The regioselectivity of malonate addition to (3-methylpentadienyl)Fe(CO)3+ is controlled by the malonate−counterion association. The Li+ salt of malonate proceeds via C1 nucleophilic attack to afford the 1,3Z-diene complex 4a, while reaction of highly dissociated ion pair (i.e., Na+ or Li+/12-crown-4) salt proceeds at the C2 internal carbon to eventually afford cyclohexenone products 6. Reaction of 1a with the sodium salt of bis(8-phenylmenthyl)malonate proceeds with excellent diastereocontrol to afford a single diastereomeric cyclohexenone

Chaudhury, Subhabrata

Donaldson, William

English

Donaldson, William A.

epublications@Marquette

Marquette Universitye-Publications@MarquetteChemistry Faculty Research and Publications Chemistry, Department of1-1-2006Nucleophilic Addition to(3-Methylpentadienyl)iron(1+) Cations:Counterion Control of Regioselectivity;Application to the Enantioselective Synthesis of4,5-Disubstituted CyclohexenonesSubhabrata ChaudhuryMarquette UniversityWilliam DonaldsonMarquette University, william.donaldson@marquette.eduAccepted version. Journal of the American Chemical Society, Vol. 128. No. 18 (2006) pp 5984-5985.DOI. © 2006 American Chemical Society. Used with permission.NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Journal of the American Chemical Society, Vol 128, No. 18 (2006): pg. 5984-5985. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 1     Nucleophilic Addition to (3-Methylpentadienyl)iron(1+) Cations:  Counterion Control of Regioselectivity; Application to the Enantioselective Synthesis of 4,5-Disubstituted Cyclohexenones   Subhabrata Chaudhury Department of Chemistry, Marquette University Milwaukee, WI William A. Donaldson Department of Chemistry, Marquette University Milwaukee, WI         NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Journal of the American Chemical Society, Vol 128, No. 18 (2006): pg. 5984-5985. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 2  Abstract  The regioselectivity of malonate addition to (3-methylpentadienyl)Fe(CO)3+ is controlled by the malonate−counterion association. The Li+ salt of malonate proceeds via C1 nucleophilic attack to afford the 1,3Z-diene complex 4a, while reaction of highly dissociated ion pair (i.e., Na+ or Li+/12-crown-4) salt proceeds at the C2 internal carbon to eventually afford cyclohexenone products 6. Reaction of 1a with the sodium salt of bis(8-phenylmenthyl)malonate proceeds with excellent diastereocontrol to afford a single diastereomeric cyclohexenone.  Nucleophilic attack on coordinated polyenes is one of the paradigms of π-organometallic chemistry.1 We and others have examined the reactivity of (pentadienyl)iron(1+) cations, in particular for applications to organic synthesis.2 These studies indicate that the regioselectivity of nucleophilic attack depends on the nucleophile, substituents present on the pentadienyl ligand, and “spectator” ligands on iron. As part of our interest in the synthesis of diterpenes containing a 3-methyl-1,3Z-pentadienyl side chain3 we have recently prepared the symmetrical iron(1+) cations 1a and b (Scheme 1). As part of these studies, we now report a counterion-controlled regioselectivity of nucleophilic attack.4   Scheme 1  NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Journal of the American Chemical Society, Vol 128, No. 18 (2006): pg. 5984-5985. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 3  Reduction of the known5 dienoate complex 2a gave the alcohol 3a, which upon acid-mediated dehydration gave the (tricarbonyl)iron ligated cation 1a (Scheme 1). In a similar fashion, ligand substitution of 2a with triphenylphosphine, followed by reduction and acid-mediated dehydration, gave the PPh3(CO)2 ligated cation 1b.  