Alkynyl-2-deoxy-d-riboses, a cornucopia for the generation of families of C-nucleosides

Article abstract of DOI:10.1016/j.tet.2010.09.046

This study focuses on the preparation of some 1-alkynyl-2-deoxy-d-riboses and their application to the generation of C-nucleosides analogues. Examples are provided in which the alkyne functionality took part in alkylation or cycloaddition reactions. A discussion of the protecting group used is provided.

Full text of DOI:10.1016/j.tet.2010.09.046

Tetrahedron 66 (2010) 9242e9251
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Alkynyl-2-deoxy-
D
-riboses, a cornucopia for the generation of families
of C-nucleosides
*
Mauro F.A. Adamo , Roberto Pergoli, Maria Moccia
Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical and Medicinal Chemistry, The Royal College of Surgeons in Ireland, 123 St. Stephen’s Green,
Dublin 2, Dublin, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2010
Received in revised form 24 August 2010
Accepted 13 September 2010
Available online 18 September 2010
This study focuses on the preparation of some 1-alkynyl-2-deoxy-D-riboses and their application to the
generation of C-nucleosides analogues. Examples are provided in which the alkyne functionality took
part in alkylation or cycloaddition reactions. A discussion of the protecting group used is provided.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
C-Nucleosides
1-Alkynylsugars
Anti microbial
Diversity oriented synthesis
1. Introduction
unnatural C-nucleosides. Central to the design of compound 1 was
the synthetic versatility of the alkyne functionality (Scheme 1).
The emergence of antibiotic resistance and the occurrence of
novel virus epidemics justify research into novel anti microbial
agents. Nature has provided several nucleoside analogues that
possess pertinent biological activities: bredinine1 (Mizoribine) is an
imidazole nucleoside antibiotic clinically used as an immunosup-
pressant;2 toyocamycin,3 mycalisin A4 and thiosangivamycin3 are
three naturally occurring nucleosides capable of potent antiviral
and antitumour activity; pseudouridine,5 showdomycin,6 pyr-
azofurin7 and tiazofurin8 have potent activity against bacteria, virus
and certain cancer lines. C-Nucleosides are a peculiar class of ana-
logues in which the CeN bond linking the heterocycle and the sugar
is substituted by a CeC bond. This modification renders the
nucleoside stable towards bacterial hydrolases and enables these
molecules to interfere with DNA and RNA synthases.9,10 Several
synthetic strategies have been reported for the preparation of 2-
Lately, interest has increased on the medicinal chemistry of alkynyl
substituted nucleosides.15,16 For example, Matzuda described the
preparation and bioactivity of 30-alkynyl cytosine and 30-alkynyl
uridine.15 The presence of an additional electrophilic element
(alkyne) imparted to these molecules a high antitumour activity.
40-Alkynyl nucleosides have been prepared and found to be re-
markably active against HIV.16 The high activity displayed by
30- and 40-alkynyl nucleosides poses questions about the activity of
other alkynyl nucleosides including 1-alkynylnucleosides ana-
logues. With this in mind, we set out to develop a synthetic route to
prepare families of C-nucleosides starting from compound 1.
OBn
OBn
O
O
O
BnO
BnO
deoxy-D-ribose and D
-ribose C-nucleosides,11,12 the most prominent
O
CO Et
2
9
O
O
BnO
BnO
being (i) Heck reaction of 3,5-dihydroxy dihydrofurans and aryl
halides, (ii) addition of an aryl lithium to 20-deoxyribonolactones
followed by reduction of the resulting hemiketal, (iii) nucleophilic
substitution on a protected 10-Cl-20-deoxyribose (Hoffer’s chlor-
osugar), (iv) elaboration of 10-CN-20-deoxyribose. Our group13 and
others14 have recently shown the synthetic potential of 10-alkynyl
deoxyriboses 1, which were employed to generate several classes of
2
N
BnO
BnO
O
OH
5
O
O
O
O
RO
N
3
BnO
R = Bn 6
R = Ac 7
RO
OH
BnO
BnO
1
BnO
O
O
O
BnO
BnO
4
BnO
BnO
8
* Corresponding author. Tel.: þ353 1 4022208; fax: þ353 1 402168; e-mail
Scheme 1. Preparation of C-nucleosides analogues 2e9.
address: madamo@rcsi.ie (M.F.A. Adamo).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.046

M.F.A. Adamo et al. / Tetrahedron 66 (2010) 9242e9251
9243
In this context, we have also revisited the synthesis of scaffolds
1, identifying an improved methodology to access selectively 1
and 1b 13
Compounds 1 and 1 were subsequently used to gen-
erate C-nucleosides 2e9 in both their and anomeric series. For
simplicity, Scheme 1 shows only the less popular anomer.
We like now to give a full account of this study including the
preparation of additional types of C-nucleosides from 1 and 1
presence of suitable radical scavengers, but no improvement was
a
noted. Debenzylation of nucleosides 3a and 3b was attempted by
.
a
b
other reported methodologies including iodotrimethylsilane,17 Pd0
and formic acid,18 Pd(OH)2 and ammonium formate19 or LiAlH4,20
but in all cases gave several undesired products. Similarly, reaction
of C-nucleosides 5 and 8 and BCl3 led to extensive decomposition of
starting material without furnishing the desired diols.
a
b
a
a
b
and optimal conditions identified for the deprotection of desired C-
nucleosides.
Delightfully, dialkynes 9
a
and 9
b
, obtained by homocoupling of
and 14 in
parents 1 and 1 , reacted with BCl3 to give 14
a
b
a
b
excellent isolated yields. This indicated the benzyl group to be an
un-optimal protecting group. In order to enlarge the number of
compounds obtainable, we have explored alternative protecting
2. Results and discussion
With C-nucleosides 2e9 in hand,13 we have submitted these
compounds to a few debenzylation procedures. This step is indeed
essential as unprotected compounds are required for biological
evaluation. The choice of suitable conditions for debenzylating
compounds 2e9 was unobvious considering the presence of differ-
entfunctionalities in thesecompounds. Infirstinstance, wefocussed
on procedures employing BCl3, as this reagent was used in the
deprotection of related benzyl protected 2-deoxy-C-nucleosides.15
Propargylic alcohols 3, 4 and 1016 were then reacted with BCl3
(Table 1). Compounds 4 and 10 (Table 1) reacted promptly and the
groups for 1-alkynyl-2-deoxy-
tion, the acetyl group was selected as a useful replacement.
Hence, benzyl alkynyl nucleosides and were in-
D-riboses. After some experimenta-
1a
1b
dependently treated with BCl3 and the resulting diol reacted in situ
with excess acetic anhydride. Delightfully, this procedure gave the
desired compounds 15
(Scheme 2).13 Compounds 15
versatility compared to parents 1
a
and 15
b in excellent isolated yields
a
and 15
b
showed a higher synthetic
allowing the preparation
and 15
a
and 1b
of a wider range of derivatives. The use of compounds 15
a
b
as starting material for (i) Sonogashira coupling, (ii) 1,3-dipolar
cycloaddition, (iii) [2þ2þ2] cycloaddition and (iv) PausoneKhand
reaction is discussed below. Importantly these are modular pro-
cesses, which would allow expansion of these examples in families
of C-nucleosides by variation of one reagent at the time.
desired 11
a
,11
b,12
a
and 12
b
were obtained in good isolated yields.
containing a furyl aromatic group
Conversely, compounds 3
a
and 3
b
furnished a complex mixture of products that could not be isolated.
A possible explanation lies in the reactivity of furan with oxidizing
Lewis acids such as BCl3. Possibly, the oxygen of furan reacted with
boron starting a cascade of reactions that ultimately lead to several
unwanted products. We have also attempted this reaction in the
1) BCl 2 equiv.
3
O
O
AcO
AcO
BnO
BnO
CH Cl dry
2
2
2) Ac O,Py
2
Table 1
1β
15β 93%
DMAP, CH Cl
2
2
Isolated yields of deprotected 1-alkynyl-polyols 11, 12 and 14
Entry
1
Substrate
Product
Yieldsa (%)
60
1) BCl 2 equiv.
3
O
O
BnO
BnO
CH Cl dry
AcO
AcO
2
2
2) Ac O,Py
2
4
4
a
b
1α
15α 91%
DMAP, CH Cl
2
2
Scheme 2. Preparation of acetyl-protected 1-alkynyl-20-deoxy-D-riboses 15
a and 15b.
2
3
54
50
We reported the Sonogashira coupling of compounds 1
give only low yields of the desired cross-coupling products 1
b 13
This reaction gave compounds 9 and 9 as the major prod-
a
and 1
b
a
and
1
.
a
b
ucts, which arose from homocoupling of the starting material. A
survey of the literature revealed that copper acetylides undergo
homocoupling when exposed to air. Hay reported that the Cu(I) salt
in the presence of amine solvents promoted homocoupling of ter-
minal ethynes at room temperatures and in the presence of O2.21
Others reported the use of Pd(II) complexes to obtain butadiynes
as the major product.22 Acetylene homocoupling is sometimes
observed under Sonogashira conditions. In this context, it was
recently reported that a reducing atmosphere (H2) could reduce the
extent of homocoupling therefore improving the yield of the
10
10
a
b
4
5
6
58
desired cross-coupling compound.23 We reacted 1
2-chloropyridine under a reducing atmosphere. Nevertheless, this
reaction gave 6 or 6 in similar low yields, with the cross-coupling
product 9 or 9 , being the main product. We identified the
problem in the steric properties of starting materials 1 and 1 , in
a
or 1b with
3
a
/3
b
d
a
b
a
b
a
b
9
9
a
b
98
98
particular of their protecting group. It has been shown that steric
properties of protecting groups at 30 and 50 have an influence on the
reactivity of 2-deoxy-
that Sonogashira coupling of compounds 15
sterically demanding acetyl group may proceed more efficiently.
Reaction of acetylated 1-alkynylsugars 15 and 15 and 2-chloro or
2-iodo pyridine gave the desired 16 and 16 in improved yields
and shorter reaction times (Scheme 3). Interestingly in these ex-
periments, compounds 9 and 9
were not obtained.25 Acetylated
D
-riboses.24 With this in mind, we reasoned
a
and 15b bearing a less
7
a
b
a
b
a
Isolated yields after column chromatography.
a
b

9244
M.F.A. Adamo et al. / Tetrahedron 66 (2010) 9242e9251
The reaction of terminal alkynes and azides has become
a prominent reaction in organic synthesis since click chemistry
N
N
concept was introduced by Sharpless.27 We reacted compounds
O
(PPh3)2PdCl2, CuI,
DIPEA 3 equiv.
