Full chirality transfer in the synthesis of hindered tertiary boronic esters under: In situ lithiation-borylation conditions

Article abstract of DOI:10.1039/c6cc00536e

Hindered tertiary neopentyl glycol boronic esters can be prepared by using in situ lithiation-borylation of enantiopure secondary benzylic carbamates at -20°C with full chirality transfer.

Full text of DOI:10.1039/c6cc00536e

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Full chirality transfer in the synthesis of
hindered tertiary boronic esters under in situ
lithiation–borylation conditions†
Cite this:DOI: 10.1039/c6cc00536e
Received 19th January 2016,
Accepted 14th March 2016
D. J. Blair,‡ S. Zhong,‡ M. J. Hesse, N. Zabaleta, E. L. Myers and V. K. Aggarwal*
DOI: 10.1039/c6cc00536e
www.rsc.org/chemcomm
Hindered tertiary neopentyl glycol boronic esters can be prepared by
using in situ lithiation–borylation of enantiopure secondary benzylic
carbamates at À20 8C with full chirality transfer.
Boronic esters are versatile intermediates in synthesis and there
are now numerous methods for their preparation in enantio-
enriched form.1 In the case of tertiary boronic esters, which are
more difficult to prepare, a number of stereoselective and stereo-
specific methods have emerged over recent years (Scheme 1a (ref. 2)
and Scheme 1b (ref. 3)). The stereospecific lithiation–borylation of
enantiopure secondary carbamates (Scheme 1b), which has been
developed in our research group,3 has been employed by others4
and indeed has even been scaled up to 24 kg.5 For this scale-up, the
cryogenic conditions commonly employed (sBuLi, À78 1C)6 pre-
sented challenges. However, Fandrick5 discovered that the carb-
amate could be deprotonated by a weaker base (LDA) and that this
deprotonation could be conducted in the presence of pinacol
boronic esters (in situ conditions) at elevated temperatures (0 1C),
to give the corresponding tertiary boronic esters with high levels of
enantiospecificity (Scheme 1c). At such an elevated temperature,
having the boronic ester present in the reaction mixture during the
deprotonation prevents epimerisation and/or decomposition of
lithiated carbamate 1.
Scheme 1 State of the art: synthesis of tertiary boronic esters.
With more hindered secondary boronic esters, such as iPrBpin, by the reverse process thereby leading to high yields and high
lower levels of enantiospecificity were observed, presumably due to stereoselectivity.3a Unfortunately, the addition of MgBr2 in
reversible formation of boronate complex 2. Such a process would methanol is not compatible with an in situ lithiation–borylation
return the sensitive lithiated carbamate 1, which would undergo reaction. Herein, we address the issue of low selectivity with
racemisation and recombination with the boronic ester, thus hindered boronic esters and show that by using neopentyl glycol
leading to reduced stereoselectivity B80% es (Scheme 1b). We boronic esters7 and LTMP (lithium 2,2,6,6-tetramethylpiperidine)
have previously found that the addition of MgBr2/methanol as a base, high levels of enantiospecificity can now be achieved
following boronate complex formation enhances the rate of even with some of the most hindered boronic esters under non-
1,2-migration and quenches any lithiated carbamate generated cryogenic conditions.
During our investigations of lithiation–borylation methodology
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK.
we found that the nature of the ligand on boron sometimes
affected the enantioselectivity of the process.3b,8 This is most
E-mail: v.aggarwal@bristol.ac.uk; Fax: +44 (0)117 929 8611;
Tel: +44 (0)117 954 6315
dramatically illustrated in the case of the propargylic carbamate
† Electronic supplementary information (ESI) available: Full experimental details
3 where upon moving from the pinacol to the ethylene glycol
and characterisation. See DOI: 10.1039/c6cc00536e
‡ These authors contributed equally.
based isopropyl boronic ester, enantiospecificity increased
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complete enantiospecificity. The para-phenyl-substituted carbamate
is especially prone to racemisation and using iPrBpin gave 8 in low
enantiospecificity (83% es). However, using the neopentyl glycol
boronic ester, 8 was again obtained in high yield and enantio-
specificity. Electron-withdrawing groups on the aromatic ring
engenders reversibility in the formation of the boronate complex,
thus rendering the lithiated carbamate more prone to racemisation.
