Tetrahydrofuran Cα-tetrasubstituted amino acids: Two consecutive β-turns in a crystalline linear tripeptide

Article abstract of DOI:10.1021/jo701423w

(Chemical Equation Presented) The synthesis of tetrahydrofuran Cα-tetrasubstituted amino acids (TAAs) and their effect on the conformation in small peptides are reported. The synthesis starts from the protein amino acid methionine, which is protected at t

Full text of DOI:10.1021/jo701423w

Tetrahydrofuran Cr-Tetrasubstituted Amino Acids: Two
Consecutive â-Turns in a Crystalline Linear Tripeptide
Prantik Maity, Manfred Zabel, and Burkhard Ko¨nig*
Institut fu¨r Organische Chemie, UniVersita¨t Regensburg, D-93040 Regensburg, Germany
burkhard.koenig@chemie.uni-regensburg.de
ReceiVed June 30, 2007
The synthesis of tetrahydrofuran CR-tetrasubstituted amino acids (TAAs) and their effect on the
conformation in small peptides are reported. The synthesis starts from the protein amino acid methionine,
which is protected at the C and N terminus and converted into the corresponding sulfonium salt by
alkylation. Simple base treatment in the presence of an aryl aldehyde leads to the formation of
tetrahydrofuran tetrasubstituted CR-amino acids in a highly diastereoselective (trans/cis ratio up to 97:3)
reaction with moderate to good yields (35-78%) depending on the aldehyde used. Palladium-catalyzed
coupling reactions allow a subsequent further functionalization of the TAA. The R,S,S-TAA-Ala dipeptide
amide adopts a â-turn type I conformation, whereas its S,R,S isomer does not. The R,S,S-Gly-TAA-Ala
tripeptide amide shows in the solid state and in solution a conformation of two consecutive â-turn type
III structures, stabilized by i + 3 f i intramolecular hydrogen bonds.
Introduction
straint (Thorpe-Ingold effect) and a stereochemically stable
quaternary carbon center.4 Different methods to incorpo-
rate functionality in the R position of an amino acid or using
R,â-unsaturated amino acids as precursors have been reported.5
Toniolo6 recently reviewed the effect of CR tetrasubstitution
on the structure of homooligoamides mostly resulting in stable
The conformation of a peptide is crucial for its biological
activity.1 Most small natural peptides are conformationally
flexible, show structural dependence on the environment, and
are therefore not suitable to study or control secondary pep-
tide structures. One of the successful approaches to restrict
peptide conformation is the introduction of side chain restricted
amino acids.2,3 Disubstitution by alkyl or aryl groups in the R
position of an R-amino acid leads to a conformational con-
3
10 or R-helices.7 In short peptides, CR-alkylated R-amino acids
stabilize turn structures,8 which in general have received
particular attention because they play an important role in
globular proteins from both structural and functional points of
view.9
(1) (a) Ward, P.; Ewan, G. B.; Jordan, C. C.; Ireland, S. J.; Hagan, R.
M.; Brown, J. J. Med. Chem. 1990, 33, 1848-1851. (b) Hruby, V. J.; Agnes,
R. S.; Biopolym. Pept. Sci. 1999, 51, 391-410. (c) Bisang, C.; Weber, C.;
Inglis, J.; Schiffer, C. A.; van Gunsteren, W. F.; Jelesarov, I.; Bosshard, H.
R.; Robinson, J. J. Am. Chem. Soc. 1995, 117, 7904-7915. (d) Nikiforovich,
S. D.; Sharma, S. D.; Hadley, M. E.; Hruby, V. J. Biopolymers 1998, 46,
155-167.
(2) (a) Tourwe´, D.; Verschueren, K.; Frycia, A.; Davis, P.; Porreca, F.;
Hruby, V. J. Biopolymers 1996, 38, 1-12. (b) Hruby, V. J.; Li, G.; Haskell-
Luevano, C.; Shenderovich, M. Biopolym. Pept. Sci. 1997, 43, 219-266.
(3) (a) Hruby, V. J. Life Sci. 1992, 31, 189-199. (b) DeGrado, W. F.
AdV. Protein Chem. 1988, 39, 51-123. (c) Hruby, V. J.; Hadley, M. E.
Design and Synthesis of Organic Molecules Based on Molecular Recogni-
tion; Van Binst, G., Ed.; Springer: Heidelberg, 1986; pp 269-289.
(4) (a) Ooi, T.; Maruoka, K. In Quaternary Stereocenters-Challenges
and Solutions for Organic Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-
VCH: Weinheim, 2005; p 265. (b) Ellis, T. K.; Martin, C. H.; Tsai, G. M.;
Ueki, H.; Soloshonok, V. A. J. Org. Chem. 2003, 68, 6208-6214. (c) Xu,
P.-F.; Li, S.; Lu, T.-J.; Wu, C.-C.; Fan, B.; Golfis, G. J. Org. Chem. 2006,
71, 4364-4373. (d) Maity, P.; Ko¨nig, B. Synthesis 2006, 16, 2719-2724.
(e) For a recent review, see: Christoffers, J.; Baro, A. AdV. Synth. Catal.
2005, 347, 1473-1482.
(5) (a) Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T.
HelV. Chim. Acta 1987, 70, 237-255. (b) Seebach, D.; Boes, M.; Naef,
R.; Schweizer, W. B. J. Am. Chem. Soc. 1983, 105, 5390-5398. (c) Seebach,
D.; Burger, H. M.; Schickli, C. P. Liebigs Ann. Chem. 1991, 669-684.
10.1021/jo701423w CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/18/2007
8046
J. Org. Chem. 2007, 72, 8046-8053

Tetrahydrofuran CR-Tetrasubstituted Amino Acids
SCHEME 1. Synthesis of the Protected Methionine Sulfonium Salt rac-3 and Its Conversion to TAA rac-4
A polypeptide chain cannot fold into a compact structure
without turns, which usually occur on the solvent-exposed
surface of proteins and hence probably represent antigenic sites
involved in molecular recognition.10 Many naturally occurring
oligopeptides have been proposed to adopt turns in their
bioactive conformation.11 Different types of bends are defined
according to the number and spatial arrangement of the residues
involved, and â-turns (â-bends reverse turn) are the most
abundant and best characterized group of folded secondary
structures.12 Subclasses of â-turns are further distinguished on
the basis of the backbone dihedral angles (æ, ψ) associated with
central i + 1 and i + 2 positions. In the past years, several
artificial turn inducing structures were reported by Nowick,13
Schmuck,14 Frigel,15 Kelly,16 Gellman,17 Balaram,18 and others.
We report here the preparation and structural characterization
of tetrahydrofuran CR-tetrasubstituted amino acids (TAAs) from
methionine, which induce two consecutive â-turns as part of a
tripeptide of aliphatic R-amino acids.
the reaction conditions, the R-proton of the amino acid is
removed and its stereoinformation is lost. The ester enolate
reacts with the carbonyl group of the aromatic aldehyde, and
the intermediate alkoxide substitutes intramolecularly dimeth-
ylsulfide20 giving tetrahydrofuran amino acids rac-4 with high
diastereoselectivity of the R- and â-stereocenters. A proposed
mechanism of the reaction is outlined in Figure 1.
