Total synthesis of malayamycin A and analogues

Article abstract of DOI:10.1016/j.tet.2005.12.066

The total synthesis of the bicyclic C-nucleoside malayamycin A is described starting with d-ribonolactone. A new method was developed to obtain preparatively important quantities of β-pseudouridine, which was used as an intermediate. The synthesis of a ca

Full text of DOI:10.1016/j.tet.2005.12.066

Tetrahedron 62 (2006) 5201–5214
Total synthesis of malayamycin A and analogues
a
a
a
Stephen Hanessian,a, Stephane Marcotte, Roger Machaalani, Guobin Huang,
*
´
Julien Pierrona and Olivier Loiseleurb
a
´
´
´
Department of Chemistry, Universite de Montreal, CP 6128, Station Centre-Ville, Montreal, QC H3C 3J7, Canada
bSyngenta Crop Protection AG, Switzerland
Received 4 November 2005; revised 22 December 2005; accepted 23 December 2005
Available online 3 April 2006
Abstract—The total synthesis of the bicyclic C-nucleoside malayamycin A is described starting with D-ribonolactone. A new method was
developed to obtain preparatively important quantities of b-pseudouridine, which was used as an intermediate. The synthesis of a carba
N-nucleoside analogue of malayamycin A is also described.
Ó 2006 Elsevier Ltd. All rights reserved.
O
1. Introduction
O
H2N
NH
Nucleosides are traditionally associated with the fascinating
chemistry and biology of DNA and RNA.1 Indeed, the intri-
cate three-dimensional arrays of N-nucleotidic sequences
in DNA constitute the basis of the alphabet of life that is
responsible for all the vital processes.2 Nature has also
produced a group of N-nucleosides with potent chemothera-
peutic activities, which have been the source of extensive
chemical modification.3 In this regard, several antitumor,
antiviral, and antibiotic nucleosides are known. In contrast,
C-nucleosides4 constitute a smaller subgroup of carbon-
linked anomeric heterocycles that nature has also provided
with much less exploited potential for biological activities.5
Pseudouridine, a constituent of various RNAs,6,7 was the
first naturally occurring 5-uracilyl b-D-C-ribofuranoside.8
Its biosynthesis continues to elicit proposals for fascinating
pathways.9 Curiously, pseudouridine isolated from beer has
shown antimutagenic properties against N-methyl-N0-nitro-
N-nitrosoguanidine.10
H
NH
NH
O
O
O
HO
O
O
OH
H
OH
O
NH2
O
Ezomycin B2
O
H2N
NH
OH
OH
O
O
HO
NH
O
O
OH
H
N
OH
H
O
OH
NH2
H
Ezomycin D2
HO
OH
O
N
N
NH2
Me
O
H
H
OH
N
O
NH
N
Me
N
Quantamycin
NH
Pr
O
OH
H
N
O
A unique example of bicyclic C-nucleoside having antifun-
gal and antibiotic properties was reported by Sakata and
co-workers in 1977.11 Degradative and spectroscopic work12
revealed the structures of ezomycin B2 and ezomycin C2
as constrained pseudouridine-type C-nucleoside disaccha-
rides (Fig. 1). The perhydrofuropyran motif was also re-
vealed in the structures of N-nucleosides such as ezomycin
A1,13 miharamycin,14 and octosyl acid A.15 Quantamycin16
is a structure-based bicyclic synthetic hybrid of lincomycin
N
O
N
N
N
H2N
H
H
N
NH2
NH2
HO
HO
O
Miharamycin
HO
O
H
H2N
NH
H
O
O
N
O
MeO
NH
O
NH
O
O
NH
HO
O
H
HO
OH
OH
Keywords: C-Nucleoside; Thioglycoside; Ring closure metathesis; Perhy-
drofuropyran.
Pseudouridine
Malayamycin A, 1
* Corresponding author. Tel.: +1 514 343 6738; fax: +1 514 343 5728;
e-mail: stephen.hanessian@umontreal.ca
Figure 1. Structures of perhydrofuropyran C-nucleosides and b-pseudouri-
dine.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.066

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S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
and a natural ‘starter’ nucleotide involved in the process of
protein biosynthesis. The field of naturally occurring C-
nucleosides lay dormant for nearly 25 years before the dis-
covery of a new member by a group at the Syngenta Crop
Protection Laboratories in Jeallott’s Hill, UK.17 Malayamy-
cin A (1) was isolated from the soil organism Streptomyces
malaysiensis, and its structure was proposed by detailed
NMR studies and by degradation (Fig. 1). As in the case
of ezomycin B2 and pseudouridine, malayamycin A was
found to be unstable under strongly acidic and basic condi-
tions. In contrast to the ezomycins that exhibit antifungal and
antibiotic activities,11 malayamycin A is a potent fungi-
cide.17 The perhydrofuropyran motif in 1, which is also com-
mon to the ezomycins and octosyl acid A, has different
functionality and differs by the absence of a carboxylic
acid and a disaccharide unit. Recently, the proposed struc-
ture and absolute stereochemistry of 117 were confirmed
by a stereocontrolled total synthesis.18 Herein we give de-
tails of various aspects of this synthesis, as well as the prep-
aration of semi-synthetic analogues intended to probe the
importance of some functional groups. The total synthesis
of N-malayamycin A and related purine and pyrimidine
nucleosides was recently reported.19
controlled introduction of a vicinally disposed cis-amino
alcohol. In considering pseudouridine as a starting material,
we would already resolve the C-nucleoside issue. The pro-
hibitive cost of pseudouridine was an initial deterrent that
was soon dismissed with the knowledge that a number of
total syntheses have been reported over the years.20 The
most recent of these20a offered a preparatively viable proto-
col, although a mixture of anomers was obtained. The need
to start with a relatively large amount of 2 instigated
the search for a highly stereocontrolled synthesis of 1 and
its a-anomer from a common precursor. In our synthetic
approach to a new synthesis of pseudouridine,21 we used
a 5-(2,4-dimethoxypyrimidinyl) b-D-ribofuranose as an
intermediate.22
3. Results and discussion
The readily available D-ribonolactone 2 was treated with 2,2-
dimethoxypropane in refluxing CH2Cl2 in the presence of
PPTS and excess Na2SO4 to give the corresponding mixed
acetal, which was surprisingly stable to chromatographic pu-
rification. In the absence of Na2SO4 the bis-acetal lactone
was obtained in 40% yield only.23 Addition of 5-lithio 2,4-
dimethoxypyridine20b to the protected lactone at ꢀ78 C
ꢁ
2. The synthesis plan
led to a 75% yield of a mixture of anomers 3 in an a/b ratio
of 1:9. Treatment with L-Selectride in the presence of ZnCl2
in a mixture of CH2Cl2/THF led to the alcohol 4 as a major
isomer in 86% yield on a 1–5 mmol scale. However, on
a larger scale (22 mmol), the yield was 54%. Reduction
with NaBH4 in MeOH gave a 1:1 mixture of diastereomers.
The quasi-exclusive stereocontrolled reduction to the D-allo
alcohol 4 can be explained by the initial coordination of an
intermediate alkoxy ketone followed by Si-face-selective
hydride attack from the bulky reagent (Scheme 1).21 Inter-
estingly, the epimeric D-altro alcohol, a precursor to a-pseu-
douridine was the major product in the absence of ZnCl2.21
Similar observations have been reported in a related case.24
Treatment of 4 under Mitsunobu conditions led, via a site-
selective intramolecular cycloetherification, to the corre-
sponding 1,4-anhydro-D-ribitol C-nucleoside.25 Removal
of the acetonide in the presence of 70% acetic acid gave 5-
(2,4-dimethoxypyrimidinyl) b-D-ribofuranose 5 in excellent
overall yield. The original pseudouridine synthesis involved
the corresponding 2,4-dibutoxypyridine as intermediate in
order to facilitate the final deprotection step without anome-
rization.21 In the case of 1, however, the more robust
dimethoxypyrimidine analogue was used.
As previously remarked,18 the synthesis plan for 1 has to
consider several challenges that include as follows: (a) the
stereocontrolled formation of the anomeric C-5-uracilyl
bond, (b) the construction of a trans-fused bicylic perhydro-
furopyran ring, and (c) incorporation of usable functionality
to achieve the desired stereochemical arrangement.
The disconnection shown in Figure 2 capitalizes on the
formation of an enantiopure unsaturated C-pyrimidinyl per-
hydrofuropyran via a ring closure metathesis of a pseudouri-
dine precursor that would be prepared from D-ribonolactone
2. Although the first phase of the synthesis had precedents
(see below), a main challenge was the stereo- and regio-
O
H2N
NH
H
O
MeO
NH
NH
O
O
O
H
OH
Malayamycin A, 1
NHR
RO
H
H
N
N
O
With 5 in hand, we devised a protecting group selection pro-
tocol that would allow preferential manipulation of the triol
system. Thus, the 30,50-diol could be protected as the disilox-
ane acetal, and the 20-hydroxyl group was treated with
PMBBr to give 6 in an 86% overall yield for the two steps.
Quite unexpectedly, the disiloxane was selectively cleaved
with 1 N HCl in dioxane, exposing the primary alcohol in
7. Moreover, the primary alcohol could be oxidized to the al-
dehyde under Swern conditions and the latter converted to
the 50-C-vinyl intermediate 8 and its monosilylated deriva-
tive 9, which could be transformed to 8 in the presence of
TBAF as expected. Thus, the disiloxane served a dual pur-
pose as a protective group in three operationally different re-
actions. Allylation of 8 under standard conditions afforded
MeO
OR
O
RCM
OH
RO
H
O
N
N
OR
OR
O
H
OH
RO
O
N
N
O
O
OH
D-Ribonolactone, 2
Figure 2. Disconnective analysis of malayamycin A.
HO
HO
HO
HO
OH

S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
5203
OMe
MeO
OH OH
N
O
MeO
1. 2,2-dimethoxypropane
PPTS, Na2SO4, 60°C, 1h, 84%
O
N
N
HO
OMe
O
L-Selectride
O
MeO
OMe
O
N
OH
2. 2,4-dimethoxy-5-lithiopyrimidine
THF, -78°C, 65%
ZnCl2
CH2Cl2,THF
-78 °C to RT
86%
HO
OH
O
O
3
2
O
O
4 (> 19 : 1)
Me Me
(9:1, β/α)
Me Me
MeO
N
1. 1,3-Dichloro-1,1,3,3-
tetraisopropyl-disiloxane
pyridine, 25°C, 4 h, 95%
MeO
N
N
OMe
OMe
1. DIAD, Ph3P, THF, 86%
O
1N HCl
O
N
O
Si
O
iPr
iPr
HO
Dioxane
25°C, 1h
88%
2. 70% AcOH, reflux, 1h,
84%
2. NaH, PMBBr,
DMF/THF, 84%
HO
OH
O
OPMB
Si
iPr
iPr
5
6
MeO
MeO
O
N
N
OMe
MeO
OMe
N
N
N
O
OMe
1. DMSO, (COCl)2
i-Pr2NEt, DCM
N
O
HO
2. Ph3PCH3Br,
NaHMDS, THF
HO
OPMB
O
HO
O
OPMB
Si
iPr
Si
O
HO
O
OPMB
Si
Si
iPr
iPr
iPr
36% (2 steps)
11% (2steps)
iPr
iPr
iPr
iPr
TBAF
7
9
8
THF, 1h, 0 °C
90%
H
H
HxM
HxM
O
Het
O
Het
O
Het
O
ZnCl2
O
MeO
MeO
O
O
O
O
O
O
O
O
ZnCl2
Me
Me
Me Me
Me Me
3
4
Scheme 1.
10, which was subjected to the Grubbs ring closure meta-
thesis reaction (Scheme 2).26 In the presence of 5 mol % first
generation catalyst27 and a concentration of 0.05 M, smooth
cyclization took place to afford an 89% yield of crystalline
product 11. The reaction could be scaled up to 2 g without
appreciable loss in efficiency.28 It is of interest that in an
analogous RCM cyclization of 1,2-O-isopropylidene-3-O-
allyl-5-C-vinyl-a-D-ribofuranose to afford a tricyclic inter-
mediate, there was a significant improvement in yield
when the concentration was 0.01 M (92%)19 compared to
0.02 M (63%).28
the corresponding endo-epoxide when mCPBA is used
even in the presence of steric bulk.
Oxidation of 12 with the Dess–Martin reagent32 afforded 13,
without evidence of partial racemization of the pseudoaxial
azide group (Scheme 2). Reduction with NaBH4 in MeOH
followed by methylation gave 14 in excellent overall yield.
In order to probe the spatial importance of the ether group,
we also prepared the ethyl ether 15 by treatment of the alco-
hol with ethyl triflate and KHMDS.
In an earlier version of the synthesis we had reached inter-
mediate 19 having a benzyl ether instead of PMB (Scheme
2). However, when we attempted to remove the benzyl ether
in the penultimate step, we were dismayed to find that a sec-
ond hydrogenolysis had taken place resulting in ring opening
of the ribosyl moiety to give 20. This led us to use the PMB
group instead. Model studies showed that the PMB group
would not be stable to TMSCl and NaI required to generate
the pyrimidinone from the dimethoxy precursor 14. Thus,
a protective group adjustment was needed. Cleavage of the
PMB with DDQ proceeded smoothly and the resulting alco-
hol was esterified as a pivalate, which proved to be stable to
the demethoxylation in the presence of TMSCl and NaI
(Scheme 2). The methyl and ethyl ethers 16 and 17 were
thus obtained in good overall yield. Reduction of the azide
under Staudinger conditions,33 followed by formation of the
Our initial efforts to introduce an amino function relied on an
epoxidation of 11 with mCPBA followed by ring opening
with sodium azide. However, this protocol led to a regioiso-
meric azide.18 We adopted a different route involving initial
treatment with NBS in aqueous THF,29 which led to the cor-
responding diaxial bromohydrin via the epibromonium ion
(Scheme 3). Base-catalyzed epoxide formation followed
by treatment with sodium azide in refluxing methoxyethanol
afforded the trans diaxial azido alcohol 12 as a major product
(5:1 ratio). The preference for the endo-attack of NBS is not
clear, although there are precedents for related reactions.30 It
is possible that the endo-bromohydrin may benefit from a fa-
vorable electron-donation from the C–H s bond31 with the
developing antibonding orbital in the transition state model
A, compared to B. The same rationale can be advanced for

