1-exo-alkylidene-2,3-anhydrofuranoses: Valuable synthons in the preparation of furanose-based templates

Article abstract of DOI:10.1002/ejoc.201000612

Highly functionalized 1-exo-alkylidene-2,3-anhydro-, and 1′-halo-1-exo-alkylidene-2,3-anhydrofuranoses can be prepared in four or five steps, respectively, from D-mannose. These compounds feature a variety of functionalities, including a double bond, an oxirane, an allylic oxirane and (in the case of the 1′-halo derivative) an alkenyl halide. The reactivity of each functionality in these derivatives has been explored, and the usefulness of these substrates has been demonstrated with the preparation of furanose-based carbohydrate templates with up to four sites of molecular diversity. A highly functionalized 1-exo-alkylidene-2,3-anhydro-furanose, available in four steps from D-mannose, is a useful substrate that can be transformed into a variety of furanose derivatives including compounds with up to four sites for diversity.

Full text of DOI:10.1002/ejoc.201000612

FULL PAPER
DOI: 10.1002/ejoc.201000612
1-exo-Alkylidene-2,3-anhydrofuranoses: Valuable Synthons in the Preparation
of Furanose-Based Templates
Ana M. Gómez,*[a] Ana Pedregosa,[a] Clara Uriel,[a] Serafín Valverde,[a] and
J. Cristóbal López*[a]
Keywords: Carbohydrates / Glycals / Molecular diversity / Template synthesis / Epoxidation
Highly functionalized 1-exo-alkylidene-2,3-anhydro-, and
1Ј-halo-1-exo-alkylidene-2,3-anhydrofuranoses can be pre- ity of each functionality in these derivatives has been ex-
pared in four or five steps, respectively, from -mannose. plored, and the usefulness of these substrates has been dem-
These compounds feature a variety of functionalities, includ- onstrated with the preparation of furanose-based carbo-
case of the 1Ј-halo derivative) an alkenyl halide. The reactiv-
D
ing a double bond, an oxirane, an allylic oxirane and (in the
hydrate templates with up to four sites of molecular diversity.
Introduction
Diversity-oriented synthesis (DOS) is now recognized as
a unique tool for the generation of many structurally di-
verse and complex molecules with application in biological
studies.[1] The key elements of a successful DOS include:
i) a reduced number of steps to build up the core scaffolds,
and ii) the efficient use of chemical reactions to increase
diversity and complexity in the development of the library.
On the other hand, the design of novel molecular platforms
that allow stereodetermined, three-dimensional orientations
of pharmacophores remains an important goal in drug dis-
covery[2] approachable through diversity-oriented synthesis
(DOS). In this context, the successful use of carbohydrates
as scaffolds in the area of peptidomimetics[3] has triggered
a considerable research effort on the use of sugar derivatives
as templates in bioactive compound discovery.[4] Carbo-
hydrate templates have consequently been generated from
pyranoses, furanoses, disaccharides and bicyclic sugar de-
rivatives, with most of the strategies for their construction
having been based on the stepwise derivatization of orthogo-
nally protected carbohydrate derivatives.[5–7]
We have recently embarked on a project relating to the
design of novel furanose-based scaffolds by chemoselective
transformations of a core structure. With this in mind, we
selected compound types 1 and 2 (Figure 1). These deriva-
tives fulfil conditions i) and ii) described above for the suc-
cessful implementation of DOS strategies. Compound types
1 and 2 are readily available from inexpensive -mannose,
in four and five steps, respectively, and can be subjected to
simple chemical reactions that lead to diversified platforms
Figure 1. The epoxy-exo-glycals 1 and the halo epoxy-exo-glycals
2, precursors of the furanose-based templates 3.
(e.g., 3) in which the (three) different substituents can be
incorporated sequentially and in a completely stereocon-
trolled manner.
Compounds 1 each possess a variety of functionalities:
an exocyclic double bond, an oxirane, and – if the two are
combined – an allylic oxirane, amenable to a variety of
chemical transformations. Compounds 2, available by
stereoselective halogenation of 1, each incorporate an ad-
ditional alkenyl halide component as well as the previously
listed functionalities. We have been investigating the reactiv-
ity of derivatives 1 and 2 and in this manuscript we disclose
in detail our studies directed towards: i) exploring the reac-
tivity of the different functionalities, and ii) the develop-
ment of stepwise transformations of 1 and 2 into furanose-
based templates of type 3.
Results and Discussion
Synthesis of Epoxy-exo-glycals from D-Mannose
The synthetic strategy for epoxy-exo-glycals[8] (i.e., com-
pounds 1) takes advantage of the straightforward prepara-
View this journal online at
[a] Instituto de Química Orgánica General, CSIC,
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34-915644853
E-mail: anagomez@iqog.csic.es
clopez@iqog.csic.es
wileyonlinelibrary.com
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tion of C-1 glycals such as compounds 5 (Scheme 1) from TBAT).[17] Accordingly, treatment of 1a with bromine and
-mannose through the transformation of intermediate gly- with IDCT gave the halo-exo-glycals 2a and 2b in a
cosyl chlorides of type 4 with the aid of organolithium rea- stereocontrolled manner and in 63% and 70% yields,
gents[9] recently described by us.[10] Subsequent treatment of respectively. The Z derivatives were obtained as the sole iso-
the C-1 glycals 5a–c with bromine in triethylamine gave ac- mers (Scheme 3, a and b). On the other hand, treatment of
cess to the epoxy-exo-glycals 1a–c.[11]
1a with TBAT furnished a 7:1 mixture of isomeric (Z)- and
(E)-2a (Scheme 3, c). This mixture could be efficiently
transformed into the dibromo exo-glycal 9 by further treat-
ment with TBAT (Scheme 3, d).
Scheme 1. Strategies for the synthesis of substituted exo-glycals.
Remarkably, the one-pot process 5Ǟ1 (Scheme 1) in-
volves three well-established transformations in carbo-
hydrate chemistry: i) the bromination of glycals, pioneered
by Lemieux and Fraser-Reid,[12] ii) the formation of epox-
ides from halohydrins,[13] and iii) the base-mediated elimi-
nation of anomeric halides[14] (Scheme 2). Two possible re-
action pathways for this transformation, differing in the or-
der in which steps ii) and iii) might take place, can accord-
ingly be proposed.
Scheme 3. Electrophilic halogenation of the exo-glycals 1a and 2a.
The stereochemical outcomes of these reactions have
been interpreted previously.[18,19] In the formation of 2b, the
s-collidine released in situ could abstract a proton from a
1-iodomethyloxocarbenium ion, in which the bulky iodine
atom would be located away from the oxirane ring (Fig-
ure 2, A). Likewise, a related preferred rotamer, in which
the bromine atom is away from the epoxide, could experi-
ence NEt3-induced HBr elimination leading to 2a (Figure 2,
B).
Scheme 2. One-pot transformation of the furanosidic C-1 glycals 5
into the epoxy-exo-glycals 1.
In our opinion, the sequence will probably start with the
stereoselective bromination of the electron-rich double
bond[15] (step i, Scheme 2) to furnish the dibromide 6. No
reaction intermediate (7 or 8) has ever been observed (TLC)
in these transformations, so a 6Ǟ8Ǟ1 pathway involving
a reactive allylic bromide seems more likely.
Figure 2. Proposed reaction pathways leading to 2b and to 2a.
We also studied the hydrogenation of the enol ether
double bond. Treatment of 1a under typical hydrogenation
Reactions at the Exocyclic Olefin
We have studied the reactivity of the enol ether double conditions (H2, Pd/C, EtOH, 25 psi) led to the furan deriva-
bond in the exo-glycal 1a towards a number of halogenating tive 10 (Scheme 4, a). Additional hydrogenation attempts
agents: bromine, iodonium dicollidine triflate (IDCT)[16] in the presence of different catalysts, such as Pd(OH)2 or
and tetra-n-butylammonium tribromide (nBu4NBr3, supported Pd,[20] gave similar results, which serves to illus-
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Preparation of Furanose-Based Templates
trate the ease with which aromatization takes place in these
systems.[21] The use of EtOAc as solvent also gave similar
results (Scheme 4, b).
Scheme 5. Reactivity of the double bond in the exo-glycal 1a.
As already reported by us,[26] compound 1a reacted with
a series of amines in ethanol at reflux to give 2-deoxy-2-
amino derivatives (11, 13 and 19–25, Figure 3). Similarly,
the epoxy-exo-glycals 1b and 1c underwent regioselective
Scheme 4. Hydrogenation of the exocyclic double bonds in exo- ring-opening to give amino alcohols such as 26 and 27 (Fig-
glycals.
ure 3).
Conversely, the absence of the oxirane ring in the mole-
cule renders the hydrogenation process possible (Scheme 4,
c and d). The stereochemistry at the newly created ste-
reogenic centre in compound 12 was assigned through an
observed NOESY between H2 and the methyl group at C1.
Hydroboration of 1a with BH3SMe2, followed by oxi-
dation (NaOH, H2O2), proved to be completely stereoselec-
tive, and furnished the C-1 glycal 15 in 81% yield
(Scheme 5, a). Treatment of 1a with IDCT in the presence
of H2O yielded the ketose 16 in moderate yield (37%,
Scheme 5, b).[22] Treatment of 1a with BF3·Et2O in the pres-
ence of ethylene glycol yielded a bicyclic derivative from
which compound 17 could be obtained after acetylation
(61% yield, Scheme 5, c). The formation of compound 17
involves three processes: i) acid-mediated glycosylation of
the exo-glycal double bond,[23] most probably followed by
ii) intramolecular acid-catalysed regioselective epoxide ring-
opening, and iii) acetal deprotection, probably through eth-
ylene-glycol-mediated transacetonation. Acetylation of the
intermediate to afford 17 proved necessary for rigorous as-
signment of the location of the 2-OAc group. H-2 appeared
as a doublet at δ = 5.08 ppm, whereas H-3 showed as a dd
at δ = 3.65 ppm. Finally, ozonation of 1a gave access to the
epoxy-lactone 18, in 79% yield (Scheme 5, d).
Reactions at the Oxirane Ring
Figure 3. Amino alcohols prepared by nucleophilic ring-opening of
the epoxy exo-glycals 1a–c.
Nucleophilic ring-opening reactions of furanose-derived
2,3-oxiranes are well documented. Lowary and co-workers
studied the regiochemistry of the nucleophilic ring-opening
The behaviour of the 1Ј-bromo- and 1Ј-iodo-epoxy-exo-
of isomeric alkyl 2,3-epoxy furanosides,[24] whereas Hirota glycals 2a and 2b, respectively, towards amines proved to
and co-workers studied the nucleophilic ring-opening of fu- be similar, and their treatment with (primary or secondary)
ranosidic allylic oxirane systems, more closely related to our amines in ethanol at reflux led to the 2-deoxy-2-amino de-
derivatives.[25]
rivatives 28–30 without any effect on the anomeric alkenyl
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halide moiety (Figure 4). Higher yields of amino alcohols Reactions at the Allylic Oxirane Moiety
were consistently observed for the bromo derivatives than
for the iodine-containing compounds, probably due to the
greater lability of the latter compound class.
We had already evaluated the reactivity of the allylic ep-
oxide moiety in 1a towards palladium. Compound 1a is
able to react smoothly (through the π-allyl palladium com-
plex 36,[27] Scheme 6) with nucleophiles,[11] vinylstann-
anes[27,28] or, after treatment with ZnEt2, with electro-
philes[29] to give highly functionalized C-1 glycals[27,30] such
as 37–39.
Figure 4. Amino alcohols obtained by nucleophilic ring-opening of
the 1Ј-halo-exo-glycals 2a and 2b.
We next examined the nucleophilic ring-opening of the
allylic oxiranes 1 and 2 with hydroxide anion, to provide
allylic diol derivatives (e.g., 31–35, Table 1). Two sets of
conditions were examined, and the best results were ob-
tained by treatment of the epoxides with nBu4NOH in
THF/H2O (3:1) at reflux. Under such reaction conditions
the corresponding diols (or their acetates) could be ob-
tained in moderate yields.
Scheme 6. Pd0-catalysed reactions of the vinyl oxirane 1a with nu-
cleophiles, electrophiles and vinylstannanes.
On the other hand, treatment of 1a with sodium azide in
DMF at 50 °C yielded the primary allylic azide 40 in 62%
yield as the only isolated product (Scheme 7). Its structure
was rigorously assigned by NMR spectroscopy. Two dou-
blets, one at δ = 3.84 ppm (J = 2.6 Hz, 2 H) and the second
at δ = 5.22 ppm (J = 2.6 Hz, 1 H), corresponding to H-1Ј
and H-2, respectively, were observed. Additionally, by 13C
NMR spectroscopy, signals were observed at δ = 102.3 and
157.4 ppm and at 47.1 ppm, corresponding to an endocyclic
double bond and to CH2N3, respectively. Compound 40
should be the result of a formal SN2Ј opening of the allylic
epoxide, although a reaction pathway involving SN2 open-
ing of the oxirane followed by sigmatropic rearrangement
of an intermediate allylic azide to the thermodynamically
more stable 40 could not be ruled out on the basis of the
reactivities found in related allylic epoxides by Pauls and
Fraser-Reid.[31]
Table 1. Nucleophilic oxirane ring-opening of the allylic epoxides
1a–c and 2a and 2b with H2O.
