Formal synthesis of (-)-perhydrohistrionicotoxin via cyclic amino acid ester-enolate claisen rearrangement and ring-closing metathesis

Article abstract of DOI:10.1021/jo050608w

We have successfully synthesized an advanced synthetic intermediate, hydroxy lactam 3, which has previously been converted to perhydrohistrionicotoxin. An important feature of this synthesis is the creation of stereogenic centers by using the cyclic amino acid ester-enolate Claisen rearrangement together with a ring-closing metathesis for azaspiro-cyclic skeleton construction.

Full text of DOI:10.1021/jo050608w

Formal Synthesis of
(-)-Perhydrohistrionicotoxin via Cyclic
Amino Acid Ester-Enolate Claisen
Rearrangement and Ring-Closing
Metathesis
Sanghee Kim,*,†,‡ Hyojin Ko,‡ Taeho Lee,‡ and
Deukjoon Kim†
FIGURE 1. Chemical structures of compounds 1 and 2.
College of Pharmacy, Seoul National University, San 56-1,
Shilim, Kwanak, Seoul 151-742, Korea, and Natural
Products Research Institute, College of Pharmacy,
Seoul National University, 28 Yungun, Jongro,
Seoul 110-460, Korea
targets for synthetic chemists over the last few decades.3
Indeed, more than 70 elegant synthetic approaches to
histrionicotoxins have been reported to date. Despite
these numerous approaches, the histrionicotoxins remain
particularly attractive targets for organic synthesis,
especially in developing new synthetic strategies for the
stereoselective construction of the azaspiro[5.5]undecane
framework of these alkaloids. Herein, we wish to report
a novel formal stereoselective synthesis of (-)-perhydro-
histrionicotoxin (2). Our strategy is based on the use of
the cyclic amino acid ester-enolate Claisen rearrange-
ment and a ring-closing metathesis (RCM) reaction4 as
presented in the retrosynthetic Scheme 1.
pennkim@snu.ac.kr
Received March 28, 2005
Hydroxy lactam 3 (Scheme 1) is a key advanced
intermediate in previous total syntheses of perhydro-
histrionicotoxin, and several syntheses of 3 have been
developed.5 We envisioned that this intermediate 3 could
be synthesized from the cyclohexene 4. The azaspirocyclic
skeleton of 4 was envisaged to be constructed by a RCM
of diene 5, which then would be accessible from the
densely functionalized cyclic amino acid 6. The presence
of a γ,δ-unsaturated carbonyl unit in compound 6 sug-
gested the use of a Claisen rearrangement of cyclic amino
acid allylic ester 7. This transformation could establish
the relative stereochemistry of two contiguous stereo-
centers by controlling the enolate geometry and olefin
configuration. Further analysis indicated the commer-
cially available 6-oxopipecolic acid and the known (S)-
(E)-3-octen-2-ol6 as a source of chirality to be suitable
synthetic precursors for the Claisen rearrangement
substrate 7.
We have successfully synthesized an advanced synthetic
intermediate, hydroxy lactam 3, which has previously been
converted to perhydrohistrionicotoxin. An important feature
of this synthesis is the creation of stereogenic centers by
using the cyclic amino acid ester-enolate Claisen rearrange-
ment together with a ring-closing metathesis for azaspiro-
cyclic skeleton construction.
(3) For recent leading references to histrionicotoxins and perhydro-
histrionicotoxin syntheses, see: (a) Stockman, R. A.; Sinclair, A.; Arini,
L. G.; Szeto, P.; Hughes, D. L. J. Org. Chem. 2004, 69, 1598.
(b) McLaughlin, M. J.; Hsung, R. P.; Cole, K. P.; Hahn, J. M.; Wang,
J. Org. Lett. 2002, 4, 2017. (c) Luzzio, F. A.; Fitch, R. W. J. Org. Chem.
1999, 64, 5485.
(4) For precedents in the construction of azaspirocyclic skeleton of
histrionicotoxins using RCM, see: (a) Tanner, D.; Hagberg, L.; Poulsen,
A. Tetrahedron 1999, 55, 1427. (b) Wybrow, R. A. J.; Stevenson, N.
G.; Harrity, J. P. A. Synlett 2004, 140.
