Catalytic, one-pot synthesis of β-amino acids from α-amino acids. Preparation of α,β-peptide derivatives

Article abstract of DOI:10.1021/jo9004487

(Chemical Equation Presented) The one-pot conversion of readily available α-amino acid into β-amino acid derivatives was carried out in good yields. The method is a sequential process initiated by a tandem radical decarboxylation-oxidation reaction; the resulting acyliminium ion was trapped by silyl ketenes. Stoichiometric and catalytic versions of this reaction were developed and then applied to prepare modified di- and tripeptides. Interestingly, some tripeptides formed expanded β-turns in the solid state.

Full text of DOI:10.1021/jo9004487

VOLUME 74, NUMBER 13
July 3, 2009
 Copyright 2009 by the American Chemical Society
Catalytic, One-Pot Synthesis of ꢀ-Amino Acids from r-Amino Acids.
Preparation of r,ꢀ-Peptide Derivatives
†
,†
,†
‡
´
Carlos Saavedra, Rosendo Herna´ndez,* Alicia Boto,* and Eleuterio Alvarez
Instituto de Productos Naturales y Agrobiolog´ıa del CSIC, AVda. Astrof´ısico Francisco Sa´nchez 3,
38206-La Laguna, Tenerife, Spain, and Instituto de InVestigaciones Qu´ımicas (CSIC-USe),
Isla de la Cartuja, AVda. Ame´rico Vespucio 49, 41092-SeVilla, Spain
alicia@ipna.csic.es
ReceiVed March 2, 2009
The one-pot conversion of readily available R-amino acid into ꢀ-amino acid derivatives was carried out
in good yields. The method is a sequential process initiated by a tandem radical decarboxylation-oxidation
reaction; the resulting acyliminium ion was trapped by silyl ketenes. Stoichiometric and catalytic versions
of this reaction were developed and then applied to prepare modified di- and tripeptides. Interestingly,
some tripeptides formed expanded ꢀ-turns in the solid state.
Introduction
temperature using visible light, such as sunlight or common
lamps.3 The scission generated a C-radical (such as 2) which
was trapped by iodine, affording an R-iodoacetal (e.g., com-
pound 3). The replacement of the iodo group by acetate ions
from the reagent gave an N,O-acetal (such as product 4). When
a Lewis acid and a nucleophile were added, the acetal generated
an acyliminium ion 5,2a which was trapped by the nucleophile
(for instance, the addition of phosphites afforded R-aminophos-
phonates 6).2b In general, good yields were obtained, and the
reaction conditions were mild, compatible with most functional
groups.
The development of tandem and sequential processes has
allowed shorter and more efficient procedures to obtain a variety
of products, including drugs, catalysts, or synthetic intermedi-
ates.1 Since several transformations are performed consecutively,
and no purification of the intermediates is required, these
processes save materials, energy, and time and decrease the
amount of waste.
In previous work, we developed a one-step methodology to
prepare bioactive products from readily available substrates
(such as the amino sugar 1, Scheme 1).2 The method was a
sequential process initiated by a tandem radical fragmenta-
tion-oxidation reaction. Remarkably, the radical scission step,
which initiated the reaction cascade, took place at room
We reasoned that this process could be applied to the direct
transformation of amino acids into nonproteinogenic analogues
and, moreover, to the selective transformation of peptides
(Scheme 2). In a preliminary work, the conversion of R-amino
* To whom correspondence should be addressed. Phone: +34-922-260112
(Ext 267). Fax: +34 922260135. E-mail: alicia@ipna.csic.es.
(2) (a) Boto, A.; Herna´ndez, R.; Leo´n, Y.; Murgu´ıa, J. R.; Rodr´ıguez-Afonso,
A. Eur. J. Org. Chem. 2005, 673–682. (b) Boto, A.; Gallardo, J. A.; Herna´ndez,
R.; Saavedra, C. J. Tetrahedron Lett. 2005, 46, 7807–7811. (c) Boto, A.;
† Instituto de Productos Naturales y Agrobiolog´ıa del CSIC.
‡ Instituto de Investigaciones Qu´ımicas (CSIC-USe).
´
(1) (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 2006. (b) Enders, D.; Grondal,
C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570–1581. (c) Nicolaou,
K. C.; Edmons, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–
7186. (d) Pellissier, H. Tetrahedron 2006, 62, 1619-1665 (Part A); Tetrahedron
2006, 62, 2143-2173 (Part B). (e) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int.
Ed. 2006, 45, 354–366. (f) Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan,
G. C. Chem. ReV. 2005, 105, 1001–1020, and references cited therein.
Herna´ndez, D.; Herna´ndez, R.; Alvarez, E. J. Org. Chem. 2007, 72, 9523–9532.
(d) Boto, A.; Herna´ndez, D.; Herna´ndez, R. Org. Lett. 2007, 9, 1721–1724. (e)
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–
162.
(3) The radical scission can also be promoted by heating, but visible light
irradiation allows milder reaction conditions. To set an irradiation standard, 80
W tungsten-filament lamps (from DIY shops) were used herein.
10.1021/jo9004487 CCC: $40.75  2009 American Chemical Society
Published on Web 04/24/2009
J. Org. Chem. 2009, 74, 4655–4665 4655

Saavedra et al.
SCHEME 1. One-Pot Radical
Fragmentation-Oxidation-Addition of Nucleophile Process
bioactive R-peptide. The feasibility of this site-selective trans-
formation will be commented on later.
In recent years, the formation of ꢀ-amino acid derivatives
has received much interest, from both the synthetic6,7 and
medicinal8 standpoints. Among the synthetic methodologies, the
Arndt-Eistert homologation, the Curtius rearrangement, the
conjugate addition of nitrogen nucleophiles to unsaturated esters,
or the addition of carbon nucleophiles to imines have proven
very useful.6,7 For instance, Seebach and others have used the
Arndt-Eistert homologation to prepare ꢀ-amino acids and
ꢀ-peptides with high stereoselectivity.9 This protocol also allows
the synthesis of R-substituted R-amino acids but not R,R-
disubstituted ꢀ-amino acids; it also presents problems for large-
scale synthesis.9f
(6) (a) For some reviews, see: EnantioselectiVe Synthesis of ꢀ-Amino Acids, 2nd
ed.; Juaristi, E., Soloshonok, V. A., Eds.; Wiley-VCH: New York, 2005. (b) Sewald,
N. Angew. Chem., Int. Ed. 2003, 42, 5794–5795. (c) Liu, M.; Sibi, M. P.
Tetrahedron 2002, 58, 7991–8035. (d) Juaristi, E.; Quintana, D.; Escalante, J.
Aldrichimica Acta 1994, 27, 4397–4400. (e) See also: Liljeblad, A.; Kanerva,
L. T. Tetrahedron 2006, 62, 5831–5854. (f) Viso, A.; Ferna´ndez de la Pradilla,
R.; Garc´ıa, A.; Flores, A. Chem. ReV. 2005, 105, 3167–3196. (g) Xu, L.-W.;
Xia, C.-G. Eur. J. Org. Chem. 2005, 633–639. (h) Davies, S. G.; Smith, A. D.;
Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833–2891. (i) Seebach, D.;
Beck, A. K.; Bierbaum, D. J. Chem. BiodiV. 2004, 1, 1111–1239. (j) Ma, J.-A.
Angew. Chem., Int. Ed. 2003, 42, 4290–4299. (k) Park, K.-H.; Kurth, M. J.
Tetrahedron 2002, 58, 8629–8659. (l) Fu¨lop, F. Chem. ReV. 2001, 101, 2181–2204.
(7) (a) For some recent work on the synthesis of ꢀ-amino acid derivatives,
see: Tarrade-Matha, A.; Siqueira-Valle, M.; Tercinier, P.; Dauban, P.; Dodd,
R. H. Eur. J. Org. Chem. 2009, 673–686. (b) Yang, H.; Carter, R. G. J. Org.
Chem. 2009, 74, 2246–2249. (c) Paa´l, T. A.; Forro´, E.; Fu¨lo¨p, F.; Liljeblad, A.;
Kanerva, L. T. Tetrahedron: Asymmetry 2008, 19, 2784–2788. (d) Reyes-Rangel,
G.; Jime´nez-Gonza´lez, E.; Olivares-Romero, J. L.; Juaristi, E. Tetrahedron:
Asymmetry 2008, 19, 2839–2849. (e) Matsubara, R.; Berthiol, F.; Kobayashi, S.
J. Am. Chem. Soc. 2008, 130, 1804–1805. (f) Shen, B.; Johnston, J. N. Org.
Lett. 2008, 10, 4397–4400. (g) Herna´ndez-Toribio, J.; Go´mez-Arraya´s, R.;
Carretero, J. C. J. Am. Chem. Soc. 2008, 130, 16150–16151. (h) Yan, X. X.;
Peng, Q.; Li, Q.; Zhang, K.; Yao, J.; Hou, X. L.; Wu, Y. D. J. Am. Chem. Soc.
2008, 130, 14362–14363. (i) Wang, J.; Shi, T.; Deng, G.; Jiang, H.; Liu, H. J.
Org. Chem. 2008, 73, 8563–8570. (j) Seayad, J.; Patra, P. K.; Zhang, Y.; Ying,
J. Y. Org. Lett. 2008, 10, 953–956. (k) Tasna´di, G.; Forro´, E.; Fu¨lo¨p, F.
Tetrahedron: Asymmetry 2008, 19, 2072–2077. (l) Escalante, E.; Carrillo-Morales,
M.; Linzaga, I. Molecules 2008, 13, 340–347. (m) Katritzky, A. R.; Tao, H.;
Jiang, R.; Suzuki, K.; Kirichenko, K. J. Org. Chem. 2007, 72, 407–414. (n)
Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007, 72, 9998–10008. (o) D´ıaz-
Sa´nchez, B. R.; Iglesias-Arteaga, M. A.; Melgar-Ferna´ndez, R.; Juaristi, E. J.
Org. Chem. 2007, 72, 4822–4825. (p) Nugent, T. C.; Ghosh, A. K. Eur. J. Org.
Chem. 2007, 3863–3869. (q) Yang, J. W.; Stadler, M.; List, B. Angew. Chem.,
Int. Ed. 2007, 46, 609–611. (r) Huang, H.; Guo, X.; Hu, W. Angew. Chem., Int.
