Oxidation of peptides by methyl(trifluoromethyl)dioxirane: The protecting group matters

Article abstract of DOI:10.1021/jo061910n

Representative Boc-protected and acetyl-protected peptide methyl esters bearing alkyl side chains undergo effective oxidation using methyl(trifluoromethyl)dioxirane (1b) under mild conditions. We observe a protecting group dependency in the chemoselectivity displayed by the dioxirane 1b. N-Hydroxylation occurs in the case of the Boc-protected peptides, and side chain hydroxylation takes place in the case of acetyl-protected peptides. Both are attractive transformations since they yield derivatized peptides that serve as valuable synthons.

Full text of DOI:10.1021/jo061910n

Oxidation of Peptides by Methyl(trifluoromethyl)dioxirane:
The Protecting Group Matters
Maria Rosaria Rella and Paul G. Williard*
Department of Chemistry, Brown UniVersity, ProVidence, Rhode Island 02912
Paul_Williard@Brown.edu
ReceiVed September 15, 2006
Representative Boc-protected and acetyl-protected peptide methyl esters bearing alkyl side chains undergo
effective oxidation using methyl(trifluoromethyl)dioxirane (1b) under mild conditions. We observe a
protecting group dependency in the chemoselectivity displayed by the dioxirane 1b. N-Hydroxylation
occurs in the case of the Boc-protected peptides, and side chain hydroxylation takes place in the case of
acetyl-protected peptides. Both are attractive transformations since they yield derivatized peptides that
serve as valuable synthons.
Introduction
into “unactivated” C-H bonds of alkanes.5 This reaction mimics
that catalyzed by P450 enzymes.6 The high reactivity and high
selectivity displayed by dioxiranes, coupled with the mild
reaction conditions (typically 0 °C to room temperature, neutral
pH) and simple workup (removal of the solvent), encourage
their use as the reagents of choice to carry out oxidation of
natural products.5 Additionally these reagents are very effective
for oxidation of substrates sensitive to acidic or basic pH values.7
Several proteins and peptides are human therapeutic agents,
and considerable effort is directed at the discovery of new
analogues for novel or improved treatment of diseases.1 One
powerful approach is to chemically alter existing protein and
peptide drugs. Structural modifications of these molecules might
improve the pharmacokinetic properties of bioactive peptides
or even convert inactive peptides to new drugs. In this paper
we describe some useful transformations of peptides by diox-
iranes with the goal of creating new drugs.
It is well-established that dimethyldioxirane (1a) (DMD)2 and
methyl(trifluoromethyl)dioxirane (1b) (TFD)3 are effective
reagents to carry out a variety of synthetically useful oxidations
under mild conditions. Exemplary transformations are the syn-
stereoselective epoxidation of alkenes, oxidation of molecules
containing atoms bearing lone pairs such as sulfides, sulfoxides,
and amines, and O-insertion into C-H bonds of various
functional groups such as aldehydes, secondary or primary
alcohols, acyclic and cyclic ethers, and the Si-H bond of
silanes.4 Among these reactions is the remarkable O-insertion
It has been reported that DMD selectively hydroxylates the
alkyl side chains of N-Boc-protected R-amino acid esters.8 The
results vary depending on the structure of the amino acid. These
reactions are rather sluggish, requiring long reaction times
(several days) for sizable substrate conversion. High regiose-
lectivity for the O-insertion into the γ-CH bond of leucine (Leu)
(4) For reviews, see: (a) Curci, R. In AdVances in Oxygenated Processes;
Baumstark, A. L., Ed.; JAI: Greenwich, CT, 1990; Vol 2, Chapter I, pp
1-59. (b) Adam, W.; Hadjiarapoglou, L. P.; Curci, R.; Mello, R. In Organic
Peroxides; Ando, W., Ed.; Wiley: New York, 1992; Chapter 4, pp 195-
219. (c) Curci, R.; Dinoi, A.; Rubino, M. F. Pure Appl. Chem. 1995, 67,
811-822. See also references quoted therein.
(5) For reviews, see: Curci, R.; D’Accolti, L.; Fusco, C. Acc. Chem.
Res. 2006, 39, 1-9. See also references quoted therein.
(6) Sono, M.; Roach, M. P.; Coulter, E. D.; Dawson, J. H. Chem. ReV.
1996, 96, 2841-2887.
* Corresponding author.
(1) Ross, S. A.; Gulve, E. A.; Wang, M. Chem. ReV. 2004, 104, 1255-
1282.
(2) (a) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847-
2853. (b) Cassidei, L.; Fiorentino, M.; Mello, R.; Sciacovelli, O.; Curci, R.
J. Org. Chem. 1987, 52, 699-700. (c) Murray, R. W.; Singh, M. Org. Synth.
1996, 74, 91.
(3) (a) Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. J. Org. Chem.
1988, 53, 3890-3891. (b) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R.
J. Am. Chem. Soc. 1989, 111, 6749-6757. (c) D’Accolti, L.; Fusco, C.;
Rella, M. R.; Curci, R. Synth. Commun. 2003, 33, 3009-3016.
(7) D’Accolti, L.; Fusco, C.; Annese, C.; Rella, M. R.; Turteltaub, J. S.;
Williard, P. G.; Curci, R. J. Org. Chem. 2004, 69, 8510-8513.
(8) Saladino, R.; Mezzetti, M.; Mincione, E.; Torrini, I.; Paglialunga
Paradisi, M.; Mastropietro, G. J. Org. Chem. 1999, 64, 8468-8474.
10.1021/jo061910n CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/13/2006
J. Org. Chem. 2007, 72, 525-531
525

Rella and Williard
rather than into the R-CH bond has been reported.8,9 Thus, Boc-
Leu-OMe has been found to yield the corresponding 4,4-
dimethyl-4-butanolide derivative. The latter is believed to be
formed by selective O-insertion into the tertiary γ-CH bond of
Leu followed by cyclization (eq 1).
whether it is a rather general phenomenon with N-protected
peptides, we decided to explore the reactivity of some N-acetyl-
protected amino acid and dipeptide esters bearing alkyl side
chains. Hence, we observe high regioselective side chain
hydroxylation in the reaction with N-acetyl-protected amino
acids and dipeptides. We do not observe any oxidation of the
N-acetyl moiety of these compounds. These observations provide
easy access to side chain modifications of linear peptides
containing only amidic nitrogen atoms, and of cyclic polypep-
tides and depsipeptides.18
Results and Discussion
The results of the oxidation of the selected Boc-protected
di- and tripeptide methyl esters with methyl(trifluoromethyl)-
dioxirane are collected in Table 1.
