Diversity-oriented synthesis of enantiopure furofurans from carbohydrates: An expedient approach with built-in michael acceptor, masked aldehyde and leaving group in a single sugar derivative

Article abstract of DOI:10.1002/ejoc.201300603

A single sugar molecule containing three functional groups, namely a masked aldehyde, a Michael acceptor and a leaving group, reacts with a series of β-dicarbonyl compounds and related reagents to form up to three new bonds and up to three new stereocenters. The configuration of the sugar derivative controls the diastereoselectivity in the formation of all the new bonds without a requirement for any external reagent for asymmetric induction. This Chiral pool based diversity-oriented synthetic strategy has led to the formation of a series of furofurans based on different scaffolds and with appendage variations, and also to a hitherto unknown family of bicyclic 3,8-dioxabicyclo[4.2.1]nonanes. A single sugar molecule consisting of a masked aldehyde, a Michael acceptor, and a leaving group is capable of reacting with β-dicarbonyl compounds and related reagents to form enantiopure furo[2,3-b]furans via 3,8-dioxabicyclo[4.2.1]nonane intermediates in some cases. Three centers in the sugar molecule, namely C-1, C-2, and C-5, were usedboth in a sequential and a one-pot fashion.

Full text of DOI:10.1002/ejoc.201300603

FULL PAPER
DOI: 10.1002/ejoc.201300603
Diversity-Oriented Synthesis of Enantiopure Furofurans from Carbohydrates:
An Expedient Approach with Built-in Michael Acceptor, Masked Aldehyde and
Leaving Group in a Single Sugar Derivative
Chinmoy Manna[a] and Tanmaya Pathak*[a]
Keywords: Molecular diversity / Michael addition / Carbohydrates / Oxygen heterocycles / Diastereoselectivity
A single sugar molecule containing three functional groups,
namely a masked aldehyde, a Michael acceptor and a leav-
ing group, reacts with a series of β-dicarbonyl compounds
and related reagents to form up to three new bonds and up
to three new stereocenters. The configuration of the sugar
derivative controls the diastereoselectivity in the formation
of all the new bonds without a requirement for any external
reagent for asymmetric induction. This “Chiral pool” based
diversity-oriented synthetic strategy has led to the formation
of a series of furofurans based on different scaffolds and with
appendage variations, and also to a hitherto unknown family
of bicyclic 3,8-dioxabicyclo[4.2.1]nonanes.
most MCRs and in DOS based on carbohydrates, the ter-
minal anomeric carbon, or a functional group (such as an
amine, aldehyde, or carboxylate) attached to the anomeric
carbon, participates in the reaction, and the non-anomeric
parts of the acyclic or cyclic sugar molecules remain vir-
tually unused.[4,7] It is therefore clear that carbohydrates re-
main one of the most underused and unexplored groups of
chiral compounds of all those that have been used in recent
approaches to the generation of molecular complexity.[4]
1,3-Dicarbonyl compounds, a class of reactive molecules
with a minimum of three contiguous reaction sites con-
sisting of alternating electrophilic and nucleophilic centers,
have been extensively used for the generation of diverse and
complex structures.[8,9] Since a wide range of 1,3-dicarbonyl
compounds and related active-methylene reagents are easily
available, we proposed that carbohydrates and 1,3-dicar-
bonyl compounds should be ideal partners for the genera-
tion of enantiomerically pure complex structural motifs[1d]
through diversity-oriented molecular construction, pro-
vided that the carbohydrates are derivatized with appropri-
ate functional groups. Although it is known that the alde-
hyde groups of carbohydrates and the C-1 positions of gly-
cals react with 1,3-dicarbonyl compounds,[5g,10,11] C–C
bond formation between the active-methylene carbons of β-
dicarbonyl compounds and non-anomeric sugar carbons of
C-2 or C-3 positions are most efficient and general when
carbohydrate-derived Michael acceptors are used as sub-
strates.[12] For example, β-dicarbonyl compounds add to the
Introduction
An increasing demand for new molecules with diverse
and complex structures for use in chemical biology and me-
dicinal research has triggered a search for new routes for
the creation of small complex molecules.[1] Different ap-
proaches, such as multicomponent reactions (MCR)[2] and
diversity-oriented synthesis (DOS)[3] are being pursued to
generate diverse molecular structures. Among the three
most fundamental sources of diversity, appendage diversity
and scaffold diversity have generated a plethora of new and
exciting complex compounds. But stereochemical diversity,
the third of these fundamental sources of diversity, is ex-
pected to contribute even more significantly to the complex-
ity of the newly generated scaffolds.[3b,3c,3f] Although an ob-
vious approach towards fulfilling this goal would be to use
enantiopure substrates for the generation of new stereogenic
centers, so far, only a limited number of enantiopure sub-
strates have been used.[3c,3f] Since carbohydrates are inex-
pensive enantiomerically pure chiral molecules with several
contiguous chiral centers,[4] it is expected that carbo-
hydrates should be a valuable resource for the synthesis of
complex scaffolds. With the notable exception of glycals,
which have been used as templates for the synthesis of tricy-
clic compounds,[5a–5c] the non-anomeric carbons of acyclic
or cyclic sugar molecules[2d,5d–5f,6] have virtually never been
used in the synthetic transformations used for DOS.[5,6] In
[a] Department of Chemistry, Indian Institute of Technology C-2[12a,12b] or C-3[12c] positions of vinyl-sulfone-modified
Kharagpur,
carbohydrates in an efficient and diastereoselective fash-
Kharagpur 721302, India
ion.[4c,4e]
E-mail: tpathak@chem.iitkgp.ernet.in
Homepage: http://www.chem.iitkgp.ernet.in/faculty/PT/
We proposed that as well as containing an electron-
index.php
deficient double bond,[4c,4e] the same sugar molecule could
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300603.
6084
be used to deliver two more functional groups in a reaction,
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6084–6097

Diversity-Oriented Synthesis from Carbohydrates
namely a masked aldehyde functionality (the anomeric car- tor of E. coli. BF1 ATPase.[13e] A synthetic HIV protease
bon), and a leaving group at some other position of the inhibitor, TMC-114, contains furo[2,3-b]furan moiety.[13f]
molecule, e.g., at the C-5 position for a pentofuranoside. It The synthesis of an oligoannelated THF system with anti-
was reported earlier that the anomeric center was necessary fused rings making up a nonacyclic octaacetal has been re-
for maintaining the diastereoselectivity of the Michael ad- ported (Figure 2).[14a]
dition of 1,3-dicarbonyl compounds to a vinyl sulfone
modified hex-2-enofuranoside.[12a,12b] Therefore, we
planned to generate the free aldehyde after the Michael ad-
dition (Figure 1). We anticipated that intramolecular attack
Results and Discussion
of the enol oxygen would result in the formation of an
To test our hypothesis, a simple model compound,
acetal, and that the alternative intramolecular attack by the
namely 5-O-benzylated vinyl sulfone-modified furanoside
nucleophilic carbon [-COCH(R)CO-], which would already
1α,[12b] was treated with the potassium salt of acetylacetone
have formed one C–C bond in the Michael addition reac-
at ambient temperature. After 28 h, TLC indicated the for-
tion, would not take place.
mation of a mixture of compounds consisting of a major
isomer 4a contaminated with a minute amount of a dia-
stereomer. A “purified” mixture of 4a was treated with neat
TFA, and gave pure furofuran 2a in 53% yield over two
steps after purification (Scheme 1).
Figure 1. Proposed diversity-oriented molecular construction from
a densely functionalized carbohydrate.
We expected the product of such a reaction to be a
furo[2,3-b]furan. This motif is found as a constituent of a
wide range of natural and synthetic polycyclic com-
pounds.[13,14] For example, the aflatoxins are a group of ex-
tremely toxic compounds produced in spoiling foodstuffs,
which cause acute liver damage in a variety of animals, and
are powerful carcinogens.[13a] Asteltoxin is a potent inhibi-
Scheme 1. Furofurans from the reactions of 1,3-dicarbonyl reagents
and carbohydrate 1α with built-in vinyl sulfone and masked alde-
hyde groups.
This interesting and efficient transformation prompted
us to investigate the general utility of this synthetic strategy
by treating 1α with dibenzoylmethane, methyl acetoacetate,
ethyl acetoacetate, and a range of related active-methylene
compounds such as methylsulfonylacetone, phenylsulfon-
ylacetone, acetoacetamide, acetoacetanilide, and diethyl (2-
oxopropyl)phosphonate. In each case the reactions gave a
Figure 2. Structures of naturally occurring and synthetic com-
pounds containing a furo[2,3-b]furan moiety.
mixture of the respective major isomer (i.e., 4b–i) contami-
Eur. J. Org. Chem. 2013, 6084–6097
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6085

C. Manna, T. Pathak
FULL PAPER
nated with minute amounts of the diastereomers. Crude 4b–
i were treated with neat TFA to give pure furofurans 2b–i
in 53–72% yields over two steps after purification
(Scheme 1). The reaction was expected to proceed via inter-
mediates 5a–i, with intramolecular nucleophilic attack com-
ing from the β face of the furanose ring. The cyclic 1,3-
dicarbonyl compound dimedone gave tricyclic product 2j
via 4j and 5j (Scheme 1). The β anomer (i.e., 1β)[12b] also
reacted with acetylacetone, methyl acetoacetate, ethyl aceto-
acetate, methylsulfonylacetone, phenylsulfonylacetone,
acetoacetamide, acetoacetanilide, and diethyl (2-oxoprop-
yl)phosphonate to produce derivatives 3a–h, respectively,
under similar reaction conditions via adducts 6a–h. Under
Figure 3. ORTEP diagram of 2g and 3b.
It was also possible to synthesize these compounds in
acidic conditions, compounds 6a–h underwent intramolecu- one-pot fashion without separating the initial products (i.e.,
lar attack from the α face of pentose sugars 7a–h 4) from the reagents. Thus, 1α was treated with the potas-
(Scheme 2).
sium salt of acetylacetone at ambient temperature. After
28 h, a mixture of trifluoroacetic acid (TFA) and trifluoro-
methanesulfonic acid (TfOH) in a 3:1 ratio was added, and
the reaction mixture was stirred for a further 2 h. After
work-up and purification, furofuran 2a was isolated in
moderate yield over two steps (Scheme 3). The correspond-
ing β analogue (i.e., 1β) also gave the expected furofuran
derivative (i.e., 3a) under similar conditions.
Our success in executing the plan proposed in Figure 1
prompted us to extend this strategy by involving the C-5
position of vinyl-sulfone-modified carbohydrates. Thus, the
benzyl protection of 1α was replaced by a leaving group (in
8α),[12c] so as to have three reactive components in a single
molecule, as proposed in Figure 1. The α anomer (i.e., 8α)
was treated with the potassium salt of acetylacetone at am-
bient temperature, and a bicyclic compound 12a, with an
eight-membered ring containing two oxygen atoms, was
formed in high yield.
Although the structure of the product surprised us, the
formation of this 3,8-dioxabicyclo[4.2.1]nonane was ex-
plained easily by invoking intermediate 11aENOL, which was
formed from adduct 11aKETO; the enol tautomer (i.e.,
11aENOL) underwent intramolecular nucleophilic attack un-
der the reaction conditions because of the cis relationship
between the CH2OMs group and the 1,3-enol oxygen.
Scheme 2. Furofurans from the reactions of 1,3-dicarbonyl reagents Clearly, the enolate oxygen is a better nucleophile than the
and carbohydrate 1β with built-in vinyl sulfone and a masked alde-
hyde group.
competing carbanion at C-3, and therefore cyclopropan-
ation did not occur. This interesting and efficient transfor-
mation prompted us to investigate the general utility of this
It is reported that for cis-fused aflatoxins (Figure 2), the synthetic strategy by treating 8α with the potassium salts of
vicinal coupling constant associated with the proton at the dibenzoylmethane, methyl acetoacetate, ethyl acetoacetate,
acetal center (δ = 6.50 ppm) is typically 5.5–6.0 Hz, and the methylsulfonylacetone, phenylsulfonylacetone, acetoacet-
acetal carbon appears at δ = 107.6 ppm.[13a] For another amide, diethyl (2-oxopropyl)phosphonate, 1,3-cyclohexane-
related compound, asteltoxin (Figure 2), the acetal carbon dione, and dimedone, and a group of bicyclic compounds
appears at δ = 104.8 ppm.[13b] The methine proton of 2a 12b–j were formed in high yields via adducts 11bKETO
–
appears at δ = 6.02 ppm as a doublet (J = 6.0 Hz), and in 11jKETO and intermediates 11bENOL–11jENOL. The struc-
the 13C NMR spectrum, the corresponding carbon appears tures of these bicyclic 3,8-dioxabicyclo[4.2.1]nonanes were
at δ = 109.8 ppm. The corresponding protons and carbons established by X-ray analysis of single crystals of 12c, 12e,
of 2a–j and 3a–h appear within the ranges δ = 5.96– and 12i (Figure 4). Under acidic conditions, bicyclic com-
6.33 ppm (J = 6.0–6.8 Hz) and δ = 107.4–110.6 ppm. More- pounds 12a–j gave furofurans 9a–j, i.e., the products of de-
over, the structures and configurations of compounds 2g benzylation of 2a–j (Scheme 4). The most plausible route
and 3b were determined unambiguously by single-crystal X- for the transformation of 12a–j into 9a–j is initiated by the
ray analysis (Figure 3).
scission of the C-5–O bond (Scheme 5).
6086
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6084–6097

