Facile Access to Optically Active 2,6-Dialkyl-1,5-Diazacyclooctanes

Article abstract of DOI:10.1002/asia.201900938

The chiral substituted 1,5-diazacyclooctane (1,5-DACO) is of considerable importance and has attracted attention from a wide range of fields due to their unique chemical and biological properties. Despite the application potential, further study has not been optimized due to difficulties in their synthetic accessibility. Here, we report that the 1,5-DACO bearing a chiral auxiliary obtained from the formal [4+4] cycloaddition of N-alkyl-α,β-unsaturated imines can be further derivatized by nucleophilic alkylation to give various chiral substituted 1,5-DACO derivatives. The removal of the chiral auxiliary was effectively carried out using hydrogenation over Pearlman's catalyst. This methodology allows the production of a broad range of unprecedented optically active 2,6-dialkyl-1,5-DACO, which could not be accessed by other methods.

Full text of DOI:10.1002/asia.201900938

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Facile Access to Optically Active 2,6-Dialkyl-1,5-
Diazacyclooctanes
Authors: Dilyara R. Chulakova, Ambara R. Pradipta, Olga A.
Lodochnikova, Danil R. Kuznetsov, Kseniya S. Bulygina, Ivan
S. Smirnov, Konstantin S. Usachev, Liliya Z. Latypova, Almira
R. Kurbangalieva, and Katsunori Tanaka
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10.1002/asia.201900938
Chemistry - An Asian Journal
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Facile Access to Optically Active 2,6-Dialkyl-1,5-Diazacyclooctanes
Dilyara R. Chulakova,[a] Ambara R. Pradipta,*[b] Olga A. Lodochnikova,[a,c] Danil R. Kuznetsov,[a]
Kseniya S. Bulygina,[c] Ivan S. Smirnov,[a] Konstantin S. Usachev,[d] Liliya Z. Latypova,[a] Almira R.
Kurbangalieva,*[a] and Katsunori Tanaka*[a,b]
Abstract: The chiral substituted 1,5-diazacyclooctane (1,5-DACO) is
of considerable importance and has attracted attention from a wide
range of fields due to their unique chemical and biological properties.
Despite the application potential, further study has not been optimized
due to difficulties in their synthetic accessibility. Herewith, we reported
that the 1,5-DACO bearing chiral auxiliary obtained from the formal
[4+4] cycloaddition of N-alkyl-a,b-unsaturated imines can be further
derivatized by nucleophilic alkylation to give various chiral substituted
1,5-DACO derivatives. The removal of the chiral auxiliary was
effectively carried out using hydrogenation over Pearlman’s catalyst.
electron lone pairs, which offer several attractive features for the
molecules to be used as a framework for ligand development,[8]
as demonstrated in the (DACO)2NiII and (1-alkyl-5-py-DACO)CuII-
OO• (see Figure 1a).[9] These complex ions have a strong ligand
field, unique conformational requirements, and much space for
further functionalization. Moreover, the flexible conformation of
the 8-membered ring makes 1,5-DACO, and its derivatives
become versatile templates for novel material synthesis.[10]
(a) 1,5-DACO moiety in some important molecules
This methodology allows the production of
a broad range of
N
N
N
H
N
Ni
unprecedented optically active 2,6-dialkyl-1,5-DACO, which could not
be accessed by other methods.
N
N
H
N
N
O
HN
N
Tröger’s base
(DACO)2NiII
Bn
(−)-sparteine
(−)-cytisine
O
O
Ph
N
H
O
O
N
Introduction
N
N
O
Ph
N
N
O
N
Cu
Ph
N
Ph
N
N
2
N
O
Saturated nitrogen-containing heterocycles are an essential
scaffold for numerous natural and synthetic molecules. They
include compounds that may be used as drugs or synthons for the
synthesis of other pharmacologically active substances. Of
particular interest is compounds with 1,5-diazacyclooctane (1,5-
DACO) moiety.[1] Several 1,5-DACO containing molecules such
as (-)-sparteine,[2] (-)-cytisine,[3] Tröger’s base,[4] (-)-(S,S)-
homaline,[5] and SM-406[6] (see Figure 1a) have been widely
applied in chemistry, biology, and the medical field. From the
organic chemistry point of view, synthesis of the natural and
O
H
H
HN
(1-alkyl-5-py-DACO)CuII-OO
(−)-(S,S)-homaline
SM-406
(b) previous report for synthesis of unsubstituted 1,5-DACO
HN
Ts
1) TsNH2, NaH
1) TsNH2, NaH
N
DMF, 61%
DMF, 55%
NH
Cl
OH
2) TsCl, Et3N
2) HBr, PhOH
OTs
3-chloro-1-propanol
DMAP, CH2Cl2
65%
AcOH
86%
1,5-DACO
19% (four steps)
TsO
(c) previous report for synthesis of 3,7-dialkyl-1,5-DACO
Ac
Ac
iPrNH2
N
N
[Rh(cod)Cl]2, CO/H2
unnatural 1,5-DACO containing molecules has been
a
challenging task, and over the past decades, chemists have
attempted to accomplish a concise asymmetric synthesis of those
kinds of molecules.[7] Typically, 1,5-DACO moiety has two
120 °C, 100 bar
27%
3,7-dimethyl-1,5-DACO
cis/trans mixture (1:1)
N
N,N-diallylacetamide
iPr
(d) previous report for synthesis of 2,6-dialkyl-1,5-DACO
O
HN
O
O
Cl
B2H6
200 °C
80%
HN
HN
[a]
