Homologation of α-hydroxy acids to α-unsubstituted β-hydroxy carboxamides via Arndt-Eistert reaction

Article abstract of DOI:10.1016/j.tetlet.2006.05.001

Here we studied the homologation of leucic and phenyl lactic acid via Wolff-rearrangement of their diazoketones to the corresponding β-hydroxy acids. This reaction requires distinct conditions to that of their amino acid analogues. The choice of the O^α-substituent can selectively direct the reaction to α-unsubstituted β-hydroxy carboxamides or (E)-α,β-unsaturated carboxamides and offers a new route from α-hydroxy acids to such compounds.

Full text of DOI:10.1016/j.tetlet.2006.05.001

Tetrahedron Letters 47 (2006) 4557–4560
Homologation of a-hydroxy acids to a-unsubstituted b-hydroxy
carboxamides via Arndt–Eistert reaction
a
b
a,c,
*
Jan Spengler,a, Javier Ruız-Rodrıguez, Klaus Burger and Fernando Albericio
*
´
´
aInstitute for Research in Biomedicine, Barcelona Science Park, 08028 Barcelona, Spain
bUniversity of Leipzig, Department of Organic Chemistry, 04103 Leipzig, Germany
cUniversity of Barcelona, Department of Organic Chemistry, 08028 Barcelona, Spain
Received 25 February 2006; revised 26 April 2006; accepted 2 May 2006
Abstract—Here we studied the homologation of leucic and phenyl lactic acid via Wolff-rearrangement of their diazoketones to the
corresponding b-hydroxy acids. This reaction requires distinct conditions to that of their amino acid analogues. The choice of the
Oa-substituent can selectively direct the reaction to a-unsubstituted b-hydroxy carboxamides or (E)-a,b-unsaturated carboxamides
and offers a new route from a-hydroxy acids to such compounds.
Ó 2006 Elsevier Ltd. All rights reserved.
i) chiral auxiliary based
acetate aldol reaction
1. Introduction
O
TrtS
S
Many depsipeptides isolated from marine organisms are
attractive targets for medicinal chemistry because of
their broad range of biological activities.1 a-Unsubsti-
tuted b-hydroxy carboxylic acids are often present in
these architectures and are essential for activity. Syn-
thetic approaches toward these b-hydroxy acids are gen-
erally challenging. For example, the a-unsubstituted
b-hydroxy carboxylic acid motif of the histone deacetylase
inhibitor spiruchostatin A is synthesized via chiral aux-
iliary-based Aldol reactions with N-acetyl thiazolidine-
thione as an acetate enolate equivalent.2 This elegant
approach provides the enantiopure b-hydroxy acid
which is already carboxyl-activated for incorporation
into the depsipeptide. The aldehyde required for the
Aldol reaction is synthesized from malonic acid mono-
methylester by a four-step procedure (Scheme 1, i). A
second main approach to a-unsubstituted b-hydroxy
carboxylic acids is the reduction of the corresponding
3-oxo-carboxylates. For example, 3-hydroxy-5-methyl
hexanoic acid ester can be obtained with high enantio-
meric purity in quantitative yield by reduction of the
corresponding 3-oxo-analogue in the presence of the
Noyori catalyst.3 The 3-oxo carboxylate is prepared
N
S
OH
O
TiCl4, i-Pr2NEt,
CH2Cl2, -78°C
O
TrtS
H
S
N
ii) enantioselective reduction
100 atm. H2,
S
CO2Me
Ru((R)binap)Cl2
CO2Me
O
OH
Scheme 1. Main synthetic pathways to chiral b-hydroxy acids.
from Meldrum’s acid and isopentanoyl chloride, the cat-
alyst is generated in situ and the reduction requires
100 atm of hydrogene (Scheme 1, ii). 3-Oxo-carboxylic
acids can also be reduced enantioselectively with the chi-
ral borane DIP-Cl4 and by engineered bacteria.5
In addition to the above mentioned main approaches,
alternative and more special routes are already developed,
like asymmetric Reformatsky reactions,6 stereoselective
reduction of 1-trimethylsilyl-1-alkyn-3-ones,7 stereose-
lective Rh-catalyzed C–H insertion of a-alkoxydiazoke-
tones,8 enantioselective Al-catalyzed two-step hydration
of a,b-unsaturated imides9 and nucleophilic ring open-
ing of (S)-3-hydroxy-c-butyrolactone with subsequent
modification of the terminal hydroxy group.10
Keywords: b-Hydroxy carboxylic acids; a,b-Unsaturated carboxylic
acids; Microwave shock-heating; a-Hydroxy diazoketones.
