The first synthesis of marine sesterterpene (+)-scalarolide

Article abstract of DOI:10.1016/j.tetlet.2009.06.064

The synthesis of the first example of C12 oxygenated marine scalaranic sesterterpenes (+)-scalarolide was achieved through three key steps including the ring-opening rearrangement of epoxide, stereoselective Diels-Alder addition and one-pot γ-butenolide f

Full text of DOI:10.1016/j.tetlet.2009.06.064

Tetrahedron Letters 50 (2009) 4983–4985
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The first synthesis of marine sesterterpene (+)-scalarolide
*
*
Xiang-Jian Meng, Yang Liu, Wen-Yuan Fan, Bin Hu, Wenting Du , Wei-Ping Deng
School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the first example of C12 oxygenated marine scalaranic sesterterpenes (+)-scalarolide was
achieved through three key steps including the ring-opening rearrangement of epoxide, stereoselective
Received 12 May 2009
Revised 7 June 2009
Accepted 12 June 2009
Available online 16 June 2009
Diels–Alder addition and one-pot
ural scalarolide was confirmed.
c-butenolide formation process, and the absolute configuration of nat-
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to Professor Li-Xin Dai (Shanghai
Institute of Organic Chemistry) on the
occasion of his 85th birthday
An increasing number of compounds of the scalarane sester-
terpenoids,1 which display a variety of biological activities such
as cytotoxic,2 antifeedant,3 anti-inflammatory4 and platelet-aggre-
gation inhibitory effects5 have been isolated from different marine
organisms during the past three decades. Many members of this
group of scalaranic sesterpenes possess an ABCDE pentacyclic-
terpenes possessing the unique C12 oxygenated function are still
a real challenge to synthetic organic chemists today.
For our continuing interest in developing simple and versatile
synthetic routes for the total synthesis of terpenoids from readily
available chiral starting materials,15 we are intrigued by the fact
that not a single successful report on the synthesis of naturally
occurring scalaranes functionalized at position 12 has been pub-
lished so far. The key strategy involved in our synthesis is the
Diels–Alder addition of tricyclic diene with DMAD, which provides
the D ring. It should be noted that this Diels–Alder addition meth-
od14b has been proved a failure to construct the scalarane skeleton
with right stereochemistry in the synthesis of natural scalaranic
sesterterpenes without C12 oxygenated function. In view of the
above reported stereochemical outcome, we envisioned that the
introduction of C12 functional group might be an option poten-
tially capable of altering the stereochemistry of the Diels–Alder
addition. Herein, we would like to present the preliminary results
on the first stereoselective synthesis of marine sesterterpene scal-
arolide 1. As far as we know, this is also the first successful exam-
ple of synthetic approach to the C12 oxygen-functionalized
scalaranic sesterterpenoids since their first isolation in 1972.16
Our approach commences with the preparation of the tricyclic
intermediate 10 (50% yield over 8 steps) by a published proce-
dure12b,14a,17 from readily available sclareol 9 as starting material
(Scheme 1). Epoxidation of 10 using m-CPBA gave epoxide 11 in
78% yield. Subsequent ring-opening rearrangement of 11 to
fused ring skeleton, which contains a c-butenolide or furan as ring
E moiety, as well as a C12 oxygenated functional group as common
structural features. Some representative compounds are depicted
in Figure 1, such as scalarolide (1),2b,3a sesterstatin 7 (2),6 sesterst-
atin 6 (3),7 12-epi-acetylscalarolide (4),2a hyatolide E (5a–b),2c
heteronemin (6),8 sesterstatins 4 and 5 (7a–b)9, and scalarafuran
(8).3a
Due to their important ecological roles,3a interesting biological
properties, and unique structural skeleton, many efforts have been
made toward the total synthesis of these marine scalarane sester-
terpenes.10,11 A variety of strategies have been developed to con-
struct the scalarane framework such as the electrophilic
cyclization of bicyclic (AB ring) substrate forming the CD fused
ring,12 the biomimetic-like electrophilic cyclization13 of C25 ali-
phatic substrates providing ABCD tetracyclic ring in one step, as
well as the Diels–Alder addition14 constructing the D ring from
an ABC tricyclic ring precursor. However, to the best of our knowl-
edge, in most cases, the above mentioned synthetic routes end up
with the construction of the tetracyclic ring skeleton, none of them
has been successfully utilized to produce the scalarane sesterterp-
enes containing C12 oxygenated group, which is supposed to be a
prerequisite maintaining the biological activity. As Ungur once
pointed,10 new efficient synthetic paths toward scalaranic sester-
a,b-unsaturated ester 12 under basic condition, being our initial
strategy to introduce the C12 hydroxy group, turned out to be
completely a failure. This is probably one of the main reasons most
synthetic methods failed in the incorporation of the oxygenated
function at the C12 position of scalaranes to date.
Alternatively (Scheme 2), epoxidation of aldehyde 14, which
was prepared from 10 through LAH reduction and swern oxidation,
furnished the epoxide 16 as a major product in 70% yield, accom-
* Corresponding authors. Tel./fax: +86 021 64252431.
E-mail addresses: ddwwtt@163.com (W. Du), weiping_deng@ecust.edu.cn (W.-P.
Deng).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.064

