Application of an enyne metathesis/diels-alder cycloaddition sequence: A new versatile approach to the syntheses of C-Aryl glycosides and spiro- C-Aryl glycosides

Article abstract of DOI:10.1002/chem.201000482

An efficient approach for the synthesis of a variety of C-aryl and spiro- C-aryl glycosides is described. This diversity-oriented strategy employed here relies on a sequential enyne metathesis to generate the 1,3-diene moiety and Diels-Alder reaction with

Full text of DOI:10.1002/chem.201000482

FULL PAPER
DOI: 10.1002/chem.201000482
Application of an Enyne Metathesis/Diels–Alder Cycloaddition Sequence:
A New Versatile Approach to the Syntheses of C-Aryl Glycosides and
Spiro-C-Aryl Glycosides
Ayyagari V. Subrahmanyam, Kalanidhi Palanichamy, and Krishna P. Kaliappan*[a]
Dedicated to Professor G. K. Trivedi on the occasion of his 70th birthday
Abstract: An efficient approach for the
synthesis of a variety of C-aryl and
spiro-C-aryl glycosides is described.
This diversity-oriented strategy em-
anomeric centre for the synthesis of C-
aryl glycosides, an intramolecular
enyne metathesis on the sugar enyne is
performed to generate the 1,3-diene
moiety for the synthesis of spiro-C-aryl
glycosides. Efforts to extend this strat-
egy to the synthesis of the core struc-
ture of natural C-aryl glycoside gilvo-
carcin are also described. A combina-
tion of both C-aryl and spiro-C-aryl
glycosides in the same moiety to com-
bine the features thereof has also been
accomplished. A tandem enyne meta-
thesis/Diels–Alder reaction/aromatisa-
tion has also been attempted to directly
access the C-aryl glycosides in one pot
albeit in low yield.
ployed here relies on
a sequential
enyne metathesis to generate the 1,3-
diene moiety and Diels–Alder reaction
with different dienophiles followed by
aromatisation. Whereas cross-enyne
metathesis with ethylene gas is used to
install the 1,3-diene moiety at the
Keywords: alkynes · cycloaddition ·
dienes · glycosides · metathesis
Introduction
The C-glycosides, one of the important classes of glycosides,
differ structurally from the usual O-glycosides and N-glyco-
À
sides in containing a C C bond attached to the anomeric
carbon atom. If the carbohydrate is attached to an aromatic
À
moiety through a C C bond at the anomeric centre, then
these compounds are referred to as C-aryl glycosides.[1,2]
Owing to this change in their connectivity, these compounds
are known to be quite stable towards enzymatic and acidic
hydrolysis,[2] and hence their appearance in a large and di-
verse array of natural and synthetic products endowed with
a broad spectrum of biological activities. It is also believed
that they bind to DNA to form stable complexes and may
have interesting biological properties. Some representative
members of this class of natural products are galtamycinone
(1),[3] vineomycinone B2 methyl ester (2),[4] ravidomycin
[a] Dr. A. V. Subrahmanyam, K. Palanichamy, Prof. Dr. K. P. Kaliappan
Department of Chemistry
Indian Institute of Technology Bombay
Powai, Mumbai-400 076 (India)
Fax : (+91)22-2572-3480
E-mail: kpk@chem.iitb.ac.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000482.
Chem. Eur. J. 2010, 16, 8545 – 8556
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8545

(3),[5] gilvocarcin M (4),[6] medermycin (5), mederrhodin A
(6), and kidamycin (7).[7] Apart from C-aryl glycosides, the
area of spirocyclic C-aryl glycoside has also been explored
to some extent and a few methods have been developed for
their synthesis as part of some natural products, such as pap-
ulacandines (8)[8] containing a spiro-C-aryl glycoside frame-
work, which are found to be active against Pneumocystis
carinii pneumonia, the common opportunistic infection in
AIDS patients. Most of the methodologies for the synthesis
of C-aryl glycosides involve nucleophilic, electrophilic, and
radical reactions at the anomeric centre, as well as metathe-
sis and intramolecular etherification (Scheme 1).[9–13] How-
at the anomeric carbon atom and 2) the drastic conditions
required for the cycloaddition between furan and quinones
(Scheme 2).[16]
Scheme 2. Difficulties encountered in the Diels–Alder approach.
Likewise, albeit several strategies have been developed
for the synthesis of C-aryl glycosides, there are only a few
methods known for the synthesis of spiro-C-aryl glycosides
due to difficulties associated with the generation of a spiro
system at the anomeric carbon atom (Scheme 3).[17] Among
Scheme 1. Some of the existing methods available for the synthesis of C-
aryl glycosides. Ar=aryl.
ever, the limitation is that these methods require stereose-
lective generation of the anomeric centre. Apart from these
methods, transition-metal-catalysed reactions[14] are also
known for the synthesis of C-aryl glycosides though most of
the cases are accompanied by b-elimination products.[13]
Moreover, most of the C-aryl glycoside natural products
have been found to possess a quinone moiety as a subunit
and it could perhaps be speculated that the presence of the
quinone moiety in these natural products may also be re-
sponsible for their significant biological activity.
Only a few of the above-mentioned methods would allow
access to C-aryl glycosides with quinone as an integral sub-
ACHTUNGTRENNUNGunit. In this regard, Martin and co-workers have expertly
utilised benzyne precursors as quinone equivalents in their
synthesis of C-aryl glycosides by furan–benzyne cycloaddi-
tion.[15] Nevertheless, given the availability of quinones from
commercial sources and also in view of their synthetic utili-
ty, it would be appreciable if practical routes that utilise
Diels—Alder-like key reactions with quinones followed by
aromatisation to install the napthaquinone functionality of
C-aryl glycosides could be developed. However, this route
has seldom been explored, presumably due to 1) difficulties
associated with the introduction of a suitable diene moiety
Scheme 3. Some of the existing methods available for the synthesis of
spiro-C-aryl glycosides. Piv=pivaloyl.
these methods, addition of a lithiated aromatic precursor to
a sugar-derived lactone is commonly used.[18] However, it is
surprising that the cycloaddition strategy, which has been ef-
fectively utilised in the case of C-aryl glycosides, has not yet
been studied extensively in the area of spiro-C-aryl glyco-
sides except a few isolated reports.[19]
8546
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8545 – 8556

