Three step synthesis of single diastereoisomers of the vicinal trifluoro motif

Article abstract of DOI:10.3762/bjoc.5.61

A three step route to single diastereoisomers of the vicinal trifluoromethyl motif is described. The route starts from either syn- or anti-α,β-epoxy alcohols and takes a direct approach in that each of the three steps introduces a fluorine atom in a regio- and stereospecific manner. Starting from either the syn- or the anti-α,β-epoxy alcohol, stereospecific reactions generate two separate diastereoisomeric series of this motif. The route is a significant improvement on an earlier six step strategy.

Full text of DOI:10.3762/bjoc.5.61

Three step synthesis of single diastereoisomers of
the vicinal trifluoro motif
Vincent A. Brunet, Alexandra M. Z. Slawin and David O’Hagan*
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 61.
School of Chemistry and Centre for Biomolecular Sciences, University
of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, UK
doi:10.3762/bjoc.5.61
Received: 17 August 2009
Accepted: 26 October 2009
Published: 05 November 2009
Email:
David O’Hagan* - do1@st-andrews.ac.uk
* Corresponding author
Editor-in-Chief: J. Clayden
Keywords:
© 2009 Brunet et al; licensee Beilstein-Institut.
License and terms: see end of document.
C–F bond; organo–fluorine chemistry; stereospecific fluorination;
vicinal trifluoro motif
Abstract
A three step route to single diastereoisomers of the vicinal trifluoromethyl motif is described. The route starts from either syn- or
anti-α,β-epoxy alcohols and takes a direct approach in that each of the three steps introduces a fluorine atom in a regio- and stereo-
specific manner. Starting from either the syn- or the anti-α,β-epoxy alcohol, stereospecific reactions generate two separate diaste-
reoisomeric series of this motif. The route is a significant improvement on an earlier six step strategy.
Introduction
Selective fluorination is an important strategy for the design of chains [5]. It emerges that different diastereoisomers of other-
performance molecules in medicinal chemistry programmes and wise constitutionally identical isomers have very different prop-
in organic materials [1,2]. To date arylfluorines have domi- erties and conformations as a consequence of the preferred
nated this agenda. However molecules where the C–F bond is a alignments of the C–F bonds, and thus the specific stereogenic
constituent of a stereogenic centre are gaining in prominence, relationship between the vicinal fluorines alters the properties of
particularly as new reagents and more versatile asymmetric the compounds in a very specific manner [6-10]. Earlier contri-
methods facilitate their syntheses [3,4]. The fluorine atom is butions in this area outlined a synthetic approach to the vicinal
small, with a steric impact only a little larger than hydrogen, trifluoro motif as shown in Scheme 1 [11,12]. However this
and it is a weak hydrogen bond acceptor [4]. However the C–F method had some limitations and particularly the final step was
bond is polar and thus interactions with nearby functional susceptible to competing elimination, resulting in poor yields.
groups are largely a result of dipolar interactions rather than The route also required six steps to insert the three fluorine
hydrogen bonding or sterics. We have focused a recent atoms, with a poor overall yield. A more practical route to this
synthetic effort on the assembly of multivicinal fluorine motifs class of compounds is required if these vicinal trifluoro motifs
where contiguous fluorines have been placed along alkane are to be applied usefully.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 61.
Scheme 1: Previous six step route to the vicinal all-syn-trifluoro motif.
A three step strategy, as illustrated in Scheme 2, starting from shown to be compatible with Deoxo-Fluor® mediated deshy-
diastereoisomeric syn- or anti-α,β-epoxy alcohols A was envis- droxyfluorination reactions [7] and this would allow the
aged, each step incorporating a fluorine atom in a stereospe- prepared trifluoroalkyl motifs to be appended to more complex
cific manner. Conversion of the free hydroxyl group to fluorine structural architectures in due course.
would generate α-fluoro-epoxides B. Epoxide ring opening with
an HF source could then provide difluoroalcohols C. Insertion Results and Discussion
of the third fluorine would reasonably be achieved by fluorina- The chemistry was initiated from allylic alcohol 2 which can
tion of the free hydroxyl group of C to generate D. Such a readily be prepared in enantiomerically pure form by hydro-
strategy offers a three step route to the vicinal trifluoroalkane lytic kinetic resolution of vinyl epoxide 1 following Jacobsen’s
motif and would avoid the use of TBAF, reducing the risk of protocol [13] (Scheme 3).
