Synthesis of neplanocin A and its 3′-epimer via an intramolecular Baylis-Hillman reaction

Article abstract of DOI:10.1021/jo501248e

The key cyclopentenyl intermediate 11b was synthesized in 4 steps from d-ribose in 41% overall yield via an efficient intramolecular Baylis-Hillman reaction. This novel key intermediate can be modified easily and transformed to neplanocin A (1a) and its 3

Full text of DOI:10.1021/jo501248e

Article
pubs.acs.org/joc
Synthesis of Neplanocin A and Its 3′-Epimer via an Intramolecular
Baylis−Hillman Reaction
†
†
†
,†,‡
Yun Xuan Tan, Sridhar Santhanakrishnan, Hai Yan Yang, Christina L. L. Chai,*
,
†
and Eric Kwok Wai Tam*
†Institute of Chemical & Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 8 Biomedical Grove,
Neuros#07-01, Singapore 13866
‡
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543
*
S Supporting Information
ABSTRACT: The key cyclopentenyl intermediate 11b was synthesized in 4 steps from D-ribose in 41% overall yield via an
efficient intramolecular Baylis−Hillman reaction. This novel key intermediate can be modified easily and transformed to
neplanocin A (1a) and its 3′-epimer (1b).
INTRODUCTION
the appropriately functionalized five-membered carbocycle with
a purine or pyrimidine heterocycle. Not surprisingly, much
effort has been invested in the efficient synthesis of these
functionalized cyclopentenes from sugars: for example, through
■
Carbocyclic nucleosides are nucleoside analogues that have
attracted the interest of medicinal chemists due to their
potential applications as antivirals and anticancer agents.
Their structural similarity to conventional nucleosides suggest
that they are likely to bind and inhibit the same protein targets,
and the lack of a glycosidic linkage confers on them an
1
2
6
7
ring-closing metathesis, an intramolecular Wittig reaction, the
8
Ramberg−Backlund reaction, or C−H insertion of a
̈
9
methylidene carbene. Despite these efforts, the preparation
3
of enantiopure functionalized carbocycles is tedious, necessitat-
increased stability toward enzymatic degradation. Five-
10
ing long reaction sequences. To date, there have been several
reports on the total synthesis of neplanocin A. Of note, the
membered-ring carbocyclic nucleosides are found in both
natural and synthetic compounds and have gained much
interest due to their potent biological properties. The natural
products neplanocin A (1a) and aristeromycin (2) (Figure 1)
are potent antivirals, while synthetic derivatives such as
deazaneplanocin A (3) have recently been shown to be global
histone methyl transferase inhibitors. The majority of
carbocyclic nucleosides have been synthesized via coupling of
4q
report by Michel and Strazewski gives the highest published
overall yield to date. The key step is an improvement in the
Mitsunobu coupling of the carbocyclic core with N6-bis-BOC-
adenine. The carbocyclic core was obtained using a ring-closing
metathesis reaction which in turn utilized Neolyst dichloride as
catalyst. In this paper, we report an expedient route to a densely
functionalized cyclopentenol using an intramolecular Baylis−
4
5
1
1,12
Hillman (BH) reaction
as the key step in the formation of
the cyclopentene ring. This approach is atom economical and
simultaneously installs the desired stereocenters in a single step.
The utility of the methodology is demonstrated in the formal
synthesis of neplanocin A and synthesis of its 3′-epimer 1b.
RESULTS AND DISCUSSION
■
The retrosynthetic analysis of neplanocin A and its 3′-isomer is
summarized in Scheme 1. Neplanocin A (1a) and its 3′-epimer
Figure 1. Structures of carbocyclic nucleosides: aristeromycin, 3-
deazaneplanocin A, and neplanocin A and its 3′-epimer.
Received: June 4, 2014
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/jo501248e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Retrosynthetic Analysis of Neplanocin A and Its 3′-Epimer
1
b can be accessed from the key intermediate cyclopentenol 4
the former protocol, and no reaction ensued despite increasing
the catalyst loading to stoichiometric amounts (Table 1, entries
2 and 3). With the latter protocol, the expected BH products
11a,b were obtained, but in poor yields (total of 12%), along
with 18% of the side product 12 (Table 1, entry 1), which was
through coupling reactions with adenine 5. Cyclopentenol 4
can in turn be derived from the Baylis−Hillman adduct 6
through functional group manipulation. We intend to effect an
intramolecular BH reaction from the precursor 7, which will be
derived from readily available D-ribose.
1
2j,18
formed by a competing oxa-Michael reaction.
Other
The synthesis of (Z)-enoate 7 was completed in 3 steps from
promoters were explored in attempts to improve the yields of
the desired BH adducts. However, treatment of 7 with tertiary
amines such as DABCO and DBU (Table 1, entries 4 and 5) in
chloroform gave the oxa-Michael adducts 12 as the only major
product. Secondary amines and phosphines (piperidine,
pyrrolidine, and tributylphosphine) were also screened but
did not result in any reaction, and so the DMAP/DMAP·HCl
combination remains the best (Table 1).
D-ribose in 57% overall yield following the procedure reported
by the Argyropoulos group. Interestingly, as noted by the
authors, the Z stereoisomer was obtained. This is in contrast
13
14
with the report by Wightman et al., where the E isomer was
reported as the major product. However, closer examination of
the data reported by Wightman (J values of 12 Hz for the
olefinic protons) suggests that the Z isomer was also obtained
in their studies. The synthesis of the E isomer 10 was achieved
by refluxing alkene 9 with ethyl acrylate in DCM in the
presence of 20 mol % of Hoveyda−Grubbs second-generation
catalyst to give 10 as a single cross-coupling isomer in 46%
We therefore shifted our attention into studying the effect of
different solvents on the BH reaction with the DMAP and
DMAP·HCl promoter system. Several solvents were screened
15
(
Table 2), and significantly improved results were obtained
1
6
yield. The coupling constants for the vicinal alkene protons of
and 10 were found to be J = 11.5 and 15.6 Hz, respectively
when polar aprotic solvents such as DMSO, MeCN, and DMF
were used (Table 2, entries 5−7). These solvents gave the
desired products 11a,b in moderate to good yields without the
formation of 12, with DMF as solvent giving the best
diastereoselectivity of 11a:11b (5:1). The diastereoselectivity
of the reaction was further improved to 9:1 when the (Z)-
enoate 7 was added dropwise to the mixture of DMAP/DMAP·
HCl at 0 °C (Table 2, entry 8). The stereochemistry of 11a was
consistent with the measured coupling constant of 1.5 Hz
between H-2 and H-3, while a larger coupling constant (5.8
Hz) was observed for 11b. Next, we shifted our attention to the
development of a catalytic version of the BH reaction. After
extensive studies, we found that heating of (Z)-enoate 7 at 60
7
2
,3
1
3,17
(Scheme 2).
a
Scheme 2. Routes to the (E)- and (Z)-Alkenes
°
5
C in DMF for 18 h in the presence of 20 mol % of DMAP and
mol % of DMAP·HCl was the most optimal condition in
terms of yield and diastereoselectivity. This gave 65% and 6% of
isomers 11a,b, respectively, on gram-scale synthesis. Intrigu-
ingly, even under these optimized conditions the BH reaction
of the corresponding E isomer 10 only led to the formation of
numerous unidentified products.
a
Reagents and conditions: (a) concentrated H SO , acetone, room
2
4
temperature, 3 h, 95%; (b) (i) ethyl 2-(triphenylphosphoranylidene)-
acetate, cat. PhCO H, DCM, room temperature, 16 h, (ii) NaIO ,
2
4
With the key intermediate cyclopentenol 11a in hand, the
synthesis of neplanocin A (1a) and its epimer 1b can be
demonstrated. For the synthesis of neplanocin A, inversion of
the stereochemistry of the hydroxyl group at C-3′ is needed.
