Synthesis of polyhydroxylated pyrano-pyrrole derivatives from carbohydrate precursors

Article abstract of DOI:10.1002/ejoc.200700102

The efficient synthesis of novel polyhydroxy-tetrahydropyrano-pyrroles from acetylenic carbohydrate precursors in three to four steps is described. The methodology involves, as key steps, the ring contraction of pyridazine intermediates obtained by an inv

Full text of DOI:10.1002/ejoc.200700102

FULL PAPER
DOI: 10.1002/ejoc.200700102
Synthesis of Polyhydroxylated Pyrano-Pyrrole Derivatives from Carbohydrate
Precursors
Sébastien Naud,[a] Muriel Pipelier,[a] Guillaume Viault,[a] Ané Adjou,[a] François Huet,[b]
Stéphanie Legoupy,[b] Anne-Marie Aubertin,[c] Michel Evain,[d] and Didier Dubreuil*[a]
Keywords: Cycloaddition / Ring contraction / Pyridazine / Pyrrole / α-Pyrone / Carbohydrates
The efficient synthesis of novel polyhydroxy-tetrahydropy-
rano-pyrroles from acetylenic carbohydrate precursors in
three to four steps is described. The methodology involves,
as key steps, the ring contraction of pyridazine intermediates
obtained by an inverse-demand Diels–Alder reaction and
subsequent intramolecular lactonization.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Styryl lactones, α-pyrone derivatives (5,6-dihydro-2H-py-
ran-2-one), isolated from natural sources have attracted
much attention during the last decade owing to their medic-
inal potential, for example, as antiviral, antitumoral, anti-
malarial, or antifungal agents.[1]
The biological activities of such α,β-unsaturated δ-lac-
tones are mainly attributed to their Michael acceptor char-
acter.[2,3] However, the broad range of biological targets
aimed at by the α-pyrone skeleton can also be ascribed to
the presence of various functionalized substituents, such as
unsaturated alkyl, aryl, or hydroxylated side-chains. α-Py-
rones with a polyol system form the basic skeleton of sev-
eral natural products. For example, α-pyrones bearing free
or acetylated polyhydroxylated side-chains, such as passiflo-
ricin A (1),[4] (+)-goniotriol (2a),[5] (+)-boronolide (3a),[6]
and analogues 2b[7] and 3b, express antiprotozoal, antima-
larial, and antitumoral activities (Figure 1). (+)-Furanopy-
rone goniothalenol [(+)-4], known as altholactone, isolated
from Goniothalamus giganteus, is an example of a cis-fused
bicyclic derivative and has been found to be very toxic
towards mice during a P338 in vivo antileukemic screen-
ing.[8]
Figure 1. Examples of natural α-pyrones.
α-Pyrones fused to hydroxylated aromatic or nonaro-
matic rings (Figure 2) are also found in antimalarial dihy-
droisocoumarin derivatives 5,[9] antitumoral psymberin
(6),[10] and cytotoxic hippeastrine (7),[11] whereas dehy-
droaltenusin (8) has been observed to inhibit mammalian
DNA polymerase α.[12]
[a] Univ. Nantes, CNRS, Laboratoire de Synthèse Organique,
UMR 6513, Faculté des Sciences et des Techniques,
2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3,
France
A large number of active sesquiterpene lactones, like ver-
nolepin (9),[13] have been isolated from plant extracts and
show tumor-inhibiting activity. Recently, the indololactone
(10),[14] obtained in the course of the production of quinoli-
none analogues of pancratistatin, has been shown to act by
a different mechanism against pancreas and breast adeno-
carcinoma. In this particular case, a hydrogen-bonding do-
nor–acceptor pairing effect between the indole ring and the
keto ester group has been suggested. Bergenin (11) is a 1,2-
trans C-aryl glucoside with anti-HIV and anti-inflamma-
tory potential.[15]
E-mail: didier.dubreuil@univ-nantes.fr
[b] Univ. du Maine, CNRS, Laboratoire de Synthèse Organique,
UCO2M, UMR 6011, Faculté des Sciences et des Techniques,
Avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France
[c] Faculté de Médecine, Institut de Virologie, INSERM U 544,
Université Louis Pasteur,
3 rue Koeberlé, 67000 Strasbourg, France
[d] Univ. Nantes, CNRS, Institut des Matériaux Jean Rouxel,
UMR 6502, Faculté des Sciences et des Techniques,
2 rue de la Houssinière, B. P. 92208, 44322 Nantes Cedex 3,
France
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Polyhydroxylated Pyrano-Pyrroles from Carbohydrate Precursors
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Figure 3. Targeted polyhydroxy-tetrahydropyrano-pyrroles.
Recently, we validated a general efficient synthetic ap-
proach to pyrrolo-pyrones A bearing a polyol side-chain.[21]
The synthetic route involves the successive introduction of
pyrrolo and pyrone residues at the anomeric position of an
open ribosyl sugar. We wish here to highlight the potential
of this strategy by the preparation of furano- and pyrano-
tetrahydropyrano-pyrrole analogues B and C using a sim-
ilar synthetic approach (retrosynthesis 1, Scheme 1). Thus,
access to the polyhydroxylated pyrano-pyrrole analogues IV
was envisaged from acetylenic dienophile intermediates I,
derived from furanose (series A and B) and pyranose (series
C) sugars, by a reaction sequence involving cycloaddition,
ring contraction, and lactonization.
The formation of the α-pyrone skeletons IV is the result
of an intramolecular transesterification reaction between a
selected free hydroxy group of the sugar moiety and an ester
group of the pyrrolo heterocycles III. The intermediates III
result from the ring contraction of suitable functionalized
pyridazine heterocycles II produced by an inverse-demand
Diels–Alder cycloaddition reaction between acetylenic
sugar dienophiles I and dimethyl 1,2,4,5-tetrazine-3,6-dicar-
boxylate (12). Thus, -ribose, -galactose, and -glucose
were chosen to initiate the syntheses as these sugars seem
to be suitable precursors to express different chiral polyhy-
droxylated side-chains on the targeted α-pyrone analogues.
Figure 2. Biologically active compounds presenting an α-pyrone
backbone.
As a result of our interest in the synthesis of pyrrole het-
erocycles by ring contraction of pyridazine precursors using
Boger’s chemical strategy[16] or an alternative electrosynthe-
sis methodology developed in our laboratory,[17–20] we have
developed a synthesis of novel linear (pyrone type A) and
cyclic polyhydroxylated pyrrolo-pyrone derivatives (pyrone
types B and C) (Figure 3) structurally analogous to bo-
ronolide (3a), altholactone (4), indololactone (10), or ber-
genin (11).
Results and Discussion
Preparation of Sugar C-Acetylenic Dienophiles
We have already shown[21] that the introduction of phen-
ylacetylene and hexyne anions, generated in situ from phen-
Scheme 1. Retrosynthesis 1.
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D. Dubreuil et al.
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ylacetylene or hexyne in THF at –5 °C, onto the 2,3,5-tri-
The cyclization process, occurring by a favorable regiose-
O-benzylribofuranose (13)[22,23] gives a 1:1 ratio of the dia- lective intramolecular SN2 substitution at the C-5 center
stereoisomers 14-(5R)/14-(5S) and 15-(5R)/15-(5S) in 87 with inversion of configuration, was initiated by treatment
and 85% yields, respectively (Scheme 2). If both diols 14 with tosyl chloride in pyridine.[24] Thus, the target furanosyl
are candidates for producing linear polyhydroxylated py- α-acetylenic 16α was formed from 14-(5S) in 52% yield to-
rone analogues IV in series A, access to furanosylpyrone gether with a small amount of the -lyxose analogue 17α
derivatives IV in series B from -ribose entails the selection (7%) resulting from a tosylation side-reaction at the C-2
of the 14-(5S) isomer to produce, by intramolecular cycliza- hydroxy function. The structure of C-ribosyl 16α was un-
tion, the required anomeric acetylenic furanosyl 16α with ambiguously confirmed by X-ray crystallography
the desired α configuration (Figure 4). Indeed, the anomer (Scheme 2).[25] The formation of the  isomer 17β was not
16β, resulting from the 14-(5R) diol precursor, will not al- detected during the cyclization of the 14-(5R) isomer by the
low the final intramolecular formation of the pyrone ring.
same procedure, which occurred in a moderate 39% yield.
Alcohol activation using triflic anhydride or the Mitsu-
nobu[26] procedure does not improve the intramolecular
cyclization reaction of this series of compounds.
As Marco-Contelles et al. have already described for
2,3,4,6-tetra-O-benzylglucopyranose,[27] we also failed to
achieve acetylenic anion addition followed by intermo-
lecular cyclization to the corresponding acetylenic α-C-
pyranosyl in the galacto series.
We therefore studied
a
C-glycosylation process
(Scheme 3, Table 1) to access the target α-C-glycopyranosyl
dienophiles 21, 27, and 29 required to prepare the type C
pyrrolo-pyrone.
Scheme 2. Reagents and conditions: (a) phenylacetylene
(2.2 equiv.), nBuLi (2.0 equiv., 2.4  in hexanes), THF, –5 °C, then
13 (1.0 equiv.) at 10 °C and then 2 h at room temp., 87 %; (b)
hexyne (2.2 equiv.), nBuLi (2.0 equiv., 2.4  in hexanes), THF,
–5 °C, then 13 (1.0 equiv.) at 10 °C and then 2 h at room temp.,
85%.
Scheme 3.
2,3,4,6-Tetra-O-benzylglucopyranosyl bromide (19) and
6-O-acetyl-2,3,4-tri-O-benzylglucopyranosyl chloride (20)
are described in the literature as the best potent glycosyl
donors to provide the corresponding α-C-glucopyranosyls
21 and 22 in the presence of (phenylethynyl)tributylstan-
nane and ZnCl2 (61%)[28] or AgBF4 (73%)[29] promoters,
respectively (Table 1, entries 1 and 2). Dondoni et al.[30]
have observed that stereoselective α-C-glycosylation of 1-O-
acetyl-2,3,4,6-tetra-O-benzylglucose and -galactose donors
23 and 24 can also occur when tributylstannyl(trimethylsi-
lyl)acetylene is used in the presence of TMSOTf, providing
the α-C-acetylenic glycosyls 25 and 26 in 65 and 87% yields,
respectively (entries 3 and 4). We prepared 1,2-cis phenyl-
acetylene glucosyl 21 and galactosyl 27 from donors 23 and
24 in the presence of TMSOTf (2 equiv.) in CH2Cl2 at room
temp. in lower yields of 42 and 51%, respectively (entries 5
and 6). No improvement in the reaction was observed start-
ing from 1,6-di-O-acetylated galactoside donor 28 and the
corresponding phenylacetylene α-C-galactosyl 29 was iso-
lated in a similar yield of 52% (entry 7). Note that, surpris-
ingly, the formation of the β-C-galactosyl anomer was not
observed during these latter processes.
Figure 4. ORTEP diagram of acetylenic 16α.
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Table 1. α-C-Glycosylation yields.
Entry Glycosyl donor
R1
R4
R4Ј
R6
R
Conditions
Product, yield [%]
Ref.
[28]
1
2
19
20
Br
Cl
OBn
OBn
H
H
OBn
OAc
Ph
Ph
ZnCl2, CCl4, reflux
AgBF4, 4 Å MS, 1,2-DCE,
–30 °C
21, 61
22, 73
[29]
[30]
[30]
3
4
5
6
7
23
24
23
24
28
OAc
OAc
OAc
OAc
OAc
OBn
H
H
OBn
OBn
OBn
OBn
OAc
TMS TMSOTf, CH2Cl2, room
25, 65
26, 87
21, 42
27, 51
29, 52
temp.
OBn
H
TMS TMSOTf, CH2Cl2, room
temp.
Ph
Ph
Ph
OBn
H
TMSOTf, CH2Cl2, room
temp.
TMSOTf, CH2Cl2, room
temp.
TMSOTf, CH2Cl2, room
temp.
OBn
OBn
H
Access to Pyridazine C-Sugars
cribed to the intrinsic reactivity of the free hydroxy groups
of the acetylenic diol 14 as Seitz[34] has shown that alcohols,
thiols, or amines react by nucleophilic addition with tetra-
zine 12. This behavior could then be used to explain the
partial recyclizing process that can occur following an intra-
molecular Mitsunobu-like rearrangement and the predomi-
nant degradation of the reagents observed in the course of
this reaction.
Therefore, the acetylenic diols 14 and 15 have to be pro-
tected. Thus, after benzylation of the free hydroxy groups
at C-2 and C-4 of diols 14-(5R), 14-(5S), and 15-(5R,S), the
benzylated acetylenic dienophiles 32-(3R), 32-(3S), and 34-
We have previously achieved the [4+2] cycloaddition of
acetylenic C-ribosyls 16β and 18β with tetrazine 12, leading
to the pyridazinic ribosyl analogues 30 (56%) and 31
(65%), respectively.[31] Thus, a similar process was applied
to the acetylenic dienophiles 14-(5R), 32, 34, 16α, 21, 26,
27, and 29 (Scheme 4).
Unexpectedly, the attempted inverse-demand Diels–
Alder reaction between acetylenic 14-(5R) and the elec-
tron-deficient dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate
(12)[32,33] failed to give the expected pyridazine and the acet-
ylenic C-ribosyl 16β was obtained instead as a single iso-
lable product in a low 28% yield. This failure can be as- (7R,S) were treated with tetrazine 12 in the [4+2] cycload-
Scheme 4.
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dition step to give, after 5 d under toluene reflux, the ex- Table 3. Ring contraction process of pyridazine derivatives.
pected pyridazines 33-(1ЈR), 33-(1ЈS), and 35-(1ЈR,S) in 55,
66, and 46% yields, respectively (Scheme 4). These yields
are a result of the steric hindrance between the two partners
slowing down the reaction, during which a partial degrada-
tion of tetrazine occurred. The pyridazine isomers 35-(1ЈR)
and 35-(1ЈS) were isolated by semipreparative HPLC on a
silica gel column. Inlactosyl-, and α-C-glucosyl-phenyl-
pyridazines 36, 37, 38, and 39 were formed in 49, 46, 45,
and 50% yields, respectively, from dienophiles 16α, 27, 29,
and 21 (Scheme 4). However, we were surprised to observe
that no reaction occurred starting from trimethylsilylacetyl-
ene dienophile 26, even after increasing the amount of diene
12 and the time of the cycloaddition process (Scheme 4,
Table 2).
Table 2. [4+2] Cycloaddition process of acetylenic pyranosyls with
dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (12).
Acetylenic
pyranosyl
R4
R4Ј
R6
R
Product, %
yield
26
27
29
21
H
H
H
OBn
OBn
OBn
OBn
H
OBn
OBn
OAc
OBn
TMS no reaction
Ph
Ph
Ph
37, 46
38, 45
39, 50
Preparation of the Pyrrole C-Analogues
Pyridazines 33 and 35–39 were converted into pyrroles
40, 41, and 44–47 by a ring contraction process with
20 equiv. of zinc dust in refluxing acetic acid, according to
the Boger procedure (Scheme 5, Table 3).[16]
of a furanosyl ring under thermal conditions. However, a
decrease in the reaction time to 30 min limited the deben-
zylation side-reaction to the production of just traces of
byproducts and the targeted pyrroles 40-(1ЈR) and 41-(1ЈR)
were isolated in 46 and 68% yields, respectively (entries 2
and 4). Ring contraction of pyridazines 33-(1ЈS) and 35-
(1ЈS) was also performed over 30 min, leading to the pyr-
roles 40-(1ЈS) and 41-(1ЈS) in yields of 60% (entries 5 and
6). In this series, after 15 h, no hydroxy deprotection was
detected even though the isolated yields were somewhat
lower. The transformation of pyridazines C-ribosyl 36 and
C-pyranosyl 37, 38, and 39 was also performed similarly to
provide the pyrroles C-ribosyl 44 in 56% yield and C-gala-
cto- and glucopyranosyls 45, 46, and 47 in yields of 70, 57,
and 27%, respectively (entries 7–10).
Scheme 5.
When the reactions were carried out with the 1ЈR series
over several hours, the yields of pyrroles 40-(1ЈR) and 41-
(1ЈR) did not exceed 18% after 15 h (entries 1 and 3). Under
these reaction conditions, a surprising concomitant partial
deprotection of the benzyl ether groups at C-1Ј and C-4Ј
was observed leading to the formation of diols 42-(1ЈR) and
43-(1ЈR) as byproducts in 44 and 16% yields, respectively.
