Chiral Magnesium Bisphosphate-Catalyzed Asymmetric Double C(sp3)-H Bond Functionalization Based on Sequential Hydride Shift/Cyclization Process

Article abstract of DOI:10.1021/jacs.8b02761

Described herein is a chiral magnesium bisphosphate-catalyzed asymmetric double C(sp³)-H bond functionalization triggered by a sequential hydride shift/cyclization process. This reaction consists of stereoselective domino C(sp³)-H bond functionalization: (1) a highly enantio- and diastereoselective C(sp³)-H bond functionalization by chiral magnesium bisphosphate (first [1,5]-hydride shift), and (2) a highly diastereoselective C(sp³)-H bond functionalization by an achiral catalyst (Yb(OTf)₃, second [1,5]-hydride shift).

Full text of DOI:10.1021/jacs.8b02761

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Chiral Magnesium Bisphosphate Catalyzed Asymmetric Double C(sp)–H Bond
Functionalization Based on Sequential Hydride Shift/Cyclization Process
Keiji Mori, Ryo Isogai, Yuto Kamei, Masahiro Yamanaka, and Takahiko Akiyama
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02761 • Publication Date (Web): 09 May 2018
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Chiral Magnesium Bisphosphate Catalyzed Asymmetric Dou-
ble C(sp3)–H Bond Functionalization Based on Sequential Hy-
dride Shift/Cyclization Process
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Keiji Mori,‡* Ryo Isogai,† Yuto Kamei,§ Masahiro Yamanaka,§ and Takahiko Akiyama†*
† Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
‡ Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-
24-16 Nakacho, Koganei, Tokyo 184-8588, Japan
§
Department of Chemistry and Research Center for Smart Molecules, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-
ku, Tokyo 171-8501, Japan
Supporting Information Placeholder
doles,4n,6n and indanes,7c,f could be constructed by processes
involving a [1,n]-hydride shift (n = 4, 5, 6). Quite recently,
ABSTRACT: Described herein is a chiral magnesium
bisphosphate catalyzed asymmetric double C(sp3)–H bond
our group accomplished the application of this strategy to an
unprecedented double C(sp3)–H bond functionalization (se-
quential hydride shift system).8 The sequential [1,n]-[1,5]-
hydride shift (n = 4, 6)/cyclization processes realized the high-
ly diastereoselective synthesis of complex polycyclic frame-
works, such as bicyclo[3.2.2]nonanes and linear tricyclic com-
pounds. The catalyzed asymmetric variant of the sequential
system would be a promising tool for the rapid construction of
multi-substituted chiral tricyclic frameworks that would act as
a lead structure in important biologically active compounds.
Nevertheless, to the best of our knowledge, there is no prece-
dent for the catalytic, enantioselective variant of the double
C(sp3)–H bond functionalization involving a sequential hy-
dride shift/cyclization process.
functionalization triggered by
a
sequential hydride
shift/cyclization process. This reaction consists of stereoselec-
tive domino C(sp3)–H bond functionalization: (1) a highly
enantio- and diastereoselective C(sp3)–H bond functionaliza-
tion by chiral magnesium bisphosphate (first [1,5]-hydride
shift), and (2) a highly diastereoselective C(sp3)–H bond func-
tionalization by an achiral catalyst (Yb(OTf)3, second [1,5]-
hydride shift).
The direct functionalization of an unreactive C–H bond is a
powerful methodology for rapidly accessing useful organic
molecules.1 Because of the high synthetic potential of the
methodology, extensive efforts have been devoted to the de-
velopment of new strategies. Recently, the C(sp3)–H bond
functionalization mediated by a hydride shift/cyclization pro-
cess, namely, the “internal redox process”, has attracted much
attention because of its unique features (Scheme 1).2 The key
feature of this transformation is the [1,5]-hydride shift of the
C(sp3)–H bond α to the heteroatom. Subsequent 6-endo cy-
clization to cationic species A affords fused heterocycle 2.3–6
We wish to report herein an asymmetric double C(sp3)–H
bond functionalization catalyzed by chiral magnesium
bisphosphate (Figure 1). This reaction consists of two succes-
sive stereoselective C(sp3)–H bond functionalizations: (1) a
highly enantio- and diastereoselective C(sp3)–H bond func-
tionalization by chiral magnesium phosphate (first [1,5]-
hydride shift), and (2) a highly diastereoselective C(sp3)–H
Scheme 1. C(sp3)–H functionalization by the internal redox
process.
