Intramolecular Nozaki-Hiyama-Kishi reactions and Ln(III)-catalyzed allylic rearrangement as the key steps towards 10-membered ring enediynes

Article abstract of DOI:10.1016/S0040-4039(01)00707-9

A general and facile synthesis of the 3-substituted 10-membered ring enediynes 18-22 from the aldehydes 8 and 15 has been established by utilizing the intramolecular Nozaki-Hiyama-Kishi reaction and the lanthanide(III)-catalyzed rearrangement of allylic alkoxyacetates as the key steps. This work provides ready access to the (E)-3-acyloxy-4-(arylmethylidene)cyclodeca-1,5-diynes, which can be converted into the bioactive enediynes under physiological conditions.

Full text of DOI:10.1016/S0040-4039(01)00707-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4211–4214
Intramolecular Nozaki–Hiyama–Kishi reactions and
Ln(III)-catalyzed allylic rearrangement as the key steps towards
10-membered ring enediynes
Wei-Min Dai,* Anxin Wu and Wataru Hamaguchi
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon,
Hong Kong SAR, China
Received 4 January 2001; accepted 27 April 2001
Abstract—A general and facile synthesis of the 3-substituted 10-membered ring enediynes 18–22 from the aldehydes 8 and 15 has
been established by utilizing the intramolecular Nozaki–Hiyama–Kishi reaction and the lanthanide(III)-catalyzed rearrangement
of allylic alkoxyacetates as the key steps. This work provides ready access to the (E)-3-acyloxy-4-(arylmethylidene)cyclodeca-1,5-
diynes, which can be converted into the bioactive enediynes under physiological conditions. © 2001 Elsevier Science Ltd. All
rights reserved.
Substitution at the C3 position of the (Z)-hexa-1,5-
diyn-3-ene moiety is common to the naturally occurring
nine-membered ring enediyne antitumor antibiotics, the
kedarcidin chromophore,1 the C-1027 chromophore2
and the maduropeptin chromophore.3a The C3 substi-
tution forms a part of the macrocyclic ring incorporat-
ing the 5/9-fused bicyclic enediyne core. Moreover, the
C3 substitution in the maduropeptin chromophore is
the key structural feature that allows interconversion
between the native enediyne chromophore and its arti-
facts via allylic rearrangement.3 We demonstrated a
similar allylic rearrangement process in the formation
of a 10-membered ring enediyne that exhibits DNA
cleavage activity and cytotoxicity against cancer cell
lines.4 These results encouraged us to design and syn-
thesize a novel class of enediyne prodrugs5 that deliver
the enediyne-like biological activity but do not suffer
from instability towards cycloaromatization at physio-
logical temperature.6 We report here a general and
facile synthesis of 3-substituted7 10-membered ring
enediynes
1 from the aldehydes 3 through the
intramolecular Nozaki–Hiyama–Kishi (NHK) reaction8
to form 2 (Y=OH) followed by the lanthanide(III)-cat-
alyzed rearrangement9 of the allylic alkoxyacetates 2
(Y=ROCH2CO2) (Scheme 1).
The intramolecular NHK reaction has been successfully
applied to the construction of cyclic enediynes possess-
ing a (Z)-hexa-1,5-diyn-3-ene moiety.8 Yields of the
cyclization vary from 23 to 95% depending on the
substrate structures. Typically, ca. a 30% yield was
reported for the monocyclic 10-membered ring
enediyne.10 Suffert and Toussaint described a synthesis
of the 4-alkylidenecyclodeca-1,5-diyne skeleton fused
with a benzene ring onto the C7 and C8 positions via
the intramolecular NHK reaction.11 However, a general
synthesis of compounds 2 possessing an exocyclic dou-
ble bond via the intramolecular NHK reaction
Ln(III)-catalyzed
allylic
rearrangement
intramolecular
Nozaki-Hiyama-Kishi
reaction
b
CHO
Y
Y
Y = ROCH2CO2
path b
Ar
I
Ar
Ar
a
3
1
2
Scheme 1.
Keywords: alkynyl halides; diynes; lanthanides; rearrangement.
* Corresponding author. Fax: +852 2358 1594; e-mail: chdai@ust.hk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00707-9

4212
W.-M. Dai et al. / Tetrahedron Letters 42 (2001) 4211–4214
(path b, Scheme 1) has not appeared in the literature.