elimination reactions competing with fluorine substitution, a
problematic aspect of the last step in the earlier route shown in Diol 2 was converted to tosyl ester 3 in a regioselective manner
Scheme 1.
following the procedure of Marinelli [14]. The tosyl ester 3 was
then submitted to two cross-metathesis reactions using the
It was attractive to incorporate a peripheral tosyl group into the Grubbs II catalyst and with an excess of either hexene or allyl
developing trifluoro moiety. The tosyl group was recently benzene (5 equiv) to form allylic alcohols (S)-4 and (S)-5
Scheme 2: Novel three step successive fluorination strategy from α,β-epoxy alcohols to different diastereoisomeric series (a and b) of the vicinal
trifluoro motif.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 61.
Scheme 3: Synthesis approach to the requisite α,β-epoxy alcohols 6b and 7b.
respectively [15]. The excess of alkene favours the cross meta- structure analysis which confirmed its relative and absolute
thesis reaction and the products were obtained in good yields configuration (Figure 1).
predominantly as the (E)-isomer. It was not possible to separate
the minor (Z)-isomer at this stage, however isomer separation Generation of the syn-α,β-epoxy alcohols Aa was more challen-
was more readily achieved after the subsequent epoxidation ging. This stereoisomer will ultimately deliver the all-syn Da
step. Thus (S)-4 and (S)-5 were subjected to epoxidation reac- trifluoro motif (Scheme 1). Epoxidation of (S)-5 with L-DIPT
tions following Sharpless’ methodology [16]. The anti-epoxy showed poor stereoselectivity and under optimised conditions
alcohols were easily generated, however it proved more diffi- the resultant α,β-epoxy-alcohols 7a and 7b were obtained in a
cult to prepare the syn-epoxides cleanly. Treatment with 3:1 ratio. Epoxidation reactions with m-CPBA and Ti(OiPr)4
titanium isopropoxide (Ti(OiPr)4) and D-diisopropyl tartrate gave diastereomeric ratios of between 2:1 and 3:1, thus L-DIPT
(D-DIPT) favoured formation of the anti-α,β-epoxy alcohols. In showed only a modest improvement in the stereoselectivity.
the case of 4, epoxide 6b was obtained in 80% yield and in 97:3 These diastereoisomers were not easily separated by chromato-
dr. For 5, the resulting epoxide 7b was generated as the only graphy, however the absolute and relative stereochemistry of
observable diastereoisomer. Epoxide (2R,3R,4R)-7b was recrys- the crystalline threo-isomer (2R,3S,4S)-7a was confirmed by
tallised from diethyl ether to afford a suitable crystal for X-ray X-ray structure analysis as shown in Figure 2.
Figure 1: X-ray structure (CCDC 750307) and stereochemistry of α,β-epoxy alcohol 7b.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 61.
With a strategy to access both stereoisomeric series of the trated in Scheme 4 validated the three step fluorination protocol
allylic alcohol epoxides A in place, the fluorination reactions for this diastereoisomeric series.
were then explored.
Reaction of α,β-epoxy alcohol 7b with Deoxo-Fluor® also
The fluorination of the anti-isomers 6b and 7b was attempted proceeded smoothly generating fluoro epoxide (2S,3S,4R)-9b in
using Deoxo-Fluor® [17]. α,β-Epoxy-alcohol 7b reacted 95% yield and as a single stereoisomer. However when 9b was
smoothly with Deoxo-Fluor® at 40 °C (Scheme 4) to give treated with HF/pyridine [19,20] there was no evidence that the
fluoroepoxide (2S,3S,4R)-8b in 83% yield and with a 97:3 dr. expected difluoro alcohol 12b had formed (Scheme 5). Instead
Epoxide ring opening of 8b was then explored with HF/pyridine the fluorinated tetrahydrofuran 14 was isolated as a crystalline
and this reaction proved to be both regio- and stereo-selective product in 33% yield and its structure and stereochemistry were
[18,19]. When the reaction was carried out at 0 °C the resultant established by X-ray structure analysis (Scheme 5). This
difluoro alcohol 10 was obtained in 36% yield, whereas the deviant reaction was surprising not only because there was no
yield improved as the temperature was lowered (47% at −35 °C trace of the analogous cyclisation product after treatment of 8b
and 56% at −60 °C). Epoxide ring opening was stereospecific, with HF/pyridine, but also because cyclisation had occurred
and the (2S,3S,4S)-difluoro alcohol 10 was obtained as the with retention of configuration at C4. One explanation for this
major diastereoisomer in a 97:3 ratio. The third fluorine atom outcome is that the reaction proceeds via a bicyclic phenox-
was inserted in a smooth reaction by treatment of 10 again with onium intermediate 13 generated after HF promoted epoxide
Deoxo-Fluor® to generate (2S,3R,4S)-11. The sequence illus- ring opening. Fluoride ion triggered tosyl cleavage generates a
Figure 2: X-ray structure (CCDC 750306) and stereochemistry of α,β-epoxy alcohol 7a.
