Enantioselective synthesis of (: R)-2-cubylglycine including unprecedented rhodium mediated C-H insertion of cubane

Article abstract of DOI:10.1039/c8ob02959h

The first enantioselective synthesis of (R)-2-cubylglycine, an analogue of (R)-2-phenylglycine in which the phenyl ring has been replaced by cubane, is disclosed. The key step was a telescoped Strecker reaction using (S)-2-amino-2-phenylethanol as a chiral auxiliary. Exploration of an alternative synthetic approach resulted in unprecedented cubane C-H insertion.

Full text of DOI:10.1039/c8ob02959h

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Enantioselective synthesis of (R)-2-cubylglycine
including unprecedented rhodium mediated
C–H insertion of cubane†
Cite this: DOI: 10.1039/c8ob02959h
Received 27th November 2018,
Accepted 22nd December 2018
Sevan D. Houston, a Benjamin A. Chalmers, a G. Paul Savage b and
a
DOI: 10.1039/c8ob02959h
Craig M. Williams
*
rsc.li/obc
The first enantioselective synthesis of (R)-2-cubylglycine, an ana- (4) in 15% overall yield and in 47% ee, using asymmetric
logue of (R)-2-phenylglycine in which the phenyl ring has been Strecker methodology.18 Curry followed with racemic syntheses
replaced by cubane, is disclosed. The key step was a telescoped of two α-substituted 2-(4-carboxycubyl)glycine analogues.19
Strecker reaction using (S)-2-amino-2-phenylethanol as a chiral Duggan et al. were later successful in obtaining a t-butylsulfi-
auxiliary. Exploration of an alternative synthetic approach resulted namide masked 2-cubylglycine analogue (5) in 55% overall
in unprecedented cubane C–H insertion.
yield starting from 1,4-cubanedicarboxylic acid.20 Conditions
to remove the t-butylsulfinamide group were unfortunately not
found. Recently, a similar sulfinamide was rapidly accessed by
Baran et al. with excellent stereochemical control using a
radical cross-coupling strategy.21 A valuable contribution
was made by Wlochal et al., who were the first to synthesise
2-cubylglycine (3) as the racemate in 20% overall yield.22
Individual enantiomers were separated by derivatisation fol-
lowed by enantioselective (chiral) HPLC (Fig. 2).
The use of caged hydrocarbons as pharmaceutical scaffolds
has been well established.1 Their tactical application allows for
the modulation of key pharmacokinetic properties2 [e.g. lipo-
philicity (log P)3 and metabolism4], a design concept which
has been widely adopted in contemporary drug discovery.5 The
rigidity of certain scaffolds [e.g. adamantane,6 bicyclo[1.1.1]
pentane,7 and cubane8] allows for the precise arrangement of
pharmacophoric points in three-dimensional space. Not only
does this help facilitate an “escape from flatland”,9 it has also
created new opportunities for scaffold hopping in drug
design.10
These properties find particular utility in the synthesis of
non-proteinogenic amino acids (AAs),11 where the incorpor-
ation of rigid12 and cyclic13 scaffolds to individual AAs can
confer conformational restraints to polypeptide structure,
which in turn can increase molecular recognition at the bio-
logical target.14 A notable example is saxagliptin (1) (Fig. 1), a
pharmaceutical containing an adamantylglycine residue, used
clinically for the treatment of type 2 diabetes.15
Reported herein is the first enantioselective synthesis of (R)-
2-cubylglycine [(R)-3], which included attempts to develop the
synthesis via C–H insertion of the cubane core.
Encouraged by the elegant work of Davies et al.23 describing
metal carbenoid C–H insertion of hydrocarbons, we explored
scaffold derivatisation of cubane (7) as a potential means of
accessing each enantiomer of 3. A general trend in carbenoid
C–H insertion is the preferential reactivity of tertiary C–H
bonds over secondary and primary, due to the enhanced
nucleophilicity and ability to stabilise an accumulation of posi-
tive charge in the transition state.24 Given the wealth of evi-
dence amassed to support the existence of the cubyl cation,25
cubane presented itself as a promising candidate to meet the
electronic requirements of carbenoid C–H insertion. From a
steric perspective, although cubane is a highly encumbered
Given our recent work demonstrating the ability of cubane
to act as a phenyl ring (bio)isostere,16 and the prevalence of
phenylglycine-type amino acids (e.g. 2, Fig. 1) in natural pro-
ducts and pharmaceutical discovery,17 we embarked on devis-
ing a robust and readily accessible route to 2-cubylglycine (3)
(Fig. 2). The first reported example of a cubane AA was by
Pellicciari et al., who synthesised (S)-2-(4-carboxycubyl)glycine
aSchool of Chemistry and Molecular Biosciences, University of Queensland, Brisbane,
4072 Queensland, Australia. E-mail: c.williams3@uq.edu.au
