Synthesis of highly functionalized cyclohexenone rings: Rhodium-catalyzed 1,3-acyloxy migration and subsequent [5+1] cycloaddition

Article abstract of DOI:10.1002/anie.201006881

Lead Rh-ole: Highly substituted cyclohexenones were prepared from cyclopropyl-substituted propargyl esters by using a [{Rh(CO)₂Cl} ₂] catalyst. This metal catalyst promoted the 1,3-acyloxy migration of propargyl esters and a subsequent [5+1] cycloaddition of the resulting allenylcyclopropanes in the presence of CO with high regioselectivity.

Full text of DOI:10.1002/anie.201006881

Communications
DOI: 10.1002/anie.201006881
Rhodium Catalysis
Synthesis of Highly Functionalized Cyclohexenone Rings: Rhodium-
Catalyzed 1,3-Acyloxy Migration and Subsequent [5+1]
Cycloaddition**
Dongxu Shu, Xiaoxun Li, Min Zhang, Patrick J. Robichaux, and Weiping Tang*
The Diels–Alder cycloaddition represents the most powerful
technology for the preparation of substituted cyclohexenes
and has proven to be extremely valuable in organic syn-
thesis.[1] However, efficient syntheses of cyclohexenes having
diverse substitutions, stereochemistry, and functionalities are
still challenging and continue to stimulate the development of
novel cycloaddition reactions.[2] We report herein a stereose-
lective synthesis of highly functionalized cyclohexenones
from substituted cyclopropanes through a rhodium-catalyzed
1,3-acyloxy migration and subsequent [5+1] cycloaddition.
Given the well-documented strategies for the preparation of
optically pure cyclopropanes,[3] this promises to be a versatile
method for the synthesis of complex cyclohexenones from
cyclopropanes.[4]
We previously reported a synthesis of highly substituted
cyclobutenes from cyclopropyl metal carbenes derived from
transition metal catalyzed decomposition of diazo com-
pounds.[5,6] A more convenient and atom-economical[7] alter-
Scheme 1. Diverse products from the metal-catalyzed acyloxy migra-
tion.
native for generating metal carbene intermediates would be
the 1,2-acyloxy migration of propargyl esters, which has been
realized using AuI,[8] PtII,[9] RuII,[10] PdII,[11] and more recently
RhI,[12] the reports of which appeared while we were
conducting our investigation.[13] When we searched for
reaction conditions to form the cyclopropyl metal carbene 3
through 1,2-acyloxy migration, we isolated the highly func-
either an aryl or vinyl group.[17] The cyclopropane ring was not
required for the transformation of allene 5 into the inter-
mediate 9.[18] Clearly, allenyl ester 5 may undergo a variety of
different reactions including isomerization (e.g., formation of
8 and 9) and hydrolysis when it was generated by p-acidic
metals. We found for the first time that allenyl ester 5 could be
trapped by the [{Rh(CO)2Cl}2] catalyst for a [5+1] cyclo-
addition. The ability of this rhodium catalyst to promote both
the acyloxy migration and the subsequent cycloaddition not
only increases the synthetic efficiency but also allows the
development of new cycloaddition reactions.
tionalized cyclohexenone
7 when [{Rh(CO)2Cl}2] was
employed as the catalyst (Scheme 1).
Cyclohexenone 7 was presumably generated by insertion
of CO into the metallocyclohexene 6 (M = Rh),[14] which was
derived from the 1,3-acyloxy migration[15] of propargyl ester 1
and subsequent ring expansion of the allenyl ester 5.[16] Gold
catalysts could promote the formation of cyclopentene 8,
enone 10, and some other isomerization or hydrolysis
products from cyclopropane 1.[17,18] Cyclopentene 8 was
derived from direct ring expansion of allene 5 when R was
The cyclohexenone 12a was obtained as an mixture of
isomers (E/Z = ca. 1:1) in about 30% yield from 11a in the
presence of 20 mol% of the [{Rh(CO)2Cl}2] catalyst in
toluene at room temperature [Eq. (1); Piv = pivaloate]. The
[*] X. Li, Dr. M. Zhang, Prof. Dr. W. Tang
The School of Pharmacy, University of Wisconsin
Madison, WI 53705-2222 (USA)
Fax: (+1)608-262-5345
E-mail: wtang@pharmacy.wisc.edu
D. Shu, P. J. Robichaux
Department of Chemistry, University of Wisconsin
Madison, WI 53706-1322 (USA)
[**] We thank the NIH (R01GM088285) and the University of Wisconsin
for funding.
