Very short highly enantioselective Grignard synthesis of 2,2-disubstituted tetrahydrofurans and tetrahydropyrans

Article abstract of DOI:10.1039/c9sc00978g

Phenones with elongated chains are shown to be excellent substrates for ligand-promoted asymmetric Grignard synthesis of tertiary alcohols. In turn this enables the simple, short and highly enantioselective (up to 96% ee) preparation of chiral 2,2-disubst

Full text of DOI:10.1039/c9sc00978g

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Very short highly enantioselective Grignard synthesis of 2,2-
disubstituted tetrahydrofurans and tetrahydropyrans
Received 00th January 20xx,
Accepted 00th January 20xx
Claudio Monasterolo, Helge Müller-Bunz and Declan G. Gilheany *a
a
a,†
DOI: 10.1039/x0xx00000x
Phenones with elongated chains are shown to be excellent substrates for ligand-promoted asymmetric Grignard synthesis
of tertiary alcohols. In turn this enables the simple, short and highly enantioselective (up to 96% ee) preparation of chiral
www.rsc.org/
2
,2-disubstituted THFs and THPs. Thus, asymmetric addition of Grignard reagents to γ-chlorobutyrophenones and δ-
chlorovalerophenones takes place in the presence of chiral diaminocyclohexyl-derived tridentate ligand and subsequent
base-promoted intramolecular cyclization occurs with complete retention of asymmetry. As examples of the methodology,
we report the shortest syntheses of gossonorol, γ-ethyl-γ-phenylbutyrolactone, δ-methyl-δ-tolylvalerolactone, the joint-
shortest and flexible synthesis of boivinianin A and the shortest formal syntheses of boivinianin B and yingzhaosu C
.
devising of many diverse, highly stereoselective synthetic
6
,7,8,9,10
Introduction
strategies.
However the 2,2-disubstituted cases remain
particularly recalcitrant. There are only a handful of
asymmetric syntheses reported, all of which suffer from
limitations of very narrow scope, use of complex substrates
One of the driving forces for improvement in organic synthesis
is the relentless pressure for shorter routes to the desired
compounds. However, ultimately, there must be a limit to that
development when the shortest possible route is approached.
The question then arises as to when to cease development of
new routes to the target as the number of steps becomes very
low. In that context the Grignard synthesis of alcohols is a
powerful tool because of the inherent flexibility of its
disconnections but, until recently, it lacked a crucial aspect,
namely a complementary flexible stereoselectivity. Recently
11
and/or low selectivity.
1
2,3
we, and others, have made progress towards a general
asymmetric Grignard synthesis of tertiary alcohols. Here we
present a notable expansion of the substrate scope of our
methodology, applied in a series of very short syntheses.
Figure 1 Examples of chiral bioactive 2,2-disubstituted THF
We now report a novel general asymmetric synthesis of both
Our search for a test bed for the above ideas within our the THFs and the THPs that is complementary to those of List
own work led us to consider chiral 2,2-disubstituted and co-workers and which enables a number of extremely
tetrahydrofurans (THFs) and tetrahydropyrans (THPs). The short syntheses of products of biological interest.
former have come to prominence recently through the work of
4
List and co-workers but more generally THFs, THPs and their
derivatives are found as widespread structural motifs in many
Results and discussion
classes of bioactive compounds showing a range of biological
activities (e.g. Figure 1). The challenge to develop efficient
methods for their asymmetric construction has led to the
The route is based on our ligand-promoted asymmetric
Grignard addition to ketones. Previously we reported that
5
1
acetophenones gave only moderate selectivity but we have
now discovered that chain extension in phenones renders
them especially good substrates (illustrative examples in
Scheme 1). In turn, this allowed us to explore their application
in synthesis and we now report powerful ring-closure
protocols using the resultant alcohols.
Dr. C. Monasterolo, Dr. H. Müller-Bunz and Prof. D. G. Gilheany
Centre for Synthesis and Chemical Biology, School of Chemistry
University College Dublin
Belfield, Dublin 4, Ireland
claudio.monasterolo@ucd.ie, declan.gilheany@ucd.ie
†
To whom correspondence about the single crystal X-ray diffraction analysis
should be addressed helge.muellerbunz@ucd.ie
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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as we had previously observed,1a toluene is the solvent of
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DOI: 10.1039/C9SC00978G
choice to deliver high enantioselectivity (Table 1, entries 1-3).
But in contrast to the previous work, in this case, it is the tert-
butyl motif (L1) that gives the superior selection compared to
the trifluoromethyl substituted ligand (L2, entry 4). Also in
contrast, switching to the iodo Grignard reagent reduced
selectivity (entry 5). Finally, variation of concentration and
reactant equivalents allowed an increase in conversion
Scheme 1 Side chain influence on asymmetric Grignard addition to phenones.
