Formal total synthesis of neocarzinostatin chromophore

Article abstract of DOI:10.1021/jo052031o

An efficient route to the neocarzinostatin chromophore aglycon has been developed. The present strategy involves a stereoselective intramolecular acetylide-aldehyde cyclization to form the C5-C6 bond, followed by efficient installation of α-epoxide, napht

Full text of DOI:10.1021/jo052031o

Formal Total Synthesis of Neocarzinostatin Chromophore
Shoji Kobayashi,*,†,‡ Makiko Hori,† Guang Xing Wang,† and Masahiro Hirama*,†
Departments of Chemistry, Graduate Schools of Science, Tohoku UniVersity, Sendai 980-8578, and
Osaka Prefecture UniVersity, Sakai 599-8531, Japan
koba@c.s.osakafu-u.ac.jp
ReceiVed September 28, 2005
An efficient route to the neocarzinostatin chromophore aglycon has been developed. The present strategy
involves a stereoselective intramolecular acetylide-aldehyde cyclization to form the C5-C6 bond, followed
by efficient installation of R-epoxide, naphthoate, and carbonate functionalities. The C8-C9-olefin was
introduced by using the Martin sulfurane dehydration reaction to furnish the highly reactive aglycon.
Introduction
naphthoate intercalator, a 2′-methylamino sugar, and an epoxy
bicyclo[7,3,0]dodecadienediyne core (Figure 1).7 The naked
chromophore is highly sensitive to light,8 heat,9 base,10 and
nucleophiles11 and readily undergoes cycloaromatization to
generate bioactive diradical species.1c,12 This chemical instabil-
ity, complex structure, and fascinating mode of action make 1
a challenging target for total synthesis.
Neocarzinostatin (NCS), the first enediyne antibiotic,1 was
isolated from a culture of Streptomyces carzinostaticus var. F-41
in 1965.2 Its potent antibacterial and antitumor activities derive
from the inhibition of DNA synthesis and DNA degradation in
cells.3 The poly(styrene-maleic acid)-NCS conjugate, namely,
SMANCS, shows promising clinical activity against primary
hepatocellular carcinoma.3c,4 NCS is composed of a very
unstable chromophore5 and a carrier apoprotein.6 The bioactive
small molecular chromophore (NCS-chr, 1) consists of a
(6) (a) Crystal structure of NCS: Kim, K.-H.; Kwon, B.-M.; Myers, A.
G.; Rees, D. C. Science 1993, 262, 1042-1046. (b) Solution structure of
NCS: Tanaka, T.; Hirama, M.; Fujita, K.; Imajo, S.; Ishiguro, M. J. Chem.
Soc., Chem. Commun. 1993, 1205-1207.
(7) (a) Chromophore structure: Edo, K.; Mizugaki, M.; Koide, Y.; Seto,
H.; Furihata, K.; Otake, N.; Ishida, N. Tetrahedron Lett. 1985, 26, 331-
334. (b) Carbohydrate stereochemistry: Edo, K.; Akiyama, Y.; Saito, K.;
Mizugaki, M.; Koide, Y.; Ishida, N. J. Antibiot. 1986, 39, 1615. (c)
Chromophore stereochemistry: Myers, A. G.; Proteau, P. J.; Handel, T.
M. J. Am. Chem. Soc. 1988, 110, 7212-7214.
(8) (a) Uesawa, Y.; Kuwahara, J.; Sugiura, Y. Biochem. Biophys. Res.
Commun. 1989, 164, 903-911. (b) Gomibuchi, T.; Fujiwara, K.; Nehira,
T.; Hirama, M. Tetrahedron Lett. 1993, 36, 5753-5756. (c) Gomibuchi,
T.; Hirama, M. J. Antibiot. 1995, 48, 738-740.
(9) Edo, K.; Akiyama-Murai, Y.; Saito, K.; Mizugaki, M.; Koide, Y.;
Ishida, N. J. Antibiot. 1988, 41, 1272.
(10) (a) Hensens, O. D.; Helms, G. L.; Zink, D. L.; Chin, D.-H.; Kappen,
L. S.; Goldberg, I. H. J. Am. Chem. Soc. 1993, 115, 11030-11031. (b)
Stassinopoulos, A.; Ji, J.; Gao, X.; Gordberg, I. H. Science 1996, 272, 1943-
1946.
(11) (a) Myers, A. G. Tetrahedron Lett. 1987, 28, 4493-4496. (b)
Tanaka, T.; Fujiwara, K.; Hirama, M. Tetrahedron Lett. 1990, 31, 5947-
5950. (c) Fujiwara, K.; Sakai, H.; Tanaka, T.; Hirama, M. Chem. Lett. 1994,
457. (d) Sugiyama, H.; Yamashita, K.; Fujiwara, T.; Saito, I. Tetrahedron
1994, 50, 1311-1325. (e) Myers, A. G.; Arvedson, S. P.; Lee, R. W. J.
Am. Chem. Soc. 1996, 118, 4725-4726.
(12) (a) Goldberg, I. H. Acc. Chem. Res. 1991, 24, 191-198. (b)
Sugiyama, H.; Fujiwara, T.; Kawabata, H.; Yoda, N.; Hirayama, N.; Saito,
I. J. Am. Chem. Soc. 1992, 114, 5573-5578 and references therein.
* To whom correspondence should be addressed. Phone: +81-72-254-9698.
Fax: +81-72-254-9698.
† Tohoku University.
‡ Osaka Prefecture University.
(1) Reviews on enediyne antibiotics: (a) Nicolaou, K. C.; Dai, W.-M.
Angew. Chem., Int. Ed. Engl. 1991, 30, 1387-1416. (b) Grissom, J. W.;
Gunawardena, G. U.; Klingberg, D.; Huang, D. Tetrahedron 1996, 52,
6453-6518. (c) Xi, Z.; Goldberg, I. H. DNA-damaging Enediyne Com-
pounds. In ComprehensiVe Natural Products Chemistry; Barton, S. D.,
Nakanishi, K., Meth-Cohn, O., Eds.; Pergamon: Oxford, 1999; Vol. 7, pp
553-592.
(2) Ishida, N.; Mizugaki, K.; Kumagai, K.; Rikimaru, M. J. Antibiot.
1965, 18, 68.
(3) (a) Ono, Y.; Yatanabe, Y.; Ishida, N. Biochim. Biophys. Acta 1966,
119, 46-58. (b) Beerman, T. A.; Goldberg, I. H. Biochem. Biophys. Res.
Commun. 1974, 59, 1254-1261. (c) Neocarzinostatin, The Past, Present,
and Future of an Anticancer Drug, Maeda, H., Edo, K., Ishida, N., Eds.;
Springer: Tokyo, 1997.
(4) (a) Maeda, H. AdV. Drug DeliVery ReV. 1991, 6, 181-202. (b) Maeda,
H. AdV. Drug DeliVery ReV. 2001, 46, 169-185.
(5) Isolation of the chromophore: (a) Napier, M. A.; Holmquist, B.;
Strydom, D. J.; Goldberg, I. H. Biochem. Biophys. Res. Commun. 1979,
89, 635-642. (b) Koide, Y.; Ishii, F.; Hasuda, K.; Koyama, Y.; Edo, K.;
Katamine, S.; Kitame, F.; Ishida, N. J. Antibiot. 1980, 33, 342.
10.1021/jo052031o CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/20/2005
636
J. Org. Chem. 2006, 71, 636-644

Total Synthesis of Neocarzinostatin Chromophore
We therefore considered aglycon 2 a valuable synthetic target
for further developing NCS-chr (1). Herein we report a synthesis
of 2, featuring convergent assembly of the functionalized
cyclopentenone with the acetylenic fragment, followed by
stereoselective intramolecular acetylide-aldehyde cycliza-
tion18,19 between the C5 and C6 positions14b,20 (Figure 1). The
crucial C8-C9-olefin was efficiently installed in the final stage
by dehydration of the C9-tertiary alcohol.
Results and Discussion
Nine-Membered Ring Closure. The synthesis began with
the optically active (1R,4S,5S)-4,5-bis(methoxymethoxy)-2-
cyclopenten-1-ol (3), which was readily prepared on a large scale
from commercially available methyl D-glucopyranoside by
recently developed RCM technology21,22 (Scheme 1). Before
further details of the synthesis are presented, it should be
emphasized that the highly oxygenated nature of several
intermediates required an elaborate protecting group strategy.
Thus, the hydroxyl group of 3 was protected as the acid-stable
TBDPS ether, and the MOM ethers were cleaved selectively in
the presence of a catalytic amount of ZrCl4.23 Other deprotection
conditions, including the use of alkylboron bromide or PPTS
in t-BuOH, gave disappointing results. Selective oxidation of
the allylic alcohol with MnO2 afforded the R-hydroxy enone 4.
Despite its moderate sensitivity under oxidative conditions, the
MPM ether was determined to be the most appropriate protecting
group of the C10-alcohol moiety due to its robustness to basic,
nucleophilic, and mildly acidic conditions. However, because
of the chemical instability of enone 4 under both acidic and
basic conditions, it was necessary to employ 4-methoxybenzyl
2,2,2-trichloroacetimidate24 at low temperature to install the
MPM group. Subsequent R-iodination25 afforded the Sonogash-
ira coupling precursor 5.
FIGURE 1. Structure of the neocarzinostatin chromophore and the
strategy for the synthesis of the aglycon.
Although many notable synthetic approaches in this area have
been reported,13 total synthesis of the nine-membered enediyne
natural product has been elusive.14,15 With respect to the NCS-
chr (1), only one successful total synthesis has been achieved
by Myers and co-workers.16 Their synthesis involves the
stereocontrolled glycosidic coupling between the 2′-methylamino
sugar and the labile aglycon 2 in unprotected form.16b,c This
highly practical methodology avoids the need for protecting the
2′-methylamino group and minimizes synthetic manipulations
after installation of the labile enediyne functionality. Further-
more, aglycon 2 serves as a viable substrate for glycosylation;
the fucosyl analogue and the radiolabeled NCS-chr can both
be prepared by introducing the suitable glycoside into 2.16c,17
Parallel synthetic studies had suggested that slightly harsh
conditions were required to remove the acetonide group of the
(17) Myers, A. G.; Liang, J.; Hammond, M. Tetrahedron Lett. 1999,
40, 5129-5133.
(13) For construction of the nine-membered diyne systems, see: (a)
Wender, P. A.; Harmata, M.; Jeffrey, 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) Doi, T.; Takahashi, T. J.
Org. Chem. 1991, 56, 3465-3467. (d) Tanaka, H.; Yamada, H.; Matsuda,
A.; Takahashi, T. Synlett 1997, 4, 381-383. (e) Magnus, P.; Carter, R.;
Davies, M.; Elliott, J.; Pitterna, T. Tetrahedron 1996, 52, 6283-6306. (f)
Myers, A. G.; Harrington, P. M.; Kuo, E. Y. J. Am. Chem. Soc. 1991, 113,
694-695. (g) Myers, A. G.; Goldberg, S. D. Angew. Chem., Int. Ed. 2000,
39, 2732-2735.
