Stereodivergent syntheses of anisomycin derivatives from D-tyrosine

Article abstract of DOI:10.1021/jo050079w

Enantiomerically pure 2-alkyl-3-acetoxy-4-iodopyrrolidines with all groups cis, and all adjacent groups trans (10 and 17), important precursors for the synthesis of pyrrolidinediols, have been prepared from D-tyrosine through regio- and diastereoselective

Full text of DOI:10.1021/jo050079w

Stereodivergent Syntheses of Anisomycin Derivatives from
D-Tyrosine
Jin Hyo Kim, Marcus J. Curtis-Long,† Woo Duck Seo, Young Bae Ryu, Min Suk Yang, and
Ki Hun Park*,‡
Department of Agricultural Chemistry, Division of Applied Life Science (BK21 programs),
Gyeongsang National University, Jinju, 660-701, South Korea, Trout Beck, Wansford, Driffield,
East Yorkshire, YO25 8NX, U.K., and Institute of Agriculture & Life Sciences, Gyeongsang National
University, Jinju, 660-701, South Korea
khpark@gshp.gsnu.ac.kr
Received January 14, 2005
Enantiomerically pure 2-alkyl-3-acetoxy-4-iodopyrrolidines with all groups cis, and all adjacent
groups trans (10 and 17), important precursors for the synthesis of pyrrolidinediols, have been
prepared from D-tyrosine through regio- and diastereoselective reduction of a vinyl ketone and
subsequent iodoamidation controlled by minimization of nonbonding steric interactions. Highly
stereodivergent Woodward-Prevost methodology, applied to both iodopyrrolidines, yielded enan-
tiomerically pure (2R,3R,4R)-, (2R,3R,4S)-, and (2R,3S,4R)-deacetylanisomycin (3, 4, and 5), each
in excellent de. Incorporation of differential protection of the hydroxyl groups led to a one-pot
synthesis of (2R,3R,4R)-anisomycin 2.
Introduction
anisomycin analogues, such as deacetylanisomycin, act
as potential fungicides for bean mildew and other fungal
plant infections,2,10 and they are also expected to be
inhibitors of some enzymes.11,13a Thus, much attention
has been focused toward the development of convenient
and efficient routes to anisomycin and its derivatives, and
the following general methodologies have been used for
this purpose: (i) the transformation of carbohydrates
based on stereoselective reductive alkylation,12 (ii) dia-
stereoselective addition of cyclic imines and nitrones,13
(iii) the combined application of Sharpless asymmetric
Anisomycin, first isolated from Streptomyces species
in 1954,1 exhibits a remarkably selective activity against
several pathogenic protozoa2 and fungi3 because it specif-
ically blocks peptide bond formation on 60S eukaryotic
ribosomes4 through inhibition of the peptidyl trans-
ferase.4a,5 These properties have been used in the clinical
treatment of amoebic dysentery6 and vaginitis.7 Aniso-
mycin has also been shown to exhibit antiviral8 and
antitumor activities due to apoptotic activity.9 Some
* To whom correspondence should be addressed. Tel: +82-55-751-
5472. Fax: +82-55-757-0178.
(8) Diman, J. D.; Ruiz-Echevarria, M. J.; Czaplinski, K.; Peltz, S.
W. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 6606.
(9) (a) Stadheim, T. A.; Kucera, G. L. Leuk. Res. 2002, 26, 55. (b)
To¨ro¨csik, B.; Szebere´nyi, J. Biochem. Biophys. Res. Commun. 2000,
278, 550. (c) Lee, Y. S.; Wurster, R. D. Cancer Lett. 1995, 93, 157.
(10) Windholz, M., Ed. The Merck Index, 10th ed.: Merck: Rahway,
NJ, 1983; p 98.
(11) (a) Asano, N.; Oseki, K.; Kizu, H.; Matsui, K. J. Med. Chem.
1994, 37, 3701. (b) Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows,
L. E.; Tyms, A. S.; Petursson, S.; Namgoong, S. K.; Ramsden, N. G.;
Smith, P. W.; Son, J. C.; Wilson, F.; Witty, D. R.; Jacob, G. S.;
Rademacher, T. W. FEBS Lett. 1988, 237, 128.
(12) (a) Merino, P.; Franco, S.; Lafuente, D.; Merchan, F.; Revuelta,
J.; Tejero, T. Eur. J. Org. Chem. 2003, 2877. (b) Hutin, P.; Haddad,
M.; Larcheveˆque, M. Tetrahedron: Asymmetry 2000, 11, 2547. (c)
Schwardt, O.; Veith, U.; Gaspard, C.; Ja¨ger, V. Synthesis 1999, 1473.
(d) Baer, H. H.; Zamkanei, M. J. Org. Chem. 1988, 53, 4786.
(13) (a) Chapman, T. M.; Courtney, S.; Hay, P.; Davis, B. G. Chem.
Eur. J. 2003, 9, 3397. (b) Lombardo, M.; Fabbroni, S.; Trombini, C. J.
Org. Chem. 2001, 66, 1264. (c) Ballini, R.; Marcantoni, E.; Petrini, M.
J. Org. Chem. 1992, 57, 1316.
† Trout Beck.
‡ Gyeongsang National University.