O
NaOMe
0.3 equiv.
AcO
AcO
HO
15a and 15b with benzylazide under Cu(I) catalysis in a mixture
15β
2-I -pyridine 1 equiv.
HO
17β 84%
water/dichloromethane as the organic co-solvent (Scheme 6).
MeOH
DMF dry
16ββ 43%
Bn
N
Bn
benzyl azide 1 equiv.
CuSO4 5H2O 0.07 equiv.
Na ascorbate 0.13 equiv.
N
N
.
O
N
O
N
N
N
N
NaOMe
MeOH
AcO
AcO
HO
15β
(PPh3)2PdCl2, CuI,
O
NaOMe
0.3 equiv.
O
H2O:DCM 1:1
AcO
HO
23β 84%
DIPEA 3 equiv.
HO
15α
20β 82%
AcO
2-I- pyridine 1 equiv.
HO
17αα 83%
MeOH
DMF dry
16α 45%
Bn
Bn
N
benzyl azide 1 equiv.
N
Scheme 3. Preparation of 1-alkynylnucleosides 17a and 17b.
N
.
N
CuSO4 5H2O 0.07 equiv.
O
N
O
N
Na ascorbate 0.13 equiv.
NaOMe
MeOH
AcO
C-nucleosides 16
MeOH, a standard procedure to remove the acetoxy groups. This
reaction furnished C-nucleosides 17 and 17 in high isolated yields.
Importantly, it was verified by 1H NMR that no epimerization
occurred in the latter step for both the and anomer (Scheme 3).
The alkyne functionality is often employed as a dipolarophile in
1,3-dipolar cycloadditions. Similarly, 1-alkynyl-2-deoxy- -riboses
15 and 15 reacted with several 1,3-dipolar species. For example,
compounds 15 and 15 reacted with acetone in the presence of
cerium(IV) ammonium nitrate to give isoxazoles 18 and 18
a and 16b were subsequently reacted with NaOMe/
HO
15
AcO
H2O:DCM 1:1
HO
23α 98%
and 23
20α 88%
a
b
Scheme 6. Preparation of 1-alkynylnucleosides 23
a
b.
a
b
Delightfully, C-nucleosides 20a and 20b were obtained in high
D
yields and in short reaction times (2e4 h). As expected based on
published literature,28,29 only one regioisomer was obtained whose
structure was confirmed by NOE experiment. The new acetylated
C-nucleosides 18e20 (Schemes 3e5) were successfully deprotected
by treatment with NaOMe/MeOH to give the corresponding free
a
b
a
b
a
b
(Scheme 4). Treatment of acetone with CAN at reflux is a common
method to generate nitrile oxides in situ.26
C-nucleosides 21e23 in high isolated yields and as pure
anomers.
The transition-metal-catalyzed cyclotrimerization of alkynes is
an alternative method to build up C-nucleosides starting from
alkynyl sugars 15 and 15
30 In order to obtain useful unprotected
C-nucleosides 25 and 25 , we have submitted 15 and 15 to the
conditions reported by Hocek, obtaining acetylated C-nucleosides
24 and 24 (Scheme 7). Compounds 24 and 24 were then
treated with catalytic potassium carbonate to give C-nucleosides
25 and 25
a or
b
O
O
O
O
O
AcO
CAN 1 equiv.
HO
NaOMe
MeOH
N
N
O
15β
O
a
b.
b
AcO
HO
acetone reflux
a
a
b
18β 52%
21β 75%
a
b
a
b
O
O
O
AcO
CAN 1 equiv.
NaOMe
MeOH
HO
a
b.
15α
N
N
O
O
AcO
acetone reflux
HO
18α 47%
21α 91%
O
O
Scheme 4. Preparation of 1-alkynylnucleosides 21
a
and 21
b.
Dipropargyl ether
O
O
K2CO3
MeOH
(PPh3)3RhCl
AcO
AcO
15β
HO
Toluene dry
Reaction of 15
furnished the expected isoxazoles 18
regioisomer. Importantly in this reaction no epimerization of the
anomeric centre was observed. Compounds 18 and 18 contain
a
and 15
b
with the in situ generated nitrile oxide
HO
O
24β 36%
a
and 18 as a single
b
25β 82%
a
b
O
O
multiple H-bond acceptors and may find use in the preparation of
artificial DNAs containing unnatural nucleobases.14 Additionally,
Dipropargyl ether
O
K2CO3
MeOH
(PPh3)3RhCl
AcO
AcO
24α 35%
HO
the preparation of the isoxazole core in 18
several analogues could be prepared by variation of the ketone
employed. Similarly, alkynyl sugars 15 and 15 reacted with
benzaldehyde chloroxime to give the corresponding isoxazoles 19
and 19 in high yields (Scheme 5). The use of chloroximes is
a and 18b is modular and
15α
Toluene dry
HO
25α 77%
and 24
a
b
a
Scheme 7. Preparation of 1-alkynylnucleosides 23
a
b.
b
a common method for the in situ preparation of nitrile oxides
especially of the aromatic series.
The PausoneKhand reaction is a formal [2þ2þ1] cycloaddition
in which an alkyne reacts with an alkene in the presence of dico-
baltoctacarbonyl to yield a cyclopentenone.31 Recently, it has been
shown that reaction of the preformed dicobalthexacarbonyle
benzaldehyde
chloroxime 1 equiv.
Et3N 1 equiv.
Ph
Ph
Ph
Ph
O
HO
O
AcO
AcO
NaOMe
MeOH
alkyne complex such as 26
an excess of vinyl ethers or vinyl esters avoids the use of ethylene.32
We have reacted alkynes 15 and 15 with dicobaltoctacarbonyl
and have obtained complexes 26 and 26 in high isolated yields.
Complexes 26 and 26 were subsequently reacted with an excess
of vinyl benzoate and N-methylmorpholine N-oxide (NMO) to give
cyclopentenones 27 and 27 in high isolated yields. It must be
noted that the PausoneKhand reaction of 1-alkynyl-2-deoxy- -ri-
a and 26b (Scheme 8) in the presence of
N
O
N
15β
O
HO
DCM r.t 3d.
a
b
22β 87%
19β 85%
a
b
benzaldehyde
chloroxime 1 equiv.
Et3N 1 equiv.
a
b
O
O
AcO
AcO
HO
NaOMe
MeOH
15α
a
b
N
N
O
O
HO
DCM r.t 3d.
D
19α 84%
22α 90%
and 22
boses was unaffected by the nature of the protecting group present
Scheme 5. Preparation of 1-alkynylnucleosides 22
a
b.
on the starting material: acetylated and benzylated substrates13

M.F.A. Adamo et al. / Tetrahedron 66 (2010) 9242e9251
9245
O
with water (3ꢂ5 mL) and the water layer was then concentrated in
vacuo. The residue was purified by flash chromatography on silica
vinyl benzoate,
NMO
O
AcO
AcO
Co2(CO)8
CH3CN
O
AcO
AcO
15β
gel eluting with ethyl acetate to give the title compound 11
b as
CH2Cl2
Co2(CO)6
a red oil (354.8 mg, 54% yield); Rf¼0.16 (ethyl acetate); [
a
]
25 ꢀ46.05
D
26ββ 89%
(c 0.15, CH3CN); nmax (KBr)/cmꢀ1 3388 (br), 2932, 2851, 2357, 2338,
1450, 1350, 1084, 1041; dH (CD3CN, 400 MHz) 4.74e4.69 (m, 1H),
4.23e4.21 (m, 1H), 4.11 (t, J¼6, 1H), 3.71e3.69 (m, 1H), 3.53 (t, J¼5,
2H), 3.17e3.15 (m, 2H), 2.74 (t, J¼6, 1H), 1.85e0.89 (m, 12H); dC
(100.6 MHz, CD3CN) 88.3, 86.5, 84.9, 73.3, 68.0, 67.0, 63.5, 45.0,
43.3, 29.3, 28.9, 27.1, 26.60; HRMS found: [MþNaþ] 277.1422,
C14H22NaO4 requires 277.1416; m/z: 254 (100%, Mþ).
27β 53%
O
O
vinyl benzoate,
NMO
Co2(CO)8
CH3CN
O
AcO
AcO
AcO
AcO
15αα
CH2Cl2
Co2(CO)6
26α 90%
27α 54%
Scheme 8. Preparation of acetyl-protected 1-alkynylnucleosides 27a and 27b.
4.3. 5S-(3-Cyclohexyl-3-hydroxy-prop-1-ynyl)-2R-
hydroxymethyl-tetrahydrofuran-3S-ol (11
a)
gave the correspondent enone in comparable yields. Unfortunately,
the deacetylation of 27 and 27 was unsuccessful despite the
several attempts made using either basic or acidic conditions.
a
b
To a stirred solution of 4 (1.48 g, 3.4 mmol) in dry DCM (96 mL)
a
was added BCl3 (1 M in DCM, 13.5 mL, 13.5 mmol, 2.0 equiv) by
syringe pump over a 20 min period at ꢀ78 ꢁC and the reaction
mixture was allowed to stir at ꢀ78 ꢁC for 90 min. The reaction
mixture was then quenched with methanol (5 mL) and allowed to
stir at room temperature for 16 h. The reaction mixture was washed
with water (3ꢂ5 mL) and the water layer was then concentrated in
vacuo. The residue was purified by flash chromatography on silica
3. Conclusion
In conclusion, we have developed a practical synthesis of
acetylated 1-alkynyl-2-deoxy- -riboses 15a and 15b. A wide range
D
of transformations was identified, which could be employed for the
generation of novel C-nucleosides. The reactions described herein
are modular in nature and will allow the generation of families of
compounds by the variation of one reagent. Therefore this study
provides a synthetic platform to those involved in the generation of
families of bioactive compounds and their screening.
gel eluting with ethyl acetate to give the title compound 11
a as
25
a green oil (516.7 mg, 60% yield); Rf¼0.17 (ethyl acetate); [
a]
D
ꢀ50.10 (c 0.51, CH3CN); nmax (KBr)/cmꢀ1 3388 (br), 2929, 2857, 2244
(br), 1645, 1452, 1336, 1085, 1022, 583; dH (CD3CN, 400 MHz) 4.72
(ddd, J1¼2, J2¼6, J3¼8, 1H), 4.14 (dt, J1¼5, J2¼7, 1H), 4.10 (dt, J1¼2,
J2¼6, 1H), 3.80 (dd, J1¼5, J2¼9, 1H), 3.58 (ddd, J1¼1, J2¼4, J3¼12, 1H),
3.50 (ddd, J1¼1, J2¼5, J3¼12, 1H), 1.92e1.06 (m, 15H); dC (100.6 MHz,
CD3CN) 86.6, 86.4, 85.8, 72.7, 67.8, 67.0, 62.8, 45.1, 43.0, 29.3, 28.9,
27.1, 26.6; HRMS found: [MþNaþ] 277.1418, C14H22NaO4 requires
277.1416; m/z: 254 (100%, Mþ).
