Carbamate-directed benzylic lithiation for the diastereo- and enantioselective synthesis of diaryl ether atropisomers

Article abstract of DOI:10.3762/bjoc.7.156

Diaryl ethers carrying carbamoyloxymethyl groups may be desymmetrised enantio- and diastereoselectively by the use of the sec-BuLi-(-)-sparteine complex in diethyl ether. Enantioselective deprotonation of one of the two benzylic positions leads to atropis

Full text of DOI:10.3762/bjoc.7.156

Carbamate-directed benzylic lithiation for the
diastereo- and enantioselective synthesis
of diaryl ether atropisomers
Abigail Page and Jonathan Clayden*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1327–1333.
School of Chemistry, University of Manchester, Oxford Rd.,
Manchester M13 9PL, UK
doi:10.3762/bjoc.7.156
Received: 21 June 2011
Email:
Accepted: 24 August 2011
Published: 26 September 2011
Jonathan Clayden* - clayden@man.ac.uk
* Corresponding author
This article is part of the Thematic Series "Directed aromatic
functionalization".
Keywords:
configurational stability; diaryl ether; diastereoselective;
enantioselective; lateral lithiation; metallation
Guest Editor: V. Snieckus
© 2011 Page and Clayden; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Diaryl ethers carrying carbamoyloxymethyl groups may be desymmetrised enantio- and diastereoselectively by the use of the sec-
BuLi–(−)-sparteine complex in diethyl ether. Enantioselective deprotonation of one of the two benzylic positions leads to atropiso-
meric products with ca. 80:20 e.r.; an electrophilic quench typically provides functionalised atropisomeric diastereoisomers in up to
97:3 d.r.
Introduction
One of the first uses of the chiral diamine (−)-sparteine (1) in its methyl, alkoxymethyl or acyloxymethyl substitutents, a viable
now familiar role of controlling asymmetric deprotonation/elec- approach to the asymmetric synthesis of atropisomeric mole-
trophilic quench reactions [1] was an enantioselective benzylic cules.
deprotonation of bis(2,6-dimethylbenzene) with the aim of
generating an atropisomeric product in enantiomerically We have developed a number of methods for the synthesis of
enriched form (Scheme 1) [2]. Enantioselective lithiation has “nonstandard” atropisomer structures containing rigid frag-
since then commonly been used to generate axial or planar ments joined by a hindered single bond, but which are different
chirality [3], in many cases by desymmetrising deprotonation of from the typically well-studied biaryl compounds [4,5]. These
a functionalised aromatic system. The relative acidity of non-biaryl atropisomers have included aromatic amides [6-8],
benzylic protons makes enantioselective deprotonation in the ureas [9], ethers [10-12], sulfides and sulfones [13], and many
style of Scheme 1, of one of a pair of enantiotopic aromatic of the methods we developed for their asymmetric synthesis
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Beilstein J. Org. Chem. 2011, 7, 1327–1333.
nation and electrophilic quench of benzylic positions ortho to a
sterically hindered diaryl ether linkage.
Results
An aryloxy group is a weak director of metallation [20,23], but
in preliminary studies we were able to deprotonate and
methylate the hindered diaryl ether 6 [10] by treatment with
n-BuLi in ether at 0 °C with or without (−)-sparteine
(Scheme 2). Methylation of the resulting organolithium returned
the product 7 in up to 88% yield as a mixture of diastereoiso-
mers (by NMR). Previous data on the conformational stability
of related diaryl ether [10], coupled with our inability to sepa-
rate these diastereoisomers, and the invariant ratio in which they
were obtained, suggested that they are insufficiently hindered to
exist as stable atropisomers and they interconvert on a rela-
tively short timescale, of seconds to minutes, at room tempera-
ture.
