Stereoselective synthesis of 1,2,3-triazolooxazine and fused 1,2,3-triazolo-d-lactone derivatives

Article abstract of DOI:10.1002/hlca.201300441

The stereoselective synthesis of 1,2,3-triazolooxazine and fused 1,2,3-triazolo-d-lactone by applying chemoenzymatic methods is described. trans-2-Azidocyclohexanol was successfully resolved by Novozyme 435 with an ee value of 99%. Installation of the alkyne moiety on the enantiomerically enriched azidoalcohol by O-alkylation, followed by intramolecular azide-alkyne [3+2] cycloaddition resulted in the desired 1,2,3-triazolooxazine derivative. Enantiomerically pure azidocyclohexanol was also subjected to the Huisgen 1,3-dipolar cycloaddition reaction with dimethylacetylene dicarboxylate, followed by intramolecular cyclization of the corresponding cycloadduct, to furnish a fused 1,2,3-triazolod-λ-lactone.

Full text of DOI:10.1002/hlca.201300441

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Helvetica Chimica Acta – Vol. 97 (2014)
Stereoselective Synthesis of 1,2,3-Triazolooxazine and Fused 1,2,3-Triazolo-d-
Lactone Derivatives
by Ays¸egꢀl Gꢀmꢀs¸*a), Kudret Merta), and Cihangir Tanyelib)
a) Department of Chemistry, Faculty of Sciences, Yꢀzꢀncꢀ Yıl University, TR-65080 Van
(phone: þ 90-432-2251024/2248; e-mail: gumusa@gmail.com)
b) Department of Chemistry, Middle East Technical University, TR-06800, Ankara
The stereoselective synthesis of 1,2,3-triazolooxazine and fused 1,2,3-triazolo-d-lactone by applying
chemoenzymatic methods is described. trans-2-Azidocyclohexanol was successfully resolved by
Novozyme 435 with an ee value of 99%. Installation of the alkyne moiety on the enantiomerically
enriched azidoalcohol by O-alkylation, followed by intramolecular azideꢀalkyne [3 þ 2] cycloaddition
resulted in the desired 1,2,3-triazolooxazine derivative. Enantiomerically pure azidocyclohexanol was
also subjected to the Huisgen 1,3-dipolar cycloaddition reaction with dimethylacetylene dicarboxylate,
followed by intramolecular cyclization of the corresponding cycloadduct, to furnish a fused 1,2,3-triazolo-
d-lactone.
1. Introduction. – In recent years, the chemistry of 1,2,3-triazoles has gained new
significance due to their wide range of applications in chemical, biological, medicinal,
and materials science. Initially studied by Huisgen in the 1960s, the 1,3-dipolar
cycloaddition of azides and alkynes is the most efficient method for the synthesis of
substituted 1,2,3-triazoles [1]. These compounds are variously used as chemother-
apeutic agents, synthetic intermediates for bioactive compounds, agrochemicals, optical
brighteners, photostabilizers, anticorrosive agents, and metal chelators (for some recent
reviews on the synthesis of 1,2,3-triazoles, see [2]). The extraordinary stability towards
metabolic transformations and the aromatic nature of the triazole ring, along with its
high dipole moment and H-bonding capability, make it a paramount functional group
of great potential utility as a connecting group [3]. The asymmetric synthesis of fused
1,2,3-triazolo-d-lactone and lactam derivatives has gained further importance, since
they can easily be converted to biologically active precursors [4].
Optically pure 2-azido alcohols are very important intermediates for the synthesis
of chiral 1,2-aminoalkanols, which have received wide attention in recent years due to
their diverse applications as starting materials for the construction of bioactive
compounds such as antibiotics [5], alkaloids [6], and enzyme inhibitors [7], and also as
chiral resolving agents [8] and chiral auxiliaries for asymmetric synthesis [9].
Moreover, optically pure 2-azido alcohols can efficiently be obtained by lipase-
catalyzed resolution of their racemic forms [10].
We report here the enzymatic resolution of trans-2-azidocyclohexanol and the
asymmetric synthesis of fused 1,2,3-triazolo-d-lactone and 1,2,3-triazolooxazine by
intramolecular azideꢀalkyne 1,3-dipolar cycloaddition. To the best of our knowledge,
this is the first stereoselective synthesis of fused 1,2,3-triazolo-d-lactone and 1,2,3-
triazolooxazine derivatives.
ꢁ 2014 Verlag Helvetica Chimica Acta AG, Zꢀrich