4. Experimental section
4.1. General experimental
Melting points were determined using a Stuart scientific melt-
ing point apparatus and are uncorrected. Infrared spectra (IR) were
recorded as KBr discs using a Bruker Tensor27 FT-IR instrument.
4.4. Preparation of (L)-2R-hydroxymethyl-5R-(3-hydroxy-
pentadec-1-ynyl)-tetrahydrofuran-3S-ol (12
b)
Absorption maximum (nmax) was reported in wave numbers (cmꢀ1
)
and only selected peaks are reported. NMR experiments were
performed on a Bruker Avance 400 instrument and samples were
obtained in CDCl3 (referenced to 7.26 ppm for 1H and 77.0 ppm for
13C) in DMSO-d6 (referenced to 2.52 and 3.35 ppm for 1H and
40.0 ppm for 13C), in CD3CN (referenced to 1.96 ppm for 1H and
118.26 ppm for 13C) and D2O (referenced to 4.79 ppm for 1H).
Coupling constants (J) are in hertz. Multiplicities are reported as
follows: s, singlet, d, doublet, dd, doublets of doublets, t, triplet, q,
quartet, m, multiplet, c, complex and br, broad. High resolution
mass spectra were obtained on a Waters Micro mass LCT and low
resolution mass spectra were recorded on Waters Micro mass
Quattro LCMS spectrometers at 70 eV. Tetrahydrofuran and toluene
were freshly distilled over sodium benzophenone prior to use
according to standard procedure. All other reagents and solvents
were used as purchased from Aldrich. Reactions were checked for
completion by TLC (EM Science, silica gel 60 F254). Flash chroma-
tography was performed using silica gel 60 (0.040e0.063 mm,
230e400 mesh). Compounds 2e10 were synthesized by the
reported procedure.13
To a stirred solution of 10 (1.56 g, 3.00 mmol) in dry DCM
b
(84 mL) was added BCl3 (1 M in DCM,12.0 mL,12.0 mmol, 2.0 equiv)
by syringe pump over a 20 min period at ꢀ78 ꢁC and the reaction
mixture was allowed to stir at ꢀ78 ꢁC for 1.5 h. The reaction mixture
was then quenched with methanol (6 mL) and allowed to stir at
room temperature for 13 h. The reaction mixture was washed with
water (3ꢂ5 mL) and the organic layer was then dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash chro-
matography on silica gel eluting with chloroform/methanol 10:1 to
give the title compound 12b as a pale yellow wax (596.0 mg, 58%
25
yield); Rf¼0.30 (chloroform/methanol 10:1); [
a
]
D
ꢀ62.13 (c 0.17,
CHCl3); nmax (KBr)/cmꢀ1 3385 (b), 2925, 2843, 2362, 2343, 1471,
1361, 1092, 1052; dH (CDCl3, 400 MHz) 4.85e4.81 (m, 1H), 4.45 (br s,
1H), 4.39 (br s,1H), 3.89e3.86 (m,1H), 3.78e3.75 (m,1H), 3.69e3.66
(m,1H), 2.38 (br s, 2H), 2.23e2.18 (m, 3H),1.70e1.69 (m, 2H),1.25 (br
s, 20H), 0.88 (t, J¼6, 3H); dC (100.6 MHz, CDCl3) 86.9, 83.3, 72.9, 67.7,
62.6, 62.4, 62.3, 42.8, 37.6, 37.5, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2,
25.2, 22.7, 14.1; HRMS found: [MþNaþ] 363.2517, C20H36NaO4 re-
quires 363.2512; m/z: 340 (100%, Mþ).
4.2. 5R-(3-Cyclohexyl-3-hydroxy-prop-1-ynyl)-2R-
4.5. Preparation of (L)-2R-hydroxymethyl-5S-(3-hydroxy-
hydroxymethyl-tetrahydrofuran-3S-ol (11
b
)
pentadec-1-ynyl)-tetrahydrofuran-3S-ol (12
a)
To a stirred solution of 4 (1.11 g, 2.6 mmol) in dry DCM (72 mL)
b
To a stirred solution of 10 (1.78 g, 3.42 mmol) in dry DCM
a
was added BCl3 (1 M in DCM, 10.2 mL, 10.2 mmol, 2.0 equiv) by
syringe pump over a 20 min period at ꢀ78 ꢁC and the reaction
mixture was allowed to stir at ꢀ78 ꢁC for 90 min. The reaction
mixture was then quenched with methanol (5 mL) and allowed to
stir at room temperature for 15 h. The reaction mixture was washed
(96 mL) was added BCl3 (1 M in DCM,14.0 mL,14.0 mmol, 2.0 equiv)
by syringe pump over a 20 min period at ꢀ78 ꢁC and the reaction
mixture was allowed to stir at ꢀ78 ꢁC for 1.5 h. The reaction mixture
was then quenched with methanol (7 mL) and allowed to stir at
room temperature for 15 h. The reaction mixture was washed with

9246
M.F.A. Adamo et al. / Tetrahedron 66 (2010) 9242e9251
water (3ꢂ5 mL) and the organic layer was then dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash chro-
matography on silica gel eluting with chloroform/methanol 10:1 to
(3ꢂ5 mL) and the water layer was then concentrated in vacuo. The
crude oil so obtained was purified by flash chromatography eluting
with chloroform/methanol 4:1 to give the title compound A as
give the title compound 12
a
as a pale yellow wax (579.7 mg, 50%
a green oil (729 mg, 99% yield); Rf¼0.63 methanol/chloroform 1:4;
25
25
yield); Rf¼0.38 (chloroform/methanol 10:1); [
a
]
D
ꢀ65.41 (c 0.16,
[a
]
þ52.00 (c 0.50, CH3CN); nmax (KBr)/cmꢀ1 3385, 3291, 2955,
D
CHCl3); nmax (KBr)/cmꢀ1 3390 (br), 2933, 2868, 2373, 2350, 1482,
1331,1071,1035; dH (CDCl3, 400 MHz) 4.86e4.83 (m,1H), 4.38e4.32
(m, 2H), 4.19e4.17 (m, 1H), 4.12e4.06 (m, 2H), 3.76e3.68 (m, 2H),
3.35e3.34 (m, 1H), 2.51e2.44 (m, 1H), 2.15e2.06 (m, 1H), 1.73e1.62
(m, 2H),1.28 (br s, 20H), 0.90 (t, J¼7, 3H); dC (100.6 MHz, CDCl3) 87.4,
85.9, 84.1, 72.8, 67.7, 62.4, 62.1, 42.0, 37.6, 37.4, 31.9, 29.8, 29.7, 29.6,
29.5, 29.4, 29.3, 29.2, 22.8, 14.2; HRMS found: [MþNaþ] 363.2515,
C20H36NaO4 requires 363.2512; m/z: 340 (100%, Mþ).
2878, 1341, 1082, 1038, 658; dH (CD3CN, 400 MHz) 4.70e4.65
(m, 1H), 4.22 (q, J¼3, 1H), 3.71 (td, J1¼3, J2¼5, 1H), 3.51 (t, J¼5, 2H),
2.76 (d, J¼2, 1H), 2.13e2.02 (m, 2H); dC (100.6 MHz, CDCl3)
88.5, 84.2, 74.4, 73.3, 67.7, 63.4, 43.0; HRMS found: [MþHþ]
143.0708, C7H11O3 requires 143.0708; m/z: 142 (100%, Mþ). Part B:
Preparation of (2R,3S,5R)-acetic acid 3-acetoxy-5-ethynyl-tetrahy-
drofuran-2-ylmethyl ester (15b). To a stirred solution of A (682 mg,
4.80 mmol) in DCM (9.8 mL) were sequentially added acetic an-
hydride (9.8 mL), pyridine (4.8 mL) and a catalytic amount of N,N-
dimethylaminopyridine (40 mg). The reaction mixture was stirred
at room temperature for 40 min, then diluted with DCM, washed
with HCl 10% (2ꢂ50 mL) and with NaHCO3 satd solution in water
(2ꢂ50 mL). The organic layer was dried over Na2SO4, concentrated
in vacuo, treated with toluene to evaporate the residual acetic acid
and purified by flash chromatography eluting with petroleum
4.6. 2R-Hydroxymethyl-5R-[4-[(2R,3S,5R)-2-hydroxymethyl-
3-hydroxy-tetrahydrofuran-5-yl]-buta-1,3-diynyl]-
tetrahydrofuran-3S-ol (14
b)
To a stirred solution of 9
b
(408.9 mg, 0.64 mmol) in dry DCM
(18.5 mL) was added BCl3 (1 M in DCM, 5.3 mL, 5.3 mmol, 2.1 equiv)
by syringe pump over a 20 min period at ꢀ78 ꢁC and the reaction
mixture was allowed to stir at ꢀ78 ꢁC for 1.5 h. The reaction mixture
was then quenched with methanol (4 mL) and allowed to stir at
room temperature for 20 h. The reaction mixture was washed with
water (3ꢂ5 mL) and the water layer was then concentrated in vacuo.
The residue was purified by flash chromatography on silica gel
eluting with chloroform/methanol 4:1 to give the title compound
spirits/ethyl acetate 1:1 to give the title compound 15b as a yellow
oil (1.02 g, 94% yield); Rf¼0.33 ethyl acetate/petroleum spirits 1:4;
25
[a]
D
þ58.30 (c 0.67, CH2Cl2); nmax (KBr)/cmꢀ1 3269, 2966, 1743,
1385,1248,1049; dH (CDCl3, 400 MHz) 5.19e5.16 (m,1H), 4.75e4.70
(m, 1H), 4.29 (dd, J1¼4, J2¼11, 1H, H-5), 4.17e4.10 (m, 2H), 2.52 (d,
J¼2, 1H), 2.31e2.28 (m, 2H), 2.09 (s, 3H, CH3), 2.07 (s, 3H, CH3); dC
(100.6 MHz, CDCl3) 170.7, 170.4, 82.4, 81.6, 75.7, 74.1, 67.8, 64.0,
39.5, 20.9, 20.8; HRMS found: [MþHþ] 227.0919, C11H15O5 requires
227.0912; m/z: 226 (100%, Mþ).