Diversity-Oriented Synthesis from Carbohydrates
Scheme 3. One-pot synthesis of stereoisomeric furofurans from carbohydrates 1α and 1β and acetylacetone.
Figure 4. ORTEP diagrams of 12c, 12e, 12i, and 9j.
Since compounds 9a–j are the products of debenzylation
of 2a–j, the identities of furofurans 9a–j were established by
comparing their spectroscopic data with those of 2a–j. The
chemical shifts and coupling constants of the characteristic
acetal methine protons of compounds 9a–j, and the chemi-
cal shifts of the corresponding carbons, appeared in the ex-
pected region [i.e., δ = 5.95–6.28 ppm (J = 5.2–7.2 Hz); δ =
107.6–118.1 ppm]. The configuration of one of the com-
pounds in this series (i.e., 9j) was established clearly by sin-
gle-crystal X-ray diffraction (Figure 4).
Scheme 4. Reactions of 1,3-dicarbonyl reagents and carbohydrate
8α with built-in vinyl sulfone, masked aldehyde and a leaving group.
From the pattern of reactivity described in Scheme 4, it methylsulfonylacetone, and phenylsulfonylacetone reacted
was clear that after the Michael addition to 8α, intermedi- with 8β to give mixtures of simple addition products and
ate 11 did not follow the proposed cyclopropanation route. cyclopropanated products, 13a/14a, 13e/14e, and 13f/14f,
We therefore assumed that the β methoxy group in 8β[12c] respectively (Scheme 6). The crude mixtures were further
would direct the incoming nucleophile from the α face of treated with additional base to give the cyclopropanated de-
the furanose ring, and so lead to the formation of a cyclo- rivatives 14a, 14e, and 14f exclusively. On treatment with
propane ring. Thus, the potassium salts of acetylacetone, TFA, these cyclopropanated carbohydrates gave cycloprop-
Eur. J. Org. Chem. 2013, 6084–6097
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6087

C. Manna, T. Pathak
FULL PAPER
anated furofurans,[14] tricyclic compounds 10a, 10e, and 10f,
in moderate yields. However, to our complete surprise, the
reactions of 8β with dibenzoylmethane, methylacetoacetate,
ethyl acetoacetate, 1,3-cyclohexanedione, and dimedone
gave β methoxy compounds 16b–d and 16i–j structurally
related to compounds 12. The formation of 16b–d and 16i–
j is only possible if the corresponding 1,3-diketo com-
pounds add to C-2 of 8β to generate 15b–d and 15i–j in an
unusual fashion. Upon treatment with neat TFA, com-
pounds 16b–d and 16i–j gave, as expected, furofurans 9b–d
and 9i–j (Scheme 6).
Scheme 5. Plausible mechanism for the conversion of 12a–j to 9a–
j.
The methylene protons of 14a, 14e, and 14f resonate at
different chemical shifts (δ = 1.72–1.77 ppm and δ = 2.13–
2.16 ppm), similar to the previously reported cases.[12b,12c]
The structure of compound 14a was also unambiguously
confirmed by single-crystal X-ray diffraction (Figure 5).
The identities of tricyclic furofurans 10a, 10e, and 10f were
established by comparing chemical shifts (δ = 5.95, 6.06,
and 5.89 ppm) and vicinal coupling constants associated
with the proton at the acetal center with furofuran 2a de-
tailed above. Moreover, the configuration of 10a was unam-
biguously confirmed by single-crystal X-ray diffraction
(Figure 5). The structures of 3,8-dioxabicyclo[4.2.1]nonane
derivatives 16b–d and 16i–j were also established from the
crystal structure of compound 16j (Figure 5).
Figure 5. ORTEP diagrams of 14a, 10a, and 16j.
It was also possible to synthesize compounds 9a and 10a
in a one-pot fashion without separation of compounds 12a
and 14a. Thus, 8α was treated with the potassium salt of
acetylacetone at ambient temperature. After 10 h, a 3:1 mix-
ture of TFA and TfOH was added, and the reaction mixture
was stirred for a further 2.5 h. After the usual work-up and
purification, the reaction mixture gave furofuran 9a in mod-
erate yield over two steps (Scheme 7). The corresponding β
analogue (i.e., 8β), on the other hand, gave a tricyclic furo-
furan derivative 10a under similar reaction conditions
Scheme 6. Reactions of 1,3-dicarbonyl reagents and carbohydrate
8β with built-in vinyl sulfone, masked aldehyde and a leaving group. (Scheme 7).
6088
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6084–6097

Diversity-Oriented Synthesis from Carbohydrates
Scheme 7. One-pot synthesis of 9a and 10a from 8α and 8β.
and 13C NMR spectra of new compounds were recorded at 200/400
and 50/100 MHz respectively using CDCl3 as the solvent. DEPT
experiments were carried out to identify the methylene carbons.
Conclusions
We have successfully established that a single molecule
consisting of three components, namely a masked aldehyde, Optical rotations were recorded at 589 nm. Mass spectrometry data
were obtained from a mass analyser consisting of TOF and quadru-
a Michael acceptor, and a leaving group, is capable of re-
acting with an externally delivered fourth component, a β-
dicarbonyl compound or a related reagent, in a sequential
and one-pot fashion to form new furofurans with up to
three newly generated bonds and up to three new stereocen-
ters. Since the multifunctionalized single molecule was de-
rived from a carbohydrate, the in-built chirality gave com-
plete control over the diastereoselectivity of the formation
of all of the new bonds. The reaction did not require any
external reagent for the imposition of asymmetry in the
product. Schemes 4 and 6 also highlight the fact that cyclo-
propanated furofuran formation is not a forgone conclu-
sion, and is dependent on the nature of the β-dicarbonyl or
related reagents. Most importantly, these reactions are the
only examples of carbohydrate-based diversity-oriented
synthesis where at least three centers in the sugar molecule,
namely C-1, C-2, and C-5, have been used in the reaction.
The strategy generated furofurans with diasteromerically
different tricyclic scaffolds that were diversely decorated
with reactive functional groups or appendages, including
R–C=C–C(O)RЈ, R–C=C–SO2RЈ, R–C=C–P(O)(OEt)2,
and R–C=C–CHO. These reactive residues are capable of
combining with other suitably functionalized compounds to
generate more complex scaffolds. Work in this direction is
currently in progress in our laboratory.
pole units in either ESI+ or ESI– mode.
General Procedure for the Stepwise Synthesis of 2a–j and 3a–h from
1α and 1β, respectively: A β-dicarbonyl compound (1.6 equiv.) was
added to a suspension of tBuOK (1.2 equiv.) in dry THF (2 mL)
at ambient temperature, and the resulting solution was stirred for
30 min at that temperature under nitrogen. A solution of 1α or 1β
(1 equiv.) in dry THF (1 mL) was added dropwise to the reaction
mixture. The resulting solution was then stirred for 16–28 h at am-
bient temperature. After completion of the reaction (TLC), the re-
action mixture was concentrated under reduced pressure. The resi-
due was dissolved in EtOAc, and the organic phase was washed
with NH4Cl (satd. aq.). The organic phase was dried with anhy-
drous Na2SO4 and filtered, and the filtrate was concentrated under
reduced pressure. The residue was passed through a short column
of silica gel to remove the excess reagents. All addition compounds
were treated with TFA (2 equiv.) for 2–3 h at ambient temperature.
After completion of the reaction (TLC), the reaction mixture was
poured into NaHCO3 (satd. aq.; 30 mL) and washed with EtOAc
(3ϫ 20 mL). The combined organic extracts were dried with an-
hydrous Na2SO4 and filtered, and the filtrate was concentrated un-
der reduced pressure. The residue was purified by column
chromatography over silica gel (EtOAc/petroleum ether) to give the
pure product. Compound 1α or 1β was treated in this way with
methylsulfonylacetone, phenylsulfonylacetone, or diethyl (2-oxo-
propyl)phosphonate.
Compound 2a: Following the general procedure, acetylacetone
(0.13 mL, 1.28 mmol) was treated with 1α (0.30 g, 0.80 mmol) in
the presence of tBuOK (0.11 g, 0.96 mmol) for 28 h to give 4a,
which was treated with TFA for 2 h to give 2a (0.28 g, 60%) as a
glassy solid, m.p. 168 °C. [α]3D0 = +83.75 (c = 1.391, CHCl3). 1H
NMR: δ = 1.99 (s, 3 H), 2.09 (s, 3 H), 2.43 (s, 3 H), 3.19–3.38 (m,
2 H), 3.84 (s, 1 H, 4-H), 4.12–4.13 (m, 1 H, 3a-H), 4.30–4.40 (m,
2 H), 4.87 (m, 1 H, 5-H), 6.02 (d, J = 6.0 Hz, 1 H, 6a-H), 7.12–
7.28 (m, 5 H), 7.35 (d, J = 7.2 Hz, 2 H), 7.80 (d, J = 7.2 Hz, 2 H)
ppm. 13C NMR: δ = 15.3, 21.7, 29.3, 49.5 (C-3a), 69.3 (C-4), 70.7
(CH2), 73.1 (CH2), 79.5 (C-5), 109.8 (C-6a), 113.1, 127.7, 127.8,
128.3, 129.0, 129.6, 129.9, 133.8, 137.3, 145.3, 167.4, 192.9 ppm.
HRMS (ESI): calcd. for C24H27O6S [M + H]+ 443.1530; found
443.1528.
Experimental Section
General Methods: All reactions were conducted under a nitrogen
atmosphere. Melting points were determined in open-ended capil-
lary tubes. Carbohydrates and other fine chemicals were obtained
from commercial suppliers, and were used without purification.
Solvents were dried and distilled following standard procedures.
TLC was carried out on pre-coated plates (Merck silica gel 60,
F254), and the spots were visualized with UV light or by charring
the plate dipped in H2SO4 (5% solution in MeOH). Column
1
chromatography was carried out on silica gel (230–400 mesh). H
Eur. J. Org. Chem. 2013, 6084–6097
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6089

