Stereo- and regiocontrolled syntheses of exomethylenic cyclohexane β-amino acid derivatives

Article abstract of DOI:10.3390/molecules201219749

Cyclohexane analogues of the antifungal icofungipen [(1R,2S)-2-amino-4-methylenecy clopentanecarboxylic acid] were selectively synthesized from unsaturated bicyclic β-lactams by transformation of the ring olefinic bond through three different regio- and s

Full text of DOI:10.3390/molecules201219749

Article
Stereo- and Regiocontrolled Syntheses of
Exomethylenic Cyclohexane β-Amino
Acid Derivatives
Loránd Kiss 1, Eniko˝ Forró 1, György Orsy 1, Renáta Ábrahámi 1 and Ferenc Fülöp 1,2,
*
Received: 15 October 2015 ; Accepted: 19 November 2015 ; Published: 27 November 2015
Academic Editor: Derek J. McPhee
1
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary;
kiss.lorand@pharm.u-szeged.hu (L.K.); forro.eniko@pharm.u-szeged.hu (E.F.);
Orsy.gyorgy@pharm.u-szeged.hu (G.O.); abrahami.renata@pharm.u-szeged.hu (R.Á.)
Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged,
H-6720 Szeged, Eötvös 6, Hungary
2
*
Correspondence: fulop@pharm.u-szeged.hu; Tel.: +36-62-545-564
Abstract: Cyclohexane analogues of the antifungal icofungipen [(1R,2S)-2-amino-4-methylenecy
clopentanecarboxylic acid] were selectively synthesized from unsaturated bicyclic β-lactams
by transformation of the ring olefinic bond through three different regio- and stereocontrolled
hydroxylation techniques, followed by hydroxy group oxidation and oxo-methylene
interconversion with a phosphorane. Starting from an enantiomerically pure bicyclic β-lactam
obtained by enzymatic resolution of the racemic compound, an enantiodivergent procedure led to
the preparation of both dextro- and levorotatory cyclohexane analogues of icofungipen.
Keywords: amino acids; selectivity; hydroxylation; Wittig reaction; icofungipen
1. Introduction
As a consequence of their high biological potential, cyclic β-amino acids are of importance
in medicinal chemistry. These compounds are both elements of bioactive products and building
blocks in peptide research. Several small molecular entities, such as the cyclopentane derivative
cispentacin (1) and oxetane derivative oxetin (2), possess strong antifungal and antibacterial
activities [1–13]. An exomethylene function plays an essential role in the structures of some
cyclic β-amino acids. The β-amino acid (1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid
(icofungipen, PLD-118, 3) and several analogues (4–6) exhibit strong antifungal properties
(Figure 1). The (´)-(1R,2S)-2-Amino-4-methylenecyclopentane carboxylic acid was analyzed by
Bayer. This compound, previously known as BAY 10-8888, was licensed to Glaxo-SmithKline
Research Centre Zagreb Ltd. (formerly PLIVA) and renamed PLD-118; its generic name is
icofungipen. Icofungipen is a cyclic β-amino acid, which differs in chemistry, biology, and mechanism
of action from other antifungal compound classes. Its mechanism of action is based on the inhibition
of isoleucyl-tRNA synthetase, intracellular inhibitory concentrations at the target site being achieved
by active accumulation in susceptible fungi [14–18].
The most efficient multigram-scale asymmetric synthetic route to icofungipen involves the
asymmetric desymmetrization of the meso-anhydride of a cyclopentane exo-methylenedicarboxylic
acid. In the key step, highly enantioselective, quinine-mediated alcoholysis of the meso-anhydride,
followed by Curtius rearrangement and Pd-catalyzed removal of the protecting groups affords
icofungipen (absolute configurations 1R,2S) with ee = 99.5% [14–18].
Molecules 2015, 20, 21094–21102; doi:10.3390/molecules201219749
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Molecules 2015, 20, 21094–21102
CO2H
NH2
CO2H
CO2H
NH2
O
NH2
cispentacin (1)
icofungipen (3)
oxetin (2)
CO2H
NH2
CO2H
CO2H
NH2
NH2
5
4
6
Figure 1. Some biologically interesting cyclic β-amino acids.
