Synthesis of higher-carbon sugars by addition of organometallic reagents to aldehydes or lactols derived from carbohydrates

Article abstract of DOI:10.1016/S0040-4020(01)00410-0

The addition of different Grignard or lithium organometallic reagents to lactols (1, 6, 21) or aldehydes (10), derived from D-glucose or D-mannose, to give the new higher-carbon sugars (2, 3, 7-9, 13-19, 22 and 23) is reported.

Full text of DOI:10.1016/S0040-4020(01)00410-0

TETRAHEDRON
Pergamon
Tetrahedron 57 ,2001) 4729±4739
Synthesis of higher-carbon sugars by addition of organometallic
reagents to aldehydes or lactols derived from carbohydrates
p
Jose Marco-Contelles, Elsa de Opazo and Nieves Arroyo
Â
Laboratorio de Radicales Libres ꢀIQOG, CSIC), C/Juan de la Cierva 3, 28006Madrid, Spain
Received 17 November 2000; revised 19 February 2001; accepted 30 March 2001
AbstractÐThe addition of different Grignard or lithium organometallic reagents to lactols ,1, 6, 21) or aldehydes ,10), derived from
d-glucose or d-mannose, to give the new higher-carbon sugars ,2, 3, 7±9, 13±19, 22 and 23) is reported. q 2001 Elsevier Science Ltd. All
rights reserved.
1. Introduction
compounds with 2,3-O-isopropylidene-d-glyceraldehyde.11
The use of organozinc reagents has also been studied afford-
ing variable mixtures of the syn/anti products, the reaction
being very substrate-dependent.12 Another relevant type of
substrates submitted to organometallic addition have been
the free aldehydes derived from sugars or the O-perbenzyl-
ated lactols. With open-chain free aldehydes the addition of
Grignard reagents gives major syn products, a situation
which has been reversed to give major anti products by
using magnesium bromide as additive ,Eq. ,1), Scheme
2).13 The addition of vinyl species to O-perbenzylated aldo-
pentoses described by Nicotra has afforded consistent major
syn isomers from d-arabino, d-ribo and d-xylo precursors,
but major anti isomers from d-lyxo derivatives ,Eq. ,2),
Scheme 2).14 In Fig. 1 we show some syn/anti adducts
with the reported vicinal coupling between the newly
formed and the pre-existing stereocenters. In most of these
examples a correlation with a known stereochemically pure
compound, or a simple chemical transformation leading to
some 'cyclic' derivative, where an inequivocal spectro-
scopic proof, such as a nOe effect or a vicinal coupling
constant, could be applied, has been used to assign the
syn/anti stereochemical outcome of the organometallic
addition. In fact, this strategy has been used sometimes
for the synthesis of C-glycosides4 or azasugars15 from inter-
mediates obtained via the organometallic addition to alde-
hydes or imines, respectively.
The addition of organometallic reagents to aldehydes,
ketones or lactols is one the best known, used and exploited
methods for the synthesis of branched-chain or higher-
carbon sugar derivatives.1 This is a simple reaction which
usually affords high stereoselection and convenient chemi-
cal yields of the desired products. Although it is dif®cult to
predict the stereochemical outcome ,the syn/anti ratio) of
these processes, there is a plethora of dispersed and useful
results in literature which allow us to generalize some
general trends.2 Some examples are shown in Scheme 1.
A marked preferred anti selectivity has been reported in
the Grignard addition to 2,3-O-isopropylidene derivatives
in the manno-3 ,Eq. ,1), Scheme 1) or in the addition of
Grignard and lithium reagents in the ribo- series4 ,Eq. ,2),
Scheme 1). Conversely, in the addition of lithium reagents
to manno- 2,3-O-isopropylidene derivatives, a reversal of
this stereoselectivity has been reported ,Eq. ,3), Scheme
1).5,3c These trends have also been con®rmed in other
2,3-O-isopropylidene derivatives in furanose templates.2a,6
The same applies to precursors in the d-threose or
d-erythrose8 ,Eq. ,4), Scheme 1) series: major anti products
have been obtained, independently of the organometallic
agents used. An interesting, very synthetically useful and
highly stereoselective protocol is also the one-carbon homo-
logation protocol described by Dondoni: for a-alkoxy alde-
hydes only anti adducts have been observed ,Eq. ,5),
Scheme 1).9 The addition of 1,3-dithiane has also been
extensively studied by several authors: major syn isomers
have been obtained ,Eq. ,6), Scheme 1);10 in addition, they
have always found higher values for J1,2 in syn products than
in the similar anti compounds. This same preference ,syn
induction) has been reported in the reaction of organocopper
In summary, from all the reported data and results1±15 we
can conclude that the addition of organometallic reagents to
lactols or aldehydes derived from carbohydrates is very
complex, highly dependent on the reaction conditions,
O-protecting groups, and that each new transformation16
has to be carefully analyzed by chemical transformations
and or by very well contrasted 1H NMR spectroscopic data.
Keywords: higher-carbon sugars; organometallic reagent.
Corresponding author. Tel.: 134-91-562-2900; fax: 134-91-564-4853;
e-mail: iqoc21@iqog.csic.es
p
From the mechanistic point of view, it is important to high-
light that the formation of major anti products has been
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,01)00410-0

4730
J. Marco-Contelles et al. / Tetrahedron 57 ꢀ2001) 4729±4739
OH
O
OH
O
O
O
(eq. 1)
O
CH2=CHMgBr, THF
93%
OH
H
O
O
O
O
Ref. 3a, b
anti/syn: 5/1
OH
O
OH
MOMO
O
(eq. 2)
(J3,4= 8.6 Hz)
anti/syn: 20/1
4
HC CMgBr, THF
72%
3
MOMO
OH
H
O
O
O
Ref. 4c
O
OH
O
OH
CH3
O
O
CH3Li, THF
(eq. 3)
OH
O
H
99%
O
O
O
O
Ref. 5, 3c
O
O
OH
O
O
O
CH2=CHMgBr, THF
Ref. 8
H
H
(eq. 4)
O
H4
H3
OH
J3,4= 4.4 Hz
N
O
O
S
H
SiMe3
S
O
O
(eq. 5)
O
1
N
2
Ref. 9c
H
OH
J1,2= 5.5 Hz
OH
OH
2
O
tBuPh2SiO
S
3
S
S
tBu
Ph2SiO
H
(eq. 6)
O
O
S
O
O
Ref. 10a
syn (J2,3= 9.4 Hz)
Scheme 1. Addition of organometallic reagents to sugar derivatives.
explained by assuming a chelation or nonchelation control
in a Felkin±Ahn model ,Fig. 2).17,18
63, respectively. All new molecules showed excellent
analytical and spectroscopic data, in good agreement with
1
1
their structures. Extensive H NMR, H±1H COSY and
HMQC experiments allowed us to assign the chemical and
vicinal coupling constants. We have tentatively assigned as
syn the relative stereochemistry to the major isomer 3, and
the anti to the minor product 2. In fact, the analogous
In the course of our recent work we have analyzed the
reactivity of some organometallic reagents with several
aldehydo-sugars or lactols for the preparation of higher-
carbon sugars. In this account we show and discuss the
results we have obtained in these protocols.
derivatives
3,4,5,7-tetra-O-benzyl-1-deoxy-d-glycero-d-
gulo-heptitol ,anti product: J1,2ˆ6 Hz) and 1,3,4,5-tetra-
O-benzyl-7-deoxy-d-glycero-l-gulo-heptitol ,syn product:
J1,2ˆ2.9 Hz) ,Fig. 3) show vicinal coupling constants at
the newly formed stereocenters19a very similar to the values
found by us in compound 2 ,anti) ,J3,4ˆ4.6 Hz; d H-3: 4.88)
and in compound 3 ,syn) ,J3,4ˆ2.9 Hz; d H-3: 4.67), respec-
tively. This fact is also in agreement with the reactivity
of vinylmagnesium bromide with the `stereochemically
analogous' 2,3,5-tri-O-benzyl-xylo-d-furanose described
by Nicotra, favouring the formation of major syn adducts
,see Fig. 1, compounds D2 and D4 and Eq. ,2), Scheme 2).14
2. Results and discussion
The ®rst substrate studied was the commercially available
tetra-O-benzyl-d-glucopyranose ,1). After some experimen-
tation suitable conditions were found to promote an ef®cient
addition reaction using phenylethynylmagnesium bromide
,1.0M in THF) ,see Section 3). As shown in Scheme 3 two
compounds, 2 and 3, were isolated in 88% overall yield. The
ratio of these isomers in the crude reaction mixture was 37/

J. Marco-Contelles et al. / Tetrahedron 57 ꢀ2001) 4729±4739
4731
OBn
O
OBn
OH
OBn
BnO
BnO
BnO
BnO
BnO
BnO
CH2=CHMgBr, THF
Ref. 13
+
(eq. 1)
OH
anti/syn: 1/3
anti/syn: 8/1
Conditions: CH2Cl2: THF (5:1), -78 ºC
Conditions: CH2Cl2, MgBr2, -78 ºC
OBn
CH2=CHMgBr, THF
or
(CH2=CH)2Zn, THF
OBn
O
OH
OH
OH
OBn
H
(eq. 2)
H
BnO
Ref. 14
BnO
OBn
D-arabino, D-ribo, D-xylo
D-lyxo
syn
>
anti
syn
>
anti
Scheme 2. Addition of organometallic reagents to free aldehydes or O-perbenzylated aldoses.