Treatment of 11a under Mitsunobu conditions using
diisopropyl azodicarboxylate (DIAD) and triphenylphosphine
at 0 °C in the presence of benzoic acid gave benzoate 13
(instead of the expected Mitsunobu product 14) in 64% yield
DCM/H O, room temperature, 1 h, 60% for two steps; (c) ref 15; (d)
ethyl acrylate, 20 mol % Hoveyda−Grubbs II catalyst, DCM, reflux, 8
h, 46%.
2
With the two enoates 7 and 10 in hand, the key
intramolecular BH reaction was attempted. Two protocols
12j
had previously been developed by Keck et al.: one used
catalytic amounts of trimethylphosphine in dichloromethane
19
(
Morita-BH reaction), while another utilized 1 equiv of DMAP
(Scheme 3). This suggests that a S 2′ attack is the dominant
N
and 0.25 equiv of DMAP·HCl as promoters in refluxing
ethanol. Our initial experiments were carried out with 7 using
reaction pathway under these reaction conditions for this
substrate.
B
dx.doi.org/10.1021/jo501248e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 1. Screening of Promoters for the Baylis−Hillman Reaction
a
entry
promoter
solvent
temp, time (h)
result
b
1
2
3
4
5
6
7
8
DMAP (1 equiv), DMAP·HCl (0.25 equiv)
PMe3
EtOH
DCM
reflux, 24
11a:11b:12 (7%:5%:18%)
recovery of 7
room temp, 24
room temp, 24
room temp, 24
room temp, 24
room temp, 24
room temp, 24
room temp, 24
PMe (1 equiv)
DCM
recovery of 7
3
c
DABCO
DBU
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
12
c
12
piperidine
pyrrolidine
n-Bu3P
recovery of 7
recovery of 7
recovery of 7
a
b
c
Unless indicated otherwise, 0.2 equiv of promoter was used and the substrate concentration was 0.1 M. Based on isolated yield. Yield not
determined.
Table 2. Study of Solvent Effects on the Baylis−Hillman Reaction
a
b
entry
solvent
conditions
yield (%) 11a:11b:12
1
2
3
4
5
6
7
8
EtOH
DCM
CHCl3
THF
A
B
B
B
B
B
B
C
7:5:18
30:20:17
12:18:20
recovery of 7
50:16:0
54:20:0
58:12:0
68:8:0
DMSO
MeCN
DMF
DMF
a
1
equiv of DMAP and 0.25 equiv of DMAP·HCl were used as promoters, and the substrate concentration was 0.1 M. Conditions: (A) reflux, 24 h;
b
(
B) room temperature, 48 h; (C) addition at 0 °C and then room temperature for 48 h. Based on isolated yield.
a
Scheme 3. S 2′ Reaction of 11a under Mitsunobu Conditions
N
a
Reagents and conditions: (a) BzOH, DIAD, PPh , THF, room temperature, 18 h, 64%.
3
An alternative strategy to invert the chiral center at the C-3′
position involved the oxidation of the allylic alcohol 11a to the
enone followed by stereoselective reduction to the secondary
alcohol. Although oxidation of 11a with Dess−Martin period-
inane (DMP) followed by Luche reduction gave an excellent
yield of the desired alcohol, no stereoselectivity was observed
without further purification (Scheme 5). Selective silylation of
the primary alcohol yielded 16, and subsequent DMP oxidation
of the free secondary alcohol furnished the enone 17. To our
delight, Luche reduction of 17 gave 18 as the only stereoisomer
with an excellent yield of 97%. This was followed by acetonide
4p
shuffling to yield cyclopentenol 19 in 97% yield based on
starting material recovery (bsmr) with 50% conversion. This
constitutes the formal synthesis of neplanocin A 1a, as
(Scheme 4). In contrast, we found that high selectivities and
yields of the Luche reduction can be achieved when enone 17
2
0
was utilized instead. In this route, DIBAL-H reduction of 11a
at −78 °C gave the diol 15 in 60% yield, which was used
4q
neplanocin A can be accessed from 19 in two additional steps.
C
dx.doi.org/10.1021/jo501248e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
without further purification. All reactions requiring anhydrous
conditions were carried out under an argon atmosphere using oven-
dried glassware. Reaction progress was monitored by TLC plates
Scheme 4. Inversion of the Chiral Center at the C-3′
a
Position
(
silica gel 60F254), and spots were visualized by UV or
phosphomolybdic acid stain. Flash column chromatography was
carried out using silica gel 60 (70−230 mesh). NMR spectra were
recorded on a 400 MHz spectrometer using standard pulse sequences.
1
13
H and C NMR chemical shifts are reported on the δ scale (ppm)
relative to residual nondeuterated solvent as the internal standard.
HRMS were recorded by a TOF-MS spectrometer.
(
3aR,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyltetrahydro-
furo[3,4-d][1,3]dioxol-4-ol (8). To a stirred suspension of D-ribose
20.0 g, 0.13 mol) in acetone (250 mL) was added dropwise
concentrated H SO (0.6 mL, 11.2 mmol) at room temperature. The
a
Reagents and conditions: (a) DMP, room temperature, 18 h; (b)
(
NaBH , CeCl ·7H O, DCM, 0 °C, 2 h, 98% in two steps.
4
3
2
2
4
suspension was stirred for 3 h at room temperature until a clear
solution was obtained. The solution was then treated with NaHCO3
The synthesis of the 3′-epimer of neplanocin A (Scheme 6),
the xylo analogue of 1b, commenced with the DIBAL-H
reduction of 11a followed by benzoylation to give the
dibenzoylated 20 in 73% yield over two steps. Deprotection
of the acetal group of 20 under acidic conditions gave the diol
(10.0 g, 120 mmol) and was stirred for an additional 1 h. The reaction
mixture was filtered and concentrated in vacuo. The residue was
absorbed onto silica gel and filtered through a pad of silica gel (with
5
0/50 to 100/0 EtOAc/hexanes as eluent) to give 1 in 95% yield as a
2
1 in 70% yield. Subsequent silylation with 1.1 equiv of tert-
colorless syrup. The spectroscopic data obtained are identical with
15
butyldiphenylchlorosilane (TBDPSCl) gave monosilylated
products 22a,b (3:2) in 85% combined yield along with a
small amount of the disilylated product. The structure of 22b
was confirmed by X-ray analysis (see the Supporting
Information, Figure S1), which unambiguously validated the
suitability of our synthetic approach to construct xylo
carbocyclic nucleosides. The alcohol 22b was then subjected
those previously reported: R = 0.39 (80/20 EtOAc/hexanes).
f
(Z)-Ethyl 3-((4S,5S)-5-Formyl-2,2-dimethyl-1,3-dioxolan-4-
yl)acrylate (7). To a solution of 8 (8.00 g, 42.1 mmol) in DCM
(250 mL) was added the ylide ethyl 2-(triphenylphosphoranylidene)-
acetate (19.0 g, 54.5 mmol) at room temperature. This was followed
by the addition of benzoic acid as catalyst (250 mg, 2.0 mmol). The
reaction mixture was stirred for 16 h, following which it was cooled to
0
°C. Aqueous NaIO (11.0 g, 51.2 mmol, 100 mL of water) was
4
21
to a Mitsunobu coupling reaction with N6-bis-BOC-adenine
added, and the reaction mixture was stirred for a further 1 h at room
temperature, before it was filtered through a pad of Celite. The filtrate
was extracted with DCM and washed with water. The combined
organic layers were dried, filtered, and concentrated in vacuo. The bulk
of the triphenylphosphine oxide was removed by washing with diethyl
ether and filtered. The filtrate was concentrated in vacuo, and purified
by silica gel column chromatography (with 3/97 to 10/90 EtOAc/
to afford the coupling product 23 in 57% yield. Without further
optimization, treatment of 23 with sodium methoxide followed
by global deprotection in the presence of 2 N HCl afforded the
xylo analogue 1b as a hydrochloride salt in 51% yield. To our
knowledge, this is the first reported synthesis of the 3′-epimer
of neplanocin A.
