Enantioselective synthesis and cross-coupling of tertiary propargylic boronic esters using lithiation-borylation of propargylic carbamates

Article abstract of DOI:10.1002/anie.201203198

Lithiation-borylation of propargylic carbamates leads to tertiary propargylic boronic esters in very high e.r., provided that ethylene glycol boronic esters are used. These versatile intermediates undergo a range of highly stereoselective transformations, including protodeboronation to give tertiary allenes and Suzuki-Miyaura cross-couplings of tertiary boron species leading to tetrasubstituted allenes with high enantiospecificity. Copyright

Full text of DOI:10.1002/anie.201203198

Angewandte
Chemie
DOI: 10.1002/anie.201203198
Enantioselective Synthesis
Enantioselective Synthesis and Cross-Coupling of Tertiary Propargylic
Boronic Esters Using Lithiation–Borylation of Propargylic
Carbamates**
Benjamin M. Partridge, Laꢀtitia Chausset-Boissarie, Matthew Burns, Alexander P. Pulis, and
Varinder K. Aggarwal*
Chiral tertiary boronic esters have been shown to be useful
intermediates in organic synthesis, as they can undergo
a variety of functional group transformations, for example,
conversion to alcohols, amines, quaternary centers, or aryl-
dialkylmethines with high stereospecificity.[1] Recently, such
intermediates have become available in high ee through two
distinct methods: 1) borylation of Michael acceptors[2] or
allylic electrophiles,[3] and 2) lithiation–borylation of secon-
dary benzylic carbamates (Scheme 1),[4] which can deliver
exceptionally high enantioselectivities over a broad range of
substrates (> 99.1 e.r.).
We began our study with propargylic carbamates bearing
a terminal tBu group, as Hoppe had shown that hindered alkyl
groups were necessary for configurational stability of the
lithiated carbamate at À788C.[6] We were pleased to find that
lithiation–borylation of carbamate 1a with the hindered
isopropyl boronic acid pinacol ester (iPr-Bpin) did indeed
give the tertiary boronic ester 2aa (Table 1, entry 1). In
Table 1: Effect of the boronic ester diol on the lithiation–borylation
reaction.
Entry Diol [(OR)2]
X [equiv] Product Yield [%] e.r.[a] e.s. [%][b]
1
2
3
4
5
pinacol
pinacol
neopentyl
neopentyl
ethylene glycol
2
3
2
3
2
2aa
2aa
3aa
2aa
3aa
55[c]
55[d]
51[d]
80[c]
48[d]
51:49
52:48
68:32 38
89:11 81
98:2 100
2
4
Scheme 1. Existing methods for the synthesis of enantiomerically
enriched tertiary boronic esters. B(pin)=pinacolatoboron.
Although the lithiation–borylation method can be used in
the synthesis of tertiary boronic esters with high enantiose-
lectivities, it is limited to benzylic[4] and, more recently, allylic
substrates,[5] as unsaturation is required to enable the
deprotonation of the substituted carbamate to occur. We
were keen to broaden the scope of this useful method,
particularly towards propargylic substrates such as chiral
tertiary propargylic boronic esters, which could potentially
participate in an even broader array of functional group
transformations. Herein, we describe our success in achieving
this goal.
[a] Enantiomeric ratio determined after oxidation to alcohol 3. [b] See
ref. [8]. [c] Yield as determined by H NMR spectroscopy using 1,3,5-
trimethoxybenzene as an internal standard. [d] Yield of isolated product.
TMEDA=N,N,N’,N’-tetramethylethylenediamine.
1
contrast to other electrophiles, which had been reported to
give mixtures of a- and g-attack, or exclusively g-attack, the
regioselectivity of the homologation was exclusively a to the
carbamate.[6,7] In related reactions, high a regioselectivity
(with retention of stereochemistry) was also observed in the
case of allylic substrates.[5] In both cases, the origin of
selectivity may be a result of the coordination of the oxygen
of the boronic ester to lithium, thereby delivering the boronic
ester to the same site (and the same face as lithium).