“Position selectivity” in the oxidation of peptides containing
more than one Leu residue was also reported.8
Oxidation of N-Boc-Ala-Ala-OMe (2) with 2.4 equiv of TFD
produced the Boc-N-hydroxy derivative 2a in 78% isolated yield
as the only product after 4 h of reaction at 0 °C in CH2Cl2
(entry 1). The reaction is assumed to occur without loss of
enantiomeric excess.10 The structure of the compound 2a and
of the following oxidation products that are described in this
work were unambiguously characterized by the combination of
high-resolution mass and 1D and 2D NMR techniques. The
reaction conditions adopted in the oxidation of dipeptide 2 were
used in the oxidation of the other Boc-protected peptides bearing
alkyl side chains.
Hydroxylation of the Boc-protected nitrogen was observed
also in the case of N-Boc-Val-Ala-OMe (3) and N-Boc-Val-
Ala-Ala-OMe (4) (entries 2-3). N(OH)-Boc-Val-Ala-OMe (3a)
and N(OH)-Boc-Val-Ala-Ala-OMe (4a) were produced in 81%
and 71% isolated yields, respectively, suggesting that hydroxy-
lation of the Boc-protected nitrogen in peptides by a moderate
excess of TFD is a generally useful reaction, regardless of the
length of the peptides. Boc-Ala-Leu-OMe (5) was converted to
N(OH)-Boc-Ala-Leu-OMe (5a) in a slightly lower yield (63%
isolated yield) (entry 4).
The composition of products obtained in the oxidation of
N-Boc-Leu-Ala-OMe (6) with 2.4 equiv of TFD was more
complex (entry 5). N-Boc-Leu(γ-OH)-Ala-OMe (6b) and N(OH)-
Boc-Leu(γ-OH)-Ala-OMe (6c) were isolated in 11% and 15%
yield, respectively, in addition to the production of N(OH)-Boc-
Leu-Ala-OMe (6a) as the major product in 46% isolated yield.
In order to establish whether 6b and, in particular, the over-
oxidation product 6c were produced by the excess of dioxirane,
oxidation of N-Boc-Leu-Ala-OMe with 1.2 equiv of TFD was
investigated. Under these conditions, a similar distribution of
products was obtained as when the reaction was run with 2.4
equiv of TFD (6a, 6b, and 6c were obtained in 25%, 13%, and
5% isolated yield, respectively). This result suggests that in the
oxidation of N-Boc-Leu-Ala-OMe with TFD, O-insertion into
the tertiary γ-CH bond kinetically competes with the oxidation
of Boc-protected nitrogen, yet the N-Boc hydroxylation is the
favored process. These results are in agreement with the outcome
of the reaction of TFD with Boc-protected amino acid methyl
esters bearing an alkyl side chain.10 Hence, the terminal
N-hydroxy peptide methyl esters can be obtained by facile and
quantitative removal of the Boc protecting group using TFA.10
To the best of our knowledge, the work presented here
represents the first example of direct transformation of carbamic-
Curci reported that oxidation of Boc-Leu-OMe with TFD (5
equiv) occurs more rapidly (6 h, 91% conversion) than with
DMD, but it gives different selectivity. The major product for
the oxidation with TFD is the N-hydroxy derivative of Boc-
Leu-OMe (57% yield, no loss of enantiomeric excess) along
with the N-hydroxy derivative of the butanolide (21% yield).10
We have extended the study of the reaction of TFD with Boc-
protected di- and tripeptide esters bearing alkyl side chains. In
all the cases analyzed, we observe selective hydroxylation of
the terminal nitrogen atom in short reaction times and remark-
ably mild reaction conditions. Our results offer a novel
opportunity to directly hydroxylate linear peptides at the
N-terminal position and an easy access to hydroxamic acids.11
These studies are important because hydroxamic acids have
several biological activities. For example, they are inhibitors
of secretases involved in Alzheimer’s disease and blood pressure
regulation,12 chemotherapeutic agents,13 anti-inflammatory agents
for the treatment of asthma and rheumatoid arthritis,14 antima-
larial agents,15 iron chelators,16 and siderophores.11b Furthermore
it has recently been shown that N-hydroxy peptides react readily
with R-keto acids to form amides.17 Thus, the results reported
herein yield synthons that can be utilized in this novel
chemoselective amide ligation for polypeptide synthesis.17
In order to test whether the interesting N-terminal hydroxy-
lation of peptides by TFD is unique for the Boc protection or
(9) Shustov, G. V.; Rauk, A. J. Org. Chem. 1998, 63, 5413-5422.
(10) Detomaso, A.; Curci, R. Tetrahedron Lett. 2001, 42, 755-758.
(11) Ottenheijm, H. C. J.; Herscheid, J. D. M. Chem. ReV. 1986, 86,
697-707. (b) Miller, M. J. Chem. ReV. 1989, 89, 1563-79. (c) Maire, P.;
Blandin, V.; Lopez, M.; Vallee, Y. Synlett 2003, 5, 671-674. See also
references quoted therein.
(12) Parkin, E. T.; Trew, A.; Christie, G.; Faller, A.; Mayer, R.; Turner,
A. J.; Hooper, N. M. Biochemistry 2002, 41, 4972-4981.
(13) (a) Hsi, L. C.; Xi, X.; Lotan, R.; Shureiqi, I.; Lippman, S. M. Cancer
Res. 2004, 64, 8778-8781. (b) Gui, C. Y.; Ngo, L.; Xu, W. S.; Richon, V.
M.; Marks, P. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 1241-1246. (c)
Coussens, L. M.; Fingleton, B.; Matrisian, L. M. Science 2002, 295, 2387-
2392. (d) Jacobsen, F. E.; Lewis, J. A.; Cohen, S. M. J. Am. Chem. Soc.
2006, 128, 3156-3157. (e) Finnin, M. S.; Donigian, J. R.; Cohen, A.;
Richon, V. M.; Rifkind, R. A.; Marks, P. A.; Breslow, R.; Pavletich, N. P.
Nature (London) 1999, 401, 188-193.
(14) Ochiai, H.; Ohtani, T.; Ishida, A.; Kusumi, K.; Kato, M.; Kohno,
H.; Odagaki, Y.; Kishikawa, K.; Yamamoto, S.; Takeda, H.; Obata, T.;
Nakai, H.; Toda, M. Bioorg. Med. Chem. 2004, 12, 4645-4665.