A series of optimizations revealed that aromatic aldehydes
with an electron-withdrawing substituent and a sterically
(12) (a) Richardson, J. S. AdV. Protein Chem. 1981, 34, 167. (b) The
â-turn motif was initially recognized in silk proteins by Geddes: Geddes,
A. J.; Parker, K. D.; Atkins, E. D.; Beighton, E. J. Mol. Biol. 1968, 32,
343-358. (c) And later stereochemically defined by Venkatachalam:
Venkatachalam, C. M. Biopolymers 1968, 6, 1425-1436.
(13) (a) Nowick, J. S; Lam, K. S.; Khasanova, T. V.; Kemnitzer, W. E.;
Maitra, S.; Mee, H. T.; Liu, R. J. Am. Chem. Soc. 2002, 124, 4972-4973.
(b) Nowick, J. S.; Cary, J. M.; Tasi, J. H. J. Am. Chem. Soc. 2001, 123,
5176. (c) Nowick, J. S.; Chung, D. M.; Maitra, K.; Maitra, S.; Stigers, K.
D.; Sun, Y. J. Am. Chem. Soc. 2000, 122, 7654-7661. (d) Nowick, J. S.
Acc. Chem. Res. 1999, 32, 287-296. (e) Nowick, J. S.; Tsai, J. H.; Bui,
Q.-C. D.; Maitra, S. J. Am. Chem. Soc. 1999, 121, 8409-8410.
(14) (a) Schmuck, C.; Geiger, L. J. Am. Chem. Soc. 2004, 126, 8898-
8899. (b) Schmuck, C.; Bickert, V. Org. Lett. 2003, 5, 4579-4581. (c)
Schmuck, C.; Heil, M. ChemBioChem. 2003, 4, 1232-1238. (d) Schmuck,
C.; Heil, M. Org. Biomol. Chem. 2003, 1, 633-636.
Results and Discussion
The key step of the TAA synthesis is the aldol-type reaction
of a methionine-derived sulfonium salt19 with an aldehyde
followed by a cyclization. Scheme 1 shows the preparation of
the sulfonium salt 3 starting from the racemic natural amino
acid methionine (rac-1). Methionine sulfonium iodide rac-3a
was treated with KOH. Acidic protons are found at the
sulfonium moiety and at the R-carbon of the amino acids. Under
(15) Frigel, M. J. Am. Chem. Soc, 1986, 108, 181-182.
(16) (a) Nesloney, C. L.; Kelly, J. W. J. Am. Chem. Soc. 1996, 118,
5836-5845. (b) Diaz, H.; Tsang, K. Y.; Kelly, J. W. Tetrahedron 1993,
49, 3533-3545. (c) Diaz, H.; Kelly, J. W. Tetrahedron Lett. 1991, 32,
5725-5728.
(17) (a) Syud, F. A.; Stanger, H. E.; Gellman, S. H. J. Am. Chem. Soc.
2001, 123, 8667-8677. (b) Huck, B. R.; Fisk, J. D.; Gellman, S. H. Org.
Lett. 2000, 2, 2607-2610. (c) Fisk, J. D.; Powell, D. R.; Gellman, S. H. J.
Am. Chem. Soc. 1998, 120, 4236-4237. (d) Haque, T. S.; Little, J. C.;
Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 6975-6985. (e) Haque, T.
S.; Gellman, S. H. J. Am. Chem. Soc. 1997, 119, 2303-2304.
(18) (a) Rai, R.; Raghothama, S.; Balaram, P. J. Am. Chem. Soc. 2006,
128, 2675-2681 and related references cited therein. (b) Raghothama, S.;
Awasthi, S. K.; Balaram, P. J. Chem. Soc., Perkin Trans. 2 1998, 137-
141.
(19) The use of sulfur ylides in synthesis is well known. Typical
applications are the preparation of epoxides and more recently cyclopropane
rings. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345-
1353. (b) Aggarwal, V. K. Synlett 1998, 329-336. (c) Aggarwal, V. K.;
Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Patel, M.;
Porcelloni, M.; Rechardson, J.; Stenson, P. A.; Studley, J. R.; Vesse, J.-L.;
Winn, C. L. J. Am. Chem. Soc. 2003, 125, 10926-10940. (d) For recent
reviews, see: Aggarwal, V. K.; Richardson, J. In Science of Synthesis;
Padwa, A., Bellus, D., Eds.; George Thieme Verlag, 2004; Vol. 27, pp
21-105. (e) Li, A.-H.; Dai, L. X.; Aggarwal, V. K. Chem. ReV. 1997, 97,
2341-2372. (f) Aggarwal, V. K.; Alsono, E.; Fang, G.; Ferrara, M.; Hynd,
G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433-1436. (g)
Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2004, 43, 4641-4644. (h) Kunz, R.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 3240-3241.
(6) (a) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Biopolymers
2001, 60, 396-419. (b) The effect of chirality in the side chain on the
screw sense of the helix is of particular interest. For leading references,
see: Tanaka, M.; Demizu, Y.; Doi, M.; Kurihara, M.; Suemune, H. Angew.
Chem., Int. Ed. 2004, 43, 5360-5363. (c) Royo, S.; De Borggraeve, W.
M.; Peggion, C.; Formaggio, F.; Crisma, M.; Jimenez, A. I.; Cativiela, C.;
Toniolo, C. J. Am. Chem. Soc. 2005, 127, 2036-2037. (d) Mazaleyrat, J.-
P.; Wright, K.; Gaucher, A.; Toulemonde, N.; Wakselman, M.; Oancea,
S.; Peggion, C.; Formaggio, F.; Setnicka, V.; Keiderling, T. A.; Toniolo,
C. J. Am. Chem. Soc. 2004, 126, 12874-12879.
(7) (a) For helix parameters, see: Toniolo, C.; Benedetti, E. Trends
Biochem. Sci. 1991, 16, 350-353. (b) For an application of a stable helix
as an artificial nuclease, see: Sissi, C.; Rossi, P.; Felluga, F.; Formaggio,
F.; Palumbo, M.; Tecilla, P.; Toniolo, C.; Scrimin, P. J. Am. Chem. Soc.
2001, 123, 3169-3170.
(8) Crisma, M.; Moretto, A.; Zotti, D. M.; Formaggio, F.; Kaptein, B.;
Broxterman, B. Q.; Toniolo, C.; Biopolymers 2005, 80, 279-293 and related
references cited therein.
(9) (a) Toniolo, C. Crit. ReV. Biochem. 1980, 9, 1. (b) Rose, G. D.;
Gierasch, L. M.; Smith, J. A. AdV. Protein Chem. 1985, 37, 1. (c) Vass, E.;
Hollosi, M.; Besson, F.; Buchet, R. Chem. ReV. 2003, 103, 1917.
(10) (a) Smith, J. A.; Pease, L. G. CRC Crit. ReV. Biochem. 1980, 8,
315. (b) Kuntz, I. D. J. Am. Chem. Soc. 1972, 94, 4009.
(11) Spatola, A. F. In Bioorganic Chemistry: Peptides and Proteins;
Hecht, S. M., Ed.; Oxford University press: New York, 1998; pp 367-
394.
