Total Syntheses of the Cytotoxic Marine Natural Product, Aplysiapyranoid C

Article abstract of DOI:10.1021/jo972228j

The first total syntheses of the cytotoxic marine natural product, aplysiapyranoid C, 1c, are reported. The Wittig reaction of 4-methyl-3-pentenyltriphenylphosphorane with the THP ether of hydroxy-acetone gave in 88% yield the Z-alkene 4 which was hydrolyzed to the alcohol 5 in 72% yield. Sharpless asymmetric epoxidation of 5 afforded the epoxy alcohol 6 in 91% yield and 81% ee. Opening of the epoxide of 6 with ammonium chloride in DMSO gave in 76% yield the chloro diol 7 which was converted to the primary TBS ether 8 in 95% yield. Opening of the epoxy alcohol 6 with HCl and Ti(OiPr)₄ afforded the desired chloro diol 7 as the minor product along with the rearranged chloromethyl diol 9. This compound is presumably formed by opening of the protonated epoxide to give a butenyl cation which rearranges to the cyclopropylcarbinyl cation and is then trapped by chloride ion at the unsubstituted cyclopropyl carbon, regenerating the alkene. Cyclization of the TBS ether 8 with tetrabromocyclohexadienone (TBCO) afforded a mixture of all four possible cyclization products, the desired tetrahydropyrans 11a,b and the tetrahydrofurans 12a,b with the former being isolated in 70% yield. Hydrolysis of the TBS ether afforded the primary alcohols from which the desired isomer, 13, could be isolated (24% overall from 8). Swern oxidation furnished the aldehyde 14 which was subjected to the Takai chlorovinylation to give a mixture of aplysiapyranoid C 1c and the reduced product, dechloroaplysiapyranoid C 15. This dechlorination under these conditions is quite unusual. A second synthesis of aplysiapyranoid C avoided this problem. Selective protection of the more hindered tertiary alcohol of the chloro diol 7 afforded the primary alcohol 16 in which the tertiary alcohol was protected as the triethylsilyl ether. Swern oxidation, Takai reaction, and desilylation gave the dichloro alkenol 17 in 52% overall yield. In this case, only a small amount of the corresponding dechlorinated product was obtained. Final cyclization of 17 with TBCO afforded aplysiapyranoid C 1c as the major product in an isolated yield of 43%. Thus we have completed two total syntheses of aplysiapyranoid C 1c from the simple bromide 2 in eight or nine steps and good overall yield.

Full text of DOI:10.1021/jo972228j

2982
J . Org. Chem. 1998, 63, 2982-2987
Tota l Syn th eses of th e Cytotoxic Ma r in e Na tu r a l P r od u ct,
Ap lysia p yr a n oid C1
Michael E. J ung,* Bruce T. Fahr, and Derin C. D’Amico
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569
Received December 9, 1997
The first total syntheses of the cytotoxic marine natural product, aplysiapyranoid C, 1c, are reported.
The Wittig reaction of 4-methyl-3-pentenyltriphenylphosphorane with the THP ether of hydroxy-
acetone gave in 88% yield the Z-alkene 4 which was hydrolyzed to the alcohol 5 in 72% yield.
Sharpless asymmetric epoxidation of 5 afforded the epoxy alcohol 6 in 91% yield and 81% ee.
Opening of the epoxide of 6 with ammonium chloride in DMSO gave in 76% yield the chloro diol
7 which was converted to the primary TBS ether 8 in 95% yield. Opening of the epoxy alcohol 6
with HCl and Ti(OiPr)4 afforded the desired chloro diol 7 as the minor product along with the
rearranged chloromethyl diol 9. This compound is presumably formed by opening of the protonated
epoxide to give a butenyl cation which rearranges to the cyclopropylcarbinyl cation and is then
trapped by chloride ion at the unsubstituted cyclopropyl carbon, regenerating the alkene.
Cyclization of the TBS ether 8 with tetrabromocyclohexadienone (TBCO) afforded a mixture of all
four possible cyclization products, the desired tetrahydropyrans 11a ,b and the tetrahydrofurans
12a ,b with the former being isolated in 70% yield. Hydrolysis of the TBS ether afforded the primary
alcohols from which the desired isomer, 13, could be isolated (24% overall from 8). Swern oxidation
furnished the aldehyde 14 which was subjected to the Takai chlorovinylation to give a mixture of
aplysiapyranoid C 1c and the reduced product, dechloroaplysiapyranoid C 15. This dechlorination
under these conditions is quite unusual. A second synthesis of aplysiapyranoid C avoided this
problem. Selective protection of the more hindered tertiary alcohol of the chloro diol 7 afforded
the primary alcohol 16 in which the tertiary alcohol was protected as the triethylsilyl ether. Swern
oxidation, Takai reaction, and desilylation gave the dichloro alkenol 17 in 52% overall yield. In
this case, only a small amount of the corresponding dechlorinated product was obtained. Final
cyclization of 17 with TBCO afforded aplysiapyranoid C 1c as the major product in an isolated
yield of 43%. Thus we have completed two total syntheses of aplysiapyranoid C 1c from the simple
bromide 2 in eight or nine steps and good overall yield.
Sch em e 1
In tr od u ction
The aplysiapyranoids A-D, 1a -d , are four haloge-
nated monoterpenes isolated by Kakisawa and co-work-
ers from the marine mollusc Aplysia kurodai (Scheme
1).3 These compounds, which have an unusual polyha-
logenated tetrahydropyran structure, show good cytotox-
icity against several cell lines.3 For example, aplysiapy-
ranoid D has exhibited an IC50 of 14 µg/mL vs human
tumor cells (Moser), while the other aplysiapyranoids are
somewhat less active (IC50’s of 19-96 µg/mL vs standard
cancer cell lines, e.g., Vero, MDCK, and B16 cells). We
have previously reported the synthesis of the aplysiapy-
ranoids A and D, 1a ,d , from simple achiral allylic
alcohols.4 The approach in those syntheses involved as
key steps: (1) a Sharpless asymmetric epoxidation to give
an epoxy alcohol, from which all three of the required
stereocenters are ultimately derived; and (2) a stereose-
lective bromoetherification to furnish a product that is
normally disfavored sterically but is favored in these
cases due to a strong inductive effect on the homoallylic
halogen atom.
