Synthesis of β-hydroxy O-alkyl hydroxylamines from epoxides using a convenient and versatile two-step procedure

Article abstract of DOI:10.1055/s-0032-1317699

A simple and convenient synthetic method was developed to prepare β-hydroxy O-alkyl hydroxylamines in which base-mediated ring opening of epoxides with acetophenone oxime followed by cleavage of the oxime with 2,4-dinitrophenylhydrazine in acidic media furnished the hydroxylamine, which can be protected in situ with various N-protecting groups. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317699

PAPER
▌65
paper
Synthesis of β-Hydroxy O-Alkyl Hydroxylamines from Epoxides Using a
Convenient and Versatile Two-Step Procedure
Synthesis of β-Hydroxy O-Alkyl Hydroxylamines
Gaëlle Malik,a Angélique Ferry,a Xavier Guinchard,a David Crich*a,b
a
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
b
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA
Fax +1(313)5778822; E-mail: DCrich@chem.wayne.edu
Received: 25.09.2012; Accepted after revision: 06.11.2012
ingly, such protocols are scarcely documented in the liter-
ature. In most reports, N-Boc-hydroxylamine is used
under basic conditions, which leads to the expected β-hy-
droxy O-alkyl hydroxylamines in low to modest
Abstract: A simple and convenient synthetic method was devel-
oped to prepare β-hydroxy O-alkyl hydroxylamines in which base-
mediated ring opening of epoxides with acetophenone oxime fol-
lowed by cleavage of the oxime with 2,4-dinitrophenylhydrazine in
acidic media furnished the hydroxylamine, which can be protected yields.4b,c,8 The successful employment of N-hy-
in situ with various N-protecting groups.
droxyphthalimide in this context was also described by
Porco and co-workers9 with promotion by a Co-oligosalen
Key words: hydroxylamines, epoxides, ring opening, oxime cleav-
age, protecting groups
catalyst.10 In pursuit of our goal, we initially looked for vi-
able conditions on commercially available cyclopentene
oxide (3h; see Table 1). Because the use of potassium car-
bonate with N-Fmoc-hydroxylamine under Plenkiewicz’s
conditions8b showed no discernible conversion (Table 1,
entry 1), we decided to leave basic conditions aside and
investigate the ring opening of epoxide 3h under Lewis
acid catalysis conditions (Table 1, entries 2–15), which is
a method usually used for the insertion of alcohols and/or
amines but not yet employed with hydroxylamines as the
nucleophile component. The ring opening of epoxide 3h
with N-Fmoc-hydroxylamine was first investigated with
BF3·Et2O in dichloromethane (Table 1, entry 2), condi-
tions that are known to be efficient for the reaction of ben-
zyl alcohol with a similar epoxide,6a but this approach was
unsuccessful in this case. The use of lanthanide-based
Lewis acids [i.e., Sc(OTf)3 and Yb(OTf)3] also failed
(Table 1, entries 3–6). Changing the nucleophile to N-Boc
hydroxylamine or N-hydroxypiperidine, presumably
more nucleophilic species, was also unproductive with
numerous types of Lewis acid [LiBr, InCl3, ZrCl4,
Cu(OTf)2, or Ti(OiPr)4; Table 1, entries 7–15]. Finally,
we envisaged an alternative two-step procedure based on
the intermediate introduction of an oxime under basic
conditions as a hydroxylamine precursor, followed by its
acid-mediated cleavage to give the expected β-hydroxy
O-alkyl hydroxylamine. Oximes are more nucleophilic
than hydroxylamines under basic conditions and their
high-yield ring-opening of epoxides has been described.11
Thus, the group of Soltani Rad recently described the
aqueous-mediated ring opening of various epoxides with
a range of oximes.11a Their protocol involved the use of a
slight excess of potassium hydroxide (1.3 equiv) to depro-
tonate the oxime (1 equiv) in a mixture of water–dimethyl
sulfoxide (DMSO) (7:3) at room temperature, followed by
the addition of an excess of epoxide (1.5 equiv). Similar
conditions were evaluated on cyclopentene oxide (3h) but
with a slight excess of acetophenone oxime, as it would
ultimately represent the least precious component in reac-
tions employing more complex epoxides (Table 1, entry
O-Alkyl hydroxylamines (or aminooxy compounds),
which are non-basic substitutes for amines,1 are found in
various natural products such as L-canaline2 and in vari-
ous synthetic products displaying interesting biological
activities.2,3 Along with their β-hydroxy congeners,4 these
compounds predominantly show enzyme inhibition activ-
ities whereby the aminooxy moiety forms a stable oxime
with an aldehyde group present on the cofactor. In prepar-
ative chemistry these reactive species usually serve as
starting material for the preparation of functionalized O-
alkyl oximes by simple condensation with aldehydes or
ketones, often with quantitative yields and with almost
complete functional group compatibility. This classical
reaction has undergone a renaissance as a chemoselective
ligation strategy and has emerged as a powerful means for
the assembly of bioconjugates.5
In connection with ongoing projects in our laboratory,6 we
required a variety of β-hydroxy O-alkyl hydroxylamines 2
and conceived that these might be accessed by the open-
ing of epoxides 1 by N-protected hydroxylamines fol-
lowed by deprotection of the nitrogen atom (Scheme 1).
Toward this end, the most efficient approach leading to 2
seemed to be a direct opening of epoxide 1 with an N-pro-
tected hydroxylamine (i.e., N-Fmoc-hydroxylamine7 or
commercially available N-Boc-hydroxylamine). Surpris-
HO NHR2
OH
R1
LA catalysis
or basic
media
R1
O
NHR2
O
2
1
R2 = H or PG
Scheme 1
SYNTHESIS 2013, 45, 0065–0074
Advanced online publication: 26.11.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317699; Art ID: SS-2012-M0756-OP
© Georg Thieme Verlag Stuttgart · New York

66
G. Malik et al.
PAPER
on the cleavage of the oxime functionality to liberate the
O-alkyl hydroxylamine. After many unfruitful assays un-
der acidic conditions, we found that 2,4-dinitrophenylhy-
drazine was efficient for the liberation of O-alkyl
hydroxylamine from oximes with generation of 2,4-dini-
trophenylhydrazone as a by-product. We also established
that protection of the hydroxylamine product in situ was
possible by reaction with FmocCl, CbzCl, or AllocCl,
which provides a means to isolate the target compound in
the form of a carbamate, cleavable under basic, acidic, or
metal-catalyzed conditions. To evaluate the scope of the
process, we tested its versatility towards various epoxides
3, so as to obtain the corresponding β-hydroxy O-alkyl hy-
droxylamines 5. The results, presented in Table 2, show
regioselective ring-opening of terminal epoxides with
preferential attack at the less hindered position (Table 2,
entries 1–6). The presence of a double bond or an aromat-
ic core did not affect the yield (Table 2, entries 1 and 3).
The PMP-protected glycidol epoxide furnished α-hy-
droxyoxime 4a in 83% yield. Hydrolysis of the oxime fur-
nished free hydroxylamine 5a in 77% yield or 6a–8a in a
range of 80–89%, depending on the carbamate used (Ta-
ble 2, entry 1). A free hydroxyl group was found to be
compatible with the ring opening but decreased the yield
to 46% (Table 2, entry 4). In the case of epichlorohydrin
(Table 2, entry 5), the epoxide, which is known to be the
more reactive site,12 was opened smoothly to afford 4e
with acetophenone oxime in 73% yield. Unfortunately,
the presence of an epoxide was not compatible with 2,4-
dinitrophenylhydrazine-mediated cleavage of the oxime
(Table 2, entry 5). Thus, epoxide 4e was opened with a
second equivalent of acetophenone oxime to give 4f in
good yield (Table 2, entry 6). Highly functionalized
Cerny’s epoxide 3j was converted into its β-hydroxy O-al-
kyl hydroxylamine derivative 5j in 76% over two steps
(Table 2, entry 9). Protection as carbamates in situ was
also successful, and 5–8j were obtained in high yields
(Table 2, entry 9). Finally, the cyclopentene-derived ep-
oxide 1a was opened with acetophenone oxime at 90 °C
and converted into the Fmoc-protected targeted skeleton
2a in good yield (73%) over two steps (Table 2, entry 10).
Table 1 Ring Opening of Cyclopentene Oxide with Hydroxylamine-
Derived Nucleophiles
R1
N
HO
R2
OH
R1
O
N
O
4h
3h
R2
Entry Nucleophile
LA (cat.) or Solvent Temp Yield
base
(°C)
(%)a,b
1
2
3
4
5
6
7
8
9
HONHFmoc K2CO3
HONHFmoc BF3Et2O
Sc(OTf)3
EtOH
60
NR
NR
NR
NR
NR
NR
NR
NR
NR
CH2Cl2
CH2Cl2
MeCN
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
Sc(OTf)3
Sc(OTf)3
Yb(OTf)3
THF
HONHBoc
Sc(OTf)3
Yb(OTf)3
Sc(OTf)3
CH2Cl2
CH2Cl2
CH2Cl2
HO
N
10
11
12
13
14
15
16
Yb(OTf)3
LiBr
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
NR
NR
NR
NR
NR
NR
trace
InCl3
Ti(OiPr)4
Cu(OTf)2
ZrCl4
Ph
KOH
H2O–
N
DMSOc
HO
17
KOH
H2O–
90
23
DMSOc
18
19
KOH
KOH
DMF
DMF
r.t.
