Synthetic studies towards 4,10-diaza-1,7-dioxaspiro[5.5]undecanes: access to 3-aza-6,8-dioxabicyclo[3.2.1]octan-2-one and 2H-1,4-oxazin-3(4H)-one frameworks

Article abstract of DOI:10.1016/j.tet.2007.05.109

Synthetic approaches towards 4,10-diaza-1,7-dioxaspiro[5.5]undecanes starting from 1,3-dichloroacetone and solketal derivatives are explored. The method relies on the preparation of a key bis-substituted dihydroxy-protected oxime, which would undergo a final acidic deprotection-spiroacetalization process. Although the desired diazaspiroketal framework could not be obtained, our conditions led to the unexpected 3-aza-6,8-dioxabicyclo[3.2.1]octan-2-one 18 or to the oxazinone 32 in good yields.

Full text of DOI:10.1016/j.tet.2007.05.109

Tetrahedron 63 (2007) 8255–8266
Synthetic studies towards 4,10-diaza-1,7-dioxaspiro[5.5]-
undecanes: access to 3-aza-6,8-dioxabicyclo[3.2.1]octan-2-one
and 2H-1,4-oxazin-3(4H)-one frameworks
a
Marlene Goubert, Loıc Toupet, Marie-Eve Sinibaldi and Isabelle Canet
b
a,
a,
*
*
ꢀ
€
a
´
´
Laboratoire de Syntheꢀse Et Etude de Systeꢀmes aꢀ Intere^t Biologique, UMR CNRS 6504, Universite Blaise Pascal,
63177 Aubieꢀre Cedex, France
b
´
Groupe Matieꢀre Condensee et Materiaux, UMR CNRS 6626, Universite de Rennes 1, 35042 Rennes Cedex, France
´
´
Received 5 February 2007; revised 24 May 2007; accepted 26 May 2007
Available online 2 June 2007
Abstract—Synthetic approaches towards 4,10-diaza-1,7-dioxaspiro[5.5]undecanes starting from 1,3-dichloroacetone and solketal deriva-
tives are explored. The method relies on the preparation of a key bis-substituted dihydroxy-protected oxime, which would undergo a final
acidic deprotection–spiroacetalization process. Although the desired diazaspiroketal framework could not be obtained, our conditions led
to the unexpected 3-aza-6,8-dioxabicyclo[3.2.1]octan-2-one 18 or to the oxazinone 32 in good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ketone 5, issued from a double substitution of the dichloro-
oxime 4 by the alcohol 3a or its thiol derivative 3b, promoted
by KH in THF (Scheme 1).
Molecules owning a spiroketal core are abundant as natural
products and many of them exhibit important biological
properties.1 Moreover, the rigid spiroketal framework pos-
sesses strong conformational preferences2 and therefore
could be used as structural scaffolds for binding to a recep-
tor. Consequently, there is sustained interest in the synthesis
of these moieties and/or substituted analogues. Recently,
new spiroketals incorporating nitrogen in their cycles, pre-
senting emphasis in activities of their unsubstituted ana-
logues, have been described in the literature, such as new
antifeedant Tonghaosu analogue,3 GD3-lactam ligand used
in the development of an anti-melanoma vaccine4 and tachy-
kinin antagonists5 (Fig. 1). Additionally, spirocyclic ketal-
lactone frameworks have been designed as novel structures
amenable to combinatorial prospecting libraries.6
OH
OH
O
H
N
O
HO
O
CO2H
OR
N
Ar
O
AcHN
O
O
O
HO
HO
AcHN
HO
Tonghaosu analogue
analogues of ganglioside : GD3-lactam
R2
R3
Ar
O
R1
O
N
( )n
N
R4
O
O
N
H
Ar
R5
O
skeleton of ring systems
assembled on solid phase
NK1 antagonists
Figure 1.
Thus, the structural novelty and the biological relevance of
4- and/or 10-aza-1,7-dioxaspiro[5.5]undecane class of com-
pounds suggested to develop synthetic pathways to their
skeleton.
BnO
N
B-
OBn
N
O
O
O
+
2'
2
O
XH
c
X
O
a
O
X
b
5
Cl
Cl
1
1'
3
3'
3a X = O
3b X = S
3c X = NR
4
In a previous work,7 we disclosed an efficient two-step
procedure for the preparation of 4,10-dioxa- or 4,10-dithia-
spiroketals 1. Our method was based on an acidic one-pot
deprotection–spirocyclization process of a key protected
3
2
4
X
OH
OH
12
13
H+
OH
OH
O
5
6
O
O
OH
X
X
HO
11
10 X
8
9
* Corresponding authors. Tel.: +33 473 405 284; fax: +33 473 407 717
(M.-E.S.); tel.: +33 473 407 875; fax: +33 473 407 717 (I.C.); e-mail
addresses: m-eve.sinibaldi-troin@univ-bpclermont.fr; isabelle.canet@
univ-bpclermont.fr
1 X = O or S
2 X = NR
Scheme 1.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.109

8256
M. Goubert et al. / Tetrahedron 63 (2007) 8255–8266
We then wished to extend our pathway and focussed our at-
tention to the synthesis of aza derivatives such as 4,10-diaza-
1,7-dioxaspiro[5.5]undecane skeleton.
Aza compound 8 behaved differently than its oxa- or thia-
analogues and remained unchanged. We therefore next
tested other conditions by varying the solvent and the acidic
medium, namely using HCl 5% in THF, Zn powder in
AcOH,11 SnCl2$2H2O/SiO2 in THF12 or CeCl3$7H2O/
(COOH)2 in CH3CN.13 Once again, no spiroketal was
detected in the reaction mixture. All these attempts led either
to degradation products or to the sole deprotection of the diol
functions, leaving the O-benzyloxime group unchanged.
Heating 8 with HCl and formaldehyde in THF during 3
days, led to traces of a compound owning the expected
formula C23H30N2O4 (detected in the crude reaction mixture
by mass spectrometry, [M+H]+ at m/z¼399). Anyway, as we
were unable to isolate a pure scale of it, we could not char-
acterize this new compound.
To this purpose, we reported here our explorating studies to-
wards structure 2 (X¼NR), using oxime 4 and solketal deriv-
atives 3c as starting materials (Scheme 1).
2. Results and discussion
2.1. Approaches to the 4,10-diaza-1,7-dioxaspiro[5.5]-
undecane framework
We first investigated the alkylation of amines (ꢀ)-68 and
(ꢀ)-79 with oxime 4 in basic media (Scheme 2). Surpris-
ingly, treatment of 4 by 6 alone or in the presence of a mineral
base such as K2CO3, Cs2CO3, CsOH or KOH/18-crown-6,
led invariably to polycondensation of starting oxime 4
accompanied with numerous by-products. Modifying the
temperature or the nature of the solvent did not give better
results. At last, oxime 810 could be conveniently obtained
in a 77% yield by the condensation of 4 with an excess of
7 in refluxing methanol.
To circumvent these problems, we chose to protect the
amino groups as amides or as a carbamate. To this end, we
modified our synthetic approach and prepared solketal deriv-
atives (ꢀ)-9a and (ꢀ)-9b to examine their condensation on
dichlorooxime 4 in basic media (Scheme 3). Amides 9a,b
did not afford the expected bis-substituted oximes 10a,b.
In fact, whatever the involved basic conditions, partial di-
merization or decomposition14 of oxime 4 was observed,
all starting amides remaining unchanged. In the case of car-
bamate (ꢀ)-9c, only the use of KH (3.0 equiv) in THF at
20 ꢁC afforded cleanly the monosubstituted oxime (ꢀ)-11,
which could be isolated in an improved 33% yield. Extend-
ing the reaction time or heating the reaction mixture dam-
aged the starting materials (Scheme 3).
O
NH2
O
ref. 8
79%
6
O
OH
O
ref. 9
O
82%
solketal
NHBn
Bn
Pursuing our aim, we next envisaged another route to oximes
10a,c, introducing this time the nitrogen atom on the starting
oxime 4.
O
7
BnO
OBn
Bn
N
N
Cl
Cl
O
N
O
O
We thus synthesized the diamine 12 readily available from 4
in two steps.15 Bis-acylation of 12 furnished efficiently the
expected diamide 13a or dicarbamate 13b precursors. These
compounds were then engaged in a condensation with the
previously described iodide (ꢀ)-1416 in order to obtain
oximes 10a,c. Unfortunately, when 13a,b were subjected
to treatment by n-BuLi or LDA in THF followed by the
addition of 14, no reaction occurred. Changing the base
(KH instead of lithiated bases) led to the degradation of
both starting materials (Scheme 4).
NHBn
4
O
O
O
N
8
7
MeOH, Δ, 77%
Scheme 2.
The final step of our synthetic scheme involved deprotection
of both ketone and alcohol functions of 8 and subsequent
acid-catalyzed cyclization. This sequence was undertaken
under our preliminary optimized conditions, AmberlystÒ
15 in acetone/H2O with or without paraformaldehyde.7
OBn
(c)
N
O
O
O
R
N
R
O
O
N
NHR
O
10a R = COPh
10b R = COCF3
10c R = CO2tBu
9a R = COPh, 75%
9b R = COCF3, 76%
(a)
(b)
O
6
NH2
O
(d)
OBn
Cl
N
O
O
(e)
H
N
OtBu
O
O
N
O
tBuO
O
9c, 83%
11, 33%
Scheme 3. Reagents and conditions: (a) PhCOCl, NEt3, DMAP, CH2Cl2, 0 ꢁC then 20 ꢁC or CF3CO2Et, 20 ꢁC; (b) (Boc)2O, Na2CO3, dioxane, 20 ꢁC; (c) BuLi
or KH, THF; (d) BuLi or t-BuOK, THF; (e) KH, THF then 4, 20 ꢁC.

M. Goubert et al. / Tetrahedron 63 (2007) 8255–8266
8257
OBn
(R,R)-(17) in a 77% yield. Contrarily to the oxa- and thia-de-
rivatives,7 these mild acidic conditions were insufficient to
promote the ultimate spiroacetalization. So, we engaged ox-
ime 17 in refluxing n-butanol in the presence of a catalytic
amount of para-toluenesulfonic acid. After 6 h, we observed
the exclusive formation of the unexpected bicyclic lactam 18,
which was isolated in a nearly quantitative yield (76% after
recrystallization) (Scheme 5). The formation of 18 resulted
from the nucleophilic attack of the hydroxymethyl group of
the cycle on the oxonium intermediate.18 This attack ap-
peared indeed more favourable than the attack of the second-
ary alcohol—which could lead to a spiroketal—as this latter
required a two-step process including the isomerization of
the trans amide function prior to spiroacetalization.
N
H
N
H
N
Ph
Ph
(b)
BnO
Cl
N
BnO
68%
(c)
O
13a
O
N
(a)
H2N
NH2
OBn
84%
Cl
12
N
H
N
H
N
76%
4
Boc
Boc
13b
OBn
R
N
1) B-, THF
O
R
N
N
O
O
13a or 13b
O
O
10a R = COPh
10c R = CO2tBu
2)
O
I
14
Scheme 4. Reagents and conditions: (a) PhtNK, DMF, reflux then NH2–
NH2, MeOH, reflux; (b) PhCOCl, NEt3, DMAP, CH2Cl2, 0 ꢁC then 20 ꢁC;
(c) (Boc)2O, Na2CO3, dioxane, 20 ꢁC.
