Synthesis of enantio- and diastereomerically pure, tetra- and penta- substituted cyclopentanes by the desymmetrization of endo-norborn-5-ene-2,3- dicarboxylic anhydrides

Article abstract of DOI:10.1021/jo990140v

The desymmetrization of endo-norborn-5-ene-2,3-dicarboxylic anhydrides by methyl (S)-prolinate followed by ozonolysis of the resulting carboxylic acids is used to prepare enantio- and diastereomerically pure, tetra- and penta-substituted cyclopentane derivatives in which all of the substituents on the cyclopentane ring are syn to one another. The initial products of this chemistry (2a,b and 18a,b) contain two aldehyde groups, one of which exists as a hemiacetal. This allows subsequent chemistry to be carried out regioselectively at one of the two aldehyde groups. Hence, the sodium borohydride reduction of hemiacetals 2a,b can be controlled to give either a bicyclo[3.2.1] (4) or bicyclo[3.3.0] lactone (5) as the product. The addition of allylindium to hemiacetals 2a,b occurs both regio- and diastereoselectively to give polycyclic acetal 12, the stereochemistry of which is consistent with a chelation controlled addition. It is possible to remove the proline ester based auxiliary from the cyclopentane derivatives by γ-lactone formation under mild reaction conditions.

Full text of DOI:10.1021/jo990140v

J . Org. Chem. 1999, 64, 5413-5421
5413
Syn th esis of En a n tio- a n d Dia ster eom er ica lly P u r e, Tetr a - a n d
P en ta -Su bstitu ted Cyclop en ta n es by th e Desym m etr iza tion of
en d o-Nor bor n -5-en e-2,3-d ica r boxylic An h yd r id es
David E. Hibbs,§ Michael B. Hursthouse,§ Iwan G. J ones,† Wyn J ones,‡
K. M. Abdul Malik,§ and Michael North*,†
Department of Chemistry, University of Wales, Bangor, Gwynedd, LL57 2UW, UK, Peboc Division of
Eastman Chemical (UK) Ltd., Industrial Estate, Llangefni, Anglesey, Gwynedd, LL77 7YQ, UK, and
Department of Chemistry, University of Wales, Cardiff, P.O. Box 912, Park Place, Cardiff CF1 3TB, UK
Received J anuary 26, 1999
The desymmetrization of endo-norborn-5-ene-2,3-dicarboxylic anhydrides by methyl (S)-prolinate
followed by ozonolysis of the resulting carboxylic acids is used to prepare enantio- and diastereo-
merically pure, tetra- and penta-substituted cyclopentane derivatives in which all of the substituents
on the cyclopentane ring are syn to one another. The initial products of this chemistry (2a ,b and
18a ,b) contain two aldehyde groups, one of which exists as a hemiacetal. This allows subsequent
chemistry to be carried out regioselectively at one of the two aldehyde groups. Hence, the sodium
borohydride reduction of hemiacetals 2a ,b can be controlled to give either a bicyclo[3.2.1] (4) or
bicyclo[3.3.0] lactone (5) as the product. The addition of allylindium to hemiacetals 2a ,b occurs
both regio- and diastereoselectively to give polycyclic acetal 12, the stereochemistry of which is
consistent with a chelation controlled addition. It is possible to remove the proline ester based
auxiliary from the cyclopentane derivatives by γ-lactone formation under mild reaction conditions.
In tr od u ction
alcohols and chiral amines can be used to generate
stereochemically pure products containing two different
functional groups: an acid and either an ester or an
amide. In recent publications,2 we have shown that esters
of the naturally occurring, enantiomerically pure amino
acid (S)-proline can be used to desymmetrize a wide
range of meso anhydrides, forming amido acids with high
diastereomeric excesses. The applications of this chem-
istry to date have focused upon the synthesis of confor-
mationally constrained peptide analogues where the
proline unit is retained within the final product.3 In this
paper, however, the conversion of the enantio- and
diastereomerically pure amido acid 1, which is easily
obtained from methyl (S)-prolinate and endo-norborn-5-
ene-2,3-dicarboxylic anhydride, into enantiomerically
pure cyclopentane derivatives is reported.4
Highly substituted cyclopentane rings are found within
many biologically active natural and unnatural products
such as prostaglandins, carbocyclic nucleosides, and
carba-sugars. Specific examples include (+)-mannostatin
A which inhibits Golgi from processing mannosidase II,
sarkomycin an antibiotic, (-)-aristeromycin an antineo-
plasic antibiotic, and trehazolin an inhibitor of the
enzyme trehalase which is involved in the control of
insects and certain fungi.5 The stereocontrolled synthesis
of cyclopentane derivatives is, however, more challenging
The desymmetrization of an achiral meso compound
by reaction with a suitable enantiomerically pure reagent
provides a versatile approach to the preparation of
enantiomerically pure starting materials for asymmetric
synthesis.1 The most common classes of chemicals which
can be subjected to desymmetrization include diols,
diesters, and anhydrides. In the latter case, both chiral
* Current address: Department of Chemistry, Kings College,
Strand, London, WC2R 2LS, UK.
† University of Wales, Bangor.
‡ Peboc Division of Eastman Chemical.
§ University of Wales, Cardiff.
(1) Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic Organic
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C. G.; Hibbs, D. E.; Hursthouse, M. B.; Malik, K. M. A.; North, M.;
Uriarte, E.; Zagotto, G. Synthesis 1996, 393. J ones, I. G.; J ones, W.;
North, M.; Teijeira, M.; Uriarte, E. Tetrahedron Lett. 1997, 38, 889.
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North, M. Lett. Peptide Sci. 1998, 5, 171. Hibbs, D. E.; Hursthouse,
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10.1021/jo990140v CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

5414 J . Org. Chem., Vol. 64, No. 15, 1999
Hibbs et al.
Sch em e 1
Sch em e 2a
than the synthesis of cyclohexane derivatives since most
five-membered ring containing compounds do not have
a single, low-energy conformation.6 This is in contrast to
the situation with cyclohexane derivatives where often,
the desire for the six-membered ring to adopt a chair
conformation and for substituents attached to the ring
to adopt equatorial positions results in only one confor-
mation having a significant population.7 An attractive
solution to this problem is to use a conformationally rigid
norbornene derivative as a cyclopentane precursor. This
approach is particularly appealing given the ease with
which diastereomerically pure norbornene derivatives
bearing substituents at the 2, 3, and 7 positions can be
prepared by Diels-Alder reactions.8 Oxidative cleavage
of the alkene bond within the norbornene would then
reveal a cyclopentane ring bearing two aldehyde substit-
uents and with substituents on the remaining carbon
atoms if desired. The aldehyde groups provide sites for
further manipulation, provided that they can be distin-
guished. In this manuscript, we show how the combina-
tion of a Diels-Alder reaction between cyclopentadiene
derivatives and maleic anhydride, followed by desym-
metrization and ozonolysis can be used in an enantio-
and diastereocontrolled synthesis of highly substituted
cyclopentanes as outlined in Scheme 1.
Resu lts
Reaction of endo-norborn-5-ene-2,3-dicarboxylic anhy-
dride with methyl (S)-prolinate gave amido acid 1 as a
single stereoisomer as previously reported.2 Gratifyingly,
ozonolysis of amido acid 1 proceeded in 92% yield to give
a 1:1 mixture of two products which were identified as
either the epimeric [3.3.0]bicyclic aldehydes 2a ,b, or the
corresponding [3.2.1]bicyclic aldehydes 3a ,b as shown in
Scheme 2. It has not proven possible to unambiguously
assign structures to these two compounds, but on the
basis of subsequent results and the fact that molecular
a
Reagents: (i) O3 then Me2S; (ii) NaBH4/MeOH; (iii) CHCl3 or
p-TolSO3H; (iv) BrC6H4COCl/Et3N.
mechanics calculations suggested that [3.3.0]bicyclic
systems are thermodynamically more stable than the
corresponding [3.2.1]bicyclic compounds, the compounds
have been tentatively assigned structures 2a ,b. Notably
however, whichever aldehydes were formed, one of the
two aldehydes generated during the ozonolysis was
converted into a hemiacetal, and it was envisaged that
this would allow subsequent chemistry to be carried out
selectively on one of the aldehydes.