hexanes as eluent) to give 7 in 60% yield as a colorless oil: R = 0.52
f
4.9
1
(
40/60 EtOAc/hexanes); [α]2
= +116.0° (c = 1.0, CHCl ); H
D 3
CONCLUSION
■
NMR (400 MHz, CDCl ) δ 9.47 (d, J = 2.8 Hz, 1H), 6.22 (dd, J =
3
In summary, a stereoselective formal total synthesis of
neplanocin A was achieved in 11 steps with 17% overall yield
while the hitherto unknown xylo analogue 1b was synthesized
for the first time in 11 steps. We have presented here a simple
and practical method for the construction of an enantiopure
cyclopentenol ring in gram scale from the readily available D-
ribose via a catalytic Baylis−Hillman reaction. This cyclo-
pentenol ring should provide a good starting point to access
many novel carbocyclic nucleosides.
1
1.6, 6.8 Hz, 1H), 5.96 (dd, J = 11.6, 1.8 Hz, 1H), 5.81 (ddd, J = 7.8,
6.9, 1.8 Hz, 1H), 4.79 (dd, J = 7.8, 2.8 Hz, 1H), 4.19 (qd, J = 7.2, 1.8
1
3
Hz, 2H), 1.60 (s, 3H), 1.43 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H);
NMR (101 MHz, CDCl ) δ 199.5, 165.6, 143.6, 123.3, 111.6, 82.1,
5.9, 61.0, 27.4, 25.3, 14.3; FTIR (cm ) 3455, 1716, 1649; HRMS
C
3
−1
7
+
(ESI; m/z) [M + H] calcd for C H O 229.1076, found 229.1068.
11 17 5
(
E)-Ethyl 3-((4S,5S)-5-Formyl-2,2-dimethyl-1,3-dioxolan-4-
yl)acrylate (10). To a solution of 9 (400 mg, 2.6 mmol) in
anhydrous DCM (50 mL) was added ethyl acrylate (2.8 mL, 26.0
mmol) in one portion under an argon atmosphere. The stirred mixture
was heated to reflux before the Hoveyda−Grubbs II catalyst (80 mg,
EXPERIMENTAL SECTION
0
.13 mmol) was added in a single portion. The reaction mixture was
■
General Methods. All chemicals were used as received from
commercial sources. Dried solvents (MeCN, DCM, DMF, THF,
diethyl ether, and toluene) were drawn from a Glass Contour Solvent
Dispensing System. Anhydrous DMSO was purchased and used
refluxed for 8 h, following which it was cooled to room temperature,
concentrated in vacuo, and purified by silica gel column chromatog-
raphy (with 0/100 to 30/70 EtOAc/hexanes as eluent) to give 10 in
46% yield (270 mg, 1.2 mmol) as a colorless oil: R = 0.21 (40/60
f
a
Scheme 5. Formal Synthesis of Neplanocin A 1a from 11a
a
Reagents and conditions: (a) DIBAL-H, DCM, −78 °C to room temperature, 3 h, 60%; (b) TBDPSCl, imidazole, cat. DMF, DCM, 0 °C, 4 h, 85%;
c) DMP, room temperature, 18 h, 98%; (d) NaBH , CeCl ·7H O, DCM, 0 °C, 2 h, 97%; (e) cat. p-TsOH, acetone, room temperature, 18 h, 97%
(
(
4
3
2
bsmr); (f) ref 4q, two steps to 1a.
D
dx.doi.org/10.1021/jo501248e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 6. Synthesis of 3′-epi Neplanocin A (1b)
a
Reagents and conditions: (a) (i) DIBAL-H, DCM, −78 °C to room temperature, 3 h, (ii) BzCl, Et N, 18 h, 73% for two steps; (b) 2 N HCl, THF,
3
6
5 °C, 16 h, 70%; (c) TBDPSCl, imidazole, 0 °C, DCM, 5 h, 85%; (d) N6-bis-BOC-adenine, DIAD, PPh , toluene, room temperature, 16 h, 57%;
3
(
e) NaOMe, MeOH, room temperature, 14 h, 78%; (f) 2 N HCl, MeOH, room temperature, 48 h, 65%.
EtOAc/hexanes); [α]22.6 = +12.3° (c 1.0, CHCl ); H NMR (400
1
(s, 3H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl ) δ
D
3
3
MHz, CDCl ) δ 9.51 (d, J = 3.0 Hz, 1H), 6.81 (dd, J = 15.6, 5.2 Hz,
164.6, 143.0, 138.7, 112.1, 85.1, 83.1, 79.2, 61.3, 27.4, 25.6, 14.3; FTIR
3
−1
+
1
1
3
H), 6.14 (dd, J = 15.6, 1.7 Hz, 1H), 4.98 (ddd, J = 7.6, 5.2, 1.7 Hz,
H), 4.50 (dd, J = 7.7, 3.0 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 1.62 (s,
H), 1.44 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
(cm ) 3431, 1717; HRMS (ESI; m/z) [M + Na] calcd for
C H O Na 251.0890, found 251.0905. Anal. Calcd for C H O : C,
11
16
5
11 16
5
57.88; H, 7.07; O, 35.05. Found: C, 57.47; H, 7.10; O, 35.34.
CDCl ) δ 200.3, 165.5, 139.8, 124.0, 112.1, 82.1, 76.8, 60.9, 27.4, 25.4,
(3aR,4R,6aS)-Ethyl 4-hydroxy-2,2-dimethyl-4,6a-dihydro-3aH-
cyclopenta[d][1,3]dioxole-5-carboxylate (11b): Waters Preparative
LC-MS: initial A 20% acetonitrile and B 80% water, final A 60% and B
40%, gradient 30 min, flow rate 20 mL/min, UV@254 nm, column
Phenomenex Luna C18, 10 μm, 250 × 21.20 mm, product retention
3
−1
+
1
4.3; FTIR (cm ) 3443, 1719, 1659; HRMS (ESI; m/z) [M + Na]
calcd for C H O Na 251.0890, found 251.0887.
11
16
5
General Procedure for Study of Solvent Effects on the
Baylis−Hillman Reaction (Table 2). Methods A and B. To a stirred
solution of compound 7 (114 mg, 0.5 mmol) in 5.0 mL of solvent
were added 4-(dimethylamino)pyridine (60 mg, 0.5 mmol) and 4-
2
1.8
time 9.5 min; R = 0.39 (80/20 diethyl ether/hexanes); [α]
=
f
D
1
+35.2° (c = 0.36, CHCl ); H NMR (400 MHz, CDCl ) δ 6.68 (s,
3
3
(
dimethylamino)pyridine hydrochloride (20 mg, 0.125 mmol) at room
1H), 5.04 (dd, J = 5.6, 2.0 Hz, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.79 (d, J
= 6.4 Hz, 1H), 4.26 (m, 2H), 1.45 (s, 3H), 1.41 (s, 3H), 1.32 (t, J =
temperature. The reaction mixture was heated at 78 °C for 24 h for
method A or stirred at room temperature for 48 h for method B. The
reaction mixture was concentrated in vacuo and purified by silica gel
column chromatography.
