Total synthesis of (S)-(+)-imperanene. Effective use of regio- and enantioselective intramolecular carbon-hydrogen insertion reactions catalyzed by chiral dirhodium(II) carboxamidates

Article abstract of DOI:10.1021/jo016220s

The total synthesis of (S)-(+)-imperanene, a natural product found in Chinese medicine, has been completed in 12 steps from a commercially available cinnamic acid. The key step is highly enantioselective carbon-hydrogen insertion from a diazoacetate using a chiral dirhodium(II) carboxamidate catalyst. An elimination process essential to the construction has been optimized to avoid intramolecular Friedel-Crafts alkylation.

Full text of DOI:10.1021/jo016220s

2954
J . Org. Chem. 2002, 67, 2954-2959
Tota l Syn th esis of (S)-(+)-Im p er a n en e. Effective Use of Regio- a n d
En a n tioselective In tr a m olecu la r Ca r bon -Hyd r ogen In ser tion
Rea ction s Ca ta lyzed by Ch ir a l Dir h od iu m (II) Ca r boxa m id a tes
Michael P. Doyle,* Wenhao Hu, and Marcela V. Valenzuela
Department of Chemistry, University of Arizona, Tucson, Arizona 85721
mdoyle@u.arizona.edu
Received October 19, 2001
The total synthesis of (S)-(+)-imperanene, a natural product found in Chinese medicine, has been
completed in 12 steps from a commercially available cinnamic acid. The key step is highly
enantioselective carbon-hydrogen insertion from a diazoacetate using a chiral dirhodium(II)
carboxamidate catalyst. An elimination process essential to the construction has been optimized
to avoid intramolecular Friedel-Crafts alkylation.
(+)-Imperanene (1) is a novel phenolic compound that
has been isolated from Imperata cylindrica.1 The rhi-
zomes of I. cylindrica have been used in Chinese medicine
as diuretic and antiinflammatory agents,2a and imper-
anene has been shown to have platelet aggregation
inhibitory activity. When we first submitted this manu-
script, there was then no report of the total synthesis of
this compound, and its absolute configuration had not
been determined. A recent publication has reported its
enantioselective synthesis using a chiral auxiliary,2b but
concerns regarding the initially reported optical rotation
were not resolved.
xylono-1,4-lactone6 and baclofen.7 Both enantiomeric
forms are available by this methodology.
We envisioned a synthetic strategy to imperanene
through lactone 2 (P ) protective group) accessible by a
variety of methodologies,3 the most advantageous on the
basis of enantiocontrol and number of reaction steps
being the carbon-hydrogen insertion pathway from
diazoacetate 3.4 This methodology effects virtually re-
giospecific carbene insertion into an unactivated C-H
bond four atoms removed from the carbon center and has
been demonstrated to be effective for the highly enanti-
oselective syntheses of lignans5 ranging from enterolac-
tone and arctigenin to isodeoxypodophyllotoxin4 and for
the construction of nearly optically pure forms of 2-deoxy-
(1) Matsumaga, K.; Shibuya, M.; Ohizumim, Y. J . Nat. Prod. 1995,
58, 138.
(2) (a) Kancharapee, P. Shoyakugaku Zasshi 1967, 21, 65. (b)
Shattuck, J . C.; Shreve, C. M.; Solomon, S. E. Org. Lett. 2001, 3, 3021.
(3) (a) Garcon, S.; Vassiliow, S.; Caviccioli, M.; Hartmann, B.;
Montiero, N.; Balme, G. J . Org. Chem. 2001, 66, 4069. (b) Brinksma,
J .; vender Deen, H.; van Oeveren, A.; Feringa, B. L. J . Chem. Soc.,
Perkin Trans. 1 1998, 4159. (c) Yoshida, S.; Ogiku, T.; Ohmizu, H.;
Iwasaki, T. J . Org. Chem. 1997, 62, 1310. (d) Moritani, Y.; Fakushima,
C.; Ukita, T.; Miyagishima, T.; Ohmizu, H.; Iwasaki, T. J . Org. Chem.
1996, 61, 6922. (e) Canan Koch, S. S. C.; Chamberlin, A. R. J . Org.
Chem. 1993, 58, 2725.
Although chiral dirhodium(II) carboxamidates 4-7
have been used with varying success in C-H insertion
reactions of diazoacetates,8,9 only the Rh2(MPPIM)4 cata-
(6) Doyle, M. P.; Tedrow, J . S.; Dyatkin, A. B.; Spaans, C. J .; Ene,
D. G. J . Org. Chem. 1999, 64, 8907.
(7) Doyle, M. P.; Hu, W. Chirality 2002, 14, 169.
(8) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; J ohn Wiley &
Sons: New York, 1998; Chapter 3. (b) Doyle, M. P.; Forbes, D. C. Chem.
Rev. 1998, 98, 911.
(4) Bode, J . W.; Doyle, M. P.; Protopopova, M. N.; Zhou, Q.-L. J .
Org. Chem. 1996, 61, 9146.
(5) Ward, R. S. Nat. Prod. Rep. 1995, 12, 183.
10.1021/jo016220s CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/02/2002

Total Synthesis of (S)-(+)-Imperanene
J . Org. Chem., Vol. 67, No. 9, 2002 2955
lysts10 have led to greater than 20:1 enantioselection. This
is due primarily to the increased steric interactions of
Ta ble 1. Yield a n d % ee Va lu es for th e Syn th esis of 11
fr om 10 by Ca ta lytic In tr a m olecu la r C-H In ser tion w ith
4-7a
catalyst
yield 11, %b
ee, %c
Rh2(4S-MPPIM)4 (6)
Rh2(5R-MEPY)4 (en t-4)
Rh2(4S-MEOX)4 (5)
Rh2(4S-IBAZ)4 (7)
68
51
37
40
93
(67)d
36
42
a
Reactions performed in refluxing CH2Cl2 containing 1.0 mol
% of catalyst by 5-h addition of 10 (2.0 mmol) in 2 mL of CH2Cl2.
b
Weight yield after chromatography. c Analysis by HPLC on a
Chiralpak OD column (98:2 hexane/iPrOH). Enantiomer of 11
d
was dominant.
