First general methods toward aldehyde enolphosphates

Article abstract of DOI:10.1016/j.bioorg.2011.11.006

We herein report two innovative methods toward aldehyde enolphosphates and the first saccharidic aldehyde enolphosphates. Aldehyde enolphosphate function is worthwhile to be considered as a good phosphoenolpyruvate analogue.

Full text of DOI:10.1016/j.bioorg.2011.11.006

Bioorganic Chemistry 40 (2012) 48–56
Contents lists available at SciVerse ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
First general methods toward aldehyde enolphosphates
⇑
Nicolas Barthes , Claude Grison
CEFE UMR 5175, Campus CNRS, 1919 route de Mende, 34293 Montpellier cedex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 August 2011
Available online 9 December 2011
We herein report two innovative methods toward aldehyde enolphosphates and the first saccharidic
aldehyde enolphosphates. Aldehyde enolphosphate function is worthwhile to be considered as a good
phosphoenolpyruvate analogue.
Ó 2011 Elsevier Inc. All rights reserved.
Keywords:
Aldehyde enolphosphate
Perkow reaction
Hydroalumination
a-Iodoaldehyde
a,b-Unsaturated aldehyde
1. Introduction
to the preparation and stability of the enolates and is totally inade-
quate for enolphosphates derived from aldehyde enolates.
Enolphosphates derivatives are compounds of great interest in
metal-catalysed cross-coupling reactions. They are key intermedi-
ates in the formation of CAC bonds via ring-closing metathesis or
palladium-catalysed functionalisation of lactones, lactams, ketones
and enones. Enolphosphates constitute a promising alternative to
their analogous triflates, because they are more stable, easier to
isolate and undergo effective Pd-catalysed coupling. The synthetic
potential of the enolphosphates was demonstrated by its success-
ful application to the construction of N- and O-heterocycles, com-
plex polycyclic ethers and numerous natural products [1–9].
Moreover, enolphosphates could become of various interests in
terms of biological applications, because they incorporate the
structural part of phosphoenolpyruvate (PEP). This is biologically
interesting as the PEP is involved in essential metabolic transfor-
mations of living organisms mainly as a phosphate donor and plays
an important role in the metabolism of ulosonic acids like KDO,
DAH or KDN [10]. Previous investigations about inhibitors of
KDO 8-phosphate synthase and DAH 7-phosphate synthase sug-
gest that enolphosphate group derived from aldehyde could be a
good analogue of PEP [11–13].
The second direct way to enolphosphates is the Perkow reaction
involving trialkylphosphites and -halogenoketones [15]. Its
a
general use is first limited by the availability of the halogenated
carbonyl compounds, but its main drawback is usually the compet-
itive Michaelis–Arbuzov reaction leading to corresponding b-keto-
phosphonate [16]. Thus, the study of this reaction is restricted to
haloketones bearing nonsensitive functionality [17].
2. Results and discussion
Based on recent findings with synthetic and biological results of
enolphosphates derived from aldehydes [13], we report herein the
full details of two complementary approaches to aldehyde enol-
phosphates: the first one is based on Perkow reaction, the second
one on hydroalumination–phosphorylation tandem reaction.
2.1. Based on Perkow reaction
Previously, we reported a rapid and efficient synthesis of glucidic
phosphoenolpyruvic acid derivatives based on a Perkow reaction
However, the synthesis of aldehyde enolphosphates remains a
challenging task in organic synthesis as suppression of the carbox-
ylic acid moiety of PEP increases the fragility of the vinyl group
structure. Moreover, only few syntheses of a vinylphosphate moiety
have been reported. Most of them are based on the electrophilic
phosphorylation of enolates which reacts at the O-position with
phosphochloridate derivatives [2,14]. The method is subordinated
using a suitable halogenated precursor, b-halogeno-
-halogenoglycidic ester, and trimethylphosphite [18]. Prompted
by these results, we decided to investigate the Perkow reaction be-
tween -iodoaldehydes and trialkylphosphite in order to prepare
a-ketoester or
a
a
the first functionalised aldehyde enolphosphates (Scheme 1).
We used a large variety of functions on our model compounds
to test its compatibility with the synthesis’ conditions: alkyl chain,
free alcohol, pivaloyl or methyl ester, silyl ether, dialkylphosphate
and isopropylidene acetal. While 1a is commercial, the synthesis of
⇑
Corresponding author.
E-mail address: nicolas.barthes@cefe.cnrs.fr (N. Barthes).
0045-2068/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.bioorg.2011.11.006

N. Barthes, C. Grison / Bioorganic Chemistry 40 (2012) 48–56
49
Table 1
R
O
OR
OR
P
Mono protection for terminal alcohol of triols.
3
O
Product Conditions
Yields
(%)
R'=Me
R'=Me
R'=Me
R= a CH3
5c
5d
PivCl (1 eq.), Pyridine, 0 °C, 2 h
TBDMSCl (1.1 eq.), Et3N (1.1 eq.), DMAP (0.5 eq.), 12 h,
CH2Cl2
89
88
b
c
d
e
f
(CH2)4OH
(CH2)4OPiv
(CH2)4OTBDMS
(CH2)4OP(O)(OEt)2
5e
6d
ClP(O) (OEt)2 (1 eq.), DMAP (0.5 eq.), 12 h, 0 °C, Pyridine 96
l
TBDMSCl (2.1 eq.), Et3N (2.1 eq.), DMAP (0.5 eq.), 72 h,
CH2Cl2
80
O
R
R'=Me
6e
ClP(O) (OEt)2 (1 eq.), DMAP (0.5 eq.), 12 h, 0 °C, Pyridine 97
2
(CH2)4OP(O)(OEt)2 R'=Et
R'=Me
g
h
(CH2)5CO2Me
(even if global yield is good: 35% from commercial compound) due
to partial cleavage of the protecting group leading to 12% of com-
pound 1b.
It’s worth noting 9,10,16-trihydroxyhexadecanoic acid can be
used instead of its methyl ester 4. Selective phosphorylation or
silylation, directly carried out on the carboxylic acid, followed by
periodate oxidation (maintaining pH to 9 by direct addition of solid
NaHCO3) gave satisfactory yields of the corresponding aldehydes
1d–e.
O
O
O
O
O
R
O
1
Scheme 1. Retrosynthetic scheme for the preparation of aldehyde enolphosphates
using Perkow reaction.
Dialdose 1h has been prepared from easily accessible 1,2;3,4-di-
O-isopropylidene-dialdo-a-D-galactopyranoside [19]. Homologa-
required aldehydes 1b–g is shown in Scheme 2 and aldose 1h in
Scheme 4.
tion method used the Weinreb’s phosphonoacetamide 7, a Horner’s
reagent which is generally obtained by laborious Michaelis–Arbu-
zov reaction between triethylphosphite and chloroacetamide [20].
We re-investigated the preparation of Weinreb’s phosphonoaceta-
mide with the aim of shortening the reaction time and increasing
the effectiveness of preparation. Following our previous work on
the synthesis of C-phosphonopeptides [21], Weinreb’s phospho-
noacetamide was synthesised by the coupling of diethylphospho-
noacetic acid with N,O-dimethylhydroxylamine in presence of
BOP and triethylamine in dichloromethane. The phosphonoaceta-
mide was obtained pure after an easy chromatographic purifica-
tion in good yield (Scheme 3). This new synthesis allowed
preparing large amounts of Weinreb’s phosphonoacetamide 7
more readily than the known method.
Treatment of 9,10,16-trihydroxyhexadecanoic acid (commer-
cially available) with MeOH, in the presence of catalytic BF3.Et2O,
led to the formation of the corresponding methyl ester 4. Although
the synthesis can be carried out with the free primary alcohol (5b),
we studied various protections as diethylphosphate (5e), pivaloyl
(5c) or tert-butyldimethylsilyl (5d) functions. Selective protection
of the primary 16-OH of triols, 4 or the commercial one, was ob-
tained following conditions in Table 1.