(1) Sobin, B. A.; Tanner, F. W., Jr. J. Am. Chem. Soc. 1954, 76, 4053.
(2) Hall, S. S.; Loebenberg, D.; Schumacher, D. P. J. Med. Chem.
1983, 26, 469.
(3) Hosoya, Y.; Kameyama, T.; Naganawa, H. Okami, Y.; Takeuchi,
T. J. Antibiotics 1993, 46, 1300.
(4) (a) Grollman, A. P. J. Biol. Chem. 1967, 242, 3226. (b) Vasquez,
D. FEBS Lett. 1974, 40, S63. (c) Barbacid, M.; Vasquez, D. J. Mol.
Biol. 1974, 84, 603.
(5) (a) Kinzy, T. G.; Harger, J. W.; Carr-Schmid, A.; Kwon, J.;
Shastry, M.; Justice, M.; Dinman, J. D. Virology 2002, 300, 60. (b)
Carrasco, L.; Barbacid, M.; Vazquez, D. Biochim. Biophys. Acta 1973,
312, 368.
(6) Santander, V. M.; Cue, A. B.; Diaz, J. G. H.; Balmis, F. J.;
Miranda, G.; Urbina, E.; Portilla, J.; Plata, A. A.; Zapata, H. B.; Mufioz,
V. A.; Abreu, L. M. Rev. Invest. Niol. Univ. Guadalajara 1961, 1, 94.
(7) (a) Frye, W. W.; Mule, J. G.; Swartzwelder, C. Antibiot. Annu.
1954-1955, 820. (b) Armstrong, T.; Santa Maria, O. Ibid. 1954-1955,
824.
10.1021/jo050079w CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/16/2005
4082
J. Org. Chem. 2005, 70, 4082-4087

Stereodivergent Syntheses of Anisomycin Derivatives
SCHEME 1. Retrosynthetic Plan for the Synthesis
of Anisomycin Derivatives
SCHEME 2. Synthesis of r,â-Unsaturated Ketone
8
FIGURE 1. (-)-Anisomycin and its derivatives.
epoxidation from divinylcarbinol,14 (iv) transformation of
benzylpyrrole,15 (v) the addition of electrogenerated
anions,16 (vi) the asymmetric dihydroxylation of unsatur-
ated esters,17 (vii) the aldol coupling of glycolate and
tyrosinal,18 and (viii) nucleophilic substitution along with
aryl migration.19 However, many of these routes suffer
the disadvantage of either the use of nonstereoselective
transformations15 or having low overall yield, due to the
large number of steps used.16,19,20 Although the problem
of enantioselectivity has been solved in a few cases,12b,13a
a powerful synthetic methodology for construction of
structurally diverse dihydroxylated pyrrolidines still
remains to be fully developed.
In a previous paper, we described a new approach to
the stereodivergent synthesis of dihydroxylated pyrroli-
dine using the Woodward-Prevost reaction.21 Therefore,
as a continuation of our studies, we have directed our
interest to investigating the stereoselective synthesis of
(2R,3R,4R)-anisomycin 2, and (2R,3R,4R)-, (2R,3R,4S)-,
and (2R,3S,4R)-deacetylanisomycin (3, 4, and 5) (Figure
1).
published novel intermediate as an alternative synthetic
route, focusing on the synthesis of anisomycin deriva-
tives.22 This intermediate, generated from chiral R-amino
acids, via an iodoamidation, is attractive for a number
of reasons. First, although R-amino acids are an ideal
starting point for an enantioselective synthesis of
pyrrolidinediols as they are readily available and are of
high enantiopurity, using this precursor, selective instal-
lation of both hydroxyl groups on the pyrorrolidine ring
has proved difficult, with no general methodology being
developed. It was envisioned that Woodward-Prevost
(W-P) methodology could be used to overcome this
problem easily. Second, if successful, this methodology
would be highly stereodivergent as the Woodward-
Prevost reaction gives access to a wide range of stereo-
isomers from common intermediates. Third, with the
iodocyclization generating a â-iodoaceate stereo and
regiospecifically, the usual issues of facial selectivity of
epiiodination and regioselectivity of the subsequent ring
opening would be overcome.
The outline of the process is shown in Scheme 1,
beginning with D-tyrosine and proceeding via selective
reduction of vinyl ketone and iodocyclization22 with
anticipated total regio- and stereointegrity. The inter-
midate iodoacetates (10 and 17) should serve as a basis
for the synthesis of a wide range of pyrrolidinediols.
Synthesis of â-iodoacetates (10 and 17) was achieved
simply in a small number of steps by the following
reaction sequence. The aminoaldehyde 6 was synthesized
in a high yield from homochiral amino acid, D-tyrosine,
as previously described23 in 65% yield. The 9-phenyl-9-
fluorenyl (Pf) group was chosen for protection of the
amine since it was expected not only to inhibit of
deprotonation at the R-position of the R-amino aldehyde24
but also to provide an electron-donating effect to the
nitrogen atom, accelerating iodoamidation (Scheme 2).
Results and Discussion
The numerous flaws in the available methodologies to
synthesize pyrrolidinediols prompted us to undertake a
thorough investigation into the use of a previously
(14) Shi, Z.-C.; Lin, G.-Q. Tetrahedron: Asymmetry 1995, 6, 2907.
