Approaches to α-amino acids via rearrangement to electron-deficient nitrogen: Beckmann and Hofmann rearrangements of appropriate carboxyl-protected substrates

Article abstract of DOI:10.3762/bjoc.8.161

The titled approaches were effected with various 2-substituted benzoylacetic acid oximes 3 (Beckmann) and 2-substituted malonamic acids 9 (Hofmann), their carboxyl groups being masked as a 2,4,10-trioxaadamantane unit (an orthoacetate). The oxime mesylates have been rearranged with basic Al2O3 in refluxing CHCl3, and the malonamic acids with phenyliodoso acetate and KOH/MeOH. Both routes are characterized by excellent overall yields. Structure confirmation of final products was conducted with X-ray diffraction in selected cases. The final N-benzoyl and N-(methoxycarbonyl) products are α-amino acids with both carboxyl and amino protection; hence, they are of great interest in peptide synthesis.

Full text of DOI:10.3762/bjoc.8.161

Approaches to α-amino acids via rearrangement to
electron-deficient nitrogen: Beckmann and
Hofmann rearrangements of appropriate
carboxyl-protected substrates
Sosale Chandrasekhar* and V. Mohana Rao
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1393–1399.
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560 012, India
doi:10.3762/bjoc.8.161
Received: 06 June 2012
Accepted: 27 July 2012
Published: 29 August 2012
Email:
Sosale Chandrasekhar* - sosale@orgchem.iisc.ernet.in
* Corresponding author
Associate Editor: D. Y.-K. Chen
Keywords:
© 2012 Chandrasekhar and Rao; licensee Beilstein-Institut.
License and terms: see end of document.
amino acid; Beckmann rearrangement; Hofmann rearrangement;
orthoacetate; trioxaadamantane
Abstract
The titled approaches were effected with various 2-substituted benzoylacetic acid oximes 3 (Beckmann) and 2-substituted
malonamic acids 9 (Hofmann), their carboxyl groups being masked as a 2,4,10-trioxaadamantane unit (an orthoacetate). The oxime
mesylates have been rearranged with basic Al2O3 in refluxing CHCl3, and the malonamic acids with phenyliodoso acetate and
KOH/MeOH. Both routes are characterized by excellent overall yields. Structure confirmation of final products was conducted with
X-ray diffraction in selected cases. The final N-benzoyl and N-(methoxycarbonyl) products are α-amino acids with both carboxyl
and amino protection; hence, they are of great interest in peptide synthesis.
Introduction
The synthesis of α-amino acids remains of continuing interest via synthesis. "Non-natural amino acids" also include the ste-
for at least two reasons: Firstly, obtaining a particular amino reochemical alternative D-forms. This leads to additional chal-
acid via protein hydrolysis implies its separation from other lenges regarding chiral synthesis.
amino acids (and their possible wastage, particularly on large
scales). Secondly, the burgeoning of peptide science and protein The challenges in the synthesis of α-amino acids essentially
engineering places significant demands on the supply of non- stem from the fact that the methods which are normally
natural amino acids, which would generally be accessible only employed for the independent synthesis of the carboxyl and
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Beilstein J. Org. Chem. 2012, 8, 1393–1399.
amine functionalities, are often mutually incompatible. Thus, hydrogenation of phloroglucinol, the trans-orthoesterification
for example, the oxidation of alcohols to carboxylic acids, or being catalyzed by BF3 etherate.
the Gabriel phthalimide synthesis cannot be performed in a
routine way in the presence of the second functionality. Clas- The trioxaadamantyl group is extremely stable particularly
sical approaches essentially circumvented these limitations and under neutral and basic conditions [16]. Moreover, the trioxa-
ingenious improvements have evolved over the years [1].
adamantyl group can be selectively cleaved under acid catalysis,
either to the carboxylic acid or directly to the ester, as demon-
Classical approaches continue to be investigated (most notably strated previously [16].
the Strecker reaction) [2], but recent developments focus on
cycloadditions [3], rare amino acids [4], chiral catalysis [5], etc. This carboxyl protection prevents the strategy from complica-
It is noteworthy, however, that two of the most widely applied tions arising from the opportunistic side reactions observed in
methods for the introduction of the amine group – the previous studies [8,9,13]. This has enabled the execution of two
Beckmann [6-9] and the Hofmann [10-13] rearrangements – are approaches to amino acids in which the key step is either the
not represented in these approaches. This is perhaps surprising, Beckmann or the Hofmann rearrangement, as described in the
but understandable when the inherent instability of the requisite following.
substrates is considered.