(5) (a) Corey, E. J.; Arnett, J. F.; Widiger, G. N. J. Am. Chem. Soc.
1975, 97, 430. (b) Aratani, M.; Dunkerton, L. V.; Fukuyama, T.; Kishi,
Y. J. Org. Chem. 1975, 40, 2009. (c) Schoemaker, H. E.; Speckamp,
W. N. Tetrahedron Lett. 1978, 19, 4841. (d) Takahashi, K.; Witkop,
B.; Brossi, A. Helv. Chim. Acta 1982, 65, 252. (e) Ibuka, T.; Minakata,
H.; Mitsui, Y.; Hayashi, K.; Taga, T.; Inubushi, Y. Chem. Pharm. Bull.
1982, 30, 2840. (f) Fukuyama, T. Dunkerton, L. V.; Aratani, M.; Kishi,
Y. J. Org. Chem. 1975, 40, 2011. (g) Ibuka, T.; Mitsui, Y.; Hayashi,
K.; Minakata, H.; Inubushi, Y. Tetrahedron Lett. 1981, 22, 4425.
(h) Keck, G. E.; Yates, J. B. J. Org. Chem. 1982, 47, 3590. (i) Evans,
D. A.; Thomas, E. W. Tetrahedron Lett. 1979, 20, 411.
In 1971, Witkop and co-workers reported the isolation
and structure of a unique azaspirocyclic alkaloid desig-
nated (-)-histrionicotoxin (1, Figure 1).1 Since its isola-
tion, a further 15 alkaloids in this family have been
identified, varying only in the length and degree of
saturation present in the two side chains.2 Due to their
unique biological properties and challenging architecture,
these alkaloids along with the nonnatural perhydro-
histrionicotoxin (2) have been attractive and popular
* To whom correspondence should be addressed. Tel: 82-2-740-8913.
Fax: 82-2-762-8322.
† College of Pharmacy.
‡ Natural Products Research Institute.
(6) (a) Takeda, Y.; Matsumoto, T.; Sato, F. J. Org. Chem. 1986, 51,
4731. (b) Gung, B. W.; Wolf, M. B. J. Org. Chem. 1993, 58, 7038.
(c) Stampfer, W.; Kosjek, B. Moitzi, C.; Kroutil, W.; Faber, K. Angew.
Chem., Int. Ed. 2002, 41, 1014.
(1) Daly, J. W.; Karle, I.; Myers, C. W.; Tokuyama, T.; Waters, J.
A.; Witkop, B. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1870.
(2) Daly, J. W. J. Nat. Prod. 1998, 61, 162.
10.1021/jo050608w CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/01/2005
5756
J. Org. Chem. 2005, 70, 5756-5759

SCHEME 1. Retrosynthetic Analysis of
Perhydrohistrionicotoxin
SCHEME 2. Formal Synthesis of
(-)-Perhydrohistrionicotoxin.
Our approach commenced with the preparation of ester
7 by DCC coupling of allylic alcohol (S)-9 (98.5% ee) with
racemic 6-oxopipecolic acid 8 (91%). With multigram
quantities of diastereomeric mixture 7 in hand, we
explored the cyclic amino acid ester-enolate Claisen
rearrangement, focusing on both yield and diastereo-
selectivity. First, allylic ester 7 was exposed to LDA and
TBSCl in THF at -78 °C (Bartlett’s amino acid ester-
enolate Claisen rearrangement standard conditions),7
with gradual warming to room temperature to promote
the rearrangement. After an acidic workup followed by
treatment with diazomethane, these conditions predomi-
nantly afforded the desired ester 10, along with a minor
amount of the stereoisomer in 80% combined yield and
8:1 selectivity. Under the Kazmaier’s zinc chelated eno-
late Claisen rearrangement conditions8 (LDA, ZnCl2,
THF), the reaction took place with a higher stereoselec-
tivity (30:1) in favor of the desired isomer 10 (98.2% ee
by chiral HPLC analysis) with 75% combined yield.
