A catalytic asymmetric entry to enantioenriched tertiary naphthoquinols via a facile tandem oxidation/ring-opening sequence

Article abstract of DOI:10.1016/j.tetlet.2011.04.020

The tertiary naphthoquinol is a key structural component of the antitumor natural products spiroxins A-E. Herein we report the first catalytic asymmetric approach to the tertiary naphthoquinol C4′ stereogenic center present in the spiroxin framework, via

Full text of DOI:10.1016/j.tetlet.2011.04.020

Tetrahedron Letters 52 (2011) 3426–3428
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A catalytic asymmetric entry to enantioenriched tertiary naphthoquinols
via a facile tandem oxidation/ring-opening sequence
⇑
Alice Kwan, Johanna Stein, Dora Carrico-Moniz
Department of Chemistry, Wellesley College, Wellesley, MA 02481, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The tertiary naphthoquinol is a key structural component of the antitumor natural products spiroxins A–
E. Herein we report the first catalytic asymmetric approach to the tertiary naphthoquinol C40 stereogenic
center present in the spiroxin framework, via tandem oxidation/ring-opening of a cyclic 3,4-epoxyalco-
hol. This new route allows a facile entry into relatively inaccessible tertiary naphthoquinols with high
enantioselectivity and without the need of chiral auxiliaries.
Received 24 March 2011
Accepted 1 April 2011
Available online 13 April 2011
Keywords:
Naphthoquinols
Spiroxins
Ó 2011 Elsevier Ltd. All rights reserved.
The unique structural features of natural products bearing a bis-
naphthospiroketal structure together with their wide range of bio-
logical activities have resulted in significant interest from the
synthetic and medicinal chemistry communities.1 Spiroxins A–E
(Fig. 1) are structurally interesting members of the bisnaphthospi-
roketal family of natural products isolated by McDonald et al. in
1999 from the culture extract of a marine fungus.2 The major com-
ponent produced in culture, spiroxin A (1), has been shown to pos-
sess antibacterial activity against gram-positive bacteria and
promising antitumor activity against ovarian carcinoma (59% inhi-
bition after 21 days) in nude mice at 1 mg/kg dosing. Spiroxin A
O
OH
O
OH
O
OH
Cl
O
Cl
O
1
4
9
6
O
O
H
O
O
O
O
O
O
O
4'
1'
6'
9'
O
1'
1'
Cl
OH
O
OH
O
O
Spiroxin A (1)
2
Spiroxin C (3)
Spiroxin B ( )
also showed cytotoxicity with a mean IC50 value of 0.09
l
g/mL
OH
O
OH
HO
H
against a panel of 25 diverse cell lines. Preliminary experiments
indicated that the antitumor activity may arise from single-
stranded DNA cleavage, but its exact mechanism of action has
not been fully elucidated.2,3 The limited availability from natural
sources and the numerous synthetic challenges posed by spiroxin
A have impeded further biological studies.
The spiroxins have a unique octacyclic structure consisting of
two epoxides, five six-membered rings, and a single five-mem-
bered ring within a 20-carbon framework. To date, only two ap-
proaches towards the synthesis of the spiroxins have been
reported. Imanishi and co-workers4 reported the racemic total syn-
thesis of ( )-spiroxin C using a Suzuki–Miyaura cross-coupling
reaction as the key step, and Inoue and co-workers5 described
the racemic synthesis of the spiroxin framework using a novel
desymmetrization approach.
Cl
1
1
O
O
O
O
O
O
O
O
1'
1'
Cl
H
OH
Spiroxin E (5)
O
OH
Spiroxin D (4)
Figure 1. Spiroxins A–E.
to the asymmetric synthesis of (+)- and (ꢀ)-spiroxins A–E (1–5)
is controlling the absolute stereochemistry of the C40 quinol
carbon, since this stereogenic center likely dictates the facial selec-
tivity needed to install the epoxide stereogenic centers at C2, C20,
C3, and C30.4 Furthermore, several other natural products and
pharmaceutically relevant compounds contain the benzoquinol
or naphthoquinol moiety or other closely related structural motifs
that can be easily accessed from substituted quinols.6 Despite this,
One of the most notable structural features in the spiroxins is
the C40 tertiary naphthoquinol stereogenic center (Fig. 1). Critical
⇑
Corresponding author. Tel.: +1 781 283 2970; fax: +1 781 283 3642.
E-mail address: dcarrico@wellesley.edu (D. Carrico-Moniz).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.020

