Synthetic studies on macroviracin A: A rapid construction of C42 macrocyclic dilactone corresponding to the core

Article abstract of DOI:10.1021/jo0496392

The C₂-symmetric macrodiolide core 2 of an antiviral agent, macroviracin A (1), was constructed in a single step by the intermolecular macrodimerization of C₂₂-hydroxy carboxylic acid 3 with 2-chloro-1,3-dimethylimidazolinium chlorid

Full text of DOI:10.1021/jo0496392

Syn th etic Stu d ies on Ma cr ovir a cin A: A Ra p id Con str u ction of C42
Ma cr ocyclic Dila cton e Cor r esp on d in g to th e Cor e
Shunya Takahashi,* Kazunori Souma, Ruri Hashimoto, Hiroyuki Koshino, and
Tadashi Nakata
RIKEN (The Institute of Physical and Chemical Research), Wako-shi, Saitama 351-0198, J apan
shunyat@riken.go.jp
Received March 4, 2004
The C2-symmetric macrodiolide core 2 of an antiviral agent, macroviracin A (1), was constructed
in a single step by the intermolecular macrodimerization of C22-hydroxy carboxylic acid 3 with
2-chloro-1,3-dimethylimidazolinium chloride and DMAP in the presence of sodium hydride (NaH).
The use of potassium hydride instead of NaH caused the intramolecular cyclization, predominantly
providing the corresponding monomer 26. The acid 3 was synthesized through a series of reactions
such as the coupling reaction of acetylene 5 and oxirane 6, stereoselective glycosidation with the
trichloroacetimidate method, and J ones oxidation.
In the course of a screening program for the isolation
of antiviral agents from microorganisms, Hyodo et al.
isolated eight types of macrocyclic compounds from the
mycelium extracts of Streptomyces sp. BA-2836, and
named them macroviracins.1 These natural products
exhibit powerful antiviral activity against herpes simplex
virus type 1 (HSV-1) and varicella-zoster virus (VZV), and
their potency is reported to be 10 times that of acyclovir.
Macroviracin A (1) is a member of this family and bears
a 42-membered macrodiolide core consisting of a C22 fatty
acid dimer possessing D-glucose residues, and a long side
chain attached to the core (Figure 1). Structurally,
macroviracin A (1) is related to sugar-fatty acid lactones
such as cycloviracins2 and fattiviracins,3 differing re-
markably in the size of the macrocyclic ring systems.
Recently, these lactones have attracted much attention
from synthetic organic chemists owing to their architec-
tural complexity and biological activities with significant
therapeutic potential. Fu¨rstner et al. disclosed total
syntheses of cycloviracin B1 and glucolipsin A,4 establish-
ing the absolute configuration.5,6 We have been engaged
F IGURE 1. Structure of macroviracin A (1).
in chemical studies on macroviracins, resulting in the
determination of the absolute configuration of 1.7 In
connection with our synthetic studies on macroviracin A
(1), we describe herein a short-step synthesis of the
domain structure 2 (Scheme 1).
* Address correspondence to this author. Phone: +81-48-467-9377.
Fax: +81-48-462-4666.
(1) Hyodo, T.; Tsuchiya, Y.; Sekine, A.; Amano, T. J apanese Kokai
Tokkyo Koho J apanese patent 11246587, Sept 14, 1999.
(2) Tsunakawa, M.; Komiyama, N.; Tenmyo, O.; Tomita, K.; Kawano,
K.; Kotake, C.; Konishi, M.; Oki, T. J . Antibiot. 1992, 45, 1467.
Tsunakawa, M.; Kotake, C.; Yamasaki, T.; Moriyama, T.; Konishi, M.;
Oki, T. J . Antibiot. 1992, 45, 1472.
Resu lts a n d Discu ssion
In the synthetic study of these macrocyclic sugar
lactones, elaboration of the core is the most essential
problem throughout the synthetic course.8 We focused on
the intermolecular macrodimerization of C22 carboxylic
acid 3 because little is known about the cyclization of
such long-chain acids.5,6,9 Our synthetic strategy directed
toward the acid 3 was based on the convergent process
(3) Uyeda, M.; Yokomizo, K.; Miyamoto, Y.; Habib, E.-S. E. J .
Antibiot. 1998, 51, 823. Yokomizo, K.; Miyamoto, Y.; Nagao, K.;
Kumagae, E.; Habib, E.-S. E.; Suzuki, K.; Harada, S.; Uyede, M. J .
Antibiot. 1998, 51, 1035. Habib, E.-S. E.; Yokomizo, K.; Murata, K.;
Uyeda, M. J . Antibiot. 2000, 53, 1420.
(4) Qian-Cutrone, J .; Ueki, T.; Huang, S.; Mookhtiar, K. A.; Ezekiel,
R.; Kalinowski, S. S.; Brown, K. S.; Golik, J .; Lowe, S.; Pirnik, D. M.;
Hugill, R.; Veitch, J . A.; Klohr, S. E.; Whitney, J . L.; Manly, S. P. J .
Antibiot. 1999, 52, 245.
(5) (a) Fu¨rstner, A.; Albert, M.; Mlynarski, J .; Matheu, M. J . Am.
Chem. Soc. 2002, 124, 1168. (b) Fu¨rstner, A.; Mlynarski, J .; Albert,
M. J . Am. Chem. Soc. 2002, 124, 10274. (c) Fu¨rstner, A.; Albert, M.;
Mlynarski, J .; Matheu, M.; DeClercq, E. J . Am. Chem. Soc. 2003, 125,
13132.
(6) Fu¨rstner, A.; Ruiz-Caro, J .; Prinz, H.; Waldmann, H. J . Org.
Chem. 2004, 69, 459.
(7) Takahashi, S.; Hosoya, M.; Koshino, H.; Nakata, T. Org. Lett.
2003, 5, 1555.
10.1021/jo0496392 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/28/2004
J . Org. Chem. 2004, 69, 4509-4515
4509

Takahashi et al.
SCHEME 2. Syn th esis of Acetylen e 5a
SCHEME 1. Retr osyn th etic An a lysis of th e
Dom a in Str u ctu r e 2 of 1
a
Reagents and conditions: (a) p-anisealdehyde dimethylacetal,
CSA, DMF, 60 °C, 99%; (b) DIBAL, CH2Cl2, 0 °C, 92%; (c)
TBDPSCl, imidazole, DMF, rt, 96%; (d) OsO4, NaIO4, THF-H2O,
rt, 80%; (e) CBr4, Ph3P, Et3N, CH2Cl2, 0 °C, 92%; (f) n-BuLi, THF,
-78 °C, 94%.
was treated with benzaldehyde dimethylacetal in the pre-
sence of D-camphorsulfonic acid (CSA) in DMF at 60 °C
under reduced pressure to give benzylidene derivative 8
in 99% yield. DIBAL reduction of 8 afforded primary alco-
hol 9 in 92% yield. The liberated hydroxyl group was pro-
tected as the corresponding tert-butyldiphenylsilyl (TB-
DPS) ether, giving 10 (96%). Lemieux-J ohnson oxidation
of 10 afforded aldehyde 11 in good yield. This was trans-
formed into dibromoolefin 12 and then 5 according to Cor-
ey’s procedure.11
In previous studies,7 synthesis of a right-half epoxide
corresponding to 6 required 14 steps from methyl 3-tet-
rahydropyranyloxy butyrate. For large-scale preparation
of the benzyl analogue 6, we newly developed a short-
step synthesis based on the hydrolytic kinetic resolution
of a terminal epoxide reported by J acobsen et al (Scheme
3).12 Thus, methyl ester 139f was initially reduced (94%),
and the resulting alcohol 1413 was sulfonylated to afford
tosylate 15 in 77% yield. The chain extension from 15
was performed by the action of 1-pentenylmagnesium
bromide in the presence of CuI to give olefin 16 in 99%
yield. This was oxidized with mCPBA in CH2Cl2 to
provide a ca. 1:1 diastereomeric mixture of terminal
epoxides 17 in 87% yield. The epoxide 17 was treated
with 0.9 mol % of (R,R)-(-)-N,N′-bis(3,5-di-tert-butylsali-
cylidene)1,2-cyclohexadiamino cobalt in the presence of
water (0.65 equiv) at room temperature, giving epoxide
6 in 44% and diol 18 (44%). The optical purity of the
epoxide 6 was determined to be >99% de by NMR and
HPLC analyses, using a chiral column.14 The resolved
diol 18 was also transformed into 6 via the corresponding
benzoyl mesylate 19.
previously developed by us. Thus, removal of the sugar
residue from 3 and reduction of the carboxylic function
led to acyclic alcohol 4. Disconnection between the C-9
and -10 bond in 4 reverted to terminal acetylene 510 and
epoxide 6. Each fragment appeared readily accessible
from commercially available compounds. This approach
would enable us to prepare other congeners of this family
by changing the size of the acetylene unit.