D. R. Chulakova, Dr. O. A. Lodochnikova, D. R. Kuznetsov, I. S.
Smirnov, Dr. L. Z. Latypova, Dr. A. R. Kurbangalieva, Prof. K.
Tanaka
crotonyl chloride
N
N
N
NH
HN
THF
68%
NaOH
80%
2,6-dimethyl-1,5-DACO
cis/trans mixture (1:1)
44% (three steps)
O
O
O
Biofunctional Chemistry Laboratory
5-methylpyrazolidin-3-one
Alexander Butlerov Institute of Chemistry
Kazan Federal University
18 Kremlyovskaya Street, Kazan 420008, Russia
E-mail: A. R. K. (almira99@mail.ru)
Dr. A. R. Pradipta, Prof. K. Tanaka
Biofunctional Synthetic Chemistry Laboratory
RIKEN Cluster for Pioneering Research
2-1 Hirosawa, Wako, Saitama 351-0198, Japan
E-mail: A. R. P. (arpradipta@riken.jp)
E-mail: K. T. (kotzenori@riken.jp)
Dr. O. A. Lodochnikova, K. S. Bulygina
Arbuzov Institute of Organic and Physical Chemistry
FRC Kazan Scientific Center of RAS
8 Arbuzov Street, Kazan 420088, Russia
Dr. K. S. Usachev
(e) this work: asymmetric synthesis of 2,6-dialkyl-1,5-DACO
HN
R
O
Rchiral
H
2) RMgX
56–71%
1)
3) H2
70–96%
R
acrolein
NH
[b]
NH2 OH
2,6-dialkyl-1,5-DACO
quant
43–57% (three steps)
single isomer
aminoalcohol
Figure 1. (a) Examples of 1,5-diazacyclooctane (1,5-DACO) based compounds.
Natural alkaloids: (-)-sparteine, (-)-cytisine, and (-)-(S,S)-homaline. Synthetic
compounds: Tröger’s base and SM-406. Complex ions: (DACO)2NiII and (1-
alkyl-5-py-DACO)CuII-OO•. [alkyl = 2-phenethyl; py = 2-(2-pyridyl)ethyl]. (b)
Previous example for the synthesis of unsubstituted 1,5-DACO from 3-chloro-
1-propanol in a 19% yield over four steps. (c) Previous example for the racemic
synthesis of 3,7-dimethyl-1,5-DACO from N,N-diallylacetamide in a 27% yield.
(d) Previous example for the racemic synthesis of 2,6-dimethyl-1,5-DACO in a
44% yield over three steps. (e) Our method for the asymmetric synthesis of
various 2,6-dialkyl-1,5-DACO derivatives.
[c]
[d]
NMR Laboratory, Institute of Physics
Kazan Federal University
18 Kremlyovskaya Street, Kazan 420008, Russia
Supporting information for this article is given via a link at the end of
the document.
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Despite its potential application, the straightforward synthesis
of chiral substituted 1,5-DACO remains challenging. An example
of the synthesis of unsubstituted 1,5-DACO was reported by
Börjesson (Figure 1b).[11] They reacted p-toluenesufonamide with
3-chloro-1-propanol to give a dialkylated product, which was
subsequently tosylated, cyclized, and detosylated to give the
unsubstituted 1,5-DACO in 19% yield over four steps. On the
other hand, an example of a method that allows access to the 3,7-
dialkyl-1,5-DACO was performed by utilizing Rh-catalyzed
hydroformylation of dienes (Figure 1c).[12] However, this reaction
only gives a low yield, and the product was obtained as a 1:1
mixture of the cis and trans isomers. Also, the preparation of 3,7-
dialkyl-1,5-DACO by other methods reported in the literature are
not satisfactory.[13]
bis[N,N’-(2-indanolyl)]-2,6-dimethyl-1,5-DACO hydrochloride salt
derivative. According to the X-ray data, both the newly generated
C2 and C6 stereogenic centers of 2,6-cis-isomer of 3 have (R)
configurations. The proton is localized on one of the nitrogen
atoms, i.e., N1 (see Figure 2b). The conformation of the 8-
membered ring can be defined as a "distorted boat–distorted
boat." Compound 3 in the crystal form a spiral along a-axis via O–
H···Cl intermolecular hydrogen bonds.
