Electrophile dependent mechanisms in the asymmetric trapping of α-lithio-N-(tert-butoxythiocarbonyl)azetidine

Article abstract of DOI:10.1039/d0cc05396a

Sn-Li exchange and ‘poor man's Hoffmann tests’ establish asymmetric trapping of α-lithio-N-(tert-butoxythiocarbonyl) (Botc) azetidine to be controlled by dynamic thermodynamic resolution or dynamic kinetic resolution, depending on the electrophile. Unusually, different configurational stability is seen for the anion generated by lithiation compared to transmetallation. Configurational stability of α-lithio-N-Boc azetidine indicates instability with theN-Botc system is due to the C-S group.

Full text of DOI:10.1039/d0cc05396a

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Electrophile dependent mechanisms
in the asymmetric trapping of
a-lithio-N-(tert-butoxythiocarbonyl)azetidine†
Cite this:DOI: 10.1039/d0cc05396a
Received 7th August 2020,
Accepted 3rd September 2020
Pascal K. Delany, Claire L. Mortimer and David M. Hodgson
*
DOI: 10.1039/d0cc05396a
rsc.li/chemcomm
Sn–Li exchange and ‘poor man’s Hoffmann tests’ establish asym- electrophile dependent (Scheme 1B). This has prompted us to
metric trapping of a-lithio-N-(tert-butoxythiocarbonyl) (Botc) aze- investigate the origins of asymmetric substitution of N-Botc
tidine to be controlled by dynamic thermodynamic resolution or azetidine through a-lithiation, with emphasis on how the process
dynamic kinetic resolution, depending on the electrophile. Unu- proceeds with respect to different electrophiles (Scheme 1C).
sually, different configurational stability is seen for the anion
generated by lithiation compared to transmetallation. Configura-
tional stability of a-lithio-N-Boc azetidine indicates instability with
Q
the N-Botc system is due to the C S group.
Saturated azacycles are pervasive motifs in pharmaceutically
active compounds;1 consequently, advances in their asym-
metric synthesis are of significant interest.2 Directed deprotona-
tive lithiation—electrophile trapping sequences are synthetically
powerful approaches in enantioselective synthesis,3 especially for
a-functionalisation of saturated azacycles.4 Azetidines have
recently received increased attention due to their desirable phy-
siochemical properties and the emergence of highly bioactive
azetidine containing compounds.5 We have developed asym-
metric a-lithiation—electrophile trapping of azetidines, enabled
by a N-thiopivaloyl or -tert-butoxythiocarbonyl (Botc) directing
group (Scheme 1A and B);6–9 the latter being preferred owing to
greater levels of asymmetric induction, ease of deprotection and
accessibility to 2,4-disubstituted azetidines.7,8 Knowledge of path-
ways for enantioinduction provides insight and rationalisation of
previous observations and serves as valuable understanding to
underpin future studies. O’Brien and co-workers reported the
sense of asymmetric induction in a-lithiation—electrophile trap-
ping of N-(thiopivaloyl)azetidine (1) was electrophile dependent
Scheme 1 Investigations of a-lithiated azetidines.
Enantioselectivity can originate from three distinct path-
(Scheme 1A),10 a phenomenon rarely observed for non-benzylic sp3 ways (Scheme 2).12 An organolithium base coordinated with a
lithiated species.11 On previous evaluation of our DIANANE (S)-6- chiral ligand could preferentially remove the pro-R or pro-S
mediated asymmetric a-lithiation—electrophile trapping of N-Botc hydrogen to give a configurationally stable anion; if an introduced
azetidine 5,9 we also observed the sense of enantioinduction was electrophile reacts stereospecifically then asymmetric induction is
controlled by the lithiation rate difference (e.g., kHS c kHR).
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Enantioselectivity can also arise post-deprotonation when a con-
figurationally unstable anion is formed (Scheme 2). Dynamic
thermodynamic resolution (DTR) occurs if the lithiated complexes
(e.g., (R)-11Á6 and (S)-11Á6) equilibrate to a thermodynamically
controlled ratio and substitute with an electrophile at a rate faster
Mansfield Road, Oxford OX1 3TA, UK. E-mail: david.hodgson@chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Additional configura-
tional stability studies, experimental procedures and 1H and 13C NMR spectra.
