Divergent and scalable synthesis of α-hydroxy/keto-β-amino acid analogues by the catalytic enantioselective addition of glyoxylate cyanohydrin to imines

Article abstract of DOI:10.1021/acscatal.9b03394

The catalytic enantioselective addition of glyoxylate cyanohydrin to imines to afford α-keto-β-amino acid equivalents is reported. Sterically tuned aminobenzothiadiazine catalysts provided high yields and stereoselectivities (up to 100% yield, 99% ee, >99

Full text of DOI:10.1021/acscatal.9b03394

Subscriber access provided by - Access paid by the | UCSF Library
Letter
Divergent and Scalable Synthesis of #-Hydroxy/Keto-#-Amino Acid Analogues
by Catalytic Enantioselective Addition of Glyoxylate Cyanohydrin to Imines
Takeshi Nanjo, Xuan Zhang, Yusuke Tokuhiro, and Yoshiji Takemoto
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03394 • Publication Date (Web): 02 Oct 2019
Downloaded from pubs.acs.org on October 5, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
ACS Catalysis
1
2
3
4
5
6
7
8
9
Divergent and Scalable Synthesis of -Hydroxy/Keto--Amino Acid
Analogues by Catalytic Enantioselective Addition of Glyoxylate
Cyanohydrin to Imines
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Takeshi Nanjo, Xuan Zhang, Yusuke Tokuhiro, Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
ABSTRACT: The catalytic enantioselective addition of glyoxylate cyanohydrin to imines to afford -keto--amino acid equivalents
is reported. Sterically tuned aminobenzothiadiazine catalysts provided high yields and stereoselectivities (up to 100% yield, 99% ee,
>99:1 dr) for both aromatic and aliphatic imines and the stereodivergent synthesis of both diastereomers was achieved. The optimal
catalytic system was scalable, even with a low catalyst loading. The resulting adducts were converted into various chiral building
blocks, including -amino acid analogues, which are important motifs in medicinal chemistry, while maintaining a high enantiomeric
excess.
KEYWORDS: asymmetric synthesis, organocatalysis, -amino acid, cyanohydrin, diastereodivergent synthesis
β-Amino acids are important non-proteinogenic amino acid
motifs that can dramatically change the physical properties
and biological activity of peptides. Among them, -oxygen-
functionalized analogues, such as -hydroxy- and -keto--
amino acids, are important substructures found in various
bioactive natural products and pharmaceuticals (Scheme 1a).1
Furthermore, -keto--amino acids can be effectively used for
envisaged that glyoxylate cyanohydrin, a C2 nucleophile which
has not previously been used in catalytic enantioselective
reactions9, could be applied to the Mannich-type addition
using chiral bifunctional organocatalysts10 to afford -keto--
amino acid equivalents enantioselectively (Scheme 1d). The
adduct is expected to undergo divergent conversion to -
hydroxy-/keto--amino acids by transformation of the
cyanohydrin moiety. Herein, we describe the highly
enantioselective addition of glyoxylate cyanohydrin to N-Boc-
imines catalyzed by sterically-tuned aminobenzothiadizine and
the divergent synthesis of a series of -amino acid analogues
from the obtained adducts.
decarboxylative
transformations,
including
ketoacid-
hydroxylamine (KAHA) ligation, which enables chemoselective
coupling with complex fragments.2,3 Owing to the importance
of -amino acids, catalytic and stereoselective transformations
for their rapid preparation have recently been explored.4–6
The efficient synthetic approach, in which a C–C bond forms
simultaneously with stereoselective introduction of functional
groups at the - and -positions, can be accomplished by the
Mannich-type addition of C2 nucleophiles to imines (Scheme
1b).4 Terada and coworkers reported the asymmetric addition
of an -diazoester to N-benzoylimine catalyzed by a BINOL-
based chiral phosphoric acid.4a Matsunaga, Kumagai, and
Shibasaki have also described Mannich reactions using special
-hydroxyacetamides as nucleophiles.4b,c Although these
pioneering works have demonstrated that Mannich adducts
obtained enantioselectively can be converted into -oxygen-
functionalized -amino acids, the derivatization need relatively
harsh conditions such as strong oxidants, acids, or bases.
Therefore, a new efficient approach is needed.
