Monomers for preparation of amide linked RNA: Synthesis of C3′-homologated nucleoside amino acids from d-xylose

Article abstract of DOI:10.1016/j.tet.2010.04.110

Amides as neutral and hydrophobic internucleoside linkages in RNA are highly interesting modifications for RNA interference. However, testing amides in siRNAs is hampered by the shortage of efficient methods to synthesize the monomeric building blocks, th

Full text of DOI:10.1016/j.tet.2010.04.110

Tetrahedron 66 (2010) 4961e4964
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Monomers for preparation of amide linked RNA: synthesis of C30-homologated
nucleoside amino acids from -xylose
D
*
Paul Tanui, Martin Kullberg, Ni Song, Yashodhan Chivate, Eriks Rozners
Department of Chemistry, Binghamton University, State University of New York, Binghamton, New York, NY 13902, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Amides as neutral and hydrophobic internucleoside linkages in RNA are highly interesting modifications
for RNA interference. However, testing amides in siRNAs is hampered by the shortage of efficient
methods to synthesize the monomeric building blocks, the nucleoside amino acid equivalents. This paper
Received 24 February 2010
Received in revised form 22 April 2010
Accepted 26 April 2010
reports an efficient synthesis of protected ribonucleoside 50-amino 30-carboxylic acids from
D-xylose in
Available online 20 May 2010
14 steps 7% overall yield. The key features that ensure efficiency and ease of operations are chemo-
selective reduction of the ester and minimization of protecting group manipulation.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
RNA
Modified nucleoside
Amide internucleoside linkage
Carbohydrate synthesis
Selective reduction of ester
1. Introduction
N3
O
Base
OR
N3
OAc
OAc
O
HN
O
Base
O
O
The potential of RNA interference (RNAi) to become a new
therapeutic strategy has revitalized the interest in chemical mod-
ifications of RNA. To be useful as therapeutic agents short in-
terfering RNAs (siRNAs) need to be chemically modified to optimize
their potency, enzymatic stability, cellular uptake, biodistribution,
and pharmacokinetics.1 We have been interested in hydrophobic
non-ionic mimics of phosphate backbone, such as formacetals2 and
amides3 (Fig. 1). Non-ionic phosphate mimics may offer several
advantages for siRNAs: (1) the absence of natural phosphate will
confer high nuclease resistance, (2) the reduction of charge may
facilitate crossing of cellular membranes, and (3) the increased
hydrophobicity of siRNAs may improve their biodistribution and
pharmacokinetics.
In previous studies we found that replacement of selected
phosphates with amide linkages (Fig. 1) did not change the overall
conformation and UV melting temperature (thermal stability) of
RNA double helix.3 The amide linkages appeared to be excellent
mimics of phosphate backbone in RNA and were expected to be
compatible with RNAi machinery. In accord with such expectation,
Iwase and co-workers4 recently reported that siRNA having two
amide linkages at the overhanging uridines retained high activity in
RNAi assays. These results suggest a hypothesis that siRNAs may
tolerate even more extensive amide modification, which may
OH
Base
OH
1
3
OTBDPS
HN
O
O
OH
N3
OAc
HO
HO
O
O
O
O
OAc
O
2
OEt
4
Figure 1. Structure and retrosynthetic analysis of amide linked RNA.
realize the potential advantages of the hydrophobic RNA modifi-
cations. The bottleneck of testing the above hypothesis is the
shortage of efficient and large scale syntheses of enantiomerically
pure C30-homologated carboxylic acids 1 (Fig. 1), the monomers for
introduction of consecutive amide linkages in siRNAs.