Sch em e 2
This causes the normally disfavored opening of the
intermediate bromonium ion at the more substituted
carbon atom to occur to give the tetrahydropyran product
in preference to the tetrahydrofuran product (Scheme 2).
Thus, cyclization of the bis-homoallylic alcohol A having
either a chlorine or a bromine atom in the homoallylic
position with a source of positive bromine atom would
afford the bromonium ion B (and its stereoisomer, see
below), which could be opened at either the tertiary
position to give the tetrahydropyran C or at the second-
ary center to give the tetrahydrofuran product D. We
have shown4 that the halogen atom is crucial in
(1) Presented at the 211th National American Chemical Society
meeting, New Orleans, LA, March 1996, ORGN 319.
(2) American Chemical Society Arthur C. Cope Scholar, 1995.
(3) Kusumi, T.; Uchida, H.; Inouye, Y.; Ishitsuka, M.; Yamamoto,
H.; Kakisawa, H. J . Org. Chem. 1987, 52, 4597.
(4) (a) J ung, M. E.; Lew, W. J . Org. Chem. 1991, 56, 1347. (b) J ung,
M. E.; D′Amico, D.; Lew, W. Tetrahedron Lett. 1993, 34, 923.
S0022-3263(97)02228-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/01/1998

Total Synthesis Splysiapyranoid C
J . Org. Chem., Vol. 63, No. 9, 1998 2983
Sch em e 3
controlling this opening in the desired sense, namely to
favor the normally disfavored opening5 to give mainly the
desired product C. We believe that the inversion of the
normal opening of bromonium ions of this sort is due to
the carbon-halogen dipole (shown in B) which destabi-
lizes the carbocation at the secondary center proximal
to the halogen atom and thereby inductively favors
opening at the end distal to the halogen. This reaction
sequence affords, in the case of aplysiapyranoid D, the
all-equatorial isomer and, in the case of aplysiapyranoid
A, a less stable isomer having an axial bromine atom.
We now report herein the first two total syntheses of
aplysiapyranoid C, 1c, which has a structure possessing
an equatorial chlorine atom and an axial 2-chlorovinyl
group. These two syntheses of 1c also utilize as key steps
a Sharpless asymmetric epoxidation to produce an opti-
cally active epoxy alcohol and, after opening with chloride
ion, a 3-chloro 1,2-diol which, after protection of the
primary alcohol, then undergoes a similar stereoselective
bromoetherification to afford once again the tetrahydro-
pyran product in preference to the tetrahydrofuran one.
Once more a chlorovinylation reaction (the Takai reac-
tion) is used to produce the required vinyl chloride in both
syntheses.
a
(a) PPh3, H3CCN, 85 °C, 5 mol % TMP. (b) KHMDS, THF,
HMPA, 25 °C; 3, -78 °C to 25 °C, 88% based on 3. (c) PPTS, EtOH,
60 °C, 72%. (d) D-(-)-DIPT, Ti(OiPr)4, TBHP, CaH2, SiO2, CH2-
Cl2, -25 °C, 91% (81% ee). (e) NH4Cl, Ti(OiPr)4, DMSO, 25 °C,
76%. (f) TBSCl, ImH, DMF, 25 °C, 95%.
Sch em e 4
Resu lts a n d Discu ssion
There are two possible ways to carry out the synthesis
of aplysiapyranoid C based on our previous syntheses of
aplysiapyranoids A and D. One can first start with the
bromoetherification to give the tetrahydropyran system,
prepare the aldehyde, and then carry out the chlorovi-
nylation (Takai reaction), or one can invert the two key
processes and effect first the chlorovinylation on an
acyclic precursor and subsequently perform the bromo-
etherification as the final step in the synthesis. Since
we had no strong reason to believe a priori that one route
would be preferable to the other, we decided to look at
both routes. As it turns out, although both were suc-
cessful, the second procedure, namely first chlorovinyla-
tion and then bromoetherification, gave much better
results.
The syntheses both begin (Scheme 3) with the phos-
phonium bromide derived from the readily available
5-bromo-2-methyl-2-pentene 2. In the formation of the
phosphonium bromide, it was necessary to add a trace
amount of tetramethylpiperidine (TMP) to the reaction
to suppress migration of the double bond to form a
2-methyl-1-alkene. Although this less substituted double
bond isomer would be expected to be less stable, it was
found to be necessary to completely suppress its forma-
tion using a hindered base, since otherwise inseparable
mixtures of products resulted. Under conditions reported
by Still for similar substrates,6 the phosphonium bromide
was deprotonated with KHMDS in THF/HMPA, followed
by Wittig reaction with the tetrahydropyranyl ether of
hydroxyacetone 3, to give only the Z-alkene 4 in 88%
overall yield from 2. The resulting adduct was depro-
tected using PPTS in ethanol to yield the allylic alcohol
5.7 Sharpless epoxidation of 5 was effected in 91% yield
using the modification of Zhou, which allows rapid
asymmetric epoxidation of cis allylic alcohols, normally
poor substrates in the Sharpless epoxidation.8 The
enantiomeric excess of the epoxy alcohol 6 obtained was
determined to be 81% by the method of Alexakis.9 The
epoxy alcohol was opened by chloride ion using am-
monium chloride and titanium tetraisopropoxide in DM-
SO10 to give the chloro diol 7, which was the branch point
in the two syntheses. For the first synthesis, monopro-
tection of the diol at the primary alcohol was carried out
under the usual conditions to give 8 in 95% yield.
We had observed a novel rearrangement in an earlier
attempt to prepare the chloro diol 7 in the opening of
the epoxy alcohol 6 with hydrogen chloride and titanium
tetraisopropoxide in dichloromethane rather than with
ammonium chloride in dimethyl sulfoxide (Scheme 4). In
addition to the desired product 7 (20% yield), we also
obtained the rearranged chloromethyl diol 9 as a 2.8:1
mixture of diastereomers in 45% yield. These compounds
are presumably formed by protonation of the epoxide to
give I which can be opened by chloride in an SN2 process
to give 7 or can open via an SN1 process to give the
butenyl cation II which is stabilized as the cyclopropyl-
carbinyl cation III. Opening of this cyclopropylcarbinyl
cation with chloride ion at the unsubstituted carbon
regenerates the alkene and produces the products 9.
