Asymmetric synthesis of quaternary aryl amino acid derivatives via a three-component aryne coupling reaction

Article abstract of DOI:10.3762/bjoc.7.185

A method was developed for the synthesis of α-alkyl, α-aryl-bislactim ethers in good to excellent yields and high diastereoselectivities, consisting of a facile one-pot procedure in which the aryl group is introduced by means of a nucleophilic addition to

Full text of DOI:10.3762/bjoc.7.185

Asymmetric synthesis of quaternary aryl amino acid
derivatives via a three-component aryne
coupling reaction
Elizabeth P. Jones1, Peter Jones2, Andrew J. P. White1
and Anthony G. M. Barrett*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1570–1576.
1Department of Chemistry, Imperial College London, London, SW7
2AZ, England and 2Worldwide Medicinal Chemistry, Pfizer Limited,
Ramsgate Road, Sandwich, Kent, CT13 9NJ, England
doi:10.3762/bjoc.7.185
Received: 05 August 2011
Accepted: 07 November 2011
Published: 25 November 2011
Email:
Anthony G. M. Barrett* - agm.barrett@imperial.ac.uk
This article is part of the Thematic Series "Directed aromatic
functionalization".
* Corresponding author
Keywords:
Guest Editor: V. Snieckus
aryl amino acids; arynes; asymmetric; multicomponent; quaternary
© 2011 Jones et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A method was developed for the synthesis of α-alkyl, α-aryl-bislactim ethers in good to excellent yields and high diastereoselectiv-
ities, consisting of a facile one-pot procedure in which the aryl group is introduced by means of a nucleophilic addition to benzyne
and the alkyl group by alkylation of a resultant benzylic anion. Hydrolysis of the sterically less hindered adducts gave the corres-
ponding quaternary amino acids with no racemization, whereas hydrolytic ring opening gave the corresponding valine dipeptides
from bulkier bislactims.
Introduction
Arynes are exceptionally versatile reactive intermediates in following nucleophilic attack is allowed to react with a further
organic synthesis. Not only are they able to participate in cyclo- electrophile, providing ortho-disubstituted, functionalized
addition reactions, they also readily undergo addition reactions aromatic products in a one-pot procedure [7-9]. In particular,
with nucleophiles, and the resultant aryl anions may be proto- we have focused on the addition of carbon-based nucleophiles
nated or undergo alternative transformations [1-6]. We are in such systems (Scheme 1) and have applied this methodology
particularly interested in the use of arynes in multicomponent to the syntheses of natural products ent-clavilactone B and
coupling reactions, in which the resultant aryl carbanion dehydroaltenuene B [10,11].
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Scheme 1: 3-Component coupling reactions of arynes. E+ = elec-
trophile.
Recently, we reported the diastereoselective addition of
Schöllkopf’s bislactim ether 1 [12] to substituted arynes 2,
which, following hydrolysis of the syn-adducts 3, provided
α-aryl amino acids 4 with moderate to high enantioselectivities
(Scheme 2) [13].
The arynes were produced by a directed ortho-metallation [14]
and an elimination sequence, and after attack of 1 the ensuing
carbanion 5 was not aryl as expected but instead benzylic, due
to an inter- or intramolecular proton transfer. Kinetic protona-
tion of this anion on the face opposite to the isopropyl group
accounted for the observed diastereoselectivity of the reaction
(Scheme 3).
Scheme 3: Proposed mechanism of α-arylation.
To extend this methodology to a multicomponent system, we
considered that quenching the key aza-enolate intermediate with
an electrophile, rather than a proton source, should provide
quaternary Schöllkopf adducts 6 (Scheme 4).
The potential utility of chiral α-quaternary α-aryl amino acids in
medicinal chemistry is diverse. Incorporation of such units into
peptidomimetics, not only affects lipophilicity, but also the sec-
ondary structure and hence the conformational rigidity, which
can increase the resistance to enzymatic degradation [15-19].
Such units are also found in biologically interesting natural
products, such as the antibacterial fumimycin [20].
Herein, we describe our endeavours towards the synthesis of
such valuable compounds by utilizing the multicomponent
aryne reaction.
Scheme 4: Proposed extension of the methodology to synthesize
quaternary adducts.
Scheme 2: Aryne mediated α-arylation of amino acids. DMG = directed metallation group. BHT = 2,6-di-tert-butyl-4-methylphenol.
