Synthesis of unnatural C-2 amino acid nucleosides using NIS-mediated ring opening of 1,2-cyclopropane carboxylated sugar derivatives

Article abstract of DOI:10.1055/s-0028-1087545

We have developed a general and efficient method for the stereoselective construction of pyrimidine-based pyranosyl C-2 amino acid nucleosides using NIS-mediated ring opening of 1,2-cyclopropanated sugar derivatives. This methodology has been successfully

Full text of DOI:10.1055/s-0028-1087545

LETTER
451
Synthesis of Unnatural C-2 Amino Acid Nucleosides Using NIS-Mediated
Ring Opening of 1,2-Cyclopropane Carboxylated Sugar Derivatives
Synthesisof
U
h
nnatural
C
-2
r
A
mino
u
A
cid
N
ucleo
t
sides isagar Dattatraya Haveli, Sudipta Roy, Srinivasan Chandrasekaran*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
E-mail: scn@orgchem.iisc.ernet.in
Received 2 October 2008
Dedicated to Professor M. V. George on the occasion of his 80th birthday
cient methodology for the synthesis of 2-C-branched
glycoamino acids by ring opening of 1,2-cyclopropane
carboxylated sugar derivatives6 and it has been success-
fully applied to the synthesis of fused perhydrofuro[2,3-
Abstract: We have developed a general and efficient method for
the stereoselective construction of pyrimidine-based pyranosyl C-2
amino acid nucleosides using NIS-mediated ring opening of 1,2-
cyclopropanated sugar derivatives. This methodology has been suc-
cessfully extended to the synthesis of furanosyl nucleosides, which b]pyrano-g-butyrolactone derivatives.7 In this report, we
have potential applications in the development of novel, nontoxic
describe the synthesis of a few unnatural C-2 amino acid
antifungal therapeutics.
nucleoside derivatives of the type 6 using NIS-mediated
ring opening of 1,2-cyclopropanated sugar derivatives
(Scheme 1).
Key words: amino acid nucleoside, donor–acceptor, polyoxin, pu-
rine, pyrimidine
Cyclopropanation of tri-O-benzyl-D-glucal (1) was car-
ried out using methyl diazoacetate (MDA) in dichloro-
methane with catalytic rhodium acetate (25 °C, 90 min) to
furnish the corresponding 1,2-cyclopropane carboxylated
sugar derivative 2 in 59% yield.8 Treatment of 2 with N-
iodosuccinimide and trimethylsilyl-activated thymine9 3
(1 equiv each, CH2Cl2, 25 °C) furnished the iodo com-
pound 4 only in 10% yield after 36 hours, whereas the use
of 2.5 equivalent of each reagent (CH2Cl2, 25 °C, 48 h)
gave the iodide 4 in 82% yield.10 In the process, we have
succeeded in the attachment of the nucleobase as well as
Peptidyl nucleoside antibiotics are a unique class of sec-
ondary metabolites1 that exhibit high antifungal activity
against a wide range of pathogenic fungi.2 For making
these molecules, nature uses amino acids and nucleosides
as raw materials. Generally total synthesis of these mole-
cules requires some special strategies due to their unique
combination of functional groups.3,4 Diversity of structur-
al arrangement present in these molecules can be used to
design new compounds having interesting biological ac-
tivity.5 Earlier, we reported from our laboratory an effi-
OTMS
N
O
NH
O
N
O
N
OTMS
O
O
O
BnO
BnO
BnO
BnO
N2CHCOOCH3
3
BnO
BnO
O
OMe
Rh2(OAc)4
CH2Cl2
59%
NIS, 48 h
82%
OMe
I
OBn
2
OBn
1
OBn
H
4
NaN3
DMF, 24 h
96%
O
O
O
NH
NH
NH
N
O
O
N
O
O
N
O
BnO
BnO
O
H
O
BnO
O
H
BnO
BnO
O
H
reagent
solvent
+
OMe
BnO
OMe
PPh3
OMe
OBn N3
OBn
N
OBn NH2
6
7
5
Scheme 1 Synthesis of unnatural C-2 amino acid nucleoside 6
SYNLETT 2009, No. 3, pp 0451–0455
x
x.
x
x.
