Asymmetric synthesis of substituted anti -β-fluorophenylalanines

Article abstract of DOI:10.1021/acs.orglett.5b00880

A range of substituted anti-β-fluorophenylalanines was produced from the corresponding enantiopure α-hydroxy-β-amino esters using a stereospecific XtalFluor-E promoted rearrangement procedure as the key step. The requisite substrates are readily produced via aminohydroxylation of an α,β-unsaturated ester using our lithium amide conjugate addition methodology and, following rearrangement, deprotection of the resultant enantiopure β-fluoro-α-amino esters gives the corresponding enantiopure anti-β-fluorophenylalanines in good yield and high diastereoisomeric purity.

Full text of DOI:10.1021/acs.orglett.5b00880

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of Substituted anti-β-Fluorophenylalanines
Stephen G. Davies,* Ai M. Fletcher, Aileen B. Frost, Paul M. Roberts, and James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: A range of substituted anti-β-fluorophenylala-
nines was produced from the corresponding enantiopure
α‑hydroxy-β-amino esters using a stereospecific XtalFluor-E
promoted rearrangement procedure as the key step. The
requisite substrates are readily produced via aminohydrox-
ylation of an α,β-unsaturated ester using our lithium amide
conjugate addition methodology and, following rearrangement,
deprotection of the resultant enantiopure β-fluoro-α-amino esters gives the corresponding enantiopure anti-β-
fluorophenylalanines in good yield and high diastereoisomeric purity.
he incorporation of fluorine is known to dramatically alter
Tthe biological properties of organic molecules, and
fluorination has become an established strategy for modifying
lead compounds in medicinal chemistry.1 Fluorinated α-amino
acids have attracted significant attention in recent years, with
several studies focusing on their incorporation into synthetic
proteins and the resulting impact this may have on secondary
structure and stability.2 This research has justified synthetic
efforts targeting fluorinated α-amino acids,3,4 with approaches
ranging from ring-opening of aziridines with fluoride5 to metal-
catalyzed cross-couplings6 being employed.
As part of our research program concerning the asymmetric
synthesis of functionalized amino acids,7 we have recently
reported an efficient protocol for the asymmetric synthesis of
β‑hydroxy-α-amino acids. Stereospecific rearrangement of
enantiopure anti-α-hydroxy-β-amino esters 1 (which are readily
derived from the corresponding α,β-unsaturated esters using our
diastereoselective aminohydroxylation procedure8) upon treat-
ment with either Ms2O or Tf2O promoted formation of the
corresponding aziridinium ions 2, which was followed by
regioselective ring-opening with H2O to give β-hydroxy-α-
amino esters 3 in >99:1 dr. Subsequent N-deprotection and ester
hydrolysis gave enantiopure anti-β-hydroxy-α-amino acids 4 in
good yield and high diastereoisomeric purity (Figure 1).9
We envisaged that application of a similar protocol employing
a deoxofluorinating agent to promote the rearrangement process
(i.e., also proceeding via the intermediacy of an aziridinium ion)
would allow the introduction of a β-fluoro substituent.10
XtalFluor-E (in combination with Et3N·3HF) was originally
reported as an efficient deoxofluorinating reagent11 but has also
found utility as a coupling reagent for amidation12 and a
cyclodehydration agent.13 It has also been used as an OH-
activator in combination with other nucleophiles for the ring
expansion of prolinols and the halogenation of primary
alcohols,14 and has also been employed in the ring-opening
fluorination of N-tosyl substituted aziridines.15 Herein we
describe a XtalFluor-E promoted rearrangement procedure as
Figure 1. Asymmetric synthesis of β-hydroxy-α-amino acids 4.
the key step in the synthesis of several enantiopure anti-β-fluoro-
phenylalanines.
Our initial investigations within this area focused on using the
established reagent combination of XtalFluor-E and Et3N·3HF11
for the rearrangement and deoxofluorination of racemic anti-α-
hydroxy-β-amino ester 5.9 Treatment of 5 with XtalFluor-E and
Et3N·3HF gave anti-β-fluoro-α-amino ester 6 as a single
diastereoisomer (>99:1 dr), which was isolated in 94% yield
(Scheme 1). The relative anti-configuration within 6 was
established unambiguously via single crystal X-ray diffraction
analysis (Figure 2).16 The formation of 6 in this reaction is
entirely consistent with our proposed mechanism, whereby
XtalFluor-E promotes formation of the corresponding aziridi-
nium ion which is then regioselectively ring-opened by fluoride at
the C(3)-position; this stereochemical outcome is in complete
accordance with that observed upon formation of the
corresponding anti-β-hydroxy-α-amino esters 3.9 Reaction of
enantiopure α-hydroxy-β-amino ester 77c,17 under the same
conditions produced β-fluoro-α-amino ester 8 in 81% yield and
Received: March 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00880
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1
Scheme 2
Figure 2. X-ray crystal structures of (RS,SR)-6 [left] and (2R,3S,αR)-8
[right] (selected H atoms are omitted for clarity).
