Asymmetric intramolecular [2 + 2] photocycloadditions: α- and β-hydroxy acids as chiral tether groups

Article abstract of DOI:10.1021/jo001631e

Chiral α- and β-hydroxy acids such as (S)-lactic acid, (S)-phenyllactic acid, (S)-mandelic acid, or (3R)-3-hydroxybutyric acid have been used as tether groups for intramolecular and diastereoselective [2 + 2] photocycloaddition of 3-oxocyclohexene carboxylic acid derivatives. Total regiocontrol toward the straight adduct and high diastereoselectivities (up to 94%) were observed in the case of butenyl lactate 11. After separation of the two diastereoisomers, cleavage of the chiral tether under basic conditions afforded cyclobutane lactones in good yield and enantiomeric pure form. An X-ray structure has been recorded that confirmed the relative and absolute configuration of the three contiguous stereogenic centers assigned according to CD spectra.

Full text of DOI:10.1021/jo001631e

J . Org. Chem. 2002, 67, 1061-1070
1061
Asym m etr ic In tr a m olecu la r [2 + 2] P h otocycloa d d ition s: r- a n d
â-Hyd r oxy Acid s a s Ch ir a l Teth er Gr ou p s
Sophie Faure,† Sylvie Piva-Le-Blanc,† Cyrille Bertrand,† J ean-Pierre Pete,*,†
Rene´ Faure,‡,§ and Olivier Piva*,|
Laboratoire des Re´actions Se´lectives et Applications (CNRS, UMR 6519), Universite´ de
Reims-Champagne-Ardenne, B.P. 1039, F-51687 Reims Cedex, France, Laboratoire de
Chimie Analytique 2, Universite´ Claude Bernard-Lyon 1, 43 Boulevard du 11 Novembre 1918,
F-69622 Villeurbanne Cedex, France, and Laboratoire de Chimie Organique-Photochimie et
Synthe`se (CNRS, UMR 5622), Universite´ Claude Bernard-Lyon 1, 43 Boulevard du 11 Novembre 1918,
F-69622 Villeurbanne Cedex, France
piva@univ-lyon-1.fr
Received November 16, 2000
Chiral R- and â-hydroxy acids such as (S)-lactic acid, (S)-phenyllactic acid, (S)-mandelic acid, or
(3R)-3-hydroxybutyric acid have been used as tether groups for intramolecular and diastereoselective
[2 + 2] photocycloaddition of 3-oxocyclohexene carboxylic acid derivatives. Total regiocontrol toward
the straight adduct and high diastereoselectivities (up to 94%) were observed in the case of butenyl
lactate 11. After separation of the two diastereoisomers, cleavage of the chiral tether under basic
conditions afforded cyclobutane lactones in good yield and enantiomeric pure form. An X-ray
structure has been recorded that confirmed the relative and absolute configuration of the three
contiguous stereogenic centers assigned according to CD spectra.
Sch em e 1
[2 + 2] photocycloaddition is one of the major photo-
chemical reactions applied to total synthesis.1,2 While the
intermolecular processes suffer generally of a lack of
regio- and/or syn/anti stereocontrol, the intramolecular
reactions seem far more interesting.3 In this context, we
previously investigated intramolecular photocycloaddi-
tions starting from cycloalkenone carboxylate derivatives.
This chromophoric system has been widely used for
intermolecular reactions and applied to the synthesis of
natural products.4,5 Interestingly, the ester group com-
pared to the acetal moiety has been considered as a poor
linking unit6 before our own successful investigations.7
Irradiation of enone derivatives connected to the
alkenyl chain by a carboxylic “connector” was extremely
efficient. To our delight, only one regio- and stereoisomer
of the expected cyclobutane derivatives was usually
detected (Scheme 1). However, some dimeric side prod-
ucts7 could be observed during irradiation mainly at low
temperature or under high concentration conditions.
Sch em e 2
With the aim to develop an asymmetric version of this
process, oxoesters were first replaced by oxoamides
bearing at least one chiral group on the nitrogen atom.
Unfortunately, a competitive hydrogen abstraction took
place leading to spiranic â-lactam derivatives (Scheme
2).8 Related spiranic structures were recently reported
to exhibit important biological properties such as cho-
lesterol absorption inhibition.9
† Universite´ de Reims-Champagne-Ardenne.
‡ To whom inquiries regarding X-ray structures should be addressed.
§ Laboratoire de Chimie Analytique 2, Universite´ Claude Bernard-
Lyon 1.
| Laboratoire de Chimie Organique-Photochimie et Synthe`se, Uni-
versite´ Claude Bernard-Lyon 1.
To avoid these hydrogen abstraction processes, we
decided to turn back to oxoesters and to introduce a chiral
tether group connected both to the unsaturated oxoester
chromophore and to the alkenyl chain. While chiral
centers present on the alkenyl side-chain have been
already reported to direct efficiently diastereoselective
intramolecular [2 + 2] photocycloadditions, the use of
chiral removable tether groups could represent an im-
(1) Crimmins, M. T.; Reinhold, T. C. In Organic Reactions; Paquette,
L. A., Ed.; J ohn Wiley: New York, 1993; Vol. 44, pp 296-588.
(2) (a) Winkler, J . D.; Mazur-Bowen, C.; Liotta, F. Chem. Rev. 1995,
95, 2003. (b) Bach, T. Synthesis 1998, 683. (c) Dell, C. P. J . Chem.
Soc., Perkin Trans. 1 1998, 3873.
(3) (a) Crimmins, M. T. Chem. Rev. 1988, 88, 1453. (b) Mattay, J .
In Organic photochemistry and photobiology; Horspool, W. M., Song,
P. S., Eds.; CRC Press: Boca Raton, 1995; pp 618-633.
(4) Lange, G. L.; Furlan, L.; MacKinnon, M. C. Tetrahedron Lett.
1998, 39, 5489.
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Lange, G. L.; Gottardo, C.; Merica, A. J . Org. Chem. 1999, 64, 6738.
(c) Lange, G. L.; Merica, A. Tetrahedron Lett. 1999, 40, 7897.
(6) Pirrung, M. C.; Thomson, S. A. Tetrahedron Lett. 1986, 27, 2703.
(7) (a) Le Blanc, S.; Pete, J .-P.; Piva, O. Tetrahedron Lett. 1993, 34,
635. (b) Piva-Le Blanc, S.; Pete, J .-P.; Piva, O. Chem. Commun. 1998,
235.
(8) Le Blanc, S.; Pete, J .-P.; Piva, O. Tetrahedron Lett. 1993, 34,
1993.
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Chem. 1996, 61, 8341. (b) Dugar, S.; Clader, J . W.; Chan, T.-M.; Davis,
H., J r. J . Med. Chem. 1995, 38, 4875.
10.1021/jo001631e CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/18/2002

1062 J . Org. Chem., Vol. 67, No. 4, 2002
Faure et al.
Sch em e 3
Sch em e 4
provement for further applications to the synthesis of
natural products.10 For our purposes, chiral R- and
â-hydroxy acids that are easily prepared or commercially
available11 might be interesting chiral linkers. Therefore,
we first tested the use of (S)-lactic acid, (S)-phenyllactic
acid, (S)-mandelic acid, and (3R)-hydroxybutyric acid as
cheap reagents.12 Due to a high conformational mobility,
the intramolecular photocycloaddition of oxoesters having
a long and unsubstituted alkenyl chain (Scheme 1, n >
3) appeared to be inefficient or without regiocontrol. The
introduction of a chiral tether linked by esters groups
was expected to rigidify the system13 and to allow a
conformation favorable to the overlap of the orbitals of
the biradical intermediate14 with the π-system of the
isolated double bond. Furthermore, a chiral auxiliary
bounded by two ester functionalities could not only direct
a diastereoselective approach of the unsaturated chain
toward the enone moiety but also be easily removed in
one single step (Scheme 3).
The starting materials 10-19 were prepared from
3-oxocyclohexene and 3-oxocyclopentene carboxylic acids
1 and 215 and unsaturated hydroxyesters 3a -f, allyl (3R)-
3-hydroxybutyrate 4a , or allylbislactate 8a , respectively.
Allyl lactate 3a was conveniently obtained by heating (S)-
lactic acid 1 in pure allyl alcohol in the presence of a trace
of acid.16 Similarly, (3R)-allyl hydroxybutyrate 4a was
obtained directly from the biopolymer of 3-hydroxybutyric
acid (PHB), in the presence of diluted sulfuric acid and
allyl alcohol17 (Scheme 4).
The high cost of other unsaturated alcohols excluded
their use as the solvent for the preparation of 3b-f, and
a more suitable and general synthetic approach was
designed for these compounds (Scheme 5). Protection of
methyl lactate as a silyl ether was accomplished using
standard procedures.18 Saponification of 5 by LiOH19
produced the acid 6 esterified with 3-buten-1-ol to give
7b, using a DCC activation.20 The final deprotection to
3b was carried out in the presence of n-Bu4NF.21 Finally,
this procedure was extended to the preparation of
compounds 3c-d . Butenyl derivatives 3e and 3f were
directly prepared from (S)-phenyllactic acid and (S)-
mandelic acid by heating with 3-buten-1-ol in acetonitrile
and in the presence of catalytic amount of tetracyanoeth-
ylene (TCNE) according to a procedure first described by
Masaki et al.22
The dimeric structure 8a was prepared as pure mate-
rial from bislactic acid 9 isolated as a byproduct during
distillation of polymeric lactic acid. The moderate yield
for 8a could be explained by the formation of a side
product resulting from the condensation of the acid 9 and
DCC as already observed with other R-hydroxy acids.23
Condensation of the unsaturated hydroxy esters 3a -
f, 8a , and 4a with carboxylic acid 1 and 2, in the presence
of DCC and DMAP,20 afforded the expected substrates
10-19 in good yields (Scheme 6, Table 1).
(10) (a) Pete, J .-P. In Advances in Photochemistry; Neckers, D.-C.,
Volman, H.-D., Von Bu¨nau, G., Eds.; J ohn Wiley: New York, 1996;
Vol. 21, pp 135-216. (b) Cox, L. R.; Ley, S. V. In Templated Organic
Synthesis; Diederich, F., Stang, P. J ., Eds.; Wiley-VCH: Weiheim, 2000;
pp 275-395.
(11) Coppola, G. M.; Schuster, H. F. In R-Hydroxyacids in enantio-
selective syntheses; Walter, G. Ed.; VCH: Weinheim, 1997.
(12) Faure, S.; Piva-Le Blanc, S.; Piva, O.; Pete, J .-P. Tetrahedron
Lett. 1997, 38, 1045.
(13) (a) Illuminati, G.; Mandolini, L. Acc. Chem. Soc. 1981, 14, 95.
(b) Dietrich, B.; Viout, P.; Lehn, J .-M. Aspects de la chimie des compose´s
macrocycliques CNRS Ed.; Paris; 1991; p 3. (c) Lee, D.; Sello, J . K.;
Schreiber, S. L. J . Am. Chem. Soc. 1999, 121, 10648.
(14) (a) Schuster, D. I.; Lem, G.; Kaprinidis, N. A. Chem. Rev. 1993,
93, 3. (b) Maradyn, D. J .; Weedon, A. C. J . Am. Chem. Soc. 1995, 117,
5359. (c) Kelly, J . F. D.; Kelly, J . M.; McMurry, T. B. H. J . Chem. Soc.,
Perkin Trans. 2 1999, 1933. (d) Wilsey, S.; Gonzalez, L.; Robb, M. A.;
Houk, K. N. J . Am. Chem. Soc. 2000, 122, 5866.
