Convergent total synthesis of the racemic HIF-1 inhibitor laurenditerpenol

Article abstract of DOI:10.1016/j.tetlet.2008.05.116

The convergent total synthesis of the HIF-1 inhibitor laurenditerpenol 1a is reported. The key step is the Julia olefination-reduction process between the two components, the sulfone 4 (prepared from the dimethylfuran-maleic anhydride Diels-Alder adduct)

Full text of DOI:10.1016/j.tetlet.2008.05.116

Tetrahedron Letters 49 (2008) 4962–4964
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Tetrahedron Letters
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Convergent total synthesis of the racemic HIF-1 inhibitor laurenditerpenol
*
Michael E. Jung , G-Yoon J. Im
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The convergent total synthesis of the HIF-1 inhibitor laurenditerpenol 1a is reported. The key step is
the Julia olefination–reduction process between the two components, the sulfone 4 (prepared from
Received 11 April 2008
Revised 20 May 2008
Accepted 23 May 2008
Available online 21 June 2008
the dimethylfuran-maleic anhydride Diels–Alder adduct) and the aldehyde
3-methylcyclohexenone).
3 (prepared from
Ó 2008 Published by Elsevier Ltd.
Laurenditerpenol 1, a secondary metabolite isolated from the
Jamaican red alga Laurencia intricata in 2004 by Zhou and Nagel,1
was shown to inhibit activation of the hypoxia inducible factor-1
(HIF-1) under hypoxia using a T47D human breast tumor cell-
Me
RO
Me
H
Me
O
HO
Me
O
H
9
H
Me
Me
Me
8
H
Me
Me
Me
Me
1a
2
based reporter assay with an IC50 of 0.4 lM. Upregulation of HIF-
1 in late-stage tumors activates oxygen sensitive genes leading to
angiogenesis and results in the survival and further proliferation
of the tumor.2 Inhibition of HIF-1 represents an alternate strategy
in late-stage cancer therapy.3 In the original isolation paper, the
stereochemistry at C6 and C7 was not determined, nor was the rel-
ative stereochemistry of the oxabicycloheptane unit versus the
cyclohexenol. Very recently, Avery and coworkers published a syn-
thesis of laurenditerpenol and many of its diastereomers, which
proved the relative and absolute structure to be that shown in 1a
(Scheme 1).4 This publication prompts us to report our synthesis
of laurenditerpenol 1a and its stereoisomers in racemic form by
a completely different route to the one used by Avery. Our conver-
gent synthetic route allowed for the easy installation of the C6 and
C7 stereocenters and a late-stage coupling of the two major
subunits.
O
O
RO
Me
Me
Me
Me
Me
H
CHO
H
+
Me
MeO2C
Me
ArO2S
3
6
4
O
O
Me
O
O
O
H
Me
O
Me
H
7
5
Scheme 2.
be obtained from the ester 6, which would be prepared from the
known cyclic anhydride 7.
The retrosynthetic strategy involved a disconnection at C8 and
C9 to give two key intermediates, the aldehyde 3 and the sulfone
4, which would be coupled via a modified Julia olefination proce-
dure to give the alkene 2 and thence 1a (Scheme 2). The aldehyde
3 would be prepared from the lactone 5 while the sulfone 4 would
The synthesis of the aldehyde 3 (Scheme 3) began with the
reduction of the known ester enone 8 (prepared by alkylation of
the 3-methylcyclohexenone)5 to give a diastereomeric mixture of
the allylic alcohols 9 in 86% yield.6 Saponification to the hydroxy
acid and lactonization using DCC yielded the two lactones 10 and
11 as a separable 2:1 mixture. Methylation of the enolate of the
major lactone 10 occurred from the less hindered face to generate
in 85% yield the methyl lactone 12, which on DIBAL reduction gave
the lactol 13. Similarly, methylation of the trans lactone 11
occurred cis to the allylic hydrogen to generate the methylated
product 14 in modest yield.