14
b
as a pale yellow wax (176.7 mg, 98% yield); Rf¼0.19 (methanol/
chloroform 1:4); [
a
]
D
25 þ24.57 (c 1.38, CH3OH); nmax (KBr)/cmꢀ13407
(br), 2950, 2873, 2349, 2338; dH (D2O, 400 MHz) 4.85 (t, J¼8, 2H),
4.34e4.31 (m, 2H), 3.90e3.86(m, 2H), 3.63 (dd, J1¼4, J2¼12, 2H), 3.57
(dd, J1¼6, J2¼12, 2H), 2.21 (dd, J1¼4, J2¼8, 4H); dC (100.6 MHz, D2O)
86.8, 72.1, 67.7, 61.6, 40.7; HRMS found: [MþNaþ] 305.1009,
C14H18NaO6 requires 305.1001; m/z: 282 (100%, Mþ).
4.9. Preparation of (2R,3S,5S)-acetic acid 3-acetoxy-5-ethynyl-
tetrahydrofuran-2-ylmethyl ester (15a)
Part A: Preparation of (2R,3S,5S)-5-ethynyl-2-hydroxymethyl-tet-
rahydrofuran-3-ol (B). To a stirred solution of 1 (3.15 g, 9.8 mmol)
a
4.7. 2R-Hydroxymethyl-5S-[4-[(2R,3S,5S)-2-hydroxymethyl-3-
hydroxy-tetrahydrofuran-5-yl]-buta-1,3-diynyl]-
in dry DCM (275 mL) was added BCl3 (1 M in DCM, 40.0 mL,
40.0 mmol, 2.0 equiv) by a syringe pump over a 20 min period at
ꢀ78 ꢁC. The reaction mixture was stirred at ꢀ78 ꢁC for 1.5 h, then
quenched with methanol (16 mL), stirred at room temperature for
14 h, washed with water (3ꢂ5 mL) and the water layer was then
concentrated in vacuo. The residue was purified by flash chroma-
tography eluting with chloroform/methanol 4:1 to give the title
tetrahydrofuran-3S-ol (14
a)
To a stirred solution of 9
a
(340.0 mg, 0.53 mmol) in dry DCM
(15.4 mL) was added BCl3 (1 M in DCM, 4.4 mL, 4.4 mmol, 2.1 equiv)
by syringe pump over a 20 min period at ꢀ78 ꢁC and the reaction
mixture was allowed to stir at ꢀ78 ꢁC for 1.5 h. The reaction mix-
ture was then quenched with methanol (4 mL) and allowed to stir
at room temperature for 20 h. The reaction mixture was washed
with water (3ꢂ5 mL) and the water layer was then concentrated in
vacuo. The residue was purified by flash chromatography on silica
gel eluting with chloroform/methanol 4:1 to give the title com-
compound C as a green oil (1.36 g, 98% yield); Rf¼0.42 chloroform/
25
methanol 4:1; [
a]
ꢀ9.89 (c 0.46, CH3CN); nmax (KBr)/cmꢀ1 3379,
D
3291, 2939, 1633, 1088; dH (CD3CN, 400 MHz) 4.73e4.69 (m, 1H),
4.16 (dt, J1¼5, J2¼7, 1H), 3.82 (dd, J1¼5, J2¼9, 1H), 3.58 (dd, J1¼4,
J2¼12, 1H, H-5), 3.50 (dd, J1¼5, J2¼11, 1H, H-50), 2.88 (br s, 2H, 2-
OH), 2.76 (d, J¼2, 1H), 2.47 (dt, J1¼7, J2¼13, 1H, H-2), 1.93e1.90 (m,
1H, H-20); dC (100.6 MHz, CDCl3) 86.8, 85.1, 74.2, 72.7, 67.6, 62.7,
42.8; HRMS found: [MþHþ] 143.0709, C7H11O3 requires 143.0708;
m/z: 142 (100%, Mþ). Part B: Preparation of (2R,3S,5S)-acetic acid
pound 14
(methanol/chloroform 1:4); [
a
as a pale yellow wax (147.0 mg, 98% yield); Rf¼0.28
25
a
]
ꢀ25.64 (c 1.13, CH3OH); nmax
D
(KBr)/cmꢀ1 3429 (br), 2944, 2867, 2355, 2333; dH (D2O, 400 MHz)
4.91 (q, J¼4, 2H), 4.26 (q, J¼4, 2H), 4.02e3.99 (m, 2H), 3.63 (dd,
J1¼4, J2¼12, 2H), 3.53 (dd, J1¼6, J2¼12, 2H), 2.53e2.46 (m, 2H), 2.05
(dt, J1¼4, J2¼14, 2H); dC (100.6 MHz, D2O) 86.0, 71.5, 67.7, 61.0, 40.5;
HRMS found: [MþNaþ] 305.1005, C14H18NaO6 requires 305.1001;
m/z: 282 (100%, Mþ).
3-acetoxy-5-ethynyl-tetrahydrofuran-2-ylmethyl ester (15a). To a
stirred solution of B (1.14 g, 8.00 mmol) in DCM (12.6 mL) were
sequentially added acetic anhydride (12.6 mL), pyridine (6.3 mL)
and N,N-dimethylaminopyridine (40 mg). The reaction mixture
was stirred at room temperature for 35 min and then diluted with
DCM (50 mL), washed with HCl 10% (2ꢂ25 mL) and finally with
NaHCO3 satd (2ꢂ25 mL). The organic layer was dried over Na2SO4,
concentrated in vacuo, treated with toluene to evaporate the re-
sidual acetic acid and purified by flash chromatography eluting
with petroleum spirits/ethyl acetate 1:1 to give the title compound
4.8. Preparation of (2R,3S,5R)-acetic acid 3-acetoxy-5-
ethynyl-tetrahydrofuran-2-ylmethyl ester (15b)
Part A: Preparation of (2R,3S,5R)-5-ethynyl-2-hydroxymethyl-tet-
rahydrofuran-3-ol (A). To a stirred solution of 1 (1.66 g, 5.2 mmol)
b
15
a
as a yellow oil (1.72 g, 95% yield); Rf¼0.19 ethyl acetate/pe-
25
in dry DCM (145 mL) was added BCl3 (1 M in DCM, 21.0 mL,
21.0 mmol, 2.0 equiv) by a syringe pump over a 20 min period at
ꢀ78 ꢁC. The reaction mixture was then stirred at ꢀ78 ꢁC for 1.5 h,
then quenched with methanol (10 mL), washed with water
troleum spirits 1:4; [
a
]
þ35.69 (c 1.26, CH2Cl2); nmax (KBr)/cmꢀ1
D
3273, 2954, 1744, 1368, 1234, 1060; dH (CDCl3, 400 MHz) 5.08 (ddd,
J1¼3, J2¼4, J3¼7, 1H), 4.85 (ddd, J1¼2, J2¼4, J3¼8, 1H), 4.33 (dt, J1¼4,
J2¼5, 1H), 4.26 (dd, J1¼4, J2¼11, 1H, H-5), 4.14 (dd, J1¼5, J2¼11, 1H, H-

M.F.A. Adamo et al. / Tetrahedron 66 (2010) 9242e9251
9247
5), 2.57 (dt, J1¼8, J2¼14, 1H, H-2), 2.52 (d, J¼2, 1H), 2.18 (ddd, J1¼3,
J2¼4, J3¼14, 1H, H-2), 2.09 (s, 3H, CH3), 2.08 (s, 3H, CH3); dC
(100.6 MHz, CDCl3) 170.7,170.7, 82.5, 81.3, 74.9, 73.8, 67.7, 63.7, 39.2,
21.0, 20.8; HRMS found: [MþHþ] 227.0918, C11H15O5 requires
227.0912; m/z: 226 (100%, Mþ).
in vacuo and purified by flash chromatography eluting with chlo-
roform/methanol 4:1 to give the title compound 17 as a brown oil
b
(137.3 mg, 84%); Rf¼0.68 (methanol/chloroform 1:4); nmax (KBr)/
cmꢀ1 3383 (br), 2930, 2838, 1582, 1450, 1054, 761; dH (CDCl3,
400 MHz) 8.52e8.51 (d, J¼4, 1H), 7.67e7.63 (td, J1¼2, J2¼8, 1H),
7.44e7.42 (d, J¼8, 1H), 7.25e7.22 (m, 1H), 5.05e5.01 (at, J¼8, 1H),
4.51e4.49 (m, 1H), 4.29 (br s, 1H), 3.95 (d, J¼3, 1H), 3.77e3.69 (m,
3H), 2.34e2.31 (m, 2H); dC (100.6 MHz, CDCl3) 149.6, 142.3, 136.6,
127.3, 123.3, 88.8, 87.4, 84.3, 72.7, 67.8, 62.7, 42.4; HRMS found:
[MþHþ] 220.0964, C12H14NO3 requires 220.0974; m/z: 219
(100%, Mþ).
4.10. Preparation of acetic acid 3(S)-acetoxy-5(R)-pyridin-2-
ylethynyl-tetrahydrofuran-2(R)-ylmethyl ester (16
b)
To a stirred solution of 2-I-pyridine (240 l, 2.3 mmol, 1.2 equiv)
m
in dry DMF (16.0 mL) kept under a hydrogen atmosphere were
sequentially added dichlorobis(triphenylphosphine)-palladium(II)
(28.6 mg, 0.04 mmol, 0.02 equiv), copper(I) iodide (5.4 mg,
4.13. Preparation of (2R,3S,5S)-2-(hydroxymethyl)-5-(pyridin-
0.03 mmol, 0.02 equiv) and N,N-diisopropylethylamine (970
mL,
2-ylethynyl)-tetrahydrofuran-3-ol (17a)
5.57 mmol, 3.0 equiv) and a solution of 15 (417 mg, 1.8 mmol) in
b
dry DMF (9.0 mL). The reaction mixture was stirred at room tem-
perature for 10 days, then quenched with water and extracted with
ethyl acetate (3ꢂ50 mL). The organic layer was dried over Na2SO4,
concentrated in vacuo and treated with heptane to evaporate the
residual DMF. The crude compound obtained was purified by flash
chromatography eluting with petroleum spirits/ethyl acetate 1:1 to
To a stirred solution of 16
(13.0 mL) was added, at 0 ꢁC, a solution of sodium methoxide in
methanol 1 M (540 L, 0.54 mmol, 0.25 equiv) and the reaction
mixture was stirred at room temperature for 40 min. The reaction
was then quenched with HCl/MeOH 10% until pH¼7, concentrated
in vacuo and purified by flash chromatography eluting with chlo-
a (331.1 mg, 1.1 mmol) in methanol
m
give 16
b
as a brown oil (239 mg, 43%); Rf¼0.19 ethyl acetate/pe-
roform/methanol 4:1 to give the title compound 17a as a brown
troleum spirits 1:1; nmax (KBr)/cmꢀ1 3055, 2940, 1739, 1238; dH
(CDCl3, 400 MHz) 8.58e8.57 (m, 1H), 7.65 (td, J1¼2, J2¼8, 1H), 7.45
(dt, J1¼1, J2¼8, 1H), 7.25e7.23 (m, 1H), 5.23e5.21 (m, 1H), 5.00e4.96
(m, 1H), 4.33 (dd, J1¼3, J2¼11, 1H), 4.21e4.14 (m, 2H), 2.46e2.36 (m,
2H), 2.10 (s, 3H), 2.09 (s, 3H); dC (100.6 MHz, CDCl3) 170.7, 170.4,
150.0, 142.5, 136.2, 127.3, 123.2, 86.6, 84.9, 82.6, 75.7, 68.4, 64.0,
39.4, 21.0, 20.9; HRMS found: [MþHþ] 304.1174, C16H18NO5 re-
quires 304.1185; m/z: 304 (100%, MþHþ).
