Total synthesis of entecavir

Article abstract of DOI:10.1021/jo400607v

Entecavir (BMS-200475) was synthesized from 4-trimethylsilyl-3-butyn-2-one and acrolein. The key features of its preparation are: (i) a stereoselective boron-aldol reaction to afford the acyclic carbon skeleton of the methylenecylopentane moiety; (ii) its cyclization by a Cp₂TiCl- catalyzed intramolecular radical addition of an epoxide to an alkyne; and (iii) the coupling with a purine derivative by a Mitsunobu reaction.

Full text of DOI:10.1021/jo400607v

Article
pubs.acs.org/joc
Total Synthesis of Entecavir
Javier Velasco,†,‡ Xavier Ariza,*,†,§ Laura Badía,‡ Martí Bartra,‡ Ramon Berenguer,‡ Jaume Farras,*,†
̀
Joan Gallardo,† Jordi Garcia,†,§ and Yolanda Gasanz‡
†Departament de Química Organ
Universitat de Barcelona, Martí i Franques
‡R&D Department, Esteve Química S.A., Caracas 17-19, 08030-Barcelona, Spain
§CIBER Fisiopatología de la Obesidad y la Nutricion
(CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
̀
ica and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Facultat de Química,
1, 08028-Barcelona, Spain
̀
́
S
* Supporting Information
ABSTRACT: Entecavir (BMS-200475) was synthesized from 4-trimethyl-
silyl-3-butyn-2-one and acrolein. The key features of its preparation are: (i) a
stereoselective boron−aldol reaction to afford the acyclic carbon skeleton of
the methylenecylopentane moiety; (ii) its cyclization by a Cp2TiCl-catalyzed
intramolecular radical addition of an epoxide to an alkyne; and (iii) the
coupling with a purine derivative by a Mitsunobu reaction.
INTRODUCTION
■
B-type hepatitis is a global disease. It is one of the most
common viral infections worldwide despite an efficient vaccine
being available since 1982. According to the World Health
Organization (WHO), about two billion people are infected
worldwide and 600 000 die every year due to consequences
such as cirrhosis of the liver or liver cancer. Hepatitis B can
manifest itself in both acute and chronic forms and is especially
dangerous in children. About 90% of infants infected during the
first year of life develop chronic infections, although this ratio
drops to 30−50% in children infected between the ages of one
and four. About 25% of adults who become chronically infected
during childhood will die from hepatitis B-related liver cancer
or cirrhosis while about 90% of people who become infected
during adulthood will recover and be completely free of the
virus within six months. About 240 million people are thought
to be chronically infected with the disease worldwide.1
In its chronic form, hepatitis B can be treated with interferon
or antiviral agents. The most frequently used antiviral agents
against hepatitis B virus (HBV) are entecavir (1), tenofovir,
adefovir, telbivudine, and lamivudine (Figure 1).2
Figure 1. Antiviral agents used against HBV.
from acyclic precursors.9 As shown in Scheme 1, the
retrosynthetic analysis of this carbocyclic nucleoside10 takes
advantage of the ability of epoxides to act as effective precursors
of radicals. The key step involves the Ti(III)-mediated
generation of a β-alkoxy carbon radical11 from epoxide 4 that
can cyclize to a methylene cyclopentane 5 through the cyclic
transition state shown in Figure 2.
It is worth noting that the proposed radical cyclization has
been reported previously in a failed attempt to prepare 1. Thus,
Ziegler12 prepared epoxide 4b (PG1 = PG2 = TBS) from
protected D-glucose in 9 steps and reported very good
cyclization yields when 4b was treated with 3 equiv of
Cp2TiCl2 in the presence of an excess of Zn in THF.
Considering these precedents, we implemented an alternative
route to epoxides 4 where the key step is an enantioselective
acetate aldol addition13 of methyl ketone 2 to acrolein followed
by the in situ reduction of the corresponding β-hydroxy ketone.
Of these, entecavir is considered one of the best choices for
the treatment of chronic patients due to its lack of significant
adverse effects and the low risk of inducing long-term resistance
to the drug.3
Entecavir (BMS-200475), first synthesized by Bristol-Myers
Squibb,4 was identified as a potent inhibitor of HBV in vitro
(ED50 = 3 nM)5 and was later commercialized as Baraclude. Its
patent is due to expire in 2015 in the U.S. and soon afterward
in other countries. In anticipation of the availability of a generic
version, a plethora of patent applications has appeared
recently.6,8a,b Most of the reported synthetic approaches for
the stereoselective construction of the cyclopentane framework
are based on transformation of a cyclopentane moiety,6,7 and
only a few start with an acyclic precursor that is subsequently
cyclized.8 In this paper, we disclose a concise synthesis of 1
Received: March 22, 2013
© XXXX American Chemical Society
A
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Scheme 1
Scheme 3
the nucleobase. On the other hand, our preliminary attempts at
the cyclization of epoxide 6 led to the complete degradation of
the starting material. With a view to circumventing these
limitations, we evaluated the cyclization reactions for a series of
epoxides of type 4 with different protecting groups (Scheme 1,
PG1 ≠ PG2).
Preparation of 4 (PG1 ≠ PG2) from 3a or 7a is not trivial in
some cases because there is no reliable information in the
literature on the selective monoprotection of secondary
propargylic alcohols in the presence of secondary allylic ones.
In order to establish the viability of the monoprotection
reactions, a set of silylations and benzoylations were carried out
on these diols. Table 1 summarizes the optimized conditions
found for each substrate and highlights the fact that protection
of the propargylic position is clearly favored over the protection
of the corresponding allylic position. Moderate-to-good yields
of the desired monoprotected diol can be achieved while at the
same time maintaining the yields of diprotected byproducts
below 15%. Yields of the monoprotected allylic alcohol are less
than 5%.
Figure 2. Proposed TS for the radical cyclization of 4.
This approach drastically reduces the number of steps involved
and potentially provides more flexibility with respect to the
election of protecting groups (PG1 and PG2).
RESULTS AND DISCUSSION
■
The enantioselective aldol reaction of 4-trimethylsilyl-3-butyn-
2-one (2) with acrolein was carried out using (+)-chlorodiiso-
pinocampheylborane ((+)-DIPCl) as a source of chirality.14 As
shown in Scheme 2, the in situ reduction of the resulting
Scheme 2
On the basis of these results, we attempted to prepare the
diprotected epoxides 4g−j (Scheme 4) through selective
monoprotection of 3a followed by the removal of the TMS
group to afford 7c−e monoalcohols. The sequence was
completed by epoxidation with m-CPBA and final protection
of the remaining alcohol. The alternative pathway, in which the
epoxidation was the final step, was less convenient since the
epoxidation of protected allylic alcohols is slow, and it is even
slower with acetylated allylic alcohols. On the other hand, for
the preparation of 4k via 7f removal of the TMS group of 3a to
afford diol 7a was the first step in the sequence since this
deprotection was not compatible with a benzoate group.
With epoxides 4g−k in hand, we attempted to bring about
their Ti(III)-mediated cyclization by treatment with Cp2TiCl2
in the presence of an excess of a metal M such as Zn or Mn
(Scheme 5). In this type of reaction the metal reduces
Cp2TiCl2 to a Cp2TiCl· radical (8). Reaction of 8 with the
corresponding epoxide 4 generates the titanocene(IV) β-alkoxy
carbon radical 9 that gives rise to a cyclic vinyl radical 10. This
radical can then be quenched either by a hydrogen donor or by
another Ti(III) radical to afford 11 or 12 (X = H or Cp2TiCl,
respectively). Protonolysis of 11/12 should give methylene
cyclopentane 5. Although this reaction can be catalytic in
Cp2TiCl2, Ziegler12 described the cyclization of epoxide 4b
using an excess of Cp2TiCl2. Under these conditions, however,
we could not reproduce the reported yield. When epoxide 4b
was treated with Cp2TiCl2 in the presence of an excess of Zn
following the described procedure, the methylene cyclopropane
chelate15 with LiBH4 followed by an oxidative work up
provided 3a (PG1 = PG2 = H) as a mixture of diols in 66%
yield and moderate selectivity (80:20 er, 90:10 syn/anti ratio)
after chromatography. It is worth noting that recrystallization
from hexanes afforded pure syn diol 3a (98% er, >99% dr) in
37% overall yield. Despite the low yield, this method is very
straightforward and allows the skeleton of the cyclization
precursor 4 to be constructed from easily available commercial
starting materials in a one-pot procedure.
Conversion of 3a into the Ziegler’s epoxide 4b or its TMS-
derivative 6 is very efficient (Scheme 3). Unfortunately, the
cyclization of 4b leads to the methylene cyclopentane 5b (PG1
= PG2 = TBS, PG3 = H, Scheme 1) where the differentiation of
TBS ethers would be problematic during the introduction of
B
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Table 1. Monoprotection of Diols 3a and 7a
entry
diol
R
R′
TBS
base
solvent
t (h)
yield (product)
a
1
3a
3a
3a
7a
7a
TMS
TMS
TMS
H
Imidazole
Imidazole
Imidazole
Imidazole
DIPEA
THF
5
5
65% (3c)
62% (3d)
69% (3e)
54% (7c)
86% (7f)
2
3
TBDPS
TIPS
TBS
THF
THF
15
5
a
5
a
CH2Cl2
CH2Cl2
6
H
Bz
15
a
R′Cl (1.1 equiv) was added.
Scheme 4
Fortunately, yields could be increased to 50% by replacing
the aqueous H2SO4 workup with a treatment with saturated
NH4Cl (entry 1, Table 2). Under these optimized conditions,
Table 2. Stoichiometric Cyclization of Propargylic Epoxides
4b and 4g−k
a
entry epoxide
R
R′
TBS
product yield (%)
dr
1
2
3
4
5
6
4b
4h
4i
TBS
TBS
TBDPS
Bz
5b
5h
5i
50
95:5
>97:3
n.d.