The NMR data of 18 were in good agreement with the indi-
cated structure. The chemical shift of the deshielded C-50 at
3
d¼104.5 ppm, together with the vicinal JH,H couplings (i)
2.2. Approaches to the 4,10-diaza-1,7-dioxa-3,9-dioxo-
spiro[5.5]undecane framework
between C2–O–H (d¼5.59 ppm) and H-2 (d¼3.91 ppm)
and (ii) between H-3a (d¼3.57 ppm) or H-3b (d¼3.46 ppm)
and C3–O–H (d¼4.72 ppm), confirmed a bridged structure
for 18. The formation of this bicycle was also corroborated
by the presence of a strong correlation peak between C-50
and H-7a0 on the HMBC spectrum.
Once again, we reoriented our synthetic plan to diazaspiro-
ketals and developed an alternative route based upon the
preparation of the bis-substituted oxime 16, possessing
now the required amide groups in its linear chain.
The (S) configuration of the starting solketal imposed (R)
configurations for C-2 and C-10 in 18. Since C-50 could
only adopt an (R) configuration in the intramolecular acetal-
ization process, compound 18 possesses then a (10R, 2R, 50R)
configuration.
Thus, bis-condensation of the crude diamine 12 with
acylchloride (R)-1517 in the presence of triethylamine and
a catalytic amount of 4-dimethylaminopyridine in dichloro-
methane, furnished the oxime (R,R)-16 in a 59% overall yield
from (S)-solketal (Scheme 5). Deprotection of both diol and
ketone functions was carried out using AmberlystÒ 15 in ace-
tone/water (10/1) at reflux and gave the key intermediate
Compound 18 occurred as a fine powder and could be recrys-
tallized from ethanol; we then confirmed its structure by X-
ray crystallographic analysis. The ORTEP shown in Figure 2
exhibits a (50R) configuration and a trans conformation of the
amide in the lateral chain in 18.
1) KMnO4, KOH
H2O, 20 °C, 14 h
O
O
O
Cl
O
OH
2) (ClCO)2, pyridine
ether, 20 °C, 14 h
O
To avoid this competitive cyclization, we decided to selec-
tively protect the two primary hydroxyl groups of 17. Unfor-
tunately, the polarity and the low solubility of compound 17
in classical solvent did not permit to carry out efficiently this
protection. So we planed to perform it on the partially depro-
tected oxime 21, quantitatively prepared by refluxing 16
with a catalytic amount of D,L-camphorsulfonic acid in eth-
anol for 3 h (Scheme 6). Treatment of 21 with dibutyltin ox-
ide in toluene/methanol (10:1, v/v) followed by the addition
of benzylbromide and tetrabutylammonium iodide19 led to
22a in a 34% yield. Removal of the oxime group was real-
ized using AmberlystÒ 15 in refluxing acetone/water
(10:1, v/v) and afforded ketone 23 in a 85% yield. Unfortu-
nately, treatment of 23 under the same cyclization conditions
as that for 17 (pTsOH in n-butanol) led to the loss of the pro-
tective groups and gave once again the bicyclic compound
18. Attempts to prepare the protected di-TBDPS compound
from 21 failed. Only the monosilylether derivative 22b was
formed, in a 33% yield. No intramolecular TBDPS transfer
was observed in our conditions.
(S)-solketal
(R)-15
OBn
BnO
N
N
O
O
H
N
H
N
(b)
(a)
O
O
O
NH2 NH2
12
O
O
(R, R)-16
O
H
HN
O
OH
OH
H
N
H
(c)
2'
OH
O
HO
N
O
O
HN
OH
(R, R)-17
O
O
OH
1'
HN
4'
5'
7'
O
O
HN
OH
1
2
OH
O
3
At this stage, we envisaged the reaction of the diamine 12 on
the acylchloride 27 possessing two alcohol functions orthog-
onally protected. The choice of the protective groups of tem-
plate 27 was now crucial. Because of our condensation and
spirocyclization conditions, we chose a MOM20 protective
(2R, 6R, 8R)-18
Scheme 5. Reagents and conditions: (a) NEt3, DMAP, CH2Cl2, (R)-15,
67%; (b) AmberlystÒ 15, acetone/H2O, (10/1), D, 77%; (c) pTsOH, n-buta-
nol, D, 6 h, 76% after recrystallization.

8258
M. Goubert et al. / Tetrahedron 63 (2007) 8255–8266
Figure 2. ORTEP drawing of 18.
OBn
HO
OH
N
OH
H
N
H
N
OH
(b)
O
HO
(a)
(R, R)-16
O
O
(R, R)-21
OBn
HO
OH
H
N
H
N
HO
N
(c)
H
N
H
N
OR2
R1O
OR2
R1O
O
O
O
O
(R, R)-22a R1 = R2 = Bn
(R, R)-22b R1 = TBDPS, R2 = H
(R, R)-23 R1 = R2 = Bn
Scheme 6. Reagents and conditions: (a) CSA, EtOH, D, 3 h, quant; (b) (i) Bu2SnO, toluene/MeOH, (10/1), D, 5–6 h, (ii) BnBr, Bu4NI, D, 4–5 h, 34% in two
steps for 22a or imidazole, TBDPSCl, DMF, 0 ꢁC then 20 ꢁC, 14 h, 33% for 22b; (c) AmberlystÒ 15, acetone/H2O, (10/1), D, 85%.
group for the secondary alcohol and a TBDPS protective
group for the primary one. Thus, compound (R)-27 was
prepared, in a six-step sequence and a 58% overall yield,
starting from D-serine (Scheme 7).
problematic migration of the TBDPS group to the adjacent
oxygen atom was not observed under our reaction condi-
tions. Increasing the temperature or the duration of the reac-
tion did not improve the yield of 30b but damaged the
products. At this stage oxime 29 and ketone 30b could be
easily separated and fully characterized.
OH
NH2
OH
HO
OH
HO
OMe
OMe
(a)
TBDPSO
(b)
Oxime 29 was then re-engaged in classical cleavage condi-
tions (AmberlystÒ 15/paraformaldehyde in refluxing ace-
tone/H2O (10:1, v/v)) and was transformed into ketone
30b, but in a modest yield of 26% (see Scheme 8). However,
this deprotection-reaction step was clean and oxime 29
could be recycled after column chromatography separation.
O
O
(R)-24
O
(R)-25
D-serine
OMOM
OMOM
Cl
(c)
OMe
TBDPSO
TBDPSO
(d)
O
O
(R)-26
(R)-27
Scheme 7. Reagents and conditions: (a) (i) NaNO2, H2SO4, H2O, (ii)
HC(OMe)3, H2SO4, MeOH, 60 ꢁC, 30 min, 83% (Ref. 21); (b) imidazole,
CH2Cl2, TBDPSCl, ꢂ40 ꢁC, 1 h 30 min, 83% (Ref. 22); (c) MOMCl, (i-
Pr)2EtN, CH2Cl2, 20 ꢁC, 24 h, 84%; (d) (i) LiOH, 1 M, THF/MeOH (4/1),
20 ꢁC, 4 h, (Ref. 23) (ii) (ClCO)2, pyridine, Et2O, 20 ꢁC, 14 h, quant.
Welast attempted the isomerization–spiroacetalization of the
ketodiol 30b in various acidic media. Using AmberlystÒ 15
in acetone/H2O (10/1, v/v), Yb(OTf)3 in CH3CN, BF3$Et2O
in THF or pTsOH in THF, no reaction occurred. The use of
pTsOH in n-butanol furnished compound 31. As for com-
pound 17, the trans configuration of the amide group in the
lateral chain disfavoured the intramolecular final spirocycli-
zation for the benefit of an intermolecular reaction of the
oxonium intermediate with the butanol, which acted as a
nucleophile. Treating 30b with pTsOH for 7 h in refluxing
toluene or boiling 31 in toluene led to the same oxazinone
32, which resulted, in the case of 31, from a classical elimi-
nation of butanol in the acid medium (Scheme 8).
Condensation of crude 12 with undistilled (R)-27 gave the
bis-substituted oxime 28 in a good yield of 37%. The further
one-step cleavage of both MOM-ether and oxime groups re-
vealed to be, in fact, not so trivial. Treatment of 28 with Am-
berlystÒ 15 and paraformaldehyde in refluxing acetone/H2O
(10:1, v/v), afforded partially deprotected ketone (R,R)-30a
in a low yield of 26%, accompanied with numerous non-
polar side products we did not characterize.
To complete the deprotection, we developed a sequential
process for the removal of the different protective groups.
The best results were obtained starting by the cleavage of
the MOM groups of 28 according to a literature procedure.24
Action of trimethylsilylbromide in CH2Cl2 at 0 ꢁC for 4 h
led as expected to the diol 29, accompanied with the ketone
30b (Scheme 8). Fortunately, in our case, the potentially
Since access to spiroketals by treatment of 2-substituted
dihydropyrane in various acidic media (PPTS,25a
BF3$Et2O,25b D,L-camphorsulfonic acid25c) has been already
described, we decided to apply these conditions to the ox-
azinone 32. Unfortunately, we never detected the formation
of the desired spiroheterocycle in the reaction mixtures but
observed only degradation of the starting materials.

M. Goubert et al. / Tetrahedron 63 (2007) 8255–8266
8259
OBn
N
crude 12
H2N
NH2
(a)
OBn
OMOM
OR
MOMO
RO
O
OMOM
RO
OMOM
OR
N
H
N
H
N
H
N
H
N
(c)
O
O
O
O
(R,R)-28 R = TBDPS
(R,R)-30a R = TBDPS
(b)
OBn
OH
OH
OH
N
O
OH
H
N
H
N
H
N
H
N
RO
OR
RO
OR
+
O
O
O
O
(R,R)-30b R = TBDPS
(R,R)-29 R = TBDPS
(c)
(e)
(d)
O
H
N
O
OH
HN
(f)
OR
H
N
OH
H
RO
O
O
OR
O
RO
N
O
O
(R,R)-32 R = TBDPS
(R,R)-31 R = TBDPS
Scheme 8. Reagents and conditions: (a) NEt3, DMAP, CH2Cl2, (R)-27, 37%; (b) TMSBr, CH2Cl2, 0 ꢁC, 4 h, ((R,R)-29 54% and (R,R)-30b 20% after purifi-
cation); (c) AmberlystÒ 15, (CH2O)n, acetone/H2O (10/1), D, 24 h, 26%; (d) 0.04 equiv, pTsOH, n-butanol, D, 6 h; (e) 0.04 equiv, pTsOH, toluene, D, 7 h,
57%; (f) toluene, D, 5 h, 57% in two steps from (R,R)-30b.
3. Conclusion
spiroketals. These investigations are currently in progress
in our laboratory and will be published in due course.
