Stereospecific rearrangement of α-hydroxyepoxide: Efficient approach to the trans-bicyclo[9.3.0]tetradecane core en route to clavulactone

Article abstract of DOI:10.1016/j.tetlet.2005.11.021

We document a synthetic route to trans-bicyclo[9.3.0]tetradecanes. The strategy is based on a quantitative and stereospecific Lewis acid mediated rearrangement of α-hydroxyepoxide to β-hydroxyketone, which paved the way for the synthesis of clavulactone a

Full text of DOI:10.1016/j.tetlet.2005.11.021

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 299–302
Stereospecific rearrangement of a-hydroxyepoxide:
efficient approach to the trans-bicyclo[9.3.0]tetradecane
core en route to clavulactone
Bingfeng Sun and Xingxiang Xu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 12 September 2005; revised 4 November 2005; accepted 4 November 2005
Abstract—We document a synthetic route to trans-bicyclo[9.3.0]tetradecanes. The strategy is based on a quantitative and stereo-
specific Lewis acid mediated rearrangement of a-hydroxyepoxide to b-hydroxyketone, which paved the way for the synthesis of
clavulactone and clavirolides.
Ó 2005 Elsevier Ltd. All rights reserved.
Clavulactone and clavirolides A–F are novel tricyclic
diterpenoids of the dolabellane family isolated from
the Pacific soft coral Clavularia viridis collected off the
logical significance, as well as the limited availability of
these compounds have rendered them interesting targets
2
2e
to synthetic laboratories. In a previous paper, we
have reported an enantioselective approach to the bi-
cyclo[9.3.0] tetradecenone framework of clavulactone,
the most prominent member of this family. Herein, we
disclose our further efforts toward the total synthesis
of clavulactone.
1
Xisha Islands in the South China Sea (Fig. 1).
Clavulactone and clavirolides A–F possess interesting
1
b
and diverse biological activities, including cytotoxicity
2
+
toward carcinoma cells, blockage of Ca channels, nega-
tive inotropic activity as well as bradycardia effect. The
unusual trans-bicyclo[9.3.0]tetradecane framework, bio-
In view of the liability of the six-membered a,b-unsatu-
rated lactone moiety, clavulactone 1 could be retrosyn-
thetically reduced to the properly functionalized
bicyclo[9.3.0] tetradecenone 3 through intermediate b-
hydroxyketone 2. Enone 3 could be prepared from the
coupling/macro-cyclization sequence of allylic chloride
O
O
R
O
H
O
H
O
O
4
and protected cyanohydrin 5a/5b (Scheme 1).
O
O
O
In our previous paper, we demonstrated the synthesis of
bicyclo[9.3.0]tetradecenone 3 via ketone 8. The seg-
ment coupling of cyanohydrin 5a with allylic chloride
Clavulactone
O
Clavirolide A (R = OH)
Clavirolide B (R = H)
Clavirolide C
O
2
e
O
4
to ketone 8 was successful in terms of the conservation
O
H
O
H
O
OH
of the tethered (Z)-olefin in 8; however, it fell short of
efficiency due to the improper THP protection group.
We report herein, an improved segment coupling of
TBS protected cyanohydrin 5b with 4 (Scheme 2). Alde-
hyde 6 was treated with TMSCN to give the TMS pro-
tected cyanohydrin followed by deprotection of TMS
and THP to give diol 7. Selective silylation of the
primary hydroxyl group in 7 and protection of the
secondary one with EVE afforded 5b. Coupling between
4 (R = Bn) and 5b was successfully realized in the
O
O
O
Clavirolide D
Clavirolide E
Clavirolide F
Figure 1. Clavulactone and clavirolides.
*
Corresponding author. Fax: +86 21 64166128; e-mail: xuxx@
mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.021

