Unsymmetrical ozonolysis of carbohydrate derived norbornene systems

Article abstract of DOI:10.1016/j.tet.2007.08.070

The ozonolysis of carbohydrate derived norbornene systems in participating solvents demonstrated that different remote controlling factors could induce the regioselective fragmentation of the primary ozonide. The exo norbornene series afforded a complete

Full text of DOI:10.1016/j.tet.2007.08.070

Tetrahedron 63 (2007) 11410–11420
Unsymmetrical ozonolysis of carbohydrate derived
norbornene systems
ꢀ
ꢀ
ꢀ
Sebastian A. Testero, Marıa I. Mangione, Andres A. Poeylaut-Palena,
*
ꢀ
Manuel Gonzalez Sierra and Rolando A. Spanevello
´
Instituto de Quꢀımica Rosario, Facultad de Ciencias Bioquꢀımicas y Farmaceuticas,
Universidad Nacional de Rosario—CONICET, Suipacha 531, S2002LRK Rosario, Argentina
Received 20 July 2007; revised 20 August 2007; accepted 22 August 2007
Available online 26 August 2007
Abstract—The ozonolysis of carbohydrate derived norbornene systems in participating solvents demonstrated that different remote control-
ling factors could induce the regioselective fragmentation of the primary ozonide. The exo norbornene series afforded a complete regioselec-
tive process.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
The primary concern with the ozonolysis reaction rests on
safety issues. Ozonolysis initially generates ozonides and
other unstable peroxides species often capable of spontane-
ous and explosive decomposition reactions.3 To achieve the
direct production of the desired carbonyl products, avoiding
the formation of the high-energy ozonide intermediates gen-
erated in non-participating solvents, different methods have
been reported as safer alternatives.4
Ozonolysis is a widely applied organic reaction in academic
research and industrial developments. It is used to cleave
multiple carbon–carbon or carbon–heteroatom bonds and
even though there are many alternatives to this reaction, it
is still a clean and cost effective option to perform a sustain-
able oxidative cleavage.1 Extensive investigation of the
mechanism of alkene ozonolysis has confirmed the basic
pathway originally proposed by Criegee2 in his seminal
work several decades ago.
In a recent report, Dussault et al.5 suggested intercepting one
of the three intermediates but the ozonide appeared too sta-
ble to be a target and the primary ozonides cannot react with
nucleophiles in the presence of ozone. These facts leave only
the carbonyl oxides as suitable targets for in situ trapping in
order to develop a safer ozonolysis procedure.
The most thoroughly developed proposal view the ozonoly-
sis reaction as a three-step mechanism: (i) a [3+2] dipolar
cycloaddition reaction of ozone with the alkene leading to
formation of a primary ozonide (PO) (1,2,3-trioxolane),
(ii) a cycloreversion process to provide the transient carbonyl
oxide and a stable carbonyl compound, which may proceed
in two different ways in the case of unsymmetrically
substituted alkenes, and (iii) recombination of the carbonyl
oxide and the carbonyl compound gives the ozonide
(1,2,4-trioxolane) (Scheme 1).
Carbonyl oxides, produced by a spontaneous fragmentation
of the primary ozonides even at low temperatures, are con-
sidered as the central species to the mechanism of ozonoly-
sis. Even though the intermediates could never be directly
detected in situ, sufficient evidences were accumulated in
support of their role in the Criegee mechanism.6 Although
their structural and electronic features have aroused consid-
erable interest in this research area, all the efforts devoted to
study these transient intermediates still did not clarify their
zwitterionic or diradical character.7 Throughout this work
the zwitterionic representation will be used.
primary
ozonide
carbonyl
oxide
ozonide
R1
-
+
R1
R2
R1
R1
R2
O
O
O
O
O
O
+
O
O
O
-
O
O
O
R2
R2
In a typical procedure, the carbonyl oxide is trapped by the
newly formed carbonyl group derivative to give the 1,2,4-tri-
oxolane 4 (Scheme 2). However, the transient carbonyl ox-
ide could also be trapped by another carbonyl derivative
present in the reaction medium, producing a cross ozonide
Scheme 1. Overview of alkene ozonolysis.
* Corresponding author. Tel./fax: +54 341 4370437; e-mail: spanevello@
iquios.gov.ar
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.070

S. A. Testero et al. / Tetrahedron 63 (2007) 11410–11420
11411
R
O O
R
CH(OR2)OOH
R1
OHC
O
OHC
R2OH
R1CHO
R
6a
5a
CHO
O
-
O
+
R
R
R
O
4
3a
O
O
O3
O
O
O
R
1
2
+
O
-
O
CHO
3b
R1CHO
O O
R2OH
CH(OR2)OOH
R1
OHC
OHC
O
R
6b
R
5b
Scheme 2.
5a,b. Alternatively, when participating protic solvents such
as alcohols are used, the reactive intermediate is intercepted
by the nucleophilic attack of the solvent, yielding an a-alk-
oxy hydroperoxide 6a,b (Scheme 2).
steric effect of the allylic dialkyl substituents plays an
important role in the cycloreversion process of the PO,
since it yields the carbonyl oxide product with the gem-
inal dialkyl groups most remote from the carbonyl oxide
fragment.15
Schreiber et al.8 was the first to take advantage of the
symmetry breaking property of cyclic alkene ozonolysis in
participating solvents, providing a simple entry to linear
molecules with different functional groups at each terminus.
For non-symmetric alkenes, one could make use of the dif-
ferent possible fragmentation pathway of a primary ozonide
to generate new functionality in a regioselective manner. In
the case of cyclic or polycyclic compounds the process could
unveil a completely different carbon skeleton connectivity
with a very useful functional group arrangement.9,10
Remote factors have also been reported to control the regio-
selectivity of the PO fragmentation, but it is not clear how do
they affect the process. Schreiber’s report8 on the ozonolysis
of the endo-5-norbornen-2-ol acetate 10 is the first example
of the effect of a remote substituent on the regiochemical
outcome of the reaction (Scheme 3).
AcO
AcO
AcO
CH(OCH3)2
CHO
CHO
+
CH(OCH3)2
Since the PO fragmentation defines the regioselectivity of
the reaction course, much of the current interest in this
process centers on the factors that affect the direction of
the PO cleavage. Intense research activity has been pur-
sued during the past years to clarify the effect of different
types or number of substituents attached to the sp2
carbons11 on the fragmentation process. Many examples
reported in the literature had led to understand at least
three well known factors that play an important role in de-
termining the regiochemistry of the PO cleavage: (i) the
electronic effect of the substituent attached to the C–C
double bond, (ii) the electronic effect of the heteroatom
substituent at the allylic position, and (iii) the steric effect
of the allylic dialkyl substituent.
7
8
9
1:1
AcO
AcO
AcO
CH(OCH3)2
CHO
CHO
CH(OCH3)2
+
10
11
12
1:3
Scheme 3.
The workup procedure initially yielded the dimethyl acetal
of the carbonyl terminal and subsequently the reduction of
the alkoxy hydroperoxide afforded the free aldehyde group.
Taking into account that the preferred direction of cleavage
of 10 is opposite to that predicted by consideration of the in-
ductive effects of the acetyloxy substituent, the former re-
sults suggested that the cleavage of the PO is not governed
by the electronic effect of the remote substituent. Since
this unsymmetrical ozonolysis published in 1982, we could
only find a few examples reported in the literature with mod-
erate regiocontrol and yielding in all cases variable mixtures
of compounds.16
In the first case, it has been established that the cleavage
of the PO tends to occur along the path, which results in
the placement of electron-donating substituents on the
carbonyl oxide fragment.12 This observation means that
the carbonyl oxide will be formed on the carbon whose
substituents are better suited to stabilize a developing
positive charge.13 Literature reports8,9a,14 indicated that
simple inductive arguments should reliably predict the
electronic effect of the heteroatom substituent at the al-
lylic position of an unsymmetrical cycloalkene. The
The first observation of an exclusive fragmentation of the PO
controlled by remote carbonyl groups and stereoselective
formation of final cross ozonides through the ozonolysis of

11412
S. A. Testero et al. / Tetrahedron 63 (2007) 11410–11420
norbornene derivatives was reported by Wu et al.12,17
(Scheme 4).
2. Results and discussion
This result encourages us to further investigate the direct-
ing effects of other factors. In order to do so, we used cy-
cloadduct 15a as starting material to prepare several
analogs, in which we replaced the aldehyde group by other
functional groups with different steric and electronic de-
mands. We also released part of the cyclic system tension
by removing the benzylidene acetal group. The ozonolysis
reactions of cycloadducts 15a–g were carried out in a di-
chloromethane–methanol solution with solid NaHCO3 in
suspension. The crude reaction mixtures were then treated
with acetic anhydride and triethylamine in dichlorome-
thane.
O
O3
CDCl3
O
CH3
O
CH3
O
O
O
O
H
H
13
14
Scheme 4.
The competitive studies made by Wu’s group with different
series of endo substituted norbonene derivatives allowed
them to propose that the fragmentation of the trioxolane
ring was induced by the endo formyl group through space
rather than through bond.
