Intermolecular C-H activation at benzylic positions: Synthesis of (+)-imperanene and (-)-α-conidendrin

Article abstract of DOI:10.1016/S0957-4166(03)00154-X

An efficient C-H activation of primary benzylic positions by means of rhodium carbenoid induced C-H insertions is described. This key step was used in concise syntheses of (+)-imperanene and (-)-α-conidendrin.

Full text of DOI:10.1016/S0957-4166(03)00154-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 941–949
Intermolecular C–H activation at benzylic positions: synthesis of
(+)-imperanene and (−)-a-conidendrin
Huw M. L. Davies* and Qihui Jin
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260-3000, USA
Received 12 December 2002; accepted 4 February 2003
Abstract—An efficient C–H activation of primary benzylic positions by means of rhodium carbenoid induced C–H insertions is
described. This key step was used in concise syntheses of (+)-imperanene and (−)-a-conidendrin. © 2003 Elsevier Science Ltd. All
rights reserved.
1. Introduction
Intermolecular metal carbenoid C–H activation is toler-
ant to many functional groups and is especially favored
at benzylic and allylic sites and positions a to oxygen
and nitrogen.5,6 Even with these electronically activated
sites for C–H insertion, 1° carbons display great reluc-
tance to undergo C–H insertion. For example, tetra-
ethoxysilane is an exceptional substrate for C–H
activation while tetramethoxysilane is not.5f An impres-
sive example of the difference between a 1° and a 2° site
is the reaction of 4-ethyltoluene, which undergoes clean
benzylic C–H insertion at the methylene group to form
2 (Eq. (2)).5m
The development of practical methods for intermolecu-
lar C–H activation is of great interest because this
would offer new disconnection strategies for the synthe-
sis of complex natural products. Metal induced C–H
activation processes are areas of intense current
research.1,2 One very practical approach for C–H acti-
vation is by means of metal carbenoid induced C–H
insertion.3 The intramolecular version of this reaction is
well established and can be achieved with excellent
asymmetric induction.3 In contrast, the intermolecular
version was not considered to be synthetically useful
because it was compromised by problems of chemose-
lectivity and the propensity of the carbenoid to dimer-
ize.3,4 In the last few years, we have discovered that
donor/acceptor substituted carbenoids are capable of
undergoing highly regioselective intermolecular C–H
insertions.5,6 When the reactions are catalyzed by
Rh2(S-DOSP)4 1, high levels of asymmetric induction
are obtained (Eq. (1)). In our original studies on alka-
nes,5e C–H insertion occurred at either 2° or 3° centres,
and the regioselectivity was controlled by a delicate
balance of electronic and steric effects.
(2)
A further demonstration of this chemoselectivity is the
reaction with toluene (Eq. (3)).5m Even though ethyl-
benzene undergoes benzylic C–H activation cleanly, in
the reaction with toluene a mixture of three products
are obtained. The C–H activation product 3 is a minor
component while the major component is a mixture of
regioisomers 4a and 4b derived from double cyclo-
propanation of the aromatic ring.
(1)
As the exploration of the C–H activation chemistry of
substituted donor/acceptor carbenoids has become
more extensive, general reactivity principles and guideli-
nes have been recognized.5,6 One of these generaliza-
tions is that 1° sites are not favored for C–H activation.
* Corresponding author. Tel.: +1-716-645-6800, ext. 2186; fax: +1-
716-645-6547; e-mail: hdavies@acsu.buffalo.edu
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00154-X

942
H. M. L. Da6ies, Q. Jin / Tetrahedron: Asymmetry 14 (2003) 941–949
(3)
Thus the N-Boc protected benzylmethylamine 5 was
expected to be a good substrate for benzylic C–H
activation to form 6. In actual fact, however, this
substrate underwent an unprecedented C–H activation
at the methyl group to form 7,5l a process which allows
access to some very interesting b-amino acid deriva-
tives. With this unexpected discovery of a clean C–H
activation at a 1° site, we have carried out a study to
evaluate the generality of 1° site C–H activation and
the results of these studies are described herein (Eq.
(4)).
the electronically favored N-benzyl site is because the
carbenoid is very sterically encumbered and unable to
approach this site for reaction.5l In order to design
systems capable of clean reactions at 1° C–H sites, the
site would need to be electronically activated while the
rest of the molecule must have no activated sites or the
sites would need to be sterically protected. One obvious
system would be 4-methoxytoluene 8 as the methoxy
group would activate the 1° benzylic site and sterically
encumber the benzene ring. Rh2(S-DOSP)4 catalyzed
the decomposition of methyl bromophenyldiazoacetate
9a at 50°C resulting in efficient C–H activation generat-
ing 10a in 71% yield and 74% ee. No C–H activation of
the methyl group next to oxygen occurred, presumably
because the electron lone pairs of oxygen are delocal-
ized into the benzene ring and are not sufficiently
activating of the methyl group. In order to explore the
scope of this reaction, the effect of temperature and the
p-substituent on the diazo compound was examined
and the results are summarized in Table 1. In the case
of 9a, which would generate the most electrophilic
carbenoid, an efficient reaction was obtained at 23 and
0°C, and as expected,5,6 the enantioselectivity steadily
improved on lowering the temperature. In the case of
methyl phenyldiazoacetate 9b, good yields of 10b were
obtained at 50 and 25°C only, while in the case of
methyl p-methoxyphenyldiazoacetate 9c, a low yield of
(4)
2. Results and discussion
We propose that the reason for the unreactivity of 5 at
Table 1. C–H insertion to p-methylanisole
R
Temp. (°C)
Yield (%)a
ee (%)
a
b
c
Br
50
23
0
50
23
0
71
73
69
67
67
[14]
35
74
80
83
71
79
ND
67
H
OMe
50
a The yield in parenthesis is the NMR yield with internal standard.

H. M. L. Da6ies, Q. Jin / Tetrahedron: Asymmetry 14 (2003) 941–949
943
10c was obtained even at 50°C. The absolute stereo-
chemistry of 10b was determined to be (R) by hydroly-
sis of 10b to the known (R) acid.7 This asymmetric
induction is in agreement with our published model6
that predicts that the (R) enantiomer would be formed.