Ed. 2007, 46, 1337–1339. (s) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413–
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(8) (a) For recent work on bioactive ꢀ-amino acid derivatives, see: Dixon,
M. J.; Nathubhai, A.; Andersen, O. A.; Van Aalten, D. M. F.; Eggleston, I. M.
Org. Biomol. Chem. 2009, 7, 259–268. (b) David, R.; Gu¨nther, R.; Baumann,
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Chem. Soc. 2008, 130, 15311–15317. (c) Keresztes, A.; Szu´cs, M.; Borics, A.;
Ko¨ver, K. E.; Forro´, E.; Fu¨lo¨p, F.; To¨mbo¨ly, C.; Pe´ter, A.; Pa´hi, A.; Fabian, G.;
Mura´nyi, M.; To´th, G. J. Med. Chem. 2008, 51, 4270–4279. (d) Raghavan, B.;
Balasubramanian, R.; Steele, J. C.; Sackett, D. L.; Fecik, R. A. J. Med. Chem.
2008, 51, 1530–1533. (e) Ott, G. R.; Asakawa, N.; Lu, Z.; Anand, R.; Liu, R.-
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(f) Kim, D.; Kowalchick, J. E.; Brockunier, L. L.; Parmee, E. R.; Eiermann,
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Petrov, A.; Pryor, K. D.; Roy, R. S.; Wu, J. K.; Zhang, X.; Wyvratt, M. J.;
Zhang, B. B.; Zhu, L.; Thornberry, N. A.; Weber, A. E. J. Med. Chem. 2008,
51, 589–602. (g) Hamada, Y.; Abdel-Rahman, H.; Yamani, A.; Nguyen, J. T.;
Stochaj, M.; Hidaka, K.; Kimura, T.; Hayashi, Y.; Saito, K.; Ishiura, S.; Kiso,
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Pradilla, R.; Flores, A.; Garc´ıa, A. Tetrahedron 2007, 63, 8017–8026. (l) Jiang,
Z. X.; Yu, Y. B. J. Org. Chem. 2007, 72, 1464–1467. (m) Kvaerno, L.; Werder,
M.; Hauser, H.; Carreira, E. M. J. Med. Chem. 2005, 48, 6035–6053. (n) Singh,
G. S. Mini-ReV. Med. Chem. 2004, 4, 69–92.
SCHEME 2. One-Pot Scission-Oxidation-Mannich Process
for the Direct Conversion of r-Amino Acids into
r-Substituted ꢀ-Amino Esters and the Selective Modification
of Peptides
acids 7a into substituted ꢀ-amino esters 8a was studied.4 The
decarboxylation-oxidation was carried out, followed by addition
of a silylketene5 in the presence of a Lewis acid. A stoichio-
metric amount of the Lewis acid (BF3•OEt2 or TMSOTf) was
required in the nucleophilic addition step. In this article, a
catalytic system is reported, which affords similar results.
The sequential process would also allow the selectiVe
transformation of the C-terminal residue of peptides (conversion
7bf8b, Scheme 2). In compound 7b, the amino protecting
group Z is a peptidyl chain which would act as a chiral auxiliary,
and the reaction would be stereoselective. From a single
R-peptide substrate, a library of hybrid R,ꢀ-peptides could be
formed since the terminal ꢀ-amino acid could be mono-, di-,
or unsubstituted in the R-position (R′ ) H, alkyl, allyl, aryl,
Hal, OR, NHR, etc.), and up to four different stereoisomers
could be generated. Such procedure could be very useful in
medicinal chemistry to obtain diversity from a single (or a few)
(4) For the preliminary communications on this work, see: Saavedra, C. J.;
´
Herna´ndez, R.; Boto, A.; Alvarez, E. Tetrahedron Lett. 2006, 47, 8757–8760.
(5) (a) For reviews on the Mannich reaction and related processes, see: Ferraris,
D. Tetrahedron 2007, 63, 9581–9597. (b) Friestad, G. K.; Mathies, A. K.
Tetrahedron 2007, 63, 2541–2569. (c) Schaus, S. E.; Ting, A. Eur. J. Org. Chem.
2007, 5797–5815. (d) Petrini, M.; Torregiani, E. Synthesis 2007, 159–186. (e)
Be´gue´, J. P.; Bonnet-Delpon, D.; Crousse, B.; Legros, J. Chem. Soc. ReV. 2005,
34, 562–572. (f) Cordova, A. Acc. Chem. Res. 2004, 37, 102–112. (g) France,
S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004, 37, 592–
600. (h) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10–
19. (i) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984–995.
4656 J. Org. Chem. Vol. 74, No. 13, 2009

Catalytic, One-Pot Synthesis of ꢀ-Amino Acids
TABLE 1. One-Pot Scission-Oxidation-Silyl Ketene Addition:
Preparation of ꢀ-Amino Acids
FIGURE 1. Bioactive ꢀ-amino acids and hybrid peptides.
From the medicinal standpoint, the ꢀ-amino acid derivatives have
displayed interesting biological properties (such as the antibiotic
cispentacin 910 and the ꢀ-lactams,11 or the antihyperactivity drug
ritalin 10,12 Figure 1). In other cases, they are components of
bioactive products, such as bestatin (Ubenimex, 11),13 a microbial
ꢀ,R-dipeptide which is under clinical studies to treat lymphomas,
myeloid leukemias, and lung carcinoma. Other significant examples
are the antitumoral paclitaxel,14 the antifungal microscleroder-
mins,15 and the antihelmintic jasplakinolide.16
Besides, the replacement of R-amino acids by ꢀ-amino acids
in bioactive peptides has produced derivatives with superior
stability to proteases and with similar or increased activity.17
For instance, the R-dipeptide 12 (Figure 1) is an inhibitor of
bradykinin cleavage by aminopeptidase (APP) and thus a
potential agent against cardiovascular diseases. However, its
Pro-Leu amide bond is easily hydrolyzed by kidney peptidases.
When the proline residue in peptide 12 was replaced by a
a Method A: The scission step uses DIB (1.5 equiv), I2 (0.3 equiv).
Method B: Scission step: DIB (2 equiv), I2 (0.5 equiv). Method C:
Scission step: DIB (2 equiv), I2 (1.0 equiv).
ꢀ-homoproline, the modified ꢀ,R-peptide 13 displayed a 500-
fold increase in inhibitory activity (from Ki ) 1.28 mM to 7.0
nM); moreover, it was completely stable to peptidases in kidney
membranes after 24 h.17a
Finally, the ability of many ꢀ-peptides or hybrid R,ꢀ- or ꢀ,γ-
peptides to form turns, helices, ꢀ-sheets, or fibrils is rendering
interesting applications to medicinal chemistry and materials
science.18 For example, the ꢀ-amino acids are used to generate
turns in peptides in order to achieve bioactive conformations.19
The application of catalytic tandem-sequential processes to
the synthesis of these interesting compounds is discussed below,
with an emphasis on the preparation of hybrid R,ꢀ-peptides.
(9) (a) Seebach, D.; Overhand, M.; Ku¨hnle, F. N. M.; Martinoni, B.;
Oberer, L.; Hommel, U.; Widmer, H. HelV. Chim. Acta 1996, 79, 913–941.
(b) Guichard, G.; Abele, S.; Seebach, D. HelV. Chim. Acta 1998, 81, 187–
206. (c) Ellmermer-Mu¨ller, E. P.; Bro¨ssner, D.; Maslouh, N.; Tako´, A. HelV.
Chim. Acta 1998, 81, 59–65. (d) Mu¨ller, A.; Voge, C.; Sewald, N. Synthesis
1998, 837–841. (e) Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W.;
Roberts, E. Org. Lett. 2000, 2, 2177–2179. (f) To avoid peptide epimerization,
the Arndt-Eistert homologation can be carried out under base-free conditions
(with AgOBz, dioxane/H2O, 70 °C). While this methodology is very useful
in laboratory scale to prepare R-unsubstituted and even R-monosubstituted
ꢀ-amino acids, it is not suitable for large-scale synthesis, due to the expensive
silver catalyst and the hazardous diazoalkyl reagents. See: Belsito, E.; Gioia,
M. L.; Greco, A.; Leggio, A.; Liguori, A.; Perri, F.; Siciliano, C.; Viscomi,
M. C. J. Org. Chem. 2007, 72, 4798–4802.
(10) (a) Aggarwal, V. K.; Roseblade, S. J.; Barrell, J. K.; Alexander, R.
Org. Lett. 2002, 4, 1227–1229. (b) Langer, O.; Kahlig, H.; Zierler-Gould,
K.; Bats, J. W.; Mulzer, J. J. Org. Chem. 2002, 67, 6878–6883. (c) Theil, F.;
Ballschuh, S. Tetrahedron: Asymmetry 1996, 7, 3565–3572.
(11) Pe´rez-Faginas, P.; O’Reilly, F.; O’Byrne, A.; Garc´ıa-Aparicio, C.;
Mart´ın-Mart´ınez, M.; Pe´rez de Vega, M. J.; Garc´ıa-Lo´pez, M. T.; Gonza´lez-
Mun˜iz, R. Org. Lett. 2007, 9, 1593–1596, and references cited therein.
(12) Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Tetra-
hedron 2000, 56, 7411–7422, and references cited therein.
Results and Discussion
Development of the Radical Scission-Oxidation-Mannich
Reaction. In a first stage, the sequential process was explored
with simple substrates, derived from acylation or carbamoylation
of commercial amino acids. Thus, compounds 14-20 (Table
1) were treated with the system (diacetoxyiodo)benzene and
iodine,2 in the presence of visible light, to induce the
scission-oxidation steps, then BF3•OEt2 was added to generate
an acyliminium intermediate, which was trapped by silylketenes.
With unsubstituted ketenes (R2 ) H), the process afforded
compounds 21-27 in moderate to good yields. Several reaction
conditions were tried, showing that the amount of iodine was
critical to obtain good yields. The scission did not take place
(13) Bauvois, B.; Dauzonne, D. Med. Res. ReV. 2006, 26, 88–130.
(14) (a) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed.
Engl. 1994, 33, 15–44. (b) See also: Escalante, J.; Juaristi, E. Tetrahedron Lett.
1995, 36, 4397–4400. (c) Sa´nchez-Obrego´n, R.; Salgado, F.; Ortiz, B.; D´ıaz,
E.; Yuste, F.; Walls, F.; Garc´ıa-Ruano, J. L. Tetrahedron 2007, 63, 10521–
10527, and references cited therein.
