Synthesis of novel α-substituted and α,α-disubstituted amino acids by rearrangement of ammonium ylides generated from metal carbenoids

Article abstract of DOI:10.1021/ol017240j

(equation presented) A new and general four-step synthesis of protected a-substituted and α,α-disubstituted amino acids has been developed. The key step involves intramolecular ammonium ylide generation from a copper carbenoid with concomitant [2,3] rearr

Full text of DOI:10.1021/ol017240j

ORGANIC
LETTERS
2002
Vol. 4, No. 5
765-768
Synthesis of Novel r-Substituted and
r,r-Disubstituted Amino Acids by
Rearrangement of Ammonium Ylides
Generated from Metal Carbenoids
J. Stephen Clark* and Mark D. Middleton
School of Chemistry, UniVersity of Nottingham, UniVersity Park,
Nottingham NG7 2RD, U.K.
j.s.clark@nottingham.ac.uk
Received December 17, 2001
ABSTRACT
A new and general four-step synthesis of protected r-substituted and r,r-disubstituted amino acids has been developed. The key step
involves intramolecular ammonium ylide generation from a copper carbenoid with concomitant [2,3] rearrangement. The aromatic template
serves as a tether, protecting group, and activating group for peptide coupling. The ylide rearrangement products can be converted into
protected cyclic amino acids by ring-closing metathesis.
Rare and non-natural R-substituted and R,R-disubstituted
amino acids are of increasing importance for the preparation
of conformationally restricted peptide analogues and peptide
libraries. The lack of availability of these compounds from
natural sources necessitates the development of efficient
methods for their synthesis.1
The [2,3]-sigmatropic or [1,2]-Stevens rearrangement of
ammonium ylides generated by reaction of amines with metal
carbenoids produced by transition metal catalyzed decom-
position of diazo ketones and esters has been shown to be a
powerful strategy for the synthesis of nitrogen heterocyles.2-4
West and Naidu have used the [1,2]-Stevens rearrangement
of carbenoid-derived ammonium ylides to prepare R-amino
acid derivatives and morpholinones.5 However, the resulting
amino acid derivatives are not readily amenable to the
attachment of additional amino acids.
We now describe a general method for the rapid synthesis
of highly functionalized amino acids in a form that allows
them to be readily incorporated into polypeptides. The
method involves the generation of an ammonium ylide by
intramolecular trapping of a metal carbenoid by an allylic
amine and subsequent rearrangement to give an azalactone
(Scheme 1). In principle, this tandem reaction offers a highly
flexible route to amino acids bearing a variety of unusual
(3) (a) For examples of [2,3]-sigmatropic rearrangement of ammonium
ylides derived from metal carbenoids, see: (a) Clark, J. S.; Hodgson, P. B.
Chem. Commun. 1994, 2701. (b) Clark, J. S.; Hodgson, P. B. Tetrahedron
Lett. 1995, 36, 2519. (c) Wright, D. L.; Weekly, R. M.; Groff, R.; McMills,
M. C. Tetrahedron Lett. 1996, 36, 2165.
(1) (a) Williams, R. M.; Hendrix, J. A. Chem. ReV. 1992, 92, 889. (b)
Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9,
3517. (c) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789.
(2) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley: New York, 1998.
(4) (a) For examples of [1,2]-Stevens rearrangement of ammonium ylides
derived from metal carbenoids, see: (a) West, F. G.; Naidu, B. N. J. Am.
Chem. Soc. 1993, 115, 1177. (b) West, F. G.; Naidu, B. N. J. Am. Chem.
Soc. 1994, 116, 8420.
(5) (a) West, F. G.; Glaeske, K. W.; Naidu, B. N. Synthesis 1993, 977.
(b) West, F. G.; Naidu, B. N. J. Org. Chem. 1994, 59, 6051.
10.1021/ol017240j CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/02/2002