Chirality was conserved during the reaction, and as a
result, the stereochemistry originating from the chiral
allylic alcohol (S)-9 was transferred to the functionalized
cyclic amino ester 10. The relative stereochemistry of the
newly generated two stereocenters of 10 was tentatively
assigned as shown on the basis of the literature precedent
of Bartlett7 and Kazmaier8,9 and established by its
conversion to 3. This stereochemical outcome can be
rationalized by considering the chelation control over
enolate geometry and π-facial preferences dictated by the
chairlike transition state, as shown in the bracket
(Scheme 2).
homoallylic alcohol 13 as an inseparable mixture (ca. 7:3
ratio) in 86% yield. Our attempts at accomplishing the
removal of the sterically hindered hydroxy group in 13,
using various methods including the Barton’s protocol,12
were not successful. Thus, we decided to perform the ring-
closing metathesis before the deoxygenation step.
The crucial ring-closing metathesis of 13 was success-
fully performed with Grubbs’ phosphorylidine catalyst13
[RuCl2(dCHPh)(PCy3)2] in CH2Cl2 at 40 °C to produce
the desired azaspiro-cyclohexene derivative 14 in high
yield (84%). At this stage, the deoxygenation of the
secondary neopentyl-like alcohol was readily accom-
plished by reaction of 14 with thiocarbonyldiimidazole
and radical reduction12b to give 4 in 54% overall yield.
Efforts were next directed toward the functional group
transformation of the ∆8,9-olefin of 4 to the C-8R hydroxy
group of 3 for the completion of the formal synthesis of
perhydrohistrionicotoxin. Treatment of the olefin 4 with
m-CPBA provided the epoxide 15 and its stereoisomer
in 77% combined yield and 1.6:1 selectivity. However, the
reaction of 4 with the dioxirane, generated in situ from
Oxone with 1,1,1-trifluoroacetone,14 afforded the epoxide
We then turned our attention to the conversion of the
methyl ester into the homoallyl group for the preparation
of the metathesis precursor 5. Thus, the ester of 10 was
reduced to the primary alcohol under Luche conditions10
to give 11 in 89% yield. Initial attempts at addition of
allylmetal reagents to the corresponding primary iodide
were unsuccessful, presumably due to the high degree
of steric hindrance. Therefore, we oxidized the hydroxyl
group of 11 to form aldehyde 12 with Dess-Martin
periodinane11 (85%) and then attempted the addition of
allylmetal reagents. Grignard reaction between allyl-
magnesium bromide and aldehyde 12 successfully gave
1
15 with a high stereoselectivity (30:1 in crude H NMR
spectra) in 78% yield. The epoxide stereochemistry was
(7) Bartlett, P. A.; Barstow, J. F. J. Org. Chem. 1982, 47, 3933.
(8) (a) Kazmaier, U. Angew. Chem., Int. Ed. Engl. 1994, 33, 998.
(b) Kazmaier, U. Liebigs Ann./Recueil 1997, 285.
(12) (a) Barton, D. H. R.; Jaszberencyi, J. Cs. Tetrahedron Lett. 1989,
30, 2619. (b) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574.
(9) Kazmaier, U.; Mues, H.; Krebs, A. Chem. Eur. J. 2002, 8, 1850.
(10) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
(13) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100. (b) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am.
Chem. Soc. 1997, 119, 3887.
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(14) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887.
J. Org. Chem, Vol. 70, No. 14, 2005 5757

1.80 (m, 1H), 2.12-2.30 (m, 3H), 2.28-2.36 (m, 1H), 3.67 (s, 3H),
4.99 (dddd, J ) 9.9, 5.3, 3.0, 1.8 Hz, 1H), 5.47 (dddd, J ) 15.3,
6.6, 6.6, 6.6 Hz, 1H), 6.15 (br s, 1H); 13C NMR (CDCl3, 75 MHz)
δ 13.7, 17.9, 18.0, 22.2, 28.3, 28.8, 29.5, 30.9, 51.4, 52.3, 66.0,
128.3, 130.8, 172.7, 173.5; MS-CI m/z (rel int) 268 ([M + 1]+,
100), 156 (22), 296 (19); HRMS-CI (Calcd for C15H26NO3
([M + H]+)) 268.1913, found 268.1911.
tentatively assigned as R, on the basis of steric consid-
erations. Finally, the regioselective cleavage of the epoxy
ring with DIBAL-H in THF led to the formation of the
desired alcohol 3 (79%) as a single regioisomer, which is
an advanced intermediate in previous total syntheses of
perhydrohistrionicotoxin. The structure of 3 was con-
firmed by comprehensive 2D NMR studies (COSY, HSQC,
and HMBC), and the 1H and 13C NMR spectral data were
virtually identical to those reported.5b-e Moreover, the
structure and stereochemistry of 3 thus obtained was
confirmed by converting 3 to other known advanced
intermediates and comparing the spectral data (see the
Supporting Information).