We found that although a single meta-CF3 group was tolerated,
enabling formation of 9 with excellent enantiospecificity, two meta-
CF3 groups was a step too far and led to essentially racemic product
(10).9 A hindered ester was compatible with our conditions and gave
tertiary alcohol 11 with complete enantiospecificity. This functional
group would not have been compatible with the preformed lithiated
carbamate. Unfortunately, the use of ortho-substituted benzylic
carbamates did not lead to the expected products. In contrast, we
have previously shown these carbamates do give the expected
products in good yield and near-complete enantiospecificity when
subjected to our cryogenic lithiation–borylation conditions.3a,10
Because the stereoselectivity of the in situ lithiation–borylation
reaction is affected by the steric bulk of the boronic ester substituent
(R group), we tested a range of boronic esters of varying steric
demand and compared both the pinacol (A) and neopentyl glycol (B)
derivatives (Scheme 5). For unhindered nBu (13) and cyclopropyl (14)
boronic esters high enantiospecificity was observed by using pinacol
boronic esters (98% es), with neopentyl glycol boronic esters behav-
ing similarly. Surprisingly, with unhindered allyl boronic esters (15)
the pinacol derivative gave low es (82%) whilst the neopentyl glycol
ester provided essentially complete enantiospecificity.
Scheme 2 Influence of the boron ligand on the stereochemical outcome
of the lithiation–borylation of 3; these results are taken from ref. 8a and are
shown for comparison to results below (see Scheme 7).
from 4% to 100% (Scheme 2).8a Presumably, as the steric
hindrance around boron was reduced, the boronate complex
became less prone to reversibility and consequently the inter-
mediate lithiated carbamate suffered less racemisation.
We therefore explored Fandrick’s in situ conditions5 with
iPrBneo in place of iPrBpin. These conditions gave tertiary alcohol
5 from 4 with full stereospecificity (100% es, Scheme 3), a sub-
stantial improvement on that obtained using the pinacol boronate
(80% es).5 Other bases were tested and LTMP led to a higher yield
(74%). Further improvement in the yield was realised by reducing
the temperature from 0 1C to À20 1C, resulting in 5 being isolated
in 90% yield and 100% es.
Our optimised conditions were applied to a range of otherwise
challenging carbamates (Scheme 4). As noted by Fandrick, the in situ
conditions involving an amide base in place of an organolithium
base enables aryl bromides and iodides to be employed, and so
these were initially tested. Using our conditions, these substrates
gave the corresponding tertiary alcohols 6 and 7 in high yields and
To explore the limits in steric bulk that could be tolerated we
turned to 3-pentyl boronic esters.11 Reaction of 3-pentyl-Bpin with
12 under our in situ conditions gave only traces of 16 with poor
enantioselectivity. Simply switching to the corresponding neopentyl
glycol ester significantly increased both the yield and selectivity,
thus highlighting the advantages associated with neopentyl glycol
derivatives, particularly in their application to hindered systems.
We have previously shown that secondary benzylic pinacol
boronic esters form reversible boronate complexes with secondary
benzylic carbamates leading to loss of both diastereo- and enantio-
selectivity.8c The application of in situ conditions to the reaction of
(R)-1-phenylethyl pinacol boronic ester with 12 gave 17 in high yield
(90%, Scheme 6), high enantiospecificity (100% es) with respect to
Scheme 3 Conditions for the homologation of neopentyl glycol boronic
esters.
Scheme 5 Influence of boronic ester substituent on the in situ lithiation–
borylation reaction of 12. a Because the use of the pinacol boronic ester gave
tertiary alcohol 14 with complete diastereospecificity, the corresponding
experiment with the neopentyl glycol boronic ester was not carried out.
Scheme 4 Carbamate scope for the in situ lithiation–borylation of iPrBneo.
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We thank European Research Council (FP7/2007-2013, ERC
grant no. 246785; H2020/2015-2020, ERC grant no. 670668), and
EPSRC (EP/I038071/1) for financial support. N. Z. thanks UPV/EHU
predoctoral mobility program. S. Z. thanks the EPSRC-funded
Bristol Synthesis Centre for Doctoral Training (EP/L015366/1).
Notes and references
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tion of Organoboron Compounds, ed. E. Fernandez and A. Whiting,
Springer International Publishing, 2015.
Scheme 6 The influence of boronic ester diol on the stereochemical
outcome of homologation of (R)- and (S)-1-phenylethyl boronic esters
with 12 under in situ conditions using pinacol (A) and neopentyl glycol (B)
boronic esters.
2 (a) I. H. Chen, L. Yin, W. Itano, M. Kanai and M. Shibasaki, J. Am.