Helvetica Chimica Acta – Vol. 97 (2014)
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2. Results and Discussion. – 2.1. Enzymatic Resolution of rac-1. The key substrate
rac-1 was prepared from cyclohexene by oxidation with m-chloroperbenzoic acid
(mCPBA) and then by ring opening of 7-oxabicyclo[4.1.0]heptane, with azide as the
nucleophile (NaN3) to give (ꢁ)-trans-2-azidocyclohexanol.
Initially, the enantiomeric resolution of rac-1 was performed by using Novozyme
435, and vinyl acetate as both the acyl donor and as solvent at 408 (Scheme 1). The
reaction was carried out by using a substrate/enzyme ratio of 1:1 (w/w). The
conversion was monitored by TLC and 30% yield (for alcohol) was achieved after 7 d.
The products were separated by flash column chromatography, and relatively low ee
values of 45% for the ester (1R,2R)-2 and 77% for the alcohol (1S,2S)-1 were obtained
(Table, Entry 1). We also carried out the enzyme-mediated resolution of the same
substrate with Lipozyme, PS-C Amano, CRL (Candida rugosa lipase), and PPL
(porcine pancreative lipase) under the same conditions. Lipozyme gave the best
enantioselectivity (87% ee for (1S,2S)-1 and 60% ee for 2, Entry 2). To improve the ee
values, experimental conditions were screened in detail using a co-solvent and by
changing the reaction temperature. Resolution with Novozyme 435 using (iPr)2O as co-
solvent at 308 gave excellent enantioselectivity for alcohol (1S,2S)-1 (99% ee, Entry 6),
which is comparable with the literature values [10], and a better ee value for 2 (68% ee,
Entry 6). Also the enantioselectivity increased in PS-C Amano-catalyzed resolution
performed at 308 in (iPr)2O ((1S,2S)-1, 90% ee; and 2, 65% ee, Entry 7).
The absolute configurations of (þ)-1 and (þ)-2 were determined as (1S,2S) and
(1R,2R), respectively, by comparing the specific rotation signs determined at equal
concentrations in the same solvents, which have been reported in [10]. The
Scheme 1
Table. Results of the Enzyme Catalyzed Kinetic Resolution of rac-1
Entry Enzyme
Temp. Time (1R,2R)-2
(1S,2S)-1
c
Ee)
[8]
[h]
c
Yield [%] eepc) [%] Yield [%] ees ) [%] [%]d)
1
2
3
4
5
6
7
Novozyme 435a) 40
168
168
168
168
168
48
62
48
50
51
–
45
60
56
42
–
30
44
45
36
–
77
87
71
81
–
63
59
56
66
–
6
11
10
6
–
27
14
Lipozymea)
PS-C Amanoa)
CRLa)
40
40
40
40
PPLa)
Novozyme 435b) 30
49
52
68
65
45
43
99
90
59
58
PS-C Amanob)
30
48
a) The reactions were carried out in vinyl acetate at 408. b) The reactions were carried out in vinyl acetate
and (iPr)2O as co-solvent at 308. c) Enantiomeric excess (ee) values were determined by HPLC using
e
Chiralcel AD-H chiral column. d) c ¼ ees/(ees þ eep). ) Calculated by the method of Sih and co-workers:
E ¼ ln[(1 ꢀ c)(1 ꢀ ees)]/ln[(1 ꢀ c)(1 þ ees)] [11].

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Helvetica Chimica Acta – Vol. 97 (2014)
spectroscopic and analytical data of 1 and 2 are in accordance with the reported values
[10], confirming the assigned structures and stereochemical integrity.
2.2. Stereoselective Synthesis of 1,2,3-Triazolooxazine. After successful enzymatic
resolution and determination of absolute configuration of the key compound (1S,2S)-
(þ)-1, we turned our attention to the transformation of the vicinal azidocyclohexanol
into a triazolooxazine derivative. Installation of the alkyne group on (þ)-(1S,2S)-1 was
achieved by base-mediated O-alkylation with CHꢂCCH2Br, leading to the desired
ꢂazideꢀalkyneꢃ 3 in excellent yield (Scheme 2). Having obtained the appropriate
substrates for intramolecular azideꢀalkyne cycloaddition (ꢂclick chemistryꢃ), thermally
induced cycloaddition was performed (for racemic synthesis, see [12])1). Unlike in the
intermolecular azideꢀalkyne 1,3-dipolar cycloadditions, the appropriate positioning of
the two reacting moieties eliminated the need of any metal catalyst, and the desired
cycloaddition could be efficiently achieved at a moderate temperature. Cycloaddition
in refluxing toluene resulted in the formation of enantiomerically pure tricyclic 1,2,3-
triazolooxazine, (5aS,9aS)-(þ)-4, in 80% yield.
2.3. Stereoselective Synthesis of Fused 1,2,3-Triazolo-d-Lactone. The azido alcohol
(1S,2S)-(þ)-1 can also serve as a potential precursor for the synthesis of enantiomeri-
cally enriched triazole lactone derivatives, since the N3 moiety can be easily
transformed to many functional groups by intermolecular cyclization. The vicinal
azido alcohol (þ)-1 was exposed to ꢂclickꢃ 1,3-dipolar cycloaddition reaction with
dimethyl acetylenedicarboxylate (DMAD) by refluxing in toluene to afford the
corresponding triazol cycloadduct 5 (Scheme 3). The next step was planned to be the
construction of the lactone ring to yield the tricyclic product 6. However, the desired 6
Scheme 2
i) CHꢂCCH2Br, NaH, Bu4NI, THF. ii) Toluene, reflux.
Scheme 3
i) Dimethyl acetylenedicarboxylate (DMAD), toluene, reflux.
1
)
The spectroscopic data of 1,2,3-triazolooxazine 4 are in accordance with those of the corresponding
racemic form reported in [12].

