Stereocontrolled assembly of cis or trans angularly substituted hydrindenes by the unactivated intramolecular Diels-Alder reaction

Article abstract of DOI:10.1021/jo9610974

The unactivated intramolecular Diels-Alder reaction has become a powerful tool for the construction of polycyclic natural products. Nevertheless, the factors that govern diastereoselectivity in these cyclizations have not been fully understood. We here report that through the choice of the proper substituents, it is possible to make the unactivated intramolecular Diels-Alder reaction proceed to give either the cis angularly-substituted hydrindene 12b or the trans product 19a.

Full text of DOI:10.1021/jo9610974

7508
J . Org. Chem. 1996, 61, 7508-7512
Ster eocon tr olled Assem bly of Cis or Tr a n s An gu la r ly Su bstitu ted
Hyd r in d en es by th e Un a ctiva ted In tr a m olecu la r Diels-Ald er
Rea ction
Douglass F. Taber* and Ying Song
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
Received J une 11, 1996X
The unactivated intramolecular Diels-Alder reaction has become a powerful tool for the construction
of polycyclic natural products. Nevertheless, the factors that govern diastereoselectivity in these
cyclizations have not been fully understood. We here report that through the choice of the proper
substituents, it is possible to make the unactivated intramolecular Diels-Alder reaction proceed
to give either the cis angularly-substituted hydrindene 12b or the trans product 19a .
Sch em e 1
The activated intramolecular Diels-Alder reaction is
a powerful tool for the construction of complex polycyclic
natural products.1,2 Since its introduction by Wilson in
1978,3 the unactivated intramolecular Diels-Alder (UIDA)
reaction4 has also been widely used in natural product
synthesis. In the context of a prospective total synthesis
of the immune-suppressive steroid contignasterol (1), we
envisioned a retrosynthetic dissection to 2 and thus to
3. The difficulty with this approach was that it was well
known5-7 that trienes such as 3 often cyclize to give
preferentially the (in this case undesired) trans ring
fusion. We have therefore set out to explore substituent
effects on the stereochemical course of the UIDA reaction.
We now report that through the choice of the proper
substituents, it is in fact possible to make the UIDA
reaction proceed to give preferentially either the cis or
the trans angularly-substituted 6/5 product.
Triene 11 was prepared from 1,2-epoxy-3-(triphenyl-
methoxy)propane (4) (Scheme 1). The epoxide was
opened with allylmagnesium chloride, and the resultant
secondary alcohol was alkylated with allyl bromide and
NaH to give the trityl ether 5. Selective ozonolysis of
the more electron-rich alkene of 5 in CH2Cl2 followed by
the oxidation with PDC8 in MeOH gave the γ-alkoxy ester
6. Diazo transfer9,10 was then effected by benzoylation11
of the ester 6 followed by exposure to DBU12 and
4-nitrobenzenesulfonyl azide.13
X Abstract published in Advance ACS Abstracts, October 1, 1996.
(1) Ciganek, E. Organic Reactions; J ohn Wiley & Sons Inc.: New
York, 1984, Vol. 32, pp 1-374.
Catalytic rhodium octanoate in CH2Cl2 at room tem-
perature smoothly cyclized14 R-diazo ester 7 to a mixture
(2) (a) Grinsteiner, T. J .; Kishi, Y., Tetrahedron Lett. 1994, 35, 8333.
(b) Chu-Moyer, M. Y.; Danishefsky, S. J .; Schulte, G. K. J . Am. Chem.
Soc. 1994, 116, 11213. (c) Paquette, L. A.; Wang, T. Z.; Sivik, M. R. J .
Am. Chem. Soc. 1994, 116, 11323. (d) Grieco, P. A.; Beck, J . P.; Handy,
S. T.; Saito, N.; Daeuble, J . F. Tetrahedron Lett. 1994, 35, 6783. (e)
Ornstein, P. L.; Melikian, A.; Martinelli, M. J . Tetrahedron Lett. 1994,
35, 5759.
(3) Wilson, S. R.; Mao, D. T. J . Am. Chem. Soc. 1978, 100, 6289.
(4) (a) Toyota, M.; Nishikawa, Y.; Fukumoto, K. Tetrahedron Lett.
1994, 35, 6495. (b) Spino, C.; Crawford, J . Tetrahedron Lett. 1994, 35,
5559. (c) Takahashi, T.; Shimizu, K.; Doi, T.; Tsuji, J . J . Am. Chem.
Soc. 1988, 110, 2674.
(8) O’Connor, B.; J ust, G. Tetrahedron Lett. 1987, 28, 3235.
(9) Taber, D. F.; You, K.; Song, Y. J . Org. Chem. 1995, 60, 1093.
(10) (a) Regitz, M.; Maas, G. Diazo Compounds: Properties and
Synthesis; Academic Press: Orlando, 1986. (b) Askani, R.; Taber, D.
F. Comprehensive Organic Synthesis; Winterfeldt, E., Ed.; Pergamon:
Oxford, 1991; Vol. 6, p 103.
(11) Metcalf, B. W.; J und, K.; Burkhart, J . P. Tetrahedron Lett. 1980,
21, 15.
(12) For the use of DBU in diazo transfer, see: (a) Baum, J . S.;
Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth. Commun. 1987,
17, 1709. (b) Koteswar Rao, Y.; Nagarajan, M. J . Org. Chem. 1989,
54, 5678.
(5) Wilson, S. R.; Haque, S. M. J . Org. Chem. 1982, 47, 5411.
(6) (a) Parker, K. A.; Iqbal, T. J . Org. Chem. 1987, 52, 4369. (b)
Parker, K. A.; Iqbal, T. J . Org. Chem. 1982, 47, 337.
(13) (a) Reagan, M. T.; Nickon, A. J . Am. Chem. Soc. 1968, 90, 4096.
(b) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011.
(7) J ung, M. E.; Halweg, K. M. Tetrahedron Lett. 1984, 25, 2121.
