Synthesis and Homologation of an Azetidin-2-yl Boronic Ester with α-Lithioalkyl Triisopropylbenzoates

Article abstract of DOI:10.1021/acs.orglett.9b03901

An α-boryl azetidine, obtained by α-lithiation-borylation of N-Botc azetidine, undergoes reaction with α-triisopropylbenzoyloxy organolithiums to give homologated boronic esters that can be further oxidized, homologated, arylated, and deprotected to give

Full text of DOI:10.1021/acs.orglett.9b03901

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis and Homologation of an Azetidin-2-yl Boronic Ester with
α‑Lithioalkyl Triisopropylbenzoates
Pascal K. Delany and David M. Hodgson*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: An α-boryl azetidine, obtained by α-lithiation−
borylation of N-Botc azetidine, undergoes reaction with α-
triisopropylbenzoyloxy organolithiums to give homologated
boronic esters that can be further oxidized, homologated,
arylated, and deprotected to give a range of α-substituted
azetidines. Scalemic α-boryl azetidine−α-triisopropylbenzoy-
loxy organolithium pairings show stereospecific reagent
control, providing access to either diastereomeric series of
homologated boronic esters with very high er’s.
aturated azacycles are ubiquitous structural motifs in
natural products,1 drug designs,2 and organocatalysts.3
Scheme 1. α-Substitution of Azetidines and Pyrrolidines
through Organolithium Chemistry
S
Synthetic studies on pyrrolidines4 and piperidines5 have been
extensive and aziridines6 have also seen more attention
compared with azetidines. However, with azetidine moieties
increasingly emerging as constituents of highly bioactive
compounds,7 developing effective syntheses of substituted
azetidines has become an important and growing field of
chemistry.8
Our previous research on azetidine α-lithiation−electrophile
trapping gave 2-substituted azetidines through the use of a
thiopivaloyl or tert-butoxythiocarbonyl (Botc) N-protecting/
activating group (Scheme 1, A).9−11 The methodology enables
direct diversifying α-functionalization of the azetidine moiety.
Good enantioselectivities can be achieved by α-lithiation of N-
Botc azetidine 1 in the presence of the chiral DIANANE ligand
212 and trapping with certain electrophiles (e.g., Scheme 1,
A).10,13 However, reactions with aldehydes typically suffered
from poor diastereoselectivity and enolizable aldehydes, such
as hydrocinnamaldehyde, gave no conversion.
Boronic esters are established as highly versatile functional
groups, known to undergo many stereospecific transforma-
tions.14 In a recent synthesis of (−)-stemaphylline, Aggarwal,
Leonori, and co-workers reported the preparation and some
C−C bond-forming reactions of 2-B(pin)-pyrrolidine 3 (e.g.,
Scheme 1, B).15 We considered that if access to 2-B(pin)-
azetidine 4 was achievable (Scheme 1, C), then this could lead
on to providing a broader range of α-functionalized azetidines
than previously possible through direct α-lithiation−electro-
phile trapping. Here we communicate progress on these areas,
in both racemic and asymmetric variants.
We began by applying our azetidine α-lithiation chemistry in
a racemic sense with N-Botc azetidine 1 and TMEDA in
THF10 using i-PrOB(pin) as the electrophile; this gave boronic
ester 4 in moderate yield (53%, Scheme 2). A factor
contributing to the modest yield was likely product loss during
purification by column chromatography. Despite testing a
variety of different deactivated silica gels, chromatographed
boronic ester 4 proved impossible to isolate without partial
decomposition.16 1H NMR analysis of the crude material
indicated pinacol as a major impurity, which could not be
easily removed via aqueous wash. It was reasoned that running
the reaction in a more hydrophobic solvent than THF, such as
pentane, could enable easier removal of impurities such as
pinacol during aqueous workup. Conditions for lithiation/
Received: October 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03901
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the limiting reagent were also undertaken. Aggarwal and co-
workers previously employed stannanes in a diamine-free tin−
lithium exchange approach to α-lithiated benzoates and
carbamates.21 This latter method has the benefit of reduced
steric hindrance around α-TIBO organolithiums such as 6b, as
the only coordinating species on their generation is solvent
(Et2O). Pleasingly, following this strategy with 1.3 equiv of
tributylstannyl-derived organolithium ( )-6b gave the homo-
logated boronic ester 5a in good yield (69%, 72:28 dr, Scheme
3).
