A simple desymmetrization approach to the spiroxin framework

Article abstract of DOI:10.3987/COM-08-S(N)70

The highly strained hexacyclic framework of spiroxins, a family of 1,8-dihydroxynaphthalene-derived natural products, was efficiently constructed in ten steps from commercially available naphthalene- 1,5-diol using a symmetry-based strategy. Key reactions in this synthesis are biaryl homocoupling, oxidative desymmetrization of a C₂-symmetric intermediate, selective oxidation of the naphthalene portion, and oxidative cyclization.

Full text of DOI:10.3987/COM-08-S(N)70

HETEROCYCLES, Vol. 76, No. 2, 2008
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HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1011 - 1016. © The Japan Institute of Heterocyclic Chemistry
Received, 29th March, 2008, Accepted, 13th May, 2008, Published online, 19th May, 2008. COM-08-S(N)70
A SIMPLE DESYMMETRIZATION APPROACH TO THE SPIROXIN
FRAMEWORK
1
1
2,
Kazuyuki Nabatame, Masahiro Hirama, and Masayuki Inoue *
1
Department of Chemistry, Graduate School of Science, Tohoku University,
2
Sendai 980-8578, Japan, and Graduate School of Pharmaceutical Sciences, The
University of Tokyo, 7-3-1 Hongo, Tokyo, Japan. inoue@mol.f.u-tokyo.ac.jp
Dedicated to Professor Ryoji Noyori on the occasion of his 70th birthday.
Abstract – The highly strained hexacyclic framework of spiroxins, a family of
1
,8-dihydroxynaphthalene-derived natural products, was efficiently constructed
in ten steps from commercially available naphthalene-1,5-diol using a
symmetry-based strategy. Key reactions in this synthesis are biaryl
homocoupling, oxidative desymmetrization of a C -symmetric intermediate,
selective oxidation of the naphthalene portion, and oxidative cyclization.
2
In 1999, spiroxins A-C were isolated by McDonald and co-workers from fungal strain LL-37H248, which
1
was found in a soft orange coral collected from the waters of Vancouver Island, Canada (Scheme 1).
Their unique structures were elucidated by NMR spectroscopy and the absolute configuration of spiroxin
A was determined by exiton-coupled CD. Spiroxin A showed modest activity against Gram-positive
bacteria, potent cytotoxicity against a panel of 25 diverse cell lines, and antitumor activity against ovarian
carcinoma in nude mice. Although the single-strand DNA cleavage by spiroxin A was demonstrated,
the detailed mechanism of action has not yet been elucidated.
Structurally, the two partially saturated naphthalene rings of the spiroxins are joined together by the
2
C6-C4’ bond and the C4-spiroketal linkage, and are further elaborated by two epoxides. This highly
oxygenated and strained hexacyclic fused-ring system with six stereogenic centers is a daunting challenge
for chemical construction. In this communication, we report the concise synthesis of the entire spiroxin
3
framework (1) by utilizing a newly developed desymmetrization strategy.
To establish a general route to spiroxins A-C, we focused our attention on the common hexacyclic
skeleton 1. Further functional group manipulation has the potential to lead to all spiroxins (Scheme 1).