S0022-3263(96)01097-3 CCC: $12.00 © 1996 American Chemical Society

Assembly of Angularly Substituted Hydrindenes
J . Org. Chem., Vol. 61, No. 21, 1996 7509
Sch em e 2
of 8a and 8b, in a ratio of 1:3. Transformation of 8b into
9 was achieved by using a 4-fold excess of “salt-free”
methylenetriphenylphosphorane.15 Hydroboration and
oxidation of 9 gave the primary alcohol 10. Swern
oxidation of 10 followed by addition of (1-methyl-1-
propenyl)magnesium bromide gave the secondary allylic
alcohol.
We next faced the problem of preparing selectively the
E-diene. We reasoned that sigmatropic rearrangement
of a sulfenate ester should establish the E-trisubstituted
alkene, with subsequent sulfoxide elimination completing
the diene. Indeed, dehydration16 of allylic alcohol by 2,4-
dinitrobenzenesulfenyl chloride gave the triene 11 (E:Z
) 82:18).17
The triene 11 was cyclized6a by heating in dimethyl-
aniline in a sealed tube with 2,5-di-tert-butylhydro-
quinone as a radical inhibitor at 250 °C for 24 h to give
the tricycles 12a (trans-fused) and 12b (cis-fused) in a
ratio of 1:3. The trityl group was cleaved when the
reaction was worked up with 6 N aqueous hydrochloric
acid to remove the dimethylaniline. The relative config-
uration of the cyclized products was assigned on the basis
1
of the H NMR spectra, with the chemical shifts of both
the alkene proton (δ 5.17 vs δ 5.45) and the angular
methyl group (δ 0.76 vs δ 0.95) further upfield in the
trans diastereomer.5-7 The observation of a cis-fused
product predominating from the cyclization of 11 is in
sharp contrast to the trans product established5-7 for
related acyclic trienes.
To confirm this, acyclic triene 18 was then prepared
(Scheme 2) from the primary alcohol 10. The alcohol 10
was silylated, and the trityl group was removed to give
14. Our next objective was the oxidative cleavage of the
primary alcohol to the lactone. Room-temperature oxida-
tion with pyridinium dichromate18 and acetic anhydride
gave the lactone 15 and aldehyde 20 in a ratio of 2 to 1.
We found that if alcohol 14 was added to a refluxing
mixture of PDC and acetic anhydride in CH2Cl2 and
DMF, the predominant product was lactone 15 (lactone:
aldehyde ) 10:1). We established this route to 18
because the diene of the primary alcohol from detrityla-
tion of 11 (Scheme 1) did not survive the PDC oxidation
conditions.
bromide. Desilylation followed by diene construction as
before gave the triene 18 (E:Z ) 86:14).17
The triene 18 was heated in dimethylaniline at 250
°C for 24 h to give the cyclization products 19a (trans-
fused) and 19b (cis-fused) in a ratio of 3:1. As expected,5-7
the trans hydrindene was indeed the dominant product
from cyclization of this acyclic triene. As before, the
relative configuration of the cyclized products was as-
signed on the basis of the 1H NMR spectra, with the
chemical shifts of both the alkene proton (δ 5.24 vs δ 5.37)
and the angular methyl group (δ 0.72 vs δ 0.89) further
upfield in the trans diastereomer.5-7
This study confirms the previous experience5-7 that the
6/5 unactivated intramolecular Diels-Alder reaction is
closely balanced between cis vs trans ring-fused products.
As can be seen from the cyclization of trienes 11 and 18,
it is possible to direct the unactivated intramolecular
Diels-Alder reaction to give predominantly either the
cis or the trans angularly-substituted 6/5 product. In
pursuit of contignasterol (1), we are currently preparing
15-substituted trienes (steriod numbering) to investigate
the influence of a substituent at that position on the
diastereoselectivity of the cyclization.
The last stereogenic center of 18 (C-20, steroid num-
bering) was established by alkylation of lactone 15.
Thus, exposure to LDA followed by the addition of methyl
iodide gave methylated lactone 16 as a single dominant
diastereomer. The methylated lactone 16 was reduced
with LiAlH4, and the diol was protected with benzyl
Exp er im en ta l Section 19
Meth yl 4-(2-P r op en yloxy)-5-(tr ip h en ylm eth oxy)p en -
ta n oa te (6). At 0 °C, 100 mL of 2 M allylmagnesium chloride
was added slowly to 1-[(triphenylmethoxy)methyl]oxirane (4)
(30 g, 100 mmol) in 200 mL of dry THF. The reaction mixture
was warmed to rt. After 4 h, the reaction mixture was
sequentially partitioned between the aqueous 2 N HCl and
50% EtOAc/petroleum ether. The combined organic extract
was washed sequentially with saturated aqueous NaHCO3 and
saturated aqueous NaCl. The combined organic extract was
dried (Na2SO4) and concentrated to give 35 g of crude 1-(tri-
phenylmethoxy)-5-hexen-2-ol.
(14) Taber, D. F.; Song, Y. Tetrahedron Lett. 1995, 36, 2587.
(15) (a) Uijttewall A. P.; Froukje L. J .; van de Gen, A. J . Org. Chem.
1979, 44, 3157. (b) Uijttewall A. P.; Froukje L. J .; van de Gen, A. J .
Org. Chem. 1978, 43, 3306.
(16) To our knowledge, the Reich procedure has not previously been
employed to prepare such an internally-substituted acyclic diene. For
the development of this elimination procedure, see: (a) Reich, H. J .;
Reich, I. L.; Wollowitz, S. J . Am. Chem. Soc. 1978, 100, 5981. (b) Suzuki
T.; Sato, O.; Hirama, M.; Yamamoto, Y.; Murata, M. Yasumoto, T.;
Harada, N. Tetrahedron Lett. 1991, 32, 4505.