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Lett. 2008, 10, 841–844.
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J. Org. Chem. Vol. 74, No. 13, 2009 4657

Saavedra et al.
TABLE 2. One-Pot Decarboxylation-Alkylation: Preparation of
Cyclic ꢀ-Amino Acids
without iodine, but an excess of iodine gave complex product
mixtures. With 0.3-0.5 equiv, the reaction proceeded in
reasonable yields.
When the disubstituted ketene Me2CdC(OTMS)OMe was
used, the yields improved, in particular, with Method A [DIB
(1.5 equiv), iodine (0.3 equiv)],20 which afforded compounds
28-34 in good yields. Hence, this methodology is an interesting
alternative to the Arndt-Eistert homologation,6c not only due
to the mild, relatively inexpensive and scalable conditions9 but
also due to the ready formation of R,R-disubstituted ꢀ-amino
acids.
Similar results were obtained in the scission-alkylation of
the cyclic amino alcohol 35 (Table 2) and the cyclic amino acids
36-38. Although the scission of alcohols is less favored than
the decarboxylation of amino acids,21 the fragmentation of the
amino alcohol 35 and the alkylation with CH2dC(OTBS)OMe
proceeded in a satisfactory yield, affording compound 39.
Remarkably, products derived from possible side reactions, such
as hydrogen abstraction, were not detected.
In a similar way, the decarboxylation-alkylation of proline
derivative 36 afforded compound 40 in good yield. In the case
of hydroxyproline substrate 37, the stereogenic center on C-4
determined the stereoselectivity of the nucleophilic addition step.
Surprisingly, the 2,4-cis product 41 predominated upon the 2,4-
trans isomer 42. This result could be explained according to
the model reported by Woerpel for the addition of nucleophiles
to five-membered ring oxocarbenium and iminium ions.22
By changing the reaction conditions, different derivatives can
be obtained. For instance, when the reaction was carried out in
acetonitrile and an excess of iodine was added, the proline
carbamate 38 underwent a one-pot decarboxylation-oxidation-ꢀ-
iodination process.23a The polar solvent favored the isomeriza-
tion of the acyliminium intermediate to an encarbamate, which
reacted with iodine affording a ꢀ-iodoacyliminium ion. This
a Method A: DIB (1.5 equiv), I2 (0.3 equiv), ketene (5 equiv). Method
B: DIB (2.0 equiv), I2 (0.5 equiv), ketene (5 equiv). Method D: DIB (2
equiv), I2 (2 equiv), hν, CH3CN, 4 h; MeOH (10 equiv), 0.5 h; solvent
removal, then CH3CN, 0 °C, ketene (5 equiv), BF3•OEt2 (2 equiv), 3 h.
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1408. (c) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366–1375. (d)
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Chakraborty, T. K.; Rao, K. S.; Kiran, M. U.; Jagadeesh, B. Tetrahedron Lett.
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Chem. Soc. ReV. 2006, 35, 323–334. (d) Arvidsson, P. I.; Ryder, N. S.; Weiss,
H. M.; Hook, D. F.; Escalante, J.; Seebach, D. Chem. BiodiV. 2005, 2, 401–420.
(e) Cheng, R. P.; Gellman, S. H.; De Grado, W. F. Chem. ReV. 2001, 101, 3219–
3232.
(19) (a) For the expansion of ꢀ-turns with ꢀ- and γ-aa, see: Rai, R.; Vasudev,
P. G.; Anandz, K.; Raghothama, S.; Shamala, N.; Karle, I. L.; Balaram, P.
Chem.sEur. J. 2007, 13, 5917–5926. (b) For turns in ꢀ-peptides, see: Abele,
S.; Seiler, P.; Seebach, D. HelV. Chim. Acta 1999, 82, 1559–1571. (c) Abele,
S.; Seebach, D. Eur. J. Org. Chem. 2000, 1–15. (d) For the biological importance
of turns, see: Tyndall, J. D. A.; Pfeiffer, B.; Abbenante, G.; Fairlie, D. P. Chem.
ReV. 2005, 105, 793–826. (e) Kritzer, J. A.; Stephens, O. M.; Guarracino, D. A.;
Reznik, S. K.; Schepartz, A. Bioorg. Med. Chem. 2005, 13, 11–16.
(20) Other methods were also tried, but they are not mentioned in the sake
of clarity. For instance, a method using DIB (1.5 equiv) and iodine (0.5 equiv)
gave similar results to Method A [DIB (1.5 equiv), iodine (0.3 equiv)].
(21) (a) Zhdankin, V.; Stang, P. J. Chem. ReV. 2002, 102, 2523–2584. (b)
Togo, H.; Katohgi, M. Synlett 2001, 565–581. (c) Sua´rez, E.; Rodr´ıguez, M. S.
In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, Germany, 2001; Vol. 2, pp 440-454. (d) Brun, P.; Waegell, B. In
ReactiVe Intermediates; Abramovitch, R. A., Ed.; Plenum Press: New York, 1983;
Vol. 3, pp 367-426 and references cited therein. (e) The decarboxylation of
amino acids can also be induced electrochemically: Seebach, D.; Charczuk, R.;
Gerber, C.; Renaud, P.; Berner, H.; Schneider, H. HelV. Chim. Acta 1989, 72,
401–425. (f) Matsumura, Y.; Shirakawa, Y.; Satoh, Y.; Umino, M.; Tanaka, T.;
Maki, T.; Onomura, O. Org. Lett. 2000, 2, 1689–1691.
intermediate was trapped by addition of methanol, and a 2,3-
trans-3-iodo-2-methoxy pyrrolidine 4323a was formed. This
compound was not purified, but the solvent was evaporated and
the crude product mixture was redissolved, cooled to 0 °C, and
treated with the nucleophile and the Lewis acid, yielding the
iodinated ꢀ-amino ester 44.23b The introduction of iodine in a
previously unfunctionalized position is valuable since the iodo
group can be replaced by other functionalities. Alternatively,
the iodo derivative 43 could undergo elimination, and the
resulting 3,4-alkene could be further functionalized.
When the nucleophile was the disubstituted silylketene
Me2CdC(OTMS)OMe, the R,R-dimethyl-ꢀ-amino esters 45-49
were isolated. In most cases, yields were similar or superior to
(22) (a) The ring adopts preferentially an envelope conformation, with the
acetoxy group in a pseudoaxial position, and the nucleophile adds from the inside
face of the envelope, giving the cis product. The attack from the outside face is
disfavored, due to the eclipsing interactions developed between the substituents
at C-2 and C-3 in the transition structure for the trans product. (b) For more
information, see: Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A.
J. Am. Chem. Soc. 1999, 121, 12208–12209. (c) Smith, D. M.; Tran, M. B.;
Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 14149–14152. (d) Larsen, C. H.;
Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel, K. A. J. Am. Chem. Soc.
2005, 127, 10879–10884.
(23) (a) Boto, A.; Herna´ndez, R.; Leo´n, Y.; Sua´rez, E. J. Org. Chem. 2001,
66, 7796–7803. (b) The addition of methanol after the scission step was necessary
to obtain good yields. If the fragmentation was followed by addition of the
nucleophile and the Lewis acid, a complex product mixture was formed. The
addition of methanol probably deactivated excess reagents from the first step
and generated the stable N,O-acetal 43, which was a good acyliminium precursor.
4658 J. Org. Chem. Vol. 74, No. 13, 2009

Catalytic, One-Pot Synthesis of ꢀ-Amino Acids
TABLE 3. One-Pot Decarboxylation-Oxidation-Mannich:
Preparation of Modified Dipeptides
TABLE 4. Synthesis of Modified Dipeptides
a Method A: DIB (1.5 equiv), I2 (0.3 equiv), hν, CH2Cl2, 4 h, then 0
°C, BF3•OEt2 (2 equiv), Me2CdC(OTMS)OMe (5 equiv), 3 h.
those obtained with CH2dC(OTBS)OMe. The resolution of the
enantiomeric mixtures to form hybrid ꢀ,R-peptides will be
commented on later.
a Method A: DIB (1.5 equiv), I2 (0.3 equiv). Method B: DIB (2.0
equiv), I2 (0.5 equiv), I2 (0.5 equiv). Method C: DIB (2 equiv), I2 (1
equiv). b Method C, but using CHCl3, reflux. c Method B, but using
PhH, 26 °C.
To determine whether the previous reaction conditions were
appropriate for more complex substrates, the direct modification
of R-dipeptides to give R,ꢀ-hybrids was explored. In order to
simplify the study, a nonstereoselective scission-Mannich
process was first carried out using substrates 50-53 (Table 3),
whose N-terminal R,R-disubstituted amino acids were not chiral.
Using Method A [DIB (1.5 equiv), iodine (0.3 equiv) for the
scission step], the process afforded R,ꢀ-dipeptides 54-57 in
moderate to good yields. Since both amino acids were R,R-
disubstituted, the resulting peptides were unusually hydrophobic.
The stereoselective modification of dipeptides was then
explored with substrates 58-68 (Table 4) which presented chiral
N-terminal R-amino acids. Different reaction conditions were
studied; only the optimized ones are described in the table. Due
to differences in substrate solubility, reactivity, etc., the best
conditions varied for each peptide.
Substrate 58 underwent the scission-oxidation reaction and
was then treated with the unsubstituted ketene CH2d
C(OTBS)OMe, affording dipeptides 69 and 70 in moderate yield
(36%) and 1:1 diastereomeric ratio. However, when the process
was repeated with the disubstituted ketene Me2Cd
C(OTMS)OMe, giving dipeptides 71 and 72, the yield and the
diastereomeric ratio increased (77%; 71:72, 2:1). The X-ray
analysis of the crystalline derivative 71 showed that the major
product retained the “natural” configuration (3S).
of R-dipeptides 59-68 afforded the R,ꢀ-hybrids 73-92 in good
global yields. The X-ray analysis of compounds 78, 81, 83, and
90 showed that, in all of these cases, the major isomer possessed
the “natural” configuration. In general, the minor isomers could
be readily separated from the major ones. The isolation of the
minor isomers is interesting for medicinal SAR studies in order
to determine the influence of the stereochemistry in the
biological activity.
