Synthesis of skeletally diverse and stereochemically complex library templates derived from isosteviol and steviol

Article abstract of DOI:10.1021/ol400385w

We have applied a diversity-oriented approach for the synthesis of skeletally diverse and stereochemically complex templates for small-molecule library production by performing Beckmann rearrangement and Beckmann fragmentation reactions on the bicyclo[3.2.1]octane rings of steviol and isosteviol, aglycones derived from the diterpene natural product stevioside. The optimization of these two reaction pathways is presented along with the successful application of a photo-Beckmann rearrangement. This work also led to the discovery of cyano-Prins-type and Thorpe-Ziegler-type cyclization reactions.

Full text of DOI:10.1021/ol400385w

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1602–1605
Synthesis of Skeletally Diverse and
Stereochemically Complex Library
Templates Derived from Isosteviol and
Steviol
Oliver E. Hutt, Trinh L. Doan, and Gunda I. Georg*
Institute for Therapeutics Discovery and Development, Department of Medicinal
Chemistry, College of Pharmacy, University of Minnesota, 717 Delaware Street SE,
Minneapolis, Minnesota 55414, United States
georg@umn.edu
Received February 7, 2013
ABSTRACT
We have applied a diversity-oriented approach for the synthesis of skeletally diverse and stereochemically complex templates for small-molecule library
production by performing Beckmann rearrangement and Beckmann fragmentation reactions on the bicyclo[3.2.1]octane rings of steviol and isosteviol,
aglycones derived from the diterpene natural product stevioside. The optimization of these two reaction pathways is presented along with the successful
application of a photo-Beckmann rearrangement. This work also led to the discovery of cyano-Prins-type and ThorpeÀZiegler-type cyclization reactions.
Major issues associated with the development of high-
value information-rich small molecule libraries are achiev-
ing skeletal diversity, stereochemical complexity,1 and
mining areas of biologically relevant chemical space.2
Natural products provide a solid platform for the discov-
ery of biologically active small molecules.3 It has been
suggested that natural product-derived libraries should
provide high screening hit rates because natural products
have been evolutionarily molded by protein domains and
are therefore likely to engage in interactions with con-
served protein folds across protein families.4 To date, the
systematic exploration of many regions of natural product
chemical space has not been possible due to the scarcity of
accessible material. Steviol (1, Figure 1), however, is read-
ily available from the natural sweetener stevioside (5,
Scheme 1)5 and an attractive template because stevioside
(5) and its aglycones steviol (1) and isosteviol (6, Scheme 1)
have shown diverse pharmacological activities.6 Poten-
tially, this scaffold could also provide access to templates
representative of the large and diverse family of diterpenes
derived from the methylerythritol 4-phosphate pathway7
and subsequent metabolic processes. Representative diter-
penes from this family include gibberellic acid derivative
GA-13315 (2), oridonin (3), and cafestol (4) with antian-
giogenic,8 antitumor,9 and neuroprotective properties,10
(1) (a) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science2003, 302,
613. (b) Thomas, G. L.; Wyatt, E. E.; Spring, D. R. Curr. Opin. Drug
Discovery Dev. 2006, 9, 700. (c) Mao, S.; Probst, D.; Werner, S.; Chen, J.;
Xie, X.; Brummond, K. M. J. Comb. Chem 2008, 10, 235. (c) For a recent
related approach see: Huigens, R. W., III; Morrison, K. C.; Hicklin,
R. W.; Flood, T. A., Jr.; Richter, M. F.; Hergenrother, P. J. Nat. Chem.
2013, 5, 195.
(5) Hanson, J. R.; De Oliveira, B. H. Nat. Prod. Rep. 1993, 10, 301.
(6) Brahmachari, G.; Mandal, L. C.; Roy, R.; Mondal, S.;
Brahmachari, A. K. Arch. Pharm. Chem. Life Sci. 2011, 1, 5.
(7) Brandle, J. E.; Telmer, P. G. Phytochemistry 2007, 68, 1855.
(8) Zhang, Y.; Zhang, H.; Chen, J.; Zhao, H.; Zeng, X.; Zhang, H.;
Qing, C. Invest. New Drugs 2012, 30, 8.