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S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
MeO
PCy3
N
OMe
MeO
H
H
Cl
Cl
O
Ru
1. NBS, H2O, THF
N
N
O
N
Allyl bromide, NaH, DMF
91%
8
Ph
OMe
RO
PCy3
2. NaOH, THF
3. NaN3, CH3OCH2CH2OH
O
Grubbs catalyst
94%
O
OPMB
10
OPMB
43%
11
N3
N3
N
3 H
MeO
H
MeO
N
O
MeO
H
1. NaBH4, MeOH
O
HO
N
O
N
Dess-Martin
O
2. NaH, MeI, DMF
78%
OMe
OMe
OMe
CH2
Cl
2
N
N
O
N
O
O
O
or
H
H
H
OPMB
OPMB
OPMB
EtOTf, KHMDS
THF, 76%
12
13
14, R=Me
15, R=Et
O
N3
O
H2N
RO
NH
O
H
H
1. Me3P, H2O, THF
1. DDQ, H2O, DCM, 84%
H
RO
NH
NH
O
NH
O
NH
O
2. PivCl, DMAP, NEt3, pyridine
2. Cl3CCONCO, DCM
3. MeNH2, MeOH, H2O
O
3. TMSCl, NaI, acetonitrile
42% (3 steps)
O
H
OPiv
OH
60% (3 steps)
16, R=Me
17, R=Et
R=Me, Malayamycin A, 1
R=Et, 18
O
O
H2N
NH
O
O
H
H2N
NH
MeO
NH
NH
O
H2, Pd/C
MeOH
MeO
OH
OH
O
O
NH
H
O
OBn
H
O
N
19
H
20
Scheme 2.
trichloroacetyl urea,34 and deprotection with methylamine35
afforded malayamycin A 1 and its 6-O-ethyl analogue 18.
Synthetic 1 was found to be identical to the natural sample
in all respects including fungicidal activity. The ethyl ether
analogue, however, was considerably less effective.
Exo-attack
O
Br
N
H2O
OPMB
OPMB
H
H
O
O
O
Br
O
O
O
With the azide intermediate 16 in hand, we deemed it appro-
priate to introduce diversity at the original urea site, hoping
to gain some information regarding the nature of the func-
tional groups and activity. Thus, we prepared a series of
analogues 21–27 ranging from ureas to sulfonamides, to car-
bamates, and to a simple acetamide (Scheme 4). Unfortu-
nately, these and related modifications resulted in loss of
fungicidal activity.
OMe
OMe
Br
N
N
N
N
N
O
Endo-Attack
OMe
OMe
OH
OPMB
H
O
O
H
OPMB
O
NaOH
NaN3
O
Br
O
OMe
N3
OMe
R
NH
O
H
N
N
N
MeO
N
NH
O
a, b, c
16
N
O
OMe
OPMB
OMe
O
OH
H
N3
OH
25 R = PhNHCO
H
O
MeO
21 R = NH2CS
HO
O
N
22 R = MeONHCO 26 R = MeNHCO
O
N3
OMe
23 R = MeSO2
24 R = NH2SO2
27 R = MeCO
O
N
OMe
OPMB
N
N
12
Scheme 4. Reagents and conditions: (a) Me3P, THF–H2O; (b) BzNCS,
CH2Cl2 for 21; carbonyl diimidazole, CH2Cl2, then MeONH2$HCl, Et3N,
CH2Cl2 for 22; MeSO2Cl, pyridine for 23; FmocNHSO2Cl, pyridine, then
piperidine, DMF for 24; PhNCO, CH2Cl2 for 25; MeNCO, CH2Cl2 for
26; 40% v/v MeNH2, MeOH for 27; (c) 40% v/v MeNH2, MeOH for 21,
56%; 22, 45%; 23, 46%; 24, 22%; 25, 27%; 26, 46%; Ac2O, NaHCO3,
MeOH for 27, 30%.
Trans diaxial
OMe
H
O
X
OR
OR
O
σ*
X
O
O
O
O
OMe
OMe
H
A
B
Br,
X =
To further establish an SAR, we developed a strategy to do
functional and structural modifications on N-malayamycin,
which could be easily obtained from D-ribose or D-glucose.19
Ar
O
Scheme 3.

S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
5205
The known intermediate 2819 was methylated and the prod-
uct was subjected to an oxidative transformation of the
benzyl ether to the benzoate 29 in excellent overall yield36
(Scheme 5). Treatment with benzenethiol in the presence
of BF3-etherate gave the diphenyl dithioacetal 30, which
was converted to the phenyl thioglycoside 31 as previously
described.19,37 Protection as the pivalate ester 32 and N-gly-
coside formation19,34,38 via neighboring group participation,
gave the 10,20-trans-bicyclic nucleoside 33 in excellent
overall yield accompanied by a small amount of the 5-iodo-
nucleoside 34. Finally, Staudinger reduction of 33 and
manipulation of the amine as described above gave 60-epi-
N-malayamycin 34, which had diminished fungicidal
activity compared to 1. Thus, epimerization at C6 was not
tolerated.
in the presence of NBS followed by pivaloylation proceeded
in good overall yield to deliver 44. N-Glycosidation and
subsequent functional group manipulations proceeded
uneventfully to give the final N-cytosinyl nucleoside 46. Sur-
prisingly, the seemingly benign replacement of a tetrahydro-
2H-pyranyl by a cyclohexyl moiety resulted in a complete
loss of fungicidal activity.
O
O
O
1. AcOH, H2O
O
O
O
2. MeSO2Cl, Et3N, CH2Cl2
3. NaI, EtMeCO, 80 °C
O
I
O
36
HO
35
66%
PCy3
Cl
H
H
O
Ru
O
Cl
O
Bu3Sn(allyl)
AIBN, 100 °C
Ph
PCy3
O
O
Grubbs catalyst
55%
75%
O
37
38
N
3 H
N3
N3
N3
HO
H
PhSH
H
1. MeI, NaH,
DMF, 96%
H
H
1. NBS
O
MeO
O
HO
O
BF3.Et2O
O
O
H2O, THF
DMP, CH2Cl2
OMe
OMe
80%
O
2. RuCl3.3H2O,
NaIO4
CH3CN-CCl4-H2O,
82%
O
O
2. NaOH, THF
3. NaN3
CH3OCH2CH2OH
52%
90%
O
H
28
OBn
H
H
OBz
O
O
O
29
39
40
N3
N3
N3
N3
H
1. NaBH4
MeOH
H
H
H
H
PhSH
MeO
MeO
PivCl
1. K2CO3
MeOH, 99%
O
OH
OH
MeO
MeO
MeO
O
Amberlyst-15
SPh
SPh
SPh
SPh
DMAP
SPh
2. NaH
MeI, THF
69%
Pyridine
100%
CH2Cl2
81%
2. NBS
CH2Cl2, 77%
O
O
H
41
O
H
42
H
OH
31
OH
OBz
30
N3
N3
NBS
N3
O
O
N
TMSO
H
H
PivCl
H
CH2Cl
N3
O
2 MeO
MeO
N
MeO
O
O
NH
O
DMAP
O
H
H
OTMS
SPh
SPh
O
N
67%
Pyridine
80%
SPh
NIS, TfOH,
CH2Cl2
44
H
43
H
H
OH
N3
OPiv
R
OPiv
33, R = H
34, R = I
OTMS
OPiv
80%
32
1. Me3P, THF
2. Cl3CCONCO
CH2Cl2
OTMS
N
N
O
N
N
H
O
MeO
N
O
1. Me3P, THF
2. Cl3CCONCO
CH2Cl2
NHAc
H2N
MeO
NH
H
NIS, TfOH
CH2Cl2
83%
O
N
3. MeNH2, MeOH
60%
NH
O
H
45
OPiv
O
3. MeNH2
MeOH
77%
O
O
H
OH
H2N
MeO
NH
O
6-epi-N-Malayamycin, 34
H
N
O
N
NH2
Scheme 5.
H
OH
To probe the tolerance of N-malayamycin for deep-seated
structural modifications, we embarked on the preparation
of the N-cytosinyl carba analogue 46 in which the tetrahy-
dro-2H-pyran ring was replaced by a cyclohexane (Scheme
6). The synthesis started from the known and easily accessi-
ble 35.39 Regioselective removal of the 50,60-isopropylidene
group followed by per-mesylation of the crude triol interme-
46
Scheme 6.
4. Experimental
4.1. General procedure
ꢁ
diate and treatment with NaI in ethylmethyl ketone at 80 C
triggered the concomitant formation of a terminal olefin and
a primary iodide in 66% yield. Allylation of 36, under free
radical conditions was best performed in neat allyltributyltin
in the presence of AIBN, to give 37 in 75% yield. In the pres-
ence of 5 mol % of first generation Grubbs catalyst27 and
a concentration of 0.05 M, cyclization took place to afford
the volatile tricyclic olefin 38 in 55% yield. Application of
the bromohydrin-epoxidation and azide opening protocol,
followed by inversion of the C6–OH stereocenter and O-
methylation, led to 41 in 32% yield for six steps. Cleavage
of the acetal with concomitant dithioacetal formation in 41
was most efficiently done with benzenethiol in the presence
of Amberlyst-15 suspended in CH2Cl2 to give the corre-
sponding product 42 in 81% yield. Thioglycoside formation
Solvents were distilled under positive pressure of dry argon
before using and dried by standard methods: toluene, THF,
and ether from sodium/benzophenone ketyl; CH2Cl2 from
calcium hydride. All commercially available reagents were
used without further purification. All non-aqueous reactions
were performed under argon atmosphere with oven-dried
glassware. NMR (1H, 13C, COSY, NOESY) spectra were
recorded on AV-400 and ARX-400 spectrometers. Chemical
shifts are reported in parts per million (ppm) downfield from
tetramethylsilane (TMS) with reference to internal solvent.
High-resolution mass spectra were recorded using fast
atom bombardment (FAB), (TOF CI+). Melting points are
uncorrected. Optical rotations were recorded in a 1 dm cell