The structure determination of all products was based on
spectroscopic evidences. The 1H and 13C NMR signals
were assigned by using homo and heteronuclear 2D NMR
techniques and NOE experiments.19 In all cases, we found
the same regioselectivitiy and only one of the two possible
regioisomers was isolated in good to very good yields. The
results in Table 1 showed that the PO fragmentation regiose-
lectivity is independent of the nature of the functional group
attached at the quaternary carbon.
This regioselective process could find a wide variety of ap-
plications in organic synthesis if it could afford only one iso-
mer instead of a mixture of the two possible ones. In the
course of our ongoing research on the synthesis of penta-
lenolactone,18 we found that the non-symmetric ozonolysis
of a carbohydrate derived norbornene system (15a) showed
an exceptional high regioselectivity of the PO fragmenta-
tion, which after workup afforded a polyfunctionalized cy-
clopentane moiety bearing two aldehyde groups (one from
the original starting material attached at the quaternary cen-
ter and other from the newly formed one) and a methyl ester
as the unique product in 92% isolated yield (Scheme 5).
Ozonolysis of norbornenes 15a–g may proceed through the
mechanism depicted in Scheme 6. Since the isomeric prod-
ucts were not detected, formation of the carbonyl oxides
19a–g from the primary ozonides 17a–g should be excluded.
Once the carbonyl oxide is formed, it would be quickly trap-
ped by methanol to produce the corresponding a-alkoxy
hydroperoxide. Finally, the hydroperoxide would be
dehydrated with acetic anhydride and triethylamine to afford
the corresponding ester derivative.
O
OCH3
CO2CH3
O
OCH3
O
O
H5C6
O
i) O3, NaHCO3
CH2Cl2/CH3OH
ii) Ac2O, Et3N
CH2Cl2, 92%
H5C6
O
OHC
OHC
OHC
One of the common structural features among all these
molecular moieties is the quaternary carbon. Based on
these results, it seems reasonable to suggest that this qua-
ternary center rather than any of the susbtituents could
have a major influence on the regioselective fragmentation
of the PO.
16a
15a
Scheme 5.
This highly non-symmetric process is evidently controlled
by substituents that are at least a distance of two carbons
from the double bond. A noteworthy observation is the
fact that the carbonyl group attached at the quaternary center
is in an exo position with respect to the olefin in this norbor-
nene system.
Table 1. Ozonolysis of exo norbornene systems
O
OCH3
CO2CH3
O
OCH3
i) O3, NaHCO3
CH2Cl2/CH3OH
R1O
R1O
R1O
R1O
ii) Ac2O, Et3N
CH2Cl2
R
R
Comparison of Wu’s norbornene system 13 with 15a sug-
gests that, at least in our example, the carbonyl group does
not have a favorable spatial arrangement to induce the ozon-
ide fragmentation (Fig. 1). In this case, the carbonyl interac-
tion through the space could not be the factor that controls
the cleavage of the PO, as in the study reported by Wu and
co-workers. Hence, there must be also other remote factors
that control the outcome of this reaction.
R2
15a-g
16a-g
Entry Starting R
material
R1
R2
Yield
(%)
1
2
3
4
5
6
7
15a
15b
15c
15d
15e
15f
CHO
CH2OH
CO2CH3
Benzylidene acetal CHO
Benzylidene acetal CHO
Benzylidene acetal CHO
92
69
95
62
45
96
a
CH(OH)CH2CH3 Benzylidene acetal CHO
COCH2CH3
CH2OAc
CH2OAc
Benzylidene acetal CHO
Benzylidene acetal CHO
Acetate
]CHOAcb 86
H
H
15g
H
CHO
a
COCH3
Configuration of the secondary alcohol was not determined, only one of
the epimers was ozonized (the more polar one).
The ozonolysis of the norbornene 15g afforded the enol acetate derivative
as the only product, the stereochemistry of the double bond was not deter-
mined.
OHC
b
13
15a
Figure 1. Comparison between endo and exo norbornene systems.

S. A. Testero et al. / Tetrahedron 63 (2007) 11410–11420
11413
O
OCH3
O
OCH3
O
OCH3
O
O3, NaHCO3,
R1O
R1O
R1O
R1O
R1O
R1O
CH2Cl2, CH3OH,
-78 °C
R
R
R
O
O
15a-g
O
O
+
O
17a-g
-
19a-g
O
OCH3
O
OCH3
O
OCH3
H
R1O
R1O
R1O
R1O
R1O
CH3OH
Ac2O
Et3N
CO2CH3
R1O
R
R
R
OCH3
O
OH
+
O
OHC
O
O
O
-
16a-g
18a-g
20a-g
Scheme 6.
To test this hypothesis, we planned to synthesize a new nor-
bornene skeleton with a susbtituent attached at the other ring
fusion position.
manner. Despite of this result that positioned the carbonyl
group in an endo mode with respect to the norbornene sys-
tem and hence, could not discard the interaction of the car-
bonyl group through the space, we decided to explore the
ozonolysis of this endo cycloadduct.
In order to achieve our goal, we first prepared the dienophile
21 in an efficient manner.20 Reaction of aldehyde 21 with
cyclopentadiene provided cycloadduct 22 in only 26% yield
as the major adduct (Scheme 7).
The ozonolysis reaction of cycloadduct 22 afforded product
1
23 in 54% yield.21 We verified through the H NMR spec-
trum of the crude material that it was the only product
formed.
LiClO4
O
OCH3
CHO
O
OCH3
CHO
5M in Et2O,
O
O
The analysis of the reaction outcome and the possible alter-
native pathway that the ozonolysis reaction could undergo,
showed a high degree of regio- and stereocontrol. The reac-
tion of cycloadduct 22 with ozone yielded the primary ozon-
ide 24, which upon regioselective fragmentation afforded
only one of the two possible transient carbonyl oxide inter-
mediates. The carbonyl oxide 25 was trapped by one of
the two aldehyde groups present in the molecule at this stage
and formed the 1,2,4-trioxolane intermediate 26. It was not
possible to detect any by-products derived from the other
two possible competing processes: neither the reaction of
the carbonyl oxide with methanol and concomitant forma-
tion of the methoxy hydroperoxide 29 nor its recombination
cyclopentadiene
H5C6
O
H5C6
O
H
21
22
O
OCH3
O
i) O3, NaHCO3
CH2Cl2/CH3OH
O
O
O
H5C6
O
ii) Ac2O, Et3N
CH2Cl2
H
AcO
23
OCH3
Scheme 7.
Unfortunately, the product was the result of the diene ap-
proach from the b face of the dienophile 21 in an endo
O
O
OCH3
CHO
O
OCH3
CHO
O
OCH3
CHO
O
O
O
O
-
i) O3, NaHCO3
CH2Cl2/CH3OH
CHO
H5C6
O
H5C6
O
H5C6
O
H
H
H
O
+
O
O
O
28
22
24
O
OCH3
CHO
O
OCH3
CHO
O
OCH3
CHO
O
O
-
OH
O
O
O
O
H5C6
H5C6
O
H5C6
O
+
H
H
H
O
OCH3
OHC
OHC
O
O
29
30
25
OCH3
OCH3
OCH3
O
O
O
O
O
O
O
O
O
O
O
ii) Ac2O, Et3N,
CH2Cl2
O
H5C6
O
H
OHC
H5C6
O
H
H5C6
O
O
H
O
O
H3CO
H3CO
26
27
23
OH
OAc
Scheme 8.

11414
S. A. Testero et al. / Tetrahedron 63 (2007) 11410–11420
O
OCH3
CHO NaBH4
O
OCH3
OH
This example may demonstrate that the ability of an alcohol
group to control the PO fragmentation through the space is
lower than the aldehyde group, even though it could act as
an intramolecular trapping agent of the carbonyl oxide
once it is formed. Again, like in the previous series of com-
pounds, the major product is the regioisomer derived from
the generation of the carbonyl oxide at the more distant
position from the quaternary center.
O
O
H5C6
O
H5C6
O
83 %
H
H
31
22
O
OCH3
OAc
Ac2O, Py,
DMAP
O
H5C6
O
91 %
H
32
The acetylated derivative 32 also yielded a mixture of two
isomeric products in a ratio of 3:1 determined by H NMR
1
Scheme 9.
integration. The mixture was inseparable by flash chromato-
graphy although its spectrum revealed that each compound
was bearing an aldehyde and a methyl ester group besides
the original acetate group. This data allowed us to assume
that the mixture was formed by the two possible re-
gioisomers (Scheme 11).
with the carbonyl group generated at the other terminus of
the double bond to produce the ozonide 30. Further dia-
stereoselective reaction of the carbonyl group at C-19 with
methanol afforded a hemiacetal 27, which upon acetylation
yielded the final product 23 (Scheme 8).
To determine the regioselectivity of this reaction, it was nec-
essary to assign the structure to each isomer. For this reason,
we transformed both compounds into the corresponding pri-
mary alcohols, by reducing the aldehyde groups with sodium
borohydride.
As it could be expected, it seems evident from this result that
the carbonyl interaction through the space could be the domi-
nating effect in the regioselective fragmentation of the PO.