(7) Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J . Org. Chem. 1977,
42, 3772.
(5) (a) Broka, C. A.; Lin, Y.-T. J . Org. Chem. 1988, 53, 5876. (b)
Corey, E. J .; Ha, D.-C. Tetrahedron Lett. 1988, 29, 3171. (c) Hashimoto,
M.; Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.; Matsumoto, T.
J . Org. Chem. 1990, 55, 5088 and references in all of the above.
(6) Sreekumar, C.; Darst, K. P.; Still, W. C. J . Org. Chem. 1980, 45,
4260.
(8) Wang, Z.-m.; Zhou, W.-s.; Lin, G.-q. Tetrahedron Lett. 1985, 26,
6221.
(9) Alexakis, A.; Frutos, J . C.; Mutti, S.; Mangeney, P. J . Org. Chem.
1994, 59, 3326.
(10) (a) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1557.
(b) Chong, J . M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1560.

2984 J . Org. Chem., Vol. 63, No. 9, 1998
J ung et al.
Sch em e 5
Sch em e 7
a
(a) DMTrCl, collidine, 0 °C; Et3SiOTf (TESOTf), collidine, CH2-
Sch em e 6
Cl2, 40 °C; C12H25SH, CF3COOH, 90% from 7. (b) (COCl)2, DMSO,
Et3N, CH2Cl2, -78 °C to -20 °C, 88%. (c) CrCl2, CHCl3, THF, 60
°C, 69%. (d) HF‚pyr, pyr, CH2Cl2, -20 °C, 86%. (e) TBCO, CH3-
NO2, 25 °C, 43%.
with chromous chloride and chloroform. Interestingly,
we obtained a 1:1 mixture of aplysiapyranoid C 1c along
with compound 15, in which the vinyl chloride has been
reduced to a simple vinyl group. Presumably compound
15 is formed from 1c in a reductive process carried out
by the chromium(II) chloride. Whether the active reduc-
ing species is actually chromium(II) chloride or not is
unknown. It is possible that the reduction of the vinyl
chloride is carried out by a trace contaminant. It is
known, for example, that chromium(II) chloride can
undergo oxidative addition to vinyl chlorides in the
presence of trace amounts of nickel(II) chloride.13 Fur-
ther work is underway to determine the cause of this
unwanted reduction and to find ways to suppress it.
Thus this completes an eight-step synthesis of aply-
siapyranoid C from the bromide 2.
However, we have developed a somewhat better syn-
thesis of 1c by inverting the key steps as follows (Scheme
7). Conversion of the diol to the secondary triethylsilyl
ether was carried out in a 3-step one-pot procedure by
dimethoxytritylation of the primary alcohol, silylation of
the tertiary alcohol, and deprotection with acid and
dodecanethiol to give 16. Swern oxidation furnished in
88% yield the aldehyde which was subjected to the Takai
reaction to give a good yield of the desired E-vinyl
chloride (with little interference by an intramolecular ene
reaction).14 Final removal of the silyl ether with HF‚
pyr afforded the tertiary alcohol 17 in 86% yield.15 In
this case, only a small amount (up to ∼10%) of the
dechlorinated product was obtained in the chlorovinyla-
tion reaction, in marked contrast to the case with the
aldehyde 14 above. We believe that the abnormal Takai
reaction (to give the dechlorinated product 15) must be
due to the severe steric hindrance of this particular
aldehyde (1,3-diaxial to a methyl group in a pyran ring
system). We have not seen this abnormal process with
other simple aldehydes.16 Cyclization of the dichloro-
dienol 17 with TBCO in nitromethane gave a mixture of
a
(a) TBAF, THF, 0 °C; SiO2, yield of 13 is 24% from 8. (b)
(COCl)2, DMSO, Et3N, CH2Cl2, -78 °C to 0 °C, 98%. (c) CrCl2,
CHCl3, THF, 60 °C, 68% of a 5:5:3 mixture of 1c, 15, and 14.
For the first synthesis, the cyclization of 8 was carried
out using tetrabromocyclohexadienone (TBCO) in dichlo-
romethane at 40 °C, which yielded four products in good
yield (Scheme 5). The two major products were deter-
mined on the basis of their 1H NMR spectra to be the
stereoisomeric tetrahydropyrans 11a ,b. The two other
products have been assigned the tetrahydrofuran struc-
tures 12a ,b, based on comparison of their 1H NMR
spectra with those of similar compounds.11 The formation
of tetrahydropyrans 11a ,b is normally disfavored in
cyclizations of substituted 4-pentenols with respect to the
tetrahydrofurans due to the strong steric repulsion (1,3-
diaxial-like interactions) in the transition states leading
to these products. This mode of cyclization is favored by
the inductive effect of the chlorine atom, which destabi-
lizes build-up of positive charge at the proximal end of
the bromonium ions 10a b because of repulsion of the two
positive dipoles. The major isomer present was the
desired tetrahydropyran 11a with both halogens equato-
rial, due presumably to steric hindrance in the transition
state for cyclization leading to 11b with an axial chlorine
atom. We have observed both of these inductive and
steric effects in similar cyclizations before.4 Compound
11a could not be separated cleanly, but a mixture of it
and compound 12a was isolated in 70% yield from the
crude reaction mixture using silica gel chromatography.
The synthesis of aplysiapyranoid C was finished as
follows (Scheme 6). Treatment of the mixture of 11a and
12a with TBAF removed the TBS groups to give, after
flash chromatography on silica gel, the desired alcohol
13. This alcohol was converted by a Swern oxidation into
the aldehyde 14, which was converted to the vinyl
chloride using the method of Takai,12 namely treatment
(12) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408.
(13) J in, H.; Uenishi, J .; Christ, W. J .; Kishi, Y. J . Am. Chem. Soc.
1986, 108, 5644.
(14) Takai reports such probelms with olefinic aldehydes giving
products from ene reactions.12
(15) When less pyridine is used for the desilylation, the quaternary
fluoride, formed by Markovnikov addition of HF to the trisubstituted
alkene, is produced.
(16) The Takai reaction on several aldehydes, e.g., benzaldehyde,
dodecanal, and 2-(decyloxy)-2-methylpropanal, gave only chlorovinyl-
ation with no dechlorinated product observed.
