Stereocontrolled synthesis of cyclic ethers by intramolecular hetero- Michael addition. 5. Synthesis of all diastereoisomers of 2,3,5,6- tetrasubstituted tetrahydropyrans

Article abstract of DOI:10.1021/jo9619241

A systematic approach to the enantiomeric synthesis of all possible diastereoisomers of 2,6-dialkyl3,5-dioxytetrahydropyrans is described. The key step in the described methodology is the intramolecular cyclization of enantiomerically enriched (≤95% ee) 7-hydroxy-4-(benzoyloxy)-2,3unsaturated esters. In fused systems, six of the eight diastereoisomers for one enantiomeric series were synthesized using this procedure as a key step. Using those with the suitable stereochemistry, the two left were synthesized by simple chemical transformations: in one case by the basic isomerization of the carbon with the (methoxycarbonyl)methyl substituent or by a Mitsunobu inversion of a secondary alcohol available from the benzoyloxy group, in the remaining one by a consecutive sequence of oxidation and reduction reactions again over the free secondary alcohol. The stereochemistry of the intramolecular hetero-Michael addition leading to 2,3-disubstituted tetrahydropyrans is highly predictable when kinetic conditions (low temperature and sodium or potassium bases) are used and can be rationalized by invoking a model of a chair-like transition state in which the benzoyloxy group is located in the equatorial mode and the stereochemical course of the approach of the α,β-unsaturated ester is controlled by the geometry of the double bond. As a rule of thumb, the cyclization using E double bonds yielded cis-2,3-disubstituted tetrahydropyrans, while (Z)-unsaturated esters yielded the trans compounds. This empirical rule is followed in highly substituted systems, leading to fused 2,3,5,6-tetrasubstituted tetrahydropyrans, with the same absolute configuration in the carbon where the nucleophilic oxygen is located and the one where the benzoyloxy group is located. Those systems having opposite configurations yield the same trans2,3-disubstituted compound. The isomerization under thermodynamic conditions (room or higher temperature with excess of base) of the diastereoisomers with the (methoxycarbonyl)methyl substituent in the axial mode led quantitatively to those in which such a group was located equatorially. The scope and limitations of the method are described in both the synthesis of the unsaturated precursor and the stereochemistry reached in the cyclization step.

Full text of DOI:10.1021/jo9619241

4570
J . Org. Chem. 1997, 62, 4570-4583
Articles
Ster eocon tr olled Syn th esis of Cyclic Eth er s by In tr a m olecu la r
Heter o-Mich a el Ad d ition . 5. Syn th esis of All Dia ster eoisom er s of
2,3,5,6-Tetr a su bstitu ted Tetr a h yd r op yr a n s
J uan M. Betancort, V´ıctor S. Mart´ın,* J ose´ M. Padro´n, J ose´ M. Palazo´n,
Miguel A. Ram´ırez, and Marcos A. Soler
Instituto Universitario de Bio-Orga´nica “Antonio Gonza´lez”, Universidad de La Laguna,
Carretera de La Esperanza, 2, 38206 La Laguna, Tenerife, Spain
Received October 14, 1996X
A systematic approach to the enantiomeric synthesis of all possible diastereoisomers of 2,6-dialkyl-
3,5-dioxytetrahydropyrans is described. The key step in the described methodology is the
intramolecular cyclization of enantiomerically enriched (g95% ee) 7-hydroxy-4-(benzoyloxy)-2,3-
unsaturated esters. In fused systems, six of the eight diastereoisomers for one enantiomeric series
were synthesized using this procedure as a key step. Using those with the suitable stereochemistry,
the two left were synthesized by simple chemical transformations: in one case by the basic
isomerization of the carbon with the (methoxycarbonyl)methyl substituent or by a Mitsunobu
inversion of a secondary alcohol available from the benzoyloxy group, in the remaining one by a
consecutive sequence of oxidation and reduction reactions again over the free secondary alcohol.
The stereochemistry of the intramolecular hetero-Michael addition leading to 2,3-disubstituted
tetrahydropyrans is highly predictable when kinetic conditions (low temperature and sodium or
potassium bases) are used and can be rationalized by invoking a model of a chair-like transition
state in which the benzoyloxy group is located in the equatorial mode and the stereochemical course
of the approach of the R,â-unsaturated ester is controlled by the geometry of the double bond. As
a rule of thumb, the cyclization using E double bonds yielded cis-2,3-disubstituted tetrahydropyrans,
while (Z)-unsaturated esters yielded the trans compounds. This empirical rule is followed in highly
substituted systems, leading to fused 2,3,5,6-tetrasubstituted tetrahydropyrans, with the same
absolute configuration in the carbon where the nucleophilic oxygen is located and the one where
the benzoyloxy group is located. Those systems having opposite configurations yield the same trans-
2,3-disubstituted compound. The isomerization under thermodynamic conditions (room or higher
temperature with excess of base) of the diastereoisomers with the (methoxycarbonyl)methyl
substituent in the axial mode led quantitatively to those in which such a group was located
equatorially. The scope and limitations of the method are described in both the synthesis of the
unsaturated precursor and the stereochemistry reached in the cyclization step.
In tr od u ction
cholesterol in blood,7 etc. The structural diversity of this
kind of molecules is very wide, but all have in common
the presence of polysubstituted cyclic ethers, with a
defined stereochemistry in the substituents and ring size
changing from five to nine members.8 A particularly
interesting group of this kind of molecules, of which
maitotoxin (Scheme 1) is one of the most outstanding
examples, is a series of highly toxic complex molecules
characterized by having fused cyclic ether units usually
with a trans relationship between the two substituents
(H or CH3) in the fusion of the rings and a syn stereo-
chemistry in the substituents (H or CH3) close to the
oxygen atom of the cycle.9
The presence in nature of molecules with oxygenated
heterocycles is receiving considerable attention consider-
ing their capacity of modification of the transport of the
metallic cations Na+, K+, and Ca2+ through the lipidic
membranes,1,2 this activity being responsible for their
antibiotic,1 neurotoxic,3 antiviral,4 and cytotoxic action5
and as growth regulators1,6 or inhibitors of the level of
X Abstract published in Advance ACS Abstracts, J une 15, 1997.
(1) Wesley, J . W. Polyether Antibiotics: Naturally Occurring Acid
Ionophores; Marcel Decker: New York, 1982; Vols. I and II.
(2) (a) Painter, G. R.; Presman, B. C. Top. Curr. Chem. 1982, 101,
83. (b) Still, W. C.; Hauck, P.; Kempf, D. Tetrahedron Lett. 1987, 28,
2817. (c) Smith, P. W.; Still, W. C. J . Am. Chem. Soc. 1988, 110, 7917.
(3) (a) Shimizu, Y. Marine Natural Products; Scheuer, P., Ed.;
Academic Press: New York, 1978; Vol. I, p 1. (b) Ellis, S. Toxicon 1985,
23, 469.
Although several methods10 have been reported for the
synthesis of cyclic ethers and of tetrahydropyrans, in
particular new methodologies are desirable for the ste-
(4) Sakemi, S.; Higa, T.; J efford, C. W.; Bernardinelli, G. Tetrahe-
dron Lett. 1986, 27, 4287.
(5) (a) Suzuki, T.; Suzuki, A.; Furusaki, T.; Matsumoto, A.; Kato,
A.; Imanaka, Y.; Kurosawa, E. Tetrahedron Lett. 1985, 26, 1329. (b)
Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J .; Paul, V. J . J .
Org. Chem. 1988, 53, 3644.
(6) (a) Cohran, V. M. Physiology of Fungi; Wiley: New York, 1958.
(b) Schreiber, S. L.; Kelly, S. E.; Porco, J . A.; Sanmakia, T.; Suh, E. M.
J . Am. Chem. Soc. 1988, 110, 6210.
(7) Gonza´lez, A. G.; Mart´ın, J . D.; Mart´ın, V. S.; Norte, M.; Pe´rez,
R.; Ruano, J . Z.; Drexler, S. A.; Clardy, J . Tetrahedron 1982, 38, 1009.
(8) (a) Moore, R. E. In Marine Natural Products; Scheuer, P. J ., Ed.;
Academic Press: New York, 1978; Vol 1, pp 43-121. (b) Erickson, K.
L. In Marine Natural Products; Scheuer, P. J ., Ed.; Academic Press:
New York, 1983; Vol. V, pp 131-257. (c) Faulkner, D. J . Nat. Prod.
Rep. 1984, 1, 251; (d) 1986, 3, 1; (e) 1987, 4, 539; (f) 1988, 5, 613; (g)
1990, 7, 269; (h) 1991, 8, 97; (i) 1992, 9, 323; (j) 1993, 10, 497; (k)
1994, 11, 355; (l) 1995, 12, 223.
S0022-3263(96)01924-X CCC: $14.00 © 1997 American Chemical Society

Intramolecular Hetero-Michael Addition
J . Org. Chem., Vol. 62, No. 14, 1997 4571
Sch em e 1
reocontrolled synthesis of highly substituted rings. In
this paper we discuss a particular approach based on the
heteronuclear annelation by intramolecular alkoxide
addition to γ-(benzoyloxy)-R,â-unsaturated esters. The
intramolecular hetero-Michael addition, on the other
hand, is known in carbohydrate chemistry.11 In general
terms such a cyclization in polyhydroxylic compounds
leading to C-glycopyranosides seems to be a reaction in
which the stereoselectivity is not controlled and which
usually leads to an “epimeric mixture” which in basic
conditions (even mild basic conditions) equilibrates to the
more stable â-anomer with the C-1 substituent located
equatorially.12 In some cases, however, the intramolecu-
lar hetero-Michael cyclization of alkoxides over R,â-
unsaturated esters can prove to be a stereoselective
process, with the stereochemistry of the new stereocenter
controlled by the configuration of the nucleophilic alkox-
ide,13 the reaction conditions, and even the type of groups
present in the linear precursors.14 Stereoselectivity has
also been observed when an unsaturated ketone is
cyclized in a similar way.15 In these cases, however, the
stereochemistry in the final products is even more
sensitive to the reaction conditions since acid equilibrium
between both epimers has been reported.16
We considered the possibility that the double-bond
geometry may play an important role in the transition
state of this hetero-Michael addition. Although conjugate
additions of organometallic reagents of γ-alkoxy-R,â-
unsaturated carbonyl systems have been investigated,17
to the best of our knowledge there are no similar studies
with both (E)- and (Z)-R,â-unsaturated esters in the
intramolecular hetero-Michael addition. Our synthetic
approach could be considered to be based on the possible
biogenetic route of some natural tetrahydropyranyl sys-
tems. In this sense, it had been proposed that the
tetrahydropyranyl ring of the polyketide cladosporin is
formed by an intramolecular hetero-Michael addition of
a hydroxy group over an R,â-unsaturated carbonyl group.18
Resu lts a n d Discu ssion
Syn th esis of Isola ted Tetr a h yd r op yr a n s by In -
tr a m olecu la r Heter o-Mich a el Ad d ition . Our re-
search is focused on the study of the influence of both
the stereochemistry of the chiral centers and the double-
bond geometry in the cyclization of substituted chiral
7-hydroxy-4-(benzoyloxy)-2,3-unsaturated esters.19 We
began our studies with the linear models 9 and 11 with
unambiguous absolute configuration of the secondary
allylic center. The asymmetric induction was performed
by the Katsuki-Sharpless asymmetric epoxidation20 of
a suitable allylic alcohol (4) obtained from 1,4-butanediol
(Scheme 2). The enantiomerically enriched epoxy alcohol
5 was regioselectively opened using benzoic acid as
nucleophile and Ti(OPr-i)4 as acidic catalyst yielding the
diol benzoate 6 with excellent regioselectivity (>100:1).21
The oxidative cleavage with NaIO4 led to the aldehyde 7
ready to be submitted to Wittig homologation. Thus,
treatment of 7 with the sodium salt of trimethylphospho-
(9) (a) Murata, M.; Naoki, H.; Iwashita, T.; Matsunaga, S.; Sasaki,
M.; Yokoyama, A.; Yasumoto, T. J . Am. Chem. Soc. 1993, 115, 2060
and references cited therein. (b) Shimizu, Y.; Chou, H.-N.; Bando, H.;
Van Duyne, G.; Clardy, J . C. J . Am. Chem. Soc. 1986, 108, 514. (c)
Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J .; Golik, J .;
J ames, J . C.; Nakanishi, K. J . Am. Chem. Soc. 1981, 103, 6773. (d)
Murata, M.; Legrand, A. M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T. J .
Am. Chem. Soc. 1990, 112, 4380. (e) Murata, M.; Kumagai, M.; Lee, J .
S.; Yasumoto, T. Tetrahedron Lett. 1987, 28, 5869. (f) Satake, M.;
Murata, M.; Yasumoto, T. J . Am. Chem. Soc. 1993, 115, 361. (g) Nagai,
H.; Murata, M.; Torigoe, K.; Satake, M.; Yasumoto, T. J . Org. Chem.
1992, 57, 5448. (h) Marine Toxins: Origin, Structure and Molecular
Pharmacology; Hall, S., Strichartz, G., Eds.; 1990; American Chemical
Society: Washington, DC, ACS Symposium Series.
(10) (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309. (b) Alvarez, E.;
Candenas, M. L.; Pe´rez, R.; Ravelo, J . L.; Mart´ın, J . D. Chem. Rev.
1995, 95, 1953. (c) Nicolaou, K. C.; Sorensen, E. J . In Classics in Total
Synthesis; VCH: Weinheim, 1996.
(11) Dawe, R. D.; Fraser-Reid, B. J . Org. Chem. 1984, 49, 522.
(12) (a) Allevi, P.; Anastasia, M.; Ciuffreda, C.; Fiecchi, A.; Scala,
A. J . Chem. Soc., Perkin Trans. 1 1989, 1275. (b) Bates, H. A.; Deng,
P.-N. J . Org. Chem. 1983, 48, 4479. (c) Maurer, B.; Grieder, A.;
Thommen, W. Helv. Chim. Acta 1979, 62, 44. (d) Hori, K.; Hikage, N.;
Inagaki, A.; Mori, S.; Nomura, E.; Yoshii, K. J . Org. Chem. 1992, 57,
2888.
(13) (a) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E. J . Am. Chem.
Soc. 1989, 111, 6682. (b) 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. (c) Kim, S.; Salomon, R. G. Tetrahedron Lett. 1989,
30, 6279.
(16) Keinan, E.; Seth, K. K.; Lamed, R. J . Am. Chem. Soc. 1986,
108, 3474.
(17) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H.
J . Am. Chem. Soc. 1992, 114, 7652 and references cited therein.
(18) Rawling, B. J .; Reese, P. B.; Ramer, S. E.; Vederas, J . C. J .
Am. Chem. Soc. 1989, 111, 3382.
(19) For preliminary accounts of the matter, see: (a) Mart´ın, V. S.;
Nu´n˜ez, M. T.; Ram´ırez, M. A.; Soler, M. A. Tetrahedron Lett. 1990,
31, 763. (b) Mart´ın, V. S.; Palazo´n, J . M. Tetrahedron Lett. 1992, 33,
2399. (c) Palazo´n, J . M.; Soler, M. A.; Ram´ırez, M. A.; Mart´ın, V. S.
Tetrahedron Lett. 1993, 34, 5467.
(20) Katsuki, T.; Mart´ın, V. S. Organic Reactions; Paquette, L. A.,
et al., Eds.; Wiley: New York, 1996; Vol. 48, pp 1-299.
(21) (a) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1557.
(b) Palazo´n, J . M.; An˜orbe, B.; Mart´ın, V. S. Tetrahedron Lett. 1986,
27, 4987.
(14) Gung, B. W.; Francis, M. B. J . Org. Chem. 1993, 58, 6177.
(15) (a) Kozikowski, A. P.; Schmiesing, R. J .; Sorgi, K. L. J . Am.
Chem. Soc. 1980, 102, 6577. (b) Seebach, D.; Pohmakotr, M. Helv.
Chim. Acta 1979, 62, 843.

