New total synthesis of (±)-, (-)- and (+)-chuangxinmycins

Article abstract of DOI:10.1016/S0040-4020(01)01068-7

(±)-2-Hydroxy-3-(1H-4′-iodoindol-3′-yl)butanoate 6 was stereoselectively converted into the (±)-(2,3)-syn-2-thioacetoxy ester 13 with retention of C₂-stereochemistry in (±)-6. Palladium-catalyzed cyclization of indolyl iodide and the internal C₂ thiol group of the substrate (±)-14 gave the (±)-cis methyl ester 2 of natural chuangxinmycin (1). Stereoselective total syntheses of (-)-(4S,5R)- and (+)-(4R,5S)-chuangxinmycins 1 were achieved based on the enzymatic syntheses of (2R,3S)- and (2S,3R)-epoxy butanoates 9, respectively. Chiral intermediates such as (2R,3S)- and (2S,3R)-2-hydroxy-3-(1H-4′-iodoindol-3′-yl)butanoate 6 for the chiral synthesis of (-)- and (+)-1 were also obtained by the enantioselective hydrolysis of the corresponding acetate (±)-16 by lipase.

Full text of DOI:10.1016/S0040-4020(01)01068-7

TETRAHEDRON
Pergamon
Tetrahedron 57 !2001) 10055±10062
New total synthesis of ꢀ^)-, ꢀ2)- and ꢀ1)-chuangxinmycins
Keisuke Kato, Machiko Ono and Hiroyuki Akitap
School of Pharmaceutical Science, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
Received 21 September 2001; accepted 24 October 2001
AbstractÐ!^)-2-Hydroxy-3-!1H-40-iodoindol-30-yl)butanoate 6 was stereoselectively converted into the !^)-!2,3)-syn-2-thioacetoxy ester
13 with retention of C2-stereochemistry in !^)-6. Palladium-catalyzed cyclization of indolyl iodide and the internal C2 thiol group of
the substrate !^)-14 gave the !^)-cis methyl ester 2 of natural chuangxinmycin !1). Stereoselective total syntheses of !2)-!4S,5R)- and
!1)-!4R,5S)-chuangxinmycins 1 were achieved based on the enzymatic syntheses of !2R,3S)- and !2S,3R)-epoxy butanoates 9, respectively.
Chiral intermediates such as !2R,3S)- and !2S,3R)-2-hydroxy-3-!1H-40-iodoindol-30-yl)butanoate 6 for the chiral synthesis of !2)- and !1)-1
were also obtained by the enantioselective hydrolysis of the corresponding acetate !^)-16 by lipase. q 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
The relative structure of 1 was con®rmed by synthesis2,3 and
the absolute con®gurations were determined as 4S,5R based
on the degradation study of the natural product !1)4 and
optical resolution of !^)-1 with S-!2)-a-phenylethyl
amine.5 Synthetic attempts were carried out by the way of
two published routes. One is an internal Knoevenagel
condensation of 4-substituted-3-acetyl indole 3 and the
subsequent reduction of 4 to give a mixture of !^)-cis-
and -trans-methyl ester 2 of 1 via pathway B.2 In the
other route, treatment of 5 with the ¯uoride ion liberated
Chuangxinmycin !1), isolated from Actinoplanes
tsinanensis n. sp. in China, exhibits in vitro, an antibacterial
spectrum that includes a number of Gram-positive and
Gram-negative bacteria. This antibiotic was reported to be
active in mice against Escherichia coli and Shigella
dysenteria infections in vivo, and effective in the treatment
of septicaemia, urinary, and biliary infections caused by
E. coli in preliminary clinical results.1
Scheme 1.
Keywords: chuangxinmycins; stereoselective synthesis; enzymatic synthesis.
Corresponding author. Tel.: 181-474-72-1805; fax: 181-474-76-6195; e-mail: akita@phar.toho-u.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020!01)01068-7

10056
K. Kato et al. / Tetrahedron 57 .2001) 10055±10062
Scheme 2.
the indol-1-yl anion by desilylation, and Michael addition of
the ambident C-3 anion to the a-thioacrylate acceptor could
bring about the required cyclization via pathway C.3
!Scheme 1). But these routes were found to be unacceptable
for the synthesis of the optically active form of 1. We now
report a highly stereoselective synthesis of !^)-1 via
pathway A directed toward chiral synthesis starting with
the requisite 6 possessing two de®nite absolute con®gu-
rations at the C2- and C3-positions and the subsequent
enantioselective synthesis of both enantiomers of !2)-1
and !1)-1.
stereoselective construction of C2- and C3-con®gurations
of 6 by the reaction of 4-iodoindole 89 and !^)-9
!Scheme 2).
The reaction of 8 and !^)-9, obtained by m-chloroperben-
zoic acid oxidation of methyl crotonate, in the presence
of SnCl4 afforded !^)-40-iodoindolmycenate 6 !32%
yield) along with a 5:1 mixture !!^)-10/!^)-11 5:1) of
!^)-!2,3)-anti-3-chloro-2-hydroxy butanoate 10 and !^)-
4-iodoindole dimer 11. Treatment of !^)-6 with MsCl in
pyridine followed by treatment with CsSAc10 gave the
desired !^)-!2,3)-syn-2-thioacetoxy ester 13 in 70% overall
yield with complete retention of C2-stereochemistry.
Deacetylation of !^)-13 with K2CO3 in MeOH followed
2. Results and discussion
11
by treatment with Pd!PPh3)4 in the presence of Et3N
afforded the !^)-cis methyl ester 2 in 67% overall yield,
of which the spectral data !mp 147±1488C, IR, NMR) were
identical with those !mp 145±1468C2c) of the reported
!^)-2. An alkaline hydrolysis2c of !^)-2 was carried out
to provide the racemic 1 !mp 189±1908C), of which the
spectral data are also consistent with those of the reported
!^)-1 !mp 190±1918C,2d 186±1878C2f) !Scheme 3).
