Diastereoselective trimolecular condensation between indole, Meldrum's acid and chiral sugar-derived aldehydes

Article abstract of DOI:10.1016/j.tetasy.2009.12.017

The trimolecular condensation of indole, Meldrum's acid and chiral, sugar-derived aldehydes took place in good yield and high diastereoselectivity. The absolute configuration of the α-carbon of the chiral aldehydes ensured a predictable diastereocontrol of the newly created stereogenic centre except for (3aR,5S,6S,6aR)-6-benzyloxy-2,2-dimethyl-tetrahydrofuro[3,2-d][1,3]dioxo le-5-carbaldehyde 3i. In this case, the opposite stereochemistry may be explained by a less congested conformer of the Knoevenagel-adduct intermediate.

Full text of DOI:10.1016/j.tetasy.2009.12.017

Tetrahedron: Asymmetry 21 (2010) 208–215
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective trimolecular condensation between indole, Meldrum’s
acid and chiral sugar-derived aldehydes
Emmanuel Dardennes a,b, Stéphane Gérard a, Christian Petermann a, Janos Sapi a,
*
a Université de Reims-Champagne-Ardenne, Institut de Chimie Moléculaire de Reims (ICMR), CNRS UMR 6229, Groupe BSMA, UFR de Pharmacie, 51 rue Cognacq-Jay,
F-51096 Reims, Cedex, France
b Sygnature Chemical Services, Biocity Nottingham, Pennyfoot Street, Nottingham NG1 1GF, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The trimolecular condensation of indole, Meldrum’s acid and chiral, sugar-derived aldehydes took place
Received 30 November 2009
Accepted 21 December 2009
Available online 18 January 2010
in good yield and high diastereoselectivity. The absolute configuration of the a-carbon of the chiral alde-
hydes ensured a predictable diastereocontrol of the newly created stereogenic centre except for
(3aR,5S,6S,6aR)-6-benzyloxy-2,2-dimethyl-tetrahydrofuro[3,2-d][1,3]dioxole-5-carbaldehyde 3i. In this
case, the opposite stereochemistry may be explained by a less congested conformer of the Knoevena-
gel-adduct intermediate.
This paper is dedicated to the memory of
Professor Lajos Szabo (Technical University
of Budapest, Hungary) who passed away on
20th December 2008, at the age of 81
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
remote substituent effect on the diastereoselectivity by using sev-
eral polyfunctional sugar-derived chiral aldehydes (Scheme 1). In
Multicomponent reactions (MCRs) are one-pot reactions in
which at least three partners are combined in a single reaction ves-
sel to form new products incorporating a substantial part of the
reacting partners. Rapidity, diversity, efficiency and environmental
amiability are the key features of this widely used method.1 Over
the past decades multicomponent reactions have undoubtedly be-
come a versatile tool for the construction of highly functionalised
building blocks in the total synthesis of natural products2 and in
diversity-oriented synthesis of heterocyclic scaffolds for drug
discovery.3
The expanding claim for chiral, polyfunctionalised molecules of
biological interest triggered the development of enantio(diaste-
reo)selective multicomponent processes4 by using chiral starting
materials, chiral catalysts5 or very recently, organocatalysts.6 Despite
spectacular progress, such a multicomponent approach providing
drug-likecarbo-orheterocyclicscaffoldsbyadiastereoselectiveman-
nerremainsa challengeinsyntheticorganicandmedicinalchemistry.
Some years ago we developed a trimolecular condensation be-
tween indole 1, Meldrum’s acid 2 and aldehydes for the prepara-
tion of conformationally constrained b-substituted tryptophans.7
addition, such an experience would facilitate the synthetic applica-
tions that can be carried out on the condensation products.
2. Results and discussion
According to our previous studies trimolecular condensation
with D-glyceraldehyde 3c afforded 4c with (S) absolute configura-
tion and high diastereoselectivity.8
In this regard, we first examined the substitution effect of the b-
carbon by selecting functionalised chiral aldehydes bearing a
dioxolane ring 3d or bulky dithioacetal group 3e (Scheme 1, Ta-
ble 1). Chiral aldehyde 3d, prepared from the corresponding dithio-
acetal9 by periodic acid-mediated demercaptalation10 was reacted
crude with indole 1 and Meldrum’s acid 2 under the classical con-
ditions. We were delighted to find that the condensation product
could be obtained as a diastereomeric mixture (95:5) from which
the major isomer 4d was isolated by crystallisation (Table 1, entry
2). The stereochemistry of the newly created stereogenic centre
was determined by the conversion of 4d to the corresponding lac-
tone-ester 5d. Thus, treatment of 4d with HCl in methanol led to
5d in 95% yield. The observed large coupling constant (JH-3–H-
4 = 13.1 Hz) together with a NOE cross-peak between H-4 and H-
5 evidenced trans H-3/H-4 and cis H-4/H-5 relative configurations.
Consequently, the absolute configuration of the newly created car-
bon in 4d is (S).
By extension of this method to chiral aldehydes such as D- or L-
glyceraldehyde 3a or Garner’s aldehyde 3b we have worked out a
highly diastereoselective synthesis of chiral 3,4-furanone-, pyrro-
lidinone- or pyranone-annulated tetrahydro-b-carbolines (Fig. 1).8
In order to investigate the scope and limitation of this asym-
metric multicomponent reaction we envisioned a study of the
When a freshly prepared dithioacetal group substituted alde-
hyde 3e11 was reacted with indole 1 and Meldrum’s acid 2, the cor-
responding condensation product 4e was isolated in 71% yield with
92% de (Table 1, entry 3). Similarly, enantiomerically pure conden-
* Corresponding author. Tel.: +33 (0)326 91 80 22; fax: +33 (0)326 91 80 29.
E-mail address: janos.sapi@univ-reims.fr (J. Sapi).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.017

E. Dardennes et al. / Tetrahedron: Asymmetry 21 (2010) 208–215
209
O
X
X: O
X: NBoc
3a
3b
X
CHO
+
3
*
FG
4
*
NH
3-MCR
1. FG transformations
O
2. Pictet-Spengler
cyclisation
N
H
O
O
N
H
*
Ar
1
(ArCHO)
chiral 3,4-heterocycle-annulated
O
2
tetrahydro-β-carbolines
Figure 1.
OProt
*
R
OProt
*
3
CHO
+
*
O
R
O
R
O
D,L-Pro cat.
CH3CN
deprot.
O
(COOH)
N
H
N
H
N
H
O
O
+
5
1
4
O
O
O
2
O
Scheme 1.
sation product 4e was obtained by crystallisation. The (S) configu-
ration of the new stereogenic centre in 4e was deduced from NMR
data (couplings and NOE experiences) of lactone-acid 5e obtained
in 75% yield by aqueous HCl-assisted cleavage followed by ring
closure.
