Total syntheses of (±)-axamide-1 and (±)-axisonitrile-1 via 6-Exo-dig radical cyclization

Article abstract of DOI:10.1021/jo802672t

Total syntheses of (±)-axamide-1 (1) and (±)-axisonitrile-1 (2) were accomplished by using the α-carbonyl radical cyclization as the key step. Thienylcyanocuprate 24 mediated conjugated addition of 5-(trimethylsilyl)-4-pentynylmagnesium chloride (23) to 3

Full text of DOI:10.1021/jo802672t

Total Syntheses of (()-Axamide-1 and (()-Axisonitrile-1 via
6-Exo-dig Radical Cyclization
Yuan-Liang Kuo, Manickam Dhanasekaran, and Chin-Kang Sha*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 300, Taiwan, ROC
cksha@mx.nthu.edu.tw
ReceiVed December 5, 2008
Total syntheses of (()-axamide-1 (1) and (()-axisonitrile-1 (2) were accomplished by using the R-carbonyl
radical cyclization as the key step. Thienylcyanocuprate 24 mediated conjugated addition of 5-(trimeth-
ylsilyl)-4-pentynylmagnesium chloride (23) to 3-methylcyclopenten-1-one (22) and subsequent treatment
with TMSCl afforded silyl enol ether 25. Iodination of 25 with NaI and m-CPBA afforded R-iodoketone
21. 6-Exo-dig radical cyclization of 21 and subsequent desilylation furnished hydroindane derivative 20.
Bicyclic ketone 20 was converted to nitrile 19 via a three-step sequence involving Luche reduction,
mesylation, and SN2 substitution reaction. Finally, tandem alkylation-reduction on nitrile 19 and
subsequent functional group transformations afforded (()-axamide-1 (1) and (()-axisonitrile-1 (2).
Introduction
interesting biological properties coupled with unusual structural
features of these sesquiterpenoids have attracted considerable
attention from synthetic chemists.
(+)-Axamide-1 (1), (+)-axisonitrile-1 (2), and (+)-axisothio-
cyanate-1 (3) are representatives of a small family of sesquit-
erpenoids isolated from the marine sponge Axinella cannabina.1-7
The structural characteristics of these sesquiterpenoids are a cis-
fused hexahydroindane framework with four contiguous ste-
reogenic centers and a functionalized side chain containing a
stereogenic carbon (Figure 1). In 1973, Cafieri and co-workers1
first isolated axane-type sesquiterpenoids. Later the absolute
stereochemistry3,7 of axane sesquiterpenoids was determined on
the basis of an X-ray crystal structure analysis. Axane sesquit-
erpenoids displayed a modest number of biological properties.
Axisonitrile-1 (2) even at low concentration (8 ppm) is a potent
ichthyotoxin toward the marine damselfish Chromis chromis
and the fresh water gold fish Carassius carassius.6,8 The
In 1987, Piers et al. reported the first total syntheses of
racemic axamide-1 (1) and axisonitrile-1 (2) employing a novel
annulation sequence as the key step to assemble the perhy-
droindane skeleton.9 In a series of accounts, Hart and co-workers
reported the total syntheses of axane sesquiterpenoids using an
intramolecular conjugate addition reaction as the key step.10 The
first asymmetric total syntheses of the antipodes of the natural
products (+)-axamide-4 and (+)-axisonitrile-4 have also been
described.11 In all of these synthetic efforts, we found that six-
membered ring compounds were used as starting materials to
construct the central perhydroindane skeleton.
We envisioned that our methodology, radical cyclization of
an R-iodoketone,12 could be applied toward the total synthesis
of the axane family of natural products. Herein we describe our
concise total syntheses of axamide-1 (1) and axisonitrile-1 (2)
via the radical cyclization of R-iodoketone.
(1) Cafieri, F.; Fattorusso, E.; Magno, S.; Santacroce, C.; Sica, E. Tetrahedron
1973, 29, 4259–4262.
(2) Fattorusso, E.; Magno, S.; Mayol, L.; Santacroce, C.; Sica, D. Tetrahedron
1974, 30, 3911–3913.
(3) Adinolfi, M.; De Napoli, L.; Di Blasio, B.; Iengo, A.; Pedone, C.;
Santacroce, C. Tetrahedron Lett. 1977, 18, 2815–2816.
(4) Iengo, A.; Mayol, L.; Santacroce, C. Experentia 1977, 33, 11–12.
(5) Iengo, A.; Santacroce, C.; Sodano, G. Experentia 1979, 35, 10–11.
(6) Cimino, G.; De Rosa, S.; De Stefano, S.; Sodano, G. Comp. Biochem.
Physiol. 1982, 73B, 471–474.
(7) Fattorusso, E.; Magno, S.; Mayol, L.; Santacroce, C.; Sica, D. Tetrahedron
1975, 31, 269–270.
(8) Pawlik, J. R. Chem. ReV. 1993, 93, 1911–1922.