NaH (14 g, 0.35 mol, 60% in mineral oil) was added in
portions to the crude 1-(triphenylmethoxy)-5-hexen-2-ol (35 g)
(17) Although we report yields based on total (E + Z) triene, we
expect that only the E-triene can cyclize.
(18) Kim, J . N.; Ryu, E. K. Tetrahedron Lett. 1992, 33, 3141.
(19) Taber, D. F.; Houze, J . B. J . Org. Chem. 1994, 59, 4004.

7510 J . Org. Chem., Vol. 61, No. 21, 1996
Taber and Song
in 250 mL of dry THF at 0 °C. Allyl bromide (26 g, 0.21 mol)
and Bu4NI (200 mg) were then added. The reaction mixture
was warmed to rt. After 4 h, the reaction mixture was
partitioned between 2 N aqueous HCl and 50% EtOAc/
petroleum ether. The combined organic extract was dried (Na2-
SO4) and concentrated to give 37 g of crude 6-(triphenyl-
methoxy)-5-(2-propenyloxy)-1-hexene (5) a colorless oil.
A solution of crude 5 (3.86 g, 10 mmol) in 30 mL of CH2Cl2
was stirred at -78 °C while 10 mmol of O3 was passed through.
Ph3P (4.0 g, 15 mmol) was added, and the reaction mixture
was warmed to rt for 2 h. Evaporation of the solvent and
chromatography of the residue afforded 1.76 g of the aldehyde
as a colorless oil (44% yield from 1,2-epoxy-3-(triphenyl-
methoxy)propane): TLC Rf (15% EtOAc/petroleum ether) )
0.43; 1H NMR δ 9.74 (bs, 1H), 7.47 (m, 6H), 7.26 (m, 9H), 5.89
(m, 1H), 5.23 (m, 2H), 4.13 (m, 1H), 3.95 (m, 1H), 3.48 (m,
1H), 3.23 (dd, J ) 5.1, 9.8 Hz, 1H), 3.12 (dd, J ) 5.1, 9.8 Hz,
1H), 2.46 (m, 2H), 1.93 (m, 2H); 13C NMR δ u 144.0, 116.8,
87.8, 71.1, 65.4, 40.0, 25.0; d 202.3, 134.9, 128.7, 127.8, 127.0,
77.3; IR (cm-1) 3060, 2924, 1724, 1596, 1490, 1449, 1390, 1343,
1077, 900; MS m/z 323 (0.5), 259 (3), 243 (100), 165 (63), 127
(61), 105 (17); HRMS calcd for C21H23O3 (n-C6H5) 323.1648,
obsd 323.1729.
(3 × 7 mL). Methylene chloride was then added by filtration
through a pad of anhydrous K2CO3. Dirhodium tetraoctanoate
(1 mg) was added with stirring. The reaction was complete
in 30 min. The reaction mixture was concentrated, and the
residue was chromatographed to give 316 mg of 8a (24% yield
from 7) and 103 mg of 8b (74% yield from 7). 8a : TLC Rf (15%
EtOAc/petroleum ether) ) 0.41; 1H NMR δ 7.47 (m, 6H), 7.26
(m, 9H), 5.76 (m, 1H), 5.29 (d, J ) 17.0 Hz, 1H), 5.12 (d, J )
11.6 Hz, 1H), 4.61 (t, J ) 8.1 Hz, 1H), 4.14 (m, 1H), 3.56 (s,
3H), 3.37 (m, 1H), 3.27 (m, 1H), 3.16 (m, 1H), 2.08 (t, J ) 8.3
Hz, 2H); 13C NMR δ u 171.8, 143.9, 117.2, 86.4, 66.2, 31.0; d
135.1, 128.6, 127.6, 126.8, 80.7, 78.5, 51.5, 48.3; IR (cm-1) 3057,
2872, 2131, 1738, 1597, 1491, 1448, 1202, 1078. 8b: TLC Rf
(15% EtOAc/petroleum ether) ) 0.48; 1H NMR δ 7.45 (m, 6H),
7.29 (m, 9H), 5.92 (m, 1H), 5.36 (d, J ) 17.2 Hz, 1H), 5.17 (d,
J ) 10.3 Hz), 4.47 (t, J ) 7.0 Hz, 1H), 4.29 (m, 1H), 3.70 (s,
3H), 3.15 (m, 2H), 2.84 (q, J ) 7.7 Hz, 1 H), 2.29 (m, 1H), 2.08
(m, 1H); 13C NMR δ u 173.4, 144.0, 116.6, 86.5, 66.0, 32.7; d
137.1, 128.7, 127.7, 126.9, 83.0, 78.1, 51.9, 49.6; IR (cm-1) 2921,
2872, 1738, 1597, 1490, 1449, 1366, 1273, 1170, 1077; MS m/z
428 (0.02), 398 (1), 351 (2), 259 (12), 243 (100), 165 (60), 123
(28), 105 (17); HRMS calcd for C28H28O4 428.1988, obsd
428.2279.
(R*,R*,R*)-2-Eth en yl-3-(m eth yleth en yl)-5-[(tr ip h en yl-
m eth oxy)m eth yl]-2,3,4,5-tetr a h yd r ofu r a n (9). NaHMDS
(6.5 mL, 1 M in THF) was added to 2.4 g of methyltriphen-
ylphosphonium bromide in 6 mL of dry THF at rt. The
reaction mixture was stirred at rt for 30 min and then heated
to reflux for 1 h. After the mixture was cooled to rt, 8b (0.7 g,
1.64 mmol) in 4 mL of THF was added. After 8 h at rt, the
mixture was partitioned between H2O and 20% EtOAc/
petroleum ether. The combined organic extract was dried (Na2-
SO4), concentrated, and chromatographed to give 9 (0.51g, 76%
yield from 8b): TLC Rf (10% EtOAc/petroleum ether) ) 0.63;
1H NMR δ 7.47 (m, 6H), 7.27 (m, 9H), 5.85 (m, 1H), 5.27 (d, J
) 17.3 Hz, 1H), 5.13 (d, J ) 10.4 Hz, 1H), 4.79 (m, 2H), 4.25
(m, 1H), 4.17 (t, J ) 7.7 Hz, 1H), 3.18 (dd, J ) 5.2, 9.5 Hz,
1H), 3.09 (dd, J ) 5.2, 9.5 Hz, 1H), 5.56 (q, J ) 8.7 Hz, 1H),
1.98 (m, 2 H), 1.73 (s, 3H); 13C NMR δ u 144.1, 143.5, 116.2,
111.8, 86.4, 66.6, 34.1; d 138.1, 128.7, 127.7, 126.7, 83.7, 77.4,
51.7, 20.6; IR (cm-1) 3059, 2916, 1645, 1597, 1490, 1449, 1222,
1076; MS m/z 410 (0.1), 354 (2), 333 (1), 298 (0.3), 277 (3), 259
(3), 243 (100), 165 (70), 137 (50); HRMS calcd for C29H30O2
410.2246, obsd 410.2491.