Results and Discussion
Thus, in the Beckmann approach, the oximation of β-keto acid Beckmann rearrangement approach
derivatives would be complicated by competing deacylation, The key substrate is the known 3-phenacyl-2,4,10-trioxaada-
hydroxamic acid formation, etc. We are only aware of two mantane (1, Scheme 1) [14-16]. (An improved preparation of 1
reports [8,9] of the Beckmann rearrangement of β-keto ester is also presented herein). Ketone 1 was α-alkylated in high
oximes. A particular problem was the formation of isoxazolone yields to various 2 via sodium hydride deprotonation and reac-
byproducts, which apparently limited the synthesis to α,α-disub- tion of the resulting enolate with a variety of alkyl bromides or
stituted derivatives. Likewise, the Hofmann approach would be iodides. Alkyl derivatives 2 may be converted conventionally to
complicated by the dubious stability of the malonamic acid the corresponding oximes 3. The Beckmann rearrangement of 3
substrates; a previous report indeed suggests that these suspi- to the N-benzoyl derivative 5 is accomplished (generally) in
cions are well-founded [13].
high overall yields via a two-step sequence: Methanesulfonyla-
tion to compounds 4, which are heated under reflux in CHCl3 in
The key to success, therefore, is efficient carboxyl protection. the presence of basic Al2O3 (Table 1) [17].
Herein, we report a novel approach in which this is accom-
plished via the 2,4,10-trioxaadamantyl group, a proven masking The formation of the desired N-benzoyl-trioxaadamantylmeth-
group first described by Stetter [14] and Bohlmann [15] and ylamines 5 indicates the Z geometry at the oximes 3 with the
extended by us [16]. The trioxaadamantyl group, a tricyclic hydroxy and adamantylmethyl moieties being mutually anti.
orthoformate, may be introduced by trans-orthoesterification of This apparently enables the Beckmann reaction – with its char-
an appropriate trimethyl orthoester with all-cis 1,3,5-trihydroxy- acteristic anti-migration – to occur smoothly. The presumed Z
cyclohexane. This is accessible via Raney-Nickel catalyzed geometry has, in fact, been confirmed for the methyl derivative
Scheme 1: The transformation of the phenacyltrioxaadamantane 1 to the N-benzoyltrioxaadamantylmethylamine 5 via alkylation to 2 and the key
Beckmann rearrangement of the oxime 3 to 5 ("Mes" represents methanesulfonyl; trioxaadamantane numbering is shown in 1). Conditions: (i) NaH,
THF, rt; RX, reflux; (ii) NH2OH·HCl, pyridine, EtOH, reflux; (iii) MeSO2Cl, Et3N, CH2Cl2, −10 °C; (iv) basic Al2O3, CHCl3, reflux.
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Beilstein J. Org. Chem. 2012, 8, 1393–1399.
Table 1: Percentage yields of intermediate and final products of the transformation of 1 to 5 (Scheme 1) along with reaction times for their formation.
Entry
2–5
R–X
Yield (%) (reaction time/h)
2
3
5
1
2
3
4
5
6
a
b
c
d
e
f
MeI
96 (2)
89 (12)
79 (12)
97 (4)
96 (4)
94 (4)
77 (1)
82 (2)
74 (6)
84 (8)
76 (3)
73 (11)
98 (2)
94 (2)
93 (2)
96 (2)
97 (2)
93 (2)
n-PrI
i-BuI
PhCH2Br
CH2=CH–CH2Br
HC≡C–CH2Br
3a and the corresponding amide product 5a by X-ray diffrac- Attempted Beckmann rearrangement of 3 under several other
tion measurements (Figure 1 and Table 2) [18]. The observed conditions was largely unsuccessful. These conditions were:
oxime stereochemistry (Z) is possibly due to (putative) steric PCl5/dioxane, AlCl3/CHCl3, BF3·Et2O/CHCl3, p-toluenesul-
repulsion between the two bulky α-substituents (R and trioxa- fonic acid/MeCN (all at reflux). The products of the transforma-
adamantyl) and the hydroxy group in the alternative E isomer. tions (2–5) described above were fully characterized spectro-
scopically (including high resolution mass spectrometry,
HRMS) apart from X-ray diffraction in the cases mentioned
earlier.
