Rhodium-catalyzed enantioselective addition of organoaluminum reagents to N -tosyl ketimines

Article abstract of DOI:10.1021/ol501372u

Rhodium(I)/Binap complexes catalyze highly enantioselective additions of methyl- and arylaluminum reagents to cyclic α,β-unsaturated N-tosyl ketimines. Depending on the solvent and substituents at the ring, the reaction occurs either in a 1,2-manner to de

Full text of DOI:10.1021/ol501372u

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Enantioselective Addition of Organoaluminum
Reagents to N‑Tosyl Ketimines
Sebastian Hirner, Andreas Kolb, Johannes Westmeier, Sandra Gebhardt, Stephen Middel, Klaus Harms,
and Paultheo von Zezschwitz*
Fachbereich Chemie, Philipps-Universitat Marburg, Hans-Meerwein-Straße, 35032 Marburg, Germany
̈
S
* Supporting Information
ABSTRACT: Rhodium(I)/Binap complexes catalyze highly
enantioselective additions of methyl- and arylaluminum
reagents to cyclic α,β-unsaturated N-tosyl ketimines. Depend-
ing on the solvent and substituents at the ring, the reaction
occurs either in a 1,2-manner to deliver α-tertiary allylic
amines or in a 1,4-manner to yield, after subsequent reduction,
3-substituted cycloalkyl amines. Well known in the case of the
respective cycloalkenones, these first transformations of the
aza-analogues enable the synthesis of amine structures of
pharmaceutical and biochemical interest.
mines with an α-tetrasubstituted carbon (tertiary carbin-
enantioselective 1,2-addition of readily available methyl- and
Aamines) are important structures due to their occurrence arylaluminum reagents to cycloalkenones.10,11 This Rh(I)/
in natural and artificial biologically active molecules.1 Yet the
Binap-catalyzed transformation delivers cyclic tertiary allylic
alcohols,10c enables kinetic resolution of racemic, substituted
enantioselective construction of quaternary carbon centers
cycloalkenones,10b and can also be used as an efficient strategy
represents a synthetic challenge, and there are only a few
for natural product synthesis.10a We anticipated that a similar
addition to C,N-double bonds would result in the synthesis of
enantiopure α-tertiary amines, and we recently reported the
first synthesis of cycloalk-2-enone-derived imines which are
activated by N-sulfonyl groups toward nucleophilic attack.12
This paper now describes the first enantioselective additions to
this type of substrates.
methods available to prepare such amines.2 The catalytic
enantioselective addition of carbon nucleophiles to ketimines is
one of the most efficient approaches;3 however, this trans-
formation poses even more problems than the related addition
to ketones: with both types of substrates, the differentiation of
enantiotopic faces is more demanding than in the case of
aldehydes and aldimines. In addition, ketimines usually exist as
mixtures of E- and Z-isomers. Finally, the lower electrophilicity
of ketimines is generally a major problem, requiring the use of
strong nucleophiles, which can cause deprotonation and thus
enamide formation and lead to even higher requirements for
stereodifferentiation by the chiral catalyst. During the past
decade, considerable efforts have been made to develop novel
protocols, mainly based on asymmetric modifications of the
Strecker reaction3b,d and Mannich-type additions.3d Only a few
examples of the catalytic asymmetric addition of nonstabilized
carbon nucleophiles to ketimines have been published, namely
dialkylzinc additions to imines derived from trifluoromethyl
ketones and α-ketoesters,4 allylations5 and alkynylations,6 and
