Desymmetrization of meso-1,2-Diols by a Chiral N,N-4-Dimethylaminopyridine Derivative Containing a 1,1′-Binaphthyl Unit: Importance of the Hydroxy Groups

Article abstract of DOI:10.1021/acs.joc.7b00992

We developed an acylative desymmetrization of meso-1,2-diols using a binaphthyl-based N,N-4-dimethylaminopyridine (DMAP) derivative 1h with tert-alcohol substituents. The reaction proceeds with a wide range of acyclic meso-1,2-diols and six-membered-ring meso-1,2-diols to provide a monoacylate selectively with a high enantiomeric ratio (er). Only 0.1 mol % of the catalyst facilitated the reaction within a short reaction time (3 h) to afford enantio-enriched monoacylated products in moderate to good yield. Several control experiments revealed that the tert-alcohol units of catalyst 1h play a significant role in achieving high catalytic activity, chemoselectivity of monoacylation, and enantioselectivity.

Full text of DOI:10.1021/acs.joc.7b00992

Article
Desymmetrization of meso-1,2-Diols by a Chiral N,N-4-
Dimethylaminopyridine Derivative Containing a 1,1#-
Binaphthyl Unit: Importance of the Hydroxy Groups
Hiroki Mandai, Hiroshi Yasuhara, Kazuki Fujii, Yukihito Shimomura, Koichi Mitsudo, and Seiji Suga
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 31 May 2017
Downloaded from http://pubs.acs.org on June 1, 2017
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 36
The Journal of Organic Chemistry
1
2
3
4
5
Desymmetrization of mesoꢀ1,2ꢀDiols by a Chiral N,Nꢀ4ꢀDimethylaminopyridine Derivative
6
7
8
Containing a 1,1ʹꢀBinaphthyl Unit: Importance of the Hydroxy Groups
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
Hiroki Mandai,* Hiroshi Yasuhara, Kazuki Fujii, Yukihito Shimomura, Koichi Mitsudo and
Seiji Suga*
Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama
University, 3ꢀ1ꢀ1 Tsushimaꢀnaka, Kitaꢀku, Okayama 700ꢀ8530, JAPAN
eꢀmail: mandai@cc.okayamaꢀu.ac.jp, suga@cc.okayamaꢀu.ac.jp
This work is dedicated to Prof. Teruaki Mukaiyama on the occasion of his 90th birthday.
Table of Contents/Abstract Graphic
Abstract
We developed an acylative desymmetrization of mesoꢀ1,2ꢀdiols using a binaphthylꢀbased
N,Nꢀ4ꢀdimethylaminopyridine (DMAP) derivative 1h with tertꢀalcohol substituents. The
reaction proceeds with a wide range of acyclic mesoꢀ1,2ꢀdiols and sixꢀmemberedꢀring
mesoꢀ1,2ꢀdiols to provide a monoacylate selectively with a high enantiomeric ratio (er). Only
0.1 mol % of the catalyst facilitated the reaction within a short reaction time (3 h) to afford
enantioꢀenriched monoacylated products in moderate to good yield. Several control experiments
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 36
1
2
3
4
5
6
revealed that the tertꢀalcohol units of catalyst 1h play a significant role in achieving high
7
8
catalytic activity, chemoselectivity of monoacylation, and enantioselectivity.
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
Introduction
N,Nꢀ4ꢀDimethylaminopyridine (DMAP) and 4ꢀpyrrolidinopyridine (PPY) are powerful
catalysts for acylation and have been used in organic synthesis for many decades.1
Enantiomerically pure variants of these catalysts2 have also been well explored since the
pioneering works reported by Vedejs3 and Fu4, and have been used in the kinetic resolution of
secondary alcohols and other important enantioselective acyl transfer processes.5 However, only
a limited number of catalysts can be applied to a wide range of substrates and/or reactions with
high efficiency and enantioselectivity. Furthermore, methods to obtain such enantiomerically
pure catalysts often require a cumbersome procedure involving the optical resolution6 of a
racemic intermediate. Thus, precise modification of the catalyst (e.g., the introduction of
electronically and sterically demanding substituents) is not always easy, and this has limited
further expansion of the catalyst library. Very recently, we reported two classes of chiral
nucleophilic catalysts prepared from L
ꢀamino acid7 or (S)ꢀ1,1ʹꢀbiꢀ2ꢀnaphthol as a chiral source.8
Notably, binaphthylꢀbased catalysts with tertꢀalcohol units (Ar = Ph or 4ꢀtꢀBuC6H4, Figure 1a)
showed extremely high catalytic activity and enantioselectivity in Steglich rearrangements,8a the
kinetic resolution of benzylic carbinols8b and d,lꢀ1,2ꢀdiols,8a,c and the desymmetrization of
mesoꢀ1,2ꢀhydrobenzoin8a (Figure 1b–e).
2
ACS Paragon Plus Environment

Page 3 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
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
Figure 1. Various acyl transfer reactions catalyzed by binaphthylꢀbased chiral DMAP
derivatives.
If we wish to produce valuable chiral building blocks9 having two continuous hydroxy
groups, the desymmetrization of mesoꢀ1,2ꢀdiols is a straightforward method for obtaining
enantiomerically pure 1,2ꢀdiol derivatives5b,10 because, in principle, the desymmetrization of a
mesoꢀcompound provides an enantiomerꢀenriched product in a theoretical yield of up to 100%
and seems to be more efficient than kinetic resolution of a racemate (up to 50% theoretical
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 36
1
2
3
4
5
6
7
8
yield). Many different synthetic methods for the desymmetrization of 1,2ꢀdiols using
enzymatic11 or nonꢀenzymatic approaches (metal catalysis12 or organocatalysis13) have been
reported. However, only a few methods13a,b,e,i can be applied to a wide range of substrates
(acyclicꢀ and cyclic mesoꢀ1,2ꢀdiol) with high yield and high enantioselectivity (>95:5
enantiomeric ratio [er]). Furthermore, an ideal method for the acylative enantioselective
desymmetrization of mesoꢀ1,2ꢀdiols would need to provide a high chemoselectivity of
monoacylation and the production of only a minimum amount of an undesired diacylated
product (overꢀacylation). If the second acylation step involves kinetic resolution, the
enantiomeric ratio of the monoacylated product would be seriously affected (Scheme 1, path A
or B)14: when the major enantiomer of the monoacylate undergoes a second acylation, the
enantioselectivity of the monoacylate will decrease (Path A). In contrast, when the minor
enantiomer of the monoacylate undergoes a second acylation, the enantioselectivity of the
monoacylate will increase (Path B). To prevent this undesirable overꢀreaction, a chiral
nucleophilic catalyst would need to exhibit extremely high catalytic activity for the acylation of
a diol rather than a monofunctional alcohol.8c,15
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
Scheme 1. General scheme for the acylative desymmetrization of mesoꢀ1,2ꢀdiol.
In this paper, we describe the details of the desymmetrization of an array of
mesoꢀ1,2ꢀdiols, including acyclic and cyclic substrates, with moderate to high enantioselectivity
by binaphthylꢀbased catalyst 1h, which is known to be a highly active and enantioselective
4
ACS Paragon Plus Environment

Page 5 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
chiral DMAP derivative that uses positive interactions (hydrogenꢀbonding) between the catalyst
and substrate.8a Several key experiments were also carried out to better understand the
mechanism of the reaction.
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
Results and Discussion
We began by seeking to identify an optimal catalyst for the acylative desymmetrization of
acyclic mesoꢀ1,2ꢀdiol 2a (mesoꢀhydrobenzoin) as a model substrate. The reaction was carried
out in the presence of 5 mol % of chiral DMAP derivatives, 1.1 equiv. of isobutyric anhydride,
and 1.1 equiv. of triethylamine in tertꢀbutyl methyl ether (TBME) at 0 ºC for 3 h (Table 1).
Table 1. Catalyst screening for the desymmetrization of mesoꢀ2aa)
Entry Catalyst 3a
4a
2a
3a/4a ER of
[%]b) [%]b) [%]b)
3ac)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
32
34
47
4
29
38
29
0
35
32
31
94
39
43
43
1.1
0.89
1.6
ꢀ
49:51
43:57
42:58
ꢀ
40
38
34
28
23
20
1.4
1.7
1.7
40:60
51:49
40:60
1g
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 36
1
2
3
4
5
6
7
8
8
1h
1i
86
78
65
73
29
49
36
23
10
16
13
21
39
20
23
0
8
8.6
4.9
5.0
3.5
0.74
2.5
1.6
ꢀ
94:6
9
14
25
10
32
33
39
77
77:23
84:16
82:18
55:45
60:40
43:57
52:48
10
11
12
13
14
1j
1k
1l
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
1m
5
15[d] 1h
a) Reactions were performed on a 0.1 mmol scale in TBME (0.1 M) under an argon atmosphere. b) NMR
1
c)
yields were determined by H NMR analysis using 2ꢀmethoxynaphthalene as an internal standard.
d)
Enantiomer ratios were determined by HPLC analysis using CHIRALCEL OJꢀH. Isobutyryl chloride
was used instead of isobutyric anhydride.
Catalyst 1a without any substituents at the 3,3ʹꢀpositions of the binaphthyl unit afforded a
racemic monoacylate 3a along with a significant amount of diacylate 4a and the recovery of 2a
(3a/4a = 1.1; 32% NMR yield of 3a; 49:51 er; entry 1). Further screening of catalysts 1b–g did
not improve either the enantiomeric ratio of 3a or the chemoselectivity of monoacylation (3a/4a
= 0.89–1.7; 4–47% NMR yield; up to 40:60 er; entries 2–7). In contrast, catalyst 1h, which has
two tertꢀalcohol units (R = C(OH)Ph2) within a chiral binaphthyl unit, was effective in
producing 3a with high enantioselectivity (86% NMR yield of 3a; 94:6 er; entry 8), and
formation of the diacylate 4a was significantly suppressed (3a/4a = 8.6). Subsequent precise
tuning of the aryl moiety of the tertꢀalcohol revealed that catalysts with 4ꢀ or 3,5ꢀsubstituted
aryls 1i–l or dimethyl moieties 1m were less effective than catalyst 1h with regard to both the
enantioselectivity of 3a and the chemoselectivity of monoacylation (3a/4a = 0.74–5.0; 29–78%
NMR yield; up to 84:14 er; entries 9–13). On the other hand, αꢀamino acidꢀbased C1ꢀsymmetric
catalyst 5 developed by our group7 was also ineffective in this reaction (3a/4a = 1.6; 36% NMR
yield; 43:57 er; entry 14). Furthermore, the results clearly indicated that the leaving group of
acylation reagents (–OCOiꢀPr vs Cl), which consist of the counteranion of Nꢀacylpyridinium
–
6
ACS Paragon Plus Environment

