Photo-Fries rearrangement for the synthesis of the diazonamide macrocycle

Article abstract of DOI:10.1016/S0040-4039(01)01515-5

Irradiation of the macrolactam 15 results in a photo-Fries rearrangement to give the complete diazonamide core skeleton 16 in good yield.

Full text of DOI:10.1016/S0040-4039(01)01515-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7193–7196
Photo-Fries rearrangement for the synthesis of the
diazonamide macrocycle
Philip Magnus* and Cyrille Lescop
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
Received 25 July 2001; revised 16 August 2001; accepted 20 August 2001
Abstract—Irradiation of the macrolactam 15 results in a photo-Fries rearrangement to give the complete diazonamide core
skeleton 16 in good yield. © 2001 Published by Elsevier Science Ltd.
In 1991 Fenical and Clardy reported the structure of
diazonamide A, 1 and diazonamide B, 2 (Scheme 1).1
The structures of these unusual alkaloids was inferred
from the X-ray determination of the acetal 3, which
was formed by treatment of 2 with p-BrC6H4COCl/pyr-
idine. The diazonamides were isolated from the colonial
ascidian Diazona chinensis, collected from the ceilings
of caves along the northwest coast of Siquijor Island in
the Philippines. It was reported that 1 has potent in
vitro activity against HCT-116 human colon carcinoma
and B-16 murine melanoma cancer cells (IC50 <15
ng/mL). The diazonamides have generated some con-
siderable synthetic interest,2 and the synthesis of oxa-
zoles and bis-oxazoles has undergone renewed
interest.3–5 In this letter we report the synthesis of the
macrocyclic core structure that incorporates the CDE-
FGI rings through the use of an extremely efficient
photo-Fries rearrangement (Scheme 2).6
The overall retrosynthetic analysis we have pursued is
based upon the formation of 4 through a transannular
cyclization of 5, which can, in principle, be accom-
plished via a benzylic cation or radical. The precursor
to 5, namely 6, should be available from the photo-
Fries rearrangement of 7. In order to test the validity of
the photo-Fries rearrangement in such a complicated
environment we elected to first study a simpler sub-
strate as outlined in Scheme 3.7a–d
Hydrogenolysis of 87a gave 9, which was treated with
2-methoxybenzoyl chloride/pyridine/4-N,N-dimethyl-
aminopyridine (DMAP) to give 10 (100%) (Scheme 3).
Irradiation of 10 in benzene (0.001 M) with a medium
pressure mercury vapor lamp at 23°C gave 11 (39%)
along with about 20% of the p-isomer 11a. The charac-
teristic hydrogen-bonded phenolic hydroxyl group gave
Me
H
Me
1
rise to a singlet at 12.4 ppm in the H NMR spectrum,
Cl
N
N
HN
which is diagnostic for the o-isomer 11.
Cl
R3HN
O
O
O
30
12
The next key test of the viability of the photo-Fries
rearrangement was in the context of a macrocyclic
lactam–lactone such as compound 15 (Scheme 4).
10
NH
O
R1
Treatment of
8
with trifluoroacetic acid in
OH
O
dichloromethane provided the amine 12, which was
coupled to the acid 14d8 to give the amide 13 (80%)
(Scheme 4). Hydrogenolysis of 13 removed both benzyl
protecting groups, and the product was exposed to the
Keck9 modification of the Steglich10 esterification con-
ditions to give 15 (66% on a 1 gram scale) as a mixture
of atropisomers (1.5:1 rt) (see Fig. 1 for the X-ray
structure of one of the atropisomers).11 Photolysis of a
solution of 15 (0.001 M) in benzene resulted in forma-
tion of 16 (76%) as the main product (two atropiso-
R2
1, Diazonamide A, R1 = OH, R2 = H, R3 =
2, Diazonamide B, R1 = OH, R2 = Br, R3 = H.
NH2
3, R1 = O2 (acetal), R2 = Br, R3 = COC6H4Br-p.
Scheme 1. Structures of diazonamides.
Keywords: diazonamide; photo-Fries rearrangement; macrolactam.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01515-5

7194
P. Magnus, C. Lescop / Tetrahedron Letters 42 (2001) 7193–7196
Radical or cation
addition to F-ring
Me
H
Me
O
Me
H
Me
Cl
C
N
N
N
O
N
HN
HN
F
E
O
Cl
R2HN
R2HN
O
A
10
B
O
O
O
G
D
NH
NH
H
O
HO
OH
I
O
OR1
5
4
Me
H
Me
Me
H
Me
N
N
N
N
HN
HN
R2HN
O
R2HN
O
O
O
O
O
O
O
NH
NH
O
HO
OR1
OR1
7
6
Scheme 2. Retrosynthetic analysis of the diazonamides.
Me
H
Me
Me
H
Me
N
N
N
O
N
BocHN
BocHN
COCl
OMe
O
O
O
O
NCO2Me
NCO2Me
py/DMAP
RO
O
MeO
8 ( R = Bn)
9 (77%, R = H)
H2/Pd/C
10 (100%)
Me
Me
hν
Me
H
Me
PhH, RT, 16h
H
N
N
O
N
N
BocHN
BocHN
O
O
O
+
OH
NCO2Me
NCO2Me
O
O
MeO
MeO
O
H
11 (39%)
11a (20%)
Scheme 3.
mers, 2:1) and a small amount of the p-isomer (<10%)
16a (see Fig. 2 for X-ray structure).12 Interestingly,
photolysis of pure 16, under the same conditions as
above, gave about 5–8% conversion into the p-isomer.13
The conversion of 16 into its p-isomer presumably
proceeds via the cyclohexa-2,4-dienone tautomer
16a which can undergo 1,3-acyl shift to give 16b
(Eq. (1)).
(1)

