Enantioselective installation of adjacent tertiary benzylic stereocentres using lithiation-borylation-protodeboronation methodology. Application to the synthesis of bifluranol and fluorohexestrol

Article abstract of DOI:10.1039/c4sc03901g

1,2-Diaryl ethanes bearing 1,2-stereogenic centres show interesting biological activity but their stereocontrolled synthesis has not been reported forcing a reliance of methods involving diastereomer and enantiomer separation. We have found that this clas

Full text of DOI:10.1039/c4sc03901g

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Enantioselective installation of adjacent tertiary
benzylic stereocentres using lithiation–borylation–
protodeboronation methodology. Application to
the synthesis of bifluranol and fluorohexestrol†
Cite this: DOI: 10.1039/c4sc03901g
*
Stefan Roesner, Daniel J. Blair and Varinder K. Aggarwal
1,2-Diaryl ethanes bearing 1,2-stereogenic centres show interesting biological activity but their
stereocontrolled synthesis has not been reported forcing a reliance of methods involving diastereomer
and enantiomer separation. We have found that this class of molecules can be prepared with very high
stereocontrol using lithiation–borylation methodology. The reaction of an enantioenriched benzylic
lithiated carbamate with an enantioenriched benzylic secondary pinacol boronic ester gave a tertiary
boronic ester with complete diastereo- and enantiocontrol. It was essential to use MgBr2/MeOH after
formation of the boronate complex, both to promote the 1,2-migration and to trap any lithiated
carbamate/benzylic anion that formed from fragmentation of the ate complex, anions that would
otherwise racemise and re-form the boronate complex eroding both er and dr of the product. When the
benzylic lithiated carbamate and benzylic secondary pinacol boronic ester were too hindered, boronate
complex did not even form. In these cases, it was found that the use of the less hindered neopentyl
boronic esters enabled successful homologation to take place even for the most hindered reaction
partners, with high stereocontrol and without the need for additives. Protodeboronation of the product
boronic esters with TBAF gave the target 1,2-diaryl ethanes bearing 1,2-stereogenic centres. The
methodology was applied to the stereocontrolled synthesis of bifluranol and fluorohexestrol in just 7 and
5 steps, respectively.
Received 16th December 2014
Accepted 11th April 2015
DOI: 10.1039/c4sc03901g
www.rsc.org/chemicalscience
In recent years, we have developed lithiation–borylation
methodology of primary8 and secondary9 carbamates for the
Introduction
stereocontrolled synthesis of secondary and tertiary boronic
esters (Scheme 1A). The process is related to Blakemore's
reactions of a-lithiated alkylchlorides10 and follows the funda-
mental work of Matteson on 1,2-metallate rearrangements of
boronic esters.11 We considered the consecutive use of this
reaction coupled with protodeboronation methodology12 for the
Numerous methods have been developed for acyclic stereo-
control, the most highly developed being the aldol reaction
where high levels of 1,2- and 1,3-stereocontrol can be achieved.1
For molecules without hydroxyl functionality, 1,2- and 1,3-
stereocontrol is much more difficult and general synthetic
methods are sparse. This problem is highlighted in the
synthesis of the antiandrogen, biuranol2 (Prostarex, 1), and the
potential imaging agent, uorohexestrol3 2 (used for the visu-
alisation of human breast tumours), where neither relative nor
absolute stereocontrol could be achieved.4 These rather unusual
molecules bear a structural similarity to the hormone estradiol,
accounting for their particular biological activity.5 Other chal-
lenging molecules bearing contiguous alkyl groups but devoid
of other functionality include the lignin, (+)-guaiacin6 (3), and
the potent glucokinase-activating agent, tatanan A7 (4) (Fig. 1).
School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
E-mail: v.aggarwal@bristol.ac.uk; Fax: +44 (0)117 925 1295; Tel: +44 (0)117 954 6315
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and spectroscopic data for all new compounds. X-Ray data analysis
for compound 2. See DOI: 10.1039/c4sc03901g
Fig. 1 Representative biologically active molecules.