The reaction of 1a with lithium dimethyl malonate gave the 1,3Z-diene complex rac-4a in good yield (Table 1, entry 1). In contrast, the reaction of 1a with sodium dimethyl malonate exhibited copious decomposition upon standing. Treatment of the reaction mixture with methanolic NaHCO3 lead to isolation of the 4,5-disubstituted cyclohexenone rac-6 (entry 2).6 Furthermore, the reaction of 1a with lithium dimethyl malonate in the presence of 12-crown-4 gave only the cyclohexenone product 6, while reaction of 1a with sodium dimethyl malonate/ZnCl2 gave only the diene complex 4a. In a similar fashion, reaction of 1a with lithium methyl dimethylmalonate anion afforded the diene complex 5a (entry 5), while reaction of the sodium salt of methyl dimethylmalonate gave a separable mixture of 5a and cyclohexenone 7.6 In contrast, reaction of the (CO)2PPh3 ligated cation 1b with sodium dimethyl malonate gave the diene complex 4b. Formation of cyclohexenone products is not limited to malonate anions; reaction of 1a with the anion from methyl cyclohexanecarboxylate or with phthalimide gave 8 or 9.   Table 1.  Nucleophilic Addition to (3-Methylpentadienyl)Fe(1+) entry cation counterion/nucleophile 4a/4b/5a 6/7/8/9  1  1a  LiCH(CO2Me)2  4a (80%)    2  1a  NaCH(CO2Me2a    6 (91%)  3  1a  LiCH(CO2Me)2/12-crown-4a    6 (84%)  4  1a  NaCH(CO2Me)2/ZnCl2  4a (60%)    5  1a  LiC(Me)(CO2Me)2  5a (45%)    NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Journal of the American Chemical Society, Vol 128, No. 18 (2006): pg. 5984-5985. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 4  6  1a  NaC(Me)(CO2Me)2a  5a (34%)  7 (55%)  7  1b  NaCH(CO2Me)2  4b (93%)    8  1a  LDA/methyl cyclohexanecarboxylate    8 (80%)b  9  1a  KPhthc    9 (34%)d a After 2 h, the reaction mixture was diluted with CH2Cl2, and methanolic NaHCO3 was added. The mixture was stirred for an additional 18 h.b The product is a 6:1 mixture of 2- and 3-cyclohexenones.c Reaction solvent is acetone, and the crude reaction mixture was treated with CAN/CH3CN to effect complete decomposition of the iron acyl intermediate.d The product is a 2.5:1 mixture of 2- and 3-cyclohexenones. The (diene)iron complexes 4a/4b/5a arise via nucleophilic attack at C1, while the cyclohexenone products 6−9 are formed via nucleophilic attack at the C2 internal carbon to generate a (pentenediyl)iron complex 10 (Scheme 2).7 Carbonyl insertion8 into 10 affords the acyl complex 11 which upon reductive elimination gives the 3-cyclohexenone 12. Workup with methanolic NaHCO3 effects conjugation to give the product 6/7. It has been previously noted that the site of nucleophilic attack is dependent on the nucleophile and on “spectator” ligands present on the metal.9 The above results indicate that the regioselectivity for attack on 1a is also dependent on the counterion of the nucleophile. On the basis of 13C NMR spectroscopy10 and DFT calculations11c the C2/C4 carbons of the pentadienyl ligand are believed to bear greater partial positive charge than the C1/C3/C5 positions, while molecular orbital calculations indicate that the LUMO of the (dienyl)iron cations has greater orbital contribution from C1/C5 than from C2/C4.10a,12 Thus, nucleophilic attack at C2/C4 is believed to be due to charge control, while attack at C1/C5 is attributed to frontier orbital control.9 In the present case, for the sodium salts (and Li+/12-crown-4), the malonate anion is expected to be completely dissociated, and thus nucleophilic attack is anticipated to occur under charge control. In comparison, for the lithium salts (and Na+/ZnCl2), there should be greater association between the malonate anion and the counterion; this decreased polarization in electron density would lead to frontier orbital controlled nucleophilic attack. It should be noted that the steric bulk of the nucleophile may play an additional role on the regioselectivity of nucleophilic attack (entry 6). In the case of lithium methyl cyclohexanecarboxylate (entry 8), attack at C2 may be due to the greater strength of this nucleophile, compared to malonate (i.e., charge control).  NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Journal of the American Chemical Society, Vol 128, No. 18 (2006): pg. 5984-5985. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 5   Scheme 2  Previous efforts at the desymmetrization of achiral (cyclohexadienyl)- and (cycloheptadienyl)iron(1+) cations with chiral sulfoximinyl acetates13a or chiral N-acetyl- or N-propionyl oxazolidinones13b resulted in enantioselectivities ranging from 11 to 60% ee. With these precedents in mind, we therefore sought the desymmetrization of achiral cation 1a. To this end, reaction 1a with sodium bis[(−)-8-phenylmenthyl]malonate14 gave the cyclohexenone (−)-13 as a single diastereomer in excellent yield (Scheme 3). Luche reduction of (−)-13 gave the equatorial cyclohexenol 14.15 Assignment of the absolute stereochemistry at the carbinol carbon was based on the 1H NMR chemical shifts of the alkenyl proton (H2) of the derived (S)- and (R)- Mosher's esters 15 and 16 (δ 5.41 and 5.33 ppm, respectively). These relative chemical shifts are consistent with an (R)-stereochemical assignment at C1, and therefore C5 is assigned as (S).   Scheme 3  NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Journal of the American Chemical Society, Vol 128, No. 18 (2006): pg. 5984-5985. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 6  The diastereoselectivity for addition of the chiral malonate to 1a is rationalized in the following fashion. Nucleophilic attack occurs on the face of the pentadienyl ligand opposite to the Fe metal, and the malonate is oriented such that the π-system of the nucleophile is synclinal with respect to the electrophilic π-system (i.e., the C1−C2 bond) (Figure 1). Steric interaction between the phenyl substitutent and the pentadienyl ligand present in TS2 (see arrow) is expected to raise the energy of this transition state compared to TS1.   Figure 1 Diastereomeric transition states for attack on 1a. [Fe(CO)3], which points away from view, is not shown for clarity. In conclusion, the malonate−cation association controls the regioselectivity for nucleophilic attack on 1a. Use of strongly associated salts of malonate gave C1 nucleophilic attack, while reaction of the dissociated malonate−counterion pairs proceed at the C2 internal carbon of the pentadienyl ligand. Reaction of 1a with the sodium salt of bis(8-phenylmenthyl)malonate proceeds with excellent diastereocontrol to afford a single diastereomeric cyclohexenone.  Acknowledgment This material is based upon work supported by the National Science Foundation (CHE-0415771). Mass spectrometry was provided by the Washington University Mass Spectrometry Resource, an NIH Research Resource (Grant No. P41RR0954).  Supporting Information Available Details of experimental procedures, characterization, and analytical data for the products (18 pages, PDF). This material is available fee of charge via the Internet at http://pubs.acs.org.  NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Journal of the American Chemical Society, Vol 128, No. 18 (2006): pg. 5984-5985. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 7  References 1McQuillen, F. J.; Parker, D. G.; Stephenson, G. R. Transition Metal Organometallics for Organic Synthesis; Cambridge University Press:  Cambridge, U.K., 1990. 2(a) For a compilation of references up to 1997, see:  Donaldson, W. A. Aldrichemica Acta 1997, 30, 17−24.  (b) Motiei, L.; Marek, I.; Gottlieb, H. E.; Marks, V.; Lellouche, J.-P. Tetrahedron Lett. 2003, 44, 5909−5912. (c) Li, S.; Donaldson, W. A. Synthesis 2003, 2064−2068. (d) Yun, Y. K.; Godula, K.; Cao, Y.; Donaldson, W. A. J. Org. Chem. 2003, 68, 901−910. 3(a) Nabeta, K.; Oohata, T.; Izumi, N.; Katoh, K. Phytochemistry 1994, 37, 1263−1268. (b) Kanokmedhakul, S.; Kanokmedhakul, K.; Kanarsa, T.; Buayairaksa, M. J. Nat. Prod. 2005, 68, 183−188. (c) Gaspar-Marques, C.; Simoes, M. F.; Duarte, A.; Rodriguez, B. J. Nat. Prod. 2003, 66, 491−496. 4A dependency of nucleophile−cation association on the regioselectivity for nucleophilic attack on the terminal carbons of an unsymmetrically substituted (cyclohexadienyl)iron(1+) cation has been reported. Pearson, A. J.; Perrior, T. R.; Rees, D. C. J. Organomet. Chem. 1982, 226, C39−C42. 