De novo asymmetric syntheses of SL0101 and its analogues via a palladium-catalyzed glycosylation

Article abstract of DOI:10.1021/ol062076r

(Chemical Equation Presented) The enantioselective syntheses of naturally occurring kaempferol glycoside SL0101 (1a) and its analogues 1b-e, as well as their enantiomers, have been achieved in 7-10 steps. The routes rely upon a diastereoselective palladium-catalyzed glycosylation, ketone reduction, and dihydroxylation to introduce the rhamno-stereochemistry. The asymmetry of the sugar moiety of these kaempferol glycosides was derived from Noyori reduction of an acylfuran. An acetyl group shift from an axial (C-2) to equatorial position (C-3) under basic conditions was also described.

Full text of DOI:10.1021/ol062076r

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5149-5152
De Novo Asymmetric Syntheses of
SL0101 and Its Analogues via a
Palladium-Catalyzed Glycosylation
Mingde Shan and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
Received August 22, 2006
ABSTRACT
The enantioselective syntheses of naturally occurring kaempferol glycoside SL0101 (1a) and its analogues 1b−e, as well as their enantiomers,
have been achieved in 7−10 steps. The routes rely upon a diastereoselective palladium-catalyzed glycosylation, ketone reduction, and
dihydroxylation to introduce the rhamno-stereochemistry. The asymmetry of the sugar moiety of these kaempferol glycosides was derived
from Noyori reduction of an acylfuran. An acetyl group shift from an axial (C-2) to equatorial position (C-3) under basic conditions was also
described.
In an effort to find specific inhibitors of p90 Ribosomal S6
Kinase (RSK), Smith and Hecht screened an extensive collec-
tion of botanical extracts derived from rare plants.1 Using a
dual high-throughput screen they found only one extract that
inhibited the RSK2 isoform (RSK2) without inhibiting the
tyrosine kinase (FAK). The active extract was from a South
American dogbane plant named Forsteronia refracta. More
detailed bioactive fractionization revealed the active constitu-
ent to be a kaempferol glycoside, which was given the name
SL0101 (Figure 1).1 SL0101 (1a) is a member of a class of
acylated kaempferol L-rhamnosides that occur naturally with
various degrees of acylation (e.g., 1a-e).2 SL0101 sans
acetyl groups (1b) is also known as afzelin.2a The kaempferol
glycosides, like most flavonoids, have received a great deal
of attention because they are believed to induce many
positive biological effects.3
In addition to this unique activity, our interest in SL0101
(1a) was peaked by the report that it displayed activity some
(1) (a) Smith, J. A.; Poteet-Smith, C. E.; Xu, Y.; Errington, T. M.; Hecht,
S. M.; Lannigan, D. A. Cancer Res. 2005, 65, 1027-1034. (b) Xu, Y.;
Smith, J. A.; Lannigan, D. A.; Hecht, S. M. Bioorg. Med. Chem. 2006, 14,
3974-3977.
(2) For the isolation of 1a,d,e see ref 1b and for 1a,b, see: (a) Matthes,
H. W. D.; Luu, B.; Ourisson, G. Phytochemistry 1980, 19, 2643-2650.
For 1b, see: (b) Kaouadji, M. Phytochemistry 1990, 29, 2295-2297. For
1b and 1d, see: (c) Masuda, T.; Jitoe, A.; Kato, S.; Nakatani, N.
Phytochemistry 1991, 30, 2391-2392. For 1a and 1e, see: (d) Nakatani,
N.; Jitoe, A.; Masuda, T. Agric. Biol. Chem. 1991, 55, 455-460. For 1c,
see: (e) Usia, T.; Iwata, H.; Hiratsuka, A.; Watabe, T.; Kadota, S.; Tezuka,
Y. J. Nat. Prod. 2004, 67, 1079-1083. (f) For 1b, see: Deng, J.-Z.;
Marshall, R.; Jones, S. H.; Johnson, R. K.; Hecht, S. M. J. Nat. Prod. 2002,
65, 1930-1932.
Figure 1. Kaempferol glycoside SL0101 (1a) and its analogues
1b-e and their Rsk2 inhibitory activities.
10.1021/ol062076r CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/06/2006

