Stereoselectivity in the synthesis of conformationally constrained vicinally dihydroxylated cyclic α-amino acids

Article abstract of DOI:10.1039/b001779p

Stereoselective syntheses of precursors to vicinal cis-dihydroxy-l-aminocyclopentane- and -cyclohexane-carboxylic acid methyl esters and their methoxy analogues are described. The chiral products are isolated as pure enantiomers. The absolute configuratio

Full text of DOI:10.1039/b001779p

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Stereoselectivity in the synthesis of conformationally constrained
vicinally dihydroxylated cyclic ꢀ-amino acids
Kristin Hammer, Jing Wang, Mette Lene Falck-Pedersen, Christian Rømming and
Kjell Undheim*
1
Department of Chemistry, University of Oslo, N-0315 Oslo, Norway
Received (in Cambridge, UK) 6th March 2000, Accepted 27th March 2000
Published on the Web 5th May 2000
Stereoselective syntheses of precursors to vicinal cis-dihydroxy-1-aminocyclopentane- and -cyclohexane-carboxylic
acid methyl esters and their methoxy analogues are described. The chiral products are isolated as pure enantiomers.
The absolute configurations at the new stereogenic centres are established by X-ray analysis.
Introduction
A wide variety of conformationally constrained amino acids
are expected to be acceptable in protein biosynthesis by analogy
to the findings in Escherichia coli.1 In this organism methyl and
cyclic α,α-disubstituted amino acids were, in general, signifi-
cantly more efficiently incorporated than was -alanine. It is
also known that α-substituted α-amino acids are conforma-
tionally constrained and therefore, when incorporated into
peptides, will constitute a powerful approach for generating
structurally defined peptides as conformational probes and
bioactive agents.2 Such findings have stimulated work in the
search for ways to prepare conformationally constrained amino
acid-like structures. Our efforts have largely been directed
towards the development of stereoselective methodology for
the preparation of rigid, cyclic amino acids where the α-carbon
of the amino acid is imbedded in the ring. When the ring carries
an additional substituent in the form of a hydroxy group, our
target molecules have been rigidified analogues of serine and
homoserine.3,4 Herein we describe work for the preparation of
cyclic, sterically defined cis-dihydroxy derivatives. The chiral
information required for the preparation of these structures is
available in the bislactim substrate 1. The latter is derived from
a diketopiperazine enantiomer of valine and glycine. Prior to
our work, preparation of di- or higher hydroxylated, sterically
pure amino acids in this series had been limited to tetrahydrox-
ylated cyclopentane and cyclohexane α-amino acids that were
prepared from a sugar azidolactone.5
Results and discussion
The spirocycloalkenes 3 (Scheme 1) and 10 (Scheme 2) were the
substrates used for the hydroxylation studies. Their preparation
involves dialkylation of the bislactim ether 1 in a stepwise and
stereoselective manner (2 and 9) followed by a Ru()-catalysed
ring-closing metathesis reaction as recently described.6
The vicinal dihydroxylation reaction was effected by catalytic
amounts of osmium tetraoxide in the presence of N-methyl-
morpholine N-oxide (NMO). The stereoselectivity was moder-
ate in the dihydroxylation of the five-membered-ring structure
3, the dihydroxy product isomer ratio 4:5 being 3:1. In con-
trast, high stereoselectivity was obtained in the oxidation of
the six-membered ring 10 (Scheme 2), the ratio 11:12 being
14:1. The relative stereochemistry of the major isomers in the
two series, however, was different between 4 and 11. The struc-
tures were determined by single-crystal X-ray analyses. In the
Scheme 1 Reagents and conditions: (i) 2% Ru(), DCE; (ii) 1.0 mol%
OsO4, NMO, Me2CO, H2O, 0 ЊC, 6 h; (iii) NaH, MeI, DMF–THF,
20 ЊC, 14 h; (iv) 0.1 M TFA in MeCN–H2O 1:1, 20 ЊC, 5 d; (v) (a) 0.1 M
TFA in MeCN–H2O 1:1, 20 ЊC, 3 d; (b) Ac2O, DMAP, CH2Cl2, 20 ЊC,
2 d.