Scheme 1. General Strategy for Amino Acid Synthesis
Scheme 2a
groups (X) at the R position. Stereoselective substitution at
the â position is also possible when an appropriately
substituted (R2 and/or R3 * H) allylic amine precursor is
used. An aromatic template was chosen to tether the
diazocarbonyl group to the amine in order to deliver a high
yielding intramolecular reaction. It was anticipated that the
aromatic group would also function as a protecting group
for the carboxyl and amino groups and would activate the
carboxyl group to permit direct coupling to other amino
acids. Thus, it was anticipated that exposure of the diazoke-
tone 1 to a suitable catalyst (MLn) would result in sequential
carbenoid and ylide (2) generation (Scheme 1). Subsequent
rearrangement would deliver the azalactone 3, which would
be converted into the amino acid 4 by lactone hydrolysis
and cleavage of the benzylic groups.
a Reagents and conditions: (a) (i) H2NCH2Ph, 4 Å sieves, EtOH,
(ii) NaBH4, EtOH, 96%; (b) BrCH2CHdCH2, K2CO3, MeCN 91%;
(c) (i) KH, THF, (ii) succinimidyl diazoacetate, THF, 45% (73%
based on recovered 7); (d) diketene, p-ABSA, Et3N, MeCN, 65%;
(e) ClCOCN2CO2Et, 2,6-lutidine, CH2Cl2, 74%; (f) t-BuMe2SiOTf,
i-Pr2NEt, Et2O, -78 °C, 75%; (g) K2CO3, D2O, THF, rt, 84% (96%
D-incorporation); (h) HO2CCH2PO(OEt)2, DCC, DMAP, CH2Cl2,
85%; (i) p-ABSA, DBU, MeCN, 62%.
transfer with p-ABSA afforded the R-phosphonyl diazoac-
etate 8f (Scheme 2).
The synthesis of the diazoketones required for initial
studies commenced with reductive amination of salicylal-
dehyde (5) with benzylamine (Scheme 2). Alkylation of the
amine 6 with allyl bromide delivered the amine 7 in excellent
yield. The diazoacetate 8a was prepared in reasonable yield
by treatment of the phenol 7 with succinimidyl diazoacetate.6
Diketene addition and in situ diazo transfer following Doyle’s
procedure gave poor yields of the diazoacetoacetate 8b.7
However, when p-acetamido-benzenesulfonyl azide (p-
ABSA) and triethylamine were used instead of methane-
sulfonyl azide and sodium acetate, the diazoacetoacetate 8b
was obtained in good yield.8 Acylation of the phenol 7 using
ethyl 2-diazomalonyl chloride provided the substrate 8c in
good yield.9 The diazoacetate 8d was prepared using Regitz’s
procedure: reaction of the diazoacetate 8a with tert-
butyldimethylsilyl triflate and Hu¨nig’s base.10 The synthesis
of the deuterated diazoacetate 8e (96% D-incorporation) was
accomplished by treatment of 8a with potassium carbonate
in D2O and THF. Finally, coupling of the phenol 7 to
diethylphosphonoacetic acid gave 9 and subsequent diazo
The copper- and rhodium-catalyzed generation of am-
monium ylides was investigated. In previous studies we had
shown that copper(II) acetylacetonate [Cu(acac)2] was the
best catalyst for carbenoid generation from unsubstituted
diazoketones. However, we and West and co-workers had
found that carbenoids generated using copper(II) hexafluo-
roacetylacetonate [Cu(hfacac)2] react with ethers to produce
oxonium ylides, which rearrange to give cyclic ethers in
excellent yield,11 and rhodium(II) acetate has been used to
generate ammonium ylides in an intermolecular fashion.12
To identify the best catalyst for ylide generation, we explored
the effectiveness of all three complexes (Table 1).
It transpired that similar yields of the rearrangement
products 10 were obtained using either Cu(acac)2 or Cu-
(hfacac)2, but inferior yields were obtained when Rh2(OAc)4
was used for carbenoid generation. A variety of groups could
be accommodated adjacent to the diazo group, allowing the
preparation of protected amino acids bearing ketone (10b),
ester (10c), and phosphonate (10f) groups at the R position.
Protected R-deuterated allyl glycine was also prepared.
Unfortunately, the copper-catalyzed reaction of the trialkyl-
silyl-substituted compound 10d afforded the C-H insertion
product 11 instead of the expected ylide rearrangement
(6) Quihia, A.; Rene, L.; Guilhem, J.; Pascard, C.; Badet, B. J. Org.
Chem. 1993, 58, 1641.
(7) Doyle, M. P.; Bagheri, V.; Wandless, T. J.; Harn, N. K.; Brinker, D.
A.; Eagle, C. T.; Loh, K. L. J. Am. Chem. Soc. 1990, 112, 1906.
(8) Baum, J. S.; Shool. D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709.
(11) (a) Clark, J. S.; Krowiak, S. A.; Street, L. J.Tetrahedron Lett. 1993,
(9) Marino, J. P.; Osteerhout, A. T.; Price, A. T.; Sheehan, S. M.; Padwa,
A. Tetrahedron Lett. 1994, 35, 849.
(10) Mass, G.; Gimmy, M.; Regitz, M. J. Organomet. Chem. 1985, 290,
33.
34, 4385. (b) West, F. G.; Naidu, B. N.; Tester, R. W. J. Org. Chem. 1994,
59, 6892.
(12) Doyle, M. P.; Tamblyn, W. H.; Bagheri, V. J. Org. Chem. 1981,
46, 5094.
766
Org. Lett., Vol. 4, No. 5, 2002