Development of a Catalytic Mannich Step. In our previous
reports,2 the nucleophilic addition step required stoichiometric
amounts of the Lewis acid (e.g., BF3•OEt2 or TMSOTf); if
catalytic amounts were used, the process afforded very low
product yields. For the first time, we report an efficient
scission-nucleophilic addition process which only requires a
catalytic amount of the Lewis acid. In the modified process
(Scheme 3), the boron trifluoride (2 equiv) was replaced by the
softer copper(II) triflate (0.1 equiv), affording satisfactory yields
(41-70%) of the scission-Mannich products. In most cases,
the yields were similar or slighty inferior to those obtained with
the stoichiometric Lewis acid.
The catalytic process saves reagents and reduces the amount
of acid waste to treat. Besides, this catalytic version will be
further refined to allow the use of chiral Lewis acid catalysts,
Since we were especially interested in peptides with R-di-
substituted ꢀ-amino acids, we carried out the remaining experi-
ments with the R,R-dimethyl silyl ketene. The scission-Mannich
J. Org. Chem. Vol. 74, No. 13, 2009 4659

Saavedra et al.
TABLE 5. Resolution of ꢀ-Amino Acids: Formation of Modified
ꢀ,r-Dipeptides
SCHEME 3. Catalytic One-Pot
Decarboxylation-Oxidation-Silyl Ketene Addition
a DIB (1.5 equiv), I2 (0.3 equiv). b DIB (2.0 equiv), I2 (1.0 equiv).
such as those derived from Cu(OTf)2 and BOX ligands.24 These
catalysts, which are currently under study, will be used to
increase the stereoselectivity in the generation of ꢀ-amino acids
and hybrid R,ꢀ-dipeptides.
Separation of Isomer Mixtures: Enantiomeric ꢀ-Amino
Acids or Diastereomeric r,ꢀ-Peptides. Once the reaction
conditions were optimized, it was clear that the one-pot
scission-oxidation-Mannich process was a useful methodology
for the direct conversion of R- into ꢀ-amino acid derivatives.
However, using simple R-amino acids as substrates gave racemic
mixtures of ꢀ-amino esters since the scission generated an
achiral acyliminium intermediate. These enantiomers were
separated by formation of hybrid ꢀ,R-dipeptides (Table 5). Thus,
the ꢀ-amino esters 29-31 were hydrolyzed to the acids 93-95.
Then, the ꢀ-homoleucine derivative 93 was coupled to a
L-Phe•OMe residue with EDC/HOBt, affording the diastereo-
meric dipeptides 96 and 97, which were easily separated (89%
global yield). The stereochemistry of these compounds was
determined by X-ray analysis.
In a similar way, the ꢀ-valine derivative 94 was coupled to
L-Phe•OMe, giving dipeptides 98 and 99 (77% global yield),
and the ꢀ-phenylalanine derivative 95 was coupled to
L-Phe•OMe (affording the diastereomeric peptides 100 and 101)
or to L-Leu•OMe (giving dipeptides 102 and 103). In both cases,
good overall yields were obtained. The ꢀ,R-dipeptides were
analogues of the potent antitumoral bestatin (Ubenimex). Since
both possible diastereomers were obtained, it would be possible
a The diastereomeric dipeptides were readily separated by
chromatography on silica gel.
to study the influence of the ꢀ-amino acid configuration on the
biological activity.
On the other hand, the diastereomeric R,ꢀ-peptides result-
ing from the scission-Mannich reaction were usually sepa-
rated. In the few cases where unseparable diastereomer
mixtures were obtained, we studied the formation of R,ꢀ,R-
tripeptides (Table 6).
Thus, the mixture 75/76 was saponified and coupled to
L-Phe•OMe, affording tripeptides 104 and 105 in 81% yield.
These peptides were separated, and the X-ray analysis of
compound 105 (Figure 2) showed that it possessed the “un-
natural” configuration.
In a similar way, dipeptide 77 was transformed into tripeptide
106 in good yield, and the mixture of dipeptides 85/86 was
converted into the R,ꢀ,R-tripeptides 107 and 108. The latter
underwent Cbz removal by hydrogenolysis and acylation with
p-IBzCl, affording derivative 109, which was suitable for X-ray
analysis. Finally, the dipeptide mixture 91/92 was saponified
and coupled to L-Leu•OMe, affording tripeptides 110 and 111.
Since their crystals were not appropriate for X-ray analysis, they
were transformed into their p-iodobenzamides 112 and 113. The
X-ray analysis of compounds 112 and 113 showed that the major
isomer presented the “natural” configuration.
(24) (a) Nakamura, S.; Nakashima, H.; Sugimoto, H.; Sano, H.; Hattori, M.;
Shibata, N.; Toru, T. Chem.sEur. J. 2008, 14, 2145–2152. (b) Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000. (c)
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer-Verlag: Heilderberg, 1999. (d) Seyden-Penne, J. Chiral
Auxiliaries and Ligands in Asymmetric Synthesis; Wiley: New York, 1995.
These X-ray analysis also highlighted that, in the solid state,
the R,ꢀ,R-tripeptides 105, 109, 112, and 113 formed turns
4660 J. Org. Chem. Vol. 74, No. 13, 2009

Catalytic, One-Pot Synthesis of ꢀ-Amino Acids
TABLE 6. Separation of Diastereomeric r,ꢀ-Dipeptides:
Formation of r,ꢀ,r-Tripeptides
ꢀ-amino acid derivatives. This method is an interesting alterna-
tive to other homologation procedures, such as the Arndt-Eistert
reaction, since it allows the easy generation of R,R-disubstituted
ꢀ-amino esters. Some ꢀ-amino acid products were coupled to
R-amino esters to form hybrid ꢀ,R-dipeptides since these
compounds often display interesting biological activities.
Besides, this procedure allows the selectiVe modification of
the C-terminal residue in small peptides, which could be very
useful in medicinal chemistry (a single bioactive R-peptide could
be transformed into a library of hybrid R,ꢀ-peptides).
The method is a sequential process initiated by a tandem
radical fragmentation-oxidation reaction, which generates an
acyliminium ion. This intermediate reacts with silyl ketenes in
the presence of a Lewis acid, affording ꢀ-amino esters or R,ꢀ-
dipeptide derivatives. The process is operationally simple and
saves materials and time since no purification of the intermedi-
ates is needed. The mild reaction conditions are compatible with
most functional groups. Moreover, in the scission step, only a
catalytic amount of iodine is needed.
When R-dipeptides were used as substrates, the N-terminal
residue acted as a chiral auxiliary, and the reaction was
stereoselective (predominating the isomer with the “natural”
configuration). Some of the resulting R,ꢀ-dipeptides were
transformed into R,ꢀ,R-tripeptides, whose molecular conforma-
tion was determined by the configuration of the ꢀ-amino acid
unit. The “natural” configuration favored hydrogen bonds
between the ꢀ-amino acid CO and NH groups, and an additional
interaction was observed between the proline nitrogen lone pairs
and the ꢀ-amino acid amine proton.
Interestingly, the unnatural configuration led to the formation
of ꢀ-turns in the solid state, a structural feature found in some
efficient peptide catalysts. Since two hybrid peptides (105 and
109) lacked turn-inducing R-amino acids (such as proline,
glycine, D-, or N-alkyl amino acids), the generation of an
expanded ꢀ-turn is probably due to the introduction of the R,R-
disubstituted ꢀ-amino acid.
Finally, a new version of the scission-Mannich process was
developed, which only required a catalytic amount of the Lewis
acid [thus, boron trifluoride (2 equiv) was replaced by copper
triflate (0.1 equiv)]. The modified process, which saves expen-
sive reagents and reduces the acidic waste, took place in
moderate to good yields (40-70%). The generation of chiral
catalysts from Cu(OTf)2 and chiral ligands is currently under
study in order to prepare ꢀ-amino acids in high enantiomeric
excess and to increase the stereoselectivity in the synthesis of
R,ꢀ-hybrid peptides.
a H2, Pd (10% on carbon), THF/H2O, then NaHCO3, p-I-BzCl.
(Figure 2). In R-peptides, the generation of turns is favored by
the presence of certain amino acids, such as proline, glycine,
D-, or N-alkyl amino acids; in their absence, extended conforma-
tions are adopted.25 None of these amino acids is present in the
R,ꢀ-hybrids 105 and 109, so the formation of an expanded ꢀ-turn
is due to the introduction of the R,R-disubstituted ꢀ-amino acid.
The tripeptides whose ꢀ-amino acid unit has the “unnatural”
configuration (compounds 105, 109, and 113) adopted an
expanded ꢀ-turn,19 between the COi (benzamide) and the NHi+3
groups. Interestingly, these interactions are reinforced by a
hydrogen bond between the NHi+2 group (from the ꢀ-amino
acid) and the COi+3 group (from the C-terminal amino acid).
In the case of peptide 112, whose ꢀ-amino acid presents the
“natural” configuration, the molecular conformation of the pep-
tide is different. A hydrogen bond was formed between the
ꢀ-amino acid CO and NH groups. An additional interaction was
observed between the proline nitrogen lone pairs and the
ꢀ-amino acid amine proton.
Experimental Section
General Procedures for the One-Pot Scission-Oxidation-
Alkylation Sequence. Method A. To a solution of the starting
amino acid or peptide (0.2 mmol) in dry dichloromethane (6 mL)
were added iodine (15 mg, 0.06 mmol) and (diacetoxyiodo)benzene
(DIB) (97 mg, 0.3 mmol). The reaction mixture was stirred at 26
°C for 4 h, under irradiation with visible light. Then the solution
was cooled to 0 °C, and 1-(tert-butyldimethylsilyloxy)-1-methoxy-
ethene (218 µL, 188 mg, 1.0 mmol) or methyl trimethylsilyldim-
These interactions could be useful to design new peptide
catalysts,26 and we are currently carrying out additional studies
to clarify the conformational effects in solution.
Conclusion
In summary, we have developed a one-pot radical scission-
oxidation-Mannich process to transform R-amino acid into
(26) (a) For reviews, see: Colby Davie, E. A.; Mennen, S. M.; Xu, Y.; Miller,
S. J. Chem. ReV. 2007, 107, 5759–5812. (b) Berkessel, A. Angew. Chem., Int.
Ed. 2008, 47, 3677–3679. (c) For recent work on the subject, see: Sa´nchez-
Rosello´, M.; Puchlopek, A. L. A.; Morgan, A. J.; Miller, S. J. J. Org. Chem.
