Enantioselective catalytic transannular ketone-ene reactions

Article abstract of DOI:10.1021/ol401968m

Highly enantio-and diastereoselective transannular ketone-ene reactions are catalyzed by a new chromium(III) triflate tridentate Schiff base complex. Electronically unactivated keto-olefins undergo heteroene reactions at ambient temperature to afford enantioenriched bicyclic alcohols, common structural motifs in natural products. The kinetic resolution of a configurationally stable planar-chiral cyclodecenone is also described.

Full text of DOI:10.1021/ol401968m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Enantioselective Catalytic Transannular
KetoneꢀEne Reactions
Naomi S. Rajapaksa and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University,
Cambridge, Massachusetts 02138, United States
jacobsen@chemistry.harvard.edu
Received July 11, 2013
ABSTRACT
Highly enantio- and diastereoselective transannular ketoneꢀene reactions are catalyzed by a new chromium(III) triflate tridentate Schiff base
complex. Electronically unactivated keto-olefins undergo heteroene reactions at ambient temperature to afford enantioenriched bicyclic alcohols,
common structural motifs in natural products. The kinetic resolution of a configurationally stable planar-chiral cyclodecenone is also described.
Transannular chemical reactions are noteworthy for
generating structurally and stereochemically rich products
from relatively simple precursors in a single transforma-
tion.1 Recently, we and others identified the first appli-
cations of chiral catalysts to promote transannular trans-
formations, thereby achieving absolute stereocontrol in
DielsꢀAlder, aldol, and Claisen rearrangement reactions.2ꢀ4
Motivated by the power of ene-type reactions in organic
synthesis, we became interested in extending the asymmetric
catalytic transannular reaction concept to this important
class of CꢀC bond-forming reactions (Figure 1).5,6
Ketones are generally very poor reacting partners in
Lewis acid catalyzed processes, including heteroene reac-
tions, and to date enantioselective catalytic ketoneꢀene
reactions have only been achieved with highly electrophilic
ketones bearing strongly electron-withdrawing substitu-
ents that often allow for two-point binding to the cata-
lyst.7,8 Given that the transannular disposition of reacting
partners can confer a significant entropic advantage and
corresponding reactivity enhancements, we considered
the possibility of effecting enantioselective transannular
ene reactions of electronically unactivated ketones. We
were particularly interested in studying the intramolecular
ketone-ene reaction of (E)-cyclodecenones, as the resulting
(1) For reviews on the application of transannular reactions to the
ꢀ
synthesis of natural products, see: (a) Marsault, E.; Toro, A.; Nowak, P.;
Deslongchamps, P. Tetrahedron 2001, 57, 4243. (b) Clarke, P. A.;
Reeder, A. T.; Winn, J. Synthesis 2009, 5, 691.
(7) Examples of a Brønsted acid catalyzed enantioselective ketone-
ene reaction of R,R,R-trifluoropyruvates: (a) Clarke, M. L.; Jones,
C. E. S.; France, M. B. Beilstein J. Org. Chem. 2007, 3, 24. (b) Rueping,
M.; Thiessmann, T.; Kuenkel, A.; Koenigs, R. M. Angew. Chem., Int.
Ed. 2008, 47, 6798.
(2) (a) Balskus, E. P.; Jacobsen, E. N. Science 2007, 317, 1736. (b)
Chandler, C. L.; List, B. J. Am. Chem. Soc. 2008, 130, 6737. (c)
Jaschinski, T.; Hiersemann, M. Org. Lett. 2012, 14, 4114.
(3) (a) Hodgson, D. M.; Lee, G. P.; Marriott, R. E.; Thompson, A. J.;
Wisedale, R.; Witheringon J. Chem. Soc., Perkin Trans. 1 1998, 2151. (b)
Hodgson, D. M.; Robinson, L. A. Chem. Commun. 1999, 309.
(4) For examples of enantioselective transannular transformations
that utilize stoichiometric or superstoichiometric chiral reagents, see: (a)
Inoue, M.; Sato, T.; Hirama, M. Angew. Chem., Int. Ed. 2006, 45, 4848.
(b) Inoue, M.; Lee, N.; Kasuya, S.; Sato, T.; Hirama, M. J. Org. Chem.
2007, 72, 3065. (c) Knopff, O.; Kuhne, J.; Fehr, C. Angew. Chem., Int.
Ed. 2007, 46, 1307.
(5) For a general review of asymmetic ene reactions, see: (a) Mikami,
K.; Shimizu, M. Chem. Rev. 1992, 92, 1021.
(6) For reviews on enantioselective, catalytic carbonylꢀene reac-
tions, see: (a) Mikami, K.; Terada, M. In Comprehensive Asymmetric
Catalysis, Vol. 3; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; p 1143. (b) Clarke, M. L.; France, M. B. Tetra-
hedron 2008, 64, 9003.
