Chemistry Letters Vol.36, No.6 (2007)
727
preferred rotational isomer at the C-glycocydic bond differs
between 12 and 16c.
NOESY (500 MHz, C6D6)
H
14
N
N
Mes
Mes
Ph
In conclusion, we have described the preparation of
kendomycins’s macrocyclic core via the Nozaki–Hiyama–Kishi
coupling and a ring-closing metathesis. These results would not
only be useful for kendomycin synthesis but also would
constitute a general basis of macrocycle-synthesis by RCM
reactions. Efforts toward the total synthesis of 1 are underway
in this laboratory.
13
Cl
Cl
Ru
11
H
O
PCy3
H
O
O
H
O
OMe
H
TBSO
OMe
TBSO
MeO
MeO
OMe
OMe
(c = 2 mM)
12
10
PCy3
i-Pr
i-Pr
This research was partly supported by a Grant-in-Aid for
Scientific Research (Nos. 18032010 and 16310150 for H. A.),
and the 21st century COE program (Establishment of COE on
Materials Science) From the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan. T. S. acknowl-
edges JSPS for the Research Fellowships for Young Scientists.
Cl
N
Ru
F3C
F3C
Cl
Ph
14
Mo
PCy3
Ph
F3C
CF3
13
Figure 1.
Table 1. Macrocyclization of the precursor 10
References and Notes
Entry Catalyst (mol %) Solvent
Conditions
Yield of 12
1
a) Y. Funahashi, T. Ishimaru, N. Kawamura, Jpn. Kokai
Tokkyo Koho 08231552 [A2 960 910], 1996. b) Y. Funahashi,
N. Kawamura, T. Ishimaru, Jpn. Kokai Tokkyo Koho 08231551
[A2 960 910], 1996.
1
2
3
4
5
6
7
13 (5 mol %)
14 (10 mol %)
11 (5 mol %)
11 (5 mol %)
11 (5 mol %)
11 (5 mol %)
11 (60 mol %)
CH2Cl2
benzene
CH2Cl2
CH2Cl2
benzene
rt, 7 h
rt, 1 day
rt, 16 h
N.R.
N.R.
trace
trace
trace
2
3
a) H. B. Bode, A. Zeeck, J. Chem. Soc., Perkin Trans. 1 2000,
323. b) H. B. Bode, A. Zeeck, J. Chem. Soc., Perkin Trans. 1
2000, 2665.
reflux, 12 h
rt, 1 day
benzene 60 ꢁC, 1 day trace ꢄ 45%
a) H. J. Martin, M. Drescher, H. Kahlig, S. Schneider, J. Mulzer,
Pichlmair, M. M. B. Marques, H. J. Martin, O. Diwald, T. Berger,
Uemura, Chem. Commun. 2004, 1220. e) J. D. White, H. Smits,
7, 4161. h) K. B. Bahnck, S. D. Rychnovsky, Chem. Commun.
2006, 2388.
toluene 90 ꢁC, 5 days
53%
tion varied largely from time to time, and the higher amount of
catalyst (60 mol %) was needed to obtain reproducible results
(53%, Entry 7).
Although several products were observed in the reaction
mixture by TLC analysis, we could only isolate and characterize
the major product 12.7 The NOESY experiment of NMR analy-
sis revealed that the newly formed C13–C14 double bond existed
in an unnatural Z geometry.
It has already been shown that success of the RCM tactic
for kendomycin’s macrocyclic ether is substrate-dependent.
The first attempt by the Multzer group proved unsuccessful,3c
and Smith also met with difficulty due to the delicate substrate
dependence of the reaction (Scheme 4).4c
For example, they failed to cyclize 19-keto substrate 15a
or (19R)-alcohol 15b (Scheme 4). In literature reports, only
the alcohol 15c can cyclize to 16c.4c,8 Thus, it was really
fortunate for us to succeed in cyclizing a 19-keto compound
10. Both compounds 12 and 16c have Z configurations at
C13–C14 alkene, which may be the result of thermodynamic
stability of the macrocyclic ring. It is also noteworthy that the
4
5
6
7
15
12: R f ¼ 0:41 (SiO2, hexane:EtOAc = 7:1); ½ꢀꢃ D þ 106ꢁ (c
0.53, CHCl3); IR (CHCl3) 2960, 2930, 2860, 1460, 1410, 1380,
1050, 840 cmꢂ1
;
1H NMR (500 MHz, C6D6) ꢁ 6.14 (d, J ¼
11:2 Hz, 1H), 5.11 (d, J ¼ 8:8 Hz, 1H), 4.20 (d, J ¼ 17:1 Hz,
1H), 4.09 (d, J ¼ 17:1 Hz, 1H), 3.80 (s, 3H), 3.79 (d, J ¼
11:7 Hz, 1H), 3.61 (s, 3H), 3.50 (dd, J ¼ 6:8, 6.8 Hz, 1H), 3.45
(s, 3H), 3.38 (dd, J ¼ 10:2, 4.9 Hz, 1H), 3.21 (m, 1H), 2.69 (m,
1H), 2.39 (m, 1H), 2.28 (dd, J ¼ 13:7, 11.7 Hz, 1H), 2.22 (s,
3H), 1.97 (s, 3H), 1.94 (m, 1H), 1.71 (br. d, J ¼ 14:7 Hz, 1H),
1.60 (s, 3H), 1.58 (m, 2H), 1.52–1.47 (m, 2H), 1.32 (m, 2H),
1.27 (d, J ¼ 6:8 Hz, 3H), 1.02 (s, 9H), 0.96 (d, J ¼ 6:3 Hz, 3H),
0.93 (d, J ¼ 6:8 Hz, 3H), 0.69 (d, J ¼ 6:8 Hz, 1H), 0.17 (s, 3H),
0.12 (s, 3H); 13C NMR (151 MHz, C6D6) ꢁ 199.3, 154.1, 152.0,
150.1, 145.7, 138.2, 135.3, 134.2, 131.6, 129.5, 125.6, 82.1,
79.9, 79.8, 61.5, 60.3, 59.9, 39.7, 39.2, 38.1, 35.2, 34.3, 33.4,
31.7, 31.6, 26.1, 22.8, 21.6, 20.9, 18.4, 14.5, 12.0, 9.7, 6.6,
ꢂ3:9, ꢂ4:5; MS (FAB) m=z 665 [M + Na]þ; HRMS (FAB) calcd
for C38H62O6SiNa [M + Na]þ 665.4213, found 665.4210.
Smith succeeded in isomerizing this Z-alkene to the E geometry
via a multi-step procedure, leading to the completion of total
synthesis.
NOE
H
N
N
Mes
Mes
Ph
Cl
Cl
Ru
11
H
O
PCy3
R1
R2
OH
H
O
19
H
OMe
H
TBSO
Smith et al.
OMe
TBSO
TBSO
TBSO
OMe
16c
OMe
15a: R1= R2= O (no cyclization)
15b: R1= OH, R2= H (no cyclization)
15c: R1= H, R2= OH
8
Scheme 4. Reported selectivity in Smith’s RCM approach.4b,4c