TFA-mediated intramolecular Friedel-Crafts reaction. An efficient metal and halogen free route to stereoselective synthesis of benzocycles

Article abstract of DOI:10.1016/S0040-4020(03)01026-3

6-Acetoxy-4-alkenyl arenes undergo regio- and stereoselective intramolecular Friedel-Crafts reaction affording benzocycles in moderate to excellent yields in TFA/HOAc (3:1). It was observed that introduction of alkyls or phenyl group to the allylic acetate moiety facilitates the cyclization reaction. The optically active tricyclic (4bR,8aS)-4b,7,8,8a,9,10-hexahydrophenanthrene skeleton could also be easily obtained in excellent yields.

Full text of DOI:10.1016/S0040-4020(03)01026-3

Tetrahedron 59 (2003) 6273–6283
TFA-mediated intramolecular Friedel–Crafts reaction.
An efficient metal and halogen free route to stereoselective
synthesis of benzocycles
*
Shengming Ma and Junliang Zhang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu Road, Shanghai 200032, People’s Republic of China
Received 5 March 2003; revised 19 June 2003; accepted 24 June 2003
Dedicated to Professor Wei-shan Zhou on the occasion of his 80th birthday
Abstract—6-Acetoxy-4-alkenyl arenes undergo regio- and stereoselective intramolecular Friedel–Crafts reaction affording benzocycles in
moderate to excellent yields in TFA/HOAc (3:1). It was observed that introduction of alkyls or phenyl group to the allylic acetate moiety
facilitates the cyclization reaction. The optically active tricyclic (4bR,8aS)-4b,7,8,8a,9,10-hexahydrophenanthrene skeleton could also be
easily obtained in excellent yields.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Benzocycles are commonly observed structural units in
many natural and unnatural products with biological
potentials.1 These compounds are usually prepared by the
cyclic radical addition, carbopalladation (including acyl-
palladation) of the corresponding 2-alkenyl aryl halides or
their corresponding alkynic analogues.2–5 In spite of the
excellence of these reactions in terms of efficiency, it is
desirable to develop efficient and environmentally benign
methodologies for the synthesis of these benzocycles.
2.1. Synthesis of starting materials
The starting materials 3a–e were prepared by the alkylation
of dimethyl 2-(40-acetoxybut-20-enyl)malonate 19 with the
corresponding benzylic halides 2a–d or 1-chloromethyl-
naphthelene using sodium hydride as the base (Scheme 2).
Substrates 3f, g were prepared by the alkylation reaction of
dimethyl 2-benzylic malonates 4a, b with 2-methyl-4-
acetoxybut-2-enyl bromide 5 (Scheme 3).10
Recently, we observed an intramolecular Friedel–Crafts
reaction6,7 of 6-acetoxy-4-alkenyl arenes which provided an
efficient metal and halogen free route to stereoselective
synthesis of benzocycles (Scheme 1).8 Herein, we wish to
disclose the full account of this study.
Compounds 3h–j and 3k were prepared by the palladium-
catalyzed allylation of 2-benzylic malonates 4a, b or
N-benzyl p-toluenesulfonyl amide with 1-acetoxy-alk-2-
en-4-ols 6a, b11 followed by treatment with acetic anhydride
(Scheme 4).
The bicyclic substrates (1R p,4S p)-9a–d were synthesized
via the reaction of 2-substituted malonates 4a–d with cis-4-
chlorocyclohex-2-en-1-ol acetyl ester 8 under the catalysis
of Pd(OAc)2 and Ph3P, while the trans isomer (1R p,4R p)-9a
was prepared from the direct reaction of 4a and 8 in CH3CN
at 808C in the absence of any palladium catalyst
(Scheme 5).12
Scheme 1.
2.2. Annulation of 6-acetoxy-4-alkenylarenes
Keywords: Friedel–Crafts reaction; benzocycles; stereoselective synthesis.
*
Originally, the reaction of 3a was carried out in trifluoro-
acetic acid under the catalysis of Pd(OAc)2, however,
Corresponding author. Tel.: þ86-21-6416-3300; fax: þ86-21-6416-6128;
e-mail: masm@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01026-3

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Scheme 2.
allylic acetate part (compare entries 6–10 with entries 1–4,
Table 1).
2.3. Annulation of racemic bicyclic substrates
Under the encouragement of the above results, we are
interested in applying this transformation to the bicyclic
substrates. Tricyclic skeleton (4bR p,8aS p)-11a–d were
formed in excellent yields and stereoselectivity from
bicyclic (1S p,4R p)-9a–d. Surprisingly, we found the
reaction of (1R p,4R p)-9a afforded the same product
(4bS p,8aR p)-11a in 97% yield, indicating that the stereo-
chemistry of the newly created sp3 carbon center is
controlled by that of 4-carbon in 9a (Scheme 7). The ring
junction was established as cis-fused by an X-ray diffraction
study of (4bR p,8aS p)-11c (Fig. 1).13
Scheme 3.
control experiment showed that Pd(OAc)2 was not required
in this transformation. Finally, it is observed that the yield of
the reaction was improved to 66% by using TFA/HOAc
(3:1) as the solvent (Scheme 6).
Using TFA/HOAc (3:1) as the standard reaction medium,
the reaction of 3 with different substituents in the aryl
moiety and the allylic moiety was studied (Table 1). It is
surprising for us to observe that the rate and yields were not
improved at all with the introduction of electron-donating
groups to the aromatic ring. On the other hand, dramatic
effect was found with the introduction of substitution in the
2.4. Annulation of optically active bicyclic substrates
It is interesting to observe that this transformation could also
be applied to highly diastereoselective synthesis of optically
active tricyclic skeleton (4bR,8aS)-11a–d as exemplified by
Scheme 4.

S. Ma, J. Zhang / Tetrahedron 59 (2003) 6273–6283
6275
Scheme 5.
4. Experimental
4.1. Synthesis of starting materials
4.1.1. Typical procedure for synthesis of 3a–e: dimethyl
2-(40-acetoxybut-20(Z)-enyl)0-2-benzylmalonate
(3a).
Dimethyl 2-(40-acetoxybut-2 (Z)-enyl)malonate 1 (0.732 g,
3 mmol) was treated with NaH (120 mg, 80% in mineral oil,
4 mmol) in 10 mL of dry THF at rt for 10 min followed by
the addition of a solution of benzyl bromide 2a (0.616 g,
3.6 mmol) in THF. The reaction mixture was stirred for 10 h
at rt. After the usual work-up, the residue was purified by
column chromatography on silica gel to afford 0.902 g
(90%) of 3a: oil; 1H NMR (300 MHz, CDCl3) d 7.28–7.18
(m, 3H), 7.08–7.01 (m, 2H), 5.76–5.60 (m, 2H), 4.50 (d,
J¼5.1 Hz, 2H), 3.70 (s, 6H), 3.22 (s, 2H), 2.53 (d,
J¼6.0 Hz, 2H), 2.05 (s, 3H); 13C NMR (75.4 MHz,
CDCl3) d 170.8, 170.5, 135.5, 129.7, 129.5, 128.5, 128.2,
127.0, 64.4, 58.9, 52.2, 38.3, 35.0, 20.8; MS m/z (%) 334
Scheme 6.
the cyclization of optically active bicyclic (1R,4S)-13a–d,
which were easily prepared from the 2-substituted
malonates 4a–d and meso-cyclohexen-1,4-diol dibenzoate
12 via a method developed by B. M. Trost using the
optically active ligand Lp (Scheme 8).14
2.5. Mechanism and substituent effect
(Mþ, 2.22), 215 (100); IR (neat) 1737, 1240, 973, 703 cm21
.
The reaction was believed to proceed via the generation of
an allylic cation from the allylic acetate moiety followed by
the intramolecular electrophilic substitution reaction. Thus,
the introduction of substituents in the allylic acetate part
may facilitate the formation of the allylic cation, which will
afford the products in higher yields. As a comparison, the
corresponding reaction of the alcoholic analogue 14
afforded 10a in only 40% yield, however, higher yield
(53%) could be obtained when the reaction medium was
changed to TFA/(CF3CO)2O (4:1) (Scheme 9).
Anal. calcd for C18H22O6: C 64.66, H 6.63. Found: C 64.71,
H 6.71.
4.1.2. Dimethyl 2-(40-acetoxybut-20(Z)-enyl)-2-(400-
methylbenzyl)malonate (3b). The reaction of dimethyl
2-(40-acetoxybut-20(Z)-enyl)malonate 1 (2.44 g, 10 mmol)
with NaH (360 mg, 80% in mineral oil, 12 mmol) and
4-methylbenzyl bromide 2b (2.20 g, 12 mmol) afforded
2.11 g (61%) of 3b: oil; 1H NMR (300 MHz, CDCl3) d 7.05
(d, J¼7.7 Hz, 2H), 6.92 (d, J¼7.7 Hz, 2H), 5.76–5.55 (m,
2H), 4.55 (d, J¼6.1 Hz, 2H), 3.72 (s, 6H), 3.20 (s, 2H), 2.57
(d, J¼6.7 Hz, 2H), 2.29 (s, 3H), 2.05 (s, 3H); 13C NMR
(75.4 MHz, CDCl3) d 170.9, 170.6, 136.5, 132.2, 129.5,
128.9, 127.8, 127.2, 60.1, 58.6, 52.3, 37.8, 29.9, 20.9, 20.7;
ESI-MS m/z (%) 371.2 (MþNaþ); IR (neat) 1738,
1234 cm21. Anal. calcd for C19H24O6: C 65.50, H 6.94.