In this paper, we described our preliminary work towards
a novel rigid spiroketal framework incorporating one nitro-
gen in each cycle.
4. Experimental
4.1. General
Our strategy underlied first upon the condensation of (S)-sol-
ketal derivatives on dichloroacetone O-benzyloxime. Direct
approaches to 4,10-diaza-1,7-dioxaspiro[5.5]undecane core
were unsuccessful and showed the necessity of using amide
functions as integral parts of the skeleton of the molecule
instead of protective groups.
Melting points were measured using a Reichert melting point
apparatus and are uncorrected. Infra Red spectra were
recorded on a Perkin–Elmer 881 instrument. 1H NMR
(400 MHz) and 13C NMR (100 MHz) were recorded with
a Bruker AC 400 spectrometer. Chemical shifts (d values)
are expressed in parts per million (ppm) and coupling con-
stants (J) are expressed in Hertz. NMR spectra were recorded
in CDCl3, CD3OD or DMSO-d6, using the solvent signals as
reference. Mass spectra were recorded with a Hewlett Pack-
ard 5989B instrument and high-resolution mass spectra
(HRMS) were performed with a Q-TOF micromass. Elemen-
tal analysis was performed using an elemental analyzer. Op-
tical rotations were measured at sodium D-line (589 nm)
using a 1 dm quartz cell with a Jasco DIP-370 apparatus.
Chromatography was performed using silica gel 60 (230–
400 mesh) and thin layer chromatography (TLC) was per-
formed on silica gel 60PF254 plates (20ꢃ20 cm). Compounds
were identified using UV fluorescence (l¼254 nm) and/or
staining with a 5% phosphomolibdic acid solution in ethanol
following by heating. Commercially reagents (Aldrich,
Acros, Lancaster) were used as received without additional
Using this second approach we prepared oximes 17 and 28.
However, we were unable to achieve the final spiroacetaliza-
tion of 17 and 28, illustrating the difficulties in preparing the
4,10-diazaspiroketal compounds.
Meanwhile, we synthesized the new 3-aza-6,8-dioxabi-
cyclo[3.2.1]octan-2-one (10R, 2R, 50R)-18 in six steps in a
31% overall yield from dichloroacetone, through an unusual
intramolecular dehydration reaction.
The same protocol led to the original oxazinone 32 isolated
in nine steps and 2% overall yield starting from D-serine.
In addition, the achievement of the monosubstituted chloro-
oxime 11 allowed us to envisage an effective access to
original ‘dissymmetrical heteroatom’ 4,10-disubstituted

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M. Goubert et al. / Tetrahedron 63 (2007) 8255–8266
2
3
purification. Tetrahydrofuran (THF) was distilled from
potassium/benzophenone while dichloromethane (CH2Cl2)
was dried over calcium hydride prior to use. Suitable crystal
for structure determination was obtained by crystallization
from ethanol. Crystal was obtained with a diffractometer
Oxford Diffraction Xcalibur Saphir 3 at the University of
1H, CH2–O), 2.83 (dd, J¼13.0 Hz, J¼4.5 Hz, 1H, CH2–
2
3
N), 2.78 (dd, J¼13.0 Hz, J¼6.0 Hz, 1H, CH2–N), 1.42
(s, 3H, Me), 1.35 (s, 3H, Me), 1.26 (br s, 2H, NH2); 13C
NMR (100 MHz, CDCl3): d 109.0 (C–(CH3)3), 77.2 (CH–
O), 66.8 (CH2–O), 44.6 (CH2–N), 26.7 (CH3), 25.2 (CH3);
MS (ESI) m/z: 132 [M+H]+, 74 [Mꢂacetone+H]+.
€
Rennes I by Loıc Toupet.
4.2.3. ( )-N-Benzyl-1-(2,2-dimethyl-[1,3]dioxolan-4-yl)-
methanamine (7). To a solution of solketal (2.64 g,
20.0 mmol) and triethylamine (3.35 mL, 24.0 mmol) in
CH2Cl2 (20 mL) at 0 ꢁC and under argon, was added drop-
wise a solution of methanesulfonyl chloride (1.85 mL,
24.0 mmol) in CH2Cl2 (8 mL). The reaction mixture was
stirred for 2 h and then quenched by addition of water
(4 mL). The resulting solution was extracted with CH2Cl2
and the organic layer was washed with a saturated NaHCO3
solution and then dried (MgSO4). After filtration, the solvent
was evaporated to give quantitatively the crude mesylate de-
rivative (4.21 g, 20.0 mmol). It was then dissolved in aceto-
nitrile (55 mL), and benzylamine (8.70 mL, 80.0 mmol) was
added. The resulting mixture was heated under reflux for 2
days. After removal of the solvent, ethyl acetate (50 mL)
was added, followed by a saturated NaHCO3 solution
(10 mL). The layers were separated and the organic one
was washed with brine and dried (MgSO4). After filtration
and concentration, the residue was purified by flash column
chromatography using ethyl acetate/cyclohexane (7:3–9:1,
v/v) as eluent to give 7 as an orange liquid (3.60 g, 82%).
4.2. Synthesis
4.2.1. 1,3-Dichloropropan-2-one O-benzyloxime (4). 1,3-
Dichloroacetone (1.27 g, 10 mmol) was added to a solution
of benzylhydroxylamine hydrochloride (1.60 g, 10 mmol) in
ethanol (15 mL). The mixture was stirred at 20 ꢁC for 24 h.
The solvent was removed and the residue was treated three
times with ethanol. Then cyclohexane (150 mL) was added
before drying over MgSO4. The precipitate was filtered
off. The filtrate was concentrated to give quantitatively 4
as a colourless liquid (2.32 g). 1H NMR (400 MHz, CDCl3):
d 7.40–7.30 (m, 5H, Ph), 5.18 (s, 2H, CH2Ph), 4.38 (s, 2H,
CH2Cl), 4.28 (s, 2H, CH2Cl); 13C NMR (100 MHz,
CDCl3): d 151.4 (C]N), 136.7 (C–Ar), 128.5 (C–Ar),
128.2 (C–Ar), 128.1 (C–Ar), 76.9 (CH2Ph), 42.1 (CH2Cl),
32.8 (CH2Cl).
4.2.2. ( )-(2,2-Dimethyl-1,3-dioxolan-4-yl)methanamine
(6). To a solution of solketal (3.0 g, 22.8 mmol) in anhydrous
THF (230 mL) were added successively triphenylphosphine
(7.2 g, 27.3 mmol), phthalimide (3.4 g, 22.8 mmol) and di-
isopropyl azodicarboxylate (5.4 mL, 27.3 mmol). The re-
sulting mixture was stirred 20 h at 20 ꢁC under inert
atmosphere. After evaporation of the solvent under reduced
pressure, flash column chromatography on silica gel with
cyclohexane/ethyl acetate (7:3, v/v) as eluent gave 2-[(2,2-
dimethyl-1,3-dioxolan-4-yl)methyl}]-1H-isoindole-1,3(2H)-
dione intermediate as a white solid (5.2 g, 88%). Mp 76 ꢁC
(cyclohexane); Rf : 0.46 (ethyl acetate/cyclohexane¼1:1);
1
IR (neat): n 3300, 1250–1050 cmꢂ1; H NMR (400 MHz,
CDCl3): d 7.33–7.24 (m, 5H, H–Ar), 4.26 (quint,
2
3
3J¼6.0 Hz, 1H, CH–O), 4.03 (dd, J¼8.0 Hz, J¼6.5 Hz,
2
1H, CH2–O), 3.83 (d, J¼13.5 Hz, 1H, CH2Ph), 3.82 (d,
2J¼13.5 Hz, 1H, CH2Ph), 3.68 (dd, 2J¼8.0 Hz, 3J¼7.0 Hz,
3
1H, CH2–O), 2.74 (d, J¼5.5 Hz, 2H, CH2–N), 1.64 (br s,
1H, NH), 1.41 (s, 3H, Me), 1.35 (s, 3H, Me); 13C NMR
(100 MHz, CDCl3): d 140.1 (C–Ar), 128.3 (C–Ar), 128.0
(C–Ar), 126.9 (C–Ar), 109.0 (C–(CH3)2), 75.4 (CH–O),
67.5 (CH2–O), 53.9 (CH2Ph), 51.7 (CH2N), 26.8 (CH3),
25.4 (CH3); MS (ESI) m/z: 244 [M+Na]+, 222 [M+H]+,
164 [Mꢂacetone+H]+; HRMS (ESI) calcd for C13H20NO2
[M+H]+: 222.1494, found: 222.1508.
IR (KBr): n 1700 (C]O) cmꢂ1 1H NMR (400 MHz,
;
CDCl3): d 7.84 (dd, 3J¼5.5 Hz, 4J¼3.0 Hz, 2H, H–Ar),
7.71 (dd, 3J¼5.5 Hz, 4J¼3.0 Hz, 2H, H–Ar), 4.43 (tt,
3J¼6.5 and 5.5 Hz, 1H, CH–O), 4.06 (dd, J¼8.5 Hz, J¼
2
3
6.0 Hz, 1H, CH2–O), 3.92 (dd, 2J¼14.0 Hz, 3J¼7.0 Hz,
2
3
1H, CH2–N), 3.84 (dd, J¼8.5 Hz, J¼5.0 Hz, 1H, CH2–
4.2.4. 1,3-Bis{benzyl[(( )-2,2-dimethyl-1,3-dioxolan-
4-yl)methyl]amino}propanone O-benzyloxime (8). To
a stirred solution of amine 7 (2.00 g, 8.8 mmol) in methanol
(10 mL) was added a solution of oxime 4 (0.49 g, 2.1 mmol)
in methanol (4 mL). The resulting mixture was heated at
reflux for 3 days. After evaporating to dryness, a saturated
solution of NaHCO3 (40 mL) was added followed by
CH2Cl2 (100 mL). The organic layer was dried over
MgSO4 and concentrated. The crude mixture was purified by
flash column chromatography using cyclohexane/ethyl
acetate (1:0–4:1, (v/v)) as eluent to give 7 as an inseparable
mixture of (Z)- and (E)-isomers (0.97 g, 77%). Rf : 0.44
(cyclohexane/ethyl acetate¼4:1); IR (film): n 1250–1060
2
3
O), 3.71 (dd, J¼14.0 Hz, J¼5.5 Hz, 1H, CH2–N), 1.43
(s, 3H, Me), 1.30 (s, 3H, Me); 13C NMR (100 MHz,
CDCl3): d 168.1 (CO), 134.0 (C–Ar), 131.9 (C–Ar), 123.3
(C–Ar), 109.7 (C–(CH3)3), 73.2 (CH–O), 67.3 (CH2–O),
40.9 (CH2–N), 26.7 (CH3), 25.3 (CH3); MS (ESI) m/z: 284
[M+Na]+.