4572 J . Org. Chem., Vol. 62, No. 14, 1997
Betancort et al.
Ta ble 1. In flu en ce of th e Rea ction Con d ition s on
In tr a m olecu la r Heter o-Mich a el Ad d ition s
Sch em e 2
entry substrate
base
NaH
NaH
NaH
NaH
NaH
NaH
LiN(TMS)2
solvent
temp (°C) 12:13
1
2
9
THF
0
0
3:1
2:1
benzene
toluene
CH2Cl2
CH3CN
THF
3
4
5
6
-78
8:1
2.5:1
4:1
0
0
-78
rt
9:1
3:1
7
toluene
8
9
NaN(TMS)2 toluene
0
0
0
3.3:1
4.5:1
9:1
7:1
9:1
1:11
1:19
1:10
1:10
1:20
1:26
1:17
KN(TMS)2
KN(TMS)2
KN(TMS)2
KN(TMS)2
NaH
THF
toluene
THF
toluene
THF
10
11
12
13
14
15
16
17
18
19
-78
-78
0
0
rt
0
0
-78
-78
11
NaH
LiN(TMS)2
toluene
toluene
Sch em e 3
NaN(TMS)2 toluene
KN(TMS)2
KN(TMS)2
KN(TMS)2
toluene
toluene
THF
Sch em e 4
noacetate led to the E-unsaturated ester 8 with excellent
E:Z selectivity (>20:1). In a similar manner, when 7 was
submitted to the sodium salt of bis(phenoxy)[(methoxy-
carbonyl)methyl]phosphonate, the Z ester 11 was ob-
tained almost exclusively (Z:E, >20:1).22 Cleavage of the
THP protecting group under standard acidic conditions
gave the free alcohols 9 and 11.
The cyclization reaction of both 9 and 11 was per-
formed using different reaction conditions, changing base,
solvent, and temperature. Gratifyingly, we found a good
dependence between the geometry of the double bond in
the R,â-unsaturated ester and the stereochemistry in the
cyclization reaction (Scheme 3). As a rule of thumb, the
cyclization using E double bonds yielded cis-2,3-disub-
stituted tetrahydropyrans, while (Z)-unsaturated esters
yielded the trans compounds. As shown in Table 1, while
the stereoselectivity in the cyclization of the (E)-unsatur-
ated ester is strongly sensitive to the reaction conditions,
the trans-2,3-disubstituted tetrahydropyran was the
almost exclusively obtained product when the cyclization
of the Z isomer was performed under any basic condi-
tions. In general, we have found that potassium bases
are the most convenient regarding stereochemistry and
rate since in almost all the cases described in Table 1
the reactions were practically quantitative. Thus, when
LiN(TMS)2 was used as base, the cyclization reactions
needed to proceed overnight at rt to be completed, while
when KN(TMS)2 was used the cyclizations were com-
pleted in less than 5 min even at -78 °C. The use of
NaH at -78 °C also gave good stereoselectivity and yields
(entry 6) although longer periods of time are required
than with potassium salt.
On the other hand, we found that at temperatures
lower than 0 °C and using sodium and potassium bases
none of the obtained products suffers further transforma-
tions to the other stereoisomer even after long periods of
time (ca. 24 h). This result suggests to us that under
such conditions the cyclization is a kinetically controlled
reaction. In order to rationalize the stereochemical
results, we have performed extensive calculations as-
suming only that the cyclization occurs by a chair-like
transition state, obtaining a model summarized in Scheme
4 in which the energetically more favored transition
Sch em e 5
states reasonably explain our results.23
Taking into consideration the obtained results, we
focused our interest on a possible approach to the
stereoselective synthesis of isolated 2,3,5,6-tetrasubsti-
tuted tetrahydropyrans 14 and 17 in their enantiomeric
forms by a procedure based on the cyclization of the
suitable unsaturated precursors 15 and 18 (Scheme 5).
Our interest in such a structural unit is based on the
fact that it is widespread in a large number of highly
active natural products8 and its synthesis has not been
properly solved to date from a general point of view.10
On the other hand, we wanted to check the degree of
accuracy of our proposed model in more complicated
cases.
With these ideas in mind, we primarily prepared some
diastereoisomers of the unsaturated dibenzoates 16 and
19, for which the allylic alcohols 27 and 29 were obtained
in accordance with Scheme 6. Thus, the copper-catalyzed
(23) Ram´ırez, M. A.; Palazo´n, J . M.; Padro´n, J . M.; Mart´ın, V. S. J .
Org. Chem. 1997, 62, 4584.
(22) Ando, K. Tetrahedron Lett. 1995, 36, 4105.

Intramolecular Hetero-Michael Addition
J . Org. Chem., Vol. 62, No. 14, 1997 4573
Sch em e 6
Sch em e 7
Sch em e 8
coupling24 of the lithium salt of the tert-butyldiphenyl-
silyl-protected propargylic alcohol with the allylic bro-
mide 20 yielded after silyl cleavage the enyne 21 which
25
was reduced with LiAlH4 to the corresponding bis-(E)-
allylic alcohol 22 with excellent stereoselection, which
when submitted to a similar sequence of reactions as
those described above for the synthesis of 9 and 11
yielded through the aldehyde 25 the geometrical isomers
27 and 29.
In order to obtain some of the diastereoisomers of 16,
both 27 and 29 were submitted to asymmetric epoxida-
tion20 using the enantiomers of diethyl tartrate. We
found that while the reaction ran smoothly using (R,R)-
(+)-DET to yield the expected epoxy alcohols 30 and 32
with excellent stereoselection (>20:1), any attempt to
achieve the asymmetric epoxidation to obtain 31 and 33
using the enantiomeric chiral auxiliary was fruitless
probably due to a carbonyl participation of the benzoate
group.26 On the other hand, other attempts to achieve
the epoxidation using a non-enantioselective reagent such
as MCPBA,27 Ti(OPr-i)4/TBHP20b or VO(acac)228 led to an
inseparable mixture of 30 and 31 (1:1) or 32 and 33 (1:
1). The pure epoxides 30 and 32 were submitted to
regioselective opening with benzoic acid as mentioned
above, yielding smoothly the corresponding diol benzoates
34 and 35 ready to be cyclized (Scheme 7).
When 34 was submitted to 1.1 equiv of NaH, in THF,
at -78 °C, the tetrahydropyran 36 was obtained in 73%
yield and the diastereoisomeric mixture 37 in 20% yield.
When more base was used (2.2 equiv), the transesterified
benzoate 38 was isolated in 75% yield with the mixture
37 (15%). On the other hand, when the Z ester 35 was
treated under similar basic conditions, the tetrahydro-
furan 40 was obtained in 80% isolated yield with a small
amount of 38. Compound 40 was formed presumably via
the anion 39 by a transesterification reaction (Scheme
8).
Although the synthesis of both 38 and 40 as pure
enantiomers in high yields is a good synthetic result, the
difficulty in synthesizing all the desired epoxides and the
transesterification reactions which make it difficult to
distinguish which is the actual nucleophile at any given
moment led us to change the target for our studies in
the hetero-Michael cyclization mainly by the proper
choice of the suitable protecting group. Thus, 24, used
as a silyl-protected ether, was transformed into the
benzylidene derivative 41 which, after cleavage of the
benzoate group with NaOMe, was protected as the benzyl
ether to obtain 43 in which cleavage of the silyl ether
yielded the allylic alcohol 44. Gratifyingly, the asym-
metric epoxidation of 44 proceeded smoothly using both
enantiomers of the tartrate esters, yielding the epoxides
45 and 46 used as described above to obtain the desired
(E)- and (Z)-γ-alkoxy-R,â-unsaturated esters which, in
order to ensure the nucleophilic position, were monopro-
tected as the primary TBDPS ethers 47-50 (Scheme 9).
When the obtained R,â-unsaturated esters were treated
under basic conditions (NaH, THF) the results outlined
in Scheme 10 were obtained. The cyclization of both 47
and 48 yielded the expected stereochemistry in ac-
cordance with the empirical rule, the (Z)-unsaturated
ester yielding the trans-2,3-substituted tetrahydropyran
51 while the E compound afforded the cis-cyclic ether 52.
On the other hand, while 50 yielded the expected trans-
substituted tetrahydropyran 54, the cyclization of 49
afforded a mixture of 53 and 54 in a ratio of 1:4.
Although this result was improved when different basic
conditions were used [KN(TMS)2, in toluene at -78 °C]
affording a 1:1 mixture of 53 and 54, the ratio suggested
that again some adverse structural feature was forcing
the system to follow a different stereochemical course.
We conjecture that a possible explanation of the cases
where the stereochemical course in the cyclization is
(24) Tagirachi, H.; Mathai, I. M.; Miller, S. I. Org. Synth. 1970, 50,
97.
(25) Brandsma, L. Preparative Acetylenic Chemistry; Elsevier: New
York, 1988.
(26) J ohnston, B. D.; Oehlschlager, A. C. J . Org. Chem. 1982, 47,
5384.
(27) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
(28) Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979, 12,
63.

4574 J . Org. Chem., Vol. 62, No. 14, 1997
Betancort et al.
Sch em e 9
Sch em e 11
quently, in order to synthesize the necessary precursors
to study the ring formation in a general way we decided
to use both 12 and 13 as the starting point. Using a
similar methodology to that described above we synthe-
sized all the hydroxy-γ-(benzoyloxy)-R,â-unsaturated es-
ters necessary for our study (Scheme 12). Interestingly,
the asymmetric epoxidation of all the allylic alcohols
could now be achieved with excellent stereoselection
regardless of the chiral auxiliary used.
With the necessary precursors in our hands, we
proceeded to systematically perform the cyclization using
NaH as the base in THF at -78 °C. Although in all the
cases the yields were good (>85%), we found two different
behaviors regarding the obtained stereochemistry: those
cases in which the carbon where the nucleophilic oxygen
is located and the one where the benzoyloxy group is
located have the same absolute configuration and those
with opposite configuration. In the former the expected
stereochemistry was obtained in accordance with the
above-mentioned tendency: (E)-R,â-unsaturated esters
led to the 2,3-cis-substituted tetrahydropyrans (71 f 94,
90 f 98) while the Z esters gave the trans-isomers (73
f 97, 92 f 96). In the latter, both (E)- and (Z)-R,â-
unsaturated esters afforded the same 2,3-trans-disubsti-
tuted tetrahydropyran (65 or 67 f 93, 84 or 86 f 95)
(Scheme 13). In these cases the benzoyloxy group needs
necessarily to be located in a pseudoaxial position (99
and 101) or the approach of the unsaturated system is
disfavored by interaction with the preexisting ring (100),
eliminating in both cases the possibility of reaching the
proposed transition state (Scheme 4). In all cases, the
yield and stereochemical results were practically similar
using different bases, although the use of KN(TMS)2 in
toluene speeded up the reaction.
In order to fulfill the synthesis of the rest of the
diastereoisomers, we considered the possibility of using
the obtained products as precursors since the substitu-
ents present in such molecules may act as asymmetrical
inductors in newly created stereocenters. Since the
desired tetrasubstituted tetrahydropyrans have a sec-
ondary ester we pondered the synthesis of the new
compounds by inversion of configuration in the suitable
precursor of the carbon where such a functionality is
located. Thus, 97 was completely reduced with LiAlH4
and the resulting diol 102 was monoprotected as silyl
ether (Scheme 14). The secondary alcohol 102 was
oxidated with PCC to the corresponding ketone 104,
ready to be reduced. Satisfyingly, when 104 was treated
with LiAlH4 at -78 °C the all-cis tetrasubstituted tet-
rahydropyran 105 was obtained as the only detected
diastereoisomer. However, when a similar sequence of
reactions was applied to 96, the reduction of 108 using a
Sch em e 10
different from that obtained in the models (Scheme 3)
(cyclization of 34, 35 and 49) could be the presence of
the additional groups located in disfavored conforma-
tional positions (trans-diaxial mode) that makes it dif-
ficult to reach the proposed chair-like transition state.
Thus, the cyclization of 34 and 35 yielded respectively
38 and 40, as the main products, instead of the expected
products (Scheme 11). In such cases, a different mech-
anism could be possible.23
Syn th esis of F u sed Tetr a h yd r op yr a n s. In order
to ensure as much as possible the stereochemical path-
way of the cyclization, we decided to perform our studies
in compounds with a ring already present having a well-
defined stereochemistry in the carbon where the nucleo-
philic hydroxy group is located and which furthermore
would introduce some conformational restrictions in the
cyclization reactions. On the other hand, this model
would resemble even more the natural compound, which
obviously is the final objective of our work. Conse-

Intramolecular Hetero-Michael Addition
J . Org. Chem., Vol. 62, No. 14, 1997 4575
Sch em e 12
Sch em e 13
Sch em e 14
mers of 2,3,5,6-tetrasubstituted tetrahydropyrans were
successfully accomplished, complementing the general
methodology using the intramolecular hetero-Michael
cyclization.
Although the chemistry described above permitted us
to synthesize the eight possible diastereoisomers for each
enantiomeric series, we wondered about the possibility
of the basic isomerization of some of the obtained
products in light of the known greater stability of the
equatorial- relative to axial-substituted products.12 Thus,
we treated under such conditions the compounds 94, 98,
and 95, and gratifyingly in all the cases, complete
isomerization of the axial (methoxycarbonyl)methyl group
to the equatorial position was obtained (97 and 96)
including 110 that could not be obtained by the use of
kinetic cyclization conditions (Scheme 15).
myriad of reducing reagents yielded again 107 as the only
diastereoisomer. Fortunately, when we performed Mit-
sunobu’s methodology on 107 using p-nitrobenzoic acid
as nucleophile and DIAD as activating agent,29 the
epimeric ester 109 was obtained in 78% yield. With these
two sequences the synthesis of all possible diastereoiso-
Con clu sion s
(29) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Martin, S. F.; Dodge,
J . A. Tetrahedron Lett. 1991, 32, 3017. (c) Hughes, M. S. Org. React.
1992, 42, 335.
The intramolecular hetero-Michael addition of 7-hy-
droxy-4-(benzoyloxy)-2,3-unsaturated esters has proved

4576 J . Org. Chem., Vol. 62, No. 14, 1997
Betancort et al.
material was not detected by TLC. Then, Et3N was added
until pH ≈ 7 and the reaction mixture was poured into brine
(350 mL). The mixture was extracted with CH2Cl2 (3 × 150
mL), and the combined organic phases were dried over MgSO4,
concentrated, and purified by silica gel column chromatogra-
phy to yield 1 (8.1 g, 60% yield based on 1,4-butanediol) as an
oil: 1H NMR (CDCl3) δ 1.55 (m, 10 H), 3.01 (br s, 1 H), 3.39
(m, 2 H), 3.53 (t, J ) 5.9 Hz, 2 H), 3.73 (m, 2 H), 4.49 (s, 1 H);
13C NMR (CDCl3) δ 19.0 (t), 25.0 (t), 25.8 (t), 29.1 (t), 30.2 (t),
61.5 (t), 61.6 (t), 66.9 (t), 98.2 (d); IR (CHCl3) (cm-1) 3600, 3000,
2940, 1120; MS m/ z (relative intensity) 175 (M + 1)+ (5), 101
(19), 85 (100); HRMS calcd for C9H18O3 (M)+ 174.1256, found
174.1271.
Sch em e 15
Gen er a l Meth od for th e P r ep a r a tion of (E)-r,â-Un sa t-
u r a ted Ester s by th e Kn oeven a gel Ap p r oa ch . P r ep a r a -
t ion of Met h yl 6-[(Tet r a h yd r op yr a n -2-yl)oxy]h ex-2(E)-
en oa te (3). To a solution of alcohol 1 (9.54 g, 55 mmol) in
dry CH2Cl2 (275 mL) under argon were sequentially added
DMSO (36 mL, 0.7 mL × mmol), Et3N (38 mL, 274 mmol),
and SO3‚Py (26 g, 164 mmol) at rt. The mixture was stirred,
and after 30 min TLC showed complete conversion. Then, to
the reaction mixture was added 5% HCl aqueous solution (200
mL) and it was extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated to yield aldehyde 2 as an oil, which was used
without further purification. To the crude were sequentially
added pyridine (5.3 mL, 66 mmol), hemimalonate methyl ester
(8.0 mL, 60 mmol), and a catalytic amount of piperidine (10
drops). This mixture was heated for 2 h in a water bath at 60
°C until TLC showed complete conversion. The mixture was
diluted with Et2O (30 mL) and washed with a 5% HCl aqueous
solution. The organic layer was dried over MgSO4, filtered,
and concentrated. Flash chromatography provided pure ester
3 (10.4 g, 83% yield) as an oil: 1H NMR (CDCl3) δ 1.61 (m, 4
H), 1.77 (m, 4 H), 2.25 (m, 2 H), 3.44 (m, 2 H), 3.69 (s, 3 H),
3.79 (m, 2 H), 4.54 (m, 1 H), 5.84 (ddd, J ) 15.6, 15, 1.5 Hz, 1
H), 7.00 (ddd, J ) 15.6, 6.9, 6.9 Hz, 1 H); 13C NMR (CDCl3) δ
19.5 (t), 25.4 (t), 28.2 (t), 29.0 (t), 30.7 (t), 51.8 (q), 62.3 (t),
66.6 (t), 98.9 (d), 121.6 (d), 148.6 (d); IR (CHCl3) (cm-1) 2940,
1720, 1650, 1280; MS m/ z (relative intensity) 227 (M - 1)+
(1), 144 (10), 85 (100); HRMS calcd for C12H20O4 (M)+ 228.1361,
found 228.1357.
Gen er a l Meth od for th e Red u ction of Ester s. P r ep a -
r a tion of 6-[(Tetr a h yd r op yr a n -2-yl)oxy]h ex-2(E)-en -1-ol
(4). To a stirred solution of 3 (10.2 g, 45 mmol) in Et2O (450
mL) in an ice-cold bath was added slowly dropwise DIBAL (94
mL, 1.0 M in hexane, 94 mmol). After 30 min to the reaction
mixture were sequentially added with stirring H2O (13 mL),
NaOH aqueous solution (15% w/v, 13 mL), and H2O (39 mL).
The mixture was allowed to reach rt, dried over MgSO4,
filtered through a pad of Celite, concentrated, and purified by
silica gel column chromatography to yield 4 (7.84 g, 88% yield)
as an oil: 1H NMR (CDCl3) δ 1.53 (m, 4 H), 1.71 (m, 4 H),
2.11 (m, 2 H), 3.46 (m, 2 H), 3.65 (m, 2 H), 3.77 (m, 2 H), 4.03
(s, 1 H), 4.53 (m, 1 H), 5.64 (m, 2 H); 13C NMR (CDCl3) δ 19.4
(t), 25.3 (t), 28.8 (t), 29.0 (t), 30.6 (t), 62.1 (t), 63.1 (t), 66.8 (t),
98.7 (d), 129.6 (d), 131.7 (d); IR (CHCl3) (cm-1) 3600, 2940,
1450, 1120; MS m/ z (relative intensity) 199 (M - 1)+ (1), 169
(4), 98 (28), 85 (100); HRMS calcd for C11H20O3 (M)+ 200.1412,
found 200.1398.
to be an excellent way to obtain substituted tetrahydro-
pyrans of high stereochemical purity. The stereochemical
course of the reaction depends on the reaction conditions.
The method is particularly efficient when kinetic condi-
tions are used (low temperatures and stoichiometric
amounts of sodium or potassium bases) for the synthesis
of fused rings. Thus, the synthesis of six of the eight
possible diastereoisomers (only one enantiomeric series
is considered) was possible by direct intramolecular
hetero-Michael addition, while the remaining two were
synthesized by simple chemical transformations using as
starting material those diastereoisomers with the suit-
able stereochemistry. Using thermodynamic conditions
(room temperature or higher and excess of base), the
diastereoisomers with the (methoxycarbonyl)methyl sub-
stituent located in the axial mode isomerize to the
equatorial position. The scope and limitations of the
method have been described, the stereochemical course
of the reaction being highly predictable. Thus, we found
that under kinetic conditions, for those systems with the
same absolute configuration for both the carbon on which
the nucleophilic oxygen is located as well as the carbon
vicinal to the R,â-unsaturated ester, the cyclization of
E-unsaturated esters led to cis-2,3-disubstituted tetrahy-
dropyran, while the reaction of Z esters afforded the
trans-cyclic ether. In those systems with opposite abso-
lute configuration for such carbon atoms, both E- and
Z-unsaturated esters led to the same trans-2,3-disubsti-
tuted oxane. Although the methodology presented has
been described only for one enantiomer series, the choice
of the proper stereoisomer of the tartrate esters in the
asymmetric epoxidation steps permits the control of the
absolute configuration in the final products.
Gen er a l Asym m etr ic Ep oxid a tion P r oced u r e. P r ep a -
r ation of (2R,3S)-{3-[3-[(Tetr ah ydr opyr an -2-yl)oxy]pr opyl]-
oxir a n yl}m eth a n ol (5). Crushed, activated 3 Å molecular
sieves (5 g) were added to stirred CH2Cl2 (325 mL) under
argon. The flask was cooled to -20 °C, and Ti(OPr-i)4 (11.6
mL, 39 mmol), (R,R)-(+)-diethyl tartrate (7.26 mL, 42.4 mmol),
and 4 (7.64 g, 38 mmol) in CH2Cl2 (25 mL) were added
sequentially with stirring. The mixture was stirred for 15 min,
and tert-butyl hydroperoxide (13.6 mL, 5.2 M in isooctane, 71
mmol)20b was added slowly. After the addition, the reaction
was maintained with stirring for 2 h. Tartaric acid aqueous
solution (15% w/v, 250 mL) was added, and the stirring was
continued until clear phases were reached (30 min). The
phases were separated, and the aqueous phase was extracted
with CH2Cl2 (3 × 100 mL). The combined organic phases were
concentrated, diluted with ether (250 mL), and treated with a
Exp er im en ta l Section
Ma ter ia ls a n d m eth od s are similar to those used in ref
30.
P r ep a r a tion of 4-[(Tetr a h yd r op yr a n -2-yl)oxy]bu ta n -
1-ol (1). To a stirred solution of commercially available 1,4-
butanediol (7 g, 78 mmol) in dry CH2Cl2 (1 L) were added 3,4-
dihydro-2H-pyran (3.2 mL, 35 mmol) and a catalytic amount
of OPCl3. The reaction was stirred at 0 °C until starting
(30) Rodr´ıguez, C. M.; Mart´ın, T.; Ram´ırez, M. A.; Mart´ın, V. S. J .
Org. Chem. 1994, 59, 4461.

