Mechanistic interrogation of the asymmetric lithiation-trapping of N-thiopivaloyl azetidine and pyrrolidine

Article abstract of DOI:10.1039/c5cc08690f

A fundamental mechanistic study of the s-BuLi/chiral diamine-mediated lithiation-trapping of N-thiopivaloyl azetidine and pyrrolidine is reported. We show that lithiated thiopivalamides are configurationally unstable at -78 °C. Reaction then proceeds via a dynamic resolution of diastereomeric lithiated intermediates and this accounts for the variable sense and degree of asymmetric induction observed compared to N-Boc heterocycles.

Full text of DOI:10.1039/c5cc08690f

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Mechanistic interrogation of the asymmetric
lithiation-trapping of N-thiopivaloyl azetidine
and pyrrolidine†
Cite this:DOI: 10.1039/c5cc08690f
Received 19th October 2015,
Accepted 24th November 2015
a
a
a
a
Peter J. Rayner, Joshua C. Smith, Charline Denneval, Peter O’Brien,*
a
b
Paul A. Clarke and Richard A. J. Horan
DOI: 10.1039/c5cc08690f
www.rsc.org/chemcomm
3
a,8
A fundamental mechanistic study of the s-BuLi/chiral diamine-mediated piperidine 7 delivered a-functionalised pyrrolidine (S)-6
and
3
b,9
lithiation-trapping of N-thiopivaloyl azetidine and pyrrolidine is piperidine (S)-8.
reported. We show that lithiated thiopivalamides are configurationally Comparing the thiopivaloyl and Boc results presented
unstable at À78 8C. Reaction then proceeds via a dynamic resolution in Scheme 1, we wondered whether the cause of the difference
of diastereomeric lithiated intermediates and this accounts for was the four-membered ring, the N-thiopivaloyl group or the
the variable sense and degree of asymmetric induction observed electrophile. To explore the reasons for the difference, we set
compared to N-Boc heterocycles.
out to determine the mechanism of asymmetric induction
in the s-BuLi/chiral diamine-mediated a-lithiation-trapping of
The development of methodology for the direct asymmetric N-thiopivaloyl heterocycles 1/9 - 10 - 11 (Scheme 2).
1
a-functionalisation of saturated nitrogen heterocycles continues
Our study focused on both N-thiopivaloyl azetidine 1 and
to attract attention due to the prevalence of such motifs in pyrrolidine 9 together with a range of electrophiles to allow
2
potential pharmaceuticals. The most successful, direct approach comparison with the well-studied N-Boc pyrrolidine. Two limit-
to enantioenriched a-substituted pyrrolidines, piperidines and ing mechanisms are known: asymmetric deprotonation to give a
piperazines is Beak’s asymmetric lithiation-trapping of N-Boc configurationally stable organolithium species 10 (as is estab-
3
3a,b
heterocycles, with a number of noteworthy applications within lished for N-Boc pyrrolidine and piperidine at À78 1C
and up
3
c,4
10
the pharmaceutical industry.
In order to explore new areas to À30 1C ) or dynamic resolution of a configurationally labile
of 3-D pharmaceutical space, extension of the N-Boc-mediated
lithiation-trapping methodology to azetidines would be attrac-
tive. Unfortunately, however, Beak’s approach is not suitable
for the a-lithiation-trapping of azetidine. To solve this limita-
tion, Hodgson and Kloesges reported the use of Seebach’s
5
5
6
N-thiopivaloyl activating group, culminating with the first
example of asymmetric a-lithiation-trapping of azetidine using
s-BuLi and chiral diamines. For example, lithiation of N-thio-
pivaloyl azetidine 1 using s-BuLi/(À)-sparteine 3 or Alexakis’
7
diamine (R,R)-4 gave, after trapping with MeI, a-substituted
azetidine (R)-2 in 61 : 39 er and 80: 20 er respectively (Scheme 1).
These results piqued our interest as the sense of asymmetric
induction was opposite to that obtained with N-Boc pyrrolidine
and N-Boc piperidine. Some examples are shown in Scheme 1:
use of (À)-sparteine 3 or (R,R)-4 with N-Boc pyrrolidine 5 and
a
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK.
E-mail: peter.obrien@york.ac.uk
b
GlaxoSmithKline Research & Development Ltd., Medicines Research Centre,
Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
†
Electronic supplementary information (ESI) available: Full experimental procedures,
NMR spectra and CSP-HPLC data. CCDC 1417066–1417069. For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c5cc08690f
Scheme 1 Opposite sense of induction in asymmetric lithiation-trapping
of N-substituted heterocycles.
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Scheme 2 Investigation of the mechanism of asymmetric induction in
the lithiation-trapping of N-thiopivaloyl heterocycles.
organolithium species 10 (as reported for pyrrolidines and
1
1
piperidines at temperatures above À20 1C ). Herein, we disclose
that, unexpectedly, the a-lithiation-trapping of N-thiopivaloyl
heterocycles 1 and 9 at À78 1C proceeds via a dynamic resolution
mechanism. Our results show that the thiopivaloyl group is the
source of the difference when compared to N-Boc heterocycles.
