Harnessing the Power of the Asymmetric Grignard Synthesis of Tertiary Alcohols: Ligand Development and Improved Scope Exemplified by One-Step Gossonorol Synthesis

Article abstract of DOI:10.1021/acs.orglett.0c02629

A series of N-substituted cyclohexyldiaminophenolic ligands for the asymmetric Grignard synthesis of tertiary alcohols is reported. The 2,5-dimethylpyrrole-decorated ligand led to improved enantioselectivities and broadened the scope of the methodology. As an exemplar, we report an unprecedented highly selective one-step synthesis of gossonorol in 93% ee, also constituting the shortest formal syntheses of natural products boivinianin B and yingzhaosu C.

Full text of DOI:10.1021/acs.orglett.0c02629

pubs.acs.org/OrgLett
Letter
Harnessing the Power of the Asymmetric Grignard Synthesis of
Tertiary Alcohols: Ligand Development and Improved Scope
Exemplified by One-Step Gossonorol Synthesis
Saranna E. Kavanagh*,† and Declan G. Gilheany*,†
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02629
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ABSTRACT: A series of N-substituted cyclohexyldiaminophenolic
ligands for the asymmetric Grignard synthesis of tertiary alcohols is
reported. The 2,5-dimethylpyrrole-decorated ligand led to improved
enantioselectivities and broadened the scope of the methodology. As an
exemplar, we report an unprecedented highly selective one-step synthesis
of gossonorol in 93% ee, also constituting the shortest formal syntheses of
natural products boivinianin B and yingzhaosu C.
obel laureate, Victor Grignard, first reported the use of
methods relying solely on adding a ligand for asymmetric
1
Norganomagnesium halide nucleophiles in 1900. Since Grignard addition to ketones, and while undoubtedly
impressive, they were notably limited in terms of their scope
and generality.11
their discovery, so-called Grignard reagents have been regarded
as one of the most powerful synthetic tools in organic
chemistry.2 Their significance for C−C bond formation reaches
from core lessons in undergraduate laboratories to the
industrial-scale synthesis of compounds for the food industry,
veterinary medicine, perfumery, and pharmaceuticals.3 Derived
from magnesium, an abundant, inexpensive, and nontoxic metal,
Grignard reagents are renowned for their high reactivity and vast
synthetic scope.4 They boast superior atom economy over many
other organometallic reagents, excellent stability, and simple
preparation/disposal. Over the past 120 years, diverse syntheses
involving organomagnesium reagents have been studied,
including the development of one of Grignard’s earliest
aspirations: tertiary alcohol synthesis. Owing to the versatility
of organomagnesium reagents, a powerful three-way disconnec-
tion strategy is applicable for any given chiral tertiary alcohol.
Tertiary alcohols and their derivatives are among the most
important structural motifs in both natural and synthetic
bioactive organic compounds,5 and numerous enantioselective
syntheses have been reported. However, often the most highly
selective of these are indirect and therefore inherently
inefficient.6 The addition of a carbon nucleophile to a ketone
is the most efficient direct route to accessing tertiary alcohols but
rendering it asymmetric has proven challenging.7 Some of the
reported strategies employ less preferable/versatile carbanion
sources versus organomagnesium8 although with noteworthy
success for the addition of allyl, allenyl and propargyl
nucleophiles.8j−m In cases where Grignard reagents are the
source of the nucleophilic entity, most reported methods require
an additional metal present to induce asymmetry.9 In any event,
no method has scope in application comparable to Grignard
synthesis. Prior to our work,10 there were only two usable
In 2017, we reported, in what was a notable advance in the
field, that the use of cyclohexanediamine-derived half-salan
ligands on their own facilitated the asymmetric Grignard
synthesis of tertiary alcohols with unparalleled scope (Scheme
1).10 In its initial development, this methodology was applied in
Scheme 1. Our Reported Asymmetric Grignard Methodology
the synthesis of vitamin E,12 and its utility has since been
extended to the highly enantioselective synthesis of 2,2-
disubstituted THFs and THPs.13 However, our breakthrough
was not without limitation, a notable one being the relatively
lower selectivity for 1,2-addition to acetophenones (Scheme 1),
and it was clear that more detailed ligand studies would be
crucial to address those shortfalls. Ultimately, our aim is to have
Received: August 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02629
© XXXX American Chemical Society
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a
a suite of ligands in-hand which could be applied, depending on
the ketone/Grignard combination in question, to generate any
tertiary alcohol in high enantiomeric excess. We report now
progress toward this goal. This work details the development of
new ligands with varying substitution at the distal nitrogen
position that has led to improved enantioselectivities, broadened
scope, and an opportunity for target synthesis utilizing the full
power of the flexibility of the Grignard synthesis.
