Synthesis of (-)-delobanone

Article abstract of DOI:10.1021/jo001737+

On irradiation in the presence of Fe(CO)₅ under a CO atmosphere, the alkenyl cyclopropane 2 underwent smooth ring expansion to give the sesquiterpene (-)-delobabone 3. The alkenyl cyclopropane 2 was prepared from the enantiomerically enriched epoxide 1.

Full text of DOI:10.1021/jo001737+

J . Org. Chem. 2001, 66, 3423-3426
3423
Syn th esis of (-)-Deloba n on e
Douglass F. Taber,* Gina Bui,1 and Bei Chen
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
taberdf@del.edu
Received December 13, 2000
On irradiation in the presence of Fe(CO)5 under a CO atmosphere, the alkenyl cyclopropane 2
underwent smooth ring expansion to give the sesquiterpene (-)-delobabone 3. The alkenyl
cyclopropane 2 was prepared from the enantiomerically enriched epoxide 1.
In tr od u ction
The development of general methods for the prepara-
tion of carbocyclic natural products with control of both
relative and absolute configuration has been a longstand-
ing challenge in organic synthesis. The problem of con-
trolling the configuration of a stereogenic center on a
pendant side chain relative to the ring to which it is
control of both relative and absolute configuration. The
alkenyl cyclopropane 2 would be available by Wittig
reaction of aldehyde 8, which could in turn be derived
from nitrile 9.
attached has been particularly troublesome. We report
what promises to be a general approach to this problem,
based on the preparation of the alkenyl cyclopropane 2
from the Sharpless-derived2 epoxide 1. Irradiation of 2
3,4
in the presence of Fe(CO)5 led to smooth conversion to
Sch em e 1
(-)-delobanone 3.
Ba ck gr ou n d
The sesquiterpene (+)-delabanone 6 was isolated in
19715a from the roots of the J apanese shrub “shiomoji”,
in 0.14% yield based on the dry weight of the plant. The
1
structure was established by H NMR, UV, IR, optical
rotation and detailed 1H NMR studies on the O-ben-
zylidene ether of a 1R-hydroxydelobanone derivative.
The only synthesis5b of (+)-delobanone 6 so far reported
was based on the acid-catalyzed condensation of (S)-
(-)-carvone 4 with the allylic alcohol 5. This led to an
unseparated mixture of (+)-delobanone 6 and its dia-
stereoisomer 7. The yield of the mixture was 7.0%, and
the ratio of 6 to 7 was 1.2:1.0.
We hypothesized that the nitrile 9 might be available
by the opening of the Sharpless-derived sulfonate 11 with
an excess of lithioacetonitrile. It would not matter
whether the initial displacement was at the benzene-
sulfonate or at the epoxide. Illustrating the latter pos-
sibility, proton transfer from the initial adduct 10 (the
alkylated nitrile is much more acidic than is acetonitrile)
followed by internal SN2 displacement would generate
nitrile 9.6-8
Retr osyn th etic An a lysis
We envisioned that cyclocarbonylation3 of 2 (Scheme
1) with Fe(CO)5 would lead to (-)-delobanone 3, with
(1) Undergraduate research participant.
(2) Hanson, R. M.; Sharpless, B. K. J . Org. Chem. 1986, 51, 1922.
(3) Taber, D. F.; Kanai, K.; J iang, Q.; Bui, G. J . Am. Chem. Soc.
2000, 122, 6807.
(4) (a) The photochemical Fe(CO)5-mediated carbonylation of vinyl
cyclopropanes was first reported in 1970: Sarel, S. Acc. Chem. Res.
1978, 11, 204. For more recent references, see: (b) Khusnutdinov, R.
I.; Dzhemilev, U. M. J . Organomet. Chem. 1994, 471, 1. (c) Schulze,
M. M.; Gockel, U. Tetrahedron Lett. 1996, 37, 357. (d) Schulze, M. M.;
Gockel, U. J . Organomet. Chem. 1996, 525, 155.