Figure 3. X-ray crystal structures of (2S,3S,αR)-10 [left] and
(2S,3S,αR)-11 [right] (selected H atoms are omitted for clarity).
>99:1 dr, and reaction of β-hydroxy-α-amino ester 99 under
identical conditions also produced 8 in 75% yield and >99:1 dr
(Scheme 1). The relative configuration within 8 was established
unambiguously via single crystal X-ray diffraction analysis
(Figure 2),16 and the absolute (2R,3S,αR)-configuration of 8
was assigned by reference to the known (R)-configuration of the
α-methylbenzyl fragment. Furthermore, the determination of a
Flack x parameter18 of −0.11(11) for the structure of 8
confirmed this assignment. These data therefore confirm the
intermediacy of the corresponding aziridinium ion upon reaction
of both regioisomeric substrates 7 and 9.
chemical assignment in an enantioselective synthesis.21 As our
stereochemical assignment for 12 is completely secure, these
specific rotation data therefore suggest that the stereochemical
assignment of Lin et al. is in error.
Attempted N-deprotection of β-fluoro-α-amino ester 8 via
several hydrogenolytic protocols resulted in substantial com-
petitive defluorination. In the hope that alternative deprotection
strategies would be more efficacious, the corresponding N-allyl
substituted compound 14 was prepared in 96% yield and >99:1
dr from the known α-hydroxy-β-amino ester 13.22 Removal of
the N-α-methylbenzyl group within 14 was achieved via
N‑oxidation with m-CPBA followed by in situ Cope elimination
of the resultant N-oxide 15, which gave hydroxylamine 16 in only
13% isolated yield. The yields of this reaction were found to be
somewhat variable, and neither attempted N-deallylation of 16
nor attempted reduction of the N−O bond within 16 was
successful. N-Deallylation of 14, however, upon treatment with
Pd(PPh3)4 and N,N-dimethylbarbituric acid (DMBA) gave 17 in
39% yield and >99:1 dr. Sequential treatment of 17 with
Substituting Et3N·3HF for either TMSN3 or TMSOAc
produced the corresponding azide 10 or acetate 1119 as single
diastereoisomers (>99:1 dr) in 58% and 41% isolated yield,
respectively (Scheme 2). The relative configurations within 10
and 11 were established unambiguously via single crystal X-ray
diffraction analyses (Figure 3),16 and the absolute (2S,3S,αR)-
configurations of 10 and 11 were assigned in each case by
reference to the known (R)-configuration of the α-methylbenzyl
fragment. Furthermore, the determination of Flack x parame-
ters18 of −0.1(2) and −0.12(15) for the structures of 10 and 11,
respectively, confirmed these assignments. Subsequent tandem
reduction/hydrogenolysis of 10 followed by hydrolysis of the
tert-butyl ester moiety gave anti-α,β-diamino acid 12, which was
isolated in 82% yield (from 10) and >99:1 dr after purification on
Dowex 50WX8-200 ion-exchange resin (Scheme 2).20 The
specific rotation of this sample of 12 {[α]D20 −7.2 (c 0.4 in 6 N
HCl)} was found to be equal to the literature value reported by
23
NaBrO3 followed by HCl effected removal of the N-α-
methylbenzyl group and hydrolysis of the ester moiety to give
(2R,3S)-β-fluorophenylalanine 18, which was isolated as the
corresponding hydrochloride salt 18·HCl in 47% yield and >99:1
dr. Similar treatment of the N-benzyl substituted analogue 8 gave
18 directly in 53% isolated yield after treatment of 18·HCl with
propylene oxide24 (Scheme 3).
The spectroscopic data for 18 were in excellent agreement
with literature values.4f,25 However, the specific rotation for 18
was found to be highly solvent dependent, with a complete
Lin et al. claimed for ent-12 {lit.21 [α]D −8.0 (c 0.65 in 6 N
20
HCl)}, which was reported without evidence for their stereo-
B
DOI: 10.1021/acs.orglett.5b00880
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Scheme 3
Scheme 4
reversal in the specific rotation of 18 being observed upon
changing the solvent from H2O to MeOH {[α]D20 +14.4 (c 0.5 in
H2O); [α]D20 −13.3 (c 0.3 in MeOH)}. While this phenomenon
is interesting in its own right and has previously been observed in
related systems,26 the specific rotation recorded in MeOH was
found to be equal to the value for ent-18 reported by Davis et al.
Figure 4. X-ray crystal structures of (2R,3S,αR)-25 [left] and
(2R,3S,αR)-27 [right] (selected H atoms are omitted for clarity).
