Total synthesis of pterosines B and C via a photochemical key step

Article abstract of DOI:10.1055/s-2006-944190

A total synthesis of pterosines B and C is reported. Starting with a fourfold substituted benzene derivative, the introduction of the remaining substituents is mainly based on Sonogashira couplings followed by different transformations of the ethyne moiety. The key step is a photochemical ring-closure of an α-mesyloxy ketone forming the 1-indanone skeleton. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-944190

LETTER
1543
Total Synthesis of Pterosines B and C via a Photochemical Key Step
Total
S
ynthesi
a
s
of Pterosi
b
ne
s
B
and
C
lo Wessig,* Janek Teubner
Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
E-mail: Pablo.wessig@chemie.hu-berlin.de
Received 12 April 2006
Dedicated to Professor Jochen Mattay on the occasion of his 60th birthday
halogen–metal exchange with n-BuLi gave very low
yields of the desired products. These difficulties could be
circumvented by using RiekeTM magnesium.9 Subsequent
treatment of the thus obtained Grignard reagent with ox-
Abstract: A total synthesis of pterosines B and C is reported. Start-
ing with a fourfold substituted benzene derivative, the introduction
of the remaining substituents is mainly based on Sonogashira cou-
plings followed by different transformations of the ethyne moiety.
The key step is a photochemical ring-closure of an a-mesyloxy irane afforded the primary alcohol 4b in very good yields.
ketone forming the 1-indanone skeleton.
The same procedure was applied to bromo mesitylene (1)
giving 4a. The tert-butyl ether protective group in 4b,
necessary for the Grignard reaction, must now be replaced
by a relatively acid-stable protective group (vide infra)
and we chose acetate esters. Fortunately, deprotection of
4b and protection of both hydroxy groups could be per-
formed in one step. The alcohol 4a was protected as the
acetate as well (Scheme 1).
Key words: total synthesis, photochemistry, arenes, ketones
The pterosines constitute a class of sesquiterpene indane
derivatives occurring in several plants, e.g. in the bracken
fern (pteridium aquilinium).1 Several pterosines have
been shown to possess interesting biological activity. Es-
pecially due to their cytotoxic2 and antibacterial3 activity
the pterosines are attractive targets for pharmaceutical ap-
plications. In the past years some total syntheses of these
compounds have been reported.4 Despite their seemingly
simple structure, the fivefold-substituted aromatic core is
a considerable synthetic challenge.
Br
Br
Br
ii
i
Ot-Bu
OH
1
2
3
iii
iii
O
HO
pterosine B (R = H)
AcO
4a: iv
4b: v
HO
pterosine C (R = OH)
R
R
R
Figure 1
4a R = H
4b R = Ot-Bu
5a: R = H
5b: R = OAc
Recently we reported on the photochemical synthesis of
some indanones as well as on the mechanism of this reac-
tion.5 The method rests on an extension of the Norrish–
Yang reaction, called spin center shift. To date, this reac-
tion has been successfully applied to the synthesis of cy-
clopropanes,6 1,3-oxazine-4-ones7 and benzo[c]furanes.5
Herein we wish to describe an application of this photo-
chemical method on the synthesis of pterosines B and C
(Figure 1).
Scheme 1 Reagents and conditions: i) 1. CrO3/Ac2O/HOAc; 2.
LiAlH4, 53%; ii) isobutene, BF3·OEt2, 99%; iii) RiekeTM-Mg, oxirane
(4a, 98%; 4b, 78%); iv) Ac2O, pyridine, DMAP, 82%; v) Ac2O,
FeCl3, 92%.
An alternative route to 5b started with 2,6-dimethylphenol
(6), which was firstly converted into the 4-hydroxy benzo-
ic ester 8 by a Kolbe–Schmidt reaction followed by
esterification.10 Differing from the approach outlined in
Scheme 1, the C2 side chain was introduced by a
Sonogashira coupling11 with trimethylsilyl ethyne and
conversion of the acetylenic unit to the acetic acid accord-
ing to the procedure described by Zweifel giving diacid
10.12 Reduction of the carboxyl groups and protection as
acetate afforded 5b (Scheme 2).