Table 1. Ligand Screening
In our exploration of N-substituent effects on ligand
selectivity, compound 2a, derived from Boc-protected cyclo-
hexanediamine,14 was a reasonable starting point as it could be
subjected to Boc-deprotection and subsequent derivatization
providing access to further ligand analogues (Scheme 2a). This
Scheme 2. Synthetic Routes towards Distal N-Substituted
Ligand Library
b
c
Entry
Ligand
% ee (config.)
Conversion (%)
1
2
3
4
5
6
7
8
9
1
76 (S)
−70 (R)
−49 (R)
−39 (R)
81 (S)
75 (S)
53 (S)
93 (S)
44 (S)
62
34
30
44
59
60
70
80
56
40
late-stage diversification strategy was used in the preparation of
carbamate-containing ligands 2b−c, N-diethyl ligand 2d,
pyrrolidine ligand 2e, and piperidine ligand 2f. Ligands 2g−i
bearing pyrrole groups were synthesized by initial N-
functionalization of the parent diamine hydrochloride, followed
by reductive amination with the relevant salicylaldehyde and,
last, methylation of the proximal nitrogen (Scheme 2b).
2a
2b
2c
2d
2e
2f
2g
2h
2i
The ligand library was tested in our benchmark reaction of
acetophenone and ethylmagnesium bromide, and the enantio-
selectivities were compared (Table 1) to our previously reported
result with ligand (R,R)-1 (which gives (S)-2-phenyl-2-butanol;
76% ee). Interestingly, the presence of the carbamate motif in
Boc-ligand 2a induced a switch in selectivity to −70% ee
generating (R)-2-phenyl-2-butanol as the major product. Efforts
were made to improve this enantioselectivity with alternative N-
carbamate ligands 2b and 2c of varying size, but this proved
unfruitful. However, we noted that the inversion of enantiose-
lectivity remained constant across all carbamate-containing
ligands. Turning to alternative alkyl substitution at the remote
nitrogen, an N-diethyl motif (2d) gave a slight increase in ligand
selectivity to 81% ee. In the screening of N-cyclic pyrrolidine
(2e) and piperidine (2f) derivatives, it appeared that
enantioselectivity decreased with increasing N-alkyl ring size
suggesting that the substituents at this position should be small
in order to achieve high levels of selectivity. Ligand 2g with 2,5-
dimethylpyrrole substitution granted the sought-after increase in
selectivity of the test reaction to 93% ee with 80% conversion.
Consistent with our earlier hypothesis regarding steric effects
at the distal nitrogen, the more bulky 2,5-diphenylpyrrole
analogue 2h gave a low enantioselectivity of 44% ee. In all cases,
the reactions were clean with only product 2-phenyl-2-butanol
and starting material detected in the crude organic products. We
assume that the latter arose through partial enolization and
10
25 (S)
a
Solvent: toluene/ether (20:1); 0.1 mmol in ketone; overall
concentration: 0.06 M; quench added at −82 °C: see Supporting
Information (SI) for full procedure. Measured using chiral stationary
phase HPLC (see SI). Calculated from HPLC data using the relative
response factor of acetophenone to 2-phenyl-2-butanol; no other
products visible in crude NMRs or HPLCs.
b
c
regeneration on workup. Previous work within our group had
shown that phenolic substitution, specifically ortho- to the
hydroxyl group, was crucial for ligand efficacy. This was again
confirmed here when ligand 2i (containing an ortho-
unsubstituted phenol) showed low enantioselectivity (Table 1,
entry 10). Thus, a combination of both phenolic substitution
and nitrogen substitution appear to be required for asymmetric
induction.
We then proceeded to develop the synthesis of the successful
ligand 2g so that it could be accessed in larger quantities for
scope studies. Following the optimization of reaction conditions
across the three synthetic steps, we were able to isolate 2g in 51%
overall yield providing 6−7 g of material (Scheme 3). Most
conveniently, a single recrystallization is sufficient for
purification so that no column chromatography is required
throughout the synthesis.
