Synthesis of (S,S)-isodityrosine by Doetz benzannulation

Article abstract of DOI:10.1021/jo050363n

A synthesis of (S,S)-isodityrosine 1, a naturally occurring, key structural subunit of numerous biologically active macromolecules, is described. A formal [3 + 2 + 1] cycloaddition (Doetz benzannulation) approach was utilized to simultaneously construct a

Full text of DOI:10.1021/jo050363n

Synthesis of (S,S)-Isodityrosine by Do1tz
Benzannulation
Anuradha Gupta,† Subhabrata Sen,‡
Michael Harmata,§ and Shon R. Pulley*,|
Department of Chemistry, University of Missouri-Columbia,
Columbia, Missouri 65211
FIGURE 1. (S,S)-Isodityrosine 1.
reported.3 Central to these syntheses is the development
of improved ways of procuring the diaryl ether moiety.4a
This includes Ullmann type coupling,4b,c SNAr displace-
ment of o-nitro-substituted aryl fluorides4d or benzoqui-
nones,4e oxidative phenolic couplings,4f and Diels-Alder
reactions.4g Several alternative approaches to diaryl
ethers include displacement reactions on arene ruthe-
nium complexes,4h substitution of aryl iodonium salts by
sodium phenolates,4i ring opening of cyclohexenone oxides
with phenols,4j and substitution of 2,6-dihalo-substituted
triazenes with phenols.4k The palladium-catalyzed forma-
tion of diaryl ethers has also gained attention due to the
efforts of Buchwald and Hartwig.4l,m Jung and Lazarova
report an interesting synthesis of (S,S)-isodityrosine 1
by coupling two natural amino acid derivatives, one of
which was arylboronic acid derived from 4-iodophenyl-
alanine.3b
PULLEY_SHON_R@Lilly.com
Received February 26, 2005
A synthesis of (S,S)-isodityrosine 1, a naturally occurring,
key structural subunit of numerous biologically active
macromolecules, is described. A formal [3 + 2 + 1] cycload-
dition (Do¨tz benzannulation) approach was utilized to
simultaneously construct an aromatic ring and the diaryl
ether linkage in one step. This key step was extended to the
synthesis of (S,S)-isodityrosine in two separate convergent
synthetic routes. This method demonstrates a novel and mild
method for the synthesis of diaryl ethers.
In this note, we report a synthesis of isodityrosine by
a Do¨tz benzannulation strategy,5 formally a [3 + 2 + 1]
cycloaddition, which was reported by us for diaryl ether
formation.6 Boc-tyrosine methyl ester 2 was treated with
t-BuLi at -78 °C, followed by quenching the in situ
The aryloxyphenol moiety of isodityrosine 1 (Figure 1)
is a key structural unit found in a large class of biologi-
cally active natural products containing an endocyclic
diaryl ether.1a,b These compounds range from the mono-
cyclic macrocycles K-13 and OF4949 I-OF4949 IV to the
bicyclic bouvardins and complex polycyclic glycopeptide
antibiotics such as vancomycin.
K-13 is a noncompetitive inhibitor of angiotensin I
converting enzyme (ACE),2a while the OF4949 derivatives
I-IV are competitive inhibitors of aminopeptidase B.2b
Bouvardin and deoxybouvardin are bicyclic hexapeptides
that inhibit protein synthesis and belong to a family of
related compounds with potent antitumor properties.2c
Common to these compounds is the oxidatively cross-
linked diaryl ether amino acid isodityrosine 1. Boger has
shown that the cycloisodityrosine core of the bouvardins
is the acting pharmacophore.2d
(3) (a) Jung, M. E.; Lazrova, T. I. J. Org. Chem. 1999, 64, 2976. (b)
Jung, M. E.; Jachiet, D.; Rohloff, J. C. Tetrahedron Lett. 1989, 30, 4211.
(c) Jung, M. E.; Rohloft, J. C. J. Org. Chem. 1985, 50, 4909. (d) Boger,
D. L.; Zhou, J. J. Am Chem. Soc. 1993, 115, 11426. (e) Boger, D. L.;
Zhou, J. J. Am. Chem. Soc. 1994, 116, 1601. (f) Nishiyama, S.;
Nakamura, K.; Suzuki, Y.; Yamamura, S. Tetrahedron Lett. 1986, 27,
4481. (g) Boger, D. L.; Yohannes, D. Tetrahedron Lett. 1989, 30, 2053.