The synthesis of indolmycenate !7), an important
intermediate for the synthesis of indolmycin,6 was achieved
by the reaction of indole and !^)-trans-!2,3)-epoxy
butanoate 97 in the presence of SnCl4 along with nucleo-
philic displacement with inversion at the C-3 carbon of
the epoxide.8 This strategy appeared to be the most
promising from a stereochemical standpoint for the
Scheme 3. Reagents: !a) SnCl4; !b) MsCl/pyridine; !c) CsSAc; !d) K2CO3/MeOH; !e) Pd!Ph3)4/Et3N; !f) NaOH/EtOH/H2O; !g) Ac2O/pyridine.

K. Kato et al. / Tetrahedron 57 .2001) 10055±10062
10057
Scheme 4.
As shown in Scheme 4, it is proposed that neighboring-
group participation involving the electron-rich C-3 of the
indole ring accounts for the stereoselective conversion of
!^)-12 to !^)-13. The preferred conformation of the mesyl-
ate !^)-12 to minimize steric interactions is shown in
Scheme 4. In this rotamer, the mesyloxy group is trans to
the indol C-3, so that displacement can occur smoothly.
Nucleophilic attack by the thioacetoxy ion takes place at
the C2-position because the positive charge in the cyclo-
propylium ion intermediate locates on the C-2 carbon
atom.12 Since this is essentially a double SN 2 mechanism,
the stereochemistry of !^)-syn-2-hydroxy ester 6 is retained
in !^)-syn-2-thioacetoxy ester 13.
merically active !2R,3S)- or !2S,3R)-9 based on the asym-
metric hydrolysis of !^)-!2,3)-anti-2-acetoxy-3-chloro
butanoate 15 using lipase. The other is the synthesis of
enantiomerically active !2R,3S)- or !2S,3R)-6 and !2R,3S)-
or !2S,3R)-14 based on the asymmetric hydrolysis of the
corresponding acetates !^)-16 or !^)-13 using lipase,
respectively. The substrates !^)-15 and !^)-16 were
obtained by acetylation of !^)-10 and !^)-6, respectively
!Scheme 3).
Initially, !^)-15 was subjected to screening experiments
using several kinds of commercially available lipases in
isopropyl ether saturated with water. Among them, lipase
`Amano P' from Pseudomonas sp. was found to give the
!2R,3S)-2-hydroxy ester 10 !40, 89% ee) and acetate
!2S,3R)-15 !45, 87% ee)!entry 1, Table 1). The !2S,3R)-15
having 87% ee was again subjected to the enzymatic
hydrolysis to afford the enantiomerically pure !2S,3R)-15
![a]Dˆ17.6 !cˆ1.50, CHCl3)) in 84% yield !entry 2,
Table 1), which was consistent with the reported !2S,3R)-
158b ![a]Dˆ18.3 !cˆ3.0, CHCl3): corresponds to .99%
ee). On the contrary, the 89% ee of !2R,3S)-15, obtained
by the re-acetylation of the lipase hydrolysis product
!2R,3S)-10 !89% ee), was subjected to the enzymatic
hydrolysis again to provide the enantiomerically pure
!2R,3S)-10 ![a]Dˆ133.2 !cˆ0.85, CHCl3)) in 68% yield
According to the reported synthesis of !^)-2 via pathway B,
catalytic hydrogenation of !^)-4 gave 40% yield of !^)-2,2c
while chemical reduction of !^)-4 afforded a mixture of
!^)-cis- and -trans-2.2d,2f It is of important signi®cance in
the present synthesis via pathway A that palladium-
catalyzed coupling of the thiolate ion itself can proceed to
the cyclization without isomerization at the C5-position in
high yield.
Accordingly, we report a highly stereoselective synthesis of
both enantiomers of chuangxinmycin 1 by the following two
approaches as a key step. One is the synthesis of enantio-
Table 1.
Entry
Substrate !g, %ee)
Time !days)
Product
% Yield !%ee)
% Yield !%ee)
1
2
3
!^)-15 !14,0)
!2S,3R)-15 !6.3,87)
!2R,3S)-15 !4.4,89)a
5
3
3
!2S,3R)-15; 45 !87)
!2S,3R)-15; 84 !.99)
!2R,3S)-15; 12 !27)
!2R,3S)-10; 40 !89)
!2R,3S)-10; 12 !0)
!2R,3S)-10; 68 !.99)
a
The substrate !2R,3S)-15 !89% ee) was obtained by acetylation of !2R,3S)-10 !89% ee).

10058
K. Kato et al. / Tetrahedron 57 .2001) 10055±10062
Scheme 5. Reagents: !a) SnCl4; !b) !1) MsCl/pyridine, !2) CsSAc; !c) K2CO3/MeOH; !d) Pd!Ph3)4/Et3N; !e) NaOH/EtOH/H2O.
