A greener enantioselective synthesis of the antiviral agent North-methanocarbathymidine (N-MCT) from 2-deoxy-d-ribose

Article abstract of DOI:10.1016/j.tet.2009.08.035

An enantioselective synthesis of suitably protected (1R,2S,4S,5S)-4-amino-1-(hydroxymethyl)bicyclo[3.1.0]hexan-2-ol, a key starting material for the synthesis of conformationally locked carbocyclic nucleosides, including the antiviral active North-methano

Full text of DOI:10.1016/j.tet.2009.08.035

Tetrahedron 65 (2009) 8461–8467
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A greener enantioselective synthesis of the antiviral agent North-
methanocarbathymidine (N-MCT) from 2-deoxy- -ribose
D
*
Olaf R. Ludek, Victor E. Marquez
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2009
Received in revised form 13 August 2009
Accepted 13 August 2009
Available online 19 August 2009
An enantioselective synthesis of suitably protected (1R,2S,4S,5S)-4-amino-1-(hydroxymethyl)bicy-
clo[3.1.0]hexan-2-ol, a key starting material for the synthesis of conformationally locked carbocyclic
nucleosides, including the antiviral active North-methanocarbathymidine, is reported. Starting from
2-deoxyribose the target Boc-protected amine was prepared in 33% overall yield under conditions that
are ecologically friendlier than previous methods.
Published by Elsevier Ltd.
Keywords:
Conformationally locked carbocyclic
nucleosides
North-methanocarbathymidine
Antiviral
Enantioselective synthesis
O
1. Introduction
O
NH
O
H
NH
O
The antiviral active and conformationally locked nucleoside,
North-methanocarbathymidine (N-MCT, 1), belongs to a group of
HO
N
N
HO
carbocyclic nucleosides constructed on
a bicyclo[3.1.0]hexane
scaffold.1 This scaffold was devised as a strategy to lock the em-
bedded cyclopentane ring of N-MCT into a permanent North en-
2'
HO
HO
N-MCT (1)
0
velope (2 E) conformation as it is defined in the pseudorotational
cycle.2 The antiviral activity of N-MCT is dependent on type I thy-
midine kinase (TK) from herpes simplex viruses (HSV-1 and HSV-
2),3-5 as well as from type II TK expressed in cowpox6 and vaccinia
viruses.7 Once phosphorylated to the 50-triphosphate level,
N-MCTTP inhibits viral DNA synthesis. The compound reduces the
mortality of mice infected with orthopoxviruses when adminis-
tered intraperitoneally,6 as well as when given orally to mice
infected with HSV-1, even when treatment is initiated 76 h post-
infection.8 In addition, N-MCT has shown excellent in vitro activity
against Kaposi’s sarcoma-associated herpesvirus (KSHV), display-
ing greater potency than the reference compounds ganciclovir and
cidofovir.9 These combined properties suggest that N-MCT is bio-
available, safe, and orally effective, thus warranting further de-
velopment.
precursor.10 Both convergent and linear strategies were compared
side by side, but the linear strategy of building the pyrimidine ring
from the corresponding carbobicyclic amine was found to more
selective and easier to execute, plus the overall yield was compa-
rable to that using a convergent approach. Therefore, the linear
approach was selected for the large-scale synthesis of N-MCT. We
now wish to report a novel enantioselective route toward the other
half of the molecule, the carbobicyclic amine. This new synthesis
circumvents many of the drawbacks encountered with other
strategies reported earlier.
Historically, our first approach (Route A, Fig. 1) was based on
the orthogonally protected hexanol 2dderived from the chiral
cyclopentenone precursor (3a)dthat was used in the synthesis of
neplanocin A.11,12 In this methodology, a regioselective cleavage of
the contiguous O-isopropylidenetriol system with trimethylalu-
minum and a two-step radical deoxygenation to remove the extra
hydroxyl group were necessary. This route, however, was un-
attractive from an economical and ecological point of view
We recently reported an improved synthesis of N-MCT involving
the elaboration of the thymine ring from a suitable pseudosugar
* Corresponding author. Tel.: þ1 301 846 5953; fax: þ1 301 846 6033.
E-mail address: marquezv@mail.nih.gov (V.E. Marquez).
(4% overall yield, 13 steps from
D-ribose). Formation of the
0040-4020/$ – see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.08.035

8462
O.R. Ludek, V.E. Marquez / Tetrahedron 65 (2009) 8461–8467
H
O
O
OH
RO
HO
BnO
OH
O
O
HO
OH
O
3a, R = Bn
D-ribose
2
b, R = TBDPS
Route A
Route C
H
BnO
BnO
1
OH
Route B
BnO
HO
4
5
H
H
TBDPSO
O
O
EtO2C
OEt
AcO
AcO
OTBDPS
OH
O
( )-7
( )-8
6
Figure 1. Synthetic strategies toward N-MCT (1).
equivalent cyclopentenone precursor (3b) by Jeong et al.13 using
ring-closing metathesis (RCM) was a significant improvement.
However, for the purpose of synthesizing a 20-deoxy analogue,
such as N-MCT, the issue of removing the additional hydroxyl
function still remained.
H
BnO
BnO
BnO
HO
OH
OH
BnO
BnO
BnO
4
9
10
Another strategy that we utilized was based on the enantio-
merically pure cyclopentenol 5 that was developed by Roberts
et al.14 for the synthesis of 20-deoxycarbanucleosides (Route B,
Fig. 1). This approach was very attractive because 5 could be used as
a common precursor for making both North- and South-locked
bicyclo[3.1.0]hexane nucleosides.15,16 Although 5 could be obtained
with excellent optical purity (>97% ee), the synthesis is extremely
sensitive to air, moisture, and temperature, plus the overall yield is
not optimal. Starting from cyclopentadienedthe precursor of
5dthe critical intermediate (1S,2R,4S,5R)-4-(benzyloxy)-5-(ben-
zyloxymethyl)bicyclo[3.1.0]hexan-2-ol (4) was obtained in 10%
overall yield after 10 steps. To our knowledge, no alternative syn-
thesis of cyclopentenol 5 has been reported thus far.
