A simplified Ramberg-Baecklund approach to novel C-glycosides and C-linked disaccharides

Article abstract of DOI:10.1002/anie.200390356

Eight illustrious organic chemists in one pot! A route from protected monosaccharides to novel C-GLYCOSIDES AND C-linked disaccharides is described which involves tandem Horner-Wadsworth-Emmons/conjugate addition (Michael-type), followed by tandem halogen

Full text of DOI:10.1002/anie.200390356

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Chemie
Preparing C-Linked Disaccharides
A Simplified Ramberg–Bäcklund Approach to
Novel C-Glycosides and C-Linked
Disaccharides**
Graeme D. McAllister, Duncan E. Paterson, and
Richard J. K. Taylor*
Dedicated to Dr. Alan H. Haines
In recent years, there has been increasing interest in the
preparation and properties of C-disaccharides. Their hydro-
lytic stability and potential enzyme-inhibitory properties
make such compounds attractive as unnatural mimetics and
therefore as synthetic targets.[1] As a result, a number of
methodologies have been developed for the synthesis of this
class of compound.[2,3] As part of an ongoing program[3,4] to
investigate applications of the Ramberg–Bäcklund Reaction
(RBR),[5] we recently reported a RBR approach to C-linked
disaccharides and employed it to prepare C-isotrehalose, C-
homoisotrehalose, and methyl C-gentiobioside.[3] However,
the route involved the initial preparation of protected
monosaccharides and their subsequent conversion into thio-
glycosides and then thioglycoside dioxides and was therefore
rather lengthy. Herein we report the rapid synthesis of a range
of novel C-glycosides and C-disaccharides which commences
from readily available protected monosaccharides 1 and
involves a tandem Horner–Wadsworth–Emmons (HWE)/
conjugate-addition C-glycosidation followed by a tandem
halogenation–RBR sequence, utilizing Meyers variant of the
RBR[6] (Scheme 1). Thus, the plan was to prepare glycosyl-
sulfonylmethyl-HWE reagents 2 and then carry out the
condensation giving the vinyl sulfone intermediate 3 which
would be expected[7] to undergo conjugate cyclization in situ
to produce sulfone 4. Subsequent Meyers-type in situ a-
sulfonyl halogenation followed by tandem RBR should then
produce alkene 5 which could be elaborated/deprotected to
provide a range of novel C-disaccharides.
Proof-of-principle studies were carried out using the
benzylsulfonylphosphonate reagent 6[8] and diisopropylidene
mannofuranose 7 (Scheme 2). We were delighted to find that
the HWE/conjugate-addition process proceeded in a reason-
able 64% unoptimized yield using sodium hydride in THF
giving the C-glycoside 8 stereoselectively as the b-isomer
(J1,2 = 3.6 Hz). Sulfone 8 was next subjected to the halogen-
ation-RBR sequence. The standard Meyers conditions[6a] only
gave a 48% yield of 9 but use of the supported KOH-CBr2F2
[*] Prof. R. J. K. Taylor, G. D. McAllister, D. E. Paterson
Department of Chemistry
University of York
Heslington, York YO105DD (UK)
Fax: (+44)1904-434523
E-mail: rjkt1@york.ac.uk
[**] We thank the EPSRC for postdoctoral funding (G.D.M.) and the
University of York for studentship support (D.E.P.). Dedicated to Dr.
Alan H. Haines, to mark his retirement from the University of East
Anglia and his many contributions to carbohydrate chemistry.
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Scheme 1. Summary of overall transformation (m,n=0,1).
conditions devised by Chan et al.[6b] produced alkene 9 in
88% yield, exclusively as the 1,2-cis-diastereomer with the b-
anomeric configuration, and the E-geometry (Jvinyl = 16.0 Hz).
The thermodynamic preference for the 1,2-cis-relationship in
2,3-O-isopropylidene derivatives of furanosyl C-glycosides
has precedent.[7,9]
We extended these studies to ribose derivatives and
investigated the compatibility of a range of protecting groups
(Table 1). As can be seen, benzyl (Bn), acetonide, and tert-
butyldimethylsilyl (TBS) protecting groups were all accom-
modated within this methodology. Noteworthy is that epime-
rization at the anomeric position occurs under these con-
ditions: this is most apparent in the conversion of the 1,2-
trans-system 18 into the predominantly 1,2-cis-C-glycoside 20
(J1,2 = 6.0 Hz for 20a, 4.0 Hz for 20b; the larger coupling
constants for the cis-1,2-protons is in accord with previous[9]
observations).
Having succeeded with the model studies, the next step
was to prepare a carbohydrate-derived phosphonate reagent.