Syntheses of C-Aryl Glycosides and Spiro-C-Aryl Glycosides
FULL PAPER
We have previously communicated our initial results on a
conceptually new approach to C-aryl glycosides[20] that relies
on sequential ethylene cross-enyne metathesis[21,22] (for the
generation of an 1,3-diene at the anomeric carbon atom)/
Diels–Alder (with quinones and dimethylacetylene dicar-
boxylate (DMAD))/aromatisation reactions.[23] Our method
complements most of the existing ones in that it offers a
direct access to C-aryl glycosides containing the quinone
moiety. Herein, we wish to disclose a comprehensive ac-
count on our endeavours for the synthesis of spiro C-aryl
glycosides through a sequential intramolecular enyne meta-
thesis/Diels–Alder/aromatisation reaction strategy and also
our further studies on C-aryl glycosides (Scheme 4). Further-
Scheme 6. Methods for the synthesis of C-alkynyl glycosides. TMS=tri-
methylsilyl.
37.[25] The second approach utilises addition of lithium (tri-
methylsilyl)acetylide to the sugar lactone 39 followed by
treatment with triethylsilane in the presence of BF3·OEt2.[26]
To test the premise, we designed a set of dienes that could
be synthesised from the corresponding sugar alkynes by
using cross-enyne metathesis. Later, these dienes could be
used in the Diels–Alder reaction with 1,4-naphthaquinone
(40), 1,4-benzoquinone (41), 5-hydroxy-1,4-naphthaquinone
(42), and DMAD (43) as dienophiles for the synthesis of re-
spective C-aryl glycosides.
Scheme 4. Retrosynthesis for C-aryl glycosides and spiro-C-aryl glyco-
sides. IMDA=intermolecular Diels–Alder reaction, CEM=cross-enyne
metathesis, EM=(intramolecular) enyne metathesis.
more, the diversity for the synthesis of a variety of C-aryl
glycosides and spiro-C-aryl glycosides could be accom-
plished by 1) dienes derived from different carbohydrate
precursors, 2) a variety of dienophiles in the Diels–Alder re-
action, and 3) functionalising the free hydroxyl groups at-
tached to the sugar unit, as shown in Scheme 5. With this as-
Scheme 5. Diversity-oriented approach for the synthesis of C-aryl and
spiro-C-aryl glycosides.
Results and Discussion
Synthesis of C-aryl glycosides: Towards the synthesis of
diene 44 (Scheme 7), selective deprotection of acetonide 51
and then silica-supported NaIO4-assisted oxidative cleavage
of the corresponding diol was carried out to afford the alde-
hyde 52. Treatment of this aldehyde with Bestmann–Ohira
reagent 37[25] in the presence of K2CO3/MeOH afforded the
corresponding C-alkynyl glycoside 53 in 51% yield. With
the alkyne 53 in hand, we initially attempted the cross-
enyne metathesis by using 3 mol% of Grubbs second-gener-
piration for the development of a general route for the syn-
thesis of C-aryl glycosides, we designed and synthesised a
series of C-alkynyl glycosides from the respective sugars by
following one of the two easily adaptable routes (Scheme 6).
The first method depends mainly on the conversion of alde-
hyde 36 attached to the anomeric centre into the alkyne 38
by using either the Corey–Fuchs protocol[24] or Bestmann–
Ohira reagent (dimethyl-1-diazo-2-oxopropyl phosphonate)
Chem. Eur. J. 2010, 16, 8545 – 8556
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8547

K. P. Kaliappan et al.
Scheme 8. Synthesis of diene 45: a) IBX, CH3CN, 808C, 92%; b) CBr4,
PPh3, Zn, CH2Cl2, RT, 12 h, 88%; c) nBuLi, THF, 08C to RT, 2 h , 82%;
d) 54 (5 mol%), toluene, 808C, 12 h, 98%. IBX=2-iodoxybenzoic acid,
TBS=tert-butyldimethylsilyl.
Scheme 7. Synthesis of diene 44: a) 1) 60% AcOH, RT, 8 h, 82%;
2) Silica supp. NaIO4, CH2Cl2, 08C to RT, 2 h, 75%; b) Bestmann–Ohira
reagent, K2CO3, MeOH, 08C to RT, 12 h, 51%; c) 54 (5 mol%), toluene,
808C, 12 h, 82%. Cy=cyclohexyl, Mes=mesityl.
lowed by oxidative aromatisation to afford the respective C-
aryl glycosides in good yield (Table 1).
Later, the diene 46 was synthesised from d-mannose as
depicted in Scheme 9. The aldehyde 58 was treated with
CBr4 and PPh3 followed by treatment with nBuLi to afford
ation catalyst 54[27] under an ethylene atmosphere, and also
using Hoveydaꢁs phosphine-free catalyst.[28] Disappointingly,
both the conditions provided the diene in poor yield along
with recovered starting material. However, when 5 mol% of
catalyst 54 was used for the intermolecular cross-enyne
metathesis, the yield was significantly improved to afford
the diene 44 in 82% yield. After successfully synthesising
the diene 44, we then turned our attention to the intermo-
lecular Diels–Alder reaction with 40 for installing the re-
quired aromatic moiety. The reaction proceeded very well,
and on the basis of our earlier experiences,[30] we decided to
treat the cycloaddition product immediately with triethyl-
ACHTUNGTRENNUNGamine and silica gel for air oxidative aromatisation without
further purification. As anticipated, this protocol worked
well and allowed us to directly isolate the respective aroma-
tised/oxidised cycloadduct 71 in 42% yield. This sequence
was then repeated with 1,4-benzoquinone (41) and 5-hy-
droxy-1,4-naphthaquinone (42) to give the corresponding C-
aryl glycosides in good overall yield (Table 1). The above se-
quence was successfully extended to simple trisubstituted C-
aryl glycoside 74 by using 43 as a dienophile. In this case,
the subsequent aromatisation reaction was carried out under
standard MnO2 conditions to give the C-aryl glycoside 74 in
83% yield.[31] We also attempted a sequential tandem meta-
thesis/cycloaddition/aromatisation reaction on C-alkynyl gly-
coside 53 to give the C-aryl glycoside directly in one pot.
Though it was a single-pot reaction to directly provide the
required C-aryl glycoside, yields were lower (30–35%) than
the combined yield (more than 50%) for the two individual
steps (intermolecular enyne metathesis and cycloaddition/ar-
omatisation).
To extend the scope of our strategy, we synthesised diene
45 (Scheme 8) from d-ribose. Aldehyde 56 available from al-
cohol 55 was converted into the corresponding C-alkynyl
glycoside 57 in moderate yield by using standard Corey–
Fuchs protocol[24] followed by cross-enyne metathesis with
ethylene by using Grubbs second-generation catalyst 54 to
afford the diene 45 in good yield. The diene 45 was treated
individually with quinones 40, 41, 42, and DMAD (43) fol-
Scheme 9. Synthesis of diene 46: a) CBr4, PPh3, Zn, CH2Cl2, RT, 12 h,
96%; b) nBuLi, THF, 08C to RT, 2 h, 91%; c) 54 (5 mol%), toluene,
808C, 12 h, 89%.
alkyne 60 in good yield. The alkyne 60 upon sequential
enyne metathesis followed by Diels–Alder reactions (40–43)
and aromatisation gave the third set of C-aryl glycosides in
good yield (Table 1).
The synthesis of diene 47 began with the Corey–Fuchs re-
action[24] on the aldehyde 61 to afford the required C-alkyn-
yl glycoside 63. After converting the C-alkynyl glycoside
into a C-diene glycoside by using Grubbs second-generation
catalyst 54, quinones 40, 41, 42, and DMAD were screened
as to their effectiveness as dienophiles in the Diels–Alder
reaction and subsequent aromatisation to afford the respec-
tive C-aryl glycosides (Scheme 10, Table 1).
In the synthesis of diene 48, the aldehyde 64 was convert-
ed into the corresponding C-alkyne glycoside 66 by using
Corey–Fuchs protocol.[24] In this connection, the aldehyde
64 was reacted with CBr4 and PPh3 in the presence of zinc
powder to yield the corresponding dibromoalkene 65, which
on treatment with nBuLi afforded the alkyne 66 in 74%
yield (Scheme 11). In this event, the Diels–Alder reaction of
8548
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8545 – 8556

Syntheses of C-Aryl Glycosides and Spiro-C-Aryl Glycosides
FULL PAPER
Table 1. Synthesis of C-aryl glycosides.[a,b,c,e]
1,3-Diene/dienophile
[a] The dienes were synthesised from the respective C-alkynyl glycosides by using Grubbs second-generation catalyst (5 mol%) under an ethylene atmos-
phere in toluene at 808C. [b] All the Diels–Alder reactions were carried out in toluene at 808C followed by aromatisation with basic (Et3N) silica in
CHCl3 at RT. [c] Overall yield for 2 steps. [d] A mixture of inseparable regioisomers was obtained. [e] Yields are given in parentheses.
Scheme 10. Synthesis of diene 47: a) CBr4, PPh3, Zn, CH2Cl2, RT, 12 h,
89%; b) nBuLi, THF, 08C to RT, 2 h, 86%; c) 54 (5 mol%), toluene,
808C, 12 h, 98%.
Scheme 11. Synthesis of diene 48: a) CBr4, PPh3, Zn, CH2Cl2, RT, 12 h,
96%; b) nBuLi, THF, 08C to RT, 2 h, 74%; c) 54 (5 mol%), toluene,
808C, 12 h, 89%.
Chem. Eur. J. 2010, 16, 8545 – 8556
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8549