{lit.4f [α]D −14.5 (c 0.4 in MeOH)}. As our stereochemical
23
Crafts alkylation-type cyclization of either the N-α-methylbenzyl
or N-benzyl groups, respectively. For both 25 (X = 3-F) and 27
(X = 4-F), their relative configurations were established
unambiguously via single crystal X-ray diffraction analyses
(Figure 4).16 The absolute (2R,3S,αR)-configurations of 25
and 27 were assigned in each case by reference to the known (R)-
configuration of the α-methylbenzyl fragment. Furthermore, the
determination of Flack x parameters18 of 0.02(12) and
−0.01(10) for the structures of 25 and 27, respectively,
confirmed these assignments. The relative and absolute
configurations of 24, 26, and 28 were assigned by analogy to
those of 8, 25, and 27. Sequential treatment of 24, 25, and 27
with NaBrO3 and HCl gave the corresponding β-fluoro-α-amino
acids 29, 30, and 32 in good yield (57−72%) as single
diastereoisomers (>99:1 dr) in each case. For deprotection of
26 (X = 3-OMe), however, bromination at the C(6′)-position
was also observed upon treatment with NaBrO3 during the
N‑debenzylation step, giving 31 in 30% yield and >99:1 dr
(Scheme 4). Attempted deprotection of 28 (X = 4-OMe) led to
substantial decomposition, presumably due to the increased
lability of the β-fluoro moiety in this case.
assignment for 18 is completely secure, this literature value
appears to be incorrect; however, this discrepancy can easily be
accounted for, as the literature value was most likely recorded in
H2O, and not MeOH as originally reported,26,27 and the
stereochemical assignments of Davis et al.4f therefore remain
secure.
The substrate scope of this protocol was evaluated next upon
subjection of a range of known anti-α-hydroxy-β-amino esters
19−229 to XtalFluor-E and Et3N·3HF, which gave anti-β-fluoro-
α-amino esters 24−27 in 63−92% yield and >99:1 dr. In the case
of 23 (X = 4-OMe),9 however, an 80:20 mixture of 28 and the
corresponding 1,2,3,4-tetrahydroisoquinolines [33 + 34] was
observed in the crude reaction mixture, from which 28 was
isolated in 44% yield and >99:1 dr, and a 68:32 mixture of 33
(>99:1 dr) and 34 (>99:1 dr), respectively, was isolated in 8%
combined yield (Scheme 4). The relative 3,4-anti-configurations
within 33 and 34 were assigned from the diagnostic values of the
1H NMR 3J coupling constants observed between the C(3)H and
C(4)H protons (for 33 J3,4 = 3.7 Hz; for 34 J3,4 = 2.4 Hz).28
Presumably, 33 and 34 are formed as a result of ring-opening of
the aziridinium intermediate to give the corresponding benzylic
carbonium ion (which is assisted by the presence of the electron
donating p-methoxy group), followed by competitive Friedel−
3
3
In conclusion, a range of five enantiopure anti-β-fluorophenyl-
alanines have been prepared in three steps from the
corresponding α,β-unsaturated esters. Diastereoselective amino-
C
DOI: 10.1021/acs.orglett.5b00880
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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N‑deprotection and ester hydrolysis of these fluorinated
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and HCl to give the anti-β-fluorophenylalanines in good yield
and high diastereoisomeric purity. This is the most concise
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, copies of 1H and
13C NMR spectra, and crystallographic data (for structures
CCDC 1054001−1054006). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
Helv. Chim. Acta 2012, 95, 2265. (c) Pouliot, M.-F.; Mahe,
D.; Desroches, J.; Paquin, J.-F. Org. Lett. 2012, 14, 5428.
(15) Nonn, M.; Kiss, L.; Haukka, M.; Fustero, S.; Fulop, F. Org. Lett.
́
O.; Hamel, J.-
̈
̈
*E-mail: steve.davies@chem.ox.ac.uk.
Notes
2015, 17, 1074.
(16) Crystallographic data (excluding structure factors) for 6, 8, 10, 11,
25, and 27 have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers CCDC 1054001−
1054006, respectively.
(17) Bunnage, M. E.; Chernega, A. N.; Davies, S. G.; Goodwin, C. J. J.
Chem. Soc., Perkin Trans. 1 1994, 2373.
(18) (a) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876. (b) Flack,
H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143.
(19) A 76:24 mixture of 11 and 8, respectively, was observed in the 1H
NMR spectrum of the crude reaction mixture, from which only 11 was
isolated in 41% yield and >99:1 dr.
(20) The β-acetoxy substituted analogue 11 was not deprotected to the
corresponding β-hydroxy-α-amino acid, as the overall yield could not be
superior to our previous synthesis of this target compound from 7; see
ref 9.
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.5b00880
Org. Lett. XXXX, XXX, XXX−XXX