Efficient and stereoselective installation of isoquinoline: formal total synthesis of cortistatin A

Article abstract of DOI:10.1016/j.tetlet.2009.02.038

The highly stereoselective attachment of isoquinoline onto the steroidal framework of cortistatin A has been achieved. Our strategy features a Ce-mediated nucleophilic addition of an isoquinoline unit to the sterically congested ketone followed by formati

Full text of DOI:10.1016/j.tetlet.2009.02.038

Tetrahedron Letters 50 (2009) 3277–3279
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient and stereoselective installation of isoquinoline: formal total synthesis
of cortistatin A
a
a
a,b,
Shuji Yamashita a, , Kazuki Kitajima , Kentaro Iso , Masahiro Hirama
*
*
a Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
b Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The highly stereoselective attachment of isoquinoline onto the steroidal framework of cortistatin A
has been achieved. Our strategy features a Ce-mediated nucleophilic addition of an isoquinoline unit
to the sterically congested ketone followed by formation of the phenyl thiocarbamate, and subsequent
stereoselective radical reduction. The new method results in a formal total synthesis of cortistatin A.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 6 January 2009
Revised 3 February 2009
Accepted 6 February 2009
Available online 10 February 2009
Keywords:
Marine natural product
Cortistatin A
Isoquinoline
Total synthesis
Cortistatins have been isolated from the marine sponge Cort-
icium simplex by Kobayashi and co-workers1 Cortistatin
quinoline 11a was obtained as a byproduct, which likely arose
from the addition of n-BuLi to the C1-position of isoquinoline fol-
lowed by rapid elimination of LiH.8 To decelerate this undesired
reaction, 1-chloroisoquinoline derivatives were employed (entries
3–5).9 Treatment of 8 with a mixture of 9b,10 i-PrMgCl, and CeCl3
at À78 to 0 °C gave the desired adduct 10b in 40% yield (entry 3).
The best yield of 10b was achieved by treatment with a mixture
of 5 equiv of lithiated 9b and 10 equiv of CeCl3 in THF at À78 °C
(92%, entry 4). Surprisingly, 10b was obtained as a 1.8:1 diaste-
reomeric mixture. The minor product was determined to be an
A
(1, Fig. 1), the most potent congener, exhibits extremely strong
cytotoxicity against human umbilical vein endothelial cells (HU-
VECs: IC50 = 1.8 nM). Owing to its unique inhibition activity of
angiogenesis and unusual steroidal structure, 1 has currently
become one of the most challenging targets in total synthesis.2,3
Among the 11 isolated congeners, cortistatin A (1)–D (4), J (5), K
(6), and L (7) that possess an isoquinoline unit exhibit highly
selective inhibition of proliferation of HUVECs against other nor-
mal or tumor cell lines. SAR studies of cortistatins and simple
analogs have revealed that the isoquinoline moiety is essential
for their potent anti-angiogenesis activities.4 Although installa-
tion methods of the isoquinoline motif have been reported in
recent total syntheses of 1, there appears to be room for
improvement.2,3g We report here a new, secure method to install
isoquinoline to the steroidal framework resulting in a formal
total synthesis of 1.
First, we examined the nucleophilic addition of isoquinoline to
ketone (8) prepared from androsterone (Table 1).5 When 8 was
treated with 7-lithioisoquinoline, which was prepared from the
corresponding iodide 9a6 in THF/HMPA at À78 °C, a trace amount
of coupling product 10a was isolated (entry 1). An organocerium
reagent, which was expected to be a superior nucleophile,7 gave
10a in an even lower yield (entry 2). In both cases, 1-butyliso-
a-OH isomer by an NOE experiment.
We next focused on the deoxygenation of the newly formed
tertiary alcohol. Without separation of the diastereomers, alcohol
10b was treated with excess amounts of KH, CS2, and MeI, but in-
stead of the formation of xanthate 13a, 10b decomposed (Table 2,
entry 1). Attempted formation of the thiocarbonate using phenyl
thionochloroformate resulted in no reaction (entry 2), and treat-
ment with a thiophosgene/MeOH combination caused b-elimina-
tion of the alcohol to give 14 in 50% yield (entry 3). After careful
screening of reagents and conditions, we found that treatment of
10b with KH and phenyl isothiocyanate in THF at room tempera-
ture afforded the corresponding thiocarbamate 13d in 70% yield
(entry 4).11 Under these conditions, both C17-diastereomers of
10b were transformed to the corresponding thiocarbamates with-
out byproduct formation. Finally, radical reduction of 13d using
AIBN and n-Bu3SnH afforded 15 as the sole product in 81% yield.
It is noteworthy that the simultaneous removal of the thiocarba-
mate and chloride substituents of the isoquinoline ring was
achieved in a single operation.
* Corresponding authors. Tel./fax: +81 22 795 6566 (M.H.).
E-mail addresses: s-yamashita@mail.tains.tohoku.ac.jp (S. Yamashita), hirama@
mail.tains.tohoku.ac.jp (M. Hirama).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.038

