A regiodivergent synthesis of ring A C-prenylflavones

Article abstract of DOI:10.1021/ol800665w

(Chemical Equation Presented) Capitalizing on the use of orthogonal protecting groups and the development of a modified Robinson flavone synthesis that avoids harsh acidic conditions, a regioselective synthesis of 6- and 8-prenylflavones from the same pre

Full text of DOI:10.1021/ol800665w

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2267-2270
A Regiodivergent Synthesis of Ring A
C-Prenylflavones
Alberto Minassi, Anna Giana, Abdellah Ech-Chahad, and Giovanni Appendino*
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche,
UniVersita` del Piemonte Orientale, Via BoVio 6, 28100 NoVara, Italy
appendino@pharm.unipmn.it
Received March 22, 2008
ABSTRACT
Capitalizing on the use of orthogonal protecting groups and the development of a modified Robinson flavone synthesis that avoids harsh
acidic conditions, a regioselective synthesis of 6- and 8-prenylflavones from the same prenylated disilylated phloracetophenone (9) has been
developed, targeting cannflavin B (1d), the COX-inhibiting principle of marijuana, and its unnatural isomer isocannflavin B (1e) as model
compounds.
Over the past few decades, an impressive number of
bioactivities have been demonstrated for C-prenylated fla-
Scheme 1
.
Structure of 8PN (1a), Cannflavins A (1d), and
vonoids, including binding to several hot targets of current
biomedical research such as estrogen receptors (ERs),1 heat
shock proteins (Hsp-90),2 cyclo-oxygenases (COXs),3 P-
glycoproteins (PgPs),4 and phosphodiesterases (PDEs).5
While in most cases it is not clear whether the prenyl group
has a specific role for bioactivity, some interesting findings
emerged during the study of the estrogenic activity of
8-prenylnaringenin (8PN, Scheme 1, 1a), a hop and beer
constituent.1 Thus, while the introduction of an 8-prenyl
group induces estrogenic activity on the otherwise nonestro-
genic flavanone naringenin (1b),1 this operation is detrimental
Related Compounds
for the estrogenic properties of the isoflavone genistein,6 and
the introduction of a reversed prenyl at C-6 (1c) of naringenin
leads to a significant affinity for androgen receptors.7
Furthermore, 8PN is rapidly absorbed after oral administra-
tion, in sharp contrast to the generally poor oral bioavail-
ability of flavonoids.8 Prenylation of the phloroglucinol A
(1) Milligan, S. R.; Kalita, J.; Heyerick, A.; Rong, H.; De Cooman, L.;
De Keukeleire, D. J. Clin. Endocrinol. Metab. 1999, 84, 2249–2252.
(2) Hadden, M. K.; Galam, L.; Matts, R. L.; Blagg, B. S. J. J. Nat.
Prod. 2007, 70, 2014–2018.
(3) Barret, M. L.; Gordon, D.; Evans, F. J. Biochem. Pharmacol. 1985,
34, 2019–2024.
(4) Boumendjel, A.; Di Pietro, A.; Dumontet, C.; Barron, D. Med. Res.
ReV. 2002, 22, 512–529.
(6) Kitaoka, M.; Kadokawa, H.; Sugano, M.; Ichikawa, K.; Taki, M.;
Takaishi, S.; Iijma, Y.; Tsutsumi, S.; Boriboon, M.; Akiyama, T. Planta
Med. 1998, 64, 511–515.
(5) Shin, H. J.; Kim, H. J.; Kwak, J. H.; Chun, H. O.; Kim, J. H.; Park,
H.; Kim, D. H.; Lee, Y. S. Bioorg. Med. Chem. Lett. 2002, 12, 2313–
2316.
(7) Zierau, O.; Morissey, C.; Watson, R. W.; Schwab, P.; Kolba, S.;
Metz, P.; Vollmer, G. Planta Med. 2003, 69, 856–858.