O
OH
HO
OH
BnO
HO
2-deoxy-D-ribose
BnO
11
Figure 2. Retrosynthetic analysis of the novel strategy towards the N-MCT precursor 4.
we have already shown that compound 4 could be obtained with
high stereospecificity from the allylic cyclopentenol 9,20 which
should be accessible from the
a,u-diene 10 via ring-closing
Since the availability of 5 was a limiting factor, we next designed
a very simple chemical approach toward the requisite racemic,
bicyclo[3.1.0]hexane system that relied on a practical and efficient
enzymatic step for chiral resolution (Route C, Fig. 1). The bicyclic
system (ꢀ) 7 was formed in one step by a metal catalyzed keto-
metathesis (RCM),21–26 followed by a palladium(II) catalyzed re-
arrangement of the resulting allylic system.27,28 The RCM-precursor
10 is envisaged to arise from the stereospecific addition of a vinyl
Grignard reagent to a ketone obtained from the oxidation of the
corresponding alcohol 11. Alcohol 11 is already a known compound
that has been synthesized by Herdewijn et al.,29 in four steps
carbene cycloaddition after diazotation of the
b
-keto ester (ꢀ) 8,
which was easily obtained by an aldol reaction from cheap ethyl
acetoacetate and acrolein.17 However, despite the straightfor-
wardness of this approach, half of the material was lost during the
resolution of enantiomers, thus drastically reducing the overall
yield of the diacetate 6 (13%, eight steps).
starting from 2-deoxy-D-ribose.
2. Results and discussion
Based on the above considerations, we now wish to present an
enantioselective approach that is inexpensive, environmentally
friendlier, easy to handle, and most importantly, highlyefficient. The
recent publication by Michel and Strazewski on the improved syn-
thesis of chiral cyclopentenone 3b18 and the utilization of natural 2-
The starting lactol 14 was prepared in three steps from 2-deoxy-
-ribose according to the literature procedure (Scheme 1). Although
D
the synthesis has been described already,30 we would like to
comment on the methodology and report some useful modifica-
tions (Scheme 1). The purity of 14 greatly depends on reducing the
amount of the pyranoside isomer 120 formed during acetalization
under acidic conditions (Table 1). Since the desired furanose form
12 is the kinetic product, while the pyranoside 120 resembles the
thermodynamic product,31 we concluded that acetalization at
lower temperatures should favor formation of the five-membered
deoxy-D
-ribose as rich chiral pool,19 prompted us to investigate the
possibility of preparing the bicyclic hexanol precursor 4 from this
inexpensive building block. The retrosynthetic analysis for this
novel route (Fig. 2) resembles in great part Jeong’s initial approach
toward chiral cyclopentenone 3b.13 In a previous communication,

O.R. Ludek, V.E. Marquez / Tetrahedron 65 (2009) 8461–8467
8463
R'O
O
OH
OR
BnO
a
d
2-deoxy-D-ribose
R'O
BnO
11
12, R = Me, R' = H
b
c
13, R = Me, R' = Bn
14, R = H, R' = Bn
e
O
BnO
RO
BnO
BnO
HO
g
f
BnO
BnO
15
BnO
16, R = H
10
h
17, R = Ac
Scheme 1. Reagents and conditions: (a) CH3COCl, MeOH (Table 1); (b) NaH, BnBr, n-Bu4NI, THF; (c) CH3COCl, H2O–dioxane (85%, three steps); (d) (Ph)3PMeBr, n-BuLi, THF (91%); (e)
(COCl)2, DMSO, Et3N, CH2Cl2 (100%); (f) Table 2; (g) Grubbs’ catalyst, second generation, CH2Cl2; (h) Ac2O, DMAP, Et3N, CH2Cl2 (85%, two steps).
Table 1
Formation of the methyl glycosides 12 and 120 under acidic conditions
O
O
O
OH
CH3COCl
MeOH
O
HO
HO
O
HO
HO
OH
12'
OH
12
kinetic product
thermodynamic product
Experiment
Temperature (ꢁC)
Time
Ratio (12/120)
Yield
1
2
3
4
20
10
0
ꢂ20
15 min
30 min
4 h
85:15
90:10
93:7
Quant.
Quant.
Quant.
Quant.
10 h
96:4
isomer 12. Indeed, lowering the temperature from 20 ꢁC to ꢂ20 ꢁC
decreased the ratio of 120 from 15 to 4%, as judged by 1H NMR of the
crude reaction mixture. Therefore, the acidified solution of 2-de-
oxyribose in methanol was conveniently placed in the freezer
overnight and removal of the solvent provided the methyl furan-
oside 12, which was sufficiently pure for the next benzylation step
to the protected methyl glycoside 13 without any additional
workup. We also found it advantageous to perform the final hy-
drolysis of the methyl glycoside 13 at room temperature in an HCl–
dioxane–water mixture, instead of refluxing the acetal 13 in an
aqueous acetic acid solution. TLC-analysis of the reaction clearly
showed fewer side products and the workup involved a simple
extraction after neutralization. By applying these modifications, the
reported three-step procedure was handled as a one-pot reaction
with no intermediate chromatography, leading to lactol 14 in 85%
overall yield.
Lactol 14 was transformed into the chiral alcohol 11 by a Wittig
reaction (91%), using methyltriphenylphosphonium bromide as the
olefin-forming reagent (Scheme 1).29 Swern oxidation of the sec-
ondary alcohol 11 to the ketone 15 was quantitative and no puri-
fication was necessary at this stage. Nevertheless, a small amount of
ketone 15 was isolated to determine its stability. After standing in
chloroform solution at room temperature for 3 days, the compound
did not show any signs of epimerization/racemization due to
a possible keto–enol tautomerism as confirmed by its constant
optical rotation. Subsequent Grignard reaction with vinyl-
magnesium bromide led to the formation of two diastereomeric
alcohols (10a and 10b) in various ratios, depending on the solvent
employed (Table 2).
