Preparation of chiral 3-oxocycloalkanecarbonitrile and its derivatives by crystallization-induced diastereomer transformation of ketals with chiral 1,2-diphenylethane-1,2-diol

Article abstract of DOI:10.1039/c8ra06611f

Chiral 3-oxocycloalkanecarbonitriles were prepared by fractional crystallization and crystallization-induced diastereomer transformation (CIDT) of diastereomeric ketals with (1R,2R)-1,2-diphenylethane-1,2-diol. Investigation of the crystal structures by X

Full text of DOI:10.1039/c8ra06611f

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Preparation of chiral 3-oxocycloalkanecarbonitrile
and its derivatives by crystallization-induced
diastereomer transformation of ketals with chiral
1,2-diphenylethane-1,2-diol†
Cite this: RSC Adv., 2018, 8, 32601
ab
*
a
Yohei Yamashita,
Shoji Matsumoto
Daisuke Maki,a Shiho Sakurai,a Takumi Fuse,a
ac
*
and Motohiro Akazome
Chiral 3-oxocycloalkanecarbonitriles were prepared by fractional crystallization and crystallization-induced
diastereomer transformation (CIDT) of diastereomeric ketals with (1R,2R)-1,2-diphenylethane-1,2-diol.
Investigation of the crystal structures by X-ray diffraction analysis revealed that the difference in
hydrogen bonds caused the discrepancy of the solubilities between (R) and (S) diastereomers.
Furthermore, CIDT to afford the (R)-diastereomer in good yield (95% yield) and with high
diastereoselectivity (97% de) was accomplished, which is the first example of CIDT of neutral compounds
via formation of the diastereomeric ketal with (1R,2R)-1,2-diphenylethane-1,2-diol.
Received 6th August 2018
Accepted 10th September 2018
DOI: 10.1039/c8ra06611f
rsc.li/rsc-advances
enones. Specically, 1b was obtained in 81% ee and 90% yield,4
and nucleophilic addition of formaldehyde dialkylhydrazones to
conjugated enones has been reported.5a,b However, no optical
resolution of these neutral compounds has been reported, as
these compounds are not applicable for diastereomeric salt
separation, which is the most popular method to resolve racemic
compounds. In fact, 3-oxocyclopentanecarboxylic acid as an
acidic compound was resolved by diastereomeric salt formation
with (ꢀ)-brucine, but four sequential crystallizations were
required to obtain (R)-enantiomer in 98% ee.6
In order to introduce chiral moiety onto 1 and apply dia-
stereomeric separation, we use chiral ketals as not only a pro-
tecting group but also chiral resolving auxiliary. Among several
1,2-diols, commercially available (1R,2R)- or (1S,2S)-1,2-
diphenylethane-1,2-diol (dihydrobenzoin) shows great promise
as a chiral auxiliary.7 In fact, several articles reported the sepa-
ration of two isomers via formation of the diastereomeric ketals,
and subsequent isolation either by column chromatography or
crystallization.8a–c
Introduction
In recent years, the structure of active pharmaceutical ingredi-
ents and ne chemicals has become more complicated. To meet
the demands for synthesizing organic molecules with a sophis-
ticated design, building blocks containing chiral carbons as
a component are widely used. Developing a new chiral building
block will enable the synthesis of a new compound and provide
benets to both the chemical and pharmaceutical industries.
As new candidate building blocks, we focus on 3-oxocy-
cloalkanecarbonitriles, 1a1a,b and 1b1c (Fig. 1). In fact, active
pharmaceutical ingredients or intermediates containing 3-oxo-
cycloalkanecarbonitriles or its derivatives have been reporte-
d,2a,b which implies that 1 has potential as a building block. In
spite of its structural simplicity, the preparation of enantio-
merically pure 1 remains a challenging task.
Although 3-cyanoketones 1 are easily prepared from Michael
addition of cyanide ions to a,b-unsaturated ketones,3a,b there are
a few articles reporting the preparation of chiral 3-cyanoketones
by catalytic enantioselective conjugate addition of cyanide to
Preliminarily, we synthesized diastereomeric mixtures of 2,
but unfortunately, it was oily substance, which indicated that
diastereomer separation by recrystallization was not applicable.
aDepartment of Applied Chemistry and Biotechnology, Graduate School of Engineering,
Chiba University, 1-33 Yayoicho, Inageku, Chiba, 263-8522, Japan. E-mail: akazome@
faculty.chiba-u.jp
bProcess Chemistry Labs. Pharmaceutical Technology, Astellas Pharma Inc., 160-2,
Akahama, Takahagi-shi, Ibaraki 318-0001, Japan. E-mail: yohei.yamashita@
astellas.com
cMolecular Chirality Research Center, Chiba University, 1-33 Yayoicho, Inageku,
Chiba, 263-8522, Japan
† Electronic supplementary information (ESI) available. CCDC 1849794–1849797.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c8ra06611f
Fig. 1 Chiral separation of racemic 3-oxocycloalkanecarbonitriles.