The position of the free hydroxy groups was assigned
thanks to an HMBC NMR experiment. Indeed, the 2’-H,
3’-H, and 5’-H atoms of pyrroles 42-(1ЈR) and 43-(1ЈR) are
correlated with a benzylic methylenic carbon atom, whereas
1’-H and 4’-H do not show such correlations. These experi-
ments prove that the hydroxy groups at C-1’ and C-4’ are
deprotected under extended catalyzed reduction conditions.
This unexpected selective benzyl ether cleavage is probably
due to the prior release of the activated propargylic benzyl
group at C-1’ in the presence of zinc.[16] The subsequent
Synthesis of Pyrano Analogues
The tetrahydropyrano-pyrroles, as the (R,S) diastereoiso-
reduction of benzyl at C-4’ could be ascribed to an intermo- mers, were then synthesized over two general steps from the
lecular assistance occurring by the predominant formation protected pyrrolo sugars by debenzylation and subsequent
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intramolecular transesterification between the hydroxy the hydrolysis of pyrroles 48 and 49 by 2  aqueous NaOH
group at C-2’ and one of the ester groups of the pyrrole in methanol solution yielded the corresponding diacids 52
moiety (Scheme 6).
and 53 in a quantitative manner.
Thus, debenzylation of pyrroles 40-(1ЈR), 40-(1ЈS), 41-
However, lactonization was fully achieved in a basic me-
(1ЈR), and 41-(1ЈS) under hydrogenation conditions (H2, dium (Na2CO3, MeOH) to provide the pyrano-pyrroles 50-
Pd/C) afforded the corresponding pyrroles 48-(1ЈR), 48- (4R), 50-(4S), 51-(4R), and 51-(4S) in moderate-to-good
(1ЈS), 49-(1ЈR), and 49-(1ЈS) in good yields (85–98%).[35] yields (38–72%). The proposed structure and the stereo-
These compounds could not be purified in the pyrrolo dies- chemistry of 50-(4S) were assigned in the solid state (Fig-
ter form as a partial intramolecular lactonization occurred ure 5).[36]
spontaneously on silica gel giving the pyrano-pyrroles 50-
In more constrained structures, such as the ribosyl and
(4R), 50-(4S), 51-(4R), and 51-(4S), respectively, whereas pyranosyl series, the deprotection and lactonization events
Scheme 6.
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D. Dubreuil et al.
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Figure 5. ORTEP diagram of pyrano-pyrone 50-(4S).
take place successively during the hydrogenation reaction of
44, 45, and 47, leading to the cyclic pyrano-pyrroles 54, 55,
and 56 spontaneously in 78, 73, and 20% yields, respec-
tively (Scheme 6). The observed yields for the synthesis of
pyrano-pyrroles of the glucopyranosyl series are lower than
those of the other series. This has not yet been explained,
but new conditions are currently being investigated in an
effort to improve the results. In the case of pyrrole 46, a
deacetylation step was required before the hydrogenation to
provide the pyrone 55 in 60% yield.
Figure 6. Synthesized polyhydroxy-tetrahydropyrano-pyrroles.
Experimental Section
Solvents were purified and dried by standard methods prior to use.
All reactions were carried out under argon. 1H and 13C NMR spec-
tra were recorded with a Bruker AC 400 or AC 300 spectrometer
with TMS used as the internal standard in 1H NMR spectra.
Chemical shifts (δ) are given in ppm and coupling constants (J) in
Hz. All assignments were confirmed with the aid of two-dimen-
sional 1H,1H (COSYGPQF) or 1H,13C (INV4GPQF) or 1H,13C
(INV4GPLRNDQF) experiments using standard Bruker pulse
programs. All reactions were monitored by TLC on commercially
available precoated plates (Kieselgel 60 F254) and the products were
visualized with a mostaïne solution [250 mL H2O, 10.5 g of
(NH4)6Mo7O24·4H2O, 0.5 g of Ce(SO4)2, and 15 mL of H2SO4].
Kieselgel 60, 230–400 mesh (Merck), was used for column
chromatography. Optical rotations were measured at 20Ϯ1 °C with
a Perkin–Elmer 341 instrument in the indicated solutions whose
concentrations are expressed in g/100 mL. Mass spectra were mea-
Conclusions
We have synthesized seven novel tetrahydropyrano-pyr-
roles 50-(1ЈR), 50-(1ЈS), 51-(1ЈR), 51-(1ЈS), 54, 55, and 56
in eight or nine steps from -ribose, -galactose, and -
glucose (Figure 5). The key step of the synthesis is the ring
contraction of a pyridazine, which was achieved by a Diels–
Alder cycloaddition reaction. The biological properties of
the linear pyrano-pyrroles were evaluated on KB cells, HIV,
HSV, hepatitis C, and on Leishmania panamensis, but did
not show any significant activity. Biological tests on cyclic sured by CI with NH3 on a quad. Hewlett–Packard 5989A instru-
ment. HRMS were measured with a MS/MS ZABSpec TOF spec-
trometer from Micromass (Positive Electrospray, solvent: MeOH)
at the “Centre Régional de Mesures Physiques de l’Ouest”, Rennes,
France. FTIR spectra were obtained in the 500–4000 cm–1 range
with a Bruker Vector 22 FT-IR spectrometer using NaCl pellets.
For HPLC purification, a KROMASIL semipreparative column
was used.
pyrano-pyrroles are currently underway. Some analogues of
the tetrahydropyrano-pyrroles are presently being synthe-
sized from other furanose and pyranose sugars to study the
influence of chain length and of the hydroxy configuration.
We also plan to introduce aryl or alkyl substituents onto
the terminal part of the osidic skeleton to mimic goniotriol
(2a) and boronolide (3a) side-chains (Figure 6).
In addition, alkyl or aryl substituents will be introduced
onto the sugar skeleton, in analogy with goniotriol (2a) and
boronolide (3a). Pyrrole intermediates, such as 46, which
present a selectively different protection of 6-OH, are good
candidates to initiate such modifications. This work is cur-
rently under investigation in our group and will be reported
elsewhere.
Procedure A – Addition of Acetylene Derivatives to 2,3,5-Tri-O-ben-
zyl-D-ribose: Phenylacetylene or hexyne (2.2 equiv.) was added
dropwise under argon to a stirred solution of n-butyllithium
(2.0 equiv., 2.4  in hexanes) in THF in an ice–salt bath. The solu-
tion became dark. The mixture was warmed to 10 °C and turned
yellow. Then, 2,3,5-tri-O-benzyl--ribose (1.0 equiv.) in THF was
added dropwise. The mixture was stirred at room temperature for
2 h. Solvent was concentrated under reduced pressure and satu-
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rated aqueous N4-HCl solution was added to the resulting residue
which was then extracted with EtOAc. The organic layer was dried
with Na2SO4 and concentrated under reduced pressure.
128.0–128.6 (CH(Ar)), 137.7–138.0 (Cq(Ar)) ppm. MS (CI+, NH3):
m/z = 520 [M + NH ]+, 503 [M + H]+. IR: ν = 3456 (OH), 2230
˜
4
(CϵC) cm–1. [α]2D0 = +8.4 (c = 1.11, CHCl3). C32H38O5·0.25H2O
(507.14): C 75.79, H 7.65; found C 75.78, H 7.63. 15-(5S): White
needles; m.p. 30 °C; Rf (petroleum ether/EtOAc, 8:2) = 0.11. 1H
NMR (300 MHz, CDCl3): δ = 0.88 (t, J11,10 = 7.2 Hz, 3 H, 3ϫ11-
H), 1.35–1.50 (m, 4 H, 2ϫ9-H, 2ϫ10-H), 2.22 (td, J8,9 = 7.0, J8,10
= 1.9 Hz, 2 H, 2ϫ8-H), 3.60 (dd, J1a,1b = 9.7, J1a,2 = 6.2 Hz, 1 H,
1a-H), 3.66 (dd, J1b,1a = 9.7, J1b,2 = 3.2 Hz, 1 H, 1b-H), 3.85 (dd,
(2R,3R,4S,5R)-1,3,4-Tribenzoxy-7-phenylhept-6-yne-2,5-diol
[14-
(5R)] and (2R,3R,4S,5S)-1,3,4-Tribenzoxy-7-phenylhept-6-yne-2,5-
diol [14-(5S)]: These compounds were synthesized according to pro-
cedure A from phenylacetylene (3.4 mL, 36.60 mmol), n-butyllith-
ium (13.9 mL, 33.30 mmol) in THF (40 mL), and 2,3,5-tri-O-ben-
zyl--ribose (13) (7.0 g, 16.60 mmol) in THF (10 mL). Chromato-
graphic purification on silica gel (petroleum ether/EtOAc,
82.5:17.5) gave compounds 14-(5R) and 14-(5S) (7.59 g, 87%) in a
ratio of 1:1. 14-(5R): Syrup; Rf (petroleum ether/EtOAc, 7:3) =
J4,5 = 5.3, J4,3 = 3.3 Hz, 1 H, 4-H), 3.93 (dd, J3,2 = 7.2, J3,4
=
3.3 Hz, 1 H, 3-H), 4.20 (ddd, J2,3 = 7.2, J2,1a = 6.2, J2,1b = 3.2 Hz,
1 H, 2-H), 4.47–4.75 (m, 6 H, CH2(Bn), 5-H), 4.81 (d, 2J = 12.0 Hz,
1 H, CH2(Bn)), 7.22–7.38 (m, 15 H, H(Ar)) ppm. 13C NMR
(75 MHz, CDCl3): δ = 13.7 (C-11), 18.7 (C-8), 22.1 (C-10), 30.8
(C-9), 63.2 (C-5), 69.8 (C-2), 71.1 (C-1), 73.3, 73.3, 73.5 (3
CH2(Bn)), 79.2 (Calkyne), 79.9 (C-3), 81.0 (C-4), 87.4 (Calkyne),
127.8–128.6 (CH(Ar)), 138.0–138.2 (Cq(Ar)) ppm. MS (CI+, NH3):
1
3
0.40. H NMR (300 MHz, CDCl3): δ = 2.62 (d, J = 3.3 Hz, 1 H,
2-OH), 3.22 (d, 3J = 8.1 Hz, 1 H, 5-OH), 3.55 (dd, J1a,1b = 9.8,
J1a,2 = 3.3 Hz, 1 H, 1a-H), 3.62 (dd, J1b,1a = 9.8, J1b,2 = 6.9 Hz, 1
H, 1b-H), 3.90 (dd, J4,3 = 6.5, J4,5 = 3.6 Hz, 1 H, 4-H), 3.98 (dd,
J3,4 = 6.5, J3,2 = 4.7 Hz, 1 H, 3-H), 4.20 (m, 1 H, 2-H), 4.49 (s, 2
m/z = 520 [M + NH ]+, 503 [M + H]+. IR: ν = 3456 (OH), 2230
˜
2
4
H, CH2(Bn)), 4.71 (s, 2 H, CH2(Bn)), 4.74 (d, J = 11.3 Hz, 1 H,
(CϵC) cm–1. [α]2D0 = +10.6 (c = 1.21, CHCl3). C32H38O5·0.5H2O
2
CH2(Bn)), 4.89 (d, J = 11.3 Hz, 1 H, CH2(Bn)), 4.90 (m, 1 H, 5-
(511.75): calcd. C 75.12, H 7.68; found C 75.23, H 7.44.
H), 7.23–7.46 (m, 20 H, H(Ar)) ppm. 13C NMR (75 MHz, CDCl3):
δ = 63.0 (C-5), 71.0, 71.1 (C-1, C-2), 73.5, 74.1, 74.2 (3 CH2(Bn)),
80.2 (C-3), 80.6 (C-4), 86.1, 88.5 (2Calkyne), 122.7 (Cq(Ph)), 128.0–
131.8 (CH(Ar)), 137.6–138.0 (Cq(Bn)) ppm. MS (CI+, NH3): m/z
1-(2Ј,3Ј,5Ј-Tri-O-benzyl-α-D-ribofuranosyl)-2-phenylacetylene (16α):
The diastereoisomer 14-(5S) (1 equiv., 1.5 g, 2.87 mmol) was dis-
solved in dry pyridine (8 mL) and the resulting solution was heated
at 50–60 °C. Tosyl chloride (2 equiv., 820 mg, 4.31 mmol) was
added portionwise and the reaction mixture was stirred at this tem-
perature for 3 h. After hydrolysis and extraction with CH2Cl2, the
organic phase was dried with MgSO4 and concentrated to dryness
under reduced pressure. The crude was purified by column
chromatography on silica gel (petroleum ether/EtOAc, 95:5) to
yield 16α (753 mg, 52%), which was recrystallized from Et2O.
White needles; m.p. 88–90 °C; Rf (petroleum ether/EtOAc, 8:2) =
0.41. 1H NMR (300 MHz, CDCl3): δ = 3.57 (dd, J5Јa,5Јb = 11.1,
= 540 [M + NH ]+, 523 [M + H]+. IR: ν = 3457 (OH), 2203
˜
4
(CϵC) cm–1. [α]2D0 = –10.5 (c = 0.57, CHCl3). C34H34O5·H2O
(540.64): calcd. C 75.53, H 6.71; found C 75.69, H 6.44. 14-(5S):
White needles; m.p. 66 °C; Rf (petroleum ether/EtOAc, 7:3) = 0.32.
1H NMR (300 MHz, CDCl3): δ = 3.61 (dd, J1a,1b = 9.7, J1a,2
=
6.0 Hz, 1 H, 1a-H), 3.69 (dd, J1b,1a = 9.7, J1b,2 = 3.2 Hz, 1 H, 1b-
H), 4.00 (m, 2 H, 3-H, 4-H), 4.23 (m, 1 H, 2-H), 4.48 (d, 2J =
11.7 Hz, 1 H, CH2(Bn)), 4.52 (d, 2J = 11.2 Hz, 1 H, CH2(Bn)), 4.54
(d, 2J = 11.7 Hz, 1 H, CH2(Bn)), 4.67 (d, 2J = 11.2 Hz, 1 H,
CH2(Bn)), 4.74 (d, 2J = 11.8 Hz, 1 H, CH2(Bn)), 4.86 (d, 2J =
11.8 Hz, 1 H, CH2(Bn)), 4.97 (d, J5,4 = 5.3 Hz, 1 H, 5-H), 7.21–
7.43 (m, 20 H, H(Ar)) ppm. 13C NMR (75 MHz, CDCl3): δ = 63.4
(C-5), 69.7 (C-1), 71.1 (C-2), 73.3, 73.4, 73.5 (3 CH2(Bn)), 79.8,
80.8 (C-3, C-4), 86.4, 88.4 (2Calkyne), 122.7 (Cq(Ph)), 128.0–131.8
(CH(Ar)), 137.8–138.1 (Cq(Bn)) ppm. MS (CI+, NH3): m/z = 540
J5Јa,4Ј = 3.6 Hz, 1 H, 5Јa-H), 3.71 (dd, J5Јb,5Јa = 11.1, J5Јb,4Ј
=
3.0 Hz, 1 H, 5Јb-H), 4.12 (m, 2 H, 2Ј-H, 3Ј-H), 4.34 (m, 1 H, 4Ј-
2
2
H), 4.43 (d, J = 12.0 Hz, 1 H, CH2(Bn)), 4.48 (d, J = 12.3 Hz, 1
2
2
H, CH2(Bn)), 4.57 (d, J = 12.3 Hz, 1 H, CH2(Bn)), 4.62 (d, J =
11.7 Hz, 1 H, CH2(Bn)), 4.80 (d, 2J = 12.0 Hz, 1 H, CH2(Bn)), 4.95
2
(d, J = 11.7 Hz, 1 H, CH2(Bn)), 4.97 (d, J1Ј,2Ј = 3.0 Hz, 1 H, 1Ј-
[M + NH ]+, 523 [M + H]+. IR: ν = 3457 (OH), 2203 (CϵC) cm–1.
H), 7.18–7.48 (m, 20 H, H(Ar)) ppm. 13C NMR (75 MHz, CDCl3):
δ = 69.6 (C-5Ј), 71.5 (C-1Ј), 72.6, 73.2, 73.6 (3 CH2(Bn)), 78.4 (C-
2Ј, C-3Ј), 80.3 (C-4Ј), 85.2, 87.9 (2Calkyne), 122.9 (Cq (Ph)), 127.7–
131.9 (CH(Ar)), 138.1–138.3 (Cq(Bn)) ppm. MS (CI+, NH3): m/z
= 522 [M + NH4]+. [α]2D0 = +103.0 (c = 1.00, CHCl3).
