Concise synthesis of (±)-smenochromene D (= likonide B)

Article abstract of DOI:10.1055/s-2005-863713

The total synthesis of smenochromene D, an unusual ansa-terpenoid is described. The synthesis features an unprecedented macrocyclization proceeding through a biomimetic electrocyclization. The enantiomeric relationship between smenochromene D and likonide

Full text of DOI:10.1055/s-2005-863713

700
CLUSTER
Concise Synthesis of ( )-Smenochromene D (= Likonide B)
C
oncise Synthesi
r
s
of
(
)-S
o
menochrom
o
ene
D
ke S. Olson, Dirk Trauner*
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, CA 94720-1460, USA
Fax +1(510)6439480; E-mail: trauner@cchem.berkeley.edu
Received 30 November 2004
Abstract: The total synthesis of smenochromene D, an unusual
ansa-terpenoid is described. The synthesis features an unprecedent-
ed macrocyclization proceeding through a biomimetic electrocy-
clization. The enantiomeric relationship between smenochromene
D and likonide B is established.
Key words: smenochromenes, likonides, chromenes, macrocycli-
zation, ansa-compounds, ortho-quinone methides
The smenochromenes are a family of macrocyclic
chromenes isolated by Faulkner and Clardy in 1991 from
a Seychelles sponge of the genus Smenospongia
(Figure 1).1 In 2004, Kashman reported the structures of
likonides A and B isolated from a Kenyan sponge, Hyatel-
la sp.2 While the relative and absolute configuration of the
likonides was established by detailed NMR studies and
CD spectroscopy, respectively, their close structural
resemblance to the smenochromene family apparently
was not noticed.
Biosynthetically, these bizarre molecules are presumably
derived from various cyclizations of a common farnesyl
hydroquinone precursor.1,2 In addition to their interesting
biosynthesis, however, the smenochromenes attracted our
attention due to their unusual stereochemical properties.
Two stereogenic elements, an ansa-bridge and a quaterna-
ry stereocenter, can be identified in the molecules. These
stereogenic elements are not independent of each other,
Figure 1 The smenochromenes and likonides. The absolute
configurations of smenochromenes B and C are arbitrary.
however, due to the constraints of the 14- or 16-membered
macrocyclic ring. Notably, smenochromene A was isolat-
ed as a racemate, whereas smenochromenes B, C, and D
occur at least in enantioenriched if not enantiomerically
pure form.1 According to our work, likonide B appears to
Me
Me
O
O
O
O
O
O
be an enantiomer of smenochromene D (see below).
A probable mechanism of the racemization of smeno-
chromene A is shown in Scheme 1. Electrocyclic ring-
opening of one enantiomer 1 affords ansa-ortho-quinone
methide 2. This planar chiral intermediate can undergo
racemization through ring-slip (2 → ent-2). Subsequent
6p-electrocyclization leads to chromene ent-1. Apparent-
ly, this type of racemization is not feasible, or at least
attenuated at ambient temperatures, with smeno-
chromenes B, C and D due to the constraints of their
macrocyclic rings.
1
ent-1
O
O
O
O
O
O
2
ent-2
SYNLETT 2005, No. 4, pp 0700–0702
0
4.
0
3.
2
0
0
5
Advanced online publication: 22.02.2005
Scheme 1 Racemization of smenochromene A.
DOI: 10.1055/s-2005-863713; Art ID: Y04404ST
© Georg Thieme Verlag Stuttgart · New York

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Concise Synthesis of (±)-Smenochromene D
701
The realization that the chromene core of the natural prod- Accordingly, our synthesis of racemic smenochromene D
ucts presumably arises from the 6p-electrocyclization of (and likonide B) starts with the known allylic alcohol 7
an ortho-quinone methide guided our retrosynthetic anal- obtained from farnesyl acetate 6 through selective oxida-
ysis of smenochromene D (Scheme 2).3 A logical precur- tion of a terminal allylic methyl group.4 Mitsunobu reac-
sor of the ansa-ortho-quinone methide intermediate 3 tion of this material with phenol 8, the Baeyer–Villiger
would be the 16-membered macrocyclic phenolate 4, oxidation product of vanillin,5 gave phenolic formate 9 in
wherein X represents a benzylic leaving group. Com- good yield. Saponification of the formyl and acetyl ester
pound 4, in turn, could be traced back to methoxy hydro- followed by Parikh–Doering oxidation6 afforded the un-
quinone 5 and farnesol as the source of the fifteen saturated aldehyde 10 as a mixture of stereoisomers and
terpenoid carbons.
set the stage for the key macrocyclization. Notably, a
variety of other oxidation methods (e.g. PCC-, Swern-, or
Dess–Martin oxidation) failed to cleanly afford the unsat-
urated aldehyde due to the sensitivity of the very electron
rich phenol moiety toward oxidation.
Macrocyclization with concomitant chromene formation
was achieved under the conditions reported by Snieckus et
al.7 Refluxing a solution of 10 in the presence of one
equivalent of phenylboronic acid afforded smeno-
chromene D in 26% yield.8 Presumably, this conversion
proceeds via boronic acid-mediated hydroxyalkylation9
followed by elimination to afford ansa-ortho-quinone
methide 3 (Scheme 3). This highly reactive intermediate
then undergoes diastereoselective 6p-electrocyclization to
afford the racemic natural product. While its yield is mod-
est, this reaction does represent the first use of the meth-
odology toward the synthesis of a large (16-membered)
and strained ring.
Scheme 2 Retrosynthetic analysis of smenochromene D.
Scheme 3 Total synthesis of ( )-smenochromene D (likonide B). Reagents and conditions: (a) SeO2, salicylic acid, TBHP, CH2Cl2 (ref.4);
(b) 8, DEAD, Ph3P, THF (75%); (c) K2CO3, MeOH, H2O (84%); (d) SO3, TEA, DMSO (80%); (e) PhB(OH)2, PhMe, D (26%).
Synlett 2005, No. 4, 700–702 © Thieme Stuttgart · New York

