Synthesis of enantioenriched α-chiral bicyclo[1.1.1]pentanes

Article abstract of DOI:10.1021/acs.orglett.9b00691

Bicyclo[1.1.1]pentanes (BCPs), useful surrogates for para-substituted arenes, alkynes, and tert-butyl groups in medicinal chemistry, are challenging to prepare when featuring stereogenic centers adjacent to the BCP. We report the development of an efficie

Full text of DOI:10.1021/acs.orglett.9b00691

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Enantioenriched α‑Chiral Bicyclo[1.1.1]pentanes
Marie L. J. Wong,† James J. Mousseau,‡ Steven J. Mansfield,† and Edward A. Anderson*,†
†Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, U.K.
‡Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: Bicyclo[1.1.1]pentanes (BCPs), useful surrogates for para-
substituted arenes, alkynes, and tert-butyl groups in medicinal chemistry, are
challenging to prepare when featuring stereogenic centers adjacent to the
BCP. We report the development of an efficient route to α-chiral BCPs, via
highly diastereoselective asymmetric enolate functionalization. We also
describe the application of this chemistry to the synthesis of BCP analogues
of phenylglycine and tarenflurbil, the single enantiomer of the NSAID
flurbiprofen.
icyclo[1.1.1]pentanes (BCPs)1 are widely recognized as
useful surrogates for 1,4-disubstituted benzene rings,2
α-BCP oxazolidinones (4). Here we describe the realization of
this route, which allows installation of a wide range of
substituents adjacent to the BCP, together with high-yielding
removal and recovery of the auxiliary, and application of the
methodology to the synthesis of BCP analogues of phenyl-
glycine and the NSAID tarenflurbil.
B
alkynes,3 and tert-butyl groups4 in drug design.5 While a number
of methods are available for the preparation of BCP-containing
molecules,6 the synthesis of BCPs featuring adjacent stereogenic
centers (α-chiral BCPs) remains a significant challenge. The few
known examples focus on the synthesis of phenylglycine BCP
analogues;7 however, a general and practical approach to
enantioenriched α-chiral BCPs remains elusive.
Our studies began with a survey of reactivity of various BCP
oxazolidinones (4a−f, Table 1). These could be accessed via
We recently disclosed an efficient route to highly function-
alized disubstituted BCP derivatives via atom transfer radical
addition (ATRA) reactions.8 Using triethylborane as an
initiator, radicals derived from readily available alkyl halides
effect ring opening of tricyclo[1.1.1.01,3]pentane (1, Scheme
1a), affording 1-halo-3-substituted BCPs 2. This process is
particularly effective and rapid for electron-deficient radicals
derived from α-halo carbonyls; we recognized that this could
enable a general, stereoselective strategy to access α-chiral BCPs
(3, Scheme 1b) via reactions of enantioenriched ATRA-derived
a
Table 1. Reaction Optimization
b
c
entry
substrate
R1
R2
product, yield (%)
dr
a b
,
Scheme 1. Strategy for Enantioenriched BCP Synthesis
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
H
H
H
Me
Ph
Me
i-Pr
Ph
Bn
Ph
Bn
Bn
9a, 36
9b, 29
9c, 85
9d, 50
9e, 22
9f, 84
>20:1
3:1
14:1
>20:1
>20:1
>20:1
a
Alkylation conditions: NaHMDS (1.1 equiv), THF, −78 °C, 30 min;
MeI (3.0 equiv), −78 °C, 1−6 h. Reactions performed on a 0.15 mol
b
c
scale. Isolated yield. dr determined by 1H NMR spectroscopic
analysis of the crude reaction mixture; ratio of S:R isomers assigned
by analogy to products 9j, 9l, and 9s, the structures of which were
determined by X-ray crystallography (see below).
a
Previous work involving the triethylborane-initiated ATRA approach
b
to 1-halo-3-substituted BCPs. The approach to α-chiral BCPs
Received: February 23, 2019
described in this work.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00691
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ATRA reaction of the α-iodooxazolidinones 6a−f (Path a),
followed by deiodination using (Me3Si)3SiH (TTMSS). 4f was
also prepared by acylation of oxazolidinone 7 with acid chloride
8 (Path b); this latter route was readily performed on a
multigram scale (1.8 g of 4f obtained from 1.33 g of 8, 63%). We
quickly found that the reaction conditions and substitution
pattern of the auxiliary proved crucial to reaction efficiency:
sodium enolates9 of commonly used oxazolidinones 4a−c (R1 =
H, entries 1−3) gave modest yields (with the exception of 4c,
featuring a benzyl substituent) or dr’s (with the exception of iso-
propyl-substituted 4a) in alkylations with iodomethane. “Super-
Quat” auxiliaries (R1 = Me/Ph, entries 4−6) were next
examined, which can not only deliver enhanced stereocontrol
but also improve auxiliary cleavage/recycling efficiency.10 To
our delight, this fine-tuning of the oxazolidinone scaffold led to
the formation of adducts 9d−f as single diastereomers, with the
benzyl-substituted oxazolidinone 4f giving 9f in high yield and