Helvetica Chimica Acta – Vol. 97 (2014)
1343
was obtained without lactonization step. Enantiomerically pure methyl (5aS,9aS)-
5a,6,7,8,9,9a-hexahydro-4-oxo-4H-[1,2,3]triazolo[5, 1-c][1,4]benzoxazine-3-carboxy-
late ((þ)-6)was obtained as yellow solid in good yield.
3. Conclusions. – In conclusion, trans-2-azidocyclohexanol was successfully resolved
by Novozyme 435 with high enantioselectivity (99% ee). The enantiomerically pure
(1S,2S)-azido alcohol is a key compound for asymmetric synthesis of both intermo-
lecular and intramolecular cyclization products. We have demonstrated that the
Huisgen 1,3-dipolar cycloaddition of this enantiomerically pure azide with an alkyne
moiety introduced to the OH group yields the enantiomerically pure tricyclic 1,2,3-
triazolooxazine. Also, we have described the stereoselective synthesis of the optically
active fused 1,2,3-triazolo-d-lactone by ꢂclick reactionꢃ of the chiral azide with DMAD
as an activated alkyne, followed by intramolecular lactonization.
Experimental Part
General. Lipozyme, PS-C Amano lipase, CRL (Candida rugosa Lipase), PPL (lipase type II, from
porcine pancreas) were purchased from Aldrich. Novozyme 435 was donated by Novo Nordisk AS, DK
Bagsverd. TLC: Merck silica gel 60 F254 anal. aluminium plates (SiO2; 0.2 mm thickness). Flash column
chromatography (FC): SiO2 (60 mesh; Merck). HPLC: Thermo Separation Products, Inc., P1500-SN-
4000-UV2000 instrument, Chiralcel AD-H anal. column (250 ꢃ 4.60 mm). Optical rotations: Rudolph
1
Research Analytical Autopol III automatic polarimeter (1-dm cell). H- and 13C-NMR spectra: Bruker
Spectrospin Advance DPX 400 spectrometer; in CDCl3; d in ppm rel. to Me4Si as internal standard, J in
Hz. HR-ESI-MS: Agilent 6224 LC/TOF-MS; in m/z.
Synthesis of (ꢁ)-trans-2-Azidocyclohexanol (rac-1). To a soln. of cyclohexene epoxide (0.97 g,
1 mmol) in MeCN/H2O 1:1 (20 ml) was added NaN3 (1.92 g, 3 mmol). The mixture was stirred under
reflux for 4.5 h and then extracted with Et2O (3 ꢃ 50 ml). The org. phase was washed with brine and dried
(MgSO4), concentrated in vacuo, and the crude product was purified by FC (AcOEt/hexane 1:5) to
afford rac-1 (0.95 g, 0.98 mmol, 98%). Colorless oil (see [11]). 1H-NMR: 3.32 (td, J ¼ 8.8, 4.4, 1 H); 3.24 –
3.04 (m, 1 H); 2.74 (s, 1 H); 2.10 – 1.87 (m, 2 H); 1.78 – 1.62 (m, 2 H); 1.34 – 1.08 (m, 4 H). 13C-NMR:
73.5; 67.1; 33.1; 29.8; 24.2; 23.8.
General Procedure of the Enzymatic Resolution of rac-1. To a stirred soln. of rac-1 (155 mg, 1 mmol)
in vinyl acetate (5 ml), enzyme (155 mg; cf. the Table) was added in one portion, and the mixture was
stirred at 408. The conversion was monitored by TLC. The mixture was filtered, and vinyl acetate was
evaporated under reduced pressure. The products were purified by FC (AcOEt/hexane 1:5).
(þ)-(1S,2S)-2-Azidocyclohexanol ((þ)-(1S,2S)-1). Yield: 70 mg (45%). Colorless oil. [a]2D0 ¼ þ68.5
(c ¼ 1, CH2Cl2); 99% ee [10]. The enantiomeric purity of the product was determined by HPLC (Daicel
Chiralcel AD-H; hexane/iPrOH 90 :10; flow rate, 1 ml minꢀ1; l, 210 nm; tR 7.1 min (minor); tR 78.1 min
(major); in comparison with the racemic sample).
(þ)-(1R,2R)-2-Azidocyclohexyl Acetate (2). Yield: 90 mg (49%). Colorless oil. [a]2D0 ¼ þ8.0 (c ¼ 1,
1
CH2Cl2); 68% ee [10]. H-NMR: 4.61 (td, J ¼ 9.7, 4.6, 1 H); 3.31 (td, J ¼ 10.3, 4.4, 1 H); 2.02 (s, 3 H);
2.01 – 1.92 (m, 2 H); 1.78 – 1.60 (m, 2 H); 1.34 – 1.14 (m, 4 H). 13C-NMR: 169.2; 74.5; 62.2; 29.6; 29.3; 22.1;
22.5; 20.1.
(þ)-(1S,2S)-1-Azido-2-(prop-2-yn-1-yloxy)cyclohexane (3). A mixture of NaH (0.21 g, 60%,
1.5 mmol) and 2-azidocyclohexanol (500 mg, 1 mmol) dissolved in dry THF (10 ml) was stirred in an
ice-bath for 30 min. Then, CHꢂCCH2Br (0.72 ml, 1.3 mmol) was added slowly, followed by Bu4NI
(0.5 mmol), and the mixture was stirred overnight at r.t. After the reaction was completed, sat. NH4Cl
soln. was added, and the mixture was extracted with AcOEt (3 ꢃ 15 ml). The org. phase was washed with
brine, dried (MgSO4), and concentrated in vacuo. Since the product easily decomposes, the crude one
was used in the next step without further purification (see [11] for racemic synthesis).

