Protodeboronation of tertiary boronic esters: Asymmetric synthesis of tertiary alkyl stereogenic centers

Article abstract of DOI:10.1021/ja1084207

While tertiary boranes undergo efficient protodeboronation with carboxylic acids, tertiary boronic esters do not. Instead, we have discovered that CsF with 1.1 equiv of H₂O (on tertiary diarylalkyl boronic esters) or TBAF?3H₂O (on tertiary aryldialkyl boronic esters) effect highly efficient protodeboronation of tertiary boronic esters with essentially complete retention of configuration. Furthermore, substituting D₂O for H₂O provides ready access to deuterium-labeled enantioenriched tertiary alkanes. The methodology has been applied to a short synthesis of the sesquiterpene, (S)-turmerone.

Full text of DOI:10.1021/ja1084207

Published on Web 11/16/2010
Protodeboronation of Tertiary Boronic Esters: Asymmetric Synthesis of
Tertiary Alkyl Stereogenic Centers
Stefan Nave, Ravindra P. Sonawane, Tim G. Elford, and Varinder K. Aggarwal*
School of Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
Received September 17, 2010; E-mail: v.aggarwal@bristol.ac.uk
Table 1. Optimization of the Protodeboronation of Boronic Estersa
Abstract: While tertiary boranes undergo efficient protodebor-
onation with carboxylic acids, tertiary boronic esters do not.
Instead, we have discovered that CsF with 1.1 equiv of H2O (on
tertiary diarylalkyl boronic esters) or TBAF ·3H2O (on tertiary
aryldialkyl boronic esters) effect highly efficient protodeboronation
of tertiary boronic esters with essentially complete retention of
configuration. Furthermore, substituting D2O for H2O provides
ready access to deuterium-labeled enantioenriched tertiary al-
kanes. The methodology has been applied to a short synthesis
of the sesquiterpene, (S)-turmerone.
Boronic esters are very useful synthetic intermediates in asym-
metric synthesis since they can be easily prepared in high
enantiomeric ratios (e.r.’s) by hydroboration1 or rearrangement2
reactions and can be converted with retention of configuration into
alcohols or amines or used for C-C couplings.1-3 We4 (and
others5) have recently reported a novel, practical method for the
creation of tertiary boronic esters with very high e.r.’s (>98:2). We
recognized that if we could convert the C-B bond of the tertiary
boronic ester into a C-H bond this would provide ready access to
a Standard reaction conditions: 0.1 M in given solvent, 1.5 equiv of
a range of useful products including 1,1-diarylalkanes, which are
CsF, 1.1 equiv of water or 1.5 equiv of TBAF ·3H2O. b Consumption of
c
privileged pharmacophores in medicinal chemistry but remain
challenging to prepare.6 However, protodeboronation of alkylbo-
ronic esters had not been described previously and in fact are
reported to be stable to both acids and bases.7
SM 1a/1b determined by GC with tetradecane as internal standard.
%
es ) (product ee/starting material ee) × 100. Det. by chiral HPLC or
chiral GC (see Supporting Information). d 3a:2a
respectively 4:1 (entry 2).
) 3:1 (entry 1)
The difficulties in protodeboronation are further compounded
by the fact we are dealing with tertiary boronic esters which,
by analogy with boranes, would be expected to be the slowest
to protodeboronate.8 Our initial attempts at protodeboronation
of boronic ester 1a, a compound likely to protodeboronate most
readily, with the standard reagent used for boranes, propionic
acid, were not promising: the desired alkane 2a was obtained
as the minor product in a 1:4 mixture together with alkene 3a
(Table 1, entry 1).
Propionic acid is the reagent of choice for effecting protodebo-
ronation of boranes,9 where the high free bond enthalpy of the newly
formed B-O bond (536 kJ/mol) provides the driving force for the
reaction (C-B bond energy 356 kJ/mol).1a Since B-F bonds are
the strongest single bonds known10 (B-F bond is 613 kJ/mol),11
we reasoned that fluoride based reagents might prove more
rewarding as they would provide an even greater driving force for
protodeboronation. Thus, fluoride-based reagents were tested.
Although HF led to a complex mixture (entry 2), CsF was much
more successful. We found that excess water was detrimental to
the reaction (entry 3),12 but with just 1.1 equiv of H2O clean
protodeboronation at 100 °C was observed (entry 4). Through
further optimization, we found conditions under which protodebo-
ronation occurred in quantitative yield and with essentially complete
enantioselectivity13 (entry 5). TBAF was also tested but was found
to be a much more aggressive reagent (reaction was much more
rapid) and partial racemization of the fragile stereogenic center
occurred (entry 6).
These initial studies greatly assisted our investigation into the
protodeboronation of tertiary aryldialkyl boronic esters, which were
expected to react more slowly. Indeed, CsF in dioxane, which was
the optimum solvent for diarylalkyl boronic ester (R ) Ph), resulted
in very slow protodeboronation of aryldialkyl boronic ester 1b even
at 100 °C (entry 7, R ) Et). In contrast, the more reactive reagent,
TBAF, effected clean protodeboronation (entry 8) and without
racemization when conducted in nonpolar solvents (entries 9-10).
Having established two sets of conditions (A and B) for effective
protodeboronation of diarylalkyl and aryldialkyl tertiary boronic
esters, we investigated the scope of the methodology with a diverse
range of substrates that were readily obtained through the
lithiation-borylation reaction of secondary carbamates4 (Table 2).
In the case of diarylalkyl boronic esters, the reaction was success-
fully applied to aromatic substrates bearing electron-deficient,
electron-rich, and heteroaromatic groups. Minor adjustments to the
temperature of the reaction were required according to the ease/
difficulty of the protodeboronation process (Table 2, entries 1-4).
Substrates bearing anion stabilizing groups underwent protodebo-
ronation more easily and so lower temperatures could be employed.