(2) Feher, M.; Schmidt, J. M. J. Chem. Inf. Comput. Sci. 2003, 43,
218.
(3) Newman, D. J. J. Med. Chem. 2008, 51, 2589.
(4) Breinbauer, R.; Vetter, I. R.; Waldmann, H. Angew. Chem., Int.
Ed. 2002, 41, 2878.
(9) Zhou, G. B.; Kang, H.; Wang, L.; Gao, L.; Liu, P.; Xie, J.; Zhang,
F. X.; Weng, X. Q.; Shen, Z. X.; Chen, J.; Gu, L. J.; Yan, M.; Zhang,
D. E.; Chen, S. J.; Wang, Z. Y.; Chen, Z. Blood 2007, 109, 3441.
(10) Trinh, K.; Andrews, L.; Krause, J.; Hanak, T.; Lee, D.; Gelb,
M.; Pallanck, L. J. Neurosci. 2010, 30, 5525.
r
10.1021/ol400385w
Published on Web 03/26/2013
2013 American Chemical Society

respectively (Figure 1). These compounds have attracted
much attention from the synthetic organic chemistry com-
munity and therefore, a large amount of literature has been
produced over the last eight decades pertaining to the
synthesis11 and structural modification of stevioside (5)12
and structurally related diterpenes.13
Scheme 1. Access to Steviol (1) and Isosteviol (6)
Scheme 2. Beckmann Fragmentation and Rearrangement
Figure 1. Representative examples of diterpenes.
We decided to employ the Beckmann rearrangement for
ring expansion chemistry and the Beckmann fragmenta-
tion for ring cleavage reactions on the stevioside aglycones
steviol (1) and isosteviol (6) for efficient generation of
templates for library production.
Steviol (1) was obtained through a well-precedented
enzyme mediated hydrolysis of stevioside (5).14,15 The
D-ring isomer isosteviol (6) was obtained directly through
a modification of existing methods and proceeds via a
WagnerÀMeerwein rearrangement (Scheme 1) of steviol
(1).16 Initially, we sought to access diverse heterocyclic
intermediates through manipulation of the D-ring ketone
of isosteviol (6, Scheme 2).
Although the Beckmann rearrangement has previously
been reported17 regarding an analogous substrate (the
N-methyloxime), the lactam was sufficiently attractive
to warrant further investigation. Methylation of the car-
boxylic acid moiety of isosteviol (6) under standard con-
ditions delivered methyl ester 7. The ketone function of 7
was converted to the corresponding oxime 8 in 93% yield
on treatment with hydroxylamine and potassium acetate.
Reaction with thionyl chloride as reported17 then delivered
nitrile 9, the corresponding Beckmann fragmentation
product, in 65% yield and lactam 10 in 27% yield. The
Beckmann fragmentation is well precedented18 in systems
with a quaternary R-carbon. This pathway significantly
retarded the yield of lactam 10 if fresh thionyl chloride was
not used. Use of fresh thionyl chloride provided nitrile 9 in
11% yield and lactam 10 in 55% yield. A more robust two-
step procedure is outlined in Scheme 3. The conversion
of the oxime hydroxyl group in 8 to the mesylate followed
by treatment with acid in methanol exclusively led to the
desired lactam 10 in 87% yield. It is of interest that this
procedure appears to shut down the Beckmann fragmenta-
tion. We propose that this reaction proceeds via a tetrahedral
(11) (a) Cook, I. F.; Knox, J. R. Tetrahedron Lett. 1970, 4091. (b)
Mori, K.; Nakahara, Y.; Matsui, M. Tetrahedron Lett. 1970, 2411. (c)
Nakahara, Y.; Mori, K.; Matsui, M. Agric. Biol. Chem. 1971, 35, 918. (d)
Mori, K.; Nakahara, Y.; Matsui, M. Tetrahedron 1972, 28, 3217. (e)
Ziegler, F. E.; Kloek, J. A. Tetrahedron 1977, 33, 373. (f) Ogawa, T.;
Nozaki, M.; Matsui, M. Tetrahedron 1980, 36, 2641.
(12) (a) Coates, R. M.; Bertram, E. F. Tetrahedron Lett. 1968, 5145.