Synthesis of the left-half segment 5 started with hy-
droxy protection of diol 77 (Scheme 2). Thus, 1,3-diol 7
(8) For recent synthetic studies on complex glycolipids see: (a) Brito-
Arias, M.; Pereda-Miranda, R.; Heathcock, C. H. J . Org. Chem. p
ublished online J an 6, 2004, http://dx.doi.org/10.1021/jo030244c. (b)
Fu¨rstner, A. Eur. J . Org. Chem. 2004, 943. (c) Fu¨rstner, A.; J eanjean,
F.; Razon, P.; Wirtz, C.; Mynott, R. Chem. Eur. J . 2003, 9, 307. (d)
Fu¨rstner, A.; J eanjean, F.; Razon, P.; Wirtz, C.; Mynott, R. Chem. Eur.
J . 2003, 9, 320. (e) Fu¨rstner, A.; Radkowski, K.; Grabowski, J .; Wirtz,
C.; Mynott, R. J . Org. Chem. 2000, 65, 8758. (f) Furukawa, J .;
Kobayashi, S.; Nomizu, M.; Nishi, N.; Sakairi, N. Tetrahedron Lett.
2000, 41, 3453 and references therein.
(9) For relative small dilactones, see: (a) Su, Q.; Beeler, A. B.;
Lobkovsky, E.; Porco, J . A., J r.; Panek, J . S. Org. Lett. 2003, 5, 2149.
(b) Garcia, D. M.; Yamada, H.; Hatakeyama, S.; Nishizawa, M.
Tetrahedron Lett. 1994, 35, 3325. (c) Plattner, D. A.; Brunner, A.;
Dobler, M.; Muller, H.; Petter, W.; Zinden, P.; Seebach, D. Helv. Chim.
Acta 1993, 76, 2004. (d) Zhi-wei, G.; Ngooi, T. K.; Scilimati, A.; Fu¨lling,
G.; Sih, C. J . Tetrahedron Lett. 1988, 29, 5583. (e) Yoshida, M.; Harada,
N.; Nakamura, H.; Kanematsu, K. Tetrahedron Lett. 1988, 29, 6129.
(f) Seebach, D.; Braendli, U.; Schnurrenberger, P.; Przybylski, M. Helv.
Chim. Acta 1988, 71, 155. (g) Velarde, S.; Urbina, J .; Pen˜a, M. R. J .
Org. Chem. 1996, 61, 9541.
(11) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett., 1972, 3769.
(12) (a) Schaus, S. E.; Brandes, B. D.; Larrow, J . F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; J acobsen, E. N. J . Am.
Chem. Soc. 2002, 124, 1307. (b) Furrow, M. E.; Schaus, S. E.; J acobsen,
E. N. J . Org. Chem. 1998, 63, 6776. (c) Tokunaga, M.; Larrow, J . F.;
Kakiuchi, F.; J acobsen, E. N. Science 1997, 227, 936 and references
therein.
(13) (a) Izquierdo, I.; Plaza, M. T.; Rodriguez, M.; Tamayo, J . A.;
Martos, A. Tetrahedron: Asymmetry, 2001, 12, 293. (b) Yang, Q.;
Toshima, H.; Yoshihara, T. Tetrahedron, 2001, 57, 5377.
(10) In previous work,7 alkyl iodide was employed as a nucleophilic
precursor. However, we did not adopt this route for the large-scale
synthesis of 4 because of the lack of reproducibility of the coupling
reaction with 6.
4510 J . Org. Chem., Vol. 69, No. 13, 2004

Synthetic Studies on Macroviracin A
TABLE 1. Ma cr od im er iza tion a
SCHEME 3. Syn th esis of Ter m in a l Ep oxid e 6a
yield (%)
added
metal
molarity
(M)
entry
1
reagents
solvent
toluene
2
26
3
ArCl,b DMAP,
Et3N
0.02
16
83
2
3
4
5
6
7
8
DEAD, Ph3P
DMC,c DMAP
DMC, DMAP
DMC, DMAP
DMC, DMAP
DMC, DMAP
DMC, DMAP
THF
0.08
0.02
0.02
0.05
0.05
0.02
0.02
10
10
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
trace 24
NaH
NaH
NaH
KH
25
33
35
20
7
22 19
33 29
30 19
77
Cs2CO3 CH2Cl2
16 48
a
b
All reactions were performed at rt. ArCl ) 2,4,6-trichlo-
robenzoyl chloride. c DMC ) 2-chloro-1,3-dimethylimidazolinium
chloride.
(N,N-dimethylamino)pyridine (DMAP) in the presence of
alkaline metal improved the reaction.20 In particular,
addition of sodium hydride in toluene was effective in
this system to provide 2 in 35% yield (44% yield based
on the starting acid 3 consumed) along with 26 (30%).
On the other hand, the use of potassium hydride as a
base again afforded monomer 26 as a major product
(77%). The structures of both compounds were confirmed
by the NMR analyses coupled with MS spectra. This type
of macrodilactonization has been well-documented to
proceed efficiently in a template-directed manner assisted
by admixed metal cations by Fu¨rstner et al.5 In our case,
interesting results were obtained by changing the metal
cations (Table 1). In the case of sodium cations, the
cyclization of 3 afforded a ca. 1:1 mixture of the desired
dimer 2 and the corresponding monomer 26 (entry 4-6).
The formation of a considerable amount of 26 suggests
that the cations could not preorganize the substrate
efficiently in a head-to-tail arrangement suitable for
dimerization. Although the carboxylic acid 3 is regarded
as a molecule with some degree of ionophoric character,
the alkyl chain in 3 may be too long. In the case of KH,
the product distribution was similar to that in other
conditions (e.g., entry 1). Therefore, the possibility of
nontemplating cyclization cannot be ruled out, either. In
any case, however, the conformational flexibility of the
cyclization precursor interfered with the simple ratio-
nalization of the mechanism.
a
Reagents and conditions: (a) LiAlH4, ether, 0 °C, 94%; (b)
p-TsCl, pyridine, 0 °C, 77%; (c) 1-pentenylmagnesium bromide,
CuI, THF, 0-50 °C, 99%; (d) MCPBA, CH2Cl2, 0 °C to rt, 87%; (e)
(R,R)-(-)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanedi-
aminocobalt, H2O, tert-butyl methyl ether, rt, 44% for 6, 44% for
18; (f) BzCl, pyridine, CH2Cl2, -15 °C, and then MsCl, -15 °C to
rt, 74%; (g) 4M NaOH, THF-MeOH, -10 °C to rt, 84%.
Our attention was next turned to assembling the long
alkyl chain. Generation of a lithium acetylide derived
from 5 (n-BuLi, THF, -78 °C) followed by addition of the
epoxide 6 and BF3‚Et2O in THF at -78 °C cleanly
provided coupling product 20 in 91% yield.14 Selective
hydrogenation of the triple bond in 20 was conducted by
the use of Wilkinson catalyst in benzene, giving saturated
compound 4 in 99% yield. Introduction of a sugar residue
into the carbon backbone was performed by the use of
1.5 equiv of trichloacetimide 215,15 in the presence of
trimethylsilyl trifluoromethanesulfonate (0.15 equiv) in
acetonitrile/CH2Cl2 at -40 °C to give the desired â-gly-
coside 23 in 62% yield along with the corresponding
R-anomer 22 (17%). BF3‚Et2O-promoted glycosidation
resulted in a mixture of anomers in low yield (30-40%).
In the 1H NMR spectra of 23, the large coupling constant
value (J ) 7.0 Hz) indicates the presence of the equatorial
oriented glycosidic linkage of 23. The TBDPS group in
23 was removed by TBAF to afford 24 in good yield. J ones
oxidation of 24 followed by alkaline hydrolysis provided
seco acid 3 in good overall yield. Macrocycliztion from 3
into 2 was investigated under a variety of conditions
(Table 1).16 Lactonization of 3 under Yamaguchi’s condi-
tions17 led to monomer 26 in very high yield, while the
Mitsunobu reaction18 of 3 afforded a 1:1 mixture of the
desired dimeric compound 2 and 26 (total 20% yield). The
use of 2-chloro-1,3-dimethylimidazolinium chloride19 and
In summary, we have succeeded in rapid entry to the
core of macroviracin A (1) from the hydroxy carboxylic
acid 3 through one-step macrocyclization. Work on the
total synthesis of 1 from 2 is currently under way.