Found: C 65.23, H 6.90.
3. Conclusion
In conclusion, we have developed an efficient methodology
for the synthesis of benzocycles, the yields and rates of the
cyclization depend largely on the substituents in the
substrates. Due to the advantage of simple operation,
ready availability of starting materials, high yields and
excellent stereoselectivity and diastereoselectivity, this
reaction will show its utility in organic synthesis. Further
studies on the synthetic applications of this reaction are
being carried out in our laboratory.
4.1.3. Dimethyl 2-(40-acetoxybut-20(Z)-enyl)-2-(400-meth-
oxybenzyl)malonate (3c). The reaction of dimethyl 2-(40-
acetoxybut-20(Z)-enyl)malonate 1 (0.732 g, 3 mmol) with
NaH (120 mg, 80% in mineral oil, 4 mmol) and 4-methoxy-
benzyl chloride 2c (0.564 g, 3.6 mmol) afforded 0.756 g
1
(69%) of 3c: oil; H NMR (300 MHz, CDCl3) d 6.97 (d,

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Table 1. Cyclic Friedel–Crafts reaction of allylic acetates 1
Entry
1
Substrates
Time (h)
14
Product
Yield (%)
66
2
14
66
3
14
66
4
14
68
5
6
14
72
84
3
7
4
85
8
9
1
85
1.5
99a,b

S. Ma, J. Zhang / Tetrahedron 59 (2003) 6273–6283
6277
Table 1 (continued)
Entry
Substrates
Time (h)
0.5
Product
Yield (%)
94a,b
10
11
3
92a,b
Unless otherwise stated, the reaction was carried out using 3 (0.5 mmol) in 1.0 mL of TFA/AcOH (3:1) at 708C.
The reaction was carried out at rt.
a
b
The configuration of the CvC bond was determined by the coupling constants of the olefinic protons to be E.
2-(40-acetoxybut-20(Z)-enyl)malonate 1 (0.732 g, 3 mmol)
with NaH (160 mg, 60% in mineral oil, 4 mmol) and 3,5-
dimethylbenzyl bromide 2d (0.716 g, 3.6 mmol) afforded
1
0.847 g (78%) of 3d: oil; H NMR (300 MHz, CDCl3) d
6.85 (s, 1H), 6.65 (s, 2H), 5.80–5.60 (m, 2H), 4.51 (d,
J¼5.4 Hz, 2H), 3.71 (s, 6H), 3.14 (s, 2H), 2.52 (d,
J¼6.3 Hz, 2H), 2.25 (s, 6H), 2.05 (s, 3H); MS m/z (%)
362 (Mþ, 0.03), 361 (48), 131 (100); IR (neat) 1735, 1234,
960 cm21. Anal. calcd for C20H26O6: C 66.28, H 7.23.
Found: C 66.23, H 7.20.
4.1.5. Dimethyl 2-(40-acetoxybut-20(Z)-enyl)-2-(naph-
thalen-100-yl)methyl malonate (3e). The reaction of
dimethyl 2-(40-acetoxybut-20(Z)-enyl)malonate 1 (0.732 g,
3 mmol) with NaH (120 mg, 80% in mineral oil, 4 mmol)
and (1-chloromethyl)naphthalene (0.640 g, 3.6 mmol)
afforded 0.504 g (44%) of 3e: white solid; mp 48–498C
(Et2O–hexanes); 1H NMR (300 MHz, CDCl3) d 8.05–7.98
(m, 1H), 7.86–7.80 (m, 1H), 7.78–7.70 (m, 1H), 7.56–7.24
(m, 4H), 5.80–5.60 (m, 2H), 4.53 (d, J¼4.9 Hz, 2H), 3.76
(s, 2H), 3.59 (s, 6H), 2.68 (d, J¼5.5 Hz, 2H), 2.05 (s, 3H);
13C NMR (75.4 MHz, CDCl3) d 171.1, 170.5, 133.7, 132.5,
132.1, 129.7, 128.7, 128.5, 128.0, 127.7, 125.6, 125.3,
125.0, 123.6, 64.5, 59.0, 52.2, 36.0, 34.0, 20.8; MS m/z (%)
384 (Mþ, 0.80), 141 (100); IR (neat) 1745, 1737, 1725,
1597, 973 cm21. Anal. calcd for C22H24O6: C 68.74, H 6.29.
Found: C 68.38, H 6.32.
Scheme 7.
4.1.6. Dimethyl 2-(20-methyl-40-acetoxybut-20(E)-enyl)-2-
benzylmalonate (3f). The reaction of dimethyl 2-benzyl-
malonate 4a (1.11 g, 5 mmol) with NaH (210 mg, 60% in
mineral oil, 5.3 mmol) and 2-methyl-4-acetoxybut-2-enyl
bromide 5 (1.04 g, 5 mmol) afforded 1.50 g (86%) of 3f:
white solid; mp 52–538C (Et2O–hexanes); 1H NMR
(300 MHz, CDCl3) d 7.30–7.20 (m, 3H), 7.15–7.05 (m,
2H), 5.40 (t, J¼7.0 Hz, 1H), 4.59 (d, J¼7.0 Hz, 2H), 3.68 (s,
6H), 3.26 (s, 2H), 2.68 (s, 2H), 2.06 (s, 3H), 1.68 (s, 3H); 13C
NMR (75.4 MHz, CDCl3) d 171.2, 170.7, 136.9, 135.9,
129.8, 128.0, 126.8, 123.8, 60.8, 58.8, 52.1, 42.6, 39.3, 20.8,
17.1; MS m/z (%) 289 (Mþ2CH3CO2, 9.04), 215 (100); IR
(KBr) 1720, 1270, 690 cm21. Anal. calcd for C19H24O6: C
65.50, H 6.94. Found: C 65.50, H 6.88.
Figure 1.
J¼9.0 Hz, 2H), 6.79 (d, J¼9.0 Hz, 2H), 5.70–5.60 (m, 2H),
4.51 (d, J¼5.1 Hz, 2H), 3.80 (s, 3H), 3.71 (s, 6H), 3.16 (s,
2H), 2.53 (d, J¼6.0 Hz, 2H), 2.06 (s, 3H); ESI-MS m/z (%)
387.2 (MþNaþ); IR (neat) 1738, 1234 cm21. HRMS calcd
for C19H24O7Na: 387.1420. Found: 387.1417.
4.1.4. Dimethyl 2-(40-acetoxybut-20(Z)-enyl)-2-(300,500-
dimethylbenzyl)malonate (3d). The reaction of dimethyl

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S. Ma, J. Zhang / Tetrahedron 59 (2003) 6273–6283
Scheme 8.
silica gel to afford 3.4 g (93%) of 7h: oil; 1H NMR
(300 MHz, CDCl3) d 7.34–7.20 (m, 3H), 7.14–7.08 (m,
2H), 5.65–5.55 (m, 2H), 4.16–4.06 (m, 1H), 3.67 (s, 6H),
3.28 (s, 2H), 2.57–2.50 (m, 2H), 1.70 (bs, 1H), 1.64–1.46
(m, 2H), 1.44–1.26 (m, 4H), 0.89 (t, J¼7.0 Hz, 3H); ESI-
MS m/z (%) 371.3 (MþNaþ); IR (neat) 3475, 1737, 1674,
979, 703 cm21. HRMS calcd for C20H28O5Na: 371.1834.
Found: 371.1816.
4.1.9. Dimethyl 2-(40-hydroxyoct-20(E)-enyl)-2-(400-
methylbenzyl)malonate (7i). The reaction of dimethyl
2-(40-methylbenzyl)malonate 4b (0.708 g, 3.0 mmol) with
NaH (120 mg, 60% in mineral oil, 3.0 mmol) and 6a
(0.558 g, 3.0 mmol) in the presence of Pd(OAc)2 (17 mg,
0.08 mmol) and dppe (60 mg, 0.15 mmol) afforded 0.924 g
Scheme 9.
4.1.7. Dimethyl 2-(20-methyl-40-acetoxybut-20(E)-enyl)-2-
(400-methylbenzyl)malonate (3g). The reaction of dimethyl
2-(40-methylbenzyl)malonate 4b (0.472 g, 2 mmol) with
NaH (88 mg, 60% in mineral oil, 2.2 mmol) and 2-methyl-
4-acetoxybut-2-enyl bromide 5 (0.414 g, 2 mmol) afforded
1
(85%) of 7i: oil; H NMR (300 MHz, CDCl3) d 7.06 (d,
J¼8.1 Hz, 2H), 6.95 (d, J¼8.1 Hz, 2H), 5.65–5.50 (m, 2H),
4.10–4.00 (m, 1H), 3.70 (s, 6H), 3.18 (s, 2H), 2.52 (d,
J¼5.4 Hz, 2H), 2.30 (s, 3H), 1.70–1.40 (m, 3H), 1.40–1.20
(m, 4H), 0.90 (t, J¼6.3 Hz, 3H); 13C NMR (75.4 MHz,
CDCl3) d 171.1, 171.0, 138.2, 136.3, 132.3, 129.5, 128.8,
124.3, 72.2, 59.1, 52.10, 52.06, 37.5, 36.6, 34.6, 27.3, 22.4,
20.8, 13.8; MS m/z (%) 345 (Mþ2OH, 57.60), 285 (100);
IR (neat) 3500, 1737, 974, 733 cm21. Anal. calcd for
C21H30O5: C 69.59, H 8.34. Found: C 69.48, H 8.47.