Very recently, an intramolecular Sonogashira cross-
coupling approach to compounds 2 (Ar=Ph, 1-Naph
and Y=OH, path a) was reported from our labora-
tory.12
dene)cyclodeca-1,5-diynes 16 as shown in Scheme 3.13
The Horner–Wadsworth–Emmons reactions of aryl
aldehydes with 10 gave the a,b-unsaturated esters 11 in
excellent yields. Treatment of 11 with Br2 followed by
exposure to triethylamine furnished the a-bromoesters
12 as a mixture of E and Z isomers.4e,15 Because both
isomers can be converted into the desired aldehydes 15,
the mixtures were used for further elaborations. The
cross-coupling of 12 with 1,7-octadiyne 5 under Sono-
gashira conditions provided 13 in good yields. The
esters 13 were then subjected to Dibal-H reduction
followed by iodination to yield the alcohols 14. The E
and Z isomers of 14, upon PCC oxidation in CH2Cl2 at
20°C, gave the same E aldehydes 15 in 66–88% yield. In
a separate set of experiments, we confirmed that iso-
merization of the Z aldehydes occurred under the
slightly acidic PCC oxidation conditions.16 For
instance, the E aldehyde 15 with Ar=p-MeOC6H4 was
obtained from the pure Z-14 in 66% yield. Finally, the
intramolecular NHK reaction within 15 gave the cyclic
alcohols 16 in 17–25% yields. The effect of the aryl
group on the cyclization of 15 was observed and the
yields for the naphthalene derivatives 16 (Ar=1- and
2-Naph) were slightly lower compared to the phenyl
analogs 9 and 16 (Ar=p-MeOC6H4). Similarly, the
We first examined the intramolecular NHK reaction of
the aldehyde 8 (Scheme 2).13 The Pd(0)–Cu(I)-catalyzed
cross-coupling of the commercially available a-bro-
mocinnamaldehyde 4 with 1,7-octadiyne 5 gave the
enyne 6 in 91% yield. Because compound 6 failed to
give the iodoalkyne 8 directly, it was reduced to the
alcohol 7 by using NaBH4 in MeOH (20°C, 30 min,
91%). Iodination of 7 was carried out by using 3 equiv.
of I2 and 8 equiv. of morpholine10,14 (PhMe, 40–50°C, 6
h, 89%) to give the corresponding iodoalkyne, which
was oxidized to the aldehyde 8 by using PCC (CH2Cl2,
20°C, 2 h, 75%). Treatment of 8 with 3 equiv. of CrCl2
and 1 equiv. of NiCl2 under high dilution conditions
(0.005 M in THF, 20°C, 8 h) furnished the 10-mem-
bered ring alcohol 9 in 29% yield as the only isolated
product.
With the successful synthesis of 9, we developed a
general synthesis of (E)-3-hydroxy-4-(arylmethyli-
E
HO
CrCl2-NiCl2
CHO
Br
5
THF, 20 °C, 8 h
(29% from 8)
Pd(PPh3)4, CuI
Et3N, THF, 20 °C, 8 h
(91%)
Ph
Ph
Ph
X
4
9
6: E = CHO, X = H
7: E = CH2OH, X = H
8: E = CHO, X = I
Scheme 2.
1. nBuLi, THF, -78 °C
2. ArCHO, -78 ~ 20 °C, 4-5 h
CO2Me
Br
CO2Me
O
P
1. Br2, CH2Cl2, -78 ~ 0 °C
CO2Me
MeO
MeO
(96-100%)
2. Et3N, 20 °C, 16-18 h
Ar
Ar
(80-98%)
10
11
12
Ar = 1-Naph, 2-Naph, p-MeOC6H4
5, Pd(PPh3)4, CuI
ethylpiperidine-CH3CN (1:9)
20 °C, 1.5-5 h (66-73%)
OH
1. Dibal-H, PhMe
-78 °C, 1 h (92-94%)
CO2Me
Ar
2. I2, morpholine, PhMe
40 ~ 50 °C, 6-24 h (76-92%)
Ar
I
14
13
PCC, CH2Cl2
20 °C, 2-2.5 h
(66-88%)
CHO
Ar
HO
CrCl2-NiCl2
Ar = 1-Naph (20%)
Ar = 2-Naph (17%)
Ar = p-MeOC6H4 (25%)
THF, 20 °C, 8 h
Ar
I
15
16
Scheme 3.

W.-M. Dai et al. / Tetrahedron Letters 42 (2001) 4211–4214
4213
CHO
HO
CrCl2-NiCl2
THF, 20 °C, 8 h
(30%)
I
Z-15
Z-16
Scheme 4.