This finding may have consequences for asymmetric efforts with
the N-thiopivaloyl and the recently reported t-butoxythiocarbonyl
Scheme 4 Asymmetric lithiation-PhCHO trapping of N-thiopivaloyl aze-
tidine 1 with different chiral diamines.
and (S)-19). Such a difference is unprecedented in the lithiation-
3
13
trapping of non-benzylic sp -hybridised C–Li systems. With MeI,
products of opposite configuration were obtained with the azetidine
1
2
group.
14
and pyrrolidine systems (-(R)-2 and (S)-20, albeit with low
The lithiation-trapping of N-thiopivaloyl azetidine 1 and
pyrrolidine 9 was investigated using similar conditions to those
ers). All of these variable stereochemical outcomes appear to be
at odds with the results obtained with configurationally stable
5
originally described by Hodgson: lithiation of 1 or 9 was
3,15,16
lithiated N-Boc heterocycles.
accomplished using s-BuLi (1.2–1.3 eq.) and (À)-sparteine 3
This unpredictability continued when different chiral diamines
were employed. For example, lithiation of 1 using s-BuLi and the
(
1.2–1.3 eq.) in Et O at À78 1C for 30 min (for 1) and 1 hour (for 9).
2
Then, trapping was carried out with four electrophiles (PhCHO,
17
7,8
(
+)-sparteine surrogate 21 or diamine (S,S)-4 and subsequent
trapping with PhCHO gave (S,S)-12 and (R,S)-13 in high total yields
77–93%) but moderate enantioselectivity (Scheme 4). The difference
between (À)-sparteine 3 and (+)-sparteine surrogate 21 with azetidine
is particularly striking since the (+)-sparteine surrogate 21 was
MeO CCl, CO and MeI) at À78 1C for 1 hour before quenching
2
2
with HCl(aq) at this temperature. The results of this study are
shown in Scheme 3. The relative and absolute configurations of 2
and 12–20 were established using X-ray crystallography and inter-
conversions to/from known compounds (see ESI†).
(
1
17
originally designed based on its ‘‘sparteine-like’’ structure
and both diamines gave high er (in the expected opposite sense)
in the lithiation-trapping of pyrrolidine 9 (see ESI†).
The results in Scheme 3 immediately highlight the fact that the
sense of induction in the lithiation-trapping of 1 and 9 depends
on the electrophile employed. Indeed, when considering the
newly formed stereogenic centre a to nitrogen, the products
formed by trapping with PhCHO (-(R,R)-12 + (S,R)-13 and
The wide variation in enantioselectivity and sense of induction
under essentially the same reaction conditions appeared to preclude
asymmetric deprotonation via a configurationally stable organo-
lithium species as the mechanism that is operating with
N-thiopivaloyl heterocycles. To prove this beyond doubt, we
-
(R,R)-14 + (S,R)-15) or MeO
2
CCl (-(R)-16 and (R)-17) were of
(-(S)-18
opposite configuration to those formed using CO
2
1
8
investigated the configurational stability of the intermediate
lithiated N-thiopivaloyl azetidine and pyrrolidine 10 at À78 1C.
Initially, stannanes 22 (68 : 32 er) and 23 (72 : 28 er) of
unknown configuration were prepared by lithiation-trapping
of N-thiopivaloyl azetidine 1 and pyrrolidine 9 respectively
(
2
using (À)-sparteine 3) (see ESI†). Then, azetidine stannane
2 of 68 : 32 er was subjected to tin-lithium exchange using
n-BuLi in THF at À78 1C for 5 min and trapped with PhCHO.
This delivered racemic adducts 12 and 13 (84% total yield).
Virtually the same outcome was observed with stannane 22 using
tin-lithium exchange with n-BuLi/TMEDA in Et
2
O at À78 1C for
5
min before PhCHO trapping (Scheme 5). A similar set of results
was also obtained starting from pyrrolidine stannane 23 (72 : 28
er): essentially racemic adducts 14 and 15 were generated under
both sets of tin-lithium exchange conditions (Scheme 5). These
unexpected results establish that lithiated N-thiopivaloyl azeti-
dine and pyrrolidine 10 are configurationally unstable at À78 1C
2
in THF (no diamine) or in Et O (in the presence of TMEDA).
Scheme 3 Asymmetric lithiation-trapping of N-thiopivaloyl azetidine 1
and pyrrolidine 9 with different electrophiles.
This is in stark contrast to N-Boc pyrrolidine and other N-Boc
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Scheme 7 Dynamic resolution of racemic lithiated N-thiopivaloyl azeti-
dine 1 via direct lithiation.
