Methodology for the synthesis of the core EFGH rings of diazonamide A

Article abstract of DOI:10.1016/j.tetlet.2006.06.123

Conversion of substituted 2-oxindoles into 2-thionoindoles followed by Raney nickel desulfurization provides a mild method for synthesizing the core EFGH rings of diazonamide A.

Full text of DOI:10.1016/j.tetlet.2006.06.123

Tetrahedron Letters 47 (2006) 6461–6464
Methodology for the synthesis of the core EFGH rings of
diazonamide A
Philip Magnus* and Rachel Turnbull
Department of Chemistry and Biochemistry, University of Texas at Austin, 1 University Station A5300, Austin, TX 78712-1167, USA
Received 15 June 2006; accepted 18 June 2006
Abstract—Conversion of substituted 2-oxindoles into 2-thionoindoles followed by Raney nickel desulfurization provides a mild
method for synthesizing the core EFGH rings of diazonamide A.
Ó 2006 Elsevier Ltd. All rights reserved.
Diazonamide A was isolated from the colonial ascidian
Diazona chinensis, collected from the ceilings of caves
along the northwest coast of Siquijor Island in the Phil-
ippines. It has potent in vitro activity against HCT-116
human colon carcinoma and B-16 murine melanoma
cancer cells (IC50 < 15 ng/mL). The original structure,
as reported in 1991 by Fenical and Clardy,1 was cor-
rected in 2001 to 1 by Harran, Scheme 1.2 While there
has been a large number of research groups involved
in the total synthesis of diazonamide A,3 only the Har-
ran4 and Nicolaou5 groups have so far been successful.
functionality are outlined in Scheme 2. Harran,4 in his
biomimetically inspired route to diazonamide, reported
the hypervalent iodine mediated intramolecular oxida-
tive coupling of 3 to give 4 and 5. This elegant and direct
strategy is not applicable to our route since we use a
rearrangement of a 2-oxindole derivative to establish
the C-10 quarternary carbon atom.6 In a model study,
as a prelude to the synthesis of diazonamide, Nicolaou
et al.5 reported the reduction of 6 to give 7. Although
this model study used a variety of reducing agents
(Red-Al, LiBEt3H, BH3ÆSMe2, NaBH4, BH3ÆTHF, and
TMSOTf/Et3SiH) only DIBAL-H in toluene (10 equiv,
added portion wise) from À78 to 25 °C accomplished
the reduction of 8 to give 9. Recently Vedejs and Zajac
reported the reduction of the N-alloc activated 2-oxin-
dole 10 with NaBH4/MeOH followed by dehydration
with Ms2O/Et3N to give 11 in excellent yield.7
As part of our efforts to synthesize diazonamide A, we
required a mild method to construct the central hemi-
aminal functionality which contains the heteroatom
connections of the core EFGH rings 2. The published
methods for the synthesis of the crucial hemiaminal
Me
H
Me
Me
HO
Me
O
Cl
N
N
HN
A
H
B
O
Cl
N
O
Ar
30
O
G
10
E
16
E
C
8
NH
18
F
F
H
H
G
NH
NH
D
O
O
1, diazonamide A
2
Scheme 1.
Keywords: Diazonamide A; Hemiaminal; Thioamide; Raney nickel; Desulfurization.
*
Corresponding author. Tel.: +1 512 471 3966; fax: +1 512 471 7839; e-mail: p.magnus@mail.utexas.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.123

6462
P. Magnus, R. Turnbull / Tetrahedron Letters 47 (2006) 6461–6464
Me
Me
Me
H
Me
O
H
ArO2SHN
N
N
N
H
HN
CO2Me
CO2Me
O
ArO2SHN
O
O
10
PhI(OAc)2/LiOAc
CF3CH2OH/-20˚C
HO
Br
NH
N
H
O
3 (Ar = 2-O2NC6H4)
4 (20-25%) + 5-C10 epimer (7-8%)
Br
CO2Me
CO2Me
AcHN
AcHN
Ph
Ph
DIBAL-H/THF/25˚C
Br
Br
NH
NH
O
O
OH
6
7 (23%)
Me
H
Me
O
Me
H
Me
DIBAL-H/PhMe/-78 to 25˚C
in THF
Cl
Cl
N
N
N
HN
N
O
HN
Cl
Cl
CbzHN
CbzHN
O
O
O
O
NH
NH
NH
NH
O
OH
O
9 (56%)
8
CO2Me
CO2Me
1. NaBH4/MeOH
2. Ms2O/Et3N
BnO
BnO
Br
Br
N
N
O
O
Alloc
Alloc
OH
10
11 (93%)
Scheme 2.
Attempted application of these reductions, and others,
to some of the intermediate 2-oxindoles in our route
was not successful because of over reduction to the
2H-indoline rather than the hemiaminal. As a conse-
quence, we have developed a mild and selective proce-
dure to accomplish this difficult reduction.
desulfurized by exposure to Raney nickel to give an
imine, this reaction sequence could provide a mild meth-
od to convert compounds such as 12 into 15 (Scheme
39).
Initially, we were concerned that the conversion of an
amide into its thioamide derivative in the presence of a
phenol, using thionating reagents such as Lawesson’s
reagent, might be problematic. The only report of this
We conjectured that since thioamides are readily
S-alkylated8 and the resulting S-alkylthioimine can be
Ph
Ph
Me
Me
X
X
NH
NH
O
OH
S
OH
Lawesson's reagent
PhMe reflux
12 (X = H)
16 (X = Br)
13 (60%, X = H)
17 (60%, X = Br)
Raney Ni
acetone/reflux
MeI/acetone/25˚C/15h
Ph
Ph
Me
Me
Raney Ni
acetone/reflux
X
X
NH
NH
H
SMe
O
O
14 (80%, X = H)
18 (72% X = Br)
15 (82%, X = H, 72% from 13)
19 (60%, X = Br, 63% from 17)
Scheme 3.