4984
X.-J. Meng et al. / Tetrahedron Letters 50 (2009) 4983–4985
O
O
HO
OH
O
OH
O
OH
O
O
OAc
OH
1
2
3
O
OAc
O
OAc
19
18
13
O
O
O
12
E
R
20
11
C
17
16
1
D
2
8
B
14
9
7
15
A
3
6
10
4
5
5a R = H
5b R = OAc
4
I
AcO
OH
O
O
OH
O
OH
R1
R2
OAc
OAc
7a R1 = H, R2 = OH
7b R1 = OH, R2 = H
6
8
Figure 1.
panied with diastereoisomer 15 as minor product. To our amaze-
ment, the treatment of epoxide 16 with pyrrolidine as base in ether
at room temperature, in this case, underwent the ring-opening
OH
m-CPBA, CH2Cl2
8 steps
50%
COOCH3
OH
r.t., 78%
rearrangement with 12a-OH-a,b-unsaturated aldehyde 17 in 93%
9
yield. With the success of the establishment of C12 hydroxy group
on the tricyclic ring skeleton, we then focused on the stereoselec-
tive Diels–Alder addition. Wittig olefination of enal 17 provided
10
O
OH
the 12a-OH diene 18 in 79% yield, followed by a consecutive oxi-
dation with PDC and stereoselective reduction to produce the 12-
epimer of 18, 12b-OH diene 20 in excellent yield (Scheme 3).
As depicted in Scheme 4, the benzyl protection of 12b-OH of 20
with benzyl bromide gave diene 21 (96% yield), which was then
subjected to Diels–Alder addition with DMAD in sealed tube at
110 °C. As expected, the Diels–Alder addition afforded undesired
Bases
COOCH3
COOCH3
11
12
Scheme 1.
Swerm Oxidation
LiAlH4, Et2O, rt
97%
COOCH3
CH2OH
96%
13
10
O
O
m-CPBA, CH2Cl2,
85%
CHO
CHO
CHO
14
15 (15%)
16 (70%)
OH
Pyrrolidine, Et2O, r.t.
CHO
from 16
93%
17
Scheme 2.

