Oxidation-induced Acyl group transfer from hydroquinone esters to nucleophiles

Article abstract of DOI:10.1515/znb-1998-0717

Bivalent oxidation of 3,5-di-tert-butyl-hydroquinone monoesters leads to phenoxenium ions, which can transfer an acyl group to nucleophiles. Based on this principle, dipeptides, glyco-amino acids and N-sulfonyl-amino acids were synthesized from hydroquino

Full text of DOI:10.1515/znb-1998-0717

Oxidation-Induced Acyl Group Transfer
from Hydroquinone Esters to Nucleophiles
G erald Reischl3, M edhat El-M obayeda, Rudolf Beißwenger3, Klaus Regier3,
Cäcilia Maichle-Mössmerb, Anton Rieker*-3
a Institute of Organic Chemistry, University of Tübingen, Auf der M orgenstelle 18,
D-72076 Tübingen
b Institute of Inorganic Chemistry, University of Tübingen, A uf der M orgenstelle 18,
D-72076 Tübingen
Z. Naturforsch. 53b, 765-773 (1998); received April 17, 1998
Acyl Group Transfer, Hydroquinone Esters, Oxidation, Dipeptides, A ctive Esters
Bivalent oxidation of 3,5-di-terr-butyl-hydroquinone m onoesters leads to phenoxenium
ions, which can transfer an acyl group to nucleophiles. Based on this principle, dipeptides,
glyco-am ino acids and Af-sulfonyl-amino acids were synthesized from hydroquinone esters of
amino acids and p-toluenesulfonic acid. For this reaction, direct anodic and indirect mediated
oxidation, as well as chemical oxidation with NBS or trisarylammoniumyl salts, was used. The
mechanism of the acyl transfer is discussed in terms of a direct and/or a m ediated process.
A
spirocyclic key intermediate was isolated and its m olecular structure determ ined by X-
ray crystallography.
Introduction
If the substituent in the /w a-position of the
phenoxenium ion is an O-acyl substituent (O -R 1,
R 1 = Acyl, structure A in Scheme 1), one would
again expect addition of nucleophiles at the para-
position of the phenoxenium ion to give quinol
derivatives B. However, there is now also a reso-
nance structure with the positive charge at the acyl
ether oxygen (Ac), in other words, the cation spe-
cies reveals a phenoxenium/carbenium/quinoxo-
For the anodic oxidation of sterically hindered
phenols two selective pathways are possible [1,2],
either a CE process (one-electron oxidation) to
the phenoxy radical or an ECE process (two-elec-
tron oxidation) to the phenoxenium ion (C: chemi-
cal step, E: electrochemical step), tert-Butyl groups
ortho to the hydroxy group prevent undesired re-
actions (e.g. dimerization) and stabilize the inter-
mediates of higher oxidation states. The ECE pro-
cess occurs under neutral conditions, where the
phenol is present in undissociated form. H ere, the
phenol is first oxidized at high potentials (1.0-1.5
V)* to the cation radical. This species is very acidic
and deprotonates to the neutral phenoxy radical,
which is immediately further oxidized at the ap-
plied high potential to give selectively the phenox-
enium ion. The latter ion adds many types of nu-
cleophiles NuH, (e.g. ROH, RCO O H , A rO H ,
H 2N R etc.) preferentially in the para-position to
give quinol derivatives in yields of 50-97% [3].
nium ion charge distribution (Aa
Ab
Ac). In
the quinoxonium ion resonance structure, a qui-
none is “preform ed”, and if a heterolytic cleavage
of the R '-bond occurs, the quinone C and an acyl-
cation D would be formed. This acyl-cation D, in-
stead of the phenoxenium ion, could now react
with the nucleophile to give an acylated nucleo-
phile F and a proton via the adduct E. This trans-
form ation would not necessarily have to proceed
via a free acyl cation, one could also think of an
incipient cation, being formed during the en-
counter of the quinoxonium ion and the nucleo-
phile with a simultaneous cleavage of the qui-
none moiety.
Johnson et al. [4], had reported reactions in
which acyl groups were formally transferred to
w ater or m onofunctional alcohols on oxidation of
mono-acylated hydroquinones or aminophenols.
O ur idea was to employ hydroquinone esters of
/V-protected amino acids as substrates for the oxi-
*
A ll potentials in this publication refer to the A g/A g+
electrode (Ag/0.01 N A g+ in CH3CN).
*
Reprint requests to Prof. Dr. A. Rieker.
D
0932-0776/98/0700-0765 $06.00 © 1998 Verlag der Zeitschrift für Naturforschung. All rights reserved.