The absolute configuration of the other products is
assigned assuming a similar stereochemical effect.
Carbenoids derived from vinyldiazoacetates also
behave as donor/acceptor carbenoids,6 and further-
more, are capable of inducing intermolecular C–H acti-
vation as illustrated in Eq. (8). The methyl
p-bromophenylvinyldiazoactate 17a gave the C–H acti-
vation product 18a in 51% yield and 94% ee. Similar
reactions were possible with the phenylvinyldiazoac-
etate 17b.
Very efficient reactions were also obtained with the
even more electron-rich aromatic system 11. The reac-
tion of aryldiazoacetates 9a and 9b with 11 at 50°C
resulted in very effective C–H insertion to form 12a and
12b in 80% yield and 75–77% ee (Eq. (5)). Once again,
the methoxy derivative 9c was less effective at the C–H
activation: product 12c was formed in only 30% yield.
The demonstration that 11 with a very electron-rich
aromatic ring is an appropriate substrate underlines
how steric hindrance can protect the aromatic ring
from reaction with the carbenoid.
(8)
The potential of these methods in total synthesis is
illustrated in retrosynthetic analyses for (+)-imperanene
198 and (−)-a-conidendrin 209 (Scheme 1). (+)-Imper-
anene would be readily derived from the S enantiomer
of the C–H activation product 21, while (−)-a-coniden-
drin would be derived from the R enantiomer of 21 by
means of a Lewis acid induced cascade involving Prins
reaction, aromatic electrophilic substitution and lac-
(5)
A very intriguing example of this chemistry is the
reaction of 9a with tritolylamine 13. When the reaction
was conducted with an excess of tritolylamine (5
equiv.), the C–H activation product was obtained in
53% yield and 81% ee (Eq. (6)).
(6)
In order to determine if the C–H activation into a
methyl site required the presence of a strong electron-
donating group in the para position, the reaction was
extended to p-xylene 15. The presence of the para
substituents block the ring from cyclopropanation reac-
tions and the Rh2(S-DOSP)4 catalyzed reaction of 9a at
50°C generated the C–H activation product 16 in 70%
yield and 74% ee (Eq. (7)). This result contrasts sharply
with the outcome of the carbenoid reaction with tolu-
ene (Eq. (3)).5m
(7)
Scheme 1.

944
H. M. L. Da6ies, Q. Jin / Tetrahedron: Asymmetry 14 (2003) 941–949
tonization. Thus, the absolute stereochemistry in (+)-
imperanene and (−)-a-conidendrin would be established
during the C–H activation step.
The total synthesis of (+)-imperanene 19 is summarized
in Scheme 2. Rh2(R-DOSP)4-catalyzed decomposition
of 22 in the presence of 11 at 50°C generates the C–H
activation product (S)-21 in 43% yield and 91% ee.
Lithium aluminum hydride reduction of (S)-21 fol-
lowed by silyl deprotection generates (+)-imperanene 19
in 87% yield. The specific rotation of 19 ([h]2D5 +115.2 (c
1.05, CHCl3, 92% ee)) is in agreement with the litera-
ture value8c ([h]D25 +103 (c 1.7, CHCl3, 93% ee)) and
demonstrates that Rh2(R-DOSP)4 generates the S
configured C–H insertion product. The sense of asym-
metric induction observed in this case is in agreement
with our predictive model.6
The total synthesis of (−)-a-conidendrin combines C–H
activation with a cascade of reactions (Scheme 3). The
Prins reaction followed by electrophilic substitution has
been previously established in model studies.10 Rh2(S-
DOSP)4 catalyzed decomposition of 22 in the presence
of 11 at 50°C generates (R)-21 in 44% yield with 92%
ee. Treatment of (R)-21 with formaldehyde in a Lewis
acid catalyzed Prins reaction/electrophilic substitution
sequence followed by treatment with p-toluenesulfonic
acid afforded TBS protected (−)-a-conidendrin 23 as
the major diastereomer (12.5:1 mixture of tricyclic
products). Desilylation using TBAF affords the natural
product 20 in 78% yield. The specific rotation value of
20 ([h]2D5−50.4 (c 0.90, acetone)) is in agreement with the
literature value9b ([h]2D5 −52.5 (c 1.05, acetone)).
Scheme 3.
have presented herein offers exciting new options for
total synthesis as illustrated in the very concise routes
to (+)-imperanene and (−)-a-conidendrin.
4. Experimental
4.1. General
1H NMR spectra were run at either 400 or 500 MHz
and 13C NMR at 75 or 125 MHz with the sample
solvent being CDCl3 unless otherwise noted. Mass spec-
tral determinations were carried out at 70 eV. IR
spectra were obtained using a Nicolet Impact series 420
IR. Elemental analyses were performed by Atlantic
Microlabs Inc., Norcross, GA. Column chromatogra-
phy was carried out on silica gel 60 (230–400) mesh.
Enantiomeric excess was determined by HPLC using a
Chiralcel OD-H, Chiralpak AD-RH or (R,R)-Whelk-O
1 chiral analytical column (UV detection at 254 nm).
Melting points were measured on an Electrothermal
melting point apparatus and are uncorrected.
Degassing was carried out by bubbling Ar gas through
the solution for 5–10 min. 2,2-Dimethylbutane was
distilled from Na after passing through a pad of acti-
vated silica gel. Decalin was purchased from Aldrich as
anhydrous grade, used directly. Methylaluminum
sesquichloride was prepared by mixing equimolar
amounts of methylaluminum dichloride (1 M in hex-
anes) and dimethylaluminum chloride (1 M in hexanes).
3. Conclusions
In summary, we have demonstrated that effective C–H
activation of benzylic methyl groups can be achieved as
long as the aromatic ring is at least p-disubstituted. The
aromatic functionalization sterically protects the ring
from electrophilic attack by the rhodium carbenoid
intermediates. Thus, the C–H activation strategy we
4.2. General procedure for C–H insertion
To a degassed, refluxing solution of aromatic com-
pound (5 mmol) and Rh2(S-DOSP)4 (0.005 mmol) in
2,2-dimethylbutane (2 mL) was added a solution of
methyl p-bromophenyldiazoacetate (0.5 mmol) in 2,2-
dimethylbutane (5 mL) in 45 min using syringe-pump.