K. P. Kaliappan et al.
the diene 48 proceeded smoothly with 40–43, and the re-
spective aromatisation reactions led to the corresponding C-
aryl glycosides in good yields (Table 1).
tion/aromatisation sequence with benzoquinone to afford
the aromatised product 92, which structurally resembles the
gilvocarcin skeleton. This sequence was then repeated with
40, 42, and 43 to give the corresponding C-aryl glycosides in
good overall yield (Table 1).
Synthesis of pyranose-based C-aryl glycosides: To extend
the scope of this strategy, we intended to have some pyra-
nose-based C-aryl glycosides. Toward this end, we prepared
the known galactose aldehyde 67 from galactose in a few
steps.[36] Then, aldehyde 67 was treated with Ohira–Best-
mann reagent 37[25] in the presence of K2CO3/MeOH to
afford the C-alkynyl glycoside 68 in 68% yield. The alkyne
68 upon cross-enyne metathesis with Grubbs second-genera-
tion catalyst 54 afforded the diene 50, which was then treat-
ed with 40–43 followed by aromatisation to give a set of pyr-
anose-based C-aryl glycosides in good yield (Scheme 12,
Table 1).
C-Aryl glycosides with a hydroxyl group on the aromatic
ring: Though this methodology allows access to the synthesis
of a range of diverse C-aryl glycosides, this method as such
would not be the appropriate one for the synthesis of C-aryl
glycosides, such as gilvocarcin, with a hydroxyl group on the
aromatic ring that needs to be introduced during the Diels–
Alder reaction/aromatisation. To circumvent this problem,
we planned to modify our strategy as shown in Scheme 14.
Scheme 14. Retrosynthetic strategy for hydroxyl-substituted C-aryl glyco-
sides.
From a retrosynthetic perspective, we envisaged that the C-
aryl glycoside 99 could be obtained from the diene 100 by
using our strategy, which, in turn, could be generated by
cross-enyne metathesis between the corresponding C-alkyn-
yl glycosides 30 and either vinyl acetate or ethyl vinyl ether
in place of simple ethylene.[39]
Scheme 12. Synthesis of diene 50: a) Dimethyl-1-diazo-2-oxopropyl-
phosphonate (37), K2CO3, MeOH, RT, 12 h, 68%; b) 54 (5 mol%), tolu-
ene, 808C, 12 h, 98%.
Accordingly, the modified approach commenced with a
cross-enyne metathesis reaction of C-alkynyl glycoside 68
with ethyl vinyl ether in the presence of Grubbs second-gen-
eration catalyst 54 (5 mol%) to afford the diene 101 as a
separable mixture of cis and trans isomers in 71% yield
(Scheme 15). Unfortunately, when we subjected the diene
101 to the Diels–Alder reaction with 1,4-naphthaquinone 40
in toluene, and subsequent treatment with Et3N and silica
Synthesis of gilvocarcin analogues: With these promising re-
sults in the synthesis of C-aryl glycosides, and owing to our
current interest in developing some natural and unnatural
products,[37] we decided to utilise our strategy for the synthe-
sis of natural C-aryl glycosides and their analogues. To this
end, first we targeted the synthesis of the core structure of
gilvocarcin (4), a biologically active natural product, by
using this same strategy. In this regard, we prepared the C-
alkynyl glycoside 69 by using the more economical albeit
longer procedure of Zard and co-workers[38] by starting from
d-galactono-1,4-lactone (70) (Scheme 13). Cross-enyne
Scheme 13. Synthesis of diene 49: a) 54 (5 mol%), toluene, 808C, 12 h,
79%.
Scheme 15. Attempted strategy to synthesise hydroxyl-substituted C-aryl
glycosides: a) Grubbs second-generation catalyst (5 mol%), toluene,
reflux, 2 h, 71% (101), 43% (102); b) 1,4-naphthaquinone, toluene,
1008C, 12 h, then Et3N, silica gel, CHCl3, 58%; c) DMAD, toluene,
1008C, 12 h, 72%. EVE=ethyl vinyl ether.
metathesis of alkyne 69 with 5 mol% of Grubbs second-gen-
eration catalyst 54 under an ethylene atmosphere led to the
formation of the corresponding 1,3-diene 49 in 79% yield.
This was then subjected to our sequential Diels–Alder reac-
8550
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8545 – 8556

Syntheses of C-Aryl Glycosides and Spiro-C-Aryl Glycosides
FULL PAPER
gel for 2 h, only the C-aryl glycoside 95 that lacks the re-
quired hydroxyl group on the aromatic ring, was obtained in
62% yield. A similar result obtained from diene 101 and 43
providing 98 without a hydroxyl group on the aromatic ring,
which suggests that the ethoxyl group undergoes facile elim-
ination by the driving force of aromatisation during the re-
action conditions. When ethyl vinyl ether was replaced by
vinyl acetate, again similar results were observed for the
whole sequence and thus depicting that this may be a short-
coming of this strategy.
high b-selectivity. The stereochemistry at the anomeric
centre was assigned based on a precedent report described
by Yamamotoꢁs group.[19d] With the ribose-derived enyne
106 in hand, an initial screening of reaction conditions for
intramolecular enyne metathesis by using 10 mol% Grubbs
first-generation catalyst 107 under an ethylene atmosphere
in toluene at 808C for 12 h was carried out to give the spiro-
C-1,3-diene 108 in 72% yield as a single b- isomer.
To probe the viability of our strategy, we decided to inves-
tigate the Diels–Alder reaction of this diene with 1,4-naph-
thaquinone (40) followed by aromatisation based on our
earlier experience in the synthesis of C-aryl glycosides for
installing the required aromatic moiety. Thus, treatment of
diene 108 with 40 in toluene at 808C for 12 h gave the cyclo-
adduct in good yield. The crude cycloadduct was directly
treated with Et3N and silica without further purification to
deliver the first spiro-C-aryl glycoside 128 in 60% yield. Sur-
prisingly, when we repeated this sequence with 5-hydroxy-
1,4-naphthaquinone (42) followed by aromatisation, a well-
separable pair of regioisomers 129 and 130 (1:1) were ob-
tained in 63% yield unlike in other cases. Finally, by using
DMAD (43), the corresponding spiro-C-aryl glycoside 131
was obtained in good yield (Table 2).
Synthesis of spiro-C-aryl glycosides: After synthesising a li-
brary of C-aryl glycosides by using sequential intermolecular
cross-enyne metathesis/Diels–Alder/aromatisation reactions,
next we turned our attention to the development of a gener-
al relevant route to access a variety of spiro-C-aryl glyco-
sides. As emphasised in the Introduction, synthesis of spiro-
C-aryl glycosides has not been explored as much as C-aryl
glycosides, primarily due to the difficulty in constructing the
spiro-C-aryl moiety at the anomeric centre. However, a few
groups have made significant contributions by developing
efficient routes to both C-aryl and spiro-C-aryl glycosides.
According to our retrosynthetic strategy as outlined in
Scheme 4, we envisaged that the installation of the spiro-C-
aryl moiety at the anomeric carbon atom could be achieved
by a sequential intramolecular enyne metathesis/Diels–
Alder/aromatisation reaction. To analyse our argument, we
prepared a series of enynes from the corresponding sugar
lactones by the addition of lithiated-ethynyltrimethylsilane
followed by acid-catalysed O-allyl glycosidation.
At this stage we realised that this strategy would be one
of the most efficient entries for the synthesis of spiro-C-aryl
glycosides. After having been successful in applying our
strategy to the synthesis of spiro-C-aryl glycosides, we decid-
ed to check out if we could extend our methodology to
other sugar-related enynes. To this end, we synthesised the
known lactol intermediate 110[41a] by starting from d-man-
nose-derived lactone 109 (Scheme 17).
Synthesis of diene 108 from d-ribose: In this manner, we
synthesised diene 108 from d-ribose as depicted in
Scheme 16. Addition of 2-(trimethylsilyl)ethynyllithium to
Scheme 17. Attempts to synthesise enyne 111: a) TMS-acetylene, nBuLi,
THF, À788C, 40 min; b) allylalcohol, montmorillonite (K-10), 4 ꢂ MS
powder, CH2Cl2, RT, 8 h.
Unfortunately, all our attempts to perform O-allylglycosi-
dation by using montmorillonite K-10 and allyl alcohol
failed to provide the desired product. Similar results were
observed in the case of other lactol intermediates (112[41b]
113, and 114). In light of these rather unsatisfactory results,
,
Scheme 16. Synthesis of diene 108: a) TMS-acetylene, nBuLi, THF,
À788C, 40 min., 93%; b) allylalcohol, montmorillonite (K-10), 4 ꢂ MS
powder, CH2Cl2, RT, 8 h, 72%; c) K2CO3, MeOH, 4 h, 98%; d) 107
(10 mol%), toluene, 808C, 12 h, 72%.
we were looking for an alternative approach for the glycosi-
the TBS-protected d-ribonolactone 103[40] followed by O-
glycosidation with allyl alcohol in the presence of montmor-
illonite K-10 and 4 ꢂ MS and subsequent alkaline desilyla-
tion afforded an inseparable mixture of enynes 106 with
Chem. Eur. J. 2010, 16, 8545 – 8556
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8551