(20) No higher oligomers were observed, even if the reaction was
performed on large scale or at higher concentrations. The intramolecular
substitution is significantly favored over any intermolecular substitution
reaction.
J. Org. Chem, Vol. 72, No. 21, 2007 8047

Maity et al.
TABLE 2. Scope of the Reaction of Sulfonium Salt rac-3 with
Aromatic Aldehydes
FIGURE 1. Proposed reaction mechanism of tetrahydrofuran CR-
tetrasubstituted amino acid formation.
TABLE 1. Optimization of the Reaction Conditions Converting
Compound rac-3 to TAA rac-4a
reaction
temp [°C]
reaction
time [h]
trans/cisb
ratio
solvent
DCMa
base
yield [%]
KOH
20
5
40
47
40
55
54
52
60
78
60
65
97:3
KOtBu
KOH
4.5
3.5
2
tBuOH
DMF
-5
-5
97:3
96:4
KOH
CsOH
KOH
1.5
4
toluenea
CH3CN
20
96:4
KOtBu
KOH
3
-5
3
>97:3
KOtBu
CsOH
2
2
a
Tetrabutyl ammonium bromide (10 mol %) was added as the phase
b
transfer catalyst. The trans/cis ratio was determined by HPLC.
demanding protecting group for the carboxyl function, such as
tBu, give the best reaction conversions and stereoselectivities.
A decrease of the reaction temperature from room temperature
to -5 °C increases product yields and selectivity. Several
solvents and bases were tested. The reaction occurred smoothly
in polar solvents. As KOH is not soluble in less polar solvents,
such as dichloromethane and toluene, tetrabutylammonium
bromide was added as a phase transfer catalyst. However, yields
are moderate in these solvents. Among all solvents, CH3CN
gave the best yield of the desired product in 0.5-1 h (Table 1).
Additionally, the scope of the reaction and its dependence on
steric and electronic properties of the aryl aldehyde were
investigated (Table 2). Electronic effects on the reaction yield
are small, whereas diastereoselectivity depends on the aldehyde.
The relative stereochemistry of the major diastereoisomer was
confirmed by X-ray diffraction analysis of compound rac-4e
(Figure 2) and compound rac-4a (as benzyl ester, see Supporting
Information for data). With benzene, high selectivities (trans/
cis g 97:3) with moderate to good yields (45-78%; 50-95%
according to aldehyde conversion) of naphthalene and cinnamic
aldehyde are obtained, whereas the diastereoselectivity is poor
with furfural and p-cyanobenzaldehyde.
a
The isolated yield was determined with respect to the aryl aldehyde
used. The isolated yield with respect to the converted aryl aldehyde is given
in brackets. Selectivity was determined by HPLC on a chiral column.
Selectivity was determined by column chromatographic separation.
Determined by NMR.
b
c
d
Compound rac-4a was converted into the carboxylic acid
rac-5 (Scheme 2) by treatment with 6 M HCl in methanol
affording the hydrochloride salt of the free amino acid quan-
titatively. N-Reprotection with Boc-anhydrid gave compound
rac-6.21 Using standard peptide coupling conditions, the racemic
carboxylic acid rac-6 was coupled with L-alanine methyl ester
hydrochloride and L-phenylalanine methyl ester hydrochloride
giving dipeptides 7-10 in moderate yields. The diastereomers
FIGURE 2. X-ray diffraction analysis of the major diastereomer of
compound rac-4e confirming the trans configuration. For clarity, only
one enantiomer and only the amide hydrogen atoms are shown.
are now separable by column chromatography, and crystals
suitable for X-ray diffraction analysis were obtained for the
R,S,S-isomer 7 and S,R,S-isomer 9.
(21) Basic hydrolysis of the benzyl ester of compound 4a by KOH affords
the product in only 24% yield.
8048 J. Org. Chem., Vol. 72, No. 21, 2007

Tetrahydrofuran CR-Tetrasubstituted Amino Acids
SCHEME 2. Deprotection of TAA and Coupling with Chiral Amino Acids
a) DIPEA, EDC, HOBt, L-alanine methyl ester hydrochloride or L-phenylalanine methyl ester hydrochloride, DCM, 24 h, rt, 60% and 55%, respectively.
SCHEME 3. Incorporation of TAA rac-6 into a Short
Peptide Chain
FIGURE 3. X-ray diffraction structure of compound 11 accommodat-
ing a â I turn in the crystal state. The intramolecular i + 3 f i hydrogen
bond is indicated by a dashed line. Only the amide hydrogen atoms
are shown.
After Boc-deprotection, isomer 11 was coupled with acetyl-
ated glycine yielding tripeptide 13. Instead of a simple elongated
â-turn structure, a conformation consisting of two consecutive
â-turns type III, slightly deviating from an ideal 310 helix
structure, was observed in the solid state (Figure 4). The torsion
angles (æ, ψ) for the left-side turn Gly i + 1 (-62.4°, -21.0°)
and TAA i + 2 (-55.1°, -26.0°) and for the right-side turn
TAA i + 2 (-55.1°, -26.0°) and L-Ala (-71.6°, -31.5°)
resemble the typical values (-60°, -30° and -60°, -30°). The
structure is stabilized by two intramolecular hydrogen bonds
(N‚‚‚O: 2.92 Å; N-H‚‚‚O: 163° and N‚‚‚O: 3.26 Å; N-H‚
‚‚O: 149°). A 2D ROESY spectrum (see Supporting Informa-
tion) provides evidence for the existence of the proposed
conformation in solution. Additional support comes from a
variable-temperature NMR study in DMSO-d6: Temperature
coefficients of the amide protons Hd (-0.58 ppb/K) and Hc
(-3.17 ppb/K) possibly indicate strong intramolecular hydrogen
bonds, and temperature coefficients of Ha and Hb are signifi-
cantly higher (-5.35 ppb/K and -7.20 ppb/K, respectively; see
Supporting Information for data). However, temperature coef-
ficients are only assessed as an indication because a more
detailed analysis is required to unambiguously correlate their
values to hydrogen bonding as shown by Andersen et al.24
TAAs were incorporated into a short peptide chain to
demonstrate their ability to induce a turn structure (Scheme 3).22
Compound rac-6 was coupled with the benzyl amide of
L-alanine, and the diastereomers 11 and 12 were separated by
column chromatography. The crystalline structure of dipeptide
11 confirmed the R,S,S configuration. The molecule adopts a
â-turn type I conformation with terminal Boc-CO and benzyl-
amide NH groups intramolecularly hydrogen bonded [N‚‚‚O:
2.92 Å; N-H‚‚‚O: 163°]. The torsion angles (æ, ψ) of the TAA
i + 1 (-61.7, -25.2) and L-Ala i + 2 (-82.9, -2.0) residues
correspond to a â-turn type I (Figure 3).23 The X-ray diffraction
analysis of the S,R,S diastereomer 12 (see Supporting Informa-
tion) shows no intramolecular hydrogen bonds or turn structure
formation.
(22) (a) Jimenerz, A. I.; Ballano, G.; Cativiela, C. Angew. Chem., Int.
