A versatile Enantioselective Synthesis of Barrenazines

Article abstract of DOI:10.1021/ol902920u

A versatile enantioselectlve total synthesis of barrenazines A and B has been accomplished from 1,4-butanediol. The key steps of the synthesis are a sequential allylboration/rlng-closing metathesis for the construction of the tetrahydropyrldlne ring and t

Full text of DOI:10.1021/ol902920u

ORGANIC
LETTERS
2010
Vol. 12, No. 4
852-854
A Versatile Enantioselective Synthesis
of Barrenazines†
Miguel Pen˜a-Lo´pez, M. Montserrat Mart´ınez, Luis A. Sarandeses,* and
Jose´ Pe´rez Sestelo*
Departamento de Qu´ımica Fundamental, UniVersidade da Corun˜a,
E-15071 A Corun˜a, Spain
sestelo@udc.es; qfsarand@udc.es
Received December 18, 2009
ABSTRACT
A versatile enantioselective total synthesis of barrenazines A and B has been accomplished from 1,4-butanediol. The key steps of the synthesis
are a sequential allylboration/ring-closing metathesis for the construction of the tetrahydropyridine ring and the preparation of a functionalized
4-azidopiperidin-5-one through a stereoselective epoxidation and regioselective ring-opening reaction. The C2-symmetrical pyrazine skeleton
of barrenazines was prepared by dimerization of the azidopiperidinone, and the carbon side chain was completed by copper-catalyzed reactions
using Grignard reagents.
Barrenazines are novel marine cytotoxic alkaloids isolated
from an unidentified tunicate collected at the Barren Islands
(Madagascar) by Kashman et al. in 2003.1 These compounds
present a C2 symmetric structure that consists of a central
pyrazine ring condensed with two piperidine cycles, two
stereogenic centers, and different heptyl carbon side chains.
The low natural appearance of barrenazines has limited the
structural identification and biological evaluation to only two
members of the family, barrenazines A (1) and B (2).
Barrenazine A exhibits cytotoxic activity against LOVO-DOX
colon carcinoma and, in a mixture with other unidentified
congeners from the same tunicate, a wider biological activity
that includes cytotoxic activity against LN-caP prostate
carcinoma and K-562 leukemia cells.1
have been reported. In 2006, Focken and Charette2 published
the first enantioselective synthesis, and later on, our group
reported the total synthesis of barrenazines A and B.3 In both
cases, the carbon side chain was introduced in an early step
of the synthesis through diastereoselective nucleophilic
Grignard addition to a chiral pyridinium salt.4 An unsuc-
cessful biomimetic approach to barrenazine A using aspartic
acid as the starting material has also been reported.5 In this
letter, we report a new and versatile enantioselective synthesis
of barrenazines A and B.
The synthetic strategy was based on the preparation of
the C2-symmetrical tricyclic pyrazine core of barrenazines
(2) Focken, T.; Charette, A. B. Org. Lett. 2006, 8, 2985–2988.
(3) Mart´ınez, M. M.; Sarandeses, L. A.; Pe´rez Sestelo, J. Tetrahedron
Lett. 2007, 48, 8536–8539.
Hitherto, several research groups have pursued the syn-
thesis of barrenazines, and two independent total syntheses
(4) (a) Comins, D. L.; Joseph, S. P.; Hong, H.; Al-awar, R. S.; Foti,
C. J.; Zhang, Y.; Chen, X.; LaMuyon, D. H.; Guerra-Weltzien, M. Pure
Appl. Chem. 1997, 69, 477–481. (b) Comins, D. L.; Joseph, S. P.; Goehring,
R. R. J. Am. Chem. Soc. 1994, 116, 4719–4728. (c) Comins, D. L.; Goehring,
R. R.; Joseph, S. P.; O’Connor, S. J. Org. Chem. 1990, 55, 2574–2576.
(5) Buron, F.; Turck, A.; Ple´, N.; Bischoff, L.; Marsais, F. Tetrahedron
Lett. 2007, 48, 4327–4330.
† This work is dedicated to Professor Amos B. Smith, III, University of
Pennsylvania, on the occasion of his 65th birthday.
(1) Chill, L.; Aknin, M.; Kashman, Y. Org. Lett. 2003, 5, 2433–2435.
10.1021/ol902920u  2010 American Chemical Society
Published on Web 01/21/2010