rhodium- or palladium-catalyzed additions of aryl- and
alkenylboron reagents to aromatic N-sulfonyl and N-carbonyl
ketimines.7,8 Similar reactions on imines derived from cyclic
aliphatic ketones, however, have not been reported to date,
even though a direct access to optically pure α-tertiary
cycloalkylamines would be of high interest. This is true
especially for six-membered rings, since they occur in a large
number of biologically active compounds, including important
antagonists of the N-methyl-D-aspartate (NMDA) receptor
such as ketamine and gacyclidine.9 We have developed the first
For a model reaction, N-tosyl imine 1a was chosen which can
be prepared in 66% yield by condensing cyclohex-2-enone with
tosyl amide.12 Under conditions optimized for the 1,2-addition
to cyclic enones, that is, with in situ prepared [Rh((R)-
Binap)Cl]2 and AlMe3 in THF,10c the desired product 2a was
obtained with excellent enantioselectivity, albeit in low yield
(Table 1, entry 1).13 The (S)-configuration was determined by
X-ray crystallographic analysis, demonstrating that the facial
selectivity of the catalyst is identical for both enones and their
respective N-tosyl imines. Furthermore, substantial amounts of
enamide 3a and its tautomeric imine were obtained from a
Rh(I)/Binap-catalyzed 1,4-addition. Hydrolysis of these prod-
ucts afforded (R)-3-methylcyclohexanone with 98% ee as
proven by GC. This represents the first example of a catalytic
enantioselective conjugate addition to a cyclic α,β-unsaturated
ketimine.14 Catalysis by [Rh(cod)Cl]2 in the absence of Binap
led10c to an exclusive 1,4-addition, analogously to the
corresponding enone, and racemic 3a was formed almost
quantitatively (entry 2). Attempts to optimize the 1,2-addition
Received: May 13, 2014
Published: May 29, 2014
© 2014 American Chemical Society
3162
dx.doi.org/10.1021/ol501372u | Org. Lett. 2014, 16, 3162−3165

Organic Letters
Letter
Table 1. Rh(I)/Binap-Catalyzed Addition of AlMe3 to
Ketimine 1a
Table 2. Asymmetric Addition of Alanes to Ketimines
temp
time
(h)
1,2/1,4
a
2a, yield
2a, ee
b
a
entry
1
solvent
(°C)
ratio
(%)
(%)
THF
rt
rt
rt
rt
rt
rt
0
20
1
1:1
0:1
1:6
1:1
4:1
4:1
6:1
1:1
5:1
8:1
29
0
>99
−
99
c
2
THF
3
4
5
6
7
toluene
dioxane
DME
Et2O
1.5
20
20
1.5
20
20
20
20
<10
26
56
53
>99
99
98
d
Et2O
60 (58)
>99
99
e
8
f
Et2O
0
30
43
9
Et2O
0
>99
g
d
10
Et2O
0
75 (74)
99
a
b
Determined by 1H NMR analysis of the crude product. Determined
c
d
by HPLC. Without Binap. Numbers in parentheses are isolated
yields after chromatography. [Rh(cod)OMe]2 was used. [Rh(cod)-
OH]2 was used. 1.5 equiv of neat AlMe3 was used.
e
f
g
revealed the importance of the solvent: while toluene and
dioxane resulted in poor yields of 2a (entries 3,4), DME and
Et2O led to much higher ratios of 1,2-addition, though with
slightly decreased enantioselectivity (entries 5,6). While an
increased yield and perfect stereocontrol were achieved at 0 °C
(entry 7), varying the rhodium precatalyst did not result in any
further improvement (entries 8,9). Finally, a 74% isolated yield
was obtained when using neat AlMe3 rather than a solution of
this reagent in hexanes (entry 10).15 Since this yield is higher
than the amount of E-configured starting material 1a, an E/Z-
isomerization may have occurred during the reaction. This
protocol for enantioselective 1,2-addition of AlMe3 was then
applied to various N-tosyl ketimines 1 (Table 2).16
a
b
c
Isolated yield. Determined by HPLC prior to recrystallization. (R)-
d
Xyl-Binap as chiral ligand. 71% conversion (67% yield brsm).