Recent efforts by us7 and other groups3–6 have led to the
unveiling of the high synthetic potential of this methodology;
useful skeletons, such as tetrahydroquinolines,3 tetrahydroiso-
quinolines,4o,7e benzopyrans,4i,7b tetralins,4h,7c,d, spirooxin-
Figure 1. Asymmetric double C(sp3)–H bond functionaliza-
tion via sequential hydride shift processes.
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bond functionalization by an achiral catalyst (second [1,5]-
ee for the major diastereomer). The relative and absolute ste-
reochemistries of these products were surmised as depicted in
Figures 1–3 by analogy to 8c, whose absolute stereochemistry
was unambiguously established by single-crystal X-ray analy-
sis.
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hydride shift). The combination of these two stereoselective
reactions enabled the highly enantio- and diastereoselective
synthesis of fused tricyclic piperidine derivatives.
The desired asymmetric double C(sp3)–H bond functionali-
zation was realized by chiral magnesium bisphosphate 3 (Fig-
ure 2).9–12 Upon treatment of cinnamylidene malonate 4 with
10 mol% of 3 bearing bulky 2,4,6-tricyclohexylphenyl groups
at 3,3'-positions in mesitylene at 60 °C for 96 h, the desired
sequential reaction proceeded smoothly to give tricyclic piper-
idine 5 in 74% yield with 87% ee. Although both chemical
yield and enantioselectivity were reasonable, diastereoselectiv-
ity remained moderate (d.r. = 4.9:1).13 The determination of
the absolute configuration offered an important clue to over-
come this drawback. Subjecting p-bromobenzyl analog 6a to
the optimized reaction conditions gave single hydride
shift/cyclization adduct 7a exclusively (83%) without the for-
mation of expected tricyclic piperidine 8a. The diastereomeric
ratio could not be determined at this stage because of the
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broad nature of the H NMR spectrum of 7a. The complete
suppression of the second hydride shift process was rational-
ized by the electronic effect: the electron-deficient aryl-
substituted N-benzyl group retarded the [1,5]-hydride shift.7d
The second hydride shift/cyclization process of 7a proceeded
smoothly by using 10 mol% of achiral catalyst Yb(OTf)3 un-
der slightly modified reaction conditions (in ClCH2CH2Cl at
60 °C for 0.5 h) to furnish 8a in 96% yield. Gratifyingly, both
diastereoselectivity (d.r. = 11.5:1) and enantioselectivity (96%
ee) of the major diastereomer were improved significantly. It
should be noted that the process starting from 6a with a p-
bromobenzyl group would be effective for overriding the two
disadvantages (requirement of two-step sequence and use of
two different (chiral, achiral) catalysts).
Figure 3. Substrate scope.
The above results clearly indicate the involvement of two
stereoselective C(sp3)–H bond functionalizations, as shown in
Figure 1: (1) a highly enantio- and diastereoselective C(sp3)–H
bond functionalization by chiral magnesium bisphosphate
(first [1,5]-hydride shift), and (2) a highly diastereoselective
C(sp3)–H bond functionalization by Yb(OTf)3 (second [1,5]-
hydride shift), with the former one being the key stereo-
controlling step.14 To gain a deeper insight into the stereo-
chemical outcome, we conducted DFT calculations using sim-
plified and realistic models of the first [1,5]-hydride
shift/cyclization process (Figure 4).15,16
O
O
simplified model
realistic model
MeO
OMe
Ar
Ph
Ar
O
O
O
P
O
O
O
P
O
O
Mg
Mg
N
Ph
Ar
R
R
Ar
2
2
Ar = 2,4,6-Cy3C6H2
submodel : R = H, Ar = Ph
subreal : R = Me, Ar = 4-BrC6H4
PAmodel
PAreal
Figure 4. Chemical models for DFT calculations.
