Asymmetric N–H insertion reaction with chiral aminoalcohol as catalytic core of Cinchona alkaloids

Article abstract of DOI:10.1248/cpb.c18-00795

In order to develop an efficient organocatalyst for the enantioselective N–H insertion reaction via carbene/carbenoid, the catalytic core of the cinchona alkaloids was investigated. According to our working hypothesis of an eight-membered ring transition

Full text of DOI:10.1248/cpb.c18-00795

Vol. 67, No. 4
Chem. Pharm. Bull. 67, 393–396 (2019)
393
Note
Asymmetric N–H Insertion Reaction with Chiral Aminoalcohol as
Catalytic Core of Cinchona Alkaloids
,a
Hideyuki Shinohara,a,b Hiroaki Saito,* Taketo Uchiyama,a Muneharu Miyake,a and
Shinichi Miyairia
a School of Pharmacy, Nihon University; 7–7–1 Narashinodai, Funabashi, Chiba 274–8555, Japan: and b Yamagata
Prefectural Institute of Public Health; 1–6–6 Tohkamachi, Yamagata-shi, Yamagata 990–0031, Japan.
Received October 11, 2018; accepted January 11, 2019
In order to develop an efficient organocatalyst for the enantioselective N–H insertion reaction via
carbene/carbenoid, the catalytic core of the cinchona alkaloids was investigated. According to our working
hypothesis of an eight-membered ring transition state in the N–H insertion reaction, two pairs of enantiomers
related to 2-amino-1-phenylethanol were investigated for their chiral inducing potential. Since both (1R,2S)-
isomers gave the N-phenyl-1-phenylglycine derivative enriched in the R-form, while their enantiomers gave
the S-form, the 2-amino-1-phenylethanol structure is concluded to be the catalytic core of the cinchona
alkaloid in the enantioselective N–H insertion reaction via rhodium(II) carbenoid.
Key words N–H insertion reaction; carbenoid; cooperative catalysis; organocatalyst; aminoalcohol
loid.10,17) The highly reactive carbene or carbenoid was gener-
Introduction
The stereoselective N–H insertion reaction is one of the ated from phenyldiazoacetate by heating17) or treating with a
most attractive subjects in medicinal chemistry because dirhodium(II) complex,10) respectively. Since the enriched (R)-
pharmacological events of amino compounds depend on chi- phenylglycine derivative was produced by hydrocinchonine,
rality.1–3) While highly stereoselective C–H and Si–H inser- whereas its pseudo-isomer, hydrocinchonidine, predominantly
tion reactions using α-diazocarbonyl compounds have been gave the (S)-form, we concluded that the chiral induction
achieved by well-defined rhodium(II) carboxylates4–6) and in these N–H insertion reactions was solely dependent on
carboxamides7) as chiral catalysts, there are a few examples the chirality of the cinchona alkaloid. This chiral induction
of enantioselective N–H insertion reactions initiated by suggests that the carbene/carbenoid forms an ammonium
rhodium(II) complexes using either chiral catalysis8,9) or coop- ylide with aniline, which then undergoes a [1,2]-proton shift
erative catalysis.10–13) In cooperative catalysis for X–H (X=N, through an eight-membered ring transition state, as shown in
O, etc.) insertion reactions, cinchona alkaloids or chiral phos- Fig. 1. In order to optimize an efficient artificial organocata-
phoric acids are used in combination with achiral rhodium(II) lyst, we planned to clarify the catalytic core of the cinchona
carboxylates such as dirhodium(II) tetrakis(triphenylacetate), alkaloid in the carbene-driven N–H insertion reaction. Ac-
Rh2(TPA)4,10,11,13) or dirhodium(II) tetrakis(trifluoroacetate), cording to the structure of the transition state, the tert-amine
Rh2(TFA)4.12) Cinchona alkaloids have been used widely in and sec-alcohol moieties in the vicinal carbons are coordinat-
many types of organic transformations to generate products ed with ammonium and the anionic carbon in the ylide-type
with high optical purities.14,15) In addition to the naturally intermediate, respectively. The aromatic ring and quinuclidine
occurring cinchona alkaloids, semi-synthetic analogs have ex- moiety may cause the conformation of the catalyst to be rigid
hibited excellent utility in organic chemistry.16)
by steric hindrance and restrict the orientation of both the
amine and the alcohol. In this paper, we describe the potential
of the chiral 2-aminoethanol, which is functional groups in-
Results and Discussion
We previously reported the enantioselective N–H inser- cluded in the structure of hydrocinchonine (Fig. 2).
tion reaction on aniline with either a carbene or carbenoid
To investigate the minimum requirement of the cinchona
in the presence of a catalytic amount of a cinchona alka- alkaloid catalysts for the enantioselective N–H insertion reac-
tion, we chose two pairs of chiral 2-amino-1-phenylethanol de-
rivatives. One pair was (1R,2S)- and (1S,2R)-2-(dibutylamino)-
1-phenylpropan-1-ol (1a, 1b) and the other was (1R,2S)- and
Fig. 1. Eight Membered-Ring Transition State
Fig. 2. Catalytic Core Structure of Hydrocinchonine
*To whom correspondence should be addressed. e-mail: saito.hiroaki@nihon-u.ac.jp
© 2019 The Pharmaceutical Society of Japan