Sch em e 2a
ligands with the reacting carbene, which restrict avail-
able conformations and direct product formation. Both
enantiomeric forms of the 3-benzyl-γ-butyrolactone prod-
uct are available via this methodology; Rh2(4S-MPPIM)4
forms the S-configured lactone product, whereas Rh2(4R-
MPPIM)4 yields the R-enantiomer in all cases examined
thus far.
t
The synthesis of 3 (P ) BuPh2Si) employed standard
methods (Scheme 1)11 and use of tert-butyldiphenylsilyl
Sch em e 1a
a
(a) DIBAL-H; (b) TDBPSCl/DMF/imidazole; (c) MsCl/DBU in
PhCl, reflux; (d) TBAF.
a
(a) H2, 10% Pd/C; (b) MeOH, H+; (c) TBDPSCl/imidazole/DMF;
on the yield and % ee of 11 is presented in Table 1.
Significantly lower product yields and selectivities were
observed with catalysts other than Rh2(4S-MPPIM)4.
With the benzyl ether corresponding to 10 (Bn instead
of TBDPS), use of Rh2(4S-MPPIM)4 gave the lactone
product corresponding to 11 with 96% ee.
Lactone 11 having the S-configuration4 was reduced14
and then alkylated with aryllithium 1312 to produce a
nearly 50:50 diastereomeric diol mixture (14, Scheme 2).
The primary alcohol was selectively protected with TB-
DPSCl (95% yield)15 and then treated with MsCl/DBU
in refluxing chlorobenzene16 to produce 15 exclusively as
the E-isomer. Deprotection of 15 with tetrabutylammo-
nium fluoride gave 16, whose spectral properties were
(d) LiAlH4, THF; (e) diketene/Et3N; (f) MsN3 Et3N; (g) LiOH/H2O/
THF.
TBDPS as the phenolic protective group.12 The benzyl
ether was used in model studies instead of TBDPS, but
the difficulties of its deprotection in the presence of a
carbon-carbon double bond made this approach unreal-
istic in the overall synthetic scheme. The synthesis of 10
from 9 followed well-established procedures.13 Catalytic
intramolecular C-H insertion occurred cleanly and in
good yield with Rh2(4S-MPPIM)4; this catalyst gave the
highest enantiomeric excess of 11 (93%) without evidence
of either â- or δ-lactone products. The influence of catalyst
(9) Doyle, M. P.; Kalinin, A. V.; Ene, D. G. J . Am. Chem. Soc. 1996,
118, 8837.
(10) Doyle, M. P.; Zhou, Q.-L.; Raab, C. E.; Roos, G. H. P.; Simonsen,
S. H.; Lynch, V. Inorg. Chem. 1996, 35, 6064.
(14) (a) Sato, H.; Kim, Y. S.; Shibashi, M. Tetrahedron Lett. 1999,
40, 2973. (b) Boland, W.; Niedermeyer, U.; J aenicke, L. Helv. Chim.
Acta 1985, 68, 2062.
(15) (a) Martin, C.; Bortolussi, M.; Bloch, R. Tetrahedron Lett. 1999,
40, 3735. (b) Maioli, A. T.; Civiello, R. L.; Foxman, B. M.; Gordon, D.
M. J . Org. Chem. 1997, 62, 7413.
(11) Solladie´, G.; Ziani-Che´rif, C. J . Org. Chem. 1993, 58, 2181.
(12) Misra, R. N.; Brown, B. R.; Han, W.-C.; Harris, D. N.; Hedberg,
A.; Webb, M. L.; Hall, S. E. J . Med. Chem. 1991, 34, 2882.
(13) Doyle, M. P.; Westrum, L. J .; Wolthuis, W. N. E.; See, M. M.;
Boone, W. P.; Bagheri, V.; Pearson, M. M. J . Am. Chem. Soc. 1993,
115, 958.
(16) Honda, T.; Naito, K.; Yamane, S.; Suzuki, Y. J . Chem. Soc.,
Chem. Commun. 1992, 1218.

2956 J . Org. Chem., Vol. 67, No. 9, 2002
Doyle et al.
Sch em e 3a
Sch em e 4a
a
(a) TBAF (1.1 equiv, 0 °C, 20 min); (b) BnBr, 2 equiv, rt, 2 h).
identical to those reported for (+)-imperanene.1 The
observed rotation of 16 was +103° for a compound that
was 93% ee by the methodology employed. Since the
reported rotation for 1 was +700°,1 further characteriza-
tion of the synthetic material was performed. First of all,
the rotation of 16 was invariant with concentration over
a factor of 10. Second, conversion of 16 to the trifluoro-
acetate ester of the primary alcohol (TFAA in pyridine)
allowed HPLC determination of the enantiomeric com-
position, on a 25-cm Chiralpak OD column [14.7 min for
(R)-1 and 21.7 min for (S)-1], and this analysis confirmed
the 93% ee of 16. Furthermore, removal of the TBDPS
group from 11 and replacement with a benzyl group
(Scheme 3) allowed correlation with the lactone (R-
isomer, [R]D ) +3.7° for 96% ee) from which isolauric-
erisinol of known configuration has been produced.4
Consequently, on the basis of these results and on the
configurational preference for (S)-11 with the use of Rh2-
(4S-MPPIM)4 on diazoacetates directly related to 10,4 we
can assign the absolute configuration of 1 as S.
a
(a) DIBAL-H; (b) ArMgBr/Et2O; (c) TBDPSCl/imidazole/DMF;
(d) (MeSO2)2O/DMAP/CH2Cl2, reflux f 19:20 ) 9:91; (e) MeSO2Cl/
DBU/THF, reflux f 19:20 ) 38:62; (f) MeSO2Cl/DBU/PhCl, reflux
f 19:20 ) 71:29.
trifluoroacetic acid was recommended,17 but its use did
not form 21 from 22 as anticipated; a complex mixture
of materials was formed that was not further analyzed.
