Convergent and stereospecific synthesis of molecules containing α-functionalized guanidiniums via α-guanidino acids

Article abstract of DOI:10.1021/jo701766c

(Chemical Equation Presented) To introduce chirality and functional groups adjacent to guanidiniums to modulate specificity and affinity in recognition, N,N′-bis(Boc)-α-guanidino acids were synthesized from α-amino acid methyl esters. Protected α-guanidino acids coupled to cyclohexylamine and trans-1,4-diaminocyclohexane in good yield and with retention of stereochemistry. Boc deprotection was conducted under mild acidic conditions (0.5 M HCl/EtOAc) to minimize epimerization. The deprotected guanidinium is configurationally stable under more acidic conditions. This approach represents a practical, convergent, stereospecific methodology to introduce chiral α-substituted guanidinium groups into molecules.

Full text of DOI:10.1021/jo701766c

Many techniques have been developed to synthesize complex
guanidiniums.6-9 However, one of the simplest guanidinium
motifs containing complex functionality is that obtained by
guanylation of the amino group of an R-amino acid, generating
an R-guanidino acid (Chart 1).5,7,9 We were particularly intrigued
by the use of R-substituted guandiniums derived from R-guani-
dino acids to achieve high affinity and high specificity in
guanidinium-mediated biomolecular recognition.
Convergent and Stereospecific Synthesis of
Molecules Containing r-Functionalized
Guanidiniums via r-Guanidino Acids
Shalini Balakrishnan, Chen Zhao, and Neal J. Zondlo*
Department of Chemistry and Biochemistry, UniVersity of
Delaware, Newark, Delaware 19716
In a particularly noteworthy example highlighting the poten-
tial of R-substituted guanidiniums for macromolecular recogni-
tion, the groups of Wells and Arkin at Sunesis have incorporated
a single R-guanidino acid moiety into a series of high-affinity
small-molecule ligands for interleukin-2 (IL-2).5 In this work,
both the functional group present and the stereochemistry at
the R-position exquisitely impacted affinity for the target protein.
For example, in structure-activity studies they observed a
greater than 25-fold increase in IL-2 affinity for a molecule
derived from D-valine over molecules derived from either
L-valine or glycine.5d X-ray crystallography of the complexes
with IL-2 revealed extensive contacts between IL-2 and both
the guanidinium and side chain.5a-c,e This work highlights the
zondlo@udel.edu
ReceiVed August 13, 2007
To introduce chirality and functional groups adjacent to
guanidiniums to modulate specificity and affinity in recogni-
tion, N,N′-bis(Boc)-R-guanidino acids were synthesized from
R-amino acid methyl esters. Protected R-guanidino acids
coupled to cyclohexylamine and trans-1,4-diaminocyclo-
hexane in good yield and with retention of stereochemistry.
Boc deprotection was conducted under mild acidic conditions
(0.5 M HCl/EtOAc) to minimize epimerization. The depro-
tected guanidinium is configurationally stable under more
acidic conditions. This approach represents a practical,
convergent, stereospecific methodology to introduce chiral
R-substituted guanidinium groups into molecules.
(5) (a) Braisted, A. C.; Oslob, J. D.; Delano, W. L.; Hyde, J.; McDowell,
R. S.; Waal, N.; Yu, C.; Arkin, M. R.; Raimundo, B. C. J. Am. Chem. Soc.
2003, 125, 3714-3715. (b) Thanos, C. D.; Randal, M.; Wells, J. A. J. Am.
Chem. Soc. 2003, 125, 15280-15281. (c) Arkin, M. R.; Randal, M.;
DeLano, W. L.; Hyde, J.; Luong, T. N.; Oslob, J. D.; Raphael, D. R.; Taylor,
L.; Wang, J.; McDowell, R. S.; Wells, J. A.; Braisted, A. C. Proc. Natl.
Acad. Sci. U.S.A. 2003, 100, 1603-1608. (d) Raimunddo, B. C.; Oslob, J.