Based on the above concept, we initially screened reaction
conditions for the asymmetric Mannich-type reaction using
glyoxylate cyanohydrin 1 as a nucleophile (Table 1). First,
nucleophile 1 and Boc-imine 2a were treated with bifunctional
aminothiourea catalyst 4a10a in CH2Cl2 at 20 °C to afford the
desired adduct in 100% yield as a 1.6:1 diastereomeric mixture,
with major diastereomer 3a11 having 57% ee (entry 1). To
improve the stereoselectivity, we screened other hydrogen-
bond donors in the catalyst structure (entries 2 and 3).
Squaramide 4b12 also afforded moderate stereoselectivity,
while benzothiadiazine 4c,10b which was recently developed as
a powerful hydrogen bond-donating organocatalyst, provided
significantly better enantioselectivity (87% ee, entry 3). By
changing the solvent from CH2Cl2 to toluene, the
enantioselectivity for the major enantiomer was improved to
95% ee (entry 4). Furthermore, lowering the reaction
temperature provided better diastereoselectivity while
maintaining the high yield and enantioselectivity (entry 5).
Next, we modified the chiral amine motif in the catalysts to
achieve higher diastereoselectivity. Cinchona alkaloid-based
catalyst 4d provided lower enantioselectivity, while 1,2-
diphenylethylenediamine structure 4e did not significantly
To establish a new method that allows the divergent
synthesis of -oxygen-functionalized -amino acids, we
focused on the cyanohydrin motif, which is regarded as a
carbonyl equivalent. Rawal and coworkers recently reported
the enantioselective addition of masked acyl cyanide (MAC)7
to imines, where the adduct was transformed into -amino
acids by subsequent deprotection steps (Scheme 1c).8 We
ACS Paragon Plus Environment

ACS Catalysis
improve the selectivity (entries 6 and 7). In contrast, replacing
one methyl substituent with a benzyl group boosted the
diastereoselectivity to 9.4:1 (entry 8). Additional fine tuning of
the alkyl substituents showed that secondary alkyl groups (iPr
and cyclopentyl) afforded better diastereoselectivity (entries 9
and 10).
Page 2 of 8
aromatic imines were applied using catalyst 4j (3a’–c’). This
trend was in agreement with the results for electron-deficient
aromatic rings, while all adducts were still obtained with
excellent stereoselectivity (entries 4 and 5). These results also
indicated that the electronic properties of N- Boc-imine did not
significantly affect the diastereoselectivity of the
stereodivergent catalytic system using 4h and 4j. A methyl
substituent at the meta or ortho positions relative to the imino
1
2
3
4
5
6
7
8
Scheme 1. Strategy for catalytic enantioselective synthesis of
medicinally important α-hydroxy/keto--amino acid motifs
group also resulted in
a high yield and excellent
stereoselectivity using both catalysts (entries 6 and 7). The
reaction of
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Reaction optimizationa
yieldb
(%)
drc
eec (%)
entry
cat.
solvent, temp.
(3a:3a’)
3a
3a’
1
2
4a
4b
4c
4c
4c
4d
4e
4f
CH2Cl2, −20 °C
CH2Cl2, −20 °C
CH2Cl2, −20 °C
toluene, −20 °C
toluene, −40 °C
toluene, −40 °C
toluene, −40 °C
toluene, −40 °C
toluene, −40 °C
toluene, −40 °C
toluene, −40 °C
toluene, −40 °C
100
70
1.6:1
1.6:1
2.4:1
1.6:1
2.3:1
3.9:1
2.1:1
9.4:1
15:1
57
75
87
95
97
67d
89
96
96
97
59
81
16
59
43
63
66
79d
89
52
33
2
3
100
99
4
5
94
6
100
91
7
8
90
9
4g
4h
4i
93
10
11
12
97
31:1
82
1:3.6
1:14
85
92
Finally, the reaction using catalyst 4h provided desired adduct
3a as almost a single stereoisomer, with 97% ee and 31:1 dr
(entry 10). This catalytic system was easily scalable, with
compound 3a prepared on a gram-scale using a catalyst
loading of only 1 mol% (eq. 1). Surprisingly, substituents at the
5-position of the aromatic ring changed the
diastereoselectivity in the products (entry 11). In particular,
catalyst 4j, bearing an isopropyl group, predominantly
generated 3a’13 with excellent yield and stereoselectivity
(entry 12). The reversal of diastereoselectivity through catalyst
control remains challenging, while several organocatalytic
asymmetric transformations have been previously
reported.14,15
4j
92
With optimal conditions in hand (Table 1, entries 10 and 12),
we next examined the substrate scope of the
diastereodivergent, enantioselective addition of glyoxylate
cyanohydrin 1 to N-Boc imine (Table 2). As the electron density
on the aromatic rings increased, the stereoselectivity of
catalyst 4h improved, with corresponding adducts 3a–c
obtained in high yields (entries 1–3). In contrast, the
enantioselectivity was slightly diminished when electron-rich
a1 (0.1 mmol), 2a (0.15 mmol), and catalyst (0.005 mmol) in solvent (1 mL)
reacted at the indicated temperature for 24 h. bIsolated yield. cEstimated
by chiral HPLC analysis. dent-3a and ent-3a’ were obtained as major
enantiomers.
