Enantioselective Synthesis of α,β,α′-Trisubstituted Cyclic Ethers

Article abstract of DOI:10.1021/jo981188w

A synthetic strategy for the preparation of trisusbstituted cyclic ethers is presented, in which the stereochemistry at the carbon atoms adjacent to the oxygen of the ether was controlled by means of a hetero Diels-Alder reaction between a monoactivated diene and a chiral aldehyde. The adducts were transformed into linear ethers, which were then used for the preparation of cis and trans cyclic ethers of different sizes. A cis-oxepane, cis-oxonane, and c/s-oxocane and a frans-oxocane were prepared as examples of the scope of the strategy.

Full text of DOI:10.1021/jo981188w

9728
J . Org. Chem. 1998, 63, 9728-9738
En a n tioselective Syn th esis of r,â,r′-Tr isu bstitu ted Cyclic Eth er s†
M. Teresa Mujica, Mar´ıa M. Afonso, Antonio Galindo, and J . Antonio Palenzuela*
Instituto Universitario de Bio-Orga´nica “Antonio Gonza´lez”, Universidad de La Laguna,
38206 La Laguna, Tenerife, Spain
Received J une 18, 1998
A synthetic strategy for the preparation of trisusbstituted cyclic ethers is presented, in which the
stereochemistry at the carbon atoms adjacent to the oxygen of the ether was controlled by means
of a hetero Diels-Alder reaction between a monoactivated diene and a chiral aldehyde. The adducts
were transformed into linear ethers, which were then used for the preparation of cis and trans
cyclic ethers of different sizes. A cis-oxepane, cis-oxonane, and cis-oxocane and a trans-oxocane
were prepared as examples of the scope of the strategy.
In tr od u ction
an aldehyde as the key step in the control of the relative
stereochemistry of the centers adjacent to the oxygen
atom, followed by ozonolysis and intramolecular alkyla-
tion of the resulting linear ether (Figure 1).
In this paper, we wish to present the extension of the
methodology to enantiomerically pure, polysubstituted
compounds.
During the last years, cyclic ethers have attracted
considerable attention due to their occurrence in several
groups of natural compounds exhibiting important bio-
logical activities.1 These units can be found isolated in
monocyclic or polycyclic compounds, fused with other
cyclic ethers, or forming spiro systems.2 In nature,
monocyclic compounds with ring sizes ranging from 5 to
9 atoms are known. Most have cis stereochemistry at the
positions adjacent to the oxygen atom of the ether (R, R′
positions), such as isolaurepinnancin (1)3 and laurencin
(2),4 although trans compounds such as obtusenin (3)5
have also been obtained.
Resu lts a n d Discu ssion
To induce the desired chirality, we decided to use a
chiral aldehyde instead of chiral dienes or chiral cata-
lysts, since different aldehydes bearing chiral centers at
the R position are available in both enantiomeric forms
by literature procedures and have been used successfully
in hetero Diels-Alder reactions.10 We chose the aldehyde
R-(+)-511 since previous work by Danishefsky and col-
leagues12 has shown that it undergoes hetero Diels-Alder
reaction with mono- and diactivated dienes with a high
yield and high endo-Cram selectivity.
(6) Recent examples: (a) Ravelo, J . L.; Regueiro, A.; Mart´ın, J . D.
Tetrahedron Lett. 1992, 33, 3389. (b) Hoffmann, R. W.; Mu¨nster, I.
Tetrahedron Lett. 1995, 36, 1431. (c) Alvarez, E.; D´ıaz, M. T.; Hanxing,
L.; Mart´ın J . D. J . Am. Chem. Soc. 1995, 117, 1437. (d) Clark, J . S.;
Kettle, J . G. Tetrahedron Lett. 1997, 38, 123. (e) Clark, J . S.; Kettle,
J . G. Tetrahedron Lett. 1997, 38, 127. (f) Inoue, M.; Sasaki, M.;
Tachibana, K. Tetrahedron Lett. 1997, 38, 1611. (g) Berger, D.;
Overman, L. E.; Renhowe, P. A. J . Am. Chem. Soc. 1997, 119, 2446.
(h) Crimmins, M. T.; Choy, A. L. J . Org. Chem. 1997, 62, 7548.
(7) (a) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M.
E.; Veale, C. A. J . Am. Chem. Soc. 1989, 111, 5321. (b) Nicolaou, K.
C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J . Am. Chem. Soc.
1989, 111, 5330. (c) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.;
Hwang, C.-K. J . Am. Chem. Soc. 1989, 111, 5335. (d) Cooper, A. J .;
Salomon, R. G. Tetrahedron Lett. 1990, 31, 3813. (e) Suzuki, T.; Sato,
O.; Hirama, M. Tetrahedron Lett. 1990, 31, 4747. (f) Aicher, T. D.;
Buszek, K. R.; Fang, F. G.; Forsyth, C. J .; J ung, S. H.; Kishi, Y.; Scola,
P. M. Tetrahedron Lett. 1992, 33, 1549. (g) Mart´ın, V. S.; Palazo´n, J .
M. Tetrahedron Lett. 1992, 33, 2399. (h) Gung, B. W.; Francis, M. B.
J . Org. Chem. 1993, 58, 6177. (i) Mukai, C.; Ikeda, Y.; Sugimoto, Y.;
Hanaoka, M. Tetrahedron Lett. 1994, 35, 2179. (j) Mukai, C.; Sugimoto,
Y.; Ikeda, Y.; Hanaoka, M. Tetrahedron Lett. 1994, 35, 2183. (k)
Palazo´n, J . M.; Mart´ın, V. S. Tetrahedron Lett. 1995, 36, 3549.
(8) (a) Paquette, L. A.; Sweeney, T. J . J . Org. Chem. 1990, 55, 1703.
(b) Nicolaou, K. C.; McGarry, D. G.; Somers, P. K.; Kim, B. H.; Ogilvie,
W. W.; Yiannikouros, G.; Prasad, C. V. C.; Veale, C. A.; Hark, R. R. J .
Am. Chem. Soc. 1990, 112, 6263. (c) Carling, R. W.; Clark, J . S.;
Holmes, A. B. J . Chem. Soc., Perkin Trans. 1 1992, 83. (d) Carling, R.
W.; Clark, J . S.; Holmes, A. B.; Sartor, D. J . Chem. Soc., Perkin Trans.
1 1992, 95. (e) Fuhry, M. A.; Holmes, A. B.; Marshall, D. R. J . Chem.
Soc., Perkin Trans. 1 1993, 2743. (f) Alvarez, E.; D´ıaz, M. T.; Pe´rez,
R.; Ravelo, J . L.; Regueiro, A.; Vera, J . A.; Zurita, D.; Mart´ın, J . D. J .
Org. Chem. 1994, 59, 2848.
A number of synthetic approaches have been devised
in order to construct the cyclic ether moiety, using a
carbon-carbon6 or a carbon-oxygen7 cyclization step or
modifying cyclic precursors.8
Recently,9 we presented an approach to cyclic ethers
of different ring sizes in racemic form, using a hetero
Diels-Alder reaction between a monoactivated diene and
† Dedicated to Prof. A. G. Gonza´lez with respect and admiration on
the occasion of his 80th birthday.
(1) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897.
(2) Faulkner, D. J . Nat. Prod. Rep. 1997, 14, 259.
(3) Fukuzawa, A.; Masamune, T. Tetrahedron Lett. 1981, 22, 4081.
(4) (a) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett. 1965,
1091. (b) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron. 1968, 24,
4193. (c) Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Robertson, J .
M. J . Chem. Soc. B 1969, 559. (d) Cameron, A. F.; Cheung, K. K.;
Ferguson, G.; Robertson, J . M. J . Chem. Soc., Chem. Commun. 1965,
638.
(5) (a) King, T. J .; Imre, S.; Oztunc, A.; Thomson, R. H. Tetrahedron
Lett. 1979, 1453. (b) Howard, B. M.; Schulte, G. R.; Fenical, W.
Tetrahedron 1980, 36, 1747.
(9) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J . A.
Tetrahedron Lett. 1994, 35, 3401.
10.1021/jo981188w CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/04/1998

R,â,R′-Trisubstituted Cyclic Ethers
J . Org. Chem., Vol. 63, No. 26, 1998 9729
To test our ideas, we started by preparing a few
examples of cis-substituted cyclic ethers. For these
compounds, the sulfone should be located in the side
chain coming from the diene in the cycloaddition (R1 in
Figure 2), and thus it could be present from the beginning
of the synthesis.
The dienes chosen (8-10) were prepared from the
corresponding aldehydes as shown in eq 1.14
Syn th esis of th e cis-Oxep a n e. We first tested the
reaction of the aldehyde 5 with the diene 8, which has
the suitable side chain for the preparation of the oxepane
ring. The hetero Diels-Alder reaction between 8 and 5
was carried out using boron trifluoride etherate as
catalyst, according to our previous experiment.15 The best
results were obtained when the reaction took place at
-25 °C, at which temperature only two of the four
possible isomers (11 and 12) were obtained in a 2.6:1 ratio
and in an 82% isolated yield. The study of the relative
stereochemistry at the newly created chiral centers in
the major product was carried out using the correspond-
ing ketone 13, obtained by treatment of the cycloadduct,
after HPLC separation, with tetrabutylammonium fluo-
ride (TBAF).
F igu r e 1. Strategy used in the synthesis of racemic oxepanes
and oxocanes.9
A complete spectroscopic study of this pyrone allowed
us to identify all relevant signals in the NMR spectrum,
and a ROESY16 experiment indicated that this compound
was the cis isomer since correlation was observed be-
tween the two protons geminal to the oxygen atom of the
pyrone. The absolute stereochemistry could not be as-
certained at this point and was tentatively assigned as
shown on the basis of the previously observed tendency
of the aldehyde 5 to react through an endo approach to
the diene.12 It should be noted that, according to a
lanthanide-induced shift (LIS)17 study using Eu(hfc)3, no
racemization took place during the cycloaddition reaction
since only one enantiomer was observed to the detection
limits of 400 MHz NMR.18
F igu r e 2. Proposed strategy for the synthesis of enantiomeri-
cally pure cis and trans cyclic ethers.
Our strategy is depicted in Figure 2. The cycloadduct
is opened to give a linear ether, and the acetonide is
transformed into an epoxide. The placing of the carbanion
stabilizing group (a sulfone) in either of the two side
chains of the upper part of the molecule should allow us
to control the relative stereochemistry of the two centers
at the R and R′ position to the oxygen atom of the ether.
The size of the ring obtained depends on the length of
the chain carrying the sulfone and the regioselectivity
of the attack of the carbanion to the epoxide in the
cyclization step. Such chemistry has previously been used
to construct five- and six-membered rings and an endo
preference in the attack has been observed.13
The enolsilyl ether moiety present in the cycloadducts
was too labile to allow an efficient separation, and thus
it was decided to continue with the mixture. The cycload-
dition products were treated with ozone followed by
(13) Krief, A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 3, pp 167-
168.
(14) The aldehydes were prepared according to literature procedures
or by simple modification of commercial compounds. See the Supporting
Information section.
(10) Boger, D. L.; Weinreb, S. N. Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press: San Diego, CA, 1987. Carru-
thers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon
Press: Oxford, U.K., 1990. Oppolzer, W. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
U.K., 1991; Vol. 5, pp 401-449.
(15) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J . A.
Tetrahedron 1996, 52, 2167.
(16) Bothner-By, A. A.; Stephens, R. L.; Lee, J .; Warren, C. D.;
J eanlo, R. W. J . Am. Chem. Soc. 1984, 106, 81. Bax, A. Davis, D. G.,
J . Magn. Reson. 1985, 321.
(17) Parker, D. Chem. Rev. 1991, 91, 1441.
(11) Schmid, C. R.; Bryant, J . D. Org. Synth. 1993, 72, 6.
(18) The LIS studies were conducted comparing the displacement
of the signals with that of a racemic mixture, prepared by mixing the
enantiomers obtained using aldehyde 5 and its enantiomer in the
cycloaddition reaction.
(12) Danishefsky, S. J .; Kobayashi, S.; Kerwin, J . F., J r. J . Org.
Chem. 1982, 47, 1981. Danishefsky, S. J .; Pearson, W. H.; Harvey, D.
F.; Maring, C. J .; Springer, J . P. J . Am. Chem. Soc. 1985, 107, 1256.