CCDC 2027137. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/d0cc05396a
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deprotonation that is then reduced on equilibration. Sn–Li
exchange with enantioenriched stannane (R)-10 (67 : 33 er)
in the presence of racemic DIANANE (Æ)-6 at À98 1C for 1 min
before acetone trapping, resulted in essentially racemic alcohol
8 (51 : 49 er, 39%). Assuming stereoretentive Sn–Li exchange
(although see below), this demonstrates configurational
instability of the organolithium complexes even at À98 1C when
the anion is formed by transmetallation. However, in contrast
to anion generation through Sn–Li exchange, partial configura-
tional stability was demonstrated in deprotonations with dif-
ferent incubation temperatures and times. Lithiation of
azetidine 5 in the presence of DIANANE (S)-6 and incubation
for 1 h at À98 1C before trapping gave alcohol (R)-8 with
moderate enantioselectivity (65 : 35 er, 38%), showing incom-
plete equilibration. But when deprotonation and incubation
were performed at À78 1C for 1 h, then cooling to À98 1C before
trapping, this gave alcohol (R)-8 with good enantioselectivity
(88 : 12 er, 55%), indicating that high enantioselectivity can be
achieved with trapping at À98 1C. Deprotonation and incuba-
tion at À98 1C for 3 h before trapping gave alcohol (R)-8 in
86 : 14 er (51%), with the high er suggesting equilibration is
almost complete at À98 1C after 3 h. These time dependent
enantioselectivities imply DTR, with acetone (for a full table of
acetone trapping studies and similar results obtained with
aromatic aldehydes, see the ESI†), and indicate the organo-
lithium complexes possess greater configurational stability at
À98 1C when formed through deprotonation.
Scheme 2 Possible enantiodetermining steps.
than epimerisation (kSR and kSS 4 kepi).12 Alternatively, dynamic
kinetic resolution (DKR) could operate, where the rate of epimer-
isation between diastereomeric complexes is faster than reaction
with the electrophile (e.g., kSR 4 kSS { kepi, Scheme 2); enantios-
electivity is now determined by the difference in rate of reaction of
the two diastereomeric complexes with the electrophile (i.e., DDG‡).
We first examined the configurational stability of N-Botc
azetidine complexes ((R)-11Á6 and (S)-11Á6) with chiral diamine
ligand DIANANE (S)-6,13 when generated through a-deprotonation
and Sn–Li exchange (Scheme 3). A control reaction using pre-
viously optimised conditions for lithiation (deuteration studies)
and for enantioselectivity (pentane, 1 h, À78 1C) with acetone as
the electrophile (3 equiv.),7 gave alcohol (R)-8 (61%) in 89 : 11 er
(cf., Scheme 1B). Sn–Li exchange, a process with considerable
precedent for occurring in a stereoretentive manner,14 with
stannane (Æ)-10 in the presence of (S)-6 (1 h, À78 1C, then
acetone) gave alcohol (R)-8 in 90 : 10 er (57%). Matching levels
of enantioenrichment from these two experiments show the
intermediate organolithium complexes are configurationally
unstable at À78 1C and enantioselectivity originates after anion
formation. If DTR is occurring, then altering incubation time may
influence enantioselectivity. Following Sn–Li exchange,
decreasing incubation to 5 min gave alcohol (R)-8 in essentially
unchanged er (85 : 15, 64%), indicating either anion equili-
bration following transmetallation is effectively complete after
5 min at À78 1C, or a DKR process.
Remarkably, compared to 65 : 35 er obtained from deproto-
nation for 1 h at À98 1C, increased enantioselectivity was
observed through Sn–Li exchange of stannane (Æ)-10 when
carried out under the same conditions in the presence of
DIANANE (S)-6, giving alcohol (R)-8 in 84 : 16 er (41%). This
difference at À98 1C can be rationalised by ‘unproductive’
kinetic deprotonation (preferential generation of the thermo-
dynamically less stable lithiated complex) and a longer equili-
bration time, relative to transmetallation. Alternatively, Sn–Li
exchange with stananne (Æ)-10 could be occurring non-
stereospecifically in the presence of DIANANE (S)-6, although
precedent for non-retentive Sn–Li exchange is very limited;16 no
transmetallation occurred without the ligand present. Non-
retentive Sn–Li exchange could explain the rapid racemisation
observed at À98 1C after 1 min with enantioenriched stannane
(R)-10. The possibility of non-stereospecific Sn–Li exchange was
probed using stannane (Æ)-10 with DIANANE (S)-6 and in situ
acetone. This gave trace amounts (1%) of essentially racemic
alcohol 8 (52 : 48 er), indicating Sn–Li exchange is occurring
stereospecifically with some degree of ‘microscopic’17 config-
urational stability, relative to the rate of acetone trapping.