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766
G. Reischl et al. ■Oxidation-Induced Acyl Group Transfer from Hydroquinone Esters
OH
-20 to -10 °C
-Isobutene
R2
I
0 —C—C—NHCbz
O—C -C -N H C b z
II
I
O R3
O R3
2a R2 = R3= H(GIy)
b
c
R2 = H; R3= CH3 (Ala)
R2 = R3 =CH3(Aib)
Zeolite, 60 °C
R2
O - C - C —NHCbz
+ NuH
[R -NuH]"*
E
+
HOOC—C-NHCbz
O
R3
i
R3
3 (R2 = H, R3 = CH3)
R'-Nu + H+
F
Scheme 1
B u'^ / k
.O - C —C—NHCbz
II
L
O
R3
dation. In this way, aminoacyl groups should be
transferable to nucleophiles. If the latter were
amino acid esters or carbohydrates with free NH 2
or OH groups, a new synthetic route to dipeptides
or glyco-am ino acids would be opened. Some of
our early results with carbohydrates and amino
acid derivatives as nucleophiles were m entioned in
a review on general aspects of the anodic oxida-
tion of phenols and its application to the synthesis
of natural products [5]. Here, we report on scope
and limitation of the application of this general
electron-transfer induced reaction to peptide and
glyco-amino acid synthesis in detail. Special regard
is payed to mechanistic aspects, as we were able
to identify a key intermediate.
5 (R2 = H, R3 = CH3)
Scheme 2
C—C —NHCbz
I
R3
Results and Discussion
As acyl donors we used di-/err-butyl-hydroqui-
none esters 2 of /V-protected amino acids (Sche-
me 2), as nucleophiles we tested oxygen or nitro-
gen functions, namely amino acid esters 10
(Scheme 3) with a free amino group and hexoses or
pentoses 12 (as pyranoses or furanoses. Scheme 4),
with one free OH group and the others protected.
The only exception is 12b with two free exocyclic
(one primary and one secondary) hydroxy groups.
The hydroquinone esters 2, needed as substrates
for the oxidation, could be synthesized either from
R 4 - 0 —C - C - N H ,
R5
R2
I
o
II I
10
0
R6
I
R4—0 —C—C —N H —C —C—NHCbz
a
b
c
d
H
e
f
h
i
H
Me
Me
H
?
H
H
H
Me Me Me
Me Me Me Me
H
H
Et
H
R:
Me Me
Me Me
Me
Me
Me
Me
Rs
R“
R'
R»
Et Me Me
H
H
Et
H
H
H
H
Me
H
Pri
Pr'
Bu>
Me
Bu> Bu>
Scheme 3
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G. Reischl et al. • Oxidation-Induced Acyl Group Transfer from Hydroquinone Esters
767
divided cell using CH2C12 and platinum electrodes
containing 10% of iridium, under neutral condi-
tions. Anodic oxidations generally have the advan-
tage that no oxidant is necessary, however, in the
present case they led to long reaction times due to
adsorption phenom ena at the anode, a problem
that was partly circumvented through indirect
electrolysis with tris-(4-bromophenyl)amine [9] as
mediator.
R7-OH (12)
7 (R2=H, R3=CH3) ------------
,
I
+
8
-H R O —C—C-NHCbz
II
I
O
CH3
13
R7
Among the chemical oxidants tested was NBS,
which acts as a clean two-electron oxidant. Since
the positions ortho to the phenolic hydroxy group
are substituted in 2, the usual bromination of the
aromatic ring is not possible here. Alternatively,
the hypervalent iodine compound phenyliodo-
so(III) bis(trifluoroacetate) (PIFA) [10] was em -
ployed, or tris-(4-bromophenyl)ammoniumyl hex-
achloro antim onate [9], a stable salt with the tris-
(4-bromophenyl)ammoniumyl radical cation as
oxidizing agent. The reaction is similar to that
using this reagent in the indirect electrolysis (see
above), however, stoichiometric amounts are nec-
essary, because there is no mediated oxidation to
Scheme 4
hydroquinone 6 and the amino acids 4 with a free
C-terminus or from quinol esters 1. The quinol es- regenerate the oxidant. By all these two-electron
ters 1 in turn can be obtained by anodic oxidation oxidation m ethods the phenoxenium/quinoxonium
of the corresponding phenols in the presence of ion A is formed, either in a free or incipient form
iV-Cbz-amino acids via phenoxenium ions[6]. With
acids, the tert-butyl group at the sp3-center should
(see mechanistic considerations).