P. Magnus, C. Lescop / Tetrahedron Letters 42 (2001) 7193–7196
7195
Scheme 4.
The combination of macrolactonization to give
15, followed by photo-Fries rearrangement to 16 pro-
vides a simple and direct route to the diazonamide
skeleton.
Acknowledgements
The National Institutes of Health (CA 50512), Robert
A. Welch Foundation, Merck Research Laboratories,
Novartis and La Fondation pour La Recherche Me´d-
icale for a Fellowship (C.L.) are thanked for their
support of this research. Dr. Vince Lynch is thanked
for the X-ray structural determinations.
Figure 1. Chem 3D representation of 15 from the X-ray
crystallographic coordinates.
Figure 2. Chem 3D representation of 16a from the X-ray crystallographic coordinates.

7196
P. Magnus, C. Lescop / Tetrahedron Letters 42 (2001) 7193–7196
Scheme 5. (a) HOCH2CCl3 (1.2 equiv.)/DCC (1.2 equiv.)/DMAP (0.5 equiv.)/CH2Cl2, 23°C, 21 h, 14a (94%); (b) MeOCHCl2 (1.3
equiv.)/SnCl4 (2.0 equiv.)/CH2Cl2, −7°C to reflux, 2 h, 14b (100%, crude); (c) KMnO4 (2.5 equiv.)/acetone/H2O, 50°C, 5 h,
followed by BnBr (3.0 equiv.)/n-Bu4NI (0.5 equiv.)/NaHCO3 (5.0 equiv.)/DMF, 60°C, 16 h, 14c (78%); (d) Zn (15 equiv.)/90%
AcOH, 0–23°C, 6 h, 14d (82%). The reaction sequence was conducted on a scale that gave 4 g of 14d.
References
(g) Alvaro, M.; Garc´ıa, H.; Miranda, M. A.; Primo, J.
Tetrahedron 1992, 48, 3437; (h) Algarra, F.; Miranda, M.
A. Heterocycles 1993, 36, 2335; (i) Suau, R.; Valpuesta,
M.; Torres, G. Tetrahedron Lett. 1995, 36, 1315.
7. (a) Kreisberg, J. D.; Magnus, P.; McIver, E. G. Tetra-
hedron Lett. 2001, 42, 627; (b) Chan, F.; Magnus, P.;
McIver, E. G. Tetrahedron Lett. 2000, 41, 835; (c) Mag-
nus, P.; McIver, E. G. Tetrahedron Lett. 2000, 41, 831;
(d) Magnus, P.; Kreisberg, J. D. Tetrahedron Lett. 1999,
40, 451.
8. The acid 14d was synthesized as shown in Scheme 5.
9. Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394.
10. Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl.
1978, 17, 522.
1. Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J.
J. Am. Chem. Soc. 1991, 113, 2303.
2. (a) Moody, C.; Doyle, K.; Elliott, M.; Mowlem, T. Pure
Appl. Chem. 1994, 66, 2107; (b) Moody, C.; Doyle, K.;
Elliott, M.; Mowlen, T. J. Chem. Soc., Perkin Trans. 1
1997, 2413; (c) Konopelski, J.; Hottenroth, J.; Oltra, H.;
Veliz, E.; Yang, Z.-C. Synlett 1996, 609; (d) Hang, H. C.;
Drotleff, E.; Elliott, G. I.; Ritsema, T. A.; Konopelski, J.
P. Synthesis 1999, 398; (e) Boto, A.; Ling, M.; Meek, G.;
Pattenden, G. Tetrahedron Lett. 1998, 39, 8167; (f) Jeong,
S.; Chen, X.; Harran, P. G. J. Org. Chem. 1998, 63, 8640;
(g) Chen, X.; Esser, L.; Harran, P. G. Angew. Chem., Int.
Ed. 2000, 39, 937; (h) Vedejs, E.; Wang, J. Org. Lett.
2000, 2, 1031; (i) Vedejs, E.; Barda, D. A. Org. Lett.
2000, 2, 1033; (j) Lach, F.; Moody, C. J. Tetrahedron
Lett. 2000, 41, 6893; (k) Bagley, M. C.; Hind, S. L.;
Moody, C. J. Tetrahedron Lett. 2000, 41, 6897; (l) Bagley,
M. C.; Moody, C. J.; Pepper, A. G. Tetrahedron Lett.
