Stereocontrolled total synthesis of (-)-gleenol using Claisen rearrangement of sterically congested dihydropyran

Article abstract of DOI:10.1246/cl.2008.770

A stereocontrolled total synthesis of enantiomerically pure (-)-gleenol using an improved substrate to construct the spiro[4.5]decane through Claisen rearrangement has been achieved. The most striking feature of this synthesis is that the rearrangement of sterically congested dihydropyran, bearing all requisite substituants with proper stereochemistry, afforded the fully functionalized spiro[4.5]decane in a single step. Copyright

Full text of DOI:10.1246/cl.2008.770

770
Chemistry Letters Vol.37, No.7 (2008)
Stereocontrolled Total Synthesis of (À)-Gleenol Using Claisen Rearrangement
of Sterically Congested Dihydropyran
Atsuo Nakazaki, Tomohiro Era, and Susumu Kobayashiꢀ
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510
(Received April 28, 2008; CL-080439; E-mail: kobayash@rs.noda.tus.ac.jp)
A stereocontrolled total synthesis of enantiomerically pure
(ꢁ)-gleenol using an improved substrate to construct the spi-
ro[4.5]decane through Claisen rearrangement has been achieved.
The most striking feature of this synthesis is that the rearrange-
ment of sterically congested dihydropyran, bearing all requisite
substituents with proper stereochemistry, afforded the fully
functionalized spiro[4.5]decane in a single step.
O
5
O
OH
OP
6
6
10
OP
7
7
(−)-1
A
B
O
P'O
CHO
Me
(ꢁ)-Gleenol (1) is an axane sesquiterpene which is isolated
from Picea glehni,1a Picea koraiensis,1b Criptomeria japonica,1c
Juniperus oxycedrus,1d and the brown alga Taonia atomaria1e
(Figure 1). Its enantiomer (+)-1 was also found in marine spon-
ge,1f and exhibits several biological activities such as termitici-
dal, antihelmintic, and growth regulation effects on plant seeds.2
The structure and relative stereochemistry of (ꢁ)-1 were deter-
mined by X-ray analysis of the corresponding epoxide,1a and
Ohira and co-workers established its absolute stereochemistry
by total synthesis.3a
Because of its structural features as well as its biological
importance, the total synthesis of 1 has been reported by several
groups.3 Recently, we reported the stereoselective synthesis
of spiro[4.5]decanes based on the Claisen rearrangement of the
bicyclic 2-(alkenyl)dihydropyran system,4,5 and have achieved
the total synthesis of (ꢂ)-1.3d In this synthesis, the introduction
of the isopropyl group at C7 required several extra steps after the
Claisen rearrangement.
In this communication, we wish to report a stereocontrolled
total synthesis of enantiomerically pure (ꢁ)-1 using an improved
Claisen precursor with the C7 isopropyl group. The most striking
feature of this synthesis is that the rearrangement of sterically
congested dihydropyran, bearing all requisite substituents
with proper stereochemistry, afforded the fully functionalized
spiro[4.5]decane in a single step. The results of our research
demonstrate the utility of the Claisen rearrangement approach
to the synthesis of this structural type.
Retrosynthetic analysis of (ꢁ)-1 is depicted in Scheme 1.
(ꢁ)-Gleenol (1) could be simplified to ketone A with four
contiguous stereogenic centers. Ketone A would be accessible
through our Claisen rearrangement methodology. The C5 and
C10 stereogenic centers would be stereoselectively established
utilizing the Claisen rearrangement of bicyclic 2-(alkenyl)dihy-
dropyran B. The stereogenic center C6 could be constructed dur-
i-Pr
H
PO
D
C
Scheme 1. Retrosynthetic analysis (P and P0: protective group).