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temperature for 16 h; (ii) conditions B: addition of the boronic
ester to the lithiated carbamate at ꢀ78 ꢁC followed aer 2 h by
addition of 1.3 equivalents of a solution of MgBr2 in MeOH and
subsequent warming to room temperature for 16 h. Under
conditions A, the reaction of the least sterically hindered
carbamate 5 and boronic ester 7 gave tertiary boronic ester 13 in
high yield (81%). Increasing the steric demand of the secondary
boronic ester (conditions A) resulted in decreasing yields (15:
71%, 17: 47%, 19: 22%). Increasing the steric demand of the
carbamate 6 had an even bigger impact on the yield of the
product boronic esters, which were now only obtained in poor
yields. In fact, in the case of the most sterically hindered
substrates (carbamate 6 and boronic ester 10) the boronate
complex did not even form as determined by 11B NMR. Condi-
tions B, which used MgBr2 in MeOH, were then explored for
reactions involving pinacol boronic esters. This additive is
known to have two distinct effects on lithiation–borylation
reactions: (i) it increases the relative rate of 1,2-migration of the
intermediate boronate complex over reversibility back to the
starting components and (ii) any anions formed from revers-
ibility are quenched, thus preventing re-addition.9b In almost all
cases, the yield of the boronic ester was signicantly increased
with this additive, thus demonstrating its ability in promoting
1,2-migration over reversal. Without this additive, the lower
yields are likely to be due to decomposition of the boronate
complex back to the starting materials. Only in the case of the
most hindered boronic ester 10 was no improvement observed
(20).
The low yields observed with the hindered secondary pinacol
boronic esters 9 and 10 prompted us to explore the corre-
sponding neopentyl boronic esters, 11 and 12. In fact, these
substrates worked very well and high yields were restored even
with the highly hindered carbamates. Furthermore, with the
neopentyl boronic esters no further additives were required to
promote the 1,2-migration.14 For substrates that are prone to
reversibility due to steric hindrance of the carbamate (e.g.
secondary benzylic)9b or are electronically stabilised (e.g. prop-
argylic)15 the use of less hindered diol esters is oen benecial,
leading to both enhanced yields and selectivities.
An intriguing observation in this study was that the additive
MgBr2/MeOH had a major impact on the diastereomeric ratio
(syn/anti ratio) of the reaction. This is most dramatically illus-
trated in the reaction of carbamate 6 with boronic ester 8: under
conditions A, a ꢂ1 : 1 ratio of syn : anti isomers were formed,
but in the presence of MgBr2/MeOH (conditions B) the anti
diastereoisomer (R,S) of 16 was formed almost exclusively
(95 : 5).
Scheme
1 (A) Reactions of hindered carbamates with hindered
boronic esters. (B) Proposed reactions of hindered carbamates with
hindered boronic esters for the synthesis of contiguous chiral benzylic
centres.
synthesis of adjacent tertiary stereocentres (Scheme 1B).
Furthermore, this strategy allows control of each stereocentre
independently, thereby enabling the synthesis of any stereo-
isomer at will. Whilst key steps 1 and 3 had good literature
precedent, step 2, the reaction of the secondary carbamate with
a highly hindered boronic ester did not (Scheme 1B). Only
reactions of unhindered secondary carbamates (R1 ¼ Me) with
moderately hindered boronic esters had been reported.9a,b,13 In
this paper we show the limits of lithiation–borylation reactions
and how, under the right conditions, the coupling of even
highly hindered secondary carbamates with hindered boronic
esters can be achieved with very high stereocontrol. We have
also demonstrated its strategic use in the enantio- and dia-
stereoselective synthesis of the antiandrogen, biuranol (1),
and the potential imaging agent, uorohexestrol (2), validating
the synthetic utility of this methodology.
Results and discussion
Effect of steric hindrance in the lithiation–borylation reaction
We began our studies with a systematic investigation of the
In order to understand this reaction further, the fate of each
effect of steric hindrance on the outcome of the lithiation– stereocentre during the transformation was mapped out by
borylation reaction between a secondary racemic benzylic carrying out the reaction with enantioenriched materials
carbamate and a secondary (racemic) boronic ester (Table 1). (Scheme 2). Without any additive (conditions A) the products
Two representative secondary benzylic carbamates (5 and 6) and from equations (i) and (ii) were obtained as a mixture of dia-
four representative secondary pinacol boronic esters (7–10) stereoisomers and with substantial erosion in enantiomeric
were chosen as substrates, each of increasing steric demand. enrichment of both diastereoisomers. This means that erosion
The reactions were conducted under two sets of standard of both stereocentres occurred during the process of the reac-
conditions: (i) conditions A: addition of the boronic ester to the tion to a signicant degree. From these experiments it is clear
lithiated carbamate at ꢀ78 ꢁC followed by warming to room that reversibility is occurring but in different ways (Scheme 3).
