Stereoselective syntheses of the 2-isopropenyl-2,3-dihydrobenzofuran nucleus: Potential chiral building blocks for the syntheses of tremetone, hydroxytremetone, and rotenone

Article abstract of DOI:10.1021/jo062447h

(Chemical Equation Presented) The first enantioselective synthesis of the 2-isopropenyl-2,3-dihydrobenzofuran skeleton of tremetone and hydroxytremetone from (E)-4-(2-hydroxyphenyl)-2-methyl-2-butenyl methyl carbonate and (E)-4-(2,6-dihydroxyphenyl)-2-met

Full text of DOI:10.1021/jo062447h

Stereoselective Syntheses of the
2-Isopropenyl-2,3-dihydrobenzofuran Nucleus: Potential Chiral
Building Blocks for the Syntheses of Tremetone, Hydroxytremetone,
and Rotenone
Stephen C. Pelly,†,‡ Sameshnee Govender,† Manuel A. Fernandes,†,§
Hans-Gu¨nther Schmalz,*,| and Charles B. de Koning*,†
Molecular Sciences Institute, School of Chemistry, UniVersity of the Witwatersrand, PO Wits 2050,
Johannesburg, South Africa and Institut fu¨r Organische Chemie, UniVersita¨t zu Ko¨ln,
Grein str. 4 50939 Ko¨ln, Germany
Charles.dekoning@wits.ac.za; Schmalz@uni-koeln.de
ReceiVed NoVember 29, 2006
The first enantioselective synthesis of the 2-isopropenyl-2,3-dihydrobenzofuran skeleton of tremetone
and hydroxytremetone from (E)-4-(2-hydroxyphenyl)-2-methyl-2-butenyl methyl carbonate and (E)-4-
(2,6-dihydroxyphenyl)-2-methyl-2-butenyl methyl carbonate, respectively, is described. The key step is
a catalytic palladium-mediated reaction in the presence of the chiral Trost ligand.
Introduction
insecticidal principle, or 3′,4′-deoxypsorospermin 39 also contain
the same embedded unit.
A number of biologically active compounds possess a
2-isopropenyl-2,3-dihydrobenzofuran skeleton that contains an
asymmetric carbon at the 2-position. Simple examples would
include the toxins tremetone (also spelt trematone) 1a,1-3
hydroxytremetone (or 4-hydroxytrematone) 1c, and fomannoxin
1d.4,5 More complex compounds such as rotenone 2,6-8 an
Stereoselective syntheses of the 2-isopropenyl-2,3-dihy-
drobenzofuran skeleton have until now only been achieved by
resolution methods. The first chiral synthesis of 1a was
described in 1963 and involved a number of simple transforma-
tions from the corresponding chiral dihydrobenzofuran-2-
carboxylic acid 4 (Figure 2, eq 1), both enantiomers of 4 were
obtained by a chiral resolution procedure.1 Unfortunately, the
chiral resolution step was poor yielding but nevertheless allowed
for synthesis of tremetone 1a and its enantiomer 1b. More
recently, Yamaguchi et al. utilized the Sharpless asymmetric
dihydroxylation procedure to kinetically resolve the enantiomers
of racemic 4,6-dimethoxy-2-isopropenyl-2,3-dihydrobenzofuran.
This kinetic resolution proved not to be as efficient as expected,
and the yields of the desired enantiomers had to be severely
compromised in order to obtain acceptable enantiomeric ex-
cesses (ee’s).10
† University of the Witwatersrand.
‡ Current address: Biosciences, CSIR, Modderfontein, South Africa.
§ For correspondence regarding X-ray crystallography.
| Universita¨t zu Ko¨ln.
(1) Bowen, D. M.; DeGraw, J. I., Jr.; Shah, V. R.; Bonner, W. A. J.
Med. Chem. 1963, 6, 315-319.
(2) Banskota, A. H.; Tezuka, Y.; Prasain, J. K.; Matsushige, K.; Saiki,
I.; Kadota, S. J. Nat. Prod. 1998, 61, 896-900.
(3) Bittner, M.; Jakupovic, J.; Bohlmann, F.; Silva, M. Phytochemistry
1989, 28, 2867-2868.
(4) Bohlmann, F.; Jakupovic, J.; Schuster, A.; King, R.; Robinson, H.
Phytochemistry 1982, 21, 161-165.
(5) Ce´spedes, C. L.; Uchoa, A.; Salazar, J. R.; Perich, F.; Pardo, F. J.
Agric. Food Chem. 2002, 50, 2283-2292.
(6) Singer, T. P.; Ramsay, R. R. Biochim. Biophys. Acta: Bioenergetics
1994, 1187, 198-202.
(9) Habib, A. M.; Ho, D. K.; Masuda, S.; McCloud, T.; Reddy, K. S.;
Aboushoer, M.; McKenzie, A.; Byrn, S. R.; Chang, C.-J.; Cassady, J. M.
J. Org. Chem. 1987, 52, 412-418.
(10) Yamaguchi, S.; Muro, S.; Kobayashi, M.; Miyazawa, M.; Hirai, Y.
J. Org. Chem. 2003, 68, 6274-6278.
(7) Haley, T. J. J. EnViron. Pathol. Toxicol. 1978, 1, 315-337.
(8) Cockerill, G. S.; Levett, P. C.; Whiting, D. A. J. Chem. Soc., Perkin
Trans. 1 1995, 1103-1113.
10.1021/jo062447h CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/22/2007
J. Org. Chem. 2007, 72, 2857-2864
2857

Pelly et al.
SCHEME 1a
FIGURE 1. Natural products containing the 2-isopropenyl-2,3-
dihydrobenzofuran skeleton.
a Reagents and conditions: (i) (a) O3, CH2Cl2, (b) Zn, AcOH, 89%; (ii)
(EtO)2P(O)CH(Me)CO2Et, DBU, LiCl, MeCN, 75%; (iii) LiAlH4, THF,
65%; (iv) MeOCOCl, pyridine, CH2Cl2, 77%; (v) TBAF, THF, 0 °C, 98%;
(vi) 2 mol % Pd(dba)2, CH2Cl2, 6 mol % ligand 15a, 1 equiv of AcOH,
98%, 92% ee; (vii) Cr(CO)6, n-heptane, Bu2O, THF, reflux, 74% (two
diastereoisomers, one diastereoisomer separated by SiO2 chromatography
and recrystallized from CH2Cl2/hexane).
FIGURE 3. Synthesis of undesired 17.
1e. The second describes the stereoselective syntheses of the
(S)- and (R)-enantiomers of 1f. Elaboration of (R)-1f to
synthesize 4-hydroxytremetone 1c might be feasible via a Fries
rearrangement of the corresponding acetate (R)-26. Moreover,
(R)-1f could potentially be a building block for the synthesis
of rotenone 2. In all syntheses, Trost palladium-catalyzed
asymmetric allylic alkylation (AAA) chemistry constitutes the
key step for introduction of the stereogenic center at the
2-position of the dihydrobenzofuran nucleus.12
FIGURE 2. Previous asymmetric syntheses of 2-isopropenyl-2,3-
dihydrobenzofuran systems.
As an alternative, several attempted asymmetric cyclizations
have been reported in the literature, but these have all proven
unsuccessful in providing high enantiomeric excesses of 2-iso-
propenyl-2,3-dihydrobenzofuran 1e. For example, treatment of
2-(3-methylbut-2-enyl)phenol 5 with a chiral ligand and catalytic
palladium, as shown in Figure 2 (eq 2), afforded both the desired
product 1e and the unwanted compound 6 in a combined yield
of 8%. Moreover, this reaction only afforded 1e in 15% ee.10
Interestingly, when this same procedure was applied to 2-(2,3-
dimethylbut-2-enyl)phenol 7, which contains an extra methyl
substituent, excellent ee’s were obtained for the corresponding
dihydrobenzofuran 8 (eq 3).11
Results and Discussion
Synthesis of (R)-1e commenced by protecting commercially
available 2-allylphenol to form TBS ether 9 (Scheme 1).