The results of the oxidations of hydroquinone
be cleaved to form the hydroquinone ester. U nfor- esters 2 of ^-protected amino acids with amino
tunately, this step proved to be tricky, because al- acid esters 10 are summarized in Table I. As ex-
ways the rearranged ortho-product 5, derived from
the 3,5-di-terf-butyl-pyrocatechol, was obtained as
the main product. Finally, we succeeded by using
pected, we directly get the dipeptides 11 in reason-
able yields, without racemization*, as well as the
quinone 8 as second product (Scheme 3), which
the sulfonated resin Amberlyst 15 at low tem per- can be easily reduced to 6 with Zn/HCl. A fter this
atures.
It is known that pyrocatechol monoesters of
regeneration 6 is again available for the synthesis
of 2.
amino acids react without further activation with
amino acid esters to form dipeptides [7,8]. And
also the 3,5-di-terf-butyl-pyrocatechol ester 5 re-
acted with alanine m ethylester hydrochloride in
CH 2C12 in the presence of N-methylmorpholine at
rt to form TV-Cbz-Ala-Ala-OMe in a yield of 54%
within 24 h [6].
The yields and reaction times were mainly de-
pendent on the chosen method of oxidation. A n-
odic oxidations (entries 1 -4 ) produced variable
quantities of products. The yields were better and
more constant in the m ediated process with tris-
(4-bromophenyl)amine (entries 5 -9 ). The reac-
tion times depended on the nature of the amino
In contrast to pyrocatechol monoesters, hydro- acid ester. Along with increasing steric hindrance
quinone monoesters 2 do not undergo aminolysis
in the presence of amino acid esters. However, af-
ter oxidation, they react as acylating agents, as out-
lined above. For the oxidation of the esters 2 we
used both electrochemical and chemical methods.
Electrochemical oxidations were perform ed in a
went an increase in reaction time. Nevertheless,
the product yields were in the same range for all
* Tests for racemization were performed by GC analysis
according to ref. [15].
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768
G. Reischl et al. • Oxidation-Induced Acyl Group Transfer from Hydroquinone Esters
Table II. Reactions of 2b with monosaccharides 12.
five experiments. In general, the reaction times for
chemical oxidations were very short (entries
10,11), but only with NBS the product yield was
as high as the yields with indirect electrolysis.
Using the hydroquinone ester of N-Cbz-alanine
2b and partially protected monosaccharides 12 as
nucleophiles, we obtained the corresponding
glyco-amino acid esters 13 (Scheme 4, Table II).
For the hexoses the yields depended on the type
of the free OH group; they decreased from 12a, b
(primary exocyclic OH) over 12c (anomeric O H)
to 12d (secondary ring OH). In the case of 12b
with a free primary and a free secondary exocyclic
OH group, 7b reacted regiospecifically with the
primary OH group (direct electrolyses; entries 1-
4). Reaction with the pentose 12e gave the lowest
yields (entry 5).
As in the case of the formation of the dipeptides
11, the method of choice was the indirect electrol-
ysis (entry 6), with much shorter reaction times
and significantly higher yields compared to the di-
rect anodic oxidation. With NBS (entry 7) we re-
ceived as much product as through direct electrol-
ysis, but with a rate even faster than that of
indirect electrolysis. The use of the radical salt in
stoichiometric amounts (entry 8) again proved to
be the least effective.
Nucleophile
Method“ Product
(yield %)
Entry
Reaction
time (h)
13a (52)b
b (59)b
1
2
3
4
5
6
7
8
12a
b
c
d
e
e
e
e
A
A
A
A
A
B
C
D
48.0
65.0
20.0
43.0
22.0
2.5
c (33)b
d (19)b
13e(16)/14(6)
13e(26)/14(20)
13e( 15)/14(6)
0.8
13e(12)/14(traces) 7.0
a A: direct electrolysis, B: indirect electrolysis with (4-
BrC6H 4)3N. C: chemical oxidation with NBS. D: chem i-
cal oxidation with (4-BrC6H4)3NSbCl6; b for experim en-
tal details see reference 5.
We also examined the oxidation of a hydroqui-
none m onosulfonate 16 [16] in the presence of
amino acid esters as nucleophiles, in order to see
whether a transfer of sulfonyl groups was possible
in this way (eq. (1)). Using indirect electrochemi-
cal oxidation with (4-BrC6H 4)3N or chemical oxi-
dation with (2,4-Br2C6H 3)3NSbCl6, a transfer of a
sulfonyl group from 16 to amino acid esters was
indeed observed (Table I, entries 12-14), the
yields, however, were relatively low.