5206
S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
at ambient temperature with a sodium lamp (wavelength of
589 nm). Analytical thin-layer chromatography was per-
formed on Merck 60F254 pre-coated silica gel plates. Visual-
ization was performed by ultraviolet light and/or by staining
with ceric ammonium molybdate or potassium permanga-
nate. Chromatographic purifications were performed on
a column with 230–400 mesh silica gel with the indicated
solvent system.
tion by flash chromatography on silica gel column (hexanes/
EtOAc, 2:1) afforded 4 as a crystalline solid (12 g, 30 mmol,
1
ꢁ
54%); mp 35–37 C; [a]D ꢀ115.6 (c 1, MeOH). H NMR
(400 MHz, CD3OD) d 1.31 (s, 3H), 1.40 (s, 6H), 1.60
(s, 3H), 3.29 (s, 3H), 3.48 (m, 1H), 3.52 (m, 1H), 4.11
(s, 6H), 4.35 (m, 3H), 5.40 (s, 1H), 8.41 (s, 1H). 13C NMR
(100 MHz, CD3OD) d 24.8 (2), 25.5, 26.8 (2), 54.7, 55.3,
64.4, 65.5, 70.1, 77.9, 79.4, 101.4, 109.8, 117.1, 158.5,
165.8, 169.1; MS (ESI): 403.1 [M+H].
4.1.1. (3aR, 4R/S, 6R, 6aR)-4-(20,40-Dimethoxypyrimidin-
50-yl)-6-(100-methoxy-100-methyl-ethoxymethyl)-2,2-di-
methyltetrahydro-furo[3,4-d][1,3]dioxol-4-ol (3). To a
mixture of (+)-D-ribonolactone 2 (6.7 g, 45 mmol) and
pyridinium p-toluenesulfonate (0.84 g, 3.3 mmol) in 2,2-
dimethoxypropane (167 mL) in 500 mL round-bottomed
flask was added anhydrous Na2SO4 (67 g, 0.47 mol) at
room temperature under argon atmosphere. The mixture
4.1.3. (2S, 3S, 4R, 5R)-2-(2,4-Dimethoxy-pyrimidin-5-yl)-
5-hydroxymethyl-tetrahydro-furan-3,4-diol(5). Toasolu-
tion of 4 (12 g, 30 mmol) in THF (1.2 L) was added Ph3P
ꢁ
(15.6 g, 59.4 mmol) at 0 C under argon atmosphere. Diiso-
propyl azadicarbonate (12 mL, 59.4 mmol) was added, and
the mixture was stirred overnight and concentrated. The
residue was purified by flash chromatography on silica gel
column (2:1 hexanes/EtOAc) to afford the bis-acetal as a color-
less oil (10 g, 26.4 mmol, 86%). Rf¼0.27 (1:1 hexanes/
ꢁ
was stirred at 60 C with a condenser for 1 h, then cooled
to room temperature and concentrated. The residue was pu-
rified by flash chromatography on silica gel column to afford
the protected lactone (10 g, 38.1 mmol, 84%) as a colorless
1
EtOAc); [a]D ꢀ3.4 (c 0.9, MeOH). H NMR (400 MHz,
CD3OD) d 1.34 (s, 9H), 1.60 (s, 3H), 3.19 (s, 3H), 3.54
(dd, 1H, J¼15.0, J¼3.9 Hz), 3.63 (dd, 1H, J¼14.3,
J¼3.5 Hz), 3.94 (s, 3H), 4.07 (s, 3H), 4.18 (m, 1H), 4.72
(s, 2H), 5.01 (s, 1H), 8.32 (s, 1H). 13C NMR (100 MHz,
CD3OD) d 24.3 (2), 26.0, 28.1 (2), 54.1, 55.1, 63.1, 82.2,
83.4, 85.0, 87.1, 102.3, 114.9, 115.0, 158.5, 167.3, 170.1;
MS (ESI): 386.1 [M+H].
1
ꢁ
solid; mp 92–94 C; [a]D ꢀ45.9 (c 0.44, EtOAc). H NMR
(400 MHz, CDCl3) d 1.29 (s, 3H), 1.31 (s, 3H), 1.38 (s, 3H),
1.47 (s, 3H), 3.14 (s, 3H), 3.52 (d, 1H, J¼9.0 Hz), 3.75 (d,
1H, J¼8.44 Hz), 4.7 (m, 3H). 13C NMR (100 MHz,
CD3OD) d 24.1, 25.0, 26.0, 28.0, 62.2, 78.5, 80.4, 83.9,
103.7, 114.8, 172.2, 173.4; MS (ESI): 261.5 [M+H].
To a solution of 5-bromo-2,4-dimethoxy-pyrimidine (5.7 g,
26 mmol) in 200 mL dry THF was added t-butꢁyllithium
(1.7 M in hexanes) (31.8 mL, 54 mmol) at ꢀ78 C under
argon atmosphere. After stirring for 30 min, a solution of
protected lactone (5.2 g, 20 mmol) in 100 mL dry THF was
added to this mixture via cannula. The mixture was stirred
The bis-acetal was then treated with 70% AcOH (300 mL) at
reflux for 2 h. The mixture was then brought to room temper-
ature and concentrated to give a yellow oil. The oil was
diluted in water (150 mL) and evaporated (repeated two
times). It was then diluted in MeOH (150 mL) and evapo-
rated (repeated two times). The residue was purified by flash
chromatography on silica gel column (10:1 EtOAc/MeOH)
to afford the productꢁ 5 as a white solid (6.0 g, 22 mmol,
84%); mp 128–130 C; [a]D +10.0 (c 0.1, MeOH). 1H
NMR (400 MHz, CD3OD) d 3.68 (dd, 1H, J¼7.42,
J¼4.62 Hz), 3.81 (dd, 1H, J¼8.88, J¼3.2 Hz), 3.90 (m,
1H), 3.95 (s, 4H), 4.05 (s, 4H), 4.80 (s, 1H), 8.39 (s, 1H).
13C NMR (100 MHz, CD3OD) d 54.6, 55.3, 62.9, 75.1,
76.9, 80.0, 85.0, 114.9, 157.8, 166.3, 170.2; MS (ESI):
273.3 [M+H].
ꢁ
for 1.5 h at ꢀ78 C, and then quenched by addition of brine
(100 mL). The mixturewas warmed to room temperature and
extracted with EtOAc (200 mLꢂ3). The combined organic
layer was dried over anhydrous Na2SO4, filtered, and concen-
trated. Purification by flash chromatography on silica gel col-
umn (hexanes/EtOAc, 4:1) afforded 3 as a white solid (5.2 g,
ꢁ
13 mmol, 65%); mp 39–41 C; [a]D ꢀ56.9 (c 0.55, MeOH).
1H NMR (400 MHz, CD3OD) d 1.35 (m, 6H), 1.43 (s, 4H),
3.30 (s, 3H), 3.62 (d, 2H, J¼6.8 Hz), 3.91 (s, 3H), 4.1 (s,
3H), 4.29 (m, 2H), 4.35 (t, 1H, J¼5.83 Hz), 4.9 (m, 2H),
8.44 (s, 1H). 13C NMR (100 MHz, CD3OD) d 24.5, 25.1,
26.9, 54.8, 55.8, 64.3, 85.0, 87.3, 88.4, 102.0, 107.3, 114.6,
116.9, 158.2, 166.8, 171.2; MS (ESI): 401.1 [M+H].
4.1.4. (2S, 3S, 4R, 5R)-2,4-Dimethoxy-5-[5,5,7,7-tetraiso-
propyl-3-(4-methoxy-benzyloxy)-tetrahydro-1,4,6,8-tet-
raoxa-5,7-disila-cyclopentacycloocten-2-yl]-pyrimidine
(6). Compound 5 (1.10 g, 4.04 mmol) was dissolved in dry
pyridine (42 mL) and 1,3-dichloro-1,1,3,3-tetraisopropyldi-
siloxane (1.42 mL, 4.44 mmol) was added dropwise at room
temperature in a 100 mL round-bottomed flask. The color-
less mixture was stirred at room temperature for 4 h under
4.1.2. (1R, 400R, 500S)-2-(20-Methoxypropan-20-yloxy)-1-
(500-[(R)-hydroxy(2000,4000-dimethoxypyrimidin-5000-yl-
methyl)-200,200-dimethyl-100,300-dioxolan-400-yl] ethanol (4).
To a solution of 3 (22 g, 55 mmol) in 2 L CH2Cl2 was added
slowly a solution of ZnCl2 (1 M in Et2O) (74.8 mL,
ꢁ
argon and then concentrated (T<45 C). The white solid
ꢁ
74.8 mmol) at ꢀ78 C under argon atmosphere. After stir-
was diluted with Et2O (50 mL), then with water (50 mL),
the two phases were separated, the aqueous phase was ex-
tracted with Et2O (3ꢂ50 mL), and the combined organic
phases were washed with brine and dried over Na2SO4. After
concentration under reduced pressure, the colorless oil was
purified by flash chromatography (eluant, 3:1 hexanes/
EtOAc) to afford the mono-alcohol as a colorless oil
(1.97 g, 3.83 mmol, 95%). Rf¼0.21 (3:1 hexanes/EtOAc),
ring for 30 min, L-Selectride (1 M in THF) (190 mL,
0.19 mol) was added slowly to this solution. The mixture
was warmed slowly to room temperature and stirred over-
night. The reaction was quenched by adding MeOH
(50 mL), and then H2O (25 mL), 30% H2O2 (25 mL), 6 M
NaOH (25 mL). The mixture was extracted with CH2Cl2
(400 mLꢂ3). The combined organic layer was washed
with satd NaHCO3 sodium bicarbonate and brine, dried
over anhydrous Na2SO4, filtered, and concentrated. Purifica-
1
[a]D ꢀ1.31 (c 1.45, MeOH). H NMR (400 MHz, CDCl3)
d 1.11 (m, 28H), 2.91 (s, 1H), 3.95 (s, 3H), 4.0 (s, 3H),