Pyridinium dichromate (40 g, 114 mmol) and MeOH (0.72
g) were added to the aldehyde (7.4 g, 18.5 mmol) in 40 mL of
dry DMF. The reaction mixture was stirred at rt for 20 h.
Ether (200 mL) and Celite (24 g) were added. The mixture
was filtered, and the residue was washed with ether. The
combined filtrate was washed with saturated aqueous NaCl
and dried (Na2SO4). Evaporation of the solvent and chroma-
tography of the residue afforded ester 6 as a colorless oil (5.7
g, 33% yield from 4): TLC Rf (15% EtOAc/petroleum ether) )
0.50; 1H NMR δ 7.43 (m, 6H), 7.28 (m, 9H), 5.89 (m, 1H), 5.23
(d, J ) 17.1 Hz, 1H), 5.12 (d, J ) 17.1 Hz, 1H), 4.12 (dd, J )
5.8, 12.7 Hz, 1H), 3.93 (dd, J ) 5.8, 12.7 Hz, 1H), 3.62 (s, 3H),
3.47 (m, 1H), 3.19 (dd, J ) 4.8, 9.7 Hz, 1H), 3.09 (dd, J ) 4.8,
9.7 Hz), 2.35 (t, J ) 7.4 Hz, 2H), 1.86 (m, 2H); 13C NMR δ u
174.0, 144.0, 116.6, 86.7, 71.2, 65.6, 30.0, 27.4; d 51.4, 77.3,
126.9, 127.7, 128.7, 135.1; IR (cm-1) 2927, 2871, 1738, 1597,
1471, 1448, 1346, 1261, 1171, 1078; MS m/z 430 (1), 353 (1),
259 (2), 243 (100), 189 (2), 131 (6), 115 (24); HRMS calcd for
C28H20O4 430.2144, obsd 430.2149.
Meth yl 2-Dia zo-4-(2-p r op en yloxy)-5-(tr ip h en ylm eth ox-
y)p en ta n oa te (7). At 0 °C, NaH (3.18g, 76.4 mmol, 60% in
mineral oil) was added to 6 (8 g, 18.6 mmol) in 50 mL of dry
DME. After 10 min at 0 °C, methyl benzoate (5.21 g, 38.3
mmol) was added all at once, then the reaction mixture was
heated to reflux for 10 h. The reaction was quenched by
cautiously adding 1 N aqueous HCl, to pH ) 4. The mixture
was partitioned between 1 N aqueous HCl and 50% EtOAc/
petroleum ether (3 × 40 mL). The combined organic extract
was washed with saturated aqueous NaCl, dried (Na2SO4),
concentrated, and chromatographed to give methyl 2-benzoyl-
4-(2-propenyloxy)-5-(triphenylmethoxy)pentanoate (8.2g, 83%
yield from 6).
DBU (4.7 g, 30.8 mmol) was added to a solution of methyl
2-benzoyl-4-(2-propenyloxy)-4-(triphenylmethoxy)pentanoate
(8.2 g, 15.4 mmol) in 40 mL of CH2Cl2 at 0 °C. After 10 min,
4-nitrobenzenesulfonyl azide (7.0 g, 30.8 mmol) was added. The
reaction mixture was warmed to rt for 2 h and then sequen-
tially partitioned between 0.5 M aqueous phosphate buffer (pH
) 7.0) and CH2Cl2. The combined organic extract was dried
(Na2SO4), concentrated, and chromatographed to give 7 (6.3
g, 75% yield from 6) as a bright yellow oil: TLC Rf (15% EtOAc/
petroleum ether) ) 0.50; 1H NMR δ 7.44 (m, 6H), 7.29 (m, 9H),
5.87 (m, 1H), 5.21 (m, 2H), 4.13 (dd, J ) 5.6, 12.7 Hz, 1H),
3.95 (dd, J ) 5.6, 12.7 Hz, 1H), 3.71 (s, 3H), 3.6 (m, 1H), 3.17
(d, J ) 5.7 Hz, 2H), 2.57 (m, 2H); 13C NMR δ u 143.8, 116.8,
87.3, 71.2, 64.8, 26.5; d 134.6, 128.6, 127.7, 127.0, 77.5, 51.8;
IR (cm-1) 2921, 2088, 1693, 1490, 1449, 1344, 1132, 1075.