D.; Braisted, A. C.; Hyde, J.; McDowell, R. S.; Randal, M.; Waal, N.;
Wilkinson, J.; Yu, C. H.; Arkin, M. R. J. Med. Chem. 2004, 47, 3111-
3130. (e) Thanos, C. D.; DeLano, W. L.; Wells, J. A. Proc. Natl. Acad.
Sci. U.S.A. 2006, 103, 15422-15427.
(6) (a) Katritzky, A. R.; Rogovoy, B. V. ArkiVoc 2005 (iV), 49-87. (b)
Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. Tetrahedron Lett. 1993, 34,
3389-3392. (c) Kent, D. R.; Cody, W. L.; Doherty, A. M. Tetrahedron
Lett. 1996, 37, 8711-8714. (d) Feichtinger, K.; Zapf, C.; Sings, H. L.;
Goodman, M. J. Org. Chem. 1998, 63, 3804-3805. (e) Dodd, D. S.;
Wallace, O. B. Tetrahedron Lett. 1998, 39, 5701-5704. (f) Chen, J.;
Pattarawarapan, M.; Zhang, A. J.; Burgess, K. J. Comb. Chem. 2000, 2,
276-281. (g) Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J.
Org. Chem. 2000, 65, 1566-1568. (h) Katritzky, A. R.; Rogovoy, B. V.;
Chassaing, C.; Vvedensky, V. J. Org. Chem. 2000, 65, 8080-8082. (i)
Zapf, C. W.; Creighton, C. J.; Tomioka, M.; Goodman, M. Org. Lett. 2001,
3, 1133-1136. (j) Musiol, H. J.; Moroder, L. Org. Lett. 2001, 3, 3859-
3861. (k) Zhang, Y.; Kennan, A. J. Org. Lett. 2001, 3, 2341-2344. (l)
Manimala, J. C.; Anslyn, E. V. Tetrahedron Lett. 2002, 43, 565-567. (m)
Manimala, J. C.; Anslyn, E. V. Eur. J. Org. Chem. 2002, 3909-3922. (n)
Bartoli, S.; Jensen, K. B.; Kilburn, J. D. J. Org. Chem. 2003, 68, 9416-
9422. (o) Powell, D. A.; Ramsden, P. D.; Batey, R. A. J. Org. Chem. 2003,
68, 2300-2309. (p) Gers, T.; Kunce, D.; Markowski, P.; Izdebski, J.
Synthesis 2004, 37-42.
Guanidiniums are widely used to specifically recognize
diverse protein, DNA, and RNA targets.1 Guanidiniums achieve
affinity and specificity by virtue of potentially bidentate
electrostatic and hydrogen-bonding interactions, yielding par-
ticularly favorable interactions with phosphates and carboxy-
lates.2 Guanidiniums have been generally applied in the
development of synthetic receptors3 and have been broadly
applied in medicinal chemistry as components of ligands for
complex biomedical targets, particularly as mimics of RGD
motifs to bind integrin receptors.4,5
(7) Synthesis of protected R-guanidino acids or derivatives: (a) Poss,
M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z. X. Tetrahedron Lett.
1992, 33, 5933-5936. (b) Drake, B.; Patek, M.; Lebl, M. Synthesis 1994,
579-582. (c) Lal, B.; Gangopadhyay, A. K. Tetrahedron Lett. 1996, 37,
2483-2486. (d) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem.
1997, 62, 1540-1542. (e) Yong, Y. F.; Kowalski, J. A.; Thoen, J. C.; Lipton,
M. A. Tetrahedron Lett. 1999, 40, 53-56. (f) Xuereb, H.; Maletic, M.;
Gildersleeve, J.; Pelczer, I.; Kahne, D. J. Am. Chem. Soc. 2000, 122, 1883-
1890. (g) Suhs, T.; Ko¨nig, B. Chem.-Eur. J. 2006, 12, 8150-8157.
(8) (a) Zhang, Z. Y.; Van Aerschot, A.; Hendrix, C.; Busson, R.; David,
F.; Sandra, P.; Herdewijn, P. Tetrahedron 2000, 56, 2513-2522. (b) Mamai,
A.; Madalengoitia, J. S. Org. Lett. 2001, 3, 561-564.