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Results and Discussion
Formation of quaternary Schöllkopf adducts
Alkylations employing benzyl bromide, allyl bromide and
propargyl bromide (Table 1, entries 2, 3 and 5) proceeded
The same procedure was carried out as for the α-arylation reac- smoothly, furnishing the desired products 6b, 6c and 6e in
tions: The benzyne precursor 2a and Schöllkopf’s bislactim excellent yields and high diastereoselectivity. Interestingly,
ether 1 were allowed to react with 2.5 equivalents of sec-butyl- adduct 6b displays a large upfield shift (around 2 ppm) at the
lithium at –95 °C to carry out the required ortho-lithiation for C-3 proton compared to other analogues. This indicates that the
benzyne formation from 2a and the deprotonation of bislactim product has adopted an “aryl-inside” conformation in which the
1. During warming to room temperature, fragmentation to C-3 proton is situated in the shielding cone of the aromatic ring
dimethoxybenzyne occurred and nucleophilic attack of the [21]. A single-crystal X-ray crystallographic analysis confirmed
Schöllkopf auxiliary took place. Addition of four equivalents of the presence of this conformation, at least in the crystal lattice
iodomethane at this temperature and stirring for 1 h gave the (Figure 2).
desired quaternary species 6a in 88% yield with a dr of 85:15.
Lowering the quench temperature to –78 °C increased both the
yield and the dr to 92% and 96:4, respectively (Scheme 5).
Scheme 5: Formation of α-methyl, α-aryl Schöllkopf adduct.
Figure 2: X-ray crystal structure of 6b.
The major diastereoisomer was confirmed to have the iso- Further alkylations with methyl chloromethyl ether, tert-butyl
propyl and aryl moieties syn, by 1H NMR NOESY analysis; a bromoacetate and 2-(bromomethyl)-6-methylpyridine (Table 1,
clear NOESY correlation was observed between the methyl entries 4, 6 and 8) provided adducts 6d, 6f and 6h respectively,
group and the proton at C-3 (Figure 1).
also with high diastereoselectivity, but in more modest yields.
Acylation with acetyl chloride (Table 1, entry 7) afforded
ketone 6g in 59% yield, with a lower dr of 89:11, most likely
due to the less sterically hindered nature of this electrophile.
Replacing acetyl chloride with its corresponding Weinreb
amide gave none of the required product. An aldol type reac-
tion with benzaldehyde (Table 1, entry 9) afforded alcohol 6i in
good yield, with complete diastereoselectivity at C-6, but no
selectivity at the alcohol stereocenter (1:1). Examination of the
two possible Zimmerman–Traxler type transition states for such
reactions (Figure 3), as proposed by Schöllkopf [22], reveals
that TS≠ A, with the phenyl group axial, is consistent with there
being an unfavourable 1,3-diaxial interaction with the methoxy
group. However, there is an equally unfavourable interaction in
Figure 1: NOESY correlation observed for 6a.
The scope of the reaction was then examined to determine TS≠ B where the phenyl group occupies the equatorial position,
which electrophiles could be introduced at C-6 (Table 1).
as there is now a 1,2-gauche interaction with the bulky
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Table 1: Formation of quaternary Schöllkopf adducts employing a range of electrophiles.
Entrya
Electrophile
R
Time (h)b
Product
Yield (%)c
drd
1
2
MeI
Me
Bn
1
6
6a
6b
92
88
96:4
BnBr
>98:2
3
4
5
1
1
1
6c
6d
6e
85
53
80
>98:2
95:5
MOMCl
>98:2
6
7
3
6
6f
51
59
>98:2
89:11
AcCl
COMe
6g
8
5
6h
71
>98:2
9
PhCHO
12
1
6ie
69
50
>98:2f
>98:2
10
6j
BF3·OEt2
aReactions were carried out on a 1 mmol scale in THF (0.2 M) with 1.5 equiv of halide 2a and 2.75 equiv s-BuLi at –95 °C, followed by warming to
room temperature over 18 h, recooling to –78 °C, and the addition of 4 equiv of electrophile. bReactions were monitored by GC–MS. cIsolated yield.
dDetermined by 1H NMR integration. e6i was isolated as its benzoyl ester, due to retro-aldol reactions occurring when the free alcohol was subjected
to flash-column chromatography. fThe adduct 6i was obtained as a mixture of epimeric benzylic alcohols (1:1).
Figure 3: Transition state analysis to explain the lack of diastereoselectivity at C-2.
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Beilstein J. Org. Chem. 2011, 7, 1570–1576.
di-methoxyaryl group adjacent to it. We consider that neither of
these transition states is lower in energy, which would be
consistent with the lack of diastereoselectivity.
Finally, the addition of (R)-propylene oxide as the electrophile
in the presence of boron trifluoride etherate (Table 1, entry 10)
gave alcohol 6j. When (S)-propylene oxide was used instead
there was no reaction, and indeed Schöllkopf noted significant
levels of kinetic resolution when such reactions were performed
with racemic oxiranes [23].
