Toward the Stereoselective Synthesis of Arthrobotrisin A: Fragment Synthesis and Coupling Studies

Article abstract of DOI:10.1055/s-0036-1588950

A route towards the stereocontrolled synthesis of arthrobotrisin A based on a Nozaki-Hiyama-Kishi (NHK) coupling strategy was developed. Highlights of the fragment synthesis include enzyme-catalyzed kinetic resolution, Negishi carbometalation-iodination, quinone formation through oxidation with hypervalent iodine, chiral oxazaborolidine-catalyzed asymmetric Diels-Alder reaction with cyclopentadiene, regio- and stereoselective epoxidation, Noyori reduction, retro-Diels-Alder reaction, diastereoselective Luche reduction, and, finally, a Nozaki-Hiyama-Kishi (NHK) coupling of the vinyl iodide fragment.

Full text of DOI:10.1055/s-0036-1588950

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
R. N. Kumar et al.
Letter
Synlett
Toward the Stereoselective Synthesis of Arthrobotrisin A:
Fragment Synthesis and Coupling Studies
Rayala Naveen Kumar
OTBS
NHK coupling
Nandigama Satish Kumar
Harshadas M. Meshram*
I
OH OH
OH
4
5'
1'
O
Medicinal Chemistry and Pharmacology Division, CSIR-Indian
Institute of Chemical Technology, Hyderabad 500 007, India
hmmeshram@yahoo.com
5
+
enzymatic resolution
HO
1
OAc
O
O
Noyori
reduction
OH
arthrobotrisin A
AcO
OAc
Received: 20.11.2016
Accepted after revision: 20.01.2017
Published online: 24.02.2017
logical activities.1 They can act as antitumor agents2 or as
cytotoxins, and some also inhibit the strand-transfer reac-
tion of HIV-1 integrase.3 Arthrobotrisins A–C, which belong
to this terpenoid family, were isolated from Arthrobotrys
oligospora by Zhang and co-workers.4 These compounds ex-
hibit nematocidal and antibacterial properties.5 The relative
configuration of arthrobotrisin A was determined by single-
DOI: 10.1055/s-0036-1588950; Art ID: st-2016-b0782-l
Abstract A route towards the stereocontrolled synthesis of arthrobo-
trisin A based on a Nozaki–Hiyama–Kishi (NHK) coupling strategy was
developed. Highlights of the fragment synthesis include enzyme-cata-
lyzed kinetic resolution, Negishi carbometalation–iodination, quinone
formation through oxidation with hypervalent iodine, chiral oxazaboro-
lidine-catalyzed asymmetric Diels–Alder reaction with cyclopentadiene,
regio- and stereoselective epoxidation, Noyori reduction, retro-Diels–
Alder reaction, diastereoselective Luche reduction, and, finally, a Nozaki–
Hiyama–Kishi (NHK) coupling of the vinyl iodide fragment.
crystal X-ray diffraction and by assignment of its 1H and 13
C
NMR spectra.4 Because of their distinctive carbon skeleton
and biological activities, the synthesis of the arthrobotris-
ins attracted our attention. In continuation of our research
on the synthesis of new bioactive molecules,6 we report our
studies directed toward a stereocontrolled synthesis of ar-
throbotrisin A. There are a few literature reports on synthe-
ses of other oligosporons,7 and some are under investiga-
tion in our laboratory (Figure 1).
Key words arthrobotrisin A, Nozaki–Hiyama–Kishi coupling, Diels–
Alder reaction, Noyori reduction, Luche reduction, asymmetric synthesis
Among the vast array of terpenoidal natural products,
compounds from diverse natural sources that contain an
epoxyquinone core are being reported regularly. They have
been in the limelight in recent years on account of their
structural novelty and their promising wide-ranging bio-
A retrosynthetic pathway to arthrobotrisin A (1) is
shown in Scheme 1. We surmised that arthrobotrisin A
might be obtainable by a Nozaki–Hiyama–Kishi (NHK) cou-
pling of the vinyl iodide 6 with aldehyde 7. The substituted
OH OH
O
OH
OH OH
O
OH
R2
OH R1
OH OH
R1 = OH, R2 = H arthrobotrisins B (2)
arthrobotrisin (1)
R
1 = H, R2 = OH arthrobotrisins C (3)
O
OH
OH OH
O
O
HO
HO
OH
OH
rosnecatrol (5)
rosnecatrone (4)
Figure 1 Structures of arthrobotrisins A–C (1–3) and some other natural products with similar skeletons
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
R. N. Kumar et al.
Letter
Synlett
OAc
O
OTBS
OH OH
OH
I
5
1
1'
O
4
1
5'
1'
O
AcO
+
HO
OAc
OH
6
7
arthrobotrisin A (1)
OH
OMe
O
O
OTBDPS
O
H
O
H
geraniol (8)
OMe
10
9
Scheme 1 Retrosynthetic analysis for arthrobotrisins A (1)
vinyl iodide 6 might be accessible from commercially avail-
able geraniol (8), and we proposed that the aldehyde 7
might be obtained by a sequential Noyori reduction, retro-
Diels–Alder reaction, and Luche reduction of precursor 9,
which should be readily obtainable from easily accessible
2,5-dimethoxybenzaldehyde (10).
