Enantioselective synthesis of α-ionone derivatives using an anti SN2′ substitution of functionalized zinc organometallics

Article abstract of DOI:10.1021/ol049221q

(Equation Presented) The allylic substitution of sterically hindered (2-iodocycloalkyl)phosphates proceeds with complete anti S_N2′ stereoselectivity with mixed diorganozincs of the type RZnCH ₂SiMe₃ in the presence of CuCN·2LiCI. Only the group R of the copper-zinc reagent is transferred in the allylic substitution. This method was used to prepare odoriferous substances such as (R)-α-ionone in 97% ee and (R)-dihydro-α-ionone in 98% ee.

Full text of DOI:10.1021/ol049221q

ORGANIC
LETTERS
2004
Vol. 6, No. 14
2409-2411
Enantioselective Synthesis of r-Ionone
Derivatives Using an Anti SN2′
Substitution of Functionalized Zinc
Organometallics
Darunee Soorukram and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13, 81377,
Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received April 28, 2004
ABSTRACT
The allylic substitution of sterically hindered (2-iodocycloalkyl)phosphates proceeds with complete anti SN2′ stereoselectivity with mixed
diorganozincs of the type RZnCH SiMe3 in the presence of CuCN‚2LiCl. Only the group R of the copper−zinc reagent is transferred in the
2
allylic substitution. This method was used to prepare odoriferous substances such as (R)-r-ionone in 97% ee and (R)-dihydro-r-ionone in
98% ee.
The stereoselective formation of new carbon-carbon bonds
is an important research field. Allylic substitutions are
especially convenient for transferring the chirality of a C-X
bond to a C-C bond. A range of copper-1 and palladium-
catalyzed2 stereoselective allylic substitutions have been
reported.3 Recently, we have shown that various diorgano-
zincs undergo highly stereoselective anti SN2′ allylic sub-
stitutions in the presence of CuCN‚2LiCl4 in cyclic5 and
acyclic6 systems. Herein, we wish to demonstrate the
remarkable ability of mixed zinc-copper organometallics
prepared from mixed diorganozincs RZnCH2SiMe3 (1)7 for
undergoing SN2′ substitutions even with sterically hindered
systems. As an application, we have prepared via this method
(R)-R-ionone 2 in 97% ee and (R)-dihydro-R-ionone 3 in
98% ee starting from the readily available allylic phosphate
48 (Scheme 1).
(1) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135. (b)
Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH. (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) Arai, M.; Kawasuji, T.; Nakamura, E. J. Org.
Chem. 1993, 58, 5121. (f) Breit, B.; Demel, P. AdV. Synth. Catal. 2001,
343, 429. (g) Belelie, J. L.; Chong, J. M. J. Org. Chem. 2001, 66, 5552.
(h) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 2000, 65, 1601. (i)
Spino, C.; Beaulieu, C. J. Am. Chem. Soc. 1998, 120, 11832. (j) Denmark,
S. E.; Marble, L. K. J. Org. Chem. 1990, 55, 1984. (k) Alexakis, A.; Croset,
K. Org. Lett. 2002, 4, 4147. (l) Malda, H.; van Zijl, A. W.; Arnold, L. A.;
Feringa, B. L. Org. Lett. 2001, 3, 1169. (m) Luchaco-Cullis, C. A.; Mizutani,
H.; Murphy, K. E.; Hoveyda, A. H. Angew. Chem. 2001, 113, 1504; Angew.
Chem., Int. Ed. 2001, 40, 1456. (n) Karlstro¨m, A. S. E.; Huerta, F. F.;
Meuzelaar, G. J.; Ba¨ckvall, J. E. Synlett 2001, 923.
(2) (a) Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104. (b)
Hayashi, T.; Kawatsura, M.; Uozumi, Y. J. Chem. Soc., Chem. Commun.
1997, 561. (c) Janssen, J. P.; Helmchen, G. Tetrahedron Lett. 1997, 38,
8025. (d) Pretot, R.; Pfaltz, A. Angew. Chem. 1998, 110, 337; Angew. Chem.,
Int. Ed. Engl. 1998, 37, 323. (e) Helmchen, G.; Pfaltz, A. Acc. Chem. Res.
2000, 33, 336.
In a preliminary experiment, we have treated the allylic
phosphate 49 with dipentylzinc (2 equiv) and CuCN‚2LiCl
(1 equiv) in a 3:1 mixture of THF and N-methylpyrrolidinone
(3) For other transiton metal-catalyzed stereoselective allylations, see for
example: (a) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2003, 125,
8974. (b) Evans, P. A.; Uraguchi, D. J. Am. Chem. Soc. 2003, 125, 7158.
(c) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2002, 124, 7882. (d)
Malkov, A. V.; Spoor, P.; Vinader, V.; Kocovsky, P. J. Org. Chem. 1999,
64, 5308. (e) Dvorak, D.; Stary, I.; Kocovsky, P. J. Am. Chem. Soc. 1995,
117, 6130.
(4) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(5) Calaza, M. I.; Hupe, E.; Knochel, P. Org. Lett. 2003, 5, 1059.
(6) Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel, F. F.;
Knochel, P. Org. Lett. 2003, 5, 2111.
(7) Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T. A.; Reddy,
C. K. Angew. Chem., Int. Ed. Engl. 1997, 36, 1454.
10.1021/ol049221q CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/08/2004