In their study of amide-modified siRNAs, Iwase and co-workers4
used uridine carboxylic acids, which were prepared from uridine
following a procedure by Robins and co-workers.5 The problem
with such an approach is that four independent synthetic routes
must be pursued to prepare all four nucleoside carboxylic acids,
which is time and resources consuming. Robins and co-workers
have also developed synthesis of 1 starting from
-xylose.6 The sugar route diverges at the common intermediate
2 (Fig. 1) on which the desired heterocylces can be installed in
D-glycose or
D
* Corresponding author; E-mail address: erozners@binghamton.edu (E. Rozners).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.110

4962
P. Tanui et al. / Tetrahedron 66 (2010) 4961e4964
a straightforward manner. However, we found that Robin’s route
from sugars was complicated at the finals steps by the need to
cleave the ester (see 2) and, consequently, laborious reintroduction
of 20-OH and heterocycle protecting groups, which being base la-
bile, were lost during the ester cleavage.
Recently, we reported an asymmetric de novo synthesis of 1
starting from small molecules and proceeding through the com-
mon intermediate 3.7 The final oxidation of alcohol led to
straightforward and efficient preparation of carboxylic acids 1.
However, we encountered difficulties in scaling up the enantiose-
lective reactions during the starting steps of de novo route. The de
novo route started with a double asymmetric ene reaction that
could be performed on a 4 g scale (13 mmol) of 1-(tert-butyldi-
phenylsilanoxy)-3-pentene, but required an excess of 28 g
(130 mmol) of (10S, 20R, 50S)-menthyl glyoxalate.
later nucleophilic substitution with azide.9 Treatment of alcohol 5
with methanesulfonyl chloride, as described by Robins and co-
workers, gave mesylate 6.6
The challenge with such an approach was the selective re-
duction of the ester in the presence of potentially reactive mesyl
group. Of several reducing agents tried (Table 1), the best results
were obtained with DIBAL-H at 0 ꢀC.10 Borane dimethyl sulfide
complex11 also performed well but required elevated temperature
(60 ꢀC) and longer reaction time. While LiAlH4 and Ca(BH4)2
(formed in situ from NaBH4 and CaCl212) gave good yields, LiBH4
with catalytic amounts of 9BBN13 gave complex reaction mixture
containing no target product.
Table 1
Results of selective reduction of ester 6
Reagent
Solvent
Temp (ꢀC)
Time (h)
Yield (%)
2+
Me Me
1
2
3
4
5
DIBAL-H
BH3$Me2S
LiAlH4
NaBH4, CaCl2
LiBH4-9BBN
CH2Cl2, hexane
THF
Dimethoxyethane
THF
0
60
0
25
100
1
2
2
24
24
94
93
78
74
0
O
O
OTBDPS
N
N
Cu
OTBDPS
+
Ph
Ph
Me
Me
O
O
THF, toluene
-
Me
O
Me
O
2 SbF6
O
OH
Importantly, the mesylation and DIBAL-H reduction steps gave
Me
Me
products in acceptable purity without the need for column chro-
matography. Treatment of mesylate 7 with lithium azide gave al-
cohol 8, which was purified by silica gel column chromatography.
Treatment of 8 with TBDPCl gave 9, which was used in next step
again without chromatographic purification.
The most challenging step in our synthesis was the removal of
the 1,2-isopropylydene protecting group. Cleavage of 1,2-acetals in
carbohydrates generally requires relatively harsh conditions. In our
case, the TBDPS ether, which was relatively close on the same side
of the tetrahydrofuran ring (see 9 in Scheme 1), further complicated
the reaction. Typical protic acid hydrolysis procedures (Table 2)
gave either no reaction (entry 1) or led to concurrent cleavage of the
TBDPS group (entries 2e7).
Preparation of pure menthyl glyoxylate8 involved column
chromatography and vacuum distillation and was not practical on
scales larger than 28 g. The double asymmetric reaction involving
large excess of menthyl glyoxylate was necessary to insure good
yields and high enantiomeric purity (>98:2) of the product and it
appeared unlikely that this reaction could be scaled up to
>50 mmol required to support our planned studies.