(9) (a) Piers, E.; Yeung, B. W. A. Can. J. Chem. 1986, 64, 2475–2476. (b)
Piers, E.; Yeung, B. W. A.; Rettig, S. J. Tetrahedron 1987, 43, 5521–4535.
(10) (a) Guevel, A.-C.; Hart, D. J. Synlett 1994, 169–170. (b) Hart, D. J.;
Lai, C.-S. Synlett 1989, 49–51. (c) Chenera, B.; Chuang, C.-P.; Hart, D. J.; Lai,
C.-S. J. Org. Chem. 1992, 57, 2018–2029. (d) Guevel, A.-C.; Hart, D. J. J. Org.
Chem. 1996, 61, 473–479.
(11) Ohkubo, T.; Akino, H.; Asaoka, M.; Takei, H. Tetrahedron Lett. 1995,
36, 3365–3368.
10.1021/jo802672t CCC: $40.75
Published on Web 01/27/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2033–2038 2033

Kuo et al.
FIGURE 1. Structures of axane sesquiterpenoids.
SCHEME 1. Retrosynthetic Analysis Based on the 5-Exo-dig Radical Cyclization
SCHEME 2. Synthesis of cis-Fused Hydroindane 9
SCHEME 3. Synthesis of Hydroindane 17
Results and Discussion
ketone 13 with trifluoroacetic acid afforded ketone 9 along with
a small amount of the isomeric enone 14 (Scheme 2).
We envisaged that axamide-1 (1) and axisonitrile-1 (2) could
be obtained from ketone 10. Compound 10 could be derived
from hexahyroindanone 9. Compound 9 would be readily
available via the 5-exo-dig radical cyclization of iodoketone 8.
Iodoketone 8 would be prepared by using our method starting
from 3-methylcyclohexanone, Scheme 1.
CuI-mediated conjugated addition of 4-(trimethylsilyl)-3-
butynylmagnesium chloride (11) to 3-methylcyclohex-2-enone
(7) followed by trapping the resulting enolate with chlorotri-
methylsilane afforded the TMS-enol ether 12. As compound
12 was labile to the silica gel chromatography, crude compound
12 was used immediately for the next step. Treatment of 12
with a mixture of NaI and m-CPBA furnished unstable iodoke-
tone 8 as a mixture of diastereomers. Photolysis with a sunlamp
in the presence of hexabutylditin, R-iodoketone 8 underwent
5-exo-dig radical cyclization13,19 smoothly. Subsequent reduction
with tributyltin hydride and AIBN afforded vinylsilane ketone
13 as a mixture of E/Z isomers in 85% yield. Desilylation of
Hydroboration of ketone 9 with a solution of BH3 ·SMe2
complex in THF followed by oxidation with basic H2O2
produced a mixture of diastereomeric diol 15.12b To protect the
primary alcohol, the mixture of diastereomeric diol 15 was
treated with Ac2O in pyridine14 to furnish acetate 16 with
undesired stereochemistry along with a small amount of a
mixture of diacetates identified as side products. The stereo-
chemistry of acetate 16 was assigned on the basis of NOE
experiment. Oxidation of the alcohol 16 with PCC15 afforded
ketone 17 (Scheme 3). In an effort to attain the requisite
stereochemistry at C2 we examined various conditions for
hydroboration and acetylation reactions. But we found always
the undesired acetate 16 as the major product. Thus, the
unsuccessful establishment of stereochemistry stopped us from
proceeding with this approach toward the total syntheses.
Having unsuccessful attempts via the 5-exo-dig cyclization,
we turned our attention toward an alternative protocol, the 6-exo-
2034 J. Org. Chem. Vol. 74, No. 5, 2009

Syntheses of (()-Axamide-1 and (()-Axisonitrile-1
SCHEME 4. Retrosynthetic Analysis Based on 6-Exo-dig Radical Cyclization
SCHEME 5. Synthesis of cis-Fused Hydroindane 20
SCHEME 6. Synthesis of Nitrile 19
dig cyclization. The retrosynthetic analysis for the revised
strategy is outlined in Scheme 4. We envisioned that these
sesquiterpenoids could be obtained from Piers’s intermediate
18.9 The requisite primary amine 18 might be synthesized from
nitrile 19 according to Hall’s tandem alkylation-reduction
procedure.17 Nitrile 19 could be derived from ketone 20 by a
sequence of synthetic transformations. Bicyclic ketone 20 would
be accessible through the 6-exo-dig radical cyclization followed
by desilylation. Radical precursor 21 could be prepared accord-
ing to our method from readily available 3-methylcyclopenten-
1-one (22).