Page 7 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
ion generated from catalyst 1h and the acylation reagent, strongly affected the enantioselectivity
of 3a (52:48 er, entry 15), and the low yield of 3a (23% NMR yield) and the high
chemoselectivity of monoacylation with isobutyryl chloride may be explained by the low
solubility and reactivity of Nꢀacylpyridinium chloride.16 Accordingly, catalyst 1h and isobutyric
anhydride were selected as the optimal combination for further optimization of the reaction
conditions (entry 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
Next, we screened various solvents in the desymmetrization of 2a with the optimal
catalyst 1h and isobutyric anhydride at 0 °C for 3 h (Table 2). The reactions in ethereal solvents,
involving tꢀBuOMe (TBME), Et2O, THF, and cyclopentyl methyl ether (CPME), afforded 3a in
high yield and with high chemoselectivity of monoacylation (3a/4a = 8.0–14; 80–86% NMR
yield of 3a; 88:12 to 94:6 er; entries 1–4). A series of other common organic solvents, except
hexane, could also be used in the reaction while maintaining an acceptable chemoselectivity of
monoacylation and enantioselectivity (3a/4a = 0.83–31; 81–92% NMR yield; up to 92:8 er;
entries 5–9). With aprotic or protic polar solvents (DMF, acetonitrile, and tꢀamyl alcohol) as
reaction media, the enantiomeric ratios of 3a and in some cases the chemoselectivity of
monoacylation were decreased (3a/4a = 2.8–21; 56–84% yield; up to 87:13 er; entries 10–12).
A similar tendency was observed in our previous studies,8a,b and such solvents might inhibit
efficient hydrogenꢀbonding between catalyst 1h and substrate 2a. After taking into account
these results and extensive screening of the reaction conditions involving effects of bases,
reaction temperature, concentration of substrate (see the Supporting Information for details), we
selected the reaction in the presence of catalyst 1h and triethylamine in TBME (0.1 M) at ꢀ20 °C
for further optimizations (3a/4a = 14, 85% NMR yield of 3a; 98:2 er; entry 13).
Table 2. Solvent screening for the desymmetrization of mesoꢀ2aa)
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 36
1
2
3
4
5
6
7
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
Entry Solvent 3a
4a
2a
3a/4a ER
of
[%]b) [%]b) [%]b)
3ac)
1
TBME 86
10
10
7
8
8.6
8.0
12
94:6
88:12
91:9
93:7
2
Et2O
THF
80
83
11
10
16
57
21
6
3
4
CPME 82
hexane 19
toluene 82
CH2Cl2 92
EtOAc 81
acetone 82
6
14
5
23
8
0.83 87:13
6
10
31
14
12
3.7
21
2.8
89:11
88:12
90:10
92:8
7
3
8
6
16
12
21
15
24
9
7
10
11
12
DMF
56
15
4
54:46
87:13
MeCN 84
tꢀamyl 56
alcohol
20
71.5:28.5
13d) TBME 85
6
9
14
98:2
a) Reactions were performed on a 0.1 mmol scale in solvent (0.1 M) under an argon atmosphere. b) NMR
1
c)
yields were determined by H NMR analysis using 2ꢀmethoxynaphthalene as an internal standard.
d)
Enantiomer ratios were determined by HPLC analysis using CHIRALCEL OJꢀH. The reaction was
carried out at –20 °C for 3 h.
We next sought to reduce the catalyst loading of 1h because 5 mol % of 1h still gave a
high chemoselectivity of monoacylation and high enantioselectivity (Table 3). We found that as
little as 0.1 mol % of catalyst 1h was sufficient to facilitate the reaction without a loss of
chemoselectivity or enantioselectivity (3a/4a = 12–21; 83–86% NMR yield; 97:3 er; entries 2–4
vs 1). While the use of 0.05 mol % of 1h showed an acceptable level of efficiency, a fair amount
of mesoꢀ2a remained after 3 h (3a/4a = 26; 77% NMR yield; 97:3 er; 22% NMR yield of
recovery 2a; entry 5). After further adjusting the amounts of isobutyric anhydride and
8
ACS Paragon Plus Environment

Page 9 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
triethylamine (1.3 or 1.5 equivalents, respectively, entries 7 and 8), we identified the optimal
reaction conditions (0.1 mol % of 1h, 1.3 equiv of isobutyric anhydride, and triethylamine in
TBME (0.2 M) at –20 ºC for 3 h) (3a/4a = 14; 86% NMR yield of 3a; 98:2 er; entry 7).
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
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 36
1
2
3
4
5
Table 3. Effects of catalyst loading in the desymmetrization of mesoꢀ2aa)
6
7
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
Entry X
3a
4a
2a
3a:4a ER of
[mol %] [%]b) [%]b) [%]b)
3ac)
1d)
2e)
3
5.0
1.0
0.5
0.1
0.05
0.1
0.1
85
86
83
83
77
86
83
6
9
14
12
17
21
26
14
5.9
98:2
97:3
97:3
97:3
97:3
98:2
97:3
7
8
5
14
12
22
5
4
4
5
3
7f)
8g)
6
14
<1
a) Reactions were performed on a 0.1 mmol scale in TBME (0.1 M) under an argon atmosphere. b) NMR
1
c)
yields were determined by H NMR analysis using 2ꢀmethoxynaphthalene as an internal standard.
d)
Enantiomer ratio was determined by HPLC analysis using CHIRALCEL OJꢀH. The same result as
e)
f)
shown in entry 13 in Table 2. Reaction was performed on a 0.2 mmol scale. 1.3 equiv of isobutyric
anhydride and triethylamine were used. g) 1.5 equiv of isobutyric anhydride and triethylamine were used.
Next, the desymmetrization reactions of various mesoꢀ1,2ꢀdiols including acyclic and
cyclic variants were examined under the optimal conditions (Figure 2). The reactions with
mesoꢀhydrobenzoin derivatives 2a–d gave the products in good yields with excellent
enantioselectivities (64–79% isolated yields of 3a–d with 95:5 to 97:3 er), and the
chemoselectivities of these monoacylates were synthetically useful (3/4 = 5.3–14.6). Acyclic
diols with alkylꢀ, allylꢀ, and hetero atomꢀfunctionalized alkyl substituents 2e–j could be
subjected to this catalytic system to afford monoacylates 3e–j in moderate to good yields with
high enantioselectivities (46–85% isolated yields of 3e–j with 86:14 to 97:3 er). Among them,
substrates 2i and 2j with electronꢀwithdrawing groups gave significant amounts of diacylates 4i
and 4j : the reason for this formation of undesirable diacylates is not yet clear. Next, we tested
10
ACS Paragon Plus Environment

