A novel α,β-unsaturated nitrone-aryne [3+2] cycloaddition and its application in the synthesis of the cortistatin core

Article abstract of DOI:10.1016/j.tetlet.2008.09.019

We describe here a novel α,β-unsaturated nitrone-aryne [3+2] cycloaddition. The resulting benzoisoxazolines underwent N-O bond reduction-elimination-electrocyclization sequence to furnish a variety of polysubstituted 2H or 2-alkylated-1-benzo-pyrans. The application of this methodology was further demonstrated in the synthesis of the oxa[3.2.1]octene moiety of cortistatin A.

Full text of DOI:10.1016/j.tetlet.2008.09.019

Tetrahedron Letters 49 (2008) 6613–6616
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel
a,b-unsaturated nitrone-aryne [3+2] cycloaddition
and its application in the synthesis of the cortistatin core
Mingji Dai a, Zhang Wang a, Samuel J. Danishefsky a,b,
*
a Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
b Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe here a novel a,b-unsaturated nitrone-aryne [3+2] cycloaddition. The resulting benzoisoxazo-
Received 26 August 2008
Accepted 2 September 2008
Available online 9 September 2008
lines underwent N–O bond reduction–elimination–electrocyclization sequence to furnish a variety of
polysubstituted 2H or 2-alkylated-1-benzo-pyrans. The application of this methodology was further
demonstrated in the synthesis of the oxa[3.2.1]octene moiety of cortistatin A.
Ó 2008 Elsevier Ltd. All rights reserved.
As described in the previous Letter, we have been pursuing a
total synthesis of cortistatin A (1) in the context of an aggressive
program directed to the discovery of even more valuable cortista-
tin analogs. Isolated by Kobayashi and co-workers,1 cortistatin A
has received a great deal of attention from the synthetic commu-
nity, due to its promising biological activity and unusual structural
features.2 These efforts culminated in the first synthesis of cortist-
atin A by Baran and co-workers.3 A total synthesis of 1 was recently
accomplished by the Nicolaou group.4 In designing a synthetic
strategy toward 1 that would be amenable to a program of diverted
total synthesis,5 we envisioned an intermediate of the type 8 to be
a key launching point, from which we could prepare a range of
cortistatin analogs.6 In the preceding Letter, we demonstrated an
efficient route to the cortistatin pentacyclic core via a Snieckus
reaction and subsequent Masamune alkylation.7 Herein, we
explore a very different approach to compound 7.
cortistatin A, we sought to develop and optimize a generally useful
a,b-unsaturated nitrone-aryne [3+2] cycloaddition protocol.
Our initial investigations were focused on the sterically unen-
cumbered nitrone substrates 9a–c and the benzyne derived from
2-bromophenyl triflate 10. The ,b-unsaturated nitrones were pre-
pared from the corresponding ,b-unsaturated aldehydes by treat-
ment with alkylated hydroxylamine (see supplementary data for
a
a
details). As shown in Table 1, when a solution of
a,b-unsaturated
R2
R2
Me
Me
X
X
TBSO
Y
[3+2]
Zn
HOAc
H
H
X
+
TBSO
Z
Z
N
R1
2
N
O—
3
+
As shown in Scheme 1, we envisioned employing a defining
4
O
R1
Z
X
1,3-dipolar cycloaddition reaction8 between generic aryne 2 and
NHR1
a,b-unsaturated nitrone 3, to generate benzoisoxazoline 4. The lat-
electro-
cyclization
TBSO
Y
TBSO
Y
ter would be advanced to the desired benzopyran 7 through
sequential reductive N–O bond cleavage, 1,4-elimination, and
6p-electrocyclization. Finally, Masamune alkylation of 7 would
afford intermediate 8. Interestingly, there is little precedent for
Me
R2
Me
R2
O
R1NH2
O
H
H
H
5
6
Z
Z
X
X
the type of [3+2] cycloaddition proposed herein (2 + 3 ? 4). To
Me
R2
TBSO
F—
TBAF
O
the best of our knowledge, only one example of an a,b-unsaturated
Me
R2
O
nitrone-aryne [3+2] cycloaddition9 has been reported. Further-
more, there are a paucity of examples of even simple nitrone-aryne
[3+2] cycloadditions.10 Recognizing the potential general applica-
bility of this type of reaction to the synthesis of complex molecules,
and hoping to apply this general strategy to the synthesis of
Masamune
alkylation
Y
O
Z
H
Y
H
7
8
Z = Br
OH
Me
N
HO
O
Me
H
N
Me
cortistatin A (1)
* Corresponding author. Tel.: +1 212 639 5501; fax: +1 212 772 8691.
E-mail address: danishes@mskcc.org (S. J. Danishefsky).
Scheme 1. Proposed nitrone-aryne [3+2] cycloaddition en route to cortistatin A (1).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.019

