Secure route to the epoxybicyclo[7.3.0]dodecadienediyne core of the kedarcidin chromophore

Article abstract of DOI:10.1039/b814595d

Formation of an epoxide before 9-membered ring cyclization and SmI ₂ mediated reductive olefination in the presence of the epoxide successfully produced the epoxybicyclo[7.3.0]dodecadienediyne core of the kedarcidin chromophore. The Royal Socie

Full text of DOI:10.1039/b814595d

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Secure route to the epoxybicyclo[7.3.0]dodecadienediyne core
of the kedarcidin chromophorew
Kouki Ogawa,a Yasuhito Koyama,a Isao Ohashi,a Itaru Satob and Masahiro Hirama*ab
Received (in Cambridge, UK) 21st August 2008, Accepted 23rd September 2008
First published as an Advance Article on the web 21st October 2008
DOI: 10.1039/b814595d
Formation of an epoxide before 9-membered ring cyclization and
SmI2 mediated reductive olefination in the presence of the epoxide
successfully produced the epoxybicyclo[7.3.0]dodecadienediyne
core of the kedarcidin chromophore.
The labile chromophore (1) of antiproliferative kedarcidin1,2 has
a
highly functionalized epoxybicyclo[7.3.0]dodecadienediyne
structure (Fig. 1).3–5 In the course of our synthetic studies
on the chromophore,6,7 we found that the C8,9-epoxide
was difficult to introduce at the later stages of the synthesis.6a
Therefore, we envisaged that the formation of the epoxide
functionality should be conducted before construction of the
9-membered ring framework. We recently developed the facile
reductive elimination of vicinal bis-p-trifluoromethylbenzoates
or 1,2-mesyloxy-p-trifluoromethylbenzoate using samarium
iodide to introduce the olefins.8 Kagan’s pioneering work in
the field of SmI2 mediated reduction indicated that the epoxide
functionality would serve as a good electron acceptor.9,10
Indeed, reductive ring opening and deoxygenation reactions
of epoxides in the presence or absence of proton sources
proceeded under mild conditions.9,11 In this communication we
report a successful approach towards the epoxybicyclo[7.3.0]-
dodecadienediyne core of the kedarcidin chromophore via the
highly chemoselective reductive olefination of diol derivatives
in the presence of an epoxide. To the best of our knowledge,
this is the first example of a SmI2 mediated reductive olefina-
tion of vicinal diol derivatives with the co-existence of an
epoxide in the molecule.
Fig. 1 The structure of the kedarcidin chromophore, 1, proposed in
19973c (recent stereochemical revision, see ref. 4).
coupling of 4 with the C2–C5 moiety 513 and removal of the
trimethylsilyl group afforded the terminal alkyne 6. Oxidative
cleavage of the 2-naphthylmethyl (NAP) ether and Dess–
Martin oxidation gave the aldehyde 7. Cyclization to the
9-membered diyne ring at the C5–C6 position utilizing
CeCl3–lithium disilazide at À25 1C14 resulted in the formation
of 8 and 9 (4 : 1). Selective cleavage of the triethylsilyl ethers
using tetrabutylammonium fluoride at À78 1C and mesylation
of the C5 alcohol allowed the separation of diastereomers
10 and 12. The configuration at C5 was determined by
comparison of the attempted epoxidation of diastereomers
10 and 12. Only isomer 10 with the a-mesylate gave the
corresponding C4,5-epoxide upon treatment with DBU. The
C4 hydroxyl group in both isomers was acylated to give
p-trifluoromethylbenzoates 11 and 13. Diastereomers 11 and 13
were subjected to reductive elimination. The C5-acetoxy deriva-
tive 14, instead of the mesylate, and p-trifluoromethyl benzoate 15
shown in Table 1 were also prepared from 8 and 9, respectively.
Results of the reductive olefination8,10,15 at the C4–C5
position are listed in Table 1. When a-mesylate 11 was treated
with 2.5 molar equivalents of SmI2 in THF at À15 1C, 11
disappeared within 6 min. Work up and rapid purification
afforded enediyne 16 and its cycloaromatized product 17 in
60% combined yield (entry 1). Once the labile 9-membered
enediyne 16 was formed, 16 underwent cycloaromatization
and deterioration as in natural products.2 The ratio of 16 and
17 after chromatographic purification was estimated to be ca.
3 : 2 by 1H NMR spectroscopic analysis. It was less dependent
on the reaction conditions than the period spent on work up
and purification. The decomposition rate of 16 was also
estimated (t1/2 = 46 min at 24 1C in CDCl3).16 Excess use of
SmI2 (10 mol eq.) caused decomposition of substrate 11 even if
the reaction was conducted at À78 1C. On the other hand,
Synthesis of the 9-membered epoxydiyne precursors for the
crucial SmI2 mediated reduction was initiated by the transfor-
mation of an enantioselectively prepared cyclopentene moiety
26b to an alkynyl epoxide structure (Scheme 1). Oxidation of
diol 2 by SO3Ápyridine gave an a-hydroxyaldehyde. Addition
of ethynyl Grignard reagent to the aldehyde in CH2Cl2–THF