DOI: 10.1039/b001779p
J. Chem. Soc., Perkin Trans. 1, 2000, 1691–1695
This journal is © The Royal Society of Chemistry 2000
1691

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Fig. 1 The ORTEP plot of the X-ray structure of 4. Ellipsoids are
shown at 50% probability. For clarity only hydrogens at stereogenic
centres are shown. The absolute configurations at the stereogenic
centres were established relative to the known chirality (2R) at C-2 (4).
Crystallographic numbering scheme shown.
Fig. 2 The ORTEP plot of the X-ray structure of 13. Ellipsoids are
shown at 50% probability. For clarity only hydrogens at stereogenic
centres are shown. The absolute configurations at the stereogenic
centres were established relative to the known chirality (2R) at C-2 (13).
Crystallographic numbering scheme shown.
Scheme 2 Reagents and conditions: (i) 2% Ru(), DCE; (ii) 1.0 mol%
OsO4, NMO, Me2CO, H2O, 0 ЊC, 6 h; (iii) NaH, MeI, DMF–THF,
20 ЊC, 14 h; (iv) 0.1 M TFA in MeCN–H2O 1:1, 20 ЊC, 5 d.
with methyl iodide and sodium hydride as base gave the
dimethoxy product 6, which was subsequently hydrolysed to
its amino acid ester 7. Compounds 7 and 8 are achiral. Chiral
amino acids would require a symmetry-breaking substitution
on intermediate 3, but this was not studied because the purpose
of this work was to make available methodology for the prepar-
ation of this class of conformationally constrained amino acids.
Preparation of enantiomerically pure amino acid derivatives,
however, has been demonstrated in the six-membered-ring
series which furnished the amino acid ester analogue 14
(Scheme 2).
For stereochemical assignments, the cyclopentanediol 4 was
subjected to a single-crystal X-ray analysis (Fig. 1, vide infra).
The crystal form of the corresponding six-membered-ring diol
11 was not satisfactory under the conditions tried. In this case
a single-crystal X-ray analysis was run on the dimethoxy
analogue 13 (Fig. 2, vide infra).
five-membered-ring series the major isomer has the vicinal cis-
dihydroxy groups in a transfacial relationship to the 6-methoxy
group in the pyrazine ring whereas a cisfacial relationship exists
with the dihydroxy groups in the six-membered-ring system.
Inspection of a molecular model of structure 3 indicates a high
degree of shielding of the cyclopentenyl ring at the face that
has the overlying pyrazine 6-methoxy group (numbering of 1).
The shielding would suggest a favoured approach to the less
shielded face of the double bond, resulting in preferential
formation of the transfacial structure 4 rather than stereo-
isomer 5.
The six-membered ring in the spiroannulated structure 10
(Scheme 2) is more flexible and can assume conformations
where the double bond is more exposed than in the spiro-
annulated cyclopentene. In particular, in boat-like conform-
ations as indicated in structure A in Scheme 2, the face on the
side of the methoxy group has reduced shielding. The other
face becomes more shielded by the pyrazine 3-methoxy group
and the N-4 pyrazine nitrogen (numbering of 1). As a result,
hydroxylation occurs preferably cisfacial to the 6-methoxy
group, the preferential product being compound 11 rather than
compound 12.
In conclusion we have synthesized in a stereoselective manner
dihydroxy derivatives of rigidified cyclic α-amino acids and
have determined their absolute configurations by single-crystal
X-ray analysis.
Experimental
Hydrolytic cleavage of the pyrazine ring with formation of
the new amino acid as its methyl ester was effected by mild acid
hydrolysis using 0.1 M TFA in aq. acetonitrile. The cyclo-
pentane product was highly water soluble and was isolated after
acylation as the triacetylated amino acid ester 8 (Scheme 1).