At this point, we wonder which could be the ozonolysis out-
come if we replace the carbonyl group by other functional
group. Reduction of the aldehyde 22 to the corresponding al-
cohol 31 and subsequent acetylation of the primary hydroxyl
group afforded the acetate 32 (Scheme 9). Ozonolysis of the
primary alcohol 31 under previously described conditions
afforded a mixture of two products in a ratio of 2:1. After pu-
rification, the structure of the less polar and minor compound
was identified as the lactone 36, derived from the intramo-
lecular carbonyl oxide trapping by the adjacent primary
hydroxyl group (Scheme 10). The major and more polar
compound was identified as the hemiacetal 35 derived
from the attack of the primary alcohol on the newly formed
aldehyde.
The reaction afforded two primary alcohols: 39 as major and
40 as minor products (Scheme 12).
The major fraction was rather unstable to be isolated. This
product was quickly converted into a less polar compound,
which was identified without ambiguity as the lactone 41,
which was generated by the intramolecular attack of the pri-
mary alcohol to the methyl ester (Scheme 13). Therefore, the
major isomer obtained from the ozonolysis reaction was
compound 37. This case made evident that the directing ef-
fect of an acetate group is lower than the hydroxyl group and
much lower than the aldehyde group.
O
OCH3
OH
O
OCH3
OH
CO2CH3
O
OCH3
OH
i) O3, NaHCO3
CH2Cl2/CH3OH
O
O
O
+
CHO
H5C6
O
H5C6
O
H5C6
O
ii) Ac2O, CH2Cl2,
Et3N
H
H
H
H3CO2C
OHC
83%
33
34
31
O
O
OCH3
O
OCH3
O
O
O
+
H5C6
O
H5C6
O
OH
O
H
H
H3CO2C
OHC
35
36
2:1
Scheme 10.
O
H
OCH3
OAc
O
OCH3
OAc
CO2CH3
O
OCH3
i) O3, NaHCO3
CH2Cl2/CH3OH
O
O
O
OAc
+
CHO
H5C6
O
H5C6
O
H
OHC
H5C6
O
ii) Ac2O, Et3N,
CH2Cl2
H
H3CO2C
100%
37
38
32
3:1
Scheme 11.

S. A. Testero et al. / Tetrahedron 63 (2007) 11410–11420
11415
O
OCH3
OAc
CHO
O
OCH3
OAc
4.2. Synthesis of the exo norbornene systems
O
O
H5C6
O
H5C6
O
OH
4.2.1. (1S,2S,3S,5R,8R,10S,11S,12R) 10-Methoxy-5-
phenyl-4,6,9-trioxatetracyclo [10.2.1.02,11.03,8]pentadec-
13-ene-2-carbaldehyde (15a). It was prepared according
to the procedure described in Ref. 18.
H
H
H3CO2C
H3CO2C
NaBH4
37
39
2:1
CH2Cl2/CH3OH
0 °C, 53%
+
O
+
O
OCH3
OAc
OCH3
O
O
OAc
CO2CH3
4.2.2. (1S,2S,3S,5R,8R,10S,11S,12R) 2-Hydroxymethyl-
10-methoxy-5-phenyl-4,6,9-trioxatetracyclo [10.2.1.
H5C6
O
H
OHC
H5C6
O
H
CO2CH3
HO
0
2,11.03,8]pentadec-13-ene (15b). Cycloadduct 15a
38
40
(100.5 mg, 0.294 mmol) was dissolved in MeOH (3 mL)
and cooled to 0 ꢀC. Sodium borohydride (15.0 mg,
0.40 mmol) was added, followed by stirring at 0 ꢀC for
20 min. Solution was diluted with ethyl acetate, washed
with water, dried over Na2SO4, and concentrated in vacuo.
The resulting crude product was purified by flash chromato-
graphy to furnish the alcohol 15b (80.5 mg, 0.29 mmol,
79.6%). Colorless oil; [a]2D0 +41.7 (c 1.34, CHCl3); IR
(film): nmax (cmꢁ1) 3556, 2956, 2887, 1450, 1406, 1368,
1095, 1057, 747, 699; 1H NMR (CDCl3, 200 MHz) d 7.45–
7.34 (m, 5H), 6.43 (m, 1H), 6.35 (m, 1H), 5.42 (s, 1H),
4.32–4.22 (m, 3H), 3.93–3.81 (m, 1H), 3.60–3.50 (m, 3H),
3.36 (br s, 1H), 3.30 (s, 3H), 2.95 (br s, 1H), 2.87 (br s,
1H), 1.84 (t, J¼3.0 Hz, 1H), 1.65 (d, J¼9.0 Hz, 1H), 1.47
(br d, J¼9.1 Hz, 1H); 13C NMR (CDCl3, 50 MHz) d 139.0,
137.2, 136.3, 129.1, 128.3, 125.9, 102.0, 101.9, 82.9, 69.7,
67.7, 59.3, 54.6, 51.0, 51.0, 46.7, 46.0, 45.2; HRMS m/z
362.1979 [(M+NH4+); calcd for C20H24O5: 362.1967)].
Scheme 12.
O
OCH3
OAc
OH
O
OCH3
OAc
O
O
CDCl3, rt
H5C6
O
H5C6
O
H
H
H3CO2C
O
39
41
O
Scheme 13.
3. Conclusion
It is interesting to notice that according to these results, in
a norbornene system with substituents in an exo position,
the methyl ester and consequently the carbonyl oxide are al-
ways formed in the carbon more distant from the quaternary
carbon. In the case of the norbornene system with substitu-
ents in an endo position, the carbonyl group probably exerts
a dominant effect in the regioselectivity of the PO fragmen-
tation as proposed by Wu, but when this functional group is
replaced by probably less interacting groups (in our case an
hydroxyl or an acetate) the regioselectivity is reversed show-
ing that at least two opposing factors are taking place and the
position of the quaternary center could be the dominating
one. More studies are needed to draw a better interpretation
of the remote factors that affect the PO fragmentation path-
way but in any case these results are a starting point for
further studies that will be reported in due course.
4.2.3. (1S,2S,3S,5R,8R,10S,11S,12R) 10-Methoxy-5-
phenyl-4,6,9-trioxatetracyclo [10.2.1.02,11.03,8]pentadec-
13-ene-2-carboxylic acid methyl ester (15c). To a solution
of cycloadduct 15a (111 mg, 0.326 mmol) in t-BuOH
(1 mL) were added aqueous NaH2PO4 (0.65 M, 0.3 mL,
0.195 mmol) and 28% H2O2 (0.08 mL, 0.648 mmol). The
mixture was cooled to 0 ꢀC, and NaClO2 (1 M, 0.65 mL,
0.65 mmol) was added. The mixture was stirred at room
temperature for 20 h, then the solution was extracted with
ethyl acetate and washed with water. The aqueous phase
was treated with HCl (0.1 M) until acidic reaction to pH pa-
per and was extracted with ethyl acetate. The combined or-
ganic extract was dried (Na2SO4) and the volatiles removed
under reduced pressure. The crude product was dissolved in
a 2:3 mixture of Et2O/CHCl3 (20 mL) and the resulting so-
lution was cooled at 0 ꢀC. Ethereal solution of diazomethane
was added dropwise until the reaction mixture turned light
yellow. After stirring for 30 min at 0 ꢀC, acetic acid was
slowly added until disappearance of the yellow coloration.
The volatiles were removed in vacuo, and the residual oil
was purified by flash chromatography to furnish the methyl
ester 15c (92.1 mg, 0.25 mmol, 76%). Colorless oil; [a]D27
+41.4 (c 1.10, CHCl3); IR (film): nmax (cmꢁ1) 2940, 2870,
1735, 1465, 1455, 1380, 1370, 1240, 1220, 1100, 1065,
4. Experimental section
4.1. General
Melting points were taken on a Microscope Heating Stage
apparatus and are uncorrected. Optical rotations were re-
corded with a digital polarimeter. IR spectra were recorded
on a FTIR or dispersive spectrometer. Nuclear magnetic res-
onance spectra were recorded on a 200 MHz spectrometer
with Me4Si as internal standard and chloroform-d as solvent.
Reactions were monitored by TLC on 0.25 mm Silica Gel
plates (60F254), using UV light and anisaldehyde–H2SO4–
AcOH as detecting agents. Flash column chromatography,
using Silica Gel 60H, was performed by gradient elution cre-
ated by mixtures of hexanes and increasing amounts of
EtOAc. Reactions were performed under an argon atmo-
sphere with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. Yields refer to chromato-
graphically and spectroscopically (1H NMR) homogeneous
materials, unless otherwise stated.
