Chiral-Organotin-Catalyzed Kinetic Resolution of Vicinal Amino Alcohols

Article abstract of DOI:10.1002/anie.201909700

A highly efficient kinetic resolution of racemic amino alcohols has been achieved for the first time with a chiral tin catalyst. A chiral organotin compound with 3,4,5-trifluorophenyl groups at the 3,3′-positions of the binaphthyl framework enabled this transformation with excellent yield and high enantioselectivity. The process tolerates aryl- and alkyl-substituted amino alcohols and a variety of other substrates, affording the corresponding products in high enantioselectivity and with s factors up to >500.

Full text of DOI:10.1002/anie.201909700

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201909700
German Edition: DOI: 10.1002/ange.201909700
Chiral Amino Alcohols
Chiral-Organotin-Catalyzed Kinetic Resolution of Vicinal Amino
Alcohols
Hui Yang and Wen-Hua Zheng*
Abstract: A highly efficient kinetic resolution of racemic
amino alcohols has been achieved for the first time with a chiral
tin catalyst. A chiral organotin compound with 3,4,5-trifluor-
ophenyl groups at the 3,3’-positions of the binaphthyl frame-
work enabled this transformation with excellent yield and high
enantioselectivity. The process tolerates aryl- and alkyl-sub-
stituted amino alcohols and a variety of other substrates,
affording the corresponding products in high enantioselectivity
and with s factors up to > 500.
activation of electrophiles by chiral catalysts (Scheme 1a).[8]
Among these methods, two main approaches have been
reported for this transformation. The first is activation of the
electrophile by
a
chiral nucleophilic catalyst.[8a–d,f] For
O
ptically active 1,2-amino alcohols are valuable and
important structural motifs found in a wide variety of
biologically active compounds (Figure 1).[1] They are also
Figure 1. Examples of pharmaceutical compounds bearing a chiral b-
amino alcohol moiety.
Scheme 1. Kinetic resolution of racemic 1,2-amino alcohols.
emerging as useful chiral building blocks and chiral ligands in
asymmetric synthesis.[2] As a consequence, the preparation of
chiral 1,2-amino alcohols, particularly by catalytically enan-
tioselective methods, has received much attention recently.[3–5]
Although the asymmetric Henry reaction[4] and asymmetric
aminohydroxylation[5] are known to be elegant methods for
the preparation of chiral amino alcohols, the development of
a further efficient access to these structural motifs is highly
desirable.
Kinetic resolution (KR) is a powerful strategy with which
to obtain optically pure molecules, and it has been widely
used in industry and academia.[6] Although highly enantiose-
lective approaches for non-enzymatic KR of secondary
alcohols have been achieved in recent years,[7] practical
methods capable of delivering 1,2-amino alcohols with high
enantioselectivity are much less common.[8] Conventional
strategies for KR of amino alcohols is typically achieved with
instance, chiral DMAP derivatives, oligopeptides bearing N-
methyl imidazole, and chiral N-heterocyclic carbenes (NHCs)
have been used in catalytic KR of amino alcohols. Another
recently developed approach is the activation of electrophiles
by chiral phosphoric acid derivatives through an ion-pair
mechanism or hydrogen-bonding interactions.[8e,g,h] In sharp
contrast, highly efficient KR of amino alcohols through
activation of nucleophiles by chiral catalysts has been rarely
reported.
Organotin reagents are widely used in organic synthesis.[9]
For example, Bu3SnH is an important reagent in radical
reactions[9] and Bu2SnO/Bu2SnX2 has been found to be highly
useful in regioselective modification of hydroxyl groups in
carbohydrate synthesis.[10] However, studies on chiral organo-
tin reagents are sparse and consequently, highly enantiose-
lective transformations catalyzed by chiral organotin are
extremely limited.[11] Pioneering works by Otera[11a] and
Matsumura[11b,e] developed desymmetrization and kinetic
resolution of diols catalyzed by chiral organotin compounds
based on a binaphthyl framework, but the reaction is not
particularly enantioselective. Subsequently, Yanagisawa
et al.[11d] synthesized a series of 3,3’-subsituted BINOL-
derived chiral organotin catalysts which were used success-
fully in aldol reactions and Mannich reactions. Inspired by
these advances, and with the goal of developing efficient
[*] H. Yang, Prof. Dr. W.-H. Zheng
State Key Laboratory of Coordination Chemistry
Jiangsu Key Laboratory of Advanced Organic Materials
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing 210023 (China)
E-mail: wzheng@nju.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201909700.
