Synthesis of enantiomerically enriched (R)-13C-labelled 2-aminoisobutyric acid (Aib) by conformational memory in the alkylation of a derivative of L-alanine

Article abstract of DOI:10.3762/bjoc.7.152

The method of Kouklovsky and coworkers for the enantioselective alkylation of cyclic N-naphthoyl derivatives of amino acids was used to introduce a ¹³C label into one of the two enantiotopic methyl groups of 2-aminoisobutyric acid (Aib) by retentive alkylation of L-alanine with ¹³CH₃I. Conditions were identified for optimization of yield and enantiomeric purity, and the absolute configuration of the labelled product was established.

Full text of DOI:10.3762/bjoc.7.152

Synthesis of enantiomerically enriched
(R)-13C-labelled 2-aminoisobutyric acid (Aib) by
conformational memory in the alkylation
of a derivative of L-alanine
Stephen P. Fletcher, Jordi Solà, Dean Holt, Robert A. Brown
and Jonathan Clayden*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1304–1309.
School of Chemistry, University of Manchester, Oxford Rd.,
Manchester M13 9PL, UK
doi:10.3762/bjoc.7.152
Received: 21 June 2011
Email:
Accepted: 18 August 2011
Published: 20 September 2011
Jonathan Clayden* - clayden@man.ac.uk
* Corresponding author
Associate Editor: N. Sewald
Keywords:
© 2011 Fletcher et al; licensee Beilstein-Institut.
License and terms: see end of document.
amino acid; asymmetric synthesis; conformational memory; isotopic
label; isotopomer; quaternary stereogenic centre
Abstract
The method of Kouklovsky and coworkers for the enantioselective alkylation of cyclic N-naphthoyl derivatives of amino acids was
used to introduce a 13C label into one of the two enantiotopic methyl groups of 2-aminoisobutyric acid (Aib) by retentive alkyl-
ation of L-alanine with 13CH3I. Conditions were identified for optimization of yield and enantiomeric purity, and the absolute con-
figuration of the labelled product was established.
Introduction
In connection with our work on the control of conformation in We have previously made isotopically labelled anilines [6] for
helical foldamers [1-3] built from quaternary α-amino acids related studies on oligo-urea foldamers [7-9]. Achiral quater-
[4,5], we required a reliable source of 2-aminoisobutyric acid nary amino acids such as Aib and its substituted congeners
(Aib) 1 (Figure 1) bearing an isotopically labelled methyl are powerful promoters of 310 helix formation in peptides [10-
group in enantiomerically enriched form, i.e., (R)- or (S)-1* 13]. But since these helices lack the intrinsic bias towards a
or its derivatives. Specifically for our purposes, a high single screw-sense, which characterizes typical peptide
degree of enantiomeric enrichment was not necessary, since helices, they are ideal candidates for studying the potential of
we were aiming to make mixtures containing detectable conformational control in extended systems. Aib is furthermore
quantities of unequal pairs of diastereoisomeric derivatives. a common component of several fungal and bacterial
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Beilstein J. Org. Chem. 2011, 7, 1304–1309.
antibiotic metabolites [14], and the helix-forming properties of the synthesis and use of a 13CH3-labelled Aib probe made by
these metabolites, which encourage them to embed themselves Kouklovsky’s method [36], to gather evidence of helicity
into cell membranes, are at the origin of their biological switching in Aib oligomers. We now report in detail a practical
activity.
method for the enantioselective synthesis and enantiomeric
assignment of a derivative of (R)-1*.
Results and Discussion
L-Alanine hydrochloride 2 was converted to its sodium salt
either in situ with two equiv sodium hydride, or (preferably, and
more conveniently for storage in quantity) by treating with
sodium hydroxide and drying for several days under vacuum.
The latter method avoided the presence of yellow impurities in
the final amino acid. The alaninate salt was converted to its
Figure 1: 2-Aminoisobutyric acid (Aib).
