Enantioselective Total Synthesis of FR900482

Article abstract of DOI:10.1021/jo049862z

The development of two approaches for the enantioselective total synthesis of FR900482 is described. A precursor for the formation of the benzazocine ring was assembled effectively by a modification of the Sonogashira coupling of an aryl triflate with a chiral acetylene unit derived from tartaric acid and the subsequent novel ketone formation via conjugate addition of pyrrolidine to the o-nitrophenylacetylene derivative. The first-generation approach to the key pentacyclic intermediate of our racemic total synthesis utilizes an intramolecular Mitsunobu reaction of an ω-hydroxynitrobenzenesulfonamide to form the benzazocine ring and a stepwise sequence to construct the hydroxymethyl group at the C(7) position. The key intermediate could be synthesized in optically pure form via formation of the characteristic hydroxylamine hemiacetal and a stereoselective epoxide formation. In the second-generation approach, the N-hydroxybenzazocine ring could be constructed directly from an ω-formylnitrobenzene derivative by intramolecular reductive hydroxylamination. The crucial stereoselective hydroxymethylation and the formation of the hydroxylamine hemiacetal could be performed efficiently by a one-pot sequence. After leading to the pentacyclic key intermediate, the total synthesis of (+)-FR900482 was accomplished by a modification of our protocol established in the racemic total synthesis. Stereochemical issues involved in the hydroxymethylation at the C(7) position and formation of the hydroxylamine hemiacetal are also discussed in detail.

Full text of DOI:10.1021/jo049862z

En a n tioselective Tota l Syn th esis of F R900482
Masashi Suzuki, Mika Kambe, Hidetoshi Tokuyama, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, J apan
fukuyama@mol.f.u-tokyo.ac.jp
Received J anuary 24, 2004
The development of two approaches for the enantioselective total synthesis of FR900482 is described.
A precursor for the formation of the benzazocine ring was assembled effectively by a modification
of the Sonogashira coupling of an aryl triflate with a chiral acetylene unit derived from tartaric
acid and the subsequent novel ketone formation via conjugate addition of pyrrolidine to the
o-nitrophenylacetylene derivative. The first-generation approach to the key pentacyclic intermediate
of our racemic total synthesis utilizes an intramolecular Mitsunobu reaction of an ω-hydroxyni-
trobenzenesulfonamide to form the benzazocine ring and a stepwise sequence to construct the
hydroxymethyl group at the C(7) position. The key intermediate could be synthesized in optically
pure form via formation of the characteristic hydroxylamine hemiacetal and a stereoselective epoxide
formation. In the second-generation approach, the N-hydroxybenzazocine ring could be constructed
directly from an ω-formylnitrobenzene derivative by intramolecular reductive hydroxylamination.
The crucial stereoselective hydroxymethylation and the formation of the hydroxylamine hemiacetal
could be performed efficiently by a one-pot sequence. After leading to the pentacyclic key
intermediate, the total synthesis of (+)-FR900482 was accomplished by a modification of our protocol
established in the racemic total synthesis. Stereochemical issues involved in the hydroxymethylation
at the C(7) position and formation of the hydroxylamine hemiacetal are also discussed in detail.
SCHEME 1. F R900482 (1) a n d Der iva tives
In tr od u ction
FR900482 (1), existing as an equilibrium mixture of
two tautomeric stereoisomers (1a and 1b) and N-hy-
droxybenzazocinone (2), was isolated from the fermenta-
tion harvest of Streptomyces sandaensis No. 6897 at the
Fujisawa Pharmaceutical Co. (Scheme 1).1 This com-
pound possesses potent antitumor activity against a
number of tumor cell lines, including mitomycin C- and
vincristine-resistant P388 leukemia cells.2 In extensive
efforts to develop more potent and less toxic agents,
FK973 (3)3 and FK317 (4),4 semisynthetic derivatives
from 1, were found to be promising clinical candidates.
The mode of action of this class of compounds has
recently been proven through detailed mechanistic stud-
(1) (a) Iwami, M.; Kiyoto, S.; Terano, H.; Kohsaka, M.; Aoki, H.;
Imanaka, H.J . Antibiot. 1987, 40, 589. (b) Uchida, I.; Takase, S.;
Kayakiri, H.; Kiyoto, S.; Hashimoto, M.; Tada, T.; Koda, S.; Morimoto,
Y. J . Am. Chem. Soc. 1987, 109, 4108.
(2) (a) Kiyoto, S.; Shibata. T.; Yamashita, M.; Komori, T.; Okuhara,
M.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J . Antibiot. 1987,
40, 594. (b) Shimomura, K.; Hirai, O.; Mizota, T.; Matsumoto, S.; Mori,
J .; Shibayama, F.; Kikuchi, H. J . Antibiot. 1987, 40, 600.
(3) (a) Shimomura, K.; Manda, T.; Mukumoto, S.; Masuda, K.;
Nakamura, T.; Mizota, T.; Matsumoto, S.; Nishigaki, F.; Oku, T.; Mori,
J .; Shibayama, F. Cancer Res. 1988, 48, 1166. (b) Masuda, K.;
Nakamura, T.; Mizota, T.; Mori, J .; Shimomura, K. Cancer Res. 1988,
48, 5172.
(4) (a) Naoe, Y.; Inami M.; Kawamura, I.; Nishigaki, F.; Tsujimoto,
S.; Matsumoto, S.; Manda, T.; Shimomura, K. J pn. J . Caner Res. 1998,
89, 666. (b) Naoe, Y.; Inami, M.; Matsumoto. S.; Takagaki. S.; Fujiwara.
T.; Yamazaki, S.; Kawamura, I.; Nishigaki, F.; Tsujimoto, S.; Manda,
T.; Shimomura, K. J pn. J . Cancer Res. 1998, 89, 1306. (c) Naoe, Y.;
Kawamura, I.; Inami, M.; Matsumoto, S.; Nishigaki, F.; Tsujimoto, S.;
Manda, T.; Shimomura, K. J pn. J . Cancer Res. 1998, 89, 1318.
ies.5 FR900482 (1) is activated by a two-electron reduc-
tion of the N-O bond to afford the benzazocinone
derivative (5), which then cyclizes to give the mitosene
species (6) (Scheme 2). Due to its high electrophilicity,
this species covalently cross-links duplex DNA in the
minor groove6 and also DNA and oncoproteins, such as
HMG I/Y protein.7
10.1021/jo049862z CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/20/2004
J . Org. Chem. 2004, 69, 2831-2843
2831

Suzuki et al.
SCHEME 2. P r op osed Mech a n ism of Action of
F R900482 (1)
SCHEME 3. Retr osyn th etic An a lysis of F R900482
(1)
In addition to its highly potent activity, FR900482 (1)
possesses unique structural features, including hydroxy-
lamine hemiacetal, aziridine, and carbamoyloxymethyl
groups, making it an attractive target for synthetic
organic chemists. To date, numerous approaches8 have
been explored to construct this densely functionalized
structure, and five total syntheses,9-13 as well as two
formal total syntheses,14,15 have been reported. Our
(5) For representative examples, see: (a) Shimomura, K.; Masuda,
K.; Nakamura, T.; Mizota, T.; Mori, J . Cancer Res. 1988, 48, 5172. (b)
Williams, R. M.; Rajski, S. R. Tetrahedron Lett. 1992, 33, 2929. (c)
Woo, J .; Sigurdsson, S. T.; Hopkins, P. B. J . Am. Chem. Soc. 1993,
115, 1199. (d) Huang, H.; Rajski, S. R.; Williams, R. M.; Hopkins, P.
B. Tetrahedron Lett. 1994, 35, 9669. (e) Huang, H. Pratum, T. K.;
Hopkins, P. B. J . Am. Chem. Soc. 1994, 116, 2703. (f) Paz, M. M.;
Hopkins, P. B. J . Am. Chem. Soc. 1997, 119, 5999. (g) Rajski, S. R.;
Rollins, S. B.; Williams, R. M. J . Am. Chem. Soc. 1998, 120, 2192. (h)
Paz, M. M.; Sigurdsson, S. T.; Hopkins, P. B. Bioorg. Med. Chem. 2000,
8, 173.
continuing efforts in this area have led to the first total
synthesis of racemic FR900482 (1)9 and a synthetic
approach through development of [3 + 2] cycloaddition
strategy.16 We finally accomplished an enantioselec-
tive total synthesis of FR900482 (1) in optically pure
form.17 In this paper, we provide a full account of the
development of the enantioselective total synthesis of
FR900482 (1).
(6) For a review, see: Rajski, S. R.; Williams, R. M. Chem. Rev. 1998,
98, 2723.
(7) Williams, R. M.; Rajski, S. R.; Rollins, S. B. Chem. Biol. 1997,
4, 127.
(8) (a) Yasuda, N.; Williams, R. M. Tetrahedron Lett. 1989, 30, 3397.
(b) Fukuyama, T.; Goto, S. Tetrahedron Lett. 1989, 30, 6491. (c) J ones,
R. J .; Rapoport, H. J . Org. Chem. 1990, 55, 1144. (d) McClure, K. F.;
Danishefsky, S. J . J . Org. Chem. 1991, 56, 850. (e) McClure, K. F.;
Benbow, J . W.; Danishefsky, S. J . J . Am. Chem. Soc. 1991, 113, 8185.
(f) Dmitrienco, G. I.; Denhart, D.; Mithani, S.; Prasad, G. K. B.; Taylor,
N. J . Tetrahedron Lett. 1992, 33, 5705. (g) McClure, K. F.; Danishefsky,
S. J . J . Am. Chem. Soc. 1993, 115, 6094. (h) Utsunomiya, I.; Muratake,
H.; Natsume, M. Chem. Pharm. Bull. 1995, 43, 37. (i) Martin, S. F.;
Wagman, A. S. Tetrahedron Lett. 1995, 36, 1169. (j) Miller, S. J .; Kim,
S.-H.; Chen, Z.-R.; Grubbs, R. H. J . Am. Chem. Soc. 1995, 117, 2108.
(k) Lim, H.-J .; Sulikowski, G. A. Tetrahedron Lett. 1996, 37, 5243. (l)
Ziegler, F. E.; Belema, M. J . Org. Chem. 1997, 62, 1083. (m) Rolins, S.
B.; Williams, R. B. Tetrahedron Lett. 1997, 38, 4033. (n) Mithani, S.;
Drew, D. M.; Rydberg, E. H.; Taylor, N. J .; Mooibroek, S.; Dmitrienko,
G. I. J . Am. Chem. Soc. 1997, 119, 1159. (o) Ciufolini, M. A.; Chen,
M.-G.; Lovett, D. P.; Deaton, M. V. Tetrahedron Lett. 1997, 38, 4355.
(p) Williams, R. M.; Rollins, S. B.; J udd, T. C. Tetrahedron 2000, 56,
521. (q) Zhang, W.; Wang, C.; J imenez, L. S. Synth. Commun. 2000,
30, 351. (r) Colandrea, V. J .; Rajaraman, S.; J imenez, L. S. Org. Lett.
2003, 5, 785.
(9) Fukuyama, T.; Xu, L.; Goto, S. J . Am. Chem. Soc. 1992, 114,
383.
(10) Schkeryantz, J . M.; Danishefsky, S. J . J . Am. Chem. Soc. 1995,
117, 4722.
(11) (a) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron
Lett. 1996, 37, 3471. (b) Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto,
M.; Katoh, T.; Terashima, S. Tetrahedron Lett. 1996, 37, 3475. (c)
Katoh, T.; Yoshino, T.; Nagata, Y.; Nakatani, S.; Terashima, S.
Tetrahedron Lett. 1996, 37, 3479. (d) Katoh, T.; Terashima, S. J . Synth.
Org. Chem. J pn. 1997, 55, 946.
Resu lts a n d Discu ssion
1. Syn th etic Str a tegy. FR900482 (1) could be derived
from the epoxide 7 using the synthetic route we estab-
lished in the racemic total synthesis of 1 (Scheme 3).9
Given the equilibrium between the diastereomeric hy-
droxylamine hemiacetals proceeding via the N-hydroxy-
benzazocinone (Scheme 1), we reasoned that the penta-
cyclic structure could be constructed from an eight-
membered N-hydroxybenzazocinone intermediate such as
8. For the introduction of the hydroxymethyl group, we
planned to perform a stereoselective hydroxymethylation
using a steric bias created by the protected 1,2-diol
moiety. The eight-membered ring would be formed by an
intramolecular Mitsunobu reaction18 of the ω-hydroxyni-
trobenzenesulfonamide (Ns-amide).19 The cyclization pre-
cursor 9 would be assembled from an aromatic fragment
11 and the chiral side-chain unit 12, which would be
derived easily from tartaric acid.
(16) For an approach utilizing intramolecular [3 + 2] cycloaddition
of nitrile oxide, see: Kambe, M.; Arai, E.; Suzuki, M.; Tokuyama, H.;
Fukuyama, T. Org. Lett. 2001, 3, 2575.
(12) J udd, T. C.; Williams, R. M. Angew. Chem., Int. Ed. 2002, 41,
4683.
(13) For a total synthesis of the closely related compound, FR66979,
see: Ducray, R.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2002, 41, 4688.
(14) Fellows, I. M.; Kaelin, D. E.; Martin, S. F. J . Am. Chem. Soc.
2000, 122, 10781.
(17) Suzuki, M.; Kambe, M.; Tokuyama, H.; Fukuyama, T. Angew.
Chem., Int. Ed. 2002, 41, 4686.
(18) Mitsunobu, O. Synthesis 1981, 1.
(19) (a) Fukuyama, T.; J ow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373. (b) Fukuyama, T.; Cheung, M.; J ow, C.-K.; Hidai, Y.;
Kan, T. Tetrahedron Lett. 1997, 38, 5831. (c) Fukuyama, T.; Cheung,
M.; Kan, T. Synlett 1999, 1301. (d) Kan, T.; Fukuyama, T. J . Synth.
Org. Chem., J pn. 2001, 59, 779.
(15) Paleo, M. R.; Aurrecoechea, N.; J ung, K.-Y.; Rapoport, H. J .
Org. Chem. 2003, 68, 130.
2832 J . Org. Chem., Vol. 69, No. 8, 2004

