Intramolecular reductive cyclization of an enone-aldehyde: A new approach to the synthesis of (±)-majusculone

Article abstract of DOI:10.1016/j.tetlet.2013.01.087

A concise total synthesis of (±)-majusculone from 2,6,6-trimethyl-2-cyclohexen-1-one in seven steps is described. Intramolecular reductive cyclization of an enone-aldehyde using samarium diiodide is the key step in this synthesis.

Full text of DOI:10.1016/j.tetlet.2013.01.087

Tetrahedron Letters 54 (2013) 1751–1753
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular reductive cyclization of an enone–aldehyde: a new approach
to the synthesis of ( )-majusculone
⇑
Day-Shin Hsu , Bing-Chiuan Juo
Department of Chemistry and Biochemistry, National Chung Cheng University, Minhsiung 621, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise total synthesis of ( )-majusculone from 2,6,6-trimethyl-2-cyclohexen-1-one in seven steps is
described. Intramolecular reductive cyclization of an enone–aldehyde using samarium diiodide is the
key step in this synthesis.
Received 11 November 2012
Revised 17 January 2013
Accepted 21 January 2013
Available online 1 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Chamigrene
Majusculone
Samarium diiodide
Reductive cyclization
Chamigrenes are an abundant and continually expanding family
of sesquiterpenoids that contain a spiro[5.5]undecane carbon
framework with two vicinal quaternary carbon centers at the C-5
and C-6 positions (Fig. 1). To date, over one hundred chamigrenes
have been discovered.1 These natural products have demonstrated
a wide variety of interesting biological activities.1,2 The primary
challenge in the synthesis of chamigrenes is the presence of a qua-
ternary carbon adjacent to the spirocenter. Consequently, signifi-
cant effort has been devoted to the total synthesis of chamigrenes.3
Majusculone (1) (Fig. 1) is a novel 9-norchamigrene-type
metabolite that was first isolated from red algae, that is, Laurencia
majuscula Harvey.4 Recently, Taber5a and Zhu5b reported the total
synthesis of 1 using carbene insertion and a Diels–Alder reaction
as the key steps, respectively. Herein, we report a new approach
to the synthesis of majusculone via an intramolecular cyclization
iodide 11 is required as an intermediate for the synthesis of allylic
alcohol 4. The synthesis of iodide 11 began with diethyl 1,3-ace-
tonedicarboxylate (7). Conversion of the ketone moiety in 7 to a
ketal group and subsequent reduction with lithium aluminum hy-
dride afforded diol 9 (Scheme 2). Mono-protection of the resulting
diol followed by conversion of the residual hydroxyl group to io-
dide generated 11.
Attention now turned to the synthesis of the spirane precursor,
enone–aldehyde 3, from 2,6,6-trimethyl-2-cyclohexen-1-one (5).7
A 1,2-addition of lithium reagent 6, which was prepared in situ
from 11 and t-BuLi in ether at À78 °C to 5 generated tertiary allylic
alcohol 12 (Scheme 3). After the removal of the silyl protective
group in 12, diol 4 was then oxidized with pyridinium dichromate
(PDC) to give enone–aldehyde 3.
With enone–aldehyde 3 in hand, the next step was intramolec-
ular reductive cyclization with samarium diiodide. This was first
performed with 2 equiv of SmI2 in the presence of MeOH at 0 °C6
resulting in the desired cyclized product 13 in 30–40% yield
reaction of an aldehyde onto a cyclic a
,b-unsaturated ketone.6
Retrosynthetically, we envisioned that ketal 2 would be an
acceptable precursor to majusculone (Scheme 1). Acetal 2 could
be generated from enone–aldehyde 3 via intramolecular reductive
cyclization. Access to spiro precursor 3 could be gained from 4
through simultaneous oxidation of the primary alcohol and 1,3-
oxidative rearrangement of the tertiary allylic alcohol. Allylic alco-
hol 4 could be obtained from enone 5 and a lithium reagent, 6.
We first focused on the preparation of the lithium reagent 6,
which could easily be obtained from the corresponding iodide,
11, and t-butyllithium (t-BuLi) via a metal-halogen exchange. Thus,
O
15
9
Me
Me
7
11
Me
13
14
12
6
5
1
O
3
majusculone (1)
Figure 1. Skeleton of chamigrene and structure of majusculone (1).
⇑
Corresponding author. Tel.: +886 5 272 0411x66417; fax: +886 5 272 1040.
E-mail address: chedsh@ccu.edu.tw (D.-S. Hsu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.087