(15) Schumacher, D. P.; Hall, S. S. J. Am. Chem. Soc. 1982, 104,
6076.
(16) Shono, T.; Kise, N. Chem. Lett. 1987, 697.
(17) (a) Ikota, N. Heterocycles 1995, 41, 983. (b) Chandrasekhar, S.;
Ramachandar, T.; Reddy, M. V. Synthesis 2002, 13, 1867.
(18) Hulme, A. N.; Rosser, E. M. Org. Lett. 2002, 4, 265.
(19) Ono, M.; Tanikawa, S.; Suzuki, K.; Akita, H. Tetrahedron 2004,
60, 10187.
Treatment of 6 with vinylmagnesium bromide yielded
a fully separable mixture of the syn and anti isomers of
allylic alcohol 7, in a 1:1 ratio, in 93% total yield. To
(20) Delair, P.; Brot, E.; Kanazawa, A.; Greene, A. E. J. Org. Chem.
1999, 64, 1383.
(21) Kim, J. H.; Long, M. J. C.; Kim, J. Y.; Park, K. H. Org. Lett.
2004, 6, 2273.
(23) (a) Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96, 1825. (b)
Chang, K. T.; Jang, K. C.; Park, H. Y.; Kim, Y. K.; Park, K. H.; Lee,
W. S. Hetereocycles 2001, 55, 1173.
(22) Lee, W. S.; Jang, K. C.; Kim, J. H.; Park, K. H. Chem. Commun.
1999, 251.
(24) Park, K. H.; Rapoport, H. J. Org. Chem. 1994, 59, 394.
J. Org. Chem, Vol. 70, No. 10, 2005 4083

Kim et al.
TABLE 1. Preparation of Enantiomerically Pure Allylic
Alcohola
entry
reagents
conditions
ratiob (7a/7b) yieldc (%)
FIGURE 2. Comparison of Felkin-Ahn models for the
1
2
3
4
5
6
7
8
BH3-(CH3)2S toluene, -78 °C
1:9
>95:1
1:6
91d
89
82
e
selective reduction.
(S)-BINAL
(R)-BINAL
NaBH4
DIBAL-H
L-Selectride
THF, -78 °C
THF, -78 °C
THF, -10 °C
THF, -78 °C
THF, -78 °C
SCHEME 3. Synthesis of W-P Reaction
Substrates 10 and 17
e
1:5
1:6
1:8
45
38
20
KS-Selectride THF, -78 °C
Red-Al THF, -40 °C
a The reactions were all run at 0.1 M concentration. b Deter-
mined by 1H NMR integration. c Isolated yield. d Based on 70%
conversion of starting material. e 1,4-addition product.
improve the efficiency of this route, an efficient protocol
for the conversion of the mixture of diastereoisomers to
a single diastereoisomer of either 7a or 7b was investi-
gated. It was envisioned that stereoselective reduction
of the ketone moiety could achieve the desired goal.
Accordingly, compound 7 was reoxidized using under
Swern conditions to afford R, â-unsaturated ketone 8
(Scheme 2).
Initially, reduction of the ketone with NaBH4 was
attempted, but this gave reduction predominantly at the
â position. A further attempt with DIBAL-H also gave
the same result. However, it was shown that highly regio-
and stereoselective reduction at the carbonyl moiety
occurred when more complex reducing agents were used,
and indeed, both epimers 7a and 7b were created in high
diastereoselectivity and yields using this methodology
(Table 1).
In general, the results are in accordance with the polar
Felkin model, where the most electron-withdrawing
substituent occupies the position usually adopted by the
largest group in the classical Felkin-Ahn-type transition
state. The nature of this group being perpendicular to
the carbonyl adds extra delocalization in the transition
state, allowing electron density from the nascent bond
to overlap with the best acceptor orbital. Addition via
transition state B is responsible for the major product,
which is derived from attack of the nucleophile syn to
the C-H bond at the Burgi-Dunitz angle, reducing steric
effects and lowering its energy. The electrophilic reduc-
tant BH3‚SMe2 was found to be the best reducing agent
to give the Felkin product in terms of de and yield. On
the other hand, 7a was formed in an excellent enantio-
selective manner by the use of (S)-BINAL,25 while the
use of (R)-BINAL favored 7b (Figure 2). Subsequent
reaction with Ac2O furnished the respective acetates in
excellent yields.
by minimizing the nonbonding steric interactions be-
tween the â-center and the proximal C-H of the vinyl
group. The standard A1,3 strain model being of low
importance in this system due to there being no syn alkyl
substituent. The â-stereocenter was shown by Tamaru
and co-workers to dominate over the R-center in an
amide-based system.26 Addition of I2 to the least hindered
face (away from NHPf group) generates the desired epi-
iodonium ion, which when trapped out by the nitrogen
lone pair electron gives the desired product (Figure 3).
An analogous procedure repeated on 16 generated the
expected all syn product, again that derived from the
epiiodonium formed due to minimization of nonbonding
steric interactions.
Key intermediate 10, with a trans relationship between
iodine and acetoxy groups, is now set up for W-P
transformations, which proceed by neighboring group
participation of the acetate. Treatment of 10 with wet
AgBF4 (Woodward conditions) gave a 1:1 mixture of easily
separable â-hydroxy acetates 13a and 13b (Scheme 4).