(6) For the alkylation and polyalkylation of lithioacetonitrile, see:
Taber, D. F.; Kong, S. J . Org. Chem. 1997, 62, 8575.
(7) For the opening of a Sharpless-derived epoxide with lithioaceto-
nitrile, see: Taber, D. F.; Green, J . H.; Zhang, W.; Song, R. J . Org.
Chem. 2000, 65, 5436.
(5) (a) Takeda, K.; Sakurawi, K.; Ishii, H. Tetrahedron 1971, 27,
6049. (b) Harwood: L. M.; J ulia, M. Tetrahedron Lett. 1980, 21, 1743.
10.1021/jo001737+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/25/2001

3424 J . Org. Chem., Vol. 66, No. 10, 2001
Taber et al.
Sch em e 2
Sch em e 3
The ring-expanding reaction of alkenyl cyclopropane
3
2 irradiated in the presence of Fe(CO)5 may proceed
with the preferential cleavage of bond “b” (Scheme 3) to
give 13, or bond “a” to give 16. On the basis of the
precedent,3 we expected preferential cleavage of bond “b”.
Subsequent carbonylation followed by reductive elimina-
tion would give the enone 15, which on exposure to
DBU would be equilibrated to more stable conjugated
isomer 3.
In the event, Fe-mediated cyclocarbonylation of the
alkenyl cyclopropane 2 (isopropyl alcohol, CO balloon,
Rayonet, 23 h, monitoring by TLC, then DBU) led to (-)-
delobanone as a colorless oil, [R]18D ) -12.7° (c 0.28, CH2-
Cl2, lit. (+)-delobanone [R]D ) +10.2°). IR of 2 showed
A real concern with this approach was the potential
lability of the tertiary cyclopropyl carbinol 2. As acid-
catalyzed ring opening would be assisted by the propenyl
group, there was the possibility that 2 either could not
be handled or that it would degrade under the conditions
of Fe-mediated cyclocarbonylation.
absorption typical for an OH group (υmax ) 3472 cm-1
)
and an R,â-unsaturated ketone system (υmax ) 1660
1
cm-1). The H NMR in C6D6 revealed the presence of a
Me on the carbon carrying the OH group (δ 0.83, 3H, s),
three Me groups on two double bonds (δ 1.56, 3H, s; δ
1.67, 3Η, d, J ) 1.1 Hz; δ 1.81, 3H, d, J ) 1.2 Hz); an
alkene proton at a position â to the conjugated carbonyl
group (δ 6.14, 1Η, tq, J ) 1.3 and 5.9 Hz), and the other
alkene proton (δ 5.13, 1Η, tquint, J ) 1.4 and 7.1 Hz).
These values are congruent with those reported.5a The
13C NMR spectrum was also congruent with the assigned
structure.
Syn th esis of (-)-Deloba n on e
The key to this approach was the preparation of the
nitrile 9. As shown in Scheme 2, Sharpless epoxidation2
of commercially available geraniol followed by sulfonyl-
ation led to the benzenesulfonate 11. Initially, we tried
adding the benzenesulfonate to a large excess (5.5 equiv)
of lithioacetonitrile. The desired cyclopropane nitrile 9
was isolated, but in only 15% yield. We were pleased to
find that by lowering the amount of lithioacetonitrile and
controlling the rate of addition of the benzenesulfonate
11 the yield could be increased to 87%.
Con clu sion
The strategy outlined here for the enantioselective
construction of cyclohexenones with control of both rela-
tive and absolute configuration will have many other
applications in natural product synthesis. We expect that
the efficient conversion of the Sharpless-derived epoxide
1 to the nitrile 9 will be a useful addition to the
armamentarium of organic chemistry.
The oily nitrile so prepared appeared (13C NMR) to be
a single diastereoisomer. The combustion analysis sup-
ported the proposed empirical formula, and IR showed
absorptions typical for an OH group and a CN group. 13
C
NMR clearly showed a three-membered ring attached to
the CN group, with methines at δ -1.5 and δ 17.9, and
a methylene at δ 10.2. The preparation of nitrile 9 with
control of relative and absolute configuration (86% ee by
chiral HPLC analysis of a derivative of 8) set the stage
for the synthesis of (-)-delobanone, as neither the ensu-
ing DIBAL reduction nor the Wittig condensation would
affect the distal stereogenic centers.