(9) Synthesis of unprotected R-guanidino acids from R-amino acids: (a)
Rowley, G. L.; Greenleaf, A. L.; Kenyon, G. L. J. Am. Chem. Soc. 1971,
93, 5542-5551. (b) Miller, A. E.; Bischoff, J. J. Synthesis 1986, 777-
779. (c) Jursic, B. S.; Neumann, D.; McPherson, A. Synthesis 2000, 1656-
1658. (d) Siemion, I. Z.; Gawlowska, M.; Slepokura, K.; Biernat, M.;
Wieczorek, Z. Peptides 2005, 26, 1543-1549.
(1) (a) Berlinck, R. G. S. Nat. Prod. Rep. 2002, 19, 617-649. (b)
Berlinck, R. G. S. Nat. Prod. Rep. 1999, 16, 339-365. (c) Berlinck, R. G.
S. Nat. Prod. Rep. 1996, 13, 377-409.
(2) Schug, K. A.; Lindner, W. Chem. ReV. 2005, 105, 67-113.
(3) (a) Kneeland, D. M.; Ariga, K.; Lynch, V. M.; Huang, C. Y.; Anslyn,
E. V. J. Am. Chem. Soc. 1993, 115, 10042-10055. (b) Albert, J. S.;
Goodman, M. S.; Hamilton, A. D. J. Am. Chem. Soc. 1995, 117, 1143-
1144. (c) Peczuh, M. W.; Hamilton, A. D.; SanchezQuesada, J.; deMendoza,
J.; Haack, T.; Giralt, E. J. Am. Chem. Soc. 1997, 119, 9327-9328. (d)
Orner, B. P.; Hamilton, A. D. J. Inclusion Phenom. Macrocycl. Chem. 2001,
41, 141-147. (e) Best, M. D.; Tobey, S. L.; Anslyn, E. V. Coord. Chem.
ReV. 2003, 240, 3-15.
(4) (a) Perreault, D. M.; Cabell, L. A.; Anslyn, E. V. Bioorg. Med. Chem.
1997, 5, 1209-1220. (b) Luedtke, N. W.; Baker, T. J.; Goodman, M.; Tor,
Y. J. Am. Chem. Soc. 2000, 122, 12035-12036. (c) Luedtke, N. W.;
Carmichael, P.; Tor, Y. J. Am. Chem. Soc. 2003, 125, 12374-12375. (d)
Peterlin-Masic, L.; Kikelj, D. Tetrahedron 2001, 57, 7073-7105.
10.1021/jo701766c CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/03/2007
9834
J. Org. Chem. 2007, 72, 9834-9837

TABLE 2. Examination of Racemization under Different Coupling
Conditions
CHART 1. r-Guanidino Acids and Derivatives
TABLE 1. Synthesis of Bis(Boc)-Protected r-Guanidino Acidsa
entry coupling reagent solvent time, min yield
% ee
1
2
3
4
5
DCC
DCC/HOBt
DCC
EDCI/HOBt
EDCI/HOBt
CH2Cl2
CH2Cl2
DMF
CH2Cl2
DMF
60
60
60
120
120
95% 84%
78% 86%
40% 97%
81% 84%
84% single isomer
synthesize 2b, proceeded readily to generate 2a-e.7d,10 Saponi-
fication with LiOH generated the protected R-guanidino acids
3a-e. These reactions proceeded cleanly and in good yield,
providing ready access to protected R-guanidino acid building
blocks with chemically diverse R-substituents, including aro-
matic groups and sterically demanding hydrophobic functional
groups.