Our route commences with the commercially available
bromo mesitylene (1). After regioselective oxidation of
the 4-methyl group,8 reduction to alcohol 2 and protection
with isobutene we obtained tert-butyl ether 3 in good
yields. The introduction of the C2 side chain at C-1 proved
to be difficult due to the steric hindrance of this position
by the two methyl groups. Classic Grignard reaction and
The installation of the fifth substituent started with an
iodination using the PhI(OOCCF3)/I2 system described by
Muraki et al.13 Whereas the acetate group turned out to be
suitable for the protection of the 2-hydroxyethyl group in
all subsequent steps, problems arose with the benzylic
SYNLETT 2006, No. 10, pp 1543–1546
2
1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-944190; Art ID: G12306ST
© Georg Thieme Verlag Stuttgart · New York

1544
P. Wessig, J. Teubner
LETTER
A
B
TMS
iii
HO
i
O
HO
R1
OMs
i
16
COOR
COOMe
R2
6
9
7 R = H
8 R = Me
17
ii
ii
iv
O
R1
R1
O
R2
v
RO
vi
HOOC
OR
R2
COOH
18
19
11 R = H
5b R = Ac
10
R1
COOMe
R2
Scheme 2 Reagents and conditions: i) 1. NaH; 2. CO2, 34%; ii)
SOCl2, MeOH, 92%; iii) 1. Tf2O/pyridine, 96%; 2. TMS-ethyne,
Pd(Ph3P)2Cl2, Et3N, 92%; iv) 1. BH3·THF; 2. NaOH, H2O2, 44%; v)
LiAlH4, 76%; vi Ac2O, pyridine, DMAP, 96%.
a R1 = OAc, R2 =H
b R1 = R2 = OPiv
20
Scheme 4 Reagents and conditions: i) PhI(OH)OMs, 17a: 59%,
17b: 84%; ii) hn; for conditions and yields, see Table 1.
ester moiety in 12b. Therefore we changed the protective
group in 12b from acetate to pivalate, giving 13. Both 12a
and 13 underwent a smooth Sonogashira coupling with
trimethylsilylethyne to 14a and 14b. After removal of the
trimethylsilyl group we obtained the acetophenones 16
using a gold-catalyzed hydration (Scheme 3).14
The photochemical ring-closure to indanones5 required
the introduction of a leaving group in a-position with re-
spect to the keto group. This was achieved in good yields
by treating ketones 16 with PhI(OH)OMs (Scheme 4).15
Unfortunately, the irradiation of compounds 17 under var-
ious conditions gave the desired 1-indanones 18 only in
low yields. In this context the low site selectivity of the
initial photochemical hydrogen abstraction by the excited
carbonyl group turned out to be the main problem.
In the case of 17a this comes up to our expectations be-
cause the substituents in both ortho positions are identical.
Admittedly, we were surprised that the undesired 1-in-
danone 19 was formed in nearly the same amount as 18
from the asymmetric compound 17b as well. The C–H
bond energies of the methylene group (mode B,
Scheme 4) should be considerably lower than that of the
methyl group (mode A). Obviously, the transition states of
both modes are of very early nature and therefore the gra-
dation of the bond energies are not reflected by the site se-
lectivity. If the irradiation was performed in methanol
another problem arose. Instead of the expected 1-in-
danones 18 and 19 we obtained the methyl arylacetates 20
as main products. These compounds were formed in the
course of a photo-Favorsky rearrangement, already
known from other cases.16 Even though the preparation of
esters 20 was not the objective of this work it should be
noted that the described sequence is obviously an interest-
ing method for the introduction of acetic acid moieties
into highly substituted aromatic hydrocarbons. The results
of the irradiation of 17a and 17b are summarized in
Table 1. Best yields were achieved with tert-butanol as
solvent.17
AcO
AcO
I
i
R
R
5
12a (R = H)
12b (R = OAc)
iii
R = OAc
R = H
PivO
ii
TMS
R1
I
iii
R2
OPiv
14a: R1 = OAc, R2 = H
14b: R1 = R2 = OPiv
13
iv
O
R1
R1
v
R2
R2
15
16
To complete the total synthesis of pterosine B two steps
remained. Firstly, the acetate protective group in 18a had
to be cleaved by saponification, which succeeded in very
good yields with K2CO3/MeOH. The methylation using
two equivalents of LDA and MeI gave 21 (pterosine B)
with moderate yield.
