Efficient cleavage of the N-O bond of 3,6-dihydro-1,2-oxazines mediated by some α-hetero substituted carbonyl compounds in mild conditions

Article abstract of DOI:10.1039/b718787d

The efficient cleavage of the N-O bond of some nitroso Diels-Alder cycloadducts has been achieved in mild conditions, mediated either by 2,2-dimethyl-1,3-dioxan-5-one or 1,3-dithiolane-2-carboxaldehyde. These new and purely organic conditions allow an exc

Full text of DOI:10.1039/b718787d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Efficient cleavage of the N–O bond of 3,6-dihydro-1,2-oxazines mediated by
some a-hetero substituted carbonyl compounds in mild conditions†
Gilles Galvani,a Ge´raldine Calvet,a Nicolas Blanchard*b and Cyrille Kouklovsky*a
Received 5th December 2007, Accepted 21st January 2008
First published as an Advance Article on the web 12th February 2008
DOI: 10.1039/b718787d
The efficient cleavage of the N–O bond of some nitroso Diels–Alder cycloadducts has been achieved in
mild conditions, mediated either by 2,2-dimethyl-1,3-dioxan-5-one or 1,3-dithiolane-2-carboxaldehyde.
These new and purely organic conditions allow an excellent tolerance with respect to many functional
groups that would have been affected by previous reductive cleavage conditions.
Introduction
3,6-Dihydro-1,2-oxazines are valuable synthetic intermediates that
have found applications in numerous total syntheses of biologically
relevant targets due to the regio- and stereoselectivity of the nitroso
Diels–Alder reaction. Thus the cycloadduct may be used as a
temporary protection of the functionalities then created and be
further deprotected or transformed selectively in the synthesis,
via most usually the reductive cleavage of the N–O bond of
the six-membered heterocycle.1 The numerous methods that have
been developed for the cleavage of the N–O bond can be listed
under three different types: (a) radical-mediated,2 (b) anionic-
mediated (with3 or without4 quaternarization reaction of the
nitrogen atom) and (c) metal-mediated. The latter class includes
the majority of the reduction conditions, based on sodium or
aluminium amalgam,5 zinc in acetic acid,6 LiAlH4,7 molybdenum8
or samarium9 complexes, indium10 and catalytic hydrogenation
over Pd/C, Pd(OH)2, PtO2 or Raney Ni.11 Some of the previous
methods require harsh reaction conditions (such as strongly acidic
medium at elevated temperature)6 or lead to undesired side-
reactions and/or rearrangements.12 On the other hand, some
reductive methods do not allow the selective N–O bond cleavage
in the presence of other reducible functional groups.
Scheme 1 Tandem [4 + 2] cycloaddition/N–O bond cleavage.13
During the course of our studies concerning the recently
developed nitroso Diels–Alder dienophile 1, we observed an
unexpected N–O bond cleavage of the cycloadduct, which afforded
the 1,4-cis aminoalcohols 5 in good yields (Scheme 1).13 The
broad synthetic interest of the obtained 1,4-cis aminoalcohols
5 combined with the mild reaction conditions led us to further
investigate the direct conversion observed with the cycloaddition
conditions. Actually, we wondered whether the condensation of a
carbonyl derivative bearing a heteroatom in the a position such as
6 (Scheme 2) with a cyclic hydroxylamine derivative like 7 might
Scheme 2 Proposed organic N–O r bond heterolysis.
produce such a heterolytic N–O bond cleavage via the iminium–
enamine equilibrium observed in our previous studies.13
Such a carbonyl derivative would selectively react with the
nucleophilic nitrogen of the dihydro-1,2-oxazine and should
therefore be inert towards other reducible functional groups, such
as nitro or benzyloxy moieties.
For such an analogous reaction mediated only by a non-
reductive organic compound, we are only aware of the previous
N–O bond cleavage mediated by nitrosobenzene during a tandem
aminoxylation/O–N bond heterolysis observed by Barbas and
Ramachary.14
aLaboratoire de Proce´de´s et Substances Naturelles, ICMMO-UMR 8182,
Baˆtiment 410-Universite´ Paris-Sud XI, 15 rue Georges Cle´menceau,
91405, Orsay Cedex, France. E-mail: cykouklo@icmo.u-psud.fr; Fax: 33
169154679; Tel: 33 169157391
bLaboratoire de Chimie Organique, ENSCMu-UMR 7015, 3 rue A. Werner,
68093, Mulhouse Cedex, France, nicolas.blanchard@uha.fr; Fax: 33
389336860; Tel: 33 389336824
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra. See DOI: 10.1039/b718787d
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Table 1 N–O r bond heterolysis of dihydrooxazines with ketone 9a
Entry
Reactant
Solvent
Temp/◦C
Time/h
Promoter
10 : 11b
Yield (%)c
1
7
7
7
7
8
8
8
Tol.
Tol.
Tol.
DCE
i-PrOH
i-PrOH
i-PrOH
20
45
45
85
20
40
30
14
22
22
22
14
19
8
—
0 : 100
100 : 0
0 : 100
33 : 67
20 : 80
40 : 60
71 : 29
95
44
62
55
100
79
2
PPTS
PPTS
LiOAc
—
—
—
3d
4
5
6
7e
76
a Reaction conditions: dihydrooxazine 7 or 8, ketone 9 (1 equivalent) under the conditions of solvent (0.15 M) and time specified in the Table. Hydrolysis
with 1 N aqueous HCl followed by protection with Boc2O in aqueous NaOH. b Determined by 1H NMR analysis of the crude reaction mixture. c Isolated
combined yield. d In the absence of ketone 9. e 10 equivalents of ketone 9 were used.
In the present article, we wish to report our results concerning
the efficient and general N–O bond cleavage of nitroso Diels–
Alder cycloadducts mediated by some specific carbonyl deriva-
tives such as 2,2-dimethyl-1,3-dioxan-5-one or 1,3-dithiolane-2-
carboxaldehyde in mild conditions. We have shown that these
conditions allow selective cleavage in the presence of some other
functional groups in contrast to other previous reductive methods.
LiOAc in 1,2-dichloroethane at 85 ◦C increased only moderately
the conversion (Table 1, entry 4).
The limited stability of 3,6-dihydro-1,2-oxazine 7 under this
set of conditions and the poor solubility of PPTS in toluene
prompted us to examine other reaction conditions. Taking these
considerations into account, 3,6-dihydro-1,2-oxazinium chloride
8 might have the advantage of catalyzing the formation of the
desired iminium 2, immediate precursor of the postulated key
intermediate 3 for cleavage (Scheme 1). When 3,6-dihydro-1,2-
oxazinium chloride 8 was reacted with one equivalent of ketone
9 in iPrOH at 20 ◦C for 14h, a 10 : 11 ratio of 20 : 80 was
obtained in quantitative yield after protection (Table 1, entry
5). Increasing the temperature to 40 ◦C for 19 h led to a 10 :
11 ratio of 40 : 60 (Table 1, entry 6). TLC monitoring of the
reaction mixture showed that ketone 9 was rapidly disappearing
presumably due to some hydrolysis of the ketal, even when 9 was
used in large excess (Table 1, entry 7, 10 : 11 = 71 : 29, 76%). Such
competitive ketal deprotection could not be avoided under the
preceding acidic conditions, therefore requiring an a-heteroatom
substituted carbonyl derivative, which should be stable in the
reaction conditions, in order to optimize the desired cleavage.