The final N-benzoyltrioxaadamantylmethylamine products 5
represent α-amino acids which are protected at both the
carboxyl and the amine centers. The 2,4,10-trioxaadamantyl
group may be cleaved with acid as reported previously [16];
alternatively, selective cleavage of the N-benzoyl group in base
would furnish carboxyl-protected amino acids with a free amine
function: all attractive tactical elaborations vis-à-vis peptide
Figure 1: Crystallographic ORTEP diagram at 30% ellipsoidal proba-
bility of oxime 3a (left) and amide 5a (right, Scheme 1, Table 1) [18].
synthesis. Moreover, the transformation of 1 to 5 indicates that
1 functions as a glycine enolate equivalent with the benzoyl-
amino group in 5 being introduced in umpolung fashion (reac-
The geometry around the partial double bond of the amide C–N tion involves the migration to an electrophilic nitrogen center).
linkage in 5a is also Z (Figure 1). This is probably a conse-
quence of steric repulsion between the N-substituent and the Hofmann rearrangement approach
phenyl residue in the alternative E isomer. NMR spectra like- Our strategy was based on the known ethyl trioxaadamantylace-
wise did not indicate isomerism around the amide C–N bond in tate 6 (Scheme 2) [15]. Alkylation of this compound was
solution in any of the cases studied.
accomplished via initial deprotonation with lithium hexamethyl-
disilazide in THF at −78 °C [19]. The resulting enolate was
reacted with various alkyl bromides or iodides, initially at
−78 °C and then at room temperature over 6–8 h. The α-alkyl
derivatives 7 were formed in excellent yields (Table 3).
Table 2: Key crystallographic data for oxime 3a and amide 5a,
representative substrate and product of the Beckmann rearrangement
(Scheme 1, Figure 1) [18].
property
3a
5a
The α-alkyl derivatives 7 were hydrolyzed with potassium tert-
butoxide and water in ether [20], the corresponding acids 8
being obtained in excellent yields (Table 3). Conventional
hydrolysis with aqueous KOH was unsuccessful, probably for
steric reasons.
crystal system
space group
volume of unit cell (Å)3
Rall, Robs
orthorhombic
Pbca
monoclinic
P1 21/n 1
1431.9 (4)
0.079, 0.043
1.021
2851.29 (17)
0.100, 0.048
0.929
G.o.F.
The conversion of acids 8 to their amides was carried out via
initial activation with DCC (dicyclohexylcarbodiimide) and
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Scheme 2: The transformation of the ethyl (trioxaadamantyl)acetate 6 to the N-(methoxycarbonyl)trioxaadamantylmethylamine 10, via alkylation to 7,
hydrolysis to 8, conversion to amide 9, and its Hofmann rearrangement via putative N-acetoxy derivative I. Conditions: (i) (Me3Si)2N−Li+, THF, −78 °C,
RX, 0.5 h; warm to rt, 6–8 h; (ii) t-BuO−K+, H2O, Et2O, 12–18 h; (iii) DCC, C6F5OH, EtOAc, 10 °C, 3 h, filter; filtrate: −20 °C, NH3, 0.5 h; rt, 6 h;
(iv) PhI(OAc)2, KOH, MeOH, 5–10 °C, 15 min; then rt, 1 h.