C. Manna, T. Pathak
FULL PAPER
Compound 2b: Following the general procedure, dibenzoylmethane
(0.29 g, 1.28 mmol) was treated with 1α (0.30 g, 0.80 mmol) in the
presence of tBuOK (0.11 g, 0.96 mmol) for 30 h to give 4b, which
was treated with TFA for 4 h to give 2b (0.33 g, 72%) as white
4.52 (s, 1 H), 4.79–4.82 (m, 2 H), 6.04 (d, J = 6.4 Hz, 1 H), 7.21–
7.37 (m, 7 H), 7.47–7.51 (m, 2 H), 7.57–7.61 (m, 1 H), 7.72 (d, J
= 7.2 Hz, 2 H), 7.82 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR: δ = 13.6,
21.7, 48.7, 68.6, 70.6 (CH2), 73.2 (CH2), 80.5, 108.2, 110.2, 127.1,
127.7ϫ2, 128.3, 128.9, 129.2, 130.0, 133.2, 133.7, 137.2, 141.1,
145.3, 166.7 ppm. HRMS (ESI): calcd. for C28H29O7S2 [M + H]+
crystals, m.p. 80 °C. [α]3D0 = +14.00 (c = 0.954, CHCl3). H NMR:
1
δ = 2.45 (s, 3 H), 3.39–3.43 (m, 1 H), 3.51–3.55 (m, 1 H), 4.35–4.46
(m, 2 H), 4.50–4.52 (m, 2 H), 5.00–5.04 (m, 1 H), 6.33 (d, J = 541.1368; found 541.1355.
6.4 Hz, 1 H), 6.97–7.06 (m, 6 H), 7.13–7.41 (m, 11 H), 7.88 (d, J
Compound 2g: Following the general procedure, acetoacetamide
= 8.0 Hz, 2 H) ppm. 13C NMR: δ = 21.7, 51.9, 68.8, 71.0 (CH2),
73.0 (CH2), 79.2, 109.3, 110.4, 127.5, 127.6, 127.7ϫ2, 128.3,
128.9ϫ2, 129.0, 129.9, 130.4, 131.6, 134.0, 137.3, 137.9, 145.1ϫ2,
164.1, 192.0 ppm. HRMS (ESI): calcd. for C34H31O6S [M + H]+
567.1830; found 567.1841.
(0.14 g, 1.28 mmol) was treated with 1α (0.30 g, 0.80 mmol) in the
presence of tBuOK (0.11 g, 0.96 mmol) for 6 h to give 4g, which
was treated with TFA for 16 h to give 2g (0.21 g, 60%) as white
crystals, m.p. 154 °C. [α]3D0 = +73.15 (c = 1.441, CHCl3). 1H NMR:
δ = 2.1 (s, 3 H), 2.4 (s, 3 H), 3.09–3.14 (m, 1 H), 3.24–3.28 (m, 1
H), 3.8 (s, 1 H), 4.21–4.33 (m, 3 H), 4.55–4.58 (m, 1 H), 5.81 (br.
Compound 2c: Following the general procedure, methyl acetoacet-
ate (0.14 mL, 1.28 mmol) was treated with 1α (0.30 g, 0.80 mmol) s, 1 H), 6.13 (d, J = 6.8 Hz, 1 H), 6.57 (br. s, 1 H), 7.03 (d, J =
in the presence of tBuOK (0.11 g, 0.96 mmol) for 12 h to give 4c,
5.2 Hz, 2 H), 7.27–7.34 (m, 5 H), 7.72 (d, J = 8.0 Hz, 2 H) ppm.
which was treated with TFA for 5.5 h to give 2c (0.21 g, 57%) as 13C NMR: δ = 14.1, 21.7, 48.0, 70.3 (CH2), 70.6, 73.0 (CH2), 80.6,
1
white crystals, m.p. 139 °C. [α]3D0 = +42.08 (c = 1.625, CHCl3). H
104.0, 110.5, 127.6, 127.8, 128.3, 128.8, 130.2, 132.5, 137.0, 145.8,
NMR: δ = 2.03 (d, J = 0.8 Hz, 3 H), 2.46 (s, 3 H), 3.24–3.28 (m,
165.6, 167.1 ppm. HRMS (ESI): calcd. for C23H26NO6S [M + H]+
1 H), 3.41–3.42 (m, 1 H), 3.44 (s, 3 H), 3.87 (s, 1 H), 4.06–4.12 (m, 444.1499; found 444.1481.
1 H), 4.39 (d, J = 12.2 Hz, 1 H), 4.48 (d, J = 12.2 Hz, 1 H), 4.98–
Compound 2h: Following the general procedure, acetoacetanilide
5.00 (m, 1 H), 6.06 (d, J = 6.8 Hz, 1 H), 7.18 (d, J = 6.0 Hz, 2 H),
7.26–7.33 (m, 3 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.81 (d, J = 8.0 Hz,
2 H) ppm. 13C NMR: δ = 14.1, 21.6, 49.1, 50.9, 69.3, 70.7 (CH2),
73.0 (CH2), 79.1, 102.1, 110.1, 127.6, 127.7, 128.4, 129.0, 129.8,
134.2, 137.3, 145.1, 164.4, 168.9 ppm. HRMS (ESI): calcd. for
C24H27O7S [M + H]+ 459.1488; found 459.1478.
(0.23 g, 1.28 mmol) was treated with 1α (0.30 g, 0.80 mmol) in the
presence of tBuOK (0.11 g, 0.96 mmol) for 8.5 h to give 4h, which
was treated with TFA for 12 h to give 2h (0.27 g, 65%) as a white
1
solid, m.p. 155 °C. [α]3D0 = +191.43 (c = 1.466, CHCl3). H NMR:
δ = 2.26 (s, 3 H), 2.40 (s, 3 H), 3.13–3.18 (m, 1 H), 3.25–3.29 (m,
1 H), 3.81 (s, 1 H), 4.23 (d, J = 12.2 Hz, 1 H), 4.28 (d, J = 12.2 Hz,
1 H), 4.36 (d, J = 6.8 Hz, 1 H), 4.57–4.60 (m, 1 H), 6.20 (d, J =
6.8 Hz, 1 H), 7.02 (d, J = 2.4 Hz, 2 H), 7.10–7.14 (m, 1 H), 7.23–
Compound 2d: Following the general procedure, ethyl acetoacetate
(0.12 mL, 1.28 mmol) was treated with 1α (0.30 g, 0.80 mmol) in
the presence of tBuOK (0.11 g, 0.96 mmol) for 15 h to give 4d, 7.38 (m, 7 H), 7.71 (d, J = 8.0 Hz, 2 H), 7.85 (d, J = 8.0 Hz, 2 H),
which was treated with TFA for 6 h to give 2d (0.23 g, 65%) as a
glassy solid, m.p. 114 °C. [α]3D0 = +41.72 (c = 1.525, CHCl3). 1H
NMR: δ = 1.17 (t, J = 7.2 Hz, 3 H), 2.04 (d, J = 0.8 Hz, 3 H), 2.44
8.46 (s, 1 H) ppm. 13C NMR: δ = 14.5, 21.8, 47.7, 70.1 (CH2), 71.1,
73.0 (CH2), 80.9, 105.0, 110.7, 119.7, 123.9, 127.7, 127.9, 128.4,
128.9, 129.0, 130.4, 132.5, 137.0, 139.1, 146.1, 162.0, 167.7 ppm.
(s, 3 H), 3.19–3.24 (m, 1 H), 3.38–3.42 (m, 1 H), 3.93 (s, 1 H), 4.01 HRMS (ESI): calcd. for C29H30NO6S [M + H]+ 520.1765; found
(q, J = 6.8, 13.8 Hz, 2 H), 4.14 (d, J = 6.4 Hz, 1 H), 4.36 (d, J =
12.0 Hz, 1 H), 4.44 (d, J = 12.0 Hz, 1 H), 4.87–4.91 (m, 1 H), 6.02
(d, J = 6.4 Hz, 1 H), 7.15 (d, J = 6.4 Hz, 2 H), 7.24–7.30 (m, 3 H),
7.35 (d, J = 8.0 Hz, 2 H), 7.80 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR:
δ = 14.3, 14.4, 21.7, 49.0, 59.9 (CH2), 69.4, 70.8 (CH2), 73.0 (CH2),
79.4, 102.5, 110.0, 127.6, 127.8, 128.4, 129.1, 130.0, 134.2, 137.4,
145.2, 164.1, 168.7 ppm. HRMS (ESI): calcd. for C25H29O7S [M +
H]+ 473.1645; found 473.1634.
520.1794.
Compound 2i: Following the general procedure, diethyl (2-oxo-
propyl)phosphonate (0.25 mL, 1.28 mmol) was treated with 1α
(0.30 g, 0.80 mmol) in the presence of tBuOK (0.11 g, 0.96 mmol)
for 12 h to give 4i, which was treated with TFA for 10 h to give 2i
(0.26 g, 60%) as a colorless gum. [α]3D0 = +51.53 (c = 1.341, CHCl3).
1H NMR: δ = 1.07–1.16 (m, 6 H), 1.90–1.92 (m, 3 H), 2.30 (s, 3
H), 3.04–3.13 (m, 1 H), 3.27–3.35 (m, 1 H), 3.73–3.94 (m, 5 H),
3.99 (s, 1 H), 4.28 (s, 2 H), 4.66–4.73 (m, 1 H), 5.96 (d, J = 6.6 Hz,
1 H), 7.01–7.05 (m, 2 H), 7.12–7.22 (m, 5 H), 7.65 (d, J = 8.2 Hz,
2 H) ppm. 13C NMR: δ = 13.9, 16.1, 16.3ϫ2, 21.6, 50.4, 50.5, 61.4
(CH2), 61.5ϫ2 (CH2), 61.7 (CH2), 68.8, 70.8 (CH2), 72.9 (CH2),
79.4, 92.7, 97.1, 110.2, 110.4, 127.3, 127.6, 128.2, 128.9, 129.9,
133.9, 137.4, 145.1, 168.6, 169.2 ppm. 31P NMR: δ = 19.0 ppm.
HRMS (ESI): calcd. for C26H33O8PSNa [M + Na]+ 559.1525;
Compound 2e: Following the general procedure, methylsulfonyl-
acetone (0.18 g, 1.28 mmol) was treated with 1α (0.30 g, 0.80 mmol)
in the presence of tBuOK (0.11 g, 0.96 mmol) for 12 h to give 4e,
which was treated with TFA for 5.5 h to give 2e (0.20 g, 53%) as a
white solid, m.p. 137 °C. [α]3D0 = +55.51 (c = 0.440, CHCl3). 1H
NMR: δ = 2.02 (d, J = 1.6 Hz, 3 H), 2.44 (s, 3 H), 2.86 (s, 3 H),
3.25–3.35 (m, 2 H), 4.21–4.24 (m, 1 H), 4.40 (s, 2 H), 4.49–4.50 (m,
1 H), 4.78–4.82 (m, 1 H), 6.22 (d, J = 6.8 Hz, 1 H), 7.20–7.22 (m, found 559.1531.
2 H), 7.29–7.35 (m, 5 H), 7.82 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR:
Compound 2j: Following the general procedure, dimedone (0.18 g,
δ = 13.5, 21.7, 42.8, 49.0, 68.3, 70.6 (CH2), 73.3 (CH2), 80.7, 107.1,
110.2, 127.7, 127.8, 128.3, 128.9, 130.1, 133.5, 137.1, 145.5,
166.5 ppm. HRMS (ESI): calcd. for C23H27O7S2 [M + H]+
479.1174; found 479.1198.
1.28 mmol) was treated with 1α (0.30 g, 0.80 mmol) in the presence
of tBuOK (0.11 g, 0.96 mmol) for 48 h to give 4j, which was treated
with TFA for 12 h to give 2j (0.16 g, 42%) as a glassy solid, m.p.
1
131 °C. [α]3D0 = +95.00 (c = 0.663, CHCl3). H NMR: δ = 0.9 (s, 3
Compound 2f: Following the general procedure, phenylsulfonyl-
acetone (0.25 g, 1.28 mmol) was treated with 1α (0.30 g, 0.80 mmol)
in the presence of tBuOK (0.11 g, 0.96 mmol) for 36 h to give 4f,
which was treated with TFA for 5.5 h to give 2f (0.23 g, 53%) as a
white solid, m.p. 176 °C. [α]3D0 = +143.58 (c = 0.478, CHCl3). 1H
NMR: δ = 2.14 (d, J = 1.6 Hz, 3 H), 2.46 (s, 3 H), 3.24–3.28 (m,
1 H), 3.35–3.39 (m, 1 H), 4.12 (d, J = 7.2 Hz, 1 H), 4.42 (s, 1 H),
H), 1.0 (s, 3 H), 1.82–2.16 (m, 4 H), 2.47 (s, 3 H), 3.30–3.34 (m, 1
H), 3.39–3.43 (m, 1 H), 3.92 (s, 1 H), 3.96 (d, J = 6.0 Hz, 1 H),
4.43 (s, 2 H), 5.06–5.08 (m, 1 H), 6.26 (d, J = 6.0 Hz, 1 H), 7.21
(d, J = 7.2 Hz, 2 H), 7.28–7.34 (m, 3 H), 7.39 (d, J = 8.0 Hz, 2 H),
7.85 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR: δ = 21.8, 28.0, 28.9, 37.4
(CH2), 46.4, 50.6 (CH2), 67.4, 71.0 (CH2), 73.2 (CH2), 80.1, 110.6,
113.1, 127.8, 127.9, 128.5, 128.9, 129.9, 133.9, 137.3, 145.2, 175.3,
6090
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6084–6097

