Highly diastereoselective electrophilic fluorination of cyclic syn-β-hydroxysilanes

Article abstract of DOI:10.1055/s-2007-977428

A synthesis of enantioenriched fluorinated carbocycles has been developed combining a sequential enantioselective silylallylboration-ring-closing metathesis with a highly diastereoselective electrophilic fluorination. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977428

1166
CLUSTER
Highly Diastereoselective Electrophilic Fluorination of Cyclic syn-b-
Hydroxysilanes
F
luorinationof
o
Cyclic sy
n
-
p
b-Hydroxysi
h
lanes ie Purser,a Christopher Wilson,a Peter R. Moore,b Véronique Gouverneur*a
a
University of Oxford, The Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3IA, UK
Fax +44(1865)275644; E-mail: veronique.gouverneur@chem.ox.ac.uk
b
AstraZeneca Discovery Chemistry, Alderley Park, Macclesfield, Cheshire SK10 4TF, UK
Received 17 November 2006
Cl
Abstract: A synthesis of enantioenriched fluorinated carbocycles
has been developed combining a sequential enantioselective silyl-
allylboration–ring-closing metathesis with a highly diastereoselec-
tive electrophilic fluorination.
N
2BF4
OBn
N
SiMe3
F
(–)-2a
OBn
Selectfluor® (1.1 equiv)
OBn
OBn
F
F
Key words: allylsilane, fluorine, stereoselectivity, silicon
+
NaHCO3 (1.2 equiv),
MeCN, r.t.
OBn
(+)-1
(–)-2b
82% yield
dr = 82:18
OBn
Allylsilanes are versatile intermediates in organic syn-
thesis. They react with numerous electrophiles such as
carbonyl or imine compounds in highly stereoselective
processes leading to the formation of new C–C bonds.1
The paramount importance of organofluorine compounds
in biological and medicinal chemistry prompted us to ex-
amine the reactivity of allylsilanes with electrophilic flu-
orinating reagents.2 These studies led to the development
of a novel transformation for the preparation of allylic flu-
orides, the fluorodesilylation of allylsilanes.3 This electro-
philic fluorination process takes advantage of the
stabilizing b-effect of silicon and proceeds regioselective-
ly with full transposition of the double bond, an observa-
tion consistent with an SE2¢ mechanism. Chiral acyclic
and cyclic allylsilanes were found to react with the fluor-
inating reagent Selectfluor®, leading to valuable fluorinat-
ed building blocks with the fluorine substituent on a
stereogenic center.4 Using this approach, enantioenriched
fluorinated cyclitols were prepared from various readily
available anti,syn-allylsilanes.5 For these substrates, the
preferential stereochemical outcome of the fluorination is
the result of an anti addition of the fluorinating reagent
with respect to the silyl group. Although high-yielding, a
notable limitation of this methodology is the modest level
of stereocontrol with the best diastereomeric ratio not ex-
ceeding 82:18 (Scheme 1).
Scheme 1
"F+"
OBn
OBn
Me3Si
BnO
OBn
OBn
SiMe3
"F+"
OBn
+
F
BnO
(–)-2a (major)
BnO
(–)-2b (minor)
F
Scheme 2
These results prompted us to examine the reactivity of all-
syn cyclic allylsilanes as we anticipated that the syn posi-
tioning of all the substituents on the ring would prevent
unfavorable interactions with the approaching fluorinat-
ing reagent, thereby leading to a highly diastereoselective
fluorination process. This hypothesis was challenged with
the fluorination of the racemic syn-allylsilane 3 prepared
using a known endo Diels–Alder reaction as the key step.5
Upon fluorination, the corresponding anti,syn-product
was isolated in moderate yield but with excellent diaste-
reocontrol. The only diastereomer seen in the crude reac-
tion mixture resulted from a highly favorable axial attack
of Selectfluor® taking place anti to the trimethylsilyl
group, an approach free from steric interactions with the
ring substituents (Scheme 3).
The formation of two diastereomers upon fluorination
originates from the relative stereochemistry of the starting
allylsilane. Indeed, for the anti,syn-allylsilane precursor
1, the preferential axial approach of the fluorinating
reagent is hampered by either the benzyloxy group or the
trimethylsilyl group when the cyclohexene adopts one or
the other half-chair conformation (Scheme 2).
