An efficient and enantioselective total synthesis of naturally occurring L-783277

Article abstract of DOI:10.1016/j.tetlet.2010.07.122

Naturally occurring L-783277 which belongs to 14-membered resorcylic acid lactones (RALs) turned out to be a potent kinase inhibitor against MEK (MAP kinase kinase). We successfully accomplished efficient and enantioselective total synthesis of L-783277 based on convergent assembly of one aromatic unit and two chiral building blocks with efficient orthogonal protection-deprotection strategy. Three key steps composed of olefin cross metathesis, addition of acetylene derivative to aldehyde, and Yamaguchi macrolactonization were subsequently employed to construct the framework of L-783277. The optical rotation value of L-783277 is for the first time presented in this Letter.

Full text of DOI:10.1016/j.tetlet.2010.07.122

Tetrahedron Letters 51 (2010) 4942–4946
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Tetrahedron Letters
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An efficient and enantioselective total synthesis of naturally occurring L-783277
*
Hwan Geun Choi , Jung Beom Son , Dong-Sik Park, Young Jin Ham, Jung-Mi Hah, Taebo Sim
Life/Health Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Naturally occurring L-783277 which belongs to 14-membered resorcylic acid lactones (RALs) turned out
to be a potent kinase inhibitor against MEK (MAP kinase kinase). We successfully accomplished efficient
and enantioselective total synthesis of L-783277 based on convergent assembly of one aromatic unit and
two chiral building blocks with efficient orthogonal protection-deprotection strategy. Three key steps
composed of olefin cross metathesis, addition of acetylene derivative to aldehyde, and Yamaguchi mac-
rolactonization were subsequently employed to construct the framework of L-783277. The optical rota-
tion value of L-783277 is for the first time presented in this Letter.
Received 25 May 2010
Revised 20 July 2010
Accepted 22 July 2010
Available online 29 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
The first total synthesis of L-783277 was disclosed by Hofmann
and Altmann in 2008.12 In this Letter, a macrolactonesubstrate bear-
Naturally occurring resorcylic acid lactones (RALs)1 have been
known with the first isolation of radicicol2 (monorden) in 1953 fol-
lowed by zearalenone,3 LL-Z1640-2,4 hypothemycin,5 L-783277,6
and aigialomycin D7 (Fig. 1). As for biological activity of RALs, zearal-
enone has been shown to possess estrogen agonistic properties.
Zhao et al.6 have revealed that RALs bearing cis-enone function-
ality such as hypothemycin and L-783277 have kinase inhibitory
activities. Especially, L-783277 isolated from fruitbody of Helvella
acetabulum has turned out to be highly potent against MEK (IC50 of
4 nM). L-783290 that is the corresponding C70–C80 trans-enone
analog of L-783277 was found to be much less (IC50 of 300 nM)
active against MEK.
ing unprotected four hydroxyl groups was submitted to the final
synthetic step, oxidation reaction of C60 hydroxyl group using poly-
mer-bound IBX, which resulted in L-783277 with a concomitant sec-
ond oxidation by-product presumably derived from other
unprotected secondary hydroxyl groups. This by-product could not
be separated by thin layer chromatography or flash chromatography
and L-783277 was purified with HPLC. The second total synthesis of
L-783277 was reported13 by Dakas et al. in 2009. Homologation
between C10 and C20 using benzylic sulfide intermediate and macrol-
actonization under Mitsunobu conditions were adopted in order to
construct molecular framework in this Letter. In the meanwhile,
the synthesis of 70-fluoro L-783277 was most recently reported.14
All of kinase inhibitors could be classified into four categories
based on their binding sites (ATP- and/or allosteric binding site
on kinase) and reversibility (covalent or non-covalent binding to
kinase). The fourth class of kinase inhibitors categorized by Gray’s
proposal8 is capable of forming an irreversible bond to kinase pro-
tein.9 The RALs containing cis-enone functionality, hypothemycin,
and L-783277 undergo Michael addition reaction with a cysteine
residue located in kinase activation loop and belong to the fourth
class of kinase inhibitors. These findings have recently been cor-
roborated in a more comprehensive study by Schirmer et al. on
the mode of action and on the kinase specificity of hypothemy-
cin.10 In accordance with this Schirmer’s publication, other groups
have more recently reported that RALs containing cis-enone such
as L-783277 and 5-(Z)-7-oxozeaenol inhibit not only MEK but also
It was anticipated that a fluorine substituent at the a-position of en-
one might accentuate the Michael addition reaction. As a part of
expanding our MEK kinase program, we aimed to make a further
assessment of biological activities of L-783277 and to conduct SAR
study with L-783277 analogs. We first embarked to explore an effi-
cient synthetic route toward L-783277 to meet these goals. Hence,
we report herein an effective synthetic route with efficient orthogo-
nal protection/deprotection strategy which differs from the syn-
thetic approach reported in precedent literature12,13 and enables
to obtain L-783277 in the range of tens of milligrams with simple
purification method using flash silica chromatography.
2. Results and discussion
other kinases such as VEGFR2/3, PDGFR-
a, and FLT3 with submi-
The retrosynthetic analysis of L-783277 (1) outlined in Figure 2
involves in the construction of three key fragments (compounds 6,
13, and 22) and two successive assemblies of these fragments fol-
lowed by macrolactonization. We envisioned that the first assembly
between fragment I and II, C10–C20 bond formation could be accom-
plished by an olefin cross metathesis using Grubbs 2nd generation
catalyst. It was hoped that the incorporation of fragment III to form
cromolar IC50 values.11
* Corresponding author. Tel.: +82 2 958 6347; fax: +82 2 958 5189.
E-mail address: tbsim@kist.re.kr (T. Sim).
These authors contributed equally to this work.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.122

