Chiral tetraaryl-and tetraalkynylborates as chiral solvating agents for tetraalkylammonium salts

Article abstract of DOI:10.1002/ejoc.201801448

The application of tetracarbon-substituted chiral borate sodium salts (NaBR*₄) as NMR chiral solvating agents for various tetraalkylammonium salts (R₄NX) has been successfully demonstrated. Ion exchange between R₄NX and NaBR*₄ proceeded in excellent yields and provided the corresponding dia-stereomeric salts (R₄NBR*₄). The ee values of the R₄NX salts were determined by¹H NMR analysis of R₄NBR*₄. Two types of chiral borates, tetraaryl-and tetraalkynylborates with optically active 1,1′-binaphthyl components were used. At the beginning of this research, we investigated the efficacy of a known chiral tetraar-ylborate developed by Pommerening et al. for R₄NX. To expand the possibility of further structural design of the chiral borate, we designed chiral tetraalkynylborates as a new structure. Their synthesis and application are also described.

Full text of DOI:10.1002/ejoc.201801448

A Journal of
Accepted Article
Title: Chiral tetraaryl- and tetraalkynylborates as chiral solvating agents
for tetraalkylammonium salts
Authors: Eiji Tayama and Takeshi Sugawara
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801448
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10.1002/ejoc.201801448
European Journal of Organic Chemistry
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Chiral tetraaryl- and tetraalkynylborates as chiral solvating
agents for tetraalkylammonium salts
Eiji Tayama*[a] and Takeshi Sugawara[b]
Abstract: The application of tetra-carbon-substituted chiral borate
sodium salts (NaBR*4) as NMR chiral solvating agents for various
tetraalkylammonium salts (R4NX) has been successfully
demonstrated. Ion exchange between R4NX and NaBR*4 proceeded
in excellent yields and provided the corresponding diastereomeric
salts (R4NBR*4). The ee values of the R4NX salts were determined
by 1H NMR analysis of R4NBR*4. Two types of chiral borates,
tetraaryl- and tetraalkynylborates with optically active 1,1'-binaphthyl
components were used. At the beginning of this research, we
investigated the efficacy of a known chiral tetraarylborate developed
by Pommerening et al. for R4NX. To expand the possibility of further
structural design of the chiral borate, we designed chiral
time, and therefore we considered developing an efficient way to
determine the ee of an R4NX species. In 2017, Pommerening et
al. reported chiral sodium tetraarylborate (S)-1a as an
asymmetric catalyst (Figure 2).[6] Their work inspired us, and we
found that ion exchange of triflate salt (1R,2R)-4 with sodium
tetraphenylborate (NaBPh4) in THF gave (1R,2R)-4-BPh4 in an
almost quantitative yield (Figure 1).[5,7] Additionally, (S)-1a has a
remarkable advantage over well-known phenoxide-type chiral
borates, such as bis(1,1’-binaphthalene-2,2’-dioxy)borate.[8]
Tetra-carbon-substituted (S)-1a is less polar and more
chemically stable, which allows chromatographic purification. As
shown in Figure 1 (this work), when the chiral borate was
subjected to ion exchange, the resulting tetraalkylammonium
borate (R4NBR*4) forms a diastereomeric salt. The ees of the
starting R4NX and its precursor amine, R3N, were determined by
NMR analysis.[9] Thus, we decided to investigate the ability of
(S)-1a as a chiral solvating agent for R4NX. To facilitate the
further structural design of chiral borates and its preparation, we
designed chiral tetraalkynylborates 1b–d as a new structure
(Figure 2). The synthesis and application of these species as
chiral solvating agents were demonstrated.
tetraalkynylborates as
a
new structure.
Their synthesis and
application are also described.
Introduction
The enantiomeric excess (ee) of a chiral compound must be
determined to judge the success or failure of an asymmetric
synthesis. The most standard and widely applicable, reliable
method is HPLC analysis using a chiral column (chiral HPLC)
with a UV/Vis detector; however, this method requires a UV-
active substituent, such as an aryl moiety, in the compound.
Frequently, the UV-active substituent is introduced by further
synthetic
transformations
of
the
chiral
compounds.
Consequently, developments of chiral solvating agents such as
chiral acids, metal complexes, and cyclic receptors have been
studied to allow the determination of ee by NMR analysis, even
in the absence of a UV-active substituent.[1,2]
In our previous works on tetraalkylammonium salts (R4NX),
such as N-chiral ammonium salts 2,[3] 3,[4] and azetidine-2-
carboxylic acid derived-ammonium salt (1R,2R)-4[5] (Figure 1),
we had difficulties to determine their ees. Fortunately, some N-
chiral ammonium salt derivatives could be evaluated by chiral
HPLC with trifluoroacetic acid and diethylamine as additives in
the mobile phase. However, these conditions were ineffective
for less polar R4NX salts without hydroxy groups, such as
(1R,2R)-4, because the interactions between R4NX and the
chiral stationary phase of the column would be decreased by the
presence of the additives. Furthermore, no chiral solvating
agents applicable for R4NX species had been developed at that
Figure 1. Determination of the ee of R4NX by NMR analysis
[a]
Dr. E. Tayama
Department of Chemistry, Faculty of Science, Niigata University,
Niigata 950-2181 (Japan)
E-mail: tayama@chem.sc.niigata-u.ac.jp
http://chem.sc.niigata-u.ac.jp/~tayama/english.html
T. Sugawara
[b]
Guraduate School of Science and Technology, Niigata University,
Niigata 950-2181 (Japan)
E-mail: f17a028h@mail.cc.niigata-u.ac.jp
Figure 2. Chiral borates: (S)-1a developed by Pommerening et al. (ref. 6a)
and our designed (S)-1b, (R)-1c, and (S)-1d.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801448
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Results and Discussion
values for the chemical shifts of 2-H, N(CH3)3, and 4-H of the
enantiomers showed ratios of approximately 3/1. To check
kinds of anions are not affected for the resolution, 1H NMR
analysis of (S)-1aꞏrac-9 derived from iodide salt rac-9a-I was
conducted (iv). These results were in agreement with spectrum
(i) derived from rac-9a-OTf.
First, we selected chiral borate 1a and investigated its efficacy
as a chiral solvating agent using ammonium salts 4 as model
compounds (Scheme 1). Diastereomerically pure ammonium
salts rac-4 and (1S,2S)-4 were prepared by N-quaternization of
precursor tertiary amine 5 with methyl triflate (MeOTf).[5] Ion
exchange of 4 with a slight excess (1.1 to 1.3 equivalents) of
(S)-1a or (R)-1a in THF proceeded smoothly. Evaporation and
chromatographic purification provided ammonium chiral borate
salts 1aꞏ4 in excellent yields.
1H NMR analysis of (S)-1aꞏrac-4 in chloroform-d (CDCl3) was
conducted, and a portion of the spectrum[10] ( 4.40–2.35) is
shown as (i) in Figure 3. Clearly resolved signals from 2-H and
4-H, as in rac-4, were observed with almost baseline separation.
To assign each diastereomer, 1H NMR analyses of (S)-
1aꞏ(1S,2S)-4 and (R)-1aꞏ(1S,2S)-4 were also conducted. Their
partial spectra are shown as (ii) and (iii), respectively. Only one
diastereomer was detected. The chemical shifts were slightly
different (0.02-0.03 ppm). Small amounts of impurities such as
H2O or solvents might be affected to move the chemical shifts.
In fact, when 1H NMR analysis of (S)-1aꞏrac-4 was carried out in
acetone-d6 (iv), the chemical shifts were not resolved and almost
the same with those of triflate salt rac-4.[11] A polar solvent
would disrupt the cation-anion interactions and break the
asymmetry around the ammonium cation.
Scheme 1. Preparation of tetraalkylammonium chiral borate salts 1aꞏ4.
To clarify that chiral borate 1a is a useful chiral solvating agent
for R4NX, we attempted an anion exchange of rac-4 with a
commercially available chiral anion, such as D-camphor-10-
sulfonic acid sodium salt (D-6) (Scheme 2). Ion exchanged D-
6ꞏrac-4 was not obtained, and 90% of rac-4 was recovered. To
the best our knowledge, previous examples of ion exchanges
–
between R4NX and a sulfonate anion (RSO3 ) are usually
performed under the following combinations: (i) an ammonium
hydroxide (R4NOH) and a sulfonic acid (RSO3H) or (ii) R4NX and
silver sulfonate (RSO3Ag).[12] The use of 1a offers a great
advantage in ion exchange with R4NX because the reaction
proceeds in excellent yields under mild and simple conditions.
