Highly anti-selective SN2′ substitutions of chiral cyclic 2-lodo-allylic alcohol derivatives with mixed zinc-copper reagents

Article abstract of DOI:10.1021/ol0340742

(Figure presented) Functionalized allylic electrophilic reagents such as chiral 2-iodo-1-cyclohexenyl and -cyclopentenyl phosphates undergo highly stereoselective anti-S_N2′-allylic substitution reactions with a wide range of organozinc reagents

Full text of DOI:10.1021/ol0340742

ORGANIC
LETTERS
2003
Vol. 5, No. 7
1059-1061
Highly anti-Selective SN2′ Substitutions
of Chiral Cyclic 2-Iodo-Allylic Alcohol
Derivatives with Mixed Zinc−Copper
Reagents
M. Isabel Calaza, Eike Hupe, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13,
81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received January 16, 2003
ABSTRACT
Functionalized allylic electrophilic reagents such as chiral 2-iodo-1-cyclohexenyl and -cyclopentenyl phosphates undergo highly stereoselective
anti-SN2′-allylic substitution reactions with a wide range of organozinc reagents (R Zn and RZnI) leading to chiral products with a transfer of
2
the chiral information >95%. The use of functionalized organozinc iodides allows preparation of the bicyclic enones 8 and 9 in g93% ee.
Functionalized allylic electrophiles are useful multicoupling
reagents1 for the expeditive formation of carbon-carbon
bonds in a selective way. A variety of organometallic
compounds undergo nucleophilic substitutions on allylic
systems. Especially interesting are organocopper compounds2
which are known to undergo SN2′ substitutions with various
allylic electrophiles with high anti-selectivity.3,4 Although
catalytic allylic substitutions have also been reported,5 the
transfer of chirality with use of chiral allylic precursors has
the advantage of being highly predictable. The required
allylic alcohols are readily available by a range of asymmetric
syntheses.6,7 In the allylation reactions zinc-based organo-
coppers show high SN2′ selectivities.8,9 Herein, we wish to
report a highly anti-SN2′ substitution of chiral 2-iodo-
(4) (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) Marino, J. P.; Viso, A.;
Lee, J.-D.; Fernandez de la Pradilla, R.; Fernandez, P.; Rubio, M. B. J.
Org. Chem. 1997, 62, 645. (d) Smitrovich, J. H.; Woerpel, K. A. J. Org.
Chem. 2000, 65, 1601. (e) Spino, C.; Beaulieu, C. J. Am. Chem. Soc. 1998,
120, 11832. (f) Spino, C.; Beaulieu, C. Angew. Chem. 2000, 112, 2006;
Angew. Chem., Int. Ed. 2000, 39, 1930. (g) Spino, C.; Beaulieu, C.;
Lafreniere, J. J. Org. Chem. 2000, 65, 7091. (h) Denmark, S. E.; Marble,
L. K. J. Org. Chem. 1990, 55, 1984. (i) Fleming, I.; Winter, S. B. D.
Tetrahedron Lett. 1995, 36, 1733.
(5) (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.
(1) For the use of multicoupling reagents see: (a) Seebach, D.; Knochel,
P. HelV. Chim. Acta 1984, 67, 261. (b) Knochel, P.; Normant, J. F.
Tetrahedron Lett. 1985, 26, 425. (c) Knochel, P.; Normant, J. F. Tetrahedron
Lett. 1986, 27, 1043. (d) Chen, H. G.; Gage, J. L.; Barret, S. D.; Knochel,
P. Tetrahedron Lett. 1990, 31, 1829. (e) Rao, S. A.; Knochel, P. J. Org.
Chem. 1991, 56, 4591. (f) Rottla¨nder, M.; Palmer, N.; Knochel, P. Synlett
1996, 573.
(2) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135. (b)
Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
Germany, 2002.
(3) (a) Goering, H. L.; Singleton, V. D., Jr. J. Am. Chem. Soc. 1976, 98,
7854. (b) Goering, H. L.; Singleton, V. D., Jr. J. Org. Chem. 1983, 48,
1531. (c) Ibuka, T.; Nakao, T.; Nishii, S.; Yamamoto, Y. J. Am. Chem.
Soc. 1986, 108, 7420. (d) Ibuka, T.; Tanaka, M.; Nishii, S.; Yamamoto, Y.
J. Am. Chem. Soc. 1989, 111, 4864. (e) Karlstro¨m, A. S. E.; Ba¨ckvall, J.-
E. In Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH:
Weinheim, Germany, 2002; p 259. (f) Arai, M.; Kawasuji, T.; Nakamura,
E. J. Org. Chem. 1993, 58, 5121. (g) Breit, B.; Demel, P. AdV. Synth. Catal.
2001, 343, 429.
(6) For the asymmetric reduction with the CBS -method, see: (a) Corey,
E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986. (b) Wallbaum,
S.; Martens, J. Tetrahedron: Asymmetry 1992, 3, 1475.
10.1021/ol0340742 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/12/2003

