Journal of the American Chemical Society
Page 8 of 10
A facile activation of nonꢀactivated 1°ꢀ and 2°ꢀalkyl halides We thank Dr. Zhigao Zhang for his participation at the very
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was achieved via (1) direct Zn insertion or (2) earlyꢀtransitionꢀ
metal assisted SETꢀactivation. For alkyl bromides, lithium
iodide in DMI was found to be a special combination efficientꢀ
ly to insert zinc dust to alkyl bromides at room temperature.
Mechanistically, alkyl bromides were first transformed to the
corresponding alkyl iodides, which then reacted with zinc
dust. An orthogonal, unprecedented method was developed,
to prepare alkylzinc halides with use of a combination of CoPc
or NbCpCl4 and CrCl2, where the former serves as a radical
initiator whereas the latter serves to trap and transfer the genꢀ
erated radical to zinc halide. Through this study, a new radical
initiator, generated from NbCpCl4 and zinc dust, was discovꢀ
ered.
early phase of this work. Financial support from the Eisai
USA Foundation is gratefully acknowledged.
REFERENCES
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3(a) For a general review on ketone syntheses with organometallics,
see: Dieter, R. K. Tetrahedron 1999, 55, 4177. For selected references
for metalꢀcatalyzed ketone syntheses, see: (b) RMgX/Ni: Fiandanese,
V.; Marchese, G.; Ronzini, L. Tetrahedron Lett. 1983, 24, 3677. (c)
RMgX/Ni and RMgX/Fe: Cardellicchio, C.; Fiandanese, V.; Marcheꢀ
se, G.; Ronzini, L. Tetrahedron Lett. 1985, 26, 3595 and references
cited therein. (d) RZnX/Pd: Negishi, E.ꢀi.; Bagheri, V.; Chatterjee, S.;
Luo, F.ꢀT.; Miller, J. A.; Stoll, A. T. Tetrahedron Lett. 1983, 24,
5181. (e) RSnX3/Pd: Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L.
S. Org. Lett. 2003, 5, 3033. (f) RB(OH)2/Pd: Liebeskind, L. S.; Srogl,
J. J. Am. Chem. Soc. 2000, 122, 11260. (g) RSnX3/Cu: Li, H.; He, A.;
Falck, J. R.; Liebeskind, L. S. Org. Lett. 2011, 13, 3682. (h) R2Zn/Ni:
Zhang, Y.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 15964.
Combined with the two facile methods for preparation of
alkylzinc halides, Fukuyama coupling was then extended to
oneꢀpot ketone synthesis from alkyl halides and thioesters.
With use of the two orthogonal activation methods, three sets
of coupling conditions were developed, with Condition A
(Pd2dba3, PR3, Zn, LiI, TESCl, DMI), Condition B (A +
CrCl2), and Condition C (B + NbCpCl4 or CoPc) being useful
for simple linear and αꢀsubstituted alkyl halides, simple linear
and βꢀsubstituted alkyl halides, and complex substrates, reꢀ
spectively. Overall, Condition C was found applicable for the
broadest range of substrates. All conditions gave an excellent
synthetic efficiency, with good functional group tolerance.
4
(a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189. (b) Miyazaki, T.; Hanꢀya, Y.;
Tokuyama, H.; Fukuyama, T. Synlett 2004, 2004, 477. (c) Fukuyama,
T.; Tokuyama, H. Aldrichim. Acta 2004, 37, 87 and references cited
therein. (d) Cherney, A. H.; Reisman, S. E. Tetrahedron 2014, 70,
3259.
Controlled formation of alkylzinc halides by a combination
of CrCl2 and NbCpCl4 or CoPc was crucial for its application
to complex substrates. Interestingly, oneꢀpot ketone synthesis
did not suffer from the chemical instability due to the inevitaꢀ
ble radical pathway(s), for example 1,5ꢀH shift. Notably, even
with the increase in molecular size, no significant decrease in
coupling efficiency was noticed. For these reasons, oneꢀpot
ketone synthesis is a reliable option for a coupling at a late
stage in a convergent synthesis of complex molecules, as exꢀ
emplified in a synthesis of 4sc containing all the carbons of
Eribulin.