!entry 3, Table 1). The enantiomeric excess of !1)-15 and
!1)-10 was calculated based on NMR !400 MHz) data of
the corresponding !R)-!1)-a-methoxy-a-tri¯uoromethyl-
phenylacetates13 !!R)-MTPA esters: !R)-MTPA ester of
!2S,3R)-10 from !1)-!2S,3R)15, d 3.836, COOMe; !R)-
MTPA ester from !1)-!2R,3S)-10, d 3.785, COOMe).8b
The resulting !2S,3R)-15 was treated with NaOMe followed
by acid treatment and esteri®cation with CH2N2 to provide
enantiomerically pure !2R,3S)-epoxy butanoate !9) in 67%
overall yield. Similarly, enantiomerically pure !2R,3S)-10
was also converted to !2S,3R)-9 in 69% overall yield. The
reaction of 8 and !2R,3S)-9 in the presence of SnCl4 afforded
!2R,3S)-6 !32% yield, mp 528C, [a]Dˆ17.89 !cˆ0.5,
CHCl3)), which was treated with MsCl in pyridine followed
by treatment with CsSAc to provide !2R,3S)-2-thioacetoxy
ester 13 ![a]Dˆ184.9 !cˆ0.94, CHCl3)) in 73% overall
yield with complete retention. Deacetylation of !2R,3S)-13
with K2CO3 in MeOH provided !2R,3S)-2-mercapto ester 14
!70% yield, [a]Dˆ123.3 !cˆ0.3, CHCl3)), which was
subjected to the Pd!PPh3)4-mediated cyclization in the
presence of Et3N to give !4S,5R)-cis-methyl ester 2 !mp
1308C, [a]Dˆ2124.0 !cˆ0.45, CHCl3)) in 74% yield. An
alkaline hydrolysis of !4S,5R)-2 was carried out by the
reported procedure2c to provide the natural chuangxinmycin
!4S,5R)-1 !mp 192±1938C, [a]Dˆ226.0 !cˆ0.2, 95%
EtOH)), which is consistent with the reported !4S,5R)-1
!mp 192±192.58C,2a mp 184±1878C,4 [a]Dˆ229.0 !95%
EtOH)4). Similarly, the enantiomerically pure !2S,3R)-9
was converted to the !4R,5S)-1 !mp 181±1828C, [a]Dˆ
127.4 !cˆ0.42, 95% EtOH)) via !2S,3R)-6 !mp 558C,
[a]Dˆ27.78 !cˆ0.9, CHCl3)), !2S,3R)-13 ![a]Dˆ287.8
!cˆ0.79, CHCl3)), !2S,3R)-14 ![a]Dˆ223.1 !cˆ0.77,
CHCl3)) and !4R,5S)-2 !mp 1358C, [a]Dˆ1124.1 !cˆ
0.59, CHCl3)). The physical data of the present !4R,5S)-1
was identical with those !mp 181±1848C, [a]Dˆ129 !95%
EtOH) of the reported !4R,5S)-14 !Scheme 5).
As chemo-enzymatic synthesis of !2)-!4S,5R)- and !1)-
!4R,5S)-chuangxinmycins 1 was achieved, next enzymatic
resolution of more large molecule such as !^)-2-thio-
acetoxy ester 13 and !^)-2-acetoxy ester 16 has aroused
our interest. The enantioselective hydrolysis of !^)-13
and !^)-16 using lipase `OF-360' from Candida rugosa in
the mixed solvent !cyclohexane/i-Pr2O 19:1) saturated with
water was carried out, and the results are shown in Table 2.
Enantiomeric excess !ee) of the products was determined by
HPLC on a CHIRALCEL OD !250£4.6 mm2) column and
the absolute structure of the products was con®rmed by a
comparison of the retention times with those of the authentic
samples. Enzymatic hydrolysis of thioacetate !^)-13 gave
the corresponding thiol !2S,3R)-14 !15, 68% ee) and the
thioacetate !2R,3S)-13 !74, 14% ee) !entry 1, Table 2),
while enzymatic hydrolysis of acetate !^)-16 afforded
91% ee of the corresponding alcohol !2S,3R)-6 !35%) and
acetate !2R,3S)-16 !64, 51% ee) !entry 2, Table 2). The
recovered !2R,3S)-16 having 51 and 87% ee was again
subjected to the enzymatic reaction to provide 87 and
97% ee of !2R,3S)-16, respectively !entries 3 and 4, Table
2). Enrichment of ee of !2S,3R)-6 !.99% ee) was also
achieved by the repeated enzymatic reaction of !2S,3R)-16
!91% ee) obtained by re-acetylation of !2S,3R)-6 !91% ee)
!entry 5, Table 2).
In conclusion, !^)-4-iodoindolmycenate 6 obtained by the
reaction of 4-iodoindole 8 and !^)-trans-!2,3)-epoxy
butanoate 9 in the presence of SnCl4, was stereoselectively
converted into !^)-!2,3)-syn-40-iodo-2-thioindolmycenate
14, which is treated with Pd!PPh3)4 in the presence of

K. Kato et al. / Tetrahedron 57 .2001) 10055±10062
10059
Table 2.
Entry
Substrate !mg, %ee)
Time !days)
Products
% Yield !%ee)
% Yield !%ee)
1
2
3
4
5
!^)-13 !97,0)
!^)-16 !700,0)
!2R,3S)-16 !440,51)
!2R,3S)-16 !330,87)
!2R,3S)-16 !240,91)b
3
4
3.5
3
6.5
!2R,3S)-13; 74 !14)a
!2R,3S)-16; 64 !51)
!2R,3S)-16; 75 !87)
!2R,3S)-16; 91 !97)
!2S,3R)-16; 24 !63)
!2S,3R)-14; 15 !68)a
!2S,3R)-6; 35 !91)
!2S,3R)-6; 23 !67)
!2S,3R)-6; 5 !12)
!2S,3R)-6; 62 !.99)
a
The ee was calculated based on NMR !400 MHz) data of the corresponding !R)-!1)-MTPA ester.
The substrate !2S,3R)-16 !91% ee) was obtained by acetylation of !2S,3R)-6 !91% ee).
b
Et3N to afford the !^)-methyl ester 2 of natural chuangxin-
3.1.2. Methyl ꢀ^)-2-hydroxy-3-ꢀ4-iodo-1H-indol-3-yl)-
butanoate ꢀ6). To a well-stirred solution of 4-iodoindole
8 !1 g, 4.1 mmol) and !^)-trans-!2,3)-epoxy butanoate 9
!0.96 g, 8.3 mmol) in CH2Cl2 !10 ml) under argon
atmosphere was added SnCl4 !1 M in CH2Cl2, 25.8 ml,
25.8 mmol) at 08C and the whole mixture was stirred for
1 h at the same temperature. To the reaction mixture was
added 7% aqueous NaHCO3 !200 ml) and the whole
mixture was stirred for 30 min. The reaction mixture was
®ltered with the aid of celite and the precipitate was
washed with CH2Cl2. The ®ltrate and washing were
combined and the organic layer was dried over MgSO4.
