Synthesis of the fully functionalized nine-membered diyne core of the C-1027 chromophore

Article abstract of DOI:10.1016/j.tetlet.2004.06.136

We report the synthesis of the fully functionalized seco-acid of the C-1027 chromophore. The key reaction is a LiN(TMS)₂/CeCl ₃-promoted acetylide-aldehyde condensation to construct the highly strained nine-membered diyne. Appropriate functionalization of the substrates significantly affects the yield of the cyclization. The present findings will be the basis of further studies toward the total synthesis of the C-1027 chromophore.

Full text of DOI:10.1016/j.tetlet.2004.06.136

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6439–6442
Synthesis of the fully functionalized nine-membered diyne core
of the C-1027 chromophore
a
a,
*
Masayuki Inoue,a,b, Tsukasa Kikuchi and Masahiro Hirama
*
aDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
bResearch Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 25 May 2004; revised 21 June 2004; accepted 29 June 2004
Abstract—We report the synthesis of the fully functionalized seco-acid of the C-1027 chromophore. The key reaction is a
LiN(TMS)2/CeCl3-promoted acetylide–aldehyde condensation to construct the highly strained nine-membered diyne. Appropriate
functionalization of the substrates significantly affects the yield of the cyclization. The present findings will be the basis of further
studies toward the total synthesis of the C-1027 chromophore.
Ó 2004 Elsevier Ltd. All rights reserved.
C-1027 is a member of the subset of chromoprotein anti-
tumor agents that are composed of protein and small-
molecule (chromophore) components.1,2 The C-1027
chromophore 1,3 when separated from the binding pro-
tein, has extremely limited stability in solution and has
been shown to undergo spontaneous cycloaromatization
in the absence of any activator. This high reactivity, cou-
pled with structural features such as the chlorocatechol-
containing ansa-bridge with atropisomerism, the highly
strained bicyclo[7.3.0]trienediyne, the appended benzo-
oxazine,4 and the aminosugar5 contribute to making
the synthesis of 1 a formidable challenge.6–8
NH2
H
18
O
24
16
macrolactonization
OMe
20
HO
O
22
14
Cl
O
O
11
4
H
5
9
O
OH
O
6
HN
O
9-membered ring
formation
O
O
OH
C-1027 chromophore (1)
NMe2
Figure 1. Structure of the C-1027 chromophore (1).
We planned to construct the aglycon moiety of 1
through macrolactonization at C169 and formation of
the nine-membered ring by linking C5 and C6 (Fig. 1).
Cyclization of the nine-membered ring could be induced
with a 1:1 mixture of LiN(TMS)2 and CeCl310 in THF, a
reaction previously shown to be practical with simple
substrates.6a,11,12 However, the feasibility of this reac-
tion, particularly given the highly complex structure of
1, was uncertain. Here, we demonstrate the synthesis
of a fully functionalized diyne core bearing the b-tyro-
sine moiety through efficient nine-membered ring forma-
tion of a judiciously selected intermediate.
Construction of the bicyclo[7.3.0]diyne core began with
the previously reported aryl ether 2 (Scheme 1).9,13 The
intermolecular Sonogashira coupling14 of 2 with 3 af-
forded the adduct 6. The acetylenic TMS of 6 was selec-
tively removed in the presence of the four O-silyl groups
using TBAF at ꢀ55°C to generate 7 in 77% yield over
two steps. Liberation of the primary alcohol from
DMTr-protected 7 was realized with ZnBr2 to afford 8
(64% yield) without affecting the other acid labile pro-
tective groups (MOM, TMS, TES, TBS, and Boc). Alco-
hol 8 was smoothly oxidized to aldehyde 9 using Dess–
Martin reagent15 in 95% yield. However, treatment of 9
with LiN(TMS)2 and CeCl3 produced the cyclized prod-
uct 10 in only 13% yield.
Keywords: C-1027; Enediyne; Chromoprotein antibiotics; Nine-mem-
bered diyne; Cyclization.
