Highly stereoselective anti SN2′ substitutions of (Z)-allylic pentafluorobenzoates with polyfunctionalized zinc-copper reagents

Article abstract of DOI:10.1021/ol034525i

(Matrix presented) Allylic substitution reactions of zinc-copper organometallics on (Z)-allylic pentafluorobenzoates proceed with very high regioselectivity and excellent anti selectivity. The high fidelity in transfer of stereochemical information allowed a short synthesis of (+)-ibuprofen (97% ee).

Full text of DOI:10.1021/ol034525i

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2111-2114
Highly Stereoselective Anti SN2′
Substitutions of (Z)-Allylic
Pentafluorobenzoates with
Polyfunctionalized Zinc−Copper
Reagents
Nicole Harrington-Frost, Helena Leuser, M. Isabel Calaza, Florian F. Kneisel, and
Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13,
81377, Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received March 26, 2003
ABSTRACT
Allylic substitution reactions of zinc−copper organometallics on (Z)-allylic pentafluorobenzoates proceed with very high regioselectivity and
excellent anti selectivity. The high fidelity in transfer of stereochemical information allowed a short synthesis of (+)-ibuprofen (97% ee).
Absolute stereocontrol in acyclic systems is an important
synthetic problem.1 Especially useful are stereoselective
synthetic methods involving the formation of a new C-C
bond. Among various substitution reactions, palladium-
catalyzed allylic substitutions have been used with consider-
able success.2 However, the narrow range of nucleophiles
(only stabilized nucleophiles can be used) as well as the low
regioselectivity observed in nonsymmetrical allylic systems
have hampered the general use of this reaction. On the other
hand, copper-catalyzed allylic substitutions do not suffer from
these limitations.3 They proceed usually with anti SN2′
selectivity in cyclic and acyclic systems.4 The chiral informa-
tion can be contained either in the allylic electrophile5 or in
a chiral copper catalyst.6 This last approach, although the
ultimate solution, suffers also from generality since the chiral
ligand-copper complex has to be optimized for each class
of allylic substrates.6i The diastereoselective synthesis in
which a chiral allylic electrophile is used is more appealing
(3) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135. (b) Rona,
P.; To¨kes, L.; Tremble, J.; Crabbe´, P. J. Chem. Soc., Chem. Commun. 1969,
43. (c) Anderson, R. J.; Henrick, C. A.; Siddall, J. B.; Zurflu¨h, R. J. Am.
Chem. Soc. 1970, 92, 735. (d) Anderson, R. J.; Henrick, C. A.; Siddall, J.
B.; Zurflu¨h, R. J. Am. Chem. Soc. 1972, 94, 5379. (e) Tseng, C. C.; Paisley,
S. D.; Goering, H. L. J. Org. Chem. 1986, 51, 2884. (f) Underiner, T. L.;
Goering, H. L. J. Org. Chem. 1988, 53, 1140. (g) Underiner, T. L.; Goering,
H. L. J. Org. Chem. 1991, 56, 2563. (h) Krause, N.; Gerold, A. Angew.
Chem., Int. Ed. 1997, 36, 186.
(4) (a) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Maruyama, K. J.
Am. Chem. Soc. 1980, 102, 2318. (b) Nakamura, E.; Sekiya, K.; Arai, M.;
Aoki, S. J. Am. Chem. Soc. 1989, 111, 3091. (c) Arai, M.; Kawasuji, T.;
Nakamura, E. J. Org. Chem. 1993, 58, 5121. (d) Yanagisawa, A.; Noritake,
Y.; Nomura, N.; Yamamoto, H. Synlett 1991, 251. (e) Karlstro¨m, A. S. E.;
Ba¨ckvall, J.-E. In Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-
VCH: Weinhem, Germany, 2001; p 259.
(1) (a) Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C. Principles and Applications
of Asymmetric Synthesis; Wiley-Interscience: New York, 2001. (b) Gawley,
R. E.; Aube´, J. Principles of Asymmetric Synthesis; Pergamon: Oxford,
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(2) (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (b)
Reiser, O. Angew. Chem. 1993, 105, 576; Angew. Chem., Int. Ed. Engl.
