(-)-isosteviol as a versatile ex-chiral-pool building block for organic chemistry

Article abstract of DOI:10.1002/ejoc.201300447

(-)-Isosteviol is readily available in large quantities by the acidic treatment of a common alternative sweetener. The two functional groups of (-)-isosteviol are presented on the same side of the ent-beyerane scaffold with a mutual C-C distance of about

Full text of DOI:10.1002/ejoc.201300447

MICROREVIEW
DOI: 10.1002/ejoc.201300447
(–)-Isosteviol as a Versatile Ex-Chiral-Pool Building Block for Organic
Chemistry
Christina Lohoelter,[a] Magdalena Weckbecker,[a] and Siegfried R. Waldvogel*[a]
Keywords: Natural products / Terpenoids / Medicinal chemistry / Organocatalysis / Supramolecular chemistry
(–)-Isosteviol is readily available in large quantities by the
acidic treatment of a common alternative sweetener. The two
functional groups of (–)-isosteviol are presented on the same
side of the ent-beyerane scaffold with a mutual C–C distance
of about 7 Å. Their unique concave arrangement experiences
a strong asymmetric environment due to an adjacent methyl
group. Consequently, this building block has found several
applications in supramolecular chemistry and organocatal-
ysis. These areas and the chemical modification of this scaf-
fold as well as its biological activity are surveyed.
1. Introduction
The diterpenoid glycoside stevioside (1; Scheme 1) has
been isolated as the major component from the leaves of
the stevia plant (stevia rebaudiana Bertoni) along with a
variety of minor glycosides that differ in the number and
nature of attached glucose moieties.[1] Stevioside has been
widely used as a noncaloric artificial sweetener in Asia and
South America due to its greatly enhanced sweetness (more
than 300 times sweeter) compared with “standard” cane
sugar sucrose.[2] Stevioside has recently come into focus
again, having been accepted as a sugar substitute in the EU
as well.[3] Apart from its sweetening properties, stevioside
and its derivatives exhibit a large number of cytotoxic and
biological activities, including antihyperglycemic, antihyper-
tensive, anti-inflammatory, antitumor, antidiarrheal, and
immunomodulatory effects.[4]
The treatment of stevioside (1) with strong acids, for ex-
ample, hydrobromic acid, cleaves the glucose fragments and
renders, by the formation of a nonclassical cation, the natu-
ral diterpene (–)-isosteviol (2; Scheme 1). The diterpene 2
can be easily prepared by this cleavage method on a very
large scale of up to several hundred grams (see the Support-
ing Information).[5,6]
Scheme 1. Formation of (–)-isosteviol (2).
as cytotoxic[9] and antibacterial effects.[10] During the past
few years, (–)-isosteviol has become a focus in organic
chemistry for two major reasons. First, a large number of
(–)-isosteviol derivatives have been shown to exhibit signifi-
cantly higher biological activities than (–)-isosteviol
itself,[10,11] leading to ongoing research for further new de-
rivatives of 2 with possible applications in medicinal chem-
istry. Secondly, (–)-isosteviol is a unique building block in
organic synthesis due to its quite rare structural features,[12]
the concave array of the carboxylic acid and keto functions,
which deviate from a parallel orientation by about 60°. This
leads to a lipophilic skeleton and hydrophilic moieties on
one side of the molecule (Figure 1), thereby representing an
almost Janus-type architecture.
(–)-Isosteviol (2), being a metabolite of stevioside, also
exhibits a wide range of biological activities, which might
be the reason why the EU has reluctantly accepted stevio-
side as an alternative sweetener. Compound 2 can induce
insulin regulation[7] and exhibits cardioprotective[8] as well
[a] Johannes Gutenberg University Mainz, Institute for Organic
Chemistry,
Duesbergweg 10–14, 55128 Mainz, Germany
Fax: +49-6131-39-26777
E-mail: waldvogel@uni-mainz.de
Homepage: http://www.chemie.uni-mainz.de/OC/AK-
Waldvogel/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300447.
Figure 1. Unique structural features of (–)-isosteviol (2).
Eur. J. Org. Chem. 2013, 5539–5554
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5539

C. Lohoelter, M. Weckbecker, S. R. Waldvogel
MICROREVIEW
analyses, the structural confirmation by NMR spectro-
scopic data in most cases being less reliable because their
signals and/or coupling constants have not been assigned.
2. Chemical Transformations
Because of the hydrocarbon nature of most parts of the
(–)-isosteviol architecture, the standard repertoire of or-
ganic chemistry allows transformations at a limited number
of positions. Thus, the 15-, 16-, and 19-positions (Figure 2)
are prone to chemical conversion.
2.1. D-Ring Modifications
The five-membered ring of (–)-isosteviol, which contains
the keto function, is defined as ring D of the ent-beyerane
skeleton. Because this keto group is not sterically congested
and is the most reactive moiety in the molecule, many con-
versions of (–)-isosteviol target this part of the molecule.
Starting from (–)-isosteviol itself (Scheme 2, R = H) or its
esters 3 or 4 (R = Et, Me), variously functionalized deriva-
tives are directly accessible.
Figure 2. ent-Beyerane skeleton of (–)-isosteviol (2).
Stereoselective reduction of the keto function of 2 or 3
However, in spite of the limited number of reactive posi- with sodium borohydride in ethanol yields the correspond-
tions in (–)-isosteviol, a variety of methods can be employed ing alcohols 5, with the hydroxy function pointing down-
to synthesize a large number of derivatives. The initial driv- wards to give the (16R)-configured product;[10,13] the con-
ing force for the synthesis of most of the following (–)-iso- figuration was elucidated by X-ray analysis.[11] The stereose-
steviol derivatives (unless stated otherwise) was the possible lectivity can be rationalized by the unique three-dimen-
application of these substrates in medicinal chemistry. Thus, sional architecture of isosteviol. Attack of the hydride takes
an enormous number of the modified structures presented place from the convex side of the molecule due to increased
herein have been tested for their cytotoxic activities and bio- steric demand by the methyl group (at the 20-position). This
logical properties. In this review, individual transformations leads to the depicted (R) configuration.[11]
are grouped into reactions occurring at specific rings of the
Bromination at the α-position relative to the carbonyl of
ent-beyerane skeleton. The stereoselectivities of these trans- 3 can be achieved by treatment with an excess of bromo-
formations have in several cases been proven by X-ray ethane/DMSO under basic conditions.[14] The depicted
Christina Lohoelter was born in Arnsberg, Germany in 1984. She studied chemistry at the Rheinische Friedrich Wilhelms
University of Bonn and the University of Cardiff (4 month research internship under the supervision of Prof. T. Wirth on
hypervalent iodine chemistry). She obtained her diploma at the University of Bonn under the direction of Siegfried R.
Waldvogel in 2008. Since 2009 she has been working in the Waldvogel group on her Ph. D. thesis in the field of supramolec-
ular structures based on (–)-isosteviol. She began her studies at the University of Bonn and moved together with the
Waldvogel laboratory to the University of Mainz in August 2010.
Magdalena Weckbecker was born in Koblenz, Germany in 1988. She studied chemistry at the Johannes Gutenberg Univer-
sity of Mainz, where she obtained her diploma in 2012 under the direction of Siegfried R. Waldvogel. Since autumn 2012
she has been working on her Ph. D. thesis in the field of supramolecular structures and the resolution of menthylamine.
Siegfried R. Waldvogel was born in Konstanz, Germany in 1969. He studied chemistry at the University of Konstanz,
where he obtained his diploma under the direction of Wolfgang Pfleiderer in 1994. He completed his doctoral degree with
Manfred T. Reetz at the Max Planck Institute of Coal Research in Mülheim in 1996. After a postdoctoral year with
Julius Rebek, Jr. at The Scripps Research Institute, La Jolla, California, in 1998 he moved to the Westfälische Wilhelms
University, where he initiated his independet research programm. In October 2004 he was appointed as associate professor
at the Kekulé Institute of the University of Bonn and since 2006 he has been an external faculty member of the laser
center at the Technical University in Clausthal. In 2010 he was appointed as full professor of Organic Chemistry at the
Johannes Gutenberg University of Mainz. His research interests cover the supramolecular chemistry of C3-symmetric
receptor structures and the oxidative treatment of aryls involving molybdenum(V) chloride or electrochemical methods.
He has received the following awards (selection): German Scholarship Foundation (1990–1994), the Kekulé fellowship
(1995–1996), a NATO stipend by the DAAD (1997–1998), the Liebig fellowship (1998–2000), Bennigsen-Foerder Award
of the State North Rhine Westfalia (2001), stipend of the Otto Röhm Stiftung (2001), Hellmut Bredereck Award of the
GDCh (2003), the Up-and-coming Young Scientist Award of the Förderkreis for the Westfälische Wilhelms University
(2003), Inventors Award “Patente Erfinder” of the state of North Rhine Westphalia (2008), and the Nicolaus August
Otto Award of the city of Cologne (2008).
5540
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5539–5554