SiMe3
CO2Me
CO2Me
CO2Me
CO2Me
Selectfluor® (1.1 equiv)
NaHCO3 (1.2 equiv),
MeCN, r.t.
F
(±)-3
(±)-4
36% yield
dr = 98:2
SYNLETT 2007, No. 7, pp 1166–1168
Advanced online publication: 13.04.2007
2
4.
0
4.
2
0
0
7
Scheme 3
DOI: 10.1055/s-2007-977428; Art ID: Y01606ST
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Fluorination of Cyclic syn-b-Hydroxysilanes
1167
This preliminary result encouraged us to further explore b-hydroxyallylsilanes (+)-16–23 in yields ranging from
the electrophilic fluorodesilylation of nonracemic syn- 42% to 90%. The lowest yield was obtained for the unpro-
allylsilanes, which we obtained using alternative synthetic tected hydroxyallylsilane (+)-7. For the acyclic precursors
routes as preliminary studies suggested that the Diels– (+)-9–15, the nature of the protecting group had little in-
Alder reaction of 1-trimethylsilylbutadiene was rather fluence on the chemical yield.
limited in scope. To prepare enantioenriched cyclic syn-
allylsilanes, we selected a well-precedented synthetic se-
Table 2 Synthesis of Cyclic syn-b-Hydroxyallylsilanes (+)-16–23
quence featuring an enantioselective silylallylboration
followed by a ring-closing metathesis.6 This highly
convergent strategy developed by Roush et al. was partic-
ularly attractive as it allowed access to cyclic syn-allyl-
silanes of different ring size and with good diastereo- and
enantioselectivity. A series of enantioselective silylallyl-
borations were performed combining allyldiisopino-
campheylboranes derived from trimethylallylsilane or
dimethylphenylallylsilane with pentenal or cis-3-hexenal,
two commercially available aldehydes. cis-3-Hexenal
was used as a replacement for butenal as we anticipated
that the additional ethyl group and the Z-geometry of the
double bond should not affect the efficiency of the allyl-
boration and of the subsequent ring-closing metathesis.7
These reactions gave us access to four b-hydroxyallyl-
silanes 5–8 in moderate to good yields, excellent diaste-
reocontrol and with enantiomeric purity circa 85%. The
assignment of the anti stereochemistry for allylsilanes 5–
8 was made by comparison with spectroscopic data of
known and fully characterized structurally related com-
pounds.6 In a control experiment, a Peterson elimination
carried out on allylsilane (–)-7, under basic conditions,
gave exclusively a newly formed Z double bond, confirm-
ing the anti stereochemistry of the starting silane
(Table 1).
Mes-N
N-Mes
Cl
Cl
Ru
OR3
PCy3
Ph
SiMe2R1
OR3
Grubbs' 2nd-generation catalyst
toluene, 80 °C, 2 h
( )
n
R2
SiMe2R1
( )
n
Entry Starting
material
R1
R2
R3
n
Product
Yield
(%)
1
2
3
4
5
6
7
8
(–)-7
Ph
Et
H
H
H
H
H
Et
Et
H
1
2
2
2
2
2
1
1
(+)-16
(+)-17
(±)-18
(+)-19
(+)-20
(+)-21
(+)-22
(+)-23
42
80
87
81
90
85
62
82
(+)-9
Me
Ph
TBS
Ac
Ac
Bz
Bz
Bz
Bz
(±)-10a
(+)-11
(+)-12
(+)-13
(+)-14
(+)-15
Me
Ph
Me
Ph
Me
a Starting material prepared from allylborane derived from 9-BBN.
Notably, unless these ring-closed compounds were care-
fully purified to remove all traces of catalyst, we found
that they were slowly converted into the corresponding
oxidized b-silyl-2-cycloalkenones (Scheme 4, eq. 1). This
regioselective oxidation process is not entirely un-
precedented as Salomon et al. reported a similar trans-
formation when structurally related cyclic allylsilanes
were treated with a catalytic amount of tris(triphenylphos-
phine)rhodium(I) chloride in the presence of oxygen
(Scheme 4, eq. 2).8
Table 1 Synthesis of b-Hydroxyallylsilanes 5–8
n-BuLi, KOt-Bu, THF, –45 °C
OH
(–)-Ipc2BOMe, –78 °C
SiMe2R1
( )
n
O
R2
SiMe2R1
( )
BF3·OEt2
H
n
R2
H2O2, pH 6, Na2SO3, 0 °C
Entry R1
R2
n
Product
Yield dr
(%)
ee
(%)
SiMe2Ph
OH
SiMe2Ph
OH
a
1
2
3
4
Ph
H
2
2
1
1
(–)-5
(+)-6
(–)-7
(+)-8
70
47
45
55
>98:2
>98:2
>98:2
>98:2
–
Ru-mediated
oxidation
eq. 1
eq. 2
a
Me
Ph
H
–
O
(+)-16
Et
Et
84
85
SiMe3
SiMe3
Me
Rh(PPh3)3Cl
a The ee could not be measured.
