New highly efficient stereoselective synthesis of d-threo-PDMP

Article abstract of DOI:10.1055/s-0030-1260225

Starting from a suitably functionalized aziridine, a highly efficient stereoselective synthesis of (1R,2R)-phenyl-2-decanoyl-amino-3-morpholinopropan- 1-ol (d-threo-PDMP) is described. The approach, based on the ring expansion of the aziridine ring to oxa

Full text of DOI:10.1055/s-0030-1260225

3318
PAPER
New Highly Efficient Stereoselective Synthesis of D-threo-PDMP
A
S
tereoselective
S
i
ynthes
u
is of
D
-
threo
l
-PD
M
P
iana Righi,*a Paolo Bovicelli,b Francesca Montini,c Federica Meloni,c Emanuela Mandic,c Romina Pelagallic
a
C.N.R. Institute of Biomolecular Chemistry (ICB), Unity of Rome, c/o Department of Chemistry, Sapienza University,
P. le A. Moro 5, Box No. 34 Roma-62, 00185 Roma, Italy
Fax +39(064)9913628; E-mail: giuliana.righi@cnr.it
C.N.R. ICB, Unity of Sassari, Traversa La Crucca 3 – Baldanica, 07040 Sassari, Italy
Department of Chemistry, Sapienza University, P. le A. Moro 5, 00185 Roma, Italy
b
c
Received 16 May 2011; revised 13 July 2011
Dedicated to Prof. Alberto Brandi on the occasion of his 60th birthday.
pure synthesis is strongly required. Among the synthesis
already reported,6 generally L- or D-serine were used as
source of chirality, except for an example regarding the
regioselective elaboration of a nonactivated aziridine
Abstract: Starting from a suitably functionalized aziridine, a highly
efficient stereoselective synthesis of (1R,2R)-phenyl-2-decanoyl-
amino-3-morpholinopropan-1-ol (D-threo-PDMP) is described.
The approach, based on the ring expansion of the aziridine ring to
oxazoline, could be applicable to the synthesis of many analogues ring.7
with different amide chains and sugar mimic portions.
OH
OH
Key words: regioselectivity, ring opening, glycosidases, inhibitors,
ring expansion
O
O
S
R
S
R
Ph
N
Ph
N
HN
C9H19
HN
C9H19
OH
Glycosphingolipids (GSLs) play an important role in the
regulation of numerous cellular processes; they affect
O
O
2S
L-threo-PDMP
D-threo-PDMP
3R
GluO
C13H27
membrane physical properties, cell-cell interactions, cell
adhesion, cellular immune responses and differentiation,1
and they have also been implicated in cancer cell metabo-
lism.2 The GSLs are formed by a glucosyltransferase-cat-
alyzed transfer of glucose from UDP-glucose (UDP-Glc)
to C-1 of ceramide, whereas glucocerebrosidase catalyzes
the hydrolysis of GSLs to ceramide and glucose. Any al-
teration of this crucial equilibrium may cause serious pa-
thologies; for example a deficiency of the latter enzyme is
responsible for the Gaucher’s disease, the most common
of the lysosomal storage diseases, characterized by an ac-
cumulation of glucocere-brosides in the spleen, liver, kid-
neys, lungs, brain, and bone marrow.
NHCOR
GluCer
Figure 1 threo-PDMP enantiomers and glucosylceramide
This paper reports an expeditious synthesis of D-threo
PDMP based on a straightforward ring expansion of a
suitable phenyl-functionalized aziridine, consisting in the
formation of a syn-vicinal amino alcohol starting from a
trans-phenylaziridine. Over the last years, we have fo-
cused our attention on the use of the aziridine ring to pre-
pare functionalized fragments through regio- and
stereocontrolled ring-opening reactions;8 in particular,
very recently we were involved on the control of the
MgBr2-mediated opening of 2,3-three membered hetero-
cyclic amines.9 As delineated in Scheme 1, the nucleo-
philic attack of the bromine occurred preferentially at the
C-3 position, as expected for chelation-controlled ring-
opening reactions.
There are currently two therapies available for the treat-
ment of Gaucher’s disease, which are both aimed at reduc-
ing GSLs storage.3 The first-line treatment is based on the
administration of recombinant form of glucocerebrosi-
dase, to supplement the defective hydrolytic enzyme,
whereas a second strategy uses inhibitors of glucosylcera-
mide synthase, responsible for the glucosylation of cera-
mide.