The methods available for the asymmetric synthesis of quater- cyclic naphthamide derivative 3, following the method of
nary amino acids [15-20] fall principally into three classes. In Branca et al. [36], resulting in 57% yield and >99.5:0.5 e.r. on a
the first, exemplified by the method of Schöllkopf [21-24], a 2.5 g scale (Scheme 1). As 13C labelled MeOTf was unavail-
diastereoselective alkylation is used to relay the stereo- able, we decided to alkylate 3 with 13CH3I, despite the poorer
chemistry of an existing stereogenic centre to the new quater- results reported [36] with halide leaving groups. Optimal condi-
nary centre. In the second, exemplified by the asymmetric phase tions are shown in Scheme 1: The best enantiomeric ratios in
transfer reactions of Maruoka [25], the alkylation takes place the final products (see below) were obtained by adding 2 equiv
under the influence of a catalyst or other intermolecular influ- of a precooled THF solution of KHMDS (potassium hexam-
ence. In the third strategy, an amino acid is alkylated without ethyldisilazide) over 3 min to a THF solution of the naph-
recourse to an external controlling influence. Instead the stereo- thamide 3, allowing a further 4 min for complete deprotonation,
chemistry of the amino acid is first used to control a temporary and then quenching at –78 °C with an excess of 13CH3I. By this
stereogenic element (a centre or axis), which does not appear in method, (R)-6* was obtained in 93% yield on a 400 mg scale, as
the final product. Alkylation through a planar enolate then takes a 2.1:1 ratio of enantiomers.
place under the control of the temporary axis or centre in a
sequence where the final structure retains a “chiral memory” (in
fact a “configurational memory”) of the starting material. The
strategy was first developed, in the guise of the “self-regenera-
tion of stereocentres” by Seebach [26-29], but has more recently
been shown by Fuji and Kawabata [30-34], by Kouklovsky and
coworkers [35,36] and by others [21,37-39] to work effectively
when the temporary stereogenic element [40] is a C–N or C–C
axis, which retains its configuration at low temperature but
becomes conformationally unrestricted as the temperature rises
[41-45].
Our interest in the control and exploitation of conformation,
particularly in amides and related functional groups [4,5,46-51],
and its conceptual link with the wider aims of our work, led us
to explore the potential of this last strategy. In particular, we
made use of the method of Kouklovsky [36], which relies on a
temporary naphthamide Ar–CO axis as a chiral “aide-mémoire”
Scheme 1: Alkylation of L-alanine.
for translating the configuration of the starting amino acid into
the configuration of the product. We have previously employed
benzamide and naphthamide Ar–CO axes in “chiral memory” The products of related alkylations are reported [36] to arise
processes [52,53]. Kouklovsky reported the enantioselective from the diastereoselective alkylation of the conformationally
alkylation of alanine by this method [36], and recently Soai locked enolate 4 whose stereochemistry results from the selec-
showed that Seebach’s methods can be used to make selec- tive deprotonation of the less hindered conformer of 3. Alkyl-
tively deuterated Aib [54]. In a previous paper [55], we reported ated 5 was freed from its protecting group and the naphthamide
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Beilstein J. Org. Chem. 2011, 7, 1304–1309.
“aide-mémoire” by heating to reflux in 47% hydrobromic acid, As shown in Table 1, the d.r. of 7 (and hence the e.r. of the
followed by esterification with methanol and thionyl chloride, products 5 and 6*) was strongly dependent on the conditions of
which returned the labelled Aib as its methyl ester hydrochlo- the reaction and in particular on the time allowed between
ride salt 6* in 93% yield from 3. The 1H spectrum of 6* in deprotonation of 3 and the addition of 13CH3I. Presumably,
CD3OD consisted of a 3H CO2Me singlet at 3.85 ppm, plus two shorter reaction times minimise the extent of racemization of
coincident signals centred on 1.47 ppm: A 3H doublet (3JHC = the intermediate enolate 4 [36]. Addition of the base over a
4.3 Hz) for the unlabelled Me, and a 3H doublet (1JHC = period of three minutes was essential to avoid warming of the
130 Hz) for the labelled Me.
sample, and the delay before adding the electrophile could be
reduced to 4 min without a decrease in the yield. Isolated yields
The enantiomeric purity of the products was quantified by for- of 6 increased to >90% on a larger scale.
mation of pairs of diastereoisomeric dipeptides from small
aliquots of 6* with an excess of Cbz-L-Phe, EDC and HOBt
Table 1: Dependence of yield and e.r. on delay before alkylation.
(Scheme 2). The ratio of diastereoisomers was determined by
comparison of the peak heights of the two 13C signals by
13C NMR (Figure 2).
Time t (Scheme 2)/min
Isolated yield 6/%
d.r. of 7
8
8
5
4
70
80
80
78
1.2:1
1.4:1
1.8:1
2.1:1
Using the method of Woodard [56], we were able to confirm
that the alkylation of (S)-Ala by this method is mechanistically
retentive, producing (R)-6* as the major enantiomer. Dipeptide
7 was made, as a ca. 2.5:1 mixture of diastereoisomeric
isotopomers, on a preparative scale from enantiomerically
enriched 6*. The dipeptide was deprotected by hydrogenation
and cyclized by refluxing in methanol [56] to yield diketopiper-
azine 8. The major isotopomer displayed a 13C label in the more
downfield of the two diastereotopic methyl groups (Figure 3)
indicating that the more shielded methyl group, cis to the phe-
nyl ring, is the principally unlabelled one. Likewise, in the
1H NMR spectrum, the less shielded methyl signal exhibits a
1JHC coupling of greater magnitude than the 3JHC coupling,
Scheme 2: Determining enantiomeric purity and absolute configur-
ation of 6*.