with exceptional stereoselectivity.
Having identified optimal enolate functionalization condi-
tions, the scope of the process was explored using substrate 4f
(Figure 1). A wide range of electrophiles were successfully
installed, with the products isolated in high yields and as single
diastereomers in nearly all cases. Alkyl halides bearing saturated
and unsaturated aliphatic chains (9g−l) and heterocycles (9m,
n) were all well-tolerated; in most cases, alkylation occurred
smoothly at −78 °C, with warming to 0 °C necessary for less
reactive electrophiles (9g, 9h). 4f also underwent aldol
chemistry: for example, reaction of the dibutylboron enolate
derived from 4f with benzaldehyde afforded adduct 9o in
excellent yield and selectivity at the α-stereocenter (98%, 1:1.5
dr at the hydroxyl-bearing stereocenter). Alternatively, use of
1,3,5-trioxane as a formaldehyde equivalent, with TiCl4 and
Hunig’s base, enabled hydroxymethylation to form 9p.
̈
Consistent yields were observed on scale-up to 1.33 mmol
scale for this product (54%) and also methylated product 9f
(80%).
Figure 1. Synthesis of α-chiral BCPs. Reaction conditions unless stated
otherwise: 4 (0.15 mmol, 1.0 equiv), NaHMDS (1.1 equiv), THF, −78
°C, 30 min; electrophile E+ (3.0 equiv). Reaction times varied with the
The direct introduction of heteroatoms also proved possible:
4f could be fluorinated with high diastereoselectivity using NFSI
as the electrophile (9q, 85%, 13:1 dr), which is of interest given
the importance of fluorinated motifs in drug development.11
The analogous bromination (9r) proceeded with low selectivity
using N-bromosuccinimide, but surprisingly the same product
was isolated with high diastereoselectivity (78%, 13:1 dr) on
reaction with 2-(bromomethyl)-5-nitrofuran, instead of the
expected heterocycle installation. α-Hydroxylation and hydra-
zinylation were achieved using the Davis oxaziridine and di-tert-
butyl azodicarboxylate as respective electrophiles, with 9s and 9t
formed as single diastereomers and in excellent yields (80 and
98%). Finally, 1,3-disubstituted BCP compounds could be
accessed by construction of the corresponding disubstituted
BCP oxazolidinone prior to diastereoselective alkylation (9u,
91%).3 The structures of 9j, 9l, and 9s were determined by X-ray
crystallographic analysis,12 and the stereochemistry of all other
products was assigned by analogy. The BCP was observed to
position itself on the opposite face to the oxazolidinone benzyl
group in all three structures, demonstrating its potential utility as
a conformational control element, as well as a useful motif in
drug design.
a
electrophile; see the Supporting Information for details. Reaction
conducted on a 1.33 mmol scale (0.42 g). b−78 °C → 0 °C (12 h). c4f,
n-Bu2BOTf (1.1 equiv), i-Pr2EtN (1.2 equiv), CH2Cl2, 0 °C, 30 min;
PhCHO (1.1 equiv), −78 °C, 3.5 h. dTiCl4 (1.0 equiv), CH2Cl2, 0 °C,
10 min; i-Pr2EtN (1.1 equiv), 40 min; 1,3,5-trioxane (1.2 equiv), TiCl4
(1.0 equiv), 3 h. eE+ = NFSI (1.3 equiv), 3 h. fE+ = 2-(bromomethyl)-5-
g
h
nitrofuran, 2 h. E+ = NBS, 4 h. NaHMDS (1.2 equiv); 3-phenyl-2-
(phenylsulfonyl)-1,2-oxaziridine (1.5 equiv), 20 min. iE+ = di-tert-butyl
azodicarboxylate (1.3 equiv), 5 min.
Scheme 2. Removal of the SuperQuat Auxiliary to Access
Enantioenriched BCP Building Blocks
Crucially, the SuperQuat oxazolidinone was readily cleaved to
access functional groups that enable further manipulation of the
chiral BCP products (Scheme 2). These transformations
included hydrolysis (10), reduction (11), and transesterification
(12, 13); all products were obtained in high yields and excellent
enantiopurity, with the oxazolidinone being recovered in good
yield.
B
DOI: 10.1021/acs.orglett.9b00691
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The diastereoselective enolate functionalization chemistry
provides opportunities for the synthesis of α-chiral BCP
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: edward.anderson@chem.ox.ac.uk.
ORCID
Scheme 3. Synthetic Applications
Edward A. Anderson: 0000-0002-4149-0494
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
MLJW and SJM thank the EPSRC Centre for Doctoral Training
in Synthesis for Biology and Medicine (EP/L015838/1) for
studentships, generously supported by AstraZeneca, Diamond
Light Source, Defence Science and Technology Laboratory,
Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta,
Takeda, UCB, and Vertex. EAA thanks the EPSRC (EP/
M019195/1 and EP/S013172/1) for support.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00691.
Experimental procedures and copies of 1H and 13C NMR
spectra (PDF)
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Accession Codes
CCDC 1888813−1888815 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
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DOI: 10.1021/acs.orglett.9b00691
Org. Lett. XXXX, XXX, XXX−XXX