Enantioselective Desymmetrization of 1,3-Diols by a Chiral DMAP Derivative

Article abstract of DOI:10.1246/cl.180697

We developed an enantioselective desymmetrization of 1,3-diols by a chiral N,N-dimethyl-4-aminopyridine (DMAP) derivative containing a 1,1-binaphthyl with tert-alcohol units. The reactions required only 0.1 mol% of catalyst and showed moderate to high chemoselectivity (monoacylation vs. diacylation) and enantioselectivity (14 examples, up to 95:5 er). Several control experiments revealed that diol units in both the substrate and the catalyst are important to achieve high enantioselectivity.

Full text of DOI:10.1246/cl.180697

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Enantioselective Desymmetrization of 1,3-Diols by a Chiral DMAP Derivative
Hiroki Mandai,* Kosuke Ashihara, Koichi Mitsudo, and Seiji Suga*
Advance Publication on the web September 14, 2018
doi:10.1246/cl.180697
© 2018 The Chemical Society of Japan
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1
Enantioselective Desymmetrization of 1,3-Diols by a Chiral DMAP Derivative
Hiroki Mandai,* Kosuke Ashihara, Koichi Mitsudo, and Seiji Suga*
Division of Applied Chemistry, Graduate School of Natural Science and Technology,
Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
E-mail: mandai@cc.okayama-u.ac.jp (HM), suga@cc.okayama-u.ac.jp (SS)
1
2
3
4
5
6
7
8
9
We developed an enantioselective desymmetrization of
1,3-diols by chiral N,N-dimethyl-4-aminopyridine
43 Thus, the development of
a
high-performance
a
44 enantioselective catalyst, which accelerates the rate of the
45 first acylation much faster than that of the second acylation,
46 is highly desirable.
(DMAP) derivative containing a 1,1ʹ-binaphthyl with tert-
alcohol units. The reactions required only 0.1 mol % of
catalyst and showed moderate to high chemoselectivity
(monoacylation vs. diacylation) and enantioselectivity (14
examples, up to 95:5 er). Several control experiments
revealed that diol units in both the substrate and the catalyst
are important to achieve high enantioselectivity.
47
Our research interests involve the development of
48 chiral nucleophilic catalysts8 for acyl transfer reactions.9
49 Recently, we developed extremely active and
50 enantioselective pyridine-based catalysts on the basis of a
51 hydrogen bonding strategy.8e-h These catalysts efficiently
52 promoted various enantioselective acyl transfer reactions
53 such as Steglich-type rearrangements of O-acylated
54 oxindole derivatives,8e kinetic resolution of carbinols8f and
55 d,l-1,2-diols,8g desymmetrization of meso-1,2-diols,8h and
56 dynamic kinetic resolution of azlactone.10 Herein, we report
57 the enantioselective desymmetrization of various 2- or 2,2-
58 (di)substituted 1,3-diols in the presence of pyridine-based
59 catalyst developed by our group. Furthermore, several
60 control experiments were also carried out to better
61 understand these processes.
10 Keywords: chiral DMAP derivative, desymmetrization,
11 1,3-diol
12
Enantioselective desymmetrization of prochiral
13 substrates is a promising transformation to obtain optically
14 active compounds in organic synthesis.1 These processes
15 provide an enantiomer-enriched product in one-step in a
16 theoretical yield of up to 100% with high atom efficiency.