(–)-Isosteviol as a Building Block for Organic Chemistry
can be formed from the corresponding hydraz-
ides. Thus, reaction of 2 or 4 with pyridinecarbonylhydraz-
ides and pTsCl in methanol provides the corresponding
hydrazones in good-to-excellent yields.[23,24] Furthermore,
the reaction of 2 with benzylamine under solvent-free con-
ditions gives access to imine derivative 11 in moderate
yields.[25]
Most of the derivatives of (–)-isosteviol depicted in
Scheme 2 serve as substrates for subsequent modifications.
Oxime derivatives 9 (Scheme 3, R = H, Et) can be re-
ductively converted into the amines 12a by employing
nickel metal as catalyst in THF under hydrogen.[14] Interest-
ingly, when the reaction takes place in ethanol instead of
THF, ethylamine 12b is formed as the major product. Alter-
natively, amines 12a can be obtained when formamides 13
(R = H, Me) are heated at reflux under basic conditions.[26]
Compound 13 itself is formed by heating (–)-isosteviol or
its methyl ester with excess formamide in formic acid.
Amine 12a (R = H) can subsequently be transformed into
Schiff base derivative 14 by the reaction of the amine moi-
ety with the appropriate benzaldehyde under basic condi-
tions. A variety of substituents on the salicylaldehyde com-
ponent are compatible, including a nitro or tert-butyl group
at the para position, respectively.[26] Although the individual
reports do not discuss it in detail, the stereocenter at the
16-position is not formed with good stereoselectivity, but
usually as a mixture of diastereomers that are difficult to
separate.
Scheme 2. Transformations of (–)-isosteviol (2). Reagents and con-
ditions: a) NaBH4, EtOH, 0 °C, 1 h, 92% (R = H)/96% (R = Et)/
96% (from 6a); b) X = Br: EtBr, DMSO, KOH, 80 °C, 3 h, 96%
(R = Et); X = Cl: SO2Cl2, CHCl3, 60 °C, 30 h, 97% (R = H);
c) SeO2, xylene, 145 °C, 2 d, 80% (R = H)/85% (R = Me)/Ac2O,
SeO2, reflux, 6 h, 83% (R = Et); d) HCHO, NaOH (R = H)/NaOEt
(R = Et), EtOH, 60 °C, 1 h, 95% (R = H)/3 h, 90% (R = Et); e) RЈ
= OH: HONH3Cl, NaHCO3, EtOH, 60 °C, 2 h, 90% (R = H)/95%
(R = Et); RЈ = NHCOPyridine: Pyr-CONHNH2, pTsCl, MeOH,
6 h, 60–85%; RЈ = CH2Ph: PhCH2NH2, 4 h, 95 °C, 40% (R = H).
stereochemistry is based on analogous transformations.[15]
Surprisingly, the reduction of brominated substrate 6a with
sodium borohydride again leads to the formation of de-
brominated alcohol 5.[14] Alternatively, bromination can be
accomplished by employing the standard mixtures of Br2/
AcOH or Br2/HBr, yielding the desired product in quantita-
tive or 80% yield, respectively.[16] The corresponding chlor-
inated derivative 6b can be obtained in 97% yield by treat-
ing (–)-isosteviol (2) with sulfuryl chloride in chloroform.
The stereochemistry of these conversions was verified by
crystallographic analyses.
The introduction of a second keto function adjacent to
the existing one can be achieved by Riley oxidation[17] of
(–)-isosteviol or its methyl[18–20] or ethyl ester[21] by using
selenium dioxide as oxidant (Scheme 2). The corresponding
diketones 7 are of bright orange color. Diol derivative 8
(15R,16R) can be synthesized by a one-pot Tollens reaction
(“one-pot aldol Cannizzaro reaction”) by adding formalde-
hyde to a basic mixture of 2 or 3 in ethanol.[10,11,14] To avoid
hydrolysis of the ester moiety, sodium ethoxide instead of
sodium hydroxide was used when using the (–)-isosteviol
ethyl ester.[22]
Scheme 3. Synthesis of Schiff base derivatives at the 16-position.
Reagents and conditions: a) RЈ = H: Ni, H2, THF, 40 °C, 2 h, 82%
(R = H)/88% (R = Et); RЈ = Et: Ni, H2, EtOH, 40 °C, 2 h, 86%
(R = Et); b) HCONH2, HCO2H (90%), 18 h, 170 °C, 90% (R = H)/
6 h, 190 °C, 51% (R = Me); c) NaOMe, MeOH, 3,5-di-tert-butyl-2-
hydroxybenzaldehyde, 6 h, 20 °C, 60% (R = H).
The keto moieties in 2–4 can also be transformed into
various nitrogen-based functionalities (Scheme 2). The cor-
responding E-oximes 9 can be obtained in very good yields
by the reaction of 2 or 3 with hydroxylamine hydrochlor-
A shift in the keto function in the methyl ester 4 of iso-
ide.[14] Hydrazone derivatives 10, like the pyridinecarbonyl- steviol from the 16- to the 15-position was first reported by
substituted compounds with the nitrogen atom located at Waldvogel and co-workers in 2008.[18] As described above
all possible positions in the pyridine ring (RЈ = NHCOPyr), (Scheme 2), Riley oxidation[17] of the (–)-isosteviol methyl
Eur. J. Org. Chem. 2013, 5539–5554
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5541

C. Lohoelter, M. Weckbecker, S. R. Waldvogel
MICROREVIEW
ester renders diketo derivative 7a (Scheme 4). Subsequent
conversion with hydrazine hydrate or p-tosyl hydrazine se-
lectively yields the corresponding derivatives 15a and 15b
with the newly introduced diazene moiety located at the
sterically less hindered 16-position.
Scheme 5. Two possible pathways for the synthesis of 19.
Compound 5 is converted into numerous aromatic esters
21 upon prior activation of the appropriately substituted
benzoic acid with DCC/DMAP and reaction with 5 (R =
Me).[29] Acetates 22 (R = H, Me) can be obtained by the
reaction of 5 with excess acetic anhydride in pyridine.[30]
Scheme 4. Shift of the keto function in (–)-isosteviol and subse-
quent insertive esterification.
Wolff–Kishner reduction of 15a did not lead to the for- Mannosylation following the Schmidt imidate protocol
mation of the desired product 16. Therefore, the more reac- yields glycoside 23.[31] Derivative 5 (R = Et) can also be
tive hydrazone 15b was prepared and subjected to re- transformed into acrylates 24a and 24b (Scheme 6). Upon
duction. Thus, 16 was obtained in a yield of 68% by using DCC/DMAP activation of 1 equivalent of acrylic acid, re-
cyanoborohydride as the reducing agent in the presence of action with 5 leads to the formation of 24a in a yield of
p-toluenesulfonic acid in a mixture of DMF and sul- 85%, whereas the application of 2 equivalents of acrylic
folane.[27] With the aim of synthesizing novel building acid leads to the formation of 24b in a yield of 75%.[10,11,14]
blocks for the construction of optically active triphenylene
Diol 8 exhibits two hydroxy groups in close vicinity, de-
ketals, 16 was then subjected to ketalization with catechol. fined stereochemistry and a sterically congested environ-
However, it turns out that steric hindrance in the vicinity ment. Consequently, 8 [obtained in a one-pot reaction from
of the keto function at the 15-position prevents the ketali- (–)-isosteviol, Scheme 2] is a versatile and attractive precur-
zation reaction. Instead, an unprecedented insertive esterifi- sor for subsequent functionalization (Scheme 7).
cation occurred, leading to the formation of the guaiacol
Reaction with nitric and sulfuric acid in dichloromethane
ester 17.[18]
yields the dinitrate 25 in 80% yield.[10,11] Treatment of 8
Oxidation of the diketo derivative 7b under Baeyer– with 1 equivalent of nicotinoyl chloride and sodium car-
Villiger conditions was carried out by Zhang and co- bonate[10] or triethylamine[11] leads to the ester 26 in a yield
workers.[21] The corresponding ring-expanded anhydride 18 of 81% for both reactions. Likewise, with 2 equivalents of
(Scheme 5) was obtained in almost quantitative yield. Sub- nicotinoyl chloride, the corresponding twice-esterified prod-
sequent hydrolysis renders the monoprotected tricarboxylic uct can be obtained in a yield of 88%. α-Methylene ketone
acid 19 in 90% yield.
27 can be synthesized through a series of transformations
Alternatively, 19 can be obtained by the intermediate for- (Scheme 7).[14] First, the primary hydroxy function is re-
mation of the oxime 20 and subsequent Beckmann frag- gioselectively acylated with acetyl chloride. Subsequently,
mentation of the ketoxime, induced by p-toluenesulfonic the secondary hydroxy function is oxidized to the corre-
acid. The corresponding nitrile was isolated from this mix- sponding ketone with pyridinium dichromate (PDC). In the
ture. Acidic hydrolysis of the cyano group led to the forma- last step, reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene
tion of dicarboxylic acid 19. Upon saponification of the (DBU) in pyridine under basic conditions gives product 27
ester moiety, molecules bearing three carboxylic acid func- in a β-elimination reaction. The oxidation of the secondary
tions in a concave arrangement and in close vicinity to each hydroxy moiety of 8 can be carried out even in the presence
other might be accessible. Substrates with such a substitu- of the nonprotected primary hydroxy moiety when using
tion pattern might then find application as surface-active pyridinium chlorochromate (PCC) as oxidant.[14] The tosyl-
agents for possible reactions at phase boundaries. All the ation of 8 under standard conditions leads to the formation
acid functions are oriented almost in parallel and represent of primary tosylated alcohol 28 (Scheme 7). Treatment of
a chiral alternative to Kemp’s triacid.[28]
28 with sodium hydroxide results in Grob fragmentation,
A series of subsequent modifications can be readily made yielding ring-opened product 29 in an excellent yield of
to the alcohol derivative 5 of (–)-isosteviol (Scheme 6). 96%. The structural features were confirmed by X-ray crys-
5542
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5539–5554