In the light of these results, the preparation of D-threo-
PDMP was planned first starting from the suitable N-Boc-
aziridine 1 (Scheme 2), having already the morpholine
residue in the required position. The syn relationship of
the amino alcohol fragment would be introduced follow-
ing the above reported stereocontrolled opening of aziri-
dine by halide and subsequent hydrolysis with silver
nitrate in acetone.10
In this context, different ceramide analogues have been
developed and, among them, D-threo-PDMP [D-threo-
(1R,2R)-phenyl-2-decanoylamino-3-morpholinopropan-
1-ol] has shown to be a potent inhibitor of glucosylceram-
ide synthase (Figure 1).4 Surprisingly, the enantiomer L-
threo-PDMP increased the biosynthesis of gangliosides,
leading to enhanced synapse formation.5 Because of the
opposite bioactivity of the two, their enantiomerically
As shown in Scheme 3, the preparation of optically active
aziridine amine 1 started from the Sharpless asymmetric
epoxidation of the commercially available cinnamyl alco-
hol 2. The morpholine residue was readily introduced via
mesylate derivative 4, affording the epoxyamine 5 with an
overall yield of 83% from 3. At this point, 5 was easily
SYNTHESIS 2011, No. 20, pp 3318–3322
x
x.
x
x
.
2
0
1
1
Advanced online publication: 27.09.2011
DOI: 10.1055/s-0030-1260225; Art ID: N45511SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Stereoselective Synthesis of D-threo-PDMP
3319
Br
MgBr2
Et2O
XH
Nu
R
X
H
X
3
>>>
1
3
R
N
R
N
R
N
2
2
–20 °C to r.t.
XH
C-3 attack
Br
C-2 attack
H
Mg+2
X = O, NBoc
1
H
N
Scheme 1 Regio- and stereoselective ring opening 2,3-three membered heterocyclic amines by MgBr2
Boc
N
Br
OH
N
N
N
NH
O
O
O
BocHN
1
O
(CH2)8Me
D-threo-PDMP
Scheme 2 Retrosynthesis of D-threo-PDMP
transformed in the corresponding aziridine amine 6 in the The N-Boc-aziridine amine 1 was then treated with MgBr2
usual manner11and finally the reaction with di-tert-butyl in Et2O at low temperature affording the expected 3-bro-
dicarbonate gave 1 in satisfactory chemical yield.
mo derivative 7. Unexpectedly, this compound underwent
a slow spontaneous rearrangement (4–5 h) to the known
oxazolidinone 8, probably due to an intramolecular nu-
cleophilic substitution of the bromine in benzylic position
(Scheme 4).
a
b
O
O
Ph
OH
Ph
OH
Ph
OMs
2
3
4
The oxazolidinone 8 was already described in the D-threo-
PDMP synthesis by Polt;6b according to the authors, 8 was
transformed to D-threo-PDMP in two steps.6b
c
NH
O
f
d, e
Ph
N
Although the synthesis described above represented an ef-
ficient route to D-threo-PDMP, it was felt that an even
more straightforward synthesis based on a regio- and ste-
reocontrolled transformation of a suitable trans N-acyl-
aziridine was possible. In fact, it is known that the
aziridine nitrogen activation with an acyl group causes the
ring expansion of the aziridine to the corresponding ox-
azoline,12 which can be easily hydrolyzed to syn-hy-
droxyamino alcohol.
Ph
N
1
O
O
6
5
Scheme 3 Reagents and conditions: a) L-(+) DIPT, Ti(Oi-Pr)4,
TBHP, CH2Cl2, –20 °C, 75%; b) MsCl, Et3N, DMAP, CH2Cl2,
–20 °C; c) morpholine, pyridine, r.t., 6 h, 83% from 3; d) NaN3,
NH4Cl, MeOH, reflux; e) PPh3, MeCN, reflux; f) Boc2O, DMAP,
CH2Cl2, r.t., 63% (overall yield from 5).
