LETTERS
NATURE
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Vol 459
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11 June 2009
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naturally lead to the synthesis of related family members, closely
related analogues (for example 5 and 23) and in some cases even
structural reassignments (for example 69 R 6). Finally, the use of a
retrosynthesis pyramid when planning the oxidase phase can encour-
age the invention of useful methodology and greater insight into the
relative reactivity of different tertiary C–H bonds.
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This work represents another11–17,30 step towards the generation of a
set of rules and logic for the use of C–H oxidation in terpene synthesis.
Whether or not elements of such a strategy could be employed in the
synthesis of terpenes at the highest level of complexity (for example 2;
Fig. 1) remains to be seen. There are obvious limitations in current
synthetic methodology that will need to be overcome for the logic of
this approach to reach its full potential, such as the oxidation of
primary and secondary C–H bonds in a controllable manner, a
broader functional group tolerance and more general, high-yielding
protocols for C–H oxidation. Finally, we note that the use of a
trifluoroethyl carbamate directing group is both an advantage and a
limitation. Its use permitted site-selective oxidations of both sp3-
hybridized (15 to 17 and 16 to 18) and sp2-hybridized (20 to 21)
carbon atoms that would have been difficult to achieve in an inter-
molecular fashion with currently available reagents. Furthermore, it
shielded the reactivity of a secondary alcohol, allowing intermolecular
C–H oxidation (15 to 16) and rendering several intermediates crys-
talline for X-ray characterization purposes. Conversely, its installation
requires an additional step and this points to two directions for future
attempts to imitate the oxidase phase of terpene biosynthesis: site-
specific C–H oxidation without any directing groups and reagent-
dependent reordering of C–H bond reactivity.
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METHODS SUMMARY
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All reactions were carried out under a nitrogen atmosphere with dry solvents
under anhydrous conditions, unless otherwise noted. Yields refer to chromato-
graphically and spectroscopically homogeneous materials, unless otherwise sta-
ted. Reagents were purchased at the highest commercial quality and used
without further purification, unless otherwise stated. Reactions were monitored
using thin-layer chromatography. For full experimental details and procedures
for all reactions performed and full characterization (1H NMR, 13C NMR, high-
resolution mass spectrometry, infrared, optical rotation, melting point and Rf
value) of all new compounds, see Supplementary Information.
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26. Chi, Y. & Gellman, S. H. Diphenylprolinol methyl ether: a highly enantioselective
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Received 17 February; accepted 7 April 2009.
Published online 13 May 2009.
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H functionalization by metal
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Supplementary Information is linked to the online version of the paper at
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Acknowledgements We are grateful to A. Eschenmoser for discussions and to
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Bristol-Myers Squibb for financial support. M. Moron Galan and Y. Ishihara are
acknowledged for technical contributions to the early stages of this project. We are
grateful to B. Shi and A. Reingold for assistance with high-performance liquid
chromatography and X-ray crystallographic analyses, respectively.
5. Wilson, R. & Danishefsky, S. J. Pattern recognition in retrosynthetic analysis:
snapshots in total synthesis. J. Org. Chem. 72, 4293–4305 (2007).
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Author Information The X-ray crystallographic coordinates for the structures
reported in this paper have been deposited at the Cambridge Crystallographic Data
Centre, under deposition numbers CCDC 718278 (5), CCDC 719000 (6),
CCDC 718279 (15), CCDC 718280 (19), CCDC 718281 (21) and CCDC 718282
(22). These data can be obtained free of charge from the Cambridge
Correspondence and requests for materials should be addressed to P.S.B.
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88, 3011–3050 (2005).
9. Jennewein, S., Rithner, C. D., Williams, R. M. & Croteau, R. B. Taxol biosynthesis:
taxane 13a-hydroxylase is a cytochrome P450-dependent monooxygenase. Proc.
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