Total Synthesis of FR900482
SCHEME 4. Syn th esis of Keton e 20a
SCHEME 5. Syn th esis of Ben za zocin e 26a
a
Reagents and conditions: (i) Zn(BH4)2, Et2O, -19 °C, 2.5 h;
(ii) Ac2O, DMAP, pyridine, rt, 3 h, 92% (two steps); (iii) H2, 5%
Pt/C, MeOH, rt, 52 h, 65%; (iv) 2-NsCl, pyridine, rt, 1 h, 73%; (v)
TBAF, THF, rt, 41 h; (vi) DEAD, Ph3P, benzene, rt, 1 h, 71% (two
steps).
a
Reagents and conditions: (i) NaH, TBSCl, THF, 0 °C, 1.5 h,
76%; (ii) (COCl)2, DMSO, CH2Cl2, -78 °C, 1 h, then Et3N, -78 °C
to rt; (iii) dimethyl 1-diazo-2-oxopropylphosphonate, K2CO3, MeOH,
0 °C to rt, 2 h, 49% (2 steps); (iv) Pd(OAc)2 (10 mol %), Ph3P (20
mol %), THF/ Et3N (2/1), 65 °C, 2 h, 83%; (v) pyrrolidine, benzene,
rt, 1 h, then 50% aq AcOH, rt, 4 h, 90%.
to the o-nitroarylacetylenes occurred regioselectively to
generate the desired enamine. Thus, treatment of the
acetylene 18 with pyrrolidine gave the corresponding
enamine 19 at room temperature, which was then hy-
drolyzed under acidic conditions (50% AcOH/H2O) to
afford the ketone 20 in 90% overall yield from 18.
3. F ir st-Gen er a tion Ap p r oa ch to th e P en ta cyclic
Key In ter m ed ia te. F or m a tion of th e Eigh t-Mem -
ber ed Ben za zocin e Rin g by Ns P r otocol. Having
synthesized the ketone 20 in a straightforward manner,
we then focused our attention on the construction of the
eight-membered benzazocine ring. To this end, we ex-
amined the intramolecular Mitsunobu reaction18 of an
ω-hydroxynitrobenzenesulfonamide 25, since this proto-
col has proved to be effective for formation of medium-
sized cyclic secondary amines.26
2. Syn th esis of th e Cycliza tion P r ecu r sor via a
Novel Keton e F or m a tion Rea ction . The synthesis
began with the preparation of the arylacetylene 18
(Scheme 4). Monosilylation of 2,3-di-O-isopropylidene-D-
threitol (13),20 which is readily available from D-tartaric
acid, gave the silyl ether 14. After Swern oxidation,21 the
resultant aldehyde 15 was treated with dimethyl 1-diazo-
2-oxopropylphosphonate in the presence of K2CO3, which
led to the terminal acetylene 16.22,23 However, the Sono-
gashira coupling24 reaction of 16 with the triflate 1710
under standard conditions (PdCl2(PPh3)2 and CuI in
Et3N) gave a substantial amount of the byproduct due
to homocoupling of the acetylene 16. After screening
various conditions, we found that the desired cross-coup-
ling reaction was best effected with Pd(OAc)2 and Ph3P
in a mixture of THF and Et3N at 65 °C to afford the
arylacetylene 18 in 83% yield.
The next task was to convert the arylacetylene 18 into
the ketone 20. Conventional conditions such as the
palladium-mediated hydration reaction usually gives a
mixture of regioisomeric ketones.25 Thus, it was necessary
to devise a novel protocol to carry out this transformation
regioselectively. An extensive investigation revealed that
an unprecedented conjugate addition of secondary amines
The ketone 20 was reduced stereoselectively with
27
Zn(BH4)2 to give the alcohol 21, which was subjected
to acetylation and removal of the minor diastereomer by
column chromatography on silica gel to give 22 (Scheme
5). The nitro group was then selectively reduced by
hydrogenation over Pt/C to give the aniline 23, which was
converted to the nitrobenzenesulfonamide 24 by treat-
ment with 2-NsCl in pyridine. Finally, desilylation of 24
with TBAF provided the cyclization precursor 25. The
crucial intramolecular Mitsunobu reaction18 took place
at room temperature by slow addition of a toluene
solution of DEAD to the reaction mixture to give the
desired benzazocine 26 in 71% yield from 24.
(20) Mash, E. A.; Nelson, K. A.; Deusen, S. V.; Hemperly, S. B. Org.
Synth. 1990, 68, 92.
(21) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480.
(22) (a) Mu¨ller, S.; Liepold, B.; Roth, G. J .; Bestmann. H. J . Synlett
1996, 521. (b) Callant, P.; D’Haenens, L.; Vandewalle, M. Synth.
Commun. 1984, 14, 155.
(25) For conversion of phenylacetylenes to ketones, see; (a) Imi, K.;
Imai, K.; Utimoto, K. Tetrahedron Lett. 1987, 28, 3127. (b) Picquet,
M.; Bruneau, C.; Dixneuf, P. H. Tetrahedron 1999, 55, 3937. After
completion of this work, we learned that a similar conjugate addition
to activated phenyl acetylene derivatives occurs; see: Ivanchikova, I.
D.; Myasnikova, R. N.; Shvartsberg, M. S. Russ. Chem. Bull. (Transl.
Izv. Akad. Nauk, Ser. Khim.) 1998, 47, 1975.
(23) An alternative procedure for the preparation of 16: (a) Pandey,
G.; Kapur, M. Tetrahedron Lett. 2000, 41, 8821. (b) Iida, H.; Yamazaki,
N.; Kibayashi, C. J . Org. Chem. 1987, 52, 3337.
(24) Sonogashira, K., Tohda, Y., Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(26) (a) Kan, T.; Kobayashi, H.; Fukuyama, T. Synlett 2002, 697.
(b) Kan, T.; Fujiwara, A. Kobayashi, H.; Fukuyama, T. Tetrahedron
2002, 58, 6267.
(27) Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi, T. Chem. Pharm. Bull.
1984, 32, 1411.
J . Org. Chem, Vol. 69, No. 8, 2004 2833

Suzuki et al.
SCHEME 6. In tr od u ction of Hyd r oxym eth yl
Gr ou p a
hydroxymethyl group, including conjugate addition of a
thiol, Pummerer reaction,28 and reduction of the resulting
aldehyde. Methylenation of the ketone 29 was best
effected by treatment with Me2NH‚HCl, HCHO, and
Et3N. After Michael addition of PhSH to the R,â-unsatur-
ated ketone 30, the ketone functionality was reduced with
NaBH4 and the resulting alcohol was acetylated to give
the sulfide 32 as the sole product. The sulfide 32 was
oxidized with m-CPBA and subsequently treated with
TFAA and Et3N. Finally the reaction mixture was poured
into a suspension of NaBH4 in MeOH to furnish the
desired primary alcohol 34 in 73% overall yield from 32.
Despite the successful installation of the hydroxymethyl
group at the C(7) position, the stereochemistry of C(7),
which was determined to be the S configuration by an
NOE experiment, was opposite to that of the natural
product. However, we continued our investigation since
the correct stereoisomer ent-34 could be prepared, in
principle, using L-tartaric acid as a starting compound
instead of the D-enantiomer.
F or m a tion of th e P en ta cyclic Sk eleton . The ben-
zazocine derivative 34 bearing the hydroxymethyl group
was next advanced to the N-hydroxybenzazocinone, a
precursor of the hydroxylamine hemiacetal. The acetate
34 was reduced by DIBAL, and the resulting diol was
monosilylated regioselectively to give the silyl ether 36.
After removal of the o-nitrobenzenesulfonyl group,19 the
resultant secondary amine was oxidized with m-CPBA
to give the hydroxylamine 38, which was protected as
its acetate. Finally, Swern oxidation21 of the secondary
alcohol 39 furnished the desired ketone 40 (Scheme 7).
Upon treatment of the ketone 40 with excess hydra-
zine, the desired hydroxylamine hemiacetal 41 was
obtained as a 79:21 mixture of the diastereomers in 78%
yield. Surprisingly, however, the configuration of the C(7)
stereocenter of the major product was inverted to R,
which is same as that of the natural FR900482. The
structure was confirmed by NOE experiments of the
major isomer, in which a significant NOE between H(7)
and H(10) was observed.
Next, the hemiacetal 41 was transformed into the
pentacyclic R-epoxide 7, the key intermediate in the
synthesis of racemic FR900482 (1) (Scheme 8).9 First, the
four protected and unprotected hydroxyl groups were
manipulated to liberate the 1,2-trans-diol at the 9,10-
position. The acetonide 41 was converted to the tetraol
42 by heating with Amberlyst 15E in MeOH. The
primary alcohol and hemiacetal were selectively pro-
tected as an acetonide to give the 1,2-diol 43. Stereose-
lective construction of the R-epoxide was then executed
by a four-step sequence involving silylation of the less
hindered hydroxyl group at C(10), mesylation of the
remaining C(9) hydroxyl group, desilylation, and finally
treatment with NaH by heating in DMF to furnish the
desired R-epoxide 7, whose spectral data were identical
with those of the corresponding compound reported in
our racemic total synthesis.9
a
Reagents and conditions: (i) DIBAL, CH2Cl2, -78 °C, 75 min;
(ii) 4-methoxyphenol, DEAD, Ph3P, benzene, rt, 20 min, 68% (two
steps); (iii) (COCl)2, DMSO, CH2Cl2, -78 °C, 0.5 h, then Et3N, -78
°C to rt, 72%; (iv) Me2NH‚HCl, 37% aq HCHO, Et3N, 2-PrOH, H2O,
90 °C, 4.5 h; (v) PhSH, Et3N, THF, MeOH, rt, 3 h; then NaBH4, 0
°C, 15 min, 84% (2 steps); (vi) Ac2O, DMAP, pyridine, 0 °C to rt,
2.5 h, 80%; (vii) m-CPBA, CH2Cl2, -13 °C, 75 min; (viii) TFAA,
Et3N, toluene, 0 °C, 0.5 h; then NaBH4, MeOH, -78 °C to rt, 1 h,
73% (two steps).
Con str u ction of th e Hyd r oxym eth yl Gr ou p a t th e
C(7) P osit ion . With the eight-membered benzazocine
ring in hand, we next investigated the crucial introduc-
tion of the hydroxymethyl group at the C(7) position
(Scheme 6). Prior to this step, it was necessary to regen-
erate the ketone at the C(8) position and convert the car-
bomethoxy group to the p-methoxyphenyl ether. DIBAL
reduction of the acetate 26 gave the diol 27, whose
primary alcohol was protected as the p-methoxyphenyl
ether under Mitsunobu conditions.18 Swern oxidation21
of the remaining secondary alcohol furnished the ketone
29 in 72% yield. Unfortunately, hydroxymethylation
(HCHO, LiOH, THF/H2O) did not afford the desired
product but instead the R,â-unsaturated ketone 30 as the
major product due to elimination of the OH group.
These disappointing results prompted us to consider
a stepwise conversion of the exo-methylene group to the
4. Secon d -Gen er a tion Ap p r oa ch to th e P en ta cy-
clic Key In ter m ed ia te. Although this newly developed
synthetic route to the key epoxide 7 would formally
provide 1 in optically pure form, further improvements
were needed to circumvent various lengthy transforma-
(28) DeLucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157.
2834 J . Org. Chem., Vol. 69, No. 8, 2004