Evaporation of the organic solvent gave a residue which
was chromatographed on silica gel !60 g) to give 8 !0.35 g
35% recovery) from n-hexane/EtOAcˆ10:1 eluate, a 5:1
mixture !0.734 g) of !^)-chlorohydrin 10 and !^)-indol-
dimer 11 from n-hexane/EtOAcˆ8:1 eluate, and a crystal
!^)-6 !0.473 g, 32%) from n-hexane/EtOAcˆ5:1 eluate.
The ratio of !^)-10 and !^)-11 was determined based
on NMR analysis. Crystallization of a mixture from
benzene/n-hexane !1:1) gave a crystal 11 !0.1 g) as
colorless needles. NMR data of the mother liquid !mainly
!^)-10) were identical with those of the reported !^)-10.8b
Crystallization of !^)-6 from benzene gave colorless
needles. !^)-6: mp 121±1228C; IR !KBr) 3330, 1729,
1290 cm21; NMR !CDCl3) d 1.26 !3H, d, Jˆ6.8 Hz), 2.81
!1H, d, Jˆ4.9 Hz), 3.87 !3H, s), 4.61 !1H, dq, Jˆ2.7,
6.8 Hz), 4.68 !1H, dd, Jˆ2.7, 4.9 Hz), 6.83 !1H, t,
Jˆ7.8 Hz), 7.26 !1H, d, Jˆ4.0 Hz), 7.31 !1H, d,
Jˆ7.8 Hz), 7.60 !1H, d, Jˆ7.8 Hz), 8.25 !1H, br s). Anal.
found: C, 43.72; H, 3.76; N, 3.95. Calcd for C13H14O3NI: C,
43.45; H, 3.93; N, 3.90%. FAB MS m/z: 360 !M111). !^)-
11: mp 1638C; IR !KBr) 3243, 1564, 1436, 1281, 1182, 736
cm21; NMR !CDCl3) d 3.06 !1H, dd, Jˆ7.8, 16 Hz), 3.60
!1H, dd, Jˆ9.3, 16.1 Hz), 4.50 !1H, br s), 5.98 !1H, t,
Jˆ8.3 Hz), 6.58 !1H, d, Jˆ7.8 Hz), 6.75 !1H, t,
Jˆ7.8 Hz), 6.89 !1H, t, Jˆ7.8 Hz), 7.07 !1H, d,
Jˆ7.8 Hz), 7.32 !1H, d, Jˆ2.4 Hz), 7.35 !1H,d,
mycin !1). Stereoselective total syntheses of !2)-!4S,5R)-
and !1)-!4R,5S)-chuangxinmycins 1 were achieved based
on the enzymatic syntheses of !2R,3S)- and !2S,3R)-epoxy
butanoates 9, respectively.
3. Experimental
3.1. General
All melting points were measured on a Yanaco MP-3S
micro melting point apparatus and are uncorrected. NMR
spectra were recorded on JEOL EX 400 spectrometer in
CDCl3. The fast atom bombardment mass spectra !FAB
MS) were obtained with JEOL JMS-DX 303 spectrometer.
IR spectra were recorded a JASCO FT/IR-300 spectrometer.
The HPLC system was composed of two SSC instruments
!ultraviolet !UV) detector 3000B and ¯ow system 3100).
Optical rotations were measured with a JASCO DIP-370
digital polarimeter. All evaporations were performed
under reduced pressure. For column chromatography, silica
gel !Kieselgel 60) was employed.
3.1.1. Methyl ꢀ^)-trans-ꢀ2,3)-epoxy butanoate 9. A solu-
tion of methyl crotonate !20 g, 200 mmol) and m-chloro-
perbenzoic acid !MCPBA, 70%, 50g, 200 mmol) in
ClCH2CH2Cl !250 ml) was re¯uxed for 3 h. After cooling,
the reaction mixture was ®ltered and the precipitate was
washed with n-hexane. The ®ltrate and washing were
combined and the whole was concentrated to half-volume.
The resulting organic layer was washed with 7% aqueous
NaHCO3, 15% aqueous Na2CO3, 3% aqueous Na2S2O3 and
dried over MgSO4. Evaporation of the organic solvent gave
an oily product which was distillated to afford !^)-9 !bp
708C/30 mmHg, 18 g, 78%) as a colorless oil. The NMR
data were identical with those of the reported !^)-9.8b

10060
K. Kato et al. / Tetrahedron 57 .2001) 10055±10062
Jˆ7.8 Hz), 7.62 !1H, d, Jˆ7.3 Hz), 8.11 !1H, br s). FAB
MS m/z: 486 !M1), 487 !M111).
crystal !^)-2 as colorless plates. !^)-2: mp 147±1488C; IR
!KBr) 3380, 2959, 2856, 1729, 1159cm21; NMR !CDCl3) d
1.35 !3H, d, Jˆ7 Hz), 3.73 !overlapping 1H, m and 3H, s),
4.18 !1H, d, Jˆ3.1 Hz), 6.92±6.95 !2H, m), 7.09±7.13 !2H,
m), 8.01 !1H, br s). Anal. Found: C, 63.35; H, 5.19; N, 5.65.
Calcd for C13H13O2NS: C, 63.14; H, 5.30; N, 5.66%. FAB
MS m/z: 247 !M1).
3.1.3. Methyl ꢀ^)-2-thioacetoxy-3-ꢀ4-iodo-1H-indol-3-
yl)butanoate ꢀ13). To a well-stirred solution of !^)-6
!0.24 g, 0.67 mmol) in pyridine !2 ml) was added mesyl
chloride MsCl !0.1 ml, 1.29 mmol) at 08C and the reaction
mixture was stood for 3 days in a refrigerator. The reaction
mixture was diluted with ether. The organic layer was
washed with 10% aqueous HCl, saturated brine and dried
over MgSO4. Evaporation of the organic solvent gave a
crude mesylate !^)-12. A part of crude !^)-12 was crystal-
lized from benzene to give a crystal 12. A mixture of crude
!^)-12 and CsSAc !0.28 g, 1.35 mmol, prepared from the
reaction of Cs2CO3 !0.22 g, 0.68 mmol) and AcSH !0.103 g,
1.35 mmol) in MeOH 5 ml)) in DMF !5 ml) was stirred
under argon atmosphere for 4 days at room temperature.
