A concise synthesis of enantioenriched fluorinated carbocycles

Article abstract of DOI:10.1002/anie.200701365

(Chemical Equation Presented) A "reverse" cycloaddition- fluorination strategy has been validated to access enantioenriched fluorinated compounds featuring up to five stereogenic centers, one of which is fluorinated. This highly convergent process feature

Full text of DOI:10.1002/anie.200701365

Communications
DOI: 10.1002/anie.200701365
Chiral Allylic Fluorides
A Concise Synthesis of Enantioenriched Fluorinated
Carbocycles**
Yu-hong Lam, Carla Bobbio, Ian R. Cooper, and VØronique Gouverneur*
Angewandte
Chemie
5106
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 5106 –5110

Angewandte
Chemie
Since the discovery by Fried et al.[1] that fluoro-
cortisone is much more potent than the non-
fluorinated parent compound, the incorporation
of fluorine in drug design has been a powerful
strategy to improve properties such as bioavail-
ability and lipophilicity.[2] In addition, with the
role of chirality firmly established in medicinal
chemistry, efficient methods for the selective
formation of fluorinated stereogenic centers are
in increasing demand. With few exceptions,[3]
mainly a-fluorinated carbonyl derivatives are
accessible using the asymmetric fluorinations
reported to date.[4] Other chiral fluorinated
building blocks, especially those with multiple
stereocenters, remain difficult to access. We
reported that enantioenriched allylic fluorides
can be prepared using a reagent-controlled
enantioselective fluorodesilylation of prochiral
allylsilanes, affording fluorinated carbocycles
Scheme 1. Diels–Alder approaches to fluorinated carbocycles. FGI=functional-group
interconversion, TMS=trimethylsilyl.
with a single stereogenic center.[5] In pursuit of a general
strategy for the enantioselective synthesis of fluorinated six-
membered carbocycles featuring multiple stereocenters, one
of which is fluorinated, it is tempting to resort to the Diels–
Alder reaction using a monofluorinated diene[6] or dienophile
(Scheme 1).[7] However, an asymmetric catalytic approach has
yet to be developed, not least because of reactivity and
selectivity issues, and the need to prepare the fluorinated
reactants with perfect control of their E/Z geometry.[6c] We
reasoned that these problems could be addressed if the
cycloaddition event takes place before fluorination. Herein,
we report a general and concise strategy leading to enan-
tioenriched fluorinated carbocycles relying on asymmetric
Diels–Alder reactions of silylated dienes followed by a highly
stereoselective electrophilic fluorination of the silylated
adducts (Scheme 1). We targeted fluorinated products featur-
ing an exocyclic double bond,[8] a structural motif found, for
example, in fluorinated analogues of vitamin D3.[9]
Scheme 2. Sequential cycloaddition–fluorination.
Before embarking on the development of an asymmetric
variant of the proposed sequence, we validated its feasibility
with the fluorination of two racemic adducts, 2[10] and 4,[11]
derived from the readily accessible silylated diene 1a[12a]
(Scheme 2). The fluorination of allylsilane
2
was
performed
using
1-chloromethyl-4-fluoro-1,4-diazo-
bis(tetrafluoroborate) (Select-
niabicyclo[2.2.2]octane
fluor),[13] and afforded anti-3 as a single diastereomer (d.r.
> 20:1) in 58% yield (Scheme 2a). Adduct 4 was fluorinated
to give syn,anti-5 in 60% yield with a d.r. of > 20:1
(Scheme 2b).
[*] Y.-h Lam, Dr. C. Bobbio, Dr. V. Gouverneur
ChemistryResearch Laboratory
Prompted by these encouraging results, we considered
two asymmetric variants to access enantioenriched fluori-
nated carbocycles (Table 1). In the first approach, the Diels–
Alder reaction of 1a with the chiral N-acyloxazolidinone 6[14]
gave the pure endo adduct 7 in 50% yield (endo/exo ratio of
crude product 5:1; entry 1, Table 1). This reaction proceeded
with excellent Ca-Si facial selectivity, in accord with Evansꢀ
rationalization invoking an s-cis dienophile rigidified by
bidentate aluminum chelation.[14] The more challenging
second approach relies on a catalytic
Universityof Oxford
12 Mansfield Road, Oxford OX1 3TA (UK)
Fax: (+44)1865-27-5644
E-mail: veronique.gouverneur@chem.ox.ac.uk
Dr. I. R. Cooper
Neurologyand GI Centre of Excellence for Drug Discovery
GlaxoSmithKline
New Frontiers Science
Third Avenue, Harlow, Essex CM19 5AW (UK)
[**] This work was supported byGSK (Y.L.), the Croucher Foundation
(Y.L.), the EPSRC (C.B.), and the SNF (C.B.). We thank Dr. A. Cowley
for the X-raystudies and Dr. J. M. Brown and Prof. G. W. J. Fleet for
helpful discussions. Frontispiece illustration produced byDr. K.
Harrison (Universityof Oxford).
asymmetric Diels–Alder reaction using
the Evansꢀ mild Lewis acid derived from
Cu(OTf)2 and the bis(oxazoline) ligand
A
(entries 2–4, Table 1).[15] Dienes
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1a,b[12] reacted with the N-acyloxazolidi-
Angew. Chem. Int. Ed. 2007, 46, 5106 –5110
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5107