(8) For selected examples of metal-catalyzed enantioselective carbonylꢀ
ene reactions of R-ketoester and diketones, see: (a) Evans, D. A.; Tregay,
S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am. Chem. Soc.
2000, 122, 7936. (b) Yang, D.; Yang, M.; Zhu, N.-Y. Org. Lett. 2003, 5,
3749. (c) Mikami, K.; Aikawa, K.; Kainuma, S.; Kawakami, Y.; Saito,
T.; Sayo, N.; Kumobayashi, H. Tetrahedron: Asymmetry 2004, 15, 3885.
(d) Doherty, S.; Knight, J. G.; Smyth, C. H.; Harrington, R. W.; Clegg,
W. J. Org. Chem. 2006, 71, 9751. (e) Mikami, K.; Kawakami, Y.;
Akiyama, K.; Aikawa, K. J. Am. Chem. Soc. 2007, 129, 12950. (f) Zhao,
J.-F.; Tsui, H.-Y.; Wu, P.-J.; Lu, J.; Loh, T.-P. J. Am. Chem. Soc. 2008,
130, 16492. (g) Luo, H.-K.; Woo, Y.-L.; Schumann, H.; Jacob, C.;
van Meurs, M.; Yang, H.-Y.; Tan, Y.-T. Adv. Synth. Catal. 2010, 352,
1356. (h) Zheng, K.; Yang, Y.; Zhao, J.; Yin, C.; Lin, L.; Liu, X.; Feng,
X. Chem.;Eur. J. 2010, 16, 9969. (i) Zhao, Y.-J.; Li, B.; Tan, L.-J. S.;
Shen, Z.-L.; Loh, T.-P. J. Am. Chem. Soc. 2010, 132, 10242.
r
10.1021/ol401968m
XXXX American Chemical Society

products contain a decalinol framework that is prevalent in
terpene natural products (Figure 1).9 This effort would
necessarily take into consideration the known tempera-
ture-dependent planar chirality of medium-sized cyclic
(E)-olefin substrates.10 In that context, Barriault has studied
diastereoselective ketoneꢀene reactions of (E)-cyclodece-
nones and has shown that those cyclic structures were con-
figurationally flexible under the elevated temperatures of
the thermal reaction (140ꢀ220 °C).11 For efficient, enantio-
selective transannular ene reactions to be possible, the
reaction must necessarily occur under conditions where
interconversion of the enantiomeric conformers of the sub-
strate takes place. Herein, we report highly diastereo- and
enantioselective transannular ketoneꢀene reactions cata-
lyzed by a new chromium(III) tridentate Schiff base complex.
anionic oxy-Cope rearrangement and yielded cyclodece-
none 1a as the exclusive olefin isomer.13
Scheme 1. Synthesis of Cyclodecenone 1a
Chiral chromium(III) tridentate Schiff base complexes,14
which have been shown to activate aldehydes and quinones
through single-point binding, were uniquely effective in
catalyzing the ketoneꢀene reaction of 1a (Table 1).15 For
example, in the presence of dimeric chromium chloride
complex 5a,16 trans-decalinol 4a was obtained in modest
enantioenrichment, with excellent diastereoselectivity, and
as a single olefin regioisomer (entry 2). Pronounced effects
of the catalyst counterion on the reaction outcome were
observed, withreactivityincreasingsteadilywithdecreasing
coordinatingꢀability of thꢀe counterion. Catalysts 5e and 5f,
bearing PF6 and SbF6 counterions, respectively, pro-
moted complete conversion within 24 h, albeit with dimin-
ished enantioselectivities (entries 7 and 8).17,18 Complexes
bearing sulfonate counterions were somewhat less reactive,
but induced significantly improved enantioselectivities
(entries 3 and 4), with triflate complex 5c identified as
the optimal catalyst. The high substrate conversion along
with high product enantioenrichment confirmed that
Figure 1. Proposed enantioselective catalytic transannular ketoneꢀ
ene reaction and selected examples of natural products featuring
trans-decalinol frameworks.
5-Methyl-(E)-cyclodecenone 1a was chosen as a model
substrate and was readily synthesized from cyclohexene
oxide in four steps (Scheme 1).12 A copper-catalyzed ep-
oxide opening with isopropenyl magnesium bromide and a
subsequent Swern oxidation afforded unconjugated enone
2. Vinylmagnesium bromide addition provided the desired
trans-substituted cyclohexanol 3 in 20:1 dr and 55% iso-
lated yield over the three steps. Exposure of the divinyl
alcohol topotassium hydride and 18-crown-6promoted an
(15) See Supporting Information for the results of a screen of chiral
Lewis acids.
(16) Chavez, D. E.; Jacobsen, E. N. Org. Synth. 2005, 82, 34. See also
refs 14a, 14b, and 14f.
