One-pot conversion of α-amino acids into β-amino aldehydes or 2-acetoxyazetidines: Application to the synthesis of modified peptides

Article abstract of DOI:10.1055/s-0029-1219156

A direct method for the transformation of α-amino acids into β-amino aldehydes or 2-acetoxyazetidines is described. This work was applied to the modification of peptides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219156

LETTER
659
One-Pot Conversion of a-Amino Acids into b-Amino Aldehydes or
2-Acetoxyazetidines: Application to the Synthesis of Modified Peptides
O
ne-Pot Conversio
l
nof
a
-
i
A
mino
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A
cids into
i
b
-A
m
a
A
ldehyde
s
Boto,* Rosendo Hernández,* Carlos J. Saavedra
Instituto de Productos Naturales y Agrobiología CSIC, Avda. Astrofísico Fco. Sánchez, 3, 38206 La Laguna, Tenerife, Spain
Fax +34(922)260135; E-mail: alicia@ipna.csic.es; E-mail: rhernandez@ipna.csic.es
Received 2 November 2009
Dedicated to Prof. Gerry Pattenden on the occasion of his 70th birthday.
In order to increase the diversity of peptidyl b-aldehyde li-
braries, a-substituted b-amino aldehydes could be incor-
porated into the peptide. Such units could bear
substituents of different size and polarity, in order to allow
the study of their influence on biological activity.
Abstract: A direct method for the transformation of a-amino acids
into b-amino aldehydes or 2-acetoxyazetidines is described. This
work was applied to the modification of peptides.
Key words: amino aldehydes, heterocycles, peptides, radical reac-
tions, domino reactions
In this communication we report a one-pot methodology
to transform the C-terminal amino acid in peptides into a
b-amino aldehyde, whose a-position may be either substi-
tuted or unsubstituted. This direct transformation would
allow the preparation of a library of modified peptide al-
dehydes from a single peptide precursor 5 (Scheme 1).7
The replacement of a-amino acids in peptides by a-amino
aldehydes has been used to create peptide analogues with
remarkable biological activities.1 Thus, different peptide
aldehydes are potent inhibitors of aspartyl, serine, and
cysteine proteases, such as papain, thrombin, trypsin, and
viral proteases.2 For instance, the dipeptide SJA6017 (1)
inhibits calpain and is a promising anticataract agent.3a,b
The tetrapeptide Ac-DEVD-H (2) is a potent inhibitor of
caspase-3, an apoptosis effector.3c,d
The process is initiated by a radical decarboxylation, on
treatment of the precursor 5 with (diacetoxyiodo) benzene
(DIB) and iodine. The decarboxylation affords a C-radical
6 which reacts with iodine to give the unstable a-iodo-
amine 7.7j The iodide is replaced by acetate derived from
the DIB, to give the N,O-acetal 8. This acetal is in equilib-
rium with the acyliminium ion 9, which can be trapped by
silyl enol ethers, to afford the peptide b-aldehydes 10.
In contrast, the introduction of b-amino aldehyde units has
been scarcely explored.4 In most cases, a-unsubstituted b-
amino aldehyde5 or a-amino glyoxal units6 are used. Two
representative examples are compounds 3 and 4
(Figure 1); while product 3 is a caspase-1 inhibitor,4b the
glyoxal 4 inhibits cathepsin L, a protease which degrades
bone collagen.4c
H
N
H
N
O
OH
Z-(aa)n
Z-(aa)n
R1
R1
5
6
H
O
N
H
N
Ac-Asp-Glu-Val
O
H
O
S
CHO
PhI(OAc)2,
I2, hν,
HOOC
N
H
H
N
O
then T2,
X
Z-(aa)n
Lewis acid,
SJA6017 (1)
2
R2
OTMS
R1
F
H
O
H
O
O
R2
H
N
H
N
H
7 X = I
8 X = OAc
Ac-Tyr-Val-Ala
Cbz-Phe
HOOC
H
H
t-BuO
R2 R2
3
4
N+
O
N
Z-(aa)n
Figure 1 Bioactive peptidyl a- or b-aldehydes
Z-(aa)n
H
R1
R1
10
9
Scheme 1 One-pot conversion of peptides into peptidyl b-aldehydes
SYNLETT 2010, No. 4, pp 0659–0663
0
1.
0
3.
