Claisen rearrangement strategy in alkenyl dihydropyran leading to total synthesis of (+)-α-vetispirene and (-)-agarospirol

Article abstract of DOI:10.1246/cl.2007.42

Total synthesis of (+)-α-vetispirene and (-)-agarospirol based on a Claisen rearrangement has been achieved. This is the first example of a Claisen rearrangement in an enantio-enriched alkenyl bicyclic dihydropyran system with perfect asymmetric transmission. Copyright

Full text of DOI:10.1246/cl.2007.42

42
Chemistry Letters Vol.36, No.1 (2007)
Claisen Rearrangement Strategy in Alkenyl Dihydropyran
Leading to Total Synthesis of (+)-ꢀ-Vetispirene and (À)-Agarospirol
Atsuo Nakazaki and Susumu Kobayashiꢀ
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510
(Received October 3, 2006; CL-061158; E-mail: kobayash@rs.noda.tus.ac.jp)
Total synthesis of (+)-ꢀ-vetispirene and (ꢁ)-agarospirol
O
O
a
b
based on a Claisen rearrangement has been achieved. This is
the first example of a Claisen rearrangement in an enantio-
enriched alkenyl bicyclic dihydropyran system with perfect
asymmetric transmission.
PO
TBSO
4
O
OH
P = TBS (6)
P = H (7)
5
c
d
O
8
O
Spiro[4.5]decane scaffolds are embedded in many naturally
occurring terpenes, including candidates for medicines, per-
fumes, and agricultural chemicals (Figure 1).1 Recently, we have
reported an efficient approach to spiro[4.5]decanes based on a
Claisen rearrangement.2–5 Thus, alkenyl bicyclic dihydropyran
can be converted to a multi-functionalized spiro[4.5]decane in
a highly stereoselective manner. This protocol is applicable to
the synthesis of racemic vetivane sesquiterpenes, as we re-
ported.3b In this publication, we describe the total synthesis of
(+)-ꢀ-vetispirene (1)6 and (ꢁ)-agarospirol (2)7 based on a
Claisen rearrangement strategy.
Scheme 2. Reagents and conditions: (a) LDA, cyclopentanone,
95%; (b) TFAA, DMSO, Et3N, 93%; (c) TBAF, 84%; (d)
.
TsOH H2O, CH2Cl2, rt, 76%, 99.5% ee.
At the outset, for acid-catalyzed cyclization, we synthesized
the precursors 6 and 7 as enantio-enriched forms (Scheme 2).
Enantio-enriched aldehyde 4 [95% ee, determined by 1H and
19F NMR analyses of the MTPA ester of (R)-3] was prepared
from a racemate of 1,5-heptadien-4-ol 3 via a four-step sequence
involving Sharpless asymmetric epoxidation, according to
Paterson’s report.8 Transformation of aldehyde 4 to 6 or 7 was
then performed in two or three steps, respectively.
With the cyclization precursors, 6 and 7, now in hand, acid-
catalyzed cyclization was attempted. In the case of the attempted
cyclization of 6 with an excess of trifluoroacetic acid (TFA),
using the same conditions as previously used in the racemic syn-
thesis, the desired dihydropyrone 8 was obtained in 84% yield.
However, its enantiomeric excess was 88.4%. In contrast,
hydroxy diketone 7 was treated with a catalytic amount of TsOH
to provide 8 in respectably high yield with 99.5% ee, which
was determined by chiral HPLC Analysis (Chiralcel OD-H, rt,
254 nm, Hex/iPrOH = 99/1, flow rate: 0.4 mL/min).
HO
HO
2
1
OH
10
6
Hinesol
(+)-
α
-Vetispirene (−)-Agarospirol
(1)
(2)
Gleenol
Figure 1. Spiro[4.5]decane frameworks in terpenes.