Herein we report optimization of our synthetic route7 by
adopting the initial steps from the Robin’s synthesis to prepare the
key intermediate 3 starting from D
-xylose.6 The key features that
ensure efficiency of the new route are chemoselective reduction of
the ester and minimization of protecting group manipulation.
Table 2
Results of cleavage of isopropylydene in 9
2. Results and discussion
Reagent
Temp (ꢀC)
Time (h)
Yield (%)
Our synthesis (Scheme 1) started with the C30-homologated
ribose derivatives 5 and 6, which were prepared as described by
Robins and co-workers.6 The plan was to reduce the ester before
installation of the azide and then oxidize the alcohol after the nu-
cleoside synthesis as was successfully done in our de novo route.7
In this way we would avoid the cleavage of ester under basic con-
ditions after the nucleoside synthesis. Direct reduction of 5 would
generate two primary alcohols, which would be difficult (if at all
possible) to selectively functionalize. To avoid additional protecting
groups we decided to use the mesyl group (Ms, Scheme 1) as both
differentiating functionality for the 5-OH in 5 and leaving group for
1
2
3
4
5
6
7
8
9
Amberlyst-15/MeOH
THF/TFA/H2O (5:4:1)
80% Acetic acid
5% Methanesulfonic acid/MeOH
0.3% H2SO4/MeOH
25
25
80
25
25
50
25
Overnight
Overnight
Overnight
Overnight
Overnight
Overnight
Overnight
0.5
NRa
0b
0b
0b
0b
0.5 M HCl/THF
0b
H2SO4/AcOAc/AcOH (1:2:60)
BBr3 in hexanes/CH2Cl2 (3:40)
BCl3 in hexanes/CH2Cl2 (3:40)
29%c
0c
ꢁ78 to 0
0
0.5
38%d
a
b
c
No reaction.
Cleavage of TBDPS.
Decomposition to polar by-products.
Based on recovered starting material.
d
N
3
RO
O
MsO
LiN
O
O
O
TBDPSCl
79%
O
DIBAL-H
94%
3
Acceptable yield of 10 was achieved using BCl314 after recycling
94%
O
O
O
O
O
of the recovered starting material. Acylation with pyridine/acetic
anhydride gave the glycosyl donor 3, which serves as a common
intermediate in synthesis of the modified nucleosides.
OH
OEt
MsCl
93%
OH
7
8
5 R = H
6 R = Ms
Final steps in preparation of all four ribonucleoside 50-amino 30-
carboxylic acids from the common intermediate 3 have been pre-
viously reported by us.7 Following these procedures we used 3,
Ura(TMS)
TMSOTf
OR
Ura
O
N
3
N
3
2
N
3
O
BCl
O
3
38%
95%
O
prepared from -xylose, to synthesize uridine derivative 11. The
D
OAc
OR
O
product obtained was identical to 11 previously synthesized via the
de novo route.7 Following the reported procedures, compound 11
was further converted to the uridine azido acid 1 (Scheme 2). Re-
duction of azide with hydrogen sulfide was immediately followed
by protection of the amino group with methoxytrityl chloride to
OTBDPS
OTBDPS
11
OTBDPS
9
10 R = H
3 R = Ac
Ac O
2
85%
Scheme 1. Synthesis of C30-homologated uridine.

P. Tanui et al. / Tetrahedron 66 (2010) 4961e4964
4963
N3
O
Ura
H2N
O
Ura
MMTHN
O
Ura
hexane/ethyl acetate (4:1 v/v) to give the title compound (4.11 g,
94%) as a colorless oil. 1H NMR (CDCl3, 360 MHz)
1H), 4.67 (m, 1H), 3.98 (m, 1H), 3.75 (m, 2H), 3.62 (dd, J¼3.0,
13.7 Hz, 1H), 3.23 (dd, J¼4.7, 13.7 Hz, 1H), 2.12 (m, 1H), 1.84 (m, 1H),
1.58 (m, 1H), 1.49 (s, 3H), 1.32 (s, 3H). 13C NMR (CDCl3, 90 MHz)
O
O
O
H2S
MMT-Cl
67%
d
5.81 (d, J¼3.1 Hz,
OAc
OAc
OAc
two steps
OH
1
OH
12
OH
13
Scheme 2. Synthesis of uridine 50-amino 30-carboxylic acid.
d
111.7, 104.8, 81.2, 80.4, 60.9, 51.5, 42.5, 27.6, 26.6, 26.3.
give the amino acid 13, suitable for solid phase synthesis of
oligoamides.