Table I. Reactions of hydroquinone esters with amino acid esters 10.
Entry
Hydroquinone
ester
Nucleophile
10
M ethod3
Product*1
(yield %)
Reaction
time (h)
d
d
d
11a (50)c
b (34/44)c-e
c ( H ) c
d (42/73 )c-e
d (51)
e (55)
f (63)
g (63)
1
2
3
4
5
6
7
8
9
2b
b
b
b
b
c
c
c
a
b
b
H -Ile-O C H 3
H-Val-OCH3
H -A ib-O C H 3
H-Gly-OC->H5
H -Gly-O C2H 5
H -A la-O C H 3
H-Val-OCH3
H -Leu-O C2H 5
H -Leu-O C2H 5
H-Val-OCH3
H -A la-O C H 3
A
A
A
A
B
B
B
B
B
C
D
10.0
2.5
8.0
8.0
19.0
18.0
0.3
h (51)
b (50/69)ce
i (18)
10
11
0.8
2.0
1.5
4.0
16
B
B
E
17a (10)
b (20)
c (32)
12
13
14
H -Gly-O C2H 5
H -A la-O C H 3
H -Leu-OC2H 5
a A: direct electrolysis, B: indirect electrolysis with (4-BrC6H 4)3N, C: chemical oxidation with NBS. D: chemical
oxidation with (4-BrC6H4)3NSbCl6, E: chemical oxidation with (2,4-Br2C6H 3)3NSbCl6; h if not mentioned in the
Experimental Section, the products were identified through com parison with authentic samples synthesized accord-
ing to literature procedures [11-14]; c for experim ental data see reference 5: d the reaction was stopped after the
current had dropped to 5% of the starting value; e the second value gives the yield calculated for the conversion
of 2b.
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769
G. Reischl et al. • Oxidation-Induced Acyl Group Transfer from Hydroquinone Esters
aminal (15, Scheme 5), which would be cleaved to
the quinone and the dipeptide or the glyco-amino
acid. In the case of the dipeptide the equilibrium
might be far on the side of this product, and no
spirocyclus would be detectable.
R
10
I
-O -C —C-NHTs
-2e"; -2H
11 u
O
R6
In fact, the isolated 14 reacted in the expected
way with amino acid esters in the absence of any
coupling reagent at ambient tem perature to give
high yields of the dipeptides (Scheme 5; 14 with
H -Gly-OEt, lid 86%; with H-Leu-OEt, Ilk
100%). The transformation of the hydroquinone
ester 2b to the spirocyclus effected an activation
of the carbonyl group (cyclic active ester) for
nucleophilic attack.
It is known from the literature that other oxa-
zolidones are also active coupling agents in pep-
tide synthesis [17,18]. This rises the question,
which structural element is responsible for the ac-
tivation of the carbonyl C-atom in oxazolidones
towards nucleophilic attack, as, regardless,
w hether the substituents at position 2 of the ring
are simply hydrogen atoms [17] or CF3 groups [18]
17a
Et
b
c
(1)
R4
Me
Et
R5
R6
H
H
H
H
Me
Bu'
Mechanistic Considerations
As already indicated, there is the pertinent
question, whether the active species in the acyl
transfer is a free or an incipient acyl cation. M ore-
over, there might be a completely different m echa-
nism. Therefore, we intensively looked for an in-
termediate in the reaction. In the case of the
synthesis of 13e in the co-oxidation of hydroqui-
none ester 2b and the sugar nucleophile 12e, we
isolated a substance as a by-product (Table II),
which turned out to be the spiro-aminal ester 14
according to its spectroscopic data. It may be
formed via an intramolecular nucleophilic attack
of the NHCbz group, bound by the acyloxy spacer,
in the /w a-position of the interm ediate phenoxe-
nium ion (Scheme 5), as a reaction competing for
the intermolecular attack of the added nucleo-
phile. If the oxidation of the hydroquinone ester 2
was performed in the absence of any nucleophile*,
again the spirocyclus could be detected by mass
spectrometry in all cases, and in the case of the
alanine derivative 2b, it was even possible to iso-
late it (14, direct electrolysis: 18%; PIFA: 10%).