10.1021/ol800665w CCC: $40.75
Published on Web 05/03/2008
2008 American Chemical Society

ring can therefore dramatically affect the pharmacodynamic
and pharmacokinetic profile of flavanones, justifying a
systematic scrutiny of this issue also in flavones, by far the
most common type of prenylflavonoids and also their more
diverse group in terms of bioactivity.9
respectively) are available by Robinson synthesis from their
corresponding diprotected, meta-substituted phloracetophe-
none precursors (5 and 7, respectively). This operation
translates differences in terms of relative orientation of the
free hydroxyl and the substituent (ortho in 5 and para in 7)
at the acetophenone stage into a C-8- or a C-6-flavone
substitution pattern. We reasoned that the functional asym-
metry of 5 and 7 could be interchanged by a protection swap
between the ortho-hydroxyls and that this could be achieved
through the agency of the orthogonally triprotected inter-
mediate 6 (Scheme 2).
The shortage of systematic studies on prenylflavones is
mainly due to their limited availability by synthesis compared
to other classes of prenylated flavonoids. In general, the direct
prenylation of flavonoids is difficult to control in terms of
chemoselectivity (C- vs O-alkylation), regiochemistry, and
number of prenyls introduced, and the issue is better
addressed at the stage of their acetophenone precursors.
However, the harsh conditions required for the elaboration
of acetophenones into flavones (Robinson synthesis)10 greatly
limits the application of this strategy to prenylated deriva-
tives.11 The development of a straightforward and tunable
entry into C-6 and C-8 prenylflavones from a common
precursor would therefore represent a significant addition to
the field, paving the way to systematic structure-activity
studies for this class of compounds. To combine proof-of-
concept and relevance, we have investigated the regiodiver-
gent synthesis of cannflavin B (1d), the COX-inhibiting
principle of marijuana,3 and its unnatural C-8 regioisomer
(isocannflavin B, 1e) from a common acetophenone precur-
sor. Legal issues aside, cannflavin B is very difficult to obtain
by isolation because of its low concentration in marijuana
and the occurrence of related phenolics that complicate its
purification.3 Its biomedical potential is therefore still un-
tapped.
Scheme 2. Wessely-Moser Rearrangement of Flavones and
Regiodivergent Retrosynthesis of 8- and 6-Substituted Flavones
(P and P′ ) Orthogonal Protecting Groups)
To address the problem of the complementary synthesis
of C-6 and C-8 prenylflavones, we took inspiration from the
Wessely-Moser rearrangement (Scheme 2).12 This venerable
reaction formally interconverts C-8- and C-6-substituted
flavones (2 and 4, respectively) through a diaroylmethane
intermediate that can freely rotate around the C-4a/C-7 axis
(3).13 The C-8- and C-6-substituted flavones (2 and 4,
(8) Rad, M.; Huemperl, M.; Schaefer, O.; Schoemaker, R. C.; Schleu-
niing, W. D.; Cohen, A. F.; Burggraaf, J. Br. J. Clin. Pharmacol. 2006, 62,
288–296.
(9) For a review, see: Barron, D.; Ibrahim, R. K. Phytochemistry 1996,
43, 921–982.
To put this line of thinking into practice, we had to address
two synthetic issues, namely, (a) the design of a 3-pre-
nylphloracetophenone orthogonally protected at the ortho-
hydroxyls (6), and (b) the development of a milder version
of the Robinson synthesis, compatible with the presence of
acid-labile prenyl groups and the regiodirecting ortho-
protection of the acetophenone precursors.
Within the various combinations of ether (MEM, MOM),
ester (acetate, pivalate), carbamate (BOC, Cbz), and silyl
(TES, TBDMS) protecting groups assayed, the 2,4-TBDMS-
6-pivaloyl combination (10) proved optimal in terms of
introduction, stability during the prenylation step, and
orthogonality. Thus, the TBDMS group was superior to all
(10) There is considerable confusion in the literature regarding the
paternity of the preparation of 4H-chromones from o-hydroxyacetophenones
by reaction with an activated carboxylic acid, a transformation referred to
asRobinson,Allan-Robinson,Baker-Venkataraman,orKostanecki-Robinson
synthesis. The original Robinson reaction involved a thermal, sodium
benzoate catalyzed process, involving o-hydroxyacetophenone and aroyl
anhydrides: Allan, J.; Robinson, R. J. Chem. Soc. 1924, 125, 2192–2195.