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Table 1 Investigation of the steric influence in the lithiation–borylation reactiona,b
a
Reaction conditions: A: (i) 1.3 equiv. sBuLi, Et2O (0.3 M), ꢀ78 ꢁC, 1 h; (ii) 1.5 equiv. boronic ester in Et2O (1.0 M), ꢀ78 ꢁC, 2 h; (iii) ꢀ78 ꢁC / r.t., o/
n; B: (i) and (ii) as A; (iii) 1.3 equiv. of MgBr2 in MeOH (1.0 M), then ꢀ78 ꢁC / r.t., o/n. b The ratio of anti to syn diastereoisomers determined by 1H
NMR spectroscopy is shown in parentheses (for details see ESI). Yield determined by 1H NMR spectroscopy with internal standard. Traces of
c
d
product could be detected by GC/MS but isolation was unsuccessful.
The intermediate boronate complex 25 has three competing reversibility but because they are both benzylic, they can frag-
fates: it can undergo (i) 1,2-metallate rearrangement to give ment in either way to give stabilised benzylic anions.
boronic ester 16, (ii) fragmentation back to the starting mate-
In contrast, in the presence of MgBr2/MeOH, reaction of (S)-6
rials or (iii) fragmentation to boronic ester 26 and benzylic with (S)-8 or (R)-8 gave the anti (R,S)-16 (i) or the syn (S,S)-16 (ii)
carbanion 27. Racemisation of 6 and 27, re-addition to the
appropriate boronic ester, and 1,2-rearrangement then leads to
a mixture of diastereoisomers with low enantiomeric excess
(Scheme 3). Evidently, these reaction partners are most chal-
lenging since they are not only hindered and prone to
Scheme 2 Mapping the fate of the stereocentres when using different
reaction conditions. Reaction conditions: A: 1.3 equiv. sBuLi, Et2O (0.3
M), ꢀ78 ꢁC, 1 h; 1.5 equiv. boronic ester in Et2O (1.0 M), ꢀ78 ꢁC, 2 h;
ꢀ78 ꢁC / r.t., o/n; B: 1.3 equiv. sBuLi, Et2O (0.3 M), ꢀ78 ꢁC, 1 h; 1.5
equiv. boronic ester in Et2O (1.0 M); 1.3 equiv. of MgBr2 in MeOH (1.0 Scheme 3 Origin of the four stereoisomers observed from the reac-
M), then ꢀ78 ꢁC / r.t., o/n.
tion of (S)-6 with (S)-8 under reaction conditions A.
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isomer with high selectivity as a single enantiomer in high yield
(Scheme 2). Under these conditions, boronate complex forma-
tion is non-reversible and is followed by stereospecic 1,2-
metallate rearrangement.
Any boronate complex that does undergo fragmentation
back to the starting materials is quenched by the MeOH and no
longer participates in the reaction. The selectivity is therefore
determined in the addition step leading to the boronate
complex 25. The high diastereoselectivity observed when (rac)-6
was reacted with (rac)-8 showed that there was a strong
matched/mis-matched effect in operation, i.e. (S)-6 reacted with
(S)-8 considerably faster than with (R)-8 giving the anti (R,S)
diastereoisomer preferentially (note, there is a change in
priority of one of the centres). However, when using enan-
tioenriched materials even in the mis-matched case [(S)-6 with
(R)-8; Scheme 2, equation ii], high yield was still obtained
showing that the slower rate of formation of the boronate
complex was not accompanied by undesired side reactions.
To explore the scope of the asymmetric reactions, four
representative enantioenriched carbamates (S)-/(R)-5/6 were
reacted with two representative hindered neopentyl boronic
esters (S)-11 and 12 (Scheme 4). Neopentyl boronic esters were
chosen because they gave higher yields than pinacol boronic
esters (Table 1). In all cases, high diastereo- and enantio-selec-
tivity was observed indicating that the reactions were essentially
non-reversible. Since both diastereoisomers 21 and 22 were
formed in similar yields and selectivities it shows that once
again the reactions are dominated by reagent control. A small
but detectable matched/mis-matched effect was observed since
(2S,3R)-21 was formed with slightly higher dr than (2R,3R)-21
(>99 : 1 vs. 93 : 7). The low level of erosion of er in the case of the
highly hindered substrate 24 (95 : 5 er) is most likely due to a
small degree of reversibility in this case. Compounds 16, 21, 22
Scheme 5 Retrosynthetic scheme for the synthesis of bifluranol 1 and
fluorohexestrol 2.
and 24 were all oxidised to the corresponding tertiary alcohols
for ee determination.