prior to the completion of the side chain to facilitate the
synthesis of analogues (Scheme 1). The construction of the
alcohol 7 in good yield and with high enantioselectivity
(84%, 92% ee).9 The reaction of 7 under Mitsunobu
conditions using diphenyl phosphoryl azide (DPPA) provided
the azide 8 in quantitative yield.10 Under Staudinger condi-
tions, 8 was cleanly reduced to amine 9 with aqueous Ph3P
in 69% yield.11 At this point, the primary amine 9 was
protected to favor the selective introduction of the allyl group
and to perform the olefin metathesis. The reaction of 9 with
benzyloxycarbonyl chloride (CbzCl) and Et3N in CH2Cl2 at
0 °C and subsequent allylation provided the desired tertiary
N-allyl amine 5 in good overall yield (Scheme 2).
Scheme 1. Retrosynthetic Analysis of Barrenazines A and B
The ruthenium-catalyzed ring-closing metathesis12 of 5
using Grubbs I catalyst [5 mol %, (Cy3P)2RuCl2CHPh]
afforded tetrahydropyridine 4 at rt in 84% yield (Scheme
3). It is interesting to note that the metathesis reaction failed
on compound 5 protected as the p-methoxybenzylamine, with
starting material recovered unalterated.13
hexahydrodipyridopyrazine skeleton was proposed by reduc-
tive dimerization of a conveniently functionalized 4-azidopi-
peridin-5-one 3,6 which could be prepared from the tetrahy-
dropyridine 4 through epoxidation and regioselective
nucleophilic epoxide opening using the azide ion as a
nucleophile. For the construction of the tetrahydropyridine
ring, we devised a synthetic strategy based on a sequential
enantioselective aldehyde allylation and ring-closing me-
tathesis.7
Scheme 3. Synthesis of the Azido Alcohol 11
Our synthesis started with the preparation of the known
tert-butyldimethylsilyl ether of 4-hydroxybutyraldehyde
(6) from 1,4-butanediol (Scheme 2).8 The enantioselective
Scheme 2. Synthesis of the N-Allyl Amine 5
With tetrahydropyridine 4 in hand, we pursued the
synthesis of the R-azido ketone 3 through an epoxidation,
nucleophilic opening, and oxidation sequence. A successful
strategy should require a highly regioselective epoxide
opening to avoid the formation of a mixture of regioisomeric
pyrazines during the dimerization step.14 Initially, the reaction
of 4 with m-CPBA under several sets of reaction conditions
provided epoxide 10 with low yields and conversions.
Alternatively, the epoxidation using the methyl (trifluoro-
methyl)dioxirane, generated in situ from trifluoroacetone and
(9) The enantiomeric excess was determined in the corresponding MTPA
esters of 7 by 19F NMR. For further details see Supporting Information.
(10) (a) Mitsunobu, O. Synthesis 1981, 1–28. (b) For a recent review,
see: Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P.
Chem. ReV. 2009, 109, 2551–2651.
Brown allylation of 6 using allyl magnesium bromide and
(+)-(Ipc)2BOMe at -100 °C provided the homoallylic
(11) Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Millican, N. L.;
Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2003,
1, 3708–3715.
(6) (a) Heathcock, C. H.; Smith, S. C. J. Org. Chem. 1994, 59, 6828–
6839. (b) Dro¨gemu¨ller, M.; Flessner, T.; Jautelat, R.; Scholz, U.; Winterfeldt,
E. Eur. J. Org. Chem. 1998, 2811–2831.
(12) For a comprehensive treatment of the metathesis reaction, see:
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003.
For leading references in the metathesis reaction, see: (a) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527. (b)
Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem., Int. Ed. 2006, 45,
2664–2670. (c) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243–
251.
(7) For a general review of this strategy in the synthesis of biologically
active molecules, see: Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C.
Pure Appl. Chem. 2003, 75, 1263–1275. For additional references, see: (a)
Felpin, F.-X.; Boubekeur, K.; Lebreton, J. Eur. J. Org. Chem. 2003, 4518–
4527. (b) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R. Synthesis
2006, 4005–4012.
(13) Fu, G. C.; Neguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993,
115, 9856–9857.
(8) (a) Taillier, C.; Gille, B.; Bellosta, V.; Cossy, J. J. Org. Chem. 2005,
70, 2097–2108. (b) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am. Chem. Soc.
2008, 130, 8481–8490.
(14) It is worth noting that either of the pure regioisomeric azido ketones
should provide the same dimeric pyrazines.
Org. Lett., Vol. 12, No. 4, 2010
853

