A Tamao–Fleming oxidation route to dipeptides bearing N,O-acetal functionality

Article abstract of DOI:10.1016/j.tetlet.2017.11.036

Tamao–Fleming oxidation of the N-dimethylphenylsilylmethyl group linked to the nitrogen of a peptide bond enables access to dipeptide N,O-acetal functionality. The N-silylmethyl functionality serves as a latent form of the N,O-acetal which is revealed after peptide bond construction.

Full text of DOI:10.1016/j.tetlet.2017.11.036

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
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A Tamao–Fleming oxidation route to dipeptides bearing N,O-acetal
functionality
⇑
Sherif M.S. Ibrahim, Koushik Banerjee, Kara A. Slater, Gregory K. Friestad
Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Tamao–Fleming oxidation of the N-dimethylphenylsilylmethyl group linked to the nitrogen of a peptide
bond enables access to dipeptide N,O-acetal functionality. The N-silylmethyl functionality serves as a
latent form of the N,O-acetal which is revealed after peptide bond construction.
Ó 2017 Published by Elsevier Ltd.
Received 15 September 2017
Revised 3 November 2017
Accepted 16 November 2017
Available online xxxx
Keywords:
Peptides
Oxidation reactions
N,O-Acetals
Prodrugs
Bioconjugate chemistry
Introduction
The N,O-acetal moiety is useful in generating iminium ions and
1
related intermediates for preparation of amines, and is found in a
2
–4
5–8
variety of prodrugs
and natural products.
Our initial encoun-
ter with the methodology for preparation of N,O-acetals was a con-
sequence of our synthetic studies9
–12
on the tubulysins.
13–15
Tubulysin D (Fig. 1.1) is unusual among N,O-acetals in that its N,
O-acetal nitrogen is shared with a peptide bond.
Several preparations of amide-linked N,O-acetal functionality
Fig. 1.1. Natural product tubulysin D containing the N,O-acetal moiety.
1
6–19
have been described;
among these are oxidative decarboxyla-
oxidative fragmentations with hypervalent
2
0
4
tion with Pb(OAc) ,
2
1
22
We envisioned an umpolong approach to unveil the latent
iodine reagents, and additions to oxocarbenium ions. Prepara-
tion of a peptide-linked N,O-acetal like tubulysin D by these meth-
ods is complicated by the instability of the N,O-acetal to amidation
N,O-acetal, in which a carbon nucleophile could migrate to oxygen
2
5–27
in a Tamao–Fleming oxidation
with the electrophilic oxygen
4
originating in peracids or peroxides (Fig. 1.2b). Contrasted with
the Moeller method, this new approach would allow for greater
versatility; it removes the restriction that one reaction component
serve as a solvent, and it allows many options for further function-
alization of a free hydroxyl group. Here we present the proof-of-
principle of this approach to peptide N,O-acetals, and initial
surveys of scope with simple amino acids.
reactions, as well as the acidic and basic conditions found in typ-
ical peptide synthesis sequences. This places a premium upon mild
and selective conditions, addressable to one specific peptide bond
among many. Toward this end, we noted the precedent of Moeller
2
3,24
et al.,
indicating that N,O-acetals can be prepared from
N-silylmethyl groups through oxidation, via the intermediacy of
N-acyliminium ions (Fig. 1.2a). Thus, the N-silylmethyl group could
constitute a latent form of the N,O-acetal moiety, stable to acidic
and basic conditions.
Results and discussion
Our experimental efforts began with selection of an appropriate
silyl group which would be prone to Tamao–Fleming oxidation. For
this we envisioned use of dimethylphenylsilyl, developed by
⇑
Corresponding author.
E-mail address: gregory-friestad@uiowa.edu (G.K. Friestad).
https://doi.org/10.1016/j.tetlet.2017.11.036
040-4039/Ó 2017 Published by Elsevier Ltd.
0
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2
S.M.S. Ibrahim et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Table 1
N-Alkylations of amino esters with (chloromethyl)-dimethylphenylsilane. Typical
conditions: 10 mmol 1, 1.5 equiv KI, 1.5 equiv K CO , 1.5 equiv ClCH SiMe Ph, DMF,
0 h, 90 °C.