However, in distinct contrast to the lithiation–borylation
with secondary benzylic and allylic carbamates, the alcohol
was found to be racemic, even when an excess of the boronic
ester was used (entries 1 and 2). We believed that this was due
to reversibility in formation of the boron “ate” complex.[4b,9]
Upon warming the ate complex, it was possible that reversi-
bility back to the lithiated carbamate could compete with 1,2-
metallate rearrangement, especially as the propargylic lithi-
ated carbamate was expected to have similar stability to the
corresponding lithiated benzylic and allylic carbamates, which
[*] Dr. B. M. Partridge, Dr. L. Chausset-Boissarie, M. Burns, A. P. Pulis,
Prof. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
[**] We thank EPSRC for funding, the Swiss National Foundation for
a fellowship (L.C.B.), the University of Bristol for a Post-Graduate
Scholarship (A.P.P.), the EPSRC-funded Bristol Chemical Synthesis
Doctoral Training Centre for a PhD studentship (M.B.), Inochem-
Frontier Scientific for their generous donation of boronic acids and
esters, Dr. Mairi Haddow for X-ray analysis, and R. Sanguramath for
help in making metal–allene complexes.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203198.
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Scheme 2. The “two electrophile test” to determine the extent of the reversibility of the ate complex formation. Reaction conditions: 1) Carbamate
(1 equiv), nBuLi (1.1 equiv), TMEDA (1.1 equiv), À788C, 20 min, 2) iPr-B(pin) (3 equiv), À788C, 1 h, 3) allyl bromide, À788C, 10 min, 4) CD3OD,
À788C to RT, 16 h; yield determined by 1H NMR spectroscopy. Bn=benzyl, B(pin)=pinacolatoboron, TMEDA=tetramethylethylenediamine.
were known to react reversibly in some cases.[10] However,
above about À708C the lithiated propargylic carbamate is
configurationally unstable and so could racemize.[6] Recom-
bination of this racemic lithiated carbamate with the boronic
ester would result in an erosion of e.r. This hypothesis was
tested using the “two electrophile test”.[4b] Carbamate 1a was
deprotonated at À788C and reacted with iPrBpin (Scheme 2).
Before warming the reaction mixture to room temperature,
allyl bromide was added followed 10 min later by CD3OD.
The product of allylation (4a) would indicate that the boron
ate complex formation was incomplete whereas any allene 5a
formed by deuteration would show that the boron ate com-
plex formation was reversible. Analysis of the crude reaction
mixture by 1H NMR indicated the presence of a single
product: allene 5a, with no boronic ester 2aa or allylated
product 4a observed.
was determined by X-ray analysis of an alcohol derivative
(see the Supporting Information).[12]
We tested a range of alkyl boronic esters and propargylic
carbamates with in situ oxidation and found that tertiary
propargylic alcohols could be obtained in consistently excel-
lent e.r. (Table 2). An excess of the boronic ester was found to
give slightly higher enantioselectivities (compare entries 1
Table 2: Substrate scope of lithiation–borylation of carbamate 1.
Several conclusions can be drawn from this experiment:
1) Deprotonation was complete after 20 min at À788C, as no
starting material was recovered.
2) Formation of the boron ate complex was complete after
1 hour at À788C, as no allylation was observed.
Entry
R[a]
R1
X
Product
e.r.
e.s.
[%]
[equiv]
(% yield)[a]
1
2
3
4
5
6
7
8
CH2Bn a
CH2Bn a
CH2Bn a
CH2Bn a
CH2Bn a
CH2Bn a
CH2Bn a
CH2Bn a
Me b
iPr a
iPr a
Et b
1.5
3
1.5
3
3
3
3
3
3
3
3aa (42)
3aa (48)
3ab (57)
3ab (58)
3ac (54)
3ad (44)
3ae (52)
3af (0)
96:4
98:2
96:4
98:2
98:2
96:4
95:5
–
96
100
96
100
100
96
94
–
94
92
3) Upon warming, all of the boron ate complex formed
reverted back to lithiated carbamate and was trapped by
CD3OD to give 5 as the sole product. This means that the
rate of reversibility is greater than the rate of 1,2-metallate
rearrangement (kÀ1 @ k2), which accounts for the signifi-
cantly lower enantioselectivity observed. Furthermore,
the rate of reversibility for propargylic carbamates is
considerably greater than for benzylic and allylic carba-
mates.[11]
Et b
Cyp c
allyl d
benzyl e
Ph f
9
iPr a
Et b
3ba (48)
3cb (44)
96:4
95:5
10[b]
iBu c
[a] Yield of isolated product. [b] The reaction mixture was heated at 408C
for 48h. Bn=benzyl, Cyp=cyclopropyl, TMEDA=tetramethylethylene-
diamine.