Using periodate oxidation under Malaprade conditions on diols
5b–e afforded the target aldehydes 1b–g in good yields. In the case
of the silylated protection, 1d, yield was slightly lower for this step
Homologation has then been performed following Scheme 4.
Horner reaction was achieved on 1,2;3,4-di-O-isopropylidene-dia-
ldo-a-D-galactopyranoside using the Weinreb’s phosphonoaceta-
HO
O
HO
O
d
RO
HO
OH
OH
mide which was deprotonated by slow addition to LDA solution
at ꢀ70 °C in THF. Dialdose was then added and reaction stirred
30 min at room temperature. Usual work-up and silica-gel chro-
matography gave acetamide 8 in good yield (76%). E/Z ratio of
73/27 has been determined by 1H NMR [dHb is 6.12 ppm for (Z)-8
and 6.93 ppm for (E)-8].
Two successive reductions allowed preparing dialdose 1h. The
first one, a quantitative catalytic hydrogenation of 8 with palla-
dium on carbon led to carboxamide 9 after a simple filtration of
catalytic material. The second one was much more complicated
as the amide had to be reduced to its corresponding aldehyde.
Reduction was achieved with lithium aluminium hydride with
very good yield as long as temperature was kept between ꢀ3
and 5 °C. Likewise, no purification was required for this step as
aldehyde was of high purity after standard workup.
5
7
7
5
HO
HO
6d-e
a
e
OH
O
HO
OMe
RO
H
5
7
OH
4
5
O
1d-e
b
OH
O
RO
OMe
R=
b
c
d
e
H
Piv
TBDMS
P(O)(OEt)2
7
5
OH
5b-e
c
O
O
RO
H
+
H
OMe
EtO
EtO
5
N
O
EtO
1b-e
N
7
OH
EtO
1g
P
O
+
H
O
P
O
O
O
O
7
Scheme 2. Synthesis of aldehydes 1b–g. Reagents and conditions: (a) BF3AEt2O
cat., MeOH, 15 h, 35 °C, 75%; (b) see Table 1; (c) 1.1 eq. NaIO4, H2O/MeOH 1:3, 18 h,
20 °C, 1b: 60%–1c: 66%–1d: 53%–1e: 69%; (d) see Table 1; (e) 1.1 eq. NaIO4, solid
NaHCO3 until pH 9, H2O/MeOH 1:3, 18 h, 20 °C, 1d: 35%–1e: 59%.
Scheme 3. Preparation of Weinreb’s phosphonoacetamide. Reagents and condi-
tions: 1 eq. BOP, 1 eq. Et3N, CH2Cl2, 12 h, rt, 77%.

50
N. Barthes, C. Grison / Bioorganic Chemistry 40 (2012) 48–56
O
N
O
N
O
O
H
O
O
O
O
O
O
O
a
b
c
O
O
O
O
O
O
O
O
O
O
O
O
O
1h
O
O
9
8
Scheme 4. Homologation of 1,2;3,4-di-O-isopropylidene-dialdo-
30 min. rt, 76%; (b) H2 (10 bars), Pd/C cat., MeOH, 12 h, rt, 100%; (c) 1 eq. LiAlH4, N2, THF, 0 °C, 30 min, 87%.
a-D-galactopyranoside. Reagents and conditions: (a) 1 eq. LDA, 1 eq. Weinreb’s reagent, THF, ꢀ70 °C then
(J1HA2H = 11.8 Hz) and Z (J1HA2H = 7.7 Hz) geometrical isomers.
I
a
b
Due to deshielding by the ester phosphate group, the 2-H signal
in E-isomer (d 5.45) appeared at considerably lower field than
the corresponding Z-enolphosphate’s 2-H signal (d 4.88). Interest-
ingly, the examination of the 31P NMR spectra showed the presence
of both E- (dP ꢀ0.83) and Z- (dP ꢀ1.26) enolphosphates. It could be
noted the significant dP values’ difference between saturated (dP
0.40) and unsaturated phosphate moiety of 3e,f.
This first synthesis of 1-alkenyldiphosphates is rapid, simple,
efficient and can easily be scaled up. Chemical yields are excellent
and the reaction’s conditions allow preserving some of the func-
tionalities and avoiding uneasy purifications of fragile products
at each step. However, this method cannot be applied to com-
pounds bearing acidic sensitive function, like isopropylidene or sil-
ylether protections. It is however compatible with free alcohol,
pivaloyl or methylester and dialkylphosphate function.
O
O
R
O
OR'
OR'
R
R
P
3
2
O
1
R=
Yield (%) 2
E/Z ratio
58/42
Yield (%) 3
100
a
CH3
100
R'=Me
b
c
d
e
(CH2)4OH
97
98
100
100
/
28/72
61/39
/
R'=Me
R'=Me
(CH2)4OPiv
(CH2)4OTBDMS
(CH2)4OP(O)(OEt)2
(CH2)4OP(O)(OEt)2
(CH2)5CO2Me
0 (90% of 2b)
52/48
98
98
100
100
100
R'=Me
R'=Et
48/52
45/55
f
100
g
R'=Me
h
O
O
O
O
0
/
/
O
2.2. Hydroalumination–phosphorylation tandem reaction
This major inconvenient led us to develop another method for
those highly sensitive compounds. Inspired by Tsuda and co. about
the alkylation and silylation of the aluminium enolates generated
Scheme 5.
a-Iodination of aldehydes 1 and Perkow reaction to 3. Reagents and
conditions: (a) 1 eq. I2, 0.5 eq. HgCl2, CH2Cl2, rt, 4 h. (b) 1 eq. (R’O)3P, rt, 12 h.
by hydroalumination of
a,b-unsaturated carbonyl compounds
[23], we developed a second strategy, to the first enolphosphates
Aldehydes 1a–h were submitted to direct iodination using the
HgCl2/I2 system described by Barluenga with long chain aldehydes
(Scheme 5) [22]. The mixture reaction was stirred vigorously for
4 h at room temperature. The solution was filtered and the filtrate
washed with an aqueous sodium thiosulfate solution. After stan-
dard work up, 2a–c,e–g were cleanly obtained in nearly quantita-
tive yields without further purification. It should be noted the
very good stability of the phosphate, methyl and pivaloyl ester
functions in spite of iodination conditions’ acidic medium. How-
in glucidic series: this method is based on the hydroalumination of
a
,b-unsaturated dialdose 10gal or aldose 10ara, leading to its
respective aluminium enolates which could be activated as ate-
complexes to be phosphorylated by dialkylchlorophosphate. ,b-
Unsaturated aldoses 10gal, 10ara were prepared by homologation
of 1,2;3,4-di-O-isopropylidene-dialdo- -galactopyranoside and
2,3;4,5-di-O-isopropylidene- -arabinose (obtained from -arabi-
a
a
-D
D
D
nose according Zinner et al. procedure [24]) respectively (Scheme 6).
Horner reaction between aldoses and Weinreb’s reagent was
performed as exposed above (Schemes 3 and 4). Yield, which was
good with galactose derivative, was excellent with arabinose deriv-
ative. As presented previously, the sensitive and selective reduc-
tion of carboxamides 8gal, 8ara by AlLiH4 solution, leading to
ever 1d submitted to iodination system gave a 90% of 2b a-iodoal-
dehyde: silyl ether protection was totally cleaved leading to the
alcohol compound. Regarding the carbohydrate 1h, its isopropyli-
dene acetals and its skeleton were completely degraded by the
acidic medium.
a,b-unsaturated aldehydes 10gal, 10ara, was realised in good yield
The
a
-iodoaldehyde function being very fragile, compounds 2
as long as reaction’s temperature was maintained between ꢀ3 and
5 °C. 1H NMR allowed us to determine E/Z ratio of 91/9 for 10gal
and higher than 95/5 for 10ara. Finally, it should be noted that
must be engaged in the Perkow reaction quickly. Reaction of 2a–
c,e–g with trialkylphosphite, at room temperature, without solvent
and stirring for 12 h, led to the clean and quantitative formation of
diethyl and dimethylenolphosphates 3a–c,e–g (Scheme 5). As
clearly indicated, especially by the 31P NMR spectra of the crude
we developed a very good pathway to (E)-a,b-unsaturated alde-
hydes using the Weinreb’s phosphonoacetamide.
