Synthesis of hemitectol, tectol, and tecomaquinone i

Article abstract of DOI:10.1055/s-0032-1317541

The first total syntheses of Tectona grandis (teak) natural products hemitectol and tectol are described. The observation of spontaneous dimerisation of hemitectol to tectol suggests the monomer is the true natural product and that the dimer is an artifact of isolation. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317541

LETTER
▌2939
lSetyternthesis of Hemitectol, Tectol, and Tecomaquinone I
Hemitectol, Tectol, and Tecomaquinone
Melissa M. Cadelis, David Barker, Brent R. Copp*
School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Fax +64(9)3737422; E-mail: b.copp@auckland.ac.nz
Received: 06.09.2012; Accepted after revision: 17.10.2012
timalarial activity of scabellone B (1)1 provides great in-
centive to undertake the total synthesis of tecomaquinone
I (4), tectol (5), and hemitectol (6) to evaluate their anti-
malarial bioactivities.
Abstract: The first total syntheses of Tectona grandis (teak) natural
products hemitectol and tectol are described. The observation of
spontaneous dimerisation of hemitectol to tectol suggests the mono-
mer is the true natural product and that the dimer is an artifact of iso-
lation.
10'
Key words: cyclisation, dimerisation, quinone, ring closure, total
synthesis
11'
O
O
5'
7'
5
6'
1'
O
O
OH
O
7
Chan et al. recently isolated a family of pseudodimeric
meroterpenes, the scabellones B–D (1–3), for example,
from the New Zealand ascidian Aplidium scabellum (Fig-
ure 1).1 While scabellone B (1) was found to exhibit anti-
malarial activity with an IC50 of 4.8 μM, biological testing
was not undertaken on the other natural products in the se-
ries due to insufficient sample. Scabellones C (2) and D
(3) share a 9,10-dihydropyranobenzo[c,f]chromene-1,4-
dione core with only one other natural product, tecoma-
quinone I (4, Scheme 1), isolated from Tectona grandis
(teak).2
2'
O
OH
4
10
2
12
11
12
11
2
4
5
O
10
7
4
5
OH
6
Scheme 1 Biosynthetic/retrosynthetic analysis of tecomaquinone I
(4) via tectol (5) and hemitectol (6)
O
O
O
O
H
As a prelude to more expansive structure–antimalarial re-
lationship investigations of scabellones B–D, we sought a
scalable and flexible synthetic route to the 9,10-dihydro-
pyranobenzo[c,f]chromene-1,4-dione scaffold. We now
report a concise biomimetic synthesis of tecomaquinone I.
O
O
O
O
O
O
OH
O
Mono-TBS protection of naphthoquinol was achieved in
two steps, firstly via formation of the TBS ether of 4-me-
thoxynaphth-1-ol (8, 93% yield)5 followed by BBr3 de-
methylation to afford the product (9)6 as a dark red solid
in 75% yield (Scheme 2).
R1
R2
2 R1 = CH2CHC(Me)2, R2 = Me
3 R1 = Me, R2 = CH2CHC(Me)2
1
Figure 1 Structures of scabellones B–D (1–3)
Reaction of naphthol 9 with 3-methylbut-2-enal using eth-
ylenediamine diacetate (EDDA) as a catalyst in
chloroform7 yielded, after chromatographic purification,
protected chromenol 108 as an orange solid in 81% yield.
Deprotection of 10 using triethylamine trihydrogen fluo-
ride in THF for 24 hours afforded the target product hemi-
tectol (6)9 as a dark yellow oil, as well as tectol (5)10 as a
white solid and bischromen 1111 as a yellow oil in 21%,
19% and 33% yields, respectively (Scheme 3). During the
course of NMR characterisation of hemitectol in CDCl3,
the sample was observed to rapidly transform over hours
into a mixture with tectol (5).
