Synthesis and absolute configuration of cordiaquinone K, antifungal and larvicidal meroterpenoid isolated from the Panamanian plant, Cordia curassavica

Article abstract of DOI:10.1016/S0040-4039(03)01669-1

Total synthesis of cordiaquinone K, a new antifungal and larvicidal meroterpenoid, is reported. The absolute configuration of cordiaquinone K was confirmed by the synthesis.

Full text of DOI:10.1016/S0040-4039(03)01669-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6915–6918
Synthesis and absolute configuration of cordiaquinone K,
antifungal and larvicidal meroterpenoid isolated from the
Panamanian plant, Cordia curassavica
Arata Yajima, Fumihiro Saitou, Mayu Sekimoto, Shoichiro Maetoko and Goro Yabuta*
Department of Fermentation Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Sakuragaoka 1-1-1,
Setagaya-ku, Tokyo 156-8502, Japan
Received 11 June 2003; revised 30 June 2003; accepted 4 July 2003
Abstract—Total synthesis of cordiaquinone K, a new antifungal and larvicidal meroterpenoid, is reported. The absolute
configuration of cordiaquinone K was confirmed by the synthesis.
© 2003 Elsevier Ltd. All rights reserved.
Cordiaquinones are antifungal and larvicidal meroter-
penoids isolated from Panamanian plants such as Cor-
dia linnaei. In 1990, Messana and co-workers reported
the isolation and structures of cordiaquinones A (1)
and B (2) (Fig. 1).1 After their identification of cor-
diaquinones from the plant, several cordiaquinones
have been isolated.2,3 In 2000, Hostettmann and co-
workers reported the structures of cordiaquinones J (3)
and K (4) isolated from C. curassavica (Fig. 1).4 These
compounds exhibit antifungal activities against phyto-
pathogenic fungus such as Cladosporium cucumerinum
and larvicidal activity against the larvae of the yellow
fever-transmitting mosquito Aedes aegypti. The struc-
tures of cordiaquinone J and K were established on the
basis of HRMS, UV and 1D and 2D NMR spectra.
The synthesis and absolute configuration of cor-
diaquinone B were reported by Asaoka and his co-
workers.5 The absolute stereochemistry of other
cordiaquinones, however, remained unknown. In con-
nection with our synthetic studies of biologically active
natural terpenoids,6 we became interested in clarifying
the absolute configuration of cordiaquinones. This
communication describes the total synthesis of (+)-cor-
diaquinone K employing one-pot B-alkyl Suzuki–
Miyaura coupling7 as a key step and the determination
of the absolute configuration of the natural product.
Figure 1. Structures of cordiaquinones.
Keywords: synthesis; B-alkyl Suzuki–Miyaura coupling; cordiaquinones; absolute configuration.
* Corresponding author. Fax: +81-3-5477-2622; e-mail: yabta@nodai.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01669-1

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A. Yajima et al. / Tetrahedron Letters 44 (2003) 6915–6918
As our target, we first chose ( )-13-deoxocordiaquinone
K (5), since there was an urgent need to establish the
appropriate conditions of the coupling reaction.
Scheme 1 summarizes our synthesis of ( )-13-deoxocor-
diaquinone K (5). 6-Bromonaphtoquinone8 (6) and ( )-
g-cyclohomogeraniol9 (8) were selected as the starting
materials. 6-Bromonaphtoquinone (6) was first hydro-
genated with PtO2 followed by methylation of the
resulting hydroxyl groups to give 7.10 ( )-g-Cycloho-
mogeraniol (8) was converted to known iodide (9).6a,11
To connect the g-cyclohomogeranyl unit (9) and the
naphtoquinone derivative (7), we examined one-pot
B-alkyl Suzuki–Miyaura coupling reaction. This proto-
col would be useful for the syntheses of terpenoids such
as ambrein,12 luffarin W,13 penlanpallescensin,14 etc.
(Fig. 2), because these compounds have a common
structural feature with cordiaquinone K, namely a g-
cyclohomogeranyl unit connecting with an aryl or a
vinyl unit.