Ozonolysis of 9, affording 10, required some care to avoid
overoxidation of the benzene ring. A Horner-Wadsworth-
Emmons reaction using (EtO)2P(O)CH(Me)CO2Et and DBU
afforded the required (E)-alkene 11a. Initially, this reaction
proved to be problematic as the alkene in 11a readily isomerized
to be in conjugation with the benzene ring, forming 11b in
significant quantities (Figure 3). Moreover, these two com-
pounds (11a and 11b) proved completely inseparable by column
chromatography at this stage and through the subsequent steps.
In this paper we wish to report the asymmetric syntheses of
two different 2-isopropenyl-2,3-dihydrobenzofuran skeletons.
The first outlines the stereoselective synthesis of (R)-1e, a
precursor to R-(-)-tremetone 1a, as well as synthesis of (S)-
(11) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119,
5063-5064.
(12) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P.; Sylvain, C. J.
Am. Chem. Soc. 2004, 126, 11966-11983.
2858 J. Org. Chem., Vol. 72, No. 8, 2007

Syntheses of Tremetone, Hydroxytremetone, and Rotenone
SCHEME 2a
Only at the end of the synthesis could they be separated as the
isomerized product 17 (Figure 3) was not susceptible to the Trost
π-allyl Pd cyclization reaction (vide infra). Fortunately, this
base-induced isomerization could be completely circumvented
by altering the order of addition of the reagents and using
slightly less than 1 equiv of DBU (see Experimental Section
for details). Although these modified conditions completely
prevented isomerization of 11a to 11b, a small amount of the
unwanted (Z)-isomer of 11a was produced. Fortunately, this did
not prove to be problematic as the (E)- and (Z)-isomers could
be separated in the next step.
Having overcome the problems pertaining to the synthesis
of 11a, reduction of the ester afforded alcohol 12, which was
readily converted to carbonate 13. Treatment with TBAF cleaved
the silyl ether in excellent yield, forming 14. Exposure of 14 to
the conditions developed by Trost for the synthesis of chiral
2-substituted-2-vinyl chromans using chiral ligand 15a12 and
catalytic Pd(dba)2 furnished the required volatile 2-isopropenyl-
2,3-dihydrobenzofuran, (R)-1e, in excellent yield and with high
enantiomeric excess (92% ee), which was determined by chiral
HPLC (Chiralcel OJ). Comparison of our obtained optical
rotation ([R]D19 +10.3°, ethanol) to that previously reported (R-
1e [R]D25 +10.9°; S-1e [R]D25 -10.4°, ethanol)13 indicated that
the (R)-enantiomer had been formed. The stereochemistry was
confirmed to be (R) at the C-2 position after converting 1e to
the arene-Cr(CO)3 complex 16, which could then be crystal-
lized and analyzed by X-ray crystallography.
a Reagents and conditions: (i) CH2dCHCH2Br, THF, n-BuLi, 0 °C, 78%;
(ii) (a) cat. HCl, MeOH/THF, 99%, (b) TBSCl, imidazole, MeCN, 79%;
(iii) (a) O3, CH2Cl2, (b) Zn, AcOH, 89%; (iv) (EtO)2P(O)CH(Me)CO2Et,
DBU, LiCl, MeCN, 86%; (v) LiAlH4, THF, 77%; (vi) MeOCOCl, pyridine,
CH2Cl2, 82%, (vii) TBAF, THF, 0 °C (viii) 3 mol % Pd(dba)2, CH2Cl2,
10 mol % ligand 15b, 1.1 equiv of AcOH, 94%, 92% ee; (ix) Ac2O, Et3N,
DMAP, CH2Cl2, 97%, 92% ee; (x) 2-NO2ArSO2Cl, Et3N, CH2Cl2, 80%.
Having successfully synthesized (R)-1e using the chiral ligand
15a, the opposite enantiomer, (S)-1e, was also synthesized in
good yield and high ee (94% ee) when 14 was similarly treated
with Pd(dba)2 in the presence of acetic acid and using the
opposite Trost chiral ligand, 15b.
Encouraged by the above results, synthesis of the 2-isopro-
penyl-2,3-dihydrobenzofuran subunit of rotenone, which requires
an extra phenolic substituent at C-4, was undertaken. Initial
experiments to introduce an allyl substituent between silicon-
protected resorcinol derivatives led to complications as a result
of rearrangements of the silyl ether protecting group. Therefore,
resorcinol was initially protected as the bis-MOM derivative
18, which could then be allylated affording 19. At this point, it
was necessary to switch protecting groups so that the phenols
could be liberated near the end of the synthesis. Since this would
have to be accomplished in the presence of the required
carbonate, use of acid- or base-mediated cleavage would not
be possible. This necessitated removal of the MOM groups
directly after allylation, replacing them with silyl ether groups,
which could later be cleaved under neutral conditions. To this
end, 18 was treated with catalytic acid in refluxing methanol,
and the resulting phenols were subsequently reprotected using
TBSCl, thereby affording 20 in good yield over the two steps
(Scheme 2). Thereafter, using the same reaction conditions as
previously described in Scheme 1, it was possible to transform
20 through an analogous sequence of steps into 25. Moreover,
it should mentioned that the isomerization problem previously
encountered where 11a readily converted to 11b was not
observed during this Horner-Wadsworth-Emmons reaction to
synthesize 22, even when the original conditions were employed.
Treatment of 25 with Pd(dba)2, chiral ligand 15b, and acetic
acid afforded mainly a single enantiomer of the desired product
(S)-1f in 94% yield and 92% ee, as determined by chiral HPLC
analysis of the acetate (S)-26 (see Experimental Section). Since
1f has not previously been synthesized chirally, the stereochem-
istry at C-2 was initially uncertain yet believed to be (S) based
upon our previous work (Scheme 1). Therefore, conversion of
(S)-1f into the crystalline derivative 27 was accomplished using
2-nitrobenzenesulfonyl chloride and triethylamine (Scheme 2).
Finally, X-ray crystallography revealed that C-2 of 27 did indeed
have the absolute stereochemistry (S), consistent with our
previous work.
By utilizing the alternative Trost ligand (15a), 25 was
similarly transformed efficiently into the alternative enantiomer,
forming (R)-1f in 80% yield and 92% ee, as determined by chiral
HPLC on the acetate derivative, (R)-26.
Direct comparison of the mechanistic model proposed by
Trost for the formation of the related chiral 2-substituted-2-
vinyl chromans to our benzofuran system proved to be useful.12
We were able to rationalize the stereochemistry of all of our
benzofurans using this model. Figure 4 illustrates this model
using our allyl carbonate 14 and Trost’s representation of the
(R,R′)-ligand, 15a. Initially, upon ionization, the chiral π-pal-
ladium intermediate 28 is formed to facilitate departure of
carbonate from under the right-front flap of the ligand. However,
once this has occurred, the complex is no longer in the most
favorable steric arrangement with respect to the shape of the
ligand. The mismatched cyclization that would result from this
arrangement is not favorable, and therefore, a π-σ-π re-
arrangement occurs, forming the thermodynamically preferred
29. Following this, attack of the phenolic hydroxyl occurs from
the bottom face, leading to the (R)-benzofuran, (R)-1e, in a
matched cyclization process. The alternative argument would
(13) Kawase, Y.; Yamaguchi, S.; Inoue, O.; Sannomiya, M.; Kawabe,
K. Chem. Lett. 1980, 1981-1984.
J. Org. Chem, Vol. 72, No. 8, 2007 2859

Pelly et al.
bubbler. Acetic acid was then added (15.8 g, 262 mmol, 15.0 mL)
followed immediately by Zn powder (2.00 g, 30.6 mmol). Once
the slurry warmed to about -30 °C the ozonide rapidly reduced to
the aldehyde 10. The reaction mixture was quickly filtered while
the solution was still below 0 °C, and the acetic acid was neutralized
by careful addition of an aqueous sodium bicarbonate solution. The
organic phase was separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 100 mL). The combined organic fractions were
dried over anhydrous MgSO4 and filtered. Evaporation of the
solvent in vacuo afforded the crude product as an off-white oil,
and this was purified by column chromatography (2-5% EtOAc/
hexane), affording the desired aldehyde 10 as an oil at rt or a waxy
solid at 0 °C (3.13 g, 89%). δH/ppm (300 MHz): 9.70 (1H, t, J )
2.1), 7.24-7.10 (2H, m), 6.95 (1H, t, J ) 7.4), 6.88 (1H, d, J )
8.1), 3.64 (2H, d, J ) 1.9), 1.00 (9H, s), 0.26 (6H, s). δC/ppm (100
MHz): 200.0, 154.1, 131.5, 128.7, 123.4, 121.4, 118.4, 45.6, 25.7,
18.2, -4.2. νmax/cm-1 (film): 2956, 1732, 1584, 1495, 1296, 922.