Synthesis of glucidic enolphosphates 11gal, 11ara is presented
in Scheme 7.
materials, the
a-iodoaldehydes 2 were completely consumed and
no by-product can be detected.
a
-Iodoaldehydes were found to
Aluminium enolates were generated from a,b-ethylenic alde-
be particularly suitable substrates for the reaction of Perkow. After
a simple evaporation of residual trialkylphosphite’s excess, the
purity and yields of enolphosphates 3a-c,e-g were excellent.
Iodoaldehydes differ significantly from halogenoketones for whom
the competitive formation of the Michaelis–Arbusov reaction prod-
uct is difficult to avoid. 1H NMR spectra showed mixtures of E
hydes 10gal, 10ara by selective conjugate addition of methyl cop-
per with DIBAH–HMPA. Catalytic methyl copper was prepared
in situ reacting CuI and MeLi in presence of HMPA. DIBAH was then
added to release a ‘‘CuH’’ complex which can reduce selectively the
conjugated double CAC bond of
a,b-unsaturated aldehydes 10gal,
10ara. The aluminium enolates were then activated as lithium

N. Barthes, C. Grison / Bioorganic Chemistry 40 (2012) 48–56
3. Experimental
51
O
O
N
b
3.1. General
a
R
O
O
R
R
10
Reactions were monitored by TLC (Merck – 5535 – Kieselgel 60-
254), detection being carried out by UV, by iodine vapour or by
8
F
R=
spraying solution of H2SO4 15% in ethanol followed by heating.
NMR spectra were recorded on a Bruker DRX-250. Chemical
shifts are expressed as parts per million downfield from the inter-
nal standard tetramethylsilane for 1H and 13C and from external
standard phosphoric acid for 31P. Multiplicities are indicated by s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), bs
(broadened singlet). IR spectra were recorded on Nicolet 210 FTIR
(film between NaCl pellets).
O
O
O
O
O
O
O
O
O
gal
ara
Scheme 6. Preparation of
a,b-unsaturated aldoses. Reagents and conditions: (a)
1 eq. LDA, 1 eq. Weinreb’s reagent, THF, ꢀ70 °C then rt 30 min, 8gal: 76%–8ara:
98%; (b) 1 eq. LiAlH4, N2, THF, 0 °C, 30 min, 10gal: 87%–10ara: 71%.
3.2. Protections of 9,10,16-trihydroxyhexadecanoic acid
ate-complexes to increase their nucleophilicity. This activation was
carried out by addition of methyl lithium to the reaction. Ate-com-
plexes were finally reactive enough to be trapped by diethylchloro-
phosphate. Appropriate treatment of the reaction has been
developed to obtain crude enolphosphates 11gal, 11ara which
are extremely fragile: after evaporation of THF, diethylether was
added to precipitate aluminium, copper and lithium salts. After
centrifugation, supernatant was concentrated under high vacuum
and flash chromatographed on silica-gel. It is important to note
that a 1 h chromatography degraded the whole enolphosphates:
chromatography must be very quick.
3.2.1. Methyl 9,10,16-trihydroxyhexadecanoate 4
C17H34O5; MW = 318 g molꢀ1; bp = 72–73 °C.
6 g of 9,10,16-Trihydroxyhexadecanoic acid (19.8 mmol
–
mp = 110 °C) is refluxed for 15 min under N2 with 3 mL of BF3ꢁEt2O
in 100 mL of MeOH. Reaction is diluted in 80 mL of water and ex-
tracted three times with Et2O. Organic layers are washed with sat-
urated Na2CO3 aqueous solution and water. Crude product is
diluted with toluene and distilled, under atmospheric pressure,
to give 4.72 g of pure 4, a pale yellow oil, with 75% yield.
RMN 1H (CDCl3, 250 MHz): 1.24–1.72 (22H, m, CH2ACH2), 2.31
(2H, t, CH2ACO2Me, JHAH = 4.75 Hz), 3.34–3.58 (4H, m, CHAO,
CH2AOH), 3.68 (3H, s, Me).
Finally, the first glucidic enolphosphates derived from aldehydes
11gal, 11ara are obtained in 35% overall yields from a,b-unsaturated
IR (NaCl): m .
C@O = 1738 cmꢀ1
aldehydes, with good purity (higher than 90%). Although this yield
may seem modest, it results three successive reactions one pot.
Moreover, the only by-products identified were corresponding sat-
urated aldehydes. This observation reflects a good selectivity of
the a,b-ethylenic aldehydes’ reduction. Isopropylidene acetals were
compatible with this strategy and were not degraded.
In conclusion, our needs to synthesise PEP analogues led us to
develop two complementary methods to aldehyde enolphos-
phates. The first one is rapid, simple, efficient and leads to
1-alkenyldiphosphates with excellent chemical yields, avoiding
uneasy purifications of fragile products at each step, provided that
the compound does not contain acidic sensitive function. The sec-
ond one is much more convenient for those highly sensitive com-
pounds. We showed that use of Weinreb’s phosphonoacetamide
3.2.2. Methyl 16-[(pivaloyl)oxy]-9,10-dihydroxyhexadecanoate 5c
22H42O6; MW = 403 g molꢀ1; Rf = 0.5 – AcOEt/Hexane (1:1).
193 L of pivaloyl chloride (1 eq.) is slowly added to a solution of
C
l
500 mg of 4 (1.57 mmol) in 3 mL of Pyridine at 0 °C. After 2 h at 0 °C,
3 drops of water are added to reaction before diluting with 30 mL of
Et2O. Organic layer is washed with an HCl aqueous solution (2 N),
NaHCO3 saturated solution and NH4Cl saturated solution. After dry-
ing with Na2SO4, reaction is concentrated under vacuum to give
625 mg of 5c (90% pure), a pale yellow oil, in 89% yield.
RMN 1H (CDCl3, 250 MHz): 1.20 (9H, s, tBu), 1.24–1.72 (22H, m,
CH2ACH2), 2.32 (2H, t, CH2ACO2Me, JHAH = 4.75 Hz), 3.37–3.42 (2H,
m, CHAO), 3.67 (3H, s, OAMe), 4.06 (2H, t, CH2AOAPiv,
JHAH = 8.25 Hz).
IR (NaCl): m .
C@O = 1740 cmꢀ1
reagent is suitable to prepare
a,b-unsaturated aldehydes which
can be converted to enolphosphates by hydroalumination–phos-
phorylation tandem reaction. Yields are good considering the high
sensitivity of our model compounds.
3.2.3. Methyl 16-[(tert-butyldimethylsilyl)oxy]-9,10-
dihydroxyhexadecanoate 5d
C
23H48O5Si; MW = 433 g molꢀ1
.
1 g of 4 (3.15 mmol), 500 mg of tert-butyl(chloro)dimethylsi-
lane (1.1 eq.), 50 mg of DMAP (cat.) and 0.5 mL of Et3N (1.1 eq.)
are reacted in 15 mL of CH2Cl2 for 12 h. Reaction is concentrated
and diluted with 20 mL of Et2O. Salts are filtered to give 1.20 g of
crude 5d, a pale yellow oil, with 88% yield. Product is purified after
Malaprade oxidation.