2008, 73, 1774–1782. (d) Revell, J. D.; Wennemers, H. AdV. Synth. Catal. 2008,
350, 1046–1052. (e) Tsandi, E.; Kokotos, C. G.; Kousidon, S.; Ragoussis, V.;
Kokotos, G. Tetrahedron 2009, 65, 1444–1449, and references cited therein.
(25) (a) Sewald, N.; Jakubke, H. D. Peptides: Chemistry and Biology, Wiley-
VCH: Weinheim, Germany, 2002; pp 311-337. (b) For applications, see:
Blanchette, J. P.; Ferland, P.; Voyer, N. Tetrahedron Lett. 2007, 48, 4929–4933.
J. Org. Chem. Vol. 74, No. 13, 2009 4661

Saavedra et al.
FIGURE 2. Molecular conformation of peptides 105, 109, 112, and 113 in crystals. Intramolecular hydrogen bonds are shown as dotted lines.
ethylketene acetal (203 µL, 174 mg, 1.0 mmol) was injected,
followed by dropwise addition of BF3•OEt2 (51 µL, 57 mg, 0.4
mmol). The mixture was allowed to reach room temperature and
stirred for 3 h; then it was poured into 10% aqueous Na2S2O3/
saturated aqueous NaHCO3 (1:1, 10 mL) and extracted with CH2Cl2.
The organic layer was dried on sodium sulfate, filtered, and
evaporated under vacuum. The residue was purified by chroma-
tography on silica gel (hexanes/ethyl acetate mixtures) to give the
products.
Method B. To a solution of the starting amino acid (0.2 mmol)
in dry dichloromethane (6 mL), under nitrogen atmosphere, were
added iodine (25 mg, 0.1 mmol) and (diacetoxyiodo)benzene (DIB)
(129 mg, 0.4 mmol) and treated as in Method A.
mmol) or methyl trimethylsilyldimethylketene acetal (203 µL, 174 mg,
1.0 mmol) was injected, followed by dropwise addition of BF3•OEt2
(51 µL, 57 mg, 0.4 mmol). The mixture was allowed to reach room
temperature and stirred for 3 h; then it was poured into saturated
aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was
dried on sodium sulfate, filtered, and evaporated under vacuum. The
residue was purified by chromatography on silica gel (hexanes/ethyl
acetate mixtures) to give the products.
One-Pot Catalytic Scission-Oxidation-Alkylation Sequence.
The procedures were similar to previously described Methods A-D,
but replacing boron trifluoride by copper(II) triflate (0.1 equiv).
Resolution of ꢀ-Amino Acids. Formation of Modified
Dipeptides. General Procedure for the Generation of Acids
93-95. A solution of esters 29, 30, or 31 (0.20 mmol) in methanol
(6 mL) at 0 °C was treated with 2 N aqueous NaOH (2 mL). The
reaction mixture was allowed to reach rt and stirred overnight. Then
it was cooled to 0 °C, poured into 5% aqueous HCl, and extracted
with EtOAc. The organic layer was dried and evaporated as usual.
Decarboxylation of Dipeptides Oxidation-Alkylation. The
process was carried out according to previously described Method
A, B, or C.
Method C. To a solution of the starting amino acid or peptide
(0.2 mmol) in dry dichloromethane (6 mL) were added iodine (51
mg, 0.2 mmol) and (diacetoxyiodo)benzene (DIB) (129 mg, 0.4
mmol) and treated as in Method A.
Method D. To a solution of starting material (0.2 mmol) in dry
acetonitrile (6 mL) were added iodine (102 mg, 0.4 mmol) and
(diacetoxyiodo)benzene (DIB) (129 mg, 0.4 mmol). The reaction
mixture was stirred at 24-26 °C for 4 h, under irradiation with visible
light. Then dry methanol (1 mL) was added, and the stirring was
continued for 1 h. The mixture was poured into 10% aqueous Na2S2O3
and extracted with CH2Cl2. The organic layer was dried on sodium
sulfate, filtered, and evaporated under vacuum, and the residue was
dissolved in dry acetonitrile (6 mL). The solution was cooled to 0 °C,
and 1-tert-(dimethylsilyloxy)-1-methoxyethene (218 µL, 188 mg, 1.0
Separation of Dipeptides by Formation of Tripeptides:
N-(p-Iodobenzoyl)-L-alanyl-[r,r-dimethyl-L-ꢀ-homoalanyl]-L-
phenylalanine Methyl Ester (104) and N-(p-Iodobenzoyl)-L-
alanyl-[r,r-dimethyl-D-ꢀ-homoalanyl]-L-phenylalanine Methyl
Ester (105). To a solution of the mixture of dipeptides 75/76 (118
mg, 0.26 mmol) in methanol (6 mL) at 0 °C was slowly added 2
4662 J. Org. Chem. Vol. 74, No. 13, 2009

Catalytic, One-Pot Synthesis of ꢀ-Amino Acids
N aqueous NaOH (3 mL). The reaction mixture was allowed to
reach rt and stirred for 64 h, then it was cooled to 0 °C, diluted
with water, poured into 5% HCl, and extracted with EtOAc. The
organic layer was dried and evaporated, and the residue was
dissolved in dry CH2Cl2 (3 mL) and treated with L-phenylalanine
methyl ester hydrochloride (57 mg, 0.26 mmol). The solution was
cooled to 0 °C, and Et3N (37 µL, 27 mg, 0.26 mmol), EDC (56
mg, 0.29 mmol), and HOBt (39 mg, 0.29 mmol) were added. The
reaction mixture was stirred at 0 °C for 2 h, then it was allowed to
reach room temperature and stirred for 18 h and finally was poured
into a saturated aqueous NaHCO3 solution and extracted with
CH2Cl2. After usual drying and solvent removal, the residue was
purified by rotatory chromatography (hexanes/EtOAc, 3:2 and 1:1),
affording compounds 104 (48%) and 105 (29%).
MHz) δH 0.89 (3H, d, J ) 6.3 Hz), 0.92 (3H, d, J ) 6.3 Hz), 0.99
(3H, s), 1.07 (3H, d, J ) 6.6 Hz), 1.20 (3H, s), 1.52-1.66 (3H,
m), 3.19 (1H, dd, J ) 7.3, 13.9 Hz), 3.23 (1H, ddd, J ) 6.3, 13.9
Hz), 3.71 (3H, s), 3.87 (1H, dddd, J ) 6.6, 6.6, 6.6, 9.2 Hz), 4.46
(1H, ddd, J ) 5.0, 8.0, 8.5 Hz), 4.87 (1H, ddd, J ) 6.9, 7.0, 7.3
Hz), 6.04 (1H, d, J ) 7.9 Hz), 6.71 (1H, d, J ) 7.3 Hz), 7.21 (1H,
m), 7.26-7.30 (4H, m), 7.40 (2H, dd, J ) 7.3, 7.9 Hz), 7.48 (1H,
dd, J ) 7.3, 7.6 Hz), 7.51 (1H, d, J ) 8.9 Hz), 7.71 (2H, d, J )
7.8 Hz); 13C NMR (125.7 MHz, CDCl3) δC 16.7 (CH3), 21.9 (CH3),
22.7 (CH3), 22.9 (CH3), 24.6 (CH3), 25.0 (CH), 38.6 (CH2), 41.1
(CH2), 44.7 (C), 50.7 (CH), 52.3 (CH3), 53.0 (CH), 55.0 (CH), 127.0
(3 × CH), 128.5 (2 × CH), 128.7 (2 × CH), 129.4 (2 × CH),
131.6 (CH), 134.1 (C), 136.5 (C), 167.1 (C), 170.1 (C), 173.3 (C),
176.6 (C); MS m/z (rel intensity) 509 (M+, 2), 418 (M+ - CH2Ph,
2), 365 (M+ - NHCH(CH2CHMe2)CO2Me, 4), 105 ([PhCO]+,
100), 77 ([Ph]+, 25); HRMS calcd for C29H39N3O5, 509.2890; found,
509.2880; calcd for C7H5O, 105.0340; found, 105.0339. Anal. Calcd
for C29H39N3O5: C, 68.34; H, 7.71; N, 8.25. Found: C, 68.41; H,
7.89; N, 8.18.
Compound 104: Syrup; [R]D +53 (c 0.35, CHCl3); IR (CHCl3)
1
3438, 3401, 3089, 3062, 1738, 1652, 1503, 1477 cm-1; H NMR
(500 MHz) δH 1.08 (3H, d, J ) 6.6 Hz), 1.14 (3H, s), 1.15 (3H, s),
1.49 (3H, d, J ) 7.0 Hz), 3.08 (1H, dd, J ) 6.3, 13.9 Hz), 3.17
(1H, dd, J ) 6.0, 13.9 Hz), 3.76 (3H, s), 3.89 (1H, dddd, J ) 6.9,
6.9, 6.9, 9.3 Hz), 4.59 (1H, dddd, J ) 7.0, 7.0, 7.0, 7.0 Hz), 4.79
(1H, ddd, J ) 6.0, 6.3, 7.3 Hz), 6.16 (1H, d, J ) 7.6 Hz), 7.08
(2H, d, J ) 6.6 Hz), 7.12 (1H, d, J ) 7.0 Hz), 7.25-7.35 (3H, m),
7.42 (1H, d, J ) 9.2 Hz), 7.54 (2H, d, J ) 8.5 Hz), 7.76 (2H, d,
J ) 8.6 Hz); 13C NMR (125.7 MHz) δC 16.7 (CH3), 19.3 (CH3),
22.7 (CH3), 24.8 (CH3), 37.4 (CH2), 45.0 (C), 49.6 (CH), 52.4
(CH3), 52.7 (CH), 52.8 (CH), 98.5 (C), 127.3 (CH), 128.7 (4 ×
CH), 129.1 (2 × CH), 133.6 (C), 135.6 (C), 137.6 (2 × CH), 165.9
(C), 171.3 (C), 171.9 (C), 176.3 (C); MS m/z (rel intensity) 593
(M+, 2), 319 (M+ - CH(Me)NHBz-p-I, 55), 249 (M+ + H -
CH(Me)NHCOCH(Me)NHBz-p-I, 59), 231 ([p-I-PhCO]+, 100);
HRMS calcd for C26H32IN3O5, 593.1387; found, 593.1407; calcd
for C7H4IO, 230.9307; found, 230.9301. Anal. Calcd for
C26H32IN3O5: C, 52.62; H, 5.43; N, 7.08. Found: C, 52.79; H, 5.63;
N, 7.09. Compound 105: Crystalline solid; mp 143-144 °C (from
EtOAc/n-hexane); [R]D +33 (c 0.18, CHCl3); IR (CHCl3) 3437,
N-(Benzyloxycarbonyl)-L-valyl-[r,r-dimethyl-L-ꢀ-homophe-
nylalanyl]-L-leucine Methyl Ester (107) and N-(Benzyloxycar-
bonyl)-L-valyl-[r,r-dimethyl-D-ꢀ-homophenylalanyl]-L-leu-
cine Methyl Ester (108). They were synthesized from a mixture
of dipeptides 85/86 following the previous coupling procedure. The
residue was purified by rotatory chromatography (hexanes/EtOAc,
7:3 and 1:1), affording compounds 107 (42%) and 108 (36%).