The glucose-derived phosphonate 2a was chosen in view of
the reported efficient five-step preparation of thiol 22 from
methyl a-d-glucopyranoside (21).[3] As shown in Scheme 3, S-
alkylation of thiol 22 with diethyl iodomethylphosphonate
followed by oxidation produced the required HWE reagent
2a in 40% overall yield from 21.
With HWE reagent 2a in hand, we investigated its
reaction
with
diisopropylidene
mannofuranose
7
(Scheme 4). We were delighted to discover that the HWE/
conjugate-addition sequence proceeded in high yield (86%)
to produce the adduct sulfone 23 (as a mixture of diaster-
eomers). The key halogenation-RBR was again carried out
using the conditions devised by Chan et al.[6b] giving E-alkene
24 (Jvinyl = 15.9 Hz) as the only isolable product. Alkene
hydrogenation and concomitant debenzylation, followed by
acetylation for characterization purposes, gave the novel
disaccharide 25 in 69% yield over the two reactions. The four-
pot sequence shown in Scheme 4 involves 11 transformations
(HWE, conjugate addition, halogenation, RBR, reduction,
3 ” debenzylations, 3 ” acetylations); the overall yield of 30%
is noteworthy, though capable of improvement.
Scheme 2. Proof-of-principle studies using benzylsulfonylphosphonate 6.
The multiple roles of the sulfonyl group in this sequence
are noteworthy: it provides the stabilizing group needed for
the HWE reaction, the activating group which facilitates the
conjugate addition, and the key functionality for the RBR—
and its removal does not require a separate step, it is lost in a
cheleotropic manner during the key carbon–carbon bond
forming reaction.
1) (EtO)2P(O)CH2I
K2CO3, acetone
EtO
EtO
O
OMe
OBn
O
OMe
OBn
5 steps[3]
O
OMe
OH
P
S
O2
HS
BnO
HO
O
2) Oxone
THF, aq.-MeOH
BnO
HO
OBn
OBn
OH
40% from 21
21
Scheme 3. Preparation of glucose-derived phosphonate 2a.
22
2a
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Table 1: HWE/conjugate-addition/RBR sequence with phosphonate 6 and a range of protected carbohydrates[a,b]
Monosaccharide
HWE/conjugate-addition adduct
RBR product
BnO
O
BnO
O
BnO
O
OH
Ph
S
O2
Ph
1)
83%
(α:β = 1:2.4)
BnO
OBn
BnO
OBn
BnO
OBn
11
12
10
74% (α:β = 1:1)
TBSO
TBSO
O
TBSO
O
O
OH
Ph
S
O2
Ph
2)
77%
(α:β = 4:1)
O
O
O
O
O
O
14 (22%)[c]
13
16
+
TBSO
TBSO
O
O
Ph
S
O2
Ph
81%
(α:β = 6:1)
O
O
O
O
15 (32%)[c]
16
BnO
BnO
BnO
O
O
O
OH
Ph
S
O2
Ph
3)
78%
(α:β = 7:1)
O
O
O
O
O
O
17
18 (32%)[c]
20
+
BnO
BnO
O
O
Ph
S
O2
Ph
70%
(α:β = 8:1)
O
O
O
O
20
19 (30%)[c]
[a] 1) NaH (1.1 equiv), phosphonate 6 (1.1 equiv) in THF at RTand then add lactol (1 equiv) and stir for 6–18 h; 2) Sulfone
(1 equiv) in tert-butyl alcohol–CH2Cl2 at 08C then add KOH-Al2O3 (14 gmmolÀ1 sulfone) and then CBr2F2 (10 equiv) and stir
at 08C for 30 min; 3) Dilute with CH2Cl2, stir for 10 min, filter through Celite, concentrate and purify by column
chromatography on silica. [b] all alkenes >99% E. [c] 14/15 and 18/19 were readily separated by chromatography.
O
O
EtO
EtO
O
OMe
OBn
O
O
OMe
OBn
O
P
S
O2
OH
O
O
S
O2
O
NaH
THF,
-78°C
+
BnO
BnO
O
O
O
O
OBn
OBn
86%
23 (α:β = 1:1)
7
2a
KOH/Al2O3
CBr2F2, CH2Cl2
tBuOH, 5°C, 2 h
50%
OMe
OMe
1) H2/Pd/C,
EtOAc
RT, 7 h
OAc
OAc
OBn
OBn
O
O
O
O
O
O
O
2) Ac2O, py, RT
69% overall
for (1) + (2)
O
OAc
BnO
O
O
O
O
Scheme 4. C-disaccharide synthesis
using phosphonate 2a; py=pyri-
dine.
25
24 (E only)
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halogenating agent (KOH-Al2O3, CBr2F2)
were added and the mixture stirred for about
30 minutes. Astandard work-up (see Exper-
imental Section) produced C-glycoside 9 in
78% purified yield, a considerable increase
on the two-step method (56% overall yield).