Scheme 1: Desymmetrising metallation for the enantioselective syn-
thesis of atropisomers.
employed dynamic resolution techniques under kinetic or ther-
modynamic control [6,11,13-16]. The mechanistic possibilities
associated with dynamic resolution were initially elaborated by
Beak for organolithium compounds having varying degrees of
configurational stability [17,18], and in our studies on ureas and
amides we were able to identify correlated inversion processes
linking configurational inversion at organolithium centres with
conformational inversion of atropisomeric chirality by bond
rotation [19]. Several of the classes of atropisomers we have
studied contain functional groups which are excellent directors
of lithiation [20], and indeed our original interest in lithiation
stemmed from the need to build these atropisomeric structures
rapidly and efficiently [21].
Scheme 2: Benzylic lithiation of a diaryl ether.
In order to enhance the ease of metallation of the substrates (6
gives low yield at −78 °C unless sparteine is present), two diols
8 and 9, available from previous work, were converted to the
biscarbamates 10 and 11. The metallation of O-benzylcarba-
mates has been studied extensively by Hoppe [1,24-26], and the
deprotonation of 10 was achieved with sec-BuLi in ether and
the addition of acetone, returning 12 as a single diastereoiso-
mer (by NMR). Presumably in this case the diastereoisomers
still interconvert, but the bulk of the new substituent means that
one of the two diastereoisomers is significantly more stable than
the other [27]. However we were unable to confirm the relative
stereochemistry of the major diastereoisomer of the function-
alised products (Scheme 3).
We recently reported on the enantioselective synthesis of diaryl
ethers (a potential new class of chiral ligand having a structure
related to the wide bite angle diphosphine DPEPhos) by biocat-
alytic oxidation or reduction, and which made use of desym-
metrisation of a “pro-atropisomeric” substrate 4 to achieve the
required enantiomeric enrichment in the product 5 [22]. In this
paper we report parallel studies on the attempted asymmetric
synthesis of atropisomeric diaryl ethers in diastereomerically
and/or enantiomerically enriched form by the directed deproto-
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Beilstein J. Org. Chem. 2011, 7, 1327–1333.
Scheme 3: Benzylic metallation of a diaryl ether α to a carbamate.
Moving to the 6’-methyl analogue 11 gave products that were (−)-sparteine in Et2O, before addition of the reaction substrate
expected to be atropisomeric [10], because they have four and then the electrophile, led to products being formed in high
substituents ortho to the ether linkage, one of them tertiary. d.r. in each case and with e.r.’s between 73:27 and 81:19
Deprotonation with sec-BuLi in Et2O at −78 °C and quenching (Table 1, entries 5–8).
with acetone, cyclobutanone, TMSCl or acetic anhydride all
gave good yields of functionalised products with d.r.'s which The reaction behaviour was very revealing when the benzyl-
varied according to the electrophile but were generally high lithiums generated in the presence or absence of (−)-sparteine
(Scheme 4 and Table 1, entries 1–4). Having established good were quenched with the electrophile Bu3SnCl (Scheme 5 and
reactivity in a potentially atropisomeric substrate, we next eval- Table 2). Unlike previous examples, the quench provided a pro-
uated the ability of (−)-sparteine [1,3] to control the enantio- duct only very slowly; 16 h at −78 °C was required to reach a
selectivity of these reactions. Premixing the sec-BuLi with ca. 60% yield of the stannane 13e (Table 2, entry 3). After this
Scheme 4: Diastereo- and enantioselective synthesis of atropisomeric ethers by benzylic lithiation.
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Beilstein J. Org. Chem. 2011, 7, 1327–1333.
Table 1: Yields and selectivities in the metallation/quench of 11.
entry
1 present?
E+ =
E =
product
yield
d.r.
e.r.