Optimum conditions were realized with the use of meth-
anesulfonic anhydride and DMAP at room temperature
(eq 1), from which 21 was obtained as a mixture of two
diastereoisomers (3:1). The contrast between these condi-
tions and those used to prepare the elimination product
15 is noteworthy.
When excess TBAF is used, the yield-limiting step in
Scheme 2 is that for deprotection, and the cause is the
removal of TBDPS from the primary alkoxide. The
phenolic TBDPS comes off rapidly and quantitatively
with TBAF within 30 min at 0 °C. The remaining
protective group requires 12 h at room temperature using
a solution that contains an equivalent amount of TBAF.
Excess reagent lowers product yield.
The conditions employed for the elimination reaction
used for the preparation of 15 were established through
laborious investigations with its dibenzyl ether analogue
17, prepared from lactone 18 (Scheme 4) through a set
of steps similar to that employed for the synthesis of 15.
Use of relatively mild conditions (condition d)16 resulted
in an unexpected preponderance of the Friedel-Crafts
alkylation product 20. With the more reactive MsCl and
DBU in refluxing THF, the proportion of elimination
product 19 increased; and when the same reaction was
performed in refluxing chlorobenzene, elimination oc-
curred in preference to Friedel-Crafts alkylation. When
these same conditions were applied to the TBDPS-
protected 14 (Scheme 2), elimination was predominant
and the Friedel-Crafts alkylation product 21 was only
a minor constituent of the reaction mixture (16:21 ) 86:
14).
(S)-(+)-Imperanene has been synthesized in 12 steps
and approximately 16% overall yield. Improvements in
the overall scheme that will give higher yields are
transparent, but the core reaction, enantioselective C-H
insertion, is optimized.
Exp er im en ta l Section
Gen er a l. 1H NMR (250, 500, or 600 MHz) and 13C NMR
(62.5, 125, or 150 MHz) spectra were obtained as solutions in
CDCl3, and chemical shifts are reported in parts per million
(ppm, δ) downfield from the internal standard, Me4Si (TMS).
Mass spectra were obtained using electron ionization on a
quadruapole instrument. Elemental analyses were performed
by Desert Analytics Laboratory, Tucson, AZ. Anhydrous THF
In efforts to prepare 21 as the exclusive product, neat
(17) Brown, E.; Daugan, A. Heterocycles 1987, 26, 1169.

Total Synthesis of (S)-(+)-Imperanene
J . Org. Chem., Vol. 67, No. 9, 2002 2957
was distilled over sodium/benzophenone ketyl, and dichloro-
methane was distilled over calcium hydride. Methanesulfonyl
azide (MsN3) was prepared by reaction of methanesulfonyl
chloride with sodium azide18 and was not distilled. Dirhodium-
(II) catalysts were prepared as previously described.19-22
Unless otherwise stated, all chemicals were used without
further purification.
2.0 Hz, 1H), 3.61 (t, J ) 6.5 Hz, 2H), 3.54 (s, 3H), 2.56 (t, J )
7.5 Hz, 2H), 1.81 (tt, J ) 7.5, 6.5 Hz, 2H), 1.10 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 150.3, 143.1, 135.4, 135.0, 133.7,
129.5, 127.4, 120.2, 119.9, 112.7, 62.3, 55.4, 34.2, 31.7, 26.7,
19.7.
3-[4-(ter t-Bu t yld ip h en ylsila n oxy)-3-m et h oxyp h en yl]-
p r op yl Dia zoa ceta te (10). A solution of alcohol 9 (2.1 g, 5.0
mmol) in 10 mL of CH2Cl2 was treated with triethylamine (0.1
g, 1.0 mmol) and diketene (0.50 g, 6.0 mmol) at 0 °C. The
solution was allowed to warm to room temperature, and
stirring was continued for 16 h. The reaction mixture was then
cooled to 0 °C. Triethylamine (0.7 g, 7.0 mmol) was added,
followed by addition of MsN3 (0.67 g, 5.5 mmol). The reaction
solution was allowed to warm to room temperature, and
stirring was continued for 24 h, after which the solvent was
removed under reduced pressure. The residue was dissolved
in 100 mL of ethyl acetate and then washed with H2O (50 mL)
and brine (50 mL). After drying over anhydrous Na2SO4, the
solvent was evaporated under reduced pressure. The crude
diazoacetoacetate was purified by flash column chromatogra-
phy on silica gel (hexanes/ethyl acetate ) 10:1). To the THF
(10 mL) solution of the diazoacetoacetate was added LiOH
hydrate (2.1 g, 50.0 mmol) in H2O (10 mL) at 0 °C. The reaction
mixture was allowed to stir at room temperature for 0.5 h until
the cleavage was complete. The layers were separated, and
the aqueous layer was extracted with ethyl acetate (3 × 20
mL). The combined organic layer was washed with brine, and
the solvent was evaporated under reduced pressure. Purifica-
tion by column chromatography (hexanes/ethyl acetate ) 10:
1) yielded diazoacetate 10 as a yellow oil (1.6 g, 66% yield):
1H NMR (600 MHz, CDCl3) δ 7.80-7.73 (comp, 4H), 7.45-
7.34 (comp, 6H), 6.68 (d, J ) 7.8 Hz, 1H), 6.62 (d, J ) 2.4 Hz,
1H), 6.50 (dd, J ) 7.8, 2.4 Hz, 1H), 4.73 (s, 1H), 4.17 (t, J )
6.6 Hz, 2H), 3.59 (s, 3H), 2.59 (t, J ) 7.8 Hz, 2H), 1.93 (m,
2H), 1.17 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 150.2, 143.2,
135.3, 134.2, 133.6, 129.4, 127.4, 120.1, 120.0, 112.6, 64.0, 55.3,
46.0, 31.5, 30.3, 26.6, 19.7. Anal. Calcd for C28H32O4N2Si: C,
68.82; H, 6.60; N, 5.73. Found: C, 68.94; H, 6.42; N, 5.64.