H-5 protons and on the other hand between H-3 and indole H-2
protons corresponding to H-4/H-5 cis and H-3/H-4 trans relative
configurations.
Minor diastereomer epi-4g obtained in 3% yield with the same
aldehyde 3g was isolated by preparative thin-layer chromatogra-
phy. The diastereomeric ratio of trimolecular condensation prod-
ucts 4g/epi-4g was 94 is to 6. Regioisomeric three-component
condensation products 4h/epi-4h obtained from 3h were unex-
ploited due to the complexity of the mixture.
By replacing the dioxolane protection of a-and b-hydroxyl func-
tions by a benzyl protecting group we intended to examine the im-
pact of conformationally mobile aldehydes on diastereoselectivity.
Freshly prepared12 dibenzyloxy-substituted aldehyde 3f afforded
condensation product 4f in 67% yield with 96% de (Table 1, entry
4). Debenzylation of 4f quantitatively provided lactone-acid 5f of
trans and cis relative configuration for H-3/H-4 and H-4/H-5 hydro-
gens, respectively. The absolute configuration of the newly created
stereogenic centre in 4f was again (S).
At this point it was clear that the diastereoselectivity of the
three-component reaction was noteworthy (de >90%) and that
the (S)-absolute configuration was obtained independently from
the substitution pattern (cyclic or non-cyclic) of a,b-dihydroxy chi-
ral aldehydes. These highly efficient reactions require some mech-
anistic considerations. Three-component reactions have probably
passed through an alkylidene Meldrum’s acid intermediate 9,
formed by a proline-catalysed condensation.14 Subsequent nucleo-
philic attack of indole 1 on the electron-deficient Michael acceptor
intermediate 9 affords the corresponding condensation products 4.
The observed high syn-diastereoselectivity may be explained by
the approach of indole from the c-oxygen face on the reactive con-
formation wherein non-bonding 1,3-allyl-strain is minimized
(Scheme 3).
With these results in hand, we were keen to investigate
whether a sterically congested group in the
influence the stereochemistry.
a- or b-position would
Orthogonally protected aldehydes bearing bulky tert-butyldi-
methylsilyloxy functions in - or b-positions were prepared as de-
a
picted in Scheme 2. In both cases the other hydroxyl group was
benzylated. Dihydroxythioacetal 6 after deprotonation was sub-
mitted to subsequent O-silylation and O-benzylation giving rise
to an inseparable mixture of major 7 and minor 8 O-diprotected
thioacetals (77/23). Periodic acid-mediated deprotection of this
latter 7/8 afforded the corresponding mixture of aldehydes 3g/
3h13 that was reacted without purification with indole 1 and Mel-
drum’s acid 2 (Table 1, entry 5). The three-component condensa-
tion led to a mixture of four derivatives (total yield: 67%) from
which the major diastereomer 4g bearing a tert-butyldimethylsi-
lyloxy group on the b-carbon was isolated in 48% yield by crystal-
lisation. Since 1H NMR couplings did not allow the determination
of the stereochemistry of newly formed stereocenter, trimolecular
condensation product 4g was submitted to catalytic hydrogena-
tion. Debenzylation of 4g followed by spontaneous ring closure
led to lactone-acid 5g in quantitative yield. NOESY experiments
of 5g revealed correlations on the one hand between H-4 and
Then it was interesting to investigate the substituent effect
using bicylic O-benzyl protected aldehyde 3i15 prepared from
1,2,5,6-diisopropylidene-D-glucose according to a recently modi-
fied procedure.16 The resulting crude aldehyde 3i was directly re-
acted with indole 1, Meldrum’s acid 2 in the presence of a
catalytic amount of D,L-proline to give three-component condensa-
tion product 4i with high diastereoselectivity (de >95%) (Table 1,
entry 6). Debenzylation of 4i provoked a facile intramolecular cyc-
lisation followed by elimination. A mixture of lactone-acid 5i and
its decarboxylated counterpart 5j was isolated in 93% and 6% yield,
respectively. The trans relative configuration between the indole
ring and carboxylic acid function in 5i was suggested by a large
coupling constant JH-6–H-7 = 12.3 Hz) of
a doublet (H-6) at

210
E. Dardennes et al. / Tetrahedron: Asymmetry 21 (2010) 208–215
Table 1
Synthesis of three-component products 4 from chiral aldehydes 3, indole 1 and Meldrum’s acid 2 and their transformation to lactones 5 according to Scheme 1
Entry
Aldehydes 3a
Three-component products 4b
Deprotection
Lactones 5
OH
O
O
O
O
O
O
O
O
O
HCl–H2O, THF
25 °C, 0.5 h
CHO
CHO
1
O
COOH
N
H
N
H
3c
O
O
5c (92%)8
4c (76%, d.e. 92%)8
OH
O
O
O
OH
O
HO
5
O
O
O
2
HCl–MeOH
25 °C, 0.5 h
O
O
O
O
4
2
3
4
O
CHO
3
O
CO2Me
N
H
N
H
O
3d
5d (95%)
4d (55%, d.e. 90%)
EtS
SEt
EtS
SEt
EtS
SEt
O
O
HO
O
O
O
O
O
CHO
HCl–H2O, THF
25 °C, 48 h
O
O
N
H
CO2H
O
N
H
3e
4e (71%, d.e. 92%)
5e (75%)
OH
O
O
O
OH
O
HO
OBn
O
OBn
CHO
BnO
O
H2-PdC, AcOEt
25 °C, 24 h
BnO
O
O
CO2H
N
H
N
H
O
O
3f
5f (95%)
4f (67%, d.e. 96%)
O
O
O
O
O
O
OBn
OBn
TBDMSO
TBDMSO
O
TBDMSO
O
H2-PdC, AcOEt
25 °C, 24 h
CHO
O
O
CO2H
3g
N
H
N
H
O
O
5g (from 4g) (98%)
4g/epi-4g (48% / 3%, d.e. 88%)
5
O
O
O
O
OTBDMS
OTBDMS
BnO
O
BnO
CHO
O
N
H
O
O
3h
4h/epi-4h (15%)
3g/3h : 77/23

E. Dardennes et al. / Tetrahedron: Asymmetry 21 (2010) 208–215
211
Table 1 (continued)
Entry
Aldehydes 3a
Three-component products 4b
Deprotection
Lactones 5
O
2
O
O
O
O
O
O
3
1O
7a
3a
4
O
BnO
BnO
O
O
O
5
H2-PdC, AcOEt
25 °C, 24 h
CHO
6
7
O
6
O
R
N
H
N
H
O
3i
5i R = COOH (93%)
4i (81%, d.e. 95%)
5j R = H (6%)
a
Aldehydes were used without further purification.
b
Diastereomeric excess was determined by 1H NMR after column chromatography purification.