(11) Lew, Willard, Ph. D. dissertation, 1992, University of California,
Los Angeles.

Total Synthesis Splysiapyranoid C
J . Org. Chem., Vol. 63, No. 9, 1998 2985
four products, from which aplysiapyranoid C 1c [[R]25
crude product was dissolved in a minimum amount of warm
hexane, allowing the solution to cool and filtering off the
triphenylphosphine oxide crystals. The resulting hexane
solution was concentrated by rotary evaporation. Flash chro-
matography over silica gel (5% ethyl acetate in hexane)
afforded the Z-alkene 4 (1.74 g, 88%) as a colorless oil. 1H
NMR (360 MHz, CDCl3) δ 5.34 (br t, J ) 7.2 Hz, 1H), 5.07 (t,
J ) 7.3 Hz, 1H), 4.59 (t, J ) 3.5 Hz, 1H), 4.12 (d, J ) 11.5 Hz,
1H), 4.11 (d, J ) 11.5 Hz, 1H), 3.89 (m, 1H), 3.51 (m, 1H),
2.76 (dd J ) 7.3, 7.3 Hz, 2H), 1.9-1.5 (m, 6H), 1.83 (s, 3H),
1.68 (s, 3H), 1.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 131.7,
131.6, 128.2, 122.8, 97.4, 65.3, 62.1, 30.6, 26.8, 25.6, 25.5, 21.7,
D
) 58.4 (lit. 52)3] could be isolated in 43% yield by HPLC.17
In summary we have completed two efficient syntheses
of aplysiapyranoid C, 1c, utilizing as key steps a Sharp-
less asymmetric epoxidation and a diastereoselective
bromoetherification. Further work in this area is in
progress.
Exp er im en ta l Section
Gen er a l. 1H NMR were recorded at 200, 360, 400, or 500
MHz and are so indicated. 13C NMR were recorded at 90, 100,
or 125 MHz, respectively, and are so indicated. Infrared
spectra were recorded on an FTIR as a liquid film or as a thin
crystalline film. High-resolution mass spectra (MS) were
recorded on a double focusing instrument. Optical rotations
were obtained at ambient temperature and referenced to the
sodium D line (589 nm). Melting points were recorded on a
Thomas-Hoover Unimelt and are uncorrected. 1H NMR and
13C NMR data are reported in parts per million (δ) downfield
from tetramethylsilane, using the normal abbreviations.
Thin-layer chromatography (TLC) was performed using
silica gel 60 F254 0.2 mm plates. Visualization was ac-
complished using ultraviolet light or one of the following
stains: 1. Ceric sulfate dihydrate (0.4 g) and ammonium
molybdate tetrahydrate (4.0 g) in 10% aqueous sulfuric acid
(100 mL). 2. Potassium permanganate (0.45 g) in water (100
mL). 3. Anisaldehyde (2 mL), acetic acid (10 mL), and sulfuric
acid (2 mL) in 95% ethanol (85 mL). Flash chromatography
was carried out using silica gel 60 (230-400 mesh). Solvent
systems are reported as volume percent mixtures. Concentra-
tion or evaporation of solvent refers to removal at reduced
pressure using a Bu¨chi rotary evaporator and a Bu¨chi aspira-
tor pump. All inorganic solutions are aqueous and concentra-
tions are indicated in percent weight, except for saturated
sodium chloride and saturated sodium bicarbonate. The
following solvents and reagents were distilled from the indi-
cated agent under argon: tetrahydrofuran (THF) and diethyl
ether from sodium benzophenone ketyl; dichloromethane,
acetonitrile, and triethylamine from calcium hydride. Di-
methyl sulfoxide (DMSO) was distilled from calcium hydride
under reduced pressure. Chloroform was used as supplied by
Fisher Scientific (certified A.C.S.). Chromium(II) chloride was
used as supplied by Strem Chemicals or Aldrich Chemical. All
other reagents were purified by literature procedures. All
reactions were performed under argon unless otherwise noted.
(E)-2,6-Dim eth ylh ep ta -2,5-d ien -1-ol, Tetr a h yd r op yr a -
n yl Eth er , 4. To a solution of 5-bromo-4-methyl-2-butene 2
(2.00 g, 12.27 mmol) dissolved in 25 mL of acetonitrile were
added triphenylphosphine (3.22 g, 12.27 mmol) and tetra-
methylpiperidine (0.075 g, 0.53 mmol). The solution was
refluxed under argon for 24 h and then cooled to room
temperature. The bulk solvent was removed with a vigorous
stream of nitrogen, followed by concentration in vacuo. The
viscous oil was heated to 80 °C under argon and washed with
15 mL of benzene, cooled, and concentrated in vacuo. Hex-
amethylphosphoramide (HMPA, 4.4 mL) and tetrahydrofuran
(THF, 43 mL) were added under argon, followed by a solution
of 0.78 M potassium hexamethyldisilazide in THF (13.5 mL,
10.52 mmol), freshly prepared from potassium hydride and
hexamethyldisilazane. The reaction was heated to 70 °C and
then cooled to room temperature over 1 h with stirring. The
resulting deep red solution was cooled to -78 °C, and 1-(tet-
rahydropyranyloxy)-2-propanone 3 (1.39 g, 8.76 mmol) was
added dropwise to the reaction. After the reaction stirred for
20 min, the cold bath was removed, and the reaction was
allowed to warm to room temperature over 3 h. The reaction
was diluted with 40 mL of water and 15 mL of petroleum ether.
Following separation of the layers, the aqueous layer was
extracted with petroleum ether. The combined organic layers
were dried (MgSO4) and concentrated to give a semisolid. The
19.5, 17.6. IR (neat) 2942, 1453 cm-1
14H23O2 (M+ - H) 223.1698, found 223.1692.
