A Stille biaryl-coupling approach to dityrosines. Formal total synthesis of Hazimycin

Article abstract of DOI:10.1016/j.tetlet.2005.02.078

The Stille cross-coupling reaction between 3-tributylstannyltyrosine derivatives (15-23, 40), and 3-iodotyrosines (6-14, 39) afforded the corresponding dityrosines (24-37, 41). Additionally, this method provided a short and improved access to Hazimycin (3

Full text of DOI:10.1016/j.tetlet.2005.02.078

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2627–2630
A Stille biaryl-coupling approach to dityrosines.
Formal total synthesis of Hazimycin
Said Achab* and Laurence Velay
Institut de Chimie des Substances Naturelles, CNRS, 91 198 Gif-sur-Yvette, France
Received 17 November 2004; revised 14 February 2005; accepted 15 February 2005
Abstract—The Stille cross-coupling reaction between 3-tributylstannyltyrosine derivatives (15–23, 40), and 3-iodotyrosines (6–14,
39) afforded the corresponding dityrosines (24–37, 41). Additionally, this method provided a short and improved access to Hazimy-
cin (3) a naturally occurring anti-fungal agent.
Ó 2005 Elsevier Ltd. All rights reserved.
Recently, the aryl–aryl coupling reaction has registered
a number of valuable achievements in the area of dityro-
sine 1 and isodityrosine 2 natural products syntheses1a
(Fig. 1). Structurally, compounds 1 and 2 (Fig. 1) belong
to the family of tyrosine dimers. They have inspired sig-
nificant interest1 due to the diverse and potent biological
activities they display.
Two groups of tyrosine dimers are generally encoun-
tered, the first comprises tyrosine units linked by a
3,30-biaryl bond whereas the second, called isodityro-
sine, is characterized by a biaryl ether linkage (C3–O–
C40). With dityrosine 1 and isodityrosine 2 as the sim-
plest members, each family includes a number of biolog-
ically interesting natural products. The acyclic antibiotic
Figure 1.
Keywords: Dityrosines; Stille cross-coupling; Hazimycin; Stannyl tyrosines.
*
Corresponding author. Tel.: +33 0169823092; fax: +33 0169823072; e-mail: achab@icsn.cnrs-gif.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.078

2628
S. Achab, L. Velay / Tetrahedron Letters 46 (2005) 2627–2630
Hazimycin 3,2 and the macrocyclic ACE-inhibitor K-13
4,3 that are typical to each group, bear respectively, a
dityrosine or an isodityrosine unit. On the contrary,
both units combine within the structure of the naturally
occurring bicyclic secondary metabolite RP 66453 5.
pelski reported the synthesis of stannane 20 (see Table
1) which they needed for their Diazonamide A synthe-
sis11a whereas Williams described the preparation of
stannane 17, an intermediate in the synthesis of the pro-
teasomeÕs inhibitors TMC-95. We therefore set out to
the preparation of the required 3-tri-n-butylstannane
derivatives of tyrosine which were made through palla-
dium-catalyzed reaction of 3-iodotyrosine derivatives
(6-14) with hexabutyl-distannane12 (see Table 1). Also,
disclosed in Table 1 are some of the more reliable condi-
tions we have found, to access the corresponding 3-org-
anostannane derivatives of tyrosine13 (15–23).
Compared to dityrosines, the synthesis of isodityrosines
has focused more attention as evidenced by the number
of publications devoted to their preparations.5 Conse-
quently, only few protocols are available for the forma-
tion of dityrosines through construction of the C3–C30
aryl–aryl bond. In this regard, the Suzuki-based
aryl–aryl cross-coupling methodology6 stands, to date,
as the premier method to achieve this goal. Thus,
formation of 3-boryltyrosine derivatives7 followed by
palladium-catalyzed cross coupling with a 3-halogeno-
tyrosine has been successfully applied for accessing
both acyclic dityrosine derivatives8 and dityrosine-based
macrocyclic peptides.4d,e In these transformations,
yields range usually from moderate to good.