Exp er im en ta l Section
Each reaction with air- and moisture-sensitive components
was performed under a nitrogen atmosphere in a flame-dried
reaction flask. Tetrahydrofuran was distilled from sodium/
benzophenone, and dichloromethane was distilled from cal-
1
cium hydride. H and 13C NMR spectra were recorded at 250
and 61.72 MHz or 400 and 100 MHz, respectively, as solutions
in deuteriochloroform. Chemical shifts are reported in ppm
downfield from TMS. 13C NMR H substitution was determined
with the aid of a J VERT pulse sequence, differentiating the
signals for methyl and methine carbons as “d”, from methylene
(8) For a related double alkylation of an R-amino nitrile with a
haloepoxide, see: (a) Geraldine, G.; Aitken, D. J .; Guilaume, D.;
Hussson, H-P. Tetrahedron Lett. 1994, 35, 4355. (b) Aitken, D. J .;
Royer, J .; Husson, H-P J . Org. Chem. 1990, 55, 2814.

Synthesis of (-)-Delobanone
J . Org. Chem., Vol. 66, No. 10, 2001 3425
and quaternary carbons as “u”. IR spectra were determined
as neat oils. Mass spectra were obtained at an ionizing
potential of 100 eV. Optical rotations were determined as
solutions in dichloromethane unless otherwise noted. Rf values
indicated refer to thin-layer chromatography (TLC) on 2.5 ×
10 cm, 250 µm analytical plates coated with silica gel GF.
Solvents for TLC are reported as v/v mixtures.
warmed from -78 °C to room temperature over 2 h. The
reaction mixture was quenched by the addition of saturated
aqueous NH4Cl and 6 M HCl (6:1, v/v) at 0 °C. The THF was
removed under vacuum, and the residue was partitioned
between ethyl ether and saturated brine. The combined
organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to give 8 as a colorless oil (981
Ep oxid e 1. A mixture of activated 4Å molecular sieves (1.80
g, 15-20 wt % based on geraniol) and dichloromethane (100
mL) was cooled to -10 °C. L-(+)-Diethyl tartrate (1.00 g, 4.8
mmol), titanium(IV) isopropoxide (0.91 g, 3.2 mmol), and tert-
butylhydroperoxide (19.4 mL, 97 mmol, 5.0 M in dichloro-
methane) were added sequentially. After 10 min of stirring,
the mixture was cooled to -20 °C, and freshly distilled geraniol
(10.0 g, 65 mmol, in 10 mL of dichloromethane) was added
dropwise over 15 min. After 45 min of stirring at -20 to -15
°C, the mixture was warmed to 0 °C. After an additional 5
min of stirring at 0 °C, the mixture was quenched sequentially
with water (20 mL) and 4.5 mL of 30% aqueous NaOH
saturated with solid NaCl. After 10 min of vigorous stirring,
the reaction mixture was partitioned between dichloromethane
and water. The combined organic extract was dried (MgSO4)
and then filtered through Celite to give a clear colorless
solution. Concentration followed by bulb to bulb distillation
[bp (bath) ) 100 °C at 0.1 mm Hg] gave 2 as a colorless oil
(10.3 g, 91% yield). TLC Rf ) 0.42 (20% MTBE/petroleum
ether); [R]16 ) -4.75° (c 1.43, CHCl3), lit. [R]25 ) -5.3° (c
mg, 61% yield). TLC Rf ) 0.24 (20% MTBE/petroleum ether);
1
[R]18 ) +37.3° (c 0.8, CH2Cl2); H NMR δ 1.22 (s, 3H), 1.26
D
(m, 2H) 1.59 (m, 3H), 1.63 (s, 3H), 1.64 (s, 3H), 1.94 (m, 1H),
2.12 (q, J ) 7.5 Hz, 2H), 5.13 (tquint, J ) 1.3 and 7.1 Hz, 1H),
9.17 (d, J ) 4.3 Hz, 1H); 13C NMR δ d 18.0, 26.0, 26.1, 27.6,
32.1, 124.1, 201.6; u 11.4, 22.9, 42.9, 70.3, 132.7; IR 3478, 2960,
2925, 2729, 1715, 1678 cm-1. Anal. Calcd for C12H20O: C,
73.43; H, 10.27. Found: C, 73.20; H, 10.52.