(h) Jergensen, K. B.; Gautun O. R. Tetrahedron 1999, 55, 10527. (i)
Barry, L. Tetrahedron Lett. 1999, 40, 1389. (j) Nishiyama, S.; Kim, M.
H.; Yamamura, S. Tetrahedron Lett. 1994, 35, 8397. (k) Rama Rao, A.
V.; Chakraborty, T. K.; Reddy, K. L.; Srinivasa Rao, A. Tetrahedron
Lett. 1992, 33, 4799. (l) Evans, D. A.; Ellman, J. A. J. Am. Chem. Soc.
1989, 111, 1063. (m) Schmidt, U.; Weller, D.; Holder, A.; Lieberknecht,
A. Tetrahedron Lett. 1988, 29, 3227.
(4) (a) Thiel, F. In Organic Synthesis Highlights V; Schmalz, H.-G.,
Wirth, T., Eds.; Wiley-VCH: Weinheim, Germany, 2003; p 15. (b)
Bates, R. B.; Janda, K. D. J. Org. Chem. 1982, 47, 4374. (c) Inoue, T.;
Naitoh, K.; Kosemura, S.; Umezawa, J.; Sonobe, T.; Serizawa, N.; Mori,
N. Heterocycles 1983, 20, 397. (d) Boger, D. L.; Borzilleri, R. M. Bioorg.
Chem. Lett. 1995, 5, 1187. (e) Rama Rao, A. V.; Gurjar, M. K.; Reddy,
A. B.; Khare, V. B. Tetrahedron Lett. 1993, 34, 1657. (f) Bates, R. B.;
Gin, S. L.; Hassen, M. A.; Hruby, V. J.; Janda, K. D.; Krik, G. R.;
Michuad, J.-P.; Vine, D. B. Heterocycles 1984, 22, 785. (g) Olsen, R.
K.; Feng, X.; Campbell, M.; Shaw, R.; Math, R.; Shivanand, K. J. Org.
Chem. 1995, 60, 6025. (h) Pearson, A. J.; Bignan, G.; Zhang, P.;
Chelliah, M. J. Org. Chem. 1996, 61, 3940 and references therein. (i)
Crimmin, M. J.; Brown, A. G. Tetrahedron Lett. 1990, 31, 2017. (j)
Jung, M. E.; Starkey, L. S. Tetrahedron 1997, 53, 8815. (k) Nicolaou,
K. C.; Boddy, C. N.; Natarajan, S.; Yue, T.-Y.; Li, H.; Brase, S.;
Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421. (l) Aranyos, A.;
Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, S. P.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 4369 and references therein. (m) Mann,
G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc.
1999, 121, 3224 and references therein.
Since its isolation from the plant cell wall glycoprotein
extensin,1a,b several syntheses of isodityrosine have been
† Department of Chemistry and Biochemistry, University of Notre
Dame, Notre Dame, IN 46556.
‡ Syngene International Pvt. Ltd, 20th KM Hosur Road, Electronic
City, P. O. Bangalore 560100, India.
§ University of Missouri-Columbia.
| Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285.
(1) (a) Fry, S. C. Biochem. J. 1982, 204, 499. (b) Epistein, L.;
Lamport, D. T. A. Phytochemistry 1984, 23, 1241.
(2) (a) Kase, H.; Kaneka, M.; Yamada, K. J. Antibiot. 1987, 40, 450.
(b) Sano, S.; Ueno, M.; Yoshikawa, Y.; Nakamura, T.; Obayahi, A. J.
Antibiot. 1987, 40, 519. (c) Itokawa, H.; Takeya, K. Heterocycles 1993,
35, 1467. (d) Boger, D. L.; Pantane, M. A.; Jin, Q.; Kitos, P. A. Bioorg.
Med. Chem. 1994, 2, 85.