SEt
OH
SEt
OTBDMS
SEt
OBn
EtS
HO
EtS
EtS
OHC
OHC
H5IO6
1. NaH
2. TBDMSCl
3. BnBr
OBn
O
OTBDMS
TBDMSO
BnO
TBDMSO
BnO
+
+
O
O
O
O
O
O
O
O
O
6
7
3g
3h
(77:23)
8
Scheme 2.
O
R
O
O
+
1
+
O
O
CHO
2
O
3
D,L-Procat.
indole 1
O
O
O
O
O
H
O
O
O
O
γ
O
R
H
O
O
β
R
H
9
N
H
1
R
O
O
O
O
N
H
O
O
4
Scheme 3.

212
E. Dardennes et al. / Tetrahedron: Asymmetry 21 (2010) 208–215
derivedaldehydesoccurredwithgoodyieldandhighdiastereoselec-
tivity. We evidenced that the stereochemistry of the newly created
stereogenic centre could be controlled by the absolute configuration
H
O
2
H
H
O
O
2
of the a-carbon in the chiral aldehydes used. However, trimolecular
H
N
7a
O
condensation with bicyclic O-benzyl-protected aldehyde 3i afforded
the opposite stereochemistry probably via a less congested con-
former of the intermediate Knoevenagel product. Further extension
of these results may involve the exploration of other chiral alde-
hydes and the application of three-component condensation prod-
ucts for the synthesis of new polyfunctionalised (tetrahydro)-b-
carbolines are of biological interest.
H
3a
5
6
O
7
H
H
H
4
H
Figure 2.
d = 4.25 ppm. The small coupling (JH-7–H-7a = 3.6 Hz) of the doublet
of doublet attributed to H-7 was in accord with a cis relative con-
figuration between H-7 and H-7a.
4. Experimental
4.1. General
Further support for the stereochemistry of this functionalised
tetrahydrofuro[3,2-b]tetrahydropyranone appendage was fur-
nished by exhaustive NOESY experiments made on the more stable
decarboxylated lactone 5j (Fig. 2). Thus, cross-peaks were identi-
fied on the one side between H-7 and H-6a, H-7a and H-4 of the
indole ring, and on the other side between H-6b and H-2 of the in-
dole moiety and H-2 and indole NH. All these spectroscopic data
supported the (S) absolute configuration for the C-7 carbon. This
configuration is the opposite to that of what we observed when
All solvents were of reagent grade and, when necessary, were
purified and dried by standard methods. Reactions and products
were routinely monitored by thin-layer chromatography (TLC) on
silica gel (Kieselgel 60 F254, Merck). Flash or normal column chro-
matography purifications were performed on SDS CHROMAGELÒ
(Silica Gel 60 ACC 35–70 or 70–200 lm). Melting points were
determined on a Reichert Thermovar hot-stage apparatus and are
uncorrected. UV spectra were recorded in methanol solution on a
Unicam 8700 apparatus. IR spectra were measured with a Spec-
trum BX/RX (Perkin–Elmer) instrument. 1H NMR (300 MHz) and
13C NMR (75 MHz) spectra were recorded on a Bruker AC 300 spec-
trometer using TMS as internal standard. Couplings expressed as s,
sl, d, t and m correspond to singlet, large-singlet, doublet, triplet
and multiplet, respectively. Mass spectra were recorded on a
MSQ ThermoFinnigan apparatus using electronspray (ESI) or on a
GCT Waters apparatus using electronimpact (EI) ionisation meth-
od. Optical rotation measurements were carried out on a Perkin–
Elmer 241 polarimeter.
L
2.8
-glyceraldehyde 3a was reacted with indole 1 and Meldrum’s acid
The highly anti-selective three-component condensation oc-
curred with O-benzyl substituted aldehyde 3i and was contrary
to the results of Sabitha et al. using hydroxyl or methoxy-group
substituted analogs.17 The opposite absolute configuration ob-
served in our case may result from a more stable conformer of
Knoevenagel product 9i which is free of steric repulsion between
O-benzyl group and the carbonyl function of Meldrum’s acid
appendage (Scheme 4). The intermediacy of such alkylidene Mel-
drum’s acid in our three-component condensation was supported
by reacting 9i18 with indole 1, as depicted in Scheme 4. The con-
densation was completely diastereoselective and we isolated the
same three-component product 4i that was obtained under classi-
cal conditions.
4.2. (2R,3S,4S)-2-Benzyloxy-3-tert-butyldimethylsilyl-oxy-
4,5-dihydroxy-4,5-O-isopropylidene-pentanal-1,1-diethyl-
dithioacetal 7 and (2R,3S,4S)-3-benzyloxy-2-tert-butyldi
methylsilyloxy-4,5-dihydroxy-4,5-O-isopropylidene-
pentanal-1,1-diethyl-dithioacetal 8
3. Conclusion
To a suspension of NaH (60% suspension in oil, 700 mg,
17.5 mmol) in dry THF, were added successively diol 6 (2.00 g,
6.75 mmol) and after 1 h stirring tert-butyldimethylsilyl chloride
In conclusion, we found that the three-component reaction
between indole, Meldrum’s acid and polyfunctional, chiral sugar-
3-MCR approach
electrostatic
O
O
O
indole 1
H
H
O
O
O
O
BnO
BnO
O
O
O
O
O
H
O
O
D,L-Pro
(cat)
2
+
1 +
O
O
H
O
H
H
O
BnO
O
O
O
O
O
OBn
H
N
H
CHO
O
4i
3i
9i
steric
4i (81%, d.e. 95%)
Approach via Knoevenagel product 9i
O
O
O
O
N
H
O
O
piperidinium
acetate
1
BnO
3i
O
O
+
4i (98%, d.e. >96%)
O
O
O
9i (85%)
Scheme 4.