2
0
1
0
Advanced online publication: 22.12.2009
DOI: 10.1055/s-0029-1219156; Art ID: D30909ST
© Georg Thieme Verlag Stuttgart · New York

660
A. Boto et al.
LETTER
Table 1 Tandem Scission–Alkylation to Yield Compounds 12 and 13
H
N
O
H
N
R
R
PhI(OAc)2, I2,
hν, then T2,
H
OH
H
H
OTMS
H
Bz
OTMS
H
Bz
A:
B:
O
Lewis acid,
nucleophile
A or B
Ph
Ph
( )-11
( )-12 R = Me
( )-13 R = H
Ratio of DIB/I2 (equiv)
1.5:0.3
Nu (equiv)
Lewis acid (equiv)
TiCl4 (2)
Addition temp T2 (°C)
Product (yield, %)a
12 (25)
A (3)
A (3)
A (3)
A (3)
A (3)
A (5)
B (3)
B (3)
–78
–78
0
1.5:0.3
SnCl4 (2)
12 (51)
1.5:0.3
TMSOTf (2)
BF3·OEt2 (2)
BF3·OEt2 (2)
BF3·OEt2 (2)
BF3·OEt2 (2)
TMSOTf (2)
12 (58)
1.5:0.3
0
12 (61)
1.5:0.5
0
12 (53)
2.0:1.0
0
12 (38)
1.5:0.3
0
13 (41)
1.5:0.3
0
13 (40)
a Yields for purified products.
Initially, the tandem scission–alkylation was optimized The different results observed in the use of silyl enol
using single amino acid derivatives as substrates. Thus, ethers and vinyl acetate can be explained using substrate
Bz-DL-Phe-OH (11) was treated under the conditions list- 14 as an example (Scheme 3). The scission–oxidation
ed in Table 1, varying quantities of reagents and using dif- steps, followed by addition of the nucleophile to the
ferent Lewis acids and temperatures, to afford the b- acyliminium intermediate, generated an oxycarbenium
amino aldehydes 12 (R = Me) or 13 (R = H).
ion 34. When R = TMS, a silyl cation was readily lost to
give the aldehyde 20. However, when R = Ac, the loss of
an acyl cation was not favored, so the addition of the
amide took place instead, affording the 2-acetoxyazeti-
dine 33.
The best conditions used a catalytic amount of iodine (0.3
equiv) in the scission step, and BF3·OEt2 or TMSOTf at
0 °C in the addition step. These conditions were then used
with the other amino acid and peptide substrates 14–19
(Scheme 2), to afford the b-amino aldehyde derivatives The cyclization was stereoselective, and only the 2,4-cis-
20–28 in good global yields. Interestingly, in the case of azetidine was isolated. The 2,4-trans-isomer was not de-
peptides, TMSOTf gave better results than BF3·OEt2.
tected.9 A minimum-energy conformation for the oxycar-
benium intermediate 34 prior to ring closure is shown in
Figure 2.10 In this conformation, where unfavorable steric
interactions are greatly reduced, the nitrogen is correctly
positioned for ring closure to occur, affording the 2,4-cis-
azetidine 33. The same applied to the other substrates 29
and 30, affording the 2,4-cis-azetidines 31 and 32, respec-
tively.
In the case of substrates 18 and 19, the reacting residue is
attached to an L-amino acid which serves as a chiral aux-
iliary. Therefore, the scission–addition reaction is stereo-
selective, affording the L-b-amino aldehyde as the major
isomer (L/D ≈ 2:1 in both cases). The diastereomers were
readily separated by chromatography, in order to deter-
mine structure–biological activity relationships.
The resulting 2-acetoxyazetidines are remarkably useful,
not only as aldehyde prodrugs, but also as precursors of
azetidines. The introduction of azetidines in peptides by
conversion of common amino acids into 2-acetoxyaze-
tidines and addition of other nucleophiles to the N,O-ace-
tal is particularly interesting.11 The azetidine ring could be
used to generate turns and other secondary structure ele-
ments.12 This possibility is currently under study in our
group and will be published in due course.