2
0
0
9
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087545; Art ID: D34708ST
© Georg Thieme Verlag Stuttgart · New York

452
S. D. Haveli et al.
LETTER
the generation of amino acid precursor simultaneously in After successfully standardizing the reaction protocol, we
a single step. The iodide 4 was converted into the corre- decided to vary the pyrimidine base. In this regard, cyclo-
sponding azide 5 using NaN3 (DMF, r.t., 24 h) in quanti- propane ester 2 was treated with the TMS-activated uracil
tative yield. The crystal structure of compound 5 was in 8 and fluorouracil 129 under the same reaction conditions
accord with our stereochemical assignment at C1, C2 and to get the corresponding iodides 9 and 13, respectively, in
C7 (carbohydrate nomenclature) for the ring-opened good yields (Table 2). These iodides 9 and 13 were con-
product.11 The azide 5 was subjected to the standard verted into the corresponding azides 10 and 14, respec-
Staudinger reduction conditions12 using PPh3–THF fol- tively, using NaN3 under similar conditions as described
lowed by aqueous hydrolysis. Unfortunately, we got the earlier. The azides 10 and 14 on reduction with Zn
expected amine 6 only in 30% yield and the correspond- (AcOH–THF, 25 °C, 3 h) afforded the corresponding amino
ing imine 7 was obtained as the major product, even after acid nucleosides 11 and 15, respectively in good yields.
refluxing for 18 hours. Use of Lindlar’s catalyst13 was also
Having achieved the synthesis of glucose-derived pyri-
found to be ineffective for the reduction. Benzyltriethyl-
midine nucleosides successfully, we next explored the
ammonium tetrathiomolybdate14 [(BnNEt3)MoS4], a ver-
generality of the reaction by changing the carbohydrate
satile alternative reagent to thiols also could not give the
part to a galactal derivative. Tribenzyl galactal derived
expected product in good yield. Finally, zinc-mediated15
reduction (AcOH–THF, 1:1, 25 °C, 3 h) was found to be
the best, which gave the corresponding amine 6 in 80%
yield (Table 1).
1,2-cyclopropane carboxylated sugar derivative 168 was
treated with NIS and TMS-activated thymine 3, which
gave the corresponding iodide 17 in 80% yield. The iodide
17 was then converted into the corresponding azide 18
(87%). Using the previously established conditions for
azide reduction, the galactal-derived C-2 amino acid nu-
Table 1 Reduction of Azide 5 with Various Reagents
cleoside 19 was obtained in good yield (Table 2).
Reagent
Solvent
6 yield (%) 7 yield (%)
Among the various complex peptidyl nucleosides, poly-
oxins and nikkomycins are the nucleoamino acids that are
well known and the most effective inhibitors of chitin syn-
thase.16 Polyoxin C constitutes the basic amino acid nu-
cleoside common to the many members of the polyoxin
family. Many synthetic routes have been developed for
PPh3
THF–H2O
EtOAc
30
0
ca. 50
Lindlar’s catalyst
(BnNEt3)MoS4
Zn
0
0
0
MeCN–H2O
AcOH–THF
20
80
Table 2 Synthesis of Pyrimidine-Based Unnatural C-2 Amino Acid Nucleosides
Cyclopropane
Base
Iodide (%)a
Azide (%)a
Amino acid nucleoside (%)a
O
O
NH
OTMS
O
BnO
OMe
O
N
O
N
9 (75)
10 (96)
BnO
BnO
O
BnO
N
OTMS
OBn
OMe
8
H
2
2
OBn NH2
O
11 (69)
F
NH
O
OTMS
F
O
N
O
N
13 (75)
14 (82)
BnO
BnO
N
OTMS
OMe
12
H
OBn NH2
O
15 (68)
O
NH
OTMS
O
BnO
OMe
O
N
O
N
N
17 (80)
18 (87)
BnO
BnO
O
BnO
OTMS
OBn
OMe
3
H
16
OBn NH2
19 (69)
a Isolated yield after colomn chromatography.