S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
5207
4.12 (m, 4H), 4.35 (m, 1H), 4.95 (s, 1H), 8.34 (s, 1H). 13C
NMR (100 MHz, CDCl3) d 12.5, 12.6, 12.9, 13.2, 16.8,
16.9, 17.1, 53.6, 53.9, 54.6, 54.7, 60.2, 61.4, 71.1, 75.2,
75.3, 79.9, 79.9, 80.9, 113.2, 156.5, 164.9, 168.0; MS
(ESI): 515.7 [M+H].
added dropwise. The colorless mixture was stirred at
ꢁ
ꢀ78 C for 15 min and 7 (935 mg, 1.43 mmol) dissolved
ꢁ
for 45 min. Pr2NEt (1.99 mL, 11.44 mmol) was added and
in dry CH2Cl2 (8.5 mL) was added and stirred at ꢀ78 C
i
ꢁ
mixture was stirred at ꢀ30 C for 1 h 30 min. It was then
quenched with satd NH4Cl. (15 mL), diluted with Et2O
(15 mL) and with water (15 mL). The organic phase was
separated and concentrated. It was then dissolved in Et2O
(50 mL) and hexane (50 mL), then washed with water
(5ꢂ20 mL), brine (1ꢂ20 mL), and dried over Na2SO4. A
pale yellow oil was obtained after concentration of the
organic phase.
In a 25 mL flame-dried round-bottomed flask, NaH (135 mg,
3.4 mmol, 60% in mineral oil) was washed with dry hexane
(15 mL) under argon atmosphere. After removal of hexane,
dry DMF (1.5 mL) was added to NaH and the white hetero-
ꢁ
geneous mixture was cooled to 0 C. The mono-alcohol
(1.25 g, 2.43 mmol) was dissolved in dry THF (5 mL),
ꢁ
for 10 min at 25 C after which PMBBr (3.2 mL,
added to NaH in DMF at 0 C, and the mixture was stirred
ꢁ
In a 100 mL round-bottomed flask, Ph3PCH3Br (1.02 g,
2.86 mmol) was put in suspension in dry THF (29 mL) and
4.13 mmol, 1.3 M in toluene) was added dropwise. The
white heterogeneous mixture was stirred for 15 h and then
quenched with water (5 mL), and then diluted with Et2O
(15 mL). The two phases were separated, the aqueous phase
was extracted with Et2O (3ꢂ10 mL), and the combined
organic phase was washed with brine, dried with Na2SO4,
and concentrated to give an oil. Purification by flash chroma-
tography (eluant, 3:1 hexanes/EtOAc) gave 6 as a colorless
oil (1.3 g, 2.05 mmol, 84%). Rf¼0.34 (3:1 hexanes/EtOAc).
[a]D ꢀ5.9 (c 5, MeOH). 1H NMR (400 MHz, CDCl3) d 1.01
(m, 28H), 3.80 (s, 3H), 3.96 (s, 6H), 4.00 (dd, 1H, J¼17.0,
J¼3.1 Hz), 4.10 (m, 2H), 4.20 (d, 1H, J¼4.47 Hz), 4.29
(m, 1H), 4.66 (d, 1H, J¼11.9 Hz), 4.85 (d, 1H,
J¼11.9 Hz), 5.04 (s, 1H), 6.85 (d, 2H, J¼6.77 Hz), 7.30
(d, 2H, J¼8.6 Hz), 8.45 (s, 1H). 13C NMR (100 MHz,
CDCl3) d 12.6, 12.5, 13.3, 13.7, 14.2, 16.9, 17.2, 53.7,
53.8, 54.5, 54.6, 55.1, 55.2, 60.1, 70.1, 71.6, 78.6, 78.7,
80.2, 81.5, 81.6, 113.5, 113.9, 128.9, 130.5, 156.3, 158.9,
164.7, 167.3; MS (ESI): 635.4 [M+H].
ꢁ
THF) was added and the yellow mixture was stirred at
0 C for 1 h. The above obtained aldehyde (930 mg,
cooled to 0 C. NaHMDS (2.86 mL, 2.86 mmol, 1 M in
ꢁ
1.43 mmol) in dry THF (25 mL) was added toꢁthe ylide at
ꢁ
ꢀ40 C and stirred for 2 h. After stirring at 0 C for 16 h,
the orange-brown mixture was quenched with satd NH4Cl
and the aqueous phasewas extracted with Et2O (3ꢂ40 mL).
The combined organic phase was dried with Na2SO4 and
concentrated to give an orange oil. Purification by flash
chromatography (eluant, 1:1 hexanes/EtOAc) afforded com-
pound 9 (204 mg, 0.31 mmol, 11%) as an oil and the desired
product 8 as a white solid (200 mg, 0.51 mmol, 36% (two
ꢁ
steps)). Rf¼0.28 (1:1 hexanes/EtOAc), mp 74 C; [a]D
1
+23.8 (c 0.5, CHCl3). H NMR (400 MHz, CDCl3) d 2.75
(s, 1H), 3.80 (s, 3H), 3.87 (m, 1H), 3.93 (dd, 1H, J¼5.5,
J¼2.8 Hz,), 3.98 (s, 3H), 4.00 (s, 3H), 4.24 (dd, 1H, J¼7.5,
J¼6.5 Hz), 4.53 (d, 1H, J¼11.3 Hz),, 4.70 (d, 1H, J¼
11.3 Hz), 5.05 (d, 1H, J¼2.6 Hz), 5.28 (d, 1H, J¼10.0 Hz),
5.44 (d, 1H, J¼17.1 Hz), 5.9–6.05 (m, 1H), 6.86 (d, 2H,
J¼8.6 Hz), 7.22 (d, 2H, J¼8.6 Hz), 8.21 (s, 1H). 13C NMR
(100 MHz, CDCl3) d 53.2, 55.1, 56.0, 57.8, 72.3, 74.6,
82.5, 84.1, 113.1, 114.8, 117.5, 128.2, 130.1, 136.1, 156.3,
159.1, 165.0, 167.2; MS (ESI): 411.4 [M+Na]. Comꢁpound
9 (204 mg) was treated with TBAF in THF (1 h, 0 C) to
give 8 (108 mg, 0.28 mmol, 90%).
4.1.5. (2S, 3S, 4R, 5R)-2,4-Dimethoxy-5-[5,5,7,7-tetraiso-
propyl-3-(4-methoxy-benzyloxy)-tetrahydro-1,4,6,8-tet-
raoxa-5,7-disila-cyclopen-tacycloocten-2-yl]-pyrimidine
(7). Compound 6 (1.12 g, 1.77 mmol) was dissolved in diox-
ane (38 mL) followed by the addition of 1 N HCl (19 mL)
and the mixture was stirred at room temperature for 1 h.
The colorless mixture was quenched with Et3N (4.2 mL,
30 mmol) and diluted with water (38 mL). The organic
phase was extracted with CH2Cl2 (3ꢂ50 mL) and the
combined organic phase was dried with Na2SO4. After con-
centration, the colorless oil was purified by flash chromatog-
raphy (eluant, 1:1 hexanes/EtOAc) to afford 7 as a white
solid (1.01 g, 1,55 mmol, 88%). Rf¼0.29 (1:1 hexanes/
4.1.7. (2S, 3S, 4R, 5R)-4-Allyloxy-2-(20,40-dimethoxypyri-
midin-50-yl)-3-(p-methoxy-benzyloxy)-5-vinyl-tetrahy-
drofuran (10). To a solution of 8 (2.5 g, 6.44 mmol) in
30 mL dry DMF was added sodium hydride (0.387 g,
ꢁ
9.66 mmol) at 0 C under argon atmosphere. After stirring
for 10 min, allyl bromide (0.817 mL, 9.66 mmol) was added
to this mixture. The mixture was stirred overnight and
quenched by adding NaHCO3. The mixture was extracted
with EtOAc (200 mLꢂ3). The combined organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated. Purification by flash chromatography on
silica gel column (hexanes/EtOAc, 4:1) afforded 10 as a
colorless oil (2.5 g, 5.84 mmol, 91%); [a]D +37.7 (c 0.97,
CHCl3), IR (thin film) n 2956, 1603, 1571, 1514 cmꢀ1; 1H
1
ꢁ
EtOAc); mp 62–65 C; [a]D ꢀ6.23 (c 0.69, MeOH). H
NMR (400 MHz, CDCl3) d 1.00 (m, 28H), 3.75 (s, 3H),
3.90 (s, 4H), 4.01 (s, 4H), 4.04 (m, 1H), 4.10 (m, 1H),
4.61 (m, 3H), 5.01 (d, 1H, J¼4.26 Hz), 6.79 (d, 2H,
J¼8.65 Hz), 7.14 (d, 2H, J¼8.66 Hz), 8.25 (s, 1H). 13C
NMR (100 MHz, CDCl3) d 12.59, 13.3, 13.4, 13.5, 14.3,
14.8, 16.5, 17.2, 53.7, 53.8, 54.7, 54.8, 55.0, 55.1, 60.2,
69.9, 71.7, 78.3, 78.4, 81.6, 82.8, 112.9, 113.5, 129.4,
129.6, 157.3, 159.1, 164.8, 167.8; MS (ESI): 653.4 [M+H].
NMR (400 MHz, CDCl3)
d
3.62 (dd, 1H, J¼7.5,
J¼4.8 Hz), 3.77 (s, 3H, –OMe), 3.92 (m, 3H), 3.97 (s, 6H,
2ꢂ–OMe), 4.52 (t, 1H, J¼7.5 Hz), 4.59 (d, 1H,
J¼11.9 Hz), 4.65 (d, 1H, J¼11.9 Hz), 5.15–5.3 (m, 5H),
5.45 (d, 1H, J¼17.1 Hz), 5.75–6.0 (m, 2H), 6.82 (d, 2H,
J¼8.6 Hz), 7.23 (d, 2H, J¼8.6 Hz), 8.21 (s, 1H). 13C
NMR (100 MHz, CDCl3) d 53.8, 54.7, 55.1, 71.2 (2C),
78.1, 79.4, 80.8, 81.3, 113.5, 113.5, 117.3, 117.9, 129.3,
4.1.6. (2S, 3S, 4R, 5R)-5-(2,4-Dimethoxy-pyrimidin-5-yl)-
4-(4-methoxy-benzyloxy)-2-vinyl-tetrahydro-furan-3-ol
(8). In a 25 mL flame-dried round-bottomed flask, dry
CH2Cl2 (6.5 mL) and dry DMSO (0.63 mL, 8.87 mmol)
were adꢁded under argon atmosphere. Mixture was cooled
to ꢀ78 C and oxalyl chloride (0.37 mL, 4.29 mmol) was

5208
S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
129.7, 134.1, 135.9, 156.3, 159.1, 164.8, 167.9; MS (FAB)
429.2 (M+H+); HRMS (FAB) calcd for C23H29N2O6
429.2025; found 429.2045.
2.2 mmol) in 50 mL anhydrous CH2Cl2 was added Dess–
Martin periodinane (2.22 g, 7.0 mmol) at room temperature
under argon atmosphere. The mixture was stirred for 4 h and
quenched by adding satd NaHCO3 (30 mL) and Na2S2O3
(30 mL). The mixture was stirred for 30 min, extracted
with EtOAc (200 mLꢂ3), the combined organic phase was
dried over anhydrous Na2SO4, filtered, and concentrated.
Compound 13 was used immediately in the next step without
any purification.
4.1.8. (2S, 3S, 3aR, 7aR)-2-(20,40-Dimethoxy-pyrimidin-
50-yl)-3-(p-methoxy-benzyloxy)-3,3a,5,7a-tetrahydro-
2H-furo[3,2-b]pyran (11). To a solution of 10 (2.5 g,
5.84 mmol) in 1.2 L dry degassed CH2Cl2 was added the first
generation Grubbs catalyst (240 mg, 0.29 mmol) at room
temperature under argon atmosphere. The mixture was
refluxed for 5 h and concentrated. The residue was purified
by flash chromatography on silica gel column (hexanes/
EtOAc, 4:1) to afford the bicyclic product 11 as a white solid
4.1.11. (2S, 3S, 3aR, 6S, 7R, 7aR)-7-Azido-2-(20, 40-di-
methoxy-pyrimidin-50-yl)-6-methoxy-3-(p-methoxy-ben-
zyloxy)-hexahydro-2H-furo[3,2-b]pyran (14). Compound
13 was dissolved in 40 mL MeOH and NaBH4 (840 mg,
22.7 mmol) was added to this mixture. After stirring for
1 h, the mixture was concentrated at room temperature.
The residue was dissolved in 200 mL EtOAc and washed
with H2O (50 mLꢂ3), brine (30 mL). The organic phase
was dried over anhydrous Na2SO4, filtered, and concen-
trated. The crude product was dissolved in 20 mL anhydrous
ꢁ
(2.2 g, 5.5 mmol, 94%); mp. 80 C, [a]D ꢀ33.2 (c 1.1,
1
CHCl3), IR (thin film) n 2956, 1603, 1602, 1575 cmꢀ1; H
NMR (400 MHz, CDCl3)
d
3.42 (dd, 1H, J¼8.9,
J¼4.5 Hz), 3.77 (s, 3H, –OMe), 3.93 (m, 1H), 3.95 (s, 3H,
–OMe), 3.96 (s, 3H, –OMe), 4.40 (m, 2H), 4.54 (m, 1H),
4.65 (d, 1H, J¼11.9 Hz), 4.74 (d, 1H, J¼11.9 Hz), 5.11 (m,
1H), 5.69 (d, 1H, J¼10.3 Hz), 6.28 (d, 1H, J¼9.7 Hz), 6.85
(d, 2H, J¼8.7 Hz), 7.28 (d, 2H, J¼8.7 Hz), 8.18 (s, 1H).
13C NMR (100 MHz, CDCl3) d 53.9, 54.7, 55.1, 68.6, 71.3,
71.6, 78.8, 79.5, 81.7, 113.4, 113.6, 127.1, 127.4, 129.1,
130.0, 156.1, 159.1, 164.8, 167.6; HRMS (MAB) calcd for
C21H25N2O6 (M+H+) 401.1710; found 401.1699.
ꢁ
DMF and NaH (131 mg, 3.27 mmol) was added at 0 C un-
der argon atmosphere. The resulting mixture was stirred for
10 min, iodomethane (0.638 mL, 99 mmol) was added, and
the mixture was stirred overnight. After adding satd
NaHCO3 (30 mL), the mixture was extracted with EtOAc
(50 mLꢂ3), the organic phase was dried over anhydrous so-
dium sulfate, filtered, and concentrated. Purification by flash
chromatography on silica gel column (hexanes/EtOAc, 4:1)
afforded 14 as a white solid (800 mg, 1.7 mmol, 78%); mp
4.1.9. (2S, 3S, 3aR, 6R, 7R, 7aR)-7-Azido-2-(20,40-di-
methoxy-pyrimidin-50-yl)-6-hydroxyl-3-(p-methoxy-
benzyloxy)-hexahydro-2H-furo[3,2-b]pyran (12). To a so-
lution of 11 (1.0 g, 2.5 mmol) in 60 mLTHF and 60 mL H2O
was added NBS (0.53 g, 2.95 mmol) at room temperature.
The mixture was stirred for 1.5 h and quenched by adding
100 mL H2O containing 2 g Na2S2O3. The mixture was ex-
tracted with EtOAc (100 mLꢂ3), the combined organic
phase was washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was dis-
solved in 200 mLTHF and 1 N NaOH (33 mL). The solution
was refluxed for 1 h and cooled to room temperature, then
extracted with EtOAc (200 mLꢂ3). The combined organic
phase was dried over anhydrous Na2SO4, filtered, and con-
centrated. The intermediate epoxide was dissolved in
150 mL methoxyethanol. The solution was refluxed for
1 h, cooled to room temperature, then poured into 200 mL
brine, and extracted with EtOAc (100 mLꢂ3). The organic
layer was dried over anhydrous Na2SO4, filtered, and con-
centrated. Purification by flash chromatography on silica
gel column (hexanes/EtOAc, 3:1) afforded the trans-azido
alcohol 12 as a white solid (500 mg, 1.1 mmol, 43%); mp
ꢁ
89 C; [a]D +60.6 (c 0.88, CHCl3), IR (thin film) n 2913,
1
2105 (N3), 1602, 1572 cmꢀ1; H NMR (400 MHz, CDCl3)
d 3.47 (s, 3H, –OMe), 3.61 (m, 2H), 3.75 (m, 1H), 3.76 (s,
3H, –OMe), 3.85 (d, 1H, J¼4.63 Hz), 3.96 (s, 3H, –OMe),
3.97 (s, 3H, –OMe), 4.01 (dd, 1H, J¼10.04, J¼2.91 Hz),
4.67 (m, 3H), 5.16 (s, 1H), 6.86 (d, 2H, J¼8.6 Hz), 7.26
(d, 2H, J¼8.6 Hz), 8.44 (s, 1H). 13C NMR (400 MHz,
CDCl3) d 53.9, 54.8, 55.1, 57.1, 57.4, 59.7, 65.7, 71.2,
74.0, 75.0, 76.4, 78.9, 81.5, 113.3, 113.7, 129.7, 156.0,
159.1, 164.9, 167.2; HRMS (FAB) calcd for C22H28N5O7
(M+H+) 474.1988; found 474.2002.
The corresponding 6-ethoxy analogue 15 was similarly
prepared (76%); [a]D +68 (0.6, CHCl3); MS (FAB): 488.2
(M+H+).
4.1.12. (2S, 3S, 3aR, 6S, 7R, 7aR)-7-Azido-2-(20,40-dioxo-
10,20,30,40-tetrahydro–pyrimidin-50-yl)-6-methoxy-3-piv-
aloyloxy)-hexahydro-2H-furo[3,2-b]pyran (16). To
a
ꢁ
119 C; [a]D +93.1 (c 0.98, CHCl3), IR (thin film) n 3400,
solution of 14 (800 mg, 1.69 mmol) in 20 mL CH2Cl2 and
1 mL H2O was added DDQ (1.18 g, 5.2 mmol) at room tem-
perature. The mixture was stirred for 6 h and quenched by
adding satd NaHCO3 (200 mL). The mixture was extracted
with CH2Cl2 (50 mLꢂ4). The combined organic phase
was washed with brine (50 mL), dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was purified
by flash chromatography on silica gel column (EtOAc) to
afford the alcohol as a colorless oil (580 mg, 1.65 mmol,
97%); [a]D +93 (c 0.3, CHCl3); IR (thin film) n 3540,
1
2915, 2105 (N3), 1604, 1572 cmꢀ1; H NMR (400 MHz,
CDCl3) d 3.40 (br s, 1H, OH), 3.58 (dd, 1H, J¼10.0,
4.7 Hz), 3.68 (m, 1H), 3.73 (d, 1H, J¼12.7 Hz), 3.78 (s,
3H, –OMe), 3.89 (m, 2H), 3.97 (s, 6H, 2ꢂ–OMe), 4.33
(m, 2H), 4.67 (s, 2H), 5.10 (m, 1H), 6.86 (d, 2H,
J¼8.7 Hz), 7.27 (d, 2H, J¼8.7 Hz), 8.33 (s, 1H). 13C
NMR (100 MHz, CDCl3) d 53.9, 54.8, 55.1, 61.6, 68.3,
69.3, 71.4, 73.3, 74.2, 79.8, 80.3, 113.3, 113.7, 129.2,
129.7, 155.8, 159.2, 164.8, 167.4; HRMS (FAB) calcd for
C21H26N5O7 (M+H+) 460.1832; found 460.1842.
;
2920, 2105, 1603, 1574 cmꢀ1 1H NMR (400 MHz,
CDCl3) d 3.49 (s, 3H, OMe), 3.57 (ddd, 1H, J¼10.4,
J¼4.85, J¼2.91 Hz), 3.65 (t, 1H, J¼10.4 Hz), 3.76 (dd,
1H, J¼9.8, J¼4.64 Hz), 3.94 (m, 2H), 3.98 (m, 4H,
–OMe), 4.02 (s, 3H, –OMe), 4.10 (d, 1H, J¼4.6 Hz),
4.1.10. (2S, 3S, 3aR, 7R, 7aR)7-Azido-2-(2,4-dimethoxy-
pyrimidin-5-yl)-3-(4-methoxy-benzyloxy)-tetrahydro-
furo[3,2-b]pyran-6-one(13). To a solution of 12 (1.0 g,