1
1035, 920, 745, 705; H NMR (CDCl3, 200 MHz) d 7.34–
7.31 (m, 5H), 6.38 (br s, 2H), 5.43 (s, 1H), 4.33 (d,
J¼2.81 Hz, 1H), 4.29–4.10 (m, 2H), 3.76 (s, 3H), 3.64–
3.47 (m, 2H), 3.26 (d, J¼9.36 Hz, 1H), 3.36 (s, 3H), 2.96
(br s, 1H), 2.76 (t, J¼3.18 Hz, 1H), 1.60 (br d, J¼9.0 Hz,
1H), 1.31 (br d, J¼9.1 Hz, 1H); 13C NMR (CDCl3,
50 MHz) d 174.1, 137.5, 137.2, 129.0, 128.9, 128.1, 126.1,
102.1, 101.4, 79.5, 69.5, 59.3, 58.5, 55.0, 52.1, 51.0, 48.7,
47.5, 46.2. Anal. Calcd for C21H24O6: C 67.73, H 6.50,
O 25.78. Found: C 67.66, H 6.54.

11416
S. A. Testero et al. / Tetrahedron 63 (2007) 11410–11420
4.2.4. (1S,10undefined,2R,3S,5R,8R,10S,11S,12R) 10-Meth-
oxy-5-phenyl-2-(10-hydroxy) propyl-4,6,9-trioxatetra-
cyclo [10.2.1.02,11.03,8]pentadec-13-ene (15dless polar and
15dmore polar). Li wire (945 mg, 135 mmol) in anhydrous
THF (100 mL) was sonicated in an ultrasound cleaning
2980, 2925, 2882, 1708, 1460, 1382, 1150, 1094, 1022,
981, 768, 753, 706; H NMR (CDCl3, 200 MHz) d 7.39–
1
7.31 (m, 5H), 6.41 (t, J¼1.7 Hz, 2H), 5.38 (s, 1H), 4.32 (d,
J¼3.3 Hz, 1H), 4.22 (dd, J1¼10.5 Hz, J2¼5.2 Hz, 1H),
3.92 (m, 1H), 3.70–3.30 (m, 4H), 3.37 (s, 3H), 2.92 (br s,
1H), 2.82 (d, J¼3.2 Hz, 1H), 2.55 (m, 1H), 1.56 (d,
J¼8.8 Hz, 1H), 1.05 (d, J¼8.5 Hz, 1H), 1.04 (t, J¼8.5 Hz,
3H); 13C NMR (CDCl3, 50 MHz) d 211.7, 137.8, 137.2,
136.9, 128.8, 128.0, 126.0, 102.0, 101.7, 80.5, 69.4, 63.4,
59.5, 54.8, 49.5, 48.0, 47.0, 45.8, 34.2, 7.7; HRMS m/z
388.1131 [(M+NH4+); calcd for C22H26O5: 388.1124].
bath while
a mixture of aldehyde 15a (2.716 g,
7.94 mmol) and EtBr (8.89 mL, 119.1 mmol) in anhydrous
THF (60 mL) was slowly added at room temperature. After
2 h the reaction was completed, diluted with Et2O, poured
onto a 10% solution of NH4Cl at 0 ꢀC, and successively ex-
tracted with Et2O. The combined organic layer was washed
with brine, dried (Na2SO4), and concentrated in vacuo. The
crude product was purified by flash chromatography to fur-
nish the two separated epimeric alcohols 15d in a combined
amount (2.068 g, 70%) and a 1:1 ratio.
4.2.6. (1S,2S,3S,5R,8R,10S,11S,12R) 2-Acetoxymethyl-
10-methoxy-5-phenyl-4,6,9-trioxatetracyclo [10.2.1.
02,11.03,8]pentadec-13-ene (15f). Alcohol 15b (112 mg,
0.327 mmol) was dissolved in anhydrous CH2Cl2 (5 mL)
and cooled to 0 ꢀC. DMAP (9.0 mg, 0.072 mmol), pyridine
(0.148 mL, 1.83 mmol), and acetic anhydride (0.089 mL,
0.944 mmol) were sequentially added. The resulting mixture
was stirred at room temperature for 16 h and then diluted
with ethyl acetate, washed with water, dried with Na2SO4,
and concentrated in vacuo. The crude product was purified
by flash chromatography to furnish pure 15f (100.7 mg,
80%). Colorless oil; [a]2D3 +90.36 (c 1.91, CHCl3); IR
(film): nmax (cmꢁ1) 2980, 1745, 1475, 1460, 1385, 1375,
4.2.4.1. Compound 15d(less polar). Colorless oil; [a]D20
+36.4 (c 1.00, CHCl3); IR (film): nmax (cmꢁ1) 3550, 2970,
2875, 1475, 1410, 1375, 1162, 1096, 1064, 1012, 973, 925,
1
757, 704; H NMR (CDCl3, 200 MHz) d 7.48–7.36 (m,
5H), 6.46 (m, 1H), 6.34 (m, 1H), 5.38 (s, 1H), 4.41 (s, 1H),
4.25 (dd, J1¼10.3 Hz, J2¼5.1 Hz, 1H), 3.98 (dt,
J1¼9.8 Hz, J2¼5.1 Hz, 1H), 3.63 (d, J¼10.3 Hz, 1H), 3.58
(br s, 1H), 3.49 (t, J¼10.2 Hz, 1H), 3.37 (m, 1H), 3.30 (s,
3H), 2.94 (br s, 1H), 2.76 (d, J¼11.8 Hz, 1H), 2.20 (m,
1H), 1.98 (d, J¼3.5 Hz, 1H), 1.90 (m, 1H), 1.63 (d,
J¼9.4 Hz, 1H), 1.41 (d, J¼9.2 Hz, 1H), 1.09 (t, J¼7.2 Hz,
3H); 13C NMR (CDCl3, 50 MHz) d 140.1, 137.2, 135.9,
129.3, 128.5, 126.0, 102.6, 102.1, 83.9, 82.3, 70.2, 59.1,
54.5, 53.5, 51.0, 48.0, 46.1, 26.6, 12.7. Anal. Calcd for
C22H28O5: C 70.95, H 7.58, O 21.48. Found: C 71.00, H 7.52.
1
1290, 1250, 1150, 1110, 1070, 1050, 1040, 760, 710; H
NMR (CDCl3, 200 MHz) d 7.48–7.33 (m, 5H), 6.38 (br s,
2H), 5.43 (s, 1H), 4.44 (s, 2H), 4.35 (d, J¼2.24 Hz, 1H),
4.24 (dd, J1¼10.3 Hz, J2¼5.24 Hz, 1H), 3.97 (m, 1H), 3.49
(dd, J1¼J2¼10.3 Hz, 1H), 3.37 (d, J¼10.3 Hz, 1H), 3.31
(s, 3H), 2.98 (br s, 1H), 2.88 (br s, 1H), 2.28 (t,
J¼2.43 Hz, 1H), 2.05 (s, 3H), 1.67 (d, J¼9.0 Hz, 1H),
1.48 (br d, J¼9.0 Hz, 1H); 13C NMR (CDCl3, 50 MHz)
d 171.0, 138.7, 137.7, 136.2, 128.9, 128.1, 126.1, 101.7,
101.6, 80.1, 70.0, 67.6, 59.8, 54.6, 50.0, 49.3, 47.5, 47.3,
47.0, 20.9; HRMS m/z 409.163714 [(M+Na+); calcd for
C22H26O6: 409.162709].
4.2.4.2. Compound 15d(more polar). Colorless oil; [a]D18
+52.9 (c 1.00, CHCl3); IR (film): nmax (cmꢁ1) 3540, 2970,
2890, 1460, 1378, 1150, 1100, 1068, 1037, 988, 754, 703;
1H NMR (CDCl3, 200 MHz) d 7.45–7.37 (m, 5H), 6.42 (br
s, 2H), 5.38 (s, 1H), 4.34 (d, J¼2.6 Hz, 1H), 4.30–4.10 (m,
2H), 3.81 (m, 1H), 3.60 (d, J¼9.7 Hz, 1H), 3.50 (t,
J¼9.7 Hz, 1H), 3.34 (s, 3H), 3.19 (br s, 1H), 2.98 (br s,
1H), 2.78 (d, J¼6.9 Hz, 1H), 2.41 (t, J¼3.2 Hz, 1H), 1.95–
1.65 (m, 2H), 1.65 (d, J¼8.9 Hz, 1H), 1.38 (d, J¼8.9 Hz,
1H), 1.01 (t, J¼7.3 Hz, 3H); 13C NMR (CDCl3, 50 MHz)
d 139.9, 137.3, 137.0, 129.0, 128.3, 125.9, 102.1, 102.0,
83.5, 81.5, 70.1, 60.5, 54.9, 53.5, 52.9, 47.4, 46.8, 46.3,
27.2, 12.1; HRMS m/z 390.2287 [(M+NH+4); calcd for
C22H28O5: 390.2281].
4.2.7. (1S,2S,3S,4R,6S,7S,8R) 3-Acetoxy-2,4 bisacetoxy-
methyl-6-methoxy-5-oxatricyclo[6.2.1.02,7] undec-9-ene
(15g). A solution of the acetylated alcohol 15f (100 mg,
0.26 mmol) and pyridinium p-toluenesulfonate (20 mg,
0.08 mmol) in a 1:1 mixture of MeOH–CHCl3 (40 mL)
was heated at 40 ꢀC for 96 h. The volatiles were removed
in vacuo and the residue was dissolved in ethyl acetate,
washed with water, and dried (Na2SO4). Evaporation under
reduced pressure furnished 100 mg of the crude product,
which was used without further purification in the next step.