The mixture was heated under reflux for an additional
15 min. The solvent was removed in vacuo and the
residue was subjected to flash chromatography.
Scheme 2.

H. M. L. Da6ies, Q. Jin / Tetrahedron: Asymmetry 14 (2003) 941–949
945
4.3. (R)-Methyl 2-(4-bromophenyl)-3-(4-methoxyphenyl)-
Purified by flash chromatography on silica gel (6:1
pentane/ether) to afford product 10c (53 mg, 35% yield)
as a white solid: mp 77–79°C; Rf 0.33 (3:1 pentane/
ether); [h]2D5 −73.3 (c 2.10, CHCl3); FTIR (CHCl3) 3033,
2998, 2952, 2934, 2835, 1735, 1612, 1584, 1512, 1463,
propionate, 10a
The reaction was carried out at 0°C on 0.5 mmol scale.
Purified by flash chromatography on silica gel (6:1
pentane/ether) to afford product 10a (120 mg, 69%
yield) as a colorless oil: Rf 0.31 (5:1 pentane/ether); [h]D25
−106.3 (c 2.20, CHCl3); FTIR (film) 3000, 2951, 2837,
1735, 1611, 1512, 1488, 1440, 1295, 1248, 1160, 1034,
1
1441, 1301, 1249, 1178, 1156, 1035, 831 cm−1; H NMR
(500 MHz, CDCl3) l 7.21 (d, J=8.5 Hz, 2H), 7.01 (d,
J=8.5 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5
Hz, 2H), 3.80-3.72 (m, 1H), 3.78 (s, 3H), 3.75 (s, 3H),
3.59 (s, 3H), 3.31 (dd, J=13.7, 8.5 Hz, 1H), 2.93 (dd,
J=13.7, 6.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) l
174.1, 158.8, 158.0, 131.1, 130.7, 129.8, 128.9, 113.9,
113.6, 55.2, 55.1, 52.9, 51.9, 39.0; MS (CI) m/z (relative
intensity) 121.1 (28), 135.1 (100), 136.1 (50), 137.1 (75),
195.1 (41), 241.1 (29), 266.9 (34), 300.1 (M+, 5), 301.1
(M++H, 9); HRMS (CI) m/z calcd for [C18H20O4]+:
300.1356. Found: 300.13556. HPLC analysis: 67% ee
(Chiralcel OD-H, 1.0% i-PrOH in hexane, 0.8 mL/min,
u=254 nm, tR=15.6 min, major; tR=19.8 min, minor).
Anal. calcd for C18H20O4: C, 71.98; H, 6.71. Found: C,
71.76; H, 6.91%.
1
1012, 823, 758 cm−1; H NMR (500 MHz, CDCl3) l
7.40 (d, J=8.2 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 6.98
(d, J=8.5 Hz, 2H), 6.75 (d, J=8.5 Hz, 2H), 3.80–3.72
(m, 1H), 3.73 (s, 3H), 3.59 (s, 3H), 3.31 (dd, J=13.7,
8.2 Hz, 1H), 2.92 (dd, J=13.7, 7.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) l 173.4, 158.1, 137.5, 131.6, 130.4,
129.8, 129.7, 121.2, 113.7, 55.0, 53.2, 52.0, 38.8; MS
(EI) m/z (relative intensity) 121.1 (100), 348.0 (M+, 3);
HRMS (EI) m/z calcd for [C17H17BrO3]+: 348.0356.
Found: 348.03299. HPLC analysis: 83% ee (Chiralpak
AD-RH, 0.5% i-PrOH in hexane, 0.8 mL/min, u=254
nm, tR=14.3 min, minor; tR=15.6 min, major). Anal.
calcd for C17H17BrO3: C, 58.47; H, 4.91. Found: C,
58.72; H, 4.93%.
4.6. (R)-Methyl 2-(4-bromophenyl)-3-(4-tert-butyldi-
methylsilyloxy-3-methoxyphenyl)propionate, 12a
4.4. (R)-Methyl 3-(4-methoxyphenyl)-2-phenylpropi-
onate, 10b11
The reaction was carried out at 50°C in 0.5 mmol scale.
Purified by flash chromatography on silica gel (9:1
pentane/ether) to afford product 12a (193 mg, 80%
yield) as a colorless oil: Rf 0.37 (5:1 pentane/ether); [h]D25
−74.8 (c 8.60, CHCl3); FTIR (film) 2952, 2930, 2856,
1737, 1605, 1585, 1514, 1488, 1464, 1282, 1255, 1237,
The reaction was carried out at rt on 0.5 mmol scale.
Purified by flash chromatography on silica gel (5:1
pentane/ether) to afford product 10b (91 mg, 67% yield)
as a light yellow oil: Rf 0.33 (5:1 pentane/ether); [h]D25
−85.1 (c 1.50, CHCl3); FTIR (film) 3060, 3029, 3001,
2951, 2837, 1735, 1611, 1512, 1445, 1350, 1297, 1248,
1
1158, 901, 840 cm−1; H NMR (500 MHz, CDCl3) l
7.40 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 6.71
(d, J=7.9 Hz, 1H), 6.52 (dd, J=7.9, 1.5 Hz, 1H), 6.47
(d, J=1.5 Hz, 1H), 3.74 (pseudo t, J=7.7 Hz, 1H), 3.68
(s, 3H), 3.60 (s, 3H), 3.28 (dd, J=13.7, 8.2 Hz, 1H),
2.91 (dd, J=13.7, 7.6 Hz, 1H), 0.98 (s, 9H), 0.12 (s,
6H); 13C NMR (125 MHz, CDCl3) l 173.4, 150.5,
143.4, 137.5, 131.9, 131.5, 129.7, 121.2, 121.0, 120.7,
112.8, 55.2, 53.2, 51.9, 39.5, 25.6, 18.4, −4.76, −4.77;
HPLC analysis: 77% ee (Chiralpak AD-RH, 0.5% i-
PrOH in hexane, 1.0 mL/min, u=254 nm, tR=4.6 min,
minor; tR=6.6 min, major); LCMS (ESI) m/z (relative
intensity) 501 (M+Na+, 100), 463 (M+H+, 36), 419 (60),
251 (39), 221 (70). Anal. calcd for C23H31BrO4Si: C,
57.61; H, 6.52. Found: C, 57.97; H, 6.54%.