Scheme 7. Reaction of allylic epoxide 1a with sodium azide.
Reactions at the Alkenyl Halide Component – Generation
of Furanosidic Libraries with Two Sites of Diversity
In order to generate a library of furanosidic derivatives
each possessing two diversity points, we decided to exploit
the reactivity of the vinyl halide moieties in the amino
[a] Bu4NOH (2 equiv.), THF/H2O (3:1) reflux. [b] Characterized as
its diacetate. [c] KOH (5%, 3 mLmmol–1), 40 °C. [d] Followed by
acetylation: Ac2O, pyridine.
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Preparation of Furanose-Based Templates
alcohols 28–30. We had previously shown that structurally The observed reaction times varied from 24 to 72 h, and
related vinyl halides could be engaged in a variety of palla- the isolated yields of allylic amines ranged from 60% to
dium-catalysed reactions,[32] including Suzuki cross-cou- 90%.
plings,[33,34] leading to monosubstituted exo-glycals. We
thus carried out Suzuki couplings between the vinyl halides
Generation of Furanodisic Libraries Possessing Three – or
More – Sites for Diversity
28–30 and the boronic acids 42–44 to give the allylic amines
41, and our results are displayed in Table 2. Treatment of
the vinyl halides 28–30 with the boronic acids 42–44
(1.3 equiv.) in the presence of Pd(PPh3)4 (5%) and NaOH
(2 , 2.7 equiv.) in THF/H2O (4 mLmmol–1) at reflux led
to the allylic derivatives 41a–i in moderate to good yields.
The derivatives 41a–i, resulting from oxirane opening fol-
lowed by palladium-catalysed cross-coupling, already each
incorporate two substituents. Moreover, the presence of the
3-OH and the 5,6-O-isopropylidene acetal components
makes further derivatization of these derivatives possible.
To illustrate this point we performed the transformations of
the amino alcohols 45a and 47 into 45b, 46 and 48
(Scheme 8), thus laying the foundations for syntheses of ad-
ditional furanose-based libraries.
Table 2. Suzuki cross-couplings between the 1Ј-halo-exo-glycals 28,
29 and 30 and the boronic acids 42–44, catalysed by Pd(PPh3)4 in
the presence of NaOH, in THF/H2O as solvent at reflux.
Scheme 8. Furanose derivatives 46 and 48, each with more than
three points of diversity.
Accordingly, acetylation of 45a led to the acetate 45b,
possessing three points of diversity. Interestingly, the enol
ether double bond in 45b displayed an enhanced stability
towards acid, and consequently the 5,6-O-isopropylidene
group acetal could be removed without the anomeric func-
tionality being affected, thus affording the diol 46.
Similarly, treatment of the amino alcohol 47 with AcOH/
THF/H2O (4:2:1) under reflux yielded the triol 48.
These compounds already each possess more than three
sites for structural diversity.
Conclusions
The highly functionalized exo-glycal 1a is a useful syn-
thetic intermediate for the preparation of furanose-based
libraries. This compound contains an allylic epoxide moiety
that can undergo chemoselective reactions variously at the
double bond, at the epoxide or at the allylic oxirane system.
Halogenation of the double bond gives rise to the syntheti-
cally useful 1Ј-halo-epoxy-exo-glycals 2. Attempted hydro-
genation of 1a led to furan formation, but hydrogenation
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A. M. Gómez, A. Pedregosa, C. Uriel, S. Valverde, J. C. López
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the C-methyl glycal 5a (5.0 g, 25 mmol) by the General Procedure.
Purification (hexane/EtOAc 95:5) afforded the oxirane 1a (4.2 g,
85%): m.p. 41–42 °C, [α]2D5 = +56.2 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.32 (s, 3 H, Me), 1.40 (s, 3 H, Me), 3.87–
4.16 (m, 6 H), 4.32 (d, J = 2.0 Hz, 1 H, 1Ј-H), 4.44 (d, J = 2.0 Hz,
1 H, 1Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.0, 26.6, 55.2,
57.1, 66.9, 72.9, 79.9, 87.3, 109.3, 157.2 ppm. API-ES positive 199.1
[M + H]+. C10H14O4 (198.09): calcd. C 60.59, H 7.12; found C
60.37, H 7.03.
of exo-glycals not containing the oxirane ring permits the
hydrogenation to occur without aromatization. Addition-
ally, this process takes place in a stereocontrolled manner,
probably due to the presence of the bulky β-oriented 5,6-
O-isopropylidene ring. The oxirane moiety undergoes ring-
opening with nitrogen nucleophiles or hydroxide in a com-
pletely regioselective manner, thus leading to allylic amino
alcohols and allylic diols, respectively. Nucleophilic ring-
opening of the oxirane ring in a 1Ј-halo-epoxy-exo-glycal
leaves the vinyl halide functionality unreacted, so that it can
be engaged in Suzuki cross-coupling reactions with boronic
acids, thus allowing the generation of a library of furanose-
based allylic amines. These amines each still bear a C3–OH
component and a 5,6-isopropylidene acetal unit suitable for
further transformations. Acylation can then be performed
at O-3, to incorporate a third substituent. Remarkably,
these derivatives undergo acid-mediated chemoselective 5,6-
O-isopropylidene ring-opening without aromatization to
the corresponding furan derivatives.[21] Diols such as 46 and
triols such as 48 can be readily prepared, ready for further
derivatization. Additional transformations on these deriva-
tives are under investigation and will be reported in due
course.
(1S,4R,5S)-2-Butylidene-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,6-di-
oxabicyclo[3.1.0]hexane (1b): This compound was prepared from
the C-butyl glycal 5b (150 mg, 0.6 mmol) by the General Procedure.
Purification (hexane/EtOAc 95:5) afforded the oxirane 1b as a mix-
ture of isomers (96 mg, 65%). For the major isomer: 1H NMR
(300 MHz, CDCl3): δ = 0.87 (t, J = 7.3 Hz, 3 H, Me), 1.30 (m, 2
H, CH2), 1.36 (s, 3 H, Me), 1.44 (s, 3 H, Me), 2.04 (m, 2 H, CH2),
3.85 (br. s, 1 H, 2-H), 3.95–4.20 (m, 5 H), 4.71 (t, J = 7.3 Hz, 1 H,
1Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9, 22.8, 25.5, 27.0,
27.3, 56.1, 57.5, 67.3, 73.5, 79.8, 104.9, 109.7, 150.2 ppm. API-ES
positive 241.1 [M + H]+. C13H20O4 (240.14): calcd. C 64.98, H 8.39;
found C 64.81, H 8.19.
(1S,4R,5S)-2-(Butan-2-ylidene)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-
3,6-dioxabicyclo[3.1.0]hexane (1c): This compound was prepared
from the C-butyl glycal 5c (150 mg, 0.6 mmol) by the General Pro-
cedure. Purification (hexane/EtOAc 95:5) afforded the oxirane 1c
as a mixture of isomers (89 mg, 60%). For the major isomer: 1H
NMR (300 MHz, CDCl3): δ = 1.06 (t, J = 7.3 Hz, 3 H, Me), 1.39
(s, 3 H, Me), 1.46 (s, 3 H, Me), 1.66 (s, 3 H, Me), 2.16 (q, J =
7.3 Hz, 2 H, CH2), 4.0–4.26 (m, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 13.6, 14.0, 25.2, 25.8, 26.8, 52.9, 57.8, 67.2, 73.3, 78.9,
109.5, 114.7, 144.8 ppm. EI-MS 240.1 [M]+. C13H20O4 (240.14):
calcd. C 64.98, H 8.39; found C 64.79, H 8.33.
Experimental Section
General Remarks: All reactions were performed in dry flasks fitted
with glass stoppers or rubber septa under a positive pressure of
Ar, unless otherwise noted. Air- and moisture-sensitive liquids and
solutions were transferred by syringe or stainless steel cannula. Op-
tical rotations were determined for solutions in chloroform. Flash
column chromatography was performed with 230–400 mesh silica
gel. Thin-layer chromatography was conducted with Kieselgel
60 F254 (Merck). Spots were observed first under UV irradiation
(254 nm) and then by charring with a solution of 20% aqueous
H2SO4 (200 mL) in AcOH (800 mL). Anhydrous MgSO4 or
Na2SO4 were used to dry organic solutions during workup, and
evaporation of the solvents was performed under vacuum with a
rotary evaporator. Solvents were dried and purified by standard
methods. Unless otherwise noted 1H and 13C NMR spectra were
recorded in CDCl3 at 300 MHz and 50 MHz, respectively. Chemi-
cal shifts are expressed in parts per million (δ scale) downfield from
tetramethylsilane and are referenced to residual protium in the
NMR solvent (CHCl3: δ = 7.25 ppm). The numbering pattern used
(1S,4R,5S,Z)-2-(Bromomethylene)-4-(2,2-dimethyl-1,3-dioxolan-4-
yl)-3,6-dioxabicyclo[3.1.0]hexane (2a): A solution of the oxirane 1a
(200 mg, 1.01 mmol) and Et3N (2 mL) in dry CH2Cl2 (5 mL) was
cooled to 0 °C under argon and a solution of Br2 (52 µL, 161 mg,
1.1 mmol) in CH2Cl2 (2 mL) was added dropwise. The reaction
mixture was allowed to warm to room temperature and stirred
overnight, after which the mixture was washed with aqueous so-
dium thiosulfate (10%) containing sodium hydrogen carbonate and
then with water. The organic layer was dried and concentrated, and
the residue was purified by flash chromatography (hexane/EtOAc
95:5) to give the bromide 2a (174 mg, 63%) followed by recovered
starting material (58 mg, 29%). For (Z)-2a: m.p. 69–70 °C, [α]2D5
=
1
+56.2 (c = 1.0, CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.38 (s,
3 H, Me), 1.47 (s, 3 H, Me), 4.01–4.26 (m, 6 H), 5.43 (d, J = 2.0 Hz,
1 H, 1Ј-H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.1, 26.9, 55.3,
58.0, 67.1, 72.8, 79.7, 80.7, 109.7, 153.6 ppm. API-ES positive 299.0
[M + Na]+, 301.0 [M + Na + 2]+. C10H13BrO4 (276.00): calcd. C
43.34, H 4.73; found C 43.41, H 4.59.
1
for the H NMR is illustrated below.
(1S,2R,5S,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-(iodomethylene)-
3,6-dioxabicyclo[3.1.0]hexane (2b): A solution of the oxirane 1a
(150 mg, 0.75 mmol) in dry CH2Cl2 (5 mL) was cooled to 0 °C un-
der argon, activated molecular sieves (3 Å, 2 g) and IDCT (425 mg,
0.82 mmol) were added, and the reaction mixture was stirred for
15 min. After removal of the molecular sieves, the filtrate was
washed with aqueous sodium thiosulfate (10%) containing sodium
hydrogen carbonate and then with water. The organic layer was
dried and concentrated, and the residue was purified by flash
General Procedure for the Synthesis of Epoxy-exo-glycals (1): A
solution of Br2 (1.1 mmol) in CH2Cl2 (0.5 mL) was added dropwise
to a cooled (0 °C) solution of the corresponding C-1 alkyl glycal 5
(1 mmol) in CH2Cl2 (10 mL) containing Et3N (2 mL). The mixture
was stirred at room temperature overnight, after which the reaction
mixture was diluted with CH2Cl2 and washed with aqueous sodium
thiosulfate (10%) and water. The organic layer was then dried and
concentrated and the residue was purified by flash chromatography.
chromatography (hexane/EtOAc 90:10) to give the iodide 2b
1
(1S,2R,5S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-methylene-3,6-di- (70 mg, 70%). [α]2D5 = +57.0 (c = 0.9, CHCl3). H NMR (CDCl3,
oxabicyclo[3.1.0]hexane (1a): This compound was prepared from
300 MHz): δ = 1.37 (s, 3 H, Me), 1.46 (s, 3 H, Me), 4.02–4.22 (m,
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Preparation of Furanose-Based Templates
6 H), 5.28 (br. s, J = 2.0 Hz, 1 H, 1Ј-H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 25.4, 27.1, 48.1, 55.0, 58.6, 67.3, 73.1, 80.7, 110.0,
158.1 ppm. API-ES positive 325 [M + H]+.