The biosynthesis of tecomaquinone I has been proposed3
to proceed via two other T. grandis metabolites, the mild-
ly cytotoxic dichromenol tectol (5) and the recently re-
ported antifungal hemitectol (6, Scheme 1).2,4 It is
pertinent to note that while there are several reports of the
isolation of tectol, hemitectol has only ever been reported
once, and as a mixture with tectol.2
While a semisynthesis of 4 (from 5) has been reported,
neither 5 nor 6 have been synthesised.3 The finding of an-
SYNLETT 2012, 23, 2939–2942
Advanced online publication: 13.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317541; Art ID: ST-2012-D0747-L
© Georg Thieme Verlag Stuttgart · New York

2940
M. M. Cadelis et al.
LETTER
grandis is in fact hemitectol (6). We found no evidence
for the spontaneous dimerisation of TBS-protected hemi-
tectol 10 nor for the structurally related O-methyl ana-
logue lapachenole (12),13 which was prepared from 7 in
79% yield (Scheme 5).7 In an effort to force such a dimer-
isation, reaction of 12 with phenyliodine(III) bis(trifluoro-
acetate) (PIFA) and boron trifluoride diethyl etherate
(BF3·OEt2),14 yielded two products 1315 (48%) and 1416
(29%) as brown solids.
O
O
TBSCl
DIPEA
CH2Cl2, 72 h
93%
OH
OTBS
7
8
BBr3
CH2Cl2, 0 °C, 4 h
75%
OH
O
O
O
EDDA, CHCl3
60 °C, 24 h
81%
O
7
EDDA, CHCl3
60°C, 24 h
OTBS
OTBS
10
O
9
79%
12
Scheme 2 Synthesis of TBS-protected hemitectol 10
PIFA, BF3⋅OEt2
CH2Cl2, –40 °C, 3 h
10
Et3N⋅3HF
THF, 24 h
10'
10'
O
O
7'
7'
H
H
H
H
3'
O
O
4'
O
O
O
3
3
5'
5'
O
O
H
H
O
O
OH
4
4
10
H
H
10
5
5
OH
O
OH
O
O
7
7
O
13 48%
14 29%
6 21%
5 19%
11 33%
Scheme 5 Syntheses of furopyran dimers 13 and 14 via lapachenole
Scheme 3 Synthesis of hemitectol, tectol, and bischromen
Analysis of the mass spectrum of 13 afforded a molecular
formula of C32H33O5 [M + H]+, suggestive that lapache-
nole had indeed dimerised and with the incorporation of
an oxygen atom. The 1H NMR spectrum of 13 was similar
to that of the starting material with the exception of the
chromen ring H-3 and H-4 (δ = 5.64 and 6.39 ppm) pro-
tons being replaced by two mutually coupled doublets (δ
= 2.63 and 4.94 ppm). The 13C NMR spectrum of 13 con-
tained 16 signals, further implying the presence of sym-
metry in the compound. Analysis of HSQC NMR data
identified C-4 (δ = 73.1 ppm) as an oxymethine while in-
terfragment HMBC correlations observed between H-3
and C-3 (δ = 49.4 ppm) and between H-4 and C-4 showed
that the molecule was symmetrical through a C-4 ether
linkage and the C-3,3′ bond. NOESY cross peaks ob-
served between H-3, H-4, and one of the gem-dimethyl
groups identified a cis relationship, assigning the structure
of 13 as a symmetrical furopyran dimer as shown.
Further attempts at purification of 6, by silica gel column
chromatography using CH2Cl2–hexane solvent mixtures,
led to complete conversion into dimer 5.
Using a literature protocol, reaction of tectol with chloran-
il in toluene3 yielded a green solid (80% yield), the spec-
troscopic data for which agreed with those previously
reported for tecomaquinone I (4)12 (Scheme 4).