17 Among them, acylative desymmetrization of 2-substituted
18 1,3-propanediols is quite challenging because the pro-
19 stereogenic center is far from the reaction site, and it is
20 difficult to differentiate enantiotopic alcohols (Scheme 1;
21 target reaction in the solid-line box). In addition, after the
22 first monoacylation, the desired monoacylated product still
23 has a reactive primary alcohol, which would easily be
24 further acylated to give undesired diacylate (Scheme 1;
25 over-acylation in the dotted-line box). A more important
26 issue in this transformation is that the yield and
27 enantiomeric ratio (er) of monoacylate are significantly
28 affected by the second acylation through path A (acylation
29 of a major enantiomer of monoacylate) or B (acylation of a
30 minor enantiomer of monoacylate). Various methods of
31 desymmetrization of 2- or 2,2-(di)substituted 1,3-diols have
32 been reported using enzymes,2 metal-3, or organocatalysts
33 (e.g., silylation,4 acylation5, acetalyzation,6 and acetal
62
Initially,
the
enantioselective
acylative
63 desymmetrization of 1,3-diol 2a was carried out with
64 selected catalysts 1a–l (Table 1). The following reaction
65 conditions were selected after extensive screening of various
66 parameters:11 1 mol % of chiral DMAP derivatives 1a–l, 1.0
67 equiv. of isobutyric anhydride, and 1.0 equiv. of N,N,Nʹ,Nʹ-
68 tetramethylethylenediamine (TMEDA) in toluene at –60 ºC
69 for 1 h.
70
71 Table 1. Catalyst screening for the desymmetrization of 2aa
34 cleavage7).
However,
especially
in
acylative
35 desymmetrization approach with organocatalysts, the
36 chemoselectivity (monoacylation vs. diacylation) and
37 enantioselectivities of monoacylates need further
38 improvements.
39
72
entry catalyst 3a (%)b 4a (%)b 2a (%)b er of 3ac
1
2
3
1a
1b
1c
67
48
45
3
30
46
52
93:7
92:8
93:7
40
3
41 Scheme 1. General scheme for the acylative desymmetrization of 1,3-
42 diol.
<2

2
45 Table 2. Effects of reaction time and the molar ratio of
4
1d
1e
1f
44
58
45
47
46
32
16
13
14
2
55
38
49
50
49
53
83
87
86
91:9
46 acylating reagent and TMEDAa
5
4
91:9
6
5
90:10
91:9
7
1g
1h
1i
4
47
48
8
4
85:15
83:17
52:48
61:39
45:55
entry X
Y
time 3a
4a
2a
er
of
(equiv) (equiv) (h) (%)b (%)b (%)b 3ac
9
14
3
10
11
12
1j
1
2
3
4
5
6
7
8
9
1.2
1.2
1.2
1.2
1.2
1.1
1.1
1.1
1.1
1.2
1.2
1.2
1.2
1.2
1.1
1.2
1.3
1.5
1
60
79
85
87
84
82
90
87
91
2
5
5
8
5
6
7
5
6
38
16
10
5
93.5:6.5
92:8
1k
1l
<2
2
3
5
93:7
1
2
3
4
5
6
7
8
9
a Reactions were performed on a 0.1 mmol scale in toluene (0.1 M)
under an argon atmosphere. b NMR yields were determined by 1H NMR
7
94:6
c
analysis using benzylbenzoate as an internal standard. Enantiomer
ratios were determined by HPLC analysis using CHIRALCEL OD-H.
12
7
9
93.5:6.5
94:6
11
3
The use of catalyst 1a with tert-alcohol units having a
diphenyl group gave monoacylate 3a in moderate yield with
good enantioselectivity (entry 1, 67% NMR yield of 3a;
93:7 er), and undesired diacylate 4a was almost completely
7
94:6
7
8
94:6
10 suppressed (3% NMR yield). The use of catalyst 1b–i with
11 tert-alcohol units having an aryl group with various
12 substituents did not dramatically improve the yield of 3a or
13 the enantioselectivity (entries 2–9: 32–58% yield of 2a; up
14 to 93:7 er). On the other hand, the reaction with catalyst 1j–l
15 having carboxylic acid derivatives (-CO2Et, -CO2H, or -
16 CONHPh) was slow compared to that with catalysts 1a–i
17 having tert-alcohol units, and the enantioselectivities of 3a
18 were also moderate (entries 10–12, up to 61:39 er).
19 According to these results, catalyst 1a was selected as an
20 optimal catalyst for further screening of the reaction
21 conditions.