1
1217, 1159, 1110, 1034, 827, 733, 700 cm−1; H NMR
(400 MHz, CDCl3) l 7.30–7.20 (m, 5H), 7.01 (d, J=8.6
Hz, 2H), 6.75 (d, J=8.6 Hz, 2H), 3.80 (dd, J=8.8, 6.6
Hz, 1H), 3.72 (s, 3H), 3.57 (s, 3H), 3.34 (dd, J=13.9,
8.8 Hz, 1H), 2.95 (dd, J=13.9, 6.6 Hz, 1H); 13C NMR
(125 MHz, CDCl3) l 173.8, 158.0, 138.6, 131.0, 129.8,
128.5, 127.9, 127.3, 113.6, 55.0, 53.8, 51.9, 38.9; HPLC
analysis: 79% ee (Chiralpak AD-RH, 0.5% i-PrOH in
hexane, 1.0 mL/min, u=254 nm, tR=10.2 min, minor;
tR=11.0 min, major).
Following the procedure described in the literature,7 a
mixture of 10b (27 mg, 0.1 mmol), acetic acid (1 mL)
and hydrochloride acid (2N, 0.35 mL) was stirred for 3
h at 120°C. Purified by flash chromatography on silica
gel (4:1 pentane/ether, 0.5% acetic acid) to afford (R)-3-
(4-methoxyphenyl)-2-phenylpropionic acid (22 mg, 87%
yield) as a white solid: [h]2D5 −82.3 (c 1.40, CH2Cl2) (lit.:7
[h]2D2 −62.0 (c 1.0, CH2Cl2, 93% ee); FTIR (film) 3500–
4.7.
(R)-Methyl
3-(4-tert-butyldimethylsilyloxy-3-
methoxyphenyl)-2-phenylpropionate, 12b
The reaction was carried out at 50°C in 0.5 mmol scale.
Purified by flash chromatography on silica gel (8:1
pentane/ether) to afford product 12b (160 mg, 80%
yield) as a colorless oil: Rf 0.37 (5:1 pentane/ether); [h]D25
−58.4 (c 1.38, CHCl3); FTIR (film) 2952, 2929, 2856,
1736, 1604, 1585, 1514, 1464, 1453, 1282, 1255, 1236,
1
2500, 1706 cm−1; H NMR (500 MHz, CDCl3) l 11.29
(br, s, 1H), 7.32–7.24 (m, 5H), 7.01 (d, J=8.5 Hz, 2H),
6.75 (d, J=8.5 Hz, 2H), 3.80 (dd, J=8.3, 7.0 Hz, 1H),
3.75 (s, 3H), 3.34 (dd, J=13.7, 8.3 Hz, 1H), 2.97 (dd,
J=13.7, 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) l
179.1, 158.2, 138.0, 130.7, 129.9, 128.7, 128.1, 127.6,
113.8, 55.2, 53.7, 38.4.
1
1157, 1126, 1039, 906, 839, 781, 698 cm−1; H NMR
(400 MHz, CDCl3) l 7.28–7.18 (m, 5H), 6.70 (d, J=8.0
Hz, 1H), 6.55 (dd, J=8.0, 1.8 Hz, 1H), 6.47 (d, J=1.8
Hz, 1H), 3.77 (pseudo t, J=7.7 Hz, 1H), 3.65 (s, 3H),
3.57 (s, 3H), 3.31 (dd, J=13.7, 8.2 Hz, 1H), 2.94 (dd,
J=13.7, 7.2 Hz, 1H), 0.97 (s, 9H), 0.18 (s, 6H);
13C NMR (75 MHz, CDCl3) l 173.8 (C), 150.4 (C),
143.3 (C), 138.6 (C), 132.4 (C), 128.5 (CH), 127.9 (CH),
4.5. (R)-Methyl 2,3-bis(4-methoxyphenyl)propionate, 10c
The reaction was carried out at 50°C in 0.5 mmol scale.

946
H. M. L. Da6ies, Q. Jin / Tetrahedron: Asymmetry 14 (2003) 941–949
127.2 (CH), 121.0 (CH), 120.6 (CH), 112.9 (CH), 55.2
(CH3), 53.8 (CH), 51.8 (CH3), 39.6 (CH2), 25.6
(CH3), 18.3 (C), −4.8 (CH3); GC-MS (EI) m/z (rela-
tive intensity) 179 (100), 251 (12), 343 (M+−But, 32);
HPLC analysis: 75% ee (Chiralcel OD-H, 0.5% i-
PrOH in hexane, 0.8 mL/min, u=254 nm, tR=8.9
min, major; tR=9.7 min, minor). Anal. calcd for
C23H32O4Si: C, 68.96; H, 8.05. Found: C, 68.89; H,
8.13%.
H, 5.49; N, 2.72. Found: C, 69.96; H, 5.32; N, 2.70;
LCMS (ESI) m/z (relative intensity) 536 (M+Na+,
100), 514 (M+H+, 52), 413 (22), 286 (18).
4.10. (R)-Methyl 2-(4-bromophenyl)-3-(4-methylphenyl)-
propionate, 16
The reaction carried out at 50°C in 0.5 mmol scale.
Purified by flash chromatography on silica gel (20:1–
10:1 pentane/ether) to afford product 16 (116 mg,
70% yield) as a colorless oil: Rf 0.60 (5:1 pentane/
ether); [h]2D5 −99.0 (c 5.00, CHCl3); FTIR (film) 3021,
2950, 2920, 1737, 1515, 1488, 1435, 1215, 1157, 1011,
811 cm−1; 1H NMR (500 MHz, CDCl3) l 7.40 (d,
J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.02 (d,
J=7.9 Hz, 2H), 6.96 (d, J=7.9 Hz, 2H), 3.78 (pseudo
t, J=7.9 Hz, 1H), 3.85 (s, 3H), 3.33 (dd, J=13.7, 8.4
Hz, 1H), 2.94 (dd, J=13.7, 7.0 Hz, 1H), 2.27 (s, 3H);
13C NMR (125 MHz, CDCl3) l 173.4, 137.5, 135.9,
135.3, 131.6, 129.7, 129.0, 128.7, 121.2, 53.0, 52.0,
39.2, 21.0; HPLC analysis: 74% ee ((R,R)-Whelk-O 1,
1.0% i-PrOH in hexane, 0.8 mL/min, u=254 nm,
tR=10.4 min, major; tR=12.3 min, minor). Anal.
calcd for C17H17BrO2: C, 61.28; H, 5.14. Found: C,
61.50; H, 5.26%.
