Exploration of the diastereoselectivity in an unusual Grignard reaction and its application towards the synthesis of styryl lactones 7-: Epi -(+)-goniodiol and 8- epi -(-)-goniodiol

Article abstract of DOI:10.1039/c6ra03192g

An unusual diastereoselective Grignard reaction is explored, where the Grignard reagents are derived from 1,n-dihaloalkanes. A steric bias due to the presence of a quaternary centre adjacent to the acetonide ester at the benzylic position is responsible for the formation of an intramolecularly reduced product in almost quantitative yield. This steric hindrance is responsible for the diastereoselectivity observed with a variety of aromatic as well as aliphatic esters. The unusual Grignard reaction furnishes long chain secondary alcohols possessing a terminal olefin, which are synthetically important intermediates. As an application of this method, the diastereoselective synthesis of styryl lactones viz. 7-epi-(+)-goniodiol (29) and 8-epi-(-)-goniodiol (30) has been achieved.

Full text of DOI:10.1039/c6ra03192g

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Exploration of the diastereoselectivity in an unusual
Grignard reaction and its application towards the
synthesis of styryl lactones 7-epi-(+)-goniodiol and
8-epi-(À)-goniodiol†
Cite this: RSC Adv., 2016, 6, 50721
a
Subhash P. Chavan, Harshali S. Khatod,a Tamal Dasb and Kumar Vankab
*
An unusual diastereoselective Grignard reaction is explored, where the Grignard reagents are derived from
1,n-dihaloalkanes. A steric bias due to the presence of a quaternary centre adjacent to the acetonide ester at
the benzylic position is responsible for the formation of an intramolecularly reduced product in almost
quantitative yield. This steric hindrance is responsible for the diastereoselectivity observed with a variety
of aromatic as well as aliphatic esters. The unusual Grignard reaction furnishes long chain secondary
alcohols possessing a terminal olefin, which are synthetically important intermediates. As an application
of this method, the diastereoselective synthesis of styryl lactones viz. 7-epi-(+)-goniodiol (29) and 8-epi-
(À)-goniodiol (30) has been achieved.
Received 3rd February 2016
Accepted 7th May 2016
DOI: 10.1039/c6ra03192g
www.rsc.org/advances
The Grignard reaction is one of the most fundamental and to occur by an intramolecular reduction, as the major product
convenient tools for the formation of carbon–carbon bonds, instead of the tertiary alcohol. There was no such report for
hence it is an essential and widely performed reaction in aliphatic esters.
organic synthesis. To date, Grignard reagents have been
As a part of one of the total synthesis projects, a practical
extensively utilized organometallic species in total synthesis. synthesis of the commercially important antidepressant drug
Since its invention, a number of different modications of the (Æ)-venlafaxine 2 was reported from our laboratory.7 Here, the
original reaction have been reported in the literature. Kohler aminoester 1 was treated with a Grignard reagent derived from
et al.1 reported on the reducing power of Grignard reagents, 1,5-dibromopentane to furnish the product 2 in 50% yield
which was earlier mistaken for enolization. Whitmore and co- (Scheme 1). In order to improve the overall yield and render the
workers2a,b reported an abnormal Grignard reaction that process more efficient, we planned an enantioselective
frequently depends upon the mode of addition of the reagent to approach for synthesis of the drug. In this context, the Grignard
the carbonyl group. Nenitzesku3 reported that the reaction reaction was carried out on an acetonide protected ester 3, with
between terminal di(bromomagnesio)alkanes and esters fur- the hope of obtaining alcohol 3b. Surprisingly, this did not
nished cyclic alcohols. The addition of di(halomagnesio) furnish the desired addition product 3b. Aer careful investi-
alkanes to various lactones as well as acid anhydrides furnished gation and characterization of the product formed, it was found
diols and spirolactones, which was observed by Canonne.4 to contain a secondary alcohol with a terminal double bond. It
Ferles5 reported the reaction of 1,4-di(bromomagnesio)butane is clear that instead of routine nucleophilic addition, 3 under-
with ethyl isonicotinate, with a very low (<10%) yield for the went a simultaneous elimination–reduction sequence of reac-
annelation product. Canonne et al.,6 inspired by Ferles’ obser- tions (Scheme 1). Almost quantitative formation of compound
vation, have reported on steric effects with Grignard reagents
derived from alkyl halides, like for the reaction of 1,5- and 1,4-
dibromobutane. When these di(bromomagnesio)alkanes were
treated with different aromatic and heteroaromatic esters, this
furnished a secondary alcohol, whose formation was postulated
aDivision of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi
Bhabha Road, Pashan, Pune 411 008, India. E-mail: sp.chavan@ncl.res.in
bPhysical and Material Chemistry Division, CSIR-National Chemical Laboratory, Dr.