As expected from literature data,3 in very mild and careful
reaction conditions, preferential functionalization in the
O-propargyl side chain in the major product 3 ,syn) lead
to the C-3/O-monobenzyloxycarbonyl ,4) and C-3/O-mono-
benzoyl ,5) derivatives. Unfortunately, the reaction of
compound 3 with tosyl chloride or methanosulfonyl
chloride,4b or under Mitsunobu conditions4f,g as described,
to give the `cyclic' derivatives was very complex4b or gave
no reaction at all,4f,g and one of the expected and known
resulting C-glycosides19b ,Fig. 4) was not obtained.
With these results in mind we turned our attention to lactol 6
obtained from d-glucose diethyl dithioacetal as described.20
The reaction of this product with vinylmagnesium bromide
,1.0M in THF) at 0 8C afforded compounds 7 and 8 in
45% yield, as a mixture of two isomers, in a 3:7 ratio,
OH
O
OH
OH
O
OH
3
OH
O
OH
tBuPh2SiO
2
HO
4
2
Ph
1
tBu
Ph2SiOH2C
Ph
1
O
O
O
B1 (J1,2= 4.8 Hz) (Ref. 6)
B2 (J1,2= 4.3 Hz) (Ref. 6)
A (J3,4= 9.1 Hz) (Ref. 6)
anti
syn
OH
OH
O
2
4
BnOH2C
1
BnOH2C
3
O
O
O
O
SiMe3
C1 (J1,2= 3 Hz) (Ref. 7)
C2 (J3,4= 3.9 Hz) (Ref. 7)
anti
anti
BnO
BnO
BnO
BnO
H
OH
3
H
OH
H
BnO
OH
H
OH
3
BnO
BnO
4
BnO
4
4
4
3
3
BnO
BnO OH
OH
BnO
OH
BnO
OH
D2 (anti): J3,4= 3 Hz
D1 (anti): J3,4= 6.5 Hz
D3 (syn): J3,4= 3.5 Hz
D4 (syn): J3,4= 2 Hz
(Ref. 14)
(Ref. 14)
(Ref. 14)
(Ref. 14)
Figure 1. Some examples of anti and syn products obtained from carbohydrate derivatives with the reported vicinal coupling constants at the newly formed
stereocentres.

4732
J. Marco-Contelles et al. / Tetrahedron 57 ꢀ2001) 4729±4739
O
BnO
BnO
OH
OH
O
H
CH3
OH
CH3
OH
H
H
2
2
O
BnO
BnO
BnO
H
3
3
BnO
OBn
OBn
Figure 2. Felkin±Ahn model for the formation of anti products during the
organometallic addition to aldehydes ,Ref. 17).
syn
2,3= 2.9 Hz
anti
2,3= 6 Hz
J
J
respectively, which we could only partially separate: only
major product 8 ,anti) was isolated pure ,Scheme 4).
Performing the reaction at 2788C, in the same conditions,
the yield was quite similar, but the ratio of isomers increased
to 1:4, the anti isomer being again the major isomer in the
mixture. The assignment of anti to the major isomer was
tentatively made by comparison of the reactivity observed
for the analogous d-glucose derivative 10, which gives
major anti derivatives 14 or 19 ,see below, Scheme 6), a
very well known stereochemical outcome in Dondoni's
Figure 3. 3,4,5,7-Tetra-O-benzyl-1-deoxy-d-glycero-d-gulo-heptitol ,anti
product) and 1,3,4,5-tetra-O-benzyl-7-deoxy-d-glycero-l-gulo-heptitol
,syn product) ,Ref. 19a).
OBn
BnO
H
OBn
OBn
O
1
chemistry.9 It is interesting to note that in the H NMR
Ph
spectrum, upon addition of D2O, pure major 8 ,anti)
compound showed a vicinal coupling constant J3,4 equal
to 5.1 Hz; this value is very similar to the same vicinal
coupling constant observed in analogous derivatives
obtained from related d-glucose precursor 10 [see below,
Scheme 6, compounds 14 ,anti) and 19 ,anti)]. Unfortu-
nately, the H NMR of the mixture, H-3 ,syn) was over-
lapping other signals and an inequivocal analysis of this
signal was not possible.
Figure 4. ,2,3,4,6-Tetra-O-benzyl-a-d-glucopyransoyl) phenylacetylene
,Ref. 19b).
value of the coupling constants for stereochemical assign-
ments have to be used with caution.
1
Next we turned out our attention to the organometallic
additions to iodoaldehyde 10. This compound has been
easily prepared from alcohol 11,22 via iodide 12 as shown
in Scheme 5.
The same substrate ,6) after addition of phenylethynyl-
magnesium bromide ,1.0M in THF) at rt afforded a mixture
of 9 ,syn) and 9 ,anti) isomers in 67% yield ,91% taking into
account the recovered starting material), in 1 to 4 ratio,
respectively, which we were unable to separate. However
in the 1H NMR spectrum of the mixture the signals for H-3
were clearly detected, appearing as triplets with identical
vicinal coupling constants for H-3/OH and H-3/H-4. For
the major isomer 9 ,anti) we could observe d H-3 at 4.88,
with J3,4ˆ3.6 Hz, while for the minor isomer 9 ,syn) we
could observe d H-3 at 4.68, with J3,4ˆ5.4 Hz. In this
case the assignment as anti to the major isomer rests by
comparison with compounds 15 ,syn) and 16 ,anti) ,see
below, Scheme 6), whose absolute con®guration at the
newly formed stereocenters has been inequivocally demon-
strated by transforming 16 ,anti) into 'cyclic' derivatives.21
Note that in these examples the vicinal coupling constants in
the syn isomers are higher than in the anti, the opposite
observed in compounds 9. This is a clear case where the
Vinylmagnesium bromide addition to aldehyde 10 at 08C
gave the expected compounds 13 ,syn) and 14 ,anti) in 81%
yield, showing that the iodine atom was quite stable to the
present conditions ,Scheme 6). The ratio of isomers syn and
anti was 1 to 4, respectively. We only could isolate pure the
1
major product 14 ,anti), which in the H NMR spectrum
showed a vicinal coupling constant for H-3/H-4 equal to
4.4 Hz, in good agreement with the value observed for
compound 8 ,anti) ,see above). Unfortunately, during the
chromatography for the puri®cation, the rest of the mass for
this reaction was a mixture of products 13 ,syn) and 14
1
,anti) whose H NMR spectrum made dif®cult to analyze
the J3,4 ,syn).
The addition of phenylethynylmagnesium bromide to
compound 10 in the usual conditions afforded the mixture
BnO
H
BnO
H
8
OBn
O
OH
3
OH
Ph
1
7
Ph
BnO
BnO
Ph
MgBr
6
+
BnO
BnO
OH
4
BnO
BnO
5
2
88%
2 (anti)/ 3 (syn): 37/63
OBn
BnO OX
OH
BnO
J3,4= 2.9 Hz
1
2 (anti)
3 (syn) X= H
δH-3: 4.67
a
J3,4= 4.6 Hz
b
4 X= C(O)OBn
5 X= Bz
δH-3: 4.88
Scheme 3. Addition of pehnylethynylmagnesium bromide to hemiacetal 1 at rt. Reagents: ,a) CIC,O)OBn, py ,63%); ,b) CIBz, py ,77%).