7.2 Hz, 3H); 13C NMR (101 MHz, CDCl ) δ 164.3, 140.1, 139.8,
3
−1
113.1, 81.5, 77.8, 72.5, 61.1, 27.6, 26.4, 14.3; FTIR (cm ) 3496, 1720;
HRMS (ESI; m/z) [M + Na] calcd for C H O Na 251.0890, found
+
11
16
5
Method C. A solution of 4-(dimethylamino)pyridine (60 mg, 0.5
mmol) and 4-(dimethylamino)pyridine hydrochloride (20 mg, 0.125
mmol) in DMF (1.0 mL) was added to a solution of compound 7
251.0903.
Ethyl (3aR,4R,6aR)-4-(Benzoyloxy)-2,2-dimethyl-3a,6a-dihy-
dro-4H-cyclopenta[d][1,3]dioxole-5-carboxylate (13). To a
solution of 11a (456 mg, 2 mmol), benzoic acid (366 mg, 3 mmol),
(
114 mg, 0.5 mmol) in DMF (4 mL) at 0 °C. The mixture was
warmed to room temperature and stirred for 48 h. The reaction
mixture was concentrated in vacuo and purified by silica gel column
chromatography.
and Ph P (1.05 g, 4 mmol) in 30 mL of anhydrous THF was added
3
DIAD (0.8 mL, 4 mmol) at 0 °C under an argon atmosphere, and the
mixture was stirred for 18 h at room temperature. The reaction
mixture was adsorbed onto silica gel and then purified by silica gel
column chromatography (2/98 to 10/90 EtOAc/hexanes) to give the
Catalytic Baylis−Hillman Reaction. The catalysts 4-
dimethylamino)pyridine (0.37 g, 3.08 mmol) and 4-
dimethylamino)pyridine hydrochloride (120 mg, 0.77 mmol) were
(
(
corresponding coupled compound in 64% yield as a white amorphous
1
dissolved in anhydrous DMF (20 mL) at room temperature. To this
solution was added compound 7 (3.50 g, 15.4 mmol) in anhydrous
DMF (180 mL). The reaction mixture was heated at 60 °C for 18 h.
The reaction mixture was concentrated in vacuo and purified by silica
gel column chromatography (with 10/90 to 30/70 EtOAc/hexanes as
eluent) to give the titled compound 11a in 65% yield (2.28 g) as a
colorless oil and 11b in 6% yield (218 mg) as a colorless oil.
solid: H NMR (400 MHz, CDCl
3
) δ 8.06−7.95 (m, 2H), 7.61−7.51
(m, 1H), 7.49−7.38 (m, 2H), 7.01 (s, 1H), 6.15 (s, 1H), 5.39 (d, J =
5.5 Hz, 1H), 4.70 (d, J = 5.5 Hz, 1H), 4.30−4.10 (m, 2H), 1.45 (s,
3H), 1.36 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl ) δ 165.9, 163.3, 146.5, 135.8, 133.3, 129.9, 128.5, 112.8, 83.9,
3
−
1
83.2, 80.8, 61.2, 27.4, 25.8, 14.2; FTIR (cm ) 2986, 2937, 2360, 2341,
1723; HRMS (ESI; m/z) [M + Na] calcd for C H O Na 355.1152,
+
18
20
6
(
3aR,4S,6aS)-Ethyl 4-hydroxy-2,2-dimethyl-4,6a-dihydro-3aH-
found 355.1161.
cyclopenta[d][1,3]dioxole-5-carboxylate (11a): Waters Preparative
LC-MS initial A 20% acetonitrile, and B 80% water, final A 60% and B
4
(3aR,4S,6aS)-5-(Hydroxymethyl)-2,2-dimethyl-4,6a-dihydro-
3aH-cyclopenta[d][1,3]dioxol-4-ol (15). To a solution of 11a (1.00
g, 4.4 mmol) in DCM (50 mL) was added dropwise a solution of
DIBAL-H (1.0 M solution in hexanes) (17.6 mL, 17.6 mmol) at −78
°C. The reaction mixture was then warmed to room temperature and
stirred for 3 h. The reaction was quenched by addition of Celite (1 g)
0%, gradient 30 min, flow rate 20 mL/min, UV@254 nm, column
Phenomenex Luna C18, 10 μm, 250 × 21.20 mm, product retention
time 11.45 min; R = 0.45 (80/20 diethyl ether/hexanes); [α]
57.3° (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 6.76 (d, J =
.6 Hz, 1H), 5.32 (dt, J = 5.6, 1.6 Hz, 1H), 4.96 (d, J = 1.6 Hz, 1H),
.62 (d, J = 5.6 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 1.39 (s, 3H), 1.35
22.5
=
D
f
1
+
1
4
3
3
followed by dropwise addition of 5 mL saturated NH Cl solution at 0
°C. The mixture was then filtered through a pad of Celite and washed
4
E
dx.doi.org/10.1021/jo501248e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
with EtOAc. The filtrates were concentrated in vacuo and purified by
silica gel column chromatography (80/20 EtOAc/hexanes) to give 15
19 in a 10:9 ratio (from the H NMR spectrum). The title compound
19 was isolated by silica gel column chromatography (with 10/90 to
20/80 EtOAc/hexanes as eluent) in 97% yield (14 mg) as a colorless
oil based on starting material recovery (bsmr) (15.5 mg of 18). The
in (490 mg) 60% yield as a colorless oil: R = 0.22 (80/20 EtOAc/
f
hexanes); [α]2
5.4
= +39.0° (c = 1.0, CHCl ); H NMR (400 MHz,
1
D
3
4q
CDCl ) δ 5.86 (s, 1H), 5.25 (d, J = 5.7 Hz, 1H), 4.77 (s, 1H), 4.56 (d,
J = 5.7 Hz, 1H), 4.34 (s, 2H), 1.40 (s, 3H), 1.34 (s, 3H); C NMR
spectral data of 19 matched the data reported previously.
3
13
((3aS,4S,6aS)-4-(Benzoyloxy)-2,2-dimethyl-4,6a-dihydro-
3aH-cyclopenta[d][1,3]dioxol-5-yl)methyl Benzoate (20).
DIBAL-H (60 mL, 1 M solution in hexanes, 59.2 mmol) was added
slowly to a solution of ester 11a (3.00 g, 13.2 mmol) in DCM (120
mL) under argon at −78 °C. After the mixture was stirred at room
temperature for 3 h, MeOH (25 mL) and water (10 mL) were
sequentially added. After the mixture was stirred at room temperature
for 30 min, Na SO ·7H O (25 g) was added. The mixture was diluted
with DCM (100 mL), and stirring was continued for 18 h. When a
crystalline precipitate had fully formed, the mixture was filtered
through Celite and washed with DCM (3 × 20 mL). The solvent was
removed under reduced pressure to give diol 15 as a colorless oil. The
compound was used without further purification.
(
2
101 MHz, CDCl ) δ 146.6, 129.8, 111.8, 86.7, 83.5, 81.8, 61.1, 27.5,
5.7; FTIR (cm ) 3390; HRMS (ESI; m/z) [M + Na] calcd for
3
−
1
+
C H O Na 209.0784, found 209.0788.
9
14
4
(
3aR,4S,6aS)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-di-
methyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (16).