Table 3: Percentage yields of intermediate and final products of the transformation of 6 to 10 (Scheme 2) along with reaction times for their
formation.a
Entry
7–10
R–X
Yield (%) (reaction time/h)
7
8
9
10
1
2
3
4
5
6
a
b
c
d
e
f
MeI
93 (6)
90 (8)
86 (8)
92 (6)
94 (6)
91 (6)
89 (18)
86 (18)
91 (18)
92 (18)
88 (18)
90 (12)
91
93
92
94
90
92
94
94
93
96
91
95
n-PrI
i-BuI
PhCH2Br
CH2=CH–CH2Br
4-(MeO)–C6H4CH2Br
aIsolated yields after chromatographic purification, except in the case of 8.
pentafluorophenol in ethyl acetate solution; this was followed
by reaction with ammonia gas at −20 °C. The carboxamides 9,
substrates for the key Hofmann rearrangement step, were thus
formed in excellent yields (Table 3).
The Hofmann rearrangement of carboxamides 9 was accom-
plished with one molar equivalent of phenyliodoso acetate
[PhI(OAc)2] at 5–10 °C in methanolic KOH. The choice of the
hypervalent iodine reagent was largely dictated by precedence
[21-23]. The corresponding methyl carbamates 10 were
obtained in excellent yields (Table 3).
Figure 2: Crystallographic ORTEP diagrams at 30% ellipsoidal proba-
bility of carbamates 10a (left) and 10b (right, Scheme 2, Table 3) [24].
The reaction may well occur via the putative N-acetoxy deriva-
tive I (up to now this has not been proven). The in situ trapping
of the expected isocyanate intermediate (not shown) by
methanol would explain the final formation of 10.
Table 4: Key crystallographic data for carbamates 10a and 10b, which
are representative products of the Hofmann rearrangement of amides
9 (Scheme 2, Figure 2) [24].
property
10a
10b
crystal system
space group
volume of unit cell (Å)3
Rall, Robs
orthorhombic
Pbca
monoclinic
P1 21/n 1
1397.00 (1)
0.048, 0.040
1.092
All products were generally purified chromatographically and
fully characterized spectroscopically (including HRMS). In
addition, two of the final carbamates (10a and 10b) were
confirmed by X-ray diffraction analysis (Figure 2 and Table 4)
[24]. The carbamates 10 apparently evidenced restricted rota-
2367.22 (5)
0.045, 0.034
1.064
G.o.F.
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Beilstein J. Org. Chem. 2012, 8, 1393–1399.
tion around the amide C–N moiety (partial double-bond char- extracts were generally dried with MgSO4 prior to evaporation
acter) in the NMR as seen by twin peaks in certain cases [25]. of the solvent in vacuo in a rotary evaporator. All spectral
details of compounds 2–5 and 7–10 have been collected in
In carbamates 10, the substitution pattern α to the C=O group in Supporting Information File 1.
7–9 has shifted to the α-position next to the amino center.
Therefore, in this strategy (Scheme 2) the enolate alkylation Improved preparation of phenacyltrioxaadamantane 1.
methodology has been co-opted to generate substitution α to the (2,4,10-Trioxaadamantylmethyl) phenyl carbinol [16] (not
amino group, i.e., the (trioxaadamantyl)acetate 6 functions shown) was oxidized by 2-iodoxybenzoic acid as follows. The
potentially as a glycine enolate equivalent.
carbinol (0.500 g, 1.91 mmol) in EtOAc (10 mL) was treated
with 2-iodoxybenzoic acid (1.070 g, 3.82 mmol), and the mix-
It is also noteworthy that, as the Hofmann rearrangement ture was heated under reflux for 4 h. Then, it was cooled to
involves migration to electron-deficient nitrogen [10-12], the 25 °C and stirred with solid NaHCO3 for 0.5 h. The insolubles
amino group is being introduced in umpolung fashion in the were filtered off and the filtrate was concentrated in vacuo. The
strategy described above. Generally, the amino group is intro- resulting residue was purified by column chromatography on
duced nucleophilically, e.g., in the Gabriel method.
grade 1 neutral alumina to obtain phenacyl derivative 1
(0.468 g, 1.80 mmol, 94%), identified by mp (105–106 °C) and
The trioxaadamantylmethylamine carbamates 10 also represent spectral comparison [16].
α-amino acids with both carboxyl and amino group protection.