*
Corresponding authors. Fax: +34 93 4037126; e-mail addresses:
jspengler@pcb.ub.es; albericio@pcb.ub.es
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.001

4558
J. Spengler et al. / Tetrahedron Letters 47 (2006) 4557–4560
33% and 39% overall yield from leucic acid (1a) and
R
R
CO2H
Arndt-Eistert conditions
(established route)
CO2H
phenyllactic acid (1b), respectively, after O-Fmoc-pro-
tection18 and carboxyl-activation followed by reaction
with etheric solution of diazomethane (Refs. 11b and
15)) required elevated temperatures. On reaction with
H–Phe–NH2 as nucleophile in dioxane at 50 °C for
15 min in the presence of silver benzoate, the homologa-
tion/elimination products (S)-Na-[(E)-5-methyl-hex-2-
enoyl]-phenylalanine amide (3a, 86%)19 and (S)-Na-
[(E)-4-phenyl-but-2-enoyl]-phenylalanine amide (3b,
72%) were isolated as main products and traces of the
homologation products were detected only in the crude
reaction mixture. These findings are consistent with
other reports on diazoketones bearing an O-substituent
in a-position (Scheme 3).20
NHPG
NHPG
β-amino acids
diazotization
(established route)
R
R
CO2H
CO2H
Arndt-Eistert conditions
(scattered reports)
OPG
β-hydroxy acids
OPG
Scheme 2. Homologation of a-hydroxy acids as route to b-hydroxy
acids.
In our current research on depsipeptides, we have found
a general access to a-unsubstituted b-hydroxy carbox-
ylic acids bearing the side chains of proteinogenic amino
acids a desirable feature. Although, many of the afore-
mentioned protocols are applicable for the enantiopure
b-hydroxy-1-carboxylic acid unit, the preparation of
the required starting materials, such as the aldehydes
for the Aldol-type reactions, or the b-ketoacids for the
reductive approach, is often laborious or even not
described. On the other hand, it is well known that
a-amino acids can be homologized efficiently by the
Arndt–Eistert reaction, a synthetic application of the
Wolff-rearrangement.11 We envisioned the Arndt–Eist-
ert homologation of a-hydroxy acids (readily available
from a-amino acids by diazotization12) as a convenient
and general route to the b-hydroxy analogues of inter-
est. This approach would circumvent both the construc-
tion of the stereo-centre and the side-chain at the
b-carbon because the diazotization and the Arndt–Eist-
ert reaction proceed stereoconservatively under certain
conditions. Thus, starting from an amino acid, the cor-
responding a-unsubstituted b-hydroxy carboxylic acid
should be accessible in only four steps: (i) diazotization,
(ii) O-protection, (iii) generation of the diazoketone and
(iv) Wolff-rearrangement. With respect to the apparent
simplicity of this route, only very few applications have
been reported. The homologation of all four stereoiso-
mers of O-silyl-protected isoleucic acid after Oa-depro-
tection yields 20% of the corresponding b-hydroxy
acid methyl esters with (E)-a,b-unsaturated carboxylic
acid methyl esters as by-products.13 The homologation
of b-amino (or b-azido)-a-hydroxy acids to statins has
been reported to produce good (60–71%) yields (Scheme
2).14
The Fmoc-group of 2a and 2b were cleaved with 20%
piperidine in DMF without affecting the diazoketone
moiety, to give the Oa-unprotected diazoketones 4a21
and 4b, which have not been described before. Shock-
heating was required to induce the reaction of com-
pounds 4. Microwave irradiation was chosen because
it allows controlled heating in small-scale runs.22 Solu-
tions of 4a containing equimolar amounts of H–Phe–
NH2 as nucleophile and a catalytic amount of silver ben-
zoate in different solvents were thus reacted for 2 min at
1
150 °C in a closed microwave reactor. The H NMR
spectrum of the crude product showed b-hydroxy acid
depsipeptide 5a and the homologation/elimination
product 3a. The ratio of these two products was deter-
1
mined by comparing the H NMR integration values
for the a-CH2 of the homologation product 5a (two
dd at 2.25 ppm) and the olefinic proton R–CH@CH–
CH2–CH(CH3)2 of 3a (m at 5.92 ppm). The ratio was
strongly influenced by the solvent used. However, the
best yields were obtained in solvent-free reactions. In
this case, depsipeptide 5a was isolated in 47% yield23
and depsipeptide 5b from diazoketone 4b in 48% yield.