bCSIRO Manufacturing, Ian Wark Laboratory, Melbourne, 3168 Victoria, Australia
†Electronic supplementary information (ESI) available: Experimental procedures
and copies of NMR spectra. See DOI: 10.1039/c8ob02959h
Fig. 1 Saxagliptin (1) and the non-proteinogenic amino acid 2-phenyl-
glycine (2).
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Unfortunately, the remainder of the synthesis towards 3
relied heavily on an oxidative arene degradation strategy,28 but
disappointingly 8 was unreactive to all conditions screened,
and thus the AA precursor 13 could not be realised (Scheme 1).
This outcome prompted a return to classical AA synthetic
routes, and an asymmetric Strecker methodology based on the
work of Pellicciari seemed the most plausible.
Commercially available dimethyl 1,4-cubanedicarboxylate
(14)29 underwent half-hydrolysis,30 followed by a modified
Barton decarboxylation procedure using 2-mercaptopyridine
N-oxide sodium salt (15) and chloroform as a source of radical
hydrogen.31 Further saponification and borane reduction gave
16 in 71% yield over 5 steps. Ley–Griffith oxidation32 resulted
in cubane carboxaldehyde 17, a volatile and unstable inter-
mediate best handled in situ.8b In the key step of the synthesis,
a telescoped asymmetric Strecker reaction using TMSCN and
(S)-2-phenylglycinol (18) as a chiral auxiliary33 gave adducts 19
and 20 in a 4 : 1 ratio. The diastereomers were readily separ-
able by flash column chromatography and the major diastereo-
mer 20 was isolated in 52% yield (Scheme 2).
A pure sample of 20 underwent smooth lead tetraacetate
oxidative cleavage34 to furnish 21 in good yield. The Schiff
base 21 proved unstable and was used without delay: nitrile
hydrolysis followed by passage through an ion exchange resin
(IER) gave (R)-2-cubylglycine [(R)-3] in an overall yield of 32%.
The absolute configuration of (R)-3 (including the Strecker
adducts 19 and 20) was assigned by comparison to the work of
Pellicciari et al.,18 who used (R)-2-phenylglycinol (i.e. opposite
enantiomer of the same chiral auxiliary) and obtained (S)-2-(4-
Fig. 2 A Prior examples of cubane amino acids or derivatives thereof
(i.e. 3, 4 and 5). B: (R)-2-Cubylglycine [(R)-3].
substrate, the reported C–H insertion of isobutane with methyl
phenyldiazoacetate proceeded in 20% yield and 75% ee.23a
Gratifyingly, Rh2(S-DOSP)4 catalysed C–H insertion using
methyl phenyldiazoacetate in 2,2-dimethylbutane (2,2-DMB),
giving the corresponding adduct 8 in 27% yield and 28% ee
(Scheme 1). Notably, this was a rare example of manipulating
the cubane framework mediated by a transition metal.8b–d The
catalyst, [Rh(nbd)Cl]2, for example, is known to cause valence
isomerisation of cubane to cyclooctatetraene,26 and palladium
catalysed hydrogenation causes extensive rearrangement.27
Therefore, curious to further investigate this observation,
several variations were explored, however the scope of the reac-
tion appears limited. For example, cubane (7) reacted success-
fully with dimethyl 2-diazomalonate to give 9. In an intra-
molecular variant, diazo 10 underwent cyclisation to give
fused-cubane 11, and α-hydroxyketone 12 as a major side-
product; presumably as a result of advantageous moisture
(Scheme 1).
Scheme 2 Synthesis of (R)-2-cubylglycine [(R)-3] and the corres-
ponding Boc-protected amino ester 22.
Scheme 1 Examples of cubane C–H insertion.
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carboxycubyl)glycine (4). In order to measure the enantiomeric
excess of (R)-3, both amine and carboxylic acid functionalities
were protected, the former as the t-butyl carbamate and the
latter as the methyl ester. The resulting Boc-protected methyl
ester 22 was subjected to analytical chiral HPLC where
only one peak was observed, indicating an ee of >99.5% for
(R)-3. The optical rotation of 22 was measured as −79.7°
at 25 °C.
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Conclusions
Caged hydrocarbons boast a plethora of pharmacokinetic pro-
perties that are particularly desirable in the design of non-pro-
teinogenic AAs. The first enantioselective synthesis of (R)-2-
cubylglycine [(R)-3] has been achieved in 10 steps with an
overall yield of 32%, and in greater than 99.5% ee. Facile
access to this system will open further avenues to incorporat-
ing cubane into bioactive molecule discovery. Lastly, the first
reported examples of cubane C–H insertion are described.
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G. P. S. and C. M. W. have formal and informal commercial
relationships with companies developing and supplying
cubane intermediates.
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Acknowledgements
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