Stereoselective total synthesis of (+)-myriocin from D-mannose

Article abstract of DOI:10.1039/b104864n

The stereoselective total synthesis of myriocin 1 from D-mannose is described; the carbon framework with three contiguous chiral centers including a tetra-substituted carbon with nitrogen was effectively constructed using Overman rearrangement as the key

Full text of DOI:10.1039/b104864n

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Stereoselective total synthesis of (+)-myriocin from -mannose
D
Takeshi Oishi, Koji Ando and Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan. E-mail: chida@applc.keio.ac.jp
Received (in Cambridge, UK) 4th June 2001, Accepted 21st August 2001
First published as an Advance Article on the web 4th September 2001
The stereoselective total synthesis of myriocin 1 from
D-
mannose is described; the carbon framework with three
contiguous chiral centers including a tetra-substituted car-
bon with nitrogen was effectively constructed using Over-
man rearrangement as the key reaction.
Myriocin1 (also known as thermozymocidin2 and ISP-I3) 1 (Fig.
1) is an a,a-disubstituted a-amino acid derivative isolated from
the culture broth of Myriococcus,1 Mycelia2 and Isalia,3 and
reported to show antifungal1,2 as well as immunosuppressive
activities.3 Its promising immunosuppressive properties4 and
unique structure have attracted much synthetic interest, and
several total5 and formal syntheses6 of 1 have been reported to
date. A structural feature of 1 is the unusual a,a-disubstituted a-
amino acid framework with three contiguous chiral centers
including a tetra-substituted carbon with nitrogen. For construc-
tion of the tetra-substituted carbon, previous syntheses adopted
the Strecker synthesis,6a hydrocyanation of imines,5a the
Darzen reaction,5b,6c Pd-catalyzed hydroxyamination of a vinyl
epoxide,6b asymmetric aldol reaction of chiral dilactim ethers,5c
and Lewis acid catalyzed cyclization of an epoxytrichloro-
acetimidate.5d Our previous success in total synthesis of
lactacystin, a heterocyclic natural product with an a,a-
disubstituted a-amino acid framework, from
-glucose7 sug-
D
gested that the rearrangement of an allylic trichloroacetimidate
(Overman rearrangement)8 derived from a furanose with proper
functionalities would generate the tetra-substituted carbon
stereoselectively. This methodology was also expected to
provide an efficient approach to the highly functionalized part
in 1. Here we report the realization of this plan in a total
synthesis of 1 from
D
-mannose.
The known glycal 29 derived from
D
-mannose in three steps
(80% overall yield) (Scheme 1) was converted into a-methyl
furanoside 3† by oxymercuration-reduction followed by acid
treatment in 81% yield. The primary hydroxy group in 3 was
selectively p-methoxybenzylated10 to afford 4 (95% yield).
Swern oxidation of 4 generated ketone 5, which was submitted
to the Horner–Emmons reaction to provide an inseparable
mixture of (E)-alkene 6 and its (Z)-isomer (15+1) in 90% yield
from 4. DIBAL-H reduction of the mixture followed by
chromatographic separation afforded geometrically pure (E)-
allyl alcohol 7 and its (Z)-isomer in 93 and 6% isolated yields,
respectively. Compound 7 was converted into trichloroacetimi-
date 8, which, without isolation, was subjected to Overman
rearrangement. Thus, a xylene solution of 8 was heated at 140
11
°C in the presence of K2CO3 in a sealed tube for 72 h to
provide an inseparable mixture of rearranged products 9 and its
Scheme 1 Bn = –CH2Ph, MPM = –CH2C6H4-p-OMe. Reagents and
conditions: i see ref. 9; ii Hg(OAc)2, THF–H2O, room temp., then KI,
NaBH4, THF–H2O, 0 °C; iii AcOH–H2O (3+2), room temp., then AcCl,
MeOH, 0 °C; iv n-Bu2SnO, toluene, reflux, then MPMCl, CsF, DMF, 70 °C;
v (COCl)2, DMSO, CH2Cl2, 278 °C, then Et3N, 0 °C; vi (MeO)2-
P(O)CH2CO2Me, LiBr, DBU, CH3CN, 240 °C; vii DIBAL-H, toluene,
278 °C; viii Cl3CCN, DBU, CH2Cl2, 0 °C; ix K2CO3, o-xylene, 140 °C; x
O3, MeOH, 278 °C, then NaBH4, 0 °C; xi DBU, CH2Cl2, room temp.; xii
1 M aqueous HCl–THF (1+1), room temp., then Ac2O, DMAP, pyridine,
room temp.; xiii O3, CH2Cl2, 278 °C, then Me2S; xiv NaClO2, NaH2PO4,
HOSO2NH2, t-BuOH–H2O, room temp., then Me3SiCHN2, MeOH, room
temp.; xv 4 M aqueous HCl–THF (1+3), room temp., then Ph3PNCHCO2Et,
toluene, room temp.; xvi DIBAL-H, THF–toluene, 215 °C; xvii MsCl,
Et3N, CH2Cl2, 0 °C, then LiBr, acetone, room temp.
1
C(5) epimer in a ratio of 7+1 (determined with 300 MHz H
NMR) in 90% yield from 7.‡ The newly formed ster-
eochemistry in 9 was determined to be R by NOE experiments
Fig. 1
1932
Chem. Commun., 2001, 1932–1933
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DOI: 10.1039/b104864n