ACS Paragon Plus Environment

Page 3 of 8
ACS Catalysis
adducts with good stereoselectivities, albeit only the
1
2
3
4
5
6
7
enantioselectivity of the adduct 3k’ considerably diminished
naphthyl, thiophenyl and furanyl imines proceeded similarly,
with corresponding adducts 3h–j and 3h’–3j’ obtained with
excellent stereoselectivity (entries 8–10). Finally, the catalytic
system was applied to N-Boc-alkylimines derived from
cyclohexanecarboaldehyde and isovaleraldehyde affording the
Table 2. Substrate scopea
(entries 11 and 12).
Subsequently, we demonstrated the derivatization of
Mannich adduct 3a to obtain -oxygen-functionalized -amino
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
catalyst 4h
catalyst 4j
entry
1
yieldb
(%)
eec
(%)
yieldb
(%)
eec
(%)
product
drc
product
drc
3a
3b
3c
3d
3e
3f
97
98
97
98
99
95
94
88
94
92
86
97
31:1
3a’
3b’
3c’
3d’
3e’
3f’
92
100
74
92
89
87
92
93
95
89
93
86
91
14:1
2
3
48:1
>99:1
>99:1
18:1
10:1
18:1
10:1
7.9:1
23:1
27:1
52:1
21:1
16:1
85
4
91
93
5
100
98
100
84
6
11:1
7
3g
3h
3i
100
84
9.7:1
16:1
3g’
3h’
3i’
94
8
84
9
100
100
9.6:1
39:1
99
10
3j
3j’
94
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 8
1
2
3
4
5
6
11
12
3k
3l
100
93
82
5.9:1
3k’
3l’
52
41
74
>99:1
>99:1
quant.
12:1
100
7
8
a1 (0.1 mmol), 2a–2l (0.15 mmol), and 4h or 4j (0.005 mmol) reacted in toluene (1 mL) at 40 °C for 24 h. bIsolated yield. cEstimated by chiral HPLC analysis.
9
To gain insight into the reaction mechanism, we conducted
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
the reaction using cyanohydrins 10 and 12 bearing different
acids, as initially planned (Scheme 2). Compound 3a was a
protective groups as nucleophiles (Scheme 3a). The catalytic
stable, easy-to-handle, and storable solid, and Cbz
addition of O-methyl carbonate 10 divergently provided 11
deprotection followed by treatment with aqueous silver
nitrate provided -amino--ketoester 6 in 56% yield over two
steps. Importantly, the optical purity of the compound was
and 11’ with excellent enantioselectivity using catalysts 4h and
4j, respectively (eq 2). Furthermore, methyl ester 12 also
afforded corresponding adducts 13 and 13’ with similar
stereoselectivity (eq 3). These results indicated that the bulk of
the nucleophile was not significantly important for
stereoselectivity.
retained during this transformation, with -amino--ketoester
6 obtained with 94% ee16. This is the first report of the isolation
and full characterization of an enantioenriched N-carbamate-
protected -oxo--phenylalanine. In addition, the reductive
Considering the configuration of the benzothiadiazine
catalyst and obtained adduct 3a, we next conducted the
computational studies to determine the transition state of the
Mannich-type addition. Preliminary results suggested a
transition state in which both the deprotonated nucleophile
and the N-Boc-imine are activated by two NH protons of
benzothiadiazine and an ammonium unit in the catalyst,
respectively (Scheme 3b).19 However, it remains difficult to
explain the inverse diastereoselectivities of catalysts 4h and 4j.