The reaction mixture was diluted with H2O and extracted
with EtOAc. The organic layer was washed with saturated
brine and dried over MgSO4. Evaporation of the organic
solvent gave a residue which was chromatographed on silica
gel !20 g, n-hexane/EtOAcˆ5:1) to give !^)-13 !0.20 g
72% overall yield from !^)-6) as a colorless oil. !^)-12:
mp 118±1198C !decomp); IR !KBr) 3397, 1751, 1357,
1178, 961, 851 cm21; NMR !CDCl3) d 1.39 !3H, d,
Jˆ6.8 Hz), 2.75 !3H, s), 3.87 !3H, s), 4.90 !1H, dq, Jˆ
2.9, 6.8 Hz), 5.43 !1H, d, Jˆ2.9 Hz), 6.86 !1H, t, Jˆ
7.8 Hz), 7.30 !1H, s), 7.34 !1H, d, Jˆ7.8 Hz), 7.62 !1H, d,
Jˆ7.8 Hz), 8.27 !1H, br s). Anal. found: C, 38.52; H, 3.42;
N, 3.15. Calcd for C14H16O5NSI: C, 38.45; H, 3.69; N,
3.20%. FAB MS m/z: 437 !M1), 438 !M111). !^)-13: IR
!KBr) 3358, 2940, 1728, 1660 cm21; NMR !CDCl3) d 1.38
!3H, d, Jˆ6.8 Hz), 2.29 !3H, s), 3.64 !3H, s), 4.73 !1H, dq,
Jˆ6.8, 7 Hz), 4.78 !1H, dd, Jˆ7 Hz), 6.84 !1H, t, Jˆ
7.8 Hz), 7.21 !1H, s), 7.31 !1H, d, Jˆ7.8 Hz), 7.61 !1H, d,
Jˆ7.8 Hz), 8.25 !1H, br s). FAB MS m/z: 418 !M111).
3.1.6. ꢀ^)-Chuangxinmycin ꢀ1). A mixture of !^) 2
!0.05 g, 0.202 mmol) and NaOH !0.121 g, 3.07 mmol) in a
mixed solvent !EtOH !3 ml) and H2O !1.8 ml)) THF !10 ml)
was stirred at room temperature for 7 h. The reaction
mixture was diluted with saturated brine !5 ml), 2 M
aqueous HCl !2 ml) and extracted with CHCl3. The organic
layer was dried over MgSO4 and evaporated to give crystals
which was recrystallized from CH2Cl2/benzene !1:1) to
afford colorless plates !^)-1 !15 mg, 32%). !^)1: mp
189±1908C; IR !KBr) 3403, 3057, 2925, 1695,
1195 cm21; NMR !CDCl3/CD3ODˆ1:1) d 1.37 !3H, d,
Jˆ6.8 Hz), 3.77 !1H, dq, Jˆ3.4, 6.8 Hz), 4.23 !1H, d, Jˆ
3.4 Hz), 6.92 !1H, d, Jˆ7.6 Hz), 7.00 !1H, s), 7.09 !1H, t,
Jˆ7.6 Hz), 7.14 !1H, d, Jˆ7.6 Hz). Anal. found: C, 61.88;
H, 4.46; N,6.05. Calcd for C12H11O2NS: C, 61.79; H, 4.76;
N, 6.01%. FAB MS m/z: 233 !M1).
3.1.7. Methyl ꢀ^)-ꢀ2,3)-anti-2-acetoxy-3-chloro-butano-
ate ꢀ15). To a well-stirred solution of !^)-trans-!2,3)-
epoxy butanoate 9 !15 g, 129 mmol) in CH2Cl2 !100 ml)
under argon atmosphere was added SnCl4 !1M in CH2Cl2,
16 ml, 160 mmol) at 08C and the whole mixture was stirred
for 1 h at the same temperature. To the reaction mixture was
added 7% aqueous NaHCO3 !200 ml) and the whole mixture
was stirred for 30 min. The reaction mixture was ®ltered
with the aid of celite and the precipitate was washed with
CH2Cl2. The ®ltrate and washing were combined and the
organic layer was dried over MgSO4. Evaporation of the
organic solvent gave a crude oil !^)-10. A solution of
crude !^)-10 and Ac2O !19.8 g, 193 mmol) in pyridine
!20.5 g, 260 mmol) was stirred at room temperature for
12 h. The reaction mixture was diluted with H2O extracted
with AcOEt. The organic layer was washed with 10%
aqueous HCl, saturated brine and dried over MgSO4.
Evaporation of the organic solvent gave a residue which
was chromatographed on silica gel !200 g, n-hexane/
EtOAcˆ8:1) to afford !^)-15 !14.6 g, 58% overall yield)
as a colorless oil. The NMR data of !^)-15 were identical
with those of the reported !^)-15.8b
3.1.4. Methyl ꢀ^)-2-sulfanyl-3-ꢀ4-iodo-1H-indol-3-yl)-
butanoate ꢀ14). A mixture of !^)-13 !0.154 g, 0.369
mmol) and K2CO3 !0.051 g, 0.369 mmol) in MeOH !8 ml)
was stirred for 30 min at room temperature. The reaction
mixture was diluted with saturated brine and extracted with
CH2Cl2. The organic layer was dried over MgSO4 and
evaporated to give a residue which was chromatographed
on silica gel !20 g, n-hexane/EtOAcˆ4:1) to give !^)-14
!0.114 g 82%) as a colorless oil. !^)-14: IR !KBr) 3382,
2960, 2561, 1723 cm21; NMR !CDCl3) d 1.45 !3H, d, Jˆ
6.8 Hz), 1.83 !1H, d, Jˆ8.3 Hz), 3.69 !3H, s), 4.05 !1H, dd,
Jˆ6.3, 8.3 Hz), 4.65 !1H, dq, Jˆ6.3, 6.8 Hz), 6.86 !1H, t,
Jˆ7.8 Hz), 7.20 !1H, d, Jˆ2.4 Hz), 7.34 !1H, d, Jˆ7.3 Hz),
7.61 !1H, d, Jˆ7.3 Hz), 8.18 !1H, br s). FAB MS m/z: 376
!M111).
