Doubly Diastereocontrolled Cyclization Based on Intramolecular Conjugate Addition Reactions Involving an Allylic Radical and an Anion

Full text of DOI:10.1021/jo980188t

J . Org. Chem. 1998, 63, 4151-4157
4151
Sch em e 1
Dou bly Dia ster eocon tr olled Cycliza tion
Ba sed on In tr a m olecu la r Con ju ga te
Ad d ition Rea ction s In volvin g a n Allylic
Ra d ica l a n d a n An ion
Takashi Tokoroyama*,† and Takehiko Aoto‡
Department of Material Science, Faculty of Science, Osaka
City University, 3-3-138 Sugimoto, Sumiyoshi-ku,
Osaka 558, J apan
Received February 3, 1998
was obtained as a mixture of (E) and (Z) isomers (11a /
11b ) 1:1). Cyclization of the (E) isomer 11a was
performed by refluxing of the benzene solution with tri-
n-butyltin hydride in the presence of AIBN. The reaction,
after equilibration of the product with sodium methoxide
in methanol, afforded a mixture of trans-fused decalone
derivatives in 95% yield. Analysis of the mixture with
1H NMR revealed that it was composed of three diaster-
eomers 2a , 2b, and 2c in a 77:21:2 ratio (Scheme 3). The
diastereomeric products ratio should be invariant as
regards the double-bond geometry of the cyclization
precursor 11, since reaction of the 1:1 E/Z mixture was
found to give a mixture of decalones 2a -c in exactly the
same ratio. An attempt to conduct the cyclization at
lower temperature using triethylborane/oxygen as radical
initiator10 resulted in the recovery of the starting mate-
rial. The stereochemistry of the major product 2a was
identified by comparison of spectral data with those of
an authentic sample.1,2 Configurational assignment of
the other two products 2b and 2c was secured by
reference of the 1H NMR to that of the authentic mixture
2a -d derived from Birch reduction of the previously
obtained octalone mixture 12a -d (Scheme 4).11
As the substrate for the anionic cyclization, we de-
signed allylic phosphine oxide 13 and allylic sulfone 14.12
Compounds 13, both in (E) and (Z) forms, and 14 with
(E) configuration were synthesized stereoselectively as
shown in Scheme 5. First, (E) and (Z) side chain
synthons 8a and 8b were prepared according to the
previously reported method for the stereodivergent syn-
thesis of trisubstituted olefines.13 This time, in the
alkylation of enol phosphates 18, the reaction condition
was improved in such a way that the reagent and the
catalyst were used in fairly less amounts than those
reported before. For the (E) series, the stereoselectivity
was >99% in both phosphorylation and alkylation steps,
while in the case of the (Z) series isomerization of a minor
degree occurred in the latter reaction to afford the
product 19b with a purity ratio of 96:4. The iodides 8
were attached to the cyclohexenone moiety as before, and
after chlorination of the hydroxyl terminals, the intro-
Maximization of efficiency is nowadays a pivotal
problem for synthetic organic chemists. Stereoselective
cyclizations represented by a variety of cycloaddition
reactions are a means to meet this demand. Previously,
we reported a doubly stereocontrolled cyclization based
on the intramolecular Hosomi-Sakurai reaction (Scheme
1),1 application of which led to the efficient stereoselective
total synthesis of a cis-clerodane diterpenoid.2 One of the
involved stereoselectivities (diastereoface selection) has
been generalized in terms of folding strain stereocon-
trol,1,3,4 and the potentiality of the ring-closure reactions
based on this concept as an additional stereochemical
strategy has been pointed out.5 With the aim of develop-
ing the scope of their utility, we carried out an examina-
tion of diastereoselectivity in radical and anionic versions
of the cyclization reaction 1 f 2a . Comparison of the
diastereoselectivity in regard to the TS characteristics
associated with the reaction types6 would be intriguing,
and in particular, the stereoselectivity in radical reactions
is an issue of current interest.7
Resu lts
2-[(E)-6-Bromo-3,4-dimethyl-4-hexenyl]-2-cyclohex-
enone (11a ), the substrate for the radical cyclization, was
prepared stereoselectively as shown in Scheme 2 by the
use of Claisen rearrangement under J ohnson’s condition8
and Smith’s coupling procedure9 as the key steps. When
the conversion of allyl alcohol 10 to the corresponding
bromide was conducted by way of a mesylate, the product
* To whom correspondence should be addressed.
† Present address: 3-25-1 Makizuka-dai, Sakai-shi, Osaka, J apan
590-0114.
‡ Present address: J apan Tobacco Inc., Central Pharmaceutical
Research Institute, 1-1 Murasaki-cho, Takatsuki-shi, Osaka, J apan
569-1125.
(1) Tokoroyama, T.; Tsukamoto, M.; Iio, H. Tetrahedron Lett. 1984,
25, 5067-5070.
(2) Tokoroyama, T.; Tsukamoto, M.; Asada, T.; Iio, H. Tetrahedron
Lett. 1987, 28, 6645-6648.
(3) Tokoroyama, T.; Okada, K.; Iio, H. J . Chem. Soc., Chem.
Commun. 1989, 1572-1573.
(4) Tokoroyama, T.; Kusaka, H. Can. J . Chem. 1996, 74, 2487-2502.
(5) For review, see: Tokoroyama, T. J . Synth. Org. Chem. J pn. 1996,
54, 586-595.
(6) Paddon-Row, M. N.; Rondon, N. G.; Houk, K. N. J . Am. Chem.
Soc. 1982, 104, 7162-7166.
(9) Guaciaro, M. A.; Wovkulich, P. M.; Smith, A. B., III. Tetrahedron
Lett. 1978, 4661-4664.
(7) For review, see: (a) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions: Concepts, Guidelines, and
Synthetic Applications; VCH: Weinheim, 1996. (b) Curran, D. P. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds;
Pergamon: New York, 1991; Vol. 4, pp 778-831. (c) J asperse, C. P.;
Curran, D. P. Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286. (d) Giese,
B. Radicals in Organic Synthesis: Formation of Carbon-Carbon
Bonds; Pergamon: New York, 1986. (e) Giese, B.; Kopping, B.; Gobel,
T.; Dickhaut, J .; Thomas, G.; Kulicke, K. J .; Trach, F. In Organic
Reactions; J ohn Wiley & Sons Inc.: New York, 1996; Vol. 48, Chapter
2.
(10) (a) Nozaki, K.; Oshima, K.; Utimoto, K.Tetrahedron Lett. 1988,
29, 6125-6126. (b) Nozaki, K.; Ohshima, K.; Utimoto, K. J . Am. Chem.
Soc. 1987, 109, 2547-2549.
(11) Tokoroyama, T.; Kato, M.; Aoto, T.; Hattori, T.; Iio, H.; Odagaki,
Y. Tetrahedron Lett. 1994, 35, 8247-8250.
(12) For diastereoselectivity in intermolecular conjugate addition of
the carbanions derived from phosphine oxides and sulfones, see: (a)
Binns, M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P. A.; Vonwiller,
S. C. J . Am. Chem. Soc. 1988, 110, 5411-5423 and references therein.
(b) Haynes, R. K.; Katsifis, A. G.; P. A.; Vonwiller, S. C.; Hambley, T.
W. J . Am. Chem. Soc. 1988, 110, 5423-5433. (c) Haynes, R. K.;
Vonwiller, S. C.; Hambley, T. W. J . Org. Chem. 1989, 54, 5162-5170.
(13) Asao, K.; Iio, H.; Tokoroyama, T. Synthesis 1990, 382-386.
(8) J ohnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brockson, T.
J .; Li, T.-T.; Faukner, D. J .; Peterson, M. R. J . Am. Chem. Soc. 1970,
92, 741-743.