1993, 32, 547. (c) Hayashi, T.; Kawatsura, M.; Uozumi, Y. J. Chem. Soc.,
Chem. Commun. 1997, 561. (d) Janssen, J. P.; Helmchen, G. Tetrahedron
Lett. 1997, 38, 8025. (e) Pretoˆt, R.; Pfaltz, A. Angew. Chem. 1998, 110,
337; Angew. Chem., Int. Ed. 1998, 37, 323. (f) Trost, B. M.; Hachiya, I. J.
Am. Chem. Soc. 1998, 120, 1104. (g) Helmchen, G. J. Organomet. Chem.
1999, 576, 203. (h) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33,
336.
10.1021/ol034525i CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/14/2003

and should be generally applicable since allylic alcohols can
be readily prepared in optically enriched form by several
asymmetric syntheses.1,7,8 Herein, we wish to report a general
synthetic method allowing a highly diastereoselective anti
SN2′ substitution in open-chain systems using functionalized
zinc-copper reagents.9
Allylic substrates of type 1 can undergo anti SN2′ substitu-
tion via two conformations (1A and 1B), either of them
allowing an anti parallel arrangement of the copper reagent
and the leaving group (Scheme 1). The substitution via
reagents do not react with allylic acetates or benzoates, but
a high-yield substitution is obtained with allylic pentafluo-
robenzoates that are readily prepared from the corresponding
alcohols (C6F5COCl, pyridine, DMAP, CH2Cl2, 0 °C, 1-4
h). Thus, the reaction of the (E)-allylic pentafluorobenzoate
((E)-4, >99% (E)-; 94% ee)11 with Pent2Zn and CuCN‚
2LiCl12 in a 2:1 THF/NMP mixture at -10 °C for 2.5 h
produces the expected (S)-(E)-7-methyl-5-dodecene ((E)-5)
in 83% yield with an enantiomeric excess of 90% ee as well
as ca. 9% yield of (Z)-7-methyl-5-dodecene ((Z)-5). The
absolute stereochemistry of (S)-(E)-5 was established by
ozonolytic cleavage and in situ Jones oxidation providing
(S)-2-methylheptanoic acid.13
Scheme 1
This demonstrates unambiguously that zinc-copper re-
agents react with anti selectivity. The absolute configuration
of the minor product (R)-(Z)-5 was not established, but an
independent synthesis14 indicates that its structure was indeed
the (Z)-alkene-5.15 The formation of (Z)-5 results from an
anti substitution of the zinc-copper reagent via a conforma-
tion of type 1B (Scheme 1). By comparing the allylic 1,3-
strain16 of the two possible conformations (1A and 1B) that
can undergo an anti SN2′ substitution, we noticed a higher
allylic 1,3-strain (between H1 and R1) in conformer 1B
(Scheme 2) disfavoring the substitution reaction via this
conformer 1A would afford the trans-alkene substitution;
reaction via the conformer 1B would result in the formation
of cis-alkene (cis-3).
Scheme 2
Notice that the configuration at the carbon atom C(1) is
the opposite in products trans-2 and cis-3 (Scheme 1). Allylic
substitutions with zinc-copper reagents were known with
allylic halides,9,10 but we needed to perform this study with
allylic alcohol derivatives, since these molecules can be
readily obtained in optically enriched form contrary to allylic
halides. Preliminary experiments show that zinc-copper
(5) (a) Belelie, J. L.; Chong, J. M. J. Org. Chem. 2001, 66, 5552. (b)
Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N.; Oguchi, Y.; Uyehara, T.;
Yamamoto, Y. J. Org. Chem. 1991, 56, 4370. (c) Yamamoto, Y.; Tanaka,
M.; Ibuka, T.; Chounan, Y. J. Org. Chem. 1992, 57, 1024. (d) Marino, J.