(4S)-(-)-4-{2-[4-(ter t-Bu tyld ip h en ylsila n yloxy)-3-m eth -
oxyp h en yl]eth yl}d ih yd r ofu r a n -2-on e (11). To a refluxing
CH2Cl2 (40 mL) solution of Rh2(4S-MPPIM)4 (28 mg, 1.0 mol
%) was added diazo compound 10 (0.98 g, 2.0 mmol) in 10 mL
of CH2Cl2 during 5 h via a syringe pump. The solvent was
evaporated, and the residue was subjected to column chroma-
tography on silica gel (hexanes/ethyl acetate ) 10:1) to give
γ-lactone 11 as a viscous oil with 93% ee (0.63 g, 68% yield):
3-(4-Hyd r oxy-3-m eth oxyp h en yl)p r op ion ic Acid . A solu-
tion of ferulic acid 8 (15.0 g, 77.2 mmol) in 1.0 N aqueous
sodium hydroxide (155.0 mL, 155.0 mmol) containing 100 mg
of 10% Pd/C was hydrogenated under 30 bar of hydrogen
pressure at room temperature for 12 h. The catalyst was
filtered though Celite, sodium hydroxide (155.0 mL, 155.0
mmol) containing 100 mg of 10% Pd/C was hydrogenated
under 30 bar of hydrogen pressure, and the filtrate was
acidified with concentrated H2SO4 to pH ) 2. The water
solution was then extracted with CH2Cl2 (4 × 100 mL). The
organic layer was dried over anhydrous Na2SO4, and the
solvent was evaporated to give hydroferulic acid as a white
solid that was identical to that previously reported (14.8 g,
97% yield):23 1H NMR (600 MHz, CDCl3) δ 6.83 (d, J ) 7.8
Hz, 1H), 6.72-6.68 (comp, 2H), 3.86 (s, 3H), 2.89 (t, J ) 7.2
Hz, 2H), 2.65 (t, J ) 7.2 Hz, 2H); 13C NMR (150 MHz, CDCl3)
δ 178.9, 146.4, 144.1, 132.1, 120.9, 114.4, 111.0, 55.9, 35.9, 30.3.
Meth yl 3-(4-Hyd r oxy-3-m eth oxyp h en yl)p r op ion a te.23
A solution of hydroferulic acid (14.8 g, 75.7 mmol) in 150 mL
of MeOH containing 0.2 mL of concentrated H2SO4 was
refluxed overnight. Methanol was evaporated, and the residue
was dissolved in 150 mL of CH2Cl2 and then washed with H2O
and brine. The CH2Cl2 solution was dried over anhydrous Na2-
SO4, and the solvent was evaporated to give methyl hydrof-
erulate as a liquid (15.5 g, 97% yield): 1H NMR (600 MHz,
CDCl3) δ 6.83 (d, J ) 7.8 Hz, 1H), 6.71-6.65 (comp, 2H), 5.50
(br s, 1H), 3.88 (s, 3H), 3.68 (s, 3H), 2.88 (t, J ) 7.8 Hz, 2H),
2.60 (t, J ) 7.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 173.4,
146.4, 144.0, 132.4, 120.8, 114.3, 110.9, 55.8, 51.5, 36.1, 30.1.
3-[4-(ter t-Bu t yld ip h en ylsila n oxy)-3-m et h oxyp h en yl]-
p r op a n -1-ol (9). To an anhydrous DMF (4 mL) solution of
methyl hydroferulate (2.1 g, 10.0 mmol) and imidazole (0.82
g, 12 mmol) was added TBDPSCl (2.7 g, 10.0 mmol) at 0 °C
for 10 min. The reaction mixture was warmed to room
temperature, and stirring was continued for 50 h. Ethyl acetate
(50 mL) was added, and the resulting mixture was washed
with 1 M HCl (20 mL), H2O (20 mL), and brine. The organic
layer was dried over anhydrous Na2SO4, and solvent was
evaporated to give crude methyl TBDPS-hydroferulate: 1H
NMR (500 MHz, CDCl3) δ 7.72-7.32 (comp, 10H), 6.65 (d, J
) 1.0 Hz, 1H), 6.63 (d, J ) 8.0 Hz, 1H), 6.48 (dd, J ) 8.0 Hz,
1.0 Hz, 1H), 3.66 (s, 3H), 3.57 (s, 3H), 2.84 (t, J ) 7.5 Hz, 2H),
2.57 (t, J ) 7.5 Hz, 2H), 1.10 (s, 9H). To a THF (20 mL) solution
of the crude product was added a 1 M THF solution of LiAlH4
(17.0 mL, 17.0 mmol) at -78 °C during 30 min. Stirring was
continued for an additional 2 h. Methanol was added to quench
the reaction until no hydrogen gas was observed. To the
mixture was then added 1 M HCl (50 mL) and ethyl acetate
(100 mL). The organic layer was washed with 1 M HCl (30
mL), H2O (50 mL), and brine and then dried over anhydrous
Na2SO4. The solvent was evaporated, and the residue was
subjected to column chromatography on silica gel (hexanes/
ethyl acetate ) 2:1) to give alcohol 9 as a viscous oil (3.4 g,
82% yield): 1H NMR (500 MHz, CDCl3) δ 7.73-7.69 (comp,
4H), 7.41-7.36 (comp, 2H), 7.35-7.31 (comp, 4H), 6.62 (d,
J ) 8.0 Hz, 1H), 6.59 (d, J ) 2.0 Hz, 1H), 6.46 (dd, J ) 8.0,
[R]25 ) -0.7° (c ) 0.5, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ
D
7.69 (dd, J ) 7.8, 1.2 Hz, 4H), 7.39 (tt, J ) 7.8, 1.2 Hz, 2H),
7.33 (t, J ) 7.8 Hz, 4H), 6.64 (d, J ) 7.8 Hz, 1H), 6.50 (d, J )
2.4 Hz, 1H), 6.41 (dd, J ) 7.8, 2.4 Hz, 1H), 4.25 (dd, J ) 9.0,
7.2 Hz, 1H), 3.95 (dd, J ) 9.0, 6.6 Hz, 1H), 3.54 (s, 3H), 2.74
(m, 1H), 2.64 (dd, J ) 13.8, 7.8 Hz, 1H), 2.60 (dd, J ) 13.8,
8.4 Hz, 1H), 2.53 (dd, J ) 17.4, 8.4 Hz, 1H), 2.21 (dd, J ) 17.4,
7.2 Hz, 1H), 1.11 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 176.8,
150.6, 143.9, 135.4, 133.5, 131.4, 129.6, 127.4, 120.5, 120.4,
112.7, 72.6, 55.4, 38.5, 37.2, 34.2, 26.0, 19.7; HRMS calcd for
C
28H32O4SiCs (M + Cs+) 593.1142, found 593.1265. Enantio-
meric excess was found by HPLC using a 25-cm Chiralpak OD
column with hexane/i-PrOH eleunt of 98:2 (0.8 mL/min): tR
(minor) 53.6 min, tR (major) 58.1 min.