K. P. Kaliappan et al.
Table 2. Synthesis of spiro-C-aryl glycosides.[a,b,c,f]
1,3-Diene/dienophile
[a] The dienes were synthesised from the respective enynes by using Grubbs first-generation catalyst (10 mol%) under an ethylene atmosphere in tolu-
ene at 808C. [b] All the Diels–Alder reactions were carried out in toluene at 808C followed by aromatisation with basic (Et3N) silica in CHCl3 at RT.
[c] Overall yield for 2 steps. [d] Regioisomers were obtained in an 1:1 ratio, and were separated by column chromatography. [e] A mixture of inseparable
regioisomers was obtained. [f] Yields are given in parentheses.
dation with allyl alcohol. We anticipated that the glycosida-
tion reaction might be fertile under acidic conditions.
Synthesis of enynes from d-ribose: To investigate the glyco-
sidation reaction under acidic conditions, we planned to syn-
thesise lactol 113. To this end, methyl Grignard addition to
d-ribose monoacetonide followed by oxidative diol cleavage
and then PCC oxidation provided lactone 153, which upon
treatment with lithiated trimethylsilylacetylene furnished
lactols 113 as an inseparable mixture in 66% yield
(Scheme 18). After screening several acid-catalysed condi-
tions (CSA, p-toluene sulfonic acid (p-TSA), 60% AcOH
and HCl), TfOH proved to be the most efficient for the gly-
cosidation with allyl alcohol, delivering the allylated product
115 in good yield, with concomitant cleavage of the aceto-
nide group. The mixture of anomers 116 and 117 (2:3) were
separated by using column chromatography only after desi-
lyation of allylated diol 115 under standard conditions. Inter-
estingly, when the acid-catalysed glycosidation reaction of
113 was quenched with an excess of NH4OH, we were
Scheme 18. Synthesis of dienes 120 and 121: a) 1) MeMgI, Et2O;
pleased to see the required products 116 and 117 in the
same ratio in 71% yield; this sequence involved three reac-
tions (O-allylation, deprotection of the acetonoide, and desi-
lylation) in a single pot.
After synthesising the enynes 116 and 117, our next task
was to execute the enyne metathesis to give the correspond-
2) NaIO4, H2O, 79% (2 steps); 3) PCC, NaOAc, 4 ꢂ MS powder, 73%;
b) TMS-acetylene, nBuLi, THF, À788C, 2 h, 66%; c) allyl alcohol, TfOH,
12 h, RT, 77%; d) K2CO3, MeOH, 2 h, RT, 91% (d.r.=2:3); e) allylal-
cohol, TfOH, 12 h, then NH4OH, RT, 12 h, 71% (d.r.=2:3); f) pyridine,
Ac2O, RT, 12 h, 118 (82%), 119 (79%); g) 107 (10 mol%), toluene,
808C, 12 h, 120 (80%), 121 (96%). d.r.=diastereomeric ratio, PCC=pyr-
idinium chlorochromate.
8552
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8545 – 8556