Substrates with geminal methyl groups at C-4 or C-6 of the
six-membered ring were transformed with a similar efficiency as
the unsubstituted 1a (entries 1−3). However, substituents at C-
4 significantly lowered the reactivity and required a higher
temperature (entry 2). With the tosyl imine derived from 5,5-
dimethylcyclohex-2-enone, no 1,2-addition occurred, pointing
to a severe steric interaction between the substrate and the
catalyst.10b Indeed, in the case of the racemic 5-monosub-
stituted ketimine 1d, only the (S)-enantiomer underwent a 1,2-
addition, and (1S,5S)-2d17 was obtained in a 42% yield (entry
4). Similarly to the respective enones,10c methyl groups at C-2
or C-3 prevented 1,2-addition, and the respective ketimines
were reisolated. Regarding five-membered rings, the tosyl imine
derived from cyclopent-2-enone gradually decomposed under
the reaction conditions, while the 3-methyl and the 5,5-
dimethyl derivatives did not undergo any transformation. The
enantioselective 1,2-addition of aryl groups was attempted
using the mixed alane AlMe2Ph, which was prepared from
AlMe2Cl and PhMgBr. This once again revealed the very subtle
effects of reagents on regioselectivity: employing the standard
catalyst, ketimine 1a yielded a 2:3 mixture of the 1,2- and 1,4-
adduct.18 The chiral phosphane ligand could be used to
influence this ratio, and the highest yield (33%) of 1,2-adduct
4a17 was obtained with (R)-2,2′-bis[di(3,5-xylyl)phosphino]-
1,1′-binaphthyl (Xyl-Binap, entry 5). The 1,4-adduct was also
obtained, and upon hydrolysis, it furnished (R)-3-phenylcyclo-
hexanone in a 31% yield with 89% ee. Substituents at C-4 of the
six-membered ring suppressed the conjugate aryl addition, and
1,2-adduct 4b was obtained as the sole product in a 48% yield
(67% yield brsm, entry 6).
To gain insight into the steric effects of substituents at C-5,
enantiomerically pure (R)-1d was prepared from the respective
ketone and reacted separately with the catalysts containing (R)-
and (S)-Binap (Scheme 1). As expected based on the
transformation with rac-1d (Table 2, entry 4), 1,2-adduct
(1R,5R)-2d was obtained as the sole product using (S)-Binap
and AlMe3. Surprisingly, the same substrate underwent selective
1,4-addition with the (R)-Binap complex to furnish enamide
trans-3d, which was isolated as cyclohexylamide 5d after
subsequent reduction with NaBH4. Obviously, the 1,2-addition
pathway is sterically blocked in this setting, making the 1,4-
addition pathway the only viable reaction.19 In addition, the
discrimination of the 1,4-addition with (S)-Binap was also
revealed by transformation with AlMe2Ph, since a 5:1 ratio of
1,2- and 1,4-addition was detected and product 4d was
obtained in a 59% yield. In the case of ketimine 1e, 1,2-
3163
dx.doi.org/10.1021/ol501372u | Org. Lett. 2014, 16, 3162−3165

Organic Letters
Letter
Scheme 1. Regiodivergent Reaction on Ketimine (R)-1d and
1,4-Addition to Ketimine 1e
Figure 1. Proposed transition states involved in 1,4- and 1,2-additions
to imine (R)-1d (R = Me, Ph).
enhanced resistance to enzymatic degradation.22 Treatment of
amide 2a with RuCl3/NaIO4 at room temperature yielded the
desired amino diacid 10, while at 0 °C incomplete oxidation
occurred and α-amino aldehyde 11 was isolated (Scheme 2).