Enantioselective synthesis of biuranol
Having found conditions under which high diastereoselectivity
could be achieved, we sought to apply this methodology to the
enantioselective synthesis of biuranol (1), an antiandrogen with
the ability to treat benign prostate enlargement,2 and uorohex-
estrol (2), a potential non-steroidal oestrogen receptor based
imaging agent for the visualisation of human breast tumours.3
The retrosynthetic analysis of 1 and 2 is illustrated in Scheme 5.
By using a convergent synthetic strategy, we proposed to build up
both stereogenic centres by applying two consecutive lithiation–
borylation reactions followed by protodeboronation.
Scheme 6 Synthesis of bifluranol 1. Reagents and conditions: (a) CbCl
(1.0 equiv.), Et3N (1.3 equiv.), n-propanol, sealed tube, mW, 150 ꢁC, 1 h,
92% yield; (b) pinacol (1.0 equiv.), Et2O, r.t., 16 h; MgSO4 (3.0 equiv.), r.t.,
2 h, quant.; (c) (+)-sparteine (1.3 equiv.), sBuLi (1.3 equiv.), Et2O, ꢀ78 ꢁC,
5 h; 29 (1.5 equiv.), ꢀ78 ꢁC, 2 h; r.t., Et2O / CHCl3; reflux, 15 h, 76%
yield; (d) NaH (1.5 equiv.), THF, r.t., 75 min; CbCl (1.2 equiv.), THF, reflux,
24 h, >99% yield; (e) TMEDA (1.3 equiv.), sBuLi (1.3 equiv.), Et2O, ꢀ78 ꢁC,
1 h; (S)-30 (1.5 equiv.), ꢀ78 ꢁC, 2 h; r.t., 14 h, 95% yield; (f) TBAF$3H2O
(3.0 equiv.), toluene, reflux, 3 h, 99% yield; (g) NBS (1.1 equiv.), MeCN,
r.t., 21 h, 94% yield; (h) nBuLi (1.3 equiv.), THF, ꢀ78 ꢁC, 30 min; NFSI (1.2
equiv.), ꢀ78 ꢁC, 2 h; (j) BBr3 (3.0 equiv.), CH2Cl2, ꢀ20 ꢁC; 30 min; 4 ꢁC,
Scheme 4 Scope of stereoselective synthesis of hindered tertiary 16 h, 43% yield over 2 steps. CbCl ¼ N,N-diisopropylcarbamoyl
neopentyl boronic esters. Reaction conditions: 1 equiv. carbamate, 1.3 chloride, sBuLi ¼ sec-butyllithium, TMEDA ¼ N,N,N0,N0-tetramethy-
equiv. sBuLi, Et2O (0.3 M), ꢀ78 ꢁC, 1 h; 1.5 equiv. boronic ester in Et2O lethylenediamine, TBAF$3H2O ¼ tetrabutylammonium fluoride trihy-
(1.0 M), 3 h; then ꢀ78 ꢁC / r.t., o/n. The ratios of enantiomers and drate, NBS ¼ N-bromosuccinimide, nBuLi ¼ n-butyllithium, THF ¼
diastereoisomers were determined by chiral HPLC.
tetrahydrofuran, NFSI ¼ N-fluorobenzenesulfonimide.
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Scheme 7 Lithiation–deuteration of carbamate 32 and 36 to deter-
mine site of lithiation.
We began with the synthesis of biuranol. Carbamate 28 was
prepared from n-propanol and subsequent lithiation in the
presence of (+)-sparteine16 followed by borylation with pinacol
boronic ester 29 gave the secondary boronic ester 30 in 76%
yield and with 98 : 2 er (Scheme 6-i). Aryl groups are not good
migrating groups17 in lithiation–borylation reactions and oen
Scheme 8 Synthesis of fluorohexestrol 2. Reaction conditions: (a) 1-
bromopropane (3.0 equiv.), 2,4,6-triisopropylbenzoic acid (1.0 equiv.),
NBu4HSO4 (0.08 equiv.), NaOH (3.0 equiv.), CHCl3/H2O (1 : 1), 84%
yield; (b) neopentylglycol (1.0 equiv.), Et2O, r.t., 16 h; MgSO4 (3.0
need assistance by either using MgBr2 in Et2O8a or solvent equiv.), r.t., 2 h, 95% yield; (c) 37 (1.8 equiv.), (ꢀ)-sparteine (1.7 equiv.),
sBuLi (1.7 equiv.), Et2O, ꢀ78 ꢁC, 5 h; 38 (1 equiv.), ꢀ78 ꢁC, 1 h; reflux, 15
h, 46% yield; (d) CbCl (1.2 equiv.), Et3N (1.3 equiv.), toluene, mW, 150 ꢁC,
2 h, 98% yield; (e) TMEDA (1.3 equiv.), sBuLi (1.3 equiv.), Et2O, ꢀ78 ꢁC, 1
h; (R)-40 (1.5 equiv.), ꢀ78 ꢁC, 3 h; r.t., 14 h, 70% yield; (f) TBAF$3H2O
(3.0 equiv.), toluene, reflux, 3 h, 81% yield; (g) BBr3 (3.0 equiv.), CH2Cl2,
exchange.18 In this case we employed a solvent exchange from
diethyl ether to CHCl3 to promote the 1,2-migration and thereby
increase the yield of the reaction.