Angew. Chem. Int. Ed. 2019, 58, 1 – 5
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
selective modification of alcohols,[12] we sought to design
a novel route to chiral 1,2-amino alcohols. Although forma-
tion of stannylene N,O-aminal have been reported,[13] the
utilization of this intermediate (Scheme 1b) is unexplored.
We assumed that if a chiral stannylene N,O-aminal inter-
mediate could be formed, kinetic resolution of 1,2-amino
alcohols could be achieved through reaction with an appro-
priate electrophile. Herein, we report the first highly enan-
tioselective kinetic resolution of 1,2-amino alcohol mediated
by a chiral organotin catalyst.
Pursuing our hypothesis, we initiated a study of kinetic
resolution using racemic N-protected 2-amino-1-phenyletha-
nol (1) as a model substrate. A solution of a tosyl amino
alcohol (1a), benzoyl chloride (0.7 equiv), and K2CO3
(1 equiv) in THF was stirred at room temperature in the
presence of 2 mol% of an (S)-binaphthol-derived organotin
(Table 1). When the organotin compound (C1) without
substituents at the 3- and 3’-positions was used, the KR of
1a had low enantioselectivity and an s factor[14] of 1.9 (Table 1,
entry 1). This could be significantly improved through the
selection of catalysts bearing different steric and electronic
groups at the 3- and 3’-positions. Subsequently, a series of
chiral organotin compounds (C2–C8) were synthesized
according to Yanagisawaꢀs method[11d] and examined. Catalyst
C2 with phenyl groups at the 3- and 3’-positions gave a better
result, an s factor of 19.8 (entry 2). In further evaluation of
other catalysts (entries 3–8), C8 with 3,4,5-trifluorophenyl
groups at the 3- and 3’-positions gave the best enantioselec-
tivity with an excellent selectivity factor of 71.2 (entry 8).
Substrates with different protecting groups on the amino
group were examined. With Bz-1b (entry 9) and Cbz-1c
(entry 10) as substrates, no reaction or minimal conversion
were observed. We postulated that the acidity of the hydrogen
on the nitrogen is crucial for the transformation to proceed,
presumably because the acidity of NH with a Ts substituent
(1a) is low enough to be deprotonated by K2CO3. Similarly,
with Bs-1d (entry 11) and Ns-1e (entry 12) as substrates, the
KR proceeded well, albeit with a lower s factor. Further
optimization of the reaction conditions by changing the
solvent, the reaction temperature, base, and electrophile
failed to afford better results. The absolute configuration of
1e was unambiguously assigned to be (R).[15]
With the optimal conditions in hand, we next sought to
explore the scope of the new chiral-organotin-catalyzed KR
reaction. Moderate selectivity, an s factor < 20 in most cases,
had been found in previous enantioselective KR of arene-
substituted 1,2-amino alcohols.[8e,g] A variety of aromatic
substrates were examined, and all were found to generate the
corresponding products with high selectivity (Table 2, 1a–1k,
s factor up to 84). The variation in the electronic effect of the
phenyl substituent exerts little impact on the selectivity (1 f,
1g, 1h). A disubstituted substrate (1i) and an ortho-sub-
stituted substrate (1j) are also tolerated and provide the
corresponding products with high enantioselectivity. A sim-
ilar result was found using a 2-naphthyl compound (1k)
instead of the phenyl compound (1a). Notably, a vinyl-
substituted amino alcohol worked equally well, producing 1l
with an s factor of 32.3.
Highly enantioselective KR of 1,2-amino alcohols bearing
an acyclic primary alkyl or less hindered alkyl substituents at
the stereogenic center remains challenging. Primary alkyl
substrates 1m–1q were subjected to the optimal conditions.
All these compounds delivered the desired products with
excellent selectivity, and s factors in the range 27.6–45.5.
