Synthetic studies directed toward the AB decalin common to HMP-Y1 and hibarimicinone

Article abstract of DOI:10.1016/j.tetlet.2014.02.069

Efforts toward the synthesis of the decalin ring system common to the hibarimicin shunt metabolite HMP-Y1 and parent aglycone hibarimicinone are reported herein. An intramolecular Diels-Alder cyclization rapidly generated the decalin framework. Two approa

Full text of DOI:10.1016/j.tetlet.2014.02.069

Tetrahedron Letters 55 (2014) 2157–2159
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Tetrahedron Letters
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Synthetic studies directed toward the AB decalin common to HMP-Y1
and hibarimicinone
⇑
Jonathan E. Hempel, Darren W. Engers, Gary A. Sulikowski
Department of Chemistry, Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Efforts toward the synthesis of the decalin ring system common to the hibarimicin shunt metabolite
HMP-Y1 and parent aglycone hibarimicinone are reported herein. An intramolecular Diels–Alder cycliza-
tion rapidly generated the decalin framework. Two approaches toward completion of the AB decalin were
Received 13 February 2014
Accepted 18 February 2014
Available online 26 February 2014
vetted. Incorporation of a phenylsulfonyl leaving group b- to both a ketone and a
base-induced elimination of sulfinate led to the undesired ,b-unsaturated lactone. Methanolysis of the
-lactone followed by elimination produced the unexpected bridged cyclic ether by way of an intramo-
lecular oxy-Michael addition of the endo oriented C13 alcohol.
c-lactone followed by
a
Keywords:
c
Natural products
Diels–Alder cycloaddition
Michael addition
Stereoselective
Ó 2014 Elsevier Ltd. All rights reserved.
Total synthesis
RO
A
OMe
D
H
OMe
O
HO
Hibarimicin B (1) was isolated from the soil bacterium Microbis-
pora rosea in 1998, and its structure was proven identical to the
previously reported angelmicin B (Fig. 1).1–4 The hibarimicins were
reported to modestly inhibit src tyrosine kinase (hibarimicin A, IC50
OH
C'
O
B
C
OH
O
Sug =
Sug' =
O
Me
OH
OR'
OH
R'O
OH
D'
B'
A'
HO
O
OH OH
MeO
H
OH
O
OH
OR
= 5.8
against B16–F10 (murine melanoma) and HCT-116 (human colon
carcinoma) cells at concentrations ranging from 0.41 to 1.1 M.
lM, hibarimicin B, IC50 = 23 lM) and exhibited cytotoxicity
hibarimicin B: R = Sug; R' = Sug' (1)
hibarimicinone: R = R' =H (2)
O
OH
OMe
l
H
OMe
OH OH
HO
HO
Me
O
The 100-fold concentration difference between in vitro kinase inhi-
bition and cancer cell growth inhibition (HL-60, IC50 = 57 nM) sug-
gests further studies into their mode of action is warranted.5
Biosynthetic and structural studies demonstrated the aglycon
hibarimicinone (2) to precede the hibarimicins, and arise from
oxidation of a C2-symmetric precursor termed HMP-Y1 (3).6–8
The symmetric structure of hibarimicinone is suggestive of a
two-directional synthetic strategy, of which our laboratory9–12
and others13–16 have employed recently culminating in two total
syntheses.17–19 With this strategy in mind we planned to utilize
a biaryl D–D0 ring surrogate 4 of defined configuration in a
bis-annulation reaction with a suitable unsaturated decalin 5
(Scheme 1). Furthermore, our ability to access 4 as a single atrop-
isomer through our previously reported deracemization protocol
avoids the necessity for separation of atropisomeric mixtures en
route to the natural hibarimicinone isomer.12
O
B'
A
B
C
D
OH
OH
O
Me
OH
D'
C'
A'
OH
HO
O
OH OH
MeO
OH
Me
OH
H
O
OMe
OH
HMP-Y1 (3)
Figure 1. Hibarimicin B (1), hibarimicinone (2) and HMP-Y1 (3).
OMe
OP
OMe
OH
H
O
H
O
O
OH
OP
PO
PO
D
PhO
A
B
OPh
B'
A'
D'
O
OH
O
H
OP
HO
MeO
O
H
OP
OMe
5
aR-4
5
OH
OMe
OH
OP
13
OP
OH
OH
13
At the time we initiated a synthetic route to the AB decalin 5
the absolute stereochemistry of hibarimicinone was unknown.
O
10
9
10
OP
X
OP
H
X
O
O
OH OH
O
O
6
7
8
⇑
Corresponding author. Tel.: +1 615 343 4155; fax: +1 615 343 6199.
E-mail address: gary.a.sulikowski@vanderbilt.edu (G.A. Sulikowski).
Scheme 1. Two-directional strategy and analysis of AB decalin 5.
http://dx.doi.org/10.1016/j.tetlet.2014.02.069
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2158
J. E. Hempel et al. / Tetrahedron Letters 55 (2014) 2157–2159
Therefore, although 2 represents the now-defined absolute stereo-
chemistry of hibarimicinone, we initially targeted the opposite
absolute stereochemistry due to perceived ready access to the A-
reagent to the keto group accompanied by C10 benzoate removal.
Unfortunately, despite examination of numerous reaction
conditions and reagents, this reaction suffered from low yield
and diastereoselectivity, producing an optimized 2:1 mixture of
inseparable diastereomers (16a and 16b) in 44% yield. The isomers
were subject to esterification with b-phenylsulfonylacrylic acid, a
dienophile chosen for its reactivity, and ready introduction of B
ring unsaturation following base-mediated sulfinate elimination
of the anticipated cycloadduct.27 To this end, Mukaiyama’s esteri-
fication conditions28 afforded ester 17 in 37% yield following sepa-
ration of the minor diastereomeric ester derived from 16b. Upon
heating a solution of 17 in toluene (0.02 M) over two days, we were