Scheme 2. Racemic and Asymmetric α-Lithiation−
Borylation of N-Botc Azetidine 1
Having established conditions for homologation of azetidine
boronic ester 4 where it could be used as the limiting reagent, a
study of substrate scope with respect to the stannyl-derived α-
TIBO organolithium was carried out to examine reaction
tolerance toward steric hindrance and functional groups.
Reaction using a smaller α-TIBO ethyl stannane proceeded
smoothly; a shorter reflux time of 3 h was sufficient to give
electrophile trapping in pentane using (S)-2 as a ligand
(Scheme 1, A)10 were applied with ( )-2, to give 2-B(pin)-
azetidine 4 in excellent yield (89%) and sufficiently high purity
to negate the need for chromatographic purification. Following
acid/base extraction, the diamine ligand could also be
efficiently recovered (88%) and recycled.
Applying the above conditions using (S)-2 gave the
enantioenriched boronic ester (+)-4 also in excellent yield
(92%) and high enantioenrichment (92:8 er). The absolute
configuration of boronic ester (+)-4 was determined to be S by
derivatization to an alcohol enantiomeric to that derived from
(S)-azetidine-2-carboxylic acid.16 The sense of asymmetric
induction is opposite to that previously seen with MeI,10 but
the same as found for acetone and benzaldehyde.13 These
findings parallel observations by O’Brien and co-workers, who
noted that the sense of asymmetric induction following
lithiation of N-thiopivaloyl azetidine in the presence of
(−)-sparteine is dependent on the nature of the electrophile.17
An attractive functionalization of boronic ester 4 would be
homologation via ate complex formation with an α-
triisopropylbenzoyloxy (TIBO) organolithium and subsequent
1,2-metalate rearrangement (cf. Scheme 1, B and C).18 This
should in principle allow assembly of two contiguous
stereocenters with, ultimately, control arising from choice of
reactant configurations. Homologations of α-to-nitrogen
boronic esters have often been found to be difficult,15,19
although such transformations can benefit from a solvent
exchange to chloroform following ate complex formation to
facilitate the migration step.15,20 Following such a protocol, 2-
B(pin)-azetidine ( )-4 was reacted with α-lithiobenzoate
( )-6a (1.3 equiv) to give homologated boronic ester 5a in
moderate yield (45%, Scheme 3) as a readily separable mixture
Table 1. Homologation Scope of 2-B(pin)-azetidine 4 with
Stannane-Derived α-TIBO Organolithiums
Scheme 3. Homologation of 2-B(pin)-azetidine ( )-4
a
Unless otherwise noted, (i) reactions used 2-B(pin)-azetidine 4
(0.42 mmol), stannane (0.55 mmol), 12 h reflux in CHCl3 and (ii)
of diastereomers (74:26 dr, major diastereomer shown16).
Using boronic ester 4 in slight excess (1.5 equiv) significantly
improved the yield of 5a (71%, 83:17 dr, Scheme 3). While
these latter conditions would be appropriate when the
benzoate is the more precious material, studies to establish
an efficient method for homologation with boronic ester 4 as
amount of individual diastereomers isolated after chromatography
b
used to give dr’s and combined yields. Major diastereomer shown
c
d
(5c,d,f−h assigned by analogy to 5a,b).16 3 h reflux. Tin−B(pin)
exchange observed (71%).16 Using 2-B(pin)-azetidine 4 (0.21
mmol) and stannane (0.28 mmol). Yield for inseparable diastereo-
meric mixture and dr from H NMR analysis.
e
f
1
B
DOI: 10.1021/acs.orglett.9b03901
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Letter
homologated boronic ester 5b in 68% yield (Table 1, entry 1).