(9) For a recent review of natural sesquiterpenoids, see: Fraga, B. M.
Nat. Prod. Rep. 2011, 28, 1580.
(10) Nakazaki, M.; Yamamoto, K.; Naemura, K. Stereochemistry of
Twisted Double Bond Systems. Topics in Current Chemistry, Vol. 125;
Vogtle, F., Weber, E., Eds.; Springer: Berlin, 1984; p 1.
(11) (a) Sauer, E. L. O.; Hooper, J.; Woo, T.; Barriault, L. J. Am.
Chem. Soc. 2007, 129, 2112. (b) Sauer, E. L. O.; Barriault, L. J. Am.
Chem. Soc. 2004, 126, 8670.
(17) Catalyst 5f has been shown to induce superior reactivity and
enantioselectivity relative to catalyst 5a in hetero-DielsꢀAlder reac-
tions. See refs 14a and 16.
(18) The transannular ketoneꢀene reaction conducted with complex
5f afforded minor olefin byproducts (<10%). This outcome is an
indication of the diminished regioselectivity with this more Lewis acidic
catalyst and suggests that this catalyst may promote a stepwise ketoneꢀ
ene reaction.
(12) Divinyl alcohol 3 has been prepared by Barriault and coworkers.
The route shown in Scheme 1 is a modified version of the one reported:
Warrington, J. M.; Yap, G. P. A.; Barriault, L. Org. Lett. 2000, 2, 663.
(13) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765.
(14) (a) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 1999, 38, 2398. (b) Gademann, K.; Chavez, D. E.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2002, 41, 3059. (c) Ruck,
R. T.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 2882. (d) Joly,
G. D.; Jacobsen, E. N. Org. Lett. 2002, 4, 1795. (e) Ruck, R. T.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2003, 42, 4771. (f) Chavez,
D. E.; Jacobsen, E. N. Org. Lett. 2003, 5, 2563. (g) Jarvo, E. R.;
Lawrence, B. M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44,
6043. (h) Grachan, M. L.; Tudge, M. T.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2008, 47, 1469.
(19) Studies on related substrates suggest that 1a does not exhibit
planar chirality at 23 °C: (a) Cope, A. C.; Banholzer, K.; Keller, H.;
Pawson, B. A.; Whang, J. J.; Winkler, H. J. S. J. Am. Chem. Soc. 1965,
87, 3644. (b) Westen, H. H. Helv. Chim. Acta 1964, 47, 575. (c) Binsch,
G.; Roberts, J. D. J. Am. Chem. Soc. 1965, 87, 5158. (d) Tomooka, K.;
Ezawa, T.; Inoue, H.; Uehara, K.; Igawa, K. J. Am. Chem. Soc. 2011,
133, 1754.
(20) The requirement for desiccant is a common feature of all
reactions catalyzed by chromium(III) tridentate Schiff base complexes
(see ref 14). The crystal structures obtained for this class of catalysts
indicate that metal centers have octahedral geometry and contain water
molecules to complete the coordination sphere. We hypothesize that the
desiccant removes a water molecule from the chromium center allowing
for coordination of the substrate carbonyl group.
B
Org. Lett., Vol. XX, No. XX, XXXX

substrate 1a is configurationally dynamic under the reac-
tion conditions.19 The use of activated desiccant was found
to be essential for catalytic activity, as the corresponding
Table 2. Substrate Scope of the Enantioselective Transannular
KetoneꢀEne Reactiona
˚
reaction conducted in the absence of activated 4 A molecular
sieves afforded significantly lower conversion (entry 5).20
Table 1. Catalyst Evaluation for the Enantioselective Transan-
nular KetoneꢀEne Reaction of Cyclodecenone 1aa
conv
(%)b
4a ee
entry
catalyst
none
drc
(%)d
1
2
3
4
5e
6
7
8
<1
50
67
76
6
ꢀ
ꢀ
5a (X = Cl)
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
60
ent-5b (X = OTs)
5c (X = OTf)
5c (X = OTf)
5d (X = NTf2)
5e (X = PF6)
5f (X = SbF6)
ꢀ84
93
n.d.
46
98
100
100
50
56
a Reactions were performed on a 0.2 mmol scale with 5 mol %
˚
catalyst 5 (10 mol % based on Cr) and in the presence of powdered 4 A
molecular sieves at 23 °C in anhydrous toluene ([1a] = 4 M). b Deter-
mined by GC analysis of the crude reaction mixtures using dodecane as
an internal standard. c Determined by 1H NMR analysis of the crude
reaction mixtures. d Determined by GC analysis using commercial chiral
columns. e Reaction performed in the absence of powdered 4 A molec-
˚
ular sieves. n.d. = not determined.
