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Scheme 1. Reagents and conditions: (a) isophthaladehyde (2 equiv), LiCl, iPr2NEt, MeCN, rt, 48 h (74% from (4R)-5,5-dimethyl-4-phenyloxazolidin-2-one); (b)
vinylmagnesium chloride, toluene, ꢀ78 °C; (c) MeReO3 (3 mol %), toluene, rt, 12 h; TBSCI (1.2 equiv), imidazole, rt, 45 min (79% from 7); (d) 10 (1.2 equiv), CuI, Me2S/THF,
ꢀ40 °C ? ꢀ20 °C, 96%; (e) TBAF, THF, ꢀ10 °C, 1 h, 95%; (f) 13, Pd(PPh3)2Cl2 (2.5 mol %), CuI (5 mol %), iPr2NH, 0 °C ? rt, THF,1 h, 61%; (g) (i-Bu)2AIH (3 equiv), toluene, ꢀ78 °C;
(h) CCl3C(Me)2CO2Cl (1.4 equiv), DMAP, pyridine, DCM, ꢀ40 °C, 2 h (52% from 14).
2. Engaging structure 1 with synthetic WWY in a simple three step reaction
in multi-gram batches without incident. It has the added benefit of
introducing the diene-yne appendage incrementally in two seg-
ments, wherein both can be controllably varied in future iterations.
Along these lines, we look forward to creating numerous congeners
of this novel grafting material.
sequence (see Ref. 1) leads to products such as 5, wherein the composite has
restricted conformational mobility, increased stability and solubility and
harbors both polar and hydrophobic domains.
3. Ouellet, S. G.; Walji, A.; MacMillan, D. W. C. Acc. Chem. Res. 2007, 40, 1327. and
references therein.
4. Reactions of scalemic
1
with enantiopure polyamides generate
diastereoisomeric product mixtures which are difficult to separate. This
unnecessarily complicates analysis/characterization.
5. (a) Hobbs, D. M.; Schubert, P.; Tung, H.-H. Ind. Eng. Chem. Res. 1997, 36, 5302;
(b) Hachem, A.; Roussel, P.; Ménager, E.; Grée, D.; Le Floc’h, Y.; Grée, R.; Cerletti,
C.; Rolland, Y.; Simonet, S.; Verbeuren, T. Bioorg. Med. Chem. Lett. 2002, 12,
2511.
6. (a) Bull, S. D.; Davies, S. G.; Nicholson, R. L.; Sanganee, H. J.; Smith, A. D. Org.
Biomol. Chem. 2003, 1, 2886; For ‘SuperQuat’ auxilaries see: (b) Bull, S. D.;
Davies, S. G.; Jones, S.; Polywka, M. E. C.; Prasad, R. S.; Sanganee, H. J. Synlett
1998, 519.
7. (a) Jacob, J.; Espenson, J. H.; Jensen, J. H.; Gordon, M. S. Organometallics 1998, 17,
1835; (b) Herrmann, A. T.; Saito, T.; Stivala, C. E.; Tom, J.; Zakarian, A. J. Am.
Chem. Soc. 2010, 132, 5962; (c) Bellemin-Laponnaz, S.; Le Ny, J. P.; Osborn, J. A.
Tetrahedron Lett. 2000, 41, 1549.
Acknowledgments
Funding was provided by the National Cancer Institute (POI
CA9547106) and the Donald J. and Jane M. Cram Endowment
(UCLA). We thank Dr. Buddy Soto-Cairoli for experimental assis-
tance. High resolution mass spectra were recorded at UCLA
through the auspices of the National Center for Research Resources
grant number S10RR025631.
Supplementary data
8. Readily prepared on >300 mmol scale according to: Bian, J.; Van Wingerden,
M.; Ready, J. M. J. Am. Chem. Soc. 2006, 128, 7428.
Supplementary data (experimental procedures, characteriza-
tion data, and NMR spectra for new compounds) associated with
this article can be found, in the online version, at doi:10.1016/
9. Pinkerton, D. M.; Banwell, M. G.; Willis, A. C. Aust. J. Chem. 2009, 62, 1639.
10. Enantiomeric excess of 1 is determined via HPLC analysis of diastereoisomeric
imidazolidines formed by reaction with (R,R)-N,N0-dimethyl-1,2-diphenyl
ethylene diamine. Reaction with racemic 1 serves as a standard. See: (a)
Mangeney, P.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1988, 29, 2677; (b)
Cuvinot, D.; Mangeney, P.; Alexakis, A.; Normant, J. F.; Lellouche, J. P. J. Org.
Chem. 1989, 54, 2420.
References and notes
11. Absolute stereochemistry at C-3 in 1 is assigned as R by analogy to outcomes in
Ref. 6. Material prepared in this work shows ½a D20
ꢁ
= +29.0 (c 0.56, CHCl3). This is
signed opposite to previously synthesized 1, which was drawn incorrectly in
1. Zhao, H. D.; Negash, L.; Wei, Q.; LaCour, T. G.; Estill, S. J.; Capota, E.; Pieper, A.
A.; Harran, P. G. J. Am. Chem. Soc. 2008, 130, 13864.
our previous communication (Ref. 1).