HRMS: calcd for C14H22O2Si 250.1389; found 250.1394. MS: m/z
250.1394 (1), 209.0593 (28), 193.0632 (100), 179.0537 (49),
149.0382 (15).
FIGURE 4. Schematic diagram of Trost’s (R,R′)-ligand to rationalize
stereochemical outcome.
similarly apply for the (S,S′)-Trost ligand, 15b, leading to the
(S)-benzofuran, (S)-1e.
(E)-Ethyl 4-(2-(tert-butyldimethylsilyloxy)phenyl)-2-methyl-
but-2-enoate 11a. Into a two-neck round-bottom flask containing
Ar was placed 2-(2-(tert-butyldimethylsilyloxy)phenyl)acetaldehyde
10 (2.60 g, 10.4 mmol) followed by MeCN (150 mL). To the
solution was added ethyl 2-(diethoxyphosphoryl)propanoate (2.28
g, 9.56 mmol, 2.05 mL) and LiCl (1.05 g, 24.8 mmol). While
stirring under Ar, the solution was cooled to 0 °C, and then DBU
(1.44 g, 9.43 mmol, 1.41 mL) in MeCN (20 mL) was added
dropwise over a 20 min period. The reaction was left to proceed
for another 1 h, and then water was added (150 mL) followed by
EtOAc (300 mL). After thoroughly mixing the phases, the organic
phase was separated and then the aqueous phase extracted with
EtOAc (3 × 50 mL). The combined organic fractions were dried
over anhydrous MgSO4 and filtered. Evaporation of the solvent in
vacuo afforded a yellow oil, which was purified by column
chromatography (5% EtOAc/hexane), affording the desired (E)-
alkene 11a (2.35 g, 68% if based upon the aldehyde 10 or 75% if
based upon the limiting DBU) with slight contamination from the
(Z)-alkene. δH/ppm (300 MHz): 7.17-7.08 (2H, overlapping
signals), 7.02-6.87 (2H, overlapping signals), 6.84 (1H, d, J )
8.1), 4.20 (2H, q, J ) 7.1), 3.52 (2H, d, J ) 7.3), 1.96 (3H, s),
1.30 (3H, t, J ) 7.1), 1.04 (9H, s), 0.28 (6H, s). δC/ppm
(100 MHz): 168.1, 153.5, 140.4, 123.0, 129.7, 128.2, 127.4, 121.2,
118.4, 60.4, 29.7, 25.8, 18.3, 14.3, 12.5, -4.1. νmax/cm-1 (film):
2931, 2859, 1713, 1495, 1255. HRMS: calcd for C19H30O3Si
334.1964; found 334.1947. MS: m/z 334.1947 (3), 289.1639 (12),
277.1237 (100), 264.9920 (6), 231.0825 (45), 193.0693 (17),
161.0462 (9).
(E)-4-(2-(tert-Butyldimethylsilyloxy)phenyl)-2-methylbut-2-
en-1-ol 12. Into a two-neck round-bottomed flask containing Ar
was placed the ester 11a (1.90 g, 5.68 mmol) followed by dry THF
(30 mL). The reaction mixture was cooled to 0 °C, and then LiAlH4
(280 mg, 7.38 mmol) was added in one portion. The reaction was
stirred under Ar at 0 °C and monitored every 20 min by TLC to
observe the progress of the reaction. After 1.5 h, ice cold water
(50 mL) was carefully added. The reaction mixture was diluted
with EtOAc (50 mL), and after thoroughly mixing the phases the
organic phase was separated. The aqueous phase was extracted with
EtOAc (3 × 30 mL), and then the combined organic fractions were
washed with brine (100 mL) and finally dried over anhydrous
MgSO4. After filtration, the solvent was removed in vacuo,
affording the crude product as an off-white colored oil. Purification
by column chromatography (10% EtOAc/hexane) afforded the
desired alcohol 12 as a clear oil (1.08 g, 65%). δH/ppm
(300 MHz): 7.15-7.03 (2H, overlapping signals), 6.91-6.86 (1H,
m), 6.79 (1H, d, J ) 7.9), 5.62 (1H, dt, J ) 7.2, 1.2), 4.05 (2H, s),
3.37 (2H, d, J ) 7.1), 1.77 (3H, s), 1.33 (1H, brs), 1.02 (9H, s),
0.25 (6H, s). δC/ppm (100 MHz): 153.4, 135.6, 131.4, 129.7, 126.9,
In summary, this paper outlines the first high-yielding
enantioselective synthesis of either enantiomer of the 2-isopro-
penyl-2,3-dihydrobenzofuran skeletons of tremetone and roten-
one using a catalytic palladium-mediated reaction in the presence
of the chiral Trost ligand. Moreover, the synthesis of (R)-1e
and (S)-1e constitutes a formal synthesis of both fomannoxin
and tremetone as both compounds have previously been
converted into these natural products.14
Experimental Section
(2-Allylphenoxy)(tert-butyl)dimethylsilane 9. Into a 250 mL
round-bottom flask containing Ar was placed MeCN (200 mL)
followed by 2-allylphenol (5.01 g, 37.3 mmol). Imidazole (3.05 g,
44.8 mmol) was then added in one portion at rt followed by TBSCl
(6.75 g, 44.8 mmol), also added in one portion. The solution was
stirred at rt under Ar for 18 h. The solvent was removed in vacuo,
and then EtOAc (200 mL) was added in one portion. Water was
then added (200 mL), and after vigorous shaking the salt dissolved
into the aqueous layer. The phases were separated, and the aqueous
phase was extracted with EtOAc (3 × 100 mL). The combined
organic fractions were washed with brine (200 mL) and dried over
anhydrous MgSO4. After filtration, the solvent was removed in
vacuo, affording an orange oil which was purified by column
chromatography (2% EtOAc/hexane), affording the desired product
9 as a clear oil (8.36 g, 90%). δH/ppm (300 MHz): 7.22-7.06
(2H, overlapping signals), 6.92 (1H, t, J ) 7.4), 6.83 (1H, d, J )
8.0), 6.01 (1H, tdd, J ) 19.3, 9.4, 6.6), 5.10-5.04 (2H, overlapping
signals), 3.41 (2H, d, J ) 6.6), 1.05 (9H, s), 0.27 (6H, s). δC/ppm
(100 MHz): 153.4, 137.1, 130.7, 130.1, 127.0, 121.1, 118.4, 115.4,
34.4, 25.8, 18.3, -4.1. νmax/cm-1 (film): 3077, 2958, 1600, 1491,
1266, 936. HRMS: calcd for C15H24OSi 248.1596; found 248.1597.
MS: m/z 248.1597 (7), 191.0902 (100), 163.0522 (25), 151.0456
(13), 135.0247 (5), 115.0546 (5).
2-(2-(tert-Butyldimethylsilyloxy)phenyl)acetaldehyde 10. Into
a three-neck round-bottom flask fitted with two glass bubbling tubes
was placed CH2Cl2 (150 mL) followed by (2-allylphenoxy)(tert-
butyl)dimethylsilane 9 (3.50 g, 14.1 mmol). The reaction mixture
was cooled to -85 °C while bubbling a steady stream of N2 into
the solution. The N2 bubbler was removed, and ozone was
introduced into the reaction mixture at -85 °C for periods of
10 min followed by TLC analysis until all the starting material
had been consumed. After each 10 min period, the residual ozone
was rapidly removed from the solution by reintroducing the N2
(14) Kawase, Y.; Yamaguchi, S.; Kondo, Y.; Shimokawa, K. Chem. Lett.