Proof that the two products differed only in the position
of the acetate group was given by cleavage of a 1:1
mixture of acetates 13a and 13b to a single diol deriva-
tive 14 in >98% de. Subsequent hydrogenolysis yielded
target compound (2R,3R,4S)-deacetylanisomycin 4.
Formation of the C(4) epimer could be achieved using
Prevost conditions, where water is excluded from the
reaction mixture. Thus, treatment of 10 with AgOBz gave
the corresponding differentially protected diester in
excellent yield and with very high regioselectivity. Cleav-
With the vinylic acetate 9 in hand, treatment with I2,
leading to stereoselective formation of an epiiodonium ion
in situ, followed by subsequent highly regioselective ring
closure, furnished 10 in 90% yield (Scheme 3). The
excellent selectivity of the iodination can be explained
(25) (a) Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am.
Chem. Soc. 1984, 106, 6717. Noyori, R.; Tomino, I.; Nishizawa, M. J.
Am. Chem. Soc. 1979, 101, 5843.
(26) Tamaru, Y.; Mizutani, M.; Furukawa, Y.; Kawamura, S.;
Yoshida, Z.; Yanagi, K.; Minobe, M. J. Am. Chem. Soc. 1984, 106, 1079.
4084 J. Org. Chem., Vol. 70, No. 10, 2005

Stereodivergent Syntheses of Anisomycin Derivatives
FIGURE 3. Proposed mechanism for the stereoselective iodoamidation.
SCHEME 4. Synthesis of Target Compounds 3 and 4
SCHEME 5. Synthesis of Target Compound 2
furnished (2R,3R,4R)-anisomycin 2 in 91% yield. Thus
the synthesis of anisomycin was accomplished from 10
in two steps in overall 76% yield.
With both stereoisomers of C2-C3 trans having been
synthesized from 7a, attention turned to the C2-C3 cis
series. This series was thought to be accessible from
iodoacetate 17, which, unfortunately, has a syn arrange-
ment about the two reacting groups, making it not totally
ideal for the W-P reaction, as the departure of the
nucleofuge cannot be assisted by the neighboring acetoxy
group due to them being syn on a five-membered ring.
Initial studies focused on the use of AgOBz as the Lewis
acid, although this resulted only in the return of the
starting material, and altering amount of Lewis acid and
the temperature had no effect. However, in an analogous
manner to that documented above, 17 was treated with
AgBF4 in aqueous conditions, and as observed previously,
a 1:1 mixture of separable acetates 18a and 18b was
generated (Scheme 6). Cleavage of acetyl group from the
mixture 18a/18b using LiAlH4 gave the diol 19 as a single
product again in 70% yield. Deprotection of 19 by
hydrogenolysis furnished (2R,3S,4R)-deacetylanisomycin
5.
age of both ester protecting groups with LiAlH4 gave 12,
which was easily deprotected to the (2R,3R,4R)-deacetyl-
anisomycin 3 (Scheme 5). Under both reaction conditions,
the reaction pathway relies upon activation of the iodide
with the halophilic sliver(I) cation, allowing the acetate
to displace the iodide to generate a cyclic acetoxonium
ion, which was described extensively in our previous
report.21 With the methodology for highly selective ma-
nipulation of 10 demonstrated, and the principle of
differential protection further established in the case of
11, the synthesis of Anisomycin was attempted. Com-
pound 10 was treated with Ag(O2CCF3), using Prevost
conditions. Trapping of the cyclic acetoxonium ion by
triflouroacetate formed the trans diol derivative, with a
labile protecting group installed regioselectively in the
C4 position. Deprotection was easily effected during
chromatography on silica gel to yield N-protected aniso-
mycin 15 in 84% yield. Deprotection by hydrogenolysis
Conformation of stereochemistries were obtained by
2D-NOESY experiments on 3-5 (Figure 4). Strong
NOESY cross-peaks were observed between H3-H4 in
FIGURE 4. Selected NOESY correlation of 3-5.
J. Org. Chem, Vol. 70, No. 10, 2005 4085

Kim et al.
SCHEME 6. Synthesis of Target Compound 5
143.8, 147.2, 157.1. Anal. Calcd for C31H29NO2: C, 83.19; H,
6.53; N, 3.13. Found: C, 83.29; H, 6.60; N, 3.24.
both compounds 4 and 5, whereas a very weak cross-
peaks was observed between H3-H4 in compound 3.
In conclusion, a highly stereodivergent methodology for
the synthesis of a range of stereoisomers of deacetylani-
somycine has been demonstrated starting from a single
homochiral amino acid, with each target being isolated
in high yield and over a small number of steps, with
excellent selectivity. This highly efficient methodology
was further extended to a short enantioselective synthe-
sis of anisomycin. The value of such stereodivergency can
be seen in the relation of the relative stereochemistry of
the hydroxyl groups on the pyrrolidine ring to the
glycosidase inhibition of the natural anisomycin. Screen-
ing of the unnatural compounds for activity will allow
the effects of such variations to be assessed in a system-
atic way, and endevours toward this and over bioactivity
issues are currently underway within the group.