We next investigated the efficacy of 1a as a chiral solvating
agent towards standard amino acid esters, such as valine, that
do not have a UV-active substituent (Scheme 3). Ammonium
salts rac-9a-OTf and rac-9a-I were prepared from DL-valine tert-
butyl ester (rac-7a) via N-methylations [stepwise via rac-8a (path
a) or directly (path b)]. Anion exchange of the triflate and iodide
salts with (S)-1a under the same conditions provided (S)-1aꞏrac-
9a in good yields.
Figure 3. Partial 700 MHz 1H NMR spectra of 1aꞏ4 at 20 °C, (i) (S)-1aꞏrac-4 in
CDCl3, (ii) (S)-1aꞏ(1S,2S)-4 in CDCl3, (iii) (R)-1aꞏ(1S,2S)-4 in CDCl3, and (iv)
(S)-1aꞏrac-4 in acetone-d6.
1H NMR analysis of (S)-1aꞏrac-9a was conducted, and a
portion of the spectrum ( 2.85–0.60) is shown in Figure 4, (i).
Baseline-separated chemical shifts from 2-H, N(CH3)3, and 4-H
were observed. Similarly, the spectrum (ii) derived from (S)-
1aꞏ(S)-9a, prepared by ion exchange between (S)-1a and (S)-
9a-OTf[13] (97% yield), showed one diastereomer.
To
demonstrate that our method enables the determination of
amino acid-derived ammonium salts such as 9a and its
precursor amines, 7a and 8a, we prepared the 50% ee mixture
of (S)-9a-OTf.[13] Anion exchange with (S)-1a (98% yield)
followed by 1H NMR analysis afforded spectrum (iii). Integral
Scheme 2. Attempted ion exchange between rac-4 and D-6.
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10.1002/ejoc.201801448
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49% yield from (S)-2b. O-Propargylation of monophenol 2b–d
into 3b–d proceeded in good yields. Lithiation of 3b–d with
nBuLi in Et2O, treatment with BCl3, followed by brine treatment
afforded target chiral borates 1b–d. (S)-1b and (S)-1d were
obtained in 72% and 68% yields, respectively. On the other
hand, the yield of (R)-1c was only 14% with recovery of (R)-3c.
The 2’-OMe substituent would inhibit tetra-substitution of the
boron atom because of steric repulsion.[17] By treatment with
brine, the hydrolysis of the mono-, di-, and tri-substituted
derivatives would regenerate (R)-3c. Although the synthetic
route to (S)-2d should be optimized, we started to investigate
the efficacies of (S)-1b and (S)-1d as chiral solvating agents.
Scheme 3. Preparation of (S)-1aꞏrac-9a
Scheme 4. Preparation of chiral tetraalkynylborates 1b–d. (i) Tf2O, iPr2NEt,
CH2Cl2, 0 °C to rt, without purification. (ii) Pd-C, H2 (1 atm), iPr2NEt, EtOH, rt.
(iii) MeI, K2CO3, acetone, rt to reflux.
Figure 4. Partial 700 MHz 1H NMR spectra of (S)-1aꞏ9a in CDCl3 at 20 °C.
Derived from: (i) rac-9a-OTf, (ii) (S)-9a-OTf, (iii) (S)-9a-OTf (50% ee), (iv) rac-
9a-I.
To define the substrate scope and limitations of chiral borates
(S)-1a, 1b and 1d, we prepared various amino acid-derived
ammonium salts rac-9b–g-X and examined their resolution.
Representative resolved chemical shifts are shown in Table 1.
1H NMR analysis of (S)-1aꞏrac-9b derived from (S)-1a and
alanine derivative rac-9b-OTf afforded baseline-separated
chemical shifts such as 2-H ( 2.94 & 2.84, q) and 3-H ( 0.90 &
0.71, d) (Entry 1). The use of (S)-1b instead of (S)-1a also
provided baseline-separated chemical shifts for 3-H ( 0.47 &
0.41, d) (Entry 2). Although the peak separation value () for
3-H was smaller than those of (S)-1a [(S)-1a = 0.19, (S)-
1b = 0.06], (S)-1b also acts as a chiral solvating agent for
R4NX. The same experiment with (S)-1d showed almost the
same result (Entry 3). To clarify the efficacy of (S)-1 as a chiral
solvating agent, we examined this resolution for phenylalanine-,
Since chiral borate 1a was found to act as a chiral solvating
agent, we decided to investigate the ability of chiral
tetraalkynylborates 1b–d prepared from [1,1'-binaphthalen]-2-ol
derivatives 2b–d via O-propargylation into 3b–d (Scheme 4).
These synthetic routes do not require the use of expensive
tetrafluorobenzene linker such as (S)-1a.[6a,6b] (S)-2b[14] and 2’-
methoxy derivative (R)-2c[15] were prepared by known methods.
We next examined a substitution at the 6-position, as in (S)-2b.
Treatment of (S)-2b with Br2 in MeCN, which has been reported
for the synthesis of analogous compounds,[16] gave the desired
6-bromo derivative as the main product. However, the pure
compound could not be obtained. Thus, the product was
coupled with PhMgBr. Careful chromatographic purification of
the coupled product afforded pure 6-phenyl derivative (S)-2d in
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10.1002/ejoc.201801448
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(S)-1a as a chiral solvating agent (Entry 11). However, the
methylene protons did not separate.
Table 1. 1H NMR analysis of (S)-1ꞏrac-9 in CDCl3 at 20 °C and their
representative separated chemical shifts[a]
Finally, we examined the resolution of N-chiral ammonium salt
rac-10 with (S)-1a (Scheme 5). Their anion exchange was
carried out in THF/CH2Cl2 (2/1) to dissolve the starting salts and,
the exchange provided corresponding ammonium borate salt
(S)-1aꞏrac-10 in 98% yield. The partial 1H NMR spectrum (
4.05–3.15) showed approximately 50/50 separation of the allylic
and benzylic methylene protons (Figure 5).
Scheme 5. Preparation of (S)-1aꞏrac-10.
Entry
9-X
(S)-1
Yield[b]
[%]
Representative separated chemical
shifts  (splitting pattern)
1[c]
2
9b-OTf
9b-OTf
9b-OTf
9c-OTf
9c-I
1a
1b
1d
1b
1b
1b
1b
1a
1b
1a
1a
90
96
87
99
92
88
93
91
96
90
93
2.94, 2.84 (q)
0.90, 0.71 (d)
0.50, 0.42 (d)
0.47, 0.41 (d)
3
2.73, 2.68 (q)
4
2.58, 2.40 (dd)
2.58, 2.40 (dd)
3.32, 3.22 (dd)
0.76, 0.70 (ddd)
3.05, 2.99 (dd)
not clearly resolved
2.96, 2.88 (dd)
not clearly resolved
Figure 5. Partial 700 MHz 1H NMR spectrum of (S)-1aꞏrac-10 in CDCl3 at
20 °C.
5[d]
6[e]
7
9d-I
2.71, 2.65 (s)
Conclusions
9e-OTf
9e-OTf
9f-OTf
9f-OTf
9g-Br
8
1.06, 0.98 (ddd)
In conclusion, we successfully demonstrated that tetra-carbon-
substituted chiral borate 1 is a useful chiral solvating agent for
various types of tetraalkylammonium salts R4NX, as observed by
1H NMR analysis. This method enables the determination of the
ees of R4NX salts and their precursor amines, R3N. The
procedure is quite simple, can be performed under mild
conditions, and applicable for typical counter anions, such as
triflate (OTf), iodide (I), bromide (Br), and tosylate (OTs). While
the exact reason is unclear at present, chiral tetraarylborate 1a,
developed by Pommerening et al.,[6a] is much more effective for
resolving chemical shifts than our designed chiral
9
10
11[d]
[a] Unless otherwise noted, the reactions were performed in THF and the
products were analyzed by 700 MHz NMR. [b] Isolated yield. [c] Analyzed by
400 MHz NMR. [d] Performed in THF/CH2Cl2 (10/1). [e] Performed in
THF/MeOH (4/1).
tetraalkynylborate 1b.
The rigid structure of 1a or its
tetrafluorobenzene component might have positive effects.