*
Corresponding authors. Tel.: +81-222-17-6565; fax: +81-222-17-
6566; e-mail addresses: inoue@ykbsc.chem.tohoku.ac.jp; hirama@
ykbsc.chem.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.136

6440
M. Inoue et al. / Tetrahedron Letters 45 (2004) 6439–6442
OTBS MPMO OTBS
MPMO
MPMO
OTBS
OTES
TBSO
TBSO
TBSO
I
OTES
ODMTr
OTES
4 R3
4
O
TMSO
TMS
OMOM
TMSO
R2
TMSO
d
h
3
O
O
OMOM
O
OMOM
Cl
Cl
Cl
16
18
R1
OPiv
OPiv
18
BocHN
BocHN
(Boc)2N
15
2: R1 = CO2Me
4: R1 = CH2OH
5: R1 = CH2OPiv
11: R2 = TMS, R3 = CH2ODMTr
12: R2 = H, R3 = CH2ODMTr
13: R2 = H, R3 = CH2OH
14: R2 = H, R3 = CHO
e
a,b
c
f
i. LiN(TMS)2, CeCl3
g
82% (17)
d
i. LiN(TMS)2, CeCl3
MPMO
OTBS
MPMO
OTBS
MPMO
OTBS
TBSO
TBSO
TBSO
OTES
R3
R2
4
5
4
OH
OTES
OH
OTES
i. LiN(TMS)2, CeCl3
13%
5
TMSO
TMSO
TMSO
O
OMOM
O
O
OMOM
O
OMOM
Cl
Cl
Cl
O
16
18
16 OMe
OPiv
16 OMe
BocHN
R4BocN
16: R4 = H
17: R4 = Boc
BocHN
10
6: R2 = TMS, R3 = CH2ODMTr
7: R2 = H, R3 = CH2ODMTr
8: R2 = H, R3 = CH2OH
9: R2 = H, R3 = CHO
e
f
g
Scheme 1. Reagents and conditions: (a) DIBAL-H, CH2Cl2, ꢀ78°C; (b) NaBH4, EtOH, 0°C, 82% (two steps); (c) PivCl, DMAP, Et3N, rt, 100%; (d)
3 (1.3equiv), Pd2(dba)3ÆCHCl3 (30mol%), CuI (30mol%), i-Pr2NEt, DMF, rt; (e) TBAF, THF, ꢀ55°C, 77% (7, two steps) from 2, 52% (12, two
steps) from 5; (f) ZnBr2, CH2Cl2, 0°C, 64% (8), 61% (13); (g) Dess–Martin periodinane, CH2Cl2, rt, 95% (9), 90% (14); (h) (Boc)2O, DMAP, CH3CN,
40°C, 72%; (i) LiN(TMS)2 (30equiv), CeCl3 (31equiv), THF (2mM), ꢀ20°C to rt, 13% (10), 0% (16), 82% (17).
We therefore redesigned our substrate in an effort to
improve the cyclization yield. The C16-ester of 9 was
replaced with its reduced form in order to eliminate
acidic a-protons that could cause undesired side reac-
tions. Stepwise reduction of ester 2 led to alcohol 4, the
pivaloyl protection of which afforded 5 in 82% yield over
three steps. Sonogashira-coupling between 3 and 5, fol-
lowed by TBAF treatment, resulted in 12 (52% yield
for two steps). Selective removal of the DMTr group of
12 using ZnBr2 then produced primary alcohol 13. After
conversion of 13 to aldehyde 14, LiN(TMS)2/CeCl3-pro-
moted cyclization was attempted, but this led only to a
complex mixture with no desired product 16.
ESY experiment (Fig. 2). Interestingly, upon formation
of the nine-membered ring, the TES groupat the C4-OH
of 15 was intramolecularly transposed to the C5-hydroxy
groupof 17, thus indicating the spatial proximity
between the C4- and C5-hydroxy groups. Diyne 17
was chemically unstable upon heating (t1/2 = 3h in
C6D6 at 50°C), which is similar to previously synthe-
sized model compounds.17
As shown in Scheme 2, the new substrate design for the
cyclization was successfully applied to the differentially
protected compound 18, which was prepared through
a similar route to 15. When bis-Boc protected 18 was
subjected to the LiN(TMS)2/CeCl3-mediated cyclization
Masking the acidic C18-NH of 14 had a dramatic effect
on improving the cyclization yield. Introduction of
another Boc groupto the C18-nitrogen of 14 using
(Boc)2O and DMAP afforded bis-carbamate 15 (72%
yield), and subsequent treatment of 15 with LiN(TMS)2
(30equiv) and CeCl3 (31equiv) in THF gave rise to the
nine-membered diyne 17 in 82% yield as a sole isomer.16
The difference in the cyclization yields of 9, 14, and 15
clearly demonstrate that removal of acidic protons is
crucial for this base-promoted condensation.
N(Boc)2
H
OPiv
Cl
OTBS
O
O
13OMPM
CH3O
H
H
4
TBSO
5
OTES
HO
TMSO
17
Figure 2. ROESY correlations of 17 (500MHz, CDCl3).