Ketone 15 can be considered as an erythrulose analogue and
nucleophilic additions of organometallic compounds to the car-
bonyl group of this carbohydrate have been investigated in de-
tail.32,33 According to these studies, benzyl protected hydroxyl
groups in the
a and a
0-position compete in chelating the metal and
the carbonyl group, leading to poor diastereoselectivities (entries
1–4).34–36 However, when THF was employed as solvent, we ob-
served a moderate selectivity for one isomer (entry 5). Interes-
tingly, the diastereoselectivity was not influenced by raising the
temperature from ꢂ78 to ꢂ40 ꢁC (entries 6–9). Since both di-
astereoisomers were not separable by chromatography, we were
not able to assign the absolute stereochemistry of the major and
minor isomers of 10 at this stage. After RCM conversion to the
cyclopentenol 16 with Grubbs’ second generation catalyst and
acetylation of the tertiary hydroxyl (85%, two steps), both isomers
of 17 could be easily separated by column chromatography (Scheme
2). However, NOE experiments on both ring systems were still in-
conclusive and no absolute configuration could be assigned to
either of the two isomers of 17.
We therefore continued with the reaction scheme by separately
rearranging the allylic acetates of 17major and 17minor using bis-
(acetonitrile)dichloropalladium(II) and p-benzoquinone, which is
known to proceed with retention of configuration.27,28 Methanolysis
of acetate 18, derived from 17major, gave the known alcohol 920 and
methanolysis of 19 gave the also known epimeric alcohol 20. This
corroborated the desired (3S,4S)-stereochemistry for the major
diastereomer of 10, which is in accordance with the Felkin–Anh
model that favors the anti-addition of the Grignard reagent to the
carbonyl group in 15. Cyclopentenol 20 was converted to its

8464
O.R. Ludek, V.E. Marquez / Tetrahedron 65 (2009) 8461–8467
Table 2
Alkylation of ketone 15 with vinylmagnesium bromide in various solvents
HO
O
BnO
BnO
MgBr
solvent
BnO
+
HO
BnO
BnO
BnO
10a
10b
15
Entry
Solvent
Temperature (ꢁC)
Ratio (major/minor) %
Yield (%)
1
2
3
4
5
6
7
8
9
Et2O
MTBE
CH2Cl2
Toluene
THF
THF
THF
THF
THF
ꢂ78
ꢂ78
ꢂ78
ꢂ78
ꢂ78
ꢂ70
ꢂ60
ꢂ50
ꢂ40
56:44
56:44
64:36
63:37
75:25
75:25
75:25
75:25
75:25
93
90
89
93
91
93
88
92
93
AcO
BnO
BnO
AcO
2-deoxyribose as starting material we were able to introduce the
necessary S-configuration at C-4 of the precursor, which serves as
an anchor for the stepwise buildup of the three remaining stereo-
centers. We showed how both regioisomers obtained during the
addition of vinylmagnesium bromide to ketone 15 could be suc-
cessfully converted to the N-MCT precursor 4, minimizing waste of
material and greatly improving the economy of the strategy.
17
17
BnO
BnO
BnO
BnO
BnO
BnO
major
minor
a
a
BnO
BnO
BnO
BnO
OAc
OAc
19
18
3. Experimental section
3.1. General
b
b
OH
c
All experiments involving water-sensitive compounds were
conducted under dry conditions (positive argon pressure) using
standard syringe, cannula, and septa apparatus. All solvents were
purchased anhydrous (Aldrich) and stored over activated molecular
sieves. Hexanes, ethyl acetate, methylene chloride, and methanol
employed in chromatography were HPLC-grade. Flash chromato-
graphy was performed with Teledyne ISCO CombiFlash Companion.
Analytical thin layer chromatography was performed on Analtech
OH
OR
9
d
H
20
H
BnO
BnO
R
f
BnO
BnO
precoated plates (Uniplate, silica gel GHLF, 250
m) containing
21, R = N3
22, R = NHBoc
a fluorescence indicator; sugar-containing compounds were visu-
alized with the sugar spray reagent (5 mL of 4-methoxy-
benzaldehyde, 90 mL of ethanol, 5 mL of concentrated sulfuric acid,
and 10 mL of glacial acetic acid) by heating with a heat gun. NMR
spectra were recorded using a Varian Inova 400 MHz spectrometer.
The coupling constants are reported in hertz, and the peak shifts
are reported in the delta (ppm) scale; abbreviations s (singlet),
d (doublet), t (triplet), q (quartet), and m (multiplet). ESI mass
spectra were obtained on an Agilent Technologies 1200 Series LC
system coupled to an Agilent G1978A Multimode Ion Source
(LC/MSD SL) using the loop injection mode. HRMS Mass spectra
(FABMS) were obtained on a VG 7070E mass spectrometer at an
accelerating voltage of þ8 kV over a limited mass range at 5000
resolution. KCl/NBA was used as the sample matrix, and ionization
was effected by a beam of xenon atoms. Optical rotations were
measured on a Jasco P-1010 polarimeter at 589 nm. Infrared spec-
troscopy data was obtained neat with a Jasco FT-IR/615 spectro-
meter. Elemental analyses were performed by Atlantic Microlab,
Inc., Norcross, GA 30091.
4, R = H
4a, R = Ms
g
e
Scheme 2. Reagents and conditions: (a) p-benzoquinone, PdCl2(MeCN)2, THF (91–
93%); (b) 1% NaOH, MeOH (100%); (c) i. (Ph)3P, DIAD, PhCO2H, Et2O; ii. K2CO3, MeOH
(88%); (d) CH2I2, Et2Zn, CH2Cl2 (87%); (e) MsCl, Et3N, CH2Cl2; (f) NaN3, DMF (83%, two
steps); (g) H2, Lindlar catalyst, (Boc)2O, MeOH (92%).
regioisomer 9 by a Mitsunobu reaction,37,38 thus contributing to the
efficiency of the approach by minimizing the loss of material. Final
cyclopropanation was carried out according to the published pro-
cedure,20 providing the N-MCT precursor (1S,2R,4S,5R)-4-benzy-
loxy-5-benzyloxymethylbicyclo[3.1.0]hexan-2-ol (4) in 43% overall
yield.
Previously, we have shown that it is advantageous to construct
the thymine heterocycle by a stepwise buildup. Therefore, the bi-
cyclic hexanol 4 was converted to the inverted azide 21 by mesy-
lation and subsequent displacement by sodium azide in 83% yield.
Reduction of the azide in presence of di-tert-butyldicarbonate (92%)
afforded the carbamate 22 as a stable precursor for N-MCT (1)
synthesis.