However, 1b is easy to prepare and further functionalize, such
as into 1d.
Further studies on chiral borates 1 are necessary, e.g.,
chromatographic separation or fractional crystallization of
diastereomeric salts, determination of absolute stereochemistry
of R4NX by single-crystal X-ray diffraction, and the scope and
limitations of structural design. These studies will expand the
applications of 1 for various areas of chemistry.
leucine-, triflate-, iodide-, tert-butyl-, and methyl ester-derived
ammonium salts (Entries 4–10). The use of (S)-1b was
applicable in many cases; however, by comparing Entry 7 to
Entry 8 and Entry 9 to Entry 10, it was found that (S)-1a is a
more efficient chiral solvating agent than (S)-1b for various types
of R4NX. In the resolution of the -allylglycine derivative rac-9f-
OTf, (S)-1b did not provide any separated chemical shifts (Entry
9). In contrast, the use of (S)-1a provided baseline-separated
chemical shifts for 2-H ( 2.96, 2.88, dd) (Entry 10). Additionally,
we tried an asymmetric recognition of the methylene protons (
or allylic) as seen in glycine-derived ammonium salt 9g-Br using
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10.1002/ejoc.201801448
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and filtered. The filtrate was evaporated and the residue was purified by
chromatography on silica gel (n-hexane/CH2Cl2 = 2/1 as the eluent) to
afford (S)-3b (152 mg, 99% yield) as colorless crystals. M.p. 110-111 °C.
[α]23589 = +38.1 (c = 1.0, CHCl3). IR (KBr): vmax = 3296, 3052, 2919, 2869,
1620, 1592, 1506, 1472, 1452, 1433, 1366, 1323, 1275, 1261, 1247,
1230, 1152, 1135, 1079, 1056, 1041, 1015, 919, 905, 862, 805, 781, 741
cm−1. 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 9.2 Hz, 1H, ArH), 7.95
(d, J = 8.0 Hz, 1H, ArH), 7.93 (d, J = 8.0 Hz, 1H, ArH), 7.88 (d, J = 8.4 Hz,
1H, ArH), 7.61 (dd, J = 8.0, 7.0 Hz, 1H, ArH), 7.57 (d, J = 8.8 Hz, 1H,
ArH), 7.48-7.43 (m, 2H, ArH), 7.36-7.31 (m, 1H, ArH), 7.35 (ddd, J = 8.0,
7.0, 1.6 Hz, 1H, ArH), 7.30-7.20 (m, 2H, ArH), 7.16 (dddd, J = 8.8, 1.6,
0.8, 0.8 Hz, 1H, ArH), 4.57 (d, J = 2.4 Hz, 2H, CH2), 2.39 (t, J = 2.4 Hz,
1H, CCH) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.6, 134.2, 134.0,
133.6, 132.8, 129.6, 129.2, 128.5, 128.2, 127.9, 127.8, 126.4, 126.2,
125.9, 125.71, 125.70, 125.5, 124.8, 124.1, 115.8, 79.0, 75.4, 57.1 ppm.
HRMS (APCI): calcd. for C23H16O [M]+ 308.1196, found 308.1190.
Experimental Section
General: Specific rotations were recorded on a JASCO polarimeter P–
1010. Infrared spectra (IR) were recorded on a Perkin Elmer Spectrum
GX FT-IR or a JASCO FT/IR-4600 spectrometer. 1H, 13C and 11B NMR
spectra were measured on Varian spectrometers (1H: 700 MHz, 13C: 175
MHz; 1H: 400 MHz, 13C: 100 MHz) or a Bruker spectrometer (1H: 400
MHz, 13C: 100 MHz, 11B: 128 MHz). Me4Si (δ 0 ppm) was used as an
internal standard in CDCl3 for 1H NMR, and CDCl3 (δ 77.00 ppm) was
used for 13C NMR. The residual protons (δ 2.05 ppm) were used as an
internal standard in acetone-d6 for 1H NMR, and acetone-d6 (δ 29.92
ppm) was used for 13C NMR. Me4Si (δ 0 ppm) was used as an internal
standard in DMSO-d6 for 1H NMR, and DMSO-d6 (δ 39.51 ppm) was
used for 13C NMR. Boron trifluoride diethyl etherate (BF3ꞏOEt2) was used
as an external standard (δ 0 ppm) for 11B NMR. The splitting patterns
are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; sept,
septet; m, multiplet; and br, broad peak. High-resolution mass spectra
(ESI, APCI, positive, and negative) were measured on a Thermo Fisher
Scientific LC/FT-MS spectrometer. Reactions involving air- or moisture-
sensitive compounds were conducted in appropriate round-bottomed
flasks with a magnetic stirring bar under an argon (Ar) atmosphere.
Anhydrous tetrahydrofuran (THF) was purchased from KANTO Chemical
Co., Inc., Japan. Anhydrous diethyl ether (Et2O) was obtained by
distillation from sodium benzophenone prior to use. A 1 M BCl3 n-
heptane solution was purchased from Sigma-Aldrich. (S)- and (R)-
(S)-Sodium
tetrakis(3-([1,1'-binaphthalen]-2-yloxy)prop-1-yn-1-
yl)borate [(S)-1b]: A suspension of (S)-3b (851 mg, 2.76 mmol) in Et2O
(28 mL) was treated with a 1.6 M nBuLi hexane solution (1.6 mL, 2.6
mmol) at –78 °C under an Ar atmosphere and stirred for 1 h at the same
temperature. The resulting mixture was treated with a 1 M BCl3 n-
heptane solution (0.58 mL, 0.58 mmol) at –78 °C. The mixture was
allowed to warm to room temperature and stirred for 17 h. The resulting
mixture was quenched with H2O, treated with a small amount of brine,
and extracted with CH2Cl2. The combined organic extracts were
evaporated and the residue was dissolved in CH2Cl2 (28 mL). The
solution was treated with brine (28 mL) and the two phase mixture was
stirred for 2 days at room temperature. The CH2Cl2 layer was separated
and the aqueous layer was extracted with CH2Cl2. The combined extracts
were dried over Na2SO4. Evaporation of the solvent and purification of
the residue by chromatography on silica gel (CH2Cl2 only followed by
CH2Cl2/MeOH = 20/1, 10/1, to 5/1 as the eluent) afforded (S)-1b (603
mg) as a white solid. The obtained (S)-1b included H2O (9 wt.%) and
CH2Cl2 (4 wt.%) determined by 1H NMR analysis. Calculated yield of (S)-
sodium
tetrakis(2-[2,3,5,6-tetrafluorophenyl]-1,1′-binaphthalene)borate
[(S)-1a and (R)-1a] were prepared according to the literature.[6a-b, 18] D-
Camphor-10-sulfonic acid sodium salt (D-6) was purchased from
FUJIFILM Wako Pure Chemical Corporation.
For thin layer
chromatography (TLC) analysis throughout this work, Merck TLC plates
(silica gel 60 F254) were used. The products were purified by preparative
column chromatography on silica gel (60N, spherical neutral) purchased
from KANTO Chemical Co., Inc., Japan.
(S)-[1,1'-Binaphthalen]-2-ol [(S)-2b][14, 19]: A solution of (R)-1,1'-bi-2-
naphthol (1.43 g, 5.00 mmol) and N,N-diisopropylethylamine (0.87 mL,
5.0 mmol) in CH2Cl2 (25 mL) was treated with Tf2O (0.84 mL, 5.0 mmol)
at 0 °C and the mixture was stirred for 1 h at room temperature under an
Ar atmosphere. The resulting mixture was diluted with H2O and extracted
with CH2Cl2. The combined extracts were washed with brine, dried over
1b was 72%. M.p. 147-150 °C. [α]26 +55.0 (c = 1.0, CHCl3). IR (KBr):
589
vmax = 3057, 3008, 2925, 2863, 1621, 1591, 1506, 1470, 1459, 1433,
1370, 1326, 1274, 1217, 1147, 1134, 1081, 1034, 1011, 949, 896, 863,
805, 781, 749 cm−1 1H NMR (400 MHz, CDCl3): δ = 7.83-7.71 (m, 16H,
.