(15) Hua, D. H.; Tamura, M.; Egi, M.; Werbovetz, K.; Delfin, D.; Salem,
M.; Chiang, P. K. Bioorg. Med. Chem. 2003, 11, 4357-4361.
(16) Polomoscanik, S. C.; Cannon, C. P.; Neenan, T. X.; Holmes-Farley,
S. R.; Mandeville, W. H.; Dhal, P. K. Biomacromolecules 2005, 6, 2946-
2953.
(18) (a) Humphrey, J. M.; Chamberlin, A. R. Chem. ReV. 1997, 97,
2243-2266. (b) Hamada, Y.; Shioiri, T. Chem. ReV. 2005, 105, 4441-
4482.
(17) Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew. Chem., Int. Ed.
2006, 45, 1248-1252.
526 J. Org. Chem., Vol. 72, No. 2, 2007

Oxidation of Peptides by Methyl(trifluoromethyl)dioxirane
TABLE 1. Oxidation of Boc-Protected Di- and Tripeptide Methyl Esters 2-6 by Methyl(trifluoromethyl)dioxirane
The reactions were routinely run at 0 °C, for 4 h; the solvent composition was CH2Cl2/1,1,1-trifluoropropanone (TFP). a Molar ratio of dioxirane oxidant
to substrate.
protected peptides into the terminal N-hydroxy derivatives in
good yields and offers a valid alternative to the previous
examples of synthesis of these compounds that require multistep
procedures. The typical procedures for the preparation of
terminal N-hydroxy peptides are coupling of an activated
protected N-hydroxy amino acid with a peptide,11a coupling of
an activated R-oximino acid with a peptide followed by
reduction and separation of the diastereomers,11a and synthesis
of the oxime from a suitable R-keto amide followed by reduction
and separation of the diastereomers.11c The easy access to the
terminal N-hydroxy peptides is likely to have a positive synthetic
impact because these compounds are valuable synthons in a
novel chemoselective amide ligation for the polypeptide syn-
thesis by coupling with a peptide ketoacid,17 and in the formation
of hydroxamates by reaction with an acyl chloride.11c
N-Hydroxy peptides are biologically interesting compounds
on their own because they are involved in metabolic transforma-
tions, as demonstrated by their occurrence in animal and human
tumors.11a,19 Since they exhibit iron complexation properties,
they have been adopted as antibacterial and antifungal agents
and have been explored in the treatment of tumors.11b,13
In order to test whether the interesting N-terminal hydroxy-
lation of peptides by TFD is unique for the Boc protection or
it is a rather general phenomenon with N-protected peptides,
we investigated the reactivity of some N-acetyl-protected amino
acid and dipeptide esters, bearing alkyl side chains, toward TFD.
We adopted the same conditions utilized for the oxidation of
(19) Moller, B. L. In Cyanide in Biology; Vennesland, B., Conn, E. E.,
Knowles, C. J., Wissing, F., Eds.; Academic: London, 1981; pp 197-215.
J. Org. Chem, Vol. 72, No. 2, 2007 527

Rella and Williard
TABLE 2. Oxidation of Acetyl-Protected Amino Acid and Dipeptide Methyl Esters 7-13 by Methyl(trifluoromethyl)dioxirane
The reactions were routinely run at 0 °C; the solvent composition was acetone/1,1,1-trifluoropropanone (TFP). a Molar ratio of dioxirane oxidant to
substrate. b Reaction time.
the Boc-protected peptide methyl esters in the oxidation of
acetylamino acid and dipeptide methyl esters (2.4 equiv, 0 °C)
for comparative reasons. Acetone was the cosolvent along with
1,1,1-trifluoroacetone in these reactions, rather than methylene
chloride, because some valine-containing substrates were more
soluble in acetone. Longer reaction times (5 h) were necessary
for full consumption of the oxidant. The results of the oxidation
of the selected acetyl-protected amino acid and dipeptide methyl
esters with methyl(trifluoromethyl)dioxirane are collected in
Table 2.
Under these conditions Ac-Leu-OMe (7) was converted to
the 4,4-dimethyl-4-butanolide derivative (7a) in 48% isolated
yield by reaction with 2.4 equiv of TFD (entry 1). Compound
7a is formed by O-insertion into the tertiary γ-CH bond of
leucine, followed by cyclization. Ac-Val-OMe (8) underwent
oxidation at the tertiary â-CH bond of valine in 14% isolated
yield (entry 2). The lower yield measured in the case of the
reaction of Ac-Val-OMe with TFD with respect to 7 can be
rationalized by considering the electronic deactivation, because
the amidic functionality is closer to the â-CH bond of valine,
relative to the γ position of leucine. This rationale holds for
the observed behavior of dimethyldioxirane in the reaction with
Boc-Leu-OMe and Boc-Val-OMe, where it is reported that with
Boc-Leu-OMe, the 4,4-dimethyl-4-butanolide derivative was
produced, whereas Boc-Val-OMe did not react with DMD.8
The oxidation products of N-Ac-Leu-Ala-OMe (9) and N-Ac-
Ala-Leu-OMe (10) were N-Ac-Leu(γ-OH)-Ala-OMe (9a) (54%
isolated yield) and N-Ac-Ala-2-amino-4,4-dimethyl-4-butanolide
(10a) (36% isolated yield), respectively (entries 3 and 4). The
â-CH bond of valine in Ac-Val-Ala-OMe (11) reacted to a lower
extent, as in the simpler case 8, N-Ac-Val(â-OH)-Ala-OMe
(11a) being produced in 12% yield (entry 5). N-Ac-Leu-Val-
528 J. Org. Chem., Vol. 72, No. 2, 2007

Oxidation of Peptides by Methyl(trifluoromethyl)dioxirane
OMe (12) and N-Ac-Val-Leu-OMe (13) were transformed into
N-Ac-Leu(γ-OH)-Val-OMe (12a) (48% isolated yield) and
N-Ac-Val-2-amino-4,4-dimethyl-4-butanolide (13a) (36% iso-
lated yield), respectively (entries 6 and 7).