With the stannanes (15–23) in hand, we turned our
attention toward developing an effective route for their
conversion to dityrosines. First, we examined the effects
of varying successively: the catalyst, the ligand and/or
the solvent, on the outcome of the reaction. We identi-
fied a set of conditions that afforded the expected cou-
pling products.
Although, natural or unnatural biaryls9 are commonly
made through the use of the Stille reaction,10 there
was no example upon the application of such a method-
ology to the synthesis of dityrosines. All these reasons
led us to consider using the Stille reaction in our pro-
jected dityrosines synthesis. Accordingly, we decided to
evaluate the usefulness of the Stille cross-coupling reac-
tion en route to dityrosines. Furthermore, this method
offers an interesting alternative to the Suzuki reaction
as shown by its application to the formal total synthesis
of Hazimycin 3 (Scheme 1).
Next, we assessed the nature of the catalyst we needed, a
choice which is often far from obvious and is made usu-
ally on a trial and error basis. Several catalysts including
PdCl2(PPh3)2, Pd(PPh3)4, Pd(OAc)2 were tested and
found to furnish low to modest yields of the correspond-
ing dityrosines. Addition of some co-catalysts improved
the yield; the additives, which we used, whether alone or
combined to one another, comprise, CuI,14 or CuI–
15,16b
AsPh3
or CuI–LiCl.16 In this regard, use of the
combination CuI–AsPh3 proved to be very effective
affording the dityrosines in usually decent yields (Table
2). Finally, we turned our attention to what would be
the best solvents for these reactions. Solvents such as
DMF, toluene, dioxane, and N-methyl-pyrrolidone
were selected and evaluated. In these reactions, we were
confronted with the occasional but seemingly unavoid-
able problem of tin-hydride exchange, and that did
occur, sometimes, in a 20–30% yield. However, we were
Despite a large literature survey, we have been unable to
find a significant number of publications reporting the
preparation and use of 3-trialkylstannyl tyrosine deriva-
tives. Indeed, the only contemporaneously related
works, of which we became aware, were those of Kono-
pelski et al.11a and of Albrecht and Williams.11b Kono-
Table 1. Synthesis of 3-tributylstannyltyrosine derivatives
Entry
1
R
R1
R2
Start. mater.
Conditions
Time (h)
Prod.
Yield (%)
MOM
t-Bu
Boc
6
A
B
B
B
B
A
A
A
A
A
2.5
2
15
74
73
73
66
50
54
55
52
54
50
2
3
4
5
6
7
8
9
Me
Me
Me
Ac
Ac
Ac
Ac
Me
t-Bu
Me
Bn
Boc
Boc
7
8
2
16
17
18
19
20
21
22
23
2
Ac
Ac
9
3
Bn
10
11
12
13
14
2
Me
Me
t-Bu
Me
Ac
Boc
2
2.5
3
Boc
–CO2CH2CCl3
1
Reagents and conditions: A: (Bu3Sn)2 (2 equiv), DMF, 115 °C, PdCl2(PPh3)2 (10 mol %); B: (Bu3Sn)2 (2 equiv), PhMe, reflux, Pd(OAc)2 (10 mol %),
PPh3 (20 mol %).

S. Achab, L. Velay / Tetrahedron Letters 46 (2005) 2627–2630
2629
able to obtain the dityrosines (24–37) in a modest, but
still decent yield, ranging from 30% to 50%. Apparently,
in this transformation we took advantage of the benefi-
cial withdrawing effect of both, the C-5 acetyl and C-4
acetate groups (entries 4, 5, and 9–14). In entries 1–3
and 6–9 the presence of a methoxy group at C-4 was
found to be, somewhat detrimental to the coupling.
And this is made clear through the opposite effect exer-
cised by the methoxymethyloxy group that possesses
both alkyl ether and acetal functionalities. Consequently
this group has the ability to both complex and stabilizes
the palladium reagents.
at C-30. With the requisite iodides (entries 6–14) in hand,
we investigated their ability to undergo palladium-cata-
lyzed cross-coupling reactions with their stannanes
counterparts; the results17 we obtained are listed in
Table 2.