˜
4
[α]2D0 = –6.6 (c = 0.95, CHCl3). C34H34O5·0.5H2O (531.64): calcd.
C 76.81, H 6.64; found C 77.12, H 6.46.
(2R,3R,4S,5R)-1,3,4-Tribenzoxyundec-6-yne-2,5-diol [15-(5R)] and
(2R,3R,4S,5S)-1,3,4-Tribenzoxyundec-6-yne-2,5-diol
These compounds were synthesized according to procedure A from
hexyne (4.2 mL, 36.70 mmol), n-butyllithium (13.9 mL,
[15-(5S)]:
1-(2Ј,3Ј,5Ј-Tri-O-benzyl-α-L-lyxofuranosyl)-2-phenylacetylene (17α):
This compound was obtained as a byproduct (7%) during the syn-
33.40 mmol) in THF (40 mL), and 2,3,5-tri-O-benzyl--ribose (13)
(7.0 g, 16.70 mmol) in THF (10 mL). Chromatographic purifica-
tion on silica gel (petroleum ether/EtOAc, 75:25) afforded a mix-
ture of two inseparable isomers 15-(5R) and 15-(5S) (7.1 g, 85%).
Only a small amount was purified by semipreparative HPLC (hex-
anes/EtOAc, 85:15, 2 mL/min) for analyses. 15-(5R): Syrup; Rf (pe-
thesis of 16α. Syrup; Rf (petroleum ether/EtOAc, 8:2) = 0.46. 1H
NMR (300 MHz, CDCl3): δ = 3.70 (dd, J5Јa,5Јb = 9.9, J5Јa,4Ј
=
3.3 Hz, 1 H, 5Јa-H), 3.80 (dd, J5Јb,5Јa = 9.9, J5Јb,4Ј = 5.9 Hz, 1 H,
2
5Јb-H), 4.20 (m, 2 H, 2Ј-H, 3Ј-H), 4.50 (m, 1 H, 4Ј-H), 4.50 (d, J
= 11.9 Hz, 1 H, CH2(Bn)), 4.60 (m, 2 H, CH2(Bn)), 4.76 (m, 3 H,
CH2(Bn)), 4.93 (m, 1 H, 1Ј-H), 7.20–7.55 (m, 20 H, H(Ar)) ppm.
13C NMR (75 MHz, CDCl3): δ = 68.9 (C-5Ј), 70.4 (C-1Ј), 72.8,
73.6, 73.7 (3 CH2(Bn)), 77.6 (C-2Ј or C-3Ј), 78.9 (C-4Ј), 84.5 (C-2Ј
or C-3Ј), 86.4, 87.3 (2Calkyne), 122.6 (Cq (Ph)), 127.7–131.9
(CH(Ar)), 137.8–138.3 (Cq(Bn)) ppm. MS (CI+, NH3): m/z = 522
[M + NH4]+.
1
troleum ether/EtOAc, 8:2) = 0.16. H NMR (300 MHz, CDCl3): δ
= 0.89 (t, J11,10 = 7.2 Hz, 3 H, 3ϫ11-H), 1.37–1.53 (m, 4 H, 2ϫ9-
H, 2ϫ10-H), 2.25 (td, J8,9 = 7.0, J8,10 = 1.9 Hz, 2 H, 2ϫ8-H),
3
2.65 (m, 1 H, 2-OH), 3.06 (d, J = 7.3 Hz, 1 H, 5-OH), 3.54 (dd,
J1a,1b = 9.8, J1a,2 = 3.2 Hz, 1 H, 1a-H), 3.60 (dd, J1b,1a = 9.8, J1b,2
= 6.8 Hz, 1 H, 1b-H), 3.77 (dd, J4,3 = 6.1, J4,5 = 4.0 Hz, 1 H, 4-
H), 3.90 (dd, J3,4 = 6.1, J3,2 = 5.1 Hz, 1 H, 3-H), 4.15 (m, 1 H, 2-
Procedure B Ϫ Preparation of Glycosyl-α-D-phenylacetylene: A mix-
H), 4.49 (s, 2 H, CH2(Bn)), 4.63–4.71 (m, 4 H, CH2(Bn), 5-H), 4.83 ture of 1-O-acetyl-glycosyl, (phenylethynyl)tributylstannane
2
(d, J = 11.3 Hz, 1 H, CH2(Bn)), 7.27–7.37 (m, 15 H, H(Ar)) ppm. (2 equiv.), activated 4 Å powdered molecular sieves (same weight
13C NMR (75 MHz, CDCl3): δ = 13.7 (C-11), 18.7 (C-8), 22.2 (C- as glycosyl), and anhydrous CH2Cl2 (4 mL/mmol) was stirred at
10), 30.8 (C-9), 62.6 (C-5), 71.0 (C-1), 71.1 (C-2), 73.5, 74.0 (3
CH2(Bn)), 79.3 (Calkyne), 80.1 (C-3), 80.8 (C-4), 87.0 (Calkyne),
room temperature for 15 min, and then trimethylsilyl triflate
(2 equiv.) was added dropwise. The dark-brown mixture was stirred
Eur. J. Org. Chem. 2007, 3296–3310
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3303

D. Dubreuil et al.
FULL PAPER
at room temperature for an additional 1.5 h, diluted with Et3N
(0.6 mL/mmol) and CH2Cl2 (15 mL/mmol), filtered through a pad 4.88 (d, J = 11.8 Hz, 1 H, CH2(Bn)), 5.02 (d, J = 11.2 Hz, 1 H,
4.74 (m, 5 H, CH2(Bn), 3-H), 4.78 (d, 2J = 11.2 Hz, 1 H, CH2(Bn)),
2
2
of Celite, and concentrated. The residue was eluted from a column
of silica gel (petroleum ether/EtOAc, 95:5 to 85:15).
CH2(Bn)), 7.14–7.41 (m, 30 H, H(Ar)) ppm. 13C NMR (75 MHz,
CDCl3): δ = 70.0 (C-3), 70.9 (C-7), 71.1, 72.7, 73.2, 73.3, 74.9
(5CH2(Bn)), 78.8, 79.0 (C-6, C-5), 81.5 (C-4), 87.0, 87.8 (2Calkyne),
122.8 (Cq(Ph)), 127.6–131.8 (CH(Ar)), 138.1–139.0 (Cq(Bn)) ppm.
1-(2Ј,3Ј,4Ј,6Ј-Tetra-O-benzyl-α-D-galactopyranosyl)-2-phenylacetyl-
ene (27): This compound was synthesized according to procedure
B from 1-O-acetyl-galactosyl 24 (500 mg, 0.86 mmol), (phenylethy-
nyl)tributylstannane (602 µL, 1.72 mmol), molecular sieves
(500 mg) and trimethylsilyl triflate (310 µL, 1.72 mmol) in CH2Cl2
(4 mL). After work up with Et3N (0.6 mL) and purification, the
galactosylphenylacetylene 27 (262 mg) was obtained (51%). Syrup;
Rf (petroleum ether/EtOAc, 8:2) = 0.71. 1H NMR (300 MHz,
CDCl3): δ = 3.57 (m, 2 H, 6Ј-H), 3.93–3.99 (m, 2 H, 4Ј-H, 3Ј-H),
MS (CI+, NH ): m/z = 720 [M + NH ]+. IR: ν = 2223 (CϵC) cm–1.
˜
3
4
[α]2D0 = –53.5 (c = 0.95, CHCl3).
(3S,4S,5R,6R)-3,4,5,6,7-Pentabenzoxy-1-phenylhept-1-yne [32-(3S)]:
This compound was synthesized according to procedure C. From
NaH (553 mg, 13.80 mmol), acetylenic diol 14-(5S) (3.01 g,
5.75 mmol) in a mixture THF (30 mL)/DMF (few drops) and ben-
zyl bromide (1.65 mL, 13.80 mmol), 32-(3S) (3.12 g, 77%) was ob-
4.15–4.22 (m, 2 H, 5Ј-H, 2Ј-H), 4.37 (d, 2J = 11.6 Hz, 1 H, tained after flash column chromatography on silica gel (petroleum
CH2(Bn)), 4.48 (d, 2J = 11.6 Hz, 1 H, CH2(Bn)), 4.59 (d, 2J =
ether/EtOAc, 95:5). Syrup; Rf (petroleum ether/EtOAc, 9:1) = 0.46.
2
11.4 Hz, 1 H, CH2(Bn)), 4.72–4.78 (m, 3 H, CH2(Bn)), 4.85 (d, J 1H NMR (300 MHz, CDCl3): δ = 3.65–3.75 (m, 2 H, H-7), 3.99–
2
2
= 11.9 Hz, 1 H, CH2(Bn)), 4.95 (d, J = 11.4 Hz, 1 H, CH2(Bn)),
4.08 (m, 3 H, 6-H, 5-H, 4-H), 4.45 (s, 2 H, CH2(Bn)), 4.53 (d, J
5.05 (d, J1Ј,2Ј = 5.7 Hz, 1 H, 1Ј-H), 7.00–7.50 (m, 25 H, = 11.6 Hz, 1 H, CH2(Bn)), 4.60–4.73 (m, 5 H, CH2(Bn)), 4.82 (d,
H(Ar)) ppm. 13C NMR (75 MHz, CDCl3): δ = 67.9 (C-1Ј), 68.8 J3,4 = 4.0 Hz, 1 H, 3-H), 4.90 (d, 2J = 11.6 Hz, 1 H, CH2(Bn)),
(C-6Ј), 72.7 (C-5Ј), 72.9, 73.1, 73.6 (3 CH2(Bn)), 74.9 (C-4Ј or C- 4.98 (d, 2J = 11.4 Hz, 1 H, CH2(Bn)), 7.21–7.44 (m, 30 H,
3Ј), 75.0 (CH2(Bn)), 75.7 (C-2Ј), 79.9 (C-3Ј or C-4Ј), 84.4, 88.3
(2Calkyne), 122.6 (Cq(Ph)), 123.9–132.1 (CH(Ar)), 137.9, 138.7,
138.8 (Cq(Bn)) ppm. MS (CI+, NH3): m/z = 642 [M + NH4]+.
[α]2D0 = +8.4 (c = 1.10, CHCl3).
H(Ar)) ppm. 13C NMR (75 MHz, CDCl3): δ = 70.7 (C-7), 71.3
(CH2(Bn)), 71.9 (C-3), 72.6, 73.3, 74.0 (4 CH2(Bn)), 79.0, 79.4, 80.4
(C-6, C-5, C-4), 86.4, 87.5 (2Calkyne), 123.1 (Cq(Ph)), 127.5–132.0
(CH(Ar)), 138.1–139.0 (Cq(Bn)) ppm. MS (CI+, NH3): m/z = 720
[M + NH ]+. IR: ν = 2223 (CϵC) cm–1. [α]20 = +36.4 (c = 0.91,
˜
4
D
1-(6Ј-O-Acetyl-2Ј,3Ј,4Ј-tri-O-benzyl-α-D-galactopyranosyl)-2-phen-
CHCl3). HRMS: calcd. for C48H47O5 [M + H]+ 703.3424; found
ylacetylene (29): This compound was synthesized according to pro-
cedure B from 1-O-acetyl-galactosyl 28 (389 mg, 0.73 mmol),
(phenylethynyl)tributylstannane (510 µL, 1.46 mmol), molecular si-
703.3419.
Procedure D Ϫ [4+2] Cycloaddition: Dimethyl 1,2,4,5-tetrazine-3,6-
eves (400 mg) and trimethylsilyl triflate (264 µL, 1.46 mmol) in dicarboxylate (12) (1.1 to 2.2 equiv.) was added to a solution of
CH2Cl2 (3 mL). After work up with Et3N (0.50 mL) and purifica-
tion, the galactosylphenylacetylene 29 was obtained (235 mg,
52%). Syrup; Rf (petroleum ether/EtOAc, 8:2) = 0.47. 1H NMR
(300 MHz, CDCl3): δ = 1.98 (s, 3 H, Me(OAc)), 3.90 (m, 1 H, 4Ј-
H), 3.95 (dd, J3Ј,2Ј = 9.5, J3Ј,4Ј = 2.7 Hz, 1 H, 3Ј-H), 4.13–4.16 (m,
4 H, 2Ј-H, 5Ј-H, 6Ј-H), 4.62 (d, 2J = 11.5 Hz, 1 H, CH2(Bn)), 4.76–
4.80 (m, 3 H, CH2(Bn)), 4.82 (d, 2J = 11.8 Hz, 1 H, CH2(Bn)), 4.95
acetylene derivative (1 equiv.) in freshly distilled toluene and the
resulting mixture was stirred under argon at reflux. The solvent
was then evaporated under reduced pressure.
Dimethyl (1ЈR,2ЈS,3ЈR,4ЈR)-4-(1Ј,2Ј,3Ј,4Ј,5Ј-pentabenzoxypentyl)-5-
phenylpyridazine-3,6-dicarboxylate [33-(1ЈR)]: This compound was
synthesized according to procedure D. From dimethyl 1,2,4,5-tetra-
zine-3,6-dicarboxylate (12) (906 mg, 4.56 mmol) and alkyne 32-
(3R) (1.46 g, 2.08 mmol) in toluene (6 mL), 33-(1ЈR) (1.00 g, 55%)
was obtained after purification by flash chromatography on silica
gel (petroleum ether/EtOAc, 80:20). Syrup; Rf (petroleum ether/
2
(d, J = 11.4 Hz, 1 H, CH2(Bn)), 5.05 (d, J1Ј,2Ј = 5.5 Hz, 1 H, 1Ј-
H), 7.24–7.46 (m, 15 H, H(Ar)) ppm. 13C NMR (75 MHz, CDCl3):
δ = 21.0 (Me(OAc)), 63.5 (C-6Ј), 67.8 (C-1Ј), 72.0 (C-2Ј or C-5Ј),
73.1, 73.5 (2 CH2(Bn)), 74.6 (C-4Ј), 74.7 (CH2(Bn)), 75.9 (C-2Ј or
C-5Ј), 79.8 (C-3Ј), 84.2, 88.5 (2Calkyne), 122.6 (Cq(Ph)), 127.7–
129.0, 132.1 (CH(Ar)), 138.7, 138.5, 138.3 (Cq(Bn)), 170.8
(CO) ppm. MS (CI+, NH3): m/z = 576 [M + NH4]+.
1
EtOAc, 7:3) = 0.36. H NMR (300 MHz, CD3OD): δ = 3.37 (dd,
J5Јa,5Јb = 10.2, J5Јa,4Ј = 6.7 Hz, 1 H, 5Јa-H), 3.49 (dd, J5Јb,5Јa = 10.2,
J5Јb,4Ј = 3.8 Hz, 1 H, 5Јb-H), 3.57 (m, 4 H, OMe, 3Ј-H), 3.66 (s, 3
H, OMe), 3.89 (m, 2 H, 2Ј-H, 4Ј-H), 4.06 (d, 2J = 11.9 Hz, 1 H,
CH2(Bn)), 4.22 (d, 2J = 11.5 Hz, 1 H, CH2(Bn)), 4.32 (d, 2J =
11.9 Hz, 1 H, CH2(Bn)), 4.37–4.51 (m, 7 H, CH2(Bn)), 5.10 (d,
J1Ј,2Ј = 5.4 Hz, 1 H, 1Ј-H), 6.79–7.35 (m, 30 H, H(Ar)) ppm. 13C
NMR (75 MHz, CD3OD): δ = 53.3, 53.6 (2 OMe), 71.9 (C-5Ј),
72.4, 73.8, 74.2, 75.9 (5CH2(Bn)), 79.0 (C-1Ј, C-3Ј), 79.8, 81.4 (C-
2Ј,C-4Ј), 128.4–130.4 (CH(Ar)), 133.3–141.0 (Cq(Bn), Cq(Ph), C-
3, C-6), 155.4, 156.7 (C-4, C-5), 166.0, 167.5 (2 CO) ppm. MS (CI+,
Procedure C Ϫ Benzylation: Sodium hydride (2.4 equiv.) was added
to a stirred solution of the diol derivative (1 equiv.) in anhydrous
THF and a few drops of DMF under argon. After 15 min stirring,
benzyl bromide (2.4 equiv.) was added dropwise to the slurry. The
reaction mixture was stirred overnight at room temperature. After
adding a saturated aqueous NaCl solution, the mixture was ex-
tracted with EtOAc. The combined EtOAc fractions were dried
with Na2SO4 and concentrated in vacuo.