Results and discussion
N–O r bond cleavage mediated by 2,2-dimethyl-1,3-dioxan-5-one 9
For the first experiments, commercially available ketone 9 derived
from 1,3-dihydroxyacetone and 3,6-dihydro-1,2-oxazine 7 was
selected, and a variety of reaction conditions were screened
(Table 1).‡
In the absence of promoters, no reaction occurred at 20 ◦C
and thus, after NBOC protection for analysis and further product
isolation, 11 was obtained in 95% yield (entry 1). A slight increase
of the temperature to 45 ◦C and the addition of one equivalent
of pyridinium para-toluenesulfonate led, after NBOC protection
for chromatographic isolation, to an encouraging 44% yield of
the hydroxycarbamate 10 (Table 1, entry 2). Although this yield
was still moderate, this result clearly showed that the desired
N–O bond cleavage might be achieved, mediated by a suitable
ketone such as 9 in a pure organic medium, requiring no added
reducing agent. In the absence of ketone 9, after NBOC protection,
11 was isolated only in 62% yield, indicating that substantial
decomposition occurred under this set of conditions (Table 1,
entry 3). Switching from the Br␾nsted acid PPTS to the Lewis acid
N–O r bond cleavage mediated by 1,3-dithiolane-2-
carboxaldehyde 12
1,3-Dithiolane-2-carboxaldehyde 12 was selected as reactant, due
to its stability in the acidic conditions used previously and to its
greater electrophilicity compared to ketone 9. Aldehyde 12 was
conveniently prepared on a multigram scale by DIBAH reduction
of commercially available ethyl 1,3-dithiolane-2-carboxylate.15
When 3,6-dihydro-1,2-oxazinium chloride 8 was reacted with
one equivalent of aldehyde 12 in i-PrOH (0.15 M) at 30 ◦C for
4.5 h, a 10 : 11 ratio of 77 : 23 was obtained (Table 2, entry 1).
The best yield was then obtained with 1.5 equivalents of aldehyde
12 (0.15 M) in iPrOH, at 40 ◦C for 30 h (97% conversion), or
more conveniently at 50 ◦C after 4.5 h (86% isolated yield, Table 3,
entry 4).
‡ Simpler carbonyl derivatives (including commercially available dihydrox-
yacetone dimer and [1,3]-dithiane-2-carbaldehyde prepared according to
P. C. Bulman Page, A. P. Marchington, L. J. Graham, S. A. Harkin and
W. W. Wood, Tetrahedron, 1993, 49, 10369) were also evaluated in these
studies. Inferior results and/or complex mixtures were obtained.
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Table 2 N–O r bond heterolysis of dihydrooxazines with aldehyde 12a
good to excellent yield, without metal contamination, inherent to
classical reducing methods. The scope of this purely organic N–O
bond cleavage has been studied and the only current limitation
appeared to be dihydrooxazinium chlorides bearing electron-rich
aromatic rings as substituents in the 6-position of 3,6-dihydro-1,2-
oxazinium hydrochlorides. This new method of cleavage should
be compatible with many functional groups that tolerate the
moderately acidic conditions described. This method should also
be of interest for the selective cleavage of the N–O bond of
tetrahydro-1,2-oxazines, which are more difficult to achieve for
example by Al(Hg), Na(Hg) or even samarium iodide. We are
currently exploring the scope of this organomediated N–O bond
cleavage for acyclic N–O as well as N–N r bonds in general.
Entry
Temp/◦C
Time/h
10 : 11b
Yield (%)c
1d
2
3
30
30
40
50
4.5
20
30
77 : 23
89 : 11
97 : 3
65
94
94
86
4
4.5
98 : 2
a Reaction conditions: dihydrooxazinium chloride 8, aldehyde 12 (1.5
equivalents) in i-PrOH (0.15 M). Hydrolysis with 1 N aqueous HCl
followed by protection with Boc2O in aqueous NaOH. b Determined by
1H NMR and/or GC analysis of the crude reaction mixture. c GC yield
calibrated versus an internal standard (butylphthalate). d 1 equivalent of
aldehyde 12 was used.
Experimental
General experimental
All reactions were conducted in flame-dried or oven-dried glass-
ware under an atmosphere of dry nitrogen. All solvents were pu-
rified before use unless otherwise indicated. Tetrahydrofuran, di-
ethyl ether and toluene were distilled over sodium–benzophenone
ketyl anion under argon. Dichloromethane was distilled over
CaH2 under argon. All other reagents were purchased and used
without further purification. Solvent removal was performed at
reduced pressure using a rotary evaporator with water aspiration.
Analytical thin layer chromatography (TLC) was performed on
glass plates precoated with a 0.25 mm thickness of Kieselgel 60
F254. The TLC plates were visualized by shortwave UV light,
potassium permanganate, p-anisaldehyde or ceric ammonium
molybdate stain. Flash chromatography was performed according
to the method of Still on Kieselgel 60 (230–400 mesh) silica
gel. Infrared spectra were recorded as thin films on NaCl plates
using a Perkin–Elmer Spectrum One FT-IR spectrophotometer.
1H NMR spectra were measured at 300 MHz on Bruker Advance
300. Melting points were recorded on a Bu¨chi 510 melting point
apparatus. Chemical shifts are reported in d units to 0.01 ppm
precision, with coupling constants reported in Hertz to 0.1 Hz
precision using residual chloroform (d 7.27 ppm) as an internal
reference. Multiplicities are reported as follows: s = singlet, d =
doublet, t = triplet, q = quartet, p = pentet, m = multiplet, bs =
broad singlet. 13C NMR spectra were measured at 75 MHz using
CDCl3 (d 77.0 ppm) as an internal reference. Mass spectra were
performed at the Institut de Chimie des Substances Naturelles
(ICSN, CNRS, Gif sur Yvette, France). Compounds 7,19 8,20 1215
and 1321 were prepared according to literature procedures. The
spectroscopic data of compounds 10, 11 and 14 obtained in these
studies were identical to those reported in the literature.13
Scope of the N–O r bond cleavage mediated by
1,3-dithiolane-2-carboxaldehyde 12
We next examined the scope of this new cleavage of the N–O bond
of dihydrooxazinium hydrochlorides, mediated by the aldehyde 12
(Table 3).