A. Kwan et al. / Tetrahedron Letters 52 (2011) 3426–3428
3427
few methods exist for the asymmetric preparation of tertiary qui-
O
Zn
Valproic Acid
nols from achiral precursors. Most syntheses utilize resolution/
separation protocols7 or introduce the quinol moiety late in the
synthesis via phenolic oxidation in a diastereoselective fashion.8
Wipf has reported an auxiliary-based synthesis of chiral tertiary
quinols, but this method affords only moderate selectivity with
sp2 nucleophiles.9
Pd[(R)-binap]Cl2
88% Yield
OH
(S)-10
90% ee (95:5 er)
9
Herein we report a novel catalytic, asymmetric approach to chi-
ral tertiary quinols via a tandem oxidation/ring-opening sequence.
To the best of our knowledge, these studies represent the first cat-
alytic asymmetric entry to chiral tertiary naphthoquinols and cir-
cumvent the limitations of the few existing methods by
eliminating the need for a chiral auxiliary. Significantly, this ap-
proach should be amenable to the synthesis of a number of other
substituted tertiary chiral quinols.
Br
Sn
1) TBDPS-Cl, 76% Yield
12
2) Br2, Et3N
3) DBU, 71% Yield, 2 steps
(MeCN)2PdCl2
AsPh3
OTBDPS
57% Yield
(S)-11
As shown in Figure 2, we envisioned an enantioselective route
to chiral quinols where either tertiary naphthoquinol enantiomer
(R)- or (S)-6 could be easily obtained from its corresponding enan-
tiomeric epoxyalcohol (R)- or (S)-7 by alcohol oxidation and epox-
ide ring-opening. This could occur either stepwise or in a single
chemical operation. The epoxides (R)- or (S)-7 could in turn be pre-
pared by a directed epoxidation of either corresponding enantio-
meric homoallylic alcohol (R)- or (S)-8, which would be derived
from a common oxabicycle 9.
TBAF
mCPBA
85% Yield
OTBDPS
OH
(S)-13
(S)-14
In order to test the feasibility of this approach, we elected to
prepare the tertiary naphthoquinol (S)-16 by using the (S)-enantio-
mer of the homoallylic alcohol 10 (Scheme 1). In the forward sense,
the homoallylic alcohol (S)-10 was prepared by a stereoselective
reductive ring-opening of cyclic ether 9 using Pd[(R)-binap]Cl2,
zinc and valproic acid in 88% yield and 90% ee (95:5 er).10 Impor-
tantly, this procedure allows for the enantioselective synthesis of
either enantiomer from the single precursor 9 simply by switching
the enantiomer of the ligand. (Treatment of commercially available
cyclic ether 9 with Pd[(S)-binap]Cl2 or Pd[(R)-binap]Cl2, zinc and
valproic acid allows access to either enantiomeric homoallylic
alcohol (R)- or (S)-10, respectively.)
The protection of homoallylic alcohol (S)-10 was accomplished
using tert-butyl diphenylsilyl chloride and imidazole to generate
the TBDPS-protected (S)-10 silyl ether intermediate in 76% yield.
The vinyl bromide derivative (S)-11 was obtained by a bromina-
tion/elimination sequence11 in 71% yield. Coupling of vinyl bro-
mide (S)-11 was accomplished via Stille cross coupling12 with
trimethyl(phenyl)stannane (12), to successfully afford the desired
vinylarene (S)-13 in 57% isolated yield. Similar results were ob-
tained using Suzuki coupling conditions13 with phenylboronic acid
and Pd(PPh3)4, though the reaction did not always proceed consis-
tently. Intermediate (S)-13 was deprotected using tetrabutylam-
O
OH
(COCl)2, DMSO
DIPEA
76% from (S)-14
O
OH
83% ee (91.5:8.5 er)
(S)-15
(S)-16
Scheme 1. Synthesis of enantioenriched tertiary naphthoquinol (S)-16.
monium fluoride to give the alcohol (S)-14 in 85% isolated yield.
While successful preparation of the epoxyalcohol (S)-15 by a direc-
ted m-CPBA epoxidation14 of (S)-14 was easily confirmed by NMR
analysis, all attempts to isolate (S)-15 by flash column chromatog-
raphy resulted in decomposition. Consequently, a directed m-CPBA
epoxidation of (S)-14 followed by an oxidation/ring-opening of the
resulting intermediate epoxyalcohol (S)-15 under Swern condi-
tions15 without purification of the intermediate epoxide was inves-
tigated. To our satisfaction, this reaction sequence readily afforded
the desired chiral tertiary naphthoquinol (S)-16 in 76% isolated
yield from (S)-14 and 83% ee (91.5:8.5 er).16
R
R
R
OH
O
OH
(R)-8
O
OH
(R)-7
O
(R)-6
R
R
9
R
OH
O
OH
O
OH
(S)-8
(S)-7
(S)-6
Figure 2. Tandem oxidation/ring-opening sequence to prepare enantiomerically enriched tertiary naphthoquinols (R)- or (S)-6.

3428
A. Kwan et al. / Tetrahedron Letters 52 (2011) 3426–3428
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rected epoxidation followed by a tandem oxidation/ring-opening
sequence. Reaction conditions using the homoallylic alcohol
(S)-10 were developed resulting in the formation of the desired ter-
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enantioselectivity. The facile formation of (S)-16 demonstrates
the feasibility of the sequence as a novel route to the tertiary naph-
thoquinol stereogenic center present in the spiroxins (Fig. 1) and
their congeners. Further studies to probe the generality of the
tandem oxidation/ring-opening sequence, as well as application
of this approach towards the synthesis of the spiroxin A–E
framework, are ongoing and will be reported in due course.
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Acknowledgment
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We would like to acknowledge the Donors of the American
Chemical Society Petroleum Research Fund, for support of this
research.
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.020.
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