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HETEROCYCLES, Vol. 76, No. 2, 2008
Retrosynthetically, 1 would be prepared from pentacyclic compound 2 through C-H bond
functionalization at C1, followed by oxidative cyclization of C6’-OH to C4. Compound 2 would in turn
4
be generated from oxidative desymmetrization of C
2
-symmetric binaphthyltetraol 3. It was anticipated
that both the C4’- and C4-asymmetric stereocenters of 1 could be controlled by the intrinsic
conformational bias of the precursors upon the two oxidative reactions. The rotationally fixed C6-C4’
5
bond of 3 would only allow attachment of C4-OH on C4’ from the α-face, and the resulting rigid
five-membered ether (see 2) would force the addition of C6’-OH to C4 from the β-face. Importantly,
the key symmetric intermediate 3 was to be simply prepared by dimerization of the naphthalene
substructure. In order to prove the feasibility of this symmetry-based procedure, we first synthesized 1
as a racemate.
oxidative
cyclization
C-H bond functionalization
O
O
O
1
OH
1
O
OH
9
O
OH
O
OH
OH
dimerization
1
4
Cl
4
4
HO
6'
6
4
O
6'
O
O
HO
6'
O
6
O
O
O
6
4'
OH
6'
4'
OMe
4'
4'
oxidative
cyclization
O
1'
X
9
'
OH
3 (C -symmetry)
OH
O
O
O
O
spiroxin A (X = H)
spiroxin B (X = Cl)
spiroxin C
1
2
2
Scheme 1. Retrosynthesis of spiroxins
The five-step preparation of racemic 3 was realized from commercially available naphthalene-1,5-diol
(
Scheme 2). Diol 4 was first converted to methyl ether 5, which was selectively mono-brominated with
6
1
.1 equivalent of N-bromosuccinimide, providing 6. A number of attempts for homocoupling of 6 (e.g.,
7
using the Ullmann reaction ) were unsuccessful, likely due to the steric shield of the reacting C6/C4’ by
the C4/C6’-methoxy group. Thus, the bromide of 6 was converted into the more reactive trimethyltin.
Namely, lithium-bromine exchange of 6 with n-butyllithium, followed by addition of Me SnCl, furnished
3
8
arylstannane 7. According to the general method of Piers, treatment of 7 in dry DMF with copper (I)
chloride resulted in clean formation of the coupling adduct 8 in 67% yield. This experimentally simple,
yet powerful, procedure enabled the routine preparation of 8 on a gram scale. Demethylation of 8 using
9
BBr
3
smoothly afforded tetraol 3 in high yield, whereas treatment of 8 with iodotrimethylsilane led to
decomposition.
Direct oxidative conversion from tetraol 3 to diol 2 was realized with no protecting groups. After
careful tuning of the reaction conditions, it was found that one equivalent of diacetoxyiodobenzene in

HETEROCYCLES, Vol. 76, No. 2, 2008
1013
1
0,11,12
acetonitrile effected the cyclization to yield the desymmetrized pentacycle 2.
phenolic groups of 2 were acetylated to afford 9 in 40% yield over three steps.
Finally, the two
n-BuLi (1.7 eq), THF, -78 ºC;
OH
OMe
OMe
MeI, K CO , acetone
reflux
then Me SnCl (1.7 eq)
2
3
3
-78 ºC to rt
73%
96%
4
/6'
6/4'
6/4'
OH
MeO
SnMe3
MeO
X
4
7
NBS (1.1 eq), CCl4
reflux, 96%
5: X = H
CuCl (2.5 eq), DMF
ºC to rt, 67%
6
: X = Br
0
OH
9
OMe
OR
9
PhI(OAc) (1 eq), MeCN
BBr (10 eq), CH Cl
2
3
2
2
4
0 ºC to rt
-78 ºC to rt
HO
MeO
6
4
RO
O
6
'
4'
4'
6'
4'
OH
OMe
1'
1
'
OH
3
MeO
(±)-8
O
2
: R = H
Ac O, Et N, CH Cl
2 3 2 2
4
0% (3 steps)
9
: R = Ac
2
Scheme 2. Oxidative desymmetrization of C -symmetric intermediate
Having realized desymmetrization of the two naphthalene moieties, the next task was to raise the
1
3
oxidation level of both C1 and C4 (Scheme 3). Interestingly, lead (IV) tetraacetate selectively
functionalized C1 of the more electron-rich upper naphthalene ring in the presence of numerous other
potentially reactive sites, resulting in the formation of 10 in 54% yield. Deacetylation of tris-acetoxy
compound 10, however, was no easy task, because of the chemical instability of the phenol product.
Triol 11 was prone to oxidation under basic conditions. For instance, when 10 was subjected to
potassium carbonate in methanol (entry 1), only decomposition of the substrate was observed. Less
basic conditions using bicarbonate salt were found to be effective for this particular reaction (entries 2-4),
with potassium bicarbonate giving the highest yield. Treatment of 10 with the 1:2 mixture of saturated
3
aqueous KHCO and methanol at room temperature afforded 11 with the concomitant 1,4-addition of
methanol at C3’ (39% yield, entry 3). Finally, oxidative cyclization of triol 11 to phenol 1 was achieved
1
1
using one equivalent of diacetoxyiodobenzene in trifluoroethanol, delivering the highly strained
skeleton 1 of the spiroxins in 50% yield.
In summary, we accomplished construction of the entire hexacyclic spiroxin framework in only ten steps
from naphthalene-1,5-diol. The key reactions in this synthesis were (1) the copper (I) chloride-mediated
2
oxidative biaryl coupling (7 → 8), (2) the oxidative desymmetrization of the C -symmetric intermediate

