Exceptionally simple homologation of protected α- to β-amino acids in the presence of silica gel

Article abstract of DOI:10.1080/00397910500290466

The Wolff rearrangement of α-amino acid-derived diazoketones is simply achieved by gentle warming in a ethyl acetate/silica gel slurry containing catalytic amounts of silver trifluoroacetate. Without workup (not counting filtration and evaporation) the pr

Full text of DOI:10.1080/00397910500290466

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Exceptionally Simple
Homologation of Protected
α‐ to β‐Amino Acids in the
Presence of Silica Gel
Karen Koch a & Joachim Podlech a
a Institut für Organische Chemie , Universität
Karlsruhe (TH) , Karlsruhe, Germany
Published online: 22 Aug 2006.
To cite this article: Karen Koch & Joachim Podlech (2005) Exceptionally Simple
Homologation of Protected α‐ to β‐Amino Acids in the Presence of Silica Gel,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:21, 2789-2794
To link to this article: http://dx.doi.org/10.1080/00397910500290466
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Synthetic Communicationsw, 35: 2789–2794, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500290466
Exceptionally Simple Homologation
of Protected a- to b-Amino Acids
in the Presence of Silica Gel
Karen Koch and Joachim Podlech
¨
Institut fu¨r Organische Chemie, Universitat Karlsruhe (TH),
Karlsruhe, Germany
Abstract: The Wolff rearrangement of a-amino acid–derived diazoketones is simply
achieved by gentle warming in a ethyl acetate/silica gel slurry containing catalytic
amounts of silver trifluoroacetate. Without workup (not counting filtration and evapo-
ration) the protected b-amino acids are obtained in high yields (92–97%) without sig-
nificant impurities. This variation avoids the laborious workup after a conventional
silver-catalyzed Wolff rearrangement. This method can be similarly applied to the
synthesis of b-amino acid methyl esters when methanol is used as solvent. No
reaction occurs without silica gel.
Keywords: a-Amino acids, b-amino acids, diazo compounds, silica gel, Wolff
rearrangement
A number of protocols for the homologation of a-amino acids leading to
b-amino acids or their derivatives (Arndt–Eistert homologation) have been
presented over the past decades.[1] With these methods large amounts of enan-
tiomerically pure material can be obtained.[2] The Arndt–Eistert reaction is a
two-step reaction including preparation of a diazoketone and a subsequent
Wolff rearrangement in the presence of a protic nucleophile. The rearrange-
ment (with loss of N2) is achieved with either silver catalysts (silver
benzoate or silver trifluoroacetate) in the presence of more than stoichiometric
Received in Poland May 10, 2005
Address correspondence to Joachim Podlech, Institut fu¨r Organische Chemie,
¨
Universitat Karlsruhe (TH), Fritz-Haber-Weg 6, 76131, Karlsruhe, Germany.
Tel.: þ 49 721/608 3209; Fax: þ 49 721/608 7652; E-mail: joachim.podlech@ioc.uka.de
2789