S0022-3263(98)00188-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/27/1998

4152 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
Sch em e 2
Ta ble 1. 1,4- vs 1,2-Ad d ition in An ion ic Cycliza tion of
P h op h in e Oxid es 13
Sch em e 3
product
ratio
temp time yield
entry substrate additive
(°C)
(h)
(%)
(23:24)
1
2
3
4
5
6
13a
13a
13a
13a
13a
13b
LiBra
-78
-40
-20
-78
-40
-40
1.5
1.5
1.5
1.5
1.5
3.0
44
38
64
41
71
30
100:0
1:3
LiBra
LiBra
0:100c
1:3
HMPAb
HMPAb
HMPAb
0:100
0:100
a
b
1.1 equiv. 23%. c Contaminated with
a small amount of
diastereomers.
tion products, a hydroxyoctaline 23 and a decalone 24
(Scheme 6) and that the formation ratio was altered
depending on the presence of additives such as lithium
bromide or HMPA and the reaction temperature. The
results in these regards are summarized in Table 1.
Whereas addition of lithium bromide and lower reaction
temperature favored the formation of 23, the reaction in
the presence of HMPA and at higher temperature gave
24 preferentially. Thus exclusive formation of 23 and
24 was observed in the reactions, respectively, with
lithium bromide at -78 °C (entry 1) and with HMPA at
-40 °C (entry 5). Reaction of (Z) substrate 13b under
the latter conditions afforded 24 selectively similar to
that of (E) substrate 12a but at somewhat slower rate
(entry 6). The reaction at temperatures higher than -40
°C resulted in the contamination of diastereomers of 24.
Close spectroscopic analyses of both products revealed
that the former compound 23 represented the product of
1,2-intramolecular addition and that the latter compound
24 represented the product of intramolecular 1,4-
conjugate addition. Although the rigid stereochemical
assignment for 23 was not achieved (see Discussion), 24
was determined to have the same configuration as 2a by
a direct chemical correlation as shown in Scheme 7.
Sch em e 4
duction of phosphine oxide and sulfone groups was
performed to give the desired products 13a , 13b, and 14.
No appreciable isomerization was observed through
conversion of 19 to 13 or 14.
The cyclization was first examined for the allylic
sulfone 14. However, it showed no sign of the reaction
on treatment with LDA at -78 °C to room temperature,
being recovered unchanged. Then the preliminary ex-
periments on (E) allylic phosphine oxide 13a indicated
that treatment with LDA afforded two kinds of cycliza-
Since the decalone derivative 24 has the same stere-
ochemistry as that of clerodane diterpenoids at three
consecutive stereogenic centers (8, 9, and 10 in clerodane
numbering),14 we investigated further on the utilization
of the anionic cyclization method for their synthesis, to
(14) Meritt, A.; Ley, S. V. Nat. Prod. Rep. 1992, 243-287.
(15) (a) Hanessian, S.; Dhanoa, D. S.; Beaulieu, P. L. Can. J . Chem.
1987, 65, 1859-1866. (b) Reference 7a, pp 77-81.

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4153
Sch em e 5
which stereoselective introduction of an angular sub-
stituent at C-5 position turned out to be a requisite task.
One approach to this end is delineated in Scheme 8. The
enolate intermediate formed on the anionic cyclization
of 13a was trapped with allyl bromide to afford an allyl
enol ether, Claisen rearrangement of which gave product
26 as a single diastereomer. In the 1H NOESY NMR
spectrum, correlations were observed between 9-methyl
protons and respective axial protons at C-3 and C-7.
Thus, compound 26 was deduced to have a cis-steroidal
conformation.
Discu ssion
The cyclization of 11a under radical conditions proved
to proceed smoothly, but the diastereoselectivity was
lower in comparison with the case of an analogous
reaction involving the allylsilane substrate 1, although
the temperature effect on stereoselectivity has to be taken
into account. The cyclization involves two types of
diastereoselectionsone is simple diastereoselection as
regards mutual orientation of the two sp2 carbon atoms
which participate in bond formation and the other is
diastereoface selection with respect to the stereogenic
center (3′-C) present in the side chain of substrate 11a .
These diastereoselections would be rationalized in a
manner similar to that of the previous case respectively
in terms of orientation stereocontrol1 and folding strain
stereocontrol.1,3,4 Namely, by the orientation stereocon-
trol the preference of antiperiplanar TS 27a over syncli-
nal TS 27b (or TS 27d over TS 27c, Scheme 9) is assumed
from steric15 and stereoelectronic reasons, and the folding
strain stereocontrol predicts the prepondrance of TS 27a
over TS 27d (TS 27b over TS 27c) due to the presence of
stronger A1,3-strain and additional gauche effects4,5 in TS
27d and TS 27c. Thus, the order of preference in the
diastereomeric TS’s is 27a > 27b > 27c; hence that in
the favored formation of diastereomers, 2a > 2b > 2c, is
Sch em e 6
Sch em e 7
Sch em e 9
Sch em e 8

4154 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
Sch em e 10
explained, though the reason for preference of TS 27c
over 27d is not clear. The diastereoface selection in-
volved (27a > 27d or 27b > 27c) is also accommodated
by Beckwith’s model7,16 for the stereoselective 6-exo
radical cyclization, which predicts the preference of TS
with an equatorial-like substituent. When the contribu-
tion to the observed diastereomer ratio is compared to
the orientation and the folding strain stereocontrols, the
selectivity (normal versus reversed) is 77:23 (27a :27b +
27c) and 98:2 (27a + 27b:27c) respectivelysnamely the
folding strain stereocontrol is effective enough also in the
present radical reaction, whereas the orientation stereo-
control decreases considerably. It is noteworthy that the
folding strain stereocontrol is relatively unaffected by the
TS position in the reaction coordinate, but this is not
unexpected from the nature of major strain factors
concerned with the chain folding.6,17 The lowering of the
orientation control in the radical reaction would be
associated, partly at least, with the relatively less
constrained TS conformation due to its early nature,7
which should decrease the strain energy difference
between antiperiplanar and synclinal orientations of the
interacting two π-orbitals.
For the anionic cyclization of the substrate 13, two
selectivity problems are to be discussedsone is the
selectivity of 1,4- versus 1,2-intramolecular addition
reactions and the other is diastereoselectivity. Exclusive
formation of the 1,2-addition product 23 for the reaction
in the presence of lithium bromide at -78 °C (Table 1,
entry 1) indicates that it assists the carbonyl addition
reaction through the enhancement of charge separation
by the complexation of the lithium cation rather than the
suppression of R-proton transfer, which contrasts to the
situation in a reported12a intermolecular case. The
reaction at higher temperature (entry 2) turned out to
form a larger amount of the intramolecular 1,4-addition
product 24, until the reaction at -20 °C afforded 24,
mixed with a small amount of diastereomers, without the
formation of 1,2-product 23 (entry 3). These results are
anticipated from the reversible nature of conjugate
additions involving π-stabilized carbanions,18 as demon-
strated in many examples. The suppressing effect of
HMPA, a polar and highly coordinating solvent, on
carbonyl addition is also well documented,18,19 and in line
with this, the addition of HMPA resulted in the preferred
formation of 24, the exclusive production of which was
achieved in the reaction at -40 °C (entry 5). Thus, the
anionic cyclization of 13 is shown to proceed under the
effective orientation and folding strain stereocontrols in
a way similar to that in the case of the conversion 1 f
2a based on the Hosomi-Sakurai reaction. Different
from intermolecular reactions,12 (E) and (Z) substrates
13a and 13b exhibited the same stereoselectivity on
cyclization. The reaction of 13b, slower than that of 13a ,
might reflect the stronger A1,3 repulsion present in TS
28 derived from the former (Scheme 10).