The stereochemistry of the newly formed secondary
alcohol of 17 was unambiguously determined by a RO-

M. Inoue et al. / Tetrahedron Letters 45 (2004) 6439–6442
6441
2. For recent reviews on chromoprotein antibiotics and other
enediyne natural products, see: (a) Neocarzinostatin;
Maeda, H., Edo, K., Ishida, N., Eds.; Springer: Tokyo,
1997; (b) Xi, Z.; Goldberg, I. H. In Comprehensive Natural
Products Chemistry; Barton, D. H. R., Nakanishi, K.,
Eds.; Elsevier, 1999; Vol. 7, pp 553–592.
MPMO
OTBS
OTBS
MOMO
O
a
TESO
O
OMOM
3. (a) Minami, Y.; Yoshida, K.; Azuma, R.; Saeki, M.;
Otani, T. Tetrahedron Lett. 1993, 34, 2633–2636; (b)
Yoshida, K.; Minami, Y.; Azuma, R.; Saeki, M.; Otani, T.
Tetrahedron Lett. 1993, 34, 2637–2640; (c) Iida, K.;
Fukuda, S.; Tanaka, T.; Hirama, M.; Imajo, S.; Ishiguro,
M.; Yoshida, K.; Otani, T. Tetrahedron Lett. 1996, 38,
4997–5000.
4. Shibuya, M.; Sakurai, H.; Maeda, T.; Nishiwaki, E.;
Saito, M. Tetrahedron Lett. 1986, 27, 1351–1354.
5. (a) Iida, K.; Ishii, T.; Hirama, M.; Otani, T.; Minami, Y.;
Yoshida, K. Tetrahedron Lett. 1993, 34, 4079–4082; (b)
Semmelhack, M. F.; Jiang, Y.; Ho, D. Org. Lett. 2001, 3,
2403–2406.
6. Total syntheses of the nine-membered ring enediynes were
reported. N-1999-A2 (a) Kobayashi, S.; Ashizawa, S.;
Takahashi, Y.; Sugiura, Y.; Nagaoka, M.; Lear, M. J.;
Hirama, M. J. Am. Chem. Soc. 2001, 123, 11294–11295;
NCS chromophore (b) Myers, A. G.; Liang, J.; Ham-
mond, M.; Harrington, P. M.; Wu, Y.; Kuo, E. Y. J. Am.
Chem. Soc. 1998, 120, 5319–5320; (c) Myers, A. G.;
Glatthar, R.; Hammond, M.; Harrington, P. M.; Kuo, E.
Y.; Liang, J.; Schaus, S. E.; Wu, Y.; Xiang, J.-N. J. Am.
Chem. Soc. 2002, 124, 5380–5401.
Cl
OPiv
18
18
MPMO
OTBS
(Boc)2N
MOMO
OH
5
TESO
OTBS
19: R1 = Piv, R2 = Boc
20: R1 = H, R2 = H
b
O
OMOM
Cl
16
18
OR1
OR3
R2BocN
c,d
MPMO
MOMO
14
OH
OTBS
TESO
O
OMOM
O
Cl
16 OH
21: R3 = TBS
22: R3 = H
e
BocHN
Scheme 2. Reagents and conditions: (a) LiN(TMS)2 (26equiv), CeCl3
(28equiv), THF (2mM), ꢀ30°C to rt, 78%; (b) DIBAL-H, CH2Cl2,
ꢀ85°C, 70%; (c) Dess–Martin periodinane, CH2Cl2, rt; (d) NaClO2,
NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (5:1), 72% (two steps);
(e) PPTS, MeOH, rt, 45%.
7. Myers reported the synthesis of the protected kedarcidin
chromophore aglycon through the transannular reductive
cyclization strategy. Myers, A. G.; Hogan, P. C.; Hurd, A.
R.; Goldberg, S. D. Angew. Chem., Int. Ed. 2002, 41,
1062–1066.
8. For reviews on the syntheses of enediyne compounds, see:
(a) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1387–1416; (b) Danishefsky, S. J.; Shair,
conditions, nine-membered diyne 19 was isolated as a
single isomer in 78% yield. Subsequent DIBAL-H reduc-
tion of 19 simultaneously removed both Piv and Boc
groups to generate mono-Boc alcohol 20. The primary
alcohol was then oxidized to the corresponding carboxy-
lic acid 21 via a two-step protocol: (i) Dess–Martin peri-
odinane treatment; and (ii) NaClO2 oxidation. Finally,
the primary TBS group at C14 of 21 was selectively re-
moved using PPTS in MeOH, leading to the fully func-
tionalized seco-acid 22 (45% yield).18,19
M. D. J. Org. Chem. 1996, 61, 16–44; (c) Bruckner, R.;
Suffert, J. Synlett 1999, 657–679.