(18) (a) Iida, K.; Hirama, M. J. Am. Chem. Soc. 1994, 116, 10310-
10311. (b) Sato, I.; Akahori, Y.; Iida, K.; Hirama, M. Tetrahedron Lett.
1996, 37, 5135-5138. (c) Kawata, S.; Yoshimura, F.; Irie, J.; Ehara, H.;
Hirama, M. Synlett 1997, 250-252. (d) Das, P.; Mita, T.; Lear, M. J.;
Hirama, M. Chem. Commun. 2002, 2624-2625. (e) Mita, T.; Kawata, S.;
Hirama, M. Chem. Lett. 1998, 959-960. (f) Myers, A. G.; Harrington, P.
M.; Kuo, E. Y. J. Am. Chem. Soc. 1991, 113, 694-695. (g) Myers, A. G.;
Harrington, P. M.; Kwon, B.-M. J. Am. Chem. Soc. 1992, 114, 1086-
1087.
(14) (a) Total synthesis of N1999-A2: Kobayashi, S.; Reddy, R. S.;
Sugiura, Y.; Sasaki, D.; Miyagawa, N.; Hirama, M. J. Am. Chem. Soc. 2001,
123, 2887-2888. (b) Kobayashi, S.; Ashizawa, S.; Takahashi, Y.; Sugiura,
Y.; Nagaoka, M.; Lear, M. J.; Hirama, M. J. Am. Chem. Soc. 2001, 123,
11294-11295. (c) Synthesis of the kedarcidin chromophore aglycon:
Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem.,
Int. Ed. 2002, 41, 1062-1067.
(19) For leading examples of intramolecular acetylide-aldehyde cy-
clizations to construct 10-membered enediynes, see: (a) Kende, A. S.; Smith,
C. A. Tetrahedron Lett. 1988, 29, 4217-4220. (b) Cabal, M. P.; Coleman,
R. S.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 3253-3255.
(20) (a) Sato, I.; Toyama, K.; Kikuchi, T.; Hirama, M. Synlett 1998,
1308-1310. (b) Inoue, M.; Hatano, S.; Kodama, M.; Sasaki, T.; Kikuchi,
T.; Hirama, M. Org. Lett. 2004, 6, 3833-3836. (c) Inoue, M.; Sasaki, T.;
Hatano, S.; Hirama, M. Angew. Chem., Int. Ed. 2004, 43, 6500-6505. (d)
Inoue, M.; Kikuchi, T.; Hirama, M. Tetrahedron Lett. 2004, 45, 6439-
6442.
(15) Total syntheses of 10-membered enediyne antibiotics have been
I
reported. (a) Calicheamicin γ1 : Nicolaou, K. C.; Hummel, C. W.; Nakada,
M.; Shibayama, K.; Pitsinos, E. N.; Saimoto, H.; Mizuno, Y.; Baldenius,
K.-U.; Smith, A. L. J. Am. Chem. Soc. 1993, 115, 7625-7635. (b)
Hitchcock, S. A.; Chu-Moyer, M. Y.; Boyer, S. H.; Olson, S. H.;
Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 5750-5756. (c) Dynemicin
A: Shair, M. D.; Yoon, T.-Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S.
J. J. Am. Chem. Soc. 1996, 118, 9509-9525. (d) Myers, A. G.; Tom, N. J.;
Fraley, M. E.; Cohen, S. B.; Madar, D. J. J. Am. Chem. Soc. 1997, 119,
6072-6094.
(21) Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.;
Hirama, M. Org. Lett. 2005, 7, 267-270.
(22) For our previous synthesis of chiral trihydroxylated cyclopentenes
akin to 3, see: (a) Toyama, K.; Iguchi, S.; Oishi, T.; Hirama, M. Synlett
1995, 1243-1244. (b) Toyama, K.; Iguchi, S.; Sakazaki, H.; Oishi, T.;
Hirama, M. Bull. Chem. Soc. Jpn. 2001, 74, 997-1008.
(23) Sharma, G. V. M.; Reddy, K. L.; Lakshmi, P. S.; Krishna, P. R.
Tetrahedron Lett. 2004, 45, 9229-9232.
(16) (a) Myers, A. G.; Hammond, M.; Wu, Y.; Xiang, J.-N.; Harrington,
P. M.; Kuo, E. Y. J. Am. Chem. Soc. 1996, 118, 10006-10007. (b) Myers,
A. G.; Liang, J.; Hammond, 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.
(24) Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.; Danishefsky,
S. J. J. Org. Chem. 1989, 54, 3738-3740.
(25) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.;
Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917-
918.
J. Org. Chem, Vol. 71, No. 2, 2006 637

Kobayashi et al.
SCHEME 1. Construction of the Nine-Membered Ring
C13,C14-diol in the right half of the molecule.14a,b Heeswijk et
al. showed that cyclopentylidene ketals of 1,2-diols tend to be
3 times more susceptible to acid-catalyzed hydrolysis than their
corresponding acetonides.26 Therefore, the C13,C14-diol moiety
of the acetylenic fragment 627 was protected as its cyclopen-
tylidene ketal prior to coupling. Palladium-catalyzed coupling28
between 5 and 6, followed by TES protection, afforded the
expected enyne 7 in high yield. Addition of propargylmagnesium
bromide to 7 proceeded quantitatively, but in a nonstereose-
lective manner. During this transformation, partial loss of
pivaloyl ester was observed. Therefore, the crude products were
treated with PivCl without purification to yield a separable
mixture of 9R- and 9S-isomers (8 and 9) in a 1.2:1 ratio.
Interestingly, the proportion of the 9R-isomer (8) in the present
case was less than that reported previously,20a and there was
no significant change in product ratio upon addition of ZnCl2.29
It was thought that the protecting groups on the cyclopentenone
moiety played an important role in defining the selectivity of
the Grignard addition. Since NOE data were inconclusive, the
stereochemistry of the C9-tertiary alcohol of 9 was determined
by derivatization to its MP-acetal 10 upon anhydrous DDQ
treatment.
trans-alcohol 14 as a single stereoisomer in 73% yield. The
remarkable trans-selectivity observed in 14 was consistent with
a number of previous results14b,18a-d,20a-c and presumably arose
via the energetically favored transition state 13, in which the
cerium-chelated carbonyl oxygen is sterically remote from the
neighboring TES group. Furthermore, it should be pointed out
that the corresponding 9S-isomer derived from 9 was inactive
to the nine-membered ring closure, another strong indication
that the relative stereochemistry of the precursors is responsible
for efficient cyclization.14a,b,18a,b
Synthesis of the Neocarzinostatin Chromophore Aglycon.
On the basis of previous research, the C4,C5-epoxide was
strategically constructed by taking advantage of the different
reactivities of the three TES groups in 14 under fluoride-
mediated deprotection conditions (Scheme 2).14b Treatment of
14 with MsCl provided the corresponding mesylate, which was
exposed to 2 equiv of TBAF at -35 °C to afford the desired
epoxide 16 as a major product. The minor diol intermediate 15
was readily converted into 16 by potassium carbonate in EtOH.
Importantly, the C9-O(TES) group was left untouched during
these selective deprotection and tandem epoxidation steps,
thereby allowing the manipulations which followed. Alcohol
16 thus obtained was condensed with naphthoic acid (17)32
without concern for bisnaphthoate formation.14b Further inves-
tigation revealed that the C9-hydroxyl group must be protected
during the next carbonate formation step; otherwise the desired
carbonate was formed in less than 35% yield. To overcome this
inefficiency, selective conditions to cleave the cyclopentylidene
ketal in the presence of the acid-labile TES and epoxide
functionalities were investigated. It was found that the cyclo-
pentylidene group could be removed selectively upon treatment
with dilute aqueous hydrofluoric acid in CH3CN to give the
desired triol 18 in 69% yield. Facile carbonate formation could
Sequential protecting group manipulation and oxidation30 of
8 provided the key cyclization precursor 12. The 9R-configured
aldehyde 12 underwent ring closure smoothly using the CeCl3/
LiN(TMS)2-mediated cyclization protocol31 to afford the C4,C5-
(26) van Heeswijk, W. A. R.; Goedhart, J. B.; Vliegenthart, J. F. G.
Carbohydr. Res. 1977, 58, 337-344.
(27) (a) Nakatani, K.; Arai, K.; Hirayama, N.; Matsuda F.; Terashima,
S. Tetrahedron 1992, 48, 633-650. (b) Kobayashi, S.; Das, P.; Wang, G.
X.; Mita, T.; Lear, M. J.; Hirama, M. Chem. Lett. 2002, 300-301.
(28) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
50, 4467-4470.
(29) Tanaka, H.; Yamada, H.; Matsuda, A.; Takahashi, T. Synlett 1997,
381-383.
(30) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(31) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392-4398.
(32) (a) Takahashi, K.; Suzuki, T.; Hirama, M. Tetrahedron Lett. 1992,
33, 4603-4604. (b) Takahashi, K.; Tanaka, T.; Suzuki, T.; Hirama, M.
Tetrahedron 1994, 50, 1327-1340.
638 J. Org. Chem., Vol. 71, No. 2, 2006

Total Synthesis of Neocarzinostatin Chromophore
SCHEME 2. Completion of the NCS-chr Aglycon
then be realized, forming 20 after removal of the C9-O(TES)
group (66% yield in two steps). In view of the instability of
aglycon 2, it was advisable at this stage to cleave the MPM
ether.14a,b The MPM group in 20 was replaced by a TES group
via DDQ oxidation and selective protection. In contrast to the
behavior of the C10-deoxy substrate, which underwent dehydra-
tion at 0 °C,14b alcohol 21 remained unaltered upon treatment
with a large excess of Ms2O, Et3N, and DMAP; only incomplete
formation of the C9-mesylate resulted. Addition of DBU to the
resulting mesylate led to rapid decomposition, while other
dehydration conditions including Tf2O and 2,6-lutidine14a were
not effective. The steric hindrance due to the C10-O(TES) and
the C11-naphthoate groups is likely to inhibit such dehydrations.
After numerous trials, the desired enediyne 22 was finally
obtained by using the Martin sulfurane dehydrating reagent.33
Remarkably, the reaction proceeded quantitatively as determined
by NMR within 5 min at room temperature. The protected
aglycon 22 was found to be stable to silica gel but rapidly
decomposed in neat form. The final deprotection was carefully
achieved with a system of TFA-THF-H2O (1:10:5) to furnish
the highly unstable aglycon 2. TLC monitoring of the reaction
indicated that clean deprotection occurred, but the purified
aglycon 2 was extremely sensitive to concentration and degraded
much more rapidly than the protected aglycon 22, both in
solution and, especially, in neat form. It seems likely that the
bulkiness of the protecting groups again contributed to the
stability of the chromophore core.34 All spectroscopic data of
synthetic 2 were identical to those reported in the literature.16a
In addition, the high-resolution mass spectrum (ESI-FT-ICR-
MS (m/z) [M + Na]+, calcd for C28H20NaO9 523.1000, found
523.1002) was obtained. An efficient conversion of aglycon 2
to NCS-chr (1) has previously been accomplished by Myers’
group.16b,c
Conclusion
An efficient route to the neocarzinostatin chromophore
aglycon was developed. The present synthesis involves con-
vergent assembly of the functionalized cyclopentenone with the
acetylenic fragment, followed by stereocontrolled nine-mem-
bered ring closure. After introduction of epoxide, naphthoate,
and carbonate functionalities, a central dienediyne system was
elaborated by using sulfurane-mediated dehydration reaction.