product 12a was isolated in 93% yield by running the reaction
with an attached CO balloon for 5 hours at 608C. The
temperature can be reduced to room temperature without
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006881.
1346
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 1346 –1349

Table 2: Ring expansion of substituted cyclopropanes.[a]
decreasing the yield of 12a by lowering the CO pressure to
between 0.1 and 0.2 atm through diluting the CO in the
balloon with nitrogen.[19] Separation of the two geometric
isomers of 12a and resubmitting each of them to the reaction
conditions did not change the configuration, suggesting that
the E/Z isomers did not equilibrate under the reaction
conditions. A significant amount of the enone 13 was isolated
when a cationic rhodium catalyst (e.g., [{Rh(CO)2Cl}2]/
AgOTf or [Rh(cod)2]BF4) (cod = 1,5-cyclooctadiene) was
employed. The addition of ligands (e.g., phosphine, phos-
phite, and pyridine) either decreased the conversion or
completely shut down the reaction.
Cyclopropane
Cyclohexenones[b]
Yield [%][c]
14
17
15
16
15/16=1:2.5[b]
90[d]
95[d]
15/16=3.5:1[b]
We then examined the tandem 1,3-acyloxy migration/
[5+1] cycloaddition for substrates 11b–g, which were pre-
pared from commercially available cyclopropyl acetylene and
either an aldehyde or ketone (Table 1). The reaction was still
conducted under 1 atm of CO at 608C for convenient
operation and consistent results. High yields of products
were isolated for substrates derived from various aldehydes
and ketones. High E/Z selectivity could be obtained for
propargyl esters having bulky substituents (Table 1, entries 3
and 6), and a single product was obtained for substrate 11e
(Table 1, entry 4). The cycloaddition worked well when the
ester was changed from pivaloate to acetate (Table 1, entry 5).
A highly functionalized product can also be prepared from
11g, which is derived from steroids (Table 1, entry 6).
18
21
19
20
19/20=10:1[b]
91
93
19/20 >20:1[b,e]
22
24
23 (12:1)[b]
79
Table 1: Ring
expansion
of
nonsubstituted
cyclopropanes.[a]
25
76[f]
Entry
Substrate
E/Z
Yield [%]
26
27
74
86
1
2
3
11b, R1 =Piv, R2 =H, R3 =Ph
11c, R1 =Piv, R2 =H, R3 =iPr
11d, R1 =Piv, R2 =H, R3 =tBu
11e R1 =Piv, R2 =R3 =Me
11 f, R1 =Ac, R2 =R3 =Me
2:1
1:1
10:1
–
95[b]
87[b]
92[b]
88
4[c]
5
–
85
28 (87% ee)
29 (87% ee)
6
11g
13:1
91[b]
[a] Reaction conditions: [{Rh(CO)2Cl}2] (5 mol%), CO (1 atm), toluene,
608C, 5 h. [b] Yield of product including both isomers. [c] 2.5 mol%
catalyst, 608C, 1 h.