sion 13a f 26. This fact would widen synthetic utility
of the anionic cyclization method, the product 26 having
functionalities such as the 4-keto group and the phos-
phine oxide group which would serve for further manipu-
lation of the molecule. Thus, compound 26 could be a
useful intermediate for the synthesis of cis-clerodane
diterpenoids.2,20,21
Finally, the probable steric configuration for 1,2-
addition product 23 remains to be mentioned. Provided
that the reaction would proceed under the normal
orientation and folding strain stereocontrols as experi-
enced in conversions, 1 f 2a or 13 f 24, the stereostruc-
ture 23a for the product is readily rationalized. The
assumption of trans-decalyl TS 29 involving chelation of
the lithium cation by a carbonyl group, similar to the one
postulated in the intermolecular case,12 might also ex-
plain the simple diastereoselection in the same direction
(orientation control). Spectroscopic evidence corroborat-
ing the assignment of stereoformula 23a is provided from
the comparison of chemical shift data in the 1H NMR
spectrum of 23 with those of 1,4-addition product 24. The
product 23 exhibits the signals due to the â-proton of the
vinyl phosphine oxide group at δ 6.91, a considerably
deshielded position relative to that of 24 (δ 6.52), whereas
the signals due to secondary methyl protons appear at
similar positions in both products (δ 0.70 and δ 0.73
respectively). This fact indicates that the â-proton rather
than the secondary methyl protons in 23 is influenced
by the deshielding anisotropy effect of the hydroxyl
oxygen atom, being in conformity with the assignment
of the formula 23a .
Con clu sion
Radical and anionic cyclizations analogous to the
dually diastereoselective cyclization reaction 1 f 2a have
been investigated, aiming to see the relevance of the
stereoselectivity to the type of reaction. Lowering of the
diastereoselectivity in the radical cyclization of 11 to give
a mixture of diastereomers (2a /2b/2c ) 77:21:2) was
found to connect mainly with the orientation stereocon-
trol, and thus the folding strain stereocontrol remained
effective at a ratio as high as 98:2, which is notable in
view of early TS nature of the reaction. The anionic
cyclization of (E)- and (Z)-phosphine oxides 13a and 13b,
both prepared stereoselectively, was achieved without the
formation of 1,2-addition product 23 by treatment with
An additional advantage of the anionic cyclization 13
f 24 is the enolate trapping exemplified by the conver-
(16) (a) Beckwith, A. L. J . Tetrahedron 1981, 37, 3073-3100. (b)
Beckwith, A. L.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-3941
and references therein.
(17) Burkert, U.; Allinger, N. L. Molecular Mechanics; American
Chemical Society: Washington, DC, 1982; pp 86-88.
(18) Perlmutter, P. Conjugate Addition Reactions in Organic Syn-
thesis; Pergamon: New York, 1992; pp 7-9.
(19) Lee, V. J . In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds; Pergamon: New York, 1991; Vol. 4, pp 71-72.
(20) Tokoroyama, T. J . Synth. Org. Chem. J pn. 1993, 51, 1164-
1177.
(21) For a recent approach, see: Liu, H.-J .; Shia, K.-S.; Han, Y.;
Sun, D.; Wand, Yu. Can. J . Chem. 1997, 75, 646-655.

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4155
Hz), 1.34-1.54 (2H, m), 1.60 (3H, s), 1.97 (2H, tt, J ) 7.0, 6.1
Hz), 2.15-2.06 (3H, m), 2.34 (2H, td, J t ) 6.1, J d ) 4.3 Hz),
2.40 (2H, t, J ) 7.0 Hz), 4.16 (2H, d, J ) 7.0 Hz), 5.41 (1H, d, J
) 7.0 Hz), 6.70 (1H, t, J ) 4.3 Hz); 13C NMR (100 MHz) δ 12.6,
19.5, 23.2, 26.1, 27.7, 33.8, 38.6, 42.5, 59.4, 123.4, 140.0, 143.4,
144.9, 199.5„ MS (m/z) 222 (M+, 0.7), 95 (100); HRMS calcd for
LDA at -40 °C using HMPA as additives to afford
decalone derivative 24 as a single diastereomer, being
highly stereoselective as in the conversion 1 f 2a . The
stereoselective introduction of a cis-angular substituent
to 24 was performed via enolate trapping to give 26,
which could be a useful intermediate for the synthesis
of cis-clerodane diterpenoids.
C
14H22O2 222.1620, found 222.1638.
2-[(E )-6-Br om o-3,4-d im e t h yl-4-h e xe n yl]-2-cycloh e x-
en on e (11a ). Phosphorus tribromide (0.12 mL, 1.26 mmol) was
added to a solution of 10 (520 mg, 2.34 mmol) in hexane (2 mL)
at 0 °C and the mixture was stirred for 10 min, before it was
quenched by the addition of MeOH. A saturated NaHCO3
solution was added, and product was extracted with Et2O.
Crude product was purified by chromatography on a silica gel
column (hexane/Et2O 29/1) to afford the title bromide 11a (334
mg, 50%) without admixture of (Z) isomer. 11a : IR (neat) 1680
cm-1; 1H NMR (400 MHz) δ 1.00 (3H, d, J ) 7.0 Hz), 1.38-1.49
(2H, m), 1.66 (3H, s), 1.97 (2H, tt, J ) 7.0, 6.1 Hz), 2.07 (2H, br
Exp er im en ta l Section
NMR specta were recorded in CDCl3 solutions at either 90 or
400 MHz for 1H and at 100 MHz for 13C NMR. MS spectra were
obtained using EI ionization. Merck Art 5715 (0.25 mm thick-
ness) and 5744 (0.5 mm thickness) silica gel plates (60-F254) were
used for analytical and preparative TLC, respectively. Flash
chromatography was performed using either Fuji-Davison BW-
820MH or BW-300MH silica gel. Gas chromatographic analyses
were performed on an instrument equipped with an OV-1
column. For use in reactions at anhydrous conditions, THF,
diethyl ether, and benzene were distilled from sodium-ben-
zophenone ketyl. DMF, diisopropylamine, HMPA (highly toxic
cancer suspect agent), and DMSO were distilled from CaH2, and
dichloromethane, carbon tetrachloride, acetonitrile, and 1,2-
dichloroethane were distilled over P2O5. Usual workup was
carried out as follows: the quenched reaction mixture was
extracted three times with Et2O and the combined organic layers
were washed successively with pertinent aqueous wash solution
and saturated brine and then dried with anhydrous MgSO4. The
solvent was removed by rotary evaporation. The standard
procedure was employed for handling air-sensitive reagents, and
all reactions were carried out under Ar.
t, J ) 7.9 Hz), 2.14 (1H, sextet, J ) 7.0 Hz), 2.34 (2H, td, J t
)
6.1, J d ) 4.3 Hz), 2.41 (2H, t, J ) 7,0 Hz), 4.05 (2H, d, J ) 7.9
Hz), 5.55 (1H, t, J ) 7.8 Hz), 6.70 (1H, t, J ) 4.3 Hz); 13C NMR
(100 MHz) δ 12.3, 19.3, 23.2, 26.1, 27.9, 29.6, 33.8, 38.7, 42.5,
120.4, 139.8, 145.2, 147.6, 199.4; MS (m/z) 204 (M+ - HBr, 31),
95 (100); HRMS calcd for C14H20O (M+ - HBr) 204.1514, found
204.1542.
A mixture of 11a with (Z) isomer 11b (1:1) was obtained in
34% yield, when 8 was first mesylated by treatment of mesyl
chloride and Et3N in CH2Cl2 at 0 °C for 3 h and the mesylated
product was heated with LiBr in acetone under reflux for 1 h.
