Dynamic resolution of lithiated ortho-trifluoromethyl styrene oxide and the effect of chiral diamines on the barrier to enantiomerisation

Article abstract of DOI:10.1039/c3cc40988k

The first dynamic thermodynamic resolution of a racemic oxiranyllithium is described with selectivities of up to 82:18 from a selection of three types of chiral ligands (seven ligands in total). Both (-)-sparteine and its (+)-surrogate were surprisingly found to increase the enantiomerisation barrier. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc40988k

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Dynamic resolution of lithiated ortho-trifluoromethyl
styrene oxide and the effect of chiral diamines on the
barrier to enantiomerisation†‡
Cite this: Chem. Commun., 2013,
49, 4911
Received 5th February 2013,
Accepted 28th February 2013
Rosmara Mansueto, Filippo Maria Perna, Antonio Salomone, Saverio Florio and
Vito Capriati*
DOI: 10.1039/c3cc40988k
www.rsc.org/chemcomm
The first dynamic thermodynamic resolution of a racemic oxiranyl- it is first required that the oxiranyllithium be configurationally labile,
lithium is described with selectivities of up to 82 : 18 from a as the asymmetric substitution in the presence of a chiral ligand may
selection of three types of chiral ligands (seven ligands in total). benefit from its enantiomerisation. Second, ‘‘chemical stability’’ is
Both (ꢀ)-sparteine and its (+)-surrogate were surprisingly found to also a factor to be taken into consideration, because oxiranyllithiums
increase the enantiomerisation barrier.
(which are in all respects lithium carbenoids)8 may either undergo a
faster decomposition as the temperature progresses or exhibit
Chiral functionalised organolithiums with a stereogenic lithiated electrophilic behaviour according to the conditions employed.
carbon centre are of growing importance in the daily repertoire of As for a-lithiated aryl-substituted epoxides, our research group
synthetic organic chemistry because of their potential utility in recently reported that, whereas electron-donating groups do not alter
enantioselective chemical synthesis.1 Asymmetric substitution repre- the configurational stability in THF and at low temperatures, electron-
sents an effective alternative to asymmetric deprotonation2 for the withdrawing groups trigger racemisation in THF at a rate which is
preparation of enantiomerically enriched products. It relies upon a dependent on their position on the phenyl ring.9 Such a rate proved to
chiral racemic organolithium which is, however, required to undergo be sensitive to both the presence of additives and the nature of the
equilibration in the presence of a chiral ligand in order that a solvent. In particular, higher inversion barriers (that is, slower inter-
dynamic resolution can take place. For a dynamic thermodynamic conversion rates) were detected when TMEDA was used as the ligand
resolution (DTR), the rate of inter-conversion of the diastereomeric jointly with an apolar solvent such as hexane, which is particularly
organolithium complexes is low compared to that of the subsequent promising for a dynamic resolution under thermodynamic control.
electrophilic substitution; thus, the enantiomeric ratio (er) of the
Among the various fluorinated derivatives, a-lithiated ortho-
product is determined by the ratio of the above complexes. In trifluoromethyl styrene oxide 1-Li (Scheme 1) undergoes the fastest
contrast, in the case of a dynamic kinetic resolution, the rate of racemisation in THF, the half-life being 1.6 s at 157 K, corresponding
inter-conversion is fast, relatively to the rate of substitution and the to an inversion barrier DGaenant of 9.5 ꢁ 0.1 kcal molꢀ1 (entry 1,
organolithium may be resolved by means of the faster reaction of Table 2).9a We have now ascertained that the two a-lithiated enantio-
one of the two diastereomeric complexes, which is under Curtin– mers, (R)-1-Li and (S)-1-Li, undergo inter-conversion also in an apolar
Hammett conditions.3
solvent, and the rate proved to be sensitive to the presence of ligands.
Enantiomerically enriched epoxides are important building Indeed, running the deprotonation of a 0.2 M solution of
blocks in the production of fine chemicals and pharmaceutical
targets. Nowadays, they are usually efficiently prepared by catalytic
epoxidation4 or by a kinetic resolution promoted by chiral (salen)–Cr
and (salen)–Co(III) complexes,5 as well as by hydrolytic enzymes.6 In
light of this, we wondered whether the dynamic resolution of a
racemic lithiated oxirane7 could also be exploited for the preparation
of enantiomerically enriched derivatives. To accomplish this goal,
`
Dipartimento di Farmacia – Scienze del Farmaco, Universita di Bari ‘‘Aldo Moro’’,
Consorzio C.I.N.M.P.I.S., via E. Orabona 4, I-70125 Bari, Italy.
