Preliminary SAR analysis of novel antiproliferative N6,5′-bis-ureidoadenosine derivatives

Article abstract of DOI:10.1016/j.bmcl.2009.09.083

A preliminary library of novel N⁶,5′-bis-ureidoadenosine analogs and related derivatives was prepared and tested for activity against the NCI 60 panel of human cancers. A 2′-O-TBS group was found to be necessary, but not sufficient, for optimal

Full text of DOI:10.1016/j.bmcl.2009.09.083

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6775–6779
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Preliminary SAR analysis of novel antiproliferative
N6,50-bis-ureidoadenosine derivatives
*
Matt A. Peterson , Marcelio Oliveira, Michael A. Christiansen, Christopher E. Cutler
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, United States
a r t i c l e i n f o
a b s t r a c t
A preliminary library of novel N6,50-bis-ureidoadenosine analogs and related derivatives was prepared
and tested for activity against the NCI 60 panel of human cancers. A 20-O-TBS group was found to be nec-
essary, but not sufficient, for optimal antiproliferative activity. Neither the N6- nor 50-ureido substituents
were sufficient to achieve significant antiproliferative effects when present in the absence of the other.
The 20-O-TBS, and N6,50-bis-ureido substitution patterns were found to be necessary for optimal antipro-
liferative activity.
Article history:
Received 3 September 2009
Accepted 22 September 2009
Available online 2 October 2009
Keywords:
Purine nucleosides
Bio-active adenosine derivatives
Antiproliferative/growth inhibitory
nucleosides
Ó 2009 Elsevier Ltd. All rights reserved.
Derivatives of naturally occurring nucleosides have attracted
considerable interest over the years as their potential for providing
potent and selective treatments for viral infections and/or cancer
has been elucidated.1 Of the approximately 60 small molecule
drugs approved by the U.S. FDA for treating cancer, 10 are nucleo-
side or nucleobase derivatives, while nucleosides continue to com-
prise the single largest class of clinically useful antiviral agents.1a
In the area of HIV, 8 of the 12 currently approved reverse transcrip-
tase inhibitors are nucleoside derivatives.2 Numerous derivatives
of adenosine have been reported. Modifications of both the sugar
and the nucleobase have been examined. Many of these derivatives
have been prepared in efforts to develop potent and selective aden-
osine receptor agonists and/or antagonists.3 Adenosine receptors
play important roles in such diverse physiological processes as cell
growth and differentiation,4a platelet aggregation,4b immunosu-
pression,4c regulation of myocardial oxygen and coronary blood
flow,4d and apoptosis.4a
Of the possible ureidoadenosine derivatives studied so far, the
N6-ureido analogs have been most extensively examined.5 30-Ure-
ido derivatives have also been studied,6 while 50-ureido derivatives
have been the subject of more limited investigation.7 Until only re-
cently, N6,50-bis-ureidoadenosines appear never to have been
investigated.8 Here, we report the biological evaluation of a preli-
minary array of N6,50-bis-ureidoadenosines or N6- or 50-ureidoade-
nosine derivatives and related analogs (Fig. 1). The analogs tested
were designed to probe the minimal structural requirements for
antiproliferative activity in the NCI 60 panel of human cancers,
and variations in all four canonical quadrants of lead compound
1 were investigated (Fig. 1).
Compounds 1 and 2 had been examined previously and showed
comparable low micromolar antiproliferative activities (GI50 = 1–
6 lM) against all six leukemia cell lines and similar activities were
exhibited against numerous other cell lines in the NCI 60 panel.8b
Interestingly, in the same study, compounds 7–10 were almost
completely devoid of significant antiproliferative activities at
10 l
M compound concentration.8b This prompted us to conclude
that a minimal structural requirement for antiproliferative activity
is a lipophilic TBS group in the SE quadrant. Left in doubt from
these initial studies was the relative impact of substituents in the
NE, NW, and SW quadrants. Accordingly, compounds 3–6 and
11–13 were prepared and tested. Compounds 3, 6, 12, and 13 were
prepared as previously reported8a while compounds 4, 5, and 11
were prepared via the routes depicted (Scheme 1). Briefly, treat-
ment of 139 with 4-nitrophenyl-N-methylcarbamate gave 4 with
only trace amounts (2–3%) of N6-ureido byproduct. Treatment of
4 with phenylisocyanate gave 5.10 Compound 1411 could be con-
verted to intermediate 15 via a two-pot, three step method, and
compound 15 was converted cleanly to compound 11.10
The results from the NCI 60 single dose growth inhibition assay
are given in Table 1. Importantly, only compounds 5 and 11 gave
significant growth inhibition (GI percent 6 50). Compound 11
inhibited 45 of the 57 cell lines at this level, while compound 5
inhibited 22. Of the remaining compounds, only 12 inhibited pro-
liferation with GI percent 6 50, and this was observed for a single
cell line (ovarian cancer; IGROV1). As points of comparison, com-
pound 1 inhibited proliferation with GI percent 6 50 in 20 of the
NCI 60 cell lines in a 10
lM single dose growth inhibition assay,
* Corresponding author.