However, in the case of the reaction of a hydroqui-
none ester 2 in the presence of an amino acid ester
10 as nucleophile, we could not detect the spiro-
cyclus. This can be either explained by the fact that
the amino acid ester is a better nucleophile than
the sugar and reacts completely with the quinoxo-
nium ion, and no spirocyclus is formed, or the lat-
ter also reacts with the amino acid ester. Such a
reaction might proceed via the attack of the added
nucleophile to the carbonyl group to give a semi-
+10
HO"
R
1
'NICbz
1 Jl
H3C - C - C —NH -C—COOR44
H O
R6
15
-
8
11
R4 R5 R6
d
k
Et
Et
H
H
H
Bu'
Especially water should be excluded, because 14 is
easily hydrolyzed to 8 and N-C bz-A la-O H 4b.
Scheme 5
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I

770
G. Reischl et al. • Oxidation-Induced Acyl Group Transfer from Hydroquinone Esters
or even the bulky quinonoidal ring (see 14), all
these oxazolidones show activation towards nu-
cleophiles.
the type shown (G and H), where the nucleophile
can add at the positive carbon or sulfur center, to
give the acylated or sulfonylated products after hy-
drolysis.
For a more detailed examination we determ ined
the crystal structure of 14 (Fig. 1). The planes
through the quinonoidal six-membered ring and
the five-membered ring are perpendicular to each
other. The quinonoidal ring shows the typical boat
form, but surprisingly all five atoms of the five-
m em bered ring are in one plane, in contrast to
B urger’s CF3 substituted oxazolidones [18], with
an envelope conformation of the ring and the ni-
trogen atom out of the plane.
Conclusions
The present work dem onstrates the successful
utilization of hydroquinone esters as starting ma-
terials to form dipeptides (without racemization),
glyco-amino acids or TV-tosyl-amino acids in a pre-
parative scale. This is achieved via a formal acyl
transfer from phenoxenium/quinoxonium ions,
created by oxidation of these esters. A spirocyclic
quinol derivative could be isolated as intermediate
and structurally characterized.
The various oxidation procedures employed
show a strong impact on the product yields. The
m ethod of choice is in all cases the indirect elec-
trolysis with trisarylamines as mediators, leading
to the highest yields in short reaction times at low
potentials. In the direct anodic oxidation the reac-
tion times were very long, due to adsorption phe-
nomena at the anode, and the yields were always
low. Also chemical oxidations with NBS or trisaryl-
ammoniumyl radical salts generally were less
effective. This type of acyl transfer represents an-
other expansion of the application of electrochem-
ical oxidations and outlines the advantages of
electrocatalysts.
Fig. 1. A perspective ORTEP drawing of the molecule
of 14 with the atom numbering scheme. The thermal el-
lipsoids are scaled at 50% probability.
Thus, it can be assumed that the major effect of
the activation in 14 results from the ring tension
in the planar oxazolidone ring and especially from
the reduced angle between C15-C16-02 (110.9°),
compared to the ideal angle at an sp2-hybridized
atom (120°). In the case of CF3 substituted oxazol-
idones electronic effects may be also responsible
for the activation.
Altogether, it could be shown that in the present
case active spirocycles as 14 are intermediates in
the acyl transfer from 7 to nucleophiles. On the
other hand, a competitive acyl transfer via a free
or an incipient acyl cation cannot be ruled out def-
initely. But even in the cases of an acetyl transfer
[4] or the sulfonyl transfer (see above), we may
have interm ediate spirocyclic quinone acetals of
Experimental
General
Electrochemical oxidations were carried out po-
tential-controlled at platinum electrodes (Pt/Ir 90/
10) with A M EL or Wenking potentiostats. For the
divided cells,
a ceramic tube (Haldenwanger,
ABS) was used as diaphragm. The purification of
solvents and preparation of the supporting electro-
lytes have been described elsewhere [5]. All
electrolyses were perform ed under an argon atmo-
sphere at room tem perature. The mediator, the
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771
G. Reischl et al. • Oxidation-Induced Acyl Group Transfer from Hydroquinone Esters
General procedure for the anodic oxidation
ammoniumyl salts [9], the amino acid esters [19]
and the sugar nucleophiles [20] were prepared ac-
cording to literature procedures. Chromatography
was performed on silica gel with «-hexane/ethyl
acetate gradients. NM R values (CDC13, ’H NMR:
250 MHz; 13C NMR: 62.9 MHz) refer to Me4Si as
internal standard. J values are given in Hz. Synthe-
ses of 11a,b and 13a-d have been described pre-
viously [5].
Hydroquinone ester 2b (1.4 mmol), the nucleo-
phile (4 -5 mmol) and 2,6-lutidine (excess over 2b)
in dry C H 2C12/0.1 N E t4NBF4 (150 ml) were anod-
ically oxidized in a divided cell at 1400 mV. The
cathodic com partment contained the same sup-
porting electrolyte and lutidinium perchlorate (ca.