In conclusion, we have accomplished the stereoselective
formal synthesis of (-)-perhydrohistrionicotoxin with a
high overall yield from readily available starting materi-
als. An important feature of this synthesis is the creation
of stereogenic centers by using the cyclic amino acid
ester-enolate Claisen rearrangement followed by a ring-
closing metathesis for azaspirocyclic skeleton construc-
tion.
(6R,1′S)-6-(1′-Butylbut-2′-enyl)-6-hydroxymethylpiperi-
din-2-one (11). To a suspension of NaBH4 (6.0 g, 159 mmol)
and cerium chloride heptahydrate (8.0 g, 22 mmol) in EtOH
(100 mL) was added dropwise the solution of 10 and its minor
isomer (4.0 g, 15 mmol, 25:1 mixture) in EtOH (10 mL) for 1 h.
The reaction mixture was stirred for 2 days at room temperature.
The mixture was poured into saturated aqueous NH4Cl solution
and extracted with EtOAc three times. The combined organic
layers were dried over Na2SO4 and evaporated under reduced
pressure. This residue was purified by column chromatography
on silica gel (hexane/EtOAc ) 1:1) to give an inseparable mixture
of 11 and its minor isomer (3.2 g, 89%) as colorless sticky foam.
The ratio of two stereoisomers is 25:1 in crude 1H NMR
spectrum: IR (film) νmax 3298.6, 3049.7, 2953.3, 1714.9, 1651.2,
1456.4, 1412.0 cm-1 1H NMR (CDCl3, 300 MHz) δ 0.82
;
(t, J ) 6.9 Hz, 3H), 0.97-1.30 (m, 5H), 1.38-1.44 (m, 1H), 1.50-
1.60 (m, 2H), 1.64 (dd, J ) 6.3, 1.5 Hz, 3H) 1.68-1.81 (m, 2H),
2.03-2.11 (m, 1H), 2.14-2.28 (m, 2H), 3.45 (dd, J ) 21.0,
11.1 Hz, 2H), 4.18 (br s, 1H), 5.10 (ddd, J ) 15.0, 9.6, 3.9 Hz,
1H), 5.47 (dddd, J ) 15.0, 6.3, 6.3, 6.3 Hz, 1H), 6.70 (br s, 1H);
13C NMR (CDCl3, 75 MHz) δ 14.0, 17.9, 18.0, 22.6, 25.2, 28.1,
30.1, 31.2, 49.6, 60.2, 67.6, 129.2, 130.0, 173.8; MS-CI m/z
(rel int) 240 ([M + 1]+, 100), 128 (56); HRMS-CI (calcd for
Experimental Section
(2RS,1′S)-6-Oxopiperidine-2-carboxylic Acid 1′-Methyl-
hept-2′-enyl Ester (7). To a mixture of 6-oxopipecolic acid 8
(4.0 g, 25 mmol) and (S)-9 (3.6 g, 28 mmol) in CH2Cl2 (50 mL)
were added DMAP (310 mg, 2.5 mmol) and DCC (6.0 g, 29 mmol)
at 0 °C. After the reaction mixture was stirred for 20 min at
0 °C, it was warmed to room temperature over 1 h. The reaction
mixture was concentrated, dissolved in hexane, and filtered
through a Celite pad. The filtrate was evaporated under reduced
pressure and purified by column chromatography on silica gel
(hexane/EtOAc ) 1:1) to give a diastereomeric mixture 7 (5.8 g,
91%) as yellow oil: IR (film) νmax 3225.3, 3107.6, 2932.1, 2872.3,
C
14H26NO2 ([M + H]+)) 240.1963, found 240.1964.
(2S,1′S)-2-(1′-Butylbut-2′-enyl)-6-oxopiperidine-2-carbal-
dehyde (12). To a solution of 11 and its minor isomer (2.2 g,
9.2 mmol) in CH2Cl2 (10 mL) were added powered NaHCO3
(2.3 g, 27 mmol) and Dess-Martin periodinane (7.8 g, 18 mmol).