Met h yl (R*,S*,R*)-2-E t h en yl-5-[(t r ip h en ylm et h oxy)-
m eth yl]-2,3,4,5-tetr a h yd r o-3-fu r a n ca r boxyla te (8a ) a n d
(R*,R*,R*)-3-(Met h ylet h en yl)-5-[(t r ip h en ylm et h oxy)-
m eth yl]-2,3,4,5-tetr a h yd r ofu r a n -2-eth a n ol (10). At 0 °C,
borane-dimethyl sulfide (0.15 mL,10 M) was added to cyclo-
hexene (250 mg) in 1.5 mL of dry THF. The reaction mixture
was stirred for 45 min at 0 °C and another 45 min at rt. Then
9 (500 mg) in 0.5 mL of dry THF was added to the reaction
mixture. After 3 h, EtOH (673 mg), aqueous NaOH (0.5 mL,
3 M), and H2O2 (0.3 mL, 33%) were added. After 1 h, the
mixture was partitioned between H2O and 40% EtOAc/
petroleum ether. The combined organic extract was dried (Na2-
SO4), concentrated, and chromatographed to give 10 (438 mg,
84% yield from 9): TLC Rf (30% EtOAc/petroleum ether) )
1
0.37; H NMR δ 7.48 (m, 6H), 7.45 (m, 9H), 4.79 (d, J ) 6.1
Hz, 2H), 4.20 (m, 1H), 3.89 (dt, J ) 3.0, 9.0 Hz, 1H), 3.79 (m,
2H), 3.11 (t, J ) 5.9 Hz, 2H), 2.78 (bs, 1H), 2.52 (q, J ) 9.0
Hz, 1H), 1.93 (m, 2H), 1.86 (m, 1H), 1.72 (s, 3H), 1.68 (m, 1H);
13C NMR δ u 144.0, 143.8, 112.1, 86.5, 66.4, 61.6, 36.2, 33.7; d
128.7, 127.7, 126.9, 82.5, 77.7, 51.7, 20.1; IR (cm-1) 3032, 2938,
1643, 1597, 1491, 1449, 1378, 1222, 1071, 899, 706; MS m/z
428 (1), 351 (1), 258 (1), 243 (100), 228 (4), 185 (2), 165 (35);
HRMS calcd for C29H32O3 428.2351, obsd 428.2321.
Tr ien e 11. At -78 °C, DMSO (1.07 g, 13.8 mmol) in 4 mL
of CH2Cl2 was added dropwisely to 2.4 mL of 3.44 M (COCl)2
in 3 mL of dry CH2Cl2. After 20 min, 10 (529 mg, 1.24 mmol)
in 2 mL of CH2Cl2 was added. After 2 h at -78 °C, Et3N (2.3
g) was added. After being warmed to rt over 1 h, the mixture
was partitioned between saturated aqueous NaHCO3 and CH2-
Cl2. The combined organic extract was dried (Na2SO4) and
concentrated to give crude aldehyde as a light yellow oil.
A few drops of 2-bromo-2-butene (2.7 g, 20 mmol) in 4 mL
of dry THF was added to 0.96 g of magnesium and a catalytic
amount of I2 in 15 mL of dry THF. The mixture was heated
Met h yl
(R*,R*,R*)-2-E t h en yl-5-[(t r ip h en ylm et h oxy)-
m eth yl]-2,3,4,5-tetr a h yd r o-3-fu r a n ca r boxyla te (8b). Di-
azo ester 7 (456 mg, 1 mmol) in a 25 mL round-bottom flask
containing a magnetic stir bar was evaporated with toluene

Assembly of Angularly Substituted Hydrindenes
J . Org. Chem., Vol. 61, No. 21, 1996 7511
to reflux to initiate the reaction. When the red color of I2 had
disappeared, the rest of the 2-bromo-2-butene solution was
added dropwise. The reaction was kept at reflux for another
1 h to give 20 mL of 1 M 1-methyl-1-propenyl-2-magnesium
bromide.
1-Methyl-1-propenyl-2-magnesium bromide (1 M in THF, 4
mL, 4 mmol) was added to the crude aldehyde in 4 mL of dry
THF at rt. After 1 h, the mixture was partitioned between
saturated aqueous NH4Cl and EtOAc. The combined organic
extract was dried (Na2SO4), concentrated, and chromato-
graphed to give allylic secondary allylic alcohol as a light
yellow oil (419 mg, 70% yield from 10).
r a n (14). To a solution of 13 (150 mg, 0.26 mmol) in dry THF
and EtOH (8 mL, 1:1 v/v) and condensed ammonia (15 mL) at
-78 °C was added sodium metal (60 mg, 2.5 mmol) until the
solution was blue. After 30 min at -78 °C, solid NH4Cl was
added until the blue color disappeared. The mixture was
warmed to rt and then partitioned between H2O and EtOAc.
The combined organic extract was dried (Na2SO4), concen-
trated, and chromatographed to give 14 as a colorless oil (71
mg, 76% yield): TLC Rf (15% EtOAc/petroleum ether) ) 0.33;
1H NMR δ 4.79 (s, 2H), 4.09 (m, 1H), 3.94 (dt, J ) 3.4, 8.6 Hz,
1H), 2.07 (t, J ) 6.3 Hz, 1H), 1.92 (m, 2H), 1.85 (m, 1H), 1.73
(s, 3H), 1.68 (m, 1H), 1.06 (m, 21H); 13C NMR δ u 144.2, 111.8,
65.4, 60.7, 37.9, 33.2; d 79.2, 78.2, 52.1, 20.1, 18.0, 12.0; IR
(cm-1) 3436, 2942, 2866, 1645, 1463, 1383, 1101, 1069; MS m/z
311 (2), 299 (55), 239 (3), 187 (13), 173 (100), 157 (18), 145
(35); HRMS calcd for C19H38O3Si (n + H) 343.2866, obsd
343.2671.