1.0 g). The electrolysis was terminated after disap-
pearance of 2b (TLC). The solution was extracted
two times with 5% citric acid, once with 5%
N aH C 0 3, washed with water and dried (M gS04).
A fter evaporation the product was purified by
chrom atography (Table I, entries 1-4; Table II,
entries 1-5).
M onoesters o f 2,6-di-tert-butyl-hydroquinone
The syntheses of 2b [5] and 16[16] have been
described previously.
N-Cbz-Gly-(3,5-di-tert-butyl-4-hydroxyphenyl)~
ester (2a), N-Cbz-Aib-(3,5-di-tert-butyl-4-hydroxy-
phenyl)ester (2c). General procedure: The N -C bz-
protected amino acid 4 and 6 were dissolved in
50 ml of CH2C12, then 1 N DCC in CH 2C12 to-
gether with 30 mg of DM A P was added dropwise
at 0 °C. After 1 h at 0 °C, 24 h at rt and 72 h at
40 °C the reaction was quenched with 5 ml of 5%
citric acid. The layers were separated and the or-
ganic layer was washed with 5% N aH C 0 3, dried
over M gS04 and evaporated to a small volume.
On addition of n-hexane the colorless product pre-
cipitated and was recrystallized from n-hexane.
2a. 4.6 g (22 mmol) 4a, 5.0 g (22 mmol) 6 and
28 ml I N DCC/CH2C12. Yield 2.3 g (25%), m.p.
76-78 °C (from n-hexane). - IR (KBr): 3615; 3410;
2960; 1770; 1710; 1520 c m 1. - MS (FD): m /z = 413
(M+). - 'H-NMR: ö (ppm) = 7.35-7.30 (5H, m, Ph
Cbz); 6.86 (2H, s, 2,6-H); 5.29 (1H, br s, NH); 5.14
(2H, s,CH2Cbz); 5.11 (1H, s, OH); 4.22 (2H, d, J 5.5,
a-H ); 1.40 (18H, s, tBu). - 13C-NMR: <5(ppm) =
169.1; 156.3; 151.6; 143.0; 137.1; 136.2; 128.5; 128.2;
128.1; 117.4; 67.2; 43.0; 34.5; 30.1.
5-0-(N -C bz-A la)-2,3-0-isopropyliden e-l-0-
m ethyl-ß-D-ribofuranoside (13e) and 4-N-Cbz-7,9-
di-tert-butyl-3-m ethyl-4-aza-l-oxa-spiro[4,5]-deca-
6,9-dien-2,8-dione (14) (Table II, entry 5). First
fraction 14: m.p. 97-98 °C (from n-hexane).
-
IR(KBr): 2960; 1795; 1710 cm -1. - MS(FD): m /z =
425 (M +). - ’H-NMR: <5(ppm) = 7.35-7.15 (5H,
m, Ph Cbz); 6.18-6.14 (2H, m, 6,10-H); 5.12 (1H,
d, J 11.9, CH 2 Cbz); 4.96 (1H, br s, CH2 Cbz); 4.49
(1H, br q, J 6.0, 3-H); 1.68 (3H, d, J 6.4, 3-CH3);
1.15 (18H, br s, /Bu).- 13C-NMR: <5(ppm) = 185.4;
171.5; 150.4; 135.0; 134.0; 132.9; 128.6-128.5; 87.6;
68.0; 52.3; 35.03; 34.97; 29.2; 18.4.
C25H 31 N O s (425.5)
Calcd
C 70.6 H 7.3 N 3.3% ,
Found C 70.7 H 7.8 N 3.1% .
Second fraction 13e: colorless oil.- IR(KBr):
3330; 2940; 1715; 1520 c m '1. - MS(FD): m /z = 410
(M + + H, 20); 394 (100). - ’H-NMR: <3(ppm) =
7.38-7.34 (5H, m, Ph Cbz); 5.46 (1H, d, J 7.5, NH);
5.12 (2H, s, CH2 Cbz); 4.98 (1H, s, 1-H); 4.67 (1H,
d, J 5.9, 2-H or 3-H); 4.60 (1H, d, J 5.9, 3-H or 2-
H); 4.48-4.33 (2H, m, a-H Ala, 4-H); 4.24-4.10
(2H, m, 5-H); 3.30 (3H, s, OMe); 1.48 (3H, s, i-Pr);
1.43 (3H, d, J 7.1, ß-H Ala); 1.31 (3H, s, i-Pr). -
13C-NMR: <5(ppm) = 172.5; 155.6; 136.3; 128.6;
128.2; 128.1; 112.6; 109.7; 85.2; 84.1; 81.7; 66.9; 65.5;
55.0; 49.7; 26.4; 24.9; 18.7.
