First synthesis of 5-fluoro-(+)-MK7607, its 1-epimer and 6-deoxy derivative

Article abstract of DOI:10.1016/j.tetlet.2008.07.070

(+)-MK7607 is a patented naturally occurring unsaturated pseudo-carbasugar possessing herbicidal activity. We present herein the first synthesis of the 5-fluorinated analogue (1S, 2S, 3R, 4R)-5-fluoro-6-(hydroxymethyl)cyclohex-5-ene-1,2,3,4-tetrol as well as that of two related compounds, namely its 1-epimer and its 6-deoxy derivative.

Full text of DOI:10.1016/j.tetlet.2008.07.070

Tetrahedron Letters 49 (2008) 5548–5550
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Tetrahedron Letters
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First synthesis of 5-fluoro-(+)-MK7607, its 1-epimer and 6-deoxy derivative
João Sardinha a,b, Amelia Pilar Rauter b, Matthieu Sollogoub a,
*
a UPMC Univ Paris 06, Institut de Chimie Moléculaire (FR 2769), Laboratoire de Chimie Organique (UMR CNRS 7611), Tours 44-45, 1er étage, C. 181, 4 place Jussieu, 75005 Paris, France
b Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Edifício C8, 5 Piso, 1749-016 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
(+)-MK7607 is a patented naturally occurring unsaturated pseudo-carbasugar possessing herbicidal
activity. We present herein the first synthesis of the 5-fluorinated analogue (1S, 2S, 3R, 4R)-5-fluoro-
6-(hydroxymethyl)cyclohex-5-ene-1,2,3,4-tetrol as well as that of two related compounds, namely its
1-epimer and its 6-deoxy derivative.
Received 23 June 2008
Revised 8 July 2008
Accepted 11 July 2008
Available online 16 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Cabasugars
Fluorine
Mimics
Inositol
The (non-detachable) prefix ‘carba-’ signifies replacement of a
heteroatom by carbon in general natural product nomenclature,
and may be applied to replacement of the hemiacetal ring oxygen
in carbohydrates if there is a desire to stress homomorphic rela-
tionships.1 Therefore, carbasugars are sugar analogues in which
the endocyclic oxygen has been replaced by a methylene group
or its derivatives.1,2 However, this definition is misconstrued by
many authors, who include carbocyclic polyols containing a non-
substituted carbon, which should be called pseudo-carbasugars be-
cause they do not have a homomorphic sugar associated.2 As mim-
ics of substrates in their ground-state, carbasugars do not display
very high inhibitory activity towards glycosidases. Therefore, nat-
ure selected carbasugar-based inhibitors by adding an amine or a
double bond in the cycle to mimic transition states of the sub-
strates of these enzymes. Valienamine or (+)-MK7607 enters this
category of pseudo-carbasugars possessing interesting biological
activity (Fig. 1). (+)-MK7607 is a patented naturally occurring her-
bicide, produced through fermentation of Curvularia eragrostidis
D2452.3 Besides, its 1-epi-MK7607 also presents a high affinity to
galactose-recognizing lactin (ML I).4 So far, racemic MK7607,5
non natural enantiomer (ꢀ)-MK76076 and 1-epi-(+)-MK76077
were synthesized. In the context of biological activity, addition
of a fluorine atom is definitely a bonus as reporter group8 or to
improve physicochemical properties.9 We present herein the first
synthesis of fluoro-(+)-MK 7607, as well as that of two derivatives,
namely its 1-epimer and the 6-deoxy analogue. Preliminary studies
on their inhibitory activity against an array of glycosidases are also
reported.