3.1.1. (4S,5R)-4-Benzyloxy-5-benzyloxymethyltetrahydrofuran-2-ol
(14). Acetyl chloride (1.0 mL, 14.0 mmol) was slowly added to ice-
cold methanol (100 mL) while stirring. The cooling bath was
removed and the mixture was stirred for 30 min at room
In summary we have presented a new and efficient approach
toward the prerequisite bicyclo[3.1.0]hexane framework present in
the potent antiviral nucleoside N-MCT. Utilizing cheap and plentiful

O.R. Ludek, V.E. Marquez / Tetrahedron 65 (2009) 8461–8467
8465
temperature. The mixture was placed in a freezer (ꢂ18 ꢁC) and after
30 min, 2-deoxyribose (5.00 g, 37.3 mmol) was added in one por-
tion. The yellow solution was kept in the freezer overnight. After
neutralization with solid sodium carbonate (1.00 g, 9.43 mmol), the
solid was filtered off and the methanolic solution was evaporated
under reduced pressure. The crude methyl glycoside 12 was then
dissolved in ethyl acetate (100 mL) and filtered again. The solvent
was removed in vacuo yielding the methyl furanoside 12 (5.53 g,
100%) as a yellow oil.
Under a blanket of argon, the crude methyl glycoside 12 was
dissolved in dry THF (100 mL) and sodium hydride (60% in oil,
4.48 g, 112 mmol) was added at 0 ꢁC. The cooling bath was removed
and the mixture was stirred for 1 h at room temperature. After
cooling the mixture to 0 ꢁC, benzyl bromide (13.3 mL, 112 mmol)
and tetrabutylammonium iodide (TBAI, 400 mg) were added. The
cooling bath was removed and the mixture was stirred at room
temperature overnight. The reaction was quenched by carefully
adding methanol (10 mL) at 0 ꢁC and the reaction mixture was
stirred at room temperature for 1 h. Water was added (200 mL) and
the aqueous phase was extracted with CH2Cl2 (3ꢃ100 mL). The
combined organic extracts were dried (MgSO4) and concentrated,
yielding the crude benzylated methyl glycoside 13 (15 g) as yellow
oil.
Acetyl chloride (15.0 mL, 0.210 mol) was slowly added to ice-
cold water (150 mL, containing 1% of acetonitrile) while stirring.
The cooling bath was removed and the mixture was stirred for
30 min at room temperature. The crude benzylated methyl glyco-
side 13 (15 g) in dioxane (300 mL) was added to this aqueous
hydrochloric acid solution and the mixture was stirred overnight.
After neutralization with saturated NaHCO3 solution (150 mL), the
aqueous phase was extracted with CH2Cl2 (3ꢃ150 mL). The com-
bined organic extracts were dried (MgSO4) and concentrated. The
crude product was purified by flash chromatography on silica gel
(EtOAc in hexanes, 30/50%) to give lactol 14 (8.91 g, 76%, three
steps) as a colorless oil, together with unchanged methyl glycoside
13 (1.53 g). From the recovered 13 a repeat hydrolysis gave a second
batch of lactol 14 (1.02 g, 9%), raising the overall yield to 85%. The
spectroscopic data of lactol 14 were identical to those already
reported.39,40
The reaction was quenched by the slow addition of a saturated
ammonium chloride solution (150 mL) and the aqueous phase was
extracted with CH2Cl2 (3ꢃ100 mL). The combined organic extracts
were dried (MgSO4) and concentrated to give ketone 15 as oil,
which was deemed sufficiently pure to be used in the next step
without any further purification. IR (neat): 3073, 3030, 2864, 1730,
1641, 1496, 1454, 1327, 1208, 1098, 1026, 916, 735 cmꢂ1
(400 MHz, CDCl3):
;
1H NMR
d
¼7.35–7.25 (m, 10H, CH-arom.), 5.76 (dddd, 1H,
J¼17.1, 10.2, 7.1, 7.1 Hz, H–CH]CH2), 5.12–5.03 (m, 2H, CH]CH2),
4.54 (AB-system, 2H, J¼12.0 Hz, CH2–benzyl-A), 4.49 (s, 2H, CH2-
benzyl-B), 4.30 (s, 2H, OCH2CO), 4.03 (dd, 1H, J¼6.5, 5.3 Hz,
CHOBn), 2.55–2.40 (m, 2H, CH2CH]CH2); 13C NMR (100 MHz,
CDCl3):
d
¼208.2 (CO), 137.1 (Cq-arom.), 132.6 (CH]CH2), 128.5,
128.5, 128.0, 128.0, 127.9 (C-arom.), 118.4 (CH]CH2), 82.6 (CHOBn),
73.3, 73.0 (CH2-benzyl), 72.5 (OCH2CO), 35.2 (CH2CH]CH2); ESI-
MS (m/z): 328.2 (MþNHþ4 ), 333.1 (MþNaþ). A small amount of
ketone 15 was purified by silica gel chromatography (EtOAc in
20
hexanes 0/25%) to monitor its optical rotation. The value of [a]
D
ꢂ25.18 (c 1.0, CHCl3) remained unchanged after 3 days in chloro-
form solution.
The crude ketone 15 (5.00 g, 16.0 mmol) was dissolved in dry
THF (100 mL) under argon and the solution was cooled to ꢂ78 ꢁC.