C24H 31N 0 5 (413.5)
Calcd
C 69.7 H 7.6 N 3.4% ,
Found C 69.8 H 7.7 N 3.1% .
2c. 1.4 g (5.9 mmol) 4c, 1.3 g (5.9 mmol) 6 and
6.3 ml 1 N DCC/CH2C12. Yield 1.5 g (58%), m.p.
138-139 °C (from n-hexane).
- IR(KBr): 3622;
3362; 2958; 1740; 1685; 1515 cm "1. - MS(FD): m /
z = 441 (M+). - ’H-NMR: <3 (ppm) = 7.34-7.27
(5H, m, Ph Cbz); 6.83 (2H, s, 2,6-H); 5.41 (1H, s,
NH); 5.10 (2H, s, CH 2 Cbz); 5.08 (1H, s, OH); 1.68
HRM S (FAB, NBA + NaCl): C20H 27N NaO8
(432.1647)
Found 432.1647.
(6H, s, ß-H ); 1.40 (18H, s, tBu).
-
13C-NMR:
<5(ppm) = 173.7; 155.0; 151.4; 143.5; 136.9; 136.4;
128.5; 128.0; 127.9; 117.5; 66.6; 56.6; 34.4; 30.1; 25.2.
A n odic oxidation without nucleophile
C26H 35NO s (441.6)
Calcd
C 70.7 H 8.0 N 3.2% ,
2b (500 mg, 1.17 mmol), 42 h. Yield of 14:
Found C 71.1 H 8.3 N 3.1% .
90 mg (18%).
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772
G. Reischl et al. • Oxidation-Induced Acyl Group Transfer from Hydroquinone Esters
General procedure for the indirect electrochemical
oxidation with (4-BrC6H 4)3N
with 5% citric acid. 5% N aH C 0 3 and water.
A fter evaporation, the product was purified by
chrom atography (Table I, entry 11; Table II,
entry 8).
A solution of (4-BrC6H4)3N (0.2 mmol) in dry
CH2C12/0.1 N E t4NBF4 (150 ml) was preoxidized
in a divided cell for 30 min at 800 mV under argon.
The cathodic compartment contained the same
supporting electrolyte and lutidinium perchlorate
(ca. 1.0 g). The hydroquinone ester (0.6 mmol),
the nucleophile (1.5—6.0 mmol) and 2,6-lutidine
(excess over the hydroquinone ester) were added
to the anodic com partm ent and the reaction con-
tinued at the same potential. The electrolysis was
stopped when the current reached a value of 5%
of the starting current. The solution was extracted
two times with 5% citric acid, once with 5%
N aH C 0 3, washed with water and dried (M gS04).
A fter evaporation to dryness the resulting product
was purified by chromatography. The details are
summarized in Table I, entries 5-9,12,13 and Ta-
ble II, entry 6.
N -Ts-Leu-O C 2H5 (17c)
H ydroquinone monosulfonate 16 (750 mg,
2.0 mmol), H -Leu-O C2H 5 (1600 mg, 10.0 mmol)
and 2,6-lutidine (excess over 16) were dissolved in
25 ml of CH 2C12 under argon and (2,4-
Br2C6H 3)3NSbCl6 (2100 mg, 2.0 mmol; in 10 ml of
C H 2C12) was added. At the end of the reaction
(4 h), the solvent was evaporated and the residue
extracted with ether. A fter evaporation, the pro-
duct was purified by chromatography. Yield
154 mg (32%, calculated for conversion), m.p. 50-
52 °C (from n-hexane) and 170 mg (23%) 16.
IR(KBr): 3280; 2960; 1740 cm“ 1 . - MS(FD): m /
z = 313 (M +). - ’H-NMR: (3(ppm) = 7.65 (2H, d,
J 8.0, Ph); 7.19 (2H, d, J 8.0, Ph); 5.10 (1H, d, J
10.0, NH); 3.91-3.80 (1H, m, a-H ); 3.79 (2H, q, J
7.1, C //?C H 3); 2.33 (3H, s, CH3 Ts); 1.78-1.69
(1H, m, y-H); 1.45-1.35 (2H, m, ß -H ); 1.01 (3H,
t, J 7.1, CH 2C //3); 0.82 (6H, dd, J 6.7 and 3.7 Hz, <3-
H).- 13C-NMR: <5(ppm) = 172.3; 143.5; 136.9; 129.5;
127.4; 61.4; 54.4; 42.4; 24.3; 22.7; 21.4; 13.8.