Tertiary alcohols have not been commonly used for ring without affecting the enantioselectivity (entries 6-9).
closure before but an exception is the use of the
With optimized conditions in hand, we investigated the
sesquiterpenoid (S)-gossonorol as an intermediate in the scope of the Grignard reagent and the substitution pattern on
syntheses of a number of biologically interesting products such both
γ-chlorobutyrophenones 2a-c and δ-
12
1
as boivinianin B. Our method does indeed provide the chlorovalerophenones 3a-c (Table 2, R = H, Br, OMe). Various
shortest route to date to (S)-gossonorol (2 steps, Scheme 2) linear and branched Grignard reagents reacted well, producing
from ketone
methylacetophenone
Asymmetric addition of MeMgBr in the presence of ligand variation on the substrate was well tolerated for 4/5bb-cb
S,S)-L1 delivered (S)-(-)-gossonorol in 66% yield and 93% ee.
with just slight ee decreases for the more activated para-
1
,
itself prepared by alkylation of p- the corresponding tertiary alcohols 4ab
-4ad and 5aa-5ad in
with 3,3-dimethylallyl bromide. good yields and enantioselectivities. Similarly, electronic
,
(
bromo cases 4bb and 5bb versus the deactivated para-
methoxy cases 4cb and 5cb, which gave higher selectivity.15
Table 1 Asymmetric addition of MeMgX to γ-chlorobutyrophenone.a
Scheme 2 Two-step asymmetric synthesis of (S)-(-)-gossonorol and formal
synthesis of (-)-boivinianin B.
Entry
Solvent
Ligand
MeMgX
Conversion (%)b
ee (%)c
1
2,13
(equiv.) (equiv.)
Previous syntheses of gossonorol
show reduction in step
12b
and 6-13a to 3-steps : that via
13b
1
2
3
4
5
6
7
8
9
Toluene L1 (1.0)
Br (2.1)
Br (2.1)
Br (2.1)
Br (2.1)
I (2.1)
Br (2.1)
Br (2.1)
Br (2.4)
Br (2.6)
71
65
87
78
73
74
74
78
86
91
53
0
80
78
88
85
91
83
count with time from 7-
functionalization of ketone
relatively lower selectivity,
Et
THF
2
O
L1 (1.0)
L1 (1.0)
1
3a
with dimethylzinc showing
whereas Aggarwal and co-
1
Toluene L2 (1.0)
Toluene L1 (1.0)
Toluene L1 (1.0)
Toluene L1 (1.0)
Toluene L1 (1.3)
Toluene L1 (1.3)
workers employed the lithiation/borylation strategy, achieving
high stereoselectivity (98% ee) in 3-steps.13b That a further
step reduction was possible demonstrates the power of the
Grignard synthesis. Analogous arguments apply to the
resultant formal synthesis of boivinianin B.
Turning now to the main focus of our work, which is the
complementary and more general ring-closing of the ω-chloro
2/3 to THFs and THPs as shown in Scheme 3. This had
been reported in the racemic THF series by Capriati and co-
d
e
a
On 0.1 mmol scale using (R,R)-ligand. MeMgX solution in Et
2
O, diluted in
2
toluene (1:5). Overall concentration 0.05 M. Quenched at -78 °C with IPA/H O
species
b
1
and NH
4
Cl sat. (See ESI for details). Determined by H-NMR analysis of the
crude reaction mixture after work-up, only product and returned starting
14
workers and we thought it a good test of our methodology as
a short route to these challenging classes of heterocycles. In Overall concentration 0.08 M.
material were present. c Determined by HPLC on chiral stationary phase.
d
e
Overall concentration 0.1 M.
particular, it was important to determine if our asymmetric
Grignard reagents could tolerate the alkyl halide functionality.
Table 2 Asymmetric synthesis of γ-chloro and δ-chloro tertiary alcohols by addition of
Grignard reagents to γ-chloro and δ-chlorobutyrophenones.a,b,c
Scheme 3 Asymmetric synthesis of 2,2-disubstituted THFs and THPs
As a test, we tried the reaction of 4-chlorobutyrophenone
2a with methylmagnesium bromide in the presence of ligand
L1 (Table 1). To our delight, the reaction furnished alcohol 4aa
in high enantioselectivity (Table 1, entry 1). Notably, only
product 4aa was present in the crude reaction mixture, along
with unreacted 2a, presumably derived from enolization. In
exploring the best conditions for the process, we found that,
2
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a
Procedure as for Table 1, entry 8. b Isolated yields. c Enantiomeric excess
d
determined by HPLC analysis on chiral stationary phase.
brackets refers to the opposite enantiomer obtained by using (S,S)-L1
Absolute configuration from derived compound
determined by conversion to urethane
configurations of other compounds shown assumed by analogy, see text.