Synlett 2009, No. 3, 451–455 © Thieme Stuttgart · New York

LETTER
Synthesis of Unnatural C-2 Amino Acid Nucleosides
453
Table 3 Synthesis of Furanosyl Unnatural C-2 Amino Acid Nucleosides 23 and 26 from Mannose-Derived 1,2-Cyclopropane Carboxylate 20
Cyclopropane
Iodide (%)a
Azide (%)a
Amino acid nucleoside (%)a
O
NH
O
O
O
O
N
O
O
O
OMe
21 (71)
22 (80)
O
O
BnO
BnO
20
OMe
H2N
H
23 (70)
O
NH
O
N
O
O
20
24 (68)
25 (76)
O
O
BnO
OMe
H2N
H
26 (65)
a Isolated yield after colomn chromatography.
O
N
O
N
NH
O
NH
O
O
BnO
O
O
O
O
O
HO
HO
10% Pd/C, H2
BnO
BnO
OMe
MeOH, 12 h
82%
OMe
BnO
OBn
2
OMe
H
H
OH NH2
OBn N3
27
10
Scheme 2 Synthesis of uracil-substituted pyranosyl C-2 amino acid nucleoside 27
the synthesis of these polyoxins and their analogues.17 clearly demonstrate the potential utility of NIS-mediated
Keeping this in mind, our methodology was subsequently cyclopropane carboxylate ring-opening reaction for the
extended to the reaction of cyclopropanated furan deriva- construction of C-2 amino acid nucleoside structural
tives. The furanosyl cyclopropanated ester 20 was synthe- framework of various pyranosyl peptidyl nucleoside anti-
sized from mannose as previously reported in the biotic analogues in a short and efficient way.
literature.18
While this work was in progress we came across a report
The ester 20 when treated with NIS (2.5 equiv) and TMS- on the synthetic studies of amipurimycine.20 While this
activated thymine 3 (2.5 equiv, CH2Cl2, 25 °C, 48 h) gave group had cleverly synthesized the pyrimidine-based
the corresponding iodide 21 (71%; Table 3). The iodide thymine amipurimycine analogue, their attempts failed to
21 was converted into the corresponding azide 22 (80%), attach the purine base to get the amipurimycine. There-
followed by the reduction with Zn to get the correspond- fore, we decided to test the generality of our methodology
ing furanosyl amino acid nucleoside 23 in 70% yield. for the synthesis of purine-based C-2 amino acid nucleo-
Similarly, ester 20 when treated with NIS and TMS-acti- sides. In the preliminary studies, cyclopropyl ester 2 was
vated uracil 8 gave the corresponding iodide 24 in 68% treated with the freshly prepared TMS-activated gua-
yield, which was then converted into the azide 25 (76%). nosine 28 and NIS (2.5 equiv, CH2Cl2, 25 °C, 48 h). Un-
Reduction of 25 with Zn (AcOH–THF, 25 °C, 3 h) afford- expectedly, it gave a mixture of products which could not
ed the uracil-based furanosyl amino acid nucleoside 26 in be separated by column chromatography or by crystalliza-
65% yield.
tion (Scheme 3). However, when we treated the cyclopro-
pyl ester 2 with the freshly prepared TMS-activated N-
benzyl purine 29 and NIS (2.5 equiv, CH2Cl2, 25 °C, 48
h), it gave the corresponding iodide 30 in moderate yield.
The iodide 30 was converted into the corresponding azide
31 followed by Zn-mediated reduction to give the corre-
sponding purine-based amino acid nucleoside 32 in 71%
yield.