1
0.603 g (86%) of 3g: oil; H NMR (300 MHz, CDCl3) d
7.06 (d, J¼9.2 Hz, 2H), 6.98 (d, J¼9.2 Hz, 2H), 5.42 (t,
J¼6.7 Hz, 1H), 4.58 (d, J¼6.7 Hz, 2H), 3.68 (s, 6H), 3.22
(s, 2H), 2.66 (s, 2H), 2.30 (s, 3H), 2.06 (s, 3H), 1.65 (s, 3H);
13C NMR (75.4 MHz, CDCl3) d 171.3, 170.8, 137.0, 136.4,
132.7, 129.6, 128.8, 123.7, 60.8, 58.8, 52.1, 42.5, 38.9, 20.9,
20.8, 17.1; MS m/z (%) 271 (Mþ2CH3CO2H–OMe, 1.61),
105 (100); IR (neat) 1735, 1235 cm21. Anal. calcd for
C20H26O6: C 66.28, H 7.23. Found: C 65.97, H 7.24.
4.1.10. N-Benzyl N-(4-hydroxyoct-2(E)-enyl)(40-methyl-
phenyl)sulfonyl amide (7k). The reaction of N-benzyl
4-methylphenylsufonyl amide (522 mg, 2 mmol) with NaH
(100 mg, 60% in mineral oil, 2.5 mmol) and 6a (372 mg,
2.0 mmol) in the presence of Pd(OAc)2 (11 mg, 0.05 mmol)
and dppe (40 mg, 0.1 mmol) afforded 724 mg (94%) of 7k:
oil; 1H NMR (300 MHz, CDCl3) d 7.68 (d, J¼8.0 Hz, 2H),
7.40–7.20 (m, 7H), 5.40–5.20 (m, 2H), 4.42 (d, J¼14.7 Hz,
1H), 4.25 (d, J¼14.7 Hz, 1H), 3.90–3.80 (m, 1H), 3.77 (dd,
J¼15.3, 5.5 Hz, 1H), 3.69 (dd, J¼15.3, 5.5 Hz, 1H), 2.44 (s,
4.1.8. Typical procedure for synthesis of 7h, i, k:
dimethyl 2-(40-hydroxyoct-20(E)-enyl)-2-benzylmalonate
(7h). A solution of dimethyl 2-benzylmalonate 4a (2.1 g,
9.5 mmol) in THF was treated with NaH (400 mg, 60% in
mineral oil, 10 mmol) under Ar for 10 min. 6a (2.0 g,
10.8 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), and dppe
(40 mg, 0.1 mmol) were added. The reaction mixture was
stirred for another 10 h at rt. After the usual work-up, the
residue was purified through column chromatography on

S. Ma, J. Zhang / Tetrahedron 59 (2003) 6273–6283
6279
3H), 1.60 (s, 1H), 1.40–1.00 (m, 6H), 0.88 (t, J¼6.7 Hz,
3H); MS m/z (%) 369 (Mþ2H2O, 18.82), 91 (100); IR
(neat) 3524, 1599, 1159, 974, 732 cm21. Anal. calcd for
C22H29NO3S: C 68.18, H 7.54, N 3.61. Found: C 68.15, H
7.57, N 3.50.
4.1.15. (1R p,4R p)-4-(10,10-Bis(methoxycarbonyl)-20-
phenylethyl)cyclohex-2-en-1-ol acetyl ester (1R p,4R p-
9a). Under Ar, to a suspension of NaH (60 mg, 60% in
mineral oil, 1.5 mmol) in 4 mL of THF was added dropwise
a solution of dimethyl 2-benzyl malonate 4a (333 mg,
1.5 mmol) in THF. After being stirred for 10 min, THF was
removed and cis-4-chlorocyclohex-2-en-1-ol acetyl ester 8
(175 mg, 1.0 mmol) in 4 mL of CH3CN was added and the
mixture was refluxed for 4 h. After removal of the solvent,
the residue was purified by column chromatography on
silica gel (hexanes/ether¼20:1) to afford 339 mg (94%) of
(1R p,4R p)-9a: white solid; mp 93–948C (Et2O–hexanes);
1H NMR (300 MHz, CDCl3) d 7.30–7.20 (m, 3H), 7.13–
7.11 (m, 2H), 5.94 (d, J¼10.5 Hz, 1H), 5.63 (d, J¼10.5 Hz,
1H), 5.29 (bs, 1H), 3.64 (s, 3H), 3.58 (s, 3H), 3.33 (d,
J¼14.0 Hz, 1H), 3.23 (d, J¼14.0 Hz, 1H), 2.93 (bs, 1H),
4.1.11. Typical procedure for synthesis of 3h, i, k:
dimethyl 2-(40-acetoxyoct-20(E)-enyl)-2-benzylmalonate
(3h). To a solution of alcohol 7h (1.00 g, 2.87 mmol) in
20 mL of dichloromethane was added 1.0 mL of Ac2O,
2.0 mL of Et3N and DMAP (0.20 g, 1.5 mmol). After
stirring at rt for overnight and the usual work-up, the residue
1
was purified to afford 1.0 g (90%) of 3h: oil; H NMR
(300 MHz, CDCl3) d 7.24–7.12 (m, 3H), 7.04–6.95 (m,
2H), 5.57 (dt, J¼15.4, 6.9 Hz, 1H), 5.41 (dd, J¼15.4,
6.9 Hz, 1H), 5.13 (q, J¼6.9 Hz, 1H), 3.67 (s, 6H), 3.15 (s,
2H), 2.66 (d, J¼7.1 Hz, 2H), 1.98 (s, 3H), 1.70–1.40 (m,
2H), 1.35–1.15 (m, 4H), 0.89 (t, J¼6.7 Hz, 3H); MS m/z
(%) 331 (Mþ2CH3CO2, 100); IR (neat) 1737, 1737, 1605,
1
2.20–2.06 (m, 1H), 2.05 (s, 3H), 1.60–1.42 (m, 3H); H
NMR (300 MHz, CDCl3) d 170.8, 170.5, 170.3, 136.1,
131.8, 130.0, 128.2, 128.1, 127.0, 69.7, 62.8, 52.1, 52.0,
39.4, 38.5, 28.4, 23.0, 21.3; MS m/z (%) 361 (2.30) [Mþþ1],
301 (Mþ2CH3CO2, 100); IR (KBr) 1740, 1724, 1602, 740,
724 cm21. Anal. calcd for C20H24O6: C 66.65, H 6.71.
Found C 66.79, H 6.66.
974,
703 cm21
.
HRMS
calcd
for
C20H26O4
[Mþ2CH3CO2H]: 330.1831. Found: 330.1867.
4.1.12. Dimethyl 2-(40-acetoxyoct-20(E)-enyl)-2-(400-
methylbenzyl)malonate (3i). The reaction of 7i (181 mg,
0.5 mmol) with Ac2O (62 mg, 0.6 mmol) in the presence of
Et3N (61 mg, 0.6 mmol) and DMAP (10 mg, 0.7 mmol)
afforded 197 mg (98%) of 3i: oil; 1H NMR (300 MHz,
CDCl3) d 7.06 (d, J¼8.1 Hz, 2H), 6.95 (d, J¼8.1 Hz, 2H),
5.58 (dt, J¼15.4, 7.1 Hz, 1H), 5.49 (dd, J¼15.4, 7.0 Hz,
1H), 5.18 (q, J¼7.0 Hz, 1H), 3.70 (s, 6H), 3.18 (s, 2H), 2.51
(d, J¼7.0 Hz, 2H), 2.30 (s, 3H), 2.05 (s, 3H), 1.65–1.40 (m,
2H), 1.40–1.15 (m, 4H), 0.90 (t, J¼6.8 Hz, 3H); ESI-MS
4.1.16. Typical procedure for synthesis of 1R p,4S p-
9a– d: (1R p,4S p)-4-(10,10-bis(methoxycarbonyl)-20-
phenylethyl)cyclohex-2-en-1-ol acetyl ester (1R p,4S p-
9a). Under Ar, to a suspension of NaH (60 mg, 60% in
mineral oil, 1.5 mmol) in 15 mL of THF was added
dropwise a solution of dimethyl 2-benzylmalonate 4a
(333 mg, 1.5 mmol) in THF. After being stirred for
10 min, Pd(OAc)2 (4 mg, 0.02 mmol), PPh3 (25 mg,
0.1 mol) and cis-4-chlorocyclohex-2-en-1-ol acetyl ester 8
(175 mg, 1.0 mmol) in THF were added. The mixture was
stirred for 0.75 h at rt. After evaporation of the solvent, the
residue was purified by column chromatography on silica
gel (hexanes/ether¼20:1) to afford 354 mg (98%) of
(1R p,4S p)-9a: white solid; mp 68–698C (Et2O–hexanes);
1H NMR (300 MHz, CDCl3) d 7.30–7.16 (m, 3H), 7.16–
7.06 (m, 2H), 6.06 (d, J¼10.3 Hz, 1H), 5.82–5.74 (m, 1H),
5.12 (bs, 1H), 3.64 (s, 3H), 3.58 (s, 3H), 3.36 (d, J¼14.0 Hz,
1H), 3.25 (d, J¼14.0 Hz, 1H), 2.85–2.75 (m, 1H), 2.04 (s,
3H), 2.00–1.52 (m, 4H); 13C NMR (75.4 MHz, CDCl3) d
170.5, 170.5, 170.4, 136.1, 134.6, 130.0, 128.1, 127.0,
125.2, 65.7, 62.7, 52.0, 51.8, 39.6, 38.5, 27.8, 21.2, 19.5;
MS m/z (%) 359 (Mþ21, 2.30), 301 (Mþ2CH3CO2, 100);
IR (KBr) 1726, 1722, 1600 cm21. Anal. calcd for
C20H24O6: C 66.65, H 6.71. Found: C 66.62, H 6.54.
m/z (%) 427.3 (MþNaþ); IR (neat) 1737, 1241, 974 cm21
.
