Silyl imine electrophiles in enantioselective catalysis: A rosetta stone for peptide homologation, enabling diverse N-protected aryl glycines from aldehydes in three steps

Article abstract of DOI:10.1021/ol501297a

We report that N-(trimethylsilyl)imines serve in the Bis(AMidine)-catalyzed addition of bromonitromethane with a high degree of enantioselection. This allows for the production of a range of protected α-bromo nitroalkane donors (including Fmoc) for use in

Full text of DOI:10.1021/ol501297a

Letter
pubs.acs.org/OrgLett
Silyl Imine Electrophiles in Enantioselective Catalysis: A Rosetta
Stone for Peptide Homologation, Enabling Diverse N‑Protected Aryl
Glycines from Aldehydes in Three Steps
Dawn M. Makley and Jeffrey N. Johnston*
Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United
States
S
* Supporting Information
ABSTRACT: We report that N-(trimethylsilyl)imines serve in the
Bis(AMidine)-catalyzed addition of bromonitromethane with a high
degree of enantioselection. This allows for the production of a range
of protected α-bromo nitroalkane donors (including Fmoc) for use
in Umpolung Amide Synthesis (UmAS). Hence, peptide homo-
logation with nonnatural aryl glycine amino acids is achieved in three
steps from aromatic aldehydes, which are plentiful and inexpensive.
Epimerization during the homologation step is circumvented by
avoiding an α-amino acid intermediate.
OtBu),7 but we soon realized that alternative protecting groups at
espite the tremendous achievements of conventional
1
Ddehydrative amide synthesis, opportunities abound for
nitrogen would be desirable, if not preferred, for applications in
the study of peptides containing nonnatural amino acids. As an
increasing number of peptides reach commercial end points,2,3
the demand for new methods that might address amide and
peptide preparatory needs has only increased.4,5 Umpolung
Amide Synthesis (UmAS), an amide preparation that expresses
the ability of α-halo nitroalkanes (D, Figure 1) to function as
carboxylic acid surrogates in a direct synthesis of amides,6 may
play a key role in solving this problem. Chiral nonracemic donors
D were prepared from N-Boc-imine electrophiles (B, R =
complex peptide synthesis (e.g., aryl glycine-rich natural
products).8 This report describes access to aryl glycine donors
for UmAS using N-(trimethylsilyl)imines (A) as unlikely
electrophiles for the enantioselective aza-Henry addition of
bromonitromethane. Furthermore, the silyl amine intermediates
(C) may be functionalized by a range of protecting groups,
including Fmoc.9 The resulting procedure can be used to
homologate an amine with a non-natural amino acid in the
shortest sequence yet from inexpensive starting materials.
The early impact of N-silylimine substrates was driven heavily
by nucleophilic addition reactions of strong nucleophiles.10
Itsuno reported the use of N-silylimines in enantioselective
synthesis with organoborane additions, providing the products of
carbon nucleophilic addition in up to 96% ee.11,12 These
transformations utilize a stoichiometric amount of the chiral
amino alcohol but provide convenient access to a range of
homoallylic amines since the nitrogen−silicon bond is cleaved
hydrolytically during workup.12 More recent work has
established that silyl imines are competent electrophiles for
fluoronium catalysis13 and α-amino boronic acid synthesis.14
Insofar as N-TMS imines are considerably more Lewis basic and
less electrophilic than N-acylimines,15 a catalyst complement
would need to simultaneously activate the imine and mitigate
both imine polymerization and further addition of the desired
adduct to imine. Indeed, our early attempts were plagued by the
formation of products such as E.
Figure 1. Parallel strategies to prepare aryl glycine α-bromo nitroalkane
donors for Umpolung amide synthesis.
Received: May 7, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
−20 °C, the addition product was obtained in 28% yield (two
steps, as a mixture of diastereomers) with 84/83% ee (for the
major/minor diastereomer, respectively). While the ee of this
reaction was pleasing, the low yield led us to explore other
optionsspecifically, a direct aza-Henry addition to the N-TMS-
imine. Our experience with aza-Henry adducts from N-
alkylimines has shown that they undergo reversible addition
upon standing, leading to racemization. That behavior, combined
with the large silyl group at the putative substrate binding site and
less polarized azomethine, suggested a low possibility for success.