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M. Dai et al. / Tetrahedron Letters 49 (2008) 6613–6616
Table 1
Cycloaddition of
the tBu nitrone (9a), presumably due to acidic protons located
to the nitrogen center (entries 5 and 6).
a
a
,b-unsaturated aldehydes (9) with benzyne derived from 10a
O
With these improved conditions in hand, we sought to probe
the generality of the reaction with respect to the nature of the
bromoaryl triflate component (see supplementary data for syn-
thetic details). As shown in Table 2, the reaction is capable of effi-
+
Br
R
N
R
n
BuLi, THF
_
N
+
O_
7
8 °C
TfO
11a-c
9a-c
10
ciently accommodating
a range of functionalities. While all
Entry
–R
Ratio 9:10
Yield (11)
RSM (9)
reactions proceeded in moderate to good yield, we did observe
poor product regioselectivities when 2-bromo-4-methoxyphenyl
triflate 12b or 1-bromonaphthalen-2-yl triflate 12c was used (en-
tries 2 and 3). These findings were not unexpected, since the con-
jugation effect does not influence the electronic properties of the
aryne’s reactive orbitals, due to their perpendicular relationship
1
2
3
4
5
6
–tBu (9a)
–tBu (9a)
–tBu (9a)
–tBu (9a)
–Me (9b)
–Bn (9c)
2:1
1:1
1:1.2
1:2
1:2
1:2
49% (11a)
47% (11a)
51% (11a)
74% (11a)
50% (11b)
38% (11c)
54%
28%
37%
10%
ND
ND
to the aromatic
p-electron system. Based on this theory, elec-
a
Cycloaddition reaction condition optimization: To a solution of 9 and 10 in THF
at À78 °C was added nBuLi (1 equiv to 10). After workup, product 11 was purified
by silica gel chromatography. RSM: recovered starting material (9); ND: not
determined.
tron-withdrawing or electron-donating groups ortho to the aryne
could polarize the frontier orbital of the aryne dipolarophile, and
therefore help to control the regioselectivity. Steric factors must
also be taken into account. In fact, when 2-bromo-3-methoxy-
phenyl triflate 12d was used, only product 13d was obtained in
74% yield. The structure of 13d was unambiguously verified by
X-ray crystallography.11 The electron donating—TMS group (12e)
served to completely invert the regioselectivity, furnishing 13e as
the only cycloadduct in modest yield (41%).
nitrone 9a and 2-bromophenyl triflate 10 was treated with nBuLi
at –78 °C, the desired benzoisoxazoline 11a was isolated in moder-
ate to good yields, with recovery of starting material 9a (entries
1–4). The best yield (74%) was observed when a 1:2 ratio of
9a:10 was employed (entry 4). In this case, the reaction was com-
plete within 5 min, and longer reaction times did not lead to
improvements in yield. Methylated (9b) and benzylated (9c)
nitrones gave significantly lower reaction yields in comparison to
We next prepared a range of
a,b-unsaturated nitrone sub-
strates. Nitrones 14a–c were combined with 10, under the stan-
dard reaction conditions. Each substrate smoothly underwent
cycloaddition to furnish products 15a–c in good yield (Table 3).
However, almost no stereoselectivity was observed with nitrones
14a and 14b, presumably reflecting the remoteness of the resident
stereocenter. We note that the lack of stereocontrol observed in
these cases will not permanently impact our own synthetic efforts
toward cortistatin A, since our strategy calls for the elimination of
the newly generated stereocenter in subsequent steps.
Table 2
Substrate scope of aryne component derived from 12
Br
+
O
t
Bu
n
BuLi, THF
R1
N tBu
R1
N
+
O_
_
Having established the substrate scope of the 1,3-dipolar cyclo-
78 °C
TfO
addition between
a,b-unsaturated nitrones and arynes, we now
9a
12a-e
13a-e
sought to develop an efficient protocol to convert the cycloadduct
to a compound of the general type 16 (Table 4). First, reductive
cleavage of the N–O bond was accomplished through exposure
to Zn/AcOH. The resulting amino-phenol was heated in toluene.
Entry
1
Substrate (12)
Product (13)
Yield (%)
t
Bu
O
N
Br
O
O
56
88
70
74
41
TfO
O
12a
12b
Br
Table 3
13a
O
Substrate scope of nitrone component (14)
Br
t
Bu
+
O
t
Bu
tBu
O
R2
n
BuLi, THF
O
N
N
N
N
tBu
+
Br
OMe
O_
_
R1
78 °C
TfO
2
3
4
5
MeO
14a-c
15a-c
10
R1
TfO
R2
OMe
(1.5:1)
13b
Entry
1
Nitrone (14)
Product (15)
Yield (%)
72
O
t
Bu
tBu
t
Bu
O
N
O
N
+
N
*
tBu
H
N
O⎯
TfO
14a
12c
Me
15a (1.4:1 dr
)
Me
13c (1.7:1)
t
Bu
tBu
H
O
O
N
N
Br
+
tBu
N
*
O⎯
2
3
64
69
TfO
Me Me 14b
12d
OMe
TMS
OMe
Me
15b (1.2:1 dr
)
13d
Me
Me
t
Bu
t
Bu
O
O
Br
N
TMS
+
N
tBu
N
Me
Me
O⎯
TfO
12e
Me
14c
13e
Me
15c
Me

