Asymmetric Total Synthesis of Pseudoplexaurol and 14-Deoxycrassin, two Antitumor Marine Cembrane Diterpenoids

Article abstract of DOI:10.1055/s-2003-42077

The first asymmetric total synthesis of two naturally occurring antitumor pseudoplexaurol and 14-deoxycrassin were achieved via two convergent synthetic sequences featured a chiral pool protocol to implement C-1 stereogenic center and Ti(0)-mediated cyclization leading to cembrane ring.

Full text of DOI:10.1055/s-2003-42077

LETTER
1977
Asymmetric Total Synthesis of Pseudoplexaurol and 14-Deoxycrassin,
two Antitumor Marine Cembrane Diterpenoids
Asymmetric
To
u
tal Synthesis
o
of Pseudopl
s
exaurol an
h
d
14-Deoxyc
e
rassin ng Liu, Lizeng Peng, Weidong Z. Li, Yulin Li*
National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry Lanzhou University, Lanzhou, Gansu 730000,
P. R. China
Fax +86(931)8912283; E-mail: lilyl@lzu.edu.cn
Received 12 June 2003
as shown (Figure 1) and remained to be assigned
Abstract: The first asymmetric total synthesis of two naturally
unambiguously. Both of 2 and 1 have been shown to
occurring antitumor pseudoplexaurol and 14-deoxycrassin were
achieved via two convergent synthetic sequences featured a chiral
pool protocol to implement C-1 stereogenic center and Ti(0)-
exhibit significant cytotoxic antitumor activities against
several human tumor cell lines.4 Pseudoplexaural (3)5 and
mediated cyclization leading to cembrane ring.
pseudoplexauric acid methyl ester (4)6 have also been
found in other Caribbean marine species Eunicea
succinea (sea wip) and gorgonian Eunicea mammosa
respectively, and their structures were determined by
spectroscopic analysis and chemical correlation5,6 with
natural pseudoplexaurol (2). Epoxy alcohol 2 was
assumed to be a logical biosynthetic precursor of 1,4,6 but
attempted synthetic conversion of epoxy alcohol 2 to
lactone 1 via pseudoplexauric acid intermediate have
failed. A recent successful translactonization of euniolide
to crassin reported by Rodríguez and co-workers7 by
aqueous alkaline hydrolysis under the assistance of
sonication implies a possible conversion of 2 to 1.
Synthetic studies on the closely related natural
cembranolides bearing a 3,4-epoxy and/or lactone
functions, such as crassin, euniolide and isolobophytolide,
have been conducted over the past decades by several
groups.8 Total syntheses of 1 and 2 have not been reported
so far.
Key words: 14-deoxycrassin, diterpenoids, cembranoids, total
synthesis
Cembrane diterpenoids belong to a family of natural
products possessing
a characteristic 14-membered
carbocyclic ring skeleta.1 Although cembranes were
found in insects, animals and various terrestrial plants (i.e.
pine trees and tobaccos), marine invertebrates have
proven to be a rich source of this type of diterpenoids,2
which have emerged as a unique class of structurally
diverse and complex marine natural products. A number
of highly oxygenated cembrane diterpenoids with variety
of functionalities and intriguing biological and
physiological activities have been discovered from
tropical
or
subtropical
marine
invertebrates.2
Considerable efforts have been devoted to the chemical
synthesis of cembranolides in the past decades.3
In continuation of our ongoing program on the
stereoselective synthesis of marine cembranes, we
disclose herein the results on the asymmetric synthetic
studies of 1 and 2 in view of verifying their structural
relationship and confirming the relative and absolute
configurations accordingly. The overall strategic plan
involves (1) chemical conversion of epoxy alcohol 2 to
lactone 1 via an intramolecular lactonization, (2)
14-Deoxycrassin (1) and pseudoplexaurol (2), two novel
crassin-like cembrenoids, were first isolated from the
Caribbean gorgonian Pseudoplexaura porosa by
Rodríguez and Martínez in 1993. Although the chemical
structure of 1 and 2 were characterized on the basis of
spectral data and chemical degradation, the relative as
well as the absolute configurations of three stereogenic
centers (C-1, C-3 and C-4) were postulated biogenetically
OH
O
O
O
HO
O
O
R
H
Pseudoplexaurol (2)
Pseudoplexaural (3, R = H)
Pseudoplexauric acid
14-Deoxycrassin (1)
methyl ester (4, R = OMe)
Figure 1 Chemical structures of 14-deoxycrassin (1), pseudoplexaurol (2) and other structurally related natural cembranolides.
SYNLETT 2003, No. 13, pp 1977–1980
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-42077; Art ID: U11303ST
© Georg Thieme Verlag Stuttgart · New York