Prolonging the heating time up to 10 min did not alter
the ratio of products, therefore thermal dehydratation
of 5a to 3a was excluded as a possible origin of olefinic
compound (Scheme 4, Table 1).
To find out the most valuable candidates for the Wolff-
rearrangement, diazoketones of leucic acid bearing the
most common O-protecting groups were synthesized.
The O-acetyl protected diazoketone 624 was obtained
from O-acetyl leucic acid. The tetrahydropyranyl
(THP)-protected leucic acid (Ref. 18) gave diazoketone
2. Results and discussion
Diazoketones derived from a-amino acids are highly
reactive species and undergo Wolff-rearrangement under
mild conditions. Thus, Fmoc-homo-b-amino acids are
formed from the corresponding diazoketones by ultra-
sonication in aq dioxane in the presence of Ag+ at room
temperature.15 b-Peptides are prepared on solid-phase
from diazoketones of a-amino acids and resin-bound
amino acids at 0 °C,16 and b-aminoxy acid amides are
obtained from diazoketones of a-aminoxy acids and
amines at ꢀ78°C.17 We found diazoketones of a-hydroxy
acids to be less reactive. Conversion of Fmoc-OLeu-
CHN2 (2a) and Fmoc-OPhe-CHN2 (2b) (obtained in
°
1) Fmoc-Cl, pyridine, 0 C
O
2) isobutylchloroformate, NEt3,
then diazomethane
N2
R
CO2H
OH
R
°
(5-8 eq. etheric sol.) 0 C
OFmoc
2a,b
1a,b (a: R = isobutyl, b: R = benzyl)
Ph
1 eq. H-Phe-NH2
H
Ag-benzoate,
dioxane, 15 min 50 C
R
N
°
CONH2
3a,b
O
Scheme 3. Homologation/elimination of Oa-substituted diazoketones.

J. Spengler et al. / Tetrahedron Letters 47 (2006) 4557–4560
4559
Table 2. Effect of the O-protecting group of diazoketones on reaction
with H–Phe–NH2 as the nucleophile (Scheme 4)
nucleophile
O
Ag-benzoate
R1
N2
°
2 min 150 C (microwave)
R2 of diazoketone (R1 = iBu)
Ratio I/II (3a)a
OR2
diazoketones 2a,b; 4a,b; 6-9
H (4a)
Bzl (8)
Ca. 4:1
Ca. 0.8:1
TBDMS (9)
THP (7)
Ac (6)
Ca. 0.7:1
Ca. 0.7:1
Traces of depsipeptide
Traces of depsipeptide
R1
R1
R3
R3
+
OR2
products I (5a,b, 10a,b, 11)
O
O
Fmoc (2a)
products II (3a,b):
a Determined by 1H NMR as described above.
Scheme 4. Course of the reaction of diazoketones. Effect of solvent on
product ratio: Table 1. Effect of R2 on product ratio: Table 2. Effect of
nucleophile on product ratio: Table 3. 2a R1 = iBu, R2 = Fmoc; 2b
R1 = Bzl, R2 = Fmoc; 3a R1 = iBu, R3 = Phe–NH2; 3b R1 = Bzl,
R3 = Phe–NH2; 4a R1 = iBu, R2 = H; 4b R1 = Bzl, R2 = H; 5a
R1 = iBu, R2 = H, R3 = Phe–NH2; 5b R1 = Bzl, R2 = H, R3 = Phe–
NH2; 6 R1 = iBu, R2 = Ac; 7 R1 = iBu, R2 = THP; 8 R1 = iBu,
Table 3. Effect of the nucleophiles on the ratios of b-hydroxy acid
derivative I/dehydratation product II (Scheme 4)
Diazoketone and nucleophile
Ratio I/IIa
R2 = Bzl;
9
R1 = iBu, R2 = TBDMS; 10a R1 = iBu, R2 = H,
4a, 1 equiv L-a-methyl benzylamine
4b, 1 equiv L-a–methyl benzylamine
4a, 1 equiv H–Phe–NH2
4b, 1 equiv H–Phe–NH2
4b, 3 equiv N,N-methoxy methylamine
4a, aq dioxane
Ca. 6:1 (10a, 88%)
Ca. 7:1 (10b, 50%)
Ca. 4:1 (5a, 47%)
Ca. 4:1 (5b, 48%)
Ca. 3:1 (11, 47%)
Ca. 2.3:1
R3 = NHCHMePh; 10b R1 = Bzl, R2 = H, R3 = NHCHMePh; 11
R1 = Bzl, R2 = H, R3 = NHMeOMe.
