Novel use of a selenoalkyne within untraditionally mild D?tz benzannulation processes; total synthesis of a Calceolaria andina L. natural hydroxylated naphthoquinone

Article abstract of DOI:10.1055/s-2001-16782

A total synthesis of the Calceolaria andina L. extract 2-(1,1-dimethyl-2-propenyl)-3-hydroxy-1,4-naphthalenedione is described incorporating the first reported D?tz benzannulation of a selenoalkyne. Importantly, it has been shown that it is possible to effect this annulation at ambient temperature under dry state conditions with a significant improvement in cyclisation yield.

Full text of DOI:10.1055/s-2001-16782

1428
LETTER
Novel Use of a Selenoalkyne Within Untraditionally Mild Dötz Benzannulation
Processes; Total Synthesis of a Calceolaria andina L. Natural Hydroxylated
Naphthoquinone
John J. Caldwell,a Robert Colman,b,1 William J. Kerr,a* Euan J. Magennisa
aDepartment of Pure and Applied Chemistry, University of Strathclyde, Glasgow, G1 1XL, Scotland, U.K.
Fax +44 141 548 4246; E-mail: w.kerr@strath.ac.uk
bLancaster Synthesis Ltd., Newgate, White Lund, Morcambe, Lancashire, LA3 3DY, England, U.K.
Received 7 June 2001
2-(1,1-dimethyl-2-propenyl)-3-hydroxy-1,4-naphthalene-
Abstract: A total synthesis of the Calceolaria andina L. extract
dione 1.6 Indeed, activity of this compound was particu-
2-(1,1-dimethyl-2-propenyl)-3-hydroxy-1,4-naphthalenedione is
larly high against Bemisia tabaci (tobacco whitefly) and
Tetranychus urticae (spotted spider mite) and, significant-
described incorporating the first reported Dötz benzannulation of a
selenoalkyne. Importantly, it has been shown that it is possible to ef-
fect this annulation at ambient temperature under dry state condi- ly, no cross-resistance was observed for strains resistant to
tions with a significant improvement in cyclisation yield.
existing commercial insecticides. Furthermore, the anti-
tumour activity of compounds of this family have also
been documented.7 Herein, we now report on the further
development of our DSA protocol and how these tech-
niques have been employed to effect the first reported
Dötz benzannulation of a selenoalkyne, as the key trans-
formation in the synthesis of 2-(1,1-dimethyl-2-prope-
nyl)-3-hydroxy-1,4-naphthalenedione.
Key words: carbene complexes, chromium, Dötz benzannulation,
dry state techniques, selenium
The Dötz benzannulation is a well established and effec-
tive chromium-mediated process for the direct prepara-
tion of substituted benzenoid systems in a highly
regioselective manner (Scheme 1).2 Indeed, this reaction
has been exploited at a convergent point in many
syntheses2,3 and the diverse functionality tolerated by this
method further illustrates the usefulness of this cyclisation
technique as a tool for the synthetic organic chemist. Fur-
thermore, the utility of the reaction has been enhanced in
recent years with the drawbacks of the more traditional
thermal reaction conditions (i.e. often only low to moder-
ate product yields following prolonged reaction times) be-
ing circumvented by the establishment of some practical
modifications. In this context, we have systematically ex-
plored the use of ultrasound4 and of dry state adsorption
(DSA) techniques4,5 which have, in turn, delivered both a
reduction in the required reaction times and an improve-
ment in cyclisation yield in most cases.
From a retrosynthetic perspective it was envisaged that
the facile elimination of a 2-nitrophenylseleno moiety
would afford the requisite propenyl side chain, and intro-
duction of the hydroxyl functionality would afford the fi-
nal product 1 (Scheme 2). Therefore, the alkyne 3 was
identified as the key selenium containing substrate in what
would be a novel Dötz benzannulation process. It was an-
ticipated that the selenide could be prepared routinely in
one step from the equivalent hydroxyalkyne.8
O
O
O
O
O2N
Se
OH
2
1
OH
O
R1
R2
R1
R2
OR
O2N
Se
OR
R1
R2
[O]
(OC)5Cr
OC)5Cr
R1 > R2
+
Cr(CO)3
4; R = Me
5; R = Et
3
OR
O
Scheme 1
Scheme 2
To further demonstrate the applicability of these modified
conditions and following our total synthesis of the anti-
parasitic agent, parvaquone,3a we have continued work to-
wards other biologically active targets possessing the
2-hydroxy-1,4-naphthalenedione skeleton. In this regard,
a compound recognised as being responsible for the insec-
ticidal activity of extracts of Calceolaria andina L. (Scro-
phulariaceae) has been isolated and characterised as
To initiate our study, benzyl protected bromoethanol 8
was synthesised in two steps: monoprotection of ethylene
glycol 69 proceeded in good yield and this was followed
by efficient bromination using NBS and triphenylphos-
phine (Scheme 3). In turn, this two carbon unit was intro-
duced onto the anion of ethyl isobutyrate and subsequent
LiAlH4 reduction of the resulting ester 9 afforded the al-
Synlett 2001, No. 9, 1428–1430 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Novel Use of a Selenoalkyne Within Untraditionally Mild Dötz Benzannulation Processes
1429
cohol 10 in excellent yield. Alkyne formation was then sensitive alkyne reaction partners are employed.5b,c Fur-
carried out over two steps without isolation of the inter- thermore, this short study demonstrates that, depending
mediate aldehyde. More specifically, TPAP oxidation10 on the nature and demands of the cyclisation substrates,
was followed by use of the efficient and practically con- mild modification of the initially established DSA proto-
venient Ohira-Bestmann protocol11 to deliver the alkyne cols can lead to further improvements in reaction efficien-
11 in 84% overall yield.12 Mild and rapid debenzylation of cy.
