Asymmetric chiral ligand-directed alkene dioxygenation

Article abstract of DOI:10.1021/ol303003g

A Pd-catalyzed asymmetric alkene 1,2-dioxygenation reaction is described. The diastereoselectivity of the reaction is controlled by tethering a chiral oxime ether directing group to the alkene substrate. The best selectivities are obtained with 8-substituted menthone-derived oxime ether auxiliaries.

Full text of DOI:10.1021/ol303003g

ORGANIC
LETTERS
2013
Vol. 15, No. 1
46–49
Asymmetric Chiral Ligand-Directed
Alkene Dioxygenation
Sharon R. Neufeldt and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue,
Ann Arbor, Michigan 48109, United States
mssanfor@umich.edu
Received October 31, 2012
ABSTRACT
A Pd-catalyzed asymmetric alkene 1,2-dioxygenation reaction is described. The diastereoselectivity of the reaction is controlled by tethering a
chiral oxime ether directing group to the alkene substrate. The best selectivities are obtained with 8-substituted menthone-derived oxime ether
auxiliaries.
Alkene difunctionalization reactions are synthetically
valuable methods that generate two new bonds and up to
two stereocenters in a single operation. These transforma-
tions are frequently catalyzed by transition metals, with
osmium-based catalysts being particularly effective at
controlling the relative and absolute stereochemistry of
the products.1 Recently, a number of exciting reports
have demonstrated the feasibility of high-oxidation state
Pd-catalyzed alkene difunctionalization.2,3 These Pd-
catalyzed reactions are of particular interest because they
are mechanistically distinct from the corresponding Os
systems. Whereas Os promotes concerted syn addition of
two heteroatoms across the alkene, high valent Pd catalysis
involves the formation of each new CÀX bond in a discrete
step.2a As a result, this mechanistic manifold offers the
potential for greater reaction diversity, with the possibility
of adding two different functional groups across a CÀC
double bond in a highly selective fashion.2,3
Over the past 10 years, numerous high-valent Pd-
catalyzed alkene difunctionalization reactions have been
developed.4À12 These include methods for alkene di-
oxygenation,4 aminooxygenation,5 diamination,7 amino-
halogenation,8,9 and aryl halogenation.10 These transfor-
mations often proceed with selectivity for either syn or anti
addition of the vicinal groups. However, the stereoselective
(4) Dioxygenation: (a) Li, Y.; Song, D.; Dong, V. M. J. Am. Chem.
Soc. 2008, 130, 2962. (b) Wang, A.; Jiang, H.; Chen, H. J. Am. Chem.
Soc. 2009, 131, 3846. (c) Wang, W.; Wang, F.; Shi, M. Organometallics
2010, 29, 928. (d) Park, C. P.; Lee, J. H.; Yoo, K. S.; Jung, K. W. Org.
Lett. 2010, 12, 2450.
(5) Aminooxygenation: (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J.
J. Am. Chem. Soc. 2005, 127, 7690. (b) Liu, G.; Stahl, S. S. J. Am. Chem.
Soc. 2006, 128, 7179. (c) Desai, L. V.; Sanford, M. S. Angew. Chem., Int.
Ed. 2007, 46, 5737.
(6) Aminoarylation: (a) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.;
Michael, F. E. J. Am. Chem. Soc. 2009, 131, 9488. (b) Sibbald, P. A.;
Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009,
131, 15945.
(1) Reviews: (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483. (b) Johnson, R. A.; Sharpless, K. B. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
€
(7) Diamination: (a) Streuff, J.; Hovelmann, C. H.; Nieger, M.;
~
~ ~
Muniz, K. J. Am. Chem. Soc. 2005, 127, 14586. (b) Muniz, K. J. Am.
New York, 2000; p 357. (c) Bolm, C.; Hildebrand, J. P.; Muniz, K. In
~
€
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000; p 399.
(2) Reviews on Pd-catalyzed alkene difunctionalization: (a) Jensen,
Chem. Soc. 2007, 129, 14542. (c) Muniz, K.; Hovelmann, C. H.; Streuff,
J. J. Am. Chem. Soc. 2008, 130, 763. (d) Sibbald, P. A.; Michael, F. E.
ꢀ
ꢀ
~
Org. Lett. 2009, 11, 1147. (e) Iglesias, A.; Perez, E. G.; Muniz, K. Angew.
~
ꢀ
Chem., Int. Ed. 2010, 49, 8109. (f) Muniz, K.; Kirsch, J.; Chavez, P. Adv.
K. H.; Sigman, M. S. Org. Biomol. Chem. 2008, 6, 4083. (b) Wolfe, J. P.
~
Synth. Catal. 2011, 353, 689. (g) Martınez, C.; Muniz, K. Angew. Chem.,
~
Synlett 2008, 2913. (c) Jacques, B.; Muniz, K. In Catalyzed Carbon-
Int. Ed. 2012, 51, 7031.
Heteroatom Bond Formation; Yudin, A. K., Ed.; Wiley-VCH: Weinhem,
Germany, 2010; p 119. (d) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem.
Rev. 2011, 111, 2981.
(8) Aminofluorination: (a) Wu, T.; Yin, G.; Liu, G. J. Am. Chem.
Soc. 2009, 131, 16354. (b) Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.; Liu, G.
J. Am. Chem. Soc. 2010, 132, 2856.
~
(3) Reviews on high valent Pd: (a) Muniz, K. Angew. Chem., Int. Ed.
2009, 48, 9412. (b) Canty, A. J. Dalton. Trans. 2009, 47, 10409. (c) Xu,
L.-M.; Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712.
(d) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177.
(9) Chloroamination: (a) Michael, F. E.; Sibbald, P. A.; Cochran,
B. M. Org. Lett. 2008, 10, 793. (b) Yin, G.; Wu, T.; Liu, G. Chem.;Eur.
J. 2012, 18, 451.
r
10.1021/ol303003g
Published on Web 12/18/2012
2012 American Chemical Society