ArH), 7.48 (d, J = 9.2 Hz, 4H, ArH), 7.43 (dd, J = 7.8, 7.8 Hz, 4H, ArH),
7.37-7.25 (m, 12H, ArH), 7.25-7.04 (m, 16H, ArH), 4.38 (d, J = 16.0 Hz,
4H, OCH2), 4.34 (d, J = 16.0 Hz, 4H, OCH2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 153.1, 133.9, 133.4, 132.5, 129.51, 129.48, 128.4, 128.1,
127.9, 127.8, 126.3, 126.1, 125.9, 125.8, 125.6, 124.00, 123.98, 116.4,
102.9-100.2 (br m), 88.4-87.6 (br m), 59.8 ppm. 11B NMR (128 MHz,
CDCl3): δ = –33.6 ppm. HRMS (ESI): calcd. for C92H60BO4 [M – Na]–
1239.4590, found 1239.4572.
Na2SO4, and evaporated.
A
mixture of the residue, N,N-
diisopropylethylamine (1.74 mL, 10.0 mmol), and Pd-C (loading: 10 wt.%,
0.16 g) in EtOH (25 mL) was stirred for 12 h at room temperature under a
H2 atmosphere. The resulting mixture was filtered through a pad of Celite
and the filtrate was evaporated. The residue was purified by
chromatography on silica gel (n-hexane/CH2Cl2 = 1.5/1 to 1/1 as the
eluent) to afford (S)-2b (1.15 g, 85% yield) as colorless crystals. M.p.
169-170 °C. [α]23
= −121.6 (c = 1.0, CHCl3). IR (KBr): vmax = 3542,
589
(R)-2'-Methoxy-[1,1'-binaphthalen]-2-ol [(R)-2c][15]: A mixture of (R)-
1,1'-bi-2-naphthol (715 mg, 2.50 mmol) and K2CO3 (416 mg, 3.01 mmol)
in acetone (25 mL) was stirred for 1 h at room temperature under an Ar
atmosphere. The mixture was treated with MeI (156 L, 2.51 mmol) and
refluxed for 17 h. The resulting mixture was cooled to room temperature
and filtered. The filtrate was evaporated and the residue was purified by
chromatography on silica gel (n-hexane/CH2Cl2 = 1/1 to 1/2 as the
eluent) to obtain (R)-2c (669 mg, 89% yield) as colorless crystals. M.p.
3054, 1618, 1591, 1513, 1503, 1468, 1435, 1383, 1346, 1335, 1303,
1291, 1270, 1254, 1229, 1188, 1165, 1143, 1125, 1075, 1013, 971, 937,
819, 804, 788, 780, 753, 723 cm−1 1H NMR (400 MHz, CDCl3): δ = 8.00
.
(d, J = 8.0 Hz, 1H, ArH), 7.96 (d, J = 8.0 Hz, 1H, ArH), 7.89 (d, J = 8.8 Hz,
1H, ArH), 7.85 (d, J = 8.0 Hz, 1H, ArH), 7.63 (dd, J = 8.4, 6.8 Hz, 1H,
ArH), 7.55-7.47 (m, 2H, ArH), 7.38 (d, J = 8.8 Hz, 1H, ArH), 7.36-7.28 (m,
3H, ArH), 7.22 (ddd, J = 7.5, 7.5, 1.4 Hz, 1H, ArH), 7.09 (d, J = 8.4 Hz,
1H, ArH), 4.91 (s, 1H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.9,
134.1, 133.8, 132.8, 131.4, 129.8, 129.6, 129.2, 128.9, 128.4, 128.0,
126.8, 126.52, 126.51, 126.0, 125.7, 124.9, 123.3, 118.7, 117.4 ppm.
82-84 °C. [α]22
–44.0 (c = 1.0, CHCl3). IR (KBr): vmax = 3488, 3429,
589
3056, 2938, 2838, 1619, 1592, 1507, 1462, 1431, 1379, 1361, 1331,
1264, 1247, 1206, 1174, 1146, 1128, 1082, 1054, 1019, 972, 938, 904,
.
863, 813, 774, 750, 708 cm−1 1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J
= 8.8 Hz, 1H, ArH), 7.87 (d, J = 8.8 Hz, 1H, ArH), 7.86 (ddd, J = 8.4, 0.6,
0.6 Hz, 1H, ArH), 7.83 (ddd, J = 8.0, 0.6, 0.6 Hz, 1H, ArH), 7.41 (d, J =
8.8 Hz, 1H, ArH), 7.34 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H, ArH), 7.33 (d, J =
8.8 Hz, 1H, ArH), 7.28 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H, ArH), 7.25 (ddd, J =
(S)-2-(Prop-2-yn-1-yloxy)-1,1'-binaphthalene [(S)-3b]: A mixture of (S)-
2b (135 mg, 0.50 mmol) and K2CO3 (69 mg, 0.50 mmol) in MeCN (2.5
mL) was stirred for 30 min at room temperature under an Ar atmosphere.
The mixture was treated with propargyl bromide (49 L, 0.65 mmol) and
refluxed for 14 h. The resulting mixture was cooled to room temperature
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801448
European Journal of Organic Chemistry
FULL PAPER
8.4, 6.8, 1.2 Hz, 1H, ArH), 7.22-7.14 (m, 2H, ArH), 7.03 (dddd, J = 8.4,
1.2, 0.6, 0.6 Hz, 1H, ArH), 4.94 (s, 1H, OH), 3.74 (s, 3H, CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 155.9, 151.2, 134.0, 133.7, 131.0, 129.7,
129.3, 129.1, 128.1, 127.3, 126.4, 124.9, 124.8, 124.1, 123.2, 117.4,
115.3, 114.9, 113.7, 56.6 ppm. HRMS (ESI): calcd. for C21H15O2 [M – H]–
299.1078, found 299.1074.
a mixture of (S)-2d and impurities as a white solid. To obtain more pure
(S)-2d, the mixture was purified by 2nd and 3rd chromatography under
the same conditions. The combined yield (1st to 3rd) of pure (S)-2d was
49% (762 mg). M.p. 51-55 °C. [α]22 –198.4 (c = 1.0, CHCl3). IR (KBr):
589
vmax = 3513, 3435, 3057, 1622, 1596, 1494, 1473, 1446, 1420, 1384,
1361, 1312, 1287, 1256, 1231, 1197, 1150, 1130, 1076, 1018, 973, 940,
890, 831, 802, 779, 758, 735, 699 cm−1 1H NMR (400 MHz, CDCl3): δ =
.
8.06 (d, J = 2.0 Hz, 1H, ArH), 8.04 (d, J = 8.4 Hz, 1H, ArH), 7.99 (d, J =
8.4 Hz, 1H, ArH), 7.96 (d, J = 8.4 Hz, 1H, ArH), 7.70-7.64 (m, 3H, ArH),
7.59-7.48 (m, 3H, ArH), 7.48-7.41 (m, 3H, ArH), 7.39-7.31 (m, 3H, ArH),
7.17 (d, J = 8.4 Hz, 1H, ArH), 4.93 (s, 1H, OH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 151.1, 141.0, 136.1, 134.2, 133.1, 132.8, 131.3, 130.2, 129.6,
129.3, 129.2, 128.8, 128.5, 127.2, 127.1, 126.9, 126.6, 126.2, 126.0,
(R)-2-Methoxy-2'-(prop-2-yn-1-yloxy)-1,1'-binaphthalene
Prepared in 96% yield (777 mg) from (R)-2c (720 mg, 2.40 mmol) by the
same procedure with (S)-3b. Colorless crystals. M.p. 155-156 °C. [α]23
[(R)-3c]:
589
+38.8 (c = 1.0, CHCl3). IR (KBr): vmax = 3294, 3056, 3021, 2962, 2935,
2874, 2839, 1619, 1590, 1507, 1460, 1429, 1355, 1323, 1264, 1252,
1218, 1177, 1148, 1133, 1089, 1059, 1046, 1020, 964, 931, 910, 892,
866, 809, 780, 755, 705 cm−1 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J
.
125.9, 125.8, 125.5, 118.7, 117.9 ppm. HRMS (ESI): calcd. for C26H17
[M – H]– 345.1285, found 345.1280.