Figure 2: Portion of 13C NMR spectrum of 7 showing 2.1:1 ratio of
Figure 3: Portion of 13C NMR spectrum of 8 showing location of
diastereoisomeric isotopomers.
13C label in the less shielded methyl group.
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Beilstein J. Org. Chem. 2011, 7, 1304–1309.
white solid. The enantiomeric ratio was >99:1 (Chiralpak
AD-H, hexane/ethanol: 95/5, 1.0 mL/min: tR (S) = 28.4 min,
tR (R) = 31.1 min. Spectroscopic data was consistent with that
reported in the literature, apart from the CHN proton, which
appears to be erroneously reported [36].
Rf: 0.40 (SiO2, EtOAc/Petrol 20:80); 1H NMR (500 MHz,
CDCl3) δ 0.99 (s, 3H), 2.05 (s, 3H), 2.10 (s, 3H), 4.16 (brs, 1H),
7.50 (m, 4H), 7.84 (brm, 1H), 7.90–7.96 (m, 2H) ppm;
13C NMR (125 MHz, CDCl3) δ 20.0 (CH3), 26.1 (CH3), 27.5
(CH3), 53.8 (CH), 98.4 (C), 124.2 (CH), 124.5 (CH), 124.9
(CH), 126.7 (CH), 127.8 (CH), 128.8 (CH), 130.4 (CH), 133.50
(C), 133.54 (C), 167.6 (CO), 171.4 (CO) ppm.
Figure 4: Portion of 1H NMR spectrum of 8 showing greater 1JHC
coupling in the less shielded methyl group.
(R)-13C-Aminoisobutyric acid methyl ester hydrochloride
salt [(R)-6*]: Following the method reported in the supporting
information of reference [55], potassium hexamethyl disilazide
indicating a greater proportion of 13C in the less shielded (11.7 mL, 0.5 M in toluene 5.88 mmol) in a flame dried pear-
methyl group, trans to the phenyl ring (Figure 4).
shaped flask was evaporated to dryness. THF (20 mL) was
added through a septum, and the suspension was agitated for
By this method we were able to obtain 13C-labelled, protected several minutes, then cooled to –78 °C. The cold mixture was
Aib (R)-6* for use in the synthesis, on gram scale, of spectro- then quickly added (syringe, 5 × 4 mL portions, over 3 min) to a
scopic probes for helicity [56].
stirred solution of 3 (793 mg, 2.80 mmol) at –78 °C in THF
(20 mL). After 4 min 13CH3I (0.87 mL, 13.99 mmol) was added
in one portion. The color changed from deep red to pale yellow.
Experimental
(S)-2,2-Dimethyl-4-methyl-3-(1-naphthoyl)-oxazolidin-5-one After a further 30 min, HCl (1 N, 10 mL) was added. The reac-
(3): By a modification of the method of Branca [36,57], sodium tion mixture was allowed to warm to room temperature, parti-
hydride (575 mg of a 60% dispersion in mineral oil, 12.4 mmol) tioned between water and ethyl acetate, and the organic phase
was suspended in 5 mL of dry THF. L-Alanine hydrochloride was concentrated. HBr (47% in water, 20 mL) was added and
(1.28 g, 10.2 mmol) in 5 mL of THF was slowly added and the the mixture was heated to reflux for 18 h, then cooled to room
mixture was stirred for 2 h. The THF was removed under temperature, diluted with water and washed twice with CH2Cl2
reduced pressure to yield the sodium salt.
and once with ether. The aqueous phase was evaporated to
dryness. Methanol (20 mL) and thionyl chloride (2 mL) were
Alternatively, L-alanine (8.9 g, 0.1 mol) was dissolved in 1 M added and the reaction mixture heated to reflux for 1 h. The
NaOH (100 mL), evaporated to dryness and dried for several reaction mixture was concentrated, and excess SOCl2 was
days in a vacuum oven. The sodium alaninate formed in this removed by adding toluene and concentrating to dryness, giving
way was highly hygroscopic, and a portion (1.6 g, 14.4 mmol) 6* (400 mg, 93%) as waxy crystals, mp 168–170 °C (dec.) [lit.
was transferred to the reaction flask under a stream of argon.
for unlabelled 6 182–183 °C (dec.) [58]; lit. for doubly labelled
6** 180–182 °C (dec.) [55]].
