Vinylidene Homologation of Boronic Esters and its Application to the Synthesis of the Proposed Structure of Machillene

Article abstract of DOI:10.1002/anie.201907617

Alkenyl boronic esters are important reagents in organic synthesis. Herein, we report that these valuable products can be accessed by the homologation of boronic esters with lithiated epoxysilanes. Aliphatic and electron-rich aromatic boronic esters provided vinylidene boronic esters in moderate to high yields, while electron-deficient aromatic and vinyl boronic esters were found to give the corresponding vinyl silane products. Through DFT calculations, this divergence in mechanistic pathway has been rationalized by considering the stabilization of negative charge in the C?Si and C?B bond breaking transition states. This vinylidene homologation was used in a short six-step stereoselective synthesis of the proposed structure of machillene, however, synthetic and reported data were found to be inconsistent.

Full text of DOI:10.1002/anie.201907617

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Accepted Article
Title: Vinylidene Homologation of Boronic Esters and its Application to
the Synthesis of the Proposed Structure of Machillene
Authors: Varinder Kumar Aggarwal, James M Fordham, and Matthew
N Grayson
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Vinylidene Homologation of Boronic Esters and its Application to
the Synthesis of the Proposed Structure of Machillene
[a]
[b]
[a]
James M. Fordham, Matthew N. Grayson* and Varinder K. Aggarwal*
Abstract: Alkenyl boronic esters are important reagents in organic
synthesis. Herein, we report that these valuable products can be
accessed by the homologation of boronic esters with lithiated
epoxysilanes. Aliphatic and electron-rich aromatic boronic esters
provided vinylidene boronic esters in moderate to high yields, while
electron-deficient aromatic and vinyl boronic esters were found to give
the corresponding vinyl silane products. Through DFT calculations,
this divergence in mechanistic pathway has been rationalized by
considering the stabilization of negative charge in the C-Si and C-B
bond breaking transition states. This vinylidene homologation was
used in a short six step stereoselective synthesis of the proposed
structure of machillene, however, synthetic and reported data were
found to be inconsistent.
which could undergo a Peterson-type elimination[18] to give vinyl
boronic ester 3. If successful, this method would serve as a
transition-metal free alternative to the procedure of Morken.
Based on previous reports,[ we anticipated that the desired
Peterson elimination pathway would be favoured over the
alternative boron-Wittig reaction (forming vinyl silane 6),[
although the mechanistic rationale for this outcome remained
unclear.
19]
20]
Vinyl boronic esters are versatile intermediates in organic
chemistry, participating in a range of transformations including
cross-coupling,[ oxidation, homologation and many others.
1]
[2]
[3]
[4]
Due to their synthetic utility, new methodologies that expand the
range of accessible vinyl boronic esters are highly desirable,
3
especially those that enable the introduction of sp -rich motifs.
Many precursors have been used to prepare vinyl boronic esters
including alkynes,[5] vinyl halides,[6] alkenes,[7] carboxylic acids,[8]
aldehydes,[9] ketones[10] and, recently, boronic esters themselves.
Through modification of their conjunctive cross-coupling
methodology,[ Morken and co-workers were able to achieve the
vinylidenation of organoboronic esters 1 to prepare a range of 1,1-
Figure 1. Vinylidene homologation of boronic esters.