We began our synthesis of fragment 7 by LAH reduction
of 2,5-dimethoxybenzaldehyde (10) (Scheme 2). Silylation
of the resultant primary alcohol with TBDPSCl gave silyl
ether 11 in 97% yield. Oxidation of 11 with an equimolar
amount of the trivalent iodine reagent [bis(trifluoroace-
toxy)iodo]benzene8 in 2:1 MeCN–H2O conveniently gave
the p-quinone 12 in quantitative yield, whereas the CAN-
mediated oxidation9 gave a poor yield (46%) of the product.
The cationic chiral Lewis acid generated from the corre-
sponding oxazaborolidine by protonation with triflic acid
was found to be an excellent catalyst for the enantioselec-
tive Diels–Alder reaction10 of p-quinone 12 with cyclopen-
tadiene to afford the endo Diels–Alder adduct 13 as the
major product in 89% yield and 93% ee.11 This Corey proto-
col of an enantioselective Diels–Alder reaction catalyzed by
a cationic chiral Lewis acid, with a p-quinone as the dieno-
phile component and cyclopentadiene as the diene compo-
nent, resulted in excellent enantioselectivity. Routine func-
tional-group transformations on 13 furnished the (+)-ep-
oxy ketone
9
through regio- and stereoselective
epoxidation of the Diels–Alder adduct 13. The (+)-epoxy ke-
tone 9 was obtained in good yield and with complete exo-
stereoselectively by using t-BuOOH and DBU.12 This is the
most prominent approach to the stereoselective synthesis
of epoxyquinone derivatives that have a wide range of bio-
logical activities. Monoformylation of 9 with a 35% formalin
OMe
O
OTBDPS
OMe OTBDPS
a
O
c
b
H Ph
Ph
OMe
O
OMe
11
N
O
B
12
TfOH
10
H
o-Tol
O
O
OTBDPS
O
H
OTBDPS
O
O
O
OTBDPS
H
H
d
e
O
H
H
O
R
9
13
14: R = OH
15: R = OAc
f
Scheme 2 Reagents and conditions: (a) LiAlH4, THF, 0 °C, 30 min, 91%; then imidazole, TBDPSCl, CH2Cl2, 0 °C to r.t., 3 h, 97%; (b) [bis(trifluoroace-
toxy)iodo]benzene, 2:1 MeCN–H2O, r.t., 30 min, 91%; (c) (S)-(–)-o-tolyl-CBS-oxazaborolidine, TfOH, cyclopentadiene, CH2Cl2, –78 °C, 89% (93% ee). (d)
DBU, t-BuOOH, CH2Cl2, 30 min, 87%; (e) DBU, 35% formalin soln, THF, 0 °C, 30 min, 91% (dr 9:1); (f) Et3N, Ac2O, DMAP (cat.), CH2Cl2, r.t., 3 h, 95%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
R. N. Kumar et al.
Letter
Synlett
solution in the presence of DBU gave the desired product 14
with high regioselectivity.7c The primary alcohol group
present in the hydroxymethyl product 14 was protected as
its acetate 15 by treatment with triethylamine, Ac2O, and a
catalytic amount of DMAP.
19 under weakly basic conditions, a migration of the acetyl
group from the C4 hydroxy group to the C1′ hydroxy group
was observed. We screened various desilylation reagents,
such as TBAF and HF-Py, but in all cases, similar results
were obtained. The resulting compound 20 was character-
ized by means of 1H and 13C NMR spectral analyses. The mi-
gration of the acyl group was further confirmed by oxida-
tion of the product 20 with 2-iodooxybenzoic acid (IBX) to
give the ketone 21. This acyl migration is a problem that is
often associated with the use of TBAF,17 and is mainly due to
the presence of the C1′ hydroxy group near the O-acyl pro-
tecting group. This might be overcome by changing the pro-
tecting groups in the Luche reduction product 18; this is
under investigation and will be reported in due course.
Meanwhile, we wish to report our fragment syntheses and
coupling studies.
We began our synthesis of fragment 6 by the oxidation
of geraniol (8) with IBX in ethyl acetate under reflux condi-
tions to give geranial (Scheme 4). This was treated with
freshly prepared propargylmagnesium bromide in dry di-
ethyl ether at –10 °C to give the (±)-homopropargylic alco-
hol 22,18 which was subjected to enzyme-catalyzed resolu-
tion.19 The Amano lipase PS-catalyzed enantiomer-selective
acetylation of the racemic alcohol 22 with vinyl acetate
gave alcohol 22a and ester 22b in good yields and with high
enantiomeric excesses (>82%). The absolute configuration
of the (–)-homopropargylic alcohol 22a was assigned by
means of a mandelate ester analysis.20 The enantiopure (R)-
homopropargylic alcohol 22a was then subjected to Negi-
shi carbometalation–iodination21 with Cp2ZrCl2, Me3Al, and
iodine to provide the substituted vinyl iodide 23 in 86%
yield and with high reaction efficiency and good control of
the olefin geometry. The corresponding allylic alcohol 23
was treated with TBSCl and imidazole in CH2Cl2 at 0 °C to
give silyl ether 6 in 86% yield.