4.8. (R)-Methyl 3-(4-tert-butyldimethylsilyloxy-3-
methoxyphenyl)-2-(4-methoxyphenyl)propionate 12c
The reaction was carried out at 50°C in 0.5 mmol
scale. Purified by flash chromatography on silica gel
(5:1 pentane/ether) to afford product 12c (171 mg,
71% yield) as a colorless oil: Rf 0.26 (5:1 pentane/
ether); [h]2D5 −59.0 (c 1.70, CHCl3); FTIR (film) 2997,
2953, 2930, 2856, 1736, 1610, 1584, 1513, 1464, 1282,
1250, 1179, 1157, 1126, 1038, 901, 839, 806, 782 cm−1;
1H NMR (500 MHz, CDCl3) l 7.19 (d, J=8.5 Hz,
2H), 6.83 (d, J=8.5 Hz, 2H), 6.71 (d, J=7.9 Hz,
1H), 6.55 (dd, J=7.9, 1.8 Hz, 1H), 6.51 (d, J=1.8
Hz, 1H), 3.78 (s, 3H), 3.74 (pseudo t, J=7.8 Hz, 1H),
3.69 (s, 3H), 3.60 (s, 3H), 3.29 (dd, J=13.6, 8.4 Hz,
1H), 2.92 (dd, J=13.6, 7.2 Hz, 1H), 0.98 (s, 9H),
0.12 (s, 6H); 13C NMR (125 MHz, CDCl3) l 174.2,
158.8, 150.5, 143.3, 132.5, 130.7, 129.0, 121.0, 120.6,
113.9, 112.9, 55.3, 55.2, 53.0, 51.9, 39.7, 25.7, 18.4,
−4.7; LC-MS (ESI) m/z (relative intensity) 371 (8),
431 (M++H, 12), 453 (M++Na, 74); HPLC analysis:
67% ee (Chiralpak AD-RH, 0.5% i-PrOH in hexane,
1.0 mL/min, u=254 nm, tR=6.6 min, minor; tR=10.1
min, major). Anal. calcd for C24H34O5Si: C, 66.94; H,
7.96. Found: C, 66.80; H, 8.04%.
4.11. (R)-(E)-Methyl 3-(4-bromophenyl)-2-(4-methoxy-
benzyl)but-3-enoate, 18a
The reaction carried out at rt in 0.48 mmol scale.
Purified by flash chromatography on silica gel (5:1
pentane/ether) to afford product 18a (96 mg, 53%
yield) as a white solid: mp 66–68°C; Rf 0.24 (5:1 pen-
tane/ether); [h]D25 −130.6 (c 1.60, CHCl3); FTIR
(CHCl3) 3026, 3001, 2949, 2837, 1734, 1612, 1585,
1512, 1488, 1441, 1295, 1248, 1163, 1072, 1034, 1013,
968, 831, 809 cm−1; 1H NMR (500 MHz, CDCl3) l
7.40 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.07
(d, J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.31 (d,
J=15.9 Hz, 1H), 6.21 (dd, J=15.9, 8.8 Hz, 1H), 3.76
(s, 3H), 3.64 (s, 3H), 3.41 (pseudo q, J=7.9 Hz, 1H),
3.10 (dd, J=13.7, 7.9 Hz, 1H), 2.86 (dd, J=13.7, 7.3
Hz, 1H); 13C NMR (125 MHz, CDCl3) l 173.6,
158.2, 135.6, 131.6, 131.4, 130.3, 130.0, 127.8, 127.6,
121.3, 113.7, 55.1, 51.9, 51.6, 38.0; MS (EI) m/z (rela-
tive intensity) 121.1 (100), 122.1 (54), 374.1 (M++H,
3); HRMS (EI) m/z calcd for [C19H19BrO3]+:
374.0512; Found: 374.05051. HPLC analysis: 94% ee
(Chiralcel OD-H, 2.0% i-PrOH in hexane, 1.0 mL/
min, u=254 nm, tR=10.1 min, major; tR=12.3 min,
minor). Anal. calcd for C19H19BrO3: C, 60.81; H,
5.10. Found: C, 61.05; H, 5.28%.
4.9. (R)-Methyl 2-(4-bromophenyl)-3-(4-di-p-tolylamino-
phenyl)propionate, 14
To a degassed solution of tritolylamine (2.5 mmol)
and Rh2(S-DOSP)4 in decalin (2 mL) was added a
solution of methyl p-bromophenyldiazoacetate (0.5
mmol) in 2,2-dimethylbutane (5 mL) at 35°C in 45
min using syringe-pump. The mixture was stirred for
additional 15 min. The solvent was removed in
vacuo, and the residue was subject to flash chro-
matography on silica gel (20:1–10:1 pentane/ether) to
afford product 14 (136 mg, 53% yield) as a white
solid: mp 45–48°C; Rf 0.42 (10:1 pentane/ether); [h]D25
−105.1 (c 5.90, CHCl3); FTIR (CHCl3) 3025, 2949,
2920, 1737, 1606, 1506, 1488, 1320, 1291, 1275, 1157,
1
1011, 815, 757 cm−1; H NMR (500 MHz, CDCl3) l
7.42 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.03
(d, J=8.2 Hz, 4H), 6.95–6.87 (m, 8H), 3.78 (pseudo t,
J=7.8 Hz, 1H), 3.62 (s, 3H), 3.31 (dd, J=13.7, 8.5
Hz, 1H), 2.92 (dd, J=13.7, 7.1 Hz, 1H), 2.29 (s, 6H);
13C NMR (125 MHz, CDCl3) l 173.5, 146.6, 145.3,
137.6, 132.2, 131.8, 131.6, 129.8, 129.7, 129.4, 124.2,
122.9, 121.3, 53.0, 52.1, 39.0, 20.8; HPLC analysis:
81% ee (Chiralpak AD-RH, 5.0% i-PrOH in hexane,
1.0 mL/min, u=254 nm, tR=6.4 min, minor; tR=7.8
min, major). Anal. calcd for C30H28BrNO2: C, 70.04;
4.12. (R)-(E)-Methyl 2-(4-methoxybenzyl)-4-phenylbut-
3-enoate, 18b
The reaction carried out at rt at 0.5 mmol scale.