1978, 253-254.
2860 J. Org. Chem., Vol. 72, No. 8, 2007

Syntheses of Tremetone, Hydroxytremetone, and Rotenone
124.6, 121.1, 118.4, 69.0, 28.3, 25.8, 18.3, 13.8, -4.1. νmax/cm-1
(film): 3307, 2956, 2858, 1599, 1489, 1253. HRMS: calcd for
C17H28O2Si, 292.1859; found 292.1845. MS: m/z 292.1845 (10),
235.1124 (82), 217.1073 (89), 195.0884 (29), 177.0759 (77),
143.0834 (28).
solution. Evaporation of the solvent and purification by column
chromatography (10% EtOAc/hexane) afforded the desired ben-
zofuran (R)-1e (66.6 mg, 98%) and 92% ee as determined by chiral
HPLC. (Chiralcel OJ 10µ 250 × 4.6 mm, 2% isopropyl alcohol/
19
25
hexane). [R]D +10.3° (ethanol) (lit: R-1e [R]D +10.9°; S-1e
25
[R]D -10.4°, ethanol).13 δH/ppm (300 MHz): 7.17-7.09 (2H,
(E)-4-(2-(tert-Butyldimethylsilyloxy)phenyl)-2-methylbut-2-
enyl Methyl Carbonate 13. Into a two-neck round-bottomed flask
containing CH2Cl2 (50 mL) was placed the alcohol 12 (2.20 g, 7.52
mmol). Pyridine (2.35 g, 29.7 mmol, 2.40 mL) was added followed
by chloromethylformate (1.47 g, 15.5 mmol, 1.20 mL). The reaction
was left to proceed under Ar at rt for 18 h. Water (20 mL) was
added, and the reaction mixture was then further diluted by addition
of CH2Cl2 (50 mL) and more water (50 mL). The phases were
thoroughly mixed, and after separation, the aqueous phase was
extracted with CH2Cl2 (3 × 100 mL). The combined organic
fractions were washed with dilute HCl (2 × 100 mL), then water
(1 × 100 mL), and finally with brine (1 × 100 mL). The organic
phase was dried over anhydrous MgSO4 and concentrated in vacuo.
The resulting crude oil was purified by column chromatography
(5% EtOAc/hexane), affording (E)-4-(2-(tert-butyldimethylsilylox-
y)phenyl)-2-methylbut-2-enyl methyl carbonate 13 as a clear viscous
oil (2.04 g, 77%). δH/ppm (300 MHz): 7.11-7.06 (2H, overlapping
signals), 6.88 (1H, t, J ) 7.4), 6.79 (1H, d, J ) 8.0), 5.71 (1H, t,
J ) 7.1), 4.57 (2H, s), 3.79 (3H, s), 3.38 (2H, d, J ) 7.2), 1.77
(3H, s), 1.01 (9H, s), 0.24 (6H, s). δC/ppm (100 MHz): 155.8,
153.4, 130.8, 130.4, 129.6, 128.7, 127.0, 121.1, 118.4, 73.7, 54.7,
28.4, 25.8, 18.3, 13.9, -4.1. νmax/cm-1 (film): 2956, 2859, 1750,
1491, 1452, 1278. HRMS: calcd for C19H30O4Si 350.19134; found
350.1921. MS: m/z 350.1921 (2), 293.1217 (57), 275.1833 (34),
249.1278 (37), 217.1051 (96), 177.0738 (38), 161.0418 (31),
133.0328 (91).
(E)-4-(2-Hydroxyphenyl)-2-methylbut-2-enyl Methyl Carbon-
ate 14. Into a 250 mL round-bottom flask containing Ar was placed
dry THF (120 mL) followed by 13 (1.80 g, 5.14 mmol). The
solution was cooled to 0 °C, and then TBAF (5.20 mmol,
5.20 mL, 1 M solution in THF) was added in one portion. The
reaction was left to proceed for 5 min at 0 °C. The reaction mixture
was transferred into a separating funnel and diluted with water
(150 mL) and EtOAc (200 mL). After vigorously mixing the phases,
the organic phase was separated and the aqueous phase extracted
with EtOAc (3 × 100 mL). The combined organic fractions were
washed with brine and dried over anhydrous MgSO4. After
evaporation of the solvent in vacuo the resulting crude oil was
purified by column chromatography (10% EtOAc/hexane), affording
the desired phenol 13 as a viscous clear oil (1.19 g, 98%). δH/ppm
(300 MHz): 7.11-7.07 (2H, m), 6.89-6.75 (2H, overlapping m),
5.71 (1H, dt, J ) 7.2, 1.1), 5.02 (1H, s), 4.57 (2H, s), 3.79 (3H, s),
3.41 (2H, d, J ) 7.3), 1.81 (3H, s). δC/ppm (100 MHz): 155.8,
153.7, 131.2, 129.9, 127.7, 127.5, 126.2, 120.9, 115.4, 73.4, 54.8,
28.6, 13.9. νmax/cm-1 (film): 3454, 2958, 1722, 1594, 1456, 1274,
938. HRMS: calcd for C13H16O4 236.1049; found, 236.1033. MS:
m/z 236.1033 (2), 196.0753 (4), 160.0849 (67), 145.0621 (100),
127.0507 (7), 120.0571 (59), 107.0510 (20).
overlapping signals), 6.86-6.79 (2H, overlapping signals), 5.17 (1H,
t, J ) 8.9), 5.10 (1H, s), 4.92 (1H, s), 3.34 (1H, dd, J ) 15.6, 9.5),
3.05 (1H, dd, J ) 15.6, 8.2), 1.78 (1H, s). δC/ppm (100 MHz):
159.7, 144.0, 128.0, 126.6, 124.8, 120.3, 112.0, 109.2, 85.6, 34.7,
17.2. HRMS: calcd for C11H12O 160.0888; found 160.0888. MS:
m/z 160.0888 (80), 145.0637 (100), 127.0459 (15), 115.0533 (10),
91.0514 (17).
If 11b was formed a few steps earlier this would be carried
through to this step forming (E)-4-(2-hydroxyphenyl)-2-methylbut-
3-enyl methyl carbonate 17, which could be separated and
characterized. δH/ppm (300 MHz): 7.30 (1H, dd, J ) 7.6, 0.9),
7.10 (1H, dt, J ) 8.0, 1.4), 6.88 (1H, t, J ) 7.2), 6.79 (1H, d, J )
8.0), 6.65 (1H, d, J ) 16.1), 6.08 (1H, dd, J ) 16.1, 7.7), 5.28
(1H, s), 4.13 (2H, ddd, J ) 25.5, 10.5, 6.7), 3.77 (3H, s), 2.75
(1H, td, J ) 13.7, 6.8), 1.16 (3H, d, J ) 6.8). δC/ppm (100 MHz):
156.0, 152.7, 133.4, 128.4, 127.5, 125.2, 124.4, 120.8, 115.9, 71.9,
54.8, 37.2, 16.7. νmax/cm-1 (film): 3428 (OH str), 2961, 1725, 1454,
1270. HRMS: calcd for C13H16O4 236.1049; found 236.1047.
MS: m/z 236.1047 (1), 219.9711 (8), 160.0873 (44), 145.0672
(100), 115.0560 (8), 107.0490 (17).