Total Synthesis of FR900482
SCHEME 7. Syn th esis of Hem ia ceta l 41a
SCHEME 8. Syn th esis of th e Key In ter m ed ia te 7a
a
Reagents and conditions: (i) Amberlyst 15E, MeOH, 40 °C, 1
h, 90%; (ii) PPTS, 2-methoxypropene, 2,2-dimethoxypropane,
acetone, rt, 40 min, 78%; (iii) TESCl, Et3N, DMAP, CH2Cl2, 0 °C,
3 h; (iv) MsCl, Et3N, CH2Cl2, rt, 3 h; (v) TBAF, THF, rt, 1 h, 80%
(3 steps); (vi) NaH, DMF, 120 °C, 10 min, 90%.
a
SCHEME 9. Secon d -Gen er a tion Str a tegy
Reagents and conditions: (i) DIBAL, CH2Cl2, -78 °C, 1 h; (ii)
TBSCl, Et3N, DMAP, CH2Cl2, rt, 1 h; (iii) Cs2CO3, PhSH, MeCN,
rt, 1 h, 73% (three steps); (iv) m-CPBA, CH2Cl2, rt, 30 min; (v)
Ac2O, rt, 12 h; (vi) (COCl) 2, DMSO, CH2Cl2, -78 °C, 0.5 h, then
Et3N, -78 °C to rt, 71% (3 steps); (vii) NH2NH2‚H2O, MeOH/
CH2Cl2 (1/1), rt, 1 h, 78%.
tions, i.e., construction of the hydroxymethyl group and
subsequent conversion to the hydroxylamine hemiacetal
41a involving oxidation of nitrogen and protection/
deprotection of hydroxyl groups. Therefore, we began
reinvestigating more efficient routes.
The second-generation strategy is illustrated in Scheme
9. For construction of the eight-membered ring, we
planned to exploit an intramolecular reductive cyclization
of the functionalized ω-formyl nitrobenzene derivative 48.
We expected a direct formation of N-hydroxybenzazocine
through selective reduction of the nitro group to the
hydroxylamine29 and subsequent intramolecular nitrone
formation and reduction.30 We also thought that, in light
of the successful stereoselective hydroxymethylation of
the analogous 9,10-epoxy N-acetyl substrate in the ra-
cemic synthesis,31 the problematic hydroxymethylation
of the C(7) position could be carried out using a 9,10-
epoxy substrate.
tion synthesis commenced with the stereoselective con-
struction of the epoxide on the side chain of the cycliza-
tion precursor. The secondary alcohol in ent-21, which
was prepared according to the sequence shown in Schemes
4 and 5,32 was protected as the TIPS ether and subse-
quent selective removal of both the acetonide and TBS
Con str u ction of th e Eigh t-Mem ber ed Rin g by
Red u ctive Hyd r oxyla m in a tion . The second-genera-
(29) For examples, see; (a) Kamm, O. Organic Syntheses; Wiley:
New York, 1941; Collect. Vol. I, p 445. (b) Davey, M. H.; Lee, V. Y.;
Miller, R. D.; Marks, T. J . J . Org. Chem. 1999, 64, 4976. (c) Wood, W.
W.; Kremp, G.; Petry, T.; Simon, W. E. J . Synth. Commun. 1999, 29,
619.
(30) For a synthetic approach based on a similar concept, see; ref
8a.
(31) In the synthesis of racemic FR900482, we succeeded in obtain-
ing stereoselective installation of the side chain at the C(7) position
by using an N-acetyl-9,10-epoxybenzazocinone derivative; see ref 9.
J . Org. Chem, Vol. 69, No. 8, 2004 2835

Suzuki et al.
SCHEME 10. Syn th esis of N-Hyd r oxyben za zocin e
SCHEME 11. Syn th esis of th e P en ta cyclic
56a
In ter m ed ia te 7a
a
Reagents and conditions: (i) TIPSOTf, 2,6-lutidine, CH2Cl2,
rt, 7 h; (ii) AcOH/H2O (5/1), 100 °C, 4 h, 61% (two steps); (iii)
TBSCl, Et3N, DMAP, CH2Cl2, rt, 13 h; (iv) TsCl, DABCO, CH2Cl2,
rt, 1.5 h; (v) NaH, DMF, 0 °C to rt, 1 h, 76% (3 steps); (vi) CSA,
MeOH, rt, 1 h; (vii) Dess-Martin periodinane, CH2Cl2, 0 °C to rt,
0.5 h; (viii) H2, 5% Pt/C, MeOH, rt, 2 h, 89% (three steps).
group by heating in a mixture of AcOH and H2O
furnished the triol 50 (Scheme 10). The triol 50 was
converted to the desired R-epoxide 53 by selective protec-
tion of the primary alcohol, regioselective tosylation of
the sterically less hindered hydroxyl group, and finally
treatment with NaH to furnish the R-epoxide 53 in 76%
overall yield from 50.
With the epoxide in hand, we focused our attention on
the reductive cyclization of the eight-membered ring.
Conversion of the TBS ether 53 to the cyclization precur-
sor 55 was performed by desilylation followed by oxida-
tion of the resulting primary alcohol with Dess-Martin
periodinane.33 After screening several catalysts (Pt/C,
PtO2, Rh/C) and solvents (MeOH, THF, AcOEt), we found
that catalytic hydrogenation over Pt/C in MeOH cleanly
proceeded to give the N-hydroxybenzazocine 56 as the
sole product in 89% overall yield from 53. No product due
to overreduction was observed.
Ster eoselective Hyd r oxym eth yla tion a n d F a cile
Con str u ction of th e P en ta cyclic Hyd r oxyla m in e
Hem ia ceta l Str u ctu r e. Having successfully constructed
the N-hydroxybenzazocine ring, we were ready for the
key construction of the hydroxymethyl group at the C(7)
position. The hydroxylamine was protected as the 1-meth-
oxy-1-methylethyl ether and then the TIPS group was
removed. The liberated secondary alcohol 58 was sub-
jected to Swern oxidation21 to afford the ketone 59
a
Reagents and conditions: (i) 2-methoxypropene, TsOH‚H2O,
CH2Cl2, rt, 10 min; (ii) TBAF, THF, rt, 12 h, 91% (two steps); (iii)
(COCl)2, DMSO, CH2Cl2, -78 °C, 0.5 h, then Et3N, -78 °C to rt,
0.5 h, 82%; (iv) 37% aq HCHO, LiOH, THF/H2O (20/3), 0 °C, 5 h,
52%, 94:6; (v) 37% aq HCHO, LiOH, THF/H2O (20/3), 0 °C, 5 h;
then 1 N HCl, 0 °C to rt, 10 h, 61a /61b ) 87:13; (vi) PPTS,
2-methoxypropene, 2,2-dimethoxypropane, acetone, rt, 3 h, 65%
(from 59); (vii) DIBAL, CH2Cl2, -78 °C, 1 h, 99%; (vii) 4-methoxy-
phenol, DEAD, Ph3P, benzene, rt, 15 min, 96%.
(Scheme 11). The crucial hydroxymethylation was best
effected by treatment of the ketone 59 with a catalytic
amount of LiOH and excess formalin in aqueous THF at
0 °C to furnish the desired 7-hydroxymethyl benzazoci-
none 60 with high diastereoselectivity (94:6). The ster-
eochemistry of the major isomer was unambiguously
established to be the required C(7) R based on the NOE
observation between H(7) and H(9).
(32) For a detailed experimental procedure, see the Supporting
Information.
(33) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Meyer, S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.
In practice, we performed a more efficient one-pot
conversion of the ketone 59 into the hydroxylamine
hemiacetals. Thus, after hydroxymethylation, the reac-
2836 J . Org. Chem., Vol. 69, No. 8, 2004

Total Synthesis of FR900482
SCHEME 12. Tota l Syn th esis of F R900482 (1)a
pyridine. The p-methoxyphenyl group was removed by
treatment with ceric ammonium nitrate,34 and the re-
sulting alcohol was oxidized with PCC to afford the
corresponding benzaldehyde derivative. The relatively
unstable formyl group was protected as the dimethyl
acetal 68. Next, aziridine 69 was prepared by heating
the mesylate 68 with Ph3P in aqueous THF in the
presence of i-Pr2NEt. Removal of the two protective
groups, the benzyl ether and the dimethyl acetal, was
successfully carried out by standard hydrogenation and
cautious addition of 1% HClO4 in aqueous THF, respec-
tively. Finally, regioselective ammonolysis was executed
by bubbling ammonia gas into a THF solution of the
carbonate 71 to give FR900482. The synthetic material
was identical with an authentic sample in all respects.1b,2a
6. Ster eoch em ica l Issu es in Hyd r oxym eth yla tion
a n d Hyd r oxyla m in e Hem ia ceta l F or m a tion . Con-
trolling the stereochemistry in the hydroxymethylation
at the C(7) position and the hydroxylamine hemiacetal
formation was a critical aspect in both routes described
herein and merits more detailed discussions.
In the first generation synthesis, the stepwise sequence
for the construction of the hydroxymethyl group at the
C(7) position provided the C(7) S isomer 34 although the
C(7) R isomer was required for the synthesis of the
natural FR900482 (Scheme 6). This is probably due to a
protonation from the less-hindered R-face in the conju-
gate addition of thiophenol to the enone 30. However,
after the formation of the hydroxylamine hemiacetal, the
configuration of the C(7) chiral center of the major
product 41a was determined to be C(7) R (Scheme 7).
This observation could be explained by the fact that
during the formation of the hydroxylamine hemiacetal,
epimerization of the C(7) chiral center took place due to
enolization of the N-hydroxybenzazocinone derivative 40
with excess hydrazine, resulting in the formation of the
thermodynamically most stable isomer as the major
product.35 In fact, when the ketone 40 was treated with
excess hydrazine in a mixture of CD3OD-CDCl3, the C(7)
position of the resulting hemiacetal was completely
deuterated, suggesting a facile enolization of the ketone
40 under weakly basic conditions. In addition, the
thermal stability of the major isomer is supported by
preliminary semiempirical calculations comparing the
relative stability of all four possible isomers of the model
compounds (72-75, Figure 1).36 As shown in Figure 1,
the 7R-isomers (72, 73) are lower in energy relative to
the corresponding 7â-isomers (74, 75).
a
Reagents and conditions: (i) LiN3, DMF/H2O (10/1), 120 °C,
3.5 h, 83%; (ii) MsCl, Et3N, CH2Cl2, rt, 3 h, 80%; (iii) TFA, CH2Cl2,
rt, 3 h; (iv) (Cl3CO)2CdO, pyridine, CH2Cl2, 0°C, 30 min, 92% (two
steps); (v) (NH4)2Ce(NO3)6, MeCN/H2O (4/1), rt, 10 min, 84%; (vi)
PCC, MgSO4, CH2Cl2, rt, 1.5 h; (vii) CSA, CH(OMe)3/MeOH (1/4),
rt, 1 h, 81% (two steps); (viii) Ph3P, i-Pr2NEt, THF/H2O (10/1), 60
°C, 1.5 h, 85%; (ix) H2 (1 atm), 10% Pd/C, EtOH, rt, 2.5 h, 97%; (x)
1% HClO4, THF/H2O (10/1), rt, 3.5 h; (xi) NH3 (gas), THF, rt, 2 h,
83% (two steps).
tion mixture was acidified with 1 N HCl to remove the
mixed-acetal protecting group on the hydroxylamine. The
reaction was allowed to warm to room temperature,
and the desired hemiacetal was obtained as a mixture
of the diastereomeric tautomers (61a /61b 87:13). This
mixture was then subjected to acetonide formation to
give the pentacyclic epoxide 62a (56% isolated yield
from the ketone 59). Finally, DIBAL reduction of methyl
ester and protection of the resulting benzyl alcohol as
the p-methoxyphenyl ether34 gave the pentacyclic inter-
mediate 7, a key intermediate for the synthesis of
FR900482 (1).
5. Com p letion of th e Tota l Syn th esis. Finally, the
total synthesis of optically pure FR900482 (1) was
completed by a modification of our racemic synthesis
(Scheme 12).9 Regioselective ring-opening of the epoxide
7 took place with LiN3 in aqueous DMF at 120 °C. After
mesylation of the hydroxyl group, the acetonide was
converted to the cyclic carbonate 66 by hydrolysis with
TFA and treatment with triphosgene in the presence of
In the second-generation synthesis, the C(7) R stereo-
chemistry could be successfully established by an aldol
reaction, in which hydroxymethylation of the lithium
enolate occurred from the less hindered R-side (Scheme
11). In contrast to the formation of the hydroxylamine
hemiacetal under the weakly basic conditions discussed
above, the ketone 60 was successfully converted to the
hemiacetals 61a and 61b with retention of the C(7)
configuration under mildly acidic conditions (Scheme 13).
(34) Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetrahedron Lett.
1985, 26, 6291.
(35) For formation of a hydroxylamine hemiacetal derivative pos-
sessing the same relative stereochemistry corresponding to C(7), C(9),
and C(10), see ref 16.
(36) The minimizations were performed on the simplified models
using the SPARTAN program (SPARTAN ‘02, ver 1.0) employing PM3
parameters.
J . Org. Chem, Vol. 69, No. 8, 2004 2837