Purified by flash chromatography on silica gel (5:1
pentane/ether) to afford product 18b (79 mg, 53%
yield) a white solid: mp 50–54°C; Rf 0.34 (5:1 pen-
tane/ether); [h]2D5 −141.5 (c 0.90, CHCl3); FTIR (film)
3027, 3002, 2950, 2838, 1734, 1611, 1511, 1444, 1296,
1
1249, 1161, 1111, 1033, 967, 830, 743, 695 cm−1; H

H. M. L. Da6ies, Q. Jin / Tetrahedron: Asymmetry 14 (2003) 941–949
947
1
782 cm−1; H NMR (500 MHz, CDCl3) l 6.87 (s, 1H),
6.82–6.77 (m, 2H), 6.29 (d, J=16.2 Hz, 1H), 6.13 (d,
J=16.2 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 0.99 (s, 9H),
0.15 (s, 6H); 13C NMR (75 MHz, CDCl3) l 165.7,
151.1, 144.6, 130.8, 123.2, 120.9, 119.0, 109.0, 108.8,
55.4, 55.2, 25.6, 18.4, −4.7 (CꢀN2 is missing); MS (ESI)
m/z (relative intensity) 191.1 (58), 335.2 (M+−N2+H,
56), 363.3 (M++H, 46); HRMS (ESI) m/z calcd for
[C18H27N2O2Si]+ (M++H): 363.1735. Found: 363.17426.
NMR (500 MHz, CDCl3) l 7.33 (d, J=7.4 Hz, 2H),
7.29 (t, J=7.4 Hz, 2H), 7.24–7.19 (m, 1H), 7.09 (d,
J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.40 (d,
J=15.9 Hz, 1H), 6.22 (dd, J=15.9, 8.8 Hz, 1H), 3.76
(s, 3H), 3.64 (s, 3H), 3.43 (pseudo q, J=8.0 Hz, 1H),
3.10 (dd, J=13.7, 7.9 Hz, 1H), 2.88 (dd, J=13.7, 7.0
Hz, 1H); 13C NMR (125 MHz, CDCl3) l 173.8, 158.1,
136.7, 132.5, 130.5, 130.0, 128.5, 127.6, 126.9, 126.3,
113.7, 55.1, 51.8, 51.6, 38.1; MS (EI) m/z (relative
intensity) 121.1 (100), 122.1 (62), 237.1 (10), 296.2 (M+,
16); HRMS (EI) m/z calcd for [C19H20O3]+: 296.1407.
Found: 296.14096. HPLC analysis: 92% ee (Chiralcel
OD-H, 2% i-PrOH in hexane, 1.0 mL/min, u=254 nm,
tR=10.1 min, major; tR=13.2 min, minor). Anal. calcd
for C19H20O3: C, 77.00; H, 6.80. Found: C, 76.71; H,
6.90.
4.14. (S)-(E)-Methyl 2-(4-tert-butyldimethylsilyoxy-3-
methoxybenzyl)-4-(4-tert-butyldimethylsilyloxy-3-
methoxyphenyl)but-3-enoate, (S)-21
Under an argon atmosphere, to a refluxing degassed
solution of 11 (1.26 g, 5 mmol) and Rh2(S-DOSP)4 (9.5
mg, 1 mol%) in 2,2-dimethylbutane (2 mL), was added
a degassed solution of diazo compound 22 (181 mg, 0.5
mmol) in 2,2-dimethylbutane (5 mL) in 45 min using
syringe-pump. The reaction mixture was refluxed for
additional 15 min then cooled to rt. The solvent was
removed and the residue was purified by flash chro-
matography on silica gel (10:1–5:1 pentane/ether) to
afford product (S)-21 (130 mg, 44% yield) as a yellow
oil: Rf 0.32 (5:1 pentane/ether); [h]2D5 −85.1 (c 6.50,
CHCl3); FTIR (film) 2953, 2929, 2857, 1737, 1601,
1578, 1513, 1281, 1252, 1158, 1126, 1038, 902, 839, 782
cm−1; 1H NMR (500 MHz, CDCl3) l 6.85 (s, 1H),
6.82–6.78 (m, 2H), 6.76 (d, J=7.6 Hz, 1H), 6.67 (d,
J=1.8 Hz, 1H), 6.64 (dd, J=8.2, 1.8 Hz, 1H), 6.31 (d,
J=15.6 Hz, 1H), 6.09 (dd, J=15.6, 8.8 Hz, 1H), 3.82
(s, 3H), 3.74 (s, 3H), 3.64 (s, 3H), 3.41 (pseudo q, J=7.9
Hz, 1H), 3.10 (dd, J=13.4, 8.1 Hz, 1H), 2.86 (dd,
J=13.4, 7.0 Hz, 1H), 1.01 (s, 9H), 1.00 (s, 9H), 0.16 (s,
6H), 0.14 (s, 6H); 13C NMR (75 MHz, CDCl3) l 174.1,
150.9, 150.5, 144.9, 143.4, 132.4, 132.1, 130.6, 124.8,
121.2, 120.8, 120.6, 119.4, 113.1, 109.6, 55.35, 55.31,
51.8, 38.9, 25.66, 25.65, 18.39, 18.36, −4.72, −4.74,
−4.75; MS (ESI) m/z (relative intensity) 105.0 (57),
119.1 (100), 301.2 (54), 609.6 (M++Na, 95); HRMS
(ESI) m/z calcd for [C32H50NaO6Si2]+ (M++Na):
609.3038. Found: 609.30151. HPLC analysis: 92% ee
(Chiralcel OD-H, 1.0% i-PrOH in hexane, 0.8 mL/min,
u=254 nm, tR=7.5 min, major; tR=10.7 min, minor).