Table 2. Alkene Dioxygenation with Chiral Auxiliaries Derived
from Commercial Ketonesa
Scheme 1. Chiral Ligand-Directed Approach to Asymmetric
Alkene Difunctionalization
Table 1. Dibenzoylation of 4 and Control Reactionsa
a Conditions: substrate (1 equiv), PdCl2(PhCN)2 (0.05 equiv),
PhI(OBz)2 (2 equiv), dry toluene (0.12 M in substrate), 50 °C, 8 h.
b Isolated yield. c Product was not detected by NMR spectroscopic
analysis of the crude reaction mixture.
formation of nonracemic products in these reactions has
remained largely elusive.13
One appealing approach for achieving asymmetric
Pd-catalyzed alkene difunctionalization would involve
the use of a chiral directing group. A related strategy has
been successfully employed by Yu to achieve asymmetric
high valent Pd-catalyzed ligand-directed CÀH bond
oxidation.14 In a similar fashion, we envisioned that the
chiral directing group in substrate 1 (Scheme 1) could relay
stereochemical information to the stereocenter formed in the
product (3) via palladacycle intermediate 2. This approach
should also enable more facile difunctionalization, because
a Conditions: substrate (1 equiv), PdCl2(PhCN)2 (0.05 equiv),
PhI(OBz)2 (2 equiv), dry toluene (0.12 M in substrate), 50 °C, 8 h.
b Isolated yield. c Determined by relative integrations of at least two pairs
of peaks in the 13C and/or 1H NMR spectra; see Supporting Information
for details. d Product was not detected by NMR spectroscopic analysis of
the crude reaction mixture.
(10) Arylhalogenation: (a) Kalyani, D.; Sanford, M. S. J. Am. Chem.
Soc. 2008, 130, 2150. (b) Kalyani, D.; Satterfield, A. D.; Sanford, M. S.
J. Am. Chem. Soc. 2010, 132, 8419.
(11) Cyclopropanation: (a) Tong, X.; Beller, M.; Tse, M. K. J. Am.
Chem. Soc. 2007, 129, 4906. (b) Welbes, L. L.; Lyons, T. W.; Cychosz,
K. A.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 5836. (c) Lyons,
T. W.; Sanford, M. S. Tetrahedron 2009, 65, 3211. (d) Tsujihara, T.;
Takenaka, K.; Onitsuka, K.; Hatanaka, M.; Sasai, H. J. Am. Chem. Soc.
2009, 131, 3452.
the directing group would bring the Pd proximal to the target
olefin.
(12) Aryltrifluoromethylation: Mu, X.; Wu, T.; Wang, H.-y.; Guo,
Y.-l.; Liu, G. J. Am. Chem. Soc. 2012, 134, 878.
Our initial investigations have focused on chiral oxime
ethers as directing groups for asymmetric alkene dioxygena-
tion. These directing groups were selected based on three key
criteria: (1) oxime ethers are known to be effective directing
ligands for other Pd-catalyzed reactions (particularly CÀH
functionalization),15 (2) the substrates can easily be pre-
pared from an allyl alcohol and a chiral ketone, and (3)
diverse chiral nonracemic ketones are readily available.
(13) For an example of asymmetric alkene difunctionalization via
high valent Pd catalysis that utilizes chiral SPRIX ligands, see ref 11d.
(14) (a) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44,
2112. (b) Giri, R.; Liang, J.; Lei, J.-G.; Li, J.-J.; Wang, D.-H.; Chen, X.;
Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J.-Q. Angew. Chem., Int. Ed.
2005, 44, 7420. (c) Giri, R.; Chen, X.; Hao, X.-S.; Li, J.-J.; Liang, J.; Fan,
Z.-P.; Yu, J.-Q. Tetrahedron: Asymmetry 2005, 16, 3502. (d) Giri, R.;
Lan, Y.; Liu, P.; Houk, K. N.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134,
14118.
Org. Lett., Vol. 15, No. 1, 2013
47