(–)-Isosteviol as a Building Block for Organic Chemistry
(Scheme 8).[10,11] Oxidation of the aldehyde moiety of 29
with Jones’ reagent (CrO3/8 n H2SO4 in acetone) gives carb-
oxylic acid 30, which can be cyclized to form δ-lactone 31
on treatment with BF3·OEt2 in dichloromethane with the
newly formed methyl moiety pointing upwards (β-orienta-
tion). The reduction of 29 with sodium borohydride in eth-
anol renders alcohol 32. This substrate can also be cyclized
under the same reaction conditions as applied to the carb-
oxylic acid 30 to give the corresponding tetrahydropyran
33.
Scheme 6. Tranformations of alcohol 5. Reagents and conditions:
a) R = Me: DCC, DMAP, appropriately substituted benzoic acid,
dioxane, reflux, 1 h, 68–72%; b) Ac2O, pyridine, room temp., 2 d,
82% (R = H)/73% (R = Me); c) 2,3,4,6-tetra-O-benzyl-α-d-manno-
pyranosyl trichloroacetamidate, BF3·OEt2, 68% (R = Me); d) R =
Et: DCC/DMAP, CH2Cl2, 1 equiv. acrylic acid, room temp., 12 h,
85% (24a)/2 equiv. acrylic acid, room temp., 16 h, 75% (24b).
Scheme 8. Transformations of 29. Reagents and conditions:
a) Jones’ reagent (8 n), acetone, 2 h, 0 °C, 90%; b) NaBH4, EtOH,
10 min, 0 °C, 96%; c) mCPBA, CH2Cl2, 5 h, 0 °C, 78%; d) MeOH,
NaOH, H2O2, 4 h, 65 °C, 75%; e) NaIO4, NaBr, AcOH, 3 h, 90 °C,
84%; f) R = OH: HONH3Cl, NaHCO3, EtOH, 2 h, 60 °C, 97%/R
= NHPh: EtOH, PhNHNH2, 3 h, 10 °C, 95%/R = Ph: aniline,
CH2Cl2, 3 h, 40 °C, 84%; g) BF3·OEt2, CH2Cl2, reflux, 30 h, 74%
(for 31), 75% (for 33); h) pTsCl, pyridine, room temp., 12 h, 85%;
i) NaN3, DMF, 80 °C, 3 h, 80%; j) PPh3, H2O, 65 °C, 3 h, 85%.
Tosylation of the alcohol moiety of 32 leads to azide for-
mation and subsequent reduction of the azide moiety gives
the amine analogue 34.[10,11] Despite the neopentyl nature
of the products, the yields seem to be remarkably good.
Epoxidation of the double bond in 32 with mCPBA leads
to the intermediate epoxide, which undergoes cyclization to
give hydroxymethyl derivative 35. Baeyer–Villiger oxidation
of 29 with hydrogen peroxide under basic conditions gives
an intermediate formate. Subsequent hydrolysis or decarb-
onylation leads to alcohol 36 (Scheme 8).[11] Moreover, the
Scheme 7. Tranformations of diol 8. Reagents and conditions:
a) HNO3/H2SO4, CH2Cl2, 3 h, room temp., 80%; b) 1 equiv. nicoti-
noyl chloride, Na2CO3, CHCl3, 1 h, 60 °C, 81%; c) i. MeCOCl,
NEt3, toluene, 2 h, room temp., 96%; ii. PDC, CH2Cl2, 3 h, room
temp., 91%; iii. DBU, pyridine, 6 h, 80 °C, 85%; d) pTsCl, pyridine,
18 h, room temp., 75%; e) NaOH, CH3CN, 3 h, room temp., 96%.
tallographic analysis.[11] Aldehyde 29 itself acts as a versatile double bond in 29 can be dihydroxylated with sodium per-
starting material for a series of chemical transformations iodate and the intermediate diol then is able to undergo
Eur. J. Org. Chem. 2013, 5539–5554
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5543

C. Lohoelter, M. Weckbecker, S. R. Waldvogel
MICROREVIEW
ring closure.[10] Acetal 37 is thus obtained in a yield of 84%;
the relative configuration was confirmed by X-ray diffrac-
tion analysis. The oxime derivative 38a can be synthesized
in analogy to (–)-isosteviol by employing hydroxylamine hy-
drochloride. Upon slight heating in sulfuric acid, dehy-
dration occurs to yield the corresponding nitrile derivative.
Aromatic hydrazones 38b can be accessed by converting al-
dehyde 29 using the appropriate aromatic hydrazine sub-
strates. Thus, phenylhydrazine as well as 4-nitrophenyl-
hydrazine and 2,4-dinitrophenylhydrazine have been em-
ployed to give the corresponding hydrazones in yields of 95,
85, and 81%, respectively.[10] Imine 38c can be obtained by
treating 29 with aniline (or derivatives thereof). Reduction
with sodium borohydride also results in the formation of
the appropriate secondary amine.[10] Information about the
newly formed stereochemistry was not provided.
Scheme 10. Pyrazoles and isoxazolidines derived from (–)-isoste-
viol. Reagents and conditions: a) BF3·OEt2, toluene, 2 h, 118 °C;
b) MeI, NaH, DMF, 50 °C, 2 h, 85%.
2.2. Heterocyclic Derivatives
The stereochemical features of 41a were confirmed by
Several heterocyclic compounds can be synthesized from
the isosteviol derivatives described above. Starting from
(–)-isosteviol (2; R = H) or its ethyl ester 3 (R = Et), indoles
39 can be synthesized (Scheme 9).[10] Condensation with
phenylhydrazine leads to the formation of the hydrazone
derivative, which directly undergoes a Fischer indole reac-
tion to yield 39.
NOESY experiments.[10,11]
2.3. Biological Profile of the Presented Compounds
A large number of the derivatives described so far were
tested for their biological activities. Table 1 displays a selec-
tion of those compounds that exhibit enhanced biological
activity. The biological activities evaluated included the in-
hibition of α-glucosidase,[14] M. tuberculosis growth[23,24] as
well as seed germination and root elongation.[29] Further-
more, the cytotoxic activity against B16-F10 melanoma
cells,[11] staphylococcus aureus and bacillus subtilis,[10] were
also studied.
Several structure–activity relationships can be observed
when analyzing these results. First, derivatives displaying
one or more hydroxy moieties exhibit much higher activities
than (–)-isosteviol itself. The activity increases with the
number of hydroxy groups. This might be attributed to bet-
ter bioavailability. Secondly, it was found that the carboxylic
acid derivatives show lower bioactivity than the corre-
sponding esters. Thirdly, the introduction of amine, oxime,
or heterocyclic moieties into the (–)-isosteviol architecture
further enhances their cytotoxic activities. In addition to the
substrates listed below with enhanced biological activities, a
huge number of other (–)-isosteviol derivatives show only
moderate biological activities upon screening for their cyto-
toxic potential.[10,14]
Scheme 9. Indoles derived from (–)-isosteviol.
BF3·OEt2-induced cyclization between the hydrazone
moiety and the vinyl group in 38b (Scheme 10, Ar = Ph)
renders the aromatic pyrazole derivative 40a. Interestingly,
when subjecting the analogous p-nitrophenyl hydrazone (Ar
= p-NO2C6H5) to the same reaction conditions, the 4,5-di-
hydro-1H-pyrazole 40b was obtained. However, treatment
of the 2,4-dinitrophenyl hydrazone did not lead to any cycli-
zation product as the two electron-withdrawing groups pre-
vent Lewis-acid-catalyzed cycloaddition. It was found in-
stead that treatment with BF3·OEt2 leads to reduction of
the C=C double bond in 38b to give a minimum yield of
84%.[11]
A mechanistic rationale for the hydrogenation of the
vinyl moiety is not given and difficult to comprehend.
Treatment of the analogous oxime 38a (Scheme 10) with
2.4. Reactions at the Carboxylic Acid
Aside from standard esterification reactions, which can
BF3·OEt2 also leads to a 1,3-dipolar cyclized product, be applied to any carboxylic acid, the number of reported
which originates from the tautomeric nitrone. Thus, isox- possible modifications at the 19-position of (–)-isosteviol is
azolidine 41a was obtained in excellent yield. This deriva- relatively limited. Reduction of the carboxylic acid and, at
tive can also be modified at the nitrogen atom. Reaction the same time, the keto moiety can be carried out with lith-
with, for example, iodomethane and NaH in DMF renders ium aluminium hydride.[32] Various amino acid amides 42a–
methylated product 41b in a quite attractive yield of 85%. 42e (Figure 3) of (–)-isosteviol were synthesized upon DCC
5544
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5539–5554

(–)-Isosteviol as a Building Block for Organic Chemistry
Table 1. (–)-Isosteviol derivatives exhibiting enhanced biological ac- 43 and subsequent reaction with sodium azide renders the
tivities.
acyl azide derivative 44. Upon heating in benzene at reflux,
Curtius rearrangement occurs to give the intermediate iso-
cyanate. Amine 45 can then be obtained directly as the hy-
drochloride from the isocyanate by acid hydrolysis.[26] Com-
pound 45 can function as the starting compound for the
synthesis of a variety of Schiff bases. Reaction of the amine
with appropriately substituted aldehydes leads to the forma-
tion of derivatives 46a–46e and 47. Despite the steric de-
mand of the primary amine 45, the yields of the imines
are astonishingly good. The potential applications of these
Schiff bases as ligands for metal complex catalysis could not
be realized, however, due to the formation of insufficient
quantities of complexes with, for example, vanadium acetyl-
acetonate.[26]
Biological activity
Inhibition activity
5
8
α-Glucosidase
IC50 = 132.1 μm (R = Et)
IC50 = 156.3 μm (R = H)
B16-F10 melanoma cells IC50 = 58 μm (R = Et)
α-Glucosidase
IC50 = 86.2 μm (R = Et)
IC50 = 148.6 μm (R = H)
B16-F10 melanoma cells IC50 = 68 μm (R = Et)
Staphylococcus aureus
α-Glucosidase
66% (R = Et)[a]
9
IC50 = 88.9 μm (R = Et)
IC50 = 92.1 μm (R = H)
MIC = 10–20 μg/mL[b]
IC50 = 91.2 μm (R = Et)
IC50 Ն 200 μm (R = H)
IC50 = 113.6 μm (R = Et)
43–69%[b]
10
12a
M. tuberculosis
α-Glucosidase
12b
21a, 21b, 21c
21b, 21c, 21d
24a
24b
25
α-Glucosidase
Seed germination
Root elongation
Staphylococcus aureus
Staphylococcus aureus
Bacillus subtilis
44–78%[c]
84% (R = Et)[a]
77% (R = Et)[a]
MIC = 12.5 μg/mL[d]
75%[a]
Staphylococcus aureus
26
B16-F10 melanoma cells IC50 = 25 μm
Bacillus subtilis
Staphylococcus aureus
Bacillus subtilis
MIC = 12.5 μg/mL[d]
32%[a]
30
32
MIC = 12.5 μg/mL[d]
Staphylococcus aureus
63%[a]
B16-F10 melanoma cells IC50 = 24 μm
Bacillus subtilis
Staphylococcus aureus
Bacillus subtilis
MIC = 6.25 μg/mL[d]
59%[a]
35
MIC = 6.25 μg/mL[d]
71%[a]
Staphylococcus aureus
36
B16-F10 melanoma cells IC50 = 26 μm
Bacillus subtilis
MIC = 12.5 μg/mL[d]
38a
B16-F10 melanoma cells IC50 = 27.5 μm
Bacillus subtilis
Staphylococcus aureus
α-Glucosidase
MIC = 1.56 μg/mL[d]
40%[a]
39
IC50 = 68.2 μm (R = Et)
IC50 = 83.2 μm (R = H)
40a
40b
41a
B16-F10 melanoma cells IC50 = 19 μm
B16-F10 melanoma cells IC50 = 21 μm
B16-F10 melanoma cells IC50 = 15 μm
[a] Inhibition [%] determined at a concentration of 100 μg/mL of
the compound. [b] Inhibition [%] of seed germination. [c] Inhibition
[%] of root elongation. [d] MIC = minimum inhibition concentra-
tion.
activation and coupling with the corresponding amino acid
methyl esters,[29] some of which show inhibitory effects on
seed germination or root elongation.
Scheme 11. Formation of the amine of (–)-isosteviol and conver-
sion to Schiff base derivatives. Reagents and conditions: a) NaN3,
acetone, 15 min, room temp., 70%; b) 1. benzene, reflux, 6 h, 86%;
2. benzene, conc. HCl, 6 h, 55%; c) ArCHO, benzene, 2 h, reflux
83–93%; d) pyridine-2-carbaldehyde, benzene, 1 h, reflux, 74%.
By employing a similar reaction procedure to that in
Scheme 11, the amine 51 of the (–)-isosteviol catechol ketal
was synthesized by Waldvogel and co-workers in the course
of their studies directed towards the construction of tri-
phenylene ketals (Scheme 12).[35] As a result of the high
steric demand surrounding the ester moiety of catechol
ketal 48, it was first demethylated by using sodium cyanide
Figure 3. Amino acids 42a–42e modified with (–)-isosteviol.
In a Curtius-type rearrangement, the carboxylic acid to provide carboxylic acid 49. After activation of the carb-
moiety of 2 can be stereospecifically converted into the cor- oxylic acid by using VilsmeyerЈs reagent, the corresponding
responding amine 45 (Scheme 11).[26] Activation of the acid acyl azide was formed upon reaction with sodium azide.
with thionyl chloride[33] or phosphorus trichloride[34] to give Direct activation by using azide transfer reagents[36,37] like
Eur. J. Org. Chem. 2013, 5539–5554
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5545