4.2.5. (1S,2S,3S,5R,8R,10S,11S,12R) 10-Methoxy-5-
phenyl-2-(10-oxo) propyl-4,6,9-trioxatetracyclo [10.2.1.
0
2,11.03,8]pentadec-13-ene (15e). Jones reagent was added
The crude diol mixture (100 mg) was dissolved in anhydrous
CH2Cl2 (10 mL) and the solution was cooled in an ice bath.
Anhydrous pyridine (0.290 mL, 3.59 mmol), DMAP
(19 mg, 0.152 mmol), and acetic anhydride (0.175 mL,
1.86 mmol) were sequentially added to the solution at
0 ꢀC. After stirring 3 h at room temperature, the mixture
was diluted with ethyl acetate, washed with brine, dried
(Na2SO4), and concentrated. The crude product was purified
by flash chromatography furnished pure 15g (46.8 mg, 47%,
two steps). Colorless oil; [a]2D1 +104.88 (c 2.95, CHCl3); IR
(film): nmax (cmꢁ1) 3020, 1782 (CO, br), 1415, 1275, 1194;
1H NMR (CDCl3, 200 MHz) d 6.50 (dd, J1¼5.62 Hz,
J2¼3.19 Hz, 1H), 6.33 (dd, J1¼5.62 Hz, J2¼3.0 Hz, 1H),
4.72 (d, J¼10.1 Hz, 1H), 4.33 (d, J¼3.93 Hz, 1H), 4.27 (d,
dropwise to a cooled (0 ꢀC) solution of the mixture of epi-
meric alcohols 15d (217 mg, 0.58 mmol) in acetone
(20 mL) until the reaction mixture turned light orange. The
reaction was stirred 15 min at 0 ꢀC and isopropyl alcohol
was added to reduce the excess Jones reagent until the reac-
tion mixture turned green. Water was added to the mixture,
which was vigorously stirred to dissolve the chromium salts
and concentrated under reduced pressure (to remove the ace-
tone). Solution was extracted with ethyl acetate, washed
with brine, dried over Na2SO4, and concentrated in vacuo.
The resulting crude product was purified by flash chromato-
graphy to furnish the ketone 15e (163 mg, 76%). Colorless
oil; [a]2D4 +34.8 (c 1.07, CHCl3); IR (film): nmax (cmꢁ1
)

S. A. Testero et al. / Tetrahedron 63 (2007) 11410–11420
11417
J¼6.55 Hz, 2H), 4.28–3.99 (m, 3H, C-5 H), 3.34 (s, 3H),
2.94 (br s, 1H), 2.77 (br s, 1H), 2.20 (t, J¼3.56 Hz, 1H),
2.09 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 1.59 (d,
J¼9.17 Hz, 1H), 1.44 (br d, J¼9.17 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) d 170.6, 170.5, 169.9, 138.8, 135.9,
101.5, 70.6, 68.0, 67.2, 63.5, 54.9, 51.5, 49.7, 48.5, 46.5,
46.4, 20.8, 20.6, 20.5; HRMS m/z 405.152577 [(M+Na+);
calcd for C19H26O8: 405.152538].
J1¼9.2 Hz, J2¼1.8 Hz, 1H), 1.63 (m, 2H); 13C NMR
(CDCl3, 50 MHz) d 199.6, 139.2, 137.3, 132.3, 128.9,
128.1, 126.1, 104.7, 101.6, 79.7, 69.6, 65.5, 62.4, 56.3,
47.7, 45.2, 45.0, 44.3; HRMS m/z 341.139010 [(MꢁH+);
calcd for C20H21O5: 341.138899].
4.4.2. (1S,2S,3S,5R,8R,10S,11R,12R) 2-Hydroxymethyl-
3-methoxy-8-phenyl-4,7,9-trioxatetracyclo [10.2.1.
02,11.05,10]pentadec-13-ene (31). Cycloadduct 22 (284 mg,
0.8 mmol) was dissolved in a 1:1 mixture of CH2Cl2–
MeOH (32 mL) and cooled to 0 ꢀC. Sodium borohydride
(320 mg, 8.5 mmol) was added and the resulting mixture
was stirred at 0 ꢀC for 40 min. Acetone was added, the solu-
tion was stirred for 15 min, and concentrated in vacuo. The
oil residue was dissolved in ethyl acetate, washed with water
and brine, and concentrated. The crude product was purified
by flash chromatography to furnish pure 31 (287 mg, 100%).
Colorless oil; [a]D19 +22.0 (c 0.79, CHCl3); IR (film): nmax
(cmꢁ1) 3555, 2963, 2874, 1723, 1457, 1372, 1294, 1201,
4.3. Methyl 4,6-O-benzylidene-2,3-dideoxy-2-C-formyl-
a-D-erythro-hex-2-enopyranoside (21)
Methyl 4,6-O-benzylidene-2-C-cyano-2,3-dideoxy-a-D-ery-
thro-hex-2-enopyranoside20 (579 mg, 2.1 mmol) was azeo-
tropically dried with dry benzene under vacuum, dissolved
in anhydrous CH2Cl2 (43 mL), and cooled at ꢁ80 ꢀC under
an argon atmosphere. Diisobutylaluminum hydride (1 M so-
lution in hexane, 4.8 mL, 4.8 mmol) was slowly added to the
magnetically stirred solution. The reaction mixture was
stirred for additionally 90 min at ꢁ80 ꢀC and then quenched
with 1:1 HOAc–water solution (3.4 mL). Stirring was con-
tinued for 30 min while the temperature rose to 0 ꢀC. The
mixture was extracted with CH2Cl2, washed with H2O, 5%
NaHCO3 solution, and brine, dried (Na2SO4), and concen-
trated to furnish compound 6 (506 mg, 86%) as a white solid.
Recrystallization afforded crystals as white needles mp
195.0–196.0 ꢀC (CH2Cl2–petroleum ether); [a]2D0 +131.6 (c
0.80, CHCl3); reported22 mp 190–192 ꢀC; [a]D 100.4 (c
0.25, CHCl3); 1H NMR (CDCl3): d 9.47 (s, 1H), 7.55–7.30
(m, 5H), 6.97 (s, 1H), 5.63 (s, 1H), 5.21 (s, 1H), 4.45–
4.35 (m, 2H), 4.15–4.00 (m, 1H), 3.85 (dd, 1H,
Jgem¼J5,6¼10.2 Hz), 3.54 (s, 3H); 13C NMR (CDCl3):
d 189.8, 146.5, 139.5, 136.8, 129.3, 128.3, 126.1, 102.6,
94.6, 75.4, 69.3, 63.3, 56.5.
1
1072, 754, 699; H NMR (CDCl3, 200 MHz) d 7.55–7.30
(m, 5H), 6.19 (m, 2H), 5.50 (s, 1H), 4.79 (s, 1H), 4.36 (dd,
J¼9.8 Hz, 1H), 3.85 (d, J¼10.9 Hz, 1H), 3.73–3.64 (m,
2H), 3.58–3.43 (m, 2H), 3.50 (s, 3H), 3.22–2.90 (m, 3H),
2.94 (br s, 1H), 1.65 (d, J¼9.4 Hz, 1H), 1.52 (d, J¼9.2 Hz,
1H); 13C NMR (CDCl3, 50 MHz) d 137.4, 136.2, 135.2,
129.0, 128.2, 126.1, 105.5, 101.6, 78.9, 70.1, 67.3, 67.0,
57.0, 52.2, 46.9, 46.8, 44.1, 43.5.
4.4.3. (1S,2S,3S,5R,8R,10S,11R,12R) 2-Acetoxymethyl-3-
methoxy-8-phenyl-4,7,9-trioxatetracyclo [10.2.1.
0
2,11.05,10]pentadec-13-ene (32). The hydroxymethyl deriv-
ative 31 (136.3 mg, 0.4 mmol) was dissolved in anhydrous
CH2Cl2 (4 mL) and the solution was cooled in an ice bath.