J. Marco-Contelles et al. / Tetrahedron 57 ꢀ2001) 4729±4739
4733
1
2
HO
O
OH
O
HO
O
a
OH
3
+
4
45%
O
O
O
O
O
7(syn)/ 8 (anti): 3/7
OH
O
O
7 (syn)
8 (anti)
O
J3,4= 5.1 Hz
O
O
Ph
HO
6
3
OH
O
b
4
67 (91%)
O
O
O
9 (syn)/ 9 (anti): 1/4
9 (anti)
9 (syn)
+
J3,4= 3.6 Hz
J3,4= 5.4 Hz
δH-3: 4.68
δH-3: 4.88
Scheme 4. Addition of Grignard reagents to hemiacetal 6. Reagents: ,a) Vinylmagnesium bromide, 08C; ,b) Phenylethynylmagnesium bromide, 08C.
of compound 15 and 16, in 73% overall yield and 3/7 ratio,
respectively ,Scheme 6). Only pure major 16 ,anti) isomer
was isolated pure. In agreement with the observed data for
adducts 9 ,anti) ,see below, Scheme 4) compound 16 ,anti)
showed in the 1H NMR spectrum a vicinal coupling constant
between H-3 ,4.83 ppm) and H-4 equal at 3.3 Hz; in the
mixture of 15 ,syn) and 16 ,anti) we could analyze H-3
for 15 ,syn) at 4.70ppm as a doublet of doublets with
J3,4ˆ4.4 Hz, J3,OHˆ5.6 Hz.
as the major isomer was tentatively made by comparison
with the other related cases obtained from the same pre-
cursor ,10) ,see above).
Finally, aldehyde 10 was submitted to reaction with
2-,trimethylsilyl)thiazole. Not unexpectedly, we isolated
only one compound ,19) ,Scheme 6) to whom the anti
stereochemistry at carbons C-1 and C-2 was assigned
based on well known precedent.9 In fact, the observed
J1,2ˆ5.2 Hz is in good agreement with the reported analo-
gous vicinal coupling constant ,5.5 Hz) for ,1R)-2,3-O-
isopropylidene-1-,2-thiazolyl)-d-glycitol ,Eq. ,5), Scheme
1).9c
The ®nal assignment as anti to the major isomers 14 and 16
has been inequivocally demonstrated by transforming them
into 'cyclic' derivatives, where the relative stereochemistry
at the newly formed stereocenters has been established by
spectroscopic data and nOe effects.21
We wanted also to test the reactivity of lithium reagents
with these type of lactols. It is well known for instance
that the reaction of methyllithium with 2,3:5,6-bis-O-
isopropylidene-a-d-mannofuranose ,21)23 gives exclusively
syn product ,Eq. ,3), Scheme 1),5 while the reaction with
methylmagnesium bromide affords a major anti com-
pound.3c In our case we have submitted the hemiacetal
2123 to reaction with lithium phenylacetylide, and have
obtained products 22 ,syn) and 23 ,anti) in 82% yield, in
a 2.6 to 1 ratio, respectively ,Scheme 7). After separation by
chromatography, the usual analytical and spectroscopic data
allowed us to determine the structure of these compounds.
Major isomer showed a vicinal coupling constant for H-3
and H-4 equal to 6.8 Hz, while minor isomer showed a
vicinal coupling constant for H-3 and H-4 equal to 4.9 Hz,
showing that in this case and as expected5 the major isomer
is syn. In this case, the assignment of syn to the major isomer
was tentatively made by comparison with the other related
The addition of ethynylmagnesium bromide to compound
10 in the standard conditions gave an unseparable mixture
of compounds 17 ,syn) and 18 ,anti) in 61% yield ,70%
taking into account the recovered starting material), in a 3
to 7 ratio, respectively ,Scheme 6). Unfortunately, in the 1H
NMR spectrum protons H-3 and H-4 appeared as complex
multiplets, and the inequivocal assignment was impossible.
In addition to the assigned signals for the major 18 ,anti)
1
isomer, in the H NMR and in the 13C NMR spectra of the
mixture we could also identify some speci®c signals for the
minor 17 ,syn) isomer: 4.30,d, J6,7ˆ6.7 Hz, 1H, H-6), 4.17
,d, J4,5ˆ4.0Hz, 1H, H-5), 3.40,d, J7,8ˆ7.0Hz, 2H, 2H-8),
2.81 ,d, J3,OHˆ6.3 Hz, 1H, OH), 2.55 ,d, J1,3ˆ2.2 Hz, 1H,
±CuC±H) ppm, and 81.1 ,q, ±CuC±H), 79.2 ,q, ±CuC±
H), 77.9 ,C-7), 75.2 ,C-4), 75.1 ,C-5), 74.8 ,C-6), 62.4
,C-3), 2.5 ,C-8) ppm. In this case, the assignment of anti
SEt
SEt
I
HO
O
I
O
SEt
SEt
a
b
O
O
O
O
O
O
O
O
O
O
O
12
11
10
Scheme 5. Synthesis of precursor 10. Reagents: ,a) I2, Ph3P, toluene, imidazole ,70%); ,b) HgO, HgCl2, acetone ,75%).

4734
J. Marco-Contelles et al. / Tetrahedron 57 ꢀ2001) 4729±4739
1
2
I
OH
O
I
a
OH
3
+
4
81%
O
O
O
O
13 (syn)/ 14 (anti): 1/4
O
O
O
13 (syn)
14 (anti)
J3,4= 4.4 Hz
δH-3: 4.35
Ph
I
Ph
1
2
OH
I
OH
b
3
4
+
O
O
O
O
73%
O
O
O
O
15 (syn)/ 16 (anti): 3/7
15 (syn)
16 (anti)
I
O
J3,4= 3.3 Hz
δH-3: 4.83
J3,4= 4.4 Hz
δH-3: 4.70
O
O
1
2
O
O
I
OH
I
10
OH
c
3
4
+
O
O
O
O
O
O
61% (70%)
O
O
17 (syn)/ 18 (anti): 3/7
17 (syn)
18 (anti)
N
1
S
I
N
OH
O
CHO
O
S
I
2
OBn
O
e
+
O
d
O
O
O
O
O
O
O
O
19a12
19 (anti) (60%)
19(syn)/ 19 (anti): 1/14
J1,2= 5.2 Hz
20
δH-1: 5.15
Scheme 6. Addition of organometallic reagents to aldehyde 10. Reagents: ,a) Vinylmagnesium bromide, 08C; ,b) Phenylethynylmagnesium bromide, 08C; ,c)
Ethynylmagnesium bromide, 08C; ,d) 2-,Trimethylsilyl)thiazole, 08C; ,e) ,from 19) NaH, BnBr ,92%).
cases obtained by Corey5 and other authors3c with the same
precursor.
tion with Grignard or lithium reagents. Yields were usually
good with moderate stereoselectivities ranging from 1 to 4
or 2 to 1, in favor of anti isomers when using Grignard
reagents, while for lithium species the stereoselectivity
was reversed. The best result was obtained with any
doubt using Dondoni's formyl homologation method.9 The
In summary, we have described the synthesis of higher-
carbon sugars from readily available hemiacetals or free
aldehydes, derived from d-glucose or d-mannose, by reac-
Ph
Ph
1
O
O
3
O
OH
O
8
OH
O
2
4
O
O
OH
7
O
PhC CLi, -78 ºC
82%
O
6
+
5
HO
O
HO
O
O
O
23 (anti)
22 (syn)
21
22 (syn)/ 23 (anti): 2.6/1
J3,4= 4.9 Hz
δH-3: 5.02
J3,4= 6.8 Hz
δH-3: 5.01
Scheme 7. Addition of lithium phenylacetylide to hemiacetal 21.