Li+
a
CHO
b
-
R
O
R
O
c
R
Al(i-Bu)
2
Al(i-Bu)
2
10
Me
RMN 1H (CDCl3, 250 MHz): 0.11 (6H, s, CH3ASi), 0.91 (9H, s,
tBu), 1.24–1.72 (22H, m, CH2ACH2), 1.39 (3H, s, Me), 2.31 (2H, t,
CH2ACO2Me, JHAH = 4.75 Hz), 3.34–3.46 (2H, m, CHAO), 3.61 (2H,
t, CH2AOASi, JHAH = 6.35 Hz).
R=
O
O
O
O
O
O
O
O
P
IR (NaCl): m .
C@O = 1738 cmꢀ1
O
OEt
OEt
R
O
O
gal
ara
11
3.2.4. Methyl 16-[(diethoxyphosphoryl)oxy]-9,10-
dihydroxyhexadecanoate 5e
Scheme 7. Hydroalumination–activation–phosphorylation. Reagents and condi-
tions: (a) 0.05 eq. CuI, 0.05 eq. MeLi (1.6 M in ether), 1.5 eq. HMPA, 1.1 eq. DIBAH
(1.5 M in toluene), THF, N2, ꢀ50 °C, 1 h; (b) 1.1 eq. MeLi (1.6 M in ether), ꢀ50 °C,
15 min; (c) 1.1 eq. (EtO)2P(O)Cl, ꢀ50 °C, 2 h then rt overnight.
C
21H43O8P; MW = 456 g molꢀ1
.
1 g of 4 (3.15 mmol), 952
lL of diethylchlorophosphate (1 eq.)
and 100 mg of DMAP (0.5 eq.) are stirred in 24 mL of Pyridine for

52
N. Barthes, C. Grison / Bioorganic Chemistry 40 (2012) 48–56
12 h. Reaction is concentrated, diluted with CH2Cl2 and washed by
an HCl aqueous solution (1 M) down to pH 6. Organic layer is dried
with MgSO4 and concentrated under vacuum to give 2.01 g of
crude 5e (68% pure) and a 96% yield. Product, a pale yellow oil, is
purified after Malaprade oxidation.
4.05 (2H, t, CH2AOAPiv, JHAH = 8.3 Hz), 9.74 (1H, t, CHO,
JHAH = 1.8 Hz).
IR (NaCl): m .
C@O = 1741, 1718 cmꢀ1
3.3.3. 7-[(Tert-butyldimethylsilyl)oxy]-heptanal 1d
13H28O2; MW = 244 g molꢀ1; Rf = 0.85 – AcOEt/Hexane – 5:1;
RMN 1H (CDCl3, 250 MHz): 1.24–1.72 (22H, m, CH2ACH2), 1.39
(3H, t, Me, JHAH = 7.1 Hz), 2.32 (2H, t, CH2ACO2Me, JHAH = 4.75 Hz),
4.01–4.16 (4H, m, CHAO, CH2ACH2AOAP), 4.22–4.31 (4H, m,
CH3ACH2AOAP).
C
Yield = 35% from 6d–53% from 5d.
RMN 1H (CDCl3, 250 MHz): 0.1 (6H, s, MeASi), 0.91 (9H, s, tBu),
1.21–1.74 (8H, m, CH2ACH2), 2.45 (2H, td, CH2ACHO, JHAH = 1.8 Hz,
JHAH = 7.3 Hz), 3.62 (2H, t, CH2AOASi, JHAH = 6.3 Hz), 9.79 (1H, t,
CHO, JHAH = 1.8 Hz).
RMN 31P (CDCl3, 101 MHz): 0.2 (s).
IR (NaCl): m , m .
C@O = 1739 cmꢀ1 P@O = 1251 cmꢀ1
IR (NaCl): m .
C@O = 1719 cmꢀ1
3.2.5. 16-[(Tert-butyldimethylsilyl)oxy]-9,10-dihydroxyhexadecanoic
acid 6d
3.3.4. 7-[(Diethoxyphosphoryl)oxy]-heptanal 1e
C
22H46O5Si; MW = 419 g molꢀ1
.
C7H14O2; MW = 130 g molꢀ1; Rf = 0.35 – AcOEt/Hexane – 5:1;
Yield = 59% from 6e–69% from 5e.
2 g of 9,10,16-Trihydroxyhexadecanoic acid (6.60 mmol), 1.98 g
of tert-butyl(chloro)dimethylsilane (2 eq.), 800 mg of DMAP
(0.5 eq.) and 2.0 mL of Et3N (2.1 eq.) are reacted in 20 mL of CH2Cl2
for 72 h. Reaction is concentrated and diluted with 20 mL of hex-
ane. Salts precipitate and are filtered to lead to 2.29 g of crude
compound 6d, a pale yellow oil, in 80% yield. Product is purified
after Malaprade oxidation.
RMN 1H (CDCl3, 250 MHz): 1.34 (3H, t, CH3, JHAH = 7.1 Hz), 1.22–
1.72 (8H, m, CH2ACH2), 2.44 (2H, td, CH2ACHO, JHAH = 1.8 Hz,
JHAH = 7.25 Hz Hz), 4.03 (2H, m, CH2ACH2AOH), 4.11 (4H, m,
CH3ACH2AO), 9.76 (1H, t, CHO, JHAH = 1.8 Hz).
RMN 31P (CDCl3, 101 MHz): 0.2 (s).
IR (NaCl):
m , m .
C@O = 1719 cmꢀ1 P@O = 1247 cmꢀ1
RMN 1H (CDCl3, 250 MHz): 0.11 (6H, s, CH3ASi), 0.91 (9H, s,
tBu), 1.24–1.72 (22H, m, CH2ACH2), 2.31 (2H, t, CH2ACO2H,
JHAH = 4.75 Hz), 3.34–3.46 (2H, m, CHAO), 3.61 (2H, t, CH2AOASi,
JHAH = 6.35 Hz).
3.4. Homologation of glucidic aldoses
3.4.1. Preparation of Weinreb’s phosphonoacetamide 7
C8H18NO5P; MW = 239 g molꢀ1; Rf = 0.35 – AcOEt/EtOH – 8:2.
1.28 mL of Et3N (1 eq.) is added dropwise to 891 mg of N,O-dim-
ethylhydroxylammonium chloride (1 eq.) in suspension in 40 mL
of CH2Cl2. Check that pH is neutral. A solution of 1.8 g phosphono-
acetic acid (9.2 mmol) in 60 mL of CH2Cl2 and then 4.1 g of BOP
(1 eq.) in solution in 20 mL of CH2Cl2 are added to reaction. Finish
by adding 1.28 mL of Et3N (1 eq.) diluted in 20 mL of CH2Cl2. Check
that pH is basic (pH P 9). After stirring overnight at rt, reaction is
diluted with 50 mL of CH2Cl2 and washed with aqueous solutions
of H2SO4 (3 ꢂ 20 mL – 2 M), NaCl (10 mL – saturated), NaHCO3
(3 ꢂ 20 mL – saturated) and NaCl (10 mL – saturated). Organic lay-
ers are dried with MgSO4 and concentrated under vacuum. Crude
product is purified by silicagel chromatography (AcOEt/EtOH –
8:2) to give 1.7 g of 7, a pale yellow oil, in 77% yield.
3.2.6. 16-[(Diethoxyphosphoryl)oxy]-9,10-dihydroxyhexadecanoic
acid 6e
C
20H41O8P; MW = 441 g molꢀ1
.
5 g of 9,10,16-Trihydroxyhexadecanoic acid (16.50 mmol),
4.76 mL of diethylchlorophosphate (1 eq.) and 500 mg of DMAP
(0.5 eq.) are reacted in 120 mL of Pyridine for 24 h. Reaction is con-
centrated, diluted with CH2Cl2 and washed by an HCl aqueous
solution (1 M) down to pH 4. Organic layer is dried with MgSO4
and concentrated under vacuum to give 7.51 g of crude 6e, a pale
yellow oil, in 97% yield.