(3R,4R)-4-(N-9-Phenylfluoren-9-yl)amino-3-hydroxy-5-
(p-methoxyphenyl)-1-pentene (7b). To a solution of 8 (0.3
g, 0.67 mmol) in toluene (2 mL) was added 2.0 M BH3(CH3)2S
(0.67 mL, 1.3 mmol) at -78 °C. After being stirred for 30 min,
the reaction mixture was quenched by addition of satd
NaHCO3 (4 mL). The resulting mixture was extracted with
EtOAc (2 mL × 3), washed with brine, and dried over Na2-
SO4. The organic layer was evaporated, and the residue was
chromatographed on silica gel (hexane/EtOAc ) 8/1) to give
compound 7b (0.19 g, 91%, based on 70% conversion of starting
material 8): [R]D - 115.3 (c 2.0, CHCl3); IR (KBr) 3450, 3070,
2994, 1610 cm-1; 1H NMR (500 MHz; CDCl3) δ 2.21 (1H, dd, J
) 13.3, 5.1 Hz), 2.32 (2H, m), 2.48 (1H, dd, J ) 13.3, 8.3 Hz),
3.68 (1H, m), 3.71 (3H, s), 5.00 (1H, m), 5.13 (1H, m), 5.51
(1H, m), 7.70-6.62 (17H, m); 13C NMR (125 MHz; CDCl3) δ
36.8, 54.2, 57.7, 71.1, 71.6, 112.7, 114.1, 118.9, 124.5, 125.0,
125.3, 126.2, 126.7, 126.8, 127.3, 127.3, 127.4, 129.4, 130.0,
138.7, 139.3, 139.6, 144.3, 148.0, 149.0, 156.9. Anal. Calcd for
C31H29NO2: C, 83.19; H, 6.53; N, 3.13. Found: C, 83.25; H,
6.30; N, 3.34.
Experimental Section
(3S,4R)-4-(N-9-phenylfluoren-9-yl)amino-3-acetoxy-5-
(p-methoxyphenyl)-1-pentene (9). To a solution of enan-
tiomerically pure 7a (1.5 g, 3.35 mmol) in CH2Cl2 (20 mL) were
added Et3N (0.93 mL, 6.71 mmol), 4-(dimethylamino)pyridine
(DMAP, 0.1 g), and acetic anhydrous (0.47 mL, 5.03 mmol).
The mixture was stirred for 2 h at room temperature and
quenched by satd NaHCO3 (30 mL). The resulting mixture was
extracted with CH2Cl2 (10 mL × 3), and the extract was
washed with brine and dried over Na2SO4. The organic layer
was evaporated, and the residue was chromatographed on
silica gel (hexane/EtOAc ) 8/1) to give compound 9 (1.6 g, 98%)
as a solid: mp 44 °C; [R]D +1.42 (c 1.0, CHCl3); IR (KBr) 3327,
3063, 2934, 1737 cm-1; 1H NMR (500 MHz; CDCl3) δ 2.00 (3H,
s), 2.45 (3H, m), 4.80 (1H, m), 4.85 (1H, m), 5.08 (1H, d, J )
10.6 Hz), 5.63 (1H, m), 7.70 ∼ 6.69 (17H, m); 13C NMR (125
MHz; CDCl3) δ 17.9, 21.7, 37.7, 55.6, 58.6, 73.2, 77.1, 114.0,
117.8, 120.0, 120.2, 126.0, 126.5, 126.6, 127.5, 128.1, 128.4,
128.6, 128.8, 130.7, 131.6, 134.4, 140.7, 140.8, 146.0, 149.6,
150.0, 158.4, 170.4. Anal. Calcd for C33H31NO3: C, 80.95; H,
6.38; N, 2.86. Found: C, 81.08; H, 6.52; N, 3.01.
(2R,3R,4R)-4-(N-9-Phenylfluoren-9-yl)-3-acetoxy-4-iodo-
2-(p-methoxybenzyl)pyrrolidine (10). To a solution of 9 (1.6
g, 3.26 mmol) in biphasic solvent (satd NaHCO3/THF/Et2O )
2/1/1, 10 mL) was added iodine (2.0 g) at room temperature.