E-mail: vito.capriati@uniba.it; Fax: +39 080 5442539; Tel: +39 080 5442174
† Dedicated to Professor Francesco Naso on the occasion of his 75th birthday.
‡ Electronic supplementary information (ESI) available: Experimental procedures,
spectroscopic data and copies of 1H/13C NMR spectra of compounds 2b–d, and
Eyring plots. See DOI: 10.1039/c3cc40988k
Scheme 1
c
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enantiomerically enriched (R)-1 (95 : 5 er) (Scheme 1) with s-BuLi or at longer reaction times of up to 1 h; thus, it reflects the relative
(1.5 equiv.)–TMEDA (1 equiv.) in hexane, [D]-1 could be recovered population of the two diastereomeric organolithiums once the
with 76 : 24 er (in favour of the R enantiomer) upon quenching the equilibrium has been reached. In contrast, completely racemic
reaction mixture with MeOD, 3 min being the reaction time at 195 K. [D]-1 was recovered upon deprotonating a mixture of rac-1
The barrier to enantiomerisation of 1-Li was then calculated (1 equiv.) and (ꢀ)-sparteine (1.2 equiv.) with s-BuLi (1.2 equiv.) at
upon quenching with a deuterium source and upon aging the ꢀ78 1C in THF, with a 15 min reaction time (entry 4, Table 1). This
enantioenriched 1-Li for different times at 195 K. The obtained result may be explained in terms of a competition of (ꢀ)-sparteine
first-order plot indicated an estimated racemisation half-life (t1/2) of with bulk THF for coordination sites on lithium.10
115 s, which equates to an enantiomerisation barrier (DGaenant) of
To test for DTR, the two organolithium (ꢀ)-sparteine com-
13.5 ꢁ 0.1 kcal molꢀ1 at 195 K (entry 2, Table 2) (see the ESI‡). In the plexes were kept for 30 min at ꢀ78 1C in hexane before being
perspective of a dynamic resolution, racemic epoxide 1 was thus quenched, in a first run, with 5 equiv. MeI, and, in a second run
chosen as a model substrate.
(with pentane as the solvent), with 10 mol% MeI, the enantio-
We began our study testing (ꢀ)-sparteine as the chiral ligand meric ratios of the corresponding a-methylated adduct 2a being
(ligand 3, Scheme 1) to see whether there was a preference to 76 : 24 (R : S) (70% yield) and 52 : 48 (10% yield), respectively
complex to one enantiomer of the inter-converting organolithiums. (entries 5 and 6, Table 1). A difference in the er of the product
A preformed mixture of rac-1 (1 equiv.) and (ꢀ)-sparteine (1.2 equiv.) resulted in a changed stoichiometry of the electrophile, which
in pentane was preliminarily cooled to ꢀ120 1C, then treated with provides evidence for a dynamic resolution under thermodynamic
s-BuLi (1.2 equiv.), followed by quenching after 2 min with MeOD. control. In particular, the racemic mixture detected for 2a when
This procedure afforded a 50 : 50 mixture of (S)- and (R)-[D]-1 (86% D) using MeI in sub-stoichiometric amounts is consistent with the
(entry 1, Table 1) (Scheme 1). Once the reaction time was extended to thermodynamically less populated (less stable) diastereomeric
30 min, a-deuterated (R)-[D]-1 was formed with an er of 75 : 25 complex to react faster than the other. In cases like this,
(84% D) (entry 2, Table 1). These results intimate that the equili- re-equilibration to further successive warm–cool cycles is known
bration between the two organolithium (ꢀ)-sparteine complexes is to be detrimental to the final er. Evaluation of the use of different
prevented at least at short reaction times (2 min), but it occurs slowly solvents (Et2O and toluene) resulted in lower er in the (R)-2a (range
at longer reaction times even at a temperature as low as ꢀ120 1C.
60–63 : 40–37, 70–72% D). A variety of chiral ligands were also
Running the deprotonation of rac-1 at ꢀ78 1C in hexane (that screened at ꢀ78 1C in hexane using deuterium as the electrophile.