Exp er im en ta l Section
(R)-4-Dec-9-en yl-2-(4-m eth oxyp h en yl)[1,3]d ioxa n e (8).
A mixture of 7 (3.00 g, 14.0 mmol), p-methoxybenzaldehyde
dimethylacetal (3.39 mL, 19.9 mmol), and camphorsulfonic
acid (324 mg, 1.4 mmol) in N, N-dimethylformamide (15 mL)
was heated at 60 °C with stirring under reduced pressure (100
mmHg) for 2 h, cooled, and then poured into sat. NaHCO3
solution. The resulting mixture was extracted with ether. The
extracts were washed with water and brine, dried, and
concentrated. The residue was chromatographed on silica gel
(n-hexane:EtOAc ) 10:1) to give 8 (4.59 g, 99%) as a white
(14) The optical purity of 6 and the stereochemistry at the C-8
position in 20 were also confirmed by the modified Moshers’ method21
of the corresponding MTPA esters of 20. Differences in the chemical
shifts (∆S-R) values in δ (400 MHz) between (R)- and (S)-MTPA esters
of 20 are as follows: Me-2 (-0.01), H-2 (-0.02), H-7 (-0.11, -0.09),
H-9 (+0.02, +0.07), H-12 (+0.04).
(15) (a) Hoch, M.; Heinz, E.; Schmidt, R. R. Carbohydr. Res. 1989,
191, 21. (b) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
(c) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem. 1994,
50, 21.
(16) Attempts for macrodimerization of 3 with distannoxane trans-
esterification catalysts9a,22 failed.
(17) (a) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. J pn. 1979, 52, 1989. (b) Hikota, M.; Tone, H.;
Horita, K.; Yonemitsu, O. Tetrahedron 1990, 46, 4613.
(18) Mitsunobu, O. Synthesis 1981, 1.
(19) (a) Fujisawa, T.; Mori, T.; Fukumoto, K.; Sato, T. Chem. Lett.
1982, 1891. (b) Isobe, T.; Ishikawa, T. J . Org. Chem. 1999, 64, 6984.
(20) In these conditions several minor products that seemed to be
higher oligomers were also detected as judged by TLC analysis.
However, such compounds were not characterized.
(21) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092.
(22) Otera, J . Chem. Rev. 1993, 93, 1449.
J . Org. Chem, Vol. 69, No. 13, 2004 4511

Takahashi et al.
SCHEME 4. Cou p lin g Rea ction of 5 w ith 6 a n d Ma cr od im er iza tion a
a
Reagents and conditions: (a) n-BuLi, BF3‚Et2O, THF, -78 °C, 91%; (b) H2, (Ph3P)3RhCl, H2, benzene, rt, 99%; (c) TMSOTf, MS4A,
CH3CN-CH2Cl2, -40 °C, 17% for 22, 62% for 23; (d) TBAF, THF, rt, 82%; (e) J ones reagent, 0 °C; (f) 1 M NaOH, THF-MeOH, 0 °C, 85%
in 2 steps; (g) 2-chloro-1,3-dimethylimidazolinium chloride, NaH, DMAP, toluene, rt, 35% for 2, 30% for 26.
glass: [R]22D +18.6 (c 1.05, CHCl3); IR (neat) 2926, 2854, 1616,
sively with water snd brine, dried, and concentrated. The
1
1518, 1249, 1170, 1107, 1037, 826 cm-1; H NMR (400 MHz,
residue was chromatographed on silica gel (n-hexane:EtOAc
CDCl3) δ 7.42 (d, J ) 8.4 Hz, 2H), 6.88 (d, J ) 8.4 Hz, 2H),
5.81 (m, 1H), 5.46 (s, 1H), 5.00 (dq, J ) 17.2, 1.2 Hz, 1H), 4.93
(dq, J ) 10.4, 1.2 Hz, 1H), 4.25 (dd, J ) 12.0, 5.2 Hz, 1H),
3.94 (td, J ) 12.0, 2.4 Hz, 1H), 3.83-3.78 (m, 1H), 3.80 (s,
3H), 2.04 (q, J ) 6.8 Hz, 2H), 1.78-1.26 (m, 15H); 13C NMR
(100 MHz, CDCl3) δ 159.6, 139.0, 131.4, 127.1, 114.0, 113.4,
100.9, 77.2, 67.0, 55.2, 52.5, 36.1, 33.8, 31.4, 29.6, 29.5 (2×),
29.2, 29.0, 25.0.
) 20:1) to give 10 (1.12 g, 96%) as a colorless syrup: [R]23
D
-4.2 (c 1.13, CHCl3); IR (neat) 3072, 2930, 2856, 1614, 1514,
1428, 1248, 1112, 1087, 702 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.73-7.64 (m, 4H), 7.44-7.35 (m, 6H), 7.19 (d, J ) 8.8 Hz,
2H), 6.83 (d, J ) 8.8 Hz, 2H), 5.82 (m, 1H), 4.99 (dq, J ) 17.2,
1.2 Hz, 1H), 4.94 (dq, J ) 10.4, 1.2 Hz, 1H), 4.42 (d, J ) 11.2
Hz, 1H), 4.37 (d, J ) 11.2 Hz, 1H), 3.84-3.70 (m, 2H), 3.78 (s,
3H), 3.59 (m, 1H), 2.07-2.02 (m, 2H), 1.75 (m, 2H), 1.59-1.17
(m, 14H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.8,
139.1, 135.5, 134.7, 133.8, 131.1, 129.5, 129.2, 127.5, 114.0,
113.6, 75.7, 70.7, 60.7, 55.3, 37.2, 34.2, 33.9, 29.9, 29.7, 29.6,
29.2, 29.0, 27.0, 26.7, 25.4, 19.7, 19.1
Anal. Found: C, 75.53; H, 9.63. Calcd for C21H32O3: C, 75.86;
H.9.70.
(R)-3-(4-Meth oxyben zyloxy)tr id ec-12-en -1-ol (9). To a
stirred solution of 8 (4.27 g, 12.8 mmol) in dichloromethane
(28 mL) was added dropwise a 0.93 M solution of DIBAL (27.5
mL, 25.6 mmol) in hexane at 0 °C. After the mixture was
stirred at 0 °C for 45 min, 2-methyl-2-propanol (7 mL), water
(7 mL), and silica gel were sequentially added at the same
temperature with stirring. The resulting mixture was stirred
at room temperature for 30 min, filtered through a pad of
Celite, and then concentrated. The residue was chromato-
graphed on silica gel (n-hexane:EtOAc ) 4:1 f 2:1) to give 9
(3.96 g, 92%) as a colorless liquid: [R]20D -29.2 (c 1.57, CHCl3);
IR (neat) 3421, 3075, 2928, 2855, 1614, 1514, 1249, 1039, 822
Anal. Found: C, 77.54; H, 9.28. Calcd for C37H52O3Si: C,
77.57; H, 9.15.
(R)-12-(ter t-Bu tyld ip h en ylsila n yloxy)-10-(4-m eth oxy-
ben zyloxy)d od eca n a l (11). To a stirred solution of 10 (7.26
g, 12.7 mmol) in tetrahydrofuran (160 mL) and water (128 mL)
was added dropwise a solution of OsO4 (ca. 0.84 mmol) in
2-methyl-2-propanol (10.5 mL) at room temperature. After the
mixture was stirred for 15 min, NaIO4 (13.6 g, 63.5 mmol) was
added over 30 min. After being stirred for an additional 1.8 h,
the mixture was filtered through a pad of Celite, and the
filtrate was extracted with EtOAc. The extracts were washed
successively with 5% Na2S solution, water, and brine and
concentrated. The residue was chromatographed on silica gel
(n-hexane:EtOAc ) 6:1) to give 11 (5.85 g, 80%) as a colorless
liquid: [R]23D -3.8 (c 0.97, CHCl3); IR (neat) 3071, 2931, 2857,
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.27 (d, J ) 8.8 Hz, 2H),
6.88 (d, J ) 8.8 Hz, 2H), 5.82 (m, 1H), 4.99 (dq, J ) 17.2, 1.2
Hz, 1H), 4.94 (dq, J ) 10.4, 1.2 Hz, 1H), 4.54 (d, J ) 11.2 Hz,
1H), 4.42 (d, J ) 11.2 Hz, 1H), 3.84-3.70 (m, 2H), 3.80 (s,
3H), 3.66-3.60 (m, 1H), 2.45 (t, J ) 5.6 Hz, 1H), 2.05 (q, J )
7.2 Hz, 3H), 1.84-1.50 (m, 4H), 1.40-1.25 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 159.0, 139.0, 130.4, 129.2, 114.0, 113.7,
78.1, 70.5, 60.7, 55.2, 35.9, 33.8, 33.5, 29.8, 29.6, 29.4, 29.1,
28.9, 25.2.