9730 J . Org. Chem., Vol. 63, No. 26, 1998
Mujica et al.
Sch em e 1
Sch em e 2
NaBH4 reduction, and the resulting crude was meth-
ylated using diazomethane as shown in eq 2. At this
point, the two compounds were readily separated by
HPLC and the rest of the synthesis was carried out using
only the major compound 14, obtained in a 48% yield
from 11 + 12.
The hydroxyl group in 14 was protected as its tert-
butyldiphenylsilyl ether and the ester reduced with
DIBALH to the alcohol 15 in 91% yield (two steps). At
this point, the hydroxyl group in 15 (Scheme 2) could be
protected with a different group for possible transforma-
tion at a later stage, but since at this stage we only
wanted to demonstrate the usefulness of our synthetic
scheme, we decided to simplify the molecule by treating
the corresponding tosylate with LiAlH4, yielding 16
(82%). In the following steps, the acetonide was trans-
formed into an epoxide by deprotection with camphor-
sulfonic acid, tosylation of the primary alcohol, and
treatment with sodium hydride. The epoxide 17, obtained
in a 75% isolated yield from 16, is the linear ether
depicted in Figure 2 with the entire functionality required
for its transformation into an oxepane. This transforma-
tion was achieved in a 96% yield by treating 17 with 4
equiv of LDA at -65 °C in THF. No compound coming
from an exo attack on the epoxide could be detected. The
oxepane 18 was obtained as a 1:1 mixture of epimers at
the sulfone, and this was proven by treatment of the
tertbutyldimethylsilyl protected compounds with LDA
and MoOPh,19 yielding the ketone 19 in a 61% yield from
18 as a single compound. The spectroscopic data (ROESY)
indicated that the absolute stereochemistry of the cyclic
ether was indeed the expected one, that is, for the major
isomer of the cycloaddition reaction, the one coming from
the endo-Cram approach of the aldehyde to the diene.
Syn th esis of th e cis-Oxoca n e a n d cis-Oxon a n e.
Once the viability of this approach for the preparation
of oxepanes was demonstrated, we wanted to test its
scope in the synthesis of larger rings. The cycloaddition
of diene 9 with 5, using the same procedure, and on the
Sch em e 3
same scale, described for the cycloadducts of 8 with 5,
proceeded with higher selectivity giving a 7:1 ratio of cis:
trans isomers in an 82% yield (Scheme 3).
The other two possible isomers were observed only as
traces. Following the same synthetic sequence as de-
scribed for the oxepane, the linear ether 20 was obtained
in a 26% overall yield from the cycloadducts. The cycliza-
tion step was carried out by addition of 4 equiv of LDA
at -65 °C to a THF solution of 20 (0.1-0.7 mmol scale),
and thus 21 was obtained in a 60% yield together with
unreacted material, as a 9:1 mixture of epimers at the
carbon atom bearing the sulfone, the major isomer being
the (5S)-sulfone, according to the correlations found in
the ROESY experiment. Changing the temperature or
reaction time did not lead to improvement of the yield,
only to decomposition of the products. Again, no com-
pound coming from an exo attack of the carbanion on the
(19) Vedejs, E.; Engler, D. A.; Telschow, J . E. J . Org. Chem. 1978,
43, 188.

R,â,R′-Trisubstituted Cyclic Ethers
J . Org. Chem., Vol. 63, No. 26, 1998 9731
Sch em e 4
epoxide was detected. The mixture of epimers 21 was
partially separated and the stereochemistry at the major
isomer studied. The correlations found in the ROESY
experiment showed that the major compound in the
cycloaddition reaction was the one coming from an endo-
Cram approach of the aldehyde to the diene. When the
diene 10 was used, the hetero Diels-Alder reaction,
under the same experimental conditions used for diene
8, yielded 76% of an 8.3:1 mixture of cis:trans cycload-
ducts (the other two possible isomers being detected only
as very minor components of the crude reaction mixture).
It is interesting to note that the longer the chain carrying
the sulfone, the better the ratio of the cycloadducts
obtained. After the same transformations used for the
synthesis of the oxepane and oxocane rings were carried
out, the cyclization of the linear epoxy ether (4 equiv of
LDA at -65 °C) gave a 45% yield of a 3.5:1 mixture of
two compounds (22 and 23) and unreacted material. As
described for the oxocanes, the yield could not be in-
creased by changing the reaction conditions. In this case,
compounds 22 and 23 exhibited very different chromato-
graphic behavior (different Rf in TLC, different tR in
HPLC). After separation and by spectroscopic studies, it
was concluded that they were the expected oxonane
epimers at the sulfone-bearing carbon, both coming from
an endo-Cram cycloaddition as observed by the ROESY
correlations. The difference in their properties could be
due to the greater flexibility of the oxonane ring and the
possibility of intramolecular hydrogen bonding in one of
the isomers. When the hydroxyl group in both compounds
was protected as TBDMS ether, their chromatographic
properties were almost identical, as observed for the other
epimers with smaller ring sizes.
Working as previously described, 27, enantiomer of 21,
was obtained with a similar yield. The introduction of
the double bond in the oxocane ring was accomplished
by Swern oxidation of the hydroxyl group, elimination
of the sulfone with DBU at room temperature, and then
deconjugation of the R,â-unsaturated ketone by heating
the mixture at 100 °C,21a giving 28 in an 85% yield.
Reduction of 28 with L-Selectride at -68 °C gave a 94%
yield of the alcohol with the desired â orientation, as
determined by ROESY experiments. The benzylation of
the hydroxyl with benzyl bromide furnished 24, whose
spectroscopic data were totally consistent with the pro-
posed structure. These data, however, were different from
those reported by Holmes and co-workers for their
intermediate in the synthesis of (+)-laurencin. We then
learned of the problems encountered by the authors in
that paper, which was later retracted,23,24 and thus the
preparation of 24 was not sufficient to claim a formal
synthesis.
The preparation of the oxepane, oxocane, and oxonane
ring systems with cis stereochemistry at the positions
adjacent to the oxygen atom of the ether validates the
usefulness of our approach.
F or m a l Syn th esis of (+)-La u r en cin .20 As a further
demonstration of the utility of this approach for the
synthesis of mediocyclic ethers, we decided to carry out
the synthesis of a natural product with a cis cyclic ether
skeleton.
Fortunately, in the meantime, Overman and co-work-
ers reported on a new synthesis of (+)-laurencin25 in
which one of the intermediates (29) was easily accessible
from 28. The preparation of 29 was carried out as shown
in Scheme 5.
The compound chosen was (+)-laurencin (2), of which,
at the time this work was being conducted, two enantio-
selective syntheses had been reported.21 We decided to
prepare, using our methodology, compound 24, an inter-
Deprotection of 28 (98% yield) followed by Swern
oxidation gave the corresponding aldehyde, which was
converted into 30, using a Wittig-Horner reaction, in an
85% yield (two steps). In the latter reaction it is impor-
tant to use an excess of triethylphosphonoacetate since
a slight excess of base produces an intramolecular
Michael addition of the enolate of the ketone to the R,â-
mediate in the synthesis of Holmes and co-workers,
making it a formal synthesis of (+)-laurencin, if success-
ful. The absolute stereochemistry of the selected com-
pound at the carbons adjacent to the oxygen atom of the
ether was opposite to the one obtained in our previous
preparation of the oxocane ring. Thus, it was necessary
to start the synthesis using 25,22 the enantiomer of 5, as
the aldehyde in the hetero Diels-Alder reaction (Scheme
4).
(22) (a) Vekemans, J . A. J . M.; Bruyn, R. G. M.; Caris, R. C. H. M.;
Kokx, A. J . P. M.; Konings, J . J . H. G.; Godefroi, E. F. J . Org. Chem.
1987, 52, 1093. (b) Hubschwerlen, C.; Specklin, J .-L.; Higelin, J . Org.
Synth. 1993, 72, 1.
(23) Burton, J . W.; Clark, J . S.; Bendall, J .; Derrer, S.; Stork, T.;
Holmes, A. B. J . Am. Chem. Soc. 1996, 118, 6806.
(24) We thank Prof. Holmes for informing us of the inconsistencies
found in his paper prior to the publication of the retraction.
(25) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J . Am.
Chem. Soc. 1995, 117, 5958.
(20) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J . A.
Synlett 1996, 983.
(21) (a) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345.
(b) Robinson, R. A.; Clark, J . S.; Holmes, A. B. J . Am. Chem. Soc. 1993,
115, 10400.

9732 J . Org. Chem., Vol. 63, No. 26, 1998
Mujica et al.
Sch em e 5
Sch em e 6
unsaturated ester, giving 31 as the major product, 43%
yield, as a mixture of epimers. The preparation of 29 was
accomplished by L-Selectride reduction of 30 followed by
protection of the hydroxyl group and DIBALH reduction
of the ester (77% from 30). This compound exhibits
spectroscopic and physical data20 identical to those
reported by Overman and co-workers25 for their inter-
mediate in the synthesis of (+)-laurencin. A LIS study
of 29 using Eu(hfc)3 and comparison with its enantiomer,
prepared by using the same synthetic sequence starting
with aldehyde 5, showed only one isomer to the detection
limits of the NMR. Thus, we have accomplished a formal
synthesis of (+)-laurencin, demonstrating the viability
of our synthetic scheme. It should be noted also that the
reduction product of 28 presents spectroscopic data
identical to those reported in the recent papers on the
synthesis of (+)-laurencin by Holmes26 and in the formal
synthesis of (+)-laurencin reported by Hoffmann.27
Syn th esis of a tr a n s-oxoca n e. After completing the
formal synthesis of (+)-laurencin, we turned our atten-
tion to the preparation of cyclic ethers with trans ster-
eochemistry at the positions adjacent to the oxygen atom.
According to our synthetic scheme (Figure 2), the sulfone
group should be located in the side chain coming from
the ozonolysis of the dihydropyrane after the hetero
Diels-Alder reaction (R2 in Figure 2) and thus it must
be introduced at a later stage in the synthesis.
35 in a 34% overall yield. The alcohol was protected as
the TBDMS ether, and the ester was transformed into
an ethyl group affording 36 (65% yield). Treatment with
camphorsulfonic acid to remove the TBDMS silyl group
gave compounds 37 and 38, but the diol 38 was easily
reprotected under the standard conditions. To effect
closure of the mediocyclic ether ring, we needed to
incorporate a sulfone group into the molecule, and it was
also necessary to define the size of the ring to be formed
since this depended on the length of the side chain
bearing the sulfone. As an example, we chose to form a
trans-oxocane, and thus the chain had to be extended by
two carbons.
This was accomplished by oxidation of the alcohol,
Wittig-Horner olefination with triethylphosphonoac-
etate/NaH, and catalytic hydrogenation of the double
bond to give 39 in an 89% yield after the three steps. No
epimerization was observed to the detection limits of
NMR during these reactions. The ester was reduced, and
the resulting alcohol was tosylated and treated with
sodium iodide, giving the iodide 40 (89% yield). The
sulfone group was then introduced by displacement of
the iodine with p-toluensulfinic acid sodium salt in high
yield (98%), and the acetonide was transformed into an
epoxide (59% yield). The cyclization of the epoxysulfone
41 using 7 equiv of LDA at -40 °C gave the trans-oxocane
42 in a 38% yield as a 5.6:1 mixture of epimers at the
carbon atom bearing the sulfone (C5), together with
unreacted material. The stereochemistry was confirmed
by ROESY experiments on the major compound, as
depicted in Scheme 7.
The diene 33 needed for this synthesis was prepared
in a 68% overall yield from 32, as shown in eq 3.
The reaction of 33 and 5 (Scheme 6) under boron
trifluoride etherate catalysis gave a 4.3:1 mixture of
cycloadducts (34) in a 95% yield. The ozonolysis, followed
by sodium borohydride reduction, treatment with diazo-
methane, and HPLC separation of the major isomer, gave
Con clu sion s
(26) Burton, J . W.; Clark, J . S.; Derrer, S.; Stork, T. C.; Bendall, J .
G.; Holmes, A. B. J . Am. Chem. Soc. 1997, 119, 7483.
(27) Kru¨ger, J .; Hoffmann, R. W. J . Am. Chem. Soc. 1997, 119, 7499.
