Asymmetric synthesis of α-allyl-α-aryl α-amino acids by tandem alkylation/π-allylation of α-iminoesters

Article abstract of DOI:10.1021/ol500506t

The first asymmetric synthesis of α-allyl-α-aryl α-amino acids by means of a three-component coupling of α-iminoesters, Grignard reagents, and cinnamyl acetate is reported. Notably, the enolate from the tandem process provides a much higher level of reactivity and selectivity than the same enolate generated via direct deprotonation, presumably due to differences in the solvation/aggregation state. A novel method for removal of a homoallylic amine protecting group delivers the free amine congeners. The α-allyl group offers a means to generate further valuable α-amino acid structures as exemplified by ring closing metathesis to generate a higher ring homologue of α-aryl-proline.

Full text of DOI:10.1021/ol500506t

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of α‑Allyl-α-Aryl α‑Amino Acids by Tandem
Alkylation/π-Allylation of α‑Iminoesters
John M. Curto, Joshua S. Dickstein, Simon Berritt, and Marisa C. Kozlowski*
Department of Chemistry, Penn Merck High Throughput Experimentation Laboratory, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: The first asymmetric synthesis of α-allyl-α-aryl α-amino acids by means of a three-component coupling of α-
iminoesters, Grignard reagents, and cinnamyl acetate is reported. Notably, the enolate from the tandem process provides a much
higher level of reactivity and selectivity than the same enolate generated via direct deprotonation, presumably due to differences
in the solvation/aggregation state. A novel method for removal of a homoallylic amine protecting group delivers the free amine
congeners. The α-allyl group offers a means to generate further valuable α-amino acid structures as exemplified by ring closing
metathesis to generate a higher ring homologue of α-aryl-proline.
Scheme 1. General Approaches to α,α-Disubstituted α‑Amino
Acids
nantiomerically pure α-amino acids and their derivatives are
Evital synthetic building blocks in organic synthesis and play
an integral role in biological research. The α,α-disubstituted α-
amino acid structural motif is found in natural products1 and has
been utilized by the pharmaceutical industry in numerous
antibiotics.2 Peptides with one or more α,α-disubstituted α-
amino acid counterparts confer increased stability under
physiological conditions and stabilize secondary structure
motifs.3 The formation of α,α-disubstituted α-amino acids is
difficult and becomes increasingly difficult once structural
complexity supersedes analogs of α-Me, α-Et, and α-Bn.4
To date, synthetic access to enantioenriched α-allyl-α-aryl α-
amino acids has remained elusive.5 In nucleophilic functionaliza-
tion, both the Strecker reaction6 and addition to α-iminoesters7
fail. The Strecker reaction succeeds with an α-methyl group when
α-aryl groups are employed (Scheme 1, eq 1), but combinations
such as α-allyl-α-aryl are difficult due to the relatively unreactive
nature of ketoimines8 and difficulty in facial distinction when the
two substituents are similar in size.
Electrophilic functionalization has been tremendously suc-
cessful for generating chiral α-substituted α-amino acids,9 but the
enolates required to generate the α,α-disubstituted α-amino acid
counterparts are very hindered (Scheme 1, eq 2). As a result,
variable yields are obtained when R1 ≠ H,5a,b,d and mixed results
have been obtained when R1 = Ar.5b,d Use of cyclic surrogates has
improved the outcome of electrophilic functionalization via
asymmetric allylic alkylation, but phenylglycine analogs proved
sterically hindered and unsuccessful to date (Scheme 1, eq 3).10
To the best of our knowledge, use of achiral acyclic enolates to
generate a range of chiral α-allyl-α-aryl α-amino acids has not
been successful.
Herein, we report the N-alkylation/asymmetric π-allylation of
α-iminoesters (Scheme 2). The tandem process generates an
enolate form possessing increased reactivity, which differs from
the corresponding enolate generated via direct deprotonation.
The in situ generated enolate allows the construction of a diverse
Received: February 17, 2014
Published: March 25, 2014
© 2014 American Chemical Society
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Letter
Scheme 2. Tandem N-Alkylation/π-Allylation of
α‑Iminoesters
group of enantioenriched α-allyl-α-aryl α-amino acids that have
not been accessed to date (Scheme 1, eq 4).
Kagan and Fiaud first reported umpolung N-addition of
unstabilized anions to α-iminoesters in 1970.11 Shimizu has
expanded upon this work with doubly activated iminomalonates
and organoaluminums.12 Recently, we have reported the first
tandem reaction to utilize umpolung addition of alkyl Grignard
into α-iminoesters to generate racemic α,α-disubstituted α-
amino acids.13 In spite of these advances, this umpolung addition
has never been combined with an asymmetric process to take
advantage of the reactive nucleophile 2 that is produced (Scheme
2).
Figure 1. Ligands in Table 1.