Page 11 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
cyclic substrates 2k–2p. The enantioselective desymmetrization only proceeded with
sixꢀmemberedꢀring 1,2ꢀdiols 2m and 2n (79% isolated yield of 3m with 97:3 er, and 86%
isolated yield of 3n with 94:6 er), and the reactions of other cyclic substrates 2k, 2l, 2o, and 2p
under the optimal conditions only afforded racemate of monoacylates, albeit with high
chemoselectivity (3/4 = 7.3–14.7). A possible explanation for this result may be intramolecular
acyl migration (racemization) during the reaction (3 h).
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
Figure 2. Desymmetrization of various mesoꢀ1,2ꢀdiols promoted by catalyst 1h
To validate this assumption, the reaction of 2p in the initial stage (3 or 30 min) under otherwise
identical conditions was examined. The reaction also gave 3p with a 50:50 er.17 This suggests
that enantioselective acylation might not occur with catalyst 1h even in the initial stage of the
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 36
1
2
3
4
5
6
7
8
reaction. As shown in Scheme 2, we also check the racemization during the course of the
reaction of 2n. No racemization of enantioꢀenriched sixꢀmembered monoacylate 3n was
observed even with a different reaction time (step a) and higher reaction temperatures [0 °C
(step b) and 30 °C (step c)].
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
0.1 mol % 1h
1.3 equiv (i-PrCO)2O
1.3 equiv Et3N
OH
OH
OH
OH
OCOi-Pr
OCOi-Pr
step a
–40 ºC, 2 h
TBME (0.1 M)
–40 ºC, 1 h
2n
3n
3n
78% conv.
97:3 er
94% conv.
97:3 er
OH
OH
OCOi-Pr
OCOi-Pr
step c
step b
0 ºC, 1 h
30 ºC, 1 h
3n
3n
>98% conv.
97.5:2.5 er
>98% conv.
98:2 er
Scheme 2. Racemization studies of the acylative desymmetrization of mesoꢀ1,2ꢀdiol 2n.
Subsequently, the enantioꢀenriched sixꢀmembered monoacylate 3n (94:6 er) was subjected to
the reaction conditions in the presence of enantiomer of 1h (entꢀ1h) as depicted in eq. 1. Such
control experiments strongly suggested that intramolecular acyl transfer (racemization) of 3n
under this catalytic system is rather difficult, although further investigation is required to clarify
the reason for the lack of enantioselectivity with cyclic substrates except 2m and 2n.
Furthermore, to evaluate the possibility of kinetic resolution in the second acylation step (see
also Scheme 1), racꢀ3a was subjected to the optimal conditions to afford 4a in 25% conversion
with s = 4.2 along with recovered 3a (eq. 2).
12
ACS Paragon Plus Environment

Page 13 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
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
An analysis of the enantiomeric ratio of 3a in this control experiment pointed out that the
second acylation step consumes the major enantiomer of monoacylate 3a in the enantioselective
desymmetrization of mesoꢀ2a with catalyst 1h (e.g., Path A, Scheme 1). This indicates that the
enantiomeric ratio of monoacylate decreases when a significant amount of diacylate 4a is
generated (e.g., 3i and 3j in Figure 2).
To gain further insight into the role of the tertiary hydroxy units on the catalyst 1h, we
conducted additional experiments (Table 4). The desymmetrization of mesoꢀ2a was carried out
using bisꢀmethyl ether catalyst 1hʹ, C1ꢀsymmetric catalyst 1hʺ, pseudo C2ꢀsymmetric catalyst
1hʺʹ (lack of one hydroxy group), and C2ꢀsymmetric catalyst 1hʺʹʹ (lack of two hydroxy group)
under the optimal conditions (entries 2–5). The catalysts 1hʹ and 1hʺ were significantly less
effective than catalyst 1h with respect to both conversion and enantioselectivity (38% NMR
yield of 3a with 58:42 er, and 35% NMR yield of 3a with 52:48 er, respectively, entries 2 and 3
vs entry 1). On the other hand, the catalyst 1hʺʹnearly maintained enantiomeric ratio of 3a (95:5
er), but catalyst 1hʺʹʹ was less efficient in both the conversion and enantiomeric ratio of 3a
(10% NMR yield of 3a;69:31 er; entry 5 vs entry 1). These results clearly indicated that
C2ꢀsymmetric catalyst 1h with the two tertꢀalcohol units are essential to achieve high catalytic
activity and high enantioselectivity.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 36
1
2
3
4
5
Table 4. Effects of the tertꢀalcohol unit(s) of the catalyst in the desymmetrization of mesoꢀ2aa)
6
7
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
Entry Catalyst 3a
4a
2a
3a/4a ER of 3ac)
[%]b) [%]b) [%]b)
1d
2
1h
79
38
7
6
12
52
11
97:3
1hʹ
6.3
58:42
3
4
5
1hʺ
35
56
10
16
3
48
41
89
2.2
17
10
52:48
95:5
1hʺʹ
1hʺʹʹ
1
69:31
a) Reactions were performed on a 0.1 mmol scale in TBME (0.1 M) under an argon atmosphere. b) NMR
1
c)
yields were determined by H NMR analysis using 2ꢀmethoxynaphthalene as an internal standard.
d)
Enantiomer ratio was determined by HPLC analysis using CHIRALCEL OJꢀH. The same result as
shown in Figure 2.
14
ACS Paragon Plus Environment

Page 15 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
Conclusion
7
8
9
We have developed an acylative desymmetrization of meso-1,2ꢀdiols using a
binaphthylꢀbased DMAP derivative 1h with tertꢀalcohol units. The reaction proceeds with a
wide range of acyclic mesoꢀ1,2ꢀdiols, mesoꢀcyclohexane 1,2ꢀdiol, and mesoꢀcyclohexene
1,2ꢀdiol. Notably, as little as 0.1 mol % of the catalyst facilitates the reaction within a short
reaction time (3 h) to afford enantioꢀenriched monoacylated products in moderate to good yields
(up to 85% yield) with high enantioselectivities (up to 97:3 er). To the best of our knowledge,
this is the first example of an organocatalytic acylative desymmetrization reaction with
extremely low catalyst loading and suppression of the diacylate to a lower level than in previous
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
organocatalytic approaches 13
. Control experiments revealed that the tertꢀalcohol units of catalyst
1h play a significant role in achieving high catalytic activity, chemoselectivity of monoacylation,
and enantioselectivity. To clarify the detailed reaction mechanism and the role of the
tertꢀalcohol units, computational studies are now underway.
Experimental Section
General
Nuclear Magnetic Resonance (NMR) spectra were recorded on JEOL ECSꢀ400 (1H 400
1
MHz, 13C 100 MHz) spectrometers. Chemical shifts for H NMR are reported in parts per
million (ppm) relative to residual CHCl3 in CDCl3 (δ 7.26 ppm). Data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quin =quintet, sext =
sextet, sep = septet, b = broad, m = multiplet), coupling constants, and integration. Chemical
shifts for 13C NMR are reported in parts per million (ppm) relative to CDCl3 (δ 77.16 ppm) with
complete proton decoupling. Infrared (IR) spectra were recorded on a JASCO FT/IRꢀ4100
spectrophotometer, with Vmax in cm−1. Highꢀresolution mass spectrometry was performed on a
JEOL JMSꢀ700 MStation (FABꢀMS) or an Agilent 6520 Accurate Mass QTOF LC/MS
(ESIꢀMS). Optical rotations were measured on a JASCO DIPꢀ1000. Melting points were
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 36
1
2
3
4
5
6
7
8
recorded on a SANSYO SMPꢀ300. Enantiomeric ratios were determined by analytical liquid
chromatography (HPLC), with a Shimadzu chromatograph (DAICEL CHIRALPAK® IAꢀ3 (4.6
× 150 mm), DAICEL CHIRALPAK® ASꢀ3 (4.6 × 150 mm), and DICEL CHIRALCEL OJꢀH
(4.6 × 250 mm), in comparison with authentic racemic samples. Chiral GC analysis was
performed on a gas chromatograph (SHIMADZU GCꢀ14B) equipped with a flame ionization
detector using a fused silica capillary. Column chromatography was performed with silica gel 60
N (spherical, neutral, 40–50 µm) purchased from KANTO CHEMICAL CO., INC. All
experiments were carried out under an argon atmosphere unless otherwise noted.
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
Materials
All reagents were obtained from commercial sources and used as received unless
otherwise noted. Dry tetrahydrofuran [THF], dry diethyl ether [Et2O], diethyl ether [Et2O],
tꢀamyl alcohol, triethylamine [Et3N], Nꢀethyldiisopropylamine [iꢀPr2NEt], pyridine,
1ꢀmethylimidazole [NMI], N,N,N',N'ꢀtetramethylethylenediamine [TMEDA], tripotassium
phosphate [K3PO4], cycloheptene, mesoꢀerythritol and 2,2ꢀdimethoxypropane were purchased
from Wako Pure Chemical Industries, Ltd. Dry diisopropyl ether [iꢀPr2O],
1,8ꢀbis(dimethylamino)naphthalene
[protonꢀsponge],
sodium
hydroxide
[NaOH],
cyclohexaꢀ1,4ꢀdiene, 4,4'ꢀdifluorobenzil,
4,4'ꢀdimethylbenzil,
mesoꢀ2,3ꢀbutanediol,
cisꢀcyclopentanediol, cisꢀcyclohexanediol and cisꢀ1,2ꢀcyclooctanediol were purchased from
SigmaꢀALDRICH Japan. Ethyl acetate [EtOAc], methanol [MeOH], dichloromethane [CH2Cl2],
toluene, benzene, cesium carbonate [Cs2CO3], potassium carbonate [K2CO3], hydrochloric acid
aqueous solution [HCl], magnesium sulfate [MgSO4], ammonium chloride [NH4Cl], copper(I)
bromide [CuBr], benzyl bromide [BnBr], sodium bicarbonate [NaHCO3], iodine [I2], potassium
iodate [KIO3], pꢀnitrobenzoyl chloride and molecular sieve 4A [MS4A] were purchased from
NAKALAI TESQUE, INC. Hexane, dimethylformamide [DMF], chloroform [CHCl3], and
nꢀbutyl lithium [nꢀBuLi] were purchased from KANTO CHEMICAL CO., INC. Isobutyric
16
ACS Paragon Plus Environment