Diversity-Oriented Synthesis from Carbohydrates
193.3 ppm. HRMS (ESI): calcd. for C27H31O6S [M + H]+ 483.1831;
found 483.1841.
= 13.6, 21.8, 50.5, 67.5, 68.3 (CH2), 73.5 (CH2), 80.0, 106.2, 108.1,
126.4, 127.7, 127.8, 128.4, 129.1ϫ2, 130.0, 133.1, 135.3, 137.6,
141.3, 145.3, 169.7 ppm. HRMS (ESI): calcd. for C28H29O7S2 [M
+ H]+ 541.1367; found 541.1355.
Compound 3a: Following the general procedure, acetylacetone
(0.11 mL, 1.07 mmol) was treated with 1β (0.25 g, 0.67 mmol) in
the presence of tBuOK (0.09 g, 0.80 mmol) for 30 h to give 6a,
which was treated with TFA for 3.5 h to give 3a (0.19 g, 65%) as a
glassy solid, m.p. 193 °C. [α]3D0 = –136.49 (c = 0.763, CHCl3). 1H
NMR: δ = 2.06 (s, 3 H), 2.22 (s, 3 H), 2.44 (s, 3 H), 3.83 (d, J =
4.4 Hz, 1 H), 3.91 (d, J = 6.0 Hz, 1 H), 4.09–4.22 (m, 2 H), 4.42–
4.47 (m, 1 H), 4.54 (d, J = 11.8 Hz, 1 H), 4.67 (d, J = 11.8 Hz, 1
H), 6.12 (d, J = 6.0 Hz, 1 H), 7.24–7.34 (m, 5 H), 7.38 (d, J =
8.0 Hz, 2 H), 7.81 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR: δ = 15.5,
21.7, 29.1, 51.1, 67.8, 68.6 (CH2), 73.6 (CH2), 79.8, 107.4, 111.7,
127.7, 127.9, 128.3, 128.9, 129.8, 135.2, 137.7, 145.2, 169.4,
192.6 ppm. HRMS (ESI): calcd. for C24H27O6S [M + H]+ 443.1541;
found 443.1528.
Compound 3f: Following the general procedure, acetoacetamide
(0.12 g, 1.07 mmol) was treated with 1β (0.25 g, 0.67 mmol) in the
presence of tBuOK (0.09 g, 0.80 mmol) for 26 h to give 6f, which
was treated with TFA for 20 h to give 3f (0.19 g, 65%) as a colorless
1
gum. [α]3D0 = –61.70 (c = 1.808, CHCl3). H NMR: δ = 2.18 (s, 3
H), 2.43 (s, 3 H), 3.11–3.15 (m, 1 H), 3.26–3.29 (m, 1 H), 3.77 (s,
1 H), 4.22–4.31 (m, 3 H), 4.55–4.58 (m, 1 H), 6.14 (d, J = 6.8 Hz,
1 H), 7.04 (d, J = 4.4 Hz, 2 H), 7.26–7.32 (m, 5 H), 7.73 (d, J =
8.0 Hz, 2 H) ppm. 13C NMR: δ = 14.1, 21.7, 48.1, 70.3 (CH2), 70.7,
73.0 (CH2), 80.7, 104.0, 110.6, 127.5, 127.8, 128.4, 128.8, 130.2,
132.6, 137.0, 145.8, 165.5, 167.3 ppm. HRMS (ESI): calcd. for
C23H26NO6S [M + H]+ 444.1470; found 444.1481.
Compound 3b: Following the general procedure, methyl acetoacet-
ate (0.12 mL, 1.07 mmol) was treated with 1β (0.25 g, 0.67 mmol)
in the presence of tBuOK (0.09 g, 0.80 mmol) for 48 h to give 6b,
which was treated with TFA for 3 h to give 3b (0.17 g, 57%) as a
white solid, m.p. 167 °C. [α]3D0 = –62.94 (c = 0.470, CHCl3). 1H
NMR: δ = 2.19 (d, J = 0.8 Hz, 3 H), 2.46 (s, 3 H), 3.34 (s, 3 H),
3.81 (d, J = 4.8 Hz, 1 H), 3.88 (d, J = 6.0 Hz, 1 H), 4.15–4.27 (m,
2 H), 4.49–4.53 (m, 1 H), 4.58 (d, J = 12.2 Hz, 1 H), 4.70 (d, J =
12.2 Hz, 1 H), 6.18 (d, J = 6.4 Hz, 1 H), 7.26–7.40 (m, 7 H), 7.80
(d, J = 8.0 Hz, 2 H) ppm. 13C NMR: δ = 14.1, 21.6, 50.6, 50.7,
68.1, 68.5 (CH2), 73.6 (CH2), 79.8, 99.8, 107.9, 127.6, 127.9, 128.3,
128.8, 129.7, 135.4, 137.7, 145.0, 164.4, 171.4 ppm. HRMS (ESI):
calcd. for C24H27O7S [M + H]+ 459.1479; found 459.1478.
Compound 3g: Following the general procedure, acetoacetanilide
(0.19 g, 1.07 mmol) was treated with 1β (0.25 g, 0.67 mmol) in the
presence of tBuOK (0.09 g, 0.80 mmol) for 60 h to give 6g, which
was treated with TFA for 24 h to give 3g (0.21 g, 60%) as a glassy
1
solid, m.p. 162 °C. [α]3D0 = –179.98 (c = 0.636, CHCl3). H NMR:
δ = 2.39 (d, J = 7.6 Hz, 6 H), 3.56–3.59 (m, 1 H), 3.77–3.82 (m, 1
H), 3.90 (d, J = 5.2 Hz, 1 H), 4.21 (d, J = 12.0 Hz, 1 H), 4.37–4.42
(m, 2 H), 4.49 (d, J = 6.8 Hz, 1 H), 6.15 (d, J = 6.4 Hz, 1 H), 7.14
(d, J = 1.2 Hz, 2 H), 7.26–7.37 (m, 8 H), 7.71 (m, 4 H), 8.06 (s, 1
H) ppm. 13C NMR: δ = 14.1, 21.6, 49.0, 66.9 (CH2), 70.5, 73.2
(CH2), 78.0, 103.0, 107.6, 119.6, 123.9, 127.6, 127.8, 128.3, 128.4,
129.0, 130.3, 134.7, 137.1, 138.6, 145.8, 161.9, 169.2 ppm. HRMS
(ESI): calcd. for C29H30NO6S [M + H]+ 520.1793; found 520.1794.
Compound 3c: Following the general procedure, ethyl acetoacetate
(0.10 mL, 1.07 mmol) was treated with 1β (0.25 g, 0.67 mmol) in
the presence of tBuOK (0.09 g, 0.80 mmol) for 60 h to give 6c,
which was treated with TFA for 4 h to give 3c (0.19 g, 60%) as a
white solid, m.p. 120 °C. [α]3D0 = –90.486 (c = 0.86, CHCl3). 1H
NMR: δ = 1.07 (t, J = 7.1 Hz, 3 H), 2.23 (d, J = 1.2 Hz, 3 H), 2.48
(s, 3 H), 3.87–3.99 (m, 4 H), 4.19–4.23 (m, 2 H), 4.52–4.75 (m, 3
H), 6.17 (d, J = 6.2 Hz, 1 H), 7.29–7.42 (m, 7 H), 7.84 (d, J =
8.2 Hz, 2 H) ppm. 13C NMR: δ = 14.3, 14.4, 21.7, 50.6, 59.7 (CH2),
68.2, 68.6 (CH2), 73.6 (CH2), 79.8, 100.1, 107.8, 127.8, 128.0, 128.4,
128.9, 129.8, 135.5, 137.8, 145.1, 164.1, 171.2 ppm. HRMS (ESI):
calcd. for C25H29O7S [M + H]+ 473.1620; found 473.1634.
Compound 3h: Following the general procedure, diethyl (2-oxo-
propyl)phosphonate (0.21 mL, 1.07 mmol) was treated with 1β
(0.25 g, 0.67 mmol) in the presence of tBuOK (0.09 g, 0.80 mmol)
for 10 h to give 6h, which was treated with TFA for 8 h to give 3h
(0.22 g, 62%) as a colorless gum. [α]3D0 = –68.70 (c = 1.208, CHCl3).
1H NMR: δ = 1.09–1.14 (m, 3 H), 1.21–1.24 (m, 5 H), 2.11 (s, 3
H), 2.43 (s, 3 H), 3.74–3.90 (m, 5 H), 4.05 (d, J = 4.8 Hz, 1 H),
4.11–4.20 (m, 2 H), 4.47–4.50 (m, 1 H), 4.54 (d, J = 12.0 Hz, 1 H),
4.68 (d, J = 12.0 Hz, 1 H), 6.16 (d, J = 6.0 Hz, 1 H), 7.28–7.36 (m,
7 H), 7.77 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR: δ = 13.8, 16.0,
16.1, 16.2, 16.3, 21.6, 52.1, 52.2, 61.3ϫ2 (CH2), 61.4ϫ2 (CH2),
67.7, 68.6 (CH2), 73.5 (CH2), 79.6, 91.0, 93.2, 107.9, 108.1, 127.6,
127.8, 128.3, 128.7, 129.8, 135.3, 137.8, 145.0, 170.7, 171.1 ppm.
31P NMR: δ = 19.5 ppm. HRMS (ESI): calcd. for C26H33O8PSNa
[M + Na]+ 559.1523; found 559.1531.
Compound 3d: Following the general procedure, methylsulfonyl-
acetone (0.15 g, 1.07 mmol) was treated with 1β (0.25 g, 0.67 mmol)
in the presence of tBuOK (0.09 g, 0.80 mmol) for 48 h to give 6d,
which was treated with TFA for 5 h to give 3d (0.14 g, 43%) as
white crystals, m.p. 212 °C. [α]3D0 = –82.05 (c = 1.20, CHCl3). 1H
NMR: δ = 2.22 (s, 3 H), 2.43 (s, 3 H), 2.47 (s, 3 H), 3.96–4.13 (m,
3 H), 4.41 (d, J = 7.2 Hz, 1 H), 4.48–4.65 (m, 3 H), 6.27 (d, J =
6.4 Hz, 1 H), 7.26–7.43 (m, 7 H), 7.80 (d, J = 8.0 Hz, 2 H) ppm.
13C NMR: δ = 13.4, 21.6, 42.6, 50.6, 67.2, 68.0 (CH2), 73.5 (CH2),
79.8, 105.0, 108.2, 127.7, 127.8, 128.4, 128.9, 130.1, 135.0, 137.5,
145.4, 169.2 ppm. HRMS (ESI): calcd. for C23H27O7S2 [M + H]+
479.1216; found 479.1198.
One-Pot Synthesis of 2a: Acetylacetone (0.036 mL, 0.347 mmol)
was added to a suspension of tBuOK (0.03 g, 0.294 mmol) in dry
THF (0.5 mL) at ambient temperature, and the resulting solution
was stirred for 30 min under nitrogen. A solution of 1α (0.10 g,
0.267 mmol) in dry THF (0.5 mL) was added dropwise to the reac-
tion mixture. The resulting solution was then stirred for 28 h at
ambient temperature. After completion of the reaction (TLC), a
mixture of TFA and TfOH (3:1 ratio, 0.1 mL/mmol) was added to
the reaction mixture, and the mixture was stirred for a further 2 h
at ambient temperature. After completion of the reaction (TLC),
Compound 3e: Following the general procedure, phenylsulfonyl-
acetone (0.21 g, 1.07 mmol) was treated with 1β (0.25 g, 0.67 mmol) the reaction mixture was poured into NaHCO3 (satd. aq.; 30 mL).
in the presence of tBuOK (0.09 g, 0.80 mmol) for 51 h to give 6e,
which was treated with TFA for 6.5 h to give 3e (0.16 g, 43%) as
The reaction mixture was partitioned between NaHCO3 (aq.) and
EtOAc (3ϫ 20 mL). The organic extracts were combined, dried
with anhydrous Na2SO4, and filtered, and the filtrate was concen-
trated under reduced pressure. The residue was purified by column
white crystals, m.p. 152 °C. [α]3D0 = –80.571 (c = 1.25, CHCl3). H
1
NMR: δ = 2.31 (s, 3 H), 2.54 (s, 3 H), 3.72 (d, J = 5.6 Hz, 1 H),
4.11–4.14 (m, 2 H), 4.49–4.71 (m, 4 H), 6.13 (d, J = 6.0 Hz, 1 H), chromatography over silica gel (EtOAc/petroleum ether) to give 2a
7.19–7.59 (m, 12 H), 7.83 (d, J = 7.8 Hz, 2 H) ppm. 13C NMR: δ
(0.06 g, 54%).
Eur. J. Org. Chem. 2013, 6084–6097
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6091