2
3
2
2
2
Fig. 1.2. (a) Prior Art, using electrochemistry to prepare N,O-acetals from N-
silylmethyl peptides via iminium ions ([Si] = trimethylsilyl). (b) This Work, using
chemical oxidation and reversal of polarity (umpolung). The free hydroxyl in the
product allows for greater versatility.
pound was isolated in 89% yield by column chromatography, allay-
ing our initial concerns about its stability.
Next, several dipeptides were prepared as a preliminary evalu-
ation of the scope of this reactivity. Peptide coupling with glycine
derivatives incorporated the series of secondary amino esters 2
into glycine dipeptides 3 containing the masked N,O-acetal in the
form of the N-silylmethyl moiety. Thus, either N-Fmoc-glycine or
N-Boc-glycine engaged in peptide bond construction (Table 2) that
entailed carboxylate activation with isobutyl chloroformate or
Fig. 2.1. Representative conditions developed by Fleming28 for conversion of
dimethylphenylsilyl to hydroxyl.
3
1,32
chlorodimethoxytriazine (CDMT).
Yields ranged from 43 to
Fleming as a stable hydroxyl surrogate.28 Oxidation to reveal the
hydroxyl group is a two-stage process that may be carried out
85% in these coupling reactions, with the exception of N-silyl-
methyl valine and N-silylmethyl isoleucine; these secondary N-
silylmethyl amino acids gave 27% and 35% yields of dipeptides,
presumably impacted by the branching in the side chain.
under
a variety of conditions, including a one-pot method
(Fig. 2.1). First the phenyl is replaced by a heteroatom at silicon,
Having a series of N-silylmethyl dipeptides in hand, we exam-
by exposure to electrophilic halogenation or protodesilylation of
the phenyl. The silicon–carbon bond can be oxidized by a peracid
or peroxide, with carbon-to-oxygen migration as indicated in
Fig. 1.2. The availability of complementary conditions allows for
potential application in the presence of a broad range of amino acid
functionality.
To begin the implementation, N-alkylation of amino esters
furnished building blocks equipped with the N-silylmethyl
functionality. Hydrochloride salts of the amino esters 1 underwent
N-alkylation with chloromethyldimethylphenylsilane in the pres-
2
8
ined their Tamao–Fleming oxidations to prepare the N,O-acetals
Table 2). Oxidation by KBr and peracetic acid in the presence of
sodium acetate afforded the intermediate hemiaminals 4, which
were immediately acylated (Ac O, DMAP) to give the diacyl N,O-
(
2
acetals 5 in yields ranging from 41 to 77%. Various N-terminal pro-
tecting groups of the dipeptides were accomodated without any
noticeable impact on the success of the oxidation.
Lastly, substitution of alanine for glycine in the sequence was
examined. Coupling of 2g with N-Boc alanine (Scheme 2) via the
mixed anhydride from isobutyl chloroformate furnished dipeptide
6. In this example, one-pot oxidation and acylation was accom-
plished by simply incorporating acetic anhydride into the oxida-
tion mixture; this furnished N,O-acetal 7 in excellent yield.
ence of iodide and
dimethylphenylsilylmethyl derivatives 2 (Table 1).
K
2
CO
3
,
resulting in the desired N-
29
Preparation of N-methyldimethylphenylsilyl amino acids using
the aliphatic amino acids methyl esters alanine, valine, leucine,
and isoleucine gave the desired products in yields varying from
5
5 to 75%. The dimethyl esters of the acidic amino acids aspartate
and glutamate gave the desired products in yields of 82% and 60%
respectively. Phenylalanine methyl ester also readily afforded a
high yield of the corresponding N-silylmethyl derivative 2g.
We first tested the oxidative chemistry on the TFA-protected
glycine phenylalanine dipeptide 3g (Scheme 1), prepared by cou-
pling of 2g with the acid chloride of N-TFA glycine.30 This tertiary
dipeptide exhibited restricted rotation; rotamers observed in the
1
H NMR could be coalesced into a single spectrum at 100 °C. Apply-
ing the one-pot conditions for Tamao–Fleming oxidation, the N-
silylmethyl group of the dipeptide 3g was smoothly converted to
the N-hydroxymethyl, affording peptide 4g. Notably, this com-
Scheme 1. Initial methodology test in preparation of a GlyPhe dipeptide bearing N,
O-acetal functionality at the peptide bond nitrogen.