22 After further optimization of the reaction conditions (0.1
23 mol % of 1a, 1.2 equiv of acylating reagent and TMEDA,
24 and 0.2 M in toluene ),12 we next examined the reaction time
25 and molar ratios of both acylating reagent and TMEDA,
26 which could be a key to suppressing diacylation. (Table 2).
27 When the reaction time was increased from 1 h to 3–12 h
28 (entry 1 vs. entries 2–5), the yield of monoacylate 3a was
29 improved to a satisfactory level (entry 4, up to 87% NMR
30 yield). However, a small amount of undesired diacylate 4a
31 (5% NMR yield) and unreacted 2a (9% NMR yield) were
32 still present even when the reaction time was increased to 12
33 h (entry 5). Thus, the amount of acylating reagent was
34 reduced to 1.1 equiv to prevent such undesired diacylation,
35 and the amount of TMEDA was increased to accelerate the
36 first acylation (entries 6–9). As expected, when 1.1 equiv of
37 acylating reagent and 1.5 equiv of TMEDA were used, most
38 of 2a was consumed (1% recovery) and the desired
39 monoacylate 3a was obtained in 91% NMR yield with
40 93.5:6.5 er along with a small amount of diacylate 4a (entry
41 9). Accordingly, we identified the optimal reaction
42 conditions as follows: 0.1 mol % of 1a, 1.1 equiv of
43 isobutyric anhydride, and 1.5 equiv of TMEDA in toluene
44 (0.2 M) at –60 °C for 7 h.
7
1
93.5:6.5
49 a Reactions were performed on a 0.2 mmol scale in toluene (0.2 M)
50 under an argon atmosphere. b NMR yields were determined by 1H NMR
c
51 analysis using benzylbenzoate as an internal standard. Enantiomer
52 ratios were determined by HPLC analysis using CHIRALCEL OD-H.
53
54
Next, the desymmetrization of an array of 1,3-diols
55 was examined under the optimal conditions (Figure 1). The
56 reaction of 2a (R1 = Ph, R2 = Me) afforded monoacylate 3a
57 in high yield with high enantioselectivity (90% isolated
58 yield with 94:6 er) along with 7% of diacylate 4a and 3%
59 recovery of 2a. At the same time, we confirmed the
13
60 possibility of racemization3e,
of enantio-enriched
61 monoacylate 3a, and found that 3a was prone to racemize
62 when it was kept at room temperature for >7 days or treated
63 with basic SiO2.14 The reaction of substrates with a bulkier
64 alkyl group 2b (R1 = Ph, R2 = Et), 2c (R1 = Ph, R2 = i-Pr), or
65 allyl group 2d (R1 = Ph, R2 = allyl) gave monoacylates 3b,
66 3c, or 3d in good yields but only moderate
67 enantioselectivities (77% yield with 84:16 er for 3b; 87%
68 yield with 66:34 er for 3c; 87% yield with 79:21 er for 3d;
69 respectively). In all cases, undesired diacylates were almost
70 suppressed. The use of substrates 2e–g with various R1 =
71 aryl, R2 = Me groups delivered the desired monoacylate
72 with moderate to high enantioselectivities. However, in the
73 case of 2e having an electron-rich aryl group (R1 = p-
74 MeOC6H4, R2 = Me), the reaction gave a significant amount
75 of diacylate 4e, probably due to the high nucleophilicity
76 (reactivity) of the monoacylate 3e. On the other hand,
77 substrate 2g having an electron-deficient group (R1 = p-
78 NO2C6H4, R2 = Me) also showed poor chemoselectivity of
79 monoacylation. In this case, the solubility of 1,3-diol 2g was
80 extremely less than that of monoacylate 3g. Accordingly,
81 once 3g was generated, it was readily converted to diacylate

3
1
2
3
4
5
6
7
8
9
4g. The reaction of substrates 2h–j gave monoacylates 3h–j
with moderate to high yield and enantioselectivity (54–88%
yield and 54:46–95:5 er). The low solubility of substrates
also affected the selectivity of monoacylation and
diacylation (e.g., 2i and 2j). Next, substrates 2k–n with a
tertiary carbon atom (R1 = aryl or alkyl, R2 = H) were tested
under the optimal conditions. Monoacylates were
preferentially obtained in 48–88% yield with moderate
enantioselectivities (up to 80.5:19.5 er). The reasons for the
12 and 3k were determined to be S after derivatization of 3a
13 and 3k to known compounds.15 Other products were also
14 assigned S by analogy. According to these results, the
15 current reaction system could be applied to specific
16 substrates having a quaternary carbon atom (R1 = aryl, R2 =
17 Me) in good to high chemo- and enantioselectivities. To
18 expand the substrate generality, a new class of catalysts
19 suitable for such substrates would be required, and the issue
20 of the solubility of 1,3-diols ( vs. monoacylate), which
21 greatly affects the chemoselectivity of monoacylation, needs
22 to be addressed.
