Stereodivergent Olefination of Enantioenriched Boronic Esters

Article abstract of DOI:10.1002/anie.201610387

A stereodivergent coupling reaction between vinyl halides and boronic esters is described. This coupling process proceeds without a transition-metal catalyst, instead proceeding by electrophilic selenation or iodination of a vinyl boronate complex followed by stereospecific syn or anti elimination. Chiral, nonracemic boronic esters could be coupled with complete enantiospecificity. The process enables the highly stereoselective synthesis of either the E or Z alkene from a single isomer of a vinyl coupling partner.

Full text of DOI:10.1002/anie.201610387

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201610387
German Edition: DOI: 10.1002/ange.201610387
Alkenes
Stereodivergent Olefination of Enantioenriched Boronic Esters
Roly J. Armstrong, Cristina Garcꢀa-Ruiz, Eddie L. Myers, and Varinder K. Aggarwal*
Abstract: A stereodivergent coupling reaction between vinyl
halides and boronic esters is described. This coupling process
proceeds without a transition-metal catalyst, instead proceed-
ing by electrophilic selenation or iodination of a vinyl boronate
complex followed by stereospecific syn or anti elimination.
Chiral, nonracemic boronic esters could be coupled with
complete enantiospecificity. The process enables the highly
stereoselective synthesis of either the E or Z alkene from
a single isomer of a vinyl coupling partner.
T
he stereodefined synthesis of multiply substituted alkenes
continues to attract attention because of their importance in
natural products, pharmaceuticals, and materials.[1] Of the
many methods that exist, the Suzuki–Miyaura cross-coupling
reaction is widely used as it enables the direct union between
vinyl halides and boronates.[2] However, whilst sp2-hybridized
and primary organoborons couple efficiently, the correspond-
ing reactions with secondary or tertiary boronic esters do not,
thus limiting its broader use.[3] An attractive feature of the
Suzuki–Miyaura reaction is that it is stereospecific,[4] but if
one geometrical isomer of a given coupling partner is much
easier to make than the other, as is often the case, this again
limits its wider application.[5] Herein, we address both of these
issues and describe a stereospecific method for coupling
secondary boronic esters with a single geometrical isomer of
a vinyl halide, thus leading to either the E or Z isomer of the
coupled product.
Scheme 1. Previous work and strategy for stereodivergent olefination.
pin=pinacol.
me 1a).[8] In the realm of the more atom economic and readily
available boronic esters, syn elimination processes have been
reported for substrates with b-positioned N-oxide (Sche-
me 1b),[9] and carbamate moieties.[10] However, the lack of
suitable electrophiles for introducing such functionality
within our envisioned manifold, led us to consider syn elimi-
nation of a b-selenoxyboronic ester. We speculated that such
an intermediate could be obtained through the electrophilic
addition of ArSeCl to a vinyl boronate followed by oxidation.
If the selenoxide could attack a boron atom instead of
To develop a solution to these problems, we turned our
attention to the Zweifel olefination.[6] In this process, a vinyl
metal is combined with a boronic ester, resulting in the
formation of a boronate complex. Addition of iodine to the
double bond gives an intermediate iodonium ion, which
triggers a 1,2-metallate rearrangement leading to a b-iodo-
boronic ester. Upon treatment with methoxide, the b-
iodoboronic ester undergoes anti elimination to produce
a single isomer of the resulting alkene (Scheme 1c).[7] We
reasoned that if the anti elimination could be diverted to
a syn elimination instead, then we should be able to access the
alternative geometric isomer from the same geometry of the
vinyl metal. Such syn elimination processes are known for
boron, but most are specific for trialkyl boranes, the most
notable example being Zweifelꢀs use of cyanogen bromide,
involving the intermediacy of a b-bromo cyanoborane (Sche-
À
a hydrogen atom, with formation of the strong B O bond
providing the driving force, then the desired syn elimination
should result. However, a successful process would require
a) chemoselective oxidation of a selenide in the presence of
an easily oxidizable boronic ester[11] and b) selective elimi-
nation of the boronic ester in the presence of a b-hydrogen
atom.[12]
We commenced our study with E-vinyl bromide
1 (Table 1). Lithium–halogen exchange followed by addition
of enantioenriched boronic ester 2 gave the desired vinyl
boronate complex. Upon addition of sodium methoxide in
methanol followed by iodine we isolated coupled product 3a
in 80% yield as a single Z-isomer with complete enantiospe-
cificity (entry 1).[13] Moreover, we were pleased to find that
when the same boronate complex was treated with PhSeCl,
smooth conversion into the desired b-selenoboronic ester was
observed. This crude intermediate could be treated with
sodium methoxide in methanol, thus triggering an anti elimi-
nation to afford the product in 80% yield as a single Z isomer
without any loss of enantiomeric purity (entry 2). In certain
[*] Dr. R. J. Armstrong, Dr. C. Garcꢀa-Ruiz, Dr. E. L. Myers,
Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201610387.