Oxone at 0 °C,15 afforded 10 in high yield and stereoselec-
tivity (83%, 96:4). It seems that the high stereoselectivity
observed is controlled by the steric hindrance produced by
the Cbz group.16
of the heptyl carbon side chain by copper-catalyzed cross-
coupling reactions using Grignard reagents.21 For this
purpose, the two TBS ethers of 12 were cleaved with
TBAF at rt to give diol 13 (99% yield), which was in
turn converted into the diiodide 14 by treatment with Ph3P,
I2, and imidazole (94% yield, Scheme 4). The reaction of
14 with n-butylmagnesium bromide at -78 °C under
copper(I) catalysis (50 mol %) gave the dicoupling product
15 (Cbz-protected barrenazine A) in excellent yield (88%).
Analogously, the reaction using 3-butenylmagnesium
bromide, under the same reaction conditions, provided the
Cbz-protected barrenazine B (16) in similar yield. Finally,
treatment of 15 and 16 with TMSI at 0 °C furnished
synthetic (-)-barrenazine A and (-)-barrenazine B in 80%
and 74% yield, respectively.
In summary, a novel and versatile enantioselective syn-
thesis of (-)-barrenazine A and (-)-barrenazine B has been
accomplished from 1,4-butanediol. The key steps of the
synthesis are a sequential allylboration/ring-closing meta-
thesis strategy for the construction of the tetrahydropyridine
ring and the preparation of a functionalized 4-azidopiperidin-
5-one through a stereoselective epoxidation and regioselec-
tive ring-opening reaction. The C2-symmetrical pyrazine
skeleton of barrenazines was prepared by reductive dimeri-
zation of an R-azido ketone with reduced tellurium, and the
carbon side chain was completed by copper-catalyzed
coupling reactions using Grignard reagents. The synthesis
and biological evaluation of new derivatives of barrenazines
A and B modified at the side chain are in progress.
The reaction of epoxide 10 with sodium azide at 65 °C
during 12 h gave the azido alcohol 11 in 78% yield in a
regio- and stereoselective manner as a single stereoisomer
(Scheme 3). The regiochemistry of the reaction can be
explained by the preferred diaxial epoxide opening (Fu¨rst-
Platter rule)17 and was determined by 2D NMR experiments
(HMBC) based on the correlation observed between H-2 and
C-4. The stereochemistry of 11 was assigned on the basis
18
1
of the coupling constants in the H NMR spectra.
The next step was the conversion of 11 into the corre-
sponding R-azido ketone 3, which is suitable for reductive
dimerization through self-condensation of the corresponding
R-amino ketone.6 The oxidation of azido alcohol 11 with
Dess-Martin periodinane19 (DMP) gave the desired 4-azi-
dopiperidin-5-one 3 as the only reaction product, although
this compound proved to be unstable to the chromatographic
purification. Unfortunately, the reduction of azide 3 with
aqueous Ph3P and the spontaneous self-condensation of the
resulting amino ketone only produced the symmetrical
pyrazine 12 in low yields. Alternatively, the reaction using
reduced tellurium (Te/NaBH4) in EtOH at rt afforded the
symmetrical pyrazine 12 as a single product by 1H NMR in
86% overall yield (from 11, Scheme 4).20
Scheme 4. Synthesis of Barrenazines A and B
Acknowledgment. We are grateful to the Xunta de Galicia
(PGIDIT05BTF10301PR and INCITE08PXIB103167PR) for
financial support. MPL thanks the Xunta de Galicia and
Ministerio de Ciencia e Innovacio´n for predoctoral fellow-
ships (Mar´ıa Barbeito and FPU, respectively). MMM thanks
the Xunta de Galicia for an Isidro Parga Pondal contract.
We also thank Miss Fa´tima Nu´n˜ez (Universidade da Corun˜a)
for initial studies and Prof. Jaime Rodr´ıguez (Universidade
da Corun˜a) for spectroscopic assistance.
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL902920U
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(18) For further details, see Supporting Information.
(19) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–
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Once the tricyclic pyrazine core of the barrenazines had
been prepared, we proceeded to explore the completion
(21) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135–631.
(b) Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41, 1545–1554.
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