(2RS)-(4S)-4-{2-[4-(ter t-Butyldiph enylsilanyloxy)-3-m eth -
oxyp h en yl]eth yl}tetr a h yd r ofu r a n -2-ol (12). To an anhy-
drous CH2Cl2 (15 mL) solution of γ-lactone 11 (0.46 g, 1.0
mmol) was added 1.5 M DIBAL-H in toluene (0.67 mL, 1.0
mmol) at -78 °C during 30 min. Stirring was continued at
the same temperature for an additional 2 h. Methanol was
added to quench the reaction. The mixture was allowed to
warm to room temperature, and 30 mL of CH2Cl2 was added.
The CH2Cl2 solution was washed with 1 N HCl (2 × 20 mL),
H2O (20 mL), and brine (20 mL) and dried over anhydrous
Na2SO4. The solvent was evaporated, and the residue was
subjected to column chromatography on silica gel (hexanes/
ethyl acetate ) 5:1) to give 12 as a viscous oil (0.44 g, 95%
yield): 1H NMR (600 MHz, CDCl3) major isomer δ 7.69 (d, J
) 7.2 Hz, 4H), 7.37 (t, J ) 7.2 Hz, 2H), 7.32 (t, J ) 7.2 Hz,
(18) Boyer, J . H.; Mack, C. H.; Goebel, W.; Morgan, L. R. J . Org.
Chem. 1959, 24, 1051.
(19) Doyle, M. P.; Winchester, W. R.; Hoorn, J . A. A.; Lynch, V.;
Simonsen, S. H.; Ghosh, R. J . Am. Chem. Soc. 1993, 115, 9968.
(20) Doyle, M. P.; Dyatkin, A. B.; Protopova, M. N.; Yang, C. I.;
Miertschin, C. S.; Winchester, W. R.; Simonsen, S. H.; Lynch, V.;
Ghosh, R. Recl. Trav. Chem. Pays-Bas 1995, 114, 163.
(21) Doyle, M. P.; Zhou, Q.-L.; Raab, C. E.; Roos, G. H. P.; Simonsen,
S. H.; Lynch, V. Inorg. Chem. 1996, 35, 6064.
(22) Doyle, M. P.; Zhou, G.-L.; Simonsen, S. H.; Lynch, V. Synlett
1996, 697.
(23) Solladie´, G.; Ziani-Che´rif, C. J . Org. Chem. 1993, 58, 2181.

2958 J . Org. Chem., Vol. 67, No. 9, 2002
Doyle et al.
4H), 6.62 (d, J ) 8.4 Hz, 1H), 6.53 (d, J ) 1.8 Hz, 1H), 6.42
(dd, J ) 8.4, 1.8 Hz, 1H), 5.51 (m, 1H), 4.01 (t, J ) 7.8 Hz,
1H), 3.52 (s, 3H), 3.48 (t, J ) 7.8 Hz, 1H), 3.07 (br d, J ) 3.6
Hz, 1H), 2.54 (dd, J ) 13.8, 7.2 Hz, 1H), 2.50 (dd, J ) 13.8,
8.4 Hz, 1H), 2.68 (m, 1H), 1.93 (dd, J ) 13.2, 7.2 Hz, 1H), 1.63
(ddd, J ) 13.2, 9.0, 5.4 Hz, 1H), 1.11 (s, 9H); minor isomer δ
7.69 (d, J ) 7.2 Hz, 4H), 7.37 (t, J ) 7.2 Hz, 2H), 7.32 (t, J )
7.2 Hz, 4H), 6.62 (d, J ) 8.4 Hz, 1H), 6.54 (d, J ) 1.8 Hz, 1H),
6.44 (dd, J ) 8.4, 1.8 Hz, 1H), 5.51 (m, 1H), 3.83 (t, J ) 7.8
Hz, 1H), 3.66 (t, J ) 7.8 Hz, 1H), 3.52 (s, 3H), 3.22 (br d, J )
3.6 Hz, 1H), 2.66 (dd, J ) 13.8, 7.8 Hz, 1H), 2.62 (dd, J ) 13.8,
7.8 Hz, 1H), 2.41 (m, 1H), 2.16 (ddd, J ) 13.2, 7.2, 6.0 Hz,
1H), 1.54 (ddd, J ) 13.2, 7.2, 4.2 Hz, 1H), 1.11 (s, 9H); 13C
NMR (150 MHz, CDCl3) major isomer δ 150.3, 143.4, 135.4,
133.7, 133.6, 129.5, 127.4, 120.5, 120.0, 112.8, 98.7, 72.2, 55.3,
39.7, 39.1, 38.8, 26.7, 19.7; minor isomer δ 150.3, 143.4, 135.4,
133.9, 133.7, 129.5, 127.4, 120.4, 120.0, 112.8, 99.1, 71.9, 55.3,
40.4, 39.5, 38.9, 26.7, 19.7; HRMS calcd for C28H34O4SiCs
(M + Cs+) 595.1281, found 595.1265.