1
2
3
4
5
6
7
8
No
acetone
C(OH)Me2
C(OH)(CH2)2
SiMe3
13a
13b
13c
13d
13a
13b
13c
13d
75
56
70
69
86
26
72
66
95:5
–
No
cyclobutanone
Me3SiCl
Ac2O
85:15
95:5
–
No
–
No
COMe
85:15
>97:3
>97:3
95:5
–
Yes
Yes
Yes
Yes
acetone
C(OH)Me2
C(OH)(CH2)2
SiMe3
75:25
73:27
78:22
81:19
cyclobutanone
Me3SiCl
Ac2O
COMe
95:5
time the diastereoselectivity was good, but it was clear that this must be due to a slow change in the structure or diastereoiso-
was a result of a slow improvement in the product ratio as the meric composition of the lithiated intermediate as the reaction
reaction proceeded (Table 2, entries 1–3). Arresting the electro- progresses. The results with Bu3SnCl suggest that lithiation
philic quench after 90 min produced only a 9% yield of a 2:1 generates an approximately 20:1 mixture of configurationally
ratio of diastereoisomers of 13e, while intermediate reaction stable diastereoisomeric benzyllithiums of which the minor is
times gave ratios that slowly approached the ratio of 9:1 significantly more reactive than the major (see below). A form
observed after 16 h. The diastereoisomeric ratios of the prod- of kinetic resolution occurs in which the minor organolithium is
ucts remained unchanged even when the products were heated rapidly converted to product, followed slowly by the major
at 55 °C for 24 h, confirming that the anti and syn diastereoiso- organolithium [28]. Hoppe observed a related effect in the
mers of the stannanes are stable atropisomers.
alkylations of cinnamyllithiums [29].
Previous results from the laboratories of Hoppe indicated that
lithiated O-benzylcarbamates are typically configurationally
unstable in ether on the macroscopic timescale [1], although
Hoffmann detected microscopic configurational stability [30].
To demonstrate that the organolithium intermediates here do
have some configurational stability, we treated samples of 13e
of different diastereoisomeric and enantiomeric ratios with
n-BuLi in ether at −78 °C to induce tin–lithium exchange,
quenching the products with either acetone or Me3SiCl
(Scheme 6).
Scheme 5: Atroposelective stannylation.
Scheme 6: Stereospecific tin–lithium exchange/quench reactions.
Table 2: Variation of yield and selectivity with quench time.
entry
1 present?
t [h]
yield
d.r.
e.r.
The major product diastereoisomers were the same as those
formed by direct deprotonation quench (Scheme 2). Impor-
tantly, in Table 3, entries 1 and 3 show that the diastereoiso-
meric ratio of the product was at least partly dependent on the
d.r. of the starting stannane, necessarily indicating some degree
of macroscopic configurational stability. The ratios were not
identical, but yields were low, thus differential rates of the reac-
tion of the two diastereoisomeric organolithiums may again be
1
2
3
4
5
No
1.5
6
9
65:35
80:20
90:10
95:5
–
No
42
58
62
59
–
No
16
16
26
–
Yes
Yes
75:25
73:27
95:5
This proven conformational stability of the products 13e indi- to blame. Enantiomerically enriched stannane returned enan-
cates that the change in product ratio as the reaction proceeds tiomerically enriched product, showing that racemisation
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Beilstein J. Org. Chem. 2011, 7, 1327–1333.
(which necessarily involves either rotation about the Ar–O–Ar Fourthly, diastereoselectivity, unlike enantioselectivity, varies
axis or deprotonation–reprotonation) is also slow.
significantly according to the electrophile employed, showing
that the product d.r. is determined in the electrophilic quench
step. Precedent studies suggest that electrophilic quench of
benzylcarbamates is typically invertive [24]: All documented
stannylations of benzyllithiums are invertive [23], and all docu-
mented tin–lithium exchanges (except one, where there is no
adjacent heteroatom [31]) are retentive [23]. If these assump-
tions hold true here, then formation of the same diastereoiso-
mer of the product silane 13a or alcohol 13c, by either deproto-
nation or by stannylation tin–lithium exchange (Table 3, entries
1 and 2), therefore indicates that both of these electrophiles also
react with inversion. Lower d.r.'s may result from some elec-
trophiles by competitive reaction with up to 15% retention
Table 3: Stereospecificity in the tin–lithium exchange/quench reac-
tions.
entry 13e d.r. 13e e.r. E+ =
product, d.r. e.r.
