A. O’Byrne et al. / Tetrahedron Letters 53 (2012) 5936–5938
5937
sequence the persistent malodour associated with the use of ben-
O
O
O
zyl mercaptan has been addressed by Node et al.10 They have
shown that the introduction of substituents, particularly a 4-tert-
butyl group, onto the aromatic ring serves to reduce its odour.
However, following the synthesis of the tert-butyl substituted ad-
duct cis-9, inefficient resolution was observed using CAL-B, an
unexpected finding explained presumably by an unfavourable
interaction between the tert-butyl group and the lipase (Scheme 1).
Treatment of (+)-8 with TBSCl under basic conditions served to
introduce both the silyloxy unit and to remove the steric buttress,
thus, generating (ꢀ)-5 in reasonable yield (Scheme 2). Analysis of
this material by chiral GC [Supelco AlphaDex 120; gradient
i
ii
iii
(
+)-8
O
O
OTBS
OTBS
(+)-12
OTBS
(+)-13
iv
(
)-5
O
O
Br
Br
O
v
O
6
0–180 °C; R
t
(ꢀ)-5 = 21.5 min; R
t
(+)-5 = 21.7 min] indicated that
OX
OTBS
(+)-14
no erosion of optical purity had taken place during this step. With
a supply of optically active 5 in hand its epoxidation was next con-
sidered. Use of aqueous hydrogen peroxide with either sodium
hydroxide or benzyltrimethylammonium hydroxide (Triton
(
+)-1: X = H;
vi
(+)-2: X = Ac
i, TBSCl, DBU, CH Cl , rt, 65%; ii, TBHP, Triton B, THF,
rt, 87%; iii, (a) LDA, THF, -78 ºC; then TMSCl, -78 ºC to rt;
b) Pd(OAc) , MeCN, rt, 40%; iv, (a) Br , CH Cl , 0 ºC; (b)
2
2
3
d,11
B)
trans-epoxide 12 and its minor cis-epoxide diastereoisomer (ca.
:1) were encountered. In contrast tert-butyl hydroperoxide
TBHP) gave trans-epoxide (+)-12 as the sole isolable product in
gave good conversion. However, mixtures of the major
(
2
2
2
2
Et N, CH Cl , 0 ºC, 73%; v, HF·Py, THF, Py, rt; vi, Ac O, cat.
3
2
2
2
5
(
DMAP, Py, rt, 56%
good yield (87%). The next task was introduction of the enone.
The use of IBX at elevated temperature led to decomposition
Scheme 2. Synthesis of (ꢀ)-5 and its use in the synthesis of (+)-1 and 2.
whereas a combination of IBX and NMO at room temperature led
to poor conversion (12:13; 80:20).12 Epoxide 12, however, was
(+)-2. Purification was performed by standard flash chromatogra-
phy on silica which gave a sample of (+)-2 in 56% yield from (+)-
14 whose data were consistent with those reported. In relation
to the purification of (+)-2 it should be noted that this compound
does undergo gradual decomposition on silica over time.
found to cleanly undergo trimethylsilylenol ether formation at
1
8
2,5
3
d
ꢀ
78 °C and this material was directly treated with stoichiometric
13
amounts of Pd(OAc)
2
.
Although this Saegusa–Ito reaction gave
clean samples of (+)-13, the yield for this process was modest
which may be attributed to the formation of acetic acid during
the reaction. Nevertheless, (+)-13 could then be converted into
vinyl bromide (+)-14 on bromination followed by direct base-
The ability of 2 to inhibit the transcription factor NF
j
B was
determined with a gene reporter cell-based assay. It was found
that at 9 M, phorbol challenged NF B activation was halved
(ED50 = 9
onstrated that at 100
LD50 = 100 M).
In summary, (+)-2 was prepared in 9% overall yield from enan-
1
9
l
j
Ò
1
4
lM). However, an alamar blue cell viability assay dem-
mediated elimination.
lM significant toxicity became evident
Removal of the tert-butyldimethylsilyloxy protecting group
(
l
from this type of compound has been routinely performed using
1
5
15,16
HF. In our hands, aqueous HF in acetonitrile
led to a sluggish
tioenriched (+)-8 in a sequence requiring five chromatographic
purification operations. Based on the optical purity of (ꢀ)-5 this
material is 95% ee.
reaction during which decomposition proved to be an issue. Using
Evans’ protocol, a HFꢁpyridine solution in THF buffered with pyri-
1
7
dine led to a more controlled and efficient deprotection and
(
+)-1 could be isolated. Finally, (+)-1 underwent rapid acetylation
Acknowledgments
with acetic anhydride and pyridine in the presence of DMAP to give
We would like to thank UCD for financial support including an
Ad Astra scholarship (A.O’B.). Membership (P.E.) of COST action
CM0804 is acknowledged.