The stereochemistry of these compounds was determined
by comparison with similar peptides,7a and it was con-
firmed by oxidation of aldehyde 27 to an acid followed by
esterification,8 to the known dipeptide Bz-L-Leu-L-b-
hAla-OMe (58%).7a
Interestingly, when the silyl enol ether used as the nucleo-
phile was replaced by vinyl acetate7e (Scheme 3), the ex-
pected b-amino aldehyde derivatives were not formed,
and 2-acetoxyazetidines were obtained instead. Thus,
substrates 29, 30, and 14 were treated under the modified
scission–alkylation conditions, affording the 2-ace-
toxyazetidines 31–33 in satisfactory yields.
In conclusion, we have developed an efficient methodol-
ogy for the direct conversion of a-amino acid derivatives
into b-amino aldehydes, using a sequential procedure
which couples a radical decarboxylation to an oxidation
and to a nucleophilic addition. The procedure allows the
Synlett 2010, No. 4, 659–663 © Thieme Stuttgart · New York

LETTER
One-Pot Conversion of a-Amino Acids into b-Amino Aldehydes
661
H
O
H
N
Bz
Bz
N
R
R
N
O
NH
a
OH
52%
OAc
Bz
Bz
4
2
COOH
H
H
3
( )-29
( )-31
( )-14
( )-20 R = H (55%)
( )-21 R = Me (60%)
Bz
Bz
N
EtO2C
NH
EtO2C
49%
58%
OAc
Cbz
N
Cbz
O
COOH
H
H
N
( )-30
( )-32
Bz
a
OH
Bz
O
NH
( )-15
N
( )-22 (86%)
OAc
COOH
( )-14
H
( )-33
H
N
H
N
O
O
scission–
alkylation
C(O)H
OH
OR
N
H
N
H
Bz
Bz
a or b
R = Ac
O
Bz
H
N
N
H
( )-23
(a) 21%; (b) 50%
16
O
R = TMS
Bz
H
O+
R
Ph
O
Ph
O
H
N
H
N
O
N
Si+
34
( )-20
OH
C(O)H
a or b
N
H
Bz
Bz
Scheme 3 Formation of 2-acetoxyazetidines. Reagents and conditi-
ons: DIB (1.5 equiv), I2 (0.3 equiv), CH2Cl2, hn, r.t., 4 h, then 0 °C,
BF3·OEt2 (2 equiv), CH2=C(OAc)H (10 equiv), 3 h.
H
17
( )-24
(a) 34%; (b) 61%
selective modification of the C-terminal residue in small
peptides, and therefore, a single a-peptide could be trans-
formed into a library of a,b-peptidyl aldehydes.
Bz
N
Bz
N
O
O
OH
C(O)H
b
N
N
Moreover, by changing the reaction conditions, the a-ami-
no acids can be transformed into 2-acetoxyazetidines,
which could be useful aldehyde prodrugs. Furthermore,
the 2-acetoxyazetidines could be converted into aze-
tidines following reported procedures, in order to generate
turns or other secondary structure elements in peptides.
H
O
H
18
25 (47%)
+
Bz
N
O
C(O)H
C(O)H
N
H
26 (22%)
H
N
H
N
O
O
OH
N
Bz
N
H
Bz
b
O
H
27 (57%)
19
+
H
N
O
C(O)H
N
H
Bz
28 (29%)
Scheme 2 Reagents and conditions: Method A: DIB (1.5 equiv), I2
(0.3 equiv), CH2Cl2, hn, r.t., 4 h, then 0 °C, BF3·OEt2 (2 equiv),
R2C=C(OTMS)H (3 equiv), 3 h. Method B: similar to A but using
TMSOTf as Lewis acid.
Figure 2 Minimized conformation for oxycarbenium intermediate
34 prior to ring closure
Synlett 2010, No. 4, 659–663 © Thieme Stuttgart · New York

662
A. Boto et al.
LETTER
General Procedures for the Scission–Oxidation–Alkylation
Sequence
chromatography on silica gel (hexanes–EtOAc, 4:1), affording
compounds 27 (57%) and 28 (29%).