In a ‘poor man’s Hoffmann test’,12 azetidine 5 was deprotonated
Scheme 3 Studies on the synthesis of alcohol 8 from deprotonation or
Sn–Li exchange.
Although the enantiodetermining step occurs post-
deprotonation, asymmetric deprotonation could still be (1 h, À78 1C) and reacted with sub-stoichiometric acetone (0.5 and
occurring.15 1 min lithiation at À78 1C of azetidine 5 in the 0.1 equiv.) to give alcohol (R)-8 in 61 : 39 er (29%) and 60 : 40 er
presence of DIANANE (S)-6 before acetone trapping, gave (2%), respectively. Decreased enantioselectivity (compared with
alcohol (R)-8 in 58 : 42 er (28%). The reduced er after 1 min 89 : 11 er using 3 equiv. earlier) suggest the minor lithiated complex
indicates the lithiated diastereomeric complexes have not fully reacts marginally faster than the major complex15 ((R)-11Á6 faster
equilibrated (unlike after 1 h), and there is no favourable initial than (S)-11Á6, assuming retentive substitution, SE2ret, with
formation of one organolithium complex by asymmetric acetone11). The difference in enantioselectivity shows epimerisation
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is not occurring on the timescale of acetone trapping at À78 1C, 54 : 46 er (entry 5). The dependence of asymmetric induction
confirming a DTR process.
on lithiation time at À78 1C and À98 1C indicates DTR in
A sacrificial electrophile has been previously used to improve stannylation, similar to trapping with acetone. These results
enantioselectivity in a reaction where DTR operates.18 Generation also suggest deprotonation-derived organolithium complex
of a-lithio-N-Botc azetidine in the presence of DIANANE (S)-6 at equilibration is incomplete after 5 min at À78 1C and reinforces
À78 1C, then reaction with MeI (0.2 equiv.) for 5 min before the earlier observation with acetone of increased time required
addition of acetone (3 equiv.) only led to alcohol (R)-8 (58%) with a for complex equilibration at À98 1C, due to a less configur-
slight reduction in er (80 : 20). However, the enantioenrichment of ationally labile anion at this lower temperature. The reduced
the traces (1%) of isolated methylated azetidine (S)-7 (73 : 27 er) overall levels of enantioselectivity compared with optimised
is similar to that found at this temperature for (S)-7 (77 : 23 er) conditions for acetone trapping suggests either an interfering
using only MeI (3 equiv.), sampled as the reaction progressed DKR mechanism in which the thermodynamically less stable
(5–120 min, Scheme 4). While these results do not strictly complex reacts with at a faster rate with Me3SnCl, or possible
discriminate between DTR and DKR (as potentially kSR E kSS, competing non-stereospecific electrophile trapping (SE2ret
cf., Scheme 2), enantioselectivity independent of reaction con- and SE2inv).11
version and (also in contrast to acetone) improved enantioen-
Use of an internal electrophile such as TMSCl has been
richment at À98 1C after 1 h (91 : 9 er),7 support a DKR process previously used to ascertain the degree of an asymmetric
with this slower reacting19 electrophile.
deprotonation.15 Two parallel ‘in situ’ trapping experiments
were performed at À78 1C using N-Botc azetidine 5 and
stannane (Æ)-10 substrates (Scheme 5). These reactions gave
silane (R)-12 in identical enantioenrichment (70 : 30 er), show-
ing the level of asymmetric induction with this electrophile is
independent of the method of anion generation. TMSCl is a
slower reacting electrophile19 and the matching enantioselec-
tivity could therefore be due to DKR. A deprotonation reaction
with a 1 h incubation period at À78 1C before external addition
of TMSCl gave silane (R)-12 in 52% yield and essentially the
same enantioselectivity (68 : 32 er). A ‘poor man’s Hoffmann
test’ with 0.5 equiv. of TMSCl, gave silane (R)-12 in 69 : 31 er
(34%), providing further evidence for DKR. With TMSOTf, a
more reactive silylating agent, a change in the sense of asym-
metric induction was observed, giving (S)-12 in 58 : 42 er (28%);
this is most likely a result of diminished influence of a DKR
mechanism.
