A new and efficient total synthesis of (±)-laurencenone C

Article abstract of DOI:10.1055/s-0030-1259052

A novel total synthesis of laurencenone C, a chamigrene sesquitepenoid natural product, has been accomplished in 11 steps. In the synthetic sequence, the B-ring of the spirocyclic core was constructed by a one-pot operation involving a Knoevenagel condens

Full text of DOI:10.1055/s-0030-1259052

LETTER
3061
A New and Efficient Total Synthesis of ( )-Laurencenone C
S
ynthesis of
(
)-L
a
u
urencenone
o
C
-Ching Chu,a Hsing-Jang Liu,*a Jia-Liang Zhu*b
a
Department of Chemistry, National Tsing Hua University, Hsinchu 30043, Taiwan, Republic of China
Fax +886(3)35665; E-mail: hjliu@mx.nthu.edu.tw
Department of Chemistry, National Dong-Hwa University, Hualien 974, Taiwan, Republic of China
Fax +886(3)8633570; E-mail: jlzhu@mail.ndhu.edu.tw
b
Received 14 September 2010
reaction7 as the key operations. Besides these approaches,
the RCM strategy was also employed in an enantioselec-
tive synthesis of 1 recently reported by Stoltz and Grubbs
et al.8 As can be seen, the syntheses of 1, as well as other
Abstract: A novel total synthesis of laurencenone C, a chamigrene
sesquitepenoid natural product, has been accomplished in 11 steps.
In the synthetic sequence, the B-ring of the spirocyclic core was
constructed by a one-pot operation involving a Knoevenagel con-
densation between ethyl cyanoacetate and paraformaldehyde com- chamigrenes,3 are critically dependent on the efficient cre-
bined with a Diels–Alder reaction of the resulting ethyl 2-
ation of the quaternary spirocenter with the necessary
cyanoacrylate with isoprene. Moreover, a lithium naphthalenide-in-
functionalities for building the spiro[5.5]undecane core.
duced reductive alkylation of the Diels–Alder adduct was employed
to create the C-6 quaternary center and to set the stage for assem-
bling the A-ring.
Br
Key words: chamigrene sesquitepene, laurencenone C, Diels–
O
O
Alder reaction, natural product, total synthesis
Cl
Cl
laurencenone B
laurencenone A
14
Laurencenone C (1) belongs to an abundant family of ses-
quitepenoids known as the chamigrenes, which includes
more than one hundred members1 and is characterized by
a spiro[5.5]undecane core bearing two vicinal quaternary
carbon centers at C-5 and C-6 positions. It was first isolat-
ed from the alga of the genus Laurencia obtuse,1 along
with three other structurally related chamigrenes, namely
laurencenones A, B, and D (Figure 1).2 These natural
products contain the same A-ring bearing an enone moi-
ety, and differ from each other by the functionalities on
the B-ring. Like many other chamigrenes,3 laurencenone
C has attracted attention from the synthetic community
with five total syntheses so far having been documented in
the literature.4–8 The first total synthesis was reported by
Takeshita and co-workers.4 In their synthetic sequence, a
photo-cycloaddition of terpinolene with methyl 2,4-diox-
opentanoate followed by a base-promoted retro-benzilic
acid rearrangement of the resulting hydroxy spiro-
[3.5]nonene ester was employed to prepare the key pre-
cursor for assembling the spiro framework. Following
this, Chen’s group described the synthesis of 1 by utilizing
a crucial intramolecular radical cyclization of an a-allenic
ketone to access the spiro ring fusion.5 However, both
syntheses provided 1 in relatively low overall yields (2.9
and 6.4%, respectively) due to the formation of other re-
gio- and stereoisomers as side products in the key synthet-
ic steps. In similar approaches, Srikrishna and co-workers
twice described the total synthesis of 1 through the use of
an Ireland ester Claisen rearrangement combined with a
RCM reaction6 or an intramolecular type II carbonyl ene
13
9
15
A
B
6
1
3
O
O
Cl
7
Br
12
laurencenone C (1)
laurencenone D
Figure 1 Skeleton of chamigrenes and structures of laurencenones
A–D
Presented here is our total synthesis of 1 based on a new
approach. As outlined in our retrosynthetic analysis
(Scheme 1), we envisioned that a Diels–Alder reaction
between ethyl cyanoacrylate and isoprene could be used
to deliver the spirocyclic core and provide intermediate 2.