Method A
Compound 27: 1H NMR (500 MHz): d = 0.95 (d, J = 6.3 Hz, 6 H),
1.05 (d, J = 8.2 Hz, 3 H), 1.06 (s, 3 H), 1.07 (s, 3 H), 1.67–1.72 (m,
3 H), 4.23 (dddd, J = 6.8, 6.8, 6.8, 9.4 Hz, 1 H), 4.67 (ddd, J = 7.5,
7.5, 7.5 Hz, 1 H), 6.87 (br d, J = 9.0 Hz, 1 H), 6.94 (d, J = 7.9 Hz, 1
H), 7.40 (dd, J = 7.7, 7.7 Hz, 2 H), 7.49 (dd, J = 7.3, 7.6 Hz, 1 H),
7.78 (d, J = 7.5 Hz, 2 H), 9.45 (s, 1 H) ppm. 13C NMR (100.7 MHz):
d = 15.8 (CH3), 17.9 (CH3), 19.2 (CH3), 22.2 (CH3), 22.8 (CH3),
25.0 (CH), 41.4 (CH2), 48.6 (CH), 50.0 (C), 52.5 (CH), 127.1 (2 ×
CH), 128.6 (2 × CH), 131.8 (CH), 133.8 (C), 167.6 (C), 171.9 (C),
204.7 (CH) ppm. MS: m/z (%) = 333 (1) [M+ + H], 190 (100) [M+ –
CONHCH(Me)CMe2CHO], 105 (91) [PhCO]+. HRMS: m/z calcd
C19H29N2O3: 333.2178; found: 333.2181; calcd for C12H16NO:
190.1232; found: 190.1239.
Compound 28: 1H NMR (500 MHz): d = 0.96 (d, J = 6.5 Hz, 3 H),
0.97 (d, J = 6.3 Hz, 3 H), 1.00 (s, 3 H), 1.03 (s, 3 H), 1.13 (d, J = 6.9
Hz, 3 H), 1.63–1.82 (m, 3 H), 4.24 (1 H, dddd, J = 6.9, 6.9, 6.9, 9.5
Hz), 4.61 (ddd, J = 6.0, 6.3, 8.2 Hz, 1 H), 6.67 (d, J = 8.2 Hz, 1 H),
6.75 (d, J = 9.8 Hz, 1 H), 7.43 (dd, J = 7.4, 7.4 Hz, 2 H), 7.50 (dd,
J = 7.3, 7.6 Hz, 1 H), 7.78 (d, J = 6.9 Hz, 2 H), 9.43 (s, 1 H) ppm.
13C NMR (100.7 MHz): d = 16.0 (CH3), 17.9 (CH3), 19.0 (CH3),
22.3 (CH3), 22.9 (CH3), 25.0 (CH), 40.4 (CH2), 48.4 (CH), 50.1 (C),
52.2 (CH), 127.1 (2 × CH), 128.6 (2 × CH), 131.8 (CH), 133.9 (C),
167.9 (C), 171.3 (C), 204.8 (CH) ppm. MS: m/z (%) = 333 (2) [M+
+ H], 190 (86) [M+ – CONHCH(Me)CMe2CHO], 105 (100) [Ph-
CO]+. HRMS: m/z calcd C19H29N2O3: 333.2178; found: 333.2177;
calcd for C7H5O: 105.0340; found: 105.0340.
To a solution of the starting amino acid or peptide (0.2 mmol) in dry
CH2Cl2 (6 mL) were added I2 (15 mg, 0.06 mmol, 0.3 equiv) and
DIB (97 mg, 0.3 mmol, 1.5 equiv). The reaction mixture was stirred
at 25–26 °C for 4 h, under irradiation with visible light. Then the so-
lution was cooled to 0 °C, and vinyloxytrimethylsilane (89 mL, 70
mg, 0.6 mmol, 3 equiv) or 2-methyl-1-(trimethylsilyloxy)-1-pro-
pene (110 mL, 86 mg, 0.6 mmol, 3 equiv) or vinylacetate (184 mL,
172 mg, 2 mmol, 10 equiv) was injected, followed by dropwise ad-
dition of BF3·OEt2 (51 mL, 57 mg, 0.4 mmol, 2 equiv). The mixture
was allowed to reach r.t. and stirred for 3 h; then it was poured into
10% aq Na2S2O3–sat. aq NaHCO3 (1:1, 10 mL) and extracted with
CH2Cl2. The organic layer was dried over Na2SO4, filtered, and
evaporated under reduced pressure. The residue was purified by
chromatography on silica gel (hexanes–EtOAc) to give the prod-
ucts.
Method B
As in method A but using TMSOTf (72 mL, 89 mg, 0.4 mmol, 2
equiv) as the Lewis acid.