Suzuki et al.
Con clu sion
We have accomplished an enantioselective total syn-
thesis of the antitumor antibiotic FR900482 (1).38 The
precursor for the cyclization of the benzazocine ring could
be prepared effectively by taking advantage of the newly
developed ketone formation from the o-nitrophenylacety-
lene derivatives. For the formation of the eight-mem-
bered benzazocine ring, we devised two different meth-
ods, namely, a nitrobenzenesulfonamide protocol and an
intramolecular reductive hydroxylamination reaction.
These methods should be useful not only for this class of
compounds but also for a range of medium-sized nitrogen-
containing cyclic compounds. The critical stereoselective
construction of the hydroxymethyl side chain at the C(7)
position and the hydroxylamine hemiacetal could be
performed by a facile one-pot protocol that enabled us to
synthesize the pentacyclic key intermediate 7.
F IGURE 1. Relative energies of the four diastereoisomeric
hemiacetals.
SCHEME 13
Exp er im en ta l Section
[(4R,5R)-5-(ter t-Bu t yld im et h ylsilyloxym et h yl)-2,2-d i-
m eth yl-1,3-d ioxola n -4-yl]m eth a n ol (14). To a suspension
of NaH (60% in oil, 30.0 g, 1.25 mol) in THF (1 L) was added
a solution of 2,3-di-O-isopropylidene-D-threitol (13) (87.5 g, 0.54
mol) in THF (150 mL) dropwise over 1 h at room temperature.
The reaction mixture was stirred for an additional 1 h and
cooled to 0 °C. To the mixture was added a solution of TBSCl
(97.6 g, 0.65 mol) in THF (200 mL) dropwise over 1 h. Stirring
was continued for 30 min, and the reaction mixture was poured
into crushed ice (300 mL) and extracted with Et2O. The organic
layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. The resulting residue was
purified by flash column chromatography (hexane/EtOAc, 9:1
then 1:1) on silica gel to afford 14 (113 g, 76%) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 3.99 (td, J ) 4.6, 7.6 Hz,
1H), 3.91-3.86 (m, 2H), 3.79-3.64 (m, 3H), 2.38 (dd, J ) 4.4,
8.3 Hz, 1H), 1.42 (s, 3H), 1.40 (s, 3H), 0.90 (s, 9H), 0.09 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 109.1, 80.2, 78.1, 63.7, 62.7,
27.0, 26.9, 25.8, 18.3, -5.52, -5.55; IR (neat) 3466, 1254, 1083
cm-1; [R]23 -13.8 (c 1.09, CHCl3); MS (ESI) m/z 277 ([M +
D
H]+).
[(4R,5R)-5-(ter t-Bu t yld im et h ylsilyloxym et h yl)-2,2-d i-
m eth yl-1,3-d ioxola n -4-yl]eth yn e (16). To a solution of oxalyl
chloride (36.8 g, 0.29 mol) in CH2Cl2 (1 L) was added a solution
of DMSO (34.1 mL, 0.48 mol) in CH2Cl2 (50 mL) at -78 °C,
and the resulting solution was stirred for 10 min. A solution
of the alcohol 14 (67.3 g, 0.24 mol) in CH2Cl2 (70 mL) was
added dropwise over 30 min. After the solution had stirred
for an additional 30 min, Et3N (100 mL, 0.72 mol) was added
and the reaction mixture was allowed to warm to room tem-
perature and stirred for 1 h. The reaction mixture was poured
into 10% aqueous citric acid and extracted with CH2Cl2. The
organic layer was washed with saturated aqueous NaHCO3
and brine, dried over MgSO4, and concentrated under reduced
pressure to give the crude aldehyde 15 (57.3 g) as a pale yellow
oil. The crude aldehyde was dissolved in MeOH (1 L), to which
was added K2CO3 (58.0 g, 0.42 mol) then dimethyl 1-diazo-2-
oxopropylphosphonate (48.4 g, 0.25 mol) at 0 °C. The reaction
mixture was allowed to warm to room temperature and stirred
for 2 h. The mixture was filtered through a pad of Celite, and
concentrated. The residue was taken up in EtOAc and the
In addition, subjection of the mixture of 61a and 61b to
acidic acetalization conditions provided the corresponding
mixture of acetonides 62a and 62b in the same ratio as
61a /61b. Furthermore, removal of the acetonide from the
separated 62a or 62b gave the corresponding hemiacetal
61a or 61b, respectively, as the exclusive product with
no appreciable formation of the other isomers. Therefore,
it is likely that under acidic conditions, the formation of
the hydroxylamine hemiacetal would be a kinetically
controlled process and once the hemiacetal is formed, no
interconversion of the diastereomeric hemiacetals 61a
and 61b by ring opening back to the keto-form 60 would
take place.37
(37) The C(7) position of the tetraol 42 was not deuterated by
treatment with trifluoroacetic acid-d, suggesting no enolization under
acidic conditions.
(38) To compare the efficiency of the first and the second generation
syntheses, total number of steps and total yields from the commercially
available 2,3-di-O-isopropylidenethreitol were calculated. Total yield
of 1 was ca. 0.12% over 43 total steps by the first-generation synthesis
and ca. 2.1% over 32 steps by the second-generation synthesis.
2838 J . Org. Chem., Vol. 69, No. 8, 2004

