A stereodivergent asymmetric approach to difluorinated aldonic acids

Article abstract of DOI:10.1039/b405067c

A (bromodifluoromethyl)alkyne has been deployed in a stereoselective route to difluorinated aldonic acid analogues, in which a Sharpless asymmetric dihydroxylation reaction and diastereoisomer separation set the stage for phenyl group oxidation.

Full text of DOI:10.1039/b405067c

A stereodivergent asymmetric approach to difluorinated aldonic acids†
Christophe Audouard,a Igor Barsukov,b John Fawcett,a Gerry A. Griffith,a Jonathan M. Percy,*a
Stéphane Pintatc and Clive A. Smithd
a Department of Chemistry, University of Leicester, University Road, Leicester, UK LE1 7RH.
E-mail: jmp29@le.ac.uk; Fax: +44 116 252 3789; Tel: +44 116 252 2140
b Biological NMR Centre, University of Leicester, PO Box 138, University Road, Leicester, UK LE1 9HN
c
Evotech OAI, 151 Milton Park, Abingdon, Oxon, UK OX14 4SD
d GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, UK CM19 5AW
Received (in Cambridge, UK) 6th April 2004, Accepted 28th April 2004
First published as an Advance Article on the web 27th May 2004
A (bromodifluoromethyl)alkyne has been deployed in a ster-
eoselective route to difluorinated aldonic acid analogues, in
which a Sharpless asymmetric dihydroxylation reaction and
diastereoisomer separation set the stage for phenyl group
oxidation.†
effect of the CF2 centre was hard to predict, though we assume that
the presence of a phenyl group will facilitate the oxidation, and that
our substrates will follow the usual behaviour of b-substituted
styrenes.
Kobayashi9 developed propargylation reactions (Scheme 2) with
2a–2c for a synthesis of the sugar portion of Gemcitabine.10
However, alkyne building blocks 2a–2c could only be synthesised
in moderate yield. Hammond revisited this area profitably,
developing an efficient synthesis of TIPS acetylene 2d,11a and
showing that it reacts under zinc11b and indium11c mediated
conditions and can be used to prepare a range of functionally
complex molecules11d containing a CF2 group. Alkyne 2a was
prepared in modest yield by Wakselman and co-workers12 from
lithium phenylacetylide and dibromodifluoromethane; we found
that pre-cooling the dibromodifluoromethane electrophile (to 278
°C) before addition to the lithioalkyne allowed 2a to be isolated in
excellent (85%) yield after distillation on a 0.25 mole scale. Small
scale ( < 5 mmole) additions of 2a to commercial glycolaldehyde
proceeded smoothly under the Kobayashi conditions to afford 1,
whereas the Hammond conditions delivered only diyne 4. On a 5
mmole scale, Kobayashi’s conditions resulted in the formation of 1
in poor yield. A 24 reaction screen revealed two effective sets of
conditions based upon the common use of zinc metal. The highest
yielding reactions occurred with either 5% Hg(OAc)2/NaI/Zn in
THF or 5% Hg(OCOCF3)2/Zn in DMF. The former regime
delivered a reliable 68–70% yield of 1 at scales between 1 and 89
mmole. We were unable to obtain any product at all under aqueous
conditions.
Though there are hundreds of fluorinated sugars in the chemical
literature, some of which have extremely useful properties, few
have been made by the concise processing of readily-available
fluorinated starting materials or building blocks. Fluorination
approaches, in which an hydroxy group, or ketone carbonyl is
exposed selectively to a fluorinating agent such as DAST or
DeoxoFluor are much more common.1 However, such methods
lack the potential for stereodivergent synthesis; by this we mean
that most syntheses start from an available sugar and deliver an
unique product. Building block chemistry has the potential to
generate families of related sugar analogues in high enantiomeric
enrichment if suitable fluorinated materials can be transformed
using the modern methods of asymmetric synthesis but aside from
the asymmetric reductions of perfluoroalkylketones and related
species, there are few useful methods.2
Recently, we described the first racemic syntheses of 4-deoxy-
4,4-difluorosugars from 1-bromo-1,1-difluoropropene and a pro-
tected glycolaldehyde derivative.3 The target glycosides appear to
be of growing interest with recent publications by Liu4 and
Mobashery.5 However, our syntheses were racemic, with no
obvious potential for the control of absolute configuration.