After being stirred for 36 h, the reaction mixture was quenched
by addition of 0.1 M Na2S2O3 solution and extracted with
EtOAc (12 mL × 3). The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated. The
resulting residue was chromatographed on silica gel (hexane/
EtOAc ) 16/1) to give pyrrolidine 10 (1.81 g, 90%) as a solid:
mp 63 °C; [R]D -56.28 (c 1.0, CHCl3); IR (KBr) 3068, 2940,
1726 cm-1; 1H NMR (500 MHz; CDCl3) δ 1.62 (3H, s), 2.37 (1H,
dd, J ) 13.7, 4.0 Hz), 2.44 (1H, m), 2.67 (1H, dd, J ) 13.7, 9.6
Hz), 2.74 (1H, m), 3.00 (1H, m), 3.28 (1H, m), 3.72 (3H, s),
4.56 (1H, t, J ) 5.1 Hz), 7.75 ∼ 6.71 (17H, m); 13C NMR (125
MHz; CDCl3) δ 13.2, 20.5, 39.4, 55.2, 64.3, 65.8, 73.4, 75.8,
113.6, 119.9, 120.1, 126.8, 127.1, 127.2, 127.9, 128.1, 128.2,
128.8, 128.9, 129.6, 130.2, 140.3, 140.8, 141.4, 145.6, 146.0,
(4R)-5-(p-Methoxyphenyl)-4-(N-9-phenylfluoren-9-yl)-
aminopent-1-en-3-one (8). To a solution of 6 (1.21 g, 2.88
mmol) in THF (12 mL) was added 1.0 M vinylmagnesium
bromide (3.4 mL, 3.43 mmol) at -40 °C. After being stirred
for 30 min, the reaction mixture was quenched by addition of
satd NaHCO3. The resulting mixture was extracted with
EtOAc (10 mL × 3). The combined organic layers were washed
with brine and dried over Na2SO4. The solvent was evaporated,
and the resulting product was used for swern oxidation with
oxalyl chloride (0.62 mL, 7.15 mmol), DMSO (0.81 mL, 11.44
mmol), and Et3N (3.18 mL, 22.88 mmol) at -78 °C in CH2Cl2
(25 mL). The reaction mixture was quenched with satd
NaHCO3, and the organic layer was washed with brine and
dried over Na2SO4. The solvent was removed under reduced
pressure, and the residue was chromatographed on silica gel
(hexane/EtOAc ) 15/1) to give compound 8 (1.16 g, 91%): [R]D
+109.2 (c 1.0, CHCl3); IR (KBr) 3052, 2982, 1718 cm-1 1H
;
NMR (300 MHz; CDCl3) δ 2.57 (2H, m), 3.05 (1H, m), 3.82 (3H,
s), 5.36 (1H, d, J ) 10.6 Hz), 5.60 (1H, d, J ) 17.5 Hz), 5.96
(1H, m), 7.62 ∼ 6.77 (17H, m); 13C NMR (75 MHz; CDCl3) δ
39.9, 55.2, 60.4, 73.0, 113.6, 119.4, 119.5, 125.3, 126.1, 126.9,
127.1, 127.5, 127.9, 128.2, 128.3, 129.6, 130.6, 133.7, 139.9,
140.9, 158.3. Anal. Calcd for C31H27NO2: C, 83.57; H, 6.11; N,
3.14. Found: C, 83.64; H, 6.27; N, 3.22.
(3S,4R)-4-(N-9-Phenylfluoren-9-yl)amino-3-hydroxy-5-
(p-methoxyphenyl)-1-pentene (7a). Unsaturated ketone 8
(0.3 g, 0.67 mmol) was mixed with 3 equiv of (S)-BINAL (2.0
mmol) in THF at -78 °C and allowed to stir at the same
temperature for 1 h. The mixture was quenched by addition
of water (0.1 mL), filtered through Celite 545, and evaporated.
The residue was chromatographed on silica gel (hexane/EtOAc
) 8/1) to give compound 7a (0.26 g, 89%) as a solid: mp 53
1
°C; [R]D -153.5 (c 1.0, CHCl3); IR (KBr) 3452, 2840 cm-1; H
NMR (500 MHz; CDCl3) δ 2.32 (2H, m), 2.52 (1H, m) 3.30 (1H,
bs), 3.77 (3H, s), 5.03 (2H, m), 5.61 (1H, m), 7.62 ∼ 6.28 (17H,
m); 13C NMR (125 MHz; CDCl3) δ 33.8, 54.1, 57.8, 70.4, 71.1,
112.8, 114.1, 118.3, 118.8, 123.9, 124.0, 124.5, 126.0, 126.7,
126.9, 127.0, 127.2, 127.4, 129.2, 129.5, 135.9, 138.4, 139.6,
4086 J. Org. Chem., Vol. 70, No. 10, 2005

Stereodivergent Syntheses of Anisomycin Derivatives
158.0, 169.6. Anal. Calcd for C33H30NO3I: C, 64.40; H, 4.91;
N, 2.28. Found: C, 64.51; H, 5.03; N, 2.35.
2.27 (1H, dd, J ) 12.3, 2.9 Hz), 2.46 (2H, m), 3.25 (1H, dd, J
) 11.1, 3.9 Hz), 3.44 (1H, dd, J ) 11.2, 5.7 Hz), 3.72 (3H, s),
3.74 (1H, m), 4.01 (1H, m), 6.71-6.54 (4H, m), 7.57-7.24 (13H,
m); 13C NMR (75 MHz; CDCl3) δ 39.8, 54.8, 55.2, 68.8, 76.1,
76.4, 77.2, 81.1, 113.8, 119.9, 120.1, 126.3, 127.1, 127.3, 127.5,
127.8, 128.4, 128.5, 128.7, 130.0, 131.2, 139.6, 141.4, 143.0,
146.9, 148.7, 157.8. Anal. Calcd for C31H29NO3: C, 80.32; H,
6.31; N, 3.02. Found; C, 80.45; H, 6.48; N, 3.11.