When the allyl monolactate 10 was irradiated in
dichloromethane, no intramolecular cycloaddition could
be detected, and the head-to-tail photodimer 20 of the
cyclohexenone moiety could be isolated with quite low
yields (20-30%). In contrast, when the allyl bislactate
12 was irradiated under the same conditions, only two
(18) Hanessian, S.; Lavalle´e, P. Can. J . Chem. 1975, 53, 2975.
(19) Salomon, C. J .; Mata, E. G.; Mascaretti, O. A. Tetrahedron 1993,
49, 3691.
(20) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522.
(15) (a) Lange, G. L.; Decicco, C. P.; Willson, J .; Strickland, L. A. J .
Org. Chem. 1989, 54, 1805. (b) Herzog, H.; Koch, H.; Scharf, H. D.;
Runsink, J . Tetrahedron 1986, 42, 3547.
(16) Rehberg, C. E. Organic Syntheses; Wiley: New York, 1955;
Collect. Vol. III, pp 46-48.
(17) Seebach, D.; Zuger, M. Helv. Chim. Acta 1982, 65, 495.
(21) Morton, D. R.; Thompson, J . L. J . Org. Chem. 1978, 43, 2102.
(22) Masaki, Y.; Tanaka, N.; Miura, T. Chem. Lett. 1997, 55.
(23) Robba, M.; Maune, D. C. R. Acad. Sci. C, 1971, 272, 475.

R- and â-Hydroxy Acids as Chiral Tether Groups
J . Org. Chem., Vol. 67, No. 4, 2002 1063
Sch em e 5
Sch em e 6
Ta ble 1. Syn th esis of Su bstr a tes 10-19
cycloadducts 21 (41%) and 22 (24%) were obtained
(Scheme 7).
The structures of these cycloadducts were determined
thanks to their spectroscopic data. According to the mass
spectrum, they both presented a parent peak at m/z )
324 indicating a C16H20O7 molecular formula when their
1
respective H NMR and 13C NMR spectra showed unam-
biguously that they are regioisomers.
Sch em e 7
For 21, the proton that appeared at 4.45 ppm as a
doublet of doublet (J ) 11.2, 5.5 Hz) was identified as
Ha characteristic of a straight arrangement in this kind
of adducts.7 The relative configuration on the cyclobutane
ring was deduced from the lactone 23 obtained by
methanolysis of 21 (Scheme 8). NOE experiments indi-
cated a correlation between Ha and one Hd, and no
relationship between Ha and Hc. Moreover, due to the
high strain of the molecule, the polycyclic structures could
only possess a cis/syn/cis relative arrangement around
1
the four-membered ring.24 For 22, the H NMR presents
a doublet at 3.15 ppm (J ) 8.7 Hz) attributed to Ha,
indicating the presence of only one vicinal proton having
the trans relative configuration.
To determine the absolute configuration of the three
new contiguous stereogenic centers in 21, CD spectra
recorded for this compound and lactone 23 present a
negative Cotton effect.25 This negative value of the
dichroic band and the application of the octant’s rule
indicate a (1R,5R,7R) configuration for 23 and deter-
mines without ambiguity the configuration of the asym-
metric centers created in 21 during the cycloaddition step
(Scheme 9).
(24) (a) Meinwald, J .; Tufariello, J . J .; Hurt, J . J . J . Org. Chem. 1964,
29, 2914. (b) Scharf, H. D. Tetrahedron Lett. 1967, 4231.
(25) (a) Crabbe´, P. Applications de la dispersion rotatoire et du
dichroı¨sme circulaire optique en chimie organique; Gauthier-Villars:
Paris, 1968. (b) Kirk, D. N. Tetrahedron 1986, 42, 777.
This attribution is in agreement with those already
described from CD spectra of cyclobutane derivatives.26

1064 J . Org. Chem., Vol. 67, No. 4, 2002
Faure et al.
Sch em e 8
Sch em e 10
Sch em e 9
Sch em e 11
Furthermore, we were delighted to obtain crystals of 21
for which an X-ray structure was recorded. The ORTEP
representation (see the Supporting Information) shows
unambiguously the relative configuration of the three
stereogenic centers created after irradiation. Knowing the
absolute configuration of the stereogenic centers of the
tether groups, we were able to confirm the configuration
determined from the CD spectra.
The absolute configuration of the adduct 21 appears
to be (1R,4S,7S,11R,13R) and, therefore, (1R,5R,7R) for
23. Similarly, the configuration of the new asymmetric
centers of 22 could be elucidated using CD spectra of 22
and 24.
Irradiation of allyl 3-hydroxybutyrate derivative 13
was next performed under similar conditions (Scheme
10). Only two cycloadducts could be isolated and identi-
fied, by NMR spectroscopy, as head-to-head regioiso-
mers: 25a (62%), 25b (16%). While the regiocontrol
appeared to be total, the stereochemical control was
moderate (de ) 64%).
Nevertheless, the two adducts 25a and 25b, conve-
niently separated, underwent methanolysis under basic
conditions and led, respectively, to the two enantiomers
of butyrolactone 23. According to the study of allylbis-
lactate adduct 14 described above, we were able to assign
the configuration of the asymmetric centers and the
structures for the two major isomers 25a and 25b.
Furthermore, derivatization27 of the keto group by a
commercially available chiral 1,2-diol-like (2R,3R)-2,3-
butanediol allows the determination of the enantiomeric
purity of the cycloadduct (Scheme 11).
These results indicate that formation of a nine-
membered ring macrolide from 13 was much more
favorable than eight-membered ring derivatives from 10.
The absence of intramolecular photocycloaddition from
10 might result from conformational restrictions and a
short linking unit between the cyclohexenone and eth-
ylenic groups. Then, we turned back to the monolactate
11 bearing a butenyl chain that should deliver under
irradiation macrolactone 27, which should possess a nine-
membered ring like 25.
As expected, irradiation of ester 11 produced, in a very
clean reaction and in high yield, only two stereoisomers
1
27a and 27b identified as before using H NMR spec-
troscopy. The diastereoselectivity, measured by the same
method on the crude mixture of the irradiation carried
out in CH2Cl2 and at 20 °C, reached 86% for 92% chemical
yield (Scheme 12). The cleavage of the tether group of
the unseparable adducts 27, in situ followed by lacton-
ization, gave the tricyclic valerolactones 28a and 28b.
(27) (a) Lemie`re, G. L.; Dommisse, R. A.; Lepoivre, J . A.; Alderweir-
eldt, F. C.; Hiemstra, H.; Wynberg, H.; J ones, J . B.; Toone, E. J . J .
Am. Chem. Soc. 1987, 109, 1363. (b) Enders, D.; Whitehouse, D. L.
Synthesis 1996, 621.
(26) Cavazza, M.; Zandomeneghi, M.; Ciacchini, G.; Pietra, F.
Tetrahedron 1985, 41, 1989.

R- and â-Hydroxy Acids as Chiral Tether Groups
J . Org. Chem., Vol. 67, No. 4, 2002 1065
Sch em e 12
Sch em e 13
Ta ble 2. In flu en ce of th e Tem p er a tu r e of Ir r a d ia tion on
th e Dia ster eoselectivity for 11
be achieved by simply switching a methyl group with a
phenyl ring on the tether moiety. Lactic derivatives 16
and 17 substituted on the alkenyl chain by alkyl groups
were also irradiated and delivered cycloadducts 32 and
33 in good yields and high selectivities (88 and 94%). The
tether group was conveniently removed by methanolysis
to furnish new tricyclic valerolactones 34 and 35 without
loss of optical purity. Finally, esters 18 and 19, which
possess a cyclopentane core, were transformed into
macrocyclic lactones with still high regioselectivities but
less important diastereoselectivities, 12 and 30%, respec-
tively (Scheme 14). The exact reason for this difference
between esters prepared from 1 or 2 is still unclear.
T (°C) time (h) yield (%) 27a /27b
dea (%) oligomers
20
-20
-40
12
40
50
92
78
42
93:7
96:4
97:3
86
92
94
-
+
++
a
de determined by 1H NMR (500 MHz).
The ee (88%) determined after derivatization of lactones
28 with (2R,3R)-2,3-butanediol to ketals 29a and 29b
confirmed again that no dramatic decrease of the selec-
tivity occurred during the removal of the chiral entity.
While the relative configuration on 28 has been already
assigned thanks to previous studies,7a the determination
of the absolute configuration of the major diastereoisomer
27a was next achieved using the same method as for
bislactate adduct 21. The sign of the Cotton effect was
also negative. By using, octants’ rule, the (1R,6S,8R)
configuration was assigned to the major diastereoisomer
(-)-27a .
To improve the diastereoselectivity of the process,
irradiations of 11 were performed at various tempera-
tures (Table 2). We observed that a decrease of the
temperature was accompanied by an increase of the
selectivities. Unfortunately, the rate of the cycloaddition
dramatically slowed and the diminution of the yield
observed at -40 °C can be explained by the formation of
some oligomer species.7b The range of temperature 0-20
°C appeared as a good range for obtaining 27a with de
higher than 90% together with convenient yields.
The reaction was next generalized to other substrates
14-19. Changing the nature of the tether group from (S)-
lactic acid to more bulky compounds such as (S)-mandelic
acid or (S)-phenyllactic acid has no influence on the
regioselectivity of the process; Irradiation of 14 and 15
at rt in methylene chloride led to the straight adducts
30 and 31 with, respectively, 92% and 74% de (Scheme
13). Therefore, an increase of the diastereoselectivity can
While the determination of the relative and absolute
configuration of the asymmetric centers has been achieved,
and in order to generalize this approach, we examined
models that might explain the selective approach of the
alkene moiety toward the enone part.
The tricyclic skeleton of the cycloadducts introduces
steric restrictions, and the configurations of the three
asymmetric centers present around the cyclobutane ring
are not independent. Furthermore, we have to consider
that the asymmetric induction is obtained during the first
step of the photocycloaddition process. Despite the mul-
tistep nature of the cycloaddition process and the non-
planar structure of the triplet excited state of the
cyclohexenone chromophore, we anticipated that the
observed asymmetric induction was the result of confor-
mational restrictions in the transition step, imposed by
the carboxyl group and the methyl group on the chiral
auxiliary. We present a rationale for these results, with
a chiral induction obtained during an 9-exo-trig addition
of the distorted cyclohexenone triplet onto the terminal
alkene. In the case of the lactate tether derivative 11,
we have represented in Scheme 15 two possible diaster-
eomeric transition states A and B for the first step of a
cycloaddition process involving the formation of a nine-

1066 J . Org. Chem., Vol. 67, No. 4, 2002
Faure et al.
fragmentation of the biradical intermediates.14 Then,
further studies would be needed to give a better under-
standing of the stereochemical control of such an in-
tramolecular process.30
Sch em e 14
In conclusion, this study has shown the advantages of
the use of R- and â-hydroxy acids as chiral tethers for
highly diastereoselective intramolecular photocycloaddi-
tions. It should be pointed out that after our preliminary
communication12 diastereoselctive intramolecular cy-
cloadditions directed by chiral linkers derived from amino
acids appeared in the literature.31,32 However, even if the
diastereoselectivities are of the same order, these chiral
moieties seem difficult to remove. In our case, enantio-
merically pure tricyclic lactones could be prepared after
the cleavage in one single step of the chiral auxiliary.