C. Lohoelter, M. Weckbecker, S. R. Waldvogel
MICROREVIEW
diphenylphosphoryl azide (DPPA)[38] did not give sufficient
conversions because the environment of the carboxylic acid
is sterically too congested.
Scheme 12. Formation of the amine 51 of the (–)-isosteviol catechol
ketal. Reagents and conditions: a) NaCN, DMF, reflux, 24 h, 88%;
b) 1. oxalyl chloride, DMF, CH2Cl2; 2. pyridine, THF, NaN3, room
temp., 16 h; 3. toluene, BnOH, NEt3, reflux, 48 h, 89%; c) Pd(OH)2/
C, H2, THF, 98% (see the Supporting Information).
Upon heating in toluene at reflux, Curtius rearrangement
occurs to give the isocyanate. Trapping of the isocyanate
with benzylic alcohol leads to the formation of the Cbz-
protected amine 50, which can then be liberated under re-
ductive conditions by reaction with Pearlman’s catalyst un-
der hydrogen to yield amine 51.
Figure 4. Microbial hydroxylation reactions of (–)-isosteviol.
A large number of the hydroxylated products also exhibit
enhanced biological activity compared with (–)-isosteviol
itself. Thus, compounds 52a–52e (Figure 4) show an in-
creased inhibitory effect on the Epstein–Barr virus acti-
2.5. Microbial Hydroxylations
The treatment of organic substrates by microorganisms vation, a human herpes virus that is associated with various
often opens up the possibility of positions being attacked kinds of cancer.[44] Hydroxylated products 53a–53d exhibit
that are usually not prone to conventional transformations activities as potential androgen agonists in the treatment of
in organic chemistry. Alongside a variety of structurally re- androgen insufficiency, showing even higher activity than
lated diterpenes,[39] (–)-isosteviol (2) can be transformed by testosterone. Furthermore, compounds 54a–54d show anti-
a variety of microorganisms to yield mainly hydroxylated inflammatory properties.[45] Moreover, 52a and 53b inhibit
derivatives (Figure 4). Microbial oxidation of a total of AP-1 activation, AP-1 being a protein that is associated
eight positions (highlighted in grey, Figure 5) of the ent- with, for example, the growth of breast cancer.[46]
beyerane skeleton has been achieved so far. Upon feeding
Some of the derivatives of (–)-isosteviol have also been
(–)-isosteviol to the mutant B1-41a of Gibberella fujikuroi, subjected to microbial transformations (Figure 5). (–)-Iso-
a fungal plant pathogen, hydroxylation of the 6- and 7-posi- steviol can be transformed into the regioisomeric lactones
tions was achieved.[40] By transforming isosteviol with Gib- 55 and 58 by the Baeyer–Villiger reaction. The regioisomers
berella fujikuroi (also known as Fusarium verticilloides) can be separated by column chromatography.[47] The intro-
itself, modification of the 12-position was accomplished.[41] duction of hydroxy moieties at a total of six positions (high-
Biotransformation with other fungi leads to hydroxylation lighted in grey) in 55 has previously been reported.[47,48] Of
reactions at the 1- and/or 7-positions (Aspergillus niger/Rhi- the reported substrates, 56a–56e have been shown to inhibit
zopus arrhizus) as well as the 17-position (Penicillium AP-1 activation. The three derivatives 58a–58c of the re-
chrysogenum).[42] Metabolization of isosteviol with bacteria gioisomeric lactone show inhibitory effects against AP-1 ac-
of Actinoplanes sp. also allows hydroxylation at the 11-post- tivation (58a and 58b)[48] as well as androgen insufficiency
ion as well as at the 12- and 17-positions, whereas metabol- (58c).[47]
ization under the influence of Mucor recurvatus or Cun-
Furthermore, oxime 9c and nitriles 59 and 60a act as AP-
ninghamella blakesleeana affords hydroxylation at the 15- 1 agonists whereas oxime 9b and lactam 57a show inhibi-
and 9-positions, respectively.[43] Microbial hydroxylation of tory effects against NF-κB, a transcription factor, the acti-
a methyl group other than that at the 17-position has not vation of which is associated with inflammatory pro-
been reported so far.
cesses.[49] Recent studies have also revealed that oxime 9a,
5546
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5539–5554

(–)-Isosteviol as a Building Block for Organic Chemistry
Baeyer–Villiger reaction starting from (–)-isosteviol (Fig-
ure 6).[47,52] Through a series of subsequent modifications,
56a can, for example, be transformed into the novel neuro-
protective substances serofendic acids A and B.[53] Lactone
derivative 56f (R = Bn), with the hydroxymethylene moiety
located in the axial position, can be obtained by subjecting
the appropriately substituted benzylic ester of (–)-isosteviol
to Baeyer–Villiger reaction conditions.[54] This compound
can be converted into methylene derivative 56g after tosyl-
ation and subsequent elimination of the hydroxy moiety.
The methylene double bond in 56g also undergoes epoxid-
ation when treated with mCPBA. Lactone 31 and tetra-
hydropyran 33 (Figure 6) can be obtained upon treatment
of 30 and 32 (Scheme 8), respectively, with BF3·OEt2.
Figure 6. Heterocyclic derivatives of (–)-isosteviol with an ex-
panded ring D.
The analogous lactam 57a (Figure 6) can be obtained by
conversion of oxime derivative 9 (R = H, Et) under acidic
conditions.[14] It was found that, depending on the reaction
conditions, Beckmann fragmentation of the oxime occurs
alongside the Beckmann rearrangement. Thus, nitrile com-
ponents 59 and 60a (Figure 5) were also obtained.[6] When
employing BF3·OEt2 in the reaction, the ratio of lactam to
nitriles is around 3.5:1 (77 vs. 22%). Upon switching to sulf-
uric acid, the ratio changes to about 1:14 (6% vs. 88%) in
favor of the nitrile products. Reaction with p-toluenesulf-
onic acid renders a mixture with a ratio of about 1.4:1 (55%
vs. 38%) in favor of the lactam.
In 2012, Waldvogel and co-workers were the first to re-
port the ring enlargement of the (–)-isosteviol D ring to a
six-membered ring containing exclusively carbon atoms.[55]
Corey–Chaykovsky epoxidation[56] of 4 provides epoxide 61
as a single isomer (Scheme 13). After ring-opening of 61
with sodium azide and subsequent reduction, the corre-
sponding amine 62 was then converted in a Tiffeneau–
Demjanov-type rearrangement.[57] Surprisingly, migration
of the lower substituted alkyl fragment occurred, leading to
Figure 5. Microbial hydroxylations of (–)-isosteviol derivatives.
lactams 57a–57d, and nitriles 60a–60e, obtained by micro-
bial transformation with Absidia pseudocylindrospora and
Aspergillus niger, exhibit suppressive effects on iNOS (in-
duced nitric oxide synthase) expression, which plays a cru-
cial role in inflammatory processes.[50] Hydroxylation at the
6- and 7-positions of dihydroisosteviol 5 (Scheme 6) has
been reported by de Oliveira et al.[51]
2.6. Derivatives with an Expanded Ring D
Although a huge number of derivatives of (–)-isosteviol the formation of cyclohexanone derivative 63 in an overall
are known, only a very limited number of these exhibit dif- yield of 67% starting from 61. With the aim of synthesizing
ferent sizes of the D ring. Six-membered ring lactones 56a novel building blocks for the construction of triphenylene
(R, RЈ = H) and 58a (R, RЈ = H) can be synthesized by ketals, the keto function in 63 was then translocated in a
Eur. J. Org. Chem. 2013, 5539–5554
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5547