Our synthetic efforts commenced with readily available
3-methylcyclopenten-1-one (22). Lithium 2-thienylcyanocuprate
(24) mediated conjugated addition of 5-(trimethylsilyl)-4-
pentynylmagnesium chloride (23) to 3-methylcyclopenten-1-
one (22)18 followed by trapping the resulting enolate with
trimethylchlorosilane yielded trimethylsilyl enol ether 25 (Scheme
5). Compound 25 was labile to silica gel chromatography and
was used without purification for the next step. Thus, the crude
product 25 was treated with a mixture of NaI and m-CPBA in
THF to furnish the pivotal but rather unstable R-iodoketone 21
as a mixture of diastereoisomers. Isolation of these diastereoi-
somers and the assignments of the stereochemistry are incon-
sequential with respect to the subsequent synthetic transformations.
Irradiation of R-iodoketone 21 with a sunlamp in the presence
of hexabutylditin effected iodine atom transfer cyclization.19
Subsequent reduction with tributyltin hydride and AIBN af-
forded vinylsilane ketone 26 as a mixture of E/Z isomers (E/Z
) 1/1.3)20 along with the reduced product 27. Exposure of the
isomeric mixture of 26 to CF3COOH in CH2Cl2 afforded bicyclic
ketone 20 in good yield along with a small amount of isomeric
enone 28 as the side product. The stereochemistry of 20 was
assigned on the basis of the NOE experiments. In the literature,
(12) (a) Sha, C.-K.; Yang, J.-J.; Jean, T.-S. J. Org. Chem. 1987, 52, 3919–
3920. (b) Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-H.; Liao,
F.-L.; Wang, S.-L. J. Am. Chem. Soc. 1997, 119, 4130–4135. (c) Sha, C.-K.;
Santhosh, K. C.; Lih, S.-H. J. Org. Chem. 1998, 63, 2699–2704. (d) Sha, C.-K.;
Lee, F.-K.; Chang, C.-J. J. Am. Chem. Soc. 1999, 121, 9875–9876. (e) Sha,
C.-K.; Ho, W.-Y. Chem. Commun. 1998, 24, 2709–2710. (f) Sha, C.-K.; Liao,
H.-W.; Cheng, P.-C.; Yen, S.-C. J. Org. Chem. 2003, 68, 8704–8707. (g) Jiang,
C.-H.; Bhattacharyya, A.; Sha, C.-K. Org. Lett. 2007, 9, 3241–3243. (h) Liu,
K.-M.; Chau, C.-M.; Sha, C.-K. Chem. Commun. 2008, 1, 91–92.
(13) (a) Sha, C.-K.; Jean, T.-S.; Wang, D.-C. Tetrahedron Lett. 1990, 31,
3475–3748. (b) Lin, H.-H.; Chang, W.-S.; Luo, S.-Y.; Sha, C.-K. Org. Lett.
2004, 6, 3289–3292.
(14) Zhdanov, R. I.; Zhemodarova, S. M. Synthesis 1975, 222–245.
(15) Gormley, G.; Chan, Y.-Y.; Fried, J. J. Org. Chem. 1980, 45, 1447–
1454.
(16) (a) Blackburn, L.; Kanno, H.; Taylor, J.-K. R. Tetrahedron Lett. 2003,
44, 115–118. (b) Peterson, D. J. J. Org. Chem. 1968, 33, 780–784. (c) van Staden,
L. F.; Gravestock, D. Chem. Soc. ReV. 2002, 31, 195–200.
(17) Hall, S. S. J. Org. Chem. 1986, 51, 5338–5341.
(18) (a) Lipshutz, B. H.; Kozlowski, J. A.; Parker, D. A.; Nguyen, S. L.;
McCarthy, K. E. J. Organomet. Chem. 1985, 285, 437–447. (b) Lipshutz, B. H.;
Koerner, M.; Parker, D. A. Tetrahedron Lett. 1987, 28, 945–948.
(19) (a) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc. 1986, 108,
2489–2490. (b) Curran, D. P.; Kim, D. Tetrahedron Lett. 1986, 27, 5821–5824.
(c) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54, 3140–3157.
J. Org. Chem. Vol. 74, No. 5, 2009 2035

Kuo et al.
SCHEME 7. Total Syntheses of Axamide (1) and
Axisonitrile (2)
heated at reflux for 2 h and then cooled to -78 °C. CuI (4.2 g,
22.3 mmol) was added and the resulting mixture was stirred for 30
min. A solution of 3-methylcyclohex-2-enone (7) (1.1 g, 8.9 mmol)
in THF (20 mL) and TMSCl (2.3 mL, 17.9 mmol) was add at -78
°C. After the reaction mixture was stirred for 10 min, Et3N (2.2
mL, 17.9 mmol) was added. The reaction mixture was allowed to
reach rt and then stirred for 16 h. Diluted with diethyl ether, the
resulting mixture was filtered through Celite and the filtrate was
extracted with diethyl ether (50 mL). The combined organic extract
was washed with NaHCO3 (50 mL) and brine (20 mL) and dried
over MgSO4. Concentration gave crude 12, which was immediately
used for the next step without purification. To a solution of crude
product 12 and NaI (3.9 g, 25.9 mmol) in THF (100 mL) was added
a solution of m-CPBA (70%, 0.95 g, 3.9 mmol) in THF (10 mL)
dropwise at 0 °C. The reaction mixture was stirred for 3 h, diluted
with water (20 mL), and extracted with diethyl ether (3 × 100 mL).