Compound 107: Syrup; [R]D -49 (c 0.36, CHCl3); IR (CHCl3)
1
3435, 3090, 3067, 1728, 1667, 1499 cm-1; H NMR (500 MHz)
δH 0.64 (3H, d, J ) 6.6 Hz), 0.83 (3H, d, J ) 6.6 Hz), 0.94 (3H,
d, J ) 6.6 Hz), 0.96 (3H, d, J ) 7.0 Hz), 1.24 (3H, s), 1.34 (3H,
s), 1.55-1.75 (3H, m), 2.02 (1H, m), 2.54 (1H, dd, J ) 11.3, 13.3
Hz), 2.97 (1H, dd, J ) 4.1, 14.2 Hz), 3.76 (3H, s), 3.87 (1H, dd,
J ) 7.9, 7.9 Hz), 4.20 (1H, ddd, J ) 3.8, 10.1, 10.4 Hz), 4.58 (1H,
ddd, J ) 5.4, 8.2, 8.5 Hz), 5.01 (1H, d, J ) 8.2 Hz), 5.10 (2H, s),
6.18 (1H, d, J ) 7.6 Hz), 7.06-7.15 (6H, m), 7.31-7.38 (5H, m);
13C NMR (125.7 MHz) δC 17.1 (CH3), 19.3 (CH3), 21.9 (CH3),
22.7 (CH3), 23.4 (CH3), 24.8 (CH3), 25.0 (CH), 30.4 (CH), 37.2
(CH2), 41.0 (CH2), 45.6 (C), 50.8 (CH), 52.4 (CH3), 57.7 (CH),
60.7 (CH), 66.9 (CH2), 126.2 (CH), 128.1 (2 × CH), 128.2 (3 ×
CH), 128.5 (2 × CH), 129.2 (2 × CH), 136.3 (C), 138.4 (C), 156.2
(C), 170.6 (C), 173.4 (C), 176.8 (C); MS m/z (rel intensity) 567
(M+, 1), 476 (M+ - CH2Ph, 6), 368 (M+ - CH2Ph - HOCH2Ph,
12), 91 ([CH2Ph]+, 100); HRMS calcd for C32H45N3O6, 567.3308;
found, 567.3286; calcd for C7H7, 91.0548; found, 91.0547. Anal.
Calcd for C32H45N3O6: C, 67.70; H, 7.99; N, 7.40. Found: C, 67.74;
H, 8.11; N, 7.25. Compound 108: Syrup; [R]D +19 (c 0.52, CHCl3);
1
3370, 3090, 3068, 1730, 1655, 1507, 1477 cm-1; H NMR (500
MHz) δH ) 1.11 (3H, d, J ) 7.0 Hz), 1.14 (3H, s), 1.19 (3H, s),
1.55 (3H, d, J ) 7.3 Hz), 3.18 (1H, dd, J ) 9.9, 13.9 Hz), 3.22
(1H, dd, J ) 5.4, 13.9 Hz), 3.79 (3H, s), 4.00 (1H, dddd, J ) 6.6,
6.6, 6.6, 10.1 Hz), 4.43 (1H, dddd, J ) 7.0, 7.0, 7.0, 7.0 Hz), 4.78
(1H, ddd, J ) 5.4, 8.2, 9.8 Hz), 7.22 (1H, d, J ) 7.9 Hz), 7.25
(1H, m), 7.34-7.36 (4H, m), 7.42 (2H, d, J ) 8.6 Hz), 7.62 (2H,
d, J ) 8.5 Hz), 7.67 (1H, d, J ) 10.1 Hz), 7.83 (1H, d, J ) 6.3
Hz); 13C NMR (125.7 MHz) δC 16.3 (CH3), 17.2 (CH3), 22.5 (CH3),
23.9 (CH3), 36.5 (CH2), 46.7 (C), 51.2 (CH), 52.0 (CH), 52.7 (CH3),
54.5 (CH), 98.7 (C), 126.9 (CH), 128.6 (2 × CH), 128.8 (2 × CH),
129.2 (2 × CH), 132.5 (C), 137.0 (C), 137.5 (2 × CH), 166.7 (C),
172.7 (C), 174.7 (C), 175.2 (C); MS m/z (rel intensity) 593 (M+,
2), 249 (M+ + H - CH(Me)NHCOCH(Me)NHBz-p-I, 43), 231
([p-I-PhCO]+, 100); HRMS calcd for C26H32IN3O5, 593.1387;
found, 593.1467; calcd for C7H4IO, 230.9307; found, 230.9318.
Anal. Calcd for C26H32IN3O5: C, 52.62; H, 5.43; N, 7.08. Found:
C, 52.62; H, 5.63; N, 6.99. X-ray Analysis: C27H33Cl3IN3O5, Mr
) 712.81, colorless plate crystal (0.24 × 0.19 × 0.11 mm3) from
EtOAc/n-hexane (mp 143-144 °C); orthorhombic, space group
P21212 (no. 18), a ) 34.192(2) Å, b ) 8.269(1) Å, c ) 11.228(1)
Å, V ) 3174.5(5) Å3, Z ) 4, Fcalcd ) 1.491 g cm-3, F(000) )
1491, µ ) 1.300 mm-1; 57 660 measured reflections, of which 4044
were unique (Rint ) 0.0286); 420 refined parameters, final R1 )
0.0382, for reflections with I > 2σ(I), wR2 ) 0.1136 (all data), GOF
) 1.030. Flack parameter ) 0.015(15). The max/min residual
IR (CHCl3) 3438, 3374, 3336, 1725, 1710, 1680, 1658, 1508 cm-1
;
1H NMR (500 MHz, CDCl3) δH 0.26 (3H, d, J ) 6.7 Hz), 0.76
(3H, d, J ) 6.9 Hz), 0.95 (3H, d, J ) 6.6 Hz), 0.97 (3H, d, J ) 6.6
Hz), 1.13 (3H, s), 1.36 (3H, s), 1.60-1.69 (2H, m), 1.76-1.82
(1H, m), 1.92 (1H, ddd, J ) 4.5, 11.7, 13.6 Hz), 2.39 (1H, dd, J )
12.3, 14.5 Hz), 3.12 (1H, dd, J ) 3.5, 14.5 Hz), 3.33 (1H, dd, J )
7.9, 8.8 Hz), 3.82 (3H, s), 4.22 (1H, ddd, J ) 3.5, 10.4, 12.3 Hz),
4.70 (1H, ddd, J ) 4.1, 8.5, 11.7 Hz), 5.01 (1H, d, J ) 12.6 Hz),
5.08 (1H, d, J ) 12.3 Hz), 5.18 (1H, d, J ) 7.9 Hz), 7.10-7.16
(4H, m), 7.21 (2H, dd, J ) 7.3, 7.3 Hz), 7.27-7.35 (5H, m), 7.51
(1H, d, J ) 10.4 Hz); 13C NMR (125.7 MHz, CDCl3) δC 18.4 (CH3),
18.9 (CH3), 21.1 (CH3), 23.1 (CH3), 23.2 (CH3), 23.3 (CH3), 25.2
(CH), 29.3 (CH), 35.7 (CH2), 39.1 (CH2), 47.4 (C), 51.7 (CH), 52.7
(CH3), 57.4 (CH), 62.8 (CH), 66.9 (CH2), 126.1 (CH), 127.7 (2 ×
CH), 128.2 (CH), 128.3 (2 × CH), 128.5 (2 × CH), 129.2 (2 ×
CH), 136.1 (C), 138.9 (C), 156.8 (C), 171.7 (C), 175.3 (C), 176.4
(C); MS m/z (rel intensity) 567 (M+, 1), 476 (M+ - CH2Ph, 2),
368 (M+ - CH2Ph - HOCH2Ph, 9), 91 ([CH2Ph]+, 100); HRMS
calcd for C32H45N3O6, 567.3308; found, 567.3311; calcd for C7H7,
91.0548; found, 91.0549. Anal. Calcd for C32H45N3O6: C, 67.70;
H, 7.99; N, 7.40. Found: C, 67.83; H, 7.95; N, 7.15.
electron density: +0.589/-0.449 e ·Å-3
.
N-(Benzoyl)-L-phenylalanyl-[r,r-dimethyl-L-ꢀ-homoalanyl]-
L-leucine Methyl Ester (106). It was synthesized from dipeptide
77 following the previous coupling procedure. The residue was
purified by rotatory chromatography (hexanes/EtOAc, 3:2), afford-
ing compound 106 (83%) as a crystalline solid: mp 97-98 °C (from
EtOAc/n-hexane); [R]D +10 (c 0.26, CHCl3); IR (CHCl3) 3437,
N-(p-Iodobenzoyl)-L-valyl-[r,r-dimethyl-D-ꢀ-homophenyla-
lanyl]-L-leucine Methyl Ester (109). To a solution of tripeptide 108
1
3382, 3088, 3067, 1740, 1654, 1508, 1483 cm-1; H NMR (500
J. Org. Chem. Vol. 74, No. 13, 2009 4663

Saavedra et al.
(38 mg, 0.07 mmol) in a biphasic mixture (2:1 THF/H2O, 9 mL) was
added Pd (10% on carbon, 25 mg), and the reaction was stirred at
room temperature and under hydrogen atmosphere (1 atm) for 16 h.