Total Synthesis of FR900482
solution was washed with brine, dried over MgSO4, concen-
trated under reduced pressure, and purified by flash column
chromatography (hexane/EtOAc, 9:1 then 1:1) on silica gel to
afford 16 (31.6 g, 49%) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 4.59 (dd, J ) 2.2, 7.3 Hz, 1H), 4.12 (td, J ) 4.2, 7.3
Hz, 1H), 3.78 (d, J ) 4.2 Hz, 2H), 2.51 (d, J ) 2.2 Hz, 1H),
1.49 (s, 3H), 1.41 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 110.6, 82.1, 81.2, 74.3, 66.9, 61.9, 26.8,
crude product was purified by preparative TLC (hexane/EtOAc
4:1) to give the pure 49 as a yellow oil for the characteriza-
tion: 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J ) 1.5 Hz, 1H),
7.76 (d, J ) 1.5 Hz, 1H), 7.44-7.36 (m, 5H), 5.16 (d, J ) 11.2
Hz, 1H), 5.12 (d, J ) 11.2 Hz, 1H), 4.31-4.26 (m, 1H), 4.03-
3.99 (m, 1H), 3.95 (s, 3H), 3.64 (dd, J ) 4.4, 11.2 Hz, 1H), 3.60
(dd, J ) 3.9, 11.2 Hz, 1H), 3.56 (dd, J ) 3.9, 7.8 Hz, 1H), 3.48
(dd, J ) 7.3, 12.7 Hz, 1H), 3.33 (dd, J ) 7.8, 12.7 Hz, 1H),
1.31 (s, 3H), 1.25 (s, 3H), 0.98-0.90 (m, 21H), 0.80 (s, 9H),
-0.026 (s, 3H), -0.029 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
165.1, 158.0, 152.1, 135.3, 129.6, 128.7, 128.6, 128.0, 127.3,
117.9, 114.9, 108.9, 79.6, 77.1, 71.4, 70.6, 63.5, 52.7, 30.5, 26.9,
26.7, 25.8, 18.2, 18.1, 12.9, -5.48, -5.57; IR (neat) 2947, 1730,
26.2, 25.8, 18.3, -5.37, -5.48; IR (neat) 3313, 1255, 1087 cm-1
;
[R]23 +11.8 (c 0.92, CHCl3); MS (EI) m/z 270 ([M]+).
D
Meth yl 3-Ben zyloxy-4-[(4R,5R)-5-(ter t-bu tyld im eth yl-
silyloxym eth yl)-2,2-d im eth yl-1,3-d ioxola n -4-yl]eth yn yl-
5-n itr oben zoa te (18). To a mixture of the triflate 17 (39.2 g,
88.7 mmol), Ph3P (4.65 g, 17.7 mmol), and Pd(OAc)2 (1.99 g,
8.87 mmol) in degassed THF/ Et3N (200 mL/200 mL) under
Ar was added a solution of the acetylene 16 (27.5 g, 0.129 mol)
in THF (200 mL) dropwise over 1.5 h at 65 °C. The reaction
mixture was stirred for 30 min at the same temperature. The
solvent was removed under reduced pressure, and the resi-
due was partitioned between EtOAc and 10% aqueous citric
acid. The organic layer was washed with saturated aqueous
NaHCO3 and brine, dried over MgSO4, concentrated, and
purified by flash column chromatography (hexane/EtOAc, 9:1)
on silica gel to afford 18 (40.9 g, 83%) as a brown oil: 1H NMR
(400 MHz, CDCl3) δ 8.23 (d, J ) 1.4 Hz, 1H), 7.82 (d, J ) 1.2
Hz, 1H), 7.49-7.33 (m, 5H), 5.24 (s, 2H), 4.92 (d, J ) 7.0 Hz,
1H), 4.23 (ddd, J ) 3.6, 3.9, 7.0 Hz, 1H), 3.96 (s, 3H), 3.79 (dd,
J ) 3.9, 11.2 Hz, 1H), 3.74 (dd, J ) 3.6, 11.2 Hz, 1H), 1.46 (s,
1540, 1289, 1140 cm-1; [R]23 +23.4 (c 1.26, CHCl3); MS (ESI)
D
m/z 732 ([M + H]+).
Meth yl 3-Ben zyloxy-5-n itr o-4-[(2S,3R,4S)-3,4,5-tr ih y-
d r oxy-2-tr iisop r op ylsilyloxyp en tyl]ben zoa te (50). A solu-
tion of the preceding TIPS ether 49 (10.1 g) in AcOH/H2O (100
mL/20 mL) was heated at 100 °C for 4 h. The solvent was
removed under reduced pressure, and the resulting residue
was purified by flash column chromatography (hexane/EtOAc,
9:1 then 1:1) on silica gel to afford 50 (3.37 g, 61% from ent-
21) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J
) 1.5 Hz, 1H), 7.79 (d, J ) 1.0 Hz, 1H), 7.46-7.36 (m, 5H),
5.18 (s, 2H), 4.46-4.41 (m, 1H), 3.94 (s, 3H), 3.60-3.54 (m,
2H), 3.48-3.39 (m, 2H), 3.27 (dd, J ) 6.4, 13.2 Hz, 1H), 3.17-
3.13 (m, 1H), 2.99 (br, 1H), 2.68 (d, J ) 7.8 Hz, 1H), 2.18 (br,
1H), 0.87-0.96 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 164.9,
157.8, 151.9, 135.1, 130.2, 128.8, 128.7, 128.2, 125.7, 117.71,
117.65, 115.3, 115.2, 72.1, 71.70, 71.66, 71.5, 63.9, 52.7, 30.8,
18.0, 12.7; IR (neat) 3447, 1725, 1535, 1291 cm-1; [R]23D +30.9
(c 1.35, CHCl3); HRMS (ESI) m/z calcd for C29H44NO9Si ([M +
H]+) 578.2785, found 578.2820.
Meth yl 3-Ben zyloxy-4-[(2S,3R,4S)-5-(ter t-bu tyld im eth -
ylsilyloxy)-3,4-d ih yd r oxy-2-tr iisop r op ylsilyloxy]p en tyl-
5-n itr oben zoa te (51). To a solution of the triol 50 (3.36 g,
5.82 mmol) in CH2Cl2 (15 mL) were successively added Et3N
(1.95 mL, 14.0 mmol), DMAP (73 mg, 0.60 mmol), and TBSCl
(1.06 g, 7.00 mmol) at room temperature. The reaction mixture
was stirred for 13 h at the same temperature, diluted with
CHCl3, and washed with 10% aqueous citric acid, saturated
aqueous NaHCO3, and brine. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure to give the
TBS ether 51 (4.50 g), which was used for the next reaction
without further purification. A small portion of the crude
product was purified by preparative TLC (hexane/EtOAc, 4:1)
to give the pure 51 as a yellow oil for the characterization:
1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.74 (s, 1H), 7.43-
7.33 (m, 5H), 5.14 (s, 2H), 4.41-4.36 (m, 1H), 3.91 (s, 3H),
3.71-3.66 (m, 1H), 3.60-3.44 (m, 3H), 3.29 (dd, J ) 7.3, 13.2
Hz, 1H), 3.24-3.20 (m, 1H), 2.82 (d, J ) 2.9 Hz, 1H), 2.57 (d,
J ) 7.3 Hz, 1H), 0.94-0.82 (m, 21H), 0.77 (s, 9H), -0.03 (s,
3H), -0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.0, 157.9,
152.1, 135.2, 129.8, 128.8, 128.6, 127.9, 126.9, 117.8, 115.1,
73.1, 71.5, 71.3, 71.1, 64.5, 52.7, 30.0, 25.8, 18.1, 18.0, 17.9,
12.8, -5.6; IR (neat) 3545, 1730, 1539, 1290 cm-1; [R]25D +31.3
(c 0.96, CHCl3); HRMS (ESI) m/z calcd for C35H58NO9Si2 ([M
+ H]+) 692.3650, found 692.3624.
3H), 1.44 (s, 3H), 0.89 (s, 9H), 0.070 (s, 3H), 0.067 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 164.5, 160.7, 151.1, 135.2, 130.7,
128.7, 128.4, 127.2, 117.4, 116.2, 112.0, 110.9, 102.6, 82.2, 76.3,
71.4, 67.4, 61.8, 52.9, 26.8, 25.9, 25.8, 18.3, -5.36, -5.49; IR
(neat) 1731, 1539, 1297, 1245, 1056 cm-1; [R]23D +38.8 (c 0.70,
CHCl3); HRMS (ESI) m/z calcd for C29H41N2O8Si ([M + NH4]+)
573.2632, found 573.2695.
Meth yl 3-Ben zyloxy-4-[2-[(4S,5R)-5-(ter t-bu tyld im eth -
ylsilyloxym eth yl)-2,2-d im eth yl-1,3-d ioxola n -4-yl]-2-oxo]-
eth yl-5-n itr oben zoa te (20). To a solution of the alkyne 18
(11.5 g, 20.7 mmol) in benzene (60 mL) was added pyrrolidine
(6.00 mL, 72.5 mmol), and the mixture was stirred for 1 h at
room temperature. To the mixture was added 50% aqueous
acetic acid (40 mL), and the resulting mixture was vigorously
stirred for 4 h at room temperature. The separated organic
layer was washed with saturated aqueous NaHCO3, 10%
aqueous citric acid, and brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by
flash column chromatography (hexane/EtOAc, 50:1 then 10:
1) on silica gel to afford 20 (10.7 g, 90%) as a brown oil: 1H
NMR (400 MHz, CDCl3) δ 8.29 (d, J ) 1.5 Hz, 1H), 7.85 (d, J
) 1.2 Hz, 1H), 7.41-7.34 (m, 5H), 5.15 (s, 2H), 4.52 (d, J )
18.6 Hz, 1H), 4.45 (d, J ) 7.8 Hz, 1H), 4.40 (d, J ) 18.6 Hz,
1H), 4.08 (ddd, J ) 3.0, 3.6, 7.8 Hz, 1H), 3.96 (s, 3H), 3.85 (dd,
J ) 3.0, 11.5 Hz, 1H), 3.68 (dd, J ) 3.6, 11.5 Hz, 1H), 1.46 (s,
3H), 1.37 (s, 3H), 0.89 (s, 9H), 0.062 (s, 3H), 0.058 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 205.6, 165.3, 158.0, 150.6, 135.5,
130.9, 129.1, 128.9, 128.0, 124.6, 118.4, 116.6, 111.2, 81.1, 79.1,
71.9, 62.8, 53.1, 37.7, 27.2, 26.5, 26.2, 18.7, -4.98, -5.15; IR
(neat) 1731, 1538, 1292 cm-1; [R]23 -12.5 (c 0.56, CHCl3);
D
HRMS (ESI) m/z calcd for C29H40NO9Si ([M + H]+) 574.2472,
Meth yl 3-Ben zyloxy-4-[(2S,3R,4S)-5-(ter t-bu tyld im eth -
ylsilyloxy)-3-h yd r oxy-4-(tolu en e-4-su lfon yl)oxy-2-tr iiso-
p r op ylsilyloxy]p en tyl-5-n itr oben zoa te (52). To a solution
of the preceding TBS ether 51 (4.43 g) in CH2Cl2 (15 mL) was
added DABCO (1.23 g, 11.0 mmol) followed by TsCl (1.34 mg,
7.00 mmol) at room temperature. The reaction mixture was
stirred for 1.5 h and was partitioned between CHCl3 and 1 N
HCl. The separated organic layer was washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4, and concen-
trated under reduced pressure to afford the crude 52 (5.15 g),
which was used for the next reaction without further purifica-
tion. A small portion of the crude product was purified by
preparative TLC (benzene/EtOAc, 20:1) to give the pure 52
as a yellow oil for the characterization: 1H NMR (400 MHz,
found 574.2485.
Meth yl 3-Ben zyloxy-4-[(2S)-2-[(4R,5S)-5-(ter t-bu tyld i-
m eth ylsilyloxym eth yl)-2,2-d im eth yl-1,3-d ioxola n -4-yl]-2-
tr iisop r op ylsilyloxy]eth yl-5-n itr oben zoa te (49). To a solu-
tion of the secondary alcohol ent-21 (12.5 g, 21.7 mmol) in
CH2Cl2 (60 mL) was added 2,6-lutidine (15.1 mL, 130 mmol)
followed by TIPSOTf (17.5 mL, 65.1 mmol) at 0 °C. After being
stirred at room temperature for 7 h, the reaction mixture was
diluted with CHCl3 and washed with saturated aqueous
NaHCO3 and brine. The separated organic layer was dried over
Na2SO4 and concentrated under reduced pressure to afford the
crude TIPS ether 49 (22.7 g), which was used for the next
reaction without further purification. A small portion of the
J . Org. Chem, Vol. 69, No. 8, 2004 2839