11 was then effected by following the procedure outlined
by Holmes and co-workers13 using BCl3 SMe2, and the
free alcohol was successfully transformed into the requi-
Table Optimisation of the Dötz Benzannulation Reaction of Com-
plexes 4 and 5 with Alkyne 3.
site selenide 3, with the latter two transformations pro-
O
O
O2N
Se
OR
ceeding in 95% and 96% yield, respectively.14,15
(OC)5Cr
Se
O2N
+
2
3
4; R = Me
5; R = Et
a
b
HO
HO
Br
OH
OBn
OBn
6
7
8
O
c
d
OBn
OBn
Se
EtO
HO
9
10
3
e
f
OBn
11
O2N
Scheme 3 Reagents and conditions: (a) NaH (0.34 equiv.), BnBr
(0.33 equiv.), THF, reflux, 3 h, 79%; (b) NBS (1.2 equiv.), PPh3 (1.2
equiv.), CH2Cl2, r.t., 13 h, 89%; (c) LDA (1 equiv.), ethyl isobutyrate
(0.9 equiv.), THF, 0°C, 5 h, 83%; (d) LiAlH4 (1 equiv.), Et2O, 0°C,
1.5 h, 99%; (e) i. TPAP (5 mol%), NMO (1.5 equiv.), 4Å mol. sieves,
CH2Cl2, r.t., 10 mins; ii. Dimethyl 1-diazo-2-oxopropylphosphonate
(1.15 equiv.), K2CO3 (2 equiv.), MeOH, r.t., 1 h, 84%;
(f) i. BCl3.SMe3 (7 equiv.), CH2Cl2, r.t., 15 min, 95%; ii. 2-nitrophe-
nylselenocyanate (1.4 equiv.), nBu3P (1.4 equiv.), THF, r.t., 3h, 96%.
aAll annulations were oxidatively worked up with ammonium cerium
nitrate; see ref. 18. b))) refers to ultrasonication conditions.
To complete our synthesis, dihydroxylation of the naph-
thalenedione 2 was achieved using OsO4. This was fol-
lowed by efficient elimination of the selenyl group using
H2O2.19 Dehydration of the diol, via carbonate formation
with CDI and subsequent treatment with sodium hydride20
(without isolation of the intermediate carbonate), af-
forded the target natural naphthoquinone 1 in 87% yield
(Scheme 4).
With the desired alkyne component for the proposed Dötz
reaction in hand, efforts were then made to perform and,
in turn, optimise this key transformation using the two
readily available phenyl alkoxy carbene complexes 416
and 5.17 Initially, traditional thermal conditions were em-
ployed and despite considerable variation and analysis of
the reaction parameters, at best, a low 22% yield of the
naphthoquinone 2 was achieved, as detailed in the Table
(entries 1 & 2). In due course, the use of ultrasound
techniques4 were also investigated, again, with disap-
pointing results; all starting carbene complex was con-
sumed within minutes, however, only decomposition was
observed and none of the desired product was isolated.
The annulation process was then attempted under our es-
tablished DSA conditions at 55°C.4,5a Whilst even these
mild techniques resulted in some decomposition, as
shown by entries 5 & 6, this method provided the highest
yield of 2 observed to this stage in our study. In an effort
to further moderate the benzannulation conditions, the re-
actants were loaded onto silica in the usual manner but
were merely stirred at room temperature. Pleasingly, this
modified DSA protocol provided the desired naphtho-
quinone 2 in significantly enhanced yields (entries 7 & 8)
and with substantially less decomposition being ob-
served.18 Therefore, it would appear that dry state tech-
niques again provide the method of choice when
performing Dötz annulation processes, in particular, when
O2N
Se
12
O
O2N
Se
O
O
a
OH
OH
2
O
b
O
O
O
c
OH
OH
OH
13
O
1
Scheme 4 Reagents and conditions: (a) OsO4 (5 equiv.), pyridine
(trace), 24 h, 80%; (b) 30% H2O2, THF, 16 h, 95%; (c) CDI (1.5
equiv.), 4Å mol. sieves, NaH (2 equiv.), pyridine, r.t., 1 h, 87%.