11b: 1H NMR (400 MHz) δ 1.01 (3H, d, J ) 7.0 Hz), 1.38-1.49
(2H, m), 1.66 (3H, s), 1.97 (2H, tt, J ) 7.0, 6.1 Hz), 2.07 (2H,
brt, J ) 7.9 Hz), 2.14 (1H, sextet, J ) 7.0 Hz), 2.33 (2H, td, J t
) 6.1, J d ) 4.3 Hz), 2.41 (2H, t, J ) 7.0 Hz), 4.10 (2H, d, J ) 7.9
Hz), 5.46 (1H, t, J ) 7.9 Hz), 6.70 (1H, t, J ) 4.3 Hz); 13C NMR
(100 MHz) δ 12.4, 19.4, 23.2, 26.1, 27.9, 29.6, 33.7, 38.7, 42.3,
120.2, 139.9, 145.1, 146.6, 199.4.
2-[(E)-6-ter t-Bu tyld im eth ylsilyloxy-3,4-d im eth yl-4-h ex-
en yl]-2-cycloh exen esp ir o-2′,5′-d ioxa cyclop en ta n e (9a ). A
1.68 M hexane solution of tert-butyllithium (16 mL, 26.9 mmol)
was added dropwise to a solution of 2-bromo-2-cyclohexenespiro-
2′,5′-dioxacyclopentane (3.7 g, 16.9 mmol) in anhydrous THF (30
mL) cooled to -78 °C and the mixture was stirred for 1 h, before
a solution of (E) iodide 8a (2.1 g, 5.7 mmol) in a mixture of
HMPA (9 mL) and THF (6 mL) was added dropwise. After
removal of the cooling bath, the reaction mixture was stirred
for 2 h and was quenched by the addition of water and then
extracted with Et2O. The extract solution was dried with
anhydrous K2CO3, and the crude product thus obtained was
purified by silica gel chromatography (hexane/Et2O 19/1) to
furnish the title ketal 9a (1.78 g, 82% yield) as a colorless oil:
1H NMR (400 MHz) δ 0.06 (6H, s), 0.90 (9H, s), 0.99 (3H, d, J )
7.0 Hz), 1.41 (1H, m), 1.53 (3H, s), 1.67-1.73 (4H, m), 1.89-
2.11 (5H, m), 3.97 (4H, s), 4.20 (2H, d, J ) 6.1 Hz), 5.30 (1H, t,
J ) 6.1 Hz), 5.68 (1H, t, J ) 3.7 Hz); 13C NMR (100 MHz) δ
-5.0, 12.8, 15.3, 19.5, 20.8, 25.3, 26.0, 27.5, 34.0, 34.2, 42.8, 60.4,
65.0, 107.9, 124.2, 128.4, 138.4, 140.6; MS (m/z) 380 (M+, 5), 75
(100); HRMS calcd for C22H40O3Si 380.2747, found 380.2733.
2-[(Z)-6-ter t-Bu tyld im eth ylsilyloxy-3,4-d im eth yl-4-h ex-
en yl]-2-cycloh exen esp ir o-2′,5′-d ioxa cyclop en ta n e (9b). The
coupling reaction of 2-lithio-2-cyclohexene-spiro-2′,5′-dioxacy-
clopentane with (Z) iodide 8b in the same way as above gave
title product 9b in 75% yield: 1H NMR (400 MHz) δ 0.06 (6H,
s), 0.90 (9H, s), 0.98 (3H, d, J ) 7.0 Hz), 1.45 (2H, m), 1.60 (3H,
d, J ) 1.2 Hz), 1.67-1.75 (4H, m), 1.90 (2H, m), 2.20 (2H, m),
Cycliza tion of 11a a t Ra d ica l Con d ition s. To a solution
of the bromide 11a (49 mg, 0.173 mmol) in anhydrous benzene
(30 mL) were added tributyltin hydride (0.06 mL, 0.2 mmol) and
AIBN (3.4 mg, 0.02 mmol), and the mixture was refluxed for 2
h. After addition of water, the product was extracted with Et2O
and Et2O layers were washed successively with a saturated KF
solution and brine. The obtained crude product dissolved in
anhydrous MeOH (2 mL) was treated with sodium methoxide
(10 mg) overnight under stirring. After the reaction was
quenched by the addition of a 1 M HCl solution, the reaction
miture was worked up as usual. Purification by silica gel
chromatography (hexane/Et2O 29/1) gave a diastereomeric mix-
ture of cyclization products 2, 34 mg (95% yield), as a colorless
oil: MS (m/z) 206 (M+, 25); HRMS calcd for C14H22O 206.16,
found 206.1696. The following 1H (400 MHz) and 13C (100 MHz)
NMR signals were readable with reference to the authentic
mixture.11 1H NMR: (4a S*,5S*,6R*,8a R*)-3,4,4a ,5,6,7,8,8a -
octa h yd r o-5,6-d im eth yl-5-vin yl-1(2H)-n a p h th a len on e (2a ),
δ 0.73 (3H, d, J ) 6.7 Hz), 0.89 (3H, s), 1.14-1.59 (7H, m), 1.79
(1H, dt, J d ) 12.8, J t ) 2.4 Hz), 1.87-2.08 (2H, m), 2.16-2.39
(3H, m), 4.95 (1H, dd, J ) 17.7, 1.2 Hz), 5.47 (1H, dd, J ) 17.7,
11.0 Hz); (4a S*,5R*,6R *,8aR*)-3,4,4a ,5,6,7,8,8a -octa h yd r o-
5,6-d im eth yl-5-vin yl-1(2H)-n a p h th a len on e, (2b), δ 0.77 (3H,
d, J ) 6.1 Hz), 5.02 (1H, dd, J ) 11.0, 1.8 Hz), 5.25 (1H, dd, J
)
11.0, 1.8 Hz), 5.98 (1H, dd,
J
) 17.7, 11.0 Hz);
2.55 (1H, sextet, J ) 7.0 Hz), 3.97 (4H, m), 4.14 (1H, ddq, J d
)
(4aS*,5R*,6S*,8aR*)-3,4,4a,5,6,7,8,8a-octah ydr o-5,6-dim eth yl-
5-vin yl-1(2H)-n a p h th a len on e (2c), δ 6.38 (1H, dd, J ) 17.7,
11.0 Hz). 13C NMR: 2a , δ 8.9, 16.6, 25.5, 26.1, 26.4, 28.7, 39.8,
41.9, 44.2, 49.4, 51.8, 113.2, 147.9, 213.4; 2b, δ 16.8, 22.0, 25.7,
26.0, 26.1, 29.5, 41.3, 41.6, 43.6, 50.1, 53.2, 116.4, 137.7, 213.4.
Eth yl (Z)-6-Ben zyloxy-3-d ieth ylp h osp h or yloxy-4-m eth -
yl-2-h exa n oa te (18a ). To a suspension of NaH (60% oil
dispersion, 1.0 g, 25 mmol, washed with hexane before use) in
Et2O (100 mL), cooled to 0 °C, was added a solution of â-keto
ester 17 (5.95 g, 21.4 mmol) in Et2O (20 mL), and after stirring
of the mixture for 20 min, diethyl chlorophosphate was added.