Scheme 1
Table 1. Allylic Substitution Products 5b-h Obtained by the
Reaction of the Mixed Diorganozincs 1a-g with the Allylic
Phosphate 4 in the Presence of CuCN‚2LiCl
(NMP) at temperatures from -30 to -10 °C for 14 h and
have observed the formation of the anti substitution product
5a in 80% yield and 97% ee. Despite the presence of a qua-
ternary center bearing two methyl groups in the R-position,
only the anti SN2′ product is obtained and no SN2 substitution
can be detected (Scheme 2). We have briefly examined the
Scheme 2
use of other leaving groups instead of a phosphate and have
prepared the corresponding pentafluorobenzoate of 4. How-
ever, in this case, the desired product was obtained only in
55% yield. Since we planned to perform the allylic substitu-
tion with a range of functionalized diorganozincs,10,11 we
have prepared the mixed diorganozincs RZnCH2SiMe3 (1),
which transfer exclusively the R group to the electrophilic
reagent7,12 by the addition of commercially available solution
of Me3SiCH2Li to the corresponding alkylzinc iodide RZnI
(6) prepared by the direct insertion of zinc to the alkyl iodide
(RI).
a Isolated yield of analytically pure product. b Enantiomeric excess was
determined by chiral-GC. In each case, the racemic product was prepared
for calibration.
mixtures of THF and NMP at temperatures between -30
°C and room temperature for 14-48 h produces the desired
SN2′ substitution products 5b-h, respectively. These are the
only products obtained despite the steric hindrance of the
two adjacent methyl groups in yields between 65 and 90%
and enantioselectivities of 95-98% (Table 1 and Scheme
2). Excellent transfer of the chirality is observed, and the
use of the mixed diorganozincs of type 1 avoids the waste
of the polyfunctional zinc reagents 6. Thus, the reaction of
3-butenyl(trimethylsilylmethyl)zinc (1a) with 4 furnishes
under our standard conditions (14 h reaction time) the product
5b in 85 and 98% ee. Remarkably, a range of functionalized
zinc reagents (1b-g) can be used as well (entries 2-7). The
somewhat unreactive 2-cyanoethyl(trimethylsilylmethyl)zinc
(1b) requires a reaction time of 40 h but provides the
expected nitrile in 73% yield with a slight erosion of the
stereoisomeric purity (95% ee, entry 2). Ester-substituted
The reaction of the mixed zinc reagents 1a-g with the
allylic phosphate 4 in the presence of CuCN‚2LiCl in 3:1
(8) CBS reduction of 4,4-dimethyl-2-iodo-2-cyclohexen-1-one provides
4,4-dimethyl-2-iodo-2-cyclohexen-1-ol in 98% ee and 90% yield (see
Supporting Information).
(9) Yanagisawa, A.; Noritake, Y.; Nomura, N.; Yamamoto, H. Synlett
1991, 251.
(10) Knochel, P.; Millot, N.; Rodriguez, A. L. Org. React. 2001, 58,
417.
(11) For previous SN2′-selective allylic substitutions using organozinc
reagents, see: (a) Sekiya, K.; Nakamura, E. Tetrahedron Lett. 1988, 29,
5155. (b) Nakamura, E.; Mori, S. Angew. Chem., Int. Ed. 2000, 39, 3750.
(c) Nakamura, E.; Sekiya, K.; Arai, M.; Aoki, S. J. Am. Chem. Soc. 1989,
111, 3091.
(12) (a) Lutz, C.; Knochel, P. J. Org. Chem. 1997, 62, 7895. (b) Reddy,
C. K.; Knochel, P. Angew. Chem., Int. Ed. 1996, 35, 1700. (c) Bertz, S. H.;
Eriksson, M.; Miao, G.; Snyder, J. P. J. Am. Chem. Soc. 1996, 118, 10906.
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Org. Lett., Vol. 6, No. 14, 2004