Anal. calcd for C32H50O6Si2: C, 65.49; H, 8.59. Found:
C, 65.75; H, 8.73%.
4.13. (E)-Methyl (4-tert-butyldimethylsilyoxy-3-
methoxyphenyl)vinyldiazoacetate, 22
To a cloudy solution of 4-tert-butyldimethylsilyoxy-3-
methoxybenzylaldehyde8b (7.42 g, 27.8 mmol) and 3-
carboxypropyl-triphenylphosphonium chloride12 (15.50
g, 41.8 mmol) in anhydrous THF (90 mL) was added a
solution of t-BuOK (9.75 g, 84.0 mmol) in anhydrous
THF (20 mL) in 50 min using cannula at 0°C. The
mixture was stirred for an additional 1 h after addition
then quenched with CH3I (18 mL, 270.0 mmol). The
resulting mixture was stirred overnight. Water was
added to make a clear solution and the mixture was
extracted with Et2O (3×30 mL), then dried over
MgSO4. The solvent was removed in vacuo and the
crude product was purified by flash chromatography on
silica gel (10:1 petroleum ether/ether) to give methyl
(4 - tert - butyldimethylsilyoxy - 3 - methoxyphenyl)vinyl -
acetate (2.49 g, 26% yield) as a yellow oil: Rf 0.30 (5:1
pentane/ether); FTIR (film) 3035, 2952, 2894, 2857,
1740, 1599, 1577, 1512, 1465, 1414, 1282, 1257, 1160,
1036, 964, 905, 840, 802, 788 cm−1; 1H NMR (500
MHz, CDCl3) l 6.89 (s, 1H), 6.82 (d, J=8.4 Hz, 1H),
6.78 (d, J=8.4 Hz, 1H), 6.42 (d, J=15.9 Hz, 1H), 6.15
(dq, J=15.9, 7.0 Hz, 1H), 3.82 (s, 3H), 3.72 (s, 3H),
3.23 (d, J=7.0 Hz, 1H), 1.00 (s, 9H), 0.15 (s, 6H); 13C
NMR (125 MHz, CDCl3) l 172.1, 150.9, 144.8, 133.3,
130.7, 120.8, 119.47, 119.41, 109.4, 55.3, 51.8, 38.1,
25.6, 18.4, −4.7. DBU (1.33 mL, 8.9 mmol) was added
quickly to
a stirring mixture of methyl (4-tert-
(R)-21 (127 mg, 43% yield) was obtained following the
same procedure as (S)-21 except using Rh2(R-DOSP)4
butyldimethylsilyoxy - 3 - methoxyphenyl)vinylacetate
(2.49 g, 7.4 mol) and p-acetamidobenzenesufonyl azide
(2.13 g, 8.9 mmol) in CH3CN (30 mL) at 0°C. After 2
h, aqueous NH4Cl (40 mL) was added. The organic
layer was separated and the aqueous layer was
extracted with ether (2×30 mL). The combined organic
extract was washed with brine then dried over MgSO4.
The crude product was dissolved in pentane/ether (1:1)
and passed through a pad of silica gel. The solvent was
removed in vacuo and the crude product was purified
by flash chromatography on silica gel (10:1 pentane/
ether) to afford the product 22 (1.88 g, 70% yield) as a
purple solid: Rf 0.47 (5:1 pentane/ether); FTIR
(CH2Cl2) 2954, 2930, 2857, 2079, 1708, 1627, 1698,
1574, 1512, 1437, 1310, 1280, 1248, 1110, 906, 840, 804,
1
as catalyst: [h]2D5 +91.0 (c 6.35, CHCl3); The IR, H and
13C NMR spectra are consistent with those of com-
pound (S)-21; HPLC analysis: 91% ee (Chiralcel OD-
H, 1.0% i-PrOH in hexane, 0.8 mL/min, u=254 nm,
tR=7.8 min, minor; tR=10.5 min, major).
4.15. (+)-Imperanene, 198b,c
Under an argon atmosphere, to a stirred solution of 21
(127 mg, 0.22 mmol) in THF (4 mL) was added LAH
(0.22 mL, 1 M in THF) dropwise at −40°C. The
mixture was stirred for 30 min at −40°C then quenched
with aqueous NH4Cl. The organic phase was separated
and the aqueous layer was extracted with ether. The

948
H. M. L. Da6ies, Q. Jin / Tetrahedron: Asymmetry 14 (2003) 941–949
combined organic extract was dried over MgSO4. The
crude product thus obtained was near pure and was
used directly in the next step without purification.
FTIR (film) 3374 (br), 2954, 2929, 2857, 1601, 1578,
1513, 1471, 1417, 1281, 1254, 1234, 1158, 1128, 1039,
2.58 (ddd, J=13.5, 11.6, 5.0 Hz, 1H), 2.51 (dtd, J=
13.5, 10.7, 6.4 Hz, 1H), 0.99 (s, 9H), 0.86 (s, 9H), 0.14
(s, 6H), 0.00 (s, 3H), −0.03 9s, 3H); 13C NMR (125
MHz, CDCl3) l 177.1, 151.3, 149.7, 144.1, 143.5, 135.9,
131.0, 127.8, 121.5, 121.0, 120.8, 112.5, 111.4, 71.9,
55.56, 55.40, 49.7, 47.4, 41.8, 29.2, 26.0, 25.7, 25.6, 18.4,
18.3, −4.70, −4.72, −4.73, −4.74; MS (FAB) m/z (rela-
tive intensity) 251.1 (54), 347.1 (21), 527.2 (M+−tBu,
100), 584.3 (M+, 11), 607.2 (M++Na, 58); HRMS (FAB)
m/z calcd for [C32H48NaO6Si2]+ (M++Na): 607.2882.
Found: 607.28830.