On the contrary to the 3,7-dialkyl-1,5-DACO, there is only one
example for the preparation of 2,6-dialkyl counterpart, which
reported by Stetter in 1965 and improved later on by Kemp in
1979 (Figure 1d).[14] They utilized 5-methylpyrazolidin-3-one and
crotonyl chloride to give an adduct, which subsequently heated to
undergo cyclization. Subsequently, the diborane reduction of the
cyclized product gives a 2,6-dialkyl-1,5-DACO. However, still, the
product was obtained as a 1:1 mixture of the cis and trans isomers.
Herein, we utilize chiral aminoalcohol and acrolein to produce
8-membered heterocycles, which was then transformed by a
simple functional group manipulation to the variously substituted
chiral 2,6-dialkyl-1,5-DACO products (Figure 1e).
Results and Discussion
Previously, we reported that N-alkyl unsaturated imines
derived from (1S,2R)-(-)-cis-1-amino-2-indanol and acrolein react
rapidly through the formal [4+4] cycloaddition to give the
corresponding 8-membered heterocycle 1 (Figure 2a). Also, we
reported that the treatment of heterocycle 1 with lithium aluminum
hydride (LiAlH4) selectively reduced the hemiaminal function at
C2 and C6 to give bis[N,N’-(2-indanolyl)]-1,5-DACO 2 in 92%
Figure 2. (a) Synthesis of 8-membered heterocycle 1 via the formal [4+4]
cycloaddition of (1S,2R)-(-)-cis-1-amino-2-indanol and acrolein. Reduction of 1
by LiAlH4 gave chiral bis[N,N’-(2-indanolyl)]-1,5-DACO 2 in 92% yield. Contrarily,
alkylation of 1 by MeMgI gave chiral bis[N,N’-(2-indanolyl)]-2,6-dimethyl-1,5-
DACO•HCl 3 in 27% yield. Attempt to cleave the 2-indanol group was not
successful. (b) The absolute stereochemistry of C2 (R) and C6 (R) in the 2,6-
cis-isomer of 3 were unambiguously determined by X-ray crystallographic
analysis. Hydrogen bonds are marked with a dashed line.
yield.[15] We then, by utilizing
a simple functional group
manipulation, tested the potential for introducing stereoselectively
additional alkyl groups to the C2 and C6 positions of heterocycle
1. We achieve nucleophilic alkylation at C2 and C6 by reacting
heterocycle 1 with methylmagnesium iodide to provide the chiral
Thus, our attention turned to a more flexible optically active
aminoalcohol, i.e., (R)-(-)-2-phenylglycinol (Figure 3a), which
previously has been employed as a useful chiral auxiliary in the
synthesis of various substituted chiral 1,3-dialkyl-1,3-
diaminopropanes.[16] The heterocycle 4 was readily prepared by
mixing (R)-(-)-2-phenylglycinol and acrolein in chloroform at room
temperature. The heterocycle 4 was obtained in quantitative yield
as a 2:2:1 mixture of three diastereoisomers as evidenced by
NMR spectroscopy (Figure 3a).[15a,17]
The transformation to the various chiral 2,6-dialkyl-1,5-DACO
derivatives was then attempted (Figure 3a and Table 1). The
method used in the transformation of heterocycle 1 to 3 (see
Figure 2a) was then used to explore the potential for introducing
alkyl groups stereoselectively at the C2 and C6 of heterocycle 4.
Nucleophilic alkylation at C2 and C6 was achieved by reacting 4
bis[N,N’-(2-indanolyl)]-2,6-dimethyl-1,5-DACO
3 (Figure 2a).
However, despite the excellent diastereoselectivity, purification of
the crude product allowed isolation of one diastereomer in only a
27% yield. Also, we found that removal of the chiral auxiliary, i.e.,
2-indanol group, to give the free amine of 1,5-DACO is
problematic. Hydrogenation of 3 over various palladium catalysts
under various conditions failed to cleave the rigid structure of 1-
amino-2-indanol with only starting material recovered. To our
disappointment, the chiral auxiliary (1S,2R)-(-)-cis-1-amino-2-
indanol only gave discouraging results, possibly due to their rigid
structure, and was not suitable for this purpose.