Scheme 4: Three step sequential fluorination from α,β-epoxy alcohols to eg. the vicinyltrifluoro tosylate 11.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 61.
Scheme 5: Unexpected cyclisation of 9b to furan 14 with HF·pyridine. An X-ray structure of 14 (CCDC 750309) reveals that the cyclisation proceeds
with a retention of configuration.
sufficiently nucleophilic oxygen, to promote cation quenching group (Scheme 6). Interestingly there was no evidence for the
and formation of the cyclic ether. This process would involve formation of 14 with this less acidic reagent.
two configurational inversions at C4 giving overall retention.
Compounds 12b and 16 were isolated in 23% and 25% yields
Epoxide ring opening of the threo isomer 9b was eventually respectively, and the stereochemistry of each was established by
achieved, however this required much more forcing conditions X-ray structure analysis. Epoxide ring opening occurred in each
using 3HF·Et3N in toluene at 120 °C, and generated three case in a regio- and stereo-selective manner with the expected
products 12b, 15 and 16, two of which arose by fluoride ion inversion of configuration, and thus there was no evidence for
displacement of the tosyl group to generate a fluoromethyl the involvement of an intermediate phenoxonium ion under
Scheme 6: Epoxide ring opening of 9b with 3HF·Et3N required forcing conditions. The structure and stereochemistry 12b (CCDC 750308) and 16
(CCDC 750310) was established by X-ray analysis.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 61.
these conditions. The ring opening reaction of 9b was explored 1:1 mixture of 7a : 7b was explored. Grée and co-workers have
under a variety of conditions and the best conversion and also noticed that erythro-epoxy alcohols react relatively
selectivity was obtained using chloroform at 100 °C in a sealed smoothly but that threo-epoxy alcohols are prone to rearrange-
autoclave with a Teflon inner layer (12b 58%, 15 2% and 16 ment [21,22]. Thus the mixture of 7a and 7b was treated with
4%). For the final step of the sequence shown in Scheme 7, Deoxo-Fluor® or DAST under a variety of conditions and the
difluoro alcohol 12b reacted smoothly with Deoxo-Fluor® to outcomes are summarised in Table 1.
generate trifluoroalkane 17b which could be isolated in 78%
yield.
With this inseparable mixture of 9a and 9b (1:1.3 ratio) in hand,
a reaction to explore the introduction of the second fluorine was
Fluorination of epoxy alcohol 7b by the three step protocol carried out as illustrated in Scheme 8. Accordingly the mixture
(44% overall yield), illustrates a second substrate of this diaste- was treated with 3HF·Et3N in chloroform at 100 °C and this
reoisomeric series, and demonstrates a reasonably efficient generated 12a among other products.
protocol to the vicinal trifluoro motif, much improved over the
original six step sequence [11,12].
Separation of (2S,3R,4R)-12a was achieved from the product
mixture by chromatography (preparative TLC) in 33%. Finally,
Fluorination of the threo-α,β-epoxy alcohol 7a proved more treatment of 12a with Deoxo-Fluor® gave the desired all-syn-
challenging because of a propensity to give isomeric fluorina- trifluoro alkane (2S,3S,4R)-17a as a single enantiomer in
tion products. Due to the difficulty in purifying the diastereoiso- moderate 57% yield. In general the vicinal trifluoro compounds
merically pure epoxide a deshydroxyfluorination reaction on a were stable and showed no tendency to degrade over time.
Scheme 7: Three step sequential fluorination from α,β-epoxy alcohol 7b to vicinal trifluoro tosylate 17b.