The preparation of the cis-oxepane 19, cis-oxocanes 21
and 29, cis-oxonanes 22 and 23, and trans-oxocane 42,

R,â,R′-Trisubstituted Cyclic Ethers
J . Org. Chem., Vol. 63, No. 26, 1998 9733
ether (50 mL) and a saturated solution of NaHCO3 were added.
The phases were separated, and the aqueous one was extracted
with ether (2 × 100 mL). The combined organic layers were
dried (Na2SO4), concentrated, and chromatographed on silica
gel (15% ethyl acetate in hexane) to yield 2.68 g of 8 (80%) as
a clear oil: 1H NMR (CDCl3, 400 MHz) δ 0.13 (s, 6H), 0.93 (s,
9H), 2.46 (s, 3H), 2.49 (m, 2H), 3.12 (m, 2H), 4.20 (s, 1H), 4.23
(s, 1H), 5.84 (m, 2H), 7.36 (d, J ) 8.1 Hz, 2H), 7.78 (d, J ) 8.2
Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ -4.8, 18.1, 21.5, 25.4,
25.6, 55.5, 95.2, 125.7, 128.1, 129.8, 130.3, 135.9, 144.7, 154.1;
IR (CHCl3) 1640, 1590, 1310 cm-1; MS (EI) m/z (rel intensity)
309 (49), 211 (10).
Sch em e 7
Heter o Diels-Ald er Rea ction of 8 a n d 5. To a solution
of 8 (2.4 g, 6.5 mmol) in anhydrous ether (60 mL) was added
under argon R-(+)-2,3-O-isopropylideneglyceraldehyde (5) (850
mg, 6.5 mmol) in 10 mL of ether. The reaction was cooled to
-25 °C, and BF3‚OEt2 (0.82 mL) was added. After 15 min, TEA
(1.8 mL) was added and the reaction was allowed to reach room
temperature. Water was added, and the mixture was extracted
with ether (3 × 75 mL). The combined organic phases were
dried (Na2SO4), concentrated, and chromatographed (silica gel,
20% EtOAc in hexane), yielding 2.66 g of the Diels-Alder
adducts (82%) as a 2.6:1 mixture. A fraction of the mixture
was separated by HPLC and a small amount of the minor
isomer (12) was obtained pure.
(2S,6S)-4-((ter t-Bu tyld im eth ylsilyl)oxy)-2-[4(R)-2,2-d i-
m eth yl[1,3]d ioxola n -4-yl]-6-[2-(tolyl-4-su lfon yl)eth yl]-3,6-
d ih yd r o-2H-p yr a n (11): 1H NMR (CDCl3, 400 MHz) δ 0.10
(s, 3H), 0.11 (s, 3H), 0.88 (s, 9H), 1.31 (s, 3H), 1.35 (s, 3H),
1.73-1.79 (m, 1H), 1.98 (m, 1H), 2.03 (m, 2H), 2.42 (s, 3H),
3.14 (m, 2H), 3.44 (m, 1H), 3.80 (dd, J ) 8.3, 5.0 Hz, 1H), 3.89
(m, 1H), 4.0 (dd, J ) 8.3, 6.2 Hz, 1H), 4.21 (m, 1H), 4.57 (bs,
1H), 7.33 (d, J ) 7.9 Hz, 2H), 7.75 (d, J ) 8.3 Hz, 2H).
(2S,6R)-4-((ter t- Bu t yld im et h ylsilyl)oxy)-2-[4(R)-2,2-
d im eth yl[1,3]d ioxola n -4-yl]-6-[2-(tolyl-4-su lfon yl)eth yl]-
3,6-d ih yd r o-2H-p yr a n (12): 1H NMR (CDCl3, 400 MHz) δ
0.13 (s, 3H), 0.14 (s, 3H), 0.91 (s, 9H), 1.34 (s, 3H), 1.37 (s,
3H), 1.98-1.81 (m, 2H), 2.17-2.01 (m, 2H), 2.46 (s, 3H), 3.12
(m, 1H), 3.24 (m, 1H), 3.53 (m, 1H), 3.70 (dd, J ) 7.4, 4.7 Hz,
1H), 4.02 (m, 2H), 4.24 (m, 1H), 4.72 (bs, 1H), 7.37 (d, J ) 7.9
Hz, 2H), 7.89 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
δ -4.6, -4.4, 18.0, 21.6, 25.2, 25.6, 26.5, 27.7, 31.9, 53.3, 67.0,
70.7, 72.3, 104.0, 109.5, 128.0, 130.0, 136.2, 144.7, 148.9; IR
in enantiomerically pure form, demonstrated the versa-
tility of the strategy based on the highly regioselective
intramolecular alkylation of R-lithiosulfones with ep-
oxides, in which the chiral centers adjacent to the oxygen
atom have been established via a hetero Diels-Alder
reaction.
Exp er im en ta l Section
Ma ter ia l a n d Meth od s. 1H and 13C NMR spectra were
recorded at 400 and 100 MHz, respectively, in CDCl3 or C6D6
as solvent, and chemical shifts are quoted in ppm and reported
relative to tetramethylsilane. Flash column chromatography
was performed on Merck silica gel 60 (260-400 mesh).
Analytical thin-layer chromatography (TLC) was carried out
on Merck precoated 0.25 mm thick plates of Merck Kieselgel
60 F254. Reactions requiring anhydrous conditions were carried
out under an atmosphere of dry argon. Anhydrous THF was
distilled from sodium in a recycling still. Other solvents were
purified by standard techniques. Ether refers to diethyl ether.
3(E)-2-((ter t-Bu tyldim eth ylsilyl)oxy)-6-(tolyl-4-su lfon yl)-
h exa -1,3-d ien e (8). Step a . To a suspension of NaH (679 mg,
80% in mineral oil, 22.64 mmol) in THF (160 mL) at 0 °C under
argon was added diethyl (2-oxopropyl)phosphonate (22.63
mmol, 4.35 mL) with stirring. After 0.5 h, 3-(tolyl-4-sulfonyl)-
propionaldehyde (4 g, 18.9 mmol) was added and the reaction
was allowed to reach room temperature (1 h). Then water and
ice were added and the solution was neutralized with 1%
aqueous HCl and extracted with ether (2 × 100 mL). The
organic phases were dried (Na2SO4), concentrated, and purified
by column chromatography (silica gel, 40% ethyl acetate in
hexane) to yield 3(E)-6-(t olyl-4-su lfon yl)h ex-3-en -2-on e
(3.71 g, 78%) as a clear oil: 1H NMR (CDCl3, 400 MHz) δ 2.17
(s, 3H), 2.43 (s, 3H), 2.61 (m, 2H), 3.19 (m, 2H), 6.01 (dt, J )
16.0, 1.5 Hz, 1H), 6.62 (dt, J ) 16.0, 6.7 Hz, 1H), 7.35 (d, J )
8.0 Hz, 2H), 7.75 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3, 100
MHz) δ 21.5, 25.6, 26.9, 54.3, 128.0, 130.0, 132.5, 135.6, 142.2,
145.0, 187.0; IR (CHCl3) 1690, 1670, 1310 cm-1; MS (EI) m/z
(rel intensity) 253 (MH+, 1), 155 (7), 97 (100); HRMS (EI) m/z
calcd for C13H16O3S 252.08202, found 252.08296.
(CHCl3) 1670, 1600, 1310 cm-1
.
(2S,6S)-2-[4(R)-2,2-Dim eth yl[1,3]dioxolan -4-yl]-6-[2-(tol-
yl-4-su lfon yl)-eth yl]tetr a h yd r op yr a n -4-on e (13). To a so-
lution of compound 11 (50 mg, 0.1 mmol) in anhydrous THF
(2 mL) at 0 °C under an argon atmosphere, a small amount of
tetrabutylammonium fluoride hydrate (TBAF) was added.
After 10 min, ice and an aqueous saturated solution of NaCl
were added and the mixture was extracted with ether (3 × 50
mL). The organic phases were dried (MgSO4), concentrated,
and chromatographed on silica gel (20% EtOAc in hexane),
yielding 47 mg (98%) of 13 as a white solid: 1H NMR (CDCl3,
400 MHz) δ 1.35 (s, 3H), 1.39 (s, 3H), 1.98 (m, 2H), 2.24 (dd,
J ) 14.4, 11.6 Hz, 1H), 2.36 (m, 2H), 2.47 (s, 3H), 2.54 (dt, J
) 14.7, 2.2 Hz, 1H), 3.20 (m, 1H), 3.27 (m, 1H), 3.50 (m, 1H),
3.68 (m, 1H), 3.83 (m, 1H), 4.08 (m, 2H), 7.38 (d, J ) 8.0 Hz,
2H), 7.79 (d, J ) 8.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ
21.6, 25.0, 26.5, 29.3, 43.5, 47.4, 52.6, 66.5, 75.0, 77.4, 77.6,
110.0, 128.0, 130.0, 136.0, 144.9, 205.1; IR (CHCl3) 1715, 1590,
1310 cm-1; MS (EI) m/z (rel intensity) 383 (MH+, 2), 367 (31),
281 (7). Anal. Calcd for C19H26O6S: C, 59.66; H, 6.86; S, 8.37.
Found: C, 59.60; H, 6.73; S, 8.22.
Meth yl 3(S)-3-[4(R)-2,2-Dim eth yl[1,3]d ioxola n -4-yl]-3-
[1(S)-(h yd r oxym eth yl)-3-(tolyl-4-su lfon yl)p r op oxy]p r op i-
on a te (14). Ozone was bubbled into a cooled (-78 °C) three-
neck flask containing a solution of the mixture of isomers 11
and 12 (2.6 g, 5.24 mmol) in 100 mL of CH2Cl2/MeOH (80:20),
until a blue color persisted. The ozone flow was then replaced
by argon until the color disappeared and NaBH4 (198 mg, 5.24
mmol) was added, continuing the stirring for 1 h. Then another
portion of NaBH4 (198 mg) was added, and the solution was
allowed to reach room temperature. After being stirred for 18
h, the solution was concentrated, the residue was diluted with
Step b. tert-Butyldimethylsilyl triflate (2.35 mL, 10.13
mmol) was added to a stirred solution of 3(E)-6-(tolyl-4-
sulfonyl)hex-3-en-2-one (2.32 g, 9.20 mmol) in triethylamine
(TEA) (6.5 mL) at 0 °C under an argon atmosphere. The
reaction was stirred at room temperature until TLC showed
the complete disappearance of the starting material (1 h). Then

9734 J . Org. Chem., Vol. 63, No. 26, 1998
Mujica et al.
EtOAc, and an aqueous solution of NaCl was added. The
aqueous layer was neutralized with 10% HCl, extracted with
EtOAc (2 × 75 mL), dried (MgSO4), and concentrated. The
crude extract was dissolved in ether (10 mL) and cooled to 0
°C. Then an ethereal solution of CH2N2 was added until TLC
showed total transformation of the products. The solvent was
removed in vacuo, and the residue was chromatographed on
silica gel (70% EtOAc in hexanes), yielding 1.57 g of the
mixture of hydroxyesters. The mixture was separated by
HPLC (85% EtOAc in hexane, 5.2 mL/min) giving 410 mg of
the minor isomer (tR 22.2 min) and 1.10 g (48%) of 14 (tR 24.3
min): [R]25D -33.2 (CHCl3, c 1.37); 1H NMR (CDCl3, 400 MHz)
δ 1.31 (s, 3H), 1.40 (s, 3H), 1.90 (m, 2H), 2.45 (s, 3H), 2.57 (m,
2H), 3.22 (dd, J ) 8.0, 7.3 Hz, 2H), 3.43 (m, 1H), 3.63 (dd, J )
8.4, 6.3 Hz, 1H), 3.69 (m, 1H), 3.70 (s, 3H), 3.80 (m, 1H), 4.02
(m, 2H), 4.23 (m, 1H), 7.35 (d, J ) 8.0 Hz, 2H), 7.78 (d, J )
8.1 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 21.6, 24.6, 25.0,
26.1, 35.4, 52.1, 52.3, 64.1, 65.6, 74.3, 75.8, 76.6, 109.5, 128.0,
129.9, 136.1, 144.7, 173.2; IR (CHCl3) 3450, 1720, 1600, 1310
cm-1; MS (EI) m/z (rel intensity) 415 (9), 383 (19). Anal. Calcd
for C20H30O8S: C, 55.79; H, 7.03; S, 7.43. Found: C, 55.98; H,
7.21; S, 7.18.