To a suspension of this intermediate (3.0 g, 11.5 mmol) in
methanol (115 mL) was added hydrazine monohydrate
(1.0 mL, 20.1 mmol). The reaction mixture was heated un-
der reflux for 4–5 h. The white precipitate thus obtained
was dissolved by adding a solution of KOH (0.9 g,
16.1 mmol) in methanol (20 mL). The resulting solution
was then concentrated and CH2Cl2 was added. After filtra-
tion, the organic layer was washed with water and dried
over MgSO4. Evaporation of the solvent led to 6 as a pale
yellow liquid (1.36 g, 90%). IR (film): n 3374, 3308,
1
(C–O) cmꢂ1; H NMR (400 MHz, CDCl3): d 7.38–7.18
(m, 15H, H–Ar), 5.08 (s, 2H, OCH2Ph), 4.23–4.13 (m, 2H,
H-2,20), 3.91–3.86 (m, 2H, H-3,30), 3.71–3.35 (m, 9H,
2
H-3,30,a,c, NCH2Ph), 3.25 and 3.17 (d, J¼13.0 Hz, 1H,
H-a), 2.65–2.44 (m, 4H, H-1,10), 1.34–1.33–1.32–1.31 (s,
12H, Me); 13C NMR (100 MHz, CDCl3): d 157.5 (C-b),
138.9 (C–Ar), 137.9 (C–Ar), 129.0 (C–Ar), 128.9 (C–Ar),
128.3 (C–Ar), 128.2 (C–Ar), 128.1 (C–Ar), 128.0 (C–Ar),
1220–1060 cmꢂ1
;
1H NMR (400 MHz, CDCl3): d 4.12
3
2
(qd, J¼6.5 and 4.5 Hz, 1H, CH–O), 4.03 (dd, J¼8.0 Hz,
3J¼6.5 Hz, 1H, CH2–O), 3.66 (dd, J¼8.0 Hz, J¼6.5 Hz,
2
3

M. Goubert et al. / Tetrahedron 63 (2007) 8255–8266
8261
127.7 (C–Ar), 127.0 (C–Ar), 126.9 (C–Ar), 109.0 (C–(CH3)2),
75.8 (OCH2Ph), 74.5–74.2 (C-2,20), 68.4–68.35–68.3 (C-
3,30), 59.9–58.7–58.6 (NCH2Ph), 57.2–57.1–56.4–56.3 (C-
1,10), 55.4 (C-a), 48.7 (C-c), 26.9–26.8 (CH3), 25.7–25.6
(CH3); MS (ESI) m/z: 640 [M+K]+, 624 [M+Na]+,
602 [M+H]+; HRMS (ESI) calcd for C36H48N3O5 [M+H]+:
602.3594, found: 602.3580.
cyclohexane/ethyl acetate (7:3–3:2, v/v) as eluent and gave
9c as an oil (2.04 g, 83%). Rf: 0.43 (cyclohexane/ethyl
acetate¼7:3); IR (film): n 3363, 1712, 1250–1050 cmꢂ1
;
1H NMR (400 MHz, CDCl3): d 4.87 (br s, 1H, NH), 4.17
(m, 1H, CH–O), 4.01 (dd, 2J¼8.0 Hz, 3J¼6.5 Hz, 1H,
CH2–O), 3.63 (dd, 2J¼8.0 Hz, 3J¼6.5 Hz, 1H, CH2–O),
2
3
3.37 (m, 1H, CH2–N), 3.16 (dt, J¼14.0 Hz, J¼6.0 Hz,
1H, CH2–N), 1.42 (s, 9H, t-Bu), 1.40 (s, 3H, Me), 1.32 (s,
3H, Me); 13C NMR (100 MHz, CDCl3): d 156.0 (C]O),
109.2 (C–(CH3)2), 79.4 (C–(CH3)3), 74.9 (CH–O), 66.6
(CH2–O), 42.7 (CH2–N), 28.3 ((CH3)3), 26.7 (CH3), 25.2
(CH3); HRMS (ESI) calcd for C11H22NO4Na [M+Na]+:
254.1368, found: 254.1369.
4.2.5. N-[(( )-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl]-
benzamide (9a). To a solution of amine 6 (300 mg,
2.3 mmol) in anhydrous CH2Cl2 (10 mL) was successively
added, at 0 ꢁC and under argon, triethylamine (480 mL,
3.4 mmol) and 4-dimethylaminopyridine (56 mg, 0.5 mmol).
After stirring for 15 min, benzoyl chloride (425 mL,
4.2 mmol) was added dropwise. The reaction mixture was
stirred until the reaction was completed. The reaction was
quenched with water (4 mL) and the reaction mixture
was extracted with CH2Cl2 (3ꢃ10 mL). The organic layer
was dried over MgSO4 and the solvent was removed
in vacuo. The crude residue was purified by flash column
chromatography using cyclohexane/ethyl acetate (7:3–3:2,
v/v) as eluent and gave 9a as a white solid (405 mg, 75%).
Rf: 0.20 (cyclohexane/ethyl acetate¼7:3); mp 105 ꢁC (ethyl
4.2.8. tert-Butyl{2-[(benzyloxy)imino]-3-chloropropyl}-
[(( )-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]carbamate
(11). To a suspension of KH (160 mg, 1.20 mmol) in 25–
35% mineral oil was added, under argon, anhydrous THF
(2 mL) followed by a solution of 9c (200 mg, 0.86 mmol)
in THF (1 mL). When the bubbling had ceased, a solution
of 4 (90 mg, 0.38 mmol) in THF (1 mL) was introduced.
The reaction mixture was stirred at 20 ꢁC for 2 h. Then water
(2 mL) was slowly added and the solution was diluted with
CH2Cl2 (15 mL). The layers were separated and the aqueous
one was extracted twice with CH2Cl2 (5 mL). The organic
layer was then dried over MgSO4 and the solvent was evap-
orated. The residue was purified by flash column chromato-
graphy using cyclohexane/ethyl acetate (19:1, v/v) as eluent
to give a mixture of (Z)- and (E)-oximes 11 as an oil (54 mg,
33%). Rf: 0.63 (cyclohexane/ethyl acetate¼7:3); IR (film): n
1697 (C]O), 1250–1000 (C–O) cmꢂ1; 1H NMR (400 MHz,
CDCl3): d 7.34 (m, 5H, H–Ar), 5.13 (s, 2H, CH2Ph), 4.48–
4.10 (m, 5H, CH2Cl, CH2–C]N and CH–O), 4.00 (m, 1H,
CH2–O), 3.64–3.44 (m, 2H, CH2–O and CH2–N), 3.22 (m,
1H, CH2–N), 1.46 and 1.42 (s, 9H, t-Bu), 1.38 (s, 3H,
Me), 1.32 (s, 3H, Me); 13C NMR (100 MHz, CDCl3):
d 155.7–155.6–155.3 (C]O), 154.5 (C]N), 137.1–
137.0–128.4–128.0 (C–Ar), 109.3 (C–(CH3)2), 80.8–80.6
(C–(CH3)3), 76.7–76.4 (CH2Ph), 75.0–74.9 (CH–O), 67.0
(CH2–O), 51.1–50.8 (CH2–N), 44.1–43.8 (CH2–CN),
42.7–42.0 (CH2Cl), 28.2 ((CH3)3), 26.7 (CH3), 25.5–25.4
(CH3); HRMS (ESI) calcd for C21H31ClN2O5Na [M+Na]+:
449.1819; found: 449.1834.
1
acetate); H NMR (400 MHz, CDCl3): d 7.78 (m, 2H, H–
Ar), 7.50 (m, 1H, H–Ar), 7.43 (m, 2H, H–Ar), 6.53 (br s,
1H, NH), 4.34 (qd, J¼6.5 and 3.5 Hz, 1H, CH–O), 4.08
3
(dd, 2J¼8.5 Hz, 3J¼6.5 Hz, 1H, CH2–O), 3.75 (ddd,
3
2J¼14.0 Hz, J¼6.0 and 3.5 Hz, 1H, CH2–N), 3.71 (dd,
2J¼8.5 Hz, 3J¼6.5 Hz, 1H, CH2–O), 3.51 (dt, 2J¼14.0 Hz,
3J¼6.0 Hz, 1H, CH2–N), 1.45 (s, 3H, Me), 1.36 (s, 3H,
Me); 13C NMR (100 MHz, CDCl3): d 167.7 (C]O), 134.2
(C–Ar), 131.6 (C–Ar), 128.6 (C–Ar), 126.9 (C–Ar), 109.4
(C–(CH3)2), 74.6 (CH–O), 66.7 (CH2–O), 41.9 (CH2–N),
26.8 (CH3), 25.1 (CH3).
4.2.6. N-[(( )-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl]-
2,2,2-trifluoroacetamide (9b). A solution of amine 6
(500 mg, 4.81 mmol) and ethyl trifluoroacetate (5.70 mL,
48.1 mmol) was stirred at 20 ꢁC for 20 h. After concentra-
tion, toluene was added and the resulting solution was evap-
orated under vacuo to eliminate all traces of solvent and
reagent. Pure compound 9b was obtained as a chestnut liquid
(830 mg, 76%). 1H NMR (400 MHz, CDCl3: d 6.77 (br s, 1H,
3
NH), 4.27 (qd, J¼6.0 and 3.5 Hz, 1H, CH–O), 4.07 (dd,
3
2
2J¼8.5 Hz, J¼6.5 Hz, 1H, CH2–O), 3.65 (dd, J¼8.5 Hz,
4.2.9. 1,3-Diamino-propan-2-one O-benzyloxime (12). To
a solution of 4 (1.83 g, 7.9 mmol) in dry DMF (8 mL) was
added potassium phthalimide salt (5.88 g, 31.8 mmol). The
reaction mixture was heated to 100 ꢁC for 3–4 h. After cool-
ing, the solution was diluted with water (50 mL) and ex-
tracted three times with CH2Cl2 (30 mL). The combined
organic layers were washed with brine, dried over MgSO4
and the solvent was evaporated to dryness. The residue
was stored in a fridge until a precipitate appeared. After
filtration, 2,20-{2-[(benzyloxy)imino]propane-1,3-diyl}bis-
[1H-isoindole-1,3(2H)-dione] intermediate was obtained as
a white solid (2.84 g, 84%). Mp 178 ꢁC (ethyl acetate); IR
(KBr): n 1716 (C]O) cmꢂ1; 1H NMR (400 MHz, CDCl3):
3J¼6.0 Hz, 1H, CH2–O), 3.62 (ddd, J¼14.0 Hz, J¼6.0
and 3.5 Hz, 1H, CH2–N), 3.37 (dt, 2J¼14.0 Hz, 3J¼6.0 Hz,
1H, CH2–N), 1.43 (s, 3H, Me), 1.34 (s, 3H, Me); 13C NMR
(100 MHz, CDCl3): d 157.5 (q, 2JCF¼37 Hz, C]O), 115.7
2
3
1
(q, JCF¼287 Hz, CF3), 109.9 (C–(CH3)2), 73.4 (CH–O),
66.5 (CH2–O), 42.0 (CH2–N), 26.6 (CH3), 24.9 (CH3).