M. Dai et al. / Tetrahedron Letters 49 (2008) 6613–6616
6615
Table 4
Reduction–elimination–electrocyclization sequence
R4
H
R2
R1
Zn
AcOH
O
NHR3
R1
O
R4
R2
R1
O
O
toluene
N
R3
R4
R2
RT
160 °C
R
R
R
R4 R2
16
R1
R
Entry
Substrate
Product
Time (h)
Yield
R3
O
N
O
11a: 12
11b: 11
11c: 35
11a: 95%
11b: 82%
11c: 68%
1
11a (R3
= tBu)
16a
11b (R3 = Me)
11c (R3 = Bn)
t
Bu
O
N
O
O
O
2
3
1
71%
89%
O
16b
13a
O
t
Bu
O
N
O
12
16c
OMe
OMe
13d
t
Bu
O
N
Me
O
4
12
83%
Me
Me
15c
16d
Me
Me
Me
t
H
Bu
O
H
N
*
O
Me
*
5
6
12
12
88%
92%
16e (8:1 dr
)
15a (1.4:1 dr
)
Me
t
H
Bu
O
H
O
N
*
*
Me
Me
16f (6:1 dr
)
Me
15b (1.2:1 dr
)
Me
The hoped-for 1,4-elimination of the amino group proceeded
smoothly, presumably assisted by intramolecular deprotonation
of the phenol by the secondary amine. The quinomethide seem-
tBu
+N
OMe
CHO
⎯O
TfO
Br
OTIPS
b
a
+
ingly underwent spontaneous 6p-electrocyclization to furnish
OPMB
OMe
OPMB
19
the desired compound 16. It is worth noting that in generating
the quinomethide, it is not necessary to activate the leaving group
(for instance, through pre-formation of a quaternary ammonium
salt).12
17
18
OMe
OPMB
TIPSO
d, e
c
TIPSO
O
N
tBu
As shown in Table 4, a number of benzoisoxazolines were sub-
jected to the reduction–elimination–electrocyclization sequence.
All substrates underwent the sequence in good to excellent overall
yield (entries 1–6). The tert-butylated benzoisoxazoline (11a)
again proved superior to the methylated (11b) and benzylated
(11c) substrates (entry 1). When the 1.4:1 diastereomeric mixture
of 15a was subjected to the reaction sequence, the product, 16e,
was obtained with enhanced stereoselectivity (8:1) (entry 5). The
predominant isomer was the thermodynamically favored product,
in which the isopropenyl group is situated in the equatorial posi-
tion. Interestingly, NMR monitoring of the elimination–electrocyc-
lization sequence revealed the reaction itself to be complete within
O
21
20
OPMB
OMe
OMe
TIPSO
O
f
O
O
22
23
Br
Scheme 2. Synthesis of the core structure (23) of cortistatin A. (a) t-BuNHOH-
HOAc, TEA, CH2Cl2, rt, 6 days, 98%; (b) n-BuLi, THF, 2 h; (c) Zn, HOAc, rt, overnight;
170 °C, toluene, overnight, 55% from 18; (d) Me2BBr, i-Pr2NEt, anisole, CH2Cl2,
À78 °C, 20 min, 84%; (e) CBr4, PPh3, CH2Cl2, 1 h, 87%; (f) TBAF, THF, rt, 5 min, then
50 °C, 20 min or rt, 2 days, 52%.