(5) (a) Do¨tz, K. H. Angew Chem., Int. Ed. Engl. 1984, 23, 587. (b)
Wulf, W. D. In Comprehensive Organic Synthesis; Trost, B. M.,
Femming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 1065.
(6) Pulley, S. R.; Sen, S.; Vorgushin, A.; Swanson, E. Org. Lett. 1999,
1, 1721.
10.1021/jo050363n CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/05/2005
7422
J. Org. Chem. 2005, 70, 7422-7425

SCHEME 1a
a (a) t-BuLi, Et2O, -78 °C, 3, 45%; (b) MeI/K2CO3/DMF; (c) CF3CO2H; (d) (CF3CO)2O (overall 78%); (e) 60 °C, THF 20 h (60%); (f) Tf2O,
pyridine, 0 °C to room temperature, 60%; (g) Pd(OAc)2, dppf, TEA, HCOOH, DMF, 70 °C, 95%; (h) O3 CH2Cl2, -78 °C, 65%; (i) RhPPh3Cl,
toluene -78 °C, 78%; (j) K2CO3, MeOH, H2O; (k) 6 N HCl, reflux, (70%).
SCHEME 2a
generated lithium phenolate with acylated carbene com-
plex 37 to furnish the desired tyrosine carbene complex
4 (Scheme 1).
Commercially available L-propargylglycine 58 was de-
rivatized to (S)-methyl N-trifluoroacetylpropargylgly-
cinate 6 as shown in Scheme 1. Carbene complex 4 was
then subjected to benzannulation by heating with alkyne
6 under argon at 60 °C for 20 h. Exposure of the reaction
mixture to air oxidized the coordinated chromium, which
was removed by filtration, and the diaryl ether 7 was
obtained in 60% yield. Model reactions of carbene com-
plex 4 with racemic propargylglycinate protected with an
N-Boc group gave low yields of the desired diaryl ether,
presumably due to participation of the nitrogen atom in
unwanted side reactions.9 Trifluoroacetyl group protec-
tion was necessary to reduce the reactivity of the nitrogen
atom and increase the yield of the desired diaryl ether
7. For palladium-catalyzed reductive deoxygenation,10 the
diaryl ether 7 was reacted with Tf2O in pyridine, and the
triflate 8, obtained in 60% yield, was treated with Pd-
(OAc)2-dppf in DMF at 70 °C in the presence of Et3N and
HCOOH giving 9 in 95% yield. Ozonolysis of 9 at -78
°C furnished the aldehyde 10 in 65% yield, which was
subjected to deformylation11 with Wilkinson’s catalyst at
-78 °C. The corresponding phenol, obtained in 78% yield,
was treated with K2CO3/methanol/H2O to remove the
trifluoroacetyl group. This was followed by treatment
with 6 N HCl to hydrolyze the ester moiety as well as to
remove the Boc-protecting group providing isodityrosine
bis-hydrochloride 11 in 70% yield. The spectral data4j
were identical to those reported, and [R]D ) -28.3 (c 0.5
in MeOH).
a (a) AcBr/NaH (95%); (b) 1. 60 °C, 2. air (68%); (c) TBDMSCl/
Et3N, DMF (75%); (d) Zn, TMSCl, DMA, (dba)3Pd‚CHCl3, 1,2-
dibtromoethane (66%); (f) TBAF/THF (86%).
In an alternate route to 7, carbene complex 3 was
reacted with p-iodophenol in the presence of NaH and
CH3COBr to obtain 12 (Scheme 2) in 95% yield. Reacting
carbene complex 12 with (S)-methyl N-trifluoroacetyl-
propargylglycinate 6 under the standard conditions at
60 °C gave the furan derivative 13 in 68% yield. Protec-
tion of the phenolic group of 13 with TBDMS followed
by coupling with zinc iodoalanine 1512 under Pd(0)
catalysis gave the desired bis-amino acid derivative 16
in 66% yield. Deprotection of the TBDMS ether group
with TBAF in THF gave the phenolic diaryl ether 7 in
86% yield.