solid (199.3 mg, 83%); mp 92e94 ꢁC; Rf¼0.35 (methanol/chloro-
form 1:4); [
a
]
25 ꢀ16.95 (c 0.30, CH3OH); nmax (KBr)/cmꢀ1 3337 (br),
D
2963, 2920, 2361, 2342, 2219; dH (CD3CN, 400 MHz): 8.56e8.55 (m,
1H, Ar), 7.75 (td, J1¼2, J2¼8,1H, Ar), 7.48e7.43 (m,1H, Ar), 7.32 (ddd,
J1¼1, J2¼5, J3¼8, 1H, Ar), 4.96 (dd, J1¼8, J2¼5, 1H), 4.22 (dt, J1¼5,
J2¼7, 1H), 3.90 (dd, J1¼5, J2¼9, 1H), 3.57 (dd, J1¼4, J2¼12, 1H, H-5),
3.53 (dd, J1¼5, J2¼12, 1H, H-50), 3.24 (s, 1H, OH), 2.82 (s, 1H, OH0),
2.56 (dt, J1¼8, J2¼13, 1H, H-2), 2.08e2.02 (m, 1H, H-20); dC
(100.6 MHz, CD3CN) 150.9, 137.4, 128.0, 124.2, 90.1, 87.1, 84.8, 72.7,
68.1, 62.8, 42.6; HRMS found: [MþHþ] 220.0970, C12H14NO3 re-
quires 220.0974; m/z: 219 (100%, Mþ).
4.11. Preparation of acetic acid 3(S)-acetoxy-5(S)-pyridin-2-
ylethynyl-tetrahydrofuran-2(R)-ylmethyl ester (16
a)
To a stirred solution of 2-I-pyridine (320 l, 3.0 mmol,1.2 equiv),
m
4.14. Preparation of 1-(5-(4(S)-acetoxy-5(R)-(acetoxymethyl)-
in dry DMF (21.2 mL) kept under a hydrogen atmosphere were se-
quentially added dichlorobis(triphenylphosphine)-palladium(II)
(37.5 mg, 0.05 mmol, 0.02 equiv), copper(I) iodide (5.2 mg,
0.03 mmol, 0.01 equiv), N,N-diisopropylethylamine (1.29 mL,
tetrahydrofuran-2(R)-yl)isoxazol-3-yl)ethanone (18
b)
To a stirred solution of 15 (522.8 mg, 2.3 mmol) in acetone
b
(14.0 mL) was added cerium(IV) ammonium nitrate (1.29 g,
2.4 mmol,1.0 equiv), and the reaction mixture was allowed to stir at
reflux for 12 h and at room temperature for another 12 h. The re-
action mixture was then concentrated in vacuo and purified by
flash chromatography eluting with petroleum spirits/ethyl acetate
7.41 mmol, 3.0 equiv) and a solution of 15a (557.8 mg, 2.5 mmol) in
dry DMF (12.0 mL) and the reaction mixture was stirred at room
temperature for 14 days. The reaction mixturewas then diluted with
water and extracted with ethyl acetate (3ꢂ50 mL). The organic layer
was dried over MgSO4, concentrated in vacuo and treated with
heptane to evaporate the residual DMF. The residue was purified by
flash chromatography eluting with petroleum spirits/ethyl acetate
3:1 to give the title compound 18b as a yellow oil (372.4 mg, 52%
yield); Rf¼0.52 (ethyl acetate/petroleum spirits 1:1); [
a
]
25 þ17.48 (c
D
0.80, CH2Cl2); nmax (KBr)/cmꢀ1 3148, 2955, 1743, 1710, 1242; dH
(CDCl3, 400 MHz) 6.62 (d, J¼1, 1H, H-isox.), 5.30e5.27 (m, 2H), 4.32
(dd, J1¼4, J2¼12, 1H, H-5), 4.27 (td, J1¼2, J2¼6, 1H), 4.16 (dd, J1¼4,
J2¼12, 1H, H-50), 2.65 (s, 3H, CH3C]O), 2.48e2.35 (m, 2H, H-2þH-
20), 2.12 (s, 3H, CH3Ac), 2.09 (s, 3H, CH3Ac0); dC (100.6 MHz, CDCl3)
191.8, 172.6,170.6,170.4,161.9, 100.4, 83.1, 75.8, 72.5, 63.7, 37.6, 27.3,
21.0, 20.8; HRMS found: [MþHþ] 312.1095, C14H18NO7 requires
312.1083; m/z: 311 (100%, Mþ).
1:1 to give the title compound 16
Rf¼0.25 ethyl acetate/petroleum spirits 1:1; [
a as a brown oil (335 mg, 45%);
25
a
]
D
þ60.95 (c 0.53,
CHCl3); nmax (KBr)/cmꢀ1 3720 (br), 3037 (br), 1801, 1744, 1242, 1057;
dH (CDCl3, 400 MHz) 8.58 (ddd, J1¼1, J2¼2, J3¼5, 1H, Ar), 7.66 (td,
J1¼2, J2¼8, 1H, Ar), 7.44e7.42 (m, 1H, Ar), 7.25e7.23 (m, 1H, Ar),
5.15e5.09 (m, 2H), 4.40 (dt, J1¼4, J2¼5,1H), 4.30 (dd, J1¼4, J2¼12,1H,
H-5), 4.19 (dd, J1¼6, J2¼12, 1H, H-50), 2.68 (dt, J1¼8, J2¼14, 1H, H-2),
2.33 (dt, J1¼4, J2¼14, 1H, H-20), 2.10 (s, 3H, CH3), 2.09 (s, 3H, CH3); dC
(100.6 MHz, CDCl3) 170.8, 170.7, 150.0, 142.7, 136.1, 127.1, 123.1, 87.7,
84.9, 81.3, 74.8, 68.2, 63.7, 39.2, 21.0, 20.8; HRMS found: [MþHþ]
304.1173, C16H18NO5 requires 304.1185; m/z: 303 (100%, Mþ).
4.15. Preparation of 1-(5-(4(S)-acetoxy-5(R)-(acetoxymethyl)-
tetrahydrofuran-2(S)-yl)isoxazol-3-yl)ethanone (18
a)
To a stirred solution of 15 (760.0 mg, 3.4 mmol) in acetone
a
4.12. Preparation of (2R,3S,5R)-2-(hydroxymethyl)-5-
(pyridin-2-ylethynyl)-tetrahydrofuran-3-ol (17b)
(20.5 mL) was added cerium(IV) ammonium nitrate (1.86 g,
3.4 mmol,1.0 equiv), and the reaction mixture was allowed to stir at
reflux for 12 h and at room temperature for another 12 h. The re-
action mixture was then concentrated in vacuo and purified by
flash chromatography eluting with petroleum spirits/ethyl acetate
To a stirred solution of 16
(9.0 mL) was added, at 0 ꢁC, a solution of sodium methoxide in
methanol 1 M (370 L, 0.37 mmol, 0.25 equiv) and the reaction
b (225.1 mg, 0.74 mmol) in methanol
m
2:1 to give the title compound 18
a as a yellow oil (487.7 mg, 47%
mixture was stirred at room temperature for 40 min. The reaction
was then quenched with HCl/MeOH 10% until pH¼7, concentrated
yield); Rf¼0.23 (ethyl acetate/petroleum spirits 1:1); [
a]
25 þ55.18 (c
D
1.03, CH2Cl2); nmax (KBr)/cmꢀ1 3566 (br), 3137, 2966, 1743, 1704,

9248
M.F.A. Adamo et al. / Tetrahedron 66 (2010) 9242e9251
1457, 1363, 1236, 1054,; dH (CDCl3, 400 MHz) 6.62 (s, 1H, H-isox.),
5.36 (dd, J1¼4, J2¼8, 1H), 5.21e5.18 (m, 1H), 4.37e4.34 (m, 1H), 4.26
(dd, J1¼4.0, J2¼12, 1H, H-5), 4.19 (dd, J1¼5, J2¼12, 1H, H-50),
2.81e2.71 (m, 1H, H-2), 2.65 (s, 3H, CH3C]O), 2.40e2.35 (m, 1H, H-
20), 2.10 (s, 3H, CH3Ac), 1.98 (s, 3H, CH3Ac0); dC (100.6 MHz, CDCl3)
191.9, 174.1, 170.6, 170.4, 161.9, 100.0, 82.3, 75.0, 72.9, 63.7, 37.0, 27.3,
20.8; HRMS found: [MþHþ] 312.1090, C14H18NO7 requires
312.1083; m/z: 311 (100%, Mþ).
5.23e5.22 (m, 1H), 4.31 (dd, J1¼4, J2¼11, 1H, H-5), 4.20e4.12 (m,
2H), 2.43 (ddd, J1¼2, J2¼6, J3¼14, 1H, H-2), 2.39e2.31 (m, 1H, H-20),
0
2.10 (s, 3H, CH3), 1.98 (s, 3H, CH3 ); dC (100.6 MHz, CDCl3) 170.7,
170.5, 148.1, 134.4, 129.1, 128.8, 128.2, 121.1, 82.6, 76.3, 73.7, 64.1,
54.2, 38.6, 21.0, 20.7; HRMS found: [MþHþ] 360.1575, C18H22N3O5
requires 360.1559; m/z: 359 (100%, Mþ).