Aldehyde 8 (176 mg, 0.9 mmol) was dissolved in 20 mL of
MeOH at 0 °C, and NaBH4 (51 mg, 1.4 mmol) was added in
several portions over 5 min. After an additional 1 h, the
reaction mixture was quenched by the addition of saturated
aqueous NH4Cl. The MeOH was removed under vacuum, and
the residue was partitioned between ethyl acetate and satu-
rated brine. The combined organic extract was dried (Na2SO4)
and concentrated. The crude oil (157 mg) was dissolved in CH2-
Cl2 at 0 °C, and triethylamine (0.23 mL, 1.7 mmol), 4-DMAP
(19 mg, 0.16 mmol,) and benzoyl chloride (0.18 mL, 1.6 mmol)
were added sequentially. After stirring at room temperature
for 4 h, the reaction mixture was quenched by the addition of
saturated aqueous NH4Cl at 0 °C. The reaction mixture was
then partitioned between dichloromethane and, sequentially,
5% aqueous NaOH, 5% aqueous HCl, and saturated brine. The
combined organic extract was dried (Na2SO4) and concen-
trated. The residue was chromatographed to give the primary
benzoate as a colorless oil (116 mg, 43% yield based on
D
D
3.0, CHCl3); 1H NMR δ 1.28 (s, 3H), 1.46 (m, 1H); 1.59 (s, 3H),
1.66 (m, 4H), 2.03 (m, 2H), 2.97 (dd, J ) 4.0 and 7.2 Hz, 1H),
3.72 (m, 2H), 5.07 (tquint, J ) 1.3 and 7.1 Hz,1H); 13C NMR
δ d 16.9, 17.6, 25.8, 63.3, 123.5; u 23.8, 38.6, 61.4, 61.5, 132.2;
IR 3423, 2926, 1659, 1454, 1385, 1034 cm-1
.
Su lfon a t e 11. Triethylamine (5.30 mL, 38.2 mmol), 4-
DMAP (718 mg, 5.8 mmol), and phenylsulfonyl chloride (4.50
mL, 35.3 mmol) were added sequentially to epoxide 1 (5.00 g,
29.4 mmol) in dichloromethane (74 mL) at 0 °C. After stirring
at room temperature overnight, the reaction mixture was
quenched by the addition of 50 mL of saturated aqueous NH4-
Cl at 0 °C. The reaction mixture was then partitioned between
dichloromethane and, sequentially, 5% aqueous NaOH, 5%
aqueous HCl, and saturated brine. The combined organic
extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to give 9 as a colorless oil (8.1 g, 88% yield).
aldehyde 8). TLC Rf ) 0.57 (30% MTBE/petroleum ether);
1
[R]16 ) -4.1° (c 1.9, CH2Cl2 ); H NMR δ 0.53 (m, 1H), 0.80
D
(m, 1H), 0.96 (m, 1H), 1.27 (s, 3H), 1.30 (m,1H), 1.59 (m, 2H),
1.61 (s, 3H), 1.69 (s, 3H), 1.72 (m, 1H), 2,14 (q, J ) 7.5 Hz,
2H), 4.05 (dd, J ) 8.1 and 11.3 Hz, 1H), 4.35 (dd, J ) 6.7 and
11.3 Hz, 1H), 5.13 (m 1H), 7.44 (t, J ) 7.7 Hz, 2H), 7.56 (m,
1H), 8.06 (m, 2H); 13C NMR δ d 13.2, 17.8, 25.9, 26.7, 27.7,
124.6, 128.5, 129.7, 133.0; u 6.7, 22.8, 43.1, 69.1, 70.7, 130.5,
132.0, 166.9; IR 3507, 2967, 2923,1715, 1602, 1452 cm-1. The
benzoate was shown to be 86.6% ee by chiral HPLC on an
analytical Chiralcel OD column. Eluting with 98:2 hexanes/
2-propanol at 1.0 mL/min, the benzoate (14.0 min) and the ent-
benzoate (19.1 min) showed baseline resolution.