Table 1: Reaction of α,β-epoxy alcohol 7a and 7b under various fluorination conditions. Ratios determined by 19F NMR.
Conditions
9a
9b
18
Deoxo-Fluor®, DCM
Deoxo-Fluor®, toluene
DAST, DCM
1
1
1
1
1.43
1.41
1.64
1.29
0.56
0.53
0.66
0.44
Deoxo-Fluor®, THF
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Beilstein Journal of Organic Chemistry 2009, 5, No. 61.
Scheme 8: Epoxide ring opening with 3HF·Et3N and synthesis of the all-syn vicinal trifluoro tosylate 17a.
Conclusion
[α]D20 = −2.7 (c = 1, CHCl3). 1H NMR (CDCl3, 400 MHz): δ
In summary a direct three step route has been developed from (ppm) 7.81 (d, 2 H, J = 8.3 Hz, CH ar); 7.36 (d, 2 H, J = 8.3 Hz,
α,β-epoxy alcohols for the synthesis of the vicinal trifluoro CH ar); 4.86 (m, 1 H, J = 45.5 Hz, FCH); 4.74–4.37 (m, 3H, 2 ×
motif where a fluorine atom is introduced in each step. Two FCH + O2SOCHaHb); 4.27 (dddd, 1 H, J = 2.6, 4.2, 11.9, 29.6
different diastereoisomeric series (a and b) of the trifluoro motif Hz, O2SOCHaHb); 2.46 (s, 3 H, CH3); 1.94–1.84 (m, 1 H,
were explored. The diastereoisomeric series Db (Scheme 2) CHaHb); 1.70–1.58 (m, 1 H, CHaHb); 1.49–1.33 (m, 4 H, 2 ×
could be prepared in a relatively straightforward manner, CH2); 0.92 (t, 3 H, J = 7.4 Hz, CH3). 13C NMR (CDCl3, 100
however the diastereoisomeric series Da (Scheme 2), where all MHz): 145.3 (C ar); 132.3 (C ar); 130.0 (CH ar); 128.0 (CH ar);
three fluorines are syn with respect to an extended alkyl chain, 89.8 (ddd, J = 178.3, 18.7, 1.9 Hz, CF); 88.3 (ddd, J = 181.7,
proved to be more challenging. This is due to a greater diffi- 18.6, 29.1 Hz, CF); 85.7 (ddd, J = 179.0, 30.4, 5.6 Hz, CF);
culty in obtaining diastereoisomerically pure syn-α,β-epoxy 67.4 (d, J = 19.8 Hz, C-CH2); 29.6 (dd, J = 21.1, 4.6 Hz, CH2);
alcohols, and also a greater propensity to side product forma- 27.0 (d, J = 5.0 Hz, CH2); 22.3 (CH2); 21.6 (CH3); 13.8 (CH3).
tion during the first two fluorination reactions. Nonetheless the 19F NMR (CDCl3, 376 MHz): −199.82 to −200.12 (m, 1 F);
methods provide a direct route to this largely unexplored motif, −201.04 to −201.38 (m, 1 F), −214.61 to −214.89 (m, 1 F). 19F
and in the cases exemplified the synthesis delivers a product {1H} NMR (CDCl3, 376 MHz): −199.9 (dd, 1 F, J = 15.9, 3.2
carrying a terminal tosyl ester, which should allow the vicinal Hz); −201.2 (dd, 1 F, J = 9.5, 3.2 Hz); −214.7 (dd, 1 F, J = 9.5,
trifluoro motif to be incorporated into larger molecular architec- 15.9 Hz). νmax/cm−1 1363, 1275, 1179, 897, 758, 749. m/z
tures.
(ES+) = 361.01 (MNa+, 100%); HRMS (ES+) found 361.1047
for C15H22F2NaO4S, requires 361.1061.
Experimental
Selected experimental data is presented. Full details are in
(2S,3R,4S)-2,3,4-Trifluoro-5-phenylpentyl
Supporting Information.
4-methylbenzenesulfonate (17b)
Deoxo-Fluor® (50% in THF, 175 μL, 0.47 mmol) was added to
a solution of 12b (58 mg, 0.16 mmol) in DCM (3 mL) at RT.