TBDPS
TBS
TBS
Ac
43
a
<10
4k
4g
4j
5k
5g
5j
49
40
0
90:10
96:4
TBS
TIPS
Ac
a
1
Not chromatographically isolated. Yield estimated from H NMR.
cyclizations of epoxides 4g−k were carried out. The results are
summarized in Table 2 and it can be seen that the election of
the propargylic alcohol protecting group (R) is critical. TBS
provided the best yields (entries 1, 2, and 5) when compared
with TIPS and TBDPS (entries 3 and 6) and better selectivity
than the benzoyl group (entry 4). In sharp contrast, protection
of the allylic alcohol has little effect on yield or selectivity
(entries 1, 2, and 5). These results suggested 4b, 4g and 4h to
be the most promising candidates for cyclization. We finally
chose the transformation of 4g to 5g as the key step of the
synthesis because it provided better overall yield from diol 3a
and allowed differentiation of the protected alcohols.
Scheme 5
The Ti-catalytic version of the cyclization was also explored
in an attempt to improve the process. In the stoichiometric
process 11/12 are cleaved in the final step by treatment with
saturated NH4Cl. In the catalytic version an alternative proton
source is required to cleave 11/12 and regenerate the catalyst.
Gansauer16 described the use of collidine hydrochloride as the
̈
most convenient reagent for doing so.
After careful optimization of the reaction conditions we were
able to carry out the cyclization of 4g to 5g using 20% catalyst
and collidine hydrochloride as proton source with excellent
selectivity and comparable yields to the stoichiometric version
(Table 3, entries 1 and 4). Mn provides similar yields to Zn but
requires less metal to generate 8.
On the other hand, we found that the use of
trimethylsilylcollidinium chloride17 instead of collidine hydro-
chloride (entries 2 and 5) while not improving yields did
improve the reproducibility of the process at larger scales. A
further improvement was achieved by introducing Vaska’s
5b (PG1 = PG2 = TBS, PG3 = H) was obtained with good
diastereoselectivity but in a yield of only 30%.
C
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followed by Mitsunobu reaction with 2-amino-6-chloropurine6x
led to the chloroderivative 13 that was transformed into
protected Entecavir 14 by treatment with formic acid.
Saponification of 14 then gave Entecavir of pharmaceutical
grade. Reversal of the order of the last two steps decreased the
overall yield and increased the formation of impurities that
impeded the crystallization of the final product as did the direct
acid hydrolysis of both of the esters and the chloropurine
moiety.
Table 3. Catalytic Cyclization of 4g to Cyclopentane 5g
entry
M
collidinium salt
IrCl(CO)(PPh3)2
5%
yield (%)
1
2
3
4
5
6
7
Zn
Collidine·HCl
36
38
51
42
36
49
58
CONCLUSIONS
Zn
Collidine/TMSCl
Collidine/TMSCl
Collidine·HCl
Collidine/TMSCl
Collidine/TMSCl
Collidine/TMSCl
■
Zn
A straightforward synthesis of Entecavir was achieved in 11
steps from commercially available starting materials. The
cyclopentane skeleton was prepared from acyclic precursors
by a boron-aldol reaction and a Ti(III)-catalyzed cyclization of
an epoxide to an alkyne as key steps. The carbocylic structure
obtained in this way was attached to a purine moiety by a
Mitsunobu reaction. It is worth mentioning that the use of the
p-nitrobenzoyl group in the final steps allows purification by
crystallization thus avoiding chromatography and making the
synthesis amenable to scale-up. The selective hydrolysis of the
6-chloropurine unit with formic acid is also essential in order to
facilitate the crystallization of the final product.
Mn
Mn
Mn
Mn
5%
10%
complex, IrCl(CO)(PPh3)2 in the presence of H2 as hydrogen
donor18 (entries 3, 6, and 7).
The last step in the preparation of the carbocyclic moiety of
Entecavir was the protection of the primary hydroxyl group of
5g in the form of a p-nitrobenzoyl ester 5l. The election of this
protecting group is important because 5l can be crystallized and
purified. By this means, chromatographic purifications of
intermediates 3a to 5g (which are oils) can be avoided
(Scheme 6).
EXPERIMENTAL SECTION
■
All reactions involving moisture- or air-sensitive reagents were
performed in oven-dried glassware under N2. Chemical shifts (δ)
were quoted in parts per million and referenced for 1H NMR to
internal TMS (for CDCl3) or residual solvent peak δ 2.50 ppm (for
DMSO-d6). 13C NMR was referenced to CDCl3 (δ 77.0 ppm) or
DMSO-d6 (δ 39.5 ppm). Column chromatography was performed on
silica gel (Merck 230−400 mesh). HRMS analyses were recorded on a
LC/MSD-TOF mass spectrometer.
Final conversion of 5l to pharmaceutical-grade Entecavir was
straightforward. Selective acidic deprotection of the TBS ether
Scheme 6
(3S,5R)-7-(Trimethylsilyl)hept-1-en-6-yne-3,5-diol (3a). NEt3
(11.60 mL, 85 mmol) was added to a stirred solution of (+)−DIPCl
(90−105%) (25.000 g, 78 mmol) in anhydrous THF (40 mL) under
N2 at 0 °C. 4-Trimethylsilyl-3-butyn-2-one (98%, 9.78 g, 70 mmol)
was added dropwise and the mixture was stirred for 2 h at −5 to 0 °C.
The solution was cooled to −78 °C and a solution of acrolein (90%,
7.62 mL, 103 mmol) in anhydrous THF (20 mL) was added slowly
and the mixture was stirred for 1 h at −78 °C. A 2 M solution of
LiBH4 in hexanes (53 mL, 106 mmol) was added slowly and the
mixture was stirred for a further 1 h at −78 °C. After careful quenching
with saturated NH4Cl (40 mL) at −78 °C the mixture was allowed to
warm to rt over 30 min. After partitioning between H2O (40 mL) and
MTBE (90 mL) the aqueous layer was extracted with MTBE (25 mL).
The organic phases were combined and dried (MgSO4). Solvent
removal afforded a pale yellow oil (62 g). THF/H2O (3:1, 80 mL) was
added under N2 at rt followed by NaOAc (4.40 g, 54 mmol) and the
mixture was cooled to 0 °C. H2O2 (30%, 30 mL, 5 equiv) was added
dropwise over 10 min and the mixture was stirred for a further 10 min
at 0 °C and 30 min at rt. After cooling to 0 °C a saturated solution of
Na2S2O3 (30 mL) was added slowly and the mixture was stirred for 10
min at 0 °C and 15 min at rt. H2O (20 mL) and MTBE (35 mL) were
added and the organic phase was decanted. The aqueous layer was
extracted with MTBE (10 mL) and the combined organic extracts
were dried (MgSO4). Solvent removal gave a clear oil (49.2 g) that was
purified by flash chromatography [silica gel, hexanes−AcOEt, from
90:10 to 60:40 (gradient elution)] to give 9.130 g of a mixture of diols
(er 80:20; syn/anti 90:10).
Recrystallization from hexanes afforded the product as a white
crystalline solid (3a,9a 5.2 g, 37% overall yield, er 98%). Mp 80−82 °C.
25
[α]D +2.3 (c 1.0, CHCl3). IR (film): 3349, 2956, 2922, 2899, 2176
1
cm−1. H NMR (CDCl3, 400 MHz): δ 5.90 (ddd, J = 17.2, 10.4, 5.9
Hz, 1H), 5.29 (ddd, J = 17.2, 1.4, 1.3 Hz, 1H), 5.14 (ddd, J = 10.4, 1.4,
1.3 Hz, 1H), 4.64 (dd, J = 7.9, 5.2 Hz, 1H), 4.43−4.37 (m, 1H), 2.80
(bs, 1H), 2.46 (bs, 1H), 2.03−1.89 (m, 2H), 0.18 (s, 9H). 13C NMR
D
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(CDCl3, 101 MHz): δ 140.1, 115.1, 106.1, 89.9, 72.1, 62.0, 44.0, −0.1.
HRMS (ESI): m/z calcd for C10H18O2SiNa+ [M + Na]+ 221.0969;
found 221.0974.
solution of NH4Cl (20 mL) was added slowly and the mixture was
stirred for 10 min. The mixture was partitioned and the organic phase
was extracted with MTBE (2 × 20 mL). The combined organic phases
were dried (MgSO4), and the solvent was removed affording an oil
that was purified by flash chromatography [silica gel, hexanes−AcOEt,
from 97:3 to 80:20 (gradient elution)] to give 6.173 g (69%) of the
(3S,5R)-3,5-Bis(tert-butyldimethylsilyloxy)-7-(trimethylsilyl)-
hept-1-en-6-yne (3b). A solution of TBSCl (0.800 g, 5.30 mmol) in
anhydrous CH2Cl2 (5 mL) was added dropwise to a solution of diol 3a
(0.500 g, 2.52 mmol) and imidazole (0.377 g, 5.54 mmol) in
anhydrous CH2Cl2 (5 mL) at 0 °C under N2. The mixture was allowed
to warm to rt and was stirred for 15 h. A 22% solution of NH4Cl (5
mL) was added slowly and the mixture was stirred for 10 min. The
mixture was partitioned and the aqueous phase was extracted with
CH2Cl2 (5 mL). The organic phase was dried (MgSO4) and the
solvent was removed affording an oil that was purified by flash
chromatography (silica gel, hexanes−AcOEt 95:5) to give 1.030 g
25
title compound as a pale yellow oil. [α]D +23.5 (c 0.6, CHCl3). IR
1
(film): 3421, 3074, 2944, 2894, 2867, 2167 cm−1. H NMR (CDCl3,
300 MHz): δ 5.89 (ddd, J = 17.2, 10.5, 5.6 Hz, 1H), 5.28 (dt, J = 17.2,
1.5 Hz, 1H), 5.11 (dt, J = 10.5, 1.5 Hz, 1H), 4.71 (t, J = 6.4 Hz, 1H),
4.49−4.41 (m, 1H), 2.92 (d, J = 2.7 Hz, 1H), 1.95−1.89 (m, 2H),
1.27−1.13 (m, 3H), 1.13−1.04 (m, 18H). 13C NMR (CDCl3, 101
MHz): δ 140.5, 114.4, 106.9, 90.3, 71.1, 62.5, 45.5, 18.2, 17.9, 12.5,
−0.2. HRMS (ESI): m/z calcd for C19H39O2Si2+ [M + H]+ 355.2483;
found 355.2478.