2. Results and Discussion
A convenient and simple novel regio- and stereocontrolled synthetic procedure for the access
to cyclohexane analogues of icofungipen is described, with an exomethylene group in different
positions. Cyclohexene β-amino acids were subjected to regio- and stereoselective hydroxylation,
oxidation and oxo-methylene interconversion as illustrated in the retrosynthetic scheme (Scheme 1).
stereo- and
regioselective
CO2Et
NHBoc
CO2Et
NHBoc
CO2Et
CO2H
NH2
Wittig reaction
oxidation
O
HO
NHBoc
hydroxylation
Scheme 1. Retrosynthetic route to exomethylene cyclohexane β-amino esters.
The first synthetic approach was based on selective hydroxylation via iodolactonization.
Racemic cyclohexene cis-β-amino acid (˘)-7 underwent regio- and stereoselective iodolactonization
and deiodination by elimination to afford lactone (˘)-8. Subsequent lactone opening in (˘)-8 with
˝
NaOEt at 0 C for 1 h, followed by C-C double bond saturation, yielded 5-hydroxylated β-amino
˝
ester (˘)-9. When the lactone opening with NaOEt was performed at 20 C for 12 h, isomerization
occurred with the participation of the active hydrogen at C-1, leading, after C=C reduction, to the
thermodynamically more stable trans diastereoisomer (˘)-10 (Scheme 2) [19].
Scheme 2. Synthesis of 5-hydroxylated β-amino ester diastereoisomers (˘)-9 and (˘)-10 [19].
By a modification of an earlier-described method, [3] oxidation of (˘)-9 and (˘)-10 with
˝
pyridinium chlorochromate (PCC) in CH2Cl2 at 20 C afforded the corresponding oxo ester
stereoisomers (˘)-11 and (˘)-12 [19]. Icofungipen analogues (˘)-13 and (˘)-14 were next synthesized
from (˘)-11 and (˘)-12 via Wittig reactions by oxo-methylene exchange with the phosphorane
˝
generated from methyltriphenylphosponium bromide/t-BuOK at 0 C (Scheme 3).
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Molecules 2015, 20, 21094–21102
HO
HO
CO2Et
NHBoc
O
O
CO2Et
NHBoc
CO2Et
NHBoc
PCC, CH2Cl2
Br
Ph3P-Me
THF, t-BuOK
20 °C, 14 h, 73%
0 °C, 7 h, 66%
(±)-9
(±)-13
(±)-14
(±)-11
(±)-12
CO2Et
NHBoc
CO2Et
NHBoc
CO2Et
NHBoc
PCC, CH2Cl2
Br
Ph3P-Me
THF, t-BuOK
20 °C, 14 h, 77%
0 °C, 7 h, 70%
(±)-10
Scheme 3. Synthesis of racemic exomethylene cyclohexane β-amino esters (˘)-13 and (˘)-14.
The next synthetic approach to novel cyclohexane icofungipen analogues consisted
in hydroxylation of the olefinic bond of the cyclohexene cis-β-amino ester (˘)-15 via
cis-diastereoselective epoxidation with MCPBA and regioselective reductive oxirane opening with
NaBH4, [20,21] with the hydride attack at C-5, resulting in the 4-hydroxylated β-amino ester
diastereoisomers (˘)-17 and, at higher temperature, through isomerization at the active methyne
(˘)-18 (Scheme 4) [22]. It may be noted that (˘)-18 was synthesized earlier in an alternative way from
(˘)-15 [22].
CO2Et
NaBH4, EtOH
20 °C, 3 h, 62%
HO
NHBoc
(±)-17
CO2Et
NHBoc
CO2Et
NHBoc
MCPBA, CH2Cl2
0 °C, 5 h, 63%
O
(±)-15
CO2Et
NHBoc
(±)-16
NaBH4, EtOH
70 °C, 3 h, 53%
HO
(±)-18
Scheme 4. Synthesis of 4-hydroxylated β-amino ester diastereoisomers (˘)-17 and (˘)-18 [22].