C. Manna, T. Pathak
One-Pot Synthesis of 3a: Acetylacetone (0.036 mL, 0.347 mmol) 3 H), 3.31 (s, 1 H), 3.57 (s, 3 H), 3.63 (d, J = 12.4 Hz, 1 H), 3.75
FULL PAPER
was added to a suspension of tBuOK (0.03 g, 0.294 mmol) in dry
THF (0.5 mL) at ambient temperature, and the resulting solution
was stirred for 30 min at that temperature under nitrogen. A solu-
tion of 1β (0.10 g, 0.267 mmol) in dry THF (0.5 mL) was added
dropwise to the reaction mixture. The resulting solution was then
stirred for 30 h at ambient temperature. After completion of the
reaction (TLC), a mixture of TFA and TfOH (3:1 ratio, 0.1 mL/
mmol) was added to the reaction mixture, and the mixture was
stirred for a further 4 h at ambient temperature. After completion
of the reaction (TLC), the reaction mixture was poured into
NaHCO3 (satd. aq.; 30 mL). The reaction mixture was partitioned
between NaHCO3 (aq.) and EtOAc (3ϫ 20 mL). The organic ex-
tracts were combined, dried with anhydrous Na2SO4, and filtered,
and the filtrate was concentrated under reduced pressure. The resi-
due was purified by column chromatography over silica gel (EtOAc/
petroleum ether) to give 3a (0.058 g, 52%).
(d, J = 8.4 Hz, 1 H), 4.25 (dd, J = 4.0, 4.4 Hz, 1 H), 5.06 (s, 2 H),
7.32 (d, J = 8.0 Hz, 2 H), 7.81 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR:
δ = 21.5, 21.6, 46.7, 51.8, 55.4, 73.4, 74.4 (CH2), 77.9, 110.5, 116.1,
129.2, 129.4, 129.5, 129.6, 135.1, 144.7, 167.1, 170.0 ppm. HRMS
(ESI): calcd. for C18H22O7SNa [M + Na]+ 405.0975; found
405.0984.
Compound 12d: Following the general procedure, ethyl acetoacetate
(0.24 mL, 2.58 mmol) was treated with 8α (0.60 g, 1.61 mmol) in
the presence of tBuOK (0.22 g, 1.93 mmol) for 18 h to give 12d
(0.53 g, 80%) as a colorless gum. [α]3D0 = –51.06 (c = 0.900, CHCl3).
1H NMR: δ = 1.15 (t, J = 7.2 Hz, 3 H), 2.12 (s, 3 H), 2.39 (s, 3 H),
3.16 (s, 3 H), 3.32 (s, 1 H), 3.61 (d, J = 12.4 Hz, 1 H), 3.74 (s, 1
H), 4.01–4.06 (m, 2 H), 4.22 (dd, J = 4.4, 12.8 Hz, 1 H), 5.03 (s, 2
H), 7.29 (d, J = 8.0 Hz, 2 H), 7.79 (d, J = 8.0 Hz, 2 H) ppm. 13C
NMR: δ = 14.1, 21.5, 21.6, 46.6, 55.3, 60.8 (CH2), 73.3, 74.3 (CH2),
78.0, 110.6, 116.3, 129.4, 135.0, 144.7, 166.7, 169.5 ppm. HRMS
(ESI): calcd. for C19H24O7SNa [M + Na]+ 419.1121; found
419.1140.
General Procedure for the Synthesis of 12a–j from 8α: A β-dicarb-
onyl compound (1.6 equiv.) was added to a suspension of tBuOK
(1.2 equiv.) in dry THF (2 mL) at ambient temperature, and the
resulting solution was stirred for 30 min at that temperature under
nitrogen. A solution of 8α (1 equiv.) in dry THF (1 mL) was added
dropwise to the reaction mixture. The resulting solution was stirred
for 10–30 h at that temperature. After completion of the reaction
(TLC), the reaction mixture was concentrated under reduced pres-
sure. The residue was dissolved in EtOAc, and the organic phase
was washed with NH4Cl (satd. aq.). The organic phase was dried
with anhydrous Na2SO4 and filtered, and the filtrate was concen-
trated under reduced pressure. The residue was purified by column
chromatography over silica gel (EtOAc/petroleum ether) to give the
pure product. Compound 8α was treated in this way with methyl-
sulfonylacetone, phenylsulfonylacetone, or diethyl (2-oxopropyl)-
phosphonate.
Compound 12e: Following the general procedure, methylsulfonyl-
acetone (0.24 g, 1.78 mmol) was treated with 8α (0.40 g, 1.11 mmol)
in the presence of tBuOK (0.15 g, 1.33 mmol) for 12 h to give 12e
(0.38 g, 85%) as a crystalline solid, m.p. 153. °C. [α]3D0 = +11.13 (c
1
= 0.990, CHCl3). H NMR: δ = 2.28 (s, 3 H), 2.45 (s, 3 H), 2.94
(s, 3 H), 3.15 (s, 3 H), 3.40 (s, 1 H), 3.75 (t, J = 6.4 Hz, 2 H), 4.34
(dd, J = 4.4, 12.8 Hz, 1 H), 5.10 (s, 1 H), 5.13 (d, J = 4.0 Hz, 1 H),
7.35 (d, J = 8.0 Hz, 2 H), 7.84 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR:
δ = 21.1, 21.6, 43.1, 47.5, 55.4, 73.6, 74.8 (CH2), 78.1, 110.1, 124.9,
129.6, 134.6, 145.2, 169.0 ppm. HRMS (ESI): calcd. for
C17H22O7S2Na [M + Na]+ 425.0708; found 425.0705.
Compound 12f: Following the general procedure, phenylsulfonyl-
acetone (0.39 g, 1.99 mmol) was treated with 8α (0.45 g, 1.24 mmol)
in the presence of tBuOK (0.17 g, 1.49 mmol) for 14 h to give 12f
(0.46 g, 80%) as a crystalline solid, m.p. 160 °C. [α]3D0 = +118.22 (c
Compound 12a: Following the general procedure, acetylacetone
(0.18 mL, 1.78 mmol) was treated with 8α (0.40 g, 1.11 mmol) in
the presence of tBuOK (0.15 g, 1.33 mmol) for 20 h to give 12a
(0.35 g, 88%) as a crystalline solid, m.p. 134 °C. [α]3D0 = –130.28 (c
1
= 1.071, CHCl3). H NMR: δ = 2.26 (s, 3 H), 2.39 (s, 3 H), 3.03
(s, 3 H), 3.19 (s, 1 H), 3.61 (d, J = 12.8 Hz, 1 H), 3.72 (s, 1 H),
4.22 (dd, J = 4.2, 12.6 Hz, 1 H), 4.8 (s, 1 H), 4.99 (d, J = 3.6 Hz,
1 H), 7.29 (d, J = 7.8 Hz, 2 H), 7.43–7.74 (m, 7 H) ppm. 13C NMR:
δ = 21.5, 21.8, 47.7, 55.5, 73.2, 74.8 (CH2), 78.1, 110.4, 125.3, 127.2,
129.6, 129.8, 133.5, 135.2, 141.5, 145.2, 169.0 ppm. HRMS (ESI):
calcd. for C22H24O7S2Na [M + Na]+ 487.0877; found 487.0861.
1
= 0.683, CHCl3). H NMR: δ = 2.01 (s, 3 H), 2.16 (s, 3 H), 2.39
(s, 3 H), 3.10 (s, 3 H), 3.31 (s, 1 H), 3.53 (s, 1 H), 3.59 (d, J =
12.4 Hz, 1 H), 4.20 (dd, J = 4.0, 12.4 Hz, 1 H), 4.96 (d, J = 3.2 Hz,
1 H), 5.04 (s, 1 H), 7.30 (d, J = 7.6 Hz, 2 H), 7.77 (d, J = 8.0 Hz,
2 H) ppm. 13C NMR: δ = 21.5, 21.7, 30.0, 47.1, 55.3, 73.7, 74.0
(CH2), 78.1, 110.5, 125.0, 129.4, 129.5, 134.7, 145.0, 167.6,
198.7 ppm. HRMS (ESI): calcd. for C18H22O6SNa [M + Na]+
389.1031; found 389.1035.
Compound 12g: Following the general procedure, acetoacetamide
(0.24 g, 2.21 mmol) was treated with 8α (0.50 g, 1.38 mmol) in the
presence of tBuOK (0.19 g, 1.66 mmol) for 10 h to give 12g (0.41 g,
81%) as a glassy solid, m.p. 126 °C. [α]3D0 = –72.39 (c = 0.828,
Compound 12b: Following the general procedure, dibenzoylmeth-
ane (0.45 g, 1.99 mmol) was treated with 8α (0.45 g, 1.24 mmol) in
the presence of tBuOK (0.17 g, 1.49 mmol) for 24 h to give 12b
(0.49 g, 81%) as a crystalline solid, m.p. 150 °C. [α]3D0 = +51.70 (c
1
CHCl3). H NMR: δ = 1.83 (s, 3 H), 2.37 (s, 3 H), 3.14 (s, 3 H),
3.27 (s, 1 H), 3.52 (s, 1 H), 3.73 (d, J = 12.4 Hz, 1 H), 4.22 (dd, J
= 4.2, 12.4 Hz, 1 H), 4.93 (d, J = 4.4 Hz, 1 H), 4.99 (s, 1 H), 7.28
(d, J = 7.8 Hz, 2 H), 7.77 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR: δ
= 21.6, 28.1, 46.9, 55.4, 74.9 (CH2), 75.4, 77.4, 96.4, 111.6, 129.5,
129.6, 134.9, 145.1, 168.2, 194.6 ppm. HRMS (ESI): calcd. for
C17H22NO6S [M + H]+ 368.1173; found 368.1168.
1
= 0.850, CHCl3). H NMR: δ = 2.39 (s, 3 H), 3.22 (s, 3 H), 3.74
(d, J = 5.4 Hz, 2 H), 4.06–4.13 (m, 1 H), 4.58 (dd, J = 4.2, 4.4 Hz,
1 H), 5.26 (d, J = 7.8 Hz, 1 H), 5.40 (s, 1 H), 7.00–7.24 (m, 10 H),
7.54 (d, J = 7.2 Hz, 2 H), 7.65 (d, J = 13.2 Hz, 2 H) ppm. 13C
NMR: δ = 21.6, 49.2, 55.3, 73.5, 75.8 (CH2), 78.3, 110.5, 123.4,
128.0, 128.2, 129.2, 129.5ϫ2, 130.1, 132.6, 134.9, 135.5, 137.1,
144.8, 163.2, 196.4 ppm. HRMS (ESI): calcd. for C28H27O6S [M +
H]+ 491.1536; found 491.1528.
Compound 12h: Following the general procedure, diethyl (2-oxo-
propyl)phosphonate (0.42 mL, 2.20 mmol) was treated with 8α
(0.50 g, 1.38 mmol) in the presence of tBuOK (0.19 g, 1.66 mmol)
for 10 h to give 12h (0.42 g, 82%) as a colorless gum. [α]3D0
=
Compound 12c: Following the general procedure, methyl acetoacet-
+118.22 (c = 1.071, CHCl3). 1H NMR: δ = 1.29 (q, J = 7.2,
ate (0.23 mL, 2.21 mmol) was treated with 8α (0.50 g, 1.38 mmol) 14.4 Hz, 6 H), 2.20 (d, J = 2.2 Hz, 3 H), 2.42 (s, 3 H), 3.14 (s, 3
in the presence of tBuOK (0.19 g, 1.66 mmol) for 16 h to give 12c
H), 3.29 (s, 1 H), 3.43–3.62 (m, 2 H), 3.93–4.04 (m, 4 H), 4.21 (dd,
J = 4.4, 12.6 Hz, 1 H), 4.99–5.02 (m, 2 H), 7.32 (d, J = 8.0 Hz, 2
(0.45 g, 85%) as a glassy solid, m.p. 109 °C. [α]3D0 = –51.45 (c =
1
0.700, CHCl3). H NMR: δ = 2.15 (s, 3 H), 2.42 (s, 3 H), 3.19 (s, H), 7.80 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR: δ = 16.1, 16.2, 16.4,
6092
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6084–6097

Diversity-Oriented Synthesis from Carbohydrates
21.5, 21.7, 47.0, 47.2, 55.4, 61.8 (CH2), 61.9 (CH2), 62.0 (CH2), NMR: δ = 2.15 (s, 3 H), 2.44 (s, 3 H), 2.82 (s, 1 H), 3.34 (s, 3 H),
73.6 (CH2), 74.1, 74.2, 78.4, 108.7, 110.7, 110.8, 112.5, 129.5, 129.6,
3.40–3.54 (m, 2 H), 3.80 (s, 1 H), 3.88 (d, J = 7.2 Hz, 1 H), 4.86–
4.91 (m, 1 H), 6.07 (d, J = 6.4 Hz, 1 H), 7.38 (d, J = 7.8 Hz, 2 H),
135.3, 144.8, 170.5, 171.0 ppm. 31P NMR: δ = 23.3 ppm. HRMS
(ESI): calcd. for C20H29O8PSNa [M + Na]+ 483.1214; found 7.81 (d, J = 7.8 Hz, 2 H) ppm. 13C NMR: δ = 14.3, 21.7, 49.4,
483.1218.
51.0, 64.2 (CH2), 69.0, 80.9, 102.3, 110.1, 129.2, 130.0, 134.1, 145.4,
164.6, 169.1 ppm. HRMS (ESI): calcd. for C17H20O7SNa [M +
Na]+ 391.0828; found 391.0827.
Compound 12i: Following the general procedure, 1,3-cyclohexane-
dione (0.25 g, 2.21 mmol) was treated with 8α (0.50 g, 1.38 mmol)
in the presence of tBuOK (0.19 g, 1.66 mmol) for 25 h to give 12i
(0.42 g, 80%) as a white solid, m.p. 145 °C. [α]3D0 = +70.38 (c =
Compound 9d: Following the general procedure, compound 12d
(0.45 g, 1.14 mmol) was treated with TFA for 2 h to give 9d (0.35 g,
80%) as a white solid, m.p. 164 °C. [α]3D0 = +37.64 (c = 1.72,
1
0.818, CHCl3). H NMR: δ = 1.79–1.89 (m, 3 H), 2.17–2.59 (m, 3
1
H), 2.46 (s, 3 H), 3.26 (s, 3 H), 3.37 (s, 1 H), 3.84 (d, J = 12.8 Hz,
1 H), 4.03–4.08 (m, 1 H), 4.36 (dd, J = 3.6, 12.8 Hz, 1 H), 4.72 (s,
1 H), 5.12 (s, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.78 (d, J = 8.0 Hz,
CHCl3). H NMR: δ = 1.01–1.24 (m, 3 H), 2.07 (s, 3 H), 2.44 (s, 3
H), 3.36–3.48 (m, 2 H), 3.81 (s, 1 H), 3.86–4.10 (m, 3 H), 4.77–4.84
(m, 1 H), 6.03 (d, J = 6.4 Hz, 1 H), 7.38 (d, J = 7.4 Hz, 2 H), 7.80
2 H) ppm. 13C NMR: δ = 20.0 (CH2), 21.6, 31.1 (CH2), 36.1 (CH2), (d, J = 8.2 Hz, 2 H) ppm. 13C NMR: δ = 14.3ϫ2, 21.6, 49.2, 59.9
42.2, 54.8, 72.8, 75.2 (CH2), 77.6, 110.0, 120.2, 129.3, 129.6, 135.2,
144.8, 174.7, 195.9 ppm. HRMS (ESI): calcd. for C19H22O6SNa [M
+ Na]+ 401.1052; found 401.1035.
(CH2), 64.2 (CH2), 69.0, 81.0, 102.5, 109.8, 129.0, 130.0, 134.0,
145.3, 164.0, 168.5 ppm. HRMS (ESI): calcd. for C18H23O7S [M +
H]+ 383.1153; found 383.1165.
Compound 12j: Following the general procedure, dimedone (0.36 g,
2.58 mmol) was treated with 8α (0.60 g, 1.61 mmol) in the presence
of tBuOK (0.22 g, 1.93 mmol) for 30 h to give 12j (0.51 g, 75%) as
a glassy solid, m.p. 98 °C. [α]3D0 = –27.27 (c = 1.75, CHCl3). 1H
Compound 9e: Following the general procedure, compound 12e
(0.50 g, 1.24 mmol) was treated with TFA for 1.5 h to give 9e
(0.38 g, 78%) as a glassy solid, m.p. 195 °C. [α]3D0 = +105.10 (c =
1
1.21, CHCl3). H NMR: δ = 2.28 (s, 3 H), 2.47 (s, 3 H), 3.00 (s, 3
NMR: δ = 0.94 (s, 3 H), 1.00 (s, 3 H), 2.17–2.33 (m, 4 H), 2.42 (s, H), 3.95–4.00 (m, 2 H), 4.20 (d, J = 6.0 Hz, 1 H), 4.38 (s, 1 H),
3 H), 3.13 (s, 3 H), 3.38 (s, 1 H), 3.84 (d, J = 12.8 Hz, 1 H), 4.10
(s, 1 H), 4.39 (dd, J = 3.6, 12.8 Hz, 1 H), 4.72 (s, 1 H), 5.16 (d, J
= 3.2 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.81 (d, J = 8.4 Hz, 2 H)
ppm. 13C NMR: δ = 21.6, 26.6, 29.2, 31.2, 42.1, 44.8 (CH2), 49.8
(CH2), 54.7, 73.2, 75.1 (CH2), 77.6, 110.0, 118.9, 129.4, 129.5,
135.2, 144.8, 172.5, 195.6 ppm. HRMS (ESI): calcd. for C21H27O6S
[M + H]+ 407.1516; found 407.1528.
4.89 (s, 1 H), 6.19 (d, J = 6.4 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H),
7.83 (d, J = 7.6 Hz, 2 H) ppm. 13C NMR: δ = 21.7, 37.8, 42.9,
49.3, 67.7, 69.0 (CH2), 78.7, 106.9, 109.9, 129.0ϫ2, 130.4ϫ2,
132.9, 146.2, 167.3 ppm. HRMS (ESI): calcd. for C16H20O7S2Na
[M + Na]+ 411.0542; found 411.0548.
Compound 9f: Following the general procedure, compound 12f
(0.55 g, 1.18 mmol) was treated with TFA for 2.5 h to give 9f
(0.40 g, 75%) as a white solid, m.p. 208 °C. [α]3D0 = +106.96 (c =
General Procedure for the Conversion of Compounds 12a–j to 9a–j:
Compounds 12a–j were treated with TFA (2 equiv.) for 2–3 h at
ambient temperature, then the reaction mixture was poured into
NaHCO3 (satd. aq.; 30 mL). The mixture was partitioned between
NaHCO3 (aq.) and EtOAc (3ϫ 20 mL). The organic extracts were
combined, dried with anhydrous Na2SO4, and filtered, and the fil-
trate was concentrated under reduced pressure. The residue was
purified by column chromatography over silica gel (EtOAc/petro-
leum ether) to give the pure product.
1
0.48, CHCl3). H NMR: δ = 2.30 (s, 3 H), 2.50 (s, 3 H), 3.37–3.51
(m, 2 H), 3.89 (d, J = 6.4 Hz, 1 H), 4.37 (s, 1 H), 4.73–4.76 (m, 1
H), 6.05 (d, J = 6.8 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.47–7.51
(m, 2 H), 7.59–7.66 (m, 3 H), 7.84 (d, J = 8.4 Hz, 2 H) ppm. 13C
NMR: δ = 13.8, 21.7, 48.8, 64.1 (CH2), 68.0, 81.9, 108.3, 110.0,
127.0, 129.0, 129.2, 130.2, 133.3, 133.5, 140.8, 145.6, 166.9 ppm.
HRMS (ESI): calcd. for C21H23O7S2 [M + H]+ 451.0908; found
451.0885.
Compound 9a: Following the general procedure, compound 12a
(0.50 g, 1.37 mmol) was treated with TFA for 1.5 h to give 9a
(0.41 g, 85%) as a crystalline solid, m.p. 137 °C. [α]3D0 = +63.21 (c
Compound 9g: Following the general procedure, compound 12g
(0.45 g, 1.23 mmol) was treated with TFA for 3 h to give 9g (0.33 g,
75%) as a glassy solid, m.p. 196 °C. [α]3D0 = +17.56 (c = 0.52,
CHCl3). 1H NMR: δ = 2.23 (s, 3 H), 2.46 (s, 3 H), 3.28 (d, J =
1
= 0.65, CHCl3). H NMR: δ = 2.21 (s, 6 H), 2.46 (s, 3 H), 3.30–
3.50 (m, 2 H), 3.77 (s, 1 H), 4.13 (d, J = 6.4 Hz, 1 H), 4.77–4.83 5.6 Hz, 2 H), 3.85 (s, 1 H), 4.22 (d, J = 6.4 Hz, 1 H), 4.49–4.51 (m,
(m, 1 H), 6.06 (d, J = 6.6 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.83
(d, J = 8.2 Hz, 2 H) ppm. 13C NMR: δ = 15.5, 21.7, 29.4, 49.7, 64.2
(CH2), 69.1, 81.3, 109.8, 113.4, 129.1, 130.1, 133.7, 145.5, 167.4,
193.1 ppm. HRMS (ESI): calcd. for C17H21O6S [M + H]+ 353.1046;
found 353.1059.
1 H), 5.68 (s, 1 H), 6.10 (d, J = 7.2 Hz, 1 H), 6.65 (s, 1 H), 7.40 (d,
J = 8.0 Hz, 2 H), 7.79 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR: δ =
14.2, 21.7, 48.3, 63.4 (CH2), 69.9, 82.7, 103.9, 110.3, 128.8, 130.3,
132.4, 146.1, 165.9, 167.2 ppm. HRMS (ESI): calcd. for
C16H20NO6S [M + H]+ 354.1027; found 354.1011.
Compound 9b: Following the general procedure, compound 12b
(0.55 g, 1.12 mmol) was treated with TFA for 2.5 h to give 9b
(0.42 g, 80%) as a crystalline solid, m.p. 135 °C. [α]3D0 = +63.21 (c
Compound 9h: Following the general procedure, compound 12h
(0.45 g, 0.98 mmol) was treated with TFA for 1.5 h to give 9h
(0.31 g, 72%) as a glassy solid, m.p. 94 °C. [α]3D0 = +100.96 (c =
= 0.65, CHCl3). 1H NMR: δ = 2.43 (s, 3 H), 3.17 (br. s, 1 H), 4.38– 0.68, CHCl3). 1H NMR: δ = 1.22–1.36 (m, 6 H), 2.11 (s, 3 H), 2.47
4.43 (m, 2 H), 4.93 (s, 1 H), 5.04–5.09 (m, 1 H), 7.09–7.13 (m, 10 (s, 3 H), 3.31–3.40 (m, 1 H), 3.48–3.57 (m, 1 H), 3.87–4.10 (m, 6
H), 7.33 (d, J = 8.0 Hz, 2 H), 7.58 (d, J = 8.0 Hz, 2 H), 8.11 (s, 1
H) ppm. 13C NMR: δ = 21.7, 60.9, 66.3, 68.6 (CH2), 114.4, 120.5,
128.1, 128.2, 128.3, 128.8, 128.9, 129.2, 129.8, 130.9, 133.1, 134.2,
136.9, 144.6, 145.5, 156.4, 192.4 ppm. HRMS (ESI): calcd. for
C27H24O6SNa [M + Na]+ 499.1180; found 499.1191.
H), 4.74 (t, J = 6.8 Hz, 1 H), 6.07 (d, J = 6.2 Hz, 1 H), 7.39 (d, J
= 8.0 Hz, 2 H), 7.81 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR: δ = 14.0,
16.2ϫ2, 16.4, 21.7, 50.7, 51.0, 61.7 (CH2), 61.9 (CH2), 64.0 (CH2),
68.4, 81.1, 92.7, 97.1, 100.0, 110.0, 110.2, 128.9, 130.0, 133.8, 145.4,
168.2, 168.8 ppm. 31P NMR: δ = 19.3 ppm. HRMS (ESI): calcd.
for C19H28O8PS [M + H]+ 447.1238; found 447.1242.
Compound 9c: Following the general procedure, compound 12c
(0.50 g, 1.31 mmol) was treated with TFA for 2 h to give 9c (0.40 g, Compound 9i: Following the general procedure, compound 12i
82%) as a colorless gum. [α]3D0 = +22.98 (c = 1.37, CHCl3). 1H
(0.50 g, 1.32 mmol) was treated with TFA for 2 h to give 9i (0.36 g,
Eur. J. Org. Chem. 2013, 6084–6097
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6093

