Phosphine-catalysed cyclisation of β-hydroxy-α,α- difluoroynones

Article abstract of DOI:10.1055/s-0029-1217366

2-Benzylidene-4,4-difluorodihydrofuran-3(2H)-ones were synthesised in 58-86% yield via phosphine-promoted cyclisation of β-hydroxy-α, α-difluoroynones. The benzylidene group was found to be a suitable masked carbonyl group, thereby allowing for the validation of a novel route to 3,3-difluoro-2-hydroxy-γ-lactols. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217366

LETTER
1733
Phosphine-Catalysed Cyclisation of b-Hydroxy-a,a-Difluoroynones
Cyclisation of
b
-Hydro
a
xy-
a
,
a
-
Dif
r
ines e Schuler, Angèle Monney, Véronique Gouverneur*
Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, UK
Fax +44(1865)275644; E-mail: veronique.gouverneur@chem.ox.ac.uk
Received 9 January 2009
O
O
Abstract: 2-Benzylidene-4,4-difluorodihydrofuran-3(2H)-ones were
synthesised in 58–86% yield via phosphine-promoted cyclisation of
b-hydroxy-a,a-difluoroynones. The benzylidene group was found
F
Au(I) catalysis
6-endo-dig
F
OH
O
R1
R2
to be a suitable masked carbonyl group, thereby allowing for the
R1
validation of a novel route to 3,3-difluoro-2-hydroxy-g-lactols.
F
O
R2
F
F
Key words: phosphine, fluorine, furanone, catalysis
F
5-exo-dig
R1
phosphine
organocatalysis
O
R2
Since the publication in the mid-sixties of pioneering re-
ports, nucleophilic phosphine organocatalysis has led to
the discovery of new methods for ynone–dienone
isomerisation1 and for the construction of carbo- and
heterocycles.2 Reactions employing electron-deficient
alkenes, allenes, or alkynes have proven particularly ad-
vantageous for heterocyclic synthesis inclusive of struc-
turally diverse sulfur-containing motifs.2,3 This topic was
reviewed by Roush in 2004,4 and more recently by Tang5
and by Toy.6 Although much effort has been devoted to
this area of research, the usefulness of phosphine organo-
catalysis has not been explored with reactions involving
fluorinated reactants. As part of a program focused on the
development of novel routes to fluorinated heterocycles,
we recently disclosed the gold(I)-catalysed 6-endo-dig
ring closure of b-hydroxy-a,a-difluoroynones.7 This
chemistry led to difluorinated dihydropyranones which
are valuable precursors of pyranose carbohydrate ana-
logues. In recognition of the importance of difluorinated
furanones as potential precursors of gem-difluorinated
furanoses and nucleoside analogues,8 we reasoned that,
under phosphine catalysis, we could redirect the ring clo-
sure of b-hydroxy-a,a-difluoroynones towards a 5-exo-
dig reaction pathway. This process would deliver difluori-
nated furanones featuring an exocyclic alkene functional-
ity that could be further manipulated (Scheme 1).
Scheme 1
To probe the feasibility and the scope of the proposed
phosphine-catalysed ring closure, we synthesised a series
of b-hydroxy-a,a-difluoroynones 1a–g featuring different
substituents on the alkyne or on the group flanking the al-
cohol.9 To access 1a–g, we used a Reformatsky reaction
coupling the necessary aldehyde with chlorodifluorobut-
3-yn-2-ones that were variously substituted on position 4.
This well-documented chemistry delivered 1a–g isolated
in yields ranging from 38–86%.10 Silyl-deprotection of
unpurified 1g in the presence of catalytic amount of sodi-
um methoxide afforded the terminal ynone 1h in 35%
overall yield. The b-hydroxy-a,a-difluoroynone 1i was
made accessible reacting the corresponding Weinreb
amide with propynylmagnesium bromide (Scheme 2).
Zn ( 3 equiv)
OH
F
O
O
O
CuCl (0.3 equiv)
+
Cl
R1
R1
BF3⋅OEt2 (1.1 equiv)
Et2O–THF, r.t.
