of Tekturna, in an overall yield of 7%,6 which to the best of
our knowledge, is the shortest linear sequence to date.
the known advanced intermediate A, which has been
previously converted to the intended target compound
(Figure 1).5
The venerable Tsuji palladium-catalyzed R-allylation of
ketones7,8 has been adapted to an asymmetric variant by
Stoltz9,10 and Trost11 independently, using optimized chiral
ligands.12 Although there were only a few examples of the
asymmetric allylation of acyclic aryl ketones at the incep-
tion of our work, we initiated studies to assess the feasi-
bility of such a reaction with an isobutyl phenyl ketone
corresponding to chiron B (Figure 1). Trost and co-
workers13 had reported that while R-allylation of ethyl
phenyl ketone took place with 94% enantiomeric excess,
the selectivity and yield were drastically diminished in the
case of the more sterically demanding isobutyl phenyl
ketone (32% ee, 30% yield) (Scheme 1). We were pleased
to find that under optimized conditions, the Stoltz proto-
col, using the (S)-t-BuPHOX ligand,9 was highly effective
in converting the enol carbonate prepared from isobutyl
phenyl ketone to the corresponding R-allyl ketone in 84%
ee and 95% isolated yield intended for Tekturna (entry 2,
Table 1). We found that addition of 1 equiv of BHT had a
significant effect on the rate of the reaction (3 h to 45 min)
at 0 °C while also improving the degree of enantioselec-
tivity with up to 91% ee (entry 15, Table 1 and Scheme 1).
To the best of our knowledge, the palladium-catalyzed
asymmetric allylation of acyclic enol carbonates with the
Scheme 1. Palladium-Catalyzed Asymetric R-Allylation of
Acyclic Isopropyl Aryl Allyl Enol Carbonates
We now report on the efficient synthesis of a key
advanced intermediate to Tekturna, previously prepared
by a multistep procedure.5 Besides its novelty with regard
to published reports,4,5 our approach features a catalytic
step that provides a key intermediate expeditiously and in
high enantiomeric purity. Disconnection of Tekturna in a
retrosynthetic sense leads to the two olefinic chirons B and
C that can be joined in a cross-metathesis reaction, to give
PHOX ligand has only been recently reported.14,15
A
demonstrable 12% improvement in enantiomeric excess
was shown for ethyl phenyl ketone, in the presence of
40 mol % of AgBr (75%, 79% ee).
Studies on the screening of other BuPHOX and related
catalysts were done with regard to reaction time and the
nature of the additive (Table 1). The following observa-
tions are noteworthy: (a) the Pd2(dba)3/(S)-t-BuPHOX
catalyst was optimal at a ratio of Pd2(dba)3 2.5 mol %/
ligand 6.25 mol %; (b) protic additives including 2-methyl
diethylmalonate13 did not adversely affect the reaction
rate, except for 1-naphthol and binol; (c) t-BuOH and
especially BHT decreased the reaction time and increased
the ee in some cases; (d) reactions were more reproducible
with a freshly prepared ligand.
(5) (a) Satyanarayna Reddy, M.; Thirumalai Rajan, S.; Eswaraiah,
S.; Venkat Reddy, G.; Rama Subba Reddy, K.; Sahadeva Reddy, M.
€
WO 148392 A1, 2011. (b) Mickel, S. J.; Sedelmeier, G.; Hirt, H.; Schafer, F.;
Foulkes, M.; Prikoszich, W. WO 131304, 2006. (c) Herold, P.; Stutz, S. WO
0202500, 2002. (d) Herold, P.; Stutz, S. WO 0202487, 2002. (e) Herold, P.;
Stutz, S.; Spindler, F. WO 0202508, 2002.
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(6) Hanessian, S.; Guesne, S.; Chenard, E. Org. Lett. 2010, 12, 1816.
(7) (a) Minami, I.; Nisar, M.; Yuhara, M.; Shimizu, I.; Tsuji, J.
Synthesis 1987, 992. See also: Tsuji, J. Palladium Reagents and Catalysts;
Wiley: U.K., 2004. (b) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett.
1980, 21, 3199. (c) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron
Lett. 1965, 6, 4387.
The role of the BHT as an additive is not fully under-
stood at this time. Murakami16 reported that the addition
of phenol or 1-naphthol was essential to attain a good yield
and an improved ee in an asymmetric Carroll rearrange-
ment. Incontrast, 1-naphthol and related compounds were
detrimental in our case (entries 11 and 16, Table 1).
Trost and co-workers11,17 reported an increase in reac-
tion rate by adding 2-methyl dimethylmalonate when
(8) For a recent review on metal catalyzed decarboxylative allylation,
see: Weaver, J. D.; Recio, A., III; Grenning, A. J.; Tunge, J. A. Chem.
Rev. 2011, 111, 1846.
(9) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044.
(10) For reviews, see: (a) Mohr, J. T.; Krout, M. R.; Stoltz, B. M.
Nature 2008, 455, 323. (b) Mohr, J. T.; Stoltz, B. M. Chem.;Asian J. 2007,
2, 1476. (c) You, S.-L.; Dai, L.-X. Angew. Chem., Int. Ed. 2006, 45, 5246.
(11) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846.
(12) For the design, synthesis, and reactivity of chiral phosphinoox-
azolines (PHOX) ligands, see: (a) Helmchen, G.; Pfaltz, A. Acc. Chem.
Res. 2000, 33, 336 and references therein. (b) Williams, J. M. J. Synlett
1996, 705. (S)-t-BuPHOX is commercially available from L-tert-leuci-
nol. (R)-t-BuPHOX was prepared from D-tert-leucine. For the synthesis
(13) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131,
18343.
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of modified PHOX ligands, see: (c) Belanger, E.; Pouliot, M.-F.;
(14) For example, see: Behenna, D. C.; Stoltz, B. M.; Mohr, J. T.;
Harned, A. M. U.S. 7,235,698, B2 2007.
(15) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.;
Courtemanche, M.-A.; Paquin, J.-F. J. Org. Chem. 2012, 77, 317.
(d) McDougal, N. T.; Streuff, J.; Mukerjee, H.; Virgil, S. C.; Stoltz,
B. M. Tetrahedron Lett. 2010, 51, 5550. (e) Krout, M. R.; Mohr, J. T.;
Stoltz, B. M. Org. Synth. 2009, 86, 181. (f) Tani, K.; Behenna, D. C.;
McFadden, R. M.; Stoltz, B. M. Org. Lett. 2007, 9, 2529. For examples
of palladium-catalyzed allylation with bis(oxazoline) ligands, see:
(g) Liu, L.; Ma, H.; Fu, B. Molecules 2012, 17, 1992. (h) Bayardon, J.;
Sinou, D.; Guala, M.; Desimoni, G. Tetrahedron: Asymmetry 2004, 15,
3195 and references therein.
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Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novak, Z.; Krout, M. R.;
McFadden, R. M.; Roizen, J. L.; Enquist, J. A., Jr.; White, D. E.; Levine,
S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem.;
Eur. J. 2011, 17, 14199.
(16) Kuwano, R.; Ishida, N.; Murakami, M. Chem. Commun. 2005,
3951.
Org. Lett., Vol. 14, No. 12, 2012
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