It should be noted that the Meyers–Chan
procedure was successful in THF–CH2Cl2
and that tert-butanol, which is normally
employed as
required.
a
cosolvent,[6b] was not
In summary, we have established that a
range of protected furanoses undergo a
HWE/conjugate-addition/RBR
sequence
with benzylsulfonylphosphonate reagent 6
to produce the corresponding 2-styrenyl C-
glycosides, and shown that this sequence can
be performed in a “one-pot” variant in
excellent yield. We have also demonstrated
that monosaccharide-derived phosphonates
can be employed in this methodology by
Scheme 5. Two-directional C-disaccharide synthesis using bisphosphonate 26.
utilizing the glucose-derived phosphonate
2a to produce the mixed furanose–pyranose
C-linked system 24. Of course, by variation
We have also shown that a two-directional variant of this
methodology can be used to prepare symmetrical C-disac-
charides, as shown in Scheme 5. The requisite bisphosphonate
26 has been described for the synthesis of distyryl sulfones.[10]
The double HWE reaction using 26 and diisopropylidene
mannofuranose 7 worked extremely well in the HWE/
conjugate-addition C-glycosidation sequence giving diaster-
eomeric sulfones 27, in a combined yield of 75%. RBR on the
major stereoisomer (b,a-27) using the Meyers–Chan proce-
dure gave alkene 28 in 66% unoptimized yield, and hydro-
genation produced the novel C-linked bisfuranose disacchar-
ide 29 in 76% yield.
of the monosaccharide and the glycosyl phosphonate (1 and 2
respectively, in Scheme 1), a range of other C-disaccharides
becomes available. In addition, we have shown that a
symmetrical C-linked bisfuranose system 29 is available by
a double HWE sequence. Further work is in progress to
optimize and apply this new methodology, initially to prepare
C-linked analogues of furanose-pyranose disaccharides.[11] It
should also be noted that the HWE reaction has been shown[7]
to proceed efficiently on unprotected monosaccharides and
studies in this area are in progress.
Finally, we have established that the original model study
involving the Horner–Wadsworth–Emmons/conjugate addi-
tion sequence with substrates 6 and 7 followed by tandem
halogenation-Ramberg–Bäcklund reaction can be carried out
as a “one-pot” transformation (Scheme 6). Thus, 7 was added
to the deprotonated phosphonate 6 and the mixture stirred at
RT overnight. After cooling the mixture to 08C, the base and
Experimental Section
All new compounds were fully characterized spectroscopically and by
HRMS or elemental analysis.
Preparation of C-glycoside 9 by a “one-pot” procedure: A
solution of phosphonate 6 (139 mg, 0.45 mmol) in THF (2 mL) was
added dropwise to a suspension of NaH (18 mg, 60% dispersion in oil,
0.45 mmol) in dry THF (6 mL) under nitrogen at RT. After stirring at
RT for 10 min, a solution of 2,3:5,6-diisopropylidene d-mannofur-
anose (7) (107 mg, 0.41 mmol) in THF (2 mL) was added, and the
reaction stirred at RT. After 18 h, the reaction was cooled to 08C,
O
O
1) NaH, THF,
RT, 18 h
[6b]
KOH-Al2O3 (5.8 g) added and the suspension stirred for 10 min.
O
O
Ph
OH
O
O
CBr2F2 (0.37 mL) was added with stirring at 08C and the flask sealed,
the stirring continued at this temperature for 30 min. The suspension
was then warmed to RTand CH2Cl2 (10 mL) added. After stirring for
15 min, the reaction mixture was filtered through Celite, washing with
CH2Cl2, and then the combined organic washings were concentrated
in vacuo. Chromatography on silica (petroleum ether:EtOAc, 3:1)
gave alkene 9 (111 mg, 78%) as a colorless semi-solid, Rf (petroleum
ether:EtOAc, 3:1) 0.49, [a]D = + 91 (c. 1.2, CHCl3), Found: 347.1858.
C20H26O5 requires [MH]+ 347.1858 (0 ppm error). Consistent
1H NMR, 13C NMR, IR spectroscopy, and MS data were also
obtained.
then
2) KOH/Al2O3,
CBr2F2
0 °C, 30 min
9
O
O
7
O
O
78% overall
+
EtO
EtO
P
S
Ph
O2
O
6
Scheme 6. One-pot variant of the C-glycoside synthesis.
Received: October 21, 2002 [Z50403]
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À
Keywords: C C coupling · disaccharides · glycosides · synthetic
methods · tandem processes
.
[1] For recent reviews see: Y. Kishi, Tetrahedron 2002, 58, 6239 –
6258; T. Skrydstrup, B. Vauzeilles, J.-M. Beau, in Carbohydrates
in Chemistry and Biology, Vol. I, Part I (Eds.: B. Ernst, G. W.