(b) Coates, R. M.; Bertram, E. F. J. Org. Chem. 1971, 36, 2625. (c)
Terauchi, T.; Asai, N.; Doko, T.; Taguchi, R.; Takenaka, O.; Sakurai,
H.; Yonaga, M.; Kimura, T.; Kajiwara, A.; Niidome, T.; Kume, T.;
Akaike, A.; Sugimoto, H. Bioorg. Med. Chem. 2007, 15, 7098.
(13) (a) Wang, F.-P.; Liang, X.-T. Alkaloids Chem. Biol. 2002, 59, 1.
(b) Mander, L. N. Nat. Prod. Rep. 2003, 20, 49. (c) Hanson, J. R. Nat.
Prod. Rep. 2007, 24, 1332.
(14) Stevioside can be obtained in kilogram quantities from several
vendors.
(15) Pezzuto, J. M.; Coompadre, C. M.; Swanson, S. M.;
Nanayakkara, N. P. D.; Kinghorn, A. D. Proc. Natl. Acad. Sci. U.S.
A. 1985, 82, 2478.
(16) Avent, A. G.; Hanson, J. R.; De Oliviera, B. H. Phytochemistry
1990, 29, 2712.
(17) Militsina, O. I.; Kovyljaeva, G. I.; Bakaleynik, G. A.; Strobykina,
I. Y.; Kataev, V. E.; Alfonsov, V. A.; Musin, R. Z.; Beskrovny, D. V.;
Litvinov, I. A. Mendeleev Commun. 2005, 27.
(18) Gawley, R. E. Org. React. 1988, 35, 1.
Org. Lett., Vol. 15, No. 7, 2013
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intermediate in a similar fashion to that described by White
et al., in which the less sterically crowded antistereoisomer
favors the migration of the bridgehead carbon in lactam
formation.19 Lactam 10 was subsequently alkylated with
methyl iodide and benzyl bromide to furnish compounds
12 and 13, respectively. Despite being relatively hindered, this
amide lends itself well to alkylation and should therefore
prove useful in the development of small-molecule libraries
of lactam derivatives.
Scheme 4. Formation of Lactam 16
Scheme 3. Optimized Beckmann Rearrangement of 11
Scheme 5. Optimized Beckmann Fragmentation of Isosteviol
Oxime 8
Next, we decided to access the regioisomeric lactam
through the photolysis of an oxaziridine (Scheme 4).20
Ketone 7 was converted toimines 14throughheating inthe
presence of benzylamine under dehydrating conditions.21 The
imines were formed in a 7:1 ratio (determined by 1HNMR) in
favor of the expected E-isomer vide infra. The imines 14 were
subsequently epoxidized to furnish the oxaziridines 15 in 85%
over two steps. Photolysis of the oxaziridines (254 nm, Hg
lamp) then delivered lactam 16 in 56% yield as well as the
regioisomer 13 in 7% yield. As with the Beckmann rearrange-
ment, where the bond that migrates is that which is anti to the
oxygen on nitrogen, the outcome of the photo-Beckmann is
also stereoelectronically defined. As a general rule, the bond
that migrates is the one anti to the lone pair on the nitrogen.22
Therefore, the isolation of the regioisomeric lactam 16 con-
firms the assignment of the E-imine 14 as the major isomer.
Having established synthetic routes to the N-alkylated
isomeric lactams 13 and 16, we recognized that nitrile 9 is
also an attractive template for library design. However, in
order to generate useful quantities of 9, the Beckmann
fragmentation pathway needed to be optimized (Scheme 5).
A similar fragmentation was recently reported by the
Coates group for a closely related substrate employing
TsCl in DMF as the reagent, but these reaction conditions
delivered a 2:1 mixture of the alkenes, which required a
difficult separation.23 Modification of reaction conditions
through conversion of the oxime hydroxyl group in8 to the
corresponding acetate followed by treatment with p-TsOH
in acetonitrile at 90 °C cleanly delivered nitriles 9 and 17
in 84% overall yield and in an 8:1 ratio of alkenes
(determinedby 1H NMR). Through a single crystallization
from dichloromethane and ethyl acetate, this mixture
could be enriched to 20:1 in favor of the Δ6-alkene.