Intramolecular Hetero-Michael Addition
J . Org. Chem., Vol. 62, No. 14, 1997 4577
precooled (0 °C) 15% NaOH aqueous solution (100 mL) and
brine (100 mL). The two-phase mixture was stirred vigorously
for 15 min at 0 °C. The organic phase was separated, and the
aqueous phase extracted with ether (2 × 100 mL). The
combined organic phases were washed with brine (100 mL),
dried over MgSO4, filtered, evaporated, and purified by silica
gel column chromatography to yield 5 (6.7 g, 81% yield) as an
oil: 1H NMR (CDCl3) δ 1.52 (m, 4 H), 1.69 (m, 6 H), 2.04 (br
s, 1 H), 2.95 (m, 1 H), 2.98 (m, 1 H), 3.44 (m, 2 H), 3.70 (m, 1
H), 3.83 (m, 2 H), 3.89 (m, 1 H), 4.56 (m, 1 H); 13C NMR (CDCl3)
δ 19.8 (t), 25.6 (t), 26.3 (t), 28.7 (t), 30.9 (t), 56.0 (d), 58.5 (d),
61.9 (t), 62.6 (t), 67.0 (t), 99.1 (d); IR (CHCl3) (cm-1) 3590, 2950,
1450, 1370; MS m/ z (relative intensity) 217 (M + 1)+ (8), 199
(38), 183 (67), 122 (18), 104 (100); HRMS calcd for C11H20O4
(M)+ 216.1361, found 216.1340.
MS m/ z (relative intensity) 361 (M - 1)+ (1), 277 (12), 140
(20), 105 (100); HRMS calcd for C20H26O6 (M)+ 362.1729, found
362.1732.
Gen er a l P r oced u r e To Clea ve THP Eth er s. P r ep a r a -
tion of Meth yl (4R)-4-(Ben zoyloxy)-7-h yd r oxyh ep t-2(E)-
en oa te (9). To a stirred mixture of 8 (3.54 g, 9.8 mmol) in
MeOH (100 mL) was added concentrated HCl until pH ≈ 1.
The reaction mixture was monitored by TLC, and after 5 min
there was complete conversion. Et3N was added until pH ≈
7, and the reaction mixture was stirred for 5 min. After
evaporation of the solvent, the obtained crude was purified
by silica gel column chromatography to yield 9 (2.6 g, 95%
yield) as an oil: [R]25 ) -52.5 (c 0.52, CHCl3); 1H NMR
D
(CDCl3) δ 1.66 (m, 2 H), 1.91 (m, 2 H), 3.66 (m, 2 H), 3.69 (s,
3 H), 5.68 (m, 1 H), 6.00 (dd, J ) 15.6, 1.5 Hz, 1 H), 6.93 (dd,
J ) 15.6, 5.1 Hz, 1 H), 7.46 (m, 3 H), 8.01 (m, 2 H); 13C NMR
(CDCl3) δ 27.8 (t), 30.2 (t), 51.6 (q), 61.7 (t), 72.6 (d), 121.1 (d),
128.4 (d), 129.5 (d), 130.0 (s), 133.2 (d), 145.5 (d), 165.5 (s),
166.4 (s); IR (CHCl3) (cm-1) 2900, 2780, 1670, 1385; MS m/ z
(relative intensity) 277 (M - 1)+ (1), 156 (13), 124 (15), 105
(100); HRMS calcd for C15H18O5 (M)+ 278.1154, found 278.1125.
Gen er a l P r oced u r e for th e P r ep a r a tion of γ-(Ben zoyl-
oxy)-(Z)-r,â-u n sa tu r a ted Ester s. P r ep a r a tion of Meth yl
(4R)-4-(Ben zoyloxy)-7-[(tetr a h yd r op yr a n -2-yl)oxy]h ep t-
2(Z)-en oa te (10). To a suspension of NaH (520 mg, 17 mmol,
80% in mineral oil) in THF (850 mL) at 0 °C was added slowly
bis(phenoxy)[(methoxycarbonyl)methyl]phosphonate (6.1 g, 20
mmol). After complete addition the mixture was stirred for 5
min and cooled down to -78 °C and the crude aldehyde 7
dissolved in THF (150 mL) was added dropwise. The reaction
mixture was stirred for 30 min, allowing the temperature to
raise until rt, after which time TLC showed complete conver-
sion to the unsaturated ester. The reaction was quenched with
acetic acid (4 mL), diluted with ether (500 mL), and washed
with a saturated aqueous solution of NaHCO3 (200 mL) and
brine (200 mL). The aqueous phases were extracted with ether
(2 × 100 mL). The combined organic phases were dried over
MgSO4, filtered, and concentrated. Flash chromatography
provided pure ester 10 (4.1 g, 85% yield based on diol 6) as an
oil: 1H NMR (CDCl3) δ 1.74 (m, 10 H), 3.46 (m, 2 H), 3.75 (s,
3 H), 3.81 (m, 2 H), 4.58 (m, 1 H), 5,88 (dd, J ) 11.6, 1.0 Hz,
1 H), 6.21 (dd, J ) 11.6, 7.8 Hz, 1 H), 6.46 (m, 1 H), 7.46 (m,
3 H), 8.04 (m, 2 H); 13C NMR (CDCl3) δ 19.8 (t), 25.7 (t), 30.9
(t), 31.0 (t), 31.1 (t), 51.6 (q), 62.5 (t), 67.2 (t), 72.2 (d), 99.0
(d), 120.6 (d), 128.5 (d), 129.7 (d), 130.0 (s), 133.1 (d), 147.5
(d), 165.5 (s), 166.1 (s); IR (CHCl3) (cm-1) 2950, 1710, 1270,
1180; MS m/ z (relative intensity) 362 (M)+ (1), 276 (36), 104
(100), 85 (100); HRMS calcd for C20H26O6 (M)+ 362.1729, found
362.1727.
Gen er a l P r oced u r e for th e Regioselective Op en in g of
2,3-Ep oxy 1-Alcoh ols w ith Ben zoic Acid . P r ep a r a tion of
(1R)-1-[(1S)-1,2-Dih yd r oxyeth yl]-4-[(tetr a h yd r op yr a n -2-
yl)oxy]bu tyl Ben zoa te (6). To a stirred solution of 5 (7.44
g, 34 mmol) in dry CH2Cl2 (350 mL) under argon were
sequentially added benzoic acid (3.2 g, 26 mmol) and Ti(OPr-
i)4 (13mL, 42 mmol) at rt. The mixture was stirred for 15 min,
and benzoic acid (3.2 g, 26 mmol) was added. After the
addition, the mixture was stirred for 4 h. Tartaric acid
aqueous solution (15% w/v, 250 mL) was added, and the
solution was stirred until clear phases were reached (30 min).
The phases were separated, and the aqueous phase was
extracted with CH2Cl2 (2 × 100 mL). The combined organic
phases were washed with a saturated aqueous solution of
NaHCO3(2 × 50 mL) and brine (100 mL), dried over MgSO4,
concentrated, and purified by column chromatography to yield
6 (9.31 g, 80% yield) as an oil: 1H NMR (CDCl3) δ 1.71 (m, 10
H), 3.39 (m, 2 H), 3.57 (m, 3 H), 3.74 (m, 2 H), 4.50 (m, 1 H),
5.12 (m, 1 H), 7.45 (m, 3 H), 7.99 (m, 2 H); 13C NMR (CDCl3)
δ 19.6 (t), 25.4 (t), 27.4 (t), 30.6 (t), 62,4 (t), 62.9 (t), 67.1 (t),
67.3 (t), 73.1 (d), 74.7 (d), 99.0 (d), 128.3 (d), 128.4 (d), 129.7
(d), 130.0 (s), 133.2 (d), 166.6 (s); IR (CHCl3) (cm-1) 3600, 2950,
1700, 1120; MS m/ z (relative intensity) 337 (M - 1)+ (1), 115
(14), 104 (95), 84 (100); HRMS calcd for C18H26O6 (M)+
338.1729, found 338.1713.
Gen er a l P r oced u r e for t h e Oxid a t ive Clea va ge of
3-Ben zoyloxy 1,2-Diols. P r ep a r a tion of (1S)-1-F or m yl-
4-[(t et r a h yd r op yr a n -2-yl)oxy]b u t yl Ben zoa t e (7). To a
stirred solution of 6 (4 g, 12 mmol) in THF:H2O (5:1, 70 mL)
was added NaIO4 (16.4 g, 77 mmol) at rt. After 2 h, the
mixture was diluted with ether (175 mL) and the organic layer
separated. The organic phase was washed with water (2 ×
30 mL) and brine (30 mL), dried over MgSO4, filtered, and
concentrated, yielding the crude aldehyde 7 as an oil, which
was used without further purification.
P r ep a r a tion of Meth yl (4R)-4-(Ben zoyloxy)-7-h yd r oxy-
h ep t-2(Z)-en oa te (11). The general THP cleavage procedure
was applied to 10 on a 3.54 g (10 mmol) scale, obtaining 11
Gen er a l P r oced u r e for th e P r ep a r a tion of γ-(Ben zoyl-
oxy)-(E)-r,â-u n sa tu r a ted Ester s. P r ep a r a tion of Meth yl
(4R)-4-(Ben zoyloxy)-7-[(tetr a h yd r op yr a n -2-yl)oxy]h ep t-
2(E)-en oa te (8). To a suspension of NaH (0.46 g, 15 mmol,
80% in mineral oil) in benzene (500 mL) at 0 °C was slowly
added trimethylphosphonoacetate (2.8 mL, 18 mmol) dissolved
in benzene (50 mL). After complete addition the mixture was
stirred for 5 min and the crude aldehyde 7 dissolved in benzene
(50 mL) was added dropwise. The reaction mixture was stirred
for 30 min, after which time TLC showed complete conversion
to the unsaturated ester. The reaction was quenched with
acetic acid (4 mL), diluted with ether (500 mL), and washed
with a saturated aqueous solution of NaHCO3 (200 mL) and
brine (200 mL). The water phases were extracted with ether
(2 × 100 mL). The combined organic phases were dried over
MgSO4, filtered, and concentrated. Flash chromatography
provided pure ester 8 (3.4 g, 80% yield from diol 6) as an oil:
1H NMR (CDCl3) δ 1.74 (m, 10 H), 3.46 (m, 2 H), 3.73 (s, 3 H),
3.80 (m, 2 H), 4.56 (s, 1 H), 5.73 (m, 1 H), 6.05 (dd, J ) 14.9,
J < 1 Hz, 1 H), 6.99 (dd, J ) 14.9, 5.1 Hz, 1 H), 7.50 (m, 3 H),
8.07 (m, 2 H); 13C NMR (CDCl3) δ 19.7 (t), 25.4 (t), 25.6 (t),
30.8 (t), 31.0 (t), 51.8 (q), 62.5 (t), 67.0 (t), 72.9 (d), 99.1 (d),
121.5 (d), 128.6 (d), 129.8 (d), 130.0 (s), 133.4 (d), 145.7 (d),
165.6 (s), 166.5 (s); IR (CHCl3) (cm-1) 2950, 1710, 1450, 1270;
(2.58 g, 95% yield) as an oil: [R]25 ) -29.9 (c 0.46, CHCl3);
D
1H NMR (CDCl3) δ 1.73 (m, 2 H), 1.93 (m, 2 H), 3.74 (m, 2 H),
3.76 (s, 3 H), 5.89 (dd, J ) 11.4, 1.1 Hz, 1 H), 6.26 (dd, J )
11.4, 7.4 Hz, 1 H), 6.48 (m, 1 H), 7.48 (m, 3 H), 8.04 (m, 2 H);
13C NMR (CDCl3) δ 28.3 (t), 30.4 (t), 51.7 (q), 62.0 (t), 71.9 (d),
120.3 (d), 128.5 (d), 129.8 (d), 130.0 (s), 133.2 (d), 148.2 (d),
165.5 (s), 166.1 (s); IR (CHCl3) (cm-1) 2900, 1670, 1385, 1130;
MS m/ z (relative intensity) 278 (M)+ (1), 156 (75), 137 (47),
105 (100); HRMS calcd for C15H18O5 (M)+ 278.1154, found
278.1145.
Gen er a l P r oced u r e for th e Cycliza tion of 7-Hyd r oxy-
4-(ben zoyloxy)-2,3-u n sa tu r a ted Ester s. P r ep a r a tion of
(2R)- an d 2(S)-(1R)-2-[(Meth oxycar bon yl)m eth yl]tetr ah y-
d r op yr a n -3-yl Ben zoa tes (12 a n d 13). To a suspension of
NaH (35 mg, 80% in mineral oil, 1.2 mmol) in dry THF (7 mL)
at -78 °C was added slowly 9 (300 mg, 1.1 mmol) in THF (3
mL). The reaction was stirred for 4 h, after which TLC showed
complete conversion. Then to the reaction mixture was added
AcOH (50 µL) and H2O (5 mL), and it was extracted with ether
(3 × 10 mL). The combined organic phases were washed with
a saturated aqueous solution of NaHCO3 (10 mL) and brine,
dried over MgSO4, concentrated, and purified by column
chromatography, yielding 12 (254 mg, 85% yield) and 13 (28
mg, 9% yield), both as oils. Compound 12: [R]25 ) -19.7 (c
D