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Table 1: Optimization of reaction conditions for stereodivergent cross-
coupling.[a]
Table 2: Stereodivergent coupling: boronic ester scope.[a]
Entry
E+
Elimination
Yield [%][b]
E/Z
1[c,d]
2[d]
3
I2
NaOMe (MeOH)
NaOMe (MeOH)
H2O2 (H2O)
mCPBA (THF)
mCPBA (CH2Cl2)
mCPBA (THF)
79 (80)
78 (80)
66
71
71
<2:98
<2:98
55:45
5:95
>98:2
>98:2
PhSeCl
PhSeCl
PhSeCl
PhSeCl
PhSeCl
4
5[e]
6[d,e]
75 (74)
[a] Vinyl bromide (1.05 equiv), tBuLi (2.1 equiv), THF, À788C; then
boronic ester (1.0 equiv), THF, À788C; then either I2 (1.2 equiv), THF/
MeOH (3:1), 08C or PhSeCl (1.2 equiv), THF, À788C to RT; then
elimination. [b] Determined by NMR analysis using 1,3,5-trimethoxy-
benzene as an internal standard. Values within parentheses indicate the
yield of isolated product. [c] NaOMe added prior to I2. [d] With
enantioenriched 2 (96:4 e.r.) the product was obtained in 100% e.s.
[e] Reaction mixture filtered through silica gel prior to oxidation.
mCPBA=meta-chloroperbenzoic acid, PMP=para-methoxyphenyl,
THF=tetrahydrofuran.
cases (see later) this procedure could serve as a useful
alternative to the Zweifel coupling.
We next turned our attention to the development of
a protocol for syn elimination. Upon treatment of a THF
solution of the crude b-selenoboronic ester with aqueous
hydrogen peroxide we obtained the coupled product in
modest yield, but as a 55:45 E/Z ratio (entry 3). When
mCPBA was employed as an oxidant we obtained the
undesired Z isomer almost exclusively (entry 4). However,
these reactions showed that chemoselective oxidation of the
selenide did indeed occur in the presence of the boronic ester.
Remarkably, we found that filtration of the crude reaction
solution of b-selenoboronic ester through a short plug of silica
gel, followed by addition of mCPBA in dichloromethane
resulted in a complete switch in selectivity and 3b was
obtained as a single E isomer in 71% yield (entry 5).[14]
Changing the oxidation solvent to THF afforded the product
in slightly improved yield, and still with complete stereo- and
enantiospecificity (entry 6).
Having identified optimal reaction conditions for gener-
ating either the E or Z alkene, we explored scope, initially
focusing on variation of the boronic ester (Table 2). With
nonbranched secondary boronic esters, both coupling pro-
cesses proceeded efficiently to provide the corresponding
alkenes in excellent yields and levels of selectivity, together
with complete enantiospecificity. Notably, boronic ester 6,
bearing an electron-rich trisubstituted alkene, and ester-
containing boronic ester 4 underwent efficient coupling with
no evidence of side reactions. Benzylic, natural-product-
derived and menthol-derived boronic esters 8, 12, and 14,
coupled smoothly under our optimized reaction conditions
for selenation-oxidation (Method B; > 98:2 E/Z) but with
reduced selectivity in the Zweifel procedure (Method A).