TLC Rf ) 0.55 (20% MTBE/petroleum ether); [R]18 ) -20.3°
D
(c 1.10, CH2Cl2); 1H NMR δ 1.18 (s, 3H), 1.52 (m, 2H), 1.56 (s,
3H), 1.64 (s, 3H), 1.95 (q, J ) 7.3 Hz, 2H), 2.96 (t, J ) 5 0.6
Hz, 1H), 4.14 (m, 2H), 5.00 (tquint, J ) 1.3 and 7.1 Hz, 1H),
7.73 (m, 5H); 13C NMR δ d 16.8, 17.8, 25.8, 58.8, 123.1, 128.0,
129.5, 134.1; u 23.6, 61.0, 69.0, 132.4, 135.7; IR 2919, 1586,
1449, 1360, 1187 cm-1; MS m/z 310 (0.5), 292 (2), 201 (12),
141 (35), 109 (100); HRMS calcd for C16H22O4S 310.1240, obsd
310.1225.
Alk en yl Cyclop r op a n e 2. n-BuLi (92.68 mL, 2.19 M, 5.9
mmol) was added dropwise to ethyltriphenylphosphonium
bromide (2.27 g, 6.1 mmol) in THF (6 mL) at 0 °C. The
resulting orange suspension was stirred from 0 °C to room
temperature over 1 h. Aldehyde 8 (480 mg, 2.5 mmol) in THF
(5 mL) was added over 30 min at 0 °C. After an additional 30
min at room temperature, methanol (2 mL) was added to
quench the reaction, and the solvent was removed under
vacuum. The reaction mixture was partitioned between MTBE
and saturated brine, and the combined organic extract was
dried (Na2SO4) and concentrated. The residue was chromato-
graphed to give 2 as a colorless oil (253 mg, 50% yield). TLC
Rf ) 0.75 (20% MTBE/petroleum ether); [R]18D ) -2.67° (c 0.6,
Nitr ile 9. n-BuLi (10.20 mL, 2.25 M, 22.9 mmol) was added
to acetonitrile (1.25 mL, 23.9 mmol) in THF (28 mL) at -78
°C. After 1.5 h, sulfonate 11 (3.00 g, 9.6 mmol) in THF (20
mL) was added dropwise over 1 h. After an additional 0.5 h,
the mixture was warmed to 0 °C and stirred for 30 min. The
reaction mixture was quenched by addition of saturated
aqueous NH4Cl. The THF was removed under vacuum, and
the residue was partitioned between ethyl acetate and satu-
rated brine. The combined organic extract was dried (Na2SO4)
and concentrated. The residue was chromatographed to give
9 as a pale yellow oil (1.6 g, 87% yield). TLC Rf ) 0.37 (20%
1
CH2Cl2); H NMR δ 0.47 (m 1H), 0.88 (m, 2H), 1.16 (s, 3H),
1.64 (m, 10H), 2.10 (q, J ) 6.5 Hz, 2H), 4.80 (m, 1H), 5.16 (m,
1H), 5.34 (m, 1H); 13C NMR δ d 13.2, 13.4, 17.9, 26.0, 26.4,
30.6, 122.3, 123.1, 124.6; u 10.1, 23.0, 43.2, 43.3, 71.3, 133.9;
IR: 3418, 2969, 2918, 2857, 1654, 1451, 1375 cm-1; MS m/z
208 (5), 190 (18), 175 (15), 147 (35), 123 (100), 107 (50); HRMS
calcd for C14H24O 208.1828, obsd 208.1832.