Vinylmagnesium bromide (1 M in THF, 32.0 mL, 32.0 mmol) was
added dropwise and the reaction mixture was stirred for 30 min at
this temperature. The reaction was quenched by the dropwise ad-
dition of a saturated ammonium chloride solution (100 mL) and the
aqueous phase was extracted with CH2Cl2 (3ꢃ100 mL). The com-
bined organic extracts were dried (MgSO4) and concentrated. The
crude alcohols were purified by flash chromatography on silica gel
(EtOAc in hexanes 10/30%) to give 10a,b (4.93 g, 91%) as a 3:1
mixture of diastereomers. A small amount of the major (3S,4S)-
isomer was purified after a second chromatography to give 10a as
20
a clear oil; [
a]
0.40 (c 1.0, CHCl3), IR (neat): 3550, 3029, 2860,
D
1870, 1639, 1496, 1454, 1417, 1317, 1191, 1072, 1026, 991, 913,
733 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d¼7.35–7.25 (m, 10H, CH-
arom.), 5.98 (dd, 1H, J¼17.4, 11.0 Hz, H-2), 5.90 (dddd, 1H, J¼17.1,
10.1, 7.1, 7.1 Hz, H-6), 5.43 (dd, 1H, J¼17.4, 1.8 Hz, H-1a), 5.21 (dd, 1H,
J¼11.0, 1.8 Hz, H-1b), 5.08 (dm, 1H, J¼17.1, H-7a), 5.01 (dm, 1H,
J¼10.1, H-7b), 4.65 (d, 1H, J¼11.1 Hz, CHH-benzyl-A), 4.50 (s, 2H,
CH2-benzyl-B), 4.49 (d, 1H, J¼11.1 Hz, CHH-benzyl-A), 3.68 (dd, 1H,
J¼8.2, 4.0 Hz, H-4), 3.55 (d, 1H, J¼9.0 Hz, CHH-OBn), 3.40 (d, 1H,
J¼9.0 Hz, CHH-OBn), 2.55 (br s, 1H, 3-OH), 2.42–2.32 (m, 1H, H-5a),
3.1.2. (2R,3S)-1,3-Bis(benzyloxy)hex-5-en-2-ol (11). A solution of
n-butyl lithium (1.6 M in hexanes, 23.0 mL, 36.8 mmol) was slowly
added to a stirred suspension of methyltriphenylphosphonium
bromide (12.5 g, 35.0 mmol) in THF (140 mL) at ꢂ78 ꢁC under ar-
gon. The mixture was allowed to warm to room temperature over
30 min and cooled again to ꢂ78 ꢁC. A solution of the lactol 14
(5.50 g, 17.5 mmol) in THF (10.0 mL) was added and the reaction
mixture was allowed to reach room temperature overnight. The
reaction was quenched by carefully adding water (200 mL) and the
aqueous layer was extracted with CH2Cl2 (3ꢃ100 mL). The com-
bined organic extracts were dried (MgSO4) and concentrated. The
crude product was purified by flash chromatography on silica gel
(EtOAc in hexanes 10/30%) to yield the alcohol 11 (5.01 g, 9%) as
a colorless oil. The spectroscopic data were identical to those
reported.29
2.35–2.27 (m, 1H, H-5b); 13C NMR (100 MHz, CDCl3):
d
¼138.6, 138.3
(Cq-arom.), 137.6 (C-6), 136.1 (C-2), 128.4, 128.3, 127.9, 127.7, 127.7
(C-arom.), 116.8 (C-1), 114.9 (C-7), 81.0 (C-4), 76.7 (C-3), 74.1, 73.9
(CH2-benzyl), 73.5 (CH2-OBn), 34.8 (C-5); ESI-MS (m/z): 361.1
(MþNaþ). Elemental analysis for C22H26O3: calculated: C, 78.07; H,
7.74. Found: C, 78.06; H, 7.71.
3.1.4. (1S,5S)-5-Benzyloxy-1-benzyloxymethylcyclopent-2-enyl ace-
tate (17major) and (1R,5S)-5-Benzyloxy-1-benzyloxymethylcyclopent-
2-enyl acetate (17minor). The two diastereomers 10a,b (4.80 g,
14.2 mmol) were dissolved in dry, deoxygenated CH2Cl2 (400 mL)
under argon at room temperature and treated with second gen-
eration Grubbs’ catalyst (600 mg, 0.710 mmol), which was added in
one portion. The mixture was heated to reflux for 1 h and cooled to
room temperature. After removal of the solvent under reduced
pressure, the crude material was redissolved in dry CH2Cl2
(50.0 mL) and cooled to 0 ꢁC. Triethylamine (19.8 mL, 0.142 mol),
N,N-dimethylaminopyridine (DMAP, 174 mg, 1.42 mmol), and ace-
tic anhydride (6.71 mL, 71.0 mmol) were added and the mixture
was stirred at room temperature overnight. The reaction mixture
was diluted with CH2Cl2 (200 mL) and the organic phase was
extracted with 1 N HCl (3ꢃ100 mL). The aqueous washings were
reextracted with CH2Cl2 (100 mL) and the combined organic ex-
tracts were dried (MgSO4) and concentrated. The crude acetates
3.1.3. (3S,4S)-4-Benzyloxy-3-benzyloxymethylhepta-1,6-dien-3-ol
(10a) and (3R,4S)-4-benzyloxy-3-benzyloxymethylhepta-1,6-dien-3-
ol (10b). Oxalylchloride (2.79 mL, 32.0 mmol) was dissolved in dry
CH2Cl2 (150 mL) under argon and the solution was cooled to
ꢂ78 ꢁC. DMSO (4.55 mL, 64.0 mmol) was added dropwise and the
reaction mixture was stirred for 5 min at the same temperature.
Alcohol 11 (5.00 g, 16.0 mmol), dissolved in 30 mL of dry CH2Cl2,
was added to this mixture and the reaction mixture was stirred for
1 h at ꢂ78 ꢁC. Triethylamine (13.4 mL, 96.0 mmol) was added and
the mixture was warmed to room temperature and stirred for 1 h.

8466
O.R. Ludek, V.E. Marquez / Tetrahedron 65 (2009) 8461–8467
20
were separated by flash chromatography on silica gel (EtOAc in
hexanes 10/30%) to yield the (1S,5S)-diastereomer 17major (3.20 g,
64%) and the (1R,5S)-diastereomer 17minor (1.05 g, 21%) as colorless
oils.