Looking for an application to this method, we thought
of using it in the formal synthesis of Hazimycin 3. To
this end, we carried out the strategy described in Scheme
1. Thus, palladium-catalyzed cross-coupling between N-
formyl-2-iodotyrosine18 39 and N-formyl-2-stannyltyro-
sine 40 provided the corresponding dityrosine 41 in an
improved 56% yield. Dityrosine 41 was previously ob-
tained in 6–11% yield and this synthesis2 involved an
oxidative coupling of N-formyl-L-tyrosine methyl ester
We therefore decided to undertake the synthesis of var-
ious dityrosines bearing an electron-withdrawing group
Table 2. Synthesis of dityrosines
Entry
3-Iodo-tyr
3-Bu3Sn-tyr
R1
Conditions
Di-tyr
Yield (%)
R
R1
R2
X
R
R2
1
Me
Me
Ac
Me
Me
Ac
Boc
Z
H
MOM
Me
Me
t-Bu
t-Bu
t-Bu
t-Bu
Me
Boc
Boc
Boc
Boc
Ac
C
D
B
24
25
26
27
28
29
30
31
32
33
34
35
36
37
7–15
13
2
H
3
t-Bu
Me
H
21
30
4
Ac
Ac
Boc
Z
H
MOM
Ac
Me
D
A
D
D
B
5
t-Bu
Me
H
38–50
19
20
6
Me
Me
Me
Ac
Boc
Z
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Bn
Ac
7
Me
Me
Me
t-Bu
t-Bu
t-Bu
Me
Boc
Boc
Boc
Z
8
Z
MOM
MOM
Ac
25–40
33–43
37–40
37
9
Me
Z
B
10
11
12
13
14
Me
Me
Me
Me
Me
t-Bu
Me
Boc
Boc
Z
D
D
D
A
A
Ac
Ac
Bn
Ac
Me
t-Bu
Me
Boc
Boc
Ac
38
33
t-Bu
t-Bu
Z
Boc
Me
Ac
Me
27, 40
Reagents and conditions: A: PdCl2(PPh3)2 (10 mol%), AsPh3 (20 mol%), CuI (20 mol%), DMF, 120 °C, 4 h; B: PdCl2 (PPh3)2 (10 mol%), AsPh3
(20 mol%), CuI (20 mol%), NMP, 100, 7 h; or dioxane, 100 °C, overnight; C: Pd (PPh3)4 (5 mol%), CuI (10 mol%), DMF, 110–120 °C, 3 h; D: PdCl2
(PPh3)2 (5 mol%), AsPh3 (10 mol%), CuI (10 mol%), DMF, 120 °C, 4–8 h.
Scheme 1.

2630
S. Achab, L. Velay / Tetrahedron Letters 46 (2005) 2627–2630
10. (a) For reviews on the Stille reaction, see: Stille, J. K.
Angew. Chem., Int. Ed. Engl. 1986, 25, 508; (b) Farina, V.;
Krishnamurty, V.; Scott, W. J. Org. React. 1997, 50, 1; (c)
Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176.
as the key step. Dityrosine 41 being two steps away from
product 3, access to this compound, as indicated in
Scheme 1, represents a formal total synthesis of the
latter.
11. (a) Konopelski, J. P.; Hottenroth, J. M.; Oltra, H. M.;
´
In conclusion, we reported herein the synthesis of vari-
ous dityrosines using a Stille cross-coupling approach
extending thereby the currently available methodologies
for accessing this class of compounds. Furthermore, the
usefulness of this method was substantiated by the direct
formal total synthesis of the anti-fungal antibiotic, Haz-
imycin 3, in good overall yield.
Veliz, E. A.; Yang, Z.-C. Synlett 1996, 609; (b) Albrecht,
B. K.; Williams, R. M. Tetrahedron Lett. 2001, 42, 2755;
idem., Org. Lett. 2003, 5, 197.
12. (a) Azizian, H.; Eaborn, C.; Pidcock, A. J. Organomet.