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of bicyclic carbamate 10 derived from 9 in four steps (46%
overall yield). Ozonolysis of the mixture of 9 and its C(5)
epimer (Me2S work-up) followed by oxidation and esterifica-
tion, and subsequent chromatographic separation afforded 11 in
a diastereochemically pure form (82% yield from the mixture of
9 and its epimer). Acid hydrolysis of 11 provided an anomeric
mixture of lactol, which was then reacted with stabilized ylide
to give (E)-alkene 12 as a single isomer in 71% yield. When
compound 12 was treated with DIBAL-H in THF–toluene at
215 °C, only the a,b-unsaturated ester function was reduced to
afford allyl alcohol 13 (75% yield), which was transformed into
cyclic carbamate 14 in 86% yield. The observed coupling
constant in 14 (J6,7 = 15.6 Hz) clearly supported the (E)-
geometry of the double bond. The primary hydroxy group in 14
was converted into corresponding bromide to furnish the highly
functionalized moiety, allyl bromide 15 in 92% yield.
The hydrophobic part of myriocin, sulfone 16, was prepared
by treatment of 1-bromododecan-6-one§ with PhSO2Na, fol-
lowed by ketalization (82% yield) (Scheme 2). Sulfone 16 was
lithiated with n-BuLi, and then reacted with the allyl bromide 15
to afford the coupling product 17 in 80% yield. Saponification
of 17 and subsequent Birch reduction gave crude carboxylic
acid 18. Removal of the ketal group and carbamate function in
18 followed by conventional acetylation provided the known g-
lactone 19 {[a]D20 +54 (c 0.7, CHCl3); lit.2a [a]2D4 +57 (c 1.0,
CHCl3)} in 47% yield from 17. The spectral data for 19 were
identical in all respects to those kindly provided by Professor
Hatakeyama.5d Finally, according to the precedent,5d saponifi-
cation of 19 followed by neutralization with weak acidic resin
(Amberlite IRC-76, H+ form) furnished (+)-myriocin 1 in 82%
yield. The spectroscopic (1H and 13C NMR) data for synthetic 1
were fully identical with those of natural myriocin, and the
physical properties of 1 {mp 168–170 °C, [a]2D3 +5.1 (c 0.17,
MeOH); lit.3 mp 169–171 °C, [a]D +4.8 (c 0.286, MeOH)}
showed good agreement with those reported for the natural
product.
This synthesis established an alternative and efficient
pathway to myriocin 1 (24 linear steps and 4.9% overall yield
from -mannose), which showed almost the same efficiency as
D
previous excellent approaches (2.4–5.1% overall yield).5b–d In
addition, this work proved that the novel methodology,
Overman rearrangement on a furanose scaffold,7 is quite
effective for the chiral synthesis of both acyclic and hetero-
cyclic natural products possessing highly functionalized a,a-
disubstituted a-amino acid structures. Additional applications
of this methodology in natural product synthesis are now
warranted and will be reported in due course.
We thank Professor Susumi Hatakeyama (Nagasaki Uni-
versity, Japan) for providing us with spectral data of an
authentic sample and valuable discussions. Financial support of
the Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports and Culture, Japanese Government
is gratefully acknowledged.
Notes and references
† All new compounds described in this paper were fully characterized by
300 MHz 1H NMR, 75 MHz 13C NMR, IR and mass spectrometric and/or
elemental analyses.
‡ Overman rearrangement of an imidate derived from (Z)-allyl alcohol
afforded 9 and its C(5) epimer in a ratio of 1+5 in 70% yield.
§ 1-Bromododecan-6-one was synthesized by essentially the same proce-
dure reported by Just and Payette [see ref. 6(a)]. In place of cyclooctanone,
cyclohexanone was employed as the starting material.
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Scheme 2 Reagents and conditions: i PhSO2Na, DMF, room temp.; ii
(TMSOCH2)2, TMSOTf, CH2Cl2, room temp.; iii n-BuLi, THF, 278 °C,
then 15, 278–0 °C; iv LiOH, H2O–MeOH, room temp.; v Li, liq. NH3,
THF, 278 °C; vi 4 M aqueous HCl–THF (1+1), room temp.; vii 10%
aqueous NaOH–MeOH (1+3), reflux; viii Ac2O, pyridine, room temp.
Chem. Commun., 2001, 1932–1933
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