O
= 8.8 Hz, 1H, ArH), 7.97 (d, J = 8.8 Hz, 1H, ArH), 7.87 (ddd, J = 8.1, 1.2,
1.2 Hz, 1H, ArH), 7.86 (ddd, J = 8.1, 1.2, 1.2 Hz, 1H, ArH), 7.57 (d, J =
9.2 Hz, 1H, ArH), 7.45 (d, J = 8.8 Hz, 1H, ArH), 7.34 (ddd, J = 8.1, 6.8,
1.2 Hz, 1H, ArH), 7.31 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H, ArH), 7.21 (ddd, J =
8.8, 6.8, 1.2 Hz, 1H, ArH), 7.20 (ddd, J = 8.8, 6.8, 1.2 Hz, 1H, ArH), 7.14-
7.09 (m, 2H, ArH), 4.61 (dd, J = 16.3, 2.4 Hz, 1H, OCH2), 4.55 (dd, J =
16.3, 2.4 Hz, 1H, OCH2), 3.77 (s, 3H, OCH3), 2.37 (dd, J = 2.4, 2.4 Hz,
1H, CCH) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.9, 153.1, 134.0,
133.9, 129.8, 129.5, 129.2, 129.1, 127.9, 127.8, 126.3, 125.4, 125.3,
124.0, 123.5, 121.2, 119.0, 116.2, 114.0, 79.3, 75.1, 57.2, 56.8 ppm.
HRMS (APCI) calcd. for C24H19O2 [M + H]+ 339.1380, found 339.1373.
(S)-6-Phenyl-2-(prop-2-yn-1-yloxy)-1,1'-binaphthalene
[(S)-3d]:
Prepared in 86% yield (339 mg) from (S)-2d (354 mg, 1.02 mmol) by the
same procedure with (S)-3b. White solid. M.p 52-55 °C. [α]21 –66.7 (c
589
= 1.0, CHCl3). IR (KBr): vmax = 3286, 3058, 2953, 2926, 2871, 1623, 1593,
1493, 1475, 1446, 1370, 1359, 1333, 1276, 1222, 1190, 1159, 1141,
1086, 1058, 1035, 1016, 935, 889, 832, 798, 778, 759, 698 cm−1 1H
.
NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 2.0 Hz, 1H, ArH), 8.03 (d, J =
8.4 Hz, 1H, ArH), 7.96 (d, J = 8.4 Hz, 1H, ArH), 7.94 (d, J = 8.4 Hz, 1H,
ArH), 7.69-7.57 (m, 4H, ArH), 7.52-7.41 (m, 5H, ArH), 7.38 (d, J = 8.4 Hz,
1H, ArH), 7.34 (tt, J = 7.4, 1.2 Hz, 1H, ArH), 7.29 (ddd, J = 8.4, 7.4, 1.2
Hz, 1H, ArH), 7.24 (d, J = 8.4 Hz, 1H, ArH), 4.58 (d, J = 2.4 Hz, 2H,
OCH2), 2.39 (t, J = 2.4 Hz, 1H, CCH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 152.7, 140.9, 136.8, 133.9, 133.7, 133.4, 132.8, 129.9, 129.6, 128.8,
128.6, 128.2, 127.9, 127.23, 127.19, 126.3, 126.2, 126.1, 126.0, 125.8,
125.7, 125.5, 124.8, 116.3, 79.0, 75.4, 57.1 ppm. HRMS (APCI): calcd.
for C29H21O [M + H]+ 385.1587, found 385.1576.
(R)-Sodium
tetrakis(3-((2'-methoxy-[1,1'-binaphthalen]-2-
yl)oxy)prop-1-yn-1-yl)borate [(R)-1c]: Prepared from (R)-3c (263 mg,
0.777 mmol) and a 1 M BCl3 n-heptane solution (0.16 mL, 0.16 mmol) by
the same procedure with (S)-1b. The obtained (R)-1c (31.4 mg) included
H2O (3 wt.%) and CH2Cl2 (1 wt.%) determined by 1H NMR analysis.
Calculated yield of (R)-1c was 14%. Pale yellow solid. M.p. 153-156 °C.
[α]26 +29.8 (c = 1.0, CHCl3). IR (KBr): vmax = 3057, 3006, 2931, 2856,
589
2840, 1719, 1621, 1592, 1507, 1474, 1463, 1431, 1402, 1356, 1328,
1272, 1262, 1250, 1218, 1178, 1147, 1133, 1087, 1059, 1014, 955, 903,
(S)-Sodium tetrakis(3-((6-phenyl-[1,1'-binaphthalen]-2-yl)oxy)prop-1-
yn-1-yl)borate [(S)-1d]: Prepared from (S)-3d (302 mg, 0.785 mmol)
and a 1 M BCl3 n-heptane solution (0.14 mL, 0.14 mmol) by the same
procedure with (S)-1b. The obtained (S)-1d (156 mg) included H2O (2
wt.%) and CH2Cl2 (2 wt.%) determined by 1H NMR analysis. Calculated
862, 810, 775, 749, 707 cm−1 1H NMR (400 MHz, CDCl3): δ = 7.86-7.72
.
(m, 16H, ArH), 7.53 (d, J = 8.6 Hz, 4H, ArH), 7.30 (ddd, J = 8.0, 7.0, 1.0
Hz, 4H, ArH), 7.26-7.16 (m, 12H, ArH), 7.07-6.99 (m, 8H, ArH), 6.94 (d, J
= 8.6 Hz, 4H, ArH), 4.47 (d, J = 15.2 Hz, 4H, OCH2), 4.43 (d, J = 15.2 Hz,
4H, OCH2), 3.48 (s, 12H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
154.6, 153.6, 133.7, 133.6, 129.60, 129.55, 129.4, 129.1, 128.0, 127.9,
126.4, 126.3, 125.3, 125.1, 123.9, 123.6, 120.1, 119.1, 116.7, 114.5,
104.0-100.5 (br m), 88.4-87.6 (br m), 59.7, 57.0 ppm. 11B NMR (128 MHz,
CDCl3): δ = –33.5 ppm. HRMS (ESI): calcd. for C96H68BO8 [M – Na]–
1359.5013, found 1359.5012.
yield of (S)-1d was 68%. Pale yellow solid. M.p. 180-182 °C. [α]24
–
589
55.3 (c = 1.0, CHCl3). IR (KBr): vmax = 3055, 2864, 1621, 1592, 1492,
1473, 1444, 1359, 1331, 1274, 1218, 1187, 1140, 1083, 1026, 1011, 950,
888, 831, 799, 777, 758, 697 cm−1 1H NMR (400 MHz, CDCl3): δ = 7.86
.
(d, J = 1.4 Hz, 4H, ArH), 7.73-7.63 (m, 12H, Ar), 7.58-7.50 (m, 8H, ArH),
7.45-7.33 (m, 20H, ArH), 7.30 (tt, J = 7.2, 1.4 Hz, 4H, ArH), 7.26-7.19 (m,
8H, ArH), 7.17 (d, J = 8.4 Hz, 4H, ArH), 7.09 (d, J = 9.2 Hz, 4H, ArH),
7.05 (ddd, J = 8.4, 6.9, 1.4 Hz, 4H, ArH), 4.25 (d, J = 15.2 Hz, 4H, OCH2),
4.20 (d, J = 15.2 Hz, 4H, OCH2) ppm. 13C NMR (100 MHz, CDCl3): δ =
153.1, 140.7, 136.7, 133.9, 133.5, 133.1, 132.5, 129.9, 129.7, 128.8,
128.4, 128.2, 127.9, 127.2, 126.2, 126.14, 126.08, 125.93, 125.88, 125.6,
124.0, 116.8, 102.2-101.5 (br m), 88.4-87.6 (br m), 59.8 ppm. 11B NMR
(128 MHz, CDCl3): δ = –33.6 ppm. HRMS (ESI): calcd. for C116H76BO4 [M
– Na]– 1543.5842, found 1543.5827.
(S)-6-Phenyl-[1,1'-binaphthalen]-2-ol [(S)-2d]: (Step 1) A solution of
(S)-2a (1.21 g, 4.48 mmol) in MeCN (22 mL) was treated with Br2 (0.46
mL, 9.0 mmol) at 0 °C and the mixture was stirred for 2 h at the same
temperature. The resulting mixture was quenched with saturated aq.