NH ): m/z = 873 [M + H]+. IR: ν = 1744 (C=O) cm–1. [α]20 = –26.8
˜
3
D
(c = 0.95, CHCl3), C54H52N2O9·0.25H2O (877.50): calcd. C 73.91,
H 6.03, N 3.19; found C 73.86, H 6.05, N 3.15.
(3R,4S,5R,6R)-3,4,5,6,7-Pentabenzoxy-1-phenylhept-1-yne [32-
(3R)]: This compound was synthesized according to general pro-
cedure C. From NaH (385 mg, 9.62 mmol), acetylenic diol 14-(5R)
Dimethyl (1ЈS,2ЈS,3ЈR,4ЈR)-4-(1Ј,2Ј,3Ј,4Ј,5Ј-pentabenzoxypentyl)-5-
(2.10 g, 4.01 mmol) in a mixture THF (20 mL)/DMF (few drops) phenylpyridazine-3,6-dicarboxylate [33-(1ЈS)]: This compound was
and benzyl bromide (1.15 mL, 9.62 mmol), 32-(3R) (2.14 g, 76%)
was obtained after flash column chromatography on silica gel (pe-
troleum ether/EtOAc, 95:5). Syrup; Rf (petroleum ether/EtOAc,
synthesized according to procedure D. From dimethyl 1,2,4,5-tetra-
zine-3,6-dicarboxylate (12) (1.36 g, 6.88 mmol) and alkyne 32-(3S)
(2.20 g, 3.13 mmol) in toluene (9 mL), 33-(1ЈS) (1.80 g, 66%) was
obtained after purification by flash chromatography on silica gel
(petroleum ether/EtOAc, 75:25). Syrup; Rf (petroleum ether/
9:1) = 0.44. 1H NMR (300 MHz, CDCl3): δ = 3.70 (dd, J7a,7b
10.6, J7a,6 = 5.5 Hz, 1 H, 7a-H), 3.62 (dd, J7b,7a = 10.6, J7b,6
=
=
1
3.0 Hz, 1 H, 7b-H), 4.13 (m, 1 H, 4-H), 4.11 (m, 2 H, 6-H, 5-H),
EtOAc, 7:3) = 0.41. H NMR (300 MHz, CD3OD): δ = 3.55–3.69
(m, 8 H, OMe, 5Ј-H), 3.78 (m, 1 H, 4Ј-H), 3.94 (d, J3Ј,4Ј = 4.0 Hz,
4.44 (d, 2J = 11.6 Hz, 1 H, CH2(Bn)), 4.46 (s, 2 H, CH2(Bn)), 4.57–
3304
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Eur. J. Org. Chem. 2007, 3296–3310

Polyhydroxylated Pyrano-Pyrroles from Carbohydrate Precursors
FULL PAPER
2
1 H, 3Ј-H), 4.12 (d, J = 10.7 Hz, 1 H, CH2(Bn)), 4.20–4.40 (m, 8 (hexanes/EtOAc, 85:15, 2 mL/min). 35-(1ЈR): white needles; m.p.
2
H, CH2(Bn)), 4.53 (d, J = 10.8 Hz, 1 H, CH2(Bn)), 4.62 (d, J2Ј,1Ј
= 9.4 Hz, 1 H, 2Ј-H), 5.06 (d, J1Ј,2Ј = 9.4 Hz, 1 H, 1Ј-H), 6.81–7.33
(m, 30 H, H(Ar)) ppm. 13C NMR (75 MHz, CD3OD): δ = 53.3,
66 °C; Rf (petroleum ether/EtOAc, 75:25) = 0.32. 1H NMR
(300 MHz, CD3OD): δ = 0.59 (t, J = 6.8 Hz, 3 H, Hδ(Bu)), 0.86
(m, 3 H, 2Hγ(Bu), Hβ(Bu)), 1.10 (m, 1 H, Hβ(Bu)), 2.31 (m, 1 H,
3
53.6 (2 OMe), 70.7 (C-5Ј), 73.0, 74.0, 74.3 (5CH2(Bn)), 76.4 (C-1Ј), Hα(Bu)), 3.00 (m, 1 H, Hα(Bu)), 3.34 (m, 1 H, 2Ј-H), 3.56 (m, 1 H,
79.4 (C-3Ј, C-4Ј), 82.1 (C-2Ј), 128.5–131.8 (CH(Ar)), 133.5–142.4 5Ј-H), 3.66 (s, 3 H, OMe), 3.74 (m, 1 H, 5Ј-H), 3.88 (m, 1 H, 4Ј-
(Cq(Bn), Cq(Ph), C-3, C-6), 155.3, 155.7 (C-4, C-5), 166.2, 167.7 H), 3.95 (s, 3 H, OMe), 4.15–4.63 (m, 8 H, CH2(Bn)), 4.71 (m, 1
(2 CO) ppm. MS (CI+, NH ): m/z = 874 [M + H]+. IR: ν = 1744
H, 3Ј-H), 4.78–4.97 (m, 2 H, CH2(Bn)), 5.20 (d, J1Ј,2Ј = 8.4 Hz, 1
H, 1Ј-H), 6.81 (m, 2 H, H(Ar)), 7.13–7.44 (m, 23 H, H(Ar)) ppm.
13C NMR (75 MHz, CD3OD): δ = 14.2 Cδ(Bu)), 23.8 (Cγ(Bu)),
29.0 (Cα(Bu)), 33.7 (Cβ(Bu)), 53.5, 53.7 (2 OMe), 69.4 (C-5Ј), 71.9,
74.1 (4 CH2(Bn)), 75.4 (C-3Ј), 77.2 (CH2(Bn)), 79.1 (C-1Ј), 80.3 (C-
4Ј), 83.5 (C-2Ј), 128.7–129.9 (CH(Ar)), 138.3–143.8 (Cq(Bn), C-3,
C-6), 155.5, 156.3 (C-4, C-5), 166.3, 168.1 (2 CO) ppm. MS (CI+,
˜
3
(C=O) cm–1. [α]2D0 = –30.4 (c = 0.91, CHCl3). HRMS: calcd. for
C54H53N2O9 [M + H]+ 873.3751; found 873.3719.
(7R,8S,9R,10R)-7,8,9,10,11-Pentabenzoxyundec-5-yne [34-(7R)] and
(7S,8S,9R,10R)-7,8,9,10,11-Pentabenzoxyundec-5-yne [34-(7S)]:
These compounds were synthesized according to procedure C from
NaH (259 mg, 6.47 mmol), a mixture of acetylenic diol 15-(7R) and
15-(7S) (1.35 g, 2.70 mmol) in a mixture of THF (17 mL)/DMF
(few drops) and benzyl bromide (770 µL, 6.47 mmol). Chromato-
graphic purification on silica gel (petroleum ether/EtOAc, 95:5) af-
forded a mixture of two inseparable isomers 34-(7R) and 34-(7S)
(1.14 g, 62%). Only a small amount was purified by semiprepar-
ative HPLC (hexanes/EtOAc, 95:5, 2 mL/min) for analyses. 34-(7R):
syrup; Rf (petroleum ether/EtOAc, 95:5) = 0.27. 1H NMR
NH ): m/z = 853 [M]+. IR: ν = 1740 (C=O) cm–1. [α]20 = –52.5 (c
˜
3
D
= 0.36, CHCl3), C52H56N2O9·0.5H2O (862.01): C 72.45, H 6.66, N
3.25; found C 72.61, H 6.48, N 3.04. 35-(1ЈS): Syrup; Rf (petroleum
ether/EtOAc, 75:25) = 0.28. 1H NMR (400 MHz, CD3OD): δ =
3
0.67 (t, J = 7.0 Hz, 3 H, Hδ(Bu)), 0.98 (m, 2 H, Hγ(Bu)), 1.14 (m,
1 H, Hβ(Bu)), 1.27 (m, 1 H, Hβ(Bu)), 2.58 (m, 1 H, Hα(Bu)), 2.92
(m, 1 H, Hα(Bu)), 3.54 (s, 3 H, OMe), 3.72 (dd, J5Јa,5Јb = 10.6, J5Јa,4Ј
= 3.8 Hz, 1 H, 5Јa-H), 3.83 (dd, J5Јb,5Јa = 10.6, J5Јb,4Ј = 1.8 Hz, 1
3
(300 MHz, CD3OD): δ = 0.87 (t, J = 7.1 Hz, 3 H, 3ϫ1-H), 1.34–
2
H, 5Јb-H), 4.00 (m, 4 H, OMe, 4Ј-H), 4.09 (d, J = 11.2 Hz, 1 H,
3
5
1.51 (m, 4 H, 2ϫ2-H, 2ϫ3-H), 2.23 (td, J = 6.7, J = 1.9 Hz, 2
H, 2ϫ4-H), 3.65 (dd, J11a,11b = 10.7, J11a,10 = 5.7 Hz, 1 H, 11a-
H), 3.77 (dd, J11b,11a = 10.7, J11b,10 = 3.1 Hz, 1 H, 11b-H), 3.86 (t,
CH2(Bn)), 4.23 (m, 3 H, CH2(Bn), 3Ј-H), 4.51 (m, 4 H, CH2(Bn),
2Ј-H), 4.64 (m, 1 H, CH2(Bn)), 4.77 (m, 1 H, CH2(Bn)), 5.24 (d,
J1Ј,2Ј = 9.4 Hz, 1 H, 1Ј-H), 6.78 (m, 2 H, H(Ar)), 7.08–7.32 (m, 23
H, H(Ar)) ppm. 13C NMR (100 MHz, CD3OD): δ = 14.2 (Cδ(Bu)),
23.8 (Cγ(Bu)), 29.1 (Cα(Bu)), 33.1 (Cβ(Bu)), 53.4, 53.7 (2 OMe),
70.0 (C-5Ј), 72.7, 74.4, 74.7 (5CH2(Bn)), 76.3 (C-1Ј), 79.1 (C-3Ј),
79.5 (C-4Ј), 82.3 (C-2Ј), 128.5–129.8 (CH(Ar)), 138.0–144.2
(Cq(Bn), C-3, C-6), 155.1, 155.3 (C-4, C-5), 166.7, 167.9 (2
3
3J = 4.9 Hz, 1 H, 8-H), 4.00 (m, 1 H, 10-H), 4.06 (t, J = 4.9 Hz,
1 H, 9-H), 4.39–4.47 (m, 5 H, H-7, CH2(Bn)), 4.53 (d, 2J = 11.7 Hz,
2
2
1 H, CH2(Bn)), 4.55 (d, J = 11.4 Hz, 1 H, CH2(Bn)), 4.62 (d, J
2
= 11.7 Hz, 1 H, CH2(Bn)), 4.68 (d, J = 11.2 Hz, 1 H, CH2(Bn)),
2
2
4.73 (d, J = 11.7 Hz, 1 H, CH2(Bn)), 4.88 (d, J = 11.2 Hz, 1 H,
CH2(Bn)), 7.15–7.33 (m, 25 H, H(Ar)) ppm. 13C NMR (75 MHz,
CD3OD): δ = 14.0 (C-1), 19.2 (C-4), 23.0, 31.8 (C-2, C-3), 71.2 (C-
7), 71.4, 71.7 (C-11, CH2(Bn)), 73.3, 74.0, 74.2, 75.8 (4 CH2(Bn)),
78.4 (Calkyne), 79.8, 79.9 (C-9, C-10), 82.9 (C-8), 89.7 (Calkyne),
CO) ppm. MS (CI+, NH ): m/z = 853 [M]+. IR: ν = 1740
˜
3
(C=O) cm–1. [α]2D0 = +49.0 (c = 0.28, CHCl3). C52H56N2O9·0.5H2O
(862.01): C 72.45, H 6.66, N 3.25; found C 72.57, H 6.51, N 3.09.
128.6–129.3 (CH(Ar)), 139.4–140.0 (Cq(Ar)) ppm. MS (CI+, NH3): Dimethyl 5-Phenyl-4-(2Ј,3Ј,5Ј-tri-O-benzyl-α-
D-ribofuranosyl)pyrid-
m/z = 700 [M + NH ]+. IR: ν = 2225 (CϵC) cm–1. [α]20 = –31.6 (c
azine-3,6-dicarboxylate (36): This compound was synthesized ac-
cording to procedure D. From dimethyl 1,2,4,5-tetrazine-3,6-dicar-
boxylate (12) (652 mg, 3.30 mmol) and acetylene derivative 16α
(757 mg, 1.50 mmol) in toluene (4 mL), 36 (493 mg, 49%) was ob-
tained after purification by flash column chromatography on silica
gel (petroleum ether/EtOAc, 8:2 to 1:1). Pale yellow solid; m.p.
140–141 °C; Rf (petroleum ether/EtOAc, 7:3) = 0.25. 1H NMR
(300 MHz, CDCl3): δ = 3.43–3.58 (m, 2 H, 5Ј-H), 3.61 (s, 3 H,
OMe), 3.69 (m, 1 H, 2Ј-H), 3.87 (m, 1 H, 4Ј-H), 3.92 (s, 3 H, OMe),
˜
4
D
= 0.75, CHCl3), C46H50O5·0.25H2O (687.39): C 80.38, H 7.40;
found C 80.47, H 7.34. 34-(7S): Syrup; Rf (petroleum ether/EtOAc,
95:5) = 0.29. 1H NMR (400 MHz, CD3OD): δ = 0.89 (t, 3J =
7.0 Hz, 3 H, 3ϫ1-H), 1.42–1.51 (m, 4 H, 2ϫ2-H, 2ϫ3-H), 2.27
3
5
(td, J = 6.5, J = 1.8 Hz, 2 H, 2ϫ4-H), 3.64 (dd, J11a,11b = 10.7,
J11a,10 = 6.3 Hz, 1 H, 11a-H), 3.73 (dd, J11b,11a = 10.7, J11b,10
=
3.5 Hz, 1 H, 11b-H), 3.87 (dd, J8,9 = 6.1, J8,7 = 4.0 Hz, 1 H, 8-H),
3.93 (dd, J9,8 = 6.1, J9,10 = 3.4 Hz, 1 H, 9-H), 4.03 (m, 1 H, 10-H),
2
2
4.40 (s, 2 H, CH2(Bn)), 4.45 (d, J = 11.7 Hz, 1 H, CH2(Bn)), 4.53
3.95 (m, 1 H, 3Ј-H), 4.14 (d, J = 12.2 Hz, 1 H, CH2(Bn)), 4.38–
(dt, J7,4 = 2.1, J7,8 = 4.0 Hz, 1 H, 7-H), 4.55–4.64 (m, 5 H,
4.53 (m, 4 H, CH2(Bn)), 4.75 (d, 2J = 12.2 Hz, 1 H, CH2(Bn)), 4.29
(d, J1Ј,2Ј = 2.6 Hz, 1 H, 1Ј-H), 6.87–7.37 (m, 20 H, H(Ar)) ppm.
CH2(Bn)), 4.76 (d, 2J = 11.7 Hz, 1 H, CH2(Bn)), 4.85 (d, 2J =
11.4 Hz, 1 H, CH2(Bn)), 7.18–7.30 (m, 25 H, H(Ar)) ppm. 13C 13C NMR (75 MHz, CDCl3): δ = 52.7, 52.9 (2 OMe), 60.4 (C-5Ј),
NMR (100 MHz, CD3OD): δ = 13.9 (C-1), 19.2 (C-4), 22.9, 31.9
(C-2, C-3), 71.5 (C-11), 71.8 (CH2(Bn)), 72.4 (C-7), 73.4, 74.1, 74.7,
74.9 (5CH2(Bn)), 77.1 (Calkyne), 80.1 (C-10), 80.3 (C-9), 81.8 (C-8),
73.2, 73.4 (3 CH2(Bn)), 78.3 (C-2Ј or C-4Ј), 79.0 (C-1Ј), 79.1 (C-4Ј
or C-2Ј), 80.2 (C-3Ј), 127.4–128.9 (CH(Ar)), 132.9–138.0 (Cq(Bn),
Cq(Ph), C-3, C-6), 153.2, 154.3 (C-4, C-5), 164.8, 165.8 (2
89.3 (Calkyne), 128.4–129.3 (CH(Ar)), 139.4–140.0 (Cq(Ar)) ppm. CO) ppm. MS (CI+, NH ): m/z = 675 [M + H]+. IR: ν = 1739
˜
3
MS (CI+, NH ): m/z = 700 [M + NH ]+. IR: ν = 2225 (CϵC) cm–1.
(CO) cm–1. [α]2D0 = –58.9 (c = 1.00, CHCl3).
˜
3
4
[α]2D0 = +35.5 (c = 0.16, CHCl3).