is the upper limit value before decomposition of 1-Li starts off) for As for chiral diamines 4–7, the readily accessible (+)-sparteine
a reaction time of 30 min, the detected er was again 75 : 25 upon surrogate (O’Brien’s diamine) (ligand 4, Scheme 1)11 gave enantio-
quenching with MeOD (entry 3, Table 1). This ratio could not be enriched (S)-[D]-1 (er 25 : 75) (90% D) with the opposite absolute
improved, either by allowing the two diastereomeric complexes stereochemistry (entry 7, Table 1), whereas ligands 5–712 (Scheme 1)
first to equilibrate for 30 min at ꢀ78 1C before cooling to ꢀ90 1C furnished [D]-1 essentially as a racemic mixture (entries 8–10,
Table 1). A 50 : 50 mixture of the two enantiomers of [D]-1 was
detected, as well, using different types of ligands such as amino
Table 1 Enantiomeric ratio of [D]-1 and 2a–d by DTR using ligands 3–9
alcohol 8 and diamino alcohol 93c (Scheme 1) at ꢀ78 1C,
Time
[D]-1a Productb erc
regardless of the solvent system employed (toluene, hexane,
Et2O, and THF) (entries 11 and 12, Table 1).
Entry (min) Solvent E+ (equiv.)
Ligand (%)
(%)
(R/S)
1
2
3
4
5
6
7
8
2d
Pentane MeOD (5)
3
86
84
70
87
—
—
90
77
55
50
70
35
—
—
—
86
—
—
—
—
2a (70)
2a (10)
—
—
—
50 : 50
75 : 25
75 : 25
50 : 50
76 : 24
52 : 48
25 : 75
44 : 57
56 : 44
50 : 50
50 : 50h
50 : 50h
We next probed the scope of the reaction with other electro-
philes under the best conditions found in terms of ligands and
solvents. Lithiation/substitution of rac-1 in hexane at ꢀ78 1C in
the presence of (ꢀ)-sparteine using the electrophiles Me3SiCl,
Ph2CO and Me2CO all resulted in the formation of the expected
enantio-enriched derivatives 2b–d in both reasonable yields
(65–85%) and selectivity (er 72–77 : 28–23) (entries 13–15, Table 1)
(Scheme 1). From these data it can be seen that the enantioselectivity
does not significantly depend on the electrophile used, as expected
in the case of a DTR. Interestingly, an er higher than that fixed by
the thermodynamic ratio of the two diastereomeric complexes
(ca. 75: 25) could also be achieved using a sacrificial electrophile.
Addition to 1-Li at ꢀ78 1C in hexane of 20 mol% Me2CO, and
then quenching with MeOD (5 equiv.), provided 2d essentially
racemic (er 52: 48, R : S) in 15% yield, but allowed the recovery of
enantioenriched (R)-[D]-1 with good enantioselectivity (er 82: 18,
R : S, 86% D, 75% yield) (entry 16, Table 1).
30d
’’
’’
’’
’’
’’
’’
’’
’’
’’e
Hexane
15e
THF
Hexane MeI (5)
30e
’’ f
’’e
’’e
’’e
’’e
’’e
’’e
’’e
’’e
’’e
’’ f
’’
Pentane MeI (0.1)
MeOD (5)
4
’’
5
6
’’
’’
’’
’’
’’
’’
’’
’’
9
10
11
12
13
14
15
16
7
—
—
—
8g
9g
3
’’
Toluene
Hexane Me3SiCl (5)
2b (85) 24 : 76i
Ph2CO (5)
2c (65)
77 : 23
’’
’’
’’
’’
Me2CO (5)
’’
2d (85) 72 : 28
Pentane Me2CO (0.2)
2d (15) 52 : 48 j
a
b
Calculated by 1H NMR of the crude reaction mixture. Isolated yield by
c
column chromatography. For the absolute configuration of the major
d
e
f
enantiomer, see the ESI. Temp. = ꢀ120 1C. Temp. = ꢀ78 1C. Lithia-
tion performed at ꢀ78 1C, then cooling to ꢀ120 1C before quenching with
g
h
the electrophile. Pre-treated with s-BuLi in hexane. A racemic mixture
was also obtained in Et2O in the case of ligand 8 (70% D), and in Et2O
(86% D) and THF (92% D) in the case of ligand 9; the latter was proved to
We also investigated the influence of chiral ligands on the
racemisation rate of (R)-1-Li, obtained upon deprotonating a
0.2 M solution of enantiomerically enriched (R)-1 (er 95 : 5) (1 equiv.)
in hexane with s-BuLi (1.2 equiv.) at 195 K (ꢀ78 1C). Interestingly, the
i
be insoluble in hexane. The change in the absolute configuration was
only due to a change in the relative priorities of the substituent groups.
j
Upon quenching the mixture with MeOD (5 equiv.), the remaining 1-Li
was recovered as [D]-1 in 75% yield and with an er of 82 : 18 (R:S).
c
4912 Chem. Commun., 2013, 49, 4911--4913
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Table 2 Influence of ligands on the enantiomerisation barrier of 1-Li
for helpful discussions and for providing a sample of ligand 9.