O
10 mol % Ln(fod)3
RO
O
O
CHCl3, 20 ˚C, 24-48 h
RO
Ar
O
Ar
Ln(fod)3 =
17
Pr(fod)3
Eu(fod)3
Er(fod)3
Yb(fod)3
Eu(fod)3
Eu(fod)3
Eu(fod)3
Eu(fod)3
18: R = Me, Ar = Ph (59%)
18: R = Me, Ar = Ph (79%)
18: R = Me, Ar = Ph (57%)
18: R = Me, Ar = Ph (58%)
19: R = Me, Ar = 1-Naph (59%)
20: R = Bn, Ar = 1-Naph (60%)
21: R = PMB, Ar = 1-Naph (58%)
22: R = Me, Ar = 2-Naph (79%)
H
R
O
δ+
δ+
Ln(III)
Ar
O
O
δ-
δ-
23
Scheme 5.
In summary, we have established a general and facile
synthesis of (E)-3-hydroxy-4-(arylmethylidene)cyclode-
ca-1,5-diynes 9 and 16 via the intramolecular Nozaki–
Hiyama–Kishi reaction. The subsequent rearrangement
of the corresponding alkoxyacetates 17 under lan-
thanide(III) catalysis gave the 3-substituted enediynes
18–22 under very mild reaction conditions. Our prelim-
inary biological screening results showed that (E)-3-
acyloxy-4-(arylmethylidene)cyclodeca-1,5-diynes, such
as 17, can deliver the same or even higher DNA cleavage
activity and cytotoxicity against cancer cell lines com-
pared to the enediynes 18–22.17 Therefore, (E)-3-acyloxy-
4-(arylmethylidene)cyclodeca-1,5-diynes can be used as
lead compounds for the development of a novel class of
enediyne prodrugs.
intramolecular NHK reaction of the aldehyde Z-15,
which was obtained as a mixture with 15 (Ar=1-naph-
thyl) from the PDC oxidation of 14,16 provided the
alcohol Z-16 in 30% yield (Scheme 4).
Rearrangement of (E)-3-alkoxyacetyloxy-4-(arylmethyl-
idene)cyclodeca-1,5-diynes 17 prepared from 9 and 16
(Ar=1- and 2-Naph) was carried out in the presence of
10 mol% Ln(fod)3 (fod=6,6,7,7,8,8,8-heptafluoro-2,2-
dimethyl-3,5-octanedionate) as the catalyst at 20°C in
CHCl3 (Scheme 5).9,13 We found that the methoxy-
acetate of 16 (Ar=p-MeOC6H4) decomposed over silica
gel during flash column chromatography to give the
rearranged enediyne alcohol 1 (Ar=p-MeOC6H4, Y=
OH, Scheme 1) in 43% isolated yield. An allylic cation
stabilized by the p-MeOC6H4 group is the likely inter-
mediate of the transformation.4e We examined four
Ln(fod)3 (Ln=Pr, Eu, Er, Yb) catalysts9c for the rear-
rangement of the phenyl-substituted methoxyacetate 17
and found that the reactions were completed within 48
h in all cases to provide the enediyne 18 (Scheme 5).
The rearrangement was clean as confirmed by TLC
analysis of the reaction mixture. Due to complexation of
the product with the catalyst, the isolated yield of 18
varied from 57 to 79% depending on the scale of the
reaction. We investigated the rearrangement of three
alkoxyacetates 17 possessing the 1-naphthalene moiety in
the presence of 10 mol% Eu(fod)3. All reactions were
completed within 24 h at 20°C to form the enediynes
19–21 (Bn=benzyl and PMB=p-MeOC6H4CH2) in ca.
60% isolated yields. The 2-naphthalene-substituted
methoxyacetate 17 rearranged to the enediyne 22 after
40 h in 79% yield. In accordance with our previous
results on 1,3-chirality transfer in the Eu(fod)3-cata-
lyzed rearrangement of a chiral substrate,9b we assume
that the Ln(III)-catalyzed allylic rearrangement of 17
may involve a ‘concerted’ transition state 23.
Acknowledgements
The authors would like to thank the Department of
Chemistry, HKUST for a post-doctoral fellowship to A.
Wu. Financial support to W. Hamaguchi from an RGC
Direct Allocation Grant (DAG97/98.SC12) is also
acknowledged.
References
1. For the structure of the kedarcidin chromophore, see: (a)
Leet, J. E.; Schroeder, D. R.; Hofstead, S. J.; Golik, J.;
Colson, K. L.; Huang, S.; Klohr, S. E.; Doyle, T. W.;
Matson, J. A. J. Am. Chem. Soc. 1992, 114, 7946; (b)
Leet, J. E.; Schroeder, D. R.; Langley, D. R.; Colson, K.