(2S,3R,4R,5S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-methyl-4-(phen-
ethylamino)tetrahydrofuran-3-ol (12): Compound 11 (150 mg,
0.49 mmol) was subjected to General Procedure A to give com-
pound 12 (149 mg, 95%) as a colourless oil after silica gel column
chromatography (hexane/EtOAc 2:8). [α]2D5 = +25.0 (c = 1.0,
(1S,4R,5S,E)-2-(Bromomethylene)-4-(2,2-dimethyl-1,3-dioxolan-4-
yl)-3,6-dioxabicyclo[3.1.0]hexane [(E)-2a]: A mixture of Br2
(307 µL, 6.0 mmol) and nBu4NBr (1.9 g, 6 mmol) in CH2Cl2
(10 mL) was added under argon to a solution of the epoxide 1a
(400 mg, 2.0 mmol) in CH2Cl2. The resulting solution was stirred
for 10 min, after which Et3N (836 µL, 6 mmol) was added. After
the starting material had been consumed (10 min) the reaction mix-
ture was washed with aqueous sodium thiosulfate (10%) containing
sodium hydrogen carbonate and then with water. The organic layer
was dried and concentrated, and the residue was purified by flash
chromatography (hexane/EtOAc 95:5) to give the oxirane 2a
(397 mg, 72%) followed by the oxirane (E)-2a (55 mg, 10%). For
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.32 (d, J = 6.2 Hz, 3
H, Me), 1.33 (s, 3 H, Me), 1.40 (s, 3 H, Me), 2.85 (m, 3 H, CH2
and 2-H), 2.96 (m, 2 H, CH2), 3.64 (q, J = 6.2 Hz, 1 H, 1-H), 3.76
(dd, J = 4.6, 8.2 Hz, 1 H, 4-H), 3.91 (dd, J = 5.3, 8.4 Hz, 1 H, 6-
H), 4.13 (dd, J = 6.2, 8.6 Hz, 1 H, 6-H), 4.18 (dd, J = 2.4, J =
4.6 Hz, 1 H, 3-H), 4.30 (ddd, J = 5.5, 6.1, 8.2 Hz, 1 H, 5-H), 7.18–
7.47 (m, 5 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz): δ = 20.1,
25.4, 26.9, 36.0, 49.5, 67.9, 73.0, 74.2, 78.4, 80.3, 81.9, 109.5, 126.5,
128.7 (ϫ2), 128.8 (ϫ2), 139.4 ppm. API-ES positive 322.3 [M +
H]+. C18H27NO4 (321.19): calcd. C 67.26, H 8.47, N 4.36; found C
67.01, H 8.56, N 4.44.
1
(E)-2a: H NMR (CDCl3, 300 MHz): δ = 1.38 (s, 3 H, Me), 1.47
(s, 3 H, Me), 3.93 (dd, J = 9.0, 8.1 Hz, 1 H), 4.07–4.12 (m, 3 H),
4.19 (m, 1 H), 4.35 (m, 1 H), 5.67 (s, 1 H, 1Ј-H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 25.0, 26.7, 54.2, 56.8, 66.8, 72.9, 80.8, 83.1,
109.5, 154.2 ppm. API-ES positive 299.0 [M + Na]+, 301.0 [M +
Na + 2]+. C10H13BrO4 (275.9996): calcd. C 43.34, H 4.73; found C
43.27, H 4.62.
(2S,3R,4R,5S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-[4-(2-meth-
oxyphenyl)piperazin-1-yl]-5-methyltetrahydrofuran-3-ol (14): Com-
pound 13 (150 mg, 0.38 mmol) was subjected to General Pro-
cedure A to give compound 14 (144 mg, 97%) as a colourless oil
after silica gel column chromatography (hexane/EtOAc 1:9). [α]2D5
1
= +13.8 (c = 0.3, CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.36
(s, 3 H, Me), 1.40 (d, J = 6.1 Hz, 3 H, Me), 1.43 (s, 3 H, Me), 2.60
(dd, J = 2.2, 6.9 Hz, 1 H, 2-H), 2.73 (m, 2 H, CH2–N), 2.86 (m, 2
H, CH2–N), 3.10 (br. s, 4 H, 2ϫ CH2–N), 3.70 (dd, J = 4.5, 8.4 Hz,
1 H, 4-H), 3.86 (s, 3 H, OMe), 3.93 (q, J = 6.6 Hz, 1 H, 1-H), 3.96
(dd, J = 5.0, 8.4 Hz, 1 H, 6-H), 4.16 (dd, J = 6.2, 8.5 Hz, 1 H, 6-
H), 4.32 (ddd, J = 5.1, 6.1, 8.4 Hz, 1 H, 5-H), 4.47 (dd, J = 2.2,
4.6 Hz, 1 H, 3-H), 6.94 (m, 5 H, Harom) ppm. 13C NMR (CDCl3,
50 MHz): δ = 21.1, 25.5, 27.1, 50.8 (ϫ2), 51.8 (ϫ2), 55.6, 68.1,
74.3, 75.6, 77.1, 80.9, 82.7, 109.6, 111.3, 118.4, 121.2, 123.3, 141.2,
152.4. API-ES positive 393.2 [M + H]+. C21H32N2O5 (392.23):
calcd. C 64.26, H 8.22, N 7.14; found C 64.35, H 8.13, N 7.23.
(1S,4R,5S)-2-(Dibromomethylene)-4-(2,2-dimethyl-1,3-dioxolan-4-
yl)-3,6-dioxabicyclo[3.1.0]hexane (9): A mixture of Br2 (160 µL,
3.0 mmol) and nBu4NBr (950 mg, 3 mmol) in CH2Cl2 (5 mL) was
added under argon to a solution of the epoxides 2a and (E)-2a
(277 mg, 1.0 mmol) in CH2Cl2. The resulting solution was stirred
for 10 min, after which Et3N (420 µL, 3 mmol) was added. After
the starting material had been consumed (10 min) the reaction mix-
ture was washed with aqueous sodium thiosulfate (10%) containing
sodium hydrogen carbonate and then with water. The organic layer
was dried and concentrated, and the residue was purified by flash
chromatography (hexane/EtOAc 95:5) to give the dibromide 9
(397 mg, 70%): [α]2D5 = +60.4. (c = 1.0, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 1.37 (s, 3 H, Me), 1.46 (s, 3 H, Me), 3.99–4.04 (m,
1 H), 4.10–4.19 (m, 2 H), 4.22 (m, 2 H), 4.35 (d, J = 2.7 Hz, 1
H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.1, 26.9, 55.4, 58.0,
66.9, 68.3, 72.9, 81.4, 109.8, 152.3 ppm. API-ES positive 354.9 [M –
2]+, 356.9 [M]+, 358.9 [M + 2]+.
[(1R,2S,4R,5R)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3,6-dioxabi-
cyclo(3.1.0)hexan-2-yl]methanol (15): BH3·SMe2 (142 µL, 1.5 mmol,
3 equiv.) was slowly added to a cooled (0 °C) solution of the exo-
glycal 1a (100 mg, 0.5 mmol) in dry THF (5 mL). The resulting
solution was allowed to warm to room temperature and was then
stirred for two hours, after which it was recooled to 0 °C and
treated with aqueous NaOH solution (10%, 5 mL) and hydrogen
peroxide (30%, 5 mL). The reaction mixture was stirred overnight,
diluted with diethyl ether and washed with NaCl. The aqueous
phase was back-extracted with diethyl ether. The combined organic
phases were concentrated and the residue was purified by flash
chromatography (hexane/EtOAc 1:1) to give the alcohol 15
(87.5 mg, 81%) as a colourless oil. [α]2D5 = +18.0 (c = 0.4, CHCl3).
1H NMR (CDCl3, 300 MHz): δ = 1.32 (s, 3 H, Me), 1.39 (s, 3 H,
Me), 3.76 (m, 5 H), 3.86 (dd, J = 4.8, 8.3 Hz, 1 H, 6-H), 3.94 (t, J
= 5.5 Hz, 1 H), 4.09 (m, 2 H, CH2OH) ppm. 13C NMR (CDCl3,
50 MHz): δ = 25.2, 26.8, 56.4, 56.8, 61.8, 67.2, 73.8, 78.1, 78.5,
109.3 ppm. API-ES positive 217 [M + H]+, 234 [M + NH4]+, 239
[M + Na]+. C10H16O5 (216.10): calcd. C 55.55, H 7.46; found C
55.67, H 6.98.
General Procedure A. Pd/C-Catalysed Hydrogenation in a Parr Ap-
paratus: Argon was passed through a solution of the compound
(ca. 50–75 µmol) in EtOH (10 mL) for 5 min, after which a catalytic
amount of Pd/C (20 mg, 10 wt.-% Pd on C) was added. The reac-
tion vessel was placed under vacuum and subsequently ventilated
with hydrogen gas. This cycle was repeated one more time, after
which the vessel was placed under 25 psi of hydrogen gas and me-
chanically shaken for 1 h. The Pd/C was removed by filtration
through a Celite path, followed by thorough rinsing of the filter
cake with MeOH. The filtrate was concentrated under vacuum and
the residue was purified by silica gel flash chromatography.
(R)-2,2-Dimethyl-4-(5-methylfuran-2-yl)-1,3-dioxolane (10): Com-
pound 1a (150 mg, 0.75 mmol) was subjected to General Pro-
cedure A to give compound 10 (139 mg, 98%) as a colourless oil
after silica gel column chromatography (hexane/EtOAc 95:5). [α]2D5
(1S,4R,5S)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-(iodomethyl)-3,6-di-
oxabicyclo[3.1.0]hexan-2-ol (16): IDCT (427 mg, 0.82 mmol) was
added to a well stirred CH2Cl2/H2O (5 mL, 9:1, v/v) solution of
1
= +68.0 (c = 0.6, CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.46
(s, 3 H, Me), 1.52 (s, 3 H, Me), 2.30 (s, 3 H, Me), 4.10 (dd, J =
7.8, 8.0 Hz, 1 H, 6-H), 4.21 (dd, J = 6.3, 8.0 Hz, 1 H, 6-H), 5.04 the exo-glycal 1a (150 mg, 0.75 mmol). After the mixture had been
(dd, J = 6.4, 7.8 Hz, 1 H, 5-H), 5.94 (d, J = 3.1 Hz, 1 H, 3-H), 6.25
(d, J = 3.0 Hz, 1 H, 2-H) ppm. 13C NMR (CDCl3, 50 MHz): δ =
25.9, 26.3, 28.2, 67.6, 71.3, 106.2, 109.1, 109.6, 149.3, 152.8 ppm.
API-ES positive 183 [M + H]+. C10H14O3 (182.09): calcd. C 65.91,
H 7.74; found C 65.70, H 7.83.
stirred for 15 min, TLC analysis showed complete disappearance
of the starting material. The reaction mixture was quenched by
addition of aq. Na2S2O3 and subsequently extracted with CH2Cl2.
The combined organic phases were dried and concentrated. The
residue was purified by silica gel column chromatography (hexane/
Eur. J. Org. Chem. 2010, 5619–5632
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5625

A. M. Gómez, A. Pedregosa, C. Uriel, S. Valverde, J. C. López
FULL PAPER
EtOAc 9:1) to provide the ketose 16 (95 mg, 37 %). 1H NMR
(CDCl3, 300 MHz): δ = 1.35 (s, 3 H, Me), 1.43 (s, 3 H, Me), 2.48
300 MHz): δ = 1.36 (s, 3 H, Me), 1.43 (s, 3 H, Me), 2.80–2.88 (m,
2 H), 2.88–2.9 (m, 1 H), 2.9–3.09 (m, 1 H), 3.54 (s, 1 H, 2-H), 3.99
(s, 1 H, OH), 3.42 (m, 1 H, CH2–I), 3.79 (d, J = 2.8 Hz, 1 H), 4.01 (m, 1 H, 6-H), 4.0 (s, 1 H, 1Ј-H), 4.2–4.15 (m, 2 H, 6-H, 3-H), 4.24
(m, 5 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 9.9, 25.5, 27.0,
(dd, J = 3.4, 8.4 Hz, 1 H, 4-H), 4.33 (m, 1 H, 5-H), 4.37 (s, 1 H,
1Ј-H), 7.2–7.31 (m, 5 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz):
δ = 25.5, 27.0, 36.3, 49.2, 67.3, 67.7, 73.3, 75.2, 83.9, 84.3, 109.8,
126.5, 128.7 (ϫ 2), 128.9 (ϫ 2), 139.7, 163.2 ppm. EI-MS 319.1
[M]+. C18H25NO4 (319.18): calcd. C 67.69, H 7.89, N 4.39; found
C 67.47, H 7.88, N 4.25.
56.8, 57.5, 67.2 73.9, 77.9, 100.6, 109.8 ppm. EI-MS 342.1 [M]+.