This issue is addressed later. A vinyl boronic ester could also
[a] Vinyl bromide (1.05 equiv), tBuLi (2.1 equiv), THF, À788C; then
boronic ester (1.0 equiv), THF, À788C; then either NaOMe (3.0 equiv),
I2 (1.2 equiv), THF/MeOH (3:1), 08C or PhSeCl (1.2 equiv), THF, À788C
to RT; then SiO2 filtration; then mCPBA (2.0 equiv), THF, À788C to
À458C. [b] PhSeSePh removed by oxidation with H2O2. [c] Ate complex
formed with 16 and PhLi (1.05 equiv). [d] Ate complex formed with 16
and MeLi (1.05 equiv). [e] (E)-(4-Iodobut-3-en-1-yl)benzene also isolated
in 29% yield. TBS=tert-butyldimethylsilyl.
2
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be employed, thus enabling the stereodivergent synthesis of
Z,E or E,E dienes 17a and 17b in 71% and 79% yield,
respectively. We were also able to extend the process to the
coupling of vinyl boronic esters and organolithiums, thus
accessing styrenes 18a and 18b with excellent yields and high
stereoselectivity.
Synthesis of methyl-substituted-alkenes by Zweifel cou-
pling has previously been reported to be challenging because
of the poor migratory aptitude of a methyl group.[6g] In line
with this observation, we found that coupling of 16 with
methyl lithium led to 19a in moderate yield, an issue which is
addressed later.[15] We were pleased to find that our selena-
tion-oxidation protocol enabled the synthesis of 19b in good
yield and excellent stereoselectivity.
We were interested in the trend where bulkier coupling
partners resulted in lower Z/E selectivity in the Zweifel
reaction. In this process, the normally favored anti-elimina-
tion pathway brings the two substituents into close proximity,
and the barrier to elimination will increase as the groups get
larger. This scenario may allow the less favored syn-elimi-
nation process to compete, thus leading to a mixture of
isomers (Scheme 2A). We rationalized that if we could
disfavor the syn-elimination pathway further by using
a poorer leaving group, for example a selenide in place of
an iodide, high Z selectivity should be restored. Therefore, we
turned to the reaction conditions we had previously devel-
oped for methoxide-promoted anti elimination of a b-seleno-
boronic ester (Table 1, entry 2).
Gratifyingly, when we carried out the cross coupling of
benzylic boronic ester 8 under these conditions, the coupled
product 9a was obtained in 63% yield as a single Z-isomer
(Scheme 2B). Moreover, when these conditions were applied
to other Z-selective couplings that had previously given lower
Z selectivity, the products 11a, 13a and 15a were all obtained
in good to excellent yields as a single alkene isomer.
Additionally, under these conditions, the coupling of 16 with
MeLi proceeded smoothly, thus affording isomerically pure
19a in 61% yield.
Scheme 2. Highly Z-selective olefination. [a] Vinyl bromide
(1.05 equiv), tBuLi (2.1 equiv), THF, À788C; then boronic ester
(1.0 equiv), THF, À788C; then PhSeCl (1.2 equiv), THF, À788C to RT;
then NaOMe (5.0–20.0 equiv), THF/MeOH (1:1), 08C or RT. [b] PhSe-
SePh removed by oxidation with H2O2. [c] Ate complex formed with 16
and MeLi (1.05 equiv).
We next turned our attention to varying the vinyl halide
coupling partner, focusing our attention on trisubstituted
vinyl bromides, as stereospecific synthesis of trisubstituted
alkenes is often more difficult (Table 3).[16] We were delighted
to find that commercially available E-2-bromobut-2-ene (20)
could be successfully coupled with enantioenriched boronic
ester 2 to afford either isomer of the coupled product with
excellent yields and stereoselectivity.[17] The same coupled
products could be obtained through stereodivergent coupling
of isomeric Z-bromide 22. For many trisubstituted vinyl
halides only one geometrical isomer can be readily accessed.
