Synthesis of (±)-smenochromene D (likonide B) using a regioselective claisen rearrangement

Article abstract of DOI:10.1055/s-2008-1032090

A synthesis of the unusual ansa farnesyl hydroquinone smenochromene D (likonide B) is described, in which the key steps are a regioselective microwave-mediated Claisen rearrangement of an aryl propargyl ether to deliver the chromene ring, and macrocyclisation via an intramolecular Mitsunobu reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032090

LETTER
575
Synthesis of ( )-Smenochromene D (Likonide B) Using a Regioselective
Claisen Rearrangement
Synthesis of
(
)-Smenaochromene
r
D
via
a
R
j
egiose
o
lective
C
lais
r
en
R
ear
ieent Bruder, Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Fax +44(115)9513564; E-mail: c.j.moody@nottingham.ac.uk
Received 3 December 2007
Me
Me
Me
Me
Me
Abstract: A synthesis of the unusual ansa farnesyl hydroquinone
smenochromene D (likonide B) is described, in which the key steps
are a regioselective microwave-mediated Claisen rearrangement of
an aryl propargyl ether to deliver the chromene ring, and macrocy-
[3,3]-sigmatropic
rearrangement
O
HO
??
clisation via an intramolecular Mitsunobu reaction.
MeO
O
MeO
O
Me
Key words: natural products, ansa-macrocycles, rearrangements,
chromenes, Mitsunobu reaction
2
1
smenochromene D
(likonide B)
likonide A
Figure 1
Sesquiterpenoid quinone and hydroquinone derivatives
occur widely in nature.1–3 In 2004 Kashman and co-work-
ers reported two new examples with an unusual ansa far-
nesyl structure.4 The compounds, named likonide A and B
(1 and 2), were isolated from a marine sponge Hyatella sp.
found off the coast of Likoni, Kenya, and their structures
lective Claisen rearrangement to form the chromene and
an intramolecular Mitsunobu reaction as key steps.
The synthesis started with the known allylic alcohol 3,
readily available by allylic oxidation of commercial gera-
and absolute configurations were determined by detailed nylacetone with selenium dioxide and tert-butyl hydro-
spectroscopic studies. Although the likonides were de- peroxide.11,12 Protection as the tert-butyldimethylsilyl
scribed as new ansa compounds,4 Faulkner and Clardy (TBS) ether was followed by addition of ethynylmagne-
and colleagues had reported a series of very similar ansa sium bromide and acylation with methyl chloroformate to
farnesyl hydroquinones, the smenochromenes isolated give the tertiary propargylic alcohol carbonate 4 in prepa-
from a Seychelles sponge Smenospongia sp., in 1991.5 ration for coupling to a phenol. The first phenol investi-
The structure and spectroscopic data for one of these com-
pounds, smenochromene D, appeared to be identical to
those of likonide B in all respects except optical rotation:
smenochromene D, [a]D –68.5 (c = 0.35, CH2Cl2);5
likonide B, [a]D +27 (c = 0.08, MeOH).4 The confusion
has recently been resolved by the synthesis of ( )-smeno-
chromene D by Olson and Trauner,6 which clearly estab-
gated was 3-methoxy-4-tert-butyldimethylsiloxyphenol
(5a).13 However, attempts to couple phenol 5a with the
propargylic carbonate 4 (or the corresponding trifluoro-
acetate) in the presence of DBU and copper(II)
chloride14,15 gave only poor yields (12–26%) of the de-
sired propargylic ether 6a. Nevertheless, sufficient mate-
rial was obtained to establish that the planned Claisen
lished that smenochromene D and likonide B are identical rearrangement exhibited the required regioselectivity.15–17
in terms of relative stereochemistry. Hence the natural Thus microwave heating18 of 6a in DMF at 200 °C for 30
products appear to be enantiomers, or possibly, given the minutes gave the chromene 7a in a 4:1 mixture with the
large discrepancy in optical rotation, to have an enantio- regioisomeric product.