The organic layer was washed with Na2S2O3 (50 mL), NaHCO3
(100 mL), and brine (20 mL) and dried over MgSO4. Concentration
and chromatography on a silica gel column (hexane/EtOAc 50:1)
afforded 8 (896 mg, 76%) as a yellow liquid. Data for 8: IR (neat)
the synthesis of cis-fused hydroindane with an exocyclic double
bond has been reported with only a 7% yield via a Pd-catalyzed
cycloalkenylation of silyl enol ethers.21 It is noteworthy that
we synthesized the pivotal cis-fused hydroindane 20 with 66%
yield in two steps from iodo precursor 21.
1
ν 2959, 2175, 1710, 1220 cm-1; H NMR (300 MHz, CDCl3) δ
4.44 (s, 0.5H), 4.21 (s, 0.5H), 3.39-3.30 (m, 0.5H), 3.25-3.16
(m, 0.5H), 2.35-2.17 (m, 3H), 1.87-1.53 (m, 6H), 1.10 (s, 1.5H),
1.04 (s, 1.5H), 0.13 (s, 4.5H), 0.12 (s, 4.5H); 13C NMR (75 MHz,
CDCl3) δ 204.1, 203.7, 106.0, 105.7, 84.9, 84.5, 48.6, 46.5, 41.4,
40.5, 39.5, 35.5, 34.8, 34.3, 31.9, 31.0, 26.5, 20.8, 20.7, 19.5, 15.0,
13.8; MS (EI) m/z 362 (M+, 11), 347 (77), 234 (100); HRMS (EI)
m/z calcd for C14H23IOSi 362.0563, found 362.0580.
The cis-fused bicyclic ketone 20 was then subjected to
stereoselective Luche reduction by using NaBH4/CeCl3 ·7H2O22
to give the corresponding alcohol 29 in 80% yield (Scheme 6).
Treatment of 29 with triethylamine and methanesulfonyl chloride
produced mesylate 30. Compound 30 was then treated with
KCN to afford nitrile 19 in 70% yield. The stereochemistry of
19 was assigned on the basis of the NOE experiments.
In the final stage of total syntheses, crucial conversion of
nitrile 19 to amine 18 was accomplished with Hall’s tandem
alkylation-reduction procedure.17 Reaction of nitrile 19 with
isopropylmagnesium chloride followed by reduction with lithium
in ammonia afforded amine 18 in good yield along with a small
amount of its C-10 epimer 31 (Scheme 7). The stereochemistry
of amine 18 was assigned based on Piers’s report.23 Formylation
of amine 18 with acetic formic anhydride finally afforded (()-
axamide-1 (1) in 86% yield. Subsequently, dehydration of (()-
axamide-1 (1) with p-toluenesulphonyl chloride furnished
axisonitrile-1 (2) in 88% yield. The physical and spectral data
of (()-axamide-1 (1) and (()-axisonitrile-1 (2) were in good
agreement with the literature data.9
In summary, we have accomplished efficient total syntheses
of (()-axamide-1 (1) and (()-axisonitrile-1 (2) in 16% and 14%
overall yield, respectively. The 6-exo-dig radical cyclization was
used as the key step to construct the pivotal hydroindane ring
system 20. Hall’s tandem alkylation-reduction method was
successfully applied to afford Piers’s amine 18. Finally,
functional group transformations on 18 led to the total syntheses
of 1 and 2.
7a-Methyl-3-[(E and Z)-1-(trimethylsilyl)methylidene]per-
hydro-4-indenone (13). To a solution of 8 (0.5 g, 1.4 mmol) in
anhydrous benzene (92 mL) was added (Bu3Sn)2 (0.4 mL, 1.6
mmol). The reaction mixture was refluxed and simultaneously
irradiated with a sunlamp for 1 h. The sunlamp was removed and
the reaction mixture was allowed to cool to rt. A solution of Bu3SnH
(0.8 mL, 2.97 mmol) and AIBN (60 mg, 0.30 mmol) was added to
the reaction mixture and refluxed for 1 h. Concentration and
chromatography on a silica gel column (hexane/EtOAc 50:1) gave
13 (E/Z ) 1/2.4) (613 mg, 88%) as a colorless liquid. Data for 13:
1
IR (neat) ν 3054, 2987, 1605, 1422 cm-1; H NMR (500 MHz,
CDCl3) δ 5.57-5.56 (dd, J ) 3.2, 1.6 Hz, 0.5H), 5.12-5.10 (dd,
J ) 5.1, 2.5 Hz, 0.5 H), 2.79 (br s, 1H), 2.54-2.23 (m, 4H),
1.91-1.41 (m, 6H), 1.02 (s, 1.5H), 0.98 (s, 1.5H), -0.01 (s, 4.5H),
-0.05 (s, 4.5H); 13C NMR (125 MHz, CDCl3) δ 211.9, 210.2,
158.8, 157.1, 124.9, 121.8, 68.9, 65.6, 48.0, 46.4, 40.9, 39.2, 37.6,
34.2, 32.9, 32.4, 31.6, 30.3, 28.4, 25.0, 23.0, 22.3, -0.27, -0.77;
MS (EI) m/z 236 (M+, 7), 221 (100), 183 (29), 147 (68); HRMS
(EI) m/z calcd for C14H24OSi 236.1596, found 236.1604.