MTBE/petroleum ether), [R]18 ) +68.1°(c 1.0, CH2Cl2); 1H
D
NMR δ 1.15 (m, 3H), 1.32 (s, 3H), 1.51 (m, 3H), 1.70 (s, 3H),
1.64 (s, 3H), 2.12 (q, J ) 7.5 Hz, 2H), 5.13 (tquint, J ) 1.3 and
7.1 Hz, 1H); 13C NMR δ d -1.5, 17.9, 25.9, 27.7, 30.6, 123.9; u
10.2, 22.7, 42.5, 69.4, 122.5, 132.8; IR 3479, 2967, 2238, 1455
cm-1; MS m/z 193 (5), 176 (45), 160 (50), 135 (40), 119 (50),
107 (100); HRMS calcd for C12H19ON 193.1468, obsd 193.1535.
Anal. Calcd for C12H19ON: C, 74.56; H, 9.91; N, 7.25. Found:
C, 74.46; H, 10.01; N, 7.11.
(-)-Deloba n on e 3. Under a balloon of carbon monoxide,
Fe(CO)5 (63 µL, 481 µmol) was added to alkene 2 (50 mg, 240
µmol) in 2-propanol (5 mL). The reaction was carried out in a
Pyrex test tube, with a smaller Pyrex test tube inside, to
spread the reaction mixture in a thin layer. After irradiation
(Rayonet, 350 nm) for 23 h, DBU (180 µL, 1.2 mmol) was added
at room temperature. After 1 h, the reaction mixture was
filtered, and the solid residue was washed with MTBE. The
combined filtrate was concentrated under vacuum. The residue
Ald eh yd e 8. DIBAL-H (24.98 mL, 0.83 M in THF, 20.8
mmol) was added to nitrile 9 (1.60 g, 8.3 mmol) in THF (20
mL) at -78 °C, and the mixture was stirred and gradually

3426 J . Org. Chem., Vol. 66, No. 10, 2001
Taber et al.
was partitioned between ethyl acetate and, sequentially, 5%
aqueous HCl and saturated brine. The combined organic
extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to give 3 as a colorless oil (36.5 mg, 64%
22.9, 27.8, 36.9, 40.3, 72.9, 131.8, 135.7; IR 3472, 2925, 1660,
1453, 1372 cm1; MS m/z 218 (5), 153 (8), 135 (10), 127 (20),
110 (100); HRMS calcd for C14H22O (M+ - 18) 218.1672, obsd
218.1669.
yield). TCL Rf ) 0.18 (20% MTBE/petroleum ether); [R]18
)
D
1
-12.7° (c 0.3, CH2Cl2); H NMR (CDCl3) δ 1.13 (s, 3H), 1.21
(s, 1H), 1.46 (m, 2H), 1.56 (s, 3H), 1.63 (s, 1H), 1.72 (t, J ) 1.2
Hz, 3H), 2.26 (m, 7H), 2.54 (m, 1H), 5.05 (tquint, J ) 1.3 and
7.1 Hz, 1H), 6.70 (tq, J ) 1.4 and 5.5 Hz, 1H); 1H NMR (C6D6)
δ 0.83 (s, 3H), 1.25 (m, 2H), 1.56 (s, 3H), 1.67 (d, J ) 1.1 Hz,
3H), 1.81 (d, J ) 1.2 Hz, 3H), 1.90 (m, 7H), 2.64 (m, 1H), 5.13
(tquint, J ) 1.4 and 7.1 Hz, 1H), 6.14 (tq, J ) 1.3 and 5.9 Hz,
1H); 13C NMR (CDCl3) δ d 15.9, 18.0, 24.2, 25.9, 44.5, 124.0,
146.2; u 22.5, 27.4, 39.2, 39.7, 73.5, 132.6, 135.4, 200.6; 13C
NMR (C6D6) δ d 16.3, 18.0, 24.0, 26.1, 45.0, 125.3, 144.2; u
Ack n ow led gm en t. We thank the NIH (GM60287)
for financial support of this work. We thank M. G. Finn
for a detailed procedure for the preparation of geraniol
epoxide.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O001737+