Page 17 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
anhydride [(iꢀPrCO)2O], isobutyryl chloride [iꢀPrCOCl], cyclopentyl methyl ether [CPME],
7
8
tꢀbutyl
methyl
ether
[tꢀBuOMe],
1,8ꢀdiazabicyclo[5,4,0]ꢀ7ꢀundecene
[DBU],
9
mesoꢀ1,4ꢀdichloroꢀ2,3ꢀbutanediol, cisꢀ3,4ꢀtetrahydrofurandiol, 4,4ʹꢀdibromobenzil, erythritol
anhydride, sodium borohydride [NaBH4], sodium hydride [NaH], methylmagnesium bromide
[MeMgBr] and potassium acetate [KOAc] were purchased from Tokyo Chemical Industry Co.,
Ltd. Acetone was purchased from Japan Alcohol Trading CO., LTD. Hexane, DMF, EtOAc,
CPME, tꢀBuOMe, and tꢀamyl alcohol were used after dehydration with MS4A. CH2Cl2,
(iꢀPrCO)2O, Et3N, iꢀPr2NEt, pyridine and TMEDA were distilled over CaH2. Toluene was
distilled over CaH2 and stored in the presence of MS4A. MS4A was used after drying with a
heat gun under reduced pressure. All catalysts were synthesized according to the respective
literature8a,c except for catalyst 1m, 1hʺʹ, and 1hʺʹʹ. mesoꢀ2b–d,18 2j19 and 2n20 were
synthesized according to the literature. mesoꢀ2f, 2g, 2h and 2o were synthesized by a slight
modification of the procedures in the literature. mesoꢀ2a, 2e, 2i, 2k, 2l, 2m, and 2p were
purchased from commercial suppliers. Racemic samples of monoacylate and diacylate were
synthesized by a general acylation method with 5 mol % of DMAP, 1.5 equiv of (iꢀPrCO)2O,
and 1.5 equiv of Et3N in CH2Cl2. Benzoate was synthesized by a general benzoylation method
with 1.5 equiv of TMEDA and 1.5 equiv of benzoyl chloride [BzCl] in CH2Cl2.13a
pꢀNitrobenzoate was synthesized by a general pꢀnitrobenzoylation method with 1.5 equiv of
TMEDA and 1.5 equiv of pꢀnitrobenzoyl chloride in CH2Cl2.
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
Syntheses of catalysts 1m, 1hʺʹ, and 1hʺʹʹ
(S)ꢀ2,6ꢀbis(hydroxydimethylmethyl)ꢀ4ꢀ(pyridinꢀ4ꢀyl)ꢀ4,5ꢀdihydroꢀ3Hꢀdinaphtho[2,1ꢀc:1ʹ,2ʹ
ꢀe]azepine (1m). To a solution of 1e (50.5 mg, 97.8 µmol) in THF (1.00 mL) was added methyl
lithium (3.0 M in diethoxymethane, 666 µL, 2.0 mmol) at 0 °C. The reaction solution was
stirred for 1 h at 0 °C. After stirring for 1 h, water (2 mL) was added to reaction vessel. The
resulting solution was extracted with CH2Cl2, dried over MgSO4, and concentrated in vacuo.
The Purification of the crude product by flash column chromatography on silica gel (eluent:
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 36
1
2
3
4
5
6
7
8
9
1
CHCl3/MeOH = 5/1, v/v) gave 1m (22.8 mg, 46.7 µmol, 48% yield) as yellow solid. H NMR
(400 MHz, CDCl3 in 0.03% TMS) δ 8.19–8.08 (m, 2H), 8.00 (s, 2H), 7.90 (d, J = 8.2 Hz, 2H),
7.50–7.42 (m, 2H), 7.32–7.13 (m, 10H), 6.73 (d, J = 6.0 Hz, 2H), 6.16 (d, J = 13.0 Hz, 2H),
3.68 (d, J = 13.0 Hz, 2H), 1.84 (s, 6H), 1.62 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 153.5,
148.2, 143.4, 138.4, 132.3, 131.4, 130.8, 128.5, 128.5 (2), 127.5, 126.2, 125.6, 109.3, 73.4, 45.1,
32.8, 31.8; IR (KBr) 3333, 2976, 1595, 1508, 1234 cm–1; HRMS (ESI+) calculated for
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
C33H32N2O2 [M+H]+ 489.2537, found 489.2540; mp 169.5–170.2 °C; [α]22 –161.4 (c 0.20,
D
CHCl3, Sꢀconfiguration).
(S)ꢀ(6ꢀbenzhydrylꢀ4ꢀ(pyridinꢀ4ꢀyl)ꢀ4,5ꢀdihydroꢀ3Hꢀdinaphtho[2,1ꢀc:1ʹ,2ʹꢀe]azepinꢀ2ꢀyl)dip
henylmethanol (1hʺʹ). To a solution 1h (0.173 g, 0.23 mmol), triethylsilane (37.0 µL, 0.23
mmol) in CH2Cl2 (2.2 mL) was added trifluoroacetic acid (0.123 mL, 1.61 mmol) for 1 min at
0 °C. The reaction mixture was warm up to room temperature and stirred 2 h. Then, water (10
mL) and NaHCO3aq (10 mL) were added to the reaction mixture and extracted with CH2Cl2 (20
mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo. The purification
of the crude product by flash column chromatography on silica gel (eluent: EtOAc/MeOH =
1
15/1, v/v) gave 1hʺʹ (64.2 mg, 0.09 mmol, 38% yield) as a pale yellow solid. H NMR (400
MHz, CDCl3) δ 7.82 (bs, 2H), 7.67 (t, J = 7.3 Hz, 2H), 7.46–7.15 (m, 22H), 7.13–6.95 (m, 8H),
6.72 (d, J = 7.3 Hz, 2H), 6.16 (bs, 2H), 5.69 (s, 1H), 5.27 (d, J = 12.1 Hz, 1H), 4.80 (d, J = 13.5
Hz, 1H), 3.55 (d, J = 13.5 Hz, 1H), 3.28 (d, J = 12.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
153.4, 147.7, 146.7, 145.9, 143.5, 143.1, 142.4, 139.2, 138.7, 136.4, 132.7, 132.2, 131.8, 131.0,
130.6, 130.5, 130.3, 129.6, 128.9, 128.8, 128.5, 128.4, 128.3, 127.9, 127.8, 127.6, 127.5, 127.3,
126.9 (2), 126.6, 126.4, 126.2, 126.0, 108.5, 83.1, 54.6, 45.5, 45.2, 29.8; IR (KBr) 3057, 3024,
2360, 1595, 1508, 1242, 993, 750, 698 cm–1; HRMS (FAB+) calculated for C53H41N2O [M+H]+
721.3213, found 721.3221; mp 220 ºC dec.; [α]22D –324.1 (c 1.00, CHCl3, (S)ꢀconfiguration).
(S)ꢀ2,6ꢀdibenzhydrylꢀ4ꢀ(pyridinꢀ4ꢀyl)ꢀ4,5ꢀdihydroꢀ3Hꢀdinaphtho[2,1ꢀc:1ʹ,2ʹꢀe]azepine
(1hʺʹʹ). To a solution 1h (0.197 g, 0.27 mmol), triethylsilane (0.41 mL, 2.7 mmol) in CH2Cl2
18
ACS Paragon Plus Environment