After removal of the ice bath, the stirring was continued for 4 h
and then the reaction was quenched by the addition of a
saturated NH4Cl solution. The crude product was chromato-
graphed on a column of silica gel (hexane/Et2O 1/1) to provide
the title compound 18a (8.33 g, 94% yield) as a colorless oil. As
12.2, J d′ ) 6.1, J tq ) 1.2 Hz), 4.23 (1H, ddq, J d ) 12.2, J d′ ) 7.3,
J tq ) 1.2 Hz), 5.29 (1H, dd, J ) 7.3, 6.1, Hz), 5.68 (1H, t, J ) 3.7
Hz); 13C NMR (100 MHz) δ -5.1, 17.9, 18.4, 19.2, 20.8, 25.3,
26.1, 27.5, 34.0 (×2), 34.7, 59.6, 65.0, 107.9, 125.5, 128.4, 138.2,
141.0; MS (m/z) 380 (M+, 28.5), 225 (100); HRMS calcd for
C
22H40O3Si 380.2747, found 380.2735.
2-[(E)-3,4-Dim et h yl-6-h yd r oxy-4-h exen yl]-2-cycloh ex-
en on e (10). (E)-Ethylene ketal 9a (648 mg, 1.70 mmol) was
hydrolyzed by treatment with a 1% mixture of concentrated HCl
and EtOH (12 mL) at room temperature for 7 h under stirring.
After neutralization by addition of NaHCO3, most of the EtOH
was evaporated and the product was extracted. Purification on
a
silica gel column (CH2Cl2/MeOH 98/2) afforded the title
compound 10 (322 mg, 85% yield) as a colorless oil: IR (neat)
3425 (br), 1670 cm-1; 1H NMR (400 MHz) δ 1.00 (3H, d, J ) 7.0

4156 J . Org. Chem., Vol. 63, No. 12, 1998
Notes
shown in the 400 MHz NMR, the product was stereochemically
2-[(E)-6-H yd r oxy-3,4-d im et h yl-4-h exen yl]-2-cycloh ex-
en esp ir o-2′,5′-d ioxa -cyclop en ta n e (21a ). A solution of (E)-
ethylene ketal 9a (1.08 g, 2.84 mmol) in THF cooled to 0 °C was
mixed with a 1 M Bu4N+F- solution in THF (6 mL), and after
removal of the cooling bath, the mixture was stirred at ambient
temperature for 1 h. Water was added, the product was
extracted with Et2O, and the combined organic layers were
washed successively with a saturated NaHCO3 solution and
brine and then dried with anhydrous K2CO3. Purification of the
crude product with flash chromatography (hexane/Et2O 1/2)
furnished the title alcohol 21a (746 mg, 99% yield) as a colorless
>99% pure. 18a : IR (neat) 1730, 1660, 1280, 1030 cm-1 1H
;
NMR (400 MHz) δ 1.18 (3H, J ) 7.0 Hz), 1.28 (3H, t, J ) 7.0
Hz), 1.32 (3H, t, J ) 7.0 Hz), 1.34 (3H, t, J ) 7.0 Hz), 1.66 (1H,
dq, J d ) 14.0, J q ) 7.0 Hz), 2.01 (1H, dq, J d ) 14.0, J q ) 7.0
Hz), 2.77 (1H, sextet, J ) 7.0 Hz), 3.54 (2H, t, J ) 7.0 Hz), 4.16
(2H, q, J ) 7.0 Hz), 4.23 (2H, q, J ) 7.0 Hz), 4.24 (2H, q, J ) 7.0
Hz), 4.46 (1H, d, J ) 11.6 Hz), 4.51 (1H, d, J ) 11.6 Hz), 5.41
(1H, s), 7.28-7.34 (5H, m); 13C NMR (100 MHz) δ 14.2, 16.0,
16.1, 18.0, 34.1, 36.5, 60.0, 64.7, 67.7, 73.0, 104.9, 127.5, 127.7,
128.3, 138.5, 164.0, 165.3, 165.4; MS (m/z) 415 (MH+ 0.9), 91
(100); HRMS calcd for C20H32O7P (MH+) 415.1886, found
415.1909.
1
oil: IR (neat) 3700-3100 (br) cm-1; H NMR (400 MHz) δ 1.00
(3H, d, J ) 7.0 Hz), 1.39-1.48 (1H, m), 1.49-1.57 (1H, m), 1.59
(3H, s), 1.68-1.73 (4H, m), 1.91 (2H, br t, J ) 7.0 Hz), 2.02 (2H,
br s), 2.13 (1H, t, J ) 7.0 Hz), 3.97 (4H, brs), 4.14 (2H, br s),
5.41 (1H, t, J ) 7.0 Hz), 5.69 (1H, t, J ) 3.7 Hz); 13C NMR (100
MHz) δ 12.7, 19.5, 20.8, 25.3, 27.2, 33.9, 34.0, 42.6, 59.4, 65.0,
107.9, 123.1, 128.4, 138.1, 143.7; MS (m/z) 266 (M+, 16), 99 (100);
HRMS calcd for C16H26O3 266.1882, found 266.1865.
Eth yl (E)-6-Ben zyloxy-3-d ieth ylp h osp h or yloxy-4-m eth -
yl-2-h exa n oa te (18b). A solution of â-keto ester 15 (10.5 g,
37.7 mmol) in HMPA (100 mL) cooled at 0 °C was mixed with
Et3N (7.0 mL, 50.2 mmol) and DMAP (200 mg), and after stirring
of the mixture for 1 h, diethyl chlorophosphate (7.3 mL, 50.5
mmol) was added dropwise. The cooling bath was removed, and
the reaction mixture was allowed to react overnight at room
temperature, before it was quenched by the addition of a
saturated NH4Cl solution. The Et2O extract solution was
washed with a saturated NaHCO3 solution and brine. Purifica-
tion of the crude product with silica gel flash chromatography
(hexane/Et2O 1/1) furnished the title phosphate 18b (12.5 g, 80%
yield) as a colorless oil. From analysis of the 1H NMR spectrum
(400 MHz), the product was found to be stereochemically pure
2-[(Z)-6-H yd r oxy-3,4-d im et h yl-4-h exen yl]-2-cycloh ex-
en esp ir o-2′,5′-d ioxa -cyclop en ta n e (21b). Title alcohol 21b
was obtained in 99% yield from 9b by the same procedure as
above: IR (neat) 3700-3100 (br) cm-1 1H NMR (400 MHz) δ
;
0.99 (3H, d, J ) 7.0 Hz), 1.50 (2H, q, J ) 7.0 Hz), 1.62 (3H, s),
1.65-1.78 (4H, m), 1.92 (2H, m), 2.04 (2H, m), 2.74 (1H, sextet,
J ) 7.0 Hz), 3.98 (4H, m), 3.98 (1H, J ) 12.2, 6.7 Hz), 4.15 (1H,
dd, J ) 12.2, 7.9 Hz), 5.42 (1H, ddd, J ) 7.9, 6.7, 1.2 Hz), 5.71
(1H, m); 13C NMR (100 MHz) δ 17.9, 19.5, 20.7, 25.3, 26.5, 32.5,
33.1, 33.9 (2), 58.4, 64.9, 65.0, 107.9, 125.0, 128.4, 137.2, 143.1;
MS (m/z) 266 (M+, 3.1), 99 (100); HRMS calcd for C16H26O3
266.1882, found 266.1865.