The methoxylated analogue 7 has also been prepared. Alkyl-
ation was effected before hydrolysis. Treatment of the diol 4
1H NMR spectra were recorded in CDCl3 at 300 or 200 MHz
with a Bruker DPX 300 or DPX 200 spectrometer. The 13C
spectra were recorded in CDCl3 at 75 MHz or 50 MHz. Chem-
ical shifts are reported in ppm using residual CHCl3 (7.24 ppm)
and CDCl3 (77 ppm) as references. J-Values are given in Hz.
Mass spectra under electron-impact conditions (EI) were
recorded at 70 eV ionizing potential; ammonia was used for
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chemical ionization (CI). The spectra are presented as m/z (%
rel. int.). IR spectra were measured on a Nicolet Magna 550
spectrometer using ATR (attenuated total reflectance). Optical
rotations were measured at ambient temperature (≈20 ЊC) on
a Perkin-Elmer 241 polarimeter. [α]D-Values are given in units
of 10Ϫ1 deg cm2 gϪ1. Dry THF was distilled from sodium and
benzophenone under argon. Dry ethylene dichloride (DCE)
was distilled from calcium hydride under argon. DMF was dis-
tilled from barium oxide. Solvents were degassed by bubbling
argon through them.
(Mϩ, 1%), 227 (9), 226 (9), 209 (6), 198 (10), 184 (11), 183 (100),
154 (24).
Compound 5 (126 mg, 17%) was a white solid, mp 104 ЊC
(crude) (Found: C, 57.8; H, 8.3%); HRMS: Mϩ, 270.1572; [α]D
Ϫ34.60 (c 0.54, CHCl3); νmax(ATR)/cmϪ1 3315s, 2908, 1671,
1420, 1210, 1009; δH(300 MHz) 0.60 (3 H, d, J 7, CH3), 0.98
(3 H, d, J 7, CH3), 1.84–2.24 (5 H, m, CH, 2 × CH2), 3.90 (2 H,
m, 2 × OH), 3.55 (3 H, s, OCH3), 3.68 (3 H, s, OCH3), 3.90 (1 H,
d, J 4, H-2), 4.25 (2 H, m, CHOH); δC(75 MHz) 16.70 (CH3),
19.14 (CH3), 30.95 (CH), 46.47 (CH2), 46.66 (CH2), 52.09
(OCH3), 52.80 (OCH3), 60.77 (C-5, -2), 73.38 (2 × CHOH),
160.84 (C), 163.75 (C); m/z (EI) 270 (Mϩ, 12%), 253 (11),
228 (15), 227 (100), 209 (26), 198 (21), 195 (29), 183 (57), 154
(14).
X-Ray crystallographic analysis data for compounds 4 and 13†
X-Ray data were collected on a Siemens SMART CCD dif-
fractometer7 using graphite-monochromated Mo-Kα radiation
(λ = 0.710 73 Å). Data-collection method: ω-scan, range 0.6Њ,
crystal-to-detector distance 5 cm. Data reduction and cell
determination were carried out with the SAINT and XPREP
programs.7 Absorption corrections were applied by the use of
the SADABS program.8 The structure was determined and
refined using the SHELXTL program package.9 The non-
hydrogen atoms were refined with anisotropic thermal param-
eters; hydrogen atoms were located from difference Fourier
maps and refined with isotropic thermal parameters.
(2R,3ЈR,4ЈS,5R)-2,5-Dihydro-5-isopropyl-3,3Ј,4Ј,6-tetrameth-
oxypyrazine-2-spirocyclopentane 6
A
solution of (2R,3ЈR,4ЈS,5R)-2,5-dihydro-5-isopropyl-3,6-
dimethoxypyrazine-2-spirocyclopentane-3Ј,4Ј-diol 4 (404 mg,
1.50 mmol) in dry DMF (1 ml)–THF (1 ml) was added to a
suspension of sodium hydride (131 mg in paraffin oil, 60%; 3.00
mmol) in DMF (10 ml)–THF (10 ml) under argon at 0 ЊC. The
mixture was stirred at ambient temperature for 2 h before
methyl iodide (0.2 ml, 3.00 mmol) was added dropwise. The
resultant mixture was stirred at ambient temperature overnight.