Retrosynthetic analysis of (+)-ꢀ-vetispirene (1) and (ꢁ)-
agarospirol (2) is depicted in Scheme 1. (+)-ꢀ-Vetispirene (1)
and (ꢁ)-agarospirol (2) would be synthesized from a common
key intermediate 12, which in turn would have been derived
from spiro[4.5]decane 10 according to our racemic synthesis
of vetivane sesquiterpenes including (ꢂ)-1.3b Spiro[4.5]decane
10 could be synthesized from alkenyl bicyclic dihydropyran 9
by a Claisen rearrangement, while dihydropyrone 8, the precur-
sor of 9, would be prepared from a corresponding 5-hydroxy-
1,3-diketone 7 by means of acid-catalyzed cyclization. The
chirality of the allylic alcohol of 7 would be introduced via the
enantio-enriched known aldehyde 4.
Synthesis of a key intermediate 12 was performed in the
same manner as described in our previous publication,3b except
for the hydrogenation step (Scheme 3). A Claisen rearrangement
of enantio-enriched dihydropyran 9, derived from 8 in two steps,
was conducted in a sealed tube at 250 ꢃC to afford the desired
24
spiro[4.5]decane 10 (½ꢀꢄD ꢁ179:5) in 73% yield as a single di-
O
OP
O
O
a,b
c
OP
O
9 (>95% dr)
10 (>95% dr)
MeO2C
8 (99.6% ee)
MeO2C
O
O
d
e-j
(+)-1
(−)-2
OP
OP
O
O
O
O
10
OP
12
10
9
11
12 (99.9% ee)
Scheme 3. Reagents and conditions: (a) LiAlH4; (b) TBSCl,
imidazole, 82% (2 steps); (c) sealed tube, toluene, 250 ꢃC,
73%; (d) H2 (1 atm), [Ir(cod)(Pcy3)py]PF6, CH2Cl2, 96%; (e)
(MeO)2CO, KH, 80%; (f) NaBH4, 78%; (g) MsCl, pyridine;
(h) DBU, 98% (2 steps); (i) HF, 98%; (j) Dess–Martin periodi-
nane, 95%. P = TBS.
PO
O
HO
CHO
O
O
8
7
Known Aldehyde (4)
Scheme 1. Retrosynthetic analysis of (+)-ꢀ-vetispirene (1) and
(ꢁ)-agarospirol (2). P = TBS.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
43
MeO2C
MeO2C
MeO2C
MeO2C
MeO2C
2
HO
a
b
b-d
O
a
O
O
12 (99.9% ee)
12 (99.9% ee)
(−)-2
13
HO
Scheme 5. Reagents and conditions: (a) H2 (1 atm), [Ir(cod)-
.
(PCy3)py]PF6, CH2Cl2; (b) CH2I2, TiCl4, Zn; (b) TsOH H2O,
c
d
benzene, ꢀ; (c) MeLi, Et2O 42% (3 steps).
(+)-1
ment in enantio-enriched alkenyl bicyclic dihydropyran system
and demonstrating perfect asymmetric transmission. This strat-
egy could be applicable to the asymmetric synthesis of a variety
of terpenes based on the spiro[4.5]decane scaffold.
Scheme 4. Reagents and conditions: (a) CH2I2, TiCl4, Zn, 49%
.
(88%: based on the recovered starting material); (b) TsOH H2O,
benzene, ꢀ; (c) MeLi, Et2O; (d) CSA, benzene, ꢀ, 75% (3
steps).
astereomer. While our interest was focused on the enantiomeric
excess of 10, we were unable to determine it by chiral HPLC
assay and so we decided to convert 10 to 12. Hydrogenation
of the double bond in 10 with 5% palladium on charcoal was un-
satisfactory due to a slight epimerization at the C10 position,3b
however no epimerization was observed with Crabtree’s cata-
lyst.9 Transformation of ketone 11 to the key intermediate 12
was conducted in a six-step sequence according to the method
used for racemic synthesis of vetivanes. Then, the enantiomeric
excess of 12 was finally determined as 99.9% ee, which means
that the Claisen rearrangement of 9 proceeds with perfect asym-
metric transmission. This is the first example of a Claisen rear-
rangement in enantio-enriched alkenyl bicyclic dihydropyran
system.
We thank Shin-Etsu Chemical Co., Ltd., for the gift of
silicone oil.
The paper is dedicated to Professor Teruaki Mukaiyama on
the occasion of his 80th birthday.