4.2.7. tert-Butyl[(( )-2,2-dimethyl-1,3-dioxolan-4-yl)-
methyl]carbamate (9c). To a solution of 6 (1.39 g,
10.6 mmol) in dioxane (85 mL) was added, at 0 ꢁC, a
0.5 M aqueous solution of Na2CO3 (21.2 mL, 10.6 mmol)
followed by di-tert-butyl dicarbonate (2.5 mL, 11.7 mmol).
The reaction mixture was stirred at 20 ꢁC for 14 h and
then concentrated. The white precipitate thus obtained was
dissolved in water and the aqueous layer was extracted
with ethyl acetate. The combined organic layers were
washed with brine and dried over MgSO4. The residue
was purified by flash column chromatography using
3
4
d 7.81 (dd, J¼5.0 Hz, J¼3.0 Hz, 2H, H–Ar), 7.77 (dd,
4
3
3J¼5.0 Hz, J¼3.0 Hz, 2H, H–Ar), 7.72 (dd, J¼5.0 Hz,
4J¼3.0 Hz, 2H, H–Ar), 7.70 (dd, J¼5.0 Hz, J¼3.0 Hz,
2H, H–Ar), 7.21–7.17 (m, 5H, H–Ar), 5.04 (s, 2H,
CH2Ph), 4.59 (s, 2H, CH2–C]N), 4.84 (s, 2H, CH2–
C]N); 13C NMR (100 MHz, CDCl3): d 167.5–167.4
3
4

8262
M. Goubert et al. / Tetrahedron 63 (2007) 8255–8266
(C]O), 148.8 (C]N), 136.8 (C–Ar), 133.9 (C–Ar), 131.9
(C–Ar), 131.8 (C–Ar), 128.1 (C–Ar), 127.7 (C–Ar), 123.3
(C–Ar), 76.8 (CH2Ph), 39.0 (CH2–C]N), 34.4 (CH2–
C]N). Anal. Calcd for C26H19N3O5 (453.45): C, 68.87;
H, 4.22; N, 9.27. Found: C, 68.74; H, 4.19; N, 9.29.
28.3 (CH3). Anal. Calcd for C20H31N3O5 (393.48): C,
61.05; H, 7.94; N 10.68. Found: C, 61.22; H, 8.03; N, 10.74.
4.2.12. (D)-N,N0-{2-[(Benzyloxy)imino]propane-1,3-
diyl}bis{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]carbox-
amide} (16). To a solution of crude amine 12 (16.2 mmol)
in CH2Cl2 (170 mL) were added, at 0 ꢁC and under argon,
triethylamine (6.8 mL, 48.6 mmol) and 4-dimethylamino-
pyridine (0.8 g, 6.5 mmol). After about 15 min, acylchloride
(R)-15 (5.8 g, 35.6 mmol) was slowly added and the stirring
was continued until the reaction was completed (monitored
by TLC). The reaction was quenched by H2O and the result-
ing solution was extracted with CH2Cl2 (3ꢃ50 mL). The
combined organic layers were dried over MgSO4 and the
solvent was evaporated. The residue was subjected to flash
column chromatography using ethyl acetate/cyclohexane
(3:2, v/v) as eluent to give compound 16 as an oil (4.9 g,
67%). [a]2D5 +1.9 (c 1.1, CHCl3); IR (film): n 3413, 3337,
An aliquot of this intermediate (500 mg, 1.10 mmol) was
dissolved in methanol (10 mL) and hydrazine hydrate
(160 mL, 3.30 mmol) was added. The reaction mixture was
boiled for 3 h and a solution of KOH (186 mg, 3.30 mmol)
in methanol (5 mL) was added. The resulting solution was
stirred at 20 ꢁC overnight and the solvent and hydrazine
were evaporated. Then, CH2Cl2 was added to the residue fol-
lowed by MgSO4. After filtration, the crude amine 12 was
not isolated but kept as a solution in anhydrous CH2Cl2 un-
der argon. 1H NMR (400 MHz, CDCl3): d 7.37–7.30 (m, 5H,
H–Ar), 5.09 (s, 2H, CH2Ph), 3.57 (s, 2H, CH2–N), 3.49 (s,
2H, CH2–N), 1.45 (br s, 4H, NH2).
1736, 1682, 1300–1000 cmꢂ1
;
1H NMR (400 MHz,
4.2.10. N,N0-{2-[(Benzyloxy)imino]propane-1,3-diyl}-bis-
benzamide (13a). To a stirred and ice-cooled solution of 1,3-
diamino-propan-2-one O-benzyloxime dihydrochloride 12
(1.60 mmol) in CH2Cl2 and under argon were added triethyl-
amine (670 mL, 4.80 mmol) and 4-dimethylaminopyridine
(0.64 mmol) followed by dropwise addition of a solution of
benzoyl chloride (600 mL, 5.12 mmol). The reaction mixture
was stirred for 3 h at 20 ꢁC and CH2Cl2 (60 mL) was added.
The organic layer was washed twice with water (12 mL)
following by a saturated NaHCO3 solution (12 mL), dried
over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography using ethyl
acetate/cyclohexane (4:6–1:1, v/v) as eluent to give 13a
(435 mg, 68%) as a white solid. Mp 136 ꢁC; Rf : 0.49 (ethyl
acetate/cyclohexane¼1:1); 1H NMR (400 MHz, CDCl3):
CDCl3): d 7.37–7.31 (M, 5H, H–Ar), 7.26 (se, 1H, NHa),
7.20 (t, J¼6.0 Hz, 1H, NHc), 5.10 (s, 2H, CH2Ph), 4.48
3
3
(dd, J¼8.5 and 4.0 Hz, 1H, H-20), 4.47 (dd, J¼8.5 and
2
3
4.0 Hz, 1H, H-2), 4.26 (t, J¼8.5 Hz, J¼8.5 Hz, 2H, H-
3,30), 4.19 (dd, 2J¼16.0 Hz, 3J¼6.5 Hz, 1H, H-c), 4.12
2
3
(dd, J¼16.0 Hz, J¼6.5 Hz, 1H, H-a), 4.11–4.05 (M, 3H,
H-c,3,30), 4.01 (dd, 2J¼17.0 Hz, 3J¼5.0 Hz, 1H, H-a), 1.46
(s, 3H, Me), 1.40 (s, 3H, Me), 1.38 (s, 3H, Me), 1.36 (s,
13
3H, Me); C NMR (100 MHz, CDCl3): d 171.6 (C-10),
171.4 (C-1), 152.8 (C-b), 137.0 (C–Ar), 128.4 (C–Ar),
128.1 (C–Ar), 128.0 (C–Ar), 111.0 (C–(CH3)2), 76.6
(CH2Ph), 75.0 (C-20), 74.9 (C-2), 67.7 (C-30), 67.6 (C-3),
40.1 (C-a), 35.4 (C-c), 26.1 (CH3), 26.0 (CH3), 25.0
(CH3), 24.9 (CH3); MS m/z: 472 [M+Na]+, 450 [M+H]+.
Anal. Calcd for C22H31N3O7: C, 58.78; H, 6.95; N, 9.35.
Found: C, 58.62; H, 7.22; N, 9.25.
3
3
d 7.88 (d, J¼7.5 Hz, 2H, H–Ar), 7.78 (d, J¼7.5 Hz, 2H,
H–Ar), 7.56 (br t, 3J¼7.0 Hz, 1H, NH), 7.51 (t, 3J¼7.5 Hz,
2H, H–Ar), 7.44 (t, 3J¼7.5 Hz, 2H, H–Ar), 7.42 (t,
3J¼7.5 Hz, 2H, H–Ar), 7.33 (M, 6H, H–Bn and NH), 5.14
4.2.13. N,N0-(2-Oxopropane-1,3-diyl)bis[(2R)-2,3-di-
hydroxypropanamide] (17). To a solution of 16 (500 mg,
1.11 mmol) in acetone/water (10:1, v/v), was added Amber-
lystÒ 15 (280 mg). The resulting suspension was heated
under reflux for 15 h. After cooling and filtration, a solid
was obtained and recrystallized in ethanol to give pure 17
(226 mg, 77%). Rf: 0.05 (ethyl acetate/methanol¼4:1). The
1H NMR (DMSO-d6, at 20 ꢁC) spectrum could not be attrib-
uted because of a coalescence phenomenon; 13C NMR
(100 MHz, DMSO-d6): d 203.0 (CO), 172.4 (NHCO), 72.9
(CHOH), 63.8 (CH2OH), 46.4 (CH2NH); MS (ESI) m/z:
303 [M+K]+, 287 [M+Na]+, 265 [M+H]+, 247
[MꢂH2O+H]+.
3
(s, 2H, CH2Ph), 4.36 (d, J¼6.5 Hz, 2H, H-a), 4.27 (d,
3J¼5.0 Hz, 2H, H-c). Anal. Calcd for C24H23N3O3
(401.46): C, 71.80; H, 5.77; N, 10.47. Found: C, 72.27; H,
5.81; N, 10.44.
4.2.11. tert-Butyl{2-[(benzyloxy)imino]propane-1,3-
diyl}biscarbamate (13b). To a stirred and ice-cooled solu-
tion of crude 12 (0.48 mmol) in dioxane (4 mL), was added
an aqueous Na2CO3 solution (0.5 M aq, 2.0 mL, 0.96 mmol)
followed by di-tert-butyl dicarbonate (230 mL, 1.06 mmol).
The reaction mixture was stirred at 20 ꢁC overnight. After
removing the solvent, the residue was dissolved in water.
The aqueous layer was extracted with ethyl acetate. The or-
ganic layer was washed with brine, dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash col-
umn chromatography using ethyl acetate/cyclohexane (2:8,
v/v) as eluent to give 13b as a white solid (143 mg, 76%).
4.2.14. (L)-(2R)-2,3-Dihydroxy-N-[(1R,5R)-(2-oxo-6,8-
dioxa-3-azabicyclo[3.2.1]oct-5-yl)methyl]propanamide
(18). A stirred solution of 7 (465 mg, 1.76 mmol) was reflux-
ing in 1-butanol (120 mL) for 6 h with catalytic amounts of
pTsOH (7 mg, 0.03 mmol). The reaction mixture was then
filtered through a CeliteÒ pad and the solvent was elimi-
nated. The residue was dissolved in 80 mL of water and
washed three times with diethyl ether (20 mL). After evapo-
ration of the water, the solid was recrystallized in ethanol to
give 18 as a white powder (330 mg, 76%).