J. Marco-Contelles et al. / Tetrahedron 57 ꢀ2001) 4729±4739
4735
resulting products are useful building blocks for further
synthetic manipulation, and they will serve us in future
developments in our laboratory.21
Jˆ4.6 Hz, 1H, OH±C7); 13C NMR ,75 MHz, CDCl3) d
138.2, 138.0, 137.9, 137.6 ,q, OCH2Ph), 131.9 ,d, 2 C,
Ph±CuC), 129.0±128.0 ,23 C, aromat.), 122.7 ,q, Ph±
CuC), 88.3, 86.6 ,q, Ph±CuC), 79.5 ,2 C, C-4, C-5),
77.2 ,C-6), 71.5 ,C-7), 73.8, 73.6 ,2 C), 73.6 ,4 C,
OCH2Ph), 71.2 ,C-8), 63.3 ,C-3); MS ,70eV) m/z 403
,18), 295 ,13), 253 ,32), 193 ,44), 182 ,17), 131,26), 103
,13), 91 ,100), 65 ,12). Anal. calcd for C42H42O6: C, 78.48;
3. Experimental
3.1. General methods
25
H, 6.59. Found: C, 78.30; H, 6.81. 3 ,syn): oil; [a]D ˆ28
Reactions were monitored by TLC using precoated silica gel
aluminium plates containing a ¯uorescent indicator ,Merck,
5539). Detection was done by UV ,254 nm) followed by
charring with sulfuric±acetic acid spray, 1% aqueous potas-
sium permanganate solution or 0.5% phosphomolybdic acid
in 95% EtOH. Anhydrous Na2SO4 was used to dry organic
solutions during work-ups and the removal of solvents was
carried out under vacuum with a rotary evaporator. Flash
column chromatography was performed using silica gel 60
,230±400 mesh, Merck) and hexane/ethyl acetate mixtures
as eluent unless otherwise stated. 1H spectra were recorded
with a Varian VXR-300,400)S spectrometers, using tetra-
methylsilane as internal standard and 13C NMR spectra were
recorded with a Bruker WP-200-SY. Values with ,p) can be
interchanged. For the DEPT experiments ,qˆquaternary
carbon; dˆCH; tˆCH2).
,c 0.7, CHCl3); IR ,®lm) n 3435 ,OH), 3030, 2922, 2233
,CuC), 1598, 1490, 1454, 1357, 1210, 1070, 1027 cm21
;
1H NMR ,300 MHz, CDCl3) d 7.43±7.21 ,m, 25H, aromat),
4.96/4.88 ,AB system, Jˆ11 Hz, 2H, OCH2Ph), 4.79/4.68
,AB system, Jˆ11.2 Hz, 2H, OCH2Ph), 4.67 ,m, 1H, H-3),
4.56/4.51 ,AB system, Jˆ11 Hz, 2H, OCH2Ph), 4.59/4.52
,AB system, Jˆ11.8 Hz, 2H, OCH2Ph), 4.12±4.09 ,m, 1H,
H-7), 4.11 ,dd, J5,4ˆ7.2, J5,6ˆ3.3 Hz, 1H, H-5), 4.07 ,dd,
J4,5ˆ7.2, J4,3ˆ2.9 Hz, 1H, H-4), 3.82 ,dd, J6,7ˆ7.2, J6,5ˆ
0
3.3 Hz, 1H, H-6), 3.66 ,dd, J8,8 ˆ9.9, J8,7ˆ3.5 Hz, 1H,
H-8), 3.64 ,dd, J8,8 ˆ9.9, J8 ,7ˆ4.9 Hz, 1H, H-80), 3.07±
3.05 ,m, 2H, OH); 13C NMR ,75 MHz, CDCl3) d 138.0,
137.9, 137.7, 137.4 ,q, OCH2Ph), 131.6 ,d, 2 C, Ph±
CuC), 128.4±127.7 ,23 C, aromat.), 122.4 ,q, Ph±CuC),
84.4, 85.5 ,q, Ph±CuC), 81.8 ,C-5), 78.8 ,C-7), 76.9 ,C-6),
75.4, 74.9, 73.3, 73.0,4 C, O CH2Ph), 71.0,C-8), 70.7 ,C-4),
63.2 ,C-3); MS ,70eV) m/z 403 ,15), 295 ,11), 253 ,25),
205 ,13), 193 ,39), 182 ,15), 181 ,75), 131 ,25), 91 ,100), 65
,13). Anal. calcd for C42H42O6: C, 78.48; H, 6.59. Found: C,
78.41; H, 6.80.
0
0
3.2. General method for the addition of Grignard
reagents
To a solution of the substrate in the appropriate dry solvent,
at the selected temperature, under argon, the commercial
available Grignard reagent ,4.0equiv.) was slowly added.
The reaction was stirred at the indicated temperature and
monitored by TLC; when the reaction was complete, the
mixture was quenched by addition of aqueous saturated
solution of ammonium chloride, the solvent was removed,
the residue diluted wih ethyl acetate, washed with brine,
dried, ®ltered and evaporated to give a crude which was
submitted to chromatography eluting with hexane/ethyl
acetate mixtures.
3.2.2. 4,5,6,8-Tetra-O-benzyl-3-O-benzyloxycarbonyl-1,2-
dideoxy-1-phenyl-d-glycero-d-ido-oct-1-ynitol -4). To a
solution of compound ,3 syn) ,280mg, 0.44 mmol) in dry
methylene chloride ,5 mL), at 08C, under argon, benzyl
chloroformiate ,0.06 mL, 0.44 mmol) and pyridine
,0.04 mL, 0.44 mmol) were slowly added and the solution
was stirred to rt. This operation was repeated three times
after 28 h. The reaction was quenched after 48 h. The
mixture was treated with water and extracted with methyl-
ene chloride and washed with brine. The organic layer was
dried, ®ltered, the solvent was removed and the residue
submitted to chromatography ,hexane/ethyl acetate: 93/7)
to give compound 4 ,193 mg, 63%) and unreacted product 3
3.2.1.
4,5,6,8-Tetra-O-benzyl-1,2-dideoxy-1-phenyl-d-
glycero-d-gulo-oct-1-ynitol -2 anti) and 4,5,6,8-tetra-O-
benzyl-1,2-dideoxy-1-phenyl-d-glycero-d-ido-oct-1-ynitol
-3 syn). Following the General method for the addition of
organometallic reagents compound 1 ,1 g, 1.85 mmol),
dissolved in dry toluene ,18 mL), was treated with phenyl-
ethynylmagnesium bromide ,15 mmol, 1.0M in THF,
8 equiv.) at rt, for 24 h, to give compound 2 ,anti)
,164 mg), a mixture of 2 and 3 ,376 mg, ratio: 17/83,
respectively) and compound 3 ,syn) ,524 mg), after
chromatography ,hexane/ethyl acetate: 88/12). Overall
25
,31 mg). 4: mp 75±788C; [a]D ˆ216 ,c 0.3, CHCl3); IR
,KBr) n 3435 ,OH), 3029, 2891, 2222 ,CuC), 1754
1
,CvO), 1496, 1453, 1381, 1357, 1267, 1050 cm21; H
NMR ,300 MHz, CDCl3) d 7.36±7.19 ,m, 30H, aromat.),
5.81 ,d, J3,4ˆ6.7 Hz, 1H, H-3), 5.15/5.10,AB system, Jˆ
11.9 Hz, 2H, OCH2Ph), 4.89/4.72 ,AB system, Jˆ11.6 Hz,
2H, OCH2Ph), 4.75/4.70,AB system, Jˆ11.2 Hz, 2H,
OCH2Ph), 4.55/4.48 ,AB system, Jˆ11.5 Hz, 2H, OCH2Ph),
4.52/4.50,AB system, Jˆ11.9 Hz, 2H, OCH2Ph), 4.18±
4.12 ,m, 2H, H-5, H-4), 4.01±3.99 ,m, 1H, H-7), 3.85 ,dd,
25
yield: 1.0g ,88%). 2 ,anti): oil; [a]D ˆ121 ,c 0.4,
0
J6,7ˆ7.4, J6,5ˆ4.8 Hz, 1H, H-6), 3.65 ,dd, J8,8 ˆ9.9, J8,7ˆ
CHCl3); IR ,®lm) n 3445 ,OH), 3063, 3030, 2867, 2211
,CuC), 1598, 1490, 1453, 1071, 1027 cm21 1H NMR
;
0
0
3.3 Hz, 1H, H-8), 3.59 ,dd, J8,8 ˆ9.9, J8 ,7ˆ5.1 Hz, 1H,
H-80), 2.92 ,d, Jˆ4.4 Hz, 1H, OH±C7); 13C NMR
,75 MHz, CDCl3) d 154.2 ,OCO2CH2Ph), 139.0, 138.0,
,300 MHz, CDCl3) d 7.42±7.21 ,m, 25H, aromat.), 4.88
,m, 1H, H-3), 4.84/4.83 ,AB system, Jˆ11.3 Hz, 2H,
OCH2Ph), 4.77 ,s, 2H, OCH2Ph), 4.62/4.50,AB system,
Jˆ11.3 Hz, 2H, OCH2Ph), 4.59/4.57 ,AB system, Jˆ
12 Hz, 2H, OCH2Ph), 4.30,t, J5,6ˆJ4,5ˆ4.6 Hz, 1H, H-5),
4.02±3.99 ,m, 1H, H-7), 3.96 ,t, J4,3ˆJ4,5ˆ4.6 Hz, 1H,
H-4), 3.90,dd, J6,7ˆ7.1, J6,5ˆ4.6 Hz, 1H, H-6), 3.68±3.60
,m, 2H, 2H-8), 3.30,d, Jˆ7.5 Hz, 1H, OH±C3), 2.89 ,d,
137.8, 137.7 ,q, OCH2Ph), 135.0,q, OCO CH2Ph), 131.9
2
,d, 2 C, Ph±CuC), 128.8±127.6 ,28 C, aromat.), 121.8 ,q,
Ph±CuC), 87.9, 83.7 ,Ph±CuC), 80.0 ,C-5), 78.4 ,C-7),
76.8 ,C-6), 75.1, 74.6, 73.4, 73.4, 71.1 ,5 C, 4£OCH2Ph,
OCOCH2Ph), 69.9 ,C-8), 71.4 ,C-4), 70.2 ,C-3); MS
,70eV) m/z 403 ,10), 383 ,11), 271 ,10), 253 ,18), 193

4736
J. Marco-Contelles et al. / Tetrahedron 57 ꢀ2001) 4729±4739
,22), 182 ,11), 181 ,60), 131 ,18), 91,100), 77 ,11), 65 ,10).