Ed. 2005, 44, 396-399. (b) Jimenez, A. I.; Cativiela, C.; Aubry, A.;
Marraud, M. J. Am. Chem. Soc. 1998, 120, 9452. (c) Jimenez, A. I.;
Cativiela, C.; Gomez-Catalan, J.; Perez, J. J.; Aubry, A.; Paris, M.; Marraud,
M. J. Am. Chem. Soc. 2000, 122, 5811. (d) Jimenez, A. I.; Cativiela, C.;
Marraud, M. Tetrahedron Lett. 2000, 41, 5353. (e) Jimenez, A. I.; Marraud,
M.; Cativiela, C. Tetrahedron Lett. 2003, 44, 3141.
(23) The torsion angles closely resemble the ideal values of (-60°, -30°)
and (-90°, 0°).
(24) Andersen, N. H.; Neidigh, J. W.; Harris, S. M.; Lee, G. M.; Liu,
Z.; Tong, H. J. Am. Chem. Soc. 1997, 119, 8547-8561.
J. Org. Chem, Vol. 72, No. 21, 2007 8049

Maity et al.
FIGURE 4. Structure (i) and X-ray diffraction analysis (ii) of compound 13 exhibiting two consecutive â-turns, each stabilized by an intramolecular
i + 3 f i hydrogen bond (dashed lines). Only amide hydrogen atoms are shown. (iii) Backbone structure of the tripeptide.
SCHEME 4. Cross-Coupling Reactions
a) Methylacrylate, Et3N, Pd(Ac)2, P(o-tolyl)3, in DMF, 14 h, 80 °C, 71%; b) phenylboronic acid, Na2CO3, Pd(OAc)2, TBAB, in water/DME (1:1), 100
°C, 71%; c) benzylamine or morpholine, K3PO4, 2-isobutyryl-cyclohexanone in DMF, 100 °C, 75% or 35%.
The bromine substituent in compound rac-4a allows a
subsequent functionalization of the TAA, which may be of use
for specific labeling or modification of properties of the turn
motif. Conventional Suzuki,25 Heck,26 and Buchwald27 coupling
(Scheme 4) gave derivatives rac-14 to rac-16.
Experimental
Sulfonium Salt Cyclization, Typical Procedure. An oven- or
flame-dried flask was cooled under a stream of nitrogen and charged
with sulfonium iodide rac-3 (1 mmol) in acetonitrile (4 mL/mmol).
The colorless solution was cooled to 0 °C. Powdered KOH or KOt-
Bu or CsOH (1 mmol) was added, and the reaction mixture was
stirred for 15 min. Then the aryl aldehyde (0.9 mmol) was added,
and the mixture was stirred for another 2-4 h. After consumption
of all of the starting material, the reaction mixture was quenched
by adding water (3 mL/mmol). The reaction mixture was diluted
with diethyl ether (4 mL/mmol) and transferred to a separatory
funnel. The layers were separated, and the aqueous layer was
extracted with diethyl ether (2 × 5 mL/mmol). Then, combined
ether layers were washed with brine and dried over MgSO4, and
the solvent was removed in vacuo. The crude product was purified
by flash column chromatography on silica gel using 10-15%
diethyl ether/PE as the eluant.
tert-Butyl-2-(4-bromophenyl)-3-(tert-butoxycarbonylamino)-
tetrahydrofuran-3-carboxylate (rac-4a). Yield ) 60% using
KOtBu as a base, 82% using KOH as a base, and 65% using CsOH
as a base. Rf ) 0.23 (diethyl ether/PE ) 1:4), mp ) 131-133 °C.
1H NMR (300 MHz, CDCl3) δ ) 1.09 (s, 9H), 1.45 (s, 9H),
2.61-2.68 (m, 2H), 4.16-4.33 (m, 2H), 5.00 (bs, 1H), 5.71 (bs,
1H), 7.20 (d, J ) 8.23 Hz, 2H), 7.42 (d, J ) 8.23 Hz, 2H). 13C
NMR (75.5 MHz, CDCl3) δ ) 27.42 (+), 28.40 (+), 35.80 (-),
67.91 (-), 69.63 (+), 80.13 (Cquat), 82.62 (Cquat), 84.42 (Cquat),
121.75 (Cquat), 127.91 (+), 131.02 (+), 136.72 (Cquat), 154.3 (Cquat),
170.03 (Cquat). MS [ESI; CH2Cl2/MeOH + 10 mmol NH4OAc] )
Conclusion
In summary, we have reported the racemic diastereoselective
synthesis of tetrahydrofuran CR-tetrasubstituted amino acids
(TAA) from readily available methionine. Dipeptides of TAA
and chiral amino acids yield diastereomers, which are readily
separated by column chromatography. Short peptide sequences
containing the R,S-isomer of TAA show a stable turn structure
in the crystal state and in solution. Two consecutive â-turn type
III turns, resembling a distorted 310 helix structure, are found
for a tripeptide amide consisting of Gly-TAA-Ala. Good
accessibility and variable modification by transition-metal-
catalyzed coupling reactions make TAAs a useful addition to
the family of CR-tetrasubstituted R-amino acids and artificial
turn structures in peptide research.
(25) de Meijere, A.; Meyer, F. E.; Angew. Chem, Int. Ed. Engl. 1995,
33, 2379-2411.
(26) Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 888-892.
(27) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742-
8743.
8050 J. Org. Chem., Vol. 72, No. 21, 2007

Tetrahydrofuran CR-Tetrasubstituted Amino Acids
442.2, 444.2 [MH+] (80), 459.3, 461.3 [M - NH4+] (75). IR
(KBr): ν˜ cm-1 ) 3362, 2975, 2932, 2873, 2199, 1509, 1454, 1392.
Anal. calcd for C20H28BrNO5 (442.34): C, 54.30; H, 6.38; N 3.17.
Found: C, 54.27; H, 6.67; N, 3.16.
tert-Butyl-3-(tert-butoxycarbonylamino)-2-phenyltetrahydro-
furan-3-carboxylate (rac-4c). Yield ) 70% using KOH as a base.
Rf ) 0.21 (diethyl ether/PE ) 3:17), mp ) 61-63 °C.
compound rac-5): Compound rac-5 (1 g, 3.13 mmol), 1,4-dioxan
(5 mL), and 1.25 M aqueous NaOH (7 mL) were stirred and cooled
to 6 °C for 10 min. Then a solution of di-tert-butyl-dicarbonate
(0.75 g, 3.45 mmol) in 1,4-dioxan (2 mL) was added over 5 min.
The cooling bath was removed, and the reaction was stirred for
3.5 h. The dioxane was removed in vacuo, and the residue was
diluted with 1 M aqueous KHSO4 (2 mL) and extracted with EtOAc
(1 × 4, 1 × 3 mL). The combined organic layers were washed
with water (2 mL) and brine (2 mL) and dried over MgSO4. The
solvent was removed to give pure rac-6 as a white solid (0.72 g,
60%).
Procedure B. (Starting from compound rac-4n): Compound rac-
4n (500 mg, 1.05 mmol) was dissolved in ethanol (5 mL). Then
150 mg of KOH was added to the solution, and the mixture was
refluxed for 24 h. The reaction mixture was cooled, and ethanol
was evaporated. The obtained yellow solid was dissolved in water
(3 mL) and extracted with diethyl ether (2 × 2 mL) to remove all
organic impurities. The aqueous solution was acidified with citric
acid (10%, 2 mL) and extracted with ethyl acetate (2 × 3 mL).