Suzuki et al.
CDCl3) δ 7.98 (d, J ) 1.5 Hz, 1H), 7.77-7.74 (m, 3H), 7.46-
7.36 (m, 5H), 7.26 (d, J ) 7.3 Hz, 1H), 5.20 (d, J ) 11.2 Hz,
1H), 5.14 (d, J ) 11.2 Hz, 1H), 4.46-4.39 (m, 2H), 3.94 (s,
3H), 3.90 (dd, J ) 2.4, 12.2 Hz, 1H), 3.68 (dd, J ) 3.4, 12.2
Hz, 1H), 3.54 (dd, J ) 9.8, 12.7 Hz, 1H), 3.39 (t, J ) 7.3 Hz,
1H), 3.18 (dd, J ) 5.4, 12.7 Hz, 1H), 2.41 (s, 3H), 2.11 (d, J )
8.3 Hz, 1H), 1.00-0.87 (m, 21H), 0.67 (s, 9H), -0.08 (s, 3H),
-0.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9, 157.8,
151.9, 144.4, 135.1, 133.9, 130.1, 129.5, 128.8, 128.6, 128.2,
128.1, 125.3, 117.73, 117.69, 115.61, 115.57, 83.9, 71.68, 71.64,
70.2, 62.1, 52.7, 30.3, 25.6, 21.6, 18.08, 18.04, 13.0, -5.6, -5.7;
IR (neat) 3557, 1729, 1538, 1361, 1290, 1176 cm-1; [R]23D +17.5
(c 1.16, CHCl3); HRMS (ESI) m/z calcd for C42H67N2O11SSi2
([M + NH4]+) 863.4004, found 863.3987.
oil for the characterization: 1H NMR (400 MHz, CDCl3) δ 8.74
(d, J ) 5.4 Hz, 1H), 8.02 (d, J ) 1.5 Hz, 1H), 7.79 (s, 1H),
7.43-7.38 (m, 5H), 5.15 (d, J ) 11.2 Hz, 1H), 5.11 (d, J ) 11.2
Hz, 1H), 4.27 (dd, J ) 8.8, 15.1 Hz, 1H), 3.96 (s, 3H), 3.38 (dd,
J ) 4.9, 8.3 Hz, 1H), 3.25 (dd, J ) 6.8, 13.2 Hz, 1H), 3.14-
3.09 (m, 2H), 1.05-0.90 (m, 21H); 13C NMR (100 MHz, CDCl3)
δ 196.1, 164.7, 157.7, 151.7, 134.8, 130.7, 128.9, 128.2, 124.3,
117.6, 115.4, 71.6, 69.6, 62.4, 58.3, 52.8, 32.0, 17.9, 17.8, 12.2;
IR (neat) 1728, 1537, 1290 cm-1; [R]24 -44.0 (c 1.56, CHCl3);
D
HRMS (ESI) m/z calcd for C29H40NO8Si ([M + H]+) 558.2523,
found 558.2557.
N-Hyd r oxyben za zocin e (56). A mixture of the aldehyde
55 (663 mg) and 5% Pt/C (100 mg) in MeOH (15 mL) was
stirred under hydrogen atmosphere (ca. 1 atm) for 2 h at room
temperature. The reaction mixture was filtered through a pad
of Celite, and the filtrate was concentrated under reduced
pressure. The resulting residue was purified by flash column
chromatography (CHCl3/EtOAc, 100:1 then 100:1.5) on silica
gel to afford 56 (324 mg, 89% from 53) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 7.97 (d, J ) 1.5 Hz, 1H), 7.47-7.33
(m, 6H), 5.47 (br, 1H), 5.16 (s, 2H), 4.75-4.69 (m, 1H), 3.92
(s, 3H), 3.68 (d, J ) 12.7 Hz, 1H), 3.57 (dd, J ) 6.1, 12.7 Hz,
1H), 3.44 (dd, J ) 9.8, 16.8 Hz, 1H), 3.06 (dd, J ) 6.8, 16.8
Hz, 1H), 2.88 (dd, J ) 4.6, 7.6 Hz, 1H), 2.76-2.74 (m, 1H),
1.17-1.09 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 166.6, 156.2,
152.9, 136.6, 129.7, 128.5, 127.9, 127.2, 127.1, 115.6, 110.2,
72.0, 70.6, 62.7, 61.6, 52.2, 50.8, 33.4, 18.0, 17.9, 12.4; IR (neat)
Meth yl 3-Ben zyloxy-4-[(2S)-2-[(2R,3R)-3-(ter t-bu tyld i-
m eth ylsilyloxym eth yl)oxir an -2-yl]-2-tr iisopr opylsilyloxy]-
eth yl-5-n itr oben zoa te (53). To a solution of the tosylate 52
(4.96 g) in DMF (25 mL) was added NaH (60% in oil, 0.33 g,
8.30 mmol) at 0 °C. The reaction mixture was stirred at room
temperature for 1 h, poured into saturated aqueous NH4Cl,
and extracted with EtOAc. The separated organic layer was
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The resulting residue was purified by flash
column chromatography (hexane/EtOAc, 50:1 then 20:1) on
silica gel to afford 53 (2.82 g, 76% from 50) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.81 (s, 1H), 7.42-
7.38 (m, 5H), 5.18 (d, J ) 11.7 Hz, 1H), 5.14 (d, J ) 11.7 Hz,
1H), 3.98-3.94 (m, 1H), 3.94 (s, 3H), 3.29 (dd, J ) 7.1, 13.2
Hz, 1H), 3.21-3.15 (m, 2H), 3.05 (dd, J ) 4.4, 8.3 Hz, 1H),
2.93-2.89 (m, 1H), 2.86 (dd, J ) 2.7, 11.5 Hz, 1H), 1.05-0.85
(m, 21H), 0.82 (s, 9H), -0.04 (s, 3H), -0.05 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 164.8, 158.0, 151.8, 135.0, 130.2, 128.9,
128.7, 127.7, 125.7, 117.4, 115.2, 71.6, 71.0, 61.9, 60.3, 57.6,
52.7, 31.4, 25.8, 18.0, 17.9, 12.3, -5.3, -5.5; IR (neat) 1731,
3424, 1722, 1301, 1104 cm-1; [R]23 -83.4 (c 0.84, CHCl3);
D
HRMS (EI) m/z calcd for C29H41NO6Si ([M]+) 527.2703, found
527.2713.
Secon d a r y Alcoh ol (58). To a solution of the N-hydroxy-
benzazocine 56 (274 mg, 0.46 mmol) and 2-methoxypropene
(1 mL, 10.4 mmol) in CH2Cl2 (5 mL) was added p-toluene-
sulfonic acid monohydrate (10 mg, 0.05 mmol) at room tem-
perature. After being stirred for 10 min at room temperature,
the reaction mixture was poured into saturated aqueous
NaHCO3 and extracted with CH2Cl2. The separated organic
layer was washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. The residual material (494 mg)
was dissolved in THF (5 mL), to which was added TBAF (1 M
solution in THF, 1.6 mL, 1.6 mmol). After being stirred for 12
h at room temperature, the reaction mixture was concentrated
under reduced pressure and the residue was purified by flash
column chromatography (chromatorex NH-DM2035, hexane/
EtOAc, 9:1 then 7:3) to afford 58 (164 mg, 91% from 56) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.48-
7.33 (m, 6H), 5.15 (d, J ) 11.7 Hz, 1H), 5.11 (d, J ) 11.7 Hz,
1H), 4.91-4.86 (m, 1H), 3.93 (s, 3H), 3.65-3.56 (m, 2H), 3.41
(dd, J ) 9.3, 16.6 Hz, 1H), 3.12 (dd, J ) 7.3, 16.6 Hz, 1H),
2.95 (s, 3H), 2.86-2.83 (m, 1H), 2.76 (brs, 1H), 2.29 (d, J )
3.6 Hz, 1H), 1.38 (s, 3H), 1.25 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.6, 156.1, 152.8, 136.3, 129.8, 128.6, 128.1, 127.5,
117.5, 110.0, 104.2, 71.6, 70.7, 61.11, 61.07, 52.2, 51.3, 49.4,
31.0, 24.1, 23.7; IR (neat) 3439, 1720, 1212 cm-1; [R]24 -27.5
(c 0.78, CHCl3); HRMS (ESI) m/z calcd for C24H30NO7 ([M +
H]+) 444.2022, found 444.2087.
Keton e (59). To a stirred solution of oxalyl chloride (44 µL,
0.50 mmol) in CH2Cl2 (1 mL) was added a solution of DMSO
(71 µL, 1.00 mmol) in CH2Cl2 (0.2 mL) at -78 °C, and the
mixture was stirred for 10 min. A solution of the alcohol 58
(122 mg, 0.27 mmol) in CH2Cl2 (1 mL) was added dropwise,
and stirring continued for an additional 30 min. Et3N (0.21
mL, 1.50 mmol) was added, and the reaction mixture was
allowed to warm to room temperature. The reaction mixture
was subjected directly to flash column chromatography (chro-
matorex NH-DM2035, hexane/EtOAc, 9:1 then 4:1) to afford
the ketone 59 (98 mg, 82%) as a colorless oil: 1H NMR (400
MHz, C6D6) δ 8.18 (d, J ) 1.5 Hz, 1H), 7.62 (d, J ) 1.0 Hz,
1H), 7.16-7.05 (m, 5H), 4.64 (d, J ) 11.7 Hz, 1H), 4.60 (d, J
) 11.7 Hz, 1H), 4.16 (d, J ) 19.0 Hz, 1H), 3.87 (d, J ) 19.0
Hz, 1H), 3.55 (s, 3H), 3.46 (d, J ) 13.7 Hz, 1H), 3.28 (dd, J )
2.9, 13.7 Hz, 1H), 3.17-3.12 (m, 1H), 2.67-2.59 (m, 4H), 1.25
1537, 1289, 1098 cm-1; [R]25 +26.0 (c 1.04, CHCl3); HRMS
D
(ESI) m/z calcd for C35H59N2O8Si2 ([M + NH4]+) 691.3810,
found 691.3824.
Meth yl 3-Ben zyloxy-4-[(2S)-2-[(2R,3R)-3-h yd r oxym eth -
yloxir an -2-yl]-2-tr iisopr opylsilyloxy]eth yl-5-n itr oben zoate
(54). To a solution of the epoxide 53 (510 mg, 0.757 mmol) in
MeOH (10 mL) was added CSA (18 mg, 76 µmol) at room
temperature. After the mixture was stirred for 1 h at room
temperature, saturated aqueous NaHCO3 (1 mL) was added
to the mixture and concentrated. The resulting residue was
partitioned between EtOAc and brine. The separated organic
layer was dried over Na2SO4, and concentrated under reduced
pressure to afford the crude 54 (427 mg), which was used for
the next reaction without further purification. A small portion
of the crude product was purified by preparative TLC (hexane/
EtOAc, 7:3) to give the pure 54 as a yellow oil for the
characterization: 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J )
1.5 Hz, 1H), 7.82 (s, 1H), 7.45-7.38 (m, 5H), 5.16 (d, J ) 11.2
Hz, 1H), 5.12 (d, J ) 11.2 Hz, 1H), 4.01 (dd, J ) 7.3, 15.1 Hz,
1H), 3.96 (s, 3H), 3.33 (dd, J ) 7.8, 13.2 Hz, 1H), 3.12-3.06
(m, 2H), 2.97-2.90 (m, 3H), 1.04-0.84 (m, 21H); 13C NMR (100
MHz, CDCl3) δ 164.9, 157.9, 151.9, 135.0, 130.1, 128.9, 128.4,
125.7, 117.5, 115.0, 71.7, 70.6, 61.1, 60.6, 56.8, 52.8, 31.3, 17.9,
17.8, 12.4; IR (neat) 3521, 1729, 1537, 1290 cm-1; [R]24 -2.5
D
(c 0.87, CHCl3); HRMS (ESI) m/z calcd for C29H42NO8Si ([M +
H]+) 560.2680, found 560.2655.
Meth yl 3-Ben zyloxy-4-[(2S)-2-[(2R,3R)-3-for m yloxir a n -
2-yl]-2-tr iisop r op ylsilyloxy]eth yl-5-n itr oben zoa te (55). To
a solution of the primary alcohol 54 (391 mg) in CH2Cl2 (5 mL)
was added Dess-Martin periodinane (424 mg, 1.00 mmol) at
0 °C. After being stirred at room temperature for 30 min, the
reaction mixture was poured into saturated aqueous NaHCO3
and extracted with CHCl3. The separated organic layer was
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure to afford the crude 55 (663 mg), which was
used for the next reaction without further purification. A small
portion of the crude product was purified by preparative silica
gel TLC (hexane/EtOAc, 7:3) to give the pure 55 as a yellow
2840 J . Org. Chem., Vol. 69, No. 8, 2004