(5) For selected examples, see: Tropea, J . E.; Kaushal, G. P.;
Pastuszak, I.; Mitchell, M.; Aoyagi, T.; Molyneux, R. J .; Elbein, A. D.
Biochemistry 1990, 29, 10062. Aoyagi, T.; Yamamoto, T.; Kojiri, K.;
Morisha, H.; Nagai, M.; Hamada, M.; Takeuchi, T.; Umezawa, H. J .
Antibiot. 1989, 42, 883. Scarborough, R. M., J r.; Toder, B. H.; Smith,
A. B., III J . Am. Chem. Soc. 1980, 102, 3904. Altmann, K.-H.;
Kesselring, R.; Francotte, E.; Rihs, G. Tetrahedron Lett. 1994, 35, 2331.
Ando, O.; Satake, H.; Itoi, K.; Sato, A.; Nakajima, M.; Takahashi, S.;
Haruyama, H. J . Antibiot. 1991, 44, 1165.
To obtain a compound which could be unambiguously
identified, the mixture of aldehydes 2a ,b was treated
with sodium borohydride. This resulted in the reduction
of both the aldehyde and hemiacetal functionalities,
giving [3.2.1]bicyclic lactone 4 as the initial product. On
standing in CHCl3, or more quickly on treatment with
p-toluenesulfonic acid, lactone 4 isomerized to the cor-
responding [3.3.0]bicyclic lactone 5. 1H and 13C NMR
spectroscopy could not distinguish between the [3.2.1]
(6) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; pp 758-62.
(7) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; pp 686-754.
(8) For a review and leading reference see: March, J . Advanced
Organic Chemistry 4th ed.; Wiley: New York, 1992; pp 839-46.

endo-Norborn-5-ene-2,3-dicarboxylic Anhydrides
J . Org. Chem., Vol. 64, No. 15, 1999 5415
Sch em e 3a
a
Reagents: (i) NaBH4.
Sch em e 4a
a
Reagents: (i) Me2SO/Et3N/ClCOCOCl; (ii) NaBH4.
and [3.3.0]bicyclic structures in lactones 4 and 5; how-
ever, the structures of these lactones were unambigu-
ously determined by X-ray crystallography. Crystals of
lactone 5 suitable for X-ray analysis could be obtained.
Lactone 4 however, did not form crystals suitable for
X-ray analysis, so it was converted to the corresponding
p-bromobenzoate 6 (yield not optimized) which was
suitable for X-ray analysis. To prove that no isomerism
between the [3.2.1] and [3.3.0]bicyclic ring systems
occurred under the esterification conditions, lactone 5
was also converted into p-bromobenzoate 7. No contami-
nation of compound 7 with compound 6 or vice versa was
detected in these reactions. In addition to showing which
bicyclic ring system was present in each of lactones 4 and
5, the X-ray structures also confirmed that no epimer-
ization of any of the stereocenters in compounds 4 or 5
had occurred during the ozonolysis or reduction proc-
esses.
An explanation for the initial formation of the strained
[3.2.1]bicyclic lactone 4 is shown in Scheme 3. Thus, the
hemiacetal of compounds 2a ,b acts as a partial protecting
group for one of the aldehydes, and sodium borohydride
then preferentially reduces the other aldehyde. Cycliza-
tion of the resulting alkoxide (probably assisted by a
Lewis acid generated in situ from the sodium borohy-
dride) generates the [3.2.1]bicyclic ring system, and
simultaneously deprotects the other aldehyde, which is
then reduced to an alcohol after formation of the bicyclic
ring system. Whatever the mechanism of this transfor-
mation, it is possible to isolate either lactone 4 or lactone
5 from the reduction, and both compounds contain a
cyclopentane ring with four different substituents all
oriented syn to one another.
tions. The oxidation of lactone 5 proceeded without
difficulty under standard Swern oxidation9 conditions to
give aldehyde 8 (Scheme 4). That no rearrangement
occurred during the oxidation reaction was shown by
reduction of aldehyde 8 back to alcohol 5. In contrast,
however, oxidation of lactone 4 gave none of the expected
aldehyde attached to a [3.2.1]bicyclic ring system. The
major product of this reaction was identified as the
methylthiomethyl ester containing cyclopentane dicar-
boxaldehyde derivative 9, which was always accompanied
by about 30% of aldehyde 8, the latter presumably being
formed by the rearrangement of lactone 4 to lactone 5
under the acidic reaction conditions. The structure of
compound 9 was determined to be the methylthiomethyl
ester rather than the isomeric â-ketosulfoxide 10 on the
basis of the 1H NMR chemical shifts of the diastereotopic
SCH2O protons,10 the absence of a ketone carbonyl in the
13C NMR spectrum, and the absence of a sulfoxide stretch
in the infrared spectrum.
The unexpected formation of dialdehyde 9 can be
explained by a Pummerer rearrangement as shown in
Scheme 5. Thus, initial reaction between oxalyl chloride
and DMSO generates chloromethyl methylthioether,11
which can alkylate the lactone carbonyl. This alkylation
Having demonstrated that it was possible to prepare
diastereomerically pure lactones 4 and 5, the oxidation
of the alcohol functionality in these compounds to the
corresponding aldehyde was investigated. It was antici-
pated that this oxidation would both prevent the isomer-
ization of the [3.2.1]ring system to the thermodynami-
cally more stable [3.3.0]isomer, and provide a site for
subsequent stereoselective nucleophilic addition reac-
(9) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480.
(10) For a previous report of the 1H NMR chemical shifts of a
methylthiomethyl ester, see: Kukla, M. J . Tetrahedron Lett. 1982, 23,
4539. For the 1H NMR chemical shifts of a â-ketosulfoxide, see: Drewe,
J . A.; Groundwater, P. W. J . Chem. Soc., Perkin Trans. 1 1997, 601.

5416 J . Org. Chem., Vol. 64, No. 15, 1999
Hibbs et al.
Sch em e 5
is likely to be assisted by the strain in the [3.2.1]ring
system. Subsequent lactone ring opening by DMSO leads
to an intermediate 11 in which the methylthiomethyl
ester has been formed, and one of the two alcohols has
been converted into an intermediate which forms during
a Swern oxidation. From intermediate 11, compound 9
can be formed by standard Swern oxidations. The forma-
tion of dialdehyde 9 requires 3 equiv of DMSO, and
Swern oxidations are normally carried out using a 3-fold
excess of DMSO. The oxidation of lactone 4 was also
attempted using a stoichiometric amount of DMSO, but
this resulted in a reduced yield of dialdehyde 9 and the
isolation of lactone 5 as the only products.
In view of these results, it appeared unlikely that the
asymmetric addition of nucleophiles to aldehydes derived
from lactones 4 or 5 would provide a viable route to highly
substituted cyclopentanes. However, compounds 2a ,b
contain both a free aldehyde and an aldehyde which has
been partially protected by conversion to a hemiacetal
unit. It was apparent that if nucleophiles could be
stereoselectively added to just the free aldehyde of
compounds 2a ,b, then a short and highly versatile
cyclopentane synthesis would be achieved. In the event,
the reaction between compounds 2a ,b and Grignard or
organolithium reagents was not encouraging, with com-
plex mixtures of products being obtained. The results
reported by Paquette et al.12 on the addition of allyl-
indium reagents to aldehydes in aqueous solvent sys-
tems13 appeared to offer considerable potential for ap-
plication to our system. In particular, Bernadelli and
Paquette have reported the diastereoselective addition
of allylindium to γ-hydroxy-γ-lactones.14 The reaction of
compounds 2a ,b with 1 equiv of allylindium in an
ethanol/water mixture gave a single isolated product,
which on the basis of its spectra was assigned as acetal
12 (Scheme 6), though the configuration of the newly
created stereocenter was not clear at this stage. The
addition of 2 equiv of allylindium to compounds 2a ,b gave
a diallylated product 13a ,b, as a 4:1 ratio of diastereo-
mers which were separable by chromatography.
able to determine the absolute configuration of com-
pounds 12 and 13, and to find a way of removing the
proline based auxiliary. In the event, both aims were
achieved by acid catalyzed lactonization. Thus, treatment
of acetal 12 with sodium borohydride followed by p-
toluenesulfonic acid resulted in reductive cleavage of the
acetal unit followed by lactonization to allyl-bis-lactone
14 which was isolated as a single stereoisomer in 94%
yield. Compound 14 was crystalline, and gave crystals
suitable for X-ray analysis, which confirmed that the
stereocenter adjacent to the allyl group had the (S)-
configuration. It is notable that compound 14 which
contains five contiguous stereocenters and functionality
suitable for further manipulation can be prepared in a
completely enantio- and diastereo controlled manner in
just four steps from achiral endo-norborn-5-ene-2,3-
dicarboxylic anhydride. The structure of the major dia-
stereomer of alcohol 13 was also determined by treatment
with p-toluenesulfonic acid to give the achiral meso
compound 15. The structure of bis-lactone 15 was ap-
parent from the symmetry evident in its NMR spectra
and its lack of optical activity.