To a solution of 15 (80 mg, 0.43 mmol) in THF (12 mL) was
added 1 drop of DMF, imidazole (293 mg, 4.3 mmol), and tert-
butyldiphenylchlorosilane (TBDPSCl; 355 mg, 1.3 mmol) sequen-
tially, and the mixture was stirred at room temperature for 4 h. The
reaction mixture was concentrated in vacuo. Then 10 mL of water was
added to the reaction mixture and 3 × 10 mL of DCM was used to
extract the desired product. The combined organic layers were dried,
filtered, and concentrated in vacuo and purified by silica gel column
chromatography (with 0/100 to 20/80 EtOAc/hexanes as eluent) to
2
4
2
To a solution of 15 (13.2 mmol) in DCM (180 mL) were added
triethylamine (7.5 mL, 53.7 mmol) and BzCl (3.83 mL, 13.4 mmol)
sequentially, and the mixture was stirred at room temperature for 18 h.
give 16 in 85% yield (156 mg) as a colorless oil: R = 0.25 (20:80
f
EtOAc/hexanes); [α]2
4.7
D
= +33.6° (c = 1.0, CHCl ); H NMR (400
1
The reaction mixture was quenched with saturated NH Cl solution
3
4
MHz, CDCl ) δ 7.77−7.59 (m, 4H), 7.52−7.34 (m, 6H), 5.84 (s, 1H),
(50 mL). Extraction of the mixture with DCM (2 × 50 mL) gave the
3
5
1
9
1
.27 (d, J = 5.6 Hz, 1H), 4.74 (d, J = 3.2 Hz, 1H), 4.57 (d, J = 5.6 Hz,
combined organic layers, which were dried (MgSO ), filtered, and
4
H), 4.36 (q, J = 13.9 Hz, 2H), 1.39 (s, 3H), 1.35 (s, 3H) 1.08 (s,
concentrated in vacuo. The crude product was purified by silica gel
column chromatography (with 0/100 to 10/90 EtOAc/hexanes as
H); 13C NMR (101 MHz, CDCl ) δ 146.4, 135.7, 132.9, 130.1,
3
29.3, 128.0, 111.5, 86.4, 83.6, 81.3, 62.35, 27.6, 26.9, 25.9, 19.3; FTIR
eluent) to give 3.81 g of 20 in (73% yield in two steps) as a white
−1
+
25.2
(
cm ) 3439; HRMS (ESI; m/z) [M + Na] calcd for C H O SiNa
amorphous solid: R = 0.35 (20/80 EtOAc/hexanes); [α]
= +59.4°
25
32
4
f
D
1
4
47.1962, found 447.1964.
3aS,6aS)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-di-
(c = 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 8.07−7.93 (m, 4H),
3
3
(
7.53 (ddd, J = 9.0, 8.1, 0.7 Hz, 2H), 7.47−7.32 (m, 4H), 6.21 (d, J =
methyl-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (17). To a
solution of 16 (146 mg, 0.34 mmol) in DCM (11 mL) was added
Dess−Martin periodinane (DMP; 173 mg, 0.41 mmol), and the
reaction mixture was stirred at room temperature for 4 h. Diethyl ether
0.6 Hz, 1H), 5.97 (d, J = 0.6 Hz, 1H), 5.33 (d, J = 5.7 Hz, 1H), 4.97 (s,
1
3
2H), 4.75 (d, J = 5.8 Hz, 1H), 1.48 (s, 3H), 1.38 (s, 3H); C NMR
(101 MHz, CDCl ) δ 166.0, 139.8, 134.1, 133.3, 133.1, 129.8, 129.7,
3
−1
129.5, 128.4, 112.5, 84.3, 83.2, 82.9, 61.1, 27.4, 25.8; FTIR (cm )
1721; HRMS (ESI; m/z) [M + Na] calcd for C H O Na 417.1308,
+
(
20 mL) was then added, and the mixture was filtered through a pad of
23
22
6
Celite. The filtrate was concentrated in vacuo and purified with silica
gel column chromatography (0/100 to 10/90 EtOAc/hexanes as
eluent) to give 17 in 98% yield (143 mg) as a white amorphous solid:
found 417.1309.
((3S,4S,5S)-5-(Benzoyloxy)-3,4-dihydroxycyclopent-1-en-1-
yl)methyl Benzoate (21). To a solution of 20 (3.80 g, 9.64 mmol) in
THF (40 mL) was added 2 N HCl (16 mL), and the reaction mixture
was stirred at 65 °C for 16 h. The reaction mixture was then cooled to
room temperature and concentrated in vacuo. The residue was
dissolved in EtOAc and washed with saturated NaHCO
water, and brine and then dried (MgSO ). The solvent was removed
24.8
R = 0.72 (20/80 EtOAc/hexanes); [α]
= +12.4° (c = 1.0, CHCl );
f
D
3
1
H NMR (400 MHz, CDCl ) δ 7.63−7.621 (m, 4H), 7.55 (dd, J = 4.1,
3
2
.0 Hz, 1H), 7.50−7.30 (m, 6H), 5.22 (br s, 1H), 4.49 (d, J = 5.4 Hz,
1
H), 4.41 (t, J = 1.8 Hz, 2H), 1.42 (s, 3H), 1.40 (s, 3H), 1.09 (s, 9H);
3
solution,
1
3
C NMR (101 MHz, CDCl ) δ 201.6, 152.7, 147.2, 135.6, 133.0,
4
3
1
32.9, 130.1, 128.0, 115.5, 78.2, 58.9, 27.7, 27.0, 26.4, 19.4; FTIR
under reduced pressure, and the residue was purified by flash column
chromatography on silica gel (50/50 EtOAc/hexanes) to give 21 (2.41
−1
+
(
cm ) 1723; HRMS (ESI; m/z) [M + Na] calcd for C H O SiNa
25 30 4
2
5.1
4
45.1805, found 445.1797.
3aR,4R,6aS)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-di-
g, 70%) as a colorless oil: R
f
= 0.16 (40/60 EtOAc/hexanes); [α]
D
1
(
= +43.6° (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 8.06−7.99
3
3
methyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (18).
To a solution of 17 (70 mg, 0.17 mmol) in MeOH (10 mL) were
added CeCl ·7H O (93 mg, 0.26 mmol) and NaBH (11 mg, 0.27
(m, 4H), 7.61−7.52 (m, 2H), 7.46−7.37 (m, 4H), 6.25 (s, 1H), 5.81
(s, 1H), 4.04 (q, J = 14.8 Hz, 2H), 4.78 (d, J = 5.2 Hz, 1H), 4.26 (br s,
1H); 13C NMR (101 MHz, CDCl ) δ 168.0, 166.2, 140.9, 133.8,
3
2
4
3
mmol) sequentially at 0 °C, and the mixture was stirred for 2 h. The
reaction mixture was quenched with water and concentrated in vacuo.
The residue was purified with silica gel column chromatography (with
133.4, 132.9, 130.0, 129.8, 129.8, 129.3, 128.7, 128.6, 85.6, 72.7, 77.0,
−1
+
61.0; FTIR (cm ) 3422, 1719; HRMS (ESI; m/z) [M + Na] calcd
for C H O Na 377.0995, found 377.0994.
20
18
6
0
/100 to 10/90 EtOAc/hexanes as eluent) to give 18 in 97% yield (68
22a,b. Imidazole (692 mg, 10.21 mmol) and tert-butyldiphenyl-
chlorosilane (TBDPSCl; 2.05 g, 7.48 mmol) were added to a solution
of diol 21 (2.40 g, 6.77 mmol) in anhydrous DCM (25 mL). After it
was stirred at room temperature for 16 h, the reaction mixture was
25.3
mg) as a colorless oil: R = 0.62 (20/80 EtOAc/hexanes); [α]
+
=
f
D
1
12.5° (c = 1.0, CHCl ); H NMR (400 MHz, CDCl ) δ 7.76−7.60
3
3
(
m, 4H), 7.52−7.31 (m, 6H), 5.89 (s, 1H), 5.12−4.94 (m, 1H), 4.75
(
t, J = 5.6 Hz, 1H), 4.37 (dt, J = 16.1, 10.6 Hz, 3H), 1.42 (d, J = 13.6
quenched with a saturated NH Cl solution (100 mL) and extracted
4
13
Hz, 6H), 1.08 (s, 9H); C NMR (101 MHz, CDCl ) δ 149.4, 135.7,
with dichloromethane (2 × 20 mL). The combined organic layers
3
1
1
33.6, 129.9, 127.8, 125.2, 112.4, 82.6, 77.9, 73.6, 61.2, 27.9, 27.0, 26.8,
9.4; FTIR (cm ) 3526; HRMS (ESI; m/z) [M + Na] calcd for
were washed with brine and then dried (MgSO ). The solvent was
4
−1
+
removed under reduced pressure, and the residue was purified by flash
column chromatography on silica gel (5/95 EtOAc/hexanes) to give
22a (2.02 g, 50%) as a colorless oil and 22b (1.41 g, 35%) as a white
crystalline solid.