It is well-established that dioxiranes 1a,b are able to oxidize
amines and N-heteroarenes. The mechanism of the oxidation
of the nitrogen atom is still controversial. Ab initio calculations21
indicate that the O-transfer of DMD to primary amines has
purely electrophilic character, and experimental evidence22
supports an SN2 mechanism in the nitrogen lone pair oxidation
of N-heteroarenes by 1a. Dimethyldioxirane is incapable to
transfer oxygen to the nitrogen of unconstrained carbamates and
amides. Our observations attest to the fact that methyl(trifluoro-
methyl)dioxirane is able to hydroxylate secondary carbamic
nitrogen atoms but not the unconstrained amidic nitrogen atoms.
Although carbamates are structurally similar to amides, they
present different physicochemical features, due to the steric and
electronic perturbations introduced by the additional oxygen of
the carbamates. NMR studies and theoretical calculations23
reveal that the barriers to rotation in carbamates are typically
3-4 kcal/mol lower than in structurally related amides (∼20
kcal/mol). The effect of the additional oxygen in carbamates,
eventually as competitor of the nitrogen in conjugation with
the carbonyl, can be seen in the solid state as well. A nonplanar
distortion (( 9o to 11o)24 of the amidic moiety of carbamates is
appreciably higher than the torsion angle ω typically found in
the amidic bonds of peptides. Accordingly, the amide C-N bond
of carbamates is ∼0.03 Å longer than a C-N bond on the amide
in a planar arrangement (∼1.32 Å).24a
We observed a trend in the oxidation of the two couples of
dipeptides containing leucine: when the leucine is the C-
terminal residue (cf., N-Ac-Ala-Leu-OMe and N-Ac-Val-Leu-
OMe), the O-insertion into the tertiary γ-CH occurs to a lower
extent than in the case when leucine is the N-teminal residue
(cf., N-Ac-Leu-Ala-OMe and N-Ac-Leu-Val-OMe). This trend
can be rationalized considering that dioxiranes are sensitive to
the surrounding stereoelectronic environment of the reactive
site.4c NOESY NMR experiments in acetone-d6 at 0 °C were
carried out on one of the two couples of peptides incorporating
N-terminal leucine and C-terminal leucine respectively, 12 and
13. The choice of the solvent and the temperature in the 2D
NOE experiments reflected the conditions adopted during the
reactions of N-Ac-Leu-Val-OMe and N-Ac-Val-Leu-OMe with
TFD. The aim of these NMR investigations was to determine
whether structural features of the substrates in solution might
facilitate (in the case of 12) and/or obstruct (in the case of 13)
the approach of the oxidant to the tertiary γ-CH bond of the
leucine fragment. NOESY spectra are presented in the Sup-
porting Information, supporting this explanation.
NOE experiments reveal the presence of a more dense
network of NOE effects involving the γ-H atom of the leucine
fragment in the case of N-Ac-Val-Leu-OMe in respect to N-Ac-
Leu-Val-OMe. This observation suggests a more crowded
environment surrounding the reactive site of leucine, when
leucine is not the N-terminal residue. This steric factor might
account for the lower reactivity exhibited by the tertiary γ-CH
bond of the leucine in N-Ac-Val-Leu-OMe with respect to N-Ac-
Leu-Val-OMe.
As a complement to the NMR studies, molecular mechanics
calculations (MMX, PCMODEL) were carried out on 12 and
13, without using any conformational constraints. The lower
energy conformations of N-Ac-Leu-Val-OMe and N-Ac-Val-
Leu-OMe (see the Supporting Information) are in agreement
with the 2D NOE correlations for the γ-H atom of the leucine
obtained experimentally and show the presence of one intramo-
lecular hydrogen bond in both compounds. The specific in-
tramolecular hydrogen bonds in the structures of N-Ac-Leu-
Val-OMe and N-Ac-Val-Leu-OMe predicted by the MMX
calculations are in agreement with acid-catalyzed hydrogen/
deuterium (H/D) exchange experiments,20 carried out at 0 °C
by shaking the solution of compounds 12 and 13 in acetone-d6
with solution of TFA in D2O (for the experimental details, see
the Supporting Information).
We attempted to improve the yields of the synthetically more
promising substrates (7, 8, 9, 11, 12) by using 5 equiv of
dioxirane 1b. Ac-Leu-OMe (7) was oxidized to 7a in 82%
isolated yield in 6 h of reaction. Ac-Val-OMe (8) and Ac-Val-
Ala-OMe (11) were converted to 8a and 11a in 44% and 29%
isolated yield, respectively, in 7 h of reaction. N-Ac-Leu-Ala-
OMe (9) and N-Ac-Leu-Val-OMe (12) underwent oxidation in
6 h producing 9a and 12a in 73% and 60% isolated yield,
respectively. In general TFD oxidizes the acetyl-protected amino
acid and dipeptide methyl esters 7-13 exclusively at the tertiary
CH bond of the aliphatic side chains, leaving the terminal
protected nitrogen unaffected.
If we propose an SN2 mechanism22 for the nitrogen lone pair
of carbamate oxidation by the dioxirane TFD, the higher
conformational flexibility exerted by the carbamate functionality
with respect to the amidic functionality can be accounted for
by the ability of TFD to transfer oxygen to the lone pair of the
carbamic, but not of the amidic, nitrogen. It is reasonable to
assume that an increase in conformational flexibility might have
as a consequence an increase in the nucleophilic character of
the lone pair of nitrogen of the N-terminal residue in the Boc-
protected peptides in respect to the acetyl-protected peptides.
Conclusions
The chemoselectivity of TFD in the oxidation of protected
peptides is dictated by the protecting group of the N-terminal
residue of the peptides. Hydroxylation of the terminal nitrogen
atom in Boc-protected di- and tripeptide methyl esters bearing
alkyl side chains can be obtained in good yields by oxidation
of the corresponding Boc-protected peptides with methyl-
(trifluoromethyl)dioxirane in short reaction times and with
remarkably mild reaction conditions. This is a synthetically
useful transformation since N-hydroxy peptides are important
synthons in the preparation of biologically active molecules.11,17
N-Acetyl-protected amino acid and dipeptide methyl esters
bearing alkyl side chains undergo exclusively high regioselective
side chain hydroxylation when they react with TFD. The tertiary
γ-CH bond of the leucine residue displays higher reactivity in
comparison to the tertiary â-CH bond of the valine residue.
Furthermore, if leucine is one of the two components of N-acetyl
(21) Miaskiewicz, K.; Teich, N. A.; Smith, D. A. J. Org. Chem. 1997,
62, 6493-6497.
(22) Adam, W.; Golsch, D. Angew. Chem., Int. Ed. 1993, 32, 737-739.