O
O
chloranil
5
toluene
110 °C, 6 h
O
80%
O
4
Two similar furopyran dimers, symmetric 15 and unsym-
metric 16, were reported by Fraga et al. from the oxidative
dimerisation of precocene II using silica impregnated with
silver nitrate (Figure 2).17 X-ray crystallography was used
to determine the relative configuration of both dimers.17
Close agreement of the H-3 and H-4 chemical shifts ob-
Scheme 4 Synthesis of tecomaquinone I (4)
The spontaneous oxidative dimerisation of hemitectol (6)
to tectol (5) suggests that the latter is an artifact of natural
product isolation and that the true metabolite of Tectona
Synlett 2012, 23, 2939–2942
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hemitectol, Tectol, and Tecomaquinone I
2941
Pessoa, O. D. L.; Braz-Filho, R. Nat. Prod. Res. 2007, 21,
529.
(5) tert-Butyl(4-methoxynaphthalen-1-yloxy)dimethylsilane
(8)
served for 13 with those of dimer 15 confirmed the struc-
ture and cis,trans,cis relative configuration of 13.
ESI-HRMS analysis of 14 established a molecular formu-
la of C32H33O5 [M + H]+, being isomeric with 13, while
close analysis of COSY, HSQC, and HMBC data identi-
fied 14 to have the same planar skeleton as 13 (Scheme 5).
IR (ATR): 2929, 2857, 1625, 1596, 1461, 1384, 1273, 1095
cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.25–8.23 (m, 2 H,
H-5, H-8), 7.60–7.56 (m, 2 H, H-6, H-7), 6.86 (d, J = 8.5 Hz,
1 H, H-3), 6.73 (d, J = 8.5 Hz, 1 H, H-2), 4.03 (s, 3 H, OCH3),
1
However, unlike the symmetrical analogue 13, the H
1.20 (s, 9 H, H-4′, H-5′, H-6′), 0.36 (s, 6 H, H-1′, H-2′). 13
NMR (100 MHz, CDCl3): δ = 149.9 (C-1), 145.2 (C-4),
128.6 (ArC), 126.6 (ArC), 125.8 (ArCH), 125.5 (ArCH),
C
NMR and 13C NMR spectra of 14 were more complex,
suggesting an unsymmetrical structure. NOESY correla-
tions were observed between the tetrahydrofuran protons
H-3 (δ = 2.74 ppm), H-4′ (δ = 4.88 ppm), H-4 (δ = 5.13
ppm), and two of the gem-dimethyl groups (δ = 1.64, 1.60
ppm) indicating these protons to be cis-related. Further
NOESY correlations were observed between H-3′ (δ =
2.10 ppm) and the remaining two methyl groups (δ = 1.17,
1.70 ppm) indicating these protons to be on the opposite
face of the molecule (Scheme 5). The structure and rela-
tive configuration of 14 agreed with the configuration re-
ported by Fraga et al.17 for their second furopyran dimer
16.
122.5 (ArCH), 122.0 (ArCH), 111.9 (C-3), 103.5 (C-2), 55.7
(OCH3), 26.0 (C-4′, C-5′, C-6′), 18.5 (C-3′), –4.2 (C-1′, C-
2′). ESI-HRMS: m/z calcd for C17H25O2Si [MH+]: 289.1618;
found: 289.1624.
(6) 4-(tert-Butyldimethylsiloxy)naphthalene-1-ol (9)
IR (ATR): 3255, 2929, 1595, 1471, 1347, 1266, 1069 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.10–8.09 (m, 2 H, H-5, H-
8), 7.50–7.47 (m, 2 H, H-6, H-7), 6.68 (s, 2 H, H-2, H-3),
1.09 (s, 9 H, H-4′, H-5′, H-6′), 0.24 (s, 6 H, H-1′, H-2′). 13
NMR (100 MHz, CDCl3): δ = 145.4 (C-1), 138.7 (C-4),
126.4 (2 × Ar-C), 125.7 (ArCH), 125.5 (ArCH), 122.7
C
(ArCH), 121.5 (ArCH), 112.0 (C-2), 108.3 (C-3), 25.9 (C-4′,
C-5′, C-6′), 18.4 (C-3′), –4.3 (C-1′, C-2′). ESI-HRMS: m/z
calcd for C16H23O2Si [MH+]: 275.1462; found: 275.1462.