X.-J. Meng et al. / Tetrahedron Letters 50 (2009) 4983–4985
4985
OH
Taking into account the convenient chemical transformation of
Diels–Alder adduct 23 and
-butenolide moiety,3a we believe that
OH
c
our method would be of great benefit to the synthesis of other nat-
urally occurring C12 oxygenated scalaranes, such as sesterstatins,
hyatolides, heteronemins, and scalarafurans, which have hitherto
been beyond the reach of chemical synthesis. Investigation is cur-
rently to further improve the stereoselectivity of Diels–Alder addi-
tion, and to elaborate the attractive intermediate 23 toward
scalarafurans and other biologically active compounds in our
laboratory.
MePPh3Br, n-BuLi, THF
0 oC-r.t., 8 h, 79%
CHO
17
18
O
OH
NaBH4, CeCl3 7H2O
0 OC, 1h, 95%
PDC, CH2Cl2
r.t., 4h, 96%
Acknowledgments
This work was financially supported by the National Marine
863 Project (Grant 2006AA09Z447), the Shanghai Committee of
Science and Technology (No. 06PJ14023), the New Century Excel-
lent Talents in University, the Ministry of Education, China (No.
NCET-07-0283) and ’111’ Project (No. B07023).
19
20
Scheme 3.
OH
OBn
Supplementary data
NaH, BnBr, THF
The copies of 1H, 13C NMR spectra of key intermediates 22 and
23, final product 1 and authentic natural scalarolide.2b Supplemen-
tary data associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.06.064.
0 oC-r.t. overnight, 96%
20
21
OBn CO2Me
OBn CO2Me
CO2Me
References and notes
CO2Me
DMAD, 110 oC, N2,
sealed tube
1. (a) Liu, Y.; Wang, L.; Jung, J. H.; Zhang, S. Nat. Prod. Rep. 2007, 24, 1401; (b)
Faulkner, D. J. Nat. Prod. Rep. 1997, 14, 259. and references cited therein.
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2002, 65, 2; (c) Hernández-Guerrero, C. J.; Zubía, E.; Ortega, M. J.; LuisCarballo,
J. Tetrahedron 2006, 62, 5392.
+
24 h, 78%
22 (52%)
(26%)
23
3. (a) Walker, R. P.; Thompson, J. E.; Faulkner, D. J. J. Org. Chem. 1980, 45, 4976; (b)
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2004, 42, 454.
O
O
OBn
O
O
OH
from 23
10% Pd/C, H2
CH3OH, r.t.
LiAlH4 (0.75 eq.)
Et2O, reflux, 1h
88%
8 h, 92%
9. Pettit, G. R.; Tan, R.; Melody, N.; Cichacz, Z. A.; Herald, D. L.; Hoard, M. S.; Pettit,
R. K.; Chapuis, J.-C. Biorg. Med. Chem. Lett. 1998, 8, 2093.
24
1
10. Review for the synthetic paths towards scalaranes: Ungur, N.; Kulcißtki, V.
Scheme 4.
Phytochem. Rev. 2004, 3, 401. and references cited therein.
11. Kulcißtki, V.; Ungur, N.; Gavagnin, M.; Castelluccio, F.; Cimino, G. Tetrahedron
2007, 63, 7617.
12. (a) Herz, W.; Prasad, J. S. J. Org. Chem. 1982, 47, 4171; (b) Vlad, P. F.; Ungur, N.;
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Arellano, M. C. J. Org. Chem. 2000, 65, 4189.
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22 in 52% yield and desired 23 in 26% yield. The 2D NOESY spectra
of 22 and 23 established the above stereochemical assignment due
to an obvious crosspeak between newly formed angular methyl
group and the axial proton at C12 for 22, while the absence of such
a crosspeak for 23. This stereochemical result is different from that
of previous report.14b LAH (0.75 equiv) reduction of adduct 23 in
ether at reflux temperature resulted in highly regioselective
reduction of less hindered methyl ester group, and spontaneous
lactonization smoothly afforded
one-pot process of regioselective construction of
c
-butenolide 24 in 88% yield. This
-butenolide
c
moiety is superior to that of previously reported synthetic route
of (+)-12-deoxyscalarolide.18 Further hydrogenation of 24 using
10% Pd/C accomplished the synthesis of scalarolide 1 in 92% yield.
Comparisons of specific optical rotation (½a D18
ꢀ
+23.6, c 0.13, CH2Cl2
18. Ragoussis, V.; Liapis, M.; Ragoussis, N. J. Chem. Soc., Perkin Trans. 1 1990, 2545.
19. Data for 1: white solid, mp >300 °C; ½a D18
ꢀ
+23.6 (c 0.13, CH2Cl2); IR (KBr, m,
versus (½a 2D5
ꢀ
+24.9, c 0.15, CH2Cl2 of lit.2b), 1H NMR, 13C NMR and
cmꢁ1): 3393.0, 2928.7, 1711.3, 1442.2, 1387.3, 1060.8; 1H NMR (400 MHz,
CDCl3) d 5.94 (s, 1H), 4.75–4.65 (m, 2H), 3.67 (dd, J = 5.2, 10.9, 1H), 2.48–2.18
(m, 2H), 1.97–1.25 (m, 12H), 1.13 (s, 3H), 1.12–1.05 (m, 2H), 0.90 (s, 3H), 0.86
(s, 6H), 0.82 (s, 3H), 0.95–0.75 (m, 3H); 13C NMR (100 MHz, CDCl3) d 176.0,
162.1, 135.9, 75.6, 72.1, 58.0, 56.7, 55.2, 42.2, 42.1, 41.7, 39.7, 37.4, 37.3, 33.3,
31.0, 25.8, 25.3, 21.3, 18.6, 18.3, 17.2, 16.8, 16.5, 16.0; HRMS (ESI) calcd for
HRMS data of our synthetic 1 established the structural identity
with the natural (+)-scalarolide isolated by Youssef2b and Faulk-
ner3a reported to be structure 1.
In summary, we have finished the first synthesis of marine
C25H39O3 [M+H]+ 387.2899, found 387.2896.
(+)-scalarolide 1 in 19 steps of reaction in an overall of 4.4% yield.19
þ