Table 1. Effect of solvents on the reaction of diazoketones 4 with
H–Phe–NH2 (Scheme 4)
4a, excess allyl alcohol
Ca. 0.7:1
Ratio I (5):II (3)a
4a, H–Phe–MBHA rink amide, aq dioxane Ca. 0.6:1
Educt
Solvent, time (min)
1
a Determined by H NMR in the reaction mixture. The isolated yields
4a
4a
4a
4a
4a
4a
4b
DMF, 2
DMF, 10
MeOH, 2
MeOH, 10
EtOH, 2
Ca. 1:3
Ca. 1:3
Ca. 3:4
Ca. 3:4
Ca. 1:1
Ca. 4:1
Ca. 4:1
of products are shown in parenthesis.
acids, were used. Addition of nucleophile excess did
not improve the yields of homologation products
(Scheme 4, Table 3). However, this new variant of the
Arndt–Eistert reaction required strong heating with
amines. To detect racemization, D-leucine was con-
verted into diazoketone 4a–D and reacted with L-a-
methylbenzylamine to form the diastereomer 10a–D.
Normal phase HPLC of the product revealed a d.e. of
86%.
No solvent, 2
No solvent, 2
a Determined by 1H NMR integration.
7. The a-OH of leucic acid methylester25 was benzyl26
(Bzl)-tert-butyldimethylsilyl (TBDMS)- (Ref. 3) pro-
tected. Saponification of the methyl ester, followed by
activation and reaction of the 1-carboxylic group with
diazomethane gave diazoketones 8 and 9, respectively.
When the THP-, Bzl- and TBDMS-ethers (7, 8 and 9,
respectively) were reacted with H–Phe–NH2 following
the microwave protocol described above, the homologa-
tion and homologation/elimination products were found
in a ratio of ca. 1:1. The O-acyl-protected diazoketones
2 and 6 gave almost exclusively homologation/elimina-
tion products. However, the unprotected diazoketone
4a still produced the best yields of b-depsipeptide 5.
These findings indicate that protection of the Oa-func-
tion enhances its tendency to act as leaving group
(Scheme 4, Table 2).
3. Conclusion
To the best of our knowledge, this is the first detailed
study of the potential of a-hydroxy acids to undergo
Arndt–Eistert homologation via Wolff-rearrangement
of their diazoketones. In summary, we have found for
a-hydroxy acids a distinct reaction behaviour than that
of their amino acid analogues. The tendency of a-hydroxy
acids to undergo homologation or homologation/elimi-
nation reaction under the applied conditions is a
function of the O-substituent, the solvent and the nucleo-
phile. Oa-acyl derivates yielded (E)-a,b-unsaturated
carboxamides (72–86%). Oa-Unprotected diazoketones,
a so far unknown subclass of diazoketones, favoured
homologation to a-unsubstituted b-hydroxy carbox-
amides (47%–88% isolated yields) on reaction with
amines in the presence of catalytic amounts of silver
benzoate when shock-heated with microwave irradiation
(150 °C, 2 min). Although the scope of this protocol is
limited to the use of amines as nucleophilic trapping re-
agents and partial racemization was detected, it may be
useful for the incorporation of b-hydroxy acids in the
N-terminal position of peptides and preparation of
b-hydroxy carboxamides.
We next studied the effect of the nucleophile on the
reaction. Diazoketones 4a,b were reacted with different
amines and alcohols under the above described condi-
tions. L-a-Methyl benzylamine react with 4a and 4b to
b-hydroxy carboxamides 10a and 10b, which were iso-
lated in 88% and 50% yield, respectively. Reaction of
4a,b with phenylalanine amide yielded depsipeptides
5a and 5b in 47% and 48%, respectively. Upon reaction
of 4b with N,N-methoxy-methylamine, the Weinreb-
amide 11 (47%) was obtained. Homologation/elimina-
tion was favoured when weaker nucleophiles, such as
water, allyl alcohol and also solid phase-bound amino

4560
J. Spengler et al. / Tetrahedron Letters 47 (2006) 4557–4560
86%) as a white solid. Rf = 0.5 (AcOEt). Mp 179–181 °C.