The methyl carbamates are clearly less robust than the BOC Alkylation of 1 to 2. NaH (1.2 mmol) was washed with Na/dry
analogues which are frequently employed in peptide synthesis. hexane, covered with dry THF (1.0 mL) and treated with a solu-
However, the former do offer a measure of protection that can tion of 1 (1.0 mmol) in dry THF (6.0 mL) at 0 °C. The mixture
be selectively relinquished in base. The trioxaadamantyl group was stirred for 10 min, treated with the alkyl halide (RX,
would stay unaffected under these conditions, but may be 1.2 mmol) and heated under reflux for the indicated time
cleaved off with acid (possibly selectively). These conversions (Table 1). The reaction mixture was cooled to room tempera-
would be of considerable value in peptide synthesis strategy.
ture, worked-up with ice-water and extracted with EtOAc.
Purification by column chromatography on grade 1 neutral
alumina furnished 2.
Conclusion
Rationally designed, controlled approaches to α-amino acid
synthesis via two classical reactions have been demonstrated. Oximation of 2 to 3. Alkylketones 2 were converted to the
The key step is based on the Beckmann and the Hofmann corresponding oximes 3 with NH2OH·HCl-pyridine by stan-
rearrangements, two of the standard methods for the introduc- dard procedures [26] and purified by crystallization (solids).
tion of the amino functionality into molecules. The strategy is
enabled by efficient carboxyl protection via the 2,4,10-trioxa- Oxime methanesulfonates 4. Oximes 3 (1.0 mmol) in CH2Cl2
adamantane moiety, which stabilizes the respective precursor (3.0 mL) were cooled to −10 °C and treated with Et3N
substrates to opportunistic side reactions. Overall yields are (1.2 mmol) followed by MeSO2Cl (1.5 mmol). The mixtures
excellent and the starting materials are accessible by standard were stirred for 2 h and washed with water, etc. The crude
methods. The α-alkyl groups are introduced via an enolate mixtures were purified by column chromatography on grade 1
alkylation strategy, thus providing variety and the potential for neutral alumina to obtain 4.
molecular diversity. The key rearrangement steps are generally
effected under fairly mild conditions.
Beckmann rearrangement of 4 to final amides 5 [17]. Mesyl-
ates 4 (1.0 mmol) in CHCl3 (5.0 mL) were treated with basic
alumina (0.25 g) and the mixtures were heated under reflux for
Experimental
General comments. Instruments employed: JASCO 410 2 h. After cooling to room temperature, the alumina was filtered
(FTIR); Bruker AV-400 (NMR); Micromass Q-TOF AMPS off and the solvent was removed in vacuo. The residues were
MAX 10/6A (HRMS); Stuart SMP10 (melting point); Büchi purified by column chromatography on grade 1 neutral alumina
Rotavapor R-200 (rotary evaporator).
to obtain the pure amides 5.
The phenacyl 1 and acetate 6 derivatives of 2,4,10-trioxaada- Alkylation of ethyl trioxaadamantylacetate 6 to 7 [19]. A
mantane were prepared as reported previously [14-16]. stirred solution of 6 (2.0 mmol) in dry THF (8.0 mL) at −78 °C
However, an improved oxidation procedure for the preparation was treated with lithium hexamethyldisilazide (1.0 M in THF,
of 1 is reported below. Upon aqueous work-up and extraction, 2.4 mL, 2.4 mmol). After 0.5 h, the resulting enolate solution
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Beilstein J. Org. Chem. 2012, 8, 1393–1399.
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was treated with the alkyl halide (2.2 mmol) over ~2 min and
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temperature, stirred as indicated (Table 3), worked up with aq
NH4Cl and extracted with EtOAc etc., followed by SiO2
column chromatography.
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(1.0 mmol) and the mixture stirred at room temperature as indi-
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been deposited in the Cambridge Crystallographic Data Base,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, (U. K.), (email: deposit@ccdc.cam.ac.uk), and can be
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Supporting Information
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Supporting Information File 1
Characterization data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-161-S1.pdf]
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Acknowledgements
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We are grateful to CSIR (New Delhi) for generous fellowship
support to V. M. R.
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