B
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Letter
Scheme 3. Optimized Synthesis of Ligand 2g
Table 2. Scope of Chiral Tertiary Alcohol Synthesis with
Ligand 2g in Comparison to Previously Successful Ligand 1
We then explored the scope of the promising 2,5-
dimethylpyrrole ligand 2g with a focus on ketone/Grignard
combinations which had previously been limitations of our
methodology using our previously successful prototypic ligand 1
(Table 2). It can be seen that the new ligand 2g is
complementary in selectivity to 1. Thus, the asymmetric 1,2-
addition of ethylmagnesium bromide to acetophenones had not
proceeded with very high enantioselectivity using 1 (≤76% ee for
substrates 3a−c). In contrast substantial improvements in
selectivity were obtained with ligand 2g for acetophenones
including those containing both electron-donating and -with-
drawing substituents at the para-position (Table 2, entries 1−3)
with 3a, 3b, and 3c being generated in high ee. The latter is a
striking increase over the result with ligand 1 (46% ee), which we
had attributed to the high reactivity of the ketone.
An electron-withdrawing substituent at the meta-position of
the acetophenone (3d) was also well tolerated. A smaller but still
significant increase in selectivity was obtained with ligand 2g for
asymmetric 1,2-addition to a cyclic aryl-alkyl ketone (3e),
whereas there was a slight decrease with a chain-extended
phenone (3f).
Regarding variation of Grignard reagents used, ligand 2g
proved to be inferior to ligand 1 for the addition of
methylmagnesium bromide to propiophenone (Table 2, entry
7). However, it was reassuring that it was consistent with 1 in
giving (R)-2-phenyl-2-butanol (3g) as the major enantiomer
(the opposite configuration to that observed in the screening
reaction in Table 1). This indicates that our previously
developed mechanistic rationale for selectivity10 can be applied
to the new ligand. Pleasingly, ligand 2g performed excellently for
the 1,2-addition of a long-chain alkyl Grignard reagent to 4′-
methylacetophenone, generating compound 3h in 93% ee. Both
ligands gave ≥90% ee for the reaction of β-phenethylmagnesium
bromide and 1-indanone (3i), with ligand 2g again giving the
better result of 92% ee with a yield of 65%. To demonstrate the
utility of our method we also carried out the synthesis of product
3i on a half-gram scale. A good yield of 65% was achieved with
just a slight decrease in enantioselectivity to 90% ee.
Furthermore, we were delighted that 96% of the ligand was
recovered following column chromatography. Regrettably, the
new ligand 2g performed poorly in the synthesis of a trialkyl
tertiary alcohol 3j giving a low selectivity of 35% ee versus 88% ee
with ligand 1.
a
Solvent: toluene/ether (20:1); 0.1 or 0.2 mmol in ketone; overall
concentration: 0.06−0.07 M; quenched at −82 °C: see SI for full
procedure. Values of enantiomeric excess measured using chiral
stationary phase HPLC (see SI). Arbitrary product configurations
shown unless otherwise indicated; sign of optical rotation. Isolated
yield. Calculated from HPLC data using a relative response factor of
the ketone starting material to the tertiary alcohol product. Reaction
performed on a 0.50 g scale (3.78 mmol).
b
c
d
e
method and reactions proceeded with low, if any, induction of
asymmetry. We were pleased to find that a reasonable level of
selectivity was attainable in the reaction of 3-acetylpyridine and
ethylmagnesium bromide with ligand 2g delivering 3k in 64% ee
Prior to the development of ligand 2g, ketone substrates
containing pyridyl functionality were beyond the scope of our
C
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with a 46% isolated yield. This result piqued our interest in
exploring the tolerability of further heteroaryl-alkyl ketones in
our reaction system with ligand 2g. We were disappointed to
find that a low enantioselectivity of 45% ee was obtained in the
reaction of ethylmagnesium bromide and 2-acetylfuran to yield
product 3l. In contrast, we discovered that its sulfur-containing
counterpart, 2-acetylthiophene, showed exceptional compati-
bility under analogous reaction conditions forming 3m in 93%
ee.
We then sought an application of the new ligand 2g in the
synthesis of biologically important chiral tertiary alcohols,
ideally one that demonstrated the power of the three-way
disconnection available in Grignard synthesis. Gossonorol (5,
Scheme 4) is a natural product first isolated in 1984 from cotton
synthesis of ketone 4a, followed by the asymmetric 1,2-addition
of methylmagnesium bromide in the presence of ligand (S,S)-1
yielding the target alcohol, (S)-5, in 93% ee.