Work is now in progress to synthesize and test other
chiral hydroxy acids as tether groups, to improve the
selectivities, to generalize the process to other substrates,
and to apply this method to the synthesis of natural
products.33
Exp er im en ta l Section
Gen er a l Meth od s. All manipulations with air-sensitive
reagents were carried out under a dry argon atmosphere using
standard Schlenk techniques. Solvents were purified according
to standard procedures: THF and ether on sodium/benzophe-
none, methylene chloride on CaH2. Reagents were purchased
from Aldrich Chemical Co. or Acros Organics. Analytical TLC
was performed using Merck SI F 254 plates. Column flash
chromatography was performed by using Kieselgel 60 (230-
1
400 mesh). The H NMR and 13C NMR spectra were recorded
at 250 and 62.5 MHz, respectively, in CDCl3; chemical shifts
(δ) are given in ppm and referred to tetramethylsilane. FTIR
spectra were measured with KBr plates on a spectrafile IR
PLUS MIDAC.
Sch em e 15
Dir ect Ester ifica tion of (S)-La ctic Acid a n d (3R)-3-
Hyd r oxybu tyr ic Acid . In a 50 mL flask equipped with a
cooler were placed (S)-lactic acid (10 g, 0.11 mol), benzene (6
mL), and 12 N sulfuric acid (0.1 mL). The mixture was heated
to reflux with removal of water (Dean Stark system). Unsatur-
ated alcohol (0.44 mol, 4 equiv) was rapidly added, and reflux
was maintained for 4 h. After neutralization with sodium
acetate, the ester formed was purified by distillation under
reduced pressure.
membered ring lactone, which could lead to the major
and the minor adducts, respectively. We assume that in
both transition states the methyl group of the linker has
to adopt a pseudoequatorial position. Then, the stereo-
chemistry of the two major isomers might be the result
of a competition between s-syn or s-trans conformations
of the carboxylic connector. An s-syn conformation of the
double bond of the conjugated ester and a syn conforma-
tion of the carboxylic group and the hydrogen atom fixed
on the stereogenic center of the linker28 induce the
favorable transition state A and formation of 27a . In
contrast, formation of 27b would require transition state
B, having an s-trans conformation of the R,â-unsaturated
carboxylic moiety (Scheme 15). Such an explanation is
supported by previous observations from Lange’s and
Scharf’s groups to connect the diastereoselectivities
observed for intermolecular processes with the conforma-
tion of related oxoesters.15b,29 However, it has also been
pointed out that the structure of the cycloadducts can be
determined by the relative rates of cyclization and
Allyl la cta te34 (3a ): liquid, 90%; 1H NMR (250 MHz, CDCl3)
δ 1.40 (d, 3H, J ) 6.9 Hz), 2.58 (m, 1H, OH), 4.28 (q, 1H, q, J
) 6.9 Hz), 4.66 (ddd, 2H, J ) 5.7, 2.6, 1.1 Hz), 5.25 (ddt, 1H,
J ) 10.3, 2.6, 1.1 Hz), 5.32 (ddt, 1H, J ) 17.1, 3, 1.5 Hz), 5.90
(ddt, 1H, J ) 17.1, 10.3, 5.7 Hz); [R]21 ) -10 (1.38, CHCl3).
D
(R)-Allyl 3-h yd r oxybu tyr a te35 (4a ): liquid, 74%; 1H NMR
(250 MHz, CDCl3) δ 1.23 (d, 3H, J ) 6.4 Hz), 2.46 (dd, 1H, J AB
) 16.4 Hz, J ) 8.0 Hz), 2.51 (dd, 1H, J AB ) 16.4 Hz, J ) 4.2
Hz), 2.91 (1H, sl, OH), 4.21 (ddq, 1H, J ) 8.0, 4.2, 6.4 Hz),
4.61 (ddd, 2H, J ) 5.7, 1.5, 1.1 Hz), 5.25 (ddt, 1H, J ) 10.3,
1.5, 1.1 Hz), 5.32 (dq, 1H, J ) 17.7, 1.5 Hz), 5.92 (ddt, 1H, J
) 17.7, 10.3, 5.7 Hz); 13C NMR (62 MHz, CDCl3) δ 22.4, 42.7,
64.2, 65.2, 118.4, 131.8, 172.3; IR (neat) ν 3576, 2936, 1730,
1315, 1178 cm-1; MS (EI, 70 eV) m/z 145 (M•+ + 1, 15), 129;
[R]21 ) -36 (1.08, CHCl3).
D
(30) A control of the regiochemistry of intramolecular [2 + 2]
cycloaddition reactions by the conformation of the biradical has already
been proposed: Audley, M.; Geraghty, N. W. A. Tetrahedron Lett. 1996,
37, 1641.
(31) Booker-Milburn, K. I.; Gulten, S.; Sharpe, A. Chem. Commun.
1997, 1385.
(28) (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
organic compounds; J . Wiley & Sons: New York, 1994; pp 615-663.
(b) Oppolzer, W.; Chapuis, C.; Dao, G. M.; Reichlin, D.; Godel, T.
Tetrahedron Lett. 1982, 4781.
(29) Lange, G. L.; Decicco, C.; Lee, M. Tetrahedron Lett. 1987, 28,
2833.
(32) Bach, T.; Kru¨ger, C.; Harms, K. Synthesis 2000, 305.
(33) Faure, S.; Piva, O. Tetrahedron Lett. 2001, 42, 255.
(34) Plattner, D. A.; Brunner, A.; Dobler, M.; Mu¨ller, H.-M.; Petter,
W.; Zbinden, P.; Seebach, D. Helv. Chim. Acta 1993, 76, 2004.
(35) Rehberg, C. E. In Organic Syntheses; Horning, E. C., Ed.;
Wiley: New York, 1955; Collect. Vol. III, p 46.

R- and â-Hydroxy Acids as Chiral Tether Groups
J . Org. Chem., Vol. 67, No. 4, 2002 1067
Access to la cta tes 3b-d . Meth yl 2-[(1,1-Dim eth yleth -
yl)d ip h en ylsilyl]oxyp r op a n oa te36 (5). To a solution of (S)-
methyl lactate (2.00 g, 19.2 mmol) in DMF (70 mL) were
successively added tert-butyldiphenylsilyl chloride (28.8 mmol)
and imidazole (67.2 mmol). After being stirred overnight, the
mixture was diluted with brine (100 mL) and extracted with
ether (5 × 50 mL). The organic layer was washed successively
with a cooled aqueous 5% HCl solution and brine and dried
over MgSO4. After concentration under vacuum, the residue
was purified by flash chromatography (hexanes/AcOEt ) 97:
3) to afford 5 (89%) as a colorless oil: 1H NMR (250 MHz,
CDCl3) δ 1.11 (s, 9H), 1.39 (d, 3H, J ) 6.8 Hz), 3.58 (s, 3H),
4.30 (q, 1H, J ) 6.8 Hz), 7.30-7.50 (m, 6H), 7.60-7.75 (m,
4H); 13C NMR (62 MHz, CDCl3) δ 19.2, 21.2, 26.8, 51.5, 68.9,
127.5, 127.6, 129.7, 132.3, 132.9, 135.7, 135.8, 177.6; IR (neat)
ν 2936, 2860, 1755, 1429, 1114 cm-1; MS (EI, 70 eV) m/z 342
(M+), 285, 213, 183, 153, 105.
(4-Meth yl)-3-p en ten yl 2-[(1,1-Dim eth yleth yl)d ip h en yl-
silyl]oxyp r op a n oa te (7d ). Same procedure as for 7b using
4-methyl-3-pentenol35 instead of 3-butenol: 89%; 1H NMR (250
MHz, CDCl3) δ 1.11 (s, 9H), 1.38 (d, 3H, J ) 6.9 Hz), 1.60 (s,
3H), 1.69 (d, 3H, J ) 1.1 Hz), 2.23 (q, 2H, J ) 7.2 Hz), 3.91
(dt, 1H, J ) 10.7, 7.2 Hz), 4.00 (dt, 1H, J ) 10.3, 7.2 Hz), 4.29
(q, 1H, J ) 6.9 Hz), 5.04 (t, 1H, J ) 7.2 Hz), 7.30-7.50 (m,
6H), 7.60-7.75 (m, 4H); 13C NMR (62 MHz, CDCl3) δ 17.7,
19.2, 21.3, 25.7, 26.8, 27.4, 64.2, 68.9, 119.1, 127.5, 127.6, 129.7,
129.9, 133.2, 135.7, 135.9, 173.7; IR (neat) ν 2922, 2850, 1755,
1430, 1140 cm-1; [R]21 ) -37 (1.1, CHCl3). Anal. Calcd for
D
C25H34O3Si: C, 73.12; H, 8.34. Found: C, 73.24; H, 8.54.
(S)-3-Bu ten yl La cta te (3b). Tetrabutylammonium fluoride
(2.09 g, 8 mmol) was added at once and at 0 °C to a solution
of ester 7b (1.54 g, 4 mmol) dissolved in THF (50 mL). After
1.5 h stirring at rt, the mixture was diluted with brine (25
mL) and extracted with ether. The organic layer was washed
with a 5% HCl aqueous solution and then dried over MgSO4.
After removal of the solvents, the crude product was purified
by flash chromatography on silica (hexanes/AcOEt 70/30)
giving 3b (0.822 g, 5.7 mmol) as a liquid: 71%; 1H NMR (250
MHz, CDCl3) δ 1.41 (d, 3H, J ) 6.9 Hz), 2.30-2.50 (m, 2H),
3.61 (m, OH), 4.15-4.40 (m, 3H), 5.00-5.20 (m, 2H), 5.77 (ddt,
1H, J ) 17.1, 10.3, 6.9 Hz); 13C NMR (62 MHz, CDCl3) δ 20.2,
32.9, 64.4, 66.7, 117.5, 133.3, 177.9; IR (neat) ν 3460, 2978,
2-[(1,1-Dim eth yleth yl)d ip h en ylsilyl]oxyp r op a n oic Ac-
id 37 (6). To a solution of ester 5 (2 g, 5.8 mmol) in THF (90
mL) at 0 °C was dropwise added an ice-cooled 0.2 M solution
of LiOH (11.8 mmol) in water in 20 mn. After being stirred
overnight, the mixture was concentrated by half and extracted
with ether (2 × 20 mL). The organic layer was washed with
an aqueous saturated solution of sodium hydrogenocarbonate
(20 mL). The aqueous layers were combined, carefully acidified
to pH 4 with a 1 N solution of potassium hydrogenosulfate,
and extracted with ether (4 × 50 mL). The ethereal phase was
dried over Na2SO4, and the solvent was removed by concentra-
1738, 1269, 1211, 1126 cm-1; [R]21 ) -11.7 (0.65, CHCl3).
D
(S)-(3-Meth yl)-3-bu ten yl La cta te (3c). Same procedure
as above starting from 7c: 90%; 1H NMR (250 MHz, CDCl3) δ
1.38 (d, 3H, J ) 6.9 Hz), 1.74 (s, 3H), 2.35 (t, 2H, J ) 6.8 Hz),
2.80 (s, 1H), 4.23 (dt, 1H, J AB ) 11.1 Hz, J ) 6.8 Hz), 4.24 (d,
1H, J ) 6.9 Hz), 4.33 (dt, 1H, J AB ) 11.1 Hz, J ) 6.8 Hz), 4.72
(s, 1H), 4.80 (s, 1H); 13C NMR (62 MHz, CDCl3) δ 20.3, 22.2,
36.5, 63.4, 66.6, 112.5, 141.0, 175.6; IR (neat) ν 3440, 2990,
1
tion: solid, 89%; H NMR (250 MHz, CDCl3) δ 1.15 (s, 9H),
1.39 (d, 3H, J ) 6.7 Hz), 4.36 (q, 1H, J ) 6.7 Hz), 7.37-7.53
(m, 6H), 7.68-7.74 (m, 4H); 13C NMR (62 MHz, CDCl3) δ 19.1,
21.0, 26.8, 68.9, 127.7, 127.8, 130.1, 132.3, 132.9, 135.6, 135.7,
177.6; IR (neat) ν 3072, 1730, 1429, 1240, 1103 cm-1; MS (EI,
70 eV) m/z 271 (31), 200 (20), 199 (100), 139 (38); HMRS calcd.
for C19H25O3Si (M•+ + 1) 329.15729, found 329.15725.