Scheme 4 Unchanging er during the methylation of N-Botc azetidine 5.
With Me3SnCl as the electrophile, both variation in reaction
time and temperature altered asymmetric induction (Table 1).
Lithiation of N-Botc azetidine 5 in the presence of DIANANE
(S)-6 at À78 1C for 1 h led to stannane (S)-10 in 67 : 33 er (90%,
Table 1, entry 1). An otherwise identical reaction, but without
warming to rt following Me3SnCl addition, resulted in stannane
(S)-10 in similar enantioselectivity (61 : 39 er, entry 2) in 80%
yield. However, reducing the lithiation time to 5 min before
stannylation inverted the sense of asymmetric induction, to
give stannane (R)-10 in 54 : 46 er (62%). Decreasing the lithia-
tion temperature to À98 1C for 3 h before trapping at the same
temperature gave stannane (S)-10 in 64 : 36 er (77%, entry 4).
However, reducing the lithiation time to 1 h at À98 1C again
resulted in a change in the sense of asymmetric induction to
Scheme 5 Silylation studies.
Table 1 Asymmetric stannylation of N-Botc azetidine 5
Entry
Lithiation temp (time)
Stannylation temp (time)
Yield 10
er (R : S)
Recovered 5
1
2
3
4
5
À78 1C (1 h)
À78 1C (1 h)
À78 1C (5 min)
À98 1C (3 h)
À98 1C (1 h)
À78 1C (30 min) then rt (30 min)
À78 1C (30 min)
90%
80%
62%
77%
70%
33 : 67
39 : 61
54 : 46
36 : 64
54 : 46
0%
0%
38%
21%
24%
À78 1C (30 min) then rt (30 min)
À98 1C (30 min)
À98 1C (30 min)
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For the two electrophiles which trap through DKR (MeI and N-thiopivaloyl azetidine. In the current work, an intriguing
TMSCl), the predominant sense of asymmetric induction is difference in configurational stability of the anion formed by
opposite to those electrophiles which proceed through DTR lithiation versus transmetallation was also observed (further
(acetone, benzaldehyde† and Me3SnCl). This could be due discussed in the ESI†). Finally, the origin of configurational
either to preferential invertive SE2inv trapping, not uncommon instability was determined to be the presence of CQS group, as
for mesomerically stabilised organolithiums reacting with alkyl demonstrated by the configurational stability of a-lithiated
halides,15 or to retentive trapping in which the minor diaster- N-Boc azetidine. The stereochemical lability may be due to
eomeric organolithium complex is the faster reacting species, the longer CQS bond and/or the greater polarisability of S,
as was observed earlier in the ‘poor man’s Hoffmann test’ with compared to O, allowing greater charge transfer from N to S.8,20
acetone.
We thank the EPSRC for studentship support (to P. K. D.)
O’Brien and co-workers previously established with N- and the EPSRC and Novartis for an Organic Synthesis Student-
thiopivaloyl azetidine that asymmetric induction occurs post ship (to C. L. M.). We also thank the Martin Smith group at
deprotonation; however, no distinction between DTR or DKR Oxford for use of their HPLC equipment.
was made.10 They also speculated the origin of configurational
instability may due to the longer CQS bond leading to a weaker
C–Li bond. To discriminate between the CQS group or azacycle
size being responsible for the configurational instability of
Conflicts of interest
There are no conflicts to declare.
N-Botc azetidine lithiated complexes ((R)-11Á6 and (S)-11Á6),
we sought to access the lithiated N-Boc azetidine equivalents.
Notes and references
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is problematic,6 but access to a-lithiated N-Boc azetidine is
achievable by Sn–Li exchange from N-Boc stannane 13
(Scheme 6). Stannane 13 was accessed by deprotection/repro-
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(66%). Under identical transmetallation conditions used for
stannane 10 in the presence of DIANANE (S)-6, stannane (Æ)-13
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racemic N-Boc alcohol (Æ)-14 (47%). Transmetallation of enan-
tioenriched N-Boc stannane (S)-13 (66 : 34 er) using s-BuLi with
racemic DIANANE (Æ)-6, led to enantioenriched alcohol (R)-14
in 67 : 33 er (40%). These results demonstrate, for the first time,
access to a configurationally stable a-lithiated azetidine and
indicate the CQS group is responsible for the configurational
instability of a-lithio N-Botc azetidine.
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