30
32
34
31 (16:1)[b]
80
For unsymmetrically substituted cyclopropanes, the cleav-
À
age of different cyclopropane C C s bonds may lead to
different isomers. Our research group[5] and that of others[20,21]
33
35
80[g]
À
have found that the regioselectivity for the cleavage of C C
s bonds in cyclopropanes depends on the stereochemistry of
the cyclopropane ring, the electronic properties of the
substituents, and the nature of the metal catalysts. Indeed,
the opposite regioselectivity was observed for trans- and cis-
phenyl-substituted cyclopropanes 14 and 17, respectively
(Table 2). In the case of alkyl substituents, both trans-18 and
cis-21 gave product 19 as the major isomer and much higher
82[g]
Angew. Chem. Int. Ed. 2011, 50, 1346 –1349
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1347

Communications
Table 2: (Continued)
two diastereomeric allenes can interconvert, which is similar
to what was observed for gold catalysts.[17]
Cyclopropane
Cyclohexenones[b]
Yield [%][c]
In summary, we have developed an efficient and highly
selective method for the synthesis of polysubstituted cyclo-
À
hexenones. Regioselective cleavage of C C s bonds can be
achieved for various substituted cyclopropanes. The p-acid
property of the [{Rh(CO)2Cl}2] catalyst and its ability to
readily undergo oxidative addition/reductive elimination will
lead to a number of opportunities for mechanistic investiga-
tions, the design of new reactions, and target-oriented syn-
thesis of natural products and pharmaceutical agents, such as
cyclohexenone-containing compounds.[23]
36 (d.r.=1:1)
37 (E/Z=10:1)
74[h]
[a] Reaction conditions: see footnote [a] of Table 1, unless noted
otherwise. [b] Regioisomeric ratios were determined by 1H NMR analysis
of the crude reaction mixture. [c] Yields are of the major isomer (isolated)
unless noted otherwise. [d] Yield is for 15 and 16 combined. [e] The
reaction was run at RT. A 16:1 ratio was observed at 608C. [f] Other
unidentified by-products were observed. [g] Products without CO
insertion were also isolated. See text for details. [h] 808C, 24 h. TIPS=
triisopropylsilyl.
Received: November 2, 2010
Published online: December 29, 2010
Keywords: carbocycle · cycloaddition · rhodium · ring expansion ·
.
synthetic methods
selectivity was observed for the cis-isomer 21. The tandem
reaction worked at room temperature for the cis-isomer 21
even with 1 atm of CO and a slightly higher regioselectivity
was obtained at room temperature. The same trend of
regioselectivity was observed for the cyclopropanes 22 and
24. Substrates having quaternary carbon atoms, such as
cyclopropanes 26 and 28 yielded only one isomer. High
regioselectivity was also observed for the 1,2,3-trisubstituted
cyclopropane 30. The aryl and PMBOCH2 groups in cyclo-
[1] For selected reviews, see: a) K. Takao, R. Munakata, K. Tadano,
Chem. Rev. 2005, 105, 4779; b) J. D. Winkler, Chem. Rev. 1996,
96, 167; c) S. J. Danishefsky, Acc. Chem. Res. 1981, 14, 400.
[2] For a review on transition metal mediated cycloadditions, see:
M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996, 96, 49.
[3] H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev.
2003, 103, 977.
[4] For a recent review on transition metal mediated reactions of
cyclopropanes, see: M. Rubin, M. Rubina, V. Gevorgyan, Chem.
Rev. 2007, 107, 3117.
[5] H. Xu, W. Zhang, D. Shu, J. B. Werness, W. Tang, Angew. Chem.
2008, 120, 9065; Angew. Chem. Int. Ed. 2008, 47, 8933.
[6] For related work, see: J. Barluenga, L. Riesgo, L. A. Lopez, E.
Rubio, M. Tomas, Angew. Chem. 2009, 121, 7705; Angew. Chem.
Int. Ed. 2009, 48, 7569.
À
propane 30 should direct the cleavage of the same C C
s bond on the basis of regioselectivity observed for the
substrates 14 and 21.
The chirality of cyclopropane 28 was completely trans-
ferred to cyclohexenone 29,[22] thus confirming that cyclo-
hexenones can be enantioselectively synthesized from opti-
cally pure cyclopropanes. The highly functionalized decalin
rings 33 and 35 were also prepared in high yields from bicyclic
substrates with high regioselectivity. Five-membered ring
isomerization products were isolated in 19% and 11% yields
from substrates 32 and 34, respectively under the standard
reaction conditions.[20] Interestingly, no five-membered ring
isomerization product was observed in the monocyclic system
even in the absence of a CO atmosphere.