(2R,3R,4R)-(N-9-Phenylfluoren-9-yl)-4-O-benzoylaniso-
mycin (11). Iodoacetate 10 (0.9 g, 1.46 mmol) and silver
benzoate (0.67 g, 2.95 mmol) were refluxed in dried toluene (6
mL) for 12 h. The mixture was filtered and evaporated. The
residue was chromatographed on silica gel (hexane/EtOAc )
8/1) to give compound 11 (0.82 g, 92%): [R]D + 64.5 (c 1.0,
1
CHCl3); IR (KBr) 3063, 2924, 1752, 1722 cm-1; H NMR (300
(2R,3R,4S)-Deacetylanisomycin (4). Compound 14 (0.49
g, 1.06 mmol) was hydrogenated with Pd/C in EtOAc (6 mL)
at room temperature for 6 h. The reaction mixture was filtered
and evaporated. The residue was dissolved in MeOH (10 mL)
and mixed with Dowex 50W-X8 (2 g). The mixture was filtered
and then was washed MeOH. The remaining residue was
diluted with 3 N NH4OH solution. The solution was evaporated
and then coevaporated with toluene to give compound 3 (0.22
g, 93%): [R]D +26.8 (c 0.53, MeOH); IR (KBr) 3295, 3032, 2950
cm-1; 1H NMR (300 MHz; CDCl3) δ 2.94 (1H, dd, J ) 14.0, 8.2
Hz), 3.13 (2H, m), 3.46 (1H, m), 3.79 (3H, s), 3.94 (1H, m),
4.15 (1H, m), 6.91 (2H, d, J ) 8.6 Hz), 7.23 (2H, d, J ) 8.6
Hz); 13C NMR (75 MHz; CDCl3) δ 36.6, 51.1, 54.3, 67.8, 75.9,
79.0, 113.8, 128.9, 129.7, 158.8; MS-EI m/z 223 (M+), 144, 121,
102; HRMS calcd for C12H17NO3 223.1208, found 223.1205.
(2R,3R,4R)-(N-9-Phenylfluoren-9-yl)anisomycin (15). A
suspension of iodoacetate 10 (0.9 g, 1.46 mmol) and silver
trifluoroacetate (0.65 g, 2.95 mmol) in dried toluene (6 mL)
was refluxed for 6 h. The mixture was quenched with satd
NaHCO3 (10 mL) and extracted with EtOAc (5 mL × 3). The
extract was washed with brine and dried over Na2SO4. The
organic layer was evaporated, and the residue was chromato-
graphed on silica gel (hexane/EtOAc ) 6/1) to give compound
15 (0.62 g, 84%): [R]D + 25.1 (c 1.0, CHCl3); IR (KBr) 3321,
3068, 2980, 1746 cm-1; 1H NMR (300 MHz; CDCl3) δ 1.70 (3H,
s), 2.38 (2H, m), 2.94 (1H, OH), 3.26 (1H, dd, J ) 11.0, 5.6
Hz), 3.49 (1H, dd, J ) 11.0, 6.7 Hz), 3.73 (3H, s), 4.10 (1H, m),
4.49 (1H, t, J ) 2.2 Hz), 6.69-6.54 (4H, m), 7.78-7.24 (13H,
m); 13C NMR (75 MHz; CDCl3) δ 20.8, 38.2, 54.1, 55.1, 65.3,
75.6, 76.2, 77.2, 85.6, 113.6, 120.0, 126.4, 126.9, 127.0, 127.2,
127.4, 127.6, 128.3, 128.4, 130.1, 130.7, 140.1, 140.8, 143.4,
147.5, 148.4, 157.8, 171.7. Anal. Calcd for C33H31NO4: C, 78.39;
H, 6.18; N, 2.77. Found; C, 78.48; H, 6.24; N, 2.82.
MHz; CDCl3) δ 1.62 (3H, s), 2.47 (1H, dd, J ) 13.4, 3.9 Hz),
2.64 (1H, m), 2.80 (1H, dd, J ) 10.3, 3.2 Hz), 3.41 (1H, dd, J
) 12.0, 3.6 Hz), 3.73 (3H, s), 3.80 (1H, dd, J ) 12.0, 6.2 Hz),
5.00 (1H, m), 5.29 (1H, m), 8.13 ∼ 6.54 (22H, m); 13C NMR (75
MHz; CDCl3) δ 20.7, 39.4, 53.5, 55.1, 65.7, 76.1, 77.7, 79.6,
113.6, 119.9, 120.1, 126.7, 127.0, 127.3, 127.4, 127.7, 128.4,
128.5, 129.7, 129.8, 130.2, 130.6, 133.3, 139.7, 141.3, 142.9,
147.2, 148.6, 157.8, 165.7, 169.4. Anal. Calcd for C40H35NO5:
C, 78.80; H, 5.79; N, 2.30. Found: C, 78.91; H, 5.83; N, 2.38.