1
2
3
4
90:10
90:10
80:20
>95:5
–
Me3SiCl 13c, 94:6
–
–
–
–
acetone 13a, >95:5
Me3SiCl 13c, 88:12
–
80:20
Me3SiCl 13c, >95:5 80:20
Discussion
Due to the gummy nature of the products, it turned out to be (Table 1), and the effect of (−)-sparteine on the d.r.'s in Table 1
impossible to establish unequivocally the relative or absolute may be because its steric bulk helps to suppress this competing
stereochemistry of the products obtained from the lithiations. retentive pathway.
However, we can make several important conclusions from this
work.
Lack of crystallinity has meant that we cannot unequivocally
assign absolute or relative stereochemistry in this work.
Firstly, racemisation of the intermediate organolithiums is However, a few reasonable assumptions allow us to propose
demonstrably slow, because an enantioenriched stannane yields, likely assignments, and these are the ones used in the structural
after tin–lithium exchange and quench, products with conserved diagrams in this paper:
e.r. (Table 3, entry 4). The e.r. of the products formed by depro-
tonation with an alkyllithium-(−)-sparteine complex must there- 1. (−)-Sparteine favours deprotonation of the pro-S proton of
fore be determined during the deprotonation step, in which the carbamates. Invertive quench would result in the formation of
alkyllithium-(−)-sparteine complex elects to deprotonate one of the products with stereogenic centres as illustrated in
the two enantiotopic CH2OCb groups of the starting material. Scheme 7(a).
Every e.r. produced during this study fell between 75:25 and
81:19, irrespective of the electrophile, so our conclusion is that
this selectivity represents the enantioselectivity of the alkyl-
lithium-(−)-sparteine deprotonation step.
Secondly, since epimerisation of the organolithiums is also slow
enough for different d.r.'s of a stananne to yield different d.r.'s
of a product (Table 3, entries 1 and 3), we can be certain that
the secondary benzyllithium centre is macroscopically stable on
the timescale of these reactions. This is in contrast with
previous reports of benzyllithiums derived from primary
benzylcarbamates [1], though not for secondary benzylcarba-
mates [24], so we assume that steric bulk or electron donation
from the ether group is responsible.
Thirdly, the change in ratio of the stannane products in Table 2
with time indicates that two diastereoisomeric organolithiums
are formed in unequal quantities. Our best estimate is that the
diastereoisomeric ratio of the organolithiums is of the order of
90:10 or 95:5, perhaps better in the presence of (−)-sparteine
since d.r.'s were uniformly higher when (−)-sparteine was
present (though this may also be due to an improvement in the
Scheme 7: Proposed stereochemical pathway.
stereospecificity of the quench).
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Beilstein J. Org. Chem. 2011, 7, 1327–1333.
12.Clayden, J.; Fletcher, S. P.; Senior, J.; Worrall, C. P.
2. The slower invertive reaction of the major organolithium dia-
stereoisomer with Bu3SnCl suggests that the product of this
reaction is more hindered (Scheme 7(c)), and we therefore
propose that the major diastereoisomers of the reactions are as
shown in Scheme 7(b).
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Conclusion
Overall, we have shown in this paper that the use of an alkyl-
lithium-(−)-sparteine deprotonation can desymmetrise a pro-
atropisomeric biscarbamoyloxy diarylether, with enantiomeric
ratios of up to 81:19. Some mechanistic details of the stereo-
chemical course of the lithiation–substitution reactions have
been elucidated, and further work remains to exploit this trans-
formation for the potential synthesis of new classes of chiral
ligands [12].
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Supporting Information
Supporting Information File 1
Experimental details and spectral data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-156-S1.pdf]
23.Clayden, J. Organolithiums: Selectivity for Synthesis. Tetrahedron
Organic Chemistry, Vol. 23; Baldwin, J.; Williams, R. M.; Bäckvall J.-E.,
Eds.; Pergamon: Oxford, U.K., 2002.
Acknowledgements
We are grateful to GSK and the EPSRC for a CASE award (to
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