Homi Bhabha Road, Pashan, Pune 411008, India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra03192g
Scheme 1 Observation of an unusual Grignard reaction.
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3a, rather than the annelation product 3b, prompted us to study, two transition states, V and VII, were found corre-
investigate the observed result in detail. It could be explained by sponding to the two different pathways starting from the same
considering two transition states as shown in Fig. 1. Aer the reactant geometry IV (Fig. 2). In the case of the addition product
rst nucleophilic addition of di(bromomagnesio)pentane to the (VIII), the energy barrier was found to be 16.9 kcal molÀ1
,
carbonyl carbon of the acetonide protected ester, there are two whereas for the unusual product (VI) the energy barrier was
alternative possibilities: (i) a second intramolecular nucleo- reduced by almost 15.0 kcal molÀ1. Therefore, the second
philic addition reaction with the ketone, which is now pathway, where the energy barrier was found to be only 1.9 kcal
comparatively more electrophilic than the starting ester, or (ii) molÀ1, is kinetically much more favourable and leads to the
instead of the expected addition reaction, intramolecular formation of an undesired straight chain secondary alcohol as
elimination at the terminal carbon–carbon bond, leading to the major product. This low barrier suggests that in this reac-
hydride transfer to the carbonyl carbon of the ketone to give tion, the eventual outcome of the reaction is governed by the
a straight chain secondary alcohol containing a terminal double kinetics of the reaction.
bond as the only product and not the expected tertiary cyclo-
The reaction of in situ generated Grignard reagents obtained
hexanol. The steric hindrance of the acetonide functionality at from terminal dihalogenated alkyl compounds was systemati-
the benzylic center positioned alpha to the ester resulted in cally studied for a diverse range of esters and the results ob-
hydride transfer preferentially from one face. This hydride shi tained are depicted in Table 1. It is noteworthy that in the case
could occur either from the alpha or beta face with respect to of esters 4–9, excellent yields as well as diastereoselectivities
the orientation of the acetonide steric bulk, hence is respon- were observed not only in the case of sterically crowded
sible for the diastereoselectivity observed in the present reac- aromatic esters but also in the case of aliphatic esters. When
tion. We believe that this transformation proceeds through acetonide protection is placed on the secondary carbon alpha to
a six-membered, stable and favourable transition state (II), the carboxylic carbon and not at the benzylic position for esters
which thus explains the outcome of the reaction. This rigid and 10, 11 and 12, this resulted in a notable decrease of the yields of
sterically hindered system blocks a second nucleophilic attack the respective reduced products. So, positioning the acetonide
of the Grignard reagent on the more electrophilic intermediate functionality on the tertiary carbon proved to be critical and
ketone, as compared to hydride transfer, and so formation of essential, for high diastereoselectivity.