2790
K. Koch and J. Podlech
amounts of triethyl amine, with irradiation, or simply by heating the reaction
mixture to about 160–1808C.[3] Although silver benzoate or silver acetate[4] is
preferred as catalyst in the formation of esters (the catalyst can be removed
during the subsequent extraction process), silver trifluoroacetate turned out
to be favorable in the formation of the homologated amino acids. Here the
remnant of the catalyst, the trifluoroacetic acid, is simply removed by evapor-
ation in vacuo. A slightly modified protocol has been developed for the homo-
logation of Fmoc-protected amino acids in which the exposition time with
basic conditions (Et3N/silver salt) is significantly reduced by actively
warming the solution to 08C and quenching with acid immediately after the
rearrangement is complete.[5] Ultrasonication[6] or microwave irradiation[7]
turned out to be useful alternatives; addition of triethyl amine proved to be
redundant with this physical activation. Although preparation of the
a-amino acid–derived diazoketones is operationally simple,[2] all methods
for a Wolff rearrangement leading to carboxylic acids hamper the laborious
workup procedure especially in large-scale preparations.[2] Herein we
present a method for a b-amino acid preparation without the need for
virtually any workup.
Encouraged by our own findings and a recent publication[7] in which Patil
et al. use microwave conditions (with water/dioxane as a solvent mixture), we
tested a microwave-assisted Wolff rearrangement of diazoketones supported
on silica gel in the presence of catalytic amounts of silver catalysts.
Although this variation worked without any problems even in a conventional
household microwave (see the experimental section), we found to our great
surprise that in the presence of silica gel and silver trifluoroacetate, neither
microwave irradiation nor any other special conditions are needed to
achieve a fast and clean rearrangement. Although other slight variations are
conceivable and similarly practicable, we recommend the following especially
simple procedure:
Silica gel and catalytic amounts of silver trifluoroacetate were added to
the N-protected a-amino diazoketone[2] dissolved in a suitable solvent (we
tested ethyl acetate). The flask was attached to a rotary evaporator,
immersed in the bath (508C) and rotated for 15 min. (Stirring or even
shaking should be similarly applicable). Filtration of the mixture and evapor-
ation of the filtrate gave the b-amino acids in excellent yields (92–97%,
Table 1) without significant impurities. The purity of the products is at least
as high as with the originally proposed methods. Although the purity is
usually sufficient for further reactions, it can be increased by a single recrys-
tallization as has been reported elsewhere.[2] The silver salts stay bound to the
silica gel, and the small amount of trifluoroacetic acid is removed in vacuo (bp
728C). The water needed in this reaction obviously comes from the silica gel.
That protocol can be employed with all conventional protecting groups (i.e., Z,
Boc, Fmoc) and for a wide range of amino acids (Scheme 1).
A very slow reaction if any reaction at all is observed without addition of
silica gel. Furthermore it should be noted that silver benzoate as a catalyst

Protected a- to b-Amino Acid Homologation
2791
Table 1. Wolff rearrangement in the presence of silica gel
Parent
amino acida
b-Amino Yield
(%)
Entry
Ra
PGa
Diazoketone
acid
1
2
3
4
5
Me
iPr
Ala
Val
Z
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
96
96
94
95
92
Z
Fmoc
iBu
sBu
tBu
Leu
Ile
Z
Z
Tle (tert-
Leucine)
Phe
6
7
Bn
Z
Boc
1f
1g
2f
2g
97
93
Z-NH-(CH2)4- Lys(Z)
aZ: benzyloxycarbonyl, Fmoc: 9H-fluoren-9-ylmethyloxycarbonyl, Boc: tert-
butyloxycarbonyl.
gives similar results but leads to a significantly more sluggish reaction.
Additionally, the remnant of the catalyst, benzoic acicd, is not volatile and
thus can be hardly removed from the product.
Although the synthesis of protected b-amino acid methyl esters is simple
with the originally proposed methods (the side products are easily removed
during the extractive workup),[8] it is similarly performed with this method.
When methanol is used instead of ethyl acetate, the methyl ester is isolated
in virtually quantitative yield without significant amounts of impurities. We
tested this with diazoketone 1d derived from Z-protected valine and got its
homologated derivative 3 in 93% yield.
EXPERIMENTAL
General Procedure for a Microwave-Assisted Rearrangement
N-protected a-amino diazoketone[2] was dissolved in AcOEt. Silver trifluoroa-
cetate (4mol%) and silica gel (1 g per 100 mg of diazoketone) were added,
and the solvent was carefully evaporated at reduced pressure. The resulting
Scheme 1.