Acknowledgements
1H NMR (CD3OD): d = 0.91 (3H, d, J = 6.66 Hz), 0.92
(3H, d, J = 6.67 Hz), 1.72 (1H, m), 2.06 (2H, m), 2.91 (1H,
m), 3.16 (1H, m), 4.68 (1H, m), 5.92 (1H, dt, J = 15.35 Hz,
J = 1.3 Hz), 6.71 (1H, m), 7.17–7.28 (5H, m) ppm. 13C
NMR (CD3OD): d = 22.7, 22.7, 29.2, 39.1, 42.4, 55.8,
125.4, 127.7, 129.4, 130.3, 138.6, 145.2, 168.3, 176.3 ppm.
IR (KBr): m = 3364, 3283, 2952, 1677, 1612 cmꢀ1. HRMS:
Calcd for C16H22N2O2+Na: 297.1579. Found: 297.1581
[M+Na]+.
The authors thank Dr. Miriam Royo for access to
microwave apparatus and Dr. Xavier Verdaguer for
normal phase HPLC measurements. This work was
partially supported by CICYT (BQU 2003-00089), the
Generalitat de Catalunya (Grup Consolidat and Centre
`
de Referencia en Biotecnologia) and the Barcelona Sci-
ence Park.
20. (a) Ref. 13; (b) Pirillo, D.; Leggeri, P.; Traverso, G.
Farmaco Ed. Sci. 1984, 39, 963–967; (c) Thijs, L.;
Dommerholt, F. J.; Leemhuis, F. M. C.; Zwanenburg,
B. Tetrahedron Lett. 1990, 31, 6589–6592.
References and notes
´
´
1. (a) Sarabia, F.; Chammaa, S.; Sanchez Ruiz, A.; Martın
21. (S)-1-Diazo-3-hydroxy-5-methylhexan-2-one
(H-OLeu-
´
Ortiz, L.; Lopez Herrera, F. J. Curr. Med. Chem. 2004, 11,
CHN2) 4a: Fmoc-OLeu-CHN2 2a (3.11 g, 8.2 mmol) was
dissolved in 20% piperidine in DMF (30 mL) and stirred
for 15 min. Volatiles were evaporated under high vacuum
and the residue was purified by flash chromatography to
give 4a as a yellow oil (1.1 g, 85%). On prolonged standing
at room temperature (several days), the oil decomposes
(the colour turns to brown). Rf = 0.5 (1 hexane/1 ethyl
1309–1332; (b) Hamada, Y.; Shioiri, T. Chem. Rev. 2005,
105, 4441–4482.
2. Yurek-George, A.; Habens, F.; Brimmell, M.; Packham,
G.; Ganesan, A. J. Am. Chem. Soc. 2004, 126, 1030–1031.
3. Albert, M.; Seebach, D.; Duchardt, E.; Schwalbe, H. Helv.
Chim. Acta 2002, 85, 633–658.
4. Wang, Z.; Zhao, C.; Pierce, M. E.; Fortunak, J. M.
Tetrahedron: Asymmetry 1999, 10, 225–228.
5. Booker-Milburn, K. I.; Gillan, R.; Kimberley, M.; Tagu-
chi, T.; Ichinose, K.; Stephenson, G. R.; Ebizuka, Y.;
Hopwood, D. A. Angew. Chem., Int. Ed. 2005, 44, 1121–
1125.
1
acetate). H NMR (CDCl3): d = 0.96 (6H, m), 1.46 (2H,
m), 1.90 (1H, m), 4.10 (1H, m), 5.52 (1H, br s). 13C NMR
(CDCl3): d = 21.3, 23.3, 24.3, 43.8, 52.7, 73.8, 198.3. IR
25
(film): m = 3421, 2958, 2108, 1624, 1349 cmꢀ1. 4a: ½aꢁD
ꢀ95.6 (c 3.57, MeOH). The synthesis of 4a–D from D-
25
leucine proceeds analogously. 4a–D: ½aꢁD þ97:5 (c 3.42,
6. Fukuzawa, S.; Matsuzawa, H.; Yoshimitsu, S. J. Org.
Chem. 2000, 65, 1702–1706.
MeOH). HRMS: Calcd for C7H12N2O2+Na: 179.0797.
Found: 179.0795 [M+Na]+].
´
´
7. Alemany, C.; Bach, J.; Garcia, J.; Lopez, M.; Rodrıguez,
22. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284.
