Crystallization-based resolution of 1,4-benzodioxane-2-carboxylic acid enantiomers via diastereomeric 1-phenylethylamides

Article abstract of DOI:10.1016/j.tetlet.2016.03.100

Unlike the diastereomeric 1-phenylethylammonium salts, the diastereomeric N-1-phenylethylamides of (S)- and (R)-1,4-benzodioxane-2-carboxylic acid show significant differences in fusibility and solubility so as to be efficiently resolved by precipitation of the less soluble diastereomer (>98% de), while chromatographic purification of the unprecipitated fraction affords the more soluble one (>99% de). Overall, 95% of the former and 80% of the latter are recovered. The hydrolysis of the two resolved amides provides the two acid enantiomers and the resolving amine in quantitative yield and with unchanged stereoisomeric purity.

Full text of DOI:10.1016/j.tetlet.2016.03.100

Tetrahedron Letters 57 (2016) 2009–2011
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Crystallization-based resolution of 1,4-benzodioxane-2-carboxylic
acid enantiomers via diastereomeric 1-phenylethylamides
⇑
Laura Fumagalli, Cristiano Bolchi, Francesco Bavo, Marco Pallavicini
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, I-20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Unlike the diastereomeric 1-phenylethylammonium salts, the diastereomeric N-1-phenylethylamides of
(S)- and (R)-1,4-benzodioxane-2-carboxylic acid show significant differences in fusibility and solubility
so as to be efficiently resolved by precipitation of the less soluble diastereomer (>98% de), while chro-
matographic purification of the unprecipitated fraction affords the more soluble one (>99% de). Overall,
95% of the former and 80% of the latter are recovered. The hydrolysis of the two resolved amides provides
the two acid enantiomers and the resolving amine in quantitative yield and with unchanged stereoiso-
meric purity.
Received 9 February 2016
Revised 25 March 2016
Accepted 29 March 2016
Available online 30 March 2016
Keywords:
1-Phenylethylamine
1,4-Benzodioxane-2-carboxylic acid
Covalent diastereomers
Resolution
Ó 2016 Elsevier Ltd. All rights reserved.
1,4-Benzodioxanes functionalized at C(2) with a suitably substi-
tuted carbon are important chiral building blocks because of the
presence of the 2-benzodioxanyl residue in a number of biologi-
cally active compounds, the potency of which often greatly varies
dependently on the absolute configuration of the stereogenic
C(2). That’s what we have observed in many unichiral benzodiox-
ane-based compounds endowed with different pharmacological
activities such as subtype selective adrenergic antagonists,1 FtsZ
inhibitors,2 neuronal nicotinic agonists3 and FTase inhibitors.4
Historically, 1,4-benzodioxane-2-carboxylic acid (1) is one of the
most readily available and synthetically versatile 2-substituted
1,4-benzodioxanes. Both the enantiomers of 1 can be synthesized
from unichiral 1,2-cyclic ketals or 1-ethers of glycerol,5 accessible
from ‘chiral pool’,5 from racemic solketal6 or from prochiral
1,3-dihydroxyacetone monoethers.7 On the other hand, rac-1 can
be very easily synthesized by condensation of catechol with ethyl
2-dibromoproprionate8 and successive saponification and then it
can be resolved with (+)-dehydroabietylamine9 or with p-methyl
or p-nitro substituted 1-phenylethylamine enantiomers10 or
directly by entrainment after conversion into methyl ester.11
Our studies on a series of pairs of diastereomeric salts of (R)-1
and (S)-1 with the S enantiomer of 1-phenylethylamine (2) and
of differently p-substituted 1-phenylethylamines have shown that
the capability of resolving rac-1 is not shared by all the
phenylethylamines: only the diastereomeric p-nitro- and
p-methylphenylethylammonium benzodioxanecarboxylates have
significantly different solubilities in alcoholic solvents and thus
can be efficiently resolved, while (S)-2, and its p-halo and p-meth-
oxy analogues are ineffective as resolving agents.12 Crystallo-
graphic analyses have pointed out remarkable differences in solid
state structure between the diastereomers having different solubil-
ity, namely those of the two resolvable salts of 1 with p-nitro- and
p-methylphenylethylamine.12 However, the diastereo-discrimina-
tion conferred to 2 by the para-substitution remains unpredictable
and such a difficulty may be due to the ionic nature of the diastere-
omers and to the role played by the solvent. Differentiated interac-
tions, such as for instance hydrogen bonds or
p and hydrophobic
interactions, between the cationic enantiomer of the resolving
agent and the two anionic enantiomers of the racemate are deter-
minants for different crystal structures of the two diastereomeric
salts, but the same interactions can be negligible when these ions
are surrounded by solvent molecules in solution. Different is the
case of covalent diastereomers, much less exemplified than
diastereomeric salts in the literature:13 the resolving agent is cova-
lently attached to the two enantiomers and exerts a stricter dia-
stereo-discrimination also in solution, where non-labile
differences in conformation and in solubility can thus occur
between the two diastereomers. It is notable that variation of the
molar ratio solvent/covalent diastereomers is reported not to
greatly affect the resolution efficiency unlike what happens with
diastereomeric salts.14
⇑
Corresponding author. Tel.: +39 2 50319336; fax: +39 2 50319359.