C. Lohoelter, M. Weckbecker, S. R. Waldvogel
MICROREVIEW
series of redox reactions to yield ketone 65. The reaction
The synthesis of regioisomeric keto enol 69 (Scheme 15)
sequence includes the bromination of 63 at the position α was achieved by following the reaction strategy described
to the keto function[58] and subsequent oxidation under above for the conversion of 4, the only difference being that
strongly basic conditions to give the keto enol 64. Re- the synthesis starts with the (–)-isosteviol diketone 7a.
duction of the keto function followed by deoxygenation of Epoxidation under Corey–Chaykovsky conditions with
the newly formed hydroxy group using trimethyliodosil- 1 equivalent of SMe3I regioselectively converts the less hin-
ane[59] finally gave 65 in an overall yield of 16% starting dered keto function to yield epoxide 67.
from 4.
Scheme 15. Ring enlargement of (–)-isosteviol diketone 7a renders
keto enol 69. Reagents and conditions: a) 1 equiv. SMe3I, KOtBu,
DMF, 0 °C, 1 h, room temp., 3 h, 90%; b) NaN3, DMF, 2 d, 80 °C;
c) Pd/C, H2, THF, 2 d, room temp.; d) HOAc, NaNO2, 30 min,
0 °C, 3 h, room temp., 13% (three steps starting from 67).
The use of 2 equivalents of SMe3I gives the correspond-
ing twice-epoxidized product. Again, ring-opening with so-
dium azide and reduction leads to the formation of amine
68, which was subjected to rearrangement under Tiffeneau–
Demjanov conditions to yield keto enol 69.
In addition to these ring-enlargement transformations,
the contraction of ring D from five to four carbon atoms in
a multiple-step synthesis has been reported (Scheme 16).[19]
Starting from (–)-isosteviol methyl ester 4, the ester func-
tionality was, after protection of the keto function, removed
reductively to yield the ent-beyerane scaffold 70.
Scheme 13. Ring enlargement of (–)-isosteviol and shift of the keto
function. Reagents and conditions: a) SMe3I, KOtBu, DMF, 0 °C,
1 h, room temp., 3 h, 88%; b) NaN3, DMF, 10 d, 90 °C; c) Pd/C,
H2, THF, 4 d, room temp.; d) HOAc, NaNO2, 30 min, 0 °C, 3 h,
room temp., 67% (three steps starting from 61); e) NBS, pTsOH,
20 min, 145 °C, 83%; f) NaOH, DMF, 5 h, room temp., 69%;
g) NaBH4, MeOH, 0 °C, 1 h, room temp., 2 h, 81%; h) TMSI,
CH2Cl2, room temp., 8 h, 58%.
Derivative 65 was then subjected to ketalization with cat-
echol to yield acetal 66 in good yield (Scheme 14). The ap-
plication of this strategy to the construction of supramolec-
ular receptors is the subject of current work.
Scheme 16. Ring contraction of (–)-isosteviol derivatives. Reagents
and conditions: a) 2,2-Dimethylpropane-1,3-diol, pTsOH, benzene,
32 h, reflux; b) LiAlH4, Et2O, 2 h, room temp., 78% (two steps);
c) MeSO2Cl, NEt3, pentane, 2 h; d) PhSNa, DMF, 110 °C, 16 h;
e) Li/NH3, THF, –33 °C, 3 h; f) pTsOH, dioxane, H2O, room temp.,
24 h, 64% (four steps); g) SeO2, xylene, reflux, 42 h, 85%;
h) TsNHNH2, CHCl3, room temp., 30 h, quant.; i) Al2O3, CH2Cl2,
room temp., 62 h, 79%.
Scheme 14. Ketalization of 65 (see the Supporting Information).
5548
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5539–5554

(–)-Isosteviol as a Building Block for Organic Chemistry
Riley oxidation to the corresponding diketone and subse-
quent reaction with p-tosylhydrazine and aluminium oxide
leads to the formation of diazo compound 71. Irradiation
with a mercury lamp in the presence of water (R = H) or
methanol (R = Me) finally yields ring-contracted product
72 by a Wolff rearrangement as a mixture of isomers.
3. Applications
Figure 7. Tweezer-like structures based on (–)-isosteviol.
In addition to the testing of (–)-isosteviol and its deriva-
tives in medicinal chemistry, this unique molecular architec-
ture has found applications in various fields of organic
chemistry as a result of its superb structural features. Sig-
nificant work has been carried out in supramolecular chem-
istry and organocatalysis.
ample, diols,[65] dibromoalkanes,[66] or diamines, tweezer-
like structure 74 can be obtained.[67,68] These diamide struc-
tures have proven to be potent receptors and carriers of
amino acid picrates based on phenylalanine and tryptophan
through a liquid chloroform phase,[67] partly exhibiting bet-
ter extraction ability than dibenzo-18-crown-6. In addition
to the methylene or amide spacers depicted in Figure 7, az-
ine and hydrazide linkers[69] (showing high tuberculostatic
activity) as well as aliphatic amide linkers[67,68] have been
reported. Moreover, the anhydride of (–)-isosteviol can be
obtained by treating (–)-isosteviol with isostevioyl chlor-
ide.[33]
Macrocyclic compounds have attracted particular inter-
est in recent years due to their ability to act as host mole-
cules in supramolecular recognition processes. Various
kinds of macrocycles have been synthesized based upon
(–)-isosteviol. For example, based upon the tweezer-like
structure 73 (Figure 7), closely related macrocycle 75 (Fig-
ure 8) can be obtained by two-fold esterification with 1,3-
propanediol and malonyl chloride.[70] It was found that 75
exhibits enhanced tuberculostatic activity, inhibiting the in
vitro growth of Mycobacterium tuberculosis.
3.1. Supramolecular Chemistry
As a result of the rigid, “chemically inert” hydrocarbon
backbone of (–)-isosteviol and the two functional groups
arranged in a concave fashion, this naturally derived and
optically pure compound exhibits two fundamental struc-
tural features that can be used in supramolecular chemistry.
First, the rigid nature of the diterpenoid skeleton limits the
degrees of freedom and, secondly, ensures excellent preor-
ganization of the molecules.[60] Modification of either or
both functional groups also allows the synthesis of a variety
of derivatives with the exact characteristics that are desired
for a specific system.
(–)-Isosteviol itself shows qualities suited to supramolec-
ular interactions with other molecules. Thus, (–)-isosteviol
forms chiral complexes with aromatic compounds such as
aniline or toluene.[61] These complexes are stabilized
through hydrogen bonding between the isosteviol molecules
themselves as well as by hydrogen bonds between isosteviol
and, for example, the amine moiety of aniline. In the solid
state, these interactions lead to the formation of chiral
double helices. The helical strands are composed of isoste-
viol molecules, and the strands themselves are linked to
each other through hydrogen bonding to the aniline mole-
cules. Furthermore, each helix is linked to a neighboring
helix, again through hydrogen bonds.
Tweezer-like structures such as 73 and 74 can be formed
by linking two (–)-isosteviol molecules to spacers (Fig-
ure 7). Both the keto and carboxylic acid moieties can be
used to form the linkage. Stereoselective reduction of the
keto moiety of (–)-isosteviol with, for example, sodium
borohydride[10,62] and subsequent reaction with aliphatic
acid chlorides leads to the formation of dicarboxy deriva-
tive 73, linked by various (poly)methylene spacers.[63] These
substrates exhibit moderate tuberculostatic activities, de-
Figure 8. Isosteviol-based macrocycle 75.
Reduction of both the keto and carboxylic acid moieties
pending on the chain length.[62] Furthermore, they proved of (–)-isosteviol to the corresponding alcohols at the same
capable of transporting FeIII picrates through a liquid chlo- time and subsequent reaction with, for example, aliphatic
roform membrane, which functions as a model of a cell dicarboxylic acids renders macrocycles that are structurally
membrane.[64]
similar to tweezer structure 73 and macrocycle 75.[32] Un-
Upon activation of the carboxylic acid of (–)-isosteviol fortunately, these macrocyclic structures have been little
as the acid chloride and subsequent reaction with, for ex- characterized.
Eur. J. Org. Chem. 2013, 5539–5554
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5549

C. Lohoelter, M. Weckbecker, S. R. Waldvogel
MICROREVIEW
The two biologically active molecules isosteviol and
chlorin E6 were combined in the synthesis of macrocycle 76
and similar structures with enhanced biological properties
(Figure 9).[71] In a multistep sequence that includes amide
and oxime formation as well as esterification, bicyclic
macrocycle 76 was obtained in an overall yield of less than
16%. However, its possible application in medicinal chemis-
try and an evaluation of its biological activities have not yet
been reported.
Figure 9. Isosteviol–chlorin macrocycle 76.
Calixarenes 77 (Scheme 17) have found widespread appli-
cation in organic chemistry as receptor scaffolds for various
types of molecules.[72] Calixarenes can be easily function-
alized at the upper and lower rims. Thus, receptors capable
of forming supramolecular interactions with anions as well
as cations or neutral molecules can be accessed. Isostevioyl
chloride 43 can be obtained by conversion of (–)-isosteviol
with, for example, thionyl chloride. Reaction of 43 with
hexaaminocalix[6]arene 78 under basic conditions leads to
the functionalization of the lower rim of the calixarene and
the formation of compound 79 (Scheme 17).[73] Likewise,
the reaction of calix[4]arene 80 with isostevioyl chloride
leads to modification of the upper rim to yield compound
81.
Scheme 17. Synthesis of calixarenes based on (–)-isosteviol.
nately, the applied (–)-menthylamine building blocks[77]
completely shield the supramolecularly oriented guest pre-
venting its application in catalysis.[36] By using the optically
active (–)-isosteviol as backbone building block in the syn-
thesis of such receptor structures, subsequent chiral modifi-
cation steps can be avoided. After methylation of (–)-isoste-
viol, ester derivative 4 can be converted into the corre-
sponding catechol ketal 48 (Scheme 18).[35]
A single signal for the benzylic methylene protons in the
1H NMR spectrum of compound 79 indicates rapid in-
terconversion of the macrocycle between different conform-
ers, whereas the presence of two defined doublets for the
corresponding protons in the 1H NMR spectrum of 81 indi-
cate a cone conformation of 81 with defined equatorial and
axial positions. These substrates were synthesized with the
prospect of achieving a recognition system for saccharides
and organic anions, as well as the formation of artificial ion
channels. Studies on this topic are currently being investi-
gated by Al’fonsov and co-workers.
Over the past few years, Waldvogel and co-workers have
employed triphenylene ketal based receptor structures in
the molecular recognition and detection of various aromatic
compounds like caffeine.[37,74,75] Further modification of
Scheme 18. Ketalization and subsequent oxidative trimerization of
4.
Oxidative trimerization of 48 renders receptor scaffold 82
the binding sites of the host scaffold with optically active as a mixture of isomers (all-syn and anti,anti,syn). Separa-
entities provides an opportunity for achieving enantiofacial tion of the isomers can be achieved by column chromatog-
differentiation of the bound guest molecule.[76] Unfortu- raphy, and the all-syn-ester 82 was isolated in a yield of
5550
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5539–5554