Notwithstanding, the N-TMS-imine was subjected to bromoni-
tromethane directly with electron-rich bis(amidine) catalyst 1 at
ambient temperature. Though the resulting adduct could not be
isolated, it could be observed directly by NMR (1H/13C).19
Immediate treatment of the crude adduct with Fmoc-Cl
delivered the α-bromo nitroalkane (10e) in 43% yield and 11%
ee (for each diastereomer) from 9.
Even the low level of stereoselection observed in this reaction
was surprising, and it prompted an expanded investigation of
catalysts that might promote the addition (Table 1). The
reaction temperature was lowered to −78 °C, and acetyl bromide
was used to quench the resulting TMS-adduct. This provided an
increase in stereoselection to the 80% ee level (Table 1, entry 1).
Use of a single equivalent, as well as a slight excess of triflic acid
relative to the ligand, led to progressively lower reactivities and
enantioselectivities (Table 1, entries 2 and 3).20 Less electron-
rich bis(amidine) catalysts provided lower enantioselection
(Table 1, entries 4 and 5),21 and a catalyst that had provided
excellent enantioselection with N-Boc-imine substrates also fared
poorly with the corresponding silyl imine (Table 1, entry 6).6
Finally, an examination of two catalysts common to the thiourea
catalysis field provided disappointing preliminary results (Table
1, entries 7 and 8).22
Table 1. Enantioselective Additions of Bromonitromethane to
N-TMS Imines: Catalyst Investigation
a
b
c
entry
catalyst
PBAM (1)
ee (%)
yield (%)
1
2
3
4
5
6
7
8
80, 81
60, 61
38, 40
33, 32
24, 23
35, 32
−16, −17
8, 3
56
19
10
18
17
47
42
34
40
8
PBAM·HOTf 1:1 (2)
PBAM·HOTf 2:3 (3)
H-Quin-BAM (4)
4-MeO-BAM (5)
Anth-PBAM (6)
thiourea 7
thiourea 8
d
9
PBAM (1)
32, 30
89, 88
93, 91
d
10
PBAM (1)
d
11
PBAM (1)
78
a
Reactions stirred at −78 °C for 8 h. Then acetyl bromide was added,
and the reactions were stirred additional 2 h before being quenched
with water at −78 °C. Adducts isolated as a mixture of diastereomers
(dr = 1:1 up to 3:1, see the Supporting Information), ee’s reported for
b
c
(major, minor) diastereomer. Low yields generally correspond to
poor reactivity of the catalyst, resulting in low conversions.
d
Bromonitromethane used: entry 9, 300 mol %; entry 10, 30 mol
%; entry 11, 20 mol % added every 2 h, 100 mol % total, and 10 mol %
catalyst.
A significant sensitivity of enantioselection to bromonitro-
methane concentration was also uncovered. If an excess of
bromonitromethane was used, the apparent reactivity was
lowered along with the measured ee for the adducts (Table 1,
entry 9). Conversely, limiting the pronucleophile concentration
provided an enhancement of ee from 81 to 89% (Table 1, cf.
entries 1 and 10). Addition of bromonitromethane in 20 mol %
increments evenly over 10 h led to excellent enantioselection at
the 93/91% ee level (Table 1, entry 11) with a 10 mol % catalyst
loading to ensure low bromonitromethane concentrations
throughout the reaction.
