Catalytic enantioselective Hosomi-Sakurai conjugate allylation of cyclic unsaturated ketoesters

Article abstract of DOI:10.1002/anie.200800628

(Chemical Equation Presented) No fancy catalyst required: The copper-catalyzed enantioselective conjugate allylation of activated cyclic enones affords products in up to >98% ee. Reactions proceed to high conversion in the presence of commercially availab

Full text of DOI:10.1002/anie.200800628

Angewandte
Chemie
DOI: 10.1002/anie.200800628
Asymmetric Allylations
Catalytic Enantioselective Hosomi–Sakurai Conjugate Allylation of
Cyclic Unsaturated Ketoesters**
Manami Shizuka and Marc L. Snapper*
Despite impressive advances over the years,[1] there are still
important transformations that lack catalytic asymmetric
variants. While Lewis acid catalyzed additions of allylsilanes
to carbonyl compounds[2] and acetals[3] have been well studied
using catalytic,[4] as well as auxiliary-based methods to control
absolute configuration,[5] to the best of our knowledge, there
are no effective methods for catalyzing the asymmetric 1,4-
addition of allyltrimethylsilane to unsaturated carbonyl com-
pounds.[6] In that regard, we report herein a catalytic
Scheme 1. Copper/box-catalyzed asymmetric allylation of activated
enone substrate 1.
enantioselective conjugate addition of allyltrimethylsilane to
various activated cyclic enones with selectivities surpassing
98% ee. The 1,4-addition of the air- and moisture-stable
Table 1: Ligand evaluation studies for an enantioselective Hosomi–
nucleophile to unsaturated carbonyl compounds proceeds to
> 95% conversion in the presence of Cu(OTf)2 (10 mol%)
with the commercially available di(tert-butyl)bis(oxazoline)
(box) ligand (2).[7] We show how these products can be
Sakurai conjugate allylation.[a]
functionalized to
enriched systems.
a variety of useful enantiomerically
Our initial studies into the development of a chiral Lewis
acid catalyst indicated that simple cyclic and acyclic a,b-
unsaturated carbonyls (ketones and esters) did not react with
a variety of metal–ligand combinations.[8] We therefore
sought to activate the substrate by installation of a second
electron-withdrawing/chelating group at the a-position of the
enone (i.e., 1). In the presence of Cu(OTf)2 (7 mol%) and
bis(oxazoline) ligand 2 (8 mol%) in Cl(CH2)2Cl, we obtained
the desired 1,4-allyl-addition product 3 in > 95% conversion
(after 30 min at 08C) and 72% ee as a mixture of keto–enol
tautomers (Scheme 1). Alternative solvents (CH2Cl2, Et2O,
toluene, EtOAc, etc.) and metal salts, including other copper
salts, resulted in lower selectivities.[9] Other chiral ligands
(e.g., peptide-based,[10] salen,[11] Trost ligand[12]) led to high
conversion (> 95%), but with low selectivity (< 5% ee).
To identify a more effective catalyst, we prepared and
screened approximately 40 mono- and bis(oxazoline) ligands.
A selection of the bis(oxazoline) ligands studied are illus-
trated in Table 1. Phenylglycine- and phenylalanine-derived
ligands (7 and 8, respectively) gave high conversions, but low
Entry
Ligand
R1
R2
Conv. [%]
ee [%]
1
2
3
4
5
6
7
8
4
2
5
6
7
8
9
10
H
tBu
tBu
tBu
tBu
Ph
Bn
–
>95
>95
>95
>95
>95
>95
>5
11
72
70
70
CH3
-(CH2)2-
-(CH2)3-
CH3
CH3
–
10
<5
n.d.[b]
38
–
–
>95
[a] The reaction and conditions used are shown in Scheme 1, except the
reaction time was 14 h. [b] Not determined.
enantioselectivities were observed (Table 1, entries 5 and 6).
Modifying the gem-dimethyl head group of ligand 2 to a
cyclopropyl (5) or cyclobutyl head group (6) has been
reported to change the bite angle at the metal center, often
with drastic changes in selectivity.[13] In this case, however,
these modifications had minimal effects on the selectivity
(72% ee with 2 vs. 70% ee with 5 and 6, Table 1, entries 3and
4). A methylene linker was also examined, but the selectivity
dropped significantly to 11% ee (Table 1, entry 1). A triden-
tate Py-box ligand 9,[14] bearing an additional Lewis basic
moiety, resulted in diminished conversion (Table 1, entry 7).