Therefore, further mechanistic studies to fully explain this
unique catalytic system are currently underway.
transformation of 5 using L-Selectride afforded anti--
hydroxy--amino acid derivative 7 in 66% yield over two steps.
Changing the reductant to sodium borohydride resulted in the
reduction of not only the cyanohydrin moiety, but also the
ester, to afford aminodiol 8 in 68% yield, which is another
useful motif in the pharmaceutical sciences.17 These reductive
transformations also proceeded without any loss of
stereochemical information in the -amino group.
Futhermore, we attempted the stereo-divergent synthesis of
-amino acid analogues. The cyano groups of 3a and 3a’,
diastereoselectively prepared in Table 1, were hydrolyzed
under the palladium-catalyzed hydration conditions reported
by Naka and co-workers18 to provide complex -amino acids 9
and 9’ as single stereoisomers, respectively.
Scheme 3. Preliminary mechanistic studies
Scheme 2. Derivatization of adducts 3a and 3a’
Isolated yield. (a) Pd/C, H2 (1 atm), EtOAc. (b) AgNO3, MeCN,
H2O, 56% yield, 94% ee. (c) L-Selectride, THF, 0 °C, 66% yield, 95%
ee. (d) NaBH4, EtOH, 68% yield, 92% ee. (e) Pd(NO3)2•2H2O,
acetamide, MeCN, H2O, 50 °C. 9: 83% yield, 98% ee, 39:1 dr. 9’: 87
% yield, 90% ee, 18:1 dr.
ACS Paragon Plus Environment

Page 5 of 8
ACS Catalysis
1
2
Notes
The authors declare no competing financial interests.
3
4
5
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI, grant numbers
JP16H06384 and JP18K14865.
6
7
8
9
REFERENCES
(1) (a) Wang, Y.-F.; Shi, Q.-W.; Dong, M.; Kiyota, H.; Gu, Y.-C.; Cong, B.
Natural Taxanes: Developments Since 1828. Chem. Rev. 2011, 111,
7652-7709. (b) Kiriyama, A.; Fujita, K.; Takemura, S.; Kuramoto, H.;
Kiso, Y.; Takada, K. Plasma Pharmacokinetics and Urinary and Biliary
Excretion of a New Potent Tripeptide HIV-1 Protease Inhibitor, KNI-
272, in Rats After Intravenous Administration. Biopharm. Drug Dispos.
1994, 15, 617-626. (c) De Risi, C.; Pollini, G. P.; Zanirato, V. Recent
Developments in General Methodologies for the Synthesis of -
Ketoamides. Chem. Rev. 2016, 116, 3241-3305.
(2) (a) Bode, J. W.; Fox, R. M.; Baucom, K. D. Chemoselective Amide
Ligations by Decarboxylative Condensations of N-Alkylhydroxylamines
and -Ketoacids. Angew. Chem. Int. Ed. 2006, 45, 1248-1252. (b) Bode,
J. W. Chemical Protein Synthesis with the -Ketoacid–Hydroxylamine
Ligation Acc. Chem. Res. 2017, 50, 2104-2115.
(3) Nanjo, T.; Kato, N.; Takemoto, Y. Oxidative Decarboxylation
Enables Chemoselective, Racemization-Free Esterification: Coupling
of -Ketoacids and Alcohols Mediated by Hypervalent Iodine (III). Org.
Lett. 2018, 20, 5766-5769.
(4) (a) Uraguchi, D.; Sorimachi, K.; Terada, M. Organocatalytic
Asymmetric Direct Alkylation of -Diazoester via C−H Bond Cleavage.
J. Am. Chem. Soc. 2005, 127, 9360-9361. (b) Harada, S.; Handa, S.;
Matsunaga, S.; Shibasaki, M. Direct Catalytic Asymmetric Mannich-
Type Reactions of N-(2-Hydroxyacetyl)pyrrole as an Ester-Equivalent
Donor. Angew. Chem. Int. Ed. 2005, 44, 4365-4368. (c) Sun, B.; Pluta.
