Three component coupling of α-iminoesters via umpolung addition of organometals: Synthesis of α,α-disubstituted α-amino acids

Article abstract of DOI:10.1021/ja8073006

The synthesis of α,α-disubstituted α-amino acids by means of a three component coupling is reported. The coupling occurs through umpolung addition of organometallic reagents to the nitrogen of α-iminoesters. The resulting enolate intermediates subsequentl

Full text of DOI:10.1021/ja8073006

Published on Web 11/05/2008
Three Component Coupling of r-Iminoesters via Umpolung Addition of
Organometals: Synthesis of r,r-Disubstituted r-Amino Acids
Joshua S. Dickstein, Michael W. Fennie, Amber L. Norman, Betty J. Paulose, and
Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, UniVersity of PennsylVania, Philadelphia,
PennsylVania 19104-6323
Received September 15, 2008; E-mail: marisa@sas.upenn.edu
R-Amino acids and their derivatives are vital synthetic building
blocks in organic synthesis and play an integral role in pharma-
ceutical research. Therefore, the synthesis of both natural and non-
natural R-amino acids continues to be a subject of intense study.1
In particular, the formation of R,R-disubstituted R-amino acids is
difficult due to the quaternary center even though such compounds
have useful properties. For example, when incorporated into
peptides, R,R-disubstituted R-amino acids confer increased stability
under physiological conditions and stabilize secondary structure
motifs.2 They also have relevance in natural product total synthesis.3
Herein we report that R-iminoesters engage in an umpolung addition
with organometallic reagents providing a three component coupling
route toward R,R-disubstituted R-amino acids.
Our laboratory has discovered processes for the asymmetric
addition of diorganozinc reagents to aldehydes,4 R-ketoesters,5 and
R-aldiminoesters.6 During exploration of the related R-ketimi-
noesters (eq 1), we observed an unusual reaction pattern. In addition
to the expected C-alkylation7 (3) and reduction8 (4) products, an
N-alkylation product (2) was observed. Depending on the N-
substitution and organometallic reagent, it is possible to form any
of the three products in eq 1 selectively (Table 1). Electron-
withdrawing groups on nitrogen tend to favor reduction (4). With
N-aryl substitution, the more reactive organolithiums favor C-
alkylation (3) while the Grignard, aluminum, and zinc reagents bias
the reaction toward N-alkylation (2).
alkylation. Surprisingly, we found that the hindered R-iminoester
1d (R1 ) Ph, R3 ) PMP) departs from this trend (Table 1, entries
4, 7-9) and provides entry to 2 via the tetra-substituted enolate
(5; eq 2).14 With facile entry to such an enolate, we proposed the
synthesis of R,R-disubstituted R-amino acids via a three component
coupling process (eq 2).
Optimization of the N-alkylation reaction revealed that alkyl
magnesium bromides in THF were superior (Table 1, entry 9). Upon
protonation of the enolate adduct, products 6da and 6db (from
EtMgBr and n-pentylMgBr) could be obtained in 84 and 85% yield,
respectively (Chart 1). Furthermore, the enolate could readily be
exploited to achieve a one-pot three component coupling reaction
using a range of electrophiles (eq 2, Chart 1).
When benzaldehyde was employed as the electrophile high
conversion (∼80%) to the three component product as a single
diastereomer (6dc, Chart 1) was seen. Additional aldehydes reacted
with high diastereoselection with representative Grignard reagents
(R4 ) Et, n-pentyl) providing the three component coupling
products (6dd-6dh) in very good yield and diastereoselection. The
N-tosyl imine also proved to be an effective electrophile furnishing
a single diastereomeric product (6di). The syn diamine relative
stereochemistry was verified from the crystallographic structure and
Chart 1. Three Component Coupling of 1d with Different
Electrophiles (Eq 2: R1 ) Ph, R2 ) Me, R3 ) PMP, R4MgBr )
EtMgBr 7a or n-pentylMgBr 7b)a
A few reports9-12 indicate that Grignard reagents in the absence
of a Lewis acid yield N-alkylated products only with unhindered
(R1 ) H) or doubly activated R-iminoesters (R1 ) CO2Me).13 On
the other hand, hindered iminoesters undergo reduction or C-
Table 1. Conditions vs Addition Mode to R-Iminoesters (Eq 1)a
entry
1
R4M
solvent
2 (%)b
3 (%)b
4 (%)b
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1d
1d
1d
1d
1d
EtMgCl
Et2Zn
Et2Zn
Et2Zn
n-pentylZnBr
EtLi
Et2AlCl
EtMgCl
EtMgBr
THF
0
0
<15
0
NR
7
NR
34c
<5
21
70
100
NR
12
NR
0
<5
0
<5
CH2Cl2
PhCH3
PhCH3
THF
THF
MeCN
THF
NR
81
NR
0
>90
79