The optical purity of the tyrosine carbene complex 4
was assessed using Trost’s procedure (Scheme 3).13 Thus,
compound 4 was benzannulated with 1-pentyne to give
the desired diaryl ether 17 in 75% yield, which was
acylated to generate 18. Deprotection of the Boc group
(7) Conor, J. A. J. Chem. Soc. A 1971, 3368.
(8) (a) Abood, N. A.; Nosal, R. Tetrahedron Lett. 1994, 35, 3669. (b)
Leukhart, O.; Caviezel, M.; Eberle, A.; Escher, E.; Kyi, A.-T.; Schwyzer,
R. Helv. Chim. Acta 1976, 59, 2181. (c) N-Boc-propargylglycine was
obtained from Peptech Corp, MA.
(9) (a) Dotz, K. H.; Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187.
(b) Waters, M. L.; Bos, M. E.; Wulff, W. D. J. Am. Chem. Soc. 1999,
121, 6.
(12) (a) Jackson, R. F. W.; Wishart, N.; Wood, A.; James, K.; Wythes,
M. J. Org. Chem. 1992, 57, 3397. (b) Dunn, M. J.; Jackson, R. F. W.;
Pietruszuka, J.; Turner, D. J. Org. Chem. 1995, 60, 2210. (c) Bajgrow-
icz, J. A.; Hallaoui, A. El.; Jacquier, R.; Pigiere, Ch.; Viallefont, Ph.
Tetrahedron 1985, 41, 1833.
(13) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994, 59,
4202.
(10) Peterson, G. A.; Kunng, F.-A.; Mccallum, J. S.; Wulff, W. D.
Tetrahedron Lett. 1987, 28, 1381.
(11) Allevi, P.; Anastasia, M.; Ciuffreda, P.; Fiecchi, A.; Scala, A. J.
Org. Chem. 1987, 52, 5469.
J. Org. Chem, Vol. 70, No. 18, 2005 7423

(m, 1H); 13C NMR (125 MHz) δ 169.2, 157.4, 124.1, 77.63, 74.4,
53.1, 51.2, 21.7; IR (CH2Cl2) 3072, 2986.5, 1736, 1722.9; HRMS
mass calcd. for C8H8F3NO3: 223.045; found: 223.044.
SCHEME 3a
(S)-3-{7-[4-((S)-2-tert-Butoxycarbonylamino-2-methoxy-
carbonyl-ethyl)-phenoxy]-4-hydroxy-benzofuran-5-yl}-2-
(2,2,2-trifluoro-acetylamino)-propionic Acid Methyl Ester
7. A solution of 4 (900 mg, 1.59 mmol) and 6 (1.065 g, 4.77 mmol)
in dry THF (30.5 mL, 0.05 M) in a Schlenk flask was freeze-
thawed and degassed 3-4 times. After complete degassing, the
reaction mixture was exposed to argon, and the vessel was sealed
and heated at 55 °C for 20 h during which time the red color
turned greenish black. The reaction mixture was cooled to room
temperature, exposed to air, evaporated to dryness, and purified
by flash column chromatography (hexane/ethyl acetate, 60:40)
to yield compound 7 (596 mg, 60% yield); [R]D +48.4 (c 0.5,
CHCl3); 1H NMR (300 MHz) δ 7.74 (brs, 1H), 7.46 (brs, 1H), 7.33
(s, 1H), 7.04 (m, 2H), 6.85 (m, 3H), 6.59 (br s, 1H), 5.00 (brs,
1H), 4.76 (m, 1H), 4.53 (s, 1H), 3.63 (s, 6H), 3.26 (m, 2H), 3.21
(m, 2H), 1.41 (s, 9H); 13C NMR (75 MHz,) δ 172.2, 171.5, 170.7,
157.3, 155.2, 146.6, 144.7, 144.0, 134.5, 130.4, 130.2, 119.5, 118.6,
116.8, 115.0, 113.7, 103.9, 80.2, 60.5, 54.2, 53.0, 52.2, 37.5, 31.8,
28.3; IR (CH2Cl2) 3439.6, 3344.6, 3002.6, 2252.2, 1729.8, 1625.3,
1549.3, 1511.3; HRMS mass calcd. for C29H31F3N2O10: 624.1931;
found: 631.2112 (M + Li).
a Optical purity of the tyrosine carbene 9. (a) THF, 60 °C, 20 h;
(b) Ac2O, pyridine; (c) TFA, CH2Cl2; (d) (S)+methoxyphenylacetic
acid, DCC, CH2Cl2.
from the amide 18 followed by derivatization with S-(+)-
phenylacetic acid resulted in the desired amide 19 in 70%
1
yield. Comparing the H NMR spectral data and HPLC
results of 19 with those of the racemic amide derivative
proved that 19 is a single diastereomer, and in turn,
carbene complex 4 is also a single enantiomer, and there
is no loss of optical purity even after the benzannulation.