A highly efficient protecting group strategy was also developed
to access the sensitive substrate.
Experimental Section
Enone 4. To a solution of allyl alcohol 3 (11.0 g, 54.1 mmol) in
DMF (54 mL) were added imidazole (9.21 g, 135 mmol) and
(TBDPS)Cl (15.2 mL, 59.5 mmol). The mixture was stirred for 6
h at room temperature and poured into water. The resulting mixture
was extracted with hexane (2×), and the combined organic layer
was washed with brine and dried over anhydrous Na2SO4. Con-
centration of the solution gave the corresponding TBDPS ether (19.9
g), which was subjected to the next reaction without purification:
1H NMR (500 MHz, CDCl3) δ 1.09 (s, 9H), 3.39 (s, 3H), 3.42 (s,
3H), 4.30 (t, 1H, J ) 4.3 Hz), 4.37 (br s, 1H), 4.69 (br s, 1H), 4.73
(d, 1H, J ) 7.0 Hz), 4.75 (d, 1H, J ) 7.0 Hz), 4.75 (d, 1H, J ) 7.0
Hz), 4.81 (d, 1H, J ) 7.0 Hz), 5.58 (d, 1H, J ) 6.5 Hz), 5.76 (d,
1H, J ) 6.5 Hz), 7.38-7.45 (m, 6H), 7.71-7.77 (m, 4H); 13C NMR
(125 MHz, CDCl3) δ 19.5, 27.2, 55.7, 56.0, 81.0, 85.1, 91.9, 96.5
(2C), 127.9, 128.0, 130.0, 130.1, 131.9, 133.8, 134.5, 135.1, 136.2,
136.2; FT-IR (neat) ν 3017, 2932, 2891, 2858, 2823, 1962, 1894,
(33) (a) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1982, 104, 1116-
1118. (b) Myers et al. also succeeded in introducing the C12-C1-olefin
using the Martin sulfurane: see ref 16.
(34) Myers, A. G.; Kort, M. E.; Hammond, M. J. Am. Chem. Soc. 1997,
119, 2965-2972.
1827, 1589, 1471, 1428, 1369, 1307, 1261, 1212 cm-1
.
To a solution of the above TBDPS ether (19.9 g) in iPrOH (98
mL) was added ZrCl4 (1.14 g, 4.89 mmol) at 90 °C. The mixture
J. Org. Chem, Vol. 71, No. 2, 2006 639

Kobayashi et al.
was stirred for 4.5 h at 90 °C and cooled to 0 °C. The reaction
mixture was filtered through a pad of Celite, and the filtrate was
concentrated. The residue was purified by column chromatography
(Florisil, hexane-hexane/AcOEt ) 1) to give the corresponding
diol (12.5 g, 35.2 mmol, 65% in two steps) as a colorless oil:
1352, 1302, 1248 cm-1; HR-ESI-FT-ICR-MS (m/z) [M + Na]+,
calcd for C29H31NaIO4Si 621.0929, found 621.0930.
Cyclopentylidene Ketal 6. To a solution of (2S)-2-hydroxy-2-
[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-butyn-1-yl 2,2-dimethyl-
propanoate27 (0.219 g, 0.810 mmol) in MeOH (8.1 mL) was added
TsOH‚H2O (15.4 mg, 81.0 µmol). The mixture was stirred for 4 h
at room temperature and concentrated. The residue was dissolved
in MeOH (8.1 mL) and stirred for another 5 h at room temperature.
After concentration, 1,1-dimethoxycyclopentane (213 µL, 1.62
mmol) and cyclopentanone (3.5 mL) were added, and the mixture
was stirred for 30 min at room temperature. The reaction mixture
was quenched with Et3N (500 µL) followed by saturated NaHCO3
solution and extracted with AcOEt (2×). The combined organic
layer was washed with brine and dried over anhydrous MgSO4.
After concentration, the remaining cyclopentanone was distilled out
azeotropically with toluene. The residue was purified by flash
column chromatography (silica gel, hexane/AcOEt ) 8 to 6 to 5)
to give cyclopentylidene ketal 6, which was further purified by
recrystallization from hexane to afford 6 (0.138 g, 0.510 mmol,
30.0
1
[R]D
-9.0° (c 0.442, CHCl3); H NMR (500 MHz, CDCl3) δ
1.08 (s, 9H), 4.05 (br s, 1H), 4.35 (br s, 1H), 4.52 (br s, 1H), 5.70
(br d, 1H, J ) 6.5 Hz), 5.73 (br d, 1H, J ) 6.5 Hz), 7.39-7.45 (m,
6H), 7.67-7.75 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 19.3,
27.0, 80.2, 82.0, 89.8, 128.0, 128.1, 130.1, 130.2, 133.0, 133.7,
134.1, 134.5, 135.9; FT-IR (neat) ν 3362, 3071, 2931, 2858, 1471,
1427, 1362 cm-1; MALDI-TOF-MS (m/z) [M + Na]+, calcd for
C21H26NaO3Si 377.1549, found 377.1529.
To a solution of the above diol (7.60 g, 21.4 mmol) in CH2Cl2
(428 mL) was added MnO2 (27.9 g, 321 mol). The mixture was
stirred for 7 h at room temperature and filtered. The filter cake
was washed with hexanes-EtOAc, and the filtrate was concentrated.
The residue was purified by flash column chromatography (silica
gel, hexane/AcOEt ) 3.4) to give enone 4 (5.07 g, 14.4 mmol,
67%) as a pale yellow oil: [R]D30.0 +6.6° (c 2.36, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 1.12 (s, 9H), 2.46 (br s, 1H), 4.29 (br s, 1H),
4.76 (br d, 1H, J ) 1.5 Hz), 6.15 (dd, 1H, J ) 6.5, 1.0 Hz), 7.16
(dd, 1H, J ) 6.5, 1.8 Hz), 7.36-7.49 (m, 6H), 7.71-7.76 (m, 4H);
13C NMR (125 MHz, CDCl3) δ 19.3, 26.9, 27.0, 78.1, 81.7, 127.7,
127.8, 127.9, 127.9, 128.0, 130.3, 130.3, 131.5, 132.8, 133.4, 135.8,
135.9, 136.0, 161.0, 203.9; FT-IR (neat) ν 3436, 3071, 2932, 2892,
2858, 1729, 1472, 1427, 1363 cm-1; HR-ESI-FT-ICR-MS (m/z)
[M + Na]+, calcd for C21H24NaO3Si 375.1387, found 375.1387.
28.0
63%) as colorless needles: mp 102-103 °C (hexane); [R]D
1
+21.7° (c 1.00, CHCl3); H NMR (500 MHz, CDCl3) δ 1.25 (s,
9H), 1.67-1.70 (m, 4H), 1.74-1.77 (m, 2H), 1.87-1.95 (m, 2H),
2.49 (s, 1H), 3.03 (s, 1H), 4.05 (dd, 1H, J ) 7.3, 5.8 Hz), 4.12 (t,
1H, J ) 5.3 Hz), 4.14 (dd, 1H, J ) 7.3, 5.3 Hz), 4.19 (d, 1H, J )
12 Hz), 4.40 (d, 1H, J ) 12 Hz); 13C NMR (125 MHz, CDCl3) δ
23.4, 23.9, 27.3, 36.1, 36.4, 39.1, 65.9, 68.0, 71.7, 74.9, 77.6, 81.4,
120.5, 179.1; FT-IR (KBr) ν 3443, 3270, 2945, 1708, 1669, 1541,
1475 cm-1. Anal. Calcd for C16H24O5: C, 64.84; H, 8.16. Found:
C, 64.83; H, 8.28.
Iodide 5. To a solution of enone 4 (4.09 g, 11.6 mmol) in CH2-
Cl2 (116 mL) were added 4-methoxybenzyl 2,2,2-trichloroacet-
imidate (4.92 g, 17.4 mmol) and BF3‚Et2O (147 µL, 1.16 µmol) at
-65 °C. The mixture was stirred for 1.5 h at -65 °C and quenched
with saturated NaHCO3 solution. The resulting mixture was
extracted with AcOEt (2×), and the combined organic layer was
washed with brine and dried over anhydrous MgSO4. After
concentration, the residue was purified by flash column chroma-
tography (silica gel, hexane/AcOEt ) 12 to 10 to 8 to 5 to 3 to 2)
to give the corresponding MPM ether (2.81 g, 5.95 mmol, 51%)
Enone 7. A mixture of iodide 5 (3.09 g, 5.17 mmol), acetylenic
fragment 6 (1.84 g, 6.20 mmol), and CuI (0.394 g, 2.07 mmol)
was dissolved in DMF (50 mL). To the solution were added iPr2-
NEt (2.70 mL, 15.5 mmol) and (Ph3P)4Pd (0.598 g, 0.517 mmol),
and the mixture was stirred for 1 h at room temperature. The
reaction mixture was diluted with hexane-AcOEt and quenched
with saturated NH4Cl solution. The resulting mixture was extracted
with AcOEt (2×), and the combined organic layer was washed with
brine and dried over anhydrous MgSO4. After concentration, the
residue was purified by flash column chromatography (silica gel,
hexane/AcOEt ) 5 to 4 to 3 to 2 to 1) to give the coupling product
(3.86 g, 5.03 mmol, 97%) as a yellow oil: [R]D27.0 -21.0° (c 1.00,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.07 (s, 9H), 1.21 (s, 9H)
1.61-1.70 (m, 4H), 1.72-1.77 (m, 2H), 1.78-1.90 (m, 2H), 3.39
(s, 1H), 3.81 (s, 3H), 4.04 (dd, 1H, J ) 11, 9.0 Hz), 4.09-4.13
(m, 2H), 4.16 (d, 1H, J ) 2.5 Hz), 4.18 (d, 1H, J ) 11 Hz), 4.40
(d, 1H, J ) 11 Hz), 4.56 (d, 1H, J ) 11 Hz), 4.84 (t, 1H, J ) 2.5
Hz), 4.89 (d, 1H, J ) 11 Hz), 6.85 (d, 2H, J ) 8.5 Hz), 7.04 (d,
1H, J ) 2.5 Hz), 7.22 (d, 2H, J ) 8.5 Hz), 7.35-7.39 (m, 4H),
7.43-7.46 (m, 2H), 7.64-7.69 (m, 4H); FT-IR (neat) ν 3437, 3072,
2960, 1731, 1613, 1588, 1514, 1471, 1428, 1395, 1337, 1283, 1249
cm-1; MALDI-TOF-MS (m/z) [M + Na]+, calcd for C45H54NaO9-
Si 789.3435, found 789.3447.