The cyano moiety of 2 was intended to be elaborated into
a 1-methyl-3-oxopropyl group via a lithium naphthalen-
ide (LN)-induced reductive alkylation operation devel-
oped by us,9 while the ester group was to be converted into
an acetyl functionality to give intermediate 3. Aldol con-
densation of 3 would allow the establishment of the spiro
skeleton and afford enone 4, from which intermediate 5
was to be generated through a 1,2-addition of methyllith-
ium and a subsequent oxidative rearrangement reaction.
At the end, introduction of a methyl group to the b-posi-
tion of the enone moiety of 5 followed by installation of
the C1–C2 double bond would complete the total synthe-
sis of 1.
We initially tried to prepare ethyl cyanoacrylate by the
Knoevenagel condensation of ethyl cyanoacetate with
paraformaldehyde in pyridine according to the reported
procedure.10 However, it was found that the resulting
acrylate was extremely unstable and polymerized easily
upon usual work-up and purification. To circumvent this
problem, we turned to a strategy of conducting the con-
SYNLETT 2010, No. 20, pp 3061–3064
x
x
.x
x
.2
0
1
0
Advanced online publication: 17.11.2010
DOI: 10.1055/s-0030-1259052; Art ID: W14610ST
© Georg Thieme Verlag Stuttgart · New York

3062
K.-C. Chu et al.
LETTER
O
iodobutoxydimethylsilane13 to produce the alkylated
product 6 (70%) as a mixture of two diastereomers (1:1).
Deprotection of 6 with tetrabutylammonium fluoride
(TBAF) afforded 70% of spirolactone 7 (1.2:1) resulting
from the spontaneous intramolecular lactonization, along
with 25% of hydroxy ester 8. Upon exposure to sodium
hydride, compound 8 could be readily transformed into 7
in an almost quantitative yield (93%). Addition of meth-
yllithium to 7 was subsequently conducted to yield ketoal-
cohol 9 (1.4:1, 90% yield), which was then converted into
intermediate 3 (1.5:1) through oxidation with pyridinium
chlorochromate (PCC). Aldol condensation of 3 under ba-
sic reaction conditions established the spirocyclic frame-
work to give the key intermediate 4 (1.5:1) in 80% yield.
Subsequent elaboration of 4 into intermediate 5 also pro-
ceeded smoothly via a two-step synthetic sequence in
which 4 was first subjected to reaction with methyllithium
to produce two separable diastereomeric alcohols 10a and
10b14 in 57 and 35% yield, respectively, which were then
individually treated with PCC 15 to produce 5a and 5b14 in
an equal yield (90%). With 5a and 5b in hand, we then at-
tempted to introduce a methyl group to the b-position of
the enone moiety through a nucleophilic conjugate addi-
tion reaction. However, treatment of 5a or 5b with lithium
dimethylcuprate (Me2CuLi) in diethyl ether from 0 °C to
r.t. afforded only recovered starting materials. Additional-
ly, application of Yamamoto’s procedure (Me2CuLi,
O
1
4
5
O
CO2Et
CN
EtO2C
CN
+
O
2
3
Scheme 1 Retrosynthetic analysis of 1
densation and the subsequent Diels–Alder reaction with
isoprene in one-pot. De Keyser et al. previously described
a procedure in which anthracene was used to trap the me-
thylidenemalonates generated in situ in a Diels–Alder
process with the assistance of copper(II) acetate.11 In light
of this, we then applied similar reaction conditions to our
system, and were pleased to find that the desired cyclo-
adduct 2 could be formed in high yield (95%, Scheme 2).
After the formation of the B-ring, we moved forward to
create the spiro skeleton by utilizing a LN-induced reduc-
tive alkylation reaction of 2. Thus, 2 was first treated with
LN12 in tetrahydrofuran (THF) at –40 °C for one hour, and
the resulting enolate derived from the reductive decyana-
tion was subsequently trapped in situ by tert-butyl-3-
CO2Et
CO2Et
a)
b)
EtO2C
CN
OTBDMS
95%
70%
CN
2
6 (1:1)
c)
O
CO2Et
OH
O
+
7 (70%,1.2:1)
8 (25%, 1:1)
d)
e)
90%
93%
O
O
O
f)
g)
OH
O
80%
95%
9 (1.4:1)
3 (1.5:1)
4 (1.5:1)
h
OH
i)
O
O
5a (90%); 5b (90%)
10a (57%); 10b (35%)
Scheme 2 Reagents and conditions: (a) Paraformaldehyde (2 equiv), isoprene (3 equiv), Cu(OAc)2 (0.1 equiv), toluene–AcOH, 1:1, 80 °C,
24 h; (b) LN (3 equiv), THF, –40 °C, 1 h, then (Me)CHICH2CH2OTBDMS (1.3 equiv), r.t., 2 h; (c) TBAF (3 equiv), THF, r.t., 20 h; (d) NaH
(2 equiv), THF, 0 °C to r.t., 2 h; (e) MeLi (1.1 equiv), THF, –78 °C, 2 h; (f) PCC (2 equiv), CH2Cl2, r.t., 2 h; (g) KOH (2.8 equiv), THF–H2O,
10:1, reflux, 24 h; (h) MeLi (1.4 equiv), THF, –78 °C to r.t., 2 h; (i) PCC (1.5 equiv), Celite, CH2Cl2, r.t., 3 h.