Dimethyl 4-(2Ј,3Ј,4Ј,6Ј-Tetra-O-benzyl-α-
D
-galactopyranosyl)-5-
Dimethyl (1ЈR,2ЈS,3ЈR,4ЈR)-5-Butyl-4-(1Ј,2Ј,3Ј,4Ј,5Ј-pentabenzoxy- phenylpyridazine-3,6-dicarboxylate (37): This compound was syn-
pentyl)pyridazine-3,6-dicarboxylate [35-(1ЈR)] and Dimethyl thesized according to procedure D. From dimethyl 1,2,4,5-tetra-
(1ЈS,2ЈS,3ЈR,4ЈR)-5-Butyl-4-(1Ј,2Ј,3Ј,4Ј,5Ј-pentabenzoxypentyl)pyrid- zine-3,6-dicarboxylate (12) (138 mg, 0.69 mmol) and acetylene de-
azine-3,6-dicarboxylate [35-(1ЈS)]: These compounds were synthe-
sized according to procedure D from dimethyl 1,2,4,5-tetrazine-3,6-
dicarboxylate (12) (1.82 g, 9.18 mmol) and a mixture of alkyne 34-
(7R) and 34-(7S) (2.85 g, 4.17 mmol, ratio 7R/7S, 52:48) in toluene
(11 mL) to give a mixture of 35-(1ЈR) and 35-(1ЈS) (1.64 g, 46%,
ratio, 68:32). The mixture was purified by semipreparative HPLC
rivative 27 (216 mg, 0.35 mmol) in toluene (4 mL), 37 (119 mg,
46%) was obtained after purification by flash column chromatog-
raphy on silica gel (petroleum ether/EtOAc, 8:2 to 1:1). Yellow
syrup; Rf (petroleum ether/EtOAc, 7:3) = 0.26. 1H NMR
(300 MHz, CDCl3): δ = 3.03 (m, 1 H, 2Ј-H), 3.61 (m, 1 H, 3Ј-H),
3.65 (s, 3 H, OMe), 3.77 (dd, J6Јa,5Ј = 2.4, J6Јa,6Јb = 12.2 Hz, 1 H,
Eur. J. Org. Chem. 2007, 3296–3310
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3305

D. Dubreuil et al.
FULL PAPER
6Јa-H), 3.81–3.89 (m, 3 H, 6Јb-H, CH2(Bn)), 3.98 (s, 3 H, OMe),
tic acid (17 mL), 40-(1ЈR) (535 mg, 46%) was obtained after purifi-
4.03–4.10 (m, 3 H, 4Ј-H, CH2(Bn)), 4.35–4.47 (m, 3 H, 5Ј-H, cation by flash column chromatography on silica gel (petroleum
CH2(Bn)), 4.50 (d, 2J = 12.6 Hz, 1 H, CH2(Bn)), 4.60 (d, 2J =
ether/EtOAc, 80:20). Syrup; Rf (petroleum ether/EtOAc, 7:3) =
12.6 Hz, 1 H, CH2(Bn)), 5.12 (d, J1Ј,2Ј = 1.6 Hz, 1 H, 1Ј-H), 5.94 0.50. H NMR (400 MHz, C6D6, 320 K): δ = 3.25 (s, 3 H, OMe),
(d, 3J = 6.7 Hz, 1 H, H(Ar)), 6.69–7.34 (m, 24 H, H(Ar)) ppm. 13
3.34 (s, 3 H, OMe), 3.84–3.89 (m, 2 H, 3Ј-H, 5Јa-H), 4.03 (dd,
NMR (75 MHz, CDCl3): δ = 52.8 (2 OMe), 64.8 (C-6Ј), 66.7 (C- J5Јb,5Јa = 10.9, J5Јb,4Ј = 2.1 Hz, 1 H, 5Јb-H), 4.19–4.24 (m, 3 H, 2Ј-
1
C
2
1Ј), 71.6, 71.9, 72.4 (4 CH2(Bn)), 72.7 (C-3Ј, C-4Ј), 74.0 (C-2Ј), 76.6
H, 4Ј-H, CH2(Bn)), 4.35 (d, J = 12.1 Hz, 1 H, CH2(Bn)), 4.39 (d,
(C-5Ј), 127.3–129.0 (CH(Ar), Cq(Ph)), 132.4–138.7 (Cq(Bn), C-3, 2J = 12.1 Hz, 1 H, CH2(Bn)), 4.57–4.66 (m, 5 H, CH2(Bn)), 4.72
C-6), 152.7, 155.7 (C-4, C-5), 165.0, 166.2 (2 CO) ppm. MS (CI+, (d, 2J = 12.1 Hz, 1 H, CH2(Bn)), 4.82 (d, 2J = 11.3 Hz, 1 H,
NH ): m/z = 795 [M + H]+. IR: ν = 1746 (CO) cm–1. [α]20 = –65.4
CH2(Bn)), 5.79 (d, J1Ј,2Ј = 8.6 Hz, 1 H, 1Ј-H), 7.05–7.32 (m, 30 H,
H(Ar)), 9.47 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, C6D6,
320 K): δ = 51.7, 51.9 (2 OMe), 72.6 (CH2(Bn)), 72.9 (C-5Ј), 73.4,
73.7, 74.1, 76.4 (4 CH2(Bn)), 78.2 (C-1Ј), 81.2 (C-4Ј), 82.3 (C-3Ј),
82.5 (C-2Ј), 123.7, 123.8 (C-2, C-5), 133.0, 135.1 (C-3, C-4), 127.9–
132.6 (CH(Ar), Cq(Ph)), 140.2–140.8 (Cq(Bn)), 161.2 (2 CO) ppm.
˜
3
D
(c = 1.00, CHCl3).
Dimethyl 4-(6Ј-O-Acetyl-2Ј,3Ј,4Ј-tri-O-benzyl-α-
D
-galactopyrano-
syl)-5-phenylpyridazine-3,6-dicarboxylate (38): This compound was
synthesized according to procedure D. From dimethyl 1,2,4,5-tetra-
zine-3,6-dicarboxylate (12) (117 mg, 0.59 mmol) and acetylene de-
rivative 29 (310 mg, 0.54 mmol) in toluene (3 mL), 38 (180 mg,
45%) was obtained after purification by flash column chromatog-
raphy on silica gel (petroleum ether/EtOAc, 8:2 to 1:1). Syrup; Rf
(petroleum ether/EtOAc, 7:3) = 0.27. 1H NMR (300 MHz, CDCl3):
δ = 1.96 (s, 3 H, Me(OAc)), 3.06 (m, 1 H, 2Ј-H), 3.57 (m, 1 H, 3Ј-
H), 3.57 (s, 3 H, OMe), 3.86 (m, 1 H, 6Јa-H), 3.86 (s, 3 H, OMe),
3.90–3.99 (m, 4 H, 4Ј-H, CH2(Bn)), 4.18 (m, 1 H, 5Ј-H), 4.26 (d,
2J = 12.7 Hz, 1 H, CH2(Bn)), 4.39 (m, 2 H, CH2(Bn)), 5.10 (dd,
J6Јb,6Јa = 12.8, J6Јb,5Ј = 10.5 Hz, 1 H, 6Јb-H, ), 5.47 (br. s, 1 H, 1Ј-
IR: ν = 3282 (NH), 1716 (C=O) cm–1. [α]20 = +13.6 (c = 1.38,
˜
D
CHCl3).
Dimethyl (1ЈS,2ЈS,3ЈR,4ЈR)-3-(1Ј,2Ј,3Ј,4Ј,5Ј-Pentabenzoxypentyl)-4-
phenyl-1H-pyrrole-2,5-dicarboxylate [40-(1ЈS)]: This compound was
synthesized according to procedure E. Pyridazine 33-(1ЈS) (1.13 g,
1.29 mmol) and zinc (1.70 g, 25.90 mmol) in acetic acid (15 mL)
afforded 40-(1ЈS) (661 mg, 60%) after purification by flash column
chromatography on silica gel (petroleum ether/EtOAc, 80:20).
Syrup; Rf (petroleum ether/EtOAc, 8:2) = 0.19. 1H NMR
(400 MHz, C6D6, 328 K): δ = 3.27 (s, 3 H, OMe), 3.39 (s, 3 H,
OMe), 3.83 (dd, J5Јa,5Јb = 10.6, J5Јa,4Ј = 5.3 Hz, 1 H, 5Јa-H), 3.92
(dd, J5Јb,5Јa = 10.6, J5Јb,4Ј = 1.5 Hz, 1 H, 5Јb-H), 4.22 (m, 1 H, 4Ј-
3
3
H), 5.90 (d, J = 7.3 Hz, 1 H, H(Ar)), 6.68 (d, J = 6.9 Hz, 2 H,
H(Ar)), 6.87 (m, 2 H, H(Ar)), 7.13–7.32 (m, 14 H, H(Ar)), 7.47
(m, 1 H, H(Ar)) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.0
(Me(OAc)), 52.5, 52.8 (2 OMe), 59.3 (C-6Ј), 66.3 (C-1Ј), 71.3 (C-
3Ј), 71.6, 71.9 (3 CH2(Bn)), 72.5 (C-4Ј), 73.3 (C-2Ј), 74.8 (C-5Ј),
127.5–129.2 (CH(Ar), Cq(Ph)), 132.5, 135.4 (C-3, C-6), 137.4–
137.9 (Cq(Bn)), 155.6, 152.9 (C-4, C-5), 166.3, 164.9 (2 CO-
(CO2Me)), 171.3 (CO(OAc)) ppm. MS (CI+, NH3): m/z = 747 [M
+ H]+. [α]2D0 = –96.0 (c = 1.00, CHCl3).
H), 4.32–4.46 (m, 5 H, 3Ј-H, CH2(Bn)), 4.53–4.68 (m, 6 H, 2Ј-H,
CH2(Bn)), 4.77 (d, J = 11.5 Hz, 1 H, CH2(Bn)), 5.56 (d, J1Ј,2Ј
2
=
7.9 Hz, 1 H, 1Ј-H), 7.01–7.44 (m, 30 H, H(Ar)), 9.62 (br. s, 1 H,
NH) ppm. 13C NMR (100 MHz, C6D6, 328 K): δ = 51.0, 51.3 (2
OMe), 71.6 (CH2(Bn)), 71.9 (C-5Ј), 72.6, 73.5, 73.7, 73.8 (4
CH2(Bn)), 74.3 (C-1Ј), 79.6 (C-4Ј), 80.5 (C-3Ј), 81.3 (C-2Ј), 122.3,
123.8 (C-2, C-5), 130.0, 134.6 (C-3, C-4), 127.2–131.7 (CH(Ar),
Cq(Ph)), 139.5–140.5 (Cq(Bn)), 160.5–160.8 (2 CO) ppm. MS (CI+,
Dimethyl 4-(2Ј,3Ј,4Ј,6Ј-Tetra-O-benzyl-α-D-glucopyranosyl)-5-phen-
ylpyridazine-3,6-dicarboxylate (39): This compound was synthe-
sized according to procedure D. From dimethyl 1,2,4,5-tetrazine-
3,6-dicarboxylate (12) (139 mg, 0.70 mmol) and acetylene deriva-
tive 21 (200 mg, 0.32 mmol) in toluene (4 mL), 39 (127 mg, 50%)
was obtained after purification by flash column chromatography
on silica gel (petroleum ether/EtOAc, 8:2 to 1:1). Yellow solid; m.p.
158–160 °C; Rf (petroleum ether/EtOAc, 8:2) = 0.10. 1H NMR
(300 MHz, CDCl3): δ = 3.24 (m, 1 H, 2Ј-H), 3.44 (m, 1 H, 6Јa-H),
3.57 (s, 3 H, OMe), 3.62 (m, 2 H, 6Јb-H, 3Ј-H), 3.78 (m, 1 H, 4Ј-
H), 3.82 (s, 3 H, OMe), 4.04 (m, 4 H, 5Ј-H, CH2(Bn)), 4.37–4.52
NH ): m/z (%) = 877 [M + NH ]+. IR: ν = 3444 (NH), 1707
˜
3
4
20
(C=O) cm–1. [α] = +23.0 (c = 0.27, CHCl3). HRMS: calcd. for
546
C54H54NO9 [M + H]+ 860.3799; found 860.3760.
Dimethyl (1ЈR,2ЈS,3ЈR,4ЈR)-4-Butyl-3-(1Ј,2Ј,3Ј,4Ј,5Ј-pentabenzoxy-
pentyl)-1H-pyrrole-2,5-dicarboxylate [41-(1ЈR)]: This compound
was synthesized according to procedure E. From pyridazine 35-
(1ЈR) (1.06 g, 1.24 mmol) and zinc dust (1.62 g, 24.90 mmol) in ace-
tic acid (14 mL), 41-(1ЈR) (713 mg, 68%) was obtained after purifi-
cation by flash column chromatography on silica gel (petroleum
ether/EtOAc, 80:20). Syrup; Rf (petroleum ether/EtOAc, 7:3) =
3
(m, 5 H, CH2(Bn)), 5.17 (d, J1Ј,2Ј = 1.7 Hz, 1 H, 1Ј-H), 5.78 (d, J
1
3
0.54. H NMR (400 MHz, C6D6, 328 K): δ = 0.89 (t, J = 7.2 Hz,
3 H, Hδ(Bu)), 1.41 (m, 2 H, Hγ(Bu)), 1.70 (m, 2 H, Hβ(Bu)), 3.12
(m, 2 H, Hα(Bu)), 3.37 (s, 3 H, OMe), 3.46 (s, 3 H, OMe), 3.84
(dd, J5Јa,5Јb = 10.5, J5Јa,4Ј = 5.6 Hz, 1 H, 5Јa-H), 4.01–4.06 (m, 2
H, 3Ј-H, 5Јb-H), 4.16 (m, 1 H, 4Ј-H), 4.35–4.47 (m, 3 H, CH2(Bn)),
4.55–4.68 (m, 5 H, CH2(Bn), 2Ј-H), 4.77 (d, 2J = 11.6 Hz, 1 H,
CH2(Bn)), 4.85–5.00 (m, 2 H, CH2(Bn)), 5.82 (d, J1Ј,2Ј = 7.9 Hz, 1
H, 1Ј-H), 7.06–7.42 (m, 25 H, H(Ar)), 9.32 (br. s, 1 H, NH) ppm.
13C NMR (100 MHz, C6D6, 328 K): δ = 13.9 (Cδ(Bu)), 23.6
(Cγ(Bu)), 26.3 (Cα(Bu)), 33.8 (Cβ(Bu)), 50.9, 51.2 (2 OMe), 72.2
(C-5Ј), 72.3, 73.0, 73.3, 73.7, 75.8 (5CH2(Bn)), 77.5 (C-1Ј), 80.6 (C-
4Ј), 81.2 (C-3Ј), 83.7 (C-2Ј), 122.8, 122.9 (C-2, C-5), 134.8 (C-3 or
C-4), 127.3–128.5 (C-3 or C-4, CH(Ar)), 139.6–140.2 (Cq(Bn)),
160.6, 160.8 (2 CO) ppm. MS (CI+, NH3): m/z (%) = 857 [M +
= 7.1 Hz, 1 H, H(Ar)), 6.78 (m, 2 H, H(Ar)), 7.00–7.25 (m, 22 H,
H(Ar)) ppm. 13C NMR (75 MHz, CDCl3): δ = 52.8 (2 OMe), 66.6
(C-6Ј), 70.5 (C-1Ј), 70.6, 70.8 (2 CH2(Bn)), 72.6 (C-5Ј), 73.2, 73.7
(2 CH2(Bn)), 74.2 (C-2Ј), 77.3 (C-4Ј), 79.8 (C-3Ј), 127.8–129.8
(CH(Ar), Cq(Ph)), 132.6–138.2 (Cq(Bn), C-3, C-6), 153.2, 155.3
(C-4, C-5), 166.1, 164.8 (2 CO) ppm. MS (CI+, NH3): m/z = 795
[M + H]+. [α]2D0 = –76.1 (c = 1.00, CHCl3).
Procedure E Ϫ Ring Contraction: Zinc dust (20 equiv.) was added
to a refluxing solution of pyridazine (1 equiv.) in glacial acetic acid.
After being stirred for 30 min, the reaction mixture was cooled,
filtered through a pad of Celite, and concentrated under reduced
pressure. The crude oil was purified by flash chromatography on
silica gel.