R2
F
R2
F
F
R
R
R
R
R
R
R
1 = Cy, R2 = Ph
1 = Ph, R2 = Ph
1a
1b
1c
1d
1e
1f
38%
60%
80%
62%
53%
86%
1 = PhCH2CH2, R2 = Ph
1 = BnOCH2, R2 = Ph
1 = 4-F3CPh, R2 = Ph
1 = Ph, R2 = n-Pr
In this paper, we advance phosphine organocatalysis and
document an operationally trivial protocol for the synthe-
sis of 2-benzylidene-4,4-difluoro-furan-3(2H)-ones from
readily available precursors. We also demonstrate that the
benzylidene group of the cyclised products is a suitable
masked carbonyl group, and we present a reaction se-
quence allowing for the conversion of a representative 2-
benzylidene-4,4-difluoro-furan-3(2H)-one into the corre-
sponding 3,3-difluoro-2-hydroxy-g-lactol.
1 = PhCH2CH2, R2 = SiMe3 1g
100% (crude)
OH
O
OH
F
O
NaOMe (0.1 equiv)
CH2Cl2–MeOH, 0 °C
Ph
Ph
Ph
F
F
SiMe3
F
1h
OH
35%
MgBr
(2.5 equiv)
Me
OH
O
O
OMe
N
Ph
1i
THF, 0 °C
F
F
Me
F
F
Me
37%
Scheme 2
SYNLETT 2009, No. 11, pp 1733–1736
x
x
.x
x
.2
0
0
9
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217366; Art ID: D01309ST
© Georg Thieme Verlag Stuttgart · New York

1734
M. Schuler et al.
LETTER
Table 1 5-Exo-dig Ring-Closure of b-Hydroxy-a,a-Difluoroynones
1a–i
NOE
NOE
BnO
H
H
O
F
H
F
H
F
O
F
F
O
H
OH
O
H
dppp (0.1 equiv)
AcOH (0.4 equiv)
F
Ph
O
H
O
H
H
H
R1
R1
H
toluene, 60 °C, 5 h
O
H
R2
F
F
R2
2a–f
1a–f
dppp = 1,3-bis(diphenylphosphino) propane
4c
4d
Entry Starting R1
material
R2
Product Yield Z/Eb
Figure 1
(%)a
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Cy
Ph
Ph
Ph
Ph
Ph
n-Pr
H
2a
2b
2c
2d
2e
2f
58
62
81
75
86
11c
98:2
95:5
94:6
92:8
98:2e
98:2e
With the b-hydroxy-a,a-difluoroynones 1a–i in hand, we
undertook the organocatalysed 5-exo-dig ring-closure
step (Table 1). Treatment of 1a with 1,3-bis(diphe-
nylphosphino)propane (dppp, 10 mol%), AcOH (40
mol%) in toluene at 60 °C pleasingly led within 5 hours to
the formation of the desired difluorinated furan-3-one 2a
in 58% yield (entry 1). These reaction conditions are sim-
ilar to the ones applied for the cyclisation of the corre-
sponding nonfluorinated ynones indicating that the
presence of the gem-difluorinated group is not detrimen-
tal.11 The reaction is not sensitive to the nature of the
group flanking the alcohols. Various hydroxylated ynones
derived from enolisable or nonenolisable aldehydes were
found to cyclise efficiently with chemical yields up to
86% (entries 2–5). Ynone 1d derived from benzyloxyacet-
aldehyde also underwent the programmed 5-exo-dig
cyclisation uneventfully delivering the desired difluori-
nated furanone 2d in 75% yield (entry 5).12 Under our
standard conditions, the ring closure of b-hydroxy-a,a-di-
fluoroynone 1f with the propyl group capping the alkyne
gave 2f in only 11% yield (entry 6). This reaction afforded
73% of the 1,3-dienone 3f (Scheme 3). This result was ex-
pected since the alkynone–dienone isomerisation is a
well-precedented internal hydrogen reorganisation pro-
cess and has been extensively documented in the literature
with a range of nonfluorinated ynones.1 The substrates
which did not respond to cyclisation or isomerisation were
the terminal and the methyl-substituted ynones 1h and 1i
that both led to decomposition upon treatment with subs-
toichiometric amounts of dppp and AcOH (entries 7 and
8).