P.; Viso, A.; Lee, J.-D.; Fernandez de la Pradilla, R.; Fernandez, P.; Rubio,
M. B. J. Org. Chem. 1997, 62, 645. (e) Smitrovich, J. H.; Woerpel, K. A.
J. Org. Chem. 2000, 65, 1601. (f) Spino, C.; Beaulieu, C. J. Am. Chem.
Soc. 1998, 120, 11832. (g) Spino, C.; Beaulieu, C.; Lafreniere, J. J. Org.
Chem. 2000, 65, 7091.
(6) (a) van Klaveren, M.; Persson, E. S. M.; del Villar, A.; Grove, D.
M.; Ba¨ckvall, J.-E.; van Koten, G. Tetrahedron Lett. 1995, 36, 3059. (b)
Karlstro¨m, A. S. E.; Huerta, F. F.; Meuzelaar, G. J.; Ba¨ckvall, J.-E. Synlett
2001, 923. (c) Meuzelaar, G. J.; Karlstro¨m, A. S. E.; van Klaveren, M.;
Persson, E. S. M.; del Villar, A.; van Koten, G.; Ba¨ckvall, J.-E. Tetrahedron
2000, 56, 2895. (d) Du¨bner, F.; Knochel, P. Angew. Chem. 1999, 111, 391;
Angew. Chem., Int. Ed. 1999, 38, 379. (e) Du¨bner, F.; Knochel, P.
Tetrahedron Lett. 2000, 41, 9233. (f) Alexakis, A.; Malan, C.; Lea, L.;
Benhaim, C.; Fournioux, X. Synlett 2001, 927. (g) Alexakis, A.; Croset, K.
Org. Lett. 2002, 4, 4147. (h) Malda, H.; van Zijl, A. W.; Arnold, L. A.;
Feringa, B. L. Org. Lett. 2001, 3, 1169. (i) Luchaco-Cullis, C. A.; Mizutani,
H.; Murphy, K. E.; Hoveyda, A. H. Angew. Chem. 2001, 113, 1504; Angew.
Chem., Int. Ed. 2001, 40, 1456.
conformer. To disfavor this conformation further, we have
envisioned using the (Z)-allylic pentafluorobenzoate (Z)-4.
With such a substrate, the disfavored conformation of type
1C will now display considerable allylic 1,3-strain.16 This
was confirmed by experiments. The allylic pentafluoroben-
zoate (Z)-4 (95% ee) reacted smoothly with Pent2Zn in the
(11) The allylic alcohol derived from trans-4 was prepared by a Sharpless
kinetic resolution; see ref 8 and Supporting Information.
(12) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(7) Noyori, R. Asymmetric Catalysis in Organic Synthesis, Wiley: New
York, 1994.
(8) (a) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S.
Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. (b) Carlier, P. R.;
Mungall, W. S.; Schro¨der, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988,
110, 2978.
(9) Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E. Org. React.
2001, 58, 417.
(10) Sekiya, K.; Nakamura, E. Tetrahedron Lett. 1988, 29, 5155.
(13) Skuballa, W.; Schillinger, E.; Stu¨rzebecher, C.-St.; Vorbru¨ggen, H.
J. Med. Chem. 1986, 313.
(14) (Z)-allylic alcohol ((Z)-5; (5Z)-7-methyl-5-dodecene) was prepared
by Lindlar reduction of the corresponding alkyne (7-methyl-5-dodecyne);
see Supporting Information.
(15) Assuming that an anti substitution via the conformer 1B will lead
to the (R)-configuration for (Z)-5. Since only 9% of this isomer was formed,
it was not possible to establish its enantiomeric purity by GC analysis.
(16) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
2112
Org. Lett., Vol. 5, No. 12, 2003

presence of CuCN‚2LiCl (1.2 equiv) providing only (7R,5E)-
7-methyl-5-dodecene ((R)-(E)-5) in 97% yield and 93% ee
as indicated by GC analysis.