(S)-2-Isopropenyl-2,3-dihydrobenzofuran (S)-1e. Into a two-
neck round-bottomed flask containing Ar was placed Pd(dba)2 (2.5
mg, 0.0044 mmol) followed by dry CH2Cl2 (5 mL), thus forming
a wine-red solution. The solution was degassed by bubbling Ar
into the solution for 5 min, and then the (S,S′)-Trost ligand 15b
(9.0 mg, 0.013 mmol) was added in one portion. The solution was
stirred at room temperature for 30 min, during which time the color
changed from wine-red to yellow. Degassed acetic acid (14 mg,
23 mmol, 13 µL) was added in one portion, and after 2 min of
stirring, the allyl carbonate 14 (50.0 mg, 0.212 mmol) was added
in one portion. The reaction was left to proceed under Ar at room
temperature for 18 h. Analysis of the reaction mixture after this
time indicated that all the starting material had reacted, and so the
solvent was removed in vacuo and the crude material purified by
column chromatography (10% EtOAc/hexane), affording the desired
chiral benzofuran (S)-1e (25.0 mg, 74%) and 94% ee as determined
by chiral HPLC (Chiralcel OJ 10µ 250 × 4.6 mm, 2% isopropyl
alcohol/hexane). [R]D19 -10.8° (ethanol) (lit: R-1e [R]D25 +10.9°;
S-1e [R]D25 -10.4°, ethanol).13 The spectroscopic data were found
to be analogous to (R)-2-isopropenyl-2,3-dihydrobenzofuran (R)-
1e.
(R)-2-Isopropenyl-2,3-dihydrobenzofuran-λ6-chromium Tri-
carbonyl 16. Into a solution consisting of Bu2O (10 mL) and
heptane (10 mL) was added (R)-2-isopropenyl-2,3-dihydrobenzo-
furan (R)-1e (60.0 mg, 0.374 mmol) followed by Cr(CO)6 (149
mg, 0.677 mmol). The solution was then thoroughly degassed by
repeated evacuation and Ar purging (ca. 5 times). Dry THF (1 mL)
was added, and the solution was once again degassed before heating
the mixture to reflux for 72 h. During this time the solution
gradually changed color from clear to yellow. The solution was
allowed to cool to rt before being filtered through a plug of silica
gel that was then washed with excess EtOAc. The resulting yellow
solution was concentrated in vacuo and purified by column
chromatography (20% EtOAc/hexane), affording two products
(assumed to be diastereomers). Complete separation of these two
compounds was not possible. However, yellow solids (33.8 mg,
top spot; 29.3 mg, bottom spot on TLC) as well as a mixed fraction
containing (18.9 mg), also as a yellow solid, were isolated. In total
82 mg of product was obtained (74%). The higher Rf product was
selected for X-ray analysis, and crystals suitable for this purpose
were obtained by recrystallization from CH2Cl2/hexane. Analysis
by X-ray crystallography revealed that the identity as the anti-facial
(R)-2-Isopropenyl-2,3-dihydrobenzofuran (R)-1e. Into a two-
neck round-bottom flask was placed CH2Cl2 (10 mL) followed
by Pd(dba)2 (5.0 mg, 0.0087 mmol), thus forming a wine red
solution. The solution was thoroughly degassed by bubbling Ar
into the solution for 5 min. The (R,R′)-Trost ligand 15a (18.0 mg,
0.0261 mmol) was added in one portion, and the solution gradually
changed color from wine-red to yellow as the ligand exchange
occurred. The solution was stirred for 30 min after adding the
phosphine to ensure complete exchange of the ligand. To this yellow
solution at rt was added thoroughly degassed acetic acid (26 mg,
0.44 mmol, 25 µL), and after 5 min of stirring, the allyl carbonate
14 (100 mg, 0.423 mmol) was added in one portion. The reaction
was left to proceed for 18 h at rt, during which time it was observed
that the yellow color had faded somewhat. Analysis of the reaction
mixture by TLC indicated that a new product had formed at a higher
Rf and that a small amount of starting material still persisted in the
19
diastereomer 16. Mp 77-79 °C; [R]D -94.4° (CHCl3). HRMS:
J. Org. Chem, Vol. 72, No. 8, 2007 2861

Pelly et al.
calcd for C14H12CrO4 296.0141; found 296.0135. MS: m/z 296.0135
(36), 240.0285 (11), 212.0268 (100), 172.0086 (15), 157.9803 (15).
X-ray data for 16 C14H12CrO4; M ) 296.24; tetragonal; a )
8.33980(10) Å, b ) 8.33980(10) Å, c ) 37.0388(9) Å; U )
2576.13(8) Å3, T ) 173(2) K, space group, P4(3)2(1)2, Z ) 8;
µ(Mo KR) ) 0.073 mm-1; 18 307 reflections measured, 3100
unique [R(int) ) 0.0366] which were used in all calculations. Final
R indices [I > 2σ(I)], R1 ) 0.0261, wR(F2) ) 0.0657. CCDC
number 616087.
allowing them to separate, the organic phase was separated and
the aqueous phase was extracted with EtOAc (2 × 100 mL). The
organic phases were combined and washed with brine (200 mL),
separated, and dried over anhydrous MgSO4. After filtration and
evaporation of the solvent in vacuo, the crude product was obtained
as a clear oil. Purification by column chromatography (2% EtOAc/
hexane) afforded 20 as a clear oil (4.79 g, 79%). δH/ppm (300
MHz): 6.93 (1H, t, J ) 8.2), 6.45 (2H, d, J ) 8.1), 5.93 (1H, tdd,
J ) 5.9, 9.4, and 17.8), 4.94-4.88 (2H, overlapping signals), 3.39
(2H, d, J ) 5.8), 1.01 (18H, s), 0.23 (12H, s). δC/ppm (100 MHz):
154.8, 136.8, 126.3, 121.6, 114.0, 111.5, 28.4, 25.8, 18.3, -4.1.
2-Allyl-1,3-bis(methoxymethoxy)benzene 19. Into a dry two-
neck 250 mL round-bottomed flask, fitted with a dropping funnel
and under Ar, was placed dry THF (170 mL) followed by 1,3-bis-
(methoxymethoxy)benzene 18 (4.00 g, 20.2 mmol). The solution
was cooled to 0 °C, and the dropping funnel was charged with
n-BuLi (17.0 mL, 24.0 mmol, 1.4 M). The n-BuLi was added
dropwise over a period of 10 min, thus forming a yellow solution,
which was stirred at 0 °C for another 90 min. During this time the
yellow color intensified and eventually turned pale orange. The
dropping funnel was then charged with allyl bromide (3.50 mL,
40.0 mmol) in THF (10 mL), and this solution was added dropwise
to the reaction mixture over a period of 10 min. The reaction was
left to proceed at 0 °C for another 60 min and then allowed to
warm to rt and left for 18 h. The reaction mixture was transferred
to a separating funnel and diluted with EtOAc (100 mL) and water
(100 mL). After mixing, the organic phase was separated and the
aqueous phase extracted once with EtOAc (100 mL). The combined
organic fractions were washed with brine (200 mL) and then dried
over anhydrous MgSO4. After filtration and evaporation of the
solvent in vacuo the crude oil was purified by column chromatog-
raphy (2% EtOAc/hexane), affording the desired compound 19 as
a clear oil (3.74 g, 78%). δH/ppm (300 MHz): 7.09 (1H, t, J )
8.3), 6.77 (2H, d, J ) 8.3), 5.96 (1H, tdd, J ) 6.1, 10.0 and 16.2),
5.17 (4H, s), 5.01-4.91 (2H, overlapping signals), 3.48-3.46 (10H,
overlapping signals). δC/ppm (100 MHz): 155.8, 136.7, 127.1,
118.3, 114.1, 107.9, 94.4, 55.9, 27.6. νmax/cm-1 (film): 2901, 1596,
1471, 1154, 1041. HRMS: calcd for C13H18O4 238.1205; found
238.1216. MS: m/z 238.1216 (25), 174.0687 (6), 161.0575 (34),
147.0454 (10).