E-mail address: marco.pallavicini@unimi.it (M. Pallavicini).
http://dx.doi.org/10.1016/j.tetlet.2016.03.100
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

2010
L. Fumagalli et al. / Tetrahedron Letters 57 (2016) 2009–2011
The information provided by the binary phase diagram is very
useful, but the composition of the eutectic of this diagram is not
always independent of the nature of the crystallization solvent
and it has to be compared with solubility measurements. These
indicated that (R,R)-3, the lower melting diastereomer, has a
17.2 g/100 mL solubility in toluene at 25 °C, while (R,S)-3, the
higher melting diastereomer, has a 5.2 g/100 mL solubility under
the same conditions. Such a considerable solubility difference
prospected a maximum 0.70 resolution efficiency,22 a value close
O
O
CONH
*
H2N
Me
Me
*
O
O
COOX
*
*
1 X=H 1a X=Me
2
3
We therefore reasoned that (S)-2, though unable to resolve rac-
1 when used as a salifying agent,12 could generate diastereomers
separable by crystallization if covalently attached to rac-1. The lar-
ger availability of the enantiomers of 2, compared to that of its
para-substituted analogues, prompted us to this approach as well
as some significant successful examples reported in the litera-
ture.13,15–18
Covalent attachment was realized through an amide bond. An
equimolar mixture of the two diastereomeric amides between
(R)-2 and (R)- and (S)-1, namely (R,R)-3 and (S,R)-3, was near quan-
titatively obtained by reaction of rac-1a,9 the methyl ester of rac-1,
with an excess of (R)-2 in THF in the presence of a little more than
stoichiometric amount of magnesium chloride.19 Removal of the
excess of (R)-2, then quantitatively recovered, allowed the mixture
of (R,R)-3 and (S,R)-3 to be isolated by simple concentration and
treatment with diisopropyl ether as a white solid.
Alongside this, we analogously prepared two samples of (R,R)-3
and (S,R)-3 from the methyl esters (R)-1a9 and (S)-1a9, respec-
tively, in order to determine the physical properties of the two
diastereomeric amides and to investigate the solid phase beha-
viour of their mixtures. We found that the melting temperature
of (S,R)-3 (102.7 °C) largely exceeded that of (R,R)-3 (75.0 °C), while
DSC analysis of a series of differently proportioned (R,R)-3/(S,R)-3
mixtures revealed that the two diastereomeric amides produce a
simple eutectic. The resultant experimental binary melting-point
phase diagram, depicted in Figure 1, is typical of a conglomerate.
As can be seen in the same figure, the experimental values
acceptably fit within the theoretical ones (solid curve) calculated
on the basis of the melting points of (S,R)-3 and (R,R)-3 and of
the respective enthalpies (27.68 and 24.88 kJ molꢀ1) using the
Schröder-van Laar equation, although some difference can be
observed between the eutectic composition indicated by the inter-
to 0.75 indicated by the experimental 0.20 veu
.
The whole resolution procedure is shown in Scheme 1.