Hart, P. Sinay¨), Wiley-VCH, Weinheim, 2000, chap. 20; Y. Du,
R. J. Linhardt, I. R. Vlahov, Tetrahedron 1998, 54, 9913 – 9959;
D. E. Levy, C. Tang, The Chemistry of C-Glycosides, Pergamon,
Oxford, 1995; M. H. D. Postema, C-Glycoside Synthesis, CRC,
Boca Raton, FL, 1995.
[2] For recent references see: M. K. Gurjar, R. Nagaprasad, C. V.
Ramana, Tetrahedron Lett. 2002, 43, 7577 – 7579; L. M. Mikkel-
sen, S. L. Krintel, J. JimØnez-Barbero, T. Skrydstrup, J. Org.
Chem. 2002, 67, 6297 – 6308; A. Dondoni, A. Marra, M. Mizuno,
P. P. Giovannini, J. Org. Chem. 2002, 67, 4186 – 4199; W.-B. Yang,
Y.-Y. Yang, Y.-F. Gu, S.-H. Wang, C.-C. Chang, C.-H. Lin, J. Org.
Chem. 2002, 67, 3773 – 3782; A. M. Gómez, A. Pedregosa, S.
Valverde, J. C. López, Chem. Commun. 2002, 2022 – 2023; A. M.
Gómez, G. O. Danelón, A. Pedregosa, S. Valverde, J. C. López,
Chem. Commun. 2002, 2024 – 2025; R. Hodgson, T. Mahid, A.
Nelson, Chem. Commun. 2001, 2076 – 2077; P. Pasetto, X. Chen,
C. M. Drain, R. W. Franck, Chem. Commun. 2001, 81 – 82; X. Li,
O. Ohtake, H. Takahashi, S. Ikegami, Tetrahedron 2001, 57,
4283 – 4295.
[3] F. K. Griffin, D. E. Paterson, R. J. K. Taylor, Angew. Chem. 1999,
111, 3123 – 3125; Angew. Chem. Int. Ed. 1999, 38, 2939 – 2942.
[4] a) F. K. Griffin, P. V. Murphy, D. E. Paterson, R. J. K. Taylor,
Tetrahedron Lett. 1998, 39, 8179 – 8182; b) M.-L. Alcaraz, F. K.
Griffin, D. E. Paterson, R. J. K. Taylor, Tetrahedron Lett. 1998,
39, 8183 – 8186; c) R. J. K. Taylor, Chem. Commun. 1999, 217 –
227, and references therein; d) A. D. Campbell, D. E. Paterson,
T. M. Raynham, R. J. K. Taylor, Chem. Commun. 1999, 1599 –
1600; e) G. D. McAllister, R. J. K. Taylor, Tetrahedron Lett.
2001, 42, 1197 – 1200.
[5] L. Ramberg, B. Bäcklund, Ark. Kemi Mineral. Geol. 1940, 13A,
27, 1 – 50 [Chem. Abstr. 1940, 34, 4725]; for reviews see L. A.
Paquette, Org. React. 1977, 25, 1 – 71; J. M. Clough, Compre-
hensive Organic Synthesis, Vol. 3, Pergamon, Oxford, 1991,
chap. 3.8, pp. 880–886.
[6] a) C. Y. Meyers, A. M. Malte, W. S. Matthews, J. Am. Chem. Soc.
1969, 91, 7510 – 7512; b) T.-L. Chan, S. Fong, Y. Li, T.-O. Man,
C.-D. Poon, Chem. Commun. 1994, 1771 – 1772.
[7] A. H. Davidson, L. R. Hughes, S. S. Qureshi, B. Wright, Tetra-
hedron Lett. 1988, 29, 693 – 696, and references therein.
[8] Prepared by S-alkylation of benzyl thiol with diethyl iodome-
thylphosphonate followed by oxidation using Oxone. This
compound has recently been described: M. Sindt, S. B.
Schneider, J. L. Mieloszynski, Phosphorus Sulfur Silicon Relat.
Elem. 2001, 174, 163 – 176.
[9] H. Ohrui, G. H. Jones, J. G. Moffatt, M. L. Maddox, A. T.
Christensen, S. K. Byram, J. Am. Chem. Soc. 1975, 97, 4602 –
4613, and references therein.
[10] M. Mikolajczyk, M. Popielarczyk, S. Grzejszczak, Phosphorus
Sulfur Relat. Elem. 1981, 10, 369 – 374.
[11] M. Wang, Y. Shao, N. Zhu, M. Rangarajan, E. J. LaVoie, C.-T.
Ho, J. Nat. Prod. 1999, 62, 454 – 456; H. Matsuda, A. Ishikado, N.
Nishida, K. Ninomiya, H. Fujiwara, Y. Kobayashi, M. Yoshi-
kawa, Bioorg. Med. Chem. Lett. 1998, 8, 2939 – 2944.
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