S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
5209
4.67 (m, 2H), 5.06 (s, 1H), 8.41 (s, 1H). 13C NMR
(100 MHz, CDCl3) d 54.1, 54.8, 57.4, 59.4, 65.7, 73.0,
73.7, 74.7, 76.3, 83.5, 112.9, 155.8, 164.4, 167.6; HRMS
(FAB) calcd for C14H20N5O6 (M+H+) 353.1335; found
353.1341.
the authentic sample d 3.30 (s, 3H, OMe), 3.38 (t, 1H,
J¼10.7, H-7ax0.), 3.51 (dd, 1H, J¼10.7, J¼5.1 Hz, H-30),
3.69 (ddd, 1H, J¼5.2, J¼3.5, J¼10.7 Hz, H-60), 3.85 (dd,
1H, J¼3.5, J¼11.8 Hz, H-7eq0), 3.93 (dd, 1H, J¼10.7,
J¼5.4 Hz, H-60), 4.16 (d, 1H, J¼2.1 Hz, H-20), 4.74 (s,
1H, H-10), 4.82 (s, 1H, H-50), 7.24 (s, 1H, H-6). 13C NMR
(100 MHz, D2O) d 48.1, 57.3, 66.4, 73.2, 75.0, 76.6, 85.2,
113.8, 141.2, 154.8, 163.1, 167.5, 179.8. HRMS (FAB)
MH+ calcd 342.1176; found 342.1181.
The alcohol (580 mg, 1.64 mmol) was dissolved in 30 mL
anhydrous pyridine, and DMAP (122 mg, 1 mmol) and piv-
aloyl chloride (0.4 mL, 3.32 mmol) were added at room tem-
perature under argon atmosphere. The mixture was stirred
overnight, concentrated, and the residue was purified by
flash chromatography on silica gel column (hexanes/EtOAc,
4:1) to afford the pivalate ester as a colorless oil (650 mg,
4.1.14. (2R, 3R, 3aR, 6R, 7R, 7aR)-7-Azido-3-benzyloxy-
2,6-dimethoxy-hexahydrofuro[3,2-b]pyran (29). To a so-
lution of 28 (600 mg, 1.9 mmol) in 30 mL dry DMF were
added NaH (60% dispersion in mineral ꢁoil) (200 mg,
5.0 mmol) and MeI (0.5 mL, 8.0 mmol) at 0 C under argon
atmosphere. After stirring overnight, the reaction was
quenched by adding satd NaHCO3 and extracted with EtOAc
(30 mLꢂ4). The combined organic layer was washed with
satd NaHCO3 and brine, dried over anhydrous Na2SO4,
filtered, and concentrated. Purification by flash silica chro-
matography (hexanes/EtOAc, 10:1) afforded the product
as colorless oil (600 mg, 1.8 mmol, 96%); [a]D ꢀ16.0
1
1.49 mmol, 90%). H NMR (400 MHz, CDCl3) d 1.24 (s,
9H, –OPiv), 3.47 (s, 3H, –OCH3), 3.53 (m, 1H), 3.56 (t,
1H, J¼10.2 Hz), 3.79 (dd, 1H, J¼10.2, J¼2.6 Hz), 3.90
(ddd, 2H, J¼10.5, J¼5.2, J¼2.8 Hz), 3.97 (s, 3H, –OCH3),
3.99 (s, 3H, –OCH3), 4.67 (s, 1H), 5.05 (s, 1H), 5.27 (d,
1H, J¼3.7 Hz), 8.41 (s, 1H). 13C NMR (100 MHz, CDCl3)
d 27.5, 39.3, 54.5, 55.2, 57.9, 59.5, 66.2, 73.4, 73.8, 75.7,
76.1, 76.7, 77.0, 81.8, 112.8, 156.5, 165.7, 168.1, 177.5;
MS (FAB): 438.2 (M+H+).
1
(c 1.36, CHCl3); IR (neat): 2960, 2098, 1490 cmꢀ1; H
To a solution of the pivalate ester (650 mg, 1.49 mmol) in
27 mL dry MeCN were added NaI (740 mg, 5.22 mmol)
and TMSCl (565 mg, 5.22 mmol) at room temperature under
argon atmosphere. The mixture was stirred for 24 h and
quenched by adding 10% sodium metabisulfite (10 mL)
and satd NaHCO3 (10 mL). The mixture was stirred for
10 min and extracted with EtOAc (30 mLꢂ3), the combined
organic layer was washed with brine (35 mL), dried over an-
hydrous Na2SO4, filtered, and concentrated. Purification by
flash chromatography on silica gel column (hexanes/EtOAc,
1:1) afforded 16 as a colorless oil (214 mg, 35%). Starting
material (150 mg) and non-demethylated intermediate
(145 mg, 34%) were recovered. The latter could be recycled
as described above. For 16, [a]D +100.75 (c 0.4, CHCl3); 1H
NMR (400 MHz, CDCl3) d 1.22, (s, 9H, –OPiv), 3.46 (s, 3H,
–OMe), 3.47 (ddd, 1H, J¼10.7, J¼2.9, J¼4.0 Hz), 3.59
(t, 1H, J¼10.7 Hz), 3.75 (dd, 1H, J¼10.0, J¼2.7 Hz), 3.86
(m, 2H), 4.65 (s, 1H), 4.91 (s, 1H), 5.31 (d, 1H,
J¼4.7 Hz), 7.55 (s, 1H), 10.00 (br, 2H, 2ꢂNH). 13C NMR
(100 MHz, CDCl3) d 26.7, 38.7, 57.4, 59.1, 65.6, 72.6,
72.8, 75.2, 76.4, 80.9, 111.6, 138.8, 152.2, 162.5, 171.1;
HRMS (FAB) calcd for C17H24N5O7 (M+H+) 410.1675;
found 410.1693.
NMR (400 MHz, CDCl3, ppm): d 3.22 (m, 1H, H-6); 3.38
(s, 3H, –OMe); 3.41 (s, 3H, –OMe); 3.64 (d, 1H,
J¼12.8 Hz, H-5); 3.86 (dd, 1H, J¼10.0, 4.2 Hz, H-3a);
3.95 (d, 1H, J¼4.2 Hz, H-2); 4.03 (d, 1H, J¼12.8 Hz,
H-5); 4.40 (d, 1H, J¼3.0 Hz, H-7); 4.45 (dd, 1H, J¼10.0,
J¼3.1 Hz, H-7a); 4.62 (d, 1H, J¼12.2 Hz, PhCH2–); 4.84
(d, 1H, J¼12.2 Hz, PhCH2–); 4.86 (s, 1H, H-2); 7.26–7.38
(m, 5H, Ph–); 13C NMR (100 MHz, CDCl3, ppm): d 56.1,
57.7, 59.3, 66.9, 72.7, 74.8, 75.1, 77.8, 79.8, 128.1, 128.2,
128.8, 138.4. FABMS m/z (relative intensity): 335 (M+,
15), 275, 184 (100). HRMS (FAB) calcd for C16H21N3O5
(M+) 335.1481; found 335.1481.
To a solution of benzyl ether (590 mg, 1.84 mmol) in 25 mL
CCl4–MeCN–H2O (1:1:1.5) were added RuCl3$3H2O
(87.5 mg, 0.35 mmol) and NaIO4 (464 mg, 2.2 mmol) at
ꢁ
16 C under argon atmosphere, and then 1.2 g of NaIO4
was added in portions over 24 h. After stirring over 24 h,
the reaction was quenched by adding 3 mL isopropanol.
The mixture was extracted with CH2Cl2 (50 mLꢂ3) and
the combined organic layer was washed with satd NaHCO3
and brine, filtered, and concentrated. Purification by flash
silica chromatography (hexanes/EtOAc, 10:1) afforded benz-
oate 29 (500 mg, 1.43 mmol, 82%); [a]D +0.78 (c 1.15,
CHCl3); IR (neat, cmꢀ1): 2916, 2103, 1727, 1452, 1269,
4.1.13. Malayamycin A (1). Compound 16 (32 mg,
0.076 mmol) was dissolved in dry THF (6 mL) and argon
was bubbled in the solution for 10 min. Water (6 mL) and
PMe3 (88 mL, 1 M solution in toluene, 0.088 mmol) were
added. After 5 min at room temperature, the solution was re-
fluxed for 30 min, then concentrated and held under vacuum
for 1 h. It was then dissolved in dry CH2Cl2 (8 mL) and tri-
chloroacetylisocyanate (10 mL, 0.082 mmol) was added.
After 30 min, the solution was concentrated. The oily resi-
due was dissolved in MeOH (2 mL), 40% MeNH2 in water
(4 mL) was added and the solution was stirred for 52 h.
Concentration gave a solid that was purified by flash
chromatography (9:1 CH2Cl2/MeOH) to give pureꢁmalaya-
mycin A as a white solid (16 mg), 60%; mp 158 C (dec)
[a]D +120 (c 0.19, MeOH); (authentic sample [a]D +126
1
1199, 1115, H NMR (400 MHz, CDCl3, ppm): d 3.22 (m,
1H, H-6); 3.36 (s, 3H, –OMe); 3.47 (s, 3H, –OMe); 3.65
(d, 1H, J¼12.9 Hz, H-5); 4.0 (d, 1H, J¼12.9 Hz, H-5); 4.03
(dd, 1H, J¼10.0, J¼4.4 Hz, H-8); 4.40 (m, 2H, H-7
and H-9); 5.03 (s, 1H, H-2); 5.40 (d, 1H, J¼4.4 Hz, H-3),
7.42–8.05 (m, 5H, Ph–). 13C NMR (100 MHz, CDCl3,
ppm): d 56.4, 57.7, 59.5, 66.7, 72.6, 75.0, 75.5, 77.9, 107.6,
128.8, 129.6, 130.4, 133.7, 170.0. FABMS m/z (relative
intensity): 349 (M+, 10).
4.1.15. (10R, 2R, 3R, 4S, 5R)-4-Azido-2-(10-benzoyloxy-
20,20-bisphenylsulfanylethyl)-3-hydroxyl-5-methoxy-tet-
rahydropyran (30). To a solution of 29 (390 mg, 1.1 mmol)
in 10 mL dry CH2Cl2 was added benzenethiol (490 mg,
4.5 mmol), then BF3$Et2O (0.17 mL, 1.34 mmol) at
1
(c 0.36, MeOH)). H NMR (D2O, 400 MHz) identical to