Syntheses of C-Aryl Glycosides and Spiro-C-Aryl Glycosides
FULL PAPER
ing diene for the Diels–Alder reaction. To avoid any inter-
À
ference of the OH groups during the enyne-metathesis
process, both the diols 116 and 117 were converted to their
acetates 118 and 119 in excellent yield. To determine the
stereochemistry at the anomeric centre, we undertook some
spectroscopic studies of anomers 118 and 119. The NOE
spectra of both the isomers did not provide any significant
information regarding the stereochemistry at the anomeric
centre. Hence, both the enynes 118 and 119 were separately
subjected to enyne metathesis with Grubbs first-generation
catalyst to provide the corresponding dienes 120 and 121 in
good yield. With these dienes 120 and 121 in hand, the
Diels–Alder/aromatisation sequence was attempted with 40,
42, and 43 to give the respective spiro-C-aryl glycosides in
good overall yield (Table 2).
Scheme 20. Synthesis of diene 127: a) TMS-acetylene, nBuLi, THF,
À788C, 2 h, quant.; b) TBAF, THF, 2 h, RT, 79%; c) allylalcohol, CSA,
CH2Cl2, 12 h, RT, 61%; d) pyridine, Ac2O, RT, 12 h, 73 %; e) 107
(10 mol%), toluene, 808C, 12 h, 75%. CSA=camphorsulfonic acid,
TBAF=tetrabutylammonium fluoride.
The synthesis of a wide range of spiro-C-aryl glycosides
provided an opportunity to conclude the configuration at
the anomeric centre by means of NOE spectroscopic studies
(Scheme 19). Though the NOE spectra of enynes 118 and
we carried out this transformation by using TfOH in the
presence of allyl alcohol, as done in the earlier cases, only
the allylated tetraol was obtained in poor yield. A series of
attempts to effect the glycosidation reaction of this lactol
with allyl alcohol in the presence of several acids (60%
AcOH, trifluoroacetic acid, pTSA, etc.) were not rewarding.
Ultimately, this trouble was overcome when CSA was
used to afford the diol 125 in 61% yield as a single isomer.
The diol 125 under standard conditions was converted into
its acetate 126 in 73% yield. Intramolecular enyne metathe-
sis of 126 by using 10 mol% Grubbs first-generation catalyst
107 under an ethylene atmosphere in toluene at 808C for
12 h provided the spiro-C-1,3-diene 127 in 75% yield as a
single b-isomer. With a straightforward formula for the syn-
thesis of spiro-C-aryl glycosides in hand, we explored that
sequence on 126 to afford another set of spiro-C-aryl glyco-
sides (Table 2). The stereochemistry at the anomeric carbon
atom was established by two-dimensional NMR spectro-
scopic analysis of 138. A cross-peak between one of the ace-
tonide methyl protons and an aromatic proton was observed
in the 2D-NOESY spectrum, which confirms the b-orienta-
tion of the ketal oxygen at the anomeric centre
(Scheme 19).
Scheme 19. NOESY analysis of spiro-C-aryl glycosides 137 and 138.
À
119 were inconclusive, a strong NOE between Ar H and
À
C H a to the anomeric carbon atom was discernible in the
NOE spectrum of spiro-C-aryl glycoside 137. Assignment of
this configuration is further supported by a trend of upfield
chemical shift for protons in proximity to the aromatic ring.
For example, when the spiroketal oxygen atom is b-oriented,
À
the C H a to the anomeric carbon atom is shifted approxi-
mately d=0.8–1.0 ppm upfield relative to the other anomer
containing the spiroketal oxygen atom as a-oriented. These
shifts in chemical shift may be due to the anisotropic effect
of the aromatic ring around the proton of interest. Similar
results were obtained when we performed NOE experi-
ments on glycosides 135 and 136.
Synthesis of dienes 145 and 146 from d-ribose: After accom-
plishing the synthesis of a variety of C-aryl glycosides and
spiro-C-aryl glycosides, we projected to extend the scope of
this strategy to synthesise hybrids of C-aryl and spiro-C-aryl
glycoside scaffolds (Scheme 21). Our proposal was to com-
bine the attractive attributes and features of the privileged
C-aryl and spiro C-aryl glycosides to prepare a diverse pure
library of hybrids of C-aryl and spiro-C-aryl glycoside scaf-
folds. At the outset, the lactol intermediate 114 was of inter-
est as an appropriate starting material for the synthesis of a
range of hybrid C-aryl and spiro-C-aryl glycoside scaffolds.
The synthetic sequence commenced with the addition of a
phenyl Grignard to d-ribose monoacetonide followed by ox-
idative diol cleavage and then PCC oxidation to provide lac-
tone 154. Addition of lithium trimethylsilyl acetylide to lac-
Synthesis of an enyne from d-mannose: Encouraged by
these promising results in the synthesis of furanose-type
spiro-C-aryl glycosides, we intended to synthesise a few pyr-
anose-type analogues (Scheme 20). We chose lactone 122 as
a viable starting material, which can be prepared from d-
mannose in two steps (see the Supporting Information). Ad-
dition of 2-(trimethylsilyl)ethynyllithium to the lactone 122
afforded an inseparable anomeric mixture 123 in good yield.
After desilylation under standard conditions, the alkyne 124
was obtained in 79% yield. Our attempts to effect the O-
glycosidation reaction with allyl alcohol failed in the pres-
ence of montmorillonite K-10 and 4 ꢂ MS. Further, when
Chem. Eur. J. 2010, 16, 8545 – 8556
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8553

K. P. Kaliappan et al.
good to moderate yields (Table 3). At this stage, we con-
firmed the configuration at the anomeric centre by perform-
ing NOE spectroscopic experiments on compound 152
(Scheme 22).
Conclusion
We have described efficient strategies for the synthesis of C-
aryl glycosides and spiro-C-aryl glycosides. During this
course, seven different C-alkynyl glycosides for the synthesis
of respective C-aryl glycosides and six sugar-derived enynes
for the corresponding spiro-C-aryl glycosides were investi-
gated. Furthermore, in the case of spiro-C-aryl glycosides
we were able to identify the configuration at the anomeric
centre by using 2D-NMR spectroscopic experiments. The
strategy used for the synthesis of spiro-C-aryl glycosides per-
mits stretched out possibilities for the construction of a com-
bination of C-aryl and spiro-C-aryl glycoside scaffolds. Final-
ly, our conclusion clearly points out our efforts to construct
the core structure of gilvocarcin and introduce the diversity
on the aromatic moiety by cross-enyne metathesis of C-al-
kynyl glycosides with vinyl acetate (or ethyl vinyl ether) fol-
lowed by a Diels–Alder reaction with quinones (or DMAD)
and aromatisation.
The advantageous scope of this methodology should be
easily extendable to the synthesis of a much greater variety
of C-aryl glycosides and spiro-C-aryl glycosides by using ap-
propriate sugar-derived alkynes, sugar-derived enynes, and
dienophiles, thereby increasing the opportunities for diversi-
ty generation. This strategy to C-aryl glycosides and spiro-
C-aryl glycosides should pave the way for the construction
of several quinone-related C-aryl and spiro-C-aryl glyco-
sides.
Scheme 21. Synthesis of dienes 145 and 146: a) 1) PhMgI, Et2O;
2) NaIO4, H2O, 80% (2 steps); 3) PCC, NaOAc, 4 ꢂ MS powder, 76%;
b) TMS-acetylene, nBuLi, THF, À788C, 2 h, 93%; c) allylalcohol, TfOH,
12 h, NH4OH, RT, 12 h, 80% (d.r.=2:3); d) pyridine, Ac2O, RT, 12 h,
143 (72%), 144 (63%); e) 107 (10 mol%), toluene, 808C, 12 h, 145
(89%), 146 (94%).
tone 154 afforded hemiketal 114, which upon exposure to
allyl alcohol in the presence of catalytic amount of TfOH
followed by quenching the reaction mixture with an excess
of aqueous NH4OH furnished the required enyne–diols 141
and 142 (2:3) in good yield. Both the enyne–diols 141 and
142 were protected under standard conditions as their ace-
tates 143 and 144 in 72 and 63% yields, respectively. Later,
we applied our strategy on the enynes 143 and 144 individu-
ally. Gratifyingly, good results were obtained when enynes
were treated with Grubbs first-generation catalyst 107, af-
fording dienes 145 and 146. Subsequently, these dienes were
subjected to the Diels–Alder reaction with quinones and
DMAD, and finally aromatisation to obtain various combi-
nations of C-aryl and spiro-C-aryl glycoside scaffolds in
Table 3. Synthesis of a combination of C-aryl and spiro-C-aryl glycoside scaffolds.[a,b,c,e]
1,3-Diene/dienophile
Scheme 22. NOESY analysis of
spiro-C-aryl glycoside 152.
Acknowledgements
We thank the DST, New Delhi, and
SAIF, IIT Bombay, for financial sup-
port and the use of spectral facilities,
respectively. K.P.K. thanks the DST
for the award of the Swarnajayanti fel-
lowship. A.V.S. and K.P. thank the
CSIR New Delhi for fellowships.
[a] The dienes were synthesised from the respective enynes by using Grubbs first-generation catalyst (10
mol%) under an ethylene atmosphere in toluene at 808C. [b] All the Diels–Alder reactions were carried out
in toluene at 808C followed by aromatisation with basic (Et3N) silica in CHCl3 at RT. [c] Overall yield for
2 steps. [d] A mixture of inseparable regioisomers was obtained. [e] Yields are given in parentheses.
8554
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8545 – 8556