Results in
a
Reactions were run on 0.1 mmol scale. Method A: NaH (5.0 equiv.), THF, 0
e
.
b
°
C to r.t., 18 h. Method B: KHMDS (1.0 equiv.), THF, 0 °C to r.t., 1 h.
f
9
.
Absolute configuration
c
Isolated yields. Enantiomeric excess determined by HPLC analysis on chiral
stationary phase. Results in brackets refer to the opposite enantiomer
obtained by using (S,S)-L1
literature (ref 4a). f Absolute configuration from derived compound
8
- see text and Figure 2,
d
e
.
Absolute configuration by comparison to
g
9
.
With a successful asymmetric synthesis of chiral, non-racemic, Absolute configuration based on that of compound
8 - see text and Figure
γ- and δ-chloro tertiary alcohols in hand, it was of great 2, configurations of other compounds shown assumed by analogy, see text.
interest to see if they could be cyclised to the corresponding
Regarding the absolute configurations of our produced
materials, after much experimentation, we were able to
unequivocally determine this to be (R) for (6-chloro-2-
phenylhexan-2-ol) 5aa (obtained with R,R-L1) by single crystal
THF/THP derivatives (
6 and 7) without loss of asymmetry.
Again, we were delighted to find that this was so. Two slightly
different methods (A & B) had to be used as detailed in Table
3
. For the THFs, to avoid substitution side-products, sodium
16
X-ray crystallographic analysis of its urethane derivative
8
hydride was chosen as strong, non-nucleophilic base, with
which alcohols delivered the desired 2,2-disubstituted THFs
in excellent yields retaining the initial enantiomeric excesses
Table 3, Method A). For the THPs, NaH was a much less
(
Figure 2) prepared by reaction of 5aa with p-bromophenyl
4
6
17
isocyanate (see ESI). The functionalization of chiral tertiary
alcohols as urethanes to establish absolute configuration is
particularly effective because the neutral conditions used
avoid the risk of acid-catalyzed racemization.
(
effective and, after screening several bases (see Table 1, ESI),
we settled on KHMDS, with which chiral tertiary δ-chloro-
alcohols
THP derivatives
5
were smoothly cyclised delivering the corresponding
in high yield, again without loss of
7
asymmetry and with only minor amounts of elimination to
undesired terminal alkenes (Table 3, Method B). A one-pot
addition/cyclisation strategy proved to be unsuccessful,
resulting in complete recovery of tertiary alcohols.
Table 3 Base promoted cyclization of alcohols 4/5 to 2,2-disubstituted THFs and
THPsa,b,c
Figure 2 ORTEP diagram of
8 (thermal ellipsoids at 50% probability level).
The (R)-enantiomer obtained for compound 5aa is
consistent with the configurations observed in our
preparations of (S)-gossonorol (Scheme 2), (S)-(-)-boivinianin A
and lactones
9 & 12 (vide infra) and is consistent with our
previous observations for asymmetric Grignard addition to
1
phenones. The results suggest that the selectivity for
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asymmetric Grignard addition is such that (R,R)-L1 promotes which could be oxidised with potassium permanganate and
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addition of RMgBr to the phenone si face and we have iron (III) chloride25 to lactone (S)-12 with excellent
assumed that in showing the rest of the configurations in enantiopurity (Scheme 6). Its configuration was determined
Tables 2/3. However this is still a tentative conclusion and from the literature optical rotation.12b
more data are needed to build a definitive selectivity model.
DOI: 10.1039/C9SC00978G
We were now in a position to apply the novel asymmetric
methodology for very short syntheses of suitable targets. γ-
Ethyl-γ-phenylbutyrolactone
9, is an anticonvulsant and
hypnotic drug, and is a candidate as a potential treatment for
refractive epilepsy and Parkinson’s disease.18 Our 3-step
synthesis utilized compound (S)-6ab (Table 3, entry 2, 93% ee,
prepared using (S,S)-L1), which was oxidized with ruthenium
Scheme 6 Application of methodology to THPs. a after correcting for recovered
starting material 13 in step (i).
oxide and sodium periodate (Scheme 4) to (S)-9 in 66% yield
without loss of enantiopurity. Its configuration was
determined from the literature optical rotation.20
It seems that para-substitution on the phenyl ring (at least
with methyl) does not change the face-selectivity on the
phenone. This 3-step synthesis of lactone 12 marks a notable
improvement compared to other strategies reported so far,
12b, 26
the shortest of which were both 5-steps.