We reasoned that less hindered boronic esters would be
less prone to reversibility and so should lead to higher
enantioselectivity. Indeed, upon changing from pinacol to
neopentyl glycol to ethylene glycol, we saw a steady increase
in e.r. from ca. 50:50 to 89:11 to 98:2 (Table 1, entries 1–5).
Thus, we were able to obtain full retention of stereochemical
information from the carbamate using the ethylene glycol
boronic ester. The stereochemistry of the borylation reaction
and 2, and entries 3 and 4) as previously reported for the
corresponding reactions of aryl-stabilized lithiated carbama-
tes.[4a] In the case of phenylboronic acid glycol ester (entry 8),
whereas homologation proceeded effectively, rapid protode-
boronation of the resulting tertiary boronic ester occured
upon workup. The method was also extended to the less
hindered a-methyl carbamate 1b and the more hindered
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a-iso-butyl carbamate 1c, both of which afforded the
corresponding alcohols in high e.s. (entries 9 and 10).
This method provides a new approach to the synthesis of
tertiary propargylic alcohols in high e.r.,[13] compounds which
are of considerable value in synthesis; furthermore, this motif
is a key component in the HIV drug, Efavirenz.[14] However,
we also wanted to isolate the tertiary propargylic boronic
esters to further explore their potential in synthesis. Ethylene
glycol boronic esters are extremely moisture sensitive and so
transesterification of the homologated boronic ester with
pinacol was carried out, which enabled the isolation of a range
of tertiary propargylic pinacol boronic esters in excellent e.r.
(Table 3).
traditionally problematic owing to slow transmetallation and
competing b-hydride elimination, although there are now
several reports on the enantioselective cross-coupling of
secondary boronic esters.[18,19] However, we are not aware of
any reports on the enantioselective cross-coupling of a tertiary
boron intermediate.[20,21] The cross-coupling of tertiary prop-
argylic pinacol boronic ester brings with it further complica-
tions, as the coupling, if successful, could occur at the a or
g positions, thus leading to propargylic or allenic products,
respectively. Related examples of the cross-coupling of allylic
boronic acids/esters have been described, where the g cross-
coupled product was the major isomer observed, although
mixtures were often obtained.[22]
We began our investigations using the conditions of
Crudden,[18] and were delighted to find that cross-coupling of
2ab with phenyl iodide gave allene 7aba in high yield and
very high enantiospecificity (98% e.s.; Table 4). The reaction
was extended to a range of electron rich and electron poor
Table 3: Transesterification and protodeboronation of tertiary propar-
gylic boronic esters.
Table 4: Scope of cross-coupling of boronic ester 2 with aryl iodide.
Entry
R
R1
Ar Ratio Product
e.s.
7:6[a] (% yield)[b] [%]
Entry
R
R1 Product
(% yield)[a] [%]
e.s. Product
e.s.
[%]
(% yield)[a]
1
2
3
4
5
6
7
CH2Bn a Et b
CH2Bn a Et b
CH2Bn a Et b
Ph a 100:0 7aba (83)
pBrC6H4 b 90:10 7abb (65)
98
98
98
98
98
1
2
3
CH2Bn a iPr a 2aa (47)
CH2Bn a iPr a
CH2Bn a Et b 2ab (67)
Me b iPr a 2ba (81)
100 6aa (95)
100
pAcC6H4 c 95:5
7abc (80)
–
–
6aa (42)[b]
100
CH2Bn a Et b pMeOC6H4[c] d 80:20 7abd (72)
100 6ab (57)[b]
ND[c]
Me b iPr a
iBu c Et b
pAcC6H4 c 100:0 7bac (70)
pAcC6H4 c 100:0 7cbc (71) 100
Ph a 100:0 7 dba (75) 98
4[e]
5[e]
6
96
92
6ba (43)[b,d] ND[c]
iBu c
Et b 2cb (50)
Et b 2 db (66)
6cb (84)[d]
100
100
(CH2)2Ar[d]
d
Et b
(CH2)2Ar[f]
d
100 6 db (99)
[a] Determined by 1H NMR analysis of crude material. [b] Yield of
[a] Yield of isolated product. [b] One pot reaction from carbamate 1a.