Hydroxylated esters (˘)-17 and (˘)-18 were readily oxidized with PCC to oxo esters (˘)-19
and (˘)-20 [22]. Compounds (˘)-21 and (˘)-22, with the methylene function at position 4, isomers
of (˘)-13 and (˘)-14, were readily prepared from (˘)-19 and (˘)-20 in Wittig reactions with the
phosphorane generated in situ from methyltriphenylphosponium bromide/t-BuOK (Scheme 5).
CO2Et
NHBoc
CO2Et
CO2Et
NHBoc
PCC, CH2Cl2
Br
Ph3P-Me
THF, t-BuOK
0 °C, 7 h, 63%
20 °C, 14 h, 82%
HO
HO
NHBoc
O
(±)-17
(±)-18
(±)-19
(±)-21
(±)-22
CO2Et
CO2Et
NHBoc
CO2Et
PCC, CH2Cl2
Br
Ph3P-Me
THF, t-BuOK
0 °C, 7 h, 66%
20 °C, 14 h, 79%
O
NHBoc
NHBoc
(±)-20
Scheme 5. Synthesis of racemic exomethylene cyclohexane β-amino esters (˘)-21 and (˘)-22.
Other regio- and stereoisomers were synthesized by regio- and stereoselective iodolactonization
and deiodination of β-aminocyclohex-3-enecarboxylic acid (˘)-23, followed by selective lactone
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Molecules 2015, 20, 21094–21102
opening with NaOEt and hydrogenation of the amino lactone intermediate (˘)-24 to furnish
analogously to (˘)-8 (Scheme 2) the 3-hydroxylated β-amino ester stereoisomers (˘)-25 and (˘)-26
(Scheme 6) [23].
Scheme 6. Synthesis of 3-hydroxylated β-amino ester stereoisomers (˘)-25 and (˘)-26 [6].
A modification of an earlier-described method [23] was next used: oxidation of hydroxylated
amino esters (˘)-25 and (˘)-26 with PCC in CH2Cl2 at room temperature led to the corresponding
cis and trans keto esters (˘)-27 and (˘)-28 [23]. Although cis-keto aminocarboxylate (˘)-27
afforded the Wittig product on treatment with methyltriphenylphosphonium bromide/t-BuOK
in tetrahydrofurane due to the presence of the active hydrogen isomerization occurred at C-2
under alkaline conditions and gave the thermodynamically more stable (˘)-29 (only the relative
stereochemistry is shown), in which the amino and carboxylate functions are in a trans relationship;
trans amino ester (˘)-28 reacted with the phosphonium salt in the presence of t-BuOK to yield (˘)-29
stereoisomer with the ester and carbamate in the trans arrangement (Scheme 7).
CO2Et
NHBoc
CO2Et
NHBoc
OH
(±)-26
OH
(±)-25
PCC, CH2Cl2
PCC, CH2Cl2
20 °C, 14 h, 72%
20 °C, 14 h, 72%
CO2Et
CO2Et
NHBoc
CO2Et
NHBoc
Br
Ph3P-Me
Br
Ph3P-Me
THF, t-BuOK
0 °C, 7 h, 63%
THF, t-BuOK
0 °C, 7 h, 61%
NHBoc
O
O
(±)-27
(±)-29
Scheme 7. Synthesis of racemic (˘)-29.
(±)-28
The isomerization of cis-(˘)-27 at C-2 during the Wittig reaction with
methyltriphenylphosponium bromide/t-BuOK in THF to give (˘)-29 through trans amino ester
(˘)-28 is depicted in Scheme 8.
Scheme 8. Formation of (˘)-29 from (˘)-27 through trans-amino ester (˘)-28.
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Molecules 2015, 20, 21094–21102
The above experiments (27Ñ29 and 28Ñ29) with the racemates led us to suppose that both
enantiomers of 29 could be obtained by starting from an enantiomerically pure bicyclic lactam.
For this purpose, therefore, enantiomerically pure β-lactam (+)-30 (ee = 99%) was prepared by
CAL-B-catalyzed ring-opening of racemic lactam (˘)-30 (Scheme 9) [24].