There are some recent reports on the synthesis of pyrano-
syl nucleoside amino acid cores as higher analogues of
polyoxin.19 In light of this, we subjected the nucleoside
azide 10 to palladium-mediated hydrogenation and it is
noteworthy that we got the corresponding amino triol 27
in 82% yield (Scheme 2). All the above reaction schemes
Synlett 2009, No. 3, 451–455 © Thieme Stuttgart · New York

454
S. D. Haveli et al.
LETTER
OTMS
N
N
O
N
N
NHTMS
O
TMS
BnO
BnO
28
OMe
inseperable mixture of products
NIS, 48 h
OBn
BnTMSN
2
BnNH
N
N
N
N
N
N
TMS
O
N
O
N
O
29
BnO
BnO
BnO
BnO
O
OMe
NIS, 48 h
51%
OMe
I
OBn
OBn
H
30
2
NaN3
DMF, 24 h
78%
BnNH
BnNH
N
N
N
N
N
N
N
Zn
N
O
O
BnO
BnO
O
BnO
BnO
O
AcOH–THF
(1:1)
OMe
OMe
71%
H
H
OBn N3
OBn NH2
31
32
Scheme 3 Synthesis of unnatural C-2 amino acid nucleoside 32 having a purine base
(4) For reviews, see: (a) Zang, D.; Miller, M. J. Curr. Pharm.
Des. 1995, 5, 73; and references therein. (b) Garner, P.
Synthetic Approaches to Complex Nucleoside Antibiotics, In
Studies in Natural Products Chemistry, Stereoselective
Synthesis (Part A), Vol. 1; Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, 1988, 397. (c) Knapp, S. Chem. Rev. 1995, 95,
1859; and references therein.
(5) (a) Aggarwal, V. K.; Monteiro, N. J. Chem. Soc., Perkin
Trans. 1 1997, 2531. (b) Poon, K. W. C.; Liang, N.; Datta,
A. Nucleosides Nucleotides 2008, 27, 389.
In conclusion, we have developed a general and efficient
method for the stereoselective construction of pyrimidine-
based pyranosyl C-2 amino acid nucleosides using NIS-
mediated ring-opening reaction of 1,2-cyclopropanated
sugar derivatives,21 which yet again illustrates the utility
of donor–acceptor-substituted cyclopropane derivatives
in organic synthesis.22 This methodology has been suc-
cessfully extended to the synthesis of furanosyl nucleo-
sides, which have potential applications in the
development of novel, nontoxic antifungal therapeutics.
Partial success has been achieved in the application of this
methodology for the synthesis of purine-based pyranosyl
amino acid nucleosides. Application of this methodology
towards the synthesis of a C-2 analogue of polyoxin C is
currently in progress.
(6) Sridhar, P. R.; Ashalu, K. C.; Chandrasekaran, S. Org. Lett.
2004, 6, 1777.
(7) Haveli, S. D.; Perumal, S.; Sridhar, P. R.; Chandrasekaran,
S. Org. Lett. 2007, 9, 1331.
(8) Timmers, C. M.; Leeuwenburgh, M. A.; Verheijen, J. C.;
Marel, V. G.; Boom, J. H. Tetrahedron: Asymmetry 1996, 7,
49.
(9) González-Díaz, H.; Bonet, I.; Terán, C.; De Clercq, E.;
Bello, R.; García, M. M.; Santana, L.; Uriarte, E. Eur. J.
Med. Chem. 2007, 42, 580.
Acknowledgment
(10) Addition of further equivalence of the reagents did not result
in any noticeable increase in the yield. The use of excess NIS
in the presence of stoichiometric amount of nucleobase was
not effective as the reaction was found to be incomplete even
after 48 h.
(11) CCDC 706702 contains the supplementary crystallographic
data for the azide 5.
(12) Tian, W. Q.; Wang, Y. A. J. Org. Chem. 2004, 69, 4299.