(23) Kaur, D.; Sharma, P.; Bharatam, P. V. THEOCHEM 2005, 757,
149-153 and notes 11-18 therein.
(24) (a) Ganis, P.; Avitabile, G.; Migdal, S.; Goodman, M. J. Am. Chem.
Soc. 1971, 93, 3328-3331. (b) Oku, H.; Yamada, K.; Kataka, R. Acta
Crystallogr. 2003, E59, o1581-o1583. (c) Thirumuruhan, R. A.; Malathy
Sony, S. M.; Shanmugam, G.; Ponnuswamy, M. N. Mol. Cryst. Liq. Cryst.
2004, 414, 39-48.
(20) Rezai, T.; Yu, B.; Millhauser, G. L.; Jacobson, M. P.; Lokey, R. S.
J. Am. Chem. Soc. 2006, 128, 2510-2511.
J. Org. Chem, Vol. 72, No. 2, 2007 529

Rella and Williard
Ala2,3-CRH), 4.15 (d, 1 H, J ) 9.6 Hz, Val-CRH), 3.74 (s, 3 H,
OCH3), 2.38 (m, 1 H, Val-CâH), 1.48 (s, 9 H, Boc-CH3), 1.40 (d,
6 H, J ) 7.1 Hz, two Ala-CH3), 1.01 (m, 6 H, Val-Cγ,γ′H3); 13C
NMR (CDCl3, 100 MHz) δ 173.1 (C), 171.4 (C), 171.3 (C), 156.7
(C), 82.5 (Boc-C), 67.8 (Val-CRH), 52.5 (OCH3), 48.7 (Ala2,3-CRH),
48.1 (Ala3,2-CRH), 28.25 (Val-CâH), 28.22 (Boc-CH3), 19.5 and
19.4 (Val-Cγ,γ′H3), 18.1 (two Ala-CH3); HRMS-FAB (M + Na+)
calculated for C17H31NaN3O7 412.2060, found 412.2070.
N-Hydroxy-N-tert-butoxycarbonyl-alanylleucine methyl ester
(5a): 83.8% substrate conversion, 75.4% yield based on the
recovered starting material, 63.2% isolated yield; 1H NMR (acetone-
d6, 400 MHz) δ 8.07 (s, 1 H, Ala-NOH), 7.25 (m, 1 H, Leu-NH),
4.63 (p, 1 H, J ) 7.1 Hz, Ala-CRH), 4.54 (m, 1 H, Leu-CRH), 3.68
(s, 3 H, OCH3), 1.78-1.50 (m, 3 H, Leu-CH2 and Leu-CγH), 1.45
(s, 9 H, Boc-CH3), 1.40 (d, 3 H, J ) 7.1 Hz, Ala-CH3), 0.91 (m,
6 H, Leu-Cδ,δ′H3); 13C NMR (acetone-d6, 100 MHz) δ 174.6
(C), 173.3 (C), 158.8 (C), 82.6 (Boc-C), 59.8 (Ala-CRH), 53.3
(OCH3), 52.2 (Leu-CRH), 42.7 (Leu-CH2), 29.3 (Boc-CH3), 26.3
(Leu-CγH), 24.2 and 22.9 (Leu-Cδ,δ′H3), 15.2 (Ala-CH3); HRMS-
FAB (M + Na+) calculated for C15H28NaN2O6 355.1845, found
355.1852.
N-Hydroxy-N-tert-butoxycarbonyl-ambo-leucyl-ambo-ala-
nine methyl ester (6a): for the oxidation of 6 with 2.4 equiv of
TFD: 85.4% substrate conversion, 53.8% yield based on the
recovered starting material, 46.0% isolated yield; for the oxidation
of 6 with 1.2 equiv of TFD: 50.4% substrate conversion, 49.3%
yield based on the recovered starting material, 24.8% isolated yield;
1H NMR (acetone-d6, 400 MHz) δ 8.08 (br s, 1 H, Leu-NOH),
7.41 (m, 1 H, Ala-NH), 4.65 (m, 1 H, Leu-CRH), 4.45 (p, 1 H, J )
7.2 Hz, Ala-CRH), 3.68 (s, 3 H, OCH3), 1.92 and 1.63 (two m, 2
H, Leu-CH2), 1.68 (m, 1 H, Leu-CγH), 1.46 (s, 9 H, Boc-CH3),
1.35 (d, 3 H, J ) 7.2 Hz, Ala-CH3), 0.93 (m, 6 H, Leu-Cδ,δ′H3);
13C NMR (acetone-d6, 100 MHz) δ 174.6 (C), 173.3 (C), 158.7
(C), 82.4 (Boc-C), 62.0 (Leu-CRH), 53.4 (OCH3), 49.7 (Ala-CRH),
38.9 (Leu-CH2), 29.4 (Boc-CH3), 26.4 (Leu-CγH), 24.7 and 22.5
(Leu-Cδ,δ′H3), 18.9 (Ala-CH3); HRMS-FAB (M + Na+) calculated
for C15H28NaN2O6 355.1845, found 355.1848.
dipeptide methyl esters, the γ position of leucine is hydroxylated
more effectively when it is the N-terminal residue of the
dipeptides.
These findings provide easy access to side chain modifications
of linear peptides containing only amidic nitrogen atoms and
of cyclic peptides and depsipeptides, leaving intact the back-
bone structure. We are currently working on selective side
chain modifications by TFD of cyclic peptides of biological
relevance.
Experimental Section
Acetyl-protected amino acid methyl esters were obtained from
the corresponding amino acids. tert-Butoxycarbonyl and acetyl di-
and tripeptide methyl esters were prepared by protecting the
commercially available dipeptides or following coupling procedures
in solution.25 Solutions of TFD 1b (0.4-0.5 N) in 1,1,1-trifluoro-
acetone were isolated according to the procedure described by
Curci.3 The procedure described for the oxidation of 2 is representa-
tive for oxidations of substrates 3-6 using 2.4 equiv of TFD, unless
differently specified.