Br
Boc
To this purpose, the aziridine 6 was treated with decanoyl
chloride to give the N-decanoyl derivative, which sponta-
neously furnished the trans-oxazoline 10 in a regio- and
stereocontrolled fashion. The trans-stereochemistry of the
oxazoline 10 was unequivocally established on the basis
of the J4,5 value (J4,5 = 6.6 Hz),13 whereas the regiochem-
istry was confirmed by 1H NMR spectroscopy by employ-
ing a spin-spin decoupling technique.
N
a
Ph
N
Ph
N
NH
O
O
O
1
O
7
O
N
Finally, the hydrolysis of oxazoline 10 with Amberlyst 15
in the presence of a trace of water in acetone, complete in
few hours, afforded nearly quantitatively the desired D-
Ph
NH
O
O
1
threo-PDMP (Scheme 5), as confirmed by the H NMR,
8
OH
O
13C NMR, HR mass spectra, and specific rotation identical
to those already obtained following the Scheme 4.
OH
b
c
Ph
H19C9
N
Ph
N
NH
O
In conclusion, the efficient, but little used ring expansion
of N-acylaziridines to the corresponding oxazolines was
exploited to provide a highly stereo- and regioselective
synthesis of D-threo-PDMP and has been developed start-
ing from the cheap commercial cinnamyl alcohol in few
steps (many of which did not need of any purification)14
NH2
O
9
D-threo-PDMP
Scheme 4 Reagents and conditions: a) MgBr2, Et2O, –40 °C, 78%;
b) KOH, MeOH–H2O (4:1), 70 °C, 66%; c) 4-NO2C6H4O(C=O)C9H19,
HOBt, pyridine, r.t., 88%.
Synthesis 2011, No. 20, 3318–3322 © Thieme Stuttgart · New York

3320
G. Righi et al.
PAPER
OH
C9H19
N
CO(CH2)8Me
N
O
N
a
b
NH
COC9H19
O
6
N
N
O
87%
O
D-threo-PDMP
10
Scheme 5 Reagents and conditions: a) Me(CH2)8COCl, Et3N, CH2Cl2, –40 °C, 85%; b) Amberlyst 15, acetone, r.t., 90%.
washed with H2O (10 mL) and brine (10 mL). The organic layer was
dried (Na2SO4) and concentrated to give the azido alcohol deriva-
tive as a mixture of regioisomers. The crude mixture was dissolved
in MeCN (10 mL) and PPh3 (314.13 mg, 1.2 mmol) was added. Af-
ter 4 h at r.t., the mixture was refluxed for 6 h, and then concentrated
in vacuo to give the crude aziridine amine 6. To a solution of the
crude aziridine amine 6, (217 mg, 1 mmol) in anhyd CH2Cl2 (22
mL) at r.t. were added Boc2O (248 mg, 1.1 mmol) and DMAP (cat.).
The reaction mixture was stirred for 24 h. Upon completion of reac-
tion (TLC monitoring, eluent: PE–EtOAc, 2:8), it was filtered
through a Celite pad and the pad was washed with Et2O (5 mL). The
filtrate was washed with H2O until neutral, and the organic layer
was dried (Na2SO4) and concentrated in vacuo. The residue was
then chromatographed on silica gel (CHCl3–MeOH, 95:5) affording
1 (235 mg, 63% from 5); [a]D25 –10.7 (c 2.3, CHCl3).
with an overall yield of near to 35%. Moreover, this flex-
ible synthetic route allows the preparation of different D-
threo-PDMP analogues (or L-threo-PDMP analogues),
by changing the length of the amide chain and the sugar
mimic portion.
1H and 13C NMR spectra were recorded at 200 and 50.3 MHz, re-
spectively. Reactions were monitored by TLC using Merck silica
gel 60 F-254 plates with UV indicator; spots were also visualized
with phosphomolybdic acid (10% solution in EtOH). Flash column
chromatography on silica gel was normally used for purification of
the reaction mixtures. ESI-MS analyses were performed using a
commercial API 365 triple-quadrupole mass spectrometer from
PerkinElmer Sciex Instruments, equipped with an ESI source and a
syringe pump. The experiments were conducted in the positive ion
mode. Optical rotations were recorded at the sodium D line with a
polarimeter at r.t. All commercial reagents were purchased from
Aldrich, Lancaster, Acros, or Carlo Erba unless otherwise noted.