R.; Kumagai, N.; Shibasaki, M. Direct Catalytic Asymmetric Mannich-
Type Reaction En Route to -Hydroxy--amino Acid Derivatives. Org.
Lett. 2018, 20, 526-529.
(5) For other catalytic asymmetric syntheses of -hydroxy--amino
acid derivatives, see: (a) Commerҫon, A.; Bézard, D.; Bernard, F.;
Bourzat, J. D. Improved Protection and Esterification of a Precursor of
the Taxotere® and Taxol Side Chains. Tetrahedron Lett. 1992, 33,
5185-5188. (b) Li, G.; Chang, H.-T.; Sharpless, K. B. Catalytic
Asymmetric Aminohydroxylation (AA) of Olefins. Angew. Chem. Int.
Ed. Engl. 1996, 35, 451-454. (c) Rubin, A. E.; Sharpless, K. B. A Highly
Efficient Aminohydroxylation Process. Angew. Chem. Int. Ed. Engl.
1997, 36, 2637-2640. (d) Reddy, S. H. K.; Lee, S.; Datta, A.; Georg, G. I.
Efficient Synthesis of the 3’-Phenolic Metabolite of Paclitaxel. J. Org.
Chem. 2001, 66, 8211-8214. (e) Juhl, K.; Jørgensen, K. A. Catalytic
Asymmetric Direct -Amination Reactions of 2-Keto Esters: A Simple
Synthetic Approach to Optically Active syn--Amino--hydroxy Esters.
J. Am. Chem. Soc. 2002, 124, 2420-2421. (f) Milicevic, S.; Matovic, R.;
Saicic, R. N. Stereoselective Synthesis of ()-Cytoxazone and (+)-epi-
Cytoxazone. Tetrahedron Lett. 2004, 45, 955-957. (g) Borah, J. C.;
Gogoi. S.; Boruwa, J.; Kalita, B. Barua, N. C. A Highly Efficient Synthesis
of the C-13 Side Chain of Taxol Using Shibasaki’s Asymmetric Henry
Reaction. Tetrahedron Lett. 2004, 45, 3689-3691. (h) Torssell, S.;
Kienle, M.; Somfai, P. 1,3-Dipolar Cycloadditions of Carbonyl Ylides to
Aldimines: A Three-Component Approach to syn--Hydroxy--amino
Esters. Angew. Chem. Int. Ed. 2005, 44, 3096-3099. (i) Tosaki, S.; Tsuji.
R.; Ohshima, T.; Shibasaki, M. Dynamic Ligand Exchange of the
Lanthanide Complex Leading to Structural and Functional
Transformation: One-Pot Sequential Catalytic Asymmetric
Epoxidation–Regioselective Epoxide-Opening Process. J. Am. Chem.
Soc. 2005, 127, 2147-2155. (j) Qian, Y.; Xu, X.; Jiang, L.; Prajapati, D.;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In summary, we applied O-Cbz-protected glyoxylate
cyanohydrin as a C2 nucleophile in a catalytic Mannich-type
addition to afford chiral -keto--amino acid equivalents. An
aminobenzothiadiazine catalyst bearing strong hydrogen-
bond donor activity was found to be suitable for the
transformation, and steric tuning of the catalyst afforded
excellent stereoselectivity. The enantioenriched adducts were
also readily converted into a series of chiral motifs, including
useful -amino acids, as initially expected. This approach could
be applied to the efficient synthesis of various chiral building
blocks, and further improvements and applications of this
method are currently under investigation in our laboratory.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
publications website.
Experimental procedures and analytical data for all new
compounds (PDF)
X-ray data file (CIF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: takemoto@pharm.kyoto-u.ac.jp
ORCID
Takeshi Nanjo: 0000-0002-5679-6701
Yoshiji Takemoto: 0000-0003-1375-3821
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 8
2013, 52, 11114-11118. (e) Kobayashi, Y.; Li, S.; Takemoto, Y. Oxidant-
Resistant Hydrogen-Bond-Donating Organocatalyst for
Enantioselective Nucleophilic Epoxidation of ,-Unsaturated
Amides. Asian. J. Org. Chem. 2014, 3, 403-407. (f) Kobayashi, Y.;
Kuramoto, R.; Takemoto, Y. Catalytic Asymmetric Formal Synthesis of
Beraprost. Beilstein. J. Org. Chem. 2015, 11, 2654-2660.