In conclusion, we have successfully completed a ste-
reoselective sythesis of (S,S)-isodityrosine. The present
synthesis features a novel benzannulation strategy to
construct the C-O ether linkage. The amicable reaction
conditions make it a versatile approach to the synthesis
of this class of molecules.
(S)-3-{7-[4-((S)-2-tert-Butoxycarbonylamino-2-methoxy-
carbonyl-ethyl)-phenoxy]-4-trifluoromethanesulfonyloxy-
benzofuran-5-yl}-2-(2,2,2-trifluoro-acetylamino)-propion-
ic Acid Methyl Ester 8. Compound 7 (372 mg, 0.58 mmol) was
dissolved in dry CH2Cl2 (5 mL) under argon at 0 °C. To this was
added pyridine (91.75 mg, 1.16 mmol) followed by distilled triflic
anhydride (328.7 mg, 1.16 mmol). The reaction was stirred at
room temperature until the TLC did not show the presence of
starting material. The usual workup gave a crude product that
was purified by flash column chromatography (hexane/ethyl
acetate; 70:30), giving compound 8 (269 mg, 60% yield); [R]D
1
+67.2 (c 0.7, CHCl3); H NMR (250 MHz) δ 7.68 (m, 1H), 7.15
(m, 2H), 6.98 (m, 2H), 6.90 (m, 2H), 6.65 (br s, 1H), 5.05 (br s,
1H), 4.88 (br m, 1H), 4.58 (br s, 1H), 3.72 (s, 6H), 3.40 (m, 2H),
3.40 (m, 4H), 1.44 (s, 9H); 13C NMR (62.9 MHz) δ 172.1, 169.9,
157.0, 156.2, 154.8, 147.0, 145.5, 133.3, 131.1, 130.8, 124.5, 121.7,
119.5, 118.8, 115.3, 115.0, 114.9, 104.7, 80.0, 54.4, 53.1, 52.7,
52.2, 37.4, 32.1, 28.2; IR (CH2Cl2) 3411.1, 3050.1, 2993.1, 2318.7,
1729.8, 1520.8; HRMS mass calcd. for C30H30F6N2O12S: 756.1423;
found: 763.1564 (M + Li).
Experimental Section
Tyrosine Carbene Complex 4. To a solution of N-Boc
tyrosine 2 (400 mg, 1.30 mmol) in dry ether (5 mL) at -78 °C
under argon we added t-BuLi (1.5 mL, 1.3 mmol) and slowly
warmed it to room temperature. Freshly distilled acetyl bromide
(0.2 mL, 1.3 mmol) was added to a solution of 3 (50 mg, 0.13
mmol) in dry dichloromethane (2 mL) to give a dark purple
solution that was immediately cannulated into the solution of
tyrosine phenolate. The reaction was stirred at room tempera-
ture for 2 h around as the solution turned red. The reaction
mixture was evaporated to dryness and purified by flash column
chromatography (hexane/ethyl acetate, 80:20) to give a red
semisolid (344 mg, 45% yield); [R]D +11.1 (c 1.2, CHCl3), 1H NMR
(250 MHz) δ 7.94 (br s, 1H), 7.25 (m, 2H), 7.13 (d, m, 3H), 6.66
(m, 1H), 4.96 (br s, 1H), 4.61 (m, 1H), 3.73 (s, 3H), 3.18 (m, 2H),
1.44 (s, 9H); 13C NMR (62.9 MHz) δ 312.8, 224.4, 216.1, 171.9,
165.1, 157.6, 155.0, 146.7, 135.1, 130.6, 130.4, 122.6, 119.5, 113.3,
112.3, 79.9, 54.3, 52.2, 37.6, 28.2; IR (CH2Cl2) 3072, 2986.5,
2328.3, 2017.7, 1952.2, 1736, 1722.9.