Scheme 3 Reagents and conditions: i) I2/PhI(OOCCF3)2, 12a: 54%,
12b: 91%; ii) 1. KOH; 2. PivCl/pyridine, 90%; iii) TMS-ethyne,
Pd(PPh3)2Cl2, Et3N, 14a: 47%, 14b: 92%; iv) KF, 18-crown-6, 15a:
96%, 15b: 66%; v) Au(PPh3)CH3, TfOH–MeOH–H2O, 16a: 72%,
16b: 77%.
Synlett 2006, No. 10, 1543–1546 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Pterosines B and C
1545
Table 1 Results of Irradiation of 17a and 17b
17
a
R1
R2
H
Conditionsa
Yield of 18 (%)
Yield of 19 (%)
Yield of 20 (%)
OAc
A
B
C
A
9
0
9
0
0
67
0
17
26
17
23
b
OPiv
OPiv
0
B
C
0
31
19
23
68
0
a Conditions: A = 2.0 equiv N-methyl imidazole, CH2Cl2; B = 2.0 equiv N-methyl imidazole, MeOH; C = 2.0 equiv N-methyl imidazole,
t-BuOH.
Application of the same saponification conditions to
dipivalate 18a caused an elimination of water in the
sensitive b-hydroxyketone moiety, followed by Michael
addition of MeOH. Variation of the reaction conditions
(solvent, base) did not solve the problem but caused de-
composition of the compound at best. Finally, the diol 22
could be obtained by enzymatic saponification with
porcine liver esterase (PLE) in good yields.18,19 The
methylation with LDA/MeI completed the total synthesis
of 23 (pterosine C, Scheme 5).
Acknowledgment
The financial support of this work by the Deutsche Forschungs-
gemeinschaft (We1850-3/1-4 and Heisenberg fellowship of P.W.)
is gratefully acknowledged.
References and Notes
(1) (a) Kuroyanagi, M.; Fukuoka, M.; Yoshihira, K.; Natori, S.
Chem. Pharm. Bull. 1974, 22, 723. (b) Yoshihira, K.;
Fukuoka, M.; Kuroyanagi, M.; Natori, S.; Umeda, M.;
Morohoshi, T.; Enomoto, M.; Saito, M. Chem. Pharm. Bull.
1978, 26, 2346. (c) McMorris, T. C.; Kelner, M. J.; Wang,
W.; Estes, L. A.; Montoya, M. A.; Taetle, R. J. Org. Chem.
1992, 57, 6876. (d) Takahashi, M.; Fuchino, H.; Sekita, S.;
Satake, M. Phytother. Res. 2004, 18, 573.
(2) Kobayashi, A.; Koshimizu, K. Agric. Biol. Chem. 1980, 44,
393.
(3) Kobayashi, A.; Egawa, H.; Koshimizu, K.; Mitsui, T. Biol.
Chem. 1975, 39, 1851.
O
O
R1
HO
i
(18a)
R2
18a (R1 = OAc, R2 = H)
18b (R1 = R2 = OPiv)
pterosin B (21)
(4) (a) McMorris, T. C.; Liu, M.; White, R. Lloydia 1977, 40,
221. (b) Ng, K.-M. E.; McMorris, T. C. Can. J. Chem. 1984,
62, 1945. (c) Sheridan, H.; Lemon, S.; Frankish, N.;
McArdle, P.; Higgins, T.; James, J. P.; Bhandari, P. Eur. J.