N-Hydroxy-N-tert-butoxycarbonyl-alanylalanine methyl ester
(2a): A standardized solution of TFD (1b) in 1,1,1-trifluoropro-
panone (TFP) (0.86 mL, 0.4 M, 3.4 × 10-4 mol) was added in one
portion to a stirred solution of N-Boc-Ala-Ala-OMe (2) (0.0393,
1.43 × 10-4 mol) in CH2Cl2 (0.5 mL) at 0 °C. The progress of the
reaction was monitored by TLC (1:1:1 hexanes/Et2O/acetone;
detection phosphomolybdic acid, PMA). After 4 h of reaction time,
the solvent was removed by rotary evaporation. N-Hydroxy-N-tert-
butoxycarbonyl-alanylalanine methyl ester (2a) (0.0326 g, 1.12 ×
10-4 mol) was isolated by flash chromatography (1:1:1 hexanes/
Et2O/acetone) in 78.3% isolated yield as white solid; 78.3% yield
based on the recovered starting material; 95.0% substrate conver-
sion; 1H NMR (acetone-d6, 400 MHz) δ 8.12 (s, 1 H, Ala1-NOH),
7.32 (m, 1 H, Ala2-NH), 4.63 (q, 1 H, J ) 7.1 Hz, Ala1-CRH),
4.46 (p, 1 H, J ) 7.3 Hz, Ala2-CRH), 3.68 (s, 3 H, OCH3), 1.45 (s,
9 H, Boc-CH3), 1.37 (m, 6 H, Ala1,2-CH3); 13C NMR (acetone-d6,
75 MHz) δ 174.7 (C), 172.8 (C), 158.8 (C), 82.6 (Boc-C), 59.7
(Ala1-CRH), 53.4 (OCH3), 49.7 (Ala2-CRH), 29.2 (Boc-CH3), 18.9
and 14.9 (Ala1,2-CH3); HRMS-FAB (M + Na+) calculated for
C12H22NaN2O6 313.1376, found 313.1384.
N-Hydroxy-N-tert-butoxycarbonyl-valinylalanine methyl ester
(3a): 86.0% substrate conversion, 93.7% yield based on the
recovered starting material, 80.6% isolated yield; 1H NMR (CDCl3,
400 MHz) δ 7.82 (s, 1 H, Val-NOH), 6.94 (d, 1 H, J ) 7.3 Hz,
Ala-NH), 4.56 (p, 1 H, J ) 7.2 Hz, Ala-CRH), 4.14 (d, 1 H, J )
9.6 Hz, Val-CRH), 3.72 (s, 3 H, OCH3), 2.36 (m, 1 H, J ) 9.5 Hz,
J′ ) 6.7 Hz, Val-CâH), 1.46 (s, 9 H, Boc-CH3), 1.40 (d, 3 H, J )
7.2 Hz, Ala-CH3), 1.02 (m, 6 H, Val-Cγ,γ′H3); 13C NMR (CDCl3,
100 MHz) δ 172.9 (C), 171.0 (C), 157.0 (C), 82.5 (Boc-C), 67.8
(Val-CRH), 52.4 (OCH3), 47.9 (Ala-CRH), 28.21 and 28.18 (Val-
CâH and Boc-CH3), 19.6 and 19.2 (Val-Cγ,γ′H3), 18.0 (Ala-CH3);
HRMS-FAB (M + Na+) calculated for C14H26NaN2O6 341.1689,
found 341.1695.
N-Hydroxy-N-tert-butoxycarbonyl-valinylalanylalanine meth-
yl ester (4a): 77.5% substrate conversion, 91.4% yield based on
the recovered starting material, 70.8% isolated yield; 1H
NMR (CDCl3, 400 MHz) δ 7.31 (s, 1 H, Val-NOH), 6.84 (d, 1 H,
J ) 7.4 Hz, Ala2,3-NH), 6.73 (d, 1 H, J ) 7.3 Hz, Ala3,2-NH),
4.55 (p, 1 H, J ) 7.3 Hz, Ala3,2-CRH), 4.52 (p, 1 H, J ) 7.2 Hz,
N-tert-Butoxycarbonyl-ambo-γ-hydroxyleucyl-ambo-alanine
methyl ester (6b): for the oxidation of 6 with 2.4 equiv of TFD:
85.4% substrate conversion, 12.3% yield based on the recovered
starting material, 10.5% isolated yield; for the oxidation of 6 with
1.2 equiv of TFD: 50.4% substrate conversion, 24.7% yield based
1
on the recovered starting material, 12.5% isolated yield; H NMR
(CDCl3, 400 MHz) δ 7.03 and 6.98 (two br d, 1 H, J ) 7.2 Hz,
Ala-NH), 5.71 and 5.65 (two br d, 1 H, J ) 6.5 Hz, Leu-NH),
4.59 (p, 1 H, J ) 7.3 Hz, Ala-CRH), 4.29 (m, 1 H, Leu-CRH), 3.74
(s, 3 H, OCH3), 2.04 and 1.79 (two m, 2 H, Leu-CH2), 1.47 (s, 9
H, Boc-CH3), 1.43 and 1.42 (two d, 3 H, J ) 7.2 Hz, Ala-CH3),
1.32 (m, 6 H, Leu-Cδ,δ′H3); 13C NMR (CDCl3, 100 MHz) δ 173.3
and 173.2 (C), 172.4 (C), 155.9 and 155.8 (C), 80.3 (Boc-C), 70.4
(Leu-CγOH), 52.5 and 52.4 (OCH3), 51.9 (Leu-CRH), 48.1 and
48.0 (Ala-CRH), 44.9 (Leu-CH2), 29.7 (Leu-Cδ,δ′H3), 28.3
(Boc-CH3), 18.2 (Ala-CH3); HRMS-FAB (M + Na+) calculated
for C15H28NaN2O6 355.1845, found 355.1850.
N-Hydroxy-N-tert-butoxycarbonyl-ambo-γ-hydroxyleucyl-
ambo-alanine methyl ester (6c): for the oxidation of 6 with 2.4
equiv of TFD: 85.4% substrate conversion, 17.3% yield based on
the recovered starting material, 14.8% isolated yield; for the
oxidation of 6 with 1.2 equiv of TFD: 50.4% substrate conversion,
10.8% yield based on the recovered starting material, 5.4% isolated
1
yield; H NMR (CDCl3, 400 MHz) δ 7.61 (br s, 1 H, Leu-NOH),
7.12 (d, 1 H, J ) 7.0 Hz, Ala-NH), 4.81 (m, 1 H, Leu-CRH), 4.57
(p, 1 H, J ) 7.3 Hz, Ala-CRH), 3.75 (s, 3 H, OCH3), 2.14 (d, 2 H,
J ) 7.2 Hz, Leu-CH2), 1.50 (s, 9 H, Boc-CH3), 1.42 (d, 3 H, J )
(25) For a general procedure, see: (a) Garner, P.; Park, J. M. Org. Synth.