2935, 1745, 1455, 1265, 1215, 1130, 1055, 890 cm-1
.
(S)-(4-Meth yl)-3-p en ten yl La cta te (3d ). Same procedure
1
3-Bu ten yl 2-[(1,1-Dim eth yleth yl)d ip h en ylsilyl]oxyp r o-
p a n oa te (7b). In a two-necked flask, acid 6 (1.64 g, 5 mmol)
and DMAP (0.610 g, 5 mmol) were added to a solution of
3-butenol (0.360 g, 5 mmol) in dichloromethane (5 mL). The
mixture was flushed with argon, and after cooling with an
external ice-water bath, a solution of DCC (1.03 g, 5 mmol)
in the same solvent (2 mL) was dropwise added. The external
bath was removed and the solution stirred overnight at rt.
After filtration and wash of the urea with dichloromethane,
the resulting solution was concentrated and purified by flash
hromatography on silica (hexanes/AcOEt 10/90) giving 7b
(1.591 g, 4.1 mmol) as an oil: 83%; 1H NMR (250 MHz, CDCl3)
δ 1.13 (s, 9H), 1.39 (d, 3H, J ) 6.9 Hz), 2.30 (dq, 2H, J ) 6.87,
1.3 Hz), 4.05 (dt, 2H, J ) 6.9, 3.9 Hz), 4.32 (q, 1H, J ) 6.9
Hz), 5.03-5.12 (m, 2H), 5.73 (ddt, 1H, J ) 17.1, 10.3, 6.9 Hz),
7.35-7.50 (m, 6H); 7.68-7.76 (m, 4H); 13C NMR (62 MHz,
CDCl3) δ 19.2, 21.3, 26.8, 32.9, 63.5, 68.9, 117.1, 127.5, 127.6,
129.7, 133.2, 133.5, 133.8, 135.7, 135.8, 173.6; IR (neat) ν 2922,
2860, 1755, 1429, 1114 cm-1; MS (EI, 70 eV) m/z 382 (M•+),
325, 297, 271, 253, 199, 181, 139, 123, 105; [R]21D ) -47.6 (1.1,
CH2Cl2).
as above starting from 7d : 72%; H NMR (250 MHz, CDCl3)
δ 1.40 (d, 3H, J ) 6.9 Hz), 1.63 (s, 3H), 1.71 (d, 3H, J ) 1.1
Hz), 2.35 (q, 2H, J ) 7.25 Hz), 2.73 (s, 1H), 4.10 (dt, 1H, J AB
) 10.7 Hz, J ) 6.9 Hz), 4.19 (dt, 1H, J AB ) 10.7 Hz, J ) 6.9
Hz), 4.26 (q, 1H, J ) 6.9 Hz), 5.08 (t, 1H, J ) 7.2 Hz); 13C
NMR (62 MHz, CDCl3) δ 17.7, 20.3, 25.6, 27.4, 65.1, 66.6,
118.6, 134.9, 175.7; IR (neat) ν 3450, 2985, 2920, 1730, 1455,
1380, 1265, 1215, 1130 cm-1; MS (EI, 70 eV) m/z 173 (M•+
1, 8), 129, 119, 116. Anal. Calcd for C9H16O3: C, 62.76; H, 9.36.
Found: C, 63.07; H, 9.84.
+
E st er ifica t ion In it ia t ed w it h Tet r a cya n oet h ylen e
(TCNE ). (S)-3-Bu t en yl P h en ylla ct a t e (3e). A solution of
phenyllactic acid (1.01 g, 6.6 mmol) and 3-butenol (0.61 g, 8.5
mmol) dissolved in methylene chloride (10 mL) was heated at
50 °C in the presence of TCNE (0.169 g, 1.3 mmol). After 3
days, the solvent was removed under reduced pressure and
the mixture purified by flash chromatography (AcOEt/hexanes
1
20/80) to give 3e as an oil (0.976 g, 4.4 mmol): oil, 67%; H
NMR (250 MHz, CDCl3) δ 2.39 (dt, 2H, J ) 6.8, 6.6 Hz), 2.71
(d, 1H, J ) 6.1 Hz), 2.95 (dd, 1H, J AB ) 14.1 Hz, J ) 6.8 Hz),
3.11 (dd, 1H, J AB ) 14.4 Hz, J ) 4.6 Hz), 4.21 (t, 2H, J ) 6.8
Hz), 4.43 (ddd, 1H, J ) 6.8, 6.1, 4.6 Hz), 5.12 (m, 2H), 5.75
(ddt, 1H, J ) 17.1, 10.3, 6.6 Hz), 7.18-7.38-7 (m, 5H); 13C
NMR (62 MHz, CDCl3) δ 32.8, 40.5, 64.5, 71.1, 117.5, 126.8,
128.3, 129.4, 133.4, 136.3, 174.0; IR (neat) ν 3455, 2945, 1735,
1454, 1271, 1095 cm-1; MS (EI, 70 eV) m/z 220 (M•+, 31), 202,
(3-Meth yl)-3-bu ten yl 2-[(1,1-Dim eth yleth yl)d ip h en yl-
silyl]oxyp r op a n oa te (7c). Same procedure as for 7b using
1
3-methyl-3-butenol instead of 3-butenol: 73%; H NMR (250
MHz, CDCl3) δ 1.10 (s, 9H), 1.36 (d, 3H, J ) 6.9 Hz), 1.71 (s,
3H), 2.23 (t, 2H, J ) 6.9 Hz), 4.04 (dt, 1H, J AB ) 10.7 Hz, J )
6.9 Hz), 4.14 (dt, 1H, J AB ) 10.7 Hz, J ) 6.9 Hz), 4.27 (q, 1H,
J ) 6.9 Hz), 4.66 (sl, 1H), 4.76 (sl, 1H), 7.33-7.50 (m, 6H),
7.65-7.72 (m, 4H); 13C NMR (62 MHz, CDCl3) δ 19.2, 21.2,
22.3, 26.8, 36.4, 62.6, 68.9, 112.2, 127.5, 127.6, 129.7, 133.2,
133.5, 135.7, 135.8, 141.3, 173.6; IR (neat) ν 2922, 2860, 1755,
1140, 1105 cm-1; MS (EI, 70 eV) m/z 397 (M•+ + 1, 4), 271,
148, 131, 121, 103; [R]21 ) -15 (0.9, CHCl3). Anal. Calcd for
D
C9H16O3: C, 70.88; H, 7.32. Found: C, 70.85; H, 6.97.
(S)-3-Bu ten yl Ma n d ela te (3f). Same procedure as above
using mandelic acid (1.0 g, 6.6 mmol): oil, 62%; 1H NMR (250
MHz, CDCl3) δ 2.33 (tdd, 2H, J ) 6.9, 6.5, 1.4 Hz), 3.52 (s,
1H), 4.21 (t, 2H, J ) 6.9 Hz), 4.98 (d, 1H, J ) 17 Hz), 4.99 (d,
1H, J ) 10.7 Hz), 5.17 (s, 1H), 5.64 (ddt, 1H, J ) 17.0, 10.7,
6.9 Hz), 7.25-7.55 (m, 5H); 13C NMR (62 MHz, CDCl3) δ 32.8,
64.9, 72.8, 117.5, 126.4, 128.3, 128.4, 133.1, 138.3, 173.5; IR
(neat) ν 3425, 2985, 1750, 1720, 1625, 1375, 1255, 1215, 1160,
199, 181, 139; [R]21 ) -42 (0.4, CHCl3). Anal. Calcd for
D
C24H32O3Si: C, 72.68; H, 8.13. Found: C, 72.59; H, 8.45.
(36) Ainsworth, P. J .; Craig, D.; Reader, J . C.; Slawin, A. M. Z.;
White, A. J . P.; Williams, D. J . Tetrahedron 1995, 51, 11601.
(37) Savage, I.; Thomas, E. J .; Wilson, P. D. J . Chem. Soc., Perkin
Trans. 1 1999, 3291.
1080 cm-1; MS (EI, 70 eV) m/z 206 (M•+, 8), 131, 105. [R]21
)
D
+176 (0.4, CHCl3). Anal. Calcd for C12H14O3: C, 69.88; H, 6.84.
Found: C, 69.74; H, 7.28.

1068 J . Org. Chem., Vol. 67, No. 4, 2002
Faure et al.
Allyl Bisla cta te (8a ). Prepared from bis lactic acid and
[R]21D ) -31 (c 1.1, CHCl3). Anal. Calcd for C14H18O5: C, 63.14;
H, 6.81. Found: C, 62.91; H, 7.10.
allyl alcohol using the DCC activation as described above for
1
7b: liquid, 46%; H NMR (250 MHz, CDCl3) δ 1.48 (d, 3H, J
1-(1S)-(1-Bu ten yloxyca r bon yl-1-p h en yl)m eth yl 3-Oxo-
cycloh ex-1-en eca r boxyla te (14). Prepared by condensation
of 3-oxocyclohex-1-enecarboxylic acid with 3f according to a
) 6.9 Hz), 1.54 (d, 3H, J ) 7.1 Hz), 2.79 (sl, 1H, OH), 4.35
(dq, 1H, J ) 6.9, 5.9 Hz), 4.64 (dt, 2H, J ) 5.7, 1.5 Hz), 5.21
(q, 1H, J ) 7.1 Hz), 5.26 (ddt, 1H, J ) 10.3, 1.4, 1.3 Hz), 5.33
(ddt, 1H, J ) 17.1, 1.4, 1.5 Hz), 5.98 (ddt, 1H, J ) 17.1, 10.3,
5.7 Hz); 13C NMR (62 MHz, CDCl3) δ 16.8, 20.4, 65.9, 66.7,
69.3, 118.8, 131.3, 169.8, 175.0; IR (neat) ν 3487, 1742, 1655,
1454, 1203, 1128, 1089, 978 cm-1; MS (EI, 70 eV) m/z 204 (M+),
1
protocol similar that for to the formation of 7b: oil, 88%; H
NMR (250 MHz, CDCl3) δ 2.09 (tt, 2 H, J ) 6.9, 6.1 Hz), 2.54
(q, 2 H, J ) 6.5 Hz), 2.49 (t, 2 H, J ) 6.9 Hz), 2.66 (td, 2 H, J
) 6.1, 1.5 Hz), 4.20 (t, 2 H, J ) 6.7 Hz), 4.92-5.05 (m, 3 H),
5.66 (ddt, 1 H, J ) 16.8, 10, 6.9 Hz), 6.89 (t, 1 H, J ) 1.5 Hz),
7.35-7.53 (m, 5 H); 13C NMR (62 MHz, CDCl3) δ 22.0, 24.6,
32.7, 37.6, 64.7, 75.2, 117.4, 127.4, 128.7, 129.3, 133.1, 133.2,
133.8, 147.8, 165.7, 168.1, 199.7; IR (neat) ν 3071, 2954, 1752,
1726, 1686, 1497, 1455, 1224, 1180, 1078, 1046, 965, 916, 740,
697 cm-1; MS (70 eV) m/z 328 (M•+, 12), 316, 256, 124, 123,
145, 131, 114; [R]25 ) -38 (1.04, CHCl3). Anal. Calcd for
D
C9H14O5: C, 53.50; H, 7.00. Found: C, 53.10; H, 7.30.