Sch em e 6a
Having found conditions for the diastereoselective
addition of allylindium to compounds 2a ,b, it was desir-
(11) There is literature precedent for the conversion of DMSO into
chloromethyl methylthioether upon treatment with acid chlorides:
Bordwell, F. G.; Pitt, B. M. J . Am. Chem. Soc. 1955, 77, 572. Amonoo-
Neizer, E. H.; Ray, S. R.; Shaw, R. A.; Smith, B. C. J . Chem. Soc. 1965,
6250. Thea, S.; Cevasco, G. J . Org. Chem. 1988, 53, 4121.
(12) Paquette, L. A.; Lobben, P. C. J . Am. Chem. Soc. 1996, 118,
1917. Paquette, L. A.; Mitzel, T. M. J . Am. Chem. Soc. 1996, 118, 1931.
Paquette, L. A.; Mitzel, T. M.; Isaac, M. B.; Crasto, C. F.; Schomer, W.
W. J . Org. Chem. 1997, 62, 4293. Isaac, M. B.; Paquette, L. A. J . Org.
Chem. 1997, 62, 5333.
(13) For reviews on the use of organometallic reagents including
organoindium reagents in aqueous solvent systems, see: Chan, T. H.;
Li, C.-J .; Lee, M. C.; Wei, Z. Y. Can. J . Chem. 1994, 72, 1181. Li, C.-J .
Tetrahedron 1996, 52, 5643.
a
Reagents: (i) In (1.1 equiv), H2CdCHCH2Br (1.5 equiv)/HCl/
EtOH; (ii) NaBH4; (iii) In (2.1 equiv), H2CdCHCH2Br (2.5 equiv)/
HCl/EtOH; (iv) p-TolSO3H.
(14) Bernadelli, P.; Paquette, L. A. J . Org. Chem. 1997, 62, 8284.

endo-Norborn-5-ene-2,3-dicarboxylic Anhydrides
J . Org. Chem., Vol. 64, No. 15, 1999 5417
Sch em e 7a
a
Reagents: (i) HCl, (S)-Pro-OMe/Et3N; (ii) O3/MeOH then Me2S; (iii) Me2SO/ClCOCOCl/Et3N; (iv) p-TolSO3H; (v) NaBH4; (vi) K2CO3;
(vii) In (1.1 equiv)/H2CdCHCH2Br (1.5 equiv)/HCl/THF.
The origin of the asymmetric induction in the forma-
tion of allyl adducts 12 and 13 can be explained by a
chelation controlled addition of an allyl anion equivalent
to the si-face of the aldehyde as shown in Figure 1. Thus,
the indium ion complexes to both the aldehyde and amide
oxygen atoms, and the cyclic hemiacetal unit blocks the
re-face of the coordinated aldehyde. The allyl group may
be transferred intra- or intermolecularly. During the
addition of the second allyl group, a chelate involving the
aldehyde and either the acid or amide carbonyls may be
formed. The lower asymmetric induction observed during
this addition is consistent with the lack of a rigid, cyclic
group to block one face (the si-face) of the aldehyde.
ene16 and maleic anhydride, silyl groups can be trans-
formed into a wide range of other functionalities,17 and
the large size of the trimethylsilyl group was expected
to provide a stringent test of the scope of the methodol-
ogy. Desymmetrization of anhydride 16 by methyl (S)-
prolinate gave a 3:1 ratio of diastereomeric acids 17a ,b
(Scheme 7). The major isomer is assumed to have
structure 17a , based on precedent from all other endo-
norbornane derived anhydrides previously investigated
in this reaction.2 The two diastereomeric acids 17a ,b were
not readily separated; however, ozonolysis of the mixture
followed by flash chromatography to remove products
arising from diastereomer 17b, gave a product which
existed as a pair of epimers 18a ,b. Although compounds
18a ,b were clearly hemiacetals, no aldehyde group was
1
evident in the H or 13C NMR spectra of the compound.
However, additional low-field doublets were present in
1
both the H (5.8 and 5.9 ppm) and 13C (99.5 and 102.8
ppm) spectra, and on this basis, the compounds are
assigned the structure shown in Scheme 7 consisting of
F igu r e 1. Structure of the chelated complex that accounts
for the asymmetric induction during the addition of allyl-
indium to hemiacetals 2a ,b.
(15) Magnus, P.; Cairns, P. M.; Moursounidis, J . J . Am. Chem. Soc.
1987, 109, 2469.
(16) Kraihanzel, C. S.; Losee, M. L. J . Am. Chem. Soc. 1968, 90,
4701. Ranganathan, D.; Rao, C. B.; Ranganathan, S.; Mehrotra, A. K.;
Iyengar, R. J . Org. Chem. 1980, 45, 1185.
Having shown that tetrasubstituted cyclopentane de-
rivatives could be prepared using this methodology, it
was of interest to investigate whether the same meth-
odology could be used to prepare pentasubstituted cyclo-
pentanes in which all five substituents are syn to one
another. Trimethylsilyl was chosen as the fifth substitu-
ent since the required anhydride 16 is known15 and can
readily be prepared from 5-trimethylsilylcyclopentadi-
(17) Carpino, L. A.; Sau, A. C. J . Chem. Soc., Chem. Commun. 1979,
514. Boschelli, D.; Takemasa, T.; Nishitani, Y.; Masamune, S. Tetra-
hedron Lett. 1985, 26, 5239. Landais, Y. Tetrahedron 1996, 52, 7599.
Chow, H.-F.; Fleming, I. Tetrahedron Lett. 1985, 26, 397. Fleming, I.;
Kilburn, J . D. J . Chem. Soc., Chem. Commun. 1986, 1198. Polniaszek,
R. P.; Dillard, L. W. J . Org. Chem. 1992, 57, 4103. Roush, W. R.;
Grover, P. T. Tetrahedron 1992, 48, 1981. Hart, D. J .; Krishnamurthy,
R. J . Org. Chem. 1992, 57, 4457. Fleming, I.; Henning, R.; Parker, D.
C.; Plaut, H. E.; Sanderson, P. E. J . J . Chem. Soc., Perkin Trans. 1
1995, 317.

5418 J . Org. Chem., Vol. 64, No. 15, 1999
Hibbs et al.
a fused tricyclic ring system containing both acetal and
hemiacetal functionalities.
The tricyclic acetal-hemiacetal unit present in com-
pounds 18a ,b appears to be remarkably stable, since
Swern oxidation of compounds 18a ,b preserves the ring
system and forms bis-lactone 19. Even more remarkably,
treatment of epimers 18a ,b with p-toluenesulfonic acid
resulted in lactonization to give the achiral, tetracyclic
bis-lactone 20. Compound 20 has a very interesting
structure in which the top face of the molecule is
completely devoid of functionality, while the lower face
contains five rigidly located oxygen atoms. The potential
of this and similar compounds to act as metal ion
complexing agents is currently under investigation.
Sodium borohydride reduction of hemiacetals 18a ,b
produced lactone 21 which contains a [3.3.0]bicyclic ring
system and is analogous to lactone 5 produced from the
non-silylated hemiacetals 2a ,b. The presence of the
corresponding [3.2.1]ring system was not observed in this
case. Treatment of compound 21 with p-toluenesulfonic
acid gave bis-lactone 22. When hemiacetals 18a ,b were
treated with even mild base (potassium carbonate),
inversion of configuration at two of the five stereocenters
on the cyclopentane ring occurred to give dialdehyde 23.