However, despite the low reaction yield, we could
unambiguously determine the stereochemistry of 3 by using X-ray
crystallographic analysis (Figure 2b). Structure determination by
single crystal X-ray diffraction identified 3 as chloroform solvate of
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with methyl, ethyl, propyl, and isopropyl Grignard reagents to
provide the chiral bis[N,N’-(2-phenylethanolyl)]-2,6-dialkyl-1,5-
DACO 5a–5d in 59–71% yields (Figure 3a and Table 1, Entry 1–
4). Compared to the method that utilized (1S,2R)-(-)-cis-1-amino-
2-indanol, the use of (R)-(-)-2-phenylglycinol as chiral auxiliary
improves the yield of the reaction in this protocol. Herein, only one
cis isomer was isolated, and another cis and trans isomers were
not observed. Meanwhile, the reaction between heterocycle 4
with butyl and allyl Grignard reagents gives both major 2,6-cis-
and minor 2,6-trans-isomers. Thus, we isolated 5e and 5f in 68%
and 60% yields, respectively, with diastereoselectivity of ca. 10:3
ratio of cis to trans (see Table 1, Entry 5 and 6; and Supporting
Information).
provides an efficient approach to synthesis the chiral 2,6-dialkyl-
1,5-DACO derivatives. The stereochemistry produced through the
alkylation, as listed in Table 1, was unambiguously determined
using X-ray crystallographic analysis of compound 5a (Figure 3b
and Table 1, Entry 1), as well as trans-5e and trans-5f (see Table
1, Entry 5 and 6; and Supporting Information, Figure S1 and S2).
Previously, several attempts at using 2-phenylglycinol as
chiral auxiliary to dictate the stereochemical outcome of
nucleophilic reactions have been reported.[18] Herein, through a
similar approach, the stereochemical outcome of the Grignard
reactions listed in Table 1 was also mainly controlled by the (R)-
(-)-2-phenylglycinol. The mechanism involves the formation of
iminium ions, followed by the ring-opening of the hemiaminals,
and the subsequent attack of the nucleophiles to the iminium ions
from the less sterically hindered direction of the 8-membered ring.
Also, although the detail is not yet apparent, we observed that
different alkyl substituents affect the molecular properties of the
1,5-DACO; which include the decrease of diastereoselectivity
when introducing a longer alkyl group (see Table 1, Entry 5 and
6), and the resistance during auxiliary removal of 2,6-dimethyl-
1,5-DACO 5a (vide infra and Table 2, Entry 1).
Table 1. Transformation of heterocycle
4
to chiral bis[N,N’-(2-
phenylethanolyl)]-2,6-dialkyl-1,5-DACO•HCl 5a–5i.
Isolated yield
(cis isomer)
Entry
RMgX
Product
R
1[a]
2
MeMgI
EtMgBr
5a
5b
5c
5d
5e
5f
CH3-
71%
CH3CH2-
CH3CH2CH2-
(CH3)2CH-
CH3CH2CH2CH2-
CH2=CHCH2-
C6H5CH2-
62%
59%
61%
68%
60%
58%
56%
67%
3
PrMgBr
4
iPrMgBr
BuMgBr
AllylMgBr
BnMgBr
VinylMgBr
PhMgBr
5[b]
6[c]
7
5g
5h
5i
8
CH2=CH-
Figure 3. (a) Synthesis of 8-membered heterocycle 4 via the formal [4+4]
cycloaddition of (R)-(-)-2-phenylglycinol with acrolein. Subsequently, alkylation
9
C6H5-
of
4 by RMgX gives chiral bis[N,N’-(2-phenylethanolyl)]-2,6-dialkyl-1,5-
DACO•HCl 5a–5i (see Table 1 for details). (b) The absolute stereochemistry of
C2 (S) and C6 (S) in the 2,6-cis-isomer of 5a were unambiguously determined
by X-ray crystallographic analysis. Hydrogen bonds are marked with a dashed
line.
[a] The absolute stereochemistry of the 2,6-cis-isomer of 5a was determined
by X-ray crystallographic analysis (see Figure 3b). The absolute
stereochemistry for the other compounds produced was assigned by the
analogy of reaction stereochemical outcome to these compounds. [b] Both
cis and trans isomers were observed and isolated in a 68:21 ratio. [c] Both
cis and trans isomers were observed and isolated in a 60:17 ratio. The
absolute stereochemistry of the trans-5e and trans-5f isomers were
determined by X-ray crystallographic analysis (see Supporting Information,
Figure S1 and S2).