NH ]+. IR: ν = 3449 (NH), 1710 (C=O) cm–1. [α]20 = +10.9 (c =
˜
4
578
Dimethyl (1ЈR,2ЈS,3ЈR,4ЈR)-3-(1Ј,2Ј,3Ј,4Ј,5Ј-Pentabenzoxypentyl)-
4-phenyl-1H-pyrrole-2,5-dicarboxylate [40-(1ЈR)]: This compound
was synthesized according to procedure E. From pyridazine 33-
(1ЈR) (1.29 g, 1.48 mmol) and zinc dust (1.94 g, 29.60 mmol) in ace-
0.41, CHCl3).
Dimethyl (1ЈS,2ЈS,3ЈR,4ЈR)-4-Butyl-3-(1Ј,2Ј,3Ј,4Ј,5Ј-pentabenzoxy-
pentyl)-1H-pyrrole-2,5-dicarboxylate [41-(1ЈS)]: This compound
3306
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3296–3310

Polyhydroxylated Pyrano-Pyrroles from Carbohydrate Precursors
FULL PAPER
was synthesized according to procedure E. Pyridazine 35-(1ЈS)
(478 mg, 0.56 mmol) and zinc (733 mg, 11.21 mmol) in acetic acid
(6 mL), afforded 41-(1ЈS) (309 mg, 60%) after purification by flash
column chromatography on silica gel (petroleum ether/EtOAc,
80:20). Syrup; Rf (petroleum ether/EtOAc, 7:3) = 0.45. 1H NMR
and zinc dust (362 mg, 5.58 mmol) in glacial acetic acid (3 mL).
Chromatographic purification on silica gel (petroleum ether/
EtOAc, 8:2) gave compound 44 (184 mg, 56%). Syrup; Rf (petro-
1
leum ether/EtOAc, 7:3) = 0.53. H NMR (300 MHz, CDCl3): δ =
3.31 (m, 2 H, 5Ј-H), 3.42 (m, 1 H, 4Ј-H), 3.65 (s, 3 H, OMe), 3.81
(s, 3 H, OMe), 4.22–4.31 (dd, J3Ј,2Ј = 9.7, J3Ј,4Ј = 4.1 Hz, 1 H, 3Ј-
H), 4.22–4.31 (m, 3 H, CH2(Bn), 2Ј-H), 4.36–4.40 (m, 2 H,
3
(400 MHz, C6D6, 328 K): δ = 0.89 (t, J = 7.3 Hz, 3 H, Hδ(Bu)),
1.41 (m, 2 H, Hγ(Bu)), 1.70 (m, 2 H, Hβ(Bu)), 2.88–3.16 (m, 2 H,
Hα(Bu)), 3.39 (s, 3 H, OMe), 3.47 (s, 3 H, OMe), 3.93 (dd, J5Јa,5Јb CH2(Bn)), 4.47–4.55 (m, 2 H, CH2(Bn)), 5.66 (d, J1Ј,2Ј = 5.7 Hz, 1
= 10.7, J5Јa,4Ј = 5.6 Hz, 1 H, 5Јa-H), 4.05 (dd, J5Јb,5Јa = 10.7, J5Јb,4Ј H, 1Ј-H), 7.01 (m, 2 H, H(Ar)), 7.18–7.32 (m, 18 H, H(Ar)), 9.64
= 1.9 Hz, 1 H, 5Јb-H), 4.29 (d, 2J = 11.7 Hz, 1 H, CH2(Bn)), 4.40–
(br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 51.8, 51.9
4.47 (m, 4 H, CH2(Bn), 3Ј-H, 4Ј-H), 4.54–4.61 (m, 4 H, CH2(Bn), (2 OMe), 70.0 (C-5Ј), 72.8, 73.1, 73.4 (3 CH2(Bn)), 77.3 (C-2Ј), 77.9
2Ј-H), 4.76–4.88 (m, 3 H, CH2(Bn)), 5.03 (d, 2J = 11.7 Hz, 1 H,
CH2(Bn)), 5.82 (d, J1Ј,2Ј = 9.1 Hz, 1 H, 1Ј-H), 6.99–7.43 (m, 25 H,
H(Ar)), 9.37 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz, C6D6,
328 K): δ = 14.0 (Cδ(Bu)), 23.6 (Cγ(Bu)), 25.9 (Cα(Bu)), 34.0
(Cβ(Bu)), 50.9, 51.1 (2 OMe), 71.9, 72.1 (CH2(Bn), C-5Ј), 72.7,
73.7, 73.8, 74.1 (4 CH2(Bn)), 74.7 (C-1Ј), 79.9, 80.7 (C-3Ј, C-4Ј),
82.0 (C-2Ј), 122.2, 123.9 (C-2, C-5), 129.0, 134.5 (C-3, C-4), 127.4–
128.5 (CH(Ar)), 139.2–140.3 (Cq(Bn)), 160.7 (2 CO) ppm. MS
(C-4Ј), 78.4 (C-1Ј), 79.5 (C-3Ј), 120.3, 122.3 (C-2, C-5), 128.9,
132.9, 134.9 (C-3, C-4, Cq(Ph)), 126.6–132.9 (CH(Ar)), 138.0–
138.3 (Cq(Bn)), 160.4, 160.9 (2 CO) ppm. MS (CI+, NH3): m/z (%)
= 662 [M + H]+.
Dimethyl 3-(2Ј,3Ј,4Ј,6Ј-Tetra-O-benzyl-α-D-galactopyranosyl)-4-
phenyl-1H-pyrrole-2,5-dicarboxylate (45): This compound was syn-
thesized according to procedure E from pyridazine 37 (188 mg,
0.24 mmol) and zinc dust (196 mg, 3.00 mmol) in glacial acetic acid
(2 mL). Chromatographic purification on silica gel (petroleum
ether/EtOAc, 7:2) gave compound 45 (129 mg, 70%). Yellow syrup;
(petroleum ether/EtOAc, 7:3) = 0.47. 1H NMR (300 MHz, CDCl3):
δ = 3.56 (s, 3 H, OMe), 3.61 (s, 3 H, OMe), 3.61 (m, 2 H, 6Ј-H),
(CI+, NH ): m/z = 857 [M + NH ]+. IR: ν = 3451 (NH), 1713,
˜
3
4
20
1697 (C=O) cm–1. [α]
=
–23.3 (c
=
0.64, CHCl3).
365
C52H57NO9·0.5H2O (849.02): C 73.56, H 6.89, N 1.65; found C
73.73, H 6.76, N 1.29.
Dimethyl (1ЈR,2ЈS,3ЈR,4ЈR)-3-(2Ј,3Ј,5Ј-Tribenzoxy-1Ј,4Ј-dihydroxy- 3.66 (m, 2 H, 2Ј-H, 3Ј-H), 3.80 (m, 1 H, 4Ј-H), 3.88 (m, 1 H, 5Ј-
2
2
pentyl)-4-phenyl-1H-pyrrole-2,5-dicarboxylate [42-(1ЈR)]: This com-
pound was obtained as a byproduct (Ͻ10%) during the synthesis
of 40-(1ЈR). Syrup; Rf (petroleum ether/EtOAc, 7:3) = 0.13. 1H
NMR (400 MHz, CDCl3): δ = 3.31 (m, 1 H, 3Ј-H), 3.41 (d, J5Ј,4Ј
H), 4.06 (d, J = 12.1 Hz, 1 H, CH2(Bn)), 4.23 (d, J = 12.1 Hz, 1
2
2
H, CH2(Bn)), 4.32 (d, J = 11.5 Hz, 1 H, CH2(Bn)), 4.36 (d, J =
11.5 Hz, 1 H, CH2(Bn)), 4.40 (s, 2 H, CH2(Bn)), 4.48 (s, 2 H,
CH2(Bn)), 5.40 (d, J1Ј,2Ј = 1.3 Hz, 1 H, 1Ј-H), 6.83–7.27 (m, 25 H,
= 5.2 Hz, 2 H, 5Ј-H), 3.69 (s, 3 H, OMe), 3.85 (s, 3 H, OMe), 3.92 H(Ar)), 9.50 (s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ =
(t, 3J = 6.4 Hz, 1 H, 2Ј-H), 4.07 (m, 1 H, 4Ј-H), 4.32–4.39 (m, 3 H,
CH2(Bn)), 4.50–4.52 (m, 3 H, CH2(Bn)), 5.43 (d, J1Ј,2Ј = 6.4 Hz, 1
H, 1Ј-H), 7.12–7.35 (m, 20 H, H(Ar)), 9.83 (br. s, 1 H, NH) ppm.
13C NMR (100 MHz, CDCl3): δ = 51.8, 52.1 (2 OMe), 70.2 (C-5Ј),
51.0 (2 OMe), 65.6 (C-6Ј), 66.7 (C-1Ј), 71.8, 72.3, 72.7, 72.9 (4
CH2(Bn)), 73.5 (C-4Ј), 74.8 (C-5Ј), 75.5, 77.2 (C-2Ј, C-3Ј), 120.8,
121.9 (C-2, C-5), 126.4–130.5 (CH(Ar), Cq(Ph)), 133.0, 135.2 (C-
3, C-4), 138.1–138.8 (Cq(Bn)), 161.0–162.0 (2 CO) ppm. MS (CI+,
71.9, 72.1, 73.4 (3 CH2(Bn)), 77.6 (C-1Ј), 77.8 (C-3Ј), 79.4 (C-2Ј), NH3): m/z = 782 [M + H]+. [α]2D0 = –19.7 (c = 0.5, CHCl3).
81.1 (C-4Ј), 121.8, 122.8 (C-2, C-5), 132.7, 133.2 (C-3, C-4), 127.1–
Dimethyl 3-(6Ј-O-Acetyl-2Ј,3Ј,4Јtri-O-benzyl-α-D-galactopyrano-
131.3 (CH(Ar), Cq(Ph)), 138.1–138.4 (Cq(Bn)), 160.5 (2 CO) ppm.
syl)-4-phenyl-1H-pyrrole-2,5-dicarboxylate (46): This compound
was synthesized according to procedure E from pyridazine 38
(146 mg, 0.19 mmol) and zinc dust (254 mg, 3.90 mmol) in glacial
acetic acid (1.5 mL). Chromatographic purification on silica gel
(petroleum ether/EtOAc, 6:4) gave compound 46 (81 mg, 57%).
Syrup; Rf (petroleum ether/EtOAc, 8:2) = 0.41. 1H NMR
(300 MHz, CDCl3): δ = 1.92 (s, 3 H, Me(OAc)), 3.59 (s, 3 H, OMe),
MS (CI+, NH ): m/z = 679 [M + H – H O]+. IR: ν = 3436 (NH),
˜
3
2
3285 (OH), 1725, 1711 (C=O) cm–1. [α]
= +15.3 (c = 0.61,
20
365
CHCl3).
Dimethyl (1ЈR,2ЈS,3ЈR,4ЈR)-4-Butyl-3-(2Ј,3Ј,5Ј-tribenzoxy-1Ј,4Ј-di-
hydroxypentyl)-1H-pyrrole-2,5-dicarboxylate [43-(1ЈR)]: This com-
pound was obtained as a byproduct (Ͻ10%) during the synthesis
of 41-(1ЈR). Solid; m.p. 83–85 °C; Rf (petroleum ether/EtOAc, 7:3) 3.61 (s, 3 H, OMe), 3.67 (m, 2 H, 2Ј-H, 4Ј-H or 3Ј-H), 3.79 (m, 2
= 0.26. 1H NMR (400 MHz, C6D6, 328 K): δ = 0.94 (t, 3J = 7.3 Hz, H, 5Ј-H, 4Ј-H or 3Ј-H), 4.03 (d, 2J = 12.1 Hz, 1 H, CH2(Bn)), 4.17
2
3 H, Hδ(Bu)), 1.40 (m, 2 H, Hγ(Bu)), 1.60–1.86 (m, 2 H, Hβ(Bu)), (m, 2 H, CH2(Bn), 6Јa-H), 4.37 (d, J = 11.7 Hz, 1 H, CH2(Bn)),
2
2.95 (m, 1 H, Hα(Bu)), 3.13 (m, 1 H, Hα(Bu)), 3.36 (s, 3 H, OMe), 4.43 (d, J = 11.7 Hz, 1 H, CH2(Bn)), 4.51 (s, 2 H, CH2(Bn)), 4.65
3.43 (s, 3 H, OMe), 3.70 (dd, J5Јa,5Јb = 10.4, J5Јa,4Ј = 4.7 Hz, 1 H,
5Јa-H), 3.77 (dd, J5Јb,5Јa = 10.4, J5Јb,4Ј = 5.0 Hz, 1 H, 5Јb-H), 4.25
(m, 1 H, 3Ј-H), 4.36–4.48 (m, 5 H, CH2(Bn), 2Ј-H, 4Ј-H), 4.53 (d,
(dd, J6Јb,6Јa = 12.8, J6Јb,5Ј = 8.8 Hz, 1 H, 6Јb-H), 5.48 (d, J1Ј,2Ј =
1.8 Hz, 1 H, 1Ј-H), 6.82 (m, 2 H, H(Ar)), 7.01–7.27 (m, 18 H,
H(Ar)), 9.55 (s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ =
2J = 11.5 Hz, 1 H, CH2(Bn)), 4.64 (d, 2J = 12.0 Hz, 1 H, CH2(Bn)), 21.2 (Me(OAc)), 51.8 (2 OMe), 60.7 (C-6Ј), 66.2 (C-1Ј), 71.5, 72.8,
2
4.74 (d, J = 12.0 Hz, 1 H, CH2(Bn)), 5.86 (d, J1Ј,2Ј = 7.8 Hz, 1 H, 78.8 (3 CH2(Bn)), 73.1 (C-4Ј), 73.2 (C-3Ј), 74.2 (C-2Ј), 76.5 (C-5Ј),
1Ј-H), 7.03–7.39 (m, 15 H, H(Ar)), 9.33 (br. s, 1 H, NH) ppm. 13C
120.8, 121.8 (C-2, C-5), 126.4–130.4 (CH(Ar), Cq(Ph)), 132.8,
NMR (100 MHz, C6D6, 328 K): δ = 14.1 (Cδ(Bu)), 23.3 (Cγ(Bu)), 135.2 (C-3, C-4), 137.9, 138.4, 138.5 (Cq(Bn)), 160.4, 160.8 (2 CO-
25.4 (Cα(Bu)), 34.5 (Cβ(Bu)), 50.9, 51.2 (2 OMe), 71.3 (C-5Ј), 72.7,
(CO2Me)), 171.2 (CO(OAc)) ppm. MS (CI+, NH3): m/z = 734 [M
72.8, 73.8 (3 CH2(Bn)), 77.1 (C-1Ј), 79.2 (C-3Ј), 82.7 (C-2Ј), 83.0 + H]+.
(C-4Ј), 122.1, 123.0 (C-2, C-5), 134.3 (C-3 or C-4), 127.4–128.6 (C-
Dimethyl 3-(2Ј,3Ј,4Ј,6Ј-Tetra-O-benzyl-α-D-glucopyranosyl)-4-
3 or C-4, CH(Ar)), 139.3–139.5 (Cq(Bn)), 160.4, 160.6 (2 CO) ppm.
phenyl-1H-pyrrole-2,5-dicarboxylate (47): This compound was syn-
thesized according to procedure E from pyridazine 39 (60 mg,
0.07 mmol) and zinc dust (100 mg, 1.51 mmol) in glacial acetic acid
MS (CI+, NH ): m/z = 642 [M + H – H O]+. IR: ν = 3267 (NH +
˜
3
2
OH), 1711, 1687 (C=O) cm–1. [α] = +28.0 (c = 0.49, CHCl3).
20
365
Dimethyl 4-Phenyl-3-(2Ј,3Ј,5Ј-tri-O-benzyl-α-D-ribofuranosyl)-1H- (1 mL). Chromatographic purification on silica gel (petroleum
pyrrole-2,5-dicarboxylate (44): This compound was synthesized ac-
cording to procedure E from pyridazine 36 (188 mg, 0.28 mmol)
ether/EtOAc, 7:3) gave compound 47 (16 mg, 27%). Syrup; Rf (pe-
troleum ether/EtOAc, 8:2) = 0.27. H NMR (300 MHz, CDCl3): δ
1
Eur. J. Org. Chem. 2007, 3296–3310
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3307

D. Dubreuil et al.
FULL PAPER
= 2.50 (dd, J6Јa,6Јb = 10.8, J6Јa,5Ј = 2.1 Hz, 1 H, 6Јa-H), 3.20 (dd, (c = 1.50, MeOH). HRMS: calcd. for C17H28NO9 [M + H]+
J6Јb,6Јa = 10.8, J6Јb,5Ј = 2.1 Hz, 1 H, 6Јb-H), 3.45 (m, 1 H, 5Ј-H), 390.1743; found 390.1764.