4578 J . Org. Chem., Vol. 62, No. 14, 1997
Betancort et al.
0.34, CHCl3); 1H NMR (CDCl3) δ 0.87 (m, 1 H), 1.32 (m, 1 H),
1.76 (m, 1 H), 1.92 (m, 1 H), 2.56 (dd, J ) 16.0, 8.5 Hz, 1 H),
2.64 (dd, J ) 16.0, 4.9 Hz, 1 H), 3.20 (ddd, J ) 11.7, 11.7, <1
Hz, 1 H), 3.35 (s, 3 H), 3.82 (ddd, J ) 11.7, 4.5, 2.2 Hz, 1 H),
3.96 (ddd, J ) 8.5, 4.9, <1 Hz, 1 H), 5.13 (dd, J ) 3.0, <1 Hz,
1 H), 7.40 (m, 2 H), 7.53 (m, 1 H), 8.25 (m, 2 H); 13C NMR
(CDCl3) δ 20.7 (t), 28.0 (t), 37.4 (t), 51.8 (q), 68.8 (t), 69.2 (d),
75.0 (d), 128.5 (d), 129.7 (d), 130.0 (s), 133.2 (d), 166.0 (s), 171.4
(s); IR (CHCl3) (cm-1) 2940, 2830, 1720, 1270; MS m/ z (relative
intensity) 279 (M + 1)+ (3), 156 (72), 105 (100); HRMS calcd
for C15H19O5 (M + 1)+ 279.1232, found 279.1230. Compound
(460 mg, 12 mmol) in dry THF (125 mL) was added dropwise
21 (2.35 g, 11 mmol) in THF (5 mL) at -78 °C. The reaction
was stirred for 4 h and quenched sequentially with water (0.5
mL), a 15% NaOH aqueous solution (0.5 mL), and H2O (1.5
mL). The mixture was allowed to warm to rt, stirred addition-
ally for 0.5 h, and dried with MgSO4. The mixture was filtered
through a pad of Celite, and the solution was concentrated
and purified by silica gel chromatography to give 22 (1.9 g,
81% yield) as an oil: 1H NMR (CDCl3) δ 1.44-1.77 (br s, 6 H),
2.34 (s, 1 H), 2.75 (m, 2 H), 3.46 (m, 1 H) 3.87 (m, 2 H), 4.03
(d, J ) 4.0 Hz, 2 H), 4.15 (dd, J ) 11.7, 2.2 Hz, 1 H), 4.59 (t,
J ) 3.2 Hz, 1 H), 5.59 (m, 4 H); 13C NMR (CDCl3) δ 19.2 (t),
25.2 (t), 30.4 (t), 34.7 (t), 62.0 (t), 63.1 (t), 67.4 (t), 97.6 (d),
127.2 (d), 129.6 (d), 130.2 (d), 131.5 (d); IR (CHCl3) (cm-1) 3416,
2946, 1622, 1352, 1118; MS m/ z (relative intensity) 213 (M +
1)+ (1), 110 (6), 93 (23), 85 (100); HRMS calcd for C12H20O3
(M)+ 212.2902, found 212.1387.
P r ep a r a tion of (2R,3S)-{3-[4-[(Tetr a h yd r op yr a n -2-yl)-
oxy]b u t -2(E)-en yl]oxir a n yl}m et h a n ol (23). The general
asymmetric epoxidation procedure using (R,R)-(+)-DET as a
chiral auxiliary was used on 22 on a 1.8 g (8.5 mmol) scale for
2 h, yielding 23 (1.55 g, 80% yield) as an oil: 1H NMR (CDCl3)
δ 1.63 (s, 6 H), 2.33 (t, J ) 5.0 Hz, 2 H), 2.45 (br s, 1 H), 2.97
(m, 2 H), 3.56 (m, 1 H), 3.61 (d, J ) 4.5 Hz, 1 H), 3.87 (m, 2
H), 4.15 (dd, J ) 11.7, 2.2 Hz, 1 H), 4.60 (t, J ) 3.2 Hz, 1 H),
3.69 (m, 2 H); 13C NMR (CDCl3) δ 19.9 (t), 25.8 (t), 31.0 (t),
34.7 (t), 50.3 (d), 55.2 (d), 61.9 (t), 62.7 (t), 67.9 (t), 98.4 (d),
128.0 (d), 130.0 (d); IR (CHCl3) (cm-1) 3400, 2900, 1720, 1110;
MS m/ z (relative intensity) 229 (M + 1)+ (1), 93 (23), 85 (100);
HRMS calcd for C12H20O4 (M)+ 228.2896, found 228.2791.
P r ep a r a t ion of (1R)-1-[(1S)-1,2-Dih yd r oxyet h yl]-5-
[(tetr ah ydr opyr an -2-yl)oxy]pen t-3(E)-en yl Ben zoate (24).
The general procedure for the opening of 2,3-epoxy 1-alcohols
was applied to 23 on a 1.45 g (6.4 mmol) scale, yielding 24
(1.87 g, 84% yield) as an oil: 1H NMR (CDCl3) δ 1.57 (m, 6 H),
2.58 (m, 2 H), 3.39 (m, 1 H), 3.72 (m, 2 H), 3.84 (m, 2 H), 4.05
(t, J ) 11.3 Hz, 1 H), 4.51 (d, J ) 10.8 Hz, 1 H), 4.70 (br s, 2
H), 5.15 (m, 1 H), 5.68 (m, 2 H), 7.37 (m, 3 H), 7.99 (m, 2 H);
13C NMR (CDCl3) δ 19.1 (t), 19.4 (t), 19.6 (t), 24.9 (t), 25.1 (t),
30.3 (t), 33.4 (t), 33.5 (t), 61.9 (t), 62.8 (t), 67.1 (t), 69.2 (t),
69.7 (t), 97.3 (d), 97.4 (d), 99.7 (d), 100.2 (d), 126.7 (d), 128.2
(d), 129.4 (d), 129.8 (d), 130.0 (s), 132.5 (d), 133.0 (d), 166.5
(s); IR (CHCl3) (cm-1) 3650, 3400, 2850, 1700; MS m/ z (relative
intensity) 351 (M + 1)+ (1), 249 (27), 229 (30), 105 (100); HRMS
calcd for C19H26O6 (M)+ 350.4134, found 350.4083.
13: [R]25 ) -37.1 (c 0.34, CHCl3); 1H NMR (CDCl3) δ 1.74
D
(m, 3 H), 2.32 (m, 1 H), 2.49 (dd, J ) 15.0, 4.5 Hz, 1 H), 2.71
(dd, J ) 15.0, 7.9 Hz, 1 H), 3.09 (ddd, J ) 11.6, 11.1, 2.4 Hz,
1 H), 3.31 (s, 3 H), 3.62 (m, 1 H), 4.07 (ddd, J ) 9.4, 7.9, 4.5
Hz, 1 H), 4.94 (m, 1 H), 7.40 (m, 2 H), 7.52 (m, 1 H), 8.15 (m,
2 H); 13C NMR (CDCl3) δ 25.2 (t), 29.5 (t), 38.1 (t), 51.8 (q),
68.0 (t), 72.3 (d), 76.6 (d), 128.5 (d), 129.7 (d), 130.0 (s), 133.3
(d), 165.6 (s), 171.6 (s); IR (CHCl3) (cm-1) 2940, 2830, 1720,
1270; MS m/ z (relative intensity) 279 (M + 1)+ (1), 156 (55),
105 (100); HRMS calcd for C15H19O5 (M + 1)+ 279.1232, found
279.1222.
P r ep a r a tion of (1R,2S)-2-[(Meth oxyca r bon yl)m eth yl]-
tetr a h yd r op yr a n -3-yl Ben zoa te (13). The cyclization pro-
cedure described above to obtain 12 and 13 was applied to 11
on a 3.54 g (9.8 mmol) scale for 2 h at 0 °C, yielding 13 (3.36
g, 95% yield).
P r ep a r a tion of 2-[[4-Br om obu t-2(E)-en yl]oxy]tetr a h y-
d r op yr a n (20). To a stirred solution of 4-[(tetrahydropyran-
2-yl)oxy]but-2(E)-en-1-ol31 (4.0 g, 23.2 mmol) in dry CH2Cl2
(250 mL) were added Et3N (6.5 mL, 46 mmol) and MsCl (2.52
mL, 26 mmol) at 0 °C. After 15 min, the mixture was poured
into brine (200 mL) and extracted with CH2Cl2 (2 × 100 mL).
The combined organic phases were washed with brine (1 ×
100 mL), dried, and concentrated, yielding an oil of the crude
mesylate, which was used without purification.
To a suspension of LiBr (3.03 g, 35 mmol) in DMF (240 mL)
under argon was added the crude mesylate in DMF (5 mL) at
0 °C. The reaction mixture was stirred for 2 h and diluted
with ether (200 mL). The mixture was poured into H2O (500
mL) and extracted with ether (3 × 100 mL). The combined
organic phases were washed with brine, dried over MgSO4,
filtered, and concentrated. Chromatography of the crude
product on silica gel gave 20 (4.81 g, 88% yield) as an oil: 1H
NMR (CDCl3) δ 1.57 (m, 6 H), 3.41 (m, 1 H), 3.72 (m, 1 H),
3.91 (m, 3 H), 4.16 (m, 1 H), 4.53 (t, J ) 3.2 Hz, 1 H), 5.83 (m,
2 H); 13C NMR (CDCl3) δ 19.3 (t), 25.4 (t), 30.5 (t), 31.6 (t),
P r ep a r a tion of (1R)-1-[2-(Meth oxyca r bon yl)-(E)-vin yl]-
-5-[(t et r a h yd r op yr a n -2-yl)oxy]p en t -3(E)-en yl Ben zoa t e
(26). The general procedure to transform 3-benzoyloxy 1,2-
diols into γ-(benzoyloxy)-(E)-R,â-unsaturated esters was ap-
plied to 24 on a 1.67 g (4.8 mmol) scale, yielding 26 (1.57 g,
88% yield based on diol 24) as an oil: 1H NMR (CDCl3) δ 1.63
(m, 6 H), 2.58 (t, J ) 5.5 Hz, 2 H), 3.44 (m, 2 H), 3.73 (s, 3 H),
3.88 (m, 1 H), 4.17 (m, 1 H), 4.57 (m, 1 H), 5.72 (m, 3 H), 6.04
(dd, J ) 15.8, 1.6 Hz, 1 H), 6.98 (dd, J ) 15.8, 5.0 Hz, 1 H),
7.48 (m, 3 H), 8.04 (m, 2 H); 13C NMR (CDCl3) δ 19.4 (t), 25.4
(t), 30.6 (t), 36.9 (t), 51.6 (q), 62.1 (t), 67.0 (t), 72.1 (d), 97.7
(d), 121.7 (d), 126.7 (d), 128.4 (d), 129.6 (d), 130.0 (s), 131.1
62.0 (t), 66.2 (t), 98.0 (d), 128.1 (d), 131.7 (d); IR (CHCl3) (cm-1
)
3012, 2946, 1125; MS m/ z (relative intensity) 235 (M)+ (1),
135 (18), 85 (100); HRMS calcd for C9H15O2 (M - 80)+
155.1055, found 155.1072.
P r ep a r a t ion of 7-[(Tet r a h yd r op yr a n -2-yl)oxy]h ep t -
5(E)-en -2-yn -1-ol (21). Ethylmagnesium bromide (32 mL, 1.5
M in THF, 48 mmol) was added dropwise to a solution of
propargyl alcohol (1.36 g, 24.3 mmol) in THF (25 mL) at rt.
The mixture was heated at 40 °C for 50 min and then cooled
again to 0 °C. A catalytic amount of copper(I) chloride (100
mg, 1 mmol) was added to the mixture, followed by 20 (3.8 g,
16.2 mmol). After being warmed to rt and stirred for 12 h,
the reaction mixture was quenched sequentially with water
(10 mL) and a saturated aqueous solution of NH4Cl (100
mL).The aqueous phase was extracted with ether (3 × 50 mL),
and the combined organic extracts were dried over MgSO4,
concentrated, and purified by silica gel chromatography to
afford 21 (2.56 g, 75% yield) as an oil: 1H NMR (CDCl3) δ 1.52
(m, 6 H), 2.88 (m, 2 H), 3.45 (m, 1 H), 3.76 (m, 1 H), 3.91 (m,
1 H), 4.22 (m, 3 H), 4.61 (t, J ) 3.5 Hz, 1 H), 5.67 (m, 1 H),
5.81 (m, 1 H); 13C NMR (CDCl3) δ 19.3 (t), 21.7 (t), 25.4 (t),
30.2 (t), 50.8 (t), 62.0 (t), 67.0 (t), 80.8 (s), 82.7 (s), 97.8 (d),
127.2 (d), 128.1 (d); IR (CHCl3) (cm-1) 3425, 3001, 2943, 1131;
MS m/ z (relative intensity) 210 (M)+ (1), 101 (8), 85 (100);
HRMS calcd for C8H14O2 (M - 68)+ 142.0942, found 142.0915.
P r ep a r a t ion of 7-[(Tet r a h yd r op yr a n -2-yl)oxy]h ep t a -
2(E),5(E)-d ien -1-ol (22). To a stirred suspension of LiAlH4
(d), 133.2 (d), 141.9 (d), 165.5 (s), 166.2 (s); IR (CHCl3) (cm-1
)
2900, 1700, 1660, 1240; MS m/ z (relative intensity) 343 (M -
31)+ (2), 273 (62), 151 (69), 105 (100); HRMS calcd for C21H26O6
(M)+ 374.1668, found 374.1665.
P r ep a r a tion of (1R)-5-Hyd r oxy-1-[2-(m eth oxyca r bo-
n yl)-(E)-vin yl]p en t-3(E)-en yl Ben zoa te (27). The general
procedure for THP cleavage was applied to 26 on a 1.45 g (3.9
mmol) scale, yielding 27 (1.07 g, 95% yield) as an oil: [R]25
)
D
1
-45.1 (c 1.96, CHCl3); H NMR (CDCl3) δ 1.87 (s, 1 H), 2.62
(t, J ) 6.5 Hz, 2 H), 3.77 (s, 3 H), 4.11 (d, J ) 4.9 Hz, 2 H),
5.77 (m, 3 H), 6.09 (dd, J ) 15.8, 1.6 Hz, 1 H), 7.01 (dd, J )
15.8, 5.0 Hz, 1 H), 7.41 (m, 2 H), 7.61 (m, 1 H), 8.08 (m, 2 H);
13C NMR (CDCl3) δ 37.3 (t), 52.2 (q), 63.5 (t), 72.6 (d), 122.0
(d), 125.8 (d), 128.9 (d), 130.0 (s), 133.7 (d), 134.1 (d), 145.3
(d), 165.8 (s), 166.8 (s); IR (CHCl3) (cm-1) 3400, 2900, 1710,
1650; MS m/ z (relative intensity) 291 (M + 1)+ (1), 151 (10),
105 (100); HRMS calcd for C16H18O5 (M)+ 290.1104, found
260.1110.
(31) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399.
P r ep a r a tion of (1R)-1-[2-(Meth oxyca r bon yl)-(Z)-vin yl]-