(E)-2,6-Dim eth ylh ep ta -2,5-d ien e-1-ol, 5. The tetrahy-
. HRMS calcd for
C
dropyranyl ether 4 (3.60 g, 16.0 mmol) was dissolved in 125
mL of absolute ethanol. Pyridinium p-toluenesulfonate (PPTS,
0.42 g, 1.6 mmol) was added, and the flask was capped and
heated to 60 °C for 4 h. The solution was cooled to room
temperature, and the solvent was removed by rotary evapora-
tion. The crude product was dissolved in ether, washed with
saturated sodium bicarbonate solution and then with brine,
and then dried (MgSO4), filtered, and concentrated by rotary
evaporation. The resulting oil was purified by flash chroma-
tography over silica gel (20% ethyl acetate in hexane), followed
by distillation to provide the alcohol 5 (1.623 g, 72%) as a
colorless oil: bp 61-65 °C @0.21 mm Hg. 1H NMR (360 MHz,
CDCl3) δ 5.30 (br t, J ) 7.5 Hz, 1H), 5.08 (br t, J ) 7.1 Hz,
1H), 4.16 (d, J ) 5.8 Hz, 2H), 2.75 (dd, J ) 7.2, 7.2 Hz, 2H),
1.81 (s, 3H), 1.70 (s, 3H), 1.64 (s, 3H), 1.18 (br t, J ) 5.8 Hz,
1H). 13C NMR (125 MHz, CDCl3) δ 134.2, 132.0, 127.2, 122.7,
61.6, 26.6, 25.6, 21.3, 17.7. IR (neat) 3324, 2971, 1674 cm-1
HRMS calcd for C9H16O (M+) 139.1123, found 139.1117.
.
(2R,3S)-2-Meth yl-3-(3-m eth yl-2-bu ten yl)oxir a n em eth a -
n ol, 6. Crushed calcium hydride (76 mg, 1.8 mmol) and
activated silica gel (0.163 g, 2.7 mmol) were weighed under
argon into a flask. Dry dichloromethane (110 mL) was added,
and the reaction was cooled to -30 °C. Titanium tetraisopro-
poxide (4.1 mL, 19.2 mmol) and D-(-)-diisopropyl tartrate (5.6
mL, 26.2 mmol) were added, and the reaction was stirred for
15 min. A 4.77 M solution of tert-butyl hydroperoxide (7.2 mL,
34.3 mmol) was added, and the reaction was stirred an
additional 15 min while maintaining the temperature between
-30 °C and -20 °C. The allylic alcohol 5 (2.60 g, 18.5 mmol)
was added to the reaction, and the reaction was placed in a
-20 °C freezer for 18 h. The reaction was warmed to 0 °C,
and a solution of sodium hydroxide (8.6 g, 0.21 mmol) in 30
mL of brine was added to the reaction, followed by addition of
30% hydrogen peroxide (21 mL, 0.19 mmol). After the reaction
had stirred for 2 h, the reaction was warmed to room
temperature and stirred an additional 7 h. The reaction was
diluted with brine, and following separation of the layers, the
aqueous layer was washed with methylene chloride. The
combined organic layers were dried (MgSO4), filtered, and
concentrated to an oil. Flash chromatography over silica gel
(30% ethyl acetate in hexane) provided the epoxy alcohol 6
(2.48 g, 90.6%) as a colorless oil: [R]25 ) +22.8 (c 0.62, CH2-
D
Cl2). 1H NMR (400 MHz, CDCl3) δ 5.15 (br t, J ) 6.0 Hz, 1H),
3.69 (d, J ) 6.2 Hz, 2H), 2.87 (dd, J ) 6.6, 6.6 Hz, 1H), 2.40
(m, 1H), 2.23 (m, 1H), 1.72 (s, 3H), 1.63 (s, 3H), 1.39 (s, 3H),
1.25 (t, J ) 6.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 134.7,
118.7, 64.2, 64.0, 60.8, 27.4, 25.7, 20.2, 17.9; IR (neat) 3432,
2973, 1449 cm-1. HRMS calcd for C9H17O2 (M+ + H) 157.1229,
found 157.1233. 31P NMR analysis of derivative9 (10% C6D6
in C6H6, 162 MHz) δ 133.3 (90.3%), 132.1 (9.7%), 81% ee.
(2R,3R)-3-Ch lor o-2,6-d im eth yl-5-h ep ten e-1,2-d iol, 7. To
a solution of the epoxy alcohol 6 (1.00 g, 6.4 mmol) in dimethyl
sulfoxide (DMSO, 64 mL) was added ammonium chloride (0.68
g, 12.7 mmol). Titanium tetraisopropoxide (2.05 mL, 9.58
mmol) was added dropwise, under argon, with vigorous
stirring. The reaction became yellow within several minutes.
After the reaction had stirred for 1.5 h at room temperature,
ether (120 mL) was added, followed by slow addition of 5%
H2SO4 (60 mL). After the layers separated, the aqueous layer
was extracted with ether, and the organic layers were dried
(17) We thank Dr. Darko Kantoci of Loma Linda University for his
assistance is this separation.

2986 J . Org. Chem., Vol. 63, No. 9, 1998
J ung et al.
(MgSO4), filtered, and concentrated. Flash chromatography
over silica gel (40% ethyl; acetate in hexane) provided the
chloro diol 7 as white crystals (0.93 g, 76%): mp 36-37 °C.
1.09 (s, 3H), 1.03 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 198.7,
80.0, 77.5, 58.6, 52.9, 37.6, 29.3, 23.2, 22.4. IR (neat) 2988,
1736 cm-1. HRMS calcd for C9H15O2ClBr (M+ + H) 268.9944,
found 268.9934.
[R]25 ) +33.9 (c 0.66, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ
D
5.23 (br t, J ) 6.2 Hz, 1H), 4.16 (dd, J ) 10.6, 3.0 Hz, 1H),
3.62 (d, J ) 6.5 Hz, 2H), 2.51 (m, 1H), 2.49 (s, 1H), 2.35 (m,
1H), 2.00 (t, J ) 6.5 Hz, 1H), 1.74 (s, 3H), 1.64 (s, 3H), 1.25 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 134.6, 120.3, 74.8, 70.8,
67.5, 31.8, 25.8, 20.2, 18.0. IR (neat) 3400, 2977, 1673.5, 1451
cm-1. HRMS calcd for C9H18ClO2 (M+ + H) 193.1000, found
1193.0995.