10 poor chemo- and enantioselectivity for monoacylates 3k–n
11 are unclear at this time. The absolute configurations of 3a
23
24
25
26
27
Figure 1. Desymmetrization of various 1,3-diols promoted by catalyst 1a.
Control experiments to clarify the second acylation
28
40 2.0). In addition, analysis of the recovered starting materials
41 3a or 3k revealed that minor enantiomers in the
42 enantioselective desymmetrization of 1,3-diols 2a and 2k
43 were preferentially consumed. This finding suggested that
29 process were carried out (Table 3). As mentioned before,
30 controlling such over-reaction is quite challenging because
31 two primary alcohols are too reactive to suppress
32 undesirable over-acylation, which undoubtedly would have
33 a significant impact on the yield and/or enantioselectivity of
34 monoacylate (e.g., Scheme 1). Thus, racemates of
35 monoacylates 3a (R1 = Ph, R2 = Me) and 3k (R1 = Ph, R2 =
36 H) were subjected to the reaction conditions. Consequently,
37 over-acylation proceeded smoothly to give corresponding
38 diacylate 4a and 4k in 50% and 59% conversion,
39 respectively, but the selectivity factors were low (s =1.8–
44 over-acylation preferentially proceeded via path
B
45 (acylation of a minor enantiomer; the pathway tending to
46 amplifies enantio-enrichment of the monoacylate) in
47 Scheme 1, but its selectivity was rather low.16
48
Next, the importance of the catalyst structure was also
49 investigated. The desymmetrization of 2a was carried out
50 using pseudo C2-symmetric catalyst 1aʹ (lack of one
51 hydroxy group), and C2-symmetric catalyst 1aʺ (lack of two

4
1
2
3
4
5
6
7
8
9
hydroxy groups) under the optimal conditions (Figure 2).
The catalysts 1aʹ and 1aʺ were significantly less effective
than optimal catalyst 1a with respect to both catalytic
activity and enantioselectivity (65% yield of 3a with
88.5:11.5 er, and 31% yield of 3a with 46:54 er,
respectively). These results clearly indicated that C2-
symmetric catalyst 1a with two tert-alcohol units is essential
to achieve high catalytic activity and high enantioselectivity.
36 is also important for achieving high catalytic activity or
37 enantioselectivity. Further improvements in the enantio- and
38 chemoselectivity of monoacylation are now in progress.
39
40 This research was partially supported by a Grant-in-Aid for
41 Young Scientists (B) (17K17903) from JSPS, the JGC-S
42 Scholarship Foundation, Okayama Foundation for Science and
43 Technology, and a Grant-in-Aid for Scientific Research on
44 Innovative Area “Middle Molecular Strategy” from MEXT
45 (Japan). The authors thank Mr Kenko Abe for preliminary
46 experiments.
10 Table 3. Examination of the second acylation stepa
47
48 Supporting
Information
is
available
at
49 http://dx.doi.org/10.1246/cl.******.
11
12
50 References and Notes
51 1. a) Y. Shang, C. Wang, X. He, K. Ju, M. Zhang, S. Yu, J. Wu,
entry monoacylate conv (%)b er of monoacylatec sd
52
53
54
55
56
Tetrahedron 2010, 66, 9629. b) M. D. Diaz-de-Villegas, J. A.