Ph
PhCH2CH2
BnOCH2
4-F3CC6H4
Ph
d
1h
PhCH2CH2
Ph
2h
2i
–
d
1i
Me
–
a Isolated yields.
b Determined from 19F NMR of the crude reaction mixture.
c Major product is 3f (73%).
d Decomposition.
e Z/E ratio determined by 19F NMR after purification.
From a mechanistic standpoint, the cyclisation is likely to
involve the formation of a zwitterionic phosphonium in-
termediate A which deprotonates the pronucleophile. In-
tramolecular addition of the resulting conjugate base to
the vinyl-phosphonium salt gives the ylide B. The desired
cyclised product is obtained after prototropic shift and
elimination of dppp. For related organocatalytic reactions
mediated by bisphosphines, it has been suggested that the
second phosphine may function as a general base catalyst
(Scheme 4).1c
We next turned our attention on the manipulation of these
novel 2-benzylidene-4,4-difluoro-dihydrofuran-3(2H)-
ones with the view to access 3,3-difluorinated-2-hydroxy-
g-lactols. We identified the exocyclic benzylidene group
as a possible masked carbonyl unit, the unmasking event
being an oxidative cleavage that would release benzoic
acid as the only side product. This study was carried out
with the model compound 2c (Scheme 5). Upon treatment
with 2 equivalents of L-Selectride in THF at –78 °C for 6
hours, 2c was firstly reduced to the alcohol 4c in 74%
yield. Only one stereoisomer was observed in the crude
reaction mixture (dr >20:1) and its syn stereochemistry
was assigned based on NOE analysis (Figure 1). Follow-
For all substrates that cyclised successfully, the Z-isomers
were produced predominantly (Z/E ratio ranging from
92:8 to 98:2). The double-bond geometry was assigned
unambiguously based on NOE experiments conducted on
alcohols 4c and 4d, which were synthesised by reduction
(L-Selectride, THF, –78 °C) of 2c and 2d, respectively.
These NOE experiments revealed a syn relationship for
the two stereogenic centres.
F
O
OH
F
O
dppp (0.1 equiv)
AcOH (0.4 equiv)
OH
F
O
F
+
Ph
Me
Ph
toluene, 60 °C
Ph
O
F
F
n-Pr
n-Pr
2f 11%
3f 73%
1f
Scheme 3
Synlett 2009, No. 11, 1733–1736 © Thieme Stuttgart · New York

LETTER
Cyclisation of b-Hydroxy-a,a-Difluoroynones
1735
The unique reactivity of phosphines compared to amines
has stimulated the development of numerous novel reac-
tions over the past decade. Their nonbasic character is an
attractive property providing compatibility with base-sen-
sitive substrates. In this paper, we demonstrate that phos-
phine organocatalysis allows for the 5-exo-dig cyclisation
of b-hydroxy-a,a-difluoroynones, a challenging class of
substrates that did not respond well to 6-endo-dig ring clo-
sure under basic or acid conditions or using catalysts other
than gold(I) catalysts.7 The dppp-mediated 5-exo-dig ring
closure described herein is an operationally trivial route to
access unusual 2-arylidene-4,4-difluorodihydrofuran-
3(2H)-ones variously substituted at C5. The feasibility
and the clean stereochemical outcome of the cyclisation
process as well as the successful production of lactol 7c
are key results that suggest that this chemistry provides a
solid basis for the development of a de novo asymmetric
synthesis of gem-difluorinated carbohydrates and nucleo-
sides analogues. This work is currently in progress in our
laboratories.
