Synthesis of the cis-fused hexahydroxanthene system via cationic cascade cyclization

Article abstract of DOI:10.1016/j.tetlet.2009.04.052

The cis-fused hexahydroxanthene system can be obtained through a cascade cyclization initiated by Lewis acid-mediated epoxide opening and terminated by reaction with a MOM-protected phenol. Only a single diastereomer of the product was obtained with stere

Full text of DOI:10.1016/j.tetlet.2009.04.052

Tetrahedron Letters 50 (2009) 3881–3884
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Tetrahedron Letters
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Synthesis of the cis-fused hexahydroxanthene system via cationic
cascade cyclization
*
Jeffrey D. Neighbors, Joseph J. Topczewski, Dale C. Swenson, David F. Wiemer
Department of Chemistry, The University of Iowa, Iowa City, IA 52242-1294, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The cis-fused hexahydroxanthene system can be obtained through a cascade cyclization initiated by
Lewis acid-mediated epoxide opening and terminated by reaction with a MOM-protected phenol. Only
a single diastereomer of the product was obtained with stereochemistry verified by diffraction analysis.
This demonstrates the viability of this approach to natural products containing the cis-fused hexahydrox-
anthene skeleton, and supports preparation of more complex targets through a similar strategy.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 13 March 2009
Revised 13 April 2009
Accepted 14 April 2009
Available online 18 April 2009
The trans-fused hexahydroxanthene skeleton has been found in
natural products isolated from several terrestrial plants, including
seven of the eight known schweinfurthins (e.g., schweinfurthin F,
1, Fig. 1)1,2 and vedelianin.3 Still other examples have been found
in marine sources, including tribromocacoxanthene,4 puupehendi-
ol,5 and taondiol.6 In contrast, the isomeric cis-fused system is still
very rare, but known examples include cymobarbatol (2) isolated
from a marine source7 and ugonstilbene B (3) isolated from a tra-
ditional Chinese medicine.8 The cis-fused hexahydroxanthene can
also be found as a subunit in several larger terpenoids, including
kampanol A (4), which is a novel inhibitor of farnesyl:protein
transferase.9 Our interest in inhibitors of this enzyme,10,11 as well
as past work on preparation of the trans-fused schweinfurthins
and varied analogues,11 led to an exploration of a new route to
cis-fused hexahydroxanthenes that ultimately might be applied
to preparation of more complex terpenoids.12,13
From a biosynthetic perspective, formation of the trans-fused
systems can be envisioned through cyclization of a cationic inter-
mediate generated by addition of an electrophile to the distal olefin
of a geranyl arene, or via opening of a terminal epoxide to a parallel
cation. In a similar sense, addition of an electrophile could initiate a
cationic cascade leading to the cis-fused natural products if Br+ (for
cymobarbatol) or H+ (for ugonstilbene B) were added to the termi-
nal olefin of a neryl system (i.e., a 2Z-olefin). Biomimetic syntheses
leading from E-olefins to trans-fused hexahydroxanthenes have
been reported,14–16 but there is little information on the synthesis
of these cis-fused natural products. During the course of their ele-
gant studies on Lewis acid-assisted chiral Bronsted acids,17,18
Yamamoto and co-workers have shown that achiral nerylphenol
cyclizes in modest yield and low ee when treated with a nonrace-
mic catalyst, but does give only the cis-fused skeleton. In contrast,
they found that cyclization of geranylphenol under similar condi-
tions gave mixtures containing predominantly the trans- but also
the cis-fused product. Because their studies employed achiral
starting materials and thus gave hexahydroxanthenes with stereo-
chemistry only at the two bridgehead positions, their findings may
not extend to cyclization of nonracemic systems that include an
initial stereocenter, or predict the relationship between the bridge-
head positions and the A-ring substituent resulting from such a
cyclization.
Recently we reported an efficient synthesis of schweinfurthin F
(1) through a cascade cyclization initiated by BF3ÁOEt2-promoted
ring opening of geranyl epoxide and terminated through a novel
reaction with a phenolic oxygen ‘protected’ as its MOM ether.16
Based on these studies, we hypothesized that starting with an aryl
epoxide containing the 2Z-olefin geometry (e.g., 5, Fig. 2) would re-
sult in a cis ring fusion through the cascade process via one of two
reasonable transition states, affording either hexahydroxanthene 6
or 7. To determine the viability of this approach, as well as the ste-
reochemistry of any product and the stereointegrity of the reaction
OCH3
O
Br
O
9a
OH
Br
OH
HO
H
H
1 Schweinfurthin F
2 Cymobarbatol
OH
O
OH
HO
H
O
O
O
H
OH
AcO
4 Kampanol A
3 Ugonstilbene B
H
* Corresponding author. Tel.: +1 319 335 1365; fax: +1 319 335 1270.
E-mail address: david-wiemer@uiowa.edu (D.F. Wiemer).
Figure 1. Natural hexahydroxanthenes.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.052