4.19. Preparation of (2R,3S,5S)-5-(1-benzyl-1H-1,2,3-triazol-4-
yl)-2-(acetoxymethyl)-3-(acetoxy)-tetrahydrofuran (20
a)
4.16. Preparation of (2R,3S,5R)-3-(acetoxy)-2-(acetoxymethyl)-
5-(3-phenylisoxazol-5-yl)-tetrahydrofuran (19
b)
A solution of 15 (210.5 mg, 0.9 mmol), benzylazide (160.0 mg,
a
1,2 mmol, 1.3 equiv), CuSO4$5H2O (17.0 mg, 0.07 mmol, 0.07 equiv)
and sodium ascorbate (27.9 mg, 0.14 mmol, 0.15 equiv) in H2O/DCM
1:1 (1.74 mL) was stirred at room temperature for 2 h. The solution
was then concentrated in vacuo and purified by flash chromatog-
raphy eluting with petroleum spirits to eliminate the excess of
To a stirred solution of benzaldehyde chloroxime (147.1 mg,
0.95 mmol, 1.0 equiv) in DCM (10.4 mL) was added, at 0 ꢁC, trie-
thylamine (150
mL, 1.1 mmol, 1.2 equiv) and, after 10 min, a solution
of 15 (204.4 mg, 0.9 mmol) in DCM (10.4 mL). The solution was
b
allowed to stir at room temperature for 3 days and then the mixture
was concentrated in vacuo and purified by flash chromatography
eluting with petroleum spirits/ethyl acetate 2:1 to give the title
azide and then with ethyl acetate to give compound 20a as a white
25
solid (292.9 mg, 88%); mp 76e77 ꢁC; Rf¼0.57 (ethyl acetate); [
a]
D
þ34.34 (c 0.50, CH2Cl2); nmax (KBr)/cmꢀ1 3142, 2955, 2360, 1738,
1231; dH (CDCl3, 400 MHz) 7.43 (s, 1H, H-triazole), 7.38e7.34 (m,
3H, Ph), 7.28e7.27 (m, 2H, Ph), 5.52 (d, J¼15, 1H, CH2Ph), 5.48 (d,
J¼15, 1H, CH2Ph), 5.35 (dd, J1¼6, J2¼8, 1H), 5.19e5.16 (m, 1H), 4.28
(dt, J1¼4, J2¼6, 1H), 4.23 (dd, J1¼4, J2¼12, 1H, H-5), 4.15 (dd, J1¼6,
J2¼12, 1H, H-50), 2.79e2.72 (m, 1H, H-2), 2.43 (ddd, J1¼4, J2¼6,
compound 19
b as a yellow solid (264.9 mg, 85% yield); mp
25
112e113 ꢁC; Rf¼0.23 (ethyl acetate/petroleum spirits 1:2); [
a]
D
ꢀ23.53 (c 0.60, CH2Cl2); nmax (KBr)/cmꢀ1 3136, 2927, 2360, 1748,
1225; dH (CDCl3, 400 MHz) 7.81e7.78 (m, 2H, Ph), 7.47e7.44 (m, 3H,
Ph), 6.56 (s, 1H, H-isox.), 5.32e5.28 (m, 2H), 4.38 (dd, J1¼4, J2¼12,
1H, H-5), 4.29 (td, J1¼2, J2¼4, 1H), 4.19 (dd, J1¼4, J2¼12, 1H, H-50),
0
J3¼14, 1H, H-20), 2.07 (s, 3H, CH3), 1.88 (s, 3H, CH3 ); dC (100.6 MHz,
2.51e2.39 (m, 2H, H-2þH-20), 2.13 (s, 3H, CH3), 2.08(s, 3H, CH3 ); dC
CDCl3) 170.7, 170.5, 149.4, 134.5, 129.1, 128.8, 128.1, 121.1, 81.3, 75.5,
73.5, 64.0, 54.2, 37.8, 20.8, 20.8; HRMS found: [MþHþ] 360.1542,
C18H22N3O5 requires 360.1559; m/z: 359 (100%, Mþ).
0
(100.6 MHz, CDCl3) 171.4, 170.6, 170.4, 130.1, 128.9, 126.8, 99.8, 83.0,
76.0, 73.0, 63.9, 37.6, 21.0, 20.8; HRMS found: [MþHþ] 346.1278,
C18H20NO6 requires 346.1291; m/z: 345 (100%, Mþ).
4.20. Preparation of 1-(5-((2R,4S,5R)-4-hydroxy-5-
4.17. Preparation of (2R,3S,5S)-3-(acetoxy)-2-(acetoxymethyl)-
(hydroxymethyl)-tetrahydrofuran-2-yl)isoxazol-3-yl)
5-(3-phenylisoxazol-5-yl)-tetrahydrofuran (19
a
)
ethanone (21b)
To a stirred solution of benzaldehyde chloroxime (200.6 mg,
1.3 mmol, 1.1 equiv) in DCM (14.0 mL) was added, at 0 ꢁC, triethyl-
To a stirred solution of 18
(15.0 mL) was added, at 0 ꢁC, a solution of sodium methoxide in
methanol (1 M, 600 L, 0.6 mmol, 0.27 equiv) and the reaction
b (356.4 mg, 1.1 mmol) in methanol
amine (210
mL, 1.5 mmol, 1.2 equiv) and, after 10 min, a solution of
m
15 (277.1 mg, 1.2 mmol) in DCM (10.4 mL). The solution was
a
mixture was stirred at room temperature for 40 min. The reaction
was then quenched with HCl/MeOH 10% until pH¼7, concentrated
in vacuo and purified by flash chromatography eluting with chlo-
allowed to stir at room temperature for 3 days and then the mixture
was concentrated in vacuo and purified by flash chromatography
eluting with petroleum spirits/ethyl acetate 2:1 to give the title
roform/methanol 4:1 to give the title compound 21b as a yellow oil
25
compound 19
acetate/petroleum spirits 1:2); [
(KBr)/cmꢀ1 3445 (br), 2972, 1749, 1440, 1374, 1237, 1033
a
as a yellow oil (356.4 mg, 84% yield); Rf¼0.36 (ethyl
(194.1 mg, 75%); Rf¼0.61 (methanol/chloroform 1:4); [
a]
þ29.70
D
25
a
]
þ59.65 (c 0.29, CH2Cl2); nmax
(c 0.40, CHCl3); nmax (KBr)/cmꢀ1 3385 (br), 2922, 2360, 1710; dH
(CDCl3, 400 MHz) 6.62 (d, J¼1, 1H, H-isox.), 5.32 (dd, J1¼7, J2¼9, 1H),
4.51e4.48 (m, 1H), 4.04e4.01 (m, 1H), 3.75 (dd, J1¼4, J2¼12, 1H, H-
5), 3.69 (dd, J1¼4, J2¼12, 1H, H-50), 2.63 (s, 3H, CH3), 2.34e2.30 (m,
2H, H-2þH-20); dC (100.6 MHz, CDCl3) 192.1, 173.4, 161.8, 100.2, 87.5,
72.9, 71.9, 62.8, 40.4, 27.3; HRMS found: [MþHþ] 228.0866,
C10H14NO5 requires 228.0872; m/z: 227 (100%, Mþ).
D
1
;
dH
(CDCl3, 400 MHz) 7.81e7.79 (m, 2H, Ph), 7.48e7.45 (m, 3H, Ph), 6.58
(d, J¼1, 1H, H-isox.), 5.39 (dd, J1¼4, J2¼8, 1H), 5.23e5.20 (m, 1H),
4.43e4.40 (m, 1H), 4.3 (dd, J1¼4, J2¼12, 1H, H-5), 4.22 (dd, J1¼5,
J2¼12, 1H, H-50), 2.81e2.74 (m, 1H, H-2), 2.49e2.44 (m, 1H, H-20),
0
2.12 (s, 3H, CH3), 1.98 (s, 3H, CH3 ); dC (100.6 MHz, CDCl3) 172.7,
170.5, 170.4, 162.2, 130.0, 128.8, 128.7, 126.6, 99.4, 82.0, 75.0, 73.1,
63.7, 36.8, 20.8, 20.7; HRMS found: [MþHþ] 346.1289, C18H20NO6
requires 346.1291; m/z: 345 (100%, Mþ).
4.21. Preparation of 1-(5-((2S,4S,5R)-4-hydroxy-5-
(hydroxymethyl)-tetrahydrofuran-2-yl)isoxazol-3-yl)
ethanone (21a)
4.18. Preparation of (2R,3S,5R)-5-(1-benzyl-1H-1,2,3-triazol-
4-yl)-2-(acetoxymethyl)-3-(acetoxy)-tetrahydrofuran (20
b
)
To a stirred solution of 18
(18.5 mL) was added, at 0 ꢁC, a solution of sodium methoxide in
methanol (1 M, 750 L, 0.75 mmol, 0.27 equiv) and the reaction
a (444.6 mg, 1.4 mmol) in methanol
A solution of 15 (199.4 mg, 0.9 mmol), benzylazide (140.3 mg,
b
m
1,1 mmol, 1.2 equiv), CuSO4$5H2O (15.7 mg, 0.06 mmol, 0.07 equiv)
and sodium ascorbate (26.2 mg, 0.13 mmol, 0.15 equiv) in H2O/DCM
1:1 (1.64 mL) was stirred at room temperature for 4 h. The solution
was then concentrated in vacuo and purified by flash chromatog-
raphy eluting with petroleum spirits to eliminate the excess of
mixture was stirred at room temperature for 40 min. The reaction
was then quenched with HCl/MeOH 10% until pH¼7, concentrated
in vacuo and purified by flash chromatography eluting with ethyl
acetate to give the title compound 21a as a yellow oil (295.8 mg,
25
91%); Rf¼0.48 (ethyl acetate); [
a
]
D
þ49.28 (c 0.35, CHCl3); nmax
azide and then with ethyl acetate to give compound 20
b
as a white
(KBr)/cmꢀ1 3401 (br), 2928, 2360, 2338, 1705, 1446, 1347, 1088; dH
(CDCl3, 400 MHz): 6.67 (d, J¼1, 1H, H-isox.), 5.32e5.29 (m, 1H),
4.52e4.48 (m, 1H), 4.07 (dd, J1¼4, J2¼8, 1H), 3.82 (dd, J1¼4, J2¼12,
1H, H-5), 3.73 (dd, J1¼4, J2¼12, 1H, H-50), 2.74e2.67 (m, 1H, H-2),
2.65 (s, 3H, CH3), 2.29 (dt, J1¼5, J2¼13,1H, H-20),1.89 (s,1H, OH),1.78
25
solid (260.8 mg, 82%); mp 110e111 ꢁC; Rf¼0.60 (ethyl acetate); [
a]
D
ꢀ8.98 (c 0.67, CH2Cl2); nmax (KBr)/cmꢀ1 3142, 2961, 2889,1743,1231,
1055; dH (CDCl3, 400 MHz) 7.42 (s,1H, H-triazole), 7.41e7.36 (m, 3H,
Ph), 7.30e7.27 (m, 2H, Ph), 5.51 (s, 2H, CH2Ph), 5.30e5.26 (m, 1H),

M.F.A. Adamo et al. / Tetrahedron 66 (2010) 9242e9251
9249
(s, 1H, OH0); dC (100.6 MHz, CDCl3) 192.2, 174.6, 161.8, 100.05, 86.1,
4.25. Preparation of (2R,3S,5S)-5-(1-benzyl-1H-1,2,3-triazol-
4-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-ol (23
72.3, 72.0, 62.2, 39.5, 27.3; HRMS found: [MþHþ] 228.0880,
a)
C10H14NO5 requires 228.0872; m/z: 227 (100%, Mþ).