In conclusion, this 11 stage synthesis of 2-(1,1-dimethyl-
2-propenyl)-3-hydroxy-1,4-naphthalenedione 1 has been
completed with an average yield of 87% per step and an
overall yield of 19%. Furthermore and at least as impor-
tantly, we have now shown that it is possible to perform
Synlett 2001, No. 9, 1428–1430 ISSN 0936-5214 © Thieme Stuttgart · New York

1430
J. J. Caldwell et al.
LETTER
(8) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976,
41, 1485.
(9) Marshall, J. A.; Trometer, J. D.; Blough, B. E.; Crute, T. D. J.
Org. Chem. 1988, 53, 4274.
(10) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
(11) Ohira, S.; Synth. Commun. 1989, 19, 561. Müller, S.; Liepold,
B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
(12) It should be noted that at an earlier stage in this work the
benzyl protected alkyne 11 was employed directly in the key
Dötz benzannulation. Moderate to good yields (52% to 86%)
were achieved for this cyclisation under conditions similar to
those described in the Table. However, subsequent
debenzylation, under a variety of conditions, proved to be, at
best, low yielding. Furthermore, attempts to carry out the
selenation of the free alcohol were then found to be in
competition with Michael addition of the aryl selenide.
(13) For examples, see: (a) Congreve, M. S.; Davidson, E. C.;
Fuhry, M. A. M.; Holmes, A. B.; Payne, A. N.; Robinson, R.
A.; Ward, S. E. Synlett 1993, 663.
the Dötz benzannulation reaction at ambient temperatures
under DSA conditions. This protocol constitutes the most
mild method currently available for performing this orga-
nochromium-mediated transformation. In this respect, it
is likely that this developed technique could provide sig-
nificant practical advantages when the use of sensitive
alkyne substrates, such as the seleno species employed as
part of this study, is required. Additionally, the general
synthetic strategy described here will allow access to a se-
ries of less accessible hydroxylated naphthoquinones of
biological importance.
Acknowledgement
We thank The Carnegie Trust for the Universities of Scotland for a
postgraduate studentship (J.J.C.) and The University of Strathclyde
for a Science Faculty Postgraduate Research Studentship (E.J.M)
with further financial support from Lancaster Synthesis Ltd. We are
also indebted to Dr Eric Cuthbertson of Lancaster Synthesis Ltd. for
input and support, and the EPSRC Mass Spectrometry Service, Uni-
versity of Wales, Swansea, for analyses.
(14) It should be noted that the selenation reaction only proceeded
completely satisfactorily when the 2-nitrophenyl
selenocyanate was recrystallised from petrol and fresh nBu3P
was employed.
(15) All new compounds gave satisfactory spectral and analytical
data.
References and Notes
(16) Fischer, E. O.; Kreiter, C. G.; Kollmeier, H. J.; Müller, J.;
Fischer, R. D. J. Organomet. Chem. 1971, 28, 237.
(17) Darensbourg, M. Y.; Darensbourg, D. J. Inorg. Chem. 1970,
9, 32.
(1) Present address: Stylacats Ltd., Department of Chemistry,
University of Liverpool, L69 7ZD, England, U.K.
(2) Wulff, W. D. In Comprehensive Organic Synthesis, Trost B.
M.; Fleming, I., Ed.; Pergamon Press: Oxford, 1991; 5, p.