1-[(1R,6S,8R,9S)-9-Acetoxy-6-methyl-2,5,7-trioxabicyclo(4.2.1)-
nonan-8-yl]ethane-1,2-diyl Diacetate (17): Ethylene glycol (18 mg,
0.3 mmol.) and BF3·OEt2 (18.5 µL, 0.15 mmol.) were successively
added to a cooled (0 °C) solution of the exo-glycal 1a (30 mg,
0.15 mmol) in anhydrous CH2Cl2 (3 mL). After the mixture had
been stirred at 0 °C for 2 h, TLC analysis showed complete disap-
pearance of the starting material. To facilitate the separation of the
product, the reaction mixture was concentrated by coevaporation
with toluene and subsequently dissolved in pyridine (5 mL) and
treated with an excess of Ac2O (300 µL). After the mixture had
been stirred at room temperature for 10 h, the crude product was
concentrated and the residue was purified by flash chromatography
(hexane/EtOAc 6:4) to give the bicyclic derivative 17 (52 mg, 61%).
(2S,3R,4R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-[4-(2-methoxy-
phenyl)piperazin-1-yl]-5-methylenetetrahydrofuran-3-ol (13): Com-
pound 1a (250 mg, 1.26 mmol) and 1-(2-methoxyphenyl)piperazine
(726 mg, 3.78 mmol) were subjected to General Procedure B to give
compound 13 (354 mg, 88%) as a colourless oil after silica gel col-
umn chromatography (hexane/EtOAc 4:6). [α]2D5 = +23.0 (c = 0.1,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.37 (s, 3 H, Me), 1.45
(s, 3 H, Me), 2.82 (m, 4 H), 3.07 (m, 4 H), 3.44 (s, 1 H, 2-H), 3.86
(s, 3 H, OMe), 4.02 (dd, J = 4.9, 8.7 Hz, 1 H, 6-H), 4.15 (s, 1 H,
1Ј-H), 4.17–4.23 (m, 2 H, 4-H and 6-H), 4.31–4.35 (m, 1 H, 5-H),
4.51 (d, J = 3.4 Hz, 1 H, 3-H), 4.54 (s, 1 H, 1Ј-H), 6.84–7.2 (4 H,
1
[α]2D5 = –25.0 (c = 0.7, CHCl3). H NMR (CDCl3, 300 MHz): δ =
1.41 (s, 3 H, Me), 2.04 (s, 3 H, OAc), 2.12 (s, 3 H, OAc), 2.16 (s, 3
H, OAc), 3.57 (ddd, J = 3.3, 6.4, 9.8 Hz, 1 H), 3.66 (dd, J = 4.6,
H
arom) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.1, 26.8, 50.6
9.0 Hz, 1 H, 3-H), 3.73 (ddd, J = 3.4, 5.9, 9.7 Hz, 1 H), 3. 79 (m, (ϫ 2), 50.7 (ϫ 2), 55.2, 67.4, 71.9, 73.2, 74.0, 83.7, 86.7, 109.4,
1 H, 6-H), 3.89 (dd, J = 5.6, 8.2 Hz, 1 H, 6-H), 4.10 (m, 2 H), 4.59 110.9, 118.0, 120.8, 122.9, 140.9, 152.0, 159.4 ppm. EI-MS 391.1
(m, 1 H, 5-H), 5.07 (d, J = 9.0 Hz, 1 H, 2-H), 5.29 (dd, J = 2.4, J
= 4.6 Hz, 1 H, 4-H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 14.1,
19.7, 20.8, 20.9, 63.4, 66.4, 68.5, 68.8, 75.2, 75.3, 75.8, 107.1, 169.9,
170.6, 170.8 ppm. EI-MS 346.6 [M]+; ES-HRMS 347.1341 [M +
H]+, calcd. for [C15H22O9 + H]+ 347.1342.
[M]+. C21H30N2O5 (390.2155): calcd. C 64.59, H 7.74, N 7.17;
found C 67.66, H 7.81, N 6.95.
(2S,3R,4R)-4-(Benzylamino)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-5-
methylenetetrahydrofuran-3-ol (19): Compound 1a (150 mg,
0.75 mmol) and benzylamine (245 µL, 2.25 mmol) were subjected
to General Procedure B to give compound 19 (211 mg, 92%) as a
colourless oil after silica gel column chromatography (hexane/
EtOAc 4:6). [α]2D5 = +3.7 (c = 1.6, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 1.36 (s, 3 H, Me), 1.43 (s, 3 H, Me), 3.59 (s, 1 H,
2-H), 3.85 (d, J = 13.2 Hz, 1 H, CH2), 3.94 (d, J = 13.2 Hz, 1 H,
CH2), 4.02 (dd, J = 4.0, 8.8 Hz, 1 H, 6-H), 4.05 (d, J = 1.9 Hz, 1
H, 1Ј-H), 4.18 (m, 2 H, 3-H and 6-H), 4.31 (m, 2 H, 4-H and 5-
(1S,4R,5S)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3,6-dioxabicyclo-
[3.1.0]hexan-2-one (18): A flask containing a solution of the exo-
glycal 1a (150 mg, 0.75 mmol) in dry CH2Cl2 (10 mL) was placed
in a dry ice/acetone bath at –78 °C. Ozone was then generated by
passing an oxygen stream through an electrical discharge-type
ozone generator and the O2/O3 mixture was bubbled through the
cooled and stirred solution for 15 min. After this time, the contents
of the flask were bubbled through with O2 for about 20 min to
remove free O3 and then SMe2 (1 mL) was added. The reaction
mixture was allowed to warm to room temperature and then con-
centrated under reduced pressure in a rotary evaporator. The resi-
due was purified by flash chromatography (hexane/EtOAc 8:2) to
give the epoxy-lactone 18 (118 mg, 79%) as a white solid: m.p. 74–
76 °C. [α]2D5 = –40.7 (c = 0.6, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 1.37 (s, 3 H, Me), 1.46 (s, 3 H, Me), 3.83 (d, J = 2.5 Hz, 1 H,
2-H), 3.97 (dd, J = 3.6, 9.1 Hz, 1 H, 6-H), 4.11 (dd, J = 5.6, 9.1 Hz,
1 H, 6-H), 4.24–4.30 (m, 3 H, 3-H, 4-H and 5-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 25.1, 27.0, 50.6, 55.7, 67.0, 72.7, 78.2, 110.2,
169.7 ppm. EI-MS 200.0 [M]+. ES-HRMS 201.0765 [M + H]+,
calcd. for [C9H12O5 +H]+ 201.0765.
H), 4.41 (d, J = 1.9 Hz, 1 H, 1Ј-H), 7.36 (m, 5 H, Harom) ppm. 13
C
NMR (CDCl3, 50 MHz): δ = 25.6, 27.2, 52.1, 67.1, 67.7, 73.5, 75.1,
84.2, 84.6, 109.9, 127.6, 128.1, 128.5, 128.9, 129.1, 140.0,
163.4 ppm. API-ES positive 306.3 [M + H]+. C17H23NO4 (305.16):
calcd. C 66.86, H 7.59, N 4.59; found C 66.93, H 7.45, N 4.63.
(2S,3R,4R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-methylene-4-[(R)-
1-phenylethylamino]tetrahydrofuran-3-ol (20): Compound 1a
(250 mg, 1.26 mmol) and (R)-1-phenylethylamine (482 µL,
3.78 mmol) were subjected to General Procedure B to give com-
pound 20 (322 mg, 81%) as a colourless oil after silica gel column
chromatography (hexane/EtOAc 4:6). [α]2D5 = +15.1 (c = 0.4,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.36 (d, J = 6.6 Hz, 3
H, Me), 1.37 (s, 3 H, Me), 1.45 (s, 3 H, Me), 3.39 (s, 1 H, 2-H),
3.93 (q, J = 6.6 Hz, 1 H, CH), 3.94 (d, J = 1.8 Hz, 1 H, 1Ј-H), 3.99
(dd, J = 4.4, 8.4 Hz, 1 H, 6-H), 4.17 (dd, J = 5.5, 8.5 Hz, 1 H, 6-
H), 4.27 (m, 1 H, 3-H), 4.32 (m, 2 H, 4-H and 5-H), 4.33 (d, J =
1.8 Hz, 1 H, 1Ј-H), 7.30 (m, 5 H, Harom) ppm. 13C NMR (CDCl3,
50 MHz): δ = 24.3, 25.1, 26.7, 56.1, 64.4, 67.6, 73.2, 75.3, 83.2,
83.5, 109.3, 126.4, 127.2 (ϫ2), 128.7 (ϫ2), 144.9, 164.1 ppm. EI-
MS 319.1 [M]+. C18H25NO4 (319.18): calcd. C 67.69, H 7.89, N
4.39; found C 67.50, H 7.87, N 4.29.
General Procedure B. Nucleophilic Ring-Opening of Epoxy exo-Gly-
cals with Amines: A solution of the appropriate epoxide in EtOH
(10 mLmmol–1) was treated with the appropriate amine (3 equiv.).
The resulting mixture was heated to reflux until TLC showed that
all the starting material had been consumed (usually 3–5 h). The
reaction mixture was then allowed to cool to room temperature
and concentrated in vacuo, and the residue was purified by flash
chromatography.
(2S,3R,4R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-methylene-4-(phen- (2S,3R,4R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-methylene-4-
ethylamino)tetrahydrofuran-3-ol (11): Compound 1a (150 mg,
0.75 mmol) and 2-phenylethylamine (284 µL, 2.25 mmol) were sub-
jected to General Procedure B to give compound 11 (203 mg, 85%)
as a colourless oil after silica gel column chromatography (hexane/
EtOAc 4:6). [α]2D5 = +9.2 (c = 0.1, CHCl3). 1H NMR (CDCl3,
morpholinotetrahydrofuran-3-ol (21): Compound 1a (250 mg,
1.26 mmol) and morpholine (328 µL, 3.78 mmol) were subjected to
General Procedure B to give compound 21 (309 mg, 86%) as white
solid after silica gel column chromatography (hexane/EtOAc 3:7).
1
m.p. 97–99 °C. [α]2D5 = –17.1 (c = 1.6, CHCl3). H NMR (CDCl3,
5626
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5619–5632

Preparation of Furanose-Based Templates
300 MHz): δ = 1.36 (s, 3 H, Me), 1.45 (s, 3 H, Me), 2.61 (t, J =
4.6 Hz, 4 H, 2ϫ CH2–N), 3.31 (d, J = 0.6 Hz, 1 H, 2-H), 3.69 (t,
J = 4.6 Hz, 4 H, 2ϫ CH2–O), 3.99 (dd, J = 4.8, 8.8 Hz, 1 H, 6-H),
4.11 (dd, J = 0.8, 1.7 Hz, 1 H, 1Ј-H), 4.15–4.22 (m, 2 H, 4-H and
3 equiv.) were subjected to General Procedure B to give compound
25 (167.6 mg, 84 %) as a colourless oil after silica gel column
chromatography (hexane/EtOAc 1:9). [α]2D5 = +34.0 (c = 0.44,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.06 (d, J = 6.6 Hz, 3
6-H), 4.28–4.35 (m, 1 H, 5-H), 4.42 (m, 1 H, 3-H), 4.53 (dd, J = H, CH3–CH–), 1.35 (s, 3 H, Me), 1.43 (s, 3 H, Me), 3.01–3.07 (m,
0.8, 1.7 Hz, 1 H, 1Ј-H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.1, 1 H, CH3-CH-CH2-), 3.31 (dd, J = 7.6, 10.7 Hz, 1 H, CH2–OH),
26.8, 51.1 (ϫ2), 67.0, 67.4 (ϫ2), 72.0, 73.1, 74.1, 83.6, 87.1, 109.5, 3.6 (dd, J = 3.9, 10.7 Hz, 1 H, CH2–OH), 3.65 (s, 1 H, 2-H), 4.0
158.8 ppm. API-ES positive 286.2 [M + H]+. C14H23NO5 (285.16):
calcd. C 58.93, H 8.12, N 4.91; found C 58.87, H 8.25, N 4.93.
(dd, J = 4.7, 8.6 Hz, 1 H, 6-H), 4.05 (d, J = 1.8 Hz, 1 H, 1Ј-H),
4.15 (m, 2 H, 3-H and 6Ј-H), 4.25 (dd, J = 3.5, 8.3 Hz, 1 H, 4-H),
4.3–4.38 (m, 1 H, 5-H), 4.39 (d, J = 1.8 Hz, 1 H, 1Ј-H) ppm. 13C
NMR (CDCl3, 50 MHz): δ = 17.4, 25.4, 27.0, 52.2, 64.3, 66.3, 67.7,
73.4, 76.6, 83.4, 84.8, 109.9, 162.7 ppm. API-ES positive 274.1 [M
+ H]+. C13H23NO5 (273.1576): calcd. C 57.13, H 8.48, N 5.12;
found C 56.98, H 8.40, N 4.97.