4.3. 5-Azido-3,5-dideoxy-3-[2-(tert-butyldiphenylsilyoxy)-
ethyl]-1,2-O-isopropylidene- -ribofuranose (9)
a-D
3. Conclusion
tert-Butyldiphenylsilyl chloride (3.1 mL, 11.8 mmol) was added
to a solution of 8 (2.41 g, 9.9 mmol) and imidazole (1.47 g, 21.6
mmol) in anhydrous DMF (20 mL). The solution was stirred at room
temperature over night. The reaction was then quenched with
water, evaporated in vacuum and the residue was dissolved in
EtOAc (20 mL) and washed once with brine (15 mL) then with
water (3ꢂ15 mL). The organic layer was dried over Na2SO4, filtered
and evaporated in vacuum to give the title compound 9 (3.75 g, 79%)
as a crude colorless oil whose purity was acceptable for the next
In summary, we have developed a new synthesis of uridine 50-
azido 30-carboxylic acid 1 from
D-xylose in 14 steps 7% overall yield.
One step reduction followed by protection of amino group gave the
target 50-amino 30-carboxyl uridine 13 in 67% yield. Although the
yield of the new route is somewhat lower than that of our previous
de novo synthesis (nine steps and 19% to 1),7 the ability to produce
enantiomerically pure material on larger scales is an important
advantage for our current studies on solid phase synthesis of oli-
goamides. While the start of our de novo route was limited to ca.
13 mmol scale in the first step, the new route could be easily started
step. 1H NMR (CDCl3, 360 MHz)
d 7.71 (m, 4H), 7.44 (m, 6H), 5.77 (d,
J¼3.4 Hz, 1H), 4.42 (m, 1H), 3.98 (m, 1H), 3.82 (m, 2H), 3.61 (dd,
J¼3.0, 13.7 Hz, 1H), 3.20 (dd, J¼4.8, 13.2 Hz, 1H), 2.17 (m, 1H), 1.84
(m, 1H), 1.55 (m, 1H), 1.49 (s, 3H), 1.29 (s, 3H), 1.11 (s, 9H). 13C NMR
with 200 mmols (30 g) of D-xylose. We envision that the new route
should allow future preparation of the target nucleoside 50-azido
30-carboxylic acids on a gram scale.
(CDCl3, 90 MHz)
d 135.6, 129.7, 127.6, 111.6, 104.9, 80.9, 61.9, 51.6,
42.3, 27.6, 26.8, 19.1. MS (ESI) calcd for C26H35N3NaO4Si 504.2;
found 504.2.