We have been involved in the synthesis of carbasugars, and our
strategy is based on a Lewis acid induced rearrangement of a sugar
bearing an enol ether, which possesses an electron donating
group.10 This reaction was successfully applied to the synthesis
of carbamonosaccharides, carbadisaccharides,11 gem-difluorocar-
baglucose,12 and more recently to gem-difluorocarbagalactose.13
The synthesis of this compound starts from known primary alcohol
114 that was transformed into alkyne 2 through Swern oxidation
and Corey–Fuchs reaction. The PMP group was oxidatively cleaved
to obtain the corresponding lactol. Oxidation followed by olefin-
ation15 of the resulting lactone using CBr2F2 afforded the key
gem-difluoroalkene 3. Formation of the Cobalt-cluster on the triple
bond, followed by TIBAL induced rearrangement and subsequent
OH
OH
OH
OH
NH2
OH
OH
Valienamine
HO
HO
HO
HO
HO
HO
removal of the Cobalt gave the carbocyclic products 4
a and 4b in
64% yield over three-step as an almost 1:1 mixture of axial and
equatorial alcohols (Scheme 1).
OH
True carbasugar
OH
(+)-MK7607
Next steps usually comprise partial hydrogenation and reduc-
Figure 1.
tive ozonolysis. When separately applied to compounds 4
a and
4b, the expected compounds 5 and 5b were obtained as major
a
products in each case, but after careful separation, which involved
* Corresponding author. Tel.: +33 144276163.
E-mail address: matthieu.sollogoub@upmc.fr (M. Sollogoub).
an acetylation-separation sequence, a secondary product was
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.070

J. Sardinha et al. / Tetrahedron Letters 49 (2008) 5548–5550
5549
1) Swern ox.
O
OPMP
OBn
O
OPMP
OBn
HO
Ref 14
2) Corey-Fuchs
D-Galactose
BnO
BnO
BnO
OBn
1
OBn
2
1) CAN
2) PCC
1)Co2CO8
2) TIBAL
3) CAN
F
F
F
R1
R2
OBn
OBn
O
3) CBr2F2
F
BnO
OBn
OBn
3
R1=H, R2=OH: 4α
R1=OH, R2=H: 4β
Scheme 1. Synthesis of gem-difluorocarbagalactose derivatives 4a and 4b.
p
-allyl intermediate accounting for the abstraction of the acetate
F
F
F
F
F
R1
R2
R1
R2
OBn
R1
R2
OBn
group (Scheme 3). Prior deacetylation of 6b followed by hydro-
genolysis of 10b led to a complex mixture of products. Finally,
benzyl ethers were cleaved with a Lewis acid (BCl3) and the desired
5-fluoro-(+)-MK760717 and its 1-epi-(+)-MK760718 were delivered
in 78% and 75% yield from 6
sponding peracetylated 11 and 11b (Scheme 3).
These three compounds were tested as glycosidase inhibitors
for bovine kidney -fucosidase, coffee beans -galactosidase,
Escherichia coli and Aspergillus oryzae b-galactosidase, rice and
yeast -glucosidase, Aspergillus niger amyloglucosidase, almonds
b-glucosidase, jack beans -mannosidase, snail b-mannosidase, A.
AcO
AcO
i-iv
BnO
BnO
OBn BnO
OBn
R1=H, R2=OH: 4α
R1=OH, R2=H: 4β
OBn
OBn
R1=H, R2=OAc: 5α R1=H, R2=OAc: 6α
R1=OAc, R2=H: 5β R1=OAc, R2=H: 6β
a and 6b, respectively via the corre-
a
i
iii,iv
a-
L
a
O
F
F
F
F
R1
R2
OBn
R1
R2
OBn
ii
a
a
BnO
BnO
niger b-xylosidase, bovine kidney and jack beans b-N-acetylglucos-
OBn
OBn
aminidase but no interesting activity was detected.
R1=H, R2=OH: 8α
R1=OH, R2=H: 8β
R1=H, R2=OH: 7α
R1=OH, R2=H: 7β
In conclusion, we have synthesized three fluorinated deriva-
tives of the naturally occurring product (+)-MK7607, which biolog-
ical interest may rely on the evaluation of their herbicidal activity
to be carried out in the near future.
Scheme 2. Cleavage of the triple bond. Reagents and conditions: (i) Pd/CaCO3, H2,
EtOAc, 2 h; (ii) O3, CH2Cl2, ꢀ78 °C, 2 min; (iii) NaBH4, CH2Cl2/EtOH (1:5), rt, 45 min;
(iv) Ac2O, Pyr., 2 h, rt; 92% yield over four steps for both isomers 5a or b:6a or b, 3:2.