diorganozincs such as 1c-e (entries 3-5) react perfectly
affording the SN2′ substitution products (5d-f) in 97-98%
ee (entries 3-5). Whereas aldehyde and ketone functional-
ities are not readily tolerated in this procedure, the use of
the corresponding acetal or ketal is perfectly compatible with
our mild reaction conditions, leading to the desired SN2′
substitution products (5g and 5h) in 71-90% yield and 98%
ee (entries 6 and 7).
Scheme 3
Several of the products of type 5 can be used for the
preparation of optically active R-ionone derivatives. This
group of natural products having a violet-like odor are formed
by the oxidative degradation of carotenes. They are widely
distributed in vegetables and fruits, especially in tea and
tobacco.13 Thus, the palladium-catalyzed oxidation of the
cyclohexenyl iodide 5b (PdCl2 (0.52 equiv), CuCl2 (1 equiv),
O2, DMF:H2O, 25 °C, 48 h) provides the ketone 7 in 82%
yield (98% ee).14 The reaction of the ketone 7 with MeZnCl
(3 equiv) in the presence of Pd(dba)2 (5 mol %) and bis-
diphenylphosphinoferrocene (dppf)15 (5 mol %) leads to (R)-
dihydro-R-ionone 3 in 70% yield and 98% ee (Scheme 3).
(R)-R-Ionone (2) is best prepared from the iodoester 5d.
Negishi cross-coupling with Me2Zn (Pd(dba)2 (5 mol %, dppf
(5 mol %), rt, 26 h) provides the desired methylated product
in 81% yield. Reduction of this intermediate to the corre-
sponding alcohol with LiAlH4 (Et2O, 0 °C, 10 min) followed
by a reoxidation to the aldehyde 8 under Swern conditions
proceeds with an overall yield of 74%. Phenylselenation with
PhSeCl and t-BuOK (-78 °C, 5 h) followed by selenium
oxidation and elimination (30% aq H2O2, CH2Cl2, rt)
furnishes the expected unsaturated aldehyde. The synthesis
of (R)-R-ionone is completed by the addition of MeMgCl in
THF at 0 °C followed by PDC oxidation in DMF, affording
(R)-R-ionone (2) in 61% yield and 97% ee.16 Attempts to
use the iodoacetal 5g as a starting material for the synthesis
of (R)-R-ionone (2) was complicated by acid-catalyzed
cyclization side-reactions.
In summary, we have shown that polyfunctional mixed
diorganozinc compounds of the type FG-RZnCH2SiMe3 react
with sterically very hindered allylic phosphates, providing
anti SN2′ products with very high regio- and stereoselectiv-
ity.17 We have demonstrated the utility of this procedure by
preparing (R)-R-ionone (2) and (R)-dihydro-R-ionone (3).
Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support. We thank Boehringer-
Ingelheim (Vienna) and Chemetall GmbH (Frankfurt) for the
generous financial support and gifts of chemicals.
(13) (a) Brenna, E.; Fuganti, C.; Serra, S.; Kraft, P. Eur. J. Org. Chem.
2002, 967. (b) Rompp Encyclopedia Natural Products; Steglich, W.,
Fugmann, B., Lang-Fugmann, S., Eds.; Thieme Verlag: Stuttgart, 2000.
(c) See also: Fehr, C.; Galindo, J. HelV. Chim. Acta 1995, 78, 539. (d)
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2567. (e) Fehr, C.; Guntern, O.
HelV. Chim. Acta 1992, 75, 1023.
(14) (a) Henry, P. M. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002;
Vol. 2, p 2119. (b) Feringa, B. L. Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol 2, p 307.
(c) Tsuji, J. Synthesis 1984, 369.
(15) (a) Green, L.; Chauder, B.; Snieckus, V. J. Heterocycl. Chem. 1999,
36, 1453. (b) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (c) Kobayashi, M.; Negishi, E. J. Org. Chem. 1980, 45,
5223. (d) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (e) Tamaru, Y.; Ochiai,
H.; Nakamura, T.; Yoshida, Z. Tetrahedron Lett. 1986, 27, 955. (f) Klement,
I.; Rottla¨nder, M.; Tucker, C. E.; Majid, T. N.; Knochel, P.; Venegas, P.;
Cahiez, G. Tetrahedron 1996, 52, 7201.
(16) (a) Mori, K.; Puapoomchareon, P. Liebigs Ann. Chem. 1991, 1053.
(b) Mori, K.; Khlebnikov, V. Liebigs Ann. Chem. 1993, 77. (c) Mori, K.
Synlett 1995, 1097.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL049221Q
(17) Typical Procedure: Preparation of 5d. Freshly prepared 2-car-
boethoxyethyzinc iodide (1.64 M solution in THF, 0.8 mL, 1.2 mmol, 2.4
equiv) was treated with TMSCH2Li (1 M in pentane, 1.2 mL, 1.2 mmol,
2.4 equiv) at -40 °C for 1 h and then allowed to warm to -30 °C. To the
resulting mixture was added successively a solution of CuCN‚2LiCl (1 M
solution in THF, 1.2 mL, 1.2 mmol, 2.4 equiv) and NMP (1 mL). The
resulting mixture was stirred at -30 °C for 30 min. A THF solution of
allylic phosphates (194 mg, 0.5 mmol, 1 equiv) was added, and the reaction
mixture was stirred for 45 h while being warmed to 25 °C. The desired
product 5d was obtained after purification by column chromatography (SiO2,
10% Et2O/pentane) as a colorless oil (134 mg, 81% yield).
Org. Lett., Vol. 6, No. 14, 2004
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