90
trace
73
In conclusion, we have established a convenient two-step
procedure for the synthesis of β-hydroxy O-alkyl hydrox-
ylamines by oxime-mediated regioselective opening of
epoxides under basic conditions, followed by cleavage of
the resulting oxime by 2,4-dinitrophenylhydrazine. We
showed that various protecting groups could be intro-
duced for protection of the highly polar resulting O-alkyl
hydroxylamines in situ. The scope of the reaction revealed
its good tolerance for alkenes, halogens, and alcohols.
a Isolated yield.
b NR = no reaction.
c In a 7:3 ratio.
16). Surprisingly, the solvent system used by Soltani Rad
et al. was not efficient for our model epoxide and only
traces of the expected compound were obtained. Heating
to 90 °C led to formation of the desired oxime 4h in low
yield (23%; Table 1, entry 17). Switching from DMSO to
N,N-dimethylformamide (DMF) did not increase the yield
at room temperature (Table 1, entry 18) but compound 4h
was obtained in a good yield at 90 °C (73%; Table 1, entry
19).
Reactions were performed under an atmosphere of argon and mon-
itored by thin-layer chromatography on Merck silica gel plates (60
F254 aluminum sheets). All separations were carried out under flash-
chromatographic conditions on silica gel (Redi Sep prepacked col-
umn, 230–400 mesh) with the use of a CombiFlash Companion.
N,N-Dimethylformamide (DMF) was purified by filtration through
an activated alumina column under argon. MeOH was purchased
from Acros Organics at the highest commercial quality and used
without further purification. Reagent-grade chemicals were ob-
With conditions established for the ring-opening of cyclo-
pentene oxide by acetophenone oxime, we next focused
Synthesis 2013, 45, 65–74
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of β-Hydroxy O-Alkyl Hydroxylamines
67
Table 2 Scope of the Two-Step Procedure; Synthesis of β-Hydroxy O-Alkyl Hydroxylamines
OH
OH
N
O2N
NHNH2
NO2
(1.5 equiv)
OH
R2
R1
N
O
R2
R1
Ph
R1
R2
O
KOH (3 equiv)
DMF (0.1 M)
16 h
O
H2SO4 (10 equiv)
MeOH
R3HN
5: R3 = H
Ph
3
4
r.t., 16 h
PG-Cl,
6–8: R3 = PG
R1, R2 = alkyl,
alkoxy, aryloxy
NaHCO3
(in situ)
Entry Epoxide 3
O-Alkyl oxime 4
Product Yield O-Alkyl hydroxylamine 5–8
R3
H
Product Yield
(%)a
(%)a
5a
77
81c
80
89
OH
OH
Fmoc 6a
Cbz 7a
Alloc 8a
O
1
4ab
83
OPMP
O
OPMP
O
OPMP
Ph
N
R3HN
OH
OH
O
O
2
3
4b
4c
74d
84d
Fmoc 6b
95
69
93
O
O
O
O
R3HN
R3HN
Ph
Ph
N
N
HO
HO
Fmoc 6c
Fmoc 6d
OH
OH
O
O
46e
73
86
OH
Cl
4
5
6
4d
4e
4f
O
O
OH
O
O
OH
Ph
Ph
N
N
R3HN
R3HN
H
0f
0f
5e
O
O
Fmoc
6e
OH
OH
h
6f
Fmoc
–
O
O
O
O
O
N
O
O
O
Ph
Ph
N
R3HN
R3HN
NHR3
Alloc
61
Ph
N
8f
Ph
OH
OH
N
O
g
5h
H
–
7
8
4h
4i
73e
89e
Fmoc
99
6h
OH
OH
O
O
N
O
R3HN
h
6i
8i
Ph
Fmoc
Alloc
–
81
O
O
O
H
5j
76
76
88
74
OH
O
OH
O
O
O
Fmoc 6j
Cbz 7j
Alloc 8j
9
4j
89e
NAPO
O
NAPO
O
ONAP
N
O
Ph
NHR3
BnO
NAPO
BnO
BnO
NAPO
OH
N
NAPO
84e
Fmoc 2a
87
OH
NHR3
10
4k
O
O
Ph
1a
a Isolated yield.
b PMP = p-methoxyphenyl.
c The yield dropped to 54% when only 2 equiv of H2SO4 were used.
d Reaction performed at 50 °C.
e Reaction performed at 90 °C
f Formation of the expected product was not observed.
g Formation of the expected product was observed by 1H NMR spectroscopic analysis, but its isolation was troublesome.
h The expected product was obtained as an inseparable mixture with Fmoc-protected 2,4-dinitrophenylhydrazine.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 65–74

68
G. Malik et al.
PAPER
tained from Sigma–Aldrich or Acros Organics chemical companies
and were used as received. Optical rotations were measured with an
Anton Paar MCP 300 polarimeter at 589 nm and are expressed in
deg·cm3·g–1·dm–1 and c is expressed in g/100 cm3. IR spectra were
recorded with a Perkin–Elmer FT-IR system using a diamond win-
dow Dura SamplIR II and the data are reported in reciprocal centi-
meters (cm–1). 1H (500 or 300 MHz) and 13C (125 or 75 MHz) NMR
spectra were recorded with Brüker Avance spectrometers. Chemi-
cal shifts are given in ppm (δ) and are referenced to the internal sol-
vent signal or to TMS used as an internal standard. High-resolution
mass spectra (HRMS) were recorded with a Micromass LCT Pre-
mier XE instrument (Waters) and were determined by electrospray
ionization (ESI).
13C NMR (75 MHz, CDCl3): δ = 12.7 (CH3), 14.1 (C-8), 22.6 (C-7),
25.4 (C-4 or C-5), 29.3 (C-4 or C-5), 31.8 (C-6), 33.2 (C-3), 71.4
(C-2), 77.9 (C-1), 126.0 (CH-Ph), 128.4 (CH-Ph), 129.3 (CH-Ph),
136.2 (Cq-Ph), 155.6 (Cq=N).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H26NO2: 264.1964;
found: 264.1965.
(E)-Acetophenone O-(2-Hydroxy-2-methylbut-3-en-1-yl) Ox-
ime (4c)
The reaction was carried out according to General Procedure A with
2-methyl-2-vinyloxirane (84 mg, 1 mmol), acetophenone oxime
(203 mg, 1.5 mmol) and KOH (168 mg, 3 mmol) in DMF (10 mL).
The mixture was stirred at 50 °C for 16 h and worked up as de-
scribed. The crude product was purified by preparative HPLC
(NW50 column, Merck; heptane–EtOAc, 10:0→8:2 over 35 min;
100 mL/min; UV detection at 254 nm) to give 4c.
Epoxide Opening; General Procedure A
Acetophenone oxime (1.5 equiv) and KOH (3 equiv) were dis-
solved in anhydrous DMF (0.15 M in epoxide) and the solution was
stirred at r.t. for 30 min. A solution of epoxide (1 equiv) in anhy-
drous DMF (0.3 M in epoxide) was then added and the mixture was
stirred at the indicated temperature for 16 h. After addition of H2O,
aq HCl (1 M) was added dropwise until pH 1–2. The mixture was
extracted with MTBE (3×) and the combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
Purification by column chromatography with the indicated eluent
afforded β-hydroxy oxime O-ethers.
Yield: 92 mg (0.420 mmol, 84%); colorless oil; Rf = 0.24 (heptane–
MTBE, 4:1).
IR (neat): 3425, 2976, 2930, 2873, 1445, 1370, 1307, 1044, 994,
914, 758, 691 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.31 (s, 3 H, H-5), 2.25 (s, 3 H,
Me), 3.41 (br s, 1 H, OH), 4.14 (s, 2 H, H-1), 5.14 (dd, J = 1.5,
10.7 Hz, 1 H, H-4), 5.37 (dd, J = 1.5, 17.1 Hz, 1 H, H-4), 5.96 (dd,
J = 10.7, 17.1 Hz, 1 H, H-3), 7.32–7.39 (m, 3 H, Ph-H), 7.57–7.65
(m, 2 H, Ph-H).
13C NMR (75 MHz, CDCl3): δ = 12.8 (CH3), 72.5 (C-2), 77.2 (C-1),
116.3 (C-4), 115.5 (CH-Ar), 126.0 (CH-Ph), 128.4 (CH-Ph), 129.4
(CH-Ph), 136.1 (Cq-Ph), 136.4 (C-3), 155.9 (Cq=N).
(E)-Acetophenone O-[2-Hydroxy-3-(4-methoxyphenoxy)pro-
pyl]oxime (4a)
The reaction was carried out according to General Procedure A with
glycidyl 4-methoxyphenyl ether (90 mg, 0.5 mmol), acetophenone
oxime (101 mg, 0.75 mmol) and KOH (84 mg, 1.5 mmol) in DMF
(5 mL). The mixture was stirred at r.t. for 16 h and worked up as de-
scribed. The crude product was purified by column chromatography
(heptane–EtOAc, 95:5→9:1) to give 4a.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H18NO2: 220.1338;
found: 220.1336.
(S,E)-Acetophenone O-(2,3-Dihydroxypropyl) Oxime (4d)
The reaction was carried out according to General Procedure A with
(S)-glycidol (74 mg, 1 mmol), acetophenone oxime (203 mg, 1.5
mmol) and KOH (168 mg, 3 mmol) in DMF (10 mL). The mixture
was stirred at 90 °C for 16 h and worked up as described. The crude
product was purified by column chromatography (heptane–EtOAc,
1:1) to give 4d.
Yield: 131 mg (0.415 mmol, 83%); colorless oil; Rf = 0.19 (hep-
tane–EtOAc, 4:1).