Based on our previous computational study,8 the detailed
reaction pathway of the first [1,5]-hydride shift/cyclization
process was investigated using simplified models. After ex-
ploring various conformations corresponding to the free rota-
tion of three C-N bonds and the chair/boat-like six-membered
ring structures in the transition state (TS), we found the most
energetically favorable reaction pathway affording the major
product in a stereoselective manner (Figure 5). The [1,5]-
hydride shift process via TS1 located at the highest energy
level was identified as the rate- and stereo-determining step, in
good agreement with the results of D-labeling experiments
(kD/kH = 2.5, Scheme S3 in Supporting Information (SI)). The
subsequent cyclization process was found to smoothly proceed
through the lower-energy TS2 without any conformational
change. Hydrogen bonds between the phosphoryl oxygen and
the N-benzyl group controlled the relative orientation of elec-
tron-deficient olefin and amine moieties through the [1,5]-
hydride shift/cyclization process. Whereas these structural
Figure 2. Excellent stereoselective reaction by two-step se-
quence.
Having acquired the highly diastereo- and enantioselective
double C(sp3)–H bond functionalization protocol, the substrate
scope of the two-pot reaction was examined (Figure 3). Nei-
ther electron-donating groups (Me and OMe) nor electron-
withdrawing group (F) affected the reaction and corresponding
tricyclic piperidines (8a–g) were obtained in good chemical
yields with excellent diastereo- and enantioselectivities (d.r. =
>10:1, 92–96% ees for the major diastereomer). Naphthyl-
type substrate 8h was also suitable and both enantio- and dia-
stereoselectivities were likewise excellent (d.r. = >20:1, 95%
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features were also observed in other diastereomeric TSs lead-
shift), and (2) a highly diastereoselective C(sp3)–H bond func-
tionalization by an achiral catalyst (second hydride shift). The
key to achieving excellent enantioselectivity was the employ-
ment of a benzyl group having an electron-withdrawing moie-
ty. Various substrates were applicable to this asymmetric re-
action and corresponding tricyclic piperidines were obtained
in good chemical yields and with excellent diastereo- and en-
antioselectivities (d.r. = >10:1, 91–96% ees for the major dia-
stereomer). DFT calculations revealed that the cooperative
action of the hydrogen bond and the narrow chiral space con-
tributes to stereoinduction in the stereodetermining first [1,5]-
hydride shift process. Further investigations for the develop-
ment of another chiral transformation by exploiting this type
of sequential reaction are under way in our laboratory.
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ing to minor enantiomer and diastereomers in the [1,5]-
hydride shift process, TS1 was the most stable (Figure S3,
Table S2 in SI).
Mg
Mg
O
O
O
O
MeO
OMe
Mg
MeO
OMe
O
O
H
MeO
OMe
Bn
PAmodel
+
submodel
TS1
(+8.5)
NBn2
NBn2
9
TS2
(-1.9)
N
RT
(0.0)
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Bn
Mg
CP2
(-4.8)
O
H
O
MeO
OMe
RT
(-10.6)
PD
(-13.8)
NBn2
H
ASSOCIATED CONTENT
Supporting Information
Figure 5. Gibbs free energy profile of the [1,5]-hydride
shift/cyclization process (in kcal/mol). Sum of submodel and
PAmodel is set to zero.
Experimental procedures, analytical and spectroscopic data for
new compounds, and copies of NMR spectra and HPLC chart.
These materials are available free of charge via the Internet at
http://pubs.acs.org.
Focusing on the rate- and stereo-determining TS1, the origin
of the high enantioselectivity was further addressed using real-
istic models (TSmajor and TSminor affording major and minor
enantiomers, respectively, Figure 6). TSmajor is 2.4 kcal/mol
more stable than TSminor, in good agreement with the experi-
mentally observed stereochemical outcome. The introduction
of considerably bulky 2,4,6-tricyclohexylphenyl groups (or-
ange) provides a narrow chiral space to position the substrate
at the center of the chiral space. The hydrogen bond between
the phosphoryl oxygen and the N-benzyl group plays a key
role in holding the amine moiety in a suitable position for the
sequential [1,5]-hydride shift/cyclization process. Either one
of the two N-benzyl groups (red or blue) coordinates with the
phosphoryl oxygen depending on the selective hydride shift of
prochiral hydrogen atoms. The substrate fits better into the
narrow chiral space in TSmajor than in TSminor. In the energeti-
cally less favorable TSminor, the magnesium bisphosphate cata-
lyst and the malonate moiety were structurally distorted due to
the considerably bulky 3,3'-substituents (Figure S4 in SI).