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Helvetica Chimica Acta – Vol. 97 (2014)
(þ)-(5aS,9aS)-5a,6,7,8,9,9a-Hexahydro-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazine (4). Compound 3
(500 mg, 2.8 mmol) was dissolved in toluene (15 ml), and the soln. was heated at reflux for 6 h. After the
reaction was complete, the solvent was evaporated, and product 4 was obtained as white crystals. The
spectroscopic data were in accordance with those reported in [11]. Yield: 400 mg (80%). M.p. 102 – 1048.
1
[a]2D0 ¼ þ93.9 (c ¼ 1, CH2Cl2). H-NMR: 7.35 (s, 1 H); 5.01 – 4.96 (m, 1 H); 4.83 – 4.78 (m, 1 H); 3.86 –
3.80 (m, 1 H); 3.38 – 3.32 (m, 1 H); 2.89 – 2.86 (m, 1 H); 2.07 – 2.04 (m, 1 H); 1.90 – 1.74 (m, 2 H);
1.52 – 1.33 (m, 4 H). 13C-NMR: 130.8; 128.1; 78.3; 62.0; 60.9; 30.1; 27.9; 23.7; 23.6.
(þ)-Methyl (5aS,9aS)-5a,6,7,8,9,9a-Hexahydro-4-oxo-4H-[1,2,3]triazolo[5,1-c][1,4]benzoxazine-3-
carboxylate (6). To a stirred soln. of (1S,2S)-1 (80 mg, 0.57 mmol) in toluene (11 ml), DMAD
(0.456 g, 10 mmol) was added. The mixture was stirred for 4 h under reflux. The solvent was evaporated,
and the crude product was purified by FC (AcOEt/hexane 2 :3) to furnish 6. Yield: 93 mg (65%). [a]D20
¼
þ78.1 (c ¼ 1, CH2Cl2). 1H-NMR: 4.35 – 4.20 (m, 2 H); 3.94 (s, 3 H); 3.07 – 3.03 (m, 1 H); 2.33 – 2.29 (m,
1 H); 2.01 – 1.94 (m, 2 H); 1.81 – 1.65 (m, 2 H); 1.56 – 1.37 (m, 2 H). 13C-NMR: 158.7; 152.5; 140.3; 124.8;
80.0; 59.0; 51.9; 28.2; 25.9; 22.3; 22.1. HR-ESI-MS: 252.1032 ([M þ H]þ, C11H14N3O4þ ; calc. 252.0984).
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Received December 13, 2013