O2, 1.5 h
83% yield
O
Acetylation, benzoylation or silylation of 5–8 gave the
corresponding esters or silyl ethers 9–15 in good yields
using conventional procedures. The RCM reactions of
unprotected or protected allysilanes 7–15 were carried out
using 5 mol% of the second generation Grubbs’ catalyst
(Table 2) and were complete within two hours at 80 °C in
toluene. These ring closures led to the desired cyclic syn-
Scheme 4
With the enantioenriched cyclic syn-allylsilanes (+)-16–
23 in hand, we undertook the key electrophilic fluoro-
desilylation step. The fluorination of the unprotected
substrate (+)-16 was attempted using 1.1 equivalents of
Synlett 2007, No. 7, 1166–1168 © Thieme Stuttgart · New York

1168
S. Purser et al.
CLUSTER
Selectfluor® in acetonitrile at room temperature. No fluor- Table 3 Synthesis of Compounds 24–29
inated products were formed under these conditions. The
starting material was consumed to give a complex reac-
tion mixture. Similarly, the fluorination of the tert-
butyldimethylsilyl-protected precursor (+)-17 was not
successful and led to unidentified products, a result sug-
gesting that deprotection took place under these condi-
tions to release the corresponding unprotected allylsilane,
a class of substrate found unsuitable for subsequent fluo-
rination. In contrast, the protected silanes (±)-18 and (+)-
19–23 were successfully converted into the corresponding
allylic fluorides when the reactions were performed in
acetonitrile in the presence of Selectfluor® (1.1 equiv) and
sodium bicarbonate (1.2 equiv). The reactions were com-
pleted within 72 hours (Table 3). All electrophilic fluo-
rodesilylations proceeded with full transposition of the
double bond to afford cyclopentene or cyclohexene rings
with the endocyclic double bond flanked by a fluorine
substituent and the protected alcohol. The yields ranged
from 56% to 90% and the level of diastereocontrol was
consistently very good to excellent. In most cases, only
one diastereomer was detected by 1H NMR and 19F NMR
of the crude reaction mixtures. The level of diastereocon-
trol is not affected by the substituents on the silyl group or
the ring size. In contrast, the protecting group of the sec-
ondary alcohol is important. Benzoyl-protected hydroxy-
allylsilanes (+)-20–23 led to complete diastereocontrol
(dr >98:2), whereas the corresponding acetyl-protected
allylsilanes (±)-18 and (+)-19 gave two diastereomeric
products in a ratio of 94:6 and 92:8, respectively. As
hypothesized, the use of cyclic syn-allylsilanes gave pre-
dominantly the fluorinated products resulting from an anti
approach of Selectfluor® with respect to the silyl group.
Within experimental error, the enantiomeric excesses of
the fluorinated products mirrored those measured for the
starting allylsilanes.
SiMe2R1
OR3
Selectlfuor® (1.1 equiv)
OR3
( )
n
NaHCO3 (1.2 equiv),
MeCN, r.t., 72 h
F
( )
n
Entry Starting R1
material
R3
n
Product Yield
(%)
dr
eeb
c
1
2
3
4
5
6
( )-18
(+)-19
(+)-20
(+)-21
(+)-22
(+)-23
Ph
Me
Ph
Ac
Ac
Bz
Bz
Bz
Bz
2
2
2
2
1
1
( )-24
(+)-25
(+)-26
(+)-27
(+)-28
(+)-29
69
90
75
75
56
79
94:6a
92:8a
–
c
–
>98:2 77
>98:2 83
>98:2 80
>98:2 86
Me
Ph
Me
a Inseparable mixture of diastereomers by column chromatography.
b The ee determined by chiral HPLC.
c The ee could not be determined by chiral HPLC.