Me
H
Me
H
HO
Me
O
HO
Me
O
H
H
Me
Me
Me
Me
Me
Me
Laurenditerpenol (1)
1a
The oxanorbornane sulfone 4 was synthesized starting from the
known exo Diels–Alder adduct of 2,5-dimethylfuran and maleic
anhydride 7, which had been originally prepared by Diels and
Alder in 19287 (Scheme 4). Hydrogenation gave the anhydride,
Scheme 1.
* Corresponding author. Tel.: +1 310 825 7954; fax: +1 310 206 3722.
E-mail address: jung@chem.ucla.edu (M. E. Jung).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.05.116

M. E. Jung G. Y. J. Im / Tetrahedron Letters 49 (2008) 4962–4964
4963
OH CO2Et 1) KOH
O
H
CO2Et
O
NaBH4
CeCl3
MeOH
86%
TBSO
1) LiAlH4/0 ºC/85%
2) PivCl/pyr/89%
Me
EtOH
O
4
H
H
70%
LiHMDS
Me
CHO
H
3) TBSCl/Im-H
4) DIBAL/-78 ºC
86% (2 steps)
2) DCC
-78 ºC;
Me
Me
Me
DMAP
SiO2
Me
Me
8
9
55%
88%
21
12
5) TPAP/NMO 78%
O
H
Z
:
E
= 1:1
O
O
O
O
O
H
LDA
TBSO
Me
TBSO
Me
Me
Me
Me
H
H
-78 ºC;
H
H
H
Me
Me
MeI
H
H
+
+
25%
O
O
Me
Me
:
Me
Me
Me
Me
10
2
1
11
14
23E
22
E
OH
O
LDA
Me
O
Me
O
O
-78 ºC;
MeI
DIBAL
-78 ºC
84%
H
H
Me
Me
Me
Me
Me
Me
85%
O
H
H
TBSO
TBSO
H
Me
Me
+
Me
Me
13
12
Me
Me
Scheme 3.
22Z
23
Z
{HN=NH}
KCO2N NCO2K
pyr
22
and
23
E
22
and
23
Z
22
and
23
E
HN=NH
N.R.
+
O
O
AcOH/MeOH;
SiO2
Me
Me
E
33%
1) H2, Pd/C
EtOAc, 80%
2) MeOH/
99%
Z
E
O
O
5 eq
HO2C
NaOMe
MeOH/
99%
MeO2C
Me
Me
H
O
H
Me
O
Me
TBSO
Me
Me
TBSO
Me
15
7
O
H
H
H
Me
Me
O
Me
Me
1) BH3-THF
LiAlH4
Et2O
23 ºC
87%
+
HO2C
O
TsO
89%
Me
Me
Me
2) TsCl/pyr
CH2Cl2
83%
Me
30%
30%
24
25
Me
Me
MeO2C
MeO2C
Me
Me
HO
Me
Me
HO
Me
O
16
17
H
Me
Me
O
O
Me
+
H
N
O
Me
Me
Me
Me
DIAD/PPh3
CH2Cl2/25 ºC
Me
Me
+
S
1a
1b
S
Me
12 h
96%
Ar-S
HO
19
20
18
Scheme 5.