Intramolecular Hetero-Michael Addition
J . Org. Chem., Vol. 62, No. 14, 1997 4579
-5-[(t et r a h yd r op yr a n -2-yl)oxy]p en t -3(Z)-en yl Ben zoa t e
(28). The general procedure to transform 3-benzoyloxy-1,2-
diols into γ-(benzoyloxy)-(Z)-R,â-unsaturated esters was ap-
plied to diol 24, yielding 28 (2.95 g, 87% yield based on diol
24) as an oil: 1H NMR (CDCl3) δ 1.66 (m, 6 H), 2.67 (t, J )
5.8 Hz, 2 H), 3.49 (m, 2 H), 3.80 (s, 3 H), 3.90 (m, 1 H), 4.21
(m, 1 H), 4.62 (m, 1 H), 5.80 (m, 3 H), 5.94 (dd, J ) 11.6, 0.5
Hz, 1 H), 6.26 (m, 1 H), 7.40 (m, 2 H), 7.60 (m, 1 H), 8.07 (m,
2 H); 13C NMR (CDCl3) δ 19.8 (t), 25.8 (t), 31.0 (t), 37.4 (t),
51.9 (q), 62.6 (t), 67.6 (t), 72.0 (d), 98.0 (d), 120.8 (d), 128.2 (d),
128.33 (s), 128.9 (d), 130.0 (s), 130.7 (d), 133.5 (d) 147.6 (d),
165.5 (s), 166.2 (s); IR (CHCl3) (cm-1) 2900, 1710, 1640, 1440;
MS m/ z (relative intensity) 343 (M - 31)+ (2), 273 (62), 151
(69), 105 (100); HRMS calcd for C21H26O6 (M)+ 374.1668, found
374.1665.
h yd r oxybu tyl)]-3-(m eth oxyca r bon yl)-2(Z)-a llyl Ben zoa te
(35). The general procedure used above for the opening of 2,3-
epoxy 1-alcohols was applied to 32 on a 705 mg (2.3 mmol)
scale, yielding 35 (787 mg, 80% yield) as an oil: [R]25D ) -26.2
1
(c 2.03, CHCl3); H NMR (CDCl3) δ 2.35 (m, 1 H), 2.63 (m, 1
H), 2.90 (br s, 1 H), 3.65 (m, 2 H), 3.75 (s, 3 H), 3.97 (m, 1 H),
5.21 (m, 1 H), 5.89 (dd, J ) 11.3, 1.5 Hz, 1 H), 6.29 (dd, J )
11.1, 6.9 Hz, 1 H), 6.69 (m, 1 H), 7.20 (m, 4 H), 7.42 (m, 2 H),
7.80 (m, 2 H), 7.90 (m, 2 H); 13C NMR (CDCl3) δ 34.6 (t), 52.2
(q), 63.2 (t), 69.3 (d), 71.7 (d), 72.4 (d), 120.5 (d), 128.7 (d), 130.0
(s), 130.3 (s), 133.4 (d), 133.6 (d), 147.5 (s), 148.5 (d), 166.2 (s),
166.7 (s), 167.2 (s); IR (CHCl3) (cm-1) 3450, 1710, 1660, 1430;
MS m/ z (relative intensity) 429 (M + 1)+ (1), 141 (32), 105
(100); HRMS calcd for C23H24O6 (M)+ 428.1392, found 428.1390.
P r ep a r a t ion of (2S,3R,5R,6S)-5-(Ben zoyloxy)-6-(h y-
d r o x y m e t h y l)-2-[(m e t h o x y c a r b o n y l)m e t h y l]t e t r a -
h yd r op yr a n -3-yl Ben zoa te (36). The general cyclization
procedure described was applied to 34 on a 210 mg (0.5 mmol)
scale using 1.1 equiv of NaH (16 mg, 0.54 mmol, 80% in
P r ep a r a tion of (1R)-5-Hyd r oxy-1-[2-(m eth oxyca r bo-
n yl)-(Z)-vin yl]p en t-3(E)-en yl Ben zoa te (29). The general
procedure for THP cleavage was applied to 28 on a 1.39 g (3.7
mmol) scale, yielding 29 (1.02 g, 95% yield) as an oil: [R]25
)
D
1
-60.0 (c 0.99, CHCl3); H NMR (CDCl3) δ 2.39 (s, 1 H), 2.61
(t, J ) 4.2 Hz, 2 H), 3.75 (s, 3 H), 4.06 (d, J ) 2.6 Hz, 2 H),
5.77 (m, 2 H), 5.90 (dd, J ) 11.7, 1.4 Hz, 1 H), 6.23 (dd, J )
11.7, 7.8 Hz, 1 H), 6.48 (m, 1 H), 7.38 (m, 2 H), 7.55 (m, 1 H),
8.02 (m, 2 H); 13C NMR (CDCl3) δ 37.3 (t), 52.0 (q), 63.5 (t),
72.0 (d), 120.8 (d), 126.5 (d), 128.9 (d), 129.8 (d), 130.0 (s), 133.4
(d), 147.3 (d), 165.5 (s), 166.3 (s); IR (CHCl3) (cm-1) 3450, 2900,
1710, 1655; MS m/ z (relative intensity) 291 (M + 1)+ (1), 151
(10), 105 (100); HRMS calcd for C16H18O5 (M)+ 290.1104, found
290.1115.
mineral oil), yielding 36 (150 mg, 71% yield) as an oil: [R]25
D
) +5.0 (c 0.70, CHCl3); 1H NMR (CDCl3) δ 2.25 (m, 1 H), 2.44
(m, 1 H), 2.75 (t, J ) 2.0 Hz, 2 H), 2.90 (m, 1 H), 3.73 (s, 3 H),
4.02 (d, J ) 9.2 Hz, 1 H), 4.10 (m, 1 H), 4.40 (d, J ) 7.6 Hz, 1
H), 5.28 (m, 2 H), 7.46 (m, 4 H), 7.59 (m, 2 H), 8.04 (m, 4 H);
13C NMR (CDCl3) δ 31.5 (t), 36.2 (t), 52.6 (q), 59.9 (t), 68.2 (d),
69.4 (d), 69.7 (d), 75.5 (d), 128.9 (d), 128.9 (d), 130.0 (s), 130.1
(s), 133.6 (d), 133.8 (d), 165.9 (s), 166.1 (s), 172.2 (s); IR (CHCl3)
(cm-1) 3450, 3000, 1710, 1485; MS m/ z (relative intensity) 429
(M + 1)+ (1), 166 (15), 141 (27), 105 (100); HRMS calcd for
C23H23O8 (M - 1)+ 427.1393, found 427.1388.
P r ep a r a t ion of (1R)-1-[(2R,3S)-[3-(Hyd r oxym et h yl)-
oxir a n yl]m et h yl]-3-(m et h oxyca r b on yl)-2(E)-a llyl Ben -
zoa te (30). The general asymmetric epoxidation procedure
using (R,R)-DET as chiral auxiliary was used on 27 on a 1.01
g scale (3.5 mmol) for 2 h, yielding 30 (850 mg, 80% yield) as
an oil: [R]25D ) -55.2 (c 0.64, CHCl3); 1H NMR (CDCl3) δ 2.14
(m, 2 H), 2.96 (m, 1 H), 3.09 (m, 1 H), 3.65 (m, 1 H), 3.75 (s, 3
H), 3.85 (m, 1 H), 5.87 (d, J ) 5.2 Hz, 1 H), 6.12 (dd, J ) 16.0,
1.6 Hz, 1 H), 7.03 (dd, J ) 15.6, 4.8 Hz, 1 H), 7.45 (m, 2 H),
7.58 (m, 1 H), 8.06 (m, 2 H); 13C NMR (CDCl3) δ 36.7 (t), 52.2
(q), 52.5 (d), 52.4 (d), 61.8 (t), 71.2 (d), 122.2 (d), 128.9 (d), 128.9
(d), 129.8 (d), 130.1 (s), 133.8 (d), 144.9 (d), 165.8 (s), 166.6
(s); IR (CHCl3) (cm-1) 3650, 3450, 1720, 1660; MS m/ z (relative
intensity) 307 (M + 1)+ (1), 166 (16), 105 (100); HRMS calcd
for C16H18O6 (M)+ 306.1044, found 306.1045.
P r ep a r a tion of (2S,3R,5R,6S)-6-[(Ben zoyloxy)m eth yl]-
5-h ydr oxy-2-[(m eth oxycar bon yl)m eth yl]tetr ah ydr opyr an -
3-yl Ben zoa te (38). The general cyclization procedure de-
scribed above was applied to 34 on a 200 mg (0.47 mmol) scale
using 2.1 equiv of NaH (30 mg, 1.0 mmol, 80% in mineral oil),
yielding 38 (150 mg, 75% yield) as an oil: [R]25D ) +5.0 (c 0.7,
1
CHCl3); H NMR (CDCl3) δ 2.02 (m, 1 H), 2.30 (m, 1 H), 2.65
(dd, J ) 14.8, 5.2 Hz, 1 H), 2.88 (dd, J ) 14.8, 9.6 Hz, 1 H),
3.05 (d, J ) 4.7 Hz, 1 H), 3.71 (s, 3 H), 3.85 (m, 1 H), 3.95 (m,
1 H), 4.41 (dd, J ) 12.1, 2.0 Hz, 1 H), 4.89 (dd, J ) 12.1, 4.1
Hz, 1 H), 5.22 (m, 2 H), 7.28 (m, 2 H), 7.45 (m, 3 H), 7.60 (m,
1 H), 7.93 (m, 2 H), 8.10 (m, 2 H); 13C NMR (CDCl3) δ 32.4 (t),
35.7 (t), 52.4 (q), 63.2 (d), 64.2 (t), 71.2 (d), 72.5 (d), 74.5 (d),
128.7 (d), 128.9 (d), 130.0 (s), 130.3 (d), 133.6 (d), 133.8 (d),
165.9 (s), 166.1 (s), 172.2 (s); IR (CHCl3) (cm-1) 3450, 3000,
1710, 1470; MS m/ z (relative intensity) 429 (M + 1)+ (1), 397
(3), 141 (27), 105 (100), 77 (20); HRMS calcd for C23H23O8 (M
- 1)+ 427.1393, found 427.1388.
P r ep a r a t ion of (1R)-1-[(2R,3S)-[3-(Hyd r oxym et h yl)-
oxir a n yl]m et h yl]-3-(m et h oxyca r b on yl)-2(Z)-a llyl Ben -
zoa te (32). The general asymmetric epoxidation procedure
using (R,R)-DET as chiral auxiliary was used on 29 on a 950
mg scale (3.3 mmol) for 2 h, yielding 32 (793 mg, 79% yield)
P r epar ation (2S,3R,5R)-5-[2(S)-(Ben zoyloxy)-1-h ydr oxy-
eth yl]-2-[(m eth oxyca r bon yl)m eth yl]tetr a h yd r o-fu r a n -3-
yl Ben zoa te (40). The general cyclization procedure de-
scribed above was applied to 35 on a 250 mg (0.6 mmol) scale
using NaH (36 mg, 1.2 mmol, 80% in mineral oil), yielding 38
(32 mg, 13% yield) and 40 (199 mg, 80% yield) both as oils.
Compound 40: [R]25D ) -6.1 (c 0.34, CHCl3); 1H NMR (CDCl3)
δ 2.40 (m, 1 H), 2.58 (m, 1 H), 2.68 (m, 2 H), 3.71 (s, 3 H), 4.17
(br s, 1 H), 4.26 (t, J ) 6.1 Hz, 1 H), 4.39 (dd, J ) 11.7, 6.2 Hz,
1 H), 4.55 (dd, J ) 11.8, 3.6 Hz, 1 H), 4.60 (m, 1 H), 5.37 (m,
1 H), 7.45 (m, 4 H), 7.58 (m, 2 H), 8.04 (m, 4 H); 13C NMR
(CDCl3) δ 32.8 (t), 38.3 (t), 52.3 (q), 66.6 (t), 71.6 (d), 78.5 (d),
78.7 (d), 80.9 (d), 128.8 (d), 128.9 (s), 129.0 (s), 130.0 (s), 130.1
(s), 133.7 (d), 133.7 (d), 166.5 (s), 167.3 (s), 171.1 (s); IR (CHCl3)
(cm-1) 3450, 3000, 1710, 1470; MS m/ z (relative intensity) 429
(M + 1)+ (1), 105 (100), 84 (100); HRMS calcd for C23H23O8 (M
- 1)+ 427.1393, found 427.1388.
1
as an oil: [R]25 ) -43.7 (c 2.53, CHCl3); H NMR (CDCl3) δ
D
1.99 (s, 1 H), 2.10 (m, 1 H), 2.25 (m, 1 H), 3.10 (m, 1 H), 3.20
(m, 1 H), 3.67 (dd, J ) 11.7, 4.1 Hz, 1 H), 3.81 (s, 3 H), 3.91
(dd, J ) 12.2, 2.9 Hz, 1 H), 5.99 (d, J ) 11.6 Hz, 1 H), 6.36
(dd, J ) 11.6, 7.7 Hz, 1 H), 7.50 (m, 2 H), 7.62 (m, 1 H), 8.09
(m, 2 H); 13C NMR (CDCl3) δ 37.0 (t), 52.1 (q), 53.3 (d), 58.2
(d), 62.0 (t), 71.0 (d), 120.9 (d), 121.2 (s), 128.9 (d), 130.1 (s),
133.7 (d), 147.4 (d), 165.5 (s), 166.6 (s); IR (CHCl3) (cm-1) 3450,
1710, 1640, 1100; MS m/ z (relative intensity) 307 (M + 1)+
(1), 166 (16), 105 (100), 77 (80); HRMS calcd for C16H18O6 (M)+
306.1044, found 306.1050.
P r ep a r a tion of (1R)-1-[(2R,3S)-2-(Ben zoyloxy)-3,4-d i-
h yd r oxybu tyl]-3-[(m eth oxyca r bon yl)-2(E)-a llyl Ben zoa te
(34). The general procedure to obtain 3-benzoyloxy 1,2-diols
was applied to 30 on a 840 mg scale (2.7 mmol), yielding 34
(1.0 g, 87% yield) as an oil: [R]25 ) +26.0 (c 1.12, CHCl3); 1H
D
NMR (CDCl3) δ 2.31 (m, 1 H), 2.55 (m, 1 H), 3.15 (br s, 2 H),
3.60 (m, 1 H), 3.74 (s, 3 H), 3.77 (m, 2 H), 5.23 (m, 1 H), 5.86
(m, 1 H), 6.06 (dd, J ) 15.7, 1.6 Hz, 1 H), 7.00 (dd, J ) 15.7,
5.0 Hz, 1 H), 7.49 (m, 4 H), 7.52 (m, 2 H), 7.94 (m, 4 H); 13C
NMR (CDCl3) δ 34.6 (t), 51.6 (q), 62.4 (t), 69.8 (d), 70.6 (d),
72.6 (d), 121.5 (d), 129.2 (d), 129.5 (d), 130.0 (s), 133.2 (d), 133.3
P r ep a r a t ion of (2S,3S,5R,6S)-5-(Ben zyloxy)-6-[(ter t-
b u t yld ip h e n ylsiloxy)m e t h yl]-2-[(m e t h oxyca r b on yl)-
m eth yl]tetr a h yd r op yr a n -3-yl Ben zoa te (51). The general
cyclization method was applied to 47 on a 75 mg (0.11 mmol)
scale to afford 51 (68 mg, 91% yield) as an oil: [R]25 ) -21.7
D
(c 0.82, CHCl3); 1H NMR (C6D6) δ 1.24 (s, 9 H), 1.85 (ddd, J )
12.9, 9.1, 9.1 Hz, 1 H), 2.20 (ddd, J ) 12.9, 4.6, 4.6 Hz, 1 H),
2.62 (dd, J ) 15.3, 5.8 Hz, 1 H), 2.80 (dd, J ) 15.3, 8.4 Hz, 1
H), 3.33 (s, 3 H), 3.54 (m, 1 H), 3.86 (m, 1 H), 4.00 (d, J ) 3.6
Hz, 2 H), 4.21 (d, J ) 11.7 Hz, 1 H), 4.35 (d, J ) 11.7 Hz, 1 H),
4.79 (m, 1 H), 5.33 (ddd, J ) 9.1, 4.6, 4.6 Hz, 1 H), 7.08 (m, 2
(d), 145.0 (d), 165.3 (s), 166.2 (s), 166.5 (s); IR (CHCl3) (cm-1
)
3450, 1710, 1660, 1100; MS m/ z (relative intensity) 429 (M +
1)+ (1), 166 (37), 141 (86), 105 (100); HRMS calcd for C23H24O8
(M)+ 428.1392, found 428.1395.
P r ep a r a tion of (1R)-1-[(2R,3S)-2-(Ben zoyloxy)-3,4-d i-