Remarkably, an extremely high s factor (s = 317) was
observed with a compound bearing a sterically demanding
tert-butyl group (1r). Compounds with a substituted alkyl
group are also tolerated, providing the corresponding prod-
ucts (1s and 1t), with excellent selectivity. We also found that
the functionalized alkyl substrate (1u) reacted smoothly to
afford the enantiomeric product, a reaction which could be
possibly applied in the synthesis of Toliprolol.[1b]
To further understand the stereocontrol factor of the
chiral organotin compound in this process, the diastereomers
syn-1v and anti-1w were subjected to the kinetic resolution
with the catalyst C8 (Scheme 2) anti-1w is a dramatically
superior substrate for the reaction, giving an extremely high
s value > 500, while s = 8.2 was obtained with syn-1v as
substrate.[8e] Additionally, the cyclic substrate 1x undergoes
efficient kinetic resolution with excellent selectivity. Further-
more, the amino alcohol with a primary hydroxyl group (1y)
was examined with p-anisoyl chloride as the acylation
reagent, and was found to provide the desired product with
good selectivity.[16]
Table 1: Optimization of reaction conditions.[a]
Entry
Cat.
PG
Conv.
[%]
er of 2
er of 1r
s
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C8
C8
C8
C8
C8
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Bz (1b)
Cbz (1c)
Bs (1d)
Ns (1e)
65
46
55
55
58
53
52
51
59:41
90.5:9.5
89:11
91:9
81:19
85:15
92:8
95.5:4.5
–
–
67:33
85:15
97:3
99.5:0.5
92:8
90:10
95.5:4.5
96.4:3.6
–
1.9
19.8
21.2
52.0
10.9
13.6
36.2
71.2
–
9
N.D.
<10
52
10
11b
12c
–
–
56.8
6.7
93.5:6.5
80.9:19.1
98.1:19.1
73.5:26.5
43
To further probe the crucial role of the N-H group in the
substrate, we conducted the reaction with an N-Me substrate
(1z) (Scheme 3) under the optimal conditions and found
essentially no reactivity, suggesting that successful formation
of stannylene N,O-aminal (Scheme 4) is possibly a pivotal
[a] Reaction conditions: 1 (0.1 mmol), BzCl (0.07 mmol), and catalyst
(2 mol%) in 1 mL THF at room temperature, 24 h. er, conv., and s-factor
were determined by HPLC on a chiral stationary phase. N.D.=Not
determined. [b] Bs=Benzenesulfonamide. [c] Ns=4-nitrobenzenesul-
fonamide.
2
www.angewandte.org
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2019, 58, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 2: Scope of the kinetic resolution of rac-amino alcohols.[a]
Scheme 2. Kinetic resolution of rac-1,2-amino alcohols.
Scheme 3. Control experiment.
[a] Reaction conditions: 1 (0.1 mmol), BzCl (0.07 mmol), and catalyst
(2 mol%) in 1 mLTHF at room temperature (1a–1l, 16 h, 1m–1u, 24 h).
er, conv., and s-factor were determined by HPLC on a chiral stationary
phase.
Scheme 4. Proposed reaction pathway.
aspect of this catalytic process. Based on the above experi-
ments and a literature survey,[10] the organotin-catalyzed
kinetic resolution of 1,2-amino alcohols could proceed
through the mechanism shown in Scheme 4. Complexation
of the chiral organotin compound with racemic amino alcohol
substrate (1) gives the diastereomers A and B. Intermediate A
is formed preferentially, because there is serious steric
repulsion between the R group and the aryl substituent on
the catalyst in the intermediate B. Subsequent acylation of A
affords the intermediate C. Ligand exchange with another
molecule of amino alcohol and consumption of the generated
HCl by K2CO3 delivers the product, while regenerating the
intermediate A or B.
In conclusion, we have developed the first organotin-
catalyzed highly enantioselective kinetic resolution of vicinal
amino alcohols under mild conditions. The reaction has broad
substrate scope, and provides a variety of aromatic and alkyl-
substituted 1,2-amino alcohols with high enantioselectivity.
Control experiments suggest that the stannylene N,O-aminal
might be a key intermediate. A plausible reaction pathway is
proposed and awaits confirmation through further experi-
ments. Further applications of this approach in organic
synthesis and detailed mechanistic studies are ongoing and
will be reported in due course.
Angew. Chem. Int. Ed. 2019, 58, 1 – 5
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
[7] For selected reviews on kinetic resolution of secondary alcohols,
see: a) E. Vedejs, M. Jure, Angew. Chem. Int. Ed. 2005, 44, 3974;
Angew. Chem. 2005, 117, 4040; b) C. E. Mꢂller, P. R. Schreiner,
Angew. Chem. Int. Ed. 2011, 50, 6012; Angew. Chem. 2011, 123,
6136; c) H. Yang, W.-H. Zheng, Tetrahedron Lett. 2018, 59, 583.