Retrosynthetic analysis (Scheme 1), exploiting the well-known
synthetic equivalence of the phenyl group for a carboxyl function,6
suggested that alkynyl diol 1 could be a strategic precursor to a
family of 4-deoxy-4,4-difluorosugars. Key steps would include the
addition of the alkyne to a glycolaldehyde, stereoselective reduc-
tion to the E-alkene, Sharpless AD followed by diastereoisomer
separation and oxidative cleavage of the phenyl group. Very few
Sharpless AD reactions of fluorinated alkene substrates have been
reported.7 FMO influences upon the reaction are complex8 so the
The alkynyl group was reduced stereoselectively with Red-Al
(72%),13 and protection of the racemic diol as the acetonide 5 was
achieved smoothly (95%). Sharpless AD occurred slowly unless N-
methane sulfonamide was present in the reaction. Pleasingly, the
reactions reached completion after 3 days and were high yielding
(83% for AD MIX
-A, 91% for AD MIX-B). No advantage was gained
by constant pH adjustment.14
The two pairs of inseparable diastereoisomeric diols 6a and 6b
were protected as the bis-acetonides (which were separated
effectively by conventional flash column chromatography to afford
4 separate bis-acetonides 7a–8b (43, 41, 46 and 48% isolated yields
in that order). The 1,3-anti (7a and 7b) and 1,3-syn (8a and 8b)
diols have very different 19F NMR spectra as described by
Ishihara,15 and we were able to obtain a crystal structure from 7b to
confirm the assignment of relative configuration.‡§
Samples of 7a and 7b were mixed and eluted through a Chiralcel
OJ column; a good separation was obtained and the individual
components were enantiomerically-enriched to a level of 95% from
Scheme 1 Retrosynthetic analysis and identification of pivotal inter-
mediate
† Electronic supplementary information (ESI) available: preparation of 1
and 2a, NMR and electrospray for 14 (deuterium exchanged), chiral HPLC
traces for 7a and 7b, optical rotations for 7a–8b. See http://www.rsc.org/
suppdata/cc/b4/b405067c/
Scheme 2 Developing an addition methodology (see text).
1526
C h e m . C o m m u n . , 2 0 0 4 , 1 5 2 6 – 1 5 2 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

AD-mix b and 99.5% from AD-mix a. Unfortunately, we were not
able to separate 8a and 8b using any column available to us, though
the similar measured rotations show clearly that these products are
not racemic and that the ee’s are similar to those obtained for the
separated isomers.
and the EPSRC (GR/R96835, fellowship to CA). We also wish to
thank Mr M Lee for assistance with the chiral HPLC.
Notes and references
‡ Crystallographic data for 7b: C17H22F2O4, crystal size 0.33 3 0.21 3 0.14
mm, M = 328.15, orthorhombic, a = 9.7774(6), b = 11.6322(7), c =
14.7974(9) Å, a = 90, b = 90, g = 90 °, U = 1682.95(18) Å3, T = 150(2)
K, space group P2(1)2(1)2(1), Z = 4, m(Mo–Ka) = 0.105 mm21
reflections measured, 2966 unique (Rint = 0.0260) which were used in all
calculations). Final R indices [F2 > 2s(F2) R1 = 0.0298, wR2 = 0.0728;
R indices (all data) R1 = 0.0315, wR2 = 0.0735.