(96%) of the title compound9a (3b) as a yellow oil. [α]D +21.6 (c
25
1
1.0, CHCl3). IR (film): 3071, 2952, 2930, 2897, 2858, 2172 cm−1. H
(3S,5R)-Hept-1-en-6-yne-3,5-diol (7a). K2CO3 (0.348 g, 2.52
mmol) was added in one portion to a stirred solution of 3a (1.000 g,
5.04 mmol) in anhydrous MeOH (10 mL) at rt under N2. The mixture
was then stirred for 1 h. A buffer solution (pH = 7, 10 mL) and
CH2Cl2 (10 mL) were added, the mixture was partitioned and the
organic phase was dried (MgSO4). Solvent removal gave the title
NMR (CDCl3, 300 MHz): δ 5.81 (ddd, J = 17.2, 10.3, 6.4 Hz, 1H),
5.15 (dt, J = 17.2, 1.4 Hz, 1H), 5.04 (dt, J = 10.3, 1.4 Hz, 1H), 4.46
(dd, J = 7.7, 6.4 Hz, 1H), 4.33−4.24 (m, 1H), 1.90 (ddd, J = 13.2, 8.1,
6.7 Hz, 1H), 1.74 (ddd, J = 13.2, 7.7, 5.2 Hz, 1H), 0.90 (s, 9H), 0.89
(s, 9H), 0.16 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H), 0.07 (s, 3H), 0.03 (s,
3H). 13C NMR (CDCl3, 101 MHz): δ 141.3, 114.4, 107.4, 89.5, 71.3,
61.3, 46.9, 26.0, 25.9, 18.4, 18.3, 0.0, −4.1, −4.3, −4.8, −4.8. HRMS
compound (7a)12 as a yellow oil 0.628 g (98%). [α]D +5.8 (c 1.0,
25
CHCl3). IR (film): 3347, 3290, 3060, 2983, 2953, 2922, 2887, 2113
+
(ESI): m/z calcd for C22H47O2Si3 [M + H]+ 427.2878; found
1
cm−1. H NMR (CDCl3, 400 MHz): δ 5.86 (ddd, J = 17.2, 10.4, 6.0
427.2867.
Hz, 1H), 5.26 (dt, J = 17.2, 1.4 Hz, 1H), 5.11 (dt, J = 10.4, 1.4 Hz,
1H), 4.61 (ddd, J = 8.3, 5.1, 2.1 Hz, 1H), 4.41−4.34 (m, 1H), 2.75 (bs,
1H), 2.49 (d, J = 2.1 Hz, 1H), 2.35 (bs, 1H), 2.03−1.84 (m, 2H). 13C
NMR (CDCl3, 101 MHz): δ 140.1, 115.2, 84.5, 73.3, 72.0, 61.3, 43.9.
HRMS (ESI): m/z calcd for C7H10NaO2+ [M + Na]+ 149.0573; found
149.0572.
(3S,5R)-5-(tert-Butyldimethylsilyloxy)-7-(trimethylsilyl)hept-
1-en-6-yn-3-ol (3c). A solution of TBSCl (4.180 g, 27.73 mmol) in
anhydrous THF (20 mL) was added dropwise to a solution of diol 3a
(5.000 g, 25.21 mmol) and imidazole (2.060 g, 30.25 mmol) in
anhydrous THF (60 mL) at 0 °C under N2, and the mixture was
allowed to warm to rt and was stirred for 5 h. A 22% solution of
NH4Cl (25 mL) was added slowly and the mixture was stirred for 10
min. The mixture was partitioned and the organic phase was dried
(MgSO4) and the solvent was removed affording an oil that was
purified by flash chromatography [silica gel, hexanes−AcOEt, from
97:3 to 80:20 (gradient elution)] to give 5.123 g (65%) of the title
compound9a (3c) as a pale yellow oil. [α]D25 +39.9 (c 1.0, CHCl3). IR
(3S,5R)-3,5-Bis(tert-butyldimethylsilyloxy)hept-1-en-6-yne
(7b). A solution of TBSCl (2.059 g, 13.60 mmol) in anhydrous
CH2Cl2 (5 mL) was added dropwise to a solution of diol 7a (0.820 g,
6.50 mmol) and imidazole (1.062 g, 15.60 mmol) in anhydrous
CH2Cl2 (3 mL) at 0 °C under N2, and the mixture was allowed to
warm to rt and was stirred for 15 h. A 22% solution of NH4Cl (5 mL)
was added slowly and the mixture was stirred for 10 min. The mixture
was partitioned and the aqueous phase was extracted with CH2Cl2 (2
× 10 mL). The combined organic phases were dried (MgSO4) and the
solvent was removed affording an oil that was purified by flash
chromatography [silica gel, hexanes−AcOEt, from 97:3 to 80:20
(gradient elution)] to give 2.280 g (95%) of the title compound (7b)12
1
(film): 3424, 3081, 2958, 2930, 2898, 2858, 2172 cm−1. H NMR
(CDCl3, 300 MHz): δ 5.86 (ddd, J = 17.2, 10.5, 5.6 Hz, 1H), 5.28 (dt,
J = 17.2, 1.5 Hz, 1H), 5.11 (dt, J = 10.5, 1.5 Hz, 1H), 4.59 (dd, J = 7.9,
5.3 Hz, 1H), 4.42−4.30 (m, 1H), 2.98 (d, J = 2.4 Hz, 1H), 1.99−1.86
(m, 2H), 0.91 (s, 9H), 0.19 (s, 3H), 0.16 (s, 12H). 13C NMR (CDCl3,
101 MHz): δ 140.3, 114.6, 106.7, 90.3, 71.5, 62.9, 45.1, 25.9, 18.2,
−0.2, −4.1, −4.8. HRMS (ESI): m/z calcd for C16H33O2Si2+ [M + H]+
313.2014; found 313.2005.
25
as a pale yellow oil. [α]D +13.0 (c 1.0, CHCl3). IR (film): 3306,
1
3093, 2958, 2930, 2887, 2858 cm−1. H NMR (CDCl3, 400 MHz): δ
5.81 (ddd, J = 17.2, 10.4, 6.5 Hz, 1H), 5.17 (dt, J = 17.2, 1.2 Hz, 1H),
5.05 (dt, J = 10.4, 1.2 Hz, 1H), 4.47 (ddd, J = 8.2, 6.5, 2.0 Hz, 1H),
4.33−4.26 (m, 1H), 2.42 (d, J = 2.0 Hz, 1H), 1.99−1.74 (m, 2H), 0.91
(s, 9H), 0.90 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H), 0.07 (s, 3H), 0.03 (s,
3H). 13C NMR (CDCl3, 101 MHz): δ 141.3, 114.4, 85.4, 72.9, 71.1,
60.6, 47.2, 26.0, 25.9, 18.4, 18.3, −4.1, −4.4, −4.8, −4.9. HRMS (ESI):
(3S,5R)-5-(tert-Butyldiphenylsilyloxy)-7-(trimethylsilyl)hept-
1-en-6-yn-3-ol (3d). TBDPSCl (1.57 mL, 6.10 mmol) was added
dropwise to a solution of diol 3a (1.000 g, 5.04 mmol) and imidazole
(0.481 g, 7.06 mmol) in anhydrous THF (9.5 mL) at 0 °C under N2,
and the mixture was allowed to warm to rt and was stirred for 5 h. A
22% solution of NH4Cl (5 mL) was added slowly and the mixture was
stirred for 10 min. The mixture was partitioned and the organic phase
was dried (MgSO4), and the solvent was removed affording an oil that
was purified by flash chromatography [silica gel, hexanes−AcOEt,
from 95:5 to 90:10 (gradient elution)] to give 1.363 g (62%) of the
title compound (3d) as a pale yellow oil. [α]D25 +62.5 (c 1.0, CHCl3).
IR (film): 3446, 3071, 2958, 2931, 2894, 2857 cm−1. 1H NMR
(CDCl3, 400 MHz): δ 7.77−7.66 (m, 4H), 7.45−7.33 (m, 6H), 5.84
(ddd, J = 17.2, 10.5, 5.6 Hz, 1H), 5.23 (dt, J = 17.2, 1.5 Hz, 1H), 5.07
(dt, J = 10.5, 1.5 Hz, 1H), 4.54 (t, J = 6.3 Hz, 1H), 4.51−4.43 (m, 1H),
2.64 (d, J = 3.4 Hz, 1H), 2.01−1.85 (m, 2H), 1.06 (s, 9H), 0.10 (s,
9H). 13C NMR (CDCl3, 101 MHz): δ 140.4, 136.2, 136.0, 134.9,
133.6, 133.3, 130.0, 129.8, 129.7, 127.8, 127.7, 127.5, 114.5, 106.2,
91.3, 70.6, 62.8, 45.2, 27.0, 26.7, 19.4, −0.4. HRMS (ESI): m/z calcd
+
m/z calcd for C19H39O2Si2 [M + H]+ 355.2483; found 355.2486.