pleased to observe clean conversion of 17 to decalin 18 as a single
diastereomer. The assigned stereochemistry of 18 was based on the
analysis of NOESY spectroscopy correlations.
After screening various hydrogenation conditions we deter-
mined the allyl group of 18 could be selectively saturated under
one atmosphere of hydrogen in a 3:2 mixture of heptane and ethyl
acetate over 5% Pd/C (20 min) to provide 19 in 86% yield
(Scheme 4). Ketohydroxylation of the C14–C15 alkene was accom-
plished using RuO4 in the presence of excess Oxone resulting in the
stereoselective installation of the C14 hydroxyl group.29 The stere-
oselectivity of this oxidation presumably results from a combina-
tion of steric (convex approach) and electronic (allylic alcohol)
effects.30,31 Despite examining various conditions, all attempts to
purify ketone 20 resulted in decomposition. However, having final-
ly arrived at an AB decalin incorporating all six stereocenters we
subjected crude 20 to base-mediated (DBU, CH2Cl2) sulfinate
elimination. Unfortunately, we observed exclusive formation of
ring triol starting from methyl-a-D-gluco-pyranoside (8). Based
on earlier studies of an intermolecular Diels–Alder approach10 to
decalin 5 that failed to deliver the desired C9 ring fusion stereo-
chemistry we elected to pursue an intramolecular Diels–Alder
(IMDA) reaction employing 7 as the key Diels–Alder substrate.
We anticipated triene 7 to be conveniently prepared starting from
inexpensive methyl glucopyranoside 8.
Our synthesis of triene 7 proceeded by way of cyclohexenone 13
(Scheme 2). The multi-gram preparation of 13 started with a pub-
lished five-step conversion of D-glucose 8 to the 6-iodo derivative
9.20,21 The latter was then subjected to a Vasella fragmentation
by treatment with zinc dust in refluxing THF/H2O (Scheme 2).22
Due to instability upon concentration, aldehyde 10 was subjected
without purification to a solution of vinylmagnesium bromide to
afford an inconsequential mixture of secondary alcohols 11. Next,
ring closing metathesis of 11 provided cyclohexenol 12 in good
yield (46% over three steps). Finally, IBX oxidation of 12 in a solu-
tion of 1:1 DMSO/CH2Cl2 afforded enone 13 in 90% yield.
Iodination of cyclohexenone 13 using the Johnson–Uskokovic
protocol23 provided iodoenone 14, a key intermediate en route to
IMDA substrate 7 incorporating an orthogonally protected C10 hy-
droxyl group, keto group poised for introduction of the C13 tertiary
alcohol, and a C14 halide for vinylation. Suzuki cross coupling of 14
with the cyclic vinyl boronate provided dienone 15 in good yield
(Scheme 3).24–26 We then turned our attention to installation of
the C-13 stereocenter by addition of a 3-carbon allyl Grignard
a,b-unsaturated lactone 21, an intermediate which proved
unworkable in advancing to decalin 5. We reasoned the resistance
of the double bond occupying the desired C16–C17 position arose
O
OMe
from strain imparted from the fused c-lactone, and thus we moved
OBn
OBn
OBn
OBn
Zn°, THF(aq)
reflux
CH2CHMgBr
THF
-78 to -20 °C
H
O
to relieve that strain prior to sulfinate elimination.32
I
Treatment of lactone 19 with K2CO3 in methanol at a low tem-
perature followed by TES protection of the released secondary
alcohol afforded methyl ester 22 in 82% yield (Scheme 5). Oxida-
tion of the C14–C15 trisubstituted olefin with RuO4 proceeded in
OBz
9
OBz
10
OH
O
OH
OBn
OBn
OBn
OBn
OBn
OBn
Grubbs II
IBX
good yield and stereoselectivity to afford
compound once again unstable to silica gel chromatography as
experienced with -hydroxyketone 20. When treated with DBU
a-hydroxyketone 23, a
PhMe, 70 °C
46% from 9
DMSO, CH2Cl2
90%
OBz
OBz
OBz
a
13
11
12
at a low temperature the former underwent sulfinate elimination
and isomerization to bridged ether 24. This isomerization arises
by way of base-mediated intramolecular Michael addition of the
proximal C-13 tertiary alcohol. Notably, we observed no
scrambling of the methyl ester stereocenter, possibly indicating
the Michael addition perhaps proceeded by way of the desired
Scheme 2. Preparation of cyclohexenone 13 from glucopyranoside 9.
a,b-unsaturated enone. Efforts to protect the C-13 alcohol and cir-
cumvent the undesired cyclization were unsuccessful.
Scheme 3. Synthesis of decalin 18.
Scheme 4. Attempted B-ring enone formation through sulfone elimination.

J. E. Hempel et al. / Tetrahedron Letters 55 (2014) 2157–2159
2159
References and notes
OH
OBn
OH
1) K2CO3, MeOH, -78 °C
2) TESOTf, 2,6-lutidine
DMAP, CH2Cl2
82%
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OBn
OBn
OBn
PhO2S
PhO2S
H
H
O
OTES
OMe
22
O
O
19
O
O
OH
OH
OH
OBn
OBn
OBn
RuCl3, Oxone
DBU
O
EtOAc, MeCN
NaHCO3 (aq)
CH2Cl2, -78 °C
42% from 22
OBn
PhO S
H
H
2
OTES
OMe
24
OTES
OMe
O
O
23
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Acknowledgments
This work was supported by the National Institutes of Health
(CA 059515), and the Vanderbilt Institute of Chemical Biology.
Supplementary data
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Supplementary data (experimental procedures and compound
spectral data) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.069.