(1S)-1-(1-Allyloxyca r bon yl)eth yl 3-Oxocycloh ex-1-en e-
ca r boxyla te (10). Prepared by condensation of 3-oxocyclohex-
1-enecarboxylic acid with 3a according to a protocol similar
105; [R]21 ) +82 (c ) 1.10, CHCl3). Anal. Calcd for C19H20O5:
1
D
to that for the formation of 7b: oil, 55%; H NMR (250 MHz,
C, 69.49; H, 6.13. Found: C, 69.38; H, 6.42.
CDCl3) δ 1.57 (d, 3H, J ) 6.9 Hz), 2.07 (q, 2H, J ) 6.1 Hz),
2.46 (t, 2H, J ) 6.1 Hz), 2.61 (td, 2H, J ) 6.1, 1.9 Hz), 4.65
(dt, 2H, J ) 5.7, 1.1 Hz), 5.22 (q, 1H, J ) 6.9 Hz); 5.31 (2H,
m); 5.90 (1H, ddt, J ) 17.1, 10.3, 5.7 Hz); 6.82 (1H, t, J ) 1.9
Hz); 13C NMR (62 MHz, CDCl3) δ 16.7, 21.9, 24.6, 37.5, 65.8,
69.4, 118.6, 131.3, 133.5, 147.9, 165.7, 169.7, 199.6; IR (neat)
ν 2957, 2853, 1720, 1684, 1456, 1375, 1251, 1223, 1186, 1097,
1047, 966, 922, 731 cm-1; MS (EI, 70 eV) m/z 253 (M+ + 1),
1-(1S)-(1-Bu t-3-en yloxyca r bon yl-1-p h en yl)eth yl 3-Oxo-
cycloh ex-1-en eca r boxyla te (15). Prepared by condensation
of 3-oxocyclohex-1-enecarboxylic acid with 3e according to a
1
protocol similar to that for the formation of 7b: oil, 85%; H
NMR (250 MHz, CDCl3) δ 2.04 (quint, 2 H, J ) 6.1 Hz), 2.36
(dq, 2 H, J ) 1.1, 6.7 Hz), 2.44 (t, 2 H, J ) 6.1 Hz), 2.53 (t, 2
H, J ) 6.1 Hz), 3.13 (dd, 1 H, J AB ) 14.3 Hz, J ) 8.6 Hz), 3.26
(dd, 1 H, J AB ) 14.3 Hz, J ) 4.4 Hz), 4.19 (t, 2 H, J ) 6.7 Hz),
5.08 (m, 2 H), 5.29 (dd, 1 H, J ) 8.6, 4.4 Hz), 5.71 (ddt, 1 H,
J ) 17.1, 10.3, 6.7 Hz), 6.74 (s, 1 H), 7.15-7.35 (m, 5 H); 13C
NMR (62 MHz, CDCl3) δ 21.9, 24.6, 32.7, 37.3, 37.5, 64.7, 73.9,
117.4, 127.1, 128.5, 129.2, 133.4, 133.5, 135.5, 147.7, 165.5,
168.9, 199.6; IR (neat) ν 3070, 3030, 2951, 1753, 1726, 1686,
1454, 1247, 1218, 1186, 1083, 964, 916, 740, 701 cm-1; MS (70
eV) m/z 343 (M•+ + 1, 22), 202 (54), 148 (100), 131 (91), 123
167, 123; UV (CH2Cl2) λmax (ꢀ) 238 (12340), 355 (30); [R]25
)
D
+11.3 (c 1.18, CHCl3). Anal. Calcd for C13H16O5: C, 61.89; H,
6.39. Found: C, 61.71; H, 6.53.
(1S)-1-(1-Bu t-3-en yloxyca r bon yl)eth yl 3-Oxocycloh ex-
1-en eca r boxyla te (11). Prepared by condensation of 3-oxo-
cyclohex-1-enecarboxylic acid with 3b according to a protocol
similar to that for the formation of 7b: oil, 93%; 1H NMR (250
MHz, CDCl3) δ 1.55 (d, 3H, J ) 7.0 Hz), 2.08 (tt, 2H, J ) 6.5,
6.0 Hz), 2.41 (qt, 2H, J ) 6.6, 1.2 Hz), 2.47 (t, 2H, J ) 6.5 Hz),
2.61 (td, 2H, J ) 6.0, 1.8 Hz), 4.14-4.30 (m, 2H), 5.05-5.16
(m, 2H), 5.19 (q, 1H, J ) 7.0 Hz), 5.76 (ddt, 1H, J ) 17.1, 10.3,
6.7 Hz), 6.82 (t, 1H, J ) 1.8 Hz); 13C NMR (62 MHz, CDCl3) δ
16.9, 22.1, 24.7, 32.9, 64.4, 69.6, 117.5, 133.5, 133.6, 148.0,
165.8, 170.1, 199.8; IR (neat) ν 2947, 1755, 1730, 1693, 1454,
1253, 1228, 1203, 1103, 914, 738 cm-1; MS (EI, 70 eV) m/z
267 (M•+ + 1), 212, 195, 167, 148, 123, 112; [R]25D ) +6 (c 0.99,
CHCl3). Anal. Calcd for C14H18O5: C, 63.14; H, 6.81. Found:
C, 63.21; H, 6.91.
(73), 103 (46); [R]21 ) -46.6 (c ) 0.96, CHCl3). Anal. Calcd
D
for C20H22O5: C, 70.15; H, 6.48. Found: C, 70.40; H, 6.97.
1-(1S)-[1-(3-Meth yl)bu t-3-en yloxyca r bon yl]eth yl 3-oxo-
cycloh ex-1-en eca r boxyla te (16). Prepared by condensation
of 3-oxocyclohex-1-enecarboxylic acid with 3c according to a
1
protocol similar to that for the formation of 7b: oil, 88%; H
NMR (250 MHz, CDCl3) δ 1.54 (d, 3H, J ) 7.2 Hz), 1.74 (s,
3H), 2.07 (tt, 2H, J ) 6.9, 6.1 Hz), 2.35 (dd, 2H, J ) 6.9, 6.7
Hz), 2.46 (t, 2H, J ) 6.9 Hz), 2.60 (td, 2H, J ) 6.1, 1.9 Hz),
4.22 (dt, 1H, J AB ) 11.1 Hz, J ) 6.7 Hz), 4.33 (dt, 1H, J AB
)
11.1 Hz, J ) 6.9 Hz), 4.72 (s, 1H), 4.80 (s, 1H), 5.17 (q, 1H, J
) 7.2 Hz), 6.81 (t, 1H, J ) 1.9 Hz); 13C NMR (62 MHz, CDCl3)
δ 16.8, 22.0, 22.2, 24.7, 36.5, 37.6, 63.4, 69.6, 112.5, 133.6,
141.1, 148.0, 165.8, 170.1, 199.9; IR (neat) ν 2960, 1730, 1695,
1455, 1315, 1555, 1205, 1100, 965, 900 cm-1; MS (70 eV) m/z
(1S)-[1-(1-Allyloxyca r bon yl)-1-(1S)-eth yloxyca r bon yl]-
eth yl 3-Oxocycloh ex-1-en eca r boxyla te (12). Prepared by
condensation of 3-oxocyclohex-1-enecarboxylic acid with 8a
according to a protocol similar to that for the formation of 7b:
oil, 85%; 1H NMR (250 MHz, CDCl3) δ 1.55 (d, 3H, J ) 7.2
Hz), 1.64 (d, 3H, J ) 6.8 Hz), 2.07 (tt, 2H, J ) 7.2, 6.1 Hz),
2.47 (t, 2H, J ) 7.2 Hz), 2.61 (dt, 2H, J ) 6.1, 1.9 Hz), 4.64
(dt, 2H, J ) 5.7, 1.5 Hz), 5.20 (q, 1H, J ) 7.2 Hz), 5.24 (1H, q,
J ) 6.8 Hz), 5.27 (1H, dt, 1H, J ) 10.3, 1.1 Hz), 5.33 (ddt, 1H,
J ) 17.1, 1.5, 1.1 Hz), 5.90 (ddt, 1H, J ) 17.1, 10.3, 5.7 Hz),
6.83 (t, 1H, J ) 1.9 Hz); 13C NMR (62 MHz, CDCl3) δ 16.7,
16.8, 22.1, 24.7, 37.6, 65.9, 69.3, 69.4, 118.9, 131.3, 133.7 147.9,
165.9, 169.6, 169.7, 199.7; IR (neat) ν 2997, 1755, 1680, 1454,
1379, 1190, 1103, 964 cm-1; MS (EI, 70 eV) m/z 325 (M•+ + 1),
280 (M•+, 14), 213, 123; [R]21 ) +1.1 (c ) 0.5, CHCl3); HMRS
D
calcd for C15H20O2 280.13107, found 280.13130.
1-(1S)-[1-(4-Meth yl)pen t-3-en yloxycar bon yl]eth yl 3-Oxo-
cycloh ex-1-en eca r boxyla te (17). Prepared by condensation
of 3-oxocyclohex-1-enecarboxylic acid with 3d according to a
1
protocol similar to that for the formation of 7b: oil, 90%; H
NMR (250 MHz, CDCl3) δ 1.54 (d, 3H, J ) 7.0 Hz), 1.62 (s,
3H), 1.69 (d, 3H, J ) 0.8 Hz), 2.07 (m, 2H), 2.33 (td, 2H, J )
6.9, 7.2 Hz), 2.46 (t, 2H, J ) 6.9 Hz), 2.61 (td, 2H, J ) 6.1, 1.9
Hz), 4.08 (dt, 1H, J AB ) 10.7 Hz, J ) 6.9 Hz), 4.17 (dt, 1H, J AB
) 10.7 Hz, J ) 7.2 Hz), 5.06 (tt, 1H, J ) 7.5, 1.5 Hz), 5.18 (q,
1H, J ) 7.0 Hz), 6.81 (t, 1H, J ) 1.9 Hz); 13C NMR (62 MHz,
CDCl3) δ 16.8, 17.7, 22.0, 24.6, 25.6, 27.4, 37.6, 65.0, 69.5,
118.7, 133.5, 134.8, 148.0, 165.7, 170.0, 199.8; IR (neat) ν 2960,
2885, 1730, 1680, 1455, 1215, 1090, 965, 740 cm-1; MS (70
268, 195, 178, 167, 123; [R]25 ) -11.5 (c 0.12, CHCl3). Anal.
D
Calcd for C16H20O7: C, 59.25; H, 6.21. Found: C, 59.46; H,
6.41.
(1R)-1-(2-Allyloxyca r bon yl-1-m eth yl)eth yl 3-Oxocyclo-
h ex-1-en eca r boxyla te (13). Prepared by condensation of
3-oxocyclohex-1-enecarboxylic acid with 4a according to a
eV) m/z 294 (M•+, 28), 260, 213, 143, 123, 112; [R]21 ) +9 (c
D
1
protocol similar that for to the formation of 7b: oil, 85%; H
) 1.3, CHCl3). Anal. Calcd for C16H22O5: C, 65.29; H, 7.53.
Found: C, 64.89; H, 7.68.
