Efficient formal synthesis of (±)-axamide-1 and (±)- axisonitrile-1 via an intramolecular Hosomi-Sakurai reaction

Article abstract of DOI:10.1016/j.tetlet.2010.04.119

A formal synthesis of (±)-axamide-1 and (±)-axisonitrile-1 was achieved by using an intramolecular Hosomi-Sakurai reaction of the allylsilane derivative, as a key step, in which [(3-but-3-en-1-yl-3- methylcyclohex-1-en-1-yl)methyl](trimethyl)silane was transformed to a bicyclic compound possessing a core carbon framework under the oxidative dihydroxylation reaction conditions, in one step.

Full text of DOI:10.1016/j.tetlet.2010.04.119

Tetrahedron Letters 51 (2010) 3542–3544
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Tetrahedron Letters
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Efficient formal synthesis of ( )-axamide-1 and ( )-axisonitrile-1 via
an intramolecular Hosomi–Sakurai reaction
*
Kazunori Takahashi, Kentaro Takeda, Toshio Honda
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A formal synthesis of ( )-axamide-1 and ( )-axisonitrile-1 was achieved by using an intramolecular Hos-
omi–Sakurai reaction of the allylsilane derivative, as a key step, in which [(3-but-3-en-1-yl-3-methylcy-
clohex-1-en-1-yl)methyl](trimethyl)silane was transformed to a bicyclic compound possessing a core
carbon framework under the oxidative dihydroxylation reaction conditions, in one step.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 5 April 2010
Revised 23 April 2010
Accepted 28 April 2010
Available online 4 May 2010
Keywords:
Axamide-1
Axisonitrile-1
Intramolecular Hosomi–Sakurai reaction
Axane sesquiterpene
Short-step synthesis
Axamide-1 1 and axisonitrile-1 2, isolated from the marine
sponge Axinella cannabina, belong to the family of axane sesquit-
erpenoids. This class of natural products exhibit unusual structural
features based on a cis-fused hexahydroindane framework with an
exo-methylene unit and a functionalized side chain ( Fig. 1).1–7
Some of the compounds exhibit interesting biological properties.8
Regarding the synthesis of these sesquiterpenes, there have
been three racemic synthesis9–11 and one chiral synthesis.12 In
these syntheses, ingenious strategies were devised in order to con-
struct the central perhydroindane skeleton with an exo-methylene
unit. Our interest in axane sesquiterpene chemistry grew out of a
desire to develop a new, perhaps practical and general route for
the synthesis of this class of natural products.
could be obtained from alcohol 3 according to the literature proce-
dures.11 Based on the consideration of our previous results, we
OHCHN
H
CN
H
1. Axamide-1
2.
Axisonitrile-1
Figure 1. Structures of axamide-1 and axisonitrile-1.
Recently, we have developed an efficient methodology for the
construction of a bicyclo[3.3.1]nonane ring system with an exo-
methylene moiety by employing an intramolecular Hosomi–Saku-
rai reaction. We have already successfully applied the methodol-
ogy to the stereoselective synthesis of (+)-upial13 and trifarienols.14
As a part of our continuing work on the synthesis of functional-
ized polycyclic carbocyclic systems from readily available starting
material, we are interested in establishing an efficient synthetic
route to axane sesquiterpenoids having a bicyclo[4.3.0]nonane ring
system by employing an intramolecular Hosomi–Sakurai reaction
as a key reaction.15
X
X
H
H
Hosomi-Sakurai
reaction
3a
1
2
: X = α-OH
: Axamide-1, X = NHCHO
: Axisonitrile-1, X = NC
3b: X = β-OH
SiR3
O
1) 1,4-addition
2) Kumada coupling
X
The retrosynthetic route to axane sesquiterpenes is depicted in
Figure 2, in which we envisaged that the target natural products
4: X = O
5: X = CH2
6
* Corresponding author. Tel.: +81 3 5498 5791; fax: +81 3 3787 0036.