The development of ligand 2g has broadened the scope of our
asymmetric methodology to include the highly selective
addition of alkyl Grignard reagents to acetophenones. This
presented the opportunity of achieving the apotheosis of
synthetic scheme shortening: the synthesis of gossonorol (5)
in one step (starting from a commercially available ketone).
Therefore, we were gratified that the addition of alkyl Grignard
reagent 4b (from the commercially available bromide) to 4′-
methylacetophenone in the presence of (R,R)-2g delivered (S)-
5 in 93% ee with an isolated yield of 73%. We also investigated
the other possible one-step Grignard pathway toward
gossonorol using an aryl Grignard reagent. Control of
stereoselectivity in the generation of chiral tertiary alcohols
from aryl Grignard reagents tends to be more challenging;10,11b
therefore, we were not surprised that the asymmetric addition of
p-tolylmagnesium bromide in the presence of (R,R)-2g
generated (R)-5 in 48% ee. On the other hand, considering
the very small steric differences about the prochiral faces of the
alkyl−alkyl ketone starting material, sulcatone, this is still an
encouraging observation, given that it is the opposite
enantiomer that is produced.
Scheme 4. Syntheses of Gossonorol (5)
In conclusion, we have expanded our library of diaminophe-
nol ligands for the asymmetric Grignard synthesis of tertiary
alcohols, exploring the effects of substituent variation on the
distal nitrogen of the ligand. We identified a successful ligand,
2g, bearing a 2,5-dimethylpyrrole motif which has granted
improvements in the scope and selectivity of our methodology.
Exploiting the efficacy of this ligand, we have applied its (R,R)
enantiomer in the shortest possible synthesis of a biologically
relevant tertiary alcohol, (S)-gossonorol, delivering the target in
good yield with high enantioselectivity in just one synthetic step.
This result also constitutes the shortest formal syntheses of
boivinianin B and yingzhaosu C. The opposite enantiomer of
gossonorol is available either by use of (S,S)-2g or by using one
of the other potential asymmetric Grignard disconnections.
These results attest to the power of the Grignard three-way
disconnection strategy and the versatility of our method.
a
Solvent: toluene/ether (20:1); 0.1 mmol in ketone; overall
i
concentration: 0.07 M; PrOH/NH4Cl (sat.) added at −82 °C to
quench: see SI for full procedure. Values of enantiomeric excess (%)
measured using chiral stationary phase HPLC (see SI). Isolated
b
yield.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02629.
essential oil.15 This fragrant sesquiterpenoid has since been
extracted from other natural sources such as chamomile
(Chamomilla recutita)16 and marine red algae.17 It has
demonstrated promising antialgal activity against harmful red
tide microalgae17b,c and serves as a synthetic precursor to other
natural products such as boivinianin B18,19 (6a) and antimalarial
peroxide yingzhaosu C20 (6b), which can be accessed through
intramolecular cyclization reactions.
Five diverse synthetic approaches for the enantioselective
synthesis of gossonorol have been reported in the literature.
Among the strategies used are the chiral base-mediated
functionalization of chromium complexes of protected benzyl
ethers,18 bromolactonization,19 and titanium-promoted dialkyl
zinc addition to ketones.21 These methods require up to seven
synthetic steps. Most notably, in 2012, Aggarwal and co-workers
employed the lithiation−borylation strategy to generate this
target in three steps with excellent selectivity (98% ee).22 Last
year, we demonstrated that our asymmetric Grignard system can
be utilized in a two-step sequence to this target, the shortest
reported synthesis to date (Scheme 4).13 This just required the
Details of experimental procedures, compound character-
ization data and copies of NMR spectra and HPLC traces
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Saranna E. Kavanagh − Centre for Synthesis and Chemical
Biology, School of Chemistry, University College Dublin, Belfield,
Dublin 4, Ireland; Email: saranna.kavanagh@ucdconnect.ie
Declan G. Gilheany − Centre for Synthesis and Chemical Biology,
School of Chemistry, University College Dublin, Belfield, Dublin
4, Ireland; orcid.org/0000-0002-1272-4423;
Email: declan.gilheany@ucd.ie
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02629
D
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Development of Bifunctional Salen Catalysts: Rapid, Chemoselective
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Irish Research Council is acknowledged for Ph.D. funding
for S.K. (Grant GOIPG/2017/1179). Arran Chemical Com-
pany Ltd., Athlone, Ireland is gratefully acknowledged for gifts of
resolved trans-1,2-diaminocyclohexane. We thank Dr. Claudio
Monasterolo, School of Chemistry, University College Dublin,
for valuable discussions.
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