The stereochemistry of compound 23 was deduced from
F igu r e 2. The likely minimum energy conformation of
trimethylsilyl substituted cyclopentanes showing the axial
location of the carbonyl substituents. Arrows indicate cycliza-
tions which are facile due to the conformation of the molecules.
are likely to be conformationally flexible as each of the
substituents will occupy the least hindered conformation
for some of the time. Hence, there is a lower entropic cost
associated with cyclization reactions involving the silyl-
ated compounds than the corresponding non-silylated
compounds. This explains why ozonolysis of acid 1 gives
bicyclic hemiacetals 2a ,b, while ozonolysis of acid 17a
gives tricyclic hemiacetals 18a ,b, and why the further
cyclization of 18a ,b to 20 is so facile.
Con clu sion s
1
the fact that the H and 13C NMR spectra show that two
The desymmetrization of readily available, achiral
endo-norborn-5-ene-2,3-dicarboxylic anhydride deriva-
tives by methyl (S)-prolinate followed by ozonolysis of the
resulting acid provides a versatile and concise approach
to the synthesis of enantiomerically pure tetra- and
penta-substituted cyclopentanes in which the cyclopen-
tane substituents are syn to one another. The initial
products of this chemistry are hemiacetals and are highly
functionalized to allow further manipulation. It is pos-
sible to carry out regioselective reactions on the hemi-
acetals, and they react diastereoselectively with allyl-
indium to give further derivatized products. The proline
auxiliary can be removed from the cyclopentane deriva-
tives under mild conditions by acid catalyzed γ-lactone
formation.
aldehydes are present which implies that these are both
anti to the acid group or hemiacetal formation would have
been observed. This simple isomerization process opens
the possibility of preparing highly substituted cyclopen-
tanes with different stereochemical relationships between
the substituents using this methodology.
Finally, the addition of allylindium to hemiacetals
18a ,b was investigated with the hope of producing a
monoadduct analogous to compound 12. However, under
the conditions developed for the addition of allylindium
to hemiacetals 2a ,b, no reaction occurred. Changing the
organic cosolvent from ethanol to THF to better accom-
modate the more hydrophobic substrate did result in
reaction, but bis-lactone 24 was the only allylated product
isolated from this reaction, with tetracyclic bis-lactone
20 also being formed. It appears that the acid catalyzed
lactonization of hemiacetals 18a ,b to bis-lactone 20 is so
facile that it competes with the intermolecular addition
of allylindium to hemiacetals 18a ,b under the reaction
conditions. In an attempt to avoid the competing lacton-
ization, the allylindium addition reaction was carried out
in acetic acid/THF or water/THF mixtures, but no product
was obtained from these reactions.
It is apparent that the introduction of a fifth substitu-
ent onto the cyclopentane ring has markedly altered some
of the chemistry of the functional groups attached to the
ring. These effects can probably be accounted for by the
large size of the trimethylsilyl group, since this group
will want to adopt the least hindered position on the
cyclopentane ring. The conformational analysis of five-
membered rings is less straightforward than the analysis
of six-membered rings, but it is known that the lowest
energy conformation of a monosubstituted cyclopentane
has the substituent in the pseudo equatorial position
attached to the carbon atom at the flap position of an
envelope conformation.6 It is thus likely that in com-
pounds 18-21, the trimethylsilyl group occupies this
position. The effect of this will be to lock the other four
substituents into pseudo axial positions as shown in
Figure 2. In contrast, the non-silylated compounds 2a ,b
Exp er im en ta l Section
1H NMR spectra were recorded at 250 MHz and at 293K in
CDCl3. 13C NMR spectra were recorded at 62.5 MHz and at
293K in CDCl3. Infrared spectra were recorded on a FTIR
spectrometer, and only characteristic absorptions are reported.
Mass spectra were recorded using the FAB technique (Cs+ ion
bombardment at 25kV) or by chemical ionization (CI) with
ammonia. Only significant fragment ions are reported, and
only molecular ions are assigned. Optical rotations are re-
ported along with the solvent and concentration in grams/100
mL. Melting points are uncorrected. Elemental analyses were
performed within the chemistry department.
All X-ray crystallographic measurements were made at 150
K by following previously described procedures.18 Crystal data
for compound 5: C15H21NO6 (FW 311.33); orthorhombic; space
group P212121; a ) 7.891(2), b ) 18.499(4), and c ) 31.080(6)
Å; V ) 4537(2) Å3; Z ) 12; Dc ) 1.367 Mg m-3; F(000) ) 1992.
For compound 6: C22H24NO7Br (FW 494.33); orthorhombic;
space group P212121; a ) 6.376(2), b ) 10.413(2), and c )
32.604(7) Å; V ) 2164.7(9) Å3; Z ) 4; Dc ) 1.517 Mg m-3; F(000)
) 1016. For compound 14:
C12H14O4 (FW 222.23); ortho-
rhombic; space group P212121; a ) 5.712(1), b ) 12.258(1), and
c ) 15.413(2) Å; V ) 1079.2(3) Å3; Z ) 4; Dc ) 1.368 Mg m-3
F(000) ) 472. The structures were solved by direct methods
;
(18) Darr, J . A.; Drake, S. R.; Hursthouse, M. B.; Malik, K. M. A.
Inorg. Chem. 1993, 32, 5704.

endo-Norborn-5-ene-2,3-dicarboxylic Anhydrides
J . Org. Chem., Vol. 64, No. 15, 1999 5419
(SHELXS86)19 and refined on F2 by full-matrix least-squares
(SHELXL93)20 using all unique data corrected for Lorentz and
polarization factors. An absorption correction (DIFABS)21 was
applied for the data of compound 6. The structures were finally
refined (6666 data and 601 parameters for 5; 3087 data and
281 parameters for 6; 1679 data and 145 parameters for 14)
to R [on F, Fo > 4σ(Fo)] and wR [on F2, all data] values of
0.0421 and 0.0982 respectively, for 5, 0.0445 and 0.1072,
respectively, for 6, and 0.0366 and 0.0751, respectively, for 14.
The Flack parameter in SHELXL93 refined to a final value of
0.01(2) for 6, confirming that the absolute structure for this
compound had been determined correctly. However, the ab-
solute structures for 5 and 14 were uncertain due to the
absence of significant anomalous scatter in these molecules.
Further details of data collection and structure refinement,
atom coordinates, thermal coefficients, hydrogen atom param-
eters, and bond lengths and angles are available from the
Cambridge Crystallographic Data Centre.22
0.64 mmol) and p-bromobenzoyl chloride (0.14 g, 0.64 mmol)
in CH2Cl2 (3 mL). The reaction mixture was stirred at room
temperature for 18 h and subsequently washed with 0.5M HCl,
saturated aqueous Na2CO3, and H2O and dried (MgSO4). The
solvent was evaporated in vacuo, and the residue was sub-
jected to flash chromatography using EtOAc as eluent to give
(Rf ) 0.28) p-bromobenzoate 6 (0.04 g, 13%) as a clear
crystalline solid: mp 170-173 °C. [R]23D +36.8 (c ) 1, CHCl3).
1
IR: 3019, 2954, 1745, 1719, 1634. H NMR: 1.67 (dd, 1, J )
6.6, 3.7), 1.9-2.3 (m, 4), 2.4-2.55 (m, 1), 2.6-2.7 (m, 2), 3.1-
3.15 (m, 2), 3.58-3.63 (m, 2), 3.69 (s, 3), 4.1-4.6 (m, 5), 7.54
(AA′BB′-d, 2, J ) 8.5), 7.89 (AA′BB′-d, 2, J ) 8.5). 13C NMR:
24.9, 28.8, 31.3, 34.9, 39.2, 46.8, 47.7, 49.1, 52.4, 58.6, 64.8,
73.0, 128.1, 128.9, 131.3, 131.7, 165.6, 168.8, 170.1, 172.4. CI-
MS m/e (rel intensity): 513, 511 (M+ + 18, 31), 496, 494
(M+ + 1, 100), 416 (85). HRMS (CI) m/e: 494.0814 (MH+
C22H25NO779Br requires 494.0814). Anal. Calcd for C22H24NO7-
Br: C, 53.4; H, 4.9; N, 2.8. Found: C, 53.1; H, 5.1; N, 3.1.