C. Manna, T. Pathak
FULL PAPER
78%) as a crystalline solid, m.p. 161 °C. [α]3D0 = +70.09 (c = 1.15,
CHCl3). H NMR: δ = 1.99 (q, J = 6.2, 12.6 Hz, 2 H), 2.21–2.27
(m, 2 H), 2.39–2.42 (m, 2 H), 2.47 (s, 3 H), 3.47 (s, 2 H), 3.85 (s, 1
Compound 14a (0.38 g, 1.04 mmol) was treated with TFA (2 equiv.)
at ambient temperature. After 2 h (TLC), the reaction mixture was
poured into NaHCO3 (satd. aq.; 30 mL). The reaction mixture was
1
H), 3.94 (d, J = 6.0 Hz, 1 H), 4.94–4.97 (m, 1 H), 6.28 (d, J = partitioned between NaHCO3 (satd. aq.) and EtOAc (3ϫ 20 mL).
6.2 Hz, 1 H), 7.42 (d, J = 8.2 Hz, 2 H), 7.87 (d, J = 8.2 Hz, 2 H)
ppm. 13C NMR: δ = 21.2 (CH2), 21.8, 23.9 (CH2), 36.4 (CH2),
46.7, 64.4 (CH2), 67.3, 81.8, 112.2, 112.8, 129.0, 130.0, 133.8, 145.5,
176.5, 194.2 ppm. HRMS (ESI): calcd. for C18H20O6SNa [M +
Na]+ 387.0879; found 387.0878.
The organic extracts were combined, dried with anhydrous
Na2SO4, and filtered. The filtrate was concentrated under reduced
pressure. The residue was purified by column chromatography over
silica gel (EtOAc/petroleum ether) to give 10a (0.23 g, 65%) as a
crystalline solid, m.p. 130 °C. [α]3D0 = –75.23 (c = 1.30, CHCl3). H
1
NMR: δ = 1.17–1.19 (m, 1 H), 1.85 (s, 3 H), 2.17–2.20 (m, 1 H),
2.37 (s, 3 H), 2.42 (s, 3 H), 3.96 (d, J = 6.0 Hz, 1 H), 4.76–4.78 (m,
1 H), 5.95 (d, J = 5.6 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.68 (d,
J = 8.0 Hz, 2 H) ppm. 13C NMR: δ = 14.6, 21.4, 25.2 (CH2), 29.5,
48.0, 53.0, 66.8, 112.2, 115.7, 128.1, 129.6, 137.3, 144.3, 166.8,
193.5 ppm. HRMS (ESI): calcd. for C17H18O5SNa [M + Na]+
357.0765; found 357.0772.
Compound 9j: Following the general procedure, compound 12j
(0.55 g, 1.35 mmol) was treated with TFA for 2 h to give 9j (0.42 g,
75%) as a crystalline solid, m.p. 168 °C. [α]3D0 = +57.85 (c = 1.33,
1
CHCl3). H NMR: δ = 1.03 (d, J = 10.4 Hz, 6 H), 2.10 (s, 2 H),
2.27 (s, 2 H), 2.45 (s, 3 H), 3.43–3.51 (m, 2 H), 3.86 (s, 1 H), 3.94
(d, J = 5.6 Hz, 1 H), 4.94 (s, 1 H), 6.28 (d, J = 6.4 Hz, 1 H), 7.41
(d, J = 8.0 Hz, 2 H), 7.85 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR: δ
= 21.7, 28.4, 28.7, 33.8, 37.6 (CH2), 46.5, 50.7 (CH2), 64.1 (CH2),
67.2, 81.9, 110.8, 113.2, 128.9, 130.0, 133.6, 145.4, 175.4,
193.6 ppm. HRMS (ESI): calcd. for C20H25O6S [M + H]+ 393.1378;
found 393.1370.
Stepwise Synthesis of Compound 10e: Following the procedure de-
scribed for compound 10a, methylsulfonylacetone (0.24 g,
1.78 mmol) was treated with 8β (0.40 g, 1.11 mmol) in the presence
of tBuOK (0.15 g, 1.33 mmol) at ambient temperature for 24 h. Af-
ter work-up, the residue, containing 13e and 14e, was treated with
excess tBuOK (0.15 g, 1.33 mmol) in dry THF (2 mL) for 6 h to
give 14e (0.32 g, 72%) as a colorless gum. [α]3D0 = –53.44 (c = 1.60,
CHCl3). 1H NMR: δ = 1.66–1.70 (m, 1 H), 1.89–1.91 (m, 1 H),
2.45 (s, 3 H), 2.61 (s, 3 H), 2.93 (s, 3 H), 2.98 (s, 1 H), 3.28 (s, 3
H), 4.81–4.83 (m, 1 H), 5.42 (s, 1 H), 5.51 (s, 1 H), 7.39 (d, J =
8.0 Hz, 2 H), 7.74 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR: δ = 21.8,
23.1 (CH2), 33.3, 40.3, 46.3, 46.7, 55.7, 67.1, 70.8, 108.7, 127.7,
130.5, 136.5, 145.6, 200.7 ppm. HRMS (ESI): calcd. for
C17H22O7S2Na [M + Na]+ 425.0725; found 425.0705.
One-Pot Synthesis of 9a: Acetylacetone (0.043 mL, 0.414 mmol)
was added to a suspension of tBuOK (0.04 g, 0.331 mmol) in dry
THF (0.5 mL) at ambient temperature, and the resulting solution
was stirred for 30 min under nitrogen. A solution of 8α (0.10 g,
0.276 mmol) in dry THF (0.5 mL) was added dropwise to the reac-
tion mixture. The resulting solution was stirred for 8 h. Additional
tBuOK (0.04 g, 0.331 mmol) and dry THF (0.5 mL) were added to
the reaction mixture, and stirring was continued. After 2 h, a mix-
ture of TFA and TfOH (3:1 ratio, 0.1 mL/mmol) was added to the
reaction mixture, and the mixture was stirred for a further 2.5 h.
After completion of the reaction (TLC), the reaction mixture was
poured into NaHCO3 (satd. aq.; 30 mL). The reaction mixture was
partitioned between NaHCO3 (aq.) and EtOAc (3ϫ 20 mL). The
organic extracts were combined, dried with anhydrous Na2SO4,
and filtered, and the filtrate was concentrated under reduced pres-
sure. The residue was purified by column chromatography over sil-
ica gel (EtOAc/petroleum ether) to give 9a (0.057 g, 65%).
Compound 14e (0.32 g, 0.80 mmol) was treated with TFA (2 equiv.)
at ambient temperature for 2 h to give 10e (0.18 g, 60%) as a white
solid, m.p. 170 °C. [α]3D0 = –51.23 (c = 1.70, CHCl3). H NMR: δ
1
= 1.11–1.13 (m, 1 H), 1.71–1.74 (m, 1 H), 2.12 (s, 3 H), 2.45 (s, 3
H), 3.26 (s, 3 H), 4.10 (d, J = 5.6 Hz, 1 H), 4.83–4.85 (m, 1 H),
6.06 (d, J = 5.6 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.86 (d, J =
8.0 Hz, 2 H) ppm. 13C NMR: δ = 14.3, 21.6, 24.8 (CH2), 45.3,
46.7, 53.2, 67.0, 112.7, 116.5, 128.0, 129.7, 136.2, 144.8, 169.2 ppm.
HRMS (ESI): calcd. for C16H19O6S2 [M + H]+ 371.0636; found
371.0623.
Stepwise Synthesis of 10a: Acetylacetone (0.18 mL, 1.78 mmol) was
added to a suspension of tBuOK (0.15 g, 1.33 mmol) in dry THF
(2 mL) at ambient temperature, and the resulting solution was
stirred for 30 min at that temperature under nitrogen. A solution
of 8β (0.40 g, 1.11 mmol) in dry THF (1 mL) was added dropwise
to the reaction mixture. The resulting solution was then stirred for
16 h. After completion of the reaction (TLC), the reaction mixture
was concentrated under reduced pressure. The residue was dis-
solved in EtOAc, and the organic phase was washed with NH4Cl
(satd. aq.). The organic phase was dried with anhydrous Na2SO4
and filtered, and the filtrate was concentrated under reduced pres-
sure. The residue, containing 13a and 14a, was treated with excess
tBuOK (0.15 g, 1.33 mmol) and dry THF (2 mL) at room tempera-
ture for 2 h. After completion of the reaction (TLC) and usual
work-up, the resulting residue was purified by column chromatog-
raphy over silica gel (EtOAc/petroleum ether) to give 14a (0.38 g,
70%) as a crystalline solid, m.p. 118 °C. [α]3D0 = –107.17 (c = 0.51,
Stepwise Synthesis of Compound 10f: Following the procedure de-
scribed for compound 10a, phenylsulfonylacetone (0.39 g,
1.99 mmol) was treated with 8β (0.45 g, 1.24 mmol) in the presence
of tBuOK (0.17 g, 1.49 mmol) at ambient temperature for 26 h. Af-
ter work-up, the residue, containing 13f and 14f, was treated with
excess tBuOK (0.17 g, 1.49 mmol) in dry THF (2 mL) for 4 h to
give 14f (0.43 g, 72%) as a crystalline solid, m.p. 150 °C. [α]3D0
=
–137.81 (c = 1.00, CHCl3). 1H NMR: δ = 1.58–1.61 (m, 1 H), 1.76–
1.78 (m, 1 H), 2.43 (s, 3 H), 2.60 (s, 4 H), 3.15 (s, 3 H), 4.68–4.71
(m, 1 H), 5.27 (s, 1 H), 5.52 (s, 1 H), 7.27 (d, J = 8.4 Hz, 2 H),
7.50–7.55 (m, 4 H), 7.66–7.69 (m, 1 H), 7.79 (d, J = 7.2 Hz, 2 H)
ppm. 13C NMR: δ = 21.6, 23.1 (CH2), 33.7, 45.8, 46.9, 55.4, 66.4,
71.3, 108.5, 126.9, 129.2, 129.3, 130.1, 134.4, 136.5, 137.2, 144.9,
198.0 ppm. HRMS (ESI): calcd. for C22H24O7S2Na [M + Na]+
487.0838; found 487.0861.
1
CHCl3). H NMR: δ = 1.25 (s, 1 H), 1.55 (s, 3 H), 1.72–1.77 (m, 1
Compound 14f (0.43 g, 0.90 mmol) was treated with TFA (2 equiv.)
H), 2.08 (s, 3 H), 2.13–2.16 (m, 1 H), 2.43 (s, 3 H), 3.18 (d, J = at ambient temperature for 2.5 h to give 10f (0.31 g, 65%) as a
1.2 Hz, 1 H), 3.29 (s, 3 H), 4.81–4.85 (m, 1 H), 5.02 (d, J = 1.4 Hz,
1 H), 7.31 (d, J = 8.2 Hz, 2 H), 7.56 (d, J = 8.2 Hz, 2 H) ppm. 13C
NMR: δ = 21.6, 23.4, 23.7 (CH2), 24.4, 47.2, 49.6, 55.4, 67.1, 106.3,
115.2, 129.4, 129.9, 137.1, 144.8, 191.8, 195.4 ppm. HRMS (ESI):
calcd. for C18H22O6SNa [M + Na]+ 389.1032; found 389.1035.
white solid, m.p. 156 °C. [α]3D0 = –62.88 (c = 1.50, CHCl3). 1H
NMR: δ = 1.16–1.19 (m, 1 H), 1.77 (s, 3 H), 2.25–2.29 (m, 1 H),
2.43 (s, 3 H), 3.72 (d, J = 5.2 Hz, 1 H), 4.89–4.92 (m, 1 H), 5.89
(d, J = 5.2 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.45–7.49 (m, 2 H),
7.53–7.56 (m, 1 H), 7.80 (d, J = 7.8 Hz, 2 H), 7.96 (d, J = 8.0 Hz,
6094
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6084–6097