[8] a) S. J. Miller, G. T. Copeland, N. Papaioannou, T. E. Horst-
mann, E. M. Ruel, J. Am. Chem. Soc. 1998, 120, 1629; b) K.
Ishihara, Y. Kosugi, M. Akakura, J. Am. Chem. Soc. 2004, 126,
12212; c) P. Chen, J. Qu, J. Org. Chem. 2011, 76, 2994; d) S.
Kuwano, S. Harada, B. Kang, R. Oriez, Y. Yamaoka, K. Takasu,
K. Yamada, J. Am. Chem. Soc. 2013, 135, 11485; e) T. Yamanaka,
A. Kondoh, M. Terada, J. Am. Chem. Soc. 2015, 137, 1048; f) R.-
Z. Liao, S. Santoro, M. Gotsev, T. Marcelli, F. Himo, ACS Catal.
2016, 6, 1165; g) Y. Kuroda, S. Harada, A. Oonishi, H. Kiyama,
Y. Yamaoka, K. Yamada, K. Takasu, Angew. Chem. Int. Ed.
2016, 55, 13137; Angew. Chem. 2016, 128, 13331; h) S. Rajkumar,
S. He, X. Yang, Angew. Chem. Int. Ed. 2019, 58, 10315 – 10319;
Angew. Chem. 2019, 131, 10421 – 10425.
Acknowledgements
Generous financial support from National Natural Science
Foundation of China (21772086) and the Natural Science
Foundation of Jiangsu Province (BK20181254) is gratefully
acknowledged.
Conflict of interest
The authors declare no conflict of interest.
Keywords: amino alcohols · chiral resolution ·
kinetic resolution · organotin complexes
[9] A. G. Davis, M. Gielen, K. H. Pannell, E. R. Tiekink, Tin in
chemistry—Fundamentals, Frontiers and Applications, Wiley,
Chichester, 2008.
[10] a) M. J. Martinelli, N. K. Nayyar, E. D. Moher, U. P. Dhokte,
J. M. Pawlak, R. Vaidyanathan, Org. Lett. 1999, 1, 447; b) M. J.
Martinelli, R. Vaidyanathan, J. M. Pawlak, N. K. Nayyar, U. P.
Dhokte, C. W. Doecke, L. M. H. Zollars, E. D. Moher, V. V.
[1] a) S. C. Bergmeier, Tetrahedron 2000, 56, 2561; b) J. D. White, S.
Shaw, Org. Lett. 2012, 14, 6270; c) J. H. Schrittwieser, F. Coccia,
S. Kara, B. Grischek, W. Kroutil, N. dꢀAlessandro, F. Hollmann,
Green Chem. 2013, 15, 3318.
[2] D. J. Ager, I. Prakash, D. R. Schaad, Chem. Rev. 1996, 96, 835.
[3] For selected examples, see: a) S. Matsunaga, T. Yoshida, H.
Morimoto, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2004,
126, 8777; b) B. M. Trost, J. Jaratjaroonphong, V. Reutrakul, J.
Am. Chem. Soc. 2006, 128, 2778; c) J.-H. Xie, S. Liu, W.-L. Kong,
W.-J. Bai, X.-C. Wang, L.-X. Wang, Q.-L. Zhou, J. Am. Chem.
Soc. 2009, 131, 4222; d) A. B. Weinstein, D. P. Schuman, Z. X.
Tan, S. S. Stahl, Angew. Chem. Int. Ed. 2013, 52, 11867; Angew.
Chem. 2013, 125, 12083; e) L. J. Rono, H. G. Yayla, D. Y. Wang,
M. F. Armstrong, R. R. Knowles, J. Am. Chem. Soc. 2013, 135,
17735; f) K. Li, X. Shao, L. Tseng, S. J. Malcolmson, J. Am.
Chem. Soc. 2018, 140, 598; g) I. Cho, C. K. Prier, Z.-J. Jia, R. K.
Zhang, T. Gçrbe, F. H. Arnold, Angew. Chem. Int. Ed. 2019, 58,
3138; Angew. Chem. 2019, 131, 3170.
[4] a) H. Sasai, T. Suzuki, S. Arai, T. Arai, M. Shibasaki, J. Am.
Chem. Soc. 1992, 114, 4418; b) M. Shibasaki, H. Groger, M.