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Therefore, we transformed nitriles 2 into amides 3, which are
generally expected to solidify due to the formation of hydrogen
bonds. First, we examined the preparation of chiral 3-oxocy-
cloalkanecarbonitrile and their derivatives via ketalization with
(1R,2R)-1,2-diphenylethane-1,2-diol through fractional crystal-
lization (Fig. 1). Even if separation of diastereomer is achieved
through fractional crystallization, half of the diastereomeric
mixture would remain as an undesired diastereomer. To our
delight, 3 turned out to be racemized under basic conditions.
Therefore, we performed crystallization-induced diastereomer
transformation (CIDT)9a–f on 3 and demonstrated the successful
transformation of these compounds while keeping stereo-
chemistry (Fig. 2).
Scheme 1 Synthesis of ketalized 3-oxocycloalkanecarbonitrile and 3-
oxocycloalkanecarboxamide.
Results and discussion
Synthesis of ketals
In accordance with the literature,3a 3-cyanocyclopentanone 1a
was prepared from Michael addition of cyanide ions to 2-
cyclopentenone in 92%. In the case of 2-cyclohexenone, 3-cya-
nocyclohexanone 1b was obtained in lower yield (63%), but the
value is comparable in the reported yield3b (Scheme 1). Then,
acid-catalyzed ketalization of 3-cyanocyclopentanone with 1,2-
diphenylethane-1,2-diol was performed by pyridinium p-tolue-
nesulfonate (PPTS).10a,b Using an optimized reaction condition,
namely, 1a (1.00 g, 9.20 mmol) with the dioꢁ l (1.3 equiv.) and
PPTS (0.1 equiv.) in toluene (30 mL) at 110 C for 23 h, ketali-
zation of 1a proceeded in 78% yield. Similarly, ketalization of 1b
proceeded in 39% yield. Insufficient yield in ketalization of 1b is
due to the contamination in 1b.11 Both diastereomeric mixtures
of 2 were oily substance.
99% (total yield 16%). In contract, rst fractional crystallization
(toluene/CHCl3 ¼ 2/3) of diastereomeric mixture 3b was per-
formed to obtain (R)-3b13 with only 30% de (46% yield). Second
and third fractional crystallization (toluene/CHCl3 ¼ 2/3)
provided (R)-3b with 87% de and 99% de (total yield 14%). As
shown in this result, both diastereomeric mixtures were sepa-
rated by simple crystallization, and diastereomers of ve-
membered ketal 3a were more easily separated than those of
six-membered 3b.
Investigation of crystal structures by single-crystal X-ray
diffraction analysis
To determine the stereochemistry of these diastereomers and to
clarify why (R)-diastereomer crystallized preferably, we investi-
gated the crystal structures of their diastereomers by single-
crystal X-ray diffraction (SXRD) analysis. To obtain both dia-
stereomers of 3, we rst tried to separate the diastereomeric
mixture of 3a by recycling preparative HPLC. However, 3a was
inseparable due to the similar retention time of the diastereo-
mers. In contrast, the corresponding nitriles 2a could be satis-
factorily separated by recycling preparative HPLC. Here, we
conrmed that both diastereomers of 2a were denitely oil.
Then, (R)-2a and (S)-2a were transformed to crystalline amides
(R)-3a and (S)-3a under the basic conditions mentioned above
without epimerization.12 In sharp contrast with 2a, even ten
cycles of recycling preparative HPLC could not separate 2b. Aer
transformation to the corresponding amide 3b, diastereomeric
For the purpose of applying the diastereomer separation by
fractional crystallization, we hydrated nitriles 2 with a combi-
nation of hydrogen peroxide and potassium carbonate12 to
obtain crystalline amides 3.