Diethyl ether (100 ml) was added. The organic mixture was
extracted with water (5 × 40 ml) and washed with brine (40 ml).
The ethereal solution was dried (MgSO4) and evaporated. The
residual material was subjected to flash chromatography using
hexane–EtOAc (2:1) as eluent to yield compound 6 as a colour-
less oil (318 mg, 71%) (Found: C, 60.57; H, 8.61. Calc for
C15H26N2O4: C, 60.38; H, 8.78%); HRMS: Mϩ, 298.1882. Calc
for C15H26N2O4: M, 298.1893; νmax(ATR)/cmϪ1 2908, 1671,
1422, 1295, 1221; δH(300 MHz) 0.62 (3 H, d, J 7, CH3), 1.00
(3 H, d, J 7, CH3), 1.92–2.40 (5 H, m, Me2CH, 2 × CH2), 3.36
(3 H, s, CHOCH3), 3.37 (3 H, s, CHOCH3), 3.60 (3 H, s, OCH3),
3.64 (3 H, s, OCH3), 3.88–3.97 (3 H, m, 2 × CHOCH3, H-2);
δC(75 MHz) 16.80 (CH3), 19.22 (CH3), 30.99 (CH), 42.99 (CH2),
43.27 (CH2), 52.15 (OCH3), 52.49 (OCH3), 56.79 (CHOCH3),
56.86 (CHOCH3), 60.16 (C-5), 60.66 (C-2), 81.56 (CHOMe),
81.66 (CHOMe), 160.80 (C), 165.72 (C); m/z (EI) 298 (Mϩ, 2%),
283 (12), 267 (21), 255 (17), 237 (100), 226 (19), 223 (73), 197
(95).
Crystal data for C13H22N2O4 (4), M = 270.33, tetragonal, P42,
a = 12.654(1), c = 9.215(1) Å, V = 1475.5(1) Å3, Z = 4, Dx =
1.217 Mg mϪ3, µ = 0.090 mmϪ1, T = 150 K, measured 16 161
reflections in 2θ range 4.1–61.1Њ, Rint = 0.043. 266 Parameters
refined against 4323 F2, R = 0.049 for Io > 2σ(Io) and 0.058 for
all data. A disorder was observed in one of the methoxy groups.
Crystal data for C16H28N2O4 (13), M = 312.40, monoclinic,
P21, a = 9.725(1), b = 8.738(1), c = 10.903(1) Å, β = 109.0(1)Њ,
V = 876.0(2) Å3, Z = 2, Dx = 1.184 Mg mϪ3, µ = 0.085 mmϪ1
,
T = 150 K, measured 7818 reflections in 2θ range 3.6–49.4Њ,
Rint = 0.054. 311 Parameters refined against 2953 F2, R = 0.060
for Io > 2σ(Io) and 0.066 for all data.
(2R,3ЈR,4ЈS,5R)-2,5-Dihydro-5-isopropyl-3,6-dimethoxy-
pyrazine-2-spirocyclopentane-3Ј,4Ј-diol 4 and (2S,3ЈR,4ЈS,5R)-
2,5-dihydro-5-isopropyl-3,6-dimethoxypyrazine-2-spirocyclo-
pentane-3Ј,4Ј-diol 5
Osmium tetraoxide solution (0.38 ml, 0.029 mmol; 2.5%
in ButOH) was added to a solution of (5R)-2,5-dihydro-5-
isopropyl-3,6-dimethoxypyrazine-2-spiro-4Ј-cyclopentene (676
mg, 2.87 mmol) and NMO monohydrate (427 mg, 3.16 mmol)
in acetone (20 ml)–water (5 ml) at 0 ЊC. The mixture was stirred
at 0 ЊC for 6 h before the reaction was terminated by the
addition of sodium hydrogen sulfite (328 mg, 3.16 mmol).