3.1.8. Enzymatic resolution of ꢀ^)-15. !i) Table 1, entry 1;
a suspension of !^)-15 !10 g), lipase Amano P !7 g) in
H2O-saturated-isopropyl ether !750 ml) was incubated at
338C for 5 days. After the reaction mixture was ®ltered,
the precipitate was washed with diisopropyl ether. The
combined organic layer was dried over MgSO4 and evapo-
rated. The residue was chromatographed on silica gel
!200 g, n-hexane/AcOEtˆ8:1) to give !2S,3R)-15 !6.3 g,
45, 87% ee) and !2R,3S)-10 !4.39 g, 40, 89% ee) in elution
order. !ii) Table 1, entry 2; a suspension of !2S,3R)-15
!6.3 g, 87% ee), lipase Amano P !3.2 g) in H2O-saturated-
isopropyl ether !338 ml) was incubated at 338C for 3 days.
The reaction mixture was worked up in the same way as for
3.1.5. ꢀ^)-Chuangxinmycin methyl ester ꢀ2). A mixture of
!^)-14 !0.106 g, 0.282 mmol), Et3N !0.058 g, 0.56 mmol)
and tetrakis!triphenylphosphine)palladium!0) !17 mg, 0.014
mmol) in THF !10 ml) was re¯uxed for 6 h. The reaction
mixture was diluted with H2O and extracted with EtOAc.
The organic layer was washed with brine and dried over
MgSO4. Evaporation of the organic solvent provided a
residue which was chromatographed on silica gel !20 g,
n-hexane/EtOAcˆ10:1) to afford a crystal !^)-2 !0.052 g,
74%). Recrystallization of !^)-2 from benzene afforded a
22
!i) to afford !2S,3R)-15 !5.29 g, 84%, [a]D ˆ17.6 !cˆ1.5,
CHCl3) corresponding to .99% ee) and !2R,3S)-10 !0.59 g,

K. Kato et al. / Tetrahedron 57 .2001) 10055±10062
10061
12, 0% ee). !iii) A solution of !2R,3S)-10 !4.39 g, 89% ee)
and Ac2O !5.9 g, 57 mmol) in pyridine !6.8 g, 86 mmol)
was stirred at room temperature for 5 h and the reaction
mixture was worked up in the same way of !^)-15 to give
!2R,3S)-15 !5.27 g, 94%). A suspension of !2R,3S)-15
!4.4 g, 89% ee), lipase Amano P !2.2 g) in H2O-saturated-
isopropyl ether !236 ml) was incubated at 338C for 3 days.
The reaction mixture was worked up in the same way as for
!i) to afford !2R,3S)-15 !0.53 g, 12, 27% ee) and !2R,3S)-10
CHCl3) corresponding to .99% ee. NMR data of !2R,3S)-
13 were identical with those of !^)-13. !iii) A mixture of
!2R,3S)-13 !0.08 g, 0.19 mmol) and K2CO3 !0.013 g,
0.09 mmol) in MeOH !4 ml) was stirred for 20 min at
room temperature. The reaction mixture was worked up in
the same way as for the preparation of !^)-14 to afford
!2R,3S)-14 !0.05 g, 70%) as a colorless oil. !2R,3S)-14:
23
[a]D ˆ123.3 !cˆ0.3, CHCl3) corresponding to .99%
ee. NMR data of !2R,3S)-14 were identical with those of
!^)-14. !iv) A mixture of !2R,3S)-14 !0.076 g, 0.2 mmol),
Et3N !0.061 g, 0.6 mmol) and tetrakis!triphenylphosphine)-
palladium!0) !23 mg, 0.02 mmol) in THF !10 ml) was
re¯uxed for 8 h. The reaction mixture was worked up in
the same way as for the preparation of !^)-2 to afford
!4S,5R)-2 !0.037 g, 74%) as colorless plates. !4S,5R)-2:
28
!2.35 g, 68%, [a]D ˆ133.2 !cˆ0.85, CHCl3) correspond-
ing to .99% ee).
3.1.9. Methyl ꢀ2R,3S)-epoxy-butanoate 9. To a well-
stirred solution of !2S,3R)-15 !99% ee, 9.1 g, 46.7 mmol)
in MeOH !50 ml) was added NaOMe !2.52 g, 46.7 mmol) at
08C and the whole mixture was stood for 12 h at 58C. The
reaction mixture was diluted with Et2O and the water layer
was acidi®ed with 10% aqueous HCl. The water layer was
re-extracted with CHCl3 !10 times) and the organic layer
was dried over MgSO4. Evaporation of the organic solvent
afforded a residue which was treated with an excess of
CH2N2/Et2O solution to provide a crude oil. Distillation of
the crude oil gave !2R,3S)-9 !708C/30 mmHg, 3.64 g, 67%
overall yield). !2R,3S)-9: NMR data of !2R,3S)-9 were
identical with those of the reported !^)-9.8b
23
mp 1308C; [a]D ˆ2124.0 !cˆ0.45, CHCl3) corresponding
to .99% ee. NMR data of !4S,5R)-2 were identical with
those of !^)-2. !v) A mixture of !4S,5R)-2 !0.045 g,
0.18 mmol) and NaOH !0.12 g, 3 mmol) in a mixed solvent
!EtOH !3 ml) and H2O !1.8 ml)) THF !10 ml) was stirred at
room temperature for 4 h. The reaction mixture was worked
up in the same way as for the preparation of !^)-1 to afford
!4S,5R)-1 !0.014 g, 32%) as colorless plates. !4S,5R)-1: mp
23
192±1938C; [a]D ˆ226.0 !cˆ0.2, 95% EtOH) corre-
sponding to .99% ee. NMR data of !4S,5R)-1 were iden-
tical with those of !^)-1.