(7) Lee, Y. R.; Kim, Y. M. Helv. Chim. Acta 2007, 90, 2401.
(8) tert-Butyl(2,2-dimethyl-2H-benzo[h]chromen-6-
yloxy)dimethylsilane (10)
O
O
O
O
O
O
H
H
H
H
3'
IR (ATR): 2930, 1595, 1457, 1409, 1370, 1274, 1084 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.15–8.03 (m, 2 H, H-7, H-
10), 7.43–7.40 (m, 2 H, H-8, H-9), 6.54 (s, 1 H, H-5), 6.35
(d, J = 9.7 Hz, 1 H, H-4), 5.63 (d, J = 9.7 Hz, 1 H, H-3), 1.49
(s, 6 H, H-11, H-12), 1.08 (s, 9 H, H-4′, H-5′, H-6′), 0.24 (s,
6 H, H-1′, H-2′). 13C NMR (100 MHz, CDCl3): δ = 144.8 (C-
6), 142.4 (C-10b), 129.9 (C-3), 128.3 (ArC), 126.0 (ArC),
125.5 (ArCH), 125.3 (ArCH), 122.9 (C-4), 122.5 (ArCH),
121.8 (ArCH), 115.0 (C-4a), 110.9 (C-5), 76.2 (C-2), 27.6
(C-11, C-12), 25.9 (C-4′, C-5′, C-6′), 18.4 (C-3′), –4.2 (C-1′,
C-2′). ESI-HRMS: m/z calcd for C21H29O2Si [MH+]:
341.1931; found: 341.1919.
4'
3
3
H
O
O
H
O
O
4
4
H
H
O
O
O
O
15
16
Figure 2 Furopyran dimers 15 and 16
In summary, we have successfully accomplished the first
syntheses of the natural products hemitectol (6) and tectol
(5) with the use of a silyl-protected naphthol in combina-
tion with a SEAr–cycloaddition reaction. Hemitectol (6)
was discovered to spontaneously dimerise to the natural
product tectol (5) in the presence of silica or triethyl-
amine. Future work will focus on applying this strategy to
access other related analogues.
(9) Hemitectol (6)
Dark yellow oil. IR (ATR): 3419, 2973, 1586, 1451, 1402,
1369, 1360, 1257, 1070 cm–1. 1H NMR (400 MHz, DMSO-
d6): δ = 8.03–7.96 (m, 2 H, H-7, H-10), 7.46–7.37 (m, 2 H,
H-8, H-9), 6.60 (s, 1 H, H-5), 6.43 (d, J = 9.5 Hz, 1 H, H-4),
5.75 (d, J = 9.5 Hz, 1 H, H-3), 1.42 (s, 6 H, H-11, H-12). 13
NMR (100 MHz, DMSO-d6): δ = 146.4 (C-6), 143.7 (C-
C
10b), 130.4 (C-3), 125.6 (ArCH), 125.1 (ArC), 124.9 (ArC),
124.7 (ArCH), 122.6 (C-4), 122.1 (ArCH), 121.1 (ArCH),
115.2 (C-4a), 105.9 (C-5), 75.7 (C-2), 27.1 (C-11, C-12).
ESI-HRMS: m/z calcd for C15H15O2 [MH+]: 227.1067;
found: 227.1063.
Acknowledgment
We thank Dr. Michael Schmitz and Dr. Nick Lloyd for their assi-
stance with the NMR and mass spectroscopic data and the Univer-
sity of Auckland for funding this research.