O
O
OMe
i - iii
0%
iv
References and notes
SCH Ar
2
5
OH
OH
1. Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem. Rev. 2004, 104, 2857.
2. Higa, T.; Okuda, R. K.; Severns, R. M.; Scheuer, P. J.; He, C.; Changfu, X.; Clardy, J.
Tetrahedron 1987, 43, 1063.
7
(
±)-6
(±)-8: Ar = Ph; 92%;
(
±)-9: Ar = 4-t-BuC H ; 83%
3. For syntheses of racemic and optically active 1, see: (a) Gautier, E. C. L.; Lewis,
N. J.; McKillop, A.; Taylor, R. J. K. Tetrahedron Lett. 1994, 35, 8759; (b) Johnson, C.
R.; Miller, M. W. J. Org. Chem. 1995, 60, 6674; (c) Block, O.; Klein, G.; Altenback,
H. –J.; Brauer, D. J. J. Org. Chem. 2000, 65, 716; (d) Tachihara, T.; Kitahara, T.
Tetrahedron 2003, 59, 1773; (e) Barros, M. T.; Matias, P. M.; Maycock, C. D.;
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Willis, A. C. Org. Lett. 2009, 11, 4290; (g) Labora, M.; Pandolfi, E. M.; Schapiro, V.
Tetrahedron: Asymmetry 2010, 21, 153; (h) Jin, M. Y.; Hwang, G. –S.; Chae, H. I.;
Jung, S. H.; Ryu, D. H. Bull. Korean Chem. Soc. 2010, 31, 727.
6
4
v
O
O
+
ArH CS
SCH Ar
2
2
OAc
OH
4. (a) Comméiras, L.; Moses, J. E.; Adlington, R. M.; Baldwin, J. E.; Cowley, A. R.;
Baker, C. M.; Albrecht, B.; Grant, G. H. Tetrahedron 2006, 62, 9892; (b) Porco, J.
A., Jr.; Su, S.; Lei, X.; Bardhan, S.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2006,
45, 5790.
(
1
)-10: Ar = Ph; 45%;
(+)-8: Ar = Ph; 46%;
1: Ar = 4-t-BuC H , 10% 9: Ar = 4-t-BuC6H4
6
4
5
6
.
.
Pinkerton, D. M.; Banwell, M. G.; Willis, A. C. Aust. J. Chem. 2009, 62, 1639.
O’Byrne, A.; Murray, C.; Keegan, D.; Palacio, C.; Evans, P.; Morgan, B. S. Org.
Biomol. Chem. 2010, 8, 539.
i, Li, NH , t-BuOH, THF, -78 ºC; ii, HClO , CHCl -H O (1:2),
3
4
3
2
rt; iii, (a) m-CPBA, CH Cl , rt; (b) Al O (basic), CH Cl , rt;
2
2
2
3
2
2
7.
(a) Danishefsky, S. J.; Simonea, B. J. Am. Chem. Soc. 1989, 111, 2599; (b) Barros,
M. T.; Maycock, C. D.; Ventura, M. R. J. Chem. Soc., Perkin Trans. 1 2001, 166; (c)
Yamazaki, N.; Kusanagi, T.; Kibayashi, C. Tetrahedron Lett. 2004, 45, 6509; (d)
Williams, D. R.; Kammler, D. C.; Donnell, A. F.; Goundry, W. R. F. Angew. Chem.,
Int. Ed. 2005, 44, 6715; (e) Chiba, S.; Kitamura, M.; Narasaka, K. J. Am. Chem. Soc.
iv, ArCH SH, Et N (0.1 equiv.), CH Cl , rt (de >95%);
2
3
2
2
v, CAL-B, vinyl acetate, i-Pr O, rt
2
Scheme 1. Synthesis and resolution of racemic alcohol 8.