(S)-2-(2,2,2-Trifluoro-acetylamino)-pent-4-ynoic Acid
Methyl Ester 6. To a solution of commercially available
L-propargylglycine 58c (213 mg, 1 mmol) in 5 mL of dry DMF at
0 °C was added K2CO3 (276 mg, 2 mmol) followed by dropwise
addition of methyl iodide (0.3 mL, 5 mmol). Aqueous workup
and extraction with diethyl ether gave the methyl ester deriva-
tive that was used without further purification. The ester was
dissolved in CH2Cl2 (2 mL) at 0 °C under argon, and trifluoro-
acetic acid (1 mL) was added. After 12 h, the reaction mixture
was evaporated at reduced pressure and acylated without
further purification. To this ester (253 mg, 1 mmol) in dry CH2-
Cl2 at 0 °C under argon was added dry pyridine (395 mg, 5 mmol)
and trifluoroacetic anhydride (1.05 g, 5 mmol). After being
stirred at room temperature for 8 h, the usual workup gave a
crude product that was purified by flash column chromatography
(hexane/ethyl acetate, 80:20) to give a semisolid (173 mg, 78%
(S)-3-{7-[4-((S)-2-tert-Butoxycarbonylamino-2-methoxy-
carbonyl-ethyl)-phenoxy]-benzofuran-5-yl}-2-(2,2,2-triflu-
oro-acetylamino)-propionic Acid Methyl Ester 9. To a
solution of compound 8 (200 mg, 0.258 mmol) in DMF (4 mL)
was added Pd(OAc)2 (4 mg, 10 mol %), dppf (15 mg, 10 mol %),
triethylamine (78.1 mg, 0.774 mmol), and formic acid (23.7 mg,
0.774 mmol). After being heated at 70 °C for 6 h, the mixture
was filtered, washed with ethyl acetate (2 × 25 mL), and
evaporated to give a crude product that was purified by flash
column chromatography (hexane/ethyl acetate; 1:1), giving
1
compound 9 (152 mg, 95% yield); [R]D +28.5 (c 0.4, CHCl3); H
NMR (200 MHz) δ 7.60 (m, 1H), 7.15 (m, 3H), 6.89 (m, 3H), 6.77
(m, 1H), 6.57 (br s, 1H), 5.01 (br s, 1H), 4.85 (m, 1H), 4.55 (m,
1H), 3.71 (s, 6H), 3.16 (m, 4H), 1.42 (s, 9H); 13C NMR (50.3 MHz)
δ 172.2, 170.3, 162.2, 156.8, 155.0, 145.9, 145.0, 141.7, 131.3,
130.6, 130.5, 130.2, 118.5, 116.9, 114.9, 112.6, 106.7, 79.7, 60.3,
54.4, 53.9, 52.7, 52.4, 37.6, 34.3, 28.2; IR (CH2Cl2) 3420.6, 3002.6,
2252.2, 1729.8, 1606.3; HRMS mass calcd. for C29H31F3N2O9:
608.1981; found: 615.2138 (M + Li).