HRMS calcd for C23H32O6Na: 427.2097. Found: 427.2091.
4.1.13. Dimethyl 2-(40-acetoxy-40-phenylbut-20(E)-enyl)-
2-(400-methylbenzyl)malonate (3j). The reaction of 4b
(0.472 g, 2.0 mmol) with NaH (88 mg, 60% in mineral oil,
2.2 mmol) and 6b (0.412 g, 3 mmol) under the catalysis of
Pd(OAc)2 (22 mg, 0.1 mmol) and dppe (45 mg, 1.1 mmol)
afforded a crude product, which was reacted with Ac2O
(0.306 g, 3.0 mmol) in the presence of Et3N (303 mg,
3.0 mmol) and DMAP (13 mg, 0.1 mmol) to afford 0.710 g
1
(the overall yield: 84%) of 3j: oil; H NMR (300 MHz,
CDCl3) d 7.40–7.20 (m, 5H), 7.04 (d, J¼8.1 Hz, 2H), 6.90
(d, J¼8.1 Hz, 2H), 6.25–6.18 (m, 1H), 5.78–5.68 (m, 2H),
3.64 (s, 3H), 3.61 (s, 3H), 3.18 (s, 2H), 2.60–2.48 (m, 2H),
2.30 (s, 3H), 2.12 (s, 3H); ESI-MS m/z (%) 447.3 (MþNaþ);
IR (neat) 1737, 1717, 1604, 990, 713 cm21. HRMS calcd
for C25H28O6Na: 447.1784. Found: 447.1778.
4.1.17. (1R p,4S p)-4-(10,10-Bis(methoxycarbonyl)-400-
methylphenylethyl)cyclohex-2-en-1-ol acetyl ester
(1R p,4S p-9b). The reaction of dimethyl 2-(40-methyl-
benzyl)malonate 4b (283 mg, 1.2 mmol) with NaH
(48 mg, 60% in mineral oil, 1.2 mmol) and cis-4-chloro-
cyclohex-2-en-1-ol acetyl ester 8 (175 mg, 1.0 mmol) under
the catalysis of Pd(OAc)2 (6 mg, 0.03 mmol) and PPh3
(25 mg, 1 mmol) afforded 355 mg (95%) of (1R p,4S p)-9b:
white solid; mp 87–888C (Et2O–hexanes); 1H NMR
(300 MHz, CDCl3) d 7.06 (d, J¼7.9 Hz, 2H), 7.00 (d,
J¼7.9 Hz, 2H), 6.07 (d, J¼10.0 Hz, 1H), 5.90–5.72 (m,
1H), 5.13 (bs, 1H), 3.66 (s, 3H), 3.65 (s, 3H), 3.32 (d,
J¼14.0 Hz, 1H), 3.22 (d, J¼14.0 Hz, 1H), 2.80–2.70 (m,
1H), 2.30 (s, 3H), 2.02 (s, 3H), 2.00–1.40 (m, 4H); 13C
4.1.14. N-Benzyl N-(4-acetoxyoct-2(E)-enyl)(40-methyl-
phenyl)sulfonyl amide (3k). The reaction of 7k (387 mg,
1.0 mmol) with Ac2O (112 mg, 1.1 mmol) in the presence
of Et3N (151 mg, 1.5 mmol) and DMAP (13 mg, 0.1 mmol)
1
afforded 410 mg (96%) of 3k: oil; H NMR (300 MHz,
CDCl3) d 7.67 (d, J¼8.6 Hz, 2H), 7.30–7.10 (m, 7H), 5.30–
5.10 (m, 2H), 4.97 (q, J¼6.1 Hz, 1H), 4.24 (s, 2H), 3.70–
3.60 (m, 2H), 2.37 (s, 3H), 1.91 (s, 3H), 1.50–1.00 (m, 6H),
0.80 (t, J¼7.3 Hz, 3H); ESI-MS m/z (%) 452.3 (MþNaþ);
IR (neat) 1737, 1599, 1161, 973, 733 cm21. Anal. calcd for
C24H31NO4S: C 67.10, H 7.27, N 3.26. Found: C 67.13, H
7.27, N 3.19.

6280
S. Ma, J. Zhang / Tetrahedron 59 (2003) 6273–6283
NMR (75.4 MHz, CDCl3) d 170.62, 170.58, 170.5, 136.6,
134.7, 132.8, 129.8, 128.9, 125.1, 65.8, 62.6, 52.1, 51.8,
39.3, 38.1, 27.8, 21.3, 21.0, 19.5; MS m/z (%) 315
(Mþ2CH3CO2, 9.06), 105 (100); IR (KBr) 1736, 1720.
Anal. calcd for C21H26O6: C 67.36, H 7.00. Found: C 67.30,
H 7.28.
J¼7.0 Hz, 2H), 7.60–7.50 (m, 1H), 7.50–7.40 (m, 2H),
7.30–7.18 (m, 3H), 7.18–7.08 (m, 2H), 6.17 (d, J¼10.1 Hz,
1H), 6.00–5.90 (m, 1H), 5.39 (s, 1H), 3.66 (s, 3H), 3.65 (s,
3H), 3.40 (d, J¼14.0 Hz, 1H), 3.28 (d, J¼14.0 Hz, 1H),
2.92–2.82 (m, 1H), 2.10–1.60 (m, 4H); 13C NMR
(75.4 MHz, CDCl3) d 170.6, 170.5, 165.9, 136.1, 135.0,
132.9, 130.6, 130.0, 129.5, 128.3, 128.2, 127.1, 125.1, 66.2,
62.8, 52.1, 51.9, 39.7, 38.6, 27.9, 19.6; MS m/z (%) 373
(7.08), 372 (7.04), 105 (100); IR (neat) 1730, 1710, 1603,
1271, 713 cm21. Anal. calcd for C25H26O6: C 71.07, H 6.20.
Found: C 71.11, H 6.25.
4.1.18. (1R p,4S p)-4-(10,10-Bis(methoxycarbonyl)-400-
methoxyphenylethyl)cyclohex-2-en-1-ol acetyl ester
(1R p,4S p-9c). The reaction of dimethyl 2-(40-methoxy-
benzyl)malonate 4c (302 mg, 1.2 mmol) with NaH (48 mg,
60% in mineral oil, 1.2 mmol) and cis-4-chlorocyclohex-2-
en-1-ol acetyl ester 8 (175 mg, 1.0 mmol) under the
catalysis of Pd(OAc)2 (5 mg, 0.02 mmol) and PPh3
(25 mg, 1 mmol) afforded 360 mg (92%) of (1R p,4S p)-9c:
white solid; mp 87–888C (Et2O–hexanes); 1H NMR
(300 MHz, CDCl3) d 7.03 (d, J¼8.5 Hz, 2H), 6.77 (d,
J¼8.5 Hz, 2H), 6.04 (d, J¼10.3 Hz, 1H), 5.90–5.80 (m,
1H), 5.11 (bs, 1H), 3.75 (s, 3H), 3.64 (s, 3H), 3.62 (s, 3H),
3.29 (d, J¼14.2 Hz, 1H), 3.18 (d, J¼14.2 Hz, 1H), 2.85–
2.75 (m, 1H), 2.03 (s, 3H), 2.00–1.50 (m, 4H); 13C NMR
(75.4 MHz, CDCl3) d 170.6, 170.5, 170.4, 158.5, 134.6,
131.0, 127.8, 125.1, 113.4, 65.7, 62.7, 55.0, 52.0, 51.8, 39.4,
37.7, 27.8, 21.2, 19.4; MS m/z (%) 390 (Mþ, 0.47), 121
(100); IR (KBr) 1738, 1720, 1620 cm21. Anal. calcd for
C21H26O7: C 64.60, H 6.71. Found: C 64.51, H 6.67.
4.1.21. (1R,4S)-4-(10,10-Bis(methoxycarbonyl)-400-methyl-
phenylethyl)cyclohex-2-en-1-ol benzolate (1R,4S-13b).