meric excess in the opposite sense. Intriguingly, it is also
In order to improve the yield in the key copper-catalysed
noted that likonides A and B are formally related by a
coupling step, a number of simple model studies were per-
[3,3]-sigmatropic process, since Claisen rearrangement of
formed (data not shown) which established that the reac-
likonide B should give likonide A (Figure 1). However,
tion proceeded better if an electron-withdrawing
protecting group was installed on the para-hydroxyl
group. Thus the coupling reaction of propargylic carbon-
ate 4 was repeated using the mesyl-protected phenol 5b
resulting in an acceptable yield (68%) of the propargylic
ether 6b. However, the Claisen rearrangement of the me-
sylate derivative 6b exhibited poor regioselectivity (ratio
Trauner and co-workers have recently shown that heating
of likonide B (smenochromene D) does not result in such
a Claisen rearrangement, but rather in an alternative rear-
rangement to give the ring skeleton of smenochromene
B.7 In view of the continuing interest in these and other
sesquiterpene quinones and hydroquinones,8–10 we report
a new synthesis of ( )-smenochromene D using a regiose-
2:1), and therefore the mesylate group was cleaved using
LDA in THF at low temperature.19 Gratifyingly, the re-
sulting phenolic propargylic ether underwent a highly se-
SYNLETT 2008, No. 4, pp 0575–0577
x
x.
x
x.
2
0
0
8
lective Claisen rearrangement upon microwave heating in
N,N-diethylaniline at 140 °C for 40 minutes to give the de-
sired chromene 7b in 87% yield with no evidence for the
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032090; Art ID: D40107ST
© Georg Thieme Verlag Stuttgart · New York

576
M. Bruder, C. J. Moody
LETTER
Me
Me
Me
O
OMe
O
HO
TBSO
a–c
Me
Me
MeOOCO
O
Me
Me
3
4
Me
Me
RO
Me
Me
O
d
MeO
OH
Me
5a R = TBS
5b R = Ms
MeO
O
Me
9
Me
Me
Me
Me
Figure 2
TBSO
TBSO
e (for 6a)
RO
RO
References and Notes
f,g (for 6b)
MeO
O
MeO
O
Me
(1) Thomson, R. H. Naturally Occurring Quinones, 2nd ed.;
Academic Press: London, 1971.
(2) Thomson, R. H. Naturally Occurring Quinones III: Recent
Advances, 3rd ed.; Chapman and Hall: London, 1987.
(3) Thomson, R. H. Naturally Occurring Quinones IV: Recent
Advances, 4th ed.; Blackie: London, 1997.
7a R = TBS
7b R = H
6a R = TBS
6b R = Ms
h
Me
Me
Me
(4) Rudi, A.; Benayahu, Y.; Kashman, Y. Org. Lett. 2004, 6,
4013.
Me
Me
HO
(5) Venkateswarlu, Y.; Faulkner, D. J.; Steiner, J. L. R.;
Corcoran, E.; Clardy, J. J. Org. Chem. 1991, 56, 6271.
(6) Olson, B. S.; Trauner, D. Synlett 2005, 700.
(7) Rosa, C. P.; Kienzler, M. A.; Olson, B. S.; Liang, G.;
Trauner, D. Tetrahedron 2007, 63, 6529.
i
O
HO
MeO
O
MeO
O
Me
2
(8) Stahl, P.; Waldmann, H. Angew. Chem. Int. Ed. 1999, 38,
3710.
smenochromene D
(likonide B)
8
(9) Aoki, S.; Kong, D.; Matsui, K.; Rachmat, R.; Kobayashi, M.
Chem. Pharm. Bull. 2004, 52, 935.
(10) Takahashi, Y.; Kubota, T.; Fromont, J.; Kobayashi, J.
Tetrahedron 2007, 63, 8770.
(11) McMurry, J. E.; Dushin, R. G. J. Am. Chem. Soc. 1989, 111,
8928.
(12) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977,
99, 5526.
Scheme 1 Reagents and conditions: (a) t-BuMe2SiOTf, 2,6-lutidi-
ne, CH2Cl2 (89%); (b) ethynylmagnesium bromide, THF, diethylether
(85%); (c) n-BuLi, THF, then MeO2CCl (86%); (d) 5a, DBU, CuCl2,
MeCN (26%) or 5b, DBU, CuCl2, MeCN (68%); (e) DMF, microwa-
ve (300 W), 200 °C, 30 min (52% as 4:1 mixture of regioisomers); (f)
LDA, THF, –78 °C (71%); (g) PhNEt2, microwave (300 W), 140 °C,
40 min (87%); (h) H2SiF6, MeCN, 0 °C (83%); (i) 1,1¢-(azodicarbo-
nyl)dipiperidine, n-Bu3P, toluene (27% + 13% dimer 9).