Total Synthesis of FR900482
(s, 3H), 1.14 (s, 3H); 13C NMR (100 MHz, C6D6) δ 199.3, 166.4,
155.3, 153.3, 136.7, 130.6, 128.7, 127.0, 118.0, 110.9, 105.4,
70.5, 60.0, 58.3, 57.8, 51.8, 49.0, 40.1, 24.9, 23.1; IR (neat) 1720,
(t, J ) 11.2 Hz, 1H), 3.89 (s, 3H), 3.72 (d, J ) 15.1 Hz, 1H),
3.49 (d, J ) 4.4 Hz, 1H), 3.43 (dd, J ) 5.9, 11.2 Hz, 1H), 3.28
(d, J ) 4.4 Hz, 1H), 1.60 (s, 3H), 1.50 (s, 3H).
1697, 1312, 1228, 1070 cm-1; [R]24 -22.6 (c 0.75, CHCl3);
D
Tw o-Step Syn th esis of th e Hem ia ceta l Aceton id e 62a .
(1) On e-P ot Syn th esis of th e Hem ia ceta ls 61a a n d 61b.
To a solution of the ketone 59 (90 mg, 0.20 mmol) in a mixture
of THF and water (20:3 v/v, 5.75 mL) was added HCHO (37%
aqueous solution, 0.30 mL, 23.1 mmol) followed by LiOH (1
M aqueous solution, 80 µL, 80 µmol) at 0 °C. The reaction
mixture was stirred for 5 h at 0 °C, quenched by addition of 1
N HCl (0.40 mL, 0.40 mmol), and allowed to warm to room
temperature. The resulting mixture was stirred for an ad-
ditional 10 h, poured into brine, and extracted with EtOAc.
The separated organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The crude product
obtained was purified by preparative TLC (hexane/EtOAc,
1:1) to afford a mixture of the hemiacetals 61a and 61b
(62 mg, 77%, 61a /61b ) 87:13) as colorless oil: 1H NMR (400
MHz, CDCl3) δ 7.48-7.11 (m, 7H), 5.22-5.13 (m, 2H), 4.16-
3.88 (m, 6H), 3.58-3.50 (m, 2H), 3.29-3.12 (m, 3H), 1.94 (br,
1H); IR (neat) 3349, 1720, 1582, 1427, 1274, 1238, 1122, 1106
HRMS (EI) m/z calcd for C24H27NO7 441.1788 ([M]+), found
441.1836.
Th r ee-St ep Syn t h esis of t h e H em ia cet a l Acet on id e
62a . (1) 7-Hyd r oxym eth ylben za zocin on e (60). To a solu-
tion of the ketone 59 (75 mg, 0.17 mmol) in THF/H2O (4 mL/
0.6 mL) (20:3 v/v, 4.6 mL) were added HCHO (37% aqueous
solution, 0.25 mL, 19.2 mmol) and LiOH (1 M aqueous solution,
67 µL, 67 µmol) at 0 °C. The reaction was stirred at 0 °C for 5
h and quenched by addition of 1 N NH4Cl (67 µL, 67 µmol).
The mixture was allowed to warm to room temperature,
poured into brine, and extracted with EtOAc. The separated
organic layer was dried over Na2SO4 and concentrated under
reduced pressure to give the crude 7-hydroxymethyl benz-
azocinones as a 94:6 mixture of diastereomers. The crude
product was purified by preparative TLC (hexane/EtOAc, 1:1)
to afford 60 (40 mg, 50%) and 60′ (1.2 mg, 1.5%) as colorless
oils. Major isomer 60: 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J
) 1.5 Hz, 1H), 7.60 (d, J ) 1.5 Hz, 1H), 7.48-7.33 (m, 5H),
5.25 (d, J ) 11.2 Hz, 1H), 5.22 (d, J ) 11.2 Hz, 1H), 4.55 (t, J
) 9.3 Hz, 1H), 4.38 (dd, J ) 3.4, 8.3 Hz, 1H), 3.93 (s, 3H),
3.77-3.69 (m, 1H), 3.60 (dd, J ) 1.5, 12.7 Hz, 1H), 3.53 (dd, J
) 4.9, 12.7 Hz, 1H), 3.42 (d, J ) 4.9 Hz, 1H), 3.14 (br, 1H),
3.00 (dt, J ) 1.5, 4.9 Hz, 1H), 2.55 (s, 3H), 1.34 (s, 3H), 1.22
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.2, 166.0, 155.8,
151.4, 135.7, 128.8, 128.1, 127.4, 118.4, 111.0, 105.5, 70.9, 60.7,
60.5, 58.5, 53.3, 52.4, 49.6, 48.8, 24.6, 22.5, 14.1; IR (neat) 1719,
1580, 1292, 1232, 1212, 1070 cm-1; [R]25D +7.8 (c 1.23, CHCl3);
MS (ESI) m/z 472 ([M + H]+). Minor isomer 60′: 1H NMR (400
MHz, CDCl3) δ 8.01 (s, 1H), 7.61 (s, 1H), 7.48-7.39 (m, 5H),
5.15 (s, 2H), 4.79 (d, J ) 11.2 Hz, 1H), 4.36-4.30 (m, 1H),
3.95 (s, 3H), 3.92 (d, J ) 4.9 Hz, 1H), 3.83-3.77 (m, 1H), 3.70
(d, J ) 12.2 Hz, 1H), 3.61 (dd, J ) 4.9, 12.2 Hz, 1H), 3.15 (t,
J ) 4.4 Hz, 1H), 2.46 (s, 3H), 1.37 (s, 3H), 1.19 (s, 3H); IR
cm-1; [R]23 -16.9 (c 1.23, CHCl3); HRMS (EI) m/z calcd for
D
C
21H21NO7 ([M]+) 399.1318, found 399.1371.
(2) Aceton id e (62a ). To a solution of a mixture of hemi-
acetals 61a and 61b (56 mg, 0.14 mmol, 61a /61b ) 87:13) in
acetone (2.5 mL) were successively added 2,2-dimethoxypro-
pane (2.5 mL), 2-methoxypropene (67 µL, 0.70 mmol), and
pyridinium p-toluenesulfonate (5.0 mg, 20 µmol) at room
temperature. The mixture was stirred for 3 h, and the solvent
was evaporated under reduced pressure. The resulting crude
product was purified by preparative TLC (hexane/EtOAc, 3:2)
to afford the acetonide 62a (51 mg, 84%) as a colorless oil.
Ben zyl Alcoh ol (63). To a solution of the acetonide 62a
(45 mg, 0.10 mmol) in CH2Cl2 (3 mL) was added DIBAL (1 M
solution in hexane, 0.30 mL, 0.30 mmol) at -78 °C dropwise
over 5 min. The reaction mixture was stirred for 1 h, quenched
by addition of MeOH (0.21 mL), and allowed to warm to room
temperature. To the reaction mixture was added 30% aqueous
Rochelle salt (0.36 mL), and the two-phase mixture was
vigorously stirred for an additional 30 min. The mixture was
poured into brine and extracted with CHCl3. The separated
organic layer was washed with brine, dried over Na2SO4,
concentrated under reduced pressure, and purified by prepara-
tive TLC (hexane/EtOAc, 2:3) to afford 63 (42 mg, 99%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.43-7.35 (m, 5H),
6.71 (s, 1H), 6.48 (s, 1H), 5.12 (d, J ) 11.7 Hz, 1H), 5.05 (d, J
) 11.7 Hz, 1H), 4.62 (s, 2H), 4.31 (dd, J ) 5.9, 11.2 Hz, 1H),
3.94 (d, J ) 15.1 Hz, 1H), 3.89 (t, J ) 11.2 Hz, 1H), 3.50 (dd,
J ) 4.9, 15.1 Hz, 1H), 3.35 (dd, J ) 5.9, 11.2 Hz, 1H), 3.22 (t,
J ) 4.4 Hz, 1H), 3.06 (d, J ) 3.9 Hz, 1H), 2.02 (br, 1H), 1.58
(s, 3H), 1.50 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.2, 147.0,
141.9, 136.2, 128.8, 128.3, 127.5, 112.6, 110.4, 105.0, 99.9, 93.1,
70.3, 64.8, 59.3, 54.7, 51.5, 49.8, 32.6, 30.1, 24.3; IR (neat) 3482,
(neat) 1721, 1319, 1239, 1215 cm-1
.
(2) Aceton id e (62a ). To a solution of the 7-hydroxymeth-
ylbenzazocinone derivative 60 (14 mg, 30 µmol) in THF (1 mL)
was added 1 N HCl (50 µL, 50 µmol) at room temperature.
After being stirred for 1 h, the reaction mixture was poured
into brine and extracted with EtOAc. The organic layer was
dried over Na2SO4 and concentrated under reduced pressure
to give the hemiacetals 61a and 61b (12 mg, 61a :61b ) 88:
12). To a mixture of hemiacetals 61a and 61b (10 mg) in
acetone (0.5 mL) were added 2,2-dimethoxypropane (0.5 mL),
2-methoxypropene (12 µL, 0.13 mmol), and pyridinium p-
toluenesulfonate (1 mg, 4 µmol) at room temperature. After
being stirred for 3 h, the reaction mixture was poured into
saturated aqueous NaHCO3 and extracted with CH2Cl2. The
organic layer was dried over Na2SO4 and concentrated under
reduced pressure to give a mixture of acetonide 62a and 62b
(61a /62b ) 89:11). The crude product was purified by prepara-
tive TLC (hexane/EtOAc, 3:2) to afford the acetonides 62a (10
mg) and 62b (1 mg) as colorless oils. Major isomer 62a : 1H
NMR (400 MHz, CDCl3) δ 7.44-7.37(m, 5H), 7.34 (d, J ) 1.4
Hz, 1H), 7.20 (d, J ) 1.4 Hz, 1H), 5.17 (d, J ) 11.7 Hz, 1H),
5.11 (d, J ) 11.7 Hz, 1H), 4.33 (dd, J ) 5.9, 11.7 Hz, 1H), 3.98
(d, J ) 15.6 Hz, 1H), 3.91 (s, 3H), 3.91 (t, J ) 10.8 Hz, 1H),
3.55 (dd, J ) 5.4, 15.6 Hz, 1H), 3.39 (dd, J ) 5.9, 10.8 Hz,
1H), 3.22 (t, J ) 4.4 Hz, 1H), 3.07 (d, J ) 4.4 Hz, 1H), 1.59 (s,
3H), 1.51 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 157.0,
147.1, 135.8, 130.6, 128.8, 128.4, 127.7, 118.4, 114.1, 107.0,
100.0, 92.9, 70.6, 59.0, 54.7, 52.4, 51.4, 49.7, 33.0, 30.0, 24.3;
IR (neat) 2912, 1722, 1582, 1426, 1357, 1274, 1252, 1231, 1125,
1584, 1432, 1119 cm-1; [R]23 -30.3 (c 0.81, CHCl3); HRMS
D
(EI) m/z calcd for C23H25NO6 ([M]+) 411.1682, found 411.1721.
p-Meth oxyp h en yl Eth er (7). To a solution of the benzyl
alcohol 63 (40 mg, 97 µmol) in benzene (3 mL) were succes-
sively added Ph3P (50 mg, 0.19 mmol), p-methoxyphenol (24
mg, 0.19 mmol), and DEAD (40% toluene solution, 86 µL, 0.19
µmol) at room temperature. The reaction mixture was stirred
for 15 min and concentrated under reduced pressure. The
crude product was purified by preparative TLC (hexane/
EtOAc, 3:2) to afford the p-methoxyphenyl ether 7 (48 mg,
96%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.42-
7.35 (m, 5H), 6.89-6.77 (m, 4H), 6.74 (s, 1H), 6.54 (s, 1H), 5.12
(d, J ) 11.4 Hz, 1H), 5.05 (d, J ) 11.4 Hz, 1H), 4.93 (s, 2H),
4.32 (dd, J ) 5.8, 11.5 Hz, 1H), 3.96 (d, J ) 15.6 Hz, 1H), 3.91
(t, J ) 11.2 Hz, 1H), 3.77 (s, 3H), 3.50 (dd, J ) 5.1, 15.1 Hz,
1H), 3.35 (dd, J ) 5.8, 11.0 Hz, 1H), 3.22 (t, J ) 5.1 Hz, 1H),
3.06 (d, J ) 3.7 Hz, 1H), 1.59 (s, 3H), 1.50 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 157.2, 154.1, 152.6, 147.1, 138.3, 136.2,
128.8, 128.3, 127.5, 115.8, 114.7, 113.0, 111.2, 105.6, 99.9, 93.1,
1106, 1087, 880, 838, 778 cm-1; [R]25 -39.9 (c 1.02, CHCl3);
D
HRMS (EI) m/z calcd for C24H25NO7 ([M]+) 439.1631, found
439.1608. Minor isomer 62b: 1H NMR (400 MHz, CDCl3) δ
7.45-7.34 (m, 5H), 7.29 (d, J ) 1.5 Hz, 1H), 7.12 (d, J ) 1.0
Hz, 1H), 5.13 (d, J ) 11.2 Hz, 1H), 5.10 (d, J ) 11.2 Hz, 1H),
4.40 (dd, J ) 6.3, 11.7 Hz, 1H), 3.96 (d, J ) 15.1 Hz, 1H), 3.91
J . Org. Chem, Vol. 69, No. 8, 2004 2841