IR (neat): 3461, 2953, 2926, 1739, 1507, 1228, 1113, 1034, 826,
766, 742, 696 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.25 (s, 3 H, Me), 3.75 (s, 3 H,
OMe), 3.98–4.06 (m, 2 H, H-3), 4.31–4.44 (m, 3 H, H-1, H-2), 6.82
(d, J = 8.9 Hz, 2 H, ArH), 6.87 (d, J = 8.9 Hz, 2 H, ArH), 7.32–7.39
(m, 3 H, Ph-H), 7.58–7.64 (m, 2 H, Ph-H).
24
Yield: 97 mg (0.464 mmol, 46%); pale-yellow oil; [α]D –12.6 (c
0.89, CHCl3); Rf = 0.22 (heptane–EtOAc, 3:7).
IR (neat): 3277, 2927, 2872, 1467, 1441, 1058, 1046, 914, 754,
690 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.24 (s, 3 H, Me), 3.26 (br s, 2 H,
13C NMR (75 MHz, CDCl3): δ = 12.7 (CH3), 55.6 (OCH3), 69.5 (C-
3), 70.0 (C-2), 74.6 (C-1), 114.6 (CH-Ar), 115.5 (CH-Ar), 126.0
(CH-Ph), 128.4 (CH-Ph), 129.3 (CH-Ph), 136.0 (Cq-Ph), 152.7 (Cq-
O), 154.0 (Cq=N), 155.8 (Cq-OMe).
2 × OH), 3.66 and 3.74 (ABX, JAB = 11.6 Hz, JAX = 3.9 Hz, JBX
=
5.9 Hz, 2 H, H-3), 4.01–4.12 (m, 1 H, H-2), 4.25 (d, J = 5.3 Hz, 2 H,
H-1), 7.32–7.39 (m, 3 H, Ph-H), 7.55–7.63 (m, 2 H, Ph-H).
13C NMR (75 MHz, CDCl3): δ = 12.8 (CH3), 63.6 (C-3), 71.6 (C-2),
74.6 (C-1), 126.0 (CH-Ph), 128.4 (CH-Ph), 129.3 (CH-Ph), 136.0
(Cq-Ph), 156.0 (Cq=N).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H16NO3: 210.1130;
found: 210.1133.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H22NO4: 316.1549;
found: 316.1556.
(E)-Acetophenone O-(2-Hydroxyoctyl) Oxime (4b)
The reaction was carried out according to General Procedure A with
1,2-epoxyoctane (128 mg, 1 mmol), acetophenone oxime (203 mg,
1.5 mmol), and KOH (168 mg, 3 mmol) in DMF (10 mL). The mix-
ture was stirred at 50 °C for 16 h and worked up as described. The
crude product was purified by preparative HPLC (NW50 column,
Merck; heptane–EtOAc, 10:0→7:3 over 35 min; 100 mL/min; UV
detection at 254 nm) to give 4b.
(E)-Acetophenone O-Oxiran-2-ylmethyl Oxime (4e)
The reaction was carried out according to General Procedure A with
epichlorohydrin (234 μL, 3 mmol), acetophenone oxime (405 mg, 3
mmol) and KOH (336 mg, 6 mmol) in DMF (20 mL). The mixture
was stirred at r.t. for 16 h and worked up as described. The crude
product was purified by column chromatography (heptane–EtOAc,
4:1) to give 4e.
Yield: 97 mg (0.368 mmol, 74%); colorless oil; Rf = 0.39 (heptane–
EtOAc, 4:1).
IR (neat): 3411, 2954, 2927, 2857, 1444, 1369, 1313, 1036, 927,
912, 901, 758, 691 cm–1.
Yield: 420 mg (2.2 mmol, 73%); colorless oil; Rf = 0.48 (heptane–
EtOAc, 7:3).
1H NMR (500 MHz, CDCl3): δ = 0.85–0.93 (m, 3 H, H-8), 1.24–
1.56 (m, 10 H, H3–H7), 2.26 (s, 3 H, Me), 2.93 (br s, 1 H, OH),
3.94–4.04 (m, 1 H, H-2), 4.08 and 4.22 (ABX, JAB = 11.6 Hz, JAX
1.2 Hz, JBX = 8.0 Hz, 2 H, H-1), 7.33–7.40 (m, 3 H, Ph-H), 7.58–
=
IR (neat): 3056, 3001, 2926, 2876, 1497, 1445, 1370, 1311, 1038,
992, 909, 885, 759, 693 cm–1.
7.66 (m, 2 H, Ph-H).
Synthesis 2013, 45, 65–74
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of β-Hydroxy O-Alkyl Hydroxylamines
69
1H NMR (300 MHz, CDCl3): δ = 2.28 (s, 3 H, Me), 2.69 (dd, J =
2.8, 5.1 Hz, 1 H, H-3), 2.87 (d, J = 4.5 Hz, 1 H, H-3), 3.30–3.37 (m,
Yield: 104.4 mg (0.45 mmol, 89%); colorless oil; Rf = 0.32 (hep-
tane–EtOAc, 7:3).
1 H, H-2), 4.16 and 4.42 (ABX, JAB = 12.2 Hz, JAX = 3.4 Hz, JBX
6.0 Hz, 2 H, H-1), 7.33–7.41 (m, 3 H, Ph-H), 7.61–7.69 (m, 2 H,
Ph-H).
13C NMR (75 MHz, CDCl3): δ = 12.7 (CH3), 44.8 (C-3), 50.2 (C-2),
74.8 (C-1), 126.0 (CH-Ph), 128.3 (CH-Ph), 129.1 (CH-Ph), 136.3
(Cq-Ph), 155.3 (Cq=N).
=
IR (neat): 3429, 2933, 2862, 1497, 1447, 1371, 1074, 1039, 1007,
998, 936, 920, 760, 693 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.22–1.43 (m, 4 H, H-3, H-4, H-
5, H-6), 1.68–1.80 (m, 2 H, H-3, H-4), 2.02–2.15 (m, 2 H, H-6, H-
5), 2.27 (s, 3 H, Me), 3.69–3.76 (m, 1 H, H-2), 3.97–4.07 (m, 1 H,
H-1), 7.32–7.41 (m, 3 H, Ph-H), 7.58–7.66 (m, 2 H, Ph-H).
13C NMR (75 MHz, CDCl3): δ = 12.7 (CH3), 23.7 (C-3 or C-4), 24.2
(C-3 or C-4), 29.6 (C-5), 32.6 (C-6), 74.6 (C-2), 85.8 (C-1), 126.0
(CH-Ph), 128.4 (CH-Ph), 129.2 (CH-Ph), 136.2 (Cq-Ph), 155.2
(Cq=N).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H14NO2: 192.1025;
found: 192.1034.
(1E,1′E)-Acetophenone O-(2-Hydroxy-3-{[(E)-(1-phenylethyli-
dene)amino]oxy}propyl) Oxime (4f)
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H20NO2: 234.1494;
found: 234.1487.
The reaction was carried out according to General Procedure A with
4e (100 mg, 0.52 mmol), acetophenone oxime (106.1 mg, 0.78
mmol) and KOH (88 mg, 1.6 mmol) in DMF (5 mL). The mixture
was stirred at r.t. for 16 h and worked up as described. The crude
product was purified by column chromatography (heptane–EtOAc,
7:3) to give 4f.
Compound 4j
The reaction was carried out according to General Procedure A with
NAP-protected Cerny’s epoxide6a (142 mg, 0.5 mmol), acetophe-
none oxime (101 mg, 0.75 mmol) and KOH (84 mg, 1.5 mmol) in
DMF (5 mL). The mixture was stirred at 90 °C for 16 h and worked
up as described. The crude product was purified by column chroma-
tography (heptane–EtOAc, 8:2→7:3) to give 4j.
Yield: 147.5 mg (0.45 mmol, 86%); colorless oil; Rf = 0.63 (hep-
tane–EtOAc, 3:2).
IR (neat): 3423, 3059, 2931, 2877, 1497, 1444, 1369, 1311, 1042,
998, 935, 919, 889, 759 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.28 (s, 6 H, Me), 4.26–4.42 (m,
5 H, H-1, H-2), 7.32–7.41 (m, 6 H, Ph-H), 7.59–7.69 (m, 4 H, Ph-
H).
13C NMR (75 MHz, CDCl3): δ = 12.8 (CH3), 70.8 (C-2), 74.8 (C-1),
126.0 (CH-Ph), 128.4 (CH-Ph), 129.3 (CH-Ph), 136.2 (Cq-Ph),
155.6 (Cq=N).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H23N2O3: 327.1709;
found: 327.1714.
Yield: 187 mg (0.446 mmol, 89%); pale-yellow foam; [α]D24 –7.6 (c
1.09, CHCl3); Rf = 0.47 (heptane–EtOAc, 1:1).