(2S,3R,4R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-methylene-4-
(piperidin-1-yl)tetrahydrofuran-3-ol (22): Compound 1a (250 mg,
1.26 mmol) and piperidine (373 µL, 3.78 mmol) were subjected to
General Procedure B to give compound 22 (318 mg, 89 %) as a
colourless oil after silica gel column chromatography (hexane/
EtOAc 3:7). [α]2D5 = +10.9 (c = 1.0, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 1.32 (s, 3 H, Me), 1.38 (m, 2 H, CH2) 1.40 (s, 3 H,
Me), 1.52 (m, 4 H, 2ϫ CH2), 2.50 (m, 4 H, 2ϫ CH2–N), 3.32 (s,
1 H, 2-H), 3.94 (dd, J = 5.1, 8.5 Hz, 1 H, 6-H), 4.03 (d, J = 0.7 Hz,
1 H, 1Ј-H), 4.11 (dd, J = 6.3, 8.5 Hz, 1 H, 6-H), 4.13 (dd, J = 4.1,
8.3 Hz, 1 H, 4-H), 4.30 (m, 1 H, 5-H), 4.38 (br. d, J = 3.1 Hz, 1
H, 3-H), 4.45 (d, J = 0.7 Hz, 1 H, 1Ј-H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 14.3, 24.5, 25.4, 26.3 (ϫ2), 51.8 (ϫ2), 67.5, 72.5,
73.6, 75.1, 84.0, 86.4, 109.6, 159.8 ppm. API-ES positive 284.2 [M
+ H]+. C15H25NO4 (283.18): calcd. C 63.58, H 8.89, N 4.94; found
C 63.23, H 8.75, N 4.87.
(2S,3R,4R)-5-Butylidene-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-(phen-
ethylamino)tetrahydrofuran-3-ol (26): Compound 1b (200 mg,
0.83 mmol) and 2-phenylethylamine (314 µL, 2.49 mmol) were sub-
jected to General Procedure B to give compound 26 (249 mg, 83%)
as a 3:1 mixture of isomers after silica gel column chromatography
(hexane/EtOAc 3:7). For the major isomer [α]2D5 = +12.3 (c = 1.1,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 0.89 (t, J = 7.1 Hz, 3
H, Me), 1.2–1.45 (m, 2 H, CH2–CH2–), 1.38 (s, 3 H, Me), 1.45 (s,
3 H, Me), 2.0 (m, 2 H, CH2), 2.77–3.11 (m, 4 H, CH2–CH2–N),
3.47 (s, 1 H, 2-H), 4.0 (dd, J = 4.9, 8.4 Hz, 1 H, 6-H), 4.13–4.38 (m,
4 H), 7.2–7.3 (m, 5 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz): δ
= 13.7, 22.9, 25.3, 26.8, 27.0, 36.2, 48.9, 67.0, 67.7, 73.5, 75.3, 83.1,
101.0, 110.0, 126.2, 128.5 (ϫ2), 128.7 (ϫ2), 139.7, 155.3 ppm. API-
ES positive 362.2 [M + H]+. C21H31NO4 (361.23): calcd. C 69.78,
H 8.64, N 3.87; found C 69.81, H 8.53, N 3.76.
(2S,3R,4R)-4-(4-Benzylpiperazin-1-yl)-2-(2,2-dimethyl-1,3-dioxolan-
4-yl)-5-methylenetetrahydrofuran-3-ol (23): Compound 1a (200 mg,
1.01 mmol) and 1-benzylpiperazine (527 µL, 3.03 mmol) were sub-
jected to General Procedure B to give compound 23 (287 mg, 76%)
as a colourless oil after silica gel column chromatography (hexane/
EtOAc 3:7). [α]2D5 = +8.2 (c = 0.2, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 1.36 (s, 3 H, Me), 1.44 (s, 3 H, Me), 2.50 (br. s, 4
H, 2ϫ CH2–N), 2.63 (br. s, 4 H, 2ϫ CH2–N), 3.36 (s, 1 H, 2-H),
3.53 (s, 2 H, CH2–N), 3.98 (dd, J = 5.0, 8.6 Hz, 1 H, 6-H), 4.09 (d,
J = 0.8 Hz, 1 H, 1Ј-H), 4.16 (m, 2 H, 4-H and 6-H), 4.31 (m, 1 H,
5-H), 4.43 (br. d, J = 3.6 Hz, 1 H, 3-H), 4.50 (d, J = 0.8 Hz, 1 H,
(2S,3R,4R)-5-(Butan-2-ylidene)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-
4-(phenethylamino)tetrahydrofuran-3-ol (27): Compound 1c
(200 mg, 0.83 mmol) and 2-phenylethylamine (314 µL, 2.49 mmol)
were subjected to General Procedure B to give compound 27
(246 mg, 82 %) as a mixture of isomers after silica gel column
chromatography (hexane/EtOAc 3:7). Selected peaks for the major
1
isomer: H NMR (CDCl3, 300 MHz): δ = 0.8 (t, J = 7.3 Hz, 3 H
1Ј-H), 7.31 (m, 5 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz): δ Me), 1.37 (s, 3 H, Me), 1.44 (s, 3 H, Me), 1.57 (s, 3 H, Me), 1.90
= 25.4, 27.1, 50.6 (ϫ2), 53.4 (ϫ2), 63.2, 67.8, 72.4, 73.6, 74.2, 83.9,
(m, 2 H, CH2–Me), 2.7–3.0 (m, 4 H, CH2–CH2–N), 3.6 (s, 1 H, 2-
86.9, 109.8, 127.3, 128.4 (ϫ2), 129.5 (ϫ2), 138.1, 159.8 ppm. API- H), 4.0 (dd, J = 5.3, 7.8 Hz, 1 H, 6-H), 4.10–4.22 (m, 3 H), 4.3
ES positive 375.2 [M + H]+. C21H30N2O4 (374.22): calcd. C 67.35,
H 8.07, N 7.48; found C 58.87, H 8.25, N 4.93.
(m, 1 H, 5-H), 7.19–7.3 (m, 5 H, Harom) ppm. 13C NMR (CDCl3,
50 MHz): δ = 13.5, 13.7, 25.4, 26.0, 26.9, 36.3, 49.7, 65.1, 67.8,
73.6, 75.0, 82.6, 109.3, 109.5, 126.4, 128.6 (ϫ2), 128.7 (ϫ2), 139.6,
150.5 ppm. API-ES positive 362.2 [M + H]+. C21H31NO4 (361.23):
calcd. C 69.78, H 8.64, N 3.87; found C 69.70, H 8.59, N 3.68.
(2S,3R,4R)-4-(4-Benzylpiperidin-1-yl)-2-(2,2-dimethyl-1,3-dioxolan-
4-yl)-5-methylenetetrahydrofuran-3-ol (24): Compound 1a (250 mg,
1.26 mmol) and 4-benzylpiperidine (664 µL, 3.78 mmol) were sub-
jected to General Procedure B to give compound 24 (339 mg, 72%)
as a colourless oil after silica gel column chromatography (hexane/
EtOAc 3:7). [α]2D5 = +15.3 (c = 0.4, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 1.26 (td, J = 3.9, 12.6 Hz, 2 H, CH2), 1.36 (s, 3 H,
(2S,3R,4R,Z)-5-(Bromomethylene)-2-(2,2-dimethyl-1,3-dioxolan-4-
yl)-4-(phenethylamino)tetrahydrofuran-3-ol (28a): Compound 2a
(250 mg, 0.90 mmol) and 2-phenylethylamine (340 mg, 2.7 mmol)
were subjected to General Procedure B to give compound 28a
Me), 1.44 (s, 3 H, Me), 1.53 (m, 1 H, CH), 1.64 (td, J = 3.6, (294 mg, 82 %) after silica gel column chromatography (hexane/
10.2 Hz, 2 H, CH2), 2.15 (m, 2 H, CH2), 2.52 (d, J = 5.7 Hz, 2 H,
CH2), 2.94 (m, 2 H, CH2), 3.38 (s, 1 H, 2-H), 3.98 (dd, J = 5.1,
8.7 Hz, 1 H, 6-H), 4.08 (d, J = 1.2 Hz, 1 H, 1Ј-H), 4.16 (dd, J =
5.7, 8.7 Hz, 1 H, 6-H), 4.15 (m, 1 H, 4-H), 4.30 (m, 1 H, 5-H), 4.42
EtOAc 4:6). [α]2D5 = +62.3 (c = 1.0, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 1.35 (s, 3 H, Me), 1.43 (s, 3 H, Me), 2.89 (m, 4 H,
2ϫ CH2), 3.54 (s, 1 H, 2-H), 4.03 (dd, J = 4.5, 8.8 Hz, 1 H, 6-H),
4.20 (m, 2 H), 4.36 (m, 2 H), 5.06 (s, 1 H, 1Ј-H), 7.25 (m, 5 H,
(d, J = 4.2 Hz, 1 H, 3-H), 4.48 (s, 1 H, 1Ј-H), 7.26 (m, 5 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.2, 26.8, 36.1,
Harom) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.1, 26.8, 32.3 48.6, 67.2, 67.5, 73.0, 75.7, 76.3, 84.5, 109.7, 126.4, 128.6 (ϫ2),
(ϫ2), 37.8, 43.0, 50.8, 50.9, 67.4, 72.3, 73.4, 74.4, 83.7, 86.2, 109.4,
125.7, 128.1 (ϫ2), 129.0 (ϫ2), 140.5, 159.6 ppm. API-ES positive
374.2 [M + H]+. C22H31NO4 (373.23): calcd. C 70.75, H 8.37, N
3.75; found C 70.81, H 8.21, N 3.86.
128.7 (ϫ2), 139.3, 158.5 API-ES positive 398.2 [M]+. 400.2 [M +
2]+. C18H24BrNO4 (397.09): calcd. C 54.28, H 6.07, N 3.52; found
C 53.98, H 6.12, N 3.48.
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(iodomethylene)-
(2S,3R,4R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-[(S)-1-hydroxy- 4-(phenethylamino)tetrahydrofuran-3-ol (28b): Compound 2b
propan-2-ylamino]-5-methylenetetrahydrofuran-3-ol (25): Com-
pound 1a (200 mg, 0.73 mmol) and -alaninol (207 µL, 2.89 mmol,
(250 mg, 0.77 mmol) and 2-phenylethylamine (291 mg, 2.31 mmol)
were subjected to General Procedure B to give compound 28b
Eur. J. Org. Chem. 2010, 5619–5632
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5627

A. M. Gómez, A. Pedregosa, C. Uriel, S. Valverde, J. C. López
FULL PAPER
(257 mg, 75 %) after silica gel column chromatography (hexane/ N), 3.60 (s, 1 H, 2-H), 3.86 (s, 3 H, OMe), 4.10 (dd, J = 4.4, 8.8 Hz,
EtOAc 4:6). [α]2D5 = +26.2 (c = 0.9, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 1.37 (s, 3 H, Me), 1.44 (s, 3 H, Me), 2.94 (m, 4 H,
2ϫ CH2), 3.65 (s, 1 H, 2-H), 4.05 (dd, J = 4.0, 8.3 Hz, 1 H, 6-H),
1 H, 6-H), 4.23 (dd, J = 5.8, 8.8 Hz, 1 H, 6-H), 4.35 (m, 2 H, 4-H
and 5-H), 4.66 (s, 1 H, 3-H), 4.98 (s, 1 H, 1Ј-H), 7.10 (m, 4 H,
H
arom) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.5, 27.2, 46.2, 50.7
4.21 (dd, J = 5.2, 8.2 Hz, 1 H, 6-H), 4.30 (m, 1 H, 3-H), 4.40 (m, (ϫ2), 51.0 (ϫ2), 55.5, 67.7, 73.2, 73.6, 74.8, 84.7, 110.0, 111.3,
2 H, 4-H and 5-H), 4.85 (s, 1 H, 1Ј-H), 7.28 (m, 5 H, Harom) ppm.
13C NMR (CDCl3, 50 MHz): δ = 25.3, 26.9, 36.1, 49.1, 67.9 (ϫ2),
73.1, 76.1, 76.4, 84.3, 109.8, 124.5, 127.2 (ϫ4), 139.7, 162.3 ppm.
API-ES positive 446.0 [M + H]+. C18H24INO4 (445.08): calcd. C
48.55, H 5.43, N 3.15; found C 48.38, H 5.32, N 3.28.
118.4, 121.2, 123.3, 141.2, 152.4, 160.0 ppm. API-ES positive 517.3
[M]+. C21H29IN2O5 (516.1121): calcd. C 48.85, H 5.66, N 5.43;
found C 48.70, H 5.57, N 5.29.