Finally we briefly examined the utility of the method in the
preparation of chiral 2,2-disubstituted oxetanes by addition of
EtMgBr to 3-chloropropiophenone. The corresponding tertiary
alcohol was obtained with reasonable stereocontrol (85% ee)
but was contaminated with a significant amount of elimination
side-product acrylophenone.
Scheme 4 Preparation of γ-ethyl-γ-phenylbutyrolactone 9.
A 2-step preparation of
with moderate enantioselectivity (70% ee) while a previous 4-
step route (with a BINOL-derived chiral auxiliary) gave with
9
has been reported19 but this was
9
20
good selectivity (92% ee).
The method was then applied to the preparation of 2-
methyl-2-tolyltetrahydrofuran 10 by addition of
,
Conclusions
methylmagnesium bromide to commercially available 4’-
methyl-4-chlorobutyrophenone 11, followed by cyclisation.
Compound 10 could then undergo oxidation, thereby
producing (S)-(-)-boivinianin A in three steps. (Scheme 5). Its
configuration was determined from both the literature optical
rotation and CSP-HPLC comparison.4
We have shown (i) that phenones with extended chains are
excellent substrates for our ligand-promoted asymmetric
Grignard synthesis of tertiary alcohols and (ii) that the
methodology tolerates primary alkyl halides. This has enabled
us to develop a new, very short, highly enantioselective
method for the preparation of both 2,2-disubstituted THFs and
THPs. We believe this is the first asymmetric preparation of
these challenging oxygen heterocycle classes by Grignard
synthesis from simple commercially available ketones. The
avoidance of transition metals, together with the
straightforward preparation and reuse of the ligand, ensures
wide applicability of the method. This is demonstrated by the
Scheme 5 Preparation of (S)-(-)-Boivinianin A. a after correcting for recovered starting
material 11 in step (i).
extremely short and selective syntheses of lactones
9 and 11
and natural compounds boivinianin A and gossonorol, the
latter also providing formal syntheses of boivinianin B and
yingzhaosu C. In each of these cases, our methodology is
shorter and/or complementary to existing methods and easily
allows analogue generation.
It is interesting that there are four previous asymmetric
syntheses of Boivinianin A, all of which are also 3-steps. List
and co-workers reported two highly enantioselective (96% ee)
preparations, the earlier involving resolution/oxidation,21
while this year’s4 used the intramolecular hydroalkoxylation
strategy. Alternative 3-step methods were reported by Shi and
22
23
co-workers and Yeung and co-workers but these had
relatively lower selectivities (79% & 82% ee respectively).
Conflicts of interest
There are no conflicts to declare.
We also wished to check if
a similar Grignard
addition/cyclisation/oxidation strategy would work for THP
analogues. We chose lactone (S)-12, previously used as an
intermediate in the synthesis of (S)-gossonorol on route to
Acknowledgements
Entrerprise Ireland is acknowledged for postdoctoral funding
12b
24
boivinianin B and the anti-malarial yingzhaosu C. Addition
of MeMgBr to commercially available ketone 13 in the for CM (grant CF/2013/3321). Arran Chemicals, Athlone,
presence of (S,S)-L1, followed by cyclisation gave THP 14
,
Ireland are gratefully acknowledged for gifts of resolved trans-
4
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,2-diaminocyclohexane. We thank Dr. Kirill Nikitin for
ARTICLE
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DOI: 10.1039/C9SC00978G
valuable discussions.
Notes and references
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1
7
Alcohol 5aa was reacted with p-bromophenylisocyanate in the
II
presence of Sn Lewis acid to obtain urethane 8 with complete
retention of configuration, see ESI. T. Francis, M. P. Thorne, Can. J.
Chem. 1976, 54, 24. Crystallographic data for 8 have been deposited
with the Cambridge Crystallographic Data Centre [CCDC 1883098]
18
4
6, 1661.
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ꢀ
TableꢀofꢀContentsꢀEntryꢀ
ꢀ
Claudio Monasterolo, Helge Müller-Bunz, Declan G. Gilheany*
Very Short Highly Enantioselective Synthesis of 2,2-Disubstituted
Tetrahyrofurans and Tetrahydropyransꢀ
ꢀ
DirectꢀasymmetricꢀGrignardꢀsynthesisꢀofꢀTHFs/THPsꢀviaꢀchiralꢀnon-racemicꢀ
tertiaryꢀalcohols,ꢀappliedꢀforꢀveryꢀshortꢀsynthesesꢀofꢀsixꢀbiologicalꢀtargets.ꢀꢀ
ꢀ
ꢀ
ꢀ