Acknowledgments
The authors thank Fundação para a Ciência e Tecnologia (FCT
Portugal) for research grant (João Sardinha) as well as Claudia Bello
and Professor Pierre Vogel for testing inhibitory activity.
isolated and identified as the unsaturated compound 6a or 6b. The
formation of those compounds was attributed to an elimination
reaction occurring during the three-step process to convert the tri-
ple bond into CH2OH. The expected
transient aldehydes 8 and 8b with DBU was investigated and led
only to complex mixtures (Scheme 2).
a,b-elimination of HF from the
a
Supplementary data
Conventional hydrogenolysis of 6a surprisingly led to 6-deoxy-
Experimental procedure and spectroscopic data for the synthe-
5-fluoro-(+)-MK760716 via peracetylated 9
a, putatively through a
sis of 6
a
and 6b as well as 5-fluoro-(+)-MK7607, 1-epi-5-fluoro-
F
F
ii
OAc
OAc
OH
AcO
HO
HO
OH
OAc
9α
OH
6-deoxy-5-F-(+)-MK7607
i
F
F
OH
R1
iv
vi
iii
AcO
R2
Complex mixture
BnO
OBn
BnO
OBn
OBn
R1=H, R2=OAc: 6α
R1=OAc, R2=H: 6β
OBn
10β
v
F
F
R1
R2
OAc
R1
AcO
AcO
HO
R2
HO
OH
OAc
OH
R1=H, R2=OH: 11α
R1=OH, R2=H: 11β
R1=H, R2=OH: 5-F-(+)-MK7607
R1=OH, R2=H: 1-epi-5-F-(+)-MK7607
Scheme 3. Synthesis of fluoro-MK7607 and derivatives. Reagents and conditions: (i) (1) Pd/C, H2, EtOAc/MeOH, 1.5 h; (2) Ac2O, Pyr., 2 h, rt, 94% over two steps; (ii) MeONa,
MeOH, rt, 2 h, quant.; (iii) MeONa, MeOH, rt, 2 h, 89%; (iv) Pd/C, H2, EtOAc/MeOH, 1.5 h; (v) (1) BCl3, DCM, ꢀ78 °C, 3.5 h; (2) Ac2O, Pyr., 2 h, rt, 75% or 78% over two steps; (vi)
MeONa, MeOH, rt, 2 h, quant.

5550
J. Sardinha et al. / Tetrahedron Letters 49 (2008) 5548–5550
13. Sardinha, J.; Guieu, S.; Deleuze, A.; Fernández-Alonso, M. C.; Rauter, A. P.; Sinaÿ,
P.; Jiménez-Barbero, J.; Sollogoub, M. Carbohydr. Res. 2007, 342, 1689–1703.
14. Murakata, C.; Ogawa, T. Carbohydr. Res. 1992, 235, 95–114.
15. Motherwell, W. B.; Tozer, M. J.; Ross, B. C. J. Chem. Soc., Chem. Commun. 1989,
1437–1439.
(+)-MK7607 and 6-deoxy-5-fluoro-(+)-MK7607 are provided.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.070.
16. 6-Deoxy-5-fluoro-(+)-MK7607: ½ ꢁ
a 2D0 +88.5 (c 0.13, MeOH); 1H NMR (D2O,
References and notes
400 MHz): d 4.28 (ddd, 1H, J = 0.9 Hz, J5,6 = 4.6 Hz, J1,F = 9.7 Hz, H-6), 4.08 (dd,
1H, J3,4 = 4.1 Hz, J = 6.5 Hz, H-3), 3.81 (ddd, 1H, J = 1.0 Hz, J5,6 = 4.6 Hz,
J4,5 = 10.9 Hz, H-5), 3.71 (dd, 1H, J3,4 = 4.1 Hz, J4,5 = 10.9 Hz, H-4), 1.65 (d, 3H,
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1
J = 2.8 Hz, CH3); 13C NMR (CDCl3, 100 MHz) d 153.97 (d, JC,F = 256.8 Hz, C-1),
2
3
114,86 (d, JC,F = 12.1 Hz, C-2), 69.70 (d, JC,F = 11.0 Hz, C-3), 68.29 (d,
4JC,F = 1.8 Hz, C-4), 67.94 (d, JC,F = 11.0 Hz, C-3), 66.90 (d, JC,F = 25.7 Hz, C-6),
3
2
11.73 (d, JC,F = 5.0 Hz, C-7); 19F NMR (CDCl3, 235 MHz) d ꢀ118.15 (s, 1F);
3
HRCIMS calcd for C7H15FNO4 (M+NH4)+: 196.0985, found: 196.0988.