and compounds 7–10 were essentially devoid of significant
E-mail address: matt_peterson@byu.edu (M.A. Peterson).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.083

6776
M. A. Peterson et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6775–6779
N
NE
O
Ph
HN
N
H
N
N
N
NW
CH3
O
N
N
H
N
H
O
W
E
SE
O
OTBS
SW
OEt
1
NHR2
NHR2
N
N
N
N
N
N
R1
O
S
R1
N
N
O
O
OR3
O
R4
O
R1
R2
R3
R4
R1
R2
2
3
4
5
6
7
8
CH3NHCONH CONHC6H5 TBS
N(CH3)O CH3
N3
CONHC6H
CH3NHCONH
OEt
CH3NHCONH
H
H
TBS
TBS
CONHC6H5
5
CH3NHCOO
OEt
CH3NHCOO CONHC6H5 TBS
OEt
N3
OEt
CONHC6H5 TBS
O
Ph
NH2
NH2
N
HN
N
N
H
N
N
N
N
N
N
N
O
CH3
N
O
N
N
HO
HO
N
H
N
H
O
O
R1O
OTBS
OTBS
OR2
12
CO2Et
O
13
R1 = R2
(CH3)2C
OEt
9
10 H
11 TBS
Figure 1.
antiproliferative activities at this concentration. The lack of signif-
icant antiproliferative activities for compounds 3 and 4 points to
the critical nature of the substituent in the NE quadrant.
NH2
N
NH2
N
N
N
Although 3 and 4 each possess the 20-O-TBS, 30-ethoxycarbon-
ylmethyl and 50-N-methylurea or 50-N-methylcarbamate in the SE,
SW, and NW quadrants, respectively, absence of the N6-phenylu-
rea in the NE quadrant essentially abrogates their antiprolifera-
tive activities. Lack of significant activity for compound 6 on the
other hand points to the critical nature of the substituent in the
NW quadrant since activity is lost in spite of the fact that 6 pos-
sesses the NE, SE, and SW substitution patterns required by the
active analogs. The lack of activity exhibited by compounds 7–
10 had indicated that a lipophilic 20-O-TBS was an essential
requirement for optimal growth inhibition. However, the impor-
tance of this substitution relative to substituents in the other
quadrants was more fully clarified by the activities exhibited by
compounds 12 and 13, each of which lacks substituents in the
NE and NW quadrants. Clearly, 20-O-TBS substitution in the SE
quadrant is necessary, but not sufficient, for maximal antiprolifer-
ative activity as illustrated by the lack of activity exhibited by
compounds 12 and 13. We were delighted to learn that introduc-
tion of a TBS group at the 30-position in compound 11 seemed to
be well tolerated and compound 11 exhibited promising activities
in the single dose growth inhibition assay. These activities sug-
gest that the more synthetically challenging 30-ethoxycarbonylm-
ethyl substituents in the SW quadrants of 1, 2, and 5 are not
necessary for optimal activity. The synthesis of compound 11 is
N
N
O
CH3
N
a
N
b
HO
O
N
H
O
O
O
O
5
96 %
OTBS
OTBS
13
4
OEt
OEt 96 %
O
N
Ph
NH2
N
HN
N
H
N
N
N
N
N
N
Cl
N3
e,a
c,d,b
O
O
11
86 %
HO
O
OH
TBSO
OTBS
14
15
65 %
O
O
Ph
Ph
HN
N
N
HN
N
N
H
H
N
N
N
N
N
N
O
CH3
CH3
N
H
N
H
N
O
O
H
O
TBSO
O
OTBS
OTBS
11
5
OEt
Scheme 1. Reagents and conditions: (a) p-NO2–C6H4OCONHCH3/base/EtOAc, rt; (b)
PhN@C@O/CH2Cl2, rt, 5d; (c) NaN3/DMF, 150 °C, 1 h; (d) TBSCl/DMF, rt, 16 h; (e) H2/
Pd-C/EtOAc.
from
4 to 6 steps shorter than corresponding methods for
preparing compounds 1 and 2, respectively. The relatively easy

M. A. Peterson et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6775–6779
6777
Table 1
accessibility of compound 11 opens the door for more extensive
SAR studies designed to test the effect of various substituents in
the NE and NW quadrants.
Results of Single Dose Growth Inhibition Assay (GI Percent at 10
l
M)a
12
Cell line
3
4
5
6
11
13
Our original interest in exploring the activities of 50-carbamoyl
compounds 4 and 5 had been to potentially avoid the problems
inherent with preparing the 50-azido-50-deoxyadenosine interme-
diates needed to prepare 50-ureas. The classical approach for pre-
paring 50-ureidoadenosine derivatives involves activation of the
50-position with a good leaving group followed by nucleophilic
substitution with azide to give the requisite 50-azido-50-deoxya-
denosine products. Unfortunately, such syntheses are notoriously
inefficient, since intramolecular cyclonucleoside formation and
attendant decomposition compete with the desired intermolecular
nucleophilic substitution.12 The most challenging step in the con-
version of 13 to 1, for example, involves conversion of 13 to com-
pound 16 (Scheme 2). Coming relatively late in the synthesis from
adenosine as this step does, a high yield, synthetically straightfor-
ward alternative method for introducing an effective substituent in
the NW quadrant would be advantageous. We were thus delighted
to learn that the 50-N-methylcarbamoyl moiety of compound 4
could be introduced in one easy step from 13 (Scheme 1), in con-
trast to the more synthetically demanding four-step approach
needed to convert 13 to compound 3 (Scheme 2).8b
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
98
98
80
86
55
79
57
63
51
72
79
75
43
24
34
24
20
119
76
84
75
81
83
107
106
108
98
23
23
34
39
89
84
74
99
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
84
92
84
94
99
97
94
92
83
74
95
79
105
99
106
75
51
68
77
62
56
88
91
13
45
103
89
98
100
62
97
99
104
90
23
23
62
ꢀ3
49
36
87
ꢀ7
46
100
86
99
90
90
99
81
110
74
100
75
91
81
90
107
91
101
92
111
79
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW620
117
84
100
97
111
103
96
104
55
81
67
ꢀ9
17
52
9
114
121
82
ꢀ100
ꢀ1
0
76
71
52
90
65
60
88
109
104
94
91
98
87
84
21
100
102
104
104
101
101
ꢀ68
ꢀ4
36
31
72
109
103
The 50-N-methylcarbamoyl moiety is an acceptable alternative
for the 50-N-methylurea in the NW quadrant, as illustrated by a
comparison of the antiproliferative activities of compounds 1, 2,
and 5 in the multi-dose growth inhibition assay (Table 2). It is
interesting to note that the antiproliferative activities exhibited
by these compounds followed the order of 1 > 5 > 2 (determined
by comparison of the total number of cell lines with GI50 val-
Melanoma
LOX IMVI
MALME-3M
M14
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
CNS cancer
SF-268
92
95
106
91
107
94
86
88
96
100
111
106
68
49
54
57
60
72
24
60
65
96
97
101
91
116
104
88
13
49
33
57
60
48
43
42
74
105
87
94
111
75
92
93
99
106
112
81
105
73
94
77
95
79
ues 6 6.0 lM: 35, 25, and 12, respectively). The NH to O substitu-
80
83
tion involved in going from 1 to 5 is apparently well tolerated in
this class of molecules, in contrast to the well known effect of
NH to O substitution observed in the naturally occurring substitu-
97
101
97
99
86
97
92
89
92
83
86
60
66
33
99
45
52
95
94
89
92
73
95
36
45
33
76
46
17
98
88
92
88
98
53
98
97
91
103
75
99
SF-295
SF-539
SNB-19
SNB-75
tion of D-alanine by D
-lactate in Vancomycin resistant bacteria.13
Tolerance of a 50-N-methylcarbamoyl group opens the possibility
of using 5 (or a 50-N-methylcarbamoyl substituted analog of com-
pound 11) as templates for more in-depth SAR studies designed to
probe the effect of substitution in the NE, SE, and SW quadrants.
In summary, we have prepared and tested a preliminary library
of compounds that demonstrate the impact of substitution in all
four canonical quadrants of lead antiproliferative agent, compound
1. From this preliminary study it can be concluded that a 20-O-TBS
group is necessary (but not sufficient) for growth inhibition, as is
also true for the 50- and N6-ureido substitutions. When occurring
individually in the absence of the other, neither 50- nor N6-ureido
U251
98
Ovarian cancer
IGROV1
97
98
99
87
100
110
118
98
78
115
98
94
49
51
42
94
74
95
93
111
66
107
98
53
ꢀ29
30
69
33
46
65
71
88
104
102
90
98
97
101
103
103
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
101
78
Renal cancer
786-0
A498
93
109
90
96
138
88
87
98
89
79
78
96
110
95
73
77
26
61
35
35
88
42
89
121
92
87
111
81
17
–
21
77
78
70
85
105
90
97
98
102
92
112
85
94
ACHN
CAKI-1
RXF393
SN12C
TK-10
60
ꢀ37
ꢀ79
34
NH2
N
NH2
N
N
N
N
N
101
87
103
83
85
76
UO-31
48
72
N
N
HO
O
N3
O
c,d
Breast cancer
BT-549
HS578T
O
a,b
O
3
85
98
87
96
92
95
74
93
98
85
77
84
65
57
12
72
62
29
100
92
85
95
95
73
40
61
0
38
36
14
80
107
94
81
71
79
102
89
90
94
OTBS
OTBS
13
16
MCF7
OEt
OEt
O
N
MDA-MB-231/ATCC
MDA-MB-468
T-47D
Ph
NH2
N
HN
N
N
H
79
82
N
N
N
N
O
O
Prostate cancer
DU-145
PC-3
CH3
CH3
N
98
98
100
84
59
32
105
64
52
8
71
93
93
85
N
H
N
H
N
H
N
H
e
O
O
a
Growth inhibition percent calculated as: [(Ti ꢀ Tz)/C ꢀ Tz)] ꢁ 100 for Ti P Tz;
[(Ti ꢀ Tz)/Tz)] ꢁ 100 for Ti < Tz; where Tz = absorbance at t = 0; Ti = absorbance at
t = 48 h (10 M test compound); C = absorbance of control at t = 48 h.
O
OTBS
O
OT BS
3
1
OEt
OEt
l
Scheme 2. Reagents and conditions: (a) TsCl/CH2Cl2, ꢀ23 °C, 15 h; (b)
(CH3)2NC@NH2N(CH3)2N3/DMF, 100 °C, 7 h; (c) H2/Pd-C/EtOAc (d) p-NO2–
C6H4OCONHCH3/Na2CO3/EtOAc, rt, 4 h; (e) PhN@C@O/CH2Cl2, rt, 5d.

6778
M. A. Peterson et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6775–6779
Table 2
substitution gave rise to potent growth inhibition, even in the
Results of multi-dose growth inhibition assay (GI50, l
M)a
presence of the essential 20-O-TBS moiety. Substitution at the 30-
position (SW quadrant) did not seem to be as critical as substitu-
tion in the other three quadrants. Thus, bis-O-TBS analog 11 exhib-
ited comparable activity to the synthetically more challenging lead
compound 1. Substitution of a carbamoyl group for the urea in the
NW quadrant gave compound 5 which also exhibited comparable
activities to compound 1. Compounds 11 and 5 offer synthetically
viable alternatives for preparing more extensive compound li-
braries based on bis-O-TBS and/or 50-N-methylcarbamoyl-substi-
tuted adenosine templates. We are currently pursuing this line of
research.
Cell line
1
2
5
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
6.69
3.01
3.59
2.39
1.09
2.23
6.37
1.81
3.12
2.23
1.58
1.27
3.23
1.39
3.09
1.99
2.16
—
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
4.18
17.7
8.96
<0.01
>100
33.3
>100
5.54
4.36
9.35
26.4
24.9
2.71
41.9
57.2
>100
7.49
11.1
6.93
3.39
14.7
6.52
11.8
12.9
31.7
4.45
9.58
Acknowledgments
Generous support from the BYU Cancer Research Center is
gratefully acknowledged. The NCI is also thanked for performance
of cytotoxicity evaluations.
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW620
Supplementary data
3.84
>100
3.20
8.50
4.20
3.95
4.80
12.3
30.6
4.20
6.47
5.37
23.9
>100
7.70
8.76
2.33
11.7
3.97
3.21
4.59
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.09.083.
References and notes
Melanoma
LOX IMVI
MALME-3M
M14
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
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Christiansen, M. A. Nucleos. Nucleotid. Nucl. 2009, 28, 394–407.
9. (a) Robins, M. J.; Sarker, S.; Xie, M.; Zhang, W.; Peterson, M. A. Tetrahedron Lett.
1996, 37, 3921–3924; (b) Peterson, M. A.; Nilsson, B. L.; Sarker, S.;
Doboszewski, B.; Zhang, W.; Robins, M. J. J. Org. Chem. 1999, 64, 8183–8192.
10. Full experimental details for all new compounds can be found in the
Supplementary data. 1H and 13C NMR and HRMS data for new compounds
follows: 4: 1H NMR (CDCl3, 500 MHz) d 8.32 (s, 1H), 8.13 (s, 1H), 5.95 (s, 1H),
5.85 (br s, 2H), 5.01 (d, J = 4.5 Hz, 1H), 4.90 (d, J = 3.5 Hz, 1H), 4.45 (dd, J = 2.0,
12.5 Hz, 1H), 4.35 (dd, J = 4.0, 12.5 Hz, 1H), 4.26–4.24 (m, 1H), 4.10 (q,
J = 7.2 Hz, 2H), 2.79 (d, J = 5.0 Hz, 3H), 2.67–2.63 (m, 2H), 2.43 (d, J = 13.0 Hz,
1H), 1.22 (t, J = 7.0 Hz, 3H), 0.92 (s, 9H), 0.25 (s, 3H), 0.083 (s, 3H); 13C NMR
(CDCl3, 125 MHz) d 171.6, 156.5, 155.3, 152.9, 149.3, 138.6, 120.2, 91.5, 82.3,
77.1, 63.2, 60.7, 38.6, 29.3, 27.6, 25.7, 18.0, 14.1, ꢀ4.4, ꢀ5.6; MS (FAB) m/z
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
6.53
5.73
5.19
29.0
4.56
4.69
8.29
9.09
22.3
>100
12.7
5.66
5.06
2.83
11.5
49.2
10.3
7.57
Ovarian cancer
IGROV1
3.85
4.59
12.3
31.1
4.92
21.0
3.72
7.11
53.0
38.2
9.02
52.7
13.7
2.42
10.7
12.8
10.3
40.4
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
Renal cancer
786-0
A498
2.00
3.34
8.55
29.7
2.01
9.10
12.4
12.1
9.01
3.87
14.4
53.8
9.74
85.3
20.5
7.79
7.94
4.65
5.92
3.72
2.94
2.17
10.7
5.70
ACHN
CAKI-1
RXF393
SN12C
TK-10
UO-31
Breast cancer
BT-549
HS578T
>100
3.60
3.42
3.96
6.21
2.55
29.0
5.79
5.59
12.3
10.9
13.9
2.07
3.39
3.37
17.5
3.26
4.95
MCF7
MDA-MB-231/ATCC
MDA-MB-435
T-47D
Prostate cancer
DU-145
PC-3
4.97
2.25
16.6
—
5.21
2.87
a
GI50 = concentration at which cell growth is inhibited by 50%; [(Ti ꢀ Tz)/
C ꢀ Tz)] ꢁ 100 = 50; where Tz = absorbance at t = 0; Ti = absorbance at t = 48 h;
C = absorbance of control at t = 48 h.