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J. D. Neighbors et al. / Tetrahedron Letters 50 (2009) 3881–3884
OCH3
gle enantiomer. To this end, aryl bromide 14 was subjected to hal-
HO
ogen metal exchange conditions and treated with neryl bromide to
afford arene 16. Unlike the reaction of compound 14 with bromide
13, the latter reaction gave the desired alkylated arene 16 without
use of TMEDA or transmetalation to an organocopper intermediate.
Subjection of arene 16 to asymmetric dihydroxylation conditions
OTBS
O
5
with AD-mix-a generated the enantioenriched diol 17. Esterifica-
tion of diol 17 with (S)-O-methylmandelic acid followed by chro-
matographic resolution of the resulting diastereomeric esters
(18) led to isolation of the individual esters as enantiopure materi-
als. Saponification of the major diastereomer followed by forma-
tion of the secondary mesylate and base-promoted epoxidation
gave aryl epoxide 15 as a single enantiomer. This independent
synthesis allowed confirmation of the assignment of the absolute
configuration of epoxide 15 through a Mosher–Trost analysis,25,26
as well as verification of the enantiomeric excess of the Shi
epoxidation.
OCH3
OCH3
O
O
OTBS
OTBS
HO
HO
H
H
6
7
(2R, 4aR, 9aS-xanthene)
(2R, 4aS, 9aR-xanthene)
Figure 2. Possible cyclizations of a neryl arene.
process, we prepared an appropriate substrate containing a Z-ole-
fin and attempted cyclization.
With epoxide 15 in hand as a single enantiomer, attention was
turned to the cationic cascade cyclization. After experimentation
with different protic and Lewis acids, it was found that treatment
of epoxide 15 with the mild Lewis acid In(OTf)3 resulted in opening
of the epoxide but only afforded the allylic alcohol 19 and ketone
20. Other acids gave larger amounts of polymer and lower amounts
of monomeric products. Finally, treatment of compound 15 with
BF3ÁOEt2 at À78 °C gave the tricyclic alcohol 7 (Scheme 2) as a sin-
gle diastereomer along with a considerable amount of polymeric
material. The cis-fused nature of the ring system initially was as-
signed based on comparison of the 1H NMR data of this compound
with that for the corresponding trans-fused isomer9,14 as well as
literature data for cymobarbatol (2) and the trans-fused isocymo-
barbatol.7 The most notable difference was seen in the spin system
encompassing the benzylic hydrogens at C-9 and the bridgehead
hydrogen at C-9a. In the cis-fused compounds the C-9 hydrogens
are well resolved and the large geminal coupling constant
(18 Hz) can be easily recognized, whereas in the trans-fused sys-
tems the C-9 hydrogens are not resolved and appear as a complex
multiplet. The patterns for the methyl resonances are also clearly
different for the cis- and trans-fused compounds.
The epoxy olefin 15 was chosen as the target compound for this
investigation, to parallel extensive studies on cyclization of the iso-
meric trans olefin.14–16 Preparation of compound 15 began with
the synthesis of (R)-6,7-epoxyneryl bromide (13, Scheme 1). To this
end derivatization of nerol (8) through reaction with p-nitro-
benzoyl chloride (pNO2BzCl) gave ester 919 and a subsequent Shi
epoxidation20 using the sugar-derived catalyst 1021 afforded epox-
ide 11.22 Use of the p-nitrobenzoyl ester increased the yield and
stereoselectivity of the epoxidation over other potential protect-
ing/directing groups. Saponification of ester 11 afforded (R)-6,7-
epoxynerol (12) which was then converted to the desired allylic
bromide 13 via the mesylate. Immediate coupling of this allylic
bromide with the presumed cuprate23 formed from known aryl
bromide 1416 afforded the desired cyclization precursor, aryl epox-
ide 15, in moderate yield.
The stereochemistry (6R) and ee (92%) of alcohol 12 were deter-
mined by comparison to the known optical rotation,24 and later
verified by HPLC analysis of a subsequent intermediate. It was as-
sumed that the epoxide stereochemistry would be preserved
through the copper-mediated nucleophilic substitution to give
the aryl epoxide 15.16,23 This degree of enantiomeric purity is
acceptable, but it appeared prudent to explore an alternative route
to epoxide 15 that would afford this crucial intermediate as a sin-
While analysis of the 1H NMR data provided good evidence for a
cis-fused product, and supported one where the –OH group was cis
to the bridgehead methyl group, the exact diastereomer was
unproven. In the case of cymobarbatol (2) the natural product dis-
O
O
O
10
O
O
OCH3
O
H2O2
aq. buffer, CH3CN
- 20 ºC, 72 hr
TMEDA, n-BuLi, -78 ºC
MOMO
CuBr·DMS
O
14
65%
O
63%
OTBS
X
X
(based on 12)
CH3ONa
15
8 X = OH
11 X = pNO2Bz
pNO2BzCl
pyr, 95%
(n-Bu)4NI, 81%
9 X = pNO2Bz
12 X = OH
1) MsCl, TEA
2) LiBr
13 X = Br
1) MsCl, TEA
2) K2CO3
72%
AD-mix-α
t-BuOH/H2O
rt, 17.5 hr
OCH3
OCH3
OCH3
n-BuLi
MOMO
Br
MOMO
MOMO
neryl bromide
71%
THF, - 40 ºC, 2 hr
67%
OR
OTBS
OTBS
HO
OTBS
16
14
DMAP, EDC, RCO2H
rt, 2 hr, CH2Cl2
71%
17 R = H
18 R = S-O-methylmandalate
NaOH, EtOH
82%
Scheme 1. Syntheses of the neryl arene 15.