Anal. calcd for C50H48O8: C, 77.30; H, 6.23. Found: C,
77.49; H, 6.16.
,22), 59 ,100). Anal. calcd for C14H24O6: C, 58.32; H, 8.39.
Found: C, 58.30; H, 8.41.
3.2.5. 1,2-Dideoxy-4,5:6,7-bis-O--1-methylethylidene)-1-
phenyl-d-glycero-d-ido-oct-1-enitol -9 syn) and 1,2-
dideoxy-4,5:6,7-bis-O--1-methylethylidene)-1-phenyl-d-
glycero-d-gulo-oct-1-ynitol -9 anti). Following the General
method for the addition of organometallic reagents
compound 6 ,247 g, 0.95 mmol) dissolved in dry THF
,0.66 mL) was treated with phenylethynyl magnesium
bromide ,3.8 mL, 3.8 mmol, 1.0M in THF, 4 equiv.) at
08C. The reaction was warmed at rt and after stirring for
5 h, the mixture was quenched. After work-up and chroma-
tography ,hexane/ethyl acetate: 75/25), recovered com-
pound 6 ,64 mg) and compound 9 {231 mg [67% yield
,91%)], as a mixture of syn and anti isomers in 1 to 4
ratio, respectively, which we were unable to separate}
were isolated. 9 ,syn1anti): oil; IR ,®lm) n 3418 ,OH),
3.2.3. 4,5,6,8-Tetra-O-benzyl-3-O-benzoyl-1,2-dideoxy-
1-phenyl-d-glycero-d-ido-oct-1-ynitol -5). To a solution
of compound ,3 syn) ,102 mg, 0.16 mmol) and 4-dimethyl-
aminopyridine ,20mg) in dry pyridine ,1.5 mL), at 0 8C,
under argon, benzoyl chloride ,0.02 mL, 0.19 mmol) was
slowly added in 10min, and the solution was stirred to rt.
This operation was repeated after 4 h. The reaction was
quenched after 6 h. The solvent was eliminated and the
residue was dissolved in ethyl acetate, washed with a 15%
aqueous solution of sodium bicarbonate and brine. The
organic layer was dried, ®ltered, the solvent was removed
and the residue submitted to chromatography ,hexane/ethyl
acetate: 95/5) to give compound 5 ,79 mg, 77%) and
25
unreacted product 3 ,16 mg). 5: mp 92±958C; [a]D ˆ29
,c 0.7, CHCl3); IR ,KBr) n 3447 ,OH), 3029, 2925, 2244
2986, 2211 ,CuC), 1598, 1490, 1380, 1215, 1164 cm21
1H NMR ,300 MHz, CDCl3) d ,major isomer anti) 7.44±
7.39/7.35±7.29 ,m, 5H, Ph±CuC), 4.88 ,t, J3,4ˆJ3,OH
;
,CuC), 1723, 1452, 1265, 1119, 1068, 1026 cm21 1H
;
NMR ,300 MHz, CDCl3) d 8.16±7.17 ,m, 30H, aromat.),
6.20,d, J3,4ˆ6.5 Hz, 1H, H-3), 4.99/4.82 ,AB system, Jˆ
10Hz, 2H, OC H2Ph). 4.83 ,s, 2H, OCH2Ph), 4.52/4.50,AB
system, Jˆ11.6 Hz, 2H, OCH2Ph), 4.51/4.50,AB system,
Jˆ11.7 Hz, 2H, OCH2Ph), 4.32 ,dd, J4,3ˆ6.5, J4,5ˆ4.5 Hz,
1H, H-4), 4.27 ,t, J5,4ˆJ5,6ˆ4.6 Hz, 1H, H-5), 4.08±4.05
,m, 1H, H-7), 3.91 ,dd, J6,7ˆ7.2, J6,5ˆ4.8 Hz, 1H, H-6),
ˆ
3.6 Hz, 1H, H-3), 4.43 ,dd, J5,6ˆ6.7, J6,7ˆ1.3 Hz, 1H,
H-6), 4.41±4.25 ,m, 3H, H-7,5,4), 3.80,br s, 2H, 2H-8),
2.87 ,br s, 2H, 2 OH), 1.52, 1.49, 1.48, 1.34 [4 s,
2£OC,CH3)2O]; 13C NMR ,75 MHz, CDCl3) d ,major
isomer anti) 131.5 ,d, 2 C, Ph±CuC), 128.7/128.2 ,d, 3
C, Ph±CuC), 121.8 ,q, Ph±CuC), 110.2/108.5 [2£
OC,CH3)2], 86.6, 85.9 ,q, Ph±CuC), 79.3, 77.4, 75.3,
74.6 ,C-4,5,6,7), 62.0,C-3), 61.5 ,C-8), 27.1, 26.7, 26.6,
25.3 [4 C, 2£OC,CH3)2O]; MS ,70eV) m/z 362 ,M1, 1),
347 ,M1215, 14), 231 ,58), 185 ,10), 173 ,89), 157
,12), 143 ,35), 129 ,40), 115 ,58), 59 ,100). Anal. calcd
for C20H26O6: C, 66.32; H, 7.23. Found: C, 66.30; H,
7.52.
0
3.69 ,dd, J8,8 ˆ10.0, J8,7ˆ3.7 Hz, 1H, H-8), 3.64 ,dd,
J8,8 ˆ10.0, J8 ,7ˆ5.3 Hz, 1H, H-80), 2.94 ,d, Jˆ4.6 Hz, 1H,
OH/C-7); 13C NMR ,75 MHz, CDCl3) d 165.2 ,OCOPh),
138.0, 137.8, 137.8, 137.7 ,q, OCH2Ph), 133.1±127.6 ,30C,
aromat.), 129.7, 121.9 ,q, Ph±CuC), 86.9, 84.4 ,q, Ph±
CuC) 81.1 ,C5), 78.4 ,C-7), 77.0,C-6), 75.0, 74.7 ,2 C),
73.3 ,4 C, OCH2Ph), 71.2 ,C-4), 71.0,C-8), 66.4 ,C-3);
MS ,70eV) m/z 403 ,8), 253 ,9), 234 ,18), 205 ,9), 197
,11), 193 ,15), 181 ,43), 106 ,8), 91 ,100), 77 ,13). Anal.
calcd for C49H46O7: C, 78.80; H, 6.20. Found: C, 78.77; H,
6.16.