2-Allylbenzene-1,3-diol. Into a 250 mL flask fitted with a
condenser was placed 2-allyl-1,3-bis(methoxymethoxy)benzene 19
(4.20 g, 17.6 mmol) followed by THF (100 mL) and MeOH
(50 mL). The solution was acidified slightly by addition of three
drops of an aqueous 32% HCl solution and then heated to reflux
for 18 h, after which time analysis of the reaction mixture indicated
that a significant amount of starting material still persisted. Another
addition of acid was made (5 drops), and the solution was refluxed
for another 18 h. The solvent was then evaporated in vacuo,
affording a clear oil. Removal of trace amounts of water was
achieved by dissolving the crude material in EtOAc and adding
MgSO4. After filtration, the solvent was removed in vacuo,
affording the crude product, which was purified by column
chromatography (10% EtOAc/hexane), affording 2-allylbenzene-
1,3-diol as a clear oil in quantitative yield (2.97 g). δH/ppm
(300 MHz): 6.97 (1H, t, J ) 8.1), 6.43 (2H, d, J ) 8.1), 6.02 (1H,
tdd, J ) 6.0, 10.1 and 16.1), 5.41 (2H, s), 5.20-5.11 (2H,
overlapping signals), 3.50-3.48 (2H, m). δC/ppm (100 MHz):
155.0, 135.9, 127.6, 115.9, 112.1, 108.2, 27.5. νmax/cm-1 (film):
3413, 1614, 1465, 1294. HRMS: calcd for C9H10O2 150.0681;
found 150.0694. MS: m/z 150.0694 (100), 135.0457 (30), 123.0475
(20), 107.0453 (18), 103.0523 (8).
ν
max/cm-1 (film): 2931 (CH str), 1588, 1465, 1259. HRMS: calcd
for C21H38O2Si2 378.2410; found, 378.2413. MS: m/z 378.2414
(8), 321.1720 (64), 293.1399 (10), 279.1541 (15), 256.2368 (62),
149.0200 (48).
2-(2,6-Bis(tert-butyldimethylsilyloxy)phenyl)acetaldehyde 21.
Into a three-neck round-bottom flask was placed alkene 20
(4.40 g, 11.6 mmol) followed by dry CH2Cl2 (180 mL). While
bubbling N2 gas into the solution, the flask was immersed into an
acetone bath cooled to about -80 °C. After allowing the reaction
mixture to cool for several minutes and maintaining a temperature
between -80 and -70 °C, the nitrogen bubbler was removed and
ozone gas was bubbled into the solution for 5 min. The ozone
bubbler was then removed, and residual ozone was rapidly dispersed
from the solution by reintroduction of the nitrogen bubbler. Analysis
of the reaction mixture by TLC indicated that significant amounts
of the alkene still persisted, and so this process was repeated until
only trace amounts of starting material were observable by TLC
analysis. The reaction mixture was then warmed to 0 °C and
maintained at this temperature while a large excess of acetic acid
was added (ca. 10 mL) followed by an excess of Zn powder (added
in small portions every 10 min until all the ozonalide was reduced
to the aldehyde 21). The reaction mixture was then filtered, washed
twice with saturated sodium bicarbonate solution, and then finally
washed once with brine before being dried over anhydrous MgSO4.
After filtration and evaporation of the solvent in vacuo the crude
product was purified by column chromatography (2% EtOAc/
hexane), affording the desired aldehyde 21 as an oil at rt (3.92 g,
89%). δH/ppm (300 MHz): 9.61 (1H, s), 7.03 (1H, t, J ) 8.2),
6.51 (2H, d, J ) 8.2), 3.65 (2H, d, J ) 1.5), 0.98 (18H, s),
0.23 (12H, s). δC/ppm (100 MHz): 200.8, 155.3, 127.8, 115.0,
111.4, 39.4, 25.7, 18.2, -4.2. νmax/cm-1 (film): 2859 (CH str),
1729 (CdO str), 1589, 1465, 1259. HRMS: calcd for C20H36O3-
Si2 380.2203; found 380.2213. MS: m/z 380.2213 (2), 365.1962
(5), 323.1448 (100), 265.0726 (9), 237.0270 (6), 115.0918 (11).
(E)-Ethyl-4-(2,6-bis(tert-butyldimethylsilyloxy)phenyl)-2-me-
thylbut-2-enoate 22. Into a dry two-neck round-bottom flask fitted
with a dropping funnel, containing Ar, was placed LiCl (510 mg,
12.0 mmol) followed by dry MeCN (8 mL). Ethyl 2-(diethoxy-
phosphoryl)propanoate (1.70 mL, 1.89 g, 7.93 mmol) was added
in one portion, and then while cooling the reaction mixture in a
bath at ca. 5 °C, DBU (1.25 mL, 1.27 g, 8.34 mmol) was added
dropwise over a period of 5 min. After 15 min of stirring at 5 °C,
2-(2,6-bis(tert-butyldimethylsilyloxy)phenyl)acetaldehyde
21
(2.00 g, 5.25 mmol) in MeCN (2 mL) was added dropwise over a
period of 10 min and the reaction was left to proceed for 18 h at
rt. The reaction mixture was transferred to a separating funnel and
diluted with EtOAc (150 mL) and water (150 mL). After mixing
the phases, the organic phase was separated and the aqueous phase
extracted with EtOAc (3 × 100 mL). The combined organic
fractions were then washed with brine (250 mL) and dried over
anhydrous MgSO4. After filtration and evaporation of the volatiles
in vacuo, the crude oil was purified by column chromatography to
afford (E)-ethyl 4-(2,6-bis(tert-butyldimethylsilyloxy)phenyl)-2-
methylbut-2-enoate 22 as a clear oil (2.10 g, 86%). δH/ppm
(300 MHz): 6.94 (1H, t, J ) 8.2), 6.81 (1H, t, J ) 6.0), 6.46
(2H, d, J ) 8.2), 4.14 (2H, q, J ) 7.1), 3.49 (2H, d, J ) 6.3), 1.92
(3H, s), 1.23 (3H, t, J ) 7.1), 0.98 (18H, s), 0.24 (12H, s). δC/ppm
(100 MHz): 168.6, 155.3, 142.8, 127.4, 127.0, 121.6, 111.9, 60.5,
2-Allyl-1,3-bis(tert-butyldimethylsilyloxy)benzene 20. Into a
dry two-neck flask was placed 2-allylbenzene-1,3-diol (2.40 g,
16.0 mmol) followed by dry MeCN (180 mL). Imidazole was added
in one portion (3.26 g, 47.9 mmol) followed by TBSCl (6.02 g,
39.9 mmol), and the reaction was left to proceed under Ar at rt for
18 h. The MeCN was evaporated in vacuo, affording an oil
containing the imidazole hydrochloride as a white precipitate. The
crude mixture was taken up into EtOAc (150 mL), and water was
added (150 mL). After thoroughly mixing the phases and then
2862 J. Org. Chem., Vol. 72, No. 8, 2007

Syntheses of Tremetone, Hydroxytremetone, and Rotenone
26.2, 24.5, 18.7, 14.7, 13.1, -3.7. νmax/cm-1 (film): 2931 (CH str),
1712 (CdO), 1648, 1588, 1465, 1248. HRMS: calcd for C25H44O4-
Si2 464.2778; found, 464.2784. MS: m/z 464.2784 (10), 449.2502
(3), 407.2110 (100), 379.1805 (7), 361.1726 (5), 218.9856 (10).
(E)-4-(2,6-Bis(tert-butyldimethylsilyloxy)phenyl)-2-methylbut-
2-en-1-ol 23. Into a two-neck flask containing Ar was placed the
ester 22 (643 mg, 1.38 mmol) followed by dry THF (10 mL). The
solution was cooled to 0 °C by an ice bath, and LiAlH4 (68.0 mg,
1.79 mmol) was added. The reaction was then closely monitored
by TLC approximately every 20 min. After 3 h all the starting
material had been consumed, and so ice cold water was added in
small portions (50 mL). The reaction mixture was diluted with
EtOAc (50 mL), after mixing the two phases an emulsion formed,
and this was broken by addition of a small amount of 1 M HCl
solution. The phases were separated, and the aqueous phase was
extracted with EtOAc (2 × 50 mL). The combined organic phases
were filtered through Celite and then washed once with brine. The
organic phase was then dried over anhydrous MgSO4, filtered, and
evaporated, affording the crude product as a pale yellow oil. After
purification by column chromatography (2-5% EtOAc/hexane) the
desired alcohol 23 was obtained as a viscous clear oil (451 mg,
77%). δH/ppm (300 MHz): 6.91 (1H, t, J ) 8.2), 6.45 (2H, d, J )
8.1), 5.46 (1H, t, J ) 5.6), 3.96 (2H, s), 3.37 (2H, d, J ) 5.9), 2.17
(1H, s), 1.78 (3H, s), 0.99 (18H, s), 0.23 (12H, s). δC/ppm
(100 MHz): 154.7, 134.1, 126.2, 126.1, 122.8, 111.7, 69.2, 25.8,
22.9, 18.3, 14.0, -4.1. νmax/cm-1 (film): 3331, 2930, 1587, 1463,
1362, 1244, 1177, 1064, 913, 828, 732, 685. HRMS: calcd for
C23H42O3Si2 422.2672; found 422.2655. MS: m/z 422.2655 (15),
365.1943 (100), 347.1858 (12), 309.1293 (15), 273.1638 (5),
218.9856 (11).