Scheme 9. Synthesis of enantiomerically pure lactam (+)-30.
Enantiomerically pure β-lactam (+)-30 was next transformed by an earlier-published
procedure [23] to the corresponding N-Boc amino acid, which was then converted to enantiopure
bicyclic lactone (´)-24 (Scheme 10).
Boc2O, NaOH
H2O/THF
1S
O
CO2H
1S
1S
CO2H
18% HCl, 0 °C
1 h, 76%
NH
0 °C to RT
14 h, 88%
NHBoc
NH2HCl
6R
2R
2R
(+)-30
(-)-23
(-)-32
KI, I2, NaHCO3
H2O, CH2Cl2
20 °C, 18 h, 74%
1S
1S
O
O
DBU, THF
8S
8S
5S
4S
I
NHBoc
NHBoc
65 °C, 5 h, 69%
5R
O
O
(-)-24
(-)-33
Scheme 10. Synthesis of enantiomer lactone (´)-24.
˝
On treatment with NaOEt at 0 C, optically pure lactone (´)-24 gave the all-cis 3-hydroxylated
β-amino ester (´)-34, [23] whereas at room temperature for 14 h isomerization at C-1 led to (´)-35 [23].
On catalytic hydrogenation, these compounds afforded hydroxylated cyclohexane β-amino esters
(+)-25 and (´)-26, [6] respectively, in enantiomerically pure form (Scheme 11) [23].
Scheme 11. Synthesis of amino ester stereoisomers (+)-25 and (´)-26.
Analogously to the racemates, (+)-25 and (´)-26 [23] underwent oxidation to the corresponding
enantiopure cis and trans (+)-27 and (´)-28 (ee = 99%).
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Molecules 2015, 20, 21094–21102
On reaction with phosphorane generated in situ from methyltriphenyphosphonium
bromide/t-BuOK, (+)-27 participated in isomerization at C-2 to give the thermodynamically
more stable (+)-29 (ee = 90.6%), while under similar conditions (´)-28 yielded its opposite enantiomer
(´)-29 (ee = 86.6%). The chiral centers at C-1 or C-2 in (+)-27 may theoretically both be affected
(both active hydrogens) but this was not observed. Only C-2 underwent isomerization, leading to
the thermodynamically more stable derivative (+)-29 with the carbamate and ester groups in a trans
relative relationship. (Scheme 12).
1S
1S
1S
CO2Et
2S
NHBoc
CO2Et
2S
NHBoc
CO2Et
2R
NHBoc
Ph3P-MeBr
PCC, CH2Cl2
t-BuOK, THF
0 °C, 7 h, 39%
20 °C, 14 h, 70%
3R
OH
O
(+)-25
(+)-27
(+)-29
1R
1R
1R
CO2Et
2S
NHBoc
CO2Et
2S
NHBoc
CO2Et
2S
NHBoc
Ph3P-MeBr
PCC, CH2Cl2
t-BuOK, THF
0 °C, 7 h, 42%
20 °C, 14 h, 76%
3R
OH
O
(-)-26
(-)-28
(-)-29
Scheme 12. Synthesis of amino ester enantiomers (+)-29 and (´)-29.
3. Experimental Section
3.1. General Procedure for the Methylenation of Oxo Esters
To a solution of methyltriphenylphosphonium bromide (2 mmol) in THF (15 mL), t-BuOK
˝
(1 equiv.) was added and the solution was stirred for 15 min at 20 C. The β-aminooxocarboxylate
(1 equiv.) was then added and the mixture was further stirred at this temperature. After 6 h, water
(15 mL) was added, and the mixture was extracted with CH2Cl2 (2 ˆ 15 mL). The organic layer was
dried (Na2SO4) and concentrated, and the crude product was purified by column chromatography
on silica gel (n-hexane/EtOAc 9:1).