Stirring was continued for 15 min, water (20 ml) added, and the
mixture extracted with methylene dichloride (3 × 20 ml). The
combined organic extracts were dried (MgSO4) and evaporated
to dryness. The residual material was subjected to flash chrom-
atography using 5% methanol in methylene dichloride to yield
the isomers 4 and 5.
Compound 4 (402 mg, 54%) was a white solid, mp 76 ЊC
(crude) (Found: C 57.37; H, 8.03. Calc for C13H22N2O4: C,
57.76; H, 8.20%); HRMS: Mϩ, 270.1569. Calc for C13H22N2O4:
M, 270.1580; [α]D Ϫ42.20 (c 0.87, CHCl3); νmax(ATR)/cmϪ1
3315s, 2912, 1670, 1425, 1218, 1009; δH(300 MHz) 0.53 (3 H,
d, J 7, CH3), 0.90 (3 H, d, J 7, CH3), 1.51–1.66 (2 H, m, CH2),
2.04–2.34 (1 H, m, CH), 2.27–2.34 (2 H, m, CH2), 3.49 (3 H, s,
OCH3), 3.53 (3 H, s, OCH3), 3.82 (1 H, m, CHOH), 3.85 (1 H,
d, J 4, H-2), 4.10 (3 H, m, OH, 2 × CHOH); δC(75 MHz) 16.51
(CH3), 19.93 (CH3), 30.94 (CH), 45.34 (CH2), 45.25 (CH2),
52.21 (OCH3), 52.34 (OCH3), 60.29 (C-2), 63.61 (C-5), 74.38
(CHOH), 74.53 (CHOH), 161.25 (C), 162.96 (C); m/z (EI) 270
Methyl 1-amino-trans,trans-3,4-dimethoxycyclopentane-
carboxylate 7
(2R,3ЈR,4ЈS,5R)-2,5-Dihydro-5-isopropyl-3,3Ј,4Ј,6-tetrameth-
oxypyrazine-2-spirocyclopentane 6 (254 mg, 0.85 mmol) was
dissolved in a mixture of TFA (0.2 M; 43 ml, 8.5 mmol)
and acetonitrile (43 ml). The solution was stirred at ambient
temperature for 5 days and evaporated almost to dryness. Water
(10 ml) and methylene dichloride (20 ml) were added, the mix-
ture shaken, and the phases separated. The aqueous phase was
collected, and made alkaline by addition of conc. aq. ammonia
(pH 10) before extraction with methylene dichloride (3 × 10
ml). The combined extract was dried (MgSO4), evaporated and
the residual material purified by flash chromatography using
3% methanol which gave ester 7 as a colourless oily material (86
mg, 50%). HRMS: M Ϫ CO2Me, 144.1025. Calc. for C7H14NO2:
m/z, 144.1025; νmax(ATR)/cmϪ1 3350s, 2898, 1714, 1425,
1185, 1085; δH(300 MHz) 1.85 (2 H, dd, J 20, 5, CH2), 1.93
(2 H, br s, NH2), 2.33 (2 H, dd, J 14, 6, CH2), 3.54 (6 H, s,
2 × CHOCH3), 3.67 (3 H, s, OCH3), 3.78 (2 H, t, J 4.3, 2 ×
CHOCH3); δC(75 MHz) 42.49 (2 × CH2), 52.39 (OCH3), 57.31
(2 × CHOCH3), 61.56 (C), 81.65 (2 × CHOCH3), 176.65
(C᎐O); m/z (EI) 144 (Mϩ Ϫ CO Me, 100%), 145 (14), 130 (34),
᎐
2
113 (17), 112 (83), 85 (20), 71 (18); m/z (CI) 204 (Mϩ ϩ 1,
100%), 205 (10), 155 (16), 144 (10, Mϩ Ϫ CO2Me).