L.; Huang, S.; Klohr, S. E.; Lee, M. S.; Golik, J.;
Hofstead, S. J.; Doyle, T. W.; Matson, J. A. J. Am.
Chem. Soc. 1993, 115, 8432. For the revised structure,

4214
W.-M. Dai et al. / Tetrahedron Letters 42 (2001) 4211–4214
see: (c) Kawata, S.; Ashizawa, S.; Hirama, M. J. Am.
Chem. Soc. 1997, 119, 12012.
Am. Chem. Soc. 1992, 114, 7360.
7. A carbenoid coupling–elimination process toward 3-sub-
stituted 10-membered ring enediynes was reported. See:
Jones, G. B.; Plourde, II, G. W. Org. Lett. 2000, 2, 1757.
8. For recent reviews on the Takai–Kishi (Nozaki–Hiyama–
Kishi) reaction, see: (a) Wessjohann, L. A.; Scheid, G.
Synthesis 1999, 1; (b) Fu¨rstner, A. Chem. Rev. 1999, 99,
991.
9. (a) Shull, B. K.; Sakai, T.; Koreeda, M. J. Am. Chem.
Soc. 1996, 118, 11690; (b) Dai, W.-M.; Lee, M. Y. H.
Tetrahedron Lett. 1999, 40, 2397; (c) Dai, W.-M.; Mak,
W. L.; Wu, A. Tetrahedron Lett. 2000, 41, 7101.
10. Cre´visy, C.; Beau, J.-M. Tetrahedron Lett. 1991, 32, 3171.
11. Suffert, J.; Toussaint, D. Tetrahedron Lett. 1997, 38,
5507.
2. For the structure of the C-1027 chromophore, see: (a)
Yoshida, K.; Minami, Y.; Azuma, R.; Sakei, M.; Otani,
T. Tetrahedron Lett. 1993, 34, 2637; (b) Iida, K.; Ishii, T.;
Hirama, M.; Otani, T.; Minami, Y.; Yoshida, K. Tetra-
hedron Lett. 1993, 34, 4079; (c) Iida, K.; Fukuda, S.;
Tanaka, T.; Hirama, M.; Imajo, S.; Ishiguro, M.;
Yoshida, K.; Otani, T. Tetrahedron Lett. 1996, 37, 4997.
3. For the structure of the maduropeptin chromophore, see:
(a) Schroeder, D. R.; Colson, K. L.; Klohr, S. E.; Zein,
N.; Langley, D. R.; Lee, M. S.; Matson, J. A.; Doyle, T.
W. J. Am. Chem. Soc. 1994, 116, 9351. For biological
activity, see: (b) Zein, N.; Solomon, W.; Colson, K. L.;
Schroeder, D. Biochemistry 1995, 34, 11591.
4. (a) Dai, W.-M.; Fong, K. C.; Lau, C. W.; Zhou, L.;
Hamahuchi, W.; Nishimoto, S. J. Org. Chem. 1999, 64,
682. Also see: (b) Dai, W.-M.; Fong, K. C.; Danjo, H.;
Nishimoto, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 779;
(c) Dai, W.-M.; Fong, K. C. Tetrahedron Lett. 1996, 37,
8413; (d) Dai, W.-M.; Lee, M. Y. H. Tetrahedron Lett.
1998, 39, 8149; (e) Dai, W.-M.; Wu, J.; Fong, K. C.; Lee,
M. Y. H.; Lau, C. W. J. Org. Chem. 1999, 64, 5062.
5. For a review, see: Maier, M. E. Synlett 1995, 13.
6. For example, cyclodeca-1,5-diyn-3-ene has a half-life of
18 h at 37°C. See: (a) Nicolaou, K. C.; Zuccarello, G.;
Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am.
Chem. Soc. 1988, 110, 4866; (b) Nicolaou, K. C.; Zuc-
carello, G.; Riemer, C.; Estevez, V. A.; Dai, W.-M. J.
12. Dai, W.-M.; Wu, A. Tetrahedron Lett. 2001, 42, 81.
13. All new compounds are fully characterized by IR, 1H
NMR, 13C NMR, MS, and HRMS.
14. Southwick, P. L.; Kirchner, J. R. J. Org. Chem. 1962, 27,
3305.
15. The ratios of E and Z isomers are 50:50, 53:47 and 75:25
for 1-naphthalene-, 2-naphthalene- and p-methoxy-
phenyl-substituted compounds 12, respectively.
16. Isomerization could be avoided by using PDC as the
oxidant.
17. Dai, W.-M.; Wu, A. 2000 International Chemical Con-
gress of Pacific Basin Societies, Honolulu, HI, December
14–19, 2000; Abstract ORGN 376.
.