Synthesis of streptorubin B core

Article abstract of DOI:10.1016/j.tetlet.2005.09.024

A straightforward synthesis of streptorubin B core structure has been established starting from trans-4-hydroxyproline. The core structure of streptorubin B is constructed in an intramolecular ring-closing metathesis as the key step.

Full text of DOI:10.1016/j.tetlet.2005.09.024

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7705–7709
Synthesis of streptorubin B core
Meng-Yang Chang,a,* Chun-Li Paib and Hua-Ping Chena
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
Received 18 August 2005; revised 2 September 2005; accepted 7 September 2005
Available online 21 September 2005
Abstract—A straightforward synthesis of streptorubin B core structure has been established starting from trans-4-hydroxyproline.
The core structure of streptorubin B is constructed in an intramolecular ring-closing metathesis as the key step.
Ó 2005 Elsevier Ltd. All rights reserved.
Ts
N
1. Introduction
O
epibatidine
intermediate
ref. 2m
In view of structural framework of trans-4-hydroxypro-
line (1), it possesses three functional groups that can be
easily modified, including 1-amino, 2-carboxylate, and
4-hydroxy groups.1 The skeleton represents the signifi-
cant feature for producing a series of different carbon
frameworks, such as monocycles (pyrrole,2a pyrroli-
dine,2b,c,l piperidine,2d and azanucleoside,2e) fused or
N
O
Ts
OTs
HO
CO2H
N
H
O
O
O
O
1
bridged bicycles (pyrrolizidine2f or azabicycles2g,h,m
)
pancracine
intermediate
ref. 2n
and polycycles2i–k,n etc., using an efficient modification.
Recently, we introduced a facile and straightforward
approach to the 7-azabicyclo[2.2.1]heptane skeleton2m
and hexahydro-1H-indol-3-one skeleton2n ring system
via an intramolecular basic alkylation and acidic aldol
condensation of the 2-substituted pyrrolidin-4-one
framework employing trans-4-hydroxyproline (1) as
the starting material (Fig. 1).
N
N
Ts
Ts
Figure 1. The previous synthetic approaches toward intermediate of
epibatidine and pancracine from trans-4-hydroxyproline (1).
rolylpyrromethene) core, were produced by a restricted
group of eubacteria and actinomycetes of Serratia and
Streptomyces.4c In general, this alkaloid groups5 possess
identical structural features of 4-methoxy-2,20-bipyrrole
ring skeleton system except for different alkyl substitu-
tents in the pyrrole ring C such as streptorubin B (2a),
prodigiosin (2b), undecylprodigiosin (2c), nonylprodigi-
osin (2d), metacycloprodigiosin (2e), and butylcyclohep-
tylprodiginine (2f). The related biochemical functions of
the prodigiosin family have been investigated.6 Roseo-
philin (2g) with a methoxyfuran motif was isolated by
Seto in 1992 and it possesses a close structural relative
to prodigiosin alkaloids.7a Due to its unique structural
features and important biological activities, consider-
able attention is directed from synthetic chemists toward
the synthesis of these alkaloids.8 Rapoport and Holden,5a
To explore the synthetic application of our methodol-
ogy, the synthetic study of streptorubin B (2a)3 (butyl-
meta-cycloheptylprodigiosin) was investigated. In the re-
port, the synthetic study toward streptorubin B (2a) has
been established by synthesizing core structure 3 (Furst-
¨
nerÕs intermediate) from trans-4-hydroxyproline (1) as
shown in Figure 2.
The naturally occurring prodigiosin alkaloids4 with
deeply red colored chromophore, belonging to a series
of close relatives with the same prodiginine (pyr-
Keywords: Streptorubin B; trans-4-Hydroxyproline; Ring-closing
metathesis.
Wasserman et al.,5c Boger and Patel,9a Furstner and
¨
Krause,9b DÕAlessio et al.,7b,c Fuchs and co-workers,9c
*
Corresponding author. Tel.: +886 7 5919464; fax: +886 7 5919348;
e-mail: mychang@nuk.edu.tw
and Trost and Doherty9d have used various key steps,
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.024