On the other hand, the reaction between heterocycle 4 with
benzyl, vinyl, and phenyl Grignard reagents give the chiral
bis[N,N’-(2-phenylethanolyl)]-2,6-dialkyl-1,5-DACO 5g–5i in 56–
67% yields (Table 1, Entry 7–9). In this case we observed only
one cis isomer obtain from the reactions. It should be noted that
the alkenyl-substituted chiral 1,5-DACO 5f and 5h (Table 1, Entry
6 and 8) can be utilized as synthetic precursors to the larger novel
macrocyclic molecules, i.e., by ring-closing metathesis reaction,
further highlighting the importance of this protocols. This method
Structure determination by single crystal X-ray diffraction
identified bis[N,N’-(2-phenylethanolyl)]-2,6-dimethyl-1,5-DACO
5a as hydrochloride salt derivative (Figure 3b). Both C2 and C6
chiral centers of the cis-isomer have (S) configuration, the 8-
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membered ring adopts the “boat–boat” conformation, and the
methyl groups occupy equatorial positions. In the crystal 5a, a
strong intramolecular N–H···N bond was observed, as well as an
intramolecular O–H···O bond. The joint implementation of these
two interactions, apparently, leads to rigidity of the general
conformation of the molecule 5a, where C–N bonds become
sterically shielded. Also, the NMR analysis of the obtained cis
isomers of 5a–5i showed that carbon atoms of C2 and C6; C3 and
C7; C4 and C8; as well as the corresponding carbon atoms of two
introduced substituents and two 2-phenylglycinol fragments are
equivalent as they have the same chemical shift. As evidenced by
1H NMR spectra, which display a singlet for the NH proton in the
range of 13.2–15.6 ppm, suggested that the 2,6-disubstituted
products 5a–5i were obtained in their hydrochloride salt form. This
result agreed well with the X-ray fluorescence (XRF) analysis,
which confirmed the presence of chlorine in all isolated
substances.
hydrogenolysis of heterocycle 5f was accompanied by
hydrogenation of the allyl substituent to give (2S,6S)-2,6-dipropyl-
1,5-DACO 6c in 94% yield (Table 2, Entry 6). Structure analysis
of (2R,6R)-2,6-diisopropyl-1,5-DACO 6d by single crystal X-ray
diffraction observed that the 8-membered ring in the crystal has a
twist conformation (see Supporting Information, Figure S3).
Meanwhile, the hydrogenolysis of heterocycle 5a did not
proceed even under similar conditions, and only the starting
material was recovered (Table 2, Entry 1). Although we could not
rationale this phenomenon with absolute certainty, the X-ray
analysis of 5a (see Figure 3b), which revealed that the C–N bonds
were sterically shielded (vide supra), might suggest the difficulty
for hydrogenation to proceed.
OH
N
• HCl
OH • HCl
H2, Pd(OH)2/C
MeOH, AcOH
• HCl
H2N
+
2
HN
6
N
8h
7h
7%
HO
Table 2. Preparation of the chiral 2,6-dialkyl-1,5-diazacyclooctanes 6b–6g by
77%
removal of the chiral auxiliary.
5h
OH
OH
N
Ph
• HCl
Ph
• HCl
Ph
OH
• HCl
H2N
+
H2, Pd(OH)2/C
MeOH, AcOH
2
H
N
Ph
HN
N
6
R
R
• HCl
R
H2, Pd(OH)2/C
• HCl
R
2
2
N
6
6
8i
7i
MeOH, AcOH
70–96%
HO
N
NH
55%
40%
HO
5i
6b−6g
5a−5g
Scheme 1. Hydrogenation of the cis isomers of 5h and 5i did not give the
corresponding free amine compounds. Nevertheless, the vinyl substituent of 5h
completely converted to an ethyl group, and the 8-membered ring was cleaved
at allyl fragments to give the acyclic amines 7h and 8h. Similarly, the 8-
membered ring of 5i was cleaved at benzyl fragments to give the acyclic amines
7i and 8i.
Compound
(cis isomer)
Product
(isolated yield)
Entry
R-
1[a]
2
5a
5b
5c
5d
5e
5f
CH3-
CH3CH2-
-
6b (90%)
6c (96%)
6d (70%)
6e (77%)
6c (94%)
6g (82%)
In the hydrogenolysis reactions of heterocycles 5h and 5i,
which have 2,6-divinyl and 2,6-diphenyl substituents, respectively,
the formation of the targeted cyclic products was not observed.