Med. Chem. 1990, 25, 603. (d) Finkielsztein, L. M.; Alesso,
E. N.; Lantaño, B.; Aguirre, J. M.; Moltrasio Iglesias, G. Y.
J. Chem. Res., Synop. 1999, 6, 406. (e) Finkielsztein, L. M.;
Alesso, E. N.; Lantaño, B.; Aguirre, J. M.; Moltrasio
Iglesias, G. Y. J. Chem. Res., Synop. 1999, 6, 1561.
(f) Neeson, S. J.; Stevenson, P. J. Tetrahedron 1989, 45,
6239. (g) Grigg, R.; Scott, R.; Stevenson, P. J. Chem. Soc.,
Perkin Trans. 1 1988, 1357. (h) Grigg, R.; Scott, R.;
Stevenson, P. J. Chem. Soc., Perkin Trans. 1 1988, 1365.
(i) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org.
Chem. 1996, 61, 73.
(18b)
ii
O
O
HO
HO
iii
OH
pterosin C (23)
OH
22
Scheme 5 Reagents and conditions: i) 1. K2CO3/MeOH, 91%; 2.
LDA (2 equiv)/MeI, 43%; ii) PLE/HEPES, 54%; iii) 3 equiv LDA (3
equiv)/MeI, 49%.
In summary, we developed a total synthesis for pterosines
B (21) and C (23), which is based on a photochemical con-
struction of the 1-indanone skeleton. Even though the
yields of the photochemical ring-closure were low owing
to low site-selectivity, it was in principle demonstrated
that this method is suitable for the synthesis of highly sub-
stituted aromatic compounds.
(5) Wessig, P.; Glombitza, C.; Müller, G.; Teubner, J. J. Org.
Chem. 2004, 69, 7582.
(6) (a) Wessig, P.; Mühling, O. Angew. Chem. Int. Ed. 2001, 40.
(b) Wessig, P.; Mühling, O. Helv. Chim. Acta 2003, 86, 865.
(c) Wessig, P.; Mühling, O. Angew. Chem. Int. Ed. 2005,
6778.
(7) Wessig, P.; Schwarz, J.; Lindemann, U.; Holthausen, M. C.
Synthesis 2001, 1258.
(8) Ayer, W. A.; McCaskill, R. H. Can. J. Chem. 1981, 59,
2159.
(9) (a) Rieke, R. D.; Hundall, P. M. J. Am. Chem. Soc. 1972, 94,
7178. (b) Rieke, R. D.; Bales, S. E. J. Am. Chem. Soc. 1974,
96, 1775.
Synlett 2006, No. 10, 1543–1546 © Thieme Stuttgart · New York

1546
P. Wessig, J. Teubner
LETTER
(10) Moffett, R. B.; Seay, P. H. J. Med. Pharm. Chem. 1960, 2,
201.
(11) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467. (b) Negishi, E.-I.; Anastasia, L. Chem.
Rev. 2003, 103, 1979. (c) Sonogashira, K. In
H, CH2CH2O), 7.10 (s, 1 H, CHarom). 13C NMR (75 MHz,
CDCl3): d = 13.6, 21.0 (CH3-Carom), 21.1 (CH3-acetate), 24.6
(3-CH2), 27.8 (CH2CH2O), 37.1 (2-CH2), 62.7 (CH2CH2O),
125.9 (CHarom), 132.9, 133.8, 137.8, 140.1, 154.6 (Cq), 171.0
(COOR), 207.8 (RCOR).
Comprehensive Organic Synthesis, Vol. 3; Trost, B. M.;
Fleming, I.; Pattenden, G., Eds.; Pergamon Press: Oxford,
1991, 521–549.
Analytical Data for 2-{1-[(Pivaloyl)oxy]-4,6-dimethyl-3-
oxo-2,3-dihydro-1H-inden-5-yl}ethyl Pivalate (18b).