The coupling of the protected R-guanidino acids to an amine
was examined. To date, the only reported amide coupling
reactions of bis(Boc)-protected-R-guanidino acids that have
proceeded in reasonable yield have utilized the glycine
derivative.7g,11 To determine the ability of bis(Boc)-protected-
R-guanidino acids to couple with amines to form amide bonds,
we examined the coupling of 3b with cyclohexylamine under
various amide coupling conditions (Table 2). To assess the
possibility of racemization in the guanylation, saponification,
or amide coupling steps, ent-3b was synthesized from (R)-
phenylalanine methyl ester (ent-1b). Coupling of ent-3b to
cyclohexylamine generated ent-4b. Phenylalanine-derived guani-
dino acids were chosen on the basis of the greater susceptibility
to racemization of phenylalanine compared to other canonical
amino acids.
Although most conditions proceeded with good chemical
yields, significant racemization was observed when coupling
reactions were conducted in CH2Cl2 (Table 2). In contrast, chiral
HPLC analysis of 4b and ent-4b revealed that both 4b and ent-
4b exhibited high enantiopurity (no evidence of the enantiomer)
when employing the optimized conditions of EDCI/HOBt
activation and coupling in DMF (Table 2 and Supporting
Information). These results indicate that the guanylation,
saponification, and amide coupling reactions all proceeded with
minimal racemization, suggesting generality in the coupling of
protected R-guanidino acids with amines.
a (a) N,N′-Bis(tert-butoxycarbonyl)thiourea, 2-chloro-1-methylpyridi-
unium iodide (Mukaiyama’s reagent), DMF, DIPEA, 5 h. (b) 4 equiv of
b
LiOH, 6:1 acetone/H2O (3a,b) or 3:1 MeCN/H2O (3c-e), 2-5 h. Syntheses
of 2b7d and 3a7b have been reported previously.
potential of chiral R-guanidino acids in medicinal chemistry and
molecular recognition.
Molecules containing R-guanidino acid subunits are generally
synthesized via coupling of a nucleophile with a suitably
N-protected R-amino acid, followed by N-deprotection, N-
guanylation, and subsequent guanidine deprotection to generate
the R-guanidino acid-containing molecule. While this approach
takes advantage of commercially available protected R-amino
acids, it has the significant disadvantage of requiring multistep
manipulation after the initial amide bond formation. In addition,
this approach is frequently characterized by very low reported
yields.5a,d Importantly, epimerization at the R-position has not
been explicitly examined. In the synthesis of molecules contain-
ing multiple R-guanidino acid subunits for biomolecular rec-
ognition, the significant late-stage manipulation required by
standard approaches is particularly unattractive.7f We therefore
sought to employ a more convergent approach, in which
protected R-guanidino acids were directly coupled to a nucleo-
phile of interest, eliminating the first deprotection step and the
potentially problematic polyguanylation of a complex molecule.
Using the optimized coupling conditions, 3a-e were coupled
with cyclohexylamine (Table 3). Coupling of the bis(Boc)-
Coupling of N,N′-bis(Boc)-protected R-guanidino acids to
amines, followed by acidic deprotection, would allow rapid
access to complex molecules containing R-guanidino acid
subunits. Surprisingly, despite the interest in guanidiniums, the
protected R-guanidino acid building blocks 3b-e (Table 1)
required for this approach have never been reported.7 Therefore,
we sought to synthesize the protected R-guanidino acids 3a-e
to examine a convergent coupling strategy for the synthesis of
functionally rich guanidiniums.
(10) Synthesis of N,N′-bis(tert-butoxycarbonyl)thiourea: Iwanowicz, E.
J.; Poss, M. A.; Lin, J. Synth. Commun. 1993, 23, 1443-1445. The NMR
spectra of 2a-e showed the presence of a minor isomeric product,
presumably the (Z) Boc imine. The observation of one guanidino proton
doublet and one singlet in each isomer argues against the alternative
tautomeric isomer as one of the products. Similar isomerism was observed
in 3a-e, 4a-e, and 5, but was not observed in 6.
(11) (a) Pons, J.-F.; Fauche`re, J.-L.; Lamaty, F.; Molla, A.; Lazaro, R.
Eur. J. Org. Chem. 1998, 853-859. (b) Addicks, E.; Mazitschek, R.;
Giannis, A. ChemBioChem 2002, 3, 1078-1088. (c) Osterkamp, F.; Ziemer,
B.; Koert, U.; Wiesner, M.; Raddatz, P.; Goodman, S. L. Chem.-Eur. J.