E. Dardennes et al. / Tetrahedron: Asymmetry 21 (2010) 208–215
213
(1.528 g, 10.12 mmol). The reaction mixture was stirred at room
temperature for 30 min before adding a catalytic quantity of tetra-
butylammonium iodide (35 mg) and then benzyl bromide
(2.32 mL, 3.33 g, 19.5 mmol). After one night stirring at room tem-
perature the excess of sodium hydride was quenched at 0 °C by
addition of 10% K2CO3 solution (20 mL). The aqueous phase was ex-
tracted with dichloromethane (3 ꢀ 30 mL), the organic phases
were dried (MgSO4), filtered and evaporated under reduced pres-
sure. The residue was purified by column chromatography (elu-
tion: cyclohexane–CH2Cl2 6:4) to give a mixture of 7 and 8 in
77:23 proportion (3.116 g, 92%), as a colourless oil. UV (MeOH)
J = 11.6 Hz), 1.42 (s, 3H), 1.43 (s, 6H), 1.69 (s, 3H), 2.54–2.78 (m,
4H), 3.72 (d, 1H, J = 5.0 Hz), 4.03 (d, 1H, J = 3.7 Hz), 4.28 (dd, 1H,
J = 6.5, 5.0 Hz), 4.61 (dd, 1H, J = 7.2, 3.7 Hz), 4.99 (dd, 1H, J = 7.2,
6.5 Hz), 7.10–7.20 (m, 2H), 7.16–7.28 (m, 1H), 7.39 (d, 1H,
J = 2.7 Hz), 7.66–7.75 (m, 1H), 8.32 (br s, 1H) ppm; 13C NMR (CDCl3)
d 14.1, 14.3, 25.3, 25.4, 27.3, 27.5, 28.0, 28.1, 39.3, 49.3, 53.8, 79.8,
83.2, 105.3, 110.3, 110.4, 111.1, 118.6, 119.9, 122.1, 125.1, 127.5,
135.0, 165.2, 165.3 ppm; MS (EI) m/z (%) 529 (M+Å+Na, 19), 507
(7), 449 (76), 391 (100). Anal. Calcd for C25H33NO6S2: C, 59.15; H,
6.55; N, 2.76. Found: C, 58.87; H, 6.61; N, 2.95.
kmax 238, 215 nm; IR (KBr)
m
2951, 2925, 2855, 1454, 1379, 1252,
4.6. (10S,20S,30R,40S)-5-[20,30-Bis(benzyloxy)-40,50-dihydroxy-10-(1H-
indol-3-yl)-40,50-di-O-isopropylidene-pentan-10-yl]-2,2-dimethyl-
1,3-dioxane-4,6-dione 4f
1207, 1133, 1067, 833, 776, 732, 697 cmꢁ1; NMR data of 7: 1H
NMR (CDCl3) d ꢁ0.05 (s, 3H), 0.05 (s, 3H), 0.82 (s, 9H), 1.2 (m,
6H), 1.26 (s, 3H), 1.36 (s, 3H), 2.46–2.71 (m, 4H), 3.73 (dd, 1H,
J = 3.4, 6.4 Hz), 3.92 (dd, 1H, J = 2.1, 7.8 Hz), 4.04–4.10 (m, 2H),
4.23–4.26 (m, 2H), 4.74 (d, 1H, J = 11.3 Hz), 4.89 (d, 1H,
J = 11.3 Hz), 7.25–7.41 (m, 5H) ppm; 13C NMR (CDCl3) d ꢁ4.2,
ꢁ3.7, 14.3, 14.5, 18.3, 24.4, 24.9, 25.5, 25.8, 26.5, 52.4, 66.4, 73.6,
74.4, 76.2, 82.6, 108.4, 127.3, 127.6, 128.1, 138.5 ppm; MS (CI) m/
z (%) 500 (M+Å, 7), 485 (47), 446 (39), 291 (17), 231 (19), 187
(22), 161 (28), 135 (100).
Mp: 55–57 °C (cyclohexane–ethyl acetate); ½a D22
ꢂ
¼ ꢁ144 (c 0.31,
3424,
CHCl3); UV (MeOH) kmax 291, 282, 276, 219 nm; IR (KBr)
m
3356, 2988, 2928, 2886, 1775, 1742, 1456, 1381, 1294, 1211,
1072, 735, 699 cmꢁ1 1H NMR (CDCl3) d 1.23 (s, 3H), 1.32 (s, 3H),
;
1.36 (s, 3H), 1.50 (s, 3H), 3.87 (d, 1H, J = 3.5 Hz), 3.92 (d, 1H,
J = 10.5 Hz), 3.98–4.09 (m, 1H), 4.11–4.19 (m, 1H), 4.20–4.24 (m,
2H), 4.41–4.48 (m, 2H), 4.69–4.76 (m, 2H), 4.89 (d, 1H,
J = 11.7 Hz), 6.66 (d, 2H, J = 7.7 Hz), 7.02–7.15 (m, 6H), 7.22–7.43
(m, 6H), 7.81–7.85 (m, 1H), 8.31 (br s, 1H) ppm; 13C NMR (CDCl3)
d 24.6, 26.5, 27.5, 27.9, 38.1, 48.6, 65.4, 72.3, 75.0, 77.2, 77.7,
81.6, 104.8, 108.0, 110.7, 113.5, 119.9, 120.2, 122.3, 123.5, 127.4,
127.9, 128.0, 128.1, 128.5, 128.6, 135.3, 137.7, 164.7, 166.5 ppm;
MS (EI) m/z (%) 611 (M+Å+Na, 33), 589 (3), 531 (88), 473 (100). Anal.
Calcd for C34H39NO8: C, 69.25; H, 6.66; N, 2.37. Found: C, 69.01; H,
6.91; N, 2.55.
4.3. General procedure for the three-component reaction with
sugar-derived aldehydes
Aldehydes were prepared and then directly used for the con-
densation reaction. To a solution of chiral aldehyde 3 in acetonitrile
were added successively indole 1 (1.1 equiv), Meldrum’s acid 2
(1.1 equiv) and D,L-proline (0.1 equiv). The reaction mixture was
stirred at room temperature under N2 overnight, the solvent was
evaporated and the residue was purified by column chromatogra-
phy (elution: cyclohexane–ethyl acetate) to afford the title com-
pounds. Chemical yield and diastereomeric excess were
determined after chromatography and the major diastereoisomer
was then crystallised.