As a preliminary experiment for the coupling of 9 with
7, the conditions reported by Marshall and Johns15,16
{PdCl2(dppf) as a catalyst} were examined to give the
desired product (10) in only 10% yield based on 9. Then
we examined various conditions. Table 1 summarizes
reaction conditions and yields of 10. Although
PdCl2(dppf) was not an effective catalyst (entries 1–3),
Pd(PPh3)4 was superior in yield (entry 4). Moreover, by
heating the reaction mixture to 80°C, 50% yield of 10
was obtained (entry 6). This indicates that the yield
based on 7 was quantitative. Increasing the stoichiome-
try of 7, however, showed only a slight improvement
(55%, entry 7). Other palladium catalysts such as
Pd2(dba)3, PdCl2(dppe), PdCl2(dppp), Pd(PEt3)2Cl2,
Pd(OAc)2+2Cy3P and allylpalladium chloride dimer
or a combination of bases such as Ba(OH)2, TlOEt
and Cs2CO3 were also examined, but we found
Pd(PPh3)4 with K3PO4 is the best choice for the cou-
pling reaction.
Scheme 1. Synthesis of ( )-13-deoxocordiaquinone K. Reagents, conditions and yields. (a) (1) H2, PtO2, EtOAc; (2) NaH, MeI,
DMF (89%, two steps); (b) Ref. 6a (92%, two steps); (c) (1) 2 equiv. t-BuLi, ether, −78°C; (2) 2.5 equiv. B-MeO-9-BBN, hexane,
THF; (3) 2.5 equiv. base; (4) 5 mol% Pd catalyst, 7, DMF (see Table 1); (d) CAN, CH3CN, 0°C (73%).
Figure 2. Structures of natural products with related structure of cordiaquinones.
Table 1. Reaction conditions and yields of 10
Entry
Pd catalysta
Equiv. of 7
Temp. (°C)
Baseb
Time (h)
Yield (%)c
1
2
3
4
5
6
7
8
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
0.5
0.5
0.5
0.5
0.5
0.5
1
Rt
Rt
80
Rt
Rt
80
80
80
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
16
120
16
16
72
16
16
16
10
13
12
24
22
50
55
50
2
a 5 mol% of catalysts were used.
b 2.5 equiv. of bases were used.
c Based on 9.

A. Yajima et al. / Tetrahedron Letters 44 (2003) 6915–6918
6917
Scheme 2. Synthesis of (+)-cordiaquinone K. Reagents, conditions and yields. (a) TsCl, Py.; (b) NaI, acetone, reflux (96%, two
steps); (c) (i) 2 equiv. t-BuLi, ether, −78°C; (ii) 2.5 equiv. B-MeO-9-BBN, hexane, THF; (iii) 3 M K3PO4; (iv) 5 mol% Pd(PPh3)4,
7, 80°C, 16 h (43%); (d) TBAF, THF, 60°C (74%); (e) PCC, MS4A, CH2Cl2 (63%); (f) CAN, CH3CN, 0°C (quant.).
Acknowledgements
With the desired product (10) in hand (Scheme 1), the
aromatic ring of 10 was oxidized with ceric ammonium
nitrate (CAN) to afford ( )-13-deoxocordiaquinone K
(5). The spectroscopic data of synthetic 5 are in perfect
accordance with the structure of 5.17
We thank Dr. Shingo Kakita (Kyowa Hakko Kogyo
Co.) for the measurements of MS spectra.
According to the established methodology as described
above, the synthesis of optically active cordiaquinone K
was investigated (Scheme 2). The known alcohol18 (12)
derived from the known ketoalcohol (11)19 was selected
as the starting material. Alcohol 12 was converted to
the corresponding iodide 13 in two steps (96%). The
resulting iodide 13 was coupled with 7 by using the
optimized conditions to give coupled product 14 in
moderate yield (43%). After removal of the TBS group
of 14 with TBAF at 60°C (74%), the resulting hydroxyl
group was oxidized with PCC to give ketone 15 (63%).
Finally, oxidation of the aromatic ring with CAN at
0°C for 30 min gave (S)-(+)-cordiaquinone K (4)20 as a
pale yellow gum in quantitative yield. The overall yield
of (+)-1 was 19% in six steps from known alcohol (12).
References
1. Bieber, L. W.; Messana, I. C. N.; Lins, S.; Da Silva
´
Filho, A. A.; Chiappeta, A. A.; De Me´llo, J. F. Phyto-
chemistry 1990, 29, 1955.
2. Bieber, L. W.; Krebs, H. C.; Scha¨fer, W. Phytochemistry
1994, 35, 1027.
3. Ioset, J.-R.; Marston, A.; Gupta, M. P.; Hostettmann, K.
Phytochemistry 1998, 47, 729.
4. Ioset, J.-R.; Marston, A.; Gupta, M. P.; Hostettmann, K.
Phytochemistry 2000, 53, 613.
5. Kuramochi, T.; Asaoka, M.; Ohkubo, T.; Takei, H.
Tetrahedron Lett. 1996, 37, 7075.