7706
M.-Y. Chang et al. / Tetrahedron Letters 46 (2005) 7705–7709
D
C
2
N
H
MeO
N
B
9
H
N
A
N
Ts
streptorubin B (2a)
Furstner's intermediate (3)
N
H
N
H
N
H
MeO
MeO
MeO
N
N
N
H
N
H
N
H
N
prodigiosin (2b)
undecylprodigiosin (2c)
nonylprodigiosin (2d)
N
N
H
N
H
N
N
H
MeO
O
MeO
MeO
N
H
N
H
N
Cl
roseophilin (2g)
metacycloprodigiosin (2e) butylcycloheptylprodiginine (2f)
Figure 2. Structural characteristics of streptorubin B (2a), FurstnerÕs intermediate 3, and their related prodigiosin-group natural products 2b–g.
¨
for example, Paal–Knorr cyclization and intramolecular
diene or enyne ring-closing metathesis, in their respec-
tive elaborations of different prodigiosin alkaloids
analogs.
2. Results and discussion
The retrosynthetic approach is shown in Scheme 1.
Streptorubin B (2a) with prodiginine framework is easily
formed by acid-catalyzed condensations8 of the known
bipyrrole aldehyde 4 with a bicyclic pyrrole segment 5.
Therefore, the preparation of the core structure consti-
tutes the prime challenge. We envisioned the streptoru-
bin B core structure 3 could be achieved via a series of
functional group transformation to 2-substituted pyr-
rolidin-4-one 7 from trans-4-hydroxyproline (1), Grig-
nard addition of ketone 7, intramolecular ring-closing
To date, there are few reports for the synthesis of strep-
torubin B citations. Recently, Furstner et al. reported
¨
the related synthesis of streptorubin B using the intra-
molecular platinum-catalyzed enyne metathesis and
base-induced aromatization as key steps.3 This nine-
steps sequence delivered streptorubin B core structure
in 16% overall yield.
CHO
MeO
NH
ref. 3
H
N
2a
+
N
N
H
Ts
3
4
5
a series of
functional group
O
Grignard
addition
RCM
HO
1
transformations
N
N
Ts
Ts
6
7
Scheme 1. Retrosynthetic analysis of streptorubin B (2a).