the annelation product was not observed, as shown in transition
state model (I). To place our hypothesis on even rmer ground, acetic acid 13 and its p-methoxy derivative 14 were treated under
we decided to undertake DFT calculations. similar conditions, alcohols 13a and 14a were obtained in 32%
In addition to above results, when the methyl ester of phenyl
DFT calculations were done at the PBE/TZVP level of theory and 37% yields respectively (Table 2). It should be emphasized
in order to understand the mechanism as well as the formation that the introduction of one methyl group at the benzylic
of the addition (VIII) and unusual (VI) products of the reac- position, as in ester 15, results in signicant enhancement of
tion.18 In the rst step – the nucleophilic addition of the the yield of the reduced product (15a). The presence of two
Grignard reagent19 to the carbonyl carbon of the acetonide methyl groups at the benzylic position of starting ester 16,
protected ester I – the activation energy barrier via transition
state II was found to be 17.3 kcal molÀ1 (DG). The second step of
the reaction is much more important, because there are two
possibilities – (i) another nucleophilic addition of the Grignard
to the more electrophilic carbonyl carbon leading to the
formation of (VIII), or (ii) the hydride transfer to the carbonyl
carbon of the ketone to give the straight chain secondary
alcohol containing a terminal double bond (VI). From our DFT
Fig. 2 DFT calculations comparing the free energy profiles via two
Fig. 1 Transition state model for the unusual Grignard reaction.
50722 | RSC Adv., 2016, 6, 50721–50725
different transition states.
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Table 1 Unusual Grignard reaction of acetonide protected ester substrates
a
Reaction conditions: 1,5-dibromopentane, Mg, THF, 0 ꢀC–RT, 5 h. b Product yields calculated aer column chromatography purication. c Unable
to separate two alcohols using column chromatography so acetate protection of the secondary alcohol, separation of it from the respective
d
cycloalkanol and subsequent deprotection was carried out, and thus pure products were isolated in order to obtain data. Yield and dr
e
f
calculated over two steps. dr: diastereomeric ratio determined by 1H-NMR analysis. Relative stereochemistry of 4a to 9a was determined by
extensive chemical transformations of 3a into known compound.17
resulted in product 16a being obtained in 89% yield with the 17 and 18 were reacted under similar reaction conditions, they
absence of cycloalkanol 16b. Thus formation of 16a highlights led to the formation of 17a and 18a in reduced yields due to
the importance of the presence of a tertiary carbon alpha to the a decrease in the steric bulk. In order to study the scope and
carboxylic ester. It is evident from the above study that the limitations of the method using an acetonide group, some of
absence of an acetonide steric bias does affect the yield and the esters were subjected to treatment with terminal di(bro-
diastereoselectivity. Furthermore, when a,b-unsaturated esters momagnesio)alkanes of varying chain lengths. Thus, acetonide
Table 2 Exploration of the unusual Grignard reaction
a
b
c
Reaction conditions: 1,5-dibromopentane, Mg, THF, 0 ꢀC–RT, 5 h. Product yields calculated aer column chromatography purication. dr:
diastereomeric ratio determined by 1H-NMR analysis. Reaction conditions: 1,6-dibromohexane, Mg, THF, RT, 5 h. Reaction conditions: 1,4-
d
e
dibromobutane, Mg, THF, 0 ꢀC–RT, 5 h.
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protected ester 3, on reaction with 1,6-di(bromomagnesio)
hexane, in THF as a solvent at room temperature furnished
reduced product 23a in 93% yield. Interestingly, it was observed
that the reaction of 1,4-di(bromomagnesio)butane with esters 3
and 20 always resulted in the formation of the usual addition
products, cyclopentanol 24b and 25b respectively, with good
yields.
Scheme 3 Formal synthesis of 30 and 29.
As a part of our ongoing program towards the total synthesis
of bioactive natural products, we quickly realised that this
methodology could be very useful for the synthesis of styryl
lactones8 viz. 7-epi-(+)-goniodiol 29 and 8-epi-(À)-goniodiol 30,
isolated by Mu and co-workers.10 By virtue of the strong cyto-
toxic activity exhibited by these styryl lactones,11 they have been
the most sought aer phytochemicals worldwide, due to their
promising role in oncopharmacology.9 7-epi-(+)-Goniodiol 29
with a 25 mM MIC value against Listeria denitricans9a is the
stereoisomer, amongst all the other stereoisomers of styryl
lactones, which showed the highest activity against Gram
positive bacteria.14b Various synthetic approaches for styryl
lactones have been reported in the literature, highlighting
synthesis of goniodiol,12a–d as it is the source of a variety of it's
natural analogues.13,14 In light of the results obtained in the case
of ester 11 (Table 1), the diastereoselectivity observed from the
unusual Grignard reaction is noteworthy. Since the diastereo-
mers could not be separated by normal column chromatog-
raphy, it was decided to proceed towards the synthesis of 29 and
30 (Scheme 2).