Under the previously defined optimal conditions, 1,2-oxazinium
chloride 13 led to the corresponding 1,4-cis-aminoalcohol 14 in
an excellent 88% yield for two steps (Table 3, entry 1). Aromatic
substituents in the 6-position of the 1,2-oxazinium chloride allow
a clean and efficient cleavage as long as the aromatic ring is not too
electron-rich. Actually, 1,2-oxazinium chloride 15 led to a complex
mixture under our standard N–O bond cleavage conditions
(Table 3, entry 2), and extensive attempts to try to optimize
the formation of the desired cleavage product were unsuccessful.
On the other hand, 1,2-oxazinium chloride 17 bearing a meta-
bromo aryl substituent underwent a smooth N–O bond cleavage,
affording after NBOC protection, the desired hydroxycarbamate
in 77% isolated yield (Table 3, entry 3). It is worth noting that such
a C–Br bond would not be compatible with some of the previously
reported N–O bond reductive cleavage, such as some catalytic
hydrogenations, or sodium amalgam for example.16 Another
functional group incompatible with the classical conditions is
the nitro group. The latter is readily reduced by LiAlH4, Zn–
AcOH or under catalytic hydrogenation conditions.17 Only a few
examples of N–O r bond reduction in the presence of a nitro
group are known.18 In contrast, when 1,2-oxazinium chloride 19
bearing a para-nitro phenyl substituent was treated with [1,3]-
dithiolane-2-carbaldehyde 12 for 2.5 h at 50 ◦C, a clean N–O bond
scission occurred, leading after NBOC protection, to the desired
hydroxycarbamate 20 in 76% isolated yield (Table 3, entry 4).
(2E,4E)-5-(4-Benzyloxy-3-methoxy-phenyl)-penta-2,4-dienoic
acid ethyl ester (22)
To
a
solution of triethyl phosphonocrotonate22 (5.0 mL,
Conclusions
22.6 mmol) and 3-methoxy-4-benzyloxy benzaldehyde 21 (5.47 g,
We have shown that some carbonyl compounds having an a-hetero
substituent, such as 2,2-dimethyl-1,3-dioxan-5-one or preferably
1,3-dithiolan-2-carboxaldehyde, react with 1,2-oxazinium salts to
achieve efficiently in mild conditions the cleavage of the N–O
bond. The corresponding 1,4-cis aminoalcohols were isolated in
22.6 mmol) in THF (38 mL) was added molecular sieves (powdered
˚
4 A, 6.0 g) and LiOH·H2O (1.0 g, 23.7 mmol) under vigorous
◦
stirring. The suspension was warmed at 45 C for 3 h, cooled to
room temperature, filtered on a Bu¨chner funnel and the filtrate was
diluted with water. The aqueous phase was extracted with EtOAc
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Table 3 Scope of the N–O r bond heterolysis of dihydrooxazinesa
Entry
1
Oxazinium chloride
Time/h
4.5
Product
Yield (%) b
88
13
14
16
2
15
2–24
—
3
17
2.5
18
77
4
19
2.5
20
76
a Reaction conditions: dihydrooxazinium chloride, aldehyde 12 (1.5 equivalents except for entry 4, 1.4 equivalents) in i-PrOH (0.15 M, except for entry 4,
0.05 M) at 50 ◦C. Hydrolysis with 1 N aqueous HCl followed by protection with Boc2O in aqueous NaOH. b Isolated yield.
and the combined organic phases were dried over magnesium
sulfate, filtered and concentrated. The residue was purified by flash
chromatography on silica gel (cyclohexane–ethyl acetate = 90 : 10
to 80 : 20) to give 6.67 g (87%) of compound 22 as a thick yellow
oil that slowly crystallised.
1-Benzyloxy-4-((1E,3E)-5-benzyloxy-penta-1,3-dienyl)-2-
methoxy-benzene (23)
To a solution of ester 22 (6.66 g, 19.7 mmol) in CH2Cl2 (100 mL) at
0 ◦C was added DIBAL (1.5 M in toluene, 29.0 mL, 43.3 mmol).
The solution was slowly warmed to room temperature over 1 h
and transferred carefully to a saturated aqueous solution of
potassium and sodium tartrate (100 mL) via canula. Diethyl ether
(200 mL) was added and vigorous stirring was continued until both
phases were clear. The aqueous phase was extracted with EtOAc
and the combined organic phases were dried over magnesium
sulfate, filtered and concentrated. The residue was purified by
flash chromatography on silica gel (cyclohexane–ethyl acetate =
80 : 20 to 60 : 40) to give 5.26 g (79%, 2 steps) of the desired
alcohol as a white solid (mp: 86 ◦C, LRMS (ES): m/z (%) =
319.1 ([M + Na]+, 100), 267.1 (43), 320.1 (7), 228.1 (3); HRMS
Mp: 77 ◦C. 1H NMR (300 MHz, CDCl3), d (ppm): 7.46–
=
=
7.39 (6 H, Ph + CH CH); 7.04–6.80 (5 H, Ar + CH CH);
=
5.97 (1 H, d, J 15.3, CH CH); 5.20 (2 H, s, OCH2Ph), 4.25
(2 H, q, J 7.2, OCH2CH3); 3.95 (3 H, s, OCH3); 1.33 (3 H, t,
J 7.2 Hz, OCH2CH3). 13C NMR (75 MHz, CDCl3), d (ppm):
167.2 (CO), 149.7 (Ar. Quat.), 149.1 (Ar. Quat.), 144.8, 140.3,
136.7 (Ar. Quat.), 129.5, 128.6, 127.9, 127.2, 124.4, 121.0, 120.2,
113.5, 109.5, 70.8 (PhCH2O), 60.3 (CH3CH2OCO), 56.0 (OCH3),
14.3 (CH3CH2OCO). LRMS (ES): m/z (%) = 361.1 ([M + Na]+,
100), 436.1 (34). HRMS (ES, Na+): calculated for C21H22O4Na
[M + Na]+: 361.1416, found: 361.1428.
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(ES, Na+): calculated for C19H20O3Na [M + Na]+: 319.1310, found:
319.1306).
28.2 (OCMe3). LRMS (ES): m/z (%) = 540.2 ([M + Na]+, 100),
484.2 (90), 485.2 (13), 440.2 (18). HRMS (ES, Na+): calculated for
C31H35NO6Na [M + Na]+: 540.2386, found: 540.2362.
The latter compound (4.50 g, 15.18 mmol) was dissolved
in DMF (15 mL) and cooled to 0 ◦C. NaH (purum, 0.47 g,
19.7 mmol) was then added. After 10 min, BnBr (2.0 mL,
16.7 mmol) was added dropwise and the reaction mixture was
warmed to room temperature. After 12 h, the solution was
hydrolyzed with water (70 mL) and the aqueous phase was
extracted with a cyclohexane–CH2Cl2 solution (90 : 10, 3 ×
60 mL). The combined organic phases were dried over magnesium
sulfate, filtered and concentrated. The residue was purified by flash
chromatography on silica gel (cyclohexane–ethyl acetate = 95 : 5)
to give 4.04 g (69%) of compound 23 as a pale yellow oil that
slowly crystallized to white crystals.