6. (a) Yajima, A.; Takikawa, H.; Mori, K. Liebigs Ann.
1996, 891; (b) Yajima, A.; Mori, K. Eur. J. Org. Chem.
2000, 4079.
7. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
8. Cameron, D. W.; Feutrill, G. I.; Patti, A. F. Aust. J.
Chem. 1979, 32, 719.
1
The H and 13C NMR and MS spectra are identical
with those of reported data.4 Synthetic cordiaquinone
K (4) shows [h]2D6=+44.9 (c 0.35, acetone), while natu-
ral cordiaquinone K shows [h]D=−46.4 (c 0.35, ace-
tone).4 This means that our synthetic cordiaquinone K
is the antipode of the natural product. The absolute
configuration of natural cordiaquinone K is, therefore,
determined to be R.
9. Almanza, R. C.; Reyes, A. H. Synth. Commun. 1993, 23,
867.
10. All new compounds gave satisfactory spectral and ele-
mental analytical data (combustion and/or HRMS).
11. (a) Crombie, B. S.; Redhouse, A. D.; Smith, C.; Wallace,
T. W. J. Chem. Soc., Chem. Commun. 1995, 403; (b)
Crombie, B. S.; Smith, C.; Varnavas, C. Z.; Wallace, T.
W. J. Chem. Soc., Perkin. 1 2001, 206.
12. (a) Ruzicka, L.; Lardon, L. Helv. Chim. Acta 1946, 29,
912; (b) Lederer, E.; Marx, F.; Mercier, D.; Peˆrot, G.
Helv. Chim. Acta 1946, 29, 1354.
In conclusion, the total synthesis of (+)-cordiaquinone
K was achieved by using one-pot B-alkyl Suzuki–
Miyaura coupling reaction. The absolute configuration
of natural cordiaquinone K was confirmed to be R.
Further synthetic studies of other cordiaquinones or
terpennoids employing this methodology are in
progress.
13. Butler, M. S.; Capon, R. J. Aust. J. Chem. 1992, 45, 1705.

6918
A. Yajima et al. / Tetrahedron Letters 44 (2003) 6915–6918
14. Guella, G.; Guerriero, A.; Pietra, F. Helv. Chim. Acta
1985, 68, 39.
15. Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63,
7885.
126.4, 127.3, 141.0, 149.19, 149.23, 149.6; HRFABMS:
calcd for C23H30O2 [M]+: 338.2246; found: 338.2243.
17. Properties of ( )-5: pale yellow gum; IR (film) wmax
(cm−1)=3070 (w, HꢀCꢁC), 2930 (s, CꢀH), 2860 (m,
CꢀH), 1670 (s, CꢁO), 1600 (s), 1450 (m), 1390 (w), 1370
(m), 1305 (s), 1140 (w), 1045 (m), 890 (m), 835 (m), 735
(m); 1H NMR (400 MHz, CDCl3): l=0.82 (s, 3H, 19-
CH3), 0.89 (s, 3H, 18-CH3), 1.22–1.80 (m, 7H, 10,13,14-
CH2, 11-H), 2.05 (m, 2H, 15-CH2), 2.50 (m, 1H, 9-CHH),
2.14 (m, 1H, 9-CHH), 4.60 (br.s, 1H, HꢀCꢁC), 4.84 (br.s,
1H, HꢀCꢁC), 6.93 (s, 2H, 2,3-H), 7.52 (dd, J=1.5, 8.3
Hz, 1H, 7-H), 7.86 (d, J=1.5 Hz, 1H, 5-H), 7.97 (d,
J=8.3 Hz, 1H, 8-H); 13C NMR (100 MHz, CDCl3):
l=23.6, 26.5, 28.1, 28.3, 32.2, 34.8, 34.9, 35.9, 53.8,
109.7, 126.1, 126.7, 129.9, 131.2, 134.1, 138.5, 138.8,
148.7, 150.5, 184.9, 185.5; HRFABMS: calcd for
C21H24O2 [M]+: 308.1777; found: 308.1810.