150 times greater than that of the simple aglycon, kaempferol.
Similarly, we were intrigued by the importance of the specific
placement of acetyl groups on the L-rhamnose and its effect
on the SAR of SL0101 (Figure 1).4 As part of an effort to
elucidate the role of the sugar and acetyl portion of SL0101
to its activity, we decided to prepare both enantiomers of
SL0101 (1a) and its analogues 1b-e (Figure 1).
Not long after the isolation and structure elucidation of
SL0101 (1a), its first synthesis was reported by Professor
Hecht.4 The Hecht synthesis derived the absolute and relative
stereochemistry from rhamnose. In contrast, we were inter-
ested in the possibility of preparing all five members of this
class of kaempferol glycosides 1a-e via asymmetric cataly-
sis. This de novo approach would have the additional
advantage of preparing both the D- and L-enantiomers for
biological testing.
(OsO4/NMO)8 would install the manno-stereochemistry.9 The
selective introduction of the C-4 acetyl group should occur
by introducing an acylation reaction between the NaBH4
reduction and dihydroxylation. All that would remain would
be to differentiate the C-2 hydroxyl group from the C-3
hydroxyl group. For this, we planned to use a combination
of selective orthoester hydrolysis10 and acyl migration reac-
tions.11 Since pyranone 4 has been prepared in either enan-
tiomeric form,12 this procedure should be amenable to the
preparation of both enantiomers of 1a-e. Herein we describe
our successful efforts at the implementation of this strategy
to this class of kaempferol glycosides 1a-e, which is note-
worthy in that the various acetyl groups in 1a-e are installed
without any hydroxyl protecting groups on the sugar.
Recently we reported a diastereoselective palladium-cata-
lyzed glycosylation reaction that used alcohols as nucleo-
philes and pyranones such as 4 as glycosyl donors.5 We have
also found several post-glycosylation transforms, which sub-
sequently install the desired sugar stereochemistry.6 This
methodology also works well for other N-, O-nucleophiles,
such as 6-chloropurine/benzimidizole and phenol.7 In order
to produce this class of interesting compounds for activity
studies, we decided to apply this methodology toward the
syntheses of the kaempferol glycosides, SL0101 (1a) and
its analogues 1b-e. In addition to providing material for
biological study, this effort should also allow us study flavon-
3-ol as a nucleophile in the palladium-catalyzed glycosyla-
tion.
Scheme 2. Synthesis of Kaempferol Rhamnoside 1b
Scheme 1. Retrosynthetic Analysis of Kaempferol
Rhamnosides 1a-e
Our synthesis started with the known perbenzylated
kaempferol 3, which was synthesized from naringenin 6 in
three steps (Scheme 2).4 The glycosylation was carried out
with flavonol 3 and L-pyranone 4 under catalysis of 2.5 mol
(6) (a) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem.
1999, 64, 2982-2983. (b) Harris, J. M.; Keranen, M. D.; Nguyen, H.;
Young, V. G.; O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17-36.
(7) (a) Guo, H.; O’Doherty, G. A. Org. Lett. 2005, 7, 3921-3924. (b)
Guppi, S. R.; Zhou, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 293-296. (c)
Babu, R. S.; Guppi, S. R.; O’Doherty, G. A. Org. Lett. 2006, 8, 1605-1608.
(8) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973-1976.
Retrosynthetically, we envisioned that pyranone 2 could
be derived from a Pd(0)-catalyzed glycosylation between
flavonol 3 and pyranone 4 (Scheme 1). Subsequent applica-
tion of NaBH4 reduction and an Upjohn dihydroxylation
(3) (a) Muir, S. R.; Collins, G. J.; Robinson, S.; Hughes, S.; Bovy, A.;
Ric De Vos, C. H.; van Tunen, A. J.; Verhoeyen, M. E. Nat. Biotechnol.
2001, 19, 470-474. (b) Hertog, M. G. L.; Feskens, E. J. M.; Hollman, P.
C. H.; Katan, M. B.; Kromhout D. Lancet 1993, 342, 1007-1011.
(4) Maloney, D. J.; Hecht, S. M. Org. Lett. 2005, 7, 1097-1099.
(5) (a) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125,
12406-12407. (b) Babu, R. S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem.
Soc. 2004, 126, 3428-3429.
(9) According to carbohydrate nomenclature, rhamnose is 6-deoxy-
mannose.
(10) For the selective acylation of an axial alcohol, see ref 6 and (a)
King, J. F.; Allbutt, A. D. Can. J. Chem. 1970, 48, 1754-1769. (b) Lowary,
T. L.; Hindsgaul, O. Carbohydr. Res. 1994, 251, 33-67.
(11) (a) Doerschuk, A. P. J. Am. Chem. Soc. 1952, 74, 4202-4203. (b)
Pettit, G. R.; Cragg, G. M.; Suffness, M. J. Org. Chem. 1985, 50, 5060-5063.
5150
Org. Lett., Vol. 8, No. 22, 2006