J. D. Neighbors et al. / Tetrahedron Letters 50 (2009) 3881–3884
3883
OCH3
OCH3
MOMO
O
OCH3
HO
R
HO
O
In(OTf)3
H
MOMO
OTBS
-30 ºC
·
21 R = CH2OH
22 R = CHO
MnO2
100%
19 (48%)
OCH3
O
MOMO
OTBS
P(O)(OEt)2
15
NaH, 15-Crown-5
THF, 17 hr
80%
OMOM
OTBS
BF3·OEt2
OMOM
OR
21%
OCH3
20 (27%)
23
-78 ºC
·
OCH3
O
O
9
9a
HO
HO
H
H
OR
TBAF, 71%
7
R = TBS
21 R = H
OR
24 R = MOM
25 R = H
TsOH
95%
Scheme 2. Lewis acid-catalyzed reactions of epoxide 15.
Scheme 3. Synthesis of schweinfurthin analogue 25.
plays a trans relationship between the A-ring bromide and the
bridgehead methyl group, and that structure was secured by a sin-
gle crystal diffraction analysis.7 To address any potential ambigu-
ity, compound 7 was treated with TBAF to afford the benzylic
alcohol 21 (Scheme 2) and, when this compound proved to be crys-
talline, a single crystal diffraction analysis was conducted. This
information, together with the known configuration of the starting
epoxide 15, established the absolute stereochemistry as 2R, 4aR,
and 9aS. The crystal structure (Fig. 3) also identified that an orthog-
onal orientation of the A-ring relative to the rest of the ring system
places the axial methyl group of the geminal pair in the shielding
region of the aromatic group.
Once the absolute stereochemistry of diol 21 was established,
the material was used to prepare a new schweinfurthin analogue
(Scheme 3). Treatment with manganese dioxide afforded aldehyde
22 which was coupled to the known phosphonate 23 in high yield
to give stilbene 24. Removal of the methoxymethyl acetals upon
treatment of stilbene 24 with p-toluenesulfonic acid gave the de-
sired 9a-epi-3-deoxyschweinfurthin B (25).14 While this isomer
did not show significant bioactivity in preliminary assays, it may
be useful as a standard during further investigations of Macaranga
species.
mation, and longer reaction time would appear to indicate that the
transition state leading to the cis system is harder to attain than
that leading from the geranyl analogue to the trans-fused hexahy-
droxanthene. Nevertheless, because they have demonstrated the
viability of Z-olefin cyclizations to MOM-protected phenols, these
findings encourage studies that would employ still larger isopre-
noids to access systems that contain cis-fused rings such as the
kampanols9 and memnobotrins.27
Acknowledgments
Financial support in the form of a Shriner Fellowship (to J.J.T.)
and from the Roy J. Carver Charitable Trust is gratefully
acknowledged.
Supplementary data
Supplementary data (experimental procedures and/or spectral
data for compounds 9, 11–13, 15–18, and 21, 22, 24, and 25 are
available) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.04.052.
In conclusion, these studies have shown that cyclization of the
neryl derivative 15 takes place upon treatment of this epoxide with
BF3ÁOEt2 to afford the cis-fused hexahydroxanthene 7, and thus
they extend the scope of cascade cyclizations terminated by reac-
tion with a MOM acetal. The modest yield, increased polymer for-
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