To a solution of the above coupling product (1.98 g, 2.58 mmol)
in CH2Cl2 (26 mL) were added 2,6-lutidine (1.80 mL, 15.5 mmol)
and (TES)OTf (1.16 mL, 5.16 mmol) at -70 °C. The mixture was
stirred for 40 min at -70 °C and quenched with saturated NaHCO3
solution. The resulting mixture was extracted with hexane (2×),
and the combined organic layer was washed with brine and dried
over anhydrous Na2SO4. After concentration, the residue was
purified by flash column chromatography (silica gel, hexane-
hexane/AcOEt ) 25 to 20) to give TES ether 7 (2.27 g, 2.58 mmol,
100%) as a colorless oil: [R]D27.0 -31.9° (c 0.66, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 0.67 (q, 6H, J ) 8.0 Hz), 0.92 (t, 9H, J )
8.0 Hz), 1.08 (s, 9H), 1.21 (s, 9H) 1.60-1.68 (m, 4H), 1.71-1.74
(m, 2H), 1.76-1.79 (m, 1H), 1.81-1.87 (m, 1H), 3.81 (s, 3H),
4.01 (dd, 1H, J ) 8.3, 6.8 Hz), 4.05 (dd, 1H, J ) 8.3, 5.8 Hz),
4.10 (d, 1H, J ) 11 Hz), 4.14 (t, 1H, J ) 6.3 Hz), 4.18 (d, 1H,
J ) 3.0 Hz), 4.31 (d, 1H, J ) 11 Hz), 4.59 (d, 1H, J ) 11 Hz),
4.86 (t, 1H, J ) 2.5 Hz), 4.92 (d, 1H, J ) 11 Hz), 6.86 (d, 2H, J
29.0
1
as a yellow oil: [R]D
-7.9° (c 1.07, CHCl3); H NMR (500
MHz, CDCl3) δ 1.09 (s, 9H), 3.81 (s, 3H), 4.16 (d, 1H, J ) 3.0
Hz), 4.58 (d, 1H, J ) 11 Hz), 4.89 (br s, 1H), 4.90 (d, 1H, J ) 11
Hz), 6.06 (br d, 1H, J ) 6.5 Hz), 6.86 (d, 2H, J ) 6.0 Hz), 7.05
(dd, 1H, J ) 6.0, 2.0 Hz), 7.24 (dd, 2H, J ) 6.5 Hz), 7.36-7.46
(m, 6H), 7.66-7.73 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 19.3,
27.0, 55.4, 71.6, 72.7, 77.0, 86.0, 113.9, 113.9, 128.0, 129.6, 129.8,
129.9, 130.2, 132.7, 132.8, 133.5, 135.9, 136.0, 159.5, 160.0, 203.5;
FT-IR (neat) ν 3071, 2999, 2932, 2858, 1963, 1888, 1727, 1613,
1587, 1514, 1463, 1428, 1391, 1361, 1327, 1302, 1248 cm-1
;
MALDI-TOF-MS (m/z) [M + Na]+, calcd for C29H32NaO4Si
495.1968, found 495.1990.
To a solution of the above MPM ether (3.02 g, 6.36 mmol) in
THF (64 mL) were added pyridine (1.54 mL, 19.1 mmol) and I2
(3.23 g, 12.7 mmol). The mixture was stirred for 30 min at room
temperature, diluted with Et2O, and quenched with saturated
Na2S2O3 solution. The resulting mixture was extracted with AcOEt
(2×), and the combined organic phase was washed with brine and
dried over anhydrous MgSO4. After concentration, the residue was
purified by flash column chromatography (silica gel, hexane/
AcOEt ) 20) to give iodide 5 (3.09 g, 5.17 mmol, 81%) as a
colorless oil: [R]D29.0 -61.0° (c 0.602, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 1.08 (s, 9H), 3.81 (s, 3H), 4.17 (d, 1H, J ) 2.5 Hz), 4.58
(d, 1H, J ) 11 Hz), 4.84 (t, 1H, J ) 2.5 Hz), 4.92 (d, 1H, J ) 11
Hz), 6.86 (d, 2H, J ) 8.0 Hz), 7.23 (d, 2H, J ) 9.0 Hz), 7.37-
7.40 (m, 4H), 7.45 (d, 1H, J ) 2.5 Hz), 7.45-7.48 (m, 2H), 7.65-
7.70 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 19.3, 26.9, 55.4,
72.7, 78.4, 83.4, 102.3, 113.9, 128.1, 128.1, 129.4, 130.1, 130.4,
130.4, 132.5, 133.0, 135.9, 135.9, 159.6, 165.7, 198.4; FT-IR (neat)
ν 3071, 2932, 2858, 1730, 1613, 1587, 1514, 1470, 1427, 1392,
640 J. Org. Chem., Vol. 71, No. 2, 2006

Total Synthesis of Neocarzinostatin Chromophore
) 8.5 Hz), 7.00 (d, 1H, J ) 2.5 Hz), 7.23 (d, 2H, J ) 8.5 Hz),
7.36-7.39 (m, 4H), 7.44-7.47 (m, 2H), 7.65-7.70 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 6.0, 7.1, 15.4, 19.3, 23.5, 23.8, 26.9,
27.3, 36.5, 36.6, 39.0, 53.6, 55.5, 66.0, 66.5, 67.6, 72.8, 73.0, 75.6,
77.6, 77.9, 85.7, 95.1, 113.9, 120.4, 127.7, 128.0, 128.1, 129.6,
130.0, 130.3, 130.4, 132.6, 133.2, 135.9, 136.0, 159.6, 160.2, 198.5;
FT-IR (neat) ν 3072. 2957, 2876, 1732, 1613, 1588, 1514, 1463,
1428, 1395, 1336, 1283, 1249 cm-1; MALDI-TOF-MS (m/z)
[M + Na]+, calcd for C51H68NaO9Si2 903.4300, found 903.4302.
Alcohols 8 and 9. To a suspension of magnesium turnings (1.46
g, 60.0 mmol) and mercury(II) chloride (5 mg) in Et2O (30 mL)
was slowly added a solution of propargyl bromide (3.56 mL, 40.0
mmol) in Et2O (10 mL) over 20 min at room temperature. The
mixture was refluxed for 1.5 h to give a 1.0 M solution of
propargylmagnesium bromide. To a solution of enone 7 (2.27 g,
2.58 mmol) in toluene (86 mL) was added the above propargyl-
magnesium bromide solution (5.16 mL, 5.16 mmol) at -78 °C.
The mixture was stirred for 15 min at -78 °C and quenched with
saturated NH4Cl solution. The resulting mixture was extracted with
hexanes-EtOAc (2×), and the combined organic layer was washed
with brine and dried over anhydrous Na2SO4. After concentration,
the residue was dissolved in pyridine (10 mL) and treated with
PivCl (396 µL, 3.22 mmol) and DMAP (∼5 mg). The mixture was
stirred for 17 h and concentrated. The residue was purified by flash
column chromatography (silica gel, hexane/EtOAc ) 20 to 10) to
give a less polar (9R)-alcohol, 8 (1.24 g, 1.34 mmol, 52%), and a
polar (9S)-alcohol, 9 (1.05 g, 1.14 mmol, 44%), as pale yellow
NMR (500 MHz, CDCl3) δ 0.64 (q, 6H, J ) 8.0 Hz), 0.65 (q, 6H,
J ) 8.0 Hz), 0.87 (t, 9H, J ) 8.0 Hz), 0.88 (t, 9H, J ) 8.0 Hz),
1.06 (s, 9H), 1.07 (s, 9H), 1.20 (s, 9H), 1.21 (s, 9H), 1.53-1.66
(m, 8H), 1.68-1.73 (m, 4H), 1.75-1.88 (m, 4H), 2.10 (t, 1H, J )
2.5 Hz), 2.10 (t, 1H, J ) 2.5 Hz), 2.74 (dd, 1H, J ) 17, 3.0 Hz),
2.87 (dd, 1H, J ) 17, 2.5 Hz), 3.05 (dd, 1H, J ) 17, 3.0 Hz), 3.10
(dd, 1H, J ) 17, 2.5 Hz), 3.76 (s, 3H), 3.80 (s, 3H), 3.99 (t, 1H,
J ) 6.5 Hz), 4.01 (t, 1H, J ) 6.5 Hz), 4.06 (t, 1H, J ) 6.5 Hz),
4.07 (t, 1H, J ) 6.5 Hz), 4.12 (d, 1H, J ) 11 Hz), 4.13 (t, 1H,
J ) 6.5 Hz), 4.14 (d, 1H, J ) 11 Hz), 4.14 (t, 1H, J ) 6.5 Hz),
4.32 (d, 1H, J ) 11 Hz), 4.33 (d, 1H, J ) 11 Hz), 4.66 (br s, 1H),
4.75 (br d, 1H, J ) 2.5 Hz), 4.75 (br s, 1H), 4.77 (d, 1H, J ) 2.5
Hz), 5.42 (s, 1H), 5.71 (dd, 1H, J ) 2.5, 1.0 Hz), 6.00 (dd, 1H,
J ) 2.5, 1.0 Hz), 6.07 (s, 1H), 6.79 (d, 2H, J ) 9.0 Hz), 6.86 (d,
2H, J ) 8.0 Hz), 7.25 (d, 2H, J ) 9.0 Hz), 7.35-7.47 (m, 14H),
7.62-7.69 (m, 8H); ESI-TOF-MS (m/z) [M + Na]+, calcd for
C54H70NaO9Si2 941.4456, found 941.4456.