N-Benzoyl-a,a-dimethyl-DL-b-homophenylalaninal (12)
Phenylalanine derivative ( )-11 was treated as in method A, using
2-methyl-1-(trimethylsilyloxy)-1-propene as the nucleophile. The
reaction mixture was purified by column chromatography on silica
gel (hexanes–EtOAc, 9:1), giving the aldehyde ( )-12 (61%) as a
crystalline solid.
1H NMR (500 MHz, CDCl3): d = 1.25 (s, 3 H), 1.31 (s, 3 H), 2.75
(dd, J = 11.2, 14.6 Hz, 1 H), 3.10 (dd, J = 4.1, 14.2 Hz, 1 H), 4.69
(ddd, J = 4.1, 10.2, 10.8 Hz, 1 H), 6.38 (d, J = 9.8 Hz, 1 H), 7.18
(dd, J = 6.8, 6.8 Hz, 1 H), 7.23–7.28 (m, 4 H), 7.36 (dd, J = 7.5, 7.8
Hz, 2 H), 7.45 (dd, J = 7.1, 7.8 Hz, 1 H), 7.52 (d, J = 7.1 Hz, 2 H),
9.59 (s, 1 H) ppm. 13C NMR (125.7 MHz, CDCl3): d = 19.5 (CH3),
20.1 (CH3), 36.7 (CH2), 50.5 (C), 54.7 (CH), 126.7 (3 × CH), 128.5
(4 × CH), 128.9 (2 × CH), 131.3 (CH), 134.6 (C), 137.8 (C), 167.4
(C), 205.3 (CH) ppm. MS: m/z (%) = 295 (<1) [M+], 105 (100) [Ph-
CO]+, 91 (14) [PhCH2]+, 77 (28) [Ph]+. HRMS: m/z calcd for
C19H21NO2: 295.1572; found: 295.1580; calcd for C7H5O:
105.0340; found: 105.0343
1-Benzoyl-4-isobutylazetidin-2-yl Acetate (33)
Formed from leucine derivative ( )-14 according to method A, us-
ing vinyl acetate as the nucleophile. After purification by column
chromatography on silica gel (hexanes–EtOAc, 97:3) the product
was isolated as a syrup (58%).
1H NMR (500 MHz): d = 0.98 (d, J = 6.9 Hz, 3 H), 0.98 (d, J = 6.9
Hz, 3 H), 1.40 (m, 1 H), 1.58–1.69 (m, 2 H), 2.00 (ddd, J = 6.6, 6.9,
13.6 Hz, 1 H), 2.17 (s, 3 H), 2.20 (ddd, J = 3.8, 4.4, 13.2 Hz, 1 H),
3.67 (m, 1 H), 6.47 (dd, J = 3.8, 8.8 Hz, 1 H), 7.35 (dd, J = 7.3, 7.6
Hz, 2 H), 7.41 (dd, J = 6.9, 7.6 Hz, 1 H), 7.92 (d, J = 7.5 Hz, 2 H)
ppm. 13C NMR (125.7 MHz): d = 21.1 (CH3), 22.7 (CH3), 22.8
(CH3), 24.6 (CH), 32.0 (CH2), 46.2 (CH2), 49.7 (CH), 91.0 (CH),
127.4 (2 × CH), 128.0 (2 × CH), 130.6 (CH), 132.8 (C), 152.8 (C),
169.4 (C) ppm. MS: m/z (%) = 275 (7) [M+], 105 (100) [PhCO]+.
HRMS: m/z calcd for C16H21NO3: 275.1521; found: 275.1532; calcd
for C7H5O: 105.0340; found: 105.0340.
N-Benzoyl-DL-b-homophenylalaninal (13)
Amino acid ( )-11 was treated as indicated in method A, using vi-
nyloxytrimethylsilane as nucleophile. The reaction mixture was pu-
rified by column chromatography on silica gel (hexanes–EtOAc,
7:3), yielding product ( )-13 (41%) as an amorphous solid.