Hem ia ceta ls 2a ,b. A solution of amido acid 12 (1.0 g, 3.4
mmol) in CH2Cl2 (40 mL) was cooled to -78 °C and treated
with ozone until a permanent blue color was observed. Di-
methyl sulfide (1.3 mL, 17.2 mmol) was then added, and the
reaction allowed to stir at room temperature for 16 h. The
solvents were evaporated in vacuo, and the residue was
subjected to flash chromatography using EtOAc as eluent to
give (Rf ) 0.14) hemiacetals 2a ,b (1.0 g, 92%) as a white
p-Br om oben zoa te 7. Triethylamine (0.11 mL, 0.78 mmol)
was added to a cooled (0 °C) suspension of lactone 5 (0.12 g,
0.32 mmol) and p-bromobenzoyl chloride (0.11 g, 0.42 mmol)
in CH2Cl2 (3 mL). The reaction mixture was stirred at room
temperature for 18 h and subsequently washed with 0.5M HCl,
saturated aqueous Na2CO3, and H2O, and dried (MgSO4). The
solvent was evaporated in vacuo, and the residue was sub-
jected to dry flash silica chromatography, eluting with CH2Cl2
to remove the high running impurities and finally with EtOAc
to afford (Rf ) 0.35; EtOAc) p-bromobenzoate 7 (0.16 g, 84%):
powder: mp 44-47 °C. [R]22 -64.4 (c ) 1, CHCl3). IR: 3406,
D
1
3019, 2950, 1732, 163. H NMR: 1.9-2.4 (m, 5), 2.6-3.3 (m,
mp 57-61 °C. [R]23 +40.6 (c ) 1, CHCl3). IR: 2954, 1748,
3), 3.4-3.55 (m, 2), 3.6-3.9 (m, 2), 3.69 and 3.72 (2 × s, 3),
4.5-4.6 (m, 1), 5.7-5.9 (m, 1), 6.73 (d, 1, J ) 13.3), 9.68 and
9.76 (2 × d, 1, J ) 1.8 and 2.2). 13C NMR: 24.6, 24.8, 25.9,
30.8, 29.1, 29.2, 43.8, 44.2, 46.2, 47.7, 47.8, 47.9, 48.1, 49.4,
52.2, 52.3, 56.5, 58.4, 59.0, 59.1, 100.3, 103.4, 170.1, 171.2,
171.7, 172.5, 175.5, 176.5, 201.2, 201.3. CI-MS m/e (rel
intensity): 326 (M+ + 1, 8), 128 (100). HRMS (CI) m/e:
366.1240 (MH+ C15H20NO7 requires 366.1239). Anal. Calcd for
D
1
1719, 1636. H NMR: 1.8-2.3 (m, 6), 2.7-2.9 (m, 1), 3.0-3.2
(m, 1), 3.39 (dd, 1, J ) 11.8, 8.9), 3.63 (dd, 1, J ) 8.9, 7.1),
3.6-3.7 (m, 2), 3.71 (s, 3), 4.2-4.7 (m, 5), 7.61 (AA′BB′-d, 2, J
) 8.5), 7.91 (AA′BB′-d, 2, J ) 8.5). 13C NMR: 24.8, 29.2, 35.4,
38.7, 45.8, 47.0, 47.8, 48.9, 52.2, 58.6, 64.9, 74.3, 128.1, 129.1,
131.0, 131.8, 165.5, 170.7, 172.4, 177.9. CI-MS m/e (rel
intensity): 496, 494 (M+ + 1, 100), 416 (75). HRMS (CI) m/e:
494.0814 (MH+ C22H25NO7Br requires 494.0814). Anal. Calcd
for C22H24NO779Br‚EtOAc: C, 53.8; H, 5.5; N, 2.4. Found: C,
53.8; H, 5.4; N,2.5.
C
15H19NO7‚0.5H2O: C, 53.9; H, 6.0; N, 4.2. Found: C, 54.0;
H, 5.9; N, 3.8.
[3.2.1]Bicyclic La cton e 4. Hemiacetals 2a ,b (1.0 g, 3.1
mmol) were dissolved in MeOH (15 mL) and cooled (0 °C), and
sodium borohydride (0.6 g, 15.9 mmol) was cautiously added.
The resulting solution was stirred at room temperature for 5
h, the solvent was then evaporated in vacuo, and the residue
was subjected to flash chromatography using 90% EtOAc/10%
MeOH as eluent to give (Rf ) 0.22; 50% EtOAc, 50% MeOH)
lactone 4 (0.8 g, 85%) as a white powder: mp 47-50 °C. IR:
Ald eh yd e 8. A solution of oxalyl chloride (0.1 mL, 1.3 mmol)
in dry CH2Cl2 (10 mL) was cooled (-78 °C) and treated with
dimethyl sulfoxide (0.15 mL, 1.9 mmol) to give an effervescent
mixture. The resulting solution was stirred for 10 min at -78
°C before being treated with lactone 5 (0.20 g, 0.64 mmol)
dissolved in CH2Cl2 (1 mL) to give a white precipitate. After
warming to -66 °C for 10 min, the mixture was again cooled
(-78 °C) and treated with Et3N (0.5 mL, 3.8 mmol), before
being stirred at room temperature for 2 h. The solvent was
evaporated in vacuo, and the residue was subjected to flash
chromatography using EtOAc as eluent to give (Rf ) 0.07)
aldehyde 8 (0.13 g, 65%) as a white crystalline solid: mp 84-
87 °C. [R]22D -37.7 (c ) 1, CHCl3). IR: 3017, 2978, 2955, 1748,
1721, 1634. 1H NMR: 1.9-2.6 (m, 6), 2.9-3.05 (m, 1), 3.1-
3.3 (m, 1), 3.43 (dd, 1, J ) 11.2, 9.3), 3.65-3.8 (m, 3), 3.73 (s,
3), 4.34 (dd, 1, J ) 9.1, 4.8), 4.5-4.6 (m, 1), 4.52 (t, 1, J ) 8.9),
9.76 (d, 1, J ) 2.1). 13C NMR: 24.8, 29.2, 33.4, 39.3, 46.3, 47.8,
48.1, 52.2, 57.4, 58.9, 73.1, 169.7, 172.3, 176.8, 201.2. CI-MS
m/e (rel intensity): 310 (M+ + 1, 100), 282 (16), 250 (13).
HRMS (CI) m/e: 310.1291 (MH+ C15H20NO6 requires 310.1291).
Anal. Calcd for C15H19NO6: C, 58.3; H, 6.2; N, 4.5. Found: C,
58.3; H, 6.4; N, 4.3.
1
3430, 3020, 1748, 1634. H NMR: 1.8-2.3 (m, 6), 2.4-2.6 (m,
1), 2.65-2.8 (m, 1), 3.2-3.3 (m, 1), 3.41 (t, 1, J ) 7.4), 3.5-3.9
(m, 5), 3.72 (s, 3), 4.05 (dd, 1, J ) 10.9, 3.7), 4.3-5.0 (brs, 1),
4.63 (dd, 1, J ) 8.1, 2.9). FAB-MS m/e (rel intensity): 334 (M+
+ 23, 40), 312 (M+ + 1, 100). HRMS (FAB) m/e: 312.1430
(MH+ C15H22NO6 requires 312.1447).