allylamine gave the amine 12 in good yield. Unsaturated side
chains were introduced by alkylation of the amine 12. Thus,
treatment with allyl bromide at room temperature gave the
diallylamine 13a in good yield. Higher temperatures (100
°C in DMF) and the addition of sodium iodide were required
to alkylate amine 12 with butenyl and pentenyl bromide. The
synthesis of diazoacetoacetates 14a-c was accomplished in
one pot by treatment of 13a-c with diketene and in situ
diazo transfer using p-ABSA.
Table 1. Reaction of the Diazo Compounds 8 to Form the
Azalactones 10
Treatment of 14a-c with Cu(hfacac)2 resulted in efficient
ylide formation and rearrangement to deliver the azalactones
15a-c in good yield (66-76%). Subsequent ring-closing
metathesis reactions of the rearrangement products 15a-c
proved to be high yielding (Table 2). The catalyst 16
substrate
R
catalyst
product
yield (%)
8a
8a
8a
8b
8b
8b
8c
8c
8c
8d
8e
8f
H
H
H
Cu(acac)2
Cu(hfacac)2
Rh2(OAc)4
Cu(acac)2
Cu(hfacac)2
Rh2(OAc)4
Cu(acac)2
Cu(hfacac)2
Rh2(OAc)4
Cu(hfacac)2
Cu(acac)2
Cu(acac)2
Cu(hfacac)2
Rh2(OAc)4
10a
10a
10a
10b
10b
10b
10c
10c
10c
11
59
48
36
54
66
37
59
81
42
82
61
25
22
0
COMe
COMe
COMe
CO2Et
CO2Et
CO2Et
SiMe2t-Bu
D
PO(OEt)2
PO(OEt)2
PO(OEt)2
Table 2. Ring-Closing Metathesis Using Ruthenium Catalysts
16 and 17a
10e
10f
10f
10f
8f
8f
substrate
n
catalyst
product
yield (%)
product, probably as a result of the bulk of the silyl group.
None of the product arising from benzylic C-H insertion
was isolated from this reaction.
15a
15b
15b
15c
15c
1
2
2
3
3
16
16
17
16
17
18a
18b
18b
18c
18c
92
74
87
57
83
Cyclic amino acids are of great interest as conformationally
constrained analogues of natural amino acids.1b,c Having
established that tandem intramolecular ammonium ylide
generation and rearrangement offered a viable route to
protected amino acids, we explored the synthesis of cyclic
amino acids by performing tandem ylide generation and
rearrangement to give diene products followed by ring-
closing metathesis (RCM).13
a Catalyst 16: CH2Cl2, rt, 24 h. Catalyst 17: PhMe, 80 °C, 45 min.
facilitated ring closure of the diene 15a to give the tricyclic
product 18a in excellent yield.14 However, cyclization of the
dienes 15b and 15c proved to be less successful using the
catalyst 16, and so the more reactive ruthenium catalyst 17
was employed.15 This catalyst delivered excellent yields of
The precursors were prepared by the route shown in
Scheme 3. Reductive amination of salicylaldehyde with
Scheme 3a
the cyclic amino acid derivatives 18b and 18c. These results
are remarkable because dienes containing free amino groups
are not usually good substrates for ruthenium-catalyzed RCM
reactions. The success of our reactions is probably a
(13) For recent reviews concerning RCM reactions, see: (a) Grubbs, R.
H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (b) Schmalz,
H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1833. (c) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (d) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (e) Grubbs, R. H.; Chang,
S. Tetrahedron 1998, 54, 4413. (f) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3013.
(14) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039.
(15) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
a Reagents and conditions: (a) (i) H2NCH2CHdCH2, 4 Å sieves,
EtOH, (ii) NaBH4, EtOH 85%; (b) BrCH2CHdCH2, K2CO3, MeCN,
82% 13a; (c) Br(CH2)nCHdCH2, NaI, K2CO3, DMF, 100 °C, 68%
13b, 72% 13c; (d) diketene, p-ABSA, Et3N, MeCN, reflux, 61%
14a, 59% 14b, 64% 14c; (e) Cu(hfacac)2, benzene, reflux, 66%
15a, 76% 15b, 72% 15c.
Org. Lett., Vol. 4, No. 5, 2002
767