The route presents formal synthesis of all four ribonucleoside 50-
azido 30-carboxylic acids (1) because it makes the common in-
termediate 3 described in our previous work.7 The key features that
ensure efficiency and ease of operations are chemoselective re-
duction of the ester, minimization of protecting group manipula-
tion and minimization of silica gel column purification steps. The
efficiency may be further increased by optimization of the removal
of the 1,2-isopropylydene protecting group. The new route should
facilitate synthesis and testing of amide-modified siRNAs, which
have shown promising results in initial studies.4
4.4. 5-Azido-3,5-dideoxy-3-[2-(tert-butyldiphenylsilyoxy)-
ethyl]-a-D-ribofuranose (10)
A solution of 9 (1.505 g, 3.12 mmol) in anhydrous CH2Cl2
(40 mL) was cooled to 0 ꢀC and then treated with BCl3 (3.12 mL,
3.12 mmol, 1 M solution in hexanes) for 30 min. The reaction was
quenched with saturated NaHCO3 (50 mL) and brought to room
temperature, the aqueous layer was extracted with CH2Cl2
(3ꢂ50 mL). The organic layers were pooled together, dried over
Na2SO4, filtered, and evaporated in vacuum. The residue was
purified on silica gel column using hexane/ethyl acetate (4:1 v/v)
to give the title compound 10 (0.309 g, 0.718 mmol, 23%) as
a colorless oil. After chromatography 0.624 g, 40% of 9 was re-
covered bringing the yield of 10 to 38% based on the recovered
4. Experimental section
4.1. 3-Deoxy-3-(2-hydroxyethyl)-1,2-O-isopropylidene-5-O-
(methanesulfonyl)-a-D-ribofuranose (7)
DIBAL-H (46.5 mL, 45.6 mmol, 25% in hexanes) was added
slowly to a solution of 6 (7.88 g, 23.2 mmol) in anhydrous CH2Cl2
(120 mL) at 0 ꢀC. The solution was stirred at 0 ꢀC for 1 h. The re-
action was quenched by extracting with diluted HCl (0.2%, 150 mL),
the organic layer was separated, filtered to remove solid particles,
and dried over anhydrous Na2SO4. Evaporation gave the title com-
pound 7 (6.43 g, 94%) as a colorless oil, which could be used in next
starting material. The spectroscopic data are for mixture of
a and
b
diastereomers. 1H NMR (CDCl3, 360 MHz)
d
7.70e7.64 (m, 4H),
7.47e7.39 (m, 6H), 5.48 and 5.38 (d, J¼3.4 Hz, 1H), 4.31e4.25 (m,
1H), 4.10e4.04 (m, 1H), 3.83e3.65 (m, 2H), 3.57e3.48 (m, 1H),
3.31 (dd, J¼5.5, 13.2 Hz), 3.12 and 3.03 (dd, J¼4.3, 13.2 Hz),
2.40e2.30 and 2.23e2.14 (m, 1H), 1.97e1.85 (m, 1H), 1.68e1.50
(m, 1H), 1.07 (s, 9H). 13C NMR (CDCl3, 90 MHz)
d 135.5, 132.5,
step without further purification. 1H NMR (CDCl3, 360 MHz)
d 5.78
130.0, 127.8, 102.8, 98.2, 82.9, 80.0, 71.8, 63.3, 54.2, 52.4, 42.8,
28.0, 26.7, 18.9.
(d, J¼3.6 Hz, 1H), 4.69 (m, 1H), 4.44 and 4.26 (ABX, J¼2.2, 4.3,
11.5 Hz, 2H), 4.03 (m, 1H), 3.74 (m, 2H), 3.04 (s, 3H), 2.13 (m, 1H),
1.91 (s, 1H), 1.86 (m, 1H), 1.63 (m, 1H), 1.47 (s, 3H), 1.30 (s, 3H). 13C
4.5. 5-Azido-3,5-dideoxy-3-[2-(tert-butyldiphenylsilyoxy)-
NMR (CDCl3, 90 MHz) d 111.8, 104.9, 81.0, 79.2, 68.6, 60.6, 41.6, 37.6,
ethyl]-1,2-O-diacetyl-a-D-ribofuranose (3)
29.6, 27.5, 26.4. MS (ESI) calcd for 2ꢂC11H20O7SþNa 615.2; found
614.7.