We also tested unsymmetrical bis(oxazoline) and mono(ox-
azoline) ligands.[9] Ligand 10 delivered the desired product
efficiently, but in low enantioselectivity (38% ee, Table 1,
entry 8). Shorter and longer linkers between the oxazoline
[*] M. Shizuka, Prof. M. L. Snapper
Department of Chemistry
Merkert Chemistry Center
Boston College, Chestnut Hill, MA 02467 (USA)
Fax: (+1)617-552-1442
E-mail: marc.snapper@BC.edu
Homepage: http://www2.bc.edu/~snapper/
[**] Support from the NIH (GM-57212) is gratefully acknowledged. We
thank the Hoveyda group for use of their chiral GLC and HPLC. We
also thank Prof. James Morken for helpful discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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rings were introduced, such as in oxalate- and phthalic acid-
required for high conversions, resulting in decreased selectiv-
ities (55% ee and 64% ee, respectively). The smaller five-
membered ring substrate 17 was also allylated in moderate
selectivity (70% ee, 69% yield). As shown in entry 6, the
eight-membered ring enone 19 gave superior results, with the
reaction being carried out at room temperature (> 98% ee,
65% yield).[16] The use of the more nucleophilic methallyl-
trimethylsilane[17] with these substrates led to the correspond-
ing 1,4-addition products with lower enantioselectivities
(< 50% ee) even with slow addition of the nucleophile.
Presumably, the decrease in selectivity is due to a competitive,
non-catalyzed background reaction with this more reactive
nucleophile.
derived ligands; however, these ligands did not lead to
improved results compared to ligand 2.[9] In addition, we also
investigated the effect of additives upon the reaction.[15]
Various desiccants (e.g., molecular sieves, MgSO4), as well
as Lewis basic additives were tested, yet none of these
resulted in enhanced selectivities.[9]
We found that the enantioselectivity could be improved
by changing the solvent to CH2Cl2, thus allowing for lower
reaction temperatures. When run at ꢀ788C in CH2Cl2, with
ligand 2 (11 mol%) and Cu(OTf)2 (10 mol%), product 3 was
obtained in 78% yield and 90% ee (Table 2, entry 1; cf.
Table 1, entry 2).
As illustrated in Scheme 2, the optically enriched allylated
products offer functionalities that can be transformed into a
Table 2: Copper-catalyzed enantioselective Hosomi–Sakurai conjugate
allyation of unsaturated ketoesters.[a]
Entry
Enone
Product
t [h]
Yield ee
(T [8C]) [%][a] [%][b]
45
(ꢀ78)
1[d]
78
65
51
90
97
55
48
(ꢀ50)
2[e]
15
(0)
3[f]
38
(23)
4[f]
5[g]
6[d]
77[c]
64
70
Scheme 2. Representative functionalizations of allylated products.
variety of synthetically useful building blocks. For example,
the methyl ester can be readily decarboxylated by using
Krapchoꢀs method (3!21).[18] Likewise, enolization and
alkylation of the allylated product 3, followed by ring-closing
metathesis (RCM) with ruthenium alkylidene 22,[19] and
decarboxylation generates the decalin system 23. Through
the use of different ring-sized starting enones, this method
offers rapid entry into optically enriched bicyclic systems. In
the presence of second-generation Hoveyda–Grubbs catalyst
24, substrate 18 undergoes cross-metathesis with methylacry-
late to obtain selectively the E-alkene (18!25). Alterna-
tively, the ketoester functionality can be transformed into an
enolphosphate group (18!26).[20]
15
(ꢀ78)
69
17
(23)
65
>98
[a] Yields of isolated products after silica gel chromatography. [b] Deter-
mined by GLC or HPLC with a chiral stationary phase; see the Supporting
Information for details. [c] Yields of isolated products after decarbox-
ylation of the ester (2 steps). [d] Conditions: 2 (11 mol%), Cu(OTf)2
(10 mol%), allyltrimethylsilane (5 equiv) in CH2Cl2, N2. [e] CH2Cl2/
Cl(CH2)2Cl (5:1) as solvent. [f] Cl(CH2)2Cl as solvent. [g] 3 equiv of
allyltrimethylsilane.
In conclusion, we have developed the first catalytic
enantioselective Hosomi–Sakurai conjugate allylation of
cyclic unsaturated ketoesters. The protocol does not require
special catalysts and/or preparation of the nucleophile;
Cu(OTf)2 and the ligand are both commercially available, as
well as the relatively moisture-, oxygen-, and thermally-stable
allyltrimethylsilane nucleophile. Products obtained from the
reaction are easily functionalized to a variety of useful
building blocks for target- and diversity-oriented synthesis.