(E)-4-(2,6-Bis(tert-butyldimethylsilyloxy)phenyl)-2-methylbut-
2-enyl Methyl Carbonate 24. Into a dry two-neck round-bottom
flask containing Ar was placed (E)-4-(2,6-bis(tert-butyldimethyl-
silyloxy)phenyl)-2-methylbut-2-ol 23 (1.00 g, 2.37 mmol) followed
by dry CH2Cl2 (20 mL). The flask was placed into a cooling bath
(approx 5 °C), and pyridine (0.80 mL, 0.78 g, 9.9 mmol) was added
in one portion. Chloromethylformate (0.38 mL, 0.46 g, 4.9 mmol)
was then added dropwise over a period of about 2 min, and the
reaction was left to proceed for 5 min before the cooling bath was
removed. After allowing the reaction to proceed at rt for another
30 min, water was carefully added (20 mL) and the mixture
decanted into a separating funnel. The mixture was diluted with
CH2Cl2 (50 mL) and water (50 mL). After thoroughly mixing the
phases, the organic phase was separated and the aqueous phase
extracted once with CH2Cl2 (50 mL). The combined organic
fractions were then washed with HCl solution (0.2 M, 2 × 50 mL),
then water (50 mL), and finally brine (100 mL). After drying over
anhydrous MgSO4, the volatiles were removed in vacuo and the
crude oil was purified by column chromatography (5% EtOAc/
hexane), affording (E)-4-(2,6-bis(tert-butyldimethylsilyloxy)phenyl)-
2-methylbut-2-enyl methyl carbonate 24 as a clear oil (0.933 g,
82%). δH/ppm (300 MHz): 6.92 (1H, t, J ) 8.1), 6.45 (2H, d, J )
8.1), 5.56 (1H, t, J ) 5.7), 4.49 (2H, s), 3.76 (3H, s), 3.37 (2H, d,
J ) 5.9), 1.78 (3H, s), 0.99 (18H, s), 0.23 (12H, s). δC/ppm
(100 MHz): 155.8, 154.8, 130.3, 128.8, 126.2, 122.3, 111.6, 73.9,
54.6, 25.8, 23.1, 18.3, 14.2, -4.1. νmax/cm-1 (film): 2959 (CH str),
1751 (CdO str), 1588, 1464, 1261, 1068. HRMS: calcd for
C25H44O5Si2 480.2727; found 480.2720. MS: m/z 480.2720 (2),
423.2000 (77), 405.2622 (20), 379.2153 (69), 347.1747 (30),
291.1276 (5), 233.0630 (11), 215.0906 (4).
the organic phase was separated and the aqueous phase extracted
with EtOAc (5 × 30 mL). The combined organic fractions were
washed with brine (50 mL) and dried over anhydrous MgSO4. After
filtration, the solvent was removed in vacuo and the crude oil
purified by column chromatography (20% EtOAc/hexane), affording
the desired product 25 as a clear oil containing trace amounts of
EtOAc which could not be removed under vacuum (169 mg). δH/
ppm (300 MHz): 6.90 (1H, t, J ) 8.1), 6.37 (2H, d, J ) 8.1),
5.63 (1H, t, J ) 6.8), 5.80-5.00 (2H, br s), 4.52 (2H, s), 3.77 (3H,
s), 3.44 (2H, d, J ) 7.1), 1.84 (3H, s). δC/ppm (100 MHz): 155.9,
154.9, 130.6, 128.0, 127.2, 113.4, 108.0, 73.7, 54.8, 22.0, 13.8.
ν
max/cm-1 (film): 3364, 2959, 1699, 1615, 1471, 1247, 1167, 1036.
HRMS: calcd for C13H16O5 252.0998; found 252.1015. MS: m/z
252.1015 (2), 176.0842 (40), 161.0514 (84), 142.1580 (26),
123.0439 (11).
(S)-2-Isopropenyl-2,3-dihydrobenzofuran-4-ol (S)-1f. Into a
dry two-neck round-bottom flask containing Ar was placed
CH2Cl2 (2.5 mL) followed by Pd(dba)2 (6.8 mg, 0.012 mmol). The
solution was degassed for 3 min by bubbling Ar directly into the
solution by means of a Pasteur pipet. The Trost ligand 15b
(28.0 mg, 0.0405 mmol) was then added in one portion against a
gentle flow of Ar, and a color change occurred over a 15 min period
from deep purple to a light yellow color. The reaction was left to
stir at rt for another 10 min, and then degassed AcOH was added
in one portion (26 mg, 0.44 mmol, 25 µL). After 5 min of stirring
the diol 25 was added in one portion (100 mg, 0.396 mmol). The
reaction was left to proceed at rt for 18 h under Ar. The reaction
mixture was then concentrated in vacuo, and the crude material
was adsorbed onto silica gel and purified by column chromatog-
raphy (5-10% EtOAc/hexane), affording (S)-2-isopropenyl-2,3-
dihydrobenzofuran-4-ol (S)-1f (65.3 mg, 94%, 92% ee). The ee was
determined by HPLC analysis (Chiralcel OJ 10µ 250 × 4.6 mm,
10% isopropyl alcohol/hexane) after conversion of (S)-1f to the
19
O-acetate (S)-26. Spectroscopic data for (S)-1f: [R]D +17.3°,
CHCl3. δH/ppm: 6.99 (1H, t, J ) 8.0), 6.44 (1H, d, J ) 7.9),
6.32 (1H, d, J ) 8.0), 6.00-4.30 (1H, br s), 5.21 (1H, t, J ) 8.8),
5.10 (1H, s), 4.92 (1H, s), 3.31 (1H, dd, J ) 9.7 and 15.3), 2.98
(1H, dd, J ) 8.0 and 15.3), 1.78 (3H, s). δC/ppm: 161.4, 152.4,
143.8, 129.1, 112.2, 112.1, 107.7, 102.2, 86.1, 31.7, 17.1. νmax
/
cm-1: 3387 (OH str), 1607, 1464, 1317, 1278, 1233. HRMS: calcd
for C11H12O2 176.0837; found 176.0820. MS: m/z 176 (45), 161
(100), 145 (33), 117 (7), 115 (10).
(R)-2-Isopropenyl-2,3-dihydrobenzofuran-4-ol (R)-1f. Into a
dry two-neck round-bottom flask containing Ar was placed dichlo-
romethane (5 mL) followed by Pd(dba)2 (6.0 mg, 0.010 mmol).