Communications
Table 1: Enantioselective Diels–Alder reactions of 1a–b with 6, 8–9.
Scheme 3. Reductive cleavage prior to fluorination.
EntryReacting
partners
Cond.[a] Major product
Yield d.r.
[%]
ee [%]
Table 2: Fluorination of the silylated adducts 7, 10–13.[a]
endo/exo
EntrySubstr.
Product
[major shown]
d.r.[b]
Yield [%][c]
1
2
1a+6
1a+8
I
50
79
5:1[b]
–
>20:1[c]
1
2
3
4
endo-7
>20:1
75
exo/endo
9:1
II
90[d]
>20:1[c]
endo-13
exo-10
exo-13
exo-11
9:1
1:1
5:1
6:1
69
83
60
91
exo/endo
>20:1
3
4
1b+8
1b+9
II
II
45
78
94[e]
exo/endo
3:1
89[e]
>20:1[c]
[a] Conditions I: 1a (1 equiv), 6 (1 equiv), Me2AlCl (1.4 equiv), CH2Cl2,
À408C, 3 h. II: 1a–b (1.2 equiv), 8–9 (1 equiv), Cu(OTf)2 (5 mol%),
ligand A (5 mol%), 2–4 days, 3-Š MS. [b] Only two diastereomers were
5
6
1
detectable in the crude mixture by H NMR spectroscopy. [c] d.r. after
purification. [d] Determined bychiral HPLC. [e] Determined byderivati-
zation using Mosher’s ester of the alcohol obtained byreductive
cleavage of the oxazolidinone.
exo-12
6:1
82
nones 8 and 9 to give 10–12 in 45–79% yields. The cyclo-
additions were exo selective with up to 94% ee.[16] The sense
of asymmetric induction is consistent with the diene
approaching the less hindered face of the copper square-
planar complex with the dienophile.[15]
[a] Substrate (1 equiv), Selectfluor (1.1–1.3 equiv), CH3CN, RT, 2–4 h.
[b] d.r. determined on crude reaction mixtures by 1H NMR spectroscopy.
[c] Yields of isolated products.
The enantiopure silylated alcohols endo-13 and exo-13
were also prepared to study their subsequent fluorination.
These alcohols were accessed by thioesterification of endo-7
and exo-10,[17] followed by reduction (Scheme 3).
fluorination of the alcohol endo-13 afforded syn,anti,syn-15
with a d.r. of 9:1 (entry 2, Table 2)). For this pair of
stereochemically related adducts (7 and 13), the sense of
stereocontrol is identical, with the level of selectivity maximal
when the fluorination is performed prior to the cleavage of
the chiral auxiliary. The fluorination of exo-10 was not
stereoselective and led to a 1:1 mixture of epimeric fluori-
nated products (entry 3, Table 2). In contrast, exo-13, featur-
ing the primary hydroxy group, was fluorinated with a d.r. of
5:1 with the fluoro substituent anti with respect to the phenyl
group (entry 4, Table 2). These results suggest that for these
two substrates, it is critical to perform the fluorination after
reductive cleavage of the oxazolidinone to obtain a good level
of selectivity. The fluorinations of exo-11 and exo-12, which
both possess an additional methyl group at position 5, were
both diastereoselective (d.r. 6:1) and led to 18 and 19 in 91%
The enantioenriched silylated adducts 7 and 10–13 were
then submitted to electrophilic fluorodesilylations (Table 2).
All fluorinations proceeded smoothly within 4 h at room
temperature using Selectfluor in CH3CN and delivered the
1
desired fluorinated products with 60–91% yield. The H and
19F NMR spectra of the crude mixtures showed the desired
fluorinated products only. The fluorodesilylation of endo-7
gave syn,anti,syn-14 exclusively (entry 1, Table 2). The anti
relationship of the fluorine with respect to the phenyl group
1
was assigned based on its H NMR spectrum and confirmed
by X-ray crystallography,[16b] which also confirmed the sense
of facial stereocontrol for the cycloaddition step. The
5108
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 5106 –5110