(13) Mehta, G.; Mohal, N. Tetrahedron Lett. 2001, 42, 4227.
(14) Prabhu, K. R.; Deven, M. N.; Chandrasekaran, S. Synlett
2002, 1762; and references therein.
S.D.H. thanks the University Grants Commission, New Delhi, for a
senior research fellowship.
References and Notes
(1) Isono, K. J. Antibiotics 1988, 41, 1711.
(2) Isono, K. Pharmacol. Ther. 1991, 52, 269.
(3) Suhadolnik, R. J. Nucleoside Antibiotics; Wiley: New York,
1970.
(15) Habay, S. A.; Schafmeister, C. E. Org. Lett. 2004, 6, 3369.
Synlett 2009, No. 3, 451–455 © Thieme Stuttgart · New York

LETTER
Synthesis of Unnatural C-2 Amino Acid Nucleosides
455
(16) (a) Kaneko, M. J. Synth. Org. Chem., Jpn. 1991, 49, 989.
(b) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Annu.
Rep. Med. Chem. 1994, 29, 145. (c) Cabib, E. Antimicrob.
Agents Chemother. 1991, 35, 170. (d) Gaughran, J. P.; Lai,
M. H.; Kirsch, D. R.; Silverman, S. J. J. Bacteriol. 1994,
176, 5857. (e) Aoki, Y.; Kondoh, M.; Nakamura, M.; Fujii,
T.; Yamazaki, T.; Shimada, H.; Arisawa, M. J. Antibiot.
1994, 47, 909; and references therein.
(17) (a) Barrett, A. G. M.; Lebold, S. A. J. Org. Chem. 1990, 55,
3853. (b) Barrett, A. G. M.; Lebold, S. A. J. Org. Chem.
1990, 55, 5818. (c) Auberson, Y.; Vogel, P. Tetrahedron
1990, 46, 7019. (d) Barrett, A. G.; Lebold, S. A. J. Org.
Chem. 1991, 56, 4875. (e) Koizumi, K.; Kitada, Y.;
Yokoyama, C.; Ogawa, S. J. Chem. Soc., Chem. Commun.
1994, 111. (f) Dondoni, A.; Junquera, F.; Merchan, F. L.;
Merino, P.; Tejero, T. Tetrahedron Lett. 1994, 35, 9439.
(g) Evina, C. M.; Guillerm, G. Tetrahedron Lett. 1996, 37,
163. (h) Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1996, 118,
3037. (i) Knapp, S. Chem. Rev. 1995, 95, 1859.
Compound 5: mp 182 °C; Rf (EtOAc–PE, 2:3) 0.3; [a]D
+42.22 (c = 1.8, CHCl3). IR (neat): 2114, 1744, 1713, 1693,
1496, 1265, 737, 699 cm–1. 1H NMR (400 MHz, CDCl3):
d = 8.45 (s, 1 H), 7.22–7.37 (m, 15 H), 6.99 (s, 1 H), 5.77 (d,
J = 7.1 Hz, 1 H), 5.00 (d, J = 11.6 Hz, 1 H), 4.32 (d, J = 10.4
Hz, 1 H), 4.66 (dd, J = 4.8 Hz, J2 = 17.2 Hz, 2 H), 4.57 (d,
J = 12.4 Hz, 1 H), 4.49 (d, J = 12.4 Hz, 1 H), 4.39 (d, J = 1.8
Hz, 1 H), 3.83–3.72 (m, 3 H), 3.64–3.66 (m, 1 H), 3.55 (m,
4 H), 2.51 (br s, 1 H), 1.91 (s, 3 H). 13C NMR (100 MHz,
CDCl3): d = 169.4, 163.0, 149.4, 137.6, 137.5, 137.4, 128.6,
128.5, 128.4, 128.3, 128.1, 127.9, 110.8, 79.0, 78.4, 77.3,
75.2, 74.8, 73.4, 68.0, 57.9, 52.7, 47.3, 22.5. HRMS: m/z [M
+ Na] calcd for C35H37N5O8: 678.2540; found: 678.2554.