ing the synthesis of B, while the two stereogenic centers of C7
and the allylic position (gray carbons in B) would be introduced
from the (2R,3S)-aldol C. The success of this strategy depends
on whether the Claisen rearrangement does proceed in such a
sterically congested dihydropyran as B through a boat-like tran-
sition state D.6
The synthesis of alkenyl dihydropyran 11, a substrate for
the key rearrangement, commenced with the isovaleric acid
derivative 2 bearing SuperQuat chiral auxiliary,7 which was de-
rived from D-phenylglycine (Scheme 2). According to Evans’
protocol,8 treatment of a boron enolate, generated from 2, with
crotonaldehyde afforded the desired (2R,3S)-aldol adduct 3 in
56% yield (80% yield based on recovered 2) with excellent
syn selectivity (>95% dr).9 Removal of the chiral auxiliary
from 3 was achieved by using NaOMe in methanol to provide
the corresponding methyl ester 4 in 71% yield, along with
17% of the ring-opened product 5. Protection of the hydroxy
group on 4 as a TES ether, DIBAL reduction of the resulting
6, followed by oxidation utilizing the Dess–Martin periodinane10
provided the aldehyde 7. We performed the remaining steps in
the synthesis of 11 according to our previously developed proce-
dure4 with a slight modification. Treatment of aldehyde 7 with
the lithium enolate derived from cyclopentanone afforded the
corresponding aldol 8. After the Swern oxidation of 8 using
TFAA/DMSO,11 exposure of the resulting 1,3-diketone 9 to
0.01 M HCl in ethanol led to dihydropyrone 10 in 90% yield
without epimerization at the stereogenic centers. Diastereoselec-
tive 1,2-reduction of 10 with LiAlH4 in Et2O, followed by
protection by TES group, furnished the desired alkenyl dihydro-
pyran 11 as a single diastereomer (>95% dr). The relative ster-
eochemistry was determined by NOE enhancement. We were
delighted to observe that the key Claisen rearrangement of 11
in triglyme afforded the desired spiro[4.5]decane 12 in 75%
yield as a single diastereomer.12 To the best of our knowledge,
this is the first example of the Claisen rearrangement of such a
sterically congested dihydropyran to spiro[4.5]decane.
CHO
5
OH
OH
NH
NC
10
6
7
(–)-Gleenol (1)
(+)-Axenol
(–)-Axamide-3
(+)-Axisonitrile-3
Completion of the total synthesis of (ꢁ)-1 was accomplish-
Figure 1. Structures of axane sesquiterpenes.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.7 (2008)
771
hexane/2-propanol = 100:1, flow rate = 0.50 mL/min, detec-
1
O
O
O
HO
O
PO
O
tion 210-nm light, 30 ꢃC). The H and 13C NMR spectra and a
specific rotation of our synthetic 1 are consistent with those of
a
b
N
O
N
O
OMe
c
i-Pr
i-Pr
Ph
Ph
23
the natural ones1d {½ꢀꢄD ꢁ20:4 (c 0.38, CHCl3); Ref. 1d:
4 (P = H)
6 (P = TES)
20
22
3 (>95% dr)
2
½ꢀꢄD ꢁ15:02 (c 0.5, CHCl3); Ref. 3a: ½ꢀꢄD ꢁ17 (c 0.50,
CHCl3)}.
TESO
O
g
In conclusion, we have achieved a stereocontrolled total
synthesis of (ꢁ)-gleenol (1), demonstrating the Claisen
rearrangement of an alkenyl dihydropyran in constructing the
functionalized spiro[4.5]decane scaffold. We believe that the
chemistry described herein would be useful for the preparation
of a variety of axane sesquiterpenes.
TESO
d, e
f
CHO
OH
7
8
O
O
O
O
TESO
h
i, j
OTES
O
References and Notes
1
a) P. I. Kurvyakov, Y. V. Gatilov, V. Yu, V. A. Khan, Zh. V.
Dubovenko, V. A. Pentegova, Khim. Prir. Soedin. 1979, 164.
b) V. A. Khan, Zh. V. Dubovenko, V. A. Pentegova, Khim.
Prir. Soedin. 1983, 109. c) S. Nagahama, M. Tazaki, H.
Nomura, K. Nishimura, M. Tajima, Y. Iwasita, Mokuzai
11 (>95% dr)
10
9
O
OTES
k
HO
O
NH OH
i-Pr
´
Gakkaishi 1996, 42, 1127. d) A. F. Barrero, J. F. Sanchez,
5
Ph
12 (>95% dr)
J. E. Oltra, J. Altarejos, N. Ferrol, A. Barragan, Phytochemistry
1991, 30, 1551. e) S. D. Rosa, A. D. Giulio, C. Iodice, N.
Zavodink, Phytochemistry 1994, 37, 1327. f) C. J. Barrow,
J. W. Blunt, M. H. G. Munro, Aust. J. Chem. 1988, 41, 1755.
B. Bozan, T. Ozek, M. Kurkcuoglu, N. Kirimer, K. Baser, C.
Husnu, Planta Med. 1999, 65, 781.
For the synthesis of (ꢁ)-1, see: a) S. Ohira, N. Yoshihara,
T. Hasegawa, Chem. Lett. 1998, 739. b) K. Oesterreich, D.
Spitzner, Tetrahedron 2002, 58, 4331. c) G. Blay, A. M.
Scheme 2. Stereocontrolled synthesis of spiro[4.5]decane 12.