General Procedure C. Nucleophilic Ring-opening of Epoxy exo-Gly-
cals with Ion Hydroxide
(2S,3R,4R,Z)-5-(Bromomethylene)-2-(2,2-dimethyl-1,3-dioxolan-4-
yl)-4-morpholinotetrahydrofuran-3-ol (29a): Compound 2a (250 mg,
0.90 mmol) and morpholine (234 µL, 2.7 mmol) were subjected to
General Procedure B to give compound 29a (268 mg, 82%) after
Method C1: A solution of the appropriate epoxide in THF/H2O
(3:1, 3 mLmmol–1) was treated with Bu4NOH (2 equiv.). The re-
sulting mixture was heated to reflux until tlc showed that all the
starting material had been consumed. The reaction mixture was
then diluted with EtOAc and washed with water. The organic layer
was then dried and concentrated.
silica gel column chromatography (hexane/EtOAc 4:6). [α]2D5
=
1
+13.1 (c = 1.9, CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.36 (s,
3 H, Me), 1.44 (s, 3 H, Me), 2.57 (t, J = 4.6 Hz, 4 H, 2ϫ CH2–N),
3.40 (s, 1 H, 2-H), 3.67 (t, J = 4.6 Hz, 4 H, 2ϫ CH2–O), 4.07 (dd,
J = 4.1, 8.7 Hz, 1 H, 6-H), 4.20 (dd, J = 5.6, 8.7 Hz, 1 H, 6-H),
4.32 (m, 2 H, 3-H, 4-H), 4.51 (m, 1 H, 5-H), 5.14 (s, 1 H, 1Ј-
H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.6, 27.3, 51.4, 51.6,
67.4 (ϫ2), 67.8, 72.9, 73.6, 74.9, 78.8, 85.1, 110.1, 155.5 ppm. API-
ES positive 364.1 [M + H]+, 366.1 [M + 3]+. C14H22BrNO5
(363.07): calcd. C 46.17, H 6.09, N 3.85; found C 46.38, H 6.10, N
3.78.
Method C2: A solution of the appropriate epoxide in THF was
treated with KOH (5%, 2 equiv.). The resulting mixture was heated
to 40 °C and stirred at that temperature until TLC showed that all
the starting material had been consumed. The reaction mixture was
concentrated.
(2S,3R,4R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-methylenetetra-
hydrofuran-3,4-diol (31): This compound was prepared from 1a
(100 mg, 0.54 mmol) by General Procedure C1 and/or C2 to pro-
duce diol 31 (66 mg, 57% and 52 mg, 49%, respectively). 1H NMR
(CDCl3, 300 MHz): δ = 1.37 (s, 3 H, Me), 1.45 (s, 3 H, Me), 4.03
(dd, J = 4.5, 8.7 Hz, 1 H, 6-H), 4.18 (dd, J = 5.8, 8.7 Hz, 1 H, 6-
H), 4.24 (d, J = 2.0 Hz, 1 H, 1Ј-H), 4.27 (m, 1 H, 3-H), 4.33 (m, 2
H, 4-H and 5-H), 4.42 (s, 1 H, 2-H), 4.45 (d, J = 2.0 Hz, 1 H, 1Ј-
H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.4, 27.0, 67.7, 73.3,
75.8, 77.2, 83.5, 85.6, 110.0, 163.5 ppm.
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(iodomethylene)-
4-morpholinotetrahydrofuran-3-ol (29b): Compound 2b (250 mg,
0.77 mmol) and morpholine (202 mg, 2.31 mmol) were subjected to
General Procedure B to give compound 29b (228 mg, 72%) after
silica gel column chromatography (hexane/EtOAc 4:6). [α]2D5
=
1
+37.1 (c = 1.9, CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.36 (s,
3 H, Me), 1.45 (s, 3 H, Me), 2.56 (m, 4 H, 2ϫ CH2–N), 3.45 (s, 1
H, 2-H), 3.67 (m, 4 H, 2ϫ CH2–O), 4.08 (dd, J = 4.4, 8.8 Hz, 1
H, 6-H), 4.20 (dd, J = 5.8, 8.8 Hz, 1 H, 6-H), 4.33 (m, 2 H, 4-H
and 5-H), 4.55 (s, 1 H, 3-H), 4.93 (s, 1 H, 1Ј-H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 25.3, 27.0, 46.3, 51.0 (ϫ2), 67.1 (ϫ2), 67.6,
73.0, 73.3, 74.7, 84.4, 109.9, 159.3 ppm. API-ES positive 412.2 [M
+ H]+. C14H22INO5 (411.05): calcd. C 40.89, H 5.39, N 3.41; found
C 40.78, H 5.28, N 3.38.
This diol was subjected to acetylation and characterized as its di-
acetate as follows: the reaction mixture was concentrated by co-
evaporation with toluene and subsequently dissolved in pyridine
(5 mL) and treated with an excess of Ac2O (300 µL). After the mix-
ture had been stirred at room temperature for 10 h, the crude prod-
uct was concentrated and the residue was purified by chromatog-
raphy to yield the corresponding diacetate. [α]2D5 = +30.2 (c = 0.6,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.32 (s, 3 H, Me), 1.41
(s, 3 H, Me), 2.08 (s, 3 H, Me), 2.10 (s, 3 H, Me), 4.02 (dd, J =
4.8, 8.6 Hz, 1 H, 6-H), 4.10 (dd, J = 5.7, 8.8 Hz, 1 H, 6-H), 4.24
(ddd, J = 4.9, 5.7, 7.9 Hz, 1 H, 5-H), 4.35 (dd, J = 3.7, 8.0 Hz, 1
H, 4-H), 4.35 (d, J = 2.1 Hz, 1 H, 1Ј-H), 4.52 (d, J = 2.1 Hz, 1 H,
1Ј-H), 5.29 (d, J = 3.6 Hz, 1 H, 3-H), 5.47 (s, 1 H, 2-H) ppm. 13C
NMR (CDCl3, 50 MHz): δ = 20.7, 20.9, 25.2, 26.8, 66.9, 72.3, 74.3,
74.7, 81.8, 88.4, 109.5, 158.4, 169.1, 169.3 ppm. EI-MS 300.1
[M]+. C14H20O7 (300.12): calcd. C 55.99, H, 6.71; found C, 55.88;
H, 6.62.
(2S,3R,4R,Z)-5-(Bromomethylene)-2-(2,2-dimethyl-1,3-dioxolan-4-
yl)-4-[4-(2-methoxyphenyl)piperazin-1-yl]tetrahydrofuran-3-ol (30a):
Compound 2a (250 mg, 0.90 mmol) and 1-(2-methoxyphenyl)pi-
perazine (474 µL, 2.7 mmol) were subjected to General Pro-
cedure B to give compound 30a (338 mg, 80%) after silica gel col-
umn chromatography (hexane/EtOAc 4:6). [α]2D5 = +17.1 (c = 0.3,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.38 (s, 3 H, Me), 1.46
(s, 3 H, Me), 2.78 (m, 4 H, 2ϫ CH2–N), 3.06 (m, 4 H, 2ϫ CH2–
N), 3.60 (s, 1 H, 2-H), 3.86 (s, 3 H, OMe), 4.10 (m, 2 H, 2ϫ6-H),
4.35 (m, 2 H, 4-H and 5-H), 4.61 (s, 1 H, 3-H), 5.20 (s, 1 H, 1Ј-H),
6.91 (4 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.4, 27.0,
50.6 (ϫ2), 55.4 (ϫ3), 67.5, 72.6, 73.4, 74.6, 78.3, 84.9, 109.8, 111.3,
118.3, 121.1, 123.2, 141.1, 152.3, 155.8 ppm. API-ES positive 468.1
[M]+, 470.1 [M + 2]+. C21H29BrN2O5 (468.13): calcd. C 53.74, H
6.28, N 5.97; found C 53.88, H 6.16, N 5.81.
(3R,4R,5S)-2-(Butan-2-ylidene)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-
tetrahydrofuran-3,4-diol (32): Compound 1b (125 mg, 0.48 mmol)
was subjected to General Procedure C1 to give compound 32
(64 mg, 52 %) as a mixture of isomers after silica gel column
chromatography (EtOAc). Selected peaks for the major isomer: 1H
NMR (CDCl3, 300 MHz): δ = 1.04 (t, J = 7.3 Hz, 3 H, Me), 1.38
(s, 3 H, Me), 1.45 (s, 3 H, Me), 2.05 (s, 3 H, Me), 2.1 (q, J = 7.3 Hz,
2 H, CH2), 4.01–4.32 (m, 5 H), 4.62 (s, 1 H, 2-H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 13.9, 14.2, 25.3, 26.1, 26.8, 60.4, 67.5, 73.3,
74.2, 82.0, 109.6, 112.4, 150.5 ppm. API-ES positive 259.3 [M +
H]+. C13H22O5 (258.15): calcd. C 60.45, H 8.58; found C 60.19, H
8.47.
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(iodomethylene)-
4-[4-(2-methoxyphenyl)piperazin-1-yl]tetrahydrofuran-3-ol (30b):
Compound 2b (250 mg, 0.77 mmol) and 1-(2-methoxyphenyl)pi-
perazine (405 mg, 2.31 mmol) were subjected to General Pro-
cedure B to give compound 30b (250 mg, 63%) after silica gel col-
umn chromatography (hexane/EtOAc 4:6). [α]2D5 = +13.4 (c = 1.2,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.38 (s, 3 H, Me), 1.47 (3R,4R,5S)-2-Butylidene-5-(2,2-dimethyl-1,3-dioxolan-4-yl)tetra-
(s, 3 H, Me), 2.78 (m, 4 H, 2ϫ CH2–N), 3.06 (m, 4 H, 2ϫ CH2– hydrofuran-3,4-diol (33): Compound 1c (100 mg, 0.38 mmol) was
5628
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5619–5632

Preparation of Furanose-Based Templates
subjected to General Procedure C1 to give compound 33 (48 mg,
appropriate arylboronic acid (1.3 mmol) in THF (5 mL). The re-
sulting solution was degassed under argon for 10 min and then
Pd(PPh3)4 (0.05 mmol) was added. The ensuing suspension was
heated under argon to 60 °C and stirred at that temperature. After
49%) as a mixture of isomers after silica gel column chromatog-
1
raphy (EtOAc). Selected peaks for the major isomer: H NMR
(CDCl3, 300 MHz): δ = 0.90 (t, J = 7.3 Hz, 3 H, Me), 1.38 (s, 3 H,
Me), 1.45 (s, 3 H, Me), 1.39 (m, 2 H, CH2), 2.0 (m, 2 H, CH2), the starting materials had been consumed, the mixture was diluted
4.05 (dd, J = 4.7, 8.5 Hz, 1 H, 6-H), 4.19 (dd, J = 5.8, 8.6 Hz, 1 with EtOAc and washed with brine. The organic layer was dried,
H, 6-H), 4.32 (m, 4 H), 4.61 (t, J = 7.3 Hz, 1 H, 1Ј-H) ppm. 13C concentrated and subjected to silica gel column chromatography.
NMR (CDCl3, 50 MHz): δ = 13.7, 22.7, 25.2, 26.7, 27.0, 67.5, 73.3,
75.6, 77.1, 82.8, 102.6, 109.6, 156.1 ppm. API-ES positive 259.3 [M
+ H]+. C13H22O5 (258.1467): calcd. C 60.45, H 8.58; found C 60.21,
H 8.39.
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-(phenethyl-
amino)-5-(thiophen-3-ylmethylene)tetrahydrofuran-3-ol (41a): This
compound was prepared from the bromide 28a (100 mg,
0.25 mmol) or the iodide 28b (111 mg, 0.25 mmol) and thiophene-
3-boronic acid (42 mg, 0.32 mmol) by General Procedure D fol-
lowed by silica gel column chromatography (hexane/EtOAc 3:7).
Compound 41a (69 mg, 69% and 72 mg, 72%, respectively). [α]2D5
= +8.5 (c = 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ = 1.39
(s, 3 H, Me), 1.47 (s, 3 H, Me), 2.84 (m, 2 H, CH2–Ph), 3.03 (m, 2
H, CH2N), 3.65 (s, 1 H, 2-H), 4.12 (dd, J = 4.6, 8.5 Hz, 1 H, 6-H),
4.20 (d, J = 2.2 Hz, 1 H, 3-H), 4.25 (dd, J = 5.6, 9.0 Hz, 1 H, 6-
H), 4.44 (m, 2 H, 4-H and 5-H), 5.44 (s, 1 H, 1Ј-H), 7.18–7.60 (m,
8 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz): δ = 23.6, 25.3, 34.5,
47.1, 65.6, 66.7, 71.6, 73.1, 82.9, 94.6, 108.1, 119.1, 124.7, 126.5,
127.0 (ϫ2), 127.1, 127.2 (ϫ2), 134.8, 137.9, 154.2 ppm. API-ES
positive 402.1 [M + 1]+. C22H27NO4S (401.17): calcd. C 65.81, H
6.78, N 3.49; found C 65.79, H 6.57, N 3.53.