To the sodium alaninate salt, 40 mL of dry acetone and 11.0 g
of powdered molecular sieves were added. The mixture was 1H NMR (CD3OD, 400 MHz) δ 1.57 (d, 4JCH = 4.3 Hz 3H),
cooled to 0 °C, and trimethylaluminium (7.20 mL of a 2.0 M 1.57 (d, 1JCH = 130 Hz, 3 H), 3.85 (s, 3H); 13C NMR (CD3OH,
solution in toluene, 14.4 mmol) was added dropwise under 100 MHz) δ 24.2 (two superimposed singlets), 54.8 (d, J =
vigorous stirring. The mixture was allowed to reach room 9.0 Hz), 58.0 (d, J = 35.4 Hz), 174.1; IR νmax: 3365, 2919,
temperature and stirred overnight. The reaction mixture was 1743, 1506, 1318, 1175 cm–1; MS (ES+, MeOH): 141 ([M +
cooled to 0 °C and 1-naphthoyl chloride (2.16 mL, 14.4 mmol) Na]+, 60%), 119 ([M + H]+, 100%). HRMS (ES+, MeOH):
was added by syringe. The mixture was stirred for a further Calcd for C413C1H11N1O2 + H: 119.0902; found, 119.0865.
2.5 h, filtered through a pad of Celite®, washed with diethyl
ether and concentrated in vacuo. The crude product was puri- Coupling of 6* with Cbz-L-Phe to yield 7 (analytical scale):
fied by column chromatography (SiO2, EtOAc/Petrol 20:80) to Following the method described in the supporting information
yield 2.30 g (8.11 mmol, 57%) of the desired compound as of reference [55], an excess of Cbz-L-phenylalanine (40 mg,
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Beilstein J. Org. Chem. 2011, 7, 1304–1309.
0.13 mmol), HOBt (20 mg, 0.2 mmol), EDC (0.03 mL, 1H NMR (400 MHz, F3CCO2D) δ 0.70 (d, J = 4.0 Hz, 3Hmajor),
0.2 mmol) and Et3N (0.3 mL) were added to a suspension of 6* 0.70 (d, J = 132 Hz, 3Hminor), 1.41 (d, J = 4.0 Hz, 3Hminor),
(4 mg, 0.03 mmol) in CH2Cl2 (4 mL). The resulting solution 1.41 (d, J = 132 Hz, 3Hmajor), 3.10 (dd, J = 4.5, 14.4 Hz, 1H),
was stirred overnight at room temperature and partitioned 3.25 (dd, J = 4.8, 14.4 Hz, 1H), 4.67 (t, J = 4.6 Hz, 1H), 7.07 (d,
between water and ethyl acetate. The organic layer was washed J = 4.0 Hz, 2H), 7.15–7.26 (m, 3H); 13C NMR (100 MHz,
with water, NaHCO3 × 2, 1 N HCl × 2, and again with water, CDCl3) δ 28.2 (minor), 28.8 (major), 41.4, 58.6, 130.4, 131.2,
dried over MgSO4, and concentrated. All remaining organic 132.0, 135.0, 172.1, 176.6; IR νmax: 3180, 3035, 2994, 2974,
material was dissolved in CDCl3 and the d.r. of 7 was deter- 2960, 2931, 2897, 1660, 1605, 1453 cm–1; MS (ES+, MeOH):
mined by integration of the methyl signals (24.52 ppm and 256 ([M + Na]+, 100%); HRMS (ES+, MeOH): Calcd for
24.36 ppm) in the 13C NMR spectrum.
C1213C1H16N2O2 + Na+: 234.1319; found, 234.1311.
Coupling of 6* with Cbz-L-Phe to yield 7 (preparative Acknowledgements
scale): 6* (50 mg, 0.33 mmol) was suspended in DCM (5 mL), We are grateful to the Leverhulme Trust and to the EPSRC for
and to this was added Cbz-L-phenylalanine (106 mg, support of this work, and the Departament d'Innovació Univer-
0.35 mmol) and PyBOP (186 mg, 0.35 mmol). The mixture was sitats i Empresa de la Generalitat de Catalunya for a postdoc-
cooled to 0 °C. DIPEA (0.12 mL, 0.68 mmol) was added drop- toral fellowship (to JS).
wise and the resulting solution stirred overnight at room
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