Synlett 2010, No. 20, 3061–3064 © Thieme Stuttgart · New York

LETTER
Synthesis of ( )-Laurencenone C
3063
TMSCl, CH2Cl2, –78 °C to 0 °C)16 to 5 also gave no trace Supporting Information for this article is available online at
of the desired addition products.
http://www.thieme-connect.com/ejournals/toc/synlett.
Me2CuLi
Acknowledgment
O
R1
We are grateful to the National Science Council of Republic of
China (Taiwan), National Tsing Hua University for financial sup-
port.
3
2
A
O
R2
Me2CuLi
B
References and Notes
A
R1 = R2 = H or Me
(1) For examples of isolations of chemigrenes, see:
(a) Erickson, K. L. In Marine Natural Products: Chemical
and Biological Perspectives, Vol. 5; Scheuer, P. J., Ed.;
Academic Press: New York, 1990, 131–257. (b) Attaway,
D. H.; Zaborsky, O. R. In Marine Biotechnology:
Pharmaceutical and Bioactive Natural Products; Plenum
Press: London, 1993, 333–334. (c) Sim, J. J.; Lin, G. H.;
Wing, R. M. Tetrahedron Lett. 1974, 15, 3487. (d)Kikuchi,
H.; Suzuki, T.; Suzuki, M.; Kurosawa, E. Bull. Chem. Soc.
Jpn. 1985, 58, 2473. (e) Elsworth, J. F. J. Nat. Prod. 1989,
52, 893. (f) Rashid, M. A.; Gustafson, K. R.; Gardellina,
J. H.; Boyd, M. R. Nat. Prod. Lett. 1995, 6, 255.
(g) Francisco, M. E. Y.; Erickson, K. L. J. Nat. Prod. 2001,
64, 790. (h) Dorta, E.; Díaz-Marrero, A. R.; Cueto, M.;
D’Croz, L.; Maté, J. L.; Darias, J. Tetrahedron Lett. 2004,
45, 7065; and references cited therein.
(2) (a) Kennedy, D. J.; Selby, I. A.; Thomson, R. H.
Phytochemistry 1988, 27, 1761. (b) For the isolation of
laurencenone C from the other natural source, see: Asakawa,
Y.; Tori, M.; Masuya, T.; Frahm, J.-P. Phytochemistry 1990,
29, 1577.
(3) For examples on total syntheses of chamigrenes, see:
(a) Wolinsky, L. E.; Faulkner, D. J. J. Org. Chem. 1976, 41,
597. (b) Martin, J. D.; Pérez, C.; Ravelo, J. L. J. Am. Chem.
Soc. 1986, 108, 7801. (c) Niwa, H.; Yoshida, Y.; Hasegawa,
T.; Yamada, K. Tetrahedron 1991, 47, 2155. (d) White, D.
E.; Stewart, I. C.; Crubbs, R. H.; Stoltz, B. M. J. Am. Chem.
Soc. 2008, 130, 810. (e) Cui, Q.; Kang, L.; Yang, H. S.; Xu,
X. H. Chin. Chem. Lett. 2009, 554; and references cited
therein.