5210
S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
ꢁ
for 3 h, warmed to 0 C, and quenched by adding satd
ꢀ78 C under argon atmosphere. The mixture was stirred
NMR (400 MHz, CDCl3, ppm): d 1.30 (s, 9H, PivO–);
3.28 (m, 1H, H-6); 3.37 (s, 3H, –OMe); 3.63 (d, 1H,
J¼12.0 Hz, H-5), 3.73 (d, 1H, J ¼10.0, J¼4.3 Hz, H-3a);
3.98 (d, 1H, J¼12.0 Hz, H-5); 4.42 (m, 2H, H-7 and H-
7a); 5.69 (t, 1H, J¼4.3 Hz, H-3); 5.82 (d. 1H, J¼4.3 Hz,
H-2), 7.24–7.51 (m, 5H, Ph–); 13C NMR (100 MHz,
CDCl3, ppm): d 26.9, 39.2, 56.6, 58.5, 65.0, 70.5, 73.5,
73.6, 76.9, 89.9, 126.9, 128.9, 130.5, 134.8, 176.8; FABMS
m/z: 408 (M+H+, 20), 298 (M+ꢀPhS, 100); HRMS (FAB)
calcd for C19H26N3O5S (M+H+) 408.1593; found 408.1601.
ꢁ
NaHCO3. The mixture was extracted with CH2Cl2
(30 mLꢂ3), and the combined organic layer was washed
with satd NaHCO3 and brine, dried over anhydrous
Na2SO4, filtered, and concentrated. Purification by flash sil-
ica chromatography (hexanes/EtOAc, 5:1) afforded the di-
thioacetal 30 as a colorless oil (473 mg, 0.88 mmol, 80%);
[a]D +41.0 (c 0.56, CHCl3); IR (neat): l 2918, 2109, 1723,
1439, 1268 cmꢀ1 1H NMR (400 MHz, CDCl3, ppm):
;
d 2.54 (d, 1H, J¼5.6 Hz, –OH); 3.35 (s, 3H, –OMe); 3.40
(m, 1H, H-5); 3.49 (dd, 1H, J¼12.5, J¼3.5 Hz, H-6), 3.56
(dd, 1H, J¼12.5, J¼2.4 Hz, H-6); 3.94 (t, 1H, J¼4.2 Hz,
H-4); 4.07 (m, 1H, H-3); 4.18 (t, 1H, J¼7.6 Hz, H-7), 4.95
(d, 1H, J¼2.5 Hz, H-20); 5.73 (dd, 1H, J¼7.6, J¼2.5 Hz,
H-10); 7.25–8.08 (m, 15H, Ph–); 13C NMR (100 MHz,
CDCl3, ppm): d 57.1, 61.5, 62.3, 63.6, 67.9, 74.6, 74.7,
76.7, 127.7, 128.3, 128.33, 128.9, 129.0, 129.3, 130.1,
132.3, 133.3, 133.7, 134.5, 166.2; FABMS m/z (relative
intensity): 537 (M+, 3), 428 (M+ꢀPhS, 16); HRMS (FAB)
calcd for C27H28N3O5S2 (M+H+) 538.1470; found
538.1453.
4.1.17. (2R, 3R, 3aR, 6R, 7R, 7aR)-7-Azido-2-(20,40-dioxo-
30,40-dihydro-2H-pyrimidin-10-yl)-6-methoxy-3-pivaloyl-
oxy-hexahydrofuro[3,2-b]pyran and (2R, 3R, 3aR, 6R,
7R, 7aR)-7-azido-2-(50-iodo-20,40-dioxo-30,40-dihydro-
2H-pyrimidin-10-yl)-6-methoxy-3-pivaloyloxy-hexahy-
drofuro [3,2-b]pyran (32, 33). To a solution of 31 (41 mg,
0.1 mmol), bis-TMS-uracil (40 mg, 0.16 mmol) and NIS
(45 mg, 0.2 mmol) in 4 mL dry CH2Cl2 was added TfOH
(10 mL) over several minutes. After stirring for 5 h, the mix-
ture was quenched by adding satd Na2S2O3, and extracted
with CH2Cl2 (30 mLꢂ3). The combined organic layer was
washed with satd NaHCO3, dried over anhydrous Na2SO4,
filtered, and concentrated. Purification by flash silica
chromatography (CH2Cl2/MeOH, 10:1) afforded the 32
(20 mg) and iodonucleoside 33 (8 mg) as colorless oils,
the combined yield was 80% based on recovered starting
material (10 mg). For 32: [a]D +114.5 (c 1.6, CHCl3); IR
4.1.16. (2R, 3R, 3aS, 6R, 7R, 7aR)-7-Azido-6-methoxy-2-
phenylsulfanyl-hexahydrofuro[3,2-b]pyran-3-ol (31). To
a solution of 30 (420 mg, 0.78 mmol) in 10 mL MeOH
was added anhydrous K2CO3 (5 mg) at room temperature
and the mixture was stirred for 30 min. The mixture was
evaporated under vacuum and the residue was purified by
flash silica chromatography (hexanes/EtOAc, 3:1) to afford
diol as a colorless oil (335 mg, 0.77 mmol). To a solution
of above diol in 10 mL dry CH2Cl2 was added NBS
(205 mg, 1.16 mmol) at room temperature under argon
atmosphere. After stirring for 30 min, the reaction was
quenched by adding satd Na2S2O3 (10 mL), and the mixture
was extracted with CH2Cl2 (20 mLꢂ3). The combined or-
ganic layer was washed with satd NaHCO3 and brine, dried
over anhydrous Na2SO4, filtered, and concentrated. Purifica-
tion by flash silica chromatography (hexanes/EtOAc, 10:1)
afforded alcohol as a colorless oil (190 mg, 0.59 mmol,
77%); [a]D +150.5 (c 0.54, CHCl3); IR (neat): 3402, 2918,
(neat): 2971, 2106, 1695, 1458, 1147 cmꢀ1 1H NMR
.
(400 MHz, CDCl3, ppm): d 1.25 (s, 9H, PivO–); 3.39 (m,
1H, H-6); 3.40 (s, 3H, –OMe); 3.68 (d, 1H, J¼13.4 Hz, H-
5); 3.80 (dd, 1H, J¼9.8, J¼5.1 Hz, H-7a); 4.08 (d, 1H,
J¼13.4 Hz, H-5); 4.21 (dd, 1H, J¼9.8, J¼3.0 Hz, H-3a);
4.45 (m, 1H, H-7); 5.30 (d, 1H, J¼3.0 Hz, H-3); 5.79 (d,
1H, J¼8.1 Hz, H-50); 5.85 (s, 1H, H-1); 7.44 (d, 1H,
J¼8.1 Hz, H-60); 8.29 (s, 1H, –NH); 13C NMR (100 MHz,
CDCl3, ppm): d 26.9, 38.8, 56.8, 59.2, 65.2, 71.9, 73.0,
74.4, 76.6, 89.6, 102.9, 139.4, 149.4, 162.5, 176.9; FABMS
m/z (relative intensity): 410 (M+H+, 10), 391 (M+ꢀH2O,
16), 298 (M+ꢀuracilyl, 16); HRMS (FAB) calcd for
C17H24N5O7 (M+H+) 410.1675; found 410.1662. For 33:
[a]D +123.4 (c 0.87, CHCl3); IR (neat): 2978, 2104, 1691,
2103, 1584, 1482, 1069 cmꢀ1
.
1H NMR (400 MHz,
CDCl3, ppm): d 2.59 (d, 1H, J¼2.0 Hz, –OH); 3.31 (dd,
1H, J¼2.4, J¼1.3 Hz, H-6); 3.73 (m, 1H, H-7); 3.78 (dd,
1H, J¼12.9, J¼1.6 Hz, H-5); 4.06 (d, 1H, J¼12.9 Hz, H-
5); 4.46 (m, 2H, H-3a and H-7a), 4.58 (m, 1H, H-3); 5.77
(d, 1H, J¼4.0 Hz, H-2); 13C NMR (100 MHz, CDCl3,
ppm): d 57.6, 58.7, 66.7, 70.6, 70.61, 73.4, 74.7, 92.8,
127.3, 129.4, 130.8, 132.5; FABMS m/z (relative intensity):
323 (M+, 25); HRMS (FAB) calcd for C14H18N3O4S
(M+H+) 324.1018; found 324.1012.
1611, 1136 cmꢀ1 1H NMR (400 MHz, CDCl3, ppm):
;
d 1.25 (s, 9H, PivO–); 3.40 (s, 3H, –OMe); 3.42 (m, 1H,
H-6); 3.72 (d, 1H, J¼13.1 Hz, H-5); 3.79 (dd, 1H, J¼10.1,
5.0 Hz, H-3a); 4.08 (d, 1H, J¼13.1, H-5); 4.25 (dd, 1H,
J¼10.1, J¼2.4 Hz, H-7a); 4.47 (s, 1H, H-7); 5.36 (d, 1H,
J¼5.0 Hz, H-3); 5.80 (s, 1H, H-2); 8.03 (s, 1H, H-60); 8.59
(s, 1H, –NH); 13C NMR (100 MHz, CDCl3, ppm): d 27.5,
39.4, 57.4, 59.9, 65.8, 68.8, 72.2, 73.4, 75.4, 77.3, 90.3,
144.7, 149.5, 159.8, 177.2; FABMS m/z (relative intensity):
536 (M+H+, 10), 298 (M+ꢀiodouracilyl, 26); HRMS (FAB)
calcd for C17H23N5O7I (M+) 536.0642; found 536.0664.
To a solution of 31 (170 mg, 0.53 mmol) in 5 mL dry pyri-
dine was added DMAP (200 mg), then pivaloyl chloride
(0.2 mL) at room temperature under argon atmosphere.
The mixture was stirred overnight and pyridine was removed
under reduced pressure. The residue was dissolved with
50 mL CH2Cl2, washed with satd NaHCO3, brine, dried
over anhydrous Na2SO4, filtered, and concentrated. Purifica-
tion by flash silica chromatography (hexanes/EtOAc, 5:1)
afforded the pivalate ester 31 as a colorless oil (214 mg,
0.53 mmol, quant.); [a]D +149.6 (c 0.51, CHCl3); IR
4.1.18. (2R, 3R, 3aS, 6S, 7R, 7aR)-[2-(20,40-Dioxo-30,40-
dihyro-2H-pyrimidin-10-yl)-3-hydroxyl-6-methoxy-
hexahydrofuro[3,2-b]pyran-7-yl]-urea (6-epi-N-
malayamycin) (34). To a solution of 32 (37 mg, 0.09 mmol)
in 4 mL anhydrous THF was added Me3P (1 M in toluene)
(250 mL, 0.25 mmol) at room temperature under argon at-
mosphere. After stirring for 30 min, 10 mL of H2O was
added, and the resulting mixture was refluxed for 40 min,
then evaporated. The residue was dried under reduced
(neat): 2977, 2931, 2104, 1742, 1480, 1146 cmꢀ1 1H
;