1
Mp 112 ꢁC (cyclohexane); H NMR (400 MHz, CDCl3):
d 7.37–7.31 (M, 5H, H–Ar), 5.19 (se, 1H, NH), 5.10 (s,
2H, CH2Ph), 5.07 (se, 1H, NH), 4.02 (de, J¼5.0 Hz, 2H,
3
3
H-c), 3.92 (dd, J¼5.0 Hz, 2H, H-a), 1.45 (s, 9H, t-Bu),
1.44 (s, 9H, t-Bu); 13C NMR (100 MHz, CDCl3): d 156.0
(CO), 155.7 (C-c), 154.8 (CO), 137.4 (C–Ar), 128.4 (CH–
Ar), 128.0 (CH–Ar), 127.9 (CH–Ar), 79.9 (C–(CH3)3),
79.6 (C–(CH3)3), 76.3 (CH2Ph), 41.6 (C-c), 37.0 (C-a),
(ꢂ)-(2R,6S,8R)-18: mp 156 ꢁC (ethanol); Rf 0.18 (ethyl ace-
tate/methanol¼4:1); [a]2D5 ꢂ21.7 (c 0.5, H2O); IR (KBr) n

M. Goubert et al. / Tetrahedron 63 (2007) 8255–8266
8263
3362, 3291, 1664, 1637 cmꢂ1
;
1H NMR (400 MHz,
(NOCH2Ph), 73.5 (OCH2Ph), 73.4 (OCH2Ph), 71.4
(CHOH), 71.3 (CH2O), 39.9 (C-a), 35.4 (C-c).
CD3OD): d 7.77 (se, 1H, NH), 7.65 (t, 3J¼6.0 Hz, 1H,
NH), 5.59 (d, 3J¼5.5 Hz, 1H, OH), 4.72 (t, 3J¼5.5 Hz,
3
1H, OH), 4.64 (d, J¼5.0 Hz, 1H, H-10), 4.02 (d,
4.2.17. N,N0-(2-Oxopropane-1,3-diyl)bis[(2R)-3-(benzyl-
oxy)-2-hydroxypropanamide] (23). To a solution of 22
(38 mg, 0.069 mmol) in acetone/water (10/1, v/v) was added
AmberlystÒ 15 (20 mg). The reaction mixture was heated at
reflux for 48 h. After filtration on a CeliteÒ pad, the residue
was purified by flash column chromatography using ethyl
acetate/methanol (1:0–24:1, v/v) as eluent to give 23
(26 mg, 85%); Rf 0.24 (ethyl acetate); 1H NMR (400 MHz,
CDCl3): d 7.51 (t, J¼5.0 Hz, 2H, NH), 7.26–7.32 (M, 10H,
H–Ar), 4.54 (s, 4H, OCH2Ph), 4.25 (m, 2H, CHOH), 4.14
(dd, 2J¼18.0 Hz, 3J¼6.0 Hz, 2H, H-a,c), 4.06 (dd, 2J¼
3J¼7.5 Hz, 1H, H-70a), 3.91 (td, J¼5.5, 5.5 and 3.5 Hz,
3
1H, H-2), 3.79 (dd, 2J¼7.5 Hz, J¼5.0 Hz, 1H, H-70b),
3
2
3
3.57 (ddd, J¼11.0 Hz, J¼5.5 and 3.5 Hz, 1H, H-3), 3.51
(d, 3J¼6.0 Hz, 2H, CH2–N), 3.46 (dt, 2J¼11.0 Hz,
3J¼5.5 Hz, 1H, H-3), 3.33 (m, 1H, H-40a), 3.01 (dd,
3
2J¼12.5 Hz, J¼3.0 Hz, 1H, H-40b); 13C NMR (100 MHz,
DMSO-d6): d 172.4 (C-1), 168.3 (C-20), 104.5 (C-50), 74.9
(C-10), 72.8 (C-2), 69.9 (C-70), 63.7 (C-3), 47.7 (C-40),
41.1 (CH2–N). Anal. Calcd for C9H14N2O6 (246.2): C,
43.90; H, 5.73; N, 11.38. Found: C, 44.08; H, 5.83; N,
11.14; MS m/z: 269 [M+Na]+, 247 [M+H]+.
3
18.0 Hz, J¼5.0 Hz, 2H, H-a,c), 3.85 (m, 2H, CH2O), 3.74
3
(m, 2H, CH2O), 3.72 (d, J32¼5.5 Hz, 2H, OH); 13C NMR
4.2.15. N,N0-{2-[(Benzyloxy)imino]propane-1,3-diyl}-
bis[(2R)-2,3-dihydroxypropanamide] (21). A solution of
16 (1.00 g, 2.23 mmol) was heated at reflux in ethanol
(30 mL) with catalytic amount of D,L-camphorsulfonic
acid (0.01 g, 0.04 mmol). After the reaction was completed,
K2CO3 was added and the reaction mixture was filtered off.
The solvent was evaporated to dryness to give 21 (0.82 g,
quantitative yield). Rf : 0.30 (ethyl acetate/methanol, 4:1);
1H NMR (400 MHz, CD3OD): d 7.38–7.25 (M, 5H, H–
(100 MHz, CD3OD): d 201.2 (CO), 172.4 (NHCO), 137.3
(C–Ar), 128.5 (C–Ar), 128.0 (C–Ar), 127.9 (C–Ar), 73.5
(OCH2Ph), 71.2 (CH2O), 70.9 (CHOH), 46.9 (CH2NH).
4.2.18. (L)-Methyl-(2R)-3-(tert-butyldiphenylsilyloxy)-
2-hydroxypropanoate (25). To a solution of (+)-methyl-
(2R)-2,3-dihydroxypropanoate 24 in anhydrous dichloro-
methane under argon was added imidazole (0.57 mg,
8.3 mmol). The resulting mixture was cooled at ꢂ40 ꢁC
and tert-butyldiphenylchlorosilane (1.37 g, 5.0 mmol) was
added. The stirring was pursued for 1 h 30 min and then the
reaction was quenched by a saturated solution of ammonium
chloride (5 mL). The solution was allowed to warm to room
temperature and then the layers were separated. The aqueous
layer was extracted with dichloromethane (3ꢃ5 mL) and the
combined organic layers were dried over MgSO4 and con-
centrated in vacuo. The residue was purified by flash column
chromatography with cyclohexane/ethyl acetate (19:1–9:1,
v/v) as eluent and give 25 as an oil (1.21 g, 83%). Rf: 0.47 (cy-
clohexane/AcOEt¼4:1); [a]2D5 ꢂ22.8 (c 1.8, CHCl3); IR
(film): n 3518, 1747, 1245–1025; 1H NMR (400 MHz,
CDCl3): d 7.68–7.63 (m, 4H, H–Ar), 7.47–7.38 (M, 6H, H–
Ar), 4.26 (dt, 3J¼8.0 and 3.0 Hz, 1H, CHO), 3.99 (dd,
2J¼10.5 Hz, 3J¼3.0 Hz, 1H, CH2O), 3.94 (dd, 2J¼10.5 Hz,
3
Ar), 5.09 (s, 2H, CH2Ph), 4.21 (s, 2H, H-c), 4.13 (t, J¼
3
4.0 Hz, 1H, H-20), 4.11 (t, J¼4.0 Hz, 1H, H-2), 4.01 (d,
2J¼16.0 Hz, 1H, H-a), 3.98 (d, 2J¼16.0 Hz, 1H, H-a),
3.80–3.72 (M, 4H, H-3,30); 13C NMR (100 MHz, CD3OD):
d 175.7 (C-10), 175.1 (C-1), 155.5 (C-b), 139.0 (C–Ar),
129.4 (C–Ar), 129.3 (C–Ar), 128.9 (C–Ar), 77.4 (CH2Ph),
74.3 (C-2,20), 65.3 (C-30), 65.2 (C-3), 40.7 (C-a), 36.5 (C-c).
4.2.16. N,N0-{2-[(Benzyloxy)imino]propane-1,3-diyl}bis-
[(2R)-3-(benzyloxy)-2-hydroxypropanamide] (22a). A so-
lution of 21 (0.10 g, 0.27 mmol) in toluene/methanol
(5.5 mL, 10:1, v/v) was heated at reflux until complete dis-
solution. Then, di-n-butyltin oxide (0.14 g, 0.57 mmol)
was added and the resulting solution was heated using
a Dean–Stark apparatus for 5–6 h. To the stirred resulting
mixture were added benzylbromide (0.13 mL, 1.10 mmol)
and tetrabutylammonium iodide (0.07 g, 0.19 mmol) and
the heating was continued for 5 h. After cooling, ethyl ace-
tate (15 mL) and water (5 mL) were poured in the reaction
mixture. The layers were separated and the aqueous one
was further extracted with ethyl acetate (3ꢃ10 mL), dried
(MgSO4) and the solvent evaporated until dryness. The res-
idue was purified by flash column chromatography using
ethyl acetate/cyclohexane (19:1–1:0, v/v) as eluent and
3
3J¼3.0 Hz, 1H, CH2O), 3.80 (s, 3H, Me), 3.18 (d, J¼
8.0 Hz, 1H, OH), 1.05 (s, 9H, Me); 13C NMR (100 MHz,
CDCl3): d 173.2 (CO), 135.5 (C–Ar), 132.9 and 132.8 (C–
Ar), 129.8 (C–Ar), 127.7 (C–Ar), 71.9 (CHO), 65.8
(CH2O), 52.4 (Me), 26.6 (Me), 19.2 (C–(CH3)3).
4.2.19. (D)-Methyl-(2R)-3-(tert-butyldiphenylsilyloxy)-
2-(methoxymethoxy)propanoate (26). To a solution of 25
(8.50 g, 23.7 mol) in CH2Cl2 (55 mL) were added, at
20 ꢁC and under argon, diisopropylethylamine (12.4 mL,
71.1 mmol) and chloromethylmethylether (5.4 mL,
71.1 mmol). The resulting mixture was stirred overnight at
20 ꢁC. Then were added more diisopropylethylamine
(4.1 mL, 23.7 mmol) and chloromethylmethylether (1.8 mL,
23.7 mmol). After 8 h at 20 ꢁC, the reaction was finally com-
pleted and quenched by water (16 mL). The layers were sep-
arated and the organic one was washed with water (16 mL),
dried (MgSO4) and concentrated. Purification by column
chromatography using cyclohexane/ethyl acetate (39:1, v/v)
as eluent gave 26 (8.04 g, 84%). Rf: 0.51 (cyclohexane/ethyl
acetate¼4:1); [a]2D5 +7.0 (c 1.3, CHCl3); IR (film): n 1752,
1
gave 22a (50 mg, 34%). Rf: 0.30 (ethyl acetate); H NMR
(400 MHz, CDCl3): d 7.31–7.23 (M, 17H, H–Ar and NH),
2
5.03 (s, 2H, OCH2Ph), 4.51 (d, J¼12.5 Hz, 2H, H–Ar),
2
3
4.49 (d, J¼12.5 Hz, 2H, H–Ar), 4.20 (q, J¼5.0 Hz, 1H,
CHOH), 4.19 (q, 3J¼5.0 Hz, 1H, CHOH), 4.13 (dd,
3
2
2J¼16.5 Hz, J¼6.5 Hz, 1H, H-c), 3.96 (dd, J¼16.5 Hz,
3
3J¼6.5 Hz, 1H, H-c), 3.93 (d, J¼6.0 Hz, 2H, H-a), 3.74
2
3
3
(dd, J¼9.5 Hz, J¼5.0 Hz, 1H, H–CH2O), 3.69 (d, J¼
2
3
4.0 Hz, 2H, CH2O), 3.67 (dd, J¼9.5 Hz, J¼4.5 Hz, 1H,
3
3
CH2O), 3.64 (d, J¼5.0 Hz, 1H, OH), 3.57(d, J¼5.0 Hz,
1H, OH); 13C NMR (100 MHz, CD3OD): d 172.3
(NHCO), 172.1 (NHCO), 154.0 (CO), 137.4 (C–Ar), 137.3
(C–Ar), 137.2 (C–Ar), 128.5 (C–Ar), 128.4 (C–Ar), 128.2
(C–Ar), 128.0 (C–Ar), 127.9 (C–Ar), 127.8 (C–Ar), 76.4
1
1260–1045 cmꢂ1; H NMR (400 MHz, CDCl3): d 7.71–
7.67 (m, 4H, H–Ar), 7.46–7.36 (M, 6H, H–Ar), 4.73 (s,

8264
M. Goubert et al. / Tetrahedron 63 (2007) 8255–8266
2H, O–CH2–O), 4.31 (dd, 3J¼5.5 Hz, 3J¼4.5 Hz, 1H,
4.2.22. (D)-N,N0-{2-[(Benzyloxy)imino]propane-1,3-
diyl}-bis[(2R)-3-(tert-butyldiphenylsilyloxy)-2-hydroxy-
propanamide] (29) and (D)-N,N0-(2-oxopropane-1,3-
diyl)bis[(2R)-3-(tert-butyldiphenylsilyloxy)-2-hydroxy-
propanamide] (30b). Method A: to a solution of oxime 28
(950 mg, 1.01 mmol) in anhydrous CH2Cl2 (35 mL) was
added, at 0 ꢁC and under argon, trimethylsilylbromide
(1.07 mL, 8.11 mmol). The reaction mixture was stirred
for 4 h. After quenching by adding a saturated solution of
NaHCO3 (30 mL), the layers were separated. The aqueous
layer was extracted with CH2Cl2. The combined organic
layers were dried (MgSO4) and concentrated under vacuo.