The substrate scope of the enantioselective transannular
ketoneꢀene reaction with catalyst 5c was evaluated (Table 2).21
Full conversion of cyclodecenone 1a was achieved by
extending the reaction time to 48 h, and product 4a was
obtained in 81% yield and 93% ee. While gem-dimethyl-
substitutedtrans-decalinols 4band 4cwere accessedin high
yield and enantioselectivity (entries 2 and 3), the closely
analogous product 4d was obtained in low yield and as a
racemate (entry 4). Analysis of the chairꢀchair conforma-
tions of these substrates provides a plausible explanation
(Figure 2).22 Only cyclodecenone 1d possesses a syn-
pentane relationship between its methyl substituents, and
the pseudoaxial methyl substituent at C3 is also likely to
interfere with complexation of the Lewis acidic catalyst
a Reactions were performed on a 0.2 mmol scale with 5 mol %
˚
catalyst 5c (10 mol % based on Cr) and in the presence of powdered 4 A
molecular sieves at 23 °C in anhydrous toluene ([substrate] = 4 M).
Unless otherwise noted, reactions showed complete conversion after
48 h and the bicyclic alcohol product was obtained as a single regioi-
somer. b The absolute configuration of 4a was determined by X-ray crys-
tallographic analysis of the corresponding p-bromobenzoate. The
stereochemistry of all other products is assigned by analogy. c Isolated
yield of the ketoneꢀene products following purification by flash chro-
1
matography. d Determined by H NMR analysis of the crude reaction
mixtures. e Determined by GC analysis using commercial chiral columns.
f Combined yield of 4d and an inseparable regioisomeric product. This
reaction went to 70% conversion after 48 h. g Reaction time was 24 h.
With these substitution effects in mind, we probed
more highly functionalized substrates (entries 5 and 6).
The acid-sensitive acetal 1e and unconjugated diene 1f
both proved to be effective substrates, affording the
corresponding ene products in high enantioselectivities
and good yields. Additionally, ether 6 and cyclononenone
8 underwent enantioselective ketoneꢀene reactions to
(21) Substrates were synthesized via anionic or palladium-catalyzed
oxy-Cope rearrangements of divinyl alcohols: (a) Reference 13. (b)
Bluthe, N.; Malacria, M.; Gore, J. Tetrahedron Lett. 1983, 24, 1157.
(22) Chair-like transition structures that are consistent with reaction
outcomes have been determined computationally for diastereoselective
thermal ketoneꢀene reactions of (E)-cyclodecenones: Terada, Y.;
Yamamura, S. Tetrahedron Lett. 1979, 20, 1623.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Kinetic Resolution of Planar Chiral Cyclodecenone
(()-10 by a Cr(III)-Catalyzed Transannular KetoneꢀEne Reaction
Figure 2. Conformational analysis to account for the low re-
activity observed for cyclodecenone 1d relative to 1b and 1c.
transannular strategy allows electronically unactivated
ketones to be engaged as substrates in a chiral Lewis acid
catalyzed process. This approach is most effective in the
case of (E)-cyclodecenones that lack β-substitution, as the
reactive components are held in close proximity and in
proper alignment for the productive ketoneꢀene reaction.
afford the corresponding bicyclic alcohol products, al-
though in diminished yields and enantioselectivities.
Tetrasubstituted alkene 10 proved much less reactive
than trisubstituted olefins 1aꢀf under the catalytic condi-
tions, undergoing only 19% conversion after 24 h at 50 °C.
The transannular ketoneꢀene reaction afforded trans-
decalinol 11, bearing a quaternary stereocenter, in 12%
yield and 73% ee (Scheme 2). Cyclodecenone (þ)-10 was
recovered in 69% yield and in 10% ee, confirming that
this substrate undergoes racemization slowly under the
catalytic conditions and that complex 5c had induced a
measurable kinetic resolution.23
Acknowledgment. This work was supported by the
NIH (GM-43214) and by predoctoral fellowship support
to N.S.R. from Boehringer Ingelheim. We thank Dr.
Shao-Liang Zheng at the Center for Crystallographic
Studies at Harvard University for his help with X-ray data
collection and structure determination.
In conclusion, we have demonstrated that chiral
chromium(III) tridentate Schiff base complex 5c cata-
lyzes transannular ketoneꢀene reactions of medium-sized
cyclic keto-(E)-olefins in high diastereo- and enantioselec-
tivity to access fused bicyclic alcohols. Significantly, the
Supporting Information Available. Complete experi-
1
mental procedures, characterization data, H and 13C
NMR spectra of all ketoneꢀene substrates and products,
and crystallographic data for the p-bromobenzoate of 4a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) A kinetic resolution of planar chiral cyclic ethers has been
achieved through an enantioselective transannular [2,3]-Wittig rearran-
gement: Tomooka, K.; Komine, N.; Fujiki, D.; Nakai, T.; Yanagitsuru,
S. J. Am. Chem. Soc. 2005, 127, 12182.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX