.
Angewandte
Communications
3P3X-based model that renders a reaction at C7 in inter-
mediate 20 most plausible (binding energy À8.76 kcalmolÀ1).
The 7-hydroxy group is directed toward the heme iron
(distance heme iron and C7: 5.08 ꢀ, distance Fe-O7 3.84 ꢀ;
Fe-C7-O-angle = 25.88) whereas the (7R)-proton points away
from the Fe-C7 axis (distance Fe-(7R)H 4.98 ꢀ; Fe-C7-
(7R)H-angle = 78.88). This model supports the hypothesis of
an oxidative attack of the (7S)-hydroxy group. In contrast, an
oxidative attack of the remotely positioned C8 is unlikely
(distance Fe-C8 5.92 ꢀ; distance Fe-H8 4.49 ꢀ) as it is
shielded by the 7-hydroxy group. Furthermore, the carbon
backbone of the substrate is twisted in a way that the side
chain at C9a points away from the active site (distance Fe-
C9a = 8.02 ꢀ). Consequently, an oxidative attack of C9a as in
(R)-10 is impossible in this state. To support this hypothesis,
we also modeled intermediate 18 into both template struc-
tures using the same approach. In this case, we found a model
with the 3P3L structure as template, thus explaining the
natural reaction sequence. It shows the highest of all binding
energies (À9.34 kcalmolÀ1) observed here. Remarkably, the
distance between heme iron and C9a (5.72 ꢀ) is smaller than
between heme iron and C7 (6.01 ꢀ). The model described
shows a possible binding mode of (S)-10, which can explain
the formation of the unusual pyran structure of 15 through
intermediate 20.
548 – 553; b) J. E. Moses, J. E. Baldwin, R. Marquez, R. M.
d) M. F. Jacobsen, J. E. Moses, R. M. Adlington, J. E. Baldwin,
G. Liang, C. M. Beaudry, D. Trauner, C. Hertweck, Angew.
[7] a) Y. Ishibashi, S. Ohba, S. Nishiyama, S. Yammamura, Bull.
[8] For reviews, see: a) A. K. Miller, D. Trauner, Synlett 2006, 2295 –
Awaad, J. E. Moses, Synthesis 2011, 2865 – 2892.
[9] For reports of base and acid epimerisation, see Refs. [7a,b].
After four hours of exposure to sunlight, half of aureothin is
converted into at least two products (see the Supporting
Information for details).
16742 – 16743; b) M. E. A. Richter, N. Traitcheva, U. Knꢁpfer, C.
In conclusion, the umpolung strategy we have designed
and applied to the desymmetrization of 6 allowed the one-pot
construction of the complete carbon backbone 8 of aureothin
with maximized convergence. The last steps include the
À
2066; b) M. Werneburg, B. Busch, J. He, M. E. A. Richter, L.
Xiang, B. S. Moore, M. Roth, H.-M. Dahse, C. Hertweck, J. Am.
regioselective aerobic C H bond oxidation and cyclization of
rac-10, which proceeded according to an unprecedented
regiodivergent PKR pathway promoted at a synthetically
relevant scale by AurH, a multifunctional cytochrome P450
monooxygenase. This transformation completed the asym-
metric stereoselective synthesis of aureothin in eight steps
from 4-nitrobenzaldehyde and 8% overall yield with ee val-
ues as high as 99%. On this basis, the extension of the strategy
to the synthesis of other natural products is ongoing.
a review on
(bio)synthesis, see: A. A. Roberts, K. S. Ryan, B. S. Moore,
[13] The use of large excess of magic methyl (methyl fluorosulfonate)
is mandatory for chemoselective methylation of a-pyrone into
the corresponding g-pyrone. P. Beak, J.-k. Lee, G. B. McKinnie,
Received: June 1, 2012
[15] a) M. De Paolis, H. Rosso, M. Henrot, C. Prandi, F. d’Herouville,
J. Maddaluno, Chem. Eur. J. 2010, 16, 11229 – 11232; b) H.
Rosso, M. De Paolis, S. Dey, V. Collin, S. Hecht, C. Prandi, J.
Published online: && &&, &&&&
Keywords: aureothin · cytochrome P450 · natural products ·
.
oxidation · parallel kinetic resolution
[16] When the synthesis of product 13 was intended, the yield of the
transformation reached 75%, which explained to some extend
the moderate yield (51%) observed when the more complex 8
was prepared (Ref. [15a]). In addition, interactions between
enolate 14 and nitroarene substituent of 7 and 8 could lead to
radical anion intermediates or dearomatized products. See: F.
Lꢂpez Ortiz, M. J. Iglesias, I. Fernꢃndez, C. M. Andffljar Sꢃn-
chez, G. Ruiz Gꢂmez, Chem. Rev. 2007, 107, 1580 – 1691.
[17] For a definition of regiodivergent PKR, see: a) E. Vedejs, X.
of PKR in total synthesis, see: L. C. Miller, J. M. Ndungu, R.
[1] a) Y. Hirata, H. Nakata, K. Yamada, K. Okuhara, T. Naito,
1790 – 1791; c) K. Maeda, J. Antibiot. 1953, 6, 137 – 138.
[2] K. Otoguro, A. Ishiyama, M. Namatame, A. Nishihara, T.
Furusawa, R. Masuma, K. Shiomi, Y. Takahashi, H. Yamada, S.
[3] a) K. Kakinuma, C. A. Hanson, K. L. Rinehart, Tetrahedron
[4] J. Ueda, J. Hashimoto, A. Nagai, T. Nakashima, H. Komaki, K.
Anzai, S. Harayama, T. Doi, T. Takahashi, K. Nagazawa, T.
[5] a) T. Kawamura, T. Fujimaki, N. Hamanaka, K. Torii, H.
Kobayashi, Y. Takahashi, M. Igarashi, N. Kinoshita, Y. Nishi-
[18] For examples of Baeyer–Villiger monooxygenase dynamic
resolution, see: a) A. Rioz-Martínez, G. de Gonzalo, D. E.
Torres Pazmin ~ o, M. W. Fraaije, V. Gotor, J. Org. Chem. 2010,
75, 2073 – 2076; b) C. Rodríguez, G. de Gonzalo, A. Rioz-
4
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!