11]
disubstituted vinyl boronic esters 3 (Figure 1).[12] As sp3-rich
organoboronic esters are readily available,[13-15] vinylidene
Encouraged by this precedent, we reacted phenethyl boronic
ester 1a with lithiated epoxysilane 4a (Table 1).[ After stirring at
21]
4
0 °C for 1 h, 11B NMR analysis of the reaction mixture indicated
homologations have the potential to greatly expand the range of
available vinyl boronic esters. Furthermore, we envisaged a
process wherein iterative homologation of a boronic ester could
be interrupted by a vinylidenation protocol to create more diverse
polyketide-type structures.[16]
Inspired by our previous work on the reaction of lithiated
epoxides with boronic esters,[17] we set out to exploit the reaction
of lithiated epoxysilane 4 with boronic esters 1 in a novel
vinylidene homologation (Figure 1). We postulated that after
formation of a boron-ate complex, 1,2-metallate rearrangement
would occur to give β-alkoxy-α-silyl boronic ester intermediate 5,
that full 1,2-migration had occurred and, after chromatographic
purification, vinyl boronic ester 3a was obtained as the exclusive
product in 77% yield (see S.I. for optimisation). The methodology
was found to be compatible with more sterically hindered
secondary and tertiary boronic esters (products 3b and 3c),
although the latter case required higher stoichiometry of 4 for
optimum yield. Boronic esters containing base and nucleophile-
sensitive groups were also employed and the corresponding
homologated products 3d and 3e were obtained in 49% and 38%
yield, respectively. We were eager to investigate more elaborate
and pharmaceutically relevant boronic esters. Thus, cyclobutyl
and azetidinyl substrates were subjected to the vinylidenation
reaction and gave the corresponding products 3f and 3g in 72%
and 55% yield, respectively, the former being obtained with
complete diastereospecificity (d.s.). The sensitive vinyl
cyclopropyl boronic ester 3h was isolated in 51% yield (75% NMR
yield). Sterically hindered menthyl and cholesteryl-derived
boronic esters gave vinylidene products 3i and 3j in lower yield
[
[
a]
b]
Mr. J. Fordham, 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
Dr. M. N. Grayson
Department of Chemistry, University of Bath
Claverton Down, Bath, BA2 7AY (UK)
E-mail: M.N.Grayson@bath.ac.uk
(
32% and 46%, respectively) with a small amount of over-
homologation apparent. A polyketide-type substrate was also
subjected to the reaction conditions, giving the desired product 3k
Supporting information for this article is given via a link at the end of
the document.
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in 47% yield. This substrate is notable considering the potential
for β-elimination via intermediate 8, which was not observed
under our reaction conditions.[22] As lithiated epoxysilanes are
configurationally stable at low temperature,[21] we expected that a
trans-substituted epoxysilane would furnish the trisubstituted (E)-
olefin with high selectivity via intermediate 5iii (Table 1B). Indeed,
epoxysilanes 7b and 7c,[23] gave the corresponding products 3l
and 3m in 30% and 73% yield respectively and as a single isomer.
gave a mixture of vinyl boronic ester 3o and vinyl silane 6o in 31%
and 28% yield, respectively. This divergence in elimination
pathway was even more pronounced for electron deficient aryl
systems. For example, p-chlorophenyl boronic ester 1p gave vinyl
silane 6p as the major product and, in the most extreme case, p-
trifluoromethylphenyl boronic ester 1q gave exclusively vinyl
silane 6q in 55% yield. Vinyl boronic ester starting materials also
gave vinyl silane products 6r and 6s instead of the corresponding
vinyl boronic esters.
Table 1. Vinylidene homologation of aliphatic boronic esters.
2
Table 2. Vinylidene homologation of sp -hybridised boronic esters.
DFT calculations were performed to better understand the
factors that determined the outcome of the elimination pathway.
All calculations were performed with Gaussian 16[
25]
at the
B3LYP-D3(BJ)/6-311G(d,p)−IEFPCM(n-pentane)//B3LYP/6-
1G(d) level of theory (see S.I. for computational details).