1H NMR (500 MHz, CDCl3): d = 2.73 (ddd, J = 1.6, 6.0, 17.3 Hz, 1
H), 2.77 (ddd, J = 1.3, 5.4, 17.7 Hz, 1 H), 2.97 (dd, J = 7.6, 13.6 Hz,
1 H), 3.09 (dd, J = 6.9, 13.6 Hz, 1 H), 4.76 (m, 1 H), 6.58 (d, J = 8.2
Hz, 1 H), 7.21–7.25 (m, 3 H), 7.32 (dd, J = 7.3, 7.6 Hz, 2 H), 7.40
(dd, J = 7.6, 7.6 Hz, 2 H), 7.48 (dd, J = 7.3, 7.6 Hz, 1 H), 7.68 (d,
J = 7.6 Hz, 2 H), 9.77 (dd, J = 0.6, 0.9 Hz, 1 H) ppm. 13C NMR
(125.7 MHz, CDCl3): d = 40.1 (CH2), 46.7 (CH2), 46.9 (CH), 126.9
(3 × CH), 128.6 (2 × CH), 128.8 (2 × CH), 129.2 (2 × CH), 131.6
(CH), 134.3 (C), 137.3 (C), 167.0 (C), 201.2 (CH) ppm. MS: m/z
(%) = 268 (12) [M+ + H], 176 (69) [M+ – PhCH2], 105 (100) [Ph-
CO]+, 91 (37) [PhCH2]+, 77 (81) [Ph]+. HRMS: m/z calcd for
C17H18NO2: 268.1338; found: 268.1327; calcd for C7H5O:
105.0340; found: 105.0341.
Acknowledgment
This work was supported by the Investigation Programmes
CTQ2006-14260/PPQ of the Plan Nacional de Investigación
Científica, Desarrollo e Innovación Tecnológica, Ministerio de
Educación y Ciencia and Ministerio de Ciencia e Innovación, Spain.
We also acknowledge financial support from FEDER funds. C.J.S.
thanks the Gobierno de Canarias for a predoctoral fellowship.
References and Notes
(1) For a review on the subject, see: Moulin, A.; Martinez, J.;
Fehrentz, J. A. J. Pept. Sci. 2007, 13, 1.
(2) For other recent references on the synthesis of bioactive
peptidyl a-aldehydes, see: (a) Balamurugan, D.;
(Benzoyl-L-leucyl)-a,a-dimethyl-L-b- (27) and (Benzoyl-L-
leucyl)-a,a-dimethyl-D-b-homoalaninal (28)
The products were generated from dipeptide 19 according to meth-
od B, using 2-methyl-1-(trimethylsilyloxy)-1-propene as the nu-
cleophile. The reaction mixture was purified by rotatory
Muraleedharan, K. M. Tetrahedron 2009, 65, 10074.
(b) Jones, M. A.; Morton, J. D.; Coxon, J. M.; McNabb, S.
B.; Lee, H. Y.-Y.; Aitken, S. G.; Mehrtens, J. M.; Robertson,
L. J. G.; Neffe, A. T.; Miyamoto, S.; Bickerstaffe, R.;
Synlett 2010, No. 4, 659–663 © Thieme Stuttgart · New York

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One-Pot Conversion of a-Amino Acids into b-Amino Aldehydes
663
Gately, K.; Wood, J. M.; Abell, A. D. Bioorg. Med. Chem.
Tetrahedron Lett. 2000, 41, 1275. (c) Darkins, P.; Groarke,
M.; McKervey, M. A.; Moncrieff, H. M.; McCarthy, N.;
Nieuwenhuyzen, M. J. Chem. Soc., Perkin Trans. 1 2000,
381.
2008, 16, 6911. (c) Al-Gharabli, S. I.; Shah, S. T. A.; Weik,
S.; Schmidt, M. F.; Mesters, J. R.; Kuhn, D.; Klebe, G.;
Hilgenfeld, R.; Rademann, J. ChemBioChem 2006, 7, 1048.
(d) Ede, N. J.; Eagle, S. N.; Wickham, G.; Bray, A. M.;
Warne, B.; Shoemaker, K.; Rosenberg, S. J. Pept. Sci. 2000,
6, 11.
(7) (a) Saavedra, C.; Hernandez, R.; Boto, A.; Alvarez, E.
J. Org. Chem. 2009, 74, 4655. (b) Boto, A.; Hernández, D.;
Hernández, R. Tetrahedron Lett. 2009, 50, 3974. (c) Boto,
A.; Hernández, D.; Hernández, R. Tetrahedron Lett. 2008,
49, 455. (d) Boto, A.; Hernández, D.; Hernández, R.;
Álvarez, E. J. Org. Chem. 2007, 72, 9523. (e) Boto, A.;
Gallardo, J. A.; Hernández, D.; Hernández, R. J. Org. Chem.