300
B. Sun, X. Xu / Tetrahedron Letters 47 (2006) 299–302
O
H
O
OH
OR
O
OEE
DIBAL-H
OMOM -78 ˚C
6%
+
OR
OMOM
NC
7
O
5a R = THP
5b R = TBS
Cl
O
4
3
9
1
t-BuOOH
VO(acac)2
Benzene
OH
O
OH
H
O
OH
O
OMOM
OMOM
OMOM
OMOM
2
3
10
11
Scheme 1. Retrosynthetic analysis of clavulactone.
>99% (1:1)
Scheme 3. Synthesis of a-hydroxyepoxides 10 and 11.
(
1) TMSCN, 18-C-6,
then H2O
OH
(
1) TBSCl, imid.
OHC
DMAP
4.18
OH
nOe
OH
2
.20
NC
3
.45
nOe
nOe
(
2) CH OH,CSA
(2) EVE, PPTS
0% from 6
nOe
6
OTHP
OR
3
7
O
OH
O
7
nOe
OTBS
(
1) NaHMDS,
OBn
then 4
OMOM
2.08, 2.82
OMOM
no nOe
ref. [2d]
1.23
5.30
(
2) CH OH,
OEE
3
3
dry HCl
Et O
2
NC
O
1.71
6
6%
5
5
a R = THP
b R = TBS
8
Figure 2. Selected NOE correlations of 10.
Scheme 2. Modified synthesis of ketone 8.
reformation, depending on the reaction conditions.3
Considering the presence of MOM protection in our
substrates 10 and 11, application of Br o¨ nsted acids or
strong Lewis acids as the catalysts for the rearrangement
presence of NaHMDS. Ketone 8 was obtained in 66%
overall yield from 5b, compared to 34% in the case of
were precluded. A modest Lewis acid, LiBF , was
4
5
a. Ketone 8 could be converted to 3 through a known
2
e
attempted. When the mixture of 10 and catalytic
amount of LiBF in CH CN was maintained at 60 °C
pathway.
4
3
for 1 h, b-hydroxy ketone 12 was generated quantita-
tively and stereospecifically. No byproduct was detected.
The stereochemistry of 12 was assigned by 2D NMR
studies, and the result validated previous assignments
for 10. The transferring hydrogen opened the epoxide
from the anti-face, which accounts for the stereochemis-
try of 12. The rearrangement could be either stepwise or
concerted (Scheme 4).
Enone 3 was subsequently reduced to allylic alcohol 9
with DIBAL-H in 76% yield. Although extensive 2D
NMR studies including COSY, NOESY, DEPT,
HMQC, and HMBC of 9 were performed, the configura-
tion of the newly generated stereo center could not be
determined at this time. Subsequent hydroxyl-directed
epoxidation of 9 with t-BuOOH catalyzed by VO(acac)2
delivered quantitatively two separable a-hydroxyepox-
ides, 10 and 11, in an approximately 1:1 ratio. This neg-
ligible selectivity could be ascribed to the significant
hindrance over the b-face of the double bond (Scheme 3).
LiBF4
OH
O
O
HO
H
CH CN
3
o
6
0 C
OMOM
nOe
OMOM
Again the stereochemistry of the newly generated epox-
ide moiety of 10 and 11 could not be determined by 2D-
NMR experiments. However, a significant NOE correla-
tion was observed between hydrogens of the hydroxyl
and the methyl group. Based on the data, we could as-
sign the hydroxyl group in 10 and 11 as a b-OH, and
so is the hydroxyl group in 9. Selected NOE correlations
were depicted in Figure 2.
quant.
1
0
12
H
O
LAO
H
OMOM
OMOM
_
L.A.
L.A.
LA
H
O
O
It is known that a-hydroxyepoxides can rearrange in the
presence of either Br o¨ nsted acids or Lewis acids to
afford a variety of products, including triol via OH
opening of the epoxide ring, b-hydroxyketone via
hydrogen transfer, b-hydroxyketone via pinacol rear-
rangement, as well as products from extensive skeletal
H
Scheme 4. Rearrangement of 10 and the possible mechanism.