Then the mixture was filtered through Celite, and the filtrate was cooled
to 0 °C and treated with saturated aqueous NaHCO3 (6 mL) and
4-iodobenzoyl chloride (23 mg, 0.09 mmol). The mixture was allowed
to reach rt and stirred for 16 h, then it was poured into 5% aqueous
HCl and extracted with EtOAc. After usual drying, the residue were
purified by rotatory chromatography (hexanes/EtOAc, 85:15), giving
product 109 (31 mg, 70%) as a crystalline solid: mp 131-132 °C
(from EtOAc/n-pentane); [R]D +44 (c 0.41, CHCl3); IR (CHCl3) 3434,
3359, 3089, 1726, 1676, 1654, 1514 cm-1; 1H NMR (500 MHz) δH
0.22 (3H, d, J ) 6.7 Hz), 0.85 (3H, d, J ) 6.7 Hz), 0.98 (3H, d, J )
6.3 Hz), 0.99 (3H, d, J ) 7.0 Hz), 1.20 (3H, s), 1.38 (3H, s), 1.66
(1H, ddd, J ) 4.1, 10.1, 13.6 Hz), 1.84-1.95 (2H, m), 2.05 (1H, m),
2.46 (1H, dd, J ) 12.7, 14.5 Hz), 3.15 (1H, dd, J ) 3.5, 14.5 Hz),
3.69 (1H, dd, J ) 7.6, 10.1 Hz), 3.83 (3H, s), 4.27 (1H, ddd, J ) 3.5,
10.4, 12.5 Hz), 4.72 (1H, ddd, J ) 3.8, 8.2, 12.1 Hz), 7.13 (1H, dd,
J ) 6.9, 7.0 Hz), 7.16-7.24 (4H, m), 7.415 (2H, d, J ) 8.5 Hz),
7.416 (1H, d, J ) 8.5 Hz), 7.55 (1H, d, J ) 8.5 Hz), 7.65 (2H, d, J )
8.5 Hz), 7.80 (1H, d, J ) 10.7 Hz); 13C NMR (125.7 MHz) δC 18.3
(CH3), 19.5 (CH3), 21.1 (CH3), 23.1 (CH3), 23.2 (CH3), 23.5 (CH3),
25.2 (CH), 28.7 (CH), 35.6 (CH2), 39.0 (CH2), 47.4 (C), 51.9 (CH),
52.6 (CH3), 57.4 (CH), 62.5 (CH), 98.9 (C), 126.1 (CH), 128.3 (2 ×
CH), 128.7 (2 × CH), 129.1 (2 × CH), 132.7 (C), 137.6 (2 × CH),
138.9 (C), 167.2 (C), 172.1 (C), 175.3 (C), 176.5 (C); MS m/z (rel
intensity) 664 (M+ + H, <1), 519 (M+ - NHCH(CH2CHMe2)CO2Me,
4), 449 (M+ - C(Me)2CONHCH(CH2CHMe2)CO2Me, 3), 330 (M+
- NHCH(CH2Ph) - C(Me)2CONHCH(CH2CHMe2)CO2Me, 11), 302
(M+ - CONHCH(CH2Ph) - C(Me)2CONHCH(CH2CHMe2)CO2Me,
17), 243 (M+ - HOMe - CHMe2 - ΝHCOCH(CHMe2)NH-Bz-p-I,
100); HRMS calcd for C31H43IN3O5, 664.2247; found, 664.2260; calcd
for C15H17NO2, 243.1259; found, 243.1249. Anal. Calcd for
C31H42IN3O5: C, 56.11; H, 6.38; N, 6.33. Found: C, 56.42; H, 6.60;
N, 6.07. X-ray Analysis: C31H42IN3O5, Mr ) 663.58, colorless prism
crystal (0.42 × 0.23 × 0.22 mm3) from EtOAc/n-pentane (mp
131-132 °C); trigonal, space group R3 (no. 146), a ) b ) 44.8052(13)
(CH2CHMe2)CO2Me + H, 28), 91 ([CH2Ph]+, 100); HRMS calcd for
C32H44N3O6, 566.3230; found, 566.3239; calcd for C7H7, 91.0548;
found, 91.0544. Anal. Calcd for C32H43N3O6: C, 67.94; H, 7.66; N,
7.43. Found: C, 68.19; H, 7.76; N, 7.14. Compound 111: Syrup; [R]D
+65 (c 0.86, CHCl3); IR (CHCl3) ν 3364, 3090, 3067, 1726, 1685,
1657, 1552 cm-1; 1H NMR (500 MHz) δH 0.94 (3H, d, J ) 6.6 Hz),
0.96 (3H, d, J ) 6.3 Hz), 1.25 (3H, s), 1.35 (3H, s), 1.55 (1H, m),
1.61 (1H, ddd, J ) 4.1, 9.4, 13.5 Hz), 1.68-1.91 (4H, m), 2.08 (1H,
m), 2.44 (1H, dd, J ) 12.3, 14.2 Hz), 3.10 (1H, dd, J ) 3.5, 14.5 Hz),
3.40 (1H, ddd, J ) 6.8, 7.0, 10.4 Hz), 3.54 (1H, ddd, J ) 5.1, 7.3,
10.4 Hz), 3.80 (3H, s), 3.88 (1H, dd, J ) 4.8, 7.3 Hz), 4.09 (1H, ddd,
J ) 3.5, 11.5, 12.0 Hz), 4.63 (1H, ddd, J ) 3.8, 8.2, 11.7 Hz), 5.05
(1H, d, J ) 12.6 Hz), 5.08 (1H, d, J ) 12.6 Hz), 7.13-7.17 (3H, m),
7.24 (2H, dd, J ) 7.6, 7.6 Hz), 7.27-7.34 (5H, m), 7.38 (1H, d, J )
8.2 Hz), 7.55 (1H, d, J ) 10.4 Hz); 13C NMR (100.6 MHz) δC 21.1
(CH3), 22.8 (CH3), 23.2 (CH3), 23.8 (CH3), 24.8 (CH2), 25.2 (CH),
29.2 (CH2), 35.6 (CH2), 39.0 (CH2), 46.9 (CH2), 47.3 (C), 51.9 (CH),
52.6 (CH3), 56.9 (CH), 61.1 (CH), 66.8 (CH2), 125.8 (CH), 127.5 (2
× CH), 127.9 (CH), 128.0 (2 × CH), 128.4 (2 × CH), 129.0 (2 ×
CH), 136.5 (C), 139.2 (C), 154.8 (C), 172.0 (C), 175.6 (C), 176.6 (C);
MS m/z (rel intensity) 566 (M+ + H, 7), 474 (M+ - CH2Ph, 16), 303
(M+ + H - CH2Ph - CONHCH(CH2CHMe2)CO2Me, 41), 215
(C(Me)2CONHCH(CH2CHMe2)CO2Me + H, 53), 91 ([CH2Ph]+, 100);
HRMS calcd for C32H44N3O6, 566.3230; found, 566.3215; calcd for
C7H7, 91.0548; found, 91.0547. Anal. Calcd for C32H43N3O6: C, 67.94;
H, 7.66; N, 7.43. Found: C, 67.92; H, 7.72; N, 7.29.
N-(p-Iodobenzoyl)-L-prolyl-[r,r-dimethyl-L-ꢀ-homophenyla-
lanyl]-L-leucine Methyl Ester (112). To a solution of tripeptide 110
(98 mg, 0.17 mmol) in a biphasic mixture (2:1 THF/H2O, 15 mL)
was added Pd (10% on carbon, 50 mg), and the reaction was stirred
at room temperature and under hydrogen atmosphere (1 atm) for 16 h.
Then the mixture was filtered through Celite, and the filtrate was cooled
to 0 °C and treated with saturated aqueous NaHCO3 (6 mL) and
4-iodobenzoyl chloride (69 mg, 0.26 mmol). The mixture was allowed
to reach rt and stirred for 16 h, then it was poured into 5% aqueous
HCl and extracted with EtOAc. After usual drying and purification
by rotatory chromatography (hexanes/EtOAc, 3:2), product 112 was
isolated (71 mg, 62%) as a crystalline solid: mp 169-170 °C (from
EtOAc/n-pentane); [R]D +80 (c 0.21, CHCl3); IR (CHCl3) 3447, 3362,
1739, 1659, 1504 cm-1; 1H NMR (500 MHz, 70 °C) δH 0.86 (3H, d,
J ) 6.2 Hz), 0.91 (3H, d, J ) 6.3 Hz), 1.26 (3H, s), 1.34 (3H, s),
1.50-1.65 (5H, m), 1.80 (1H, m), 1.94 (1H, m), 2.66 (1H, dd, J )
11.5, 13.6 Hz), 3.02 (1H, dd, J ) 4.5, 13.9 Hz), 3.28-3.36 (2H, m),
3.74 (3H, s), 4.29 (1H, ddd, J ) 4.1, 9.8, 10.7 Hz), 4.47 (1H, ddd, J
) 6.9, 7.2, 7.9 Hz), 4.57 (1H, m), 6.18 (1H, d, J ) 7.9 Hz), 7.13 (1H,
m), 7.18-7.21 (4H, m), 7.26 (2H, d, J ) 8.2 Hz), 7.44 (1H, brb),
7.74 (2H, d, J ) 8.4 Hz); 13C NMR (125.7 MHz, CDCl3) δC 21.7
(CH3), 22.7 (CH3), 23.1 (CH3), 24.6 (CH3), 25.0 (CH + CH2), 28.6
(CH2), 36.5 (CH2), 40.7 (CH2), 46.2 (C), 50.3 (CH2), 51.0 (CH), 52.3
(CH3), 56.9 (CH), 60.8 (CH), 96.5 (C), 126.1 (CH), 128.1 (2 × CH),
129.1 (2 × CH), 129.2 (2 × CH), 135.7 (C), 137.4 (2 × CH), 138.9
(C), 170.0 (C), 170.8 (C), 173.7 (C), 176.9 (C); MS m/z (rel intensity)
Å, c ) 8.8254(4) Å, γ ) 120°, V ) 15343.4(9) Å3, Z ) 18, Fcalcd
)
1.293 g cm-3, F(000) ) 6156, µ ) 0.978 mm-1; 91 627 measured
reflections, of which 13 671 were unique (Rint ) 0.0921); 783 refined
parameters, final R1 ) 0.0442, for reflections with I > 2σ(I), wR2 )
0.1238 (all data), GOF ) 1.028. Flack parameter ) -0.033(13). The
max/min residual electron density: +0.645/-0.750 e ·Å-3.