The solution was degassed for 3 min by bubbling Ar directly into
the solution by means of a Pasteur pipet. The (R,R′)-Trost ligand
(20.0 mg, 0.0290 mmol) 15a was then added in one portion against
a gentle flow of Ar, and a color change occurred over a 15 min
period from deep purple to a light yellow color. The reaction was
left to stir at room temperature for another 10 min, then degassed
acetic acid was added in one portion (23 mg, 0.38 mmol, 22 µL),
and after 5 min of stirring, the carbonate 25 was added in one
portion (90.0 mg, 0.357 mmol). The reaction was left to proceed
at rt overnight under Ar at 25 °C. The reaction mixture was then
concentrated in vacuo, and the crude material was adsorbed onto
silica gel and purified by column chromatography, affording (R)-
(-)-2-isopropenyl-2,3-dihydrobenzofuran-4-ol (R)-1f (50.5 mg,
80%, 92% ee). The ee was determined by HPLC (Chiralcel OJ
10µ 250 × 4.6 mm, 10% isopropyl alcohol/hexane) after conversion
19
to the acetate (R)-26. Optical rotation for (R)-1f: [R]D -18.1°,
(E)-4-(2,6-Dihydroxyphenyl)-2-methylbut-2-enyl Methyl Car-
bonate 25. Into a 100 mL round-bottom flask containing Ar was
placed (E)-4-(2,6-bis(tert-butyldimethylsilyloxy)phenyl)-2-methyl-
but-2-enyl methyl carbonate (300 mg, 0.624 mmol) followed by
dry THF (50 mL). The solution was cooled to 0 °C under Ar, and
TBAF (1.24 mmol, 1.24 mL, 1 M) was added in one portion. The
reaction was left for 5 min, during which time the color changed
to deep purple. Water was added (50 mL), and the mixture was
diluted with EtOAc (100 mL). After thoroughly mixing the phases,
CHCl3. The spectroscopic data were found to be analogous to (S)-
2-isopropenyl-2,3-dihydrobenzofuran-4-ol (S)-1f.
(S)-2-Isopropenyl-2,3-dihydrobenzofuran-4-yl Acetate (S)-26.
Into a two-neck round-bottom flask containing Ar was placed
2-isopropenyl-2,3-dihydrobenzofuran-4-ol (S)-1f (25.0 mg, 0.142
mmol) followed by CH2Cl2 (1.5 mL). To the solution, at rt, was
added Et3N (28 mg, 0.28 mmol, 39 µL) followed by DMAP
(5 mg, 0.01 mmol) and Ac2O (19 mg, 0.19 mmol, 18 µL), and the
J. Org. Chem, Vol. 72, No. 8, 2007 2863

Pelly et al.
reaction was left to proceed for 18 h at rt under Ar. The solvent
was evaporated in vacuo, and the crude material was adsorbed onto
silica gel and purified by column chromatography (10% EtOAc/
hexane), affording the desired acetate (S)-26 as a clear oil
(30.0 mg, 97%). Analysis of the acetate by HPLC (Chiralcel OJ
10µ 250 × 4.6 mm, 10% isopropyl alcohol/hexane) confirmed that
chloride (43.0 mg, 0.194 mmol). The solution was stirred at rt for
18 h under Ar. The reaction mixture was concentrated in vacuo
and purified by column chromatography (20% EtOAc/hexane),
affording 27 as a white solid (45.9 mg, 80%). Recrystallization of
this compound from diethyl ether afforded white needle-like
20
crystals. Mp 82-83 °C. [R]D + 12.0°, CHCl3. δH/ppm (300
19
(S)-26 had been produced in 92% ee. [R]D + 25.0°, CHCl3. δH/
MHz): 8.00 (1H, d, J ) 7.8), 7.89-7.81 (2H, m), 7.76-7.66 (1H,
m), 7.05 (1H, t, J ) 8.1), 6.73 (1H, d, J ) 8.0), 6.55 (1H, d, J )
8.2), 5.18 (1H, t, J ) 8.7), 5.05 (1H, s), 4.90 (1H, s), 3.44 (1H, dd,
J ) 16.3 and 9.6), 3.03 (1 H, dd, J ) 16.3 and 7.9), 1.71 (3H, s).
δC/ppm (100 MHz): 161.8, 145.6, 143.2, 135.4, 132.0, 132.0, 129.3,
ppm (300 MHz): 7.12 (1H, t, J ) 8.0), 6.69 (1H, d, J ) 8.0), 6.57
(1H, d, J ) 8.1), 5.20 (1H, t, J ) 8.8), 5.08 (1H, s), 4.91 (1H, s),
3.23 (1H, dd, J ) 9.6 and 15.7), 2.93 (1H, dd, J ) 8.1 and 15.7),
2.28 (3H, s), 1.76 (3H, s). δC/ppm (100 MHz): 168.4, 161.3, 147.3,
143.6, 129.0, 119.3, 113.4, 112.4, 107.0, 86.2, 32.7, 20.9, 17.1.
128.9, 124.9, 120.8, 113.9, 112.6, 108.7, 86.5, 32.7, 17.0. νmax
/
ν
max/cm-1 (film): 2920, 1767 (CdO str), 1462, 1370, 1036.
cm-1 (film): 2924, 1654, 1621, 1594, 1192, 1006. HRMS: calcd
for C17H15NO6S 361.0620; found 361.0627. MS: m/z 361.0627
(100), 346.0342 (41), 264.9931 (8), 175.0756 (70), 159.0790 (82).
X-ray data for 25: C17H15NO6S; M ) 361.36; orthorhombic;
0.71073 Å; P2(1)2(1)2(1); a ) 5.7422(8) Å, b ) 13.106(2) Å, c
) 22.274(3) Å, U ) 1676.3(4) Å;3 173(2) K, space group, P2-
(1)2(1)2(1), Z ) 4;. µ(Mo KR) ) 0.073 mm-1; 13 907 reflections
measured, 4041 unique [R(int) ) 0.0355], which were used in all
calculations. Final R indices [I > 2σ(I)] R1 ) 0.0382, wR(F2) )
0.0916. CCDC number 616088.
HRMS: calcd for C13H14O3 218.0943; found 218.0945. MS: m/z
218.0945 (24), 176.0804 (30), 161.0628 (100).
(R)-2-Isopropenyl-2,3-dihydrobenzofuran-4-yl Acetate (R)-
26. Into a two-neck round-bottom flask containing Ar was placed
(R)-2-isopropenyl-2,3-dihydrobenzofuran-4-ol (R)-1f (48.2 mg,
0.274 mmol) followed by CH2Cl2 (5 mL). To the solution, at rt,
was added Et3N (56 mg, 0.55 mmol, 77 µL) followed by DMAP
(5 mg) and Ac2O (37 mg, 0.36 mmol, 34 µL). The reaction was
left to proceed for 18 h at rt under Ar. Analysis of the reaction
mixture indicated that all of the starting material had been
consumed, and so the solvent was evaporated in vacuo and the
crude material adsorbed onto silica gel. Purification by column
chromatography (10% EtOAc/hexane) afforded the desired acetate
as a clear oil (59.0 mg, 99%). Analysis of the acetate by chiral
HPLC (Chiralcel OJ 10µ 250 × 4.6 mm, 10% isopropyl alcohol/
hexane) confirmed that the (R)-26 had been produced in 92% ee.
Acknowledgment. This work was supported by the National
Research Foundation (NRF, GUN 2053652), the University of
the Witwatersrand. SG thanks the NRF for a Scarce Skills
bursary. SCP thanks the Council for Scientific and Industrial
Research (CSIR), Modderfontein for additional funding. We
thank Dr WAL van Otterlo, Dr A Lanver (Ko¨ln) and Prof JP
Michael for many helpful discussions.
19
[R]D -25.8°, CHCl3. The spectroscopic data were found to be
analogous to (S)-2-isopropenyl-2,3-dihydrobenzofuran-4-yl acetate
(S)-26
1
Supporting Information Available: H and 13C NMR of 9-14,
(S)-2-Isopropenyl-2,3-dihydrobenzofuran-4-yl-2-nitrobenze-
nesulfonate 27. Into a two-neck round-bottom flask was placed
the chiral benzofuran (S)-1f (28.0 mg, 0.159 mmol) followed by
dry CH2Cl2 (5 mL). To the solution, at rt, was added triethylamine
(30 mg, 0.30 mmol, 42 µL) followed by 2-nitrobenzenesulfonyl
17, 19-27, 1e, and 1f. This material is available free of charge via
the Internet at http://pubs.acs.org. X-ray crystallographic data for
compounds 16 and 27 have been deposited into the CCDC.
JO062447H
2864 J. Org. Chem., Vol. 72, No. 8, 2007