4.7. (10S,20S,30R,40S)-5-[20-Benzyloxy-30-tert-butyldimethylsilyloxy-
40,50-dihydroxy-10-(1H-indol-3-yl)-40,50-di-O-isopropylidene-pentan
-10-yl]-2,2-dimethyl-1,3-dioxane-4,6-dione 4g and (10R,20S,30R,40S)-5-
[20-benzyloxy-30-tert-butyldimethylsilyloxy-40,50-dihydroxy-10-(1H-
indol-3-yl)-40,50-di-O-isopropylidene-pentan-10-yl]-2,2-dimethyl-
1,3-dioxane-4,6-dione epi-4g
4.4. (10S,20S,30R,40S)-5-[20,30,40,50-Tetrahydroxy-10-(1H-indol-3-yl)-
(2,3:4,5)-di-O-isopropylidene-pentan-10-yl]-2,2-dimethyl-1,3-
dioxane-4,6-dione 4d
A solution of the mixture of thioacetals 7 and 8 (1.882 g,
3.76 mmol) in dry ether (20 mL) was treated with periodic acid
(H5IO6) (944 mg, 4.14 mmol) at 0 °C and the reaction mixture was
stirred at room temperature for 20 min. After quenching with 10%
Na2SO3 (20 mL)at 0 °C the organiclayer was separated and theaque-
ous phase was extracted with ether (2 ꢀ 20 mL). The combined or-
ganic layers were dried (Na2SO4), filtered and carefully evaporated
under reduced pressure. The crude aldehyde mixture 3g/3h was dis-
solved in dry acetonitrile (20 mL) and to the solution indole 1
(484 mg, 3.76 mmol), Meldrum0s acid 2 (596 mg, 3.76 mmol) and
Isolated by crystallisation from cyclohexane–ethyl acetate (1:1).
Mp: 80–82 °C (cyclohexane–ethyl acetate); ½a D23
ꢂ
¼ ꢁ58 (c 0.35,
CHCl3); UV (MeOH) kmax 290, 281, 274, 222 nm; IR (KBr)
m
3406,
2985, 2937, 2870, 1776, 1743, 1457, 1381, 1324, 1295, 1209,
1152, 1062, 1009, 971, 848, 767, 743 cmꢁ1 1H NMR (CDCl3) d
;
1.29 (s, 3H), 1.30 (s, 3H), 1.36 (s, 3H), 1.38 (s, 3H), 1.39 (s, 3H),
1.68 (s, 3H), 3.84–3.97 (m, 2H), 4.15–4.22 (m, 2H), 4.36 (dd, 1H,
J = 9.2, 3.0 Hz), 4.47 (d, 1H, J = 3.0 Hz), 5.08 (dd, 1H, J = 9.2,
7.2 Hz), 7.08–7.27 (m, 4H), 7.66–7.71 (m, 1H), 8.18 (br s, 1H)
ppm; 13C NMR (CDCl3) d 25.6, 26.7, 26.9, 26.95, 27.8, 28.0, 39.8,
49.3, 68.2, 76.9, 82.0, 82.2, 104.9, 108.9, 109.9, 110.8, 112.1,
119.5, 119.6, 121.9, 127.8, 135.2, 165.3, 165.6 ppm; MS (EI) m/z
(%) 495 (M+Å+Na, 24), 473 (5), 415 (57), 357 (100). Anal. Calcd for
C25H31NO8ꢃ0.5H2O: C, 62.23; H, 6.68; N, 2.90. Found: C, 62.17; H,
6.39; N, 3.21.
D,L-proline (35 mg, 0.3 mmol) were added. After stirring at room
temperature for 16 h the solvent was evaporated and the residue
was purified by flash chromatography (elution: cyclohexane–ethyl
acetate 7:3) affording a mixture (1.602 g, 67%) of four distereomers
4g, epi-4g, 4h and epi-4h. Major diastereomer 4g (1.150 g, 48%) was
isolated by crystallisation in a mixture of cyclohexane–ethyl acetate
(4:1). From themotherliquorminordiastereomerepi-4g(83 mg, 3%)
and the unseparable diastereomeric mixture 4h/epi-4h (369 mg,
15%) were isolated by preparative thin-layer chromatography (elu-
tion: cyclohexane–ethyl acetate 6:4). Compound 4g: Mp: 138–
4.5. (10S,20S,30R)-5-[40,40-Bis(ethylsulfanyl)-20,30-dihydroxy-10-(1H-
indol-3-yl)-20,30-di-O-isopropylidene-butan-10-yl]-2,2-dimethyl-1,3-
dioxane-4,6-dione 4e
139 °C (cyclohexane–ethyl acetate); ½a D22
ꢂ
¼ ꢁ57:1 (c 0.3, CHCl3);
UV (MeOH) k 290, 281, 273, 219, 198 nm; IR (KBr)
m
3836, 3396,
2947, 2889, 1776, 1743, 1290, 1248, 1205, 1162, 1086, 1062, 1005,
Isolated by crystallisation from ether. Mp: 114–116 °C (ether);
833, 771, 743 cmꢁ1 1H NMR (CDCl3) d 0.01 (s, 3H), 0.25 (s, 3H),
;
½
a 2D2
ꢂ
¼ ꢁ50 (c 1.0, CHCl3); UV (MeOH) kmax 290, 281, 273, 221,
207 nm; IR (KBr) 3427, 2978, 2916, 2837, 1780, 1745, 1458,
1384, 1370, 1287, 1216, 1155, 1084, 1049, 1014, 992, 908,
741 cmꢁ1 1H NMR (CDCl3) d 1.20 (t, 3H, J = 11.6 Hz), 1.25 (t, 3H,
0.88 (s, 9H), 1.32 (s, 3H), 1.36 (s, 3H), 1.51 (s, 3H), 1.65 (s, 3H),
4.02–4.12 (m, 3H), 4.20–4.23 (m, 1H), 4.34–4.44 (m, 4H), 4.68 (m,
1H), 6.74 (d, 2H, J = 6.8 Hz), 7.03–7.30 (m, 7H), 7.79–7.83 (m, 1H),
8.08 (br s, 1H) ppm; 13C NMR (CDCl3) d ꢁ3.4, ꢁ3.3, 18.4, 25.3, 26.0,
m
;

214
E. Dardennes et al. / Tetrahedron: Asymmetry 21 (2010) 208–215
26.8, 27.8, 28.1, 38.0, 49.1, 66.0, 74.6, 75.1, 75.5, 81.6, 104.9, 108.7,
110.6, 114.0, 119.8, 120.0, 122.1, 123.5, 127.1, 127.7, 127.8, 128.3,
135.2, 138.2, 165.1, 166.0 ppm; MS (EI) m/z (%) 660 (M+Å+Na, 43),
638 (4), 580 (100), 558 (23), 522 (15), 451 (8). HRMS calcd for
