LETTER
Synthesis of the Dimeric Pyranonaphthoquinone Core of the Cardinalins
869
OMe
MeO
OH
(i)
O
HO
9
O
OMe
(ii)
10
MeO
O
O
OMe
OMe
O
O
MeO
H
NOE
O
O
(iii)
O
O
H
1
11
MeO
Scheme 5 Reagents and conditions: (i) TBAF, THF, r.t., 72 h (ii) TFA, CH2Cl2, –78 °C, 30 min then Et3SiH, r.t., 16 h, 70% (2 steps);
(iii) CAN, MeCN–H2O, r.t., 45 min, 63%.
(3) For racemic syntheses of dimeric pyranonaphthoquinones,
see: (a) Brimble, M. A.; Duncalf, L. J.; Neville, D. J. Chem.
Soc., Perkin Trans. 1 1998, 4165. (b) Brimble, M. A.; Lai,
M. Y. H. Org. Biomol. Chem. 2003, 1, 4227. (c) Brimble,
M. A.; Lai, M. Y. H. Org. Biomol. Chem. 2003, 1, 2084.
(d) For a racemic synthesis of cardinalin 3, see: Govender,
S.; Mmutlane, E. M.; van Otterlo, W. A. L.; de Koning, C.
B. Org. Biomol. Chem. 2007, 5, 2433.
tert-butyldiphenylsilyl ether protecting groups with con-
comitant in situ cyclization. Due to the unstable nature of
bislactol 10 it was immediately reduced to the bis-cis-1,3-
dimethylpyran 1116 with trifluoroacetic acid and triethyl-
silane following the procedure described by Kraus.6 The
1
formation of a single product was observed by H NMR
indicating the formation of the all cis-diastereomer result-
ing from pseudo-axial delivery of the hydride during the
reduction step.6
(4) (a) Gill, M.; Buchanan, M. S.; Yu, J. J. Chem. Soc., Perkin
Trans. 1 1997, 919. (b) Gill, M.; Buchanan, M. S.; Yu, J.
Aust. J. Chem. 1997, 50, 1081.
The 1,3-cis stereochemistry was confirmed unequivocally
by the NOE correlation between the axial protons at C1
and C3 on the pyran ring. Finally, CAN-mediated oxida-
tive demethylation provided the bisquinone 7,7¢-
demethoxy-9,9¢-deoxycardinalin 3 (1,17 Scheme 5).
(5) Gibson, J. S.; Andrey, O.; Brimble, M. A. Synthesis 2007,
2611.
(6) Kraus, G. A.; Molina, M. T.; Walling, J. A. J. Chem. Soc.,
Chem. Commun. 1986, 1568.
(7) (a) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178.
(b) Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 19,
2263.
(8) For recent reviews on the Hauser–Kraus annulation, see:
(a) Rathwell, K.; Brimble, M. A. Synthesis 2007, 643.
(b) Mal, D.; Pahari, P. Chem. Rev. 2007, 107, 1892.
(9) Andrey, O.; Sperry, J.; Larsen, U. S.; Brimble, M. A.
Tetrahedron 2008, in press.
(10) (a) Denes, B.; Szantay, C. Arch. Pharm. 1958, 342. (b) For
a similar example employing molecular bromine, see:
Abaev, V. T.; Dmitriev, A. S.; Gutnov, A. V.; Podelyakin, S.
A.; Butin, A. V. J. Heterocycl. Chem. 2006, 43, 1195.
(11) Brimble, M. A.; Burgess, C. V. Synthesis 2007, 754.
(12) Mill, R. J.; Taylor, N. J.; Snieckus, V. J. Org. Chem. 1989,
54, 4372.
In conclusion, we have achieved an efficient synthesis of
the dimeric core structure of cardinalin 3, representing the
first enantioselective synthesis of a dimeric pyranonaph-
thoquinone. The combined use of a Hauser–Kraus annu-
lation followed by a Suzuki–Miyaura homocoupling
provides a flexible synthetic strategy for the synthesis of
the cardinalins and related dimeric pyranonaphthoquino-
nes. Work towards this end is in progress.
Acknowledgment
The authors thank the Royal Society of New Zealand Marsden fund
for financial support.
(13) Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett. 1997,
38, 8749.
(14) Kaiser, F.; Schwink, L.; Velder, J.; Schmalz, H.-H. J. Org.
Chem. 2002, 67, 9248; and references therein.
References and Notes
(15) Compound 9: colorless oil; [a]D25 –21.8 (c 2.5, CH2Cl2); IR
(oil): nmax = 3070, 3049, 2959, 2932, 2894, 1679, 1588,
1450, 1427, 1348, 1330, 1204, 1112 cm–1. 1H NMR (400
MHz, CDCl3): d = 0.97 [18 H, s, 2 × C(CH3)3], 0.98 (6 H, d,
3JHH = 6.0 Hz, 2 × CH3), 2.48 (6 H, s, 2 × C=OCH3), 2.90 (2
H, dd, 2JHH = 13.4 Hz, 3JHH = 7.5 Hz, 2 × CHH), 3.11 (2 H,
dd, 2JHH = 13.4 Hz, 3JHH = 6.7 Hz, 2 × CHH), 3.81 (6 H, s,
2 × OCH3), 3.90 (6 H, s, 2 × OCH3), 4.27 [2 H, ddq (app.
sext), 3JHH = 7.5, 6.7, 6.0 Hz, 2 × CH], 7.27 (4 H, m, ArH),
7.38 (8 H, m, ArH), 7.54 (4 H, dd, J = 8.1, 1.3 Hz, ArH), 7.66
(4 H, dd, J = 8.1, 1.6 Hz, ArH), 7.93 (2 H, dd, J = 8.8, 1.8
Hz, ArH), 8.15 (2 H, d, J = 8.8 Hz, ArH), 8.36 (2 H, d, J =
(1) For reviews regarding isolation, structure, and synthesis of
pyranonaphthoquinone antibiotics, see: (a) Brimble, M. A.;
Duncalf, L. J.; Nairn, M. R. Nat. Prod. Rep. 1999, 16, 267.
(b) Brimble, M. A.; Nairn, M. R.; Prabaharan, H.
Tetrahedron 2000, 56, 1937. (c) Sperry, J.; Bachu, P.;
Brimble, M. A. Nat. Prod. Rep. 2008, in press; DOI:
10.1039/b708811f.
(2) Moore, H. W.; Czerniak, R. Med. Res. Rev. 1981, 1, 249.
Synlett 2008, No. 6, 867–870 © Thieme Stuttgart · New York