(10 : 1) proceeded diastereoselectively and the alkynyl alcohol
3 was obtained as a single diastereomer.12 Selective mesylation
of the newly formed secondary alcohol and subsequent treat-
ment with DBU provided the desired cis-epoxide 4 after
C-silylation of the alkyne terminus. The geometry of the
C8,9-epoxide was unambiguously determined by the NOE
correlation between H8 and H10. Hagihara–Sonogashira
a Department of Chemistry, Graduate School of Science, Tohoku
University, Sendai 980-8578, Japan.
E-mail: hirama@mail.tains.tohoku.ac.jp; Fax: +81-22-795-6566
b Research and Analytical Center for Giant Molecules, Graduate
School of Science, Tohoku University, Japan.
E-mail: isato@mail.tains.tohoku.ac.jp
w Electronic supplementary information (ESI) available: Experimental
details and characterisation data. See DOI: 10.1039/b814595d
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Scheme 1 Reagents and conditions. (a) SO3Ápyridine, Et3N, DMSO, CH2Cl2; (b) ethynyl Grignard reagent, CH2Cl2, THF, 0 1C; (c) MsCl, Et3N,
CH2Cl2, À45 1C then DBU, 0 1C; (d) TMSCl, LiN(TMS)2, THF, À30 1C, 44% (4 steps); (e) Pd2(dba)3ÁCHCl3, CuI, i-Pr2NEt, DMF; (f) K2CO3,
MeOH, 72% (2 steps); (g) DDQ, H2O, CH2Cl2; (h) Dess–Martin periodinane, NaHCO3, CH2Cl2, 85% (2 steps); (i) CeCl3, LiN(TMS)2, THF, À20 1C,
58% (4 : 1); (j) Bu4NF, THF, À78 1C; (k) Ms2O, pyridine, CH2Cl2, 0 1C then separation; (l) p-CF3C6H4COCl, DMAP, CH2Cl2, 59% (3 steps) for 11,
19% (3 steps) for 13. Abbreviations. TBPS: tert-butyldiphenylsilyl; TMS: trimethylsilyl; MOM: methoxymethyl; TES: triethylsilyl; NAP:
2-naphthylmethyl; TFBz: p-trifluoromethybenzoyl; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinone.
Table 1 Chemoselective reductive olefination mediated by SmI2
were treated with excess 1,4-cyclohexadiene in CH2Cl2 (entry 3),
cycloaromatized 17 was isolated as the sole product. Observed
yields in the reductive elimination of 11 and 13 indicated
that the relative configuration of the leaving group at C5 did
not affect the efficiency of the elimination. The C5-acetate 14
and the C5-p-trifluoromethyl benzoate 15 were also found to
act as substrates for the SmI2 mediated reductive elimination
(entries 4 and 5), but the reaction rate of 14 was slower as
anticipated.
Thus, it is apparent that the electron transfer to the
C8,9-epoxide is slower than that to the p-trifluoromethyl-
benzoate, which generates a tertiary radical at C4. The second
electron transfer affords an anionic intermediate leading to the
conjugate enediyne via elimination of mesylate.8 The overall
procedure corresponds to the highly chemoselective and facile
reductive olefin formation from 1,2-diol derivatives under mild
conditions.
Substrate
16 + 17b
Yield (%)
In conclusion, we succeeded in the construction of the
epoxybicyclo[7.3.0]dodecadienediyne framework of the kedar-
cidin chromophore via 9-membered ring cyclization at the
C5–C6 position and subsequent SmI2 mediated reductive
olefination. The latter reduction shows unique chemo-
selectivity and the epoxide functionality survives under the
reaction conditions. Further studies towards the total synth-
esis of the kedarcidin chromophore utilizing the present
methodology are currently under investigation.
R1
R2
Entrya
Conditions
1
11
13
13
14
15
OMs
H
H
OAc
H
H
À15 1C, 6 min
À20 1C, 10 min
À20 1C, 10 min
0 1C, 17 min
60
72
59
53
50
2
OMs
OMs
H
3c
4
5
OTFBz
À15 1C, 8 min
a
b
For detailed reaction conditions, see ref. 17. For the ratio of 16 and
c
17, see text. After the completion of the reaction, products were
treated with excess 1,4-cyclohexadiene in CH2Cl2.
This work was supported financially by a Grant-in-Aid for
Specially Promoted Research from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) and
SORST, Japan Science and Technology Agency (JST).
treatment of the b-mesylate 13 with 2.5 mol eq. of SmI2 at
À20 1C afforded a mixture of enediyne 16 and its aromatized
product 17 in 72% yield (entry 2).17 When the crude products
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17 Typical experimental procedure for SmI2 mediated reductive ole-
fination. A 0.1 M THF solution of SmI2 was prepared from
samarium and diiodomethane according to the procedure reported
by Kagan (ref. 9b). To a solution of 13 (4.2 mg, 3.7 mmol) in
freshly distilled THF (0.64 mL) was added a solution of SmI2
(0.1 M, 90 ml, 9.1 mmol) at À20 1C. After stirring for 10 min, the
mixture was exposed to open air and diluted with diethyl ether. The
suspension was filtrated through pads of Celite and silica gel.
Concentration under reduced pressure and silica gel flash chroma-
tography (hexane–ethyl acetate) gave a mixture of enediyne 16 and
aromatized product 17 in a ratio of 3 : 2 (2.3 mg, 72% as a
combined yield).
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