Total synthesis of myriocin

Article abstract of DOI:10.1016/S0040-4039(02)02371-7

A concise, stereocontrolled synthesis of myriocin was achieved. Key features involve diastereoselective oxazoline formation catalyzed by palladium(0), MgBr₂-promoted allylic stannane addition, and palladium(0)-catalyzed coupling of a vinyl iodide with an organozinc reagent.

Full text of DOI:10.1016/S0040-4039(02)02371-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9361–9363
Total synthesis of myriocin
Kee-Young Lee, Chang-Young Oh, Yong-Hyun Kim, Jae-Eun Joo and Won-Hun Ham*
College of Pharmacy, SungKyunKwan University, Suwon 440-746, South Korea
Received 3 October 2002; accepted 16 October 2002
Abstract—A concise, stereocontrolled synthesis of myriocin was achieved. Key features involve diastereoselective oxazoline
formation catalyzed by palladium(0), MgBr2-promoted allylic stannane addition, and palladium(0)-catalyzed coupling of a vinyl
iodide with an organozinc reagent. © 2002 Elsevier Science Ltd. All rights reserved.
Myriocin (Fig. 1, 1)1 was first isolated from the fermen-
tation broth of the thermophilic fungi, Myriococcus
albomyces and Mycelia sterila as an antifungal principle
in 1972.2 Recently, this potent immunosuppressant
compound, shown to be 10ꢀ100 times more potent
than cyclosporin A, was also isolated from culture
broth of Isaria sinclairri by a Fujita group.3
NMR) in 70% yield.7 Acetylation of hydroxyl group
yielded the secondary allylic acetate. A standard oxazo-
line ring formation [Pd(PPh3)4, K2CO3, in CH3CN] of
the allylic acetate gave the desired trans-oxazoline 7 as
a single isomer and in good yields (87%). Fluoride-
induced removal of the silyl protection group, and the
resulting alcohol was oxidized with ruthenium chloride8
to afford the acid. The resulting carboxylic acid was
converted to its methyl ester 8 with diazomethane in
68% yield for three steps. The hydroxymethylation of 8
with formaldehyde gave the anti hydroxymethylation9
product 9 as the major isomer with high diastereoselec-
tivity (20:1) and in modest yield (58%). Protection of 9
with MOMCl gave 10 in 90% yield.
Myriocin has a quaternary center, three consecutive
chiral centers, and trans-olefinic group in polar
hydroxyl amine head group. A number of its synthetic
approaches have been reported due to its novel struc-
ture and its interesting biological activity.4
Recently, we have been investigating the stereoselective
intramolecular cyclization of homoallyl benzamide via
p-allylpalladium complex catalyzed by Pd(0) (Scheme
1).5 In our laboratory, we have been exploring the
utility of enantiopure oxazoline as chiral building
blocks for the stereocontrolled synthesis of natural
products. As part of this program, we developed a
novel strategy for a concise synthesis of the myriocin.
Herein we describe a novel asymmetric synthesis of
myriocin that utilizes oxazoline as a chiral building
block.
Figure 1.
The synthesis proceeded as shown in Scheme 2. Oxida-
tion of protected -N-benzoyl-serinol 5 with Dess–Mar-
L
tin periodinane5b,6 gave the corresponding aldehyde
without racemization,5b,6b which was reacted with vinyl
magnesium bromide in THF at 0°C to afford the allyl
alcohol 6 as an ca. 1.1:1 mixture of syn/anti isomers (1H
* Corresponding author. Tel.: 82-31-290-7706; fax: 82-31-292-8800;
e-mail: whham@speed.skku.ac.kr
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02371-7

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K.-Y. Lee et al. / Tetrahedron Letters 43 (2002) 9361–9363
Scheme 2. Reagents and conditions: (a) (i) Dess–Martin periodinane, CH2Cl2; (ii) CH2ꢀCHMgBr, THF, 0°C, 70% for two steps;
(b) Ac2O, pyr., CH2Cl2, 95%; (c) Pd(PPh3)4, K2CO3, CH3CN, 60°C, 87%; (d) (i) TBAF, THF, 99%; (ii) RuCl3, K2S2O8, 1 M
NaOH, CH3CN; (iii) CH2N2, Et2O, 68% for two steps; (e) HCHO, KHMDS, HMPA, THF, −78°C, 58%; (f) MOMCl, Hu¨nig
base, CH2Cl2, 90%.
Ozonolysis of 10 gave the unstable aldehyde, which was
treated with MgBr2·OEt2 in CH2Cl2 at −20°C followed
by allyl tributyltin10 and warming to 25°C gave the
allylating product 11 in 82% yield with >20:1 stereose-
lectivity.11 Upon subjection of 11 to ozone and CrCl2-
mediated iodomethylenation,12 vinyl iodide 12 was
generated. Application of the Negishi protocol for pal-
ladium-catalyzed reaction of 12 with alkyl iodide 1313
provided the fully protected 14 in 71% yield.14
(Amberlite IRC-50) afforded myriocin. The spectro-
scopic (1H and 13C NMR) data for synthetic 1 were
fully identical with those of synthetic myriocin,4e and
the physical properties of 1 {mp 167–170°C, [h]2D5 of
+4.0 (c 0.25, DMSO); lit.4e mp 165–168°C, [h]2D1 of +3.7
(c 0.26, DMSO)} showed good agreement with those
reported (Scheme 3).
In summary, the asymmetric total synthesis of myriocin
has been accomplished from
L
-serinol 5 with a high
Removal of MOM group by 2N HCl in THF effected
simultaneous hydrolysis of the ethylene ketal and oxa-
zoline to give ketolactone. Finally, a base-promoted
hydrolysis cleaved the lactone and the amide group,
and subsequent neutralization with an acidic resin
degree of stereocontrol. Our synthesis has demonstrated
the versatility of oxazoline as a chiral building block.
Work is in progress on the enantioselective synthesis of
natural products using oxazoline as a chiral building
block.
Scheme 3. Reagents and conditions: (a) (i) O3, MeOH, −78°C, then DMS; (ii) Bu3SnCH2CHꢀCH2, MgBr2–Et2O, CH2Cl2, 82% for
two steps; (b) (i) O3, MeOH, −78°C, then DMS; (ii) CrCl2, CHI3, THF, 63% for two steps; (c) 13, t-BuLi, −78°C; then, ZnCl2,
−78°Cꢀrt, Pd(PPh3)4, THF, 71%; (d) (i) 2N HCl, THF, 78%; (ii) 1N NaOH, reflux, 79%.

K.-Y. Lee et al. / Tetrahedron Letters 43 (2002) 9361–9363
9363
Acknowledgements
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This study was supported by a grant of the Korea
Health 21 R&D Project, Ministry of Health and Wel-
fare, Republic of Korea (01-PJ1-PG1-01CH13-0002).
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