Instead, the hydrogenolysis of heterocycle 5h reduced the vinyl
substituent and gave acyclic amines 7h and 8h in 7% and 77%
yields, respectively (Scheme 1). Meanwhile, treatment of 5i under
similar conditions gives acyclic amines 7i and 8i in 40% and 55%
yields, respectively (Scheme 1). The cleavage of carbon-nitrogen
bonds in the 8-membered ring, which facilitated near the allyl and
benzyl fragments of molecules 5h and 5i, can explain the
formation of those acyclic amines. This phenomenon is consistent
with the literature data for related systems.[19]
3
CH3CH2CH2-
(CH3)2CH-
4[b]
5
CH3CH2CH2CH2-
CH2=CHCH2-
C6H5CH2-
6[c]
7
5g
[a] Starting material 5a was recovered quantitatively. [b] The absolute
stereochemistry of (2R,6R)-2,6-diisopropyl-1,5-DACO•2HCl 6d was confirmed
by X-ray crystallographic analysis (Supporting Information, Figure S3). [c] Allyl
substituent of 5f underwent catalytic hydrogenolysis and was converted entirely
to propyl group to give (2S,6S)-2,6-dipropyl-1,5-DACO•HCl 6c.
Conclusions
Finally, the 2-phenylethanol group used as the chiral auxiliary
was removed without incident by hydrogenolysis over Pearlman's
catalyst in the presence of acetic acid in methanol. Thus, the
hydrogenolysis of the cis-isomer of 5b–5g gives the
corresponding chiral 2,6-dialkyl-1,5-DACO 6b–6g in 70–96%
yields (Table 2, Entry 2–7). Under the reaction conditions, the
In contrast to the all-carbon-containing 8-membered ring, a
well-studied class of compound,[20] the two-nitrogen-containing 8-
membered ring vie for scarce attention due to difficulties in their
synthetic accessibility. Herewith, we utilized the formal [4+4]
cycloaddition of N-alkyl-a,b-unsaturated imines obtained from
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C6), 71.19 (C2', C2''), 71.83 (C1', C1''), 125.98, 127.10, 127.13, 129.71,
135.87, 143.11 ppm (Carom); IR (ATR): νmax 3257 br, 2961, 2926, 2855,
1604, 1478, 1459, 1262, 1056, 739 cm–1; HRMS (ESI): m/z calcd for
C26H35ClN2O2+H+–HCl: 407.2693 [M+H–HCl]+; found: 407.2695.
acrolein and (R)-(-)-2-phenylglycinol to produce the 8-membered
ring 1,5-DACO. Further treatment of the [4+4] cycloaddition
product by nucleophilic alkylation, followed by hydrogenolysis,
produced the various optically active 2,6-disubstituted-1,5-DACO
derivatives. Although the method used two chiral auxiliaries, the
simple procedure and high diastereoselectivity of the asymmetric
reaction are advantageous for the synthesis of chiral disubstituted
1,5-DACO, a class of compound that has unique properties and
high potentials for widespread application in various fields.
Representative procedure for nucleophilic alkylation: Preparation of
bis[N,N’-(2-phenylethanolyl)]-2,6-dimethyl-1,5-DACO•HCl (5a). To a
1.0 M solution of methylmagnesium iodide in Et2O (10.0 mL, 10.0 mmol,
10 eq), prepared from methyl iodide (0.93 mL, 15.0 mmol), magnesium
turning (240 mg, 10.0 mmol) and Et2O (10 mL) was added dropwise
solution of heterocycle 4 (350 mg, 1.0 mmol, 1 eq) in Et2O (12 mL) at
ambient temperature. After the reaction mixture was refluxed under argon
for 2 hours and stirred for another 2 hours at room temperature, saturated
aqueous NH4Cl solution (20 mL) was added and the resulting mixture was
extracted with CHCl3 (3×10 mL). The organic layers were combined,
washed with water (30 mL), dried over Na2SO4, filtered, and concentrated
to dryness under reduced pressure. The resulting residue was re-
dissolved in a mixture of 2N HCl (10 mL) and CHCl3 (10 mL). After mixing,
the phases are allowed to separate and the aqueous phase is removed.