AUTHOR INFORMATION
Corresponding Author
k_mori@cc.tuat.ac.jp
takahiko.akiyama@gakushuin.ac.jp
ORCID
Keiji Mori: 0000-0002-9878-993X
Masahiro Yamanaka: 0000-0001-7978-620X
Takahiko Akiyama: 0000-0003-4709-4107
ACKNOWLEDGMENT
We thank Dr. Koya Inomata and Professor Kunio Mochida of
Gakushuin University for X-ray analysis. This work was partially
supported by Grants-in-Aid for Scientific Research (B) (26288053,
17KT0011, and 17H03060) from the Japan Society for the Pro-
motion of Science, and grants from The Uehara Memorial Foun-
dation, The Naito Foundation, and Inoue Foundation of Science.
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(10) For reviews on chiral phosphoric acid catalysis, see: (a) Akiyama, T.;
Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999. (b) Akiyama,
T. Chem. Rev. 2007, 107, 5744. (c) Terada, M. Chem. Commun.
2008, 4097. (d) Terada, M. Synlett, 2010, 1929. (e) Zamfir, A.;
Schenker, S.; Freund, M.; Tsogoeva, S. M. Org. Biomol. Chem. 2010,
8, 5262. (f) Terada, M. Curr. Org. Chem. 2011, 15, 2227. g) Rueping,
M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539. (h)
Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114,
9047. (i) Yang, Z.-P.; Zhang, W.; You, S.-L. J. Org. Chem. 2014, 79,
7785. (j) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev.
2017, 117, 10608. (k) Merad, J.; Lalli, C.; Bernadat, G.; Maury, J.;
Masson, G. Chem. Eur. J. 2018, 24, 3925.
(11) For recent reviews combining metals and Brønsted acids, see: (a)
Lacour, J.; Moraleda, D. Chem. Commun. 2009, 7073. (b) Shao, Z.
H.; Zhang, H. B. Chem. Soc. Rev. 2009, 38, 2745. (c) Rueping, M.;
Koenigs, R. M.; Atodiresei, I. Chem. Eur. J. 2010, 16, 9350. (d)
Hashmi, A. S. K.; Hubbert, C. Angew. Chem. Int. Ed. 2010, 49, 1010.
(e) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem. 2012, 4,
603. (f) Parra, A.; Reboredo, S.; Martín Castroa, A. M.; Aleman, J.
Org. Biomol. Chem. 2012, 10, 5001. (g) Mahlau, M.; List, B. Angew.
Chem. Int. Ed. 2013, 52, 518. (h) Brak, K.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2013, 52, 534. (i) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-
L.; Gong, L.-Z. Acc. Chem. Res. 2014, 47, 2365.
(12) Asymmetric reaction with chiral magnesium bisphosphate, see: (a)
Ingle, G. K.; Liang, Y.; Mormino, M.; Li, G.; Fronczek, F. R.; Antil-
la, J. C. Org. Lett. 2011, 13, 2054. (b) Larson, S. E.; Li, G.; Rowland,
G. B.; Junge, D.; Huang, R.; Woodcock, H. L.; Antilla, J. C. Org. Lett.
2011, 13, 2188. (c) Li, G.; Liang, T.; Wojtas, L.; Antilla, J. C. Angew.
Chem. Int. Ed. 2013, 52, 4628. (d) Sala, G. D. Tetrahedron 2013, 69,
50. See also, ref 6f,g.
(13) Only two diastereomers were observed in this reaction even though 5
have three stereogenic centers.
1
(14) Judged by H NMR analysis, relative stereochemistries of the two
diastereomers of 5 were determined to be cis and trans in the ring
junction (JH-H = 10.8 Hz in 5a, JH-H = 3.2 Hz in 5b). These results
further support our proposal, in which stereoselectivity was mostly
determined at the first hydride shift/cyclization process.