Hu, W. A Strategy to Synthesize Taxol Side Chain and ()-epi-
1
2
3
4
5
6
7
8
Cytoxazone via Chiral Brønsted Acid-Rh2(OAc)4 Co-catalyzed
Enantioselective Three-Component Reactions. J. Org. Chem. 2010, 75,
7483-7486. (k) Jiang, Y.; Chen, X.; Zheng, Y.; Xue, Z.; Shu, C.; Yuan, W.;
Zhang, X. Highly Diastereoselective and Enantioselective Synthesis of
-Hydroxy -Amino Acid Derivatives: Lewis Base Catalyzed
Hydrosilylation of -Acetoxy -Enamino Esters. Angew. Chem. Int. Ed.
2011, 50, 7304-7307. (l) Goodman, C. G.; Do, D. T.; Johnson, J. S.
Asymmetric Synthesis of anti--Amino--Hydroxy Esters via Dynamic
Kinetic Resolution of -Amino--Keto Esters. Org. Lett. 2013, 15,
2446-2449. (m) Wang, Q.; Huang. W.; Yuan, H.; Cai, Q.; Chen, L.; Lv, H.;
Zhang, X. Rhodium-Catalyzed Enantioselective Hydrogenation of
Tetrasubstituted -Acetoxy -Enamido Esters: A New Approach to
Chiral -Hydroxyl--amino Acid Derivatives. J. Am. Chem. Soc. 2014,
136, 16120-16123.
(6) To our knowledge, the oxidation of enantioselectively prepared -
diazoester is the only reported catalytic method for the preparation
of -keto--amino acids, see ref 4a. Two approaches to the
preparation of -keto--amino acids from commercially available -
amino acids have been reported, see: (a) Wasserman, H. H.; Ho, W.-B.
(Cyanomethylene)phosphoranes as Novel Carbonyl 1,1-Dipole
Synthons: An Efficient Synthesis of -Keto Acids, Esters, and Amides.
J. Org. Chem. 1994, 59, 4364-4366. (b) Ju, L.; Lippert, A. R.; Bode, J. W.
Stereoselective Synthesis and Chemoselective Amide-Forming
Ligations of C-Terminal Peptide -Ketoacids. J. Am. Chem. Soc. 2008,
130, 4253-4255.
(11) The structure of 3a was determined by X-ray crystallography; see
Supporting Information for details.
(12) (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. Chiral Squaramide
Derivatives Are Excellent Hydrogen Bond Donor Catalysts J. Am. Chem.
Soc. 2008, 130, 14416-14417. (b) Qian, Y.; Ma, G.; Lv, A.; Zhu, H.-L.;
Zhao, J.; Rawal, V. H. Squaramide-Catalyzed Enantioselective Friedel-
Crafts Reaction of Indoles with Imines. Chem. Commun. 2010, 46,
3004-3006.
(13) The absolute configuration of 3a’ was determined by comparison
with the optical rotation of 8 derived from Mannich adduct 3a’ in
Table 1, entry 12; see Supporting Information for details.
(14) For recent reviews on stereodivergent asymmetric synthesis, see:
(a) Zhan, G.; Du, W.; Chen, Y.-C. Switchable Divergent Asymmetric
Synthesis via Organocatalysis. Chem. Soc. Rev. 2017, 46, 1675-1692.
(b) Krautwald, S.; Carreira, E. M. Stereodivergence in Asymmetric
Catalsis. J. Am. Chem. Soc. 2017, 139, 5627-5639. (c) Lin, L.; Feng, X.
Catalytic Strategies for Diastereodivergent Synthesis. Chem. Eur. J.
2017, 23, 6464-6482. (d) Beletskaya, I. P.; Nájera, C.; Yus, M.
Stereodivergent Catalysis. Chem. Rev. 2018, 118, 5080-5200.