Remarkably, this behavior is rather general and various
diorganozincs react with chiral (Z)-allylic pentafluoroben-
zoates (Z)-4 and (Z)-6 furnishing the SN2′ substitution
products 5 and 7-12 with the (E)-stereochemistry in 89-
95% ee (Table 1).
and 95% ee (entries 2 and 3). Dimyrtanylzinc obtained after
hydroboration of (-)-â-pinene17 reacts somewhat slower (21
h) and leads to the substitution product ((E)-10) in 80% yield
and 92% ee (entry 4). Dibenzylzinc18 in toluene leads, after
reaction for 17 h at -10 °C, to the substitution product (E)-
11 in 83% yield and 95% ee. Diphenylzinc obtained by
transmetalation from PhLi with ZnBr2 reacts also with high
anti SN2′ selectivity leading to the chiral product (E)-12 in
74% yield and 93% ee. Finally, the use of (Z)-5-pentafluo-
robenzoate-6-dodecene ((Z)-6) demonstrates the versatility
of this method, since its reaction with Me2Zn and CuCN‚
2LiCl provides the alkene (S)-(E)-5 in 90% yield and 89%
ee (compare entry 7 of Table 1 with Scheme 2). Thus, the
two enantiomeric products are available either by changing
the substituent stereochemistry of the double bond or by
changing the configuration of the allylic alcohol.
Table 1. Allylic Substitution Products (E)-5 and (E)-7-12
Obtained by the Reaction of (Z)-Allylic Pentafluorobenzoates
((Z)-4 and (Z)-6) with Polyfunctional Diorganozinc Reagents
The asymmetric preparation of quarternary centers is an
important synthetic problem,19 and this copper-mediated
allylic substitution reaction provides a solution in the case
of cinnamic alcohol derivatives. The (E)- and (Z)- penta-
fluorobenzoates ((E)- and (Z)-13) were prepared in 98% ee
(see Supporting Information) and reacted with Pent2Zn and
CuCN‚2LiCl in THF at -10 °C for 16 h (Scheme 3). The
Scheme 3
a Enantiomeric excess of (Z)-4 was 98%. b Enantiomeric excess of (Z)-4
was 95% in this case. c Enantiomeric excess of (Z)-6 was 90%. d Reaction
was carried out in THF/NMP (N-methylpyrrolidinone)/toluene 2:1:1. e Yield
of analytically pure products. f Enantiomeric excess was determined using
GC or HPLC analysis. In each case, the racemic product was prepared for
calibration.
two enantiomeric alkenes (S)- and (R)-14 were obtained in
84-92% yield and 94% ee, showing the high synthetic
potential of this method for the construction of quaternary
centers otherwise difficult to prepare with high enantio-
selectivity.19
In all cases, no products derived from SN2 substitutions
could be detected and pure (E)-substitution products of type
2 were obtained (E:Z > 99:1). Various diorganozincs
undergo the allylic substitution. Dicyclohexylzinc17 leads to
the desired product (E)-7 in 79% yield and 95% ee within
12 h of reaction time (entry 1 of Table 1). Functionalized
diorganozincs such as (EtO2C(CH2)3)2Zn and (AcO(CH2)4)2-
Zn furnish the functionalized products in 68 and 71% yields
Interestingly, the olefin (R)-14 can be converted by
ozonolysis (reductive conditions: (1) O3, -78 °C, CH2Cl2;
(2) PPh3, -78 °C to room temperature, 2 h) to the chiral
aldehyde (S)-15 in 71% yield and 94% ee. As an application
of this method, we have prepared (+)-ibuprofen (16), an
(18) Dibenzylzinc was prepared by reaction of benzylmagnesium bromide
with diethylzinc.
(19) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem. 1998, 110, 402;
Angew. Chem., Int. Ed. 1998, 37, 389. (b) Spino, C.; Beaulieu, C. Angew.
Chem. 2000, 112, 2006; Angew. Chem., Int. Ed. 2000, 39, 1930.
(17) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.;
Knochel, P. J. Org. Chem. 1996, 61, 8229.