Fractional crystallization
To obtain a single diastereomer, we performed fractional crys-
tallization on these amides 3 from the solution (toluene/CHCl3
¼ 2/3, Table 1). First, fractional crystallization of diastereomeric
mixture 3a provided (R)-3a13 with 84% de (32% yield). An
additional crystallization of the (R)-3a (84% de) achieved de of
Table 1 Fractional crystallization of 3a and 3ba
Crystallizations
Starting material
(R)-3a
None
1st
2nd
>99
16
87
26
3rd
% deb
3
—
10
—
84
32
30
46
—
—
>99
14
Yield (%)
(R)-3b
% deb
Yield (%)
a
In toluene/CHCl3 ¼ 2/3. b % de was determined by HPLC.
Fig. 2 Functional group transformation of ketal 3.
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mixtures of 3b were satisfactorily separated into (R)-3b and (S)-
3b by recycling preparative HPLC.
All amides 3 were crystallized to obtain crystals suitable for
SXRD analysis and we were able to determine the stereochem-
istry (Fig. 3 and 4). As shown in Fig. 3, both (R)-3a and (S)-3a had
the same space group (P21) and a similar molecular arrange-
ment to construct hydrogen bonding networks. Their amide
groups act as hydrogen donor and acceptor to construct the
same number of hydrogen bonds, namely, two amide protons
bound to two oxygen atoms of the amide and the ketal. While
the cis proton against the carbonyl oxygen in (R)-3a constructed
hydrogen bonds with the amide functional group, the trans one
did in (S)-3a. The parameters of the hydrogen bonds in (R)-3a
and (S)-3a are summarized in Table 2. The hydrogen bonding
distances in (R)-3a crystals were shorter than those of (S)-3a. The
crystals of (R)-3a (mp 139–140 ꢁC, 1.26 g cmꢀ3) had a higher
melting point and larger calculated density than those of (S)-3a
(mp 135–136 ꢁC, 1.23 g cmꢀ3). We performed solubility tests on
each diastereomer in toluene at 25 ꢁC and found that the values
of (R)-3a and (S)-3a were 16.0 g Lꢀ1 and 21.5 g Lꢀ1, respectively,
as anticipated. These results suggest that the difference of
strength of the hydrogen bonds caused the discrepancy of the
solubility and consequently enabled fractional crystallization
providing (R)-3a.
As shown in Fig. 4, the crystals of (R)-3b and (S)-3b had space
groups of P21 and P212121, respectively. Similar molecular
Fig. 4 X-ray crystallographic structure: (a) (R)-3b, (b) (S)-3b.
arrangements of constructing hydrogen bonding networks were
observed in both diastereomers. While the cis proton against
the carbonyl oxygen in (R)-3b constructed hydrogen bonds with
amide functional groups, the cis one did not in (S)-3b. In other
words, a cis proton of (S)-3b did not bind to an oxygen atom of
ꢁ
the ketal. The crystals of (R)-3b (mp 164–165 C) ꢁhad a higher
melting point than those of (S)-3b (mp 152–154 C), but both
had the same calculated density (1.24 g cmꢀ3). Solubility tests
on each diastereomer in toluene at 25 ꢁC revealed that the
values of (R)-3b and (S)-3b were 35.3 g Lꢀ1 and 49.0 g Lꢀ1
,
respectively. As discussed above, we conclude that the different
hydrogen bonding networks caused the difference in both
melting point and solubility and enabled fractional crystalliza-
tion providing (R)-3b.
Table 2 Hydrogen-bonding distances and angles of (R)-3a, (S)-3a,
(R)-3b, and (S)-3b
N/Oamide interaction
N/Oketal interaction
N–H/O/ꢁ
N/O (H/O)/A
N–H/O/ꢁ
˚
˚
N/O (H/O)/A
(R)-3a
(S)-3a
(R)-3b
(S)-3b
2.829 (1.983)
3.195 (2.311)
2.878 (2.001)
2.917 (2.039)
160.80
151.76
175.90
176.77
3.099 (2.295)
3.239 (2.352)
3.071 (2.194)
157.21
178.40
175.14
a
a
—
—
a
(S)-3b did not bind to an oxygen atom of the ketal.
Fig. 3 X-ray crystallographic structure: (a) (R)-3a, (b) (S)-3a.