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B. S. Olson, D. Trauner
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What is the relationship between smenochromene D and
likonide B? The possibility had to be taken into account
that likonide B ([a]D +27) is an atropisomer of smeno-
chromene D ([a]D –68.5). Careful comparison of the
NMR spectra of our synthetic material in various solvents
with the reported spectra of smenochromene D and
likonide B,1,2 respectively, as well as a detailed NOE
study, however, showed that the two compounds are iden-
tical with respect to their relative stereochemistry. Smeno-
chromene D and likonide B, therefore, appear to be
enantiomers, or at least enantioenriched in an opposite
sense, explaining the wide discrepancy in the absolute nu-
merical value of their reported optical rotation.
References
(1) Clardy, J.; Faulkner, D. J.; Venkateswarlu, Y.; Rios Steiner,
J. L.; Corcoran, E. J. Org. Chem. 1991, 56, 6271.
(2) Kashman, Y.; Rudi, A.; Benayahu, Y. Org. Lett. 2004, 6,
4013.
(3) For a comprehensive review on the chemistry of ortho-
quinone methides, see: Van de Water, R. W.; Pettus, T. R. R.
Tetrahedron 2002, 58, 5367.
(4) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977,
99, 5526.
(5) Banwell, M. G.; Flynn, B. L.; Stewart, S. G. J. Org. Chem.
1998, 63, 9139.
(6) Parikh, J. R.; von Doering, W. E. J. Am. Chem. Soc. 1967,
89, 5505.
(7) (a) Snieckus, V.; Chauder, B. A.; Lopes, C. C.; Lopes, R. S.
C.; da Silva, A. J. M. Synthesis 1998, 279. (b) Murphy, W.
S.; Tuladhar, S. M.; Duffy, B. J. Chem. Soc., Perkin Trans.
1 1992, 605. (c) Bissada, S.; Lau, C. K.; Bernstein, M. A.;
Dufresne, C. Can. J. Chem. 1994, 72, 1866.
In summary, we have achieved a concise, five-step syn-
thesis of racemic smenochromene D (likonide B), starting
from commercially available farnesyl acetate. Synthetic
studies directed at other members of the smenochromene
family are well underway in our laboratories and asym-
metric versions involving chiral Lewis acids or arylboron-
ic acids will be attempted. The conversion of likonide B
into likonide A via [3,3] sigmatropic rearrangement, as
well as the conversion of the hetero-macrocyclic into the
carba-macrocyclic smenochromene series is under active
investigation as well and will be reported in due course.
(8) Experimental Procedure.
To a solution of 10 (20.0 mg, 0.0558 mmol) in toluene (4
mL) was added phenylboronic acid (14.0 mg, 0.0837 mmol)
and HOAc 0.400 mL. The reaction mixture was then fitted
with a Dean Stark apparatus and heated at reflux for 3 h. The
mixture was cooled to r.t., diluted with CH2Cl2, washed with
H2O, sat. NaHCO3, and brine, dried over MgSO4, and
concentrated in vacuo. The product was purified by column
chromatography (10% EtOAc in hexane) to afford 4.9 mg
(26%) of smenochromene D as a clear oil. Rf = 0.26 (10%
EtOAc in hexane, CAM). IR: 3394, 2921, 2852, 1616, 1505
cm–1. 1H NMR: (500 MHz): d = 6.52 (s, 1 H), 6.31 (d,
J = 12.8 Hz, 1 H), 6.29 (s, 1 H), 5.31 (d, J = 12.8 Hz, 1 H),
4.93 (t, J = 7.2 Hz, 1 H), 4.82 (t, J = 8, 1 H), 4.52 (d, J = 15.2
Hz, 1 H), 4.14 (d, J = 15.2 Hz, 1 H), 3.76 (s, 3 H), 2.09 (m,
4 H), 1.77 (m, 2 H), 1.69 (s, 3 H), 1.58 (m, 2 H), 1.47, (s, 3
H), 1.36 (s, 3 H). 13C NMR (500 MHz): d = 153.4, 150.3,
139.3, 132.0, 131.8, 129.8, 126.6, 125.8, 123.5, 119.1,
113.3, 99.9, 80.3, 79.0, 55.6, 41.4, 38.9, 30.2, 24.6, 23.1,
14.4, 14.1. HRMS: m/z calcd for C22H2803 [M+]: 340.2038;
found: 340.2033.
Acknowledgment
Financial support by Eli Lilly, Glaxo-Smith-Kline, Merck & Co.,
and Astra Zeneca is gratefully acknowledged.
(9) Nagata, W.; Okada, K. Synthesis 1979, 365.
Synlett 2005, No. 4, 700–702 © Thieme Stuttgart · New York