Kanai in Comprehensive Asymmetric Catalysis, Supplement
1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Heidelberg, 2004, pp. 131; c) C. Claudio, M. Oiarbide, A. Laso,
Eur. J. Org. Chem. 2007, 2561.
[5] For selected references of enantioselective oxyamination of
olefins, see: a) G. Li, H. T. Chang, K. B. Sharpless, Angew. Chem.
Int. Ed. Engl. 1996, 35, 451; Angew. Chem. 1996, 108, 449;
b) K. S. Williamson, T. P. Yoon, J. Am. Chem. Soc. 2012, 134,
12370; c) H.-C. Shen, Y.-F. Wu, Y. Zhang, L.-F. Fan, Z.-Y. Han,
L.-Z. Gong, Angew. Chem. Int. Ed. 2018, 57, 2372; Angew.
Chem. 2018, 130, 2396.
[6] For selected reviews, see: a) J. M. Keith, J. F. Larrow, E. N.
Jacobsen, Adv. Synth. Catal. 2001, 343, 5; b) F. Huerta, A. B. E.
Minidis, J. B. Bꢁckwall, Chem. Soc. Rev. 2001, 30, 321; c) H.
Pellissier, Adv. Synth. Catal. 2011, 353, 1613; d) M. Rachwalski,
N. Vermue, F. P. J. T. Rutjes, Chem. Soc. Rev. 2013, 42, 9268.
ˇ
Khau, B. Kosmrlj, J. Am. Chem. Soc. 2002, 124, 3578; c) W.
Muramatsu, J. Org. Chem. 2012, 77, 8083; d) W. Muramatsu, Y.
Takemoto, J. Org. Chem. 2013, 78, 2336; e) M. Giordano, A.
Iadonisi, J. Org. Chem. 2014, 79, 213; f) X. Li, Q. Yang, Org.
Process Res. Dev. 2017, 21, 1653.
[11] a) J. Otera, K. Sakamoto, T. Tsukamoto, A. Orita, Tetrahedron
Lett. 1998, 39, 3201; b) F. Iwasaki, T. Maki, W. Nakashima, O.
Onomura, Y. Matsumura, Org. Lett. 1999, 1, 969; c) T. Hoshi, H.
Shionoiri, M. Katano, T. Suzuki, M. Ando, H. Hagiwara, Chem.
Lett. 2002, 31, 600; d) A. Yanagisawa, K. Yoshida, Chem. Rec.
2013, 13, 117; e) F. Iwasaki, T. Maki, O. Onomura, W. Naka-
shima, Y. Matsumura, J. Org. Chem. 2000, 65, 996.
[12] a) S.-S. Meng, Y. Liang, K.-S. Cao, L. Zou, X.-B. Lin, H. Yang,
K. N. Houk, W.-H. Zheng, J. Am. Chem. Soc. 2014, 136, 12249;
b) H. Yang, K.-S. Cao, W.-H. Zheng, Chem. Commun. 2017, 53,
3737; c) S.-S. Meng, W.-B. Tang, W.-H. Zheng, Org. Lett. 2018,
20, 518.
[13] a) S. Sakai, Y. Fujimura, Y. Ishii, J. Organomet. Chem. 1973, 50,
113; b) D. P. Gaur, G. Srivastava, R. C. Mehrotra, J. Organomet.
Chem. 1974, 65, 195.
[14] The s value was calculated using the calculated conversion (C)
and ee2 following the equation: s = ln[(1ÀC)(1Àee2)/ ln[(1ÀC)(1
+ ee2)].
[15] P. V. Balaji, S. Chandrasekaran, Chem. Commun. 2014, 50, 70.
[16] The absolute configuration of 1yr was determined by compar-
ison of the optical rotation with that of the known compound in
the literature (see the Supporting Information).
Manuscript received: August 1, 2019
Accepted manuscript online: September 6, 2019
Version of record online: && &&, &&&&
4
www.angewandte.org
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2019, 58, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Chiral Amino Alcohols
H. Yang, W.-H. Zheng*
&&&& — &&&&
Chiral-Organotin-Catalyzed Kinetic
Resolution of Vicinal Amino Alcohols
A valuable structural motif in many
of the racemate. A chiral organotin com-
biologically active compounds, the vicinal
amino alcohol unit can be obtained in
optically active form by kinetic resolution
plex catalyzes this reaction, which is
thought to proceed via a stannylene N,O-
aminal intermediate.
Angew. Chem. Int. Ed. 2019, 58, 1 – 5
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!