Na2SO3 and extracted with EtOAc. The combined extracts were washed
with saturated aq. NaHCO3 followed by brine, dried over Na2SO4, and
evaporated. The residue was purified by chromatography on silica gel (n-
hexane/CH2Cl2 = 3/1 to 1/1 as the eluent) to afford 6-bromo-[1,1'-
binaphthalen]-2-ol with impurities (1.55 g) as a white solid. This product
was not pure and used in next step without further purification. (Step 2) A
solution of the solid (1.55 g) and NiCl2(PPh3)2 (0.14 g, 0.21 mmol) in Et2O
(9 mL) was treated with a ca. 1 M PhMgBr Et2O solution (13.5 mL, 13.5
mmol, prepared from PhBr and Mg) at 0 °C under an Ar atmosphere. The
mixture was refluxed for 12 h, quenched with saturated aq. NH4Cl at 0 °C,
and extracted with EtOAc. The combined extracts were washed with
brine, dried over Na2SO4, and evaporated. Careful chromatographic
purification of the residue on silica gel (n-hexane/CH2Cl2 = 2/1 to 1/1 as
the eluent) afforded pure (S)-2d (117 mg, 8% yield) as a white solid and
1-(4-Bromobenzyl)-2-(tert-butoxycarbonyl)-1-methylazetidin-1-ium
trifluoromethanesulfonate (rac-4): (Step 1)
bromobenzylamine (253 L, 2.00 mmol),
A
mixture of 4-
tert-butyl 2,4-
dibromobutanoate[5] (604 mg, 2.00 mmol), and K2CO3 (0.83 g, 6.0 mmol)
in MeCN (10 mL) was refluxed for 4 h. The resulting mixture was cooled
to room temperature followed by filtered. The filtrate was evaporated and
the residue was purified by chromatography on silica gel (n-
hexane/EtOAc = 6/1 to 4/1 as the eluent) to obtain tert-butyl 1-(4-
bromobenzyl)azetidine-2-carboxylate (rac-5) (334 mg, 51% yield) as
colorless crystals, m.p. 34-36 °C. Spectroscopic data: see (S)-5. (Step 2)
A mixture of rac-5 (334 mg, 1.02 mmol) and NaHCO3 (0.26 g, 3.1 mmol)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801448
European Journal of Organic Chemistry
FULL PAPER
in CH2Cl2 (5 mL) was treated with MeOTf (139 L, 1.23 mmol) at 0 °C
and stirred for 2 h at room temperature. The resulting mixture was
evaporated to ca. 1/2 to 1/3 volume and the residue was purified by
chromatography on silica gel (CH2Cl2/MeOH = 20/1 to 10/1 as the eluent)
to obtain rac-4 (449 mg, 90% yield) as a white solid, m.p. 142-145 °C.
Spectroscopic data: see (1S,2S)-4.
Representative procedure for preparation of (S)-1aꞏrac-4: A mixture
of (S)-1a (36 mg, 0.022mmol) and rac-4 (9.8 mg, 0.020 mmol) in THF
(2.0 mL) was stirred for 2 days at room temperature. The resulting
mixture was evaporated and the residue was purified by chromatography
on silica gel (n-hexane/CH2Cl2 = 1/1 followed by CH2Cl2/MeOH = 20/1 to
10/1 as the eluent) to obtain (S)-1aꞏrac-4 (34.7 mg, 89% yield) as a white
solid.
(1S,2S)-1-(4-Bromobenzyl)-2-(tert-butoxycarbonyl)-1-methylazetidin-
1-ium trifluoromethanesulfonate [(1S,2S)-4][5]: (Step 1) A solution of L-
azetidine-2-carboxylic acid (490 mg, 4.85 mmol) and NaOH (388 mg,
9.70 mmol) in H2O (4.9 mL) was treated with benzyl chloroformate (0.73
mL, 5.1 mmol) at 0 °C. After stirring for 1 h at 0 °C and for 1 h at room
temperature, the resulting aqueous mixture was washed with Et2O. The
aqueous solution was acidified with 4 M aq. HCl and extracted with
EtOAc. The combined organic extracts were washed with H2O followed
by brine, dried over Na2SO4, and evaporated. A solution of the residue in
CH2Cl2 (10 mL) was treated with H2SO4 (0.05 mL) and isobutene
(excess) at room temperature. The resulting solution was stirred for 11 h
at room temperature. The resulting mixture was treated with saturated aq.
NaHCO3 and extracted with EtOAc. The combined extracts were washed
with brine, dried over Na2SO4, and evaporated. Purification of the residue
by chromatography on silica gel (n-hexane/EtOAc = 4/1 to 3/1 as the
eluent) gave (S)-1-benzyl 2-tert-butyl azetidine-1,2-dicarboxylate (1.02 g,
72% yield) as a colorless oil. (Step 2) A mixture of (S)-1-benzyl 2-tert-
butyl azetidine-1,2-dicarboxylate (242 mg, 0.831 mmol) and Pd-C
(loading: 10 wt.%, 18 mg) in EtOAc (4.2 mL) was stirred for 2 h at room
temperature under a H2 atmosphere. The resulting mixture was filtered
through a pad of Celite and the filtrate was evaporated. A mixture of the
residue, 4-bromobenzyl chloride (171 mg, 0.832 mmol), and NaHCO3
(0.21 g, 2.5 mmol) in MeCN (4.2 mL) was refluxed for 4 h. The resulting
mixture was cooled to room temperature and filtered. The filtrate was
evaporated and the residue was purified by chromatography on silica gel
(n-hexane/EtOAc = 7/1 to 4/1 as the eluent) to give (S)-tert-butyl 1-(4-
bromobenzyl)azetidine-2-carboxylate [(S)-5] (215 mg, 79% yield) as
colorless crystals, m.p. 33-35 °C. [α]22589 = –58.6 (c = 1.0, EtOH). 98% ee
[determined by HPLC analysis: Daicel Chiralpak AD-H column (25 cm),
n-hexane/EtOH = 95/5 as the eluent, flow rate = 0.50 mL/min, tR = 8.6
min (1.1%) for (R) and 9.3 min (98.9%) for (S)]. IR (film): vmax = 3002,
2974, 2931, 2829, 1734, 1591, 1485, 1452, 1400, 1391, 1365, 1294,
1239, 1154, 1095, 1068, 1011, 979, 940, 845, 814, 791, 744, 682 cm-1.
1H NMR (400 MHz, CDCl3): δ = 7.42 (ddd, J = 8.6, 2.2, 2.2 Hz, 2H, ArH),
7.19 (ddd, J = 8.6, 2.2, 2.2 Hz, 2H, ArH), 3.77 (d, J = 12.8 Hz, 1H, CH2Ar),
3.60 (ddd, J = 8.4, 8.2, 0.6 Hz, 1H, 2-H), 3.49 (d, J = 12.8 Hz, 1H, CH2Ar),
3.27 (dddd, J = 8.2, 6.6, 2.5, 0.6 Hz, 1H, 4-H), 2.86 (ddd, J = 9.2, 8.0, 6.6
Hz, 1H, 4-H), 2.31 (dddd, J = 10.5, 9.2, 8.4, 8.2 Hz, 1H, 3-H), 2.16 (dddd,
J = 10.5, 8.2, 8.0, 2.5 Hz, 1H, 3-H), 1.41 (s, 9H, tBu) ppm. 13C NMR (100
MHz, CDCl3): δ = 171.8, 136.5, 131.3, 130.7, 121.0, 80.8, 65.2, 61.8,
50.7, 28.0, 21.4 ppm. HRMS (ESI): calcd. for C15H21BrNO2 [M + H]+
326.0750, found 326.0737. (Step 3) A mixture of (S)-5 (161 mg, 0.494
mmol) and NaHCO3 (0.13 g, 1.5 mmol) in CH2Cl2 (2.5 mL) was treated
with MeOTf (67 L, 0.59 mmol) at 0 °C and stirred for 2 h at room
temperature. The resulting mixture was purified by chromatography on
silica gel (CH2Cl2/MeOH = 20/1 to 10/1 as the eluent) to obtain (1S,2S)-4
(203 mg, 84% yield) as a colorless gum. [α]21589 = –23.3 (c = 1.0, EtOH).