The aqueous layer was extracted again with CHCl3 (3×10 mL). The organic
layers were combined, washed with water (40 mL), dried over Na2SO4,
filtered, and concentrated to dryness under reduced pressure. The
resulting crude product was purified using preparative thin layer
chromatography [eluent: CHCl3/MeOH (15:1)] to give the desired
compound 5a as light-yellow solid (300 mg, 71%). Rf 0.23 (CHCl3/MeOH
15:1); m.p. 210−220 °С (dec.); [α] = + 6.11 (CHCl3, c = 1.00); 1H NMR (400
MHz, CDCl3): δ = 0.46 (d, 3JH,H = 6.2 Hz, 6H; С9Н3, С10Н3), 1.74–2.04 (m,
Experimental Section
General Experimental Procedures. All commercially available reagents
were used without further purification. The preparative separation was
performed by column chromatography on Silica gel 60A (Acros, 0.06-0.20
mm). Preparative thin-layer chromatography was performed on Merck
PLC Silica gel 60 F254, 1 mm. 1H and 13C NMR spectra were recorded on
a Bruker Avance III 400 NMR spectrometer. Unless otherwise mentioned,
CDCl3 and CD3OD were used as the solvents, and chemical shifts were
represented as d-values relative to the residual solvent peak. High-
resolution mass spectrometry (HRMS) was recorded on a micrOTOF-Q III
spectrometer. IR spectra were recorded on
a Bruker Tensor-27
spectrometer fitted with a Pike MIRacle ATR accessory (diamond/ZnSe
crystal plate). X-ray fluorescence spectra were obtained using an energy-
dispersive X-ray spectrometer Shimadzu EDX 800HS2. Optical rotations
were measured on a JASCO P-2200 polarimeter at the Sodium D-line (589
nm) and are reported as follows: [a] concentration (solvent, and c in g /
100 mL). The X-ray diffraction data for the single crystals of compound 3
were collected on a Bruker Smart Apex II CCD diffractometer; for the single
crystals of 5a, trans-5e, trans-5f, and 6d were collected on a Bruker
Kappa Apex CCD diffractometer using graphite monochromated MoKa
(0.71073 Å) radiation. The crystallographic data have been deposited in
the Cambridge Crystallographic Data Centre. Deposition numbers CCDC-
1937031 for compound 3, CCDC-1937032 for compound 5a, CCDC-
1938847 for compound trans-5e, CCDC-1938848 for compound trans-5f,
and CCDC-1937033 for compound 6d contain the supplementary
crystallographic data for this paper. Copies of the data can be obtained
free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge,
CB2 1EZ, UK; Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
2
4H; С3Н2, С7Н2), 3.12–3.26 (m, 2H; С4Н2, С8Н2), 3.75 (dd, JH,H = – 12.4
Hz, 3JН,Н = 4.5 Hz, 2H; С2'Н2, C2''Н2), 3.95 (td, 3JН,Н = 12.1 Hz, 2JН,Н = – 5.4
Hz, 2H; C4H2, C8H2), 4.07–4.28 (m, 4H; С2Н, С6Н, С2'Н2, C2''Н2), 4.66 (dd,
3JН,Н = 12.4 Hz, 3JН,Н = 4.5 Hz, 2H; C1'H, C1''H,), 6.82 (br, 2H; OH), 7.32 (s,
10H; Harom), 15.30 ppm (s, 1H; NH); 13C NMR (100 MHz, CDCl3): δ = 15.79
(С9, С10), 31.58 (С3, С7), 40.28 (С4, С8), 59.60 (С2, С6), 60.90 (С2', C2''),
69.66 (С1', C1''), 129.14, 129.23, 129.46, 134.38 ppm (Сarom); IR (ATR):
νmax 3237 br, 2972, 2925, 2877, 1581, 1488, 1450, 1090, 770, 705 cm–1
;
HRMS (ESI): m/z calcd for C24H35ClN2O2+H+–HCl: 383.2693 [M+H–HCl]+;
found: 383.2698.
Representative procedure for auxiliary cleavage: Preparation of
(2S,6S)-2,6-diethyl-1,5-DACO•HCl (6b).