Ethyl (1R*,2S*)-2-(tert-butoxycarbonylamino)-5-methylenecyclohexanecarboxylate [(˘)-13]. A colorless oil,
yield: 66%. Rf = 0.65 (n-hexane/EtOAc 4:1); 1H-NMR (CDCl3, 400 MHz): δ = 1.22 (t, 3H, CH3,
J = 7.00 Hz), 1.41 (s, 9H, t-Bu), 1.71–1.80 (m, 1H, CH2), 1.83–1.90 (m, 1H, CH2), 2.09–21 (m, 1H,
CH2), 2.23–2.30 (m, 1H, CH2), 2.32–2.38 (m, 1H, CH2), 2.57–2.63 (m, 1H, CH2), 2.82–2.88 (m, 1H,
H-1), 3.96–4.02 (m, 1H, H-2), 4.07–4.20 (m, 2H, OCH2), 4.63–4.70 (m, 2H, CH2), 5.38 (brs, 1H, N-H).
13C-NMR (DMSO, 100 MHz): δ = 14.9, 29.1, 30.1, 32.3, 32.8, 46.8, 47.9, 60.6, 78.6, 109.4, 147.1, 158.0,
173.0. Anal. Calcd for C15H25NO4: C 63.58, H 8.89, N 4.94; found: C 63.20, H 8.61, N 4.68.
Ethyl (1S*,2S*)-2-(tert-butoxycarbonylamino)-5-methylenecyclohexanecarboxylate [(˘)-14]. A white solid,
˝
1
mp 102–103 C; yield: 70%. Rf = 0.6 (n-hexane/EtOAc 4:1); H-NMR (CDCl3, 400 MHz): δ = 1.21
(t, 3H, CH3, J = 7.00 Hz), 1.41 (s, 9H, t-Bu), 2.06–2.19 (m, 1H, CH2), 2.24–2.43 (m, 5H, CH2, H-1),
3.79–3.86 (m, 1H, H-2), 4.11–4.20 (m, 2H, OCH2), 4.42 (brs, 1H, N-H), 4.70–4.73 (m, 2H, CH2).
13C-NMR (DMSO, 100 MHz): δ = 14.9, 29.1, 33.3, 33.6, 36.7, 50.3, 50.9, 60.7, 78.3, 110.2, 146.0, 156.0,
173.7. Anal. Calcd for C15H25NO4: C 63.58, H 8.89, N 4.94; found: C 63.22, H 9.11, N 4.69.
Ethyl (1R*,2S*)-2-(tert-butoxycarbonylamino)-4-methylenecyclohexanecarboxylate [(˘)-21]. A white solid,
˝
mp 56–58 C; yield: 63%. Rf = 0.6 (n-hexane/EtOAc 4:1); 1H-NMR (CDCl3, 400 MHz): δ = 1.16 (t, 3H,
CH3, J = 7.10 Hz), 1.43 (s, 9H, t-Bu), 1.79–1.86 (m, 1H, CH2), 1.88–2.03 (m, 1H, CH2), 2.11–2.19 (m, 1H,
CH2), 1.23–1.33 (m, 1H, CH2), 2.38–2.45 (m, 2H, CH2), 2.77–2.82 (m, 1H, H-1), 4.09–4.23 (m, 3H,
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Molecules 2015, 20, 21094–21102
OCH2, H-2), 4.78–4.80 (m, 1H, =CH), 4. 83–4.86 (m, 1H, =CH), 5.06 (brs, 1H, N-H). 13C-NMR (CDCl3,
100 MHz): δ = 14.6, 26.4, 28.8, 32.5, 39.8, 45.4, 49.7, 60.9, 79.6, 111.4, 144.5, 155.4, 173.7. Anal. Calcd for
C15H25NO4: C 63.58, H 8.89, N 4.94; found: C 63.23, H 8.60, N 4.68.