Compound 10 (0.8 g, 1.81 mmol) was dissolved in pyridine/
acetic anhydride (6 mL,1:1 v/v) and stirred at room temperature for
12 h. The solution was concentrated in vacuum, the residue was
dissolved in EtOAc (50 mL) and washed with saturated aqueous
NaHCO3 (3ꢂ50 mL). The organic layer was dried over anhydrous
Na2SO4, filtered, and evaporated under vacuum to give the title
compound 3 (0.809 g, 1.54 mmol, 85%) as colorless oil of purity ac-
ceptable for the next step. The spectroscopic data are for mixture of
4.2. 5-Azido-3,5-dideoxy-3-(2-hydroxyethyl)-1,2-O-
isopropylidene-a-D-ribofuranose (8)
LiN3 (4.48 g, 89.5 mmol) was added to a solution of 7 (5.30 g,
17.9 mmol) in anhydrous DMF (50 mL). The solution was heated to
60 ꢀC and stirred at this temperature for 14 h. The solution was
concentrated in vacuum, the residue was dissolved in ethyl acetate
(40 mL) and washed with brine (30 mL) and water (3ꢂ30 mL), the
organic layer was dried over Na2SO4, filtered, and evaporated in
vacuum. The crude product was purified on silica gel column using
a
and b d 7.69e7.61 (m,
diastereomers. 1H NMR (CDCl3, 360 MHz)
4H), 7.46e7.36 (m, 6H), 6.38 and 6.08 (d, J¼3.1 Hz, 1H), 5.24e5.16
(m, 1H), 4.24e4.18 and 4.13e4.08 (m, 1H), 3.74e3.58 (m, 3H),
3.27e3.23 and 3.18e3.14 (dd, J¼4.3, 13.7 Hz, 1H), 2.77e2.68 and

4964
P. Tanui et al. / Tetrahedron 66 (2010) 4961e4964
2.55e2.46 (m, 1H), 2.09 (s, 3H), 2.03 (s, 3H), 1.81e1.50 (m, 2H), 1.06
(s, 9H). 13C NMR (CDCl3, 90 MHz)
135.5, 129.7, 127.7, 98.7, 83.8,
82.7, 61.7, 38.0, 29.7, 27.4, 26.8, 20.6.
137.9, 130.1, 128.7, 128.1, 126.6, 113.5, 102.5, 90.3, 84.3, 78.4, 70.5,
55.4, 45.4, 45.2, 39.6, 31.2, 29.9, 20.8, 8.6. HRMS (ESI) calcd for
C33H33N3NaO8, 622.2165; found, 622.2157.
d
4.6. 20-O-Acetyl-50-azido-30-[2-(tert-butyldiphenylsiloxy) ethyl]-
Acknowledgements
30,50-dideoxyuridine (11)
We thank Binghamton University and NIH (R01 GM071461) for
support of this research.
The title compound 11 was prepared from
3 (0.222 g,
0.412 mmol) as previously described by us7 in 95% yield (0.226 g).
The 1H and 13C NMR matched the reported data.7 Elemental anal-
ysis (C29H35N5O6Si): calculated C, 60.29; H, 6.11; N, 12.12; found C,
60.44; H, 6.17; N, 11.78.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.04.110. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
4.7. 20-O-Acetyl-30,50-dideoxy-30-carboxymethyl-50-(mono-
methoxytrityl)amino-uridine triethylammonium salt (13)
Hydrogen sulfide was passed through a solution of 1 (275 mg,
0.78 mmol) in pyridine/water (25 mL, 4:1 v/v) for 1 h at room tem-
perature. The solution was stirred over night and evaporated in
vacuum. The residue was dissolved in water (50 mL) and washed
with CH2Cl2 (4ꢂ50 mL). The organic layers were discarded and the
water phase was evaporated to give amine 12 (w230 mg,
w0.70 mmol, w90%), which was used in the next step without fur-
ther purification. Amine 12 was dissolved in anhydrous pyridine
(10 mL) and 4-methoxytrityl chloride (1.08 g, 3.5 mmol) was added.