Oxidative cleavage of 11a (dr 7 : 3, ee 98%),15 resulted in the
formation of lactol 26, which was further oxidised using tetra-
propylammonium perruthenate in the presence of N-methyl-
morpholine-N-oxide to furnish lactone 27 in 87% yield. Lactone
27 was alkylated at À78 ꢀC using phenylselenyl bromide and
employing LDA, and subsequent oxidation–elimination in the
presence of hydrogen peroxide and pyridine provided
compound 28 in good yield, which aer acetonide deprotection
furnished 7-epi-(+)-goniodiol 29 and 8-epi-(À)-goniodiol 30. The
spectral data of 29 and 30 thus obtained are in agreement with
those reported in the literature.14 One of the diastereomers
became enriched during chromatographic purication, at the
lactol step. Hence, the diastereomeric ratio of the nal
compounds was observed to be 8 : 2 with respect to 29 and 30.
On the other hand, a mixture of 11a1 and 11a2 (dr 7 : 3),
when subjected to acetonide deprotection, produced the
corresponding triols 31a1 and 31a2 (dr 8 : 2), which have been
reported as intermediates in the total synthesis of Goniodiol
and 8-epi-(À)-goniodiol 30 by Prasad et al.14f (Scheme 3) and
thus this also constitutes an alternative route for the formal
synthesis of styryl lactones 29 and 30.
Using the above protocol for the unusual Grignard reaction,
a regioselective route for the preparation of substituted 3-cap-
rolactone in a reduced number of steps was developed.
Accordingly, when methyl benzoate 20 was treated under
Grignard reaction conditions in the presence of 1,6-di(bromo-
magnesio)hexane with THF as a solvent at room temperature,
this afforded a seven carbon long chain alcohol 32 containing
a terminal double bond, which proved to be an immensely
important intermediate for the facile synthesis of seven
membered lactones.16 As shown in Scheme 4, alcohol 32 was
treated under Lemieux–Johnson oxidation conditions to furnish
aldehyde 33 in 79% yield, which was then subjected to TEMPO
catalyzed oxidative lactonization in the presence of (diacetox-
yiodo)benzene to afford lactone 34 in 61% yield.
In summary, an unusual diastereoselective Grignard reac-
tion has been explored using diverse and synthetically impor-
tant substrates. The presence of an acetonide protecting group,
and its orientation and position in the starting ester, deter-
mines the fate of the product formation as well as the diaster-
eoselectivity of the intramolecularly reduced product. As an
application, the diastereoselective synthesis of styryl lactones 7-
epi-(+)-goniodiol (29) and 8-epi-(À)-goniodiol (30) was accom-
plished in a reduced number of steps. Also, the synthesis of 7-
membered lactones can be achieved, exemplied by the prep-
aration of lactone 34. The exploration and investigation of the
unusual Grignard reaction with a wide range of aliphatic and
aromatic substrates demonstrates the potential scope of this
protocol and its applicability for the total synthesis of struc-
turally challenging natural products, which will be reported in
future.17
Scheme 4 Synthesis of caprolactone 34.
Scheme 2 Diastereoselective synthesis of 29 and 30.
50724 | RSC Adv., 2016, 6, 50721–50725
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Acknowledgements
H. S. K. and T. D. thank CSIR, New Delhi, India, for the award of
a research fellowship. S. P. C. thanks CSIR, New Delhi, India, for
nancial support as part of XIIth Five Year plan programme
under the titles ACT (CSC-0301) and ORIGIN (CSC-0108). T. D.
and K. V. acknowledge the Centre of Excellence in Scientic
Computing, NCL, Pune for providing computational resources
and also acknowledge the Multi-Scale simulation and Modeling
project (MSM) for nancial assistance. The authors thank Dr U.
R. Kalkote and Dr H. B. Borate for helpful discussions.
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