H. G. Choi et al. / Tetrahedron Letters 51 (2010) 4942–4946
4943
Figure 1. Naturally occurring resorcylic acid lactone polyketides.
Figure 2. Retrosynthetic analysis of L-783277.
Scheme 1. Synthesis of fragment I.

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H. G. Choi et al. / Tetrahedron Letters 51 (2010) 4942–4946
Scheme 2. Synthesis of fragment II.
C60–C70 bond followed by Yamaguchi macrolactonization could fur-
nish the framework of L-783277.
ation on the 4-hydroxy group of compound 3 was accomplished by
Mitsunobu reaction17 in 82% yield. The phenol 4 was readily con-
verted into the corresponding triflate 5. This triflate was subjected
to Stille coupling reaction18 to furnish styrene 6 in a yield of 75%.
The fragment I (6) was prepared according to known synthetic
route15 as described in Scheme 1. This synthesis commenced with
commercially available 2,4,6-trihydroxybenzoic acid
2
(50 g),
Enantiomerically pure
D-(R)-glyceraldehyde acetonide 9 was
which was treated with TFA and TFAA in acetone to afford 35 g
(57% yield) of the corresponding acetonide 3 on the basis of mod-
ified Danishefsky’s method.16 The crude acetonide 3 was purified
through recrystallization (24 g of crystalline 3) with EtOH (crude
1 g/2 mL) and the resulting mother liquor was subjected to SiO2
flash column chromatography purification. Regioselective methyl-
prepared from -mannitol in two steps according to the literature
D
method.19 The asymmetric Brown allylation20 of aldehyde 9 using
(ꢀ)-Ipc2BOMe yielded the desired allylic alcohol 10 in high diaste-
reoselectivity (92:8 determined with 1H NMR). The deprotection of
acetonide group on compound 10 was carried out with AcOH to
afford the triol 11. The primary alcohol group of triol 11 was
Scheme 3. Assembly of fragments I and II.