1978
Z. Liu et al.
LETTER
construction of the 14-membered cembrane ring with geo- dehalogenation as described previously gave the 3,4-
metrically defined double bonds and substituents, (3) im- epoxy alcohol 13 in 87% yield, which was desilylated to
plementation of C-1 stereogenic center via a readily produce the pseudoplexaurol (2).11 Finally, the proposed
available chiral pool [i.e. (S)-limonene], and (4) synthetic conversion of epoxy alcohol 2 to lactone 1 was
introduction of chiral epoxide function via Sharpless detailed in Scheme 4, which involved (1) MnO2 oxidation
asymmetric epoxidation of corresponding macrocyclic al- to form aldehyde derivative 3, (2) Corey oxidative
lylic alcohol intermediates. The key reaction we em- esterification12 leading to methyl ester 4, and (3) ZnCl2-
ployed for the effective construction of the 14-membered catalyzed lactonization with inversion of configuration at
carbocyclic ring includes the low-valent titanium- C-3 to produce the desired 14-deoxycrassin (1).13 The
mediated macrocyclization which is either an identity of synthetic 1 was confirmed to be natural 1 by
intramolecular pinacol-type or olefination coupling (Mc- spectroscopic comparison as well as the optical rotation
Murry coupling of dicarbonyl compounds).9 The value. We are currently working on the optimization of
synthetic strategy along those lines have been this synthetic route and determination of the relative and
demonstrated in our recent total asymmetric synthesis of absolute configurations of C-3 and C-4 unambiguously by
several natural epoxy cembrenoids.10
NOE experiment of 1 bearing a S-configurated C-1
carbon.
Shown in this poster is the mode of McMurry coupling
leading to the cembrane ring system and chiral pool In summary, first asymmetric total synthesis of two
protocol to set the C-1 stereogenic center. As shown in naturally occurring antitumor cembranolides 1 and 2 were
Scheme 1, the strategy (Scheme 3) devised a ring closure achieved via two convergent synthetic sequences featured
at C-11, 12 by McMurry coupling leading to a double a chiral pool protocol to implement C-1 stereogenic
bond and Sharpless asymmetric epoxidation of allylic center and Ti(0)-mediated cyclization leading to cem-
alcohol 5 to install the 3,4-epoxy function. Cyclization brane ring. Chemical conversion of pseudoplexaurol (2)
precursor
6 was constructed by Horner–Emmons to 14-deoxycrassin (1) was realized by a Lewis acid-
coupling of fragments 810a and 9 prepared readily as catalyzed lactonization process, which will provide a
shown (Scheme 2). The synthetic sequence was outlined direct means for the determination of the relative and
in Scheme 3. Corresponding keto aldehyde ester absolute stereochemistry of both of 2 and 1.
derivative of intermediate 7 synthesized by selective
removal of THP and Swern oxidation was found to be
reluctant for the proposed Ti(0)-mediated McMurry
Acknowledgment
This work was financially supported by the National Natural Sci-
ence Foundation of China (Grant No. 20072012) and the Special
Research Grant for Doctoral Sites in Chinese Universities (Grant
No. 20010730001).
coupling and to give low yield of the cyclization product.
Reduction of methyl ester and protection of hydroxy
group and subsequent Swern oxidation furnished 6 in
good overall yield. Cyclization of keto aldehyde 6 was
effected by TiCl4–Zn system in DME under reflux
condition to give cyclized product 11 in 69% yield, which References
was desilylated selectively under mild acidic condition
(1) Tursch, B.; Braeckman, J. C.; Dolaze, D.; Kaisin, M. In
and the resulting allylic alcohol was epoxidized by
standard Sharpless epoxidation condition with L-(+)-DET
as chiral mediator to afford the desired epoxy alcohol 12.
Standard iodination of 12 followed by reductive
Marine Natural Products: Chemical and Biological
Perspectives, Vol. 2; Scheuer, P. J., Ed.; Academic Press:
New York, 1978, 247–296.
(2) Rodríguez, A. D. Tetrahedron 1995, 51, 4571.
OPG2
OH
O
HO
OPG1
OPG1
O
CHO
Pseudoplexaurol (2)
5
6
CO2Et
CO2Et
CHO
OPG1
P(O)(OEt)2
OPG1
+
O
O
OTHP
OTHP
8
9
7
Scheme 1 Retrosynthesis of pseudoplexaurol (2) based on McMurry macro-olefination and Sharpless Asymmetric Epoxidation (SAE).
Synlett 2003, No. 13, 1977–1980 © Thieme Stuttgart · New York