After the mixture was stirred for 24 h, NaHCO3 (1.0 g, 12 mmol)
and Dess-Martin periodinane (4.0 g, 9.4 mmol) were added once
more. The reaction mixture was stirred for an additional 24 h,
and isopropyl alcohol (5 mL) was added. The mixture was poured
into saturated aqueous NaHCO3 solution and extracted with
EtOAc three times. The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated. This residue
was purified by column chromatography on silica gel (hexane/
EtOAc ) 1:1) to give an inseparable mixture of 12 and its minor
isomer (1.9 g, 85%) as yellow oil. The ratio of two stereoisomers
is 25:1 in the crude 1H NMR spectrum: IR (film) νmax 3211.8,
1
1743.8, 1680.2 cm-1; H NMR (CDCl3, 300 MHz) δ 0.88 (t, J )
7.8 Hz, 3H), 0.25-1.38 (m, 7H), 1.72-1.94 (m, 3H), 2.02
(dd, J ) 12.9, 6.9 Hz, 2H), 2.14-2.24 (m, 1H), 2.34-2.40
(m, 2H), 4.04 (t, J ) 11.7 Hz, 1H), 5.37 (dd, J ) 13.5, 6.6 Hz,
1H), 5.46 (m, 1H), 5.71 (dt, J ) 14.4, 6.9 Hz, 1H), 6.27 (br s,
1H); 13C NMR (CDCl3, 75 MHz) δ 13.7, 19.1, 19.3, 20.1, 21.9,
22.0, 25.2, 25.2, 30.79, 30.81, 30.83, 31.6, 54.65, 54.68, 72.7, 72.8,
128.4, 128.5, 134.3, 134.4, 170.3, 171.36, 171.39; MS-CI m/z
(rel int) 254 ([M + 1]+, 50), 144 (100), 98 (37), 172 (28); HRMS-
CI (calcd for C14H24NO3 ([M + H]+)) 254.1756, found 254.1757.
(2S,1′S)-2-(1′-Butylbut-2′-enyl)-6-oxopiperidine-2-car-
boxylic Acid Methyl Ester (10). To a solution of 7 (120 mg,
0.47 mmol) in THF (10 mL) was added LDA (0.7 mL, 2.0 M in
THF) at -78 °C. After the mixture was stirred for 5 min, ZnCl2
(2.4 mL, 0.5 M in THF) was added. This reaction mixture was
allowed to warm to room temperature and continued to stir for
15 h. The mixture was treated with 1 N NaHSO4 and extracted
with CH2Cl2 twice. The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated. This residue
(6) was dissolved in Et2O and treated with diazomethane. The
mixture was evaporated under reduced pressure and purified
by column chromatography on silica gel (hexane/EtOAc ) 1:1)
to give an inseparable mixture of 10 and its minor isomer
(90 mg, 75%) as yellow oil. The ratio of two stereoisomers is 30:1
3088.3, 2955.2, 2860.7, 1732.2, 1668.6, 1466.0, 1396.6 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.86 (t, J ) 6.9 Hz, 3H), 1.04-
1.27 (m, 4H), 1.29-1.36 (m, 2H), 1.38-1.53 (m, 2H), 1.64
(dd, J ) 13.5, 3.3 Hz, 1H), 1.72 (dd, J ) 6.3, 1.8 Hz, 3H) 1.75-
1.85 (m, 1H), 2.10-2.22 (m, 1H), 2.23-2.31 (m, 1H), 2.33-2.42
(m, 1H), 5.05 (dddd, J ) 15.3, 10.2, 3.3, 1.5 Hz, 1H), 5.59 (dddd,
J ) 15.0, 6.3, 6.3, 6.3 Hz, 1H), 6.09 (br s, 1H), 9.51 (s, 1H);
13C NMR (CDCl3, 75 MHz) δ 13.9, 17.5, 17.9, 22.3, 25.9, 28.1,
29.7, 31.0, 50.3, 67.8, 127.6, 131.8, 172.8, 201.6; MS-CI m/z
(rel int) 238 ([M + 1]+, 100), 208 (70), 114 (49), 128 (22); HRMS-
CI (calcd for C14H24NO2 ([M + H]+)) 238.1807, found 238.1806.