Our studies began with the preparation of p-chloro N-TMS
benzaldimine 9 (A, Figure 1) using the Collet protocol16 and its
conversion to the corresponding N-Fmoc derivative (A → B,
Figure 1) by treatment with Fmoc-Cl. This acylation suffered
from poor conversion, and the N-Fmoc derivative was not
isolated in pure form. However, when the crude product was
subjected to bromonitromethane and catalyst PBAM (1)17,18 at
Our primary goal of this study was to address the need to
extend UmAS to carboxylic acid surrogates containing N-
protecting groups other than Boc. Therefore, immediately after
formation of the aza-Henry adduct, the acylation reagent was
a
Table 2. Enantioselective α-Bromo Nitroalkane Synthesis: Functionalization of the Silyl Amine Adduct
b
b
entry
RX
ee (%)
yield (%)
entry
RX
ee (%)
yield (%)
1
2
3
4
AcBr
AcCl
BzCl
PivCl
a
a
b
c
93, 91
92, 91
94, 95
96, 97
78
83
70
67
5
6
7
8
N3AcCl
FmocCl
CbzCl
d
e
f
91, 91
91, 91
91, 90
91, 91
82
76
72
85
AllocCl
g
a
100 mol % bromonitromethane added in aliquots over 10 h (0.2 equiv/2 h) before stirring overnight. The acylating agent (1 equiv) was then added
b
and an ice−water bath applied. Adducts isolated in dr = 1:1 up to 3:1 (see the Supporting Information); ee’s reported for (major, minor).
B
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Organic Letters
Letter
a
Table 3. Enantioselective Synthesis of Fmoc-Protected α-Bromonitroalkanes
a
100 mol % bromonitromethane added in aliquots over 10 h (0.2 equiv/2 h) before stirring overnight. The acylating agent (1 equiv) was then added
b
and an ice−water bath applied. See the Supporting Information for complete experimental details and analytical data. Adducts isolated as a mixture
of diastereomers (dr = 1:1 up to 3:1, see the Supporting Information), ee’s reported for (major, minor) diastereomer.
silyl amine. Both acetyl bromide and acetyl chloride provided
similar outcomes (Table 2, entries 1 and 2). Aromatic and
hindered acid chlorides provided highly enantioenriched
products in comparable yield (Table 2, entries 3 and 4). α-
Azido acetyl chloride also performed well, delivering the product
in 82% yield and 91% ee for both diastereomers (Table 2, entry
5). The heavy reliance on Fmoc-protected amino acids in solid-
phase peptide synthesis made it a priority problem to solve
(Table 2, entry 6). The versatile Cbz- and Alloc-protected amino
acids are also now available through the synthesis of both 10f and
10g in good yield and with good enantioselection (Table 2,
entries 7 and 8).
Table 4. Coupling of Protected α-Bromo Nitroalkane Donors
to Amines Using UmAS
a
The initial scope of this approach to aryl glycine donors for use
in UmAS was elucidated in the context of Fmoc-protected donor
synthesis (Table 3). Halogenated aryl glycines bearing a variety
of substitution patterns provided good enantioselection and
good overall isolated yields of the Fmoc-protected α-bromo
nitroalkanes 12a-e (Table 3, entries 1−5). Electron-deficient and
neutral silyl aldimines (Table 3, entries 6 and 7, respectively)
provided slightly depressed enantioselection that would
correspond to approximately 9:1 dr after UmAS coupling with
a chiral amine. This behavior is improved slightly with the tolyl
and 2-naphthyl cases (Table 3, entries 8 and 9), and our initial
investigation of the p-methoxy case (Table 3, entry 10) places it
within this category as well. In all cases, it is significant to note
that the diastereomeric addition products are homochiral (R) at
the benzylic carbon.23
The enantioselectivity with which adducts 10a−g are formed
(Table 2) correlates directly to the diastereomeric ratio of the
amide products resulting from their coupling to enantiopure
amino acids using UmAS (Table 4). For example, α-
bromonitroalkanes 10d−g, listed in Table 2, were coupled to a
variety of chiral nonracemic α-amino esters and amines to
establish the overall efficiency of this approach to aryl
glycinamide synthesis (Table 4). In all cases, the enantiomeric
ratio of the donors translated into high diastereomeric ratios for
the amide products, indicating the absence of epimerization. Of
a
Reaction run in THF, with 1.2 equiv of amine for 24 h at 0 °C.
b
Reaction run with 2 equiv of amine, for 24 h at 0 °C, under an
c
atmosphere of O2. Reaction run with 1.2 equiv of amine, for 4 h at 0
°C, under an atmosphere of O2. Measured by H HMR.
d
1
added to the reaction mixture at low temperature. We found it
prudent to replace the cryogenic bath with an ice−water bath at
this point, since the acylation was relatively slow in some cases.