The residue was purified by flash column chromatography
using cyclohexane/ethyl acetate (3:2–1:4) as eluent and
gave (R,R)-29 (0.460 g, 54%) and (R,R)-30 (0.150 g, 20%).
2
3
CHO), 3.97 (dd, J¼10.5 Hz, J¼5.5 Hz, 1H, CH2O), 3.94
(dd, 2J¼10.5 Hz, 3J¼4.5 Hz, 1H, CH2O), 3.75 (s, 3H, Me),
3.37 (s, 3H, Me), 1.05 (s, 9H, Me); 13C NMR (100 MHz,
CDCl3): d 171.1 (CO), 135.6 and 135.5 (C–Ar), 133.1 and
133.0 (C–Ar), 129.7 (C–Ar), 127.7 (C–Ar), 96.2 (O–CH2–
O), 76.5 (CHO), 64.7 (CH2O), 55.8 (CH3), 51.9 (CH3),
26.6 (CH3), 19.2 (C–(CH3)3); HRMS (ESI) calcd for
C22H30O5SiNa [M+Na]+: 425.1760, found: 425.1757.
4.2.20. (2R)-3-(tert-Butyldiphenylsilyloxy)-2-(methoxy-
methoxy)propanoyl chloride (27). To a solution of ester
26 (6.04 g, 15.0 mmol) in tetrahydrofuran/methanol
(420 mL, 4:1, v/v) was added, under argon, a 1 M solution
of lithium hydroxide (60 mL) in THF/MeOH (4:1, v/v).
The reaction mixture was stirred 4 h at 20 ꢁC and then the
solvents were evaporated in vacuo. Traces of water were
eliminated by washing the residue twice with anhydrous tol-
Method B: to a solution of 29 (0.344 g, 0.41 mmol) in ace-
tone/water (8 mL, 10/1, v/v), were added AmberlystÒ 15
(0.100 g) and paraformaldehyde (0.120 g, 4.07 mmol). The
resulting mixture was heated under reflux for 24 h. After fil-
tration on a CeliteÒ pad and concentration, the residue was
purified by flash column chromatography with cyclohex-
ane/ethyl acetate (3:2–1:4) as eluent and gave 29 (0.130 g,
38%) and 30 (0.078 g, 26%).
1
uene. The lithium salt of 26 was characterized by its H
NMR spectrum. 1H NMR (400 MHz, CD3OD): d 7.76–
7.71 (m, 4H, H–Ar), 7.43–7.35 (M, 6H, H–Ar), 4.76 (d,
2
2J¼7.0 Hz, 1H, O–CH2–O), 4.74 (d, J¼7.0 Hz, 1H, O–
CH2–O), 4.26 (dd, 3J¼7.5 and 3.0 Hz, 1H, CHO), 3.98
(dd, 2J¼10.5 Hz, 3J¼3.0 Hz, 1H, CH2O), 3.88 (dd,
2J¼10.5 Hz, 3J¼7.5 Hz, 1H, CH2O), 3.40 (s, 3H, Me),
1.04 (s, 9H, Me). The lithium salt of 26 (2.5 mmol) was dis-
solved, under argon at 0 ꢁC, in anhydrous ether (10 mL) be-
fore adding pyridine (55 mL, 0.5 mmol) followed by freshly
distilled oxalyl chloride (430 mL, 5.0 mmol). The reaction
mixture was stirred overnight. Elimination of the solvent
furnished quantitatively acyl chloride 27.
Compound (+)-(R,R)-(29). Rf: 0.45 (cyclohexane/ethyl
acetate¼3:2); [a]2D5 +12.1 (c 5.6, CHCl3); IR (film): n
1
3396, 1666 cmꢂ1; H NMR (400 MHz, CDCl3): d 7.69–
7.64 (M, 8H, H–Ar), 7.49–7.30 (M, 19H, H–Ar and NH),
5.10 (s, 2H, CH2Ph), 4.27–4.13 (M, 5H, CHO, H-a and H-
c), 3.99–3.90 (M, 5H, CH2O and H-a), 3.51 (d, 3J¼5.0 Hz,
3
1H, OH), 3.50 (d, J¼5.0 Hz, 1H, OH), 1.07 (s, 18H, Me);
4.2.21. (D)-N,N0-{2-[(Benzyloxy)imino]propane-1,3-
diyl}bis[(2R)-3-(tert-butyldiphenylsilyloxy)-2-(methoxy-
methoxy)propanamide] (28). Amine (12) (1.13 mmol) was
dissolved, under argon and at 0 ꢁC, into CH2Cl2 (7 mL). Tri-
ethylamine (1.0 mL, 7.47 mmol) and 4-dimethylaminopyri-
dine (0.05 g, 0.45 mmol) were then added followed, after
15 min, by 27 (1.02 g, 2.49 mmol). The stirring was contin-
ued for 18 h. The reaction mixture was diluted with
CH2Cl2 (55 mL). The solution was washed twice with water
(16 mL) followed by a saturated solution of Na2CO3 (8 mL)
and dried (MgSO4). Purification of the crude residue by flash
column chromatography with cyclohexane/ethyl acetate
(7:3, v/v) as eluent gave 28 as a gum (0.39 g, 37%). Rf :
0.30 (cyclohexane/ethyl acetate¼7:3); [a]2D5 +19.7 (c 1.2,
13C NMR (100 MHz, CDCl3): d 172.2 (CO), 172.0 (CO),
153.7 (C-b), 137.1 (C–Ar), 135.4 (C–Ar), 132.7 (C–Ar),
132.6 (C–Ar), 129.9 (C–Ar), 128.4 (C–Ar), 128.2 (C–Ar),
128.0 (C–Ar), 127.8 (C–Ar), 76.5 (CH2Ph), 72.4 (CHO),
72.3 (CHO), 65.15 (CH2O), 65.1 (CH2O), 39.9 (C-a), 35.2
(C-c), 26.7 (CH3), 19.2 (CH3); HRMS (ESI): calcd for
C48H59N3O7Si2Na [M+Na]+: 868.3789, found: 868.3792.
Compound (+)-(R,R)-(30b). Rf : 0.12 (cyclohexane/ethyl
acetate¼3:2); [a]2D5 +10.5 (c 1.8, CHCl3); IR (film): n
3397, 1665, 1111 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d 7.66–7.62 (M, 8H, H–Ar), 7.46–7.36 (M, 14H, H–Ar and
2
3
NH), 4.23 (dd, J¼19.0 Hz, J¼5.5 Hz, 2H, H-a and H-c),
4.23 (m, 2H, CHO), 4.16 (dd, 2J¼19.0 Hz, 3J¼5.0 Hz, 2H,
H-a and H-c), 3.93 (dd, 2J¼10.5 Hz, 3J¼5.0 Hz, 2H, CH2O),
3.91 (dd, 2J¼11.0 Hz, 3J¼5.0 Hz, 2H, CH2O), 3.38 (se, 2H,
OH), 1.06 (s, 18H, Me); 13C NMR (100 MHz, CDCl3)
d 199.9 (C-b), 172.0 (CO), 135.5 and 135.4 (C–Ar), 132.6
and 132.4 (C–Ar), 130.0 (C–Ar), 127.9 (C–Ar), 71.9
(CHO), 65.1 (CH2O), 46.8 (C-a and C-c), 26.8 (CH3), 19.2
(CH3). HRMS (ESI): calcd for C41H52N2O7Si2Na
[M+Na]+: 763.3211, found: 763.3181.
CHCl3); IR (film) n 3425, 3322, 1680, 1110–1028 cmꢂ1
;
1H NMR (400 MHz, CDCl3): d 7.69–7.63 (M, 8H, H–Ar),
7.42–7.30 (M, 19H, H–Ar and NH), 5.06 (s, 2H, CH2Ph),
4.74 (d, 2J¼6.5 Hz, 1H, O–CH2–O), 4.69 (d, 2J¼6.5 Hz, 1H,
2
O–CH2–O), 4.67 (d, J¼6.5 Hz, 1H, O–CH2–O), 4.63 (d,
2J¼6.5 Hz, 1H, O–CH2–O), 4.26–4.18 (M, 3H, CHO and
H-c), 4.14 (dd, 2J¼12.0 Hz, 3J¼6.0 Hz, 1H, H-a), 4.10 (dd,
2J¼11.0 Hz, 3J¼6.0 Hz, 1H, H-c), 4.01–3.93 (M, 5H,
CH2OSi and H-a), 3.32, (s, 3H, H–Me), 3.29 (s, 3H, Me),
1.02 (s, 18H, Me); 13C NMR (100 MHz, CDCl3): d 170.4
(CO), 170.1 (CO), 153.1 (C-b), 137.2 (C–Ar), 135.6 (C–Ar),
133.1 (C–Ar), 133.0 (C–Ar), 129.7 (C–Ar), 128.4 (C–
Ar), 128.2 (C–Ar), 128.0 (C–Ar), 127.7 (C–Ar), 96.2 (C–
Ar), 78.4 (CHO), 78.3 (CHO), 76.5 (CH2Ph), 65.0 (CH2O),
64.7 (CH2O), 56.0 (CH3), 55.9 (CH3), 40.3 (C-a), 35.3
(C-c), 26.7 (CH3), 19.2 (CH3); HRMS (ESI): calcd for
C52H67N3O9Si2Na [M+Na]+: 956.4314, found: 956.4340.