A more general two-step protocol based on the base-catalyzed isomerization
of o-acyloxyacetophenones to o-hydroxybenzoylacetophenones followed by
cyclization under acidic conditions was later developed and became known
as the Baker-Venkataraman synthesis: Baker, W. J. Chem. Soc. 1933,
1381–1389. Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1934, 1767–
1769. While Kostanecki had reported prior to Robinson the formation of
flavones by reaction of acetophenones with alkylated salycilic acids in the
presence of sodium: von Kostanecki, S.; Rozycki, A. Ber. 1901, 349, 102–
109. For sake of clarity, we refer to the transformation of o-hydroxyac-
etophenones to flavones simply as the “Robinson reaction”. For a discussion,
see: Finar, I. L. Organic Chemistry; Longman: London, 1977; Vol. 2, pp
782-784.
(14) MOM-Cl has been reported to selectively diprotect phloracetophe-
none (Bu, X. Y.; Zhao, L. Y.; Li, Y. L. Synthesis 1997, 1246–1248), but,
in our hand, this procedure gave a chromatographically difficult to separate
2.5:1 mixture of di- and triprotected derivatives, in analogy with what
observed with ester and carbamate protecting groups. An improved
procedure has been recently reported: Khupse, R. S.; Erhardt, P. W. J. Nat.
Prod. 2007, 70, 1507–1509.
(11) Alternative strategies are the dehydrogenation of prenylflavanones
to prenylflavones by treatment with iodine in pyridine (Dong, X.; Fan, Y.;
Yu, L.; Hu, Y. Arch. Pharm. Chem. Life Sci. 2007, 340, 372–376. ) or the
use of robust acid-sensitive, but difficult to remove, protecting groups.
(12) Wessely, F.; Moser, G. H. Monatsch. Chem. 1930, 56, 97–105.
(13) Flavone numbering.
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Org. Lett., Vol. 10, No. 11, 2008

other groups investigated for the protection of the nonch-
elated hydroxyls of phloracetophenone (8a).14 Furthermore,
unlike the MOM and the pivaloyl groups,15 it remained
unscathed during the conditions [heating in toluene in the
presence of Eu(fod)3] required for the tandem Claisen-Cope
rearrangement that installed the C-prenyl group from its
corresponding O-prenyl derivative,16 the result of the Mit-
sunobu alkylation of 8b (Scheme 3).17
lated by mild acidolysis with TFA in THF/water. Overall,
the protection swap between the ortho-hydroxyls could be
achieved in 72% yield. In this way, a pair of acetophenones
(9 and 11) complementary in terms of further elaboration to
flavones was obtained.
During the harsh acidic conditions required for the
conversion of acetophenones to flavones, protection at the
ortho-hydroxyls is generally lost, even with robust protecting
groups like MOM,18 making the acid-labile prenyl prone to
cyclization with the adjacent hydroxyl(s).19 Furthermore,
phenolic protection was also at the basis of the functional
asymmetry required by the regiodivergent elaboration of 10
into the target flavones. Given the potential lability of
phenolic silyl ether and the pivaloyl group to basic condi-
tions, the C-acylation of 9 and 11 was an additional source
of concern. In practice, this step could be achieved without
loss of ortho-protection by treatment of 9 and 11 with
pivaloyl-protected vanilloyl chloride20 under NaH promo-
tion,21 affording in excellent yield the diaroylmethanes 12
and 14. For their dehydration to flavones, we screened a
variety of Lewis acids as an alternative to the Brønsted acids
currently used for this purpose.22 The agents investigated
proved either unreactive (CeCl3·7H2O), led to massive
degradation of the substrate [BF3, BBr3, Eu(fod)3], or gave
an equimolecular mixture of 7-TBDMS-4′-pivaloyl cann-
flavin B (13) and isocannflavin B (15a) and their corre-
sponding 7-desilyl derivatives (FeCl3·6H2O,23 CuCl2, scan-
dium and ytterbium triflates). Variable amounts of pyranyl
ethers were also formed by cyclization of the prenyl group
on the adjacent C-7 hydroxyl.24 The formation of equimo-
lecular mixtures of 6- and 8-substituted flavones is surprising
since,atleastunderBrønstedacidcatalysis,theWessely-Moser
rearrangement is biased toward 6-substituted flavones, and
a prevalence of compounds from the cannflavin series was
therefore expected.25
Scheme 3
.