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Table 1. Enantioselective N–H Insertion Reaction of Phenyldiazoacetate and Aniline Using Rh(II) and Chiral 2-Amino-1-phenylethanol Derivativesa)
α-Amino esters
Entry
Rh(Il)
Organocatalyst (mol%)
Aniline (equiv.)
Solvent
Yield, %b)
Ee, %c)
1
2
Rh2(TPA)4
Rh2(TPA)4
Rh2(TPA)4
Rh2(TPA)4
Rh2(TPA)4
Rh2(TPA)4
Rh2(TPA)4
Rh2(TPA)4
Rh2(TPA)4
Rh2(TPA)4
Rh2(TPA)4
Rh2(TPA)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(R-PTTL)4
Rh2(TPA)4
Rh2(TPA)4
Rh2(TPA)4
Hydrocinchonine (1)
la (10)
la (10)
la (10)
la (10)
la (5)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.0
5.0
1.2
1.2
1.2
1.2
1.2
1.2
CH2Cl2
CH2Cl2
CHC13
Toluene
Hexane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
83
96
87
91
45
97
99
95
75
92
88
74
86
89
89
96
93
88
58 (R)
48 (R)
33 (R)
44 (R)
21 (R)
50 (R)
51 (R)
45 (R)
39 (R)
45 (R)
45 (R)
38 (R)
43 (R)
rac
3
4
5
6
7
la (2)
8
la (1)
9d)
10e)
11
12
13
14
15
16
17
18
la (2)
la (2)
la (2)
la (2)
la (2)
—
la (2)
46 (R)
51 (S)
31 (R)
33 (S)
lb (2)
2a (2)
2b (2)
a) All the reactions were carried out as follows; A mixture of diazocompound 3 (0.2mmol) and aniline in the indicated solvent (2mL) was added to a solution of Rh(II)
complex and organocatalyst in the same solvent (2mL). b) Isolated yield. c) Determined by HPLC (Daicel Chiralpak AD-H). d) The reaction was carried out at 0°C. e) The
reaction was carried out at reflux.
Fig. 3. Structures of Organocatalysts and Rhodium Complexes
(1S,2R)-1-phenyl-2-(pyrrolidin-1-yl)propan-1-ol (2a, 2b)18,19)
(Fig. 3). Fortunately, when the rhodium carbenoid gener-
ated from methyl phenyldiazoacetate (3a) and dirhodium(II)
tetrakis(triphenylacetate) [Rh2(TPA)4, 1mol%] was subjected
to the N–H insertion reaction with aniline (4a) in the presence
of a (1R,2S)-aminoalcohol, methyl 2-phenyl-2-(phenylamino)-
acetate (5a) was obtained enriched in the R-isomer (Table 1).
Methylene chloride was found to be the most suitable solvent
among the four solvents tested, and the highest chemical
Fig. 4. Proposed Transition State for N–H Insertion Reaction
yields (99%) with enantioselectivities (51%) were observed
when 2mol% of 1a and 1.2eq of aniline were used (Entry 7). chloride, the chemical yield and enantioselectivity decreased
Interestingly, when the reaction was conducted at 0°C, the slightly (Entries 7 vs. 10).
enantioselectivity decreased to 39% enantiomeric excess (ee),
Next, we addressed whether the chirality of the rhodium
as did the chemical yield (Entries 7 vs. 9). When the reaction complex used for generating the carbenoid influenced the
temperature was increased to the boiling point of methylene chirality of the product. For this purpose, a pair of chiral