(3S,5R)-5-(tert-Butyldimethylsilyloxy)hept-1-en-6-yn-3-ol
(7c). K2CO3 (0.101 g, 0.73 mmol) was added in one portion to a
stirred solution of 3c (0.455 g, 1.46 mmol) in anhydrous MeOH (4.5
mL) at rt under N2 and the mixture was stirred for 1 h. After solvent
removal CH2Cl2 (10 mL) was added to the residue and the solution
was filtered and dried (MgSO4). Solvent removal gave the title
compound (7c)9a as a pale yellow oil (0.366 g, 99%). [α]D25 +32.7 (c
1.0, CHCl3). IR (film): 3417, 3311, 3079, 2956, 2930, 2886, 2858,
2109 cm−1. (CDCl3, 300 MHz): δ 5.88 (ddd, J = 17.2, 10.4, 5.7 Hz,
1H), 5.29 (dt, J = 17.2, 1.5 Hz, 1H), 5.12 (dt, J = 10.4, 1.5 Hz, 1H),
4.61 (ddd, J = 7.8, 5.8, 2.1 Hz, 1H), 4.42−4.33 (m, 1H), 2.71 (d, J =
2.7 Hz, 1H), 2.47 (d, J = 2.1 Hz, 1H), 2.03−1.85 (m, 2H), 0.92 (s,
9H), 0.19 (s, 3H), 0.16 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ
140.3, 114.8, 84.9, 73.5, 71.2, 62.0, 45.2, 25.9, 18.2, −4.2, −4.9. HRMS
(ESI): m/z calcd for C13H24NaO2Si+ [M + Na]+ 263.1438; found
263.1431.
+
for C26H37O2Si2 [M + H]+ 437.2327; found 437.2325.
(3S,5R)-5-(Triisopropylsilyloxy)-7-(trimethylsilyl)hept-1-en-
6-yn-3-ol (3e). TIPSCl (5.20 mL, 30.25 mmol) was added dropwise
to a solution of diol 3a (5.000 g, 25.21 mmol) and imidazole (2.230 g,
32.77 mmol) in anhydrous THF (40 mL) at 0 °C under N2, and the
mixture was allowed to warm to rt and was stirred for 15 h. A 22%
(3S,5R)-5-(tert-Butyldiphenylsilyloxy)hept-1-en-6-yn-3-ol
(7d). K2CO3 (0.080 g, 0.57 mmol) was added in one portion to a
stirred solution of 3d (0.500 g, 1.14 mmol) in anhydrous MeOH (5
E
dx.doi.org/10.1021/jo400607v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mL) at rt under N2 and the mixture was stirred for 3 h. A buffer
solution (pH = 7, 5 mL) and MTBE (15 mL) were added, the mixture
was partitioned and the organic phase was dried (MgSO4). Solvent
removal gave the title compound (7d) as a pale yellow oil (0.350 g,
84%). [α]D25 +34.3 (c 1.0, CHCl3). IR (film): 3453, 3303, 3071, 2956,
NaHCO3 (2 × 10 mL), dried (MgSO4) and the solvent was removed
to give an oily residue that was purified by flash chromatography [silica
gel, hexanes−AcOEt, from 90:10 to 50:50 (gradient elution)] to give
the title compound (4b)12 as a pale yellow oil (2.240 g, 95%). IR
1
(film): 3311, 3045, 2954, 2928, 2886, 2857 cm−1. H NMR (CDCl3,
1
2930, 2891, 2858 cm−1. H NMR (CDCl3, 400 MHz): δ 7.78−7.69
300 MHz): δ 4.58 (m, 1H), 3.83 (dd, J = 7.8, 4.7 Hz, 0.4H), 3.49
(ddd, J = 8.7, 6.9, 4.3 Hz, 0.6H), 2.97 (ddd, J = 6.9, 4.1, 2.7 Hz, 0.6H),
2.93 (ddd, J = 4.5, 3.9, 2.7 Hz, 0.4H), 2.79 (dd, J = 4.8, 4.2 Hz, 0.6H),
2.72−2.64 (m, 0.8H), 2.57 (dd, J = 4.9, 2.7 Hz, 0.6H), 2.43 (d, J = 2.1
Hz, 0.4H), 2.41 (d, J = 2.1 Hz, 0.6H), 2.06−1.79 (m, 2H), 0.92−0.88
(m, 18H), 0.16−0.06 (m, 12H). 13C NMR (CDCl3, 101 MHz): δ 85.0,
84.9, 73.3, 73.3, 72.4, 68.6, 60.5, 56.0, 54.7, 45.1, 44.7, 44.1, 43.5, 26.1,
26.0, 25.9, 18.4, 18.3, 18.2, −4.2, −4.5, −4.9, −5.0, −5.1. HRMS
(m, 4H), 7.47−7.36 (m, 6H), 5.88−5.78 (m, 1H), 5.22 (dt, J = 17.2,
1.4 Hz, 1H), 5.08 (dt, J = 10.5, 1.4 Hz, 1H), 4.60 (td, J = 6.5, 2.1 Hz,
1H), 4.47−4.39 (m, 1H), 2.35 (d, J = 2.1 Hz, 1H), 2.15 (m, 1H),
1.96−1.90 (m, 2H), 1.10 (s, 9H). 13C NMR (CDCl3, 101 MHz): δ
140.5, 136.2, 136.0, 133.3, 133.3, 130.4, 129.9, 127.8, 127.6, 114.6,
84.5, 74.2, 70.3, 62.1, 45.3, 27.0, 19.4. HRMS (ESI): m/z calcd for
C23H28NaO2Si+ [M + Na]+ 387.1751; found 387.1752.
(3S,5R)-5-(Triisopropylsilyloxy)hept-1-en-6-yn-3-ol (7e).
K2CO3 (0.526 g, 3.81 mmol) was added in one portion to a stirred
solution of 3e (6.000 g, 15.23 mmol) in anhydrous MeOH (50 mL) at
rt under N2 and the mixture was stirred for 1 h. A buffer solution (pH
= 7, 15 mL) and MTBE (15 mL) were added, the mixture was
partitioned and the organic phase was dried (MgSO4). Solvent
removal gave the title compound (7e) as a pale yellow oil (4.084 g,
95%). [α]D25 +15.7 (c 1.0, CHCl3). IR (film): 3421, 3311, 3083, 2944,
2893, 2867 cm−1. 1H NMR (CDCl3, 300 MHz): δ 5.97−5.83 (m, 1H),
5.29 (ddd, J = 17.3, 2.7, 1.4 Hz, 1H), 5.12 (ddd, J = 10.4, 2.6, 1.4 Hz,
1H), 4.74 (td, J = 6.7, 2.1 Hz, 1H), 4.50−4.39 (m, 1H), 2.55 (d, J = 3.0
Hz, 1H), 2.49−2.46 (m, 1H), 1.99−1.91 (m, 2H), 1.24−1.06 (m,
21H). 13C NMR (CDCl3, 101 MHz): δ 140.5, 114.6, 85.0, 73.6, 70.9,
61.8, 45.5, 18.2, 18.1, 17.8, 12.4. HRMS (ESI): m/z calcd for
C16H31O2Si+ [M + H]+ 283.2088; found 283.2077.
+
(ESI): m/z calcd for C19H39O3Si2 [M + H]+ 371.2432; found
371.2425.
(1S,3R)-3-(tert-Butyldimethylsilyloxy)-1-(oxiran-2-yl)pent-4-
yn-1-ol (4c). A suspension of m-CPBA (77%, 13.640 g, 60.83 mmol)
in anhydrous CH2Cl2 (30 mL) at rt under N2 was added to a stirred
solution of 7c (5.849 g, 24.33 mmol) in anhydrous CH2Cl2 (20 mL)
and the mixture was stirred at rt for 15 h. The mixture was filtered and
the organic phase was washed with saturated Na2S2O3 (35 mL),
saturated NaHCO3 (2 × 15 mL), dried (MgSO4) and the solvent was
removed to give the title compound (4c)9a as a yellow oil (6.048 g,
1
97%). IR (film): 3454, 3318, 3083, 2962, 2930, 2895, 2860 cm−1. H
NMR (CDCl3, 400 MHz): δ 4.58−4.54 (m, 1H), 3.89−3.83 (m,
0.4H), 3.72−3.65 (m, 0.6 H), 2.95 (ddd, J = 8.0, 4.1, 2.0 Hz, 1H),
2.71−2.63 (m, 2H), 2.38 (d, J = 2.1 Hz, 0.4H), 2.47 (d, J = 2.1 Hz,
0.6H), 1.98−1.81 (m, 2H), 0.81 (s, 9H), 0.08 (s, 1.2H), 0.08 (s, 1.8H),
0.06 (s, 1.2H), 0.05 (s, 1.8H). 13C NMR (CDCl3, 101 MHz): δ 84.5,
84.4, 73.6, 73.5, 69.7, 68.2, 61.7, 61.3, 55.2, 54.3, 44.9, 44.4, 42.4, 41.9,
25.8, 18.2, 18.1, −4.3, −4.4, −5.0, −5.1. HRMS (ESI): m/z calcd for
C13H25O3Si+ [M + H]+ 257.1568; found 257.1559.
(3R,5S)-5-Hydroxyhept-6-en-1-yn-3-yl benzoate (7f). i-
Pr2NEt (0.76 mL, 4.37 mmol) was added dropwise to a solution of
7a (0.460 g, 3.64 mmol) in anhydrous CH2Cl2 (9 mL) at 0 °C under
N2. BzCl (0.46 mL, 3.96 mmol) was added dropwise at 0 °C and the
mixture was warmed to rt and stirred for 15 h. MeOH (2 mL) was
added and the mixture was stirred for 10 min. After solvent removal
the resulting oily residue was purified by flash chromatography [silica
gel, hexanes−AcOEt, from 90:10 to 80:20 (gradient elution)] to give
the title compound (7f, as the major isomer in a 91:9 mixture of
monobenzoylated regioisomers) as a pale yellow oil (0.741 g, 86%).