1
2710, 1726, 1514, 1248, 1112, 1087, 703 cm-1; H NMR (400
MHz, CDCl3) δ 9.76 (t, J ) 2.0 Hz, 1H), 7.73-7.64 (m, 4H),
7.44-7.35 (m, 6H), 7.18 (d, J ) 8.8 Hz, 2H), 6.83 (d, J ) 8.8
Hz, 2H), 4.41 (d, J ) 11.2 Hz, 1H), 4.37 (d, J ) 11.2 Hz, 1H),
3.84-3.71 (m, 2H), 3.79 (s, 3H), 3.59 (m, 1H), 2.42 (td, J )
7.6, 2.0 Hz, 2H), 1.75 (m, 2H), 1.68-1.42 (m, 2H), 1.35-1.21
(m, 12H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 202.6,
158.8, 135.4, 134.6, 133.8, 131.0, 129.5, 129.4, 129.2, 127.6,
113.6, 75.6, 70.6, 60.7, 55.3, 43.9, 37.2, 34.2, 29.8, 29.5, 29.4,
29.2, 27.0, 26.6, 25.4, 22.2, 19.3, 19.1.
Anal. Found: C, 75.19; H, 8.76. Calcd for C36H50O4Si: C,
75.22; H, 8.77.
(R)-ter t-Bu tyl[13,13-d ibr om o-3-(4-m eth oxyben zyloxy)-
tr id ec-12-en yloxy]d ip h en ylsila n e (12). To a stirred solution
Anal. Found: C, 75.08; H, 10.29. Calcd for C21H34O3: C,
75.41; H.10.29.
(R)-ter t-Bu tyl-[3-(4-m eth oxyben zyloxy)tr id ec-12-en y-
loxy]d ip h en ylsila n e (10). To a stirred solution of 9 (683 mg,
2.04 mmol) and imidazole (278 mg, 4.08 mmol) in N,N-
dimethylformamide (3.7 mL) was added dropwise chloro-tert-
butyldiphenylsilane (637 µL. 2.45 mmol) at 0 °C. After the
mixture was stirred at 0 °C for 1 h, ice water was added. The
resulting mixture was stirred at room temperature for 1.5 h,
then extracted with ether. The extracts were washed succes-
4512 J . Org. Chem., Vol. 69, No. 13, 2004

Synthetic Studies on Macroviracin A
of carbon tetrabromide (1.02 g, 3.08 mmol) in dichloromethane
(6.6 mL) was added dropwise a solution of triphenylphosphine
(1.62 g, 6.16 mmol) in dichloromethane (2.0 mL) at 0 °C. After
the mixture was stirred for 15 min, triethylamine (1.71 mL,
12.3 mmol) was added. To the resulting mixture was added a
solution of 11 (885 mg, 1.54 mmol) in dichloromethane (1.0
mL) at 0 °C with stirring. The mixture was stirred at 0 °C for
21 h, poured into sat. NaHCO3-Na2S2O3 (1:1) solution, and
then extracted with ether. The extracts were washed succes-
sively with sat. Na2S2O3 solution, water, and brine and
concentrated. The residue was chromatographed on silica gel
(n-hexane:EtOAc ) 15:1) to give 12 (1.03 g, 92%) as a light-
yellow syrup: [R]21D -3.2 (c 1.27, CHCl3); IR (neat) 3071, 2930,
into ice water, and then extracted with ether. The extracts
were washed successively with water, cold HCl solution, water,
sat. NaHCO3 solution, water, and brine and concentrated. The
residue was chromatographed on silica gel (n-hexane:EtOAc
) 6:1) to give 15 (5.65 g, 77%) as a white solid: [R]24 -37.0
D
(c 1.03, CHCl3); IR (KBr) 2974, 2889, 1597, 1462, 1370, 1357,
1191, 1180, 1064, 1026, 939, 888 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.78 (d, J ) 8.0 Hz, 2H), 7.34-7.28 (m, 5H), 7.23 (d,
J ) 8.0 Hz, 2H), 4.51 (d,J ) 11.2 Hz, 1H), 4.27 (d, J ) 11.2
Hz, 1H), 4.22-4.07 (m, 2H), 3.54 (m, 1H), 2.42 (s, 3H), 1.84
(m, 1H), 1.18 (d, J ) 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 144.5, 138.3, 132.9, 130.0, 128.2, 127.7, 127.4 (2x), 71.0, 70.6,
67.6, 36.2, 21.7, 19.6.
1
2856, 1614, 1513, 1428, 1248, 1112, 1086, 822, 702 cm-1; H
Anal. Found: C, 64.92; H, 6.69; S, 9.43. Calcd for
NMR (400 MHz, CDCl3) δ 7.68-7.65 (m, 4H), 7.44-7.35 (m,
6H), 7.19(d, J ) 8.8 Hz, 2H), 6.83 (d, J ) 8.5 Hz, 2H), 6.39 (t,
J ) 7.2 Hz, 1H), 4.41 (d, J ) 11.2 Hz, 1H), 4.37 (d, J ) 11.2
Hz, 1H), 3.85-3.71 (m, 2H), 3.79 (s, 3H), 3.60 (m, 1H), 2.09
(q, J ) 7.2 Hz, 2H), 1.75 (m, 2H), 1.58-1.21 (m, 14H), 1.05 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 158.8, 138.7, 135.4, 134.6,
133.8, 131.0, 129.5, 129.2, 127.5, 113.6, 88.4, 75.6, 70.7, 60.7,
55.3, 37.2, 34.2, 33.1, 29.8, 29.6, 29.4, 29.1, 27.9, 27.0, 26.6,
25.4, 19.3.
C
18H22O4S: C, 64.64; H, 6.63; S, 9.59.
(R)-8-Ben zyloxyn on a n -1-en e (16). To a stirred solution
of pentenylmagnesium bromide prepared from magnesium
turnings (3.68 g, 0.15 mol) and 5-bromo-1-pentene (19.9 mL,
0.17 mol) in tetrahydrofuran (300 mL) was added a solution
of 15 (18.7 g, 55.9 mmol) in tetrahydrofuran (40 mL) at 0 °C
over 30 min. Then CuI (1.28 g, 6.72 mmol) was added and the
resulting mixture was stirred at 0 °C for 1.5 h, 50 °C for 1.5
h, and room temperature for 12 h. After being quenched with
the addition of sat. NH4Cl solution, the mixture was extracted
with ether. The extracts were washed with water and brine
and concentrated. The residue was chromatographed on silica
gel (n-hexane:EtOAc ) 50:1) to give 16 (12.8 g, 99%) as a light-
Anal. Found: C, 60.67; H, 6.98; Br, 22.01. Calcd for
C
37H50O3Br2Si: C, 60.82; H, 6.90; Br, 21.87.
(R)-ter t-Bu t yl[3-(4-m et h oxyb en zyloxy)t r id ec-12-yn y-
loxy]d ip h en ylsila n e (5). To a stirred solution of 12 (1.03 g,
1.41 mmol) in tetrahydrofuran (8.4 mL) was added dropwise
a 1.59 M solution of n-BuLi (1.86 mL, 2.96 mmol) in hexane
at -78 °C. The mixture was stirred at -78 °C for 3 h and 0 °C
for 40 min. After being quenched with sat. NH4Cl solution,
the resulting mixture was extracted with ether. The extracts
were washed with water and brine, dried, and concentrated.
The residue was chromatographed on silica gel (n-hexane:
EtOAc ) 10:1) to give 5 (760 mg, 94%) as a light-yellow
syrup: [R]23D -3.6° (c 1.06, CHCl3); IR (neat) 3309, 3071, 2932,
yellow liquid: [R]22 -18.0 (c 1.23, CHCl3); IR (neat) 3067,
D
3030, 2930, 2858, 1640, 1455, 1373, 1069, 910, 733, 696 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.25-7.15 (m, 5H), 5.73 (ddt, J
) 17.2, 10.4, 6.8 Hz, 1H), 4.91 (dq, J ) 17.2, 1.2 Hz, 1H), 4.85
(dq, J ) 10.4, 1.2 Hz, 1H), 4.48 (d, J ) 12.0 Hz, 1H), 4.37 (d,
J ) 12.0 Hz, 1H), 3.42 (m, 1H), 1.95-1.88 (m, 2H), 1.57-1.22
(m, 8H), 1.11 (s, J ) 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 139.0, 138.9, 128.1, 127.5, 127.2, 114.0, 74.8, 70.3, 36.7, 33.8,
29.3, 29.0, 25.5, 19.7.