4.2.23. (D)-(2R)-3-(tert-Butyldiphenylsilyloxy)-2-hy-
droxy-N-({(6R)-2-butoxy-6-[(tert-butyldiphenylsilyloxy)-
methyl]-5-oxomorpholin-2-yl}methyl)propanamide (31)
and (L)-(2R)-3-(tert-Butyldiphenylsilyloxy)-2-hydroxy-
N-({(2R)-2-[(tert-butyldiphenylsilyloxy)methyl]-3-oxo-
2,3-dihydro-2H-1,4-oxazin-6-yl}methyl)propanamide
(32). A solution of 30b (0.078 g, 0.105 mmol) and pTsOH
(0.001 g) in 1-butanol (2.5 mL) were heated under reflux

M. Goubert et al. / Tetrahedron 63 (2007) 8255–8266
8265
ꢁ
2. (a) Deslongchamps, P.; Rowan, D. D.; Pothier, N.; Sauve, G.;
Saunders, J. K. Can. J. Chem. 1981, 59, 1105–1121; (b)
Pothier, N.; Goldstein, S.; Deslongchamps, P. Helv. Chim.
Acta 1992, 75, 604–620.
for 6 h. After concentration a mixture of starting material
30b, compound 31 and compound 32, which could be easily
separated by flash column chromatography was obtained.
These three new compounds could be fully characterized
at this stage. A mixture of 30b, 31 and 32 was then dissolved
in toluene (2.4 mL) and heated under reflux for 5 h. After
evaporation of the solvent the crude residue was flash chro-
matographed with cyclohexane/ethyl acetate (1:1, v/v) as
eluent and gave (R,R)-31 (0.044 g, 57%).
3. Yin, B.-L.; Yang, Z.-M.; Hu, T.-S.; Wu, Y.-L. Synthesis 2003,
13, 1995–2000.
4. Hossain, N.; Zapata, A.; Wilstermann, M.; Nilsson, U. J.;
Magnusson, G. Carbohydr. Res. 2002, 337, 569–580.
5. (a) Seward, E. M.; Carlson, E.; Harrison, T.; Haworth, K. E.;
Herbert, R.; Kelleher, F. J.; Kurtz, M. M.; Moseley, J.; Owen,
S. N.; Owens, A. P.; Sadowski, S. J.; Swain, C. J.; Williams,
B. J. Bioorg. Med. Chem. Lett. 2002, 12, 2515–2518; (b)
Williams, B. J.; Cascieri, M. A.; Chicchi, G. G.; Harrison, T.;
Owens, A. P.; Owen, S. N.; Rupniak, N. M. J.; Tattersall,
D. F.; Williams, A.; Swain, C. J. Bioorg. Med. Chem. Lett.
2002, 12, 2719–2722; (c) Raubo, P.; Kulagowski, J. J.;
Swain, C. J. Synlett 2003, 2021–2024.
6. Trump, R. P.; Bartlett, P. A. J. Comb. Chem. 2003, 5, 285–291.
7. Goubert, M.; Canet, I.; Sinibaldi, M.-E. Eur. J. Org. Chem.
2006, 23, 4805–4812.
8. Amine 6 was classically prepared from commercially available
solketal in two steps and 79% overall yield via its phthalimide
derivative (Lohray, B. B.; Sekar Reddy, A.; Bhushan, V.
Tetrahedron: Asymmetry 1996, 7, 2411–2416).
9. Amine 7 was obtained from the mesylate of solketal (Kim,
H. S.; Barak, D.; Harden, T. K.; Boyer, J. L.; Jacobson, K. A.
J. Med. Chem. 2001, 44, 3092–3108) by treatment with benzyl-
amine in CH3CN as previously mentionned by; Lemaire, M.;
Posada, F.; Gourcy, J.-G.; Jeminet, G. Synthesis 1995, 6,
627–629.
10. For facilities, all new oximes prepared and described in the
experimental part were depicted using the same numeroation
we indicated in Scheme 1.
11. Ryu, I.; Kuriyama, H.; Minakata, S.; Komatsu, M.; Yoon, J. Y.;
Kim, S. J. Am. Chem. Soc. 1999, 121, 12190–12191.
12. Das, N. B.; Nanda, B.; Nayak, A. Synth. Commun. 2002, 32,
3647–3651.
Compound (+)-(R,R)-(31). Gum; Rf: 0.50 (cyclohexane/
ethyl acetate¼1:1); [a]D25 +25.9 (c 0.2, CHCl3); IR (film): n
3412, 1682, 1113 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d 7.69 (m, 4H, H–Ar), 7.62 (m, 4H, H–Ar), 7.48–7.35 (M,
3
3
12H, H–Ar), 6.94 (t, J¼6.5 Hz, 1H, NH), 5.60 (d, J¼
3
3
4.5 Hz, 1H, NH-cycle), 4.19 (dd, J¼4.0 Hz, J¼2.0 Hz,
1H, CHO), 4.17–4.11 (M, 2H, CHOH and CH-cycle-
2
3
CH2O), 3.99 (dd, J¼10.5 Hz, J¼2.0 Hz, 1H, CH-cycle-
CH2O), 3.98 (dd, 2J¼10.5 Hz, 3J¼5.0 Hz, 1H, CH–CH2O),
3.93 (dd, 2J¼10.5 Hz, 3J¼4.5 Hz, 1H, CH–CH2O), 3.66 (dd,
2J¼14.0 Hz, 3J¼7.0 Hz, 1H, –CH2NH), 3.58–3.46 (M, 4H,
–CH2NH, –CH2-cycle-NH and OCH2CH2–), 3.23 (dd,
2J¼12.5 Hz, 3J¼5.0 Hz, 1H, –CH2-cycle-NH), 3.02 (de,
3J¼4.5 Hz, 1H, OH), 1.55 (Q, 2J¼7.0 Hz, 2H, –OCH2CH2),
1.36 (h, 3J¼7.5 Hz, 2H, CH3CH2), 1.07 (s, 9H, Me), 1.03 (s,
9H, Me), 0.91 (t, 3J¼7.5 Hz, 3H, Me); 13C NMR (100 MHz,
CDCl3): d 171.7 (NHCO), 168.2 (NHCO-cycle), 135.7–
135.6–135.4 (C–Ar), 133.4–133.1–132.5 (C–Ar), 130.1–
129.7 (C–Ar), 127.9–127.7 (C–Ar), 96.1 (O–C–O), 74.1
(CH-cycle-O), 72.0 (CH–O), 65.1 (CH2–O), 64.2 (CH-
cycle-CH2–O), 61.4 (–O–CH2CH2–), 47.4 (N–CH2-cycle–),
41.3 (NH–CH2–), 31.8 (O–CH2CH2–), 26.9–26.7 (CH3),
19.4 (CH3CH2–), 19.3 (C–(CH3)3), 13.9 (CH3); HRMS
(ESI): calcd for C45H60N2O7Si2Na [M+Na]+: 819.3837,
found: 819.3867.
Compound (ꢂ)-(R,R)-(32). Rf¼0.45 (ethyl acetate/cyclo-
hexane¼3:2); [a]2D5 ꢂ10.3 (c 0.2, CHCl3); IR (film): n
13. Xiao, X.; Bai, D. Synlett 2001, 535–537.
3392, 1682, 1113 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d 7.70–7.61 (M, 8H, H–Ar), 7.46–7.35 (M, 13H, H–Ar and
14. (a) Tsuritani, T.; Yagi, K.; Shinokubo, H.; Oshima, K. Angew.
Chem., Int. Ed. 2003, 42, 5613–5615; (b) Kaiser, A.; Wiegrebe,
W. Monatsh. Chem. 1996, 127, 763–774; (c) Blake, J. A.;
Ingold, K. U.; Lin, S.; Mulder, P.; Pratt, D. A.; Sheeller, B.;
Walton, J. C. Org. Biomol. Chem. 2004, 2, 415–420.
15. Plate, R.; Plaum, M. J. M.; Pintar, P.; Jans, C. G.; de Boer, T.;
Dijcks, F. A.; Ruigt, G.; Andrews, J. S. Bioorg. Med. Chem.
1998, 6, 1403–1420.
NH-cycle–), 7.06 (t, 3J¼5.5 Hz, 1H, NH), 5.59 (d, 3J¼
3
5.0 Hz, 1H, CH–NH-cycle–), 4.54 (dd, J¼4.5 and 2.5 Hz,
2
3
1H, O–CH-cycle–), 4.14 (dd, J¼11.0 Hz, J¼4.5 Hz, 1H,
3
CH-cycle-CH2), 4.13 (t, J¼5.5 Hz, 1H, CH–O), 3.97 (dd,
2J¼11.5 Hz, 3J¼2.5 Hz, 1H, CH-cycle-CH2), 3.94–3.85
3
(M, 4H, CH2NH and CH–CH2O), 3.15 (d, J¼4.5 Hz, 1H,
OH), 1.06 (s, 9H, Me), 1.04 (s, 9H, Me); 13C NMR
(100 MHz, CDCl3): d 171.4 (–NH–CO–), 163.8 (–NH–CO-
cycle), 136.0 (O–C]CH), 135.6 and 135.5 (C–Ar), 135.5
and 135.4 (C–Ar), 133.1 and 132.9 (C–Ar), 132.6 and
132.4 (C–Ar), 130.0 (C–Ar), 129.8 (C–Ar), 127.9 (C–Ar),
127.7 (C–Ar), 102.1 (C]CH), 78.0 (CH-cycle-CH2), 71.8
(CH–O), 65.1 (–CH–CH2–O), 64.1 (CH-cycle-CH2–), 38.8
(CH2NH), 26.8 (CH3), 26.6 (CH3), 19.2 (C–(CH3)3);
HRMS (ESI): calcd for C41H50N2O6Si2Na [M+Na]+:
745.3105, found: 745.3133.
16. Tursun, A.; Aboab, B.; Canet, I.; Sinibaldi, M.-E. Tetrahedron
Lett. 2005, 46, 2291–2294.
17. (S)-Solketal was first transformed into its carboxylate potas-
sium salt using KMnO4 in H2O/KOH in 93% yield according
to the procedure described by: Beau, J.-M.; Sinay, P.
Tetrahedron Lett. 1985, 26, 6193–6196; Acylation of this salt
by (COCl)2 in ether with catalytic amounts of pyridine using
the method of: Tanaka, A.; Yamashita, K. Agric. Biol. Chem.
1980, 44, 199–202; furnished the attempted (R)-15 in 95%
yield.
18. For related processes, see: (a) Ostrowski, J.; Altenbach, H.-J.;
Wishnat, R.; Brauer. Eur. J. Org. Chem. 2003, 68, 1104–
1110; (b) Garna, A.; Guidi, A.; Machetti, F.; Menchi, G.;
Occhiato, E. G.; Scarpi, D.; Sisi, S.; Trabocchi. J. Org.
Chem. 1999, 64, 7347–7364.
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