Ethyl (1S*,2S*)-2-(tert-butoxycarbonylamino)-4-methylenecyclohexanecarboxylate [(˘)-22]. A white solid,
˝
1
mp 99–101 C; yield: 66%. Rf = 0.55 (n-hexane/EtOAc 4:1); H-NMR (CDCl3, 400 MHz): δ = 1.21
(t, 3H, CH3, J = 7.10 Hz), 1.41 (s, 9H, t-Bu), 1.78–1.88 (m, 1H, CH2), 1.89–1.98 (m, 1H, CH2), 2.00–2.10
(m, 2H, CH2), 2.29–2.38 (m, 1H, CH2), 2.56–2.61 (m, 1H, CH2), 2.62–2.69 (m, 1H, H-1), 3.83–3.96
(m, 1H, H-2), 4.17–4.24 (m, 2H, OCH2), 4.60 (brs, 1H, N-H), 5.79–5.82 (m, 2H, =CH), 13C-NMR
(DMSO, 100 MHz): δ = 14.6, 27.8, 28.8, 32.8, 40.5, 48.2, 61.0, 78.0, 110.9, 144.9, 152.0, 173.8. Anal. Calcd
for C15H25NO4: C 63.58, H 8.89, N 4.94; found: C 63.78, H 8.66, N 5.23.
Ethyl (1S*,2R*)-2-(tert-butoxycarbonylamino)-3-methylenecyclohexanecarboxylate [(˘)-29]. A white solid,
˝
1
mp 75–77 C; yield: 63%. Rf = 0.65 (n-hexane/EtOAc 4:1); H-NMR (CDCl3, 400 MHz): δ = 1.22
(t, 3H, CH3, J = 7.10 Hz), 1.22–1.30 (m, 1H, CH2) 1.40 (s, 9H, t-Bu), 1.75–1.84 (m, 2H, CH2), 1.95–2.02
(m, 1H, CH2), 2.07–2.19 (m, 1H, CH2), 2.21–2.28 (m, 1H, CH2), 2.39–2.43 (m, 1H, H-1), 4.11–4.20
(m, 2H, OCH2), 4.24–4.35 (m, 1H, H-2), 4.39 (brs, 1H, N-H), 4.79–4.83 (m, 2H, CH2). 13C-NMR (DMSO,
100 MHz): δ = 14.9, 26.6, 29.1, 29.7, 34.8, 50.7, 55.0, 60.6, 78.3, 107.7, 147.9, 155.7, 173.9. Anal. Calcd for
C15H25NO4: C 63.58, H 8.89, N 4.94; found: C 63.80, H 8.60, N 5.22.
3.2. Characterization of the Enantiomerically Pure Substances
The ee values for (+)-27 and (´)-28 were determined on a HPLC (ChiralPak IA, Chiral
Technologies Europe, Illkirch-Graffenstaden, France) 5 µ column (0.4 cm ˆ 1 cm): for (+)-27 (ee 99%),
mobile phase: n-hexane/2-propanol (80/20); flow rate 0.5 mL/min; detection at 205 nm; retention
time (min): 11.14 (for antipode: 10.68); for (´)-28 (ee 99%), mobile phase: n-hexane/2-propanol
(70/30); flow rate 0.5 mL/min; detection at 205 nm; retention time (min): 11.8 (for antipode: 25.1).
The ee values for (´)-29 and (+)-29 were determined on a HPLC (ChiralPak IA) 5 µ column
(0.4 cm ˆ 1 cm), for (´)-29 (ee 90%): mobile phase: n-hexane/2-propanol (70/30); flow rate
0.5 mL/min; detection at 205 nm; retention time (min): 9.25; for (+)-29 (ee 86%): mobile phase:
n-hexane/2-propanol (70/30); flow rate 0.5 mL/min; detection at 205 nm; retention time (min): 10.36.
All 1H-NMR spectra recorded for the enantiomeric substances were the same as for the
corresponding racemic counterparts.
(1S,2R)-2-Aminocyclohex-3-enecarboxylic acid hydrochloride [(´)-32] [20,21].
A
white solid;
mp 203–206 C; yield: 76%. rαs2D5 = ´89.5 (c 0.335, EtOH).
˝
˝
(1S,2R)-2-(tert-Butoxycarbonyl)cyclohex-3-enecarboxylic acid [(´)-23]. A white solid; mp 115–118 C;
yield: 88%. rαs2D5 = ´26.6 (c 0.315, EtOH), (for the opposite enantiomer see reference [23]).
tert-Butyl (1S,4S,5S,8S)-4-iodo-7-oxo-6-oxabicyclo[3.2.1]octan-8-ylcarbamate [(´)-33]. A white solid;
mp 50–53 C; yield: 74%. rαs2D5 = ´54.4 (c 1.9, EtOH) (for the opposite enantiomer, see reference [23]).