a colorless oil; [
a]
ꢂ57.23 (c 1.0, CHCl3); IR (neat): 3030, 2856,
D
1730, 1496, 1454, 1370, 1238, 1156, 1069, 1026, 914, 864, 735 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
¼7.35–7.25 (m, 10H, CH-arom.), 5.94
(m, 1H, H-2), 5.75–5.70 (m, 1H, H-1), 4.74 (m, 1H, H-4), 4.55 (d, 1H,
J¼12.0 Hz, CHH-benzyl-A), 4.54 (d, 1H, J¼11.8 Hz, CHH-benzyl-B),
4.50 (d, 1H, J¼12.0 Hz, CHH-benzyl-A), 4.43 (d, 1H, J¼11.8 Hz, CHH-
benzyl-B), 4.16 (br s, 2H, CH2-OBn), 2.31 (ddd, 1H, J¼14.7, 7.0,
3.5 Hz, H-5a), 2.12 (ddd, 1H, J¼14.7, 6.8, 2.8 Hz, H-5b), 1.98 (s, 3H,
3.1.4.1. Compound 17minor. [
3029, 2859, 1733, 1496, 1453, 1365, 1240, 1100, 1017, 734, 696 cmꢂ1
1H NMR (400 MHz, CDCl3):
¼7.35–7.25 (m, 10H, CH-arom.), 6.05
a]
D
20 32.48 (c 1.0, CHCl3); IR (neat): 3073,
;
d
(dt, 1H, J¼6.2, 2.0 Hz, H-2), 5.92 (dt, 1H, J¼6.2, 2.4 Hz, H-3), 4.66 (d,
1H, J¼12.0 Hz, CHH-benzyl-A), 4.57 (d, 1H, J¼12.0 Hz, CHH-benzyl-
A), 4.55 (d, 1H, J¼12.0 Hz, CHH-benzyl-B), 4.51 (d, 1H, J¼12.0 Hz,
CHH-benzyl-B), 4.39 (dd, 1H, J¼7.0, 5.0 Hz, H-5), 3.93 (AB-system,
2H, J¼10.0 Hz, CH2-OBn), 2.70 (dddd, 1H, J¼16.7, 7.0, 2.4, 2.0 Hz, H-
4a), 2.33 (ddt, 1H, J¼16.7, 5.0, 2.0 Hz, H-4b), 2.00 (s, 3H, OAc); 13C
OAc); 13C NMR (100 MHz, CDCl3):
d¼170.9 (C]O), 148.4 (C-3)
138.2, 138.0, 128.4, 127.7 (C-arom.), 127.6 (C-2), 81.8 (C-1), 78.1 (C-
4), 72.8, 71.4 (CH2-benzyl), 66.5 (CH2-OBn), 37.9 (C-5), 21.2 (CH3,
OAc); ESI-MS (m/z): 370.1 (MþNHþ4 ), 375.1 (MþNaþ). Elemental
analysis for C22H24O4: calculated: C, 74.98; H, 6.86. Found: C, 74.69;
H, 6.84.
NMR (100 MHz, CDCl3):
d
¼170.3 (C]O), 138.5, 138.4 (Cq-arom.),
133.2 (C-2), 130.8 (C-3), 128.3, 128.2, 127.6, 127.5, 127.4 (C-arom.),
94.4 (C-1), 84.0 (C-5), 73.6, 72.6 (CH2-benzyl), 68.9 (CH2-OBn), 37.4
(C-4), 22.0 (CH3, OAc); ESI-MS (m/z): 375.1 (MþNaþ). Elemental
analysis for C22H24O4: calculated: C, 74.98; H, 6.86. Found: C, 74.72;
H, 6.64.
3.1.7. (1S,2R,4S,5R)-4-Benzyloxy-5-benzyloxymethylbicyclo[3.1.0]-
hexan-2-ol (4). The bicyclic hexanol 4 was prepared from the allylic
acetates 18 and 19 as previously described from the corresponding
allylic benzoates.20 All analytical data were identical to those
reported before.
20
3.1.4.2. Compound 17major. [
a
]
D
ꢂ11.03 (c 1.0, CHCl3); IR (neat):
3.1.8. (1R,2S,4S,5S)-4-Azido-2-benzyloxy-1-benzyloxymethyl-
bicyclo[3.1.0]hexane (21). Under a blanket of argon the bicyclic
hexanol 4 (800 mg, 2.47 mmol) was dissolved in dry CH2Cl2 (25 mL)
at 0 ꢁC, followed by the addition of triethylamine (1.03 mL,
3029, 2859, 1730, 1496, 1454, 1364, 1243, 1097, 1016, 910, 733,
697 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d¼7.35–7.25 (m, 10H, CH-
arom.), 6.03 (dt, 1H, J¼6.1, 2.0 Hz, H-2), 5.93 (dt, 1H, J¼6.1, 2.4 Hz, H-
3), 4.56 (AB-system, 2H, J¼12.0 Hz, CH2-benzyl-A), 4.50 (AB-sys-
tem, 2H, J¼12.0 Hz, CH2-benzyl-B), 4.17 (dd, 1H, J¼6.1, 4.4 Hz, H-5),
3.84 (d, 1H, J¼9.7 Hz, CHH-OBn), 3.73 (d, 1H, J¼9.7 Hz, CHH-OBn),
2.58–2.52 (m, 1H, H-4a), 2.51–2.45 (m, 1H, H-4b), 2.00 (s, 3H, OAc);
7.40 mmol) and methansulfonyl chloride (MsCl, 287 mL,
3.71 mmol). The reaction mixture was stirred for 1 h at 0 ꢁC and
then poured into a mixture of ice-cold phosphate buffer (pH, 7.2,
100 mL) and Et2O (100 mL). The aqueous phase was extracted with
Et2O (2ꢃ100 mL) and the combined extracts were dried (MgSO4)
and concentrated. The crude mesylate 4a was used in the next
substitution reaction without any further purification (de-
composition occurred during chromatography on silica gel). The
mesylate 4a (995 mg, 2.47 mmol) was dissolved in dry DMF
(25.0 mL). After the addition of sodium azide (1.61 g, 24.7 mmol),
the solution was heated to 60 ꢁC and stirred overnight. The reaction
mixture was allowed to reach room temperature and poured into
a mixture of water (100 mL) and Et2O (100 mL). The aqueous phase
was further extracted with Et2O (2ꢃ100 mL) and the combined
organic extracts were dried (MgSO4) and concentrated. Flash
chromatography on silica gel (EtOAc in hexanes 25/45%) yielded
the azide 21 (751 mg, 87%) as a colorless oil.41 The analytical data
were identical to those reported earlier.
13C NMR (100 MHz, CDCl3):
d
¼170.4 (C]O),138.4,138.0 (Cq-arom.),
133.6 (C-2), 130.9 (C-3), 128.3, 128.2, 127.9, 127.6, 127.6, 127.6
(C-arom.), 90.5 (C-1), 79.5 (C-5), 73.4, 72.5 (CH2-benzyl), 70.7 (CH2-
OBn), 37.5 (C-4), 21.9 (CH3, OAc); ESI-MS (m/z): 375.1 (MþNaþ).