extracted with CH2Cl2 (3 × 15 mL), and the combined organic
phases were dried (MgSO4), concentrated, and filtered through
a short column of silica gel (20% EtOAc in hexane) yielding
the corresponding tosylate which was immediately used in the
following reaction. The tosylate, dissolved in 5 mL of ether,
was added to a suspension of LiAlH4 (31 mg, 0.82 mmol) in
ether (3 mL) at 0 °C under an atmosphere of argon. After being
refluxed until TLC showed that no tosylate remained, the
reaction was cooled and water (0.03 mL), 10% aqueous NaOH
solution (0.09 mL), and more water (0.09 mL) were added. The
suspension was stirred for 20 min, filtered through Celite,
concentrated, and chromatographed on silica gel (20% EtOAc
in hexane) yielding 420 mg (82%) of 16: [R]25 -3.7 (CHCl3, c
D
1
0.87); H NMR (CDCl3, 400 MHz) δ 0.78 (t, J ) 7.4 Hz, 3H)
1.01 (s, 9H), 1.25-1.44 (m, 2H), 1.33 (s, 3H), 1.35 (s, 3H), 1.93
(m, 1H), 2.06 (m, 1H), 2.44 (s, 3H), 3.22 (m, 2H), 3.35 (ddd, J
) 5.3, 5.2, 5.0 Hz, 1H), 3.45 (m, 1H), 3.62 (m, 2H), 3.67 (dd, J
) 7.6, 7.5 Hz, 1H), 3.89 (dd, J ) 7.6, 6.7 Hz, 1H), 4.01 (m,
1H), 7.33-7.46 (m, 8H), 7.62 (m, 4H), 7.79 (d, J ) 8.2 Hz, 2H);
13C NMR (CDCl3, 100 MHz) δ 9.3, 19.0, 21.5, 24.1, 25.1, 25.3,
26.4, 26.7, 52.2, 65.0, 65.5, 76.4, 76.8, 78.5, 108.7, 127.7, 128.1,
129.8, 133.0, 133.1, 135.5, 136.2, 144.4; IR (CHCl3) 1600, 1310
cm-1; MS (EI) m/z (rel intensity) 609 (1), 567 (12), 465 (10).
Anal. Calcd for C35H48O6SiS: C, 67.28; H, 7.75; S, 5.12.
Found: C, 67.62; H, 7.81; S, 5.01.
3(S)-3-[1(S)-(((ter t-Bu t yld ip h en ylsilyl)oxy)m et h yl)-3-
(tolyl-4-su lfon yl)p r op oxy]-3-[4(R)-2,2-d im eth yl[1,3]d ioxo-
la n -4-yl]p r op a n -1-ol (15). Step a . To a solution of 14 (380
mg, 0.88 mmol) in CH2Cl2 (109 mL) was added imidazole (181
mg, 2.56 mmol) and tert-butyldiphenylsilyl chloride (0.25 mL,
0.97 mmol). The reaction was stirred at room temperature
until TLC showed disappearance of the starting material. Then
ice and a saturated aqueous solution of NaCl were added, and
the mixture was extracted with CH2Cl2 (2 × 20 mL). The
combined organic extracts were dried (MgSO4), concentrated,
and chromatographed on silica gel (30% EtOAc in hexane)
yielding 590 mg (98%) of the protected compound: [R]25D -12.7
2(S)-1-((ter t-Bu t yld ip h en ylsilyl)oxy)-2-[1(S)-[1(R)-ox-
ir a n yl]p r op oxy]-4-(tolyl-4-su lfon yl)bu ta n e (17). Step a .
To a solution of 16 (310 mg, 0.50 mmol) in MeOH (5 mL) was
added camphorsulfonic acid (12 mg, 0.05 mmol). After stirring
of the reaction at 4 °C for 12 h, one drop of TEA was added
and MeOH was removed under reduced pressure. The residue
was chromatographed on silica gel (45% EtOAc in hexane)
yielding 35 mg of unreacted 16 and 245 mg (85%) of the
corresponding deprotected diol: [R]25 -7.83 (CHCl3, c 1.15);
D
1
(CHCl3, c 0.935); H NMR (CDCl3, 400 MHz) δ 1.00 (s, 9H),
1H NMR (CDCl3, 400 MHz) δ 0.79 (t, J ) 7.5 Hz, 3H), 1.01 (s,
9H), 1.35 (m, 1H), 1.49 (m, 1H), 1.93 (m, 1H), 2.12 (m, 1H),
2.44 (s, 3H), 3.24 (m, 2H), 3.36 (m, 1H), 3.44 (m, 1H), 3.65 (m,
5H), 7.33-7.46 (m, 8H), 7.61 (m, 4H), 7.78 (d, J ) 8.2 Hz, 2H);
13C NMR (CDCl3, 100 MHz) δ 9.6, 19.0, 21.6, 23.3, 25.1, 26.7,
51.9, 62.7, 65.0, 72.0, 76.4, 81.2, 127.7, 128.0, 129.8, 129.9,
132.9, 133.0, 135.5, 135.9, 144.6; IR (CHCl3) 3450, 1600, 1310
cm-1; MS (EI) m/z (rel intensity) 527 (4), 347 (37), 199 (87).
Anal. Calcd for C32H44O6SiS: C, 65.72; H, 7.59; S, 5.47.
Found: C, 65.89; H, 7.60; S, 5.07.
1.32 (s, 3H), 1.36 (s, 3H), 1.85 (m, 1H), 2.05 (m, 1H), 2.39-
2.48 (m, 2H), 2.43 (s, 3H), 3.18 (t, J ) 7.9 Hz, 2H), 3.38 (m,
1H), 3.50 (s, 3H), 3.63 (m, 3H), 3.79 (m, 1H), 3.95 (dd, J ) 8.0,
6.9 Hz, 1H), 4.05 (m, 1H), 7.32-7.45 (m, 8H), 7.60 (m, 4H),
7.78 (d, J ) 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 19.0,
21.5, 24.9, 25.2, 26.1, 26.7, 36.8, 51.4, 51.9, 64.7, 65.7, 75.3,
76.6, 76.7, 109.3, 127.7, 128.0, 129.8, 132.9, 133.0, 135.4, 136.0,
144.5, 171.3; IR (CHCl3) 1730, 1600, 1310 cm-1; MS (EI) m/z
(rel intensity) 553 (3), 385 (16), 273 (24), 101 (100). Anal. Calcd
for C36H48O8SiS: C, 64.64; H, 7.24; S, 4.78. Found: C, 64.49;
H, 7.27; S, 4.47.
Step b. Pyridine (0.2 mL) and tosyl chloride (88 mg, 0.46
mmol) were added to a flask containing the deprotected diol
(245 mg) described before. The mixture was kept at room
temperature for 16 h, and then ice was added and the reaction
was extracted with ether (3 × 15 mL). The extract was dried
(MgSO4) and concentrated. The crude tosylate obtained was
added to a suspension of NaH (19 mg of 80% suspension in
mineral oil, 0.63 mmol) in THF (8 mL) at 0 °C. After the
mixture was stirred for 30 min, ice and a 1% aqueous solution
of HCl were added, the organic layer was extracted with ether
(3 × 15 mL), and the combined organic extracts were dried
(MgSO4), concentrated, and chromatographed on silica gel
Step b. The previous compound (590 mg, 0.88 mmol) was
dissolved in ether (10 mL) and cooled to -60 °C under argon.
Then DIBALH (4.4 mL, 1 M in hexanes) was added and the
stirring was continued until TLC showed the end of the
reaction (30 min). The reaction was poured into an aqueous
solution of potassium sodium tartrate and was vigorously
stirred until the phases became clear. After phase separation,
the aqueous phase was extracted with ether (3 × 20 mL), and
the combined organic extracts were dried (MgSO4), concen-
trated, and chromatographed on silica gel (40% EtOAc in
hexane) yielding 526 mg (93%) of 15: [R]25 -14.8 (CHCl3, c
(20% EtOAC in hexane) yielding 209 mg of 17 (88%): [R]25
D
D
1
1
1.15); H NMR (CDCl3, 400 MHz) δ 1.03 (s, 9H), 1.32 (s, 3H),
-23.8 (CHCl3, c 1.2); H NMR (CDCl3, 400 MHz) δ 0.85 (t, J
1.37 (s, 3H), 1.63 (dt, J ) 5.9, 5.8 Hz, 2H), 1.95 (m, 2H), 2.44
(s, 3H), 3.15 (m, 2H), 3.53-3.71 (m, 7H), 3.94 (dd, J ) 8.0, 6.7
Hz, 1H), 4.05 (m, 1H), 7.32-7.46 (m, 8H), 7.61 (m, 4H), 7.76
(d, J ) 8.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 19.1, 21.6,
24.9, 25.4, 26.3, 26.8, 33.7, 52.3, 59.3, 65.1, 65.7, 75.9, 76.5,
77.2, 109.1, 127.8, 128.1, 129.8, 129.9, 132.8, 135.6, 136.1,
144.6; IR (CHCl3) 3500, 1600, 1310 cm-1; MS (EI) m/z (rel
intensity) 525 (1), 465 (4), 347 (54). Anal. Calcd for C35H48O7-
SiS: C, 65.60; H, 7.56; S, 4.99. Found: C, 65.84; H, 7.67; S,
4.69.
) 7.4 Hz, 3H) 1.01 (s, 9H), 1.41-1.58 (m, 2H), 1.85 (m, 1H),
2.04 (m, 1H), 2.45 (s, 3H), 2.56 (m, 1H), 2.69 (m, 1H), 2.77 (m,
1H), 3.13 (m, 1H), 3.21 (dd, J ) 8.1, 7.9 Hz, 2H), 3.41 (dd, J )
10.1, 6.2 Hz, 1H), 3.54 (m, 1H), 3.60 (dd, J ) 10.1, 4.7 Hz,
1H), 7.34-7.47 (m, 8H), 7.61 (m, 4H), 7.79 (d, J ) 4.2 Hz, 2H);
13C NMR (CDCl3, 100 MHz) δ 9.3, 19.0, 21.6, 25.8, 26.0, 26.7,
44.8, 52.3, 53.0, 65.0, 76.9, 77.9, 127.7, 128.1, 129.8, 132.9,
133.1, 135.5, 136.1, 144.4; IR (CHCl3) 1600, 1310 cm-1; MS
(EI) m/z (rel intensity) 510 (2), 347 (10). Anal. Calcd for
C
32H42O5SiS: C, 67.81; H, 7.48; S, 5.65. Found: C, 67.63; H
2(S)-1-((ter t-Bu tyldiph en ylsilyl)oxy)-4-(tolyl-4-su lfon yl)-
2-[1(S)-[4(R)-2,2-d im eth yl-[1,3]d ioxola n -4-yl]p r op oxy]bu -
ta n e (16). To a solution of 15 (525 mg, 0.82 mmol) in CH2Cl2
(10 mL) were added (dimethylamino)pyridine (104 mg, 0.82
mmol), TEA (0.11 mL, 0.82 mmol), and tosyl chloride (235 mg,
1.23 mmol). The reaction was stirred at room temperature for
12 h, and then iced water was added. The aqueous layer was
7.47; S, 5.55.
(2S,6R,7S)-6-((ter t-Bu tyld im eth ylsilyl)oxy)-2-(((ter t-bu -
tyld ip h en ylsilyl)oxy)m eth yl)-7-eth yloxep a n -4-on e (19).