(3R,6S)-6-(4-Benzyloxy-3-methoxy-phenyl)-3-benzyloxy-methyl-
3,6-dihydro-2H-[1,2]oxazin-2-ium chloride (15)
To a solution of dihydrooxazine 24 (0.30 g, 0.58 mmol) in dioxane
(1 mL) at 0 ◦C was added HCl (4 N in dioxane, 0.58 mL,
2.32 mmol). White crystals precipitated after 1 h at 0 ◦C. After
filtration, the solids were washed with pentane and dried under
high vacuum to give 0.178 g (68%) of the desired 15 as white
crystals.
Mp: 143 ◦C (decomp.). 1H NMR (300 MHz, CD3OD), d (ppm):
7.47–7.30 (10 H, 2 × Ph); 7.01 (1 H, d, J 8.1, Ar.); 6.94–6.88 (2
◦
1
Mp: 43 C. H NMR (300 MHz, CDCl3), d (ppm): 7.50–7.30
(10 H, 2 × Ph); 7.01 (1 H, d, J 1.7, H Ar); 6.90 (1 H, dd, J 1.7
and 8.2, H Ar); 6.84 (1 H, d, J 8.2, H Ar); 6.70 (1 H, dd, J 10.5
=
H, Ar.); 6.23 (1 H, br. dt, J 1.3 and 10.8, OCH–CH CH–CHN);
=
6.13 (1 H, ddd, J 1.9, 4.3 and 10.8, OCH–CH CH–CHN); 5.81 (1
=
=
H, br. d, J 1.7, OCH–CH CH–CHN or OCH–CH CH–CHN);
5.15 (2 H, s, ArOCH2Ph); 4.67 (2 H, s, CH2OCH2Ph); 4.33 (1 H, m,
=
=
and 15.2, Ar–CH CH–CH CH–CH2); 6.52 (1 H, d, J 15.2, Ar–
=
=
=
=
CH CH–CH CH–CH2); 6.42 (1 H, m, Ar–CH CH–CH CH–
=
=
OCH–CH CH–CHN or OCH–CH CH–CHN); 3.83–3.79 (5 H
including 3.80 (3 H, s, OCH3), CH2OCH2Ph). 13C NMR (75 MHz,
CD3OD), d (ppm): 151.2 (Ar. Quat.), 150.9 (Ar. Quat.), 138.6 (Ar.
Quat.), 138.3 (Ar. Quat.), 130.4, 129.5, 129.2, 129.1, 129.0, 128.6,
122.8, 120.8 (Ar.), 115.1 (Ar.), 113.5 (Ar.), 81.6 (OCMe3), 74.4
(OCHPh), 71.8 (OCH2Ph), 67.5 (OCH2Ph), 56.6 (CH2OCH2Ph
or CH3O), 55.8 (CH2OCH2Ph or CH3O). LRMS (ES): m/z (%) =
440.1 ([M − Cl + Na]+, 100), 418.2 (28), 409.2 (22). HRMS (ES,
Na+): calculated for C26H28NO4Na [M − Cl + Na]+: 441.1916,
found: 441.1903.
=
=
CH2); 5.92 (1 H, dt, J 6.1 and 15.2, Ar–CH CH–CH CH–CH2);
5.19 (2 H, s, CH2OCH2Ph); 4.57 (2 H, s, ArOCH2Ph); 4.14 (2 H,
d, J 6.1, Ar–CH CH–CH CH–CH2); 3.94 (3 H, s, OCH3). 13C
NMR (75 MHz, CDCl3), d (ppm): 149.6 (Ar. Quat.), 148.0 (Ar.
Quat.), 138.2 (Ar. Quat.), 137.0, 133.2, 132.5 (Ar. Quat.), 130.7,
129.1, 128.5, 128.4, 127.8, 127.75, 127.6, 127.2, 126.6, 119.6 (Ar),
113.8 (Ar), 109.1 (Ar), 72.0 (CH2O), 70.9 (CH2O), 70.5 (CH2O),
55.9 (OCH3). LRMS (ES): m/z (%) = 459.2 (40), 443.2 (24), 425.2
(45), 358.2 (14), 357.1 (100).
=
=
(3R,6S)-6-(4-Benzyloxy-3-methoxy-phenyl)-3-benzyloxymethyl-
3,6-dihydro-[1,2]oxazine-2-carboxylic acid tert-butyl ester (24)
(2E,4E)-5-(3-Bromo-phenyl)-penta-2,4-dienoic acid ethyl ester
(26)
To a solution of 1,3-diene 23 (2.27 g, 5.80 mmol) and tert-butyl-
N-hydroxycarbamate20 (0.78 g, 5.80 mmol) in CH2Cl2 (15 mL) at
To a suspension of 3-ethoxycarbonylallylidenetriphenyl-arsonium
bromide23 (2.0 g, 4 mmol) in THF (10 mL) was added n-BuLi
(2.5 M in hexanes, 1.6 mL, 4 mmol) dropwise at 0 ◦C. The
red solution was stirred for 30 min at that temperature. 3-
Bromobenzaldehyde (0.23 mL, 2 mmol) was then added and the
reaction mixture was stirred for 1 h at 0 ◦C and 1 h at room
temperature before being quenched with a saturated aqueous
solution of NH4Cl. The aqueous phase was extracted with EtOAc
and the combined organic phases were dried over magnesium
sulfate, filtered and concentrated. The residue was purified by flash
chromatography on silica gel (cyclohexane–ethyl acetate = 90 : 10)
to give 339 mg (60%) of compound 26 as a slightly yellow oil.
1H NMR (300 MHz, CDCl3), d (ppm): 7.62 (1 H, t, J 1.7,
H Ar.); 7.47–7.37 (2 H, Ar.); 7.28–7.21 (2 H); 6.92–6.78 (2 H,
0
◦C was added Bu4NIO4 (2.51 g, 5.8 mmol) portionwise over
◦
30 min. After 1 h 30 min at 0 C, additional BocNHOH (0.2 g,
1.50 mmol) and Bu4NIO4 (0.4 g, 0.92 mmol) were added. The
reaction mixture was then hydrolyzed with water and the aqueous
phase was extracted with EtOAc. The combined organic phases
were washed with a 10% aqueous Na2S2O3 solution, dried over
magnesium sulfate, filtered and concentrated. The residue was
purified by flash chromatography on silica gel (cyclohexane–ethyl
acetate = 95 : 5 to 90 : 10) to give 2.15 g (71%) of compound 24
as a yellow oil that crystallized slowly to white crystals. 372 mg of
1,3-diene 23 (16%) were also recovered.