C35H47NO8SiNa 660.2969, found 660.2958. Anal. Calcd for
C35H47NO8Si: C, 65.91; H, 7.43; N, 2.20. Found: C, 65.70; H, 7.39; N,
2.22. epi-4g: Mp: 141–142 °C (cyclohexane–ethyl acetate);
4.10. (3S,4S,5S)-5-[20,20-Bis(ethylsulfanyl)-(10R)-10-
hydroxyethyl]-4-(1H-indol-3-yl)-2-oxo-tetrahydrofuran-3-
carboxylic acid 5e
To a solution of 4e (1.05 g, 2.17 mmol) in tetrahydrofuran
(10 mL) was added an aqueous 4 M solution of HCl (5 mL). After
two days stirring at room temperature the solvent was removed,
the residue was dissolved in dichloromethane (10 mL) and washed
with 10% K2CO3 solution (3 ꢀ 5 mL). The aqueous phase was acid-
ified with solid citric acid and extracted with dichloromethane
(3 ꢀ 10 mL). The combined organic phases were dried (MgSO4), fil-
tered and evaporated giving 5e (666 mg, 75%), as a white solid. Mp:
½
a 2D2
ꢂ
¼ ꢁ138:4 (c 0.42, CHCl3); UV (MeOH) k 291, 281, 274, 223,
213 nm; IR (KBr) 3427, 2978, 2943, 2881, 1775, 1740, 1458,
1379, 1326, 1296, 1256, 1097, 1067, 1005, 891, 868, 833 cmꢁ1 1H
m
;
NMR (CDCl3) d ꢁ0.86 (s, 3H), ꢁ0.17 (s, 3H), 0.40 (s, 9H), 1.19 (s,
3H), 1.27 (s, 3H), 1.34 (s, 3H), 1.45 (s, 3H), 3.93–4.03 (m, 3H), 4.19
(dd, 1H, J = 7.1, 6.3 Hz), 4.59–4.71 (m, 3H), 4.78 (d, 1H, J = 2.7 Hz),
4.99 (dd, 1H, J = 10.6, 4.2 Hz), 6.97–7.32 (m, 9H), 7.68–7.70 (m,
1H), 8.05 (br s, 1H) ppm; 13C NMR (CDCl3) d ꢁ6.0, ꢁ4.9, 17.5, 25.3,
25.4, 26.2, 26.7, 28.0, 38.1, 49.1, 65.0, 72.0, 74.1, 74.8, 81.7, 104.5,
107.8, 110.4, 114.6, 119.4, 119.8, 121.9, 122.8, 127.9, 128.4, 128.5,
135.0, 137.7, 164.9, 166.2 ppm; MS (EI) m/z (%) 660 (M+Å+Na, 32),
638 (7), 580 (100), 558 (10). Anal. Calcd for C35H47NO8Si: C, 65.91;
H, 7.43; N, 2.20. Found: C, 65.48; H, 7.59; N, 2.02.
71–72 °C; ½a 2D4
ꢂ
¼ þ189:5 (c 0.4, CHCl3); UV (MeOH) kmax 290, 281,
3406, 2966, 2918, 1771, 1729, 1457, 1424,
1H
274, 220 nm; IR (KBr)
m
1376, 1338, 1314, 1262, 1233, 1148, 1100, 1009, 743 cmꢁ1
;
NMR (CDCl3) d 1.11 (t, 3H, J = 11.2 Hz), 1.21 (t, 3H, J = 7.6 Hz),
2.31–2.69 (m, 4H), 3.17 (d, 1H, J = 10.6 Hz), 3.91 (d, 1H,
J = 10.6 Hz), 4.50 (d, 1H, J = 12.8 Hz), 4.66 (dd, 1H, J = 12.8,
8.3 Hz), 5.59 (d, 1H, J = 8.3 Hz), 7.09–7.26 (m, 3H), 7.34 (d, 1H,
J = 7.9 Hz), 7.54 (d, 1H, J = 7.6 Hz), 8.25 (br s, 1H) ppm; 13C NMR
(CDCl3) d 14.3, 25.4, 26.9, 40.1, 50.5, 55.5, 70.4, 79.2, 109.1,
111.6, 118.3, 120.1, 122.5, 122.6, 126.5, 136.2, 172.4 ppm; MS
(EI) m/z (%) 399 (M+Å+Na, 18), 378 (25), 377 (23), 333 (100), 218
(53). Anal. Calcd for C19H23NO5S2ꢃ0.5H2O: C, 54.53; H, 5.78; N,
3.35. Found: C, 54.87; H, 5.70; N, 3.49.
4.8. 5-{(S)-[(3a0R,50R,60S,6a0R)-60-Benzyloxy-20,20-dimethyl-
dihydro-5H-furo[3,2-d][1,3]dioxol-50-yl](1H-indol-3-
yl)methyl}-2,2-dimethyl-1,3-dioxane-4,6-dione 4i
Isolated by crystallisation from cyclohexane–ethyl acetate (4:1).
4.11. (3S,4S,5S)-4-(1H-Indol-3-yl)-2-oxo-5-[(10S,20S)-10,20,30-
Mp: 157 °C (cyclohexane–ethyl acetate); ½a D24
¼ þ22:2 (c 0.4,
ꢂ
trihydroxypropan-10-yl]-tetrahydrofuran-3-carboxylic acid 5f
CHCl3); UV (MeOH) kmax 290, 280, 272, 221, 198 nm; IR (KBr)
m
3366, 3056, 2982, 2923, 2864, 1775, 1746, 1455, 1381, 1352,
A solution of 4f (142 mg, 0.23 mmol) in ethyl acetate (10 mL)
was hydrogenated over 10% PdC (50 mg) for 24 h. The catalyst
was removed by filtration on a CeliteÒ pad, the filtrate was evapo-
rated and the residue was purified by chromatography (elution:
ethyl acetate–methanol 8:2 and some drops of acetic acid) to af-
1289, 1211, 1164, 1123, 1097, 1068, 1046, 950, 887, 858, 773,
740 cmꢁ1 1H NMR (CDCl3) d 0.90 (s, 3H), 1.33 (s, 6H), 1.56 (s,
;
3H), 3.35 (d, 1H, J = 3.0 Hz), 4.18 (d, 1H, J = 3.0 Hz), 4.47 (d, 1H,
J = 12.0 Hz), 4.54 (dd, 1H, J = 10.6, 3.0 Hz), 4.78 (d, 1H, J = 4.0 Hz),
4.88 (d, 1H, J = 12.0 Hz), 5.32 (dd, 1H, J = 10.6, 3.0 Hz), 5.91 (d,
1H, J = 4.0 Hz), 7.04–7.47 (m, 9H), 7.73–7.78 (m, 1H); 8.22 (br s,
1H) ppm; 13C NMR(CDCl3) d 26.5, 26.9, 27.9, 28.1, 35.8, 48.3,
71.0, 80.4, 81.2, 81.9, 104.8, 105.2, 110.9, 111.7, 112.1, 119.8,
119.9, 122.1, 123.4, 126.7, 128.5, 128.6, 128.8, 135.6, 136.8,
165.1, 169.9 ppm; MS (EI) m/z (%) 521 (M+Å, 65), 494 (15), 463
(8), 419 (21), 377 (23), 346 (15), 329 (28); HRMS calcd for
C29H31NO8 521.2050, found 521.2056.