The combined organic layers were washed with brine (1 mL) and
dried over MgSO4. The solvent was removed to give pure
compound rac-6 (97 mg) as a white solid in 24% yield. This
compound was used for next step without further purification.
1H NMR (300 MHz, CDCl3) δ ) 1.44 (s, 9H), 2.68-2.78 (m,
1H, CHH), 3.30 (m, 1H, CHH), 4.15-4.25 (m, 1H, -OCHH), 4.32
(m, 1H, OCHH-), 5.10 (bs, 1H), 5.61 (bs, 1H), 7.10-7.22 (m, 2H),
7.40-7.50 (m, 2H). 13C NMR (75.5 MHz, CDCl3) δ ) 28.40 (+),
35.80 (-), 67.91 (-), 69.63 (+), 82.62 (Cquat), 84.42 (Cquat), 121.75
(Cquat), 127.91 (+), 131.02 (+), 136.72 (Cquat), 154.3 (Cquat), 170.03
(Cquat). MS [ESI; CH2Cl2/MeOH + 10 mmol NH4OAc] ) 0.442.2
[M+H] (80), 459.3 [M - NH4+]. IR (KBr): ν˜ cm-1 ) 3362, 2975,
2932, 2873, 2199, 1509, 1454, 1392.
1H NMR (300 MHz, CDCl3) δ ) 1.09 (s, 9H), 1.45 (s, 9H),
2.50-2.80 (m, 2H), 4.23 (m, 1H, -OCHH-), 4.33 (m, 1H, -OCHH-),
5.02 (bs,1H), 5.60 (bs, 1H), 7.25-7.30 (m, 5H). 13C NMR (75.5
MHz, CDCl3) δ ) 27.92 (+), 28.12 (+), 35.83 (-), 67.04 (-),
82.65 (Cquat), 84.87 (Cquat), 123.44 (+), 128.08 (Cquat), 133.53 (+),
137.52 (+), 150.61 (+), 154.54 (+), 155.36 (Cquat), 170.09 (Cquat).
MS [ESI; CH2Cl2/MeOH + 10 mmol/1 NH4OAc] ) 364.3 [MH+]
(100), 381 [M - NH4+] (50). IR (KBr): ν˜ cm-1 ) 3358, 2978,
2932, 2872, 1720, 1494, 1454, 1365. Anal. calcd for C20H29NO5
(363.45): C, 66.09; H, 8.04; N, 3.85. Found: C, 65.89; H, 8.32;
N, 3.32.
tert-Butyl-3-(tert-butoxycarbonylamino)-2-(4-methoxy-phen-
yl)-tetrahydrofuran-3-carboxylate (rac-4d). Yield ) 50% using
KOH as a base and 45% using KOtBu as a base. Rf ) 0.25 (diethyl
ether/PE ) 1:4), mp ) 97-99 °C.
1H NMR (300 MHz, CDCl3) δ ) 1.13 (s, 9H), 1.49 (s, 9H),
2.52-2.65 (m, 1H, -CHH-), 2.68-2.82 (m, 1H, -CHH-), 3.78 (s,
3H), 4.11-4.23 (m, 1H, -OCHH-), 4.27-4.35 (m, 1H, -OCHH-),
4.93 (bs, 1H), 5.48 (bs, 1H), 6.80 (d, J ) 7.96 Hz, 2H), 7.25 (d, J
) 7.96 Hz, 2H). 13C NMR (75.5 MHz, CDCl3) δ ) 27.49 (+),
28.41 (+), 55.00, 67.74 (-), 69.14, 82.08 (Cquat), 113.00 (+), 127.57
(Cquat), 129.50 (+), 154.54 (Cquat), 159.46 (Cquat), 170.08 (Cquat).
MS [ESI; CH2Cl2/MeOH + 10 mmol/1 NH4OAc] 394.2 [MH+]
(60), 411.2 [M - NH4+] (20). IR (KBr): ν˜ cm-1 ) 3359, 2975,
2931, 2881, 1707, 1613, 1583, 1510. Anal. calcd for C21H31NO6
(393.47): C, 64.10; H, 7.94; N, 3.56. Found: C, 64.33; H, 7.64;
N, 3.37.
Dipeptide Esters 7 and 9. Compound rac-6 (100 mg, 0.26
mmol) was dissolved in CH2Cl2 (1.5 mL), and the hydrochloride
salt of alanine methylester (36 mg, 0.26 mmol), EDC (40 mg, 0.26
mmol), HOBT (35 mg, 0.26 mmol), and DIPEA (84 mg, 0.65
mmol) were added. The reaction mixture was stirred at room
temperature for 24 h and quenched with water (2 mL) and 1 M
KHSO4 (3 mL), diluted by adding 3 mL of diethyl ether and
transferred to a separating funnel. The aqueous layer was extracted
with diethyl ether (2 × 3 mL). Then combined ether layers were
washed with brine solution (2 mL) and dried over MgSO4, and the
solvent was removed in vacuo. The crude product was purified by
flash column chromatography on silica gel using 30-40% diethyl
ether/petrol ether as the eluant to give 73.2 mg (60%) of compounds
tert-Butyl-3-(tert-butoxycarbonylamino)-2-(4-methylphenyl)-
tetrahydrofuran-3-carboxylate (rac-4e). Yield ) 55% using KOH
as a base. Rf ) 0.22 (diethyl ether/PE ) 3:17), mp ) 135-138 °C.
1H NMR (300 MHz, CDCl3) δ ) 1.09 (s, 9H), 1.47 (s, 9H),
2.30 (s, 3H), 2.65 (m, 1H, -CHH-), 2.72 (m, 1H, -CHH-), 4.11 (m,
1H, -OCHH-), 4.32 (m, 1H, -OCHH), 5.02 (bs, 1H, CH-), 5.65
(bs, 1H), 6.92 (d, J ) 7.95 Hz, 2H), 7.45 (m, J ) 7.95 Hz, 2H).
13C NMR (75.5 MHz, CDCl3) δ ) 21.12 (+), 27.41 (+), 29.94
(+), 35.73 (-), 67.78 (-), 69.74 (+), 82.05 (Cquat), 82.07 (Cquat),
85.74 (Cquat), 126.21 (+), 128.61 (+), 134.38 (Cquat), 137.63 (Cquat),
154.57 (Cquat), 170.07 (Cquat). MS [ESI; CH2Cl2/MeOH + 10mmol/1
NH4OAc] ) 378.2 [MH+] (100), 395.2 [M - NH4+] (20). IR
(KBr): ν˜ cm-1 ) 3357, 2978, 2930, 2870, 2783, 2199, 1703, 1610,
1514, 1450. Anal. calcd for C21H31NO5 (377.47): C, 66.82; H, 8.28;
N, 3.71. Found: C, 66.91; H, 8.62; N, 3.58.
3-Amino-2-(4-bromo-phenyl)-tetrahydrofuran-3-carboxylic
Acid Hydrochloride (rac-5). To a solution of compound rac-4a
(2 g, 4.5 mmol) in 20 mL of methanol was added 10 mL of 6 M
HCl. The reaction mixture was heated to reflux temperature for 6
h, then cooled to room temperature and stirred for another 2 h.