Chem. 1981, 215, 49; (b) Kosugi, M.; Ohya, T.; Migita, T.
Bull. Chem. Soc. Jpn. 1983, 56, 3855.
13. Representative procedure: To a solution of iodide 6
(1.2 g,1.6 mmol) in DMF (20 ml), was added Pd(PPh3)2Cl2
(120 mg, 10 mol%) followed by hexabutylditin (2.5 ml),
the mixture was stirred and warmed at 120 °C for 2.5 h.
The reaction mixture was cooled to room temperature,
extracted in Et2O, washed three times with brine and then
evaporated to dryness to afford an oily residue (4.3 g).
Purification by silica gel column chromatography eluting
with hexanes: 10% EtOAc:1% Et3N gave tributylstannane
Acknowledgements
We gratefully acknowledge Dr. G. Massiot for his inter-
est in this work. We are thankful to the Aventis Com-
pany for financial support and also for a doctoral
fellowship (to L.V.).
25
15 (1.18 g) as a colorless oil, in 74% yield. ½aꢀD +23.0
(c 0.4, CHCl3); I.R. (m cmꢁ1): 3368–3443, 2957, 2930, 1719;
MS (EI) m/z: 614 (M+ꢁn-Bu, 100); 612 (M+ꢁn-Bu, 77);
1H NMR, (300 MHz, CDCl3) d ppm: 0.87 (t, 9H,
J = 7.3 Hz); 1.03 (t, 6H, J = 7.5 Hz); 1.28 (m, 6H); 1.39
(s, 9H); 1.43 (s, 9H); 1.51 (m, 6H); 2.99 (dl, 2H,
J = 5.7 Hz); 3.5 (s, 3H); 4.38–4.42 (m, 1H); 4.97 (dl, 1H,
J = 7.9 Hz); 5.12 (s, 2H); 6.97 (d, 1H, J = 8.3 Hz); 7.08
(ddl, 1H, J=2.1, 8.3 Hz); 13C NMR, (DMSO-d6,
75.4 MHz), d ppm: 9.46, 13.6, 26.7, 27.7, 28.2, 28.8,
36.1, 55.5, 56.1, 78.1, 80.2, 93.8, 111.2, 129.1, 130.6, 130.7,
137.4, 155.4, 160.0, 171.4.
References and notes
1. See for example: (a) Guo, Z.-W.; Machiya, K.; Sala-
monczyk, G. M.; Sih, C. J. J. Org. Chem. 1998, 63, 4269;
(b) , Dityrosines:Malencik, D. A.; Sprouse, J. F.; Swan-
son, C. A.; Anderson, S. R. Anal. Biochem. 1996, 242, 202;
Nomura, K.; Suzuki, N. Arch. Biochem. Biophys. 1995,
319, 525; Li, J.; Hodgeman, B. A.; Christensen, B. A.
Insect. Biochem. Mol. Biol. 1996, 26, 309; (c) Isodityro-
sines: Brady, J. D.; Sadler, J. H.; Fry, S. C. Phytochemistry
1998, 47, 349; (d) Ito, M.; Yamanaka, M.; Kutsumura, N.;
Nishiyama, S. Tetrahedron Lett. 2003, 44, 7949.
2. Kim Wright, J. J.; Cooper, A. B.; McPhail, A. T.; Merrill,
Y. T.; Nagabhushan, L.; Puar, M. S. Chem. Commun.
1982, 1188.
3. (a) Yasuzawa, T.; Shirahata, K.; Sano, H. J. Antibiot.
1987, 40, 455; (b) Nishiyama, S.; Suzuki, Y.; Yamamura,
14. Mee, S. P. H.; Lee, V.; Baldwin, J. E. Angew. Chem., Int.
Ed. 2004, 43, 1132, see also, Refs. 4,6 and 7 cited therein.
15. Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55,
5359; Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.;
Liebeskind, L. S. J. Org. Chem. 1994, 59, 5905.
16. (a) Han, X.; Soltz, B. M.; Corey, E. J. J. Am. Chem. Soc.