(R*,R*)-3-(Meth yleth en yl)-4-[2-[[tr is(m eth yleth yl)silyl]-
oxy]eth yl]-d ih yd r ofu r a n -2-on e (15). Compound 15 (80 mg,
0.24 mmol) was added to a refluxing solution of pyridinium
dichromate (356 mg, 0.95 mmol) and Ac2O (292 mg, 2.88 mmol)
in 1 mL of CH2Cl2 and 0.5 mL of DMF. After 2 h, Et2O (10
mL) and Celite (3 g) were added. The mixture was filtered,
and the residue was washed with ether. The combined filtrate
was washed sequentially with saturated aqueous NaHCO3 and
saturated aqueous NaCl and dried (Na2SO4). Evaporation of
the solvent and chromatography of the residue afforded lactone
15 as a colorless oil (48 mg, 63% yield from 14): TLC Rf (15%
EtOAc/petroleum ether) ) 0.62; 1H NMR δ 4.90 (bs, 2H), 4.62
(dt, J ) 3.1, 8.5 Hz, 1H), 3.85 (m, 2H), 2.86 (q, J ) 8.4 Hz,
1H), 2.62 (m, 2H), 1.92 (m, 1H), 1.80 (m, 1H), 1.76 (s, 3H),
1.04 (m, 21H); 13C NMR δ u 175.8, 141.5, 113.5, 59.3, 37.6,
34.1; d 79.9, 48.6, 19.5, 17.8, 11.8; MS m/z 327 (0.1), 297 (2),
283 (72), 253 (100), 239 (17), 211 (9), 187 (82), 157 (30), 145
(95), 131 (49), 103 (59); HRMS calcd for C18H34O3Si 327.2355,
obsd 327.2486.
At 0 °C, 2,4-dinitrobenzenesulfenyl chloride (282 mg, 1.2
mmol), 0.5 mg of methylene blue, and Et3N (202 mg, 2 mmol)
were added to the allylic alcohol (419 mg) in 8 mL of
dichloroethane. After 10 min at 0 °C, the mixture was heated
to 80 °C for 4 h. After being cooled to rt, the reaction mixture
was partitioned between saturated aqueous NaHCO3 and CH2-
Cl2. The combined organic extract was dried (Na2SO4),
concentrated, and chromatographed to give triene 11 as a light
yellow oil (289 mg, 50% yield from 10): TLC Rf (10% EtOAc/
petroleum ether) ) 0.75; 1H NMR δ 7.49 (m, 6H), 7.46 (m, 9H),
6.75 (dd, J ) 11.2, 10.5 Hz, 0.2H), 6.36 (dd, J ) 10.7, 10.8 Hz,
0.8H), 5.64 (t, J ) 7.2 Hz, 0.8H), 5.54 (t, J ) 7.0 Hz, 0.2H),
5.07 (bd, J ) 17.1 Hz, 1H), 4.91 (bd, J ) 10.7 Hz, 1H), 4.77
(m, 2H), 4.19 (m, 1H), 3.84 (m, 1H), 3.11 (m, 2H), 2.53 (m,
2H), 2.42 (m, 1H), 1.95 (m, 2H), 1.72 (s, 3H), 1.71 (s, 3H); 13C
NMR δ u 144.5, 144.2, 135.4, 113.6, 111.7, 110.7, 86.4, 66.6,
34.2, 33.1 (trans), 32.2 (cis); d 141.5, 133.7, 128.8, 127.7, 126.9,
82.1, 77.3, 50.8 (trans), 50.7 (cis), 20.2 (trans), 19.8 (cis), 11.9;
IR (cm-1) 3032, 2916, 1643, 1597, 1490, 1448, 1221, 1075, 990,
897; MS m/z 465 (10), 386 (4), 243 (100), 215 (3), 165 (37);
HRMS calcd for C33H36O2 (M + H) 465.2794, obsd 465.2750.
Tr icyclic Hyd r in d en es 12a a n d 12b. A mixture of triene
11 (142 mg, 0.31 mmol, E/Z ratio ) 82:18) and 2,5-di-tert-
butylhydroquinone (1 mg) in N,N-dimethylaniline (10 mL) was
heated in a sealed tube at 250 °C for 24 h. After being cooled
to rt, the reaction mixture was partitioned between EtOAc and,
sequentially, 3 N aqueous HCl and saturated aqueous NaH-
CO3. The combined organic extract was dried (Na2SO4),
concentrated, and chromatographed to give pure 12b (69 mg)
and a mixture of 12a and 12b (34 mg) as colorless oils (73%
overall yield). 12a : TLC Rf (40% EtOAc/petroleum ether) )
(S*,R*,R*)-2-Meth yl-3-(m eth yleth en yl)-4-[2-[[tr is(m eth -
yleth yl)silyl]oxy]eth yl]dih ydr ofu r an -2-on e (16). LDA (0.4
mL, 0.5 M in THF) was added to the lactone 15 (160 mg,
0.5mmol) in 4 mL of dry THF at -78 °C. After 1 h, MeI (284
mg) was added. The mixture was warmed to rt. After 4 h,
the mixture was partitioned between H2O and EtOAc. The
combined organic extract was dried (Na2SO4) and concen-
trated. The residue was chromatographed to give 16 as a
colorless oil (113 mg, 67% yield from 15): TLC Rf (10% EtOAc/
1
0.22; H NMR δ 5.17 (m, 1H), 4.48 (m, 1H), 4.18 (q, J ) 9.3
Hz, 1H), 3.65 (m, 2H), 2.94 (bs, 1H), 2.36-1.68 (m, 6H), 1.67
(s, 3H), 1.57-1.25 (m, 4H), 0.76 (s, 3H); 13C NMR δ u 138.0,
65.7, 35.2, 23.6, 23.4; d 119.1, 82.8, 82.7, 58.5, 56.7, 25.2, 20.9;
MS m/z 222 (22), 191 (39), 181 (40), 167 (30), 147 (100); HRMS
calcd for C14H22O2 222.1620, obsd 222.1601. 12b: TLC Rf (40%
1
petroleum ether) ) 0.49; H NMR δ 4.92 (d, J ) 1.5 Hz, 2H),
4.87 (d, J ) 6.9 Hz, 1H), 4.44 (dt, J ) 2.8, 9.5 Hz, 1H), 3.80
(m, 2H), 2.54 (m, 1H), 2.37 (m, 1H), 1.84 (m, 1H), 1.69 (s, 3H),
1.67 (m, 1H), 1.14 (d, J ) 6.8 Hz, 3H), 1.00 (m, 21H); 13C NMR
δ u 178.2, 139.8, 115.9, 59.4, 37.1; d 77.2, 58.3, 39.7, 18.5, 17.9,
13.1, 11.8; IR (cm-1) 2943, 2867, 1781, 1462, 1382, 1220, 1171,
1100; MS m/z 341 (1), 297 978), 267 (100), 253 (37), 225 (5),
187 (33), 157 (29); HRMS calcd for C19H36O3Si 340.2434, obsd
340.2459.