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M. Dai et al. / Tetrahedron Letters 49 (2008) 6613–6616
1 h, although adduct was observed with no diastereoselectivity.
Prolonged heating yielded higher diastereoselectivities, with the
highest selectivity (12:1) observed after 18 h of heating (see
supplementary data for details). A similar result was observed in
the transformation of 15b to 16f (entry 6).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.019.
Having developed an efficient cycloaddition/cyclization proto-
col, we now explored the application of the method to the synthe-
sis of the core structure of cortistatin A. Intermediate 23 was
selected as a model system. As outlined in Scheme 2, aldehyde
17 was converted to nitrone 18. Next, 1,3-dipolar cycloaddition
between 18 and the aryne generated from 1913 provided benzois-
oxazoline 20, which was submitted to the standard reduction–
elimination–electrocyclization sequence to afford 21 in 55% overall
yield from 18. Alcohol deprotection, followed by bromination, gave
compound 22, which, upon exposure to TBAF, readily underwent
cyclization to provide the target intermediate, 23.14
References and notes
1. (a) Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku, N.; Kobayashi,
M. J. Am. Chem. Soc. 2006, 128, 3148; (b) Watanabe, Y.; Aoki, S.; Tanabe, D.;
Setiawan, A.; Kobayashi, M. Tetrahedron 2007, 63, 4074; (c) Aoki, S.; Watanabe,
Y.; Tanabe, D.; Setiawan, A.; Arai, M.; Kobayashi, M. Tetrahedron Lett. 2007, 48,
4485.
2. When we were preparing this manuscript, three elegant syntheses of the
cortistatin core were reported, see: (a) Yamashita, S.; Iso, K.; Hirama, M. Org.
Lett. 2008, 10, 3413; (b) Simmons, E. M.; Hardin, A. R.; Guo, X.; Sarpong, R.
Angew. Chem., Int. Ed. 2008, 47, 6650; (c) Craft, D. T.; Gung, B. W. Tetrahedron
Lett. 2008, 49, 5931.
3. Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008,
130, 7241.
4. Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem., Int.
Ed. 2008, 47, 7310.
5. (a) Njardarson, J. T.; Gaul, C.; Shan, D.; Huang, X.-Y.; Danishefsky, S. J. J. Am.
Chem. Soc. 2004, 126, 1038; (b) Wilson, R. M.; Danishefsky, S. J. J. Org. Chem.
2006, 71, 8329.
6. Dai, M.; Danishefsky, S. J. Heterocycles; published online, April 17th, 2008.
COM-08-S(F)6.
7. Dai, M.; Danishefsky, S. J. Tetrahedron Lett. 2008, preceding paper.
8. Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863.
9. Nagy, I.; Hajos, G.; Riedl, Z. Heterocycles 2004, 63, 2287.
10. For examples of nitrone-aryne [3+2] cycloaddition: (a) Hart, H.; Ok, D. J. Org.
Chem. 1986, 51, 979; (b) Bigdeli, M. A.; Tipping, A. E. J. Fluorine Chem. 1992, 58,
101; (c) Matsumoto, T.; Sohma, T.; Hatazaki, S.; Suzuki, K. Synlett 1993, 843; (d)
Cambie, R. C.; Higgs, P. I.; Rutledge, P. S.; Woodgate, P. D. Aust. J. Chem. 1994, 47,
1815; (e) Kitamura, T.; Todaka, M.; Shin-machi, I.; Fujiwara, Y. Heterocycl.
Commun. 1998, 205; (f) Hamura, T.; Arisawa, T.; Matsumoto, T.; Suzuki, K.
Angew. Chem., Int. Ed. 2006, 45, 6842.
In summary, a general method for the 1,3-dipolar cyclization
between
a,b-unsaturated nitrones and arynes has been
developed. In addition, a highly efficient N–O bond reduction–
elimination–electrocyclization sequence furnishes polysubstituted
2H or 2-alkylated-1-benzo-pyrans. Finally, Masamune alkylation
has been used to synthesize the oxa[3.2.1]octene moiety of
cortistatin A.
Acknowledgments
We are grateful to the National Institutes of Health (HL25848
and CA103823) for the financial support of this research. M.D.
thanks the Guthikonda Fellowship in Organic Chemistry, the
Bristol-Myers Squibb Graduate Fellowship in Synthetic Organic
11. CCDC 690676 contains the supplementary crystallographic data for compound
13d.
Chemistry, and the Sylvia
& Victor Fourman Fellowship for
12. Reference for synthesis of quinomethide by 1,4-elimination of quaternary
ammonium salts: (a) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2001, 123,
8089; (b) Breuer, E.; Melumad, D. Tetrahedron Lett. 1969, 23, 1875.
13. See Supplementary data for synthetic details.
14. (a) Masamune, S. J. Am. Chem. Soc. 1961, 83, 1009; (b) Lalic, G.; Corey, E. J. Org.
Lett. 2007, 9, 4921.
generous support. Z. W. thanks Eli Lilly for a graduate fellowship.
We thank Ms. Daniela Buccella (Parkin Group) for the crystal struc-
ture analysis and the National Science Foundation (CHE-0619638)
for acquisition of an X-ray diffractometer. Ms. Rebecca Wilson is
thanked for valuable help in editing this Letter.