C O M M U N I C A T I O N S
Acknowledgment. We thank Jianrong (Steve) Zhou for im-
portant preliminary studies. Support has been provided by the
National Institutes of Health (National Institute of General Medical
Sciences, R01-GM62871), Merck Research Laboratories, and
Novartis. Funding for the MIT Department of Chemistry Instru-
mentation Facility has been furnished in part by the National
Science Foundation (CHE-9808061 and DBI-9729592).
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
Chiral indanes have served as intermediates in the synthesis of
a variety of bioactive compounds,1 and we have established that
our new method provides ready access to such targets. For example,
Ligand Pharmaceuticals’ route to LG 121071, the first orally active,
nonsteroidal androgen receptor agonist, proceeds via (R)-3-ethylin-
danone, which was generated in three steps from propiophenone
0,11
References
(
1) For recent reviews, see the following: (a) Metal-catalyzed cross-coupling
reactions of unactivated alkyl halides: Frisch, A. C.; Beller, M. Angew.
Chem., Int. Ed. 2005, 44, 674-688. (b) Nickel-catalyzed couplings of
unactivated alkyl electrophiles: Netherton, M. R.; Fu, G. C. AdV. Synth.
Catal. 2004, 346, 1525-1532.
via a copper-catalyzed enantioselective conjugate reduction (86%
ee).1
2,13
Through a nickel-catalyzed asymmetric Negishi cross-
coupling, we can synthesize the key intermediate in 92% ee in two
steps from commercially available 1-indanone (eq 5).
(2) Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594-4595.
(
3) For a few examples, see: (a) Tamao, K.; Sumitani, K.; Kumada, M. J.
Am. Chem. Soc. 1972, 94, 4374-4376. (b) Wolfe, J. P.; Buchwald, S. L.
J. Am. Chem. Soc. 1997, 119, 6054-6058. (c) Lipshutz, B. H.; Blomgren,
P. A. J. Am. Chem. Soc. 1999, 121, 5819-5820.
(
4) Our current hypothesis is that the benzylic halide is transformed into a
benzylic radical, which then combines with nickel to generate a ben-
zylnickel intermediate.
(
5) General procedure: In the air (no special precautions are necessary), a 4
2
mL glass vial was charged with NiBr ‚diglyme (35.3 mg, 0.100 mmol),
(
S)-(i-Pr)-Pybox (39.2 mg, 0.130 mmol), and the benzylic halide (1.00
mmol). The vial was fitted with a septum cap and purged with argon for
5 min. DMA (1.75 mL) was added, and the resulting orange mixture
was placed in a 0 °C bath and stirred for 15 min. The organozinc reagent
1.6 M in DMA; 1.0 mL, 1.6 mmol) was added in a single portion, and
1
(
the resulting homogeneous brown solution was stirred at 0 °C for 24 h.
Then, the remaining organozinc reagent was quenched by the addition of
ethanol (0.3 mL), and the resulting orange solution was purified directly
by flash chromatography.
MacLeod has employed racemic trans-1,3-dimethylindane in his
syntheses of trans-trikentrin A14 and iso-trans-trikentrin B, both
of which have been isolated from the marine sponge Trikentrion
flabelliforme and exhibit antibacterial activity. We have established
that this indane can be prepared enantioselectively using two
Negishi cross-couplings (Figure 1). Both diastereomers of inter-
15
(6) Notes: (a) Use of a commercially available organozinc reagent (Aldrich)
led to a lower enantiomeric excess and yield. We recommend that
organozinc reagents be prepared from the corresponding alkyl bromides
according to the straightforward procedure of Huo: Huo, S. Org. Lett.
2
003, 5, 423-425. (b) Less than 2% of the desired product is generated
in the absence of NiBr ‚diglyme. (c) Under our standard conditions, we
cannot effectively (yield and/or ee) cross-couple 1,3-dibromoindane,
-bromotetralin, benzylzincs, or arylzincs.
2
1
(
7) The product of the Negishi reaction depicted in entry 4 (Table 1) has
been used as an intermediate in the synthesis of selective σ ligands:
Berardi, F.; Ferorelli, S.; Colabufo, N. A.; Leopoldo, M.; Perrone, R.;
Tortorella, V. Bioorg. Med. Chem. Lett. 2001, 9, 1325-1335.
8) The product of the coupling illustrated in entry 10 (Table 1) has been
employed in the total synthesis of natural products such as (+)-nuciferol
and (+)-nuciferal. The two previous routes to this compound proceeded
in 13 steps from mannitol (Takano, S.; Goto, E.; Ogasawara, K.
Tetrahedron Lett. 1982, 23, 5567-5570) and 9 steps from trans-2-butene-
(
1
,4-diol (Takano, S.; Sugihara, T.; Samizu, K.; Akiyama, M.; Ogasawara,
K. Chem. Lett. 1989, 1781-1784).
(
9) (a) Negishi: Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-
1
1
2
4727. (b) Suzuki: Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126,
340-1341. (c) Hiyama: Powell, D. A.; Fu, G. C. J. Am. Chem. Soc.
004, 126, 7788-7789. (d) Stille: Powell, D. A.; Maki, T.; Fu, G. C. J.
Am. Chem. Soc. 2005, 127, 510-511.
(
10) (a) For a review of the synthesis of indanes, see: Hong, B.-C.; Sarshar,
S. Org. Prep. Proc. Int. 1999, 31, 1-86. (b) For a review of indane
derivatives of biological interest, see: Ganellin, C. R. AdV. Drug Res.
1967, 4, 163-249.
(
11) (a) For leading references to progress on the catalytic asymmetric
hydrogenation of indenes, see: Halterman, R. L. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 2004; Supplement 2, pp 1-6. (b) For a specific
example, see: Troutman, M. V.; Appella, D. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 4916-4917.
(
12) (a) Hamann, L. G.; Mani, N. S.; Davis, R. L.; Wang, X.-N.; Marschke,
K. B.; Jones, T. K. J. Med. Chem. 1999, 42, 210-212. (b) Mani, N. S.;
Wu, M. Tetrahedron: Asymmetry 2000, 11, 4687-4691.
Figure 1. Catalytic enantioselective synthesis of trans-1,3-dimethylindane.
mediate A react to generate the desired trans-1,3-dimethylindane.16
In conclusion, we have described the first highly enantioselective
cross-couplings of secondary benzylic halides, specifically, Negishi
reactions of racemic bromides and chlorides with organozinc rea-
gents. Our method employs commercially available catalyst com-
ponents and is not highly air- or moisture-sensitive. Current efforts
are directed at further expanding the scope of nickel-catalyzed
coupling reactions of alkyl electrophiles.
(13) For a five-step synthesis of (S)-3-ethylindanone, see: (a) Stephan, E.;
Rocher, R.; Aubouet, J.; Pourcelot, G.; Cresson, P. Tetrahedron: Asym-
metry 1994, 5, 41-44. (b) Brienne, M.-J.; Ouannes, C.; Jacques, J. Bull.
Soc. Chim. Fr. 1967, 613-623.
(
14) MacLeod, J. K.; Monahan, L. C. Aust. J. Chem. 1990, 43, 329-337.
15) MacLeod, J. K.; Ward, A.; Willis, A. C. Aust. J. Chem. 1998, 51, 177-
(
187.
(16) To the best of our knowledge, this is the first synthesis of enantioenriched
trans-1,3-dimethylindane.
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