3.1.10. Methyl ꢀ2S,3R)-epoxy-butanoate 9. To a well-
stirred solution of !2R,3S)-10 !99% ee, 5.3 g, 34.6 mmol)
in MeOH !25 ml) was added NaOMe !3.9 g, 72.2 mmol) at
08C and the whole mixture was stood for 7 h at room
temperature. The reaction mixture was diluted with Et2O
and the water layer was acidi®ed with 10% aqueous HCl.
The water layer was re-extracted with CHCl3 !10 times) and
the organic layer was dried over MgSO4. Evaporation of the
organic solvent afforded a residue which was treated with
an excess of CH2N2/Et2O solution to provide a crude oil.
Distillation of the crude oil gave !2S,3R)-9 !708C/30 mmHg,
2.78 g, 69% overall yield). !2S,3R)-9: NMR data of !2S,3R)-
9 were identical with those of the reported !^)-9.8b
3.1.12. Preparation of ꢀ4R,5S)-ꢀ1)-chuangxinmycin ꢀ1)
from ꢀ2S,3R)-9. !i) To a mixture of iodoindole 8 !2.8 g,
11.5 mmol) and !2S,3R)-9 !2.7 g, 23.3 mmol) in CH2Cl2
!40 ml) under argon atmosphere was added SnCl4 !1 M in
CH2Cl2, 23.3 ml, 23.3 mmol) at 08C and the whole mixture
was stirred for 1 h at the same temperature. The reaction
mixture was worked up in the same way as for the prepara-
tion of !^)-6 to afford !2S,3R)-6 !1.48 g, 32%). !2S,3R)-6:
27.78
25
mp 558C !cyclohexane/i-Pr2Oˆ1:1), [a]D
ˆ
!cˆ0.9, CHCl3) corresponding to .99% ee. NMR data of
!2S,3R)-6 were identical with those of !^)-6. !ii) To a well-
stirred solution of !2S,3R)-6 !1.1 g, 3.1 mmol) in pyridine
!4 ml) was added mesyl chloride MsCl !0.25 ml, 3.2 mmol)
at 08C and the reaction mixture was stood for 2 days in a
refrigerator. The reaction mixture was worked up in the
same way as for the preparation of !^)-12 to afford crude
!2S,3R)-12. A mixture of crude !2S,3R)-12 and CsSAc
!2.32 g, 11.2 mmol) in DMF !15 ml) was stirred for 6 days
at room temperature. The reaction mixture was worked up in
the same way as for the preparation of !^)-13 to afford
!2S,3R)-13 !0.212 g, 73% overall yield from !2S,3R)-12)
3.1.11. Preparation of ꢀ4S,5R)-ꢀ2)-chuangxinmycin ꢀ1)
from ꢀ2R,3S)-9. !i) To a well-stirred solution of 4-iodo-
indole 8 !3.14 g, 12.9 mmol) and !2R,3S)-9 !3 g, 25.8
mmol) in CH2Cl2 !40 ml) under argon atmosphere was
added SnCl4 !1 M in CH2Cl2, 25.8 ml, 25.8 mmol) at 08C
and the whole mixture was stirred for 1 h at the same
temperature. The reaction mixture was worked up in the
same way as for the preparation of !^)-6 to afford
!2R,3S)-6 !1.48 g, 32%). !2R,3S)-6: mp 528C !cyclo-
21
as a colorless oil. !2S,3R)-13: [a]D ˆ287.8 !cˆ0.79,
23
hexane/i-Pr2Oˆ1:1), [a]D ˆ17.57 !cˆ0.7, CHCl3) corre-
CHCl3) corresponding to .99% ee. NMR data of !2S,3R)-
13 were identical with those of !^)-13. !iii) A mixture of
!2S,3R)-13 !0.1 g, 0.24 mmol) and K2CO3 !0.013 g,
0.09 mmol) in MeOH !4 ml) was stirred for 6 min at room
temperature. The reaction mixture was worked up in the
same way as for the preparation of !^)-14 to afford
!2S,3R)-14 !0.057 g, 63%) as a colorless oil. !2S,3R)-14:
sponding to .99% ee. NMR data of !2R,3S)-6 were
identical with those of !^)-6. !ii) To a well-stirred solution
of !2R,3S)-6 !0.25 g, 0.7 mmol) in pyridine !1 ml) was
added mesyl chloride MsCl !0.081 ml, 1 mmol) at 08C and
the reaction mixture was stood for 2 days in a refrigerator.
The reaction mixture was worked up in the same way as for
the preparation of !^)-12 to afford crude !2R,3S)-12. A
mixture of crude !2R,3S)-12 and CsSAc !0.578 g, 2.78
mmol) in DMF !6 ml) was stirred for 4 days at room
temperature. The reaction mixture was worked up in the
same way as for the preparation of !^)-13 to afford
!2R,3S)-13 !0.212 g, 73% overall yield from !2R,3S)-12)
25
[a]D ˆ223.1 !cˆ0.77, CHCl3) corresponding to .99%
ee. NMR data of !2S,3R)-14 were identical with those of
!^)-14. !iv) A mixture of !2S,3R)-14 !0.3 g, 0.8 mmol),
Et3N !0.242 g, 2.4 mmol) and tetrakis!triphenylphosphine)-
palladium!0) !93 mg, 0.08 mmol) in THF !15 ml) was
re¯uxed for 8 h. The reaction mixture was worked up in
the same way as for the preparation of !^)-2 to afford
24
as a colorless oil. !2R,3S)-13: [a]D ˆ184.9 !cˆ0.94,

10062
K. Kato et al. / Tetrahedron 57 .2001) 10055±10062
!4R,5S)-2 !0.10 g, 51%) as colorless plates. !4R,5S)-2: mp
temperature for 3 h. The reaction mixture was worked up
in the same way as for the preparation of !^)-16 to afford
!2S,3R)-16 !0.24 g, 98, 91% ee). A suspension of !2S,3S)-16
!0.24 g, 91% ee), lipase OF-360 !0.24 g) in H2O-saturated-
cyclohexane !114 ml)/isopropyl ether !6 ml) was incubated
at 338C for 6.5 days. The reaction mixture was worked up in
the same way as for the preparation of !^)-16 to afford
!2S,3R)-16 !0.058 g, 24, 63% ee) and !2S,3R)-6 !0.134 g,
22
1358C !benzene/n-hexaneˆ1:1); [a]D ˆ1124.1 !cˆ0.41,
CHCl3) corresponding to .99% ee. NMR data of !4R,5S)-
2 were identical with those of !^)-2. !v) A mixture of
!4R,5S)-2 !0.10 g, 0.4 mmol) and NaOH !0.12 g, 3 mmol)
in a mixed solvent !EtOH !4 ml) and H2O !2 ml)) was stirred
at room temperature for 4 h. The reaction mixture was
worked up in the same way as for the preparation of
!^)-1 to afford !4R,5S)-1 !0.021 g, 22%) as colorless plates.
