Concise synthesis of the xenibellols core

Article abstract of DOI:10.1016/j.tetlet.2009.08.131

We describe herein a concise synthesis of an intermediate, via 2,3-Wittig rearrangement and Williamson etherification, en route to the natural products, xenibellols A and B.

Full text of DOI:10.1016/j.tetlet.2009.08.131

Tetrahedron Letters 50 (2009) 6440–6441
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise synthesis of the xenibellols core
Woo Han Kim a, Angie R. Angeles a, Jun Hee Lee b, Samuel J. Danishefsky a,b,
*
a Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
b Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein a concise synthesis of an intermediate, via 2,3-Wittig rearrangement and Williamson
etherification, en route to the natural products, xenibellols A and B.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 22 August 2009
Accepted 24 August 2009
Available online 12 September 2009
In 2005, Duh and co-workers reported the isolation of two novel
diterpenoids, xenibellols A (1) and B (2) from the Formosan soft
coral Xenia umbellata of Green Island, Taiwan1 (Fig. 1). These natu-
ral products were found to exhibit cytotoxicity against P-388 cell
undergo 2,3-Wittig rearrangement to afford 6, possessing the qua-
ternary bridgehead carbon. We expected that 6 could be converted
to the target compound, 7, through a short sequence featuring a
Williamson etherification.
with ED50 levels of 3.6 (1) and 2.8
l
g/mL (2). In the same year,
The synthesis of proposed intermediate 5 commenced with
selective LiAl(O-tBu)3H-mediated reduction of the Hajos–Parrish
ketone (3). Silyl protection of the resultant secondary alcohol fur-
Xenibellol A (1) was separately isolated from Xenia florida samples
collected in Taiwan by Shen et al., who assigned it the name xenio-
lactone A (1).2 The researchers found 1 to exhibit mild cytotoxicity
against human colon adenocarcinoma (WiDr) and medullocarcino-
nished the a
,b-unsaturated ketone 8 in good yield and selectivity.6
Elongation of the carbon chain was accomplished through the
treatment of 8 with methyl magnesium carbonate,6 and the global
reduction of the corresponding keto-acid with LAH provided the
desired diol, 9. Following protection of the primary alcohol, the
2,3-Wittig rearrangement precursor 5 was obtained through reac-
tion of the secondary alcohol, 10, with nBu3SnCH2I (Scheme 2).7
ma (Daoy) tumor cells at 13.6 and 15.3 lg/mL, respectively. The
key structural features of the xenibellols include an unusual oxo-
lane linkage between C8 and C11 in the context of a bicy-
clo[4.3.0]nonane skeleton, in conjunction with a conjugated (E,E)-
dienol moiety. The dialdehyde motif of xenibellol B (2) has been
suggested as the precursor to the lactone ring of xenibellol A (1).
The gross structure of the xenibellols was elucidated by the analy-
sis of one- and two-dimensional NMR spectroscopy, including
COSY, HMQC, and HMBC experimentation. The assignments of
the relative stereochemical relationships of 1 and 2 rest on a com-
bination of NOESY correlations and comparison of their spectro-
scopic data to those of the xenia diterpenes. The absolute
stereochemistries of the xenibellols have not yet been established.
We sought to undertake a program directed toward the synthe-
sis of the xenibellols primarily due to their interesting structural
features. We report herein a concise synthesis of the common xeni-
bellol core, 7.
OH
Me
OH
Me
Me
Me
O
O
Me8
Me8
11
O
11
O
O
O
xenibellol A (1)
(xeniolactone A)
xenibellol B (2)
Figure 1. Xenibellols A and B.
O
OTBS
OTBS
Me
Me
Me
Using the logic of pattern recognition3 to guide retrosynthetic
analysis,4 one could discern a cis-fused hydrindane matrix, with
the caveat that the bridgehead is further engaged in a tetrahydro-
furan motif. The pattern analysis soon leads one back to the
Hajos–Parrish ketone (3),5 with its rich and informing history.
For the case at hand, we envisioned, as outlined in Scheme 1, that
key intermediate 5 could be derived from the Hajos–Parrish
ketone.5 Under appropriate conditions, it was hoped that 5 would
2,3-Wittig
rearrangement
O
O
O
Hajos-Parrish
ketone (3)
CO2H
Bu3Sn
OMOM
4
5
OTBS
Me
O
Me
Williamson
etherification
xenibellols A (1)
and B (2)
OH
MOMO
6
HO
7
* Corresponding author.
E-mail address: s-danishefsky@ski.mskcc.org (S.J. Danishefsky).
Scheme 1. Synthetic strategy toward 7.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.131