LETTER
Asymmetric Total Synthesis of Pseudoplexaurol and 14-Deoxycrassin
CHO
1979
OR
a
b
28%
79%
OR
O
(S)-Limonene
R = TBDPS
9
O
Br
c
+
THPO
79%
THPO
OH
84%
d
CO2Et
P(O)(OEt)2
e
THPO
Br
79%
E/ Z = 85 : 15
OTHP
8
Scheme 2 Synthesis of fragments 8 and 9. Reagents and conditions: (a) 1. n-BuLi, TMEDA, THF, 23 °C, 24 h, then O2; 2. TBDPS-Cl,
imidazole, DMF; (b) O3, CH2Cl2, –78 °C, then Me2S; (c) Li, THF, r.t., then cyclopropyl methyl ketone; (d) LiBr, TMSCl, CH2Cl2, r.t.;
(e) (EtO)2P(O)CH2CO2Et, NaH, DMF, 60 °C.
OTBS
P(O)(OEt)2
CO2Et
RO
RO
CHO
CO2Et
OR
a
b
+
57%
77%
O
HO
O
OTHP
8
R = TBDPS
9
10
OTHP
7
OTHP
c
58%
OH
OTBS
OTBS
O
RO
RO
RO
e
d
82%
69%
O
12
CHO
11
6
87%
f
O
O
RO
HO
[α]D20 −19.4 (c 0.4, CHCl3)
g
93%
3
Lit. [α]D26 −21.6 (c 3.4, CHCl3)
13
Pseudoplexaurol (2)
Scheme 3 Reagents and conditions: (a) n-BuLi, THF, –78 °C; (b) 1. DIBALH, CH2Cl2, –78 °C; 2. TBSCl, imidazole, DMF; (c) 1. MgBr2,
Et2O, r.t.; 2. Swern oxidation; (d) TiCl4, Zn, pyridine, DME, reflux; (e) 1. PPTs, EtOH, r.t.; 2. Ti(i-PrO)4, L-(+)-DET, t-BuOOH, CH2Cl2,
–20 °C; (f) 1. I2, Ph3P, imidazole, Et2O–CH3CN, 0 °C; 2. NaBH3(CN), THF–HMPA, 60 °C; (g) TBAF, THF.
(3) (a) Tius, M. A. Chem. Rev. 1988, 88, 719. (b) Cox, N. J. G.;
Mills, S. D.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1
1992, 1313; and references cited therein.
(4) Rodríguez, A. D.; Martínez, N. Experientia 1993, 49, 179.
(5) Rodríguez, A. D.; Acosta, A. L. J. Nat. Prod. 1997, 60, 1134.
(6) Rodríguez, A. D.; Li, Y. X.; Dhasmana, H.; Barnes, C. L. J.
Nat. Prod. 1993, 56, 1101.
3605. (b) Dauben, W. G.; Wang, T. Z.; Stephens, R. W.
Tetrahedron Lett. 1990, 31, 2393. (c) McMurry, J. E.;
Dushin, R. G. J. Am. Chem. Soc. 1990, 112, 6942.
(d) McMurry, J. E.; Dushin, R. G. J. Am. Chem. Soc. 1989,
111, 8928. (e) Marshall, J. A.; Andrews, R. C.; Lebioda, L.
J. Org. Chem. 1987, 52, 2378. (f) Dauben, W. G.; Saugier,
R. K.; Fleischhauer, I. J. Org. Chem. 1985, 50, 3767.
(g) Marshall, J. A.; Royce, R. D. Jr. J. Org. Chem. 1982, 47,
693.
(7) Rodríguez, A. D.; Piña, I. C.; Acosta, A. L.; Ramírez, C.;
Soto, J. J. J. Org. Chem. 2001, 66, 648.
(8) (a) Tius, M. A.; Reddy, N. K. Tetrahedron Lett. 1991, 32,
Synlett 2003, No. 13, 1977–1980 © Thieme Stuttgart · New York