† CCDC reference number 207/418. See http://www.rsc.org/suppdata/
p1/b0/b001779p/ for crystallographic files in .cif format.
J. Chem. Soc., Perkin Trans. 1, 2000, 1691–1695
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Methyl 1-acetamido-trans,trans-3,4-diacetoxycyclopentane-
carboxylate 8
53.06 (OCH3), 58.24 (C-5), 60.82 (C-2), 71.07 (CHOH), 71.22
(CHOH), 163.16 (C), 164.34 (C); m/z (EI) 284 (Mϩ, 72%),
269 (25), 241 (100), 225 (37), 223 (40), 197 (81), 196 (36),
183 (23).
(2R,3ЈR,4ЈS,5R)-2,5-Dihydro-5-isopropyl-3,6-dimethoxy-
pyrazine-2-spirocyclopentane-cis-3Ј,4Ј-diol 4 (162 mg, 0.60
mmol) was stirred with TFA (30 ml, 6.00 mmol; 0.2 M)–
acetonitrile (30 ml) at ambient temperature for 3 days. The solu-
tion was evaporated almost to dryness and water (1 ml) and
methylene dichloride (10 ml) were added. The aqueous layer
was collected and made alkaline by addition of conc. aq.
ammonia (pH 10) before extraction with methylene dichloride
(2 × 10 ml) and ethyl acetate (10 ml). The combined organic
layers were dried (MgSO4), evaporated and the residual
material dissolved in methylene dichloride (10 ml) with sub-
sequent addition of 4-(dimethylamino)pyridine (DMAP) (450
mg, 3.68 mmol) and acetic anhydride (0.35 ml, 3.68 mmol).
The mixture was stirred at ambient temperature for 2 days
before the solvent was evaporated off. The residual material
was subjected to flash chromatography using 3% methanol in
methylene dichloride to yield 8 as a colourless oily material
(107 mg, 60%). HRMS: Mϩ, 301.1157. Calc for C13H19NO7:
M, 301.1161; δH(300 MHz) 1.96 (3 H, s, CH3), 2.01 (6 H, s,
2 × CH3), 2.05 and 2.10 (2 H, dd, J 5, CH2), 2.69 and 2.73 (2 H,
dd, J 6, CH2), 3.69 (3 H, s, CH3O), 5.25 (2 H, m, 2 × CH),
6.30 (1 H, s, NH); δC(75 MHz) 20.75 (2 × CH3), 22.81 (CH3),
40.09 (2 × CH2), 53.00 (CH3O), 61.25 (C-1), 72.50 (2 × CH),
(2S,3ЈR,4ЈS,5R)-2,5-Dihydro-5-isopropyl-3,3Ј,4Ј,6-tetrameth-
oxypyrazine-2-spirocyclohexane 13
(2S,3ЈR,4ЈS,5R)-2,5-Dihydro-5-isopropyl-3,6-dimethoxypyr-
azine-2-spirocyclohexane-3Ј,4Ј-diol 11 (359 mg, 1.26 mmol) in
a solution of dry DMF (3 ml) and THF (3 ml) was added to a
suspension of sodium hydride (138 mg in paraffin oil, ≈60% pur-
ity; 3.16 mmol) in a mixture of DMF (20 ml) and THF (20 ml)
under argon at 0 ЊC. The resultant mixture was stirred at ambi-
ent temperature for 2 h before methyl iodide (0.2 ml, 3.16
mmol) was added dropwise. The mixture was stirred at ambient
temperature overnight. Diethyl ether (100 ml) was added. The
organic mixture was extracted successively with water (5 × 40
ml) and brine (1 × 40 ml), and the ethereal solution dried
(MgSO4) and evaporated. The product was isolated from the
residual material after flash chromatography using EtOAc–