(–)-Isosteviol as a Building Block for Organic Chemistry
39%. This is a higher yield than statistics would predict.
The formation of a template due to the molybdenum salts
can be assumed.[78] The three-dimensional structure was
elucidated by X-ray analysis (Figure 10), showing the
planar triphenylene platform and the cavity formed by the
(–)-isosteviol backbone.[35]
Figure 11. Amphiphilic (–)-isosteviol-proline conjugate 84.
This kind of amphiphilic conjugate has found applica-
tion, for example, in the stereoselective Mannich reac-
tion.[79] The Mannich reaction is a widely applied C–C
bond-forming reaction used for the construction of β-
amino carbonyl structures. By application of optically
active auxiliaries, stereoselective conversion has become
possible, leading to valuable substrates for employment in
medicinal chemistry or natural product synthesis. Tao and
co-workers have shown that the addition of 10 mol-% of
conjugate 84 to the reaction of cyclohexanone with, for ex-
ample, p-chloraniline and p-nitrobenzaldeyhde yields the
corresponding Mannich product quantitatively with a dia-
stereomeric ratio of 94:6 and an ee of Ͼ99% (Scheme 20).
This reaction can be carried out in the absence of any ad-
ditional organic solvent.
Figure 10. Molecular structure of 82 obtained by X-ray analysis.
The binding of a substrate (for example, electron-de-
ficient heterocyclic compounds) in this kind of host mole-
cule occurs through π–π interactions with the electron-rich
triphenylene platform and, more importantly, through hy-
drogen-bonding interactions with the binding sites of the
receptor.[37,74] Over a series of steps that include demethyl-
ation, azide formation, and Curtius rearrangement, 82 can
be transformed into the corresponding triamine 83
(Scheme 19).[35]
Scheme 20. Mannich reaction using the isosteviol–proline conju-
gate 84.
Scheme 19. Receptor scaffold based on (–)-isosteviol.
all-syn-Triamine 83 can be further modified by introduc-
ing suitable binding sites that might be capable of forming
hydrogen-bonding interactions with an intercalated guest
molecule.
Thus, an asymmetric one-pot three-component Mannich
reaction under very mild reaction conditions has been es-
tablished, offering the opportunity of converting a variety
of substrates into the corresponding β-amino carbonyl
structures.
Apart from the Mannich reaction, the (–)-isosteviol-pro-
line conjugate 84 has found application in α-aminoxylation
reactions (Scheme 21).[80] Upon employment of 10 mol-%
3.2. Organocatalysis
Because (–)-isosteviol is a readily available ex-chiral-pool of catalyst 84 in the reactions of aldehydes with ni-
building block, it has become an attractive substrate as a trosobenzene and subsequent reduction with sodium
chiral auxiliary in organocatalytic chemistry. In combina- borohydride, the corresponding products 85 can be ob-
tion with amino acids such as proline, conjugates like 84 tained in yields of up to 98% with excellent enantio-
can be formed (Figure 11) that exhibit amphiphilic proper- selectivities of up to 99% ee. In addition to aldehydes,
ties, thereby allowing reactions of organic compounds to be ketones can also be converted with equally good selectivity.
performed in aqueous media. This presents a highly envi-
Furthermore, catalyst 84 can be applied in the asymmet-
ronmentally friendly alternative for a variety of stereoselec- ric aldol reaction (Scheme 22).[81] Again, water was used as
tive conversions that, so far, had been carried out exclu- solvent. In fact, it was found that reactions in solvents other
sively in organic solvents.
than water proceeded with significantly lower yields, if any
Eur. J. Org. Chem. 2013, 5539–5554
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5551

C. Lohoelter, M. Weckbecker, S. R. Waldvogel
MICROREVIEW
yields and enantioselectivities for both enantiomeric forms
can be observed in both organic and aqueous media.
Furthermore, enantioselective addition of isobutyral-
dehyde to N-phenylmaleimide proceeded to give pyrrolidine
derivatives 89 in excellent yields and ees. This presents a
highly promising method for the construction of α-chiral
succinimide derivatives, a substrate class for which there are
only a few procedures available. In combination with other
chiral auxiliaries, (–)-isosteviol is a powerful organocata-
lytic agent in a variety of stereoselective transformations
under extremely mild reaction conditions.
Scheme 21. α-Aminoxylation reaction using 84 as catalyst.
conversion was observed at all. In addition, the catalyst
loading could be reduced to 1 mol-%, making this a highly
atom-economic process.
4. Conclusions
(–)-Isosteviol is a readily available, inexpensive, ex-chiral-
pool building block with unique structural features. The
very rigid and concave arrangement of the functional
groups is unparalleled. (–)-Isosteviol and a variety of deriv-
atives thereof exhibit significant enhanced biological and
cytotoxic activities and are thus promising substrates in me-
dicinal chemistry. A broad range of chemical modifications
can be carried out on this particular scaffold. The unique
stereochemical arrangement leads to initial and significant
applications of (–)-isosteviol as a building block in synthetic
organic chemistry, functioning as a chiral auxiliary in vari-
ous organocatalytic conversions and in the construction of
supramolecular systems. Because the use of (–)-isosteviol in
organic chemistry is a strongly emerging field, promising
applications are expected in due course.
Scheme 22. Aldol reaction with 84 as catalyst.
The proposed transition state of the reaction involves the
formation of a hydrophobic chiral pocket on the surface of
the water phase due to hydrogen bonding of the hydrophilic
proline moieties to water molecules (thus activating the sys-
tem) and the hydrophobic isosteviol backbone. The reaction
takes place within this pocket. Optimal transfer of chirality
is ensured as a result of the very confined reaction space.
In addition to the (–)-isosteviol-proline conjugate 84,
thiourea derivatives 86 and 87 are known to induce stereo-
information
in
asymmetric
Michael
reactions
(Scheme 23).[82] In the reaction of isobutyraldehyde with
variously functionalized nitroalkenes, good-to-excellent
Supporting Information (see footnote on the first page of this arti-
cle): Preparation and characterization of 2, 49, 50, 51, 66.
Acknowledgments
Support by the Kompetenzzentrum der Integrierten Naturstoff-
Forschung (University of Mainz) is appreciated. The authors thank
Dr. M. Bomkamp for providing supporting information for the
synthesis of various (–)-isosteviol derivatives.
[1] a) M. Bridel, R. Lavieille, B Soc. Chim. Biol. 1931, 781–796;
b) H. B. Wood, R. Allerton, H. W. Diehl, H. G. Fletcher, J.
Org. Chem. 1955, 20, 875–883; c) E. Mosettig, W. R. Nes, J.
Org. Chem. 1955, 20, 884–899; d) G. I. Kovylyaeva, G. A. Bak-
aleinik, I. Y. Strobykina, V. I. Gubskaya, R. R. Sharipova,
V. A. Al’fonsov, V. E. Kataev, A. G. Tolstikov, Chem. Nat.
Compd. 2007, 43, 81–85; e) J. R. Hanson, B. H. de Oliveira,
Nat. Prod. Rep. 1993, 10, 301–309.
[2] J. Geuns, Phytochemistry 2003, 64, 913–921.
[3] “COMMISSION REGULATION (EU) No 1131/2011 of 11
November 2011 amending Annex II to Regulation (EC) No.
1333/2008 of the European Parliament and of the Council with
regard to steviol glycosides”, under http://eur-lex.europa.eu/
LexUriServ/LexUriServ.do?u-
ri=OJ:L:2011:295:0205:0211:EN:PDF.
[4] a) V. Chatsudthipong, C. Muanprasat, Pharmacol. Ther. 2009,
121, 41–54; b) K. Yasukawa, S. Kitanaka, S. Seo, Biol. Pharm.
Bull. 2002, 25, 1488–1490.
[5] a) A. G. Avent, J. R. Hanson, B. H. de Oliveira, Phytochemistry
1990, 29, 2712–2715; b) A. D. Kinghorn, D. D. Soejarto,
N. P. D. Nanayakkara, C. M. Compadre, H. C. Makapugay,
Scheme 23. Asymmetric Michael reactions.
5552
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5539–5554