Elemental analysis for C22H24O4: calculated: C, 74.98; H, 6.86.
Found: C, 74.86; H, 6.79.
3.1.5. (1R,4S)-4-Benzyloxy-3-benzyloxymethylcyclopent-2-enyl ace-
tate (18). The acetate 17major (3.10 g, 8.80 mmol) was dissolved in
dry THF (60.0 mL) at room temperature under argon and treated
with p-benzoquinone (761 mg, 7.04 mmol) and PdCl2(CH3CN)2
(228 mg, 0.88 mmol) as catalyst. The mixture was heated to reflux
for 4 h while the color changed slowly to dark brown. The solvent
was evaporated under vacuum and the crude was directly purified
by flash chromatography on silica gel (EtOAc in hexanes, 5/30%)
to give the rearranged acetate 18 (2.82 g, 91%) as a colorless oil;
3.1.9. tert-Butyl (1S,2S,4S,5R)-4-benzyloxy-5-benzyloxymethylbicyclo-
[3.1.0]hexan-2-ylcarbamate (22). Under a blanket of argon, azide 21
(700 mg, 2.00 mmol) was dissolved in MeOH (30 mL) at room
temperature. Di-tert-butyldicarbonate ((Boc)2O, 481 mg, 2.20 mmol)
and Lindlar’s catalyst (150 mg) were added and the reaction vessel
was flushed with H2. Stirring at room temperature continued until
all starting material was consumed according to TLC-analysis (1.0 h).
The solvent was filtered through a short pad of Celite and the filtrate
was concentrated. The crude was purified by flash chromatography
20
[
a
]
59.60 (c1.0, CHCl3); IR (neat): 3029, 2856, 1732, 1496, 1454,
D
1370, 1237, 1155, 1091, 1025, 913, 851, 735 cmꢂ1
;
1H NMR
¼7.35–7.25 (m, 10H, CH-arom.), 5.93–5.91 (m,
(400 MHz, CDCl3):
d
1H, H-2), 5.47 (m, H-1), 4.56 (d, 1H, J¼12.0 Hz, CHH-benzyl-A), 4.54
(d, 1H, J¼12.0 Hz, CHH-benzyl-B), 4.48 (d, 1H, J¼12.0 Hz, CHH-
benzyl-A), 4.47 (d, 1H, J¼12.0 Hz, CHH-benzyl-B), 4.47–4.43 (m, 1H,
H-4), 4.19–4.17 (m, 2H, CH2-OBn), 2.75 (overlapped dt, J¼14.5,
7.5 Hz, H-5a), 2.01 (s, 3H, OAc), 1.80 (dt, 1H, J¼14.5, 3.8 Hz, H-5b);
13C NMR (100 MHz, CDCl3):
d
¼170.9 (C]O), 147.4 (C-3) 138.3,
on silica gel (EtOAc in hexanes 15/35%) to yield the carbamate 22
20
138.0, 128.4, 128.3, 128.2 (C-arom.), 127.7 (C-2), 80.4 (C-1), 76.1 (C-
4), 72.8, 71.2 (CH2-benzyl), 66.4 (CH2-OBn), 37.8 (C-5), 21.2 (CH3,
OAc); ESI-MS (m/z): 370.1 (MþNHþ4 ), 375.1 (MþNaþ). Elemental
analysis for C22H24O4: calculated: C, 74.98; H, 6.86. Found: C, 75.15;
H, 7.01.
(788 mg, 93%) as a colorless syrup; [
a
]
30.15 (c 1.0, CHCl3); IR
D
(neat): 3328, 2976, 2862, 1699, 1496, 1454, 1364, 1243, 1165, 1073,
1027, 909, 779, 696 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d¼7.35–7.25
(m, 10H, CH-arom.), 4.66 (br d, 1H, J¼5.7 Hz, H-2), 4.55–4.43 (m, 5H,
2ꢃCH2-benzyl, H-4), 4.03 (br s, 1H, NH), 3.93 (br d, 1H, J¼10.2 Hz,
CHH-OBn), 3.13 (d, 1H, J¼10.2 Hz, CHH-OBn), 1.97 (dd, 1H, J¼13.9,
7.5 Hz, H-3a), 1.50–1.40 (m, 10H, H-3b, t-Bu), 1.26 (m, 1H, H-1), 0.89
(br t, 1H, Jz5 Hz, H-6a), 0.59 (dd, 1H, J¼7.5, 5.5 Hz, H-6b); 13C NMR
3.1.6. (1S,4S)-4-Benzyloxy-3-benzyloxymethylcyclopent-2-enyl ace-
tate (19). The acetate 17minor (1.00 g, 2.84 mmol) was dissolved in
dry THF (20.0 mL) at room temperature under argon and treated
with p-benzoquinone (245 mg, 2.27 mmol) and PdCl2(CH3CN)2
(73.7 mg, 0.284 mmol) as catalyst. In a similar manner as described
for 18, the rearranged acetate 19 (931 mg, 93%) was obtained as
(100 MHz, CDCl3):
d
¼155.0 (C]O), 138.7, 138.5, 128.4, 128.3, 127.7,
127.6, 127.5, 127.5 (C-arom.), 78.7 (C(CH3)3), 77.4 (C-4), 72.8 (CH2-
OBn), 71.9, 71.7 (2ꢃCH2-benzyl), 51.3 (C-2), 35.9 (C-5), 32.3 (C-3),
28.4 (C(CH3)3), 27.1 (C-1), 10.2 (C-6); ESI-MS (m/z): 446.2 (MþNaþ).

O.R. Ludek, V.E. Marquez / Tetrahedron 65 (2009) 8461–8467
8467
HRMS (FAB): m/z¼424.2054 (calculated for [C26H33O4NþK]þ¼
12. Marquez, V. E.; Lim, M.-I.; Tseng, C. K. H.; Markovac, A.; Priest, M. A.; Khan, S.;
Kaskar, B. J. Org. Chem. 1988, 53, 5709–5714.
13. Choi, W. J.; Moon, H. R.; Kim, H. O.; Yoo, B. N.; Lee, J. A.; Shin, D. H.; Jeong, L. S. J.
Org. Chem. 2004, 69, 2634–2636.