Crystallization of 5 g of equimolar mixture of (R,R)-3 and (S,R)-3
from a toluene volume (14.5 mL) sufficient to keep 2.5 g of (R,R)-3
dissolved at 25 °C gave results in line with the foreseen 0.70–0.75
resolution efficiency: a precipitate of (S,R)-3 was isolated in 70.4%
yield (1.76 g) and with >98% diastereomeric excess.23 Moreover,
the mother liquors were concentrated and chromatographed on
silica gel to yield 2.0 g of (R,R)-3 and additional 0.61 g of (R,S)-3,
both with >99% de. Overall, at the end of the procedure, 94.8% of
(S,R)-3 and 80% of (R,R)-3 were, respectively, recovered.23
Successive hydrolyses, accomplished in dioxane and 6 N HCl,
provided (S)-1 and (R)-1 in quantitative yield and with no less
enantiomeric excess than the diastereomeric excess of the respec-
tive parent amides, as demonstrated by chiral HPLC analysis
according to a previously reported method. Also the recovery of
(R)-2 was near quantitative.24
We have recently reported that mandelic acid efficiently
resolves 2-aminomethyl-1,4-benzodioxane (5)25 and we have suc-
cessively demonstrated that (S)-5 and (R)-5 are valuable interme-
diates which give access, among others, to the enantiomers of
1,4-benzodioxane-2-carboxamide (4).26 Indeed, the conversion of
(R,R)-3 and (S,R)-3 into the enantiomers of 4 and subsequently of
5 has poor atom economy and implies deletion of the valuable chi-
ral auxiliary (Scheme 2). Nevertheless, we wished to verify on
(S,R)-3 whether this route is practicable in terms of yield and of
stereoisomeric purity preservation. In order to remove ethylben-
zene and to obtain (S)-4, the resolved diastereomer (S,R)-3 was ini-
tially submitted to hydrogenolysis under different conditions but
section of the two branches of the theoretical curve (0.32 veu of the
rac-1a + (R)-2
higher melting diastereomer (S,R)-3) and the composition of the
mixture exhibiting the lowest experimental melting point
(0.20 veu of (S,R)-3). The latter veu value prospects, under the best
crystallization conditions, a maximum 0.75 resolution efficiency
(S),20 that is the precipitation of 75% of (R,S)-3 diastereomerically
O
O
O
O
O
O
NH
NH
+
Me
Me
pure, whereas the former
veu value (0.32) a modest 0.53 resolution
efficiency.21
(R,R)-3
(S,R)-3
crystallization
(S,R)-3
chromatography
150
140
130
120
110
100
90
(R,R)-3
(S)-1 + (R)-2
(R)-1 + (R)-2
Scheme 1. Resolution of 1 via diastereomeric phenethylamides.
80
O
O
NH2
70
O
O
O
O
60
NH
NH2
50
Me
O
O
0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0
(R)-5
molar ratio of (R,R)-3
(S,R)-3
(S)-4
Figure 1. Binary melting-point phase diagram for the diastereomeric system (R,R)-
3/(S,R)-3. The solid curve represents the values calculated on the basis of the
Schröder-van Laar equation.
Scheme 2. Unichiral 1,4-benzodioxane-2-carboxamide and 2-aminomethyl-1,4-
benzodioxane from the resolved phenethylamide of 1,4-benzodioxane-2-carboxylic
acid.

L. Fumagalli et al. / Tetrahedron Letters 57 (2016) 2009–2011
2011
overnight at room temperature and then concentrated. The residue was
treated with dichloromethane (50 mL) and 10% HCl (25 mL). The organic phase
was separated and washed with 10% HCl (25 mL) again. The aqueous phases
were combined, made alkaline, and extracted with ethyl acetate (2 ꢁ 40 mL) to
recover the excess of (R)-2. Evaporation of ethyl acetate gave 1.79 of (R)-2,
while the concentration of the dichloromethane solution yielded a residue
which became a white solid upon stirring in diisopropyl ether (5.5 mL). Such a
solid (1.39 g, 95.2%) was isolated by filtration. Its HPLC analysis showed the
presence of two peaks of equal area corresponding to (S,R)-3 and (R,R)-3 (see
with no success. The conversion was instead accomplished by
treatment of (S,R)-3 with p-toluenesulfonic acid in refluxing
toluene;27 (S)-4 was isolated in a very good 80% yield and with
98.4% enantiomeric excess.28 The successive reduction of (S)-4
with LiAlH4 in THF afforded (R)-5 in an excellent 90% yield and
with 97.5% enantiomeric excess.29
In summary, we have developed an alternative method for the
resolution of 1,4-benzodioxane-2-carboxylic acid through the
preparation and facile separation of the corresponding diastere-
omeric mixture of amides with (R)-1-phenylethylamine. It should
be emphasized that one enantiomer of the resolving 1-phenylethy-
lamine afforded both the enantiomers of 1,4-benzodioxane-2-car-
boxylic acid and was able, covalently linked to the racemic
substrate, to produce that significant diastereo-discrimination
which had failed to effect when used as a salifying agent. Though
less advantageously, the two diastereomeric amides also allow to
access to the enantiomers of 1,4-benzodioxane-2-carboxamide
and 2-aminomethyl-1,4-benzodioxane.
