General synthetic approach to bicyclo[9.3.0]tetradecenone: A versatile intermediate to clavulactone and clavirolides

Article abstract of DOI:10.1016/j.tetlet.2005.09.106

An efficient and stereoselective approach to the bicyclo[9.3.0] tetradecenone core structure of clavulactone starting from readily and abundantly available 2-methyl-1,3-cyclopentandione employing microbial desymmetrization and cyanohydrin alkylation as th

Full text of DOI:10.1016/j.tetlet.2005.09.106

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8431–8434
General synthetic approach to bicyclo[9.3.0]tetradecenone:
a versatile intermediate to clavulactone and clavirolides
Bingfeng Sun and Xingxiang Xu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 6 July 2005; revised 16 September 2005; accepted 20 September 2005
Available online 14 October 2005
Abstract—An efficient and stereoselective approach to the bicyclo[9.3.0]tetradecenone core structure of clavulactone starting from
readily and abundantly available 2-methyl-1,3-cyclopentandione employing microbial desymmetrization and cyanohydrin alkyl-
ation as the key steps is described. The synthetic route described herein is applicable to the syntheses of the core structures of Clavi-
rolides A–F.
Ó 2005 Elsevier Ltd. All rights reserved.
Since the first structure elucidation some 30 years ago,
dolabellanes have become one of the principal groups
among the wide array of diterpenoids.1 Dolabellanes
are obtained mainly from marine sources and character-
ized as an unusual trans-bicyclo[9.3.0]tetradecane
nucleus decorated with one angular methyl group. Of
considerable interest are the findings that many dolabel-
lanes exhibit pharmacologically important effects.1f,2c
They are also biogenetic and chemical precursors of fusi-
coccanes, dolastanes, neodolabellanes, and recently
revealed guanacastepens.1f,2 These features have
rendered the dolabellanes irresistible to the synthetic
community.1f,2c,3 Clavulactone and clavirolides A–F
are novel tricyclic diterpenoids of the dolabellane family
isolated from the Pacific soft coral Clavularia viridis col-
lected off the Xisha Islands in South China Sea (Fig. 1).4
O
O
R
O
H
O
O
O
H
O
O
O
Clavulactone
O
Clavirolide A ( R = OH )
Clavirolide B ( R = H )
Clavirolide C
O
O
O
H
O
H
O
OH
O
O
O
Clavirolide D
Clavirolide E
Clavirolide F
Figure 1. Clavulactone and clavirolides.
Clavulactone and clavirolides A–F possess interesting
and diverse biological activities,4b including cytotoxicity
toward carcinoma cells, blockage of Ca+ channels, neg-
ative inotropic activity as well as bradycardia effect. The
unusual trans-bicyclo[9.3.0]tetradecane framework, bio-
logical significance, as well as limited availability of
these compounds have rendered them interesting targets
for synthetic laboratories.5 We herein disclose a stereo-
selective approach to the bicyclo[9.3.0]tetradecenone
core structure of clavulactone, the most prominent
member of this class of compounds.
In view of the lability of the six-membered a,b-unsatu-
rated lactone moiety, clavulactone could be retrosyn-
thetically reduced to the properly functionalized
bicyclo[9.3.0] tetradecenone 1 with chemically differenti-
ated olefins. Enone 1 could be visualized from the cou-
pling/macrocyclization sequence of segment 2 and the
known aldehyde 3 (Scheme 1).
In our approach to segment 2, a reliable and efficient
method was explored to construct the desired asymmet-
ric quaternary carbon center6 as well as a proper func-
tionalization on the five-membered ring part. The
sequence of reactions was outlined in Scheme 2. Our
establishment of the five-membered ring with quater-
nary carbon center took advantage of the literature
*
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.2005.09.106