0
0
3.2.6. 6-Deoxy-6-iodo-2,3:4:5-bis-O--1-methylethylidene)-
d-glucose diethyldithioacetal -12). Alcohol 1111 ,1 g,
2.7 mmol), dissolved in dry toluene ,60mL) was treated
with triphenylphosphine ,2.1 g, 8.2 mmol, 3 equiv.), imida-
zole ,557 mg, 8.2 mmol, 3 equiv.) and iodine ,1.3 g,
5.5 mmol, 2 equiv.), at re¯ux for 10min. Then, the
mixture was diluted with an aqueous saturated solution of
NaHCO3 and an 5% aqueous solution of Na2S2O3. The
organic layer was dried, ®ltered and evaporated. The
residue was submitted to chromatography ,hexane/ethyl
acetate: 98/2) to give product 12 ,911 mg, 70%): oil;
3.2.4. 1,2-Dideoxy-4,5:6,7-bis-O--1-methylethylidene)-d-
glycero-d-ido-oct-1-enitol -7 syn) and 1,2-dideoxy-4,5:
6,7-bis-O--1-methylethylidene)-d-glycero-d-gulo-oct-1-
enitol -8 anti). Following the General method for the
addition of organometallic reagents compound 6 ,124 mg,
0.48 mmol) dissolved in dry THF ,0. 4 mL) was treated with
vinyl magnesium bromide ,1.91 mL, 1.91 mmol, 1.0M in
THF, 4 equiv.) at 08C, for 1 h, to give a mixture of
compounds 7 ,syn)18 ,anti) ,21 mg, 1:1) and pure
compound 8 ,anti) ,20mg), after chromatography ,hexane/
ethyl acetate: 75/25). Overall yield: 41 mg ,45%). 8 ,anti):
25
[a]D ˆ261 ,c 0.9, CHCl3); IR ,®lm) n 2910, 2800,
1
1450, 1350, 1260, 1180, 1020 cm21; H NMR ,300 MHz,
0
CDCl3) d 4.56 ,q, J4,5ˆJ5,6ˆJ5,6 ˆ6.9 Hz, 1H, H-5), 4.42
,d, J4,5ˆ6.9 Hz, 1H, H-4), 4.32 ,dd, J1,2ˆ5.4, J2,3ˆ7.9 Hz,
1H, H-2), 4.22 ,d, J2,3ˆ7.9, 1H, H-3), 3.90,d, J1,2ˆ5.4 Hz,
1H, H-1), 3.44 ,d, J5,6ˆ7.0Hz, 2H, 2H-6), 2.78±2.70
,m, 4H, 2£SCH2CH3), 1.50, 1.44, 1.43, 1.36 [4 s,
2£OC,CH3)2O], 1.27 ,t, Jˆ7.3 Hz, 6H, 2£SCH2CH3);
25
oil; [a]D ˆ241 ,c 0.3, CHCl3); IR ,®lm) n 3419 ,OH),
2986, 2936, 1645 ,CvC), 1381, 1215, 1164, 1044 cm21
;
1H NMR ,300 MHz, CDCl3) d 5.88 ,ddd, J1,2ˆ17.3, J1 ,2
ˆ
0
0
10.7, J2,3ˆ5.1 Hz, 1H, H-2), 5.39 ,dt, J1,2ˆ17.3, J1,1 ˆJ1,3ˆ
0
0
0
1.5 Hz, 1H, H-1), 5.24 ,dt, J1 ,2ˆ10.7, J1,1 ˆJ1 ,3ˆ1.5 Hz,
1H, H-10), 4.36 ,br s, J2,3ˆJ3,4ˆ5.1 Hz, 1H, H-3), 4.24±
4.09 ,m, 4H, H-4, 5, 6, 7), 3.75 ,br s, 2H, 2H-8), 2.88 ,br
s, 1H, OH), 2.39 ,br s, 1H, OH), 1.48, 1.44, 1.42, 1.33 [4 s,
2£OC,CH3)2O]; 13C NMR ,75 MHz, CDCl3) d 135.4 ,C-2),
116.9 ,C-1), 109.9, 108.5 [2£OC,CH3)2O], 79.3/77.5 ,C-6p,
C-7p), 75.2/74.5 ,C-4p, C-5p), 71.6 ,C-3), 61.6 ,C-8), 27.4,
26.9, 26.5, 25.5 [4 C, 2£OC,CH3)2]; MS ,70eV) m/z 273
,M1215, 32), 173 ,24), 143 ,11), 129 ,10), 113 ,11), 101
13C NMR ,75 MHz, CDCl3)
d
109.9, 108.9
[2£OC,CH3)2O], 79.7 ,C-3), 78.1 ,C-5), 77.3 ,C-2), 75.7
,C-4), 52.5 ,C-1), 27.3, 26.9, 26.8, 25.3 [4 C, 2£
OC,CH3)2], 25.4/25.2 ,2£SCH2CH3), 14.4/14.3 ,2£
SCH2CH3), 3.2 ,C-6); MS ,70eV) m/z 477 ,M111, 2),
476 ,M1, 10), 357 ,15), 341 ,21), 299 ,16),283 ,83), 225
,46), 135 ,100), 87 ,24), 59 ,18). Anal. calcd for
C16H29IO4S2: C, 40.34; H, 6.14; S, 13.46. Found: C,
40.45; H, 6.09; S, 13.75.

J. Marco-Contelles et al. / Tetrahedron 57 ꢀ2001) 4729±4739
4737
3.2.7. 6-Deoxy-6-iodo-2,3:4:5-bis-O--1-methylethylidene)-
d-glucose -10). Iodide 12 ,291 mg, 0.61 mmol) was
dissolved in a mixture of acetone/water ,9.5 mL, 1/18)
and was treated with HgCl2 ,363 mg, 1.3 mmol, 2.2
equiv.) and HgO ,278 mg, 1.28 mmol, 2.1 equiv.). After
re¯uxing for 6 h, the mixture was cooled, hexane was
added, and after stirring for 10min at rt, the mass was
®ltered over Celite-545, washing the cake with acetone.
The organic layer was evaporated, the residue was dissolved
in methylene chloride and washed with a 5% aqueous solu-
tion of KI and brine. After drying, ®ltration, evaporation and
chromatography ,hexane/ethyl acetate: 4/1) compound 10
{1H NMR ,300 MHz, CDCl3) d 9.82 ,d, J1,2ˆ1.7 Hz, 1H,
after chromatography ,hexane/ethyl acetate: 9/1) were
25
isolated. 16 ,anti): oil; [a]D ˆ210, c 0.8, CHCl3); IR
,®lm) n 3436 ,OH), 2986, 2934, 2243 ,CuC), 1598,
1
1490, 1453, 1381, 1161, 1065 cm21; H NMR ,300 MHz,
CDCl3) d 7.46±7.31 ,m, 5H, Ph±CuC), 4.83 ,dd, J3,4ˆ3.3,
0
J6,OHˆ4.6 Hz, 1H, H-3), 4.56 ,q, J6,7ˆJ7,8ˆJ7,8 ˆ7.0Hz,
1H, H-7), 4.45 ,dd, J6,7ˆ7.0, J5,6ˆ0.9 Hz, 1H, H-6), 4.35
,dd, J4,5ˆ8.3, J5,6ˆ0.9 Hz, 1H, H-5), 4.30 ,dd, J4,5ˆ8.3,
J3,4ˆ3.3 Hz, 1H, H-4), 3.45 ,d, J7,8ˆ7.0Hz 2H, 2H-8),
2.62 ,d, J6,OHˆ4.6 Hz, 1H, OH), 1.53, 1.48, 1.47, 1.37 [4
s, 2£OC,CH3)2O]; 13C NMR ,75 MHz, CDCl3) d 131.7 ,d,
2 C, Ph±CuC), 128.8 ,d, C, Ph±CuC), 128.4 ,d, 2 C, Ph±
CuC), 121.9 ,q, Ph±CuC), 110.2/109.0 [2£OC,CH3)2],
87.1, 85.5 ,q, Ph±CuC), 78.9 ,C-7), 78.1 ,C-4), 75.8
,C-5), 74.8 ,C-6), 62.1 ,C-3), 27.2, 26.9, 26.8, 25.5 [4 C,
2£OC,CH3)2O], 3.1 ,C-8); MS ,70eV) m/z 250,1), 205
,100), 188 ,52), 145 ,39), 119 17), 73 ,10). Anal. calcd
for C20H25IO5: C, 50.86; H, 5.34. Found: C, 50.77; H, 5.81.
0
H-1), 4.56 ,q, J4,5ˆJ5,6ˆJ5,6 ˆ7.0Hz, 1H, H-5), 4.38 ,dd,
J1,2ˆ1.7, J2,3ˆ7.9 Hz, 1H, H-2), 4.24 ,dd, J4,5ˆ7.0, J3,4ˆ
1.6 Hz, 1H, H-4), 4.18 ,dd, J2,3ˆ7.9, J3,4ˆ1.6 Hz, 1H,
0
H-3), 3.39 ,dd, J5,6ˆ7.0, J6,6 ˆ1.1 Hz, 2H, 2H-6), 1.51,
1.43 ,2 s), 1.38 [4 s, 2£OC,CH3)2O]} was isolated
,170mg, 75%) and immediately submitted to further
reaction.