2000, 6, 666-683. Osterkamp et al. reported that the attempted coupling
of the glycine derivative failed, producing only the creatinine-like side
product.
Guanylation of the R-amino group of a series of R-amino
acid methyl esters, following the method used by Lipton to
J. Org. Chem, Vol. 72, No. 25, 2007 9835

TABLE 3. Coupling of Cyclohexylamine and Bis(Boc)-r-guanidino
TABLE 4. Effect of Guanidine Deprotection Conditions on
Stereochemical Integrity
Acidsa
entry
substrate
guanidino acid
product
yield (%)
diastereomer ratio
(S,S)+(R,R):(S,R)
1
2
3
4
5
3a
3b
3c
3d
3e
Gly
Phe
Trp
Val
Leu
4a
4b
4c
4d
4e
61%
84%
60%
71%
65%
entry
reagent
solvent
time, min
1
2
3
4
5
50% TFA
90% TFA
0.35 M SnCl4
1 M HCl
CH2Cl2
H2O
EtOAc
EtOAc
EtOAc
60
60
180
60
50:50
50:50
60:40
81:19
94:6
a (a) Cyclohexylamine, EDCI, HOBt, DIPEA, DMF, 2 h.
0.5 M HCl
60
SCHEME 1. Coupling of a Protected r-Guanidino Acid to a
conjugation and multiple electron-withdrawing protecting groups
on the guanidine. Examination of the effects of deprotection
conditions on epimerization is thus generally applicable for all
applications employing R-guanidino acids.
Diaminea
When Boc deprotection of 5 to generate 6 was conducted
using standard Boc deprotection conditions of 50% TFA/
CH2Cl2 or 90% TFA/H2O, two isomeric products 6 were ob-
served (dr 50:50) (Table 4). The diastereomers of 6 were readily
resolved by reverse phase HPLC and were distinguishable by
1H NMR (Supporting Information). Even under mild Lewis acid-
mediated deprotection with SnCl4,13 significant epimerization
was observed. In contrast, predomainantly a single diastereomer
of 6 was observed (dr 94:6, indicating epimerization at 3% of
R-positions) when conducting the Boc deprotection under mild
conditions (0.5 M HCl in EtOAc). These results further indicate
that the guanylation, saponification, amide coupling, and Boc
deprotection steps all proceeded with minimal racemization or
epimerization (Supporting Information).
In order to determine the generality of this approach to
synthesize chiral guanidiniums as a single stereoisomer, the
effect of deprotection conditions was further examined. Notably,
epimerization occurred only in the protected molecule 5, not in
the deprotected bis-guanidinium 6: subjection of purified (S,R)-6
to either 50% TFA/CH2Cl2 or 90% TFA/H2O resulted in no
evidence of epimerization (Supporting Information). In total,
these results indicate that Boc-protected chiral R-substituted
guanidines are readily deprotected under mildly acidic conditions
and should be amenable to incorporation in complex molecular
libraries.
We have described and demonstrated the feasibility of a
general approach to the convergent synthesis of compounds
containing chiral R-substituted guanidiniums derived from
R-amino acids. The syntheses are practical and straightforward
and, due to the wide availability of chemically and structurally
diverse R-amino acids, should be readily applicable to the
preparation of molecular libraries with complex functionality.
Coupling of R-guanidino acids to a diamine and acidic depro-
tection under mild conditions proceeded readily with retention
of stereochemistry, providing a route to rapidly generate diverse
and functionally complex chiral polyguanidiniums.
a (a) 3b (2.5 equiv), DCC, DIPEA, MeCN, 0 °C f RT, 2 h, 56%.
protected R-guanidino acids to cyclohexylamine proceeded
readily under the optimized, mild amide coupling conditions,
generating the protected products 4a-e in good yields at room
temperature.12 The syntheses of 4b-e are the first reported
examples of amide coupling reactions proceeding in good yield
using a non-glycine bis(Boc)-R-guanidino acid.