Mp: 97 ◦C. 1H NMR (300 MHz, CDCl3), d (ppm): 7.46–7.28 (10
H, 2 × Ph); 6.93 (1 H, s, Ar.); 6.87 (2 H, s, Ar.); 6.10 (1 H, ddd, J
=
=
=
Ar–CH CH–CH CH–CO); 6.04 (1 H, d, J 15.3, Ar–CH CH–
=
2.2, 4.3 and 10.3, OCH–CH CH–CHN); 5.99 (1 H, br. d., J 10.3,
=
CH CH–CO); 4.25 (2 H, q, J 7.2, OCH2CH3); 1.33 (3 H, t, J 6.9,
=
=
OCH–CH CH–CHN); 5.50 (1 H, br. s, OCH–CH CH–CHN
OCH2CH3). 13C NMR (75 MHz, CDCl3), d (ppm): 166.9 (CO),
143.8, 138.4, 138.1, 131.7, 130.3, 129.8, 127.6, 125.8, 122.4, 60.5
(OCH2CH3), 14.3 (OCH2CH3). LRMS (ES): m/z (%) = 598.0
(14), 473.0 (14), 438.2 (19), 416 (19), 237 (100).
=
or OCH–CH CH–CHN); 5.19 (2 H, s, CH2OCH2Ph); 4.76 (1 H,
=
=
br. s., OCH–CH CH–CHN or OCH–CH CH–CHN); 4.65 (1
H, d, J 12.0, ArOCH2Ph); 4.60 (1 H, d, J 12.0, ArOCH2Ph); 3.87 (3
H, s, OCH3); 3.84 (1 H, dd J 7.2 and 9.7, CH2OCH2Ph); 3.71 (1 H,
dd J 6.2 and 9.7, CH2OCH2Ph); 1.55 (9 H, s, OC(CH3)3). 13C NMR
(75 MHz, CDCl3), d (ppm): 154.4 (Ar. Quat.), 149.5 (Ar. Quat.),
148.5 (Ar. Quat.), 138.0 (Ar. Quat.), 136.8 (Ar. Quat.), 129.9, 128.8,
128.4, 128.2, 127.7, 127.4, 127.0, 124.7, 120.8 (Ar.), 113.5 (Ar.),
111.8 (Ar.), 81.5 (OCMe3), 78.3 (OCHPh), 73.1 (OCH2Ph), 70.8
(OCH2Ph), 70.5 (CH2OCH2Ph), 55.8 (CH3O), 53.7 (br, CHN),
1-((1E,3E)-5-Benzyloxy-penta-1,3-dienyl)-3-bromo-benzene (27)
To a solution of ester 26 (0.275 g, 0.98 mmol) in CH2Cl2 (4.9 mL) at
0 ◦C was added DIBAL (1.5 M in toluene, 1.57 mL, 2.35 mmol).
The solution was slowly warmed to room temperature over 1 h
and transferred carefully to a saturated aqueous solution of
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◦
potassium and sodium tartrate via canula. Diethyl ether (30 mL)
was added and vigorous stirring was continued until both phases
were clear. The aqueous phase was extracted with EtOAc and
the combined organic phases were dried over magnesium sulfate,
filtered and concentrated to give a colorless oil that was used
without purification in the next step. The residue was dissolved in
DMF (4.9 mL) and cooled to 0 ◦C. NaH (purum, 47 mg, 2 mmol)
was then added. After 10 min, BnBr (0.175 mL, 1.47 mmol)
was added dropwise and the reaction mixture was warmed to
room temperature. After 12 h, the solution was hydrolyzed with
water (10 mL) and the aqueous phase was extracted with a
cyclohexane–CH2Cl2 solution (90 : 10, 3 × 30 mL). The combined
organic phases were dried over magnesium sulfate, filtered and
concentrated. The residue was purified by flash chromatography
on silica gel (cyclohexane–ethyl acetate = 99 : 1 to 95 : 5) to give
223 mg (69%, 2 steps) of compound 27 as a colorless oil.
White crystals precipitated after 1 h at 0 C. After filtration, the
solids were washed with pentane and dried under high vacuum to
give 0.234 g (79%) of the desired 17 as white crystals.
Mp: >160 ◦C (decomp.). 1H NMR (300 MHz, CD3OD),
d (ppm): 7.65–7.57 (2 H, Ar.); 7.44–7.32 (7 H, Ar. + Ph);
6.24 (1 H, dt, J 1.4 and 10.7, OCH–CH CH–CHN); 6.16 (1
H, ddd, J 1.9, 4.3 and 10.7, OCH–CH CH–CHN); 5.88 (1
H, br. s, OCH–CH CH–CHN or OCH–CH CH–CHN); 4.66
=
=
=
=
=
(2 H, s, PhCH2O); 4.35 (1 H, m, OCH–CH CH–CHN or
OCH–CH CH–CHN); 3.88–3.77 (2 H, CHN–CH2O). 13C NMR
=
(75 MHz, CD3OD), d (ppm): 138.4 (Ar. Quat.), 134.2, 132.4, 131.9,
129.7, 129.6, 129.2, 129.1, 128.4, 123.7, 122.6 (Ar. Quat.), 121.2,
80.8 (CHOAr), 74.4 (PhCH2OCH2), 67.4 (PhCH2OCH2), 55.8
(CHN). LRMS (ES): m/z (%) = 385.0 (13), 384.0 (92), 382.0
([M − HCl + Na]+, 100), 362.1 (8), 360.2 (8), 353.0 (12), 351.0
(12). HRMS (ES, Na+): calculated for C18H18BrNO2Na [M −
HCl + Na]+: 382.0419, found: 382.0430.
1H NMR (300 MHz, CDCl3), d (ppm): 7.55 (1 H, t, J 1.9, Ar.);
7.42–7.30 (7 H, Ph + Ar.); 7.19 (1 H, t, J 7.8, Ar.); 6.80 (1 H, dd,
=
=
J 10.0 and 15.0, Ar–CH CH–CH CH–CH2O); 6.51–6.40 (2 H,
[(Z)-(1R*,4S*)-1-Benzyloxymethyl-4-(3-bromo-phenyl)-4-
hydroxy-but-2-enyl]-carbamic acid tert-butyl ester (18)
=
=
Ar–CH CH–CH CH–CH2O); 5.97 (1 H, dt, J 6.2 and 15.0, Ar–
=
=
CH CH–CH CH–CH2O); 4.57 (2 H, OCH2Ph); 4.14 (2 H, d, J
6.2, CH2OCH2Ph). 13C NMR (75 MHz, CDCl3), d (ppm): 132.3,
131.3, 130.9, 130.3, 130.1, 129.6, 129.1, 128.4, 127.8, 127.7, 125.0,
122.8, 122.0, 72.2 (CH2OCH2Ph), 70.2 (CH2OCH2Ph). LRMS
(ES): m/z (%) = 459.3, 441.3, 425.3, 385.2, 357.3, 331.3.