3.2.10. 1,2,8-Trideoxy-8-iodo-4,5:6,7-bis-O--1-methyl-
ethylidene)-d-glycero-d-ido-oct-1-ynitol -17 syn)1 1,2,8-
trideoxy-8-iodo-4,5:6,7-bis-O--1-methylethylidene)-d-
glycero-d-gulo-oct-1-ynitol -18 anti). Following the
General method for the addition of organometallic reagents
compound 10 ,241 mg, 0.65 mmol) dissolved in dry THF
,0.66 mL) was treated with ethynyl magnesium bromide
,2.6 mL, 2.6 mmol, 1.0M in THF, 4 equiv.) at 0 8C. An
unseparable mixture of compounds 17 ,syn) and 18 ,anti)
,157 mg, in a 3 to 7 ratio, respectively) [overall yield: 61%
,70%)], after chromatography ,hexane/ethyl acetate: 85/15)
were isolated: oil; IR ,®lm) n 3444 ,OH), 3284, 2987, 2118
,CuC), 1456, 1381, 1216, 1063 cm21; 1H NMR ,300 MHz,
CDCl3) d ,major isomer 18 anti) 4.58±4.50,m, 2H, H-3,
H-7), 4.35 ,dd, J6,7ˆ6.7, J5,6ˆ1.0Hz, 1H, H-6), 4.22 ,dd,
J4,5ˆ8.2, J5,6ˆ1.0Hz, 1H, H-5), 4.16±4.14 ,m, 1H, H-4),
3.41 ,d, J7,8ˆ7.0Hz, 2H, 2H-8), 2.78 ,d, J3,OHˆ5.0Hz, 1H,
OH), 2.56 ,d, J1,3ˆ2.3 Hz, 1H, ±CuC±H), 1.49, 1.43, 1.41,
1.35 [4 s, 2£OC,CH3)2O]; 13C NMR ,75 MHz, CDCl3) d
,major isomer 18 anti) 110.1/108.9 [2£OC,CH3)2], 80.7 ,q,
±CuC±H), 78.6 ,q, ±CuC±H), 78.0,C-7), 75.8 ,C-4),
75.4 ,C-5), 74.9 ,C-6), 61.6 ,C-3), 27.0, 26.9, 26.7, 25.3
[4 C, 2£OC,CH3)2O], 2.8 ,C-8); MS ,70eV) m/z 381
,M1215, 283 ,28), 263 ,11), 195 ,34), 113 ,22), 85 ,32),
59 ,100). Anal. calcd for C14H21IO5: C, 42.44; H, 5.34.
Found: C, 42.30; H, 5.63.
3.2.8. 1,2,8-Trideoxy-8-iodo-4,5:6,7-bis-O--1-methylethyl-
idene)-d-glycero-d-ido-oct-1-enitol -13 syn) and 1,2,8-
trideoxy-8-iodo-4,5:6,7-bis-O--1-methylethylidene)-d-
glycero-d-gulo-oct-1-enitol -14 anti). Following the
General method for the addition of organometallic reagents
compound 10 ,439 mg, 1.18 mmol) dissolved in dry THF
,2.4 mL) was treated with vinyl magnesium bromide
,1.6 mL, mmol, 1.0M in THF, 4 equiv.) at 0 8C, for 4 h
,this protocol was repeated three times each hour), to give
a mixture of compounds 13 ,syn) and 14 ,anti) ,127 mg, in a
6:4 ratio) and pure compound 14 ,anti) ,255 mg), after
chromatography ,hexane/ethyl acetate: 93/7). Overall
25
yield: 382 mg ,81%). 14 ,anti): oil; [a]D ˆ239 ,c 0.3,
CHCl3); IR ,®lm) n 3500±3200 ,OH), 2920, 2870, 1350,
1240, 1170, 1050 cm21; 1H NMR ,300 MHz, CDCl3) d 5.88
0
,ddd, J1,2ˆ17.3, J1 ,2ˆ10.6, J2,3ˆ5.3 Hz, 1H, H-2), 5.41 ,dt,
0
J1,2ˆ17.3, J1,1 ˆJ1,3ˆ1.6 Hz, 1H, H-1), 5.25 ,dt, J1,2ˆ10.6,
J1,1 ˆJ1 ,3ˆ1.6 Hz, 1H, H-10), 4.50,q, J6,7ˆJ7,8ˆJ7,8
ˆ
0
0
0
6.9 Hz, 1H, H-7), 4.37-4.33 ,m, 1H, H-3), 4.18 ,dd,
J6,7ˆ6.9, J5,6ˆ0.8 Hz, 1H, H-6), 4.11 ,dd, J4,5ˆ8.2, J5,6ˆ
0.8 Hz, 1H, H-5), 4.05 ,dd, J4,5ˆ8.2, J3,4ˆ4.4 Hz, 1H,
H-4), 3.40,d, J7,8ˆ6.9 Hz, 2H, 2H-8), 2.30,br s, 1H,
OH), 1.48, 1.41, 1.39, 1.34 [4 s, 2£OC,CH3)2O]; 13C
NMR ,75 MHz, CDCl3) d 135.7 ,C-2), 116.7 ,C-1),
100.9, 100.8 [2£OC,CH3)2O], 78.9 ,C-4), 78.1 ,C-7), 75.7
,C-6), 74.7 ,C-5), 71.7 ,C-3), 27.3, 26.8 ,2 C), 25.4
[2£OC,CH3)2], 3.1 ,C-8); MS ,70eV) m/z 383 ,M1215,
24), 283 ,27), 195 ,15), 183 ,18), 157 ,26), 101 ,41), 43
,100). Anal. calcd for C14H23IO5: C, 42.24; H, 5.82. Found:
C, 42.55; H, 5.67.
3.2.11. 6-Deoxy-6-iodo-2,3:4,5-bis-O--1-methylethylidene)-
1--2-thiazolyl)-d-glycero-d-gulo-hexitol -19 anti). Com-
pound 10 ,197 mg, 0.53 mmol) dissolved in dry CH2Cl2
,1 mL) was treated with 2-,trimethylsily)thiazole ,0.094
mL, 0.58 mmol, 1.1 equiv.) at 08C, under argon. The reac-
tion mixture was warmed and stirred to rt for 18 h. The
solvent was removed and the residue was treated with
Bu4NF ,0.53 mL, 1.1 M in THF) as usual until complete
desilylation. The solvent was evaporated, diluted with
water and extracted with CH2Cl2 several times. The organic
layer was dried, ®ltered and evaporated. Flash chroma-
tography ,hexane/ethyl acetate: 9/1) gave compound 19
,anti) ,141 mg, 60%) and the unexpected product 19a12
3.2.9. 1,2,8-Trideoxy-8-iodo-4,5:6,7-bis-O--1-methylethyl-
idene)-1-phenyl-d-glycero-d-ido-oct-1-ynitol -15 syn)
and 1,2,8-trideoxy-8-iodo-4,5:6,7-bis-O--1-methylethyl-
idene)-1-phenyl-d-glycero-d-gulo-oct-1-ynitol -16 anti).
Following the General method for the addition of organo-
metallic reagents compound 10 ,164 mg, 0.44 mmol)
dissolved in dry THF ,0.66 mL) was treated with phenyl-
ethynyl magnesium bromide ,4.7 mL, 4.7 mmol, 1.0M in
THF, 4 equiv.) at 08C. A mixture of compounds 15 ,syn) and
16 ,anti) ,66 mg, in 6 to 4 ratio, respectively) and pure
compound 16 ,anti) ,86 mg) ,overall yield: 152 mg, 73%),
25
,9.3 mg, 7%). 19 ,anti): oil; [a]D ˆ223 ,c 0.2, CHCl3);
IR ,®lm) n 3435 ,OH), 2986, 1630, 1508, 1381, 1161,
1
1068 cm21; H NMR ,300 MHz, CDCl3) d 7.80/7.37 ,AB
system: 2 d, Jˆ3.2 Hz, 2H, aromat.), 5.15 ,dd, J1,2ˆ5.2,

4738
J. Marco-Contelles et al. / Tetrahedron 57 ꢀ2001) 4729±4739
J1,OHˆ3.3 Hz, 1H, H-1), 4.40,dd, J1,2ˆ5.2, J2,3ˆ7.9 Hz,
,hexane/ethyl acetate: 85/15) to give products 22 ,syn)
,590mg) and 23 ,210mg) ,Total: 800mg; overall yield:
0
1H, H-2), 4.33 ,q, J4,5ˆJ5,6ˆJ5,6 ˆ6.7 Hz, 1H, H-5), 4.20
25
,dd, J2,3ˆ7.9, J3,4ˆ1.2 Hz, 1H, H-3), 3.67 ,d, J1,OH
ˆ
82%). 22 ,syn): oil; [a]D ˆ212 ,c 0.2, CHCl3); IR ,®lm)
3.3 Hz, 1H, OH), 3.61 ,dd, J4,5ˆ6.7, J3,4ˆ1.2 Hz 1H,
H-4), 3.34 ,d, J5,6ˆ6.7 Hz, 2H, 2H-6), 1.50, 1.47, 1.45,
1.31 [4 s, 2£OC,CH3)2O]; 13C NMR ,75 MHz, CDCl3) d
170.0 ,q, aromat.), 142.1/119.1 ,d, d, aromat.), 110.2/108.7
[2£OC,CH3)2], 79.2 ,C-2), 78.0,C-5), 75.4 ,C-4), 75.2
,C-3), 71.4 ,C-1), 27.2, 26.8 ,2 C), 25.1 [4 C, 2£
OC,CH3)2O], 3.5 ,C-6); MS ,70eV) m/z 455 ,M1, 1), 440
,M1215, 60), 341 ,25), 283 ,100), 270 ,18), 224 ,37), 195
,14), 183 ,25), 85 ,18). Anal. calcd for C15H22INO5S: C,
39.57; H, 4.87; N, 3.08; S, 7.04. Found: C, 39.44; H, 4.81;
N, 2.87; S, 6.86.