4580 J . Org. Chem., Vol. 62, No. 14, 1997
Betancort et al.
H), 7.19 (m, 6 H), 7.29 (m, 6 H), 7.88 (m, 4 H), 8.16 (m, 2 H);
13C NMR (C6D6) δ 19.2 (s), 26.8 (q), 29.4 (t), 33.5 (t), 51.0 (q),
63.6 (t), 68.4 (d), 69.9 (d), 70.5 (t), 71.5 (d), 74.7 (d), 129.7 (d),
129.8 (d), 130.4 (s), 132.7 (d), 133.5 (s), 133.7 (s), 135.8 (d),
135.9 (d), 138.7 (s), 165.1 (s), 170.4 (s); IR (CHCl3) (cm-1) 3018,
2954, 1730, 1274; MS m/ z (relative intensity) 595 (M - 57)+
(1), 105 (77), 91 (100). Anal. Calcd for C39H44O7Si: C, 71.75;
H, 6.79. Found: C, 71.53; H, 6.80.
p yr a n -3-ol (74). The general method for the reduction of
esters was applied to 13 on a 2.26 g (8 mmol) scale using
LiAlH4 (12 mL, 1.0 M in ether, 12 mmol) to afford 74 (850 mg,
73% yield) as a solid: mp ) 58-59 °C; [R]25 ) -32.3 (c 2.03,
D
1
CHCl3); H NMR (CDCl3) δ 1.38 (m, 1 H), 1.60 (m, 2 H), 1.76
(m, 1 H), 2.01 (m, 1 H), 2.08 (dd, J ) 12.0, 2.4 Hz, 1 H), 3.16
(m, 1 H), 3.29 (m, 2 H), 3.34 (br s, 1 H), 3.77 (m, 2 H), 3.87 (d,
J ) 10.8 Hz, 1 H); 13C NMR (CDCl3) δ 25.4 (t), 32.5 (t), 35.3
(t), 60.5 (t), 67.6 (t), 70.1 (d), 82.5 (d); IR (CHCl3) (cm-1) 3619,
3413, 2942, 1090; MS m/ z (relative intensity) 147 (M + 1)+
(3), 128 (41), 89 (48), 75 (100). Anal. Calcd for C7H14O3: C,
57.50; H, 9.66. Found: C, 57.17; H, 9.58.
Gen er a l Met h od for Ben zoyla t ion . P r ep a r a t ion of
2-[(2S,3R)-3-H yd r oxyt et r a h yd r op yr a n -2-yl]et h yl Ben -
zoa te (75). To a solution of diol 74 (850 mg, 6 mmol) in dry
CH2Cl2 (58 mL) were sequentially added Et3N (4 mL, 29 mmol)
and benzoyl chloride (1.4 mL, 12 mmol) at 0 °C. The reaction
was stirred for 1 h, after which time TLC showed complete
conversion. Then the mixture was washed with a 5% HCl
aqueous solution (50 mL), a saturated aqueous solution of
P r ep a r a tion of (2R,3S,5R,6S)-5-(Ben zyloxy)-6-[(ter t-
b u t yld ip h e n ylsiloxy)m e t h yl]-2-[(m e t h oxyca r b on yl)-
m eth yl]tetr a h yd r op yr a n -3-yl Ben zoa te (52). The general
cyclization method was applied to 48 on a 96 mg (0.15 mmol)
scale to afford 52 (84 mg, 88% yield) as an oil: [R]25 ) -0.7
D
1
(c 1.13, CHCl3); H NMR (CDCl3) δ 1.07 (s, 9 H), 1.69 (ddd, J
) 11.4, 11.4, 11.4 Hz, 1 H), 2.56 (dd, J ) 15.4, 8.2 Hz, 1 H),
2.67 (dd, J ) 15.4, 4.0 Hz, 1 H), 2.87 (ddd, J ) 11.4, 4.7, 4.7
Hz, 1 H), 3.46 (m, 1 H), 3.6 (s, 3 H), 3.84 (m, 1 H), 3.95 (d, J
) 3.2 Hz, 2 H), 4.05 (m, 1 H), 4.53 (d, J ) 11.3 Hz, 1 H), 4.67
(d, J ) 11.3 Hz, 1 H), 4.88 (m, 1 H), 7.28 (m, 4 H), 7.42 (m, 9
H), 7.59 (m, 1 H), 7.73 (m, 4 H), 8.04 (m, 2 H); 13C NMR (CDCl3)
δ 19.3 (s), 26.7 (q), 26.8 (q), 35.2 (t), 37.8 (t), 51.7 (q), 62.9 (t),
71 (d), 71.6 (t), 71.7 (d), 75.9 (d), 81.4 (d), 127.5 (d), 127.6 (d),
127.7 (d), 128.4 (d), 129.5 (d), 129.7 (d), 130.0 (s), 133.3 (d),
133.4 (d), 133.8 (s), 135.6 (d), 135.8 (d), 138.0 (s), 165.5 (s),
171.2 (s); IR (CHCl3) (cm-1) 3020, 2954, 1720, 1274; MS m/ z
(relative intensity) 595 (M - 57)+ (1), 199 (23), 163 (28), 105
(100). Anal. Calcd for C39H44O7Si: C, 71.75; H, 6.79. Found:
C, 71.43; H, 6.96.
P r ep a r a tion of (2S,3R,5R,6S)-5-(Ben zyloxy)-6-[(ter t-
b u t yld ip h e n ylsiloxy)m e t h yl]-2-[(m e t h oxyca r b on yl)-
m eth yl]tetr a h yd r op yr a n -3-yl Ben zoa te a n d Ben zoic a cid
(2R,3R,5R,6S)-5-(Ben zyloxy)-6-[(ter t-bu tyldiph en ylsiloxy)-
m eth yl]-2-[(m eth oxyca r bon yl)m eth yl]tetr a h yd r op yr a n -
3-yl Ester (53 + 54). The general cyclization method was
applied to 49 on a 100 mg (0.15 mmol) scale to afford 53 + 54
(90 mg, 90% yield) as an oil: 1H NMR (C6D6) δ 1.24 (s, 9 H),
1.28 (s, 9 H), 1.95 (m, 2 H), 2.25 (m, 2 H), 2.33 (dd, J ) 14.8,
5.1 Hz, 1 H), 2.50 (dd, J ) 14.9, 5.4 Hz, 1 H), 2.62 (dd, J )
14.8, 9.1 Hz, 1 H), 2.73 (dd, J ) 14.9, 8.1 Hz, 1 H), 3.35 (s, 3
H), 3.40 (s, 3 H), 3.85 (m, 1 H), 3.99 (m, 4 H), 4.11 (m, 2 H),
4.29 (d, J ) 11.9 Hz, 1 H), 4.37 (d, J ) 11.9 Hz, 2 H), 4.46 (d,
J ) 11.9 Hz, 1 H), 4.67 (m, 1 H), 5.32 (m, 1 H), 5.36 (m, 1 H),
7.10-7.36 (m, 30H), 7.84 (m, 2 H), 7.90 (m, 4 H), 8.01 (m, 1
H), 8.24 (m, 2 H), 8.30 (m, 1 H); 13C NMR (C6D6) δ 19.3 (s),
19.4 (s), 26.8 (q), 29.8 (t), 29.9 (t), 36.0 (t), 36.5 (t), 51.0 (q),
63.3 (t), 63.4 (t), 70.6 (d), 70.7 (d), 71.0 (t), 71.9 (d), 74.7 (d),
74.8 (d), 81.5 (d), 127.0 (d), 127.5 (d), 127.6 (d), 127.7 (d), 128.0
(d), 128.1 (d), 128.2 (d), 128.3 (d), 128.4 (d), 128.6 (d), 129.1
(d), 129.5 (d), 129.6 (d), 129.7 (d), 129.8 (d), 130.4 (s), 130.6
(s), 132.8 (d), 132.9 (d), 133.3 (d), 133.6 (d), 133.7 (d), 135.7
(d), 136.0 (d), 136.1 (d), 138.7 (s), 165.2 (s), 165.4 (s), 170.1 (s),
170.3 (s); IR (CHCl3) (cm-1) 3020, 2954, 2932, 1730; MS m/ z
(relative intensity) 595 (M - 57)+ (1), 199 (25), 167 (21), 105
(100). Anal. Calcd for C39H44O7Si: C, 71.75; H, 6.79. Found:
C, 71.54, H, 6.82.
NaHCO3
(50 mL), and brine (50 mL). The organic layer was
dried over MgSO4, filtered, and concentrated. Purification by
silica gel column chromatography provided pure ester 75 (1.35
g, 93% yield) as an oil: [R]25D ) -35.7 (c 2.00, CHCl3); 1H NMR
(CDCl3) δ 1.41 (m, 1 H), 1.65 (m, 2 H), 1.86 (m, 1 H), 2.10 (dd,
J ) 12.4, 3.2 Hz, 1 H), 2.35 (m, 1 H), 2.82 (br s, 1 H), 3.19
(ddd, J ) 8.8, 8.8, 2.8 Hz, 1 H), 3.33 (m, 2 H), 3.87 (dd, J )
10.4, 1.6 Hz, 1 H), 4.46 (m, 2 H), 7.40 (m, 2 H), 7.52 (m, 1 H),
8.03 (m, 2 H); 13C NMR (CDCl3) δ 25.6 (t), 31.4 (t), 32.9 (t),
61.9 (t), 67.5 (t), 70.3 (d), 79.4 (d), 128.3 (d), 129.5 (d), 130.3
(s), 132.8 (d), 166.7 (s); IR (CHCl3) (cm-1) 3477, 2944, 1716,
1271; MS m/ z (relative intensity) 251 (M + 1)+ (1), 110 (42),
105 (100). Anal. Calcd for C14H18O4: C, 67.17; H, 7.25.
Found: C, 67.02; H, 7.18.
Gen er a l Meth od for Silyl P r otection . P r ep a r a tion of
2-[(2S,3R)-3-(ter t-Bu tyld ip h en ylsiloxy)tetr a h yd r op yr a n -
2-yl]eth yl Ben zoa te (76). To a stirred solution of 75 (1.2 g,
4.8 mmol) in dry CH2Cl2 (25 mL) under argon were added
imidazole (652 mg, 9.6 mmol) and tert-butylchlorodiphenylsi-
lane (1.4 mL, 5.3 mmol) sequentially added at rt. After 12 h
TLC showed complete conversion. Then the mixture was
diluted with CH2Cl2 (25 mL) and washed with a 5% HCl
aqueous solution (50 mL) and brine (50 mL). The organic layer
was dried over MgSO4, filtered, and concentrated, and the
crude was purified by silica gel column chromatography to
yield 76 (1.98 g, 85% yield) as an oil: [R]25 ) -23.1 (c 2.12,
D
1
CHCl3); H NMR (CDCl3) δ 1.06 (s, 9 H), 1.44 (m, 3 H), 1.58
(m, 1 H), 1.85 (m, 1 H), 2.44 (m, 1 H), 3.28 (dd, J ) 11.0 Hz,
1 H), 3.33 (dd, J ) 9.0, 9.0 Hz, 1 H), 3.41 (m, 1 H), 3.78 (d, J
) 11.0 Hz, 1 H), 4.40 (m, 2 H), 7.40 (m, 8 H), 7.57 (m, 1 H),
7.69 (m, 4 H), 8.07 (m, 2 H); 13C NMR (CDCl3) δ 19.3 (s), 25.5
(t), 27.0 (q), 31.6 (t), 33.3 (t), 62.0 (t), 67.6 (t), 72.2 (d), 79.5
(d), 127.4 (d), 127.7 (d), 128.3 (d), 129.6 (d), 129.7 (d), 130.7
(s), 132.7 (d), 133.6 (s), 134.5 (s), 135.9 (d), 166.6 (s); IR (CHCl3)
(cm-1) 3073, 2961, 1715, 1270; MS m/ z (relative intensity) 431
(M - 57)+ (21), 309 (25), 303 (100), 105 (100). Anal. Calcd
P r ep a r a tion of (2R,3R,5R,6S)-5-(Ben zyloxy)-6-[(ter t-
b u t yld ip h e n ylsiloxy)m e t h yl]-2-[(m e t h oxyca r b on yl)-
m eth yl]tetr a h yd r op yr a n -3-yl Ben zoa te (54). The general
cyclization method was applied to 50 on a 100 mg (0.15 mmol)
for C30
H36O4Si: C, 73.73; H, 7.43. Found: C, 73.64; H, 7.36.
Gen er a l Meth od for Ben zoa te Clea va ge. P r ep a r a tion
of 2-[(2S,3R)-3-(ter t-Bu tyldiph en ylsiloxy)tetr ah ydr opyr an -
2-yl]eth a n ol (77). To a stirred solution of 76 (1.8 g, 3.7 mmol)
in dry CH2Cl2 (40 mL) were added NaH (125 mg, 4.1 mmol,
80% in mineral oil) and dry MeOH (0.25 mL, 7.4 mmol) at rt.
After 5 min the reaction mixture was quenched with a
saturated aqueous solution of NH4Cl (40 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 15 mL), and the
combined organic extracts were dried over MgSO4, concen-
trated, and purified by silica gel chromatography to afford 77
scale to afford 54 (91 mg, 91% yield) as an oil: [R]25 ) +19.3
D
(c 0.50, CHCl3); 1H NMR (C6D6) δ 1.24 (s, 9 H), 1.95 (m, 1 H),
2.25 (m, 1 H), 2.33 (dd, J ) 14.8, 5.1 Hz, 1 H), 2.62 (dd, J )
14.8, 9.1 Hz, 1 H), 3.35 (s, 3 H), 3.85 (m, 1 H), 3.99 (m, 2 H),
4.10 (m, 1 H), 4.36 (d, J ) 11.8 Hz, 1 H), 4.46 (d, J ) 11.8 Hz,
1 H), 4.68 (m, 1 H), 5.31 (m, 1 H), 7.21 (m, 8 H), 7.30 (m, 5 H),
7.76 (m, 1 H), 7.84 (m, 2 H), 7.90 (m, 2 H), 8.25 (m, 2 H); 13C
NMR (CDCl3) δ 19.3 (s), 26.8 (q), 29.8 (t), 36.0 (t), 51.0 (q),
63.4 (t), 70.6 (t), 71.0 (d), 71.9 (d), 74.8 (d), 81.5 (d), 127.5 (d),
127.6 (d), 127.7 (d), 128.0 (d), 128.1 (d), 128.2 (d), 128.3 (d),
128.4 (d), 129.5 (d), 129.6 (d), 129.8 (d), 130.6 (d), 132.8 (s),
135.7 (d), 135.9 (d), 136.1 (d), 138.7 (s), 165.5 (s), 171.2 (s); IR
(CHCl3) (cm-1) 3020, 2954, 1730, 1274; MS m/ z (relative
intensity) 595 (M - 57)+ (1), 243 (10), 199 (25), 105 (100). Anal.
Calcd for C39H44O7Si: C, 71.75; H, 6.79. Found: C, 71.50, H,
6.95.
(1.36 g, 96% yield) as an oil: [R]25 ) -27.9 (c 2.05, CHCl3);
D
1H NMR (CDCl3) δ 1.03 (s, 9 H), 1.41 (m, 2 H), 1.59 (m, 1 H),
1.81 (m, 1 H), 2.16 (m, 1 H), 2.71 (m, 1 H), 3.29 (m, 1 H), 3.43
(m, 2 H), 3.72 (m, 2 H), 3.79 (dd, J ) 9.3, 2.0 Hz, 1 H), 7.40
(m, 6 H), 7.67 (m, 4 H); 13C NMR (CDCl3) δ 19.3 (s), 25.3 (t),
27.0 (q), 33.1 (t), 33.9 (t), 61.7 (t), 67.6 (t), 71.8 (d), 83.7 (d),
127.5 (d), 127.7 (d), 129.6 (d), 129.8 (d), 133.5 (s), 134.5 (s),
135.9 (d); IR (CHCl3) (cm-1) 3510, 3071, 2954, 1471; MS m/ z
(relative intensity) 327 (M - 57)+ (19), 269 (43), 249 (31), 199
P r ep a r a tion of (2S,3R)-2-(2-Hyd r oxyeth yl)tetr a h yd r o-