conditions and tR reported in note 23 for the two separated diastereomers). 1
H
NMR spectrum consisted of the signals of the two diastereomeric amides given
below (cf. with the spectra reported in note 23).
20. Calculated from S = (1 ꢀ 2
v
eu)/(1 ꢀ
v
eu) = (1 ꢀ 2ꢂ0.20)/(1 ꢀ 0.20) = 0.75.
21. Calculated from S = (1 ꢀ 2
v
eu)/(1 ꢀ
veu) = (1 – 2ꢂ0.32)/(1 ꢀ 0.32) = 0.53.
22. Calculated from S = (17.2 ꢀ 5.2)/17.2 = 0.70.
23. An equimolar mixture of (S,R)-3 and (R,R)-3 (5 g, 17.65 mmol) obtained from
rac-1a and (R)-2 was dissolved in boiling toluene (14.5 mL). After stirring at
room temperature overnight, a white precipitate was recovered by filtration
and
dried
to
give
(2S,10R)-N-(10-phenylethyl)-1,4-benzodioxane-2-
carboxamide [(S,R)-3] (1.76 g, 70.4%) as a white solid: mp 102.7 °C; 98.02%
de (by HPLC on a RP-18 LichrospherÒ-100 column; water/acetonitrile 50/50;
0.5 mL/min; k = 276 nm; tR 18.5 min); 1H NMR (300 MHz, CDCl3) d ppm 7.31–
7.15 (m, 5H), 6.98–6.91 (m, 4H), 6.89 (d, 1H, J = 6.9 Hz) 5.18 (quintet, 1H,
J = 6.9 Hz), 4.71 (dd, 1H, J = 7.2, 2.8 Hz), 4.52 (dd, 1H, J = 11.3, 2.8 Hz), 4.15 (dd,
1H, J = 11.3, 7.2 Hz), 1.55 (d, 3H, J = 6.9 Hz). The mother liquor was
concentrated and the residue was chromatographed on silica gel
(cyclohexane/ethylacetate; 80/20) to yield (2R,10R)-N-(10-phenylethyl)-1,4-
References and notes
benzodioxane-2-carboxamide [(R,R)-3] (2.0 g, 80%) as
a white solid: mp
1. (a) Villa, L.; Valoti, E.; Villa, A. M.; Pallavicini, M.; Ferri, V.; Iuliano, E.; Brunello,
N. Farmaco 1994, 49, 587–606; (b) Fumagalli, L.; Bolchi, C.; Colleoni, S.; Gobbi,
M.; Moroni, B.; Pallavicini, M.; Pedretti, A.; Villa, L.; Vistoli, G.; Valoti, E. Bioorg.
Med. Chem. 2005, 13, 2547–2559; (c) Pallavicini, M.; Budriesi, R.; Fumagalli, L.;
Ioan, P.; Chiarini, A.; Bolchi, C.; Ugenti, M. P.; Colleoni, S.; Gobbi, M.; Valoti, E. J.
Med. Chem. 2006, 49, 7140–7149.
2. Chiodini, G.; Pallavicini, M.; Zanotto, C.; Bissa, M.; Radaelli, A.; Straniero, V.;
Bolchi, C.; Fumagalli, L.; Ruggeri, P.; De Giuli Morghen, C.; Valoti, E. Eur. J. Med.
Chem. 2015, 89, 252–265.