Figure 2 Proposed unfavorable steric interactions for 1,4-addition
of 5 and favorable co-planar state of the A-ring
We envisioned that the failure of the addition reaction
might be attributed to the unfavorable steric interactions
between the nucleophile and the C2–C3 subunit of the A-
ring (Figure 2, state A) and the C-1 axial methyl group
(R2 = Me). Nevertheless, it was possible that such interac-
tions could be minimized when the A ring was forced to
adopt a planar conformation by the introduction of an ex-
tra double bond (state B). In this regard, we then rerouted
our original synthetic plan by transforming the mixture of
5a and 5b into dienone 11 using the well-established sele-
nylation–oxidative elimination method (Scheme 3). To
our delight, when 11 was allowed to react with Me2CuLi
in the presence of trimethylsilyl chloride,16 the target mol-
ecule 1 could be produced in high yield (88%), indicating
that a planar conformation of the A-ring was indeed favor-
able for the conjugate addition. The spectral data (1H, 13C
NMR) of 1 were found to agree well with those reported
for the natural product.2,1,7
a)
b)
O
5a + 5b
( )-1
60%
88%
(4) Hatsui, T.; Wang, J.; Takeshita, H. Bull. Chem. Soc. Jpn.
1994, 67, 2507.
11
(5) Chen, Y. J.; Wang, C. Y.; Lin, W. Y. Tetrahedron 1996, 52,
Scheme 3 Reagents and conditions: (a) LDA (1.2 equiv), PhSeCl
(1.2 equiv), THF, –78 °C, 30 min, then work-up, aq H2O2 (30%, 10
equiv), CH2Cl2, 10 min; (b) Me2CuLi (3 equiv), TMSCl (3 equiv),
CH2Cl2, –78 °C to r.t., 3 h.
13181.
(6) Srikrishna, A.; Lakshmi, B. V.; Mathews, M. Tetrahedron
Lett. 2006, 47, 2103.
(7) Srikrishna, A.; Babu, R. R. Tetrahedron 2008, 64, 10501.
(8) White, D. E.; Stewart, I. C.; Seashore-Ludlow, B. A.;
Grubbs, R. H.; Stoltz, B. M. Tetrahedron 2010, 66, 4668.
(9) Shia, K. S.; Chang, N. Y.; Yip, J.; Liu, H. J. Tetrahedron
Lett. 1998, 39, 7713.
(10) Khalafallah, A. K.; Elal, R. M. A.; Kanzi, N. A. A.
Heterocycl. Commun. 2002, 397.
(11) De Keyser, J.-L.; De Cock, C. J. C.; Poupaert, J. H.;
Dumont, P. J. Org. Chem. 1998, 53, 4859.
(12) For preparing a stock solution of LN, see: Liu, H. J.; Yip, J.;
Shia, K. S. Tetrahedron Lett. 1997, 38, 2253.
(13) Yefidoff, R.; Albeck, A. Tetrahedron 2004, 60, 8093.
(14) The relative stereochemistry of two diastereoisomers
remains to be determined.
(15) Mehta, G.; Nandakumar, J. Tetrahedron Lett. 2001, 42,
7667.
(16) Asao, N.; Lee, S.; Yamamoto, Y. Tetrahedron Lett. 2003,
44, 4265.
In summary, a concise total synthesis of ( )-laurencenone
C (1) has been accomplished in 11 steps. This new one-
pot approach, involved a Knoevenagel condensation com-
bined with a Diels–Alder reaction, and a reductive alkyla-
tion reaction of the resulting Diels–Alder adduct, as
efficient key steps in the creation of the B-ring as well as
the spiro quaternary center. Compared with other prece-
dents, our synthesis has the advantage of offering straight-
forward access to 1 in relatively high overall yield
(17.4%), at low cost and without the formation of side
products or isomers. The synthetic strategies employed
for the synthesis of 1 are being applied to the syntheses of
other chamigrenes, and the results will be reported in due
course.
(17) The spectral data of 1 are as follows. IR (neat): 3023, 2960,
2932, 1668, 1610, 1445 cm–1; 1H NMR (CDCl3, 400 MHz):
Synlett 2010, No. 20, 3061–3064 © Thieme Stuttgart · New York

3064
K.-C. Chu et al.
LETTER
d = 5.77 (s, 1 H), 5.41 (s, 1 H), 2.53 (d, J = 18.2 Hz, 1 H),
2.15 (d, J = 18.2 Hz, 1 H), 1.88 (s, 3 H), 1.98–1.91 (m, 2 H),
1.82–1.78 (m, 2 H), 1.68–1.64 (m, 2 H), 1.59 (s, 3 H), 0.94
(s, 3 H), 0.86 (s, 3 H); 13C NMR (CDCl3, 100 MHz): d =
198.5 (C), 170.3 (C), 133.9 (C), 126.8 (CH), 121.4 (CH),
48.8 (CH2), 43.2 (C), 40.2 (C), 30.5 (CH2), 28.1 (CH2), 27.8
(CH2), 24.7 (CH3), 24.1 (CH3), 23.7 (CH3), 23.2 (CH3);
HRMS (EI): m/z [M]+ calcd for C15H22O: 218.1671; found:
218.1669.