C H O SiNa 447.1962, found 447.1961.
2
5
32
4
(
3aS,4S,6aR)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-di-
methyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (19).
To a solution of 18 (30 mg, 0.07 mmol) in anhydrous acetone (10
mL) was added p-TsOH·H O (4.0 mg, 0.02 mmol), and the reaction
mixture was stirred at room temperature for 18 h. The mixture was
concentrated in vacuo, redissolved in DCM, and washed with
saturated NaHCO solution. The organic layer was dried, filtered,
((3S,4R,5S)-5-(Benzoyloxy)-3-((tert-butyldiphenylsilyl)oxy)-4-hy-
droxycyclopent-1-en-1-yl)methyl benzoate (22a): R = 0.65 (50/50
2
f
diethyl ether/hexanes); [α]2
5.1
= +12.4° (c = 1.0, CHCl ); H NMR
D 3
1
(400 MHz, CDCl ) δ 8.01−7.93 (m, 2H), 7.92−7.87 (m, 2H), 7.69
3
(d, J = 6.8 Hz, 4H), 7.57−7.49 (m, 2H), 7.48−7.31 (m, 10H), 6.03 (s,
3
1
3
and concentrated in vacuo. The crude residue contained both 18 and
1H), 5.63 (s, 1H), 5.04−4.65 (m, 3H), 4.26 (s, 1H), 1.10 (s, 9H); C
F
dx.doi.org/10.1021/jo501248e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
NMR (101 MHz, CDCl ) δ 166.2, 165.8, 140.6, 135.8, 135.7, 133.1,
(101 MHz, CD OD) δ 152.2, 151.9, 150.4, 145.1, 144.0, 121.8, 120.1,
3
3
−1
1
1
33.0, 132.7, 132.3, 130.2, 130.1, 129.8, 129.7, 129.6, 128.3, 128.0,
88.1, 80.7, 65.6, 59.7; FTIR (cm ) 3366, 1365; HRMS (ESI; m/z)
−1
+
27.8, 83.4, 76.3, 74.7, 61.1, 26.9, 19.3; FTIR (cm ) 3464, 1366;
[M + H] calcd for C H N O 264.1091, found 264.1094.
11
14
5
3
+
HRMS (ESI; m/z) [M + Na] calcd for C H O SiNa 615.2173,
36
36
6
found 615.2143.
ASSOCIATED CONTENT
Supporting Information
■
(
(3S,4S,5S)-5-(Benzoyloxy)-4-((tert-butyldiphenylsilyl)oxy)-3-hy-
*
S
droxycyclopent-1-en-1-yl)methyl benzoate (22b): R = 0.48 (50/50
f
Figures, tables, and a CIF file giving H NMR and 13C NMR
spectra of all compounds prepared and crystallographic data of
22b. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
diethyl ether/hexanes); white crystalline solid, mp 93−94 °C (diethyl
ether/hexane); [α]2
5.3
= +36.0° (c = 1.0, CHCl ); H NMR (400
1
D
3
MHz, CDCl ) δ 7.93−7.89 (m, 2H), 7.80−7.76 (m, 2H), 7.76−7.65
3
(
1
m, 2H), 7.62−7.59 (m, 2H), 7.55−7.46 (m, 2H), 7.44−7.12 (m,
0H), 6.16 (d, J = 4.0 Hz, 1H), 6.11 (m, 1H), 4.83 (q, J = 14.8 Hz,
13
2
H), 4.52−4.50 (m, 1H), 4.45 (br s, 1H), 1.10 (s, 9H); C NMR
AUTHOR INFORMATION
Corresponding Authors
*E-mail for C.L.L.C.: phacllc@nus.edu.sg or christina_chai@
ices.a-star.edu.sg.
*E-mail for E.K.W.T.: eric_tam@ices.a-star.edu.sg.
Notes
The authors declare no competing financial interest.
■
(
101 MHz, CDCl ) δ 165.9, 165.7, 141.1, 135.7, 135.6, 133.0, 132.9,
3
1
32.7, 132.6, 132.3, 130.2, 130.0, 129.8, 129.6, 128.2, 128.1, 128.0,
−
1
1
27.8, 82.5, 77.7, 72.4, 61.1, 26.9, 19.2; FTIR (cm ) 3233, 1272;
+
HRMS (ESI; m/z) [M + Na] calcd for C H O SiNa 615.2173,
found 615.2159.
36
36
6
(
(3R,4S,5S)-5-(Benzoyloxy)-3-(6-((bis-tert-butoxycarbonyl)-
amino)-9H-purin-9-yl)-4-((tert-butyldiphenylsilyl)oxy)-
cyclopent-1-en-1-yl)methyl Benzoate (23). To a suspension of
2
1
2
2b (900 mg, 1.52 mmol), N6-bis-BOC-adenine (1.01 g, 3.04
ACKNOWLEDGMENTS
mmol), and Ph P (797 mg, 3.04 mmol) in 20 mL of anhydrous
■
3
toluene was added DIAD (600 μL, 3.04 mmol) at 0 °C under an argon
atmosphere. After the mixture was stirred at room temperature for 16
h, the solvent was evaporated and the residue was purified by flash
column chromatography on silica gel (40/60 diethyl ether/hexanes) to
The authors thank Exploit Technologies, A*STAR, for
providing financial support for this project in the form of a
Flagship COT grant.
give 23 (794 mg, 57%) as a foam: R = 0.29 (50/50 diethyl ether/
f
hexanes); [α]2
5.3
1
REFERENCES
= −3.8° (c = 1.0, CHCl ); H NMR (400 MHz,
■
D
3
CDCl ) δ 8.78 (s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.82 (s, 1H), 7.78 (d,
(1) Tseng, C. K. H.; Marquez, V. E.; Fuller, R. W.; Goldstein, B. M.;
Haines, D. R.; McPherson, H.; Parsons, J. L.; Shannon, W. M.; Arnett,
G.; Hollingshead, M.; Driscollt, J. S. J. Med. Chem. 1989, 32, 1442.
3
J = 7.2 Hz, 2H), 7.53 (dt, J = 15.1, 7.4 Hz, 2H), 7.43−7.27 (m, 10H),
7
1
1
1
1
8
.21−7.02 (m, 4H), 6.19 (d, J = 4.1 Hz, 1H), 5.95 (s, 1H), 5.75 (br s,
(
2) (a) Chai, C. L. L.; Tam, E. K. W.; Yang, H.; Yu, Q.; Nguyen, T.
H), 5.10−4.94 (m, 1H), 4.89 (s, 1H), 4.83 (t, J = 4.6 Hz, 1H).1.47 (s,
8H), 0.95 (s, 9H); 13C NMR (101 MHz, CDCl ) δ 165.8, 165.7,
M. WO2010036213 A1, 2010. (b) Tan, J.; Yang, X.; Zhuang, L.; Jiang,
X.; Chen, W.; Lee, P. L.; Karuturi, R. K. M.; Tan, P. B. O.; Liu, E. T.;
Yu, Q. Genes Dev. 2007, 21, 1050.