General Procedure for the Reduction of Azides Using
Zn; Synthesis of Amino Acid Nucleoside 6: To a stirred
solution of azide 5 (0.105 g, 0.16 mmol) in AcOH–THF (1:1,
5 mL) was added zinc (0.0009 g, 10 mmol%) and the
reaction was stirred for 3 h at r.t. (25 °C). After the
disappearance of the starting material (by TLC), Zn was
removed by filtration and the filtrate was diluted with EtOAc
(15 mL). The organic layer was thoroughly washed with
NaHCO3 solution. It was separated and dried over anhyd
Na2SO4. The filtrate was concentrated and the crude product
was purified by flash chromatography on silica gel (230–400
mesh) using 20% MeOH–CHCl3 to obtain the corresponding
C-2 amino acid nucleoside 6 as a colorless gummy solid
(0.080 g, 80%).
(18) Kim, C.; Hoang, R.; Theodorakis, A. Org. Lett. 1999, 1,
1295.
(19) (a) Bhaket, P.; Stuaffer, C. S.; Dutta, A. J. Org. Chem. 2004,
69, 8594. (b) Bhaket, P.; Stuaffer, C. S.; Fothergill, A. W.;
Rinaldi, M. G.; Dutta, A. J. Org. Chem. 2007, 72, 9991.
(20) Stuaffer, C. S.; Dutta, A. J. Org. Chem. 2008, 73, 4166.
(21) General Procedure for the NIS-Mediated Ring Opening
of Cyclopropyl Carboxylates; Synthesis of Iodide 4: To a
solution of cyclopropyl carboxylate 2 (0.488 g, 1 mmol) in
CH2Cl2 (10 mL), freshly prepared TMS-activated thymine 3
(0.675 g, 2.5 mmol) and NIS (0.562 g, 2.5 mmol) were added
under an argon atmosphere at r.t. (25 °C). After 48 h the
reaction mixture was diluted with CHCl3 (10 mL) and then
neutralized with dilute Na2S2O3 solution. Insoluble material
was removed by filtration. The organic layer was separated
and dried over anhyd Na2SO4.The filtrate was concentrated
and the crude product was purified by flash chromatography
on silica gel (230–400 mesh) using 40% EtOAc–PE, which
gave the corresponding iodide 4 as a gummy solid (0.606 g,
82%).
Compound 6: Rf (MeOH–CHCl3, 4:1) 0.35; [a]D +12 (c = 2,
CHCl3). IR neat): 3584, 3064, 3031, 2953, 2919, 1739, 1733,
1694, 1455, 1368, 1267, 1155, 1111, 736, 698, 666 cm–1. 1H
NMR (400 MHz, CDCl3): d = 8.92 (br s, 1 H), 7.21–7.33 (m,
15 H), 7.06 (s, 1 H), 5.77 (d, J = 10.4 Hz, 1 H), 4.99 (d, J =
11.6 Hz, 1 H), 4.86 (d, J = 11.2 Hz, 1 H), 4.73 (d, J = 11.6
Hz, 1 H), 4.65 (d, J = 11.2 Hz, 1 H), 4.50–4.60 (m, 3 H),
4.10–4.04 (m, 1 H), 3.61–3.80 (m, 6 H), 3.46 (s, 3 H), 2.41
(m, 1 H), 1.93 (s, 3 H). 13C NMR (100 MHz, CDCl3): d =
176.0, 163.8, 150.7, 138.5, 138.3, 136.0, 129.0, 128.9,
128.4, 128.3, 128.2, 111.6, 80.0, 79.5, 75.7, 75.3, 73.8, 68.8,
52.5, 51.0, 49.9, 30.8, 12.9. HRMS: m/z [M + Na] calcd for
C35H39N3O8: 652.2635; found: 652.2662.