O
Me
Me
mCPBA,
0 ºC
95%
and reductive removal of the pivalate (86%), and final oxidation
to give the aldehyde 21 in 78% yield (Scheme 5).10 The modified
Julia olefination of the protected hydroxyaldehyde 21 and the sul-
fone 4 yielded the desired set of racemic trans products 22E and
23E, along with the racemic cis products 22Z and 23Z in 88% yield
as a 1:1 mixture of the Z and E isomers.11 The E isomers could be
separated from the Z isomers by flash chromatography. We
planned to carry out selective reduction of the disubstituted alkene
in the presence of the cyclic trisubstituted alkene via reduction
with diimide12 (prepared by protonation of dipotassium azodicar-
boxylate by acetic acid in a solution of pyridine and methanol). The
hindered Z isomers—22Z and 23Z—did not react with diimide and
the starting alkenes were recovered unchanged. However, the mix-
ture of the E isomers, 22E and 23E, underwent diimide reduction to
afford, in addition to 15% starting material, a 1:1 mixture of the
desired reduced products 24 and 25 in 80% yield, as observed in
the NMR. Unfortunately, the unreduced olefin and the desired
alkane diastereomers were difficult to separate via column chro-
matography, and only the diastereomer 25 was isolated in small
quantities. Desilylation of the TBS ether of 25 with TBAF afforded
the laurenditerpenol diastereomer 1b in 72% yield. TBAF deprotec-
tion of the TBS ethers of the mixture of the alkenes and alkanes
gave both laurenditerpenol diastereomers 1a and 1b, which were
partially separated by careful chromatography. The proton, and
especially the carbon, NMRs of these isolated diastereomers
matched those reported by Avery and coworkers (which were
numbered 1c and ent-1g in their paper).1
Me
Ar = 2-benzthiazole
ArO2S
4
Scheme 4.
which was opened to the known carboxylic acid ester 157c via
methanolysis. Treatment of 15 with sodium methoxide in metha-
nol took advantage of the difference in pKa for protons
a to an ester
versus those to a carboxylate salt, a principle we had used before
a
in the synthesis of cyclobut-A analogues,8 to give cleanly the epi-
merized ester 16. Selective reduction of the carboxylic acid with
borane furnished in 89% yield the alcohol, which was converted
to the tosylate 17 in 83% yield. Reduction of both the ester and
the tosylate with lithium aluminum hydride unveiled the third
methyl group to afford the trimethyl oxanorbornane alcohol 18
in 87% yield. The alcohol was converted to the sulfide 20 (96%)
via treatment with 2-mercaptobenzothiazole 19 under Mitsunobu
conditions, for example, diisopropyl azodicarboxylate (DIAD) and
triphenylphosphine, which was then oxidized with m-CPBA to
yield the desired sulfone 4 in 95% yield.
Unfortunately, the key Julia–Kocienski olefination9 between the
lactol 13 and the sulfone 4 was unsuccessful presumably due to the
fact that the lactol exists predominately in the cyclic isomer with
little or none of the hydroxyaldehyde being present. The required
free aldehyde 21 was therefore prepared via the 5-step protecting
group manipulation starting from the lactone 12, that is, reduction
to the diol (85%), monoprotection as the pivalate (89%), silylation
We have also prepared several analogues of laurenditerpenol
and are submitting them for biological evaluation as potential

4964
M. E. Jung G. Y. J. Im / Tetrahedron Letters 49 (2008) 4962–4964
Acknowledgments
Me
O
Me
O
HO
Me
HO
HO
Me
H
H
Me
Me
We thank the National Science Foundation (CHE 0614591) for
generous support of this work.
Me
Me
26E
Me
Me
Me
27E
Me
Me
Me
Me
References and notes
O
O
Me
HO
Me
H
H
1. Mohammed, K. A.; Hossain, C. F.; Zhang, L.; Bruick, R. K.; Zhou, Y.-D.; Nagle, D.
G. J. Nat. Prod. 2004, 67, 2002–2007.
2. Schumaker, P. T. Crit. Care Med. 2005, 33, S423–S425.
3. Giaccia, A.; Siim, B. G.; Johnson, R. S. Nat. Rev. Drug Disc. 2003, 2, 803–811.
4. Chittiboyina, A. G.; Kumar, G. M.; Carvalho, P. B.; Liu, Y.; Zhou, Y.-D.; Nagle, D.
G.; Avery, M. A. J. Med. Chem. 2007, 50, 6299–6302.
Me
Me
Me
27Z
26Z
5. Podraza, K. F.; Bassfield, R. L. J. Org. Chem. 1989, 54, 5919–5922.
6. Podraza, K. F. US Patent 5,114,493, 1992.
Scheme 6.