E-mail address: honda@hoshi.ac.jp (T. Honda).
Figure 2. Retrosynthetic route to axane sesquiterpenes.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.119

K. Takahashi et al. / Tetrahedron Letters 51 (2010) 3542–3544
3543
Table 2
One-pot conversion of 5 to 3
CuI (1.2 eq)
MeLi (2.5 eq)
Et2O
OTf
(2.5 eq)
MgCl
TMS
Pd(PPh3)4 (3 mol%)
TMS
O
TMS
6
OsO4 (5 mol%)
oxidant
dioxane-H2O (3:1)
OH
OH
then PhNTf2 (2.3 eq)
-40 °C, 12 h, 76%
THF reflux, 2.5 h, 93%
H
H
7
+
+
then reagent
rt
TMS
TMS
OsO4 (5 mol%)
NMO (2.0 eq)
5
3a
3b
4
Entry
Concn
Oxidant
(equiv)
Reagent
(equiv)
Products
dioxane-H2O (3:1)
rt, 5 h, 73%
OH
3a (%)
3b (%)
4 (%)
OH
5
8
1
2
3
4
5
0.02
0.02
0.1 to 0.02
0.1 to 0.02
0.1 to 0.02
None
None
NMO (2.0)
NMO (2.0)
NMO (2.0)
NaIO4 (2.0)
NaIO4 (4.0)
NaIO4 (2.0)
NaIO4 (4.0)
NaIO4 (8.0)
None
None
None
None
17
None
None
None
28
None
None
59
25
None
Scheme 1. Preparation of diol 8.
decided to exploit an intramolecular Hosomi–Sakurai reaction of
aldehyde 4 for the synthesis of 3, since the basic carbon framework
and an exo-methylene unit of the target compounds could be con-
structed by this reaction simultaneously. Aldehyde 4 would easily
be obtained from the corresponding olefin 5 by oxidation, and ole-
fin 5 might be transformed from the literature-known 3-(but-3-en-
1-yl)cyclohex-2-en-1-one 610c via Michael addition of a methyl
group, followed by Kumada coupling of the resulting triflate with
trimethylsilylmethylmagnesium chloride in the presence of a pal-
ladium catalyst as shown in our previous work.
62
ported.11 Thus, a formal synthesis of axane sesquiterpenes was
achieved at this stage; however, some modification is required to
improve the reaction sequences.
Since diol 8 could be transformed to 3 in one step, we next
investigated one-pot conversion of olefin 5 to 3b without isolation
of diol 8, hopefully under mild reaction conditions, to prove that
the reaction sequence is efficient.
As can be seen in Table 2, the attempted one-pot conversion did
not take place in the absence of oxidant NMO (entries 1 and 2).
When 2 equiv of NMO and 2 equiv of NaIO4 were employed for this
reaction, aldehyde 4 was isolated as the major product in 59% yield
(entry 3). The best result was obtained when this reaction was car-
ried out by using 2 equiv of NMO and 8 equiv of NaIO4 in dioxane/
H2O = 3:1 (v/v) at room temperature for 1 day, providing 3b in 62%
yield. The stereoselectivity exhibited in the formation of 3b as the
major product can be rationalized by assuming that this cyclization
would proceed via the more favorable dipolar model TS-A rather
than TS-B as depicted in Figure 3.18
Since we were able to establish an efficient synthetic route for
the core carbon framework having an exo-methylene unit of the
target compounds in very short steps, further transformation of
b-alcohol 3b to the known intermediate11 for the synthesis of
( )-axamide-1 and ( )-axisonitrile-1 was then investigated.
Although difficulties were initially encountered in the conversion
of the hydroxyl group to a cyano group and also in inversion of
the secondary hydroxyl group using Mitsunobu reaction under var-
ious reaction conditions, Parikh–Doering oxidation19 of 3b finally
afforded the known ketone 9 in 61% yield (Scheme 2).
The requisite key compound 5 was prepared as follows.