2792
K. Koch and J. Podlech
powder was exposed in an open vessel to microwave irradiation (in a conven-
tional household microwave) for 50s. After cooling, the mixture was
extracted with AcOEt. Evaporation of the washings yielded the N-protected
b-amino acid.
General Procedure for a Rearrangement in the Presence
of Silica Gel in a Water Bath
N-protected a-amino diazoketone[2] was dissolved in AcOEt (5–10 ml per
100 mg of diazoketone). Silver trifluoroacetate (4 mol%) and silica gel (1 g
per 100 mg of diazoketone) were added, and the flask was immersed with
shaking or stirring into a water bath (508C) for 15 min. We preferred to
rotate it attached to a rotary evaporator. The mixture was filtrated and
washed with AcOEt, and the filtrate was evaporation to yield the
N-protected b-amino acid. When MeOH was used as solvent, the respective
methyl ester was isolated.
2a.[9] (S)-3-(Benzyloxycarbonylamino)butanoic acid: [a]2D0 225.6
1
(c ¼ 0.80, CHCl3); H NMR (500.0 MHz, CDCl3): d ¼ 1.30 (d, J ¼ 6.7 Hz,
3H, 4-H3), 2.62 (br. s, 2H, 2-H2), 4.15 (br. s, 1H, 3-H), 5.10–5.24 (m, 3H,
OCH2, NH), 7.32–7.42 (m, 5H, Ph), 10.5 (br. s, 1H, COOH).
2b[10] (R)-3-(Benzyloxycarbonylamino)-4-methylpentanoic acid: [a]2D0
1
216.5 (c ¼ 1.1, CHCl3); H NMR (500.0 MHz, CDCl3): d ¼ 0.95 and 0.96
(2d, J ¼ 6.3, 6.3 Hz, 6H, 2CH3), 1.91 (dqq, J ¼ 7.1 Hz, 1H, 4-H), 2.63 (dd,
J ¼ 16.2, 7.7 Hz, 1H, 2-HA), 2.72 (dd, J ¼ 16.1, 4.5 Hz, 1H, 2-HB), 3.89
(mc, 1H, 3-H), 5.04–5.13 (m, 3H, OCH2, NH), 7.31–7.38 (m, 5H, Ph).
2c[7a] (S)-3-[(9H)-Fluoren-9-ylmethoxycarbonylamino]-5-methylhexa-
noic acid: [a]2D0 230.0 (c ¼ 0.15, CHCl3); H NMR (400.0 MHz, CDCl3):
1
d ¼ 0.90 and 0.91 (2d, J ¼ 6.2, 6.2 Hz, 6H, 2 CH3), 1.24–1.38, 1.51–1.64
(2 m, 3H; 5-H, 4-H2), 2.61 (dd, J ¼ 16.5, 5.5 Hz, 1H, 2-HA), 2.72 (dd,
J ¼ 16.5, 5.1 Hz, 1H, 2-HB), 4.07 (dddd, J ¼ 5.1 Hz, 1H, 3-H), 4.17
(dd, J ¼ 6.7 Hz, fluorenyl-9-H), 4.34 (dd, J ¼ 10.6, 7.0 Hz, 1H, OCHA),
4.38 (dd, J ¼ 10.7, 7.6 Hz, 1H, OCHB), 5.05 (d, J ¼ 9.1 Hz, 1H, NH), 7.28
(dd, J ¼ 7.8 Hz, 2H, fluorenyl-H), 7.37 (dd, J ¼ 7.3 Hz, 2H, fluorenyl-H),
7.55 (d, J ¼ 7.1 Hz, 2H, fluorenyl-H), 7.74 (d, J ¼ 7.5 Hz, 2H, fluorenyl-H).
2d[11] (3R,4S)-3-(Benzyloxycarbonylamino)-4-methylhexanoic acid:
[a]2D0 230.4 (c ¼ 1.0, CHCl3); 1H NMR (400.0 MHz, CDCl3): d ¼ 0.88
(d, J ¼ 6.6 Hz, 3H, CH-CH3), 0.89 (t, J ¼ 7.8 Hz, 3H, CH2-CH3), 1.09
(dddq, J ¼ 6.6 Hz, 1H, 4-H), 1.43–1.55 (m, 1H, 5-HA), 1.55–1.70 (m, 1H,
5-HB), 2.57 (dd, J ¼ 16.0, 7.9 Hz, 1H, 2-HA), 2.67 (dd, J ¼ 16.0, 4.2 Hz,
1H, 2-HB), 3.89–3.98 (m, 1H, 3-H), 5.01 (d, J ¼ 12.2, 1H, OCHA), 5.07
(d, J ¼ 12.3, 1H, OCHB), 5.11 (d, J ¼ 9.6 Hz, 1H, NH), 7.27–7.35
(m, 5H, Ph).
2e: (R)-3-(Benzyloxycarbonylamino)-4,4-dimethylpentanoic acid: [a]D20
211.2 (c ¼ 1.4, CHCl3); 1H NMR (500.0 MHz, CDCl3, major–minor