ford 5f (73 mg, 95%), as
¼ þ139:3 (c 0.22, acetone); UV (MeOH) kmax 291, 282, 275,
223, 207 nm; IR (KBr) 3401, 2925, 1740, 1603, 1384, 1344,
1229, 1181, 1089, 1053, 1005, 745 cmꢁ1 1H NMR (acetone-d6) d
a white solid. Mp: 192–193 °C;
½ ꢂ
a 2D4
m
;
3.41 (d, 1H, J = 9.1 Hz), 3.51–3.67 (m, 3H), 4.48 (d, 1H,
J = 12.9 Hz), 4.72 (dd, 1H, J = 12.9, 8.7 Hz), 5.45 (d, 1H, J = 8.7 Hz),
7.02–7.18 (m, 2H), 7.39–7.45 (m, 2H), 7.70 (d, 1H, J = 7.8 Hz),
10.28 (br s, 1H) ppm; 13C NMR (acetone-d6) d 41.3, 52.1, 64.6,
70.9, 72.1, 80.6, 110.5, 112.3, 119.4, 120.1, 122.7, 123.6, 128.2,
137.6, 170.3, 173.3 ppm; MS (EI) m/z (%) 341 (M+Å+Na, 12), 320
(11), 319 (9), 275 (100), 160 (43). Anal. Calcd for C16H17NO6: C,
60.18; H, 5.38; N, 4.39. Found: C, 59.89; H, 5.70; N, 4.49.
4.9. (3S,4S,5S)-4-(1H-Indol-3-yl)-2-oxo-5-[(10S,20S)-10,20,30-
trihydroxypropan-10-yl]-tetrahydrofuran-3-carboxylic acid
methyl ester 5d
4.12. (3S,4S,5S)-4-(1H-Indol-3-yl)-2-oxo-5-[(10R,20S)-10-tert-butyldi
methylsilyloxy-20,30-dihydroxy-20,30-di-O-isopropylidene-propan-
10-yl]-tetrahydrofuran-3-carboxylic acid 5g
To a solution of 4d (204 mg, 0.43 mmol) in methanol (2 mL) was
added a solution of methanol saturated with HCl (5 mL) at 0 °C.
After 30 min stirring at room temperature the solvent was re-
moved and the residue was purified by column chromatography
(elution: CH2Cl2–methanol 9:1) to give 5d (142 mg, 95%), as a
A solution of 4g (184 mg, 0.27 mmol) in ethyl acetate (20 mL)
was hydrogenated over 10% PdC (50 mg) for 24 h. The catalyst
was removed by filtration on a CeliteÒ pad, the filtrate was evapo-
rated to give 5g (132 mg, 100%), as a white solid. Mp: 76–80 °C;
white solid. Mp: 131–133 °C (MeOH–toluene); ½a D23
¼ þ134:6 (c
ꢂ
0.23, MeOH); UV (MeOH) kmax 290, 281, 274, 221 nm; IR (KBr)
m
3410, 2943, 1749, 1723, 1458, 1432, 1379, 1335, 1296, 1229,
1199, 1150, 1093, 1057, 1040, 1009, 996, 750 cmꢁ1 1H NMR
;
½
a 2D5
ꢂ
¼ þ70 (c 0.13, CHCl3); UV (MeOH) kmax 291, 282, 275,
(CD3OD) d 3.28 (d, 1H, J = 9.4 Hz), 3.41–3.45 (m, 1H), 3.56–3.66
(m, 5H), 4.56 (d, 1H, J = 13.1 Hz), 4.71 (dd, 1H, J = 13.1, 8.4 Hz),
5.45 (d, 1H, J = 8.4 Hz), 7.01–7.20 (m, 2H), 7.27 (s, 1H), 7.31 (d,
1H, J = 8.1 Hz), 7.56 (d, 1H, J = 7.8 Hz) ppm; 13C NMR (CD3OD) d
41.7, 52.5, 53.3, 64.4, 71.3, 72.0, 81.8, 109.9, 112.5, 119.2, 120.4,
123.0, 123.6, 128.1, 129.2, 129.9, 138.1, 170.8, 174.9 ppm; MS
(EI) m/z (%) 349 (M+Å, 45), 291 (23), 189 (100). Anal. Calcd for
C17H19NO7: C, 58.44; H, 5.48; N, 4.01. Found: C, 58.71; H, 5.56;
N, 4.30.
221 nm; IR (KBr)
m 3415, 2956, 2927, 1776, 1733, 1633, 1457,
1381, 1257, 1157, 1067, 833, 781 cmꢁ1
;
1H NMR (CDCl3) d ꢁ0.09
(s, 3H), ꢁ0.01 (s, 3H), 0.85 (s, 9H), 1.22 (s, 3H), 1.23 (s, 3H), 3.67
(dd, 1H, J = 7.5, 6.4 Hz), 3.80 (dd, 1H, J = 4.9, 4.1 Hz), 3.93–4.02
(m, 2H), 4.05 (d, 1H, J = 8.7 Hz), 4.47 (dd, 1H, J = 8.7, 7.2 Hz), 5.17
(dd, 1H, J = 7.2, 4.1 Hz), 7.10–7.25 (m, 3H), 7.40 (d, 1H, J = 8.1 Hz),
7.50 (d, 1H, J = 7.5 Hz), 8.40 (br s, 1H) ppm; 13C NMR (CDCl3) d
ꢁ3.9, ꢁ3.7, 18.4, 24.9, 25.9, 26.0, 40.1, 52.7, 66.2, 71.8, 76.0, 82.2,
109.1, 110.6, 111.7, 118.8, 120.4, 122.1, 123.0, 125.9, 136.3,
171.1, 171.6 ppm; MS (EI) m/z (%) 511 (M+Å+Na, 17), 490 (21),

E. Dardennes et al. / Tetrahedron: Asymmetry 21 (2010) 208–215
215
489 (11), 445 (100), 330 (23). Anal. Calcd for C25H35NO7Si: C, 61.32;
H, 7.20; N, 2.89. Found: C, 61.09; H, 7.60; N, 3.09.
Research for a fellowship. Spectroscopic measurements by D. Pati-
gny and P. Sigaut (MS) are gratefully acknowledged.
4.13. (2S,3R,3aR,6S,7S,7aR)-2,3-Dihydroxy-2,3-di-O-isopropylidene-
7-(1H-indol-3-yl)-5-oxo-hexahydro-2H-furo[3,2-b]pyran-6-
carboxylic acid 5i
References
1. For some recent reviews, see: (a) Orru, R. V. A.; de Greef, M. Synthesis 2003,
1471–1499; (b)Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.Wiley-
VCH; Weinheim: Germany, 2005.