17. 5-Fluoro-(+)-MK7607: ½a D20
ꢁ
+41.3 (c 0.14, MeOH); 1H NMR (D2O, 400 MHz): d
4.31–4.25 (m, 3H, H-3, H-6, H-7a), 3.93 (ddd, 1H, J = 1.1 Hz, J5,6 = 3.4 Hz,
J4,5 = 12.7 Hz, H-7b), 3.80 (ddd, 1H, Jx,x = 0.7 Hz, J5,6 = 4.6 Hz, J4,5 = 10.7 Hz, H-4),
3.67 (dd, 1H, J3,4 = 4.1 Hz, J4,5 = 10.7 Hz, H-4); 13C NMR (CDCl3, 100 MHz) d
7. Grondal, C.; Enders, D. Synlett 2006, 3507–3509.
1
2
155.79 (d, JC,F = 266.7 Hz, C-1), 116.61 (d, JC,F = 9.5 Hz, C-2), 68.00 (d,
4JC,F = 1.6 Hz, C-4), 67.28 (d, JC,F = 10.9 Hz, C-5), 66.38 (d, JC,F = 25.2 Hz, C-6),
3
2
8. Feeney, J.; McCormick, J. E.; Bauer, C. J.; Birdsall, B.; Moody, C. M.; Starkmann, B.
A.; Young, D. W.; Francis, P.; Havlin, R. H.; Arnold, W. D.; Oldfield, E. J. Am.
Chem. Soc. 1996, 118, 8700–8706.
65.45 (d, JC,F = 10.2 Hz, C-3), 54.40 (d, JC,F = 6.2 Hz, C-7); 19F NMR (CDCl3,
235 MHz) d ꢀ115.80 (s, 1F); HRCIMS calcd for C7H15FNO5 (M+NH4)+: 212.0934,
found: 212.0935.
3
3
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18. 1-epi-5-Fluoro-(+)-MK7607: ½a D20
ꢁ
+17.5 (c 0.2, MeOH); 1H NMR (D2O, 400 MHz):
d 4.44–4.31 (m, 2H, H-3, H-7a), 4.19 (d, 1H, J5,6 = 7.6 Hz, H-6), 4.03 (ddd, 1H,
J = 0.6 Hz, J = 3.8 Hz, J4,5 = 12.5 Hz, H-7b), 3.73 (dd, 1H, J5,6 = 7.6 Hz,
J4,5 = 10.8 Hz, H-5), 3.53 (dd, 1H, J3,4 = 4.0 Hz, J4,5 = 10.8 Hz, H-4); 13C NMR
(D2O, 100 MHz) d 155.67 (d, 1JC,F = 266.6 Hz, C-1), 115.16 (d, 2JC,F = 9.6 Hz, C-2),
71.85 (d, 3JC,F = 8.2 Hz, C-5), 70.04 (d, 2JC,F = 21.6 Hz, C-6), 70.03 (d, 4JC,F = 2.6 Hz,
C-4), 66.04 (d, JC,F = 9.9 Hz, C-3), 54.60 (d, JC,F = 6.4 Hz, C-7); 19F NMR (D2O,
235 MHz) d ꢀ122.06 (s, 1F); HRCIMS calcd for C7H15FNO5 (M+NH4)+: 212.0934,
found: 212.0933.
3
3
12. Deleuze, A.; Menozzi, C.; Sollogoub, M.; Sinaÿ, P. Angew. Chem., Int. Ed. 2004, 43,
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