Arginine residues are broadly employed in biological recog-
nition. However, the linear alkyl side chain attached to the
guanidinium of arginine likely contributes only minimally
toward target specificity in most cases. The introduction of
functional groups adjacent to the guanidinium group of arginine
mimetics can result in very significant increases in affinity and
specificity of the interaction of guanidiniums.1-5 To examine
the utility of R-guanidino acids in the synthesis of molecules
containing multiple R-functionalized guanidiniums, the coupling
of two protected R-guanidino acid monomers to a single
molecule was examined. 5 was synthesized by coupling trans-
1,4-diaminocyclohexane to the protected phenylalanine R-guani-
dino acid 3b (Scheme 1). The coupling reaction proceeded
readily under amide coupling conditions chosen for optimal
solubility of the starting material and product. 5 is the first
reported example of the coupling of two bis(Boc)-R-guanidino
acid monomers to a single molecule.
Stereochemistry at the R-position critically affects function
for molecules containing R-guanidino acids.5 However, the
effect of deprotection conditions on stereochemical integrity has
not been reported, despite the potentially greater susceptibility
to racemization for protected R-guanidino acid derivatives
compared to protected R-amino acids, owing to extended
Experimental Section
Representative Synthesis of Protected Guanylated Amino
Acid Esters: Synthesis of 2e. Following the approach of Lipton,7d
to a solution of L-leucine methyl ester (1.27 g, 7 mmol) (1e) in
(12) These results are in contrast to those of Wen et al., who observed
that the coupling of highly sterically hindered R-N,N′-bis(Boc)-guanidino-,
â-N-Fmoc-amino acids to amines did not proceed: Wen, K.; Han, H. S.;
Hoffman, T. Z.; Janda, K. D.; Orgel, L. E. Bioorg. Med. Chem. Lett. 2001,
11, 689-691.
(13) Miel, H.; Rault, S. Tetrahedron Lett. 1997, 38, 7865-7866.
9836 J. Org. Chem., Vol. 72, No. 25, 2007

anhydrous DMF (2 mL) were added diisopropylethylamine
(3.9 mL, 21 mmol) and N,N′-bis(tert-butoxycarbonyl)thiourea10
(1.95 g, 7 mmol). A slurry of 2-chloro-1-methylpyridinium iodide
(Mukaiyama’s reagent) (1.8 g, 7 mmol) in anhydrous DMF
(10 mL) was added dropwise via syringe to the reaction mixture,
and the reaction was stirred at room temperature until product
formation ceased (5 h). The reaction mixture was quenched with
water (10 mL) and extracted with ethyl acetate (3 × 80 mL). The
combined organic layers were dried (Na2SO4), and the solvent was
evaporated to give a crude oil. The crude mixture was purified
(SiO2, 70:30 hexanes/EtOAc) to give the protected guanylated
R-amino acid methyl ester 2e (2.01 g, 71%): 1H (400 MHz, CDCl3)
δ 11.36 (s, 1H), 8.60 (d, J ) 7.7 Hz, 1H), 4.46 (m, 1H), 3.71 (s,
3H), 1.91-1.86 (m, 1H), 1.78-1.65 (m, 2H), 1.50 (s, 9H), 1.48
(s, 9H), 0.98 (d, J ) 6.1 Hz, 3H), 0.94 (d, J ) 6.5 Hz, 3H); 13C
(CDCl3) δ 172.7, 161.9, 157.2, 153.1, 83.5, 80.0, 52.5, 39.6, 30.1,
28.5, 28.4, 24.9; HRMS calculated mass ) 387.2447 (M + H),
observed mass ) 388.2458 (M + H); IR (CH3OH, cm-1) 1724,
1642, 1614, 1561, 1416, 1366, 1318, 1283, 1155, 810; specific
22.3, 22.1; HRMS calculated mass ) 374.2291 (M + H), observed
mass ) 374.2300 (M + H); IR (CH3OH, cm-1) 3424, 3281, 2935,
25
1744, 1709, 1655, 1568, 1133, 1020; specific rotation [R]D
-44.0.