7a-Methyl-3-methyleneperhydro-4-indenone (9). To a solution
of 13 (359 mg, 1.5 mmol) in CH2Cl2 (30 mL) was added CF3COOH
(0.1 mL, 1.5 mmol) at 0 °C. The reaction mixture was stirred for
10 min and neutralized with NaOH (1 N) solution. The resulting
mixture was extracted with CH2Cl2 (100 mL). The combined
organic layer was washed with NaHCO3 (20 mL) and brine (20
mL) and dried over MgSO4. Concentration and chromatography
on a silica gel column (hexane/EtOAc 50:1) afforded 9 (226 mg,
97%) as a colorless liquid. Data for 9: IR (neat) ν 3054, 2987,
1703, 1606 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.93 (q, J ) 2.4
Hz, 1H), 4.70 (q, J ) 2.4 Hz, 1H), 2.81 (br s, 1H), 2.59-2.34 (m,
3H), 1.90-1.60 (m, 5H), 1.58-1.36 (m, 2H), 1.09 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 212.0, 150.4, 108.3, 66.1, 47.4, 38.5,
37.7, 31.9, 30.0, 25.3, 22.4; MS (EI) m/z 164 (M+, 1), 150 (12),
149 (100), 71 (11); HRMS (EI) m/z calcd for C11H16O 164.1201,
found 164.1215.
Experimental Section
2-Iodo-3-methyl-3-[4-(trimethylsilyl)-3-butynyl]-1-cyclohex-
anone (8). To a suspension of magnesium turnings (0.6 g, 26.8
mmol) in anhydrous THF (10 mL) was added 1,2-dibromoethane
(0.05 mL). The reaction mixture was heated at reflux and then a
solution of 1,2-dibromoethane (0.1 mL) in THF (25 mL) and
4-chloro-1-trimethylsilyl-1-butyne (11) (3.2 g, 19.6 mmol) was
added dropwise over a period of 1 h. The reaction mixture was
(20) The ratio of E and Z isomer was determined from the 1H NMR spectrum
of compounds 13 and 27.
(21) Toyota, M.; Ilangovan, A.; Okamoto, R.; Masaki, T.; Arakawa, M.; Ihara,
M. Org. Lett. 2002, 4, 4293–4296.
(22) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
(23) Compounds 1 and 2 were prepared according to the modified Piers’s
procedure (see ref 9a).
3-(Hydroxymethyl)-7a-methylperhydro-4-indenol (15). To a
solution of 9 (146 mg, 0.9 mmol) in THF (2.5 mL) was added
BH3 ·SMe2 (0.7 M in THF, 0.7 mL, 0.9 mmol) dropwise at 25 °C.
The reaction mixture was stirred at 25 °C for 12 h and then cooled
to 0 °C. At this temperature MeOH (2 mL) was added dropwise.
The resulting mixture was concentrated and diluted with THF (5
2036 J. Org. Chem. Vol. 74, No. 5, 2009

Syntheses of (()-Axamide-1 and (()-Axisonitrile-1
mL). To the resulting solution was added a mixture of of 3 N NaOH
(5 mL), H2O2 (30%, 5 mL), and THF (10 mL) at 25 °C. The reaction
mixture was stirred for 24 h and brine (10 mL) was added. The
mixture was extracted with ether (20 mL). The combined extract
was washed with brine (10 mL) and dried over MgSO4. Concentra-
tion and chromatography on a silica gel column (hexane/EtOAc
2:1) gave 15 (134 mg, 82%) as a colorless liquid. Data for 15: IR
(neat) ν 3298, 2931, 2868, 1071 cm-1; 1H NMR (300 MHz, CDCl3)
δ 4.10-4.00 (m, 1 H), 3.87 (dd, J ) 10.6, 10.6 Hz, 1H), 3.66-3.60
(m, 2H), 3.57-3.49 (m, 1H), 2.74-2.66 (m, 1H), 2.60-2.53 (m,
1H), 1.87-1.18 (m, 20H), 1.07 (s, 3H), 0.99 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 69.5, 68.5, 64.9, 63.7, 53.9, 52.3, 43.5, 43.0,
39.0, 35.6, 35.5, 33.0, 32.6, 32.3, 30.7, 27.2, 25.4, 23.7, 19.9, 19.8;
MS (EI) m/z 184 (M+, 1), 135 (19), 82 (41), 57 (100); HRMS (EI)
m/z calcd for C11H20O2 184.1463, found 184.1470.
mmol) in THF (20 mL) dropwise at 0 °C. The reaction mixture
was stirred for 3 h and then diluted with water (20 mL) and
extracted with diethyl ether (3 × 100 mL). The organic layer was
washed with saturated Na2S2O3 solution (50 mL), saturated NaHCO3
solution (100 mL), and brine (20 mL) and dried over MgSO4.