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HETEROCYCLES, Vol. 76, No. 2, 2008
(
3 → 2), (3) the site-selective acetoxylation (9 → 10), and (4) the oxidative cyclization to the highly
strained hexacycle (11 → 1).
H
1
OAc
1
OH
1
OAc
OAc
OH
9
9
9
Pb(OAc) (2 eq)
4
4
4
4
AcOH/CH Cl =2/1
conditions
2
2
AcO
AcO
HO
O
O
O
6
'
6'
6'
OMe
5
4%
3'
3'
O
9
O
10
O
11
O
1
entry
conditions
yield (%)
OH
PhI(OAc) (1 eq)
9
2
CF CH OH, rt
4
3
2
1
2
3
4
K CO (cat), MeOH, rt
0
2
3
O
O
6
'
5
0%
OMe
sat.aq. NaHCO
/MeOH=1/2, rt 28
3
sat. aq. KHCO /MeOH=1/2, rt 39
3
sat. aq. CsHCO /MeOH=1/2, rt 31
3
(±)-1
O
Scheme 3. Synthesis of the spiroxin framework
ACKNOWLEDGEMENTS
This paper is dedicated to the memory of Dr. Kazuyuki Nabatame (September 13, 1976 - April 9, 2006).
This work was supported financially by SORST, Japan Science and Technology Agency (JST).
REFERENCES AND NOTES
1
.
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HETEROCYCLES, Vol. 76, No. 2, 2008
1015
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2
5
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1
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2
1
1
(
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2
002, 67, 2735.
14. Physical data of (±)-1: FT-IR (film) ν 3342, 2932, 1693, 1663, 1581, 1478, 1276, 1174, 1088, 1007,
-1 1
9
53, 800, 735 cm ; H NMR (500 MHz, CDCl ) δ 7.58 (1H, d, J=10.5 Hz, H2), 7.45 (1H, d, J=7.5
3
Hz, H9’), 7.39 (1H, t, J=7.5 Hz, H8’), 6.97 (1H, d, J=9.5 Hz, H7), 6.96 (1H, d, J=7.5 Hz, H7’), 6.94

1016
HETEROCYCLES, Vol. 76, No. 2, 2008
(1H, d, J=9.5 Hz, H8), 6.60 (1H, d, J=10.5 Hz, H3), 4.62 (1H, dd, J=3.0, 2.5 Hz, H3’), 3.91 (3H, s,
1
3
Me), 3.39 (1H, dd, J=18.5, 3.0 Hz, H2’), 3.01 (1H, dd, J=18.5, 2.5 Hz, H2’); C NMR (125 MHz,
CDCl
3
) δ 192.9, 184.1, 158.2, 155.6, 147.9, 135.7, 135.6, 132.7, 131.4, 130.6, 125.2, 124.3, 120.0,
+
1
18.0, 116.5, 115.7, 84.6, 76.0, 75.5, 56.7, 40.1; HRMS (EI) calcd for C H O (M ) 362.0790,
2
1
14
6
found 362.0788.