OH
F
O
R
F
O
F
Ph
F
3
Ph2P
PPh2
R
O
F
nucleophilic
addition
Ph
elimination
F
OH O+PPh2
PPh2
O
3
PPh2
Ph2P+
R
Ph
–
–
R
3
O
F
F
A
prototropic shift
prototropic shift
+
O–
O Ph2P
PPh2
3
F
O
F
R
PPh2
Ph
Ph2P+
3
F
F
R
–
O
Ph
oxy-cyclisation
B
Scheme 4
Acknowledgment
ing protection of the newly formed secondary alcohol
(TBDMSCl, imidazole, DMF, 0 °C to r.t., 24 h, 51%), the
benzylidene group was successfully oxidatively cleaved
with a catalytic amount of RuCl3·H2O used in combina-
tion with 6 equivalents of NaIO4 in a solvent mixture of
H2O–CCl4–MeCN. This reaction delivered lactone 6c in
68% yield.13 Reduction of 6c with DIBAL-H (4 equiv in
CH2Cl2, –78 °C, 1 h) afforded the lactol 7c as a mixture of
anomers (ratio 1:3) in 65% overall yield. Alternative
routes to structurally related gem-difluorinated lactols and
their conversion into gem-difluorinated nucleosides ana-
logues have been reported in great detail by Qing and co-
workers.8h,i
We thank the European Community for funding through a Marie
Curie Fellowship (MEIF-CT-2006-039270 for MS). We also ack-
nowledge Dr. Barbara Odell for performing the NOE analyses on
compounds 4c and 4d.
References and Notes
(1) (a) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114,
7933. (b) Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 1
1993, 1921. (c) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc.
1994, 116, 10819.
(2) For selected examples, see: (a) Lu, X.; Du, Y.; Lu, C. Pure
Appl. Chem. 2005, 77, 1985. (b) Ludovic, J.; Marinetti, A.
Tetrahedron Lett. 2006, 47, 2141. (c) Fleury-Brégeot, N.;
Ludovic, J.; Retailleau, P.; Marinetti, A. Tetrahedron 2007,
63, 11920. (d) Kuroda, H.; Tomita, I.; Endo, T. Org. Lett.
2003, 5, 129. (e) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.;
Jiao, L.; Huang, F.; Liu, S.; Li, Y.; Yu, Z.-X. J. Am. Chem.
Soc. 2007, 129, 3470. (f) Wilson, J. E.; Fu, G. C. Angew.
Chem. Int. Ed. 2006, 45, 1426. (g) Wurz, R. P.; Fu, G. C.
J. Am. Chem. Soc. 2005, 127, 12234. (h) Cowen, B. J.;
Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988.
(i) Castelano, S.; Fiji, H. D. G.; Kinderman, S. S.; Watanabe,
M.; de Leon, P.; Tamanoi, F.; Kwon, O. J. Am. Chem. Soc.
2007, 129, 5843. (j) Ye, L.-W.; Sun, X.-L.; Wang, Q.-G.;
Tang, Y. Angew. Chem. Int. Ed. 2007, 46, 5951. (k) Nair,
V.; Mathew, S. C.; Biju, A. T.; Suresh, E. Angew. Chem. Int.
Ed. 2007, 46, 2070. (l) McDougal, N. T.; Shaus, S. E.
Angew. Chem. Int. Ed. 2006, 45, 3117. (m)Sriramurthy, V.;
Barcan, G. A.; Kwon, O. J. Am. Chem. Soc. 2007, 129,
12928.
