Communication
ChemComm
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
1 E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem., 2014,
We previously found that direct a-lithiation of N-Boc azetidine
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-
tection of N-Botc stannane 10, using TMSI for deprotection
(66%). Under identical transmetallation conditions used for
stannane 10 in the presence of DIANANE (S)-6, stannane (Æ)-13
underwent Sn–Li exchange and trapping with acetone to give
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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Scheme 6 Transmetallation of N-Boc stannane 13.
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¨
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Chem. Commun.
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