Science - USA (2020-02-07)

factors on compounds (–)- 9 and (–)- 13 by
Parsons’x-ray analysis (see the supplementary
materials) ( 28 ). In addition, we determined
the absolute configuration of (–)- 9 by circular
dichroism (CD) spectroscopy and compared
this with the simulated CD spectrum (see the
supplementary materials). Both methods re-
vealed that use of the (–)-TADDOL–based aux-
iliary gives the desired enantiomer (–)- 9 as
the major product. With compound (–)- 13 in
hand, we repeated the synthesis and obtained
(–)-canataxpropellane ( 2 ). The optical rotation
([a]D^22 =–18.2) of our pure synthetic material
was consistent with the literature ([a]D^22 =–39),
the difference originating from the second spe-
cies in the isolated material, as stated by the
authors ( 17 ).
Our total synthesis of (–)-canataxpropellane
( 2 ) presents an efficient method for prepa-
rationofthecomplextaxanecoreonthemul-
tigram scale. The natural product itself was
obtained in 0.5% yield. Our synthesis now
renders (–)-canataxpropellane ( 2 )available
in amounts suitable for biological investiga-
tions, which have been hampered by the lack
of materials. Our synthesis demonstrates the
capability of photochemistry to rapidly assem-
ble the most intricate and complex molecular
scaffolds. We have furthermore demonstrated
the robustness of our synthesis by carrying out
18 of 26 steps on decagram to gram scale. With
enantiopure access to (–)-canataxpropellane
( 2 ), we established a previously unknown chiral

siloxane as directing group Cl(iPr)Si-TADDOL

in the Diels–Alder reaction. The use of this

chiral siloxane group was not only suitable on

the multigram scale, but also enabled the fac-

ile separation of diastereomeric Diels–Alder

products.

REFERENCES AND NOTES

1. E. Baloglu, D. G. I. Kingston,J. Nat. Prod. 62 , 1448– 1472
   (1999).


2. D. Schinzer,“Taxanes: An unusual class of natural products”
   inOrganic Synthesis Set, H. Waldman, Ed. (Wiley, 2008),
   pp. 335–347.


3. Y.-F. Wanget al.,Chem. Rev. 111 , 7652–7709 (2011).


4. M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon, A. T. McPhail,
   J. Am. Chem. Soc. 93 , 2325–2327 (1971).


5. P. B. Schiff, J. Fant, S. B. Horwitz,Nature 277 , 665–667 (1979).


6. C. M. Spencer, D. Faulds,Drugs 48 , 794–847 (1994).


7. R. A. Holtonet al.,J. Am. Chem. Soc. 116 , 1597–1598 (1994).


8. R. A. Holtonet al.,J. Am. Chem. Soc. 116 , 1599–1600 (1994).


9. K. C. Nicolaouet al.,Nature 367 , 630–634 (1994).


10. S. J. Danishefskyet al.,J. Am. Chem. Soc. 118 , 2843– 2859
    (1996).


11. P. A. Wenderet al.,J. Am. Chem. Soc. 119 , 2755–2756 (1997).


12. P. A. Wenderet al.,J. Am. Chem. Soc. 119 , 2757–2758 (1997).


13. H. Kusamaet al.,J. Am. Chem. Soc. 122 , 3811–3820 (2000).


14. T. Mukaiyamaet al.,Chemistry 5 , 121– 161 (1999).


15. A. Mendoza, Y. Ishihara, P. S. Baran,Nat. Chem. 4 ,21– 25
    (2011).


16. S. Maliket al.,Process Biochem. 46 ,23–34 (2011).


17. C.-H. Huoet al.,Tetrahedron Lett. 48 , 2721–2724 (2007).


18. A. M. Dilmaç, T. Wezeman, R. M. Bär, S. Bräse,Nat. Prod. Rep.
    (2019).


19. A. Gilbert,Pure Appl. Chem. 52 , 2669–2682 (1980).


20. For a review, see: R. Remy, C. G. Bochet,Chem. Rev. 116 ,
    9816 – 9849 (2016).


21. J. Kollonitsch, O. Fuchs, V. Gàbor,Nature 175 , 346 (1955).


22. N. Kornblum, H. E. DeLaMare,J. Am. Chem. Soc. 73 , 880– 881
    (1951).


23. T. Mukaiyama, T. Sato, J. Hanna,Chem. Lett. 2 ,1041–1044 (1973).
    24. A. Chatterjee, N. N. Joshi,Tetrahedron 62 , 12137– 12158
    (2006).
    25. K. Ishihara, A. Sakakura,“Intermolecular Diels–Alder reactions”
    inComprehensive Organic Synthesis II, G. A. Molander,
    P. Knochel, Ed. (Elsevier, ed. 2, 2014), pp. 351–408.
    26. P. Merino, E. Marqués-López, T. Tejero, R. P. Herrera,
    Synthesis 2010 ,1–26 (2010).
    27. D. Seebach, A. K. Beck, R. Imwinkelzied, S. Roggo,
    A. Wonnacott,Helv. Chim. Acta 70 , 954–974 (1987).
    28. S. Parsons, H. D. Flack, T. Wagner,Acta Crystallogr. B Struct.
    Sci. Cryst. Eng. Mater. 69 , 249–259 (2013).

ACKNOWLEDGMENTS

WethankProf.Dr.R.W.HoffmannfromtheUniversityof

Marburg (Germany) for continuous, very helpful, and

interesting discussions during the project. We thank the

NMR department of the University of Konstanz (A. Friemel

and U. Haunz) for extensive analyses. We thank I. Göttker,

M. Linseis, T. Huhn, and B. Weibert (Universität Konstanz) for

x-ray analysis.Funding:Financial support was granted by

the Landesgraduiertenförderung (LGFG stipend) by the state of

Baden-Württemberg, Germany, and by the Georg Christoph

Lichtenberg Stipendium by the state of Lower Saxony, Germany.

Author contributions:F.S., K.S., and S.Z. contributed with

experimental work and intellectual input; T.G. contributed

with project planning/managing and intellectual input.

Competing interests:The authors declare no competing

interests.Data and materials availability:The x-ray data for

compounds (–)- 13 ,(–)- 9 ,(±)- 13 , 17 ,and 23 have been

depositedattheCambridgedatabaseandareavailablefreeof

charge under CCDC numbers 1966216 for (–)- 13 , 1966215

for (–)- 9 , 1966212 for (±)- 13 , 1966213 for 17 , and 1966214 for 23.

SUPPLEMENTARY MATERIALS

science.sciencemag.org/content/367/6478/676/suppl/DC1

Materials and Methods

Figs. S1 to S7

Tables S1 to S7

References ( 29 – 45 )

29 July 2019; accepted 14 January 2020

10.1126/science.aay9173

Schneideret al.,Science 367 , 676–681 (2020) 7 February 2020 5of5

Fig. 5. Access to enantiopure key intermediate (–)-9 and (–)-13 for the enantiopure synthesis of (–)-(2).

RESEARCH | REPORT