The solution was stirred at room temperature over night. The re-
action was quenched with saturated aqueous triethylammonium
bicarbonate (1 mL) and evaporated in vacuum. The residue was
dissolved in CH2Cl2 (50 mL) and extracted with saturated aqueous
NaHCO3 (3ꢂ50 ml). The organic phase was dried over Na2SO4, fil-
tered, and concentrated in vacuum. The residue was purified on
silica gel column eluting with a stepwise gradient of MeOH (0e10%)
in CH2Cl2 containing 100 ppm of triethylamine to give the title
compound 13 (362 mg, 0.52 mmol, 67% for two steps). 1H NMR
References and notes
1. Watts, J. K.; Deleavey, G. F.; Damha, M. J. Drug Discovery Today 2008, 13, 842e855;
Corey, D. R. J. Clin. Invest. 2007,117, 3615e3622;Rozners, E. Curr. Org. Chem. 2006,10,
675e692; Manoharan, M. Curr. Opin. Chem. Biol. 2004, 8, 570e579.
2. Kolarovic, A.; Schweizer, E.; Greene, E.; Gironda, M.; Pallan, P. S.; Egli, M.;
Rozners, E. J. Am. Chem. Soc. 2009, 131, 14932e14937; Rozners, E.; Katkevica, D.;
€
€
Stromberg, R. ChemBioChem 2007, 8, 537e545; Rozners, E.; Stromberg, R. J. Org.
Chem. 1997, 62, 1846e1850.
€
3. Rozners, E.; Katkevica, D.; Bizdena, E.; Stromberg, R. J. Am. Chem. Soc. 2003, 125,
12125e12136.
4. Iwase, R.; Toyama, T.; Nishimori, K. Nucleosides, Nucleotides Nucleic Acids 2007,
26, 1451e1454; Iwase, R.; Miyao, H.; Toyama, T.; Nishimori, K. Nucleic Acids
Symp. Ser. 2006, 175e176.
5. Peterson, M. A.; Nilsson, B. L.; Sarker, S.; Doboszewski, B.; Zhang, W.; Robins, M.
J. J. Org. Chem. 1999, 64, 8183e8192.
6. Robins, M. J.; Doboszewski, B.; Timoshchuk, V. A.; Peterson, M. A. J. Org. Chem.
2000, 65, 2939e2945.
7. Rozners, E.; Liu, Y. J. Org. Chem. 2005, 70, 9841e9848; Rozners, E.; Liu, Y. Org.
Lett. 2003, 5, 181e184.
8. Whitesell, J. K.; Lawrence, R. M.; Chen, H.-H. J. Org. Chem. 1986, 51, 4779e4784.
9. Matin, M. M. J. Appl. Sci. Res. 2008, 4, 1478e1482.
10. Yoon, N. M.; Gyoung, Y. S. J. Org. Chem. 1985, 50, 2443e2450.
11. Brown, H. C.; Choi, Y. M.; Narasimhan, S. J. Org. Chem. 1982, 47, 3153e3163.
12. Hou, D.; Reibenspies, J. H.; Burgess, K. J. Org. Chem. 2001, 66, 206e215.
13. Piers, E.; Chong, J. M. J. Org. Chem. 1982, 47, 1604e1606.
14. Nicolaou, K. C.; Daines, R. A.; Uenishi, J.; Li, W. S.; Papahatjis, D. P.; Chakraborty,
T. K. J. Am. Chem. Soc. 1988, 110, 4672e4685.
(CDCl3, 300 MHz)
d
7.65 (d, J¼8.6 Hz, 1H), 7.29 (m, 12H), 6.80 (d,
J¼9.0 Hz, 2H), 5.81 (s, 1H), 5.60 (d, J¼8.1 Hz, 1H), 5.46 (d, J¼5.7 Hz,
1H), 4.04 (m, 1H), 3.76 (s, 3H), 2.95 (q, J¼7.1 Hz, 6H), 2.72 (m, 2H),
2.26 (m, 3H), 2.06 (s, 3H), 1.17 (t, J¼7.14 Hz, 9H). 13C NMR (CDCl3,
72 MHz)
d 175.7, 169.6, 163.7, 158.2, 150.7, 150.1, 146.2, 146.1, 140.4,