NMR (250 MHz, CDCl3) δ 1.37 (d, 3H, J ) 6.5 Hz), 2.04 (tt,
2H, J ) 6.5, 6.1 Hz), 2.43 (2H, t, J ) 6.1 Hz), 2.55 (dt, 2H, J
) 6.5, 1.9 Hz), 2.60 (dd, 1H, J ) 15.6, 5.3 Hz), 2.72 (dd, 1H, J
) 15.6, 7.6 Hz), 4.57 (dt, 2H, J ) 5.7, 1.5 Hz), 5.22 (ddt, 1H,
J ) 10.3, 1.5, 1.1 Hz), 5.30 (ddt, 1H, J ) 17.1, 1.5, 1.4 Hz),
5.40 (ddq, 1H, J ) 7.6, 6.5, 5.3 Hz), 5.88 (ddt, 1H, J ) 17.1,
10.3, 6.1 Hz), 6.69 (t, 1H, J ) 1.9 Hz); 13C NMR (62 MHz,
CDCl3) δ 19.6, 21.9, 24.6, 37.5, 40.4, 65.3, 68.6, 118.5, 131.7,
132.9, 148.8, 165.9, 169.4, 199.9; IR (neat) ν 2941, 1735, 1724,
1685, 1246, 1070, 995 cm-1; MS (EI, 70 eV) m/z 267 (M+ + 1),
178, 124, 123, 112; UV (CH2Cl2) λmax (ꢀ) 239 (14 100), 358 (30);
1-(1S)-(1-Bu t-3-en yloxyca r bon yl-1-p h en yl)eth yl 3-Oxo-
cyclop en t-1-en eca r boxyla te (18). Prepared by condensation
of 3-oxocyclopent-1-enecarboxylic acid with 3b according to a
1
protocol similar to that for the formation of 7b: oil, 53%; H
NMR (250 MHz, CDCl3) δ 1.58 (d, 3H, J ) 6.8 Hz), 2.41 (dddt,
2H, J ) 6.7, 1.5, 1.1, 6.5 Hz), 2.54 (m, 2H), 2.88 (dt, 2H, J )
2.3, 4.6 Hz), 5.05-5.16 (m, 2H), 5.23 (q, 1H, J ) 6.8 Hz), 5.76
(ddt, 1H, J ) 17.1, 10.3, 6.7 Hz), 6.83 (t, 1H, J ) 2 Hz); 13C
NMR (62 MHz, CDCl3) δ 16.7, 27.2, 32.8, 35.4, 60.1, 64.3, 69.5,
117.4, 133.3, 138.7, 162.8, 163.5, 208.5; IR (neat) ν 2950, 1730,

R- and â-Hydroxy Acids as Chiral Tether Groups
J . Org. Chem., Vol. 67, No. 4, 2002 1069
1275, 1205, 1130 cm-1; MS (70 eV) m/z 252 (M•+, 11), 224, 199,
NMR (62 MHz, CDCl3) δ 22.2, 27.1, 27.4, 36.9, 40.4, 44.9, 51.1,
71.8, 180.6, 210.7; IR (neat) ν 3022, 1768, 1705, 1228, 1153
cm-1; MS (EI, 70 eV) m/z 180 (M•+), 152, 136, 121, 118, 107;
HMRS calcd for C10H12O3 (M•+) 180.07864, found 180.07862;
153, 109; UV (CH2Cl2) λmax (ꢀ) 235 (13 700), 339 (30); [R]21
+2.4 (c ) 1.0, CHCl3).
)
D
1-(1R)-(2-Allyloxyca r bon yl-1-m eth yl)eth yl 3-Oxocyclo-
p en t -1-en eca r boxyla t e (19). Prepared by condensation of
3-oxocyclopent-1-enecarboxylic acid with 4a according to a
[R]21 ) -103 (c 0.16, CHCl3).
D
Meth yl 7-Hyd r oxym eth yl-5-oxa bicyclo[4.2.01,6]octa n e-
ca r boxyla te (24). Cleavage of 22 according to procedure B:
liquid, 82%; 1H NMR (250 MHz, CDCl3) δ 1.60-1.80 (OH, m),
1.75-2.15 (m, 4H), 2.15-2.30 (m, 2H), 2.35-2.50 (m, 2H), 2.56
(ddt, 1H, J ) 8.7, 6.1, 2.6 Hz), 3.15 (d, 1H, J ) 8.7 Hz), 3.67
(d, 2H, J ) 6.1 Hz); 13C NMR (62 MHz, CDCl3) δ 20.5, 30.8,
31.7, 36.7, 38.4, 44.4, 49.4, 52.2, 65.5, 175.9, 211.7; IR (neat)
ν 3474, 3022, 2947, 1730, 1693, 1454, 1228 cm-1; MS (EI, 70
eV) m/z 212 (M•+), 182, 164, 155, 135, 123, 95, 79; HMRS calcd
1
protocol similar to that for the formation of 7b: oil, 72%; H
NMR (250 MHz, CDCl3) δ 1.40 (d, 3 H, J ) 6.5 Hz), 2.52 (m,
2 H), 2.64 (dd, 1 H, J ) 15.6, 5.7 Hz), 2.75 (dd, 1 H, J ) 15.6,
7.2 Hz), 2.83 (dt, 2 H, J ) 2.3, 4.6 Hz), 4.59 (dt, 2 H, J ) 5.7,
1.1 Hz), 5.20-5.36 (m, 2 H), 5.45 (ddq, 1 H, J ) 6.5, 5.7, 7.2
Hz), 5.89 (ddt, 1 H, J ) 17.1, 10.3, 5.7 Hz), 6.72 (t, 1 H, J ) 2
Hz); 13C NMR (62 MHz, CDCl3) δ 19.7, 27.3, 35.4, 40.5, 65.3,
68.7, 118.5, 131.7, 138.1, 163.4, 164.0, 169.4, 208.8; IR (neat)
ν 2985, 2936, 1727, 1612, 1439, 1280, 1250, 1219, 1185, 1060,
990, 741 cm-1; MS (70 eV) m/z 252 (M•+, 2), 195, 127, 126,
for C11H16O4 (M•+) 212.10486, found 212.10485; [R]21 ) +99
D
(c 0.31, CHCl3).
109; [R]21 ) -31.3 (c ) 0.3, CHCl3). Anal. Calcd for
(1S,4R,9S,11S)-4-Meth yl-3,7-d ioxa tr icyclo[9.4.01,11.01,9]-
p en ta d eca -2,6,12-tr ion e (25a ): solid, 62%; 1H NMR (250
MHz, CDCl3) δ 1.38 (d, 3H, J ) 6.5 Hz), 1.85-2.48 (m, 9H),
2.63-2.75 (m, 1H), 2.78 (dd, 1H, J AB ) 11.4 Hz, J ) 6.1 Hz),
3.47 (dd, 1H, J ) 6.1, 9.9 Hz), 4.06 (dd, 1H, J AB ) 12.2 Hz, J
) 6.9 Hz), 4.33 (dd, 1H, J AB ) 12.2 Hz, J ) 4.6 Hz), 5.36 (tq,
1H, J ) 6.5, 6.1 Hz); 13C NMR (62 MHz, CDCl3) δ 19.8, 21.1,
23.7, 28.7, 39.1, 42.0, 43.2, 52.6, 65.6, 67.4, 171.1, 173.9, 211.9;
IR (neat) ν 2986, 2936, 2860, 1730, 1693, 1454, 1354, 1253,
1190, 1064 cm-1; MS (EI, 70 eV) m/z 266 (M•+), 198, 180, 162,
D
C13H16O5: C, 61.89; H, 6.39. Found: C, 61.68; H, 6.57.
Ir r a d ia tion of Oxoester s. Typ ica l P r oced u r e. Ester 12
(0.324 g, 1 mmol) dissolved in methylene chloride (200 mL)
was poured into Pyrex tubes that were deoxygenated with an
argon stream, fitted with septa, and placed around a HPW
125 Philips lamp. The solution was irradiated at rt until
complete disappearance of the starting material. The solvent
was removed by concentration and the crude product purified
by flash chromatography (AcOEt/hexanes 30/70).
(1R,4S,7S,11R,13R)-4,7-Dim et h yl-3,6,9-t r ioxa t r icyclo-
152, 135, 124, 112, 107; [R]21 ) +130 (c 0.21, CHCl3). Anal.
D
[11.4.01,13.01,11]h ep ta d eca -2,5,8,14-tetr a on e (21): solid, 40%;
Calcd for C14H18O5: C, 63.14; H, 6.81. Found: C, 63.04; H,
6.93.
1
mp ) 151 °C; H NMR (250 MHz, CDCl3) δ 1.53 (d, 3H, J )
7.2 Hz), 1.58 (d, 3H, J ) 6.8 Hz), 1.65-2.20 (m, 4H), 2.25-
2.50 (m, 3H), 2.55-2.70 (m, 2H), 3.66 (t, 1H, J ) 10 Hz), 3.96
(dd, 1H, J AB ) 11.2 Hz, J ) 12.4 Hz), 4.45 (dd, 1H, J AB ) 11.2
Hz, J ) 5.5 Hz), 5.12 (q, 1H, J ) 6.8 Hz), 5.40 (q, 1H, J ) 7.2
Hz); 13C NMR (62 MHz, CDCl3) δ 15.4, 16.1, 20.8, 23.1, 29.3,
37.8, 41.3, 42.5, 49.1, 63.7, 69.8, 71.3, 168.9, 172.6, 210.7; IR
(neat) ν 2961, 2885, 1743, 1705, 1454, 1265, 1078 cm-1; MS
(EI, 70 eV) m/z 324 (M•+), 181, 135, 123; UV (CH2Cl2) λmax (ꢀ)
240 (100), 297 (25); [R]21D ) -146 (c 0.36, CHCl3). Anal. Calcd
for C16H20O7: C, 59.25; H, 6.21. Found: C, 59.20; H, 6.34.
(1S,4S,7S,11S,12S)-4,7-Dim et h yl-3,6,9-t r ioxa t r icyclo-
[9.5.1.01,12]h ep ta d eca -2,5,8,13-tetr a on e (22): solid, 27%; 1H
NMR (250 MHz, CDCl3) δ 1.53 (d, 3H, J ) 7.2 Hz), 1.54 (d,
3H, J ) 6.8 Hz), 1.70-2.25 (m, 4H), 2.26-2.65 (m, 3H), 3.42
(d, 1H, J ) 2.7 Hz), 4.06 (d, 1H, J AB ) 11.1 Hz), 4.30 (dd, 1H,
J AB ) 11.1 Hz, J ) 2.3 Hz), 4.96 (q, 1H, J ) 7.2 Hz), 5.27 (q,
1H, J ) 6.8 Hz); 13C NMR (62 MHz, CDCl3) δ 15.9, 16.8, 20.0,
30.8, 31.3, 34.1, 40.0, 45.6, 48.0, 66.8, 69.8, 71.8, 169.2, 169.9,
176.5, 212.4; IR (neat) ν 2947, 2872, 1755, 1705, 1454, 1265,
1190, 1078 cm-1; MS (EI, 70 eV) m/z 324 (M•+), 181, 135, 123;
HMRS calcd for C16H21O7 (M•+ + 1) 325.12872, found 325.12883;
(1R,4R,9R,11R)-4-Meth yl-3,7-d ioxa tr icyclo[9.4.01,11.01,9]-
p en ta d eca -2,6,12-tr ion e (25b): solid, 16%; 1H NMR (250
MHz, CDCl3) δ 1.43 (d, 3H, J ) 6.5 Hz), 1.80-2.20 (m, 4H),
2.25-2.70 (m, 7H), 3.65 (dd, 1H, J ) 11.4, 7.2 Hz), 3.88 (dd,
1H, J AB ) 11.8 Hz, J ) 1.5 Hz), 4.56 (dd, 1H, J AB ) 11.8 Hz,
J ) 3.0 Hz), 5.48 (ddq, 1H, J ) 6.5, 6.1, 2.7 Hz); 13C NMR (62
MHz, CDCl3) δ 20.2, 20.3, 24.4, 31.0, 38.7, 40.8, 42.9, 43.7,
51.3, 65.9, 68.4, 170.8, 174.8, 212.4; IR (neat) ν 2936, 2885,
1743, 1705, 1454, 1253, 1178, 989 cm-1; MS (EI, 70 eV) m/z
266 (M•+), 180, 140, 135, 124, 107; [R]21 ) -150 (c 0.20,
D
CHCl3).