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X. Liu, G. Li and W. Tang, J. Am. Chem. Soc., 2015, 137, 6746; For
recent syntheses of racemic tertiary boronic esters see: ( f ) A. J.
Wommack and J. S. Kingsbury, Tetrahedron Lett., 2014, 55, 3163;
(g) K. Hong, X. Liu and J. P. Morken, J. Am. Chem. Soc., 2014, 136, 10581.
3 (a) J. L. Stymiest, V. Bagutski, R. M. French and V. K. Aggarwal, Nature,
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F. G. Buono, A. Duran, R. Schmid, J. Daeubler, J.-N. Desrosier, X. Zeng,
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the boronic ester starting material, but low diastereoselectivity
(85 : 15 dr).12 Simply switching to the corresponding neopentyl
glycol boronic ester gave 17 in 94 : 6 dr, 100% es and high yield.
In contrast, reaction of 12 with both pinacol and neopentyl glycol
(S)-1-phenylethyl boronic esters gave 18 in high yield and selectivity
(Z95 : 5 dr, 100% es).13 Evidently, there is a significant matched/
mis-matched effect operating under the reversible conditions with
the pinacol boronic esters that can be minimised by using the
neopentyl glycol boronic esters.
As noted above, for substrates that are especially prone to
reversibility in boronate formation and therefore racemisation
(e.g. 8), the in situ conditions using neopentyl glycol boronic
esters can lead to considerably higher levels of enantiospecificity.
We therefore tested our in situ conditions with the secondary
propargylic carbamate 19, a substrate that only gave 81% es
under conditions where the lithiated carbamate was preformed8a
(Scheme 7). Under the new in situ conditions the tertiary pro-
pargylic alcohol 20 was obtained in high yield and excellent
enantiospecificity (98% es).14 This highlights the broad applic-
ability of the new in situ lithiation–borylation protocol.15
In summary, we have found that almost complete enantio-
specificity can be achieved in the lithiation–borylation reactions
of secondary benzylic carbamates under in situ conditions when
neopentyl glycol boronic esters are used in place of pinacol
boronic esters. These conditions expand the range of tertiary
boronic esters that can be prepared with very high selectivity
with both increased functional-group and steric tolerance. The
improved stereoselectivity results from reduced reversibility in
boronate complex formation, a process that otherwise causes
racemisation of the sensitive lithiated carbamate.
6 (a) D. Hoppe, A. Carstens and T. Kramer, Angew. Chem., Int. Ed.
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1994, 50, 6097.
7 Neopentyl glycol boronates, which are less sterically hindered than
the corresponding pinacol boronic esters, have found application in
other organoboron transformations besides lithiation–borylation.
For selected examples, see: (a) F. J. Lawlor, N. C. Norman, N. L.
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´
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Scheme 7 Enhanced stereospecificity using in situ conditions in the
lithiation–borylation reaction of secondary propargylic carbamates.
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9 Reducing the steric bulk of the boronic ester reaction partner from
iPr to Et had no effect on the stereochemical outcome.
corresponding boronate complex towards fragmentation to Li-12
rather than fragmentation of the C–B bond of the secondary boronic
ester substrate to form a benzylic anion.
10 The ortho-bromo isomer of
6 and an ortho-methyl substrate
(not depicted), did not lead to the expected products. The former 14 For the propargylic carbamates, unfortunately the use of a trialkyl-
substrate did not react whereas the latter gave a mixture of isomeric
species derived from its fragmentation into the corresponding
silyl substituent in place of a t-butyl group led to desilylated products
not incorporating the boronic ester organic group.
ortho-quinodimethane followed by (4+2) cycloaddition. See the ESI,† 15 We have previously shown that when substituted allylic carbamates
for further details on this side reaction.
11 tBu boronic esters were also tested but both pinacol and neopentyl
glycol esters failed to react under the in situ conditions.
12 Enantiospecificity was determined for the major diastereoisomer.
13 No epimerisation of the secondary boronic ester stereocentre was
observed in either 17 or 18 with pinacol or neopentyl glycol esters.
The presence of an electron-withdrawing group in 12 must bias the
are subjected to lithiation–borylation reactions under cryogenic
conditions with neopentyl glycol boronic esters as partners, a
mixture of products derived from a- and g-borylation are obtained:
(a) A. P. Pulis, PhD thesis, University of Bristol, 2012. However, the
use of pinacol boronic esters lead to predominantly the required
a-borylation: (b) A. P. Pulis and V. K. Aggarwal, J. Am. Chem. Soc.,
2012, 134, 7570.
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