Expansion of the substrate and nucleophile scope, as well as
applications to natural product synthesis are currently under
investigation.
With this optimal chiral catalyst, we examined the scope
of the catalytic enantioselective Hosomi–Sakurai allylation
(Table 2). Five-, six-, and eight-membered ring substrates
were effectively allylated with commercially available allyl-
trimethylsilane. The six-membered ring enone 11, with gem-
dimethyl substitution at the 6-position, gave excellent enan-
tioselectivity (97% ee, 65% yield). For sterically hindered
substrates 13 and 15, higher reaction temperatures were
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Chemie
Appl. Chem. 1999, 71, 1407 – 1415; c) J. S. Johnson, D. A. Evans,
Experimental Section
Acc. Chem. Res. 2000, 33, 325 – 335; d) A. K. Ghosh, P.
Mathivanan, J. Cappiello, Tetrahedron: Asymmetry 1998, 9, 1 –
45; e) H. A. McManus, P. J. Guiry, Chem. Rev. 2004, 104, 4151 –
4202; f) A. Pfaltz in Asymmetric Synthesis—The Essentials
(Eds.: H. Christmann, S. Bräse), Wiley-VCH, Weinheim, 2007,
pp. 131 – 135.
Representative procedure: Cu(OTf)2 (14.1 mg, 38.9 mmol) and ligand
2 (12.6 mg, 42.8 mmol) were weighed into a 13” 100 mm test tube in a
glovebox. The test tube was sealed with a rubber septum and then
removed from the glovebox. CH2Cl2 (1.65 mL) was added under N2.
The solution was stirred for 10 min at 238C. A solution of enone 1
(60.0 mg, 0.39 mmol) in CH2Cl2 (0.3mL) was added at 23 8C, at which
point the solution turned dark purple-brown. The reaction mixture
was cooled to ꢀ788C and allyltrimethylsilane (309 mL, 1.95 mmol)
was added dropwise. The septum was wrapped with Teflon tape and
the mixture was stirred at ꢀ788C for 45 h. The reaction was quenched
with saturated aqueous NH4Cl at ꢀ788C, and was then allowed to
warm to room temperature. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3” 1.5 mL). The organic
layers were combined, dried over Na2SO4, filtered, and concentrated.
The residue was purified by silica gel column chromatography (10:1
to 5:1, hexanes/Et2O) to yield product 3 as a pale yellow oil mixture of
keto–enol tautomers (59.0 mg, 0.30 mmol, 78% yield).
[8] A combination of 15 different Lewis acids and various ligands
(peptide-based, box-type, salen ligands) were examined. For
more details, see the Supporting Information.
[9] See the Supporting Information for more details on ligand
screening and reaction optimization.
[10] a) J. R. Porter, W. G. Wirschun, K. W. Kuntz, M. L. Snapper,
A. H. Hoveyda, J. Am. Chem. Soc. 2000, 122, 657 – 658; b) J. F.
Traverse, Y. Zhao, A. H. Hoveyda, M. L. Snapper, Org. Lett.
2005, 7, 3151 – 3154; c) M. A. Kacprzynski, A. H. Hoveyda, J.
Am. Chem. Soc. 2004, 126, 10676 – 10681; d) N. S. Josephsohn,
K. W. Kuntz, M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc.
2001, 123, 11594 – 11599; e) Y. Zhao, J. Rodrigo, A. H. Hoveyda,
M. L. Snapper, Nature 2006, 443, 67 – 70.
[11] For recent reviews, see: a) T. Katsuki, Adv. Synth. Catal. 2002,
344, 131 – 147; b) J. F. Larrow, E. N. Jacobsen, Top. Organomet.
Chem. 2004, 6, 123– 152; c) E. M. McMarrigle, D. G. Gilheany,
Chem. Rev. 2005, 105, 1563– 1602.
Received: February 8, 2008
Revised: March 7, 2008
Published online: May 27, 2008
Keywords: allylation · asymmetric synthesis · copper ·
[12] a) B. M. Trost, R. Radinov, E. M. Grenzer, J. Am. Chem. Soc.
1997, 119, 7879 – 7880; b) B. M. Trost, G. M. Schroeder, J. Am.
Chem. Soc. 1999, 121, 6759 – 6760.
.
homogeneous catalysis · Michael reaction
[13] a) B. M. Trost, D. L. Van Vranken, C. Bingel, J. Am. Chem. Soc.