To a stirred solution of 20
(10.0 mL) was added, at 0 ꢁC, a solution of sodium methoxide in
methanol (1 M, 400 L, 0.40 mmol, 0.26 equiv) and the reaction
mixture was stirred at room temperature for 40 min. The reaction
was then quenched with HCl/MeOH 10% until pH¼7, concentrated in
vacuo and purified by flash chromatographyeluting with chloroform/
a (272.1 mg, 0.76 mmol) in methanol
4.22. Preparation of (2R,3S,5R)-2-(hydroxymethyl)-5-(3-
phenylisoxazol-5-yl)-tetrahydrofuran-3-ol (22b)
m
To a stirred solution of 19
DCM 2:1 (13.5 mL) was added, at 0 ꢁC, a solution of sodium
methoxide in methanol (1 M, 720 L, 0.72 mmol, 0.52 equiv) and
b (240.0 mg, 0.69 mmol) in methanol/
methanol 4:1 to give the title compound 23
a as a yellow solid
m
(203.5 mg, 98%); mp 106e109 ꢁC; Rf¼0.50 (methanol/chloroform
the reaction mixture was stirred at room temperature for 50 min.
The reaction was then quenched with HCl/MeOH 10% until pH¼7,
concentrated in vacuo and purified by flash chromatography elut-
25
1:4); [a]
þ65.45 (c 1.15, CHCl3); nmax (KBr)/cmꢀ1 3386 (br), 3110,
D
3061, 2923; dH (CDCl3, 400 MHz) 7.46 (s, 1H, H-triazole), 7.42e7.35
(m, 3H, Ph), 7.30e7.27 (m, 2H, Ph), 5.55e5.43 (m, 3H), 5.29 (dd, J1¼2,
J2¼9, 1H), 4.39e4.34 (m, 1H), 4.16e4.12 (m, 1H), 3.77e3.72 (m, 1H),
3.67e3.61 (m, 1H), 2.56 (ddd, J1¼7, J2¼8, J3¼16, 1H), 2.31 (dt, J1¼2,
J2¼14,1H),1.91 (t, J¼6,1H); dC (100.6 MHz, CDCl3) 129.2, 129.0, 128.3,
121.8, 88.2, 73.6, 72.3, 63.3, 54.3, 40.0; HRMS found: [MþHþ]
276.1341, C14H18N3O3 requires 276.1348; m/z: 275 (100%, Mþ).
ing with ethyl acetate to give the title compound 22b as a yellow
solid (158.8 mg, 87%); mp 122e124 ꢁC; Rf¼0.48 (ethyl acetate);
[
a]
25 þ9.58 (c 0.73, CH3OH); nmax (KBr)/cmꢀ1 3385 (br), 3137, 2933,
D
2355, 1617; dH (CDCl3, 400 MHz) 7.81e7.78 (m, 2H, Ph), 7.47e7.45
(m, 3H, Ph), 6.57 (d, J¼1, 1H, H-isox.), 5.37 (dd, J1¼6, J2¼9, 1H),
4.59e4.55 (m, 1H), 4.10e4.07 (m, 1H), 3.84 (ddd, J1¼4, J2¼5, J3¼12,
1H), 3.78e3.73 (m, 1H), 2.47e2.33 (m, 2H, H-2þH-20), 1.94e1.90 (m,
2H); dC (100.6 MHz, CDCl3) 171.8, 130.1, 128.9, 128.7, 126.8, 100.0,
87.5, 73.4, 72.3, 63.1, 40.7, 29.7; HRMS found: [MþHþ] 262.1067,
C14H16NO4 requires 262.1079; m/z: 261 (100%, Mþ).
4.26. Preparation of acetic acid 3(S)-acetoxy-5(R)-(1,3-dihydro-
isobenzofuran-5-yl)tetrahydrofuran-2(R)-ylmethyl ester (24
b)
To a stirred solution of compound 15 (490.1 mg 2.17 mmol) in
b
dry toluene (32 mL) was added chlorotris(triphenylphosphine)
rhodium(I) (212.0 mg, 0.23, mmol, 0.1 equiv) and dipropargyl ether
(800 mL, 7.77 mmol, 3.6 equiv) and the mixture was allowed to stir
4.23. Preparation of (2R,3S,5S)-2-(hydroxymethyl)-5-(3-
phenylisoxazol-5-yl)-tetrahydrofuran-3-ol (22a)
at room temperature for 44 h. The mixture was then concentrated
in vacuo and purified by flash chromatography on silica gel eluting
with ethyl acetate/petroleum ether (1:4) to give the title compound
To a stirred solution of 19
(4.8 mL) was added, at 0 ꢁC, a solution of sodium methoxide in
methanol (1 M, 200 L, 0.20 mmol, 0.24 equiv) and the reaction
mixture was stirred at room temperature for 1 h. The reaction
was then quenched with HCl/MeOH 10% until pH¼7, concen-
trated in vacuo and purified by flash chromatography eluting
a (141.0 mg, 0.41 mmol) in methanol
m
24
b
as a brown oil (249.5 mg 36%); Rf¼0.41 (ethyl acetate/petro-
leum ether 1:1); nmax (KBr)/cmꢀ1 3392, 2970, 2856, 1754, 1267; dH
(CDCl3, 400 MHz) 7.25e7.20 (m, 3H), 5.22 (d, J¼6,1H), 5.15e5.10 (m,
5H), 4.41e4.36 (m, 1H), 4.28e4.23 (m, 2H), 2.37e2.32 (m, 1H), 2.13
(s, 3H), 2.10e2.01 (m, 4H); dC (100.6 MHz, CDCl3) 170.7, 140.0, 139.6,
138.9, 125.1, 121.0, 118.3, 82.6, 80.5, 73.4, 73.3, 64.4, 41.4, 21.1, 20.9;
HRMS found: [MþHþ] 321.1342, C17H21O6 requires 321.1338; m/z:
320 (100%, Mþ).
with ethyl acetate to give the title compound 22
a as a yellow
25
solid (96.0 mg, 90%); mp 80e82 ꢁC; Rf¼0.50 (ethyl acetate); [
a]
D
ꢀ27.96 (c 0.61, CHCl3); nmax (KBr)/cmꢀ1 3421 (br), 2962, 2927,
2364; dH (CDCl3, 400 MHz): 7.82e7.78 (m, 2H, Ph), 7.49e7.44 (m,
3H, Ph), 6.61 (s, 1H, H-isox.), 5.32 (dd, J1¼5, J2¼8, 1H), 4.51e4.47
(m, 1H), 4.15e4.12 (m, 1H), 3.87e3.82 (m, 1H), 3.77e3.72 (m, 1H),
2.77e2.70 (m, 1H, H-2), 2.35 (dt, J1¼5, J2¼13, 1H, H-20), 1.97 (d,
J¼6, 1H, OH), 1.80 (t, J¼6, 1H, OH0); dC (100.6 MHz, CDCl3) 173.2,
162.4, 130.1, 128.9, 128.7, 126.8, 99.7, 86.1, 72.6, 72.3, 62,5, 39.8,
29.7; HRMS found: [MþHþ] 262.1070, C14H16NO4 requires
262.1079; m/z: 261 (100%, Mþ).
4.27. Preparation of acetic acid 3(S)-acetoxy-5(S)-(1,3-dihydro-
isobenzofuran-5-yl)tetrahydrofuran-2(R)-ylmethyl ester (24
a)
To a stirred solution of compound 15 (1.36 g, 6.01 mmol) in dry
a
toluene (90 mL) was added chlorotris(triphenylphosphine) rho-
dium(I) (555 mg, 0.60 mmol, 0.1 equiv) and dipropargyl ether
(2.2 mL, 21.37 mmol, 3.6 equiv) and the mixture was allowed to stir
at room temperature for 48 h. The mixture was then concentrated in
vacuo and purified by flash chromatography on silica gel eluting
with ethyl acetate/petroleum ether 1:4 to give the title compound
4.24. Preparation of (2R,3S,5R)-5-(1-benzyl-1H-1,2,3-triazol-
4-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-ol (23b)
To a stirred solution of 20
(9.0 mL) was added, at 0 ꢁC, a solution of sodium methoxide in
methanol (1 M, 360 L, 0.36 mmol, 0.26 equiv) and the reaction
mixture was stirred at room temperature for 40 min. The reaction
was then quenched with HCl/MeOH 10% until pH¼7, concentrated
in vacuo and purified by flash chromatography eluting with chlo-
b
(247.4 mg, 0.69 mmol) in methanol
24
a
as a yellow oil (671.5 mg 35%); Rf¼0.10 (ethyl acetate/petroleum
ether 1:4); nmax (KBr)/cmꢀ1 3390, 2967, 2853, 1753, 1260; dH (CDCl3,
400 MHz) 7.30e7.22 (m, 3H), 5.26e5.17 (m, 2H), 5.12 (br s, 4H),
4.45e4.42 (m, 1H), 4.31e4.25 (m, 2H), 2.88e2.81 (m,1H), 2.14e2.04
(m, 7H); dC (100.6 MHz, CDCl3); 170.8,141.2,138.7,125.1,120.9,118.4,
81.4, 79.9, 75.6, 73.5, 73.4, 64.0, 40.6, 21.0, 20.9; HRMS found:
[MþHþ] 321.1348, C17H21O6 requires 321.1338; m/z: 320 (100%, Mþ).