References and Notes
1
Some biologically active spirocyclic terpenes have been
isolated. For gleenol, see: a) P. I. Kurvyakov, Y. V. Gatilov,
V. Yu, V. A. Khan, Zh. V. Dubovenko, V. A. Pentegova,
Khim. Prir. Soedin. 1979, 164. For hinesol, see: b) M.
Morita, H. Nakanishi, H. Morita, S. Mihashi, H. Itokawa,
Chem. Pharm. Bull. 1996, 44, 1603.
2
3
For recent review on Claisen rearrangement, see: A. M.
´
a) A. Nakazaki, H. Miyamoto, K. Henmi, S. Kobayashi,
Synlett 2005, 1417. b) A. Nakazaki, T. Era, Y. Numada, S.
Kobayashi, Tetrahedron 2006, 62, 6264.
Next, our attention was turned to the total synthesis of (+)-
ꢀ-vetispirene (1) (Scheme 4). Following the methods for our
synthesis of (ꢂ)-1, the total synthesis of (+)-1 was achieved in
four steps. The 1H and 13C NMR spectra and the optical rotation
of our synthetic (+)-1 are consistent with the natural ones6b
Martın Castro, Chem. Rev. 2004, 104, 2939.
4
5
6
For recent review on the synthesis of spirocyclic compounds,
see: R. Pradhan, M. Patra, A. K. Behera, B. K. Mishra, R. K.
Behera, Tetrahedron 2006, 62, 779.
For an example of synthesis of spirocycles by Claisen
rearrangement of bicyclic dihydropyrans, see: R. E. Ireland,
P. A. Aristoff, J. Org. Chem. 1979, 44, 4323.
23
{½ꢀꢄD þ226 (c ꢅ 0:367, MeOH); Ref. 6a: ½ꢀꢄD þ220 (c ꢅ
0:04, MeOH)}. This is the first asymmetric total synthesis of
(+)-ꢀ-vetispirene.
The final task was to synthesize (ꢁ)-agarospirol (2)
(Scheme 5). In order to construct the C2 stereogenic center in
2, we envisaged that stereoselective hydrogenation of 12 would
be controlled by iridium-based catalyst because of its oxophilic
nature. Thus, the double bond in 12 was saturated by Crabtree’s
catalyst9 to afford the desired ester 13 in 87% yield with >95%
diastereomeric ratio. When Pd on charcoal was used as a
catalyst, the undesired C2-epimer of 13, which is a synthetic in-
termediate of hinesol, was mainly obtained.10 After final three-
step sequence, total synthesis of (ꢁ)-agarospirol (2) was accom-
For the structure of (+)-1, see: a) N. H. Andersen, M. S.
Falcone, D. D. Syrdal, Tetrahedron Lett. 1970, 11, 1759.
For the total synthesis of (ꢂ)-1, see: b) N. Maulide, J.-C.
´
Vanherck, I. E. Marko, Eur. J. Org. Chem. 2004, 3962.
7
For the structure of (ꢁ)-2, see: a) K. R. Varma, M. L.
Maheshwari, S. C. Bhattacharyya, Tetrahedron 1965, 21,
115. For the total synthesis of (ꢁ)-2, see: b) M. Deighton,
C. R. Hughes, R. Ramage, J. Chem. Soc., Chem. Commun.
1975, 662.
1
plished. The H NMR spectrum and the optical rotation of our
synthetic (ꢁ)-2 are consistent with the natural ones7b {½ꢀꢄD
8
9
I. Paterson, S. P. Wren, J. Chem. Soc., Chem. Commun.
1993, 1790.
R. H. Crabtree, M. W. Davis, J. Org. Chem. 1986, 51, 2655.
20
25
ꢁ4:69 (c 0.20, CHCl3); Ref. 7a: ½ꢀꢄD ꢁ5:7 (c 28.7, CHCl3)}.
In conclusion, we described the total synthesis of (+)-ꢀ-
vetispirene and (ꢁ)-agarospirol based on a Claisen rearrange-
ment strategy. This is the first example of a Claisen rearrange-
10 Similar observation was reported, see: Y. Du, X. Lu, J. Org.
Chem. 2003, 68, 6463.
Published on the web (Advance View) December 9, 2006; doi:10.1246/cl.2007.42