(13) Fischer, J.; Reynolds, A. J.; Sharp, L. A.; Sherburn, M. S.
Org. Lett. 2004, 6, 1345.
(14) Godfrey, J. D.; Mueller, R. H.; Sedergran, T. C.;
Soundararajan, N.; Colandrea, V. J. Tetrahedron Lett. 1994,
35, 6405.
(15) For related Claisen rearrangements, see ref. 16 and the
following: Kahn, P. H.; Cossy, J. Tetrahedron Lett. 1999, 40,
8113.
(16) Yamaguchi, S.; Maekawa, M.; Murayama, Y.; Miyazawa,
M.; Hirai, Y. Tetrahedron Lett. 2004, 45, 6971.
(17) For a discussion of regioselectivity in rearrangements of aryl
propargyl ethers, see: Yamaguchi, S.; Ishibashi, M.;
Akasaka, K.; Yokoyama, H.; Miyazawa, M.; Hirai, Y.
Tetrahedron Lett. 2001, 42, 1091.
(18) For an earlier example of a microwave-assisted Claisen
rearrangement of an aryl propargyl ether, see: Moghaddam,
F. M.; Sharifi, A.; Saidi, M. R. J. Chem. Res., Synop. 1996,
338.
formation of the alternative regioisomer.20 Thereafter the
silyl protecting group was removed from the side chain to
give the precursor 8 for the macrocyclisation reaction.
The cyclisation was effected using an intramolecular Mit-
sunobu reaction [tri-n-butylphosphine, 1,1¢-(azodicarbon-
yl)dipiperidine] and gave smenochromene D (likonide B)
in 27% yield (Scheme 1),21 the poor yield probably re-
flecting the strained nature of the ansa ring.22 A small
amount of a dimer assigned as structure 9 (Figure 2; mix-
ture of diastereomers) was also isolated. The NMR spec-
troscopic data for synthetic smenochromene D were
identical to those described for the natural product4,5 and
the aforementioned synthetic racemic material.6
(19) Ritter, T.; Stanek, K.; Larrosa, I.; Carreira, E. M. Org. Lett.
2004, 6, 1513.
Acknowledgment
(20) 6-Hydroxy-2-[(3E,7E)-9-tert-butyldimethylsilyloxy-4,8-
dimethylnona-3,7-dienyl]-7-methoxy-2-methyl-2H-
chromene (7b): A solution of the propargyl aryl ether (98
mg, 0.21 mmol) in N,N-diethylaniline (3.5 mL) in a sealed
tube was heated at 140 °C for 40 min at 300 W in a CEM
We thank Professor Dirk Trauner for copies of the NMR spectra of
synthetic ( )-likonide B.
Synlett 2008, No. 4, 575–577 © Thieme Stuttgart · New York

LETTER
Synthesis of (±)-Smenochromene D via a Regioselective Claisen Rearrangement
577
Discover™ microwave reactor. The reaction mixture was
The reaction mixture was then allowed to reach r.t. and was
stirred for 24 h. A second batch of dipiperidinyl
evaporated and the resulting oil was purified by flash
chromatography on silica gel, eluting with light PE–Et2O
(8:2), to give the title compound (85 mg, 87%) as a orange-
yellow oil. IR (CHCl3): 3630, 3553, 2929, 2856, 1628, 1583,
1501, 1458, 1360, 1290, 1124 cm–1. 1H NMR (400 MHz,
CDCl3): d = 6.56 (s, 1 H, H-5), 6.41 (s, 1 H, H-8), 6.27 (d,
J = 9.8 Hz, 1 H, H-4), 5.47 (d, J = 9.8 Hz, 1 H, H-3), 5.38 (m,
1 H, CH=CMe), 5.19 (s, 1 H, OH), 5.13–5.16 (m, 1 H,
CH=CMe), 4.02 (s, 2 H, OCH2), 3.86 (s, 3 H, OMe), 2.10–
2.14 [m, 4 H, OC(Me)CHHCH2, =CHCH2CH2], 2.00–2.03
(m, 2 H, =CHCH2CH2), 1.66–1.75 [m, 2 H,
OC(Me)CHHCH2], 1.61 (s, 6 H, 2 × CMe=CH), 1.39 (s, 3 H,
Me), 0.93 (s, 9 H, CMe3), 0.08 (s, 6 H, SiMe2). 13C NMR
(100 MHz, CDCl3): d = 146.7 (C), 146.6 (C), 139.2 (C),
135.0 (C), 134.3 (C), 127.6 (CH), 124.3 (CH), 122.4 (CH),
121.5 (CH), 113.9 (CH), 111.7 (C), 100.0 (CH), 78.1 (C),
68.6 (CH2), 55.9 (Me), 40.9 (CH2), 39.3 (CH2), 26.0 (CH2),
25.9 (Me), 25.8 (Me), 22.6 (CH2), 18.4 (C), 15.9 (Me), 13.4
(Me), –5.3 (Me). HRMS (EI): m/z [M + Na]+ calcd for
C28H44O4Si: 495.2901; found: 495.2918.