The reaction of 4b (96 mg, 0.4 mmol) with NaH (20 mg,
60%in mineral oil, 0.5 mmol) and 12 (97 mg, 0.3 mmol)
under the catalysis of [Pd(h3-C3H5)]2Cl2 (2.0 mg,
0.0055 mmol) and the chiral ligand Lp (20 mg,
0.025 mmol) afforded 119 mg (91%) of (1R,4S)-13b: oil;
96% ee (HPLC Conditions: Chiralcel AD Column
(0.46 cmf£25 cm), l¼254 nm, rate: 1 mL/min, eluent:
n-hexane/iso-propanol¼100:1.25); 1H NMR (300 MHz,
CDCl3) d 8.03 (d, J¼7.0 Hz, 2H), 7.60–7.50 (m, 1H),
7.46–7.38 (m, 2H), 7.10–6.90 (m, 4H), 6.09 (d, J¼10.4 Hz,
1H), 5.98–5.88 (m, 1H), 5.39 (bs, 1H), 3.68 (s, 3H), 3.63 (s,
3H), 3.36 (d, J¼14.0 Hz, 1H), 3.26 (d, J¼14.0 Hz, 1H),
2.90–2.80 (m, 1H), 2.31 (s, 3H), 2.10–1.60 (m, 4H); ESI-
MS m/z (%) 459.3 (MþNaþ); IR (neat) 1731, 1716, 1602,
1271, 713 cm21. HRMS calcd for C26H28O6Na: 459.1789.
Found: 459.1778.
4.1.19. (1R p,4S p)-4-(10,10-Dimethoxycarbonyl-300,500-
dimethylphenylethyl)cyclohex-2-en-1-ol acetyl ester
(1R p,4S p-9d). The reaction of dimethyl 2-(30,50-dimethyl-
benzyl)malonate 4d (275 mg, 1.1 mmol) with NaH (44 mg,
60% in mineral oil, 1.1 mmol) and cis-4-chlorocyclohex-2-
en-1-ol acetyl ester 8 (175 mg, 1.0 mmol) under the
catalysis of Pd(OAc)2 (6 mg, 0.03 mmol) and PPh3
(26 mg, 1 mmol) afforded 342 mg (88%) of (1R p,4S p)-9d:
mp 81–828C (Et2O–hexanes); 1H NMR (300 MHz, CDCl3)
d 6.84 (s, 1H), 6.70 (s, 2H), 6.04 (d, J¼10.2 Hz, 1H), 5.80–
5.70 (m, 1H), 5.12 (bs, 1H), 3.65 (s, 3H), 3.64 (s, 3H), 3.27
(d, J¼14.0 Hz, 1H), 3.18 (d, J¼14.0 Hz, 1H), 2.82–2.74
(m, 1H), 2.25 (s, 6H), 2.01 (s, 3H), 2.00–1.40 (m, 4H); 13C
NMR (75.4 MHz, CDCl3) d 170.6, 170.5, 170.4, 137.4,
135.7, 134.7, 128.6, 127.8, 125.0, 65.7, 62.5, 51.9, 51.7,
39.2, 38.2, 27.8, 21.24, 21.20, 19.5; MS m/z (%) 388 (Mþ,
0.47), 119 (100); IR (KBr) 1736, 1720, 1602 cm21. Anal.
calcd for C22H28O6: C 68.02, H 7.27. Found: C 68.01, H
7.25.
4.1.22. (1R,4S)-4-(10,10-Bis(methoxycarbonyl)-400-meth-
oxyphenylethyl)cyclohex-2-en-1-ol benzolate (1R,4S-
13c). The reaction of 4c (150 mg, 0.6 mmol) with NaH
(16 mg, 60% in mineral oil, 0.4 mmol) and 12 (97 mg,
0.3 mmol) under the catalysis of [Pd(h3-C3H5)]2Cl2
(2.0 mg, 0.0055 mmol) and the chiral ligand Lp (20 mg,
0.025 mmol) afforded 100 mg (74%) of (1R,4S)-13c: oil;
95% ee (HPLC Conditions: Chiralcel OJ Column
(0.46 cmf£25 cm), l¼254 nm, rate: 0.7 mL/min, eluent:
n-hexane/iso-propanol¼80:20); 1H NMR (300 MHz,
CDCl3) d 7.94 (d, J¼7.0 Hz, 2H), 7.56–7.44 (m, 1H),
7.40–7.30 (m, 2H), 7.01 (d, J¼6.7 Hz, 2H), 6.72 (d,
J¼6.7 Hz, 2H), 6.04 (d, J¼10.4 Hz, 1H), 5.90–5.80 (m,
1H), 5.31 (bs, 1H), 3.71 (s, 3H), 3.57 (s, 3H), 3.56 (s, 3H),
3.27 (d, J¼14.0 Hz, 1H), 3.16 (d, J¼14.0 Hz, 1H), 2.86–
2.76 (m, 1H), 2.04–1.58 (m, 4H); 13C NMR (75.4 MHz,
CDCl3) d 170.6, 170.5, 165.9, 158.5, 135.0, 132.8, 131.0,
130.5, 129.4, 128.3, 127.9, 125.0, 113.5, 66.2, 62.8, 55.1,
52.1, 51.8, 39.5, 37.7, 27.9, 19.5; MS m/z (%) 452 (Mþ,
4.1.20. Typical procedure for synthesis of (1R,4S)-13a–
d: (1R,4S)-4-(10,10-bis(methoxycarbonyl)-phenylethyl)-
cyclohex-2-en-1-ol benzolate (1R,4S-13a). Under Ar, 4a
(133 mg, 0.6 mmol) was added to a suspension of NaH
(24 mg, 60% in mineral oil, 0.6 mmol) in 5 mL of THF.
After being stirred for 15 min, the mixture was cooled to
08C, [Pd(h3-C3H5)]2Cl2 (1.8 mg, 0.005 mmol) and the
chiral ligand Lp (9.9 mg, 0.0125 mmol) were added. After
being stirred for 10 min, 12 (161 mg, 0.5 mmol) was added
and the reaction mixture was warmed up to rt. After being
stirred for 2 h, the mixture was concentrated and the residue
was purified by column chromatography on silica gel to
afford 177 mg (84%) of (1R,4S)-13a: oil; 98% ee (HPLC
Conditions: Chiralcel OJ Column (0.46 cmf£25 cm),
l¼254 nm, rate: 0.8 mL/min, eluent: n-hexane/iso-
0.95), 121 (100); IR (neat) 1730, 1716, 1613, 713 cm21
.
Anal. calcd for C26H28O7: C 69.01, H 6.24. Found: C 69.09,
H 6.23.
4.1.23. (1R,4S)-4-(10,10-Bis(methoxycarbonyl)-300,500-
dimethylphenylethyl)cyclohex-2-en-1-ol benzolate
(1R,4S-13d). The reaction of 4d (150 mg, 0.6 mmol) with
NaH (24 mg, 60% in mineral oil, 1.0 mmol) and 12 (97 mg,
0.3 mmol) under the catalysis of [Pd(h3-C3H5)]2Cl2
(2.0 mg, 0.0055 mmol) and the chiral ligand Lp (20 mg,
0.025 mmol) afforded 84 mg (64%) of (1R,4S)-13d: oil;
97% ee (HPLC Conditions: Chiralcel AD Column
(0.46 cmf£25 cm), l¼254 nm, rate: 0.7 mL/min, eluent:
1
propanol¼80:20); H NMR (300 MHz, CDCl3) d 8.03 (d,

S. Ma, J. Zhang / Tetrahedron 59 (2003) 6273–6283
6281
n-hexane/iso-propanol¼97:3); 1H NMR (300 MHz, CDCl3)
d 8.08–8.00 (m, 2H), 7.60–7.50 (m, 1H), 7.50–7.35 (m,
2H), 6.85 (s, 1H), 6.74 (s, 2H), 6.12 (d, J¼10.1 Hz, 1H),
5.97–5.90 (m, 1H), 5.39 (bs, 1H), 3.66 (s, 3H), 3.63 (s, 3H),
3.32 (d, J¼14.0 Hz, 1H), 3.22 (d, J¼14.0 Hz, 1H), 2.92–
2.82 (m, 1H), 2.25 (s, 6H), 2.15–1.60 (m, 4H); ESI-MS m/z
(%) 473.3 (MþNaþ); IR (neat) 1736, 1716, 1604, 1271,
990, 713 cm21. HRMS calcd for C27H30O6Na (MþNaþ):
473.1940. Found: 473.1943.
(181 mg, 0.5 mmol) afforded 103 mg (68%) of 10d: oil; 1H
NMR (300 MHz, CDCl3) d 6.82 (s, 2H), 5.71 (ddd, J¼17.3,
10.2, 6.2, 1 Hz), 4.97 (dd, J¼10.2, 1.5 Hz, 1H), 4.67 (dd,
J¼17.3, 1.5 Hz, 1H), 3.83–3.65 (m, 1H), 3.70 (s, 3H) 3.66
(s, 3H), 3.48 (d, J¼16.1 Hz, 1H), 3.00 (d, J¼16.1 Hz, 1H),
2.54 (dd, J¼13.8, 7.2 Hz, 1H), 2.37 (dd, J¼13.8, 4.4 Hz,
1H), 2.25 (s, 3H), 2.15 (s, 3H); MS m/z (%) 302 (Mþ,
99.14), 211 (100); IR (neat) 1730, 1620, 920 cm21. HRMS
calcd for C18H22O4: 302.1518. Found: 302.1538.