1
2857, 1612, 1514, 1428, 1248, 1112, 1085, 822, 702 cm-1; H
Anal. Found: C, 82.52; H, 10.43. Calcd for C16H24O: C,
82.70; H, 10.41.
NMR (400 MHz, CDCl3): δ 7.67-7.64 (m, 4H), 7.46-7.35 (m,
6H), 7.19 (d, J ) 8.8 Hz, 2H), 6.83 (d, J ) 8.8 Hz, 2H), 4.41 (d,
J ) 11.2 Hz, 1H), 4.37 (d, J ) 11.2 Hz, 1H), 3.84-3.71 (m,
2H), 3.79 (s, 3H), 3.59 (m, 1H), 2.19 (td, J ) 7.2, 2.4 Hz, 2H),
1.94 (t, J ) 2.4 Hz, 1H), 1.75 (m, 2H), 1.57-1.21 (m, 14H),
1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.8, 135.4, 133.8,
131.0, 129.4, 129.2, 127.5, 113.6, 84.7, 75.6, 70.6, 68.1, 60.7,
55.3, 37.2, 34.2, 29.8, 29.5, 29.1, 28.8, 28.6, 27.0, 25.4, 19.3,
18.5.
(2RS,6R)-2-(6-Ben zyloxyh eptyl)oxir an e (17). To a stirred
solution of 16 (12.8 g, 55.3 mmol) in dichloromethane (300 mL)
was added m-chloroperoxybenzoic acid (>65% assay, 33.4 g,
194 mmol) at 0 °C, and the mixture was stirred for 1 d.
Triethylamine was added and the mixture was stirred for an
additional 30 min and concentrated. The residue was chro-
matographed on silica gel (n-hexane:EtOAc ) 20:1) to give 17
(12.0 g, 87%) as a ca. 1:1 diastereomeric mixture: IR (neat)
3032, 2970, 2933, 2859, 1455, 1374, 1136, 1068, 736, 697 cm-1
;
Anal. Found: C, 77.51; H, 8.86. Calcd for C37H50O3Si: C,
77.84; H, 8.83.
1H NMR (400 MHz, CDCl3) δ 7.34-7.31 (m, 5H), 4.57 (d, J )
12.0 Hz, 1H), 4.45 (d, J ) 12.0 Hz, 1H), 3.51 (m, 1H), 2.92-
2.85 (m, 1H), 2.74 (t, J ) 4.8 Hz, 1H), 2.46 (dd, J ) 4.8, 2.0
Hz, 1H), 1.61-1.27 (m, 8H), 1.19 (d, J ) 6.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 138.9, 128.1, 127.4, 127.1, 74.7, 70.2, 52.3,
47.0, 36.6, 32.4, 29.5, 26.0, 25.5, 19.7.
(R)-3-Ben zyloxybu ta n -1-ol (14). To a stirred suspension
of lithium aluminum hydride (1.38 g, 36.4 mmol) in ether (80
mL) was added dropwise a solution of 13 (10.0 g, 48.0 mmol)
in ether (30 mL) at 0 °C, and the mixture was stirred at 0 °C
for 2 h. Water (1.4 mL), 10% NaOH solution (1.4 mL), and
water (4.2 mL) were sequentially added at 0 °C with stirring.
The resulting mixture was filtered through a pad of Celite,
and then concentrated. The residue was chromatographed on
silica gel (n-hexane:EtOAc ) 4:1 f 2:1) to give 14 (8.11 g, 94%)
as a colorless liquid: [R]23D -63.8 (c 2.09, CHCl3) {[R]23D -57.5
(c 1.0, CHCl3),13a [R]23D -48.1 (c 8.3, CHCl3)13b}; IR (neat) 3401,
Anal. Found: C, 77.34; H, 9.79. Calcd for C16H24O2: C, 77.38;
H, 9.74.
Hyd r olytic Kin etic Resolu tion of 17. A mixture of (R,R)-
(-)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanedi-
aminocobalt (91 mg, 0.15 mmol) and acetic acid (17 µL, 0.30
mmol) in toluene (0.4 mL) was stirred while open to the air
for 1 h at room temperature. The solvent was removed by
rotary evaporation to leave a brown solid. The resulting
catalyst residue and 17 (4.0 g, 16.1 mmol) were dissolved in
tert-butylmethyl ether (3.8 mL), the mixture was cooled to 0
°C, and water (0.19 mL, 10.5 mmol) was added dropwise at 0
°C with stirring. The resulting mixture was allowed to warm
to room temperature with stirring over 20 h, and concentrated.
The residue was chromatographed on silica gel (n-hexane:
EtOAc ) 10:1 f 6:1 f 1:1 f 1:0) to give 6 (1.77 g, 44%) and
18 (1.90 g, 44%).
3032, 2969, 2932, 2873, 1455, 1375, 1094, 1054, 737, 697 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.29-7.16 (m, 5H), 4.55 (d, J )
11.6 Hz, 1H), 4.37 (d, J ) 11.6 Hz, 1H), 3.72-3.65 (m, 3H),
2.63 (br s, 1H), 1.72-1.68 (m, 2H), 1.18 (d, J ) 6.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 138.2, 128.3, 127.5, 127.4, 74.4,
70.4, 60.6, 38.8, 19.4.
Anal. Found: C,73.02; H, 8.92. Calcd for C11H16O2: C, 73.30;
H.8.95.
(R)-3-Ben zyloxybu tyl p-Tolu en esu lfon a te (15). To a
stirred solution of 14 (3.99 g, 22.1 mmol) in pyridine (25 mL)
was added p-TsCl (6.03 g, 31.6 mmol) at 0 °C, and the mixture
was stirred at 0 °C for 3 h. After addition of crashed ice, the
resulting mixture was stirred vigorously for 30 min, poured
6: light-yellow liquid; [R]26D -11.6 (c 1.27, CHCl3); IR (neat)
2970, 2933, 2859, 1455, 1374, 1136, 1068, 735, 697 cm-1; H
NMR (400 MHz, CDCl3) δ 7.34-7.31 (m, 5H), 4.57 (d, J ) 12.0
1
J . Org. Chem, Vol. 69, No. 13, 2004 4513

Takahashi et al.
Hz, 1H), 4.45 (d, J ) 12.0 Hz, 1H), 3.51 (m, 1H), 2.89 (m, 1H),
2.74 (t, J ) 4.7 Hz, 1H), 2.46 (dd, J ) 4.8, 2.7 Hz, 1H), 1.61-
1.28 (m, 8H), 1.19 (d, J ) 6.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 138.9, 128.0, 127.4, 127.1, 74.6, 70.2, 52.2, 46.9, 36.5,
32.4, 29.5, 25.9, 25.4, 19.6.
2.42 (ddt, J ) 16.8, 4.4, 2.4 Hz, 1H), 2.28 (ddt, J ) 16.8, 6.8,
2.4 Hz, 1H), 2.19 (m, 2H), 1.99 (d, J ) 4.8 Hz, 1H), 1.77 (m,
2H), 1.67-1.26 (m, 24H), 1.20 (d, J ) 6.0 Hz, 3H), 1.07 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 158.8, 139.0, 135.4, 133.8,
131.0. 129.4, 129.2, 128.1, 127.5(2x), 127.2, 113.6, 83.2, 76.1,
75.6, 74.8, 70.6, 70.3, 70.1, 60.7, 55.3, 37.2, 36.6, 36.2, 34.2,
29.8, 29.7, 29.6, 29.2, 29.1, 29.0, 27.9, 27.0, 25.7, 25.6, 25.4,
19.7, 19.3, 18.9.
Anal. Found: C, 77.42; H, 9.84. Calcd for C16H24O2: C, 77.38;
H, 9.74.
18: light-yellow liquid; [R]22D -19.6 (c 1.09, CHCl3); IR (neat)
1
3378, 2933, 2860, 1454, 1277, 1069, 697 cm-1; H NMR (400
Anal. Found: C, 77.49; H, 9.24. Calcd for C53H74O5Si: C,
77.70; H, 9.10.