¨
9. Sasaki, T.; Inoue, M.; Hirama, M. Tetrahedron Lett. 2001,
42, 5299–5303.
10. Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392–4398.
11. (a) Iida, K.; Hirama, M. J. Am. Chem. Soc. 1994, 116,
10310–10311; (b) Sato, I.; Toyama, K.; Kikuchi, T.;
Hirama, M. Synlett 1998, 1308–1310.
12. For other studies on bicyclo[7.3.0]diyne formation, see: (a)
Wender, P. A.; Harmata, M.; Jeffery, D.; Mukai, C.;
Suffert, J. Tetrahedron Lett. 1988, 29, 909–912; (b)
Wender, P. A.; McKinney, J. A.; Mukai, C. J. Am. Chem.
Soc. 1990, 112, 5369–5370; (c) Myers, A. G.; Harrington,
P. M.; Kuo, E. Y. J. Am. Chem. Soc. 1991, 113, 694–695;
(d) Doi, T.; Takahashi, T. J. Org. Chem. 1991, 56,
3465–3467; (e) Magnus, P.; Carter, R.; Davies, M.; Elliott,
J.; Pitterna, T. Tetrahedron 1996, 52, 6283–6306; (f)
Tanaka, H.; Yamada, H.; Matsuda, A.; Takahashi, T.
Synlett 1997, 381–383; (g) Caddick, S.; Delisser, V. M.;
Doyle, V. E.; Khan, S.; Avent, A. G.; Vile, S. Tetrahedron
1999, 55, 2737–2754, and references cited therein.
13. Sato, I.; Kikuchi, T.; Hirama, M. Chem. Lett. 1999,
511–512.
In conclusion, the highly strained nine-membered diyne
22 possessing the b-tyrosine moiety was synthesized
via LiN(TMS)2/CeCl3-promoted acetylide–aldehyde
condensation. The key feature in this synthesis is
the exploitation of a variety of protective groups that
enabled not only the timely exposure of suitable func-
tional groups, but also the effective cyclization of highly
functionalized substrates (15 and 18). Further studies on
the total synthesis of the C-1027 chromophore based on
the above findings are currently underway in this labora-
tory.
14. (a) Sonogashira, K.; Tohda, Y.; Hagiwara, N. Tetra-
hedron Lett. 1975, 16, 4467–4470; (b) Sonogashira, K. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: London, 1990; Vol. 3, pp 521–549.
15. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
References and notes
1. (a) Otani, T.; Minami, Y.; Marunaka, T.; Zhang, R.; Xie,
M.-Y. J. Antibiot. 1988, 41, 1580–1585; (b) Zhen, Y.;
Ming, S.; Bin, Y.; Otani, T.; Saito, H.; Yamada, Y. J.
Antibiot. 1989, 42, 1294–1298.
20
16. 17: pale yellow oil; ½aꢁD ꢀ61.7 (c 0.89, CHCl3); FT-IR
(film) m 2956, 1731, 1612, 1576, 1514, 1392, 1345, 1251,

6442
M. Inoue et al. / Tetrahedron Letters 45 (2004) 6439–6442
1157, 1080, 1006, 913cmꢀ1; 1H NMR (500MHz, CDCl3) d
17. Cope rearrangement of the nine-membered cyclic 1,5-
diyne 17 to the bis-allene is considered to be the major
decomposition pathway (see Ref. 11a).