hexane 1:2 and was obtained as a white solid (312 mg, 79%), mp
61 ЊC (crude) (Found: C, 61.81; H, 8.74. Calc for C16
H28N2O4:
C, 61.51; H, 9.03%); HRMS: Mϩ
, 312.2034. Calc for C16H28-
N2
O : 312.2049; [α] ϩ0.67 (c 1.20, CH2Cl2); νmax(ATR)/cmϪ1
4
D
2928, 1690, 1435, 1230, 1088; δH(300 MHz) 0.60 (3 H, d, J 7,
CH3), 1.00 (3 H, d, J 7, CH3), 0.98–1.02 (1 H, m, CHH), 1.39–
1.44 (1 H, m, CHH), 1.81–1.85 (2 H, m, CH2), 2.11–2.25 (3 H,
m, CH and CH2), 3.27 (3 H, s, CHOCH3), 3.37 (3 H, s,
CHOCH3), 3.57 (3 H, s, OCH3), 3.58 (3 H, s, OCH3), 3.63–
3.70 (2 H, m, 2 × CHOCH3), 3.87 (1H, d, J 4, H-2); δC(75
MHz) 16.82 (CH3), 19.20 (CH3), 22.33 (CH2), 29.88 (CH),
30.83 (CH2), 35.98 (CH2), 51.92 (OCH3), 52.20 (OCH3), 55.95
(CHOCH3), 56.63 (CHOCH3), 58.28 (C-5), 60.15 (C-2), 75.28
(CHOHMe), 77.06 (CHOMe), 160.69 (C), 165.05 (C); m/z
312 (Mϩ, 8%), 297 (27), 281 (82), 269 (100), 237 (74), 211
(13), 197 (7), 153 (30).
169.86 (C᎐O), 169.93 (C᎐O), 173.37 (C᎐O); m/z (EI) 301
᎐
᎐
᎐
(Mϩ, 0.2%), 183 (11), 182 (100), 140 (15), 130 (11), 122 (60),
80 (77), 43 (66).
(2S,3ЈR,4ЈS,5R)-2,5-Dihydro-5-isopropyl-3,6-dimethoxy-
pyrazine-2-spirocyclohexane-3Ј,4Ј-diol 11 and (2S,3ЈS,4ЈR,5R)-
2,5-dihydro-5-isopropyl-3,6-dimethoxypyrazine-2-spirocyclo-
hexane-3Ј,4Ј-diol 12
Osmium tetraoxide solution (108 µl, 0.016 mmol; 2.5% in
ButOH) was added to a solution of (2S,5R)-2,5-dihydro-5-
isopropyl-3,6-dimethoxypyrazine-2-spiro-3Ј-cyclohexene (402
mg, 1.61 mmol) and NMO monohydrate (240 mg, 1.77 mmol)
in acetone (20 ml)–water (5 ml) at 0 ЊC. Sodium bisulfite (184
mg, 1.77 mmol) was added after 6 h at 0 ЊC and the stirring was
continued for 15 min. Methylene dichloride (20 ml) was added.
The aqueous layer was extracted with methylene dichloride
(3 × 10 ml). The combined organic layers were dried (MgSO4)
and evaporated to dryness. The two products were separated
by flash chromatography using 5% methanol in methylene
dichloride.
Compound 11 was a white solid (374 mg, 82%), mp 145 ЊC
(crude) (Found: C, 59.13; H, 8.75. Calc for C14H24N2O4: C,
59.14; H, 8.51%); HRMS: Mϩ, 284.1728. Calc for C14H24-
N2O4: M, 284.1736; [α]D ϩ33.5 (c 0.71, CHCl3); νmax(ATR)/cmϪ1
3369s, 2942, 1687, 1435, 1227; δH(300 MHz) 0.63 (3 H, d, J 7,
CH3), 1.02 (3 H, d, J 7, CH3), 1.03–2.30 [7 H, m, (CH3)2CH-,
3 × CH2], 2.59 (2 H, br s, 2 × OH), 3.59 (3 H, s, OCH3), 3.63
(3 H, s, OCH3), 3.91 (1 H, d, J 4, H-2), 4.01 (1 H, m, CHOH),
4.14 (1 H, m, CHOH); δC(75 MHz) 16.91 (CH3), 19.23 (CH3),
21.62 (CH2), 29.48 (CH2), 30.93 (CH), 38.50 (CH2), 52.06
(OCH3), 52.39 (OCH3), 58.44 (C-5), 60.23 (C-2), 67.77
(CHOH), 68.89 (CHOH), 160.77 (C), 164.92 (C); m/z (EI) 284
(Mϩ, 7%), 267 (45), 242 (14), 241 (100), 223 (16), 212 (13), 209
(20), 167 (11).