1992, 70, 18-27. (b) Bodanszky, M.; Bodanszky, A. The Practice of Peptide
Synthesis; Springer-Verlag: New York, 1984; pp 103-104. (c) Zielinski,
T.; Achmatowicz, M.; Jurczak, J. Tetrahedron: Asymmetry 2002, 13, 2053-
2059. (d) Bretschneiter, T.; Miltz, W.; Munster, P.; Steglich, W. Tetrahedron
1988, 44, 5403-5414. (e) Reddy, A. V.; Ravindranath, B. Synth. Commun.
1992, 22, 257-264. (f) Sprout, C. M; Seto, C. T. J. Org. Chem. 2003, 68,
7788-7794.
7.2 Hz, Ala-CH3), 1.34 and 1.33 (two br s, 6 H, Leu-Cδ,δ′H3); 13
C
NMR (CDCl3, 100 MHz) δ 173.2 and 173.0 (C), 171.7 and 171.5
(C), 156.4 and 156.3 (C), 82.6 and 82.5 (Boc-C), 70.4 (Leu-Cγ-
OH), 59.4 (Leu-CRH), 52.5 and 52.4 (OCH3), 48.1 (Ala-CRH), 40.0
(Leu-CH2), 31.2 and 31.0 (Leu-Cδ,δ′H3), 28.3 and 28.2 (Boc-CH3),
530 J. Org. Chem., Vol. 72, No. 2, 2007

Oxidation of Peptides by Methyl(trifluoromethyl)dioxirane
18.1 (Ala-CH3); HRMS-FAB (M + Na+) calculated for C15H28-
NaN2O7 371.1794, found 371.1780.
The procedure described for the oxidation of 7 is representative
for oxidations of substrates 8-13 using 2.4 equiv of TFD, unless
differently specified.
2-(Acetylamino)-4,4-dimethyl-4-butanolide (7a): A standard-
ized solution of TFD (1b) in 1,1,1-trifluoropropanone (TFP) (3.50
mL, 0.4 M, 1.41 × 10-3 mol) was added in one portion to a stirred
solution of Ac-Leu-OMe (7) (0.1099 g, 5.870 × 10-4 mol) in
acetone (1 mL) at 0 °C. The reaction progress was monitored by
TLC (1:1:1 hexanes/Et2O/acetone; detection PMA). After 5 h of
reaction time, the solvent was removed by rotary evaporation.
2-(Acetylamino)-4,4-dimethyl-4-butanolide (2a) (0.0484 g, 2.83 ×
10-4 mol) was isolated by flash chromatography (1:1:1 hexanes/
Et2O/acetone) in 48.2% yield as white solid.
(C), 82.5 (C4), 50.3 (C2H), 48.6 (Ala-CRH), 41.1 (CH2), 28.8 and
27.2 (two CH3), 23.1 (C(O)CH3), 18.1 (Ala-CH3); HRMS-FAB (M
+ Na+) calculated for C11H18NaN2O4 265.1164, found 265.1170.
N-acetyl-ambo-â-hydroxyvalyl-ambo-alanine methyl ester (11a):
For the oxidation of 11 with 2.4 equiv of TFD: 34.4% substrate
conversion, 35.9% yield based on the recovered starting material,
12.3% isolated yield; for the oxidation of 11 with 5.0 equiv of
TFD: 42.0% substrate conversion, 68.1% yield based on the
recovered starting material, 28.6% isolated yield; 1H NMR (CDCl3,
400 MHz) δ 7.11 and 6.93 (two d, 1 H, J ) 6.5 Hz, Ala-NH), 6.50
(d, 1 H, J ) 7.3 Hz, Val-NH), 4.51 (m, 1 H, Ala-CRH), 4.30 (m,
1 H, Val-CRH), 3.75 and 3.74 (two s, 3 H, OCH3), 2.06 and 2.04
(two s, 3 H, C(O)CH3), 1.42 (m, 3 H, Ala-CH3), 1.33 and 1.18
(two s, 6 H, Val-Cγ,γ′H3); 13C NMR (CDCl3, 100 MHz) δ 172.8
and 172.5 (C), 171.5 and 171.2 (C), 170.9 and 170.5 (C), 71.8 and
71.4 (Val-CâOH), 58.7 and 58.3 (Val-CRH), 52.6 (OCH3), 48.1 (Ala-
CRH), 27.3, 27.2, 25.7 and 25.3 (Val-Cγ,γ′H3), 23.1 and 23.0 (C(O)-
CH3), 17.8 and 17.6 (Ala-CH3); HRMS-FAB (M + Na+) calculated
for C11H20NaN2O5 283.1270, found 283.1275.
2-(Acetylamino)-4,4-dimethyl-4-butanolide (7a): for the oxida-
tion of 7 with 2.4 equiv of TFD: 48.2% isolated yield; for the
oxidation of 7 with 5.0 equiv of TFD: 95.0% substrate conversion,
82.3% yield based on the recovered starting material, 82.3% isolated
1
yield; H NMR (CDCl3, 400 MHz) δ 7.15 (d, 1 H, J ) 7.3 Hz,
N-Acetyl-γ-hydroxyleucylvaline methyl ester (12a): for the
oxidation of 12 with 2.4 equiv of TFD: 48.2% isolated yield; for
the oxidation of 12 with 5.0 equiv of TFD: 95.0% substrate
conversion, 59.7% yield based on the recovered starting material,
59.7% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 7.36 (d, 1 H,
J ) 8.6 Hz, Val-NH), 6.88 (d, 1 H, J ) 6.7 Hz, Leu-NH), 4.62 (q,
1 H, J ) 6.4 Hz, Leu-CRH), 4.45 (m, 1 H, Val-CRH), 3.72 (s, 3 H,
OCH3), 2.17 (m, 1 H, Val-CâH), 2.05 and 1.81 (two m, 2 H, Leu-
CH2), 2.00 (s, 3 H, C(O)CH3), 1.33 and 1.28 (two s, 6 H, Leu-
NH), 4.75 (m, 1 H, CH), 2.45 and 1.94 (two m, 2H, CH2), 1.93 (s,
3 H, C(O)CH3), 1.40 and 1.34 (two s, 6 H, two CH3); 13C NMR
(CDCl3, 100 MHz) δ 175.0 (C), 170.6 (C), 82.4 (C4), 49.7 (CH),
41.1 (CH2), 28.6 and 26.8 (two CH3), 22.5 (C(O)CH3); HRMS-
FAB (M + Na+) calculated for C8H13NaNO3 194.0793, found
194.0796.