3.56 (s, 3 H, OMe), 3.59 (s, 3 H, OMe), 3.70 (m, 1 H, 3Ј-H), 3.79
Dimethyl (1ЈS,2ЈS,3ЈR,4ЈR)-4-Butyl-3-(1Ј,2Ј,3Ј,4Ј,5Ј-pentahy-
(m, 1 H, 4Ј-H), 3.90 (m, 1 H, 2Ј-H), 4.33–4.60 (m, 8 H, CH2(Bn)),
droxypentyl)-1H-pyrrole-2,5-dicarboxylate [49-(1ЈS)]: This com-
5.56 (d, J1Ј,2Ј = 3.0 Hz, 1 H, 1Ј-H), 6.91–7.16 (m, 25 H, H(Ar)),
pound was synthesized according to procedure F. From pyrrole 41-
9.61 (s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 52.9 (2
(1ЈS) (309 mg, 0.37 mmol) and Pd/C (310 mg) in MeOH (3 mL),
OMe), 60.0 (C-6Ј), 70.2 (C-1Ј), 71.3, 71.9 (2 CH2(Bn)), 72.3 (C-5Ј),
49-(1ЈS) (136 mg, 95%) was obtained. Syrup; Rf (dichloromethane/
72.8, 73.4 (2 CH2(Bn)), 77.3 (C-2Ј), 78.2 (C-4Ј), 80.9 (C-3Ј), 120.1,
1
MeOH, 86:14) = 0.47. H NMR (300 MHz, CD3OD): δ = 0.95 (t,
122.2 (C-2, C-5), 126.4–130.2 (CH(Ar), Cq(Ph)), 132.6, 135.7 (C-
3
3 H, Hδ(Bu), J = 7.2), 1.34–1.62 (m, 4 H, Hβ(Bu), Hγ(Bu)), 2.77–
2.95 (m, 2 H, Hα(Bu)), 3.66 (dd, J5Јa,5Јb = 11.2, J5Јa,4Ј = 6.1 Hz, 1
H, 5Јa-H), 3.78–3.84 (m, 2 H, 3Ј-H, 5Јb-H), 3.87 (s, 3 H, OMe),
3, C-4), 137.7–138.6 (Cq(Bn)), 160.4, 160.9 (2 CO) ppm. MS (CI+,
NH3): m/z = 782 [M + H]+.
3.91–3.96 (m, 4 H, 4Ј-H, OMe), 4.02 (dd, J2Ј,1Ј = 8.1, J2Ј,3Ј = 5.5 Hz,
1 H, 2Ј-H), 5.15 (d, J1Ј,2Ј = 8.1 Hz, 1 H, 1Ј-H) ppm. 13C NMR
(75 MHz, CD3OD): δ = 14.3 (Cδ(Bu)), 23.9 (Cγ(Bu)), 25.6
(Cα(Bu)), 34.7 (Cβ(Bu)), 52.0, 52.7 (2 OMe), 64.1 (C-5Ј), 69.5 (C-
1Ј), 73.8 (C-4Ј), 75.3 (C-3Ј), 76.0 (C-2Ј), 123.0, 123.1 (C-2, C-5),
Procedure F Ϫ Debenzylation of Pyrroles: A solution of benzylated
pyrrole in MeOH was hydrogenated at room temperature over Pd/
C (100% w/w) for 1 h under a slight overpressure of hydrogen. The
mixture was then filtered trough a bed of Celite and the solvent
was removed under reduced pressure.
132.3, 134.4 (C-3, C-4), 162.5, 163.9 (2 CO) ppm. IR: ν = 3350
˜
Dimethyl (1ЈR,2ЈS,3ЈR,4ЈR)-3-(1Ј,2Ј,3Ј,4Ј,5Ј-Pentahydroxypentyl)-4-
phenyl-1H-pyrrole-2,5-dicarboxylate [48-(1ЈR)]: This compound
was synthesized according to procedure F. From pyrrole 40-(1ЈR)
(454 mg, 0.54 mmol) and Pd/C (450 mg) in MeOH (5 mL), 48-(1ЈR)
(188 mg, 89%) was obtained. White solid; m.p. 94 °C; Rf (dichloro-
methane/MeOH, 85:15) = 0.49. 1H NMR (400 MHz, CD3OD): δ
= 3.46 (dd, J5Јa,5Јb = 11.7, J5Јa,4Ј = 6.0 Hz, 1 H, 5Јa-H), 3.52–3.59
(m, 2 H, 5Јb-H, 3Ј-H), 3.65 (s, 4 H, OMe, 4Ј-H), 3.92 (s, 3 H,
(NH + OH), 1686 (C=O) cm–1. [α] = –31.0 (c = 1.35, MeOH).
20
436
Procedure G Ϫ Lactonization: Na2CO3 (1 equiv.) was added to a
solution of pyrrole (1 equiv.) in MeOH. The mixture was stirred
for 1 h at room temperature and filtered trough a pad of Celite.
After concentration, the crude was purified by preparative TLC
(CH2Cl2/MeOH, 88:12).
Methyl (4R,5S,1ЈR,2ЈR)-4-Hydroxy-7-oxo-3-phenyl-5-(1Ј,2Ј,3Ј-tri-
hydroxypropyl)-1,4,5,7-tetrahydropyrano[3,4-b]pyrrole-2-carboxylate
[50-(4R)]: This compound was synthesized according to procedure
G. From pyrrole 48-(1ЈR) (90 mg, 0.22 mmol) in MeOH (3 mL),
50-(4R) (41 mg, 49%) was obtained. White solid; m.p. 125 °C; Rf
(dichloromethane/MeOH, 85:15) = 0.39. 1H NMR (400 MHz,
CD3OD): δ = 3.72 (dd, J3Јa,3Јb = 11.5, J3Јa,2Ј = 6.5 Hz, 1 H, 3Јa-H),
3.77 (s, 3 H, OMe), 3.81 (dd, J3Јb,3Јa = 11.5, J3Јb,2Ј = 3.9 Hz, 1 H,
3Јb-H), 3.95 (m, 1 H, 2Ј-H), 4.17 (dd, J1Ј,5 = 7.7, J1Ј,2Ј = 4.7 Hz, 1
H, 1Ј-H), 4.59 (dd, J5,1Ј = 7.7, J5,4 = 1.9 Hz, 1 H, 5-H), 4.79 (d,
J4,5 = 1.9 Hz, 1 H, 4-H), 7.31–7.53 (m, 5 H, H(Ph)) ppm. 13C NMR
(100 MHz, CD3OD): δ = 52.1 (OMe), 60.9 (C-4), 64.0 (C-3Ј), 72.1
(C-1Ј), 73.8 (C-2Ј), 84.3 (C-5), 122.1, 125.8 (C-2, C-5), 129.8, 131.9,
133.9 (C-3, C-4, Cq(Ph)), 128.5–131.3 (CH(Ph)), 160.7, 162.4 (2
3
OMe), 4.13 (t, J = 6.9 Hz, 1 H, 2Ј-H), 5.06 (d, J1Ј,2Ј = 6.9 Hz, 1
H, 1Ј-H), 7.32–7.38 (m, 5 H, H(Ph)) ppm. 13C NMR (100 MHz,
CD3OD): δ = 51.9, 52.4 (2 OMe), 63.8 (C-5Ј), 72.4 (C-3Ј), 75.2 (C-
2Ј), 79.6 (C-1Ј), 86.2 (C-4Ј), 123.5, 124.3 (C-2, C-5), 134.0 135.3
(C-3, C-4), 128.2–132.2 (CH(Ph), Cq(Ph)), 162.3 (2 CO) ppm. MS
(CI+, NH ): m/z (%) = 392 [M + H – H O]+. IR: ν = 3427 (NH +
˜
3
2
OH), 1709 (C=O) cm–1. [α]2D0 = –12.3 (c = 1.50, MeOH)
Dimethyl (1ЈS,2ЈS,3ЈR,4ЈR)-3-(1Ј,2Ј,3Ј,4Ј,5Ј-Pentahydroxypentyl)-4-
phenyl-1H-pyrrole-2,5-dicarboxylate [48-(1ЈS)]: This compound was
synthesized according to procedure F. From pyrrole 40-(1ЈS)
(300 mg, 0.35 mmol) and Pd/C (300 mg) in MeOH (3 mL), 48-(1ЈS)
(140 mg, 98%) was obtained. White solid; m.p. 86 °C; Rf (dichloro-
methane/MeOH, 85:15) = 0.60. 1H NMR (400 MHz, CD3OD): δ
= 3.57 (dd, J5Јa,5Јb = 11.2, J5Јa,4Ј = 5.8 Hz, 1 H, 5Јa-H), 3.64 (s, 3
H, OMe), 3.68 (dd, J5Јb,5Јa = 11.2, J5Јb,4Ј = 3.4 Hz, 1 H, 5Јb-H),
3.74–3.82 (m, 2 H, 3Ј-H, 4Ј-H), 3.95 (s, 3 H, OMe), 4.03 (dd, J2Ј,1Ј
= 8.9, J2Ј,3Ј = 5.0 Hz, 1 H, 2Ј-H), 4.86 (d, J1Ј,2Ј = 8.9 Hz, 1 H, 1Ј-H),
7.26–7.38 (m, 5 H, H(Ph)) ppm. 13C NMR (100 MHz, CD3OD): δ
= 51.9, 52.8 (2 OMe), 64.2 (C-5Ј), 69.6 (C-1Ј), 73.9 (C-4Ј), 75.0 (C-
2Ј), 75.8 (C-3Ј), 123.2, 123.4 (C-2, C-5), 132.7, 133.7, 135.1 (C-3,
C-4, Cq(Ph)), 128.2–132.0 (CH(Ph)), 162.3, 163.7 (2 CO) ppm. MS
CO) ppm. IR: ν = 3420 (NH + OH), 1720 (C=O) cm–1. [α]20
=
˜
D
–31.3 (c = 2.05, MeOH). HRMS: calcd. for C18H20NO8 [M + H]+
378.1189; found 378.1174.
Methyl (4S,5S,1ЈR,2ЈR)-4-Hydroxy-7-oxo-3-phenyl-5-(1Ј,2Ј,3Ј-tri-
hydroxypropyl)-1,4,5,7-tetrahydropyrano[3,4-b]pyrrole-2-carboxylate
[50-(4S)]: This compound was synthesized according to procedure
G. From pyrrole 48-(1ЈS) (400 mg, 0.98 mmol) in MeOH (5 mL),
50-(4S) (178 mg, 48%) was obtained after purification by prepara-
tive TLC. White needles; m.p. 142 °C; Rf (dichloromethane/MeOH,
(CI+, NH ): m/z = 410 [M + H]+. IR: ν = 3353 (NH + OH), 1685
˜
3
(C=O) cm–1. [α] = –12.3 (c = 2.14, MeOH).
20
1
85:15) = 0.46. H NMR (400 MHz, CD3OD): δ = 3.63–3.75 (m, 7
436
H, 1Ј-H, 2Ј-H, 3Ј-H, OMe), 4.83 (dd, J5,1Ј = 7.5, J5,4 = 1.6 Hz, 1
H, 5-H), 4.99 (d, J4,5 = 1.6 Hz, 1 H, 4-H), 7.32–7.53 (m, 5 H,
H(Ph)) ppm. 13C NMR (100 MHz, CD3OD): δ = 52.1 (OMe), 61.2
(C-4), 64.1 (C-3Ј), 73.2 (C-1Ј), 73.9 (C-2Ј), 89.1 (C-5), 121.8, 125.5
(C-2, C-5), 129.9, 132.1, 134.0 (C-3, C-4, Cq(Ph)), 128.2–131.3
Dimethyl (1ЈR,2ЈS,3ЈR,4ЈR)-4-Butyl-3-(1Ј,2Ј,3Ј,4Ј,5Ј-pentahy-
droxypentyl)-1H-pyrrole-2,5-dicarboxylate [49-(1ЈR)]: This com-
pound was synthesized according to procedure F. From pyrrole 41-
(1ЈR) (735 mg, 0.88 mmol) and Pd/C (740 mg) in MeOH (7 mL),
49-(1ЈR) (290 mg, 85%) was obtained. Syrup; Rf (dichloromethane/
(CH(Ph)), 159.9, 162.4 (2 CO) ppm. IR: ν = 3439 (NH + OH),
˜
1
MeOH, 85:15) = 0.52. H NMR (400 MHz, CD3OD): δ = 0.94 (t,
1727, 1700 (2 C=O) cm–1. [α]2D0 = +53.2 (c = 1.68, MeOH). HRMS:
3J = 7.3 Hz, 3 H, Hδ(Bu)), 1.36–1.45 (m, 2 H, Hγ(Bu)), 1.47–1.56
(m, 2 H, Hβ(Bu)), 2.74 (m, 1 H, Hα(Bu)), 2.87 (m, 1 H, Hα(Bu)),
3.64–3.69 (m, 2 H, 2Ј-H, 5Јa-H), 3.74–3.83 (m, 3 H, 3Ј-H, 4Ј-H,
calcd. for C18H19NO8Na [M + Na]+ 400.1008; found 400.1009.
Methyl (4R,5S,1ЈR,2ЈR)-3-Butyl-4-hydroxy-7-oxo-5-(1Ј,2Ј,3Ј-trihy-
droxypropyl)-1,4,5,7-tetrahydropyrano[3,4-b]pyrrole-2-carboxylate
[51-(4R)]: This compound was synthesized according to procedure
G. From pyrrole 49-(1ЈR) (197 mg, 0.51 mmol) in MeOH (2 mL),
5Јb-H), 3.87 (s, 3 H, OMe), 3.92 (s, 3 H, OMe), 5.26 (d, J1Ј,2Ј
=
2.8 Hz, 1 H, 1Ј-H) ppm. 13C NMR (100 MHz, CD3OD): δ = 14.2
(Cδ(Bu)), 23.7 (Cγ(Bu)), 25.4 (Cα(Bu)), 34.5 (Cβ(Bu)), 52.0, 52.9 (2
OMe), 64.3 (C-5Ј), 68.4 (C-1Ј), 73.3 (C-3Ј), 74.2 (C-4Ј), 77.7 (C-2Ј), 51-(4R) (69 mg, 38%) was obtained after purification by prepara-
123.0, 123.2 (C-2, C-5), 132.4, 132.5 (C-3, C-4), 162.3, 164.0 (2
tive TLC. Syrup; Rf (dichloromethane/MeOH, 88:12) = 0.28. 1H
NMR (400 MHz, CD3OD): δ = 0.94 (t, J = 7.3 Hz, 3 H, Hδ(Bu)),
3
CO) ppm. IR: ν = 3416 (NH + OH), 1692 (C=O) cm–1. [α]20 = +8.2
˜
D
3308
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3296–3310

Polyhydroxylated Pyrano-Pyrroles from Carbohydrate Precursors
FULL PAPER
1.40 (m, 2 H, Hγ(Bu)), 1.50–1.67 (m, 2 H, Hβ(Bu)), 2.85 (m, 2 H,
Hα(Bu)), 3.74 (dd, J3Јa,3Јb = 11.5, J3Јa,2Ј = 6.6 Hz, 1 H, 3Јa-H), 3.83
(dd, J3Јb,3Јa = 11.5, J3Јb,2Ј = 4.0 Hz, 1 H, 3Јb-H), 3.87 (s, 3 H, OMe),
J1Ј,2Ј = 8.2 Hz, 1 H, 1Ј-H), 7.28–7.40 (m, 5 H, H(Ar)) ppm. 13C
NMR (75 MHz, CD3OD): δ = 64.0 (C-5Ј), 69.5 (C-1Ј), 73.8–75.3
(C-3Ј, C-4Ј), 75.7 (C-2Ј), 123.4, 123.9, 133.4, 135.2 (4 Cpyrrole),
4.00 (m, 1 H, 2Ј-H), 4.19 (dd, J1Ј,5 = 7.9, J1Ј,2Ј = 4.6 Hz, 1 H, 1Ј- 128.1–132.1 (CH(Ar), Cq(Ph)), 163.3, 164.9 (2 CO) ppm. IR: ν =
˜
H), 4.56 (dd, J5,1Ј = 7.9, J5,4 = 2.1 Hz, 1 H, 5-H), 5.00 (d, J4,5
=
3350 (NH + OH) cm–1.