A solution of bis[N,N’-(2-
phenylethanolyl)]-2,6-diethyl-1,5-DACO 5b (130 mg, 0.29 mmol) and
Pearlman’s catalyst (200 mg, 0.29 mmol) in a mixture of methanol (5 mL)
and acetic acid (0.34 mL, 5.8 mmol) was stirred for 7 days under hydrogen
atmosphere at ambient temperature. The catalyst was removed by
filtration through Celite and washed with a mixture solution of acetic acid
(0.4 mL) in methanol (40 mL). The filtrate was evaporated to dryness under
reduced pressure. The crude product was purified using preparative thin
layer chromatography [eluent: CHCl3/MeOH (8:1)] to give the desired
compound 6b as colourless oil (53 mg, 90%). Rf 0.47 (CHCl3/MeOH 5:1);
[α] = + 13.48 (CH3OH, c = 1.00); 1H NMR (400 MHz, CD3OD): δ = 1.01 (t,
3JH,H = 7.5 Hz, 6H; С10Н3, С12Н3), 1.58–1.75 (m, 6H; С9Н2, С11Н2, С3Н2,
С7Н2), 2.05–2.16 (m, 2H; С3Н2, С7Н2), 3.01–3.13 (m, 4H; С4Н2, С8Н2, С2Н,
С6Н), 3.28–3.43 ppm (m, 2H; С4Н2, С8Н2, including CH3OH); 13C NMR
(100 MHz, CD3OD): δ = 10.57 (С10, С12), 27.98 (С9, С11), 28.32 (С3, С7),
44.77 (С4, С8), 60.21 ppm (С2, С6); IR (ATR): νmax 3380 br, 2963, 2933,
2875, 2851, 2740, 1624, 1593, 1461, 1382 cm–1; HRMS (ESI): m/z calcd
for C10H23ClN2+H+–HCl: 171.1856 [M+H–HCl]+; found: 171.1856.
Preparation of bis[N,N’-(2-indanolyl)]-2,6-dimethyl-1,5-DACO•HCl (3).
To a 1.0 M solution of methylmagnesium iodide in Et2O (7.0 mL, 7.0 mmol,
10 eq), prepared from methyl iodide (0.65 mL, 10.5 mmol), magnesium
turning (170 mg, 7.0 mmol) and Et2O (7 mL) was added dropwise solution
of heterocycle 1 (250 mg, 0.67 mmol, 1 eq) in Et2O (10 mL) at ambient
temperature. After the reaction mixture was refluxed under argon for 2
hours and stirred for another 2 hours at room temperature, saturated
aqueous NH4Cl solution (20 mL) was added and the resulting mixture was
extracted with CHCl3 (3×10 mL). The organic layers were combined,
washed with water (50 mL), dried over Na2SO4, filtered, and concentrated
to dryness under reduced pressure. The resulting crude mixture was
purified using preparative thin layer chromatography [eluent: CHCl3/MeOH
(10:1)] to give the desired compound 3 as light-yellow solid (80 mg, 27%).
Rf 0.19 (CHCl3/MeOH 15:1); m.p. 180−195 °С (dec.); [α] = – 53.09 (CH3OH,
c = 1.00); 1H NMR (400 MHz, CDCl3): δ = 1.31 (d, 3JH,H = 6.7 Hz, 6Н; С9Н3,
С10Н3), 1.55–1.68, 2.12–2.26 (both m, 2Н each; C3H2, C7H2), 2.74–2.86
(m, 2Н; C4H2, C8H2), 2.96–3.14 (m, 4Н; C4H2, C8H2, C3'H2, C3''H2), 3.27 (m,
2JН,Н = – 16.8 Hz, 3JН,Н = 7.7 Hz, 2Н; C3'H2, C3''H2), 3.95–4.06 (m, 2H; C2H,
C6H), 4.72 (d, 3JH,H = 7.7 Hz, 2H; C1'H, C1''H), 4.95 (ddd, 3JН,Н = 7.7 Hz, 2Н;
C2'H, C2''H), 7.15–7.38 ppm (m, 8H, Нarom); 13C NMR (100 MHz, CDCl3): δ
= 17.65 (С9, С10), 31.23 (C3, C7), 39.83 (C3', C3''), 41.82 (C4, C8), 61.08 (C2,
Acknowledgments
This work was funded by the subsidy allocated to Kazan Federal
University for the state assignment in the sphere of scientific
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Entry for the Table of Contents
FULL PAPER
The 1,5-diazacyclooctane (1,5-DACO)
obtained from formal [4+4]
cycloaddition reaction of N-alkyl-a,b-
unsaturated imines can be
transformed to chiral substituted 1,5-
DACO derivatives via nucleophilic
alkylation, followed by hydrogenolysis.
This method provides useful and facile
access to various optically active 2,6-
dialkyl-1,5-DACO, which might have
unique chemical or biological
Dilyara R. Chulakova, Ambara R.
Pradipta,* Olga A. Lodochnikova, Danil
R. Kuznetsov, Kseniya S. Bulygina, Ivan
S. Smirnov, Konstantin S. Usachev,
Liliya Z. Latypova, Almira R.
Kurbangalieva,* and Katsunori Tanaka*
Page No. – Page No.
Facile Access to Optically Active 2,6-
Dialkyl-1,5-Diazacyclooctanes
properties.
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