The spectral data of the key intermediate 4 are as follows.
IR (neat): 3035, 2960, 2912, 1674, 1447 cm–1; 1H NMR
(CDCl3, 600 MHz): d = 6.67–6.64 (m, 1 H, major), 6.63–
6.61 (m, 1 H, minor), 5.87–5.82 (m, 2 H), 5.31 (d,
J = 1.3 Hz, 1 H, minor), 5.26 (d, J = 1.5 Hz, 1 H, major),
2.69 (ddt, J = 17.7, 5.4, 2.7 Hz, 1 H, minor), 2.55 (ddt,
J = 20, 5.5, 2.8 Hz, 1 H, major), 2.46–2.43 (m, 1 H, minor),
2.19–2.17 (m, 2 H), 2.13–2.04 (m, 4 H), 1.92–1.64 (m, 9 H),
1.59–1.57 (m, 6 H), 0.91–0.86 (m, 6 H); 13C NMR (CDCl3,
150 MHz): d (major) = 204.6 (C), 145.8 (CH), 133.5 (C),
128.3 (CH), 118.2 (CH), 46.7 (C), 35.8 (CH), 37.5 (CH2),
31.2 (CH2), 26.5 (CH2), 24.3 (CH2), 23.2 (CH3), 15.5 (CH3).
13C NMR d (minor) = 203.9 (C), 145.0 (CH), 132.1 (C),
127.9 (CH), 119.0 (CH), 47.5 (C), 32.4 (CH), 31.5 (CH2),
29.6 (CH2), 28.9 (CH2), 27.9 (CH2), 23.2 (CH3), 15.5 (CH3);
HRMS (EI): m/z [M]+ calcd for C13H18O: 190.1358; found:
190.1362.
The spectral data of the key intermediate 6 are as follows.
IR (neat): 2957, 2929, 2857, 1726, 1447 cm–1; 1H NMR
(CDCl3, 600 MHz): d = 5.28 (br s, 2 H), 4.06–4.03 (m, 4 H),
3.61–3.59 (m, 2 H), 3.51–3.48 (m, 2 H), 2.44–2.36 (m, 2 H),
1.96–1.72 (m, 14 H), 1.60 (s, 6 H), 1.17–1.15 (m, 6 H),
1.10–1.02 (m, 2 H), 0.84–0.81 (m, 24 H), –0.02 to –0.03 (m,
12 H); 13C NMR (CDCl3, 150 MHz): d = 175.8 (C), 175.7
(C), 133.0 (C), 132.9 (C), 119.8 (CH), 119.6 (CH), 61.6
(CH2), 61.5 (CH2), 59.8 (CH2), 48.3 (C), 36.3 (CH), 36.1
(CH), 29.6 (CH2), 29.4 (CH2), 28.6 (CH2), 28.5 (CH2), 28.0
(CH2), 27.9 (CH2), 25.8 (CH3), 23.1 (CH3), 18.2 (C), 14.7
(CH3), 14.1 (CH3), 13.9 (CH3), –5.35 (CH3), –5.43 (CH3);
HRMS (EI): m/z [M]+ calcd for C20H38O3Si: 354.2590;
found: 354.2593.
The spectral data of the key intermediate 11 are as follows.
IR (neat): 2920, 1651, 1614 cm–1; mp 106.3–107.6 °C;
1H NMR (CDCl3, 600 MHz): d = 5.96 (s, 2 H), 5.46 (t,
J = 1.6 Hz, 1 H), 2.13–2.11 (m, 2 H), 2.03–2.01 (m, 2 H),
1.95 (s, 6 H), 1.67–1.65 (m, 5 H); 13C NMR (CDCl3, 150
MHz): d = 185.9 (C), 166.5 (C), 133.5 (C), 126.8 (2CH),
119.5 (CH), 44.1 (C), 31.9 (CH2), 29.5 (CH2), 27.3 (CH2),
23.4 (CH3), 21.4 (CH3), 21.3 (CH3); HRMS (EI): m/z [M]+
calcd for C14H18O: 202.1358; found: 202.1358cc.
Synlett 2010, No. 20, 3061–3064 © Thieme Stuttgart · New York

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