MHz, CDCl3) δ 7.37-7.29 (m, 5H), 4.57 (d, J ) 12.0 Hz, 1H),
4.45 (d, J ) 12.0 Hz, 1H), 3.74-3.63 (m, 2H), 3.50 (m, 1H),
3.43 (ddd, J ) 11.2, 7.6, 5.2 Hz, 1H), 2.00 (d, J ) 4.4 Hz, 1H),
1.86 (t, J ) 6.0 Hz, 1H), 1.60-1.28 (m, 10H), 1.19 (d, J ) 6.0
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 138.9, 128.1, 127.5,
127.2, 72.2, 71.6, 70.3, 66.7, 36.6, 33.1, 29.7, 25.5, 25.3, 19.7.
Anal. Found: C, 70.75; H, 9.70. Calcd for C16H26O3‚0.3H2O:
C, 70.71; H, 9.87.
(2R,8S,20R)-2-Ben zyloxy-22-(ter t-bu tyld ip h en ylsila n y-
loxy)-20-(4-m eth oxyben zyloxy)d ocosa n -8-ol (4). A mixture
of 20 (200 mg, 0.24 mmol) and tris(triphenylphosphine)-
rhodium chloride (11.3 mg, 12.2 µmol) in benzene (1.0 mL) was
stirred at rt under hydrogen atmosphere for 10 h, and
concentrated. The residue was chromatographed on silica gel
(n-hexane:EtOAc ) 4:1) to give 4 (201 mg, 99%) as a colorless
syrup: [R]25D -6.5 (c 0.99, CHCl3); IR (neat) 3448, 2929, 2856,
Tr a n sfor m a tion of 18 in to 6 via 19. To a stirred solution
of 18 (1.8 g, 6.8 mmol) in dichloromethane (10 mL) and
pyridine (5 mL) was added dropwise benzoyl chloride (0.82 mL,
7.1 mmol) at -15 °C, and the mixture was stirred for 1.5 h.
Methanesulfonyl chloride (1.05 mL, 13.5 mmol) was added at
-15 °C and stirring was continued for 1 d at -15 °C to rt.
After addition of crashed ice, the resulting mixture was stirred
vigorously for 6 h, and then extracted with ether. The extracts
were washed successively with water, cold HCl solution, water,
sat. NaHCO3 solution, water, and brine and concentrated. The
residue was chromatographed on silica gel (n-hexane:EtOAc
) 20:1 f 10:1 f 4:1) to give 19 (2.25 g, 74%) as a light-yellow
syrup; [R]23D -2.7° (c 1.13, CHCl3); IR (neat) 3032, 2937, 2862,
1613, 1514, 1464, 1248, 1112, 735, 702 cm-1 1H NMR (400
;
MHz, CDCl3) δ 7.68-7.65 (m, 4H), 7.44-7.32 (m, 9H), 7.28-
7.26 (m, 2H), 7.19 (d, J ) 8.8 Hz, 2H), 6.83 (d, J ) 8.8 Hz,
2H), 4.57 (d, J ) 12.0 Hz, 1H), 4.46 (d, J ) 12.0 Hz, 1H), 4.42
(d, J ) 11.2 Hz, 1H), 4.37 (d, J ) 11.2 Hz, 1H), 3.85-3.72 (m,
2H), 3.80 (s, 3H), 3.60 (m, 2H), 3.51 (m, 1H), 1.76 (m, 2H),
1.64-1.23 (m, 32H), 1.20 (d, J ) 6.0 Hz, 3H), 1.06 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 139.0, 135.4, 133.9, 131.1, 129.4,
129.2, 128.2, 127.5, 127.2, 113.6, 75.7, 74.8, 72.0, 70.7, 70.3,
60.7, 55.3, 37.6, 37.5, 37.2, 36.7, 34.3, 29.9 (2×), 29.8 (2×), 29.7,
27.0, 25.8, 25.7, 25.6, 25.4, 19.7, 19.3.
Anal. Found: C, 77.24; H, 9.55. Calcd for C53H78O5Si: C,
77.32; H, 9.55.
1
1725, 1453, 1344, 1274, 1176, 1114, 918, 714 cm-1; H NMR
(400 MHz, CDCl3) δ 8.07 (d, J ) 8.0 Hz, 2H), 7.59 (t, J ) 8.0
Hz, 1H), 7.46 (t, J ) 8.0 Hz, 2H), 7.34-7.23 (m, 5H), 5.02 (dtd,
J ) 7.6, 6.0, 2.8 Hz, 1H), 4.57 (d, J ) 12.0 Hz, 1H), 4.53 (dd,
J ) 12.4, 2.8 Hz, 1H), 4.44(d, J ) 12.0 Hz, 1H), 4.39 (dd, J )
12.4, 7.6 Hz, 1H), 3.51 (m, 1H), 3.03 (s, 3H), 1.87-1.71 (m,
2H), 1.61-1.36 (m, 8H), 1.19 (d, J ) 6.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.9, 138.9, 133.2, 129.6, 129.3, 128.4,
128.2, 127.5 (2×), 127.2, 80.2, 74.6, 70.3, 65.5, 38.8, 65.5, 38.8,
36.5, 31.7, 29.3, 25.3, 25.0, 19.7.
Glycosid a tion of 4. To a stirred solution of 4 (1.56 g, 1.93
mmol), 21 (2.01 g, 2.89 mmol), and MS 4A (600 mg) in
dichloromethane (11 mL) and acetonitrile (11 mL) was added
dropwise trimethylsilyl trifluoromethanesulfonate (52 µL, 289
µmol) at -40 °C, and the mixture was stirred at the same
temperature for 2.5 h. After addition of sat. NaHCO3 solution,
the resulting mixture was filtered through a pad of Celite. The
filtrate was diluted with water and extracted with dichlo-
romethane. The extracts were washed with water and brine
and concentrated. The residue was chromatographed on silica
gel (n-hexane:EtOAc ) 10:1 f 8:1) to give 23 (1.57 g, 62%)
and the corresponding R-anomer 22 (420 mg, 17%).
Anal. Found: C, 64.27; H, 7.19; S, 7.12. Calcd for
C
24H32O6S: C, 64.26; H, 7.19; S, 7.15.
To a stirred solution of 19 (2.03 g, 4.53 mmol) in tetrahy-
22: colorless syrup; [R]25 +27.2 (c 0.47, CHCl3); IR (neat)
drofuran (10 mL) and methanol (10 mL) was added dropwise
4 M NaOH solution (2.3 mL, 9.1 mmol) at -10 °C, and the
mixture was stirred for 20 h at -10 °C to rt. After addition of
crashed ice, the resulting mixture was extracted with ether.
The extracts were washed successively with water and brine
and concentrated. The residue was chromatographed on silica
gel (n-hexane:EtOAc ) 20:1) to give 6 (946 mg, 84%).
(2R,8R,20R)-2-Ben zyloxy-22-(ter t-bu tyld ip h en ylsila n y-
loxy)-20-(4-m eth oxyben zyloxy)d ocos-10-yn -8-ol (20). To
a stirred solution of 5 (3.00 g, 5.25 mmol) in tetrahydrofuran
(30 mL) was added dropwise a 1.59 M solution of n-BuLi (3.1
mL, 4.85 mmol) in hexane at -78 °C, and the mixture was
stirred at the same temperature for 1 h. A solution of 6 (1.00
g, 4.04 mmol) in tetrahydrofuran (4.0 mL) was added dropwise
at -78 °C, followed by addition of BF3‚Et2O (0.61 mL, 4.85
mmol). After being stirred for 1.5 h, the mixture was quenched
with sat. NH4Cl solution and extracted with ether. The
extracts were washed with water and brine and concentrated.
The residue was chromatographed on silica gel (n-hexane:
EtOAc ) 20:1 f 10:1 f 2:1) to give 20 (3.02 g, 91%) as a light-
yellow syrup. The acetylene 5 (891 mg, 30%) was also
recovered.