3) Stoeckler, J.; Cambor, C.; Parks, R., Jr. Biochemistry 1980, 19,
02.
4) (a) Arita, M.; Adachi, K.; Ito, Y.; Sawai, H.; Ohno, M. J. Am.
3
53.1, 152.0, 150.6, 150.2, 143.0, 141.8, 135.3, 133.4, 133.2, 132.0,
31.7, 130.1, 129.8, 129.6, 129.4, 129.0, 128.4, 128.2, 127.7, 84.3, 83.7,
−1
(
1
(
2.2, 63.9, 60.7, 27.8, 26.7, 19.0; FTIR (cm ) 1728, 1366; HRMS
+
(
ESI; m/z) [M + Na] calcd for C H N O SiNa 932.3661, found
51 55 5 9
9
32.3665.
Chem. Soc. 1983, 105, 4049. (b) Lim, M.-I.; Marquez, V. E.
Tetrahedron Lett. 1983, 24, 5559. (c) Medich, J. R.; Kunnen, K. B.;
Johnson, C. R. Tetrahedron Lett. 1987, 28, 4131. (d) Marquez, V. E.;
Lim, M.-I.; Tseng, C. K.-H.; Markovac, A.; Priest, M. A.; Khan, M. S.;
Kaskar, B. J. Org. Chem. 1988, 53, 5709. (e) Bestmann, H. J.; Roth, D.
Angew. Chem., Int. Ed. Engl. 1990, 29, 99. (f) Da Silva, A. D.; Coimbra,
Bis-tert-butyl (9-((1R,4S,5S)-5-((tert-Butyldiphenylsilyl)oxy)-
4
-hydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl)-9H-purin-6-
yl)carbamate (24). Sodium methoxide (95 mg, 1.75 mmol) was
added to a solution of 23 (800 mg, 0.88 mmol) in MeOH (10 mL) at
room temperature. After it was stirred at room temperature for 14 h,
the reaction mixture was quenched with a saturated NH Cl solution
4
(
10 mL) and the mixture was extracted with EtOAc (2 × 60 mL). The
combined organic layers were washed with water and brine and then
́
E. S.; Fourrey, J.-L.; Machado, A. S.; Robert-Gero, M. Tetrahedron Lett.
1993, 34, 6745. (g) Nokami, J.; Matsuura, H.; Takahashi, H.;
Yamashita, M. Synlett 1994, 491. (h) Ohira, S.; Sawamoto, T.; Yamato,
M. Tetrahedron Lett. 1995, 36, 1537. (i) Niizuma, S.; Shuto, S.;
Matsuda, A. Tetrahedron 1997, 53, 13621. (j) Yoshida, N.; Kamikubo,
T.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 4677. (k) Trost, B. M.;
Madsen, R.; Guile, S. D.; Brown, B. J. Am. Chem. Soc. 2000, 122, 5947.
(l) Hegedus, L. S.; Geisler, L. J. Org. Chem. 2000, 65, 4200. (m) Ono,
M.; Nishimura, K.; Tsubouchi, H.; Nagaoka, Y.; Tomioka, K. J. Org.
Chem. 2001, 66, 8199. (n) Gallos, J. K.; Stathakis, C. I.; Kotoulas, S. S.;
Koumbis, A. E. J. Org. Chem. 2005, 70, 6884. (o) Paquette, L. A.; Tian,
Z.; Seekamp, C. K.; Wang, T. Helv. Chim. Acta 2005, 88, 1185.
(p) Khan, F. A.; Rout, B. J. Org. Chem. 2007, 72, 7011. (q) Michel, B.
Y.; Strazewski, P. Tetrahedron 2007, 63, 9836. (r) Keller, B. T.;
Borchardt, R. T. In Biological Methylation and Drug Design; Borchardt,
R. T., Creveling, C. R., Ueland, P. M., Eds.; Humana Press: Clifton,
NJ, 1986; pp 385−396.
dried (MgSO ). The solvent was removed under reduced pressure,
4
and the residue was purified by flash column chromatography on silica
gel (75/25 EtOAc/hexanes) to give 24 (484 mg, 78%) as a foam: R =
f
1
0
.23 (50/50 EtOAc/hexanes); [α]25.1D = −50.9° (c = 1.0, CHCl ); H
3
NMR (400 MHz, CDCl ) δ 8.70 (s, 1H), 7.62−7.56 (m, 2H), 7.51−
3
7
1
9
1
6
.31 (m, 7H), 7.28−7.21 (m, 2H), 5.60 (s, 1H), 5.15 (s, 1H), 4.73 (s,
H), 4.59 (s, 1H), 4.42 (q, J = 14.8 Hz, 2H), 1.45 (s, 18H), 1.04 (s,
H); 13C NMR (101 MHz, CDCl ) δ 152.1, 151.4, 150.9, 150.3,
3
44.2, 135.5, 135.4, 132.1, 132.0, 130.2, 127.9, 122.3, 86.5, 84.1, 82.6,
−1
6.8, 59.9, 27.8, 26.8, 19.0; FTIR (cm ) 3503, 1790, 1370; HRMS
+
(
7
ESI; m/z) [M + H] calcd for C H N O Si 702.3318, found
37 48 5 7
02.3330.
1S,2S,5R)-5-(6-Amino-9H-purin-9-yl)-3-(hydroxymethyl)-
cyclopent-3-ene-1,2-diol Hydrochloride (1b). To a solution of 18
200 mg, 0.28 mmol) in MeOH (5 mL) was added 2 N HCl (500 μL),
(
(
and the mixture was stirred at room temperature for 48 h. The
reaction mixture was filtered through a plug of cotton wool and
azeotroped with MeOH (3 × 10 mL) to remove water. The final
product was purified by precipitation, in which the residue was washed
with diethyl ether followed by DCM (2 × 5 mL) to afford pure 1b (49
(5) Miranda, T. B.; Cortez, C. C.; Yoo, C. B.; Liang, G.; Abe, M.;
Kelly, T. K.; Marquez, V. E.; Jones, P. A. Mol. Cancer Ther. 2009, 8,
1579.
́
(6) (a) Ovaa, H.; Codee, J. D. C.; Lastdrager, B.; Overkleeft, H. S.;
van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 1998, 39, 7987.
(b) Seepersaud, M.; Al-Abed, Y. Org. Lett. 1999, 1, 1463. (c) Callam,
C. S.; Lowary, T. L. J. Org. Chem. 2001, 66, 8961. (d) Choi, W. J.;
Park, J. G.; Yoo, S. J.; Kim, H. O.; Moon, H. R.; Chun, M. W.; Jung, Y.
2
5.3
mg, 65%) as a pale yellow solid: [α]
= −50.0° (c = 1.0, MeOH);
D
1
H NMR (400 MHz, CD OD) δ 8.38 (s, 1H), 8.34 (s, 1H), 5.79 (s,
H), 5.37 (br s, 1H), 4.56 (br s, 1H), 4.41−4.22 (m, 3H); C NMR
3
13
1
G
dx.doi.org/10.1021/jo501248e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
H.; Jeong, L. S. J. Org. Chem. 2001, 66, 6490. (e) Lee, K.; Cass, C.;
Jacobson, K. A. Org. Lett. 2001, 3, 597. (f) Moon, H. R.; Kim, H. O.;
Lee, K. M.; Chun, M. W.; Kim, J. H.; Jeong, L. S. Org. Lett. 2002, 4,
(14) Cooper, R. D.; Jigajinni, V. B.; Wightman, R. H. Tetrahedron
Lett. 1984, 25, 5215.