The reaction mixture was concentrated by removal of methanol;
remaining parts of the reaction mixture were lypophilized yielding
quantitatively a white solid of the corresponding hydrochloride salt
(1.4 g). The compound was used in the next step without further
purification.
25°
7 and 9 as white solids. Compound 7: mp ) 117-118 °C, [R]D
) +34.3 (c ) 1.0, CHCl3). 1H NMR (600 MHz, CDCl3) δ ) 0.90
(bs, 3H), 1.49 (s, 9H), 2.50 (m, 1H, -CHH-), 2.85 (m, 1H, -CHH-),
3.65 (s, 3H), 4.10 (qn, J ) 6.79 Hz, 1H), 4.27-4.38 (m, 2H),
5.43 (bs, 1H), 6.25 (bs, 1H), 6.45 (bs, 1H), 7.20 (d, J ) 8.25 Hz,
2H), 7.40 (d, J ) 8.25 Hz, 2H). 13C NMR (75.5 MHz, CDCl3) δ
) 17.55 (+), 28.43 (+), 36.08 (-), 48.01(+), 52.47 (+), 66.62
(-), 67.11 (+), 80.07 (Cquat), 121.44 (Cquat), 126.82 (+), 131.13
(+), 136.12 (Cquat), 154.51 (Cquat), 170.79 (Cquat), 172.98 (Cquat).
MS [PI-LSIMS; MeOH/Glycerine] ) 0.471.3, 473.3 [MH+] (60),
415.3, 417.3 [M+ - C4H8] (50). IR (KBr): ν˜ cm-1 ) 3356, 3348,
3303, 3061, 3029, 2978, 2941, 2887, 2867, 2800, 2199, 1668. Anal.
calcd for C20H27BrN2O6 (476.19): C, 50.96; H, 5.77; N, 5.94.
Found: C, 50.92; H, 6.05; N, 5.87. Compound 9: mp ) 127-
1H NMR (300 MHz, MeOD) δ ) 2.32 (m, 1H, -CHH-), 2.92
(m, 1H, -CHH-), 4.17 (m, 1H, -OCHH-), 4.56(m, 1H, -OCHH-),
5.00 (bs, 1H), 7.34 (d, J ) 8.23 Hz, 2H), 7.53 (d, J ) 8.23 Hz,
2H). 13C NMR (75.5 MHz, MeOD) δ ) 36.23 (-), 68.59 (-),
69.91 (+), 87.77 (Cquat), 123.89 (+), 129.76 (Cquat), 132.45 (Cquat),
25°
1
130 °C, [R]D ) -34.3 (c ) 1.0, CHCl3). H NMR (600 MHz,
CDCl3) δ ) 0.92 (d, J ) 6.24 Hz, 3H), 1.49 (s, 9H), 2.53 (m, 1H,
-CHH-), 2.88 (m, 1H, -CHH-), 3.72 (s, 3H), 4.24 (qn, J ) 7.34
Hz, 1H), 4.34 (m, 2H), 5.44 (bs, 1H), 6.28 (bs, 1H), 6.47 (d, J )
5.87 Hz, 1H), 7.22 (d, J ) 8.44 Hz, 2H), 7.41 (d, J ) 8.44 Hz,
2H). 13C NMR (75.5 MHz, CDCl3) δ ) 18.26 (+), 28.38 (+), 35.91
(-), 48.18 (+), 52.46 (+), 66.69 (-), 67.78 (+), 80.27 (Cquat),
121.65 (Cquat), 127.30 (+), 131.01 (+), 135.71 (Cquat), 154.32 (Cquat),
170.61 (Cquat), 172.66 (Cquat). MS [PI-LSIMS; MeOH/Glycerine]
) 0.471.3, 473.3 [M+H] (60), 415.3, 417.3 [M+ - C4H8] (50). IR
136.24 (+), 170.39 (+). MS [ESI; CH2Cl2/MeOH + 10 mmol NH4-
+
OAc] ) 0.286.1, 288.1 [MH+ - Cl] (30), 303.2, 305.2 [M + NH4
(100).
]
2-(4-Bromophenyl)-3-(tert-butoxycarbonylamino)-tetrahydro-
furan-3-carboxylic Acid (rac-6). Procedure A. (Starting from
J. Org. Chem, Vol. 72, No. 21, 2007 8051

Maity et al.
(KBr): ν˜ cm-1 ) 3348, 3303, 3061, 3029, 2978, 2941, 2887, 2867,
2800, 2199, 1668, 1591, 1517, 1452. Anal. calcd for C20H27BrN2O6
(476.19): C, 50.96; H, 5.77; N, 5.94. Found: C, 51.02; H, 6.12;
N, 5.86.
(dd, 1H, J ) 15.94 Hz, 5.14 Hz, COSY, HMBC: H-8b/a), 3.87 (m,
1H, COSY, HMBC: H-5a/b), 4.15 (m, 1H, COSY, HMBC: H-17a/b),
4.25 (m, 2H, COSY, HMBC: H-17b/c and H-5b/a), 4.98 (s, 1H,
COSY, HMBC: H-2), 7.16 (m, 3H, aromatic), 7.27 (m, 4H,
aromatic), 7.35 (d, J ) 7.47 Hz, 1H, COSY, HMBC: H-13), 7.49
(m, 2H, aromatic), 7.58 (t, J ) 6.36 Hz, 1H, COSY, HMBC: H-16),
8.20 (t, J ) 5.25 Hz, COSY, HMBC: H-9), 9.00 (s, 1H, COSY,
HMBC: H-6). 13C NMR (151 MHz, DMSO) δ ) 16.40 (+,
HSQC: C-24), 22.10 (+, HSQC: C-11), 35.67 (-, HSQC: C-4),
41.82 (-, HSQC: C-8 or C-17), 43.10 (-, HSQC, C-8 or C-17),
48.61(+, HSQC: C-14), 67.31 (-, HSQC: C-5), 69.65 (+,
HSQC: C-2), 84.83 (Cquat, HSQC, C-3), 121.00 (Cquat), 126.51 (+),
126.77 (+), 127.04 (+), 128.09 (+), 128.23 (+), 128.67 (+), 130.40
(+), 137.30 (Cquat), 139.19 (+), 168.50 (Cquat, HMBC: C-12),
170.45 (Cquat, HMBC: C-10), 171.46 (Cquat, HMBC: C-7), 171.70
(Cquat, HMBC: C-15). MS [PI-LSIMS; MeOH/glycerine] ) 0.545.3,
547.3 [MH+] (100).
(E)-tert-Butyl-3-(tert-butoxycarbonylamino)-2-[4-(3-methoxy-
3-oxoprop-1-enyl)-phenyl]-tetrahydrofuran-3-carboxylate (rac-
14). A mixture of 0.57 mmol of compound rac-4a (250 mg), 0.68
mmol of methylacrylate (58 mg), 0.68 mmol of triethyl amine, 1
mol % of palladium acetate, and 0.03 mmol of tris(o-tolyl)phosphine
in 2 mL of DMF was heated to 100 °C under argon for 14 h. After
the consumption of all of the starting material, the mixture was
cooled to room temperature and 2 mL of 1 M KHSO4 was added.