RMN 1H (CDCl3, 250 MHz): 1.24–1.72 (22H, m, CH2ACH2), 1.32
(3H, t, Me, JHAH = 7.0 Hz), 2.32 (2H, t, CH2ACO2H, JHAH = 4.75 Hz),
4.01–4.16 (4H, m, CHAO, CH2ACH2AOAP), 4.22–4.31 (4H, m,
CH3ACH2AOAP).
RMN 1H (250 MHz, CDCl3): 1.37 (6H, t, CH3ACH2, JHAH = 4.8 Hz),
RMN 31P (CDCl3, 101 MHz): 0.0 (s).
3.19 (2H, d, PACH2, 2JHAP = 22 Hz), 3.24 (3H, s, NAMe), 3.79 (3H, s,
3
OAMe), 4.20 (4H, dq, CH2AOAP, JHAP = JHAH = 4.9 Hz).
3.3. Malaprade oxidation
RMN 31P (101 MHz, CDCl3): 21.37 (s).
IR (NaCl): m , m .
C@O = 1660 cmꢀ1 P@O = 1253 cmꢀ1
4 mmol of diol 5 or 6 in 10 mL of MeOH are agitated in a flask
with CaCl2 protection. In case of 6, 2.5 g of NaHCO3 powdered is
added to pH 9. 1 eq. of NaIO4 suspended in 3 mL of water is then
slowly added. After 18 h, reaction is concentrated, diluted with
CH2Cl2 and neutralised by an HClꢁEt2O solution. Precipitate is cen-
trifuged, supernatant dried with Na2SO4 and evaporated. Aldehyde,
a pale yellow oil, is purified by silicagel chromatography.
3.4.2. Wittig–Horner reaction on aldoses
Under nitrogen, 1 eq. of diisopropylamine (MW = 101 g molꢀ1
–
d = 0.7255 g Lꢀ1) in solution in 30 mL of THF is slowly added to
3.0 mL of BuLi (1.4 M in Hexane – 1 eq.) in solution in 30 mL of
THF at ꢀ50 °C. Reaction is allowed to warm to rt for 20 min, then
cooled to ꢀ70 °C for the addition of a solution of 1 g of Weinreb’s
phosphonoacetamide 7 (4.18 mmol) in 30 mL of THF. Reaction is
stirred for 15 min at ꢀ70 °C before being allowed to warm slowly
to rt. 1 eq. of dialdogalactose in solution in 30 mL of THF are added
to reaction. After 30 min at rt, 20 mL of NH4Cl saturated solution
are added to reaction. Mixture is extracted three times with
40 mL of CH2Cl2 and organic layers dried with MgSO4. Concentra-
tion under vacuum lead to crude product being purified by silicagel
chromatography (AcOEt/Hexane – 1:1) and give carboxamides
8gal and 8ara, pale yellow oils.
3.3.1. 7-Hydroxyheptanal 1b
C7H14O2; MW = 130 g molꢀ1; Rf = 0.35 – AcOEt/Hexane – 5:1;
Yield = 60%.
RMN 1H (CDCl3, 250 MHz): 1.22–1.71 (8H, m, CH2ACH2), 2.40
(2H, td, CH2ACHO, JHAH = 1.8 Hz, JHAH = 7.2 Hz), 3.63 (2H, t,
CH2AOH, JHAH = 7.2 Hz), 9.74 (1H, t, CHO, JHAH = 1.8 Hz).
IR (NaCl): m ; m .
OH = 3360–3050 cmꢀ1 C@O = 1718 cmꢀ1
3.3.2. 7-[(Pivaloyl)oxy]-heptanal 1c
C12H22O3; MW = 214 g molꢀ1; Rf = 0.50 – AcOEt/Hexane – 1:3;
Yield = 66%.
3.4.2.1. Compound 8gal. C16H25NO7; MW = 343 g molꢀ1; Rf = 0.50
(Z)-8gal and 0.35 (E)-8gal – AcOEt/Hexane – 1:1.
RMN 1H (CDCl3, 250 MHz): 1.19 (9H, s, tBu), 1.22–1.71 (8H, m,
CH2ACH2), 2.45 (2H, td, CH2ACHO, JHAH = 1.8 Hz, JHAH = 7.2 Hz),
240 mg of (Z)-8gal and 655 mg of (E)-8gal in a global 76% yield.

N. Barthes, C. Grison / Bioorganic Chemistry 40 (2012) 48–56
53
(Z)-8gal. RMN 1H (CDCl3, 400 MHz): 1.25 (3H, s, H isopropyli-
3.4.3. Catalytic hydrogenation of 8gal
dene), 1.26 (3H, s, H isopropylidene), 1.42 (3H, s, H isopropylidene),
1.50 (3H, s, H isopropylidene), 3.14 (3H, s, MeAN), 3.63 (3H, s,
MeAOAN), 4.25 (1H, dd, H2, JHAH = 1.5 Hz, JHAH = 3.1 Hz), 4.55
(2H, 2 dd, H3, H4, JHAH = 1.5 Hz, JHAH = 5.0 Hz, JHAH = 1.25 Hz,
JHAH = 5.0 Hz), 5.41 (1H, m, H5), 5.49 (1H, d, H1, JHAH = 3.1 Hz),
6.12 (1H, dd, H6, JHAH = 4.5 Hz, JHAH = 9.8 Hz), 6.37 (1H, m,
H7).
C
16H27NO7; MW = 345 g molꢀ1; Rf = 0.45 – AcOEt/Hexane – 1:1.
A 400 mg mixture of (Z)-8gal and (E)-8gal (1.16 mmol) in solu-
tion in 20 mL of MeOH and 50 mg of Palladium on carbon are stir-
red in a reactor under 10 bars of hydrogen overnight. Filtration on
Celite and concentration under vacuum give 890 mg of pale yellow
oil. Yield in compound 9gal is quantitative.
RMN 1H (CDCl3, 400 MHz): 1.31 (3H, s, H isopropylidene), 1.35
(3H, s, H isopropylidene), 1.46 (3H, s, H isopropylidene), 1.48 (3H,
s, H isopropylidene), 1.89–2.00 (2H, m, H6), 2.46–2.76 (2H, m, H7),
3.17 (3H, s, MeAN), 3.70 (3H, s, MeAOAN), 4.79–4.83 (1H, m, H5),
4.17 (1H, d, H4, JHAH = 7.8 Hz), 4.28 (1H, dd, H2, JHAH = 1.8 Hz,
JHAH = 5.2 Hz), 4.58 (1H, dd, H3, JHAH = 1.8 Hz, JHAH = 7.8 Hz), 5.52
(1H, d, H1, JHAH = 5.2 Hz);
RMN 13C (CDCl3, 101 MHz): 24.3; 25.1; 26.0; 26.1 (CH3 isopro-
pylidene), 32.6 (MeAN), 61.7 (MeAOAN), 65.7 (C5), 70.3 (C2),
71.0 (C3), 73.5 (C4), 96.4 (C1), 108.8; 109.1 (C isopropylidene),
118.2 (C7), 143.8 (C6).