Concentration and chromatography on a silica gel column (hexane/
EtOAc 50:1) afforded 21 (5.7 g, 77%) as a yellow liquid. Data for
1
21: IR (neat) νmax 2959, 2173, 1708, 1220 cm-1; H NMR (400
MHz, CDCl3) δ 4.41 (s, 0.5H), 4.18 (s, 0.5H), 2.45 (dd, J ) 9.6,
3.2 Hz, 0.4H), 2.40 (dd, J ) 10, 3.2 Hz, 0.7H), 2.35-2.17 (m,
7H), 2.05-1.84 (m, 3H), 1.76-1.68 (m, 1H), 1.60-1.44 (m, 9H),
1.11 (s, 1.5H), 1.08 (s, 1.5H), 0.12 (s, 4.5H), 0.11 (s, 4.5H); 13C
NMR (100 MHz, CDCl3) δ 211.3, 211.2, 106.7, 106.4, 85.3, 85.0,
45.5, 44.5, 42.4, 42.1, 41.6, 37.2, 32.8, 32.4, 32.3, 31.4, 25.7, 23.9,
23.8, 20.4, 20.2, 20.1, 0.1, 0.1; MS (EI) m/z 362 (M+, 11), 347
(77), 234 (100); HRMS (EI) m/z calcd for C14H23IOSi 362.0563,
found 362.0580.
3-Methyl-7-[(trimethylsilyl)methylene]octahydro-1H-inden-
1-one (26). To a solution of 21 (1.0 g, 2.76 mmol) in dry benzene
(6 mL) was added (Bu3Sn)2 (0.28 mL, 0.55 mmol). The reaction
mixture was heated to reflux and simultaneously irradiated with a
sunlamp for 1 h. The sunlamp was removed and the reaction mixture
was allowed to cool to rt. A solution of Bu3SnH (0.74 mL, 2.79
mmol) and AIBN (60 mg, 0.30 mmol) was added. The reaction
mixture was heated at reflux for 1 h. Concentration and chroma-
tography on a silica gel column (hexane/EtOAc 50:1) gave 26 (E/Z
) 1/1.3) (430 mg, 66%) as a colorless liquid. Data for 26: IR (neat)
(7-Hydroxy-3a-methyloctahydro-1H-inden-1-yl)methyl Ac-
etate (16). To a solution of 15 (297 mg, 1.6 mmol) in pyridine
(0.13 mL) was added acetic anhydride (0.07 mL, 0.75 mmol) at 0
°C. The reaction was stirred for 24 h at 0 °C. Diluted with ethyl
acetate (20 mL), the organic layer was washed with brine (5 mL)
and dried over MgSO4. Concentration and chromatography on a
silica gel column (hexane/EtOAc 50:1) gave 16 (209 mg, 54%).
1
Data for 16: IR (neat) ν 3385, 1740 cm-1; H NMR (600 MHz,
CDCl3) δ 4.44 (dd, J ) 10.4, 8 Hz, 1H), 4.25 (dd, J ) 10.4, 8 Hz,
1H), 3.98 (dd, J ) 8.8, 4 Hz, 1H), 2.67-2.60 (m, 1H), 1.97 (s,
3H), 1.85-1.19 (m, 11H), 0.89 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 171.1, 67.7, 66.8, 50.7, 41.9, 39.7, 36.2, 34.9, 33.4, 30.2,
26.8, 21.1, 16.8; MS (EI) m/z 226 (M+, <1), 166 (10), 148 (31),
96 (47), 85 (100); HRMS (EI) m/z calcd for C13H22O3 226.1569,
found 226.1576.
ν
max 3053, 2987, 1609, 1422 cm-1; 1H NMR (400 MHz, CDCl3) δ
5.57 (br s, 0.5H), 5.19 (br s, 0.5H), 2.75 (br s, 1H), 2.45 (br s,
1H), 2.35-2.29 (m, 5H), 2.14-2.10 (m, 1H), 1.81-1.35 (m, 14H),
1.14 (s, 1.5H), 1.10 (s, 1.5H), 0.09 (s, 4.5H), 0.05 (s, 4.5H); 13C
NMR (100 MHz, CDCl3) δ 217.9, 217.2, 151.7, 151.7, 129.0, 70.1,
64.7, 42.0, 41.9, 37.3, 35.4, 35.3, 35.0, 34.4, 33.2, 33.2, 31.5, 25.5,
25.4, 23.3, 23.3, 0.38, 0.23; MS (EI) m/z 236 (M+, 5), 221 (90),
145 (31), 75 (100); HRMS (EI) m/z calcd for C14H24OSi 236.1596,
found 236.1579.