(6S,1′S,1′′RS)-6-(1′-Butylbut-2′-enyl)-6-(1′′-hydroxybut-
3′′-enyl)piperidin-2-one (13). To a solution of 12 (700 mg,
3.0 mmol) in THF (7 mL) was added allylmagnesium bromide
(6.0 mL, 1.0 M in EtO2) at 0 °C. After the reaction mixture was
stirred for 40 min at 0 C, the reaction was quenched with
saturated aqueous NH4Cl. The aqueous layer was then extracted
with EtOAc and dried (Na2SO4), and the solvent was removed
in vacuo. The residue was purified by column chromatography
on silica gel (hexane/EtOAc ) 1:2 to hexane/EtOAc ) 1:4) to
give yellowish oil 13 (712 mg, 86%) as a diastereomeric mix-
ture: IR (film) νmax 3377.7, 3074.8, 2955.2, 1653.1, 1454.5,
1412.0 cm-1; 1H NMR (CDCl3, 300 MHz) (diastereomer ratio 7:3)
major δ 0.84 (t, J ) 6.9 Hz, 3H), 0.98-1.38 (m, 6H), 1.53-1.62
(m, 1H), 1.67 (dd, J ) 6.3, 1.5 Hz, 3H), 1.71-1.86 (m, 2H), 1.98-
2.44 (m, 6H), 2.65 (br s, 1H), 3.52 (dd, J ) 10.2, 2.4 Hz, 1H),
5.08-5.20 (m, 3H), 5.39-5.54 (m, 1H), 5.74-5.87 (m, 1H), 6.10
(br s, 1H); minor δ 0.84 (t, J ) 6.9 Hz, 3H), 0.98-1.38 (m, 6H),
1
in the crude H NMR spectrum.
Compound 10 was isolated from its minor isomer for analyti-
cal purposes by column chromatography on silica gel (hexane/
EtOAc ) 5:1, taking a small quantity on the top of the mixture).
The enantiopurity was determined by chiral HPLC analysis
(CHIRALCEL OD-H, 2% isopropyl alcohol in hexane, flow rate
0.2 mL/min, retention time: 71.82 min (-)-isomer, detected at
215 nm, 98.2% ee): IR (film) νmax 3221.4, 3094.1, 2955.2, 2874.2,
1
1738.0, 1688.6 cm-1; H NMR (CDCl3, 300 MHz) δ 0.80 (t, J )
6.9 Hz, 3H), 1.01-1.27 (m, 6H), 1.43-1.56 (m, 1H), 1.58
(dd, J ) 13.2, 2.7 Hz, 1H) 1.65 (dd, J ) 6.6, 1.8 Hz, 3H), 1.70-
5758 J. Org. Chem., Vol. 70, No. 14, 2005

1.53-1.62 (m, 1H), 1.67 (dd, J ) 6.3, 1.5 Hz, 3H), 1.71-1.86
(m, 2H), 1.98-2.44 (m, 6H), 2.65 (br s, 1H), 3.58 (dd, J ) 10.5,
2.4 Hz, 1H), 5.08-5.20 (m, 3H), 5.39-5.54 (m, 1H), 5.74-5.87
(m, 1H), 6.20 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.87,
13.90, 17.8, 17.9, 18.5, 18.8, 22.4, 22.5, 23.9, 25.4, 27.7, 28.2,
29.75, 29.82, 31.2, 31.3, 35.4, 35.8, 50.1, 50.5, 61.6, 61.9, 74.1,
76.2, 117.2, 117.4, 128.5, 129.9, 130.3, 135.3, 135.7, 173.9, 174.5;
MS-CI m/z (rel int) 280 ([M + 1]+, 100), 168 (55), 208 (35);
HRMS-CI (calcd for C17H30NO2 ([M + H]+)) 280.2276, found
280.2271.