General procedure for the chemical oxidation
with NBS
NBS (3.0 mmol) was added to a solution of hy-
droquinone ester 2b (0.3 mmol), the nucleophile
(1.8 mmol) and 2,6-lutidine (0.9 mmol) in 25 ml of
CH2C12. A fter 45 min the reaction was quenched
with an aqueous solution of Na2S20 3/N aH C 0 3.
The organic layer was washed twice with 5% citric
acid, then with 5% N aH C 0 3 and water. After dry-
ing over M gS04 and evaporation of the solvent,
the product was purified by chromatography (Ta-
ble I, entry 10; Table II, entry 7).
C 15H 23N 0 4S (313.4)
Calcd
C 57.5 H 7.4 N 4.5 S 10.2%,
Found C 57.2 H 7.3 N 4.7 S 10.0%.
D ipeptides from the active ester 14
General procedure. 20 mg (0.047 mmol) of the
spirocyclus 14 and the corresponding amino acid
ester were dissolved in 5 ml of CH 2C12 and stirred
until 14 had reacted completely (TLC). Then the
solvent was evaporated in vacuo and the crude
product purified by chromatography.
Spirocyclus 14, chemical oxidation o f 2b with PIFA
2b (250 mg, 0.58 mmol) and 2,6-lutidine
(124 mg, 1.16 mmol) were dissolved in 20 ml of
CH3CN. A t 0 °C PIFA (260 mg, 0.6 mmol in 20 ml
of CH3CN) was added under argon. A fter 20 min,
water was added and the mixture extracted with
ether. The organic layer was washed with satu-
rated NaCl-solution, 5% citric acid, water and
dried. After evaporation of the organic phase, the
residue was purified by chromatography. Yield:
25 mg (10%).
1. N -C bz-A la-G ly-O C 2H 5 (lid ). H-Gly-OC2H 5
(7.2 mg, 0.07 mmol), 15
h at rt. Yield: 12 mg
(86%).
2. N -C bz-A la-L eu-O C 2H5 (Ilk ). H-Leu-OC2H 5
(10 mg, 0.06 mmol), 50 h at 45 °C. Yield: 17 mg
(99%). Identified through comparison with an au-
thentic sample [11].
Crystal data and structure refinement o f 14
General procedure for the chemical oxidation with
(4-BrC6H4)3N SbC l6
C25H 31N 0 5, M = 425.51, triclinic, space group
P 1, a = 10.8011(8), b = 15.0951(12), c = 15.900(2)
A, a = 83.118(7), ß = 73.209(8), y = 82.776(7)°, V =
2452.7(4) A 3, Z = 4. D c = 1.152 Mg i r r 3, F(000) =
912, ^(C u-K a) = 0.646 m m -1, colorless crystal 0.5
x 0.2 x 0.2 mm.
Hydroquinone ester 2b (0.4 mmol), the nucleo-
phile (2.4 mmol) and 2,6-lutidine (0.8 mmol)
were dissolved in 25 ml of CH2C12 and
(4-BrC6H 4)3NSbCl6 (0.8 mmol) was added. At
the end of the reaction, the solution was washed
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G. Reischl et al. • Oxidation-Induced Acyl Group Transfer from Hydroquinone Esters
773
The data collection was carried out with a CAD-
diffractometer by using graphite-monochro-
0.043 and w R 2 = 0.1143. The results of the crystal
structure analysis unequivocally support the struc-
4
mated Cu-Ka radiation, k = 1.54056 A. scan = &>/ ture of 14.
20. Unit cell determination and refinem ent were
carried out with 25 reflections of the reference list.
All 9792 recorded reflections merged to give 9185
unique reflections [/ > 2o(I), Rmt = 0.0471], The
structure was solved by direct methods using the
SHELXS-86 program [21].The full-matrix least-
squares structure refinement was perform ed with
the SHELXL-93 program [22] against F2. All hy-
drogen atoms were found on a difference Fourier
Further details can be requested to the Cam-
bridge Crystallographic Data Centre, The Director
CCDC, 12 U nion Road, Cambridge CB2 1EZ,
UK, quoting the full literature citation and the ref-
erence num ber 101748.
A cknow ledgm ents
This research was supported by the Deutsche
Forschungsgemeinschaft. Experimental work by
map and considered in the structure factor calcula- Prof. Dr. R. A. Misra and Dr. A. Hutinec is grate-
tion. The structure afforded a final
value of
fully acknowledged.
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