8432
B. Sun, X. Xu / Tetrahedron Letters 46 (2005) 8431–8434
macrocyclization
O
7a/7b was oxidized with Dess–Martin periodinane to
O
H
give ketone 8 in nearly quantitative yield. Aconvenient
four-step procedure was then carried out to furnish the
key aldehyde 11. Treatment of 8 with Me3S+Iꢀ/NaH
produced the epoxide,11 which, upon exposure to
LDA, rearranged12 to the allylic alcohol 9 in satisfactory
yield. Subsequent protection of the hydroxy group fol-
lowed by cleavage of the protected dihydroxy group
converted 9 to aldehyde 11, which underwent smooth
Horner–Emmons reaction13 with (PhO)2P(O)CH(CH3)-
CO2Et/NaH to deliver the (Z)-favored a,b-unsaturated
ester 12 along with trace of its (E)-isomer. It is worthy
of note that the (E)-isomer, which should be utilizable
in syntheses of clavirolides, could be obtained as the ma-
jor product when the corresponding Wittig reagent
(Ph3P@C(CH3)CO2Et) was applied in the olefination.14
Ester 12 was then reduced with DIBAL-H to afford
the desired allylic alcohol 13a, which was subsequently
converted to the halide 13b. The geometry of the teth-
ered double bond in 13a remained intact in terms of
its spectral data.
O
OR
O
1
segments coupling
Clavulactone
OR
H
+
OR
O
3
2
X
Scheme 1. Retrosynthetic analysis of clavulactone.
O
O
(1) NMO, cat. OsO4
(2) ethaneditiol
baker's
yeast
65%
BF3.Et2O
S
O
HO
HO
O
O
(3) DMOP, H+
45~50%
S
4
5
6a/6b
With segment 2 in hand, we turned our attention to the
procurement of aldehyde 3. From the commercially
available chiron, methyl (S)-3-hydroxy-2-methylpropio-
nate (14), segment C was efficiently achieved in four
steps. By the known sequence,15 14 was transformed
to iodide 15 in excellent yield. Then, 15 was treated with
t-BuLi at ꢀ78 °C to effect halogen–lithium exchange fol-
lowed by quenching with anhydrous DMF to furnish
the aldehyde 16 as a mixture of the THP acetals in
rather good yield (Scheme 3).
O
O
O
O
O
O
(1) Me2S=CH2
Raney
Nickel
DMP
HO
(2) LDA,
O
HO
quant.
86%
92%
7a/7b
8
9
O
O
OBn
OBn
NaH,
BnBr
HWE
reaction
HIO4,
EtOAc,
quant.
O
95%
91%
BnO
H
10
OBn
11
12
Initially, we attempted to accomplish the coupling of
13b and 16 in the following sequence: conversion of
iodide 13b to the allyl carbanion followed by the addi-
tion to aldehyde 16 to deliver a homoallylic alcohol.
Hence, we attempted to lithiate 13b (X = I) with n-BuLi
or t-BuLi at ꢀ78 °C followed by an addition of 16,
which to our disappointment resulted in a complex mix-
ture. This could be ascribed to the possible decomposi-
tion of the labile allyl benzyl ether moiety. Thus, an
alternative pathway was entailed to circumvent these
disadvantages and difficulties.
O
Et
DIBAL-H
94%
X
MsCl, Et3N, LiCl 97% ( for X = Cl )
Ph3P, imid., I2 quant. ( for X = I )
13a X = OH
13b X = Cl or I
Scheme 2. Synthesis of allylic halide 13b.
precedence7 so that the readily available prochiral dike-
tone 4 was desymmetrized through microbial reduction
to provide keto alcohol 5 with consistent >99% ee value.
To the best of our knowledge, keto alcohol 5 was never
employed in syntheses of complex molecules, partly due
to the inconvenience of removal of the hydroxy or car-
bonyl group from the cycle suffering from their bulky
neighboring quaternary center. In fact, our initial
attempts to reduce the carbonyl group in 5 or its various
hydroxy protected versions employing Clemmensen
reduction8 or Wolff–Kishner reduction (Huang–Minlon
modification)9 was abortive. Eventually, 5 was success-
fully transformed to a separable mixture of 6a/6b
through sequential dihydroxylation of the terminal ole-
fin, protection of the carbonyl group, and protection
of the dihydroxy group in good overall yield. Subse-
quent desulfurization of 6a/6b with Raney nickel10 affor-
ded 7a/7b in excellent yield. Since the stereochemistry of
the newly generated tethered stereogenic centers in 7a/7b
was of no significance and would be extinguished later,
Protected cyanohydrin alkylation proved to be an effec-
tive method in connecting two segments and was well
applied in total synthesis of natural products.16 Thus,
aldehyde 16 was treated with TMSCN to give the
TMS protected cyanohydrin followed by manipulation
into its EE protected version 17 as a mixture of eight
possible diastereomers. Coupling between substrates 17
and 13b (X = Cl) was successfully realized in the pres-
ence of NaHMDS affording mixture 18 in good yield.
The configuration of the tethered trisubstituted alkene
(1) DHP,
cat. PPTS
t-BuLi, -78 oC;
anhydr. DMF,
-78 oC to rt,
79 %
(2) LAH
I
OHC
O
(3) Ph3 P,
imid. I2
92%
OTHP
OTHP
O
14
OH
15
16
Scheme 3. Synthesis of aldehyde 16.