1
EtOAc/petroleum ether) ) 0.25; H NMR δ 5.45 (dd, J ) 3.8,
4.8 Hz, 1H), 4.58 (m, 1H), 3.92 (dt, J ) 5.7, 11 Hz, 1H), 3.71
(m, 1H), 3.69 (m, 1H), 2.31 (m, 2H), 2.25 (bs, 1H), 1.94 (m, 3
H), 1.77 (m, 1H), 1.62 (s, 3H), 1.56 (m, 2H), 1.44 (m, 1H), 1.17
(m, 1H), 0.95 (s, 3H); 13C NMR δ u 138.0, 65.9, 34.9, 34.1, 25.2,
21.4; d 120.5, 86.7, 84.3, 56.4, 54.8, 25.2, 22.2; IR (cm-1) 3020,
2911, 1456, 1376, 1249, 1114, 1055; MS m/z 222 (24), 191 (10),
173 (15), 149 (11), 147 (50), 141 (100), 121 (8), 107 (30); HRMS
calcd for C14H22O2 222.1620, obsd 222.1618.
(R*,R*,S*)-3,6-Diben zyl-4-(m eth yleth en yl)-5-m eth yl-1-
h exa n ol (17). LiAlH4 (46 mg, 1.2 mmol) was added to 16 (100
mg, 0.3 mmol) in 4 mL of dry THF at 0 °C. After 3 h at rt, the
mixture was partitioned between saturated aqueous NH4Cl
and EtOAc. The combined organic extracts were dried (Na2-
SO4) and concentrated. The residue was chromatographed to
give the diol as a colorless oil (96 mg, 94% from 16): TLC Rf
(40% EtOAc/petroleum ether) ) 0.51; 1H NMR δ 4.88 (bs, 1H),
4.81 (bs, 1H), 4.73 (bs, 1H), 4.20 (bs, 1H), 4.17-3.86 (m, 3H),
3.72 (m, 1H), 3.50 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.78
(m, 1H), 1.68 (m, 1H), 1.60 (d, J ) 0.5 Hz, 3H), 1.08 (m, 21H),
0.87 (d, J ) 6.9 Hz, 3H); 13C NMR δ u 145.4, 114.0, 67.4, 64.2,
36.4; d 74.2, 57.6, 37.8, 20.8, 17.9, 16.6, 11.7; IR (cm-1) 2961,
1642, 1464, 1382, 1260, 1088, 884, 801; MS m/z 283 (100), 253
(11), 211 (5), 171 (6), 157 (12), 135 (26); HRMS calcd for
C19H40O3Si (n - H2O) 326.2641, obsd 326.2652.
(R*,R*,R*)-2-[2-[[Tr is(m et h ylet h yl)silyl]oxy]et h yl]-3-
(m et h ylet h en yl)-5-[(t r ip h en ylm et h oxy)m et h yl]-2,3,4,5-
tetr a h yd r ofu r a n (13). Imidazole (381 mg) and DMAP (10
mg) were added to 10 (400 mg, 0.93 mmol) in 5 mL of dry CH2-
Cl2. Then TIPSiCl (2.5 mL, 0.5 M in CH2Cl2) was added. After
4 h, the mixture was partitioned between H2O and CH2Cl2.
The combined organic layer was washed with saturated
NaHCO3, dried (Na2SO4), concentrated, and chromatographed
to give 13 (510 mg, 94% yield from 10): TLC Rf (15% EtOAc/
petroleum ether) ) 0.72; 1H NMR δ 7.47 (m, 6H), 7.27 (m, 9H),
4.78 (s, 2H), 4.18 (m, 1H), 3.88 (m, 3H), 3.15 (m, 1H), 3.07 (m,
1H), 2.48 (q, J ) 8.4 Hz, 1H), 1.92 (t, J ) 7.5 Hz, 2 H), 1.82
(m, 2H), 1.72 (s, 3H), 1.08 (m, 21H); 13C NMR δ u 144.3, 144.1,
111.6, 86.7, 66.7, 60.7, 38.2, 34.2; d 128.7, 127.6, 126.8, 78.8,
77.0, 51.6, 20.0, 17.9, 11.9; IR (cm-1) 3061, 2942, 2845, 1644,
1597, 1490, 1449, 1382, 1090, 995.
At 0 °C, NaH (10 mg, 60% in mineral oil) was added to the
diol (20 mg) and benzyl bromide (31 mg) in 1 mL of dry THF.
After 18 h at rt, the mixture was partitioned between water
and EtOAc. The combined organic extract was dried (Na2SO4),
concentrated, and chromatographed to give the diprotected
benzyl ether as a colorless oil (29 mg, 97% yield from the
(R*,R*,R*)-2-[2-[[Tr is(m et h ylet h yl)silyl]oxy]et h yl]-3-
(m eth yleth en yl)-5-(h yd r oxym eth yl)-2,3,4,5-tetr a h yd r ofu -

7512 J . Org. Chem., Vol. 61, No. 21, 1996
Taber and Song
1
diol): TLC Rf (20% EtOAc/petroleum ether) ) 0.84; H NMR
δ 7.31 (m, 10H), 4.93 (s, 1H), 4.70 (s, 1H), 4.56 (s, 2H), 4.46 (s,
2H), 3.82 (m, 3H), 3.44 (dd, J ) 5.7, 9.1 Hz, 1H), 3.34 (dd, J )
5.7, 9.1 Hz, 1H), 2.52 (t, J ) 7.3 Hz, 1H), 2.25 (m, 1H), 1.83
(m, 1H), 1.74 (s, 3H), 1.71 (m, 1H), 1.06 (m, 21H), 0.95 (d, J )
6.8Hz, 3H); 13C NMR δ u 143.9, 139.0, 138.8, 114.3, 74.1, 72.9,
71.7, 60.1, 35.5; d 128.2, 127.8, 127.5, 127.3, 76.0, 50.8, 32.9,
23.7, 18.1, 14.9, 12.0; IR (cm-1) 2942, 2866, 2360, 1460, 1496,
1453, 1365, 1259, 1097; MS m/z 373 (4), 283 (98), 229 (12),
187 (31), 157 (23), 145 (100); HRMS calcd for C33H52O3Si (n -
C3H7) 481.3137, obsd 481.3141.