Org. Lett., Vol. 5, No. 12, 2003
2113

important antiinflammatory agent.20 The reaction of aryl
iodide 17 (1 equiv) with t-BuLi (2 equiv) followed by the
transmetalation with ZnBr2 (0.5 equiv) generates an inter-
mediate zinc reagent that, in the presence of CuCN‚2LiCl
(0.25 equiv), reacts in THF with (S)-(Z)-4 (99.3% ee)21 to
provide the allylic substitution product 18 in 91% yield and
97.2% ee. Ozonolysis followed by Jones oxidation gives (+)-
ibuprofen (16) in 80% yield and 97.2% ee (Scheme 4).
selectivity with (Z)-allylic pentafluorobenzoates allowing
excellent stereocontrol for the synthesis of acyclic molecules.
Quaternary centers can be created by this method with
excellent transfer of the stereochemical information. Further
applications of this method for the synthesis of natural
products are currently underway.22
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft (KN 347/6-1) and the Alexander von Hum-
boldt-Foundation for financial support. M.I.C. thanks the
European Community (Marie Curie Fellowship of the
program “Improving Human Research Potential and the
Socio-economic Knowledge Base” contract number HPM-
FCT-2000-01024) for a fellowship. We thank the BASF AG
(Ludwigshafen) and Chemetall GmbH (Frankfurt) for the
generous gift of chemicals.
Scheme 4
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL034525I
(22) Typical Procedure: Preparation of (R)-(E)-5. A flame-dried 25
mL flask equipped with a magnetic stirring bar, an argon inlet, and a septum
was charged with a solution of CuCN‚2LiCl (1 M solution in THF; 0.6
mL, 0.6 mmol) and cooled to -30 °C under an argon atmosphere. NMP
was added as a cosolvent (overall ratio of THF/NMP ) 2:1). Pent2Zn (5.1
M solution in THF, 0.24 mL, 1.2 mmol) was added dropwise, and the
resulting mixture was stirred for 0.5 h at -30 °C. Then, the pentafluo-
robenzoate ester ((R)-(Z)-4) (160 mg, 0.5 mmol, 95% ee) was added
dropwise as a solution in THF (0.8 mL), and the reaction mixture was
allowed to warm to -10 °C and stirred for 2.5 h. Water (20 mL) was added
followed by 25% aqueous ammonia solution (2 mL); then, the reaction
mixture was stirred at 25 °C until the copper salts had dissolved. The mixture
was extracted with Et2O (3 × 20 mL). The combined extracts were washed
with brine and dried over MgSO4. Evaporation of the solvents and
purification by column chromatography (SiO2, pentane) afforded the desired
alkene (R)-(E)-5 as a colorless liquid (88 mg, 97%, 93% ee).
In summary, we have demonstrated that various function-
alized zinc-copper reagents react with high anti SN2′
(20) (a) Akkari, R.; Calmes, M.; Mai, N.; Rolland, M.; Martinez, J. J.
Org. Chem. 2001, 66, 5859. (b) Chen, A.; Ren, L.; Crudden, C. M. J. Org.
Chem. 1999, 64, 9704. (c) Beaulieu, C.; Spino, C. Tetrahedron Lett. 1999,
40, 1637. (d) Jung, M. E.; Anderson, K. L. Tetrahedron Lett. 1997, 38,
2605. (e) Oppolzer, W.; Rosset, S.; de Brabander, J. Tetrahedron Lett. 1997,
38, 1539. (f) Uemura, T.; Zhang, X.; Matsumura, K.; Sayo, N.; Kumoba-
yashi, H.; Ohta, T.; Nozaki, K.; Takaya, H. J. Org. Chem. 1996, 61, 5510.
(21) Although it is stated that the allyl pentafluorobenzoate (S)-(Z)-4 has
99.3% ee, it contains 0.5% of the trans isomer (S)-(E)-4. As a result, the
“real” ee for the pure cis compound (S)-(Z)-4 would be 98.6% ee, so the
loss of enantiomeric excess during the allylation reaction is even less
important.
2114
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