Keta l 26. A solution of lactone 23 (0.114 g, 0.63 mmol) and
(2R,3R)-2,3-butane diol in toluene (5 mL) was heated in the
presence of a catalytic amount of p-toluenesulfonic acid under
reflux for 4 h using a Dean-Stark apparatus. The solvent was
removed by concentration under vacuo. The crude product was
purified by flash chromatography on silica (AcOEt/hexanes 20/
80) (0.148 g, 0.59 mmol): 92%; 1H NMR (500 MHz, CDCl3)
(major diastereoisomer) δ 1.21 (d, 3H, J ) 6.0 Hz), 1.27 (d,
3H, J ) 6.0 Hz), 1.50-1.60 (m, 2H), 1.60-1.87 (m, 4H), 1.94
(ddd, 1H, J ) 12.2, 8.2, 6.8 Hz), 2.37 (ddd, 1H, J ) 11.8, 8.2,
3.4 Hz), 2.47 (dd, 1H, J ) 8.2, 3.4 Hz), 2.98 (dt, 1H, J ) 13.6,
6.8 Hz), 3.56 (dq, 1H, J ) 8.5, 6.0 Hz), 3.69 (dq, 1H, J ) 8.5,
6.0 Hz), 4.14 (dd, 1H, J AB ) 9.5 Hz, J ) 1.0 Hz), 4.24 (dd, 1H,
J AB ) 9.5 Hz, J ) 5.7 Hz); 1H NMR (500 MHz, CDCl3) (minor
diastereoisomer) δ (characteristic signal) 3.06 (dt, 1H, J ) 13.6,
6.8 Hz); 13C NMR (62 MHz, CDCl3) δ ) 16.3, 17.2, 19.5, 25.1,
33.0, 37.9, 42.9, 49.0, 71.6, 78.4, 78.7, 107.4, 182.5; IR (neat)
ν 2972, 2936, 1768, 1379, 1165, 1090 cm-1; MS (EI, 70 eV)
m/z 252 (M•+, 33), 224 (29), 127 (100).
[R]21 ) +33 (c 0.36, CHCl3).
D
P r oced u r es for t h e Clea va ge of t h e Tet h er Gr ou p .
P r oced u r e A. Cycloadduct 21 (0.100 g, 0.31 mmol) was
dissolved in methanol (3 mL) in a 5 mL flask. Sodium
methylate (0.054 g, 1 mmol) was introduced at once, and the
resulting mixture was stirred for 4 h. The solvent was next
removed by concentration, and the crude product was dissolved
in methylene chloride and acidified with an aqueous 1 N HCl
solution. The aqueous solution was extracted with dichlo-
romethane, and the combined organic layers were dried over
MgSO4 and concentrated. The crude mixture was purified by
flash chromatography on silica (AcOEt/hexanes 30/70).
P r oced u r e B. Adduct 22 (0.081 g, 0.25 mmol) was first
cleaved following procedure A. The crude mixture obtained
after extraction was dissolved in toluene and heated under
reflux in the presence of a catalytic amount of (-)-camphor-
sulfonic acid and by using a Dean-Stark apparatus. After the
mixture was heated for 4 h, toluene was distilled and the crude
material purified by flash chromatography on silica (AcOEt/
hexanes 30/70).
(1R,4S,9S,11R)-4-Meth yl-3,6-d ioxa tr icyclo[9.4.01,11.01,9]-
1
p en ta d eca -2,5,12-tr ion e (27a ): H NMR (250 MHz, CDCl3)
δ 1.51 (d, 3H, J ) 6.9 Hz), 1.70-2.50 (m, 10H), 2.50-2.67 (m,
1H), 3.55 (dd, 1H, J ) 11.0, 7.2 Hz), 3.79 (ddd, 1H, J AB ) 11.0,
J ) 12.2, 3.4 Hz), 4.77 (ddd, 1H, J AB ) 11.0 Hz, J ) 5.0, 1.5
Hz), 5.21 (q, 1H, J ) 6.8 Hz); 13C NMR (62 MHz, CDCl3) δ )
15.3, 21.1, 28.0, 28.8, 31.4, 38.3, 42.1, 42.9, 52.8, 64.9, 74.5,
171.5, 176.1, 211.6; IR (neat) ν 2947, 1755, 1718, 1466, 1253,
1053 cm-1; MS (EI, 70 eV) m/z 266 (M•+, 18), 238 (21), 148
(55), 110 (24); [R]21 ) -232 (0.41, CHCl3).
D
(1S,4S,9R,11S)-4-Meth yl-3,6-d ioxa tr icyclo[9.4.01,11.01,9]-
1
10-Oxatr icyclo[6.3.01,6.01,8]u n deca-5,11-dion e (23). Cleav-
p en ta d eca -2,5,12-tr ion e (27b): H NMR (250 MHz, CDCl3)
1
age of 21 according to procedure A: solid, 67%; H NMR (250
(characteristic signal) δ 4.58 (ddd, 1H, J AB ) 11.0 Hz, J ) 5.0,
MHz, CDCl3) δ 1.60-2.10 (m, 3H), 2.10-2.60 (m, 5H), 2.83
(dd, 1H, J ) 4.0, 10.0 Hz), 2.94 (tq, 1H, J ) 1.1, 7.0 Hz), 4.14
(dd, 1H, J ) 1.1, 9.5 Hz), 4.30 (dd, 1H, J ) 6.0, 9.5 Hz); 13C
1.5 Hz).
(1R,6S,8R)-3-Oxa tr icyclo[6.4.01,6.01,8]-2,9-d od eca d ion e
1
(28): 88%; H NMR (250 MHz, CDCl3) δ 1.73-1.87 (m, 2H),

1070 J . Org. Chem., Vol. 67, No. 4, 2002
Faure et al.
1.93-2.25 (m, 3H), 3.13 (dd, 1H, J ) 11.0, 6.6 Hz), 4.29 (ddd,
1H, J AB ) 11.4 Hz, J ) 8.8, 2.9 Hz), 4.48 (ddd, 1H, J AB ) 11.4
Hz, J ) 6.1, 3.4 Hz); 13C NMR (62 MHz, CDCl3) δ 20.1, 27.6,
28.9, 31.4, 35.3, 38.8, 45.0, 46.6, 67.3, 175.3, 211.1; IR (neat)
ν 2936, 2872, 1718, 1265, 1293, 1153, 1064 cm-1. Anal. Calcd
for C11H14O3: C, 68.03; H, 7.27. Found: C, 68.11; H, 7.58.
Keta l (29). Prepared using the same protocol than 26, from
(2R,3R)-2,3-butanediol and 28a /28b: 1H NMR (250 MHz,
CDCl3) major adduct: δ 1.20 (d, 3H, J ) 5.6 Hz), 1.21 (d, 3H,
J ) 5.4 Hz), 1.52 (ddd, 1H, J AB ) 14.2 Hz, J ) 11.4, 4.2 Hz),
1.70-1.90 (m, 5H), 1.95 (m, 1H), 2.03 (m, 1H), 2.16 (d, 1H,
J AB ) 14.2 Hz), 2.30-2.40 (m, 2H), 2.64 (dd, 1H, J ) 9.2, 8.6
Hz), 3.53 (dq, 1H, J ) 8.2, 6.0 Hz), 3.61 (dq, 1H, J ) 8.2, 6.0
Hz), 4.29 (ddd, 1H, J AB ) 11.0 Hz, J ) 7.1, 3.4 Hz), 4.54 (ddd,
1H, J AB ) 11.0 Hz, J ) 7.9, 2.9 Hz); 1H NMR (250 MHz, CDCl3)
minor adduct (characteristic signal): δ 2.57 (dd, 1H, J ) 9.2,
8.6 Hz); 13C NMR (62 MHz, CDCl3) major adduct: δ 16.8, 16.9,
19.8, 25.2, 28.3, 30.8, 32.7, 36.0, 42.0, 43.7, 67.3, 78.0, 78.1,
107.3, 174.9; IR (neat) ν 2922, 2860, 1718, 1454, 1265, 1178,
1089 cm-1; MS (EI, 70 eV) m/z 266 (M•+, 14), 149 (16), 141
(25), 127 (100).
(dd, 1H, J ) 12.5, 8.1 Hz), 2.17 (dd, 1H, J ) 12.5, 10.5 Hz),
3.07 (dd, 1H, J ) 10.5, 8.1 Hz), 4.26 (ddd, 1H, J AB ) 11.6 Hz,
J ) 8.1, 3.1 Hz), 4.42 (ddd, 1H, J AB ) 11.6 Hz, J ) 6.8, 3.2
Hz); 13C NMR (CDCl3) δ 21.0, 23.1, 25.7, 35.3, 37.4, 38.3, 38.6,
42.8, 49.2, 66.2, 175.4, 211.5; IR (neat) ν 2935, 2875, 1730,
1695, 1455, 1405, 1265, 1190, 1065 cm-1; MS (70 eV) m/z 208
(M•+, 14), 190, 149, 139, 135, 126, 123, 109; [R]21 ) -89 (c
D
0.9, CHCl3). Anal. Calcd for C12H16O3: C, 69.19; H, 7.75.
Found: C, 69.03; H, 7.91.
(1R,6S,8R)-7,7-Dim et h yl-3-oxa t r icyclo[6.4.01,6.01,8]d o-
d eca n e-2,9-d ion e (35): solid, 78%; 1H NMR (500 MHz,
CDCl3) δ 1.05 (s, 3H), 1.14 (s, 3H), 1.86-2.06 (m, 5H), 2.13
(m, 1H), 2.29 (ddd, 1H, J AB ) 18.0 Hz, J ) 9.5, 5.3 Hz), 2.41
(ddd, 1H, J AB ) 18.0 Hz, J ) 5.6, 5.1 Hz), 2.53 (t, 1H, J ) 9.5
Hz), 2.88 (s, 1H), 4.19 (ddd, 1H, J AB ) 11.0 Hz, J ) 2.0, 12.1
Hz), 4.46 (ddd, 1H, J AB ) 11.0 Hz, J ) 3.9, 2.6 Hz); 13C NMR
(CDCl3) δ 18.9, 23.8, 26.7, 32.1, 38.2, 40.0, 41.0, 45.3, 55.9,
67.5, 176.9, 209.4; IR (neat) ν 2960, 2895, 1730, 1680, 1480,
1390, 1205, 1055, 980 cm-1; MS (70 eV) m/z 222 (M•+, 25), 194,
179, 167, 149, 137, 124, 118, 111, 107; [R]21 ) -63 (c 0.9,
D
CHCl3). Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found:
C, 70.36; H, 8.21.