Methyl (1S,3R,4S)-1-amino-3,4-dimethoxycyclohexanecarb-
oxylate 14
(2S,3ЈR,4ЈS,5R)-2,5-Dihydro-5-isopropyl-3,3Ј,4Ј,6-tetrameth-
oxypyrazine-2-spirocyclohexane 13 (192 mg, 0.62 mmol) was
stirred in a solution of TFA (0.2 M; 31 ml, 6.20 mmol) and
acetonitrile (31 ml) at ambient temperature for 5 days. The
mixture was evaporated almost to dryness and water (5 ml)
and methylene dichloride (10 ml) were added. The aqueous
phase was collected, and made alkaline by addition of conc. aq.
ammonia (pH 10) before extraction with methylene dichloride
(3 × 10 ml). The combined extracts were dried (MgSO4),
evaporated and the residual material subjected to flash chrom-
atography using 3% methanol in methylene dichloride. The
product (127 mg, 96%) was a colourless oil. HRMS: m/z,
158.1189. Calc for C8H16NO2 (M Ϫ CO2Me): m/z, 158.1181;
νmax(ATR)/cmϪ1 3510s, 2900, 1710, 1440, 1200, 1090; δH(500
MHz) 1.22–1.39 (1 H, m, CHH), 1.52 (2 H, br s, NH2), 1.58
(1 H, dd, J 12.3, 2.7, CHH), 1.69–1.75 (1 H, m, CHH),
1.90–1.96 (1 H, m, CHH), 2.00–2.06 (1 H, m, CHH), 2.21
(1 H, dd, J 12.8, 10.3, CHH), 3.32 (3 H, s, CHOCH3),
3.36 (3 H, s, CHOCH3), 3.55–3.59 (2 H, m, 2 × CHOCH3),
3.67 (3 H, s, OCH3); δC(50 MHz) 22.54 (CH2), 28.80 (CH2),
34.54 (CH2), 52.20 (OCH3), 56.32 (CHOCH3), 56.50
(CHOCH3), 57.33 (C), 75.86 (CHOCH3), 76.90 (CHOCH3),
Compound 12 was a white solid (27 mg, 6%), mp 89 ЊC
(crude) (Found: C, 58.82; H, 8.41%); HRMS: Mϩ, 284.1750.
Calc for C14H24N2O4: M, 284.1736; [α]D ϩ43.70 (c 0.62,
CHCl3); νmax(ATR)/cmϪ1 3338s, 2945, 1686, 1436, 1236;
δH(300 MHz) 0.67 (3H, d, J 7, CH3), 1.03 (3 H, d, J 7, CH3),
1.47–2.21 [7 H, m, (CH3)2CH, 3 × CH2], 2.54 (1 H, d, J 10,
OH), 3.57 (1 H, m, CHOH), 3.62 (3 H, s, OCH3), 3.64 (3 H, s,
OCH3), 3.94 (1 H, m, CHOH), 3.97 (1 H, d, J 4, H-2), 5.62
(1 H, d, J 10, OH); δC(75 MHz) 17.68 (CH3), 19.79 (CH3), 25.24
(CH2), 31.45 (CH), 35.94 (CH2), 39.72 (CH2), 53.00 (OCH3),
177.64 (C᎐O); m/z (CI) 218 (Mϩ ϩ 1, 100%), 158 (5, Mϩ Ϫ
᎐
CO2Me), 126 (11).
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