Syntheses of C-Aryl Glycosides and Spiro-C-Aryl Glycosides
FULL PAPER
Tetrahedron Lett. 1989, 30, 1115–1118; i) V. Bellosta, S. Czernecki,
J. Chem. Soc. Chem. Commun. 1989, 199–200; j) T. Matsumoto, T.
Hosoya, K. Suzuki, Tetrahedron Lett. 1990, 31, 4629–4632; k) T.
Matsumoto, T. Hosoya, K. Suzuki, J. Am. Chem. Soc. 1992, 114,
3568–3570; l) K. Toshima, G. Matsuo, T. Ishizuka, M. Nakata, M.
Kinoshita, J. Chem. Soc. Chem. Commun. 1992, 1641–1642; m) C.
Booma, K. K. Balasubramanian, J. Chem. Soc. Chem. Commun.
1993, 1394–1395; n) M. Yokoyama, H. Toyoshima, M. Shimizu, J.
Mito, H. Togo, Synthesis 1998, 409–412; o) T. Kuribayashi, N.
Ohkawa, S. Satoh, Tetrahedron Lett. 1998, 39, 4537–4540; p) J. D.
Rainier, J. M. Cox, Org. Lett. 2000, 2, 2707–2709; q) B. Sobhana Ba-
bu, K. K. Balasubramanian, Tetrahedron Lett. 2000, 41, 1271–1274;
r) A. V. Malkov, B. P. Farn, N. Hussain, P. Kocovsky, Collect. Czech.
Chem. Commun. 2001, 66, 1735–1745; s) J. S. Yadav, B. V. S. Reddy,
J. V. Raman, N. Niranjan, K. K. Kumar, A. C. Kunwar, Tetrahedron
Lett. 2002, 43, 2095–2098; t) D. P. Steinhuebel, J. J. Fleming, J. Du
Bois, Org. Lett. 2002, 4, 293–295.
[1] For general reviews on glycosides, see: a) “Chemistry of C-nucleo-
sides”: K. A. Watanabe in Chemistry of Nucleosides and Nucleotides
(Ed.: L. B. Townsend), Plenum Press, New York, 1994, pp. 421–535;
b) D. E. Levy, C. Tang in The Chemistry of C-Glycosides, Elsevier,
Tarrytown, 1995; c) M. H. D. Postema in C-Glycoside Synthesis,
CRC Press, Boca Raton, 1995; d) M. A. E. Shaban, A. Z. Nasr, Adv.
Heterocycl. Chem. 1997, 68, 223–432; e) M. A. E. Shaban, Adv. Het-
erocycl. Chem. 1997, 70, 163–337; f) J. M. Beau, T. Gallagher, Top.
Curr. Chem. 1997, 187, 1–54; g) F. Nicotra, Top. Curr. Chem. 1997,
187, 55–83; h) K. Krohn, J. Rohr, Top. Curr. Chem. 1997, 188, 127–
195; i) Y. G. Du, R. J. Linhardt, I. R. Vlahov, Tetrahedron 1998, 54,
9913–9959; j) A. Dondoni, A. Marra, Chem. Rev. 2000, 100, 4395–
4421; k) L. Somsꢃk, Chem. Rev. 2001, 101, 81–135; l) M. H. D. Post-
ema, L. Liu, M. KcKee, Curr. Org. Chem. 2001, 5, 1133–1167; m) P.
Meo, H. M. I. Osborn in Best Synthetic Methods: Carbohydrates,
Elsevier, New York, 2003, pp. 337–384; n) D. Y. W. Lee, M. S. He,
Curr. Top. Med. Chem. 2005, 5, 1333–1350; o) X. Yuan, R. J. Lin-
hardt, Curr. Top. Med. Chem. 2005, 5, 1393–1430; p) C.-H. Lin, H.-
C. Lin, W.-B. Yang, Curr. Top. Med. Chem. 2005, 5, 1431–1457;
q) M. F. A. Adamo, R. Pergoli, Curr. Org. Chem. 2008, 12, 1544–
1569; r) J. Stambasky, M. Hocek, P. Kocovsky, Chem. Rev. 2009, 109,
6729–6764, and references therein.
[2] a) G. D. Daves, Jr., Acc. Chem. Res. 1990, 23, 201–206; b) M. H. D.
Postema, Tetrahedron 1992, 48, 8545–8599; c) H. Togo, W. He, Y.
Waki, M. Yokoyama, Synlett 1998, 700–717; d) M. Isobe, R. Nishiza-
wa, S. Hosokawa, T. Nishikawa, Chem. Commun. 1998, 2665–2676;
e) I. P. Smoliakova, Curr. Org. Chem. 2000, 4, 589–608; f) C. Taille-
fumier, Y. Chapleur, Chem. Rev. 2004, 104, 263–292; g) W. Zou,
Curr. Top. Med. Chem. 2005, 5, 1363–1391; h) R. Saeeng, M. Isobe,
Chem. Lett. 2006, 35, 552–557; for recent reviews in C-glycoside
biology and biosynthesis, see: i) P. Compain, O. R. Martin, Bioorg.
Med. Chem. 2001, 9, 3077–3092; j) P. G. Hultin, Curr. Top. Med.
Chem. 2005, 5, 1299–1331; k) T. Bililign, B. R. Griffith, J. S. Thor-
son, Nat. Prod. Rep. 2005, 22, 742–760; l) K. W. Wellington, S. A.
Benner, Nucleosides Nucleotides Nucleic Acids 2006, 25, 1309–1333.
[3] T. Matsumoto, H. Yamaguchi, K. Suzuki, Tetrahedron 1997, 53,
16533–16544.
[4] a) S. Danishefsky, B. J. Uang, G. Quallich, J. Am. Chem. Soc. 1984,
106, 2453–2455; b) S. Danishefsky, B. J. Uang, G. Quallich, J. Am.
Chem. Soc. 1985, 107, 1285–1293; c) M. A. Tius, X. Gu, J. Gomez-
Galeno, J. Am. Chem. Soc. 1990, 112, 8188–8189; d) M. A. Tius, J.
Gomez-Galeno, X. Gu, J. H. Zaidi, J. Am. Chem. Soc. 1991, 113,
5775–5783; e) V. Bolitt, C. Mioskowski, R. O. Kollah, S. Manna, D.
Rajapaksa, J. R. Falck, J. Am. Chem. Soc. 1991, 113, 6320–6321;
f) T. Matsumoto, M. Katsuki, H. Jona, K. Suzuki, J. Am. Chem. Soc.
1991, 113, 6982–6992.
[5] a) J. A. Findlay, J.-S. Lin, L. Radics, S. Rachit, Can. J. Chem. 1981,
59, 3018–3020; b) S. N. Sehgel, H. Czerkawski, A. Kudelski, K.
Pander, R. Saucier, C. Vezina, J. Antibiot. 1983, 36, 355–361.
[6] K. Takahashi, M. Yoshida, F. Tomita, K. Shirahata, J. Antibiot. 1981,
34, 271–275.
[7] N. Kanda, M. Kono, K. Asano, J. Antibiot. 1972, 25, 553–556.