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Table 1 shows that the separation capacity of 3a is superior to the ltrate. Therefore, epimerization of the remaining diaste-
that of 3b in the aspect of fractional crystallization. To elucidate reomer (S)-3 into (R)-3 is desirable from the viewpoint of yield.
the reason for this difference, both diastereomeric mixtures (3a The screening of the epimerization conditions using (S)-3a and
and 3b) were crystallized simply from the solution (toluene/ (S)-3b is summarized in Table 3. DBU in toluene and potassium t-
CHCl3 ¼ 2/3) and the precipitated solid was analyzed using butoxide in dioxane or THF were not effective (entries 1–3). (S)-3a
powder X-ray diffraction (PXRD) analysis. Fig. 5 shows the PXRD (>99% de) was smoothly epimerized with potassium t-butoxide (2
ꢁ
patterns of the crystallized diastereomeric mixture of 3 along equiv.) at 50 C for 3.5 h in t-butanol, and the opposite diaste-
with those of each single diastereomer as well as their simulated reomer (R)-3a was slightly enriched with 7% de (entry 4). Under
patterns calculated from SXRD. In the case of 3a, the PXRD the same conditions, epimerization of (S)-3b (>99% de) pro-
pattern showed a superposition pattern of each diastereomer ceeded more slowly than (S)-3a, where the % de of (S)-3b was 20%
((R)-3a and (S)-3a), which means the two diastereomers depos- even aer 7 h (entry 5). Other bases such as NaH and KOH were
ited separately. In contrast, the PXRD pattern of the solid not effective (entries 6 and 7). The combination of potassium t-
precipitation of 3b shows a broad pattern with a partial butoxide and t-butanol for CIDT has been reported,14 so we
component of (R)-3b. The pattern of (S)-3b was particularly hard consider strong basic and protic conditions is appropriate for
to identify. These results suggest that the mixture of (R)-3b and this epimerization. This positive result encouraged us to apply
(S)-3b might exist as an amorphous material and be what CIDT (Table 4). The treatment of 3a (0.25 mmol, 2% de) with
caused the broad PXRD pattern. If so, it would explain why the potassium t-butoxide (0.5 equiv.) in t-butanol (0.20 mL) at room
separation capacity of 3a is superior to that of 3b.
temperature precipitated (R)-3a with 80% de (87% yield, entry 1).
An increased amount of t-butanol (0.40 mL) with an extended
stirring time (96 h) improved % de to 97% (95% yield, entry 2).
Meanwhile, a similar procedure to entry 2 using 3b precipitated
(R)-3b with 14% de (85% yield, entry 3). Although the attempt to
increase the reaction temperature to 80 ꢁC in order to accelerate
CIDT with addition of i-octane as a poor solvent provided better
% de (44% de and 51% de, entries 4 and 5), these gures were not
as high as those of 3a. As with the fractional crystallization of 3,
the CIDT of 3a was superior to 3b. Anyway, we are convinced that
the ketal moiety acted as not only a protecting group but also
a chiral resolving auxiliary which is a useful tool for CIDT.
Epimerization and crystallization-induced diastereomer
transformation (CIDT)
Even if a racemic compound is optically resolved by the diaste-
reomer method, half of the undesired diastereomer remains in
Deprotection and derivatization of ketals
In order to show synthetic applications, derivatization of (R)-3a
and (R)-3b was demonstrated (Scheme 2). (R)-3a and (R)-3b were
dehydrated into nitrile (R)-2a and (R)-2b by treatment with tri-
uoroacetic anhydride15 and triethylamine in 92% and 91%
yield, respectively. Subsequent deprotection of ketal groups by
usual acidic condition provided 3-oxocycloalkanecarbonitriles
(R)-1a and (R)-1b without epimerization.
Meanwhile, (R)-2a was reduced by hydrogenation using
sponge cobalt16 to give primary amine (R)-4a which was imme-
diately converted into benzoylated derivative (R)-5a. Depro-
tected ketone (R)-6a was nally obtained by usual acidic
condition in 93% yield with 98% ee.
Table 3 Screening of epimerization conditions of 3a
Entry
Base
Solvent
Temp. (ꢁC)
Time (h)
% deb
1
2
3
4
5
6
7
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3b
(S)-3b
(S)-3b
DBU
Toluene
Dioxane
THF
t-BuOH
t-BuOH
THF
110
100
50
50
50
24
24
48
3.5
7
98
98
87
ꢀ7
20
96
88
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NaH
50
50
24
8
KOH
EtOH
a
Conditions: (S)-3a or (S)-3b (>99% de, 0.050 mmol), base (2.0 equiv.),
and solvent (1.5 mL) was used. b % de was determined by HPLC.
Fig. 5 PXRD pattern: (a) 3a, (b) 3b.
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