D
3032, 2930, 2856, 1744, 1514, 1455, 1247, 1090, 1029, 700
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.66-7.64 (m, 4H), 7.36-
7.28 (m, 24H), 7.18 (d, J ) 8.8 Hz, 2H), 6.82 (d, J ) 8.8 Hz,
2H), 5.01 (d, J ) 11.2 Hz, 1H), 4.92 (d, J ) 3.2 Hz, 1H), 4.87
(d, J ) 10.0 Hz, 1H), 4.82 (d, J ) 10.0 Hz, 1H), 4.73 (d, J )
12.0 Hz, 1H), 4.67 (d, J ) 12.0 Hz, 1H), 4.56 (d, J ) 11.2 Hz,
1H), 4.55 (d, J ) 12.0 Hz, 1H), 4.45 (d, J ) 12.0 Hz, 1H), 4.41
(d, J ) 11.2 Hz, 1H), 4.36 (d, J ) 11.2 Hz, 1H), 4.29 (dd, J )
12.0, 4.0 Hz, 1H), 4.24 (d, J ) 12.0 Hz, 1H), 4.01 (t, J ) 9.6
Hz, 1H), 3.90 (m, 1H), 3.81-3.73 (m, 2H), 3.78 (s, 3H), 3.60-
3.45 (m, 5H), 2.01 (s, 3H), 1.75 (m, 2H), 1.55-1.19 (m, 5H),
1.17 (d, J ) 6.0 Hz, 3H), 1.05 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.5, 158.8, 139.0, 138.6, 138.0, 137.7, 135.4, 133.8,
131.1, 129.4, 129.2, 128.4, 128.3 (2×), 128.2, 128.1, 127.8 (2×),
127.7, 127.5, 127.2, 113.6, 95.5, 82.0, 80.1, 78.4, 77.5, 75.7, 75.6,
75.1, 74.8, 73.2, 70.7, 70.3, 68.9, 63.2, 60.7, 55.3, 37.2, 36.7,
34.5, 34.3, 33.3, 30.1, 30.0, 29.9 (2×), 29.8, 29.7, 27.0, 25.9,
25.6, 25.5, 25.1, 20.9, 19.7, 19.3.
Anal. Found: C, 75.78; H, 8.44. Calcd for C82H108O11Si: C,
75.89; H, 8.39.
23: colorless syrup; [R]23 +3.4 (c 1.15, CHCl3); IR (neat)
D
20: [R]24 -7.2 (c 0.98, CHCl3); IR (neat) 3449, 3070, 2931,
3032, 2930, 2856, 1745, 1613, 1513, 1455, 1361, 1247, 1071,
D
2857, 1613, 1513, 1248, 1112, 735, 702 cm-1
;
1H NMR (400
700 cm-1 1H NMR (400 MHz, CDCl3) δ 7.67-7.64 (m, 4H),
;
MHz, CDCl3) δ 7.70-7.66 (m, 4H), 7.44-7.35 (m, 9H), 7.24-
7.26 (m, 2H), 7.20 (d, J ) 8.4 Hz, 2H), 6.84 (d, J ) 8.4 Hz,
2H), 4.58 (d, J ) 12.0 Hz, 1H), 4.47 (d, J ) 12.0 Hz, 1H), 4.45
(d, J ) 11.2 Hz, 1H), 4.39 (d, J ) 11.2 Hz, 1H), 3.86-3.73 (m,
2H), 3.78 (s, 3H), 3.62 (m, 1H), 3.58 (m, 1H), 3.52 (m, 1H),
7.44-7.24 (m, 24H), 7.18 (d, J ) 8.8 Hz, 2H), 6.82 (d, J ) 8.8
Hz, 2H), 4.97 (d, J ) 11.2 Hz, 2H), 4.94 (d, J ) 11.2 Hz, 1H),
4.85 (d, J ) 11.2 Hz, 1H), 4.78 (d, J ) 10.8 Hz, 1H), 4.71 (d,
J ) 11.2 Hz, 1H), 4.55 (d, J ) 10.8 Hz, 1H), 4.54 (d, J ) 12.0
Hz, 1H), 4.44 (d, J ) 12.0 Hz, 1H), 4.43 (d, J ) 7.0 Hz, 1H),
4514 J . Org. Chem., Vol. 69, No. 13, 2004

Synthetic Studies on Macroviracin A
4.41 (d, J ) 11.2 Hz, 1H), 4.36 (d, J ) 11.2 Hz, 1H), 4.32 (dd,
J ) 12.0, 2.2 Hz, 1H), 4.18 (dd, J ) 12.0, 4.6 Hz, 1H), 3.84-
3.71 (m, 2H), 3.78 (s, 3H), 3.68-3.56 (m, 3H), 3.53-3.40 (m,
4H), 2.05 (s, 3H), 1.75 (m, 2H), 1.58-1.19 (m, 32H), 1.16 (d, J
) 6.2 Hz, 3H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
170.5, 158.8, 139.0, 138.4, 138.3, 137.7, 135.4, 133.8, 131.1,
129.4, 129.2, 128.3 (2×), 128.2 (2×), 128.0, 127.8, 127.7, 127.5
(2×), 113.6, 102.6, 84.9, 82.3, 80.3, 77.7, 75.7, 74.9, 74.8, 72.6,
70.6, 70.2, 63.3, 60.7, 55.3, 37.2, 36.7, 34.9, 34.2, 30.2, 29.9,
29.8, 29.7 (3×), 26.7, 25.6, 25.4, 25.3, 20.9, 19.7, 19.3.
113.7, 102.4, 84.7, 82.3, 80.1, 77.7, 77.3, 76.7, 75.6, 75.3, 74.9,
72.8 (2×), 74.7, 71.1, 70.2, 62.2, 55.2, 39.5, 39.4, 36.7, 34.9,
34.2, 30.1, 29.8, 29.7 (2×), 29.6 (2×), 25.5, 25.4, 25.2, 25.1, 19.7.
Anal. Found: C, 74.65; H, 8.57. Calcd for C64H86O11: C,
74.53; H, 8.40.
Ma cr ocycliza tion of 3. To a stirred solution of 3 (18.6 mg,
18.0 µmol) in toluene (0.35 mL) was added dropwise a 25%
solution of 2-chloro-1,3-dimethylimidazolidium chloride (30 µL,
43.9 µmol) in dichloromethane at 0 °C. After 5 min, sodium
hydride (60% suspension in mineral oil, 1.5 mg, 38 µmol) was
added and the mixture was stirred at 0 °C for 1 h. (N,N-
Dimethylamino)pyridine (5.2 mg, 42.5 µmol) was then added
and stirring was continued for 90 h at room temperature. The
reaction mixture was directly poured onto a column of silica
gel (n-hexane:EtOAc )10:1). Elution with n-hexane:EtOAc )
10:1 f 4:1 gave a syrup, which was further purified by
preparative TLC (n-hexane:EtOAc ) 4:1,three developments)
to give 2 (6.4 mg, 35%) and 26 (5.5 mg, 30%). In addition,
starting material 3 (3.6 mg, 19%) was also recovered.
Anal. Found: C, 76.11; H, 8.48. Calcd for C82H108O11Si: C,
75.89; H, 8.39.
(3R,15S,21R)-15-(6-O-Acetyl-2,3,4-tr i-O-ben zyl-â-D-glu co-
p yr a n osyloxy)-21-b en zyloxy-3-(4-m et h oxyb en zyloxy)-
d ocosa n -1-ol (24). To a stirred solution of 23 (1.79 g, 1.32
mmol) in tetrahydrofuran (12.7 mL) was added dropwise a 1.0
M solution of n-tetrabutylammonium fluoride (1.98 mL, 1.98
mmol) in tetrahydrofuran at rt, and the mixture was stirred
at the same temperature for 6 h. After addition of water, the
resulting mixture was extracted with ether. The extracts were
washed with water and brine and concentrated. The residue
was chromatographed on silica gel (n-hexane:EtOAc ) 4:1 f
2: white solid; [R]23 +3.7 (c 1.05, CHCl3); IR (neat) 3032,
D
2923, 2853, 1740, 1514, 1455, 1249, 1070, 743, 697 cm-1; H
1
NMR (400 MHz, CDCl3) δ 7.33-7.28 (m, 44H), 6.83 (d, J )
8.8 Hz, 4H), 4.96 (d, J ) 10.8 Hz, 2H), 4.93 (d, J ) 11.2 Hz,
2H), 4.84 (d, J ) 11.2 Hz, 2H), 4.78 (d, J ) 11.2 Hz, 2H), 4.69
(d, J ) 11.2 Hz, 2H), 4.57 (d, J ) 10.8 Hz, 2H), 4.54 (d, J )
12.0 Hz, 2H), 4.49-4.41 (m, 8H), 4.37 (d, J ) 7.9 Hz, 2H),
4.42-4.37 (m, 2H), 4.10 (dd, J ) 11.6, 6.8 Hz, 2H), 3.86 (m,
2H), 3.74 (s, 6H), 3.64 (t, J ) 8.8 Hz, 2H), 3.56 (m, 2H), 3.50-
3.36 (m, 8H), 2.58 (dd, J ) 15.6, 8.0 Hz, 2H), 2.43 (dd, J )
15.6, 5.6 Hz, 2H), 1.55-1.22 (m, 64H), 1.16 (d, J ) 6.0 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 171.3, 158.9, 139.0, 138.4,
138.3, 137.6, 130.6, 129.2, 128.3, 128.2 (2×), 127.9, 127.8, 127.7
(2×), 127.5, 127.4, 127.2, 113.6, 102.9, 84.9, 82.4, 80.8, 78.0,
75.8, 75.7, 75.0, 74.8 (2×), 72.7, 71.3, 70.2, 63.5, 55.2, 39.9,
36.7, 35.1, 34.6 (2×), 30.2, 30.1 (2×), 30.0 (3×), 29.9 (2×), 25.6
(2×), 25.5, 25.3, 19.7; ESI-FTMS calcd for C128H168O20Na [M
+ Na]+ 2049.2055, found 2049.1980.