TES Ether 11. To a solution of alcohol 8 (944 mg, 1.03 mmol)
in THF (10 mL) was added TBAF (1.0 M solution in THF, 2.56
mL, 2.56 mmol). The mixture was stirred for 1.5 h at room
temperature and concentrated. The residue was purified by flash
column chromatography (silica gel, hexane/AcOEt ) 2 to 1) to
give the corresponding triol (429 mg, 0.755 mmol, 74%) as a
colorless amorphous solid: [R]D27.0 -6.9° (c 2.35, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 1.25 (s, 9H), 1.63-1.76 (m, 6H), 1.92-1.96
(m, 2H), 2.04 (s, 1H), 2.64 (t, 2H, J ) 2.8 Hz), 3.18 (s, 1H), 3.58
(s, 1H), 3.80 (s, 3H), 3.89 (d, 1H, J ) 5.0 Hz), 4.04 (dd, 1H, J )
9.0, 7.0 Hz), 4.09 (dd, 1H, J ) 7.0, 3.3 Hz), 4.16 (d, 1H, J ) 12
Hz), 4.31 (dd, 1H, J ) 8.5, 3.3 Hz), 4.52 (d, 1H, J ) 11 Hz), 4.64
(d, 1H, J ) 12 Hz), 4.68 (dd, 1H, J ) 5.0, 1.5 Hz), 4.83 (d, 1H,
J ) 11 Hz), 6.04 (d, 1H, J ) 2.0 Hz), 6.89 (d, 2H, J ) 9.0 Hz),
7.34 (d, 2H, J ) 8.5 Hz); 13C NMR (125 MHz, CDCl3) δ 23.3, 23
8, 26.1, 27.3, 36.0, 36.0, 39.1, 55.4, 66.1, 67.7, 71.4, 72.2, 72.9,
77.1, 77.4, 79.5, 79.9, 83.5, 92.5, 93.9, 114.0, 120.7, 129.0, 129.5,
130.4, 138.2, 159.3, 179.2; FT-IR (film) ν 3417, 3307, 2961, 2875,
26.0
1
oils. Data for 8: [R]D
-28.9° (c 2.00, CHCl3); H NMR (500
MHz, CDCl3) δ 0.65 (q, 6H, J ) 7.8 Hz), 0.91 (t, 9H, J ) 7.8
Hz), 1.06 (s, 9H), 1.23 (s, 9H) 1.65-1.71 (m, 6H), 1.76 (t, 1H,
J ) 2.3 Hz), 1.90 (m, 2H), 2.47 (dd, 1H, J ) 16, 2.8 Hz), 2.59
(dd, 1H, J ) 16, 2.8 Hz), 3.34 (s, 1H), 3.81 (s, 3H), 4.00 (t, 1H,
J ) 6.5 Hz), 4.11-4.17 (m, 2H), 4.13 (d, 1H, J ) 11 Hz), 4.14 (d,
1H, J ) 5.5 Hz), 4.32 (d, 1H, J ) 11 Hz), 4.56 (d, 1H, J ) 11
Hz), 4.78 (d, 1H, J ) 11 Hz), 4.82 (dd, 1H, J ) 5.5, 1.5 Hz), 5.76
(d, 1H, J ) 2.0 Hz), 6.85 (d, 2H, J ) 8.5 Hz), 7.24 (d, 2H, J ) 8.5
Hz), 7.30-7.43 (m, 6H), 7.65-7.70 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 6.0, 7.0, 19.3, 23.3, 23.8, 26.4, 27.1, 27.3, 35.9, 36.0,
39.1, 55.4, 66.3, 67.4, 70.8, 72.9, 73.2, 77.4, 78.5, 79.6, 80.7, 83.2,
92.2, 93.9, 113.7, 114.0, 120.4, 127.7, 127.8, 127.9, 128.0, 128.1,
129.4, 129.7, 129.8, 129.9, 130.7, 133.4, 134.0, 135.9, 136.0, 136.0,
139.3, 159.2, 178.0; FT-IR (neat) ν 3443, 3311, 2958, 1732, 1613,
1588, 1514, 1463, 1428, 1336, 1248, 1112 cm-1; MALDI-TOF-
MS (m/z) [M + Na]+, calcd for C54H72NaO9Si2 943.4613, found
1730, 1613, 1514, 1480, 1398, 1337, 1285, 1248, 1172, 1107 cm-1
;
MALDI-TOF-MS (m/z) [M + Na]+, calcd for C32H40NaO9 591.2570,
found 591.2592.
To a solution of the above triol (429 mg, 0.755 mmol) in CH2-
Cl2 (10 mL) were added 2,6-lutidine (703 µL, 6.04 mmol) and
(TES)OTf (680 µL, 3.02 mmol) at -50 °C. The mixture was stirred
for 1 h at -50 °C and quenched with saturated NaHCO3 solution.
The resulting mixture was extracted with hexanes-EtOAc (2×),
and the combined organic layer was dried over anhydrous Na2-
SO4. After concentration, the residue was purified by flash column
chromatography (silica gel, hexane-hexane/AcOEt ) 10) to give
26.0
1
943.4591. Data for 9: [R]D -11.4° (c 1.77, CHCl3); H NMR
(500 MHz, CDCl3) δ 0.68 (q, 6H, J ) 7.7 Hz), 0.93 (t, 9H, J )
7.8 Hz), 1.09 (s, 9H), 1.23 (s, 9H) 1.58-1.69 (m, 4H), 1.72-1.77
(m, 2H), 1.79-1.91 (m, 2H), 2.07 (t, 1H, J ) 2.5 Hz), 2.66 (dd,
1H, J ) 17, 2.8 Hz), 2.76 (dd, 1H, J ) 17, 2.5 Hz), 3.21 (s, 1H),
3.80 (s, 3H), 4.02 (dd, 1H, J ) 8.0, 7.0 Hz), 4.07 (dd, 1H, J ) 8.5,
6.5 Hz), 4.12 (d, 1H, J ) 2.5 Hz), 4.14 (d, 1H, J ) 11 Hz), 4.16
(t, 1H, J ) 6.5 Hz), 4.34 (d, 1H, J ) 12 Hz), 4.43 (d, 1H, J ) 11
Hz), 4.52 (d, 1H, J ) 11 Hz), 4.81 (t, 1H, J ) 2.5 Hz), 5.82 (d,
1H, J ) 2.0 Hz), 6.85 (d, 2H, J ) 8.0 Hz), 7.16 (d, 2H, J ) 8.5
Hz), 7.38-7.41 (m, 4H), 7.44-7.47 (m, 2H), 7.65-7.72 (m, 4H);
13C NMR (125 MHz, CDCl3) δ 6.0, 7.0, 19.3, 23.5, 23.8, 27.0,
27.3, 29.0, 36.3, 36.5, 39.0, 55.4, 66.5, 67.7, 70.9, 73.0, 73.1, 77.7,
80.2, 80.3, 81.4, 81.7, 86.6, 92.2, 113.9, 120.2, 127.9, 128.0, 129.7,
129.7, 130.1, 130.1, 130.7, 133.3, 133.6, 135.9, 136.0, 139.6, 159.6,
178.0; FT-IR (neat) ν 3522, 3311, 2957, 1732, 1613, 1588, 1514,
1462, 1428, 1337, 1249, 1111 cm-1; MALDI-TOF-MS (m/z)
[M + Na]+, calcd for C54H72NaO9Si2 943.4613, found 943.4599.
Identification of the C9 Stereochemistry. To a solution of
alcohol 9 (30.0 mg, 0.0326 mmol) in CH2Cl2 (8 mL) was added
DDQ (29.6 mg, 0.130 mmol). The mixture was stirred for 19 h at
room temperature and concentrated. The residue was purified by
flash column chromatography (silica gel, hexane/EtOAc ) 12 to
11 to 10 to 6 to 4) to give MP-acetal 10 (1.1:1 diastereomeric
mixture, 12.9 mg, 0.0140 mmol, 43%) as a colorless syrup: 1H
tris(TES ether) 11 (619 mg, 0.680 mmol, 90%) as a pale yellow
22.0
syrup: [R]D
-23.9° (c 2.45, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 0.61 (q, 6H, J ) 8.0 Hz), 0.63 (q, 6H, J ) 8.0 Hz), 0.71
(q, 6H, J ) 8.0 Hz), 0.93 (t, 9H, J ) 8.0 Hz), 0.95 (t, 9H, J ) 8.0
Hz), 0.97 (t, 9H, J ) 8.0 Hz), 1.23 (s, 9H), 1.60-1.69 (m, 4H),
1.72-1.75 (m, 2H), 1.83-1.94 (m, 2H), 1.87 (t, 1H, J ) 2.5 Hz),
2.50 (dd, 1H, J ) 16, 2.8 Hz), 2.73 (dd, 1H, J ) 16, 2.3 Hz), 3.81
(s, 3H), 4.01 (d, 1H, J ) 4.5 Hz), 4.02 (dd, 1H, J ) 8.5, 7.0 Hz),
4.07 (dd, 1H, J ) 8.5, 7.0 Hz), 4.12 (d, 1H, J ) 12 Hz), 4.17 (t,
1H, J ) 6.8 Hz), 4.35 (d, 1H, J ) 11 Hz), 4.63 (d, 1H, J ) 12
Hz), 4.77 (d, 1H, J ) 11 Hz), 4.83 (dd, 1H, J ) 5.0, 2.0 Hz), 6.04
(d, 1H, J ) 2.0 Hz), 6.88 (dd, 2H, J ) 7.0, 2.0 Hz), 7.32 (d, 2H,
J ) 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 5.2, 6.0, 6.1, 6.5, 6.6,
6.9, 7.1, 7.2, 23.5, 23.8, 27.0, 27.3, 36.4, 36.6, 39.0, 55.4, 66.5,
67.7, 69.9, 72.2, 73.0, 77.6, 78.7, 80.6, 82.6, 86.2, 90.9, 95.0, 113.7,
113.7, 120.1, 129.0, 129.4, 129.7, 130.9, 139.8, 159.1, 177.9; FT-
IR (neat) ν 3313, 2955, 1732, 1614, 1587, 1515, 1463, 1416, 1397,
1336, 1282, 1247 cm-1; MALDI-TOF-MS (m/z) [M + Na]+, calcd
for C50H82NaO9Si3 933.5164, found 933.5162.
Aldehyde 12. To a solution of pivalate 11 (688 mg, 0.755 mmol)
in Et2O (10 mL) was added DIBAL (0.94 M solution in hexane,
3.21 mL, 3.02 mmol) at -78 °C. The mixture was stirred for 30
min at -78 °C and quenched with saturated Rochelle salt solution.
J. Org. Chem, Vol. 71, No. 2, 2006 641

Kobayashi et al.
-46.4° (c 0.450, CHCl3); H NMR (500 MHz,
24.0
1
The resulting mixture was stirred at room temperature until the
two phases were clearly separated. The organic phase was separated,
and the aqueous phase was extracted with hexane. The combined
organic layer was dried over anhydrous Na2SO4. After concentra-
tion, the residue was purified by flash column chromatography
(silica gel, hexane/AcOEt ) 7) to give the corresponding alcohol
(553 mg, 0.672 mmol, 89%) as a colorless oil: [R]D20.0 -28.9° (c
0.59, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.61 (q, 6H, J ) 7.5
Hz), 0.63 (q, 6H, J ) 7.5 Hz), 0.74 (q, 6H, J ) 7.5 Hz), 0.93 (t,
9H, J ) 7.5 Hz), 0.97 (t, 18H, J ) 7.5 Hz), 1.60-1.69 (m, 4H),
1.70-1.81 (m, 2H), 1.85-1.95 (m, 2H), 1.88 (t, 1H, J ) 2.5 Hz),
2.18 (dd, 1H, J ) 10, 3.8 Hz), 2.51 (dd, 1H, J ) 16, 2.5 Hz), 2.71
(dd, 1H, J ) 16, 2.5 Hz), 3.68 (dd, 1H, J ) 11, 3.3 Hz), 3.77 (t,
1H, J ) 10 Hz), 3.81 (s, 3H), 4.00 (d, 1H, J ) 5.0 Hz), 4.03 (dd,
1H, J ) 8.5, 7.0 Hz), 4.07 (dd, 1H, J ) 8.5, 6.0 Hz), 4.17 (t, 1H,
J ) 6.5 Hz), 4.62 (d, 1H, J ) 12 Hz), 4.77 (d, 1H, J ) 11 Hz),
4.83 (dd, 1H, J ) 5.0, 2.0 Hz), 6.02 (d, 1H, J ) 2.0 Hz), 6.89 (d,
2H, J ) 9.0 Hz), 7.32 (d, 2H, J ) 8.5 Hz); 13C NMR (125 MHz,
CDCl3) δ 5.2, 6.1, 6.4, 6.9, 7.1, 7.2, 23.5, 23.7, 27.0, 36.3, 36.7,
55.4, 55.4, 66.6, 68.1, 70.0, 72.2, 74.4, 77.9, 78.7, 78.8, 80.6, 83.0,
86.1, 91.4, 95.0, 113.8, 120.2, 129.0, 129.5, 130.9, 139.5, 159.2;
FT-IR (neat) ν 3499, 3312, 2955, 1614, 1514, 1462, 1415, 1336,
1247, 1110 cm-1; MALDI-TOF-MS (m/z) [M + Na]+, calcd for
C45H74NaO8Si3 849.4589, found 849.4596.