To a suspension of dihydrooxazinium chloride 17 (59 mg,
0.15 mmol) in i-PrOH (1 mL) was added [1,3]-dithiolane-2-
carbaldehyde3 (30 mg, 0.22 mmol) via a syringe. The reaction
mixture became homogeneous at 30–35 ◦C and was stirred at 50 ◦C
for 2 h 30 min. The solution was then cooled to room temperature
and hydrolyzed with aqueous HCl (1 N, 0.5 mL). After 15 min,
aqueous NaOH (3 N) was added dropwise until pH > 10 and
a solution of Boc2O (65 mg, 0.3 mmol) in THF (2 mL) was then
added. The reaction mixture was stirred 12 h at room temperature,
diluted with water and extracted with diethyl ether. The combined
organic phases were dried over magnesium sulfate, filtered and
concentrated. The residue was purified by flash chromatography
on silica gel (cyclohexane–ethyl acetate = 70 : 30 to 50 : 50) to give
53 mg (77%) of compound 18 as a white solid.
(3R*,6S*)-3-Benzyloxymethyl-6-(3-bromo-phenyl)-3,6-dihydro-
[1,2]oxazine-2-carboxylic acid tert-butyl ester (28)
To a solution of 1,3-diene 27 (0.22 g, 0.67 mmol) and tert-butyl-
N-hydroxycarbamate20 (0.13 g, 1.0 mmol) in CH2Cl2 (3.4 mL) at
0
◦C was added Bu4NIO4 (0.29 g, 0.67 mmol) portionwise over
30 min. After 2 h at 0 ◦C, additional Bu4NIO4 (0.29 g, 0.67 mmol)
was added portionwise over 30 min. The reaction mixture was
then hydrolyzed with a saturated aqueous solution of NH4Cl and
the aqueous phase was extracted with EtOAc. The combined
organic phases were dried over magnesium sulfate, filtered and
concentrated. The residue was purified by flash chromatography
on silica gel (cyclohexane–ethyl acetate = 90 : 10) to give 515 mg
(61%) of compound 28 as a colorless oil.
Mp: 52–53 ◦C. 1H NMR (300 MHz, CDCl3), d (ppm): 7.58 (1
H, br. s, Ar.); 7.43–7.19 (8 H, Ph + Ar.); 5.75 (1 H, dd, J 8.6 and
=
=
10.7, OCH–CH CH–CHN); 5.67–5.58 (2 H, OCH–CH CH–
CHN + NH/OH); 5.28 (1 H, br. d, J 6.4, CHO); 4.80–4.70 (2 H,
CHN + NH/OH); 4.60 (1 H, d, J 11.9, OCH2Ph); 4.55 (1 H, d, J
11.9, OCH2Ph); 3.66 (1 H, dd, J 3.8 and 9.3, CH2OCH2Ph); 3.54
(1 H, dd, J 4.5 and 9.3, CH2OCH2Ph); 1.47 (9 H, s, OC(CH3)3).
13C NMR (75 MHz, CDCl3), d (ppm): 156.0 (CO), 145.3 (Ar.
Quat.), 137.4 (Ar. Quat.), 134.8, 130.1, 129.8, 129.0, 128.8, 128.5,
128.0, 127.7, 124.5, 122.4 (Ar. Quat.), 80.5 (OC(CH3)3), 73.4
(CHO), 71.2 (PhCH2OCH2), 67.4 (PhCH2OCH2), 47.6 (CHN),
28.3 (OC(CH3)3). LRMS (ES): m/z (%) = 487.1 (10), 486.1
(98), 484.1 ([M + Na]+, 100), 428.0 (18), 384.1 (13). HRMS (ES,
Na+): calculated for C23H28BrNO4Na [M + Na]+: 484.1099, found:
484.1082
1H NMR (300 MHz, CDCl3), d (ppm): 7.52–7.47 (2 H, Ar.);
7.37–7.21 (7 H, Ar. + Ph); 6.10 (1 H, ddd, J 2.4, 4.5 and 10.5, OCH–
CH CH–CHN); 5.93 (1 H, dt, J 1.4 and 10.5, OCH–CH CH–
CHN); 5.50 (1 H, br. s, OCH–CH CH–CHN); 4.72 (1 H, br. s,
OCH–CH CH–CHN); 4.64 (1 H, d, J 11.9, PhCH2OCH2); 4.59
(1 H, d, J 11.9, PhCH2OCH2); 3.82 (1 H, dd, J 7.2 and 9.8,
PhCH2OCH2); 3.69 (1 H, dd, J 6.2 and 9.8, PhCH2OCH2); 1.53
(9 H, s, OC(CH3)3). 13C NMR (75 MHz, CDCl3), d (ppm): 154.4
(CO), 139.2 (Ar. Quat.), 138.0 (Ar. Quat.), 132.0, 131.1, 130.2,
128.3, 127.6, 126.8, 125.2, 122.6 (Ar. Quat.), 81.9 (OC(CH3)3),
77.8 (CHO), 73.2 (PhCH2O), 70.5 (HN–CH2O), 53.7 (CHN),
28.3 (OC(CH3)3). LRMS (ES): m/z (%) = 482.1 ([M + Na]+,
57), 428.0 (93), 426.0 (100). HRMS (ES, Na+): calculated for
C23H26BrNO4Na [M + Na]+: 482.0943, found: 482.0964.
=
=
=
=
(2E,4E)-5-(4-Nitro-phenyl)-penta-2,4-dienoic acid ethyl ester (30)
To a solution of triethyl phosphonocrotonate23 (1.46 mL,
6.6 mmol) and 4-nitrobenzaldehyde 29 (1.0 g, 6.6 mmol) in
THF (11 mL) was added molecular sieves (powdered 4 A, 1.0 g)
(3R*,6S*)-3-Benzyloxymethyl-6-(3-bromo-phenyl)-3,6-dihydro-
2H-[1,2]oxazin-2-ium chloride (17)
˚
and LiOH·H2O (0.29 g, 6.9 mmol) under vigorous stirring. The
To a solution of dihydrooxazine 28 (0.345 g, 0.75 mmol) in dioxane
suspension was warmed at 45 ◦C for 10 min, cooled to room
(1 mL) at 0 ◦C was added HCl (4 N in dioxane, 0.75 mL, 3 mmol).
temperature, filtered through Celiteꢀ and rinsed thoroughly with
R
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diethyl ether. The black filtrate was diluted with water and
the aqueous phase was extracted with EtOAc, the combined
organic phases were dried over magnesium sulfate, filtered and
concentrated. The residue was purified by flash chromatography
on silica gel (cyclohexane–ethyl acetate = 90 : 10 to 80 : 20) to give
613 mg (40%) of compound 30 as a yellow crystals.