1H NMR (300 MHz, CDCl3): d = 1.14, 1.17 (s, 9 H, Piv),
2.46 (s, 3H, Me-Carom), 2.51 (dd, J3 = 3.0 Hz, J2 = 18.8 Hz, 1
H, CH2CH), 2.68 (s, 3 H, Me-Carom), 3.03 (t, J3 = 7.7 Hz, 2
H, CH2CH2O), 3.08 (dd, J3 = 7.1 Hz, J2 = 18.8 Hz, 1 H,
CH2CH), 4.10 (t, J3 = 7.7 Hz, 2 H, CH2CH2O), 6.15 (dd,
J3 = 3.0 Hz, J3 = 7.1 Hz, 1 H, CHOPiv), 7.19 (s, 1 H,
CHarom). 13C NMR (75 MHz, CDCl3): d = 13.8, 21.3 (CH3-
(12) (a) Backlund, S. J.; Zweifel, G. J. Am. Chem. Soc. 1977, 99,
3184. (b) 4-(Carboxymethyl)-3,5-dimethylbenzoic Acid
(10).
Compound 9 (1.00 g, 3.78 mmol) in 10 mL dry THF was
cooled to 0 °C and 6.8 mL (6.8 mmol, 1.8 equiv) 1 M BH3–
THF solution was dropped in slowly. After stirring at 0 °C
for 2 h a mixture of 10 mL (0.02 mol, 5 equiv) 2 M NaOH
and 5 mL (0.06 mol, 15 equiv) aq H2O2 solution (30%) was
added. After additional stirring for 2 h further 20 mL of 1 M
NaOH and 50 mL of Et2O were added. The phases were
separated and the aqueous phase was extracted several times
with Et2O. Then the aqueous phase was acidified to pH 1
with HCl and the product was extracted with several portions
of Et2O. The combined organic phases were dried and
evaporated, giving 350 mg (1.68 mmol, 44%) of 10 as a
white solid; mp 285 °C. 1H NMR (300 MHz, DMSO-d6):
d = 2.29 (s, 6 H, 3,5-Me), 3.65 (s, 2 H, CH2), 7.59 (s, 2 H,
CHarom). 13C NMR (75 MHz, DMSO-d6): d = 19.8 (3,5-Me),
35.2 (CH2), 128.5 (CHarom), 128.8, 137.3, 137.9 (Cq), 167.4,
171.8 (COOH). IR (KBr): 2959 (br s), 2923 (s), 2858 (s),
1718 (s), 1667 (s), 1425 (s), 1413 (s), 1303 (s), 1244 (s),
1230 (s), 1182 (m). HRMS (ESI): m/z calcd for C11H13O4
[MH+]: 209.0808. Found: 209.0809.
Carom), 27.0, 27.1 (CH3, Piv), 28.0 (CH2CH2O), 38.6, 38.6
(Cq, Piv), 44.6 (2-CH2), 62.3 (CH2CH2O), 68.5 (3-CH), 73.2
(CH2O), 125.4 (CHarom), 132.8, 136.7, 137.5, 145.1, 151.0
(Cq), 178.5, 178.6 (COOR), 202.9 (RCOR). IR (film): 2973
(s), 1717 (vs), 1599 (s), 1478 (s), 1458 (s), 1396 (s), 1281 (s),
1148 (s), 1033 (s), 1010 (s), 984 (m). HRMS (ESI): m/z calcd
for C23H33O5 [MH+]: 389.2323; found: 389.2324.
(18) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley-Interscience: New York,
1999, 171. (b) Kosmol, H.; Hill, F.; Kerb, U.; Kieslich, K.
Tetrahedron Lett. 1970, 11, 641. (c) Poijärvi, P.; Orivanen,
M.; Lönnberg, H. Lett. Org. Chem. 2004, 1, 183.
(19) Experimental Procedure for 3-Hydroxy-6-(2-
hydroxyethyl)-5,7-dimethyl-1-indanone (22).
To a solution of 65 mg (0.17 mmol) 18b in 10 mL DMSO
was added a mixture of 100 mL 0.01 M aq HEPES buffer
solution (pH 7.5, I = 0.1 M NaCl) and 90 mg (2160 units)
porcine liver esterase (EC 3.1.1.1, Sigma). The mixture was
stirred 2 d at r.t. in which the reaction course was monitored
by HPLC analysis (see below). After complete
saponification of both ester groups the mixture was treated
with 50 mL CH2Cl2, filtrated and the phases were separated.