2.1 Hz, 1 H, 4-H) ppm. 13C NMR (100 MHz, CD3OD): δ = 14.2
(Cδ(Bu)), 23.7 (Cγ(Bu)), 25.3 (Cα(Bu)), 34.3 (Cβ(Bu)), 52.1 (OMe),
60.7 (C-4), 63.9 (C-3Ј), 72.1 (C-1Ј), 73.8 (C-2Ј), 84.1 (C-5), 121.5,
126.2 (C-2, C-5), 130.8, 131.8 (C-3, C-4), 160.7, 162.5 (2 CO) ppm.
(1ЈR,2ЈS,3ЈR,4ЈR)-3-Butyl-4-(1Ј,2Ј,3Ј,4Ј,5Ј-pentahydroxypentyl)-
1H-pyrrole-2,5-dicarboxylic Acid [53-(1ЈR)]: This compound was
synthesized according to the general procedure H. From pyrrole
diester 41-(1ЈR) (50 mg, 0.060 mmol) in MeOH (3 mL), 53-(1ЈR)
IR: ν = 3491 (NH + OH), 1715 (C=O) cm–1. [α]20 = +21.2 (c =
˜
D
1
(18 mg) was obtained. Syrup. H NMR (300 MHz, CD3OD): δ =
1.65, MeOH). HRMS: calcd. for C16H24NO8 [M + H]+ 358.1502;
0.94 (t, 3J = 7.3 Hz, 3 H, Hδ(Bu)), 1.27–1.63 (m, 4 H, Hγ(Bu),
Hβ(Bu)), 2.72–2.96 (m, 2 H, Hα(Bu)), 3.69–3.89 (m, 3 H, 4Ј-H, 5Ј-
H), 4.12 (m, 1 H, 3Ј-H), 4.31 (m, 1 H, 2Ј-H), 5.14 (d, J1Ј,2Ј = 7.7 Hz,
1 H, 1Ј-H) ppm. 13C NMR (75 MHz, CD3OD): δ = 14.3 (Cδ(Bu)),
23.9 (Cγ(Bu)), 25.6 (Cα(Bu)), 35.2 (Cβ(Bu)), 63.7 (C-5Ј), 72.5 (C-
3Ј), 76.2 (C-2Ј), 79.3 (C-1Ј), 87.0 (C-4Ј), 120.8, 127.4, 134.7 (4
found 358.1490.
Methyl (4S,5S,1ЈR,2ЈR)-3-Butyl-4-hydroxy-7-oxo-5-(1Ј,2Ј,3Ј-trihy-
droxypropyl)-1,4,5,7-tetrahydropyrano[3,4-b]pyrrole-2-carboxylate
[51-(4S)]: This compound was synthesized according to procedure
G. From pyrrole 49-(1ЈS) (110 mg, 0.28 mmol) in MeOH (2 mL),
51-(4S) (73 mg, 72%) was obtained after purification by prepara-
tive TLC. Syrup; Rf (dichloromethane/MeOH, 86:14) = 0.37. 1H
Cpyrrole), 163.4, 163.7 (2 CO) ppm. IR: ν = 3421 (NH + OH), 1678
˜
(C=O) cm–1.
3
NMR (400 MHz, CD3OD): δ = 0.95 (t, J = 7.3 Hz, 3 H, Hδ(Bu)),
3
(1ЈS,2ЈS,3ЈR,4ЈR)-3-Butyl-4-(1Ј,2Ј,3Ј,4Ј,5Ј-pentahydroxypentyl)-1H-
pyrrole-2,5-dicarboxylic Acid [53-(1ЈS)]: This compound was syn-
thesized according to the general procedure H. From pyrrole dies-
ter 41-(1ЈS) (40 mg, 0.048 mmol) in MeOH (3 mL), 53-(1ЈS)
1.40 (m, 2 H, Hγ(Bu)), 1.56–1.62 (m, 2 H, Hβ(Bu)), 2.86 (t, J =
7.8 Hz, 2 H, Hα(Bu)), 3.68–3.88 (m, 7 H, 1Ј-H, 2Ј-H, 3Ј-H, OMe),
4.79 (dd, J5,1Ј = 6.6, J5,4 = 3.0 Hz, 1 H, 5-H), 5.20 (d, J4,5 = 3.0 Hz,
1 H, 4-H) ppm. 13C NMR (100 MHz, CD3OD): δ = 14.2 (Cδ(Bu)),
23.7 (Cγ(Bu)), 25.4 (Cα(Bu)), 34.2 (Cβ(Bu)), 52.0 (OMe), 61.6 (C-
4), 64.2 (C-3Ј), 73.2 (C-1Ј), 73.7 (C-2Ј), 88.8 (C-5), 121.1, 126.2 (C-
1
(11 mg) was obtained. Syrup. H NMR (400 MHz, CD3OD): δ =
3
0.93 (t, J = 7.2 Hz, 3 H, Hδ(Bu)), 1.39 (m, 2 H, Hγ(Bu)), 1.55 (m,
2 H, Hβ(Bu)), 2.74 (m, 1 H, Hα(Bu)), 2.91 (m, 1 H, Hα(Bu)), 3.68
(dd, J5Јa,5Јb = 11.1, J5Јa,4Ј = 6.0 Hz, 1 H, 5Јa-H), 3.77 (m, 2 H, 3Ј-
H, 5Јb-H), 3.91 (m, 1 H, 4Ј-H), 3.98 (t, 3J = 6.3 Hz, 1 H, 2Ј-H),
4.89 (d, J1Ј,2Ј = 6.9 Hz, 1 H, 1Ј-H) ppm. 13C NMR (100 MHz,
CD3OD): δ = 14.4 (Cδ(Bu)), 23.9 (Cγ(Bu)), 25.4 (Cα(Bu)), 34.8
(Cβ(Bu)), 64.1 (C-5Ј), 70.1 (C-1Ј), 74.2 (C-4Ј), 75.2 (C-3Ј), 77.9 (C-
2, C-5), 130.3, 131.7 (C-3, C-4), 160.2, 162.7 (2 CO) ppm. IR: ν =
˜
3357 (NH + OH), 1714 (C=O) cm–1. [α]2D0 = +16.0 (c = 1.00,
MeOH). HRMS: calcd. for C16H23NO8Na [M + Na]+ 380.1321;
found 380.1325.
General Procedure H Ϫ Debenzylation Followed by Saponification
of the Ester Groups: A solution of benzylated pyrrole in MeOH in
the presence of Pd/C (100% w/w) under H2 was allowed to stir for
1 h at room temperature. The suspension was filtered through a
pad of Celite and the filtrate was evaporated. Aqueous NaOH
(0.5 mL, 2 ) was immediately added to the crude debenzylated
pyrrole intermediate dissolved in THF (2 mL). After total hydroly-
sis as monitored by TLC, acidic resin (Dowex 50W*8) was added
to neutralize the mixture. Filtration through a pad of Celite and
concentration under vacuum gave the diacid. No suitable purifica-
tion methods were found (silica gel, neutral alumina, reversed
phase).
2Ј), 120.6, 128.4, 133.8 (4 Cpyrrole), 164.5 (2 CO) ppm. IR: ν = 3421
˜
(NH + OH), 1678 (C=O) cm–1.
(2R,3R,3aR,8bR)-7-Methoxycarbonyl-3-hydroxy-2-(hydroxymeth-
yl)-5-oxo-8-phenyl-2,3,3a,5,6,8b-hexahydrofuro[2Ј,3Ј:5,6]pyrano-
[3,4-b]pyrrole 54: This compound was synthesized according to pro-
cedure F. From pyrrole 44 (86 mg, 0.13 mmol) and Pd/C (110 mg)
in methanol (2.5 mL), 54 (39 mg, 78%) was obtained. Syrup; Rf
1
(EtOAc) = 0.41. H NMR (400 MHz, CD3OD): δ = 3.65 (m, 1 H,
5Јa-H), 3.76 (s, 3 H, OMe), 3.79 (m, 1 H, 5Јb-H), 3.91 (m, 1 H, 4Ј-
H), 4.39 (m, 1 H, 3Ј-H), 4.92 (m, 1 H, 1Ј-H), 4.99 (m, 1 H, 2Ј-H),
7.39–7.17 (m, 5 H, H(Ar)) ppm. 13C NMR (75 MHz, CDCl3): δ =
52.2 (OMe), 62.7 (C-5Ј), 69.2 (C-1Ј), 73.8 (C-3Ј), 84.1 (C-4Ј), 84.9
(C-2Ј), 121.6, 125.7 (C-2, C-5), 127.6, 130.8, 133.5 (C-3, C-4,
Cq(Ph)), 127.6–131.6 (CH(Ar)), 159.2, 162.1 (2 CO) ppm. MS (EI):
m/z = 359 [M]+.
(1ЈR,2ЈS,3ЈR,4ЈR)-3-(1Ј,2Ј,3Ј,4Ј,5Ј-Pentahydroxypentyl)-4-phenyl-
1H-pyrrole-2,5-dicarboxylic Acid [52-(1ЈR)]: This compound was
synthesized according to the general procedure H. From pyrrole
diester 40-(1ЈR) (92 mg, 0.105 mmol) in MeOH (3 mL), 52-(1ЈR)
1
(60 mg) was obtained. Syrup. H NMR (300 MHz, CD3OD): δ =
3.32 (dd, J5Јa,5Јb = 11.9, J5Јa,4Ј = 4.5 Hz, 1 H, 5Јa-H), 3.42 (dd,
J5Јb,5Јa = 11.9, J5Јb,4Ј = 3.4 Hz, 1 H, 5Јb-H), 3.55–3.64 (m, 2 H, 3Ј-
H, 4Ј-H), 4.21 (dd, J2Ј,1Ј = 7.5, J2Ј,3Ј = 6.3 Hz, 1 H, 2Ј-H), 5.09 (d,
J1Ј,2Ј = 7.5 Hz, 1 H, 1Ј-H), 7.09–7.29 (m, 5 H, H(Ar)) ppm. 13C
NMR (75 MHz, CD3OD): δ = 63.7 (C-5Ј), 72.5, 86.1 (C-3Ј, C-4Ј),
75.8 (C-2Ј), 80.0 (C-1Ј), 123.1, 130.0, 138.0 (4 Cpyrrole), 127.0–132.7
(2R,3R,4S,4aR,9bR)-8-Methoxycarbonyl-3,4-dihydroxy-2-(hy-
droxymethyl)-6-oxo-9-phenyl-2,3,4,4a,7,9b-hexahydro-2H-pyrano-
[2Ј,3Ј:5,6]pyrano[3,4-b]pyrrole (55): This compound was synthesized
according to procedure F. From pyrrole 45 (52 mg, 0.07 mmol) and
Pd/C (50 mg) in methanol (2 mL), 55 (19 mg, 73%) was obtained.
White solid; m.p. 145–146 °C; Rf (EtOAc) = 0.49. 1H NMR
(CH(Ph), Cq(Ph)), 169.1 (2 CO) ppm. IR: ν = 3350 (NH +
˜
(300 MHz, CDCl3): δ = 3.47 (m, 1 H, 6Јa-H), 3.59 (dd, J6Јb,5Ј
=
OH) cm–1.
5.1, J6Јb,6Јa = 11.5 Hz, 1 H, 6Јb-H), 3.70 (m, 1 H, 5Ј-H), 3.77 (s, 3
H, OMe), 3.98 (dd, J3Ј,4Ј = 3.4, J3Ј,2Ј = 6.1 Hz, 1 H, 3Ј-H), 4.05 (t,
(1ЈS,2ЈS,3ЈR,4ЈR)-3-(1Ј,2Ј,3Ј,4Ј,5Ј-Pentahydroxypentyl)-4-phenyl-
1H-pyrrole-2,5-dicarboxylic Acid [52-(1ЈS)]: This compound was J4Ј,3Ј = 3.4 Hz, 1 H, 4Ј-H), 4.60 (dd, J1Ј,2Ј = 3.6, J2Ј,3Ј = 6.1 Hz, 1
synthesized according to the general procedure H. From pyrrole
H, 2Ј-H), 5.19 (d, J1Ј,2Ј = 3.6 Hz, 1 H, 1Ј-H), 7.20–7.40 (m, 5 H,
H(Ar)) ppm. 13C NMR (75 MHz, CDCl3): δ = 50.8 (OMe), 58.6
(C-6Ј), 61.6 (C-1Ј), 66.9 (C-4Ј), 69.4 (C-3Ј), 75.6 (C-5Ј), 81.7 (C-
2Ј), 120.7–132.2 (CH(Ar), 4 Cpyrrole), 158.3, 160.8 (2 CO) ppm. MS
(CI+, NH3): m/z = 407 [M + NH4]+. [α]2D0 = +42.0 (c = 0.23,
diester 40-(1ЈS) (155 mg, 0.178 mmol) in MeOH (3 mL), 52-(1ЈS)
1
(70 mg) was obtained. Syrup. H NMR (300 MHz, CD3OD): δ =
3.51 (dd, J5Јa,5Јb = 11.1, J5Јa,4Ј = 5.8 Hz, 1 H, 5Јa-H), 3.67 (dd,
J5Јb,5Јa = 11.1, J5Јb,4Ј = 3.8 Hz, 1 H, 5Јb-H), 3.71–3.80 (m, 2 H, 3Ј-
H, 4Ј-H), 3.97 (dd, J2Ј,1Ј = 8.2, J2Ј,3Ј = 5.1 Hz, 1 H, 2Ј-H), 4.80 (d, MeOH).
Eur. J. Org. Chem. 2007, 3296–3310
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3309

D. Dubreuil et al.
FULL PAPER
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Methyl (2R,3S,4S,4aR,9bR)-3,4-Dihydroxy-2-(hydroxymethyl)-6-
oxo-9-phenyl-2,3,4,4a,7,9b-hexahydro-2H-pyrano[2Ј,3Ј:5,6]pyrano-
[3,4-b]pyrrole-8-carboxylate (56): This compound was synthesized
according to procedure F. From pyrrole 47 (50 mg, 0.06 mmol) and
Pd/C (20%, 50 mg) in methanol (2 mL), 56 (5 mg, 20%) was ob-
tained. Syrup; Rf (EtOAc) = 0.35. H NMR (300 MHz, CDCl3): δ
= 2.71 (dd, J6Јa,6Јb = 11.5, J6Јa,5 = 2.5 Hz, 1 H, 6Јa-H), 3.03 (m, 1
H, 5Ј-H), 3.36 (m, 1 H, 6Јb-H), 3.48 (t, J4Ј,5Ј = J4Ј,3Ј = 8.9 Hz, 1 H,
1
4Ј-H), 3.74 (s, 3 H, OMe), 3.76 (m, 1 H, 3Ј-H), 4.42 (dd, J2Ј,3Ј
=
8.4, J2Ј,1Ј = 6.0 Hz, 1 H, 2Ј-H), 5.61 (d, J1Ј,2Ј = 6.0 Hz, 1 H, 1Ј-H),
7.26–7.40 (m, 5 H, H(Ar)) ppm. 13C NMR (75 MHz, CDCl3): δ =
50.8 (OMe), 59.6 (C-6Ј), 66.6 (C-1Ј), 68.8 (C-4Ј), 73.2 (C-3Ј), 74.8
(C-5Ј), 81.7 (C-2Ј), 120.7–132.2 (CH(Ar), 4 Cpyrrole), 157.8, 160.7
(2 CO) ppm.
[25] C34H31O4: reflection intensities were collected on a Nonius-
Bruker Kappa CCD diffractometer using Mo-KL2,3 radiation.
C34H31O4 (M = 503.6): monoclinic, space group P21, Dc =
1.267 gcm–3, a = 20.366(4), b = 4.6292(8), c = 14.686(2) Å, β
= 107.63(2)°, V = 1319.5(4), Z = 2, λ = 0.71069 Å, µ =
0.082 mm–1, T = 120 K, R(F2) = 0.071 for 4378 observed reflec-
tions [I Ͼ 2σ(I)] and Rw(F2) = 0.149 for all 5561 reflections.
CCDC-293348 contains 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.
Acknowledgments
This work was supported by the Ministère de l’Education Nation-
ale, de l’Enseignement Supérieur et de la Recherche with a doctoral
fellowship to S. N.
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[36] C18H19NO8·2H2O: The data set was collected on a Nonius-
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tions [I Ͼ 2σ(I)] and Rw(F2) = 0.1179 for all 3971 reflections.
CCDC-290600 contains 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.
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Received: February 6, 2007
Published Online: May 25, 2007
3310
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Eur. J. Org. Chem. 2007, 3296–3310