2. For a recent review, see: Tourré, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–
4486.
A solution of 4i (150 mg, 0.29 mmol) in ethyl acetate (10 mL)
was hydrogenated over 10% PdC (50 mg) for 24 h. The catalyst
was removed by filtration on a CeliteÒ pad, the filtrate was evapo-
rated to give a mixture of 5i/5j (94:6) (110 mg, 99%) from which 5i
3. Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J. 2009, 15, 1300–1308.
4. For a recent review on asymmetric MCR, see: (a) Ramón, D. J.; Yus, M. Angew.
Chem., Int. Ed. 2005, 44, 1602–1634; for some additional recent papers, see: (b)
Rondot, C.; Zhu, J. Org. Lett. 2005, 7, 1641–1644; (c) Garner, P.; Kaniskan, H. Ü.;
Hu, J.; Youngs, W. J.; Panzner, M. Org. Lett. 2006, 8, 3647–3650; (d) Ghosh, A. K.;
Kulkarni, S.; Xu, C.-X.; Fanwick, P. E. Org. Lett. 2006, 8, 4509–4511; (e) Ghosh, A.
K.; Kulkarni, S. S.; Xu, C.-X.; Shurrush, K. Tetrahedron: Asymmetry 2008, 19,
1020–1026.
5. For some selected recent papers, see: (a) Chapman, C. J.; Frost, C. G. Synthesis
2007, 1–21; (b) Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem.,
Int. Ed. 2008, 47, 388–391; (c) González-Gómez, J. C.; Foubelo, F.; Yus, M.
Tetrahedron Lett. 2008, 49, 2343–2347; (d) Xu, X.; Zhou, J.; Yang, L.; Hu, W.
Chem. Commun. 2008, 6564–6566; (e) Lou, S.; Schaus, S. E. J. Am. Chem. Soc.
2008, 130, 6922–6923; (f) Liu, H.; Dagousset, G.; Masson, G.; Retailleau; Zhou, J.
J. Am. Chem. Soc. 2009, 131, 4598–4599.
was isolated by crystallisation. Compound 5i: ½a D24
¼ ꢁ12 (c 0.88,
ꢂ
acetone); 1H NMR (DMSO-d6) d 1.29 (s, 3H), 2.10 (s, 3H), 3.68
(dd, 1H, J = 12.3, 3.6 Hz), 4.25 (d, 1H, J = 12.3 Hz), 4.51–4.58 (m,
1H), 4.89 (d, 1H, J = 3.7 Hz), 5.23 (d, 1H, J = 2.5 Hz), 6.04 (d, 1H,
J = 3.7 Hz), 7.00–7.20 (m, 2H), 7.25 (s, 1H), 7.41 (d, 1H, J = 7.9 Hz),
7.63 (d, 1H, J = 7.9 Hz), 11.10 (s, 1H) ppm; 13C NMR (DMSO-d6) d
26.1, 26.5, 36.4, 50.4, 80.6, 81.3, 82.7, 111.5, 112.1, 113.3, 118.5,
119.1, 121.7, 123.0, 125.7, 136.6, 168.8, 169.2 ppm; MS (EI) m/z
(%) 395 (M+Å+Na, 23), 373 (7), 329 (100), 214 (34).
4.14. (2S,3R,3aR,7S,7aR)-2,3-Dihydroxy-2,3-di-O-isopropylidene-
7-(1H-indol-3-yl)-hexahydro-2H-furo[3,2-b]pyran-5-one 5j
6. For
a recent review on organocatalytic enantioselective MCR, see: (a)
Guillena, G.; Ramón, D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693–
700; For some additional references, see: (b) Pan, C. S.; List, B. Org. Lett.
2007, 9, 1149–1151; (c) Kotame, P.; Hong, B.-C.; Liao, J.-H. Tetrahedron Lett.
2009, 50, 704–707.
A suspension of 5i (150 mg, 0.40 mmol) in toluene (10 mL) was
refluxed for 1 h. After evaporation of the solvent the residue was
crystallised from ether to give 5j (125 mg, 95%) as a white solid.
7. Nemes, C.; Jeannin, L.; Sapi, J.; Laronze, M.; Seghir, H.; Augé, F.; Laronze, J.-Y.
Tetrahedron 2000, 56, 5479–5492.
8. Dardennes, E.; Kovács-Kulyassa, A.; Boisbrun, M.; Petermann, C.; Laronze, J.-Y.;
Sapi, J. Tetrahedron: Asymmetry 2005, 16, 1329–1339.
9. Aslani-Shotorbani, G.; Buchanan, J. G.; Edgar, A. R.; Shahidi, P. K. Carbohydr. Res.
1985, 136, 37–52.
Mp: 182–183 °C (ether); ½a D24
ꢂ
¼ ꢁ213 (c 0.29, CHCl3); UV (MeOH)
kmax 290, 280, 274, 223 nm; IR (KBr)
m
3415, 3386, 2985, 2960,
2937, 2910, 1748, 1624, 1457, 1424, 1381, 1338, 1248, 1224, 1157,
1081, 1052, 1035, 1014, 890, 862, 728 cmꢁ1; 1H NMR (CDCl3) d 1.31
(s, 3H), 1.45 (s, 3H), 2.82 (dd, 1H, J = 16.9, 3.7 Hz), 3.18 (dd, 1H,
J = 16.9, 6.1 Hz), 3.89–3.92 (m, 1H); 4.59 (d, 1H, J = 3.1 Hz), 4.71 (d,
1H, J = 3.8 Hz), 4.76 (dd, 1H, J = 3.3, 3.1 Hz), 6.05 (d, 1H, J = 3.8 Hz),
7.03 (d, 1H, J = 3.8 Hz), 7.16–7.29 (m, 2H), 7.42 (d, 1H, J = 8.1 Hz),
7.66 (d, 1H, J = 8.0 Hz), 8.29 (br s, 1H) ppm; 13C NMR (CDCl3) d 26.2,
26.6, 30.8, 31.1, 75.9, 82.5, 83.7, 105.1, 111.6, 112.4, 114.3, 118.5,
120.1, 120.9, 122.8, 126.0, 136.3, 169.8 ppm; MS (EI) m/z (%) 329
(M+Å, 17), 272 (19), 214 (100). Anal. Calcd for C18H19NO5: C, 65.64;
H, 5.81; N, 4.25. Found: C, 65.45; H, 5.84; N, 4.18.
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Financial support of CNRS and University of Reims is gratefully
acknowledged. E.D. thanks the French Ministry of Education and