Diversity-Oriented Synthesis from Carbohydrates
2 H) ppm. 13C NMR: δ = 13.6, 21.5, 25.3 (CH2), 46.7, 53.3, 68.1,
111.4, 118.1, 126.4, 129.0, 129.2, 129.6, 132.8, 137.2, 143.9, 144.3,
168.2 ppm. HRMS (ESI): calcd. for C21H21O6S2 [M + H]+
433.0780; found 433.0780.
109.1, 128.6, 130.0, 134.5, 145.3, 167.8, 170.0 ppm. HRMS (ESI):
calcd. for C19H24O7NaS [M + Na]+ 419.1121; found 419.1140.
Compound 16h: Following the general procedure, 1,3-cyclohexane-
dione (0.25 g, 2.21 mmol) was treated with 8β (0.50 g, 1.38 mmol)
in the presence of tBuOK (0.19 g, 1.66 mmol) at ambient tempera-
ture for 20 h to give 16h (0.42 g, 80%) as a white solid, m.p. 132 °C.
[α]3D0 = –39.09 (c = 1.55, CHCl3). 1H NMR: δ = 1.82–1.89 (m, 3
H), 2.27–2.40 (m, 3 H), 2.45 (s, 3 H), 3.34 (s, 3 H), 3.42 (s, 1 H),
3.89–3.96 (m, 1 H), 4.37–4.45 (m, 2 H), 5.01 (s, 1 H), 5.28 (d, J =
5.2 Hz, 1 H), 7.39 (d, J = 7.8 Hz, 2 H), 7.85 (d, J = 8.0 Hz, 2 H)
ppm. 13C NMR: δ = 20.2 (CH2), 21.7, 31.2 (CH2), 36.2 (CH2),
38.0, 57.3, 73.2, 74.0 (CH2), 74.7, 106.4, 115.4, 128.7, 130.1, 134.6,
145.4, 174.9, 196.7 ppm. HRMS (ESI): calcd. for C19H22O6NaS [M
+ Na]+ 401.1052; found 401.1035.
One-Pot Synthesis of 10a: Acetylacetone (0.043 mL, 0.414 mmol)
was added to a suspension of tBuOK (0.04 g, 0.331 mmol) in dry
THF (1 mL) at ambient temperature, and the resulting solution was
stirred for 30 min at that temperature under nitrogen. A solution of
8β (0.10 g, 0.276 mmol) in dry THF (0.5 mL) was added dropwise
to the reaction mixture. The resulting solution was stirred for 18 h.
Additional tBuOK (0.04 g, 0.331 mmol) and dry THF (0.5 mL)
were added to the reaction mixture, and stirring was continued.
After 2 h, a mixture of TFA and TfOH (3:1 ratio, 0.1 mL/mmol)
was added to the reaction mixture, and the mixture was stirred for
a further 3 h at ambient temperature. After completion of the reac-
tion (TLC), the reaction mixture was poured into NaHCO3 (satd.
aq.; 30 mL). The mixture was partitioned between NaHCO3 (aq.)
and EtOAc (3ϫ 20 mL). The organic extracts were combined,
dried with anhydrous Na2SO4, and filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography over silica gel (EtOAc/petroleum ether) to
give 10a (0.050 g, 54%).
Compound 16i: Following the general procedure, dimedone (0.36 g,
2.58 mmol) was treated with 8β (0.60 g, 1.61 mmol) in the presence
of tBuOK (0.22 g, 1.93 mmol) at ambient temperature for 15 h to
give 16i (0.51 g, 75%) as a crystalline solid, m.p. 155 °C. [α]3D0
=
1
–67.28 (c = 2.30, CHCl3). H NMR: δ = 1.0 (2 s, 6 H), 2.07–2.19
(m, 2 H), 2.22–2.34 (m, 2 H), 2.43 (s, 3 H), 3.31 (d, J = 2.4 Hz, 4
H), 3.82 (d, J = 12.8 Hz, 1 H), 4.39–4.43 (m, 2 H), 4.98 (d, J =
3.2 Hz, 1 H), 5.28 (d, J = 5.2 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 2 H),
7.82 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR: δ = 21.6, 25.7, 29.6,
31.4, 37.3, 44.9 (CH2), 49.9 (CH2), 57.2, 73.3 (CH2), 73.6, 74.5,
106.5, 114.2, 128.6, 130.1, 134.4, 145.4, 173.4, 196.5 ppm. HRMS
(ESI): calcd. for C21H27O6S [M + H]+ 407.1516; found 407.1528.
General Procedure for the Synthesis of 16b–d and 16i–j from 8β:
Following the general procedure described for the synthesis of 12a–
j from 8α, dibenzoylmethane, methyl acetoacetate, ethyl acetoacet-
ate, 1,3-cyclohexanedione, and dimedone were treated with 8β to
give 16b–d and 16i–j.
General Procedure for the Conversion of Compounds 16b–d and 16i–
j into 9b–d and 9i–j, Respectively: Compounds 16b–d and 16i–j were
treated with TFA (2 equiv.) for 2–3 h at ambient temperature, then
the reaction mixture was poured into NaHCO3 (satd. aq.; 30 mL).
The mixture was then partitioned between NaHCO3 (aq.) and
EtOAc (3ϫ 20 mL). The organic extracts were combined, dried
with anhydrous Na2SO4, and filtered, and the filtrate was concen-
trated under reduced pressure. The residue was purified by column
chromatography over silica gel (EtOAc/petroleum ether) to give 9b–
d and 9i–j.
Compound 16b: Following the general procedure, dibenzoylmeth-
ane (0.45 g, 1.99 mmol) was treated with 8β (0.45 g, 1.24 mmol) in
the presence of tBuOK (0.17 g, 1.49 mmol) at ambient temperature
for 12 h to give 16b (0.49 g, 80%) as a crystalline solid, m.p. 161 °C.
[α]3D0 = +43.09 (c = 1.85, CHCl3). 1H NMR: δ = 2.45 (s, 3 H), 3.35
(s, 3 H), 4.26 (s, 1 H), 4.52–4.66 (m, 3 H), 5.11–5.13 (m, 1 H), 5.36
(d, J = 5.2 Hz, 1 H), 6.94–7.16 (m, 8 H), 7.39 (d, J = 8.0 Hz, 2 H),
7.54 (d, J = 7.2 Hz, 2 H), 7.87 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR:
δ = 21.6, 46.3, 57.0, 70.7, 75.5, 76.8 (CH2), 107.5, 117.6, 127.3,
127.6, 128.6, 129.5, 129.9, 130.0, 130.1, 131.3, 134.6, 136.0, 138.4,
145.4, 165.6, 197.5 ppm. HRMS (ESI): calcd. for C28H27O6S [M +
H]+ 491.1536; found 491.1528.
CCDC-891089 (for 2g), -891090 (for 3b), -893517 (for 9j), -891081
(for 10a), -891085 (for 12c), -891082 (for 12e), -891083 (for 12i),
-891084 (for 14a), and -891086 (for 16j) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Compound 16c: Following the general procedure, methyl acetoacet-
ate (0.23 mL, 2.21 mmol) was treated with 8β (0.50 g, 1.38 mmol)
in the presence of tBuOK (0.19 g, 1.66 mmol) at ambient tempera-
ture for 24 h to give 16c (0.41 g, 78%) as a colorless gum. [α]3D0
=
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all new compounds.
1
–445.62 (c = 1.75, CHCl3). H NMR: δ = 2.03 (s, 3 H), 2.46 (s, 3
H), 3.41 (s, 3 H), 3.61 (s, 3 H), 3.67 (s, 1 H), 3.88 (dd, J = 3.2,
13.2 Hz, 1 H), 4.18 (d, J = 5.6 Hz, 1 H), 4.24 (dd, J = 3.6, 12.8 Hz,
1 H), 4.85–4.86 (m, 1 H), 5.32 (d, J = 5.2 Hz, 1 H), 7.39 (d, J =
8.0 Hz, 2 H), 7.82 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR: δ = 21.6,
22.3, 42.7, 51.7, 57.2, 72.5, 73.8 (CH2), 75.1, 106.5, 108.9, 128.6,
130.0, 134.4, 145.3, 168.2, 170.9 ppm. HRMS (ESI): calcd. for
C18H22O7SNa [M + Na]+ 405.0975; found 405.0984.
Acknowledgments
T. P. thanks the Department of Science and Technology (DST),
New Delhi for financial support. C. M. thanks Council of Scientific
and Industrial Research, New Delhi for a fellowship. DST is also
thanked for the creation of the 400 MHz facility under the IRPHA
program, and DST-FIST for single-crystal X-ray facility.
Compound 16d: Following the general procedure, ethyl acetoacetate
(0.24 mL, 2.58 mmol) was treated with 8β (0.60 g, 1.61 mmol) in
the presence of tBuOK (0.22 g, 1.93 mmol) at ambient temperature
for 30 h to give 16d (0.49 g, 75%) as a colorless gum. [α]3D0 = –51.27
(c = 1.18, CHCl3). 1H NMR: δ = 1.16–1.19 (m, 3 H), 2.14 (s, 3 H),
2.44 (s, 3 H), 3.39 (s, 3 H), 3.69 (s, 1 H), 3.89 (dd, J = 3.2, 12.8 Hz,
1 H), 4.05–4.10 (m, 2 H), 4.18 (d, J = 5.6 Hz, 1 H), 4.23 (dd, J =
3.6, 12.8 Hz, 1 H), 4.86 (s, 1 H), 5.31 (d, J = 5.2 Hz, 1 H), 7.37 (d,
J = 8.0 Hz, 2 H), 7.81 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR: δ =
14.1, 21.6, 22.3, 42.8, 57.3, 60.5 (CH2), 72.3, 73.8, 75.0, 106.6,
[1] Selected reviews on the importance of small molecules in chem-
ical biology and medicinal research: a) W. R. J. D. Galloway,
A. I.-Llobet, D. R. Spring, Nat. Commun. 2010, 1–13; b) R.
Scheffelaar, E. Ruijter, R. V. A. Orru, Top. Heterocycl. Chem.
2010, 25, 95–126; c) S. Wetzel, R. S. Bon, K. Kumar, H. Wald-
mann, Angew. Chem. 2011, 123, 10990–11018; Angew. Chem.
Eur. J. Org. Chem. 2013, 6084–6097
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6095