˝
tert-Butyl (1S,5R,8S)-7-oxo-6-oxabicyclo[3.2.1]oct-3-en-8-ylcarbamate [(´)-24].
A
white solid;
25
˝
mp 157–159 C; yield: 69%. rαsD = ´107.6 (c 0.35, EtOH) (for the opposite enantiomer, see
reference [23]).
Ethyl (1S,5R,6S)-6-(tert-butoxycarbonyl)-5-hydroxycyclohex-3-enecarboxylate [(´)-34]. A colorless oil;
yield: 92%. rαs2D5 = ´21.6 (c 0.375, EtOH) (for the opposite enantiomer, see reference [23]).
Ethyl (1R,5R,6S)-6-(tert-butoxycarbonyl)-5-hydroxycyclohex-3-enecarboxylate [(´)-35]. A colorless oil;
yield: 56%. rαs2D5 = ´79.6 (c 0.48, EtOH) (for the opposite enantiomer, see reference [23]).
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Molecules 2015, 20, 21094–21102
Ethyl (1S,2S,3R)-2-(tert-butoxycarbonyl)-3-hydroxycyclohexanecarboxylate [(+)-25].
A
A
white solid;
white solid;
mp 76–79 C; yield: 87%. rαs2D5 = +24.6 (c 0.62, EtOH).
˝
Ethyl (1R,2S,3R)-2-(tert-butoxycarbonyl)-3-hydroxycyclohexanecarboxylate [(´)-26].
mp 92–94 C; Yield: 47%. rαs2D5 = ´38.4 (c 0.61, EtOH), (for the opposite enantiomer see reference [23]).
˝
Ethyl (1S,2S)-2-(tert-butoxycarbonyl)-3-oxocyclohexanecarboxylate [(+)-27]. A colorless oil; yield: 70%.
rαs2D5 = +54.3 (c 0.415, EtOH), (for the racemic compound, see reference [23]).
˝
Ethyl (1R,2S)-2-(tert-butoxycarbonyl)-3-oxocyclohexanecarboxylate [(´)-28]. A white solid; mp 85–88 C;
25
yield: 76%. rαsD = ´12.7 (c 0.53, EtOH) (for the racemic compound see reference [23]).
Ethyl (1S,2R)-2-(tert-butoxycarbonyl)-3-methylenecyclohexanecarboxylate [(+)-29]. A colorless oil; yield:
39%. rαs2D5 = +25.8 (c 0.38, EtOH); ee = 90.6%.
Ethyl (1R,2S)-2-(tert-butoxycarbonyl)-3-methylenecyclohexanecarboxylate [(´)-29]. A colorless oil; yield:
42%. rαs2D5 = ´14.1 (c 0.33, EtOH); ee = 86.7%.
4. Conclusions
Cyclohexane β-amino esters with an extracyclic methylene at position 3, 4 or 5 have been
regio- and stereoselectively synthetized from 2-aminocyclohexenecarboxylic acid regioisomers by
transformation of the ring olefinic bond via three different regio- and stereocontrolled hydroxylation
procedures, followed by deoxygenation through oxo-methylene interconversion via Wittig reactions.
An enantiodivergent route starting from a bicyclic β-lactam enantiomer permitted the synthesis of
both enantiomers of a cyclohexane icofungipen analogue.
Acknowledgments: We are grateful to the Hungarian Research Foundation (OTKA No K100530 and K115731)
for financial support. This paper was supported by the János Bolyai Research Scholarship (L.K.) of the Hungarian
Academy of Sciences.
Author Contributions: L.K. and F.F. designed, planed research and interpreted the results. E.F., G.O. and R.A.
carried out of the synthetic work. All authors discussed the results, prepared and commented on the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors in mg quantities.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open
access article distributed under the terms and conditions of the Creative Commons by
Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
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