We also explored the generation of a racemic lithiated
intermediate in the absence of any tin-based species. Thus,
2
N-thiopivaloyl azetidine 1 was deprotonated using s-BuLi in Et O
2
0
at À40 1C and then, after cooling to À78 1C, (À)-sparteine 3
was added and incubated at À78 1C for 1 h before trapping
with PhCHO. Under these conditions, adducts 12 and 13 were
generated in 50: 50 er (62% combined yield). To rationalise the
lack of asymmetric induction, we speculated that the rate of
complexation of (À)-sparteine 3 to the lithiated azetidine might
be too slow at À78 1C. Thus, incubation of the racemic lithiated
azetidine with (À)-sparteine 3 was carried out at a higher
temperature (À40 1C) for 1 hour before cooling to À78 1C and
trapping with PhCHO. This time, high enantioselectivity
was restored and (R,R)-12 in 71 : 29 er and (S,R)-13 in 59: 41 er
were isolated (Scheme 7). This supports our conjecture that
Scheme 5 Investigation of the configurational stability of lithiated
N-thiopivaloyl azetidine and pyrrolidine 10 via tin-lithium exchange.
heterocycles. It appears that there is a fundamental difference
between carbamates (CQO) and thioamides (CQS) in terms of the
configurational stability of their lithiated intermediates. This differ-
1
9
ence may be due to the longer bond lengths in thioamides
compared to carbamates) leading to a weaker C–Li bond.
The results of the configurational stability study establish
(
that a dynamic resolution mechanism must be occurring in the
s-BuLi/diamine-mediated reactions of N-thiopivaloyl azetidine
(
À)-sparteine 3 was unable to coordinate to the lithiated azetidine
1
and pyrrolidine 9 (see Schemes 3 and 4). If so, for a given
at À78 1C due to the coordination kinetics. To our knowledge, this
N-thiopivaloyl heterocycle, chiral diamine and electrophile, it
should be possible to start with a racemic lithiated species, add
the chiral diamine and recreate the same level of enantioselec-
tivity as that obtained in Schemes 3 and 4. To investigate this,
tin-lithium exchange from racemic stannanes 22 and 23 was
initially used (Scheme 6). Thus, azetidine stannane rac-22 was
subjected to tin-lithium exchange using n-BuLi and (À)-sparteine
is the first documented example of such an effect.
In conclusion, the results from our mechanistic studies
indicate that the lithiation-trapping of N-thiopivaloyl azetidine
and pyrrolidine are very different to N-Boc heterocycles. Lithiated
N-thiopivaloyl azetidine/pyrrolidine are not configurationally
stable at À78 1C in THF or Et
2
O (in the presence of a diamine).
Thus, dynamic resolution of interconverting diastereomeric,
lithiated species accounts for the enantioselectivity of the
lithiation-trappings of the N-thiopivaloyl heterocycles shown
3
in Et O at À78 1C for 5 min and then trapped with PhCHO. This
2
gave (R,R)-12 in 73 : 27 er (88% yield) and (S,R)-13 in 62 : 38 er (10%
yield) which was comparable to the s-BuLi/(À)-sparteine 3-mediated
5
in Schemes 3 and 4 and those previously reported by Hodgson.
lithiation-PhCHO trapping of azetidine 1 in Et
2
O at À78 1C ((R,R)-12
The range of enantioselectivities with different electrophiles
in 75 : 25 er and (S,R)-13 in 58 : 42 er, Scheme 3). A similar result was
obtained starting from pyrrolidine stannane rac-23: (R,R)-14 in
(under otherwise identical conditions) presumably arises due
to different rates of trapping and this can lead to a difference
in the configuration of the major product. We conclude
with three comments. First, given the variation in configuration
that we have observed with the four electrophiles studied
8
2 : 18 er (35% yield) and (S,R)-15 in 88 : 12 er (39% yield) were
formed, results which match very well with the direct reaction
(R,R)-14 in 82 : 18 er and (S,R)-15 in 86 : 14 er, Scheme 3).
(
(
PhCHO, MeO CCl, CO and MeI), we recommend that atten-
2 2
tion is paid to establishing the sense of induction with all novel
products formed from these types of reactions. Second, opti-
misation of enantioselectivity in the future should focus on
1
1
chiral diamines that work well in dynamic resolutions. Finally,
our results could explain the stereoselective lithiation-trapping
2
1
of N-thiopivaloylazetidin-3-ol and suggest that asymmetric
1
2
lithiation-trapping of N-t-butoxythiocarbonyl azetidine could
proceed via dynamic resolution of a configurationally unstable
lithiated intermediate.
This work was supported by EPSRC, GlaxoSmithKline, FERA
and the University of York. We thank Dr A. C. Whitwood for
X-ray crystallography.
Scheme 6 Dynamic resolution of racemic lithiated N-thiopivaloyl azetidine
and pyrrolidine via tin-lithium exchange.
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