S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
5211
pressure (1 mmHg) for 1.5 h and dissolved in 2 mL dry
CH2Cl2. To this solution was added trichloroacetylisocya-
nate (20 mL) at room temperature under argon atmosphere.
After stirring for 60 min, CH2Cl2 was removed and the resi-
due was dissolved with MeOH (3 mL) and 40% MeNH2 in
H2O (3 mL), and stirred over 3 days. The mixture was evap-
orated and purified by flash silica chromatography (CH2Cl2/
MeOH, 9:1) to afford 6-epi-N-malayamycin 34 as a white
solid (25 mg, 0.073 mmol, 77%); [a]D +30.0 (c 0.45,
36 as a yellowish oil (5.2 g, 82%). Rf¼0.68 (7:3 AcOEt/hex-
1
anes); [a]D +14.1 (c 1.11 in CHCl3); H NMR (300 MHz,
CDCl3) d 5.84 (d, 1H, J¼3.7 Hz), 5.76 (ddd, 1H, J¼17.8,
J¼10.5, J¼7.8 Hz), 5.35 (d, 1H, J¼17.8 Hz), 5.29 (d, 1H,
J¼10.5 Hz), 4.72 (app. t, 1H, J¼4.1 Hz), 4.10 (dd, 1H, J¼
10.0, J¼7.8 Hz), 3.25 (dd, 1H, J¼11.9, J¼9.6 Hz), 3.06
(dd, 1H, J¼9.6, J¼3.7 Hz), 2.14 (ddt, 1H, J¼11.9,
J¼10.0, J¼4.1 Hz), 1.54 (s, 3H), 1.37 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 134.8, 119.2, 111.7, 103.9, 81.2,
81.1. 53.4, 26.4, 26.1, ꢀ2.9; HRMS calcd for C10H16IO3
[M+H]+ 311.0144; found 311.0146.
1
MeOH); H NMR (400 MHz, CD3OD, ppm): d 3.39 (m,
1H, H-60); 3.44 (s, 1H, –OMe); 3.59 (dd, 1H, J¼10.7,
J¼5.2 Hz, H-3a); 3.79 (d, 1H, J¼13.2 Hz, H-5); 4.12 (d,
1H, J¼13.2 Hz, H-5); 4.22 (dd, 1H, J¼10.7, J¼4.2 Hz, H-
7a); 4.31 (d, 1H, J¼5.2 Hz, H-3); 4.65 (m, 1H, H-7); 5.62
(s, 1H, H-2); 5.70 (d, 1H, J¼8.1 Hz, H-50); 7.62 (d, 1H,
J¼8.1 Hz, H-60); 13C NMR (100 MHz, CD3OD, ppm)
d 48.7, 56.4, 66.6, 72.6, 73.5, 74.1, 78.7, 93.8, 101.7,
141.7, 150.9, 160.6, 165.2; FABMS m/z 343 (M+H+);
HRMS (FAB) calcd for C13H19N4O7 (M+H+) 343.1253;
found 343.1284.
4.1.20. (3aR, 5R, 6R, 6aR)-6-(But-3-enyl)-dihydro-2,2-
dimethyl-5-vinyl-5H-furo[2,3-d][1,3]dioxole (37). A mix-
ture of 36 (3.0 g, 9.7 mmol), allyltributyltin (54 mL,
174 mmol) and AIBN (159 mg, 0.97 mmol) under an argon
ꢁ
atmosphere was heated at 100 C for 1 h. An additional por-
tion of AIBN (159 mg, 0.97 mmol) was then added and the
reaction mixture was heated for 1 h. The product was iso-
lated by two successive flash silica gel chromatography
(CH2Cl2), which afforded 1.86 g of 37 (75%) as a colorless
oil. Rf¼0.52 (3:1.5:0.5 toluene/hexanes/AcOEt); [a]D +26.4
(c 1.10 in CHCl3); 1H NMR (300 MHz, CDCl3) d 5.89–5.76
(m, 1H), 5.80 (d, 1H, J¼3.7 Hz), 5.73 (ddd, 1H, J¼17.4, J¼
10.5, J¼7.8 Hz), 5.31 (ddd, 1H, J¼10.5, J¼1.8, J¼0.9 Hz),
5.03 (dm, 1H, J¼17.4 Hz), 4.97 (dm, 1H, J¼10.5 Hz), 4.13
(app. t, 1H, J¼3.7 Hz), 2.35–2.19 (m, 1H) 2.18–2.02 (m,
1H), 1.76–1.63 (m, 2H), 1.52 (s, 3H), 1.47–1.35 (m, 1H),
1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) d 138.3, 136.0,
118.5, 114.9, 111.4, 105.0, 83.1, 80.7, 49.1, 31.8, 26.7,
26.6, 23.3.
4.1.19. (3aR, 5R, 6R, 6aR)-Dihydro-6-(iodomethyl)-2,2-
dimethyl-5-vinyl-5H-furo[2,3-d][1,3]dioxole (36). A solu-
tion of 3539 (10 g, 36.5 mmol) in AcOH/H2O 75:25 v/v
(70 mL) was kept at room temperature for 15 h, and then
ꢁ
concentrated in vacuo at 30 C to afford the triol as a color-
less oil, which did not require further purification. Rf¼0.27
(100:3 AcOEt/MeOH).
To a solution of the above triol, triethylamine (21 mL,
151 mmol) and DMAP (400 mg, 3.27 mmol) in CH2Cl2
ꢁ
(45 mL) at ꢀ20 C under an argon atmosphere was added
4.1.21. (3aR, 4aR, 8aR, 8bR)-7,8,8a,8b-Tetrahydro-2,2-
dimethyl-4aH-benzofuro[2,3-d][1,3]dioxole (38). A solu-
tion of 37 (7.0 g, 31.2 mmol) and Grubbs first generation
catalyst (1.28 g, 1.56 mmol) in CH2Cl2 (620 mL) saturated
with argon was refluxed under a slight flow of argon for
2 h. The reaction mixture was concentrated at 400 mbar
without heating. Purification of the residue by flash silica
gel chromatography (CH2Cl2) afforded 3.37 g of 38 (55%)
as a brown oil, which is volatile. Rf¼0.38 (3:1.5:0.5 tolu-
dropwise methanesulfonic chloride (10 mL, 129 mmol)
(strongly exothermic). The reaction mixture was stirred at
room temperature for 1 h. Aq satd NaHCO3 (50 mL) was
added and the phases were separated. The aqueous layer
was extracted with CH2Cl2 (50 mL). The organic extracts
were combined, dried over MgSO4, and concentrated
in vacuo. Purification of the residue by flash silica gel chro-
matography (hexanes/EtOAc 7:3) afforded the intermediate
trimesylate as a colorless oil (13.8 g, 81% for two steps).
Rf¼0.42 (8:3 AcOEt/hexanes); 1H NMR (300 MHz,
CDCl3) d 5.85 (d, 1H, J¼3.6 Hz), 4.92 (td, 1H, J¼6.4,
J¼2.7 Hz), 4.79 (dd, 1H, J¼4.1, J¼3.6 Hz), 4.57 (dd, 1H,
J¼11.9, J¼2.7 Hz), 4.53–4.45 (m, 2H), 4.41 (dd, 1H, J¼
11.9, J¼6.4 Hz), 4.18–4.10 (m, 1H), 3.18 (s, 3H), 3.09 (s,
3H), 3.08 (s, 3H), 2.65–2.52 (m, 1H), 1.52 (s, 3H), 1.34
(s, 3H); 13C NMR (100 MHz, CDCl3) d 113.2, 105.2, 80.4,
78.6, 77.2, 67.6, 65.8, 46.6, 39.0, 37.7, 37.2, 26.9, 26.4.
1
ene/hexanes/AcOEt); [a]D ꢀ14.1 (c 1.01 in CHCl3); H
NMR (400 MHz, CDCl3) d 6.04 (dm, 1H, J¼10.5 Hz),
5.90 (d, 1H, J¼3.7 Hz), 5.64 (ddd, 1H, J¼10.5, J¼6.4,
J¼3.2 Hz), 4.62 (app. t, 1H, J¼3.7 Hz), 4.34–4.25 (m,
1H), 2.30–2.19 (m, 2H), 2.03–1.92 (m, 1H), 1.85–1.68 (m,
1H), 1.65–1.51 (m, 1H), 1.53 (s, 3H), 1.35 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 128.7, 127.3, 111.5, 106.6,
80.0, 75.9, 47.0, 30.9, 26.1, 25.9, 19.6; HRMS calcd for
C11H17O3 [M+H]+ 197.1178; found 197.1176.
A solution of the above trimesylate (9.5 g, 20.3 mmol) in
ethylmethyl ketone (80 mL) was treated with NaI (15.2 g,
101 mmol). The resulting suspension was refluxed for
15 h, whereas a dark-brown coloration corresponding to the
formation of iodine developed gradually. The reaction mix-
ture cooled down to room temperature was treated with satd
Na2S2O3 (200 mL). After stirring for 15 min, t-butyl methyl
ether (200 mL) was added and the phases were separated.
The aqueous layer was extracted with t-butyl methyl ether
(100 mLꢂ2). The organic extracts were combined, washed
with brine (100 mLꢂ2), dried over MgSO4, and concen-
trated in vacuo. Purification of the residue by flash silica
gel chromatography (hexanes/EtOAc 9:1) afforded the diene
4.1.22. (3aR, 4aS, 5R, 6S, 8aR, 8bR)-5-Azido-hexahydro-
2,2-dimethyl-4aH-benzofuro[2,3-d][1,3]dioxol-6-ol (39).
To a solution of 38 (2.80 g, 14.3 mmol) in THF–H2O (1:1
v/v, 340 mL) at room temperature was added NBS (4.82 g,
27.1 mmol). The mixture was stirred at room temperature
for 2 h and then diluted with aq satd Na2S2O3 (100 mL)
and extracted with EtOAc (100 mLꢂ3). The combined
organic layer was dried over MgSO4, filtrated, and concen-
trated in vacuo. The resulting brown oil was engaged in
the next reaction. Rf¼0.68 (AcOEt).
A solution of the above residue in THF (240 mL) was treated
with aq 1 N NaOH (120 mL) and then refluxed for 1 h. The