1065. Harrington, P. J. Transition Metals in Total Synthesis;
Wiley: New York, 1990, p. 346. Dötz, K. H. In
(18) Representitive experimental procedure: Selenoalkyne 3
(400 mg, 1.59 mmol) and phenyl ethoxy chromium carbene
complex 5 (518 mg, 1.59 mmol) were dissolved in ether (200
mL) and stirred with silica gel (14 g) for 5 min. The solvent
was then removed in vacuo and the loaded silica was stirred
under nitrogen at r.t. for 3 days. Ether (200 mL) was then
added and the mixture was stirred for a further 1 h before
being filtered. The silica was washed with ether (2 200 mL)
and to the filtrate and combined washings was added a
solution of ammonium cerium nitrate (4 g, 7.30 mmol) in
water (200 mL). The resulting mixture was stirred at r.t. for a
further 1 h, the phases separated, and the aqueous layer
extracted with ether (200 mL). The organic extracts were
combined and washed with saturated NaHCO3 solution
(2 300 mL), dried (MgSO4), filtered and then concentrated
in vacuo. Flash column chromatography (eluting with petrol/
ether 4:1) afforded 2-(1,1-dimethyl-3-(2-nitrophenyl-
selenyl)propyl)-1,4-naphthalenedione 2 (350 mg, 66%) as a
pale yellow solid. Mp 123-124 °C. IR (film): 3063, 2984,
1661, 1593, 1514, 1331 cm-1. 1H NMR (CDCl3, 400 MHz):
1.43 (6H, s, 2 CH3), 2.36-2.41 (2H, m, CCH2), 2.68-2.72
(2H, m, CH2Se), 6.89 (1H, s, CH), 7.28-7.49 (3H, m, 3 Ar-
H), 7.69-7.74 (2H, m, 2 Ar-H), 8.05-8.10 (2H, m, 2 Ar-H),
8.27 (1H, dd, J = 1.4, 8.3 Hz, Ar-H). 13C NMR (CDCl3, 100
MHz): 21.8, 28.0, 39.4, 40.2, 125.6, 126.0, 126.7, 127.2,
129.2, 131.8, 133.6 (2), 133.7, 133.8, 134.2, 136.0, 146.9,
156.0, 185.0, 185.5. HRMS: C21H23N2O4Se, M+NH4 requires
447.0823; found 447.0825.
Organometallics in Organic Synthesis, de Meijere, A.; tom
Dieck, H., Ed.; Springer: Berlin, 1988, p. 85. Dötz, K. H.
Angew. Chem. Int. Ed. Engl. 1984, 23, 587. Dötz, K. H. Pure
Appl. Chem. 1983, 55, 1689. Dötz, K. H. Angew. Chem. Int.
Ed. Engl. 1975, 14, 644.
(3) For examples see: (a) Harrity, J. P. A.; Kerr, W. J.;
Middlemiss, D.; Scott, J. S. J. Organomet. Chem. 1997, 532,
219.
(b) Boger, D. L.; Hüter, O.; Mbiya, K.; Zhang, M. J. Am.
Chem. Soc. 1995, 117, 11839. (c) Dötz, K. H.; Popall, M.
Angew. Chem. Int. Ed. Engl. 1987, 26, 1158.
(4) Harrity, J. P. A.; Kerr, W. J.; Middlemiss, D. Tetrahedron
1993, 49, 5565.
(5) (a) Harrity, J. P. A.; Kerr, W. J.; Middlemiss, D. Tetrahedron
Lett. 1993, 34, 2995. For the use of DSA conditions by other
workers, as the method of choice for effecting Dötz
benzannulation reactions, see: (b) Eastham, S. A.; Herbert, J.;
Painter, J. E.; Patel, P.; Quayle, P. Synlett 1998, 61.
(c) Painter, J. E.; Quayle, P.; Patel, P. Tetrahedron Lett. 1995,
36, 8089. (d) Neidlein, R.; Gürtler, S.; Krieger, C. Helv. Chim.
Acta 1994, 77, 2303.
(6) Khambay, B. P. S.; Batty, D.; Cahill, M.; Denholm, I.; Mead-
Briggs, M.; Vinall, S.; Niemeyer, H. M.; Simmonds, M. S. J.
J. Agric. Food. Chem. 1999, 47, 770. Khambay, B. P. S.;
Batty, D.; Beddie, D. G.; Denholm, I.; Cahill, M. R. Pestic.
Sci. 1997, 50, 291. It should also be noted that compound 1 has
also been isolated from Calceolaria sessilis: Chamy, M. C.;
Jimenez, I.; Piovano, M.; Garbarino, J. A.; Didyk, B. Bol. Soc.
Chil. Quim. 1993, 38, 187.
(19) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947.
(20) Staroske, T.; Hennig, L.; Welzel, P.; Hofmann, H.-J.; Müller,
D.; Häusler, T.; Sheldrick, W. S.; Zillikens, S.; Gretzer, B.;
Pusch, H.; Glitsch, H. G. Tetrahedron 1996, 52, 12723.
(7) Morello, A.; Pavani, M.; Garbarino, J. A.; Chamy, M. C.;
Frey, C.; Mancilla, J.; Guerrero, A.; Repetto, Y.; Ferreira, J.
Comp. Biochem. Physiol., C: Pharmacol., Toxicol.
Endocrinol. 1995, 112C, 119.
Article Identifier:
1437-2096,E;2001,0,09,1428,1430,ftx,en;D14201ST.pdf
Synlett 2001, No. 9, 1428–1430 ISSN 0936-5214 © Thieme Stuttgart · New York