2007, 72, 7260. (f) Boto, A.; Hernández, D.; Hernández, R.;
Montoya, A.; Suárez, E. Eur. J. Org. Chem. 2007, 325.
(g) Boto, A.; Hernández, D.; Hernández, R. Org. Lett. 2007,
9, 1721. (h) Saavedra, C. J.; Hernández, R.; Boto, A.;
Álvarez, E. Tetrahedron Lett. 2006, 47, 8757. (i) Boto, A.;
Gallardo, J. A.; Hernández, R.; Saavedra, C. J. Tetrahedron
Lett. 2005, 46, 7807. (j) Boto, A.; Hernández, R.; León, Y.;
Murguía, J. R.; Rodríguez-Afonso, A. Eur. J. Org. Chem.
2005, 673. (k) For a review on the modification of amino
acids and carbohydrates through radical chemistry, see:
Hansen, S. G.; Skrydstrup, T. Top. Curr. Chem. 2006, 264,
135.
(3) (a) Payne, R. J.; Brown, K. M.; Coxon, J. M.; Morton, J. D.;
Lee, H. Y.-Y.; Abell, A. D. Austr. J. Chem. 2004, 57, 877.
(b) See also: Abell, A. D.; Jones, M. A.; Neffe, A. T.; Aitken,
S. G.; Cain, T. P.; Payne, R. J.; McNabb, S. B.; Coxon, J. M.;
Stuart, B. G.; Pearson, D.; Lee, H. Y.-Y.; Morton, J. D.
J. Med. Chem. 2007, 50, 2916. (c) Ac-DEVD-H:Isabel, E.;
Aspiotis, R.; Black, C.; Colucci, J.; Fortin, R.; Giroux, A.;
Grimm, E. L.; Han, Y.; Mellon, C.; Nicholson, D. W.;
Rasper, D. M.; Renaud, J.; Roy, S.; Tam, J.; Tawa, P.;
Vaillancourt, J. P.; Xanthoudakis, S.; Zamboni, R. J. Bioorg.
Med. Chem. Lett. 2007, 17, 1671. (d) Nakagawa-Yagi, Y.;
Ogane, N.; Inoki, Y.; Kitoh, N. Life Sci. 1996, 58, 1461.
(e) Bauvois, B.; Dauzonne, D. Med. Res. Rev. 2006, 26, 88.
(4) Bioactive peptidyl b-aldehydes: (a) Yin, B.; Dhal, R.;
Maisonneuve, V.; Dujardin, G. Eur. J. Org. Chem. 2006,
3309. (b) Bajusz, S.; Fauszt, I.; Németh, K.; Barabás, E.;
Juhász, A.; Patthy, M. Bioorg. Med. Chem. Lett. 1998, 8,
1477. (c) Lynas, J. F.; Hawthorne, S. J.; Walker, B. Bioorg.
Med. Chem. Lett. 2000, 10, 1771. (d) See also: Richard, A.;
Bourel-Bonnet, L. Chem. Eur. J. 2005, 11, 7315. (e) Choe,
Y.; Brinen, L. S.; Price, M. S.; Engel, J. C.; Lange, M.;
Grisostomi, C.; Weston, S. G.; Pallai, P. V.; Cheng, H.;
Hardy, L. W.; Hartsough, D. S.; McMakin, M.; Tilton, R. F.;
Baldino, C. M.; Craik, C. S. Bioorg. Med. Chem. 2005, 13,
2141. (f) Nkemgu-Njinkeng, J.; Rosenkranz, V.; Wink, M.;
Steverding, D. Antimicrob. Agents Chemother. 2002, 46,
2038. (g) Lynas, J. F.; Harriott, P.; Healy, A.; McKervey,
M. A. Bioorg. Med. Chem. Lett. 1998, 8, 373. (h) Iqbal, M.;
Messina, P. A.; Freed, B.; Das, M.; Chatterjee, S.; Tripathy,
R.; Tao, M.; Josef, K. A.; Dembofsky, B.; Dunn, D.; Griffith,
E.; Siman, R.; Senadhi, S. E.; Biazzo, W.; Bozyczko-Coyne,
D.; Meyer, S. L.; Ator, M. A.; Bihovsky, R. Bioorg. Med.