(–)-Isosteviol as a Building Block for Organic Chemistry
J. M. Hovanec-Brown, P. J. Medon, S. K. Kamath, J. Nat.
Prod. 1984, 47, 439–444.
e) A. Bauer, F. Westkämper, S. Grimme, T. Bach, Nature 2005,
436, 1139–1140.
[29] J. Hershenhorn, M. Zohar, B. Crammer, Z. Ziv, V. Weinstein,
Y. Kleifeld, Y. Lavan, R. Ikan, Plant Growth Regul. 1997, 23,
173–178.
[30] V. A. Al’fonsov, G. A. Bakaleinik, A. T. Gubaidullin, V. E. Ka-
taev, G. I. Kovylyaeva, A. I. Konovalov, I. A. Litvinov, I. Y.
Strobykina, O. V. Andreeva, M. G. Korochkina, Russ. J. Gen.
Chem. 2001, 71, 1144–1148.
[31] T. Ikeda, T. Kajimoto, H. Kondo, C.-H. Wong, Bioorg. Med.
Chem. Lett. 1997, 7, 2485–2490.
[32] B. F. Garifullin, I. Y. Strobykina, O. A. Lodochnikova, R. Z.
Musin, A. T. Gubaidullin, V. E. Kataev, Chem. Nat. Compd.
2011, 47, 422–427.
[33] V. A. Al’fonsov, G. A. Bakaleinik, A. T. Gubaidullin, V. E. Ka-
taev, G. I. Kovylyaeva, A. I. Konovalov, I. A. Litvinov, I. Y.
Strobykina, O. V. Andreeva, M. G. Korochkina, Russ. J. Gen.
Chem. 2001, 71, 1299–1306.
[34] V. L. Mamedova, K. A. Nikitina, V. A. Al’fonsov, Russ. Chem.
Bull. 2009, 58, 244–247.
[35] M. Bomkamp, A. Artiukhov, O. Kataeva, S. R. Waldvogel,
Synthesis 2007, 1107–1114.
[36] M. C. Schopohl, A. Faust, D. Mirk, R. Froehlich, O. Kataeva,
S. R. Waldvogel, Eur. J. Org. Chem. 2005, 2987–2999.
[37] S. R. Waldvogel, R. Froehlich, C. A. Schalley, Angew. Chem.
2000, 112, 2580–2583; Angew. Chem. Int. Ed. 2000, 39, 2472–
2475.
[38] O. Wolff, S. R. Waldvogel, Synthesis 2004, 1303–1305.
[39] J. R. Hanson, Nat. Prod. Rep. 1992, 9, 139–152.
[40] J. R. Bearder, V. M. Frydman, P. Gaskin, J. MacMillan, C. M.
Wels, B. O. Phinney, J. Chem. Soc. Perkin Trans. 1 1976, 173–
178.
[6]
[7]
A. Roy, F. G. Roberts, P. R. Wilderman, K. Zhou, R. J. Peters,
R. M. Coates, J. Am. Chem. Soc. 2007, 129, 12453–12460.
a) I. Nordentoft, P. B. Jeppesen, J. Hong, R. Abudula, K. Her-
mansen, Diabetes Obes. Metab. 2008, 10, 939–949; b) J. Ma, Z.
Ma, J. Wang, R. W. Milne, D. Xu, A. K. Davey, A. M. Evans,
Diabetes Obes. Metab. 2007, 9, 597–599.
[8]
[9]
D. Xu, Y. Li, J. Wang, A. K. Davey, S. Zhang, A. M. Evans,
Life Sci. 2007, 80, 269–274.
a) L. H. Lin, L. W. Lee, S. Y. Sheu, P. Y. Lin, Chem. Pharm.
Bull. 2004, 52, 1117–1122; b) K.-L. Wong, J.-W. Lin, J.-C. Liu,
H.-Y. Yang, P.-F. Kao, C.-H. Chen, S.-H. Loh, W.-T. Chiu, T.-
H. Cheng, J.-G. Lin, Pharmacology 2006, 76, 163–169.
Y. Wu, C.-J. Liu, X. Liu, G.-F. Dai, J.-Y. Do, J.-C. Tao, Helv.
Chim. Acta 2010, 93, 2052–2069.
Y. Wu, G.-F. Dai, J.-H. Yang, Y.-X. Zhang, Y. Zhu, J.-C. Tao,
Bioorg. Med. Chem. Lett. 2009, 19, 1818–1821.
a) E. Mosettig, U. Beglinger, P. Quitt, F. Dolder, H. Lichti,
J. A. Waters, J. Am. Chem. Soc. 1963, 85, 2305–2309; b) F.
Dolder, H. Lichti, E. Mosettig, P. Quitt, J. Am. Chem. Soc.
1960, 82, 246–247.
[10]
[11]
[12]
[13]
[14]
J. Hanson, Tetrahedron 1967, 23, 801–804.
Y. Wu, J.-H. Yang, G.-F. Dai, C.-J. Liu, G.-Q. Tian, W.-Y. Ma,
J.-C. Tao, Bioorg. Med. Chem. 2009, 17, 1464–1473.
V. A. Al’fonsov, O. V. Andreeva, G. A. Bakaleynik, D. V. Be-
skrovny, V. E. Kataev, G. I. Kovyljaeva, I. A. Litvinov, O. I.
Militsina, I. Y. Strobykina, Mendeleev Commun. 2003, 13, 234–
235.
V. A. Mamedov, V. A. Al’fonsov, G. A. Bakaleinik, V. E. Ka-
taev, G. I. Kovylyaeva, O. I. Militsina, I. Y. Strobykina, D. V.
Beskrovnyi, A. T. Gubaidullin, I. A. Litvinov, Russ. J. Gen.
Chem. 2005, 75, 583–589.
[15]
[16]
[41] B. H. de Oliveira, R. A. Strapasson, Phytochemistry 1996, 43,
393–395.
[17]
[18]
H. L. Riley, J. F. Morley, N. A. C. Friend, J. Chem. Soc. 1932,
1875–1883.
[42] B. de Oliveira, Phytochemistry 1999, 51, 737–741.
[43] F. L. Hsu, C. C. Hou, L. M. Yang, J. T. Cheng, T. C. Chi, P. C.
Liu, S. J. Lin, J. Nat. Prod. 2002, 65, 273–277.
[44] T. Akihisa, Y. Hamasaki, H. Tokuda, M. Ukiya, Y. Kimura,
H. Nishino, J. Nat. Prod. 2004, 67, 407–410.
M. Bomkamp, K. Gottfried, O. Kataeva, S. R. Waldvogel, Syn-
thesis 2008, 1443–1447.
R. M. Coates, H. Y. Kang, J. Org. Chem. 1987, 52, 2065–2074.
G. I. Kovylyaeva, R. R. Sharipova, I. Y. Strobykina, O. I. Mil-
itsina, R. Z. Musin, D. V. Beskrovnyi, A. T. Gubaidullin, V. A.
Al’fonsov, V. E. Kataev, Russ. J. Gen. Chem. 2009, 79, 2663–
2667.
T. Zhang, L.-H. Lu, H. Liu, J.-W. Wang, R.-X. Wang, Y.-X.
Zhang, J.-C. Tao, Bioorg. Med. Chem. Lett. 2012, 22, 5827–
5832.
J. C. Tao, G. Q. Tian, Y. B. Zhang, Y. Q. Fu, G. F. Dai, Y. Wu,
Chin. Chem. Lett. 2005, 16, 1441–1444.
V. E. Kataev, I. Y. Strobykina, O. V. Andreeva, B. F. Garifullin,
R. R. Sharipova, V. F. Mironov, R. V. Chestnova, Russ. J. Bi-
oorg. Chem. 2011, 37, 483–491.
O. V. Andreeva, R. R. Sharipova, I. Y. Strobykina, O. A. Lo-
dochnikova, A. B. Dobrynin, V. M. Babaev, R. V. Chestnova,
V. F. Mironov, V. E. Kataev, Russ. J. Gen. Chem. 2011, 81,
1643–1650.
V. A. Al’fonsov, O. V. Andreeva, G. A. Bakaleinik, D. V. Be-
skrovnyi, A. T. Gubaidullin, V. E. Kataev, G. I. Kovylyaeva,
A. I. Konovalov, M. G. Korochkina, I. A. Litvinov, Russ. J.
Gen. Chem. 2003, 73, 1255–1260.
O. I. Militsina, I. Y. Strobykina, G. I. Kovylyaeva, G. A. Baka-
leinik, V. E. Kataev, A. T. Gubaidullin, R. Z. Musin, A. G. Tol-
stikov, Russ. J. Gen. Chem. 2007, 77, 285–296.
[19]
[20]
[45]
S.-F. Chang, L.-M. Yang, C.-H. Lo, J.-H. Liaw, L.-H. Wang,
S.-J. Lin, J. Nat. Prod. 2008, 71, 87–92.
Y. Liu, J. Ludes-Meyers, Y. Zhang, D. Munoz-Medellin, H.-T.
Kim, C. Lu, G. Ge, R. Schiff, S. G. Hilsenbeck, C. K. Osborne,
Oncogene 2002, 21, 7680–7689.
B.-H. Chou, L.-M. Yang, S.-F. Chang, F.-L. Hsu, C.-H. Lo, J.-
H. Liaw, P.-C. Liu, S.-J. Lin, J. Nat. Prod. 2008, 71, 602–607.
B.-H. Chou, L.-M. Yang, S.-F. Chang, F.-L. Hsu, C.-H. Lo,
W.-K. Lin, L.-H. Wang, P.-C. Liu, S.-J. Lin, Phytochemistry
2009, 70, 759–764.
S.-F. Chang, B.-H. Chou, L.-M. Yang, F.-L. Hsu, W.-K. Lin,
Y. Ho, S.-J. Lin, Bioorg. Med. Chem. 2009, 17, 6348–6353.
B.-H. Chou, L.-M. Yang, S.-F. Chang, F.-L. Hsu, L.-H. Wang,
W.-K. Lin, P.-C. Liu, S.-J. Lin, J. Nat. Prod. 2011, 74, 1379–
1385.
B. H. de Oliveira, J. D. S. Filho, P. C. Leal, J. Braz. Chem. Soc.
2005, 16, 210–213.
W. Braguini, Toxicol. Lett. 2003, 143, 83–92.
T. Terauchi, N. Asai, T. Doko, R. Taguchi, O. Takenaka, H.
Sakurai, M. Yonaga, T. Kimura, A. Kajiwara, T. Niidome, Bi-
oorg. Med. Chem. 2007, 15, 7098–7107.
Y.-F. Zeng, J.-Q. Wu, L.-Y. Shi, K. Wang, B. Zhou, Y. Tang,
D.-Y. Zhang, Y.-C. Wu, W.-Y. Hua, X.-M. Wu, Bioorg. Med.
Chem. Lett. 2012, 22, 1922–1925.
[46]
[21]
[47]
[48]
[22]
[23]
[49]
[50]
[24]
[25]
[26]
[51]
[52]
[53]
[54]
[27]
[28]
B. Frey, J. Schnaubelt, H. U. Reissig, Eur. J. Org. Chem. 1999,
1385–1393.
[55]
[56]
C. Lohoelter, D. Schollmeyer, S. R. Waldvogel, Eur. J. Org.
Chem. 2012, 6364–6371.
a) T. Calogeropoulou, N. Avlonitis, V. Minas, X. Alexi, A.
Pantzou, I. Charalampopoulos, M. Zervou, V. Vergou, E. S.
Katsanou, I. Lazaridis, J. Med. Chem. 2009, 52, 6569–6587; b)
E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1962, 84, 3782–
3783; c) E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965,
a) S. Breitenlechner, T. Bach, Angew. Chem. 2008, 120, 8075–
8077; Angew. Chem. Int. Ed. 2008, 47, 7957–7959; b) F. Voss, T.
Bach, Synlett 2010, 1493–1496; c) C. Müller, A. Bauer, M. M.
Maturi, M. C. Cuquerella, M. A. Miranda, T. Bach, J. Am.
Chem. Soc. 2011, 133, 16689–16697; d) T. Bach, H. Bergmann,
B. Grosch, K. Harms, J. Am. Chem. Soc. 2002, 124, 7982–7990;
Eur. J. Org. Chem. 2013, 5539–5554
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5553