1752
D.-S. Hsu, B.-C. Juo / Tetrahedron Letters 54 (2013) 1751–1753
Table 1
O
O
Intramolecular reductive cyclization of 3 with SmI2
O
O
O
Me
Me
O
Me
O
O
OH
Me
Me
Me
O
Me
Me
Me
Me
SmI , ROH
2
Me
O
O
Me
O
THF, T
majusculone (1)
2
OH
3
13
OH
O
Entry
SmI2
ROH
T (°C)
Yield (%)
O
O
O
1
2
3
4
5
6
2
2
2
MeOH
MeOH
MeOH
MeOH
MeOH
t-BuOH
0
30–40
20–30
10–20a
30–40
O
rt
À20
0
0
0
HO
Me
Me
Me
Me
Me
O
Me
4
2b
2
—
c
46
4
3
a
b
c
Recovered 40% of 3.
Additional HMPA (0.1 equiv) was added.
Complex mixture of products.
O
Me
Me
O
O
Me
+
Li
OTBS
O
7.4%
O
H
5
6
O
Me
Scheme 1. Retrosynthesis of majusculone.
Me
Me
2.6%
HO
13
HO
OH
O
O
O
O
O
Figure 2. NOE studies for 13.
, pTSA
O
O
EtO
OEt
O
EtO
OEt
PhH, reflux,
12 h
7
8
LiAlH4
TBSCl, NaH
O
O
O
O
O
THF, rt,
2 h
THF, rt, 2 h
51% (3 steps)
HO
OH
9
Me
Me
OH
Me
Amberlyst-15
LiAlH4
Me
Me
Me
O
I2, PPh3,
imidazole
THF, rt,
12 h
80%
PhH, reflux,
12 h
O
O
O
O
OH
OH
90%
PhH/ether,
rt, 12 h
13
14
HO
OTBS
I
OTBS
10
11
O
64%
O
t-BuOOH, O2,
Scheme 2. Preparation of iodide 11.
Mn(OAc)3
Me
Me
Me
Me
Me
Me
EtOAc, rt,
16 h
65%
O
OTBS
O
1
O
O
O
o
15
O
HO
Me
Me
Me
Li
OTBS
Me
Me
6
Scheme 4. Completion of the total synthesis of ( )-majusculone (1).
Me
Et O, −78 C, 0.5 h
2
64%
5
12
3). Increasing the amount of SmI2 from 2 to 4 equiv did not affect
the yield (entry 4), while the addition of 0.1 equiv of HMPA8 to
the reaction mixture resulted in a complex mixture (entry 5).
However, when t-BuOH9 was used instead of MeOH, the desired
product 6 was obtained in 46% yield (entry 6).
The structure of 13 was assigned via IR, NMR, and mass spectral
analyses,10 and its stereostructure was determined using NOE
experiments (Fig. 2).
O
O
O
OH
O
O
HO
Me
Me
Me
Me
TBAF
PDC, celite
CH Cl ,
reflux, 12 h
73% (2 steps)
Me
O
Me
THF, rt,
1 h
2
2
4
3
The stage was now set to complete the total synthesis of
( )-majusculone (1). Hemiketal 13 was first reduced with lithium
aluminum hydride to give alcohol 14 as a single diastereomer
(Scheme 4). The stereostructure of 14 was confirmed by single-
crystal X-ray diffraction analysis (Fig. 3).11 Upon treatment with
Amberlyst-15 in refluxing benzene, 14 easily converted to 15 in
Scheme 3. Preparation of enone–aldehyde 3 from 2,6,6-trimethyl-2-cyclohexen-1-
one.
(Table 1, entry 1). Attempts to improve the yield by changing the
reaction temperatures were unsuccessful. Lower yields were
observed at both higher and lower temperatures (entries 2 and