The mixture was extracted (3 × 1 mL) with diethyl ether. The
combined organic fraction was dried over MgSO4, and the solvent
was evaporated to give a solid crude product, which was purified
by column chromatography (silica gel, 1:1 diethyl ether/petrol ether)
affording 180 mg (71%) of the white solid product rac-14: mp )
146-149 °C.
Dipeptide Esters 8 and 10. The compounds were prepared
following the same procedure as that given for the preparation of
7 and 9, using phenylalanine hydrochloride salt instead of alanine
hydrochloride salt. The reaction gave 55% isolated product yield.
Compound 8: 1H NMR (300 MHz, CDCl3) δ ) 1.47 (s, 9H), 2.79
(m, 1H, -CHH-), 2.97-3.10 (m, 1H, -CHH-), 3.60 (s, 3H), 4.02
(m, 1H), 4.15-4.31 (m, 3H), 4.41 (m, 1H), 5.38 (bs, 1H), 6.19
(bs, 1H), 6.57 (bs, 1H), 7.02-7.14 (m, 4H), 7.26-7.37 (m, 5H).
13C NMR (75.5 MHz, CDCl3) δ ) 28.43 (+), 35.45 (-), 37.61
(-), 52.38 (+), 53.19 (+), 53.82 (+), 66.21 (-), 80.08 (Cquat),
121.46 (Cquat), 126.82 (+), 127.28 (+), 127.40 (+), 128.62 (+),
128.94 (Cquat), 129.13 (+), 131.19 (+), 135.77 (Cquat), 154.06 (Cquat),
171.05 (Cquat), 171.67 (Cquat). MS [PI-LSIMS; MeOH/Glycerine]
) 546.14, 547.4 [MH+] (60). IR (KBr): ν˜ cm-1 ) 3356, 3348,
3303, 3061, 3029, 2978, 2941, 2887, 2867, 2800, 2199, 1668.
Compound 10: 1H NMR (300 MHz, CDCl3) δ ) 1.49 (s, 9H),
2.81 (m, 1H, -CHH-), 2.95 (m, 1H, -CHH-), 3.65 (s, 3H), 4.04 (m,
1H), 4.20-4.34 (m, 3H), 4.43 (m, 1H), 5.40 (bs, 1H), 6.23 (bs,
1H), 6.60 (bs, 1H), 7.00-7.12 (m, 4H), 7.22-7.35 (m, 5H). 13C
NMR (75.5 MHz, CDCl3) δ ) 29.43 (+), 36.45 (-), 37.61 (-),
52.38 (+), 53.19 (+), 53.82 (+), 66.21 (-), 80.08 (Cquat), 121.46
(Cquat), 123.82 (+), 127.38 (+), 127.45 (+), 128.69 (+), 128.94
(Cquat), 129.13 (+), 131.19 (+), 135.77 (Cquat), 155.06 (Cquat), 171.06
(Cquat), 171.77 (Cquat).
Dipeptide Amides 11 and 12. The compounds were prepared
as described above. The reaction gave an isolated yield of 50% of
the two diastereomers. Compound 11: 1H NMR (300 MHz, CDCl3)
δ ) 1.15 (d, J ) 7.12 Hz, 3H), 1.43 (s, 9H), 2.55-2.64 (m, 1H,
-CHH-), 2.69-2.81 (m, 1H, -CHH-), 4.00 (m, 1H), 4.20-4.28 (m,
2H), 4.34-4.44 (m, 3H), 5.12 (bs, 1H), 5.88 (bs, 1H), 6.24 (bd,
1H), 6.34 (t, 1H), 7.17-7.39 (m, 9H). 13C NMR (75.5 MHz, CDCl3)
δ ) 17.98 (+), 28.29 (+), 36.08 (-), 43.34 (-), 49.20 (+), 67.16
(-), 68.42 (+), 80.91 (Cquat), 83.01 (Cquat), 122.05 (Cquat), 127.35
(+), 127.50 (+), 128.58 (+), 131.32 (+), 135.74 (Cquat), 137.99
(Cquat), 154.78 (Cquat), 170.54 (Cquat), 171.22 (Cquat). MS [ESI; CH2-
Cl2/MeOH + 10 mmol NH4Ac] ) 0.546.2, 548.2 [MH+] (100),
490.1, 492.1 [M+ - C4H8] (26).
1H NMR (300 MHz, CDCl3) δ ) 1.09 (s, 9H), 1.46 (s, 9H),
2.61-2.68 (m, 2H), 3.80 (s, 3H), 4.16-4.33 (m, 2H), 5.09 (bs,
1H), 5.65 (bs, 1H), 6.41 (d, J ) 15.92 Hz, 1H), 7.35 (d, J ) 8.23
Hz, 2H), 7.50 (d, J ) 8.23 Hz, 2H), 7.65 (d, J ) 15.92 Hz, 1H).
13C NMR (75.5 MHz, CDCl3) δ ) 27.38 (+), 28.41 (+), 35.94
(-), 51.72 (+), 67.97 (-), 69.71 (+), 80.10 (Cquat), 82.50 (Cquat),
84.72 (Cquat), 117.73 (+), 126.72 (Cquat), 127.66 (+), 131.95 (+),
140.16 (Cquat), 144.47 (+), 154.3 (Cquat), 167.45 (Cquat), 170.05
(Cquat). MS [ESI; CH2Cl2/MeOH + 10 mmol NH4OAc] ) 0.448.2
[MH+] (40), 465.3 [M - NH4+] (35), 409.2 [M - NH4+ - C4H8]
(100). IR (KBr): cm-1 ) 3362, 2975, 2932, 2873, 2199, 1509,
1454, 1392. Anal. calcd for C24H33NO7 (447.34): C, 64.41; H, 7.43;
N, 3.13. Found: C, 64.27; H, 7.67; N, 3.16.
Compound 12: 1H NMR (300 MHz, CDCl3) δ ) 0.93 (d, J )
6.82 Hz, 3H), 1.48 (s, 9H), 2.38-2.53 (m, 1H, -CHH-), 2.69-
2.81 (m, 1H, -CHH-), 4.00-4.10 (m, 1H), 4.25-4.48 (m, 4H), 5.32
(bs, 1H), 6.12 (bs, 1H), 6.25 (bt, 1H), 6.60 (d, J ) 6.60 Hz, 1H),
7.16-7.40 (m, 9H). 13C NMR (75.5 MHz, CDCl3) δ ) 17.76 (+),
28.42 (+), 35.82 (-), 43.53 (-), 49.02 (+), 66.75 (-), 67.70 (+),
80.35 (Cquat), 81.24 (Cquat), 121.60 (Cquat), 127.08 (+), 127.59 (+),
128.77 (+), 131.14 (+), 136.16 (Cquat), 137.81 (+), 154.20 (Cquat),
170.92 (Cquat), 171.38 (Cquat).
tert-Butyl-2-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-tet-
rahydrofuran-3-carboxylate (rac-15). In a 25 mL Schlenk flask
were placed compound rac-4a (250 mg, 0.567 mmol), phenylbo-
ronic acid (83 mg, 0.68 mmol), Na2CO3 (240 mg, 2.27 mmol), Pd-
(OAc)2 (2 mg, 6 µmol), tetrabutylammonium bromide (183 mg,
0.567 mmol), and 2 mL of a water/DMF (1:1) mixture. The flask
was sealed with a septum and placed into an oil bath preheated to
100 °C. The reaction mixture was held at this temperature for 20
h and cooled to room temperature. Water and diethyl ether (10 mL
of each) were added, and organic material was removed by
extraction. After further extraction of the aqueous layer with diethyl
ether, the organic phases were combined and dried over MgSO4,
and the diethyl ether was removed in vacuo, leaving the crude
product, which was purified by column chromatography (silica gel,
1:4 diethyl ether/PE) affording 250 mg (71%) of the white solid
product rac-15: mp ) 80-83 °C.