[3.3.0]Bicyclic La cton e 5. Lactone 4 (0.5 g, 1.6 mmol) was
dissolved in CHCl3 (20 mL) and allowed to stand at room
temperature for 2 days. The solvent was then evaporated in
vacuo to give lactone 5 (0.5 g, 100%) as a crystalline solid: mp
91-93 °C. [R]22 -48.4 (c ) 1, CHCl3). IR: 3448, 3017, 2961,
D
1747, 1634. 1H NMR: 1.3-2.3 (m, 6), 2.6-2.85 (m, 1), 3.0-
3.2 (m, 1), 3.3-3.4 (m, 2), 3.6-3.8 (m, 3), 3.77 (s, 3), 3.9-4.0
(m, 1), 4.31 (dd, 1, J ) 8.9, 5.0), 4.52 (t, 1, J ) 8.9), 4.67 (dd,
1, J ) 8.8, 3.4). 13C NMR: 24.7, 29.2, 35.2, 39.1, 46.0, 47.8,
48.6, 50.7, 52.6, 58.1, 62.1, 74.4, 171.7, 173.3, 178.4. CI-MS
m/e (rel intensity): 312 (M+ + 1, 76), 200 (100). HRMS (CI)
m/e: 312.1447 (MH+ C15H22NO6 requires 312.1447).
[3.3.0]Bicyclic La cton e 5 fr om Ald eh yd e 8. Aldehyde 8
(0.05 g, 0.16 mmol) was dissolved in methanol (5 mL) and
cooled to 0 °C, after which, sodium borohydride (0.012 g, 0.32
mmol) was added. After 14 h of stirring, the solvent was
evaporated in vacuo, and the residue was subjected to dry flash
chromatography23 using EtOAc as eluent to give (Rf ) 0.07),
lactone 5 (0.04 g, 80%) as a white powder. Spectroscopic data
for compound 5 were reported above.
p -Br om oben zoa t e 6. Triethylamine (0.2 mL, 1.3 mmol)
was added to a cooled (0 °C) suspension of lactone 4 (0.20 g,
(19) Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467.
(20) Sheldrick, G. M. SHELXL93 Program for Crystal Structure
Refinement; University of Gottingen: Germany, 1993.
(21) Walker, N. P. C.; Stuart, D. Acta Crystallogr. 1983, A39, 158.
(22) The authors have deposited the atomic coordinates for 5, 6, and
14 with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
Dia ld eh yd e 9. A solution of oxalyl chloride (0.06 mL, 0.64
mmol) in dry CH2Cl2 (8 mL) was cooled (-78 °C) and treated
with dimethyl sulfoxide (0.1 mL, 1.9 mmol) to give an effer-
(23) Harwood, L. M. Aldrichimica Acta 1985, 18, 25.

5420 J . Org. Chem., Vol. 64, No. 15, 1999
Hibbs et al.
vescent mixture. The resulting solution was stirred for 10 min
at -78 °C before being treated with lactone 4 (0.20 g, 0.64
mmol), dissolved in CH2Cl2 (1 mL) to give a white precipitate.
After 10 min of warming to -66 °C, the mixture was again
cooled (-78 °C) and treated with Et3N (0.5 mL, 3.8 mmol),
before being stirred at room temperature for 2 h. The solvent
was evaporated in vacuo, and the residue was subjected to
flash chromatography using EtOAc as eluent to give (Rf ) 0.24)
3.4-3.5 (m, 2), 4.09 (dd, 1, J ) 9.5, 3.5), 4.20 (q, 1, J ) 6.0),
4.44 (dd, 1, J ) 9.5, 6.5), 5.1-5.2 (m, 2), 5.65-5.9 (m, 1). 13C
NMR: 36.1, 39.3, 43.2, 47.3, 47.6, 48.8, 72.1, 84.7, 119.5, 131.5,
174.6, 175.7. CI-MS m/e (rel intensity): 240 (M+ + 18, 100),
223 (M+ + 1, 9). HRMS (CI) m/e: 240.1236 (M + NH4
+
C12H18NO4 requires 240.1236).
Bis-la cton e 15. A solution of alcohol 13a (0.08 g, 0.20 mmol)
and p-toluenesulfonic acid monohydrate (0.4 g, 2.0 mmol) in
CH2Cl2 (2 mL) was stirred at room temperature for 18 h. The
reaction mixture was subsequently washed with saturated
aqueous Na2CO3 solution and dried (MgSO4), and the solvent
was evaporated in vacuo. Purification by flash chromatography
using 70% Petrol/30% EtOAc yielded (Rf ) 0.14) meso bis-
lactone 15 (0.03 g, 56%) as a clear oil. [R]23D 0.0 (c ) 1, CHCl3).
IR: 3078, 2932, 1772, 1642. 1H NMR: 1.62 (dt, 1, J 14.5, 5.0),
2.3-2.6 (m, 5), 2.8-3.0 (m, 2), 3.3-3.4 (m, 2), 4.24 (q, 2, J 5.0),
5.0-5.2 (m, 4), 5.1-5.4 (m, 2). 13C NMR: 36.2, 39.4, 47.5, 48.1,
84.2, 119.6, 131.6, 174.6. CI-MS m/e (rel intensity): 280 (M+
+ 18, 100), 263 (M+ + 1, 15). HRMS (CI) m/e: 280.1549 (M +
dialdehyde 9 (0.121 g, 49%) as a clear oil. [R]23 -31.8 (c )
D
1
0.5, CHCl3). IR: 2953, 1736, 1632. H NMR: 2.05-2.2 (m, 5),
2.25 (s, 3), 2.7-2.9 (m, 1), 2.9-3.05 (m, 1), 3.1-3.2 (m, 1), 3.47
(dd, 1, J ) 10.0, 6.8), 3.6-3.7 (m, 3), 3.74 (s, 3), 4.57 (dd, 1, J
) 8.5, 3.7), 5.06 (d, 1, J ) 11.8), 5.34 (d, 1, J ) 11.8 Hz), 9.73
(d, 1, J ) 3.2), 9.89 (d, 1, J ) 1.9). 13C NMR: 15.6, 24.8, 26.7,
29.2, 45.8, 47.7, 50.0, 50.4, 52.3, 53.6, 58.7, 69.3, 169.8, 170.1,
172.0, 200.7, 201.8. CI-MS m/e (rel intensity): 386 (M+ + 1,
100), 368 (7), 324 (10). HRMS (CI) m/e: 386.1273 (MH+
C17H24NO7S requires 386.1273).
Aceta l 12. To a well-stirred solution of hemiacetals 2a ,b
(1.0 g, 3.1 mmol) in 0.5 M HCl (10 mL), containing 10% ethanol
was added allyl bromide (0.3 mL, 3.4 mmol) and indium
powder (0.55 g, 4.0 mmol). The reaction was allowed to proceed
until no hemiacetal 2a ,b remained (ca. 14 h), after which the
solvent was evaporated in vacuo. The resulting residue was
subjected to flash chromatography using 80% EtOAc/20%
Petrol as eluent to give (Rf ) 0.12; EtOAc) acetal 12 (0.35 g,
+
NH4 C12H18NO4 requires 280.1549).
Am id o Acid s 17a ,b. Triethylamine (2.7 mL, 19.1 mmol)
was added to a cooled (0 °C) suspension of anhydride 1615 (1.5
g, 6.4 mmol) and methyl (S)-prolinate hydrochloride (2.1 g, 12.7
mmol) in CH2Cl2 (16 mL). The resulting mixture was stirred
at room temperature for 24 h and subsequently washed with
0.5 M HCl and H2O and dried (MgSO4). The solvent was
evaporated in vacuo to leave amido acids 17a ,b (2.2 g, 94%)
as a 3:1 ratio of diastereomers as a yellow oil. IR: 3500-2300,
3008, 2953, 1735, 1654. 1H NMR (only peaks corresponding
to the major diastereomer 17a are reported): 0.09 (s, 9), 1.04
(s, 1), 2.0-2.3 (m, 4), 3.3-3.5 (m, 4), 3.6-3.9 (m, 2), 3.77 (s,
3), 4.50 (dd, 1, J ) 8.7, 3.9), 6.2-6.3 (m, 2), 9.25 (brs, 1). 13C
NMR (only peaks corresponding to the major diastereomer 17a
are reported): -0.3, 24.8, 29.0, 47.0, 49.7, 49.9, 50.5, 51.2, 51.7,
52.1, 58.9, 133.7, 135.1, 172.1, 172.7, 176.2. CI-MS m/e (rel
intensity): 366 (M+ + 1, 5), 294 (11), 130 (100). HRMS (CI)
m/e: 366.1737 (MH+ C18H28NO5Si requires 366.1737).