Petroleum ether (PE) used refers to the fraction boiling in the range
of 40–60 °C.
IR (neat): 3012, 2952,1620, 1220 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.38–7.19 (m, 5 H), 3.72 (t, J =
4.4 Hz, 4 H, CH2O), 3.26 (d, J = 2.9 Hz, 1 H, PhCHN), 2.95–2.81
(m, 2 H), 2.62–2.35 (m, 5 H), 1.30 (s, 9 H).
13C NMR (50 MHz, CDCl3): d = 159.5, 132.0, 128.2, 127.9, 126.9,
81.1, 66.7, 59.2, 53.6, 45.0, 42.4, 27.7.
HRMS: m/z calcd for C18H26N2O3 + H+: 319.2022; found:
(2¢S,3¢S)-4-(3¢-Phenyloxiranylmethyl)morpholine (5)
To a solution of 315 (235 mg, 1 mmol) in CH2Cl2 (1.6 mL) were add-
ed Et3N (0.27 mL, 2 mmol) and a catalytic amount of DMAP. After
stirring at 0 °C, MeSO2Cl (0.08 mL, 1 mmol) was added dropwise.
After 2 h (TLC monitoring, eluent: PE–EtOAc, 8:2), the reaction
was quenched with ice cold water (5 mL), and the mixture was ex-
tracted with CH2Cl2 (3 × 8 mL). The combined organic extracts
were washed with ice cold aq 1 N HCl (10 mL), sat. aq NaHCO3 (10
mL) and brine (10 mL), dried (Na2SO4), and then evaporated in vac-
uo. The crude mesylate 4 was then dissolved in pyridine (1 mL) and
morpholine (2 mmol (0.20 mL) was added. The reaction mixture
was stirred at r.t. overnight. The mixture was diluted with EtOAc (8
mL), washed with H2O (6 mL) and brine (6 mL), dried (Na2SO4),
and concentrated in vacuo. The crude mixture was purified by flash
chromatography affording 5 (227.9 mg, 83% from 3); [a]D25 –40.7
(c 1.6, CHCl3).
319.2025.
(1S,2R)-1-Phenyl-2-tert-butoxycarbonylamino-3-(N-morpholi-
no)-1-bromopropane (7)
To a cold (–40 °C) stirred solution of 1 (400 mg, 1 mmol) in anhyd
Et2O (10 mL) was added MgBr2·Et2O (516.5 mg, 2 mmol). The
mixture was stirred for 6 h (TLC monitoring, eluent: PE–EtOAc,
2:8) and then filtered through a pad of Celite. The filtrate was dilut-
ed with EtOAc (5 mL), washed with brine (5 mL), dried (Na2SO4),
and then evaporated in vacuum. The crude mixture was analyzed
spectroscopically without any purification.
1H NMR (200 MHz, CDCl3): d = 7.35–7.18 (m, 5 H), 5.38 (br d,
J = 4.4 Hz, 1 H, NH), 4.86 (d, J = 2.9 Hz, 1 H, CHBr), 4.31–4.11
(m, 1 H, CHN), 3.70 (t, J = 4.4 Hz, 4 H, CH2Omorph), 2.66–2.26 (m,
6 H, CH2Nmorph + CH2N).
IR (neat): 3010, 2843, 1090 cm–1.
13C NMR (50 MHz, CDCl3): d = 158.5, 137.4, 128.9, 128.5, 127.7,
80.41, 66.4, 60.2, 59.2, 53.8, 53.1, 28.1.
1H NMR (200 MHz, CDCl3): d = 7.40–7.14 (m, 5 H), 3.67 (t, J =
4.8 Hz, 4 H, CH2O), 3.61 (d, J = 1.4 Hz, 1 H, PhCHO), 3.19–3.10
(m, 1 H, CHO), 2.74 (dd, J = 13.2, 3.6 Hz, 1 H, CHAN), 2.66–2.42
(m, 5 H, CHBN, 2 CH2N).
13C NMR (50 MHz, CDCl3): d = 136.7, 128.1, 127.8, 125.2, 66.5,
60.3, 60.1, 56.3, 53.7.
