i) benzyloxycarbonylation of
amine 6 with triethylamine and benzyloxycarbonyl chlo-
ride in tetrahydrofuran in ice bath for 1 h, (ii) oxidation
of the resulting alcohol with Jones reagent in acetone in
ice bath for 15 min, (iii) Grignard addition of ketone 79a
with different Grignard reagents(a, Ar = C 6H5; b,
Ar = 4-FC6H4; c, Ar = 3,4-CH2O2C6H3) in tetrahydro-
furan at À78 °C for 2 h, (iv) dehydration of the resulting
tertiary alcoholswith boron trifluoride etherate in
dichloromethane in ice bath for 15 min, (v) dihydroxyla-
tion of olefins 3a–c9b with N-methylmorpholine N-oxide
and a catalytic amount of osmium tetroxide in the co-
solvent of tert-butanol and water at reflux temperature
for 2 h,9c and (vi) rearrangement of diols 8a–c with
boron trifluoride etherate in ice bath for 15 min. Thus,
3-aryl-3-formylpyrrolidines 5a–c could be obtained in
good yield. The total synthetic procedure was monitored
by TLC until the reaction wascompleted. The overall
procedure wasachieved within one working day.
With compound 5a in hand, aldehyde 5a wastran-s
formed into acid 9 by Jonesoxidation ashsown in
Scheme 3. Treatment of acid 9 with dicyclohexylcarbo-
diimide and benzylamine gave a benzyl amide product.
Intramolecular electrophilic cyclization8 of the benzyl
amide with tert-butylhypochlorite followed by zinc ace-
tate gave the compound 4. The known approach had
been investigated by Kikugawa and co-workers.8 Com-
pound 4 wasa known intermediate of horfis line ( 2) in
7e
FujiÕsreport.
According to thisreport, compound 4
could be transformed to horsfiline (2) via regioselective
oxidation with lead tetrakis(trifluoroacetate) at the C-5
position and O-methylation of the resulting phenolic
compound. This constitutes a formal synthesis of ( )-
horsfiline (2). Finally, ( )-coerulescine (1) wasachieved
by hydrogenation of compound 4 with hydrogen in the
presence of a catalytic amount of 10% palladium on car-
bon followed by N-methylation with sodium boro-
hydride and formaldehyde. The 1H NMR spectral
data of compounds 1 and 4 were in accordance with
those reported in the literature.7e,l
While searching the related literature of 3-substituted 3-
formylpyrrolidine, we found that it wasa useful building
OH
O
1) CbzCl, Et3N
1) ArMgBr
Jones ox.
(88%)
1) BnNH2, DCC
CO2H
CHO
2) Jones ox.
(two-step 90%)
2) BF3-OEt2
2) t-BuOCl, then
Zn(OAc)2
(two steps 53%)
N
H
N
N
N
Cbz
Cbz
Cbz
a, Ar=C6H5;
b, Ar=4-FC6H4;
c, Ar=3,4-CH2O2C6H3
6
7
5a
9
Ar
N
Ar
OH
OH
Ar
Bn
OsO4, NMO
BF3-OEt2
CHO
1) H2, Pd/C
NH
N
N
N
2) CH2O, NaBH4
(two steps 65%)
O
N
O
Cbz
Cbz
Cbz
N
3a (85%)
3b (80%)
3c (83%)
8a (84%)
8b (89%)
8c (87%)
5a (94%)
5b (91%)
5c (92%)
Me
Cbz
coerulescine (1)
4
Scheme 2.
Scheme 3.

M.-Y. Chang et al. / Tetrahedron Letters 46 (2005) 8463–8465
8465
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We explored a Lewisacid catalyzed rearrangement reac-
tion of 4-aryl-N-benzyloxycarbonyl-3,4-dihydroxy-
piperidine to form 3-aryl-3-formylpyrrolidine skeleton.
Thisstrategy of intramolecular electrophilic cyclization
is synthetically useful for constructing ( )-coerulescine
(1) and ( )-horsfiline (2) with 3,3-spirocyclic oxindole
alkaloids. We are currently studying the scope of this
processaswell asadditional applicationsof the method-
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Supplementary data
Experimental proceduresand photocopiesof 1H NMR
(CDCl3) spectral data for 1, 3a–c, 4, 5a–c, 7, 8a–d,
and 9 were supported. Supplementary data associated
with thisarticle can be found, in the online version, at
doi:10.1016/j.tetlet.2005.10.015.
Acknowledgements
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The authorswould like to thank the National Science
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China for financial support.
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