B. Sun, X. Xu / Tetrahedron Letters 46 (2005) 8431–8434
8433
(1) TMSCN, 18-C-6,
then H2O
OEE
ketone function led to the formation of the desired bicy-
clo[9.3.0]tetradecenone, as a 4:1 mixture of the MOM
protected hydroxy group. The major component was
determined as 24 through analysis of its data including
1H, 13C, ESI, HRESI, COSY, NOESY, HMQC, and
HMBC.18
OHC
OTHP
NC
(2) EVE, PPTS
94%
16 OTHP
17
OTHP
OBn
OBn
NaHMDS,
then 13b
CN
49%
OEE
In summary, we have developed a very efficient ap-
proach for the bicyclo[9.3.0]tetradecenone core structure
of the novel diterpene Clavulactone starting from the
readily and abundantly available 2-methyl-1,3-cyclo-
pentandione by employing microbial desymmetritiza-
tion and cyanohydrin alkylation as the key steps. The
synthetic route devised is efficient and convergent, and
should be readily adapted for the syntheses of claviro-
lides A–F. The focus of future investigations will lie in
the incorporation of the six-membered a,b-unsaturated
lactone moiety into the framework. Studies are currently
well underway in our laboratories and will be reported
in due course.
13b
18
Cl
Scheme 4. Segments coupling.
in 18 was confirmed by its spectral data. And in this
reaction, neither the regioisomer nor the stereoisomer
of the tethered double bond was detected (Scheme 4).
After successful assembly of the two segments, the fol-
lowing task was to achieve the annulation of the 11-
membered carbocycle. Protected cyanohydrin alkylation
also proved to be an excellent tool in cyclizing carbocy-
cles of various sizes, including those constrained rings of
medium sizes,17 so we were to employ it in our synthesis
again.
Acknowledgments
We thank the National Natural Science Foundation of
China, Chinese Academy of Sciences for their financial
support (Grant Number: 20472100).
As shown in Scheme 5, concomitant deprotection of the
two hydroxy groups in compound 18 gave a mixture of
diol 19, of which the primary hydroxy group was then
selectively silylated followed by basic elimination of
HCN to afford the unstable b,c-unsaturated ketone 20
as a single isomer. Treatment of 20 with NaBH4 fol-
lowed by protection of the alcohol with MOMCl gave
mixture 21, which was further converted into a,b-unsat-
urated aldehyde 22 as two diastereomers through suc-
cessive removal of the benzyl group and oxidation of
the corresponding deprotected allylic alcohol. Enal 22
was then elaborated into the protected cyanohydrin fol-
lowed by desilylation to furnish alcohol 23 as a mixture
of eight possible diastereomers. Iodation of alcohol 23
afforded the proper substrate for macrocyclic alkylation,
which proceeded smoothly in the presence of LiHMDS
under high dilution condition. Subsequent release of the
References and notes
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¨
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´
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OH
OTHP
OTBS
O
(1) TBSCl,
imid.
OBn
OBn
OBn
CH3OH,
PPTS
(2) NaOH
H2O
CN
OH
CN
81%
86%
OEE
18
19
20
OTBS
OTBS
O
OBn
(1)NaBH4,
(2) MOMCl,
DIPEA
(1) Li-Naph.
(2) DMP
98%
87%
OMOM
OMOM
21
22
(1) Ph3P, imid., I2
(2) LiHMDS,
(3) CH3OH,
PPTS,
OH
OEE
(1) TMSCN,
cat. 18-C-6,
(2) Et3N.HF
O
NC
PPTS
(3) EVE,
(4) NaOH,
H2O,
OMOM
OMOM
(4) NH4F,
CH3OH,
81%
70%
24
23
Scheme 5. Synthesis of bicyclo[9.3.0]tetradecenone 24.

8434
B. Sun, X. Xu / Tetrahedron Letters 46 (2005) 8431–8434
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20
18. Characteristic data of compound 24: ½aꢁD +82.8 (c 0.625,
CHCl3); 1H NMR (400 MHz, CDCl3): d 6.66 (br, 1H),
5.29 (dd, 1H, J1 = 11.4 Hz, J2 = 5.8 Hz), 4.61 (AB, 2H,
J = 7.4 Hz, J = 6.8 Hz), 3.90 (m, 1H), 3.35 (s, 3H), 2.83 (d,
1H, J = 11.4 Hz), 2.80 (d, 1H, J = 11.5 Hz), 2.48–2.25 (m,
3H), 2.15 (m, 1H), 2.00 (d, 1H, J = 11.9 Hz), 1.85–1.55 (m,
3H), 1.64 (s, 3H), 1.49 (m, 2H), 1.38 (s, 3H), 1.095 (d, 3H,
J = 6.85 Hz); 13C NMR (100 MHz, CDCl3): d 201.33,
150.82, 145.89, 134.34, 124.60, 94.64, 73.29, 55.29, 50.94,
47.69, 37.21, 36.72, 34.94, 31.23, 28.58, 27.97, 26.20, 24.34;
ESI-MS (m/z): 345.1 ([M+K]+), 329.2 ([M+Na]+), 307.2
([M+H]+); HRMS(ESI) m/z calcd for [C19H30O3Na]+:
329.2087; found: 329.2079; IR(film): 2952, 2928, 1653,
1608, 1449, 1149, 1098, 1042 cmꢀ1
.
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404.
C1 50.94
C2 36.72
C3 124.60
C4 134.43
C5 24.34
C6 34.94
C7 73.29
C8 94.64
C9 55.29
C10 37.21
C11 27.97
C12 26.20
C13 47.69
C14 201.33
C15 150.82
C16 145.89
C17 31.23
C18 36.04
C19 28.58
2.80,2.00
1.10
12
O
O
15
14
6.66
2.15
16
13
1.49
3.90
4.61
10
O
2.35,2.40
2.10,1.65
11
7
17
1
8
18
19
6
2
3.35
9
O
1.38
2.83,1.74
O
O
3
5.29
4
5
1.65
2.34,1.80