Scheme 2. Possible Mechanistic Pathways for Oxime-Directed Dibenzoylation
Literature precedent suggests that this transformation
proceeds via a mechanism involving oxime ether coordina-
tion, oxypalladation, oxidation from PdII to PdIV, and
then CÀO bond forming reductive elimination (Scheme 2).
Within the context of this general manifold, there are
several unresolved details that are critical for the stereo-
chemical outcome of the reaction. In particular, the initial
step could proceed via either trans (paths a and b) or cis
oxypalladation (paths c and d);2,4 furthermore, the final
reductive elimination could proceed by direct (paths a
and c) or SN2-type (paths b and d) mechanisms.2,4,5 In
an achiral system, these four pathways would lead to two
different products (overall syn or anti addition).
Scheme 3. Syn Diastereoselectivity in the Dibenzoylation of
trans and cis Internal Alkenes 7
To probe these possibilities, we examined the stereoche-
mical outcome of Pd-catalyzed dibenzoylation with cis-
and trans-7 as substrates. Under our optimal conditions, di-
oxygenation of both alkenes proceeded with high (g10:1)
selectivity for the syn addition product (Scheme 3).19
The syn selectivity suggests that the primary operative
mechanism is either (b) or (c) in Scheme 2. The observation
of high diastereoselectivity in this transformation is critical
for our goal of achieving asymmetric dioxygenation, as it
indicates that the stereocenter-forming steps proceed with
high stereochemical fidelity.
We next examined a series of chiral allyl oxime ethers
derived from commercially available chiral ketones (8À12,
Table 2). Notably, the E and Z oxime isomers of the same
parent ketone present significantly different steric environ-
ments to a coordinated Pd center. Therefore, the E and Z
diastereomers were separated and studied individually
when possible (substrates 8 and 10).
We first examined the Pd-catalyzed dioxygenation
of achiral oxime ether substrate 4 with PhI(O2CPh)2.4
Using PdCl2(PhCN)2 as the catalyst, this transformation
proceeded in good yield under mild conditions (8 h at
50 °C in toluene) (Table 1, entry 1).16 Importantly, no
dioxygenation was observed in the absence of Pd under
these conditions, even upon the addition of 5À10 mol % of
TfOH or BF3•OEt2.17 Although allyl propyl ether (5) and
oxime ether 4 both contain an olefin allylic to an oxygen
atom, 5 was completely unreactive under the optimized
conditions. This result demonstrates that the oxime ether
moiety in 4 is necessary to facilitate the dioxygenation
reaction under these mild conditions.18
(15) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147 and
references therein. (b) Chan, C.-W.; Zhou, Z.; Chan, A. S. C.; Yu, W.-Y.
Org. Lett. 2010, 12, 3926. (c) Neufeldt, S. R.; Sanford, M. S. Org. Lett.
2010, 12, 532. (d) Kalyani, D.; McMurtrey, K. B.; Neufeldt, S. R.;
Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 18566.
Oxime stereoisomers E-8 and Z-8 underwent Pd-cata-
lyzed dibenzoylation to afford two spectroscopically dif-
ferent sets of products. This result demonstrates that the
oxime ether is configurationally stable under the mild
reaction conditions. The stereocenter R to the oxime will
be in closer proximity to the coordinated Pd center in E-8
relative to Z-8. Thus, as expected, the former afforded the
(16) See Supporting Information for full details of the optimization
of this transformation.
(17) For TfOH- or BF3•OEt2-catalyzed alkene dioxygenation with
PhI(OAc)2, see: (a) Kang, Y.-B.; Gade, L. H. J. Am. Chem. Soc. 2011,
133, 3658. (b) Zhong, W.; Yang, J.; Meng, X.; Li, Z. J. Org. Chem. 2011,
76, 9997.
(18) A remote alkene was also tolerated:
(19) Relative stereochemistry was determined by deprotection of
each product to the diol and spectroscopic comparison to an authentic
sample of the erythro diol prepared by dihydroxylation of cis-7 with
AD-mix-R; see Supporting Information for details.
48
Org. Lett., Vol. 15, No. 1, 2013

