Synthesis of BCD tricyclic analogues of the novel cardiac glycoside rhodexin A

Article abstract of DOI:10.1016/j.tetlet.2011.06.114

A concise synthesis of novel cardiac glycoside analogues of rhodexin A, 14 and 24, having the BCD tricyclic system is described. The key constructive step is an inverse-electron demand Diels-Alder reaction of the silyl enol ether 4 and the 2-acetyldiene,

Full text of DOI:10.1016/j.tetlet.2011.06.114

Tetrahedron Letters 52 (2011) 4512–4514
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of BCD tricyclic analogues of the novel cardiac glycoside rhodexin A
⇑
Michael E. Jung , Hiufung V. Chu
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise synthesis of novel cardiac glycoside analogues of rhodexin A, 14 and 24, having the BCD tricy-
clic system is described. The key constructive step is an inverse-electron demand Diels–Alder reaction of
the silyl enol ether 4 and the 2-acetyldiene, 7 and 15.
Received 3 June 2011
Revised 23 June 2011
Accepted 28 June 2011
Available online 2 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Diels–Alder reaction
Inverse-electron-demand
Terpene synthesis
Glycoside synthesis
Cardiac glycosides are an important class of naturally occurring
toxins1 that have been used clinically for the treatment of conges-
tive heart failure for over 200 years.2 Named for their dramatic ef-
fect on heart, the cardiac glycosides elicit their effect by binding to
myocardial Na+,K+ ATPase.3 The inhibition of the Na+ pump causes
an increase in the intracellular Ca2+ concentration and, thus an in-
crease of heart contraction and blood pressure.4 This positive ino-
tropic effect benefits the patient’s weak heart by creating stronger
cardiac interaction, while the increase in blood pressure is the
main contributor to the toxicity of these drugs. Recently these
drugs have been identified as having value in cancer therapy.5
Much effort toward the synthesis of new cardiac glycoside ana-
logues has been focused on manipulation of the steroid core, as a
possible method to lower the inherent toxicity of these com-
pounds. As part of our studies toward the total synthesis of the car-
diac glycosides, such as ouabain6 and rhodexin A (1),7 we have
developed an efficient method8 to synthesize the BCD system of
the steroidal nucleus via an inverse-electron demand Diels–Alder
reaction (Scheme 1), which would set the four desired contiguous
stereocenters at C8, C13, C14, and C17 in a single step. Thus the in-
verse-electron demand Diels–Alder reaction between the diene 3,
which possesses the functionality required to attach the rhamnose
unit, and the dienophile 4, the terminal alkene unit of which could
be easily converted into a butenolide moiety. Here, we report the
synthesis of novel cardiac glycoside analogues in which the A-ring
is absent.
(Scheme 2). The terminal alkyne was acetylated with the acetyl
Weinreb amide to give in 83% yield the enyone 6, which was sub-
jected to enyne metathesis conditions using Grubbs first genera-
tion catalyst to yield the desired dienone 7 in 86% yield. The
vinyl silyl enol ether 4 was prepared in one step by the copper-cat-
alyzed 1,4-addition of vinyllithium to the enone followed by trap-
ping of the enolate in the presence of TESCl and HMPA.10 Treating
the dienone 7 and the dienophile 4 with 50 mol % of MeAlCl2 at
À78 °C gave the desired exo cycloadduct 8 in 60% yield as a 1:1
mixture of the two diastereomers at the secondary silyl ether
group. Using other Lewis acids, such as AlBr3/AlMe3, SnCl4, or trifli-
mide (Tf2NH), resulted in a lower yield of the cycloadduct.8d The
O
O
O
O
Me
OH
Me
O 11
HO
Me
17
13
H
14
H
Me
HO
H
8
OH
O
H
1
Me
HO
O
2
HO
OH
O
Me
PO
Me
TESO
The synthesis of the BCD tricyclic core began with the protec-
tion of the known enynol 59 as the PMB ether in 81% yield
+
3
4
⇑
Corresponding author. Tel.: +1 310 825 7954; fax: +1 310 206-3722.
E-mail address: jung@chem.ucla.edu (M.E. Jung).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.114