[8] a) D. M. Schmatz, M. A. Romancheck, L. A. Pittarelli, R. E.
Schwarts, R. A. Fromtling, K. H. Nollstadt, F. L. Vanmiddlesworth,
K. E. Wilson, M. J. Turner, Proc. Natl. Acad. Sci. USA 1990, 87,
5950–5954; b) M. Debono, R. S. Gordee, Annu. Rev. Microbiol.
1994, 48, 471–497.
[9] For selected reviews on C-aryl glycosides, see: a) K. A. Parker, Pure
Appl. Chem. 1994, 66, 2135–2138; b) C. Jaramillo, S. Knapp, Synthe-
sis 1994, 1–20; c) S. F. Martin, Pure Appl. Chem. 2003, 75, 63–70.
[10] a) C. D. Hurd, W. A. Bonner, J. Am. Chem. Soc. 1945, 67, 1664–
1668; b) C. D. Hurd, R. P. Holysz, J. Am. Chem. Soc. 1950, 72,
1732–1735; c) R. M. Williams, A. Stewart, J. Am. Chem. Soc. 1985,
107, 4289–4296; d) O. R. Martin, Tetrahedron Lett. 1985, 26, 2055–
2058; e) R. R. Schmidt, G. Effenbergter, Liebigs Ann. Chem. 1987,
825–831; f) T. Kometani, H. Kondo, Y. Fujimori, Synthesis 1988,
1005–1007; g) S. Czernecki, G. Ville, J. Org. Chem. 1989, 54, 610–
612; h) Y. Araki, E. Mokubo, N. Kobayashi, J. Nagasawa, Y. Ishido,
[11] a) S. R. Pulley, J. P. Carey, J. Org. Chem. 1998, 63, 5275–5279; b) D.
Paetsch, K. H. Dotz, Tetrahedron Lett. 1999, 40, 487–488; c) C. Fu-
ganti, S. Sera, Synlett 1999, 1241–1242.
[12] a) S. J. Danishefsky, G. Phillips, M. Giufolini, Carbohydr. Res. 1987,
171, 317–327; b) K. Maruoka, T. Itoh, T. Shiraska, H. Yamamoto, J.
Am. Chem. Soc. 1988, 110, 310–312; c) M. Yamaguchi, A. Horigu-
chi, C. Ikeura, T. Minami, J. Chem. Soc. Chem. Commun. 1992,
434–436; d) D. J. Hart, V. Leroy, G. H. Merriman, D. G. J. Young, J.
Org. Chem. 1992, 57, 5670–5680; e) D. J. Hart, G. H. Merriman,
D. G. J. Young, Tetrahedron 1996, 52, 14437–14458; f) B. Schmidt, T.
Sattelkau, Tetrahedron 1997, 53, 12991–13000; g) B. Schmidt, J.
Chem. Soc. Perkin Trans.
1 1999, 2627–2637; h) D. Calimente,
M. H. D. Postema, J. Org. Chem. 1999, 64, 1770–1771; i) B. Schmidt,
Org. Lett. 2000, 2, 791–794; j) F. M. Hauser, X. Hu, Org. Lett. 2002,
4, 977–978; k) S. Vijayasaradhi, I. S. Aiden, Org. Lett. 2002, 4,
1739–1742; l) M. A. Brimble, G. S. Pavia, R. J. Stevenson, Tetrahe-
dron Lett. 2002, 43, 1735–1738.
[13] a) K. A. Parker, C. A. Coburn, J. Org. Chem. 1992, 57, 5547–5550;
b) K. A. Parker, Y. Koh, J. Am. Chem. Soc. 1994, 116, 11149–11150;
c) K. A. Parker, C. A. Goburn, Y. Koh, J. Org. Chem. 1995, 60,
2938–2941; d) K. A. Parker, D.-S. Su, J. Org. Chem. 1996, 61, 2191–
2194.
[14] a) S. Czernecki, V. Dechavanne, Can. J. Chem. 1983, 61, 533–540;
b) L. V. Dunkerton, J. M. Euske, A. J. Serino, Carbohydr. Res. 1987,
171, 89–107; c) C. Moineau, V. Bolitt, D. Sinou, J. Org. Chem. 1988,
53, 582–591; d) G. D. Daves, Jr., A. Hallberg, Chem. Rev. 1989, 89,
1433–1445; e) R. N. Farr, R. A. Outten, J. C. Cheng, G. D. Da-
ves, Jr., Organometallics 1990, 9, 3151–3156; f) E. Dubois, J.-M.
Beau, Tetrahedron Lett. 1990, 31, 5165–5168; g) R. W. Friesen,
A. K. Daljeet, Tetrahedron Lett. 1990, 31, 6133–6136; h) R. Benhad-
dou, S. Czernecki, G. Ville, J. Org. Chem. 1992, 57, 4612–4616;
i) R. W. Friesen, R. W. Loo, C. F. Sturino, Can. J. Chem. 1994, 72,
1262–1272; j) J. Ramnauth, O. Poulin, S. Rakhit, S. P. Maddaford,
Org. Lett. 2001, 3, 2013–2015; k) J. Ramnauth, O. Poulin, S. S. Bra-
tovanov, S. Rakhit, S. P. Maddaford, Org. Lett. 2001, 3, 2571–2573;
l) H. Gong, M. R. Gagne, J. Am. Chem. Soc. 2008, 130, 12177–
12183.
[15] a) D. E. Kaelin, Jr., O. D. Lopez, S. F. Martin, J. Am. Chem. Soc.
2001, 123, 6937–6938; b) D. E. Kaelin, Jr., S. M. Sparks, H. R.
Plake, S. F. Martin, J. Am. Chem. Soc. 2003, 125, 12994–12995; c) B.
Apsel, J. A. Bender, M. Escobar, D. E. Kaelin, Jr., O. D. Lopez, S. F.
Martin, Tetrahedron Lett. 2003, 44, 1075–1077; d) C.-L. Chen, S. M.
Sparks, S. F. Martin, J. Am. Chem. Soc. 2006, 128, 13696–13697.
[16] a) J. Jurczak, T. Kozluk, S. Filipek, Helv. Chim. Acta 1983, 66, 222–
225; b) J. Jurczak, A. L. Kawczynski, T. Kozluk, J. Org. Chem. 1985,
50, 1106–1107.
[17] a) R. R. Schmidt, W. Frick, Tetrahedron 1988, 44, 7163–7169;
b) R. W. Friesen, C. F. Sturnio, J. Org. Chem. 1990, 55, 2572–2574;
c) R. W. Friesen, C. F. Sturnio, J. Org. Chem. 1990, 55, 5808–5810;
d) E. Dubois, J.-M. Beau, J. Chem. Soc. Chem. Commun. 1990,
1191–1192; e) E. Dubois, J.-M. Beau, Tetrahedron Lett. 1990, 31,
5165–5168; f) R. W. Friesen, C. F. Sturnio, A. K. Daljeet, A. Kolac-
Chem. Eur. J. 2010, 16, 8545 – 8556
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8555