[α]D25 +26.0 (c 1.0, CHCl3). IR (film): 3467, 3294, 3071, 2959, 2928,
(1S,3R)-3-(tert-Butyldiphenylsilyloxy)-1-(oxiran-2-yl)pent-4-
yn-1-ol (4d). A suspension of m-CPBA (77%, 0.516 g, 2.26 mmol) in
anhydrous CH2Cl2 (3 mL) at rt under N2 was added to a stirred
solution of 7d (0.275 g, 0.754 mmol) in anhydrous CH2Cl2 (2 mL)
and the mixture was stirred at rt for 2.5 h. After filtration the organic
phase was washed with saturated Na2S2O3 (5 mL), saturated NaHCO3
(2 × 15 mL) and dried (MgSO4). Solvent removal gave the title
compound (4d) as a pale yellow oil (0.290 g, 99%). IR (film): 3447,
1
2885, 2121, 1719 cm−1. H NMR (CDCl3, 400 MHz): δ 8.11−8.03
1
3287, 2960, 2930, 2891, 2857, 2117 cm−1. H NMR (CDCl3, 400
(m, 2H), 7.63−7.54 (m, 1H), 7.50−7.41 (m, 2H), 5.93 (ddd, J = 17.1,
10.4, 6.0 Hz, 1H), 5.79 (ddd, J = 7.6, 6.5, 2.2 Hz, 1H), 5.30 (dt, J =
17.1, 1.2 Hz, 1H), 5.17 (dt, J = 10.4, 1.2 Hz, 1H), 4.53−4.42 (m, 1H),
2.56 (d, J = 2.2 Hz, 1H), 2.30−2.05 (m, 2H). 13C NMR (CDCl3, 101
MHz): δ 165.4, 140.0, 133.4, 129.9, 129.8, 128.5, 115.5, 81.0, 74.7,
69.9, 62.2, 41.7. HRMS (ESI): m/z calcd for C14H14NaO3+ [M + Na]+
253.0835; found 253.0837.
MHz): δ 7.77−7.66 (m, 4H), 7.47−7.35 (m, 6H), 4.67−4.59 (m, 1H),
4.10−4.04 (m, 0.4H), 3.84−3.76 (s, 0.6H), 3.05 (dd, J = 6.6, 3.7 Hz,
0.4H), 2.98 (td, J = 4.3, 2.8 Hz, 0.6H), 2.79−2.68 (m, 2H), 2.37 (d, J =
2.1 Hz, 1H), 2.02−1.85 (m, 3H), 1.08 (s, 9H). 13C NMR (CDCl3, 101
MHz): δ 136.2, 136.1, 135.9, 133.2, 133.2, 133.2, 130.10, 130.1, 130.0,
127.9, 127.8, 127.6, 127.5, 84.1, 84.1, 74.3, 74.2, 68.8, 66.7, 61.9, 61.7,
55.2, 54.4, 45.0, 43.9, 42.7, 41.7, 27.0, 19.4. HRMS (ESI): m/z calcd
for C23H28NaO3Si+ [M + Na]+ 403.1700; found 403.1702.
(1S,3R)-1,3-Bis(tert-butyldimethylsilyloxy)-1-(oxiran-2-yl)-5-
(trimethylsilyl)pent-4-yne (6). A solution of 3b (0.900 g, 2.11
mmol) in anhydrous CH2Cl2 (5 mL) was added to a suspension of m-
CPBA (77%, 1.417 g, 6.32 mmol) in anhydrous CH2Cl2 (10 mL) at rt
under N2 and the mixture was stirred at rt for 15 h. The mixture was
filtered and the organic phase was washed with saturated Na2S2O3 (5
mL), saturated NaHCO3 (10 mL), dried (MgSO4) and the solvent was
removed to give the title compound (6) as a yellow oil (0.853 g, 91%).
IR (film): 3048, 2956, 2929, 2887, 2857 cm−1. 1H NMR (CDCl3, 400
MHz): δ 4.61−4.54 (m, 1H), 3.88 (ddd, J = 6.5, 6.4, 4.2 Hz, 0.4H),
3.49 (ddd, J = 8.7, 7.0, 4.5 Hz, 0.6H), 3.00−2.92 (m, 1H), 2.83−2.76
(m, 0.6H), 2.70−2.64 (m, 0.8H), 2.56 (dd, J = 4.9, 2.7 Hz, 0.6H),
2.02−1.80 (m, 2H), 0.92−0.90 (m, 18H), 0.16−0.08 (m, 21H). 13C
NMR (CDCl3, 101 MHz): δ 106.8, 106.7, 90.1, 90.0, 72.7, 68.4, 61.2,
61.1, 56.0, 54.8, 45.2, 44.3, 43.7, 43.2, 26.0, 25.9, 18.4, 18.3, 0.0, −0.1,
−4.2, −4.4, −4.5, −4.8, −4.9, −5.1. HRMS (ESI): m/z calcd for
(1S,3R)-1-(Oxiran-2-yl)-3-(triisopropylsilyloxy)pent-4-yn-1-ol
(4e). A solution of 7e (4.900 g, 17.34 mmol) in anhydrous CH2Cl2 (7
mL) was added to a suspension of m-CPBA (77%, 9.500 g, 42.48
mmol) in anhydrous CH2Cl2 (33 mL) at rt under N2 and the mixture
was stirred at rt for 15 h. After filtration the organic phase was washed
with saturated Na2S2O3 (20 mL), saturated NaHCO3 (2 × 20 mL) and
dried (MgSO4). Solvent removal gave the title compound (4e)9a as a
pale yellow oil (4.920 g, 95%). IR (film): 3447, 3310, 2944, 2867, 2109
cm−1. 1H NMR (CDCl3, 400 MHz): δ 4.80−4.74 (m, 1H), 4.09−4.02
(m, 0.4H), 3.87−3.79 (m, 0.6H), 3.11−3.04 (m, 1H), 2.84−2.79 (m,
1H), 2.78−2.74 (m, 1H), 2.49 (d, J = 2.1 Hz, 0.4H), 2.47 (d, J = 2.1
Hz, 0.6H), 2.10−1.91 (m, 2H), 1.13−1.04 (m, 21H). 13C NMR
(CDCl3, 101 MHz): δ 84.7, 84.6, 73.6, 73.6, 69.5, 67.5, 61.5, 61.2,
55.4, 54.4, 45.0, 44.2, 42.8, 42.1, 18.1, 18.1, 12.4, 12.3. HRMS (ESI):
m/z calcd for C16H31O3Si+ [M + H]+ 299.2037; found 299.2035.
(3R,5S)-5-Hydroxy-5-(oxiran-2-yl)pent-1-yn-3-yl Benzoate
(4f). A solution of 7f (0.500 g, 2.17 mmol, 91:9 mixture of
monobenzoylated regioisomers) in anhydrous CH2Cl2 (3 mL) was
added to a suspension of m-CPBA (77%, 1.460 g, 6.51 mmol) in
anhydrous CH2Cl2 (2 mL) at rt under N2 and the mixture was stirred
at rt for 15 h. After filtration the organic phase was washed with
+
C22H47O3Si3 [M + H]+ 443.2828; found 443.2827.
(1S,3R)-1,3-Bis(tert-butyldimethylsilyloxy)-1-(oxiran-2-yl)-
pent-4-yne (4b). A solution of 7b (2.260 g, 6.37 mmol) in anhydrous
CH2Cl2 (5 mL) was added to a suspension of m-CPBA (77%, 3.180 g,
19.12 mmol) in anhydrous CH2Cl2 (25 mL) at rt under N2 and the
mixture was stirred at rt for 15 h. The mixture was filtered and the
organic phase was washed with saturated Na2S2O3 (10 mL), saturated
F
dx.doi.org/10.1021/jo400607v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
saturated Na2S2O3 (7 mL), saturated NaHCO3 (2 × 10 mL) and dried
(MgSO4). Solvent removal gave an oily residue that was purified by
flash chromatography [silica gel, hexanes−AcOEt, from 90:10 to 50:50
(gradient elution)] to give the title compound (4f) as a pale yellow oil
(0.465 g, 87%, single monobenzoylated regioisomer). IR (film): 3446,
the mixture was stirred for 10 min and partitioned. The organic phase
was dried (MgSO4), and the solvent was removed. The resulting oily
residue was purified by flash chromatography [silica gel, hexanes−
AcOEt, from 99:1 to 90:10 (gradient elution)] to give the title
compound (4i) as a colorless oil (0.203 g, 71%). IR (film): 3307,
3288, 3063, 2997, 2929, 2121, 1719 cm−1. H NMR (CDCl3, 400
3071, 2955, 2928, 2892, 2856 cm−1. H NMR (CDCl3, 300 MHz): δ
1
1
MHz): δ 8.07−8.01 (m, 2H), 7.60−7.53 (m, 1H), 7.44 (t, J = 7.7 Hz,
2H), 5.89−5.81 (m, 1H), 4.18 (ddd, J = 7.9, 4.8, 3.3 Hz, 0.4H), 3.86
(dt, J = 9.0, 4.6 Hz, 0.6H), 3.09 (ddd, J = 7.4, 6.0, 2.9 Hz, 1H), 2.88−
2.81 (m, 1H), 2.79−2.74 (m, 0.6H), 2.72 (dd, J = 5.0, 4.0 Hz, 0.4H),
2.56 (t, J = 1.9 Hz, 1H), 2.32−2.13 (m, 2H). 13C NMR (CDCl3, 101
MHz): δ 165.4, 133.5, 133.4, 129.9, 129.9, 129.6, 129.6, 128.6, 128.5,
80.7, 80.6, 74.9, 74.8, 68.5, 65.9, 62.1, 62.0, 55.1, 54.2, 45.1, 43.7, 39.3,
7.89−7.78 (m, 4H), 7.60−7.46 (m, 6H), 4.71−4.62 (m, 1H), 3.93 (dt,
J = 8.0, 4.1 Hz, 0.3H), 3.64−3.54 (m, 0.7H), 3.07−2.96 (m, 1H), 2.88
(dd, J = 4.8, 4.2 Hz, 0.7H), 2.80 (dd, J = 5.4, 4.2 Hz, 0.3H), 2.74 (dd, J
= 5.4, 2.8 Hz, 0.3H), 2.66 (dd, J = 4.9, 2.8 Hz, 0.7H), 2.50 (d, J = 2.1
Hz, 0.3H), 2.48 (d, J = 2.1 Hz, 0.7H), 2.20−2.00 (m, 2H), 1.22 (bs,
9H), 0.87 (bs, 6H), 0.84 (s, 3H), 0.19 (s, 2H), 0.14 (s, 1H), 0.11 (s,
1H), 0.04 (s, 2H).13C NMR (CDCl3, 101 MHz): δ 136.2, 136.1, 135.9,
135.9, 133.5, 133.4, 130.0, 129.9, 129.8, 129.7, 127.8, 127.8, 127.6,
127.5, 84.5, 84.4, 74.1, 74.0, 72.4, 68.6, 61.8, 56.0, 54.7, 45.0, 44.7,
43.6, 43.0, 27.0, 25.9, 25.9, 19.4, 18.1, 18.1, −4.4, −4.3, −5.1, −5.3.