1
(>99%): IR (neat) 1720, 1650, 1280, 1040 cm-1; H NMR (400
MHz) δ 1.14 (3H, d, J ) 7.0 Hz), 1.25 (3H, t, J ) 7.0 Hz), 1.35
(3H, t, J ) 7.0 Hz), 1.36 (3H, t, J ) 7.0 Hz), 1.72 (1H, m), 1.88
(1H, m), 3.49 (2H, t, J ) 7.0 Hz), 4.03 (1H, m), 4.13 (2H, q, J )
7.0 Hz), 4.17 (2H, q, J ) 7.0 Hz), 4.18 (2H, q, J ) 7.0 Hz), 4.45
(1H, d, J ) 12.2 Hz), 4.49 (1H, d, J ) 12.2 Hz), 5.89 (1H, d, J )
1.2 Hz), 7.23-733 (5H, m); 13C NMR (100 MHz) δ 14.2, 16.05,
16.1, 17.8, 31.7, 33.5, 60.1, 64.8, 68.4, 73.0, 104.2, 127.5, 127.6,
128.3, 138.6, 166.0, 168.6, 168.7; MS (m/z) 415 (MH+, 0.2), 155
2-[(E)-6-Ch lor o-3,4-d im eth yl-4-h exen yl]-2-cycloh exen e-
2′,5′-d ioxa cyclo-p en ta n e (22a ). A solution of NCS (3 g, 22.5
mmol) in THF (280 mL) was mixed with triphenylphosphine (6
g, 22.9 mmol), and the mixture was stirred at room temperature
for 1 h, before a solution of alcohol 21a (3.05 g, 11.4 mmol) in
THF (20 mL) was added. Stirring of the reaction mixture was
continued overnight. After addition of water, most of the solvent
was evaporated, the product was extracted with hexane, and
the organic layers were washed with brine and dried with
anhydrous K2CO3. Crude product was purified by chromatog-
raphy on alumina (Activity II, hexane/Et2O 8/1) to provide the
title chloride 22a (2.90 g, 90% yield) as a colorless oil: 1H NMR
(400 MHz) δ 1.01 (3H, d, J ) 7.0 Hz), 1.44 (1H, m), 1.55 (1H,
m), 1.65 (3H, d, J ) 1.2 Hz), 1.68-1.74 (4H, m), 1.91 (2H, td, J t
) 7.0, J d ) 1.8 Hz), 2.02 (2H, br t, J ) 1.8 Hz), 2.15 (1H, sextet,
J ) 7.0 Hz), 3.98 (4H, s), 4.10 (2H, dd, J ) 7.9, 3.7 Hz), 5.46
(1H, t, J ) 7.9 Hz), 5.69 (1H, t, J ) 3.7 Hz); 13C NMR (100 MHz)
δ 12.5, 19.4, 20.8, 25.3, 27.3, 34.0, 41.1, 42.8, 65.0, 107.9, 120.0,
128.5, 138.2, 147.0.
2-[(Z)-6-Ch lor o-3,4-d im eth yl-4-h exen yl]-2-cycloh exen e-
2′,5′-d ioxa cyclo-p en ta n e (22b). Treatment of (Z)-alcohol 21b
with NCS and triphenylphosphine in the same way as above
gave the title (Z)-chloride 22b in 59% yield: 1H NMR (100 MHz)
δ 1.02 (3H, d, J ) 7.0 Hz), 1.51 (2H, m), 1.66 (3H, s), 1.68-1.72
(4H, m), 1.92 (2H, m), 2.03 (2H, m), 2.70 (1H, sextet, J ) 7.0
Hz), 3.98 (4H, s), 4.08 (1H, dd, J ) 11.6, 7.9 Hz), 4.11 (1H, dd,
J ) 11.6, 7.9 Hz), 5.43 (1H, td, J t ) 7.9, J d ) 1.2 Hz), 5.69 (1H,
m); 13C NMR (100 MHz) δ 18.1, 19.3, 20.8, 25.3, 27.5, 33.7, 34.0,
34.2, 40.4, 65.0, 107.8, 211.0, 128.5, 138.0, 146.9.
(100); HRMS calcd for
415.1904.
C
20H32O7P (MH+) 415.1886, found
Eth yl (E)-6-Ben zyloxy-3,4-d im eth yl-2-h exen oa te (19a ). A
suspension of trans-bis(triphenylphosphine)palladium(II) chlo-
ride (100 mg, 0.14 mmol) in THF 5 mL) was reduced with a 2 M
DIBALH toluene solution (0.15 mL, 0.3 mmol) at 0 °C for 10
min, and the so-formed zerovalent palladium solution was
diluted with anhydrous 1,2-dichloroethane (25 mL). To this
mixture was added a solution of (Z)-enol phosphate 18a (5.73 g,
13.8 mmol) in 1,2-dichloroethane (10 mL), followed by the
dropwise addition of a 1.4 M trimethylaluminum solution in
hexane (15 mL, 21 mmol). The ice bath was removed, and the
mixture was allowed to react for 72 h at room temperature. After
having been cooled to 0 °C, it was quenched by the addition of
1 M HCl. The crude product, isolated by Et2O extraction, was
purified by silica gel chromatography (hexane/Et2O 8/1) to afford
(E)-conjugated ester 19a (3.56 g, 94% yield) as a colorless oil.
19a : IR (neat) 1710, 1640 cm-1; 1H NMR (400 MHz) δ 1.06 (3H,
d, J ) 7.0 Hz), 1.28 (3H, t, J ) 7.0 Hz), 1.65 (1H, m), 1.77 (1H,
m), 2.10 (3H, s), 2.44 (1H, sextet, J ) 7.0 Hz), 3.39 (1H, dt, J d
)
9.2, J t ) 7.0 Hz), 3.44 (1H, dt, J d ) 9.2, J t ) 7.0 Hz), 4.14 (2H,
q, J ) 7.0 Hz), 4.46 (2H, s), 5.69 (1H, s), 7.25-7.36 (5H, m); 13
C
NMR (100 MHz) δ 14.3, 15.4, 19.2, 34.6, 40.7, 59.5, 68.3, 73.1,
115.4, 127.6, 127.7, 128.4, 138.5, 163.5, 167.0; MS (m/z) 276 (M+,
1.1), 91 (100); HRMS calcd for
276.1697.
Eth yl (Z)-6-Ben zyloxy-3,4-d im eth yl-2-h exen oa te (19b).
Starting from (E)-enol phosphate 18a , preparation of the title
(Z)-conjugated ester 19b was carried out in the same way as
C
17H24O3 276.1725, found
2-[(E)-6-Dip h en ylp h osp h or yl-4-h exen yl]-3,4-d im eth yl-2-
cycloh exen on e (13a ). To a solution of diphenylphosphine (0.8
mL, 4.6 mmol) in THF (10 mL), cooled to 0 °C, was added a 1.6
M n-butyllithium solution in hexane (3.0 mL, 4.8 mmol), and
the mixture was stirred for 30 min. The solution, thus prepared,
was added dropwise to a solution of chloride 22a (662 mg, 2.32
mmol) in THF (10 mL) at -78 °C until an orange color persisted
in the solution, which was stirred further for 30 min. The
reaction mixture was queched by the addition of water, and the
solvent was evaporated. The residue, dissolved in CH2Cl2 (40
mL), was treated with a 30% H2O2 solution (5 mL) for 5 min
under stirring. The organic layer was separated, and after being
washed with a saturated Na2SO3 solution, the solvent was
evaporated. The residue was dissolved in EtOH (20 mL)
containing a 1% concd hydrochloric acid solution, and the
solution was stirred for 1 h. After evaporation of most of the
EtOH, the product was extracted with CH2Cl2 and the organic
1
that of (E) isomer 19a . Analysis of 400 MHz H NMR revealed
that the product obtained in 93% yield was contaminated by (E)
isomer 19a in a 96:4 ratio (comparison of vinyl methyl signals
at δ 1.78 and δ 2.10, respectively). 19b: IR (neat) 1720, 1650
1
cm-1; H NMR (400 MHz) δ 1.05 (3H, d, J ) 7.0 Hz), 1.25 (3H,
t, J ) 7.0 Hz), 1.73 (2H, m), 1.78 (3H, d, J ) 1.2 Hz), 3.44 (2H,
m), 4.00 (1H, sextet, J ) 7.0 Hz), 4.12 (2H, q, J ) 7.0 Hz), 4.45
(1H, d, J ) 11.6 Hz), 4.48 (1H, d, J ) 11.6 Hz), 5.63 (1H, q, J )
1.2 Hz), 7.23-7.35 (5H, m); 13C NMR (100 MHz) δ 14.3, 19.0,
19.2, 31.6, 34.6, 59.5, 69.1, 73.0, 116.7, 127.4, 127.6, 128.3, 138.7,
163.1, 166.2; MS (m/z) 276 (M+, 3.8), 91 (100); HRMS calcd for
C
17H24O3 276.1725, found 276.1728.