W. H. Kim et al. / Tetrahedron Letters 50 (2009) 6440–6441
6441
OTBS
primary alcohol 6 with p-TsCl in pyridine at room temperature
afforded tosylate 11. The TBS group was removed with TBAF, and
the resulting secondary alcohol was treated with KH in the pres-
ence of 18-crown-6-ether to furnish the desired oxolane derivative
12. Finally, we explored deprotection of the MOM group to com-
plete construction of the xenibellols core, 7. Interestingly, the
allylic alcohol formed under conventional acidic conditions was
found to open the oxolane moiety to produce the secondary alco-
hol 13 in 96% yield. We note that this tricyclic compound, 13, con-
stitutes the core of another structurally related natural product,
umbellactal (14).9 After conducting careful studies on the depro-
tection of the MOM group, we found Kim’s protocol10 to be opti-
mal, successfully providing the desired xenibellol core, 7, in 95%
yield.
In summary, a concise, though not yet high yielding approach to
the construction of the core structure of xenibellols A (1) and B (2)
has been developed. The heterotricyclic skeleton of the bicy-
clo[4.3.0]nonane system was constructed efficiently, with 2,3-Wit-
tig rearrangement and classical Williamson etherification serving
as the key transformations. Efforts to complete the total syntheses
of xenibellols A (1) and B (2) continue beyond these milestones.
O
OTBS
Me
Me
Me
a,b
c,d
HO
O
O
Hajos-Parrish
8
9
OH
ketone (3)
OTBS
OTBS
Me
Me
e
f
HO
O
OMOM
OMOM
Bu3Sn
10
5
Scheme 2. Synthesis of the 2,3-Wittig rearrangement precursor 5. Reagents and
conditions: (a) LiAl(O-tBu)3H, THF, 0 °C, 40 min; (b) TBSCl, imidazole, DMF, rt, 12 h,
70% for two steps; (c) magnesium methyl carbonate, DMF, 125 °C, 2 h, 71%; (d) LAH,
THF, À78 °C to rt, 4 h, 66% (dr = 7.5:1); (e) MOMCl, Hünig’s base, DCM, À78 °C to
0 °C, 12 h, 83%; and (f) KH, THF, 0 °C, 10 min; then nBu3SnCH2I, rt, 3 h, 71%.
OTBS
OTBS
OTBS
Me
Me
Me
a
b
O
OTs
OH
MOMO
MOMO
e
OMOM
Bu3Sn
6
11
5
Acknowledgments
O
Me
Support was provided by the NIH (HL25848 to S.J.D.). W.H.K. is
grateful for a Korea Research Foundation Grant funded by the Kor-
ean Government (KRF-2007-357-c00060). We thank Rebecca Wil-
son for editorial assistance and Dana Ryan for assistance with the
preparing of the manuscript. We also thank Dr. George Sukenick,
Ms. Hui Fang, and Sylvi Rusli (NMR Core Facility, Sloan-Kettering
Institute) for mass spectral and NMR spectroscopic analysis.
O
Me
OH
Me
HO
c,d
Me
7
OH
Me
O
OH
Me
12
f
OMOM
O
O
O
13
umbellactal (14)
Supplementary data
H
O
OH
Me
O
Me
Me
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.131.
O
13
References and notes
MOMO
O
H
12
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Scheme 3. Synthesis of the xenibellols core, 7. Reagents and conditions: (a) nBuLi,
THF, À78 °C to rt, 12 h, 31%; (b) TsCl, pyridine, DMAP, rt, 12 h, 89%; (c) TBAF, THF,
reflux, 3 h; (d) KH, 18-crown-6, THF, 0 °C, 1 h, 87% for two steps; (e) EtSH, MgBr2–
OEt2, Et2O, 0 °C, 1 h, 95%; and (f) 1 N HCl, THF, 50 °C, 8 h, 96%.
With intermediate 5 in hand, we next sought to investigate the
key 2,3-Wittig rearrangement8 of 5, which would serve to install
the bridgehead quaternary carbon (Scheme 3). As shown, upon
exposure to nBuLi, the desired rearrangement product 6 was ob-
tained, albeit in only 31% yield. The efficiency of the rearrangement
was compromised by two competing pathways. One involves sim-
ple reduction, and the other entails 1,2-Wittig rearrangement.
With compound 6 in hand, we next examined the formation of
the oxolane moiety of the xenibellol core. Thus, treatment of the