Ap lysia p yr a n oid C, 1c, a n d (2R,3R,5S)-5-Br om o-3-
ch lor o-2-eth en yl-2,6,6-tr im eth yltetr a h yd r op yr a n , 15. To
a glass ampule containing chromium(II) chloride (27 mg, 0.22
mmol) was added the aldehyde 14 (9.9 mg, 0.037 mmol) in
THF (0.4 mL) under argon. Chloroform was added (7 µL, 0.083
mmol), and the ampule was sealed under argon. The ampule
was placed in a oil bath at 60 °C for 56 h, at which point the
ampule was cooled to room temperature and opened, and the
reaction was quenched with ether (2 mL) and water (2 mL).
After the layers separated, the aqueous layer was extracted
with ether, and the organic layers were dried (MgSO4), filtered,
and concentrated to give a yellow oil (7.5 mg, 68%) containing
(2R,3R)-3-Ch lor o-2,6-d im eth yl-1-[(1,1-d im eth yleth yl)-
d im eth ylsilyloxy]-5-h ep ten -2-ol, 8. To a solution of the
chloro diol 7 (0.472 g, 2.45 mmol) in anhydrous dimethylfor-
mamide (5.5 mL) was added imidazole (0.416 g, 6.12 mmol)
and tert-butyldimethylsilyl chloride. After the reaction had
stirred at room temperature for 10 h, the reaction was
quenched with hexane and water. After the layers were
separated, the aqueous layer was extracted with hexanes. The
organic layers were washed with brine, dried (MgSO4), filtered,
and concentrated. Flash chromatography of the crude product
over silica gel (5% ethyl acetate in hexane) provided 0.72 g of
the silyl ether 8 as a colorless oil (95%). [R]25D ) +22.8 (c 0.62,
CH2Cl2). 1H NMR (200 MHz, CDCl3) δ 5.23 (m, 1H), 4.04 (dd,
J ) 10.7, 2.9 Hz, 1H), 3.61 (d, J ) 9.9 Hz, 1H), 3.60 (d, J )
9.9 Hz, 1H), 2.57-2.50 (m, 1H), 2.55 (s, 1H), 2.45-2.30 (m,
1H), 1.74 (s, 3H), 1.63 (s, 3H), 1.25 (s, 3H), 0.91 (s, 9H), 0.08
(s, 6H). 13C NMR (100 MHz, CDCl3) δ 134.1, 120.9, 74.4, 70.0,
67.9, 31.5, 25.82, 25.77, 21.3, 18.2, 18.0, -5.51, -5.53. IR
(neat) 3567, 2955, 1464 cm-1. HRMS calcd for C15H32ClO2Si
(M+ - H) 307.1860, found 307.1858.
1
a 5:5:3 mixture of 1c:15:14, as determined by H NMR. The
1H NMR for 1c matched that reported in the literature.3
Compound 15: 1H NMR (C6D6, 360 MHz) δ 6.11 (dd, J ) 17.6,
11.2 Hz, 1H), 5.34 (d, J ) 17.6 Hz, 1H), 5.04 (d, J ) 11.1 Hz,
1H), 3.36 (dd, J ) 12.6, 4.0 Hz, 1H), 3.24 (m, 1H), 2.30 (ddd,
J ) 12.6, 12.6, 12.6 Hz, 1H), 2.13 (m, 1H), 1.31 (s, 3H), 1.21
(s, 3H), 1.20 (s, 3H).
(2R,3R)-3-Ch lor o-2,6-d im et h yl-2-(t r iet h ylsilyloxy)-5-
h ep ten -1-ol, 16. A solution of 4,4′-dimethoxytrityl chloride
(0.14 g, 0.73 mmol) in dichloromethane (4 mL) was prepared
under argon, and the reaction was cooled to 0 °C. Collidine
was added (0.2 mL, 1.5 mmol), followed by the chloro diol 7
(0.130 g, 0.68 mmol). After the reaction had stirred for 1.5 h,
collidine was added (0.6 mL, 4.5 mmol), followed by triethyl-
silyl trifluoromethanesulfonate (0.5 mL, 2.2 mmol). The
reaction was heated to 40 °C in an oil bath for 16 h, at which
point the reaction was diluted with dichloromethane (5 mL)
and quenched with saturated sodium bicarbonate solution (5
mL). After the layers were separated, the aqueous layer was
extracted with dichloromethane, and the organic layers were
dried (MgSO4), filtered, and concentrated to a brown oil. The
oil was redissolved in dichloromethane and filtered through
silica gel in a filter funnel using 10% ethyl acetate in hexane.
The resulting solution was concentrated to a yellow oil. The
oil was dissolved in dichloromethane (10 mL), and to this
solution was added dodecanethiol (0.35 mL, 1.5 mmol). The
reaction was cooled to 0 °C, and trifluoroacetic acid (44 µL,
0.57 mmol) was added. After the reaction had stirred for 1.5
h, the reaction was quenched with saturated sodium bicarbon-
ate solution (5 mL). After the layers were separated, the
aqueous layer was extracted with dichloromethane, and the
organic layers were dried (MgSO4), filtered, and concentrated
onto silica gel. Flash chromatography over silica gel (10%
ethyl acetate in hexane) provided the silyl ether 16 as a
colorless oil (0.186 g, 90%). [R]25D ) +28.5 (c 0.85, CHCl3). 1H
NMR (500 MHz, CDCl3) δ 5.21 (br t, J ) 7.5 Hz, 1H), 3.86
(dd, J ) 11.1, 2.3 Hz, 1H), 3.65 (d, J ) 11.1 Hz, 1H), 3.60 (d,
J ) 11.1 Hz, 1H), 2.65 (m, 1H), 2.34 (m, 1H), 1.85 (br s, 1H),
1.73 (s, 3H), 1.63 (s, 3H), 1.35 (s, 3H), 0.97 (t, J ) 7.9 Hz, 9H),
0.65 (q, J ) 7.9 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 134.0,
121.2, 77.9, 69.9, 67.7, 31.4, 25.8, 22.6, 18.0, 7.0, 6.7. IR (neat)
3428, 2957, 1458, 1238 cm-1. HRMS calcd for C15H32ClO2Si
(M+ + H) 307.1860, found 307.1868.