IR (neat): 3411, 2925, 2905, 1445, 1359, 1318, 1304, 1039, 972,
918, 905, 886, 760, 690 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.23 (s, 3 H, Me), 3.23 (br s, 1 H,
OH), 3.43 (s, 1 H, H-2), 3.64 (dd, J = 6.4 Hz, 1 H, H-6), 3.84 (d, J =
7.3 Hz, 1 H, H-6), 4.07–4.14 (m, 2 H, H-3, H-4), 4.60 (d, J = 4.9 Hz,
1 H, H-5), 4.77 and 4.84 (AB, JAB = 12.2 Hz, 2 H, CH2-NAP), 5.63
(s, 1 H, H-1), 7.28–7.36 (m, 3 H, ArH), 7.39–7.51 (m, 3 H, ArH),
7.56–7.63 (m, 2 H, ArH), 7.73–7.82 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 13.0 (CH3), 66.5 (C-6), 71.0 (C-3),
71.8 (CH2-NAP), 75.6 (C-5), 79.9 (C-2), 83.3 (C-4), 100.6 (C-1),
125.7 (CH-Ar), 125.9 (CH-Ar), 126.1 (CH-Ar), 126.1 (CH-Ar),
126.5 (CH-Ar), 127.6 (CH-Ar), 127.8 (CH-Ar), 128.2 (CH-Ar),
128.4 (CH-Ar), 129.4 (CH-Ar), 132.9 (Cq-NAP), 133.1 (Cq-NAP),
135.3 (Cq-NAP), 136.0 (Cq-Ph), 156.8 (Cq=N).
(E)-Acetophenone O-[(trans)-2-Hydroxycyclopentyl] Oxime
(4h)
The reaction was carried out according to General Procedure A with
cyclopentene oxide (50 mg, 0.6 mmol), acetophenone oxime (121
mg, 0.9 mmol) and KOH (100 mg, 1.8 mmol) in DMF (6 mL). The
mixture was stirred at 90 °C for 16 h and worked up as described.
The crude product was purified by column chromatography (hep-
tane–EtOAc, 80:20) to give 4h.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C25H25NNaO5:
442.1630; found: 442.1631.
Yield: 96 mg (0.44 mmol, 73%); colorless oil; Rf = 0.31 (heptane–
EtOAc, 4:1).
(1R,2S,3R,5S)-2-[(Benzyloxy)methyl]-3-(naphthalen-2-yl-
methoxy)-6-oxabicyclo[3.1.0]hexane (1a)
IR (neat): 3358, 3056, 2961, 1496, 1445, 1369, 1316, 1083, 1037,
995, 973, 914, 760, 693 cm–1.
To a solution of (1R,2S,3R,5S)-2-[(benzyloxy)methyl]-6-oxabicyc-
lo[3.1.0]hexan-3-ol6a (205 mg, 0.931 mmol, 1 equiv) in anhydrous
DMF (10 mL) were added NaH (60% in mineral oil, 67 mg, 1.68
mmol, 1.8 equiv) and 2-bromomethylnaphthalene (309 mg, 1.40
mmol, 1.5 equiv) and the mixture was stirred at r.t. for 4 h. After ad-
dition of crushed ice, the mixture was extracted with MTBE (3 × 10
mL). The combined organic layers were washed with brine (20
mL), dried over Na2SO4, and concentrated in vacuo. Purification by
column chromatography (heptane–EtOAc, 7:3) gave 1a.
1H NMR (300 MHz, CDCl3): δ = 1.56–1.83 (m, 4 H, H-3, H-4, H-
5), 1.93–2.18 (m, 2 H, H-3, H-5), 2.21 (s, 3 H, Me), 2.87 (br s, 1 H,
OH), 4.28 (td, J = 4.1, 6.2 Hz, 1 H, H-2), 4.53 (ddd, J = 3.8, 4.8,
7.3 Hz, 1 H, H-1), 7.31–7.38 (m, 3 H, Ph-H), 7.57–7.65 (m, 2 H,
Ph-H).
13C NMR (75 MHz, CDCl3): δ = 12.7 (CH3), 20.8 (C-4), 28.5 (C-5),
31.6 (C-3), 77.8 (C-2), 89.7 (C-1), 126.0 (CH-Ph), 128.3 (CH-Ph),
129.1 (CH-Ph), 136.5 (Cq-Ph), 155.1 (Cq=N).
Yield: 322 mg (0.893 mmol, 96%); pale-yellow oil; [α]D24 –48.0 (c
0.89, CHCl3); Rf = 0.43 (heptane–EtOAc, 3:2).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H18NO2: 220.1338;
found: 220.1339.
IR (neat): 2925, 2856, 1362, 1121, 1084, 1027, 839, 815, 737,
697 cm–1.
(E)-Acetophenone O-[(trans)-2-Hydroxycyclohexyl] Oxime (4i)
The reaction was carried out according to General Procedure A with
cyclohexene oxide (46.1 mg, 0.5 mmol), acetophenone oxime
(101.3 mg, 0.75 mmol) and KOH (84 mg, 1.5 mmol) in DMF (5
mL). The mixture was stirred at r.t. for 16 h and worked up as de-
scribed. The crude product was purified by preparative HPLC
(Eurospher 100–5 Si column, Knauer; 250 × 20 mm; heptane–
EtOAc, 10:0→7:3 over 40 min; 12 mL/min; UV detection at 254
nm) to give 4i.
1H NMR (500 MHz, CDCl3): δ = 2.04 (ddd, J = 0.9, 7.6, 15.3 Hz,
1 H, H-5), 2.18 (d, J = 15.3 Hz, 1 H, H-5), 2.65 (t, J = 5.8 Hz, 1 H,
H-2), 3.37 and 3.40 (ABX, JAB = 9.5 Hz, JAX = 6.1 Hz, JBX = 6.1 Hz,
2 H, CH2-OBn), 3.46 (d, J = 2.1 Hz, 1 H, H-4), 3.54 (br s, 1 H, H-
3), 3.93 (d, J = 7.6 Hz, 1 H, H-1), 4.45 (s, 2 H, CH2-Bn), 4.61 and
4.68 (AB, JAB = 12.8 Hz, 2 H, CH2-NAP), 7.20–7.33 (m, 5 H, ArH),
7.40–7.50 (m, 3 H, ArH), 7.69–7.84 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 34.8 (C-5), 47.4 (C-2), 57.9 (C-3),
59.7 (C-4), 69.2 (CH2-OBn), 70.9 (CH2-NAP), 73.2 (CH2-Bn), 80.9
© Georg Thieme Verlag Stuttgart · New York
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70
G. Malik et al.
PAPER
(C-1), 125.7 (CH-Ar), 125.9 (CH-Ar), 126.0 (CH-Ar), 126.4 (CH-
Ar), 127.4 (CH-Ar), 127.6 (CH-Ar), 127.8 (CH-Ar), 128.0 (CH-
Ar), 128.3 (CH-Ar), 132.9 (Cq-NAP), 133.2 (Cq-NAP), 135.9 (Cq-
NAP), 138.0 (Cq-Bn).
(d, J = 5.6 Hz, 2 H, H-3), 4.22–4.30 (m, 1 H, H-2), 6.79–6.89 (m,
4 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 55.7 (OCH3), 69.5 (C-3), 70.0 (C-
2), 75.8 (C-1), 114.6 (CH-Ar), 115.5 (CH-Ar), 152.7 (Cq-O), 154.0
(Cq-OMe).
HRMS (ESI-TOF): m/z [M + NH4]+ calcd for C24H28NO3:
378.2069; found: 378.2070.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H16NO4: 214.1079;
found: 214.1076.
(E)-Acetophenone O-{(1R,2R,3R,4R)-3-[(Benzyloxy)methyl]-2-
hydroxy-4-(naphthalen-2-ylmethoxy)cyclopentyl} Oxime (4k)
The reaction was carried out according to General Procedure A with
1a (23 mg, 0.064 mmol), acetophenone oxime (13 mg, 0.096 mmol)
and KOH (11 mg, 0.192 mmol) in DMF (850 μL). The mixture was
stirred at 90 °C for 16 h and worked up as described. The crude
product was purified by column chromatography (heptane–MTBE,
4:1) to give 4k.
(9H-Fluoren-9-yl)methyl 2-Hydroxy-3-(4-methoxyphen-
oxy)propoxycarbamate (6a)
The reaction was carried out according to General Procedure B with
4a (79 mg, 0.25 mmol), 2,4-dinitrophenylhydrazine (99 mg, 0.5
mmol), H2SO4 (135 μL, 2.5 mmol) in MeOH (2 mL), and then with
NaHCO3 (420 mg, 5 mmol) and FmocCl (323 mg, 1.25 mmol) in
MeOH (10 mL). The mixture was worked up as described and the
crude product was purified by column chromatography (heptane–
EtOAc, 8:2→7:3) to give 6a.
Yield: 27 mg (0.054 mmol, 84%); colorless oil; [α]D24 +3.6 (c 0.72,
CHCl3); Rf = 0.41 (heptane–MTBE, 1:1).
IR (neat): 3441, 3058, 3027, 2924, 2858, 1366, 1065, 1028, 995,
913, 855, 815, 756, 736, 693 cm–1.
Yield: 88 mg (0.202 mmol, 81%); pale-yellow amorphous solid;
Rf = 0.22 (heptane–EtOAc, 3:2).
1H NMR (300 MHz, CDCl3): δ = 2.03–2.15 (m, 1 H, H-5), 2.20 (s,
IR (neat): 3238, 1707, 1508, 1269, 1230, 1124, 1107, 1042, 822,
755, 737 cm–1.