m
roform/methanol 4:1 to give the title compound 23b as a yellow
solid (159.4 mg, 84%); mp 77e78 ꢁC; Rf¼0.50 (methanol/chloro-
25
form 1:4); [
a]
ꢀ15.17 (c 0.73, CHCl3); nmax (KBr)/cmꢀ1 3271 (br),
4.28. Preparation of 5(R)-(1,3-dihydro-isobenzofuran-5-yl)-2
(R)-hydroxymethyl-tetrahydrofuran-3(S)-ol (25
D
3117, 2924, 2362, 1051; dH (CDCl3, 400 MHz) 7.44 (s, 1H, H-triazole),
7.39e7.37 (m, 3H, Ph), 7.29e7.27 (m, 2H, Ph), 5.50 (s, 2H), 5.30 (dd,
J1¼6, J2¼10, 1H), 4.56e4.54 (m, 1H), 4.04 (d, J¼2, 1H), 3.81 (dd, J1¼3,
J2¼12, 1H, H-5), 3.69 (dd, J1¼4, J2¼12, 1H, H-50), 2.41 (ddd, J1¼6,
J2¼9, J3¼13, 1H, H-2), 2.28 (ddd, J1¼2, J2¼6, J3¼13, 1H, H-20); dC
(100.6 MHz, CDCl3) 148.8, 134.3, 129.1, 128.8, 128.2, 121.5, 87.9, 73.5,
72.3, 63.2, 54.2, 42.2; HRMS found: [MþHþ] 276.1335, C14H18N3O3
requires 276.1348; m/z: 275 (100%, Mþ).
b)
To a stirred solution of 15 (241.6 mg, 0.75 mmol) in methanol
b
(11 mL), was added a catalytic amount of potassium carbonate and
the solution was allowed to stir at room temperature for 30 min.
The mixture was then concentrated in vacuo and purified by flash
chromatography on silica gel eluting with chloroform/methanol
8:1 to give the title compound 25b as a green oil (145.5 mg, 82%);

9250
M.F.A. Adamo et al. / Tetrahedron 66 (2010) 9242e9251
Rf¼0.38 (chloroform/methanol 8:1); nmax (KBr)/cmꢀ1 3398, 2920,
2852, 1043; dH (CDCl3, 400 MHz) 7.24e7.20 (m, 3H), 5.20 (dd, J1¼6,
J2¼10, 1H), 5.10 (s, 4H), 4.47e4.44 (m, 1H), 4.04e4.01 (m, 1H), 3.85
(dd, J1¼4, J2¼12, 1H), 3.76 (dd, J1¼5, J2¼12, 1H), 2.27 (ddd, J1¼2,
J2¼6, J3¼13, 1H), 2.08e2.00 (m, 1H), 1.92 (br s, 2H); dC (100.6 MHz,
CDCl3); 140.5, 139.6, 138.8, 125.3, 121.0, 118.5, 87.3, 80.0, 73.8, 73.4,
73.3, 63.4, 44.3; HRMS found: [MþHþ] 237.1120, C13H17O4 requires
237.1127; m/z: 236 (100%, Mþ).
recrystallized from moist acetone (567.9 mg, 4.9 mmol, 12.8 equiv)
in DCM (11.6 mL) and the reaction mixture was stirred at room
temperature for 17 h. The reaction mixture was then concentrated
in vacuo and purified by flash chromatography eluting firstly with
ethyl acetate to eliminate cobalt salts, and then with petroleum
spirits/ethyl acetate 1:1 to give the title compound 27b as a pale
brown oil (57.4 mg, 53% yield); Rf¼0.30 (ethyl acetate/petroleum
25
spirits 1:1); [
a
]
þ22.99 (c 0.26, CH2Cl2); nmax (KBr)/cmꢀ1 2961
D
2917, 2867, 1738, 1705, 1231; dH (CDCl3, 400 MHz) 7.59e7.57 (m, 1H,
H-6), 5.17 (d, J¼6, 1H), 4.83e4.79 (m, 1H), 4.33e4.28 (m, 1H),
4.18e4.12 (m, 2H), 2.62e2.60 (m, 2H), 2.46e2.43 (m, 2H), 2.38 (dd0d,
J1¼1, J2¼5, J3¼14, 1H, H-2), 2.08 (s, 3H, CH3), 2.07 (s, 3H, CH3 ),
1.88e1.80 (m, 1H, H-20); dC (100.6 MHz, CDCl3) 207.9, 170.7, 170.6,
158.6, 145.9, 82.1, 76.3, 74.1, 64.1, 37.9, 35.2, 26.8, 21.0, 20.8; HRMS
found: [MþHþ] 283.1192, C14H19O6 requires 283.1182; m/z: 282
(100%, Mþ).
4.29. Preparation of 5(S)-(1,3-dihydro-isobenzofuran-5-yl)-2
(R)-hydroxymethyl-tetrahydrofuran-3(S)-ol (25
a)
To a stirred solution of 15 (671.5 mg, 2.10 mmol) in methanol
a
(30 mL), was added a catalytic amount of potassium carbonate and
the solution was allowed to stir at room temperature for 30 min.
The mixture was then concentrated in vacuo and purified by flash
chromatography on silica gel eluting with chloroform/methanol
8:1 to give the title compound 25a as a green oil (379.2 mg 77%);
4.33. Preparation of 2-[(2S,4S,5R)-4-acetoxy-5-acetoxymethyl-
25
Rf¼0.34 (chloroform/methanol 8:1); [
a
]
ꢀ20.74 (c 2.17, CHCl3);
tetrahydrofuran-2-yl]-cyclopent-2-enone (27
a)
D
nmax (KBr)/cmꢀ1 3395, 2918, 2848, 1038; dH (CDCl3, 400 MHz)
7.32e7.23 (m, 3H), 5.16e5.12 (m, 5H), 4.49 (dd, J1¼7, J2¼13, 1H), 4.11
(dd, J1¼5, J2¼9, 1H), 3.85 (dd, J1¼4, J2¼12, 1H), 3.76 (dd, J1¼5, J2¼12,
1H), 2.74e2.68 (m, 1H), 2.11e1.99 (m, 3H); dC (100.6 MHz, CDCl3);
142.1, 139.6, 138.6, 125.0, 121.0, 118.2, 85.4, 79.5, 73.5, 73.4, 73.1,
62.6, 43.8; HRMS found: [MþHþ] 237.1127, C13H17O4 requires
237.1127; m/z: 236 (100%, Mþ).
To a stirred solution of 26 (848.1 mg, 1.7 mmol) in vinyl ben-
a
zoate (4.7 mL, 33.9 mmol, 20.4 equiv) was added, by syringe pump
over a 3 h period, a solution of N-methylmorpholine N-oxide
recrystallized from moist acetone (2.44 g, 20.8 mmol, 12.6 equiv) in
DCM (50.0 mL) and the reaction mixture was stirred at room
temperature for 16 h. The reaction mixture was then concentrated
in vacuo and purified by flash chromatography eluting firstly with
ethyl acetate to eliminate cobalt salts, and then with petroleum
4.30. Preparation of hexacarbonyl [(2R,3S,5R)-3-acetoxy-2-
acetoxymethyl-5-[m-[(1,2-h:1,2-h)-ethynyl]]-tetrahydrofuran]
spirits/ethyl acetate 1:1 to give the title compound 27a as a pale
dicobalt-(CoeCo) (26
b
)
brown oil (250.7 mg, 54% yield); Rf¼0.28 (ethyl acetate/petroleum
25
spirits 1:1); [
a]
þ21.99 (c 0.86, CH2Cl2); nmax (KBr)/cmꢀ1 2923,
D
To a stirred solution of 15b (97.8 mg, 0.43 mmol) in acetonitrile
1741, 1696, 1236; dH (CDCl3, 400 MHz) 7.60 (dd, J1¼3, J2¼4, 1H, H-6),
5.17e5.14 (m, 1H), 4.90e4.86 (m, 1H), 4.29 (dt, J1¼4, J2¼6, 1H), 4.25
(dd, J1¼4, J2¼12, 1H, H-5), 4.15 (dd, J1¼6, J2¼12, 1H, H-50), 2.72e2.67
(m, 1H, H-2), 2.65e2.60 (m, 2H), 2.46e2.44 (m, 2H), 2.09 (s, 3H,
(1.8 mL) was added cobalt carbonyl (182.5 mg, 0.53 mmol,
1.2 equiv) and the reaction mixture was stirred at room tempera-
ture for 24 h. The reaction mixture was then concentrated in vacuo
and purified by flash chromatography on silica gel eluting with
0
CH3), 2.02 (s, 3H, CH3 ), 2.00e1.97 (m, 1H, H-20); dC (100 MHz,
petroleum spirits/ethyl acetate 9:1 to give the title compound 26
b
CDCl3) 208.0, 170.8, 170.4, 158.3, 146.6, 81.3, 75.6, 74.1, 64.1, 37.0,
35.3, 26.6, 20.9, 20.9; HRMS found: [MþHþ] 283.1169, C14H19O6
requires 283.1182; m/z: 282 (100%, Mþ).
as a red oil (196.6 mg, 89% yield); Rf¼0.15 (ethyl acetate/petroleum
spirits 1:9); nmax (KBr)/cmꢀ1 2932, 2106, 2067, 2018, 1746, 1236; dH
(CDCl3, 400 MHz) 6.08 (s, 1H), 5.21 (s, 2H), 4.20 (s, 4H), 2.35 (s, 1H),
1.25 (s, 6H); dC (100.6 MHz, CDCl3) 199.3, 82.5, 78.6, 76.5, 72.1, 64.3,
41.0, 29.7, 21.1, 20.7.
Acknowledgements
We acknowledge financial support from Health Research Board
(HRB), Science Foundation Ireland (SFI, RFP2007) and Enterprise-
Ireland.
4.31. Preparation of hexacarbonyl [(2R,3S,5S)-3-acetoxy-2-
acetoxymethyl-5-[m-[(1,2-h:1,2-h)-ethynyl]]-tetrahydrofuran]
dicobalt-(CoeCo) (26
a
)
Supplementary data
To a stirred solution of 15a (504.5 mg, 2.2 mmol) in acetonitrile
(9.4 mL) was added cobalt carbonyl (920 mg, 2.7 mmol, 1.2 equiv)
and the reaction mixture was stirred at room temperature for 24 h.
The reaction mixture was then concentrated in vacuo and purified
by flash chromatography on silica gel eluting with petroleum
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.09.046.
References and notes
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M.F.A. Adamo et al. / Tetrahedron 66 (2010) 9242e9251
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