N-Acetyl-â-hydroxyvaline methyl ester (8a): for the oxidation
of 8 with 2.4 equiv of TFD: 49.8% substrate conversion, 29.0%
yield based on the recovered starting material, 14.4% isolated yield;
for the oxidation of 8 with 5.0 equiv of TFD: 60.0% substrate
conversion, 73.0% yield based on the recovered starting material,
43.8% isolated yield; 1H NMR (CDCl3, 300 MHz) δ 6.38 (m, 1 H,
NH), 4.52 (d, 1 H, J ) 8.8, CRH), 3.77 (s, 3 H, OCH3), 2.05 (s, 3
H, C(O)CH3), 1.26 and 1.25 (two s, 6 H, Cγ,γ′H3); 13C NMR (CDCl3,
100 MHz) δ 172.2 (C), 170.4 (C), 71.8 (CâOH), 59.7 (CRH), 52.3
(OCH3), 26.8 and 26.5 (Cγ,γ’H3) 23.1 (C(O)CH3); HRMS-FAB (M
+ Na+) calculated for C8H15NaNO4 212.0899, found 212.0891.
N-Acetyl-ambo-γ-hydroxyleucyl-ambo-alanine methyl ester
(9a): for the oxidation of 9 with 2.4 equiv of TFD: 69.6% substrate
conversion, 77.0% yield based on the recovered starting material,
53.6% isolated yield; for the oxidation of 9 with 5.0 equiv of
TFD: 95.0% substrate conversion, 72.6% yield based on the
recovered starting material, 72.6% isolated yield; 1H NMR (CDCl3,
300 MHz) δ 7.41 (d, 1 H, J ) 7.1 Hz, Ala-NH), 6.90 (m, 1 H,
Leu-NH), 4.61 (m, 1 H, Leu-CRH), 4.50 (p, 1 H, J ) 7.3 Hz, Ala-
CRH), 3.73 and 3.72 (two s, 3 H, OCH3), 2.07 - 2.02 and 1.87 -
1.76 (m, 2 H, Leu-CH2), 2.01 and 2.00 (two s, 3 H, C(O)CH3),
1.39 (d, 3 H, J ) 7.2 Hz, Ala-CH3), 1.28 (m, 6 H, Leu-Cδ,δ′H3);
13C NMR (CDCl3, 75 MHz) δ 173.3 and 173.2 (C), 172.1 and 172.0
(C), 170.8 and 170.5 (C), 70.2 (Leu-CγOH), 52.5 (OCH3), 50.6
and 50.4 (Leu-CRH), 48.2 (Ala-CRH), 45.1 and 44.4 (Leu-CH2),
30.3, 30.0, 29.9 and 29.6 (Leu-Cδ,δ′H3), 23.2 (C(O)CH3), 17.8 (Ala-
CH3); HRMS-FAB (M + Na+) calculated for C12H22NaN2O5
297.1426, found 297.1435.
Cδ,δ′H3), 0.92 and 0.88 (two d, 6 H, J ) 6.9 Hz, Val-Cγ,γ′H3); 13
C
NMR (CDCl3, 100 MHz) δ 172.6 (C), 172.4 (C), 170.4 (C), 70.3
(Leu-CγOH), 57.4 (Val-CRH), 52.2 (OCH3), 50.4 (Leu-CRH), 45.1
(Leu-CH2), 30.7 (Val-CâH), 30.4 and 29.6 (Leu-Cδ,δ′H3), 23.2
(C(O)CH3), 19.0 and 17.6 (Val-Cγ,γ′H3); HRMS-FAB (M + Na+)
calculated for C14H26NaN2O5 325.1739, found 325.1728.
2-(N-acetyl-valinylamino)-4,4-dimethyl-4-butanolide (13a):
51.5% substrate conversion, 69.9% yield based on the recovered
starting material, 36.0% isolated yield; 1H NMR (CDCl3, 400 MHz)
δ 7.63 (d, 1 H, J ) 7.3 Hz, C2NH), 6.60 (d, 1 H, J ) 8.9 Hz,
Val-NH), 4.76 (m, 1 H, C2H), 4.38 (m, 1 H, Val-CRH), 2.51 and
2.07 (two m, 3 H, CH2 and Val-CâH), 2.00 (s, 3 H, C(O)CH3),
1.49 and 1.42 (two s, 6 H, CH3), 0.98 and 0.95 (two d, 6 H, J )
6.8, Val-Cγ,γ′H3), 13C NMR (CDCl3, 100 MHz) δ 174.1 (C), 172.0
(C), 170.4 (C), 82.2 (C4), 58.2 (Val-CRH), 50.0 (C2H), 41.0 (CH2),
31.3 (Val-CâH), 28.8 and 27.1 (two CH3), 23.1 (C(O)CH3), 19.1
and 18.4 (Val-Cγ,γ′H3), HRMS-FAB (M + Na+) calculated for
C13H22NaN2O4 293.1477, found 293.1479.
Acknowledgment. We thank Prof. Ruggero Curci (Univer-
sita` degli Studi di Bari, Bari, Italy) for the very useful
discussions, Dr. Tun-Li Shen (Brown University, Providence,
RI) for performing the high-resolution mass analysis and Dr.
Russell Hopson (Brown University) for the help in setting up
the low-temperature NOESY experiments and the molecular
mechanic calculations. This work was supported by NIH grant
GM-35982.
2-(N-Acetyl-alanylamino)-4,4-dimethyl-4-butanolide (10a):
65.5% substrate conversion, 54.3% yield based on the recovered
starting material, 35.6% isolated yield; 1H NMR (CDCl3, 300 MHz)
δ 7.37 (d, 1 H, J ) 6.9 Hz, C2NH), 6.48 (d, 1 H, J ) 7.3 Hz,
Ala-NH), 4.67 (m, 1 H, C2H), 4.53 (p, 1 H, J ) 7.1 Hz, Ala-CRH),
2.54 and 2.11 (two m, 2 H, CH2), 2.00 (s, 3 H, C(O)CH3), 1.50
and 1.42 (two s, 6 H, two CH3) 1.38 (d, 3 H, J ) 7.0 Hz, Ala-
CH3); 13C NMR (CDCl3, 100 MHz) δ 174.2 (C), 172.9 (C), 170.4
Supporting Information Available: Experimental details and
supplemental characterization data of starting materials and the
oxidation products. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO061910N
J. Org. Chem, Vol. 72, No. 2, 2007 531