Hz, 0.5H), 4.43 (dd, J ) 9.0, 3.5 Hz, 0.5H), 3.59 (dd, J ) 11.0,
4.0 Hz, 0.5H), 3.53 (m, 0.5H), 3.50 (s, 1.5H), 3.49 (s, 1.5H),
3.47 (s, 1.5H), 3.45 (s, 1.5H), 3.40 (dd, J ) 11.0, 6.0 Hz, 0.5H),
3.39 (dd, J ) 9.5, 7.0 Hz, 0.5H), 2.49 (dd, J ) 13.5, 7.5 Hz,
0.5H), 2.46 (dd, J ) 14.0, 7.5 Hz, 0.5H), 2.41 (dd, J ) 14.0, 7.5
Hz, 0.5H), 2.34 (dd, J ) 13.5, 7.5 Hz, 0.5H), 1.91-1.59 (comp,
3H), 1.10 (s, 18H); 13C NMR (125 MHz, CDCl3) mixture of
diastereomers δ 150.47(150.44), 150.3, 144.35(144.30), 143.3,
138.35(137.96), 135.3, 133.64(133.55), 133.48(133.42), 129.54-
(129.50), 127.43(127.38), 120.99(120.91), 119.91(119.78), 117.7,
113.21(113.12), 109.76(109.65), 73.75(71.36), 66.07(65.29), 55.3,
42.29(41.45), 40.89(39.06), 38.61(37.40), 26.6, 19.7; HRMS
calcd for C51H60O6Si2Cs (M + Cs+) 957.2983, found 957.2981.
(3S)-1,4-Bis[4-(ter t-b u t yld ip h en ylsila n yloxy)-3-m et h -
oxyp h en yl]-3-(ter t-bu tyld ip h en ylsila n yl-oxym eth yl)bu -
ta n -1-ol. To a stirred DMF (5 mL) solution of diol 14 (120 mg,
0.15 mmol) and imidazole (21 mg, 0.30 mmol) was added
TBDPSCl (49 mg, 0.18 mmol) at 0 °C. Stirring was continued
until no starting material was left in the reaction mixture as
determined by TLC. Ethyl acetate (20 mL) was added, and
the resulting mixture was washed with 0.5 N HCl (10 mL),
H2O (10 mL), and brine (10 mL). After drying over anhydrous
Na2SO4, the solvent was evaporated, and the residue was
subjected to column chromatography on silica gel (hexanes/
ethyl acetate ) 50:1) to give the monoprotected diol as a
viscous oil (155 mg, 98% yield): 1H NMR (600 MHz, CDCl3) δ
7.72-7.67 (comp, 8H), 7.63-7.55 (comp, 4H), 7.40-7.25 (comp,
18H), 6.69 (d, J ) 1.8 Hz, 0.5H), 6.63 (d, J ) 1.8 Hz, 0.5H),
6.62 (d, J ) 8.4 Hz, 0.5H), 6.60 (d, J ) 8.4 Hz, 0.5H), 6.55 (d,
J ) 8.4 Hz, 0.5H), 6.46 (dd, J ) 8.4, 1.8 Hz, 0.5H), 6.45-6.43
(comp, 1H), 6.37 (dd, J ) 8.4, 1.8 Hz, 0.5H), 6.30 (dd, J ) 8.4,
1.8 Hz, 1H), 4.55 (m, 0.5H), 4.35 (m, 0.5H), 3.56-3.47 (comp,
2H), 3.48 (s, 1.5H), 3.47 (s, 1.5H), 3.41 (s, 1.5H), 3.40 (s, 1.5H),
2.55 (dd, J ) 13.2, 7.2 Hz, 0.5H), 2.54 (dd, J ) 13.8, 7.2 Hz,
0.5H), 2.45 (dd, J ) 13.2, 6.0 Hz, 0.5H), 2.36 (dd, J ) 13.8, 7.8
Hz, 0.5H), 1.86-1.76 (comp, 1H), 1.76-1.69 (comp, 1.5H),
1.61-1.57 (comp, 0.5H), 1.11 (s, 4.5H), 1.10 (s, 9H), 1.06 (s,
9H), 1.05 (s, 4.5H); 13C NMR (150 MHz, CDCl3) for mixture of
4-Br om o-2-m eth oxyp h en ol.24 To a 100-mL three-necked
round-bottom flask containing 20 mL of carbon disulfide was
added guaiacol (12.6 g, 0.100 mol). A mixture of bromine (16.8
g, 0.105 mol) in 5 mL of CS2 was added dropwise to the solution
(5 drops/min) by an addition funnel. The solution was stirred
at 0 °C for 18 h, then washed with water (3 × 50 mL) and
brine, and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure to give a viscous liquid
that was identical to that previously reported (18.27 g, 90%
yield):25 1H NMR (200 MHz, CDCl3) δ 6.96 (dd, J ) 6.0 Hz,
2.5 Hz, 1H), 6.93 (d, J ) 2.0 Hz, 1H), 6.77 (d, J ) 8.5 Hz, 1H),
3.80 (s, 3H), 5.75 (s, 1H); 13C NMR (125 MHz) δ 147.1, 144.7,
124.0, 115.7, 114.0, 111.4. 56.0.