M.-Y. Chang et al. / Tetrahedron Letters 46 (2005) 7705–7709
7707
TBSO
TBSO
1) H2, Pd/C (99%)
CO2Et 2) LAH (94%)
1) Swern ox.
OH
N
N
2) Ph3P=CHCO2Et
(two steps 90%)
Ts
Ts
8
9
TBSO
TBSO
OH
TBAF, THF
1) PCC, Celite( 88%)
N
N
then PCC, DCM
(one-pot 89%)
2) Ph3P=CH2 (85%)
Ts
Ts
10
11
O
1)
1) H2, Pd/C
Br
12, Mg
HO
3
2) Grubbs catalyst
(0.39 mM)
(two steps 58%)
2) BF3-OEt2
(two steps 65%)
N
N
Ts
Ts
7
13
Scheme 2. Synthesis of streptorubin B core structure (FurstnerÕs intermediate 3).
¨
metathesis reaction of diene 6, and followed by hydroge-
nation and dehydration.
Bromide 12 was prepared from Grignard addition of
valeraldehyde with the freshly prepared 1-butenyl-4-
magnesium bromide followed by bromination of the
corresponding secondary alcohol with carbon tetrabro-
mide and triphenylphosphine in overall 75% yield.
With diene 6 in hand, we turn the attentions to build
up the bicyclic pyrrolophane skeleton 13 via intramo-
lecular ring-closing metathesis reaction. The reaction
has been established as a powerful method for the elab-
oration of medium-sized rings, including carbohy-
drates, heterocycles, and alkaloids.11,12 When diene 6
was subjected to a ring-closing metathesis reaction
employing the first generation Grubbs catalyst [Cl2-
(PCy3)2Ru@CHPh], the expected macrocyclic skeleton
13 was generated in trace yield (<5%).
We first studied the approach to streptorubin B core
structure 3 from prolinol 8 as shown in Scheme 2. Syn-
thesis of prolinol 8 contains the following four-step reac-
tions from trans-4-hydroxyproline (1): (i) esterification
with thionyl chloride and methanol, (ii) tosylation with
p-toluenesulfonyl chloride and triethylamine, (iii) silyla-
tion with tert-butyldimethylsilyl chloride and imidazole,
and (iv) reduction of the resulting ester with sodium
borohydride in the presence of lithium chloride. Thus,
prolinol 8 was given in 90% overall yield with only once
purification.2m,n
Prolinol 8 was transformed into a,b-unsaturated ethyl
ester 9 by Swern oxidation and Wittig olefination under
the standard conditions. Compound 10 was hydro-
genated with hydrogen and a catalytic amount of 10%
palladium on activated carbon followed by reduction of
the resulting ester with lithium aluminum hydride. Alco-
hol 10 was transformed to olefin 11 by oxidation with
pyridinium chlorochromate and olefination with n-butyl-
lithium and methyltriphenylphosphonium iodide. The
overall yield of the easy six-step approach was approxi-
mately provided 62%. For shortening the synthesis of
olefin 11, two-step synthetic route10 of O-tosylation and
allyl group elongation was also studied. The poor yield
(<30%) was provided in our case. Although the synthetic
efficiency is decreased, we believe the rather lengthy six-
step route with good yield will be valuable to report. To
synthesize ketone 7 easily, compound 11 was desilylated
with tetra-n-butylammonium fluoride in tetrahydrofuran
followed by oxidation with pyridinium chlorochromate
in dichloromethane in one-pot conditions.
We next turn our focus to examine the second genera-
tion Grubbs catalyst with higher thermal stability and
lower sensitivity to double bond migration.11c Following
a similar approach, attempts to form compound 13
using second generation Grubbs catalyst under a variety
of conditions (prolonged reaction time, elevated temper-
ature, different solvents) were unsuccessful. Finally, the
product 13 was obtained in 58% yield in the diluted solu-
tion (0.39 mM). In order to simplify the complexity of
bicyclic skeleton, product 13 was further transformed
to known FurstnerÕs intermediate 3 by hydrogenation
¨
with 10% palladium on activated carbon followed by
dehydration of the resulting compound with boron tri-
flouride etherate.
The major signal peaks in 1H NMR spectral data
of compound
3 were in accordance with those
reported in the literature.3 In our technology, we
cannot separate the diastereomers 3 with a pair of
(2S,9R) and (2R,9R) chiral centers such that correct
stereochemistry of major product cannot be addressed.
According to the report,3 the related stereochemistry
Grignard addition of ketone 11 with 1-nonenyl-5-mag-
nesium bromide gave diene 6 as the mixture product.

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M.-Y. Chang et al. / Tetrahedron Letters 46 (2005) 7705–7709
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of diastereomers 3 is not an important factor to yield
a sole compound 5 in the following base-induced
aromatization for the synthesis of the streptorubin B
(2a).
3. Conclusion
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¨
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In summary, we have developed a straightforward
approach to the bicyclic pyrrolophane skeleton ring
system based on the intramolecular ring-closing meta-
thesis reaction as the key step and applied this route
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to synthesize FurstnerÕs intermediate 3 toward the study
¨
of streptorubin B (2a). For the application and investi-
gation of trans-4-hydroxyproline (1), synthetic study
toward macrocyclic framework has not been reported
in the literature. In the objective of our paper, a novel
approach for synthesis of streptorubin B core structure
based on the trans-4-hydroxyproline (1) has been
explored. We are currently studying the scope of this
process as well as additional applications of this
approach to the synthesis of various potential biological
activity compounds using trans-4-hydroxyproline (1) as
the starting material.
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Acknowledgment
The authors would like to thank the National Science
Council (NSC 94-2113-M-390-001) of the Republic of
China for financial support.
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Experimental procedures and photocopies of 1H and
13C NMR (CDCl3) spectral data were supported.
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2005.09.024.
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