Step a . To a solution of 17 (24 mg, 0.042 mmol) in 9 mL of
THF at -65 °C under atmosphere of argon, was added LDA
(0.7 mL, 0.17 mmol, 0.24 M in THF). After the mixture was
stirred for 25 min, 2 mL of a saturated aqueous solution of

R,â,R′-Trisubstituted Cyclic Ethers
J . Org. Chem., Vol. 63, No. 26, 1998 9735
NH4Cl was added and the mixture was extracted with ether
(3 × 10 mL), dried (MgSO4), concentrated, and chromato-
graphed on silica gel (25% EtOAc in hexane) yielding 23 mg
(96%) of an inseparable mixture of epimers 18.
room temperature. Water was added, and the reaction was
extracted with ether. The combined organic extracts were
washed with 5 mL each of 1% aqueous solution of HCl, 5%
Na2CO3, and saturated solution of NaCl. The solution was
dried (MgSO4), concentrated, and purified by column chroma-
tography (silica gel, 20% EtOAc in hexanes) yielding 125 mg
(94%) of the corresponding ketone (2R,5R,8R)-8-(((ter t-bu -
tyld ip h en ylsilyl)oxy)m eth yl)-2-eth yl-5-(tolyl-4-su lfon yl)-
Step b. To a solution of 18 (23 mg, 0.04 mmol) in TEA (0.1
mL) at 0 °C under argon was added tert-butyldimethylsilyl
triflate (19 µL, 0.08 mmol). The reaction was stirred at room
temperature for 15 min, and then ether (5 mL) and a saturated
aqueous solution of NaHCO3 (5 mL) were added. The layers
were separated, and the aqueous phase was extracted with
ether (3 × 10 mL); the combined organic extracts were dried
(MgSO4), concentrated, and chromatographed on silica gel
(10% EtOAc in hexane), yielding 25 mg (92%) of the corre-
sponding protected epimers. Those compounds (25 mg, 0.037
mmol) were dissolved in THF (1 mL) and cooled to -78 °C
under an argon atmosphere, and then LDA (0.92 mL, 0.22
mmol, 0.24 M in THF) was added. After the reaction was
stirred for 10 min, a solution of MoOPh (48 mg, 0.11 mmol) in
THF (2 mL) was added, and after 5 min, 1 mL of saturated
aqueous solution of Na2SO3 was added and the mixture was
poured into water and extracted with ether (3 × 10 mL). The
combined organic extracts were washed with 0.6 N HCl (5 mL)
and saturated aqueous NaCl (5 mL), dried (MgSO4), concen-
trated, and chromatographed on silica gel (5% EtOAc in
hexane) yielding 12 mg (61%) of 19 as a single compound:
[R]25D -31.8 (CHCl3, c 0.67); 1H NMR (CDCl3, 400 MHz) δ 0.08
(s, 3H), 0.10 (s, 3H), 0.90 (s, 9H), 0.98 (t, J ) 7.4 Hz, 2H), 1.06
(s, 9H), 1.37 (m, 1H), 1.66 (m, 1H), 2.45 (dd, J ) 16.4, 10.8
Hz, 1H), 2.70 (dd, J ) 16.4, 3.6 Hz, 1H), 2.74 (dd, J ) 12.2,
2.4 Hz, 1H), 2.86 (dd, J ) 12.1, 9.4 Hz, 1H), 3.41 (m, 1H), 3.52
(dd, J ) 10.4, 5.4 Hz, 1H), 3.65 (m, 1H), 3.70 (dd, J ) 10.4,
6.1 Hz, 1H), 4.11 (m, 1H), 7.37-7.46 (m, 6H), 7.68 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ -4.8, -4.5, 10.3, 17.9, 19.2, 25.7,
26.5, 26.8, 47.8, 50.0, 66.8, 72.3, 76.7, 88.8, 127.7, 129.6, 129.7,
133.3, 133.4, 135.5, 135.6, 207.8.
oxoca n -3-on e (major epimer at C5): [R]25 +46.2 (CHCl3, c
D
1
1.41); H NMR (CDCl3, 400 MHz) δ 0.91 (t, J ) 7.4 Hz, 3H),
1.06 (s, 9H), 1.35 (m, 1H), 1.45-1.60 (m, 2H), 1.82 (m, 1H),
2.03 (m, 2H), 2.46 (s, 3H), 2.49 (bs, 1H), 3.08 (m, 1H), 3.19
(dd, J ) 12.4, 9.9 Hz, 1H), 3.39 (dd, J ) 8.3, 5.7 Hz, 1H), 3.57
(m, 2H), 3.76 (m, 1H), 7.35-7.64 (m, 8H), 7.66 (m, 4H), 7.73
(d, J ) 8.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 9.6, 19.2,
20.9, 21.7, 25.5, 25.6, 26.8, 35.6, 64.3, 65.3, 80.7, 87.3, 127.7,
128.9, 129.8, 129.9, 133.2, 133.8, 135.5, 145.0, 215.1; IR
(CHCl3) 1710, 1600, 1310 cm-1; MS (EI) m/z (rel intensity) 521
(27), 365 (85). Anal. Calcd for C33H42O5SiS: C, 68.48; H, 7.32;
S, 5.53. Found: C, 68.76; H, 7.54; S, 5.14.
Step b. DBU (48 µL, 0.32 mmol) was added to a solution of
the previously described ketone (124 mg, 0.21 mmol) in toluene
(5 mL) at room temperature under an argon atmosphere. The
reaction mixture was stirred for 2 h, and then another 48 µL
of DBU (0.32 mmol) was added and the reaction heated at 100
°C for 3 h. After cooling, ice and a saturated aqueous solution
of NaCl were added and the reaction was extracted with CH2-
Cl2. The combined organic extracts were dried (MgSO4),
concentrated, and chromatographed (silica gel, 15% EtOAc in
hexanes), yielding 82 mg (90%) of 28: [R]25 +281 (CHCl3, c
D
1
1.65); H NMR (CDCl3, 400 MHz) δ 0.90 (t, J ) 7.4 Hz, 3H),
1.07 (s, 9H), 1.54 (m, 1H), 1.69 (m, 1H), 2,36 (m, 2H), 2.76
(dd, J ) 12.2, 6.8 Hz, 1H), 3.50 (m, 1H), 3.58 (dd, J ) 10.1,
6.8 Hz, 1H), 3.71 (dd, J ) 8.6, 4.3 Hz, 1H), 3.78 (dd, J ) 10.1,
5.7 Hz, 1H), 3.87 (dd, J ) 12.2, 7.4 Hz, 1H), 5.61 (dt, J ) 10.6,
7.2 Hz, 1H), 5.77 (m, 1H), 7.37-7.45 (m, 6H), 7.67 (d, J ) 6.9
Hz, 4H); 13C NMR (CDCl3, 100 MHz) δ 10.0, 19.2, 26.1, 26.8,
29.9, 41.0, 66.2, 84.1, 87.1, 125.8, 127.7, 128.6, 129.7, 133.4,
133.5, 135.6, 135.7, 214.0; IR (CHCl3) 1705, 1310 cm-1; MS
(EI) m/z (rel intensity) 365 (57), 323 (9). Anal. Calcd for
(2S,3R,5S,8S)-8-(((ter t-Bu tyld ip h en ylsilyl)oxy)m eth yl)-
2-eth yl-5-(tolyl-4-su lfon yl)oxoca n -3-ol (21). Major epimer
at C5: 1H NMR (CDCl3, 400 MHz) δ 0.91 (t, J ) 7.3, Hz, 3H),
1.03 (s, 9H), 1.32 (m, 1H), 1.75 (m, 3H), 1.90 (m, 1H), 2.05 (m,
1H), 2.13 (ddd, J ) 14.8, 9.3, 1.9 Hz, 1H), 2.27 (ddd, J ) 14.8,
4.8, 1.6 Hz, 1H), 2.46 (s, 3H), 3.06 (dt, J ) 8.5, 3.0 Hz, 1H),
3.30 (m, 1H), 3.45 (dd, J ) 10.0, 6.6 Hz, 1H), 3.58 (m, 1H),
3.66 (dd, J ) 10.0, 5.5 Hz, 1H), 3.77 (m, 1H), 7.40 (m, 8H),
7.64 (m, 4H), 7.76 (d, J ) 8.2 Hz, 2H); 13C NMR (CDCl3, 100
MHz) δ 10.3, 19.1, 21.6, 23.7, 26.8, 27.7, 27.8, 31.1, 59.4, 66.0,
72.6, 80.4, 81.2, 127.6, 127.7, 129.0, 129.6, 129.7, 129.8, 133.4,
C
26H34O3Si: C, 73.89; H, 8.11. Found: C, 73.51; H, 7.99.
(2R,3R,8R)-8-(((ter t-Bu tyld ip h en ylsilyl)oxy)m eth yl)-3-
(ben zyloxy)-2-eth yl-3,4,7,8-tetr ah ydr o-2H-oxocin (24). Step
a . To a solution of 28 (39.2 mg, 0.092 mmol) in THF (1 mL) at
-78 °C under argon was added L-Selectride (0.18 mL, 1 M in
THF). After 30 min, TLC showed total conversion of the
starting material, and EtOH (0.1 mL), water (1 drop), a 10%
aqueous solution of NaOH (2 drops), and 30% H2O2 (3 drops)
were added. The reaction was allowed to reach room temper-
ature, and a saturated aqueous solution of K2CO3 was added.
The aqueous layer was extracted with ether (3 × 5 mL), and
the combined organic extracts were dried (MgSO4), concen-
trated, and chromatographed (silica gel, 20% EtOAc in hex-
anes), yielding 37 mg (94%) of the corresponding alcohol
(2R,3R,8R)-8-(((ter t-b u t yld ip h en ylsilyl)oxy)m et h yl)-2-
eth yl-3,4,7,8-tetr ah ydr o-2H-oxocin -3-ol: [R]25D +3.5 (CHCl3,
c 1.465); 1H NMR (CDCl3, 400 MHz) δ 0.87 (t, J ) 7.4 Hz,
3H), 1.07 (s, 9H), 1.37-1.45 (m, 1H), 1.60-1.68 (m, 1H), 1.72
(bs, 1H), 2.27-2.42 (m, 3H), 2.53 (m, 1H), 3.40 (dd, J ) 9.2,
4.4 Hz, 1H), 3.53 (m, 2H), 3.65 (m, 1H), 3.73 (dd, J ) 12.8, 8.3
Hz, 1H), 5.70-5.81 (m, 2H), 7.36-7.45 (m, 6H), 7.68 (m, 4H);
13C NMR (CDCl3, 400 MHz) δ 10.5, 19.2, 25.9, 26.9, 30.4, 33.5,
66.4, 74.3, 81.1, 82.3, 127.6, 127.7, 129.1, 129.5, 129.6, 133.6,
135.6; MS (EI) m/z (rel intensity) 424 (M+, 1), 414 (19), 289
(100).
Step b. To a solution of the previously reported alcohol (8.4
mg, 0.02 mmol) in THF (1.5 mL) at 0 °C was added DMF (0.05
mL) and NaH (1 mg, 80% in mineral oil, 0.03 mmol). The
reaction was kept at room temperature for 20 min, and then
benzyl bromide (5 µL, 0.04 mmol) and potassium iodide (3.3
mg, 0.02 mmol) were added. After 20 h ice was added and the
reaction was extracted with ether (3 × 5 mL). The combined
extracts were dried, concentrated, and chromatographed on
silica gel (4% EtOAc in hexanes) yielding 5 mg (50%) of 24:
1H NMR (CDCl3, 400 MHz) δ 0.78 (t, J ) 7.4 Hz, 3H), 1.05 (s,
133.5, 134.6, 135.6, 144.5; IR (CHCl3) 3710, 1600, 1300 cm-1
;
MS (EI) m/z (rel intensity) 523 (3), 337 (7), 273 (36). Anal.
Calcd for C33H44O5SSi: C, 68.24; H, 7.64; S, 5.51. Found: C,
68.10; H, 7.68; S, 5.63.
(2S,3R,5S,9S)-9-(((ter t-Bu tyld ip h en ylsilyl)oxy)m eth yl)-
2-et h yl-5-(t olyl-4-su lfon yl)oxon a n -3-ol (22): 1H NMR
(CDCl3, 400 MHz) δ 0.92 (t, J ) 7.4 Hz, 3H), 1.04 (s, 9H), 1.38-
1.80 (m, 8H), 2.26 (m, 2H), 2.48 (s, 3H), 3.18 (m, 1H), 3.25 (m,
1H), 3.40 (m, 2H), 3.61 (m, 2H), 3.78 (m, 1H), 7.35-7.44 (m,
8H), 7.64 (m, 4H), 7.78 (d, J ) 8.1 Hz, 2H); 13C NMR (CDCl3,
100 MHz) δ 9.3, 16.5, 19.2, 21.7, 24.5, 25.7, 26.8, 27.2, 29.2,
58.1, 64.9, 70.7, 78.2, 127.6, 127.6, 129.2, 129.7, 129.9, 133.5,
133.5, 133.7, 135.6, 135.6, 145.0.