After 1 h 30 min at 0 ◦C, additional BocNHOH (0.2 g, 1.50 mmol)
and Bu4NIO4 (0.4 g, 0.92 mmol) were added. The latter addition
was repeated 4 times. The reaction mixture was then hydrolyzed
with water and the aqueous phase was extracted with EtOAc.
The combined organic phases were washed with a 10% aqueous
Na2S2O3 solution, dried over magnesium sulfate, filtered and
concentrated. The residue was purified by flash chromatography
on silica gel (cyclohexane–ethyl acetate = 80 : 20 to 60 : 40) to give
0.69 g (48%) of compound 32 as a yellow oil.
Mp: 101 ◦C. 1H NMR (300 MHz, CDCl3), d (ppm): 8.24 (2 H,
=
=
d, J 8.8, O2N–C CH–CH C × 2); 7.61 (2 H, d, J 8.8, O2N–
=
=
=
C CH–CH C × 2); 7.45 (1 H, dd, J 9.8 and 15.3, Ar–CH CH–
CH CH–CO); 7.01–6.91 (2 H, Ar–CH CH–CH CH–CO);
1H NMR (300 MHz, CDCl3), d (ppm): 8.10 (2 H, d, J 8.4, O2N–
=
=
=
=
=
=
=
=
=
6.11 (1 H, d, J 15.3, Ar–CH CH–CH CH–CO); 4.26 (2 H, q, J
7.2, OCH2CH3); 1.34 (3 H, t, J 7.2, OCH2CH3). Spectroscopic
data identical with the reported NMR.23 LRMS (ES): m/z
(%) = 518.2 (8), 517.2 (100). HRMS (ES, Na+): calculated for
C26H26N2O8Na [2M + Na]+: 517.1587, found: 517,1593.
C CH–CH C × 2); 7.42 (2 H, d, J 8.4, O2N–C CH–CH C ×
2); 7.29–7.18 (5 H, Ph); 6.04 (1 H, ddd, J 2.1, 4.3 and 10.4,
=
=
CHO–CH CH–CHN); 5.82 (1 H, br. d, J 10.4, CHO–CH CH–
=
CHN); 5.56 (1 H, br. s, CHO–CH CH–CHN); 4.65 (1 H, br. s,
=
CHO–CH CH–CHN); 4.55 (1 H, d, J 12.0, CH2OCH2Ph); 4.50
(1 H, d, J 12.0, CH2OCH2Ph); 3.75 (1 H, dd, J 7.2 and 9.7,
CH2OCH2Ph); 3.62 (1 H, dd, J 6.0 and 9.7, CH2OCH2Ph); 1.44
(9 H, s, OC(CH3)3). 13C NMR (75 MHz, CDCl3), d (ppm): 154.1
1-((1E,3E)-5-Benzyloxy-penta-1,3-dienyl)-4-nitro-benzene (31)
=
To a solution of ester 30 (2.89 g, 12.5 mmol) in CH2Cl2 (60 mL) at
0 ◦C was added DIBAL (1.5 M in toluene, 18.3 mL, 27.5 mmol).
The solution was slowly warmed to room temperature over 1 h
and transferred carefully to a saturated aqueous solution of
potassium and sodium tartrate (100 mL) via canula. Diethyl ether
(200 mL) was added and vigorous stirring was continued until both
phases were clear. The aqueous phase was extracted with EtOAc
and the combined organic phases were dried over magnesium
sulfate, filtered and concentrated. The residue was purified by
flash chromatography on silica gel (cyclohexane–ethyl acetate =
70 : 30) to give 1.49 g (58%) of the desired alcohol. The latter
compound (1.49 g, 7.27 mmol) was dissolved in DMF (18 mL) and
cooled to 0 ◦C. NaH (purum, 0.26 g, 10.9 mmol) was then added.
After 10 min, BnBr (1.12 mL, 9.4 mmol) was added dropwise
and the reaction mixture was warmed to room temperature. After
12 h, the solution was hydrolyzed with water (70 mL) and the
aqueous phase was extracted with a cyclohexane–CH2Cl2 solution
(90 : 10, 3 × 60 mL). The combined organic phases were dried
over magnesium sulfate, filtered and concentrated. The residue
was purified by flash chromatography on silica gel (cyclohexane–
toluene–ethyl acetate = 80 : 20 : 0 then 50 : 50 : 0 then 50 : 40 : 10)
to give 1.07 g (50%) of compound 31 as a pale yellow oil.
(CO), 147.7 (O2N–C=CH–CH C), 143.8 (Ar. Quat.), 137.6 (Ar.
Quat.), 128.5, 128.1, 127.4, 125.2, 123.5, 81.9 (OC(CH3)3), 76.3
(CHO), 72.9 (CH2OCH2Ph), 70.0 (CH2OCH2Ph), 53.6 (CHN),
28.0 (OC(CH3)3). LRMS (ES): m/z (%) = 449.2 (18), 394.1
(6), 393.1 (100), 349.1 (3). HRMS (ES, Na+): calculated for
C23H26N2O6Na [M + Na]+: 449.1689, found: 449.1668.
(3R*,6S*)-3-Benzyloxymethyl-6-(4-nitro-phenyl)-3,6-dihydro-2H-
[1,2]oxazin-2-ium chloride (19)
To a solution of dihydrooxazine 32 (0.65 g, 1.52 mmol) in dioxane
(1 mL) at 0 ◦C was added HCl (4 N in dioxane, 1.5 mL, 9.1 mmol).
From the purple solution, pink crystals precipitated after 1 h
at 0 ◦C. After filtration, the solids were washed with pentane
and dried under high vacuum. Recrystallization from EtOH gave
0.308 g (56%) of the desired 19 as light pink crystals.
Mp: >170 ◦C (decomp.). 1H NMR (300 MHz, CD3OD), d
=
=
(ppm): 8.22 (2 H, d, J 8.4, O2N–C CH–CH C × 2); 7.62 (2
=
=
H, d, J 8.4, O2N–C CH–CH C × 2); 7.44–7.33 (5 H, Ph); 6.24
=
=
(1 H, br. d, J 10.7, CHO–CH CH–CHN or CHO–CH CH–
=
CHN); 6.18 (1 H, ddd, J 1.7, 3.8 and 10.7, CHO–CH CH–CHN
=
or CHO–CH CH–CHN); 6.05 (1 H, br. s, CHO); 4.67 (2 H, s,
PhCH2OCH2); 4.38 (1 H, m, CHN); 3.88 (1 H, dd, J 4.3 and
1H NMR (300 MHz, CDCl3), d (ppm): 8.20 (2 H, d, J 8.8,
=
=
=
O2N–C CH–CH C × 2); 7.53 (2 H, d, J 8.8, O2N–C CH–
11.0, PhCH2OCH2); 3.83 (1 H, dd, J 6.5 and 11.0, PhCH2OCH2).