B. Sun, X. Xu / Tetrahedron Letters 47 (2006) 299–302
301
LiBF4
O
OH
OH
O
HO
HO
H
O
HO
H
H
CH CN
3
o
60
C
see text
nOe
OMOM
OMOM
OMOM
OMOM
quant.
1
4
12
1
1
13
Ac O,Et N, 92%
2
3
H
O
O
O
LAO
CH3
OH
O
H3C
O
H
HO
H
H
OMOM
_
L.A.
L.A.
OMOM
OMOM
nOe
nOe
H
O
L.A.O
1
5
16
H
Scheme 6. Reduction of 12 and monoacetylation of 14.
OMOM
Scheme 5. Rearrangement of 11 and the possible mechanism.
tion of Et BOMe/LiBH /Et O did not alter the compo-
2
4
2
nent ratio of the product, but accelerated the reaction
Scheme 7). The major product, obtained as crystals
(
It is gratifying that such a transformation could recur in
1, giving the desired b-hydroxyketone 13 quantitatively
by recrystallization of the mixture from dichlorometh-
ane, was determined as 1,3-anti-diol 17 by an X-ray
diffraction study (Fig. 3). This stereochemistry outcome
of the reduction could be ascribed to the steric hindrance
over the b face of the carbonyl group. Based on the crys-
tallographic result of 17, we confirmed our previous
assignment of the stereochemistry of the OMOM group
on the macrocycle as b in configuration.
1
and stereospecifically. The stereochemistry of 13 was
determined by 2D NMR studies, which confirmed the
structure of 11. The stereochemistry outcome indicated
a possible process of syn opening of the epoxide; how-
ever, a more plausible mechanism for this rearrange-
ment could be through a carbocation intermediate or a
3
c
Payne intermediate, either of which would involve anti
opening of the epoxide. Anyhow, the rearrangement
should be stepwise (Scheme 5).
In summary, we have developed a novel and efficient
approach for the construction of trans-bicyclo[9.3.0]
tetradecane core structure. By extensive spectral data
studies, we assigned the stereochemistry of all the rear-
rangement products, which paved the way for the total
synthesis of clavulactone. The strategy applied herein
Hence, two b-hydroxyl ketones with the desired trans-
bicyclo[9.3.0]tetradecane core were successfully pre-
pared, which made it possible for further elaboration.
The next task was to reduce the carbonyl group in 12
or 13 to the desired b-hydroxyl group on the macrocycle.
O
Et BOMe
OH
HO
2
HO
H
H
The outstanding reductive system developed by Evans
et al., (CH ) NHB(OAc) /CH COOH/CH CN, could
LiBH4
Et O
3
4
3
3
3
2
convert b-hydroxyketones to 1,3-anti-diols with excel-
lent diastereomeric selectivity. When 12 was subject to
the above system, however, 1,3-syn-diol 14 was obtained
in 70% yield and no desired anti-diol product was
detected. We also tried TishchenkoÕs conditions using
OMOM
OMOM
9
3%
4
1
7
13
Scheme 7. Reduction of 13.
p-nitrobenzaldehyde or acetaldehyde with catalytic
5
SmI . Substrate 12 was mostly recovered and no reac-
2
tion occurred at all, probably due to the grave steric
hindrance posed by the bicyclic ring system. Other
attempts including systems LiBH /LiBr/Et O and
4
2
LiBH /Et O were also dissatisfactory. The former sys-
4
2
tem afforded 14 exclusively in 90% yield, while the latter
provided a 2:1 diastereomeric mixture in 90% yield with
1
4 as the major product. The relative stereochemistry of
diol 14 was determined via extensive 2D NMR studies
of its monoacetyl derivatives 15 and 16 (Scheme 6).
Prasad and co-workers realized a highly 1,3-syn diaste-
reoselective reduction of b-hydroxyketones by employ-
ing Et BOMe/NaBH /CH OH/THF as the reductive
2
4
3
6
reagents. When 13 was treated with the above reagents,
Figure 3. Molecular structure of compound 17 (Deposited Data—
we obtained a 4:1 mixture in 93% overall yield. Utiliza-
CCDC 287379).

302
B. Sun, X. Xu / Tetrahedron Letters 47 (2006) 299–302
could be readily adapted for the syntheses of clavirolides
A–F. The focuses of future investigations will lie in the
procurement of the precursors from 14 or 17, and the
ring closure of the six-membered a,b-unsaturated lac-
tone. Studies are currently well underway in our
laboratories.
Rodr ´ı guez, A. D.; Gonz a´ lez, E.; Ram ´ı rez, C. Tetrahedron
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support (Grant number: 20472100).
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