(10) Tectol (5)
White solid; 206–209 °C (lit.2 207–208 °C). IR (ATR):
3420, 2973, 1586, 1451, 1402, 1369, 1361, 1221, 1071 cm–
1. 1H NMR (400 MHz, DMSO-d6): δ = 8.17–8.08 (m, 4 H, H-
7, H-7′, H-10, H-10′), 7.52–7.44 (m, 4 H, H-8, H-8′, H-9, H-
9′), 5.78 (d, J = 9.9 Hz, 2 H, H-4, H-4′), 5.59 (d, J = 9.9 Hz,
2 H, H-3, H-3′), 1.45 (s, 6 H, H-11, H-11′), 1.43 (s, 6 H, H-
12, H-12′). 13C NMR (100 MHz, DMSO-d6): δ = 144.1 (C-
6, C-6′), 140.6 (C-10b, C-10b′), 130.0 (C-3, C-3′), 125.5
(2 × ArC), 125.4 (2 × ArCH), 125.1 (2 × ArC), 125.0
(2 × ArCH), 122.5 (2 × ArCH), 121.2 (2 × ArCH), 120.9
(C-4, C-4′), 115.9 (C-4a, C-4a′), 113.2 (C-5, C-5′), 75.2 (C-
2, C-2′), 27.0 (C-11, C-11′, C-12, C-12′). ESI-HRMS: m/z
calcd for C30H26O4Na [MNa+]: 473.1723; found: 473.1714.
References and Notes
(1) Chan, S. T. S.; Pearce, A. N.; Januario, A. H.; Page, M. J.;
Kaiser, M.; McLaughlin, R. J.; Harper, J. L.; Webb, V. L.;
Barker, D.; Copp, B. R. J. Org. Chem. 2011, 76, 9151.
(2) Sumthong, P.; Romero-González, R. R.; Verpoorte, R. J.
Wood. Chem. Tech. 2008, 28, 247.
(3) Sandermann, W.; Simatupang, M. H. Chem. Ber. 1964, 97,
588.
(4) Lemos, T. L. G.; Monte, F. J. Q.; Santos, A. K. L.; Fonseca,
A. M.; Santos, H. S.; Oliveira, M. F.; Costa, S. M. O.;
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2939–2942

2942
M. M. Cadelis et al.
LETTER
(11) Bandaranayake, W. M.; Crombie, L.; Whiting, D. A. J.
Chem. Soc. 1971, 811.
(12) Tecomaquinone I (4)
2.63 (d, J = 6.5 Hz, 2 H, H-3, H-3′), 1.57 (s, 6 H, H-11, H-
11′), 1.46 (s, 6 H, H-12, H-12′). 13C NMR (100 MHz,
CDCl3): δ = 149.7 (C-6, C-6′), 142.8 (C-10b, C-10b′), 126.3
(2 × ArC), 126.3 (2 × ArC), 126.0 (2 × ArCH), 126.0
(2 × ArCH), 122.0 (2 × ArCH), 121.8 (2 × ArCH), 115.4
(C-4a, C-4a′), 77.3 (C-2, C-2′), 73.1 (C-4, C-4′), 55.8
(OCH3, OCH3′), 49.4 (C-3, C-3′), 27.9 (C-12, C-12′), 26.9
(C-11, C-11′). ESI-HRMS: m/z calcd for C32H33O5 [MH+]:
497.2323; found: 497.2307.
Green solid; mp 187–189 °C (lit.2 188–189 °C). IR (ATR):
3360, 2978, 1690, 1568, 1277, 1237, 1197, 1109 cm–1. 1H
NMR (400 MHz, DMSO-d6): δ = 8.14–8.09 (m, 2 H, H-7, H-
10), 8.07–8.05 (m, 1 H, H-2), 8.04–8.01 (m, 1 H, H-5
7.95–7.86 (m, 2 H, H-3′, H-4′), 7.65–7.60 (m, 1 H, H-9),
7.57–7.53 (td, J = 7.0, 1.5 Hz, 1 H, H-8), 6.36 (d, J = 9.9 Hz,
1 H, H-4), 6.34 (d, J = 9.1 Hz, 1 H, H-7′), 5.62 (d, J = 9.9 Hz,
1 H, H-3), 5.44 (td, J = 9.0, 1.5 Hz, 1 H, H-8′), 2.03 (br s, 3
H, H-11′), 1.60 (s, 3 H, H-12), 1.59 (s, 3 H, H-10′), 1.55 (s,
3 H, H-11). 13C NMR (100 MHz, DMSO-d6): δ = 182.8 (C-
6′), 181.6 (C-1′), 146.5 (C-6), 142.4 (C-10b), 141.7 (C-9′),
135.9 (ArC), 135.4 (ArC), 134.0 (ArC), 133.8 (2 × ArCH),
132.9 (ArC), 131.3 (ArC), 128.2 (ArCH), 126.7 (ArCH),
126.5 (ArCH), 125.3 (ArCH), 125.3 (C-3), 124.7 (ArC),
123.8 (C-4), 122.5 (ArCH), 121.8 (ArCH), 117.6 (C-8′),
113.0 (C-4a), 111.2 (C-5), 75.5 (C-2), 67.3 (C-7′), 28.2 (C-
12), 25.5 (C-10′), 25.2 (C-11), 18.7 (C-11′). ESI-HRMS: m/z
calcd for C30H25O4 [MH+]: 449.1747; found: 449.1726.