Suzuki et al.
70.3, 59.3, 55.7, 54.8, 51.5, 49.8, 32.6, 30.1, 24.3; IR (neat)
(ESI) m/z calcd for C29H32N5O10S ([M + NH4]+) 642.1870, found
642.1876.
1585, 1507, 1228, 1120 cm-1; [R]23 -24.2 (c 0.39, CHCl3);
D
HRMS (EI) m/z calcd for C30H31NO7 ([M]+) 517.2101, found
Ben zyl Alcoh ol (67). To a solution of the carbonate 66 (132
mg, 0.21 mmol) in MeCN/H2O (4 mL/1 mL) and water (4:1 v/v,
5 mL) was added ammonium cerium(IV) nitrate (290 mg, 0.53
mmol) at room temperature. The reaction mixture was stirred
for 10 min, poured into brine, and extracted with EtOAc. The
separated organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by flash column chromatography (hexane/EtOAc,
7:3 then 1:1) on silica gel to afford 67 (92 mg, 84%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.43-7.33 (m, 5H),
6.82 (s, 1H), 6.62 (s, 1H), 5.17 (s, 2H), 4.75-4.71 (m, 2H), 4.63
(s, 2H), 4.20 (t, J ) 11.0 Hz, 1H), 4.17-4.08 (m, 2H), 3.64 (dd,
J ) 4.9, 11.2 Hz, 1H), 3.37 (d, J ) 13.4 Hz, 1H), 3.30 (s, 3H),
2.21 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 156.3, 146.8, 145.8,
143.5, 135.7, 128.8, 128.4, 127.3, 109.9, 109.0, 106.9, 97.0, 75.7,
70.4, 65.7, 64.4, 57.2, 53.3, 38.9, 33.2; IR (neat) 3548, 2117,
517.2145.
Hyd r oxya zid e (64). A solution of the epoxide 7 (176 mg,
0.34 mmol) and LiN3 (450 mg, 9.19 mmol) in DMF/H2O (3.5
mL/0.35 mL) was heated at 120 °C for 3.5 h. The reaction
mixture was cooled to room temperature, poured into crushed
ice in water, and extracted with EtOAc. The separated organic
layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by
flash column chromatography (hexane/EtOAc, 4:1) on silica
gel to afford 64 (158 mg, 83%) as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 7.41-7.31 (m, 5H), 6.87-6.80 (m, 4H),
6.74 (s, 1H), 6.57 (s, 1H), 5.09 (s, 2H), 4.93 (s, 2H), 4.36 (dd, J
) 6.1, 11.7 Hz, 1H), 4.11 (dd, J ) 4.9, 14.2 Hz, 1H), 3.93-3.84
(m, 2H), 3.76 (s, 3H), 3.57 (dd, J ) 3.2, 4.9 Hz, 1H), 3.32
(d, J ) 3.3 Hz, 1H), 3.21 (dd, J ) 6.1, 10.7 Hz, 1H), 3.18 (dd,
J ) 3.6, 13.6 Hz, 1H), 1.59 (s, 3H), 1.49 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 157.0, 154.1, 152.7, 148.2, 138.4, 136.3, 128.7,
128.2, 127.5, 115.9, 114.8, 113.7, 110.6, 106.3, 100.8, 94.5, 71.9,
70.3, 59.4, 57.8, 55.7, 55.0, 33.6, 30.0, 24.3; IR (neat) 3534,
1783, 1359 cm-1; [R]22 +38.8 (c 0.22, CHCl3); HRMS (ESI)
D
m/z calcd for C22H26N5O9S ([M + NH4]+) 536.1451, found
536.1464.
Dim eth yl Aceta l (68). To a solution of the benzyl alcohol
67 (90 mg, 0.17 mmol) in CH2Cl2 (3 mL) were added anhydrous
MgSO4 (84 mg, 0.70 mmol) and PCC (75 mg, 0.35 mmol) at
room temperature. The reaction mixture was stirred for 1.5
h. Et2O (5 mL) was added, and the mixture was stirred for an
additional 30 min. The reaction mixture was passed through
a pad of Celite, and the filtrate was concentrated. The resulting
residue (81 mg) was dissolved in MeOH (4 mL), to which were
added trimethyl orthoformate (1 mL) and CSA (3 mg, 13 µmol).
The resulting mixture was stirred for 1 h at room tempera-
ture. The solution was poured into brine, and extracted with
CH2Cl2. The separated organic layer was dried over Na2SO4
and concentrated under reduced pressure. The residue was
purified by flash column chromatography (hexane/EtOAc, 7:3)
on silica gel to afford 68 (77 mg, 81% from 67) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 7.43-7.34 (m, 5H), 6.91 (s,
1H), 6.74 (s, 1H), 5.30 (s, 1H), 5.18 (s, 2H), 4.77-4.73 (m, 2H),
4.21 (t, J ) 11.0 Hz, 1H), 4.16-4.12 (m, 2H), 3.64 (dd, J )
4.9, 11.0 Hz, 1H), 3.39 (dd, J ) 1.2, 14.9 Hz, 1H), 3.33 (s, 3H),
3.28 (s, 3H), 3.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.0,
146.6, 145.7, 140.7, 135.7, 128.8, 128.4, 127.4, 110.7, 110.2,
107.2, 101.8, 96.9, 75.8, 70.5, 65.7, 57.3, 53.3, 52.7, 52.5, 39.0,
2104, 1508, 1227 cm-1; [R]22 +58.2 (c 0.40, CHCl3); HRMS
D
(ESI) m/z calcd for C30H33N4O7 ([M + H]+) 561.2349, found
561.2383.
Mesyloxya zid e (65). To a solution of hydroxyazide 64 (174
mg, 0.31 mmol) in CH2Cl2 (1 mL) were added Et3N (0.14 mL,
0.98 mmol) and MsCl (0.05 mL, 0.66 mmol) at room temper-
ature. The reaction mixture was stirred for 3 h, poured into
saturated aqueous NaHCO3, and extracted with EtOAc. The
separated organic layer was washed with 10% aqueous citric
acid and brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (hexane/EtOAc, 8:2 then 7:3) on silica gel to
afford 65 (157 mg, 80%) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 7.39-7.32 (m, 5H), 6.86-6.80 (m, 4H), 6.78 (s, 1H),
6.59 (s, 1H), 5.12 (s, 2H), 4.93 (s, 2H), 4.67 (d, J ) 4.6 Hz,
1H), 4.39 (dd, J ) 6.1, 10.7 Hz, 1H), 4.13 (dd, J ) 4.6, 13.9
Hz, 1H), 4.13-4.07 (m, 1H), 3.88 (t, J ) 10.7 Hz, 1H), 3.77 (s,
3H), 3.33 (dd, J ) 6.1, 10.5 Hz, 1H), 3.28 (dd, J ) 2.7, 13.9
Hz, 1H), 3.15 (s, 3H), 1.58 (s, 3H), 1.47 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 156.6, 154.0, 152.6, 147.2, 138.4, 136.2, 128.6,
128.0, 127.3, 115.8, 114.6, 114.1, 110.6, 106.9, 100.4, 93.3, 78.3,
70.2, 70.1, 59.2, 57.2, 55.6, 54.4, 38.5, 33.1, 29.7, 24.3; IR (neat)
33.4; IR (neat) 2117, 1786, 1361, 1116 cm-1; [R]22 +18.4 (c
D
2113, 1508, 1361, 1228 cm-1; [R]22 +45.2 (c 0.28, CHCl3);
0.88, CHCl3); HRMS (ESI) m/z calcd for C24H30N5O10S ([M +
D
NH4]+) 580.1713, found 580.1721.
HRMS (ESI) m/z calcd for C31H35N4O9S ([M + H]+) 639.2125,
found 639.2186.
Azir id in e (69). To a solution of the dimethyl acetal 68
(35 mg, 62 µmol) in THF/H2O (1 mL/0.1 mL) were added
i-Pr2NEt (13 µL, 75 µmol) and Ph3P (31 mg, 0.12 mmol). The
reaction mixture was heated at 60 °C for 1.5 h and cooled to
room temperature. The mixture was poured into brine and
extracted with CH2Cl2. The separated organic layer was dried
over MgSO4 and concentrated under reduced pressure. The
resulting residue was purified by preparative TLC (EtOAc/
benzene, 1:1) to afford 69 (23 mg, 85%) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 7.44-7.34 (m, 5H), 6.77 (s, 1H), 6.56
(s, 1H), 5.32 (s, 1H), 5.11 (s, 2H), 4.70 (dd, J ) 5.4, 10.8 Hz,
1H), 4.25 (dd, J ) 10.8, 11.5 Hz, 1H), 3.95 (d, J ) 13.2 Hz,
1H), 3.67-3.62 (m, 2H), 3.31 (s, 3H), 3.29 (s, 3H), 3.00 (br,
1H), 2.43 (br, 1H), 0.54 (br, 1H); 13C NMR (100 MHz, CDCl3)
δ 156.2, 149.2, 146.3, 139.5, 136.4, 128.9, 128.4, 127.5, 110.6,
109.7, 104.8, 102.5, 97.6, 70.5, 66.1, 53.0, 52.8, 52.7, 36.3, 33.6,
Ca r bon a te (66). To a solution of the mesyloxyazide 65 (147
mg, 0.23 mmol) in CH2Cl2 (3 mL) was added TFA (0.14 mL,
1.84 mmol) at room temperature. The reaction mixture was
stirred for 3 h, diluted with CH2Cl2, and washed with saturated
aqueous NaHCO3. The organic layer was dried over MgSO4
and concentrated under reduced pressure to afford a yellow
residue (145 mg). To a stirred solution of triphosgene (297 mg,
1.00 mol) and pyridine (97 µL, 1.20 mmol) in CH2Cl2 (1 mL)
was added a solution of the preceding residue (145 mg) in
CH2Cl2 (1 mL) over a period of 10 min at 0 °C. The reaction
mixture was stirred for 20 min and then partitioned between
CHCl3 and saturated aqueous NaHCO3. The separated organic
layer was washed with 10% aqueous citric acid and brine, dried
over MgSO4, and concentrated under reduced pressure. The
resulting material was purified by flash column chromatog-
raphy (hexane/EtOAc, 3:1) on silica gel to afford 66 (132 mg,
92% from 65) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ
7.41-7.32 (m, 5H), 6.86-6.78 (m, 5H), 6.65 (s, 1H), 5.15 (s,
2H), 4.95 (s, 2H), 4.74-4.71 (m, 2H), 4.21 (t, J ) 11.0 Hz, 1H),
4.17-4.11 (m, 2H), 3.75 (s, 3H), 3.64 (dd, J ) 4.9, 11.0 Hz,
1H), 3.35 (dd, J ) 1.5, 14.9 Hz, 1H), 3.30 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 156.4, 154.2, 152.4, 147.0, 145.7, 140.1,
135.6, 128.9, 128.5, 127.4, 115.8, 114.7, 110.3, 109.4, 107.4,
97.0, 75.8, 70.6, 69.9, 65.7, 57.3, 55.7, 53.6, 39.1, 33.4; IR (neat)
25.1; IR (neat) 3308, 1771, 1082 cm-1; [R]22 +30.2 (c 0.45,
D
CHCl3); HRMS (ESI) m/z calcd for C23H25N2O7 ([M + H]+)
441.1662, found 441.1699.
P h en ol (70). To a solution of the benzyl ether 69 (22 mg,
50 µmol) in EtOH (1.5 mL) was added 10% Pd/C (8 mg). The
suspension was stirred at room temperature under hydrogen
atmosphere (ca. 1 atm) for 2.5 h. The reaction mixture was
filtered through a pad of Celite, and the filtrate was concen-
trated to afford 70 (17 mg, 97%) as a colorless oil, which was
used for the next reaction without further purification: 1H
2117, 1790, 1507 cm-1; [R]22 +26.1 (c 0.30, CHCl3); HRMS
D
2842 J . Org. Chem., Vol. 69, No. 8, 2004

Total Synthesis of FR900482
NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 6.41 (s, 1H), 5.24 (s,
1H), 4.80 (dd, J ) 5.4, 10.7 Hz, 1H), 4.23 (t, J ) 11.2 Hz, 1H),
3.94 (d, J ) 14.4 Hz, 1H), 3.69-3.60 (m, 2H), 3.31 (s, 3H),
3.30 (s, 3H), 3.01 (d, J ) 6.6 Hz, 1H), 2.41 (d, J ) 4.6 Hz, 1H);
13C NMR (CDCl3) δ 154.9, 148.8, 147.1, 138.6, 109.1, 107.9,
107.8, 102.7, 97.9, 65.9, 52.9, 52.7, 52.6, 35.9, 33.3, 24.7; IR
(neat) 3533, 1748, 1162, 1090 cm-1; MS (ESI) m/z 351 ([M +
H]+).
Ben za ld eh yd e (71). To a solution of the dimethyl acetal
70 (17 mg, 49 µmol) in THF/H2O (5 mL/0.5 mL) was added
1% perchloric acid (0.1 mL) at room temperature. The mixture
was stirred for 3.5 h, poured into brine, and extracted with
Et2O. The separated organic layer was washed with brine,
dried over MgSO4, and concentrated under reduced pressure
to afford the crude 71 (13 mg) as a colorless oil, which was
used for the next reaction without further purification: 1H
NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 6.96 (d, J ) 1.5 Hz,
1H), 6.81 (d, J ) 1.5 Hz, 1H), 4.83 (dd, J ) 5.4, 10.8 Hz, 1H),
4.25 (t, J ) 11.0 Hz, 1H), 4.01 (dd, J ) 2.2, 14.6 Hz, 1H), 3.74-
3.66 (m, 2H), 3.04 (d, J ) 6.6 Hz, 1H), 2.47 (dd, J ) 2.2, 6.6
Hz, 1H); IR (neat) 3301, 1757, 1692, 1159 cm-1; MS (ESI) m/z
305 ([M + H]+).
3.51 (d, 1H, J ) 5.1 Hz), 2.72-2.65 (m, 2H); minor isomer: δ
9.75 (s, 1H), 7.11 (d, 1H, J ) 1.5 Hz), 6.96 (d, 1H, J ) 1.2 Hz),
4.65 (dd, 1H, J ) 5.6, 11.5 Hz), 4.44 (dd, 1H, J ) 2.2, 11.5
Hz), 3.85 (dd, 1H, J ) 2.4, 14.6 Hz), 3.61 (d, 1H, J ) 14.9 Hz),
3.42 (dd, 1H, J ) 1.9, 5.6 Hz), 2.88 (d, 1H, J ) 6.8 Hz), 2.49
(dd, 1H, J ) 2.4, 6.8 Hz); 13C NMR (100 MHz, D2O) major
isomer: δ 197.8, 161.8, 159.0, 150.8, 138.5, 121.9, 116.5, 112.7,
96.0, 63.4, 56.1, 46.2, 32.5, 32.0; minor isomer: δ 198.0, 162.1,
157.5, 152.1, 138.4, 121.9, 115.1, 113.7, 96.2, 64.6, 55.2, 42.6,
40.3, 28.0; IR (KBr) 3287, 1692, 1587, 1347, 1087 cm-1; [R]25
D
+10.0 (c 0.48, H2O); MS (ESI) m/z 322 ([M + H]+).
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid for Scientific Research in the Priority
Area (A) “Exploitation of Multi-Element Cyclic Mol-
ecules” from the Ministry of Education, Culture, Sports,
Science, and Technology, J apan, and CREST and
PRESTO, the J apan Science and Technology Corpora-
tion (J ST).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 21-24, 26,
28-32, 34-37, and 39-46; copies of 1H and 13C spectra of
compounds 14, 16, 18, 20-24, 26, 28-32, 34-37, 39-46, 7,
49-56, 58-60, 61a ,b, 62a , 63-70, and 1; 1H NMR of
compounds 60′, 62b, and 71. This material is available free of
charge via the Internet at http://pubs.acs.org.
F R900482 (1). To a solution of the crude carbonate 71 (13
mg) in THF (3 mL) was bubbled ammonia gas for 15 min at
room temperature. The reaction mixture was stirred for 2 h
and then concentrated under reduced pressure. The crude
product was purified by trituration with hexane/EtOAc to
afford FR900482 (1) (13 mg, 83% from 70) as a white powder:
1
mp 165-175 °C dec; H NMR (400 MHz, D2O) major isomer:
δ 9.76 (s, 2H), 7.08 (s, 1H), 7.06 (s, 1H), 5.13 (dd, 1H, J ) 6.6,
11.5 Hz), 4.66 (dd, 1H, J ) 1.2, 11.5 Hz), 3.79-3.75 (m, 2H),
J O049862Z
J . Org. Chem, Vol. 69, No. 8, 2004 2843