1992, 114, 9327 – 9343; b) I. W. Davies, L. Gerena, L. Caston-
guay, C. H. Senanayake, R. D. Larsen, T. R. Verhoeven, P. J.
Reider, Chem. Commun. 1996, 1753– 1754; c) I. W. Davies, R. J.
Deeth, R. D. Larsen, P. J. Reider, Tetrahedron Lett. 1999, 40,
1233 – 1236; d) S. E. Denmark, C. M. Stiff, J. Org. Chem. 2000,
65, 5875 – 5878; e) M. P. Sibi, J. Ji, J. Org. Chem. 1997, 62, 3800 –
3801.
[14] For a review, see: H. Nishiyama in Advances in Catalytic
Processes, Vol. 2 (Ed.: M. P. Doyle), JAI Press, Greenwich, 1997,
pp. 153– 188.
[15] For a review on additive effects in asymmetric catalysis, see:
E. M. Vogl, H. Grꢁger, M. Shibasaki, Angew. Chem. 1999, 111,
1672 – 1680; Angew. Chem. Int. Ed. 1999, 38, 1570 – 1577.
[16] The corresponding seven-membered ring gave diminished
selectivity (> 95% conversion, 28% ee).
[1] Comprehensive Asymmetric Catalysis, Vols. I–III (Eds: E. N.
Jacobson, A. Pfaltz, H. Yamamoto), Springer, New York, 1999.
[2] A. Hosomi, H. Sakurai, Tetrahedron Lett. 1976, 17, 1295 – 1298.
[3] A. Hosomi, M. Endo, H. Sakurai, Chem. Lett. 1976, 941 – 942.
[4] For a review of catalytic enantioselective allylations to aldehydes
and ketones, see: a) S. E. Denmark, J. Fu, Chem. Rev. 2003, 103,
2763– 2793. See also: b) A. Yanagisawa in Comprehensive
Asymmetric Catalysis, Supplement Vol. 2, Springer, New York,
2004, pp. 97 – 107.
[5] For selected examples, see: a) L. F. Tietze, K. Schiemann, C.
Wegner, C. Wulff, Chem. Eur. J. 1998, 4, 1862 – 1869; b) S. V.
Pansare, R. G. Ravi, R. P. Jain, J. Org. Chem. 1998, 63, 4120 –
4124.
[6] We are aware of only one catalytic enantioselective conjugate
allylation of enones using allylboranes: a) J. D. Sieber, S. Liu,
J. P. Morken, J. Am. Chem. Soc. 2007, 129, 2214 – 2215; b) J. D.
Sieber, S. Liu, J. P. Morken, J. Am. Chem. Soc. 2008, 130, 4978 –
4983. For diastereoselective conjugate allylations, see: c) M.
Sato, S. Aoyagi, S. Yago, C. Kibayashi, Tetrahedron Lett. 1996,
37, 9063– 9066; d) M. D. Groaning, A. I. Meyers, Tetrahedron
Lett. 1999, 40, 8071 – 8074; e) L. R. Pan, T. Tokoroyama,
Tetrahedron Lett. 1992, 33, 1469 – 1472. For earlier studies, see:
f) G. Majetich, A. Casares, D. Chapman, M. Behnke, J. Org.
Chem. 1986, 51, 1745 – 1753; g) A. Hosomi, H. Sakurai, J. Am.
Chem. Soc. 1977, 99, 1673– 1675.
[17] For a review detailing the reactivity of various p-basic nucleo-
philes, see: H. Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res.
2003, 36, 66 – 77.
[18] A. P. Krapcho, Synthesis 1982, 893– 914.
[19] a) A. K. Chatterjee, J. P. Morgen, M. Scholl, R. H. Grubbs, J.
Am. Chem. Soc. 2000, 122, 3783 – 3784. For a tandem process
using this ruthenium catalyst, see b) R. P. Murelli, M. L.
Snapper, Org. Lett. 2007, 9, 1749 – 1752.
[20] For early applications of this functionality, see: a) F.-W. Sum, L.
Weiler, Can. J. Chem. 1979, 57, 1431 – 1441; b) M. Sletzinger, T.
Liu, R. A. Reamer, I. Shinkai, Tetrahedron Lett. 1980, 21, 4221 –
4224.
[7] For reviews on bis(oxazoline) ligands in asymmetric catalysis,
see: a) G. Desimoni, G. Faita, K. A. Jorgensen, Chem. Rev. 2006,
106, 3561 – 3651; b) D. A. Evans, T. Rovis, J. S. Johnson, Pure
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