Anhydrous pyridine (0.48 mL, 5.9 mmol), DMAP (catalytic
amount), and acetic anhydride (0.34 mL, 3.6 mmol) were se-
quentially added to the solution at 0 ꢀC. The mixture was
stirred overnight at room temperature. MeOH was added;
the mixture was diluted with ethyl acetate, washed with
brine, dried (Na2SO4), and concentrated. The crude product
was purified by flash chromatography furnished pure 32
(138.8 mg, 91%). Colorless oil; [a]2D0 +11.6 (c 1.17,
CHCl3); IR (film): nmax (cmꢁ1) 2970, 1734, 1453, 1372,
1243, 1084, 755, 696; 1H NMR (CDCl3, 200 MHz)
d 7.60–7.25 (m, 5H), 6.20 (dd, J1¼5.6 Hz, J2¼3.0 Hz,
1H), 6.06 (dd, J1¼5.6 Hz, J2¼3.0 Hz, 1H), 5.52 (s, 1H),
4.69 (s, 1H), 4.36 (dd, J1¼10.2 Hz, J2¼4.6 Hz, 1H), 4.12
(d, J¼10.1 Hz, 1H), 3.97 (d, J¼11.1 Hz, 1H), 3.85 (m,
1H), 3.66 (dd, J1¼J2¼10.0 Hz, 1H), 3.55 (dd,
J1¼J2¼9.6 Hz, 1H), 3.45 (s, 3H), 2.98 (br s, 1H), 2.75 (br
s, 1H), 2.04 (s, 3H), 1.73 (d, J¼9.2 Hz, 1H), 1.59 (d,
J¼9.6 Hz, 1H), 1.53 (d, J¼9.6 Hz, 1H); 13C NMR (CDCl3,
50 MHz) d 170.6, 137.5, 137.1, 134.6, 128.9, 128.2, 126.1,
103.7, 101.6, 79.6, 70.3, 66.8, 66.2, 57.0, 50.7, 48.3, 46.0,
45.1, 44.5, 21.1; HRMS m/z 404.2087 [(M+NH+4); calcd
for C22H26O6: 404.2072].
4.4. Synthesis of the endo norbornene systems
4.4.1. (1S,2S,3S,5R,8R,10S,11R,12R) 3-Methoxy-8-phen-
yl-4,7,9-trioxatetracyclo[10.2.1.02,11.05,10] pentadec-13-
ene-2-carbaldehyde (22). Methyl 4,6-O-benzylidene-2,3-
dideoxy-2-C-formyl-a-D-erythro-hex-2-enopyranoside (21)
(583.0 mg, 2.10 mmol) was azeotropically dried with dry
benzene under vacuum and dissolved in anhydrous ethyl
ether (35 mL) at room temperature under argon atmosphere.
Anhydrous lithium perchlorate (18.6 g, 0.17 mol) and
freshly cracked cyclopentadiene (1.4 mL, 21.20 mmol)
were sequentially added under argon atmosphere at room
temperature to the stirred solution. After seven days of stir-
ring at room temperature, extra ethyl ether (35 mL) and
cyclopentadiene (1.4 mL, 21.20 mmol) were added to the
reaction mixture and stirred for seven additional days at
the same temperature. The mixture was diluted with ethyl
acetate, washed with water, dried (Na2SO4), and concen-
trated in vacuo. The crude product was purified by flash
chromatography to furnish pure 22 (189 mg, 26%). Color-
less oil; [a]D23 +35.8 (c 8.24, CHCl3); IR (film): nmax
(cmꢁ1) 2972, 2854, 1721, 1454, 1374, 1212, 1086, 974,
850, 755, 699; 1H NMR (CDCl3, 200 MHz) d 9.53 (s, 1H),
7.55–7.30 (m, 5H), 6.19 (dd, J1¼5.6 Hz, J2¼2.8 Hz, 1H),
6.08 (dd, J1¼5.6 Hz, J2¼3.2 Hz, 1H), 5.53 (s, 1H), 4.84 (s,
1H), 4.33 (dd, J1¼10.0 Hz, J2¼4.6 Hz, 1H), 3.81 (m, 1H),
3.65 (dd, J1¼J2¼10.0, 1H), 3.49 (dd, J1¼J2¼9.5 Hz, 1H),
3.42 (s, 3H), 3.14 (br s, 1H), 2.96 (br s, 1H), 2.36 (dd,
4.5. Representative experimental procedure for the
ozonolysis of norbornenes
The cycloadduct 15a (880.5 mg, 2.57 mmol) was dis-
solved in a 5:1 mixture of CH2Cl2–MeOH (5 mL) and
solid NaHCO3 (865 mg, 10.3 mmol) was added. The sus-
pension was cooled to ꢁ78 ꢀC and an ozone stream was

11418
S. A. Testero et al. / Tetrahedron 63 (2007) 11410–11420
bubbled through the stirred suspension. Ozone addition
was stopped when complete consumption of 15a was ob-
served by TLC analysis. The mixture was then flushed
with argon, and NaHCO3 was removed by filtration. The
filtrate was concentrated in vacuo to give the crude mate-
rial as a colorless oil, which was taken up in CH2Cl2
(13 mL). The mixture was cooled to 0 ꢀC, and acetic an-
hydride (1.2 mL, 12.85 mmol) and triethylamine (0.5 mL,
3.08 mmol) were added. The mixture was stirred at room
temperature for 1 h and then partitioned between diethyl
ether and, sequentially, 0.5 M aqueous HCl, 0.625 M
aqueous KOH, and brine. The combined organic extract
was dried (Na2SO4) and concentrated in vacuo to give es-
sentially pure 16a. This crude material was purified by
column chromatography (hexane–AcOEt) to provide
960.5 mg (92.3%) of 16a.
m/z 457.147448 [(M+Na+); calcd for C22H26O9:
457.147453].
4.5.4. (1S,2S,4R,7R,9S,10S,11S,13R) 13-Formyl-1-(10-hy-
droxy)propyl-9-methoxy-4-phenyl-3,5,8-trioxatricyclo
[8.3.0.02,7]tridecane-11-carboxylic acid methyl ester
(16d). Colorless oil; 62% yield; [a]2D5 +35.21 (c 2.14,
CHCl3); IR (film): nmax (cmꢁ1) 3533, 2947, 2863, 1731
(br), 1460, 1372, 1365, 1314, 1227, 1211, 1175, 1131,
1094, 1050, 1006, 977, 918, 845, 735, 699; 1H NMR
(CDCl3, 200 MHz) d 10.02 (d, J¼1.12 Hz, 1H), 7.38–7.27
(m, 5H), 5.47 (s, 1H), 4.80 (br s, 1H), 4.39 (d, J¼10.3 Hz,
1H), 4.33 (d, J¼9.73 Hz, 1H), 4.24 (dd, J1¼10.11 Hz,
J2¼4.68 Hz, 1H), 4.09 (m, 1H), 3.70 (s, 3H), 3.65 (dd,
J1¼J2¼9.92 Hz, 1H), 3.41 (br s, 1H), 3.33 (s, 3H), 3.21–
2.96 (m, 3H), 2.66 (d, J¼11.04 Hz, 1H), 2.03–1.90 (m,
1H), 1.78–1.64 (m, 1H), 1.51–1.36 (m, 1H), 1,04 (t,
J¼7.1 Hz, 1H); 13C NMR (CDCl3, 50 MHz) d 201.8,
174.8, 136.9, 128.8, 128.1, 125.8, 102.1, 97.2, 77.7, 73.0,
69.1, 59.3, 55.9, 55.4, 54.9, 52.1, 49.0, 42.3, 24.5, 23.0,
10.8; HRMS m/z 457.184886 [(M+Na+); calcd for
C23H30O8: 457.183838].
4.5.1. (1S,2S,4R,7R,9S,10S,11S,13R) 1,13-Dicarbalde-
hyde-9-methoxy-4-phenyl-3,5,8-trioxatricyclo [8.3.
0
1,10.02,7]tridecane-11-carboxylic acid methyl ester
(16a). Colorless oil; [a]2D1 ꢁ20.4 (c 1.13, CHCl3); IR
(film): nmax (cmꢁ1) 2926, 2864, 1724 (br), 1452, 1438,
1372, 1212, 1174, 1130, 1086, 962, 758; 1H NMR (CDCl3,
200 MHz) d 10.23 (s, 1H), 9.65 (s, 1H), 7.37–7.31 (m,
5H), 5.48 (s, 1H), 4.90 (s, 1H), 4.33–4.21 (m, 2H), 4.08 (d,
J¼9.7 Hz, 1H), 3.72 (s, 3H), 3.73–3.66 (m, 1H), 3.65–3.41
(m, 1H), 3.39 (s, 3H), 3.35–2.96 (m, 2H), 2.70 (d,
J¼11.4 Hz, 1H), 2.16–1.97 (m, 1H); 13C NMR (CDCl3,
50 MHz) d 200.8, 198.6, 173.9, 136.7, 128.9, 128.1, 125.7,
102.0, 96.8, 73.9, 69.2, 59.8, 58.8, 56.2, 55.0, 52.8, 52.3,
41.6, 23.6; HRMS m/z 427.13585 [(M+Na+); calcd for
C21H24O8: 427.13688].