+
38.4. HRMS (ESI): m/z calcd for C14H15O4 [M + H]+ 247.0965;
found 247.0966.
(1S,3R)-3-(tert-Butyldimethylsilyloxy)-1-(oxiran-2-yl)pent-4-
ynyl Acetate (4g). NEt3 (3.80 mL, 27.89 mmol) was added dropwise
to a solution of 4c (5.499 g, 21.45 mmol) and a catalytic amount of
DMAP in anhydrous CH2Cl2 (50 mL) at 0 °C under N2. Ac2O (2.40
mL, 25.74 mmol) was added dropwise at 0−5 °C and the mixture was
allowed to warm to rt and stirred for 1 h. Saturated NH4Cl (35 mL)
was added slowly and the mixture was stirred for 10 min. After
partitioning the aqueous phase was extracted with CH2Cl2 (20 mL)
and the combined organic phases were washed with saturated
NaHCO3 (30 mL). The aqueous phase was extracted with CH2Cl2
(20 mL) and the combined organic phases were dried (MgSO4) and
the solvent was removed to give the title compound9a (4g) as a pale
yellow oil (6.300 g, 98%). IR (film): 3295, 3075, 2970, 2947, 2903,
2873, 1750 cm−1. 1H NMR (CDCl3, 400 MHz): δ 5.07−4.99 (m, 1H),
4.54−4.48 (m, 1H), 3.16 (ddd, J = 5.7, 4.1, 2.6 Hz, 0.6H), 3.05 (ddd, J
= 4.9, 3.9, 2.7 Hz, 0.4H), 2.82 (dd, J = 4.9, 4.2 Hz, 0.6H), 2.77−2.70
(m, 0.8H), 2.67 (dd, J = 4.8, 2.7 Hz, 0.6H), 2.44 (d, J = 2.1 Hz, 0.6H),
2.43 (d, J = 2.1 Hz, 0.4H), 2.08 (s, 1.2H), 2.06 (s, 1.8H), 2.16−1.97
(m, 2H), 0.90 (s, 9H), 0.15 (s, 1.8H), 0.14 (s, 1.2H), 0.12 (s, 1.8H),
0.12 (s, 1.2H). 13C NMR (CDCl3, 101 MHz): δ 171.1, 85.1, 74.5, 74.4,
72.0, 70.9, 60.8, 54.1, 53.2, 46.3, 40.9, 40.7, 26.8, 22.1, 22.0, 19.2, −3.5,
−4.1. HRMS (ESI): m/z calcd for C15H27O4Si+ [M + H]+ 299.1674;
found 299.1665.
+
HRMS (ESI): m/z calcd for C29H42NaO3Si2 [M + Na]+ 517.2565;
found 517.2572.
(1S,3R)-1-(Oxiran-2-yl)-3-(triisopropylsilyloxy)pent-4-yn-1-yl
Acetate (4j). NEt3 (0.29 mL, 2.15 mmol) was added dropwise to a
solution of 4e (0.495 g, 1.66 mmol) and a catalytic amount of DMAP
in anhydrous CH2Cl2 (5 mL) at 0 °C under N2. Ac2O (0.19 mL, 1.99
mmol) was added dropwise at 0 °C and the mixture was allowed to
warm to rt and stirred for 1 h. Saturated NH4Cl (5 mL) was added
slowly and the mixture was stirred for 10 min. After partitioning the
aqueous phase was extracted with CH2Cl2 (5 mL) and the organic
phases were combined and washed with saturated NaHCO3 (2 × 5
mL). The combined organic phases were dried (MgSO4), and solvent
removal gave the title compound (4j) as a yellow oil (0.508 g, 90%).
IR (film): 3301, 3064, 2944, 2867, 2118 cm−1. 1H NMR (CDCl3, 400
MHz): δ 5.12−5.06 (m, 1H), 4.64−4.55 (m, 1H), 3.17 (ddd, J = 5.6,
4.2, 2.7 Hz, 0.6H), 3.07 (ddd, J = 4.4, 3.7, 2.6 Hz, 0.4H), 2.83 (dd, J =
4.9, 4.2 Hz, 0.6H), 2.75 (m, 0.8H), 2.68 (dd, J = 4.9, 2.6 Hz, 0.6H),
2.44 (m, 1H), 2.15−1.99 (m, 5H), 1.18−0.98 (m, 21H). 13C NMR
(CDCl3, 101 MHz): δ 170.1, 84.1, 73.5, 73.4, 70.9, 69.8, 60.0, 59.9,
53.2, 52.2, 45.3, 40.2, 39.7, 21.0, 20.9, 18.1, 18.0, 17.8, 12.4, 12.3, 12.2.
HRMS (ESI): m/z calcd for C18H33O4Si+ [M + H]+ 341.2143; found
341.2141.
(3R,5S)-5-(tert-Butyldimethylsilyloxy)-5-(oxiran-2-yl)pent-1-
yn-3-yl Benzoate (4k). A solution of TBSCl (0.464 g, 3.08 mmol) in
anhydrous THF (2 mL) was added dropwise to a solution of 4f (0.400
g, 1.62 mmol) and imidazole (0.330 g, 4.86 mmol) in anhydrous THF
(3 mL) at 0 °C under N2, and the mixture was warmed to 30 °C and
stirred for 24 h. A 22% solution of NH4Cl (5 mL) was added slowly
and the mixture was stirred for 10 min. MTBE (15 mL) and H2O (5
mL) were added and the mixture was stirred for 10 min and
partitioned. The organic phase was dried (MgSO4), and the solvent
was removed. The resulting oily residue was purified by flash
chromatography [silica gel, hexanes−AcOEt, from 95:5 to 90:10
(gradient elution)] to give the title compound (4k) as a white waxy
solid (0.390 g, 67%). IR (film): 3270, 3066, 2954, 2928, 2886, 2856,
2121, 1724 cm−1. 1H NMR (CDCl3, 300 MHz): δ 8.09−8.03 (m, 2H),
7.62−7.53 (m, 1H), 7.48−7.41 (m, 2H), 5.83−5.75 (m, 1H), 3.90 (dt,
J = 7.4, 4.6 Hz, 0.3H), 3.60 (ddd, J = 8.7, 6.8, 4.4 Hz, 0.7H), 3.02−2.80
(m, 1H), 2.70−2.66 (m, 0.6H), 2.53 (m, 1.4H), 2.29−2.18 (m, 1H),
2.14−2.03 (m, 1H), 0.93 (bs, 9H), 0.16 (s, 1.5H), 0.14 (s, 3H), 0.09
(s, 1.5H). 13C NMR (CDCl3, 101 MHz): δ 165.3, 165.2, 133.4, 133.4,
129.9, 129.8, 129.7, 128.6, 128.5, 80.8, 74.8, 74.7, 72.0, 68.6, 62.1, 61.8,
55.7, 54.5, 45.2, 45.0, 40.1, 39.6, 26.0, 25.9, 18.2, −4.2, −4.3, −4.9,
−5.1. HRMS (ESI): m/z calcd for C20H32NO4Si+ [M + NH4]+
378.2095; found 378.2099.
(5R,7S)-5-Ethynyl-2,2,3,3,10,10-hexamethyl-7-(oxiran-2-yl)-
9,9-diphenyl-4,8-dioxa-3,9-disilaundecane (4h). TBDPSCl (0.17
mL, 0.66 mmol) was added dropwise to a solution of 4c (0.085 g, 0.33
mmol) and imidazole (0.050 g, 0.73 mmol) in anhydrous THF (3 mL)
at 0 °C under N2, and the mixture was warmed to 30 °C and stirred
for 48 h. A 22% solution of NH4Cl (5 mL) was added slowly and the
mixture was stirred for 10 min. MTBE (15 mL) and H2O (5 mL) were
added and the mixture was stirred for 10 min and partitioned. The
organic phase was dried (MgSO4), and the solvent was removed. The
resulting oily residue was purified by flash chromatography (silica gel,
hexanes−AcOEt 98:2) to give the title compound (4h) as a colorless
oil (0.130 g, 79%). IR (film): 3309, 3049, 2956, 2930, 2892, 2857
cm−1. 1H NMR (CDCl3, 400 MHz): δ 7.73−7.68 (m, 4H), 7.44−7.32
(m, 6H), 4.70 (ddd, J = 7.6, 6.9, 2.1 Hz, 0.4H), 4.57 (dt, J = 6.8, 2.1
Hz, 0.6H), 3.69−3.57 (m, 1H), 3.11−3.04 (m, 0.6H), 2.90−2.84 (m,
0.4H), 2.67 (dd, J = 4.8, 4.3 Hz, 0.6H), 2.46 (dd, J = 4.9, 2.7 Hz,
0.6H), 2.32−2.28 (m, 0.6H), 2.20 (d, J = 2.1 Hz, 0.4H), 1.99 (m, 1H),
1.91−1.82 (m, 1H), 1.08 (s, 9H), 0.85 (s, 9H), 0.12 (s, 0.6H), 0.09 (s,
2.4H), 0.07 (s, 0.6H), 0.07 (s, 2.4H). 13C NMR (CDCl3, 101 MHz): δ
136.2, 136.1, 136.1, 136.0, 134.0, 133.8, 133.7, 133.4, 130.0, 129.9,
129.8, 129.7, 127.8, 127.7, 127.7, 127.5, 85.1, 84.7, 73.1, 73.0, 72.9,
71.3, 60.1, 60.0, 55.6, 54.5, 46.5, 45.2, 44.6, 43.5, 27.2, 27.1, 25.9, 25.8,
19.6, 19.5, 18.3, 18.2, −4.4, −4.5, −4.9. HRMS (ESI): m/z calcd for
+
C29H46NO3Si2 [M + NH4]+ 512.3011; found 512.3005.