IR (KBr): vmax = 3049, 2983, 2935, 1736, 1595, 1492, 1468, 1412, 1396,
1371, 1325, 1263, 1225, 1155, 1074, 1031, 1013, 979, 936, 885, 829,
787, 757, 725 cm-1. 1H NMR (400 MHz, acetone-d6): δ = 7.72 (d, J = 8.8
Hz, 2H, ArH), 7.69 (d, J = 8.8 Hz, 2H, ArH), 5.72 (dd, J = 9.8, 9.8 Hz, 1H,
2-H), 4.92-4.80 (m, 1H, 4-H), 4.86 (s, 2H, CH2Ar), 4.07 (ddd, J = 9.8, 9.8,
3.6 Hz, 1H, 4-H), 3.34 (s, 3H, NCH3), 3.15 (dddd, J = 12.0, 9.8, 9.8, 9.8
Hz, 1H, 3-H), 2.78-2.65 (m, 1H, 3-H), 1.44 (s, 9H, tBu) ppm. 13C NMR
(100 MHz, acetone-d6): δ = 164.5, 135.3, 133.3, 128.5, 125.6, 122.3 (q, J
= 320 Hz), 85.9, 71.7, 67.9, 62.9, 45.5, 27.9, 19.3 ppm. HRMS (ESI):
calcd. for C16H23BrNO2 [M – OTf]+ 340.0907, found 340.0893.
tert-Butyl 2-amino-3-methylbutanoate (rac-7a): (Step 1) A solution of
DL-valine (630 mg, 5.38 mmol) and NaOH (430 mg, 10.8 mmol) in H2O
(5.4 mL) was treated with benzyl chloroformate (0.83 mL, 5.9 mmol) at
0 °C. After stirring for 0.5 h at 0 °C and for 3 h at room temperature, the
resulting aqueous mixture was washed with toluene. The aqueous
solution was acidified with 4 M aq. HCl and extracted with EtOAc. The
combined organic extracts were washed with H2O followed by brine,
dried over Na2SO4, and evaporated to obtain crude N-carbobenzoxy-DL-
valine (1.12 g, 83% yield) as a white solid. (Step 2) A solution of the
crude N-carbobenzoxy-DL-valine (762 mg, 3.03 mmol) in CH2Cl2 (6 mL)
was treated with H2SO4 (0.06 mL) and isobutene (excess) at room
temperature. The resulting solution was stirred for 2 days at room
temperature. The resulting mixture was treated with saturated aq.
NaHCO3 and extracted with EtOAc. The combined extracts were washed
with brine, dried over Na2SO4, and evaporated. Purification of the residue
by chromatography on silica gel (n-hexane/EtOAc = 10/1 to 5/1 as the
eluent) gave tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate
(827 mg, 89% yield) as a colorless oil. (Step 3) A mixture of tert-butyl 2-
(((benzyloxy)carbonyl)amino)-3-methylbutanoate (316 mg, 1.03 mmol)
and Pd-C (loading: 10 wt.%, 22 mg) in EtOAc (5 mL) was stirred for
overnight at room temperature under a H2 atmosphere. The resulting
mixture was filtered through
a pad of Celite and the filtrate was
evaporated to obtain rac-7a (143 mg, 80% yield) as a colorless oil. The
product was pure without purification. IR (film): vmax = 3386, 3320, 2966,
2933, 2874, 1727, 1600, 1466, 1391, 1368, 1339, 1282, 1251, 1154,
1048, 974, 958, 911, 851, 777, 748 cm-1. 1H NMR (400 MHz, CDCl3): δ =
3.17 (d, J = 4.8 Hz, 1H, 2-H), 2.00 (sept d, J = 6.8, 4.8 Hz, 1H, 3-H), 1.47
(s, 9H, tBu), 1.43 (br, 2H, NH2), 0.97 (d, J = 6.8 Hz, 3H, 4-H), 0.90 (d, J =
6.8 Hz, 3H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.8, 80.7, 60.3,
32.1, 28.0, 19.2, 17.0 ppm. HRMS (ESI): calcd. for C9H20NO2 [M + H]+
174.1489, found 174.1486.
tert-Butyl 2-(dimethylamino)-3-methylbutanoate (rac-8a): A mixture of
rac-7a (143 mg, 0.825 mmol), Pd-C (loading: 10 wt.%, 19 mg), and 37
wt.% aq. HCHO (0.82 mL, 11 mmol) in EtOH (4.1 mL) was stirred for
overnight at room temperature under a H2 atmosphere. The resulting
mixture was filtered through
a pad of Celite and the filtrate was
evaporated. Purification of the residue by chromatography on silica gel
(n-hexane/EtOAc = 8/1 as the eluent) gave rac-8a (95.1 mg, 57% yield)
as a colorless oil. IR (film): vmax = 2967, 2935, 2871, 2831, 2787, 1723,
1469, 1454, 1389, 1367, 1347, 1290, 1272, 1248, 1215, 1147, 1124,
1040, 976, 928, 912, 859, 830, 791, 740 cm-1. 1H NMR (400 MHz,
CDCl3): δ = 2.60 (d, J = 10.4 Hz, 1H, 2-H), 2.32 (s, 6H, N(CH3)2), 1.97 (d
sept, J = 10.4, 6.6 Hz, 1H, 3-H), 1.48 (s, 9H, tBu), 0.96 (d, J = 6.6 Hz, 3H,
4-H), 0.90 (d, J = 6.6 Hz, 3H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
171.1, 80.5, 75.0, 41.3, 28.3, 27.4, 19.5, 19.3 ppm. HRMS (ESI): calcd.
for C11H24NO2 [M + H]+ 202.1802, found 202.1798.
1-(tert-Butoxy)-N,N,N,3-tetramethyl-1-oxobutan-2-aminium
trifluoromethanesulfonate [rac-9aꞏOTf]: A mixture of rac-8a (95.1 mg,
0.472 mmol) and NaHCO3 (120 mg, 1.43 mmol) in CH2Cl2 (2.4 mL) was
treated with MeOTf (64 L, 0.57 mmol) at room temperature and stirred
for 3 h. The resulting mixture was evaporated to ca. 1/2 to 1/3 volume
and the residue was purified by chromatography on silica gel
(CH2Cl2/MeOH = 20/1 to 10/1 as the eluent) to obtain rac-9aꞏOTf (135
mg, 78% yield) as a white gum. IR (KBr): vmax = 3034, 2984, 2946, 1730,
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10.1002/ejoc.201801448
European Journal of Organic Chemistry
FULL PAPER
1634, 1498, 1481, 1421, 1397, 1372, 1297, 1263, 1223, 1160, 1029, 977,
[5]
[6]
E. Tayama, K. Watanabe, Y. Matano, Eur. J. Org. Chem. 2016, 3631–
3641.
963, 930, 894, 848, 798, 755, 715 cm−1 1H NMR (400 MHz, CDCl3): δ =
.
3.97 (d, J = 1.6 Hz, 1H, 2-H), 3.37 (s, 9H, N(CH3)3), 2.54-2.41 (m, 1H, 3-
H), 1.55 (s, 9H, tBu), 1.29 (d, J = 7.2 Hz, 3H, 4-H), 1.10 (d, J = 6.8 Hz,
3H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.3, 120.6 (q, J = 318
Hz), 85.6, 78.9, 52.2, 27.9, 26.5, 23.1, 19.0 ppm. HRMS (ESI): calcd. for
C12H26NO2 [M – OTf]+ 216.1958, found 216.1949.
a) P. Pommerening, J. Mohr, J. Friebel, M. Oestreich, Eur. J. Org.
Chem. 2017, 2312–2316. See also the related works on chiral
tetraarylborates: b) C. K. De, R. Mitra, B. List, Synlett 2017, 28, 2435–
2438. c) D. J. Owen, D. VanDerveer, G. B. Schuster, J. Am. Chem.
Soc. 1998, 120, 1705–1717. d) K. Torssell, Acta. Chem. Scand. 1962,
16, 87–93.
[7]
Recent examples of ion exchange of R4NX with NaBAr4: a) M. W.
Drover, K. Nagata, J. C. Peters, Chem. Commun. 2018, 54, 7916–7919.
b) S. Konishi, T. Iwai, M. Sawamura, Organometallics 2018, 37, 1876–
1883. c) S. B. Beil, S. Möhle, P. Enders, S. R. Waldvogel, Chem.
Commun. 2018, 54, 6128–6131. d) B. Setner, M. Wierzbicka, L.
Jerzykiewicz, M. Lisowski, Z, Szewczuk, Org. Biomol. Chem. 2018, 16,
825–831. e) S. Pusch, D. Schollmeyer, T. Opatz, Eur. J. Org. Chem.
2018, 1204–1207. f) E. Tayama, K. Watanabe, S. Sotome, Org. Biomol.
Chem. 2017, 15, 6668–6678. g) M. Honda, T. Iwamoto, T. Ohnogi, K.-K.