Treatment of 3-(but-3-en-1-yl)cyclohex-2-en-1-one
6 with
methyllithium in the presence of copper(I) iodide in ether at -
40 °C for 20 min afforded the addition product, which on further
treatment with PhNTf2 at the same temperature for 12 h gave tri-
flate 7 in 76% yield. Coupling reaction of 7 with trimethylsilylmeth-
ylmagnesium chloride in the presence of Pd(PPh3)4 in refluxing
THF for 2.5 h gave the desired allylsilane 516 in 93% yield. To obtain
aldehyde 4, dihydroxylation of 5 with a catalytic amount of OsO4
and NMO was carried out to give diol 8 in 73% yield (Scheme 1).
Oxidative cleavage of 8 with NaIO4 in dioxane–H2O (3:1) was first
attempted at room temperature for 1 day; however, the desired
aldehyde 4 was isolated in only 3% yield. Interestingly, the major
product in this reaction was identified to be the cyclization com-
pound 3b17 (12% yield), where an intramolecular Hosomi–Sakurai
reaction probably took place instantaneously via aldehyde 4 by
the presence of NaIO4 (entry 1). It is notable that this one-step con-
version of 8 to 3 proceeded in a concentration-dependent manner. In
fact, when theoxidative cleavage was carried out in 0.01 Mor 0.02 M
solution, the yield of 3b was improved to 53% (entries 4 and 5). The
results obtained in this study are summarized in Table 1.
The a-alcohol 3a obtained as a minor product in this conversion
was the key intermediate in Kuo’s synthesis of the target com-
pounds, and its spectroscopic data were identical with those re-
TMS
TMS
H+
O
H
H
Table 1
H
H
One-pot conversion of 8 to 3 under the oxidative cleavage reaction condition
O
Me
Me
TMS
OH
TMS
OH
OH
H+
NaIO4 (2.0 eq)
dioxane-H2O (3:1)
H
H
OH
O
TS-A
TS-B
+
+
rt, 1 day
Figure 3. Plausible stereochemical pathway in the Hosomi–Sakurai reaction to give
3b predominantly.
8
3a
3b
4
DMSO (6.0 eq)
SO3·Py (4.0 eq)
DIPEA (8.0 eq)
Entry
Concn
Products
OH
O
H
H
ref. 11
3a (%)
3b (%)
4 (%)
axamide-1
axisonitrile-1
1
2
3
4
5
0.5
0.1
0.05
0.02
0.01
—
—
5
15
16
12
15
16
53
53
3
5
1
4
10
CH2Cl2
0 °C to rt
61%
3b
9
Scheme 2. Conversion of 3b to the known ketone 9.

3544
K. Takahashi et al. / Tetrahedron Letters 51 (2010) 3542–3544
9. (a) Piers, E.; Yeung, B. W. A. Can. J. Chem. 1986, 64, 2475–2476; (b) Piers, E.;
Since ketone 9 was already transformed into ( )-axamide-1 and
Yeung, B. W. A.; Rettig, S. J. Tetrahedron 1987, 43, 5521–5535.
10. (a) Guevel, A.-C.; Hart, D. J. Synlett 1994, 169–170; (b) Hart, D. J.; Lai, C.-S.
Synlett 1989, 49–51; (c) Chenera, B.; Chuang, C.-P.; Hart, D. J.; Lai, C.-S. J. Org.
Chem. 1992, 57, 2018–2029; (d) Guevel, A.-C.; Hart, D. J. J. Org. Chem. 1996, 61,
473–479.
11. Kuo, Y.-L.; Dhanasekaran, M.; Sha, C.-K. J. Org. Chem. 2009, 74, 2033–2038.
12. Ohkubo, T.; Akino, H.; Asaoka, M.; Takei, H. Tetrahedron Lett. 1995, 36, 3365–
3368.
( )-axisonitrile-1 by Kuo et al.,11 this synthesis constitutes their
formal synthesis.