(3R,4S,5R,Z)-2-(Bromomethylene)-5-(2,2-dimethyl-1,3-dioxolan-4-
yl)tetrahydrofuran-3,4-diyl Diacetate (34): This compound was pre-
pared from 2a (125 mg, 0.45 mmol) by General Procedure C1. To
facilitate the purification of the product, the reaction mixture was
subsequently dissolved in pyridine (5 mL) and treated with an ex-
cess of Ac2O (300 µL). After the mixture had been stirred at room
temperature for 10 h, the crude product was concentrated and the
residue was purified by chromatography (hexane/EtOAc 8:2) to
give compound 34 (101 mg, 59%). [α]2D5 = +55.7 (c = 1.14, CHCl3).
1H NMR (CDCl3, 300 MHz): δ = 1.31 (s, 3 H, Me), 1.40 (s, 3 H,
Me), 2.06 (s, 3 H, Me), 2.09 (s, 3 H, Me), 4.13 (m, 2 H, 6-H), 4.29
(m, 1 H, 5-H), 4.47 (dd, J = 3.6, 8.0 Hz, 1 H, 4-H), 5.35 (dd, J =
0.9, 3.6 Hz, 1 H, 3-H), 5.41 (d, J = 0.9 Hz, 1 H, 2-H), 5.52 (s, 1 H,
1Ј-H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 20.7, 20.8, 25.3, 26.8,
66.9, 72.2, 74.4, 74.7, 82.3, 82.8, 109.7, 154.6, 169.0, 169.2 ppm.
API-ES positive 379.0 [M + H]+, 402 [M + Na]+. C14H19BrO7
(378.03): calcd. C 44.34, H 5.05; found C 44.26, H 5.12.
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(4-methoxy-
benzylidene)-4-(phenethylamino)tetrahydrofuran-3-ol (41b): This
compound was prepared from the bromide 28a (100 mg,
0.25 mmol) or the iodide 28b (111 mg, 0.25 mmol) and p-methoxy-
phenylboronic acid (49 mg, 0.32 mmol) by General Procedure D
followed by silica gel column chromatography (hexane/EtOAc 3:7).
Compound 41b (66 mg, 63% and 70 mg, 66%, respectively). [α]2D5
(2R,3S,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(iodomethylene)-
tetrahydrofuran-3,4-diyl Diacetate (35): This compound was pre-
pared from 2b (125 mg, 0.38 mmol) by General Procedure C1. To
facilitate the purification of the product, the crude reaction mixture
was dissolved in pyridine (5 mL) and treated with an excess of
Ac2O (300 µL). After the mixture had been stirred at room tem-
perature for 10 h, the crude product was concentrated and the resi-
due was purified by chromatography (hexane/EtOAc 8:2) to yield
1
= +60.7 (c = 1.1, CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.38
(s, 3 H, Me), 1.46 (s, 3 H, Me), 2.80 (m, 2 H, CH2–Ph), 3.01 (m, 2
H, CH2N), 3.63 (s, 1 H, 2-H), 3.78 (s, 3 H, OMe), 4.10 (dd, J =
4.6, 8.8 Hz, 1 H, 6-H), 4.16 (m, 1 H, 3-H), 4.22 (dd, J = 5.6, 8.8 Hz,
1 H, 6-H), 4.39 (m, 2 H, 4-H and 5-H), 5.25 (s, 1 H, 1Ј-H), 6.82
(d, J = 9.0 Hz, 2 H, Harom), 7.26 (m, 5 H, Harom), 7.42 (d, J =
9.0 Hz, 2 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.3,
26.8, 36.1, 48.9, 55.2, 67.5, 68.7, 73.2, 74.2, 84.8, 100.9, 109.6, 113.6
(ϫ2), 126.3, 128.5 (2), 128.7 (ϫ4), 130.2, 139.4, 154.8, 157.4 ppm.
EI-MS 425.3 [M]+. C25H31NO5 (425.22): calcd. C 70.57, H 7.34, N
3.29; found C 70.53, H 7.27, N 3.33.
compound 35 (104 mg, 64%). [α]2D5 = +56.6 (c = 1.06, CHCl3). H
1
NMR (CDCl3, 300 MHz): δ = 1.33 (s, 3 H, Me), 1.43 (s, 3 H, Me),
2.08 (s, 3 H, Me), 2.10 (s, 3 H, Me), 4.10 (dd, J = 5.1, 8.9 Hz, 1 H,
6-H), 4.13 (dd, J = 5.8, 8.8 Hz, 1 H, 6-H), 4.29 (ddd, J = 5.1, 5.8,
7.8 Hz, 1 H, 5-H), 4.52 (dd, J = 3.7, 7.7 Hz, 1 H, 4-H), 5.38 (s, 1
H, 1Ј-H), 5.41 (dd, J = 1.3, 3.7 Hz, 1 H, 3-H), 5.48 (d, J = 1.3 Hz,
1 H, 2-H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 20.7, 20.8, 25.2,
26.7, 50.7, 66.7, 72.1, 73.9, 75.1, 82.3, 109.6, 158.5, 169.0,
169.2 ppm. API-ES positive 427.1 [M + H]+, 449.1 [M + Na]+.
C14H19IO7 (426.02): calcd. C 39.45, H 4.49; found C 39.33, H 4.52.
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(4-methyl-
benzylidene)-4-(phenethylamino)tetrahydrofuran-3-ol (41c): This
compound was prepared from the bromide 28a (100 mg,
0.25 mmol) or the iodide 28b (111 mg, 0.25 mmol) and p-methyl-
phenylboronic acid (44 mg, 0.32 mmol) by General Procedure D
followed by silica gel column chromatography (hexane/EtOAc 3:7).
Compound 41c (68 mg, 67% and 65 mg, 64%, respectively). [α]2D5
(2S,3R)-5-(Azidomethyl)-2-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-
2,3-dihydrofuran-3-ol (40): A suspension of 1a (150 mg, 0.75 mmol)
and sodium azide (244 mg, 3.75 mmol) in DMF (5 mL) was heated
at 50 °C for 4 h. The reaction mixture was concentrated and the
residue was purified by silica gel column chromatography (hexane/
1
= +32.1 (c = 0.6, CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.39
(s, 3 H, Me), 1.47 (s, 3 H, Me), 2.31 (s, 3 H, Me), 2.79 (m, 2 H,
CH2–Ph), 3.01 (m, 2 H, CH2–N), 3.66 (s, 1 H, 2-H), 4.12 (dd, J =
4.9, 8.8 Hz, 1 H, 6-H), 4.18 (d, J = 3.2 Hz, 1 H, 3-H), 4.25 (dd, J
= 5.9, 8.8 Hz, 1 H, 6-H), 4.45 (m, 2 H, 4-H and 5-H), 5.29 (s, 1 H,
1Ј-H), 7.09 (d, J = 7.8 Hz, 2 H, Harom), 7.26 (m, 5 H, Harom), 7.38
(d, J = 8.0 Hz, 2 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz): δ
= 21.4, 25.5, 27.1, 36.5, 49.2, 67.8, 69.1, 73.5, 74.7, 85.2, 101.5,
109.9, 126.6, 127.9 (ϫ 2), 128.8 (ϫ 2), 128.9 (ϫ2), 129.1 (ϫ 2),
133.1, 135.4, 139.8, 156.2 ppm. EI-MS 409.2 [M]+. C25H31NO4
(409.23): calcd. C 73.32, H 7.63, N 3.42; found C 73.39, H 7.57, N
3.36.
1
EtOAc 6:4) to give the azide 40 (112 mg, 62%). H NMR (CDCl3,
300 MHz): δ = 1.39 (s, 3 H, Me), 1.46 (s, 3 H, Me), 3.84 (d, J =
2.6 Hz, 2 H, CH2–), 4.02 (dd, J = 5.0, 8.7 Hz, 1 H, 6-H), 4.17 (dd,
J = 6.2, 8.8 Hz, 1 H, 6-H), 4.26 (dd, J = 6.5, 8.0 Hz, 1 H, 4-H),
4.49 (ddd, J = 5.0, 6.2, 8.0 Hz, 1 H, 5-H), 4.96 (dd, J = 2.6, J =
6.5 Hz, 1 H, 3-H), 5.22 (d, J = 2.6 Hz, 1 H, 2-H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 25.1, 26.8, 47.1, 66.9, 72.7, 73.3, 85.6, 102.3,
109.4, 157.4 ppm. EI-MS 241.1 [M]+.
General Procedure D. Suzuki Cross-Couplings between 1Ј-Halo-exo-
glycals and Boronic Acids: NaOH (2 , 3 mmol) was added to a
mixture of the appropriate alkenyl halide (28–30, 1 mmol) and the
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-morpholino-5-
(thiophen-3-ylmethylene)tetrahydrofuran-3-ol (41d): This compound
Eur. J. Org. Chem. 2010, 5619–5632
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5629

A. M. Gómez, A. Pedregosa, C. Uriel, S. Valverde, J. C. López
FULL PAPER
was prepared from the bromide 29a (91 mg, 0.25 mmol) or the io-
dide 29b (103 mg, 0.25 mmol) and thiophene-3-boronic acid
(41 mg, 0.32 mmol) by General Procedure D followed by silica gel
column chromatography (hexane/EtOAc 3:7). Compound 41d
(79 mg, 86% and 85 mg, 93%, respectively) [α]2D5 = +29.7 (c = 1.3,
27.2, 50.9 (ϫ2), 51.1 (ϫ2), 55.6, 67.7, 71.6, 73.6, 75.5, 85.3, 98.7,
109.9, 111.3, 118.4, 121.0, 121.2, 123.3, 124.8, 128.4, 136.7, 141.3,
152.4, 153.1 ppm. EI-MS 472.0 [M]+. C25H32N2O5S (472.20): calcd.
C 63.54, H 6.82, N 5.93; found C 63.61, H 6.60, N 5.78.
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(4-methoxy-
benzylidene)-4-[4-(2-methoxyphenyl)piperazin-1-yl]tetrahydrofuran-
3-ol (41h): This compound was prepared from the bromide 30a
(117 mg, 0.25 mmol) or the iodide 30b (130 mg, 0.25 mmol) and p-
methoxyphenylboronic acid (49 mg, 0.32 mmol) by General Pro-
cedure D followed by silica gel column chromatography (hexane/
EtOAc 3:7). Compound 41h (92 mg, 74 % and 102 mg, 82 %,
respectively) [α]2D5 = +54.9 (c = 0.6, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 1.42 (s, 3 H, Me), 1.52 (s, 3 H, Me), 2.86 (m, 4 H,
2ϫ CH2–N), 3.10 (m, 4 H, 2ϫ CH2–N), 3.59 (s, 1 H, 2-H), 3.83
(s, 3 H, OMe), 3.89 (s, 3 H, OMe), 4.15 (dd, J = 4.3, 8.6 Hz, 1 H,
6-H), 4.29 (dd, J = 5.9, 8.9 Hz, 1 H, 6-H), 4.49 (m, 2 H, 4-H and
5-H), 4.50 (s, 1 H, 3-H), 5.50 (s, 1 H, 1Ј-H), 6.92 (m, 6 H, Harom),
7.52 (d, J = 8.8 Hz, 2 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz):
δ = 25.6, 27.3, 51.1 (ϫ2), 55.7 (ϫ2), 59.5, 67.9, 71.6, 73.8, 76.2,
85.5, 103.7, 110.0, 111.5, 114.1, 118.6, 121.4, 123.4, 129.1 (ϫ2),
129.5 (ϫ2), 141.5, 152.6, 157.9 ppm. API-ES positive 497.3 [M +
H]+. C28H36N2O6 (496.26): calcd. C 67.72, H 7.31, N 5.64; found
C 67.68, H 7.16, N 5.41.
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.39 (s, 3 H, Me), 1.48
(s, 3 H, Me), 2.63 (m, 4 H, 2ϫ CH2–N), 3.43 (s, 1 H, 2-H), 3.69
(m, 4 H, 2ϫ CH2–O), 4.13 (dd, J = 4.1, 8.2 Hz, 1 H, 6-H), 4.24
(dd, J = 4.7, 7.8 Hz, 1 H, 6-H), 4.48 (m, 3 H, 3-H, 4-H, 5-H),
5.50 (s, 1 H, 1Ј-H), 7.27 (m, 3 H, Harom) ppm. 13C NMR (CDCl3,
50 MHz): δ = 25.2, 26.9, 51.2 (ϫ2), 67.1 (ϫ2), 67.5, 71.5, 73.3,
75.3, 84.8, 98.8, 109.7, 120.9, 124.6, 128.1, 136.2, 152.1 ppm. API-
ES positive 368.0 [M + 1]+. C18H25NO5S (367.15): calcd. C 58.83,
H 6.86, N 3.81; found C 58.71, H 6.69, N 3.67.