3. (a) Pallavicini, M.; Moroni, B.; Bolchi, C.; Cilia, A.; Clementi, F.; Fumagalli, L.;
Gotti, C.; Meneghetti, F.; Riganti, L.; Vistoli, G.; Valoti, E. Bioorg. Med. Chem. Lett.
2006, 16, 5610–5615; (b) Bolchi, C.; Gotti, C.; Binda, M.; Fumagalli, L.; Pucci, L.;
Pistillo, F.; Vistoli, G.; Valoti, E.; Pallavicini, M. J. Med. Chem. 2011, 54, 7588–
7601; (c) Bolchi, C.; Valoti, E.; Gotti, C.; Fasoli, F.; Ruggeri, P.; Fumagalli, L.;
Binda, M.; Mucchietto, V.; Sciaccaluga, M.; Budriesi, R.; Fucile, S.; Pallavicini, M.
J. Med. Chem. 2015, 58, 6665–6677.
4. Bolchi, M.; Pallavicini, M.; Fumagalli, L.; Ferri, N.; Corsini, A.; Rusconi, C.; Valoti,
E. Bioorg. Med. Chem. Lett. 2009, 19, 5500–5504.
5. Rouf, A.; Aga, M. A.; Kumar, B.; Taneja, S. C. Tetrahedron Lett. 2013, 54,
6420–6422.
6. Bolchi, C.; Catalano, P.; Fumagalli, L.; Gobbi, M.; Pallavicini, M.; Pedretti, A.;
Villa, L.; Vistoli, G.; Valoti, E. Bioorg. Med. Chem. 2004, 12, 4937–4951.
7. Cesarotti, E.; Antognazza, P.; Pallavicini, M.; Villa, L. Helv. Chim. Acta 1993, 76,
2344–2349.
8. Koo, J.; Avakian, S.; Martin, G. J. J. Am. Chem. Soc. 1955, 77, 5373–5375.
9. Bolchi, C.; Fumagalli, L.; Moroni, B.; Pallavicini, M.; Valoti, E. Tetrahedron:
Asymmetry 2003, 14, 3779–3785.
10. Bolchi, C.; Pallavicini, M.; Fumagalli, L.; Marchini, N.; Moroni, B.; Rusconi, C.;
Valoti, E. Tetrahedron: Asymmetry 2005, 16, 1639–1643.
11. Bolchi, C.; Pallavicini, M.; Fumagalli, L.; Rusconi, C.; Binda, M.; Valoti, E.
Tetrahedron: Asymmetry 2007, 18, 1038–1041.
12. Marchini, N.; Bombieri, G.; Artali, R.; Bolchi, C.; Pallavicini, M.; Valoti, E.
Tetrahedron: Asymmetry 2005, 16, 2099–2106.
13. Siedlecka, R. Tetrahedron 2013, 69, 6331–6363.
14. Sakai, K.; Hashimoto, Y.; Kinbara, K.; Saigo, K.; Murakami, H.; Nohira, H. Bull.
Chem. Soc. Jpn. 1993, 66, 3414–3418.
15. Jourdain, F.; Hirokawa, T.; Kogane, T. Tetrahedron Lett. 1999, 40, 2509–2512.
16. Juaristi, E.; Escalante, J.; León_Romo, J. L.; Reyes, A. Tetrahedron: Asymmetry
1998, 9, 715–740.
17. Kato, Y.; Kitamoto, Y.; Morohashi, N.; Kuruma, Y.; Oi, S.; Sakai, K.; Hattori, T.
Tetrahedron Lett. 2009, 50, 1998–2002.
18. Pallavicini, M.; Valoti, E.; Villa, L.; Resta, I. Tetrahedron: Asymmetry 1994, 5,
363–370.
75.0 °C; 99.2% de (by HPLC on a RP-18 LichrospherÒ-100 column; water/
acetonitrile 50/50; 0.5 mL/min; k = 276 nm; tR 20.0 min); 1H NMR (300 MHz,
CDCl3) d ppm 7.41–7.25 (m, 5H), 6.98–6.90 (m, 4H), 6.85 (d, 1H, J = 6.9 Hz) 5.18
(quintet, 1H, J = 6.9 Hz), 4.61 (dd, 1H, J = 7.2, 2.8 Hz), 4.57 (dd, 1H, J = 11.3,
2.8 Hz), 4.19 (dd, 1H, J = 11.3, 7.2 Hz), 1.49 (d, 3H, J = 6.9 Hz). The
chromatography of the residue resultant from the mother liquor afforded
also additional 0.61 g of (S,R)-3, whose total recovery thus raised to 2.37 g
(94.8%).