Vol. 67, No. 4 (2019)
Chem. Pharm. Bull.
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Table 2. Enantioselective N–H Insertion Reaction of Phenyldiazoacetate and Aniline Using Rh(II) and Chiral 2-Amino-1-phenylethanol Derivativesa)
Diazo
Aniline
α-Amino esters
Entry
R1
R2
Yield, %a)
Ee, %b)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3a
3a
3a
3a
3a
3a
Me
Et
4a
4a
4a
4b
4c
4d
4e
4f
H
H
5a
5b
5c
5d
5e
5f
99
51
43c)
42
40
45
45
41
40
94
isoBu
Me
Me
Me
Me
Me
Me
H
90
F
90
Cl
Br
I
94
94
93
5g
5h
Me
OMe
95
4g
No reaction
a) Isolated yield. b) Determined by HPLC (Daicel Chiralpak AD-H) unless otherwise stated. c) Determined by HPLC (Daicel Chiralcel OJ-H).
Chart 1
dirhodium(II) tetracarboxylates [Rh2(PTTL)4]20–24) was used The loss of enantioselectivity suggests the participation of
for the carbenoid generation. In the N–H insertion reaction the secondary hydroxyl group for the enantiomeric induction.
using either Rh2(S-PTTL)4 or Rh2(R-PTTL)4 in the presence of This result supports the proposed transition state as shown in
aminoalcohol (1a), the R-form of the product was generated in Fig. 4.
43% and 46% ee, respectively (Entries 13 and 15), while the
In summary, we have demonstrated a catalytic system of
N–H insertion reaction in the absence of aminoalcohol (2a) Rh2(TPA)4 and simple chiral aminoethanol is effective for
gave a racemic mixture (Entry 14). These results suggested enantiomeric induction in intermolecular N–H insertion reac-
that the chirality of the product is only due to the chirality tions. We are continuing to pursue more efficient catalytic
of the organocatalyst and that the rhodium complex does not systems in terms of enantioselectivities.
influence the formation of the eight-membered ring transition
state17) (Fig. 4). We compared the potential of four aminoal-
Acknowledgments This work was in part supported by
cohols (1a, 1b, 2a, 2b) as organocatalysts in the enantioselec- the “Private University Research Branding Project” from the
tive N–H insertion reaction. The chemical yields were nearly Ministry of Education, Culture, Sports, Science and Technol-
quantitative (88–99%) in all cases. In these reactions, (1R,2S)- ogy (MEXT). We thank Dr. Koichi Metori (Chemical Analysis
conformers (1a, 2a) gave the enriched R-enantiomer of 5a, Center, School of Pharmacy, Nihon University) for performing
51% ee with 1a and 31% ee with 2a (Entries 7 vs. 17), while mass measurements. We also thank Mr. Yudai Tanaka, Mr.
(1S,2R)-conformers (1b, 2b) gave the enriched S-enantiomer Yukio Fukuzono, and Mr. Syunta Tayama for technical as-
of 5a, 51% ee with 1b and 33% ee with 2b (Entries 16 vs. 18). sistance.
We then investigated the substrate scope of the reaction
with respect to the ester groups and aniline component (Table
Conflict of Interest The authors declare no conflict of
2). In all cases, high yield and similar degree of enantioselec- interest.
tivities were consistently observed. However, no reaction oc-
curred when p-anisidine was used (Entry 9).
Supplementary Materials The online version of this ar-
We performed additional study to obtain information on ticle contains supplementary materials.
the reaction mechanism. We prepared O-methyl analog (1c)
of β-aminoethanol catalyst.25) The N–H insertion product 5a
was obtained in 94% yield as a racemic compound (Chart 1).
References
1) Moody C. J., Angew. Chem. Int. Ed., 46, 9148–9150 (2007).