Synthesis of Cannflavin B (1d) and Isocannflavin B
(1e)
Taken together, our observations suggest that functional
symmetrization by loss of the ortho-protecting group (TB-
DMS for 12, pivaloyl for 14) is faster than the intramolecular
dehydration of the o-hydroxy-1,3-diaroylmethane system.26
Both 12 and 14 were completely enolized in solution,27 and
(18) Urgaonkar, S.; Shaw, J. T. J. Org. Chem. 2007, 72, 4582–4585.
(19) Wilhelm, H.; Wessjohan, L. A. Tetrahedron 2006, 62, 6961–6966.
(20) Alkoxy-substituted aroyl chlorides are poor acylating agents in
flavone synthesis (Patonay, T.; Molnar, D.; Muranyi, Z. Bull. Soc. Chim.
Fr. 1995, 32, 233–242), and the pivaloyl group was chosen to increase
the electrophilicity of the acyl carbon. No reaction took place when
pivaloylvanillic acid was reacted with 9 under Steglich conditions (DCC,
DMAP).
(21) The reaction takes place with a Baker-Venkataraman oxygen-to-
carbon acyl shift, and its course could be followed by TLC (see Supporting
Information). The best conditions for the reaction required the treatment
with 1 equiv of NaH to produce an O-acyl ester, next converted in situ into
the C-acylated product by treatment with 2 further equiv of NaH. The direct
addition of a large excess of NaH gave a lower yield, while LDA and
NaHMDS led to desilylated products.
The key C-prenyl disilylated intermediate 9 was next
pivaloylated to 10 and then chemoselectively ortho-desily-
(15) While the thermal instability of the MOM group, especially in the
presence of Lewis acids, has been observed previously (Khupse, R. S.;
Erhardt, P. W. J. Nat. Prod. 2007, 70, 1507–1509), that of the pivaloyl
group was unexpected and might be related to traces of triphenylphosphine
oxide from the Mitsunobu O-prenylation step. Nicolaou, K. C.; Lister, T.;
Denton, R. M.; Gelin, C. F. Angew. Chem., Int. Ed. 2007, 46, 7501–7505.
(16) Gester, S.; Metz, P.; Zierau, O.; Vollmer, G. Tetrahedron 2001,
57, 1015–1018.
(22) Due to a decreased basicity, aryl tert-butyldimethylsilyl ethers are
more stable to Lewis acids than their alkyl analogues: Collington, E. W.;
Finch, H.; Smith, I. J. Tetrahedron Lett. 1985, 26, 681–684.
(23) Hard Lewis acids such as BBr3 gave exclusively pyranyl derivatives:
Kumar, K. H.; Perumal, P. T. Tetrahedron 2007, 63, 9531–9535.
(24) Narender, T.; Reddy, K. P. Tetrahedron Lett. 2007, 48, 7628–7632.
(25) Kazuki, S.; Yoshio, H.; Taro, N. Heterocycles 2000, 53, 877–886.
(26) CuCl2 has been reported to dehydrate o-hydroxy-1,3-diaroyl-
methanes to flavones under microwave irradiation: Kabalka, G. W.;
Mereddy, A. R. Tetrahedron Lett. 2005, 46, 6315–6317.
(17) Williamson prenylation (prenyl bromide, K2CO3, acetone) gave a
complex mixture of desilyated products.
Org. Lett., Vol. 10, No. 11, 2008
2269

In conclusion, we have developed a regiodivergent entry
into ring A prenylflavones based on the synthesis of a pair
of acetophenones (9 and 11) complementary in terms of
further elaboration to flavones and on their cyclodehydration
by a milder version of the Robinson synthesis. Despite the
considerable efforts requested for its completion, the final
synthesis is operatively simple and has general application
for the preparation of 6- and 8-substituted flavones, circum-
venting the harsh conditions required for the Robinson
synthesis and making it possible to address the issue of
prenylation, as well as the introduction of other labile
functionalities, at the “easier” phloracetophenone stage.
Flavonoids and polyphenolics have an enormous biomedi-
cal and nutritional interest, but their chemistry is still
substantially undeveloped and highly dependent on protecting
groups. In carbohydrates, the “aliphatic” version of polyphe-
nolics in terms of hydroxy functionalities, protecting groups
have acquired a status that goes beyond the simple masking
of a specific hydroxyl and encompasses a critical strategic
role.31 Our regiodivergent synthesis of prenylflavonoids
demonstrates that these concepts can be successfully applied
in polyphenolic chemistry as well.