To a solution of the above alcohol (482 mg, 0.583 mmol) in
CH2Cl2 (12 mL) were added pyridine (236 µL, 2.92 mmol) and
Dess-Martin periodinane (494 mg, 1.17 mmol). The mixture was
stirred for 2 h at room temperature, diluted with hexane, and
quenched with saturated Na2S2O3 solution and then saturated
NaHCO3 solution. The resulting mixture was extracted with hexane
(2×), and the combined organic layer was dried over anhydrous
MgSO4. After concentration, the residue was purified by column
chromatography (Florisil, hexane/AcOEt ) 10) to give aldehyde
12 (433 mg, 0.525 mmol, 90%) as a colorless syrup: [R]D24.0 +2.1°
(c 0.570, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.60 (q, 6H, J )
7.8 Hz), 0.63 (q, 6H, J ) 7.8 Hz), 0.71 (q, 6H, J ) 7.8 Hz), 0.92
(t, 9H, J ) 7.8 Hz), 0.97 (t, 9H, J ) 7.8 Hz), 0.97 (t, 9H, J ) 7.8
Hz), 1.63-1.69 (m, 4H), 1.71-1.76 (m, 2H), 1.84-1.95 (m, 2H),
1.88 (brs, 1H), 2.52 (dd, 1H, J ) 16, 1.8 Hz), 2.73 (dd, 1H, J )
16, 1.5 Hz), 3.81 (s, 3H), 4.01 (d, 1H, J ) 5.0 Hz), 4.04 (dd, 1H,
J ) 8.5, 7.0 Hz), 4.12 (dd, 1H, J ) 8.5, 6.0 Hz), 4.16 (t, 1H, J )
6.5 Hz), 4.62 (d, 1H, J ) 12 Hz), 4.77 (d, 1H, J ) 11 Hz), 4.83 (d,
1H, J ) 5.0 Hz), 6.08 (s, 1H), 6.89 (d, 2H, J ) 8.0 Hz), 7.32 (d,
2H, J ) 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 5.2, 6.1, 6.4, 6.9,
7.0, 7.2, 23.5, 23.8, 27.0, 36.2, 36.4, 55.4, 55.4, 66.3, 70.0, 70.1,
72.3, 78.1, 78.7, 78.7, 79.7, 80.5, 85.1, 86.1, 87.9, 95.0, 113.8,
120.9, 129.0, 129.1, 130.8, 140.5, 159.2, 195.5, 195.6; FT-IR (neat)
ν 3312, 2956, 2877, 1745, 1614, 1515, 1462, 1415, 1337, 1248,
1172, 1120 cm-1; MALDI-TOF-MS (m/z) [M + Na]+, calcd for
C45H72NaO8Si3 847.4433, found 847.4418.
syrup: [R]D
CDCl3) δ 0.64 (q, 6H, J ) 7.5 Hz), 0.67 (q, 6H, J ) 8.3 Hz), 0.73
(q, 6H, J ) 7.8 Hz), 0.96 (t, 9H, J ) 7.5 Hz), 0.97 (t, 9H, J ) 8.0
Hz), 0.98 (t, 9H, J ) 7.5 Hz), 1.57-1.67 (m, 4H), 1.70-1.77 (m,
2H), 1.79-1.85 (m, 2H), 2.25 (dd, 1H, J ) 17, 3.8 Hz), 2.36 (br
s, 1H), 2.67 (dd, 1H, J ) 17, 1.8 Hz), 3.81 (s, 3H), 4.01 (d, 1H,
J ) 4.5 Hz), 4.06 (dd, 1H, J ) 8.0, 7.0 Hz), 4.09 (dd, 1H, J ) 8.5,
6.0 Hz), 4.35 (t, 1H, J ) 6.5 Hz), 4.54 (dd, 1H, J ) 4.8, 2.3 Hz),
4.58 (d, 1H, J ) 11 Hz), 4.67 (br s, 1H), 4.70 (d, 1H, J ) 11 Hz),
5.87 (d, 1H, J ) 2.0 Hz), 6.89 (d, 2H, J ) 9.0 Hz), 7.26 (d, 2H,
J ) 8.5 Hz); 13C NMR (125 MHz, CDCl3) δ 5.2, 5.9, 6.5, 7.0,
23.4, 23.8, 29.5, 29.9, 36.3, 36.6, 55.5, 67.0, 72.7, 75.3, 75.4, 78.7,
78.8, 78.9, 82.8, 84.5, 85.3, 91.0, 91.8, 95.3, 97.2, 113.9, 119.6,
129.3, 130.3, 131.4, 135.8, 135.9, 159.4; FT-IR (neat) ν 3469, 2955,
2877, 1614, 1515, 1457, 1415, 1337, 1302, 1247, 1108 cm-1; HR-
ESI-FT-ICR-MS (m/z) [M + Na]+, calcd for C45H72NaO8Si3
847.4427, found 847.4425.
Epoxide 16. To a solution of the nine-membered ring alcohol
14 (983 mg, 1.19 mmol) in CH2Cl2 (24 mL) were added Et3N (1.66
mL, 11.9 mmol) and MsCl (138 µL, 1.79 mmol) at -20 °C. The
mixture was stirred for 15 min at -20 °C and quenched with
saturated NaHCO3 solution. The resulting mixture was extracted
with hexane (2×), and the combined organic layer was washed
with brine and dried over anhydrous MgSO4. Concentration of the
solution gave the corresponding mesylate (1.06 g), which was
subjected to the next reaction without purification: 1H NMR (500
MHz, CDCl3) δ 0.65 (q, 6H, J ) 8.0 Hz), 0.67 (q, 6H, J ) 8.0
Hz), 0.77 (q, 6H, J ) 8.0 Hz), 0.98 (t, 9H, J ) 8.0 Hz), 0.98 (t,
18H, J ) 8.0 Hz), 1.59-1.70 (m, 4H), 1.71-1.77 (m, 2H), 1.79-
1.85 (m, 2H), 2.29 (dd, 1H, J ) 17, 4.0 Hz), 2.72 (dd, 1H, J ) 17,
1.8 Hz), 3.12 (s, 3H), 3.81 (s, 3H), 3.40 (dd, 1H, J ) 9.0, 7.0 Hz),
4.03 (d, 1H, J ) 4.5 Hz), 4.04 (dd, 1H, J ) 9.0, 6.0 Hz), 4.32 (dd,
1H, J ) 7.0, 6.0 Hz), 4.55 (dd, 1H, J ) 4.5, 2.0 Hz), 4.57 (d, 1H,
J ) 11 Hz), 4.70 (d, 1H, J ) 11 Hz), 5.35 (dd, 1H, J ) 4.0, 1.8
Hz), 5.93 (d, 1H, J ) 2.0 Hz), 6.89 (d, 2H, J ) 8.5 Hz), 7.26 (d,
2H, J ) 9.0 Hz); 13C NMR (125 MHz, CDCl3) δ 5.2, 5.8, 6.5, 6.9,
7.0, 7.2, 23.4, 23.9, 29.7, 29.9, 36.1, 36.4, 38.9, 55.5, 66.6, 72.7,
78.4, 78.8, 80.1, 80.8, 81.3, 84.4, 91.6, 95.0, 95.9, 97.3, 114.0,
119.6, 128.5, 129.4, 130.1, 130.8, 136.6, 159.5; FT-IR (neat) ν 2956,
2877, 1614, 1515, 1462, 1415, 1370, 1336, 1248, 1180, 1109 cm-1
;
HR-ESI-FT-ICR-MS (m/z) [M + Na]+, calcd for C46H74NaO10SSi3
925.4203, found 925.4207.
To a solution of the above mesylate (1.06 g) in THF (23 mL)
was added TBAF (1.0 M solution in THF, 2.57 mL, 2.57 mmol) at
-40 °C. The mixture was stirred for 15 min at -40 to -35 °C and
quenched with saturated NH4Cl solution. The resulting mixture was
extracted with AcOEt (3×), and the combined organic layer was
washed with brine and dried over anhydrous MgSO4. After
concentration, the residue was purified by flash column chroma-
tography (silica gel, hexane/AcOEt ) 8 to 3 to 2 to 1) to give
epoxide 16 (393 mg, 0.679 mmol, 58% in two steps) and diol 15
(121 mg, 0.180 mmol, 15% in two steps) as yellow syrups. To a
solution of diol 15 (121 mg, 0.180 mmol) in EtOH (3.6 mL) was
added K2CO3 (24.9 mg, 0.180 mmol). The mixture was stirred for
17 h at room temperature and concentrated. The residue was purified
by flash column chromatography (silica gel, hexane/AcOEt ) 3)
Alcohol 14. To well-ground anhydrous CeCl3 (1.00 g, 4.06
mmol) was slowly added THF (50 mL) with vigorous stirring at 0
°C. The suspension was stirred for 36 h at room temperature. A
cooled (0 °C) solution of LiN(TMS)2 in THF, which was freshly
prepared from 1,1,1,3,3,3-hexamethyldisilazane (1.04 mL, 4.91
mmol) and nBuLi (1.56 M solution in hexane, 2.85 mL, 4.45 mmol)
in THF (50 mL), was added to the above suspension at -40 °C.