Notes
J . Org. Chem., Vol. 63, No. 12, 1998 4157
layers were washed with saturated NaHCO3 and brine. Puri-
fication of the crude product by silica gel chromatography (CH2-
Cl2/MeOH 99/1) afforded (E)-phosphine oxide 13a (893 mg, 95%
hexane (1.1 mL, 1.76 mmol), was added dropwise to a solution
of phosphine oxide 13a (400 mg, 0.98 mmol), cooled at -78 °C,
and the mixture was allowed to react for 30 min under stirring.
After quenching, it was worked up as above to yield the crude
product, which was purified by flash chromatography on a silica
gel column (CH2Cl2/MeOH 98/2). 24: colorless oil (283 mg, 71%
yield) as a viscous oil: IR (CH2Cl2) 1660 cm-1 1H NMR (400
;
MHz) δ 0.85 (3H, d, J ) 7.0 Hz), 1.19-1.35 (2H, m), 1.37 (3H,
d, J ) 1.8 Hz), 1.87-1.97 (4H, m), 2.07 (1H, sextet, J ) 7.0 Hz),
2.29 (2H, td, J t ) 6.1, J d ) 3.7 Hz), 2.38 (2H, t, J ) 7.0 Hz),
3.08 (1H, ddd, J ) 14.6, 14.6, 7.3 Hz), 3.11 (1H, ddd, J ) 14.6,
14.6, 7.3 Hz), 5.27 (1H, brt, J ) 7.3 Hz), 6.58 (1H, t, J ) 3.7
Hz), 7.29-7.59 (6H, m), 7.61-7.81 (4H, m); 13C NMR (100 MHz)
δ 12.5, 19.6, 23.2, 26.0, 27.8, 30.6, 33.6, 38.6, 42.7, 112.2 (d, J )
4 Hz), 128.4, 128.5, 131.0 (d, J ) 4 Hz), 131.1 (d, J ) 3 Hz),
131.6 (2), 132.6, 133.5, 139.8, 144.9 (d, J ) 12 Hz), 145.1, 199.3;
MS (m/z) 406 (M+, 28), 202 (100); HRMS calcd for C26H31O2P
406.2062, found 406.2043.
2-[(Z)-6-Dip h en ylp h osp h or yl-4-h exen yl]-3,4-d im eth yl-2-
cycloh exen on e (13b). Conversion of (Z)-chloride 22b in man-
ner similar to that above provided (Z)-phosphine oxide 13b in
87% yield: 1H NMR (400 MHz) δ 0.75 (3H, d, J ) 7.0 Hz), 1.31
(2H, m), 1.57 (3H, d, J ) 3.7 Hz), 1.90-2.02 (4H, m), 2.31 (2H,
td, J t ) 6.1, J d ) 4.3 Hz), 2.39 (2H, t, J ) 6.7 Hz), 2.49 (1H,
sextet, J ) 7.0 Hz), 3.05 (1H, ddd, J ) 15.9, 14.7, 6.7 Hz), 3.18
(1H, ddd, J ) 14.7, 14.0, 8.5 Hz), 5.27 (1H, ddd, J ) 8.5, 6.7, 6.7
Hz), 6.64 (1H, t, J ) 4.3 Hz), 7.44-7.53 (6H, m), 7.69-7.76 (4H,
m); 13C NMR (100 MHz) δ 18.2, 18.6, 23.2, 26.1, 27.9, 30.1 (d, J
) 70 Hz), 33.8, 34.4, 38.6, 112.7, 128.5 (d, J ) 4 Hz), 128.6 (d,
J ) 3 Hz), 131.0 (d, J ) 4 Hz), 131.6 (×2), 132.5, 133.5, 139.9,
144.6 (d, J ) 12 Hz), 144.9, 199.4.
2-[(E)-6-P h en ylsu lfon yl-4-h exen yl]-3,4-d im eth yl-2-cyclo-
h exen on e (14). To a solution of chloride 22a (500 mg, 1.76
mmol) in anhydrous DMF (10 mL) was added sodium phenyl-
sulfinate (300 mg, 1.83 mmol), and the mixture was stirred
overnight at ambient temperature, before a 1 M HCl solution
was added. After being stirred for 20 min, the mixture was made
basic by the addition of a saturated NaHCO3 solution and was
worked up. Purification of the crude product by flash chroma-
tography on silica gel (hexane/Et2O 1/1) provided the title sulfone
14 (573 mg, 93% yield) as a colorless oil: IR (neat) 1680, 1310,
1150 cm-1; 1H NMR (400 MHz) δ 0.91 (3H, d, J ) 7.0 Hz), 1.26
(3H, s), 1.25-1.43 (2H, m), 1.94-2.04 (4H, m), 2.11 (1H, sextet,
J ) 7.0 Hz), 2.34 (2H, td, J t ) 6.1, J d ) 3.7 Hz), 2.40 (2H, t, J
) 7.0 Hz), 3.83 (2H, d, J ) 7.9 Hz), 5.20 (1H, t, J ) 7.9 Hz),
6.67 (1H, t, J ) 3.7 Hz), 7.51-7.55 (2H, m), 7.60-7.64 (1H, m),
7.85-7.88 (2H, m); 13C NMR (100 MHz) δ 12.5, 19.3, 23.1, 26.1,
27.8, 33.6, 38.6, 42.9, 56.0, 110.2, 128.5, 128.9, 133.5, 138.8,
139.7, 145.0, 150.3, 199.3; MS (m/z) 346 (M+, 15), 205 (100);
HRMS calcd for C20H26O3S 346.1603, found 346.1617.
(3R*,4S*,4a R*)-1,2,3,4,4a ,5,6,7-Oct a h yd r o-4-[(E)-2-(d i-
p h en ylp h osp h or yl)et h en yl]-3,4-d im et h yl-4a -n a p h t h a le-
n ol (23). To a solution of i-Pr2NH (0.35 mL, 2.50 mmol), cooled
to 0 °C, was added a 1.65 M BuLi solution in hexane (1.5 mL,
2.48 mmol), and the mixture was stirred for 30 min. An LDA
solution, thus prepared, was added dropwise to a solution of (E)-
phosphine oxide 13a (600 mg, 1.47 mmol), mixed with LiBr (130
mg, 1.50 mmol), and cooled to -78 °C, and the mixture was
stirred for 30 min. The reaction was quenched by the addition
of a saturated NH4Cl solution, and the product was extracted
with CH2Cl2. The combined organic layers were washed in
succession with a saturated NaHCO3 solution and brine. The
crude product purified by flash chromatography on silica gel
(CH2Cl2/MeOH 98/2) gave the cyclized product 23 (440 mg, 74%
yield) as a colorless oil: IR (CCl4) 3275 (br), 1610, 1180, 1125
cm-1; 1H NMR (400 MHz) δ 0.70 (3H, d, J ) 7.0 Hz), 0.91 (3H,
s), 1.28 (1H, qd, J q ) 13.4, J d ) 4.8 Hz), 1.41-1.59 (4H, m), 1.68
(1H, td, J t ) 14.1, J d ) 3.7 Hz), 1.84 (1H, m), 1.92 (1H, m), 2.04
(1H, m), 2.37 (1H, m), 2.49 (1H, m), 5.61 (1H, brs), 6.21 (1H, dd,
J ) 23.8, 17.7 Hz), 6.91 (1H, dd, J ) 21.4, 17.7 Hz), 7.44-7.53
(6H, m), 7.68-7.73 (4H, m); 13C NMR (100 MHz) δ 12.7, 16.9,
19.3, 25.5, 29.9, 31.0, 32.9, 33.4, 50.1 (d, J ) 13 Hz), 74.2, 121.9
(d, J ) 103 Hz), 125.6, 128.5 (d, J ) 12 Hz), 131.4 (d, J ) 6 Hz),
131.6, 133.5 (d, J ) 110 Hz), 137.4, 158.2; MS (m/z) 406 (M+,
57), 283 (100); HRMS calcd for C26H31O2P 406.2062, found
406.2038.