4.2. Typical procedure for intramolecular Friedel–
Crafts reaction
4.2.5. 1-Vinyl-3,3-bis(methoxycarbonyl)-1,2,3,4-tetra-
hydrophenanthrene (10e). The reaction of 3e (192 mg,
0.5 mmol) afforded 116 mg (72%) of 10e: oil; H NMR
1
4.2.1. 2,2-Bis(methoxycarbonyl)-4-vinyl-1,2,3,4-tetra-
hydronaphthalene (10a). 3a (167 mg, 0.5 mmol) in 1 mL
of TFA/HOAc (v/v¼3:1) was stirred at 708C under Ar
atmosphere for 14 h. The reaction mixture was quenched
with saturated NaCl (10 mL) and extracted with ether
(15£3 mL). The combined organic phase was successively
washed with water, saturated NaHCO3, and dried over
MgSO4. After evaporation, the residue was purified by flash
chromatography on silica gel (eluent: hexanes/ether¼5:1) to
afford 90 mg (66%) of 10a: oil; 1H NMR (300 MHz,
CDCl3) d 7.30–6.95 (m, 4H), 5.90–5.60 (m, 1H), 5.40–
5.10 (m, 2H), 3.75 (s, 3H), 3.69 (s, 3H), 3.60–3.40 (m, 1H),
3.41 (dd, J¼16.3 Hz, 1H), 3.18 (d, J¼16.3 Hz, 1H), 2.59
(ddd, J¼13.5, 6.0, 2.1 Hz, 1H), 2.03 (dd, J¼13.5, 11.1 Hz,
1H); MS m/z (%) 274 (Mþ, 0.31), 155 (100); IR (neat) 1737,
1639, 921 cm21. HRMS calcd for C16H18O4: 274.1205.
Found: 274.1217.
(300 MHz, CDCl3) d 7.95 (d, J¼8.3 Hz, 1H), 7.72 (d,
J¼8.0 Hz, 1H), 7.57 (d, J¼8.6 Hz, 1H), 7.50–7.35 (m, 2H),
7.24 (d, J¼8.6 Hz, 1H), 5.75–5.60 (m, 1H), 5.17 (d,
J¼15.0 Hz, 1H), 5.13 (d, J¼9.6 Hz, 1H), 3.87 (d,
J¼16.8 Hz, 1H), 3.72 (s, 3H), 3.68–3.54 (m, 1H), 3.59 (s,
3H), 3.35 (d, J¼16.8, 1 Hz), 2.60 (dd, J¼13.3, 5.9 Hz, 1H),
2.04 (dd, J¼13.3, 10.6 Hz, 1); MS m/z (%) 324 (Mþ, 22.33),
205 (100); IR (neat) 1732, 1610, 910, 820 cm21. HRMS
calcd for C20H20O4: 324.1362. Found: 324.1366.
4.2.6. 2,2-Bis(methoxycarbonyl)-4-methyl-4-vinyl-
1,2,3,4-tetrahydronaphthalene (10f). The reaction of 3f
1
(174 mg, 0.5 mmol) afforded 121 mg (84%) of 10f: oil; H
NMR (300 MHz, CDCl3) d 7.20–7.00 (m, 4H), 5.74 (dd,
J¼17.3, 10.5 Hz, 1H), 4.87 (d, J¼10.5 Hz, 1H), 4.48 (d,
J¼17.3 Hz, 1H), 3.65 (s, 3H), 3.54 (s, 3H), 3.36 (d,
J¼20.7 Hz, 1H), 2.97 (d, J¼20.7 Hz, 1H), 2.46 (d,
J¼14.2 Hz, 1H), 2.17 (d, J¼14.2 Hz, 1H), 1.33 (s, 3H);
MS m/z (%) 288 (Mþ, 16.75), 169 (100) IR (neat) 1737,
4.2.2. 2,2-Bis(methoxycarbonyl)-4-vinyl-6-methyl-
1,2,3,4-tetrahydronaphthalene (10b). The reaction of 3b
(174 mg, 0.5 mmol) afforded 95 mg (66%) of 10b: colorless
needles; mp 74–758C (Et2O–hexanes). 1H NMR
(300 MHz, CDCl3) d 6.95 (d, J¼7.6 Hz, 1H), 6.90 (s, 1H),
6.89 (d, J¼7.6 Hz, 1H), 5.68 (ddd, J¼18.6, 10.0, 8.8 Hz,
1H), 5.12 (d, J¼18.6 Hz, 1H), 5.11 (d, J¼10.0 Hz, 1H), 3.68
(s, 3H), 3.61 (s, 3H), 3.40–3.28 (m, 1H), 3.30 (d,
J¼16.2 Hz, 1H), 3.06 (d, J¼16.2 Hz, 1H), 2.51 (ddd,
J¼13.6, 6.1, 2.2 Hz, 1H), 2.20 (s, 3H), 1.93 (dd, J¼13.6,
11.1 Hz, 1H); 13C NMR (CDCl3, 75.4 MHz) d 172.1, 171.2,
141.1, 135.8, 135.7, 130.0, 128.9, 128.6, 127.4, 116.5,
53.41, 52.75, 52.65, 41.26, 35.03, 34.63, 21.02; MS m/z (%)
288 (Mþ, 2.12), 169 (100); IR (neat) 1748, 1725, 1640, 929,
815 cm21. Anal. calcd for C17H20O4: C 70.81, H 6.99.
Found: C 70.95, H 7.08.
1635, 919, 762 cm21
288.1362. Found: 288.1365.
. HRMS calcd for C17H20O4:
4.2.7. 2,2-Bis(methoxycarbonyl)-4,6-dimethyl-4-vinyl-
1,2,3,4-tetrahydronaphthalene (10g). The reaction of 3g
(181 mg, 0.5 mmol) afforded 129 mg (85%) of 10g: oil; 1H
NMR (300 MHz, CDCl3) d 7.20–6.90 (m, 3H), 5.82 (dd,
J¼17.1, 10.4 Hz), 4.95 (d, J¼10.4 Hz, 1H), 4.60 (d,
J¼17.1 Hz, 1H), 3.73 (s, 3H), 3.61 (s, 3H), 3.32 (d,
J¼16.2 Hz, 1H), 3.08 (d, J¼16.2 Hz, 1H), 2.51 (d,
J¼14.0 Hz, 1H), 2.30 (s, 3H), 2.22 (d, J¼14.0 Hz, 1H),
1.26 (s, 3H); MS m/z (%) 364 (Mþ, 35.76), 245 (100); IR
(neat) 1746, 1732, 1635, 918, 826 cm21. Anal. calcd for
C18H22O4: C 71.50, H 7.33. Found: C 71.60, H 7.36.
4.2.8. 2,2-Bis(methoxycarbonyl)-4-hex-10(E)-enyl-
1,2,3,4-tetrahydronaphthalene (10h). The reaction of 3h
(190 mg, 0.487 mmol) afforded 136 mg (85%) of 10h: oil;
1H NMR (300 MHz, CDCl3) d 7.10–6.90 (m, 4H), 5.56 (dt,
J¼15.1, 6.7 Hz, 1H), 5.29 (dd, J¼15.1, 8.6 Hz, 1H), 3.68 (s,
3H), 3.61 (s, 3H), 3.40–3.34 (m, 1H), 3.34 (dd, J¼16.3 Hz,
1H), 3.10 (d, J¼16.3 Hz, 1H), 2.50 (ddd, J¼13.5, 6.0,
2.2 Hz, 1H), 1.99 (q, J¼6.7 Hz, 2H), 1.92 (dd, J¼13.5,
11.4 Hz, 2H), 1.34–1.10 (m, 4H), 0.85 (t, J¼7.0 Hz, 3H);
MS m/z (%) 330 (Mþ, 3.16), 141 (100); IR (neat) 1737,
4.2.3. 2,2-Bis(methoxycarbonyl)-4-vinyl-6-methoxy-
1,2,3,4-tetrahydronaphthalene (10c). The reaction of 3c
(182 mg, 0.5 mmol) afforded 100 mg (66%) of 10c: white
1
solid; mp 57–588C (Et2O–hexanes). H NMR (300 MHz,
CDCl3) d 7.04 (d, J¼9.2 Hz, 1H), 6.75–6.65 (m, 2H), 5.73
(ddd, J¼18.5, 9.8, 8.9 Hz, 1H), 5.23–5.15 (m, 2H), 3.74 (s,
6H), 3.70 (s, 3H), 3.58–3.44 (m, 1H), 3.34 (d, J¼16.0,
1.9 Hz, 1H), 3.10 (d, J¼16.0 Hz, 1H), 2.57 (ddd, J¼13.5,
6.1, 2.2 Hz, 1H), 1.98 (dd, J¼13.5, 11.1 Hz, 1H); MS m/z
(%) 304 (Mþ, 7.35), 185 (100); IR (KBr) 1740, 1720, 1620,
910, 805 cm21. HRMS calcd for C17H20O5: 304.1311.
Found: 304.1341.