(6S,7S,8R,9S)-7-Butyl-8,9-epoxy-1-azaspiro[5.5]undecan-
2-one (15). To a solution of 4 (30 mg, 0.14 mmol) in CH3CN
(1.5 mL) and Na2EDTA aqueous solution (1 mL, 4 × 10-4 M in
H2O) was added 1,1,1-trifluoroacetone (0.14 mL, 1.56 mmol) by
using a precooled syringe at 0 °C, followed by treatment with a
mixture of Oxone (420 mg, 0.68 mmol) and NaHCO3 (86 mg,
1.02 mmol) in several portions at 0 °C. After this reaction
mixture was stirred for 2 h at 0 °C, it was diluted with EtOAc
and washed with H2O. The organic layer was dried over
Na2SO4 and evaporated under reduced pressure. This residue
was purified by column chromatography on silica gel (hexane/
EtOAc ) 1:3) to give compound 15 and its minor isomer (30:1
in crude 1H NMR, 25 mg, 78%) as a yellow oil: IR (film) νmax
(6S,7S,11RS)-7-Butyl-11-hydroxy-1-azaspiro[5.5]undec-
8-en-2-one (14). To a solution of 13 (700 mg, 2.5 mmol) in
degassed CH2Cl2 (40 mL) was added Grubbs’ phosphorylidine
catalyst [RuCl2(dCHPh)(PCy3)2] (103 mg, 0.13 mmol). The
reaction mixture was heated (40 °C) for 20 h. The mixture was
evaporated under reduced pressure and directly purified by
column chromatography on silica gel in EtOAc to give colorless
oil 14 (500 mg, 84%) as a diastereomeric mixture: IR (film) νmax
2955.2, 2932.1, 2870.3, 1676.3, 1462.2 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 0.92 (t, J ) 7.2 Hz, 3H), 1.20-2.00 (m, 12H), 2.09-
2.22 (m, 2H), 2.27 (dd, J ) 10.2, 6.9 Hz, 1H), 2.31-2.40 (m, 2H),
3.00 (d, J ) 3.9 Hz, 1H), 3.17 (t, J ) 3.9 Hz, 1H), 6.12 (br s, 1H);
13C NMR (CDCl3, 75 MHz) δ 14.0, 16.3, 22.1, 22.7, 26.7, 27.2,
27.4, 29.6, 34.3, 43.3, 51.2, 55.2, 67.8, 168.7; MS-EI m/z (rel int)
237 (M+, 3), 236 (17), 218 (14), 148 (37), 124 (54), 96 (52), 82
(74), 55 (100); HRMS-CI (calcd for C14H22NO2 ([M - H]+))
236.1650, found 236.1649.
3277.4, 2928.2, 1645.4, 1458.3, 1406.2 cm-1 1H NMR (CDCl3,
;
D2O, 300 MHz) (diastereomer ratio 7:3) major δ 0.84 (t, J )
6.6 Hz, 3H), 1.09-1.43 (m, 4H), 1.43-1.55 (m, 2H), 1.58-1.81
(m, 3H), 1.84-1.92 (m, 1H), 2.05-2.36 (m, 4H), 2.40-2.52
(m, 1H), 3.65 (dd, J ) 9.9, 6.6 Hz, 1H), 5.45-5.65 (m, 2H); minor
δ 0.84 (t, J ) 6.6 Hz, 3H), 1.09-1.43 (m, 4H), 1.43-1.55
(m, 2H), 1.58-1.81 (m, 3H), 1.84-1.92 (m, 1H), 2.05-2.36
(m, 4H), 2.40-2.52 (m, 1H), 3.76 (dd, J ) 3.6, 3.6 Hz, 1H), 5.45-
5.65 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 14.0, 17.5, 18.5,
19.6, 22.7, 22.8, 24.7, 28.4, 28.5, 29.9, 30.1, 31.0, 31.8, 32.0, 40.7,
46.9, 59.0, 60.6, 71.5, 73.2, 122.6, 124.7, 127.6, 127.9, 173.5,
175.7; MS-CI m/z (rel int) 238 ([M + 1]+, 100), 236 (31), 127 (16);
HRMS-CI (Calcd for C14H24NO2 ([M + H]+)) 238.1807, found
238.1815.
(6S,7S,8S)-7-Butyl-8-hydroxy-1-azaspiro[5.5]undecan-2-
one (3). To a solution of 15 (15 mg, 0.06 mmol) in THF (2 mL)
was added DIBAL-H (0.12 mL, 1.0 M in CH2Cl2) at 0 °C. The
reaction mixture was stirred at 0 °C for 1 h, warmed to room
temperature for 30 min, and quenched with saturated aqueous
NH4Cl. It was diluted with EtOAc and washed with 1 N HCl.