(E)-8gal. RMN 1H (CDCl3, 400 MHz): 1.25 (3H, s, H isopropyli-
dene), 1.26 (3H, s, H isopropylidene), 1.42 (3H, s, H isopropylidene),
1.50 (3H, s, H isopropylidene), 3.10 (3H, s, MeAN), 3.65 (3H, s,
MeAOAN), 4.31 (1H, dd, H4, JHAH = 1.25 Hz, JHAH = 5.0 Hz), 4.36
(1H, dd, H2, JHAH = 1.5 Hz, JHAH = 3.25 Hz), 4.51 (1H, m, H5), 4.64
(1H, dd, H3, JHAH = 1.5 Hz, JHAH = 5.0 Hz), 5.62 (1H, d, H1,
JHAH = 3.25 Hz), 6.68–6.73 (1H, m, H7), 6.93 (1H, dd, H6,
JHAH = 2.25 Hz, JHAH = 9.5 Hz);
RMN 13C (CDCl3, 101 MHz): 24.4; 25.0; 25.9; 26.0 (CH3 isopro-
pylidene), 24.9 (C6), 27.0 (C7), 32.3 (MeAN), 61.3 (MeAOAN),
66.5 (C5), 70.7 (C2), 70.9 (C3), 73.0 (C4), 96.5 (C1), 108.4; 109.1 (C
isopropylidene).
3.4.4. Reduction of 9gal to 1h
RMN 13C (CDCl3, 101 MHz): 24.4; 24.9; 25.9; 26.1 (CH3 isopro-
pylidene), 32.3 (MeAN), 61.8 (MeAOAN), 67.6 (C5), 70.5 (C2),
70.9 (C3), 72.7 (C4), 96.4 (C1), 108.7; 109.5 (C isopropylidene),
119.6 (C7), 141.4 (C6).
C
14H22O6; MW = 286 g molꢀ1; Rf = 0.45 – AcOEt/Hexane – 1:1.
1.2 mL of AlLiH4 (1 M in Et2O – 1 eq.) is added on a solution of
405 mg of carboxamide 9gal (1.17 mmol) in 10 mL of THF under
nitrogen at 0 °C. Temperature must be controlled between ꢀ3
and +5 °C. After 30 min, a solution of 190 mg of KHSO4 (1.40 mmol)
in 1.5 mL of water is added to reaction. After concentration under
vacuum, aqueous layer is extracted 3 times with CH2Cl2. Organic
layers are washed with aqueous solutions of HCl (3 N), NaCl
(sat.), NaHCO3 (sat.) and NaCl (sat.) before being dried with Na2SO4
and concentrated under vacuum to give 292 mg of pure 1h, a pale
yellow oil, without further purification, in 87% yield.
IR (NaCl): m , m .
C@O = 1668 cmꢀ1 C@C = 1639 cmꢀ1
3.4.2.2. Compound 8ara. C15H25NO6; MW = 315 g molꢀ1; Rf = 0.55 –
AcOEt/Hexane – 6:4.
749 mg of (Z)-8ara (17%) and (E)-8ara (83%) mixture in a global
98% yield.
(Z)-8ara. RMN 1H (250 MHz, CDCl3): 1.37 (3H, s, H isopropyli-
dene), 1.45 (3H, s, H isopropylidene), 1.44 (3H, s, H isopropylidene),
1.47 (3H, s, H isopropylidene), 3.23 (3H, s, MeAN), 3.69 (3H, s,
MeAOAN), 3.90–4.38 (4H, m, H5, H6, H7), 5.33 (1H, m, H4),
6.07 (1H, dd, H3, JHAH = 9.2 Hz, JHAH = 12.0 Hz), 6.44–6.53 (1H, m,
H2).
RMN 1H (CDCl3, 400 MHz): 1.33 (3H, s, H isopropylidene), 1.36
(3H, s, H isopropylidene), 1.47 (3H, s, H isopropylidene), 1.50 (3H, s,
H isopropylidene), 1.89–2.40 (2H, m, H6), 2.54–2.72 (2H, m, H7),
4.74–4.83 (1H, m, H5), 4.17 (1H, dd, H4, JHAH = 1.6 Hz,
JHAH = 8.9 Hz), 4.31 (1H, dd, H2, JHAH = 2.4 Hz, JHAH = 5.2 Hz), 4.60
(1H, dd, H3, JHAH = 2.4 Hz, JHAH = 8.9 Hz), 5.52 (1H, d, H1,
JHAH = 5.2 Hz), 9.64 (1H, t, H aldehyde, JHAH = 1.2 Hz).
RMN 13C (63 MHz, CDCl3): 25.3; 26.7; 26.9; 27.0 (Me isopropyl-
idene), 64.6 (C7), 72.9 (C6), 79.4 (C5), 81.2 (C4), 110.1 (C isopropyl-
idene), 119.2 (d, C2), 143.8 (C3), 192.1 (C1).
IR (NaCl):
m .
C@O = 1718 cmꢀ1
(E)-8ara. RMN 1H (250 MHz, CDCl3): 1.37 (3H, s, H isopropyli-
dene), 1.45 (3H, s, H isopropylidene), 1.44 (3H, s, H isopropylidene),
1.47 (3H, s, H isopropylidene), 3.28 (3H, s, MeAN), 3.73 (3H, s,
MeAOAN), 3.90–4.38 (4H, m, H5, H6, H7), 4.62 (1H, m, H4), 6.75
(1H, dd, H2, JHAH = 2.4 Hz, JHAH = 15.8 Hz), 7.05 (1H, dd, H3,
JHAH = 4.75 Hz, JHAH = 15.8 Hz).
3.5. Iodation of aldehydes 1a–h
In a dark flask protected by CaCl2, 3 mmol of aldehyde 1, mercu-
ric chloride and iodine are mixed in 10 mL of CH2Cl2 at rt. Suspen-
sion is agitated 2–4 h before being filtered. Filtrate is washed by an
aqueous solution of Na2S2O3 (0.1 N) recently prepared and KI (sat.).
Organic layer is dried with Na2SO4 and concentrated under vac-
uum. Crude product 2 is used for the Perkow reaction.
RMN 13C (63 MHz, CDCl3): 25.3; 26.7; 26.8; 27.0 (Me isopropyl-
idene), 67.4 (C7), 72.5 (C6), 78.2 (C5), 80.6 (C4), 110.1 (C isopropyl-
idene), 119.2 (d, C2), 143.8 (C3), 192.1 (C1).
Aldehyde substrate
Halogenation
system
Product
Yield%
0.5 HgCl2/1 I2/2 h
C4H7IO MW = 198
g molꢀ1
100
1a
2a
0.5 HgCl2/1 I2/4 h
C7H13IO2 MW = 256
g molꢀ1
97
1b
2b
(continued on next page)

54
N. Barthes, C. Grison / Bioorganic Chemistry 40 (2012) 48–56
Aldehyde substrate
Halogenation
system
Product
Yield%
98
0.5 HgCl2/1 I2/4 h
0.5 HgCl2/1 I2/4 h
1.5 HgCl2/1 I2/4 h
C12H21IO3 MW = 340
g molꢀ1
1c
2c
2b
C7H13IO2 MW = 256
g molꢀ1
90
98
1d
C11H22IO5P MW = 392
g molꢀ1
1e
1e
0.5 HgCl2/1 I2/4 h
0.5 HgCl2/1 I2/4 h
C10H17IO3 MW = 312
g molꢀ1
90
0
1g
2g
C14H21IO6 MW = 412
g molꢀ1
1h
2h
3.6. Preparation of enolphosphates 3a–g
1 Eq. of trialkylphosphite is added on 1 mmol of
des 2a–g at 0 °C. Reaction is allowed to warm to rt overnight. Mix-
ture is concentrated under high vacuum and enolphosphates 3a–g
are obtained, as pale yellow oils, with great purity and quantitative
yield.
MS (FAB+): m/z 239 ([M+H]+, 21%); MS (FABꢀ): m/z 237
([MAH]ꢀ, 18%).
a-iodoaldehy-
IR (NaCl):
m
PAOAC = 1021 cmꢀ1
,
m
P@O = 1279 cmꢀ1
,
mC@C =
1670 cmꢀ1 OH = 3300 cmꢀ1
, m .