M. E. Jung, H. V. Chu / Tetrahedron Letters 52 (2011) 4512–4514
4513
Attachment of 2.3,4-tri-O-acetyl-
a
-
L
-rhamnopyranosyl trichlo-
Me
roacetimidate (12)12 to the tricyclic alcohol 11 was unsuccessful
1) NaH
PMBBr
O
1st gen
.
using TMSOTf or BF3 Et2O as Lewis acids. However, the use of a
Grubbs catalyst
81%
milder Lewis acid, such as ZnBr2, gave the desired coupled product
in 90% yield13 (Scheme 3). Deprotection of the tertiary triethylsilyl
ether protecting group with HF-pyridine in acetonitrile gave the
tertiary alcohol in 92% yield. Final deprotection of the acetates on
the sugar moiety with potassium carbonate yielded the cardiac
glycoside analogue 14 in 49% yield. It should be noted that since
the tricyclic system is racemic and the sugar is optically pure, there
are four diastereomers formed in this process, the two alcohol ster-
eoisomers in the B ring and the two different enantiomeric forms
of the tricycle coupled to the pure sugar.
The inverse-electron demand Diels–Alder reaction was opti-
mized by altering the protecting group on the diene and by the
use of the strong Brønsted acid, triflimide (Tf2NH).14 Treatment
of the triethylsilyl protected diene 15 (prepared from 5 by an anal-
ogous route to that described for 7) and the dienophile 4 with
10 mol % of triflimide as the acid in dichloromethane at À78 °C
for 5 min afforded the tricyclic system 16 in 86% yield as an
approximate 2.5:1 mixture of the two diastereomers, with the
equatorial being the major (Scheme 4). As we have shown previ-
ously, the actual catalyst is TESNTf2, formed by the cleavage of a
small amount of the TES silyl enol ether of 4.14 Mild cleavage of
the less hindered silyl ether (PPTS, MeOH, 96% yield) was then fol-
lowed by an unusual multi-step oxidation process using excess
Dess–Martin periodinane. The secondary alcohol from 16 is oxi-
2)
n
BuLi;
PhH, 23 °C
86%
AcNMe(OMe)
83%
HO
PMBO
5
6
O
O
Me
Me
Me
Me
MeAlCl2
H
CH2Cl2
OTES
-78 °C
60%
TESO
PMBO
PMBO
OH
H
4
(1:1)
8
7
HO
Me
O
1) Ac2O, DMAP
0 °C, 76%
Me
OsO4, NMO
H
2) DMP, 83%
3) aq K2CO3
85%
t
BuOH/THF/ H2O
OTES
23 °C, 66%
PMBO
9
O
OH
O
O
O
O
Me
PO(OEt)2
Me
1)
Me
H
Me
COOH
H
C6H2Cl3COCl
DMAP, 86%
OTES
OTES
2) 18-crown-6
K2CO3, tol
66%
PMBO
HO
11
10
3) DDQ, 78%
O
Scheme 2.
O
Me
Me
Me
Me
Tf2NH
H
CH2Cl2
+
terminal double bond of the cycloadduct 8 was dihydroxylated to
give the diol 9 in 66% yield. Selective protection of the primary
alcohol as the monoacetate, followed by oxidation of the secondary
OTES
-78 °C
5 min
86%
TESO
TESO
TESO
4
H
O
16
(2.5 α-H:1 β-H)
15
alcohol and deprotection of the acetate group furnished the
a-
hydroxyketone 10 in 53% yield over three steps. The primary alco-
hol group in 10 was then coupled with diethylphosphonoacetic
acid using Yamaguchi’s reagent to furnish the phosphonate ester
in 86% yield. Intramolecular Horner-Wadsworth-Emmons reaction
utilizing potassium carbonate and 18-crown-611 yielded the de-
sired butenolide in 66% yield. Finally, deprotection of the PMB
ether with DDQ gave the desired alcohol 11 in 78% yield.
Me
O
Me
OH
O
1) PPTS,MeOH
23 °C, 96%
2) a) DMP;
b) Pb(OAc)4
PhH
Me
O
H
H
OTES
OTES
18
48%
17
Me
O
1) CH2N2
0 °C, 87%
1) Li(tBuO)3AlH
O
O
THF, 23 °C, 77%
2) TESCl/ImH
CH2Cl2, 23 °C
97%
H
Me
O
2) 1,2-C6H4Cl2
180 °C
OTES
CCl3
O
Me
98%
11
Me
OH
O
19
NH
ZnBr2
4 Å MS
H
O
Me
AcO
O
Me
Me
1) OsO4,NMO
45%
OTES
CH2Cl2
23 °C
90%
O
O
OAc
O
OAc
Me
OAc
H
2) Ac2O, DMAP
0 °C, 96%
H
Me
Me
Me
AcO
12
O
OTES
OTES
3) TPAP, NMO
O
TESO
OAc
13
71%
TESO
20
4) aq K2CO3
21
O
72%
O
Me
O
O
PO(OEt)2
COOH
1)
H
1) HF-pyr
CH3CN
Me
C6H2Cl3COCl
OH
O
DMAP, 73%
23 °C/92%
O
H
2) 18-crown-6
K2CO3, tol
34%
3) PPTS,MeOH
23 °C, 99%
2) K2CO3
aq MeOH
23 °C/49%
Me
HO
Me
HO
O
OTES
HO
OH
14
22
Scheme 3.
Scheme 4.

4514
M. E. Jung, H. V. Chu / Tetrahedron Letters 52 (2011) 4512–4514
In conclusion, we have successfully synthesized three novel car-
O
diac glycoside analogues containing only the BCD tricyclic system,
which was derived from a very efficient inverse-electron-demand
Diels–Alder reaction. The biological activity of the analogues will
be reported in due course. We also plan to utilize this synthetic
strategy to prepare other cardiac glycoside analogues.
O
CCl3
Me
22
O
O
NH
ZnBr2
4 Å MS
H
Me
AcO
Me
O
O
CH2Cl2
23 °C
90%
OTES
OAc
OAc
Acknowledgments
12
Me
O
AcO
O
HVC gratefully acknowledges the National Institutes of Health
for support via Grant No. GM08496.
AcO
23
OAc
O
Me
O
Supplementary data
H
Me
O
1) HF-pyr
CH3CN
OTES
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.114.
23 °C/92%
2) K2CO3
aq MeOH
23 °C/49%
Me
HO
O
References and notes
HO
OH
24
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uct 23 in 90% yield13 (Scheme 5). Deprotection of the tertiary tri-
ethylsilyl ether with HF-pyridine in acetonitrile gave the tertiary
alcohol in 92% yield and final deprotection of the acetates provided
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