D.-S. Hsu, B.-C. Juo / Tetrahedron Letters 54 (2013) 1751–1753
1753
References and notes
1. (a) Martín, J. D.; Darias, J. Algal Sesquiterpenoids In Marine Natural Products:
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1978; Vol. I, p 125; (b) Erickson, K. L. Constituents of Laurencia In Marine
Natural Products: Chemical and Biological Perspectives; Scheuer, P. J., Ed.;
Academic: New York, NY, 1983; Vol. V, p 131; (c) Kikuchi, H.; Suzuki, T.;
Suzuki, M.; Kurosawa, E. Bull. Chem. Soc. Jpn. 1985, 58, 2473; (d) Elsworth, J. F. J.
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Nat. Prod. 2001, 64, 790; (g) Davyt, D.; Fernandez, R.; Suescun, L.; Mombrú, A.
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Darias, J. Tetrahedron Lett. 2004, 45, 7065; (i) Chokpaiboon, S.; Sommit, D.;
Teerawatananond, T.; Muangsin, N.; Bunyapaiboonsri, T.; Pudhom, K. J. Nat.
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O
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(g) Chen, Y.-J.; Wang, C.-Y.; Lin, W.-Y. Tetrahedron 1996, 52, 13181; (h)
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White, D. E.; Stewart, I. C.; Crubbs, R. H.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130,
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4668; (m) Chu, K.-C.; Liu, H.-J.; Zhu, J.-L. Synlett 2010, 3061.
OH
Me
Me
Me
OH
14
Figure 3. ORTEP plot of the structure of 14 (numbering is arbitrary).
90% yield. Finally, regioselective allylic oxidation of 15 with t-butyl
hydroperoxide and oxygen in the presence of manganese(III)
acetate12 furnished the target molecule, 1. The 1H and 13C NMR
spectra of 113 were in good agreement with those reported in the
literature.4,5
4. Suzuki, M.; Kurasawa, E.; Kurata, K. Bull. Chem. Soc. Jpn. 1987, 60, 3795.
5. (a) Taber, D. F.; Sikkander, I.; Storck, P. H. J. Org. Chem. 2007, 72, 4098; (b) Zhu,
J.-L.; Huang, P.-W.; You, R.-Y.; Lee, F.-Y.; Tsao, S.-W.; Chen, I-. C. Synthesis 2011,
715.
6. Hsu, D.-S.; Hsu, C.-W. Tetrahedron Lett. 2012, 53, 2185.
In conclusion, we accomplished the total synthesis of
( )-majusculone (1) from known 2,6,6-trimethyl-2-cyclohexen-1-
one (5) in seven synthetic steps. It is noteworthy that this is a
new approach to the synthesis of a spiro natural product with
intramolecular reductive cyclization as the key step. Furthermore,
we believe that hemiketal 13 will be a useful intermediate for the
synthesis of other chamigrene sesquiterpenes.
7. (a) Puglisi, C. J.; Elsey, G. M.; Prager, R. H.; Skouroumounis, G. K.; Sefton, M. A.
Tetrahedron Lett. 2001, 42, 6937; (b) Jung, M. E.; Allen, D. A. Org. Lett. 2008, 10,
2039.
8. Li, Z.; Nakashige, M.; Chain, W. J. J. Am. Chem. Soc. 2011, 133, 6553.
9. Cha, J. Y.; Yeoman, J. T. S.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964.
10. The spectral data of the hemiketal 13 are as follows: white solid, mp 142–
143 °C; IR (neat)
m ;
3274, 2959, 2867, 1460, 1108, 987 cmÀ1 1H NMR (500 MHz,
CDCl3) d 4.07–4.04 (m, 1H), 3.97–3.78 (m, 4H), 2.77–2.72 (m, 1H), 2.68 (br s,
1H), 2.27 (q, J = 7.5 Hz, 1H), 2.02–1.92 (m, 2H), 1.75–1.60 (m, 4H), 1.51–1.42
(m, 3H), 1.29–1.27 (m, 2H), 1.09 (d, J = 7.5 Hz, 3H), 0.94 (s, 3H), 0.87 (s, 3H); 13
C
NMR (125 MHz, CDCl3): d 106.3, 98.2, 76.2, 59.5, 59.3, 47.5, 42.0, 38.1, 36.6,
35.8, 29.4, 28.2, 27.3, 25.5, 25.2, 20.9, 10.5; MS (EI) m/z (% base peak) 296 (M+,
1), 267 (2), 225 (28), 195 (3), 181 (7), 129 (100), 113 (45), 100 (48), 87 (4);
HRMS (EI) Calcd for C17H28O4 296.1988. Found 296.1988.
Acknowledgments
We are grateful to Professor Ju-Hsiou Liao for the X-ray
crystallographic measurement. We thank the National Science
Council (NSC) of the Republic of China for financial support (NSC
101-2113-M-194-004).
11. CCDC 917162 contains the supplementary crystallographic data for 14. These
data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
12. Shing, T. K. M.; Yeung, Y.-Y.; Su, P. L. Org. Lett. 2006, 8, 3149.
13. The spectral data of majusculone (1) are as follows: white solid, mp 78–79 °C;
IR (neat)
m ;
2966, 1668, 1386, 1326, 1234, 904 cmÀ1 1H NMR (400 MHz, CDCl3)
d 6.76 (d, J = 10.4 Hz, 1H), 6.27 (d, J = 10.4 Hz, 1H), 5.96 (br s, 1H), 2.68–2.30 (m,
5H), 2.12–2.04 (m, 1H), 1.95 (br s, 3H), 1.10 (s, 3H), 1.08 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 197.5, 197.3, 163.0, 149.7, 131.9, 127.3, 48.5, 47.3, 40.9,
35.1, 27.5, 25.5, 25.0, 23.0; MS (EI) m/z (% base peak) 218 (M+, 3), 192 (30), 163
(81), 162 (100), 147 (41), 134 (100), 133 (100), 120 (58), 119 (52), 106 (45), 105
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.087.
(49), 91 (100), 77 (44); HRMS (EI) Calcd for
218.1306.
C14H18O2 218.1307. Found