Hem ia ceta ls 18a ,b. A solution of amido acids 17a ,b (0.5
g, 1.4 mmol) in CH2Cl2 (50 mL) was cooled to -78 °C and
treated with ozone until a permanent blue color was observed.
Dimethyl sulfide (1.1 mL, 13.7 mmol) was then added, and
the reaction mixture was allowed to stir at room temperature
for 16 h. The solvents were evaporated in vacuo, and the
residue was subjected to flash chromatography using EtOAc
as eluent to give (Rf ) 0.52) hemiacetals 18a ,b (0.43 g, 79%)
as a yellow powder: mp 79-83 °C. [R]23D -26.9 (c ) 1, CHCl3).
IR: 3388, 2953, 1744, 1630. 1H NMR: 0.17 (s, 9), 0.98 and
1.10 (2 × t, 1, J ) 3.3 and 3.5), 1.85-2.2 (m, 4), 2.2-3.8 (m,
6), 3.71 and 3.73 (2 × s, 3), 4.5-4.6 (m, 1), 5.43 (dd, 1, J ) 9.6,
4.3), 5.78 and 5.89 (2 × d, 1, J ) 6.7 and 6.3), 8.55 (d, 1, J )
9.6). 13C NMR: -0.7 and -0.3, 24.82 and 24.84, 28.9 and 29.1,
31.4 and 34.0, 43.8 and 44.0, 44.4 and 44.9, 46.0 and 47.8, 47.2
and 47.9, 52.4 and 53.0, 55.0 and 55.6, 59.0 and 59.7, 92.8 and
96.9, 99.5 and 102.8, 168.2 and 171.0, 172.2 and 172.7, 176.0
and 177.0. CI-MS m/e (rel intensity): 398 (M+ + 1, 10), 286
(8), 130 (100). HRMS (CI) m/e: 398.1635 (MH+ C18H28NO7Si
requires 398.1635).
33%) as a white powder: mp 129-131 °C. [R]23 -36.6 (c ) 1,
D
1
CHCl3). IR: 3073, 3018, 2928, 1742, 1613. H NMR: 1.9-2.5
(m, 8), 3.35-4.05 (m, 6), 3.77 (s, 3), 4.59 (dd, 1, J ) 5.5, 3.0),
5.1-5.3 (m, 2), 5.75-6.0 (m, 2), 7.23 (d, 1, J ) 13.5). 13C
NMR: 24.5, 28.0, 29.1, 40.6, 44.3, 45.8, 47.9, 49.0, 52.7, 54.8,
58.4, 71.0, 100.9, 117.7, 134.4, 173.2, 173.6, 176.2. CI-MS m/e
(rel intensity): 350 (M+ + 1, 15), 259 (12). HRMS (CI) m/e:
350.1604 (MH+ C18H24NO6 requires 350.1604).
Alcoh ols 13a ,b. To a well-stirred solution of hemiacetals
2a ,b (0.25 g, 0.77 mmol) in 0.5 M HCl (5 mL), containing 10%
ethanol was added allyl bromide (0.15 mL, 1.9 mmol) and
indium powder (0.2 g, 1.6 mmol). The reaction was allowed to
proceed until no hemiacetal 2a ,b remained (ca. 14 h), after
which the solvent was evaporated in vacuo. The resulting
residue was subjected to flash chromatography using 80%
EtOAc/20% Petrol as eluent to give (Rf ) 0.46; EtOAc) minor
diastereomer 13b (0.04 g, 13%) and (Rf ) 0.41; EtOAc) major
diastereomer 13a (0.15 g, 50%) as clear oils. Data for 13b .
[R]23 +6.4 (c ) 1, CHCl3). IR: 3466, 3074, 2925, 1750, 1640.
D
1H NMR: 1.9-2.6 (m, 11), 2.7-2.85 (m, 1), 3.3-3.4 (m, 2), 3.65
(m, 3), 3.72 (s, 3), 4.53 (dd, 1, J ) 9.0, 5.0), 4.61 (q, 1, J ) 6.5),
5.1-5.3 (m, 4), 5.7-6.0 (m, 2). 13C NMR: 25.0, 29.2, 32.6, 40.0,
41.4, 44.2, 46.3, 48.2, 50.2, 52.5, 52.9, 58.7, 69.4, 86.2, 117.8,
118.9, 132.1, 135.1, 172.9, 173.6, 177.9. CI-MS m/e (rel
intensity): 392 (M+ + 1, 100), 350 (5). HRMS (CI) m/e:
392.2073 (MH+ C21H30NO6 requires 392.2073). Data for 13a .
[R]23 -4.2 (c ) 1, CHCl3). IR: 3486, 3075, 2952, 1747, 1633.
D
1H NMR: 1.9-2.25 (m, 11), 3.2-3.4 (m, 1), 3.36 (dd, 1, J )
11.5, 9.5), 3.6-4.0 (m, 3), 3.64 (dd, 1, J ) 9.5, 7.5), 4.55-4.7
(m, 2), 5.1-5.3 (m, 4), 5.7-6.0 (m, 2). 13C NMR: 24.6, 29.3,
35.2, 40.1, 40.7, 45.0, 46.4, 47.8, 49.5, 52.6, 54.3, 58.2, 70.8,
86.3, 117.4, 119.0, 132.1, 134.7, 172.3, 174.2, 177.8. CI-MS m/e
(rel intensity): 392 (M+ + 1, 100), 350 (6). HRMS (CI) m/e:
392.2073 (MH+ C21H30NO6 requires 392.2073).
Bis-la cton e 19. A solution of oxalyl chloride (0.09 mL, 1.0
mmol) in dry CH2Cl2 (3 mL) was cooled (-78 °C) and treated
with dimethyl sulfoxide (0.1 mL, 1.5 mmol) to give an effer-
vescent mixture. The resulting solution was stirred for 10 min
at -78 °C before being treated with hemiacetals 18a ,b (0.2 g,
0.50 mmol) dissolved in CH2Cl2 (1 mL) to give a white
precipitate. After 10 min of warming to -60 °C, the mixture
was again cooled (-78 °C) and treated with Et3N (0.4 mL, 3.0
mmol), before being stirred at room temperature for 2 h. The
solvent was evaporated in vacuo, and the residue was sub-
jected to flash chromatography using EtOAc as eluent to give
(Rf ) 0.31) bis-lactone 19 (0.11 g, 55%) as a white powder:
Bis-la cton e 14. A solution of acetal 12 (0.05 g, 0.14 mmol)
and sodium borohydride (0.027 g, 0.72 mmol) in MeOH (2 mL)
was stirred at room temperature for 5 h. The solvent was
subsequently evaporated in vacuo, and the residue was
subjected to dry flash silica chromatography,23 eluting with
50% EtOAc/50% MeOH. Following evaporation of the solvent,
the resulting diol was redissolved in CH2Cl2 (2 mL), and
p-toluenesulfonic acid monohydrate (0.25 g, 1.4 mmol) was
added. After 18 h of stirring, the mixture was washed with
saturated aqueous Na2CO3 and dried (MgSO4), and the solvent
was evaporated in vacuo. Purification by flash chromatography
using 80% EtOAc/20% Petrol as eluent yielded (Rf ) 0.20) bis-
mp 114-117 °C. [R]22 -43.0 (c ) 1, CHCl3). IR: 3019, 2956,
D
1798, 1765, 1648. 1H NMR: 0.13 (s, 9), 1.4-1.5 (m, 1), 1.7-
2.2 (m, 4), 3.0-3.7 (m, 6), 3.66 (s, 3), 4.4-4.5 (m, 1), 5.99 (d, 1,
J ) 4.9). 13C NMR: -1.5, 24.7, 29.7, 32.9, 43.8, 45.2, 47.3, 47.9,
50.2, 52.2, 59.0, 100.2, 167.5, 169.4, 172.2, 175.5. CI-MS m/e
(rel intensity): 413 (M+ + 18, 16), 396 (M+ + 1, 9). HRMS
lactone 14 (0.03 g, 94%) as a white solid: mp 62-65 °C. [R]23
D
1
-3.9 (c ) 1, CHCl3). IR: 2924, 1773. H NMR: 1.62 (dt, 1, J
) 14.5, 5.5), 2.3-2.7 (m, 3), 2.8-3.0 (m, 1), 3.3-3.4 (m, 1),

endo-Norborn-5-ene-2,3-dicarboxylic Anhydrides
J . Org. Chem., Vol. 64, No. 15, 1999 5421
(CI) m/e: 396.1479 (MH+ C18H26NO7Si requires 396.1479).