F
F
OH
O
F
F
L-Selectride (2 equiv)
THF, –78 °C, 6 h
74% yield
PhCH2CH2
PhCH2CH2
O
O
2c
4c
Ph
Ph
d.r > 20:1
TBSCl ( 2 equiv)
Imidazole (3 equiv)
CH2Cl2, 0 °C, r.t., 24 h
51% yield
F
OTBS
O
F
F
OTBS
Ph
F
RuCl3⋅H2O (0.04 equiv)
NaIO4 ( 6 equiv)
H2O–MeCN–CCl4
r.t., 0.5 h
PhCH2CH2
PhCH2CH2
O
O
6c
5c
68% yield
DIBAL-H ( 4 equiv)
CH2Cl2, –78 °C, 1 h
65% yield
(3) (a) Gabillet, S.; Lecercle, D.; Loreau, O.; Carboni, M.;
Dezard, S.; Gomis, J.-M.; Taran, F. Org. Lett. 2007, 9, 3925.
(b) Carboni, M.; Gomis, J.-M.; Loreau, O.; Taran, F.
Synthesis 2008, 417.
F
OTBS
F
(4) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346,
1035.
OH
(5) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37,
1140.
PhCH2CH2
O
7c
(6) Kwong, C. K.-W.; Fu, M. Y.; Lam, C. S.-L.; Toy, P. H.
Synthesis 2008, 2307.
Scheme 5
Synlett 2009, No. 11, 1733–1736 © Thieme Stuttgart · New York

1736
M. Schuler et al.
LETTER
(Z)-2-Benzylidene-4,4-difluoro-5-(2-phenylethyl)-
(7) Schuler, M.; Silva, F.; Bobbio, C.; Tessier, A.; Gouverneur,
V. Angew. Chem. Int. Ed. 2008, 47, 7927.
dihydrofuran-3 (2H)-one (2c)
(8) (a) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M.
J. Org. Chem. 1988, 53, 2406. (b) Chou, T. S.; Heath, P. C.;
Patterson, L. E.; Poteet, L. M.; Lakin, R. E.; Hunt, A. H.
Synthesis 1992, 565. (c) Kotra, J. P.; Xiang, Y.; Newton,
M. G.; Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K. J. Med.
Chem. 1997, 40, 3635. (d) Fernández, R.; Matheu, M. I.;
Echarri, R.; Castillón, S. Tetrahedron 1998, 54, 3523.
(e) Gumina, G.; Schinazi, R. F.; Chu, C. K. Org. Lett. 2001,
3, 4177. (f) Zhang, X. G.; Xia, H.-R.; Dong, X.-C.; Jin, J.;
Meng, W.-D.; Qing, F.-L. J. Org. Chem. 2003, 68, 9026.
(g) Zhou, W.; Gumina, G.; Chong, Y.; Wang, J.; Schinazi,
R. F.; Chu, C. K. J. Med. Chem. 2004, 47, 3399. (h) Xu,
X.-H.; Qiu, X.-L.; Zhang, X.; Qing, F.-L. J. Org. Chem.
2006, 71, 2820. (i) Xu, X.-H.; Trunkfield, A. E.; Bugg,
D. H.; Qing, F.-L. Org. Biomol. Chem. 2008, 6, 157.
(9) For additional details on the synthesis of b-hydroxy-a,a-
difluoroynones, see the Electronic Supporting Information
of ref. 7.
(10) (a) Hallinan, E. A.; Fried, J. Tetrahedron Lett. 1984, 25,
2301. (b) Kuroboshi, M.; Ishihara, T. Bull. Chem. Soc. Jpn.
1990, 63428. (c) Yamaguchi, M.; Shibato, K.; Fujiwara, S.;
Hirao, I. Synthesis 1986, 421. (d) Iseki, K.; Asada, D.;
Kuroki, Y. J. Fluorine Chem. 1999, 97, 85.
(11) Silva, F.; Sawicki, M.; Gouverneur, V. Org. Lett. 2006, 8,
5417.