23. (S)-Na-[(3S)-3-Hydroxy-5-methyl-hexanoyl]-phenylalanine
amide, 5a: Diazoketone 4a (60 mg, 0.38 mmol) was placed
with H–Phe–NH2 (63 mg, 0.38 mmol) at the bottom of a
microwave reactor tube. A catalytic quantity of silver
benzoate was added (ca. 7 mg). Caution: After addition of
silver benzoate to the reaction mixture an exothermic
reaction starts with evolution of gas. It origin is not clear,
because the 1H NMR spectrum shows an unaltered
mixture of starting materials. The tube was sealed, placed
in the microwave oven and heated for 2 min to 150 °C
(ramp time: 2 min, hold time: 2 min) with 150 W. After
reaction, the product was purified by flash chromatogra-
phy to give 5a (52 mg, 47%) as a white solid. Rf = 0.28 (9
CHCl3/1 MeOH). Mp 158–162 °C. 1H NMR (CD3OD):
d = 0.87 (6H, m), 1.07 (1H, m), 1.32 (1H, m), 1.72 (1H, m),
2.22 (1H, dd, J = 14.0 Hz, J = 5.2 Hz), 2.27 (1H, dd,
J = 13.9 Hz, J = 7.9 Hz), 2.86 (1H, dd, J = 14.0 Hz,
J = 9.8 Hz), 3.22 (1H, dd, J = 14.0 Hz, J = 4.9 Hz), 3.96
(1H, m), 4.66 (1H, m), 7.17–7.30 (5H, m) ppm. 13C NMR
(CD3OD): d = 22.3, 23.8, 25.5, 38.7, 45.2, 47.5, 55.7, 68.1,
127.8, 129.5, 130.2, 138.7, 174.3, 176.5 ppm. IR(KBr):
m = 3398, 3299, 2954, 1638, 1539 cmꢀ1. HRMS Calcd for
C16H24N2O3+Na: 315.1685. Found: 315.1668 [M+Na]+.
24. Spectroscopical date were found identical to: Sengupta, S.;
Sarma, D. S.; Mondal, S. Synth. Commun. 1998, 28, 4409–
4417.
A. B. Tetrahedron 2000, 56, 9305–9312.
8. Yakura, T.; Tanaka, T.; Ikeda, M.; Uenishi, J. Chem.
Pharm. Bull. 2003, 51, 471–473.
9. Vanderwal, C. D.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 14724–14725.
10. Jaipuri, F. A.; Jofre, M. F.; Schwarz, K. A.; Pohl, N. L.
Tetrahedron Lett. 2004, 45, 4149–4152.
11. (a) Kirmse, W. Eur. J. Org. Chem. 2002, 2193–2256; (b)
Podlech, J.; Seebach, D. Liebigs Ann. 1995, 1217–1228.
12. Deechongkit, S.; You, S.-L.; Kelly, J. W. Org. Lett. 2004,
6, 497–500.
13. Murai, A.; Amino, Y.; Ando, T. J. Antibiot. 1985, 38,
1610–1613.
14. (a) Kondekar, N. B.; Kandula, S. R. V.; Kumar, P.
Tetrahedron Lett. 2004, 45, 5477–5479; (b) Ko, S. Y.
J. Org. Chem. 2002, 67, 2689–2691.
15. Muller, A.; Vogt, C.; Sewald, N. Synthesis 1998, 837–841.
16. Marti, R. E.; Bleicher, K. H.; Bair, K. W. Tetrahedron
Lett. 1997, 38, 6145–6148.
17. Yang, D.; Zhang, Y.-H.; Li, B.; Zhang, D.-W. J. Org.
Chem. 2004, 69, 7577–7581.
18. Kuisle, O.; Quinoa, E.; Riguera, R. J. Org. Chem. 1999,
¨
´
˜
64, 8063–8075.
19. (S)-Na-[(E)-5-Methyl-hex-2-enoyl]-phenylalanine amide,
3a: Diazoketone 2a (117 mg, 0.31 mmol) and H–Phe–
NH2 (51 mg, 0.31 mmol) were dissolved in dioxane
(10 mL). Silver benzoate (7 mg) was added (the solution
immediately became brown) and it was heated to 50 °C.
After consumption of 2a (TLC), it was filtered, lyophilized
and purified by flash chromatography to give 3a (73 mg,
25. Kolasa, T.; Miller, M. J. J. Org. Chem. 1987, 52, 4978–
4984.
26. Aubele, D. L.; Lee, C. A.; Floreancig, P. E. Org. Lett.
2003, 5, 4521–4523.