% Pd2(dba)3‚CHCl3 and 10 mol % of PPh3 in CH2Cl2 at 0
°C, which afforded pyranone 2 in 85% yield with complete
R-selectivity (Scheme 2). Reduction of the enone 2 by
NaBH4 at -78 °C in CH2Cl2/MeOH resulted in allylic
alcohol 7 in 73% yield with excellent diastereoselectivity
(dr >20:1). The rhamno-stereochemistry in 8 was diaste-
reoselectively introduced upon exposure of 7 to the Upjohn
conditions (OsO4/NMO, 96%). Debenzylation of 8 using
Pearlman’s catalyst (10% Pd/C) in the presence of hydrogen
gave kaempferol rhamnoside 1b in 80% yield.
Scheme 4. Synthesis of Kaempferol Rhamnoside
4′′-Acetate 1d
In addition to the unacylated rhamno-sugar 1b, the
peracylated sugar 1c could also be easily prepared in two
steps from triol 8. Exhaustive acylation of the triol 8 with
the excess acetic anhydride in presence of pyridine and 10%
DMAP gave triacetate 9 in 86% yield (Scheme 3). Deben-
zylation of triacetate 9 by hydrogen using Pearlman’s catalyst
(10% Pd/C) again produced kaempferol rhamnoside triacetate
1c in 86% yield.
Scheme 3. Synthesis of Kaempferol Rhamnoside Triacetate 1c
Acylation of the C-2 axial hydroxyl group of diol 11 was
selectively introduced using orthoester chemistry in excellent
yield (99%).6 Exposure of diol 11 to trimethyl orthoacetate
in the presence of 10% p-TsOH in CH2Cl2 was followed by
hydrolysis with excess 90% HOAc/H2O (Scheme 5). Once
again, reductive debenzylation of 12 with hydrogen and 10%
Pd/C produced kaempferol rhamnoside 2′′,4′′-diacetate 1e
in 88% yield.
Scheme 5. Synthesis of Kaempferol Rhamnoside
2′′,4′′-Diacetate 1e
The selective installation of the C-4 acetyl group in 1d
was easily achieved without the need of additional protecting
groups from the previously described allylic alcohol 7
(Scheme 2). In this route (Scheme 4), the NaBH4 reduction
of enone 6 was followed by an acylation of the resulting
allylic alcohol with acetic anhydride in the presence of
pyridine and DMAP. This two-step procedure afforded
acetate 10 in 70% overall yield. Once again, dihydroxylation
using the Upjohn condition stereoselectively converted allylic
acetate 10 into the rhamno-diol 11 in 77% yield. Global
deprotection was accomplished under hydrogenolysis condi-
tions by exposure of diol 11 to 1 atm of H2 in the presence
of Pearlman’s catalyst (Pd/C), which furnished kaempferol
rhamnoside 4′′-acetate 1d in 87% yield.
(12) Pyranones such as 4 and its enantiomer ent-4 can be prepared in
three steps from achiral acylfurans such as 5 in either enantiomeric form
(D/L). The pyranone asymmetry is derived from a Noyori reduction; see
refs 5b, 7a, and Li, M.; Scott, J. G.; O’Doherty, G. A. Tetrahedron Lett.
2004, 45, 1005-1009.
In contrast to the selective C-2 acylation of the axial
alcohol in 11 (Scheme 5), our synthesis of SL0101 required
the selective acylation of the C-3 equatorial alcohol (Scheme
6). Unfortunately all of our attempts with Ac2O/Py at various
temperature only furnished mixtures of diacetate 13 and 12,
as well as triacetate 9 (∼1:1:1). We next turned to the
isomerization of the less stable axial C-2 acetate in 12 to
the more stable equatorial C-3 acetate in 13.
Org. Lett., Vol. 8, No. 22, 2006
5151

tography. Finally, debenzylation of 13 under the similar
condition as before produced SL0101 (1a) in 91% yield. Our
synthetic products 1a-e were physically and spectroscopi-
cally identical to the isolated natural materials in terms of
melting point, optical rotation, Rf, 1H NMR, 13C NMR, and
MS.2,4
Scheme 6. Synthesis of SL0101 (1a)
In conclusion, a divergent and highly enantio- and dias-
tereoselective procedure for the preparation of naturally
occurring SL0101 (1a) as well as four kaempferol rhamno-
side analogues 1b-e has been developed. This approach
provides either enantiopode of kaempferol glycosides 1a-e
without protecting any of the sugar hydroxyl groups. Our
approach relied upon a diastereoselective palladium(0)-
catalyzed glycosylation followed by a sequence of reduction/
dihydroxylation reaction, as well as acylation. An acetyl
group shift from an axial position to an equatorial position
provided an alternative way for selective acylation of the
equatorial hydroxyl group of a cis-diol in carbohydrate
chemistry. The evaluation of the biological activities of these
kaempferol glycosides is in progress.
Acknowledgment. We thank the NIH (GM63150) and
NSF (CHE-0415469) for their generous support of our
research program. Funding for a 600 MHz NMR and an
LTQ-FT Mass Spectrometer by the NSF-EPSCoR (#0314742)
is also gratefully acknowledged.
All attempts to shift the axial acetyl group of diacetate 12
to the equatorial position by using 10 mol % p-TsOH in CH2-
Cl2 at room temperature failed to give desired diacetate 13
(Scheme 6). In contrast, more promising results were seen
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
with basic conditions. For instance, analysis of crude H
NMR of dilute toluene solutions of 12 with 1 equiv of DBU
showed clean conversion to a 2:1 mixture of 13 and 12. In
practice good yields of 13 (62%) could be obtained along
with recovered starting material (34%) after SiO2 chroma-
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Org. Lett., Vol. 8, No. 22, 2006