Galvez, R. Badorrey, M. P. Lopez-Ram-de-Viu, Chem. Eur. J.
2012, 18, 13920. c) X.-P. Zeng, Z.-Y. Cao, Y.-H. Wang, F. Zhou, J.
Zhou, Chem. Rev. 2016, 116, 7330. d) T. Suzuki, Tetrahedron Lett.
2017, 58, 4731.
1
2
3a
3k
50
59
62:38
63:37
2.0
1.8
57 2. a) A. Fadel, P. Arzel, Tetrahedron: Asymmetry 1997, 8, 283. b) B.
13 a Reactions were performed on a 0.1 mmol scale in toluene (0.2 M)
58
59
60
61
62
Morgan, D. R. Dodds, A. Zaks, D. R. Andrews, R. Klesse, J. Org.
Chem. 1997, 62, 7736. c) S. Akai, T. Naka, Y. Takebe, Y. Kita,
Chem. Pharm. Bull. 2000, 48, 1519. d) S. Akai, T. Tsujino, E.
Akiyama, K. Tanimoto, T. Naka, Y. Kita, J. Org. Chem. 2004, 69,
2478.
14 under an argon atmosphere. b NMR yields were determined by 1H NMR
c
15 analysis using benzylbenzoate as an internal standard. Enantiomer
16 ratios were determined by HPLC analysis using CHIRALCEL OD-H. d
17 The s factors were calculated using Kagan's equation.17
18
19
63 3. a) B. M. Trost, T. Mino, J. Am. Chem. Soc. 2003, 125, 2410. b) T.
64
65
66
67
68
69
70
71
72
Harada, K. Shiraishi, Synlett 2005, 2005, 1999. c) T. Honjo, M.
Nakao, S. Sano, M. Shiro, K. Yamaguchi, Y. Sei, Y. Nagao, Org.
Lett. 2007, 9, 509. d) J. Byunghyuck, H. M. Sook, K. S. Ho, Angew.
Chem. Int. Ed. 2007, 46, 2616. e) T. B. M., M. Sushant, M. Takashi,
R. N. S., Chem. Eur. J. 2008, 14, 7648. f) H. M. Sook, K. T. Woo,
J. Byunghyuck, K. S. Ho, Chem. Eur. J. 2008, 14, 3290. g) J. Y.
Lee, Y. S. You, S. H. Kang, J. Am. Chem. Soc. 2011, 133, 1772. h)
Y. S. You, T. W. Kim, S. H. Kang, Chem. Commun. 2013, 49,
9669.
0.1 mol % catalyst
1.1 equiv (i-PrCO)2O
1.5 equiv TMEDA
OH
OH
OCOi-Pr
OCOi-Pr
OCOi-Pr
+
Ph
Me
Ph
Me
OH
Ph
Me
toluene (0.2 M)
60 °C, 7 h
2a
3a
4a
Ph Ph
OH
Ph Ph
OH
Ph Ph
H
73 4. a) Z. You, A. H. Hoveyda, M. L. Snapper, Angew. Chem. Int. Ed.
74
75
2009, 48, 547. b) Z. X. Giustra, K. L. Tan, Chem. Commun. 2013,
49, 4370.
N
N
N
N
N
N
76 5. a) T. Oriyama, H. Taguchi, D. Terakado, T. Sano, Chem. Lett.
OH
H
H
Ph Ph
1a
77
78
79
80
81
82
83
2002, 31, 26. b) C. A. Lewis, B. R. Sculimbrene, Y. Xu, S. J.
Miller, Org. Lett. 2005, 7, 3021. c) A. Sakakura, S. Umemura, K.
Ishihara, Adv. Synth. Catal. 2011, 353, 1938. d) H. Aida, K. Mori,
Y. Yamaguchi, S. Mizuta, T. Moriyama, I. Yamamoto, T. Fujimoto,
Org. Lett. 2012, 14, 812. e) B.-S. Li, Y. Wang, R. S. J. Proctor, Z.