C. Manna, T. Pathak
FULL PAPER
Int. Ed. 2011, 50, 10800–10826; d) E. Ruijter, R. Scheffelaar,
R. V. A. Orru, Angew. Chem. 2011, 123, 6358–6371; Angew.
Chem. Int. Ed. 2011, 50, 6234–6246; e) C. J. O’ Connor,
H. S. G. Beckmann, D. R. Spring, Chem. Soc. Rev. 2012, 41,
4444–4456.
h) J. S. Yadav, B. V. S. Reddy, D. N. Chary, C. S. Reddy, Tetra-
hedron Lett. 2008, 49, 2649–2652; i) Z. Hong, L. Liu, M. Sugi-
yama, Y. Fu, C.-H. Wong, J. Am. Chem. Soc. 2009, 131, 8352–
8353; j) D. Crich, K. Sasaki, M. Y. Rahaman, A. A. Bowers, J.
Org. Chem. 2009, 74, 3886–3893; k) D. R. B. Ducatti, A. Massi,
M. D. Noseda, M. E. R. Duarte, A. Dondoni, Org. Biomol.
Chem. 2009, 7, 1980–1986; l) V. K. Rai, S. Singh, P. Singh,
L. D. S. Yadav, Synthesis 2010, 4051–4056; m) F. Ding, R. Wil-
liam, S. Wang, B. K. Gorityala, X.-W. Liu, Org. Biomol. Chem.
2011, 9, 3929–3939; n) L. Li, R. Li, A. Zhu, G. Zhang, L.
Zhang, Synlett 2011, 874–878; o) M. Samarasimhareddy, P. H.
Hemantha, V. V. Sureshbabu, Tetrahedron Lett. 2012, 53, 3104–
3107.
Selected reviews on the applications of β-dicarbonyls in organic
synthesis: a) J. Christoffers, Eur. J. Org. Chem. 1998, 1259–
1266; b) P. Langer, Chem. Eur. J. 2001, 7, 3858–3866; c) J.
Christoffers, Chem. Eur. J. 2003, 9, 4862–4867; d) C. Simon, T.
Constantieux, J. Rodriguez, Eur. J. Org. Chem. 2004, 4957–
4980; e) T. Constantieux, J. Rodriguez, Target Het. System
2005, 9, 39–65; f) T. Ikariya, K. Murata, R. Noyori, Org. Bio-
mol. Chem. 2006, 4, 393–406; g) M. D. Hill, M. Movassaghi,
Chem. Eur. J. 2008, 14, 6836–6844; h) G. Hilt, D. F. Weske,
Chem. Soc. Rev. 2009, 38, 3082–3091; i) D. Bonne, Y. Coquerel,
T. Constantieux, J. Rodriguez, Tetrahedron: Asymmetry 2010,
21, 1085–1109; j) M. D. M. S. Duque, C. Allais, N. Isambert,
T. Constantieux, J. Rodriguez, Top. Heterocycl. Chem. 2010,
23, 227–277; k) J.-P. Wan, Y. Liu, Synthesis 2010, 3943–3953;
l) S. Chassaing, S. Specklin, J.-M. Weibel, P. Pale, Tetrahedron
2012, 68, 7245–7273; m) A. Russo, C. D. Fusco, A. Lattanzi,
RSC Adv. 2012, 2, 385–397.
Selected references on the use of β-dicarbonyls in DOS: a) E. E.
Wyatt, S. Fergus, W. R. J. D. Galloway, A. Bender, D. J. Fox,
A. T. Plowright, A. S. Jessiman, M. Welchd, D. R. Spring,
Chem. Commun. 2006, 3296–3298; b) I. Freifeld, E. Holtz, G.
Dahmann, P. Langer, Eur. J. Org. Chem. 2006, 3251–3258; c)
E. Comer, E. Rohan, L. Deng, J. A. Porco Jr., Org. Lett. 2007,
9, 2123–2126; d) D. B. Ramachary, C. Venkaiah, Y. V. Reddy,
M. Kishor, Org. Biomol. Chem. 2009, 7, 2053–2062; e) D. S.
Bose, M. Idrees, N. M. Jakka, J. V. Rao, J. Comb. Chem. 2010,
12, 100–110; f) Y. Li, H. Chen, C. Shi, D. Shi, S. Ji, J. Comb.
Chem. 2010, 12, 231–237; g) C.-S. Yao, C.-H. Wang, B. Jiang,
S.-J. Tu, J. Comb. Chem. 2010, 12, 472–475; h) F. Shi, S. Zhang,
S.-S. Wu, Y. Gao, S.-J. Tu, Mol. Diversity 2011, 15, 497–505.
[2]
Selected reviews on MCR: a) A. Dömling, I. Ugi, Angew.
Chem. 2000, 112, 3300–3344; Angew. Chem. Int. Ed. 2000, 39,
3168–3210; b) A. Dömling, Chem. Rev. 2006, 106, 17–89; c)
D. M. D’Souza, T. J. J. Müller, Chem. Soc. Rev. 2007, 36, 1095–
1108; d) B. Ganem, Acc. Chem. Res. 2009, 42, 463–472; e) J. D.
Sunderhaus, S. F. Martin, Chem. Eur. J. 2009, 15, 1300–1308;
f) B. B. Touré, D. G. Hall, Chem. Rev. 2009, 109, 4439–4486;
g) L. H. Choudhury, T. Parvin, Tetrahedron 2011, 67, 8213–
8228; h) D. B. Ramachary, S. Jain, Org. Biomol. Chem. 2011,
9, 1277–1300; i) S. S. Bhojgude, A. T. Biju, Angew. Chem. 2012,
124, 1550–1552; Angew. Chem. Int. Ed. 2012, 51, 1520–1522; j)
A. Dömling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083–
3135.
Selected reviews on DOS: a) S. L. Schreiber, Science 2000, 287,
1964–1969; b) M. D. Burke, S. L. Schreiber, Angew. Chem.
2004, 116, 48–60; Angew. Chem. Int. Ed. 2004, 43, 46–58; c) P.
Arya, S. Quevillon, R. Joseph, C.-Q. Wei, Z. Gan, M. Parisien,
E. Sesmilo, P. T. Reddy, Z.-X. Chen, P. Durieux, D. Laforce,
L.-C. Campeau, S. Khadem, S. Couve-Bonnaire, R. Kumar, U.
Sharma, D. M. Leek, M. Daroszewska, M. L. Barnes, Pure
Appl. Chem. 2005, 77, 163–178; d) D. Tejedor, D. G.-Cruz,
A. S.-Expósito, J. J. M.-Tellado, P. de Armas, F. G.-Tellado,
Chem. Eur. J. 2005, 11, 3502–3510; e) J. E. B.-Houck, A. You-
nai, J. T. Shaw, Curr. Opin. Chem. Biol. 2010, 14, 371–382; f)
S. Dandapani, L. A. Marcaurelle, Curr. Opin. Chem. Biol. 2010,
14, 362–370; g) M. C. Bellucci, A. Volonterio, Org. Chem. In-
sight 2012, 4, 1–24; h) H. Eckert, Molecules 2012, 17, 1074–
1102; i) C. D. Graaff, E. Ruijter, R. V. A. Oru, Chem. Soc. Rev.
2012, 41, 3969–4009.
Selected reviews on the application of carbohydrates in syn-
thetic chemistry: a) K. C. Nicolaou, H. J. Mitchell, Angew.
Chem. 2001, 113, 1624–1672; Angew. Chem. Int. Ed. 2001, 40,
1576–1624; b) M. M. K. Boysen, Chem. Eur. J. 2007, 13, 8648–
8659; c) T. Pathak, Tetrahedron 2008, 64, 3605–3628; d) P. K.
Vemula, G. John, Acc. Chem. Res. 2008, 41, 769–782; e) T.
Pathak, R. Bhattacharya, C. R. Chim. 2011, 14, 327–342.
Selected references on the use of carbohydrates in DOS: a) J. A.
Tallarico, K. M. Depew, H. E. Pelish, N. J. Westwood, C. W.
Lindsley, M. D. Shair, S. L. Schreiber, M. A. Foley, J. Comb.
Chem. 2001, 3, 312–318; b) H. Kubota, J. Lim, K. M. Depew,
S. L. Schreiber, Chem. Biol. 2002, 9, 265–276; c) S. Hotha, A.
Tripathi, J. Comb. Chem. 2005, 7, 968–976; d) Z. Hong, L. Liu,
C.-C. Hsu, C.-H. Wong, Angew. Chem. 2006, 118, 7577–7581;
Angew. Chem. Int. Ed. 2006, 45, 7417–7421; e) L. D. S. Yadav,
V. P. Srivastava, V. K. Rai, R. Patel, Tetrahedron 2008, 64,
4246–4253; f) S. K. Yousuf, S. C. Taneja, D. Mukherjee, J. Org.
Chem. 2010, 75, 3097–3100; g) J. Yin, T. Linker, Tetrahedron
2011, 67, 2447–2461.
[8]
[3]
[9]
[4]
[5]
[10]
[11]
A review on reactions of carbohydrates with β-dicarbonyl com-
pounds: M.-C. Scherrmann, Top. Curr. Chem. 2010, 295, 1–18.
Selected references on the reactions between carbohydrates and
β-dicarbonyl compounds: a) F. G. González, M. G. Guillén,
J. A. G. Pérez, E. R. Galán, Carbohydr. Res. 1980, 78, 17–23;
b) T. H. Al-Tel, Y. Al-Abed, W. Voelter, J. Chem. Soc., Chem.
Commun. 1994, 1735–1736; c) G. Bartoli, J. G. F.-Bolanos,
G. D. Antonio, G. Foglia, S. Giuli, R. Gunnella, M. Manci-
nelli, E. Marcantoni, M. Paoletti, J. Org. Chem. 2007, 72,
6029–6036; d) J. S. Yadav, B. V. S.-Reddy, M. Srinivas, C. Di-
vyavani, A. C. Kunwar, C. Madavi, Tetrahedron Lett. 2007, 48,
8301–8305; e) C. R. A.-Cruz, R. Freire, M. S. Rodríguez, E.
Suárez, Synlett 2007, 2723–2727; f) B. Li, G. Wang, Z. Li, X.
Meng, Tetrahedron Lett. 2011, 52, 3891–3894; g) B. Voigt, U.
Scheffler, R. Mahrwald, Chem. Commun. 2012, 48, 5304–5306.
a) T. Sakakibara, K. Tokuda, T. Hayakawa, A. Seta, Car-
bohydr. Res. 2000, 327, 489–496; b) A. K. Sanki, C. G. Suresh,
U. D. Falgune, T. Pathak, Org. Lett. 2003, 5, 1285–1288; c) I.
Das, T. K. Pal, T. Pathak, J. Org. Chem. 2007, 72, 9181–9189;
d) R. Bhattacharya, D. Dey, T. Pathak, Eur. J. Org. Chem.
2009, 5255–5260.
[6]
[7]
Reviews on MCRs using carbohydrates as scaffolds: M. Brash-
olz, H.-U. Reissig, R. Zimmer, Acc. Chem. Res. 2009, 42, 45–
56.
Selected references on the use of carbohydrates in MCRs: a)
O. Lockhoff, Angew. Chem. 1998, 110, 3634–3637; Angew.
Chem. Int. Ed. 1998, 37, 3436–3439; b) A. Dondoni, A. Massi,
S. Sabbatini, V. Bertolasi, Tetrahedron Lett. 2004, 45, 2381–
2384; c) B. Westermann, S. Dörner, Chem. Commun. 2005,
2116–2118; d) T. M. Chapman, I. G. Davies, B. Gu, T. M.
Block, D. I. C. Scopes, P. A. Hay, S. M. Courtney, L. A. McNe-
ill, C. J. Schofield, B. G. Davis, J. Am. Chem. Soc. 2005, 127,
506–507; e) M. S. M. Timmer, M. D. P. Risseeuw, M. Verdoes,
D. V. Filippov, J. R. Plaisier, G. A. van der Marel, H. S. Overk-
leeft, J. H. van Boom, Tetrahedron: Asymmetry 2005, 16, 177–
185; f) A. Dondoni, A. Massi, M. Aldhoun, J. Org. Chem.
2007, 72, 7677–7687; g) S. Mandal, H. M. Gauniyal, K. Pram-
anik, B. Mukhopadhyay, J. Org. Chem. 2007, 72, 9753–9756;
[12]
[13]
Selected references on furofurans: a) G. A. Kraus, B. E. John-
ston, J. M. Applegate, J. Org. Chem. 1991, 56, 5688–5691; b)
M. C. Pirrung, Y. R. Lee, J. Am. Chem. Soc. 1995, 117, 4814–
4821; c) Y. Okamoto, Y. Kaneda, T. Yamasaki, T. Okawara,
M. Furukawa, J. Chem. Soc. Perkin Trans. 1 1997, 1323–1327;
d) R. Roggenbuck, A. Schmidt, P. Eilbracht, Org. Lett. 2002,
6096
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6084–6097

Diversity-Oriented Synthesis from Carbohydrates
4, 289–291; e) K. D. Eom, J. V. Raman, H. Kim, J. K. Cha, J.
Am. Chem. Soc. 2003, 125, 5415–5421; f) P. J. L. M. Quaed-
flieg, B. R. R. Kesteleyn, P. B. T. P. Wigerinck, N. M. F. Goyva-
erts, R. J. Vijn, C. S. M. Liebregts, J. H. M. H. Kooistra, C. Cu-
san, Org. Lett. 2005, 7, 5917–5920; g) S. D. Haveli, P. R. Srid-
har, P. Suguna, S. Chandrasekaran, Org. Lett. 2007, 9, 1331–
1334; h) W. L. Canoy, B. E. Cooley, J. A. Corona, T. C. Love-
lace, A. Millar, A. M. Weber, S. Xie, Y. Zhang, Org. Lett. 2008,
10, 1103–1106; i) S. Cai, Z. Liu, W. Zhang, X. Zhao, D. Z.
Wang, Angew. Chem. 2011, 123, 11329–11333; Angew. Chem.
Int. Ed. 2011, 50, 11133–11137.
Selected references on cyclopropanated furofurans: a) T. F.
Schneider, J. Kaschel, B. Dittrich, D. B. Werz, Org. Lett. 2009,
11, 2317–2320; b) T. F. Schneider, J. Kaschel, S. I. Awan, B.
Dittrich, D. B. Werz, Chem. Eur. J. 2010, 16, 11276–11288.
Received: April 25, 2013
[14]
Published Online: August 6, 2013
Eur. J. Org. Chem. 2013, 6084–6097
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6097