N-(Benzyloxycarbonyl)-L-prolyl-[r,r-dimethyl-L-ꢀ-homophe-
nylalanyl]-L-leucine Methyl Ester (110) and N-(Benzyloxycar-
bonyl)-L-prolyl-[r,r-dimethyl-D-ꢀ-homophenylalanyl]-L-leu-
cine Methyl Ester (111). They were synthesized from a mixture
of dipeptides 91/92 following the previous coupling procedure. The
residue was purified by rotatory chromatography (hexanes/EtOAc,
75:25 and 3:2), affording compounds 110 (42%) and 111 (24%).
Compound 110: Syrup; [R]D +14 (c 0.50, CHCl3); IR (CHCl3)
3448, 3415, 3090, 3067, 1739, 1696, 1684, 1664 cm-1; 1H NMR (500
MHz, 70 °C) δH 0.96 (3H, d, J ) 6.2 Hz), 0.97 (3H, d, J ) 6.3 Hz),
1.20 (3H, s), 1.30 (3H, s), 1.37 (1H, m), 1.55-1.75 (4H, m), 1.77-1.85
(2H, m), 2.52 (1H, dd, J ) 11.4, 14.2 Hz), 3.00 (1H, dd, J ) 4.1,
14.2 Hz), 3.26 (1H, ddd, J ) 3.5, 9.3, 9.3 Hz), 3.37 (1H, ddd, J )
8.2, 8.5, 9.8 Hz), 3.75 (3H, s), 4.23 (1H, dd, J ) 5.7, 5.7 Hz), 4.34
(1H, ddd, J ) 4.1, 10.1, 11.0 Hz), 4.59 (1H, ddd, J ) 5.4, 7.9, 8.5
Hz), 5.10 (1H, d, J ) 12.3 Hz), 5.20 (1H, d, J ) 12.6 Hz), 6.15 (1H,
br b), 7.08 (1H, br b), 7.12 (1H, m), 7.13 (2H, d, J ) 7.3 Hz), 7.18
(2H, dd, J ) 6.3, 8.2 Hz), 7.29 (1H, dd, J ) 6.9, 7.0 Hz), 7.30-7.40
(4H, m); 13C NMR (125.7 MHz) δC 22.1 (CH3), 22.8 (CH3), 23.4
(CH3), 23.5 (CH3), 23.7 (CH2), 25.3 (CH), 29.2 (CH2), 37.2 (CH2),
41.4 (CH2), 46.5 (C), 47.1 (CH2), 51.2 (CH), 52.1 (CH3), 56.7 (CH),
61.1 (CH), 67.4 (CH2), 126.2 (CH), 128.1 (2 × CH), 128.15 (CH),
128.2 (2 × CH), 128.5 (2 × CH), 129.2 (2 × CH), 136.7 (C), 138.9
(C), 155.8 (C), 171.4 (C), 173.4 (C), 176.3 (C); MS m/z (rel intensity)
566 (M+ + H, 3), 474 (M+ - CH2Ph, 10), 303 (M+ + H - CH2Ph
- CONHCH(CH2CHMe2)CO2Me, 19), 215 (C(Me)2CONHCH-
661 (M+, 1), 570 (M+
-
CH2Ph, 6), 328 (M+
-
NHCH(CH2Ph)C(Me)2 - CONHCH(CH2CHMe2)CO2Me, 99), 300
(M+ - CONHCH(CH2Ph)C(Me)2CO - NHCH(CH2CHMe2)CO2Me,
57), 231 ([p-I-PhCO]+, 100); HRMS calcd for C31H40IN3O5, 661.2013;
found, 661.2015; calcd for C7H4IO, 230.9307; found, 230.9308. Anal.
Calcd for C31H40IN3O5: C, 56.28; H, 6.09; N, 6.35. Found: C, 56.63;
H, 6.43; N, 6.01. X-ray Analysis: C31H40IN3O5, Mr ) 661.56, colorless
needle crystal (0.15 × 0.11 × 0.10 mm3) from EtOAc/n-pentane (mp
169-170 °C); orthorhombic, space group P212121 (no. 19), a )
6.1613(3) Å, b ) 15.2508(7) Å, c ) 32.8063(17) Å, V ) 3082.6(3)
Å3, Z ) 4, Fcalcd ) 1.425 g cm-3, F(000) ) 1360, µ ) 1.081 mm-1;
35 963 measured reflections, of which 9373 were unique (Rint
)
0.0737); 372 refined parameters, final R1 ) 0.0472, for reflections with
I > 2σ(I), wR2 ) 0.0945 (all data), GOF ) 0.984. Flack parameter )
0.005(17). The max/min residual electron density: +1.126/-1.692
e·Å-3.
4664 J. Org. Chem. Vol. 74, No. 13, 2009

Catalytic, One-Pot Synthesis of ꢀ-Amino Acids
N-(p-Iodobenzoyl)-L-prolyl-[r,r-dimethyl-D-ꢀ-homophenyla-
lanyl]-L-leucine Methyl Ester (113). A solution of tripeptide 111
(40 mg, 0.07 mmol) underwent hydrogenolysis of the Cbz group,
followed by acylation with 4-iodobenzoyl chloride, as in the previous
case. After purification by rotatory chromatography (hexanes/EtOAc,
85:15), product 113 was isolated (31 mg, 67%) as a crystalline solid:
mp 162-163 °C (from EtOAc/n-pentane); [R]D +19 (c 0.50, CHCl3);
IR (CHCl3) 3354, 3089, 3065, 1725, 1683, 1655, 1620, 1558, 1425
cm-1; 1H NMR (500 MHz) δH 0.90 (3H, d, J ) 6.6 Hz), 0.93 (3H, d,
J ) 6.7 Hz), 1.29 (3H, s), 1.36 (3H, s), 1.55-1.65 (2H, m), 1.71 (1H,
m), 1.78-1.85 (2H, m), 1.92 (1H, ddd, J ) 4.8, 11.4, 13.3 Hz), 2.01
(1H, m), 2.47 (1H, dd, J ) 12.3, 14.2 Hz), 3.12 (1H, dd, J ) 3.8,
14.2 Hz), 3.43 (1H, ddd, J ) 4.4, 6.9, 10.5 Hz), 3.62 (1H, ddd, J )
6.6, 6.9, 10.4 Hz), 3.83 (3H, s), 4.09-4.16 (2H, m), 4.61 (1H, ddd, J
) 4.1, 7.9, 11.4 Hz), 7.16 (1H, dd, J ) 7.3, 8.5 Hz), 7.18 (2H, d, J )
7.3 Hz), 7.26 (2H, dd, J ) 6.6, 7.9 Hz), 7.27 (2H, d, J ) 8.5 Hz),
7.59 (1H, d, J ) 7.9 Hz), 7.68 (1H, d, J ) 10.4 Hz), 7.73 (2H, d, J )
8.2 Hz); 13C NMR (125.7 MHz) δC 21.2 (CH3), 22.8 (CH3), 23.1
(CH3), 24.0 (CH3), 25.1 (CH), 25.7 (CH2), 28.8 (CH2), 35.6 (CH2),
39.1 (CH2), 47.3 (C), 50.6 (CH2), 52.1 (CH), 52.6 (CH3), 57.0 (CH),
61.7 (CH), 96.7 (C), 125.9 (CH), 128.1 (2 × CH), 129.1 (2 × CH),
129.2 (2 × CH), 135.5 (C), 137.3 (2 × CH), 139.3 (C), 168.3 (C),
171.6 (C), 175.8 (C), 176.8 (C); MS m/z (rel intensity) 661 (M+, 1),
570 (M+ - CH2Ph, 2), 328 (M+ - NHCH(CH2Ph)C(Me)2CONHCH-
space group P1 (no. 1), a ) 9.8375(13) Å, b ) 10.8487(14) Å, c )
14.9223(18) Å, R ) 95.264(4)°, ꢀ ) 90.527(4)°, γ ) 91.967(4)°, V
) 1584.8(3) Å3, Z ) 2, Fcalcd ) 1.386 g cm-3, F(000) ) 680, µ )
1.052 mm-1; 42 926 measured reflections, of which 14 751 were
unique (Rint ) 0.0447); 743 refined parameters, final R1 ) 0.0589, for
reflections with I > 2σ(I), wR2 ) 0.1712 (all data), GOF ) 1.060.
Flack parameter ) 0.02(2). The max/min residual electron density:
+3.953/-2.157 e ·Å-3.
Acknowledgment. This work was supported by the Inves-
tigation Programmes CTQ2006-14260/PPQ and PPQ2003-
01379 of the Plan Nacional de Investigacio´n Cient´ıfica, Desar-
rollo e Innovacio´n Tecnolo´gica, Ministerio de Educacio´n y
Ciencia and Ministerio de Ciencia y Tecnolog´ıa, Spain. We also
acknowledge financial support from FEDER funds. C.J.S. thanks
the CSIC for an I3P contract, and the Gobierno de Canarias-
BIOSIGMA SL for a research contract.
Supporting Information Available: Experimental proce-
dures to prepare substrates 37, 50-53, 58-64, 66, and 67, and
characterization of these compounds. Preparation and spectro-
scopic data of the scission-Mannich products 21-34, 39-49,
54-57, and 69-92. Synthesis and spectroscopic data of acids
93-95 and dipeptides 96-103. X-ray analysis of compounds
(CH2CHMe2)CO2Me, 44), 300 (M+
- CONHCH(CH2Ph)-
C(Me)2CONHCH(CH2CHMe2)CO2Me, 35), 231 ([p-I-PhCO]+, 100);
HRMS calcd for C31H40IN3O5, 661.2013; found, 661.1989; calcd for
C7H4IO, 230.9307; found, 230.9314. Anal. Calcd for C31H40IN3O5:
C, 56.28; H, 6.09; N, 6.35. Found: C, 56.60; H, 6.28; N, 5.95. X-ray
Analysis: C31H40IN3O5, Mr ) 661.56, colorless block crystal (0.41 ×
0.35 × 0.24 mm3) from EtOAc/n-pentane (mp 162-163 °C); triclinic,
1
71, 78, 81, 83, 90, 96, 98-101, and 103. H and 13C NMR
spectra of the new compounds (21-34, 37, 39-64, 66, 67,
69-113). This material is available free of charge via the
Internet at http://pubs.acs.org.
JO9004487
J. Org. Chem. Vol. 74, No. 13, 2009 4665