scaffold. Improved diastereoselectivity (75:25) was ob-
served in E-10, which contains a 4°-R stereocenter. How-
ever, the overall yield was low, likely due to the highly
congested steric environment proximal to the oxime. In
keeping with this hypothesis, the opposite oxime isomer
(Z-10) afforded a lower dr (66:33) but better reactivity.
Furthermore, the use of substrate 11, which contains an
even more hindered 4°-R stereocenter, resulted in drama-
tically decreased reactivity (no dioxygenated product was
observed in this case). Among the substrates in Table 2, the
best balance between reactivity and selectivity was ob-
tained with menthone-derived substrate 12, which features
β-branching adjacent to a 3°-R stereocenter.
Table 3. Alkene Dioxygenation with Chiral Auxiliaries Derived
from 8-Substituted Menthonea
To improve further on the selectivity seen with 12, we
prepared a number of 8-substituted menthone auxiliaries.
Interestingly, the addition of a third methyl group to
the β-position of the ketone (13) provided a substantial
improvement in stereoselectivity (dr = 86:14 for 13a,
compared to 74:26 for 12a). The selectivity remained un-
changed upon additional monosubstitution at the γ-posi-
tion. However, a further improvement in dr (to 90:10)
was observed with 17, which contains a 3°-carbon center at
the γ-position. Notably, as shown in Table 3, a decline in
reaction yield was seen as the steric bulk of the auxiliary
increased (compare 17a and 15a to 13a). Overall, auxili-
aries 13 and 17 provide particularly promising results and
have potential for further applications in this field.
In summary, the results presented herein demonstrate
that a chiral oxime ether directing group can be used
to control the stereochemical outcome of high valent Pd-
catalyzed alkene dioxygenation. Readily accessible menthone
derivatives are particularly effective auxiliaries for these
transformations. Ongoing investigations are focused on
broadening the scope of this work to a more diverse set
of nucleophiles and alkene substrates. In addition, current
studies seek to expand this strategy to the use of related
chiral auxiliaries as catalysts via reversible in situ forma-
tion of oxime ether and/or imine derivatives.
a Conditions: substrate (1 equiv), PdCl2(PhCN)2 (0.05 equiv),
PhI(OBz)2 (2À3 equiv), dry toluene (0.12 M in substrate), 50 °C, 8 h.
b Isolated yield. c Determined by relative integrations of at least two pairs
of peaks in the 13C and/or 1H NMR spectra; see Supporting Information
for details.
dibenzoylated product in higher dr than the latter (63:37
versus 52:48, respectively).
Acknowledgment. Thisworkwas supportedbythe NIH
NIGMS (GM073836).
In keeping with the trend observed with E-8 and Z-8,
the dr’s obtained with substrates derived from other
commercial chiral ketones tracked with the steric environ-
ment at the R-position of the oxime. For example, the
diastereoselectivity of the reaction of 9 was lower than that
seen with E-8. This can be rationalized based on the fact
that the 3°-R stereocenter of 9 is tied back into a bicyclic
Supporting Information Available. Experimental de-
tails and spectroscopic and analytical data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
49