(12) General Procedure for Cyclisation of 1c
Rf = 0.68 (hexane–EtOAc, 80:20). 1H NMR (400 MHz,
CDCl3): d = 2.25 (q, J = 7.3 Hz, 2 H, CH2CH), 2.91–3.04 (m,
2 H, CH2Ph), 4.44–4.55 (m, 1 H, CF2CH), 6.65 (s, 1 H,
C=CHPh), 7.25–7.46 (m, 8 H, 8 × ArH), 7.79 (br d, J = 6.8
Hz, 2 H, 2 × ArH). 13C NMR (100 MHz, CDCl3): d = 29.5
(d, J = 6.4 Hz, CH2), 30.8 (CH2), 79.7 (dd, J = 27.2, 24.0 Hz,
CH), 112.7 (CH), 113.3 (dd, J = 268.8, 256.4 Hz, CF2),
126.6 (CH), 128.6 (CH), 128.8 (CH), 129.0 (CH), 130.0
(CH), 131.3 (CH), 132.5 (C), 140.0 (C), 144.1 (dd, J = 4.8,
3.2 Hz, C), 186.5 (t, J = 25.2 Hz, C). 19F NMR (377 MHz,
CDCl3): d = –125.17 (dd, J = 282.3, 14.9 Hz, 1 F), –120.62
(dd, J = 281.7, 12.1 Hz, 1 F). IR (CH2Cl2): n = 3055, 1751,
1266, 1135, 738 cm–1. HRMS (CI+): m/z calcd for
C19H17F2O2 [M + H]+: 315.1197; found: 315.1209.
(13) Procedure for the Synthesis of 6c
To a stirred solution of 5c (47.6 mg, 0.11 mmol, 1 equiv) in
MeCN–CCl4–H2O (1.5:1:1, 1 mL) were added NaIO4 (141
mg, 0.66 mmol, 6 equiv) and RuCl3·H2O (0.9 mg, 4.4 mmol,
4 mol%). After 30 min, the reaction mixture was quenched
by addition of H2O, and it was extracted three times with
EtOAc. The combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated in
vacuo. Purification by column chromatography on silica gel
(hexane–Et2O, 95:5 to 90:10) gave the product as a white
solid (26.5 mg, 74 mmol) in a 68% yield. Rf = 0.23 (hexane–
Et2O, 95:5). 1H NMR (400 MHz, CDCl3): d = 0.14 and 0.17
(2 × s, 6 H), 0.92 (s, 9 H), 2.05–2.15 (m, 2 H), 2.70–2.91 (m,
2 H), 4.25–4.36 (m, 1 H), 4.48 (dd, J = 14.8, 9.4 Hz, 1 H),
7.16–7.22 (m, 3 H), 7.25–7.32 (m, 2 H). 13C NMR (126
MHz, CDCl3): d = –4.8 (CH3), –5.1 (CH3), 18.5 (C), 25.5
(CH3), 28.8 (d, J = 5.2 Hz, CH2), 30.7 (CH2), 71.2 (dd,
J = 19.5, 19.6 Hz, CH), 77.8 (dd, J = 25.3, 24.6 Hz, CH),
120.8 (dd, J = 254.0–254.1 Hz, CF2), 126.7 (CH), 128.7
(CH), 128.9 (CH), 139.9 (C), 169.3 (d, J = 17.1 Hz, C=O).
19F{1H} NMR (377 MHz, CDCl3): d = –131.30 (d, J = 232.0
Hz, 1 F), –116.62 (d, J = 232.0 Hz, 1 F). IR (CH2Cl2): n =
2950, 2900, 2833, 1810, 1263, 1153, 910, 735 cm–1. MS
(CI+): m/z = 374.25 [M + NH4]+.
To a solution of 1c (200 mg, 0.64 mmol, 1 equiv) in
anhydrous toluene (64 mL) was added under argon AcOH
(15 mL, 0.255 mmol, 40 mol%) followed by dppp (26.3 mg,
0.064 mmol, 10 mol%). The reaction mixture was stirred at
60 °C for 4 h. The crude mixture was concentrated in vacuo
at r.t., and the resulting solution was directly purified by
column chromatography on silica gel (hexane–Et2O, 80:20)
to give the product as a yellow oil (120 mg, 0.38 mmol) in a
60% yield.
Synlett 2009, No. 11, 1733–1736 © Thieme Stuttgart · New York