Kunimoto, M. Segi, Tetrahedron Lett. 2017, 58, 3191–3193.
1-(tert-Butoxy)-N,N,N,3-tetramethyl-1-oxobutan-2-aminium
iodide
[rac-9a-I]: A mixture of rac-7a (50 mg, 0.29 mmol), MeI (90 L, 1.4
mmol), and K2CO3 (0.20 g, 1.4 mmol) in MeCN (1.5 mL) was stirred for 2
h at room temperature and refluxed for 1 h. The mixture was cooled to
room temperature and filtered. The filtrate was evaporated and the
residue was purified by chromatography on silica gel (CH2Cl2/MeOH =
10/1 to 5/1 as the eluent) to afford rac-9a-I (92.8 mg, 93% yield) as a
pale yellow gum. IR (KBr): vmax = 3053, 3009, 2971, 2938, 1736, 1541,
1492, 1474, 1456, 1412, 1393, 1369, 1312, 1286, 1249, 1210, 1148,
1133, 971, 957, 930, 892, 846, 794, 727, 708 cm−1 1H NMR (400 MHz,
.
[8]
Representative works using bis(1,1’-binaphthalene-2,2’-dioxy)borate
derivatives: a) G. Hu, A. K. Gupta, L. Huang, W. Zhao, X. Yin, W. E. G.
Osminski, B. H. Huang, W. D. Wulff, J. A. Izzo, M. J. Vetticatt, J. Am.
Chem. Soc. 2017, 139, 10267–10285. b) M. Ueda, Y. Yagyu, I. Ryu.
Tetrahedron: Asymmetry 2017, 28, 1070–1077. c) J. A. Raskatov, A. L.
Thompson, A. R. Cowley, T. D. W. Claridge, J. M. Brown, Chem. Sci.
2013, 4, 3140–3147. d) M. Martin, A. E. Hellani, J. Yang, J. Collin, S.
Bezzenine-Lafollée, J. Org. Chem. 2011, 76, 9801–9808. e) J. A.
Raskatov, J. M. Brown, A. L. Thompson, CrystEntgComm 2011, 13,
2923–2929. f) D. Chen, B. Sundararaju, R. Krause, J. Klankermayer, P.
H. Dixneuf, W. Leitner, ChemCatChem 2010, 2, 55–57. g) T. Tu, T.
Maris, J. D. Wuest, Cryst. Grouth Des. 2008, 8, 1541–1546.
CDCl3): δ = 4.22 (d, J = 1.6 Hz, 1H, 2-H), 3.62 (s, 9H, N(CH3)3), 2.74-
2.61 (m, 1H, 3-H), 1.56 (s, 9H, tBu), 1.33 (d, J = 7.2 Hz, 3H, 4-H), 1.11 (d,
J = 6.8 Hz, 3H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.0, 85.5,
78.8, 52.8, 27.9, 26.4, 23.1, 19.1 ppm. HRMS (ESI): calcd. for C12H26NO2
[M – I]+ 216.1958, found 216.1947.
Representative procedure for preparation of (S)-1bꞏrac-9b (Table 1,
Entry 2): A mixture of (S)-1b (20 mg, 0.016 mmol) and rac-9b-OTf (5.2
mg, 0.015 mmol) in THF (1.5 mL) was stirred for 48 h at room
temperature. The resulting mixture was evaporated and the residue was
purified by chromatography on silica gel (n-hexane/CH2Cl2 = 1/1 followed
by CH2Cl2/MeOH = 20/1 to 10/1 as the eluent) to obtain (S)-1bꞏrac-9b
(20.5 mg, 96% yield) as a white gum.
[9]
Optical resolution of racemic tetraarylborates by ion exchange with N-
chiral tetraalkylammonium salts were reported. See ref. 6c and 6d.
[10] The full range and detailed spectra of the ammonium borates are
shown in the Supporting Information.
Preparation of (S)-1aꞏrac-10: A mixture of (S)-1a (34 mg, 0.021 mmol)
and rac-10 (7.0 mg, 0.017 mmol) in THF (1.1 mL) and CH2Cl2 (0.6 mL)
was stirred for 3.5 days at room temperature. The resulting mixture was
evaporated and the residue was purified by chromatography on silica gel
(n-hexane/CH2Cl2 = 1/1 followed by CH2Cl2/MeOH = 20/1 to 10/1 as the
eluent) to obtain (S)-1aꞏrac-10 (31.2 mg, 98% yield) as a white gum.
[11] The comparison of spectra between borate salt (S)-1aꞏrac-4 and triflate
salt rac-4 is shown in the Supporting Information.
[12] Representative examples: a) R. Echarri, M. I. Matheu, C. Claver, S.
Castillón, Tetrahedron Lett. 1997, 38, 6457–6460. b) N. Komatsuzaki,
M. Uno, K. Shirai, Y. Takai, T. Tanaka, M. Sawada, S. Takahashi, Bull.
Chem. Soc. Jpn. 1996, 69, 17–24. c) A. C. Cope, W. R. Funke, F. N.
Jones, J. Am. Chem. Soc. 1966, 88, 4693–4699. See also: ref. 6c.
[13] (S)-9a-OTf was prepared from L-valine by the same procedure that was
used for rac-9a-OTf. The 50% ee mixture of (S)-9a-OTf was prepared
Conflict of interest
from
a 75/25 mixture of L-valine and D-valine. The results are
The authors declare no conflict of interest.
described in the Supporting Information.
[14] S. Zhu, C. Wang, L. Chen, R. Liang, Y. Yu, H. Jiang, Org. Lett. 2011,
13, 1146–1149.
Keywords: ammonium salts • amino acids • chiral borates •
[15] D. Zhang, J.-C. Mulatier, J. R. Cochrane, L. Guy, G. Gao, J.-P. Dutasta,
A. Martinez, Chem. Eur. J. 2016, 22, 8038–8042.
chiral anions • chiral resolution
[16] H. Hocke, Y. Uozumi, Tetrahedron 2003, 59, 619–630.
[17] We attempted to prepare other chiral tetraalkynyl borates derived from
3-phenyl-(1,1'-binaphthalen)-2-ol and 2-ethynyl-1,1'-binaphthalene.
The attempts were also unsuccessful. Steric factors are quite important
in the formation of tetraalkynylborates.
[1]
[2]
For a review: T. J. Wenzel, Differentiation of Chiral Compounds Using
NMR Spectroscopy, Wiley, 2018.
Representative recent studies on chiral solvating agents for the
determination of ee by NMR analysis: a) T. Ema, T. Yamasaki, S.
Watanabe, M. Hiyoshi, K. Takaishi, J. Org. Chem. 2018, 83, 10762–
10769. b) B. Benedict, C. E. Lietz, T. J. Wenzel, Tetrahedron 2018, 74,
4846–4856. c) J. C. Merino, A. F. Keppler, M. S. Silva, J. Braz. Chem.
Soc. 2018, 29, 1638–1644. d) M.-S. Seo, S. Jang, H. Kim, Chem.
Commun. 2018, 54, 6804–6807. e) N. Jain, A. N. Khanvilkar, S. Sahoo,
A. V. Bedekar, Tetrahedron 2018, 74, 68–76.
[18] Our experimental details are provided in the Supporting Information.
[19] Procedure: see ref. 14. See also compounds data: a) G. Ma, J. Deng,
M. P. Sibi, Angew. Chem. Int. Ed. 2014, 53, 11818–11821. b) K.
Kabuto, F. Yasuhara, S. Yamaguchi, Bull. Chem. Soc. Jpn. 1983, 56,
1263–1264.
[3]
[4]
E. Tayama, H. Tanaka, Tetrahedron Lett. 2007, 48, 4183–4185.
E. Tayama, S. Otoyama, H. Tanaka, Tetrahedron: Asymmetry 2009, 20,
2600–2608.
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10.1002/ejoc.201801448
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Tetra-carbon-substituted chiral borate
sodium salts (NaBR*4) act as chiral
solvating agents for various
Chiral Resolution
Eiji Tayama*, Takeshi Sugawara
tetraalkylammonium salts (R4NX).
The ees of R4NX species could be
determined by 1H NMR analysis of ion
exchanged diastereomeric
Page No. – Page No.
Chiral tetraaryl- and
tetraalkynylborates as chiral
solvating agents for
tetraalkylammonium borate salts.
tetraalkylammonium salts
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