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S.M.S. Ibrahim et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
Table 2
Preparation of glycine N-silylmethyl dipeptides and oxidation to N,O-acetals.
a
Entry
R
P
Yield, 3
Yield, 5
1
2
3
4
5
6
7
Me
Boc
Boc
85%, 3a
75%, 3b
27%,b 3c
35%, 3d
43%, 3e
60%, 3f
52%, 5a
64%, 5b
77%, 5c
72%, 5d
41%, 5e
59%, 5f
71%, 5g
i-Bu
i-Pr
s-Bu
Fmoc
Fmoc
Fmoc
Fmoc
TFA
CH
2
CH
2
CH
2
CO
CH
Ph
2
Me
CO
2
2
Me
c
72%, 3g
a
Typical conditions: 1) 4 mmol N-Boc-glycine or N-Fmoc-glycine, 3 equiv N-methylmorpholine, 1.5 equiv i-BuOCOCl, 1.5 h, then 2.7 mmol 2, 20 h, CH
2
2
Cl , À15 °C to rt; 2)
33
0
.2 mmol 3, 1.5 equiv KBr, 17 equiv NaOAc, 48 equiv peracetic acid, 3 h, À15 °C to rt; 3) 12 mol% DMAP, 2.5 equiv Ac
2
O.
b
Modified conditions: 4 mmol 2c, 1.1 equiv N-Fmoc-glycine, 3.5 equiv N-methylmorpholine, 1.2 equiv chlorodimethoxytriazine (CDMT), 20 h, rt.
c
Modified conditions: 1.0 mmol 2g, 3 mmol N-TFA-glycine acid chloride, 1.1 mmol NEt
3
, 1 h, À15 °C to rt.
1
1
1
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2
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A Tamao-Fleming oxidation methodology supports the prepara-
tion of N,O-acetals linked at the peptide bond nitrogen of a variety
of dipeptides. The intermediate N,O-acetal bearing a free hydroxyl
may be acylated in situ or isolated and subsequently acylated; this
sets the stage for preparation of peptide bioconjugates via a
hydrolyzable, traceless N,O-acetal linkage.
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3
3
Acknowledgment
33. Representative procedure: To a solution of N-silylmethyl dipeptide 3d (358.4
mg, 0.63 mmol), potassium bromide (100.9 mg, 0.85 mmol), and sodium
acetate (165.7 mg, 2.02 mmol) in acetic acid (1.9 mL) was added additional
sodium acetate (465.3 mg, 5.67 mmol) at 0 °C followed by 32% peracetic acid
(2.0 mL, 8.84 mmol). After 15 min, an additional portion of 32% peracetic acid
was added (5.3 mL, 23.42 mmol), and the reaction mixture was allowed to
warm to room temperature over 1 h. The reaction mixture was quenched
We gratefully acknowledge the generous support of this work
by NSF (CHE-1362111).
A. Supplementary data
carefully with saturated Na
bicarbonate. The mixture was extracted with dichloromethane (3 Â 10 mL).
The organics were dried over anhydrous Na SO and concentrated to afford 4d
360.0 mg). To this material was added pyridine (5 mL), 4-
dimethylaminopyridine (15.1 mg, 0.12 mmol) and acetic anhydride (0.18 mL,
.41 mmol). After 20 min, the reaction mixture was partitioned between 2 N
aqueous hydrochloric acid (20 mL) and ethyl acetate (3 Â 10 mL). The organics
were dried over anhydrous Na SO . Concentration and flash chromatography
silica gel, 70:30 petroleum ether/ethyl acetate) afforded the O-acylated N,O-
acetal 5d (225.2 mg, 72% yield) as a colorless oil; IR (liquid film) max 3355 (br),
066, 2961, 2924, 2880, 1738, 1727, 1678, 1450, 1365, 1230, 1198, 1043, 1015
S
2 2
O
3
(aq), and neutralized with sodium
2
4
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2017.11.036.
(
1
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Please cite this article in press as: Ibrahim S.M.S., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.11.036