4-(ter t-Bu t yld ip h en ylsila n oxy)-3-m et h oxybr om ob en -
zen e. To a round-bottom flask containing 2-bromo-5-methoxy
phenol (3.66 g, 18 mmol) and imidazole (1.46 g, 22 mmol) was
added 5 mL of DMF. The resulting solution was stirred at room
temperature under argon for 10 min, then tert-butylchlo-
rodiphenylsilane (4.95 g, 18 mmol) was added, and the
resulting solution was allowed to stir for 52 h. Ethyl acetate
was added, then washed with water and brine, and dried over
anhydrous sodium sulfate. The solution was concentrated to
give the title product as a viscous liquid (7.73 g, 97% yield):
1H NMR (200 MHz, CDCl3) δ 7.72-7.70 (comp, 4H), 7.42-
7.34 (comp, 6H), 6.87 (d, J ) 2.5 Hz, 1H), 6.77 (dd, J ) 8.5
Hz, 2.5 Hz, 1 H), 6.59 (d, J ) 8.5 Hz, 1H), 3.55 (s, 3H), 1.11 (s,
9H); 13C NMR (125 MHz) δ 151.27, 144.30, 135.26, 133.13,
129.69, 127.53, 123.27, 121.22, 115.53, 113.20, 55.41, 26.57,
19.70.
diastereomers
δ
150.41(150.39), 150.1, 144.20(144.19),
143.11(143.07), 138.2, 135.6, 135.5, 135.4, 135.3, 133.8,
133.71(133.69), 133.63(133.60), 133.58(133.52), 133.40(133.36),
133.33(133.31), 129.7, 129.62(129.61), 129.54(129.52),
129.47(129.46), 127.6, 127.42(127.37), 121.0, 119.8,
119.71(119.68), 118.03(117.90), 113.28(113.20), 109.91(109.80),
72.93(71.78), 66.66(66.63), 60.37(55.20), 55.22(55.17),
41.43(40.96), 40.09(39.02), 37.81(37.64), 26.94(26.65),
26.64(26.54), 20.97(18.97), 19.73(19.72), 19.25(19.23).
(3S)-(+)-1,4-Bis[4-(ter t-bu tyldiph en ylsilan yloxy)-3-m eth -
oxyp h en yl]-3-(ter t-bu tyld ip h en ylsila n yl-oxym eth yl)bu t-
1-en e (15). To a refluxing chlorobenzene (5 mL) solution of
the monoprotected diol (0.40 g, 0.375 mmol) and DBU (0.56 g,
3.75 mmol) was added methanesulfonyl chloride (0.21 g, 1.88
mmol) in 5 mL of chlorobenzene during 2 h via syringe pump.
To the reaction mixture was added 20 mL of ethyl acetate,
which was then washed with H2O (15 mL), saturated NH4Cl
(15 mL), and brine. After drying over anhydrous Na2SO4,
solvent was evaporated under reduced pressure and the
residue was subjected to column chromatography on silica gel
(hexanes/ethyl acetate ) 99:1) to give olefin 15 as a solid (280
mg, 61% yield + 10% 21): 1H NMR (600 MHz, CDCl3) δ 7.56-
7.51 (comp, 12H), 7.41-7.22 (comp, 18H), 6.69 (s, 1H), 6.61
(d, J ) 8.4 Hz, 1H), 6.59 (d, J ) 8.4 Hz, 1H), 6.54 (s, 1H), 6.52
(d, J ) 8.4 Hz, 1H), 6.43 (d, J ) 8.4 Hz, 1H), 6.10 (d, J ) 15.6
Hz, 1H), 5.86 (dd, J ) 15.6, 8.4 Hz, 1H), 3.62-3.55 (comp, 2H),
3.53 (s, 3H), 3.41 (s, 3H), 2.84 (dd, J ) 13.2, 6.0 Hz, 1H), 2.58
(dd, J ) 13.2, 7.2 Hz, 1H), 2.52-2.47 (comp, 1H), 1.11 (s, 9H),
1.09 (s, 9H), 1.04 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 150.4,
150.0, 144.4, 143.1, 135.6, 135.4, 135.3, 133.8, 133.7, 133.6,
133.5, 131.5, 130.5, 129.6, 129.5, 129.4, 129.3, 127.6, 127.5,
127.4, 121.2, 120.0, 119.8, 118.7, 113.6, 109.7, 66.1, 55.3, 55.2,
47.1, 37.2, 26.9, 26.7, 19.7, 19.3; HRMS calcd for C67H76Si3O5
(M+) 1044.5001, found 1044.5038. HPLC analysis on a 25 cm
Chiralpak OD column with hexane: i-PrOH of 90:10 (1.0 mL/
min): tR (R-isomer) 20.5 min, tR (S-isomer) 25.4 min.
(1RS)-(3R)-3-[4-(ter t-Bu tyld ip h en ylsila n yloxy)-3-m eth -
oxyben zyl]-1-[4-(ter t-bu tyld ip h en ylsila n yl-oxy)-3-m eth -
oxyp h en yl]bu ta n e-1,4-d iol (14). To a THF (20 mL) solution
of 4-(tert-butyldiphenylsilanoxy)-3-methoxybromobenzene (1.33
g, 3.0 mmol) was added 1.7 M t-BuLi in hexanes (3.5 mL, 6.0
mmol) at -78 °C. Stirring was continued for 2 h. To the
solution was added 12 (0.5 g, 1.08 mmol) in 5 mL of THF. The
reaction mixture was allowed to warm to room temperature.
After stirring for 12 h at room temperature, the reaction was
quenched by addition of aqueous NH4Cl. Solvent was evapo-
rated under reduced pressure, H2O (20 mL) was added, and
the resulting mixture was extracted with EtOAc (2 × 20 mL).