(15) (a) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. Control of
Diastereoselectivity in Tandem Asymmetric Reactions Generating
Nonadjacent Stereocenters with Bifunctional Catalysis by Cinchona
Alkaloids. J. Am. Chem. Soc. 2007, 129, 768-769. (b) Dong, S.; Liu, X.;
Zhang, Y.; Lin, L.; Feng, X. Asymmetric Synthesis of 3,4-
Diaminochroman-2-ones Promoted by Guanidine and Bisguanidium
Salt. Org. Lett. 2011, 13, 5060-5063. (c) Feng, X.; Zhou, Z.; Zhou, R.;
Zhou, Q.-Q.; Dong, L. Chen, Y.-C. Stereodivergence in Amine-Catalyzed
Regioselective [4+2] Cycloadditions of -Substituted Cyclic Enones
and Polyconjugated Malononitriles. J. Am. Chem. Soc. 2012, 134,
19942-19947. (d) Li, X.; Lu, M.; Dong, Y.; Wu, W.; Qian, Q.; Ye, J.; Dixon,
D. J. Diastereodivergent Organocatalytic Asymmetric Vinylogous
Michael Reactions. Nat. Commun. 2014, 5, 4479-4487. (e) Belmessieri,
D; de la Houpliere, A.; Calder, E. D. D. Taylor, J. E.; Smith, A. D.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) Nemoto, H.; Kubota, Y.; Yamamoto, Y. Development of a New Acyl
Anion Equivalent for the Preparation of Masked Activated Esters and
Their Use to Prepare a Dipeptide. J. Org. Chem. 1990, 55, 4515-4516.
(8) Yang, K. S.; Rawal, V. H. Synthesis of -Amino Acid Derivatives and
Peptides via Enantioselective Addition of Masked Acyl Cyanides to
Imines. J. Am. Chem. Soc. 2014, 136, 16148-16151.
(9) There are only five reports on the use of glyoxylate cyanohydrins
as nucleophile, while O-carbamate-protected cyanohydrin has not
been synthesized previously. More importantly, no enantioselective
reaction using glyoxylate cyanohydrins has been reported previously,
see: (a) Mukaiyama, T.; Oriyama, T.; Murakami, M. A Convenient
Method for the Preparation of Enol Acetates of -Keto Esters by the
Alkylation of Cyanohydrin Silyl Ethers Derived from Glyoxylic Esters
with Benzyl and Allyl Halides. Chem. Lett. 1983, 12, 985-988. (b)
Cativiela, C.; Diaz-de-Villegas, M. D.; Gálvez, J. A. The Synthesis of
Enantiomerically Pure (2R)--Methylisoserine. Tetrahedron 1996, 52,
687-694. (c) Tsukamoto, H.; Takahashi, T. New Route to 3-Deoxy-2-
Ulosonic Acids; Total Syntheses of KDO and KDN. Tetrahedron Lett.
1997, 38, 6415-6418. (d) Zhuang, Z.; Pan, F.; Fu, J.-G.; Chen, J.-M.; Liao,
W.-W. Construction of Highly Functional Quaternary Carbon
Stereocenters via an Organocatalytic Tandem Cyanation–Allylic
Alkylation Reaction. Org. Lett. 2011, 13, 6164-6167. (e) Yan, Y.; En, D.;
Zhuang, Z.; Guo, Y.; Liao, W.-W. Synthesis of Densely Functionalized -
Methylene -Butyrolactones via an Organocatalytic One-Pot Allylic-
Alkylation-Cyclization Reaction. Tetrahedron Lett. 2014, 55, 479-482.
(10) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. Enantioselective Michael
Reaction of Malonates to Nitroolefins Catalyzed by Bifunctional
Organocatalysts. J. Am. Chem. Soc. 2003, 125, 12672-12673. (b)
Inokuma, T.; Furukawa, M.; Uno, T.; Suzuki, Y.; Yoshida, K.; Yano, Y.;
Matsuzaki, K.; Takemoto, Y. Bifunctional Hydrogen-Bond Donors That
Bear a Quinazoline or Benzothiadiazine Skeleton for Asymmetric
Organocatalysis. Chem. Eur. J. 2011, 17, 10470-10477. (c) Inokuma, T.;
Furukawa, M.; Suzuki, Y.; Kimachi, T.; Kobayashi, Y.; Takemoto, Y.
Organocatalyzed Isomerization of -Substituted Alkynoates into
Trisubstituted Allenoates by Dynamic Kinetic Resolution. Chem. Cat.
Chem. 2012, 4, 983-985. (d) Kobayashi, Y.; Taniguchi, Y.; Hayama, N.;
Inokuma, T.; Takemoto, Y. A Powerful Hydrogen-Bond-Donating
Organocatalyst for the Enantioselective Intramolecular Oxa-Michael
Reaction of ,-Unsaturated Amides and Esters. Angew. Chem. Int. Ed.