(2S,3R,5R,9S)-9-(((ter t-Bu tyld ip h en ylsilyl)oxy)m eth yl)-
2-et h yl-5-(t olyl-4-su lfon yl)oxon a n -3-ol (23): 1H NMR
(CDCl3, 400 MHz) δ 0.76 (t, J ) 7.4 Hz, 3H), 1.04 (s, 9H), 1.13-
1.27 (m, 1H), 1.51-1.64 (m, 5H), 1.75-1.99 (m, 4H), 2.35 (bs,
J ) 15.2 Hz, 1H), 2.46 (s, 3H), 3.18 (m, 1H), 3.27 (m, 1H),
3.38 (dd, J ) 10.1, 6.8 Hz, 1H), 3.46 (m, 1H), 3.61 (dd, J )
10.2, 5.0 Hz, 1H), 3.84 (m, 1H), 7.33-7.46 (m, 8H), 7.65 (d, J
) 6.7 Hz, 4H), 7.78 (d, J ) 7.8 Hz, 2H).
(2R,8R)-8-(((ter t-Bu tyldiph en ylsilyl)oxy)m eth yl)-2-eth yl-
7,8-d ih yd r o-4H-oxocin -3-on e (28). Step a . To a solution of
DMSO (25 µL, 0.35 mmol) in CH2Cl2 (2 mL) under argon at
-78 °C was slowly added a solution of oxalyl chloride (24 µL,
0.28 mmol) in CH2Cl2 (0.5 mL). After 30 min the alcohol 27,
mixture of epimers at C5 (134 mg, 0.23 mmol), was added in
CH2Cl2 (1 mL). After the mixture was stirred for 1 h, TEA
(0.16 mL) was added, and the reaction was allowed to reach

9736 J . Org. Chem., Vol. 63, No. 26, 1998
Mujica et al.
9H), 1.20-1.34 (m, 1H), 1.61-1.71 (m, 1H), 2.26-2.44 (m, 3H),
2.68 (ddd, J ) 11.1, 10.9, 10.7 Hz, 1H), 3.31-3.44 (m, 3H),
3.52 (dd, J ) 9.9, 8.0 Hz, 1H), 3.80 (dd, J ) 10.0, 5.1 Hz, 1H),
4.43 (d, J ) 12.4 Hz, 1H), 4.66 (d, J ) 12.4 Hz, 1H), 5.67 (m,
1H), 5.84 (m, 1H), 7.29-7.41 (m, 11H), 7.66 (m, 4H); 1H NMR
(C6D6, 400 MHz) δ 0.92 (t, J ) 7.4 Hz, 3H), 1.23 (s, 9H), 1.38-
1.51 (m, 1H), 1.91-2.02 (m, 1H), 2.27 (m, 2H), 2.46 (m, 1H),
2.90 (ddd, J ) 11.0, 10.9, 10.9 Hz, 1H), 3.28 (m, 1H), 3.41 (m,
2H), 3.70 (dd, J ) 10.1, 6.3 Hz, 1H), 3.97 (dd, J ) 10.2, 5.4
Hz, 1H), 4.28 (d, J ) 11.9 Hz, 1H), 4.56 (d, J ) 11.9 Hz, 1H),
5.60 (m, 1H), 5.80 (m, 1H), 7.11-7.39 (m, 11H), 7.87 (m, 4H).
(2R,8R)-2-E t h yl-8-(2-(m et h oxyca r b on yl)vin yl)-7,8-d i-
h yd r o-4H-oxocin -3-on e (30). Step a . To a solution of 28 (100
mg, 0.24 mmol) in THF (3 mL) at 0 °C under argon was added
TBAF (31 mg, 0.12 mmol). After 3 h, the reaction was
quenched with ice and a saturated aqueous solution of NaCl.
After extraction with ether (3 × 15 mL), the combined extracts
were dried (MgSO4), concentrated, and chromatographed on
silica gel (40% EtOAc in hexanes), yielding 42 mg (98%) of
0.05 mmol) and tert-butyldimethylsilyl triflate (11 µL, 0.05
mmol). After 5 min the reaction was allowed to reach room
temperature and was followed by TLC. When it was finished
(1 h), ether (5 mL) and saturated aqueous solution of NaHCO3
(5 mL) were added, the phases were decanted, and the aqueous
one was extracted with ether (3 × 5 mL). The combined organic
extracts were dried (MgSO4), concentrated, and chromato-
graphed (silica gel, 3% EtOAc in hexanes), yielding 11 mg
(93%) of the protected alcohol. (2R,3R,8R)-3-((ter t-bu tyld i-
m et h ylsilyl)oxy)-2-et h yl-8-(2-(m et h oxyca r b on yl)vin yl)-
3,4,7,8-tetr a h yd r o-2H-oxocin : [R]25D +42.3 (CHCl3, c 0.68);
1H NMR (CDCl3, 400 MHz) δ 0.07 (s, 3H), 0.09 (s, 3H), 0.89 (t,
J ) 7.4 Hz, 3H), 0.92 (s, 9H), 1.30 (m, 1H), 1,31 (t, J ) 7.1 Hz,
3H), 1.65 (m, 1H), 2.16 (m, 2H), 2.48 (m, 1H), 2.72 (dd, J )
10.9, 10.6 Hz, 1H), 3.42 (dt, J ) 9.7, 2.7 Hz, 1H), 3.74 (ddd, J
) 10.8, 4.9, 2.5 Hz, 1H), 3.90 (dd, J ) 10.4, 4.0 Hz, 1H), 4.21
(dq, J ) 7.1, 1.7 Hz, 2H), 5.77 (m, 2H), 6.13 (dd, J ) 15.6, 1.6
Hz, 1H), 6.94 (dd, J ) 15.6, 4.2 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ -4.8, -4.1, 10.8, 14.3, 18.3, 25.9, 26.0, 33.6, 34.4, 60.3,
75.9, 80.7, 84.4, 120.3, 128.8, 130.1, 148.8, 166.9; MS (EI) m/z
(rel intensity) 323 (5), 311 (30), 197 (43), 145 (100).
the corresponding alcohol, as a white solid: [R]25 +568
D
1
(CHCl3, c 0.81); H NMR (CDCl3, 400 MHz) δ 0.96 (t, J ) 7.4
Hz, 3H), 1.63-1.76 (m, 2H), 2.05 (m, 1H), 2.25-2.32 (m, 2H),
2.80 (dd, J ) 12.3, 6.7 Hz, 1H), 3.55-3.64 (m, 3H), 3.81 (dd, J
) 8.2, 4.5 Hz, 1H), 3.87 (dd, J ) 12.3, 7.5 Hz, 1H), 5.64 (m,
1H), 5.81 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 10.0, 26.1,
29.9, 41.0, 65.9, 84.1, 86.8, 126.0, 128.1, 213.1; MS (EI) m/z
(rel intensity) 156 (3), 125 (4), 84 (100). Anal. Calcd for
Step c. Following the procedure given for the DIBALH
reduction of TBDPS-protected 14, the ethyl ester described
before (11 mg, 0.04 mmol) afforded, after column chromatog-
raphy (3% EtOAc in hexane), 6.5 mg (95%) of 29, whose
spectroscopic and physical data were identical to those de-
scribed in the literature:25 [R]25D -5.3 (CHCl3, c 1.21) [lit. [R]25
D
1
C
10H16O3: C, 65.19; H, 8.75. Found: C, 65.25; H, 8.89.
-6.3 (CHCl3, c 0.85)]; H NMR (CDCl3, 400 MHz) δ 0.06 (s,
Step b. Following the procedure given for the Swern
3H), 0.08 (s, 3H), 0.91 (c, 12H), 1.28 (m, 1H), 1.64 (m, 2H),
2.10 (m, 2H), 2.49 (m, 1H), 2.74 (q, J ) 10.9 Hz, 1H), 3.43 (dt,
J ) 9.8, 3.0 Hz, 1H), 3.74 (m, 2H), 4.16 (d, J ) 4.0 Hz, 2H),
5.67-5.92 (m, 4H); 13C NMR (CDCl3, 400 MHz) δ -4.7, -4.2,
10.9, 18.3, 26.0, 33.6, 35.1, 63.3, 76.1, 81.8, 84.1, 128.9, 129.4,
129.5, 133.4.
oxidation of 27, from the alcohol previously described (38 mg,
0.20 mmol), DMSO (22 µL, 0.31 mmol) and oxalyl chloride
(0.12 µL, 0.24 mmol), the expected aldehyde was obtained and
it was used without further purification.
Step c. To a suspension of NaH (7.2 mg, 80% in mineral
oil, 0.24 mmol) in THF (2 mL) was added triethyl phospho-
noacetate (0.07 mL, 0.36 mmol) at 0 °C under argon. After 30
min this solution was added to a solution of the aldehyde in
THF (1 mL). The reaction was followed by TLC until comple-
tion (15 min). Then ice was added and the solution was
neutralized with 1% aqueous HCl. The two phases were
separated, and the aqueous one was extracted with ether (3
× 10 mL). The combined extracts were dried and concentrated,
and the resulting crude was purified by column chromatog-
raphy (silica gel, 10% EtOAc in hexanes), yielding 51 mg (85%)
of 30: [R]25D +518 (CHCl3, c 0.74); 1H NMR (CDCl3, 400 MHz)
δ 0.98 (t, J ) 7.4 Hz, 3H), 1.31 (t, J ) 7.2 Hz, 3H), 1.63 (m,
1H), 1.73 (m, 1H), 2.35 (m, 1H), 2.43 (m, 1H), 2.83 (dd, J )
12.9, 6.3 Hz, 1H), 3.79 (dd, J ) 8.7, 4.3 Hz, 1H), 3.86 (m, 1H),
4.18 (m, 1H), 4.22 (q, J ) 7.1 Hz, 2H), 5.70 (m, 2H), 6.13 (dd,
J ) 15.6, 1.8 Hz, 1H), 6.91 (dd, J ) 15.6, 4.2 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 10.0, 14.2, 26.2, 32.5, 41.4, 60.5, 81.4, 86.9,
121.0, 126.7, 127.1, 147.0, 166.4, 213.5; IR (CHCl3) 1712, 1660
cm-1; MS (EI) m/z (rel intensity) 252 (M+, 2), 166 (29). Anal.
Calcd for C14H20O4: C, 66.65; H, 7.99. Found: C, 66.66; H,
7.68.
Heter o Diels-Ald er Rea ction of 33 a n d 5. Following the
same procedure described for the reaction of 8 and 5, using
33 (6.0 g, 12.5 mmol), 5 (1.62 g, 12.5 mmol), BF3‚OEt2 (1.58
mL), and TEA (3.5 mL, 25.0 mmol) at -65 °C, 7.3 g of a 4.3:1
mixture of two adducts 34 (95%) was obtained. A fraction of
the mixture was purified by HPLC (µ-Porasil 300 × 19 mm
column, 8% EtOAc in hexanes, 4 mL/min). The major isomer
was (2S,6R)-4-((ter t-b u t yld im et h ylsilyl)oxy)-6-[3-((ter t-
bu tyld ip h en ylsilyloxy) p r op yl]-2-[4(R)-2,2-d im eth yl-[1,3]-
d ioxola n -4-yl]-3,6-d ih yd r o-2H-p yr a n : tR ) 22.4 min; 1H
NMR (CDCl3, 400 MHz) δ 0.16 (s, 3H), 0.17 (s, 3H), 0.95 (s,
9H), 1.07 (s, 9H), 1.38 (s, 3H), 1.43 (s, 3H), 1.55-1.69 (m, 4H),
2.13 (m, 2H), 3.50 (ddd, J ) 7.0 Hz, 1H), 3.50 (t, J ) 6.2 Hz,
2H), 3.92 (dd, J ) 8.0, 5.0 Hz, 1H), 3.98 (dd, J ) 6.1, 5.1 Hz,
1H), 4.07 (dd, J ) 8.0, 6.1 Hz, 1H), 4.13 (m, 1H), 4.76 (bs, 1H),
7.37-7.43 (m, 6H), 7.68 (m, 4H); 13C NMR (CDCl3, 100 MHz)
δ -4.6, -4.3, 18.0, 19.2, 25.4, 25.6, 26.8, 26.9, 28.2, 32.6, 33.2,
63.9, 67.3, 74.1, 75.3, 78.1, 106.6, 109.3, 127.6, 129.5, 134.1,
135.6, 148.5. The minor isomer was (2S,6S)-4-((ter t-Bu -
tyld im eth ylsilyl)oxy)-6-[3-((ter t-bu tyld ip h en ylsilyl)oxy)-
p r op yl]-2-[4(R)-2,2-d im eth yl-[1,3]d ioxola n -4-yl]-3,6-d ih y-
1
(2R,3R,8R)-3-((ter t-Bu tyld im eth ylsilyl)oxy)-2-eth yl-8-
(3-h yd r oxy-1(E )-p r op e n yl)-3,4,7,8-t e t r a h yd r o-2H -oxo-
cin (29). Step a . Following the procedure given for the
L-Selectride reduction of 28, ketone 30 (11 mg, 0.04 mmol)
afforded, after column chromatography (silica gel, 20% EtOAc
in hexanes), 9.7 mg (87%) of the corresponding alcohol
(2R,3R,8R)-2-eth yl-3-h yd r oxy-8-(2-(m eth oxyca r bon yl)vi-
d r o-2H-p yr a n : tR ) 24.3 min; H NMR (CDCl3, 400 MHz) δ
0.16 (s, 9H), 0.94 (s, 9H), 1.06 (s, 9H), 1.37 (s, 3H), 1.42 (s,
3H), 1.48-1.74 (m, 4H), 2.09-2.16 (m, 2H), 3.64 (m, 1H), 3.69
(t, J ) 5.8 Hz, 2H), 3.86 (dd, J ) 7.8, 5.4 Hz, 1H), 4.02 (dd, J
) 12.5, 6.3 Hz, 1H), 4.09 (m, 1H), 4.19 (bs, 1H), 4.82 (bs, 1H),
7.37-7.45 (m, 6H), 7.67 (m, 4H); 13C NMR (CDCl3, 100 MHz)
δ -4.5, -4.3, 18.0, 19.2, 25.3, 25.6, 26.7, 26.9, 29.2, 31.2, 32.5,
63.7, 67.5, 69.7, 72.3, 77.6, 106.0, 109.4, 127.6, 129.5, 134.0,
135.6, 147.6.