3 H, Me), 2.23–2.39 (m, 2 H, H-2, H-5), 3.63 and 3.67 (ABX, JAB
=
9.3 Hz, JAX = 5.3 Hz, JBX = 5.7 Hz, 2 H, CH2-OBn), 3.95–4.03 (m,
1 H, H-1), 4.11 (dd, J = 6.2, 8.3 Hz, 1 H, H-3), 4.49 and 4.53 (AB,
JAB = 12.0 Hz, 2 H, CH2-Bn), 4.62 and 4.70 (AB, JAB = 12.1 Hz,
2 H, CH2-NAP), 4.71–4.85 (m, 1 H, H-4), 7.20–7.50 (m, 11 H,
ArH), 7.55–7.64 (m, 2 H, ArH), 7.72–7.86 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 12.8 (CH3), 34.7 (C-5), 51.7 (C-2),
69.4 (CH2-OBn), 71.2 (CH2-NAP), 73.2 (CH2-Bn), 77.1 (C-1), 78.1
(C-3), 86.9 (C-4), 125.8 (CH-Ar), 126.0 (CH-Ar), 126.0 (CH-Ar),
126.3 (CH-Ar), 127.5 (CH-Ar), 127.6 (CH-Ar), 127.7 (CH-Ar),
127.9 (CH-Ar), 128.1 (CH-Ar), 128.3 (CH-Ar), 128.4 (CH-Ar),
128.4 (CH-Ar), 129.2 (CH-Ar), 132.9 (Cq-NAP), 133.3 (Cq-NAP),
135.9 (Cq-Ph), 136.4 (Cq-NAP), 138.3 (Cq-Bn), 155.4 (Cq=N).
1H NMR (500 MHz, CDCl3): δ = 3.76 (s, 3 H, OMe), 3.91–4.07 (m,
4 H, H-1, H-3), 4.16–4.21 (m, 1 H, H-2), 4.23 (t, J = 7.0 Hz, 1 H,
CH-Fmoc), 4.52 and 4.56 (ABX, JAB = 10.7 Hz, JAX = 6.7 Hz, JBX
=
6.7 Hz, 2 H, CH2-Fmoc), 6.79–6.87 (m, 4 H, ArH), 7.31 (t, J =
7.6 Hz, 2 H, ArH), 7.40 (t, J = 7.3 Hz, 2 H, ArH), 7.56 (d, J =
7.6 Hz, 2 H, ArH), 7.64 (s, 1 H, NH), 7.76 (d, J = 7.3 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 47.0 (CH-Fmoc), 55.7 (OCH3),
67.5 (C-2), 67.7 (CH2-Fmoc), 69.1 (C-3), 78.9 (C-1), 114.7 (CH-
Ar), 115.5 (CH-Ar), 120.1 (CH-Ar), 124.9 (CH-Ar), 124.9 (CH-
Ar), 127.2 (CH-Ar), 127.9 (CH-Ar), 141.3 (Cq-Fmoc), 143.2 (Cq-
Fmoc), 143.3 (Cq-Fmoc), 152.6 (Cq-O), 154.1 (Cq-OMe), 158.6
(C=O).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C32H33NNaO4:
518.2307; found: 518.2313.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C25H25NNaO6:
458.1580; found: 458.1573.
Synthesis of N-Protected O-Alkyl Hydroxylamine; General
Procedure B
Benzyl 2-Hydroxy-3-(4-methoxyphenoxy)propoxycarbamate
(7a)
To a solution of β-hydroxy oxime O-ether (1 equiv) in anhydrous
MeOH (0.13 M) were added H2SO4 (10 equiv) and 2,4-dinitro-
phenylhydrazine (2 equiv) and the mixture was stirred at r.t. for 16
h. After dilution with MeOH (4 × initial volume), powdered
NaHCO3 (20 equiv) was added slowly at 0 °C, followed by protect-
ing reagent (5 equiv). The reaction mixture was stirred for 3 h at r.t.
and diluted with EtOAc (2 × volume of MeOH). The organic layer
was washed with H2O (×2), brine, dried over Na2SO4 and concen-
trated in vacuo. Purification by column chromatography with the in-
dicated eluent gave the expected N-protected β-hydroxy O-alkyl
hydroxylamine.
The reaction was carried out according to General Procedure B with
4a (79 mg, 0.25 mmol), 2,4-dinitrophenylhydrazine (99 mg, 0.5
mmol), H2SO4 (135 μL, 2.5 mmol) in MeOH (2 mL), and then with
NaHCO3 (420 mg, 5 mmol) and CbzCl (188 µL, 1.25 mmol) in
MeOH (10 mL). The mixture was worked up as described and the
crude product was purified by column chromatography (heptane–
EtOAc, 8:2→7:3) to give 7a.
Yield: 69 mg (0.199 mmol, 80%); yellow amorphous solid; Rf =
0.24 (heptane–EtOAc, 3:2).
IR (neat): 3406, 3160, 2954, 1724, 1506, 1266, 1232, 1129, 1109,
1041, 823, 739, 696 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.76 (s, 3 H, OMe), 3.92–4.12 (m,
4 H, H-1, H-3), 4.20–4.29 (m, 1 H, H-2), 5.19 (s, 2 H, CH2-Bn),
6.78–6.87 (m, 4 H, ArH), 7.33–7.40 (m, 5 H, H-Bn), 7.63 (s, 1 H,
NH).
13C NMR (75 MHz, CDCl3): δ = 55.7 (OCH3), 67.5 (C-2), 68.1
(CH2-Bn), 69.1 (C-3), 79.0 (C-1), 114.7 (CH-Ar), 115.5 (CH-Ar),
128.4 (CH-Ar), 128.7 (CH-Ar), 135.1 (Cq-Bn), 152.6 (Cq-O), 154.1
(Cq-OMe), 158.7 (C=O).
1-(Aminooxy)-3-(4-methoxyphenoxy)propan-2-ol (5a)
To a solution of 4a (79 mg, 0.25 mmol, 1 equiv) in anhydrous
MeOH (2 mL) were added H2SO4 (135 μL, 2.5 mmol, 10 equiv) and
2,4-dinitrophenylhydrazine (99 mg, 0.5 mmol, 2 equiv) and the
mixture was stirred at r.t. for 16 h. Powdered NaHCO3 (420 mg, 5
mmol, 20 equiv) was then added slowly and the reaction mixture
was diluted with H2O (20 mL). The aqueous layer was extracted
with EtOAc (3 × 15 mL) and the combined organic layers were
washed with H2O (20 mL), brine (20 mL), dried over Na2SO4 and
concentrated in vacuo. Purification by column chromatography
(heptane–EtOAc, 1:1→3:7) gave 5a.
HRMS (ESI-TOF): m/z [M – H]– calcd for C18H20NO6: 346.1291;
found: 346.1306.
Yield: 41 mg (0.192 mmol, 77%); pale-yellow amorphous solid;
Rf = 0.10 (heptane–EtOAc, 1:4).
IR (neat): 3301, 3249, 2935, 1513, 1240, 1046, 1033, 825 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.76 (s, 3 H, OMe), 3.83 and 3.90
(ABX, JAB = 11.7 Hz, JAX = 3.1 Hz, JBX = 6.5 Hz, 2 H, H-1), 3.96
Allyl 2-Hydroxy-3-(4-methoxyphenoxy)propoxycarbamate (8a)
The reaction was carried out according to General Procedure B with
4a (79 mg, 0.25 mmol), 2,4-dinitrophenylhydrazine (99 mg, 0.5
mmol), H2SO4 (135 μL, 2.5 mmol) in MeOH (2 mL), and then with
NaHCO3 (420 mg, 5 mmol) and AllocCl (133 μL, 1.25 mmol) in
Synthesis 2013, 45, 65–74
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Synthesis of β-Hydroxy O-Alkyl Hydroxylamines
71
MeOH (10 mL). The mixture was worked up as described and the
crude product was purified by column chromatography (heptane–
EtOAc, 8:2→7:3) to give 8a.
(d, J = 10.7 Hz, 1 H, H-4), 5.36 (dd, J = 1.1, 17.1 Hz, 1 H, H-4),
5.87 (dd, J = 10.7, 17.3 Hz, 1 H, H-3), 7.30 (t, J = 7.3 Hz, 2 H,
ArH), 7.39 (t, J = 7.3 Hz, 2 H, ArH), 7.55 (d, J = 7.3 Hz, 2 H, ArH),
7.75 (d, J = 7.3 Hz, 2 H, ArH), 7.85 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 24.4 (C-5), 46.9 (CH-Fmoc), 67.6
(CH2-Fmoc), 72.6 (C-2), 84.4 (C-1), 113.8 (C-4), 120.0 (CH-Ar),
124.9 (CH-Ar), 127.1 (CH-Ar), 127.8 (CH-Ar), 141.3 (Cq-Fmoc),
141.6 (C-3), 143.3 (Cq-Fmoc), 143.3 (Cq-Fmoc), 158.0 (C=O).
Yield: 66 mg (0.222 mmol, 89%); yellow amorphous solid; Rf =
0.18 (heptane–EtOAc, 3:2).
IR (neat): 3351, 3177, 2933, 2913, 1708, 1507, 1267, 1220, 1104,
994, 827, 756 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.76 (s, 3 H, OMe), 3.92–4.12 (m,
4 H, H-1, H-3), 4.21–4.29 (m, 1 H, H-2), 4.64 (t, J = 1.3 Hz, 1 H,
CH2-CH=CH2), 4.66 (t, J = 1.3 Hz, 1 H, CH2-CH=CH2), 5.23–5.38
(m, 2 H, CH2-CH=CH2), 5.83–5.98 (m, 1 H, CH2-CH=CH2), 6.78–
6.87 (m, 4 H, ArH), 7.89 (s, 1 H, NH).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H21NNaO4:
362.1368; found: 362.1371.