5
(a) Shimizu, T.; Seki, M. Tetrahedron Lett. 2001, 42, 429. (b)
Mori, Y.; Seki, M. Adv. Synth. Catal. 2007, 349, 2027 and references
cited therein.
6 (a) Zheng, W.; Seletsky, B. M.; Palme, M. H.; Lydon, P. J.; Singꢀ
er, L. A.; Chase, C. E.; Lemelin, C. A.; Shen, Y.; Davis, H.; Tremꢀ
blay, L.; Towle, M. J.; Salvato, K. A.; Wels, B. F.; Aalfs, K. K.; Kiꢀ
shi, Y.; Littlefield, B. A.; Yu, M. J. Bioorg. Med. Chem. Lett. 2004,
14, 5551. (b) For a review on discovery/development of Eribulin, see:
Yu, M. J.; M.; Kishi, Y.; Littlefield, B. A. Anticancer Agents from
Natural Products; CRC Press: 2005, p 241; Yu, M. J.; Zheng, W.;
Seletsky, B. M.; Littlefield, B. A.; Kishi, Y. Annu. Rep. Med. Chem.;
John, E. M., Ed.; Academic Press: 2011, Vol. 46, p 227. (c) Austad,
B. C.; Calkins, T. L.; Chase, C. E.; Fang, F. G.; Horstmann, T. E.; Hu,
Y.; Lewis, B. M.; Niu, X.; Noland, T. A.; Orr, J. D.; Schnaderbeck,
M. J.; Zhang, H.; Asakawa, N.; Asai, N.; Chiba, H.; Hasebe, T.;
Hoshino, Y.; Ishizuka, H.; Kajima, T.; Kayano, A.; Komatsu, Y.;
Kubota, M.; Kuroda, H.; Miyazawa, M.; Tagami, K.; Watanabe, T.
Synlett 2013, 24, 333 and references cited therein.
It is worthwhile noting that all the required reagents are
commercially available and can be conveniently preꢀmixed
and stored without loss of activity. We believe that the reportꢀ
ed, facile preparation of alkylzinc halides at room temperature
will find various applications beyond this work. Extension of
oneꢀpot ketone synthesis to an intramolecular setting is in proꢀ
gress and will be reported in due course.
7
Commercial Eribulin is produced via ketone i, which is syntheꢀ
sized by coupling phenylsulfone ii and aldehyde iii. This coupling
was originally used in drugꢀdiscovery efforts and then optimized in
processꢀdevelopment efforts.6 Recently, the efficiency of
phenylsulfoneꢀaldehyde coupling was dramatically improved by use
of a flowꢀsystem even at 10 °C; 96% HPLC yield; 1.1 equiv. of iii at
10 °C; Fukuyama, T.; Chiba, H.; Kuroda, H.; Takigawa, T.; Kayano,
A.; Tagami, K. Org. Process Res. Dev. 2016, 20, 503. For recent
related work, see: (a) Inanaga, K.; Fukuyama, T.; Kubota, M.; Koꢀ
matsu, Y.; Chiba, H.; Kayano, A.; Tagami, K. Org. Lett. 2015, 17,
3158. (b) Fukuyama, T.; Chiba, H.; Takigawa, T.; Komatsu, Y.;
Kayano, A.; Tagami, K. Org. Process Res. Dev. 2016, 20, 100.
ASSOCIATED CONTENT
Supporting Information
Additional data for Tables 1 and 2, experimental procedures,
characterization data, and copies of spectra. The Supporting Inꢀ
formation is available free of charge on the ACS Publications
website.
AUTHOR INFORMATION
Corresponding Author
Author Contributions
The manuscript was written through contributions of both authors.
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