[7] B. M. Trost, Science 1991, 254, 1471.
[8] a) M. J. Johansson, D. J. Gorin, S. T. Staben, F. D. Toste, J. Am.
Chem. Soc. 2005, 127, 18002; b) D. J. Gorin, P. Dube, F. D. Toste,
J. Am. Chem. Soc. 2006, 128, 14480; c) D. J. Gorin, I. D. G.
Watson, F. D. Toste, J. Am. Chem. Soc. 2008, 130, 3736; d) G. Li,
G. Zhang, L. Zhang, J. Am. Chem. Soc. 2008, 130, 3740.
[9] a) E. Mainetti, V. Mouries, L. Fensterbank, M. Malacria, J.
Marco-Contelles, Angew. Chem. 2002, 114, 2236; Angew. Chem.
Int. Ed. 2002, 41, 2132; b) Y. Harrak, C. Blaszykowski, M.
Bernard, K. Cariou, E. Mainetti, V. Mouries, A. L. Dhimane, L.
Fensterbank, M. Malacria, J. Am. Chem. Soc. 2004, 126, 8656;
c) B. A. B. Prasad, F. K. Yoshimoto, R. Sarpong, J. Am. Chem.
Soc. 2005, 127, 12468; d) B. G. Pujanauski, B. A. B. Prasad, R.
Sarpong, J. Am. Chem. Soc. 2006, 128, 6786; e) K. Ji, X. Shu, J.
Chen, S. Zhao, Z. Zheng, L. Lu, X. Liu, Y. Liang, Org. Lett. 2008,
10, 3919.
[10] a) K. Miki, K. Ohe, S. Uemura, J. Org. Chem. 2003, 68, 8505;
b) K. Miki, K. Ohe, S. Uemura, Tetrahedron Lett. 2003, 44, 2019;
c) A. Tenaglia, S. Marc, J. Org. Chem. 2006, 71, 3569.
[11] a) V. Rautenstrauch, Tetrahedron Lett. 1984, 25, 3845; b) V.
Rautenstrauch, J. Org. Chem. 1984, 49, 950.
[12] a) Y. Shibata, K. Noguchi, K. Tanaka, J. Am. Chem. Soc. 2010,
132, 7896; b) C. Brancour, T. Fukuyama, Y. Ohta, I. Ryu, A. L.
Dhimane, L. Fensterbank, M. Malacria, Chem. Commun. 2010,
46, 5470.
À
Cleavage of the less hindered C C s bonds occurred
selectively for most cyclopropanes in Table 2. The substituent
that is cis to the propargyl ester generally has a more
significant steric effect than the corresponding trans substitu-
À
ent. For cyclopropanes 14 and 34, the C C s bonds that are
adjacent to aryl or vinyl groups were selectively cleaved
presumably because of the electronic effect of the adjacent
p system.[5,20,21] Relatively low regioselectivities observed for
the phenyl-substituted cyclopropanes 14 and 17 may be the
result of competing steric and electronic effects.
The E/Z ratio is 10:1 for the product 37 when a mixture of
cyclopropane 36 (d.r. = 1:1) is employed as the starting
material. We demonstrated that the two Z/E isomers of
cyclohexenone 12a did not equilibrate under the reaction
conditions. If the RhI-catalyzed 1,3-acyloxy migration of the
propargyl ester is stereospecific and the configuration of the
resulting allene is stable under the reaction conditions, one
would expect a 1:1 E/Z ratio for 37. Our result suggests that
either the 1,3-acyloxy migration is not stereospecific or the
[13] For recent reviews, see: a) K. Miki, S. Uemura, K. Ohe, Chem.
Lett. 2005, 34, 1068; b) N. Marion, S. P. Nolan, Angew. Chem.
2007, 119, 2806 – 2809; Angew. Chem. Int. Ed. 2007, 46, 2750 –
2752; c) A. Fꢀrstner, P. W. Davies, Angew. Chem. 2007, 119,
3478 – 3519; Angew. Chem. Int. Ed. 2007, 46, 3410 – 3449;
1348
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 1346 –1349

d) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180; e) A. S. K.