(2R,3R,4R)-(N-9-Phenylfluoren-9-yl)deacetylanisomy-
cin (12). To a suspended LiAlH4 (0.11 g, 2.70 mmol) solution
in dried THF (6 mL) was added compound 11 (0.82 g, 1.34
mmol) in THF (4 mL) and the mixture stirred for 30 min at 0
°C. The reaction mixture was quenched with water (0.4 mL),
filtered, and evaporated under reduced pressure. The residue
was chromatographed on silica gel (hexane/EtOAc ) 2/1) to
give compound 12 (0.58 g, 94%) as a solid: mp 93 °C; [R]D
+111.2 (c 1.0, CHCl3); IR (KBr) 3301, 3063, 2924 cm-1 1H
;
NMR (300 MHz; CDCl3) δ 0.75 (1H, OH), 1.99 (1H, OH), 2.28
(1H, dd, J ) 12.3, 2.8 Hz), 2.46 (2H, m), 3.26 (1H, dd, J )
11.2, 3.8 Hz), 3.44 (1H, dd, J ) 11.2, 5.7 Hz), 3.72 (3H, s),
3.75 (1H, m), 4.01 (1H, m), 6.70 ∼ 6.54 (4H, m), 7.60-7.24
(13H, m); 13C NMR (75 MHz; CDCl3) δ 39.9, 54.9, 55.2, 68.8,
76.1, 76.4, 77.2, 81.1, 113.9, 119.9, 120.1, 127.1, 127.3, 127.5,
127.8, 128.4, 128.5, 128.8, 130.3, 131.2, 139.6, 141.4, 143.0,
146.9, 148.7, 157.8. Anal. Calcd for C31H29NO3: C, 80.32; H,
6.31; N, 3.02. Found: C, 80.43; H, 6.46; N, 3.09.
(2R,3R,4R)-Deacetylanisomycin (3). N-Protected com-
pound 12 (0.58 g, 1.25 mmol) was hydrogenated with Pd/C in
EtOAc (6 mL) at room temperature for 6 h. The reaction
mixture was filtered and evaporated. The residue was dis-
solved in MeOH (10 mL) and mixed with Dowex 50W-X8 (2
g). The mixture was filtered and then was washed MeOH. The
remaining residue was diluted with 3 N NH4OH solution. The
solution was evaporated and then coevaporated with toluene
to give compound 3 (0.25 g, 89%) as a solid: mp 120 °C; [R]D
(2R,3R,4R)-Anisomycin (2). N-Protected anisomycin 15
(0.62 g, 1.23 mmol) was hydrogenated with Pd/C in EtOAc (5
mL) at room temperature for 6 h. The reaction mixture was
filtered and evaporated. The residue was chromatographed on
silica gel (CH2Cl2/MeOH ) 8/1) to give anisomycin 2 (0.29 g,
91%) as a solid: [R]D -15.4 (c 1.0, MeOH); IR (KBr) 3321, 2991,
1752 cm-1; 1H NMR (300 MHz; CDCl3) δ 1.81 (3H, s), 2.68 (1H,
dd, J ) 13.7, 7.9 Hz), 2.80 (3H, m), 3.04 (1H, m), 3.62 (3H, s),
3.96 (1H, m), 4.63 (1H, m), 6.71 (2H, d, J ) 8.5 Hz), 7.01 (2H,
d, J ) 8.5 Hz); 13C NMR (75 MHz; CDCl3) δ 19.4, 38.1, 52.1,
54.3, 65.1, 75.9, 83.8, 113.6, 129.7, 130.2, 158.4, 170.7; MS-EI
m/z 265 (M+), 144, 121, 102; HRMS calcd for C14H19NO4
265.1314, found 265.1305.
1
+ 20 (c 1.0, MeOH); IR (KBr) 3314, 2924 cm-1; H NMR (300
MHz; CDCl3) δ 2.76 (1H, dd, J ) 13.7, 8.1 Hz), 2.94 (2H, m),
3.12 (2H, m), 3.77 (3H, s), 3.79 (1H, m), 4.05 (1H, m), 6.87
(2H, d, J ) 8.5 Hz), 7.20 (2H, d, J ) 8.5 Hz); 13C NMR (75
MHz; CDCl3) δ 37.9, 51.4, 54.2, 66.9, 77.3, 80.9, 113.2, 113.6,
129.7, 130.3, 158.4; MS-EI m/z 223 (M+), 144, 121, 102; HRMS
calcd for C12H17NO3 223.1208, found 223.1201.
(2R,3R,4S)-(N-9-Phenylfluoren-9-yl)deacetylanisomy-
cin (14). A suspension of 3-acetyl-4-iodopyrrolidine 10 (0.9 g,
1.46 mmol) and silver tetrafluoroborate (0.71 g, 3.67 mmol)
in toluene/water (9/1, 8 mL) was stirred at room temperature
for 12 h. The reaction mixture was quenched with MeOH (20
mL) and satd NaCl (0.7 mL), filtered, and evaporated. The
residue was reduced with LiAlH4 (0.12 g, 3.0 mmol) in THF
(10 mL) at 0 °C and quenched with water (0.5 mL). The
mixture was filtered and concentrated. The residue was
chromatographed on silica gel (hexane/EtOAc ) 2/1) to give
N-protected compound 14 (0.49 g, 73%) as a solid: mp 95 °C;
Acknowledgment. This work was supported by the
Korea Research Foundation Grant (KRF-2004-002-
C00117). We are also thankful for support from the
Brain Korea 21 program.
Supporting Information Available: General procedures,
product characterization data, and NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
[R]D +116.5 (c 1.0, CHCl3); IR (KBr) 3298, 3011, 2950 cm-1
1H NMR (300 MHz; CDCl3) δ 0.80 (1H, OH), 2.03 (1H, OH),
;
JO050079W
J. Org. Chem, Vol. 70, No. 10, 2005 4087