23
62%, [a]D ˆ28.12 !cˆ0.67, CHCl3) corresponding to
21
!4R,5S)-1: mp 181±1828C; [a]D ˆ127.4 !cˆ0.42, 95%
.99% ee).
EtOH) corresponding to .99% ee. NMR data of !4R,5S)-
1 were identical with those of !^)-1.
Acknowledgements
3.1.13. Methyl ꢀ^)-2-acetoxy-3-ꢀ4-iodo-1H-indol-3-yl)-
butanoate ꢀ16). A solution of !^)-6 !0.9 g, 2.51 mmol)
and Ac2O !0.307 g, 3 mmol) in pyridine !4 ml) was stirred
at room temperature for 30 min. The reaction mixture was
diluted with H2O and extracted with AcOEt. The organic
layer was washed with 10% aqueous HCl, saturated brine
and dried over MgSO4. Evaporation of the organic solvent
gave a residue which was chromatographed on silica gel
!20 g, n-hexane/EtOAcˆ4:1) to afford !^)-16 !0.97 g,
97%) as crystal. Recrystallization of !^)-16 from benzene
gave colorless needless !^)-16. !^)-16: mp 1218C; IR
!KBr) 3348, 2944, 1723, 1214 cm21; NMR !CDCl3) d
1.39 !3H, d, Jˆ6.8 Hz), 2.08 !3H, s), 3.77 !3H, s), 4.80
!1H, dq, Jˆ6.8, 3.9 Hz), 5.48 !1H, d, Jˆ3.9 Hz), 6.86
!1H, t, Jˆ7.8 Hz), 7.20 !1H, br s), 7.35 !1H, d, Jˆ7.8 Hz),
7.62 !1H, d, Jˆ7.8 Hz), 8.25 !1H, br s). Anal. found: C,
44.93; H, 3.77; N, 3.41. Calcd for C15H16O4IN: C, 44.91;
H, 4.02; N, 3.49%. FAB MS m/z: 402 !M111), 401 !M1).
The authors are grateful to Professor M. Ikeda, Kyoto
Pharmaceutical University, for generously providing the
spectral data !NMR) of chuangxinmycin !^)-1 and its
methyl ester !^)-2 and to Amano Pharmaceutical Co., Ltd
!Japan) and Meito Sangyo Co., Ltd !Japan) for providing the
lipases `Amano P' and `OF-360', respectively.
References
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2. !a) Ghi-ping, C.; Hsien-Dong, H.; Lung-Chen, H.; Yin-Ching,
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3.1.14. Enzymatic resolutions of ꢀ^)-13 and ꢀ^)-16.
!i) Table 2, entry 1; a suspension of !^)-13 !0.097 g), lipase
OF-360 !0.05 g) in H2O-saturated-cyclohexane !47.5 ml)/
isopropyl ether !2.5 ml) was incubated at 338C for 3 days.
The reaction mixture was worked up in the same way as for
the preparation of !^)-14 to afford !2R,3S)-13 !0.072 g, 74,
14% ee) and !2S,3R)-14 !0.013 g, 15, 68% ee). !ii) Table 2,
entry 2; a suspension of !^)-16 !0.7 g), lipase OF-360
!0.7 g) in H2O-saturated-cyclohexane !332.5 ml)/isopropyl
ether !17.5 ml) was incubated at 338C for 4 days. The reac-
tion mixture was worked up in the same way as for the
preparation of !^)-6 to afford !2R,3S)-16 !0.448 g, 64,
51% ee) and !2S,3R)-6 !0.22 g, 35, 91% ee). !iii) Table 2,
entry 3; a suspension of !2R,3S)-16 !0.44 g, 51% ee),
lipase OF-360 !0.44 g) in H2O-saturated-cyclohexane
!237.5 ml)/isopropyl ether !127.5 ml) was incubated at
338C for 3.5 days. The reaction mixture was worked up in
the same way as for the preparation of !^)-6 to afford
!2R,3S)-16 !0.33 g, 75, 87% ee) and !2S,3R)-6 !0.091 g,
23, 67% ee). !iv) Table 2, entry 4; a suspension of !2R,
3S)-16 !0.33 g, 87% ee), lipase OF-360 !0.33 g) in H2O-
saturated-cyclohexane !160 ml)/isopropyl ether !8.5 ml)
was incubated at 338C for 3 days. The reaction mixture
was worked up in the same way as for the preparation of
3. Michael, J. D.; Timothy, J. M.; David, A. W.; Alexandra,
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8. !a) Chan, T. H.; Hill, R. K. J. Org. Chem. 1970, 35, 3519±
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29
!^)-6 to afford !2R,3S)-16 !0.3 g, 91%, [a]D ˆ155.3
!cˆ0.55, CHCl3) corresponding to 97% ee) and !2S,3R)-6
!0.015 g, 5, 12% ee). !v) A solution of !2S,3R)-16 !0.22 g,
0.61 mmol, 91% ee), Ac2O !0.093 g, 0.91 mmol), pyridine
!0.48 g, 6.1 mmol) in CH2Cl2 !6 ml) was stirred at room
13. !a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543±2549. !b) Dale, J. A.; Mosher, H. S. J. Am. Chem.
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