396
Chem. Pharm. Bull.
Vol. 67, No. 4 (2019)
2) Nicoud J.-F., Kagan H. B., Tetrahedron Lett., 12, 2065–2068 (1971).
3) Taber D. F., Berry J. F., Martin T. J., J. Org. Chem., 73, 9334–9339
(2008).
4) Ford A., Miel H., Ring A., Slattery C. N., Maguire A. R., McKervey
M. A., Chem. Rev., 115, 9981–10080 (2015).
14) Dolling U. H., Davis P., Grabowski E. J. J., J. Am. Chem. Soc., 106,
446–447 (1984).
15) O’Donnell M. J., Bennett W. D., Wu S., J. Am. Chem. Soc., 111,
2353–2355 (1989).
16) Saito H., Miyairi S., Curr. Top. Med. Chem., 14, 224–228 (2014).
5) Hashimoto S., Watanabe N., Anada M., Ikegami S., J. Synth. Org. 17) Saito H., Morita D., Uchiyama T., Miyake M., Miyairi S., Tetrahe-
Chem. Jpn. (Engl.), 54, 988–999 (1996).
dron Lett., 53, 6662–6664 (2012).
6) Davies H. M. L., Beckwith R. E. J., Chem. Rev., 103, 2861–2904 18) Soai K., Yokoyama S., Hayasaka T., J. Org. Chem., 56, 4264–4268
(2003).
(1991).
7) Doyle M. P., Duffy R., Ratnikov M., Zhou L., Chem. Rev., 110, 19) Soai K., Niwa S., Chem. Rev., 92, 833–856 (1992).
704–724 (2010).
20) Saito H., Oishi H., Kitagaki S., Nakamura S., Anada M., Hashimoto
S., Org. Lett., 4, 3887–3890 (2002).
21) Minami K., Saito H., Tsutsui H., Nambu H., Anada M., Hashimoto
S., Adv. Synth. Catal., 347, 1483–1487 (2005).
22) Natori Y., Tsutsui H., Sato N., Nakamura S., Nambu H., Shiro M.,
Hashimoto S., J. Org. Chem., 74, 4418–4421 (2009).
23) Ito M., Namie R., Krishnamurthi J., Miyamae H., Takeda K.,
Nambu H., Hashimoto S., Synlett, 25, 288–292 (2014).
24) Ito M., Kondo Y., Nambu H., Anada M., Takeda K., Hashimoto S.,
Tetrahedron Lett., 56, 1397–1400 (2015).
8) García C. F., McKervey M. A., Ye T., Chem. Commun., 1465–1466
(1996).
9) Buck R. T., Moody C. J., Pepper A. G., ARKIVOC, viii, 16–33
(2002).
10) Saito H., Uchiyama T., Miyake M., Anada M., Hashimoto S., Taka-
batake T., Miyairi S., Heterocycles, 81, 1149–1155 (2010).
11) Xu B., Zhu S.-F., Xie X.-L., Shen J.-J., Zhou Q.-L., Angew. Chem.
Int. Ed., 50, 11483–11486 (2011).
12) Xu B., Zhu S.-F., Zuo X.-D., Zhang Z.-C., Zhou Q.-L., Angew.
Chem. Int. Ed., 53, 3913–3916 (2014).
25) Mealy M. J., Luderer M. R., Bailey W. F., Sommer M. B., J. Org.
Chem., 69, 6042–6049 (2004).
13) Guo J.-X., Zhou T., Xu B., Zhu S.-F., Zhou Q.-L., Chem. Sci, 7,
1104–1108 (2016).