1
906, 840, 806, 782 cm−1; H NMR (500 MHz, CDCl3) l
6.83 (d, J=1.5 Hz, 1H), 6.80 (dd, J=8.0, 1.5 Hz, 1H),
6.76 (d, J=8.0 Hz, 1H), 6.66 (d, J=1.8 Hz, 1H), 6.63
(dd, J=7.9, 1.8 Hz, 1H), 6.34 (d, J=15.9 Hz, 1H), 5.93
(dd, J=15.9, 8.2 Hz, 1H), 3.81 (s, 3H), 3.74 (s, 3H),
3.66 (dd, J=10.7, 4.7 Hz, 1H), 3.54 (dd, J=10.7, 7.3
Hz, 1H), 2.75–2.60 (m, 2H), 0.99 (s, 9H), 0.98 (s, 9H),
0.15 (s, 6H), 0.13 (s, 6H); 13C NMR (75 MHz, CDCl3)
l 150.9, 150.5, 144.6, 143.2, 133.1, 132.0, 131.1, 128.7,
121.3, 120.8, 120.6, 119.0, 113.3, 109.7, 65.2, 55.4, 47.5,
37.6, 29.6, 25.7, 18.39, 18.35, −4.7. The crude was
dissolved in THF (4 mL), and TBAF (0.45 mL, 1 M in
THF) was added. The resulting mixture was stirred for
20 min at rt then quenched with aqueous NH4Cl. The
organic layer was separated and the aqueous layer was
extracted with ether. The combined organic extract was
dried over MgSO4. The crude product was purified by
flash chromatography on silica gel (1:2 pentane/ether)
to afford the product (+)-imperanene 19 (62 mg, 87%)
as a white solid: [h]D25 +115.2 (c 1.05, CHCl3); FTIR
(film) 3423 (br), 3013, 2935, 2848, 1600, 1514 1463,
TBAF (0.25 mL, 1 M in THF) was added to a stirred
solution of 23 (66 mg, 0.11 mmol) in THF (5 mL) at rt.
The resulting solution was stirred for 30 min at rt then
quenched with saturated aqueous NH4Cl. The mixture
was extracted with CH2Cl2, washed with brine and
dried over Na2SO4. The solvent was removed in vacuo
and the crude product was purified by flash chromatog-
raphy on silica gel (1:1–1:2 pentane/ether then 1:1
ether/CH2Cl2) to afford (−)-a-conidendrin 20 (32 mg,
78% yield) as a white solid: mp 255°C (lit14 mp 256°C);
Rf 0.65 (1:1 ether/CH2Cl2); [h]2D5 −50.4 (c 0.90, acetone);
1H NMR (500 MHz, CDCl3) l 6.87 (d, J=8.0 Hz, 1H),
6.64 (br s, 2H), 6.54 (s, 1H), 6.40 (s, 1H), 5.57 (s, 1H),
5.41 (s, 1H), 4.23 (dd, J=8.5, 6.1 Hz, 1H), 4.01 (pseudo
t, J=9.5 Hz, 1H), 3.89 (s, 3H), 3.85 (d, J=10.0 Hz,
1H), 3.82 (s, 3H), 3.21 (dd, J=15.6, 4.5 Hz, 1H), 2.98
(dd, J=15.6, 11.0 Hz, 1H), 2.62–2.50 (m, 2H); 13C
NMR (125 MHz, CDCl3, three drops of DMSO-d6 was
added to dissolve the sample) l 176.9, 147.2, 145.8,
145.0, 144.4, 133.7, 131.3, 125.6, 121.1, 115.4, 114.8,
111.4, 110.5, 71.7, 55.74, 55.70, 49.5, 47.2, 41.6, 29.0.
1
1450, 1429, 1370, 1271, 1236, 1154, 1033, 754 cm−1; H
NMR (500 MHz, CDCl3) l 6.84 (s, 3H), 6.82 (d, J=8.2
Hz, 1H), 6.70–6.66 (m, 2H), 6.35 (d, J=16.0 Hz, 1H),
5.92 (dd, J=16.0, 8.3 Hz, 1H), 5.64 (br s, 1H), 5.51 (br
s, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.67 (dd, J=10.7, 4.9
Hz, 1H), 3.56 (dd, J=10.7, 7.2 Hz, 1H), 2.77–2.68 (m,
2H), 2.68–2.60 (m, 1H); 13C NMR (125 MHz, CDCl3)
l 146.6, 146.3, 145.2, 143.8, 132.1, 131.5, 129.7, 128.3,
121.8, 119.6, 114.4, 114.2, 111.7, 108.2, 65.2, 55.83,
55.81, 47.5, 37.6; HPLC analysis: 92% ee (Chiralcel
OD-H, 30.0% i-PrOH in hexane, 1.0 mL/min, u=254
nm, tR=13.8 min, minor; tR=16.6 min, major).
Acknowledgements
Financial support of this work by the National Science
Foundation (CHE 0092490) and the National Institutes
of Health (CA85641) is gratefully acknowledged.
4.16. (−)-a-Conidendrin, 2013
To a stirred suspension of paraformaldehyde (40 mg,
1.32 mmol) in a solution of (R)-21 (130 mg, 0.22 mmol)
in CH2Cl2 (5 mL) was added methylaluminum
sesquichloride (1.32 mL, 1 M in hexanes) at 0°C. The
resulting mixture was allowed to stir for 1 h then
quenched with water. The mixture was extracted with
ether, washed with brine then dried over Na2SO4. This
crude product was treated with TsOH·H2O (6 mg, 0.03
mmol) in CH2Cl2 for 1 h at rt. Water (5 mL) was added
and extracted with ether. The organic extract was
washed with brine then dried over Na2SO4. The solvent
was removed in vacuo and the crude product was
purified by flash chromatography on silica gel (10:1–5:1
pentane/ether) to afford product 23 (75 mg, 58% yield)
as a white solid: Rf 0.41 (1:1 pentane/ether); FTIR
(CDCl3) 2954, 2958, 2856, 1783, 1511, 1292, 1255, 902,
839 cm−1; 1H NMR (500 MHz, CDCl3) l 6.80 (d,
J=8.0 Hz, 1H), 6.64 (s, 1H), 6.60 (dd, J=8.0, 1.4 Hz,
1H), 6.52 (br s, 1H), 6.28 (s, 1H), 4.19 (dd, J=8.5, 6.4
Hz, 1H), 4.00 (dd, J=10.7, 8.5 Hz, 1H), 3.84 (d,
J=10.7 Hz, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.20 (dd,
J=15.5, 5.0 Hz, 1H), 2.96 (dd, J=15.5, 11.6 Hz, 1H),
References
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