424.2047).
14. Biggadike, K.; Borthwick, A. D.; Evans, D.; Exall, A. M.; Kirk, B. E.; Roberts, S. M.;
Stephenson, L.; Youds, P. J. Chem. Soc., Perkin Trans. 1 1988, 549–554.
15. Ezzitouni, A.; Russ, P.; Marquez, V. E. J. Org. Chem. 1997, 62, 4870–4873.
16. Ezzitouni, A.; Marquez, V. E. J. Chem. Soc., Perkin Trans. 1 1997, 1073–1078.
17. Yoshimura, Y.; Moon, H. R.; Choi, Y.; Marquez, V. E. J. Org. Chem. 2002,
5938–5945.
18. Michel, B. Y.; Strazewski, P. Tetrahedron 2007, 63, 9836–9841.
19. Wang, D. J.; Nugent, W. A. J. Org. Chem. 2007, 72, 7307–7312.
20. Marquez, V. E.; Russ, P.; Alonso, R.; Siddiqui, M. A.; Hernandez, S.; George, C.;
Nicklaus, M. C.; Dai, F.; Ford, H. Helv. Chim. Acta 1999, 82, 2119–2129.
21. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
22. Ko, O. H.; Hong, J. H. Tetrahedron Lett. 2002, 43, 6399–6402.
23. Davis, F. A.; Wu, Y. Z. Org. Lett. 2004, 6, 1269–1272.
24. Hong, J. H.; Shim, M. J.; Ro, B. O.; Ko, O. H. J. Org. Chem. 2002, 67, 6837–6840.
25. Hong, J. H.; Oh, C. H.; Cho, J. H. Tetrahedron 2003, 59, 6103–6108.
26. Seepersaud, M.; Al-Abed, Y. Org. Lett. 1999, 1, 1463–1465.
27. Overman, L. E.; Knoll, F. M. Tetrahedron Lett. 1979, 321–324.
28. Medich, J. R.; Kunnen, K. B.; Johnson, C. R. Tetrahedron Lett. 1987, 28, 4131–4134.
29. Hossain, N.; Blaton, N.; Peeters, O.; Rozenski, J.; Herdewijn, P. A. Tetrahedron
1996, 52, 5563–5578.
Acknowledgements
This research was supported in part by the Intramural Research
Program of the NIH, National Cancer Institute, Center for Cancer
Research. The authors wish to thank Dr. James A. Kelley for the
HRMS analysis.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.08.035.
References and notes
1. Marquez, V. E.; Hughes, S. H.; Sei, S.; Agbaria, R. Antiviral Res. 2006, 71, 268–275.
2. Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94, 8205–8212.
3. Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.; Wang, J. Y.; Wagner, R. W.;
Matteucci, M. D. J. Med. Chem. 1996, 39, 3739–3747.
4. Zalah, L.; Huleihel, M.; Manor, E.; Konson, A.; Ford, H.; Marquez, V. E.; Johns, D.
G.; Agbaria, R. Antiviral Res. 2002, 55, 63–75.
30. Bhat, C. C. 2-Deoxy-3,5-di-O-p-toluoyl-D-erythro-pentosyl chloride. In Synthetic
Procedures in Nucleic Acid Chemistry; Zorbach, W. W., Tipson, R. S., Eds.; John
Wiley & Sons: New York, NY, 1968; Vol. 1, pp 521–522.
31. Deriaz, R. E.; Overend, W. G.; Stacey, M.; Wiggins, L. F. J. Chem. Soc. 1949,
2836–2841.
32. Marco, J. A.; Carda, M.; Gonzalez, F.; Rodriguez, S.; Castillo, E.; Murga, J. J. Org.
Chem. 1998, 63, 698–707.
5. Prichard, M. N.; Keith, K. A.; Quenelle, D. C.; Kern, E. R. Antimicrob. Agents
Chemother. 2006, 50, 1336–1341.
33. Carda, M.; Castillo, E.; Rodriguez, S.; Gonzalez, F.; Marco, J. A. Tetrahedron:
Asymmetry 2001, 12, 1417–1429.
6. Smee, D. F.; Wandersee, M. K.; Bailey, K. W.; Wong, M. H.; Chu, C. K.; Gadthula,
S.; Sidwell, R. W. Antiviral Res. 2007, 73, 69–77.
34. Frye, S. V.; Eliel, E. L. J. Am. Chem. Soc. 1988, 110, 484–489.
35. Annunziata, R.; Cinquini, M.; Cozzi, F.; Fuchicello, A. Tetrahedron 1991, 47,
3853–3868.
36. Bai, X.; Eliel, E. L. J. Org. Chem. 1992, 57, 5166–5172.
37. Mitsunobu, O. Synthesis 1981, 1–28.
7. Smee, D. F.; Hurst, B. L.; Wong, M. H.; Glazer, R. I.; Rahman, A.; Sidwell, R. W.
Antiviral Res. 2007, 76, 124–129.
8. Greenstone, H. L. Program Officer, Virology Branch, Division of Microbiology
and Infectious Diseases, NIAID, NIH. Personal communication 2009.
9. Zhu, W. M.; Burnette, A.; Dorjsuren, D.; Roberts, P. E.; Huleihel, M.; Shoemaker,
R. H.; Marquez, V. E.; Agbaria, R.; Sei, S. Antimicrob. Agents Chemother. 2005, 49,
4965–4973.
10. Ludek, O. R.; Marquez, V. E. Synthesis 2007, 3451–3460.
11. Siddiqui, M. A.; Ford, H.; George, C.; Marquez, V. E. Nucleosides Nucleotides 1996,
15, 235–250.
38. Hughes, D. L. Org. React. 1992, 42, 335–655.
39. Wierenga, W.; Skulnick, H. I. Carbohydr. Res. 1981, 90, 41–52.
40. Vandendriessche, F.; Snoeck, R.; Janssen, G.; Hoogmartens, J.; Vanaerschot, A.;
Declercq, E.; Herdewijn, P. J. Med. Chem. 1992, 35, 1458–1465.
41. Hernandez, S.; Ford, H.; Marquez, V. E. Bioorg. Med. Chem. 2002, 10, 2723–2730.