3
Previous computational studies of organic reactions with similar
methods provided results in accord with experiment.[26-28]
The thermodynamically favoured product was calculated to be
the vinyl silane by over 3 kcal mol-1 for sp - and sp -hybridised
boronic ester substituents (Table S12). To gain insight into the
origins of product selectivity, C-Si and C-B bond breaking
transition states (TSs) 9a and 9b were located and their relative
energies determined (Table 3). For aliphatic substrates, the R
group was modelled as a methyl substituent to reduce the number
of possible conformations. In this case, the C-Si bond breaking
TS was favoured by over 9 kcal mol-1 relative to the C-B bond
breaking TS (entry 1), indicating a strong preference for the vinyl
boronic ester product, as observed. For substrate 1n, with a p-
methoxyphenyl substituent, the C-Si bond breaking TS was
favoured by 1.2 kcal mol-1 (entry 2), whilst for indolyl substrate 1o
the TSs were separated by only 0.2 kcal mol-1 (entry 3). On the
other hand, for p-trifluoromethylphenyl substrate 1q, the C-B bond
breaking TS was favoured by 1.4 kcal mol-1 (entry 4), and in the
case of styrenyl boronic ester 1s, this increased to 5.6 kcal mol-1
3
2
Yields are of isolated products. Diastereomeric ratios were determined by 1
NMR analysis of the isolated products. a Reaction performed using 2.5–3.0
equiv of lithiated epoxide, see SI for details. b Yield in parentheses was
H
determined by 1H NMR using CH
Br
as an internal standard. Cy: cyclohexyl;
2
2
i
TMS = trimethylsilyl; TES: triethylsilyl; TBS: tert-butyldimethylsilyl; Bu: isobutyl;
nOe = nuclear Overhauser effect.
(
entry 5). These calculated TS energies are in good agreement
with the experimentally observed product distributions. The
results can be understood by considering how the developing
negative charge on carbon is stabilized in the TS of the C-Si and
C-B bond breaking step.[29-30] Evidently, the charge is better
stabilized by the electron deficient boron than by silicon, leading
to the vinyl boronic ester products. Indeed, our calculations show
2
The reaction conditions were then applied to sp -hybridised
boronic esters, which required longer reaction times due to the
reduced migratory aptitude of vinyl and aryl groups (Table 2).[24]
While the electron rich, p-methoxyphenyl boronic ester 1n gave
the vinyl boron product 3n in 79% yield, indolyl boronic ester 1o
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that boron is better able to stabilize negative charge than silicon
to a low yield of 11 with significant decomposition.[34] We therefore
investigated alternative conditions and found that using
Pd(dppf)Cl and K PO in dioxane/water gave tetraene 11 in 69%
2 3 4
yield together with migratory insertion product 18 (see S.I. for a
mechanistic proposal).[35]
-1
by 9.1 kcal mol (Table S10). However, for substrates that already
bear anion stabilizing groups, elimination takes place
preferentially at the more Lewis acidic boron atom, leading to the
vinyl silane products.
The end game was particularly challenging and required (i)
selective reaction of the styrene over the 1,1-disubstituted alkene
(ii) reagent-controlled diastereoselective epoxidation (iii) isolation
of the monoepoxide from the statistical mixture of SM, mono- and
di-epoxides that would be expected. Following this reaction, a
second epoxidation of the monoepoxide with the enantiomeric
epoxidation reagent should occur on the remaining styrene with
the correct stereochemical outcome. Our initial attempts were
based around the Shi epoxidation but no conversion to the
desired mono-epoxide 19 was observed and instead starting
material was recovered.[36] We then explored the Sharpless
dihydroxylation,[37] a reaction where styrenes are known to be
more reactive than 1,1-disubstituted alkenes.[38] To our delight,
the reaction provided diol 20 in 34% yield, with excellent
diastereoselectivity, and with no evidence of reaction at the 1,1-
disubstituted double bond. Starting material 11 was recovered
Table 3. Comparison of C-Si and C-B bond breaking TSs for vinylidenation of
MeBpin (1t), 1n, 1o, 1q and 1r. B3LYP-D3(BJ)/6-311G(d,p)−IEFPCM(n-
pentane)//B3LYP/6-31G(d)
a
(37%) and the C -symmetric bis-dihydroxylation product 21 was
Aliphatic boronic esters gave exclusively the vinyl boronic ester products. The
2
C-Si and C-B bond breaking TSs for 9t (R = Me) are shown.
obtained in 13% yield. After a second dihydroxylation reaction
using the pseudo-enantiomeric reagent and subsequent ring-
closing,[39] the target molecule was obtained.