H. G. Choi et al. / Tetrahedron Letters 51 (2010) 4942–4946
4945
Scheme 4. Synthesis of fragment III.
selectively protected with TBDPSCl to provide diol 12 which was
then elaborated into acetonide 13, C20–C60frament II (Scheme 2).
With fragments I and II in hand, we were in a position to address
their assembly and adopted olefin cross metathesis strategy using
Grubbs 2nd generation catalyst to furnish the styrene 14 (cis:
trans = 3:7 determined with 1H NMR) as described in Scheme 3.
This ruthenium carbene-based olefin metathesis reaction was
effected in 55% yield. The transesterification of compound was con-
ducted with NaOMe to provide methyl ester 16. Almost quantita-
tive (96%) protection of phenol group in 16 with MOM group,
followed by TBAF-mediated desilylation of compound 17, fur-
nished compound 18. It is instructive to recognize that the protec-
tion of phenol group in compound 16 is necessary to avoid a side
reaction called decarboxylation during the course of saponification
of methyl ester which is a critical step for macrolactonization as
illustrated in Scheme 5.21
The preparation of the fragment III, alkyne 22, commenced with
commercially available (S)-(ꢀ)-propylene oxide 19, which under-
went ready conversion into secondary alcohol 20 upon treatment
with lithium trimethylsilylacetylene at ꢀ78 °C in the presence of
BF3ꢁEt2O (Scheme 4).22 TBS-protection of the alcohol 20 followed
by TMS-deprotection of silyl ether 21 using K2CO3 provided the de-
sired fragment III in 93% yield over two steps.
of allylicalcohol diastereomers 23 in 42% yield. The resulting C60 sec-
ondary alcohol in compound 23, which causes a diastereomeric mix-
ture, should be oxidized to the corresponding ketone and it was not
necessary to separate these diastereomers. This acetylene addition
reaction satisfied the completion of the entire carbon framework
construction of L-783277. In exploring most suitable base for this
acetylene addition reaction, the use of EtMgBr instead of n-BuLi re-
quired higher reaction temperature (50 °C) and led to cleavage of
MOM protecting group on C2 oxygen. The acetylene 23 was submit-
ted to partial hydrogenation reaction using Lindlar catalyst to give
the corresponding cis-olefin 24 in a yield of 99%. PMB group which
is an orthogonalprotecting group to TBS was installed on allylicalco-
hol in compound 24 using NaH in the presence of NaI in a yield
exceeding 95%. TBS group in 25 was then selectively deprotected
with TBAF. Saponification of the methyl ester of compound 26 pro-
ceeded with sodium hydroxide in ethanol at 120 °C for 8 h to give
a pivotalintermediatewhichconstitutestheretronforthelactoniza-
tion. The stage was set for the crucial macrolatonization event which
was accomplished using modified Evans version23 of Yamaguchi’s
method.24 It is noteworthy that Hofmann and Altmann performed
this macrolactonization under Mitsunobu conditions12 in over 59%
yields and Mukaiyama conditions25 were also adopted by Tatsuta
et al. for this macrolactonization in the course of LL-Z1640-2 synthe-
sis. Theselectivedeprotection of PMBgroupin 27wasreadilycarried
out with DDQ to yield allylic alcohol 28, which was then oxidized to
cis-enone compound 29 with Dess–Martin periodinane. Finally,
The primary alcohol 18 was smoothly oxidized to the corre-
sponding aldehyde with Dess–Martin periodinane. This aldehyde
was attacked by lithium acetylide derivative 22 to afford a 1:2 ratio
Scheme 5. Total synthesis of L-783277.

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H. G. Choi et al. / Tetrahedron Letters 51 (2010) 4942–4946
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simultaneous cleavage of acetonide and MOM protecting groups in
compound 29 using TFA furnished L-783277 in 93% yield. This syn-
thetic L-783277 proved to be identical with the naturally occurring
L-783277, as judged by NMR26 and high-resolution mass spectral
data (calcd [M+Na]+ = 387.1420, found [M+Na]+ = 387.1416). To
the best of our knowledge, we report here for the first time the opti-
cal rotation value of L-783277, ½a D24:5
þ 8:8 (c 0.5, CHCl3).
ꢂ
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Acknowledgment
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MODHRD, KRF-2007-
355-C00027).
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