13
=
=
CH C × 2); 7.40–7.19 (5 H, Ph); 6.97 (1 H, dd, J 10.5 and
C NMR (75 MHz, CD3OD), d (ppm): 150.1 (O2N–C CH–
=
=
=
15.7, Ar–CH CH–CH CH–CH2O); 6.61 (1 H, d, J 15.7, Ar–
CH CH–CH CH–CH2O); 6.51 (1 H, dd, J 10.7 and 15.0, Ar–
CH CH–CH CH–CH2O); 6.08 (1 H, dt, J 5.3 and 15.0, Ar–
CH C), 142.9 (Ar. Quat.), 138.6 (Ar. Quat.), 130.5, 129.6, 129.4,
=
=
129.3, 129.2, 125.0, 121.4, 80.4 (CHO), 74.4 (CH2OCH2Ph), 67.5
(CH2OCH2Ph), 55.8 (CHN). LRMS (ES): m/z (%) = 350.1 (30),
349.1 (100), 327.1 (8), 318.1 (12), 188.1 (4). HRMS (ES, Na+):
calculated for C18H18N2O4Na [M − HCl + Na]+: 349.1164, found:
349.1162.
=
=
=
=
CH CH–CH CH–CH2O); 4.47 (2 H, s, OCH2Ph); 4.18 (2 H,
dd, J 0.7 and 5.3, CH2OCH2Ph). 13C NMR (75 MHz, CDCl3),
=
=
d (ppm): 146.7 (O2N–C CH–CH C), 143.7, 138.1, 133.7, 132.7,
131.5, 130.0, 128.4, 127.7, 126.7, 124.0, 72.4 (CH2OCH2Ph), 70.0
(CH2OCH2Ph). LRMS (ES): m/z (%) = 352.1 ([M + Na]+, 100),
350.1 (41), 279.1 (9).
[(Z)-(1R*,4S*)-1-Benzyloxymethyl-4-hydroxy-4-(4-nitro-phenyl)-
but-2-enyl]-carbamic acid tert-butyl ester (20)
To a suspension of dihydrooxazinium chloride 19 (25 mg,
0.07 mmol) in i-PrOH (1.4 mL) was added [1,3]-dithiolane-2-
carbaldehyde3 (14 mg, 0.10 mmol) via a syringe. The reaction
(3R*,6S*)-3-Benzyloxymethyl-6-(4-nitro-phenyl)-3,6-dihydro-
[1,2]oxazine-2-carboxylic acid tert-butyl ester (32)
◦
To a solution of 1,3-diene 31 (1.0 g, 3.40 mmol) and tert-butyl-N-
hydroxycarbamate20 (0.45 g, 3.40 mmol) in CH2Cl2 (17 mL) at 0 ◦C
was added Bu4NIO4 (0.74 g, 1.70 mmol) portionwise over 30 min.
mixture became homogeneous at 40 C and was stirred at 50 ◦C
for 2 h 30 min. The solution was then cooled to room temperature,
hydrolyzed with aqueous HCl (1 N, 0.5 mL). After 15 min, aqueous
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NaOH (3 N) was added dropwise until pH > 10 and a solution
of Boc2O (30 mg, 0.14 mmol) in THF (2 mL) was then added.
The reaction mixture was stirred for 12 h at room temperature,
diluted with water and extracted with diethyl ether. The combined
organic phases were dried over magnesium sulfate, filtered and
concentrated. The residue was purified by flash chromatography
on silica gel (cyclohexane–ethyl acetate = 80 : 20 to 70 : 30) to give
22.3 mg (76%) of compound 20 as a white solid.
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A. Martel, L. B. Snyder, S. V. Andrea, J. J. Bronson, M. Frosco, D.
Beaulieu, G. A. Glen, K. L. DenBleyker, T. M. Stickle, H. Yang, S. E.
Chaniewski, C. A. Ferraro, D. Taylor, J. W. Russell, K. S. Santone, J.
Clarke, R. L. Drain, J. O. Knipe, K. Mosureb and J. F. Barret, Bioorg.
Med. Chem. Lett., 2005, 15, 2728.
18 W. Adam, H.-G. Degen, O. Krebs and C. R. Saha-Mo¨ller, J. Am. Chem.
Soc., 2002, 124, 12938; T. Peglow, S. Blechert and E. Steckhan, Chem.
Commun., 1999, 433.
19 P. Ding, M. J. Miller, Y. Chen, P. Helquist, A. J. Oliver and O. Wiest,
Org. Lett., 2004, 6, 1805.
20 A. Defoin, M. Joubert, J.-M. Heuchel, C. Strehler and J. Streith,
Synthesis, 2000, 1719.
◦
1
Mp: 103 C. H NMR (300 MHz, CDCl3), d (ppm): 8.18 (2
=
=
H, d, J 8.8, O2N–C CH–CH C × 2); 7.54 (2 H, d, J 8.8, O2N–
=
=
C CH–CH C × 2); 7.42–7.33 (6 H, Ph + OH/NH); 5.78–5.61 (3
=
H, HNCH–CH CH–CHOH + OH/NH); 5.28 (1 H, br. d, J 6.9,
CHO); 4.75 (1 H, m, CHN); 4.60 (1 H, d, J 11.9, CH2OCH2Ph);
4.54 (1 H, d, J 11.9, CH2OCH2Ph); 3.67 (1 H, dd, J 4.1 and 9.3,
CH2OCH2Ph); 3.55 (1 H, dd, J 4.5 and 9.3 CH2OCH2Ph); 1.46
(9 H, s, OC(CH3)3). 13C NMR (75 MHz, CDCl3), d (ppm): 156.1
(CO), 150.5 (Ar. Quat.), 147.0 (Ar. Quat.), 137.3 (Ar. Quat.), 134.1,
129.6, 128.5, 128.0, 127.8, 126.6, 123.5, 80.7 (OC(CH3)3), 73.5
(CHO), 71.1 (CH2OCH2Ph), 67.3 (CH2OCH2Ph), 47.6 (CHN),
28.3 (OC(CH3)3). LRMS (ES): m/z (%) = 452.2 (11), 451.2
(100), 396.1 (4), 395.1 (53). HRMS (ES, Na+): calculated for
C23H28N2O6Na [M + Na]+: 451.1845, found: 451.1833.
Acknowledgements
This work was supported by the CNRS (UMR 8182), the
University Paris-Sud XI and the Ministe`re de la Recherche
(MRT grant to G. C.). Dr Robert Lett and Prof. Yves Langlois
are gratefully acknowledged for their continuous support and
stimulating discussions.
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1070 | Org. Biomol. Chem., 2008, 6, 1063–1070
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