Conditions B were also successfully applied to a related set of
9
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10.1021/ja1084207  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Investigation into the Scope of the Reactiona
a All yields are isolated yields unless stated otherwise. E.r. was determined by chiral HPLC or chiral GC (see Supporting Information). b E.r. of the
alcohol resulting from oxidation of the boronic ester with NaOH/H2O2. c Conditions: (A) CsF (1.5 equiv), H2O (1.1 equiv), 1,4-dioxane (0.1 M); (B)
TBAF·3H2O (1.5 equiv), n-pentane (0.1 M), 45 °C, 2 h. d 7 ) E-2-Phenyl-2-butene.
Scheme 2. Mechanism of Protodeboronation of Tertiary Boronic
Esters
aryldialkyl boronic esters (entries 5-12). Particularly noteworthy
is the ꢀ-branched substrate (entry 8) which demonstrates that this
novel process shows broad scope since it tolerates even severe steric
hindrance. Note, although toluene was the optimum solvent, pentane
was found to be more practical as it facilitated the isolation of
especially volatile products. The only substrate that failed (as
expected) was the one employing vinyl boronic ester in the
borylation step (entry 9) since the intermediate allyl boronic ester
5i underwent protodeboronation at the γ position forming E alkene
entries 4, 6, and 8), and so further investigations were conducted.
7 exclusively. Use of allyl boronic ester in the borylation step
Protodeboronation of 1a with TBAF (Table 1, entry 6) was
(entries 10, 11) gave intermediate homoallylic boronic esters 5j
monitored over 12 h, but no change in ee was observed; it remained
and 5k which, as expected, underwent smooth protodeboronation
at the R position. In all cases, protodeboronation occurred with
constant at 70%.14 This showed that the lower enantioselectivity
observed under such conditions was due to a competing inversion
retention of configuration.
pathway during protodeboronation and not due to product lability.
The methodology provides a unique protocol for the introduction
The competing inversion pathway will be more important in polar
of deuterium by simply substituting H2O for D2O, as demonstrated
solvents, where water will be less tightly bound to the ate complex
by two representative examples (Scheme 1).
and so will lead to lower e.r., as observed (compare entries 8, 9,
Table 1).
Scheme 1. Deuterodeboronation of Tertiary Boronic Esters
In order to obtain a more complete picture of the protodebor-
onation process, we monitored the reaction by 11B NMR in THF
at RT. Immediately after addition of TBAF, the signal for the
starting boronic ester disappeared (δ ) 32.5 ppm) and a new signal
at δ ) 7.3 ppm appeared, which we believe corresponds to the
intermediate ate complex 8.15 Over time, this signal slowly decayed
and a new signal at 3.9 ppm grew in intensity. We believe that this
peak corresponds to the dihydroxy borate byproduct 9 (δ ) 3.9
ppm).16 The initial byproduct formed in the reaction, FBpin, is not
expected to be stable to the hydrolytic conditions of the reaction.17
These studies demonstrate that the intermediate ate complex 8 is
observable in THF and its decay can be followed by NMR.
A possible mechanism, analogous with the cyclic rearrangement
leading to protodeboronation of boranes, is shown in Scheme 2. In
nonprotic media, the water will interact strongly with fluoride ion
both prior to and after formation of ate complex 8, ensuring ‘front-
side’ proton delivery and hence stereoretention. Under certain
conditions the degree of stereoretention was not perfect (Table 1,
Finally, the methodology was applied to a short synthesis of (S)-
turmerone (Scheme 3), a sesquiterpene isolated from rhizomes of
curuma longa,18 which has been a popular target for the synthetic
community. However, there have been very few enantioselective
syntheses reported to date.19 Our synthesis commenced with
enantioenriched (S)-carbamate 10, derived from the corresponding
9
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C O M M U N I C A T I O N S
Scheme 3. Total Synthesis of (S)-Turmerone
pp 1-85. Recent examples for C-C coupling using aliphatic pinacol
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BuLi in the presence of TMEDA for 10 min. Subsequent reaction
with 1.5 equiv of allyl pinacol boronic ester furnished the tertiary
boronic ester 11, which was used in the key protodeboronation step
without further purification. Treatment of 11 with 1.5 equiv of
TBAF ·3H2O in pentane at 45 °C smoothly afforded the protode-
boronated product 12, installing the benzylic tertiary center in
excellent yield (76% over two steps) and selectivity (99:1 e.r.).
Finally, oxidation21 of alkene 12 to aldehyde 13 followed by
addition of 2-methyl-1-propenylmagnesium bromide and subsequent
oxidation with PDC furnished the target compound, (S)-turmerone.
The synthesis was completed in seven steps from p-methylac-
etophenone and delivered the target compound in (99:1 e.r.).
In conclusion, we have discovered a new and simple way to
effect protodeboronation of boronic esters using CsF-H2O or
TBAF·3H2O with essentially complete stereocontrol, thus providing
ready access to enantioenriched tertiary alkanes.22 The method also
provides access to highly enantioenriched deuterated tertiary alkanes
by simply substituting H2O for D2O. The utility of the methodology
has been illustrated in a short and highly enantioselective synthesis
of (S)-turmerone.
Acknowledgment. We thank Frontier Scientific for generous
donations of organoboron compounds, the Deutsche Forschungs-
gemeinschaft (Postdoctoral Fellowship for S.N.) and the EPSRC
for support (inc. Senior Fellowship for V.K.A.). We thank Dr. Mairi
Haddow for X-ray analysis of a derivative of 6b and Prof. Jeremy
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Supporting Information Available: Experimental procedures and
characterization data. This material is available free of charge via the
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