The mixture was gradually warmed to -20 °C over 1 h, and a
solution of aldehyde 12 (386 mg, 0.468 mmol) in THF (50 mL)
was added in one portion. The resulting mixture was allowed to
warm to room temperature and stirred for 1 h. The reaction mixture
was quenched with phosphate buffer (pH 7.0) and filtered through
a pad of Celite. The precipitate was washed with Et2O, and the
combined filtrate was concentrated. The residue was again extracted
with hexane, and the organic extracts were washed with saturated
NH4Cl solution and brine and dried over anhydrous Na2SO4. After
concentration, the residue was purified by flash column chroma-
tography (silica gel, hexane/EtOAc ) 10 to 8) to give the nine-
membered alcohol 14 (282 mg, 0.342 mmol, 73%) as a yellow
23.0
to give epoxide 16 (54.2 mg, 0.0936 mmol, 52% from 15): [R]D
1
+7.6° (c 0.810, CHCl3); H NMR (500 MHz, CDCl3) δ 0.64 (q,
6H, J ) 8.0 Hz), 0.95 (t, 9H, J ) 8.0 Hz), 1.66-1.73 (m, 4H),
1.74-1.81 (m, 2H), 1.88-1.97 (m, 2H), 2.35 (d, 1H, J ) 18 Hz),
2.74 (d, 1H, J ) 18 Hz), 3.52 (s, 1H), 3.81 (s, 3H), 3.94 (d, 1H,
J ) 5.0 Hz), 4.01 (dd, 1H, J ) 5.5, 8.0 Hz), 4.05 (t, 1H, J ) 5.8
Hz), 4.13 (dd, 1H, J ) 6.0, 8.0 Hz), 4.53-4.56 (m, 1H),4.65 (d,
1H, J ) 11.5 Hz), 4.69 (d, 1H, J ) 11.5 Hz), 5.91 (d, 1H, J ) 2.0
Hz), 6.90 (d, 2H, J ) 8.0 Hz), 7.29 (d, 2H, J ) 8.0 Hz); 13C NMR
(125 MHz, CDCl3) δ 6.4, 7.2, 23.5, 23.8, 29.3, 36.2, 36.3, 54.3,
55.5, 64.3, 67.5, 72.9, 74.4, 78.1, 83.2, 85.1, 88.1, 88.6, 95.1, 96.3,
114.1, 120.8, 129.4, 130.2, 131.7, 134.3, 159.6; FT-IR (neat) ν 3480,
2954, 2875, 1613, 1514, 1455, 1337, 1302, 1247, 1108 cm-1; HR-
642 J. Org. Chem., Vol. 71, No. 2, 2006

Total Synthesis of Neocarzinostatin Chromophore
ESI-FT-ICR-MS (m/z) [M + Na]+, calcd for C33H42NaO7Si
Diol 20. To a solution of triol 18 (24.1 mg, 0.0332 mmol) in
THF (1 mL) was added 1,1′-carbonyldiimidazole (10.8 mg, 0.066
mmol). The mixture was stirred for 15 h at room temperature, and
1,1′-carbonyldiimidazole (5.4 mg, 0.033 mmol) was further added.
The resulting mixture was stirred for 24 h and concentrated. The
residue was purified by flash column chromatography (silica gel,
601.2592, found 601.2592.
Triol 18. To a suspension of epoxide 16 (86.8 mg, 0.150 mmol)
and naphthoic acid 17 (105 mg, 0.450 mmol) in CH2Cl2 (3.0 mL)
were added EDC‚HCl (115 mg, 0.600 mmol) and DMAP (1.8 mg,
0.015 mmol) at 0 °C. The mixture was stirred for 10 min at 0 °C,
and naphthoic acid 17 (21.5 mg, 0.0926 mmol), EDC‚HCl (17.8
mg, 0.0926 mmol), and DMAP (1.1 mg, 0.0093 mmol) were further
added. The resulting mixture was stirred for 10 min at 0 °C and
quenched with water. The mixture was extracted with EtOAc (3×),
and the combined organic layer was washed with brine and dried
over anhydrous Na2SO4. After concentration, the residue was
purified by flash column chromatography (silica gel, hexane/
AcOEt ) 8 to 6) to give the corresponding ester (74.3 mg, 0.0937
mmol, 64%) as a colorless syrup: [R]D24.0 -14.5° (c 0.510, CHCl3);
1H NMR (500 MHz, CDCl3) δ 0.64 (q, 6H, J ) 7.8 Hz), 0.93 (t,
9H, J ) 7.8 Hz), 1.66-1.73 (m, 4H), 1.74-1.80 (m, 2H), 1.88-
1.98 (m, 2H), 2.52 (d, 1H, J ) 18 Hz), 2.65 (s, 3H), 2.82 (d, 1H,
J ) 18 Hz), 3.56 (s, 1H), 3.72 (s, 3H), 3.83 (s, 3H), 4.03 (dd, 1H,
J ) 7.5, 5.0 Hz), 4.06 (t, 1H, J ) 5.3 Hz), 4.14 (dd, 1H, J ) 7.5,
5.8 Hz), 4.40 (d, 1H, J ) 5.0 Hz), 4.61 (d, 1H, J ) 11 Hz), 4.65
(d, 1H, J ) 11 Hz), 5.93 (dd, 1H, J ) 5.0, 2.0 Hz), 6.12 (d, 1H,
J ) 2.0 Hz), 6.72 (d, 2H, J ) 8.5 Hz), 6.92 (br s, 1H), 7.05 (d, 1H,
J ) 9.5 Hz), 7.16 (d, 2H, J ) 8.5 Hz), 8.07 (br s, 1H), 8.07 (d, 1H,
J ) 9.5 Hz), 12.12 (s, 1H); FT-IR (neat) ν 2954, 2876, 1644, 1614,
1514, 1455, 1414, 1376, 1337, 1306, 1248, 1203 cm-1; HR-ESI-
FT-ICR-MS (m/z) [M + Na]+, calcd for C46H52NaO10Si 815.3222,
found 815.3226.
hexane/AcOEt ) 3 to 2) to give the corresponding carbonate (19.4
22.0
mg, 0.0258 mmol, 78%) as a colorless syrup: [R]D
-57.7° (c
1
0.388, CHCl3); H NMR (500 MHz, CDCl3) δ 0.63 (q, 6H, J )
7.5 Hz), 0.93 (t, 9H, J ) 7.5 Hz), 2.55 (d, 1H, J ) 18 Hz), 2.66 (s,
3H), 2.84 (d, 1H, J ) 18 Hz), 3.63 (s, 1H), 3.73 (s, 3H), 3.84 (s,
3H), 4.41 (d, 1H, J ) 5.0 Hz), 4.55 (dd, 1H, J ) 7.5, 5.5 Hz),
4.57-4.66 (m, 4H, H14), 5.96 (dd, 1H, J ) 5.0, 2.0 Hz), 6.21 (d,
1H, J ) 2.0 Hz), 6.73 (d, 2H, J ) 8.5 Hz), 6.92 (d, 1H, J ) 1.5
Hz), 7.05 (d, 1H, J ) 9.5 Hz), 7.16 (d, 2H, J ) 8.5 Hz), 8.05 (d,
1H, J ) 1.5 Hz), 8.08 (d, 1H, J ) 9.5 Hz), 12.08 (s, 1H); 13C
NMR (125 MHz, CDCl3) δ 6.4, 7.2, 20.4, 29.6, 55.2, 55.4, 55.4,
63.6, 67.3, 73.1, 74.8, 80.8, 82.4, 85.1, 89.7, 90.4, 91.0, 94.2, 104.2,
105.2, 114.1, 115.9, 116.4, 123.3, 129.3, 129.5, 131.8, 133.3, 133.6,
134.2, 137.4, 153.9, 159.7, 159.7, 165.4, 172.0; FT-IR (film) ν 2955,
2876, 1821, 1644, 1615, 1514, 1464, 1412, 1377, 1344, 1306, 1248,
1205 cm-1; HR-ESI-FT-ICR-MS (m/z) [M+Na]+, calcd for C42H44-
NaO11Si 775.2545, found 775.2546.
To a solution of the above carbonate (19.4 mg, 0.0258 mmol)
in THF (1 mL) was added TBAF (1.0 M solution in THF, 38.7
µL, 0.0387 mmol) at 0 °C. The mixture was stirred for 40 min at
0 °C and concentrated. The residue was purified by flash column
chromatography (silica gel, hexane/AcOEt ) 1.5 to 0.5 followed
by AcOEt/MeOH ) 20) to give diol 20 (13.9 mg, 0.0218 mmol,
To a solution of the above ester (147 mg, 0.186 mmol) in CH3-
CN (6.2 mL) was added 46% aqueous hydrofluoric acid (67.4 µL)
at 0 °C. The mixture was stirred for 1.6 h at 0 °C and quenched
with saturated NaHCO3 solution. The resulting mixture was diluted
with Et2O and stirred for 30 min at 0 °C. The mixture was extracted
with AcOEt (3×), and the combined organic layer was washed with
brine and dried over anhydrous MgSO4. After concentration, the
residue was purified by flash column chromatography (silica gel,
hexane/AcOEt ) 2 to 1 to 0.33, containing 2.5% MeOH) to give
triol 18 (93.0 mg, 0.128 mmol, 69%) as a colorless syrup and tetrol
19 (31.8 mg, 0.0520 mmol, 28%) as colorless solid. Data for 18:
22.0
1
84%) as a colorless solid: [R]D
-119° (c 0.560, CHCl3); H
NMR (500 MHz, CDCl3) δ 2.64 (s, 3H), 2.71 (d, 1H, J ) 18 Hz),
2.78 (br s, 1H), 2.87 (d, 1H, J ) 18 Hz), 3.65 (s, 3H), 3.71 (s,
1H), 3.72 (s, 3H), 4.41 (d, 1H, J ) 5.0 Hz), 4.55-4.59 (m, 2H),
4.64 (d, 1H, J ) 12 Hz), 4.66 (t, 1H, J ) 11 Hz), 4.70 (d, 1H,
J ) 12 Hz), 6.02 (dd, 1H, J ) 5.0, 2.0 Hz), 6.21 (d, 1H, J ) 2.0
Hz), 6.67 (d, 2H, J ) 9.0 Hz), 6.89 (br s, 1H), 7.05 (d, 1H, J ) 9.5
Hz), 7.16 (d, 2H, J ) 9.0 Hz), 7.90 (br s, 1H), 8.07 (d, 1H, J ) 9.5
Hz), 11.99 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 20.2, 28.4,
55.1, 55.2, 55.2, 63.3, 67.2, 73.2, 74.3, 80.2, 82.8, 83.6, 88.2, 88.3,
88.8, 94.6, 104.2, 104.2, 114.0, 116.1, 116.6, 123.2, 128.9, 129.6,
131.8, 132.3, 133.2, 134.2, 137.1, 153.6, 159.6, 159.6, 165.1, 171.8;
FT-IR (film) ν 3387, 2932, 1820, 1644, 1614, 1514, 1465, 1412,
1378, 1307, 1249, 1204 cm-1; HR-ESI-FT-ICR-MS (m/z) [M +
Na]+, calcd for C36H30NaO11 661.1680, found 661.1677.
22.0
1
[R]D -55.1° (c 0.482, CHCl3); H NMR (500 MHz, CDCl3) δ
1.93 (br s, 1H), 2.38 (br s, 1H), 2.63 (s, 3H), 2.68 (d, 1H, J ) 18
Hz), 2.86 (d, 1H, J ) 18 Hz), 3.65 (s, 3H), 3.72 (s, 3H), 3.76 (s,
1H), 3.80 (br dd, 1H, J ) 12, 5.7 Hz), 3.96 (br dd, 1H, J ) 12, 2.5
Hz), 4.02 (br dd, 1H, J ) 4.5, 3.5 Hz), 4.42 (d, 1H, J ) 5.0 Hz),
4.63 (d, 1H, J ) 12 Hz), 4.71 (d, 1H, J ) 12 Hz), 6.00 (dd, 1H,
J ) 5.0, 2.0 Hz), 6.12 (d, 1H, J ) 2.0 Hz), 6.66 (d, 2H, J ) 8.5
Hz), 6.88 (d, 1H, J ) 2.0 Hz), 7.04 (d, 1H, J ) 9.5 Hz), 7.16 (d,
2H, J ) 8.5 Hz), 7.91 (d, 1H, J ) 2.0 Hz), 8.06 (d, 1H, J ) 9.5
Hz), 12.02 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 6.4, 7.2, 20.3,
29.5, 53.0, 55.3, 55.3, 63.5, 64.0, 69.6, 73.0, 80.8, 83.4, 85.0, 87.9,
88.5, 91.1, 97.3, 104.2, 105.0, 114.0, 115.8, 116.3, 123. 2, 129.3,
129.4, 130.6, 133.2, 134.2, 134.3, 137.3, 159.5, 159.6, 165.2, 172.0;
FT-IR (film) ν 3417, 2954, 2876, 1644, 1615, 1514, 1463, 1412,
1377, 1345, 1306, 1248, 1204 cm-1; HR-ESI-FT-ICR-MS (m/z)
[M + Na]+ calcd for C41H46NaO10Si 749.2752, found 749.2755.