Finally, we sought to apply our chemistry in natural product
synthesis. We were attracted to machillene (10a), a bis-steryl
epoxide isolated from the stem wood of machilus zuihoensis
Unfortunately, upon comparison of the reported NMR data
with that of our synthetic sample, significant differences were
observed. The considerable deviations (see S.I. for tabulated
data) led us to the conclusion that the issue was not related to
stereochemistry, but instead was likely due to a misassignment in
the connectivity of the molecule. Further efforts to elucidate the
structure of machillene are currently underway in our laboratory
using a combination of computational and synthetic methods.
(
Figure 2A), because it showed significant anticancer activity.[31]
Furthermore, the relative configuration of the molecule remained
unknown, apart from the epoxide groups, which were assigned as
trans from analysis of the coupling constants (J = 2.4 Hz). From
the reported data, it was apparent that the molecule was neither
1
13
23
2 D
C -symmetric ( H and C NMR data) nor meso ([α] = + 22.2°),
allowing us to eliminate six of the possible eight diastereoisomers.
Based on chemical shift differences between the methylene
protons, Breit assigned the methyl substituents of 10a as having
an anti-relationship (∆δ = 0 ppm observed, ∆δ > 0.5 ppm for the
syn isomer).[32] Compound 10b was therefore identified as the
most likely structure of the natural product and we set out to
confirm its structure through synthesis. Our retrosynthetic
analysis began with sequential epoxidation reactions from
tetraene 11. We envisaged the carbon skeleton would be
constructed through a bidirectional approach from methylene
diboron (14), comprised of homologations with lithiated TIB ester
In summary, we have developed a new protocol for the vinylidene
homologation of boronic esters that provides access to a diverse
range of 1,1-disubstituted and trisubstituted vinyl boronic esters.
Computational studies have revealed that both the Peterson and
boron-Wittig pathways are feasible but the Peterson pathway is
favoured because boron can better stabilize the negative charge
developing on the α-carbon in the transition-state of the
elimination step. The methodology was used in
a short,
stereoselective synthesis of machillene but, upon comparing the
reported and synthetic NMR data, it was clear that the structure
of the natural product had been mis-assigned.
[
33]
13
and lithiated epoxysilane 4a, followed by a Pd-catalysed
allylic cross-coupling reaction. If successful, the route would give
access to machillene in just 6 steps from commercially available
diboron 14, and without the need for protecting groups.
Acknowledgements
Our synthesis began with homologation of 14 with lithiated
species 13, giving bis-boronic ester 15 in 83% yield, and as a
single diastereoisomer (Figure 2B). The vinylidene homologation
reaction gave bis-vinyl boronic ester 16 in 58% yield together with
mono-vinyl boronic ester 17 in 9% yield. The next step involved a
Pd-catalysed allylic cross-coupling reaction between 16 and
allylic acetate 12. To our knowledge there is just a single report
that describes the coupling of a vinyl boronic ester with an allylic
J.M.F. thanks the Bristol Chemical Synthesis Centre for Doctoral
Training and the EPSRC (EP/G036764/1) for funding. M.N.G.
thanks the University of Bath for financial support. We thank H. A.
Sparkes for X-ray analysis.
Keywords: organoboron • homologation • stereospecific •
natural product • vinyl boronic ester
2
acetate, however these conditions (PdCl /TFP, KF, MeOH, rt) led
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Figure 2. A) Structure determination and retrosynthesis of machillene. B) Total synthesis of the proposed structure of machillene.
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Angewandte Chemie International Edition
10.1002/anie.201907617
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J. M. Fordham, M. N. Grayson* V. K.
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Vinylidene boronic esters can be obtained by the homologation of boronic esters with lithiated epoxysilane in a process where the selectivity
for the vinyl boronic ester or vinyl silane product depends on the anion stabilizing ability of the R group. The methodology was applied in a short
stereoselective synthesis of the proposed structure of machillene, however, synthetic and reported data did not match.
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