(S)-(9H-Fluoren-9-yl)methyl 2,3-Dihydroxypropoxycarbamate
(6d)
13C NMR (75 MHz, CDCl3): δ = 55.7 (OCH3), 66.8 (CH2-
CH=CH2), 67.5 (C-2), 69.1 (C-3), 78.8 (C-1), 114.6 (CH-Ar), 115.5
(CH-Ar), 119.0 (CH2-CH=CH2), 131.5 (CH2-CH=CH2), 152.6 (Cq-
O), 154.0 (Cq-OMe), 158.5 (C=O).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H19NNaO6:
320.1110; found: 320.1106.
The reaction was carried out according to General Procedure B with
4d (80 mg, 0.382 mmol), 2,4-dinitrophenylhydrazine (152 mg,
0.765 mmol), and H2SO4 (205 μL, 3.82 mmol) in MeOH (3 mL),
and then with NaHCO3 (642 mg, 7.64 mmol) and FmocCl (494 mg,
1.91 mmol) in MeOH (15 mL). The mixture was worked up as de-
scribed and the crude product was purified by column chromatogra-
phy (heptane–EtOAc, 1:1→0:1) to give 6d.
(9H-Fluoren-9-yl)methyl (2-Hydroxyoctyl)oxycarbamate (6b)
The reaction was carried out according to General Procedure B with
4b (70 mg, 0.266 mmol), 2,4-dinitrophenylhydrazine (105 mg,
0.532 mmol), and H2SO4 (143 μL, 2.66 mmol) in MeOH (2 mL),
and then with NaHCO3 (447 mg, 5.32 mmol) and FmocCl (344 mg,
1.33 mmol) in MeOH (10 mL). The mixture was worked up as de-
scribed and the crude product was purified by column chromatogra-
phy (heptane–EtOAc, 8:2→7:3) to give 6b.
Yield: 117 mg (0.355 mmol, 93%); pale-yellow amorphous solid;
[α]D24 +7.9 (c 1.11, MeOH); Rf = 0.13 (heptane–EtOAc, 3:7).
IR (neat): 3496, 3336, 3149, 2959, 2934, 2905, 2874, 1699, 1510,
1447, 1261, 1118, 1103, 1071, 755, 733 cm–1.
1H NMR (300 MHz, CD3OD): δ = 3.49–3.63 (m, 2 H, H-3), 3.73–
3.91 (m, 3 H, H-1, H-2), 4.14 (t, J = 6.6 Hz, 1 H, CH-Fmoc), 4.40
(d, J = 6.6 Hz, 2 H, CH2-Fmoc), 7.27 (dt, J = 1.1, 7.3 Hz, 2 H, ArH),
7.35 (t, J = 7.3 Hz, 2 H, ArH), 7.58 (d, J = 7.3 Hz, 2 H, ArH), 7.73
(d, J = 7.3 Hz, 2 H, ArH).
13C NMR (75 MHz, CD3OD): δ = 48.2 (CH-Fmoc), 64.1 (C-3), 68.2
(CH2-Fmoc), 70.6 (C-2), 79.2 (C-1), 120.9 (CH-Ar), 126.0 (CH-
Ar), 128.1 (CH-Ar), 128.8 (CH-Ar), 142.5 (Cq-Fmoc), 144.9 (Cq-
Fmoc), 159.8 (C=O).
Yield: 97 mg (0.253 mmol, 95%); pale-rose crystals; Rf = 0.27 (hep-
tane–EtOAc, 7:3).
IR (neat): 3319, 3271, 2954, 2925, 2855, 1698, 1495, 1479, 1465,
1447, 1268, 1127, 755, 736, 725 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.78–0.94 (m, 3 H, H-8), 1.18–
1.54 (m, 10 H, H3–H7), 3.62 (dd, J = 9.8, 11.3 Hz, 1 H, H-1), 3.75
(br s, 1 H, OH), 3.78–3.85 (m, 2 H, H-1, H-2), 4.22 (t, J = 6.7 Hz,
1 H, CH-Fmoc), 4.50 and 4.54 (ABX, JAB = 10.5 Hz, JAX = 6.4 Hz,
JBX = 7.1 Hz, 2 H, CH2-Fmoc), 7.30 (t, J = 7.3 Hz, 2 H, ArH), 7.40
(t, J = 7.3 Hz, 2 H, ArH), 7.55 (d, J = 7.3 Hz, 2 H, ArH), 7.67 (s,
1 H, NH), 7.75 (d, J = 7.3 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 14.1 (C-8), 22.6 (C-7), 25.5 (C-4
or C-5), 29.3 (C-4 or C-5), 31.7 (C-6), 32.1 (C-3), 46.9 (CH-Fmoc),
67.6 (CH2-Fmoc), 68.1 (C-2), 81.8 (C-1), 120.0 (CH-Ar), 124.9
(CH-Ar), 124.9 (CH-Ar), 127.1 (CH-Ar), 127.8 (CH-Ar), 141.3
(Cq-Fmoc), 143.3 (Cq-Fmoc), 143.3 (Cq-Fmoc), 158.7 (C=O).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H19NNaO5:
352.1161; found: 352.1157.
Diallyl [(2-Hydroxypropane-1,3-diyl)bis(oxy)]dicarbamate (8f)
The reaction was carried out according to General Procedure B with
4f (74 mg, 0.227 mmol), 2,4-dinitrophenylhydrazine (90 mg, 0.453
mmol), and H2SO4 (122 μL, 2.27 mmol) in MeOH (1.75 mL), and
then with NaHCO3 (381 mg, 4.54 mmol) and AllocCl (120 μL, 1.14
mmol) in MeOH (7 mL). The mixture was worked up as described
and the crude product was purified by column chromatography
(heptane–EtOAc, 4:1→1:1) to give 8f.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C23H29NNaO4:
406.1994; found: 406.1999.
Yield: 40 mg (0.138 mmol, 61%); pale-yellow oil; Rf = 0.19 (hep-
tane–EtOAc, 1:1).
IR (neat): 3262, 2924, 2851, 1714, 1249, 1109, 1042, 992, 930,
768 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.92 and 3.98 (ABX, JAB
=
11.3 Hz, JAX = 2.9 Hz, JBX = 7.8 Hz, 4 H, H-1), 4.14–4.20 (m, 1 H,
H-2), 4.65 (d, J = 5.2 Hz, 4 H, CH2-CH=CH2), 5.26 (d, J = 10.7 Hz,
2 H, CH2-CH=CH2), 5.34 (d, J = 17.4 Hz, 2 H, CH2-CH=CH2),
5.86–5.97 (m, 2 H, CH2-CH=CH2), 7.99 (br s, 2 H, NH).
13C NMR (75 MHz, CDCl3): δ = 66.7 (CH2-CH=CH2), 67.0 (C-2),
77.7 (C-1), 118.9 (CH2-CH=CH2), 131.7 (CH2-CH=CH2), 158.1
(C=O).
(9H-Fluoren-9-yl)methyl (2-Hydroxy-2-methylbut-3-en-1-
yl)oxycarbamate (6c)
The reaction was carried out according to General Procedure B with
4c (96 mg, 0.438 mmol), 2,4-dinitrophenylhydrazine (173 mg,
0.876 mmol), and H2SO4 (235 μL, 4.38 mmol) in MeOH (3 mL),
and then with NaHCO3 (736 mg, 8.76 mmol) and FmocCl (567 mg,
2.19 mmol) in MeOH (12 mL). The mixture was worked up as de-
scribed and the crude product was purified by column chromatogra-
phy (heptane–EtOAc, 8:2→7:3) to give a mixture of 6c and Fmoc-
protected 2,4-dinitrophenylhydrazine (304 mg) as an orange solid.
This mixture was purified by preparative HPLC (NW50 column,
Merck; heptane–EtOAc, 10:0→6:4 over 35 min; 100 mL/min; UV
detection at 254 nm) to give 6c.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H18N2NaO7:
313.1012; found: 313.1004.
Yield: 102 mg (0.301 mmol, 69%); pale-yellow oil; Rf = 0.31 (hep-
tane–EtOAc, 3:2).
(9H-Fluoren-9-yl)methyl (2-Hydroxycyclopentyl) Oxycarba-
mate (6h)
The reaction was carried out according to General Procedure B with
4h (100 mg, 0.457 mmol), 2,4-dinitrophenylhydrazine (175 mg,
0.914 mmol), and H2SO4 (244 μL, 4.57 mmol) in MeOH (3 mL),
and then with NaHCO3 (1.47 g, 18.28 mmol) and FmocCl (1.13 g,
IR (neat): 3262, 2975, 1716, 1449, 1252, 1115, 757, 737 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.25 (s, 3 H, H-5), 3.10 (br s, 1 H,
OH), 3.77 and 3.83 (AB, JAB = 10.5 Hz, 2 H, H-1), 4.21 (t, J =
6.6 Hz, 1 H, CH-Fmoc), 4.49 (d, J = 6.6 Hz, 2 H, CH2-Fmoc), 5.12
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 65–74

72
G. Malik et al.
PAPER
5.48 mmol) in MeOH (15 mL). The mixture was worked up as de-
scribed and the crude product was purified by column chromatogra-
phy (heptane–EtOAc, 9:1→8:2) to give 6h.