Hashmi, Angew. Chem. 2008, 120, 6856 – 6858; Angew. Chem.
Int. Ed. 2008, 47, 6754 – 6756; f) E. Jimenez-Nunez, A. M.
Echavarren, Chem. Rev. 2008, 108, 3326; g) D. J. Gorin, B. D.
Sherry, F. D. Toste, Chem. Rev. 2008, 108, 3351.
[16] The independently prepared allene 5 yielded the same product
under the standard reaction conditions in Table 1.
[14] For recent examples of [5+1] cycloadditions of vinyl and allenyl
cyclopropanes, see: a) D. F. Taber, K. Kanai, Q. Jiang, G. Bui, J.
Am. Chem. Soc. 2000, 122, 6807; b) T. Kurahashi, A. de Meijere,
Synlett 2005, 2619; c) N. Iwasawa, Y. Owada, T. Matsuo, Chem.
Lett. 1995, 115; d) Y. Owada, T. Matsuo, N. Iwasawa, Tetrahe-
dron 1997, 53, 11069; e) M. Murakami, K. Itami, M. Ubukata, I.
Tsuji, Y. Ito, J. Org. Chem. 1998, 63, 4; For [6+1] cycloaddition of
allenylcyclobutanes, see: f) P. A. Wender, N. M. Deschamps, R.
Sun, Angew. Chem. 2006, 118, 4061 – 4064; Angew. Chem. Int.
Ed. 2006, 45, 3957 – 3960.
[17] a) P. Mauleon, J. L. Krinsky, F. D. Toste, J. Am. Chem. Soc. 2009,
131, 4513; b) D. Garayalde, E. Gomez-Bengoa, X. G. Huang, A.
Goeke, C. Nevado, J. Am. Chem. Soc. 2010, 132, 4720.
[18] S. Wang, L. Zhang, J. Am. Chem. Soc. 2006, 128, 8414.
[19] Similar effects were also observed in other cycloaddition
reactions: a) T. Kobayashi, Y. Koga, K. Narasaka, J. Organomet.
Chem. 2001, 624, 73; b) Y. Wang, J. Wang, J. Su, F. Huang, L.
Jiao, Y. Liang, D. Yang, S. Zhang, P. A. Wender, Z. Yu, J. Am.
Chem. Soc. 2007, 129, 10060.
[20] For a report on regioselective isomerization of allenylcyclopro-
pane to cyclopentene, see: M. Hayashi, T. Ohmatsu, Y. P. Meng,
K. Saigo, Angew. Chem. 1998, 110, 877 – 879; Angew. Chem. Int.
Ed. 1998, 37, 837 – 839.
[21] For discussions on regioselectivity of vinyl cyclopropane in
metal-catalyzed cycloadditions, see: a) P. A. Wender, A. J.
Dyckman, C. O. Husfeld, D. Kadereit, J. A. Love, H. Rieck, J.
Am. Chem. Soc. 1999, 121, 10442; b) P. A. Wender, A. J.
Dyckman, Org. Lett. 1999, 1, 2089; c) P. Liu, L. E. Sirois,
P. H. Y. Cheong, Z. X. Yu, I. V. Hartung, H. Rieck, P. A.
Wender, K. N. Houk, J. Am. Chem. Soc. 2010, 132, 10127;
d) P. A. Wender, J. Nuss, D. B. Smith, A. Suarez-Sobrino, J.
Vgberg, D. Decosta, J. Bordner, J. Org. Chem. 1997, 62, 4908;
e) B. M. Trost, H. C. Shen, Org. Lett. 2000, 2, 2523; f) B. M.
Trost, H. C. Shen, Angew. Chem. 2001, 113, 2375 – 2378; Angew.
Chem. Int. Ed. 2001, 40, 2313 – 2316; g) B. M. Trost, H. C. Shen,
D. B. Horne, E. D. Toste, B. G. Steinmetz, C. Koradin, Chem.
Eur. J. 2005, 11, 2577.