In our previous publication, we demonstrated the scope of the
methodology over a range of ortho-lithiation benzyne precur-
sors. To establish that any one of these precursors could be used
to form quaternary adducts, we subjected the benzylation condi-
tions to precursor 2b and the allylation conditions to precursor
2c, affording adducts 7b and 7c, respectively, again in good
yields and dr’s and with complete regioselectivity for these
asymmetric benzynes (Scheme 6).
Scheme 6: Formation of quaternary adducts.
Hydrolysis of quaternary adducts
methyl esters as their corresponding dipeptides, 8a, 8d and 8e,
The next task to be undertaken was the hydrolysis of the steri- in good yields (Scheme 7). The less shielded imidate group
cally restricted quaternary bislactim ethers. A selection of the underwent complete hydrolysis, but the imidate functional
relatively less bulky products, 6a, 6d and 6e, was subjected to group α to the quaternary center experienced incomplete
standard, mild hydrolysis conditions, employing 0.5 M HCl in cleavage to the peptide bond, a trend which is common in the
THF at room temperature [12], affording the desired quaternary literature for quaternary adducts [21,24-26]. Subjecting
Scheme 7: Hydrolysis of quaternary adducts.
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analogue 7c, with just one methoxy group on the aromatic ring,
to the same conditions yielded the dipeptide 9 and the desired
methyl ester 10 in a 1:1 ratio (Scheme 7).
Screening of various acidic hydrolysis reaction conditions in
these systems led to the observation that when either 6a or 7c
was stirred in neat 6 M sulfuric acid for three days, the required
constituent amino acid 11 or 10 was isolated in reasonable
yields (Scheme 8). Chiral HPLC analysis confirmed the
expected high enantioselectivity of these esters.
Scheme 9: Hydrolysis of analogue 6j.
Scheme 8: Hydrolysis to amino acids.
Scheme 10: Epimerization at C-3 of 6g.
These results are promising, as they demonstrate that if the aryl
group is derived from a less sterically hindered benzyne Conclusion
precursor, hydrolysis is more facile, as was observed by Lee The extension of the aryne α-arylation methodology allowed for
[27] for unsubstituted aryl, quaternary bislactim ethers. Using the synthesis of quaternary aryl bislactim ethers in good to
high concentrations of acids with more-nucleophilic conjugate excellent yields and high diastereoselectivity by means of a
bases resulted in the predominate formation of diketopiper- three-component coupling reaction in which the reaction of an
azines, and low concentrations of all of the acids tested gave the electrophile with the intermediate benzylic anion gave a range
dipeptide as the major product for all analogues with two of C–alkyl and hydroxyalkyl derivatives. Hydrolysis of these
methoxy groups (6a–6i).
quaternary adducts gave the constituent amino acid methyl
esters in high enantioselectivity for less substituted compounds.
The only example where the use of low concentrations of acid Adducts with two methyl ethers on the aryl unit underwent
coupled with a dimethoxy aryl group resulted in the principal hydrolysis to the corresponding valine dipeptides.
formation of the desired ester was in the case of alcohol 6j.
Mild acidic hydrolysis with 0.5 M HCl gave lactone 12 in 80%
Supporting Information
yield and 96% ee (Scheme 9). The ability of the alcohol to
undergo lactonization under the reaction conditions clearly
Supporting Information File 1
aided the hydrolysis of this more sterically hindered imidate.
Detailed experimental procedures and analytical data for
compounds 6a–j, 7b–c, 8a, 8d, 8e and 9–13.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-185-S1.pdf]
We assumed that ketone 6g would also undergo hydrolysis due
to its nonbulky nature. However, upon exposure to 0.5 M HCl,
epimerization of the isopropyl group at C-3 occurs in near quan-
titative yield, giving adduct 13 (Scheme 10). The electron-with-
drawing effect of the carbonyl moiety must increase the acidity
of the C-3 proton to such an extent that the acidic media simply
epimerizes at this center to afford the more thermodynamically
stable anti-adduct.
Supporting Information File 2
NMR spectral data for compounds 6a–j and 7b–c.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-185-S2.pdf]
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Beilstein J. Org. Chem. 2011, 7, 1570–1576.
23.Gull, R.; Schöllkopf, U. Synthesis 1985, 1052–1055.
Acknowledgements
doi:10.1055/s-1985-31425
We thank Glaxo for providing the generous Glaxo Endowment
(to A. G. M. B.), the EPSRC and Pfizer for providing funding
through the collaborative EPSRC-Pharma Synthesis Programme
(to E. P. J.) and P. R. Haycock and R. N. Sheppard (Imperial
College London) for H NMR spectroscopy.
24.Krikstolaityte, S.; Sackus, A.; Romming, C.; Undheim, K. Chemija
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