(15) Smith, A. B., III; Han, Q.; Breslin, P. A. S.; Beauchamp, G. K.
Org. Lett. 2005, 7, 5075.
(16) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
3501. (g) Hong, J. H.; Shim, M. J.; Ro, B. O.; Ko, O. H. J. Org. Chem.
2002, 67, 6837. (h) Jin, Y. H.; Chu, C. K. Tetrahedron Lett. 2002, 43,
4141. (i) Jin, Y. H.; Liu, P.; Wang, J.; Baker, R.; Huggins, J.; Chu, C. K.
J. Org. Chem. 2003, 68, 9012. (j) Banerjee, S.; Ghosh, S.; Sinha, S.;
Ghosh, S. J. Org. Chem. 2005, 70, 4199. (k) Mishra, G. P.; Rao, B. V.
Tetrahedron: Asymmetry 2011, 22, 812.
(17) (a) Hall, A.; Meldrum, K. P.; Therond, P. R.; Wightman, R. H.
Synlett 1997, 123. (b) Freiría, M.; Whitehead, A. J.; Motherwell, W. B.
Synthesis 2005, 3079.
(
7) (a) Borcherding, D. R.; Scholtz, S. A.; Borchardt, R. T. J. Org.
Chem. 1987, 52, 5457. (b) Comin, M. J.; Rodriguez, J. B. Tetrahedron
000, 56, 4639.
8) McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42,
197.
9) (a) Nguyen Van Nhien, A.; Soriano, E.; Marco-Contelles, J.;
(18) Nising, C. F.; Bras
references cited therein.
̈
e, S. Chem. Soc. Rev. 2008, 37, 1218 and
2
(
1
(
(19) (a) Shull, B. K.; Sakai, T.; Nichols, J. B.; Koreeda, M. J. Org.
Chem. 1997, 62, 8294. (b) Liao, X.; Butora, G.; Olsen, D. B.; Carroll,
S. S.; McMasters, D. R.; Leone, J. F.; Stahlhut, M.; Doss, G. A.; Yang,
L.; MacCoss, M. Tetrahedron Lett. 2008, 49, 4149.
(20) Comin, M. J.; Vu, B. C.; Boyer, P. L.; Liao, C.; Hughes, S. H.;
Marquez, V. E. ChemMedChem 2008, 3, 1129.
Postel, D. Carbohydr. Res. 2009, 344, 1605. (b) Liao, X.; Butora, G.;
Olsen, D. B.; Carroll, S. S.; McMasters, D. R.; Leone, J. F.; Stahlhut,
M.; Doss, G. A.; Yang, L.; MacCoss, M. Tetrahedron Lett. 2008, 49,
(21) Dey, S.; Garner, P. J. Org. Chem. 2000, 65, 7697.
4
(
149.
10) Shin, D. H.; Lee, H. W.; Park, S. S.; Kim, J. H.; Jeong, L. S.;
Chun, M. W. Arch. Pharm. Res. 2000, 23, 302.
(
11) For recent reviews on the Baylis−Hillman reaction, see:
(
(
a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103.
b) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007,
4
2
6, 4614. (c) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev.
007, 36, 1581. (d) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 2905.
(
e) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511. (f) Declerck, V.;
Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1. (g) Ma, G.-N.; Jiang,
J.-J.; Shi, M.; Wei, Y. Chem. Commun. 2009, 5496. (h) Wei, Y.; Shi, M.
Acc. Chem. Res. 2010, 43, 1005. (i) Basavaiah, D.; Reddy, B. S.;
Badsara, S. S. Chem. Rev. 2010, 110, 5447. (j) Basavaiah, D.;
Veeraraghavaiah, G. Chem. Soc. Rev. 2012, 41, 68. (k) Liu, T.-Y.; Xie,
M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41, 4101. (l) Basavaiah, D.;
Sahu, B. C. Chimia 2013, 67, 8. (m) Wei, Y.; Shi, M. Chem. Rev. 2013,
1
13, 6659.
12) For selected examples of intramolecular Baylis−Hillman
reactions, see: (a) Roth, F.; Gygax, P.; Frater, G. Tetrahedron Lett.
992, 33, 1045. (b) Drewes, S. E.; Njamela, O. L.; Emslie, N. D.;
(
́
1
Rameser, N.; Field, J. S. Synth. Commun. 1993, 23, 2807. (c) Black, G.
P.; Dinon, F.; Fratucello, S.; Murphy, P. J.; Nielsen, M.; Williams, H.
L.; Walshe, N. D. A. Tetrahedron Lett. 1997, 38, 8561. (d) Dinon, F.;
Richards, E.; Murphy, P. J.; Hibbs, D. E.; Hursthouse, M. B.; Malic, K.
M. A. Tetrahedron Lett. 1999, 40, 3279. (e) Richards, E. L.; Murphy, P.
J.; Dinon, F.; Fratucello, S.; Brown, P. M.; Gelbrich, T.; Hursthouse,
M. B. Tetrahedron 2001, 57, 7771. (f) Wang, L.-C.; Luis, A. L.;
Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124,
2
2
402. (g) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc.
002, 124, 2404. (h) Mergott, D. J.; Frank, S. A.; Roush, W. R. Org.
Lett. 2002, 4, 3157. (i) Yagi, K.; Turitani, T.; Shinokubo, H.; Oshima,
K. Org. Lett. 2002, 4, 3111. (j) Keck, G. E.; Welch, D. S. Org. Lett.
2
002, 4, 3687. (k) Methot, J. L.; Roush, W. R. Org. Lett. 2003, 5, 4223.
(
(
l) Yeo, J. E.; Yang, X.; Kim, H. J.; Koo, S. Chem. Commun. 2004, 236.
m) Krishna, P. R.; Kannan, V.; Sharma, G. V. M J. Org. Chem. 2004,
6
9, 6467. (n) Chen, S.-H.; Hong, B.-C.; Su, C.-F.; Sarshar, S.
Tetrahedron Lett. 2005, 46, 8899. (o) Aroyan, C. E.; Vasbinder, M. M.;
Miller, S. J. Org. Lett. 2005, 7, 3849. (p) Krafft, M. E.; Wright, J. A.
Chem. Commun. 2006, 2977. (q) Seidel, F.; Gladysz, J. A. Synlett 2007,
9
86. (r) Zhou, A.; Hanson, P. R. Org. Lett. 2008, 10, 2951. (s) Sirasani,
G.; Andrade, R. B. Org. Lett. 2009, 11, 2085. (t) Song, H.-L.; Yuan, K.;
Wu, X.-Y. Chem. Commun. 2011, 47, 1012. (u) Ghandi, M.;
Bozcheloei, A. H.; Nazari, S. H.; Sadeghzadeh, M. J. Org. Chem.
2
011, 76, 9975. (v) Selig, P. S.; Miller, S. J. Tetrahedron Lett. 2011, 52,
2
148. (w) Ressault, B.; Jaunet, A.; Geoffroy, P.; Goudedranche, S.;
Miesch, M. Org. Lett. 2012, 14, 366. (x) Tong, K.; Tu, J.; Qi, X.; Wang,
M.; Wang, Y.; Fu, H.; Pittman, C. U., Jr.; Zhou, A. Tetrahedron 2013,
6
9, 2369. (y) Basavaiah, D.; Reddy, G. C.; Bharadwaj, K. C. Eur. J. Org.
Chem. 2014, 1157.
13) Argyropoulos, N. G.; Panagiotidis, T. D.; Gallos, J. K.
Tetrahedron: Asymmetry 2006, 17, 829.
(
H
dx.doi.org/10.1021/jo501248e | J. Org. Chem. XXXX, XXX, XXX−XXX