16. Representative procedure for the synthesis of ( )-10: To a
stirred and cooled (−78°C) solution of 9 (97 mg, 0.35
mmol) in dry ether (5 ml) was added dropwise 530 ml of
tert-BuLi (1.4 M in pentane, 0.75 mmol) under Ar. After
stirring for 3 min, 820 ml of B-methoxy-9-borabicy-
clo[3.3.1]-nonane (1 M in hexane, 0.82 mmol) was added
dropwise, followed by addition of dry THF (5 ml). After
stirring for 10 min. at the same temperature, the resulting
solution was allowed to warm to rt for 75 min. To the
mixture, 3 M K3PO4 solution 0.27 ml (0.80 mmol) was
added, followed by a solution of 7 (85 mg, 0.32 mmol) in
DMF (5 ml). After addition of Pd(PPh3)4 (18 mg, 0.016
mmol), the mixture was stirred at 80°C for 16 h. After
cooling to rt, the mixture was diluted with ether. The
organic layer was washed with water and brine, and the
combined aqueous layers were extracted with ether three
times. The combined organic layers were dried with
Na2SO4. After concentration in vacuo, the residue was
chromatographed on silica gel (SiO2: 8 g, hexane) to give
65 mg of ( )-10 (55%). Properties of ( )-10: colorless
amorphous solid; IR (KBr) wmax (cm−1)=3080 (m,
HꢀCꢁC), 2920 (s, C–H), 1645 (m), 1635 (m), 1610 (s,
Ar-O-CH3), 1460 (s), 1390 (s), 1345 (m), 1270 (s), 1165
(m), 1090 (m), 1000 (m), 970 (m), 895 (s), 825 (s), 795 (s),
715 (m); 1H NMR (400 MHz, CDCl3): l=0.81 (s, 3H,
6¦-CH3), 0.89 (s, 3H, 6¦-CH3), 1.71–1.99 (m, 7H, 2%,4¦,5¦-
CH2), 2.05 (m, 1H, 3¦-CHH), 2.06 (m, 1H, 3¦-CHH),
2.50 (m, 1H, 1%-CHH), 2.75 (m, 1H, 1%-CHH), 3.93, 3.94
(2×s, 6H, 2×CH3-O), 4.64 (br.s, 1H, HꢀCꢁC), 4.83 (br.s,
1H, H–CꢁC), 6.60, 6.66 (d, J=8.6 Hz, 2H, 2,3-H), 7.29
(dd, J=2.0, 8.8 Hz, 1H, 7-H), 7.94 (d, J=2.9 Hz, 1H,
5-H), 8.07 (d, J=8.8 Hz, 1H, 8-H); 13C NMR (100 MHz,
CDCl3): l=23.7, 26.4, 28.3, 28.7, 32.4, 34.88, 34.93, 36.1,
53.9, 55.70, 55.70, 102.3, 103.2, 109.3, 120.2, 121.7, 124.7,
18. Mori, K.; Suzuki, N. Liebigs Ann. Chem. 1990, 287.
19. Mori, K.; Mori, H. Org. Syn. Col. Vol. 8, 312.
20. Properties of synthetic (+)-cordiaquinone K (4): pale
yellow gum; [h]2D6=+44.9 (c 0.35, acetone); IR (film) wmax
(cm−1)=3080 (w, HꢀCꢁC), 2950 (s, CꢀH), 2850 (s, CꢀH),
1710 (s, CꢁO), 1670 (m), 1600 (s), 1420 (s), 1310 (m), 935
1
(m), 900 (m); H NMR (400 MHz, acetone-d6): l=0.99
(s, 3H, 19-CH3), 1.18 (s, 3H, 18-CH3), 1.49 (m, 1H,
10-CHH), 1.94 (m, 1H, 10-CHH), 2.24 (m, 1H, 14-
CHH), 2.34 (dd, J=3.7, 12.0 Hz, 1H, 11-H), 2.55–2.98
(m, 5H, 9,15-CH2, 14-CHH), 4.94 (br.s, 1H, HꢀCꢁC),
5.13 (br.s, 1H, HꢀCꢁC), 6.88 (s, 2H, 2,3-H), 7.58 (dd,
J=1.8, 6.4 Hz, 1H, 7-H), 7.71 (d, J=1.8 Hz, 1H, 5-H),
7.82 (d, J=7.8 Hz, 1H, 8-H); 13C NMR (100 MHz,
acetone-d6): l=21.6 (C-19), 27.4 (C-18), 29.9 (C-10), 31.1
(C-15), 34.6 (C-9), 38.0 (C-14), 49.4 (C-12), 56.7 (C-11),
113.9 (C-17), 126.5 (C-5), 127.0 (C-8), 130.9 (C-8a), 132.9
(C-4a), 134.9 (C-7), 139.3 (C-3), 139.5 (C-2), 150.2 (C-6),
185.4 (C-4), 185.7 (C-1), 213.6 (C-13); HREIMS: calcd
for C21H22O3 [M]+: 322.1569; found: 322.1581.