1H NMR (500 MHz, CDCl3): δ = 3.39 (d, J = 3.4 Hz, 1 H, H-4), 3.49
(d, J = 3.4 Hz, 1 H, H-2), 3.64 (dd, J = 5.5, 7.0 Hz, 1 H, H-6), 3.80
(d, J = 7.0 Hz, 1 H, H-6), 3.95 (t, J = 3.7 Hz, 1 H, H-3), 4.57 (d, J =
5.5 Hz, 1 H, H-5), 4.83 and 4.91 (AB, JAB = 12.2 Hz, 2 H, CH2-
NAP), 5.52 (s, 1 H, H-1), 7.44–7.55 (m, 3 H, ArH), 7.79–7.88 (m,
4 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 66.5 (C-6), 70.7 (C-3), 72.0 (CH2-
NAP), 75.5 (C-5), 79.6 (C-4), 84.0 (C-2), 100.1 (C-1), 125.8 (CH-
Ar), 126.0 (CH-Ar), 126.2 (CH-Ar), 126.8 (CH-Ar), 127.7 (CH-
Ar), 127.9 (CH-Ar), 128.4 (CH-Ar), 133.0 (Cq-NAP), 133.2 (Cq-
NAP), 135.3 (Cq-NAP).
Yield: 152.8 mg (0.451 mmol, 99%); pale-yellow oil; Rf = 0.13
(heptane–EtOAc, 7:3).
IR (neat): 3270, 2957, 1723, 1450, 1251, 1115, 908, 758, 728 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.49–1.58 (m, 1 H, H-3), 1.59–
1.73 (m, 3 H, H-4, H-5), 1.89–2.00 (m, 2 H, H-3, H-5), 2.36 (br s,
1 H, OH), 4.04–4.09 (m, 1 H, H-1), 4.13–4.18 (m, 1 H, H-2), 4.20
(t, J = 6.7 Hz, 1 H, CH-Fmoc), 4.50 (d, J = 6.7 Hz, 2 H, CH2-Fmoc),
7.29 (td, J = 0.9, 7.6 Hz, 2 H, ArH), 7.38 (t, J = 7.3 Hz, 2 H, ArH),
7.55 (br s, 1 H, NH), 7.56 (d, J = 7.3 Hz, 2 H, ArH), 7.74 (d, J =
7.6 Hz, 2 H, ArH).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H20NO5: 318.1341;
found: 318.1350.
13C NMR (75 MHz, CD3OD): δ = 20.5 (C-4), 27.9 (C-5), 31.7 (C-
3), 47.3 (CH-Fmoc), 67.6 (CH2-Fmoc), 75.8 (C-2), 93.5 (C-1),
120.2 (CH-Ar), 125.1 (CH-Ar), 127.3 (CH-Ar), 128.0 (CH-Ar),
141.5 (Cq-Fmoc), 143.6 (Cq-Fmoc), 158.3 (C=O).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H22NO4: 340.1549;
found: 340.1561.
Fluorenylmethyl {(1R,2R,3S,4R,5R)-3-Hydroxy-2-(naphthalen-
2-ylmethoxy)-6,8-dioxabicyclo[3.2.1]octan-4-yl}oxycarbamate
(6j)
The reaction was carried out according to General Procedure B with
4j (100 mg, 0.238 mmol), 2,4-dinitrophenylhydrazine (94 mg,
0.477 mmol), and H2SO4 (128 μL, 2.38 mmol) in MeOH (2 mL).
THF (100 μL) was added to improve the solubility of the starting
material. After 16 h at r.t., 2,4-dinitrophenylhydrazine (47 mg,
0.238 mmol, 1 equiv) was added to complete the reaction and the
mixture was stirred for 2 h before being diluted with MeOH (8 mL).
NaHCO3 (400 mg, 4.76 mmol) and FmocCl (308 mg, 1.19 mmol)
were added and the reaction mixture was stirred at r.t. for 4 h. Ad-
dition of NaHCO3 (200 mg, 2.38 mmol) and FmocCl (154 mg,
0.595 mmol) were necessary to complete the reaction. The mixture
was then stirred overnight and worked up as described. Purification
by column chromatography (heptane–EtOAc, 4:1→3:2) afforded
6j.
Allyl [(1S,2S)-2-Hydroxycyclohexyl]oxycarbamate (8i)
The reaction was carried out according to General Procedure B with
4i (63 mg, 0.27 mmol), 2,4-dinitrophenylhydrazine (107 mg, 0.54
mmol), and H2SO4 (145 μL, 2.70 mmol) in MeOH (2 mL), and then
with NaHCO3 (454 mg, 5.40 mmol) and AllocCl (145 μL, 1.35
mmol) in MeOH (8 mL). The mixture was worked up as described
and the crude product was purified by column chromatography
(heptane–EtOAc, 8:2→6:4) to give an inseparable mixture of 8i and
Alloc-protected 2,4-dinitrophenylhydrazine (117 mg) as an orange
solid. This mixture was purified by preparative HPLC (NW50 col-
umn, Merck; heptane–EtOAc, 10:0→6:4 over 40 min; 100 mL/min;
UV detection at 254 nm) to give 8i.
Yield: 98 mg (0.182 mmol, 76%); pale-yellow amorphous solid;
[α]D24 –2.6 (c 0.94, CHCl3); Rf = 0.21 (heptane–EtOAc, 1:1).
Yield: 47 mg (0.218 mmol, 81%); pale-yellow oil; Rf = 0.44 (hep-
tane–EtOAc, 1:1; visualized by KMnO4 only).
IR (neat): 3264, 1725, 1450, 1249, 1102, 1073, 1009, 757,
739 cm–1.
IR (neat): 3223, 2938, 2863, 1718, 1453, 1256, 1111, 1084, 993,
920, 770 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.36 (dd, J = 0.8, 4.5 Hz, 1 H, H-
4), 3.56–3.63 (m, 2 H, H-2, H-6), 3.74 (d, J = 7.5 Hz, 1 H, H-6),
3.95 (t, J = 4.5 Hz, 1 H, H-3), 4.18 (t, J = 6.6 Hz, 1 H, CH-Fmoc),
1H NMR (500 MHz, CDCl3): δ = 1.13–1.51 (m, 4 H, CH2-cyclohex-
ane), 1.64–1.84 (m, 2 H, CH2-cyclohexane), 1.92–2.13 (m, 2 H,
CH2-cyclohexane), 3.47–3.62 (m, 2 H, H-1, H-2), 4.50 (br s, 1 H,
OH), 4.65 (d, J = 5.5 Hz, 2 H, CH2-CH=CH2), 5.27 (d, J = 10.4 Hz,
1 H, CH2-CH=CH2), 5.34 (d, J = 17.1 Hz, 1 H, CH2-CH=CH2),
5.87–5.97 (m, 1 H, CH2-CH=CH2), 7.86 (br s, 2 H, NH).
13C NMR (75 MHz, CDCl3): δ = 23.7, 24.3 (C-4, C-5), 28.8, 32.3
(C-3, C-6), 66.7 (CH2-CH=CH2), 71.0 (C-2), 90.4 (C-1), 118.8
(CH2-CH=CH2), 131.6 (CH2-CH=CH2), 158.8 (C=O).
4.42–4.56 (m, 3 H, H-5, CH2-Fmoc), 4.76 and 4.87 (AB, JAB
=
12.4 Hz, 2 H, CH2-NAP), 5.55 (s, 1 H, H-1), 7.22–7.57 (m, 9 H,
ArH), 7.68–7.84 (m, 6 H, ArH), 7.91 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 46.9 (CH-Fmoc), 66.5 (C-6), 67.7
(CH2-Fmoc), 69.4 (C-3), 72.0 (CH2-NAP), 75.7 (C-5), 79.4 (C-4),
86.4 (C-2), 100.1 (C-1), 120.0 (CH-Ar), 124.9 (CH-Ar), 125.8 (CH-
Ar), 126.0 (CH-Ar), 126.2 (CH-Ar), 126.8 (CH-Ar), 127.2 (CH-
Ar), 127.7 (CH-Ar), 127.9 (CH-Ar), 128.3 (CH-Ar), 133.0 (Cq-
NAP), 133.2 (Cq-NAP), 135.1 (Cq-NAP), 141.3 (Cq-Fmoc), 143.2
(Cq-Fmoc), 143.3 (Cq-Fmoc), 158.3 (C=O).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H18NO4: 216.1236;
found: 216.1219.
HRMS (ESI-TOF): m/z [M+NH4]+ calcd for C32H33N2O7:
557.2288; found: 557.2264.
(1R,2R,3S,4R,5R)-4-(Aminooxy)-2-(naphthalen-2-ylmethoxy)-
6,8-dioxabicyclo[3.2.1]octan-3-ol (5j)
Benzyl {(1R,2R,3S,4R,5R)-3-Hydroxy-2-(naphthalen-2-yl-
methoxy)-6,8-dioxabicyclo[3.2.1]octan-4-yl}oxycarbamate (7j)
The reaction was carried out according to General Procedure B with
4j (100 mg, 0.238 mmol), 2,4-dinitrophenylhydrazine (141 mg,
0.714 mmol, 3 equiv), and H2SO4 (128 μL, 2.38 mmol) in MeOH (2
mL) and THF (100 μL, added to improve the solubility of the start-
ing material) and then with NaHCO3 (400 mg, 4.76 mmol) and Cbz-
Cl (179 μL, 1.19 mmol) in MeOH (8 mL). The mixture was worked
up as described and the crude product was purified by column chro-
matography (heptane–EtOAc, 8:2→6:4) to give 7j.