Reagents and conditions: a) crotonaldehyde, n-Bu2BOTf, Et3N,
CH2Cl2, ꢁ78 ! 0 ꢃC, 56% (brsm 80%); b) NaOMe, MeOH, rt,
71% of 4, 17% of 5, c) TESCl, imidazole, DMAP, DMF, rt;
d) DIBAL, CH2Cl2, ꢁ78 ꢃC, 75% (two steps); e) Dess–Martin
periodinane, CH2Cl2, rt; f) LDA, cyclopentanone, THF,
ꢁ78 ꢃC, 82% (two steps); g) TFAA, DMSO, Et3N, CH2Cl2,
ꢁ78 ꢃC, 67% (brsm 79%); h) 0.01 M HCl, EtOH, rt, 90%; i)
LiAlH4, Et2O, 0 ꢃC; j) TESCl, imidazole, DMAP, DMF, rt,
42% (two steps); k) triglyme, 250 ꢃC, 75%.
2
3
´
Collado, B. Garcıa, J. P. Pedro, Tetrahedron 2005, 61,
10853. For the synthesis of (ꢂ)-1, see: d) A. Nakazaki, T.
Era, S. Kobayashi, Chem. Pharm. Bull. 2007, 55, 1606.
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. c) A. Nakazaki, S. Kobayashi,
Chem. Lett. 2007, 36, 42.
For the pioneering work of the synthesis of spirocycles by
Claisen rearrangement of bicyclic dihydropyrans, see: R. E.
Ireland, P. A. Aristoff, J. Org. Chem. 1979, 44, 4323.
2
4
5
O
O
O
OTES
OTES
a
b
c-e
OTES
12 (>95% dr)
13
14
OTES
OH
f
6
7
G. Buchi, J. E. Powell, Jr., J. Am. Chem. Soc. 1970, 92, 3126.
¨
(−)-Gleenol (1)
S. G. Davies, H. J. Sanganee, P. Szolcsanyi, Tetrahedron 1999,
55, 3337.
23
D
[α
]
−20.4 (c 0.38, CHCl3)
15
8
a) D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981,
103, 2127. b) D. A. Evans, J. M. Takacs, L. R. McGee,
M. D. Ennis, D. J. Mathre, J. Bartroli, Pure Appl. Chem.
1981, 53, 1109.
The absolute stereochemistry at C3 in 3 was determined by a
modified Mosher’s method of its MTPA derivatives. The syn
stereochemical assignment was made from the J2;3 coupling
constant of 6.6 Hz observed in its 1H NMR spectrum. In
general, anti-ꢀ-alkyl-ꢁ-hydroxy-N-acyl-oxazolidin-2-ones ex-
hibit J2;3 coupling constants of ꢅ7:0 Hz. For detail, see: M.
Cheeseman, S. D. Bull, Synlett 2006, 1119, and references
therein.
Scheme 3. Completion of the total synthesis of (ꢁ)-1. Reagents
and conditions: a) H2 (1 atm), [Ir(cod)(PCy3)py]PF6, CH2Cl2,
rt; b) LDA, MeI, THF, ꢁ78 ꢃC, 88% (two steps); c) LiAlH4,
Et2O, ꢁ78 ꢃC; d) MsCl, pyridine, 0 ꢃC; e) DBU, toluene,
150 ꢃC; f) TBAF, THF, rt, 78% (four steps).
9
ed from the fully functionalized key intermediate 12 through
conventional transformations (Scheme 3). Reduction of the dou-
ble bond in ketone 12 under 1 atm of hydrogen gas in the pres-
ence of Crabtree’s catalyst,13 followed by methylation at C2, led
to ketone 14 as a mixture of diastereomers in 88% yield for the
two steps. After reduction of the carbonyl group in 14 with
LiAlH4, the hydroxyl group was mesylated and subjected to
elimination with DBU at 150 ꢃC to provide the desired alkene
15. Finally, removal of the TES group of 15 with tetra-n-butyl-
ammonium fluoride in THF produced gleenol (1) in 78% yield
from 14.
10 D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277.
11 S. L. Huang, K. Omura, D. Swern, J. Org. Chem. 1976, 41,
3329.
12 Although the relative stereochemistry of 12 was not deter-
mined at this point, the stereochemistry was eventually as-
signed by leading to (ꢁ)-1.
Chiral HPLC analysis revealed that synthetic 1 is in enantio-
merically pure form (99.8% ee; CHIRALCEL OD-H column,
13 R. H. Crabtree, M. W. Davis, J. Org. Chem. 1986, 51, 2655.
Published on the web (Advance View) June 14, 2008; doi:10.1246/cl.2008.770