Angewandte
Chemie
and 82% yield, respectively. For both reactions, the sense of
diastereocontrol was opposite to that in the reaction of exo-
13. Indeed, the fluorine substituent in 18 and 19 was found to
be syn with respect to the phenyl group (entries 5 and 6,
Table 2). This was confirmed by X-ray analysis of 19.[16b] The
the two possible conformers. However, the presence of the
primary alcohol for the structurally related adduct exo-13
restores some degree of stereocontrol (d.r. 5:1) allowing for
the preferential formation of 17 with the Fand Ph groups anti.
A clearer understanding of how the primary alcohol acts as a
remote stereodirecting group for the fluorination of exo-13,
and how it is responsible for the eroded diastereocontrol for
the fluorination of endo-13 versus that of endo-7 will require
further studies.
In summary, enantioenriched, densely functionalized
fluorinated carbocycles are made accessible using a short
synthesis featuring an operationally simple “reverse” cyclo-
addition–fluorination sequence. The late introduction of
fluorine is advantageous as this avoids the complications
associated with the synthesis and reactivity of fluorinated
reactants. This study offers a unique platform to delineate the
effects responsible for the level and sense of stereocontrol of
the fluorination as the substitution pattern of the adducts
varies. Extension of this chemistry to the preparation of
fluorinated heterocycles is in progress.
Scheme 4. Reductive cleavage after fluorination.
Experimental Section
General procedure for fluorination: To a stirred solution of silylated
adduct (1 equiv) in CH3CN (0.1m) under Ar was added Selectfluor
(1.1–1.3 equiv) at RT. After the substrate was consumed (TLC), the
solvent was evaporated in vacuo. The residue was fractionated
between Et2O and saturated NaHCO3(aq). The organic phase was
dried over MgSO4, filtered, and concentrated to dryness to afford the
crude product, which was purified by silica gel chromatography.
cleavage of the oxazolidinone after fluorination was per-
formed successfully on adducts 14, 18, and 19 (Scheme 4).
The stereochemical preference of fluorinations of the
endo and exo adducts could be rationalized in the light of the
SE2’ mechanism[18] consistent with the clean double-bond
transposition observed upon fluorodesilylation.[13a] In a pri-
mary analysis, it is also reasonable to assume that the
electrophilic fluorinating reagent approaches the silylated
Received: March 29, 2007
Published online: June 5, 2007
Keywords: allylic compounds ·
.
asymmetric catalysis · Diels–Alder reaction ·
electrophilic fluorination
[1] J. Fried, A. Borman, W. B. Kessler, P. Grabowich, E. F. Sabo, J.
Am. Chem. Soc. 1958, 80, 2338 – 2339.
[2] a) C. Isanbor, D. OꢀHagan, J. Fluorine Chem. 2006, 127, 303 –
319; b) J.-P. BØguØ, D. Bonnet-Delpon, J. Fluorine Chem. 2006,
127, 992 – 1012; c) K. L. Kirk, J. Fluorine Chem. 2006, 127, 1013 –
1029; d) H.-J. Böhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn,
K. Müller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5,
637 – 643.
[3] a) A. Ros, A. Magriz, H. Dietrich, R. Fernµndez, E. Alvarez,
J. M. Lassaletta, Org. Lett. 2006, 8, 127 – 130; b) G. Haufe, S.
Bruns, M. Runge, J. Fluorine Chem. 2001, 112, 55 – 61.
[4] a) G. K. S. Prakash, P. Beier, Angew. Chem. 2006, 118, 2228 –
2230; Angew. Chem. Int. Ed. 2006, 45, 2172 – 2174; b) P. M.
Pihko, Angew. Chem. 2006, 118, 558 – 561; Angew. Chem. Int. Ed.
2006, 45, 544 – 547; c) N. Shibata, J. Synth. Org. Chem. Jpn. 2006,
64, 14 – 24; d) C. Bobbio, V. Gouverneur, Org. Biomol. Chem.
2006, 4, 2065 – 2075; e) S. France, A. Weatherwax, T. Lectka,
Eur. J. Org. Chem. 2005, 475 – 479; f) H. Ibrahim, A. Togni,
Chem. Commun. 2004, 1147 – 1155.
Figure 1. Stereochemical outcome of the fluorodesilylations.
cyclohexene preferentially axially and anti with respect to the
trimethylsilyl group (Figure 1).[18b] For the endo adduct 7
adopting conformation I with the phenyl positioned pseu-
doaxial, the axial approach of Selectfluor followed by ring flip
gives the experimentally observed fluorinated epimer with
the F substituent anti with respect to the phenyl group. For
exo-11 and exo-12 both delivering the major fluorinated
products with the F substituent syn to the phenyl group,
conformer II is likely to prevail in order to minimize the A1,2
strain arising from the presence of the additional methyl
group at position 5. The axial attack of Selectfluor on this
conformer led to fluoro adducts 18 and 19 with the F and Ph
groups syn. The stereochemical outcome is more subtle for
adducts exo-10 and exo-13 lacking the methyl group at
position 5. The lack of stereocontrol for the fluorination of
exo-10 suggests that Selectfluor reacts indiscriminately with
[5] B. Greedy, J. M. Paris, T. Vidal, V. Gouverneur, Angew. Chem.
2003, 115, 3413 – 3416; Angew. Chem. Int. Ed. 2003, 42, 3291 –
3294.
[6] a) T. B. Patrick, J. Rogers, K. Gorrell, Org. Lett. 2002, 4, 3155 –
3156; b) G.-q. Shi, M. Schlosser, Tetrahedron 1993, 49, 1445 –
Angew. Chem. Int. Ed. 2007, 46, 5106 –5110
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5109