5212
S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
mixture was poured into H2O (120 mL) and extracted with
EtOAc (150 mLꢂ2). The combined organic layer was
washed with brine (150 mL), dried over MgSO4, and con-
centrated in vacuo to give a brown oil, which was engaged
in the next reaction. Rf¼0.60 (AcOEt).
adding satd NH4Cl (50 mL). The mixture was extracted with
EtOAc (30 mLꢂ2). The combined organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by flash silica gel chromatography
(hexanes/EtOAc, 4:1) to afford 41 (2.5 g, 69%) as a colorless
ꢁ
oil, which crystallized upon conservation at 4 C. Rf¼0.32
1
The above material was dissolved in 2-methoxyethanol
(300 mL) and sodium azide (13.9 g, 214 mmol) was added.
(4:1 hexanes/AcOEt); [a]D +16.1 (c 0.86 in CHCl3); H
NMR (300 MHz, CDCl3) d 5.84 (d, 1H, J¼3.2 Hz), 4.54
(app. t, 1H, J¼3.7 Hz), 4.45 (br app. t, 1H, J¼2.7 Hz),
3.63 (dd, 1H, J¼11.0, J¼2.7 Hz), 3.41 (s, 3H), 3.32 (ddd,
1H, J¼11.4, J¼4.6, J¼3.2 Hz), 1.97–1.75 (two m, 3H),
1.58 (ddd, 1H, J¼24.7, J¼12.8, J¼4.1 Hz), 1.48 (s, 3H),
1.41–1.23 (1H, obscured by CH3), 1.30 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 111.9, 106.4, 79.9, 79.5, 78.5, 60.0,
56.6, 41.7, 26.3, 26.0, 25.9, 14.1; HRMS calcd for
C12H20N3O4 [M+H]+ 270.1454; found 270.1460.
ꢁ
The mixture was heated at 130 C for 2 h, diluted with brine
(300 mL), and extracted with EtOAc (100 mLꢂ3). The com-
bined organic layer was dried over MgSO4 and concentrated
in vacuo. The residue was purified by flash silica gel chroma-
tography (hexanes/EtOAc 2:1) to afford 1.9 g of azide 39
(52%) as an orange oil. Rf¼0.24 (2:1 hexanes/AcOEt);
1
[a]D ꢀ7.5 (c 0.80 in CHCl3); H NMR (300 MHz, CDCl3)
d 5.85 (d, 1H, J¼3.7 Hz), 4.60 (app. t, 1H, J¼3.7 Hz), 4.22–
4.15 (m, 2H), 4.09–4.05 (br m, 1H), 2.10 (d, 1H, J¼3.7 Hz),
1.89–1.79 (m, 1H), 1.79–1.63 (m, 4H), 1.52 (s, 3H), 1.33 (s,
3H); 13C NMR (100 MHz, CDCl3) d 112.0, 105.3, 80.2,
76.8, 69.3, 62.3, 42.1, 28.0, 26.3, 26.0, 18.3; HRMS calcd
for C11H18N3O4 [M+H]+ 256.1297; found 256.1299.
4.1.25. (1S, 2S, 3R, 6R)-2-Azido-6-((R)-1-hydroxy-2,2-
bis(phenylthio)ethyl)-3-methoxycyclohexanol (42). To
a solution of 41 (1.00 g, 3.71 mmol) in CH2Cl2 (22 mL) at
ꢁ
5 C, PhSH (1.73 mL, 16.9 mmol) was added followed by
ꢁ
Amberlyst-15 (1.0 g). The mixture was stirred at 5 C for
4.1.23. (3aR, 4aS, 5S, 8aR, 8bR)-5-Azido-tetrahydro-2,2-
dimethyl-7H-benzofuro[2,3-d][1,3]dioxol-6(8bH)-one
(40). To a solution of 39 (1.80 g, 7.05 mmol) in CH2Cl2
(32 mL) at room temperature was added Dess–Martin peri-
odinane (3.59 g, 8.46 mmol). The mixture was stirred for
2.5 h. Aq satd NaHCO3 (50 mL) and Na2S2O3 (50 mL)
were added sequentially. The mixture was stirred for
20 min and the phases were separated. The aqueous layer
was extracted with CH2Cl2. The combined organic layer
was dried over MgSO4 and concentrated in vacuo. Purifica-
tion of the residue by flash silica gel chromatography (hex-
anes/EtOAc, 4:1) afforded the product 40 as a colorless oil
(1.6 g, 90%). Rf¼0.25 (4:1 hexanes/AcOEt); [a]D +12.4 (c
3.5 h and at room temperature for 2 h before being filtrated
and concentrated. Purification of the crude product by flash
silica gel chromatography (hexanes/EtOAc, 4:1) afforded
the product 42 as a colorless oil (1.30 g, 81%). Rf¼0.10
1
(4:1 hexanes/AcOEt); [a]D ꢀ18.5 (c 1.15 in CHCl3); H
NMR (300 MHz, CDCl3) d 7.58–7.50 (m, 2H), 7.43–7.29
(m, 8H), 4.61 (d, 1H, J¼3.2 Hz), 4.23 (d, 1H, J¼3.7 Hz),
4.15 (br app. t, 1H, J¼3.7 Hz), 3.88 (d, 1H, J¼2.3 Hz),
3.70 (app. dt, 1H, J¼8.2, J¼2.7 Hz), 3.64 (app. dt, 1H,
J¼10.0, J¼3.2 Hz), 3.38 (s, 3H), 3.16 (ddd, 1H, J¼11.4,
J¼4.6, J¼2.7 Hz), 2.40–2.25 (m, 1H), 1.78–1.65 (m, 1H),
0.84–0.68 (m, 1H); 13C NMR (100 MHz, CDCl3) d 133.5,
133.3, 133.0, 132.6, 129.4, 129.2, 128.5, 128.1, 79.0, 77.2,
74.5, 64.8, 64.3, 56.3, 39.6, 24.4, 23.4; HRMS calcd for
C21H25N3O3S2Na [M+Na]+ 454.1235; found 454.1239.
1
0.95 in CHCl3); H NMR (300 MHz, CDCl3) d 5.93 (d,
1H, J¼3.7 Hz), 4.65 (app. t, 1H, J¼3.7 Hz), 4.35 (d, 1H,
J¼3.7 Hz), 3.88 (dd, 1H, J¼11.0, 3.7 Hz), 2.60 (ddd, 1H,
J¼15.0, J¼13.2, J¼7.3 Hz), 2.38 (ddm, 1H, J¼15.1, J¼
5.0 Hz), 2.37–2.24 (m, 1H), 2.06–1.96 (m, 1H), 1.65 (ddd,
1H, J¼26.0, J¼13.2, J¼5.0 Hz), 1.48 (s, 3H), 1.33 (s,
3H); 13C NMR (100 MHz, CDCl3) d 203.4, 112.5, 106.8,
79.4, 79.2, 68.4, 41.0, 36.2, 26.3, 26.0, 18.8; HRMS calcd
for C11H16N3O4 [M+H]+ 254.1141; found 254.1144.
4.1.26. (2R, 3R, 3aS, 6R, 7R, 7aS)-7-Azido-octahydro-6-
methoxy-2-(phenylthio)benzofuran-3-ol (43). To a solu-
ꢁ
tion of 42 (1.00 g, 2.32 mmol) in CH2Cl2 (58 mL) at 0 C,
NBS (615 mꢁg, 3.46 mmol) was added and the mixture was
stirred at 0 C for 1 h. A saturated solution of Na2S2O3
(50 mL) was added and the solution was stirred at room tem-
perature until it became colorless. The two phases were sep-
arated and the aqueous phase was extracted with CH2Cl2
(25 mLꢂ2). The combined organic phase was washed with
brine (50 mL), dried with MgSO4, filtrated, and concen-
trated. Flash silica gel chromatography (hexanes/EtOAc,
6:4) afforded the product 43 as pale yellowish oil (499 mg,
67%). Rf¼0.46 (1:1 hexanes/AcOEt); [a]D ꢀ12.1 (c 1.09
4.1.24. (3aR, 4aS, 5R, 6R, 8aR, 8bR)-5-Azido-hexahydro-
6-methoxy-2,2-dimethyl-4aH-benzofuro[2,3-d][1,3]diox-
ole (41). To aꢁsolution of 40 (3.4 g, 13.4 mmol) in MeOH
(68 mL) at 0 C was added NaBH4 (761 mg, 20.1 mmol).
The resulting mixture was stirred at room temperature for
3 h, and then concentrated in vacuo without heating. The res-
idue was taken up with EtOAc (30 mL) and washed with
water (30 mL). The aqueous layer was extracted with EtOAc
(30 mLꢂ2). The organic extracts were combined, dried over
MgSO4, and concentrated in vacuo to afford a crude oil that
did not require further purification. Rf¼0.13 (4:1 hexanes/
AcOEt).
1
in CHCl3); H NMR (300 MHz, CDCl3) d 7.56–7.48 (m,
2H), 7.38–7.22 (m, 8H), 5.74 (d, 1H, J¼3.7 Hz), 4.52 (br
app. t, 1H, J¼2.7 Hz), 4.44 (app. t, 1H, J¼4.1 Hz), 3.95 (dd,
1H, J¼11.4, J¼2.7 Hz), 3.44 (s, 3H), 3.33 (ddd, 1H, J¼11.4,
J¼4.6, J¼3.2 Hz), 2.33 (d, 1H, J¼3.2 Hz), 2.10 (app. tt, 1H,
J¼11.4, J¼4.1 Hz), 1.92 (dm, 1H, J¼12.3 Hz), 1.88–1.77
(m, 1H), 1.63 (ddd, 1H, J¼12.8, J¼11.4, J¼4.1 Hz), 1.53–
1.40 (m, 1H); 13C NMR (100 MHz, CDCl3) d 135.3,
131.1, 129.1, 127.2, 95.4, 79.8, 79.6, 72.8, 60.3, 56.7,
42.2, 25.8, 19.1; HRMS calcd for C15H20N3O3S [M+H]+
322.1225; found 322.1229.
ꢁ
To a solution of the above alcohol in THF (20 mL) at 0 C
under an argon atmosphere was added NaH (60% suspꢁen-
sion, 1.07 g, 26.7 mmol). After stirring for 1 h at 0 C,
MeI (1.71 mL, 27.5 mmol) was added. The reaction mixture
was stirred at room temperature for 1 h and was quenched by

S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
5213
4.1.27. (2R, 3R, 3aR, 6R, 7R, 7aS)-7-Azido-octahydro-
6-methoxy-2-(phenylthio)benzofuran-3-yl pivalate (44).
To the alcohol 43 (360 mg, 1.12 mmol) in pyridine
(6.5 mL), DMAP (684 mg, 5.60 mmol) and pivaloyl chloride
(1.38 mL, 11.2 mmol) was added and the mixture was stirred
MeOH (6.6 mL), 40% MeNH2 in water (6.6 mL) was added
and the solution was stirred for 30 h. Concentration gave
a solid, which was purified successively by flash silica gel
chromatography (CH2Cl2/MeOH/25% aq NH3, 10:3:0.3)
and reverse phase HPLC (LiChrospher 100 RP 18, CH3CN
0–100% gradient) to give 46 as a colorless crystalline solid
(45 mg, 0.0233 mmol, 60%). Rf¼0.18 (10:3:0.3 CH2Cl2/
[a]D +8.1 (c 0.56 in CHCl3); 1H NMR (300 MHz,
CD3OD) d 7.85 (d, 1H, J¼7.8 Hz), 5.83 (d, 1H,
J¼7.8 Hz), 5.62 (s, 1H), 5.94–4.86 (br m, 1H), 4.09 (d,
1H, J¼4.6 Hz), 3.92 (dd, 1H, J¼11.0, J¼3.0 Hz), 3.47–
3.40 (m, 1H), 3.37 (s, 3H), 1.95–1.89 (br m, 1H), 1.78–
1.71 (m, 1H), 1.63–1.53 (br m, 1H), 1.52–1.38 (m, 2H);
13C NMR (75 MHz, CD3OD) d 167.9, 162.5, 158.4, 142.0,
96.0, 95.2, 83.7, 79.1, 76.8, 56.5, 49.5, 40.5, 27.9, 19.5;
HRMS calcd for C14H22N5O5 [M+H]+ 340.1621; found
340.1624.
ꢁ
at 50 C for 4 h. Aq satd NaHCO3 (10 mL) and EtOAc
(10 mL) were added and the two phases were separated.
The organic phase was washed with NH4Cl (10 mL) and
brine (10 mLꢂ2), dried over MgSO4, and concentrated inva-
cuo. Purification of the crude residue by flash silica gel chro-
matography (EtOAc) afforded the product 44 as pale
yellowish oil (363 mg, 80%). Rf¼0.77 (1:1 hexanes/AcOEt);
[a]D ꢀ12.1 (c 1.09 in CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.53–7.47 (m, 1H), 7.35–7.20 (m, 4H), 5.83 (d, 1H,
J¼4.1 Hz), 5.65 (app. t, 1H, J¼4.6 Hz), 4.44 (br app. t, 1H,
J¼2.7 Hz), 3.87 (dd, 1H, J¼11.4, J¼2.7 Hz), 3.43 (s, 3H),
3.32 (ddd, 1H, J¼11.4, J¼4.6, J¼3.2 Hz), 2.22 (app. tt,
1H, J¼11.9, J¼4.1 Hz), 1.96–1.85 (m, 1H), 1.85–1.74 (m,
1H), 1.69–1.53 (m, 1H), 1.30 (s, 9H), 1.16–0.99 (m, 1H);
13C NMR (100 MHz, CDCl3) d 175.9, 135.3, 131.1, 129.1,
127.2, 95.4, 83.1, 79.6, 72.8, 60.3, 56.7, 42.2, 19.5, 27.4,
25.8, 19.5; HRMS calcd for C20H28N3O4S [M+H]+
406.1801; found 406.1803.
ꢁ
MeOH/NH3 aq 25%); mp 278–288 C (decomposition);
Acknowledgments
We thank NSERC and Syngenta for financial assistance. We
´
also thank Celine Pace for technical assistance and Patrice
Selles and Dr. Patrick Crowley for useful discussions.
`
4.1.28. (2R, 3R, 3aR, 6R, 7R, 7aS)-2-(40-Acetylamino-20-
oxo-2H-pyrimidin-10-yl)-7-azido-octahydro-6-methoxy-
benzofuran-3-yl pivalate (45). To a solution of 44 (180 mg,
0.43 mmol), N-4-acetyl bis-O-TMS cytosine (316 mg,
1.06 mmol) and NIS (238 mg, 1.06 mmol) in CH2Cl2
(3.0 mL) at room temperature, TfOH (92 mL, 1.06 mmol)
was added portionwise over a period of 20 min. The mixture
was stirred at room temperature for 6 h, which was followed
by the addition of a saturated solution of Na2S2O3 (3 mL)
and the two phases were separated. The aqueous phase
was extracted with CH2Cl2 (6 mLꢂ2), the organic layer
was washed with aq satd NaHCO3 (6 mL), and dried with
MgSO4. After concentration, the crude product was purified
by flash silica gel chromatography (EtOAc/MeOH, 99:1) to
afford the product 45 as pale yellowish oil (160 mg, 83%).
Rf¼0.35 (100:2 AcOEt/MeOH); [a]D +6.5 (c 1.10 in
References and notes
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2. See for example, Li, Y.; Liu, D. R. Angew. Chem., Int. Ed. 2004,
43, 4848.
3. For selected recent reviews, see (a) Rachakonda, S.; Cartee, L.
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2002, 102, 1623; (c) Gumina, G.; Chong, Y.; Choo, H.; Song,
G.-Y.; Chu, C. K. Curr. Top. Med. Chem. 2002, 2, 1065;
(d) Hosmane, R. S. Curr. Top. Med. Chem. 2002, 2, 1093;
(e) Simons, C. Nucleoside Mimetics, their Chemistry and
Biological Properties; Gordon and Breach Science: Australia,
2001; (f) Gao, H.; Mitra, A. K. Synthesis 2000, 329; (g)
Mansour, T. S.; Storer, R. Curr. Pharm. Des. 1997, 3, 227.
4. (a) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
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CHCl3); H NMR (300 MHz, CDCl3) d 10.18 (br s, 1H),
8.31 (d, 1H, J¼7.8 Hz), 7.46 (d, 1H, J¼7.8 Hz), 5.94 (s,
1H), 5.23 (d, 1H, J¼4.6 Hz), 4.60 (br app. t, 1H,
J¼2.7 Hz), 3.74 (dd, 1H, J¼11.9, J¼2.7 Hz), 3.44 (s, 3H),
3.39 (ddd, 1H, J¼11.4, J¼4.6, J¼2.7 Hz), 2.26 (s, 3H),
2.12–1.99 (m, 1H), 1.99–1.88 (m, 1H), 1.87–1.55 (m, 1H),
1.73–1.55 (m, 1H), 1.23 (s, 9H), 1.04–0.87 (m, 1H); 13C
NMR (100 MHz, CDCl3) d 176.6, 171.1, 163.0, 154.7,
144.2, 96.6, 91.9, 81.4, 76.6, 67.9, 60.3, 56.8, 38.9, 38.5,
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2H-pyrimidin-10-yl)-octahydro-3-hydroxy-6-methoxy-
benzofuran-7-yl]urea (46). The azide 45 (100 mg,
0.22 mmol) was dissolved in dry THF (6.6 mL) and argon
was bubbled in the solution for 10 min. Water (17 mL) and
Me3P (0.66 mL, 1 M solution in toluene, 0.66 mmol) were
added. After 5 min at room temperature, the solution was
refluxed for 30 min, then concentrated, and kept in vacuo
for 1 h. The residue was then dissolved in dry CH2Cl2
(6.6 mL) and trichloroacetylisocyanate (30 mL, 0.25 mmol)
was added. After 1 h at room temperature, the solution
was concentrated. The oily residue was dissolved in
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