(2R,3R,5S)-5-Br om o-3-ch lor o-2,6,6-t r im et h ylt et r a h y-
d r op yr a n -2-m et h a n ol, 13. To a solution of the alkenol 8
(86.8 mg, 0.28 mmol) in dichloromethane (8.5 mL) was added
tetrabromocyclohexadienone (TBCO, 139 mg, 0.34 mmol). The
reaction flask was covered in aluminum foil and was stirred
under argon at room temperature for 16 h. The reaction was
quenched with ether (20 mL) and 1 N sodium hydroxide
solution (10 mL). After the layers were separated, the aqueous
layer was extracted with ether. The organic layers were dried
(MgSO4), filtered, and concentrated to an oil. Flash chroma-
tography over silica gel (5% benzene in hexane) provided
several fractions. The third fraction contained 11a and 12a
and was concentrated to give an oil (76.3 mg, 70% yield). The
oil was dissolved in THF (2.5 mL), and a THF solution of
tetrabutylammonium fluoride (TBAF, 0.15 mL, 150 mmol) was
added. After the reaction had stirred for 24 h, the reaction
was concentrated to a semisolid. Flash chromatography over
silica gel (20% ethyl acetate in hexane) provided the alcohol
13 as white crystals (18.1 mg, 24% based on 8). mp 77-80
°C. [R]25 ) +2.8 (c 0.88, CH2Cl2). 1H NMR (400 MHz, C6D6)
D
δ 3.59 (m, 2H), 3.25 (dd, J ) 12.9, 4.0 Hz, 1H), 3.19 (dd, J )
12.6, 4.5 Hz, 1H), 2.19 (ddd, J ) 12.9, 12.9, 12.9 Hz, 1H), 2.00
(ddd, J ) 13.1, 4.2, 4.2 Hz, 1H), 1.52 (s, 3H), 1.38 (s, 3H), 1.34
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 77.6, 76.6, 63.2, 61.3,
53.3, 37.7, 30.5, 25.4, 21.9. IR (neat) 3494, 2984 cm-1. HRMS
calcd for C9H17O2ClBr (M+ - H) 271.0100, found 271.0103.
(2R,3R,5S)-5-Br om o-3-ch lor o-2,6,6-t r im et h ylt et r a h y-
d r op yr a n -2-ca r boxa ld eh yd e, 14. To a solution of DMSO
(60 µL, 0.77 mmol) in dichloromethane (1.5 mL) at -78 °C was
added oxalyl chloride (50 µL, 0.57 mmol). The reaction was
stirred for 30 min, at which point the alcohol 13 (0.104 g, 0.38
mmol) was added to the reaction as a dichloromethane solution
(2.5 mL). After the reaction had stirred for an additional 30
min, triethylamine (0.20 mL, 1.4 mmol) was added. The
reaction was warmed to 0 °C and quenched with a 10%
solution of potassium dihydrogen phosphate. After the layers
were separated, the aqueous layer was extracted with dichlo-
romethane. The organic layers were dried (MgSO4), filtered,
and concentrated to a solid. Flash chromatography over silica
gel provided the aldehyde 14 as white crystals (0.101 g, 98%).
(E)-(3R,4R)-1,4-Dich lor o-3,7-d im et h yloct a -1,6-d ien -3-
ol, 17. A solution of DMSO (90 µL, 1.27 mmol) in dichlo-
romethane (2 mL) under argon was cooled to -78 °C. Oxalyl
chloride was added (80 µL, 0.92 mmol), and the reaction was
stirred for 30 min. A solution of the alcohol 16 (0.183 g, 0.616
mmol) was added, and the reaction was stirred an additional
30 min. Triethylamine was added (0.26 mL, 1.87 mmol), and
the reaction was stirred for 10 min, at which point the reaction
was warmed to -20 °C and quenched with a 10% potassium
dihydrogen phosphate solution. After the layers were sepa-
rated, the aqueous layer was extracted with dichloromethane,
and the organic layers were dried (MgSO4), filtered, and
concentrated. Flash chromatography over silica gel (5% ethyl
acetate in hexane) provided the aldehyde (0.166 g, 88% yield).
mp 49-50 °C. [R]25 ) +78.3 (c 0.46, CHCl3). 1H NMR (360
D
MHz, C6D6) δ 9.54 (br s, 1H), 3.21 (dd, J ) 12.8, 4.0 Hz, 1H),
3.06 (dd, J ) 12.7, 4.4 Hz, 1H), 2.42 (ddd, J ) 12.9, 12.9, 12.9
Hz, 1H), 2.09 (ddd, J ) 13.2, 4.3, 4.3 Hz, 1H), 1.12 (s, 3H),
[R]25 ) +9.4 (c 1.10, CH2Cl2). 1H NMR (CDCl3, 360 MHz) δ
D
9.63 (s, 1H), 5.19 (br t, J ) 7.0 Hz, 1H), 3.85 (dd, J ) 10.5, 2.9

Total Synthesis Splysiapyranoid C
J . Org. Chem., Vol. 63, No. 9, 1998 2987
Hz, 1H), 2.63 (m, 1H), 2.36 (m, 1H), 1.73 (s, 3H), 1.62 (s, 3H),
1.40 (s, 3H), 0.97 (t, J ) 7.8 Hz, 9H), 0.65 (q, J ) 7.8 Hz, 6H).
13C NMR (100 MHz, CDCl3) δ 201.9, 135.1, 120.0, 81.5, 67.6,
30.7, 25.8, 21.2, 18.0, 6.9, 6.6. IR (neat) 2957, 1738, 1456, 1238
complished using reverse phase HPLC (acetonitrile/water).
[R]25D ) +58.4 (c 0.25, CHCl3). lit. [R]25D ) +52 (c 1.0, CHCl3).3
(2S,3RS)-3-(Ch lor om eth yl)-2,5-d im eth yl-4-h exen e-1,2-
d iol, 9. Using a gas dispersion tube, hydrogen chloride was
bubbled into dichloromethane to give a solution 0.17 M in
hydrogen chloride (titrated against 0.15 M sodium hydroxide).