1
yield); IR (CH2Cl2) 1700, 1605, 1180, 1120 cm-1; H NMR (400
MHz) δ 0.73 (3H, d, J ) 7.0 Hz), 1.02 (3H, s), 1.17-1.27 (1H,
m), 1.32-1.56 (4H, m), 1.57-1.66 (2H, m), 1.93-2.00 (2H, m),
2.14-2.27 (2H, m), 2.36 (1H, m), 6.19 (1H, dd, J ) 25.0, 17.7
Hz), 6.52 (1H, dd, J ) 20.8, 17.7 Hz), 7.43-7.56 (6H, m), 7.64-
7.22 (4H, m); 13C NMR (100 MHz) δ 9.5, 16.8, 25.3, 25.7, 26.7,
28.5, 39.4, 41.8, 46.0, 120.9 (d, J ) 101 Hz), 128.5, 128.6, 131.1,
131.2, 131.7, 133.4 (d, J ) 104 Hz), 160.8, 212.4; MS (m/z) 406
(M+, 55), 202 (100); HRMS calcd for C26H31O2P 406.2062, found
406.2041.
(4a S*,5R*,6R*,8a R*)-3,4,4a ,5,6,7,8,8a -Octa h yd r o-8a -a llyl-
5-[(E)-2-(d ip h en ylp h osp h or yl)eth en yl]-5,6-d im eth yl-1(2H)-
n a p h th a len on e (26). To a solution of LDA, prepared from
i-Pr2NH (0.06 mL, 0.43 mmol) in THF (5 mL) and a 1.65 M BuLi
solution in hexane (0.26 mL, 0.43 mmol) and cooled at -40 °C,
was added dropwise a solution of phosphine oxide 13a (100 mg,
0.25 mmol) in a mixture of HMPA (5 mL) and THF (15 mL),
and mixture was stirred for 30 min, before allyl bromide (0.05
mL, 0.58 mmol) was added. After the reaction mixture was
stirred for 1 h, it was quenched by the addition of water and
then extracted with CH2Cl2. The organic layers were washed
with brine and were dried with anhydrous K2CO3. The crude
product was purified by silica gel chromatography (hexane/Et2O)
to give (3R*,4S*,4a R*)-1,2,3,4,4a ,5,6,7-octa h yd r o-8-a llyloxy-
4-[(E)-2-(d ip h en ylp h osp h or ylet h en yl]-3,4-d im et h yln a p h -
th a len e (59 mg, 52% yield) as a colorless oil: 1H NMR (400
MHz) δ 0.72 (3H, d, J ) 6.7 Hz), 0.85 (3H, s), 1.21 (2H, m), 1.30-
1.71 (6H, m), 2.01 (2H, brs), 2.14 (1H, t, J ) 6.7 Hz), 3.02 (1H,
dd, J ) 14.3, 2.7 Hz), 4.14 (1H, ddt, J d ) 12.8, J d′ ) 5.5, J t ) 1.2
Hz), 4.20 (1H, ddt, J d ) 12.8, J d′ ) 5.5, J t ) 1.2 Hz), 5.17 (1H,
dd, J ) 10.4, 1.8 Hz), 5.29 (1H, dd, J ) 17.1, 1.8 Hz), 5.94 (1H,
ddt, J d ) 17.1, J d′ ) 10.4, J t ) 5.5 Hz), 6.13 (1H, dd, J ) 25.0,
17.7 Hz), 6.56 (1H, dd, J ) 20.8, 17.7 Hz), 7.44-7.57 (6H, m),
7.64-7.72 (4H, m); 13C NMR (100 MHz) δ 10.2, 17.0, 22.3, 24.7,
25.3, 25.9, 29.6, 30.3, 40.0, 47.2 (d, J ) 13 Hz), 69.4, 116.7, 117.0,
120.1 (d, J ) 103 Hz), 128.4, 128.7, 131.1 (2), 131.6, 133.1 (d, J
) 6 Hz), 134.2 (d, J ) 6 Hz), 134.9, 148.0, 161.7.
A solution of this allyl enol ether (25 mg, 0.06 mmol) in
anhydrous 2,6-lutidine (1 mL) was heated under reflux for 1 h.
The residue, left after evaporation in vacuo of the solvent, was
chromatographed on silica gel column (CH2Cl2/MeOH 99/1) to
afford the title product 26 (25 mg, 100% yield) as a colorless oil:
IR (CH2Cl2) 1700, 1640, 1180, 1120 cm-1; 1H NMR (400 MHz) δ
0.68 (3H, d, J ) 6.1 Hz), 0.94 (3H, s), 0.97 (1H, m), 1.30-1.43
(3H, m), 1.54 (1H, m), 1.93-2.12 (4H, m), 2.15 (dd, J ) 14.0, 7.3
Hz), 2.25 (1H, m), 2.40 (1H, m), 2.58 (1H, m), 2.77 (1H, dd, J )
14.0, 7.3 Hz), 5.06 (2H, m), 5.56 (1H, ddt, J d ) 17.1, J d′ ) 9.8, J t
) 7.3 Hz), 6.15 (1H, dd, J ) 25.0, 17.4 Hz), 6.48 (1H, dd, J )
20.8, 17.4 Hz), 7.43-7.56 (6H, m), 7.64-7.72 (4H, m); 13C NMR
(100 MHz) δ 13.0, 16.9, 20.7, 23.9, 26.6, 31.2, 36.6, 40.3, 46.3,
47.5 (d, J ) 13 Hz), 50.5, 51.5, 118.6, 120.8 (d, J ) 101 Hz),
128.5 (d, J ) 3 Hz), 128.7 (d, J ) 3 Hz), 131.1, 131.2, 131.3,
131.7, 132.1, 133.0 (d, J ) 13 Hz), 134.0 (d, J ) 13 Hz), 162.1,
215.0.
Ack n ow led gm en t. We thank Drs. Hideo Iio and
Yoshinosuke Usuki for their helpful discussion and
support of this work.
Su p p or tin g In for m a tion Ava ila ble: Complete syntheses
of 4-8a , 15-17, 19a -8a , and 19b-8b along with experimen-
tal and characterization data for all intermediates, and 1H
NMR spectra for 2a , 2a -c (mixture in 77:21:2 ratio), 5, 7a ,b-
9a ,b, 10a , 11a , 13a ,b, 14-17, 18a ,b-22a ,b, and 23-26 (39
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(4a S*,5R*,6R*,8a R*)-3,4,4a ,5,6,7,8,8a -Octa h yd r o-5-[(E)-2-
(d ip h en ylp h osp h or yl)et h en yl]-5,6-d im et h yl-1(2H )-n a p h -
th a len on e (24). An LDA solution, prepared from i-PrNH2 (0.25
mL, 1.7 mmol) in THF (10 mL) and a 1.65 M BuLi solution in
J O980188T