Page 19 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(2.2 mL)was added trifluoroacetic acid (0.145 mL, 1.89 mmol) for 1 min at 0 °C. The reaction
mixture was warm up to room temperature and stirred for 2 h. Then, water (10 mL) and
NaHCO3 aq (10 mL) were added to the reaction mixture and extracted with CH2Cl2 (20 mL × 3).
The organic layer was dried over MgSO4 and concentrated in vacuo. The purification of the
crude product by short pad of silica gel (eluent: EtOAc) gave 1hʺʹʹ (0.196 g, 0.27 mmol, >98%
yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 4.6 Hz, 2H), 7.71 (d, J
= 8.2 Hz, 2H), 7.48–7.39 (m, 4H), 7.37–7.23 (m, 10H), 7.18–7.02 (m, 10H), 6.83 (d, J = 6.9 Hz,
4H), 6.35 (d, J = 5.0 Hz, 2H), 5.79 (s, 2H), 4.75 (d, J = 13.4 Hz, 2H), 3.40 (d, J = 13.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 153.0, 149.5, 143.4, 142.6, 139.7, 136.7, 132.7, 132.2, 130.3,
129.6, 129.5, 128.8, 128.5, 128.4, 127.6, 126.8, 126.7, 126.2, 126.0, 108.5, 54.7, 44.9; IR (KBr)
3059, 3024, 2360, 1593, 1508, 750, 700 cm–1; HRMS (FAB+) calculated for C53H41N2 [M+H]+
705.3264, found 705.3259; mp >280 ºC; [α]22D –370.7 (c 1.00, CHCl3, (S)ꢀconfiguration).
Synthesis of mesoꢀ2f, 2g, 2h and 2o
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
Synthesis of (4R,5S)ꢀoctaꢀ1,7ꢀdieneꢀ4,5ꢀdiol (mesoꢀ2f). To a suspension of CuBr (2.75 g, 19.2
mmol) in THF (5.9 mL) at –40 °C is added vinyl magnesium bromide (1.0 M in THF, 28.8 mL,
28.8 mmol) dropwise. After 0.5 h, a solution of erythritol anhydride (1.05 g, 12.2 mmol) in THF
(6.6 mL) is added dropwise. After 4 h, the mixture was allowed to slowly warm to 0 °C and
saturated aqueous NaHCO.3 (15 mL) was added. The precipitates were filtered off, and the
filtrate was separated and the aqueous layer was extracted with EtOAc. The organic extracts
were combined, dried MgSO4, concentrated under reduced pressure and purified by Gel
Permeation Chromatography (elution: toluene) to give the a colorless solid 2f (123 mg, 0.865
mmol, 7% yield). The spectroscopic data of 2f was in good agreement with previously reported
1
data.21 Colorless solid. H NMR (400 MHz, CDCl3) δ 5.90–5.76 (m, 2H), 5.21–5.05 (m, 4H),
3.65 (dd, J = 7.3, 3.2 Hz, 2H), 2.53–2.05 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 134.8, 118.3,
72.9, 36.4; IR (KBr) 3310, 3076, 2899, 1645, 989 cmꢀ1
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 36
1
2
3
4
5
6
Synthesis of (2R,3S)ꢀ1,4ꢀbis(benzyloxy)butaneꢀ2,3ꢀdiol (mesoꢀ2g). This compound was
7
8
prepared through fourꢀstep telescoped reactions as follows:
9
(1)
((4R,5S)ꢀ2,2ꢀdimethylꢀ1,3ꢀdioxolaneꢀ4,5ꢀdiyl)bis(methylene)
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
bis(2,2ꢀdimethylpropanoate). 2h (8.69 g, 29.9 mmol), 2,2ꢀdimethoxypropane (20 mL, 162.7
mmol), and pꢀtoluenesulfonic acid (576 mg, 3.03 mmol) were stirred in anhydrous toluene (300
mL) under argon. After stirring for 30 min at 50 °C, the reaction mixture was further stirred at
40 °C for 6 h. A saturated aqueous solution of NaHCO3 was added and the mixture was stirred
for 30 min. The aqueous layer was extracted with ethyl acetate. The organic layers were
combined and washed with brine. After drying over MgSO4, solvent was concentrated in vacuo
and the residue was passed through a short pad of silica gel (eluent: Et2O) to give yellow oil 5
(9.70 g, 29.4 mmol, 98% yield). This crude product was used for next reaction without further
purification and characterization.
(2) ((4R,5S)ꢀ2,2ꢀdimethylꢀ1,3ꢀdioxolaneꢀ4,5ꢀdiyl)dimethanol. The crude product from
previous reaction (9.20 g, 27.9 mmol) was stirred in methanol (70 mL) at room temperature.
KOH aq (6 M, 70 mL, 420 mmol) was added, then the reaction mixture was stirred for 4 h at
60 °C. After methanol was removed in vacuo, the aqueous layer was extracted with THF. The
organic layers were combined and washed with brine. After drying over MgSO4, solvent was
concentrated in vacuo and the residue was passed through a pad of silica gel (eluent: EtOAc) to
give yellow oil (2.64 g, 16.26 mmol, 58% yield). The spectroscopic data was in good agreement
with previously reported data.22 This crude product was used for next reaction without further
purification.
(3) (4R,5S)ꢀ4,5ꢀbis((benzyloxy)methyl)ꢀ2,2ꢀdimethylꢀ1,3ꢀdioxolane. To a suspension of NaH
(60% dispersion in paraffin liquid, 487 mg, 12.2 mmol) in THF (60 mL) was added dropwise
the crude product from previous reaction (629.7 mg, 0.22 M in THF, 18.2 mL, 3.88 mmol) at
room temperature. The resulting mixture was stirred for 10 min, and then BnBr (1.05 mL, 8.8
mmol) was added to reaction vessel at room temperature. The reaction mixture was stirred for
20
ACS Paragon Plus Environment

Page 21 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
24 h, and then saturated aqueous NH4Cl was added to reaction vessel. The resulting solution
was extracted with EtOAc, dried over MgSO4, and concentrated in vacuo to give the crude
product (939 mg, 2.74 mmol, 71% yield). The crude product was directly used next reaction
without further purification and characterization.
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
(4) To a solution of the crude product from previous reaction (825.1 mg, 2.49 mmol) in MeOH
(25 mL) was added aqueous HCl (6.0 M, 5 mL, 30 mmol) at 0 °C. The reaction mixture was
heated up to room temperature and stirred for 24 h. After stirring for 24 h, saturated aqueous
NaHCO3 was added to reaction vessel. The resulting solution was concentrated in vacuo. The
residue was dissolved EtOAc and water. The resulting solution was extracted with EtOAc, dried
over MgSO4, and concentrated in vacuo to give the crude product. The purification of the crude
product by recrystallization from Et2Oꢀhexane gave colorless solid 2g (438.2 mg, 1.45 mmol,
58% yield, first crop). The spectroscopic data of 2g was in good agreement with previously
reported data.18 Colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.44–7.27 (m, 10H), 4.55 (s, 4H),
3.90–3.79 (m, 2H), 3.71–3.60 (m, 4H), 2.67 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 137.9,
128.6, 128.0 (2), 73.7, 71.5, 71.2; IR (KBr) 3462, 3277, 2903, 1456, 1213, 752 cmꢀ1
Synthesis of (2R,3S)ꢀ2,3ꢀdihydroxybutaneꢀ1,4ꢀdiylꢀbis(2,2ꢀdimethylpropanoate) (mesoꢀ2h)
Mesoꢀerythritol (10.0 g, 81.9 mmol) was stirred in pyridine (400 mL) at room temperature. The
solution was cooled to 0 °C and then pivaloyl chloride (20.2 mL, 164 mmol) was added. The
reaction mixture was stirred for 2 h at room temperature. Then the resulting mixture was
concentrated in vacuo. The purification of the crude product by recrystallization from
Et2Oꢀhexane gave colorless solid 2h (11.5 g, 39.7 mmol, 48% yield). Colorless solid. 1H NMR
(400 MHz, CDCl3) δ 4.40–4.29 (m, 4H), 3.79–3.73 (m, 2H), 1.23 (s, 18H); 13C NMR (100 MHz,
CDCl3) δ 179.6, 70.7, 65.6, 39.1, 27.3; IR (KBr) 3499, 2986, 2972, 1705, 1180 cmꢀ1; HRMS
(FAB+) [M+H]+ calculated for C14H27O6 291.1802, found 291.1774; mp 82.7–83.0 °C
(1R,2S)ꢀcycloheptaneꢀ1,2ꢀdiol (mesoꢀ2o). This compound was prepared through twoꢀstep
reactions as follows:
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 36
1
2
3
4
5
6
7
8
(1) cisꢀ2ꢀhydroxycycloheptyl acetate. Cycloheptene (4.23 g, 43.9 mmol) was added to a stirred
solution of KIO3 (2.36 g, 11.0 mmol) and I2 (5.59 g, 22.0 mmol) in AcOH (73.3 mL) at room
temperature under argon. The resulting mixture was stirred at 60 °C for 4 h. After cooling,
KOAc (4.33 g, 44.1 mmol) was added and the mixture was heated at reflux for 4 h. After
cooling, water (2 mL) was added and the solvent was evaporated under reduced pressure over a
period of 1 h. Et2O (100 mL) was added and the organic layer was washed with saturated
aqueous Na2SO3 until the brown color was removed, dried MgSO4 and evaporated under
reduced pressure to give a crude mixture of mono and diacetate. Then, the purification of the
crude product by flash column chromatography on a silica gel (eluent: hexane/Et2O = 5/1 to 3/1
to 1/1 to Et2O, v/v) gave the monoacetate (3.54 g, 20.6 mmol, 47% yield). The spectroscopic
data of monoacetate was in good agreement with previously reported data.23
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
(2) K2CO3 (6.09 g, 44.1 mmol) was added to a stirred solution of monoacetate (3.44 g, 20.0
mmol) from previous reaction in 10% aqueous methanol (78.5 mL) at room temperature. After
stirring vigorously for 2 h, methanol was removed under reduced pressure. Then, a minimum of
saturated aqueous NH4Cl, followed by solid brine were added to the mixture and the water layer
was extracted six times with EtOAc. The combined organic layers were dried over MgSO4 and
concentrated in vacuo. The purification of the crude product by recrystallization from
Et2Oꢀhexane gave colorless solid 2o (591 mg, 4.54 mmol, 23% yield). The spectroscopic data of
2o was in good agreement with previously reported data.24 Colorless solid. 1H NMR (400 MHz,
CDCl3) δ 3.89–3.79 (m, 2H), 2.62 (brs, 2H), 1.87–1.26 (m, 10H); 13C NMR (100 MHz, CDCl3)
δ 73.8, 30.8, 27.8, 22.1; IR (KBr) 3354, 2928, 1458, 1074, 930 cm–1.
General procedure for the desymmetrization of mesoꢀ1,2ꢀdiol with catalyst 1h
When 0.1 mol % of the catalyst was used in the reaction, a solution of the catalyst in
chloroform (10.0 mM) was prepared in advance. This stock solution was added to a test tube,
and the solvent was removed. The resulting catalyst was used for the following reaction.
22
ACS Paragon Plus Environment