7. (a) Diels, O.; Alder, K.; Naujoks, E. Ber. Deutsch. Chem. Gesell. Abteilung B 1929,
62B, 554–562; (b) Brickwood, D. J.; Ollis, W. D.; Stephanatou, J. S.; Stoddart, J. F.
J. Chem. Soc., Perkin Trans. 1 1978, 1398–1414; (c) Imagawa, T.; Matsuura, K.;
Murai, N.; Akiyama, T.; Kawanisi, M. Bull. Chem. Soc. Jpn. 1983, 56, 3020–3022;
(d) Akiyama, T.; Fujii, T.; Ishiwari, H.; Imagawa, T.; Kawanisi, M. Tetrahedron
Lett. 1978, 19, 2165–2166.
8. Jung, M. E.; Sledeski, A. W. J. Chem. Soc., Chem. Commun. 1993, 589–591.
9. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130,
336–357; (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc.
Chim. Fr. 1993, 130, 856–878; (c) Bellingham, R.; Jarowicki, K.; Kocienski, P.;
Martin, V. Synthesis 1996, 285–296.
10. (a) Nielsen, T. E.; Le Quement, S.; Juhl, M.; Tanner, D. Tetrahedron 2005, 61,
8013–8024; (b) Tanner, D.; Tedenborg, L.; Somfai, P. Acta Chem. Scand. 1997, 51,
1217–1223.
11. For a discussion of the various effects on the stereochemistry of the Julia–
Kocienski reaction, see: Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26–28.
HIF-1 inhibitors (Scheme 6). Thus hydrolysis of the silyl ethers of
the four alkene stereoisomers—22E/23E and 22Z/23Z—with TBAF
in THF afforded the dienols 26E/27E and 26Z/27Z, which were sep-
arated by careful flash column chromatography.13 The results of
the biological assays of these compounds will be reported in due
course.
Finally, we were able to prepare the correct (S)-enantiomer of
the allylic alcohol 9 using the Corey–Bakshi–Shibata (CBS) reduc-
tion14 of the cyclohexenone 8, even though 8 has a stereocenter
a
to the ketone. This reduction gave a diastereomeric mixture of
the allylic alcohols 9 in 60% yield and 85% de.15 We are currently
investigating a chiral synthesis of the oxabicyclo[2.2.1]heptane
sulfone 4 (via a chemical or enzymatic resolution of the anhydride
7) with the idea of carrying out a more efficient chiral synthesis of
the correct enantiomer. Our results will be reported in due course.
In summary, we have described a convergent synthesis of race-
mic laurenditerpenol 1a and its diastereomer 1b, in 13 steps from
3-methyl-2-cyclohexen-1-one. The methylated oxanorbornane
fragment 4 was successfully synthesized from 2,5-dimethylfuran
and coupled to the aldehyde 21 via a high-yielding modified Julia
olefination procedure. A more detailed account of the synthesis,
along with efforts toward the synthesis of analogues, will be
forthcoming.
12. (a) Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc. 1972, 94, 9256–9258;
(b) Pasto, D. J.; Taylor, R. T. Org. React. 1991, 40, 91–155.
13. The structures of 26E and 27E are secure since they could be correlated with
the reduction products 1ab by NMR data. However, the relative configurations
of 26EZ could be inverted since we have not yet been to convert them into the
reduced products which would have allowed a direct correlation.
14. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553;
(b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925–7926.
15. (a) For other preparations of 9, see: Omoto, M.; Yukawa, C.; Saijo, T. Jpn. Kokai
Tokkyo Koho (2004) JP 2004269463; Chem. Abstr. 2004, 141, 314460.; For the
synthesis of the racemic cis-lactone, see: (b) Bartlett, P. A.; Pizzo, C. F. J. Org.
Chem. 1981, 46, 3896–3900; (c) Guth, H. Helv. Chim. Acta 1996, 79, 1559–
1571.