ARTICLES
Trioxacarcinose A donors
Trioxacarcinose B donor
OAc
CH3
OAc
O
H
CH3
H
CH3
CH3
OAc
O
OAc
H3C
H3C
OAc
SPh
O
O
HO
HO
OH
H
H
H
5
3
23
AgPF6
TMSNTf2
BF3·OEt2
O
CH3
OAc
O+
H
+
O
CH3
CH3
OAc
CH3
CH3
OAc
CH3
HO
AcO
H
CH3
OH
O
CH3
O
+O
OH
H
H
+
H
OH
36
37
38
39
Axial
addition
Axial
addition
ROH
ROH
ROH
ROH
H
OAc
OAc
O
OR
CH3
CH3
H
CH3
CH3
OAc
O
CH3
CH3
OAc
O
OR
H
H3C
H3C
O
HO
H
OR
O
O
HO
OH
OH
OR
H
H
α-anomer
(exclusive product)
β-anomer
(not observed)
α-anomer
(exclusive product)
β-anomer
(not observed)
Figure 6 | Rationalizations of the stereochemical outcome of glycosylation reactions with trioxacarcinose A and B donors. Axial addition to the
stereoelectronically favoured half-chair 36 is relatively less impeded by steric interactions than addition to the alternative conformer 37, which offers one
rationalization for the high a-selectivities observed in glycosylation reactions of trioxacarcinose B donor 5 (see text for another). Similar considerations apply
to explain the highly a-selective couplings of trioxacarcinose A donors 3 and 23.
8. Cassidy, J. et al. Phase I clinical study of LL-D49194a1 with retrospective
nucleophiles that benefit from p-stacking interactions with the
aromatic core, such as a guanosine base of duplex DNA29.
pharmacokinetic investigations in mice and humans. Cancer Chemother. Pharm.
31, 395–400 (1993).
9. Gerber, H-P., Koehn, F. E. & Abraham, R. T. The antibody–drug conjugate: an
The synthetic sequence to trioxacarcin A we describe pro-
ceeds in 11 linear steps, four of these convergent coupling
reactions, and assembles five components of comparable syn-
enabling modality for natural product-based cancer therapeutics. Nat. Prod. Rep.
30, 625–639 (2013).
ˇ
thetic complexity: the cyanophthalide 17, the cyclohexenone 10. Svenda, J., Hill, N. & Myers, A. G. A multiply convergent platform for the
synthesis of trioxacarcins. Proc. Natl Acad. Sci. USA 108, 6709–6714 (2011).
18, the epoxydiazodiketone 21, the trioxacarcinose A donor
23 and the trioxacarcinose B donor 5. Each of these com-
11. Myers, A. G., Gin, D. Y. & Rogers, D. H. Synthetic studies of the tunicamycin
antibiotics. Preparation of (þ)-tunicaminyluracil, (þ)-tunicamycin-V, and
ponents was synthesized by a short scalable sequence in multi-
gram amounts. A great virtue of the component-based assembly
strategy that we pursued both here and elsewhere30 is that deep-
seated structural modifications can be introduced and explored
relatively rapidly by independent modification of components,
as illustrated by the subset of structures presented in Fig. 5.
Simultaneous structural variation of more than one component
leads to multiplicative expansion of the pool of structures acces-
sible for study.
5′-epitunicamycin-V. J. Am. Chem. Soc. 116, 4697–4718 (1994).
12. Maiese, W. M. et al. LL-D49194 antibiotics, a novel family of antitumor
agents: taxonomy, fermentation and biological properties. J. Antibiot. 43,
253–258 (1990).
ˇ
13. Smaltz, D. J., Svenda, J. & Myers, A. G. Diastereoselective additions of
allylmetal reagents to free and protected syn-a,b-dihydroxyketones
enable efficient synthetic routes to methyl trioxacarcinoside A. Org. Lett. 14,
1812–1815 (2012).
14. Magauer, T. & Myers, A. G. Short and efficient synthetic route to methyl
a-trioxacarcinoside B and anomerically activated derivatives. Org. Lett. 13,
5584–5587 (2011).
15. Mathieu, B. & Ghosez, L. N-trimethylsilyl-bis(trifluoromethanesulfonyl)imide: a
better carbonyl activator than trimethylsilyl triflate. Tetrahedron Lett. 38,
5497–5500 (1997).
Received 9 April 2013; accepted 31 July 2013;
published online 8 September 2013
16. Kimura, Y., Suzuki, M., Matsumoto, T., Abe, R. & Terashima, S. Trimethylsilyl
trifluoromethanesulfonate (trimethylsilyl triflate) as an excellent glycosidation
reagent for anthracycline synthesis: simple and efficient synthesis of optically
pure 4-demethoxydaunorubicin. Chem. Lett. 4, 501–504 (1984).
17. Kimura, Y., Suzuki, M., Matsumoto, T., Abe, R. & Terashima, S. Novel
glycosidation of 4-demethoxyanthracyclinones by the use of trimethylsilyl
triflate. Syntheses of optically-active 4-demethoxydaunorubicin and
4-demethoxyadriamycin. B. Chem. Soc. Jpn 59, 423–431 (1986).
18. Lear, M. J., Yoshimura, F. & Hirama, M. A direct and efficient a-selective
glycosylation protocol for the kedarcidin sugar, L-mycarose: AgPF6 as a
remarkable activator of 2-deoxythioglycosides. Angew. Chem. Int. Ed. 40,
946–949 (2001).
References
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