cycloallylic alcohol derivatives of type 1 or 2 (n ) 1, 2)
with various functionalized zinc reagents (FG-R)2Zn or FG-
RZnI)10 in the presence of CuCN‚2LiCl11 leading to products
of type 3 which can be converted to chiral bicyclic products
of type 4 with g93% ee, if the functional group FG is an
ester or nitrile (Scheme 1).
Table 1. Products 3a-e Obtained by the Reaction of
Diorganozincs (R2Zn) with the Chiral Allylic Derivatives 1 and
2a,b
Scheme 1
First, we have studied the substitution reaction using
various unfunctionalized diorganozinc reagents (R2Zn).
Chiral (R)-2-iodocyclopentenol (5, 94% ee) and (R)-2-
iodocyclohexenol (6, 94% ee) were converted into the
corresponding phosphates 1 (76%) and 2a (87%), which give
SN2′ products when reacting with organocoppers.12 The
alcohol 6 was also converted into the pentafluorobenzoate
2b in 93% yield (Scheme 2).
a Yield of analytically pure product. b The enantiomeric excess was
determined by capillary GC analysis on products 3 or derivatives of them
(see Supporting Information). c The reaction was performed in THF at -50
°C for 16 h.
Scheme 2
The enantiomeric excess (% ee) determined by capillary
GC (see Supporting Information) was 91-94% ee, showing
a high transfer of the stereochemical information.14 The anti-
selectivity was determined by converting vinylic iodide 3a
into ketone 7 of known configuration (Scheme 2).15
Thus, the reaction of 3a with t-BuLi (2 equiv, THF, -78
°C, 20 min) followed by reaction with CuCN‚2LiCl (1.0
equiv, THF, 0 °C, 10 min) and CH3COCl (2 equiv, 0 °C, 30
min) furnishes ketone 7 in 95% yield and 94% ee. Com-
parison with the optical rotation of 7 and the literature
indicates that an anti-SN2′ substitution has taken place. The
complete transfer of the stereochemical information from 1
(9) For previous SN2′ selective allylic substitutions with organozinc
reagents see: (a) Sekiya, K.; Nakamura, E. Tetrahedron Lett. 1988, 29,
5155. (b) Reference 3f. (c) Nakamura, E.; Mori, S. Angew. Chem., Int. Ed.
2000, 39, 3750. (d) Nakamura, E.; Sekiya, K.; Arai, M.; Aoki, S. J. Am.
Chem. Soc. 1989, 111, 3091.
(10) (a) Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E. Org.
React. 2001, 58, 417. (b) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93,
2117. (c) Knochel, P.; Joned, P. Organozinc Reagents. A practical approach;
Oxford University Press: Oxford, UK, 1999.
(11) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(12) Yanagisawa, A.; Noritake, Y.; Nomura, N.; Yamamoto, H. Synlett
1991, 251.
Both the allylic phosphates and pentafluorobenzoates (1,
2) reacted with diorganozincs in the presence of CuCN‚2LiCl
(1.1 equiv) in a 3:1 mixture of THF:N-methylpyrrolidinone
(NMP)13 at -30 to -10 °C in 14 h furnishing the anti-SN2′
products 3a-e. Primary as well as secondary diorganozincs
undergo the substitution reaction in good yields (70-91%,
Table 1).
(13) We have observed that NMP strongly enhances the reactivity of
these zinc-copper reagents, especially those of the copper species prepared
from RZnI.
(7) (a) Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed.;
Wiley: New York, 1994. (b) Gao, Y.; Klunder, J. M.; Hanson, R. M.;
Masamune, H.; Ko, S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109,
5765. (c) Carlier, P. R.; Mungall, W. S.; Schro¨der, G.; Sharpless, K. B. J.
Am. Chem. Soc. 1988, 110, 2978.
(8) For an example of a mixed zinc-copper reagent derived from a
diorganozinc reagent see: Reddy, C. K.; Knochel, P. Angew. Chem., Int.
Ed. 1996, 35, 1700.
(14) (a) We have compared the reactivity of cuprates MeCu(CN)Li,
MeMgBr‚CuCN, and Me2CuLi with the one derived from Me2Zn toward
phosphate 1. The first two organocoppers undergo also a highly stereose-
lective anti-SN2′ substitution to afford 3a with 94% ee in good unoptimized
yields (70 and 76%), whereas Me2CuLi gives 3a in only 18% ee and 74%
yield. (b) The use of catalytic CuCN‚2LiCl for the preparation of mixed
zinc-copper reagents lowers yields by ca. 20-30%.
(15) Graf, C.-D.; Knochel, P. Tetrahedron 1999, 55, 8801.
1060
Org. Lett., Vol. 5, No. 7, 2003