M. A. Peterson et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6775–6779
6779
509.2565 (MH+ [C22H37N6O6Si]) = 509.2538; 5: 1H NMR (CDCl3, 500 MHz) d
11.98 (s, 1H), 9.50 (s, 1H), 8.65 (s, 1H), 8.60 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.35
(t, J = 8.0 Hz, 2H), 7.14–7.11 (m, 1H), 6.04 (s, 1H), 5.75 (q, J = 5.0 Hz, 1H), 4.86
(d, J = 3.5 Hz, 1H), 4.51 (dd, J = 2.8, 12.8 Hz, 1H), 4.40 (dd, J = 1.5, 12.5 Hz, 1H),
4.26 (d, J = 8.5 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H), 2.66–2.60 (m, 5H), 2.53–2.50 (m,
1H), 1.21 (t, J = 7.2 Hz, 3H), 0.92 (s, 9H), 0.24 (s, 3H), 0.08 (s, 3H); 13C NMR
(CDCl3, 125 MHz) d 171.6, 156.8, 152.1, 150.6, 150.04, 149.98, 141.9, 137.9,
129.0, 124.1, 121.0, 120.7, 91.4, 82.8, 77.5, 62.4, 60.7, 38.3, 29.2, 27.4, 25.8,
18.0, 14.1, ꢀ4.4, ꢀ5.6; MS (FAB) m/z 628.2906 (MH+ [C29H42N7O7Si]) =
628.2909; 15: 1H NMR (CDCl3, 500 MHz) d 11.78 (s, 1H), 8.61 (s, 1H), 8.46
(br s, 1H), 8.33 (br s, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.11 (t,
J = 7.3 Hz, 1H), 5.97 (d, J = 4.0 Hz, 1 H), 4.84 (t, J = 4.5 Hz, 1H), 4.30 (t, J = 4.3 Hz,
1H), 4.22 (t, J = 4.5 Hz, 1H), 3.70 (dd, J = 6.3, 4.8 Hz, 2H), 0.92 (s, 9H), 0.82 (s,
9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.00 (s, 3H), ꢀ0.17 (s, 3H); 13C NMR (CDCl3,
125 MHz) d 151.3, 150.8, 150.1, 142.5, 138.0, 129.0, 123.9, 121.2, 120.4, 89.7,
82.9, 74.7, 72.3, 51.6, 25.8, 25.7, 18.0, 17.9, ꢀ4.38, ꢀ4.68, ꢀ4.84, ꢀ4.88; MS
(FAB) m/z 640.3204 (MH+ [C29H45N9O4Si2]) = 640.3206; 11: 1H NMR (CDCl3,
500 MHz) d 11.92 (br s, 1H), 9.03 (br s, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 7.57 (d,
J = 7.5 Hz), 7.39 (t, J = 8.3 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 6.51 (d, J = 6.0 Hz, 1 H),
6.01 (d, J = 8.0 Hz, 1H), 4.74–4.73 (m, 1H), 4.64 (dd, J = 7.5, 4.5 Hz, 1 H), 4.36 (d,
J = 4.5 Hz, 1H), 4.18 (t, J = 2.5 Hz, 1H), 3.99 (ddd, J = 14.5, 9.0, 2.5 Hz, 1H), 3.19
(dt, J = 14.5, 3.1 Hz, 1H), 2.72 (d, J = 4.5 Hz, 3H), 0.95 (s, 9H), 0.70 (s, 9H), 0.15 (s,
3H), 0.13 (s, 3H), ꢀ0.13 (s, 3H), ꢀ0.49 (s, 3H); 13C NMR (CDCl3, 125 MHz) d
159.1, 152.9, 151.0, 150.4, 150.3, 144.1, 137.1, 129.2, 125.0, 121.8, 121.2, 88.0,
87.8, 75.9, 73.5, 41.6, 26.8, 25.9, 25.6, 18.0, 17.7, ꢀ4.53, ꢀ4.79, ꢀ5.65; MS (FAB)
m/z 671.3525 (MH+ [C31H51N8O5Si2]) = 671.3516.
11. Robins, M. J.; Hansske, F.; Wnuk, S. F.; Kanai, T. Can. J. Chem. 1991, 69, 1468–
1474.
12. (a) Clark, V. M.; Todd, A. R.; Zussman, J. J. Chem. Soc. 1951, 2952–2958; (b)
Anzai, K. Agric. Biol. Chem. 1976, 40, 373–376; (c) Liu, F.; Austin, D. J.
Tetrahedron Lett. 2001, 42, 3153–3154; (d) Liu, F.; Austin, D. J. J. Org. Chem.
2001, 66, 8643–8645.
13. Dancer, R. J.; Try, A. C.; Sharman, G. J.; Williams, D. H. J. Chem. Soc., Chem.
Commun. 1996, 1445.