Communications
1456; c) S. Eddarir, H. Mestdagh, C. Rolando, Tetrahedron Lett.
[13] a) P. T. Nyffeler, S. G. Durón, M. D. Burkart, S. P. Vincent, C. H.
Wong,Angew. Chem. 2005, 117, 196 – 217; Angew. Chem. Int. Ed.
2005, 44, 192 – 212; b) R. E. Banks, J. Fluorine Chem. 1998, 87,
1 – 17.
[14] D. A. Evans, K. T. Chapman, J. Bisaha, J. Am. Chem. Soc. 1988,
110, 1238 – 1256.
[15] D. A. Evans, D. M. Barnes, J. S. Johnson, T. Lectka, P. von Matt,
S. J. Miller, J. A. Murry, R. D. Norcross, E. A. Shaughnessy,
K. R. Campos, J. Am. Chem. Soc. 1999, 121, 7582 – 7594.
[16] a) The stereochemistry of exo-11 was assigned by X-ray crys-
tallography. The absolute configuration of exo-10 and exo-12 was
assigned by analogy with exo-11; b) CCDC 641269–641271
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
´
1991, 32, 69 – 72; d) B. Spahic, T. T. M. Thu, M. Schlosser, Helv.
Chim. Acta 1980, 63, 1236 – 1241.
[7] a) T. B. Patrick, C. Fianu, E. Pak, K. Zaksas, B. E. Neal, J.
Fluorine Chem. 2006, 127, 861 – 864; b) M. Essers, C. Mück-
Lichtenfeld, G. Haufe, J. Org. Chem. 2002, 67, 4715 – 4721; For
enantioselective Diels–Alder reactions mediated by a chiral
auxiliary: c) H. Ito, A. Saito, T. Taguchi, Tetrahedron: Asymme-
try 1998, 9, 1979 – 1987; d) H. Ito, A. Saito, T. Taguchi,
Tetrahedron: Asymmetry 1998, 9, 1989 – 1994; For catalytic
asymmetric Diels–Alder reactions: e) M. Essers, T. Ernet, G.
Haufe, J. Fluorine Chem. 2003, 121, 163 – 170.
[8] M. Prakesch, D. GrØe, R. GrØe, Acc. Chem. Res. 2002, 35, 175 –
181.
[9] J. L. Napoli, M. A. Fivizzani, H. K. Schnoes, H. F. DeLuca,
Biochemistry 1979, 18, 1641 – 1646.
[10] H. Sakurai, A. Hosomi, M. Saito, K. Sasaki, H. Iguchi, J.-I.
Sasaki, Y. Araki, Tetrahedron 1983, 39, 883 – 894.
[11] M. G. Organ, D. D. Winkle, J. Huffmann, J. Org. Chem. 1997, 62,
5254 – 5266.
[12] a) B. A. Narayanan, W. H. Bunnelle, Tetrahedron Lett. 1987, 28,
6261 – 6264; b) T. Hayashi, Y. Katsuro, M. Kumada, Tetrahedron
Lett. 1980, 21, 3915 – 3918.
[17] R. E. Damon, G. M. Coppola, Tetrahedron Lett. 1990, 31, 2849 –
2852.
[18] a) M. J. C. Buckle, I. Fleming, S. Gil, K. L. C. Pang, Org. Biomol.
Chem. 2004, 2, 749 – 769; b) S. E. Denmark, N. G. Almstead, J.
Org. Chem. 1994, 59, 5130 – 5132.
5110
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 5106 –5110