In summary, we were able to establish an efficient formal syn-
thesis of ( )-axamide-1 and ( )-axisonitrile-1 by employing an
intramolecular Hosomi–Sakurai reaction as a key step. The syn-
thetic strategy is quite general and the reaction sequence is rela-
tively short with reasonable yields. The strategy developed here
provides a further useful example of an intramolecular Hosomi–
Sakurai reaction in the synthesis of natural products.
13. Takahashi, K.; Watanabe, M.; Honda, T. Angew. Chem., Int. Ed. 2008, 47, 131–
133.
14. Takahashi, K.; Akao, R.; Honda, T. J. Org. Chem. 2009, 74, 3424–3429.
15. For recent reports on the Sakurai reaction, see: (a) Denmark, S. E.; Henke, B. R.;
Weber, E. J. Am. Chem. Soc. 1987, 109, 2512–2514; (b) Hatakeyama, S.;
Kawamura, M.; Shimanuki, E.; Saijo, K.; Takano, S. Synlett 1992, 114–116; (c)
Markó, I. E.; Bayston, D. J. Tetrahedron 1994, 50, 7141–7156; (d) Denmark, S. E.;
Almstead, N. G. J. Org. Chem. 1994, 59, 5130–5132; (e) Cordes, M. Synthesis
2001, 2470–2476; (f) Leroy, B.; Markó, I. E. J. Org. Chem. 2002, 67, 8744–8752;
(g) Pospisil, J.; Kumamoto, T.; Markó, I. E. Angew. Chem. 2006, 118, 3435–3438; .
Angew. Chem., Int. Ed. 2006, 118, 3357–3360; (h) JimInéz-González, L.; Garcia-
Munoz, S.; Alvarez-Corral, M.; Munoz-Dorado, M.; Rodriguez-Garcia, I. Chem.
Eur. J. 2007, 13, 557–568.
Acknowledgments
This research was supported financially in part by a grant for
the Open Research Center Project and a Grant-in-Aid from the Min-
istry of Education, Culture, Sports, Science, and Technology of
Japan.
16. Selected data for compound 5: IR
m ;
max 1248 cmÀ1 1H NMR (CDCl3; 400 MHz) d
5.82 (ddt, J = 6.6, 10.2, 16.8 Hz, 1H), 4.99 (ddt, J = 1.6, 3.6, 16.8 Hz, 1H), 4.93 (s,
1H), 4.90 (ddt, J = 1.6, 2.2, 10.2 Hz, 1H), 2.08–1.95 (m, 2H), 1.89–1.76 (m, 2H),
1.65–1.55 (m, 2H), 1.46–1.26 (m, 4H), 1.38 (s, 2H), 0.93 (s, 3H), 0.00 (s, 9H); 13C
NMR (CDCl3; 100 MHz) d 140.0, 133.9, 128.7, 113.6, 114.5, 42.6, 34.6, 34.5,
31.2, 28.8, 27.9, 19.9, À1.18 (3); MS (EI): 236 (M+); HRMS (EI): calcd for
C15H28Si: 236.1960, found; 236.1970.
References and notes
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17. Selected data for compound 3b: IR
m ;
max 1646, 1721 and 3371 cmÀ1 1H NMR
(CDCl3; 400 MHz) d 4.79 (d, J = 2.3 Hz, 1H), 4.73 (d, J = 2.3 Hz, 1H), 4.26 (ddd,
J = 6.3, 8.7, 8.7 Hz, 1H), 2.23–2.14 (m, 2H), 2.11–2.02 (m, 2H), 1.94 (d, J = 8.7 Hz,
1H), 1.69–1.54 (m, 3H), 1.51–1.31 (m, 4H), 1.27–1.22 (m, 1H), 0.97 (s, 3H); 13C
NMR (CDCl3; 100 MHz) d 146.9, 110.9, 75.1, 63.9, 42.2, 38.5, 34.5, 31.4, 30.8,
25.6, 23.6; MS (CI): 167 (M++1); HRMS (CI): calcd for C11H18O+H: 167.1436,
found; 167.1436.
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