Stereodivergent
Organocatalytic
Intramolecular
Michael
Addition/Lactonization for the Asymmetric Synthesis of Substituted
Dihydrobenzofurans and Tetrahydrofurans. Chem. Eur. J. 2014, 20,
9762-9769. (f) Martínez, J. I.; Villar, L.; Uria, U.; Carrillo, L.; Reyes, E.;
Vicario, J. L. Bifunctional Squaramide Catalysts with the Same Absolute
Chirality for the Diastereodivergent Access to Densely Functionalised
Cyclohexanes through Enanioselective Domino Reactions. Synthesis
and Mechanistic Studies. Adv. Synth. Catal. 2014, 356, 3627-3648. (g)
Verrier, C.; Melchiorre, P. Diastereodivergent Organocatalysis for the
Asymmetric Synthesis of Chiral Annulated Furans. Chem. Sci. 2015, 6,
4242-4246. (h) Wei, Y.; Wen, S.; Liu, Z.; Wu, X.; Zeng, B.; Ye, J.
Diastereodivergent Catalytic Asymmetric Michael Addition of 2-
Oxindoles to α,β-Unsaturated Ketones by Chiral Diamine Catalysts.
Org. Lett. 2015, 17, 2732-2735. (i) Zhan, G.; Shi, M.-L.; He, Q.; Lin, W.-
J.; Quyang, Q.; Du, W.; Chen, Y.-C. Catalyst-Controlled Switch in
Chemo- and Diastereoselectivities: Annulations of Morita-Baylis-
Hillman Carbonates from Isatins. Angew. Chem. Int. Ed. 2016, 55,
2147-2151.
(16) The enantiomeric excess of 6 was determined after isolation of 6
followed by reduction of the carbonyl group using sodium
borohydride. HPLC or SFC conditions to separate the enantiomers of
6
were not found. See Supporting Information for further
experimental details.
(17) (a) Kakeya, H.; Morishita, M.; Kobinata, K.; Osono, M.; Ishizuka,
M.; Osada, H. Isolation and Biological Activity of a Novel Cytokine
Modulator, Cytoxazone. J. Antibiot. 1998, 51, 1126-1128. (b) Kakeya,
H.; Morishita, M.; Koshino, H.; Morita, T.; Kobayashi, K.; Osada, H.
ACS Paragon Plus Environment

Page 7 of 8
ACS Catalysis
Cytoxazone:
A
Novel Cytokine Modulator Containing
a
2-
Competing Routes to C–C Bond Formation. J. Am. Chem. Soc. 2006,
Oxazolidinone Ring Produced by Streptomyces sp. J. Org. Chem. 1999,
64, 1052-1053.
(18) Kanda, T.; Naraoka, A.; Naka, H. Catalytic Transfer Hydration of
Cyanohydrins to -Hydroxyamides. J. Am. Chem. Soc. 2019, 141, 825-
830.
128, 13151-13160. (b) Azuma, T.; Kobayashi, Y.; Sakata, K.; Sasamori,
T.; Tokitoh, N.; Takemoto, Y. Synthesis and Characterization of Binary-
Complex Models of Ureas and 1,3-Dicarbonyl Compounds: Deeper
Insights into Reaction Mechanisms Using Snap-Shot Structural
Analysis. J. Org. Chem. 2014, 79, 1805-1817.
1
2
3
4
5
6
7
(19) Hamza, A.; Schubert, G.; Soós, T.; Pápai, I. Theoretical Studies on
the Bifunctionality of Chiral Thiourea-Based Organocatalysts:
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 8
1
2
3
4
5
6
7
8
O
S
O
NC
CO2R'
OCbz
Boc
Boc
Boc
HN
N
HN
HN
N
H
N
CO2R'
CO2R'
OH
H
CO2R'
N
R
R
R
Me
C2 nucleophile
NC OCbz
up to 99% ee, dr > 99:1
O
+
Boc
easily scalable
HN
Boc
N
-keto- -amino acid


equivalent
OH
R
R
H
OH
R = aryl or alkyl
useful -amino acid analogues

9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
ACS Paragon Plus Environment