3.6.3. 3c
C14H27O6P; MW = 322 g molꢀ1; Ratio E/Z: 61/39; Yield: 100%.
RMN 1H (CDCl3, 250 MHz): 1.22 (9H, s, tBu); 1.30–2.28 (8H, m,
CH2); 3.83 (6H, 2 d, CH3AOAP, JHAP = 11.25 Hz, stereoisomer Z and
E); 4.89 (0.61H, tdd, CH2ACH, stereoisomer Z, JHAH = JHvinyl = 7.7 Hz,
JHAP = 2.3 Hz); 5.46 (0.39H, tdd, CH2ACH, stereoisomer E,
JHAH = 7.7 Hz, JHAH = 10.7 Hz, JHAP = 1.3 Hz); 6.41 (1H, m, CHAOAP).
RMN 31P (CDCl3, 101 MHz): ꢀ1.23 (s, enolphosphate E); ꢀ0.80
(s, enolphosphate Z).
3.6.1. 3a
C6H13O4P; MW = 180 g molꢀ1; Ratio E/Z: 58/42; Yield: 100%.
RMN 1H (CDCl3, 250 MHz): 1.00 (3H, t, CH3ACH2, JHAH = 7.1 Hz);
2.00 (0.84H, td, CH3ACH2, JHAH = 7.1 Hz, JHAH = Hz); 2.17 (1.16H, td,
CH3ACH2, JHAH = 7.1 Hz, JHAH = Hz); 3.82 (6H, 2 d, CH3AOAP,
JHAP = 11.25 Hz, stereoisomer Z and E); 4.89 (0.58H, tdd, CH2ACH,
stereoisomer Z, JHAH = JHvinyl = 7.7 Hz, JHAP = 2.3 Hz); 5.49 (0.42H,
tdd, CH2ACH, stereoisomer E, JHAH = 7.7 Hz, JHAH = 10.7 Hz,
JHAP = 1.3 Hz); 6.39 (1H, m, CHAOAP).
MS (FAB+): m/z 323 ([M+H]+, 100%).
IR (NaCl):
m
PAOAC = 1021 cmꢀ1
,
m
P@O = 1279 cmꢀ1
,
mC@C =
1670 cmꢀ1 OH = 3300 cmꢀ1
, m .
RMN 31P (CDCl3, 101 MHz): ꢀ0.88 (s, stereoisomer Z), ꢀ1.20 (s,
stereoisomer E).
3.6.4. 3e
C13H28O8P2; MW = 374 g molꢀ1; Ratio E/Z: 52/48; Yield: 100%.
RMN 1H (CDCl3, 250 MHz): 1.35 (6H, t, CH3ACH2, JHAH = 7.0 Hz);
1.30–2.50 (8H, m, CH2); 3.82 (6H, 2 d, CH3AOAP, JHAP = 11.25 Hz,
stereosiomer Z and E); 4.03 (4H, m, CH2ACH2AOAP); 4.13 (4H,
m, CH3ACH2AOAP); 4.88 (0.58H, tdd, CH2ACH, stereoisomer Z,
JHAH = JHvinyl = 7.7 Hz, JHAP = 2.3 Hz); 5.45 (0.42H, tdd, CH2ACH, ste-
reoisomer E, JHAH = 7.7 Hz, JHAH = 10.7 Hz, JHAP = 1.3 Hz); 6.39 (1H,
m, CHAOAP).
3.6.2. 3b
C9H19O5P; MW = 238 g molꢀ1; Ratio E/Z: 28/72; Yield: 100%.
RMN 1H (CDCl3, 250 MHz): 1.25–2.23 (8H, m, CH2); 2.36 (2H, t,
CH2AOH); 3.80 (6H, 2 d, CH3AOAP, JHAP = 11.78 Hz, stereosiomer Z
and E); 4.82–5.03 (0.28H, m, CH2ACH, stereoisomer Z); 5.17–5.52
(0.72H, m, CH2ACH, stereoisomer E); 6.34–6.45 (1H, m, CHAOAP).
RMN 31P (CDCl3, 101 MHz): ꢀ1.23 (s, enolphosphate E); ꢀ0.81
(s, enolphosphate Z).
RMN 31P (CDCl3, 250 MHz): ꢀ1.26 (s, enolphosphate Z); ꢀ0.83
(s, enolphosphate E); 0.40 (s, phosphate).

N. Barthes, C. Grison / Bioorganic Chemistry 40 (2012) 48–56
55
RMN 13C (CDCl3, 63 MHz): 15.9 (CH3ACH2); 23.0–30.1 (4 CH2);
3.7.2. 10ara
13H20O5; MW = 256 g molꢀ1; Rf = 0.40 – AcOEt/Hexane – 6:4 –
pale yellow oil.
54.4 (CH3AOAP); 62.7 (CH2ACH2AOAP); 67.3 (CH3ACH2AOAP);
116.1 (CH@CHAO); 134.8 (CH@CHAO).
C
MS (FAB+): m/z 375 ([M+H]+, 100%).
Pure 10ara is obtained, without further purification, in 71%
yield. (E)-stereoisomer is the major product (>95%).
RMN 1H (250 MHz, CDCl3): 1.38 (3H, s, H isopropylidene), 1.43
(3H, s, H isopropylidene), 1.44 (3H, s, H isopropylidene), 1.47 (3H,
s, H isopropylidene), 3.62–4.23 (4H, m, H5, H6, H7), 4.67 (1H, m, H4),
6.46 (1H, ddd, H2, JHAH = 1.5 Hz, JHAH = 7.75 Hz, JHAH = 15.75 Hz),
6.92 (1H, dd, H3, JHAH = 4.0 Hz, JHAH = 15.75 Hz), 9.62 (1H, d, H1,
JHAH = 8.0 Hz).
IR (NaCl):
m
PAOAC = 1015 cmꢀ1
,
m
P@O = 1271 cmꢀ1
,
mC@C =
1665 cmꢀ1
.
3.6.5. 3f
C15H32O8P2; MW = 402 g molꢀ1; Ratio E/Z: 48/52; Yield: 100%.
RMN 1H (CDCl3, 250 MHz): 1.35 (12H, t, CH3ACH2,
JHAH = 7.0 Hz); 1.30–2.50 (8H, m, CH2); 4.03 (4H, m,
CH2ACH2AOAP); 4.09–4.17 (8H, m, CH3ACH2AOAP); 4.88
(0.58H, tdd, CH2ACH, stereoisomer Z, JHAH = JHvinyl = 7.7 Hz,
JHAP = 2.3 Hz); 5.45 (0.42H, tdd, CH2ACH, stereoisomer E,
JHAH = 7.7 Hz, JHAH = 10.7 Hz, JHAP = 1.3 Hz); 6.39 (1H, m, CHAOAP).
RMN 31P (CDCl3, 250 MHz): ꢀ1.26 (s, enolphosphate Z); ꢀ0.83
(s, enolphosphate E); 0.40 (s, phosphate).
IR (NaCl): m , m .
C@O = 1721 cmꢀ1 C@C = 1690 cmꢀ1
3.8. Hydroalumination–phosphorylation to 11gal–ara
0.05 Eq. (MW = 190 g molꢀ1) of dried CuI are suspended in 4 mL
of anhydrous THF at ꢀ50 °C in a dried flask, under nitrogen.
0.05 eq. of MeLi (1.6 M in Et2O) is added dropwise followed by
1.5 eq. of HMPA (MW = 179 g molꢀ1 – d = 1.03 g.mLꢀ1) and then
1.1 eq. of DIBAL (1.5 M in Toluene). Reaction is stirred at ꢀ50 °C
RMN 13C (CDCl3, 63 MHz): 15.9 (CH3ACH2); 23.0–30.1 (4 CH2);
62.7 (CH2ACH2AOAP); 67.3 (CH3ACH2AOAP); 116.1 (CH@CHAO);
134.8 (CH@CHAO).