The hydrogen chloride solution (41 mL, 7.0 mmol) was cooled
to -78 °C under argon. Titanium tetraisopropoxide (0.9 mL,
4.2 mmol) was added. To the cloudy solution was added the
epoxy alcohol 6 (0.59 g, 3.8 mmol) as a solution in di-
choromethane (6 mL). The reaction was placed in a -25 °C
freezer for 12 h, followed by quenching with saturated sodium
bicarbonate solution. After the layers were separated, the
aqueous layer was extracted with dichloromethane. The
organic layers were dried (MgSO4), filtered, and concentrated
onto silica gel. Flash chromatography over silica gel (40%
ethyl acetate in hexane) provided the chloromethyl diol 9 as a
2.8:1 mixture of two diastereomers (0.33 g, 45%), as well as
the expected chloro diol 7 (0.15 g, 20%). Major diastereomer
of 9: 1H NMR (DMSO-d6, 360 MHz) δ 5.05 (br d, J ) 10.6 Hz,
1H), 3.96 (dd, J ) 10.3, 3.1 Hz, 1H), 3.46 (dd, J ) 10.5, 10.5
Hz, 1H), 3.19 (d, J ) 10.8 Hz, 1H), 3.18 (d, J ) 10.8 Hz, 1H),
2.63 (ddd, J ) 10.5, 10.5, 3.1 Hz, 1H), 1.70 (s, 3H), 1.54 (s,
3H), 1.02 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 138.6, 121.1,
74.6, 67.9, 47.7, 45.6, 26.2, 22.3, 18.6. Minor diastereomer of
9: 1H NMR (DMSO-d6, 360 MHz) δ 4.93 (br d, J ) 10.1 Hz,
1H), 3.96 (m, 1H), 3.51 (d, J ) 8.5 Hz, 1H), 3.41 (d, J ) 8.5
Hz, 1H), 3.33 (dd, J ) 7.9, 5.4 Hz, 1H), 2.82 (m, 1H), 1.67 (s,
3H), 1.62 (s, 3H), 1.07 (s, 3H). IR (neat, mixture of diastere-
omers) 3410, 2980, 1470 cm-1. HRMS (mixture of diastereo-
mers) calcd for C9H18ClO2 193.0995, found 193.1000.
cm-1
305.1700.
To a mixture of chromium(II) chloride (0.37 g, 3.0 mmol) in
.
HRMS calcd for C15H30ClO2Si (M+) 305.1704, found
THF (1.5 mL) under argon was added chloroform (98 µL, 1.17
mmol). The reaction was heated to 65 °C for 10 min, by which
time the solution had turned dark red. The above aldehyde
(0.139 g, 0.46 mmol) was added as a solution in THF (1.6 mL),
and the reaction was stirred at 65 °C for 4.5 h. The reaction
was cooled to room temperature, diluted with ether (5 mL),
and quenched with water (6 mL). Using centrifugation to
separate the layers, the organic layer was removed and the
aqueous layer was extracted with ether. The organic layers
were dried (MgSO4), filtered, and concentrated to an oil. The
oil was washed through silica gel in a fritted funnel using 1%
ethyl acetate in hexane, and the resulting solution was
concentrated to give the vinyl chloride as a colorless oil (0.1054
g, 69%).
The vinyl chloride (12.1 mg, 0.036 mmol) was dissolved in
dichloromethane (3 mL) and cooled to 0 °C in a polyethylene
tube open to air. Pyridine (50 µL) was added, and hydrogen
fluoride-pyridine was added in portions, until TLC indicated
that the reaction was complete (approximately 300 µL). The
reaction was quenched with saturated sodium bicarbonate
solution. After the layers were separated, the aqueous layer
was extracted with dichloromethane, and the organic layers
were dried (MgSO4), filtered, and concentrated to an oil. Flash
chromatography over silica gel (10% ethyl acetate in hexane)
provided the dichloro alcohol 17 as a colorless oil (6.9 mg, 86%).
The structure of the major diastereomer of 9 was confirmed
by preparation of the monoacetate. 1H NMR (CDCl3, 500 MHz)
δ 4.96 (br d, J ) 9.9 Hz, 1H), 4.08 (d, J ) 9.9 Hz, 1H), 4.04
(dd, J ) 8.4, 6.7 Hz, 1H), 3.83 (d, J ) 9.9 Hz, 1H), 3.49 (dd, J
) 8.4, 6.7 Hz, 1H), 3.35 (m, 1H), 2.02 (s, 3H), 1.75 (s, 3H),
1.72 (s, 3H), 1.44 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 170.5,
136.3, 120.6, 89.0, 76.9, 72.2, 47.6, 26.0, 22.0, 18.4, 17.9. IR
[R]25 ) +20.9 (c 0.118, CHCl3). 1H NMR (500 MHz, CDCl3)
D
δ 6.36 (d, J ) 13.3 Hz, 1H), 6.08 (d, J ) 13.3 Hz, 1H), 5.21 (br
t, J ) 7.0 Hz, 1H), 3.81 (dd, J ) 10.2, 3.4 Hz, 1H), 2.58 (m,
1H), 2.32 (m, 2H), 1.73 (s, 3H), 1.62 (s, 3H), 1.41 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 136.1, 134.9, 120.4, 120.2, 75.3, 71.7,
31.8, 25.7, 24.6, 18.1. IR (neat) 3459, 2977, 1622, 1451, 1267
cm-1
.
(neat) 2977, 1738, 1447 cm-1
.
Ap lysia p yr a n oid C, 1c. To a solution of the dichloroalk-
enol 17 (36.0 mg, 0.161 mmol) in nitromethane (1.1 mL) was
added TBCO (135 mg, 0.33 mmol). The flask was covered with
aluminum foil, and the reaction was stirred at room temper-
ature under argon for 12 h. The reaction was diluted with
dichloromethane (3 mL), then washed with sodium hydroxide
solution (1 N). The organic solution was dried (MgSO4),
filtered, and concentrated to an oil. The oil was dissolved in
hexane and filtered through a plug of silica gel using 5% ethyl
acetate in hexane. The resulting solution was concentrated,
and flash chromatography of the resulting oil (10% benzene
in hexane) provided aplysiapyranoid C 1c (21.1 mg, 43%). The
1H NMR, 13C NMR, and IR spectra of 1c matched those
reported in the literature.3 Further purification was ac-
Ack n ow led gm en t. We thank the National Insti-
tutes of Health, the Agricultural Research Division of
American Cyanamid Co., and Zeneca for generous
financial support.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR spec-
tra (23 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.
J O972228J