(S)-3-{3-[4-((S)-2-tert-Butoxycarbonylamino-2-methoxy-
carbonyl-ethyl)-phenoxy]-5-formyl-4-hydroxy-phenyl}-2-
(2,2,2-trifluoro-acetylamino)-propionic Acid Methyl Ester
10. Compound 9 (140 mg, 0.224 mmol) in dry CH2Cl2 (2 mL)
was cooled to -78 °C, and ozone was bubbled through it for 10
min. The reaction mixture was stirred with Ph3P for 2 h and
then diluted with water (5 mL), worked up with CH2Cl2 (3 × 25
mL), and evaporated at reduced pressure. Quick chromatography
gave 91 mg (65%) of compound 10; [R]D +32.0 (c 0.2, CHCl3); 1H
NMR (250 MHz) δ 10.96 (s, 1H), 9.89 (s, 1H), 7.10 (m, 3H), 6.90
(m, 4H), 5.05 (m, 1H), 4.83 (m, 1H), 4.68 (br s, 1H), 3.72 (s, 6H),
1
overall yield); [R]D +134.67 (c 0.3, CHCl3); H NMR (500 MHz)
δ 7.26 (br s, 1H), 4.74 (m, 1H), 3.84 (s, 3H), 2.86 (m, 2H), 2.09
7424 J. Org. Chem., Vol. 70, No. 18, 2005

3.11 (m, 4H), 1.42 (s, 9H); 13C NMR (75 MHz) δ 195.9, 172.2,
170.1, 156.0, 155.1, 152.7, 144.8, 131.9, 130.7, 128.8, 127.7, 126.5,
121.9, 117.2, 115.4, 77.4, 54.5, 53.5, 53.1, 52.2, 37.6, 36.3, 29.7;
IR (CH2Cl2) 3430.1, 2993.1, 2261.7, 1703.3, 1682.3, 1520.8;
HRMS mass calcd. for C28H31F3N2O10: 612.1931; found: 619.2082
(M + Li).
Isodityrosine Bis-hydrochloride 11. Compound 10 (71 mg,
0.11 mmol) was dissolved in dry toluene and degassed thor-
oughly. To this was added Ph3RhCl (71 mg, 0.11 mmol). After
being refluxed for 3 h, the reaction mixture was evaporated and
dry-loaded to a column (hexane/ethyl acetate; 1:1) to give 52 mg
(78%) of the deformylated compound; [R]D +40.4 (c 0.5, CHCl3);
1H NMR (200 MHz) δ 7.61 (m, 1H), 7.28 (m, 1H), 7.11 (m, 2H),
6.92 (m, 3H), 5.69 (br s, 1H), 4.83 (br s, 1H), 4.68 (br s, 1H),
3.75 (s, 3H), 3.68 (s, 3H), 3.05 (m, 4H), 1.42 (s, 9H); 13C NMR
(50.3 MHz) δ 172.2, 170.2, 156.7, 155.5, 146.1, 142.7, 134.5,
131.6, 128.2, 126.8, 125.4, 119.2, 118.2, 116.5, 54.4, 53.5, 52.8,
37.6, 36.5, 28.3; IR (CH2Cl2) 3430.1, 2993.1, 2261.7, 1703.3,
1682.3, 1520.8; HRMS mass calcd. for C27H31F3N2O9: 584.1981;
found: 591.2118 (M + Li).
adjusted to pH 7 by careful addition of 10% HCl. The aqueous
layer was extracted with CH2Cl2 (6 × 5 mL), and the combined
extracts were dried and concentrated in a vacuum. The crude
amine (20 mg) was directly used for the next step. Aqueous 6 N
HCl (1 mL) was added after refluxing for 6 h, the mixture was
extracted with ethyl acetate (2 × 2 mL), and the aqueous phase
was concentrated in a vacuum to give 13 mg (70%) of a pale
white solid; [R]D -28.16 (c 0.5, MeOH), [R]D -28.2 (c 0.5,
MeOH);4i 1H NMR (500 MHz, methanol-d4) δ 7.15 (m, 2H), 6.85
(m, 5H), 4.10 (m, 2H), 3.09 (m, 4H).
Acknowledgment. Financial support of this work
by the National Institutes of Health, NIGMS Grant
GM59350-01, and the University of Missouri is grate-
fully acknowledged.
Supporting Information Available: Procedures for the
preparation of compounds 12-14 and 16, spectroscopic data
of compound 19, 1H and 13C NMR spectra of compounds 4,
6-10, 12-14, 16, and 1H NMR of 11 and 19. This material is
available free of charge via the Internet at http://pubs.acs.org.
This deformylated compound (28 mg, 0.046 mmol) was dis-
solved in 5 mL of solution of 10% of K2CO3 in methanol/water
(5:2) at 25 °C. The reaction mixture was stirred for 6 h and
extracted with ether (1 × 3 mL), and the aqueous layer was
JO050363N
J. Org. Chem, Vol. 70, No. 18, 2005 7425