Dr Francesco Secci is also thanked for his help with the
preparation of ligand 4.
Entry
Ligand
Temperature (K)
DGa (kcal molꢀ1
)
1
2
3
—
TMEDA
3
157a
195
’’
9.5 ꢁ 0.1
13.5 ꢁ 0.1
Notes and references
14.5 ꢁ 0.1 (R - S)
14.1 ꢁ 0.1 (S - R)
14.0 ꢁ 0.1 (R - S)
14.3 ꢁ 0.1 (S - R)
1 J. Clayden, Tetrahedron Organic Chemistry Series, in Organolithiums
Selectivity for Synthesis, ed. J. E. Baldwin and R. M. Williams,
Pergamon, Amsterdam, 2002, vol. 26.
2 J.-C. Kizirian, in Topics in Stereochemistry, Stereochemical Aspects of
Organolithium Compounds: Mechanism and Stereochemical Features in
Asymmetric Deprotonation Using RLi/(–)-Sparteine Bases, ed. R. E. Gawley,
Helvetica Acta, Zu¨rich, 2010, ch. 6, vol. 26, p. 189.
4
4
’’
a
Reaction performed in THF–Et2O (3 : 2).
3 For some recent papers on the subject, see: (a) I. Coldham,
D. Leonori, T. K. Beng and R. E. Gawley, Chem. Commun., 2009,
5239; (b) I. Coldham, S. Raimbault, D. T. E. Whittaker,
P. T. Chovatia, D. Leonori, J. J. Patel and N. S. Sheikh, Chem.–Eur.
J., 2010, 16, 4082; (c) T. K. Beng, W. S. Tyree, T. Parker, C. Su,
P. G. Williard and R. E. Gawley, J. Am. Chem. Soc., 2012, 134, 16845.
4 K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2024.
Scheme 2
5 (a) J. M. Keith, J. F. Larrow and E. N. Jacobsen, Adv. Synth. Catal.,
2001, 343, 5; (b) S. E. Schaus, B. D. Brandes, J. F. Larrow,
M. Tokunaga, K. B. Hansen, A. E. Gould, M. E. Furrow and
E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124, 1307.
6 J. Deregnaucourt, A. Archelas, F. Barbirato, J.-M. Paris and
R. Furstoss, Adv. Synth. Catal., 2007, 349, 1405.
7 (a) For reviews on oxiranyllithiums, see: F. Chemla and E. Vranken, in
The Chemistry of Organolithium Compounds, ed. Z. Rappoport and
I. Marek, Wiley, New York, 2004, ch. 18, vol. 2, p. 1165; (b) V. Capriati,
S. Florio and R. Luisi, Chem. Rev., 2008, 108, 1918; (c) V. Capriati,
S. Florio and A. Salomone, in Topics in Stereochemistry, Stereochemical
Aspects of Organolithium Compounds: Oxiranyllithiums as Chiral
Synthons for Asymmetric Synthesis, ed. R. E. Gawley, Helvetica Acta,
Zu¨rich, 2010, ch. 4, vol. 26, p. 135.
8 For reviews on lithium carbenoids, see: (a) G. Boche and J. C.
W. Lohrenz, Chem. Rev., 2001, 101, 697; (b) V. Capriati and
S. Florio, Chem.–Eur. J., 2010, 16, 4152 and references therein;
(c) V. Capriati, in Contemporary Carbene Chemistry: Modern Lithium
Carbenoid Chemistry, ed. R. A. Moss and M. P. Doyle, John Wiley &
Sons, Hoboken, NJ, 2013, in press.