azodicarboxylate was added at 0 °C, tributylphosphine was
added over 1 h and the whole was stirred for 8 h at r.t. H2O
was added to the mixture and the aqueous phase was
extracted into EtOAc (2 ×). The organic layer was reduced
in vacuo, the crude product was taken up in light PE and
filtered. The resulting solution was dried over MgSO4,
filtered and evaporated in vacuo. The crude oil was purified
by flash chromatography on silica gel, eluting with hexane–
EtOAc (9:1), to give the title compound (13 mg, 27%). IR
(CHCl3): 3630, 2930, 1618, 1503, 1450, 1365, 1289, 1124
cm–1. 1H NMR (400 MHz, DMSO): d = 6.61 (s, 1 H, H-16),
6.38 (d, J = 9.9 Hz, 1 H, H-1), 6.34 (s, 1 H, H-19), 5.41 (d,
J = 9.8 Hz, 1 H, H-2), 4.85–4.87 (m, 1 H, H-6), 4.74–4.78
(m, 1 H, H-10), 4.38 (d, J = 11.4 Hz, 1 H, H-12), 4.07 (d,
J = 11.4 Hz, 1 H, H-12¢), 3.66 (s, 3 H, H-22), 1.96–2.12 (m,
4 H, H-9, H-5, H-8), 1.83–1.92 (m, 1 H, H-5¢), 1.64–1.68 (m,
1 H, H-4), 1.53–1.62 (m, 5 H, H-8, H-15, H-4¢), 1.41 (s, 3 H,
H-13), 1.32 (s, 3 H, H-14). 13C NMR (100 MHz, DMSO):
d = 153.0 (C), 149.8 (C), 138.9 (C), 131.2 (CH), 131.0 (C),
129.6 (C), 126.3 (CH), 125.6 (CH), 123.2 (CH), 118.9 (CH),
112.9 (C), 99.9 (CH), 78.9 (CH), 78.6 (C), 55.3 (OMe), 40.7
(CH2), 38.5 (CH2), 29.7 (Me), 24.0 (CH2), 22.5 (CH2), 14.2
(Me), 13.9 (Me). HRMS (ES): m/z [M + Na]+ calcd for
C22H28O3: 363.1931; found: 363.1919. The cyclic dimer 9
(13 mg, 13%) was also isolated.
(21) ( )-Smenochromene D [( )-Likonide B](2): Into a stirring
8 mM solution of 6-hydroxy-2-[(3E,7E)-9-hydroxy-4,8-
dimethylnona-3,7-dienyl]-7-methoxy-2-methyl-2H-
chromene (8; 50 mg, 0.14 mmol) and dipiperidinyl
azodicarboxylate (105 mg, 0.42 mmol) in anhyd toluene
(17.4 mL) was bubbled argon for 10 min, while cooling the
solution to 0 °C. A first batch (40 mL) of tributylphosphine
(140 mL, 0.55 mmol) was added dropwise and the reaction
mixture was stirred for 20 min at 0 °C followed by the
addition of a second batch of tributylphosphine (100 mL).
(22) A similarly modest yield in the macrocyclisation step was
also observed in the previous synthesis of smenochromene D
(ref. 6).
Synlett 2008, No. 4, 575–577 © Thieme Stuttgart · New York

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