To incorporate the required stereocenter at C1, we ini-
tially focused on the stereoselective reduction of 15 with
DIBAL-H. Unfortunately, however, the diastereoselectivity
of this reduction was poor, resulting in about a 70:30 ratio.
Although a variety of methods exist for the stereocontrolled
reduction of epoxy ketones, modest diastereoselectivities
are often observed.13 Recently, McIntosh and co-workers
described a modification of Noyori’s asymmetric catalytic-
transfer hydrogenation that is considered to be an attractive
alternative procedure for the reduction of epoxy ketones.14
In the context of our synthesis, the successful implementa-
tion of the Noyori reduction on 15 should permit controlled
reduction and generation of the appropriate stereocenter at
C1 by using Ru(p-cymene)[(S,S)-TsDPEN] (TsDPEN = N-tosyl-
1,2-diphenylethane-1,2-diamine) as a chiral catalyst (Scheme
3). Indeed, treatment of epoxy ketone 15 with this rutheni-
um catalyst in CH2Cl2 provided the desired allylic alcohol
1615 in 81% yield with 20:1 diastereoselectivity. We ob-
served that the stereoselectivity of the reduction of the ep-
oxy ketone 15 was completely under the control of the cata-
lyst.
The alcohol 16 was subjected to a retro-Diels–Alder re-
action10 by heating the reaction mixture to 220 °C for two
hours in diphenyl ether as solvent, giving enone 17 in 84%
yield. The α,β-unsaturated ketone 17 was immediately sub-
jected to a Luche reduction in the presence of CeCl3·7H2O
and NaBH4 at –40 °C to give allylic alcohol 18 in 86% yield
and 9:1 diastereoselectivity.16 In this Luche reduction, hy-
dride ion addition was supposed to take place from the face
opposite the TBDPS group, due to steric hindrance. The re-
sulting secondary allylic alcohol groups in 18 were protect-
ed as acetate groups in 19 by treatment with Et3N, Ac2O,
and a catalytic amount of DMAP. During the desilylation of
The Nozaki–Hiyama–Kishi (NHK) coupling reaction is a
promising protocol for many synthetic strategies.22 Here,
we studied the NHK coupling23 of vinyl iodide 6 with 3-
O
OTBDPS
O
OTBDPS
O
O
OTBDPS
H
H
a
b
c
O
O
1
O
OH
OAc OH
OAc
OAc
17
16
15
OH OAc
OH OTBDPS
OAc OTBDPS
O
OAc
O
1'
4
4
e
f
d
1'
O
O
O
1
1
1
OAc OAc
OAc OH
18
OAc OAc
19
OAc OAc
20
21
Scheme 3 Reagents and conditions: (a) Ru(p-cymene)[(S,S)-TsDPEN], HCO2H, Et3N, CH2Cl2, 0 °C to r.t., 24 h, 81%; (b) Ph2O, 220 °C, 2 h, 84%; (c) CeCl3·7H2O,
NaBH4, –40 °C, 20 min, 86%; (d) Et3N, Ac2O, DMAP (cat.), CH2Cl2, 0 °C to r.t., 3 h, 93%; (e) TBAF, THF, 0 °C, 4 h, 84%; (f) IBX, EtOAc, 85 °C, 3 h, 92%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
R. N. Kumar et al.
Letter
Synlett
OH
OAc
OH
OH
a
b
+
22
22a
22b
geranol (8)
OR
I
c
22a
23: R = H
6: R = TBS
d
Scheme 4 Reagents and conditions: (a) IBX, EtOAc, 85 °C, 1 h, then HC≡CCH2MgBr (1 M), Et2O, –10 °C, 30 min, 85% (two steps); (b) Amano lipase PS,
vinyl acetate, 1:1 hexane–THF, 7 d, 46% of 22a, 45% of 22b; (c) Cp2ZrCl2, Me3Al, I2, CH2Cl2, 0 °C to r.t., 14 h, 86%; (d) TBSCl, imidazole, CH2Cl2, 0 °C to
r.t., 3 h, 93%.
phenylpropanal (24) (Scheme 5). Treating the vinyl iodide 6
and 3-phenylpropanal (24) with a large excess of chromi-
um(II) chloride (6 equiv) and a catalytic amount of nickel(II)
chloride (0.1 equiv) in dry DMF gave the coupled product
25 in 82% yield and with 65:35 diastereoselectivity. The
overall yield for the synthetic fragment 20 was 24.6%, and
that of the vinyl iodide fragment 6 was 31.3%.
Acknowledgment
R.N.K. thanks CSIR, New Delhi, for the award of a fellowship, and Dr.
Ahmed Kamal, Outstanding Scientist and Head of the MCP Division,
IICT, for his support and encouragement. The authors thank CSIR,
New Delhi, for financial support as part of the XII Five Year Plan pro-
gram under the title ORIGIN (CSC-0108).
Supporting Information
OTBS
I
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588950.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
OTBS
OH
6
References and Notes
a
Ph
+
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E