The combined organic layer was dried over anhydrous Na2-
SO4. The solvent was evaporated, and the residue was
subjected to column chromatography on silica gel (hexanes/
ethyl acetate ) 2:1) to give 14 as a viscous oil (0.66 g, 74%
yield): 1H NMR (500 MHz, CDCl3) an approximately 1:1
mixture of diastereomers δ 7.71-7.66 (comp, 8H), 7.37-7.26
(comp, 12H), 6.68 (br s, 1H), 6.61 (d, J ) 8.0 Hz, 0.5H), 6.60
(d, J ) 8.0 Hz, 0.5H), 6.59 (d, J ) 8.0 Hz, 0.5H), 6.58 (d, J )
8.0 Hz, 0.5H), 6.50 (d, J ) 2.0 Hz, 0.5H), 6.48-6.46 (comp,
1H), 6.45 (dd, J ) 8.0, 2.0 Hz, 0.5H), 6.38 (dd, J ) 8.0, 2.0 Hz,
0.5H), 6.35 (dd, J ) 8.0, 2.0 Hz, 0.5H), 4.65 (dd, J ) 8.0, 4.0
(24) Adams, R.; Marvel, C. S Organic Syntheses; Wiley: New York,
1941; Collect. Vol. I, p 128.
(25) Oberhauser, T. J . Org. Chem. 1997, 62, 4504.
Im p er a n en e (16). To a 1.0 mL THF solution of 11 (112

Total Synthesis of (S)-(+)-Imperanene
J . Org. Chem., Vol. 67, No. 9, 2002 2959
mg, 0.107 mmol) was added 1.0 M TBAF in THF (0.37 mL,
0.37 mmol) with stirring. After 12 h at room temperature, 20
mL of ethyl ether was added, and the organic solution was
saturated with NH4Cl solution (1.0 mL), H2O (5 mL), and brine
(5 mL). After drying over anhydrous Na2SO4, the solvent was
evaporated under reduced pressure, and the residue was
subjected to column chromatography on silica gel (hexanes/
ethyl acetate ) 4:1) to give 16 as a colorless oil (30 mg, 85%
yield): [R]25D ) +103° (c ) 1.7, CHCl3), +97° (c ) 0.68, CHCl3),
+96° (c ) 0.14, CHCl3); note that {[3(180°) + 103]/0.93} ) 691,
which is very close to the reported [R]D of +700°, but we see
no justification for adding 3(180°); 1H NMR (600 MHz, CDCl3)
δ 6.86-6.84 (comp, 3H), 6.82 (d, J ) 8.4 Hz, 1H), 6.70-6.67
(comp, 2H), 6.35 (d, J ) 16.2 Hz, 1H), 5.92 (dd, J ) 16.2, 8.4
Hz, 1H), 5.59 (s, 1H), 5.47 (s, 1H), 3.89 (s, 3H), 3.83 (s, 3H),
3.67 (dd, J ) 10.2, 4.5 Hz, 1H), 3.56 (dd, J ) 10.2, 7.8 Hz,
1H), 2.74 (dd, J ) 13.2, 7.2 Hz, 1H), 2.69 (dd, J ) 13.2, 7.2
Hz, 1H), 2.66-2.61 (comp, 1H); 13C NMR (150 MHz, CDCl3) δ
146.6, 146.3, 145.3, 143.9, 132.2, 131.5, 129.7, 128.4, 121.8,
119.7, 114.4, 114.1, 111.7, 108.2, 65.2, 55.9, 55.8, 47.6, 37.7;
HRMS calcd for C19H22O5 (M+) 330.1467, found 330.1469.
7-(ter t-Bu tyldiph en ylsilan yloxy)-1-[4-(ter t-bu tyldiph en -
ylsila n yloxy)-3-m eth oxyp h en yl]-3-(ter t-bu tyl-d ip h en yl-
sila n yloxym et h yl)-6-m et h oxy-1,2,3,4-t et r a h yd r on a p h -
th a len e (21). To an oven-dried vial was added DMAP (2.9 mg,
0.024 mmol), methanesulfonic anhydride (14.2 mg, 0.08 mmol),
22 (20 mg, 0.019 mmol), and 1 mL of anhydrous dichloro-
methane, and the solution was allowed to stir for 4 h. The
resulting solution was subjected to column chromatography
on silica gel (hexanes/ethyl acetate ) 9:1) to give 21 as a
viscous oil in 93% yield. NMR analyses indicated the presence
of two isomers for 21 in a ratio of 3:1 and only a trace amount
of elimination product 15 (1:50): 1H NMR (500 MHz, CDCl3)
major isomer δ 7.77-7.14 (comp, 30H), 6.50 (d, J ) 8.0 Hz,
1H), 6.46 (s, 1H), 6.32 (d, J ) 2.0 Hz, 1H), 6.19 (dd, J ) 2.0,
8.0 Hz, 1H), 6.15 (s, 1H), 3.63-3.55 (comp, 2H), 3.54 (s, 3H),
3.39 (s, 3H), 2.76 (dd, J ) 3.5, 16.0 Hz, 1H), 2.52 (dd, J )
12.0, 16.0 Hz, 1H) 2.01-1.95 (comp, 2H), 1.40-1.20 (comp,
2H), 1.13 (S, 9H), 1.04 (S, 9H), 1.00 (S, 9H); 13C NMR (150
MHz, CDCl3) δ 150.1, 148.5, 143.0, 142.8, 140.0, 136.0-135.3
(comp), 134.0-133.6 (comp), 132.2, 129.7-129.2 (comp), 120.7,
120.5, 119.6, 112.4, 112.3, 68.8, 55.5, 55.2, 45.7, 37.8, 37.0, 33.1,
26.9, 26.8, 26.7, 19.8, 19.7, 19.3; HRMS calcd for C67H75SI3O5
1043.4922, found 1044.4954.
Ack n ow led gm en t. We are grateful to the National
Science Foundation and the National Institutes of
Health (GM 46503) for their support of this research.
The 500 MHz NMR spectrometer was provided to the
University of Arizona through a grant from the National
Science Foundation.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 11, 12, 14, 16, and 21. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O016220S