0.06 (3H, s, TBS), 0.07 (3H, s, TBS), 0.11 (3H, s, TBS),
0.12 (3H, s, TBS), 0.20 (9H, s, TMS), 0.50 (6H, dq,
J = 15.5, 8.0Hz, TES), 0.84 (9H, t, J = 8.0Hz, TES), 0.89
(9H, s, TBS), 0.94 (9H, s, TBS), 1.16 (9H, s, Piv), 1.40
(18H, s, Boc), 1.94 (1H, dd, J = 13.5, 4.5Hz, H10), 2.20–
2.30 (1H, m, H17), 2.57 (1H, ddd, J = 15.0, 10.5, 4.5Hz,
H17), 3.13 (1H, dd, J = 13.5, 7.0Hz, H10), 3.38 (1H, s, C4-
OH), 3.49 (3H, s, MOM), 3.68 (1H, dd, J = 8.5, 2.0Hz,
H13), 3.77 (3H, s, MPM), 3.96 (1H, dd, J = 11.0, 8.5Hz,
H14), 4.10–4.20 (2H, m, H16), 4.24 (1H, dd, J = 11.0,
2.0Hz, H14), 4.40 (1H, s, H5), 4.42 (1H, d, J = 11.0Hz,
MPM), 4.82 (1H, ddd, J = 7.0, 4.5, 2.5Hz, H11), 4.84 (1H,
d, J = 11.0Hz, MPM), 5.04 (1H, s, H8), 5.21 (1H, d,
J = 7.0Hz, MOM), 5.22 (1H, d, J = 7.0Hz, MOM), 5.35
(1H, dd, J = 10.5, 5.5Hz, H18), 6.07 (1H, d, J = 2.5Hz,
H12), 6.77 (2H, d, J = 8.5Hz, MPM), 7.07 (1H, d,
J = 2.0Hz, H20), 7.09 (1H, d, J = 2.0Hz, H24), 7.16
(2H, d, J = 8.5Hz, MPM); 13C NMR (50MHz, CDCl3) d
ꢀ5.4, ꢀ5.3, ꢀ4.7, 2.2, 4.4, 6.6, 18.0, 18.2, 25.8, 26.0, 27.1,
27.9, 30.8 (C17), 38.7, 47.0 (C10), 55.0 (C18), 55.2, 56.3,
61.3 (C16), 65.7 (C14), 67.3 (C11), 73.5, 74.9 (C5), 76.8
(C8), 79.7 (C4), 82.5, 83.2 (C13), 87.7 (C9), 89.3 (C7), 89.5
(C6), 90.6 (C2), 95.1, 98.5 (C3), 113.5, 114.1 (C24), 122.4
(C20), 128.5 (C21), 128.7 (C1), 129.8, 131.0, 137.2 (C19),
141.5 (C12), 141.7 (C22), 150.9 (C23), 152.9, 159.1, 178.4;
MALDI-TOFMS calcd for C69H112ClNO16Si4Na 1380.66
(M+Na+), found 1380.62.
28
18. 22: pale yellow oil; ½aꢁD ꢀ84.6 (c 0.98, CHCl3); FT-IR
(film) m 2954, 2066, 1715, 1613, 1514, 1367, 1251, 1104,
1
922cmꢀ1; H NMR (500MHz, CD3OD) d ꢀ0.05 (6H, s,
TBS), 0.73 (6H, q, J = 8.0Hz, TES), 0.81 (9H, s, TBS),
1.00 (9H, t, J = 8.0Hz, TES), 1.40 (9H, s, Boc), 2.04 (1H,
dd, J = 14.0, 5.0Hz, H10), 2.50–2.70 (2H, m, H17), 3.18
(1H, dd, J = 14.0, 7.5Hz, H10), 3.37 (3H, s, MOM), 3.51
(3H, s, MOM), 3.65 (1H, dd, J = 7.5, 3.0Hz, H13), 3.78
(3H, s, MPM), 3.83 (1H, dd, J = 11.0, 7.5Hz, H14), 4.01
(1H, dd, J = 11.0, 3.0Hz, H14), 4.48 (1H, d, J = 11.0Hz,
MPM), 4.51 (1H, s, H5), 4.70 (2H, s, MOM), 4.70 (1H, br,
H11), 4.76 (1H, d, J = 11.0Hz, MPM), 4.92 (1H, br, H18),
5.19 (1H, s, H8), 5.24 (1H, d, J = 6.5Hz, MOM), 5.29 (1H,
d, J = 6.5Hz, MOM), 6.21 (1H, d, J = 2.0Hz, H12), 6.79
(2H, d, J = 8.5Hz, MPM), 7.05 (1H, br s, H20), 7.10 (1H,
br s, H24), 7.20 (2H, d, J = 8.5Hz, MPM); MALDI-
TOFMS calcd for C52H76ClNO15Si2Na (M+Na+)
1068.43, found 1068.23.
19. Macrolactonization of 22 under Yamaguchi conditions
(Ref. 9) afforded the cyclized product albeit in low yield
(5%). Optimization of the reaction is now in progress, and
will be reported in due course. For Yamaguchi esterifica-
tion, see: Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52,
1989–1993.