Anal. Calcd for C18H25NO7Si: C, 54.7; H, 6.4; N, 3.5. Found:
C, 54.9; H, 6.4; N, 3.8.
Dia ld eh yd e 23. A suspension of hemiacetals 18a ,b (0.05
g, 0.13 mmol) and K2CO3 (0.09 g, 0.63 mmol) in CH2Cl2 (1 mL)
was stirred at room temperature for 2 h. The reaction mixture
was subsequently washed with 1 M HCl to yield dialdehyde
Bis-la cton e 20. A solution of hemiacetals 18a ,b (0.10 g,
0.25 mmol) and p-toluenesulfonic acid (0.10 g, 0.50 mmol) in
CH2Cl2 (1 mL) was stirred at room temperature for 24 h. The
reaction mixture was subsequently washed with saturated
aqueous Na2CO3 and H2O and dried (MgSO4), and the solvent
was evaporated in vacuo. Purification by flash chromatography
using 50% Petrol/50% EtOAc as eluent yielded (Rf ) 0.42) bis-
lactone 20 (0.024 g, 36%) as a white powder: mp 216-218 °C.
IR: 3020, 2976, 1776. 1H NMR: 0.21 (s, 9), 1.4-1.5 (m, 1), 3.3-
3.4 (m, 4), 5.84 (d, 1, J ) 5.4). 13C NMR: -0.5, 29.3, 45.5, 46.4,
100.3, 172.8. CI-MS m/e (rel intensity): 286 (M+ + 18, 100).
23 (0.05 g, 100%) as a clear oil. [R]23 -49.6 (c ) 1, CHCl3).
D
1
IR: 3500-2500, 3021, 2955, 1723, 1644. H NMR: 0.81 (s, 9),
1.64 (dd, 1, J ) 11.4, 9.2), 1.9-2.3 (m, 4), 3.0-3.2 (m, 2), 3.5-
3.9 (m, 4), 3.69 (s, 3), 4.55 (dd, 1, J ) 8.8, 3.7), 5.65 (brs, 1),
9.63 (s, 1), 9.89 (d, 1, J ) 1.7). 13C NMR: -2.7, 24.7, 28.2, 28.9,
44.8, 47.2, 50.8, 52.3, 54.5, 56.1, 58.6, 171.6, 172.7, 175.0, 199.1,
202.3. CI-MS m/e (rel intensity): 398 (M+ + 1, 12), 370 (4), 90
(100). HRMS (CI) m/e: 398.1635 (MH+ C18H28NO7Si requires
398.1635).
+
Bis-la cton e 24. To a well-stirred solution of hemiacetals
18a ,b (0.5 g, 1.25 mmol) in 0.5 M HCl (5 mL) and THF (5 mL)
were added allyl bromide (0.15 mL, 1.8 mmol) and indium
powder (0.15 g, 1.4 mmol). After 20 h of stirring at room
temperature, the mixture was extracted with CH2Cl2. The
combined CH2Cl2 layers were washed with H2O, dried (Mg-
SO4), and evaporated to dryness in vacuo. Addition of hot
EtOAc and filtration of the impurities, followed by evaporation
of the filtrate in vacuo yielded meso bis-lactone 24 (0.18 g, 43%)
as a clear crystalline solid: mp 80-81 °C. [R]23D (c ) 1, CHCl3).
HRMS (CI) m/e: 286.1111 (M + NH4 C12H20NO5Si requires
286.1111).
La ct on e 21. Hemiacetals 18a ,b (0.25 g, 1.1 mmol) were
dissolved in MeOH (8 mL) and cooled (0 °C), and sodium
borohydride (0.2 g, 5.0 mmol) was cautiously added. The
resulting solution was stirred at room temperature for 16 h,
the solvent was then evaporated in vacuo, and the residue was
redissolved in CH2Cl2. The solution was subsequently washed
with 1 M HCl and dried (MgSO4), and the solvent was
evaporated in vacuo. Purification by flash chromatography
using 2% MeOH/98% ether as eluent afforded (Rf ) 0.40; 10%
MeOH/90% ether) lactone 21 (0.27 g, 61%) as a white powder:
mp 55-59 °C. [R]22D -56.9 (c ) 1, CHCl3). IR: 3450, 3018, 2954,
1757, 1634. 1H NMR: 0.12 (s, 9), 1.57 (dd, 1, J ) 9.3, 6.3),
2.0-2.3 (m, 4), 2.94 (ddd, 1, J ) 12.0, 9.1, 3.0), 3.1-3.3 (m, 2),
3.55-4.0 (m, 5), 3.73 (s, 3), 4.21 (t, 1, J ) 8.9), 4.34 (t, 1, J )
8.9), 4.53 (dd, 1, J ) 8.8, 3.1), 4.65 (brs, 1). 13C NMR: -0.2,
24.7, 29.2, 36.6, 45.4, 47.5, 49.2, 49.7, 49.9, 52.6, 58.9, 62.7,
71.5, 170.5, 173.7, 178.4. CI-MS m/e (rel intensity): 384 (M+
+ 1, 79), 272 (43), 130 (100). HRMS (CI) m/e: 384.1842 (MH+
C18H30NO6Si requires 384.1842).
1
IR: 3019, 2958, 1780. H NMR: 0.22 (s, 9), 1.74 (s, 1), 2.35-
2.5 (m, 2), 2.55-2.7 (m, 2), 3.0-3.15 (m, 2), 3.40 (dd, 2, J )
6.0, 3.0), 4.40 (td, 2, J ) 6.5, 3.5), 5.15-5.25 (m, 4), 5.8-6.0
(m, 2). 13C NMR: 0.0, 36.5, 40.0, 50.1, 50.2, 81.7, 119.5, 131.7,
174.4. CI-MS m/e (rel intensity): 352 (M+ + 18, 28), 335
(M+ + 1, 11), 286 (100). HRMS (CI) m/e: 335.1693 (MH+
C18H27O4Si requires 335.1679).
Ack n ow led gm en t. The authors thank Peboc Divi-
sion of Eastman Chemical (UK) Ltd. and the EPSRC
for a studentship to I.G.J . and the EPSRC for access to
the national mass spectrometry and X-ray crystal-
lography services.
Bis-la cton e 22. A solution of lactone 21 (0.05 g, 0.13 mmol)
and p-toluenesulfonic acid (0.024 g, 0.13 mmol) in CH2Cl2 (0.5
mL) was stirred at room temperature for 18 h. The reaction
mixture was subsequently washed with 0.5M HCl, saturated
aqueous Na2CO3, and H2O and dried (MgSO4), and the solvent
was evaporated in vacuo. Purification by flash chromatography
using ether as eluent yielded (Rf ) 0.23) bis-lactone 22 (0.025
g, 75%) as a crystalline solid: mp 155-157 °C. IR: 3023, 2951,
Su p p or tin g In for m a tion Ava ila ble: Copies of the NMR
spectra for compounds 4, 5, 9, 12, 13a , 13b, 14, 15, 17a ,b,
18a ,b, 20, 21, 23, and 24 as well as ORTEP diagrams and
tables of atomic coordinates, bond lengths, bond angles, and
anisotropic displacement factors for compounds 5, 6, and 14.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
1782. H NMR: 0.15 (s, 9), 1.83 (t, 1, J ) 8.1), 3.2-3.4 (m, 4),
4.11 (dd, 1, J ) 9.7, 6.5), 4.43 (dd, 1, J ) 9.7, 8.8). 13C NMR:
-2.2, 35.4, 45.6, 48.8, 70.6, 175.4. CI-MS m/e (rel intensity):
+
272 (M+ + 18, 100). HRMS (CI) m/e: 272.1318 (M + NH4
C12H22NO4Si requires 272.1318). Anal. Calcd for C12H18O4Si:
C, 56.7; H, 7.1. Found: C, 56.6; H, 7.3.
J O990140V