n 3600±3200 ,OH), 2211 ,CuC), 1470, 1360, 1090 cm21
;
1H NMR ,300 MHz, CDCl3) d 7.45±7.42 ,m, 2H, Ph±
CuC), 7.33±7.26 ,m, 3H, Ph±CuC), 5.01 ,dd, J3,4ˆ6.8,
J3,OHˆ4.2 Hz, 1H, H-3), 4.52 ,dd, J5,6ˆ0.7, J4,5ˆ7.3 Hz,
1H, H-5), 4.45 ,t, J4,5ˆJ3,4ˆ6.8 Hz, 1H, H-4), 4.11±4.03
,m, 3H, 2H-8, H-7), 2.88 ,d, J3,OHˆ4.2 Hz, 1H, OH±C3),
2.60,d, J6,OHˆ7.9 Hz, 1H, OH±C6), 1.56, 1.44, 1.33, 1.31
[4 s, 2£OC,CH3)2O]; 13C NMR ,75 MHz, CDCl3) d 131.8
,d, 2 C, Ph±CuC), 128.8 ,d, 1 C, Ph±CuC), 128.3 ,d, 2 C,
Ph±CuC), 125.0,q,
Ph±CuC), 109.4/109.0 [2£
OC,CH3)2], 80.0 ,C-4), 79.6, 77.2 ,q, Ph±CuC), 76.1
,C-7), 75.2 ,C-5), 69.9 ,C-6), 67.1 ,C-8), 62.0,C-3), 26.8,
26.6, 25.3, 24.5 [4 C, 2£OC,CH3)2O]; MS ,70eV) m/z 362
,M1, 1), 231 ,65), 173 ,98), 131 ,33), 115 ,66), 73 ,37), 59
,100). Anal. calcd for C20H26O6: C, 66.28; H, 7.23. Found:
3.2.12. 1-O-Benzyl-6-deoxy-6-iodo-2,5:4,5-bis-O--1-methyl-
ethylidene)-1--2-thiazolyl)-d-glycero-d-gulo-hexitol -20).
Compound 19 ,101 mg, 0.22 mmol) dissolved in dry THF
,1 mL, 0.2 M), under argon and at 08C, was treated with
sodium hydride ,13.3 mg, 0.33 mmol, 1.5 equiv.), a cata-
lytic amount of tetrabutylammonium iodide and benzyl bro-
mide ,0.03 mL, 0.24 mmol, 1.1 equiv.). After stirring at rt
for 15 h, when the reaction was complete some drops of
AcOH were added and the mass was ®ltered over Celite-
545. The solvent was evaporated, diluted with water,
extracted with CH2Cl2 several times and washed with
brine. The organic layer was dried, ®ltered and evaporated.
Flash chromatography ,hexane/ethyl acetate: 85:15) gave
25
C, 66.44; H, 7.42. 23 ,anti): oil; [a]D ˆ212 ,c 0.9,
CHCl3); IR ,®lm) n 3429 ,OH), 2988, 2211 ,CuC), 1373,
1
1066 cm21; H NMR ,300 MHz, CDCl3) d 7.45±7.42 ,m,
2H, Ph±CuC), 7.33±7.27 ,m, 3H, Ph±CuC), 5.02 ,d,
J3,4ˆ4.9 Hz, 1H, H-3), 4.54 ,d, J4,5ˆ7.2 Hz, 1H, H-5),
4.43 ,dd, J4,5ˆ7.2, J3,4ˆ4.9 Hz, 1H, H-4), 4.25±4.23 ,m,
1H, H-6), 4.13±4.06 ,m, 3H, H-7, 2H-8), 3.60±3.40 ,br s,
2H, OH), 1.57, 1.42, 1.35, 1.34 [4 s, 2£OC,CH3)2O]; 13C
NMR ,75 MHz, CDCl3) d 131.9 ,d, 2 C, Ph±CuC), 128.8
,d, 1 C, Ph±CuC), 128.4 ,d, 2 C, Ph±CuC), 122.1 ,q, Ph±
CuC), 109.6/108.9 [2£OC,CH3)2], 86.7, 85.6 ,q, Ph±
CuC), 78.6 ,C-4), 76.1 ,C-7), 75.8 ,C-5), 73.3 ,C-6),
69.7 ,C-8), 61.6 ,C-3), 26.9, 26.6, 25.4, 24.9 [4 C, 2£
OC,CH3)2O]; MS ,70eV) m/z 362 ,M1, 1), 347 ,M1215,
10), 231 ,52), 173 ,84), 131 ,37), 115 ,64), 101 ,60), 59
,100). Anal. calcd for C20H26O6: C, 66.28; H, 7.23. Found:
C, 66.04; H, 7.02.
25
compound 20 ,111 mg, 92%). 20: oil; [a]D ˆ25 ,c 0.4,
CHCl3); IR ,®lm) n 2986, 2934, 1498, 1380, 1161,
1
1082 cm21; H NMR ,300 MHz, CDCl3) d 7.83/7.42 ,AB
system: 2 d, Jˆ3.3 Hz, 2H, aromat.), 7.39±7.33 ,m, 5H,
OCH2C6H5), 4.93 ,d, J1,2ˆ5.3 Hz, 1H, H-1), 4.71/4.57
,AB system: 2 d, Jˆ11.5 Hz, 2H, OCH2C6H5), 4.51 ,dd,
0
J1,2ˆ5.3, J2,3ˆ8.0Hz, 1H, H-2), 4.43 ,q, J4,5ˆJ5,6ˆJ5,6
ˆ
7.0Hz, 1H, H-5), 4.13 ,dd, J2,3ˆ8.0, J3,4ˆ1.5 Hz, 1H,
H-3), 3.94 ,dd, J4,5ˆ6.9, J3,4ˆ1.5 Hz 1H, H4), 3.36 ,d,
J5,6ˆ7.0Hz, 2H, 2H-6), 1.50, 1.47, 1.31 ,2 C) [4 s,
2£OC,CH3)2O]; 13C NMR ,75 MHz, CDCl3) d 169.5 ,q,
aromat.), 142.9/120.5 ,d, d, aromat.), 137.2, 128.7, 128.5,
128.3 ,OCH2C6H5), 110.8/109.2 [2£OC,CH3)2], 79.6 ,C-2),
79.0,C-1), 78.3 ,C-5), 76.3 ,C-3), 75.7 ,C-4), 72.8
,OCH2C6H5), 27.3, 27.1 ,2 C), 25.6 [4 C, 2£OC,CH3)2O],
3.6 ,C-6); MS ,70eV) m/z 546 ,M1, 1), 530,M 1215, 57),
304 ,26), 341 ,84), 283 ,67), 225 ,39), 205 ,51), 114 ,71),
91 ,100). Anal. calcd for C22H28INO5S: C, 48.45; H, 6.21;
N, 2.57; S, 5.88. Found: C, 48.40; H, 6.33; N, 2.41; S,
5.52.
Acknowledgements
This work was supported by CICYT, CAM, COST Action
No. D12 ,European Union) and Mizutani Foundation. Elsa
de Opazo is a fellow of the Consejerõa de Eduacion y
Cultura ,CAM). J. M.-C. thanks the referees for the useful
comments and suggestions.
Â
Â
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