Chem. 1997, 7, 539.
(8) Itokawa, H.; Kondo, K.; Hitotsuyanagi, Y.; Isomura, M.;
Takeya, K. Chem. Pharm. Bull. 1993, 41, 1402.
(9) (a) The proposed stereochemistry was deduced from the
value of the 1H NMR coupling constants, which showed a cis
relationship 2-H/3-Ha/4-H and a trans relationship 2-H/3-Hb
and 4-H/3-Hb (J3a = 6.6, 6.9 Hz, while J3b = 3.8, 4.4 Hz).
(b) The experimental coupling constants matched theoretical
coupling constants, which were calculated over minimized
structures by using the Karplus–Altona equation
implemented in the Macromodel 7.0 program. The
calculations were performed with a MMFF force field, using
high-quality parameters.
(10) (a) Representation using ChemDraw 3D 8.0 (CambridgeSoft),
which agrees with calculations performed with Macromodel
7.0. The aldehyde 20 adopts a similar conformation. (b) For
the formation of related 2,4-cis-azetidines, see: Ghorai, M.
K.; Kumar, A.; Halder, S. Tetrahedron 2007, 63, 4779.
(11) (a) Arrieta, A.; Cossío, F. P.; García, J. M.; Lecea, B.;
Palomo, C. Tetrahedron Lett. 1988, 29, 3129. (b) Häbich,
D.; Hartwig, W. Tetrahedron Lett. 1987, 28, 781. (c) See
also: Martel, S. R.; Wisedale, R.; Gallagher, T.; Hall, L. D.;
Mahon, M. F.; Bradbury, R. H.; Hales, N. J. J. Am. Chem.
Soc. 1997, 119, 2309. (d) Brown, D.; Brown, G. A.;
Andrews, M.; Large, J. M.; Urban, D.; Butts, C. P.; Hales, N.
J.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1 2002, 2014.
(e) For reviews on the Mannich reaction and related
processes, see: Ferraris, D. Tetrahedron 2007, 63, 9581.
(f) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63,
2541. (g) Schaus, S. E.; Ting, A. Eur. J. Org. Chem. 2007,
5797. (h) Petrini, M.; Torregiani, E. Synthesis 2007, 159;
and references cited therein.
(5) For the synthesis of b-amino aldehydes, see: (a) Yang, H.;
Carter, R. G. J. Org. Chem. 2009, 74, 2246. (b) Terada, M.;
Toda, Y. J. Am. Chem. Soc. 2009, 131, 6354. (c) Zhang, H.;
Chuan, Y.; Li, Z.; Peng, Y. Adv. Synth. Catal. 2009, 351,
2288. (d) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413.
(e) Labonne, A.; Zani, L.; Hintermann, L.; Bolm, C. J. Org.
Chem. 2007, 72, 5704. (f) Chi, Y.; English, E. P.;
Pomerantz, W. C.; Horne, W. S.; Joyce, L. A.; Alexander,
L. R.; Fleming, W. S.; Hopkins, E. A.; Gellman, S. J. Am.
Chem. Soc. 2007, 129, 6050. (g) Yang, J. W.; Stadler, M.;
List, B. Angew. Chem. Int. Ed. 2007, 46, 609. (h) Kano, T.;
Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc.
2005, 127, 16408. (i) Gizecki, P.; Dhal, R.; Poulard, C.;
Gosselin, P.; Dujardin, P. J. Org. Chem. 2003, 68, 4338.
(j) Mann, A.; Quaranta, L.; Reginato, G.; Taddei, M.
Tetrahedron Lett. 1996, 37, 2651.
(12) Baeza, J. L.; Gerona-Navarro, G.; Pérez de Vega, M. J.;
García-López, M. T.; González-Muñiz, R.; Martín-
Martínez, M. J. Org. Chem. 2008, 73, 1704; and references
cited therein.
(6) For the synthesis of a-aminoglyoxals, see: (a) El-Dahshan,
A.; Weik, S.; Rademann, J. Org. Lett. 2007, 9, 949.
(b) Groarke, M.; McKervey, M. A.; Nieuwenhuyzen, M.
Synlett 2010, No. 4, 659–663 © Thieme Stuttgart · New York