1604, 971, 744 cm21
330.1831. Found: 330.1864.
. HRMS calcd for C20H26O4:
4.2.9. 2,2-Bis(methoxycarbonyl)-6-methyl-4-hex-10(E)-
enyl-1,2,3,4-tetrahydronaphthalene (10i). The reaction
of 1i (180 mg, 0.446 mmol) afforded 152 mg (99%) of 10i:
4.2.4. 2,2-Bis(methoxycarbonyl)-4-vinyl-5,7-dimethyl-
1,2,3,4-tetrahydronaphthalene (10d). The reaction of 3d

6282
S. Ma, J. Zhang / Tetrahedron 59 (2003) 6273–6283
oil; 1H NMR (300 MHz, CDCl3) d 7.00–6.85 (m, 3H), 5.54
(dt, J¼15.1, 6.7 Hz, 1H), 5.26 (dd, J¼15.1, 8.7 Hz, 1H),
3.68 (s, 3H), 3.61 (s, 3H), 3.40–3.30 (m, 1H), 3.30 (dd,
J¼16.0, 1.9 Hz, 1H), 3.05 (d, J¼16.0 Hz, 1H), 2.59 (ddd,
J¼13.6, 6.0, 2.2 Hz, 1H), 2.20 (s, 3H), 2.02 (q, J¼6.7 Hz,
2H), 1.89 (dd, J¼13.6, 11.3 Hz, 1H), 1.30–1.10 (m, 4H),
0.85 (t, J¼7.2 Hz, 3H); MS m/z 344 (Mþ, 38.87), 225 (100);
IR (neat) 1737, 1604, 971, 744 cm21. HRMS calcd for
C21H28O4: 344.1988. Found: 344.1966.
4.2.14. (4bR p,8aS p)-3-Methyl-9,9-bis(methoxycar-
bonyl)-4b,7,8,8a,9,10-hexahydro-phenanthrene (4bR p,8-
aS p-11b). The reaction of (1R p,4S p)-9b (38 mg, 0.1 mmol)
in TFA/AcOH (3:1) afforded 31 mg (99%) of (4bR p,8aS p)-
1
11b: white solid; mp 87–888C (Et2O–hexanes); H NMR
(300 MHz, CDCl3) d 7.30–6.85 (m, 3H), 6.40–6.20 (m,
1H), 5.95–5.75 (m, 1H), 3.78 (s, 3H), 3.75–3.65 (m, 1H),
3.63 (s, 3H), 3.50–3.40 (m, 2H), 3.10–2.85 (m, 1H), 2.27
(s, 3H), 2.25–1.85 (m, 2H), 1.70–1.30 (m, 2H); 13C NMR
(75.4 MHz, CDCl3) d 171.1, 170.8, 137.3, 136.0, 129.0,
128.8, 128.6, 128.3, 127.3, 126.6, 57.8, 52.82, 52.77, 37.1,
35.5, 30.0, 25.6, 21.5, 21.2; MS m/z (%) 314 (Mþ, 6.77), 195
(100); IR (neat) 1736, 1610, 1500, 1196, 1180 cm21. HRMS
calcd for C19H22O4: 314.1518. Found: 314.1517.
4.2.10. 2,2-Bis(methoxycarbonyl)-4-(20-phenylethenyl)-
6-methyl-1,2,3,4-tetrahydronaphthalene
(10j).
The
reaction of 3j (212 mg, 0.5 mmol) afforded 171 mg (94%)
of 10j: white solid; mp 90–918C (Et2O–hexanes); 1H NMR
(300 MHz, CDCl3) d 7.46–7.40 (m, 2H), 7.40–7.28 (m,
2H), 7.26–7.20 (m, 1H), 7.16–6.90 (m, 3H), 6.58 (d,
J¼15.6 Hz, 1H), 6.17 (dd, J¼15.6, 8.9 Hz, 1H), 3.76 (s,
3H), 3.73 (s, 3H), 3.75–3.60 (m, 1H), 3.43 (d, J¼16.2 Hz,
1H), 3.21 (d, J¼16.2 Hz, 1H), 2.68 (ddd, J¼13.6, 6.1,
2.1 Hz, 1H), 2.27 (s, 3H), 2.12 (dd, J¼13.6, 11.0 Hz, 1H),;
MS m/z (%) 302 (Mþ, 40.94), 242 (100); IR (neat) 1745,
1728, 1614, 971 cm21. Anal. calcd for C23H24O4: C 75.80,
H 6.64. Found: C 75.88, H 6.86.
4.2.15. (4bR,8aS)-3-Methyl-9,9-bis(methoxycarbonyl)-
4b,7,8,8a,9,10-hexahydro-phenanthrene (4bR,8aS-11b).
The reaction of (1R,4S)-13b (60 mg, 96% ee) in TFA/
AcOH (3:1) afforded 42 mg (97%) of (4bR,8aS)-11b: 98%
ee
(HPLC
Conditions:
Chiralcel
OJ
Column
(0.46 cmf£25 cm), l¼254 nm, rate: 0.7 mL/min eluent:
n-hexane/iso-propanol¼80:20).
4.2.16. (4bR p,8aS p)-3-Methoxy-9,9-bis(methoxycar-
bonyl)-4b,7,8,8a,9,10-hexahydrophenanthrene (4bR p,8-
aS p-11c). The reaction of (1R p,4S p)-9c (100 mg,
0.256 mmol) afforded 80 mg (95%) of (4bR p,8aS p)-11c:
white solid; mp 88–898C (Et2O–hexanes). 1H NMR
(300 MHz, CDCl3) d 7.03 (d, J¼8.4 Hz, 1H), 6.78 (s, 1H),
6.67 (d, J¼8.4 Hz, 1H), 6.24–6.15 (m, 1H), 5.85–5.75 (m,
1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.72–3.65 (m, 1H), 3.62 (s,
3H), 3.34 (d, J¼17.0 Hz, 1H), 3.19 (d, J¼17.0 Hz, 1H),
2.90–2.80 (m, 1H), 2.30–1.90 (m, 2H), 1.50–1.20 (m, 2H);
MS m/z (%) 330 (Mþ, 8.88), 211 (100); IR (KBr) 1730,
1610, 1500, 1560, 1260, 1230, 1196, 1180 cm21. Anal.
calcd for C19H22O5: C, 69.07, H, 6.71. Found: C, 68.91, H,
6.84.
4.2.11. 4-Hex-10-enyl-2-(p-methylphenylsulfonyl)-
1,2,3,4-tetrahydroisoquinlone (10k). The reaction of 3k
(170 mg, 0.396 mmol) afforded 135 mg (92%) of 10k: oil;
1H NMR (300 MHz, CDCl3) d 7.53 (d, J¼8.0 Hz, 2H), 7.13
(d, J¼8.0 Hz, 2H), 6.99–6.88 (m, 3H), 6.85–6.76 (m, 1H),
5.45 (dt, J¼15.3, 6.7 Hz, 1H), 5.18 (dd, J¼15.3, 8.6 Hz,
1H), 4.14 (d, J¼15.3 Hz, 1H), 3.92 (d, J¼15.3 Hz, 1H),
3.46–3.36 (m, 1H), 3.32 (dd, J¼11.0, 4.9 Hz, 1H), 2.77 (dd,
J¼11.0, 7.3 Hz, 1H), 2.23 (s, 3H), 1.90–1.76 (m, 2H),
1.24–1.02 (m, 4H), 0.71 (t, J¼7.3 Hz, 3H); MS m/z 370
(Mþþ1, 10.74), 129 (100); IR (neat) 3208, 1598, 970, 958,
814 cm21. Anal. calcd for C22H27NO2S: C 71.51, H 7.36, N
3.79. Found: C 71.51, H 7.49, N 3.89.
4.2.12. (4bR p,8aS p)-9,9-Bis(methoxycarbonyl)-4b,7,8,
8a,9,10-hexahydro-phenanthrene (4bR p,8aS p-11a). The
reaction of (1R p,4S p)-9a (108 mg, 0.3 mmol) afforded
87 mg (97%) of (4bR p,8aS p)-11a: white solid; mp 77–
788C (Et2O–hexanes); 1H NMR (400 MHz, CDCl3) d 7.26
(d, J¼7.6 Hz, 1H), 7.18–7.05 (m, 3H), 6.26–6.20 (m, 1H),
5.85–5.75 (m, 1H), 3.78 (s, 3H), 3.70 (bs, 1H), 3.62 (s, 3H),
3.41 (d, J¼17.2 Hz, 1H), 3.29 (d, J¼17.2 Hz, 1H), 2.89 (dd,
J¼12.3, 4.7 Hz, 1H), 2.26–2.00 (m, 2H), 1.55–1.20 (m,
4.2.17. (4bR,8aS)-3-Methoxy-9,9-bis(methoxycarbonyl)-
4b,7,8,8a,9,10-hexahydro-phenanthrene (4bR,8aS-11c).
The reaction of (1S,4R)-13c (80 mg, 0.177 mmol, 95% ee)
in TFA/AcOH (3:1) afforded 54 mg (93%) of (4bR,8aS)-
11c. 95% ee (HPLC Conditions: Chiralcel AD Column
(0.46 cmf£25 cm), l¼254 nm, rate: 0.7 mL/min, eluent:
n-hexane/iso-propanol¼100:2).