K. P. Kaliappan et al.
zewska, J. Org. Chem. 1991, 56, 1944–1947; g) R. W. Friesen, R. W.
Loo, J. Org. Chem. 1991, 56, 4821–4825; h) E. Dubois, J.-M. Beau,
Carbohydr. Res. 1992, 223, 157–167; i) M. A. Brimble, S. G. Robin-
son, Tetrahedron 1996, 52, 9553–9562; j) D. Balachari, G. A. OꢁDoh-
erty, Org. Lett. 2000, 2, 863–866; k) D. Balachari, G. A. OꢁDoherty,
Org. Lett. 2000, 2, 4033–4036; l) K. A. Parker, A. T. Georges, Org.
Lett. 2000, 2, 497–499; m) M. A. Brimble, V. Caprio, A. Johnston,
M. Sidford, Tetrahedron Lett. 2000, 41, 3955–3958; n) M. A. Brim-
ble, V. Caprio, A. Johnston, M. Sidford, Synthesis 2001, 0855–0862;
o) M. M. Ahmed, G. A. OꢁDoherty, Tetrahedron Lett. 2005, 46,
4151–4155.
2808; g) D. Bentz, S. Laschat, Synthesis 2000, 1766–1773; h) S.
Kotha, N. Sreenivasachary, E. Brahmachary, Eur. J. Org. Chem.
2001, 787–792; i) Y.-K. Yang, J. Tae, Synlett 2003, 2017–2020; j) M.
Rosillo, G. Dominguez, L. Casarrubios, U. Amador, J. Perez-Cas-
tells, J. Org. Chem. 2004, 69, 2084–2093; k) K. C. Majumdar, H. Ra-
haman, S. Muhuri, B. Roy, Synlett 2006, 466–468; l) L. Evanno, A.
Deville, B. Bodo, B. Nay, Tetrahedron Lett. 2007, 48, 4331–4333;
m) R. Ben-Othman, M. Othman, S. Coste, B. Decroix, Tetrahedron
2008, 64, 559–567; for a recent excellent review on these topics, see:
n) S. Kotha, M. Meshram, A. Tiwari, Chem. Soc. Rev. 2009, 38,
2065–2092.
[18] a) S. Czernecki, M.-C. Perlat, J. Org. Chem. 1991, 56, 6289–6292;
b) A. G. M. Barrett, M. Pena, J. A. Willardsen, J. Chem. Soc. Chem.
Commun. 1995, 1145–1146; c) A. G. M. Barrett, M. Pena, J. A. Will-
ardsen, J. Chem. Soc. Chem. Commun. 1995, 1147–1148;
d) A. G. M. Barrett, M. Pena, J. A. Willardsen, J. Org. Chem. 1996,
61, 1082–1100.
[24] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769–3772.
[25] a) S. Ohira, Synth. Commun. 1989, 19, 561–564; b) S. Mꢄller, B. Lie-
pold, G. J. Roth, H. J. Bestmann, Synlett 1996, 521–522.
[26] G. A. Kraus, M. T. Molina, J. Org. Chem. 1988, 53, 752–753.
[27] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953–
956.
[19] a) F. E. McDonald, H. Y. H. Zhu, C. R. Holmquist, J. Am. Chem.
Soc. 1995, 117, 6605–6606; b) Y. Yamamoto, T. Saigoku, H. Nishiya-
ma, T. Ohgai, K. Itoh, Org. Biomol. Chem. 2005, 3, 1768–1775;
c) Y. Yamamoto, T. Hashimoto, K. Hattori, M. Kikuchi, H. Nishiya-
ma, Org. Lett. 2006, 8, 3565–3568; d) Y. Yamamoto, K. Yamashita,
T. Hotta, T. Hashimoto, M. Kikuchi, H. Nishiyama, Chem. Asian J.
2007, 2, 1388–1399.
[28] A. H. Hoveyda, D. G. Gillingham, J. J. Van Veldhuizen, O. Kataoka,
S. B. Garber, J. S. Kingsbury, J. P. A. Harrity, Org. Biomol. Chem.
2004, 2, 8–23.
[29] H. B. Sinclair, Carbohydr. Res. 1984, 127, 146–148.
[30] a) K. P. Kaliappan, V. Ravikumar, Org. Biomol. Chem. 2005, 3, 848–
851; b) K. P. Kaliappan, V. Ravikumar, Synlett 2007, 0977–0979;
c) K. P. Kaliappan, V. Ravikumar, J. Org. Chem. 2007, 72, 6116–
6126.
[31] a) R. R. Schmidt, A. Wagner, Synthesis 1981, 273–275; b) S. Mash-
raqui, P. Keehn, Synth. Commun. 1982, 12, 637–645.
[32] J. S. Yadav, S. Pamu, D. C. Bhunia, S. Pabbaraja, Synlett 2007, 0992–
0994.
[33] For the corresponding alcohol, see: G. H. Veeneman, L. J. F. Gomes,
J. H. van Boom, Tetrahedron 1989, 45, 7433–7448.
[34] S. Hanessian, G. Huang, C. Chenel, R. Machaalani, O. Loiseleur, J.
Org. Chem. 2005, 70, 6721–6734.
[35] M. Arun, S. N. Joshi, V. G. Puranik, B. M. Bhawal, A. R. A. S. Desh-
mukh, Tetrahedron 2003, 59, 2309–2316.
[36] H. H. Lee, P. G. Hodgson, R. J. Bernacki, W. Korytnyk, M. Sharma,
Carbohydr. Res. 1988, 176, 5 9–72.
[37] a) K. P. Kaliappan, R. S. Nandurdikar, Chem. Commun. 2004, 2506–
2507; b) K. P. Kaliappan, R. S. Nandurdikar, Org. Biomol. Chem.
2005, 3, 3613–3614; c) K. P. Kaliappan, V. Ravikumar, Org. Lett.
2007, 9, 2417–2419; d) K. P. Kaliappan, P. Das, S. T. Chavan, S. G.
Sabharwal, J. Org. Chem. 2009, 74, 6266–6274.
[38] A. Cordero-Vargas, B. Quiclet-Sire, S. Z. Zard, Org. Biomol. Chem.
2005, 3, 4432–4443.
[39] a) A. J. Giessert, S. T. Diver, Org. Lett. 2005, 7, 351–354; b) S. T.
Diver, A. J. Giessert, Synthesis 2003, 466–471.
[40] a) B. Kaskar, G. Heise, R. S. Michalak, B. R. Vishnuvajjala, Synthesis
1990, 1031–1032; b) N. E. Batoux, F. Paradisi, P. C. Engel, M. E.
Migaud, Tetrahedron 2004, 60, 6609–6617.
[41] a) W. Pitsch, A. Russel, M. Zabel, B. Konig, Tetrahedron 2001, 57,
2345–2347; b) S. Castro, C. S. Johnson, B. Surana, M. W. Peczuh, Te-
drahedron 2009, 65, 7921–7926.
[20] K. P. Kaliappan, A. V. Subrahmanyam, Org. Lett. 2007, 9, 1121–
1124.
[21] For recent reviews on enyne metathesis and/or cross-metathesis, see:
a) M. Schuster, S. Blechert, Angew. Chem. 1997, 109, 2124–2144;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2036–2056; b) M. Mori, Top.
Organomet. Chem. 1999, 1, 133–154; c) R. H. Grubbs, S. Chang, Tet-
rahedron 1998, 54, 4413–4450; d) S. K. Armstrong, J. Chem. Soc.
Perkin Trans. 1 1998, 371–378; e) A. Fꢄrstner, Angew. Chem. 2000,
112, 3140–3172; Angew. Chem. Int. Ed. 2000, 39, 3012–3043; f) C. S.
Poulsen, R. Madsen, Synthesis 2003, 1–18; g) C. S. Connon, S. Ble-
chert, Angew. Chem. 2003, 115, 1944–1968; Angew. Chem. Int. Ed.
2003, 42, 1900–1923; h) R. R. Schrock, A. H. Hoveyda, Angew.
Chem. 2003, 115, 4740–4782; Angew. Chem. Int. Ed. 2003, 42, 4592–
4633; i) S. T. Diver, A. J. Giessert, Chem. Rev. 2004, 104, 1317–1382.
[22] For ethylene cross-enyne metathesis, see: a) J. A. Smulik, S. T.
Diver, J. Org. Chem. 2000, 65, 1788–1792; b) J. A. Smulik, S. T.
Diver, Org. Lett. 2000, 2, 2271–2274; c) K. Tonogaki, M. Mori, Tet-
rahedron Lett. 2002, 43, 2235–2238; d) A. J. Giessert, L. Snyder, J.
Markham, S. T. Diver, Org. Lett. 2003, 5, 1793–1796.
[23] For selected examples on sequential ethylene cross-enyne metathesis
and Diels–Alder reactions with quinones and other dienophiles, see:
a) S. Kotha, S. Halder, E. Brahmachary, T. Ganesh, Synlett 2000,
853–855; b) S. Kotha, S. Halder, E. Brahmachary, Tetrahedron 2002,
58, 9203–9208; c) J. A. Smulik, A. J. Giessert, S. T. Diver, Tetrahe-
dron Lett. 2002, 43, 209–211; d) R. Lauchli, K. J. Shea, Org. Lett.
2006, 8, 5287–5289; e) S. Kotha, K. Mandal, S. Banerjee, S. M.
Mobin, Eur. J. Org. Chem. 2007, 1244–1245; for selected examples
on sequential intramolecular enyne metathesis and Diels–Alder re-
actions with quinones and other dienophiles, see: f) S. Kotha, N. Sre-
nivasachary, E. Brahmachary, Tetrahedron Lett. 1998, 39, 2805–
Received: February 23, 2010
Published online: June 14, 2010
8556
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8545 – 8556