24. (2S,10R)-N-(10-Phenylethyl)-1,4-benzodioxane-2-carboxamide [(S,R)-3] (1 g,
3.53 mmol) was suspended in 6 N HCl (100 mL) and dioxane 10 mL. The
suspension was heated at 90 °C overnight and, after cooling, ethyl acetate was
added (50 mL). The aqueous phase was separated, made alkaline, and treated
with ethyl acetate to extract (R)-2, which was near quantitatively recovered
(400 mg) by evaporation of ethyl acetate. On the other hand, the organic layer
resulting from the addition of ethyl acetate to the reaction mixture was
separated and extracted with 10% NaHCO3. The alkaline aqueous extract was
washed with ethyl acetate, acidified and extracted with ethyl acetate. The ethyl
acetate extract was dried and concentrated under vacuum to give (S)-1,4-
benzodioxane-2-carboxylic acid [(S)-1] (636 mg, ꢃ100%) as a white solid: mp
25
97.3 °C; [
a
]
D
ꢀ61.7 (c 1, CHCl3); 98.5% ee (determined as reported in Ref. 9);
1H NMR identical to that previously reported.9 (2R,10R)-N-(10-Phenylethyl)-1,4-
benzodioxane-2-carboxamide [(R,R)-3] (1 g, 3.53 mmol) was hydrolysed by the
same procedure to give (R)-2 and (R)-1,4-benzodioxane-2-carboxylic acid [(R)-
25
1] in quantitative yield. (R)-1: mp 97.5 °C; [
a
]
D
+62.0 (c 1, CHCl3); 99.0% ee
(determined as reported in Ref. 9); 1H NMR identical to that previously
reported.9
25. Bolchi, C.; Pallavicini, M.; Fumagalli, L.; Ruggeri, P.; Valoti, E. Tetrahedron:
Asymmetry 2013, 24, 796–800.
26. Bolchi, C.; Valoti, E.; Straniero, V.; Ruggeri, P.; Pallavicini, M. J. Org. Chem. 2014,
79, 6732–6737.
27. Chern, C. Y.; Huang, Y. P.; Kan, W. M. Tetrahedron Lett. 2003, 44, 1039–1041.
28. A mixture of (S,R)-3 (800 mg, 2.82 mmol) and p-toluenesulfonic acid (2.15 g,
11.28 mmol) in toluene (10 mL) was refluxed for 2 h. After cooling to room
temperature, dichloromethane (20 mL) and 10% NaHCO3 (20 mL) were added.
The aqueous phase was removed and the organic phase was washed with
water (10 mL), dried and concentrated to give (S)-1,4-benzodioxane-2-
carboxamide [(S)-4] (404 mg, 80.0%) as a white solid: mp 139.2 °C; [
25
a]
D
ꢀ103.7 (c 1, MeOH); 98.4% ee (determined as reported in Ref. 26).
29. A solution of (S)-4 (200 mg, 1.12 mmol) in THF (8 mL) was added dropwise to a
suspension of LiAlH4 (127.5 mg, 3.36 mmol) in THF (2 mL) cooled at 0 °C. The
mixture was refluxed for 2 h and then quenched with water and diluted with
dichloromethane. The organic phase was separated, washed with brine, dried
and concentrated to give (R)-2-aminomethyl-1,4-benzodioxane [(R)-5]
19. Magnesium chloride (534.2 mg, 5.61 mmol) was added to a solution of rac-1a
(1 g, 5.15 mmol) in THF (10 mL). After stirring at room temperature for 1 h, (R)-
25
(167 mg; 90.0%) as
a
colourless oil:
[
a
]
+56.8 (c 1 CHCl3), 97.5% ee
D
determined as reported in Ref. 25).
2
(2.66 mL, 20.6 mmol) was added dropwise. The mixture was stirred