Interestingly, treating oxime 8 with Ac2O, followed by
reaction with p-TsOH in benzene as the solvent at reflux
delivered a 2:0.2:1 ratio of nitriles 9/17 to lactam 10. This
suggests that the solvent plays an important role in the
stabilization of the intermediates leading to either the
lactam or nitrile. Attempts to drive the equilibrium to
further favor the Δ6-alkene (Scheme 5) unexpectedly led to
the formation of bicyclo[2.2.2]octane19(36%) and lactone
18 (37%). The former most likely proceeds through a
(19) White, J. D.; Hrncliar, P.; Stappenbeck, F. J. Org. Chem. 1999,
64, 7871.
(20) Judd, W. R.; Katz, C. E.; Aube, J. Sci. Synth. 2005, 21, 133.
(21) Al’fonsov, V. A.; Andreeva, O. V.; Bakaleinik, G. A.; Beskrovnyi,
D. V.; Gubaidullin, A. T.; Kataev, V. E.; Kovylyaeva, G. I.; Konovalov,
A. I.; Korochkina, M. G.; Litvinov, I. A.; Militsina, O. I.; Strobykina, I. Y.
Russ. J. Gen. Chem. 2003, 73, 1255.
(23) Roy, A.; Roberts, F. G.; Wilderman, P. R.; Zhou, K.; Peters,
R. J.; Coates, R. M. J. Am. Chem. Soc. 2007, 129, 12453.
(22) Aube, J. Chem. Soc. Rev. 1997, 26, 269.
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Org. Lett., Vol. 15, No. 7, 2013

Scheme 6. Beckmann Fragmentation of Steviol Derivative 21
Figure 2. Proposed mechanisms for the formation of 18, 19,
and 23.
optimization of the Beckmann rearrangement of isosteviol
to form lactam derivative 10 as the exclusive reaction
product. Lactam 10 provides a classical point for diversi-
fication viaN-alkylation. The regioisomeric lactams of type
16 can be obtained from ketone 7 as shown in Scheme 4 by
reaction with diverse amines. Alternatively, a library can be
prepared by removal of the N-benzyl group of 16, followed
by N-alkylation. Additionally, we demonstrated that the
Beckmann fragmentation of isosteviol- and steviol-derived
compounds form nitrile derivatives. The nitriles 9 and
22 will allow double functionalization via the ester and
nitrile functional groups. The formation of 19 via a cyano-
Prins-type cyclization and of 23 by a ThorpeÀZiegler-type
reaction have not been previously reported. These types of
reactions are underrepresented in the literature.
cyano-Prins-type cyclization, while the latter is derived
through hydration of 17 followed by cyclization (Figure 2).
After having established the chemistry of the isosteviol
system, we turned our attention to the steviol (1) scaffold
since it seemed reasonable that a similar fragmentation
would occur in this ring system (Scheme 6). Again, methy-
lation of the acid function under standard conditions
delivered the methyl ester (96%), which was subsequently
treated with Ac2O to provide acetate 20 (85%). The exo-
methylene group in 20 was then ozonized to deliver the
corresponding ketone in 67% yield. The ketone was con-
verted to the oxime 21 in 90% yield and then treated with
Ac2O and p-TsOH in acetonitrile at 90 °C to deliver the
expected nitrile 22 in 67% yield (Scheme 6). More vigorous
heating in toluene initiated a ThorpeÀZiegler-type cycliza-
tion delivering the bicyclo[2.2.2]octane 23.24 The forma-
tion of 23 proceeds presumably in an analogous fashion to
19 (Figure 2).
Acknowledgment. We gratefully acknowledge financial
support from the National Institutes of Health Grant No.
GM081267 and the University of Minnesota through the
Vince and McKnight Endowed Chairs.
In conclusion, we devised practical methods to access
a number of diverse chemotypes, possessing high stereo-
chemical complexity, and as single enantiomers from
stevioside, which is readily available in kilogram quanti-
ties. We have shown a different approach toward the
Supporting Information Available. Experimental de-
1
tails and copies of H and 13C NMR spectra for com-
pounds 6À10, 12, 13, 15, 16, and 18À23. This material
is available free of charge via the Internet at http://pubs.
acs.org
(24) Compound 23 has been prepared previously by a different route.
Mori, K.; Nakahara, Y.; Matsui, M. Tetrahedron 1972, 28, 3217.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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