This practice ensured complete conversion of the intermediate
C
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the basic reaction conditions.
In summary, we have discovered that N-TMS imines are
effective electrophiles in the BAM-catalyzed enantioselective
addition of bromo nitromethane and that the intermediate N-
TMS adduct can be acylated in situ. This provides a range of
adducts that can be used in Umpolung amide synthesis,
delivering the amino acid derivative, homologated by an aryl
glycine, with high diastereomeric purity. In some cases, such as
Fmoc-protected 10e, the product can be prepared by either
pathway via B or C (Figure 1) with similarly high
enantioselection.24 However, the low yield observed in the
former case further emphasizes the practical value of the pathway
through C. In other comparisons, such as the acyl-protected 10a,
the increased reactivity of the acyl imine intermediate leads to
poor enantioselection and yield. The development of N-TMS
imines as substrates in the enantioselective synthesis of amides
and peptides both decreases the length from aryl aldehyde to
peptide to three steps and broadens the nitrogen substituent
choices, including Fmoc protection without extensive redevelop-
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(12) However, Brown’s subsequent work revealed the importance of
water in this reaction, suggesting that addition occurs after hydrolytic
cleavage of the silyl protecting group. Therefore, enantioselective
addition occurs to the free aldimine/borane complex, not to the putitive
N-TMS imine: Chen, G. M.; Ramachandran, P. V.; Brown, H. C. Angew.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Complete preparatory and analytical data for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jeffrey.n.johnston@vanderbilt.edu.
Notes
(13) Bew, S. P.; Fairhurst, S. A.; Hughes, D. L.; Legentil, L.; Liddle, J.;
Pesce, P.; Nigudkar, S.; Wilson, M. A. Org. Lett. 2009, 11, 4552.
(14) Hong, K.; Morken, J. P. J. Am. Chem. Soc. 2013, 135, 9252.
(15) Cainelli, G.; Panunzio, M.; Andreoli, P.; Martelli, G.; Spunta, G.;
Giacomini, D.; Bandini, E. Pure Appl. Chem. 1990, 62, 605.
(16) Vidal, J.; Damestoy, S.; Guy, L.; Hannachi, J. C.; Aubry, A.; Collet,
A. Chem.Eur. J. 1997, 3, 1691.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Unrestricted support from Amgen and the ACS Division of
Organic Chemistry (graduate fellowship to D.M.M.) is gratefully
acknowledged, as is partial support by the NIH (GM 063557
(exploratory) and GM 084333 (catalyst development)).
(17) Davis, T. A.; Wilt, J. C.; Johnston, J. N. J. Am. Chem. Soc. 2010,
132, 2880.
(18) Davis, T. A.; Johnston, J. N. Chem. Sci. 2011, 2, 1076.
(19) Observation of this intermediate indicates that enantioselective
addition does occur to the N-TMS imine and that the silyl group is not
lost until acid chloride quench. See the Supporting Information for
spectroscopic details.
(20) For similar observations with an indolenine electrophile, see:
Dobish, M. C.; Johnston, J. N. Org. Lett. 2010, 12, 5744.
(21) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc.
2004, 126, 3418.
(22) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672. Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
(23) The absolute configuration was confirmed by quenching the
intermediate pCl-TMS-adduct with Boc2O to form the N-Boc-protected
α-bromo nitroamine, a known compound. See the Supporting
Information for details.
(24) To the best of our knowledge, only one enantioselective synthesis
of α-amino acids has shown some degree of tolerance to Fmoc
protection directly (two substrates, hydrogenation to phenylalanine
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