1980
Z. Liu et al.
LETTER
O
O
O
HO
MnO2, NaCN
MeOH, HOAc
CHO
CO2Me
MnO2
91%
3
3
3
58%
3
Pseudoplexaurol (2)
[α]D20 −1.8 (c 0.37, CHCl3)
Lit. [α]D25 −2.8 (c 1.4, CHCl3)
4
OMe
H3C OH
O
O
O
ZnCl2, CH2Cl2
0 °C to 20 °C
O
4
3
H
3
1
H
H
71%
inversion at C-3
4
14-Deoxycrassin (1)
[α]D20 −11.7 (c 0.42, CHCl3)
Lit. [α]D25 −15.2 (c 2.7, CHCl3)
[α]D20 +21 (c 0.06, CHCl3)
Lit. [α]D25 +29.6 (c 0.24, CHCl3)
Scheme 4 Chemical conversion of 2 to 1 by Lewis acid-catalyzed lactonization.
(9) For reviews, see: (a) Fürstner, A.; Bogdanovic, B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2442. (b) McMurry, J. E.
Chem. Rev. 1989, 89, 1513. (c) Lenoir, D. Synthesis 1989,
883. (d) McMurry, J. E. Acc. Chem. Res. 1983, 16, 405.
(10) For recent synthetic works on epoxy cembranolides from
CH2O), 2.65 (1 H, dd, J = 3.7, 7.0 Hz, epoxy H), 2.25–2.00
(11 H, m, 5 CH2, CH), 1.72–1.52 (4 H, m, 2 CH2), 1.63 (3 H,
s, CH3), 1.59 (3 H, s, CH3), 1.22 (3 H, s, CH3). HRMS (ESI)
calcd for C20H32O2Na: 327.2295. Found for [M + Na]+:
327.2295.
this laboratory, see: (a) Liu, Z. S.; Li, W. D. Z.; Li, Y. L.
Tetrahedron: Asymmetry 2001, 12, 95. (b) Liu, Z. S.; Li, W.
D. Z.; Peng, L. Z.; Li, Y.; Li, Y. L. J. Chem. Soc., Perkin
Trans. 1 2000, 4250. (c) Li, Y. L.; Liu, Z. S.; Lan, J.; Li, J.;
Peng, L. Z.; Li, W. D. Z.; Li, Y.; Chan, A. S. C. Tetrahedron
Lett. 2000, 41, 7465. (d) Lan, J.; Liu, Z. S.; Yuan, H.; Peng,
L. Z.; Li, W. D. Z.; Li, Y.; Li, Y. L.; Chan, A. S. C.
(12) Corey, E. J.; Gilman, N. M.; Ganem, B. E. J. Am. Chem. Soc.
1968, 90, 5616.
(13) Data of 14-deoxycrassin (1): [a]D20 +21 (c 0.06, CHCl3).
IR (film): nmax = 3393 (brs), 2928, 2851, 1726, 1642, 1437,
1382, 1105, 1065, 906 cm–1. LRMS (EI): m/z (%) = 318 (M,
14), 300 (M – 18, 43), 285 (25), 272 (14), 257 (18), 247 (9),
243 (14), 229 (22), 215 (21), 193 (82), 175 (52), 161 (41),
147 (66), 133 (55), 121 (69), 107 (73), 93 (73), 81 (100), 79
(68), 67 (22), 55 (48), 53 (46), 43 (44). 1H NMR (400 MHz,
CDCl3): d = 6.58 (1 H, s, CH=), 5.76 (1 H, s, 1 H), 5.19 (1
H, t, J = 6.5 Hz, CH=), 5.07 (1 H, t, J = 6.4 Hz, CH=), 4.48
(1 H, d, J = 11.5 Hz, CHO), 2.74–2.67 (1 H, m, CH), 2.55–
2.48 (2 H, m, CH2), 2.16–2.06 (6 H, m, 3 CH2), 1.95–1.81 (4
H, m, 2 CH2), 1.76 (3 H, s, CH3), 1.72 (3 H, s, CH3), 1.46–
1.40 (2 H, m, CH2), 1.25 (3 H, s, CH3). HRMS (ESI) calcd
for C21H32O3Na: 341.2087. Found for [M + Na]+: 341.2082.
Tetrahedron Lett. 2000, 41, 2181.
(11) Data of pseudoplexaurol (2): [a]D20 –19.5 (c 0.40, CHCl3).
IR (film): nmax = 3413 (brs), 2924, 2855, 1647, 1449, 1381,
1031, 898 cm–1. LRMS (EI): m/z (%) = 304 (M, 0.9), 286
(2.8), 273 (7.2), 255 (4.9), 215 (7.2), 201 (8.3), 189 (12), 173
(15), 161 (27), 147 (39), 133 (78), 119 (70), 107 (77), 93
(90), 81 (100), 79 (77), 67 (87), 55 (67), 43 (55), 41 (59). 1H
NMR (400 MHz, CDCl3): d = 5.14 (1 H, d, J = 1.0 Hz,
CH=), 5.06 (1 H, t, J = 6.4 Hz, CH=), 5.05 (1 H, dd, J = 6.4
Hz, CH=), 4.96 (1 H, d, J = 1.4 Hz, CH=), 4.11 (2 H, s,
Synlett 2003, No. 13, 1977–1980 © Thieme Stuttgart · New York