(3a-Methyl-7-oxooctahydro-1H-inden-1-yl)methyl Acetate (17).
To a mixture of PCC (437.6 mg, 2.04 mmol) and NaOAc (166.9
mg, 2.04 mmol) in CH2Cl2 (2 mL) was added a solution of 16 (77
mg, 0.34 mmol) in CH2Cl2 (1 mL). The reaction mixture was heated
at reflux for 1 h. The resulting mixture was filtered through Celite
and the filtrate was extracted with CH2Cl2 (20 mL). The combined
organic extract was washed with brine (5 mL) and dried over
MgSO4. Concentration of CH2Cl2 gave 17 (73 mg, 97%). Data for
2-Methyl-1-[(1S*)-3a-methyl-7-methyleneoctahydro-1H-inden-
1-yl]propan-1-amine (18). To a solution of 19 (114 mg, 0.65
mmol) in THF (6 mL) was added isopropylmagnesium bromide (2
M in THF, 0.97 mL). The reaction mixture was heated to for 72 h.
After cooling to -78 °C, ammonia (25 mL) was condensed into
the vessel. Lithium wire (122.7 mg, 1.73 mmol) was then added.
After stirring for 20 min, sodium benzoate (111 mg, 2.45 mmol)
was added. After evaporation of ammonia, the residue was diluted
with diethyl ether (20 mL) and quenched with HCl (2 N, 5 mL).
The resulting mixture was extracted with diethyl ether (30 mL).
The combined organic extract was washed with saturated NaHCO3
solution (30 mL) and brine (20 mL) and dried over MgSO4.
Concentration and chromatography on a silica gel column (hexane/
EtOAc 10:1) furnished 18 (115 mg, 80%) as a colorless liquid.
Data for 18: IR (neat) νmax 3396, 3067, 1642, 1462, 889 cm-1; 1H
NMR (400 MHz, CDCl3) δ 4.73 (br s, 2H), 2.48 (dd, J ) 8.4, 3.6
Hz, 1H), 2.27-2.00 (m, 3H), 1.92 (d, J ) 10 Hz, 1H), 1.83-1.32
(m, 8H), 1.17-1.11 (m, 2H), 0.90 (s, 3H), 0.88 (d, J ) 6.9 Hz,
3H), 0.78 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
152.0, 110.0, 63.0, 60.9, 45.3, 44.8, 39.8, 33.6, 31.3, 30.6, 26.7,
24.7, 24.6, 20.9, 15.1; MS (EI) m/z 221 (M+, 12), 178 (81), 161
(45), 149 (35), 113 (34), 91 (35), 70 (100); HRMS (EI) m/z calcd
for C15H27N 221.2143, found 221.2156.
1
17: IR (neat) νmax 1741, 1708 cm-1; H NMR (600 MHz, CDCl3)
δ 4.23 (dd, J ) 11.1, 5.4 Hz, 1H), 4.18 (dd, J ) 11.1, 5.4 Hz, 1H),
2.62-2.58 (m, 1H), 2.41 (d, J ) 9.3 Hz, 1H), 2.35-2.33 (m, 1H),
2.15-2.08 (m, 1H), 1.98 (s, 3H), 1.90-1.81 (m, 3H), 1.70-1.53
(m, 4H), 1.42-1.38(m, 1H), 1.08 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 213.7, 170.9, 65.9, 60.5, 46.4, 41.5, 41.2, 38.2, 34.8,
28.7, 27.4, 21.8, 20.9; MS (EI) m/z 224 (M+, <1), 164 (30), 111
(100); HRMS (EI) m/z calcd for C13H20O3 224.1412, found
224.1413.
2-Iodo-3-methyl-3-[5-(trimethylsilyl)pent-4-yn-1-yl]cyclopen-
tanone (21). To a suspension of magnesium turnings (1.5 g, 61.2
mmol) in anhydrous THF (10 mL) was added 1,2-dibromoethane
(0.05 mL). The heterogeneous reaction mixture was heated to reflux.
Then a solution of 1,2-dibromoethane (0.1 mL) in THF (25 mL)
and 5-chloro-1-trimethylsilyl-1-pentyne (3.6 g, 20.4 mmol) was
added dropwise over a period of 1 h. The reaction mixture was
heated at reflux for 2 h and then cooled to -78 °C. A solution of
thienyl cyanocuprate 24 (20.4 mmol) in THF (20 mL) was added.