)
Representative Amide Coupling Reaction of Cyclohexylamine
with a Protected Guanidino Acid: Synthesis of 4e. To a stirred
solution of the Boc-protected R-guanidino acid 3e (0.516 g, 0.8
mmol) were added 1-ethyl-3-(3′-dimaminopropyl)carbodiimide
(EDCI) (0.153 g, 0.8 mmol) and N-hydroxybenzotriazole (HOBt)
(0.108 g, 0.8 mmol) at room temperature and allowed to stir for
15 min, followed by slow addition of cyclohexylamine (0.092 mL,
0.079 g, 0.8 mmol) over 5 min and the subsequent addition of
DIPEA (0.260 mL, 0.208 g, 1.6 mmol). Stirring was continued for
2 h at room temperature. The reaction mixture was quenched by
addition of water and extracted with EtOAc (3 × 30 mL). The
combined EtOAc layers were washed with a saturated brine solution
and dried (Na2SO4), and the solvent was evaporated to give the
product 4e as a colorless oil (0.24 g, 65%) after purification (SiO2,
60:40 hexanes/EtOAc): 1H (400 MHz, CDCl3) δ 11.35 (s, 1H),
8.69 (d, J ) 7.7 Hz, 1H), 6.50 (d, J ) 8.2 Hz, 1H), 4.15-4.09 (m,
1H), 3.83-3.72 (m, 1H), 2.28-2.19 (m, 1H), 1.91-1.80 (m, 2H),
1.71-1.62 (m, 4H), 1.51-1.47 (m, 20H), 1.41-1.14 (m, 6H),
1.03-0.95 (m, 6H); 13C (CDCl3) δ 169.8, 163.5, 156.6, 153.2, 83.8,
79.7, 79.6, 60.8, 48.2, 33.3, 33.0, 29.7, 28.6, 28.5, 26.0, 24.8, 19.8,
19.0; HRMS calculated mass ) 455.3233 (M + H), observed mass
) 455.3252 (M + H); IR (CH3OH, cm-1) 3751, 3681, 2934, 1708,
25
rotation [R]D ) -21.0.
Representative Synthesis of Protected Guanidino Acids:
Synthesis of 3e. To the protected guanylated amino acid methyl
ester 2e (1.5 g, 4 mmol) was added a solution of LiOH (0.480 g,
20 mmol, 5 equiv) in 3:1 MeCN/H2O (10 mL). The reaction was
allowed to stir at room temperature for 2 h. The reaction mixture
was cooled to 0 °C and quenched by dropwise addition of a 0.5 N
solution of HCl with continuous stirring. When the pH of the
reaction mixture was between pH 4 and pH 6, the solution was
allowed to warm to room temperature and extracted with EtOAc
(3 × 25 mL). The combined EtOAc layers were dried (Na2SO4)
and the solvent was evaporated to give the protected guanylated
R-amino acid 3e as a white solid (1.01 g, 72%) after purification
(SiO2, 60:40 hexanes/EtOAc): 1H (400 MHz, CDCl3) δ 11.34 ((s,
1H), 9.30 (br s, 1H), 8.61 (d, J ) 4.4 Hz, 1H), 4.51-4.43 (m, 1H),
1.90-1.85 (m, 1H), 1.78-1.63 (m, 2H), 1.49 (s, 9H), 1.47 (s, 9H),
0.97 (d, J ) 6.3 Hz, 3H), 0.92 (d, J ) 6.1 Hz, 3H); 13C (CDCl3)
δ 172.7, 161.9, 157.2, 153.2, 84.8, 80.9, 53.6, 32.1, 28.4, 28.1,
25
1655, 1568, 1519, 1401, 1318, 1129, 1052; specific rotation [R]D
) -46.0.
Acknowledgment. We thank the NIH (1P20 RR17716-01)
(COBRE) for funding this work.
Supporting Information Available: Experimental procedures,
characterization data, HPLC chromatograms, and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO701766C
J. Org. Chem, Vol. 72, No. 25, 2007 9837