time-dependent deuteration (see the ESI‡) of 1-Li in the presence of
stoichiometric (1.2 equiv.) chiral ligands 3 and 4 revealed in both
cases slower enantiomerisation kinetics in comparison to TMEDA
(vide supra) (entries 3 and 4, Table 2). To date, there have been
relatively a few data on the effects of chiral diamines on the barrier
to enantiomerisation of chiral organolithiums.3a,13
The above results are noteworthy because, in the case of
N-Boc-2-lithiopyrrolidine, a chiral ligand such as (ꢀ)-sparteine
contributes to lower the enantiomerisation barrier, thereby
accelerating the rate of inversion.14 In an effort to generalise
this result, optically active aryloxirane (R)-10 (er 98 : 2), having
two CF3 groups in a meta, meta0 orientation, was also subjected
to lithiation. Previous studies showed that deprotonation of
(R)-10 (er 98 : 2) with s-BuLi–TMEDA (1 equiv.) in hexane at
ꢀ78 1C, followed by quenching with MeOD, gave enantio-
enriched (R)-[D]-10 with er 90 : 10 after a deprotonation time of
9 (a) V. Capriati, S. Florio, F. M. Perna and A. Salomone, Chem.–Eur. J.,
2010, 16, 9778; (b) F. M. Perna, A. Salomone, M. Dammacco,
S. Florio and V. Capriati, Chem.–Eur. J., 2011, 17, 8216.
40 s. Running the same reaction with ligands 3 and 4, in place of 10 (a) V. Capriati, S. Florio, F. M. Perna, A. Salomone, A. Abbotto,
M. Amedjkouh and S. O. N. Lill, Chem.–Eur. J., 2009, 15, 7958;
(b) G. Carbone, P. O’Brien and G. Hilmersson, J. Am. Chem. Soc.,
2010, 132, 15445.
TMEDA, a more dramatic effect was noted upon quenching with
MeOD: enantio-enriched (R)-[D]-10 could be recovered, in each
case, with the same enantiopurity of the starting oxirane (er 98 : 2) 11 (a) M. J. Dearden, C. R. Firkin, J.-P. R. Hermet and P. O’Brien, J. Am.
Chem. Soc., 2002, 124, 11870; (b) P. O’Brien, Chem. Commun., 2008,
655; (c) A. J. Dixon, M. J. McGrath and P. O’Brien, Org. Synth., 2006,
after a reaction time of 20 min (Scheme 2).
In conclusion, the chiral ligand (ꢀ)-sparteine, widely used for
83, 141.
asymmetric deprotonation,2 was found to promote a DTR of a 12 (a) J.-C. Kizirian, J.-C. Caille and A. Alexakis, Tetrahedron Lett., 2003,
44, 8893; (b) D. Stead, P. O’Brien and A. Sanderson, Org. Lett., 2008,
highly reactive lithiated oxirane such as 1-Li with a range of
10, 1409.
electrophiles, albeit with moderate final er (ca. 75 : 25). By using a
13 (a) T. Heinl, S. Retzow, D. Hoppe, G. Fraenkel and A. Chow,
sacrificial electrophile, the er in the recovered [D]-1 increased up to
82 : 18. Interestingly, both chiral ligands 3 and 4 proved also to be
more effective than TMEDA in hampering the progress of racemi-
sation of lithiated aryloxiranes (R)-1-Li and (R)-10-Li when employed
in hexane at a temperature as low as ꢀ78 1C. Elucidation of the
structure–reactivity relationship15 of the above lithiated oxiranes
would certainly be helpful in unravelling their mechanism of
enantiomerisation in the presence of different ligands.16 Solid
structure and stereodynamics of lithiated oxirane 1-Li will be
discussed in a forthcoming paper from our group.
Chem.–Eur. J., 1999, 5, 3464; (b) I. Coldham, S. Dufour, T. F.
N. Haxell, J. J. Patel and G. Sanchez-Jimenez, J. Am. Chem. Soc.,
2006, 128, 10943.
14 T. I. Yousaf, R. L. Williams, I. Coldham and R. E. Gawley, Chem.
Commun., 2008, 97.
15 (a) T. Stey and D. Stalke, in The Chemistry of Organolithium
Compounds, Part 1, ed. Z. Rappoport and I. Marek, John Wiley &
Sons, Inc., New York, 2004, ch. 2, p. 47; (b) V. Capriati, S. Florio,
R. Luisi, F. M. Perna and A. Spina, J. Org. Chem., 2008, 73, 9552;
¨
(c) V. H. Gessner, C. Daschlein and C. Strohmann, Chem.–Eur. J.,
2009, 15, 3320.
16 (a) D. M. Hodgson, E. H. M. Kirton, S. M. Miles, S. L. M. Norsikian,
N. J. Reynolds and S. J. Coote, Org. Biomol. Chem., 2005, 3, 1893;
(b) T. K. Beng, J. S. Woo and R. E. Gawley, J. Am. Chem. Soc., 2012,
134, 14764; (c) N. S. Sheikh, D. Leonori, G. Barker, J. D. Firth,
K. R. Campos, A. J. H. M. Meijer, P. O’Brien and I. Coldham, J. Am.
Chem. Soc., 2012, 134, 5300.
This work was financially supported by MIUR-FIRB (Code:
CINECA RBF12083M5N) and the Interuniversities Consortium
C.I.N.M.P.I.S. We are especially grateful to Professor Robert E. Gawley
c
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Chem. Commun., 2013, 49, 4911--4913 4913