General Procedure for the Reduction of Azide 10 Using
Pd/C: A suspension of 10% Pd/C (0.040 g) and azide 10
(0.040 g, 0.06 mmol) in MeOH (2 mL) under hydrogen
atmosphere was stirred for 12 h at ambient temperature (25
°C). The catalyst was filtered and washed with MeOH (20
mL). The filtrate was concentrated and the crude product
was purified by flash column chromatography (10% CHCl3–
MeOH) to get the corresponding amino triol 27 as a gummy
solid (0.017 g, 82%).
Compound 27: Rf (MeOH–CHCl3, 1:9) 0.2; [a]D +6.5 (c = 2,
DMF). IR (neat): 3417, 1659, 1651, 1644, 1049, 1026, 1004,
826, 764 cm–1. 1H NMR (400 MHz, DMSO): d = 10.32 (s, 1
H), 7.50 (d, J = 8.1 Hz, 1 H), 5.60 (d, J = 8.0 Hz, 1 H), 5.56
(d, J = 10.0 Hz, 1 H), 4.45 (t, J = 6.0 Hz, 1 H), 3.73 (d, J =
12.0 Hz, 1 H), 3.53–3.66 (m, 5 H), 3.20–3.35 (m, 2 H), 1.89–
2.13 (m, 5 H). 13C NMR (100 MHz, DMSO): d = 177.2,
163.8, 151.5, 141.9, 103.0, 81.1, 79.9, 72.0, 61.9, 52.6, 51.1,
50.1, 21.6. HRMS: m/z [M + Na] calcd for C13H19N3O8:
368.1070; found: 368.1065.
Compound 4: Rf (EtOAc–PE, 2:3) 0.35; [a]D +31.0 (c = 2,
CHCl3). IR (neat): 3214, 3064, 3032, 1721, 1714, 1694,
1454, 1368, 1267, 1027, 736, 698 cm–1. 1H NMR (400 MHz,
CDCl3): d = 9.05 (s, 1 H), 7.10–7.34 (m, 18 H), 5.97 (d, J =
9.9 Hz, 1 H), 5.00 (d, AB type, J = 10.5 Hz, 1 H), 4.74 (d,
AB type, J = 10.5, 1 H), 4.31 (d, AB type, J = 10.2 Hz, 1 H),
4.46–4.63 (m, 3 H), 3.98 (q, J = 7.8 Hz, 2 H), 3.81 (dd, J1 =
3.6 Hz, J2 = 11.1 Hz, 1 H), 3.62–3.71 (m, 2 H), 3.84 (s, 3 H),
1.94 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 167.2, 163.1,
150.2, 137.9, 137.7, 137.4, 134.9, 128.4, 127.7, 127.5,
112.3, 82.0, 78.9, 77.4, 74.7, 74.6, 73.4, 68.3, 53.6, 48.8,
23.3, 12.5. HRMS: m/z [M + Na] calcd for C35H37IN2O8:
763.1492; found: 763.1559.
General Procedure for the Preparation of Azides;
Synthesis of Azide 5: To a stirred solution of iodide 4 (0.236
g, 0.31 mmol) in anhyd DMF (2 mL) was added sodium
azide (0.040 g, 0.62 mmol) and the reaction was stirred for
24 h at r.t. (25 °C). Most of the DMF was removed under
vacuum followed by dilution with CHCl3 (10 mL), which
was washed with H2O. The organic layer was separated and
dried over anhyd Na2SO4. The filtrate was concentrated and
the crude product was purified by flash chromatography on
silica gel (230–400 mesh) using 40% EtOAc–PE to obtain
the corresponding azide 5 as a pale yellow solid (0.200 g,
96%).
(22) For reviews, see: (a) Reissig, H. U. Top. Curr. Chem. 1988,
144, 73. (b) Reissig, H. U.; Zimmer, R. Chem. Rev. 2003,
103, 1151. (c) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005,
61, 321.
Synlett 2009, No. 3, 451–455 © Thieme Stuttgart · New York

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