Oxidative cleavage of the phenyl ring has been reported in the
presence of an acetonide protecting group.16 We attempted the
oxidation, believing that the presence of the CF2 centre would make
acetal cleavage more difficult by suppressing the pre-equilibrium
protonation at the beginning of the hydrolysis pathway. However,
a complex mixture of products was obtained from which we
identified desired product 9, along with 10 and 11. Given the
measured pH of 2.9 at the start of the reaction, acetal hydrolysis is
not surprising, so the literature observation is remarkable.
Methanolysis of the bis-acetonide 7a and per-acetylation to 12¶§
set the stage for successful oxidative cleavage and 13 was isolated
after work-up with TMS diazomethane (42% over 2 steps). No
epimerisation was detected by GC or 19F NMR. Exposure to
catalytic K2CO3 in methanol delivered a product with the mass
(revealed by ES-MS) and NMR spectra of aldonic acid 14.∑ HMBC
analysis was used to confirm the acyclic structure.
, 11573
§ CCDC 235709 and 235710. See http://www.rsc.org/suppdata/cc/b4/
b405067c/ for crystallographic data in .cif or other electronic format.
¶ A crystal structure confirmed the stereochemistry was unchanged.
Crystallographic data for 12: C19H22F2O8, crystal size 0.36 3 0.19 3 0.06
mm, M = 416.37, monoclinic, a = 11.5206(15), b = 5.7277(7), c =
15.792(2) Å, a = 90, b = 107.137(2), g = 90 °, U = 995.8(2) Å3, T =
150(2) K, space group P2(1), Z = 2, m(Mo–Ka) = 0.120 mm21, 7293
reflections measured, 3466 unique (Rint = 0.0257) which were used in all
calculations). Final R indices [F2 > 2s(F2) R1 = 0.0413, wR2 = 0.0877;
R indices (all data) R1 = 0.0484, wR2 = 0.0910.
∑ Data for 14. Semi solid, dH (D2O, 500 MHz) 4.35–4.25 (2H, m, H-2, H-3),
3
2
4.10–4.01 (1H, m [app. d, JH–F 20.7], H-5), 3.85 (1H, broad d, , H6a, J
14.1), 3.68 (1H, dd, H6b, J 8.4, 2J 14.1); dC (D2O, 125 MHz) : 180.6 (C-1),
124.6 (t, 1JC–F 212.5, C-4), 72.7 (C-2), 72.5 (dd, 2JC–F 19.1, 14.4, C-3), 72.1
(dd, 2JC–F 33.6, 28.1, C-5), 62.8 (C-6); dF (D2O, 282 MHz) 2121.7 (1F, dd,
We have described the first total synthesis of a difluorosugar
which gives rise to highly enantiomerically-enriched products. The
method is direct and stereodivergent, assuming the other three
diastereoisomers can be treated in the same way and breaks new
ground in the stereoselective synthesis of difluoroanalogues of
natural products.
2JF–F 260.0, JH–F 19.4), 2123.3 (1F, dd, JF–F 260.0, JH–F 20.7); m/z
3
2
3
(ES2) 215 (M 2 H+, 100%).
1 K. Dax, M. Albert, J. Ortner and B. J. Paul, Carbohydr. Res., 2000, 327,
47; R. P. Singh and J. M. Shreeve, Synthesis, 2002, 2561.
2 See for example: P. V. Ramachandran, B. Q. Gong, A. V. Teodorovic
and H. C. Brown, Tetrahedron: Asymmetry, 1994, 5, 1061; H. Abe, H.
Amii and K. Uneyama, Org. Lett., 2001, 3, 313.
We wish to thank the EPSRC (GR/K84882) and the Universities
of Leicester and Birmingham and GSK (CASE studentship to SP)
3 C. Audouard, J. Fawcett, G. A. Griffith, J. M. Percy, S. Pintat and C. A.
Smith, Org. Biomol. Chem., 2004, 2, 528.
4 H. W. Chen, Z. B. Zhao, T. M. Hallis, Z. H. Guo and H. W. Liu, Angew.
Chem. Int. Ed., 2001, 40, 607.
5 C. Kim, J. Haddad, S. B. Vakulenko, S. O. Meroueh, Y. Wu, H. Yan and
S. Mobashery, Biochemistry, 2004, 43, 2373.
6 P. H. J. Carlsen, T. Katsuki, V. S. Martin and K. B. Sharpless, J. Org.
Chem., 1981, 46, 3936.For applications of this methodology, see F.
Matsuura, Y. Hamada and T. Shiori, Tetrahedron, 1993, 49, 8211; J.
Clayden, F. E. Knowles and C. J. Menet, Tetrahedron Lett., 2003, 44,
3397; T. S. Cooper, P. Laurent, C. J. Moody and A. K. Takle, Org.
Biomol. Chem., 2004, 2, 265.For a review, see L. N. Mander and C. M.
Williams, Tetrahedron, 2003, 59, 1105.
7 K. P. M. Vanhessche and K. B. Sharpless, Chem. Eur. J., 1997, 3, 517;
F. A. Davis, P. V. N. Kasu, G. Sundarababu and H. Qi, J. Org. Chem.,
1997, 62, 7546.
8 D. W. Nelson, A. Gypser, P. T. Ho, H. C. Kolb, T. Kondo, H. L. Kwong,
D. V. McGrath, A. E. Rubin, P. O. Norrby, K. P. Gable and K. B.
Sharpless, J. Am. Chem. Soc., 1997, 119, 1840.
Scheme 3 Stereoselective reduction and dihydroxylation reactions. Rea-
gents and conditions. i, 5% Hg(OAc)2/NaI/Zn, THF; ii, Red-Al, PhMe, rt;
iii, acetone, TsOH, CuSO4; iv, MeSO2NH2 and AD mix-b for 7a; v,
MeSO2NH2 and AD mix-a for 7b; vi, flash column chromatography.
9 Y. Hanzawa, K. Inazawa, A. Kon, H. Aoki and Y. Kobayashi,
Tetrahedron Lett., 1987, 28, 659.
10 T. S. Chou, P. C. Heath, L. E. Patterson, L. M. Poteet, R. E. Lakin and
A. H. Hunt, Synthesis, 1992, 565.
11 (a) Z. G. Wang and G. B. Hammond, Chem. Commun., 1999, 2545; (b)
Z. G. Wang and G. B. Hammond, J. Org. Chem., 2000, 65, 6547; (c) Z.
G. Wang and G. B. Hammond, Tetrahedron Lett., 2000, 41, 2339; (d) Q.
L. Shen and G. B. Hammond, J. Am. Chem. Soc., 2002, 124, 6534.
12 I. Rico, D. Cantacuzene and C. Wakselman, J. Chem. Soc., Perkin
Trans. 1, 1982, 1063.
13 T. Yamazaki, K. Mizutani and T. Kitazume, J. Org. Chem., 1995, 60,
6046.
14 G. M. Mehltretter, C. Dobler, U. Sundermeier and M. Beller,
Tetrahedron Lett., 2000, 41, 8083.
15 M. Kuroboshi and T. Ishihara, Bull. Chem. Soc. Jpn., 1990, 63, 1185.
16 T. Yokomatsu, Y. Yoshida, K. Suemune, T. Yamagishi and S. Shibuya,
Tetrahedron: Asymmetry, 1995, 6, 365.
Scheme 4 Elaboration of the protected AD products. i, RuCl3, NaIO4,
MeCN/CCl4/H2O, rt; ii, TMSCHN2, THF; iii, Amberlyst-15, MeOH, 40 °C,
24 hours, 75%; iv, Ac2O, pyridine, rt, 24 hours, 96%; v, 10% K2CO3,
MeOH, 0 °C.
C h e m . C o m m u n . , 2 0 0 4 , 1 5 2 6 – 1 5 2 7
1527