General Procedure for Noncatalytic 5-Exo Cyclization.
Strictly deoxygenated anhydrous THF (76 mL) was added to a
mixture of Cp2TiCl2 (1.711 g, 6.87 mmol) and activated Zn powder
(1.800 g, 27.48 mmol) under N2 and the suspension was stirred at rt
until it turned lime green. This suspension was then added slowly to a
solution of 4b (0.850 g, 2.29 mmol) over 3 h and the mixture was
stirred for 15 h at rt. A 22% solution of NH4Cl (60 mL) was added
slowly and the mixture was stirred for 2 h, filtered and the solvent was
removed. AcOEt (100 mL) was added and the mixture was stirred for
(5R,7S)-5-Ethynyl-2,2,9,9,10,10-hexamethyl-7-(oxiran-2-yl)-
3,3-diphenyl-4,8-dioxa-3,9-disilaundecane (4i). A solution of
TBSCl (0.230 g, 1.53 mmol) in anhydrous THF (2 mL) was added
dropwise to a solution of 4d (0.220 g, 0.58 mmol) and imidazole
(0.110 g, 1.62 mmol) in anhydrous THF (3 mL) at 0 °C under N2,
and the mixture was warmed to 30 °C and stirred for 24 h. A 22%
solution of NH4Cl (5 mL) was added slowly and the mixture was
stirred for 10 min. MTBE (15 mL) and H2O (5 mL) were added and
G
dx.doi.org/10.1021/jo400607v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
10 min. The mixture was partitioned and the aqueous phase was
extracted with AcOEt (2 × 50 mL). The combined organic phases
were dried (MgSO4) and the solvent was removed. The resulting oily
residue was purified by flash chromatography [silica gel, hexanes−
AcOEt, from 95:5 to 80:20 (gradient elution)] to give the title
compound as a pale yellow oil (0.424 g, 50%).
mL, 4.62 mol) was added dropwise to a solution of 5g (1.000 g, 3.33
mmol) and a catalytic amount of DMAP in anhydrous CH2Cl2 (9 mL)
at 0 °C under N2. A solution of p-nitrobenzoyl chloride (0.740 g, 3.99
mmol) in anhydrous CH2Cl2 (4 mL) was added dropwise at 0−5 °C.
The mixture was allowed to warm to rt and was stirred for 2 h.
Saturated NH4Cl (10 mL) was added slowly and the mixture was
stirred for 15 min. The mixture was partitioned and the organic phase
was washed with H2O and dried (Na2SO4). The solvent was removed
and the resulting oily residue was purified by flash chromatography
(silica gel, hexanes−AcOEt 90:10) to give the title compound (5l) as
((1R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-methylene-
cyclopentyl)methanol (5b).12 [α]D −30.4 (c 1.0, CHCl3). IR
25
1
(film): 3460, 3070, 2956, 2930, 2887, 2858 cm−1. H NMR (CDCl3,
400 MHz): δ 5.21 (t, J = 2.3 Hz, 1H), 5.01 (t, J = 2.3 Hz, 1H), 4.33
(ddd, J = 9.3, 4.8, 2.3 Hz, 1H), 4.00 (ddd, J = 10.1, 8.0, 6.2 Hz, 1H),
3.82−3.69 (m, 2H), 2.66−2.59 (m, 1H), 2.24 (dd, J = 11.6, 6.2 Hz,
1H), 1.67−1.61 (m, 1H), 0.92 (s, 9H), 0.89 (s, 9H), 0.10 (s, 3H), 0.09
(s, 6H), 0.08 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 152.1, 108.4,
72.4, 71.0, 63.0, 53.2, 43.9, 26.0, 25.9, 18.4, 18.1, −4.1, −4.4, −4.6,
−4.7. HRMS (ESI): m/z calcd for C19H41O3Si2+ [M + H]+ 373.2589;
found 373.2592.
25
white solid (1.102 g, 74% yield). Mp 83 °C. [α]D −8.6 (c 1.0,
CHCl3). IR (ATR): 2981, 2959, 2944, 2884, 2858, 1730, 1713 cm−1.
1H NMR (CDCl3, 400 MHz): δ 8.31−8.13 (m, 4H), 5.27 (t, J = 2.3
Hz, 1H), 5.13 (t, J = 2.3 Hz, 1H), 5.05 (dt, J = 8.4, 6.6 Hz, 1H), 4.48
(m, 3H), 3.18−3.08 (m, 1H), 2.59−2.44 (m, 1H), 1.99 (s, 3H), 1.79−
1.64 (m, 1H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H). 13C NMR
(CDCl3, 101 MHz): δ 170.9, 164.6, 150.7, 150.5, 135.5, 130.8, 123.7,
110.1, 73.2, 72.5, 66.3, 46.9, 40.5, 25.9, 21.2, 18.3, −4.5, −4.6. HRMS
(ESI): m/z calcd for C22H32NO7Si+ [M + H]+ 450.1943; found
450.1947.
(1S,2R,4R)-4-(tert-Butyldimethylsilyloxy)-2-hydroxymethyl-
3-methylenecyclopentyl acetate (5g).9a [α]D −43.5 (c 1.0,
25
CHCl3). IR (film): 3462, 3083, 2955, 2930, 2887, 2858, 1734 cm−1.
1H NMR (CDCl3, 400 MHz): δ 5.24 (t, J = 2.3 Hz, 1H), 5.1 (t, J = 2.3
Hz, 1H), 4.99 (dt, J = 8.4, 6.4 Hz, 1H), 4.42 (m, 1H), 3.70 (d, J = 5.8
Hz, 2H), 2.84−2.73 (m, 1H), 2.48−2.38 (m, 1H), 2.07 (s, 3H), 1.81−
1.69 (m, 1H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H). 13C NMR
(CDCl3, 101 MHz): δ 171.9, 151.7, 109.0, 73.5, 72.7, 63.7, 51.0, 40.5,
25.9, 21.3, 18.3, −4.5, −4.7. HRMS (ESI): m/z calcd for C15H29O4Si+
[M + H]+ 301.1830; found 301.1816.
((1R,3R,5S)-5-Acetoxy-3-hydroxy-2-methylenecyclopentyl)-
methyl 4-Nitrobenzoate (5m). (+)-Camphorsulfonic acid
((+)-CSA, 0.034 g, 0.15 mmol) was added to a solution of 5l
(0.660 g, 1.47 mmol) in anhydrous MeOH (7 mL) at rt under N2. The
mixture was stirred for 2 h and was then cooled to 0 °C and stirred for
1 h. The pH was adjusted to 6.5 by adding 1% NaHCO3 solution. The
MeOH was removed in vacuo and the aqueous layer was extracted with
MTBE. The organic phase was dried (Na2SO4), the solvent was
removed and the resulting oily residue was purified by flash
chromatography (silica gel, hexanes−AcOEt 60:40) to give the title
((1R,3R,5S)-3-(tert-Butyldimethylsilyloxy)-5-(tert-butyldiphe-
25
nylsilyloxy)-2-methylenecyclopentyl)methanol (5h). [α]D
−18.3 (c 1.0, CHCl3). IR (ATR): 3454, 3070, 2955, 2929, 2888,
2856 cm−1. 1H NMR (CDCl3, 400 MHz): δ 7.73−7.65 (m, 4H),
7.47−7.35 (m, 6H), 5.17 (t, J = 2.3 Hz, 1H), 4.99 (t, J = 2.3 Hz, 1H),
4.18−4.09 (m, 1H), 4.02 (dt, J = 9.5, 6.7 Hz, 1H), 3.60 (dd, J = 11.1,
4.8 Hz, 1H), 3.49 (dd, J = 11.1, 4.5 Hz, 1H), 2.75−2.71 (m, 1H),
2.01−1.92 (m, 1H), 1.63 (dt, J = 11.4, 9.5 Hz, 1H), 1.06 (s, 9H), 0.86
(s, 9H), 0.00 (s, 3H), −0.02 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ
152.4, 136.0, 134.3, 134.0, 131.0, 130.0, 129.9, 128.0, 127.9, 127.8,
126.7, 108.2, 72.4, 71.6, 62.7, 53.6, 43.7, 27.1, 26.0, 19.3, 18.3, −4.5,
25
compound (5m) as a white solid (0.439 g, 89%). Mp 73 °C. [α]D
−32.7 (c 1.0, CHCl3). IR (KBr): 3460, 3109, 3074, 3050, 2990, 2927,
1722 cm−1. 1H NMR (CDCl3, 400 MHz): δ 8.26−8.22 (m, 4H), 5.44
(bs, 1H), 5.25 (d, J = 1.5 Hz, 1H), 5.17 (q, J = 5.5 Hz, 1H), 4.56−4.54
(m, 1H), 4.52−4.43 (m, 1H), 4.42−4.30 (m, 1H), 3.21−3.18 (m, 1H),
2.53−2.49 (m, 1H), 2.02 (s, 3H), 1.85 (dt, J = 12.4, 5.5 Hz, 1H). 13C
NMR (CDCl3, 101 MHz): δ 170.6, 164.6, 151.3, 150.8, 135.4, 130.8,
123.8, 112.3, 74.8, 73.2, 65.9, 47.9, 40.1, 21.3. HRMS (ESI): m/z calcd
+
−4.7. HRMS (ESI): m/z calcd for C29H48NO3Si2 [M + NH4]+
+
for C16H21N2O7 [M + NH4]+ 353.1343; found 353.1328.