Table 2. Variation of the α-Iminoester in the Tandem
N‑Alkylation/π-Allylation
Parallel microscale experimentation (PME), a valuable tool for
rapidly screening conditions and drawing out trends,14 was used
to optimize the tandem N-alkylation/π-allylation of 1a.15 Table 1
Table 1. Results from PME and Scale Up Reactions with
Diverse Ligands
b
bench scale
a
c
d
c
entry
ligand (Figure 1)
PME ee (%)
conv (%)
ee (%)
1
BINAP, L1
40
>90
>90
>90
<10
15
80
e
2
BINAP, L1
66
3
H8-BINAP, L2
DACH Trost, L3
Pfaltz, L4
20
0
48
ND
14
4
5
0
6
SEGPHOS, L5
DIFLUORPHOS, L6
TUNEPHOS, L7
SONIPHOS, L8
P-PHOS, L9
42
38
36
50
36
36
>90
>90
>90
>90
>90
>90
>90
40
7
88
78
8
9
72
a
b
c
10
11
12
80
48
PMP = 4-MeOC6H4. Isolated yield. Determined by CSP HPLC.
WALPHOS, L10
MANDYPHOS, L11
34
66
(R1) containing electron-donating and electron-withdrawing aryl
groups (Table 2, entries 3−5; see ref 5d), while ortho-substituted
aryls (2-Me, 2-OMe) resulted in lower yields of the desired
product.16 Thiophene could also be employed to good effect
(Table 2, entry 8), but the indole tandem product was not
stable.16 Variation from the PMP activating group on nitrogen to
phenyl, p-Me2NC6H4 or 3,4-Me2C6H3 (Table 2, entries 9−11),
had a small effect on selectivity, whereas moving from the methyl
ester to the ethyl or benzyl ester reduced selectivity further.16
In contrast to most other reports of N-alkylation of α-
iminoesters,17 a range of Grignard reagents could be employed
here to provide unique N-alkyl α-aryl-α-allyl α-amino acid
derivatives (Table 3, entries 1−5). Notably, more functional
Grignards provided terminal silyl and alkenyl derivatives (Table
3, entries 2−5). For alkenyl substrates, the alkene must be distal
to the reacting center as allyl, benzyl, and vinyl Grignard reagents
were not successful.
a
b
8.6 μmol of 1a at −50 °C. 0.372 mmol of 1a at −78 °C.
c
d
Determined by chiral stationary phase (CSP) HPLC. Conv
e
1
determined by H NMR. Conducted at −55 °C to simulate PME
conditions.
displays results for 11 of >190 enantiopure mono- and
bisphosphine ligands conducted at −50 °C utilizing PME.16
Nearly all ligands gave minimal conversion and selectivity, but
axial chiral bisphosphines, such as L1, L2, and L5−L9 (Figure 1),
were most effective in generating 3a as confirmed in larger scale
reactions at −78 °C (Table 1). Trost ligands possessing central
chirality and Pfaltz ligands with planar chirality (Table 1, entries 4
and 5) were unsuccessful, showing both poor reactivity and poor
selectivity.
With the optimal conditions, a range of α-iminoesters reacted
with satisfactory yields and enantioselectivity (3a−j) (Table 2).
Notably, the reaction was equally effective with keto substituents
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these results suggest16 a delicate balance where the most selective
species is a solvated dimer, such as B, that lies in between poorly
selective forms including a deaggregated form, such as monomer
C, and a less solvated form, such as a tetramer or dimer A (Figure
2).19
Table 3. Variation of the Grignard in the Tandem N-
Alkylation/π-Allylation (1a)
Figure 2. Possible enolate forms in solution (sol = solvent).
The method provides ready access to N-alkyl α-allyl-α-aryl α-
amino acids including a number of N-alkyl substitutions that
would be difficult to generate via reductive amination. In
addition, routes to the free amine analogs were assessed by means
of functionalized Grignard reagents (Table 3), which also offer
the option for removal. Surprisingly, the β-silyl group in product
3l could not be removed with fluoride or other nucleophiles
under a variety of acidic and basic conditions. Recent reports on
the isomerization of alkenes along a longer alkyl chain inspired us
to examine whether homoallyl analog 3m could be transformed
to the primary amine as shown in Scheme 4. An extensive survey
Scheme 4. Reduction of the Tandem N-Alkylation/π-
Allylation Product to the α-Allyl-α-Aryl α-Amino Acids
a
b
c
CPME = cyclopentyl methyl ether. Isolated yield. Determined by
CSP HPLC.
Reasoning that the same products 3 ought to be available from
racemic α-phenylgylcine derivatives, the reaction in Scheme 3
Scheme 3. Allylation of N-Alkylated Intermediate
was undertaken. A wide range of bases provided good conversion
(>85%), but poor enantioselectivity (ee =18−34%), compared
to the tandem reaction (Table 2).16 Notably, treatment of 4 with
EtMgBr should generate the exact same enolate (2) as in the
tandem reaction (2) (Scheme 2). However, this enolate provided
low conversion and significantly lower selectivity. We conclude
that the exact structural form of the enolate is critical to the
outcome. Specifically, the aggregate of 2 obtained from 1 differs
from that obtained from 4.18
In line with this reasoning, a strong solvent dependence was
observed, with ethereal solvents being far superior. Depending
on the exact structure of the Grignard reagent, subtle differences
were seen among the ethereal solvents THF, 2-MeTHF, Et2O,
and CPME (see Tables 2 and 3). On the other hand, amine base
additives reduced the selectivity to less than 30% ee.16 Together,
of olefin isomerizing catalysts20 revealed that the Grotjahn
catalyst21 was uniquely effective. Elevated temperatures,
combined with the addition of water and trifluoroacetic acid,
caused the terminal alkene 3m to isomerize by two carbons to the
enamine, which underwent hydrolysis in situ. Notably, the
sensitive styryl moiety remained intact. Treatment of the product
8 with CAN provided the primary amine 7. Thus, the reaction
method described herein can be used to generate both the free
amino and the N-alkyl (via PMP deprotection)16 versions of
novel α-allyl-α-aryl α-amino ester derivatives (Scheme 4).