For example, vinyl bromide 23, prepared stereoselectively by
hydrozirconation of the corresponding alkyne,[18] underwent
coupling to afford either 24a or 24b in excellent yields and
with near perfect stereocontrol. Similarly, vinyl bromide 25,
prepared from 2-butyn-1-ol by hydroxyl-directed hydroalu-
mination,[19] underwent stereodivergent coupling with 2 to
afford the coupled products 26a and 26b in 61% and 55%
yield, respectively. Finally, the methodology can be applied in
settings relevant to complex molecule synthesis, as illustrated
with boronic ester 27, which is readily prepared in high Z-
selectivity by cross-metathesis. Reaction with an alkyl lithium
derived from the Roche ester and subsequent olefination
gave either the E or Z trisubstituted alkene with high
À
selectivity. Z-alkene 28a represents the C9 C17 fragment
of discodermolide and its ease of synthesis is especially
notable. In Novartisꢀs formidable synthesis of discodermolide
the synthesis of this trisubstituted alkene was one of the most
challenging reactions they encountered.[20]
The putative syn elimination of b-selenoxyboronic esters
was investigated by DFT calculations using the B3LYP
functional with a cc-PVDT(H,C)/cc-PVTZ(B,O)/RECP-DZ-
(Se) basis set. Both diastereomers of the b-selenoxyboronic
ester (diastereomeric at the selenium center) which would
give (E)-but-2-ene (Scheme 3) show global minima involving
a strong interaction between the selenoxide oxygen atom and
the boron atom. These conformers were primed to undergo
elimination with remarkably low barriers (0.4–2.2 kcalmolÀ1),
which were more accessible than rotation about the Se-C-C-B
dihedral.[21] Traditional selenoxide eliminations, involving the
expulsion of phenylselenenic acid from other conformers,
were also calculated for comparison, and showed significantly
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Table 3: Stereodivergent coupling: vinyl partner scope.[a]
Scheme 3. Computational results.
aromatic coupling partners. Where chiral, nonracemic bor-
onic esters were employed, the coupling took place with
complete enantiospecificity, and the process has been suc-
cessfully applied to the stereodivergent synthesis of trisub-
stituted alkenes. DFT studies probing the mechanism of this
interesting transformation suggest that syn elimination of a b-
selenoxyboronic ester is a remarkably facile process. We
believe that this approach will find widespread application in
the stereoselective synthesis of polysubstituted alkenes.
Acknowledgements
C. G.-R. thanks the Ramꢁn Areces Foundation for a post-
doctoral fellowship. We are grateful to Dr. Natalie Fey for
helpful discussions. We thank Bin Zhou for assistance with the
synthesis of 27. We thank EPSRC (EP/I038071/1) and Bristol
University for financial support.
[a] Vinyl bromide (2.0 equiv), tBuLi (4.0 equiv), THF, À788C; then
boronic ester (1.0 equiv), THF, À788C; then either NaOMe (3.0 equiv),
I2 (1.2 equiv), THF/MeOH (3:1), À788C to 08C or PhSeCl (1.2 equiv), 1:1
CF3CH2OH/THF, À788C to RT; then SiO2 filtration; then mCPBA
(2.0 equiv), THF, À788C to À458C. [b] Vinyl lithium formed in situ by
addition of tBuLi to a mixture of 2 and 25. [c] Boronate complex formed
between (S)-LiCH2CH(CH3)CH2OPMB and 27. [d] Using Method C.
[e] The intermediate b-selenoboronate was isolated (yield based on 2
steps). PMB=para-methoxybenzyl, TBDPS=tert-butyldiphenylsilyl.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkenes · boron · isomers · oxidation · selenium
higher barriers. Interestingly, elimination to give the vinyl
boronic ester was calculated to be considerably more facile
than elimination to give the allyl boronic ester (5.6–7.0 versus
10.0–11.0 kcalmolÀ1), thus suggesting that hydrogen atoms
geminal to trivalent boron substituents are more activated.
This observation is in agreement with related eliminations of
b-sulfoxysilanes, which undergo faster eliminations (to give
vinyl silanes) relative to nonsilyl derivatives.[12a,b]
In conclusion, we have developed an efficient method for
the stereodivergent coupling of vinyl halides with boronic
esters. This reaction proceeds with no requirement for
a transition metal and tolerates aliphatic, vinylic, and
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Manuscript received: October 24, 2016
Final Article published: && &&, &&&&
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Communications
Alkenes
Which way to go? A stereodivergent
coupling process enables a highly ste-
reoselective synthesis of alkenes, thus
providing access to either isomer of the
coupled product from a single isomer of
a vinyl metal precursor. This coupling
process proceeds without a transition-
metal catalyst, instead taking place by
electrophilic iodination or selenation of
a vinyl boronate complex followed by
stereospecific anti or syn elimination.
R. J. Armstrong, C. Garcꢁa-Ruiz,
E. L. Myers,
V. K. Aggarwal*
&&&& — &&&&
Stereodivergent Olefination of
Enantioenriched Boronic Esters
6
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