(13) Gonzalez, A. G.; Barroso, J. T.; Cardona, R. J.; Medina, J.
M.; Luis, F. R. An. Quim. 1977, 73, 538.
(16) Furan Dimer B (14)
Brown solid; mp 216.0–218.6 °C. IR (ATR): 2938, 1637,
1598, 1457, 1382, 1100 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 8.23–8.15 (m, 4 H, H-7, H-7′, H-10, H-10′), 7.52–7.42
(m, 4 H, H-8, H-8′, H-9, H-9′), 7.06 (s, 1 H, H-5), 6.96 (s, 1
H, H-5′), 5.13 (d, J = 8.3 Hz, 1 H, H-4), 4.88 (d, J = 10.5 Hz,
1 H, H-4′), 4.07 (s, 3 H, OCH3), 4.01 (s, 3 H, OCH3′), 2.74
(t, J = 8.3 Hz, 1 H, H-3), 2.10 (dd, J = 10.5, 8.3 Hz, 1 H, H-
3′), 1.70 (s, 3 H, H-12′), 1.64 (s, 3 H, H-11), 1.60 (s, 3 H, H-
11′), 1.17 (s, 3 H, H-12). 13C NMR (100 MHz, CDCl3): δ =
150.0 (C-6′), 149.1 (C-6), 141.5 (C-10b), 141.0 (C-10b′),
126.6 (2 × ArCH), 126.1 (2 × ArCH), 125.9 (ArC), 125.9
(ArC), 125.5 (ArC), 125.1 (ArC), 122.0 (ArCH), 121.9
(2 × ArCH), 121.6 (ArCH), 119.8 (C-4a′), 116.6 (C-4a),
102.8 (C-5), 99.4 (C-5′), 80.6 (C-2′), 77.8 (C-4), 76.6 (C-2′),
76.2 (C-4′), 56.0 (OCH3), 55.8 (OCH3′), 55.6 (C-3′), 49.6 (C-
3), 31.7 (C-12′), 29.9 (C-11), 24.0 (C-11′), 22.6 (C-12). ESI-
HRMS: m/z calcd for C32H33O5 [MH+]: 497.2323; found:
497.2305.
(14) Tohma, H.; Morioka, H.; Takizawa, S.; Arisawa, M.; Kita,
Y. Tetrahedron 2001, 57, 345.
(15) Furan Dimer A (13)
Brown solid; mp 112.1–115.1 °C. IR (ATR): 2938, 1637,
1598, 1457, 1382, 1100 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 8.18–8.17 (m, 4 H, H-8, H-8′, H-9, H-9′), 7.52–7.46 (m,
4 H, H-7, H-10, H-7′, H-10′), 6.77 (s, 2 H, H-5, H-5′), 4.94
(d, J = 6.5 Hz, 2 H, H-4, H-4′), 3.97 (s, 6 H, OCH3, OCH3′),
(17) Fraga, B. M.; Garcia, V. P.; Gonzalez, A. G.; Hernandez, M.
G.; Hanson, J. R.; Hitchcock, P. B. J. Chem. Soc. 1983,
2687.
Synlett 2012, 23, 2939–2942
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