4.2.18. (4bR p,8aS p)-1,4-Dimethyl-9,9-bis(methoxy-
carbonyl)-4b,7,8,8a,9,10-hexahydro-phenanthrene
(4bR p,8aS p-11d). The reaction of (1R p,4S p)-9d (64 mg) in
TFA/AcOH (3:1) afforded 53 mg (98%) of a mixture of
(4bR p,8aS p)-11d (cis) and trans isomer (cis/trans.90:10).
1
2H); H NMR (75.4 MHz, CDCl3) d 170.9, 170.7, 137.4,
131.6, 129.0, 128.7, 127.7, 127.2, 126.5, 125.6, 57.6, 52.8,
52.7, 36.9, 35.4, 30.3, 25.5, 21.3; MS m/z (%) 300 (Mþ,
6.28), 181 (100); IR (KBr) 1730, 1610, 1500, 760 cm21
HRMS calcd for C18H20O4: 300.1362. Found: 300.1337.
.
1
(4bR p,8aS p)-11d: oil; H NMR (300 MHz, CDCl3) d 6.86
(s, 1H), 6.78 (s, 1H), 5.90–5.80 (m, 2H), 3.90 (bs, 1H), 3.80
(s, 3H), 3.55 (s, 3H), 3.36 (d, J¼14.8 Hz, 1H), 3.18 (d,
J¼17.2 Hz, 1H), 3.12–3.05 (m, 1H), 2.35 (s, 3H), 2.36 (s,
3H), 2.20–2.00 (m, 2H), 1.30–1.05 (m, 2H); MS m/z (%)
The reaction of (1R p,4R p)-9a (108 mg, 0.3 mmol) afforded
81 mg (90%) of (4bR p,8aS p)-11a.
4.2.13. (4bR,8aS)-9,9-Bis(methoxycarbonyl)-4b,7,8,
8a,9,10-hexahydro-phenanthrene (4bR,8aS-11a). The
reaction of (1R,4S)-13a (80 mg, 98%ee) in TFA/AcOH
(3:1) afforded 56 mg (99%) of (4bR,8aS)-11a: 98% ee
328 (Mþ, 30.39), 209 (100); IR, 1730, 1610, 1250 cm21
HRMS calcd for C20H24O4 328.1675. Found: 328.1654.
.
4.2.19. (4bR,8aS)-1,4-Dimethyl-9,9-bis(methoxycar-
bonyl)-4b,7,8,8a,9,10-hexahydro-phenanthrene
(4bR,8aS-11d). The reaction of (1S,4R)-13d (80 mg, 97%
ee) in TFA/AcOH (3:1) afforded 56 mg (97%) of a mixture
(HPLC
Conditions:
Chiralcel
AD
Column
(0.46 cmf£25 cm), l¼254 nm, rate: 0.7 mL/min, eluent:
n-hexane/iso-propanol¼100:2).

S. Ma, J. Zhang / Tetrahedron 59 (2003) 6273–6283
6283
T.; Mitsuhashi, K.; Nozawa, T.; Kurobe, A.; Futsukaichi, O.
J. Med. Chem. 1976, 19, 803–806.
of (4bR,8aS)-11d (cis) and trans isomer (cis/trans.90:10).
(4bR,8aS)-11d: 97% ee (HPLC conditions: Chiralcel OJ
Column (0.46 cmf£25 cm), l¼254 nm, rate: 0.7 mL/min,
eluent: n-hexane/iso-propanol¼95:5).
2. For radical cyclization, see: (a) Citterio, A.; Fancelli, D.; Finzi,
C.; Pesce, L.; Santi, R. J. Org. Chem. 1989, 54, 2713–2718.
(b) Shundo, R.; Nishiguchi, I.; Matsubara, Y.; Hirashima, T.
Tetrahedron 1991, 47, 831–840.
4.3. Synthesis of 14 and its annulation to 10a
3. For carbopalladation, see: (a) Takemoto, T.; Sodeoka, M.;
Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115,
8477–8478. (b) Gaudin, J. M. Tetrahedron Lett. 1991, 32,
6113–6116. (c) O’connor, B.; Zhang, Y.-T.; Negishi, E.; Luo,
F.-T.; Cheng, J.-W. Tetrahedron Lett. 1988, 29, 3903–3906.
(d) Wang, R.-T.; Chou, F.-L.; Luo, F.-T. J. Org. Chem. 1990,
55, 4846–4849.
4. For Pd-catalyzed cyclization of 2-(60-trimethylsilyl-40-hex-
enyl)phenyl iodide, see: Tietze, L. F.; Schimpf, R. Angew.
Chem. Int. Ed. Engl. 1994, 33, 1089–1091.
4.3.1. Dimethyl 2-(40-hydroxy-but-2-enyl)-2-benzylmalo-
nate (14). A solution of dimethyl 2-benzyl-malonate 4a
(3.330 g, 15 mmol) in THF was treated with NaH (60%,
0.600 g, 15 mmol) for 10 min under Ar. 4-Chloro-but-2-en-
1-ol (1.704 g, 16 mmol) in THF was added and the mixture
was stirred for overnight. After the usual work-up, the
residue was purified through column chromatography on
1
silica gel afforded 3.466 g (79%) of 14: liquid; H NMR
(300 MHz, CDCl3) d 7.32–7.18 (m, 3H), 7.10–7.01 (m,
2H), 5.76–5.60 (m, 2H), 4.10 (d, J¼5.1 Hz, 2H), 3.71 (s,
6H), 3.22 (s, 2H), 2.54 (d, J¼6.0 Hz, 2H); MS m/z (%) 275
(Mþ2OH, 40.63), 91 (100); IR (neat) 3429, 1735, 974,
703 cm21. Anal. calcd for C16H20O5: C 65.74, H 6.90.
Found: C 65.58, H 6.64.
5. For acylpalladation, see: (a) Tour, J. M.; Negishi, E. J. Am.
˙
Chem. Soc. 1985, 107, 8289–8291. (b) Negishi, E.-I.; Coperet,
C.; Ma, S.; Mita, T.; Sugihara, T.; Tour, J. M. J. Am. Chem.
Soc. 1996, 118, 5904–5918.
6. (a) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S.
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 293–339 Chapter
1.8. (b) Roberts, R. M.; Khalaf, A. A. Friedel–Crafts
Alklation Chemistry. A Centry of Discovery; Marcel Dekker:
New York, 1984. (c) Friedel–Crafts and Related Reactions;
Olah, G. A., Ed.; Wiley: New York, 19631965; Vols. 1–4.
7. For acid-catalyzed cyclization of 4-phenyl-1-alkanols at a very
high temperature yielding benzocyclic compounds with a low
selectivity, see: (a) Khalaf, A. A.; Roberts, R. M. J. Org.
Chem. 1969, 34, 3571–3574. (b) Khalaf, A. A.; Roberts, R. M.
J. Org. Chem. 1972, 37, 4227–4235.
The reaction of 14 (146 mg, 0.5 mmol) in TFA/AcOH (3:1)
afforded 54 mg (39%) of 10a.
The reaction of 14 (146 mg, 0.5 mmol) in TFA:(CF3CO)2O
(4:1) afforded 72 mg (53%) of 10a.
Acknowledgements
Financial support from the Major State Basic Research
Development Program (Grant G2000077500), the National
Natural Science Foundation of China, Chinese Academy of
Sciences, Shanghai Municipal Committee of Science and
Technology are greatly appreciated. Shengming Ma is the
recipient of 1999 Qiu Shi Award for Young Scientific
Workers issued by Hong Kong Qiu Shi Foundation of
Science and Technology (1999–2003).
8. Ma, S.; Zhang, J. Tetrahedron Lett. 2002, 43, 3435–3438.
9. Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1993, 115,
12491–12509.
10. Babler, J. H.; Buttner, W. J. Tetrahedron Lett. 1976, 239–242.
11. Colobert, F.; Genet, J. P. Tetrahedron Lett. 1985, 26,
2779–2782.
¨ ¨
12. Backvall, J. E.; Nystrom, J. E.; Nordberg, R. E. J. Am. Chem.
Soc. 1985, 107, 3676–3686.
13. Crystal data for (4bR p,8aS p)-11c: C19H22O5, Mw¼330.37,
triclinic, space group P-1, m(Mo Ka) 0.093 mm21, R1¼
˚
˚
References
0.0659, wR1¼0.1408, a¼9.721(5) A, b¼13.201(7) A, c¼
˚
13.494(7) A, a¼90.000(8)8, b¼80.202(10)8, g¼90.000(9)8,
3
˚
1. (a) Kuramoto, M.; Yamada, K.; Shikano, M.; Yazawa, K.;
Arimoto, H.; Okamura, T.; Uemura, D. Chem. Lett. 1997,
885–886. (b) Dictionary of Natural Products, Chapman &
Hall, 1994, Vol. 1; pp 812–813. (c) Palmer, D. C.; Strauss,
M. J. Chem. Rev. 1977, 77, 1–92. (d) Shiotani, S.; Kometani,
V¼1706.5(15) A , T¼293(2) K, Z¼4, reflections collected/
unique 7551/6044 (Rint¼0.0846), no observation (I.2.0s(I))
2647, parameters 576 CCDC 178671.
14. Trost, B. M.; Tanimori, S.; Dunn, P. T. J. Am. Chem. Soc.
1997, 119, 2735–2736.