5Adams, C. M.; Cerioni, G.; Hafner, A.; Kalchhauser, H.; von Philipsborn, W.; Prewo, R.; Schwenk, A. Helv. Chim. Acta 1988, 71, 1116−1142. 6The 4,5-cis stereochemistry was assigned on the basis of 1H NMR spectral data. In particular, the signals for H3 of 6 and 7 (δ 6.11 and 6.20 ppm, respectively) each appear as dd (J = 10.1, 6.1 Hz). The 6.1 Hz coupling is consistent with a pseudoequatorial disposition for H4. For example, a cis-4-methyl-5-substituted cyclohexenone was prepared as an intermediate in the synthesis of mevinolin/compactin:  Clive, D. L. J.; Murthy, K. S. K.; Wee, A. G. H.; Prasad, J. S.; da Silva, G. V. J.; Majewski, M.; Anderson, P. C.; Evans, C. F.; Haugen, R. D.; Heerze, L. D.; Barrie, J. R. J. Am. Chem. Soc. 1990, 112, 3018−3028. 7The formation of cyclohexenones from nucleophilic attack of organolithiums on (pentadienyl)iron(1+) cations has previously been reported:  McDaniel, K. F.; Kracker, L. R., II; Thamburaj, P. K. Tetrahedron Lett. 1990, 31, 2373−2376. 8Carbonyl insertion into (pentenediyl)iron complexes and reductive elimination have previously been reported:  (a) Aumann, R. J. Am. Chem. Soc. 1974, 96, 2631−2632. (b) Schulze, M. M.; Gockel, U. J. Organomet. Chem. 1996, 525, 155−158. (c) Taber, D. F.; Kanai, K.; Jiang, Q.; Bui, G. J. Am. Chem. Soc. 2000, 122, 6807−6808. NOT THE PUBLISHED VERSION; this is the author’s final, peer-reviewed manuscript. The published version may be accessed by following the link in the citation at the bottom of the page. Journal of the American Chemical Society, Vol 128, No. 18 (2006): pg. 5984-5985. DOI. This article is © American Chemical Society and permission has been granted for this version to appear in e-Publications@Marquette. American Chemical Society does not grant permission for this article to be further copied/distributed or hosted elsewhere without the express permission from American Chemical Society. 8  9Donaldson, W. A.; Shang, L.; Tao, C.; Yun, Y. K.; Ramaswamy, M.; Young, V. G., Jr. J. Organomet. Chem. 1997, 539, 87−98. Pearson, A. J.; Yoon, J. Tetrahedron Lett. 1985, 26, 2399−2402. 10(a) Dobosh, P. A.; Gresham, D. G.; Lillya, C. P.; Magyar, E. S. Inorg. Chem. 1978, 17, 1775−1781. (b) Birch, A. J.; Westerman, P. W.; Pearson, A. J. Aust. J. Chem. 1976, 29, 1671−1677. 11(a) Clack, D. W.; Monshi, M.; Kane-Maguire, L. A. P. J. Organomet. Chem. 1976, 107, C40−C42. (b) Hoffmann, R.; Hofmann, P. J. J. Am. Chem. Soc. 1976, 98, 598−604. (c) Pfletschinger, A.; Schmalz, H.-G.; Koch, W. Eur. J. Inorg. Chem. 1999, 1869−1880. 12(a) Eisenstein, O.; Butler, W. M.; Pearson, A. J. Organometallics 1984, 3, 1150−1157. (b) Pearson, A. J.; Burello, M. P. Organometallics 1992, 11, 448−456. 13(a) Pearson, A. J.; Blystone, S. L.; Nar, H.; Pinkerton, A. A.; Roden, B. A.; Yoon, J. J. Am. Chem. Soc. 1989, 111, 134−144. (b) Pearson, A. J.; Khetani, V. D.; Roden, B. J. Org. Chem. 1989, 54, 5141−5147. Notably, the greatest % ee values were observed for addition to the (3-methoxycyclohexadienyl)Fe(CO)3+ cation. 14Quinkert, G.; Schwartz, U.; Stark, H.; Weber, W. D.; Adam, F.; Baier, H.; Frank, G.; Duerner, G. Liebigs Ann. Chem. 1982, 1999−2040. 15A similar reduction of chiral 4,5-disubstituted cyclohexenones (prepared by nucleophilic addition/protonation of (arene)Cr(CO)3 complexes) was previously reported:  Pearson, A. J.; Gontcharov, A. V. J. Org. Chem. 1998, 63, 152−162. 

Nucleophilic Addition to (3-Methylpentadienyl)iron(1+) Cations: Counterion Control of Regioselectivity; Application to the Enantioselective Synthesis of 4,5-Disubstituted Cyclohexenones

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Nucleophilic Addition to (3-Methylpentadienyl)iron(1+) Cations: Counterion Control of Regioselectivity; Application to the Enantioselective Synthesis of 4,5-Disubstituted Cyclohexenones

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