Page 23 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Catalyst 1h, mesoꢀdiol 2a–p, and Et3N were stirred in tꢀBuOMe (TBME) at room temperature.
The mixture was cooled to −20 °C, and then isobutyric anhydride was added. The reaction
9
mixture was stirred for 3 h. Methanol was added to quench the reaction and the mixture was
stirred for 1 h at room temperature. After the mixture was concentrated in vacuo, the catalyst
was separated from the crude product by flash column chromatography on a short pad of silica
gel (eluent: Et2O). Purification of the crude product by flash column chromatography on a silica
gel (eluent: hexane/Et2O = 5/1 to 3/1 to1/1 to Et2O, v/v) gave the monoacylate 3a–p, diacylate
4a–p, and recovered substrate 2a–p. The enantiomeric ratios of 3a–d and 3f–p were determined
by chiral HPLC analysis, and that of 3e was determined by chiral GC analysis. The analytical
data for 3a, 4a and 2a have been reported previously.8a
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
Analytical data for products 3b–p and 4b–p
(1S,2R)ꢀ2ꢀhydroxyꢀ1,2ꢀdiꢀpꢀtolylethyl isobutyrate (3b). According to the general procedure,
substrate 2b (72.3 mg, 0.298 mmol) with catalyst 1h (0.3 ꢁmol), Et3N (54.2 ꢁL, 0.390 mmol),
and isobutyric anhydride (64.6 ꢁL, 0.390 mmol) in TBME (3 mL) at −20 °C gave monoacylate
3b (68.3 mg, 0.219 mmol, 73% yield, 97:3 er), diacylate 4b (6.0 mg, 0.0157 mmol, 5% yield),
and recovered 2b (11.4 mg, 0.0470 mmol, 16% yield). Colorless solid. Enantiomeric ratio was
determined by HPLC with DAICEL CHIRALPAK® IAꢀ3 (hexane/i-PrOH = 95/5, v/v, flow rate
= 1.0 mL/min, 30 °C, UV = 254 nm), TR = 10.5 min (minor) and TR = 12.7 min (major), 97:3 er;
1H NMR (400 MHz, CDCl3) δ 7.22–7.08 (m, 8H), 5.84 (d, J = 6.7 Hz 1H), 4.90 (d, J = 6.7 Hz,
1H), 2.45 (sep, J = 7.0 Hz, 1H), 2.34 (s, 3H), 2.34 (s, 3H), 2.07 (s, 1H), 1.04 (d, J = 7.0 Hz, 3H),
1.01 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.7, 137.9, 137.5, 137.0, 134.2,
128.9, 128.7, 127.5, 127.0, 78.3, 76.3, 34.0, 21.2, 21.1, 18.7; IR (KBr) 3536, 2974, 2866, 1717,
1452, 1389, 1152, 970, 748, 706 cmꢀ1; HRMS (FAB+) [M+Na]+ calculated for C20H24O3Na
335.1617, found 335.1625; mp 83.6–84.2 °C; [α]24D +14.9 (c 1.00, CHCl3, 97:3 er)
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 36
1
2
3
4
5
6
7
8
9
(1R,2S)ꢀ1,2ꢀdiꢀpꢀtolylethaneꢀ1,2ꢀdiyl bis(2ꢀmethylpropanoate) (4b). Colorless solid. 1H NMR
(400 MHz, CDCl3) δ 7.15–7.05 (m, 8H), 6.02 (s, 2H), 2.47 (sep, J = 7.2 Hz, 2H), 2.32 (s, 6H),
1.57 (s, 1H), 1.05 (d, J = 7.2 Hz, 6H), 1.03 (d, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
175.5, 138.0, 133.7, 128.8, 127.7, 76.2, 34.2, 21.3, 18.9, 18.8; IR (KBr) 2974, 1736, 1516, 1354,
1182, 762 cmꢀ1; HRMS (FAB+) [M+Na]+ calculated for C24H30O4Na 405.2036, found 405.2029;
mp 108.8–109.9 °C
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
(1S,2R)ꢀ1,2ꢀbis(4ꢀbromophenyl)ꢀ2ꢀhydroxyethyl isobutyrate (3c). According to the general
procedure, substrate 2c (111.7 mg, 0.300 mmol) with catalyst 1h (0.3 ꢁmol), Et3N (54.2 ꢁL,
0.390 mmol), and isobutyric anhydride (64.6 ꢁL, 0.390 mmol) in TBME (3 mL) at −40 °C gave
monoacylate 3c (85.4 mg, 0.193 mmol, 64% yield, 95:5 er), diacylate 4c (19.0 mg, 0.0371
mmol, 12% yield), and recovered 2c (25.2 mg, 0.0677 mmol, 23% yield). Colorless solid.
Enantiomeric ratio was determined by HPLC with DAICEL CHIRALPAK® IAꢀ3
(hexane/i-PrOH = 98.5/1.5, v/v, flow rate = 1.0 mL/min, 30 °C, UV = 254 nm), TR = 44.9 min
(minor) and TR = 53.5 min (major), 95:5 er; 1H NMR (400 MHz, CDCl3) δ 7.46–7.41 (m, 4H),
7.12–7.06 (m, 4H), 5.80 (d, J = 5.6 Hz, 1H), 4.93 (q, J = 5.6, 3.1 Hz, 1H), 2.52 (sept, J = 6.9 Hz,
1H), 2.15 (d, J = 3.1 Hz, 1H), 1.09 (d, J = 6.9 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 175.8, 138.4, 135.6, 131.6, 131.4, 129.3, 128.8, 122.7, 122.3, 77.8, 75.9, 34.1,
18.9; IR (KBr) 3524, 3503, 2976, 1728, 1489, 745 cmꢀ1; HRMS (FAB+) calculated for
C18H1879Br81BrO3Na [M+Na]+ 464.9494, found 464.9470; mp 110.0–111.1 °C; [α] 22 +7.2 (c
D
1.0, CHCl3, 94:6 er).
(1R,2S)ꢀ1,2ꢀbis(4ꢀbromophenyl)ethaneꢀ1,2ꢀdiyl bis(2ꢀmethylpropanoate) (4c). Colorless
1
solid. H NMR (400 MHz, CDCl3) δ 7.45–7.39 (m, 4H), 7.10ꢀ7.03 (m, 4H), 5.98 (s, 2H), 2.51
(sep, J = 7.0 Hz, 2H), 1.08 (d, J = 7.0 Hz, 6H), 1.07 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.4, 135.2, 131.5, 129.3, 122.7, 75.5, 34.1, 18.9, 18.8; IR (KBr) 2974, 1728, 1558,
1489, 1153, 808 cmꢀ1; HRMS (FAB+) calculated for C22H2479Br81BrO4Na [M+Na]+ 534.9913,
found 534.9938; mp 151.4–152.5 °C
24
ACS Paragon Plus Environment