The aqueous layer was extracted with EtOAc twice. The
combined organic layers were dried over Na2SO4 and concen-
trated. The crude product was purified by silica gel column
chromatography in EtOAc only to give 3 (12 mg, 79%) as a
colorless form: mp 98-99 C; [R]17 -59.2 (c 0.8, CHCl3)
D
(6S,7S)-7-Butyl-1-azaspiro[5.5]undec-8-en-2-one (4). To a
mixture of 14 (330 mg, 1.4 mmol) and DMAP (17 mg, 0.14 mmol)
in CH2Cl2 (4 mL) was added thiocarbonyldiimidazole (1.5 g,
7.6 mmol). After being stirred for 20 h at room temperature,
the reaction mixture was evaporated under reduced pressure
and directly loaded on silica gel column chromatography (hex-
ane/EtOAc ) 1:1 to hexane/EtOAc ) 1:3) to give imidazole
derivatives (401 mg, 83%) as a diastereomeric mixture. To a
mixture of imidazole derivatives (300 mg, 0.86 mmol) and AIBN
(14 mg, 0.09 mmol) in degassed toluene (12 mL) was added
tributyltin hydride (0.58 mL, 2.2 mmol). After the mixture was
heated to reflux for 2 h, it was cooled to room temperature. The
crude mixture was evaporated under reduced pressure and
loaded on silica gel column chromatography (hexane/EtOAc )
1:1 to hexane/EtOAc ) 1:3) to give a single isomer 4 (125 mg,
65%) as colorless oil: [R]21D -157.6 (c 1.0, CHCl3); IR (film) νmax
[lit.5d [R]25D -65.3 (c 1.01, CHCl3)]; IR (film) νmax 3273.5, 2935.9,
2870.3, 1645.4, 1466.0, 1406.2 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 0.88 (t, J ) 4.2 Hz, 3H); 1.11-1.15 (m, 1H), 1.24-1.50
(m, 8H), 1.52-1.60 (m, 1H), 1.62-1.84 (m, 6H), 1.85-1.89
(m, 1H), 2.22-2.26 (m, 1H), 2.31-2.36 (m, 1H), 4.01 (br s, 1H;
dd, W1/2 ) 7.8 Hz at 300 MHz), 4.68 (br s, 1H), 8.28 (br s, 1H);
13C NMR (CDCl3, 125 MHz) δ 14.2, 16.5, 16.8, 23.2, 27.6, 29.3,
30.9, 31.6, 32.0, 33.8, 50.3, 57.9, 70.5, 172.0; MS-EI m/z (rel int)
239 (M+, 29), 196 (26), 124 (41), 112 (100), 55 (89); HRMS-EI
(calcd for C14H25NO2) 239.1885, found 239.1884.
Acknowledgment. This work was supported by the
Korea Research Foundation (Grant No. KRF-2004-015-
C00274).
Supporting Information Available: Experimental pro-
cedures for the synthesis of 9 and other known advanced
intermediates; copies of 1H NMR and 13C NMR spectra of
compounds 3, 4, 7, 10, and 13-15, 1H NMR spectrum of
mixture of 15 and epi-15, and COSY, HSQC, and HMBC
spectra of compound 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
3188.6, 3022.7, 2930.1, 1660.9, 1456.4, 1402.4 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 0.88 (t, J ) 6.9 Hz, 3H), 1.01-1.16 (m, 1H),
1.20-1.46 (m, 5H), 1.49-1.73 (m, 5H), 1.74-1.91 (m, 3H), 2.08-
2.12 (m, 1H), 2.19-2.41 (m, 2H), 5.60-5.70 (m, 2H), 5.98 (br s,
1H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 17.0, 22.7, 22.9, 28.8,
29.5, 30.8, 30.9, 31.3, 46.3, 55.6, 126.1, 128.4, 172.2; MS-CI m/z
(rel int) 222 ([M + 1]+, 100), 111 (17), 112 (13); HRMS-CI (Calcd
for C14H24NO ([M + H]+)) 222.1858, found 222.1858.
JO050608W
J. Org. Chem, Vol. 70, No. 14, 2005 5759