Jin, Y. R. Chi, Chem. Commun. 2016, 52, 8313. f) Z. Wu, J. Wang,
ACS Catalysis 2017, 7, 7647.
Ph Ph
Ph Ph
1a
1a
3a: 31% yield, 46:54 er
4a: 7% yield
3a: 65% yield, 88.5:11.5 er
4a: 6% yield
3a: 90% yield, 94:6 er
4a: 7% yield
2a: 60% yield
2a: 31% yield
2a: 3% yield
20
21 Figure 2. Effects of the tert-alcohol unit(s) of the catalyst in
84 6. Z. Chen, J. Sun, Angew. Chem. Int. Ed. 2013, 52, 13593.
22 the desymmetrization of 2a
23
24
85 7. S.-S. Meng, Y. Liang, K.-S. Cao, L. Zou, X.-B. Lin, H. Yang, K. N.
86
Houk, W.-H. Zheng, J. Am. Chem. Soc. 2014, 136, 12249.
In conclusion, we developed an enantioselective
87 8. a) H. Mandai, S. Irie, K. Mitsudo, S. Suga, Molecules 2011, 16,
25 desymmetrization of 1,3-diols by a chiral N,N-dimethyl-4-
26 aminopyridine (DMAP) derivative 1a containing a 1,1ʹ-
27 binaphthyl with tert-alcohol units. The reactions required
28 only 0.1 mol % of catalyst and showed moderate to high
29 chemoselectivity of monoacylation and enantioselectivity
30 (14 examples, up to 90% yield, and up to 95:5 er).
31 Furthermore, several control experiments revealed that
32 enantioselective acylation proceeded smoothly when 1,3-
33 diols were used, whereas there was almost no
34 enantioselectivity in the second acylation of monoacylate
35 (mono-ol). A catalyst structure having two tert-alcohol units
88
89
90
91
92
93
94
95
96
97
98
8815. b) H. Mandai, K. Murota, K. Mitsudo, S. Suga, Org. Lett.
2012, 14, 3486. c) H. Mandai, S. Irie, M. Akehi, K. Yuri, M.
Yoden, K. Mitsudo, S. Suga, Heterocycles 2013, 87, 329. d) H.
Mandai, T. Fujiwara, K. Noda, K. Fujii, K. Mitsudo, T. Korenaga,
S. Suga, Org. Lett. 2015, 17, 4436. e) H. Mandai, K. Fujii, H.
Yasuhara, K. Abe, K. Mitsudo, T. Korenaga, S. Suga, Nat.
Commun. 2016, 7, 11297. f) K. Fujii, K. Mitsudo, H. Mandai, S.
Suga, Bull. Chem. Soc. Jpn. 2016, 89, 1081. g) K. Fujii, K.
Mitsudo, H. Mandai, S. Suga, Adv. Synth. Catal. 2017, 359, 2778.
h) H. Mandai, H. Yasuhara, K. Fujii, Y. Shimomura, K. Mitsudo, S.
Suga, J. Org. Chem. 2017, 82, 6846.
99 9. a) R. P. Wurz, Chem. Rev. 2007, 107, 5570. b) H. Mandai, K. Fujii,
S. Suga, Tetrahedron Lett. 2018, 59, 1787.
100

5
1
2
10. H. Mandai, K. Hongo, T. Fujiwara, K. Fujii, K. Mitsudo, S. Suga,
Org. Lett. 2018, 20, 4811.
11. See the Supporting Information for details.
12. See the Supporting Information for details.
13. S. Akai, T. Naka, T. Fujita, Y. Takebe, T. Tsujino, Y. Kita, J. Org.
Chem. 2002, 67, 411.
14. See the Supporting Information for racemization studies.
15. See the Supporting Information for details.
16. We also check the possibility of transesterification of monoacylate
by catalyst 1a: Rac-3c was subjected to the optimal reaction
conditions (without acylating reagent), but compleate recovery of
3c with 50:50 er was observed.
3
4
5
6
7
8
9
10
11
12
13 17. H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 249.
14