In an effort to access an even greater diversity of the α-allyl-α-
aryl α-amino ester derivatives, a preliminary study of metathesis
to functionalize the allyl group was undertaken. Microwave
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(3) (a) Graver, A.; Konig, B. Eur. J. Org. Chem. 2009, 30, 5099.
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Scheme 5. Synthesis of Higher Ring Homologue of
α‑Substituted Proline
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but asymmetric methods for the synthesis of higher ring
homologues of α-substituted prolines23 have not received
much attention.24
(8) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873−888.
(9) Maruoka, K. Org. Process Res. Dev. 2008, 12, 679.
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In summary, we have disclosed the first asymmetric tandem N-
alkylation/π-allylation of α-iminoesters, which gives rise to
complex enantioenriched α-allyl-α-aryl α-amino acids in one step
from three commercially available components. This report
represents the first enantioselective synthesis of this class of
compounds beyond α-allyl-α-phenylglycine. The dramatic effect
of enolate aggregation observed herein provides a cautionary tale
for other systems. The nature of these effects are the subject of
further exploration.
(13) Dickstein, J. S.; Fennie, M. W.; Norman, A. L.; Paulose, B. J.;
Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 15794.
(14) (a) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A.
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D.; Kozlowski, M. C. Org. Lett. 2012, 3, 760.
(15) For racemic entries to α-allyl compounds from α-iminoesters, see
ref 12d, e.
(16) See Supporting Information for further details.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
(17) Dickstein, J. S.; Kozlowski, M. C. Chem. Soc. Rev. 2008, 37, 1166.
(18) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J. Am. Chem. Soc.
1976, 98, 567.
*E-mail: marisa@sas.upenn.edu.
Notes
(19) Magnesium enolates exist as monomers or as dimers bridged
through either the halide or the enolate oxygen. The coordination
sphere of the magnesium ranges from tetrahedral to octahedral with
solvent molecules occupying remaining coordination sites. For the X-ray
crystal structure of a dimeric bidentate enolate with Mg, see: (a) Di
Noto, V.; Bandoli, G.; Dolmella, A.; Zarli, B.; Vivani, M.; Vidali, M. J.
Chem. Cryst. 1995, 25, 375. For the X-ray crystal structure of dimeric
monodentate enolates with Mg, see: (b) Allan, J. F.; Clegg, W.;
Henderson, K. W.; Horsburgh, L.; Kennedy, A. R. J. Organomet. Chem.
1998, 559, 173. (c) Williard, P. G.; Salvino, J. M. J. Chem. Soc., Chem.
Commun. 1986, 153.
(20) (a) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.;
Nishida, A. J. Org. Chem. 2006, 71, 4255. (b) Nelson, S. G.; Bungard, C.
J.; Wang, K. J. Am. Chem. Soc. 2003, 125, 13000.
(21) (a) Erdogan, G.; Grotjahn, D. B. J. Am. Chem. Soc. 2009, 131,
10354. (b) Larsen, C. R.; Grotjahn, D. B. J. Am. Chem. Soc. 2012, 134,
10357.
(22) Park, K. H.; Kurth, M. J. Tetrahedron 2002, 58, 8629.
(23) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem. Soc.
1983, 105, 5390.
(24) For reviews on the asymmetric synthesis of cyclic α,α-
disubstituted α-amino acids, see: (a) Cativiela, C.; Ordonez, M.
Tetrahedron: Asymmetry 2009, 20, 1. (b) Cativiela, C.; Diaz-De-Villegas,
M. D. Tetrahedron: Asymmetry 2000, 11, 645.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NIH (GM-087605) and the NSF
(CHE0911713) for financial support of this research. The NSF
provided for funding of the High Throughput Laboratory
(GOALI CHE-0848460). Partial instrumentation support was
provided by the NIH for MS (1S10RR023444) and NMR
(1S10RR022442) and by the NSF for an X-ray diffractometer
(CHE 0840438). The invaluable assistance of Dr. D. B. Grotjahn
(San Diego State) for providing his catalyst and expertise on
alkene isomerization. Our collaboration with Dr. P. Carroll
(UPenn) in obtaining the crystal structure is gratefully
acknowledged. Also, the contributions of J. Hun (UPenn) and
the assistance from Dr. C. Stanciu (Merck) and Dr. S. D. Dreher
(Merck) with the PME experiments.
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