The reaction mixture was stirred for 30 min at -78 °C. A solution
of compound 22 (1.96 g, 20.4 mmol) in THF (20 mL) and TMSCl
(5.1 mL, 40.8 mmol) was added at -78 °C. After the reaction
mixture was stirred for 10 min, Et3N (5.0 mL, 40.8 mmol) was
added. The reaction mixture was allowed to warm to rt and stirred
for 16 h. The reaction mixture was diluted with diethyl ether (20
mL). The resulting mixture was filtered through Celite and extracted
with diethyl ether (50 mL). The combined organic extract was
washed with saturated NaHCO3 (50 mL) and brine (20 mL) and
dried over MgSO4. Concentration gave crude 25. The crude 25 was
immediately used for the next step without purification. To a
solution of crude product 25 and NaI (9.4 g, 62.4 mmol) in THF
(200 mL) was added a solution of m-CPBA (70%, 10.8 g, 62.4
{2-Methyl-1-[(1S*)-3a-methyl-7-methyleneoctahydro-1H-in-
den-1-yl]propyl}formamide (1). To a solution of 18 (20 mg, 0.09
mmol) in diethyl ether (1 mL) was added acetic formic anhydride
(15 mg, 0.18 mmol) and the mixture was stirred for 10 h at rt. The
reaction mixture was quenched with water (3 mL) and extracted
with diethyl ether (10 mL). The combined organic extract was
washed with brine (5 mL) and dried over MgSO4. Concentration
and chromatography on a silica gel column (hexane/EtOAc 3:1)
furnished 1 (19 mg, 90%) as a colorless liquid. Data for 1: IR (neat)
ν
max 3270, 1658 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J )
J. Org. Chem. Vol. 74, No. 5, 2009 2037

Kuo et al.
1.6 Hz, 0.66H), 7.85 (d, J ) 12 Hz, 0.34H), 5.60 (br s, 0.34H),
5.14 (br s, 0.66H), 4.77 (t, J ) 1.6 Hz, 0.34H), 4.71 (t, J ) 1.5 Hz,
0.66H), 4.64 (d, J ) 2.4 Hz, 0.66H), 4.60 (br s, 0.34H), 3.87 (td,
J ) 9.8, 3.6 Hz, 0.66H), 2.91 (ddd, J ) 10.4, 8.8, 4.0 Hz, 0.34H),
2.42-1.81 (m, 6H), 1.63-1.30 (m, 5H), 1.17-1.12 (m, 1H), 0.90
(s, 1.02H), 0.88 (s, 1.98H), 0.85 (d, J ) 6.8 Hz, 1.02H), 0.84 (d,
J ) 6.8 Hz, 1.98H), 0.76 (d, J ) 6.8 Hz, 1.02H), 0.75 (d, J ) 6.8
Hz, 1.98H); 13C NMR (100 MHz, CDCl3) δ 164.4, 161.7, 149.9,
148.3, 111.7, 110.8, 64.0, 59.5, 58.9, 58.2, 45.2, 44.8, 42.1, 40.8,
39.7, 33.1, 32.8, 31.2, 31.1, 30.4, 30.1, 27.8, 27.7, 24.5, 24.3, 20.6,
16.3, 16.2; MS (EI) m/z 249 (M+, 2), 220 (5), 161 (14), 119 (10),
88 (100); HRMS (EI) m/z calcd for C16H27NO 249.2093, found
249.2103.
(1S*,3aS*)-1-(1-Isocyano-2-methylpropyl)-3a-methyl-7-meth-
yleneoctahydro-1H-indene (2). To a solution of 1 (9 mg, 0.04
mmol) in pyridine (0.2 mL) was added toluenesulfonyl chloride
(12 mg, 0.09 mmol). The reaction mixture was stirred for 3 h at rt
and then quenched with water (3 mL) and extracted with pentane
(10 mL). The combined extract was washed with brine (5 mL) and
dried over MgSO4. Concentration and chromatography on a silica
gel column (hexane/EtOAc 3:1) furnished 2 (7.35 mg, 88%) as a
colorless solid. Data for 2: mp 45-46 °C; IR (neat) νmax 2138,
1
1640, 1390, 1375, 895 cm-1; H NMR (600 MHz, CDCl3) δ 4.78
(dd, J ) 3.6, 2.4 Hz, 2H), 3.23-3.18 (m, 1H), 2.48-2.42 (m, 1H),
2.19-1.91 (m, 5H), 1.65-1.39 (m, 5H), 1.23-1.19 (m, 2H), 0.99
(d, J ) 6.4 Hz, 3H), 0.96 (s, 3H), 0.85 (d, J ) 6.4 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 148.3, 111.7, 67.6, 57.2, 45.2, 40.2,
39.7, 33.4, 31.3, 29.8, 27.7, 24.4, 24.4, 19.8, 19.1; MS (EI) m/z
231 (M+, 27), 176 (47), 134 (100), 96 (97), 54 (77); HRMS (EI)
m/z calcd for C16H25N 231.1987, found 231.1998.
Acknowledgment. The financial support from National
Science Council of the Republic of China (Taiwan) is gratefully
acknowledged.
Supporting Information Available: Detailed experimental
1
procedures, complete characterization data, and copies of H
and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO802672T
2038 J. Org. Chem. Vol. 74, No. 5, 2009