n yl)-3,4,7,8-tetr a h yd r o-2H-oxocin : [R]25 +60.0 (CHCl3, c
D
1
0.87); H NMR (CDCl3, 400 MHz) δ 0.92 (t, J ) 7.4 Hz, 3H),
1.31 (t, J ) 7.2 Hz, 3H), 1.47 (m, 1H), 1.74 (m, 1H), 2.36 (m,
3H), 2.55 (m, 1H), 3.50 (dddd, J ) 9.4, 5.5, 4.2, 1.3 Hz, 1H),
3.72 (m, 1H), 4.14 (m, 1H), 4.21 (q, J ) 7.2 Hz, 2H), 5.80 (m,
2H), 6.10 (dd, J ) 15.6, 1.8 Hz, 1H), 6.90 (dd, J ) 15.6, 4.1
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 10.4, 14.2, 25.9, 33.3,
33.5, 60.4, 74.3, 78.9, 82.7, 120.6, 128.4, 129.9, 147.8, 166.6;
IR (CHCl3) 3689, 1712 cm-1; MS (EI) m/z (rel intensity) 255
(MH+, 6), 209 (10), 129 (46). Anal. Calcd for C14H22O4: C, 66.10;
H, 8.72. Found: C, 66.20; H, 8.64.
Meth yl 3(S)-3-[1(S)-4-((ter t-Bu tyld ip h en ylsilyl)oxy)-1-
(h yd r oxym eth yl)bu toxy]-3-[4(R)-2,2-d im eth yl-[1,3]d iox-
ola n -4-yl]p r op ion a te (35). Following the procedure described
in the preparation of 14, from the mixture of epimers 34 (3.44
g, 5.63 mmol), after ozonolysis, esterification, and HPLC
separation, 1.0 g (34% overall yield) of 35 was obtained: [R]25
D
+1.5 (CHCl3, c 1.68); 1H NMR (CDCl3, 400 MHz) δ 1.06 (s,
9H), 1.34 (s, 3H), 1.41 (s, 3H), 1.50-1.65 (m, 5H), 2.65 (d, J )
5.5 Hz, 2H), 3.36 (m, 1H), 3.46 (m, 1H), 3.58 (m, 1H), 3.66 (m,
2H), 3.73 (s, 3H), 3.76 (dd, J ) 8.3, 6.1 Hz, 1H), 3.96 (ddd, J
) 5.5, 5.5, 5.5 Hz, 1H), 4.03 (dd, J ) 8.2, 6.6 Hz, 1H), 4.11
Step b. To a solution of the alcohol (8 mg, 0.031 mmol) in
CH2Cl2 (1 mL) at 0 °C under argon were added TEA (7 µL,

R,â,R′-Trisubstituted Cyclic Ethers
J . Org. Chem., Vol. 63, No. 26, 1998 9737
(dd, J ) 11.9, 6.1 Hz, 1H), 7.37-7.45 (m, 6H), 7.66 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ 19.2, 25.0, 26.4, 26.9, 27.9, 28.5,
35.9, 52.0, 63.8, 64.9, 66.4, 75.1, 76.6, 79.8, 109.5, 127.6, 129.6,
133.9, 135.5, 173.0; IR (CHCl3) 3450, 1720 cm-1; MS (EI) m/z
(rel intensity) 530 (4), 430 (10), 386 (28). Anal. Calcd for
C30H44O7Si: C, 66.14; H, 8.15. Found: C, 66.04; H, 8.36.
2(S)-1-((ter t-Bu t yld im et h ylsilyl)oxy)-5-((ter t-b u t yld i-
ph en ylsilyl)oxy)-2-[1(S)-1-(4(R)-2,2-dim eth yl[1,3]dioxolan -
4-yl)p r op oxy]p en ta n e (36). Following a procedure similar
to that described for the preparation of 16, using TBDMS
instead of TBDPS as protecting group in the first step, 1.25 g
the solution was concentrated and chromatographed on silica
gel (5% EtOAc in hexanes) affording 387 mg (98% yield) of
1
39: [R]25 +24.8 (CHCl3, c 0.96); H NMR (CDCl3, 400 MHz)
D
δ 0.96 (t, J ) 7.5 Hz, 3H), 1.08 (s, 9H), 1.27 (t, J ) 7.1 Hz,
3H), 1.35 (s, 3H), 1.40 (s, 3H), 1.45-1.70 (m, 6H), 1.71-1.79
(m, 1H), 1.81-1.90 (m, 1H), 2.39 (m, 2H), 3.45 (m, 2H), 3.69
(t, J ) 5.9 Hz, 2H), 3.83 (dd, J ) 6.7, 6.4 Hz, 1H), 4.02 (m,
2H), 4.14 (q, J ) 7.1 Hz, 2H), 7.37-7.44 (m, 6H), 7.68 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ 8.8, 14.2, 19.2, 23.5, 25.4, 26.6,
26.8, 28.0, 29.0, 29.6, 30.1, 60.2, 63.9, 66.7, 75.8, 76.6, 77.0,
108.7, 127.6, 129.5, 133.9, 135.5, 173.7; IR (CHCl3) 1720 cm-1
;
of 36 was prepared in 4 steps and in a 65% overall yield: [R]25
MS (EI) m/z (rel intensity) 555 (3), 513 (35), 411 (26). Anal.
Calcd for C33H50O6Si: C, 69.43; H, 8.84. Found: C, 69.05; H,
9.06.
D
+7.2 (CHCl3, c 0.98); 1H NMR (CDCl3, 400 MHz) δ 0.06 (s,
6H), 0.91 (s, 9H), 0.97 (t, J ) 7.5 Hz, 3H), 1.06 (s, 9H), 1.35 (s,
3H), 1.40 (s, 3H), 1.57-167 (m, 6H), 3.49-3.55 (m, 3H), 3.60
(m, 1H), 3.66 (m, 2H), 3.84 (dd, J ) 7.4, 6.9 Hz, 1H), 4.02 (m,
2H), 7.37-7.43 (m, 6H), 7.68 (m, 4H); 13C NMR (CDCl3, 100
MHz) δ -5.4, 9.1, 18.3, 19.2, 24.3, 25.4, 25.9, 26.6, 26.9, 28.2,
28.4, 64.2, 65.3, 66.6, 77.1, 78.5, 79.0, 108.7, 127.6, 129.5, 134.0,
135.6; MS (EI) m/z (rel intensity) 600 (1), 543 (1), 283 (20),
159 (52). Anal. Calcd for C35H58O5Si2: C, 68.36; H, 9.51.
Found: C, 68.19; H, 9.70.
4(S)-1-((ter t-Bu tyld ip h en ylsilyl)oxy)-4-[1(S)-1-(4(R)-2,2-
d im eth yl[1,3]d ioxola n -4-yl)p r op oxy]-7-iod oh ep ta n e (40).
Step a . Following the procedure given for the DIBALH
reduction of TBDPS-protected 14, second step in the prepara-
tion of compound 15, ethyl ester 39 (376 mg, 0.66 mmol)
afforded, after column chromatography (silica gel, 25% EtOAc
in hexanes), 340 mg (98%) of the corresponding alcohol 4(R)-
7-((ter t-bu tyldiph en ylsilyl)oxy)-4-[1(S)-1-(4(R)-2,2-dim eth -
2(S)-5-((ter t-Bu tyld ip h en ylsilyl)oxy)-2-[1(S)-1-(4(R)-2,2-
d im eth yl[1,3]d ioxola n -4-yl)p r op oxy]p en ta n -1-ol (37). To
a stirred solution of 36 (1.19 g, 1.94 mmol) in MeOH (10 mL)
at 0 °C was added camphorsulfonic acid (22 mg, 0.1 mmol).
After 3 h, TEA was added (3 drops) and the solvent was
removed under reduced pressure. The residue was chromato-
graphed on silica gel (30% EtOAc in hexanes) yielding 450 mg
of 37 (46%) and 280 mg of 38 (31%). Compound 37: [R]25D +22.4
(CHCl3, c 1.195); 1H NMR (CDCl3, 400 MHz) δ 0.98 (t, J ) 7.5
Hz, 3H), 1.07 (s, 9H), 1.36 (s, 3H), 1.41 (s, 3H), 1.53-1.74 (m,
6H), 3.51 (m, 2H), 3.57 (m, 1H), 3.65 (m, 3H), 3.85 (dd, J )
7.7, 6.8 Hz, 1H), 4.02 (dd, J ) 7.8, 6.4 Hz, 1H), 4.08 (dd, J )
12.2, 6.3 Hz, 1H), 7.37-7.46 (m, 6H), 7.67 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ 9.0, 19.2, 23.9, 25.3, 26.6, 26.8, 27.2, 28.3,
63.8, 64.2, 66.4, 76.7, 77.7, 78.1, 108.9, 127.6, 129.6, 133.8,
135.5; IR (CHCl3) 3600, 3450 cm-1; MS (EI) m/z (rel intensity)
485 (3), 399 (3), 283 (82). Anal. Calcd for C29H44O5Si: C, 69.56;
H, 8.86. Found: C, 69.13; H, 8.86.
yl[1,3]d ioxola n -4-yl)p r op oxy]h ep t a n -1-ol: [R]25 +22.0
D
(CHCl3, c 0.855); 1H NMR (CDCl3, 400 MHz) δ 0.96 (t, J ) 7.5
Hz, 3H), 1.07 (s, 9H), 1.35 (s, 3H), 1.40 (s, 3H), 1.47-1.71 (m,
10H), 3.47 (m, 2H), 3.64 (m, 2H), 3.68 (t, J ) 5.8 Hz, 2H), 3.83
(m, 1H), 4.03 (m, 2H), 7.37-7.45 (m, 6H), 7.68 (m, 4H); 13C
NMR (CDCl3, 100 MHz) δ 8.9, 19.2, 23.7, 25.3, 26.6, 26.8, 28.2,
28.3, 29.5, 30.3, 63.1, 64.0, 66.8, 76.6, 77.0, 77.4, 108.8, 127.6,
129.5, 134.0, 135.5; IR (CHCl3) 3400 cm-1; MS (EI) m/z (rel
intensity) 513 (2), 311 (100). Anal. Calcd for C31H48O5Si: C,
70.41; H, 9.16. Found: C, 70.47; H, 9.25.