Scheme 4a
Scheme 5a
a Reagents and conditions: (a) NaOMe, MeOH; (b) Pd(OH)2-
C, H2 (300 psi), EtOH, rt; (c) HCO2H, Pd-C, rt, 66% 21 (2 steps),
73% 22 (2 steps).
a Reagents and conditions: EtO2CCH2NH2.HCl, DMAP, Et3N,
DMF, 84% (8 h) 19a, 91% (120 h) 19b, 85% (120 h) 20.
reflection of the steric hindrance in the dienes 15a-c, which
prevents coordination of the amine to ruthenium.16
In summary, we have developed a concise and general
metal-catalyzed route for the synthesis of both R-substituted
and R,R-disubstituted amino acids. The development of an
asymmetric variant of the reaction is currently under
investigation, and the results of these studies will be reported
in due course.
The reactive nature of the phenolic ester allows it to
function as an activating group for direct dipeptide synthesis.
To demonstrate the viability of this procedure, three of the
azalactones 10 were treated with glycine ethyl ester (Scheme
4). Gratifyingly, the monosubstituted compound 10a coupled
to give the dipeptide 19 in good yield after 8 h. The
azalactones 10b and 18b proved to be less reactive, presum-
ably as a result of hindrance due to the adjacent quaternary
center. However, good yields of the coupled products 19b
and 20 were obtained using extended reaction times.
Amino group deprotection has also been explored (Scheme
5). Attempts to deprotect the amino group by direct hydro-
genolysis of the azalactone failed. However, a two-step
sequence involving cleavage of the azalactone with sodium
methoxide and subsequent catalytic hydrogenation resulted
in debenzylation and delivered amino acid esters 21 and 22.
Acknowledgment. We thank the University of Notting-
ham for the award of a studentship to M.D.M. and Aventis
Pharmaceuticals, Bridgewater, NJ for financial support. We
thank Dr. Paul Cox (Aventis Pharmaceuticals, Bridgewater,
NJ) for his interest in this work.
Supporting Information Available: Experimental pro-
cedures and data for compounds 10a-c, 10e, 10f, 11, 18a-
c, 19a, 19b, and 20-22. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993,
115, 9856.
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Org. Lett., Vol. 4, No. 5, 2002