The organic phase was dried with MgSO4, evaporated and
purified by FCC (CH2Cl2–MeOH, 10:1, Rf = 0.39) affording
20.0 mg (90.8 µmol, 54%) 22 as a white solid.
(13) Muraki, T.; Togo, H.; Yokoyama, M. J. Org. Chem. 1999,
64, 2883.
(14) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew.
Chem. Int. Ed. 2002, 114, 4563.
(15) (a) Koser, G. F.; Relenyi, A. G.; Kalos, A. N.; Rebrovic, L.;
Wettach, R. H. J. Org. Chem. 1982, 47, 2487. (b) Lodaya,
J. S.; Koser, G. F. J. Org. Chem. 1988, 53, 210.
(16) (a) Bergmark, W. R. J. Chem. Soc., Chem. Commun. 1978,
61. (b) Bergmark, W. R.; Barnes, C.; Clark, J.; Paparian, S.;
Marynowski, S. J. Org. Chem. 1985, 50, 5612.
HPLC conditions: column: Eurospher 100 C-18 (Knauer),
5 mm, 250 × 4 mm; mobile phase: gradient MeOH–H2O
(70:30 → 90:10) linear in 20 min, then 90:10 flow: 1 mL/
min. peaks: tR(22) = 2.6 min, tR(18b) = 31.9 min.
(c) Favorskii, A. J. Russ. Phys. Chem. Soc. 1905, 37, 643.
(d) Kende, A. S. Org. React. 1960, 11, 261.
(17) Irradiation of 17a and 17b.
Mp 143–145 °C. 1H NMR (300 MHz, DMSO-d6): d = 2.34
(dd, J3 = 3.0 Hz, J2 = 18.5 Hz, 1 H, CH2CH), 2.40, 2.56 (s, 3
H, Me-Carom), 2.84 (t, J3 = 7.5 Hz, 2 H, CH2CH2OH), 2.90
(dd, J3 = 7.0 Hz, J2 = 18.5 Hz, 1 H, CH2CH), 3.41–3.46 (m,
2 H, CH2CH2OH), 4.78 (t, J3 = 5.5 Hz, 1 H, CH2OH), 5.02–
5.06 (m, 1 H, 3-CH), 5.57 (d, J3 = 6.0 Hz, 1 H, OH), 7.31 (s,
1 H, CHarom). 13C NMR (75 MHz, DMSO-d6): d = 13.3, 21.0
(CH3-Carom), 32.1 (CH2CH2OH), 47.7 (2-CH2), 59.8
(CH2CH2OH), 65.6 (3-CH), 125.0 (CHarom), 131.5, 135.6,
137.1, 144.2, 155.6 (Cq), 204.3 (RCOR). IR (KBr): 3391 (br
s), 2923 (m), 1687 (vs), 1596 (s), 1408 (m), 1326 (m), 1308
(s), 1260 (m), 1065 (s), 1025 (s), 804 (m). HRMS (ESI):
m/z calcd for C13H17O3 [MH+]: 221.1172; found: 221.1173.
For solvents, conditions and yields see Table 1. The
irradiation was performed in a 500 mL reactor vessel,
equipped with a 150 W high-pressure mercury arc lamp (TQ
150, Heraeus) and monitored by TLC. The solvent was
removed in vacuo and the residue was purified by flash
chromatography.
Analytical Data for 2-(4,6-Dimethyl-3-oxo-2,3-dihydro-
1H-inden-5-yl)ethyl Acetate (18a).
Mp 39–41 °C. 1H NMR (300 MHz, CDCl3): d = 2.03 (s, 3 H,
CH3-acetate), 2.42 (s, 3 H, Me-Carom), 2.60–2.64 (m, 2 H, 2-
CH2), 2.67 (s, 3 H, Me-Carom), 2.94–2.98 (m, 2 H, 3-CH2),
3.03 (t, J3 = 7.7 Hz, 2 H, CH2CH2O), 4.12 (t, J3 = 7.7 Hz, 2
Synlett 2006, No. 10, 1543–1546 © Thieme Stuttgart · New York