The reaction mixture was then heated at 40 °C for 1 h, and the
(2S,3R,4S)-2,3,4-Trifluorooctyl 4-methylben-
zenesulfonate (11)
Deoxo-Fluor® (55 μL of solution 50% in THF, 0.15 mmol) was reaction was quenched by the addition of silica gel. Solvents
added to a solution of 10 (25 mg, 0.07 mmol) in DCM (3 mL), were removed under reduced pressure, and the product was
and the reaction was heated at 40 °C for 1 h. The reaction was purified over silica (hexane 5 /DCM 3 /Et2O 1). The title
then cooled to RT and was quenched by the addition of silica compound was recovered as a colourless oil (45 mg, 78%).
gel. DCM was then removed under reduced pressure and the
product was purified over silica (hexane 8/EtOAc 2) and was [α]D20 = −2.8 (c = 0.7, CDCl3). 1H NMR (CDCl3, 300 MHz): δ
recovered as a colourless oil (12 mg, 48%).
(ppm) 7.78 (d, 2 H, J = 8.4 Hz, CH ar); 7.35 (d, 2 H, J = 8.4 Hz,
CH ar); 7.31–7.21 (m, 5 H, CH ar); 4.88 (m, 1 H, J = 45.9 Hz,
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Beilstein Journal of Organic Chemistry 2009, 5, No. 61.
HCF); 4.73–4.38 (m, 2 H, 2 × HCF); 4.42 (ddd, 1 H, J = 1.9,
12.1, 23.4 Hz, SO3CHaHb); 4.26 (ddd, 1 H, J = 4.5, 12.1, 28.9
Hz, SO3CHaHb); 3.21 (ddd, 1 H, J = 7.5, 13.8, 22.2 Hz,
CHaHbPh); 3.01 (ddd, 1 H, J = 6.8, 13.8, 21.1 Hz, CHaHbPh);
2.46 (s, 3 H, CH3). 13C NMR (CDCl3, 75 MHz): 145.2 (C ar);
135.1 (C ar); 132.3 (C ar); 129.9 (2 CH ar); 129.3 (CH ar);
128.9 (CH ar); 128.0 (CH ar); 127.2 (CH ar); 90.1 (ddd, J =
181.8, 20.0, 2.3 Hz, CF); 87.0 (ddd, J = 183.0, 29.7, 18.1 Hz,
CF); 86.0 (ddd, J = 179.5, 30.7, 5.5 Hz, CF); 67.4 (d, J = 19.7
Hz, CH2); 36.3 (dd, J = 22.5, 5.2 Hz, CH2); 21.7 (CH3). 19F
NMR (CDCl3, 376 MHz): −198.80 to −199.23 (m, 1 F);
−200.27 to −200.69 (m, 1 F), −215.48 to −215.78 (m, 1 F). 19F
{1H} NMR (CDCl3, 376 MHz): −198.61 (dd, 1 F, J = 9.6, 2.8
Hz); −200.03 (dd, 1 F, J = 15.4, 2.8 Hz); −215.18 (dd, 1 F, J =
9.6, 15.4 Hz). νmax/cm−1 1365, 1261, 1267, 1208, 1190, 1177,
1151, 749. m/z (ES+) = 394.95 (MNa+, 100%); HRMS (ES+)
found 395.0906 for C18H19F3NaO3S, requires 395.0905.
Supporting Information
Supporting Information File 1
Experimental methods and full characterisation and spectral
data of all prepared compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-61-S1.doc]
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[α]D20 = +1.75 (c = 0.4, CDCl3). 1H NMR (CDCl3, 300 MHz):
δ (ppm) 7.74 (d, 2 H, J = 8.3 Hz, H ar); 7.37–7.22 (m, 7 H, H
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fluorine were not observed, even with an extended number of
scans (12000 scans). 19F NMR (CDCl3, 376 MHz): −195.84 to
−196.29 (m, 1 F); −201.07 to −201.51 (m, 1 F), −212.23 to
−212.63 (m, 1 F). 19F {1H} NMR (CDCl3, 376 MHz): −196.1
(d, 1 F, J = 10.8 Hz); −201.29 (d, 1 F, J = 13.6 Hz); −212.43
(dd, 1 F, J = 10.8, 13.6 Hz). νmax/cm−1 1360, 1269, 1208, 1190,
1146, 983, 910, 740. m/z (ES+) = 394.96 (MNa+, 100%);
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