to 3a shows also that neither a syn-SN2′ substitution nor an
SN2 substitution had occurred since these reaction pathways
would lower the enantiomeric purity of 3a. Remarkably, a
range of functionalized zinc reagents undergo the SN2′
substitution with comparable selectivities and yields (Table
2).
can be converted into bicyclic ketones 817 and 918 respectively
in 75 and 52% yield and 93-95% ee by reaction with n-BuLi
(1.2 equiv) and TMSCl (1.5 equiv) in THF at -70 °C for 2
h (Scheme 3).
Scheme 3
Table 2. Products 3f-m Obtained by Reaction of
Functionalized Organozinc Halides with the Chiral Phosphates 1
and 2a
In summary, we have described highly enantioselective
anti-SN2′-allylic substitutions of cyclic 2-iodoallylic alcohols
with a wide range of zinc-copper reagents and have shown
their utility for preparing chiral bicyclic ketones such as 8
and 9 in g93% ee. Applications to the preparation of natural
products are currently underway.19
Acknowledgment. We thank the Fonds der Chemischen
Industrie for generous 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 also thank BASF
AG (Ludwigshafen), Degussa AG (Hanau), and Chemetall
GmbH (Frankfurt) for the generous gift of chemicals.
a Yield of analytically pure product. b The enantiomeric excess was
determined by capillary GC analysis on 3 (see Supporting Information).
c Enantiomeric excess of 1. d Enantiomeric excess of 2a.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0340742
Only zinc-copper reagents made from equimolecular
amounts of zinc reagents and copper salts have been
examined.16
(17) (a) Naasz, R.; Arnold, L. A.; Pineschi, M.; Keller, E.; Feringa, B.
L. J. Am. Chem. Soc. 1999, 121, 1104. (b) Agami, C.; Platzer, N.; Puchot,
C.; Sevestre, H. Tetrahedron 1987, 43, 1091. (c) Bal, S. A.; Marfat, A.;
Helquist, P. J. Org. Chem. 1982, 47, 5045. (d) Abbott, R. E.; Spencer, T.
A. J. Org. Chem. 1980, 45, 5398.
(18) (a) Jones, T. K.; Denmark, S. E. HelV. Chim. Acta 1983, 66, 2377.
(b) Paquette, L. A.; Fristad, W. E.; Dime, D. S.; Bailey, T. R. J. Org. Chem.
1980, 45, 3017.
(19) Typical Procedure: Preparation of 3j. 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; 1.7 mL, 1.7
mmol, 2.0 equiv) and cooled to -30 °C. The freshly prepared alkylzinc
halide reagent (1.5 M solution in THF, 1.2 mL, 1.7 mmol, 2.0 equiv) was
added dropwise and the resulting mixture was stirred 0.5 h at -30 °C. Then
(R)-2-iodo-2-cyclopenten-1-yl diethyl phosphate 1 (94% ee; 0.300 g, 0.87
mmol, 1.0 equiv) was added dropwise as a solution in NMP (sufficient to
give an overall ratio of THF:NMP of 3:1) and the reaction mixture was
allowed to stir for 16 h while warming up to 25 °C. Saturated aqueous
NH4Cl solution (20 mL) was added followed by 25% aqueous ammonia
solution (1 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 Na2-
SO4. Evaporation of the solvents and purification by column chromatography
(SiO2, pentane:Et2O 9:1) afforded 198 mg (77% yield, 94% ee) of 3j as a
colorless oil.
Thus, the reaction of 3-carboethoxypropylzinc iodide (2
equiv) with 1 (or 2a) in the presence of CuCN‚2LiCl (2
equiv) proceeds in THF:NMP (3:1) at -30 to 25 °C within
12 h affording the functionalized substituted products 3f and
3g respectively in 81% and 68% yield and 93-94% ee
(entries 1 and 2 of Table 2). Similarly the reaction of allylic
phosphates 1 and 2a with 3-acetoxypropylzinc iodide
provides the products 3h and 3i respectively in 91% (94%
ee) and 84% (97.8% ee) (entries 3 and 4). Organozincs
bearing an acetal function (entries 5 and 6) or a nitrile (entries
7 and 8) react with high anti-SN2′ selectivity affording the
products 3j-m in 91-97% ee and 62-90% yield (entries
5-8). The functionalized cyclohexenyl iodides 3g and 3m
(16) For use of RLi/ZnCl2/CuCN see: Yamamoto, Y.; Chounan, Y.;
Tanaka, M.; Ibuka, T. J. Org. Chem. 1992, 57, 1024.
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