114.4, 113.4, 110.4, 74.6, 72.8, 71.4, 30.5; d 141.7, 134.0, 129.5,
128.3, 127.9, 127.8, 127.6, 127.4, 127.3, 79.0, 50.9, 32.7, 23.9,
19.9, 13.9, 11.9; MS m/z 405 (3), 313 (24), 205 (42), 189 (24);
HRMS calcd for C28H36O2 (n + H) 4.5,2793, obsd 405.2779.
Bicyclic Hyd r in d en es (19a a n d 19b). A mixture of triene
18 (10 mg, 0.029 mmol, E/Z ratio ) 86:14) and 1,4-di-tert-
butylhydroquinone (1 mg) in N,N-dimethylaniline (2 mL) was
heated in a sealed tube at 250 °C for 24 h. After being cooled
to rt, the reaction mixture was partitioned between ethyl
acetate and, sequentially, 3 N aqueous HCl and saturated
aqueous NaHCO3. The combined organic extract was dried
(Na2SO4), concentrated, and chromatographed to give a mix-
ture of 19a and 19b as a colorless oil (7 mg, 70% yield). 19a
and 19b : TLC Rf (15% EtOAc/petroleum ether) ) 0.75; 1H
NMR δ 7.31 (m, 10H), 5.37 (bs, 0.25H, cis), 5.24 (bs, 0.75H,
trans), 4.45 (m, 3H), 4.21 (m, 1H), 3.76 (m, 1H), 3.59 (m, 1H),
3.20 (t, 1H, J ) 9.3 Hz), 2.36 (m, 1H), 2.01-1.82 (m, 4H), 1.63
(s, 3H), 1.45-1.25 (m, 4H), 1.11 (d, 3H, J ) 6.4 Hz), 0.89 (s,
0.75H, cis), 0.72 (s, 2.25H, trans); 13C NMR δ u 138.8, 138.4,
134.0, 75.4, 72.9, 71.5, 42.7, 36.2, 30.6; d 128.4, 128.3, 128.0,
127.6, 127.5, 127.4, 120.1, 84.6, 59.8, 48.9, 35.9, 20.9, 17.6, 14.1
(cis), 12.9 (trans); MS m/z 404 (3), 313 (24), 205 (42), 189 (24);
HRMS calcd for C28H36O2 404.2715, obsd 404.1730.
Aqueous 1 M HCl (1 mL) was added to the diprotected
benzyl ether (40 mg, 0.076 mmol) in 1 mL of THF at rt. After
14 h, the mixture was partitioned between saturated aqueous
NaHCO3 and EtOAc. The combined organic extract was dried
(Na2SO4), concentrated, and chromatographed to give 17 as a
colorless oil (27 mg, 89% yield from 16): TLC Rf (20% EtOAc/
petroleum ether) ) 0.29; 1H NMR δ 7.32 (m, 10H), 4.96 (s,
1H), 4.71 (s, 1H), 4.60 (d, J ) 11.1 Hz, 1H), 4.52 (d, J ) 11.1
Hz, 1H), 4.47 (s, 2H), 3.83 (dt, J ) 3.0, 7.7 Hz, 1H),3.78 (m,
2H), 3.35 (m, 2H), 2.61 (t, J ) 7.4 Hz, 1H), 2.21 (m, 1H), 2.11
(m, 1H), 1.86 (m, 1H), 1.74 (s, 3H), 1.70 (m, 1H), 0.93 (d, J )
6.9 Hz, 3H); 13C NMR δ u 143.6, 138.3, 114.5, 74.1, 73.0, 71.4,
60.5, 33.2; d 128.4, 128.3, 128.0, 127.7, 127.5, 78.0, 50.2, 33.0,
23.9, 15.1; IR (cm-1) 3030, 2963, 1496, 1453, 1366, 1261, 1095,
1028.
(R *,R *,S *)-3-Me t h yl-6-(p h e n ylm e t h oxy)-7-(m e t h yl-
eth en e)-8-m eth yl-9-(p h en ylm eth oxy)-1,3-n on a d ien e (18).
Triene 18 was prepared as triene 11 (15 mg, 56% yield from
17): TLC Rf (10% EtOAc/petroleum ether) ) 0.56; 1H NMR δ
7.3 (m, 10H), 6.73 (dd, J ) 10.8, 11.2 Hz, 0.25H), 6.33 (dd, J
) 10.7, 10.8 Hz, 0.75H), 5.63 (t, J ) 7.2 Hz, 0.75H), 5.54 (t, J
) 8.1 Hz, 0.25H), 5.09 (bd, J ) 17.2 Hz, 1H), 4.92 (bs, 2H),
4.63 (bd, J ) 10.3 Hz, 1H), 4.45 (s, 4H), 3.67 (m, 1H), 3.37 (m,
1H), 3.26 (m, 1H), 2.55-2.26 (m, 4H), 1.71 (s, 3H), 1.7 (s, 3H),
0.90 (d, J ) 6.8 Hz, 3H); 13C NMR δ u 143.8, 138.8, 135.1,
Ack n ow led gm en t. We thank Dr. Gordon Nichol for
high-resolution mass spectra and Dr. Martha Bruch for
high-resolution NMR spectra.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds are available (32 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
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