MS (FAB+): m/z 403 ([M+H]+, 100%).
for 30 min before adding 1.5 mmol of
a,b-unsaturated aldehyde
IR (NaCl):
m
PAOAC = 1015 cmꢀ1
,
m
P@O = 1271 cmꢀ1
,
mC@C =
10gal (426 mg) or 10ara (384 mg) in solution in 4 mL of THF. Reac-
tion is stirred one more hour at ꢀ50 °C before adding 1.1 eq. of
MeLi (1.6 M in Et2O). After 15 min at ꢀ50 °C, 1.1 eq. of diethylchlo-
rophosphate (MW = 172 g molꢀ1 – d = 1.194) are added and reac-
tion is kept 2 h at ꢀ50 °C. Reaction is finally stirred at rt
overnight. THF is evaporated under vacuum and Et2O is added to
the obtained mixture. After centrifugation of precipitated salts, fil-
trate is concentrated, and taken up in 25 mL of CH2Cl2. Solution is
rapidly washed with 5 mL of water, dried with Na2SO4 and concen-
trated under vacuum. A very fast silicagel chromatography on filter
(AcOEt/Hexane – 6:4) is realised in less than 15 min to give 35% of
expected product 11gal–ara (60 % (E)/40% (Z)), as pale oils, with a
great purity.
1665 cmꢀ1
.
3.6.6. 3g
C12H23O6P; MW = 294 g molꢀ1; Ratio E/Z: 45/55; Yield: 100%.
RMN 1H (CDCl3, 250 MHz): 1.30–2.50 (10H, m, CH2); 2.32 (2H, t,
CH2ACO2Me, JHAH = 4.75 Hz); 3.68 (3H, s, CO2Me); 3.82 (6H, 2 d,
CH3AOAP, JHAP = 11.23 Hz, stereosiomer Z and E); 4.88 (0.45H,
tdd, CH2ACH, stereoisomer Z, JHAH = JHvinyl = 7.7 Hz, JHAP = 2.3 Hz);
5.45 (0.55H, tdd, CH2ACH, stereoisomer E, JHAH = 7.7 Hz,
JHAH = 10.7 Hz, JHAP = 1.3 Hz); 6.39 (1H, m, CHAOAP).
RMN 31P (CDCl3, 101 MHz): ꢀ1.25 (s, enolphosphate Z); ꢀ0.83
(s, enolphosphate E).
MS (FAB+): m/z 295 ([M+H]+, 54%).
IR (NaCl):
m
PAOAC = 1015 cmꢀ1
,
m
P@O = 1271 cmꢀ1
,
mC@C =
3.8.1. 11gal
1736 cmꢀ1
.
C
18H31O9P; MW = 422 g molꢀ1
.
RMN 1H (400 MHz, CDCl3): 1.31 (3H, s, H isopropylidene), 1.32
(3H, s, H isopropylidene), 1.34 (6H, t, CH3ACH2, JHAH = 7.0 Hz), 1.39
(3H, s, H isopropylidene), 1.50 (3H, s, H isopropylidene), 2.04–2.12
(2H, m, H6), 3.85–4.45 (8H, m, H2, H3, H4, H5, CH3ACH2AO), 4.60–
4.79 (1H, m, H7), 5.60 (1H, d, H1, JHAH = 3.0 Hz), 5.68–6.03 (1H, m,
H8);
3.7. Preparation of a,b-unsaturated aldehydes 10gal–ara
1 eq. of AlLiH4 (1 M in Et2O) is added on a solution of 400 mg of
carboxamide 8gal (1.16 mmol) or 8ara (1.27 mmol) in 20 mL of
THF under nitrogen at 0 °C. Temperature must be controlled be-
tween ꢀ3 and +5 °C. After 30 min, a solution of 1.2 eq. of KHSO4
in 3.0 mL of water is added to reaction. After concentration under
vacuum, aqueous layer is extracted three times with CH2Cl2. Or-
ganic layers are washed with aqueous solutions of HCl (3 N), NaCl
(sat.), NaHCO3 (sat.) and NaCl (sat.) before being dried with Na2SO4
and concentrated under vacuum.
RMN 31P (162 MHz, CDCl3): ꢀ0.84 (s, enolphosphate (E)), ꢀ0.70
(s, enolphosphate (Z)).
RMN 13C (CDCl3, 101 MHz): 24.4; 24.9; 25.9; 26.1 (CH3 isopro-
pylidene), 29.6 (C6), 67.6 (C5), 70.5 (C2), 70.9 (C3), 72.7 (C4), 96.4
(C1), 108.7; 109.5 (C isopropylidene), 132.8 (C7), 151.5 (C8).
MS (FAB+): m/z 423 ([M+H]+, 68%).
3.7.1. 10gal
3.8.2. 11ara
C14H20O6; MW = 284 g molꢀ1; Rf = 0.40 – AcOEt/Hexane – 6:4 –
pale yellow oil.
C17H31O8P; MW = 394 g molꢀ1
.
RMN 1H (400 MHz, CDCl3): 1.27; 1.29; 1.31; 1.34 (18H, m, iso-
Pure 10gal is obtained, without further purification, in 87%
yield. (E)-stereoisomer is the major product (91%).
RMN 1H (CDCl3, 400 MHz): 1.31 (3H, s, H isopropylidène), 1.32
(3H, s, H isopropylidène), 1.39 (3H, s, H isopropylidène), 1.50 (3H, s,
H isopropylidène), 4.32 (1H, dd, H4, JHAH = 4.8 Hz, JHAH = 1.5 Hz),
4.35 (1H, dd, H2, JHAH = 3.1 Hz, JHAH = 1.6 Hz), 4.54 (1H, m, H5),
4.65 (1H, dd, H3, JHAH = 1.6 Hz, JHAH = 4.8 Hz), 5.58 (1H, d, H1,
JHAH = 3.1 Hz), 6.35 (1H, ddd, H7, JHAH = 1.25 Hz, JHAH = 5.0 Hz,
JHAH = 9.8 Hz), 6.77 (1H, dd, H6, JHAH = 2.75 Hz, JHAH = 9.8 Hz),
9.64 (1H, d, H aldehyde, JHAH = 5 Hz).
propylidene; CH3ACH2), 2.16 (1H, m, H3), 2.40 (1H, m, H0 ), 3.84–
3
4.20 (9H, m, H4, H5, H6, H7, CH3ACH2AO), 5.01 (0.4H, m, H2(Z)),
5.46
(0.6H,
ddt,
H2(E),
3JHAP = 0.75 Hz,
JHAH = 4.75 Hz,
JHAH = 7.6 Hz), 5.60–6.02 (0.4H, m, H1(Z)), 6.41 (0.6H, dd, H1(E),
JHAH = 3.5 Hz, JHAH = 7.6 Hz);
RMN 31P (162 MHz, CDCl3): ꢀ4.60 (s);
RMN 13C (101 MHz, CDCl3): 16.1; 16.2 (CH3ACH2), 25.2; 26.7;
27.0; 27.2 (isopropylidene), 30.6 (C3), 64.3; 64.4 (CH3ACH2), 67.8
(C7), 77.1 (C6), 79.8 (C5), 80.2 (C4), 110.2; 110.3 (C isopropylidene),
112.3; 112.4 (C2), 137.7 (C1).
IR (NaCl):
m
C@O = 1721 cmꢀ1
,
m
C@C = 1690 cmꢀ1
.
MS (FAB+): m/z 395 ([M+H]+, 77%).

56
N. Barthes, C. Grison / Bioorganic Chemistry 40 (2012) 48–56
[12] C. Grison, S. Petek, C. Finance, P. Coutrot, Carbohydr. Res. 340 (2005) 529–537.
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