(6) For examples of enantioselective internal redox reactions, see: (a)
Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2009,
131, 13226. (b) Kang, Y. K.; Kim, S. M.; Kim, D. Y. J. Am. Chem.
Soc. 2010, 132, 11847. (c) Cao, W.; Liu, X.; Wang, W.; Lin, L.;
Feng, X. Org. Lett. 2011, 13, 600. (d) Zhou, G.; Liu, F.; Zhang, J.
Chem. Eur. J. 2011, 17, 3101. (e) He, Y.-P.; Du, Y.-L.; Luo, S.-W.;
Gong, L. Z. Tetrahedron Lett. 2011, 52, 7064. (f) Chen, L.; Zhang,
L.; Lv, Z.; Cheng, J.-P.; Luo, S. Chem. Eur. J. 2012, 18, 8891. (g)
Zhang, L.; Chen, L.; Lv, Z.; Cheng, J.-P.; Luo, S. Chem. Asian J.
2012, 7, 2569. (h) Jiao, Z.-W.; Zhang, S.-Y.; He, C.; Tu, Y.-Q.;
Wang, S.-H.; Zhang, F.-M.; Zhang, Y.-Q.; Li, H. Angew. Chem. Int.
Ed. 2012, 51, 8811. (i) Kang, Y. K.; Kim, D. Y. Adv. Synth. Catal.
2013, 355, 3131. (j) Suh, C. W.; Woo, S. B.; Kim, D. Y. Asian J.
Org. Chem 2014, 3, 399. (k) Kang, Y. K.; Kim, D. Y. Chem. Com-
mun. 2014, 50, 222. (l) Suh, C. W.; Kim, D. Y. Org. Lett. 2014, 16,
5374. (m) Yu, J.; Li, N.; Chen, D.-F.; Luo, S.-W. Tetrahedron Lett.
2014, 55, 2859. (n) Cao, W.; Liu, X.; Guo, J.; Lin, L.; Feng, X.
Chem. Eur. J. 2015, 21, 1632. See also, ref 7i.
(15) Computational details are shown in supporting information.
(16) Selected examples of theoretical study of chiral phosphoric acid
catalysis: (a) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am.
Chem. Soc. 2007, 129, 6756. (b) Simón, L.; Goodman, J. M. J. Am.
Chem. Soc. 2008, 130, 8741. (c) Marcelli, T.; Hammar P.; Himo, F.
Chem. Eur. J. 2008, 14, 8562. (d) Yamanaka, M.; Hirata, T. J. Org.
Chem. 2009, 74, 3266. (e) Simón, L.; Goodman, J. M. J. Org. Chem.
2011, 76, 1775. (f) Mori, K.; Ichikawa, Y.; Kobayashi, M.; Shibata,
Y.; Yamanaka, M.; Akiyama,T. J. Am. Chem. Soc. 2013, 135, 3964.
(g) Reid, J. P.; Goodman, J. M. J. Am. Chem. Soc. 2016, 138, 7910.
(h) Champagne, P. A.; Houk, K. N. J. Am. Chem. Soc. 2016, 138,
12356. (i) Li, F.; Korenaga, T.; Nakanishi, T.; Kikuchi, J.; Terada, M.
J. Am. Chem. Soc. 2018, 140, 2629. See also, ref 6f,g.
(7) For the internal redox reaction developed by our group, see: (a) Mori,
K.; Ohshima, Y.; Ehara, K.; Akiyama, T. Chem. Lett. 2009, 38, 524.
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O
O
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O
H
O
MeO
OMe
MeO
H
OMe
Ar
H
H
Yb(OTf)3
(10 mol %)
H
H
CO2Me
CO2Me
3 (10 mol %)
H
H
H
[1,5]-H shift
[1,5]-H shift
N
Ar
N
N
Ar
H
H
Ar
Ar
Ar
up to d.r. = >20:1, 96% ee
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highly enantio-, diastereo-
selective reaction
highly diastereoselective
reaction
Ar
Br
X
O
O
O
O
P
Mg
X
2
3
X = 2,4,6-Cy3C6H2
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