(4R,5R)-4-[(N-morpholino)methyl]-5-phenyloxazolidin-2-one
(8)
Compound 7 was stirred for 6 h at r.t. in CHCl3 (5 mL) and only 8
was isolated; [a]D25 +32.0 (c 2.7, CHCl3, lit.6b [a]D20 +36.5).
IR (neat): 3430, 3016, 1751 cm–1.
HRMS: m/z calcd for C13H17NO2 + H+: 220.1338; found: 220.1340.
1H NMR (200 MHz, CDCl3): d = 7.51–7.28 (m, 5 H), 5.96 (br s, 1
H, NH), 5.22 (d, J = 5.9 Hz, 1 H, CHO), 3.84 (dd, J = 5.9, 6.6 Hz, 1
H, CHNH), 3.67 (t, J = 4.4 Hz, 4 H, CH2Omorph), 2.66–2.34 (m, 6 H,
CH2Nmorph + CH2N).
13C NMR (50 MHz, CDCl3): d = 158.8, 138.5, 128.8, 125.6, 81.5,
66.7, 62.5, 57.5, 53.9.
(2R,3R)-4-(1-tert-Butoxycarbonyl-3-phenylaziridine-2-ylmeth-
yl)morpholine (1)
To a solution 5 (219.28 mg, 1 mmol) in MeOH (10 mL) were added
NaN3 (325 mg, 5 mmol) and NH4Cl (106 mg, 2 mmol). The mixture
was refluxed for 24 h, cooled to r.t. and concentrated in vacuo. The
residue was diluted with EtOAc (15 mL), and the EtOAc layer was
Synthesis 2011, No. 20, 3318–3322 © Thieme Stuttgart · New York

PAPER
A Stereoselective Synthesis of D-threo-PDMP
3321
HRMS: m/z calcd for C14H19N2O3 + H+: 263.1396; found:
CHBN), 1.74–1.56 (m, 2 Hdecanoyl), 1.40–1.05 (m, 12 Hdecanoyl), 0.82
263.1392.
(t, J = 5.9 Hz, 3 H, CH3).
13C NMR (50 MHz, CDCl3): d = 167.8, 141.1, 128.5, 127.8, 125.4,
(1R,2R)-2-Amino-3-(N-morpholino)-1-phenylpropan-1-ol (9)
To a stirred solution of 8 (263 mg, 1 mmol) in MeOH–H2O (4:1, 8
mL) was added aq 2 M KOH (4 mL). The solution was heated to
70 °C for 16 h (TLC monitoring, eluent: PE–EtOAc, 1:9) and then
concentrated in vacuo. The residue was dissolved in CH2Cl2 (10
mL), washed with sat. aq NaHCO3 (7 mL), dried (Na2SO4), and
evaporated in vacuum to give 9 (156 mg, 66%); [a]D25 +5.8 (c 2.5,
CHCl3, lit.6b [a]D20 +5.86).
84.9, 72.6, 66.7, 63.4, 54.0, 31.7, 29.3, 29.1, 28.2, 26.0, 22.5, 13.9.
HRMS: m/z calcd for C23H36N2O2 + H+: 373.2856; found:
373.2855.
(1R,2R)-1-Phenyl-2-decanoylamino-3-(N-morpholino)propan-
1-ol (D-threo-PDMP)
To a stirred solution of 10 (373 mg, 1 mmol) in acetone (10 mL) was
added Amberlyst 15 (217 mg, 1 mmol). The mixture was stirred for
6 h (TLC monitoring, eluent: CHCl3–MeOH, 9:1), filtered, and di-
luted with EtOAc (15 mL). The organic layer was washed with
brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The
crude mixture was purified by flash chromatography (EtOAc–PE,
8:2) affording D-threo-PDMP as a light brown oil (340 mg, 87%);
[a]D20 +7.7 (c 1.12, CHCl3, lit.6b,7 [a]D20 +8.05).
IR (neat): 3430, 3016, 1640 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.51–7.22 (m, 5 H, C6H5), 4.55 (d,
J = 3.9 Hz, 1 H, CHOH), 3.69 (t, J = 4.4 Hz, CH2Omorph), 3.23 (ddd,
J = 8.8, 5.1 Hz, 1 H, CHNH2), 2.77 (br d, 3 H, OH + NH2), 2.56 (dd,
J = 11.3, 4.3 Hz, 1 H, CHA), 2.32 (dd, J = 12.5, 5.3 Hz, 1 H, CHB),
2.48–2.39 (m, 4 H, CH2Nmorph).