[c] We were unable to separate the enantiomers by HPLC, SFC, or GC
(see the Supporting Information). [d] Pentane was used as the reaction
solvent. [e] The reaction mixture was heated at 408C for 48 h.
[f] Ar=pMeOC6H4. Bn=benzyl, gly=glycol, ND=not determined,
TBAF=tetrabutylammonium fluoride.
isolated product. [c] [Pd(PPh3)4] (5 mol%) was used as the Pd/ligand
source. [d] Ar=pMeOC6H4. dba=dibenzylideneacetone, DME=1,2-
dimethoxyethane, MS=molecular sieves.
aryl iodides, as well as a range of tertiary propargylic boronic
esters, which lead to fully substituted allenes in good yield and
essentially perfect e.s.[23] Competing protodeboronation of the
boronic ester was observed in some cases. This method
enables the preparation of all-carbon tetrasubstituted allenes
in highly enantiomerically enriched form, compounds which
have only rarely been previously described.[24]
Our proposed mechanism of the cross coupling reaction,
which accommodates the regio- and stereoselectivity
observed, is shown in Scheme 3. We propose that activation
of the boronic ester through a palladium–hydroxy species[25]
would facilitate transmetallation through a six-membered
transition state structure 9.[26] This would lead to an allenyl
palladium intermediate[22c] 10, which after reductive elimina-
tion would give the all-carbon tetrasubstituted allene 7ab.
Although the tetrasubstituted allenes prepared in Table 4
were either oils or solids which did not lead to crystals suitable
for X-ray crystallography, we were able to prepare a crystal-
line derivative that was suitable for analysis, which clearly
The fluoride-mediated protodeboronation of tertiary
benzylic boronic esters has been reported to give tertiary
alkanes in high e.r. and with retention of configuration.[15] In
the case of propargylic boronic esters, the reaction with
tetrabutylammonium fluoride (TBAF) proceeded through
a syn-SE’ mechanism[16] to give trisubstituted allenes[17] 6 in
excellent yield and enantioselectivity (Table 3). The stereo-
chemistry of the protodeboronation reaction was determined
by X-ray analysis[12] (see the Supporting Information), which
indicated that protonation had once again occurred with
retention of configuration. A one-pot procedure from carba-
mate 1a gave allene 6aa directly, without detriment to the
yield or e.r. (entry 2). The reaction was successfully applied to
a range of tertiary propargylic boronic esters (entries 3–6).
We next turned our attention to the significantly more
challenging enantioselective Suzuki–Miyaura cross-coupling.
The use of sp3 hybridized organoboron species has been
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Scheme 3. Proposed mechanism to account for the stereochemistry of
the cross-coupling. Bn=benzyl, B(pin)=pinacolatoboron, TMEDA=
tetramethylethylenediamine.
shows the orientation of the four substituents around the
allene moiety (Figure 1).[12] This enabled us to determine the
absolute configuration of the tetrasubstituted allene, which
showed that cross-coupling had occurred with retention of
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variable and electrophile-dependent when tBu is in the g-
position. MeOH reacts solely at the g-position, but TMSCl reacts
exclusively at the a-position. Allyl bromide (a:g = 8:1) and MeI
(a:g = 1:1.2) give intermediate selectivities.
Figure 1. X-ray structure of a tetrasubstituted allene derived from
7 dba. Thermal ellipsoids set at 30% probability.
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In conclusion, we have found that the lithiation–boryla-
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tertiary propargylic boronic esters in very high e.r. provided
that the less hindered ethylene glycol boronic esters are
employed. These versatile intermediates undergo a range of
highly stereoselective transformations, including protode-
boronation to give tertiary allenes, and Suzuki–Miyaura
cross-couplings of tertiary boron species leading to tetrasub-
stituted allenes with essentially perfect enantiospecificity.
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propargylic susbtrates (63); see: R. Breslow, J. L. Grant, J. Am.
Chem. Soc. 1977, 99, 7745 – 7746.
[12] CCDC 878283 (for the ester derived from alcohol 3aa), 878284
(for an allene related to 6), and 878285 (for the allene derived
from 7abd), contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
Received: April 25, 2012
Published online: October 17, 2012
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Keywords: allenes · boronic esters · cross-coupling · lithiation ·
propargylic alcohols
.
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