514.3167; found 514.3165.
((1R,3S,5S)-5-Acetoxy-3-(2-amino-6-chloro-9H-purin-9-yl)-2-
methylenecyclopentyl)methyl 4-Nitrobenzoate (13). A mixture
of 2-amino-6-chloropurine (7.380 g, 43.54 mmol) and triphenylphos-
phine (11.400 g, 43.54 mmol) in anhydrous THF (927 mL) at rt
under N2 was stirred for 15 min. After cooling to −10 °C, diisopropyl
azodicarboxylate (DIAD, 8.60 mL, 43.54 mmol) was added dropwise
and the mixture was stirred for 10 min. A solution of 5m (7.300 g,
21.77 mmol) in anhydrous THF (160 mL) was added over 1 h. The
mixture was stirred for 3 h at −10 °C and was then allowed to warm to
rt, filtered and the residue was washed with THF (109 mL). The
solvent was removed and the resulting oily residue was purified by
crystallization from isopropanol (440 mL) to afford the title
compound as a pale yellow solid (6.510 g, 61%). Mp 113 °C.
(1R,3R,4S)-4-(tert-Butyldimethylsilyloxy)-3-hydroxymethyl-
25
2-methylenecyclopentyl Benzoate (5k). [α]D −26.4 (c 1.0,
CHCl3). IR (ATR): 3503, 3064, 2954, 2929, 2885, 2856, 1718 cm−1.
1H NMR (CDCl3, 400 MHz): δ 8.10−8.04 (m, 2H), 7.61−7.53 (m,
1H), 7.49−7.40 (m, 2H), 5.66−5.61 (m, 1H), 5.37 (t, J = 2.4 Hz, 1H),
5.19 (t, J = 2.4 Hz, 1H), 4.19−4.10 (m, 1H), 3.86−3.80 (m, 2H),
2.81−2.71 (m, 1H), 2.64−2.55 (m, 1H), 1.83 (dt, J = 12.7, 8.4 Hz,
1H), 0.90 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H). 13C NMR (CDCl3, 101
MHz): δ 166.5, 147.7, 133.1, 130.3, 129.8, 128.5, 112.0, 74.2, 72.2,
62.5, 53.5, 40.5, 25.9, 18.0, −4.3, −4.8. HRMS (ESI): m/z calcd for
C20H31O4Si+ [M + H]+ 363.1986; found 363.1988.
Catalytic 5-Exo Cyclization of 4g. Strictly deoxygenated
anhydrous THF (15 mL) was added to a mixture of IrCl(CO)(PPh3)2
(0.260 g, 0.34 mmol) and manganese powder (0.368 g, 6.70 mmol). A
solution of 2,4,6-collidine (3.5 mL, 26.8 mmol) and 4g (1.000 g, 3.35
mmol) in strictly deoxygenated anhydrous THF (22 mL) was added at
rt. TMSCl (1.7 mL, 13.4 mmol) was added followed by a solution of
Cp2TiCl2 (0.167 g, 0.67 mmol) in strictly deoxygenated anhydrous
THF (12 mL) and the mixture was stirred for 4 h under H2 (4 bar) at
rt. Water (5 mL) was added and the mixture was stirred for 10 min
and filtered through Celite. The pad was washed with MTBE (20 mL)
and the organic phases were combined and acidified to pH = 2 with 2
M HCl. The mixture was stirred for 15 min and the phases were
separated. The organic phase was washed with H2O (20 mL) and
dried (Na2SO4). The solvent was removed and the resulting oily
residue was purified by flash chromatography [silica gel, hexanes−
AcOEt, from 90:10 to 60:40 (gradient elution)] to give the title
compound (5g) as a pale yellow oil (0.582 g, 58%).
25
[α]D +9.8 (c 1.0, CHCl3). IR (KBr): 3498, 3382, 3213, 3082, 2970,
1
1728, 1715 cm−1. H NMR (CDCl3, 400 MHz): δ 8.28 (dd, J = 20.6,
8.9 Hz, 4H), 7.80 (s, 1H), 5.58−5.40 (m, 2H), 5.35−5.30 (m, 1H),
4.91 (bs, 1H), 4.85 (dd, J = 11.4, 9.3 Hz, 1H), 4.62 (dd, J = 11.4, 6.3
Hz, 1H), 3.28−3.24 (m, 1H), 2.85 (ddd, J = 14.3, 10.6, 5.2 Hz, 1H),
2.42 (dd, J = 14.3, 8.1 Hz, 1H), 2.08 (s, 3H). 13C NMR (CDCl3, 101
MHz): δ 170.3, 165.0, 158.9, 153.1, 151.8, 150.8, 146.2, 141.9, 135.2,
130.9, 125.9, 123.8, 113.6, 74.6, 65.9, 57.4, 48.7, 35.5, 21.3. HRMS
+
(ESI): m/z calcd for C21H20ClN6O6 [M + H]+ 487.1127; found
487.1132.
((1R,3S,5S)-5-Acetoxy-3-(2-amino-6-oxo-1H-purin-9(6H)-yl)-
2-methylenecyclopentyl)methyl 4-Nitrobenzoate (14). A sol-
ution of 13 (6.300 g, 12.94 mmol) in formic acid 80% (126 mL) at 50
°C under N2 was stirred for 9 h. The solvent was removed, H2O (72
mL) was added and the suspension was stirred for 18 h at rt. The
suspension was filtered and the solid was dried to afford the title
25
compound (14) as a yellow solid (5.590 g, 92%). Mp 282 °C. [α]D
((1R,3R,5S)-5-Acetoxy-3-(tert-butyldimethylsilyloxy)-2-
methylenecyclopentyl)methyl 4-Nitrobenzoate (5l). NEt3 (0.65
+2.9 (c 1.0, DMSO). IR (KBr): 3408, 3315, 3210, 3110, 2934, 2868,
H
dx.doi.org/10.1021/jo400607v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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1728, 1706 cm−1. 1H NMR (DMSO-d6, 400 MHz) δ: 11.08 (bs, 1H),
8.37 (d, J = 8.8 Hz, 2H), 8.24 (d, J = 8.8 Hz, 2H), 7.74 (s, 1H), 6.66
(bs, 2H), 5.42−5.35 (m, 1H), 5.35−5.31 (m, 1H), 5.27 (bs, 1H), 4.67
(bs, 1H), 4.59−4.55 (m, 2H), 3.17−3.10 (m, 1H), 2.70 (ddd, J = 13.6,
11.3, 5.3 Hz, 1H), 2.34−2.25 (m, 1H), 2.01 (s, 3H). 13C NMR
(DMSO-d6, 101 MHz) δ: 169.9, 164.3, 156.8, 153.5, 151.2, 150.3,
147.8, 136.1, 135.1, 130.7, 123.9, 116.5, 111.2, 74.1, 65.6, 55.2, 47.8,
Seifer, M.; Bisacchi, G. S.; Standring, D. N.; Zahler, R.; Colonno, R. J.
Antimicrob. Agents Chemother. 1997, 41, 1444−1448.
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+
35.2, 21.0. HRMS (ESI): m/z calcd for C21H21N6O7 [M + H]+
469.1466; found 469.1461.
2-Amino-9-((1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-
methylenecyclopentyl)-1H-purin-6(9H)-one Monohydrate (1).
A solution of MeONa (30%, 4.10 mL, 22.20 mmol) was added
dropwise to a solution of 14 (5.200 g, 11.10 mmol) in anhydrous
MeOH (40 mL) at rt under N2. The mixture was stirred for 30 min at
rt and cooled to 0 °C. MTBE (52 mL) was added and the mixture was
neutralized (pH = 7) with HCl. The phases were separated and the
aqueous layer was extracted with MTBE (50 mL). The volume of the
aqueous phase was reduced to 45 mL by distillation. The suspension
was heated at 85 °C and was slowly cooled to rt and stirred for 15 h.
After filtration the isolated solid was dried under vacuum to afford the
title compound (1) as a white solid with a 6.5% water content (as
determined by Karl Fischer titration) and 98.8% HPLC purity (2.370
g, 72% yield). This white solid 15a was recrystallized from water to
afford 1 (2.102 g, 64% overall yield, 99.47% HPLC purity) with a 6.7%
water content (as determined by Karl Fischer titration). Mp 248 °C.
25
[α]D +35.0 (c 0.4, H2O). IR (ATR): 3445, 3361, 3296, 3175, 3113,
1
2951, 2858, 2626, 1709 cm−1. H NMR (DMSO-d6, 400 MHz) δ:
10.59 (s, 1H), 7.66 (s, 1H), 6.42 (bs, 2H), 5.36 (ddt, J = 10.6, 7.8, 2.7
Hz, 1H), 5.10 (dd, J = 2.7, 2.2 Hz, 1H), 4.87 (d, J = 3.1 Hz, 1H), 4.84
(t, J = 5.3 Hz, 1H), 4.56 (t, J = 2.4 Hz, 1H), 4.23 (m, 1H), 3.53 (m,
2H), 2.52 (m, 1H), 2.22 (ddd, J = 12.6, 10.8, 4.6 Hz, 1H), 2.04 (ddt, J
= 12.6, 7.7, 1.9 Hz, 1H). 13C NMR (DMSO-d6, 101 MHz) δ: 156.9,
153.5, 151.5, 151.3, 136.0, 116.2, 109.3, 70.4, 63.1, 55.2, 54.1, 39.2.
HRMS (ESI): m/z calcd for C12H16N5O3+ [M + H]+ 278.1253; found
278.1262.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of 1, 3a-e, 4b−k, 5b, 5g−h, 5k−m, 6,
7a−f, 13 and 14. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel.: +34 934021248. Fax: +34 933397878. E-mail: jfarras@
ub.edu, xariza@ub.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Spanish Ministerio de
■
Educacion
1005-900000).
́
y Ciencia (Grants PET2008-0209 and IPT-2011-
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