Protected a- to b-Amino Acid Homologation
2793
rotamer ¼ 70 : 30): major rotamer: d ¼ 0.95 [s, 9H, C(CH3)3], 2.32 (dd,
J ¼ 15.3, 9.8 Hz, 1H, 2-HA), 2.66 (dd, J ¼ 15.2, 3.8 Hz, 1H, 2-HB), 4.01
(ddd, J ¼ 9.9, 3.9 Hz, 1H, 3-H), 5.07 (d, J ¼ 10.2 Hz, 1H, NH), 5.08
(d, J ¼ 12.3 Hz, 1H, OCHA), 5.14 (d, J ¼ 12.2 Hz, 1H, OCHB), 7.29–7.38
(m, 5H, Ph), 9.75 (br. s, 1H, OH); minor rotamer: d ¼ 0.91 [s, 9H,
C(CH3)3], 2.32 (dd, J ¼ 15.3, 9.8 Hz, 1H, 2-HA), 2.62 (dd, J ¼ 15.7, 3.2 Hz,
1H, 2-HB), 3.95 (ddd, J ¼ 10.4, 3.3 Hz, 1H, 3-H), 5.13 (d, J ¼ 12.0 Hz, 1H,
OCHA), 5.19 (d, J ¼ 12.3 Hz, 1H, OCHB), 6.08 (d, J ¼ 10.2 Hz, 1H, NH),
7.29–7.38 (m, 5H, Ph), 9.9 (br. s, 1H, OH).
[9]
2f:
(S)-3-(Benzyloxycarbonylamino)-4-phenylbutanoic acid: [a]D20
1
235.8 (c ¼ 0.90, CHCl3); H NMR (400.0 MHz, CDCl3): d ¼ 2.49–2.70
(m, 2H, 4-H2), 2.89 (dd, J ¼ 13.5, 7.7 Hz, 1H, 2-HA), 2.97 (dd, J ¼ 13.6,
6.7 Hz, 1H, 2-HB), 4.19–4.29 (m, 1H, 3-H), 5.02 (d, J ¼ 13.4 Hz, 1H,
OCHA), 5.08 (d, J ¼ 13.3 Hz, OCHB), 5.19 (d, J ¼ 8.6 Hz, 1H, NH), 7.17–
7.36 (m, 10H, 2 Ph).
2g: (S)-7-(Benzyloxycarbonylamino)-3-(tert-butyloxycarbonylamino)-
heptanoic acid: [a]2D0 210.9 (c ¼ 1.2, CHCl3); 1H NMR (500.0 MHz,
CDCl3): d ¼ 1.34–1.59 (m, 6H, 4-H2, 5-H2, 6-H2), 1.44 [s, 9H, C(CH3)3],
2.52–2.57 (m, 2H, 2-H2), 3.15–3.23 (m, 2H, 7-H2), 3.80–3.95 (m, 1H,
3-H), 4.98–5.20 (m, 4H, OCH2, 2NH), 7.30–7.39 (m, 5H, Ph), 8.8
(br. s, 1H, COOH).
3:[12] Methyl (R)-3-(benzyloxycarbonylamino)-4-methylpentanoate:
[a]2D0 226.7 (c ¼ 1.4, CHCl3); 1H NMR (400.0 MHz, CDCl3): d ¼ 0.94
(d, J ¼ 6.8 Hz, 5-H3, 4-CH3), 1.85 (dqq, J ¼ 6.8, 6.8, 6.8 Hz, 4-H), 2.53
(dd, J ¼ 15.2, 6.5 Hz, 2-HA), 2.57 (dd, J ¼ 15.2, 4.6 Hz, 2-HB), 3.67
(s, 100-H3), 3.84 (dddd, J ¼ 9.6, 6.8, 6.0, 6.0 Hz, 3-H), 5.11 (s, 40-H2), 5.16
(d, J ¼ 9.1 Hz, NH), 7.28–7.38 (m, 5 Ar-H).
ACKNOWLEDGMENT
This work was supported by the Deutsche Forschungsgemeinschaft.
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