Intramolecular Hetero-Michael Addition
J . Org. Chem., Vol. 62, No. 14, 1997 4581
(100). Anal. Calcd for C23H32O3Si: C, 71.84; H, 8.39. Found:
C, 71.89; H, 8.52.
1 H), 6.06 (d, J ) 15.7 Hz, 1 H), 7.00 (dd, J ) 15.7, 5.6 Hz, 1
H), 7.40 (m, 8 H), 7.57 (m, 1 H), 7.66 (m, 4 H), 8.04 (m, 2 H);
13C NMR (CDCl3) δ 19.2 (s), 25.3 (t), 27.0 (s), 33.2 (t), 36.7 (t),
51.6 (q), 67.3 (t), 71.2 (d), 72.1 (d), 79.4 (d), 121.2 (d), 127.5
(d), 127.7 (d), 128.3 (d), 129.6 (d), 130.2 (s), 133.0 (d), 133.5
(s), 134.2 (s), 135.9 (d), 145.6 (d), 165.4 (s), 166.5 (s); IR (CHCl3)
(cm-1) 3075, 2957, 1719, 1659; MS m/ z (relative intensity) 515
(M - 57)+ (4), 303 (48), 105 (100). Anal. Calcd for C34H40O6-
Si C, 71.30; H, 7.04. Found C, 71.05; H, 7.19.
Gen er a l Meth od for Silyl Clea va ge. P r ep a r a tion of
(1R)-1-[[(2S,3R)-3-Hyd r oxytetr a h yd r op yr a n -2-yl]m eth yl]-
-3-(m eth oxyca r bon yl)-(E)-a llyl Ben zoa te (90). To a stirred
mixture of 89 (750 mg, 1.3 mmol) in CH3CN (10 mL) was added
HF (3 mL, 48% in aqueous solution) at rt. The reaction was
stirred for 12 h, until TLC showed complete conversion. The
mixture was diluted with CH2Cl2 (50 mL) and washed with
water (2 × 50 mL) and brine (50 mL). The organic layer was
dried over MgSO4, concentrated, and purified by column
P r ep a r a tion of Meth yl 4-[(2S,3R)-3-(ter t-Bu tyld ip h e-
n ylsiloxy)tetr ah ydr opyr an -2-yl]bu t-2(E)-en oate (79). The
general method for the preparation of (E)-R,â-unsaturated
esters was applied to 77 on a 1.1 g (2.9 mmol) scale to afford
79 (1.1 g, 89% yield) as an oil: [R]25 ) +2.41 (c 2.24, CHCl3);
D
1H NMR (CDCl3) δ 1.10 (s, 9 H), 1.48 (m, 3 H), 1.85 (m, 1 H),
2.17 (ddd, J ) 15.2, 7.6, 7.6 Hz, 1 H), 2.81 (dd, J ) 15.2, 2.0
Hz, 1 H), 3.28 (m, 2 H), 3.38 (m, 1 H), 3.72 (s, 3 H), 3.78 (d, J
) 11.3 Hz, 1 H), 5.83 (d, J ) 15.7 Hz, 1 H), 6.98 (ddd, J )
15.7, 7.1, 7.1 Hz, 1 H), 7.41 (m, 6 H), 7.68 (m, 4 H); 13C NMR
(CDCl3) δ 19.3 (s), 25.4 (t), 27.0 (q), 33.3 (t), 35.0 (t), 51.3 (q),
67.7 (t), 71.9 (d), 81.4 (d), 122.6 (d), 127.4 (d), 127.7 (d), 129.7
(d), 129.8 (d), 133.4 (s), 134.3 (s), 135.7 (d), 135.9 (d), 146.6
(d), 166.9 (s); IR (CHCl3) (cm-1) 3009, 2952, 2859, 1717; MS
m/ z (relative intensity) 381 (M - 57)+ (100), 213 (35), 199 (55).
Anal. Calcd for C26H34O4Si: C, 71.20; H, 7.82. Found: C,
71.34; H, 7.83.
chromatography to afford 90 (400 mg, 92% yield) as an oil:
1
[R]25 ) -58.1 (c 1.93, CHCl3); H NMR (CDCl3) δ 1.38 (m, 1
P r ep a r a tion of 4-[(2S,3R)-3-(ter t-Bu tyld ip h en ylsiloxy)-
tetr a h yd r op yr a n -2-yl]bu t-2(E)-en -1-ol (80). The general
method for reduction of esters was applied to 79 on a 1.1 g
(2.5 mmol) scale using DIBAL (5.6 mL, 1.0 M in hexane, 5.6
mmol) to afford 80 (800 mg, 78% yield) as an oil: [R]25D ) -10.2
D
H), 1.63 (m, 2 H), 2.04 (m, 2 H), 2.18 (br s, 1 H), 2.31 (m, 1 H),
3.14 (ddd, J ) 8.8, 8.8, 2.8 Hz, 1 H), 3.24 (m, 2 H), 3.34 (m, 1
H), 3.72 (s, 3 H), 3.81 (m, 1 H), 5.89 (m, 1 H), 6.07 (d, J ) 15.7
Hz, 1 H), 7.03 (dd, J ) 15.7, 5.5 Hz, 1 H), 7.43 (m, 2 H), 7.55
(m, 1 H), 8.04 (m, 2 H); 13C NMR (CDCl3) δ 25.5 (t), 32.9 (t),
36.6 (t), 51.7 (q), 67.5 (t), 70.8 (d), 71.0 (d), 79.2 (d), 121.2 (d),
128.4 (d), 129.7 (d), 129.9 (s), 133.1 (d), 145.5 (d), 165.6 (s),
166.5 (s); IR (CHCl3) (cm-1) 3529, 2948, 1718, 1659; MS m/ z
(relative intensity) 335 (M + 1)+ (1), 213 (39), 105 (99), 71 (100).
Anal. Calcd for C18H22O6 C, 64.64; H, 6.64. Found C, 64.42;
H, 6.76.
1
(c 2.08, CHCl3); H NMR (CDCl3) δ 1.45 (m, 2 H), 1.62 (m, 1
H), 1.81 (m, 1 H), 2.07 (m, 1 H), 2.70 (m, 1 H), 3.24 (m, 2 H),
3.38 (m, 1 H), 3.78 (d, J ) 11.2 Hz, 1 H), 4.05 (d, J ) 3.9 Hz,
2 H), 5.65, (m, 2 H), 7.39 (m, 6 H), 7.68 (m, 4 H); 13C NMR
(CDCl3) δ 19.3 (s), 25.4 (t), 27.0 (q), 33.3 (t), 34.9 (t), 63.6 (t),
67.6 (t), 71.8 (d), 82.2 (d), 127.4 (d), 127.6 (d), 129.6 (d), 129.7
(d), 131.0 (d), 133.6 (s), 134.5 (s), 136.0 (d); IR (CHCl3) (cm-1
)
3458, 3071, 2944, 1684; MS m/ z (relative intensity) 353 (M -
57)+ (4), 299 (28), 199 (100), 105 (100), 77 (37). Anal. Calcd
for C25H34O3Si: C, 73.13; H, 8.35. Found: C, 73.18; H, 8.36.
P r ep a r a t ion of (2R,3S)-{3-[[(2S,3R)-3-(ter t-Bu t yld i-
p h en ylsiloxy)t et r a h yd r op yr a n -2-yl]m et h yl]oxir a n yl}-
m eth a n ol (87). The general asymmetric epoxidation proce-
dure using as chiral auxiliary (R,R)-(+)-DET was used on 80
on a 1.6 g (3.9 mmol) scale for 2 h, yielding 87 (1.3 g, 80%
P r ep a r a tion of (1R)-1-[[(2S,3R)-3-(ter t-Bu tyld ip h en yl-
siloxy)t et r a h yd r op yr a n -2-yl]m et h yl]-3-(m et h oxyca r b o-
n yl)-(Z)-a llyl Ben zoa te (91). The general procedure to
transform 3-benzoyloxy 1,2-diols into γ-(benzoyloxy)-(Z)-R,â-
unsaturated esters was applied to 88 on a 1.2 g (2.8 mmol)
scale, yielding 91 (1.2 g, 75% yield) as an oil: [R]25 ) -30.7
D
1
(c 1.98, CHCl3); H NMR (CDCl3) δ 1.04 (s, 9 H), 1.75 (m, 1
H), 1.44 (m, 3 H), 1.79 (m, 1 H), 2.52 (dd, J ) 14.5, 6.3 Hz, 1
H), 3.23 (dd, J ) 10.7,10.7 Hz, 1 H), 3.43 (m, 2 H), 3.67 (d, J
) 11.4 Hz, 1 H), 3.76 (s, 3 H), 5.89 (d, J ) 11.7 Hz, 1 H), 6.27
(dd, J ) 11.7, 8.4 Hz, 1 H), 6.68 (m, 1 H), 7.36 (m, 4 H), 7.43
(m, 4 H), 7.54 (m, 1 H), 7.68 (m, 4 H), 8.05 (m, 2 H); 13C NMR
(CDCl3) δ 19.3 (s), 25.3 (t), 27.0 (q), 33.2 (t), 36.5 (t), 51.4 (q),
67.2 (d), 70.3 (d), 71.9 (d), 79.8 (d), 119.9 (d), 127.4 (d), 127.6
(d), 128.3 (d), 129.6 (d), 130.6 (s), 132.7 (d), 133.6 (s), 134.5
yield) as an oil: [R]25 ) -34.4 (c 2.15, CHCl3); 1H NMR
D
(CDCl3) δ 1.04 (s, 9 H), 1.47 (m, 3 H), 1.85 (m, 2 H), 2.09 (m,
1 H), 2.87 (m, 1 H), 3.08 (m, 1 H), 3.31 (dd, J ) 11.3, 11.3 Hz,
1 H), 3.37 (m, 2 H), 3.57 (d, J ) 11.2 Hz, 1 H), 3.79 (m, 1 H),
3.85 (d, J ) 12.7 Hz, 1 H), 7.40 (m, 6 H), 7.67 (m, 4 H); 13C
NMR (CDCl3) δ 19.2 (s), 25.5 (t), 26.9 (q), 33.3 (t), 34.6 (t), 53.3
(d), 59.0 (d), 61. 8 (t), 67.6 (t), 72.2 (d), 80.0 (d), 127.4 (d), 127.6
(s), 135.8 (d), 147.0 (d), 165.7 (s), 165.8 (s); IR (CHCl3) (cm-1
)
(d), 129.8 (d), 133.5 (s), 134.4 (s), 135.9 (d); IR (CHCl3) (cm-1
)
3071, 2955, 1719, 1652; MS m/ z (relative intensity) 515 (M -
57)+ (30), 303 (52), 105 (100). Anal. Calcd for C34H40O6Si C,
71.30; H, 7.04. Found C, 71.23; H, 7.29.
3510, 3077, 2935, 1729; MS m/ z (relative intensity) 369 (M -
57)+ (3), 199 (100), 135 (48), 97 (73). Anal. Calcd for C25H34O4-
Si C, 70.39; H, 8.04. Found C, 70.34; H, 8.26.
P r ep a r a t ion of (1R,2R)-1-[[(2S,3R)-3-(ter t-Bu t yld i-
p h e n y ls ilo x y )t e t r a h y d r o p y r a n -2-y l]m e t h y l]-2,3-d i-
h yd r oxyp r op yl Ben zoa te (88). The general procedure for
the opening of 2,3-epoxy 1-alcohols was applied to 87 on a 1.2
P r ep a r a tion of (1R)-1-[[(2S,3R)-3-Hyd r oxytetr a h yd r o-
p yr a n -2-yl]m eth yl]-3-(m eth oxyca r bon yl)-(Z)-a llyl Ben -
zoa te (92). Using the procedure described above to cleave silyl
ethers, 91 (835 mg, 1.46 mmol) yielded 92 (458 mg, 94% yield)
1
g (2.8 mmol) scale, yielding 88 (1.34 g, 87% yield) as an oil:
as an oil: [R]25 ) -54.0 (c 2.08, CHCl3); H NMR (CDCl3) δ
D
1
[R]25 ) -38.0 (c 2.07, CHCl3); H NMR (CDCl3) δ 1.00 (s, 9
1.42 (m, 1 H), 1.64 (m, 2 H), 2.08 (m, 2 H), 2.30 (ddd, J ) 14.6,
4.4, 4.4 Hz, 1 H), 2.67 (br s, 1 H), 3.28 (m, 2 H), 3.40 (m, 1 H),
3.75 (s, 3 H), 3.81 (d, J ) 9.9 Hz, 1 H), 5.88 (d, J ) 11.6 Hz,
1 H), 6.29 (dd, J ) 11.6, 7.8 Hz, 1 H), 6.62 (dd, J ) 12.4, 7.5
Hz, 1 H), 7.43 (m, 2 H), 7.55 (m, 1 H), 8.04 (m, 2 H); 13C NMR
(CDCl3) δ 25.5 (t), 32.6 (t), 37.8 (t), 51.7 (q), 67.5 (t), 70.8 (d),
71.0 (d), 79.4 (d), 119.7 (d), 128.3 (d), 129.6 (d), 130.2 (s), 133.0
(d), 148.1 (d), 166.0 (s), 166.2 (s); IR (CHCl3) (cm-1) 3516, 2948,
1716, 1645; MS m/ z (relative intensity) 335 (M + 1)+ (2), 213
(76), 105 (100), 77 (100). Anal. Calcd for C18H22O6 C, 64.64;
H, 6.64. Found C, 64.56; H, 6.88.
D
H), 1.45 (m, 3 H), 1.80 (m, 2 H), 2.51 (br s, 1 H), 2.59 (dd, J )
15.5, 3.9 Hz, 1 H), 3.37 (m, 2 H), 3.57 (m, 2 H), 3.76 (m, 2 H),
3.90 (d, J ) 2.6 Hz, 1 H), 5.26 (m, 1 H), 7.33 (m, 4 H), 7.43 (m,
4 H), 7.56 (m, 1 H), 7.63 (m, 4 H), 8.07 (m, 2 H); 13C NMR
(CDCl3) δ 19.1 (s), 25.2 (t), 26.8 (q), 32.5 (t), 33.2 (t), 63.5 (t),
67.6 (t), 71.4 (d), 71.8 (d), 72.0 (d), 79.2 (d), 127.3 (d), 127.7
(d), 128.3 (d), 129.6 (d), 130.1 (s), 133.1 (d), 133.3 (s), 134.3
(s), 135.7 (d), 166.0 (s); IR (CHCl3) (cm-1) 3449, 2944, 1716,
1272; MS m/ z (relative intensity) 492 (M - 57)+ (3), 199 (27),
135 (22), 105 (100). Anal. Calcd for C32H40O6Si C, 70.04; H,
7.35. Found C, 70.06; H, 7.42.
P r ep a r a tion of (2R,3S,4a R,8a R)-2-[(Meth oxyca r bon yl)-
m eth yl]octa h yd r op yr a n o[3,2-b]p yr a n -3-yl Ben zoa te (93).
The general cyclization method was applied to 67 (85 mg, 0.25
mmol) to afford 93 (74 mg, 87% yield) as an oil: [R]25D ) +44.1
P r ep a r a tion of (1R)-1-[[(2S,3R)-3-(ter t-Bu tyld ip h en yl-
siloxy)t et r a h yd r op yr a n -2-yl]m et h yl]-3-(m et h oxyca r b o-
n yl)-(E)-a llyl Ben zoa te (89). The general procedure to
transform 3-benzoyloxy 1,2-diols into γ-(benzoyloxy)-(E)-R,â-
unsaturated esters was applied to 88 on a 1.2 g (2.8 mmol)
1
(c 2.73, CHCl3); H NMR (CDCl3) δ 1.45 (m, 1 H), 1.68 (m, 1
H), 1.95 (m, 2 H), 2.15 (m, 2 H), 2.63 (m, 2 H), 3.47 (m, 1 H),
3.67 (s, 3 H), 3.75 (m, 1 H), 3.82 (m, 2 H), 4.46 (ddd, J ) 8.9,
5.2, 5.2 Hz, 1 H), 4.90 (dd, J ) 10.4, 5.2 Hz, 1 H), 7.43 (m, 2
H), 7.55 (m, 1 H), 8.07 (m, 2 H); 13C NMR (CDCl3) δ 22.1 (t),
26.2 (t), 28.9 (t), 36.3 (t), 51.8 (q), 65.1 (t), 66.9 (d), 69.1 (d),
scale, yielding 89 (1.14 g, 71% yield) as an oil: [R]25 ) -27.2
D
1
(c 2.02, CHCl3); H NMR (CDCl3) δ 1.04 (s, 9 H), 1.44 (m, 3
H), 1.70 (m, 1 H), 1.83 (m, 1 H), 2.35 (m, 1 H), 3.24 (m, 2 H),
3.39 (m, 1 H), 3.70 (d, J ) 11.5 Hz, 1 H), 3.77 (s, 3 H), 5.85 (m,