(1R,4S,9S,11R)-4-P h en yl-3,6-d ioxa tr icyclo[9.4.01,11.01,9]-
pen tadecan e-2,5,12-tr ion e (30): solid, 62%; 1H NMR (CDCl3)
δ 1.49 (d, 1 H, J ) 15.2 Hz), 1.80-2.20 (m, 4 H), 2.20-2.65
(m, 5 H), 2.67-2.80 (m, 1 H), 3.60 (dd, 1 H, J ) 11.2, 8.2 Hz),
3.74 (ddd, 1 H, J AB ) 11.2 Hz, J ) 12.2, 3.2 Hz), 4.89 (dd, 1 H,
J AB ) 11.2 Hz, J ) 5.0 Hz), 6.07 (s, 1 H), 7.39-7.41 (m, 3 H,),
7.50-7.55 (m, 2 H); 13C NMR (CDCl3) δ 21.0, 28.2, 29.9, 31.6,
38.2, 42.0, 43.0, 52.9, 65.4, 79.9, 126.9, 128.8, 129.4, 132.1,
169.3, 175.7, 211.4; IR (neat) ν 2947, 2860, 1743, 1705, 1454,
1228, 1103, 1028, 702 cm-1; MS (70 eV) m/z 328 (M+•, 17), 222,
(1S,4S,9S,11R)-4-Meth yl-3,6-d ioxa tr icyclo[9.3.01,11.01,9]-
tetr adecan e-2,5,12-tr ion e (36a): solid, 36%; 1H NMR (CDCl3)
δ 1.67 (d, 3H, J ) 6.9 Hz), 1.70-1.90 (m, 1H), 1.90-2.55 (m,
6H), 2.65-2.90 (m, 2H), 3.14 (dd, 1H, J ) 11.2, 4.4 Hz), 4.19
(ddd, 1H, J AB ) 11.4 Hz, J ) 7.2, 4.2 Hz), 4.53 (ddd, 1H, J AB
) 11.4 Hz, J ) 6.5, 4.6 Hz), 5.00 (q, 1H, J ) 6.9 Hz); 13C NMR
(CDCl3) δ 16.1, 25.8, 29.9, 33.1, 37.3, 42.9, 44.1, 55.1, 63.8,
74.9, 171.1, 176.5, 218.6; IR (neat) ν ) 2922, 2850, 1743, 1440,
1280, 1165, 1055 cm-1; MS (70 eV) m/z 252 (M•+, 22), 224, 109;
195, 178, 150, 123, 118, 105; [R]21 ) -141 (c ) 0.97, CHCl3).
[R]21 ) +197 (c ) 0.3, CHCl3).
D
D
Anal. Calcd for C19H20O5: C, 69.49; H, 6.13. Found: C, 69.70;
H, 6.07.
(1R,4S,9R,11S)-4-Meth yl-3,6-d ioxa tr icyclo[9.3.01,11.01,9]-
tetr adecan e-2,5,12-tr ion e (36b): solid, 28%; 1H NMR (CDCl3)
δ 1.67 (d, 3H, J ) 6.9 Hz), 1.70-1.90 (m, 1H), 1.90-2.55 (m,
6H), 2.65-2.90 (m, 2H), 3.14 (dd, 1H, J ) 12.2, 4.4 Hz), 4.19
(ddd, 1H, J AB ) 11.4 Hz, J ) 7.2, 4.2 Hz), 4.53 (ddd, 1H, J AB
) 11.4 Hz, J ) 6.5, 4.6 Hz), 5.00 (q, 1H, J ) 6.9 Hz); 13C NMR
(CDCl3): δ 15.5, 27.3, 29.1, 32.4, 37.2, 43.5, 54.9, 65.1, 74.6,
171.8, 175.7, 218.1.
(1R,4S,9S,11R)-4-Ben zyl-3,6-d ioxa tr icyclo[9.4.01,11.01,9]-
pen tadecan e-2,5,12-tr ion e (31): solid, 50%; 1H NMR (CDCl3)
δ 1.50-2.55 (m, 11 H), 3.05 (d, 2 H, J ) 6.7 Hz), 3.41 (dd, 1 H,
J ) 11.2, 7.8 Hz), 3.64 (td, 1 H, J AB ) 11.4 Hz, J ) 11.4, 3.0
Hz), 4.72 (dd, 1 H, J AB ) 11.4 Hz, J ) 4.0 Hz), 5.22 (t, 1 H, J
) 6.7 Hz), 7.10-7.30 (m, 5 H); 13C NMR (CDCl3) δ 20.8, 28.0,
28.8, 31.5, 36.2, 38.2, 42.1, 42.7, 52.8, 65.3, 78.9, 127.1, 128.5,
129.2, 135.5, 170.5, 176.1, 211.9; MS (70 eV) m/z 342 (M•+, 14),
148, 131. Anal. Calcd for C20H22O5: C, 70.15; H, 6.48. Found:
C, 69.88; H, 6.82.
(1S,4R,9S,11S)-4-Meth yl-3,7-d ioxa tr icyclo[9.4. 01,11.01,9]-
tetr adecan e-2,6,12-tr ion e (37a): solid, 58%; 1H NMR (CDCl3)
δ 1.39 (d, 3 H, J ) 6.1 Hz), 1.90-2.50 (m, 5 H), 2.51 (ddd, 1 H,
J ) 9, 3, 1.9 Hz), 3.65-2.83 (m, 3 H), 3.07 (dd, 1 H, J ) 9.3,
5 Hz), 3.87 (d, 1 H, J AB ) 12.2 Hz), 4.61 (dd, 1 H, J AB ) 12.2
Hz, J ) 2 Hz), 5.50 (m, 1 H); 13C NMR (CDCl3) δ 20.1, 23.1,
30.2, 36.7, 40.7, 42.9, 44.1, 52.7, 64.9, 67.4, 170.6, 173.9, 218.6;
(1 R ,4 S ,9 S ,1 1 R )-4 ,9 -D i m e t h y l -3 ,6 -d i o x a t r i c y c l o -
[9.4.0.1,11.01,9]tetr a d eca n e-2,5,12-tr ion e (32): solid, 65%; 1H
NMR (CDCl3) δ 1.29 (s, 3H), 1.51 (s, 3H), 1.60-1.80 (m, 1H),
1.96 (td, 1H, J ) 13.0, 3.3 Hz), 1.98 (t, 2H, J ) 10.8 Hz), 2.05-
2.15 (m, 1H), 2.10 (t, 1H, J ) 11.0 Hz), 2.30-2.42 (m, 2H),
2.50-2.60 (m, 2H), 3.57 (t, 1H, J ) 10.4 Hz), 3.93 (ddd, 1H,
J AB ) 12.0 Hz, J ) 12.2, 3.9 Hz), 4.74 (dd, 1H, J AB ) 12.0 Hz,
J ) 6.0 Hz), 5.14 (q, 1H, J ) 7.0 Hz); 13C NMR (CDCl3) δ 15.3,
19.7, 21.4, 24.4, 36.6, 37.3, 38.2, 69.6, 112.5, 133.6, 141.1, 148.0,
165.8, 170.1, 199.9; IR (neat) ν 2980, 2870, 1755, 1720, 1465,
IR (neat) ν ) 2961, 2922, 1743, 1454, 1304, 1190, 1039 cm-1
MS (70 eV) m/z 252 (M•+, 27), 166, 148, 138, 127, 120, 109.
;
(1R,4R,9R,11R)-4-Meth yl-3,7-d ioxa tr icyclo[9.4 01,11.01,9]-
tetr adecan e-2,6,12-tr ion e (37b): solid, 31%; 1H NMR (CDCl3)
δ 1.40 (d, 3 H, J ) 6.5 Hz), 2.05 (ddd, 1 H, J ) 12.6, 8.5, 4.6
Hz), 2.15-2.44 (m, 4 H), 2.51 (ddd, 1 H, J ) 9.1, 4.6, 1.9 Hz),
2.60-2.80 (m, 2 H), 2.94 (m, 1 H), 3.14 (dd, 1 H, J ) 11, 4.6
Hz), 4.26 (dd, 1 H, J AB ) 11.8 Hz, J ) 8.8 Hz), 4.31 (dd, 1 H,
J AB ) 11.8 Hz, J ) 6.8 Hz), 5.42 (ddq, 1 H, J ) 8.0, 4.6, 6.5
Hz); 13C NMR (CDCl3) δ 19.9, 23.4, 29.0, 37.5, 39.9, 42.9, 43.1,
1380, 1240, 1140, 1105, 1065 cm-1; MS (70 eV) m/z 280 (M•+
,
17), 213, 209, 163, 135, 123, 107; [R]21D ) -156 (c 0.9, CHCl3).
Anal. Calcd for C15H20O5: C, 69.27; H, 7.19. Found: C, 64.26;
H, 7.31.
52.8, 67.1, 67.5, 171.2, 173.2, 217.9; [R]21 -224 (c ) 0.6,
D
(1R,4S,9R,11R)-4,10,10-Tr im et h yl-3,6-d ioxa t r icyclo-
[9.4.01,9.01,11]p en ta d eca n e-2.5 12-tr ion e (33): oil, 81%; 1H
NMR (CDCl3) δ 1.10 (s, 3H), 1.15 (s, 3H), 1.38 (dd, 1H, J )
15.4, 1.2 Hz), 1.51 (d, 3H, J ) 7.0 Hz), 1.71 (m, 1H), 1.80-
2.20 (m, 3H), 2.25-2.40 (m, 3H), 2.72 (ddd, 1H, J ) 14.2, 7.4,
2.8 Hz), 3.16 (s, 1H), 3.69 (ddd, 1H, J AB ) 11.0 Hz, J ) 13.0,
2.5 Hz), 4.89 (ddd, 1H, J AB ) 11.0 Hz, J ) 4.6, 1.0 Hz), 5.17
(q, 1H, J ) 7.0 Hz); 13C NMR (CDCl3) δ 15.6, 20.3, 25.6, 26.7,
27.3, 30.2, 38.6, 40.1, 49.3, 53.1, 53.3, 65.7, 74.7, 172.0, 177.5,
210.7; IR (neat) ν 2960, 2895, 1755, 1695, 1455, 1240, 1055
cm-1; MS (70 eV) m/z 294 (M•+, 28), 222, 213, 176, 149, 135,
CHCl3).
Ack n ow led gm en t. S.F. and S.P.L.B. warmly thank
M.E.N.R.T. and Re´gion Champagne-Ardenne, respec-
tively, for Ph.D. grants. Professor Alix and Mrs. Charton
(Inserm U. 314, Reims) are acknowledged for their help
in recording the CD spectra. O.P. acknowledges C.N.R.S.
for substantial support (AIP 1999-2001).
Su p p or tin g In for m a tion Ava ila ble: ORTEP structure
1
and tables of X-ray crystallography data of compound 21. H
123, 111, 107; [R]21 ) -232 (c 0.9, CHCl3). Anal. Calcd for
and 13C spectra of 3b,c, 7b, 16, 18, 22-24, 27, 36, and 37.
This material is available free of charge via the Internet at
htpp://pubs.acs.org.
D
C
16H22O5: C, 65.29; H, 7.53. Found: C, 65.53; H, 7.81.
(1R,6S,8R)-6-Meth yl-3-oxatr icyclo[6.4.01,6.01,8]dodecan e-
1
2,9-d ion e (34): solid, 69%; H NMR (CDCl3) δ 1.13 (s, 3H),
1.74 (ddd, 1H, J ) 14.5, 6.8, 3.1 Hz), 1.80-2.40 (m, 7H), 2.07
J O001631E