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(4-methoxy-
benzylidene)-4-morpholinotetrahydrofuran-3-ol (41e): This com-
pound was prepared from the bromide 29a (91 mg, 0.25 mmol) or
the iodide 29b (103 mg, 0.25 mmol) and p-methoxyphenylboronic
acid (49 mg, 0.32 mmol) by General Procedure D followed by silica
gel column chromatography (hexane/EtOAc 3:7). Compound 41e
(73 mg, 75% and 84 mg, 86%, respectively) [α]2D5 = +38.6 (c = 0.6,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.37 (s, 3 H, Me), 1.46
(s, 3 H, Me), 2.62 (m, 4 H, 2ϫ CH2–N), 3.42 (s, 1 H, 2-H), 3.69
(m, 4 H, 2ϫ CH2–O), 3.79 (s, 3 H, OMe), 4.08 (dd, J = 4.3, 8.6 Hz,
1 H, 6-H), 4.20 (dd, J = 5.6, 8.5 Hz, 1 H, 6-H), 4.41 (m, 3 H, 3-H,
4-H and 5-H), 5.38 (s, 1 H, 1Ј-H), 6.84 (d, J = 8.8 Hz, 2 H, Harom),
7.46 (d, J = 8.8 Hz, 2 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz):
δ = 25.6, 27.2, 51.6 (ϫ2), 55.7, 67.6 (ϫ2), 71.5, 73.9, 74.7, 76.4,
85.5, 103.9, 109.7, 114.1 (ϫ2), 129.4 (ϫ2), 133.5, 152.0, 157.9 ppm.
API-ES positive 392.1 [M + 1]+. C21H29NO6 (391.20): calcd. C
64.43, H 7.47, N 3.58; found C 64.25, H 7.31, N 3.49.
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-[4-(2-methoxy-
phenyl)piperazin-1-yl]-5-(4-methylbenzylidene)tetrahydrofuran-3-ol
(41i): This compound was prepared from the bromide 30a (117 mg,
0.25 mmol) or the iodide 30b (130 mg, 0.25 mmol) and p-methyl-
phenylboronic acid (44 mg, 0.32 mmol) by General Procedure D
followed by silica gel column chromatography (hexane/EtOAc 3:7).
Compound 41i (79 mg, 66% and 81 mg, 67%, respectively). [α]2D5
=
1
+39.8 (c = 1.6, CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.38 (s,
3 H, Me), 1.46 (s, 3 H, Me), 2.32 (s, 3 H, Me), 2.82 (m, 4 H, 2ϫ
CH2–N), 3.08 (m, 4 H, 2ϫ CH2–N), 3.57 (s, 1 H, 2-H), 3.86 (s, 3
H, OMe), 4.10 (m, 2 H, 4-H and 6-H), 4.23 (dd, J = 4.9, 8.5 Hz, 1
H, 6-H), 4.38 (m, 1 H, 5-H), 4.60 (s, 1 H, 3-H), 5.46 (s, 1 H, 1Ј-
H), 6.86 (d, J = 8.0 Hz, 2 H, Harom), 7.01 (m, 4 H, Harom), 7.45 (d,
J = 8.0 Hz, 2 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz): δ =
21.1, 25.3, 26.9, 50.5 (ϫ2), 50.8 (ϫ2), 55.3, 67.5, 72.5, 73.3, 74.4,
84.8, 103.6, 109.7, 111.1, 118.2, 120.9, 123.1, 127.8 (ϫ2), 128.9
(ϫ2), 132.9, 135.2, 140.9, 152.2, 155.6 ppm. EI-MS 480.2 [M]+.
C28H36N2O5 (480.26): calcd. C 69.98, H 7.55, N 5.83; found C
69.73, H 7.37, N 5.61.
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(4-methyl-
benzylidene)-4-morpholinotetrahydrofuran-3-ol (41f): This com-
pound was prepared from the bromide 29a (91 mg, 0.25 mmol) or
the iodide 29b (103 mg, 0.25 mmol) and p-methylphenylboronic
acid (44 mg, 0.32 mmol) by General Procedure D followed by silica
gel column chromatography (hexane/EtOAc 3:7). Compound 41f
(68 mg, 73% and 71 mg, 76%, respectively). [α]2D5 = +63.1 (c = 0.4,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.39 (s, 3 H, Me), 1.49
(s, 3 H, Me), 2.32 (s, 3 H, Me), 2.65 (m, 4 H, 2ϫ CH2–N), 3.44 (s,
1 H, 2-H), 3.70 (m, 4 H, 2ϫ CH2–O), 4.12 (dd, J = 4.4, 9.0 Hz, 1
H, 6-H), 4.25 (dd, J = 5.6, 8.5 Hz, 1 H, 6-H), 4.41 (m, 3 H, 3-H,
4-H, 5-H), 5.41 (s, 1 H, 1Ј-H), 7.10 (d, J = 8.0 Hz, 2 H, Harom),
7.42 (d, J = 8.0 Hz, 2 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz):
δ = 21.6, 25.6, 27.3, 51.6 (ϫ2), 67.6 (ϫ2), 67.9, 71.7, 73.8, 76.3,
85.4, 104.4, 110.1, 129.0 (ϫ2), 132.3 (ϫ2), 133.1, 135.8, 152.6 ppm.
API-ES positive 376.1 [M + 1]+. C21H29NO5 (375.20): calcd. C
67.18, H 7.79, N 3.73; found C 66.94, H 7.65, N 3.58.
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-(piperidin-1-
yl)-5-(pyridin-3-ylmethylene)tetrahydrofuran-3-yl acetate (45b): A
solution of compound 45a (50 mg, 0.14 mmol) in pyridine (5 mL)
was treated with an excess of Ac2O (500 µL). After the mixture had
been stirred at room temperature for 10 h, the crude product was
concentrated and the residue was purified by chromatography (hex-
ane/EtOAc 1:1) to give the acetyl derivative 45b (54.5 mg, 97%).
1
[α]2D5 = +18.7 (c = 0.6, CHCl3). H NMR (CDCl3, 300 MHz): δ =
(2S,3R,4R,Z)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-[4-(2-methoxy-
phenyl)piperazin-1-yl]-5-(thiophen-3-ylmethylene)tetrahydrofuran-3-
ol (41g): This compound was prepared from the bromide 30a
(117 mg, 0.25 mmol) or the iodide 30b (130 mg, 0.25 mmol) and
thiophene-3-boronic acid (42 mg, 0.32 mmol) by General Pro-
cedure D followed by silica gel column chromatography (hexane/
EtOAc 3:7). Compound 41g (85 mg, 72% and 91 mg, 77%, respec-
tively) [α]2D5 = +36.6 (c = 0.7, CHCl3). 1H NMR (CDCl3, 300 MHz):
δ = 1.39 (s, 3 H, Me), 1.49 (s, 3 H, Me), 2.86 (m, 4 H, 2ϫ CH2–
N), 3.09 (m, 4 H, 2ϫ CH2–N), 3.59 (s, 1 H, 2-H), 3.89 (s, 3 H,
OMe), 4.16 (dd, J = 4.9, 8.7 Hz, 1 H, 6-H), 4.27 (dd, J = 6.2,
8.1 Hz, 1 H, 6-H), 4.44 (m, 2 H, 4-H and 5-H), 4.59 (s, 1 H, 3-H),
1.36 (s, 3 H, Me), 1.47 (s, 3 H, Me), 1.56 (m, 6 H), 2.05 (s, 3 H,
Me), 2.54 (m, 2 H), 2.67 (m, 2 H), 3.57 (s, 1 H, 2-H), 4.13 (m, 2
H, 4-H and 6-H), 4.32 (dd, J = 5.8, 12.8 Hz, 1 H, 6-H), 4.64 (dd,
J = 4.7, 7.3 Hz, 1 H, 5-H), 5.41 (d, J = 1.8 Hz, 1 H, 3-H), 5.49
(dd, J = 1.8, 4.4 Hz, 1 H, 1Ј-H), 7.42 (dd, J = 4.7, 8.3 Hz, 1 H),
8.06 (d, J = 8.1 Hz, 1 H), 8.34 (dd, J = 1.3, 4.7 Hz, 1 H), 8.70 (d,
J = 1.4 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 21.2, 25.3,
27.1, 51.6 (ϫ2), 66.7, 67.2 (ϫ2), 72.4, 72.9, 74.1, 77.4, 84.5, 98.6,
109.9, 125.0, 133.9, 136.9, 143.9, 146.7, 157.5, 169.9 ppm. API-ES
positive 403.3 [M + H]+. C22H30N2O5 (402.22): calcd. C 65.65, H
7.51, N 6.96; found C 65.48, H 7.38, N 6.83.
5.59 (s, 1 H, 1Ј-H), 6.96 (m, 4 H, Harom), 7.25 (m, 2 H, Harom), General Procedure E. Cleavage of the Isopropylidene Acetal Units in
7.33 (m, 1 H, Harom) ppm. 13C NMR (CDCl3, 50 MHz): δ = 25.5,
Compounds 45b and 47: A solution of the corresponding compound
5630
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5619–5632

Preparation of Furanose-Based Templates
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(0.12 mmol) in a THF/H2O mixture (3 mL, 2:1, v/v) was acidified
with AcOH (2 mL). The reaction mixture was heated at 75 °C for
10 h, after which it was concentrated and the residue was purified
by flash chromatography.
(2R,3R,4R,Z)-2-(1,2-Dihydroxyethyl)-4-(piperidin-1-yl)-5-(pyridin-
3-ylmethylene)tetrahydrofuran-3-yl Acetate (46): This compound
was prepared from the acetonide 45a (50 mg, 0.12 mmol) by Gene-
ral Procedure E, giving compound 46 (32 mg, 75%) after silica gel
column chromatography (EtOAc/MeOH 8:2). 1H NMR (CDCl3,
300 MHz): δ = 1.42 (m, 2 H), 1.58 (m, 4 H), 2.10 (s, 3 H), 2.59 (m,
4 H), 3.59 (s, 1 H), 4.34 (m, 2 H), 4.48 (m, 2 H), 4.61 (dd, J = 1.5,
4.4 Hz, 1 H), 5.34 (s, 1 H), 7.44 (dd, J = 4.6, 8.2 Hz, 1 H), 8.16 (d,
J = 8.1 Hz, 1 H), 8.35 (dd, J = 1.2, 4.6 Hz, 1 H), 8.76 (d, J =
1.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 21.2, 24.5,
26.3 (ϫ2), 51.9 (ϫ2), 66.4, 69.2, 71.8, 77.1, 83.9, 99.5, 123.6, 132.4,
134.9, 145.4, 148.5, 156.8, 171.8 ppm. API-ES positive 363.5 [M +
H]+. C19H26N2O5 (362.18): calcd. C 62.97, H 7.23, N 7.73; found
C 62.81, H 7.17, N 7.82.
[4]
1-[(2S,3R,4R,Z)-3-Hydroxy-4-morpholino-5-(pyridin-3-ylmeth-
ylene)tetrahydrofuran-2-yl]ethane-1,2-diol (48): This compound was
prepared from the acetonide 47 (50 mg, 0.12 mmol) by General
Procedure E, giving compound 46 (21 mg, 56%) after silica gel col-
umn chromatography (EtOAc/MeOH 8:2). 1H NMR (CDCl3,
300 MHz): δ = 3.40 (m, 4 H), 3.51 (s, 1 H, 2-H), 3.56 (m, 4 H),
3.75 (dd, J = 6.6, 11.6 Hz, 1 H), 3.99 (d, J = 3.3 Hz, 1 H), 4.25 (m,
2 H), 4.62 (dd, J = 3.3, 8.3 Hz, 1 H, 1 H), 5.59 (s, 1 H), 7.40 (dd,
J = 4.9, 8.0 Hz, 1 H), 8.15 (d, J = 8.3 Hz, 1 H), 8.30 (dd, J = 1.5,
4.9 Hz, 1 H), 8.74 (d, J = 1.5 Hz, 1 H) ppm. 13C NMR (CDCl3,
50 MHz): δ = 51.6 (ϫ2), 63.9, 66.9 (ϫ2), 69.2, 70.6, 76.8, 84.8,
99.2, 123.7, 133.2, 135.3, 144.9, 147.8, 157.2 ppm. API-ES positive
323.2 [M + H]+. C16H22N2O5 (322.15): calcd. C 59.61, H 6.88, N
8.69; found C 59.70, H 6.97, N 8.83.
Acknowledgments
[5]
[6]
[7]
This research was supported with funds from the Ministerio de
Ciencia e Innovación (MICINN) (Grants CTQ2006-15279-C03-02
and CTQ2009-10343), the Comunidad de Madrid (Grant S2009/
PPQ-1752), and Janssen-Cilag SA. A. P. is thankful to Janssen-
Cilag SA for financial support. We are grateful to Ms. Marina Rod-
riguez for skilful technical assistance and to Dr. Aitor Barrio for
the preparation of compound 9.
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Received: May 3, 2010
Published Online: August 24, 2010
5632
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