This made it easy to differentiate the carboxy groups: aldehyde
11 was converted into methyl ester 12 by treating it with oxone
in methanol.23 Similar α-methyl α-amino acids with carbox-
yalkyl side chains have been used to synthesize highly active
Grb2-SH2 peptide inhibitors.24
addition was hindered, resulting in an enantioselective 1,4-
addition. The imine 3e thus obtained was diastereoselectively
reduced with NaBH4 to afford cyclopentylamide 5e17 in a high
yield (Scheme 1). This sequence of 1,4-addition and
subsequent reduction should be applicable to the stereo-
selective synthesis of a variety of 3-substituted cycloalkylamines,
which are constituents of several pharmaceutically active
compounds.20
Scheme 2. Detosylation of Amide 2a and Synthesis of a
Quaternary α-Amino Diacid
As observed in the transformations of ketimine 1a, the facial
selectivity is the same for the addition of both methyl and
phenyl groups, which points to similar catalytic cycles.
However, the facial selectivities of the 1,2- and the 1,4-addition
are reversed; the selectivity of the latter corresponds to that of a
standard Hayashi−Miyaura reaction with arylboronic acids and
Binap as a chiral ligand.21 Thus, the 1,4-addition of aluminum
reagents may proceed through a similar mechanism comprising
transmetalation of the carbon nucleophile to rhodium and
involving, in the case of imine (R)-1d and (R)-Binap, the
transition state A (Figure 1). The 1,2-addition, observed with
(S)-Binap using the same substrate, may also proceed through
transmetalation, but may involve the transition state B, which
allows for addition of the group R to C-1 and explains the
reversed facial selectivity. The regiodivergence observed in the
transformation of (R)-1d might then stem from unfavorable
steric interactions of the methyl group at the substrate and the
Binap ligand in the transitions states C and D. However, alanes
are strong Lewis acids and may be bound to the tosyl groups in
these structures A−D, which should also influence the regio-
and stereoselectivity.
To show the synthetic applicability of the 1,2-addition,
detosylation of amide 2a was performed with sodium
naphthalide, and the highly volatile amine 6 was isolated as
carbamate 7 (Scheme 2). Alternatively, magnesium in methanol
can be used for this purpose after prior allylation of 2a. 1,2-
Adducts 2 can also be used to synthesize quaternary α-methyl
α-amino acids. In the fields of biochemistry and medicine, these
compounds are attracting increasing interest for the preparation
of modified peptides, which, due to their higher conformational
rigidity, have improved pharmacological properties and
In conclusion, we have developed the first enantioselective
1,2-addition of methyl- and arylaluminum reagents to cyclo-
alkenone-derived N-tosyl imines, yielding α-tertiary allylamides.
The applied Rh(I)/Binap catalyst can also result in
enantioselective 1,4-additions to these substrates, and both
1,2- and 1,4-adducts are interesting building blocks for
biologically important targets. Moreover, the reversed facial
selectivity and the regiodivergence observed with ketimine (R)-
3164
dx.doi.org/10.1021/ol501372u | Org. Lett. 2014, 16, 3162−3165

Organic Letters
Letter
(8) For diastereoselective additions to chiral N-sulfinyl ketimines,
see: (a) Guo, T.; Song, R.; Yuan, B.-H.; Chen, X.-Y.; Sun, X.-W.; Lin,
G.-Q. Chem. Commun. 2013, 49, 5402. (b) Sirvent, J. A.; Foubelo, F.;
Yus, M. Chem. Commun. 2012, 48, 2543. (c) McMahon, J. P.; Ellman,
J. A. Org. Lett. 2004, 6, 1645. (d) Cogan, D. A.; Ellman, J. A. J. Am.
Chem. Soc. 1999, 121, 268.
(9) (a) Salvadore, G.; Singh, J. B. CNS Neurosci. Ther. 2013, 19, 428.
(b) Childers, W. E.; Baudy, R. B. J. Med. Chem. 2007, 50, 2557.
(c) Hirbec, H.; Gaviria, M.; Vignon, J. CNS Drug Rev. 2001, 7, 172.
(d) Haas, D. A.; Harper, D. G. Anaesth. Prog. 1992, 39, 61.
(10) (a) Kolb, A.; Zuo, W.; Siewert, J.; Harms, K.; von Zezschwitz, P.