2:1 f 1:1) to give 24 (1.14 g, 82%) as a colorless syrup: [R]26
D
-3.8 (c 1.04, CHCl3); IR (neat) 3484, 3032, 2929, 2855, 1744,
1514, 1455, 1247, 1069, 736, 698 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.33-7.23 (m, 22H), 6.87 (d, J ) 8.8 Hz, 2H), 4.96
(d, J ) 11.2 Hz, 1H), 4.94 (d, J ) 11.2 Hz, 1H), 4.85 (d, J )
10.8 Hz, 1H), 4.78 (d, J ) 11.2 Hz, 1H), 4.71 (d, J ) 10.8 Hz,
1H), 4.56 (d, J ) 11.2 Hz, 1H), 4.54 (d, J ) 12.0 Hz, 1H), 4.53
(d, J ) 11.2 Hz, 1H), 4.44 (d, J ) 11.2 Hz, 1H), 4.42 (d, J )
7.7 Hz, 1H), 4.41 (d, J ) 12.0 Hz, 1H), 4.31 (dd, J ) 12.0, 2.4
Hz, 1H), 4.18 (dd, J ) 12.0, 5.6 Hz, 1H), 3.80-3.60 (m, 5H),
3.79 (s, 3H), 3.50-3.41 (m, 4H), 2.45 (dd, J ) 6.0, 4.8 Hz, 1H),
2.02 (s, 3H), 1.58-1.19 (m, 34H), 1.16 (d, J ) 6.0 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 170.4, 159.0, 138.9, 138.3 (2×),
137.6, 130.4, 129.2, 128.3, 128.2, 128.1 (2×), 127.9, 127.7 (2×),
127.6, 127.4, 127.2, 113.7, 102.5, 84.8, 82.3, 80.2, 78.2, 77.6,
75.6, 74.9, 74.8 (2×), 72.5, 70.5, 70.2, 63.3, 60.7, 55.2, 36.7,
35.9, 34.9, 34.2, 33.5, 30.1, 29.8, 29.7 (2×), 25.5, 25.3, 25.2,
20.9, 19.7.
26: colorless glass; [R]21 +1.9 (c 0.99, CHCl3); IR (neat)
D
3032, 2926, 2855, 1741, 1513, 1455, 1355, 1248, 1071, 737, 697
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 22H), 6.84
Anal. Found: C, 74.80; H, 8.64. Calcd for C66H90O11: C,
74.82; H, 8.56.
(d, J ) 8.8 Hz, 2H), 4.96 (d, J ) 10.8 Hz, 1H), 4.94 (d, J )
10.8 Hz, 1H), 4.86 (d, J ) 11.2 Hz, 1H), 4.78 (d, J ) 10.8 Hz,
1H), 4.70 (d, J ) 11.2 Hz, 1H), 4.57 (d, J ) 10.8 Hz, 1H), 4.55
(d, J ) 11.2 Hz, 1H), 4.48 (br s, 2H), 4.45 (d, J ) 12.0 Hz, 1H),
4.43 (d, J ) 7.5 Hz, 1H), 4.40 (dd, J ) 12, 1.5 Hz, 1H), 4.17 (d,
J ) 12.0, 6.8 Hz, 1H), 3.88 (m, 1H), 3.76 (s, 3H), 3.66 (t, J )
9.2 Hz, 1H), 3.60-3.56 (m, 1H), 3.53-3.37 (m, 4H), 2.62 (dd,
J ) 15.6, 6.8 Hz, 1H), 2.46 (dd, J ) 15.6, 6.0 Hz, 1H), 1.61-
1.22 (m, 32H), 1.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2,
158.9, 139.0, 138.4, 138.3, 137.7, 130.6, 129.2, 128.4, 128.2
(2×), 128.0, 127.9, 127.8 (3×), 127.7 (2×), 127.6, 127.5 (2×),
127.4, 127.2, 113.7, 102.9, 84.9, 82.3, 81.0, 78.2, 77.3, 75.7, 75.3,
75.0, 74.8, 72.8, 71.0, 70.2, 63.7, 55.3, 39.4, 36.7, 35.1, 34.5,
33.2, 30.2, 29.4, 28.6, 28.1, 27.5, 27.3, 26.9, 26.8, 25.6, 25.5,
25.2, 23.5, 19.7; FABMS calcd for C64H84O10Na [M + Na]+
1035.5962, found 1035.5956.
(3R,15S,21R)-21-Ben zyloxy-15-(2,3,4-t r i-O-b en zyl-â-D-
glu cop yr a n osyloxy)-3-(4-m et h oxyb en zyloxy)d ocosa n o-
ic Acid (3). To a stirred solution of 24 (106 mg, 0.10 mmol) in
acetone (5 mL) was added dropwise J ones reagent (ca. 0.13
mL) at 0 °C, and the mixture was stirred at the same
temperature for 20 min. 2-Methyl-2-propanol was added
followed by addition of water, and the resulting mixture was
extracted with chloroform. The extracts were washed with
water and brine and concentrated to give 25 (99.5 mg), which
was dissolved in methanol (0.53 mL) and tetrahydrofuran (0.53
mL). To this solution was added dropwise 1.0 M NaOH solution
(0.37 mL) at 0 °C with stirring. The mixture was stirred at 0
°C for 20 min, acidified with Dowex-50W X-8 (H+) resin, and
filtered through a pad of Celite. The filtrate was evaporated
to give a syrup, which was chromatographed on silica gel (n-
hexane:EtOAc:acetic acid ) 400:100:1) to give 3 (87.4 mg, 85%)
as a white glass; [R]23 -2.7° (c 1.05, CHCl3); IR (neat) 3434,
D
Ack n ow led gm en t. We are grateful to Mr. S. Hy-
oudo (Kaken Pharm. Co.) for providing us natural
macroviracins. We also thank Dr. T. Nakamura (RIK-
EN) for mass spectral measurements and Dr. T. Chi-
hara and his collaborators in RIKEN for the elemental
analyses.
3032, 2922, 2850, 1717, 1614, 1515, 1455, 1350, 1251, 1072,
1
819, 738, 697 cm-1; H NMR (400 MHz, CDCl3) δ 7.33-7.29
(m, 22H), 6.88 (d, J ) 8.8 Hz, 2H), 4.95 (d, J ) 11.2 Hz, 1H),
4.93 (d, J ) 10.8 Hz, 1H), 4.86 (d, J ) 11.2 Hz, 1H), 4.80 (d,
J ) 11.2 Hz, 1H), 4.71 (d, J ) 10.8 Hz, 1H), 4.63 (d, J ) 11.2
Hz, 1H), 4.55 (d, J ) 12.0 Hz, 1H), 4.53 (d, J ) 11.2 Hz, 1H),
4.49 (d, J ) 11.2 Hz, 1H), 4.48 (d, J ) 7.7 Hz, 1H), 4.44 (d, J
) 12.0 Hz, 1H), 3.87-3.82 (m, 2H), 3.80 (s, 3H), 3.71-3.64
(m, 3H), 3.56 (t, J ) 9.6 Hz, 1H), 3.49-3.30 (m, 3H), 2.59 (dd,
J ) 16, 2.4 Hz, 1H), 2.55 (dd, J ) 16, 1.2 Hz, 1H), 1.66-1.19
(m, 32H), 1.16 (d, J ) 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 176.0, 159.0, 138.9, 138.4, 138.3, 137.8, 130.1, 129.3, 128.3,
128.2 (2×), 128.1, 127.9, 127.7 (3×), 127.6, 127.4 (2×), 127.2,
Su p p or tin g In for m a tion Ava ila ble: General procedures
and copies of 1H and 13C NMR spectra of compounds 2 and
26. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0496392
J . Org. Chem, Vol. 69, No. 13, 2004 4515