13C NMR (50 MHz, CDCl3): d = 142.6, 128.2, 127.2, 126.0, 75.1,
66.9, 62.0, 54.0, 52.8.
The analytical data were identical with those reported above for the
D-threo-PDMP prepared from 9.
HRMS: m/z calcd for C13H21N2O2 + H+: 237.1603; found:
237.1602.
Acknowledgment
(1R,2R)-1-Phenyl-2-decanoylamino-3-(N-morpholino)propan-
1-ol (D-threo-PDMP)
We thank MIUR (Ministry of University and Research, Rome) for
partial financial support (PRIN 2008: Stereoselective synthesis and
biological evaluation of new compounds active towards proteic tar-
gets involved in viral pathologies, cell growth, and apoptosis).
Compound 9 (236 mg, 1 mmol) was dissolved in pyridine (1 mL,
dried over molecular sieves) and was sequentially treated with 4-ni-
trophenyl decanoate (293.6 mg, 1 mmol) and 1-hydroxybenzotri-
azole (10 mol%, 15.3 mg, 0.01 mmol). Upon completion of the
reaction as judged by TLC (eluent: CHCl3–MeOH, 9:1), the solvent
was removed, and the residue was dissolved in CH2Cl2 (20 mL) and
washed with aq 1 M NaOH (5 × 20 mL). The crude product ob-
tained after evaporation of CH2Cl2 was chromatographed to give D-
threo-PDMP (344 mg, 88%); [a]D20 +7.7 (c 1.12, CHCl3, lit.7
[a]D20 +8.05).
References
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IR (neat): 3430, 3016, 2936, 1650, 1510 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.38–7.22, (m, 5 H), 5.96 (br d,
J = 7.3 Hz, 1 H, NH), 4.96 (d, J = 3.7 Hz, 1 H, CHOH), 4.35–4.18
(m, 1 H, CHNH), 3.73 (t, J = 4.4 Hz, 4 H, CH2Omorph), 3.68 (m, 4
H), 2.65–2.37 (m, 6 H), 2.13–2.00 (m, 2 H), 1.57–1.37 (m, 12 H),
0.89 (t, J = 5.9 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.7, 140.8, 128.3, 127.6, 126.0,
75.1, 66.7, 59.6, 54.2, 51.1, 36.6, 31.7, 29.3, 29.1, 29.0, 25.5, 22.6,
14.0.
HRMS: m/z calcd for C23H38N2O3 + H+: 391.2958; found:
391.2961.
(4R,5R)-4-(2-Nonyl-5-phenyl-4,5-dihydrooxazol-4-ylmeth-
yl)morpholine (10)
To a solution of crude aziridine amine 6 (217 mg, 1 mmol) in
CH2Cl2 (5 mL) at –40 °C were added Et3N (0.17 mL, 1.2 mmol) and
decanoyl chloride (0.25 mL, 1.2 mmol). The reaction mixture was
stirred for 24 h. Upon completion of reaction (TLC monitoring, elu-
ent: PE–EtOAc, 3:7), it was filtered through a Celite pad and the pad
was washed with Et2O (10 mL). The filtrate was washed with H2O
until neutral, and the organic layer was dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash chromatography
(PE–Et2O, 6:4) affording 10 (317 mg, 85%); [a]D25 +5.8 (c 2,
CHCl3).
(7) Shin, S.; Han, E. Y.; Park, C. S.; Lee, W. K.; Ha, H.
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IR (neat): 3010, 1661, 1310 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.39–7.15 (m, 5 H), 5.18 (d, J =
6.6 Hz, 1 H, PhCHNCO), 4.10–3.93 (m, 1 H, CHNCO), 3.64 (t, J =
4.8 Hz, 4 H, CH2Omorph), 2.66 (dd, J = 12.4, 5.1 Hz, 1 H, CHAN),
2.45–2.34 (m, 6 H, CH2N + CH2), 2.34 (dd, J = 2.4, 8.0 Hz, 1 H,
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Synthesis 2011, No. 20, 3318–3322 © Thieme Stuttgart · New York