[22] The stereochemistry of the cyclopropane ring was not com-
pletely retained in the gold-catalyzed reaction. See Ref. [17] and
the following reference for details: Y. Zou, D. Garayalde, Q. R.
Wang, C. Nevado, A. Goeke, Angew. Chem. 2008, 120, 10264 –
10267; Angew. Chem. Int. Ed. 2008, 47, 10110.
[23] a) K. Stratmann, R. E. Moore, R. Bonjouklian, J. B. Deeter,
G. M. L. Patterson, S. Shaffer, C. D. Smith, T. A. Smitka, J. Am.
Chem. Soc. 1994, 116, 9935; b) J. I. Jimenez, U. Huber, R. E.
Moore, G. M. L. Patterson, J. Nat. Prod. 1999, 62, 569.
[15] For selected examples of tandem reactions involving gold-,
copper-, silver-, or platinum-catalyzed 1,3-acyloxy migration of
propargyl esters, see: a) A. W. Sromek, A. V. Kel’in, V.
Gevorgyan, Angew. Chem. 2004, 116, 2330; Angew. Chem. Int.
Ed. 2004, 43, 2280; b) L. Zhang, J. Am. Chem. Soc. 2005, 127,
16804; c) L. Zhang, S. Wang, J. Am. Chem. Soc. 2006, 128, 1442;
d) J. Zhao, C. O. Hughes, F. D. Toste, J. Am. Chem. Soc. 2006,
128, 7436; e) A. Buzas, F. Gagosz, J. Am. Chem. Soc. 2006, 128,
12614; f) N. Marion, S. Diez-Gonzalez, P. de Fremont, A. R.
Noble, S. P. Nolan, Angew. Chem. 2006, 118, 3729; Angew. Chem.
Int. Ed. 2006, 45, 3647; g) A. Buzas, F. Istrate, F. Gagosz, Org.
Lett. 2006, 8, 1957; h) S. Wang, L. Zhang, Org. Lett. 2006, 8, 4585;
i) J. Barluenga, L. Riesgo, R. Vicente, L. A. Lopez, M. Tomas, J.
Am. Chem. Soc. 2007, 129, 7772; j) T. Schwier, A. W. Sromek,
D. M. L. Yap, D. Chernyak, V. Gevorgyan, J. Am. Chem. Soc.
2007, 129, 9868; k) G. Zhang, V. J. Catalano, L. Zhang, J. Am.
Chem. Soc. 2007, 129, 11358; l) G. Lemiere, V. Gandon, K.
Cariou, T. Fukuyama, A. L. Dhimane, L. Fensterbank, M.
Malacria, Org. Lett. 2007, 9, 2207; m) C. H. M. Amijs, V. Opez-
Carrillo, A. M. Echavarren, Org. Lett. 2007, 9, 4021; n) T. P. Luo,
S. L. Schreiber, Angew. Chem. 2007, 119, 8398 – 8401; Angew.
Chem. Int. Ed. 2007, 46, 8250 – 8253; o) A. S. Dudnik, T. Schwier,
V. Gevorgyan, Org. Lett. 2008, 10, 1465; p) X. Shu, K. Ji, S. Zhao,
Z. Zheng, J. Chen, L. Lu, X. Liu, Y. Liang, Chem. Eur. J. 2008, 14,
10556; q) Y. Peng, L. Cui, G. Zhang, L. Zhang, J. Am. Chem. Soc.
2009, 131, 5062; r) M. Yu, G. Zhang, L. Zhang, Tetrahedron 2009,
65, 1846; s) L. Lu, X. Y. Liu, X. Z. Shu, K. Yang, K. G. Ji, Y. M.
Liang, J. Org. Chem. 2009, 74, 474; t) A. S. Dudnik, T. Schwier,
V. Gevorgyan, Tetrahedron 2009, 65, 1859; u) A. S. Dudnik, T.
Schwier, V. Gevorgyan, J. Organomet. Chem. 2009, 694, 482;
v) T. M. Teng, R. S. Liu, J. Am. Chem. Soc. 2010, 132, 9298.
Angew. Chem. Int. Ed. 2011, 50, 1346 –1349
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1349