Page 25 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(1S,2R)ꢀ1,2ꢀbis(4ꢀbromophenyl)ꢀ2ꢀhydroxyethyl isobutyrate (3d). According to the general
procedure, substrate 2d (75.0 mg, 0.300 mmol) with a catalyst 1h (0.3 ꢁmol), Et3N (54.2 ꢁL,
0.390 mmol), and isobutyric anhydride (64.6 ꢁL, 0.390 mmol) in TBME (3 mL) at −20 °C gave
monoacylate 3d (74.9 mg, 0.234 mmol, 78% yield, 95:5 er), diacylate 4d (13.5 mg, 0.0346
mmol, 12% yield), and recovered 2d (7.4 mg, 0.0296 mmol, 10% yield). Colorless solid.
Enantiomeric ratio was determined by HPLC with DAICEL CHIRALPAK® IAꢀ3
(hexane/i-PrOH = 98.5/1.5, v/v, flow rate = 1.0 mL/min, 30 °C, UV = 254 nm), TR = 29.4 min
(minor) and TR = 31.4 min (major), 95:5 er; 1H NMR (400 MHz, CDCl3) δ 7.25–7.15 (m, 4H),
7.05–6.91 (m, 4H), 5.82 (d, J = 6.2 Hz, 1H), 4.91 (dd, J = 6.2, 2.7 Hz, 1H), 2.49 (sept, J = 7.0
Hz, 1H), 2.31 (bs, 1H), 1.06 (d, J = 7.0 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.8, 162.8 (d, J = 247.3 Hz), 162.6 (d, J = 246.3 Hz), 135.3 (d, J = 2.8 Hz), 132.6 (d,
J = 2.9 Hz), 129.4 (d, J = 7.7 Hz), 128.8 (d, J = 8.6 Hz), 115.4 (d, J = 22.0 Hz), 115.2 (d, J =
22.0 Hz) 77.8, 75.9, 34.1, 18.8; IR (KBr) 3516, 2974, 1717, 1609, 1512, 1236, 797 cmꢀ1; HRMS
(FAB+) calculated for C18H18F2O3Na [M+Na]+ 343.1116, found 343.1131; mp 104.1–104.6 °C;
[α] 22D +7.1 (c 1.00, CHCl3, 95:5 er).
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
(1R,2S)ꢀ1,2ꢀbis(4ꢀfluorophenyl)ethaneꢀ1,2ꢀdiyl bis(2ꢀmethylpropanoate) (4d). Colorless
solid. 1H NMR (400 MHz, CDCl3) δ 7.23–7.14 (m, 4H), 6.99 (t, J = 8.5 Hz, 4H), 6.02 (s, 2H),
2.49 (sep, J = 6.9 Hz, 2H), 1.10–0.97 (m, 12H); 13C NMR (100 MHz, CDCl3) 175.5, 162.8 (d, J
= 247.3 Hz), 132.3 (d, J = 2.9 Hz), 129.4 (d, J = 8.6 Hz), 115.3 (d, J = 22.0 Hz), 75.5, 34.2, 18.9,
18.8; IR (KBr) 2976, 1728, 1605, 1514, 123.1, 773 cmꢀ1; HRMS (FAB+) calculated for
C22H24F2O4Na [M+Na]+ 413.1514, found 413.1518; mp 118.7–119.5 °C.
(2S,3R)ꢀ3ꢀhydroxybutanꢀ2ꢀyl isobutyrate (3e).25. According to the general procedure, substrate
2e (56.6 mg, 0.628 mmol) with a catalyst 1h (0.6 ꢁmol), Et3N (108 ꢁL, 0.780 mmol), and
isobutyric anhydride (129 ꢁL, 0.778 mmol) in TBME (6 mL) at −40 °C gave monoacylate 3e
(85.5 mg, 0.534 mmol, 85% yield, 97:3 er), diacylate 4e (10.5 mg, 0.0456 mmol, 7% yield), and
recovered 2e (3.8 mg, 0.0422 mmol, 7% yield). Pale yellow oil. Enantiomeric ratio was
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 36
1
2
3
4
5
6
7
8
determined by chiral GC with CPꢀCyclodextrinꢀBꢀ2,3,6ꢀMꢀ19 (65 °C hold), TR = 46.7 min
(major) and TR = 51.4 min (minor), 97:3 er; 1H NMR (400 MHz, CDCl3) δ 4.85 (dq, J = 6.4, 3.2
Hz, 1H), 3.87 (dq, J = 6.4, 3.2 Hz, 1H), 2.55 (sep, J = 6.9 Hz, 1H), 1.92 (s, 1H), 1.23–1.11 (m,
12H); 13C NMR (100 MHz, CDCl3) δ 177.0, 74.2, 69.8, 34.2, 19.1 (2), 18.0, 14.4; IR (neat)
3447, 2978, 1734, 1716, 1206, 1082 cmꢀ1; [α] 21D ꢀ0.49 (c 1.00, CHCl3, 97:3 er).
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
1
(2R,3S)ꢀbutaneꢀ2,3ꢀdiyl bis(2ꢀmethylpropanoate) (4e).13h Pale yellow oil. H NMR (400
MHz, CDCl3, 0.03% TMS) δ 5.03–4.95 (m, 2H), 2.53 (sep, J = 6.9, 1H), 1.21 (d, J = 6.4 Hz,
1H), 1.16 (d, J = 6.9 Hz, 6H), 1.15 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 176.3,
71.0, 34.2, 19.0, 18.4, 15.1; IR (neat) 2965, 2924, 1738, 1096, 1016, 800 cmꢀ1
(4S,5R)ꢀ5ꢀhydroxyoctaꢀ1,7ꢀdienꢀ4ꢀyl isobutyrate (3f). According to the general procedure,
substrate 2f (40.7 mg, 0.286 mmol) with a catalyst 1h (0.286 ꢁmol), Et3N (51.6 ꢁL, 0.371
mmol), and isobutyric anhydride (61.6 ꢁL, 0.372 mmol) in TBME (2.86 mL) at −20 °C gave
monoacylate 3f (49.0 mg, 0.231 mmol, 81% yield, 91:9 er), diacylate 4f (3.1 mg, 0.0110 mmol,
4% yield), and recovered 2f (6.2 mg, 0.0436 mmol, 15% yield). Colorless oil. Enantiomeric
ratio was determined by HPLC with DAICEL CHIRALPAK® IAꢀ3 (hexane/i-PrOH = 98.5/1.5,
v/v, flow rate = 1.0 mL/min, 30 °C, UV = 205 nm), TR = 8.4 min (major) and TR = 9.0 min
1
(minor), 91:9 er; H NMR (400 MHz, CDCl3) δ 5.87–5.66 (m, 2H), 5.15 (d, J = 3.7 Hz, 1H),
5.13–5.08 (m, 3H), 4.89 (dt, J = 8.5, 4.6 Hz, 1H), 3.74 (dt, J = 8.5, 4.6 Hz, 1H), 2.54 (sep, J =
6.9 Hz, 1H), 2.48–2.24 (m, 3H), 2.23–2.05 (m, 1H), 1.15 (d, J = 6.9 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 176.9, 134.2, 133.8, 118.6, 117.9, 75.1, 71.6, 37.3, 34.5, 34.3, 19.2, 19.0; IR
(neat) 3464, 3078, 2976, 1732, 1472, 914 cmꢀ1; HRMS (FAB+) calculated for C12H21O3 [M+H]+
213.1485, found 213.1476; [α]23D +17.5 (c 1.00, CHCl3, 91:9 er).
1
(4R,5S)ꢀoctaꢀ1,7ꢀdieneꢀ4,5ꢀdiyl bis(2ꢀmethylpropanoate) (4f). Colorless oil. H NMR (400
MHz, CDCl3) δ 5.79–5.65 (m, 2H), 5.14–5.01 (m, 6H), 2.53 (sep, J = 7.0 Hz, 2H), 2.44–2.25 (m,
4H), 1.16 (d, J = 7.0 Hz, 6H), 1.15 (d, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3, 0.03%
26
ACS Paragon Plus Environment