Chem.Eur. J. 2013, 19, 16366. (b) Kolb, A.; Hirner, S.; Harms, K.;
von Zezschwitz, P. Org. Lett. 2012, 14, 1978. (c) Siewert, J.;
Sandmann, R.; von Zezschwitz, P. Angew. Chem., Int. Ed. 2007, 46,
7122.
1d provide insight into the mechanisms of both addition
modes. We are now working on gaining a better understanding
of the catalytic cycles and on optimizing the asymmetric
conjugate addition of alkyl and aryl groups.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analytical data for all compounds;
crystallographic data for compounds (S)-2a, (1S,5S)-2d, (S)-4a,
and (1R,4S)-5e. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(11) For reviews, see: (a) Kolb, A.; von Zezschwitz, P. Top.
Organomet. Chem. 2013, 41, 245. (b) von Zezschwitz, P. Synthesis
2008, 1809. (c) Oishi, M. Sci. Synth. 2004, 7, 261.
*E-mail: zezschwitz@chemie.uni-marburg.de.
Notes
(12) Hirner, S.; Westmeier, J.; Gebhardt, S.; Muller, C. H.; von
̈
Zezschwitz, P. Synlett 2014, DOI: 10.1055/s-0034-1378203.
(13) For a preparation of compound 2a via enantioselective
aziridination and subsequent Wharton reaction, see: Jiang, H.;
Holub, N.; Jorgensen, K. A. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
20630.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This manuscript is dedicated to Professor Armin de Meijere on
the occasion of his 75th birthday. The authors thank the Bengt
Lundqvist Foundation, the Fonds der Chemischen Industrie,
and the Konrad-Adenauer-Stiftung for providing scholarships
for S.H., A.K., and J.W., respectively, and Sophie Schlondorff
for careful proofreading.
(14) For diastereoselective conjugate additions of cuprates to chiral
cyclic and acyclic ketimines or hydrazones, see: (a) Sammet, K.; Gastl,
C.; Baro, A.; Laschat, S.; Fischer, P.; Fettig, I. Adv. Synth. Catal. 2010,
352, 2281. (b) McMahon, J. P.; Ellman, J. A. Org. Lett. 2005, 7, 5393.
For asymmetric Cu-catalyzed conjugate additions of organozinc
reagents to acyclic imines, see: (c) Palacios, F.; Vicario, J. Org. Lett.
2006, 8, 5405. (d) Esquivias, J.; Arrayas, R. G.; Carretero, J. C. J. Org.
́
Chem. 2005, 70, 7451. (e) Soeta, T.; Kuriyama, M.; Tomioka, K. J.
Org. Chem. 2005, 70, 297.
(15) Caution: neat AlMe3 is highly pyrophoric; thus, we recommend
use of commercially available solutions of AlMe3 in hexanes if not
familiar with the handling of pyrophoric compounds.
(16) The N-tert-butylsulfonyl imine of cyclohex-2-enone underwent
1,2-addition of AlMe3 in a 32% yield with >99% ee while the respective
N-diphenylphosphinoyl imine was deprotonated by AlMe3. Use of
AlEt3 led to reduction of N-tosyl ketimine 1a, presumably due to β-
hydride elimination.
REFERENCES
■
(1) (a) Kang, S. H.; Kang, S. Y.; Lee, H.-S.; Buglass, A. J. Chem. Rev.
2005, 105, 4537. (b) Reynolds, T. Phytochemistry 2005, 66, 1399.
(c) Moldvai, I.; Temesvar
́
i-Major, E.; Incze, M.; Dornyei, G.;
̈
́
Szentirmay, E.; Szan
́
tay, C. Helv. Chim. Acta 2005, 88, 1344.
(2) Rearrangements: (a) Clayden, J.; Donnard, M.; Lefranc, J.;
Tetlow, D. J. Chem. Commun. 2011, 47, 4624. C,H-aminations:
(b) Collet, F.; Lescot, C.; Dauban, P. Chem. Soc. Rev. 2011, 40, 1926.