4.5.5. (1S,2S,4R,7R,9S,10S,11S,13R) 13-Formyl-9-meth-
oxy-1-(10-oxo) propyl-4-phenyl-3,5,8-trioxatricyclo
[8.3.0.02,7]tridecane-11-carboxylic acid methyl ester
(16e). Colorless oil; 45% yield; [a]2D0 +24.04 (c 1.60,
CHCl3); IR (film): nmax (cmꢁ1) 3460, 2937, 2853, 1735
(br), 1698, 1457, 1435, 1376, 1208, 1178, 1134, 1091,
1047, 1010, 922, 739, 695, 651; 1H NMR (CDCl3,
200 MHz) d 9.63 (s, 1H), 7.42–7.32 (m, 5H), 5.49 (s, 1H),
4.80 (br s, 1H), 4.31–4.16 (m, 2H), 4.05 (d, J¼10.11 Hz,
1H), 3.71 (s, 3H), 3.69 (dd, J1¼J2¼11.4 Hz, 1H), 3.31 (s,
3H), 3.43–3.20 (m, 2H), 3.11 (dd, J1¼10.8 Hz, J2¼1.1 Hz,
1H), 3.07–2.87 (m, 3H), 2.17–2.01 (m, 1H), 1.07 (t,
J¼7.11 Hz, 3H); 13C NMR (CDCl3, 50 MHz) d 211.1,
198.6, 174.2, 136.7, 128.9, 128.2, 125.6, 102.5, 97.1, 74.2,
69.5, 61.0, 60.4, 60.3, 54.8, 53.6, 52.2, 41.7, 35.8, 24.6,
8.2; HRMS m/z 455.168139 [(M+Na+); calcd for
C23H28O8: 455.168188].
4.5.2. (1S,2S,4R,7R,9S,10S,11S,13R) 13-Formyl-1-(hy-
droxy) methyl-9-methoxy-4-phenyl-3,5,8-trioxatricyclo
[8.3.0.02,7]tridecane-11-carboxylic acid methyl ester
(16b). Colorless oil; 69% yield; [a]2D5 +14.52 (c 1.12,
CHCl3); IR (film): nmax (cmꢁ1) 3502, 2937, 2853, 1727
(br), 1457, 1376, 1369, 1281, 1208, 1200, 1171, 1134,
1091, 1047, 966, 915, 732, 702; 1H NMR (CDCl3,
200 MHz) d 9.96 (d, J¼1.31 Hz, 1H), 7.34 (m, 5H), 5.45
(s, 1H), 4.85 (s, 1H), 4.35–4.12 (m, 3H), 4.03–3.91 (m,
1H), 3.71 (s, 3H), 3.81–3.58 (m, 2H), 3.36 (s, 3H), 3.25–
2.95 (m, 3H), 2.57 (d, J¼11.2 Hz, 1H), 2.09–1.90 (m, 1H);
13C NMR (CDCl3, 50 MHz) d 201.4, 174.6, 136.9, 128.8,
128.1, 125.7, 101.8, 97.4, 76.1, 69.2, 64.5, 59.4, 57.4,
55.0, 52.3, 52.2, 48.8, 42.0, 24.6; HRMS m/z 429.154574
[(M+Na+); calcd for C21H26O8: 429.152538].
4.5.6. (1S,2S,4R,7R,9S,10S,11S,13R) 1-Acetoxymethyl-
13-formyl-9-methoxy-4-phenyl-3,5,8-trioxatricyclo
[8.3.0.02,7]tridecane-11-carboxylic acid methyl ester
(16f). Colorless oil; 96% yield; [a]2D2 +16.43 (c 5.18,
CHCl3); IR (film): nmax (cmꢁ1) 2940, 2880, 1745 (br),
1470, 1445, 1390, 1380, 1245, 1100, 1060, 940, 930, 765,
1
715; H NMR (CDCl3, 200 MHz) d 9.86 (d, J¼1.68 Hz,
1H), 7.42–7.30 (m, 5H), 5.44 (s, 1H), 4.86 (s, 1H), 4.78 (d,
J¼12.0 Hz, 1H), 4.42 (d, J¼12.0 Hz, 1H), 4.21 (dd,
J1¼10.1 Hz, J2¼4.68 Hz, 1H), 4.08 (d, J¼9.74 Hz, 1H),
3.92 (ddd, J1¼9.74 Hz, J2¼9.73 Hz, J3¼4.68 Hz, 1H), 3.72
(s, 3H), 3.61 (dd, J1¼10.11 Hz, J2¼9.73 Hz, 1H), 3.33 (s,
3H), 3.21–2.88 (m, 3H), 2.72 (d, J¼11.8 Hz, 1H), 2.09–
2.00 (m, 1H), 1.96 (s, 3H); 13C NMR (CDCl3, 50 MHz)
d 200.5, 174.4, 170.3, 137.0, 128.7, 127.9, 125.8, 101.7,
97.5, 74.7, 69.1, 63.7, 59.1, 55.9, 55.0, 52.1, 50.0, 48.0,
41.9, 24.5, 20.6; HRMS m/z 471.161544 [(M+Na+); calcd
for C23H28O9: 471.163103].
4.5.3. (1S,2S,4R,7R,9S,10S,11S,13R) 13-Formyl-9-meth-
oxy-4-phenyl-3,5,8-trioxatricyclo [8.3.0.02,7]tridecane-
1,11-carboxylic acid methyl ester (16c). Colorless oil;
95% yield; [a]D26 +14.45 (c 1.61, CHCl3); IR (film): nmax
(cmꢁ1) 2860, 2760, 1675 (br), 1390, 1330, 1315, 1230,
1150, 1135, 1080, 1040, 995, 970, 890, 705, 650; 1H NMR
(CDCl3, 200 MHz) d 9.71 (s, 1H), 7.42–7.30 (m, 5H), 5.43
(s, 1H), 4.83 (s, 1H), 4.49–4.37 (m, 1H), 4.27–4.19 (m,
1H), 3.88 (d, J¼9.5 Hz, 1H), 3.80 (s, 3H), 3.72 (s, 3H),
3.60–3.47 (m, 2H), 3.32 (s, 3H), 3.29–3.19 (m, 1H), 3.05
(d, J¼12.7 Hz, 1H), 3.04–2.88 (m, 1H), 2.19–2.03
(m, 1H); 13C NMR (CDCl3, 50 MHz) d 198.5, 173.8,
172.4, 137.2, 128.7, 128.0, 125.9, 102.0, 96.8, 73.7, 69.4,
59.8, 59.0, 54.8, 54.4, 53.0, 52.4, 52.3, 41.8, 24.6; HRMS
4.5.7. (1S,2S,3R,5S,6S,7S) 2-Acetoxy-1,3-bisacetoxy-
methyl-5-methoxy-4-oxabicyclo [6.3.01,6]-9-acetoxy-
methylene-nonane-7-carboxylic acid methyl ester (16g).

S. A. Testero et al. / Tetrahedron 63 (2007) 11410–11420
11419
Colorless oil; 86% yield; [a]2D0 +68.09 (c 3.21, CHCl3); IR
(film): nmax (cmꢁ1) 2940, 1750 (br), 1683, 1460, 1445,
1365, 1250, 1220, 1045; 1H NMR (CDCl3, 200 MHz)
d 6.97 (t, J¼2.4 Hz, 1H), 5.34 (d, J¼9.8 Hz, 1H), 4.95 (s,
1H), 4.49 (d, J¼11.34 Hz, 1H), 4.40 (d, J¼11.34 Hz, 1H),
4.17–3.89 (m, 3H), 3.74 (s, 3H), 3.34 (s, 3H), 3.19–3.04
(m, 2H), 2.83 (d, J¼9.18 Hz, 1H), 2.60 (m, 1H), 2.12
(s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H); 13C NMR
J2¼10.2 Hz, 1H), 3.65 (d, J¼10.9 Hz, 1H), 3.42 (s, 3H),
3.28 (dd, J1¼J2¼9.7 Hz, 1H), 3.22 (dd, J1¼9.3 Hz,
J2¼3.1 Hz, 1H), 3.03 (dd, J1¼11.5 Hz, J2¼5.3 Hz, 1H),
2.82 (d, J¼9.9 Hz, 1H), 2.67–2.48 (m, 2H); 13C NMR
(CDCl3, 50 MHz) d 200.3, 177.5, 136.9, 129.2, 128.2,
126.1, 102.4, 98.7, 78.5, 71.5, 69.0, 61.2, 56.7, 55.3, 55.1,
46.5, 44.8, 26.0; HRMS m/z 375.1437 [(M+H+); calcd for
C20H22O7: 375.1444].
(CDCl3, 50 MHz)
d
174.2, 170.5, 170.4, 169.3,
167.3, 126.9, 126.4, 97.4, 67.4, 65.4, 63.3, 62.9, 55.0,
52.0, 48.3, 47.4, 42.7, 29.2, 20.6, 20.5, 20.4, 20.3; HRMS
m/z 509.164747 [(M+Na+); calcd for C22H30O12: 509.
163497].
4.5.10. Ozonolysis of 32. The crude product (141.2 mg,
100%) was analyzed by 1H NMR as a 3:1 mixture of com-
pounds 37 and 38. The isomeric mixture was used without
further purification in the next reaction step.
4.5.8. (1S,2S,3S,5R,8R,10S,11R,12S,14R,15S,19unde-
fined) 12-Acetoxymethoxy-methyl-3-methoxy-8-phenyl-
4,7,9,16,17,18-hexoxapentacyclo [13.2.1.02,11.02,14.05,10]-
octadecane (23). Colorless oil; 54% yield; [a]2D5 +21.5 (c
0.44, CHCl3); IR (film): nmax (cmꢁ1) 2931, 2854, 1761,
1733, 1456, 1376, 1229, 1161, 1122, 1076, 1053, 1018,
4.6. Preparation of 39 and 40
The mixture of 37/38 (90 mg, 0.2 mmol) was dissolved in
a 1:1 mixture of CH2Cl2–MeOH (8 mL). The solution was
cooled in an ice bath. Sodium borohydride (44 mg,
1.2 mmol) was added and the resulting mixture was stirred
at 0 ꢀC for 15 min. Acetone was added; the solution was
stirred for additional 15 min and concentrated in vacuo.