C. Lohoelter, M. Weckbecker, S. R. Waldvogel
MICROREVIEW
87, 1353–1364; d) E. J. Corey, M. Chaykovsky, J. Am. Chem.
Soc. 1965, 87, 1345–1353.
[57] a) N. J. Demjanov, M. Luschnikov, J. Russ. Phys. Chem. Soc.
1901, 279–283; b) N. J. Demjanov, M. Luschnikov, J. Russ.
Phys. Chem. Soc. 1903, 26–42; c) M. Tiffeneau, B. Tchoubar,
Compt. Rend. 1937, 1411–1413.
[58] I. Pravst, M. Zupan, S. Stavber, Tetrahedron Lett. 2006, 47,
4707–4710.
[59] T.-L. Ho, Synth. Commun. 1979, 9, 665–668.
[68]
[69]
V. A. Al’fonsov, V. E. Kataev, I. Y. Strobykina, M. G. Koroch-
kina, G. I. Kovylyaeva, G. A. Bakaleinik, D. V. Beskrovnyi,
A. T. Gubaidullin, I. A. Litvinov, R. Z. Musin, Russ. J. Gen.
Chem. 2005, 75, 248–253.
a) I. Y. Strobykina, B. F. Garifullin, G. I. Kovylyaeva, V. E. Ka-
taev, R. Z. Musin, Russ. J. Gen. Chem. 2007, 77, 1356–1358;
b) B. F. Garifullin, I. Y. Strobykina, G. G. Mordovskoi, V. F.
Mironov, V. E. Kataev, Chem. Nat. Compd. 2011, 47, 55–58.
R. N. Khaybullin, I. Y. Strobykina, A. B. Dobrynin, A. T. Gu-
baydullin, R. V. Chestnova, V. M. Babaev, V. E. Kataev, Bioorg.
Med. Chem. Lett. 2012, 22, 6909–6913.
a) D. V. Belykh, M. V. Mal’shakova, M. G. Korochkina, V. E.
Kataev, A. V. Kuchin, Chem. Nat. Compd. 2011, 47, 612–614;
b) M. V. Mal’shakova, M. G. Korochkina, D. V. Belykh, V. E.
Kataev, A. V. Kuchin, Chem. Nat. Compd. 2009, 45, 187–192;
c) M. V. Mal’shakova, Candidate Dissertation in Chemical Sci-
ences, Russian Academy of Science, Syktyvkar, 2006.
[70]
[71]
[60] a) J. W. Steed, D. R. Turner, K. J. Wallace, Core Concepts in
Supramolecular Chemistry and Nanochemistry, 1st ed., Wiley,
Chichester, 2007; b) J. W. Steed, J. L. Atwood, Supramolecular
Chemistry, 2nd ed., Wiley, Chichester, 2009; c) J.-M. Lehn, Sup-
ramolecular Chemistry. Concepts and Perspectives, VCH,
Weinheim, Germany, 1995; d) J. Kim, S. K. McHugh, T. M.
Swager, Macromolecules 1999, 32, 1500–1507; e) T. Weilandt,
R. W. Troff, H. Saxell, K. Rissanen, C. A. Schalley, Inorg.
Chem. 2008, 47, 7588–7598; f) F. Diederich, P. J. Stang, R. R.
Tykwinski, Modern Supramolecular Chemistry. Strategies for
Macrocycle Synthesis Wiley-VCH, Weinheim, Germany, 2008;
g) K. Raatikainen, N. K. Beyeh, K. Rissanen, Chem. Eur. J.
2010, 16, 14554–14564; h) D. J. Cram, Science 1988, 240, 760–
767; i) Z. Hou, C. J. Sunderland, T. Nishio, K. N. Raymond,
J. Am. Chem. Soc. 1996, 118, 5148–5149; j) D. Fiedler, D. H.
Leung, R. G. Bergman, K. N. Raymond, Acc. Chem. Res. 2005,
38, 349–358.
[61] a) V. A. Al’fonsov, O. V. Andreeva, G. A. Bakaleinik, D. V. Be-
skrovnyi, A. T. Gubaidullin, V. E. Kataev, G. I. Kovylyaeva,
A. I. Konovalov, M. G. Korochkina, I. A. Litvinov, Russ. J.
Gen. Chem. 2003, 73, 1249–1254; b) O. V. Andreeva, B. F. Gari-
fullin, A. T. Gubaidullin, V. A. Al’fonsov, V. E. Kataev, D. V.
Ryzhikov, J. Struct. Chem. 2007, 48, 540–546.
[62] V. E. Kataev, O. I. Militsina, I. Y. Strobykina, G. I. Kovylyaeva,
R. Z. Musin, O. V. Fedorova, G. L. Rusinov, M. N. Zueva,
G. G. Mordovskoi, A. G. Tolstikov, Pharm. Chem. J. 2006, 40,
473–475.
[63] V. E. Kataev, A. P. Timosheva, A. I. Nugmanov, A. T. Gubaid-
ullin, I. Y. Strobykina, R. R. Shagidullin, L. V. Avvakumova,
O. I. Militsina, Russ. J. Gen. Chem. 2007, 77, 1069–1077.
[64] V. E. Kataev, O. I. Militsina, I. Y. Strobykina, A. T. Gubaidul-
lin, V. V. Zverev, O. N. Kataeva, O. V. Fedorova, M. S. Valova,
G. L. Rusinov, J. Incl. Phenom. Macrocycl. Chem. 2008, 60, 51–
58.
[65] V. A. Al’fonsov, O. V. Andreeva, G. A. Bakaleinik, D. V. Be-
skrovnyi, A. T. Gubaidullin, V. E. Kataev, G. I. Kovylyaeva,
A. I. Konovalov, M. G. Korochkina, S. K. Latypov, Russ. J.
Gen. Chem. 2003, 73, 1119–1129.
[66] O. V. Andreeva, O. I. Militsina, G. I. Kovylyaeva, M. G. Kor-
ochkina, I. Y. Strobykina, G. A. Bakaleinik, V. A. Al’fonsov,
V. E. Kataev, R. Z. Musin, Russ. J. Gen. Chem. 2007, 77, 469–
473.
[67] V. E. Kataev, I. Y. Strobykina, O. I. Militsina, M. G. Koroch-
kina, O. V. Fedorova, I. G. Ovchinnikova, M. S. Valova, G. L.
Rusinov, Tetrahedron Lett. 2006, 47, 2137–2139.
[72]
[73]
a) T. Schrader, Nature Chem. 2012, 4, 519–520; b) R. Joseph,
C. P. Rao, Chem. Rev. 2011, 111, 4658–4702.
M. Korochkina, M. Fontanella, A. Casnati, A. Arduini, F.
Sansone, R. Ungaro, S. Latypov, V. E. Kataev, V. Alfonsov, Tet-
rahedron 2005, 61, 5457–5463.
[74]
[75]
S. R. Waldvogel, Tetrahedron Lett. 1999, 40, 3515–3518.
a) C. Siering, B. Beermann, S. R. Waldvogel, Supramol. Chem.
2006, 18, 23–27; b) C. Siering, H. Kerschbaumer, M. Nieger,
S. R. Waldvogel, Org. Lett. 2006, 8, 1471–1474.
[76] a) M. C. Schopohl, C. Siering, O. Kataeva, S. R. Waldvogel,
Angew. Chem. 2003, 115, 2724; Angew. Chem. Int. Ed. 2003,
42, 2620–2623; b) C. Siering, S. Grimme, S. R. Waldvogel,
Chem. Eur. J. 2005, 11, 1877–1888.
[77] a) J. Kulisch, M. Nieger, F. Stecker, A. Fischer, S. R. Waldvo-
gel, Angew. Chem. 2011, 123, 5678; Angew. Chem. Int. Ed.
2011, 50, 5564–5567; b) N. Welschoff, S. Waldvogel, Synthesis
2010, 3596–3601.
[78] a) N. M. Boshta, M. Bomkamp, G. Schnakenburg, S. R. Wald-
vogel, Chem. Eur. J. 2010, 16, 3459–3466; b) N. M. Boshta,
M. Bomkamp, G. Schnakenburg, S. R. Waldvogel, Eur. J. Org.
Chem. 2011, 1985–1992.
[79] a) Y. An, Q. Qin, C. Wang, J. Tao, Chin. J. Chem. 2011, 29,
1511–1517; b) Y.-J. An, C.-C. Wang, Z.-P. Liu, J.-C. Tao, Helv.
Chim. Acta 2012, 95, 43–51.
[80] Y.-J. An, C.-C. Wang, Y.-Z. Xu, W.-J. Wang, J.-C. Tao, Catal.
Lett. 2011, 141, 1123–1129.
[81] Y. An, Y.-X. Zhang, Y. Wu, Z.-M. Liu, C. Pi, J.-C. Tao, Tetra-
hedron: Asymmetry 2010, 21, 688–694.
[82] a) Z.-W. Ma, Y.-X. Liu, W.-J. Zhang, Y. Tao, Y. Zhu, J.-C. Tao,
M.-S. Tang, Eur. J. Org. Chem. 2011, 6747–6754; b) Z.-W. Ma,
Y.-X. Liu, L.-j. Huo, X. Gao, J.-C. Tao, Tetrahedron: Asym-
metry 2012, 23, 443–448.
Received: March 26, 2013
Published Online: June 12, 2013
5554
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5539–5554