>90
THF
<5
a PMP ) 4-MeOC6H4. Reaction conditions: 0.19 M 1d, 1.2-2.0 equiv
of R4MgBr, THF, -78 °C to rt, followed by 5 equiv of E+.
a Reaction conditions: 0.19 M 1a-d, 1.5-3.0 equiv R4M, -78 °C to
rt. b Conversion by 1H NMR spectroscopy. c With 49% 1d.
9
15794 J. AM. CHEM. SOC. 2008, 130, 15794–15795
10.1021/ja8073006 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Intramolecular Three Component Coupling to Form
Cyclic R-Amino Acid Derivatives
Figure 1. ORTEP of 6di and putative transition structure.
is in accord with a chair-like transition state commencing from the
Z enolate 5Z (Figure 1).
Initial attempts to use alkyl halide electrophiles provided very
low yields of the three component coupling products (<10%). We
discovered that DMF as a solvent greatly increased the yield in
this instance. For example, reaction with BnBr or EtI afforded 72%
and 66% yield (6dj and 6dk, Chart 1). Furthermore, tert-butyl
bromoacetate provided 6dl in 48% yield.
Conjugate acceptors were also effective electrophiles. For example,
trans-ꢀ-nitrostyrene furnished the three component products in good
yields (6dm 77% and 6dn 67%, Chart 1). In contrast to aldehydes or
imines (Figure 1), poor diastereoselection (1.3-1.4:1) was observed
indicating poor organization of the incoming nitrostyrene and the
intermediate enolate compared to that shown in Figure 1.
In conclusion, the rapid construction of R,R-disubstituted R-ami-
no acid derivatives can be achieved in high yields from R-imi-
noesters. The reaction proceeds through an umpolung addition of
an organometallic reagent to the nitrogen. The resultant enolate
reacts with a variety of electrophiles to form a quaternary center.
Furthermore, high diastereoselection occurred in the three compo-
nent coupling reactions with aldehydes and imines. This methodol-
ogy provides straightforward access to a variety of pharmacologi-
cally and synthetically useful products. Further details into the scope
of the reaction and other aspects of this methodology will be
reported in due course.
While acid chlorides gave poor yields, acyl cyanides such as
pyruvonitrile were particularly effective, furnishing the product in
85-87% yield (Chart 1, 6do and 6dp). As a result, pyruvonitrile was
employed with a range of R-iminoesters (Table 2). The identity of the
ester group could be readily changed while retaining good yields
(68-87%; entries 1-4). Variation of the electronic and steric features
of the keto-group was also well tolerated (58-86%, entries 5-8). The
role of the R-iminoester N-substitution on chemoselectivity has been
well documented (See Table 1, entries 1-4).13 Nonetheless, replacing
the PMP group with a phenyl still provided the three component
coupling product with good yield (73%, entry 9).
Cyclic R-amino acid derivatives are also of great synthetic and
pharmaceutical interest.2a,b,15 Therefore, we envisioned an intramo-
lecular three component coupling reaction in which the organometal
and electrophile are tethered (Scheme 1). Much to our delight, this
intramolecular cyclization was found to occur to afford piperidine
9a and azepane 9b in a one-pot procedure.16 This protocol proceeds
well with other R-iminoesters as illustrated by formation of 9c.
Also, removal of the PMP group was straightforward with ceric
ammonium nitrate (CAN).
Acknowledgment. Financial support was provided by the PRF
(47616-AC1). The invaluable assistance of Dr. Patrick Carroll in
obtaining the X-ray structure is gratefully acknowledged. We thank
Dr. Patrick Walsh for helpful discussions.
Supporting Information Available: Experimental procedures and
spectral data. This material is available free of charge via the internet
at http://pubs.acs.org.
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1
2
3
4
5
6
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1d
1e
1f
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1h
1i
1j
1k
1l
Ph
Ph
Ph
Ph
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t-Bu
Bn
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Me
Et
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Ph
6do
6eo
6fo
6go
6ho
6io
6jo
6ko
6lo
87
68
78
68
86
58
71
72
73
p-MeOC6H4
p-ClC6H4
o-MeC6H4
N-Bn-Indole
Ph
Me
Me
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(16) 9a and 9b could also be obtained in a stepwise fashion in 50 and 62%
overall yields, respectively.
a Reaction conditions: 0.10-0.17 M 1, 1.5-2.0 equiv of EtMgBr,
THF, -78 °C to rt, followed by 5 equiv of E+.
JA8073006
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J. AM. CHEM. SOC. VOL. 130, NO. 47, 2008 15795