Step b. To a solution of the alcohol previously prepared (335
mg, 0.63 mmol) in CH2Cl2 (6 mL) at 0 °C were added DMAP
(86 mg, 0.7 mmol), TEA (0.10 mL, 0.7 mmol), and tosyl chloride
(174 mg, 0.91 mmol). The reaction was stirred at room
temperature for 12 h, and then ice was added and the reaction
was extracted with CH2Cl2 (3 × 10 mL). The ethereal extracts
were dried (MgSO4), concentrated, and quickly filtered on silica
gel (15% EtOAc in hexanes) to give 427 mg (98% yield) of the
corresponding tosylate, which was used immediately in the
subsequent transformation.
Step c. To a solution of the tosylate (427 mg) in anhydrous
acetone (6 mL) was added NaI (369 mg, 2.46 mmol), and the
reaction was stirred for 14 h at room temperature. The solvent
was removed in vacuo, water was added to the residue, and
the resulting suspension was extracted with CH2Cl2 (3 × 10
mL). The combined organic phases were washed with a
saturated aqueous solution of Na2S2O3, concentrated, and
E t h yl 4(S)-7-((ter t-Bu t yld ip h en ylsilyl)oxy)-4-[1(S)-1-
(4(R)-2,2-d im et h yl[1,3]d ioxola n -4-yl)p r op oxy]h ep t a n o-
a te (39). Step a . Following the procedure given for the Swern
oxidation of 27, alcohol 37 (450 mg, 0.9 mmol) afforded the
expected aldehyde, which was used in the subsequent reaction
without purification.
Step b. To a suspension of NaH (81 mg, 80% in mineral
oil, 2.7 mmol) in THF (5 mL) was added triethylphosphono-
acetate (0.8 mL, 4.05 mmol) at 0 °C under argon. After 30 min,
2.4 mL of this solution was added to a solution of the previously
prepared aldehyde in THF (10 mL). After 30 min, TLC showed
that no starting material remained, and ice and 10 mL of a
1% aqueous solution of HCl were added. The reaction was
extracted with ether (3 × 20 mL), and the combined ethereal
extracts were dried (MgSO4), concentrated, and chromato-
graphed (silica gel, 10% EtOAc in hexanes), yielding 465 mg
(91%) of the expected R,â-unsaturated ester eth yl 4(S)-7-
((ter t-bu tyldiph en ylsilyl)oxy)-4-[1(S)-1-(4(R)-2,2-dim eth yl-
[1,3]d ioxola n -4-yl)p r op oxy]h ep t-2-en oa te: [R]25D -2.8 (CH-
chromatographed on silica gel (5% EtOAc in hexanes) yielding
1
375 mg of 40 (93%): [R]25 +15.5 (CHCl3, c 1.375); H NMR
D
(CDCl3, 400 MHz) δ 0.98 (t, J ) 7.4 Hz, 3H), 1.10 (s, 9H), 1.37
(s, 3H), 1.42 (s, 3H), 1.50-1.70 (m, 8H), 1.82-1.97 (m, 2H),
3.21 (t, J ) 6.9 Hz, 2H), 3.47 (m, 2H), 3.71 (t, J ) 5.7 Hz, 2H),
3.84 (dd, J ) 6.9, 6.3 Hz, 1H), 4.04 (m, 2H), 7.44 (m, 6H), 7.70
(m, 4H); 13C NMR (CDCl3, 100 MHz) δ 7.2, 8.9, 19.1, 23.7, 25.3,
26.6, 26.8, 28.1, 29.2, 29.7, 34.8, 63.9, 66.6, 76.1, 76.7, 77.3,
108.7, 127.6, 129.5, 133.9, 135.5; MS (EI) m/z (rel intensity)
623 (1), 479 (13), 437 (29), 283 (68). Anal. Calcd for C31H47O4-
SiI: C, 58.29; H, 7.42. Found: C, 58.12; H, 7.48.
1
Cl3, c 0.78); H NMR (CDCl3, 400 MHz) δ 0.92 (t, J ) 7.4 Hz,
3H), 1.06 (s, 9H), 1.32 (t, J ) 7.2 Hz, 3H), 1.35 (s, 3H), 1.40 (s,
3H), 1.47 (m, 2H), 1.51-1.67 (m, 3H), 1.75 (m, 1H), 3.47 (m,
1H), 3.67 (m, 2H), 3.86 (dd, J ) 7.6, 7.5 Hz, 1H), 3.98 (dd, J )
7.5, 6.4 Hz, 1H), 4.06 (m, 1H), 4.16 (m, 1H), 4.22 (q, J ) 7.2
Hz, 2H), 5.95 (d, J ) 15.8 Hz, 1H), 6.79 (dd, J ) 15.8, 7.3 Hz,
1H), 7.36-7.45 (m, 6H), 7.67 (m, 4H); 13C NMR (CDCl3, 100
MHz) δ 9.6, 14.2, 19.2, 24.7, 25.2, 26.6, 26.9, 28.0, 31.4, 60.4,
63.7, 65.7, 77.6, 77.7, 78.4, 108.7, 122.2, 127.6, 129.5, 133.9,
135.5, 148.8, 166.2; IR (CHCl3) 1710, 1650 cm-1; MS (EI) m/z
(rel intensity) 511 (7), 409 (6), 331 (6), 283 (21). Anal. Calcd
for C33H48O6Si: C, 69.68; H, 8.51. Found: C, 69.75; H, 8.61.
Step c. To a suspension of 10% Pd on carbon (40 mg) in
EtOAc (5 mL), under an H2 atmosphere, was added the
unsaturated ester previously obtained (393 mg, 0.69 mmol)
in EtOAc (2 mL). After 4 h the catalyst was filtered out and
4(S)-1-((ter t-Bu tyld ip h en ylsilyl)oxy)-4-[1(S)-1-(2(R)-ox-
ir a n yl)p r op oxy]-7-(tolyl-4-su lfon yl)h ep ta n e (41). Step a .
In a two-neck flask equipped with a reflux condenser were
placed 40 (180 mg, 0.28 mmol), DMF (3 mL), and p-toluene-
sulfinic acid sodium salt (72 mg, 0.4 mmol). The mixture was
stirred at 65 °C for 2 h, and then it was cooled, poured into 50
mL of water, and vigorously stirred for 30 min. The two phases
were decanted, and the aqueous one was extracted with ether
(3 × 10 mL). The combined organic extracts were washed with
a saturated aqueous solution of Na2S2O3 (5 mL), dried (Mg-
SO4), concentrated, and chromatographed on silica gel (15%
hexanes in EtOAc), yielding 183 mg (98%) of the corresponding
sulfone 4(S)-1-((ter t-bu tyld ip h en ylsilyl)oxy)-4-[1(S)-1-(4-
(R)-2,2-d im et h yl[1,3]d ioxola n -4-yl)p r op oxy]-7-(t olyl-4-
su lfon yl)h ep ta n e: [R]25 +17.05 (CHCl3, c 1.12); 1H NMR
D

9738 J . Org. Chem., Vol. 63, No. 26, 1998
Mujica et al.
(CDCl3, 400 MHz) δ 0.86 (t, J ) 7.4 Hz, 3H), 1.06 (s, 9H), 1.33
(s, 3H), 1.37 (s, 3H), 1.41-1.62 (m, 8H), 1.69-1.83 (m, 2H),
2.44 (s, 3H), 3.07 (t, J ) 8.0 Hz, 2H), 3.36 (m, 2H), 3.65 (t, J
) 6.0 Hz, 2H), 3.76 (m, 1H), 3.97 (m, 2H), 7.34-7.45 (m, 8H),
7.66 (m, 4H), 7.78 (d, J ) 8.2 Hz, 2H); 13C NMR (CDCl3, 100
MHz) δ 8.7, 19.0, 19.1, 21.5, 23.5, 25.3, 26.6, 26.8, 28.0, 29.6,
32.5, 56.5, 63.8, 66.6, 76.2, 76.5, 77.1, 108.7, 127.6, 128.1, 129.5,
organic extracts were dried (MgSO4), concentrated, and chro-
matographed on silica gel (25% hexanes in EtOAc) yielding 9
mg (38%) of a mixture (85:15) of trans-oxocane epimers at the
sulfone-bearing carbon and unreacted compound 41 (12 mg).
A pure fraction of the major isomer was isolated by HPLC (µ
Porasil, 300 × 19 mm, 30% EtOAC in hexanes, 3 mL/min, tR
) 9.7 min): 1H NMR (C6D6, 400 MHz) δ 0.81-0.95 (m, 1H),
0.99 (t, J ) 7.4 Hz, 3H), 1.21 (s, 9H), 1.33-1.44 (m, 4H), 1.45-
1.65 (m, 3H), 1.70-1.89 (m, 3H), 1.92 (s, 3H), 2.77 (dd, J )
14.2, 4.0 Hz, 1H), 3.18 (m, 1H), 3.25 (m, 1H), 3.42 (m, 1H),
3.62 (m, 2H), 3.89 (m, 1H), 6.82 (d, J ) 8.0 Hz, 2H), 7.28 (m,
6H), 7.81 (m, 6H); 13C NMR (C6D6, 100 MHz) δ 7.5, 19.4, 21.1,
25.8, 27.1, 27.2, 27.4, 29.8, 30.6, 33.3, 60.0, 64.0, 70.9, 73.5,
78.0, 127.9, 128.1, 129.3, 129.7, 130.0, 134.3, 135.9, 143.8.
129.8, 133.8, 135.5, 136.1, 144.5; IR (CHCl3) 1590, 1310 cm-1
;
MS (EI) m/z (rel intensity) 651 (2), 609 (71), 449 (39). Anal.
Calcd for C38H54O6SiS: C, 68.43; H, 8.17. Found: C, 68.18; H,
8.52.
Step b. Following the three-step procedure described for
the preparation of 17 from 16, starting from 67 mg of the
compound reported above, 36 mg of the epoxysulfone 41 was
obtained (59% yield): [R]25 -1.0 (CHCl3 c 0.89); 1H NMR
D
(CDCl3, 400 MHz) δ 0.89 (t, J ) 7.4 Hz, 3H), 1.05 (s, 9H), 1.45-
1.63 (m, 7H), 1.65-1.83 (m, 3H), 2.44 (s, 3H), 2.58 (dd, J )
5.2, 2.5 Hz, 1H), 2.67 (dd, J ) 5.0, 4.1 Hz, 1H), 2.77 (m, 1H),
2.98 (ddd, J ) 5.9, 5.9, 5.6 Hz, 1H), 3.07 (t, J ) 7.9 Hz, 2H),
3.33 (m, 1H), 3.65 (m, 2H), 7.34-7.45 (m, 8H), 7.66 (m, 4H),
7.78 (d, J ) 8.1 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 9.4,
18.8, 19.2, 21.6, 26.0, 26.8, 28.2, 30.4, 32.4, 45.7, 53.2, 56.5,
63.8, 77.3, 78.1, 127.6, 128.1, 129.6, 129.8, 133.9, 135.5, 136.1,
144.6; MS (EI) m/z (rel intensity) 551 (8), 449 (5), 283 (66).
Anal. Calcd for C35H48O5SiS: C, 69.04; H, 7.95; S, 5.26.
Found: C, 69.23; H, 7.95; S, 5.14.
(2S,3R,5R,8S)-8-((3-ter t-Bu tyld ip h en ylsilyl)oxy)p r op yl-
2-eth yl-5-(tolyl-4-su lfon yl)oxoca n -3-ol (42). To a solution
of 41 (23.7 mg, 0.038 mmol) in THF (7 mL) at -65 °C under
argon was added LDA (1.15 mL, 0.27 mmol, 0.24 M in THF).
The reaction was stirred at -40 °C for 30 min, and then 2 mL
of a saturated aqueous solution of NH4Cl was added and the
reaction was extracted with ether (3 × 10 mL). The combined
Ackn owledgm en t. Financial support from the DGES
(Grants PB93-0577 and PB96-1041) is gratefully ac-
knowledged. M.T.M. thanks the Comunidad Auto´noma
de Canarias for a fellowship. We thank Professor A. B.
Holmes, Cambridge, U.K., for a preprint of his latest
synthesis of (+)-laurencin.26
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures for the synthesis of 4, 7, 9, 10, 31, and 33, H NMR
spectra for 11 and 23, and 1H and 13C NMR spectra for 21
and new compounds for which no elemental analysis could be
obtained (40 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 O981188W