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Soc. 1991, 113, 9585; (c) Jeanneret, V.; Meerpoel, L.;
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see: Andersen, N. G.; Keay, B. L. Chem. Rev. 2001, 101,
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S. Tetrahedron Lett. 1989, 30, 379; (c) Perez-Gonzalez, M.;
Jackson, R. F. W. Chem. Commun. 2000, 2423.
4. (a) Helynck, G.; Dubertret, C.; Frechet, D.; Leboul, J.
J. Antibiot. 1998, 5, 512; (b) Krenitsky, P. J.; Boger, D. L.
Tetrahedron Lett. 2002, 43, 407; (c) Krenitsky, P. J.;
Boger, D. L. Tetrahedron Lett. 2003, 44, 4019; (d)
Boisnard, S.; Zhu, J. Tetrahedron Lett. 2002, 43, 2577;
(e) Bois-Choussy, M.; Cristau, P.; Zhu, J. Angew. Chem.,
Int. Ed. 2003, 42, 4238.
5. (a) Synthesis of isodityrosines, see for example: Lygo, B.
Tetrahedron Lett. 1999, 40, 1389; (b) Jorgensen, K. B.;
Gautun, O. R. Tetrahedron 1999, 55, 10527; (c) Jung, M.
E.; Lazarova, T. I. J. Org. Chem. 1999, 64, 2976; (d)
Janetka, J. W.; Rich, D. H. J. Am. Chem. Soc. 1997, 119,
6488; (e) Evans, D. A.; Ellman, J. A. J. Am. Chem. Soc.
1989, 111, 1063; (f) Boger, D. L.; Yohannes, D. Tetrahe-
dron Lett. 1989, 30, 2053; (g) Eickhoff, H.; Jung, G.;
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6. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
7. (a) Ma, D.; Wu, Q. Tetrahedron Lett. 2001, 42, 5279; (b)
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17. Dityrosine 27: To a solution of stannane 15 (102 mg,
0.15 mmol) and iodide 12 (64 mg, 1 equiv) in DMF (4 ml)
was added CuI (3 mg, 10 mol%) and AsPh3 (10 mg,
5 mol%) followed by Pd(PPh3)2Cl2 (5 mg, 5 mol%). The
reaction mixture was warmed at 120 °C for 4.5 h. Then,
the reaction mixture was cooled to room temperature,
diluted with DCM and washed successively with 10%
aqueous NH4OH and brine, evaporation of the solvent
provided 230 mg of a yellow colored residue. Column
chromatography on silica gel, eluting with hexanes: 30%
EtOAc furnished the dityrosine 27 as a colorless gum in
25
30% yield. ½aꢀD +32.3 (c 4.7, CHCl3); I.R. (m cmꢁ1): 3385,
2978, 2932, 1761, 1715; MS (EI) m/z: 660 (M+–C4H8, 40);
543 (660-BocNH2, 70); H NMR, (300 MHz, DMSO-d6),
1
d ppm: 1.33–1.37 (2s, 27H); 2.0 (s, 3H); 2.89 (m, 3H); 3.05
(ddl, 1H, J = 5.0 Hz, 13.5 Hz); 3.34 (s, 3H); 3.64 (s, 3H);
4.01 (m, 1H); 4.21 (m, 1H); 5.01 (s, 2H); 7.01 (sl, 1H); 7.12
(dd, 2H, J = 6.8 Hz); 7.21 (sl, 1H); 7.28 (d, 1H,
J = 8.5 Hz); 7.33 (d, 1H, J = 8.5 Hz); 13C NMR,
(DMSO-d6, 75.4 MHz), d ppm: 20.7, 27.7, 28.3, 35.9,
51.9, 55.3, 55.6, 56.3, 78.3, 78.5, 80.5, 94.8, 115.4, 122.7,
127.7, 129.1, 130.1, 130.6, 131.0, 131.6, 132.0, 134.9, 146.9,
152.9, 155.6, 168.8, 171.4, 172.7.
18. Chancellor, T.; Morton, C. Synthesis 1994, 1023.