The second partner, carbamate 36, was prepared from the
corresponding ketone. However, in test reactions we found that ꢀ20 ꢁC, 30 min; 4 ꢁC, 15 h, 72% yield. TIB ¼ 2,4,6-triisopropylbenzoyl,
sBuLi ¼ sec-butyllithium, TMEDA ¼ N,N,N0,N0-tetramethylethylene-
lithiation–deuteration of carbamate 36 gave complete H/D
diamine, TBAF$3H2O ¼ tetrabutylammonium fluoride trihydrate.
exchange, not at the benzylic position as required, but instead
in the position ortho to the methoxy group, presumably as a
result of its greater acidity and the directing effects of the F and
OMe substituents (Scheme 7).19 We therefore decided to intro-
duce this uorine substituent at the end of the synthesis.
Carbamate (S)-32 was prepared from alcohol (S)-31 in
quantitative yield and with 98% ee (Scheme 6-ii).20 Lithiation
followed by addition of boronic ester (S)-30 gave tertiary boronic
ester 33 in 95% yield and with >95 : 5 dr in favour of the desired
anti isomer. Surprisingly, no additives were necessary to accel-
erate the 1,2-migration of the intermediate boronate complex,
presumably because the p-MeO group on the carbamate accel-
erates the 1,2-migration by electron donation. Tertiary boronic
ester 33 was protodeboronated in nearly quantitative yield to
furnish 34 using TBAF$3H2O with retention of stereochemistry
and without any erosion of dr. Electrophilic aromatic bromi-
nation with NBS, lithiation and uorination with NFSI (N-uo-
robenzenesulfonimide)21 and nally deprotection of both
methoxy groups gave 1 in 40% yield over three steps. Overall,
biuranol was synthesised in 7 steps (longest linear sequence)
and 27% overall yield as a single stereoisomer.
gave the homologated boronic ester 41 in 70% yield and 95 : 5
dr (Scheme 8). Subsequent protodeboronation using
TBAF$3H2O gave diarylethane 42 in 81% yield with minimal
erosion of dr. Deprotection of the methoxy groups using BBr3
and separation of the minor syn diastereoisomer by column
chromatography gave uorohexestrol 2. The anti conguration
of uorohexestrol was conrmed by single-crystal X-ray
diffraction analysis (see ESI†). Fluorohexestrol was obtained in
18% overall yield in just 5 linear steps from commercially
available starting materials and with very high selectivity.
Conclusions
In conclusion, by studying the reactions of the most challenging
of substrates we have been able to dene the scope and limi-
tations of the lithiation–borylation reaction between a hindered
secondary benzylic carbamate and a hindered benzylic pinacol
boronic ester. The ate complexes derived from these very
hindered substrates are especially prone to revert back to either
stabilised benzylic anions, which can undergo racemisation
and re-addition. However, by using MgBr2/MeOH as an additive
Enantioselective synthesis of uorohexestrol
The synthesis of uorohexestrol (2) was expected to be more to promote 1,2-migration over reversion back to starting mate-
challenging as it required the lithiation–borylation reaction of a rials the yield and the diastereo- and enantioselectivity of this
more hindered carbamate, a reaction that was especially chal- reaction can be enhanced dramatically. For the most hindered
lenging with hindered boronic esters. Indeed, the lithiation– of coupling partners where no boronate complexes even form,
borylation reaction between carbamate (R)-39 (>99 : 1 er) and the use of neopentyl boronic esters enables coupling to take
pinacol boronic ester (R)-30 under conditions A or B failed to place in high yield and with high selectivity. Furthermore, we
provide the desired boronic ester. However, using the corre- have demonstrated the application of this methodology in the
sponding neopentylglycol boronic ester (R)-40 (95 : 5 er) instead rst enantioselective and diastereoselective synthesis of
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biuranol and uorohexestrol in a short number of steps (7 and
5 steps respectively).
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