Tripeptide Amide 13. Compound 11 (100 mg, 0.26 mmol) was
dissolved in 5 mL of DCM. To this solution was added 2 mL of
HCl saturated diethyl ether solution, and the mixture was stirred
for 20 min at room temperature. The solvent was evaporated, and
the resulting white solid was dissolved in DMF (1.5 mL). DIPEA
(89 mg, 0.67 mmol), Ac-Gly-OH (36 mg, 0.32 mmol), EDC (65
mg, 0.41 mmol), and HOBT (66 mg, 0.41 mmol) were added. The
reaction mixture was stirred at room temperature for 3 days,
quenched with water (2 mL) and 1 M KHSO4 (3 mL), diluted by
adding 3 mL of diethyl ether, and transferred into a separatory
funnel. The aqueous layer was extracted with diethyl ether (2 × 3
mL); the combined ether layers were washed with brine solution
(2 mL) and dried over MgSO4; and the solvent was removed in
vacuo. The crude product was purified by HPLC to give 41 mg of
compound 13 (40% yield).
1H NMR (300 MHz, CDCl3) δ ) 1.12 (s, 9H), 1.50 (s, 9H),
2.57-2.85 (m, 2H), 4.18-4.41 (m, 2H), 5.09 (bs, 1H), 5.56 (bs,
1H), 7.31-7.59 (m, 9H). 13C NMR (75.5 MHz, CDCl3) δ ) 27.40
(+), 28.44 (+), 35.95 (-), 67.49 (-), 69.89 (+), 80.07 (Cquat), 82.26
(Cquat), 85.47 (Cquat), 126.73 (Cquat), 127.08 (+), 127.32 (+), 127.41
(+), 127.59 (+), 127.97 (+), 128.89 (+), 131.04 (+), 136.65 (Cquat),
1H NMR (600 MHz, DMSO) δ ) 0.80 (d, J ) 7.47 Hz, 3H,
COSY, HSQC: H-24), 1.74 (s, 3H, COSY, HSQC: H-11), 1.99
(m, 1H, COSY, HSQC: H-4a/b), 2.97 (m, 1H, COSY, HSQC:
H-4b/a), 3.50-3.7 (m, 2H, COSY, HMBC: H-14 and H-8a/b), 3.82
140.94 (Cquat), 154.3 (Cquat), 170.10 (Cquat). MS [ESI; CH2Cl2/MeOH
+
+ 10 mmol NH4OAc] ) 440.3 [MH+] (65), 457.3 [M - NH4
]
(60), 401.2 [M - NH4+ - C4H8] (100). IR (KBr): cm-1 ) 3362,
8052 J. Org. Chem., Vol. 72, No. 21, 2007

Tetrahydrofuran CR-Tetrasubstituted Amino Acids
2975, 2932, 2873, 2199, 1509, 1454, 1392. Anal. calcd for C26H33-
NO5 (439.54): C, 71.05; H, 7.57; N, 3.19. Found: C, 70.82; H,
7.66; N, 3.15.
(d, J ) 8.50 Hz, 2H), 7.15 (d, J ) 8.50 Hz, 2H), 7.27-7.35 (m,
5H). 13C NMR (75.5 MHz, CDCl3) δ ) 27.53 (+), 28.40 (+),
35.59 (-), 48.09 (-), 67.62 (-), 69.85 (+), 79.90 (Cquat), 81.81
(Cquat), 86.56 (Cquat), 112.40 (+), 126.00 (Cquat), 127.16 (+), 127.31
(+), 127.56 (+), 128.59 (+), 139.36 (Cquat), 147.97 (Cquat), 154.74
(Cquat), 170.05 (Cquat). MS [ESI; CH2Cl2/MeOH + 10 mmol NH4-
OAc] ) 0.469.3 [MH+] (100), 486.3 [M - NH4+] (65). IR (KBr):
cm-1 ) 3362, 2975, 2932, 2873, 2199, 1509, 1454, 1392. Anal.
calcd for C27H36N2O5 (468.58): C, 69.21; H, 7.74; N, 5.98.
Found: C, 69.17; H, 7.67; N, 6.00.
tert-Butyl-2-(4-(benzylamino)phenyl)-3-(tert-butoxycarbony-
lamino)-tetrahydrofuran-3-carboxylate (rac-16a). An oven-dried
Schlenk flask equipped with a Teflon septum was charged with a
magnetic stir bar, 3 mL of DMF, compound rac-4a (250 mg, 0.567
mmol), CuI (5.5 mg, 0.028 mmol, 5 mol %), and K3PO4 (240 mg,
1.134 mmol). The flask was evacuated and filled with argon (this
procedure was repeated three times). Under a flow of argon, the
appropriate amine (91 mg, 0.851 mmol) was added by syringe.
Finally, 2-isobutyryl-cyclohexanone (20 mg, 0.113 mmol, 20 mol
%) was added via syringe. The mixture was heated to 100 °C for
10 h. Upon completion of the reaction, the mixture was allowed to
cool to room temperature and diluted with 5 mL of water. The
aqueous layer was extracted with diethyl ether (3 × 3 mL); the
total organic fraction was dried over MgSO4; and the solvent was
removed in vacuo. The crude product was purified by column
chromatography (silica gel, diethyl ether/PE 2:3) affording 200 mg
(yield, 75%) of pure compound rac-16a as a white solid: mp )
122-125 °C.
Acknowledgment. We thank the Fonds der Chemischen
Industrie and the University of Regensburg for support.
Supporting Information Available: Experimental procedures
and characterization data for the synthesis of compounds rac-2a,
rac-2b, rac-3a, rac-3b, rac-4b, rac-4c, rac-4f, rac-4n, and rac-
16b. Copies of 1H NMR spectra of all new compounds, temperature-
dependent NMR spectra of compounds 11 and 13, ROESY
spectrum of 13, and X-ray diffraction analyses of compounds rac-
4a, 7, 9, and 12. This material is available free of charge via the
Internet at http://pubs.acs.org.
1H NMR (300 MHz, CDCl3) δ ) 1.15 (s, 9H), 1.47 (s, 9H),
2.47-2.60 (m, 1H), 2.72-2.84 (s, 1H), 4.10 (q, J ) 8.05 Hz, 1H),
4.25-4.30 (m, 1H), 4.32 (s, 2H), 4.80 (bs, 1H), 5.40 (bs, 1H), 6.55
JO701423W
J. Org. Chem, Vol. 72, No. 21, 2007 8053