4582 J . Org. Chem., Vol. 62, No. 14, 1997
Betancort et al.
69.9 (d), 70.9 (d), 128.2 (d), 129.7 (d), 130.2 (s), 132.9 (d), 165.7
(s), 170.9 (s); IR (CHCl3) (cm-1) 3019, 2948, 1716, 1277; MS
m/ z (relative intensity) 335 (M + 1)+ (6), 212 (44), 303 (40),
105 (100). Anal. Calcd for C18H22O6: C, 64.64; H, 6.64.
Found: C, 64.46; H, 7.02.
J ) 12.0, 4.4, 4.4 Hz, 1 H), 2.76 (dd, J ) 14.8, 5.6 Hz, 1 H),
2.90 (dd, J ) 14.8, 8.8 Hz, 1 H), 3.11 (m, 1 H), 3.29 (m, 1 H),
3.40 (ddd, J ) 11.6, 11.6, 4.4 Hz, 1 H), 3.59 (s, 3 H), 3.91 (dd,
J ) 11.2, 4.0 Hz, 1 H), 4.69 (dd, J ) 5.6, 2.8 Hz, 1 H), 5.39
(ddd, J ) 12.8, 5.2, 5.2 Hz, 1 H), 7.43 (m, 2 H), 7.55 (m, 1 H),
7.97 (m, 2 H); 13C NMR (CDCl3) δ 25.9 (t), 29.7 (t), 31.2 (t),
32.7 (t), 52.2 (q), 68.4 (t), 68.9 (d), 70.7 (d), 71.0 (d), 77.0 (d),
128.8 (d), 130.0 (s), 130.0 (d), 133.7 (d), 165.4 (s), 170.7 (d); IR
(CHCl3) (cm-1) 3026, 2953, 1723, 1271; MS m/ z (relative
intensity) 335 (M + 1)+ (7), 212 (27), 105 (100), 77 (83). Anal.
Calcd for C18H22O6: C, 64.64; H, 6.64. Found: C, 64.82; H,
6.56.
P r ep a r a tion of (2R,3R,4a R,8a R)-2-[(Meth oxyca r bon -
yl)m et h yl]oct a h yd r op yr a n o[3,2-b]p yr a n -3-yl Ben zoa t e
(94). The general cyclization method was applied to 71 (112
mg, 0.3 mmol) to afford 94 (101 mg, 90% yield) as an oil: [R]25
D
1
) +46.3 (c 0.35, CHCl3); H NMR (CDCl3) δ 1.33 (d, J ) 5.2
Hz, 1 H), 1.64 (ddd, J ) 12.8, 12.8, 3.4 Hz, 1 H), 1.92 (m, 3 H),
2.22 (m, 1 H), 2.65 (dd, J ) 14.9, 5.2 Hz, 1 H), 2.83 (dd, J )
14.9, 9.2 Hz, 1 H), 3.43 (ddd, J ) 11.2, 11.2, 2.0 Hz, 1 H), 3.59
(s, 3 H), 3.68 (s, 1 H), 3.73 (s, 1 H), 3.95 (d, J ) 10.9 Hz, 1 H),
4.73 (m, 1 H), 5.60 (m, 1 H), 7.42 (m, 2 H), 7.54 (m, 1 H), 7.97
(m, 2 H); 13C NMR (CDCl3) δ 20.5 (t), 27.5 (t), 30.0 (t), 32.5 (t),
51.8 (q), 65.1 (d), 66.8 (d), 67.3 (t), 70.2 (d), 72.3 (d), 128.3 (d),
129.6 (d), 129.9 (s), 133.1 (d), 165.2 (s), 171.3 (s); IR (CHCl3)
(cm-1) 3013, 2955, 1723, 1271; MS m/ z (relative intensity) 335
(M + 1)+ (3), 212 (53), 111 (27), 105 (100). Anal. Calcd for
C18H22O6: C, 64.64; H, 6.64. Found: C, 64.91; H, 6.73.
P r ep a r a tion of (2R,3S,4a S,8a R)-2-[(Meth oxyca r bon yl)-
m eth yl]octa h yd r op yr a n o[3,2-b]p yr a n -3-yl Ben zoa te (95).
The general cyclization method was applied to 86 (94 mg, 0.28
mmol) to afford 95 (83 mg, 88% yield) as a solid: mp ) 88-89
P r ep a r a t ion of (2S,3R,4a R,8a R)-2-[2-(ter t-Bu t yld i-
p h en ylsiloxy)et h yl]oct a h yd r op yr a n o[3,2-b]p yr a n -3-ol
(103). The general method for reduction of esters was applied
to 97 on a 180 mg (0.54 mmol) scale using LiAlH4 (1.1 mL, 1.0
M in ether, 1.1 mmol) to afford 102 as an oil. The crude was
dissolved in dry CH2Cl2 (5 mL) under argon, and imidazole
(110 mg, 1.6 mmol) and tert-butylchlorodiphenylsilane (0.3 mL,
1.1 mmol) were sequentially added at rt. After 1 h TLC
showed complete conversion. The solvent was evaporated, and
the crude was purified by silica gel column chromatography
to yield 103 (170 mg, 72% yield based on 97) as an oil: [R]25
D
1
) -8.9 (c 1.43, CHCl3); H NMR (CDCl3) δ 1.05 (s, 9 H), 1.26
(dd, J ) 7.3, 7.3 Hz, 1 H), 1.61 (m, 2 H), 1.89 (m, 3 H), 2.04
(m, 1 H), 2.27 (dd, J ) 10.4, 3.0 Hz, 1 H), 3.24 (m, 1 H), 3.37
(s, 1 H), 3.42 (dd, J ) 12.4, 12.4 Hz, 1 H), 3.55 (s, 1 H), 3.79
(m, 1 H), 3.85 (m, 2 H), 3.98 (dd, J ) 11.4, 2.1 Hz, 1 H), 7.41
(m, 4 H), 7.69 (m, 2 H); 13C NMR (CDCl3) δ 19.0 (s), 20.6 (t),
26.7 (q), 28.6 (t), 36.5 (t), 38.0 (t), 61.0 (t), 66.3 (d), 68.2 (t),
71.8 (d), 74.0 (d), 80.5 (d), 127.7 (d), 129.7 (d), 133.0 (s), 135.5
(d); IR (CHCl3) (cm-1) 3394, 3006, 2956, 1426; MS m/ z (relative
intensity) 383 (M - 57)+ (7), 365 (48), 199 (100), 149 (95). Anal.
Calcd for C26H36O4Si: C, 70.87; H, 8.24. Found: C, 70.96; H,
8.48.
P r ep a r a tion of (2S,4a R,8a R)-2-[2-(ter t-Bu tyld ip h en yl-
siloxy)et h yl]h exa h yd r op yr a n o[3,2-b]p yr a n -3-on e (104).
To a stirred solution of 103 (146 mg, 0.3 mmol) in dry CH2Cl2
(1.5 mL) were sequentially added NaOAc (5 mg, 0.07 mmol)
and PCC (140 mg, 0.7 mmol) at rt. The reaction was stirred
overnight until TLC showed complete conversion. After this
time the reaction mixture was diluted with ether (10 mL),
filtered through a pad of Celite, concentrated, and purified by
silica gel column chromatography to afford 104 (130 mg, 90%
yield) as an oil: [R]25D ) -6.5 (c 2.01, CHCl3); 1H NMR (CDCl3)
δ 1.05 (s, 9 H), 1.30 (dd, J ) 11.2, 2.1 Hz, 1 H), 1.76 (m, 2 H),
1.94 (m, 1 H), 2.03 (dd, J ) 13.1, 3.2 Hz, 1 H), 2.27 (m, 1 H),
2.60 (dd, J ) 4.3, 4.3 Hz, 2 H), 3.45 (ddd, J ) 12.5, 12.5, 2.3
Hz, 1 H), 3.79 (m, 2 H), 3.90 (m, 2 H), 3.97 (dd, J ) 11.2, 4.4
Hz, 1 H), 4.11 (m, 1 H), 7.40 (m, 4 H), 7.67 (m, 2 H); 13C NMR
(CDCl3) δ 19.2 (s), 20.2 (t), 26.8 (q), 28.2 (t), 32.1 (t), 44.8 (t),
59.6 (t), 68.2 (t), 71.3 (d), 76.0 (d), 78.5 (d), 127.5 (d), 129.5 (d),
133.9 (s), 134.0 (s), 135.5 (d), 206.0 (s); IR (CHCl3) (cm-1) 3077,
2959, 1729, 1428; MS m/ z (relative intensity) 381 (M - 57)+
(15), 303 (55), 199 (100), Anal. Calcd for C26H34O4Si: C, 71.20;
H, 7.82. Found: C, 71.04; H, 7.88.
°C; [R]25 ) +6.7 (c 1.35, CHCl3); 1H NMR (CDCl3) δ 1.54 (m,
D
1 H), 1.76 (m, 2 H), 1.87 (m, 1 H), 1.96 (m, 1 H), 2.25 (dd, J )
11.2, 2.9 Hz, 1 H), 2.65 (dd, J ) 14.7, 6.0 Hz, 1 H), 2.93 (dd, J
) 14.7, 9.3 Hz, 1 H), 3.42 (m, 3 H), 3.73 (s, 3 H), 3.92 (dd, J )
11.3, 1.7 Hz, 1 H), 4.49 (dd, J ) 9.3, 6.1 Hz, 1 H), 5.21 (dd, J
) 2.3, 2.3 Hz, 1 H), 7.44 (m, 2 H), 7.58 (m, 1 H), 8.06 (m, 2 H);
13C NMR (CDCl3) δ 25.7 (t), 29.4 (t), 30.3 (t), 35.1 (t), 52.0 (q),
68.1 (t), 70.9 (d), 71.7 (d), 72.8 (d), 74.4 (d), 128.3 (d), 129.7
(d), 130.0 (s), 133.1 (d), 165.6 (s), 170.3 (s); IR (CHCl3) (cm-1
)
3026, 2948, 1716, 1275; MS m/ z (relative intensity) 335 (M +
1)+ (10), 212 (79), 105 (100), 77 (100). Anal. Calcd for
C18H22O6: C, 64.64; H, 6.64. Found: C, 64.63; H, 6.59.
P r ep a r a tion of (2S,3R,4a S,8a R)-2-[(Meth oxyca r bon yl)-
m eth yl]octa h yd r op yr a n o[3,2-b]p yr a n -3-yl Ben zoa te (96).
The general cyclization method was applied to 92 (108 mg,
0.32 mmol) to afford 96 (96 mg, 89% yield) as a solid: mp )
1
76-77 °C; [R]25 ) -39.2 (c 3.12, CHCl3); H NMR (CDCl3) δ
D
1.44 (m, 1 H), 1.70 (m, 3 H), 2.08 (dd, J ) 12.0, 2.8 Hz, 1 H),
2.51 (dd, J ) 15.6, 8.2 Hz, 1 H), 2.55 (m, 1 H), 2.62 (dd, J )
15.6, 4.0 Hz, 1 H), 3.13 (ddd, J ) 10.4, 10.4, 4.0 Hz, 2 H), 3.40
(m, 1 H), 3.59 (s, 3 H), 3.92 (dd, J ) 9.2, 2.0 Hz, 1 H), 4.02
(ddd, J ) 8.2, 8.2, 4.0 Hz, 1 H), 4.91 (ddd, J ) 10.4, 10.4, 4.8
Hz, 1 H), 7.45 (m, 2 H), 7.58 (m, 1 H), 8.02 (m, 2 H); 13C NMR
(CDCl3) δ 25.3 (t), 29.1 (t), 35.5 (t), 37.7 (t), 51.7 (q), 67.9 (t),
71.0 (d), 76.2 (d), 78.1 (d), 128.3 (d), 128.5 (d), 129.6 (d), 129.7
(s), 133.3 (d), 165.3 (s), 171.3 (s); IR (CHCl3) (cm-1) 3026, 2952,
2872, 1721; MS m/ z (relative intensity) 335 (M + 1)+ (1), 212
(43), 105 (100). Anal. Calcd for C18H22O6: C, 64.64; H, 6.64.
Found: C, 64.48; H, 6.65.
P r ep a r a tion of (2S,3R,4a R,8a R)-2-[(Meth oxyca r bon yl)-
m eth yl]octa h yd r op yr a n o[3,2-b]p yr a n -3-yl Ben zoa te (97).
The general cyclization method was applied to 73 (92 mg, 0.27
mmol) to afford 97 (81 mg, 88% yield) as a solid: mp ) 82-83
°C; [R]25D ) -22.1 (c 1.83, CHCl3); 1H NMR (CDCl3) δ 1.24 (m,
1 H), 1.62 (ddd, J ) 12.1, 12.1, 4.4 Hz, 1 H), 1.74 (ddd, J )
11.3, 11.3, 3.3 Hz, 1 H), 1.96 (m, 2 H), 2.44 (dd, J ) 13.1, 4.8
Hz, 1 H), 2.60 (m, 2 H), 3.40 (dd, J ) 11.3, 11.3 Hz, 1 H), 3.54
(s, 1 H), 3.58 (s, 3 H), 3.99 (m, 2 H), 5.13 (m, 1 H), 7.41 (m, 2
H), 7.54 (m, 1 H), 7.99 (m, 2 H); 13C NMR (CDCl3) δ 20.4(t),
28.3 (t), 35.4 (t), 38.0 (t), 51.5 (q), 68.1 (t), 69.1 (d), 72.3 (d),
73.3 (d), 76.1 (d), 128.3 (d), 129.6 (d), 129.9 (s), 133.0 (d), 165.2
(s), 171.7 (s); IR (CHCl3) (cm-1) 3003, 2957, 1718, 1266; MS
m/ z (relative intensity) 335 (M + 1)+ (2), 212 (98), 139 (45),
105 (100). Anal. Calcd for C18H22O6: C, 64.64; H, 6.64.
Found: C, 64.72; H, 6.73.
P r ep a r a t ion of (2S,3S,4a R,8a R)-2-[2-(ter t-Bu t yld i-
p h en ylsiloxy)et h yl]oct a h yd r op yr a n o[3,2-b]p yr a n -3-ol
(105). To a stirred solution of 104 (80 mg, 0.18 mmol) in dry
ether (1.5 mL) was added LiAlH4 (0.1 mL, 1.0 M in ether, 0.1
mmol) at -78 °C. After 5 min, H2O (0.1 mL), a 15% aqueous
NaOH solution (0.1 mL), and H2O (0.3 mL) were sequentially
added to the reaction mixture with vigorous stirring. The
mixture was allowed to reach rt, dried over MgSO4, filtered
through a pad of Celite, concentrated, and purified by silica
gel column chromatography to yield 105 (68 mg, 85% yield)
1
as an oil: [R]25 ) -17.1 (c 0.93, CHCl3); H NMR (CDCl3) δ
D
1.05 (s, 9 H), 1.29 (m, 1 H), 1.62 (m, 1 H), 1.77 (d, J ) 13.7 Hz,
1 H), 1.85 (m, 1 H), 1.98 (m, 3 H), 2.17 (d, J ) 13.7 Hz, 1 H),
3.37 (dd, J ) 11.5 Hz, 1 H), 3.40 (s, 1 H), 3.47 (s, 1 H), 3.51 (s,
1 H), 3.62 (dd, J ) 8.5, 4.6 Hz, 1 H), 3.79 (m, 1 H), 3.88 (m, 1
H), 4.00 (dd, J ) 11.3, 2.1 Hz, 1 H), 7.39 (m, 6 H), 7.67 (m, 4
H); 13C NMR (CDCl3) δ 19.2 (s), 20.6 (t), 26.9 (q), 29.0 (t), 34.9
(t), 35.8 (t), 60.3 (t), 66.4 (d), 68.6 (t), 72.3 (d), 73.1 (d), 76.3
P r ep a r a tion of (2R,3R,4a S,8a R)-2-[(Meth oxyca r bon yl)-
m eth yl]octa h yd r op yr a n o[3,2-b]p yr a n -3-yl Ben zoa te (98).
The general cyclization method was applied to 90 (98 mg, 0.29
mmol) to afford 98 (88 mg, 90% yield) as a solid: mp ) 79-80
°C; [R]25D ) +28.6 (c 3.40, CHCl3); 1H NMR (CDCl3) δ 1.42 (m,
1 H), 1.76 (m, 2 H), 1.97 (dd, J ) 12.0, 3.2 Hz, 1 H), 2.33 (ddd,
(d), 127.5 (d), 129.5 (d), 134.0 (s), 135.4 (d); IR (CHCl3) (cm-1
3503, 3077, 2957, 1426; MS m/ z (relative intensity) 441 (M +
)

Intramolecular Hetero-Michael Addition
J . Org. Chem., Vol. 62, No. 14, 1997 4583
1)+ (1), 199 (67), 149 (92), 55 (100). Anal. Calcd for C26H36O4-
Si: C, 70.87; H, 8.24. Found: C, 70.51; H, 8.20.
P r ep a r a tion of (2S,3S,4a S,8a R)-2-[(Meth oxyca r bon yl)-
m eth yl]octah ydr opyr an o[3,2-b]pyr an -3-yl Ben zoate (110).
To a solution of the fused bicycle 95 (45 mg, 0.13 mmol) in
dry THF (1.3 mL) was added NaH (12 mg, 0.4 mmol, 80% in
mineral oil) at rt. The reaction mixture was stirred for 12 h,
after which time TLC showed complete conversion. Then to
the reaction mixture were sequentially added HOAc (50 µL)
and H2O (5 mL). The mixture was extracted with ether (3 ×
10 mL), and the combined organic phases were washed with
a saturated aqueous solution of NaHCO3 (10 mL) and brine,
dried over MgSO4, concentrated, and purified by column
P r ep a r a t ion of (2S,3R,4a S,8a R)-2-[2-(ter t-Bu t yld i-
p h en ylsiloxy)et h yl]oct a h yd r op yr a n o[3,2-b]p yr a n -3-ol
(107). The general method for reduction of esters was applied
to 96 on a 100 mg (0.3 mmol) scale using LiAlH4 (0.4 mL, 1.0
M in ether, 0.4 mmol) to afford 106 as an oil. The crude was
dissolved in dry CH2Cl2 (3 mL) under argon, and imidazole
(60 mg, 0.9 mmol) and tert-butylchlorodiphenylsilane (0.15 mL,
0.6 mmol) were added at rt. After 1 h TLC showed complete
conversion. The solvent was evaporated, and the crude was
purified by silica gel column chromatography to yield 107 (99
chromatography, yielding 110 (39 mg, 90% yield) as an oil:
mg, 75% yield based on 96) as an oil: [R]25 ) -16.5 (c 2.20,
[R]25 ) +12.0 (c 1.89, CHCl3); H NMR (CDCl3) δ 1.57 (m, 1
1
D
D
1
CHCl3); H NMR (CDCl3) δ 1.06 (s, 9 H), 1.26 (s, 1 H), 1.39
H), 1.76 (m, 2 H), 1.82 (ddd, J ) 12.8, 12.8, 2.8 Hz, 1 H), 2.07
(m, 1 H), 2.35 (ddd, J ) 13.8, 3.4, 3.4 Hz, 1 H), 2.51 (dd, J )
16.1, 5.2 Hz, 1 H), 2.64 (dd, J ) 16.1, 8.1 Hz, 1 H), 3.20 (ddd,
J ) 10.8, 10.8, 4.2 Hz, 1 H), 3.33 (m, 1 H), 3.40 (m, 1 H), 3.66
(s, 3 H), 3.90 (dd, J ) 13.3, 3.6 Hz, 1 H), 4.13 (m, 1 H), 5.35 (s,
1 H), 7.46 (m, 2 H), 7.58 (m, 1 H), 8.07 (m, 2 H); 13C NMR
(CDCl3) δ 25.5 (t), 29.2 (t), 34.4 (t), 36.5 (t), 51.8 (q), 68.0 (t),
70.9 (d), 74.2 (d), 74.9 (d), 78.4 (d), 128.4 (d), 129.7 (d), 129.9
(s), 133.2 (d), 165.7 (s), 171.1 (s); IR (CHCl3) (cm-1) 3023, 2954,
1716; MS m/ z (relative intensity) 335 (M + 1)+ (1), 111 (98),
105 (100). Anal. Calcd for C18H22O6: C, 64.64; H, 6.64.
Found: C, 64.49; H, 6.83.
(m, 1 H), 1.50 (m, 1 H), 1.70 (m, 1 H), 1.83 (m, 1 H), 2.00 (m,
2 H), 2.39 (m, 1 H), 2.98 (m, 2 H), 3.27 (m, 1 H), 3.78 (m, 1 H),
3.53 (m, 1 H), 3.84 (dd, J ) 4.1, 4.1 Hz, 2 H), 3.92 (d, J ) 10.5
Hz, 1 H), 7.41 (m, 6 H), 7.68 (m, 4 H); 13C NMR (CDCl3) δ 19.1
(s), 25.5 (t), 26.7 (q), 29.2 (t), 36.3 (t), 38.4 (t), 61.0 (t), 67.8 (t),
69.9 (d), 77.0 (d), 77.6 (d), 80.7 (d), 127.7 (d), 129.8 (d), 133.0
(s), 135.5 (d); IR (CHCl3) (cm-1) 3374, 3010, 2933, 1110; MS
m/ z (relative intensity) 383 (M - 57)+ (16), 199 (55), 97 (100).
Anal. Calcd for C26H36O4Si: C, 70.87; H, 8.24. Found: C,
70.86; H, 8.41.
P r ep a r a tion of (2S,3S,4a S,8a R)-2-(2-Hyd r oxyeth yl)-
octah ydr opyr an o[3,2-b]pyr an -3-yl 4-Nitr o-ben zoate (109).
To a stirred solution of 107 (40 mg, 0.1 mmol) in dry benzene
(1 mL) were sequentially added Ph3P (52 mg, 0.2 mmol),
p-nitrobenzoic acid (30 mg, 0.18 mmol), and diisopropyl
azodicarboxylate (0.04 mL, 0.2 mmol) at rt. The stirred
mixture was maintained for 5 h at 50 °C after which time it
was concentrated and the crude purified by silica gel column
Ack n ow led gm en t. This research was supported by
the DGICYT (PB92-0489, PB95-0751), the Human
Capital and Mobility Program (ERBCHRXCT93-0288)
of the European Community, and the Consejer´ıa de
Educacio´n, Cultura y Deportes del Gobierno de Canar-
ias. J .M.B. and M.A.S. thank the M.E.C, and J .M.P the
Gobierno Auto´nomo de Canarias, for a fellowship.
chromatography to give 109 (46 mg, 78% yield) as an oil: [R]25
D
1
) -7.3 (c 0.92, CHCl3); H NMR (C6D6) δ 1.06 (s, 9 H), 1.26
(m, 2 H), 1.57 (m, 2 H), 1.75 (m, 2 H), 2.34 (d, J ) 10.2 Hz, 1
H), 3.10 (m, 1 H), 3.30 (m, 1 H), 3.42 (m, 1 H), 3.74 (m, 1 H),
3.84 (m, 1 H), 3.93 (m, 2 H), 5.30 (s, 1 H), 7.28 (m, 6 H), 7.70
(m, 4 H), 7.83 (m, 4 H); 13C NMR (C6D6) δ 19.2 (s), 25.6 (t),
26.8 (q), 29.6 (t), 34.6 (t), 34.7 (t), 60.3 (t), 67.7 (t), 72.9 (d),
74.7 (d), 74.8 (d), 78.4 (d), 123.2 (d), 129.7 (d), 130.3 (d), 133.9
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for the
compounds 1, 3-6, 8-13, 20-24, 26-30, 32, 34-36, 38, 40,
93-98, 105, and 110 and experimental details for the syn-
thesis of 44-50, 55-73, and 81-86 (58 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.
(s), 135.0 (s), 135.6 (d), 150.4 (s), 163.6 (s); IR (CHCl3) (cm-1
3568, 2955, 1720, 1271; MS m/ z (relative intensity) 532 (M -
57)+ (2), 167 (52), 150 (33), 97 (100). Anal. Calcd for C33H39
)
-
NO7: C, 67.20; H, 6.67; N, 2.38. Found: C, 66.96; H, 7.02; N,
2.36.
J O9619241