To a solution of 4j (100 mg, 0.238 mmol, 1 equiv) in anhydrous
MeOH (2 mL) and THF (100 μL) were added H2SO4 (128 μL, 2.38
mmol, 10 equiv) and 2,4-dinitrophenylhydrazine (94 mg, 0.477
mmol, 2 equiv) and the mixture was stirred at r.t. for 16 h. 2,4-Di-
nitrophenylhydrazine (47 mg, 0.238 mmol, 1 equiv) was then added
to complete the reaction and the mixture was stirred for 1 h before
being neutralized with powdered NaHCO3 (400 mg, 4.76 mmol, 20
equiv). After addition of H2O (20 mL), the aqueous layer was ex-
tracted with EtOAc (3 × 15 mL) and the combined organic layers
were washed with H2O (20 mL), brine (20 mL), dried over Na2SO4,
and concentrated in vacuo. Purification by column chromatography
(heptane–EtOAc, 1:1→3:7) gave 5j.
24
Yield: 95 mg (0.210 mmol, 88%); pale-yellow oil; [α]D –0.3 (c
1.02, CHCl3); Rf = 0.15 (heptane–EtOAc, 3:2).
24
Yield: 57 mg (0.180 mmol, 76%); pale-yellow oil; [α]D –22.4 (c
0.86, MeOH); Rf = 0.15 (heptane–EtOAc, 3:7).
IR (neat): 3384, 3209, 1721, 1511, 1269, 1116, 1101, 1076, 1011,
993, 973, 877, 826, 751, 735 cm–1.
IR (neat): 3524, 3327, 2912, 1102, 1029, 1016, 896, 860, 813 cm–1.
Synthesis 2013, 45, 65–74
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of β-Hydroxy O-Alkyl Hydroxylamines
73
1H NMR (300 MHz, CDCl3): δ = 3.36 (dd, J = 0.8, 4.5 Hz, 1 H, H-
4), 3.57 (dd, J = 5.7, 7.5 Hz, 1 H, H-6), 3.66–3.75 (m, 2 H, H-2, H-
6), 3.99 (d, J = 4.7 Hz, 1 H, H-3), 4.51 (d, J = 5.3 Hz, 1 H, H-5),
4.75 and 4.87 (AB, JAB = 12.3 Hz, 2 H, CH2-NAP), 5.10 and 5.11
(AB, JAB = 12.2 Hz, 2 H, CH2-Cbz), 5.60 (s, 1 H, H-1), 7.26–7.31
(m, 5 H, ArH), 7.41–7.49 (m, 3 H, ArH), 7.74–7.82 (m, 6 H, ArH),
8.13 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 66.4 (C-6), 67.9 (CH2-Cbz), 69.4
(C-3), 71.9 (CH2-NAP), 75.6 (C-5), 79.5 (C-4), 86.6 (C-2), 100.1
(C-1), 125.7 (CH-Ar), 126.0 (CH-Ar), 126.1 (CH-Ar), 126.7 (CH-
Ar), 127.6 (CH-Ar), 127.8 (CH-Ar), 128.2 (CH-Ar), 128.5 (CH-
Ar), 128.5 (CH-Ar), 133.0 (Cq-NAP), 133.1 (Cq-NAP), 135.1 (Cq-
NAP), 135.2 (Cq-Cbz), 158.3 (C=O).
3.88 (m, 1 H, H-1), 3.97 (dd, J = 6.4, 8.3 Hz, 1 H, H-3), 4.20 (t, J =
6.8 Hz, 1 H, CH-Fmoc), 4.34 (dt, J = 6.3, 7.8 Hz, 1 H, H-4), 4.46
and 4.50 (AB, JAB = 11.9 Hz, 2 H, CH2-Bn), 4.47 (s, 2 H, CH2-
Fmoc), 4.56 and 4.63 (AB, JAB = 12.1 Hz, 2 H, CH2-NAP), 7.20–
7.50 (m, 12 H, ArH), 7.52–7.58 (m, 2 H, ArH), 7.59 (s, 1 H, NH),
7.69–7.84 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 33.6 (C-5), 46.9 (CH-Fmoc), 51.1
(C-2), 67.5 (CH2-Fmoc), 69.7 (CH2-OBn), 71.2 (CH2-NAP), 73.2
(C-3), 76.3 (CH2-Bn), 76.5 (C-1), 90.4 (C-4), 120.0 (CH-Ar), 125.0
(CH-Ar), 125.7 (CH-Ar), 125.8 (CH-Ar), 126.1 (CH-Ar), 126.4
(CH-Ar), 127.1 (CH-Ar), 127.6 (CH-Ar), 127.6 (CH-Ar), 127.6
(CH-Ar), 127.8 (CH-Ar), 128.1 (CH-Ar), 128.4 (CH-Ar), 132.9
(Cq-NAP), 133.2 (Cq-NAP), 135.6 (Cq-NAP), 138.1 (Cq-Bn), 141.3
(Cq-Fmoc), 143.3 (Cq-Fmoc), 143.4 (Cq-Fmoc), 158.1 (C=O).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C25H25NNaO7:
474.1529; found: 474.1534.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C39H37NNaO6:
638.2519; found: 638.2529.
Allyl {(1R,2R,3S,4R,5R)-3-Hydroxy-2-(naphthalen-2-ylmeth-
oxy)-6,8-dioxabicyclo[3.2.1]octan-4-yl}oxycarbamate (8j)
The reaction was carried out according to General Procedure B with
4j (100 mg, 0.238 mmol), 2,4-dinitrophenylhydrazine (141 mg,
0.714 mmol, 3 equiv), and H2SO4 (128 μL, 2.38 mmol) in MeOH (2
mL) and THF (100 μL, added to improve the solubility of the start-
ing material) and then, with NaHCO3 (400 mg, 4.76 mmol) and Al-
locCl (126 μL, 1.19 mmol) in MeOH (8 mL). The mixture was
worked up as described and the crude product was purified by col-
umn chromatography (heptane–EtOAc, 8:2→6:4) to give 8j.
Acknowledgment
A.F. and G.M. thank the ICSN for financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Yield: 71 mg (0.177 mmol, 74%); pale-yellow solid; [α]D24 –1.1 (c
0.92, CHCl3); Rf = 0.15 (heptane–EtOAc, 3:2).
References
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IR (neat): 3381, 3217, 1714, 1507, 1258, 1099, 1076, 996, 819,
749 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.38 (d, J = 4.5 Hz, 1 H, H-4), 3.60
(dd, J = 5.7, 7.5 Hz, 1 H, H-6), 3.67–3.77 (m, 2 H, H-2, H-6), 4.00
(t, J = 4.7 Hz, 1 H, H-3), 4.54 (d, J = 5.3 Hz, 1 H, H-5), 4.59 (d, J =
5.7 Hz, 2 H, CH2-CH=CH2), 4.78 and 4.90 (AB, JAB = 12.4 Hz, 2 H,
CH2-NAP), 5.18–5.34 (m, 2 H, CH2-CH=CH2), 5.63 (s, 1 H, H-1),
5.79–5.94 (m, 1 H, CH2-CH=CH2), 7.42–7.51 (m, 3 H, ArH), 7.75–
7.84 (m, 4 H, ArH), 8.18 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 66.5 (C-6), 66.7 (CH2-CH=CH2),
69.4 (C-3), 71.9 (CH2-NAP), 75.7 (C-5), 79.5 (C-4), 86.6 (C-2),
100.1 (C-1), 118.8 (CH2-CH=CH2), 125.8 (CH-Ar), 126.0 (CH-Ar),
126.1 (CH-Ar), 126.7 (CH-Ar), 127.6 (CH-Ar), 127.8 (CH-Ar),
128.3 (CH-Ar), 131.5 (CH2-CH=CH2), 133.0 (Cq-NAP), 133.1 (Cq-
NAP), 135.2 (Cq-NAP), 158.2 (C=O).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H23NNaO7:
424.1372; found: 424.1355.
(9H-Fluoren-9-yl)methyl {(1R,2R,3R,4R)-3-[(Benzyloxy)meth-
yl]-2-hydroxy-4-(naphthalen-2-ylmethoxy)cyclopentyl}oxycar-
bamate (2a)
The reaction was carried out according to General Procedure B with
4k (37 mg, 0.075 mmol), 2,4-dinitrophenylhydrazine (30 mg, 0.150
mmol), and H2SO4 (40 μL, 0.750 mmol) in MeOH (600 μL), and
then with NaHCO3 (126 mg, 1.5 mmol) and FmocCl (97 mg, 0.375
mmol) in MeOH (2.5 mL). The mixture was worked up as described
and the crude product was purified by column chromatography
(heptane–EtOAc, 8:2→6:4) to give 2a.
Yield: 40 mg (0.065 mmol, 87%); pale-yellow foam; [α]D24 –36.6 (c
1.63, CHCl3); Rf = 0.12 (heptane–EtOAc, 3:2).
IR (neat): 3256, 3061, 2887, 2863, 1723, 1451, 1250, 1114, 1096,
1074, 755, 741 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.90–2.04 (m, 1 H, H-5), 2.07–
2.30 (m, 2 H, H-2, H-5), 3.18 (br s, 1 H, OH), 3.56 and 3.63 (ABX,
JAB = 9.3 Hz, JAX = 5.2 Hz, JBX = 6.2 Hz, 2 H, CH2-OBn), 3.80–
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 65–74

74
G. Malik et al.
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(11) (a) Soltani Rad, M. N.; Behrouz, S.; Dianat, M. Synthesis
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20080528, 2008; Chem. Abstr. 2008, 632048.
(12) Huber, J. E.; Raushel, J. Epichlorohydrin, In Encyclopedia
of Reagents for Organic Synthesis [Online]; John Wiley &
Sons Ltd.: New York, 2011,
www.mrw.interscience.wiley.com/eros/.
DOI: 10.1002/047084289X.re005.pub2.
Synthesis 2013, 45, 65–74
© Georg Thieme Verlag Stuttgart · New York