Scheme 4. Possible Mechanism for the Desilylation of the
Diaroylmethane 12 by Lewis Acids (R )
tert-Butyldimethylsilyl)
it is not unconceivable that the premature functional sym-
metrization takes place by intramolecular silyl or acyl
migration from the phenolic hydroxyl to the proximal (or
distal) enol oxygen (see Scheme 4 for silyl migration to the
proximal enolic hydroxyl).28 While deprotection is essentially
an irreversible step, cyclodehydration involves a series of
equilibria,27 and we reasoned that removal of water formed
in the reaction might be beneficial to prevent, or at least limit,
the premature ortho-deprotection of 12 and 14 during their
elaboration to flavones. Within the Lewis acids assayed,
CuCl2 was remarkable since, while leading to symmetriza-
tion, it nevertheless left the prenyl and the 7-silyl unaffected
in the course of the reaction, and we therefore focused on
this reagent to further explore the reaction.
Acknowledgment. This work was supported by Ministero
dell’Istruzione, dell’Universita` e della Ricerca (MIUR,
Roma), and by Universita` del Piemonte Orientale.
After considerable experimentation with various dehydrat-
ing agents, we eventually found that loss of functional
asymmetry could be greatly limited for 12 and totally
prevented for 14 by the addition of dehydrating agents such
as TMS-chloride. Under these conditions, 12 cleanly afforded
a reproducible 5:1 mixture of 13 and 15a, while 14 was
regioselectively converted to 15b.29 Despite the potential
detrimental effect caused by HCl generated from the reaction
of TMS-Cl with water, desilylation of the ortho-hydroxyl
was substantially delayed to the flavone level, while the
ortho-pivaloyl group remained unscathed also at the flavone
level. Global deprotection of 13 and 15b was then uneventful
and afforded cannflavin B (1d) and isocannflavin B (1e) in
overall 31 and 19% yield, respectively, from the prenylated
acetophenone 9.30
Supporting Information Available: Experimental details,
spectroscopic characterization, and H NMR spectra of all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
OL800665W
(29) TBDMS-chloride and TES-chloride were less effective, while TMS-
triflate gave 4′-pivaloylcyclocannflavin B (i) as the major reaction product.
Heterogeneous dehydrating agents (activated molecular sieves) were inef-
fective, as was trimethylorthoformate or azeotropic removal of water with
Dean-Stark distillation. The mechanism by which TMS-chloride postpones
desilylation of the ortho-hydroxyl to the flavone level might be more
complex than a simple water trapping and might involve amplification of
the oxyphilicity of the metal catalyst, activation of the “distal” carbonyl of
the diaroylmethanes 12 and 14, or a combination of both.
(27) Nagarathnam, D. Cushman, M. Tetrahedron 1991, 47, 5071–5076.
In general, enolization of 1,3-diaroylmethanes is fast in the presence of a
ortho-phenolic hydroxyl (see ref 16).
(28) o-Hydroxy-1,3-diaroylmethanes exist as an equilibrating mixture
of the dicarbonyl form, two enol forms, and one 2-hydroxyflavanone
structure, whose composition depends on the aryl substitution pattern:
Borbe´ly, J.; Szabo´, V.; Soha´r, P. Tetrahedron 1981, 37, 2307–2312.
Dehydration of the 2-hydroxyflavanone cyclic tautomer affords flavones:
Cunnigham, B. D. M.; Lowe, P. R.; Threadgill, M. D. J. Chem Soc., Perkin
Trans. 2 1989, 1275–1283.
(30) For the spectroscopic characterization of cannflavins, see: Choi,
Y. H.; Hazekamp, A.; Peltenburg-Looman, A. M. G.; Fre´de´rich, M.;
Erkelens, C.; Lefeber, A. W. M.; Verpoorte, R. Phytochem. Anal. 2004,
15, 345–354.
(31) For a discussion, see: Kocien´ski, P. J. Protecting Group, 3rd ed.;
Thieme: Stuttgard, 2003; pp 26-36.
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