P. Magnus, R. Turnbull / Tetrahedron Letters 47 (2006) 6461–6464
6463
type of conversion involved a hexa-substituted phenol,10
and it is possible for a phenol with vacant ortho- and/or
para-positions to undergo electrophilic aromatic substi-
tution by the thiophosphoryl functionality in Lawes-
son’s reagent. In the event this potential competing
reaction did not occur, treatment of 12 and 16 with
Lawesson’s reagent in toluene heated at reflux (2–3 h)
gave the thioamides 13 (60%) and 17 (60%) respectively,
Scheme 3. As a control experiment, p-cresol was exposed
to Lawesson’s reagent in toluene heated at reflux, and
only after approximately 20 h was some decomposition
observed.
analogues (Scheme 4), we found that the thioamide
could be converted into the hemiaminal using Raney
nickel without the need for S-methylation. Applying this
to 13 and 17 resulted in 15 (72%) and 19 (63%),
respectively.
While we could convert 20 into its thioamide derivative
21 (69%), its S-methylation to give 22 (57%) was accom-
panied by hydrolysis to give 20 (12%) and recovered 21
(30%), Scheme 4. Moreover, attempted desulfurization
of 22 with Raney nickel in dry acetone in the presence
˚
of 4 A molecular sieves only gave 20 (69%). Conse-
quently, we treated 21 directly with Raney nickel in ace-
tone and isolated 23 in 86% yield.
The thioamide 13 was treated with MeI/acetone at 25 °C
for 15 h to give 14 (80%). Exposure of 14 to deactivated
Raney nickel resulted in clean desulfurization to provide
15 (82%, structure by X-ray, see Fig. 1).11 Similarly, the
thioamide 17 was converted into 18 and desulfurized to
give 19 (60%). In the course of investigating the –NMe
The conversion of the amides 12, 16, and 20 into the
hemiaminals 15, 19, and 23 requires two steps for each,
and proceeds in an overall yield of 43%, 37%, and
59%, respectively (not optimized). The mild reaction
Figure 1. ORTEP of 15.
Ph
Ph
Me
Me
Lawesson's reagent
PhMe reflux
NMe
NMe
O
OH
S
OH
21 (69%)
20
Raney Ni
acetone/reflux
MeI/acetone/25˚C/15h
Ph
Ph
O
Me
Me
Raney Ni
acetone/reflux
NMe
H
NMe
SMe
O
23 (86%)
22 (57%)
Scheme 4.

6464
P. Magnus, R. Turnbull / Tetrahedron Letters 47 (2006) 6461–6464
3495–3499; Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy,
M. V.; Rassias, G.; Huang, X.; Chen, D. Y.-K.; Snyder, S.
A. Angew. Chem., Int. Ed. 2003, 42, 1753–1758; Nicolaou,
K. C.; Chen, D. Y.-K.; Huang, X.; Ling, T.; Bella, M.;
Snyder, S. A. J. Am. Chem. Soc. 2004, 126, 12888–12896;
Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Rao, P. B.;
Rassias, G.; Snyder, S. A.; Huang, X.; Chen, D. Y.-K.;
Brenzovich, W. E.; Giuseppone, N.; Giannakakou, P.;
O’Brate, A. J. Am. Chem. Soc. 2004, 126, 12897–12906.
6. Goldberg, F. W.; Magnus, P.; Turnbull, R. Org. Lett.
2005, 7, 4531–4534.
conditions bode well for the success of this methodology
on more complicated 2-oxindoles required for the total
synthesis of diazonamide A.
Acknowledgements
The NIH (CA RO1 50512) and the Welch Chair
(F-0018) are thanked for their support of this research.
7. Zajac, M. A.; Vedejs, E. Org. Lett. 2004, 6, 237–240.
8. Eicher, T.; Krause, D. Synthesis 1986, 899–907; Eicher, T.;
Weber, J. L.; Kopf, J. Liebigs Ann. Chem. 1978, 1222–
1240.
9. For a similar desulfurization on a physostigmine precur-
sor see: Marino, J. P.; Bogdan, S.; Kimura, K. J. Am.
Chem. Soc. 1992, 114, 5566–5572; Marino, J. P.; Kim,
M.-W.; Lawrence, R. J. Org. Chem. 1989, 54, 1784–1785;
Wang, Q.; Nara, S.; Padwa, A. Org. Lett. 2005, 7, 839–
841.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.06.123.
References and notes
10. Tichenor, M. S.; Kastrinsky, D. B.; Boger, D. L. J. Am.
Chem. Soc. 2004, 126, 8396–8398; For this conversion on a
protected phenol see: Occhiato, E. G.; Ferrali, A.; Menchi,
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Serio, M.; Garotta, G.; Cavalli, A.; De Vivo, M.;
Recanatini, M. J. Med. Chem. 2004, 47, 3546–3560.
11. Crystallographic data (excluding structure factors) for the
compound 15 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion number CCDC 611305. Copies of the data can be
obtained free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [Fax: +44 (0)
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
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