Data for 19: [R]D22.0 -110° (c 0.610, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 0.64 (q, 6H, J ) 8.0 Hz), 0.94 (t, 9H, J ) 8.0 Hz), 1.98
(br s, 1H), 2.36 (br s, 1H), 2.54 (d, 1H, J ) 18 Hz), 2.65 (s, 3H),
2.82 (d, 1H, J ) 18 Hz), 3.70 (s, 1H), 3.72 (s, 3H), 3.79 (br dd,
1H, J ) 12, 5.5 Hz), 3.83 (s, 3H), 3.96 (br dd, 1H, J ) 12, 2.5
Hz), 4.04-4.08 (m, 1H), 4.40 (d, 1H, J ) 5.0 Hz), 4.61 (d, 1H,
J ) 12 Hz), 4.65 (d, 1H, J ) 12 Hz), 5.93 (dd, 1H, J ) 5.0, 2.0
Hz), 6.13 (d, 1H, J ) 2.0 Hz), 6.73 (d, 2H, J ) 8.5 Hz), 6.92 (d,
1H, J ) 2.0 Hz), 7.05 (d, 1H, J ) 9.0 Hz), 7.16 (d, 2H, J ) 8.5
Hz), 8.06 (d, 1H, J ) 2.0 Hz), 8.07 (d, 1H, J ) 9.0 Hz), 12.11
(s, 1H); FT-IR (film) ν 3391, 2932, 1644, 1614, 1514, 1454, 1414,
1378, 1307, 1248, 1204 cm-1; HR-ESI-FT-ICR-MS (m/z) [M +
Na]+, calcd for C35H32NaO10 635.1888, found 635.1892.
TES Ether 21. To a solution of diol 20 (35.9 mg, 0.0562 mmol)
in CH2Cl2 (2 mL) were added H2O (100 µL) and DDQ (38.3 mg,
0.169 mmol). The mixture was stirred for 10 h at room temperature
and quenched with saturated NaHCO3 solution and then saturated
Na2S2O3 solution. The resulting mixture was extracted with EtOAc
(3×), and the combined organic layer was washed with brine and
dried over anhydrous MgSO4. After concentration, the residue was
purified by flash column chromatography (silica gel, hexane/
AcOEt ) 2 to 0.5) to give the corresponding triol (23.5 mg, 0.0453
mmol, 81%) as a colorless solid: [R]D23.0 -39.0° (c 0.384, CHCl3);
1H NMR (500 MHz, CDCl3) δ 2.63 (s, 3H), 2.65 (d, 1H, J ) 18
Hz), 2.83 (br s, 1H), 2.97 (d, 1H, J ) 18 Hz), 3.63 (br s, 1H), 3.71
(s, 1H), 3.90 (s, 3H), 4.51 (d, 1H, J ) 4.5 Hz), 4.53 (dd, 1H, J )
8.0, 5.5 Hz), 4.61 (dd, 1H, J ) 9.0, 5.5 Hz), 4.68 (t, 1H, J ) 8.5
Hz), 5.73 (dd, 1H, J ) 4.5, 2.0 Hz), 6.22 (d, 1H, J ) 2.0 Hz), 6.91
(d, 1H, J ) 2.0 Hz), 7.04 (d, 1H, J ) 9.0 Hz), 7.98 (d, 1H, J ) 2.0
Hz), 8.08 (d, 1H, J ) 9.0 Hz), 11.83 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 20.2, 28.2, 55.3, 55.4, 63.4, 67.3, 74.5, 83.4, 83.5, 84.0,
84.3, 88.3, 88.9, 94.7, 103.7, 104.1, 116.1, 116.6, 123.2, 130.9,
132.5, 133.7, 134.1, 137.4, 153.7, 159.8, 165.4, 173.4; FT-IR (film)
ν 3461, 2930, 1818, 1790, 1644, 1615, 1454, 1413, 1379, 1310,
1265, 1206 cm-1; HR-ESI-FT-ICR-MS (m/z) [M + Na]+, calcd
for C28H22NaO10 541.1105, found 541.1107.
To a solution of the above triol (19.2 mg, 0.0370 mmol) in CH2-
Cl2 (2 mL) were added 2,6-lutidine (129 µL, 1.11 mmol) and (TES)-
J. Org. Chem, Vol. 71, No. 2, 2006 643

Kobayashi et al.
OTf (66.9 µL, 0.296 mmol) at -90 °C. The mixture was stirred
for 15 min at -90 °C and quenched with saturated NaHCO3
solution. The resulting mixture was extracted with AcOEt (2×),
and the combined organic layer was washed with brine and dried
over anhydrous Na2SO4. After concentration, the residue was
purified by flash column chromatography (silica gel, hexane-
subjected to HPLC (Mightysil Si 60, 250-10 (5 µm), flow rate 4
mL/min, eluent hexane/AcOEt ) 1, UV detection 254 nm). The
fractions including pure aglycon 2 (retention time 10 min 15 s)
were concentrated to 0.2 mL, diluted with MeOH (3 mL), and
concentrated to 0.2 mL. This process was repeated, and the
concentrate was taken up in MeOH (5 mL). A 0.5 mL solution
was diluted to 10 mL with MeOH. UV absorbance was determined
hexane/AcOEt ) 4 to 3 to 2) to give bis(TES ether) 21 (19.5 mg,
21.5
to quantitate 2 (A302 ) 0.51, ꢀ302 ) 7040 M-1 cm-1 16c
2.3 mg,
,
0.0261 mmol, 71%) as a pale yellow syrup: [R]D
-17.7° (c
1
0.0032 mmol, 61% in two steps from 21): 1H NMR (400 MHz,
CD3CN) δ 2.60 (s, 3H), 3.83 (s, 3H), 4.06 (d, 1H, J ) 1.6 Hz),
4.24 (brd, 1H, J ) 5.2 Hz), 4.39 (dd, 1H, J ) 9.2, 5.2 Hz), 4.62 (t,
1H, J ) 8.8 Hz), 4.91 (dd, 1H, J ) 8.4, 5.6 Hz), 4.89-4.93 (m,
1H), 5.66 (br s, 1H), 6.01 (t, 1H, J ) 3.0 Hz), 6.67 (br s, 1H), 6.92
(br s, 1H), 7.04 (d, 1H, J ) 9.2 Hz), 7.95 (br s, 1H), 8.13 (d, 1H,
J ) 9.2 Hz), 11.59 (s, 1H); FT-IR (film) ν 3677, 3068, 2926, 1820,
1739, 1613, 1465, 1380 cm-1; HR-ESI-FT-ICR-MS (m/z) [M +
Na]+, calcd for C28H20NaO9 523.1000, found 523.1002; CD
(MeOH) λext 330.4 nm (∆ꢀ +1.06), 314.7 (0.0), 294.1 (-1.92),
289.8 (-1.86), 264.1 (-5.84), 243.9 (0.0).
0.390, CHCl3); H NMR (500 MHz, CDCl3) δ 0.56 (q, 6H, J )
8.0 Hz), 0.81 (q, 6H, J ) 8.0 Hz), 0.85 (t, 9H, J ) 8.0 Hz), 1.00
(t, 9H, J ) 8.0 Hz), 2.58 (d, 1H, J ) 18 Hz), 2.61 (s, 3H), 2.76 (d,
1H, J ) 18 Hz), 3.69 (s, 1H), 3.84 (s, 3H), 4.45 (d, 1H, J ) 5.0
Hz), 4.57 (dd, 1H, J ) 7.3, 5.0 Hz), 4.60 (dd, 1H, J ) 7.3, 5.0
Hz), 4.67 (t, 1H, J ) 7.5 Hz), 5.57 (dd, 1H, J ) 5.0, 2.0 Hz), 6.36
(d, 1H, J ) 2.0 Hz), 6.88 (d, 1H, J ) 2.0 Hz), 6.90 (d, 1H, J ) 2.0
Hz), 6.94 (d, 1H, J ) 9.0 Hz), 7.85 (d, 1H, J ) 9.0 Hz); 13C NMR
(125 MHz, CDCl3) δ 4.8, 5.5, 6.7, 6.8, 19.7, 28.1, 55.0, 55.2, 63.3,
67.1, 74.3, 82.6, 82.7, 83.3, 88.7, 89.4, 94.1, 100.8, 116.9, 117.8,
118.5, 123.6, 127.7, 131.2, 132.9, 133.3, 136.5, 152.0, 153.7, 158.7,
168.6; FT-IR (film) ν 2956, 2877, 1822, 1730, 1621, 1512, 1465,
1410, 1338, 1267, 1205 cm-1; HR-ESI-FT-ICR-MS (m/z) [M +
Na]+, calcd for C40H50NaO10Si2 769.2835, found 769.2839.
Neocarzinostatin Chromophore Aglycon (2). To a solution of
alcohol 21 (3.9 mg, 0.0052 mmol) in CH2Cl2 (1.2 mL) was added
Martin sulfurane dehydrating reagent (23.0 mg, 0.0340 mmol). The
mixture was stirred for 10 min at room temperature and concentrated
to 0.1 mL. A solution of trifluoroacetic acid-THF-water (1:10:5)
was added, and the mixture was stirred for 35 min at 0 °C. Et2O
(10 mL) and saturated NaHCO3 solution (5 mL) were added, and
the resulting mixture was stirred for 1 h at 0 °C. The aqueous phase
was extracted with Et2O-AcOEt (2×), and the combined organic
layer was dried over anhydrous MgSO4. After filtration, the solution
was concentrated to 0.3 mL and exposed to flash column chroma-
tography (silica gel, hexane/AcOEt ) 1.5 at 0 °C). The fractions
containing aglycon were pooled, concentrated to 0.2 mL, and then
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (Wakate B) from the Japan
Society for the Promotion of Science (JSPS). We are grateful
to Mr. Hiroyuki Monma, Research and Analytical Center for
Giant Molecules, Tohoku University, for measurement of ESI-
FT-ICR mass spectrometry, and to Prof. Masahiro Toyota,
Osaka Prefecture University, for his generous support.
Supporting Information Available: 1H and 13C NMR spectra
of compounds 4-22, and 1H NMR, UV, CD, and mass spectra of
aglycon 2. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO052031O
644 J. Org. Chem., Vol. 71, No. 2, 2006