(c) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(3) For reviews about catalytic enantioselective additions to ketones
and ketimines, see: (a) Shibasaki, M.; Kanai, M. Chem. Rev. 2008, 108,
2853. (b) Connon, S. J. Angew. Chem., Int. Ed. 2008, 47, 1176.
(c) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873. For
reviews about such additions to C,N-double bonds in general, see:
(d) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev.
2011, 111, 2626. (e) Marques, C. S.; Burke, A. J. ChemCatChem. 2011,
3, 635. (f) Yamada, K.-i.; Tomioka, K. Chem. Rev. 2008, 108, 2874.
(4) (a) Fu, P.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2008, 130, 5530. (b) Lauzon, C.; Charette, A. B. Org. Lett. 2006, 8,
2743.
(17) Configuration determined by X-ray crystallographic analysis.
(18) For a related Rh(I)/Binap-catalyzed 1,4-addition of arylalumi-
num reagents to 3-substituted cycloalkenones, see: Hawner, C.;
Muller, D.; Gremaud, L.; Felouat, A.; Woodward, S.; Alexakis, A.
̈
Angew. Chem., Int. Ed. 2010, 49, 7769.
(19) This pair of 1,2- and 1,4-addition corresponds to an unsusual
regiodivergent reaction on a racemic mixture; see: Vedejs, E.; Jure, M.
Angew. Chem., Int. Ed. 2005, 44, 3974.
(20) For leading references, see: Zhou, J.; List, B. J. Am. Chem. Soc.
2007, 129, 7498.
(21) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
(22) (a) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron:
(5) (a) Nakamura, S.; Hyodo, K.; Nakamura, M.; Nakane, D.;
Masuda, H. Chem.Eur. J. 2013, 19, 7304. (b) Luo, Y.; Hepburn, H.
B.; Chotsaeng, N.; Lam, H. W. Angew. Chem., Int. Ed. 2012, 51, 8309.
(c) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687.
(6) (a) Yin, L.; Otsuka, Y.; Takada, H.; Mouri, S.; Yazaki, R.;
Kumagai, N.; Shibasaki, M. Org. Lett. 2013, 15, 698. (b) Huang, G.;
Yang, J.; Zhang, X. Chem. Commun. 2011, 47, 5587.
Asymmetry 2007, 18, 569. (b) Vogt, H.; Brase, S. Org. Biomol. Chem.
̈
2007, 5, 406.
(23) Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org. Lett.
2003, 5, 1031.
(24) Long, Y.-Q.; Xue, T.; Song, Y.-L.; Liu, Z.-L.; Huang, S.-X.; Yu,
Q. J. Med. Chem. 2008, 51, 6371.
(7) (a) Yang, G.; Zhang, W. Angew. Chem., Int. Ed. 2013, 52, 7540.
(b) Nishimura, T.; Noishiki, A.; Ebe, Y.; Hayashi, T. Angew. Chem., Int.
Ed. 2013, 52, 1777. (c) Wang, H.; Jiang, T.; Xu, M.-H. J. Am. Chem.
Soc. 2013, 135, 971. (d) Nishimura, T.; Ebe, Y.; Fujimoto, H.; Hayashi,
T. Chem. Commun. 2013, 49, 5504. (e) Luo, Y.; Carnell, A. J.; Lam, H.
W. Angew. Chem., Int. Ed. 2012, 51, 6762. (f) Nishimura, T.; Noishiki,
A.; Chit Tsui, G.; Hayashi, T. J. Am. Chem. Soc. 2012, 134, 5056.
(g) Shintani, R.; Takeda, M.; Soh, Y.-T.; Ito, T.; Hayashi, T. Org. Lett.
2011, 13, 2977. (h) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J.
Am. Chem. Soc. 2010, 132, 13168.
3165
dx.doi.org/10.1021/ol501372u | Org. Lett. 2014, 16, 3162−3165