3278
S. Yamashita et al. / Tetrahedron Letters 50 (2009) 3277–3279
Me
Me
OH
N
N
Me2N
O
19
HO
10
H
9
18
Me
1
cortistatin J (5)
7'
N
Me2N
O
17
R1
R2
cortistatin A (1): R1 = H, R2 = H, H
R3
6
1'
H
Me2N
O
H
cortistatin B (2): R1 = H, R2 = H (α), OH (β)
cortistatin C (3): R1 = H, R2 = O
cortistatin D (4): R1 = OH, R2 = O
cortistatin K (6): R3 = H
cortistatin L (7): R3 = OH
Figure 1. Structures of cortistatins.
Table 1
Table 2
Nucleophilic addition of isoquinoline moiety
Formation of thiocarbamate and radical reduction
S
R3
OH
17
O
Me
H
Me
N
R2
N
O
1
Me
1'
R1
17
9a-c
N
R1
Me
H
Me
H
13a: R3 = SMe
13b: R3 = OPh
13c: R3 = OMe
13d: R3 = NHPh
see below
Me
H
10b
Cl
see below
H
H
H
10a: R1 = H
10b: R1 = Cl
H
H
TBSO
TBSO
H
H
8
TBSO
H
Entry
R1
R2
Conditions
Results
Entry
Conditions
Results
1
2
3
4
5
H
H
Cl
Cl
Cl
I (9a)
I
I (9b)
I
Br (9c)
n-BuLi, HMPA, THF, À78 °C
n-BuLi, CeCl3, THF, À78 °C
10a:Trace, 11a:5%
10a:Trace, 11a:Trace
10b:40%, 12:38%
10b:92% (dr = 1.8:1)
10b:68% (dr = 1.7:1)
1
2
3
4
5
KH, CS2; MeI
Decomposed
DMAP, PhOC(S)Cl, CH3CN, reflux
KH, CSCl2, THF, rt; MeOH
KH, PhNCS, THF, rt
No reaction
14:50%
i-PrMgBr, CeCl3, THF, À78 to 0 °C
n-BuLi, CeCl3, THF, À78 °C
n-BuLi, CeCl3, THF, À78 °C
13d:70%a
13d:30%a
NaH, PhNCS, THF, rt
a
13d was obtained as a mixture of diastereomeric and atrop-isomers.
OH
Me
i-Pr
N
N
N
AIBN, n-Bu3SnH
H
n
-Bu
H
12
toluene, 80 °C
Me
Cl
11a
13d
H
Me
H
81%
Me
H
H
H
NOE
TBSO
H
14
15
(single isomer)
Having successfully established the new installation method,
we then applied it to the cortistatin framework (Scheme 1). The ke-
tone 18 was synthesized from dienone 163a according to the Nico-
laou–Chen protocol.2b Treatment of 18 with the organocerium
reagent generated from 9b, n-BuLi, and CeCl3 gave the desired ad-
duct 19 in quantitative yield. In this case, the resultant alcohol 19
and (3) stereoselective radical reduction. We believe that the
methodology developed here will accelerate not only the total syn-
thesis and SAR studies of cortistatins, but also the development of
new angiogenesis inhibitors.
was a single isomer, which was produced through the a-face attack
of isoquinoline. Formation of the phenyl thiocarbamate from 19
provided 20 as a 4:1 mixture of atrop-isomers. Finally, one-pot re-
moval of the thiocarbamate and chloride substituents of 20 fur-
nished the isoquinoline diene 21 as a single stereoisomer in 73%
overall yield from ketone 18. A formal total synthesis of 1 was
achieved by acid hydrolysis of 21 to give dienone 22 (71% yield),
whose proton and carbon NMR spectra are identical with those
of Nicolaou-Chen’s intermediate.2b
Acknowledgments
This work was supported financially by a Grant-in-Aid for Sci-
entific Research from Ministry of Education, Culture, Sports, Sci-
ence and Technology in Japan, and by Suntory institute for
bioorganic research (SUNBOR).
In conclusion, we have developed a highly convenient and ste-
reocontrolled isoquinoline installation methodology to the penta-
cyclic framework of cortistatins. This method requires only three
synthetic steps to attach the isoquinoline moiety, including (1)
Ce-mediated nucleophilic addition to a sterically congested ketone,
(2) formation of phenyl thiocarbamate from the tertiary alcohol,
Supplementary data
Experimental section and 1H NMR spectra. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.02.038.

S. Yamashita et al. / Tetrahedron Letters 50 (2009) 3277–3279
3279
1. TMSO
OTMS
TMSOTf, CH2Cl2
-60 to -20 °C
O
O
O
2. TBAF, THF, 0 °C
Me
OTBS
Me
OH
73%
(2 steps)
O
O
H
16
H
17
Dess-Martin
periodinane
NaHCO3
100%
O
CH2Cl2, rt
9b
O
O
O
n-BuLi, CeCl3
THF, -78 °C
Me
Me
O
N
O
O
H
18
99%
H
19 (single isomer)
OH
Cl
KH, PhNCS
THF, rt
AIBN
n-Bu3SnH
toluene, 90 °C
O
O
O
O
Me
O
Me
74%
(2 steps)
N
N
O
O
H
H
Cl
21 (single isomer)
S
NHPh
20 (4:1 mixture of atropisomers)
TsOH·H2O
acetone, H2O
71%
O
ref. 2b
Me
1
N
O
H
22
Scheme 1. Formal total synthesis of cortistatin A.
5247–5250; Review, see: (i) Nising, C. F.; Bräse, S. Angew. Chem. Int. Ed. 2008,
47, 9389–9391.
References and notes
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