2000, 41, 6901; (m) Fuerst, D. E.; Stoltz, B. M.; Wood, J.
L. Org. Lett. 2000, 2, 3521; (n) Nicolaou, K. C.; Snyder,
S. A.; Simonsen, K. B.; Koumbis, A. E. Angew. Chem.,
Int. Ed. 2000, 39, 3473; (o) Vedejs, E.; Zajac, M. A. Org.
Lett. 2001, 3, 2451; (p) Li, J.; Chen, X.; Burgett, A. W.
G.; Harran, P. G. Angew. Chem., Int. Ed. 2001, 40, 2682.
3. (a) Molina, P.; Fresneda, P. A.; lmendros, P. Synthesis
1993, 54; (b) Ang, K.; Prager, R.; Smith, J.; Weber, B.;
Williams, C. Tetrahedron Lett. 1996, 37, 675; (c) Barrett,
A. G. M.; Kohrt, J. Synlett 1995, 415; (d) Bagley, M.;
Buck, R.; Hind, S. L.; Moody, C.; Slawin, A. Synlett
1996, 825.
4. (a) Doyle, K.; Moody, C. Tetrahedron Lett. 1992, 33,
7769; (b) Doyle, K.; Moody, C. Tetrahedron 1994, 50,
3761; (c) Wipf, P.; Miller, C. J. Org. Chem. 1993, 58,
3604; (d) Yoo, S.-K. Tetrahedron Lett. 1992, 33, 2159.
5. Wipf, P.; Venkatraman, S. Synlett 1997, 1.
6. (a) Anderson, J. D.; Reese, C. R. Proc. Chem. Soc.
(London) 1960, 217; (b) Kobsa, H. J. Org. Chem. 1962,
27, 2293; (c) Taub, D.; Kuo, C. H.; Slates, H. L.;
Wendler, N. L. Tetrahedron 1963, 19, 1; (d) Adam, W. J.
Chem. Soc., Chem. Commun. 1974, 289; (e) Kende, A. S.;
Belletire, J.; Bentley, T. J.; Hume, E.; Airey, J. J. Am.
Chem. Soc. 1975, 97, 4425; (f) Farin˜a, F.; Martinez-
Utrilla, R.; Paredes, M. C. Tetrahedron 1982, 38, 1531;
11. Crystals of 15 were grown from dichloromethane/isooc-
tane (Dr. Jon Clardy is thanked for his advice concerning
appropriate crystallization solvents).
12. Spectral data for 16: IR (neat): 3418, 2925, 1747, 1644,
1
1615; H NMR (CDCl3): two atropisomers, l 0.84–1.00
(m, 6H major and 6H minor, CH3), 2.00–2.23 (m, 1H,
CH major), 2.25–2.32 (m, 1H, CH minor), 2.62–3.01 (m,
3H major and 3H minor, CH2), 3.10–3.19 (m, 1H major
and 1H minor, CH2), 3.62 (s, 3H, CH3O, major), 3.66 (s,
3H, CH3O, minor), 4.08 (s, 3H major and 3H minor,
CH3CO2), 4.97 (dd, 1H, CH major, J=8.8, 6.4 Hz), 5.04
(dd, 1H, CH minor, J=9.2, 6.8 Hz), 6.24 (d, 1H, NH
minor, J=9.2 Hz), 6.50 (brs, 1H, NH major), 6.57–7.45
(m, 9H major and 9H minor, CH), 7.47–7.54 (m, 1H
major and 1H minor, CH), 7.81 (s, 1H, CH, minor), 7.84
(s, 1H, CH major), 8.30–8.36 (m, 1H major and 1H
minor, CH), 12.2 (s, 1H, OH major), 12.4 (s, 1H, OH
minor); 13C NMR (CDCl3): two atropisomers, l 18.1,
18.3, 18.6, 19.0, 30.5, 30.9, 31.6, 32.7, 36.5, 37.8, 52.0,
52.5, 54.2, 55.5, 55.6, 109.3, 109.7, 111.4, 111.6, 114.8,
114.9, 117.9, 118.3, 119.4, 119.5, 125.3, 125.5, 125.6,
125.8, 126.3, 126.6, 126.9, 127.1, 127.2, 127.3, 128.2,
128.6, 129.1, 129.6, 130.4, 130.6, 131.2, 131.5, 131.7,
132.0, 133.2, 135.5, 135.6, 136.6, 136.7, 137.8, 138.0,
144.1, 145.1, 150.9, 154.4, 154.5, 155.0, 159.4, 159.7,
164.7, 164.9, 171.3, 171.4, 201.9, 202.6. HRMS (CI) calcd
for C37H32N4O8 (M+H)+ 661.2298. Found: 661.2300.
13. Transient cyclohexa-2,4-dienones have been observed in
photo-Fries rearrangement. See: Jime´nez, M. C.;
Miranda, M. A.; Scaiano, J. C.; Tormos, R. Chem.
Commun. 1997, 1487.