S.; Nishida, T.; Yamada, D.; Nagaki, A.; Yoshida, J. J. Am.
Chem. Soc. 2004, 14338. (e) Fernandes, R. A.; Yamamoto,
Y. J. Org. Chem. 2004, 735. (f) Evans, D. A.; Aye, Y.; Wu,
J. Org. Lett. 2006, 2071. (g) Nair, V.; Dhanya, R.; Vidya,
N.; Devipriya, S. Synthesis 2006, 107. (h) Conchon, E.;
Gelas-Mialhe, Y.; Remuson, R. Tetrahedron: Asymmetry
2006, 1253. (i) Friestad, G. K.; Korapala, C. S.; Ding, H.
J. Org. Chem. 2006, 281.
(2) (a) For a recent review on the importance of fluorine in
biological and medicinal chemistry, see a special issue of:
ChemBioChem 2004, 5. (b) Bégué, J.-P.; Bonnet-Delpon,
D. J. Fluorine Chem. 2006, 992. (c) Kirk, K. L. J. Fluorine
Chem. 2006, 1013. (d) Isanbor, C.; O’Hagan, D. J. Fluorine
Chem. 2006, 303. (e) Smart, B. J. Fluorine Chem. 2001, 3.
(3) (a) Gouverneur, V.; Greedy, B. Chem. Eur. J. 2002, 766.
(b) Tredwell, M.; Gouverneur, V. Org. Biomol. Chem. 2006,
26.
(4) (a) Greedy, B.; Paris, J.-M.; Vidal, T.; Gouverneur, V.
Angew. Chem. Int. Ed. 2003, 3291. (b) Thibaudeau, S.;
Gouverneur, V. Org. Lett. 2003, 4891. (c) Thibaudeau, S.;
Fuller, R.; Gouverneur, V. Org. Biomol. Chem. 2004, 1110.
(d) Tredwell, M.; Tenza, K.; Pacheco, M. C.; Gouverneur,
V. Org. Lett. 2005, 4495. (e) Giuffredi, G.; Bobbio, C.;
Gouverneur, V. J. Org. Chem. 2006, 5361.
In conclusion, we have developed an efficient approach to
enantioenriched fluorinated carbocycles featuring an en-
docyclic allylic fluoride functional group, by electrophilic
fluorodesilylation of the corresponding allylsilanes. For
the syn-allylsilanes under investigation, the chirality
transfer upon fluorination was highly efficient and pro-
ceeded preferentially anti with respect to the silyl group.
The use of these novel fluorinated building blocks in the
synthesis of biologically important targets is under way in
our laboratory and will be reported in due course.
(5) (a) Purser, S.; Odell, B.; Claridge, T. D. W.; Moore, P. R.;
Gouverneur, V. Chem. Eur. J. 2006, 9176. (b) For the
synthesis of 3, see: Carter, M. J.; Fleming, I.; Percival, A. J.
Chem. Soc., Perkin Trans. 1 1981, 2415.
(6) (a) Heo, J.-N.; Micalizio, G. C.; Roush, W. R. Org. Lett.
2003, 1693. (b) Heo, J.-N.; Holson, E. B.; Roush, W. R. Org.
Lett. 2003, 1697. For sequential allyltitanation–ring-closing
metathesis see: (c) de Fays, L.; Adam, J.-M.; Ghosez, L.
Tetrahedron Lett. 2003, 7197. (d) Adam, J.-M.; de Fays, L.;
Laguerre, M.; Ghosez, L. Tetrahedron 2004, 7325.
(7) The synthesis of butenal is not trivial. For a multistep
sequence, see: Crimmins, M. T.; Kirincich, S. J.; Wells, A.
J.; Choy, A. L. Synth. Commun. 1998, 3675.
Acknowledgment
We thank the EPSRC and AstraZeneca for generous financial
support (S.P.).
References and Notes
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2063. (b) Sarkar, T. K. In Science of Synthesis; Fleming, I.,
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(8) Reuter, J. M.; Sinha, A.; Salomon, R. G. J. Org. Chem. 1978,
43, 2438.
(c) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 2763. (d)Suga,
Synlett 2007, No. 7, 1166–1168 © Thieme Stuttgart · New York

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