Page 27 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
TMS) δ 176.3, 133.3, 118.2, 72.4, 34.6, 34.3, 19.1 (2); IR (neat) 2976, 1732, 1470, 1258, 918
cmꢀ1; HRMS (FAB+) calculated for C16H26O4Na [M+Na]+ 305.1723, found 305.1710.
9
(2S,3R)ꢀ1,4ꢀbis(benzyloxy)ꢀ3ꢀhydroxybutanꢀ2ꢀyl isobutyrate (3g). According to the general
procedure, substrate 2g (90.8 mg, 0.300 mmol) with a catalyst 1h (0.300 ꢁmol), Et3N (54.2 ꢁL,
0.390 mmol), and isobutyric anhydride (64.6 ꢁL, 0.390 mmol) in TBME (3 mL) at −20 °C gave
monoacylate 3g (70.7 mg, 0.190 mmol, 63% yield, 94.5:5.5 er), diacylate 4g (25.2 mg, 0.0569
mmol, 19% yield), and recovered 2g (14.8 mg, 0.0489 mmol, 16% yield). Colorless oil.
Enantiomeric ratio was determined by HPLC with DAICEL CHIRALPAK® IAꢀ3
(hexane/i-PrOH = 98.5/1.5, v/v, flow rate = 1.0 mL/min, 30 °C, UV = 254 nm), TR = 31.6 min
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
1
(minor) and TR = 34.3 min (major), 94.5:4.5 er; H NMR (400 MHz, CDCl3) δ 7.39–7.23 (m,
10H), 5.07 (ddd, J = 6.6, 4.6, 3.7 Hz, 1H), 4.54 (d, J = 2.7 Hz, 2H), 4.53 (d, J = 3.7 Hz, 2H),
4.12–4.01 (m, 1H), 3.77 (dd, J =11.0, 4.8 Hz, 1H), 3.71 (dd, J = 10.5, 3.4 Hz, 1H), 3.56 (dd, J =
9.6, 3.7 Hz, 1H), 3.49 (dd, J = 10.1, 6.2 Hz, 1H) 2.74 (bd, J = 5.5 Hz, 1H), 2.55 (sep, J = 7.0 Hz,
1H), 1.14 (d, J = 4.1 Hz, 3H), 1.12 (d, J = 3.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.5,
137.9, 137.8, 128.5, 128.4, 127.9, 127.8, 127.7, 73.5, 73.4, 72.1, 70.7, 69.8, 68.9, 34.0, 19.0,
18.9; IR (KBr) 3468, 3446, 2974, 1732, 1454, 1194, 739 cmꢀ1; HRMS (FAB+) calculated for
C22H28O5Na [M+Na]+ 395.1828, found 395.1838; [α]23D +18.1 (c 1.0, CHCl3, 94.5:5.5 er)
(2R,3S)ꢀ1,4ꢀbis(benzyloxy)butaneꢀ2,3ꢀdiyl bis(2ꢀmethylpropanoate) (4g). Colorless solid. δ
7.35–7.24 (m, 13H), 5.38–5.32 (m, 2H), 4.50 (d, J = 11.9 Hz, 2H), 4.45 (d, J = 11.9 Hz, 2H),
3.64 (dd, J = 10.7, 3.4 Hz 2H), 3.57 (dd, J = 10.7, 5.7 Hz, 2H), 2.50 (sep, J = 7.1 Hz, 1H), 1.11
(d, J = 7.1 Hz, 12H); 13C NMR (100 MHz, CDCl3) δ 176.1, 138.0, 128.5, 127.8, 127.7, 73.2,
70.6, 68.2, 34.1, 19.1, 18.9; IR (KBr) 2972, 1730, 1356, 1188, 746 cmꢀ1; HRMS (FAB+)
calculated for C26H34O6Na [M+Na]+ 465.2247, found 465.2228; mp 57.4–58.2 °C
(2R,3S)ꢀ2ꢀhydroxyꢀ3ꢀ(isobutyryloxy)butaneꢀ1,4ꢀdiyl bis(2,2ꢀdimethylpropanoate) (3h).
According to the general procedure, substrate 2h (87.2 mg, 0.300 mmol) with a catalyst 1h (0.3
ꢁmol), Et3N (54.2 ꢁL, 0.390 mmol), and isobutyric anhydride (64.6 ꢁL, 0.390 mmol) in TBME
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 36
1
2
3
4
5
6
7
8
(3 mL) at −40 °C gave monoacylate 3h (55.1 mg, 0.153 mmol, 51% yield, 91:9 er), diacylate 4h
(21.8 mg, 0.0506 mmol, 17% yield), and recovered 2h (27.8 mg, 0.0957 mmol, 32% yield).
Colorless oil. Enantiomeric ratio was determined by HPLC with DAICEL CHIRALPAK® IAꢀ3
(hexane/i-PrOH = 98.5/1.5, v/v, flow rate = 1.0 mL/min, 30 °C, UV = 205 nm), TR = 17.6 min
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
1
(major) and TR = 18.9 min (minor), 91:9 er; H NMR (400 MHz, CDCl3) δ 5.04 (ddd, J = 4.6,
5.1, 3.2 Hz, 1H), 4.44 (dd, J = 12.3, 2.7 Hz, 1H), 4.32 (dd, J = 12.3, 5.0 Hz, 1H), 4.24 (dd, J =
11.9, 2.7 Hz, 1H), 4.16 (dd, J = 11.9, 5.6 Hz, 1H), 4.02–3.91 (m, 1H), 2.80 (bs, 1H), 2.56 (sep, J
= 7.0 Hz, 1H), 1.20 (s, 9 H), 1.18 (s, 9H), 1.17 (d, J = 7.0 Hz, 3H), 1.17 (d, J = 7.0 Hz); 13C
NMR (100 MHz, CDCl3) δ 179.0, 178.6, 175.9, 70.9, 68.7, 65.1, 62.4, 39.0 (2), 34.1, 27.2, 19.0,
18.9; IR (KBr) 3501, 2978, 1732, 1157, 767 cmꢀ1; HRMS (FAB+) calculated for C18H32O7Na
[M+Na]+ 383.2045, found 383.2048; [α] 24D +15.0 (c 1.030, CHCl3, 91:9 er)
(2R,3S)ꢀ2,3ꢀbis(isobutyryloxy)butaneꢀ1,4ꢀdiyl bis(2,2ꢀdimethylpropanoate) (4h). Pale
yellow solid. 1H NMR (400 MHz, CDCl3) δ 5.22–5.16 (m, 2H), 4.36 (dd, J = 12.1, 2.5 Hz, 2H),
4.13 (dd, J = 12.1, 5.7 Hz, 2H), 2.55 (sep, J = 6.9 Hz, 2H), 1.23–1.13 (m, 30H); 13C NMR (100
MHz, CDCl3) δ 178.1, 175.7, 69.0, 61.9, 39.0, 34.1, 27.2, 19.0, 18.9; IR (KBr) 2978, 2941,
1734, 1140, 768 cmꢀ1; HRMS (FAB+) calculated for C22H38O8Na [M+Na]+ 453.2458, found
453.2455; mp 47.1–47.9 °C
(2R,3S)ꢀ1,4ꢀdichloroꢀ3ꢀhydroxybutanꢀ2ꢀyl isobutyrate (3i). According to the general
procedure, substrate 2i (79.2 mg, 0.498 mmol) with a catalyst 1h (0.5 ꢁmol), Et3N (90.2 ꢁL,
0.649 mmol), and isobutyric anhydride (108 ꢁL, 0.651 mmol) in TBME (5 mL) at −20 °C gave
monoacylate 3i (52.2 mg, 0.228 mmol, 46% yield, 86:14 er), diacylate 4i (53.0 mg, 0.177 mmol,
36% yield), and recovered 2i (14.2 mg, 0.0893 mmol, 18% yield). Colorless oil. Enantiomeric
ratio was determined with 4ꢀnitro benzoate by HPLC with DAICEL CHIRALPAK® IAꢀ3
(hexane/i-PrOH = 98.5/1.5, v/v, flow rate = 1.0 mL/min, 30 °C, UV = 254 nm), TR = 13.4 min
1
(minor) and TR = 21.9 min (major), 86:14 er; H NMR (400 MHz, CDCl3) δ 4.99 (dt, J = 8.4,
3.7 Hz, 1H), 4.16 (ddd, J = 8.4, 6.0, 2.7 Hz, 1H), 3.90 (d, J = 3.7 Hz, 2H), 3.75 (dd, J = 11.6, 2.7
28
ACS Paragon Plus Environment

Page 29 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Hz, 1H), 3.63 (dd, J = 11.6, 6.0 Hz, 1H), 2.68–2.55 (m, 1H), 2.52–2.32 (bs, 1H), 1.21 (d, J = 6.9
Hz, 3H), 1.20 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.8, 70.2, 42.8, 34.1, 19.0,
18.9; IR (neat) 3335, 2974, 1740, 1153, 1070, 708 cmꢀ1; HRMS (ESI+) calculated for
C8H14Cl2O3Na [M+Na]+ 251.0212, found 251.0218; [α]22D +5.3 (c 0.6, CHCl3, 86:14 er)
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
1
(2R,3S)ꢀ1,4ꢀdichlorobutaneꢀ2,3ꢀdiyl bis(2ꢀmethylpropanoate) (4i). Colorless oil. H NMR
(400 MHz, CDCl3) δ 5.35–5.28 (m, 2H), 3.85–3.82 (m, 1H), 3.81–3.77 (m, 1H), 3.67 (d, J = 2.9,
1.4 Hz, 1H), 3.64 (d, J = 2.9, 1.8 Hz, 1H), 2.61 (sep, J = 7.0 Hz, 2H), 1.20 (d, J = 7.0 Hz, 6H),
1.20 (d, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 175.8, 70.2, 42.8, 34.1, 19.0, 18.9; IR
(neat) 2976, 2938, 1746, 1470, 1144 cmꢀ1; HRMS (ESI+) calculated for C12H20Cl2O4Na
[M+Na]+ 321.0632, found 321.0621
(2S,3R)ꢀ1,4ꢀdiazidoꢀ3ꢀhydroxybutanꢀ2ꢀyl isobutyrate (3j). According to the general
procedure, substrate 2j (68.4 mg, 0.397 mmol) with a catalyst 1h (0.4 ꢁmol), Et3N (72.2 ꢁL,
0.519 mmol), and isobutyric anhydride (86.2 ꢁL, 0.520 mmol) in TBME (4 mL) at −20 °C gave
monoacylate 3j (48.6 mg, 0.201 mmol, 50% yield, 86:14 er), diacylate 4j (29.4 mg, 0.0941
mmol, 24% yield), and recovered 2j (17.6 mg, 0.102 mmol, 26% yield). Colorless oil.
Enantiomeric ratio was determined by HPLC with DAICEL CHIRALPAK® IAꢀ3
(hexane/i-PrOH = 98.5/1.5, v/v, flow rate = 1.0 mL/min, 30 °C, UV = 205 nm), TR = 21.5 min
(major) and TR = 24.3 min (minor), 86:14 er; 1H NMR (400 MHz, CDCl3) δ 4.93 (ddd, J = 7.6,
4.5, 3.2 Hz, 1H), 4.04–3.95 (m, 1H), 3.62 (dd, J = 13.4, 3.2 Hz, 1H), 3.58 (J = 13.4, 4.5 Hz, 1H),
3.48 (dd, J = 12.6, 3.2 Hz, 1H), 3.37 (dd, J = 12.6, 6.4 Hz, 1H), 2.62 (sep, J = 6.9 Hz, 1H), 2.45
(d, J = 6.0 Hz, 1H), 1.21 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 176.4, 72.5, 69.4, 53.7, 50.8, 34.1, 18.9, 18.8; IR (neat) 3564, 2976, 2104, 1732, 1472
cmꢀ1; HRMS (ESI+) calculated for C8H14N6O3Na [M+Na]+ 265.102, found 265.1011; [α] 22
D
+8.6 (c 1.0, CHCl3, 86:14 er).
1
(2R,3S)ꢀ1,4ꢀdiazidobutaneꢀ2,3ꢀdiyl bis(2ꢀmethylpropanoate) (4j). Colorless oil. H NMR
(400 MHz, CDCl3) δ 5.23–5.17 (m, 2H), 3.57 (dd, J = 13.4, 3.2 Hz, 2H), 3.41 (dd, J = 13.4, 5.5
29
ACS Paragon Plus Environment