Applying this shorter reflux time with α-TIBO organolithium
6b also gave 5a in 65% yield and unchanged dr. More sterically
demanding β-branched stannanes remained effective, giving
homologated isobutyl and methylcyclopentyl boronic esters 5c
and 5d in good yields (Table 1, entries 2 and 3). However,
further increase of the steric bulk at the β-position, using an α-
TIBO neopentyl stannane, failed to give any of the desired
homologated product 5e (entry 4). In this last case, isolation of
the B(pin) neopentyl benzoate (71%)16 from overall
tributyltin−B(pin) exchange suggests generation of the
intermediate ate complex proceeded, but its collapse occurred
without 1,2-metalate rearrangement. Homologations per-
formed using stannanes bearing alkenyl, silyloxy and ketal
functionality all proved viable (entries 5−7).
Scheme 5. Transformations of Homologated Boronic Ester
(R*,R*)-5a
The observation of diastereoselectivity in the above
boronate homologations suggests possible matched/mis-
matched effects depending on reactants configurations.22
This could potentially render the asymmetric approach less
effective in enabling access to the enantiomers of both
diastereomers. To examine this aspect, separate reactions
were carried out (Scheme 4) of S and R boronic ester 4 with α-
azetidinium chloride salt 11 (quant), which further demon-
strates the utility/lability of this recently introduced protect-
ing/activating group.10 Whiting and co-workers have shown
homoboroprolines to be effective organocatalysts for asym-
metric aldol reactions,19 and the current formation of a similar
azetidinium boronic ester could lead to applications in this
area.
Scheme 4. Asymmetric Homologation of S and R Boronic
Ester 4
In conclusion, we have developed a synthetic route to
enantioenriched 2-B(pin)-azetidine 4, and the latter has been
converted to homologated azetidine boronic esters, by
boronate formation with α-lithiobenzoates and subsequent
1,2-metalate rearrangement. This process can be performed
with high diastereo- and enantioselectivity. The homologated
boronic esters can be further transformed into α-substituted
azetidines which cannot be accessed through direct α-
lithiation−electrophile trapping chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03901.
lithiobenzoate (S)-6b [generated by stereoretentive Sn−Li
exchange23 from the corresponding S stannane (95:5 er)].18
Pleasingly, both reactions proceeded to give homologated
boronic esters (R,R)- and (S,R)-5a, respectively, in high
diastereoselectivities and excellent enantioselectivities (up to
99:1 er), albeit with slightly lower yields compared with the
racemic homologation. Similar selectivities (up to 99:1 er) and
yields were also achieved for 5b.16
Full experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: david.hodgson@chem.ox.ac.uk.
ORCID
To demonstrate synthetic versatility of the homologated
boronic esters, further transformations of boronic ester 5a were
performed [Scheme 5, shown for (R*,R*)-5a; separately
examined (R*,S*)-5a behaved similarly].16 Oxidation of
boronic ester 5a to alcohol 7 was achieved using sodium
perborate in good yield (66%). Matteson homologation, using
dibromomethane, successfully gave the one-carbon homolo-
gated boronic ester 8 in high yield (79%). Arylation was
achieved using DDQ as the activating electrophile24 to give the
furanylated product 9 in moderate yield (55%). This reaction
also resulted in the formation of homoallylic amine 10 (28%).
The latter likely arises from a competitive 1,2-elimination/ring-
opening pathway, indicating that these C−B derivatizations, on
a system with a β-electron withdrawing functional group
incorporated within a strained ring, are not always straightfor-
ward. Finally, Botc deprotection of 5a in ethereal HCl gave the
David M. Hodgson: 0000-0001-7201-9841
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the EPSRC for studentship support (to P.K.D.).
■
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Org. Lett. XXXX, XXX, XXX−XXX