The oil residue was dissolved in ethyl acetate, washed
with water, brine, and concentrated in vacuo. The crude
product was purified by flash chromatography to furnish
pure 39 (32.8 mg, 36%) and pure 40 (15.2 mg, 17%) as col-
orless oils. Compound 39 was unstable when it was dis-
solved in chloroform-d at room temperature and was
gradually converted into lactone 41.
1
978, 941, 755, 700; H NMR (CDCl3, 200 MHz) d 7.53–
7.49 (m, 2H), 7.44–7.38 (m, 3H), 6.50 (s, 1H), 5.94 (s,
1H), 5.55 (s, 1H), 4.92 (s, 1H), 4.63 (s, 1H), 4.33 (dd,
J1¼10.3, J2¼5.0 Hz, 1H), 3.92 (m, 1H), 3.71 (dd,
J1¼J2¼10.4 Hz, 1H), 3.51 (s, 3H), 3.43 (s, 3H), 3.25 (dd,
J1¼J2¼10.0 Hz, 1H), 2.77 (dd, J1¼11.8, J2¼3.2 Hz, 1H),
2.71 (d, J¼7.9 Hz, 1H), 2.55 (d, J¼10.1 Hz, 1H), 2.31
(dm, J¼14.9 Hz, 1H), 2.11 (s, 3H), 2.08 (dd, J1¼14.9,
J2¼6.6 Hz, 1H); 13C NMR (CDCl3, 50 MHz) d 169.7,
137.2, 129.3, 128.4, 126.2, 111.4, 107.8, 106.6, 102.4,
97.3, 78.2, 69.2, 62.4, 60.8, 57.5, 55.2, 50.9, 46.7, 43.6,
26.6, 21.3; HRMS m/z 482.2032 [(M+NH+4); calcd for
C23H28O10: 482.2026].
4.6.1. (1R,2S,4R,7R,9S,10R,11S,13R) 1-Acetoxymethyl-
11-hydroxymethyl-2-ethoxy-7-phenyl-3,6,8-trioxatricy-
clo [10.3.01,10.04,9]tridecane-13-carboxylic acid methyl
ester (40). Colorless oil; 17% yield; [a]2D1 +11.3 (c 0.55,
CHCl3); IR (film): nmax (cmꢁ1) 3462, 2924, 2853, 2359,
2342, 1738, 1732, 1456, 1368, 1244, 1109, 1080, 1038,
4.5.9. Ozonolysis of 31, preparation of hemiacetal 35, and
lactone 36.
1
4.5.9.1. (1R,2S,4R,7R,9S,10R,11S,13R,14R) 14-Hydr-
oxy-2-methoxy-7-phenyl-3,6,8,15-tetraoxatetracyclo [10.3.
2.01,10.01,13.04,9]hexadecane-11-carboxylic acid methyl
ester (35). Colorless oil; 54% yield; [a]2D4 +4.7 (c 1.61,
CHCl3); IR (film): nmax (cmꢁ1) 3437, 2948, 2926, 1730,
1005, 758; H NMR (CDCl3, 200 MHz) d 7.52–7.31 (m,
5H), 5.52 (s, 1H), 5.02 (s, 1H), 4.29 (dd, J1¼9.9 Hz,
J2¼4.8 Hz, 1H), 4.11 (br s, 2H), 3.92 (m, 1H), 3.77–3.63
(m, 1H), 3.72 (s, 3H), 3.54 (m, 2H), 3.37 (dd, J1¼J2¼4.8 Hz,
1H), 3.37 (s, 3H), 3.16 (dd, J1¼7.9 Hz, J2¼11.8 Hz, 1H),
2.29 (m, 1H), 2.21 (d, J¼8.1 Hz, 1H), 2.11 (m, 1H), 1.98
(dd, J1¼J2¼4.5 Hz, 1H), 1.98 (s, 3H), 1.60 (br s, 1H); 13C
NMR (CDCl3, 50 MHz) d 172.4, 169.8, 137.2, 128.9,
128.2, 126.0, 102.1, 98.9, 80.5, 69.3, 66.5, 64.3, 61.7,
55.4, 53.0, 51.6, 46.9, 45.3, 43.6, 28.3, 20.5; HRMS m/z
451.1971 [(M+H+); calcd for C23H30O9: 451.1967].
1
1457, 1372, 1213, 1117, 1091, 973, 755, 699; H NMR
(CDCl3, 200 MHz) d 7.52–7.29 (m, 5H), 5.49 (s, 1H), 5.32
(s, 1H), 4.81 (s, 1H), 4.28 (dd, J1¼10.0 Hz, J2¼4.8 Hz,
1H), 4.11 (d, J¼9.9 Hz, 1H), 3.91 (m, 1H), 3.80 (d,
J¼10.1 Hz, 1H), 3.72–3.60 (dd overlap, 1H), 3.65 (s, 3H),
3.38 (s, 3H), 3.17 (dd, J1¼J2¼9.8 Hz, 1H), 3.01 (m, 2H),
2.70 (br s, 1H), 2.59 (dd, J1¼10.4 Hz, J2¼3.8 Hz, 1H),
2.34 (m, 1H), 2.17 (m, 1H); 13C NMR (CDCl3, 50 MHz)
d 173.7, 137.4, 128.9, 128.1, 126.1, 104.5, 102.07, 101.7,
78.9, 73.3, 69.4, 61.3, 58.3, 55.1, 51.7, 51.5, 48.2, 45.8,
30.1; HRMS m/z 407.1695 [(M+H+); calcd for C21H26O8:
407.1706].
4.6.2. (1S,2S,4R,7R,9R,10S,11R,15R) 1-Acetoxymethyl-2-
methoxy-12-oxo-7-phenyl-3,6,8,13-tetraoxatetracy-
clo[10.3.1.01,10.04,9]hexadecadene (41). Colorless oil; [a]2D4
+1.3 (c 0.55, CHCl3); IR (film): nmax (cmꢁ1) 2924, 2853,
2342, 1746 (C]O), 1454, 1371, 1231, 1125, 1092, 1055,
1
974, 756, 700; H NMR (CDCl3, 200 MHz) d 7.55–7.30
4.5.9.2. (1R,2S,4R,7R,9S,10R,11S,13R) 2-Methoxy-14-
[10.3.2.01,10
.
(m, 5H), 5.53 (s, 1H), 4.70 (s, 1H), 4.50–4.10 (m, 5H),
3.88 (m, 1H), 3.75 (dd, J1¼J2¼9.9 Hz, 1H), 3.49 (dd,
J1¼J2¼9.7 Hz, 1H), 3.39 (s, 3H), 3.11 (d, J¼6.7 Hz, 1H),
2.82 (m, 1H), 2.63 (d, J¼10.3 Hz, 1H), 2.48 (m, 1H), 2.07
(s, 3H), 1.68 (dd, J1¼14.6 Hz, J2¼4.7 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) d 172.2, 170.3, 136.9, 129.1, 128.2,
125.9, 101.9, 98.1, 73.8, 71.8, 69.0, 64.2, 62.0, 55.3, 48.6,
45.2, 42.2, 37.9, 30.2, 20.7; HRMS m/z 419.1717
[(M+H+); calcd for C22H26O8: 419.1705].
oxo-7-phenyl-3,6,8,15-tetraoxatetracyclo
1,13.04,9]hexadecane-11-carbaldehyde (36). Colorless
0
oil; 29% yield; [a]2D1 +20.8 (c 0.95, CHCl3); IR (film):
nmax (cmꢁ1) 3422, 3015, 2926, 1771, 1719, 1453, 1372,
1287, 1213, 1113, 1087, 755, 699, 662; H NMR (CDCl3,
1
200 MHz) d 9.73 (s, 1H), 7.52–7.29 (m, 5H), 5.53 (s, 1H),
4.59 (d, J¼11.2 Hz, 1H), 4.56 (s, 1H), 4.31 (dd,
J1¼10.1 Hz, J2¼4.9 Hz, 1H), 3.93 (m, 1H), 3.69 (dd, J1¼

11420
S. A. Testero et al. / Tetrahedron 63 (2007) 11410–11420
9. (a) Schreiber, S. L.; Liew, W. F. Tetrahedron Lett. 1983, 24,
Acknowledgements
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This research was supported by the International Foundation
for Science, Stockholm, Sweden and the Organization for
the Prohibition of Chemical Weapons, The Hague, The
Netherlands, CONICET and Agencia Nacional de
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Promocion Cientıfica y Tecnologica, Argentina through
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for fellowships.
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Supplementary data
1H and 13C NMR spectra and complete assignment of all
NMR data are available online. Supplementary data associ-
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doi:10.1016/j.tet.2007.08.070.
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References and notes
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ꢁ